leukemia research author guidelines

Instructions for Authors

Contact Monica Mungle for help if edits are needed to the top section.

Original Investigation

Brief report, research letter, systematic review (without meta-analysis), narrative review, special communication, clinical challenge, diagnostic test interpretation, clinical evidence synopsis, cancer care chronicles, letter to the editor, letter in reply.

• Randomized Clinical Trial
• Parallel-Design Double-blind Trial
• Crossover Trial
• Equivalence and Noninferiority Trial
• Cluster Trial
• Nonrandomized Controlled Trial

Meta-analysis

• Cohort Study
• Case-Control Study
• Cross-sectional Study
• Case Series
• Economic Evaluation
• Decision Analytical Model
• Comparative Effectiveness Research
• Genetic Association Study
• Diagnostic/Prognostic Study
• Quality Improvement Study
• Survey Study
• Qualitative Study

Manuscript Submission

Copies of previous editorial and reviewer comments, cover letter, manuscript style, manuscript components, recommended file sizes, manuscript file formats, abbreviations, units of measure, names of drugs, devices, and other products, gene names, symbols, and accession numbers, reproduced and re-created material, online-only supplements and multimedia.

What to Expect

Editorial and Peer Review

Open access, authorship form and publishing agreement, publication.

• Postpublication Online Commenting

Reprints/e-Prints

Corrections, previous publication, related manuscripts and reports, and preprints, previous or planned meeting presentation or release of information, embargo policy, research article public access, depositing in repositories, and discoverability.

Editorial Policies for Authors

Authorship and Disclosures

Authorship criteria and contributions, role of the corresponding author, changes in authorship, name change policy, group authorship, conflicts of interest and financial disclosures, funding/support and role of funder/sponsor, data access, responsibility, and analysis, acknowledgment section, equator reporting guidelines, use of causal language, timeliness of data, statistical methods and data presentation, reporting demographic information for study participants, ethical approval of studies and informed consent, patient identification, use of ai in publication and research, personal communications and unpublished data, manuscripts that pose security risks.

Journal Policies, Forms, Resources

Decisions and Management of Editorial Conflicts of Interest

Publishing agreement, unauthorized use.

• Patient Permission Form
• Permission to Republish Material
• AMA Manual of Style
• EQUATOR Network
• About This Journal

Contact Information

JAMA Oncology , Mary L. (Nora) Disis, MD, Editor, Cancer Vaccine Institute, University of Washington, 850 Republican St, Box 358050, Seattle, WA 98109-4714; email: [email protected] . Manuscripts should be submitted online at http://manuscripts.jamaonc.com .

Determine My Article Type

Categories of articles.

Original Investigation full info

Clinical trial Meta-analysis Intervention study Cohort study Case-control study Epidemiologic assessment Survey with high response rate Cost-effectiveness analysis Decision analysis Study of screening and diagnostic tests Other observational study

• ≤5 tables and/or figures
• Structured abstract

Data Sharing Statement

Follow EQUATOR Reporting Guidelines

Brief Report full info

Short reports of original studies or evaluations or unique, first-time reports of clinical case series.

It is very rare for this journal to publish case reports.

• 15 references
• ≤3 tables and/or figures

Research Letter full info

Concise, focused reports of original research. Can include any of the study types listed under Original Investigation.

• No more than 7 authors
• ≤6 references
• ≤2 small tables and/or figures
• No Abstract or Key Points

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Clinical Review and Education

Systematic Review (without meta-analysis) full info

Critical assessments of the literature and data sources pertaining to clinical topics, emphasizing factors such as cause, diagnosis, prognosis, therapy, or prevention.

Systematic Reviews without meta-analysis are published as Reviews; those with meta-analysis are published as Original Investigations (see Meta-analysis ).

• 50-75 references
• A PRISMA-style flow diagram should be included as an online supplement
• Include a table with ratings of the quality of the studies/evidence
• Subtitle should be "A Systematic Review"

Narrative Review full info

Up-to-date review for clinicians on a topic of general common interest from the perspective of internationally recognized experts in these disciplines.

The focus should be an update on current understanding of the physiology of the disease or condition, diagnostic consideration, and treatment.

These reviews should address a specific question or issue that is relevant for clinical practice.

• 2000-3500 words
• 3-part structured abstract
• No Key Points
• Subtitle should be "A Review"

Special Communication full info

This journal publishes very few of these types of articles.

These manuscripts describe an important issue in clinical medicine, public health, health policy, or medical research in a scholarly, thorough, well-referenced, systematic, and evidence-based manner.

• 50 references
• ≤4 tables and/or figures
• Requires a presubmission inquiry

Clinical Challenge full info

Presents an actual patient case with a specific disease or condition with an accompanying clinical image.

• "What Is Your Diagnosis?" with 4 single-phrase plausible diagnosis options with 1 being preferred
• Case presentation: 250 words
• Discussion: 500-600 words
• ≤10 references
• 1-2 small figures
• Patient permission required

Diagnostic Test Interpretation full info

This article requires a presubmission inquiry.

Presentation of the results of a diagnostic test from a single patient with exploration of the clinical application of the test result; intended to help clinicians understand the underlying rationale in ordering tests, interpreting test results, and acting on the diagnostic test findings.

• How Do You Interpret These Test Results? (or What Would You Do Next?) with 4 plausible responses
• Case presentation: 200 words
• Discussion: 650 words

Clinical Evidence Synopsis full info

Synopsis is intended to help clinicians apply evidence to practice by summarizing new evidence from recently published data-driven reviews and reports.

• Begins with 1-sentence clinical question and 1-sentence clinical application statement
• 1 Evidence Profile box
• 1 table or figure
• ≤7 references

Viewpoint full info

May address virtually any important topic in medicine, public health, research, discovery, prevention, ethics, health policy, or health law and generally are not linked to a specific article.

• 1200 words (or 1000 words with 1 small table or figure)
• ≤7 references at submission
• ≤3 authors, with no more than 2 affiliations per author

Cancer Care Chronicles full info

Personal vignettes (eg, exploring the dynamics of the patient-physician relationship) taken from wide-ranging experiences in medicine; occasional pieces express views and opinions on the myriad issues that affect the profession.

• ≤1600 words
• Patient permission may be needed

Poetry full info

Original poems related to the medical experience, whether from the point of view of a health care worker or patient, or simply an observer.

• No longer than 44 lines

Correspondence

Letter to the Editor full info

Letters discussing a recent article in this journal should be submitted within 4 weeks of the article's publication online.

• ≤5 references (1 of which should be to the recent article)

Letter in Reply full info

Replies by authors of original articles to letters from readers.

Study Types

Determine my study type.

Randomized Clinical Trial full info

A trial that prospectively assigns participants to intervention or comparison groups to study the cause-and-effect relationship between an intervention and a health outcome. Interventions include but are not limited to drugs, surgical procedures, devices, behavioral treatments, educational programs, dietary interventions, quality improvement interventions, process-of-care changes, and the like.

• ≤5 tables and/or figures, including CONSORT flow diagram
• Subtitle should be "A Randomized Clinical Trial"
• Trial registration and ID
• Trial protocol
• CONSORT checklist
• Follow CONSORT Reporting Guidelines

Parallel-Design Double-blind Trial full info

A randomized trial that prospectively assigns participants to 2 or more groups to receive different interventions. Participants and those administering the interventions are unaware of which intervention individual participants are receiving.

Crossover Trial full info

A trial in which participants receive more than 1 of the treatments under investigation, usually in a randomly determined sequence, and with a prespecified amount of time (washout period) between sequential treatments.

Equivalence and Noninferiority Trial full info

A trial designed to assess whether the treatment or intervention under study (eg, a new intervention) is no worse than an existing alternative (eg, an active control). In these trials, authors must prespecify a margin of noninferiority that is consistent with all relevant studies and within which the new intervention can be assumed to be no worse than the active control.

Cluster Trial full info

A trial that includes random assignment of groups rather than individuals to intervention and control groups.

Nonrandomized Controlled Trial full info

A trial that prospectively assigns groups or populations to study the efficacy or effectiveness of an intervention but in which the assignment to the intervention occurs through self-selection or administrator selection rather than through randomization. Control groups can be historic, concurrent, or both. This design is sometimes called a quasi-experimental design.

• ≤5 tables and/or figures, including a trial flow diagram
• Subtitle should be "A Nonrandomized Controlled Trial"
• TREND checklist

Meta-analysis full info

A systematic review that includes a statistical technique for quantitatively combining the results of multiple studies that measure the same outcome into a single pooled or summary estimate.

• Subtitle should include "A Meta-analysis"
• Follow PRISMA Reporting Guidelines or MOOSE Reporting Guidelines

Cohort Study full info

An observational study that follows a group (cohort) of individuals who are initially free of the outcome of interest. Individuals in the cohort may share some underlying characteristic, such as age, sex, diagnosis, exposure to a risk factor, or treatment.

• Follow STROBE Reporting Guidelines

Case-Control Study full info

An observational study designed to determine the association between an exposure and outcome in which study participants are selected by outcome. Those with the outcome (cases) are compared with those without the outcome (controls) with respect to an exposure or event. Cases and controls may be matched according to specific characteristics (eg, age, sex, or duration of disease).

Cross-sectional Study full info

An observational study of a defined population at a single point in time or during a specific interval, in which exposure and outcome are ascertained simultaneously.

Case Series full info

An observational study that describes a selected group of participants with similar exposure or treatment and without a control group. A case series may also involve observation of larger units such as groups of hospitals or municipalities, as well as smaller units such as laboratory samples.

• Follow Reporting Guidelines

Economic Evaluation full info

A study using formal, quantitative methods to compare 2 or more treatments, programs, or strategies with respect to their resource use and expected outcomes. This includes cost-effectiveness, cost-benefit, and cost-minimization analyses.

• Follow CHEERS Reporting Guidelines

Decision Analytical Model full info

A mathematical modeling study that compares consequences of decision options by synthesizing information from multiple sources and applying mathematical simulation techniques, usually with specific software. Reporting should address the relevant non-cost aspects of the CHEERS guideline.

Comparative Effectiveness Research full info

A study that compares different interventions or strategies to prevent, diagnose, treat, and monitor health conditions to determine which work best for which patients, under what circumstances, and are associated with the greatest benefits and harms.

• Follow ISPOR Reporting Guidelines

Genetic Association Study full info

A study that attempts to identify and characterize genomic variants that may be associated with susceptibility to multifactorial disease.

• Follow STREGA Reporting Guidelines

Diagnostic/Prognostic Study full info

A prospective study designed to develop, validate, or update the diagnostic or prognostic accuracy of a test or model.

• Follow STARD Reporting Guidelines or TRIPOD Reporting Guidelines

Quality Improvement Study full info

A study that uses data to define, measure, and evaluate a health care practice or service to maintain or improve the appropriateness, quality, safety, or value of that practice or service.

• Follow SQUIRE Reporting Guidelines

Survey Study full info

A survey study includes a representative sample of individuals who are asked to describe their opinions, attitudes, or behaviors. Survey studies should have sufficient response rates (generally ≥60%) and appropriate characterization of nonresponders to ensure that nonresponse bias does not threaten the validity of the findings.

• Follow AAPOR Best Practices for Survey Research
• Optional: Survey instrument as supplemental file

Qualitative Study full info

A study based on observation and interview with individuals that uses inductive reasoning and a theoretical sampling model and that focuses on social and interpreted, rather than quantifiable, phenomena and aims to discover, interpret, and describe rather than to test and evaluate. This includes mixed-methods studies that combine quantitative and qualitative designs in a sequential or concurrent manner.

• Follow SRQR Reporting Guidelines or COREQ Reporting Guidelines

These reports typically include randomized trials (see Clinical Trial ), intervention studies, cohort studies, case-control studies, epidemiologic assessments, other observational studies, surveys with high response rates (see Reports of Survey Research ), cost-effectiveness analyses and decision analyses (see Reports of Cost-effectiveness Analyses and Decision Analyses ), and studies of screening and diagnostic tests (see also Reports of Diagnostic Tests ). A study type is required. Each manuscript should clearly state an objective or hypothesis; the design and methods (including the study type and setting and dates, patients or participants with inclusion and exclusion criteria and/or participation or response rates, or data sources, and how these were selected for the study); the essential features of any interventions; the main outcome measures; the main results of the study; a discussion section placing the results in context with the published literature and addressing study limitations; and the conclusions and relevant implications for clinical practice or health policy. Data included in research reports must be original and should be as timely and current as possible (see Timeliness of Data ). Follow EQUATOR Reporting Guidelines .

A structured abstract is required; for more information, see instructions for preparing Abstracts for Reports of Original Data . A list of 3 Key Points is required (see guidance on preparing Key Points ). Maximum length: 3000 words of text (not including abstract, tables, figures, acknowledgments, references, and online-only material) with no more than a total of 5 tables and/or figures.

These manuscripts are short reports of original studies or evaluations or unique, first-time reports of clinical case series. Follow EQUATOR Reporting Guidelines . A structured abstract is required; for more information, see instructions for preparing Abstracts for Reports of Original Data . A list of 3 Key Points is required (see guidance on preparing Key Points ). Recommended length: 1200 words (not including abstract, tables, figures, acknowledgments, references, and online-only material) with no more than a total of 3 tables and/or figures and no more than 15 references. Note: It is very rare for this journal to publish case reports.

Research Letters are concise, focused reports of original research. These should not exceed 600 words of text and 6 references and may include up to 2 tables or figures. Online supplementary material is only allowed for brief additional and absolutely necessary methods but not for any additional results or discussion. Research Letters may have no more than 7 authors. The text should include the full name, academic degrees, and a single institutional affiliation for each author and the email address for the corresponding author. Other persons who have contributed to the study may be indicated in an Acknowledgment, with their permission, including their academic degrees, affiliation, contribution to the study, and an indication if compensation was received for their role. Letters must not duplicate other material published or submitted for publication. In general, Research Letters should be divided into the following sections: Introduction, Methods, Results, and Discussion. They should not include an abstract or key points, but otherwise should follow all of the guidelines in Manuscript Preparation and Submission Requirements . Letters not meeting these specifications are generally not considered.

The journal will consider 2 types of review articles:

Systematic Reviews

These types of Review articles differ by the scope and level of analysis of the literature searches and the titles used. Systematic Reviews require a complete systematic search of the literature using multiple databases, covering many years, and grading of the quality of the cited evidence. Narrative Reviews do not require a rigorous literature search but should rely on evidence and should be written by established experts in the field. See below for more detail on each type of Review.

Titles for these Reviews should include a concise description of the main topic. Use specific and not overly broad wording for the title; the type of review should be indicated in the subtitle. For example:

Behavioral Treatment of Obesity: A Systematic Review

Behavioral Treatment of Obesity: A Review (note: the word "narrative" is not included in the subtitle)

Systematic Reviews are critical assessments of the literature and data sources pertaining to clinical topics, emphasizing factors such as cause, diagnosis, prognosis, therapy, or prevention. Systematic Reviews without meta-analysis are published as Reviews; those with meta-analysis are published as Original Investigations (see Meta-analysis ). Systematic Reviews should address a specific question or issue that is relevant for clinical practice and provide an evidence-based, balanced, patient-oriented review on a focused topic. Follow EQUATOR Reporting Guidelines .

The basic structure of manuscripts reporting Systematic Reviews should include the following: Abstract (structured abstract of no more than 350 words); Introduction (150-250 words); Methods (150-250 words); Results (1000-1250 words, with the following subsections, if appropriate, depending on the specific question or issue addressed: Pathophysiology, Clinical Presentation, Assessment and Diagnosis, Treatment, and Prognosis); Discussion (1000 words); and Conclusions (2-3 sentences).

Maximum length: 3000 words of text (not including abstract, tables, figures, acknowledgments, references, and online-only material), with no more than a total of 5 tables and/or figures and no more than 50-75 references. For an example of a published Systematic Review, see JAMA . 2014;312(6):631-640 and below for the general structure of a Systematic Review article.

Specific Components of a Systematic Review

Key Points (75-100 words)

This feature provides a quick structured synopsis of the Review, following 3 key points: Question, Findings, and Meaning. Limit to no more than 100 words. This is different from the Abstract.

Question: What are the most effective medical treatments for adult chronic sinusitis? Findings: In this systematic review, symptoms of chronic sinusitis were improved with saline irrigation and topical corticosteroid therapy compared to no therapy. Compared with placebo, 3-week courses of systemic corticosteroids or oral doxycycline were associated with reduced polyp size, and a 3-month course of macrolide antibiotic was associated with improved symptoms in patients without polyps. Meaning: First-line therapy for chronic sinusitis should begin with daily topical intranasal corticosteroid in conjunction with saline irrigation; subsequent therapies should be based on the patient's polyp status and severity of symptoms.

Abstract (350 words)

A structured abstract is required; Systematic Review articles should include a structured abstract of no more than 350 words using the headings listed below.

Importance: Include 1 or 2 sentences describing the clinical question or issue and its importance in clinical practice or public health. Objective: State the precise primary objective of the review. Indicate whether the review emphasizes factors such as cause, diagnosis, prognosis, therapy, or prevention and include information about the specific population, intervention, exposure, and tests or outcomes that are being reviewed. Evidence Review: Describe the information sources used, including the search strategies, years searched, and other sources of material, such as subsequent reference searches of retrieved articles. Methods used for inclusion of identified articles and quality assessment should be explained. Findings: Include a brief summary of the number of articles included, numbers of various types of studies (eg, clinical trials, cohort studies), and numbers of patients/participants represented by these studies. Summarize the major findings of the review of the clinical issue or topic in an evidence-based, objective, and balanced fashion, with the highest-quality evidence available receiving the greatest emphasis. Provide quantitative data. Conclusions and Relevance: The conclusions should clearly answer the questions posed if applicable, be based on available evidence, and emphasize how clinicians should apply current knowledge. Conclusions should be based only on results described in the abstract Findings subsection.

Introduction (150-250 words)

The first 2 to 3 sentences of the Introduction should draw in readers such that they want to continue reading the article and should establish the importance of the Review. Reviews should include the clinical question or issue and its importance for general medical practice, specialty practice, or public health. The first paragraph should provide a general summary of the clinical problem (eg, obesity). The next paragraph should focus on the specific aspect of the clinical problem the article will explore (eg, treatments for obesity). The epidemiology of the disease or condition should be briefly summarized and generally should include disease prevalence and incidence. The third paragraph should discuss exactly what material will be covered in the Review (eg, obesity treatments reported in trials with a minimum follow-up of 2 years including 80% of the original cohort).

Methods/Literature Search (150-250 words)

The literature search should be as current as possible, ideally with end dates within a month or two before manuscript submission. A search of the primary literature should be conducted, including multiple bibliographic databases (eg, PubMed/MEDLINE, Embase, CINAHL, PsycINFO). This can be facilitated by collaborating with a medical librarian to help with the search.

Briefly describe characteristics of the literature searched and included in the review, following the PRISMA reporting guidelines , including the bibliographic databases and other sources searched, search terms used, dates included in the search, date the literature search was conducted, screening process, language limitations, and inclusion and exclusion criteria. The rating system used to evaluate the quality of the evidence should be specified (see table below) and the methods used to evaluate quality should be described, including number of quality raters, how agreement on quality ratings was assessed, and how disagreements on quality ratings were resolved.

The highest-quality evidence (eg, randomized clinical trials, meta-analyses, systematic reviews, and high-quality prospective cohort studies) should receive the greatest emphasis. Clinical practice guidelines ordinarily should not be used as a primary component of the evidence base for the systematic review, although relevant guidelines should be addressed in the Discussion section of the article.

The search methods should be described in sufficient detail so the search can be reproduced based on the information provided in the manuscript. A summary of the methods of the literature search including this information should be included in the main article; details can be included in an online-only supplement. A PRISMA-style flow diagram showing this information should also be included as an online-only supplement. In addition, a completed PRISMA checklist should be submitted for the items completed that apply to systematic reviews (the checklist items that apply to meta-analyses do not need to be completed for systematic reviews without meta-analysis). The checklist will be used during review but will not be published.

Results (1000-1250 words)

First, briefly report the results of the literature search, including the number of articles reviewed and included, numbers of various types of studies (eg, clinical trials, cohort studies) included, and the aggregate numbers of patients included in the reviewed studies. Also provide a brief summary of the quality of the evidence. Details of this information can be included in a PRISMA-style flow diagram and table(s).

Next, the subsections listed below should generally appear in the Results sections of most Reviews although all of these subsections may not be necessary for some topics, depending on the specific question or issue addressed. The word counts following each subsection are suggested to assist with keeping the overall Results section limited to 1000-1250 words.

Pathophysiology (150-250 words). Provide a brief overview of the pathophysiology of the disease. The intent is to provide readers with sufficient background information about the underpinnings of a disease to provide context for the rest of the article. Clinical Presentation (150-250 words). Briefly describe the clinical characteristics that result in a patient seeking medical care for the condition or what features of the disease should lead a clinician to evaluate or treat it. Assessment and Diagnosis (250-300 words). Describe the clinical examination for evaluation of the disease and explain the most salient physical examination findings. If laboratory or imaging studies are necessary, provide the sensitivity and specificity and diagnostic accuracy of these tests and consider providing positive and negative likelihood ratios. Sequences of diagnostic tests are best presented as algorithms or in tables. Treatment (250-500 words). Treatments should be based on the most recently available and highest level of evidence. Treatment options should be summarized in the text and presented in detail in tables along with an indication of the strength of evidence supporting the individual treatments. In general, treatment recommendations should be supported by a systematic review of the literature, either performed by the author of the Review or published in the form of a high-quality review or guideline. If possible, the costs for various treatments should be provided. Prognosis (100-150 words). A section outlining the overall prognosis for the condition, once treated, should be included. Discussion (Approximately 1000 words)

Key findings should be summarized in the first paragraph of the Discussion section. All statements made should be supported by evidence. It is very important to not simply list findings from the studies reviewed. This information is best presented in tables. The Discussion should provide a critical synthesis of data and information based on the results of the review, an assessment of the quality of studies summarized, and a description of how studies can be interpreted and used to guide clinical practice. The limitations of the evidence and of the review should be discussed, and gaps in evidence should be addressed. A discussion of controversial or unresolved issues and topics in need of future research also should be included.

Clinical Practice Guidelines: In the Discussion section, describe current clinical practice guidelines, relevant to the topic of the review, if available, and whether the conclusions of this review agree with, or disagree with, the current clinical practice guidelines. If this is done and there is more than 1 guideline, a table should be prepared comparing the major features that differ between the guidelines. Guideline quality should be discussed using the standards outlined for the JAMA Clinical Guidelines Synopsis .

Conclusions

Include a 2- to 3-sentence summary of the major conclusions of the review.

Construct tables that summarize the search results. Tables summarizing treatments should have information organized by category of treatment and then by individual treatments. Columns should include the name of the treatment, strength of evidence supporting the treatment, the treatment's effect (preferably shown as the treatment's effect as compared to control on the measured outcome together with 95% confidence intervals), adverse effects, and very brief comments, if necessary. Lengthy text-based tables should be avoided. Additional or lengthy tables may be published online only, if justified.

Ratings of the quality of the evidence. Tables summarizing evidence should include ratings of the quality of the evidence. Use the rating scheme listed below with ratings of 1-5 for Reviews that include individual studies (modified from the Oxford Centre for Evidence-based Medicine for ratings of individual studies).

There are several other preferred systems for rating the quality of evidence in Review articles. For Reviews that synthesize findings from numerous studies into a single summary recommendation, use the rating scale shown above or the Oxford Centre for Evidence-based Medicine's Levels of Evidence and Grades of Recommendation or the recommendations in the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines . For reviews that include diagnostic studies, use The Rational Clinical Examination Levels of Evidence table .

Follow additional instructions for preparation and submission of Tables .

A PRISMA-style flow diagram should be included as an online supplement that summarizes the results of the literature search and the numbers of articles/records/studies and patients/participants represented in the studies identified, screened, eligible, and included in the final review.

Additional figures that illustrate pathophysiology or clinical presentation may be considered. We encourage videos, if appropriate, to illustrate a point made or process described in the Review.

Follow additional instructions for preparation and submission of Figures and Video .

Narrative Reviews on clinical topics provide an up-to-date review for clinicians on a topic of general common interest from the perspective of internationally recognized experts in these disciplines. The focus of Narrative Reviews will be an update on current understanding of the physiology of the disease or condition, diagnostic consideration, and treatment. These reviews should address a specific question or issue that is relevant for clinical practice. Narrative Reviews do not require (but may include) a systematic review of the literature search. Recommendations should be supported with evidence and should rely on recent systematic reviews and guidelines, if available, emphasizing factors such as cause, diagnosis, prognosis, therapy, or prevention.

The basic structure of manuscripts reporting Narrative Reviews should include the following: Abstract (structured abstract of no more than 300 words); Introduction (150-250 words); Methods, if included (150-250 words); Discussion/Observations (1000-1250 words, with the following subsections, if appropriate: Pathophysiology, Clinical Presentation, Assessment and Diagnosis, Treatment, and Prognosis); and Conclusions (2-3 sentences).

Typical length: 2000-3500 words (maximum), with no more than a total of 5 tables and/or figures, and no more than 50-75 references. For an example of this type of article, see JAMA . 2015;314(23):2544-2554 .

Specific Components of a Narrative Review

Abstract (300 words)

Narrative Review articles should include a 3-part structured abstract of no more than 300 words using the headings listed below:

Importance: An overview of the topic and discussion of the main objective or reason for this review. Observations: The principal observations and findings of the review. Conclusions and Relevance: The conclusions of the review that are supported by the information, along with clinical applications. How the findings are clinically relevant should be specifically stated.

The first 2 to 3 sentences of the Introduction should draw in readers in such that they want to continue reading the article and should establish the importance of the Review. Reviews should include the clinical question or issue and its importance for general medical practice, specialty practice, or public health. The first paragraph should provide a general summary of the clinical problem (eg, obesity). The next paragraph should focus on the specific aspect of the clinical problem the article will explore (eg, treatments for obesity). Briefly summarize the epidemiology of the disease. This information should include disease prevalence and incidence and perhaps discussion of the presence and frequency of any relevant subpopulations and any geographic or seasonal variations of the disease if these are relevant. The third paragraph should discuss exactly what material will be covered in the Review (eg, obesity treatments).

Methods (150-250 words)

A Methods section is not required for Narrative Reviews, but may be included to summarize a literature search that was conducted for this Review. If included, briefly describe the characteristics of the literature searched and included in the review, including the bibliographic databases and other sources searched, search terms used, dates included in the search, date the literature search was conducted, and any process used to evaluate the literature.

Discussion/Observations (1000-1250 words)

The principal observations of the Narrative Review generally should include the subsections listed below, although each section may not be necessary for some topics. The word counts following each subsection are suggested to assist with keeping the overall Observations section limited to 1000-1250 words.

Pathophysiology (150-250 words). Provide a brief overview of the pathophysiology of the disease. The intent is to provide readers with sufficient background information about the underpinnings of a disease to provide context for the rest of the article. Clinical Presentation (150-250 words). Briefly describe the clinical characteristics that result in a patient seeking medical care for the condition or what features of the disease should lead a physician to evaluate or treat it. Assessment and Diagnosis (250-300 words). Describe the clinical examination for evaluation of the disease and explain the most salient physical examination findings. If laboratory or imaging studies are necessary, provide the sensitivity and specificity and diagnostic accuracy of these tests and consider providing positive and negative likelihood ratios. Sequences of diagnostic tests are best presented as algorithms or in tables. Treatment (250-500 words). Treatments should be based on the most recently available and highest level of evidence. Treatment options should be summarized in the text and presented in detail in tables along with an indication of the strength of evidence supporting the individual treatments. In general, treatment recommendations should be supported by a systematic review or a high-quality guideline. If possible, the costs for various treatments should be provided. Prognosis (100-150 words). A section outlining the overall prognosis for the condition, once treated, should be included.

For most Narrative Reviews, tables should be included that summarize the epidemiology, diagnostic tools, and therapies available for the disease. In some cases, these 3 topics may not all be relevant to the review topic and tables may be appropriately modified to fit the review. Include a fourth table that compares the findings of the review and current clinical practice recommendations or diagnostic and therapeutic uncertainty or controversies.

Table 1: Major epidemiologic and burden of disease facts Table 2: Major diagnostic tools available Table 3: Major therapies available Table 4: Current clinical practice recommendations and/or diagnostic and therapeutic uncertainty, and controversies

Tables summarizing treatments should have information organized by category of treatment and then by individual treatments. Columns may include the treatment, strength of evidence supporting the treatment, the effect of the treatment (preferably shown as the treatment's effect as compared to control on the measured outcome together with 95% confidence intervals), adverse effects, and very brief explanatory comments, if necessary. Lengthy text-based tables should be avoided. Additional or lengthy tables may be published online only, if justified.

Figures that illustrate pathophysiology or clinical presentation may be included. Note: All figures will be re-created. We encourage videos, if appropriate, to illustrate a point made or process described in the Review.

Note: This journal publishes very few of these types of articles. These manuscripts describe an important issue in clinical medicine, public health, health policy, or medical research in a scholarly, thorough, well-referenced, systematic, and evidence-based manner.

A structured abstract is required. Maximum length: 3000 words of text (not including tables, figures, or references) with no more than a total of 4 tables and/or figures and no more than 50 references. For a recently published example, see JAMA . 2019;322(20):1996-2016 .

This article type requires a presubmission inquiry to [email protected] .

Clinical Challenge presents an actual patient scenario about a specific disease or condition with an accompanying clinical image.

Authors should provide 4 single-phrase plausible diagnosis options with one of these being the most correct response for the question "What Is Your Diagnosis?" Manuscripts should include a brief discussion of the relevant clinical issues and provide well-supported (evidence-based) explanations for why 1 of the 4 potential diagnoses is correct and the other options are not. For a recently published example, see JAMA Oncology . 2021;7(9):1392-1393. doi:10.1001/jamaoncol.2021.1707 .

All diagnostic and treatment recommendations should be supported by referencing recent authoritative texts or journal articles. Preferably, these recommendations should be supported by governmental or multisociety guidelines, clinical trials, meta-analyses, or systematic reviews. The text should have a maximum length of 850 words, consisting of no more than 250 words for the case presentation, question, and 4 one-sentence answers, followed by no more than 600 words that include the diagnosis and a brief discussion. There should be no more than 3 authors. At least 1 of the authors, ideally the corresponding author, should have sufficient expertise and experience with the topic. There should be no more than 10 references, and no more than 2 small figures totaling 3 image components (Figure 1, with no more than 2 components, for the case presentation; and Figure 2, with no more than 1 component, for the diagnosis and discussion).

Provide a short title that briefly describes the disease entity or case presentation and does not include the diagnosis. Do not include the patient's race, ethnicity, or country of origin in the title or the first line of the article. If this information is clinically relevant and necessary, it can be included in the case description.

In addition, the JAMA Network Patient Permission form must be completed and signed by the patient (or a family member if the patient has died, is a minor, or is an adult without decisional capacity) and included at the time of manuscript submission. Please read Patient Identification before submitting your manuscript.

The image and case presentation should be from the same patient and must not have been published previously. In some cases, additional figures may be included to accompany the answer explanations (see description of additional figure(s) above). All images submitted should be high-quality .jpg or .tif files. Submit the original version of all image files at the highest resolution possible without labels. In general, the original image file should have a minimum resolution of 350 dpi at a width of about 5 inches. Do not increase the original resolution, resize, or crop the image; where applicable, we will crop to maintain patient confidentiality. If any labels, arrowheads, or A/B panel indicators are desired, provide a separate labeled version of the figure(s) for reference. All labels will be reformatted to journal style.

For more information on how to submit figures, see Figures.

We would like to receive common problems presenting uncommonly, rather than unusual or rare conditions (ie, "zebras"). These cases should be of interest to clinicians; they should be problems that clinicians are likely to encounter and have an outstanding image that illustrates the disorder and contributes to the diagnostic challenge.

Manuscripts not meeting these guidelines will not be considered.

Diagnostic Test Interpretation presents the results of a diagnostic test from a single patient and explores the clinical application of the test result. The Diagnostic Test Interpretation is intended to help clinicians understand the underlying rationale in ordering tests, interpreting test results, and acting on the diagnostic test findings.

The diagnostic test result must be obtained from the care of an actual patient and must include that patient's written permission. The JAMA Network Patient Permission form should be read and completed and signed by the patient (or a family member if the patient has died, is a minor, or is an adult without decisional capacity) and included at the time of manuscript submission. The results of laboratory, pathologic, or radiographic tests are appropriate but clinical images are not. Results of the diagnostic test of interest (and related tests) and the range of reference values should be included after the case. Authors of manuscripts based on clinical images should consult the instructions for Clinical Challenge .

Provide a short title that briefly describes the disease entity or case presentation and does not include the diagnosis. Do not include the patient's race, ethnicity, or country of origin in the title or first line of the article. If this information is clinically relevant and necessary, it can be included in the case description.

Manuscripts for Diagnostic Test Interpretation should have the following sections:

Case presentation. The case presentation should be brief and focus on the diagnostic test in question. At the end of the case presentation the pertinent diagnostic test results and reference ranges should be provided (200 words). Include: JAMA Exclude: Specialty Journals, JNO Comments: How do you interpret these test results? Include: CAR,ONC Exclude: JAMA, DER, IMD, NEU, OPH, PED, OTO, PSY, SUR, JNO Comments: How do you interpret these test results? How do you interpret these test results? (or What would you do next?) Four plausible responses should be provided. While most Diagnostic Test Interpretation articles will pose the question "How do you interpret these results?" a subset may more appropriately focus on the next best step regarding the workup of the abnormal test result. In these cases, the question "How do you interpret these test results?" can be replaced with "What would you do next?" Either question should be presented in the format of a multiple choice question with a single correct (or best) answer. The answers may be brief phrases or short sentences, should be similar in length, and should be arranged alphabetically by first word in the answer. Response options should not describe treatments (about 50 words). Test characteristics. A brief review of the diagnostic test should be provided (approximately 200 words). For biomarkers, this should include a brief description of the related physiology. Test accuracy should be reported using sensitivity and specificity or likelihood ratios, and predictive values should be provided for common clinical scenarios. Please use likelihood ratios whenever possible, since they do not depend on disease prevalence. The prevalence of the disease should be stated so that the pretest probability may be estimated. For example, "For patients with a typical disease prevalence of 10%, the predictive values of positive and negative test results are approximately 50% and 1%, respectively." Discussion of the application and utility of the diagnostic test should be based on a high-quality systematic review or authoritative practice guideline. If a more recent, original study supersedes or adds meaningfully to the prior synthesis of research, that article also should be cited. The approximate fee for the test should be provided. For example, some fees for laboratory tests can be obtained from the Medicare fee schedules . Radiology procedure fees can be found at the Medicare Physician Fee Schedule website . Application of test result to this patient. A brief discussion of how the diagnostic test result will facilitate the next steps in a patient's management should be presented. Please also address the correct answer to the question about test interpretation in this section (200 words). What Are Alternative Diagnostic Testing Approaches? If there are different testing strategies that can be used to evaluate patients to establish a diagnosis, please discuss them (100 words). Patient Outcome. Long-term follow-up (most recent as possible) regarding the patient's condition and outcome of treatment is necessary (100 words). Clinical Bottom Line. Please provide a bulleted list of 3-5 items that reflect the most important message readers should obtain from this article.

The overall text of the manuscript should have a maximum of 850 words, no more than 10 references, and no more than 3 authors. At least 1 of the authors, ideally the corresponding author, should have sufficient expertise and experience with the topic. The case presentation must not have been previously published.

For an example of this article type, see JAMA Oncology . 2017;3(7):991-992. doi:10.1001/jamaoncol.2017.0257 .

Clinical Evidence Synopsis is intended to help clinicians apply evidence to practice by summarizing new evidence from recently published data-driven reviews and reports, such as the Cochrane Database of Systematic Reviews or the US Preventive Services Task Force Reports. Manuscripts submitted for the Clinical Evidence Synopsis section should begin with a 1-sentence Clinical Question (such as, "Clinical Question: What hemoglobin threshold for prescribing red blood cell transfusions is best for minimizing both red blood cell use and adverse clinical outcomes in anemic patients?") and a 1-sentence Clinical Application statement (such as, "Clinical Application: Compared with higher hemoglobin thresholds, a hemoglobin threshold of 7 g/dL or 8 g/dL reduces the number of red blood cell units transfused without adverse associations with mortality, cardiac morbidity, functional recovery, or length of hospital stay."). The manuscript should include the following main headings and subsections:

Introduction: 1 brief paragraph of background and context for the clinical question Evidence Profile: In a Box or list include the following bulleted sections: No. of studies overall No. of randomized controlled trials Study years (eg, 1956 to 2012) (not years of publication) No. of patients Men XX% Women XX% Race/ethnicity Age (mean XX and range xx-xxx) Setting Countries Comparison (eg, higher vs lower hemoglobin threshold for transfusion of patients with anemia) Primary outcomes Secondary outcomes

If the manuscript summarizes a Cochrane Collaboration review, please indicate at the bottom of the Evidence Profile whether the full review represents an original review or an update. The original publication (eg, Cochrane review or US Preventive Services Task Force) should be referenced.

Summary of Findings: a brief summary of the results of the review or report with no more than 1 simple table or figure. Results must include absolute rates or absolute differences and number needed to treat. Discussion: a brief summary of the key results placed in context for the clinician. This section should include 3 subheadings: Limitations; Comparison of Findings With Current Practice Guidelines (if applicable); and Areas in Need of Future Study.

The text length (complete manuscript and Evidence Profile excluding the title, references, and acknowledgment section) should have a maximum length of 800 words with 1 table or figure and no more than 7 references. Manuscripts submitted for the Clinical Evidence Synopsis section should have no more than 3 authors. For an example, see JAMA . 2013;309(1):83-84 . Please submit the original full review at the time the Clinical Evidence Synopsis is submitted.

Viewpoints may address virtually any important topic in medicine, public health, research, discovery, prevention, ethics, health policy, or health law and generally are not linked to a specific article. Viewpoints should be well focused, scholarly, and clearly presented but should not include the findings of new research or data that have not been previously published.

Viewpoints must have no more than 3 authors. Editors encourage diversity of gender, race, ethnicity, geographic location, and discipline for Viewpoint authors, and the first author should have sufficient expertise and experience with the topic to provide an authoritative opinion. The text should include the full name, academic degrees, and no more than 2 institutional affiliations for each author. Maximum length: up to 1200 words of text—or 1000 words of text with 1 small table or figure—and no more than 7 references, which should be as current as possible. Viewpoints not meeting these guidelines will not be considered.

Most essays published in Cancer Care Chronicles are personal vignettes (eg, exploring the dynamics of the patient-physician relationship) taken from wide-ranging experiences in medicine; occasional pieces express views and opinions on the myriad issues that affect the profession. If the patient(s) described in these manuscripts is identifiable, a Patient Permission form , which provides consent for publication, must be completed and signed by the patient(s) or family member(s) and submitted with the manuscript. Manuscripts that describe identifiable patients that do not have a signed form will not be reviewed. Omitting data or making data less specific to deidentify patients is acceptable, but changing any such data is not acceptable. Fictional or composite accounts are not permitted.

Manuscripts are not published anonymously or pseudonymously and must have no more than 3 authors. Length limit: 1600 words.

Poems related to the medical experience, whether from the point of view of a health care worker or patient, or simply an observer, will be considered. Poems should be original, not previously published or under consideration elsewhere, no longer than 44 lines, and with individual lines no longer than 55 characters (including spaces). Authors should submit each poem separately (ie, one poem per submission record, and only one author per poem). Submissions containing multiple poems will be returned with instructions to split into individual files. Do not submit artwork, music/audio, or other accompanying materials, which are not considered. All poems must be submitted online via the online manuscript submission and review system . Authors of poems that are accepted for publication are required to complete Authorship Forms and transfer copyright to the publisher as part of a publishing agreement. An email with links to the Authorship Form will be sent to authors for completion before final acceptance. Author requests to republish poems are generally granted by our permissions department following a formal request.

Letters discussing a recent article in this journal should be submitted within 4 weeks of the article's publication online. 3 Letters received after 4 weeks will rarely be considered. Letters should not exceed 400 words of text and 5 references, 1 of which should be to the recent article. Letters may have no more than 3 authors. The text should include the full name, academic degrees, and a single institutional affiliation for each author and the email address for the corresponding author. Letters must not duplicate other material published or submitted for publication and should not include unpublished data. Letters not meeting these specifications are generally not considered. Letters being considered for publication ordinarily will be sent to the authors of the original article, who will be given the opportunity to reply. Letters will be published at the discretion of the editors and are subject to abridgement and editing for style and content.

Replies by authors should not exceed 500 words of text and 6 references. They should have no more than 3 authors.

Clinical Trial

These manuscripts include reports of Randomized Clinical Trials, Parallel-Design Double-blind Trials, Crossover Trials, Equivalence and Noninferiority Trials, Cluster Trials, and Nonrandomized Controlled Trials.

The ICMJE defines a clinical trial as any research project that prospectively assigns human participants to intervention or comparison groups to study the cause-and-effect relationship between an intervention and a health outcome. 4 Interventions include but are not limited to drugs, surgical procedures, devices, behavioral treatments, educational programs, dietary interventions, quality improvement interventions, process-of-care changes, and the like. All manuscripts reporting clinical trials, including those limited to secondary exploratory or post hoc analysis of trial outcomes, must include the following:

• Copy of the original trial protocol, including the complete statistical analysis plan and any amendments. The journal recommends using the SPIRIT reporting guidelines when preparing original protocols (see Protocols ).
• CONSORT flow diagram (see Figure ).
• Completed trial checklist (see Checklist ).
• Registry at an appropriate online public clinical trial registry (see Trial Registration requirements).
• A Data Sharing Statement to indicate if data will be shared or not. Specific questions regarding the sharing of data are included in the manuscript submission system.

For additional guidance on reporting Randomized Clinical Trial, Parallel-Design Double-blind Trial, Crossover Trial, Equivalence and Noninferiority Trial, Cluster Trial, and Nonrandomized Controlled Trial, see Study Types .

Each manuscript should clearly state an objective or hypothesis; the design and methods (including the study setting and dates, patients or participants with inclusion and exclusion criteria, or data sources, and how these were selected for the study); the essential features of any interventions; the primary and secondary outcome measures (consistent with those reported in the trial protocol); the main results of the study; a discussion section placing the results in context with the published literature and addressing study limitations; and the conclusions.

A structured abstract is required, and trial registration information (registry name, trial ID, and URL) must be listed at the end of the abstract; for more information, see instructions for preparing Abstracts for Reports of Original Data . A list of 3 Key Points is required (see guidance on preparing Key Points ). Maximum length: 3000 words of text (not including abstract, tables, figures, acknowledgments, references, and supplemental material) with no more than a total of 5 tables and/or figures and no more than 50-75 references. The subtitle should include the phrase "A Randomized Clinical Trial" or, for Nonrandomized Controlled Trials, "A Nonrandomized Controlled Trial." To read more about clinical trials, see the AMA Manual of Style .

Trial Registration:

In concert with the ICMJE, JAMA Network requires, as a condition of consideration for publication, registration of all trials in a public trials registry that is acceptable to the ICMJE (ie, the registry must be owned by a not-for-profit entity, be publicly accessible, and require the minimum registration data set as described by ICMJE). 4 , 8 , 9

Acceptable trial registries include the following and others listed at http://www.icmje.org :

• anzctr.org.au
• clinicaltrials.gov
• trialregister.nl
• umin.ac.jp/ctr

All clinical trials, regardless of when they were completed, and secondary analyses of original clinical trials must be registered before submission of a manuscript based on the trial. Secondary data analyses of primary (parent) clinical trials should not be registered as separate clinical trials, but instead should reference the trial registration number of the primary trial. Please note: for clinical trials starting patient enrollment after July 2005, trials must have been registered before onset of patient enrollment. For trials that began before July 2005 but that were not registered before September 13, 2005, trials must have been registered before journal submission. Trial registry name, registration identification number, and the URL for the registry should be included at the end of the abstract and also in the space provided on the online manuscript submission form.

Authors of manuscripts reporting clinical trials must submit trial protocols (including the complete statistical analysis plan) along with their manuscripts. Protocols in non-English languages should be translated into English. This should include the original approved protocol and statistical analysis plan, and all subsequent amendments to either document. Do not submit a summary version that was published as an article in another journal. If the manuscript is accepted, the protocol and statistical analysis plan will be published as a supplement.

CONSORT Flow Diagram and Checklist:

Manuscripts reporting the results of randomized trials must include the CONSORT flow diagram showing the progress of patients throughout the trial. The CONSORT checklist also should be completed and submitted with the manuscript. 10

Figure. Profile of a Randomized Clinical Trial

Trial Protocol

These manuscripts are documents that describe the organization and plan for a randomized clinical trial, including the trial's objective(s), design, methodology, all outcomes to be measured, and statistical analysis plan. All trial protocol manuscripts must include a copy of the trial protocol including the complete statistical analysis plan (see Protocols ). All clinical trials that have begun randomization must be registered at an appropriate online public registry (see Trial Registration requirements). Follow SPIRIT Reporting Guidelines .

A structured abstract is required, and trial registration information (registry name, trial ID, and URL) must be listed at the end of the abstract; for more information, see instructions for preparing Abstracts for Trial Protocols . A list of 3 Key Points is required (see guidance on preparing Key Points ). Maximum length: 3000 words of text (not including abstract, tables, figures, acknowledgments, references, and supplemental material) with no more than a total of 5 tables and/or figures and no more than 50-75 references. The subtitle should include the phrase "A Trial Protocol."

These manuscripts are systematic, critical assessments of literature and data sources pertaining to clinical topics, emphasizing factors such as cause, diagnosis, prognosis, therapy, or prevention, and that includes a statistical technique for quantitatively combining the results of multiple studies that measure the same outcome into a single pooled or summary estimate. All articles or data sources should be searched for and selected systematically for inclusion and critically evaluated, and the search and selection process should be described in the manuscript. The specific type of study or analysis, population, intervention, exposure, and tests or outcomes should be described for each article or data source. The data sources should be as current as possible, ideally with the search having been conducted within several months of manuscript submission. Authors of reports of meta-analyses of clinical trials should submit the PRISMA flow diagram and checklist . Authors of meta-analyses of observational studies should submit the MOOSE checklist . Follow EQUATOR Reporting Guidelines .

A structured abstract is required; for more information, see instructions for preparing Abstracts for Meta-analysis . A list of 3 Key Points is required (see guidance on preparing Key Points ). Maximum length: 3000 words of text (not including abstract, tables, figures, acknowledgments, references, and online-only material), with no more than a total of 5 tables and/or figures and no more than 50-75 references. The subtitle should include the phrase "A Meta-analysis." To read more about meta-analyses, see the AMA Manual of Style .

Other Observational Studies

These manuscripts include Cohort Study, Case-Control Study, Cross-sectional Study, Case Series, Economic Evaluation, Decision Analytical Model, Comparative Effectiveness Research, Genetic Association Study, Diagnostic/Prognostic Study, Quality Improvement Study, Survey Study, and Qualitative Study. Each manuscript should clearly state an objective or hypothesis; the design and methods (including the study setting and dates, patients or participants with inclusion and exclusion criteria and/or participation or response rates, or data sources, and how these were selected for the study); the essential features of any interventions or exposures; the main outcome measures; the main results of the study; a discussion section placing the results in context with the published literature and addressing study limitations; and the conclusions and relevant implications for clinical practice or health policy. Data included in research reports must be original and should be as timely and current as possible (see Timeliness of Data ). Follow EQUATOR Reporting Guidelines .

A structured abstract is required; for more information, see instructions for preparing Abstracts for Reports of Original Data . A list of 3 Key Points is required (see guidance on preparing Key Points ). Maximum length: 3000 words of text (not including abstract, tables, figures, acknowledgments, references, and supplemental material) with no more than a total of 5 tables and/or figures and no more than 50-75 references.

Format My Manuscript

Manuscript preparation and submission requirements.

All manuscripts must be submitted online via the online manuscript submission and review system .

At the time of submission, complete contact information (affiliation, postal/mail address, email address, and telephone numbers) for the corresponding author is required. First and last names, email addresses, and institutional affiliations of all coauthors are also required. After the manuscript is submitted, the corresponding author will receive an acknowledgment confirming receipt and a manuscript number. Authors will be able to track the status of their manuscripts via the online system. After manuscript submission, all authors of papers under consideration for publication will be sent a link to the Authorship Form to complete and submit. See other details in these instructions for additional requirements. 2 , 4

As recommended by the ICMJE, "if the manuscript has been submitted previously to another journal, it is helpful to include the previous editors' and reviewers' comments with the submitted manuscript, along with the authors' responses to those comments." 4 It is not uncommon for manuscripts to have been submitted to and peer reviewed by other journals and sharing this information will not bias an editor's decision for this journal. Thus, authors are encouraged to submit these previous comments in their entirety and indicate how they have revised the manuscript in response to these comments, which may expedite the review process. In the submission system, there is a file type for Previous Peer Review and Editorial Comments.

Include a cover letter and complete contact information for the corresponding author (affiliation, postal/mail address, email address, and telephone number) and whether the authors have published, posted, or submitted any related papers from the same study (see Previous Publication, Related Manuscripts and Reports, and Preprints ).

Manuscripts should be prepared in accordance with the AMA Manual of Style , 11th edition, 2 and/or the ICMJE Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals . 4

Include in the manuscript file a title page, abstract, text, references, and as appropriate, figure legends and tables. Start each of these sections on a new page, numbered consecutively, beginning with the title page. Figures should be submitted as separate files (1 file per figure) and not included in the manuscript text.

We recommend individual file sizes of no more than 500 kB and not exceeding 1 MB, with the total size for all files not exceeding 5 MB (not including any video files).

For submission and review, please submit the manuscript as a Word document. Do not submit your manuscript in PDF format.

Use 10-, 11-, or 12-point font size, double-space text, and leave right margins unjustified (ragged).

The title page should be the first page of your manuscript file. It should include a manuscript title; the full names, highest academic degrees, and affiliations of all authors (if an author's affiliation has changed since the work was done, the new affiliation also should be listed); name and complete contact information for corresponding author; and manuscript word count (not including title, abstract, acknowledgment, references, tables, and figure legends).

Titles should be concise, specific, and informative. 2(p8) Please limit the length of titles to 100 characters (including spaces) for reports of research and other major articles and 60 characters for shorter article types such as opinion articles and Letters as well as for subtitles to major articles. For scientific manuscripts, do not use overly general titles, declarative titles, titles that include the direction of study results, or questions as titles. For reports of clinical trials, meta-analyses, and systematic reviews, include the type of study as a subtitle (eg, A Randomized Clinical Trial, A Meta-analysis, A Systematic Review). For reports of other types of research, do not include study type or design in the title or subtitle. Depending on the context, avoid inclusion of specific locations (eg, state, province, or country) and specific years. To read more about titles, see the AMA Manual of Style .

In the manuscript, include a separate section called "Key Points" before the Abstract.

This feature provides a quick structured synopsis of the findings of your manuscript (required only for research and review manuscripts), following 3 key points: Question, Findings, and Meaning. Limit this section to 75-100 words or less.

Question: Focused question based on the study hypothesis or goal/purpose. Limit to 1 sentence. Findings: Results of the study/review. Include the design (eg, clinical trial, cohort study, case-control study, meta-analysis). Focus on primary outcome(s) and finding(s). Do not emphasize secondary outcomes. Report basic numbers only but state if results are statistically significant or not significant; do not include results of statistical tests or measures of variance (see example below). Can include 1 to 2 sentences. Meaning: Key conclusion and implication based on the primary finding(s). Limit to 1 sentence. Example of Research Article Question: What is the immunogenicity of an inactivated influenza A vaccine with and without adjuvant? Findings: In this randomized clinical trial that included 980 adults, the proportion achieving an effective antibody response was 84% with adjuvant vs 2% without adjuvant, a significant difference. Meaning: In an influenza pandemic the use of an adjuvant with inactivated influenza A vaccine may be warranted. Include: All Journals except JNO and JHF Exclude: JNO and JHF Comments: Example of Review Article Example of Review Article Question: What are the most effective medical treatments for adult chronic sinusitis? Findings: In this systematic review, symptoms of chronic sinusitis were improved with saline irrigation and topical corticosteroid therapy compared to no therapy. Compared with placebo, 3-week courses of systemic corticosteroids or oral doxycycline were associated with reduced polyp size, and a 3-month course of macrolide antibiotic was associated with improved symptoms in patients without polyps. Meaning: First-line therapy for chronic sinusitis should begin with daily topical intranasal corticosteroid in conjunction with saline irrigation; subsequent therapies should be based on the patient's polyp status and severity of symptoms.

Include a structured abstract for reports of original data, meta-analyses, and systematic reviews. Abstracts should be prepared in JAMA Network style—see instructions for preparing abstracts below. Abstracts are not required for Editorials, Viewpoints, and special features. No information should be reported in the abstract that does not appear in the text of the manuscript. To read more about abstracts, see the AMA Manual of Style .

Abstracts for Reports of Original Data:

Reports of original data should include an abstract of no more than 350 words using the headings listed below. For brevity, parts of the abstract may be written as phrases rather than complete sentences. Each section should include the following content:

Importance: The abstract should begin with a sentence or 2 explaining the clinical (or other) importance of the study question. Objective: State the precise objective or study question addressed in the report (eg, "To determine whether..."). If more than 1 objective is addressed, the main objective should be indicated and only key secondary objectives stated. If an a priori hypothesis was tested, it should be stated. Design: Describe the basic design of the study and include the specific study type (eg, randomized clinical trial, cohort, cross-sectional, case-control, case series, survey, meta-analysis, bibliometric analysis). State the years of the study and the duration of follow-up. For older studies (eg, those completed >3 years ago), add the date of the analysis being reported. If applicable, include the name of the study (eg, the Framingham Heart Study). As relevant, indicate whether observers were blinded to patient groupings, particularly for subjective measurements. Setting: Describe the study setting to assist readers to determine the applicability of the report to other circumstances, for example, multicenter, population-based, primary care or referral center(s), etc. Participants: State the clinical disorders, important eligibility criteria, and key sociodemographic features of patients (or other study participants). The numbers of eligible participants and how they were selected should be provided, including the number approached but who refused or were excluded. For selection procedures, these terms should be used, if appropriate: random sample (where random refers to a formal, randomized selection in which all eligible individuals have a fixed and usually equal chance of selection); population-based sample; referred sample; consecutive sample; volunteer sample; convenience sample. If matching is used for comparison groups, characteristics that are matched should be specified. In follow-up studies, the proportion of participants who completed the study must be indicated.

Note: The preceding 3 sections are usually combined for accepted papers during the editing process as "Design, Setting, and Participants," but for manuscript submission these sections should be kept separate.

Intervention(s) (for clinical trials) or Exposure(s) (for observational studies): The essential features of any interventions, or exposures, should be described, including their method and duration. The intervention, or exposure, should be named by its most common clinical name, and nonproprietary drug names should be used. Main Outcome(s) and Measure(s): Indicate the primary study outcome measurement(s) as planned before data collection began. If the manuscript does not report the main planned outcomes of a study, this fact should be stated and the reason indicated. State clearly if the hypothesis being tested was formulated during or after data collection. Explain outcomes or measurements unfamiliar to a general medical readership. Results: Summary demographic information (eg, characteristics such as sex and age) and the number of study participants should be reported in the first sentence of the Results paragraph. The main outcomes of the study should be reported and quantified, including final included/analyzed sample. When possible, present numerical results (eg, absolute numbers and/or rates) with appropriate indicators of uncertainty, such as confidence intervals. Include absolute numbers and/or rates with any ratio measures and avoid redundant reporting of relative data (eg, % increase or decrease). Use means and standard deviations (SDs) for normally distributed data and medians and ranges or interquartile ranges (IQRs) for data that are not normally distributed. Avoid solely reporting the results of statistical hypothesis testing, such as  P  values, which fail to convey important quantitative information. For most studies,  P  values should follow the reporting of comparisons of absolute numbers or rates and measures of uncertainty (eg, 0.8%, 95% CI −0.2% to 1.8%;  P  =.13).  P  values should never be presented alone without the data that are being compared. See also Reporting Standards and Data Presentation . Measures of relative risk also may be reported (eg, relative risk, hazard ratios) and should include confidence intervals. Studies of screening and diagnostic tests should report sensitivity, specificity, and likelihood ratio. If predictive value or accuracy is reported, prevalence or pretest likelihood should be given as well. All randomized clinical trials should include the results of intention-to-treat analysis as well. In intervention studies, the number of patients withdrawn because of adverse effects should be given. Approaches such as number needed to treat to achieve a unit of benefit may be included when appropriate. All surveys should include response/participation rates. Conclusions and Relevance: Provide only conclusions of the study that are directly supported by the results. Give equal emphasis to positive and negative findings of equal scientific merit. Also, provide a statement of relevance indicating implications for clinical practice or health policy, avoiding speculation and overgeneralization. The relevance statement may also indicate whether additional study is required before the information should be used in clinical settings. Trial Registration: For clinical trials only (not nontrial observational studies), the name of the trial registry, registration number, and URL of the registry must be included. See Trial Registration .

Abstracts for Meta-analysis:

Manuscripts reporting the results of meta-analyses should include an abstract of no more than 350 words using the headings listed below. The text of the manuscript should also include a section describing the methods used for data sources, study selection, data extraction, and data synthesis. Each heading should be followed by a brief description:

Importance: A sentence or 2 explaining the importance of the systematic review question that is used to justify the meta-analysis. Objective: State the precise primary objective of the meta-analysis. Indicate whether the systematic review for the meta-analysis emphasizes factors such as cause, diagnosis, prognosis, therapy, or prevention and include information about the specific population, intervention, exposure, and tests or outcomes that are being analyzed. Data Sources: Succinctly summarize data sources, including years searched. The search should include the most current information possible, ideally with the search being conducted within several months before the date of manuscript submission. Potential sources include computerized databases and published indexes, registries, meeting abstracts, conference proceedings, references identified from bibliographies of pertinent articles and books, experts or research institutions active in the field, and companies or manufacturers of tests or agents being reviewed. If a bibliographic database is used, state the exact indexing terms used for article retrieval, including any constraints (for example, English language or human study participants). If abstract space does not permit this level of detail, summarize sources in the abstract including databases and years searched, and place the remainder of the information in the Methods section. Study Selection: Describe inclusion and exclusion criteria used to select studies for detailed review from among studies identified as relevant to the topic. Details of selection should include particular populations, interventions, outcomes, or methodological designs. The method used to apply these criteria should be specified (for example, blinded review, consensus, multiple reviewers). State the proportion of initially identified studies that met selection criteria. Data Extraction and Synthesis: Describe guidelines (eg, PRISMA , MOOSE ) used for abstracting data and assessing data quality and validity. The method by which the guidelines were applied should be stated (for example, independent extraction by multiple observers). Indicate whether data were pooled using a fixed-effect or random-effects model. Main Outcome(s) and Measure(s): Indicate the primary study outcome(s) and measurement(s) as planned before data collection began. If the manuscript does not report the main planned outcomes of a study, this fact should be stated and the reason indicated. State clearly if the hypothesis being tested was formulated during or after data collection. Explain outcomes or measurement unfamiliar to a general medical readership. Results: Provide the number of studies and patients/participants in the analysis and state the main quantitative results of the review. When possible, present numerical results (eg, absolute numbers and/or rates) with appropriate indicators of uncertainty, such as confidence intervals. Include absolute numbers and/or rates with any ratio measures and avoid redundant reporting of relative data (eg, % increase or decrease). Use means and standard deviations (SDs) for normally distributed data and medians and ranges or interquartile ranges (IQRs) for data that are not normally distributed. Avoid solely reporting the results of statistical hypothesis testing, such as  P  values, which fail to convey important quantitative information. For most studies,  P  values should follow the reporting of comparisons of absolute numbers or rates and measures of uncertainty (eg, 0.8%, 95% CI −0.2% to 1.8%;  P  = .13).  P  values should never be presented alone without the data that are being compared. See also Reporting Standards and Data Presentation . Meta-analyses should state the major outcomes that were pooled and include odds ratios or effect sizes and, if possible, sensitivity analyses. Evaluations of screening and diagnostic tests should include sensitivity, specificity, likelihood ratios, receiver operating characteristic curves, and predictive values. Assessments of prognosis should summarize survival characteristics and related variables. Major identified sources of variation between studies should be stated, including differences in treatment protocols, co-interventions, confounders, outcome measures, length of follow-up, and dropout rates. Conclusions and Relevance: The conclusions and their applications (clinical or otherwise) should be clearly stated, limiting interpretation to the domain of the review.

Abstracts for Systematic Reviews or Special Communications:

Systematic Review articles should include a structured abstract of no more than 350 words using the headings listed below.

Importance:  Include 1 or 2 sentences describing the clinical question or issue and its importance in clinical practice or public health. Objective:  State the precise primary objective of the review. Indicate whether the review emphasizes factors such as cause, diagnosis, prognosis, therapy, or prevention and include information about the specific population, intervention, exposure, and tests or outcomes that are being reviewed. Evidence Review:  Describe the information sources used, including the search strategies, years searched, and other sources of material, such as subsequent reference searches of retrieved articles. Methods used for inclusion of identified articles and quality assessment should be explained. Findings:  Include a brief summary of the number of articles included, numbers of various types of studies (eg, clinical trials, cohort studies), and numbers of patients/participants represented by these studies. Summarize the major findings of the review of the clinical issue or topic in an evidence-based, objective, and balanced fashion, with the highest-quality evidence available receiving the greatest emphasis. Provide quantitative data. Conclusions and Relevance:  The conclusions should clearly answer the questions posed if applicable, be based on available evidence, and emphasize how clinicians should apply current knowledge. Conclusions should be based only on results described in the abstract Findings subsection.

Abstracts for Narrative Reviews or Special Communications:

Importance:  An overview of the topic and discussion of the main objective or reason for this review. Observations:  The principal observations and findings of the review. Conclusions and Relevance:  The conclusions of the review that are supported by the information, along with clinical applications. How the findings are clinically relevant should be specifically stated.

Ratings of the quality of the evidence

Tables summarizing evidence should include ratings of the quality of the evidence. Use the rating scheme listed below with ratings of 1-5 for Reviews that include individual studies (modified from the Oxford Centre for Evidence-based Medicine for ratings of individual studies).

Do not use abbreviations in the title or abstract and limit their use in the text. Expand all abbreviations at first mention in the text. To read more about abbreviation use, see the AMA Manual of Style .

Laboratory values are expressed using conventional units of measure, with relevant Système International (SI) conversion factors expressed secondarily (in parentheses) only at first mention. Articles that contain numerous conversion factors may list them together in a paragraph at the end of the Methods section. In tables and figures, a conversion factor to SI should be presented in the footnote or legend. The metric system is preferred for the expression of length, area, mass, and volume. For more details, see the Units of Measure conversion table on the website for the AMA Manual of Style . 2

To read more about units of measure, click here .

Use nonproprietary names of drugs, devices, and other products and services, unless the specific trade name of a drug is essential to the discussion. 2(pp567-569) In such cases, use the trade name once and the generic or descriptive name thereafter. Do not include trademark symbols. To read more about names of drugs, see the AMA Manual of Style .

Authors describing genes or related structures in a manuscript should include the names and official symbols provided by the US National Center for Biotechnology Information (NCBI) or the HUGO Gene Nomenclature Committee . Before submission of a research manuscript reporting on large genomic data sets (eg, protein or DNA sequences), the data sets should be deposited in a publicly available database, such as NCBI's GenBank , and a complete accession number (and version number if appropriate) must be provided in the Methods section or Acknowledgment of the manuscript. To read more about gene nomenclature, see the AMA Manual of Style .

Please verify that all information and materials in the manuscript are original. The journal generally does not republish text, tables, figures, or other material from other publishers, except in rare circumstances. If you believe that you must include content that is owned by a third party, please let us know and provide information about all material that has been previously published and, when applicable, include author(s), title of article, title of journal or book or other publication, and complete citation, doi, and/or URL. The publisher or other third party's permission to reproduce in print and online and in licensed versions of this journal should be submitted when the manuscript is submitted.

See Permission to Reproduce Copyright-Protected Material Form .

The submission and publication of content created by artificial intelligence, language models, machine learning, or similar technologies is discouraged, unless part of formal research design or methods, and is not permitted without clear description of the content that was created and the name of the model or tool, version and extension numbers, and manufacturer. Authors must take responsibility for the integrity of the content generated by these models and tools. See also Use of AI in Publication and Research .

Authors are responsible for the accuracy and completeness of their references and for correct text citation. Number references in the order they appear in the text; do not alphabetize. In text, tables, and legends, identify references with superscript arabic numerals. When listing references, follow AMA style and abbreviate names of journals according to the journals list in PubMed . List all authors and/or editors up to 6; if more than 6, list the first 3 followed by "et al." Note: Journal references should include the issue number in parentheses after the volume number.

Examples of reference style:

Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficileinfection. JAMA . 2014;312(17):1772-1778. Murray CJL. Maximizing antiretroviral therapy in developing countries: the dual challenge of efficiency and quality [published online December 1, 2014]. JAMA . doi:10.1001/jama.2014.16376 Centers for Medicare & Medicaid Services. CMS proposals to implement certain disclosure provisions of the Affordable Care Act. http://www.cms.gov/apps/media/press/factsheet.asp?Counter=4221 . Accessed January 30, 2012. McPhee SJ, Winker MA, Rabow MW, Pantilat SZ, Markowitz AJ, eds. Care at the Close of Life: Evidence and Experience . New York, NY: McGraw Hill Medical; 2011.

For more examples of electronic references, click here .

Tables and Figures

Restrict tables and figures to those needed to explain and support the argument of the article and to report all outcomes identified in the Methods section. Number each table and figure and provide a descriptive title for each. Every table and figure should have an in-text citation. Verify that data are consistently reported across text, tables, figures, and supplementary material.

See also Tables and Figures .

Frequency data should be reported as "No. (%)," not as percentages alone (exception, sample sizes exceeding ~10,000). Whenever possible, proportions and percentages should be accompanied by the actual numerator and denominator from which they were derived. This is particularly important when the sample size is less than 100. Do not use decimal places (ie, xx%, not xx.xx%) if the sample size is less than 100. Tables that include results from multivariable regression models should focus on the primary results. Provide the unadjusted and adjusted results for the primary exposure(s) or comparison(s) of interest. If a more detailed description of the model is required, consider providing the additional unadjusted and adjusted results in supplementary tables.

Tables have a minimum of 2 columns. Comparisons must read across the table columns.

Do not duplicate data in figures and tables. For all primary outcomes noted in the Methods section, exact values with measures of uncertainty should be reported in the text or in a table and in the Abstract, and not only represented graphically in figures.

Pie charts and 3-D graphs should not be used and should be revised to alternative graph types.

Bar graphs should be used to present frequency data only (ie, numbers and rates). Avoid stacked bar charts and consider alternative formats (eg, tables or splitting bar segments into side-by-side bars) except for comparisons of distributions of ordinal data.

Summary data (eg, means, odds ratios) should be reported using data markers for point estimates, not bars, and should include error bars indicating measures of uncertainty (eg, SDs, 95% CIs). Actual values (not log-transformed values) of relative data (for example, odds ratios, hazard ratios) should be plotted on log scales.

For survival plots, include the number at risk for each group included in the analysis at intervals along the x-axis scale. For any figures in which color is used, be sure that colors are distinguishable.

All symbols, indicators, line styles, and colors in statistical graphs should be defined in a key or in the figure legend. Axes in statistical graphs must have labels. Units of measure must be provided for continuous data.

Note: All figures are re-created by journal graphics experts according to reporting standards using the JAMA Network style guide and color palette.

• Number all tables in the order of their citation in the text.
• Include a brief title for each table (a descriptive phrase, preferably no longer than 10 to 15 words).
• Include all tables at the end of the manuscript file.
• Refer to Categories of Articles for limits on the number of tables.
• NOTE: Do not embed tables as images in the manuscript file or upload tables in image formats, and do not upload tables as separate files.

Table Creation

Use the table menu in the software program used to prepare the text. Tables can be built de novo using Insert→Table or copied into the text file from another document (eg, Word, Excel, or a statistical spreadsheet).

Avoid using tabs, spaces, and hard returns to set up the table; such tables will have to be retyped, creating delays and opportunities for error.

Tables should be single-spaced and in a 10- or 12-point font (do not shrink the point size to fit the table onto the page). Do not draw extra lines or rules—the table grid will display the outlines of each cell.

Missing data and blank space in the table field (ie, an empty cell) may create ambiguity and should be avoided; use abbreviations such as NA for not applicable or not available. Each piece of data needs to be contained in its own cell. Do not try to align cells with hard returns or tabs; alignment will be imposed in the production system if the manuscript is accepted. To show an indent, add 2 spaces.

When presenting percentages, include numbers (numerator and denominator).

Include statistical variability where applicable (eg, mean [SD], median [IQR]). For additional detail on requirements for data presentation in tables, see Statistical Methods and Data Presentation .

Place each row of data in a separate row of cells, and note that No. (%) and measures of variability are presented in the same cell as in the example Table 1 below:

Table 1. Baseline Values in the Editors' Health Study

SI conversion factors: To convert cholesterol to mmol/L, multiply values by 0.0259.

Note that JAMA Network journals report laboratory values in conventional units. In a table, provide a footnote with the conversion factor to SI units. For a calculator of SI and conventional units, see the AMA Manual of Style . 2

To present data that span more than 1 row, merge the cells vertically. For example, in Table 2 the final column presents the P value for overall age comparisons.

Table 2. Blood Pressure Values Stratified by Age

The table should be constructed such that the primary comparison reads horizontally. For example, see Table 3 (incorrect) and Table 4 (correct).

Table 3. Patient Data by Study Group

Table 4. Patient Data by Study Group

If a table must be continued, repeat the title and column headings on the second page, followed by "(continued)."

Table Footnotes

Footnotes to tables may apply to the entire table, portions (eg, a column), or an individual entry.

The order of the footnotes is determined by the placement in the table of the item to which the footnote refers.

When both a footnote letter and reference number follow data in a table, set the superscript reference number first followed by a comma and the superscript letter.

Use superscript letters (a, b, c) to mark each footnote and be sure each footnote in the table has a corresponding note (and vice versa).

List abbreviations in the footnote section and explain any empty cells.

If relevant, add a footnote to explain why numbers may not sum to group totals or percentages do not add to 100%.

For more detail on the components and recommended structure of tables, see the AMA Manual of Style . 2

Number all figures (graphs, charts, photographs, and illustrations) in the order of their citation in the text. The number of figures should be limited. Avoid complex composite or multipart figures unless justified. See Categories of Articles for limits on the number of figures and/or tables according to article type.

For initial manuscript submissions, figures must be of sufficient quality and may be embedded at the end of the file for editorial assessment and peer review. If a revision is requested and before a manuscript is accepted, authors will be asked to provide figures that meet the requirements described in Figure File Requirements for Publication .

Graphs, charts, some illustrations, titles, legends, keys, and other elements related to figures in accepted manuscripts will be re-created and edited according to JAMA Network style and standards prior to publication. Online-only figures will not be edited or re-created (see Online-Only Supplements and Multimedia ).

Image Integrity

Preparation of scientific images (clinical images, radiographic images, micrographs, gels, etc) for publication must preserve the integrity of the image data. Digital adjustments of brightness, contrast, or color applied uniformly to an entire image are permissible as long as these adjustments do not selectively highlight, misrepresent, obscure, or eliminate specific elements in the original figure, including the background. Selective adjustments applied to individual elements in an image are not permissible. Individual elements may not be moved within an image field, deleted, or inserted from another image. Cropping may be used for efficient image display or to deidentify patients but must not misrepresent or alter interpretation of the image by selectively eliminating relevant visual information. Juxtaposition of elements from different parts of a single image or from different images, as in a composite, must be clearly indicated by the addition of dividing lines, borders, and/or panel labels.

The submission and publication of images created by artificial intelligence, machine learning tools, or similar technologies is discouraged, unless part of formal research design or methods, and is not permitted without clear description of the content that was created and the name of the model or tool, version and extension numbers, and manufacturer. Authors must take responsibility for the integrity of the content generated by these models and tools. See also Use of AI in Publication and Research .

When inappropriate images or image adjustments are detected by the journal staff, authors will be asked for an explanation and will be requested to submit the image as originally captured prior to any adjustment, cropping, or labeling. Authors may be asked to resubmit the image prepared in accordance with the above standards.

Acceptable Figure Files for Initial Submission and Review

Each figure for the main article may be uploaded as a separate file or appended to the end of the manuscript with the figure titles and legends. Online-only figures must be combined into the PDF of the online-only supplement (see Online-Only Supplements and Multimedia ). Note: If a revision is requested and before acceptance, authors must upload each figure for the main article as a separate file and follow the instructions in Figure File Requirements for Publication .

See the Table of Figure Requirements for additional guidance for specific types of figures for suggested resolution and file formats. In general each figure should be no larger than 1 MB.

Figure File Requirements for Publication

Each figure for the main article must be uploaded as a separate file. Online-only figures must be combined into the PDF of the online-only supplement (see Online-Only Supplements and Multimedia ).

See the Table of Figure Requirements for additional guidance and file formats for specific types of figures.

Files created by vector programs are best for accurately plotting and maintaining data points. JAMA Network journals are unable to use file formats native to statistical software applications to prepare figures for publication; most statistical software programs allow users to save or export files in digital vector formats.

Images created digitally (by digital camera or electronically created illustrations) must meet the minimum resolution requirements at the time of creation. Electronically increasing the resolution of an image after creation causes a breakdown of detail and will result in an unacceptable poor-quality image. Each component of a composite image must be uploaded separately at submission and individually meet the minimum resolution requirement.

Color photographs should be submitted in RGB mode using profiles such as Adobe RGB or sRGB. Digital cameras capture images in RGB. Do not change any color settings once the file is on the computer. Black-and-white photographs (eg, radiographs, ultrasound images, CT and MRI scans, and electron micrographs) can be submitted in either RGB or grayscale modes.

Figure Titles and Legends (Captions)

At the end of the manuscript, include a title for each figure. The figure title should be a brief descriptive phrase, preferably no longer than 10 to 15 words. A figure legend (caption) can be used for a brief explanation of the figure or markers if needed and expansion of abbreviations. For photomicrographs, include the type of specimen, original magnification or a scale bar, and stain in the legend. For gross pathology specimens, label any rulers with unit of measure. Digitally enhanced images must be clearly identified in the figure legends as enhanced or manipulated, eg, computed tomographic scans, magnetic resonance images, photographs, photomicrographs, x-ray films.

Figures With Labels, Arrows, or Other Markers

Photographs, clinical images, photomicrographs, gel electrophoresis, and other types that include labels, arrows, or other markers must be submitted in 2 versions: one version with the markers and one without. Provide an explanation for all labels, arrows, or other markers in the figure legend. The Figure field in the File Description tab of the manuscript submission system allows for uploading of 2 versions of the same figure.

Number of Figures

Refer to Categories of Articles because there may be a limit on the number of figures by article type.

General Figure Guidelines

• Primary outcome data should not be presented in figures alone. Exact values with measure of variability should be reported in the text or table as well as in the abstract.
• All symbols, indicators (including error bars), line styles, colors, and abbreviations should be defined in a legend.
• Each axis on a statistical graph must have a label and units of measure should be labeled.
• Do not use pie charts, 3-D graphs, and stacked bar charts as these are not appropriate for accurate statistical presentation of data and should be revised to another figure type or converted to a table.
• Error bars should be included in both directions, unless only 1-sided variability was calculated.
• Values for ratio data—odds ratios, relative risks, hazard ratios—should be plotted on a log scale. Values for ratio data should not be log transformed.
• For footnotes, use letters (a, b, c, etc) not symbols.
• Do not submit figures with more than 4 panels unless otherwise justified.
• See the AMA Manual of Style for more guidance on figure types and components.

For images featuring patients or other identifiable persons, it is not acceptable to use black bars across the eyes in an attempt to deidentify. Cropping may be acceptable as long as the condition under discussion is clearly visible and necessary anatomic landmarks display. If the person in the image is possibly identifiable (not only by others but also by her/himself), permission for publication is required (see Patient Identification ).

Table of Figure Requirements

To present frequency data (numbers or percentages). Each bar represents a category.

Bar graphs are typically vertical but when categories have long titles or there are many of them, they may run horizontally.

The scale on the frequency axis should begin at 0, and the axis should not be broken.

If the data plotted are a percentage or rate, error bars may be used to show statistical variability.

Acceptable File Formats for Initial Submission: .ai, .bmp, .docx, .emf, .eps, .jpg, .pdf, .ppt, .psd, .tif, .wmf, .xls

Acceptable File Formats for Revision and Publication: .ai, .emf, .eps, .pdf, .wmf, .xls

To demonstrate the relationship between 2 or more quantitative variables, such as changes over time.

The dependent variable appears on the vertical axis (y) and the independent variable on the horizontal axis (x); the axes should be continuous, not broken.

Flow diagram

To show participant recruitment and follow-up or inclusions and exclusions (such as in a systematic review).

Acceptable File Formats for Initial Submission: .ai, .docx, .emf, .eps, .jpg, .pdf, .ppt

Acceptable File Formats for Revision and Publication: .ai, .docx, .emf, .eps, .pdf

Survival plot

To display the proportion or percentage of individuals (represented on the y-axis) remaining free of or experiencing a specific outcome over time (represented on the x-axis).

The curve should be drawn as a step function (not smoothed).

The number of individuals followed up for each time interval (number at risk) should be shown underneath the x-axis.

Box-and-whisker plot (box plot)

To show data distribution from 1 or more groups, particularly aggregate/summary data.

Each element should be described (the ends of the boxes, the middle line, and the whiskers). Data points that fall beyond the whiskers are typically shown as circles.

Forest plot

To illustrate summary data, particularly in meta-analyses and systematic reviews.

The data are presented both tabularly and graphically.

The sources (with years and citations, when relevant) should comprise the first column.

Provide indicators of both directions of results at the top of the plot on either side of the vertical line (eg, favors intervention).

Typically, proportionally sized boxes represent the weight of each study and a diamond shows the overall effect at the bottom of the plot.

To display quantitative data other than counts or frequencies on a single scaled axis according to categories on a baseline (horizontal or vertical). Point estimates are represented by discrete data markers, preferably with error bars (in both directions) to designate variability.

Scatterplot

To show individual data points plotted according to coordinate values with continuous, quantitative x- and y-axis scales.

A curve that is generated mathematically may be fitted to the data to summarize the relationship among the variables.

Illustration

To explain physiological mechanisms, describe clinical maneuvers and surgical techniques, or provide orientation to medical imaging.

Required minimum resolution for publication: ≥350 ppi

Acceptable File Formats for Initial Submission: .ai, .docx, .eps, .jpg, .pdf, .ppt, .psd., tif

Acceptable File Formats for Revision and Publication: .ai, .eps, .jpg, .pdf, .psd, .tif

Photographs and other clinical images

To display clinical findings, experimental results, or clinical procedures, including medical imaging, photomicrographs, clinical photographs, and photographs of biopsy specimens.

Legends for photomicrographs should include details about the type of stain used and magnification.

Acceptable File Formats for Initial Submission: .eps, .jpg, .pdf, .ppt, .psd, .tif

Acceptable File Formats for Revision and Publication: .eps, .jpg, .psd, .tif

Line drawings

To illustrate anatomy or procedures.

Line drawings are almost always black and white.

Required minimum resolution for publication: ≥600 ppi

Acceptable File Formats for Initial Submission: .docx, .jpg, .pdf, .ppt, .psd, .tif

Acceptable File Formats for Revision and Publication: .jpg, .psd, .tif

Authors may submit supporting material to accompany their article for online-only publication when there is insufficient space to include the material in the print article. This material should be important to the understanding and interpretation of the report and should not repeat material in the print article. The amount of online-only material should be limited and justified. Online-only material should be original and not previously published.

Online-only material will undergo editorial and peer review with the main manuscript. If the manuscript is accepted for publication and if the online-only material is deemed appropriate for publication by the editors, it will be posted online at the time of publication of the article as additional material provided by the authors. This material will not be edited or formatted; thus, authors are responsible for the accuracy and presentation of all such material.

Online-only material should be submitted in a single Word document with pages numbered consecutively. Each element included in the online-only material should be cited in the text of the main manuscript (eg, eTable in the Supplement) and numbered in order of citation in the text (eg, eTable 1, eTable 2, eFigure 1, eFigure 2, eMethods). The first page of the online-only document should list the number and title of each element included in the document.

Online-Only Text

Online-only text should be set in Times New Roman font, 10 point in size, and single-spaced. The main heading of the online-only text should be in 12 point and boldface; subheadings should be in 10 point and boldface.

Online-Only References

All references cited within the online-only document must be included in a separate reference section, including those that also were cited in the main manuscript. They should be formatted just as in the main manuscript and numbered and cited consecutively in the online-only material.

Online-Only Tables

Online-only tables should be inserted in the document and numbered consecutively according to the order of citation as eTable 1, eTable 2, etc. All online-only tables should be cited in the relevant text of the main manuscript. The text and data in online tables should be Arial font, 10 point in size, and single-spaced. The table title should be set in Arial font, 12 point, and bold. Headings within tables should be set in 10 point and bold. Table footnotes should be set in 8 point and single-spaced. See also instructions for Tables above. If a table runs on to subsequent pages, repeat the column headers at the top of each page. Wide tables may be presented using a landscape orientation.

If data are better displayed in a separate Excel file, this can be submitted, provided that the Excel file is cited as an eTable and is numbered in the order cited in the text. If multiple Excel files of data are submitted, these should be placed in a single Excel file, with multiple tabs (sheets) at the bottom of the file. The first tab (sheet) should include a table of contents with eTable numbers and titles, and the subsequent tabs (sheets) should be labeled as eTable 1, eTable 2, etc. Please note: the journal is not a data repository; large data sets should be deposited into publicly accessible data repositories, and a link should be provided in the Methods or Results section and the Data Sharing Statement .

Online-Only Figures

Online-only figures should be inserted in the document and numbered consecutively according to the order of citation as eFigure 1, eFigure 2, etc. All online-only figures should be cited in the relevant text of the main manuscript. Figure titles should be set in Arial font, 12 point, bold, and single-spaced. Text within figures should be set as Arial font, 10 point. Figure legends should be set in 8 point and single-spaced. Graphs and diagrams should be exported directly out of the software application used to create them in a vector file format, such as .wmf, and then inserted into the Word document. Image file formats such as .jpg, .tif, and .gif are generally not suitable for graphs. Photographs, including all radiological images, should be prepared as .jpg (highest option) or .tif (uncompressed) files at a resolution of 300 dpi and width of 3-5 inches, but the resolution of photographic files with an original resolution <300 dpi should not be increased digitally to achieve a 300-dpi resolution. Photographs should be inserted in the document with the "Link to File" button turned off. Wide figures may be presented using a landscape orientation.

For editorial and review of an initial submission, submit videos according to the following specifications:

• Acceptable file formats: .mov, .wmv, .mpg, .mpeg, .mp4, or .avi
• Maximum file size: ≤25 MB
• Preferred dimensions: 1920x1080 (HD) or greater (4k UHD footage is acceptable)
• Minimum dimensions: 640 pixels wide by 360 pixels deep
• Recommended frame rate: 24 fps (or 23.976 fps), 25 and 30 fps (or 29.97 fps)
• Maximum length: ≤5 minutes
• Desired aspect ratio: 4:3 (standard) or 16:9 (widescreen)
• If compression is required to reduce file size for uploading, please use a minimum bit rate of 10,000 kbit/s – 20,000 kbit/s
• When filming, please use a landscape orientation, not a portrait orientation. This is especially important when filming video or taking photographs with a smartphone or a mobile device.

Verify that the videos are viewable in QuickTime or Windows Media Player before uploading.

For each video, provide an in-text citation (eg, Video 1). At the end of the manuscript file, include a title (a brief phrase, preferably no longer than 10 to 15 words) and a caption that includes the file format and a brief explanation for each video. The same title and caption must be entered in the designated fields in the manuscript submission system when uploading each video. If multiple video files are submitted, number them in the order in which they should be viewed.

If patient(s) are identifiable in the video, authors must submit a Patient Permission form completed and signed by each patient. See also Patient Identification .

If the author does not hold copyright to the video, the author must obtain permission for the video to be published in the journal. This permission must be for unrestricted use in all print, online, and licensed versions of the journal.

NOTE: If your manuscript and accompanying videos are accepted for publication, the video files will be placed into a journal video frame and will be edited by JAMA Network video production staff according to journal style. In addition, a JAMA Network staff person may contact you to resubmit your videos to meet our production specifications. For example, a larger size may be needed, and if your videos were submitted with embedded text such as titles, annotations, labels, or captions, we will ask you to remove the text at this stage and resubmit the video without text, and JAMA Network video production will re-create all text using our house style.

Guidelines for Optimal Video Quality

• Use plenty of diffuse light; avoid shadows.
• Use the appropriate white-balance based on your lighting conditions. Different cameras have different settings, but most have presets for incandescent (yellow) light, fluorescent light, daylight, and tungsten light. Please make sure to select the correct one so that the color of your footage renders accurately.
• Do not overexpose the image; a bit underexposed is preferable.
• Use a tripod. This is especially important in close-ups.
• Avoid excessive zooming. Use the optical zoom only; do not use a digital zoom.
• Turn off all camera special effects.
• Avoid using autofocus. Manual focus is more accurate. Keep the camera at a fixed distance from the subject.
• Instruct people on camera to speak clearly and face the camera when speaking. Try to avoid large movements while speaking or immediately after speaking. Allow pauses before and after speaking for easier editing.
• If the situation permits, ensure that individuals being filmed are not wearing white clothing or clothing with busy patterns or stripes, especially shirts, jackets, and ties. Subdued medium blue, brown, tan, beige, and green colors all work well for shirt and clothing choices.
• Do not include an introduction by the physician as a "talking head" explaining a procedure. All footage should be of the procedure or relevant subject matter only.
• Record a few extra seconds before and after each cut or after changing the camera's position. This allows for easier editing.

Additional Considerations for Filming Surgical Procedures

• Coordinate with the surgical staff to establish a vantage point for the camera that has a clear view of the surgical field.
• Before the procedure, if the situation permits, identify the surgical staff's positions for access into and out of the surgical field to ensure there is no immediate obstruction of the camera.
• During the procedure, avoid typical obstructions of the camera's main view such as arms reaching across the field or soiled surgical sponges. Where possible, keep the heads, hands, and any instruments away from the immediate sightline of the camera. This will ensure that all moments of the procedure are captured in full view and focus.
• If the situation permits a choice of glove type, use brown or tan. White gloves reflect bright light; vividly colored surgical gloves can distract the viewer from the teaching point of the video.
• If the situation permits, avoid rapid movements for procedural steps that should be noticed and understood. To demonstrate a key moment or use of an instrument, movement that is deliberate and steady will allow a standard camera to focus properly.

For editorial and review of an initial submission, submit audio files according to the following minimum requirements:

• Acceptable file formats: .mp3, .wav, or .aiff
• Maximum file size: 25 MB
• To achieve the best quality, use a setting of 256 kbps or higher for stereo or 128 kbps or higher for mono.
• Sampling rate should be either 44.1 kHz or 48 kHz.
• Bit rate should be either 16 or 24 bit.
• To avoid audible clipping noise, please make sure that audio levels do not exceed 0 dBFS.

For each audio file, provide an in-text citation. At the end of the manuscript, include a title (a brief phrase, preferably no longer than 10-15 words) and a caption that includes the file format and a brief explanation for each audio.

NOTE: If your manuscript is accepted for publication, JAMA Network video production staff may contact you to request an original uncompressed audio file in .wav or .aiff format. There is no maximum file size requirement for publication at this stage.

After Submission

Authors will be sent notifications of the receipt of manuscripts and editorial decisions by email. During the review process, authors can check the status of their submitted manuscript via the online manuscript submission and review system . Authors should not disclose the fact that their manuscript has been submitted to anyone, except coauthors and contributors, without permission of the editor.

All submitted manuscripts are reviewed initially by one of the editors. Manuscripts are evaluated according to the following criteria: material is original and timely, writing is clear, study methods are appropriate, data are valid, conclusions are reasonable and supported by the data, information is important, and topic has general interest to readers of this journal. From these basic criteria, the editors assess a paper's eligibility for publication. Manuscripts with insufficient priority for publication are rejected promptly. Other manuscripts are sent to expert consultants for peer review. The journal uses a single-anonymized peer review process: peer reviewer identities are kept confidential (unless reviewers choose to reveal their names in their formal reviews); author identities are made known to reviewers. The existence of a manuscript under review is not revealed to anyone other than peer reviewers and editorial staff. Peer reviewers are required to maintain confidentiality about the manuscripts they review and must not divulge any information about a specific manuscript or its content to any third party without prior permission from the journal editors. Reviewers are instructed to not submit confidential manuscripts, abstracts, or other text into a chatbot, language model, or similar tool. At submission, authors may choose to have manuscripts that are not accepted by the journal referred to one of the JAMA Network specialty journals and/or JAMA Network Open along with reviewers' comments (if available). Information from submitted manuscripts may be systematically collected and analyzed as part of research to improve the quality of the editorial or peer review process. Identifying information remains confidential. Final decisions regarding manuscript publication are made by an editor who does not have any relevant conflicts of interest.

Authors may appeal decisions. All appeals are reviewed by the editor in chief, on a case-by-case basis, or a designated editor if the editor in chief is recused from the review.

After Revision/Acceptance

All authors are required to complete an Authorship Form and Publishing Agreement. See Authorship Criteria and Contributions .

Accepted manuscripts are edited in accordance with the AMA Manual of Style , 2 and returned to the corresponding author (or her/his designee) for approval. Authors are responsible for all statements made in their work, including changes made during editing and production that are authorized by the corresponding author.

Authors should not disclose the fact that their manuscript has been accepted to anyone, except coauthors and contributors, until it is published without permission of the editor or as described in the guidance on Previous or Planned Meeting Presentaton or Release of Information and Embargo Policy .

If accepted for publication, all articles are generally published Online First and then again in a print/online issue.

After Publication

Postpublication correspondence.

For accepted manuscripts, the corresponding author will be asked to respond to letters to the editor.

Reprints and e-prints may be ordered online when the edited manuscript is sent for approval to the corresponding author.

Requests to publish corrections should be sent to the editorial office. Errors and requests for corrections are reviewed by editors and authors, and, if warranted, a Correction notice summarizing the errors and corrections is published promptly and linked online to the original article, and the original article is corrected online with the date of correction. 15

First and last authors of peer-reviewed articles are eligible to receive CME credit. See CME From the JAMA Network .

About Previous Release of Information, Embargo, and Access

Manuscripts are considered with the understanding that they have not been published previously and are not under consideration by another publication.

Copies of all related or similar manuscripts and reports by the same authors (ie, those containing substantially similar content or using the same, similar, or a subset of data) that have been previously published or posted electronically or are under consideration elsewhere must be provided at the time of manuscript submission. All related previously published articles should be cited as references and described in the submitted manuscript along with explanation of how the submitted manuscript differs from the related previously published article(s).

Manuscripts that have been previously posted on a preprint server may be submitted for consideration for publication. When the manuscript is submitted, authors must provide information about the preprint, including a link to it and a description of whether the submitted manuscript has been revised or differs from the preprint.

See also Previous or Planned Meeting Presentation or Release of Information and Research Article Public Access, Depositing in Repositories, and Discoverability.

Meeting presentation: A complete manuscript submitted to the journal following or prior to presentation at a scientific meeting or publication of preliminary findings elsewhere (ie, as an abstract) is eligible for consideration for publication. Authors considering presenting or planning to present the work at an upcoming scientific meeting should indicate the name and date of the meeting on the manuscript submission form. For accepted papers, the editors may be able to coordinate publication with the meeting presentation. Authors of submitted papers, including those accepted but not yet published, should not disclose the status of such papers during such meeting presentations that occur before the work is published. Authors who present information contained in a manuscript that is under consideration by this journal during scientific or clinical meetings should not distribute complete reports (ie, copies of manuscripts) or full data presented as tables and figures to conference attendees or journalists. Publication of abstracts in print and online conference proceedings, as well as posting of slides or videos from the scientific presentation on the meeting website, is acceptable. However, for manuscripts under consideration by this journal, publication of full reports in meeting proceedings or online, issuing detailed news releases reporting the results of the study that go beyond the meeting abstract, or participation in formal news conferences will ordinarily jeopardize chances for publication of the submitted manuscript in this journal. 5 Media coverage of presentations at scientific meetings will not jeopardize consideration, but direct release of information through press releases or news media briefings may preclude consideration of the manuscript by this journal. 5 Rare instances of papers reporting public health emergencies should be discussed with the editor. Authors submitting manuscripts or letters to the editor regarding adverse drug or medical device reactions, reportable diseases, etc, should also report this information to the relevant government agency.

Authors should not release information about accepted manuscripts via social media until publication.

See also Previous Publication, Related Manuscripts and Reports, and Preprints . For more information, see the AMA Manual of Style .

Authors should not disclose the fact that their manuscript has been accepted to anyone, except coauthors and contributors, without permission of the editor until it is published. All information regarding the content and publication date of accepted manuscripts is strictly confidential. Unauthorized prepublication release of accepted manuscripts and information about planned publication date may result in rescinding the acceptance and rejecting the paper. This policy applies to all categories of articles, including research, review, opinion, correspondence, etc. Information contained in or about accepted articles cannot appear in print, audio, video, or digital form or be released by the news media until the specified embargo release date. 2 , 5 See also Previous or Planned Meeting Presentation or Release of Information .

Authors have the option to choose the type of Publishing Agreement, either (1) a free no-fee public access option or (2) one of two author-pay open access options. These options will be available for authors to request at the time of manuscript submission. Reviewers and editors will be unaware of the request for open access until after a final decision is made. For detailed information on public access, open access (including fees, waivers, and discounts), copyright, and licensing, please see below.

• Copyright Transfer. In consideration of the action of the American Medical Association (AMA) in reviewing and editing this submission (manuscript, tables, figures, video, audio, and other supplemental files for publication), I hereby transfer, assign, or otherwise convey all copyright ownership, including any and all rights incidental thereto, exclusively to the AMA, in the event that such work is published by the AMA.
• Federal Employment. I was an employee of the US federal government or that of another nation when this work was conducted and prepared for publication; therefore, it is not protected by the Copyright Act, and copyright ownership cannot be transferred.
• Work for Hire. I am employed by an institution that considers this submission a "work made for hire" and that requires an authorized representative of the institution to assign copyright on my behalf.
• Eligibility: Available only for authors of manuscripts reporting research funded by a not-for-profit foundation or agency or unfunded research. Note: If your open access funding source is commercial, only a CC-BY-NC-ND license is available.
• Author requirements: Payment of $5000 and transfer of a publication license to the journal.
• License rights: Immediate open access on journal website on the day of publication, retention of copyright, and a CC-BY license that permits others to distribute, remix, tweak, and build on the work, even commercially, without permission, provided that credit is given to the original authors and journal.
• Eligibility: Available for authors of manuscripts reporting research funded by a commercial funding source.
• Author requirements: Payment of $5000 and grant of a publication license to the journal.
• License rights: Immediate open access on journal website on the day of publication and a CC-BY-NC-ND license that permits others to distribute the work without permission, provided that credit is given to the original authors and journal and that the article is not altered or used commercially.
• Open Access Waivers and Discounts Waivers and discounts on open access article processing charges are available for eligible authors from Hinari Core Offer countries with limited resources.

The journal makes all research articles free public access 12 months after publication on the journal website or immediately for articles published under an open access license.

Authors of research articles may deposit the accepted version of the manuscript (ie, the peer-reviewed manuscript that you submitted on which this decision is based) in a repository of your choice on or after the date of publication provided that it links to the final published version on the journal website. You may not deposit the published article (version of record), which is the final copyedited, formatted, and proofed version published by the journal. The journal will deposit a copy of the published research article into PubMed Central (PMC) at the time of publication, where it will be publicly available 12 months after publication or immediately if you have purchased an open access license. A few weeks after publication, you may obtain your PMCID on the PMC site at https://www.ncbi.nlm.nih.gov/pmc/pmctopmid/ . These options apply only to research articles. Non-research articles may not be deposited into repositories.

In addition, the journal will add metadata to all article to ensure web-based search engine discoverability and will provide publicly discoverable information about your article to PubMed/Medline and numerous other bibliographic databases on the day of publication.

Author Responsibilities

Most of the JAMA Network journals' editorial policies for authors are summarized in these instructions. Citations and links to the AMA Manual of Style: A Guide for Authors and Editors 2 and other publications with additional information are also provided.

Each author should have participated sufficiently in the work to take public responsibility for appropriate portions of the content. 2 One or more authors should take responsibility for the integrity of the work as a whole, from inception to published article. According to the guidelines of the International Committee of Medical Journal Editors (ICMJE), 4 authorship credit should be based on the following 4 criteria:

• substantial contributions to conception or design of the work, or the acquisition, analysis, or interpretation of data for the work; and
• drafting of the work or reviewing it critically for important intellectual content; and
• final approval of the version to be published; and
• agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Each author should be accountable for the parts of the work he or she has done. In addition, each author should be able to identify which coauthors are responsible for specific other parts of the work and should have confidence in the integrity of the contributions of any coauthors.

All those designated as authors should meet all 4 criteria for authorship, and all who meet the 4 criteria should be identified as authors. Those who do not meet all 4 criteria should be acknowledged (see Acknowledgment Section ).

All authors (ie, the corresponding author and each coauthor) must read, complete, and submit an electronic Authorship Form with required statements on Authorship Responsibility, Criteria, and Contributions; Confirmation of Reporting Conflicts of Interest and Funding; and Publishing Agreement. 2(pp128-133) In addition, authors are required to identify their specific contributions to the work described in the manuscript. Requests by authors to designate equal contributions or shared authorship positions (eg, co-first authorship) may be considered if justified and within reason. 6 An email with links to the Authorship Form will be sent to authors for completion after manuscripts have been submitted.

For reports of original data, authors' specific contributions will be published in the Acknowledgment section (see Manuscript Preparation and Submission Requirements , Acknowledgment section ). 2 All other persons who have made substantial contributions to the work reported in this manuscript (eg, data collection, analysis, or writing or editing assistance) but who do not fulfill the authorship criteria should be named with their specific contributions and affiliations in an Acknowledgment in the manuscript. Written permission to include the names of individuals in the Acknowledgment section must be obtained.

Nonhuman artificial intelligence, language models, machine learning, or similar technologies do not qualify for authorship. If these models or tools are used to create content or assist with writing or manuscript preparation, authors must take responsibility for the integrity of the content generated by these tools. Authors should report the use of artificial intelligence, language models, machine learning, or similar technologies to create content or assist with writing or editing of manuscripts in the Acknowledgment section or Methods section if this is part of formal research design or methods. See also Use of AI in Publication and Research , Reproduced and Re-created Material , and Image Integrity .

The authors also must certify that the manuscript represents valid work and that neither this manuscript nor one with substantially similar content under their authorship has been published or is being considered for publication elsewhere (see also About Previous Release of Information, Embargo, and Access ). 2 Authors of manuscripts reporting original data or systematic reviews must provide an access to data statement from 1 or 2 named authors, often the corresponding author (see also Data Access, Responsibility, and Analysis ). If requested, authors should be prepared to provide the data and must cooperate fully in obtaining and providing the data on which the manuscript is based for examination by the editors or their assignees.

A single corresponding author (or coauthor designee in the event that the corresponding author is unavailable) will serve on behalf of all coauthors as the primary correspondent with the editorial office during the submission and review process. If the manuscript is accepted, the corresponding author will review an edited manuscript and proof, make decisions regarding release of information in the manuscript to the news media or federal agencies, handle all postpublication communications and inquiries, and will be identified as the corresponding author in the published article.

The corresponding author also is responsible for ensuring that the Acknowledgment section of the manuscript is complete (see Acknowledgment Section ) and that the conflict of interest disclosures reported in the Acknowledgment section of the manuscript are accurate, up-to-date, and consistent with the information provided in each author's potential conflicts of interest section in the Authorship Form (see Conflicts of Interest and Financial Disclosures ).

The corresponding author also must complete the Acknowledgment statement part of the Authorship Form confirming that all persons who have contributed substantially but who are not authors are identified in the Acknowledgment section and that written permission from each person acknowledged has been obtained (see Acknowledgment Section ).

Requests for co-corresponding authors will be considered on a very limited basis if justified, but no more than 2 co-corresponding authors will be permitted. In such cases, a primary corresponding author must be designated as the point of contact responsible for all communication about the manuscript and article, manage the tasks described above, and will be listed first in the corresponding author section. 6 To read more about the role and responsibilities of corresponding authors, see the AMA Manual of Style .

Authors should determine the order of authorship among themselves and should settle any disagreements before submitting their manuscript. Changes in authorship (ie, order, addition, and deletion of authors) should be discussed and approved by all authors. Any requests for such changes in authorship after initial manuscript submission and before publication should be explained in writing to the editor in a letter or email from all authors. 2(pp128-133)

The JAMA Network recognizes that authors may change their names for personal reasons, and the editors respect authors' rights to autonomy and privacy in this regard. Authors who request confidential name changes after publication because of changes in identity, marital status, religion, or other reasons may have their names changed in articles without indication of the reason for the change and without a formal correction notice. If an author prefers this change to be public, a formal Correction notice can be issued, with or without the reason per author preference. The journal will not request the approval of coauthors, but the requesting author may wish to notify coauthors if this change will affect subsequent citations to the article. The requester may be asked to notify the corresponding author about this change to the published article; alternatively, the journal may inform the corresponding author of this change (without explaining the reason for the change). The journal will make this change to the online and PDF versions of the published article and will notify postpublication indexes and databases as a standard process but cannot guarantee when or if the change will be reflected in these indexes and databases.

If authorship is attributed to a group (either solely or in addition to 1 or more individual authors), all members of the group must meet the full criteria and requirements for authorship as described above, and all group member authors must complete Authorship Forms. 6 If all members of a group do not meet all authorship criteria, a group must designate 1 or more individuals as authors or members of a writing group who meet full authorship criteria and requirements and who will take responsibility for the group. 2 , 6 Group names should appear at the end of the byline and should not be interspersed within the list of individually named authors. Group authors may not be included for article types with limited numbers of authors (eg, opinion articles).

For articles with a large number of authors (eg, >50), a long list of authors will not fit in the byline of a print/PDF version of the article. In such cases, a group byline will be recommended with the individual names of each author listed at the end of the article. All author names would still be individually indexed, displayed, and easily searchable in bibliographic records such as PubMed. 6

Nonauthor Collaborators: Other group members who do not meet the criteria for authorship (eg, investigators, advisors, assistants) may be identified. For group author manuscripts, a Nonauthor Collaborator Template (with names, academic degrees, institution, location, role/contribution, and subgroup) must be completed during revision. The template will be available to authors with the request for revision. The collaborators will be published in an online Supplement based on this template and will be deposited to PubMed.

To read more about authorship, click here .

A conflict of interest may exist when an author (or the author's institution or employer) has financial or personal relationships or affiliations that could influence (or bias) the author's decisions, work, or manuscript. All authors are required to report potential conflicts of interest including specific financial interests relevant to the subject of their manuscript in the Acknowledgment section of the manuscript 2 and in the Disclosure of Potential Conflicts of Interest section of the Authorship Form. Note: These forms will be requested after a manuscript has been submitted, but authors should also include conflict of interest disclosures in the Acknowledgment section of the submitted manuscript.

Definitions and Terms of Conflicts of Interest Disclosures:

Authors are expected to provide detailed information about all relevant financial interests, activities, relationships, and affiliations (other than those affiliations listed in the title page of the manuscript) including, but not limited to, employment, affiliation, funding and grants received or pending, consultancies, honoraria or payment, speakers' bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Following the guidelines of the ICMJE, 4 the definitions and terms of such disclosures include

Any potential conflicts of interest "involving the work under consideration for publication" (during the time involving the work, from initial conception and planning to present), Any "relevant financial activities outside the submitted work" (over the 3 years prior to submission), and Any "other relationships or activities that readers could perceive to have influenced, or that give the appearance of potentially influencing" what is written in the submitted work (based on all relationships that were present during the 3 years prior to submission).

Authors without conflicts of interest, including relevant financial interests, activities, relationships, and affiliations, should indicate such in their disclosures and include a statement of no such interests in the Acknowledgment section of the manuscript. Failure to include this information in the manuscript may delay evaluation and review of the manuscript. Authors should err on the side of full disclosure and should contact the editorial office if they have questions or concerns.

Although many universities and other institutions and organizations have established policies and thresholds for reporting financial interests and other conflicts of interest, the JAMA Network requires complete disclosure of all relevant financial relationships and potential financial conflicts of interest, regardless of amount or value. For example, authors of a manuscript about hypertension should report all financial relationships they have with all manufacturers and owners of products, devices, tests, and services used in the management of hypertension, not only those relationships with entities whose specific products, devices, tests, and services are mentioned in the manuscript. If authors are uncertain about what constitutes a relevant financial interest or relationship, they should contact the editorial office.

For all accepted manuscripts, the corresponding author will have been asked to confirm that each coauthor's disclosures of conflicts of interest and relevant financial interests, activities, relationships, and affiliations and declarations of no such interests are accurate, up-to-date, and consistent with the disclosures reported in the Acknowledgment section of the manuscript because this information will be published in the Acknowledgment section of the article. Decisions about whether such information provided by authors should be published, and thereby disclosed to readers, are usually straightforward. Although editors are willing to discuss disclosure of specific conflicts of interest with authors, JAMA Network policy is one of complete disclosure of all potential conflicts of interest, including relevant financial interests, activities, relationships, and affiliations (other than those affiliations listed in the title page of the manuscript). The policy requiring disclosure of conflicts of interest applies for all manuscript submissions, including letters to the editor. If an author's disclosure of potential conflicts of interest is determined to be inaccurate or incomplete after publication, a correction will be published to rectify the original published disclosure statement, and additional action may be taken as necessary.

All authors must also complete the Disclosure of Potential Conflicts of Interest section of the Authorship Form. 7

All financial and material support for the research and the work should be clearly and completely identified in an Acknowledgment section of the manuscript. At the time of submission, information on the funding source (including grant identification) must also be completed via the online manuscript submission and review system. The specific role of the funding organization or sponsor in each of the following should be specified: "design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication." 7 To read more about reporting funding and other support, see the AMA Manual of Style .

For all reports (regardless of funding source) containing original data, at least 1 named author (eg, the principal investigator), and no more than 2 authors, must indicate that she or he "had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis." 7 This exact statement should be included in the Acknowledgment section at the end of the manuscript. Modified statements or generic statements indicating that all authors had such access are not acceptable. In addition, for all reports containing original data, the names and affiliations of all authors (or other individuals) who conducted and are responsible for the data analysis must be indicated in the Acknowledgment section of the manuscript. If the individual who conducted the analysis is not named as an author, a detailed explanation of his/her contributions and reasons for his/her involvement with the data analysis should be included.

For all reports of research, authors are required to provide a Data Sharing Statement to indicate if data will or will not be shared. Specific questions regarding the sharing of data are included in the manuscript submission system. If authors choose to share or not share data, this information will be published in a Data Sharing Statement in an online supplement linked to the published article. Authors will be asked to identify the data, including individual patient data, a data dictionary that defines each field in the data set, and supporting documentation (eg, statistical/analytic code), that will be made available to others; when, where, and how the data will be available (eg, a link to a data repository); types of analyses that are permitted; and if there will be any restrictions on the use of the data. Authors also have the option to explain why data may not be shared. A list of generalist public repositories that authors may consider using is available from the National Library of Medicine .

The Acknowledgment section is the general term for the list of contributions, disclosures, credits, and other information included at the end of the text of a manuscript but before the references. The Acknowledgment section includes authors' contributions; information on author access to data; disclosure of potential conflicts of interest, including financial interests, activities, relationships, and affiliations; sources of funding and support; an explanation of the role of funder(s)/sponsor(s); names, degrees, and affiliations of participants in a large study or other group (ie, collaborators); any important disclaimers; information on previous presentation of the information reported in the manuscript; and the contributions, names, degrees, affiliations, and indication if compensation has been received for all persons who have made substantial contributions to the work but who are not authors. 2

All other persons who have made substantial contributions to the work reported in the manuscript (eg, data collection, analysis, and writing or editing assistance) but who do not fulfill the authorship criteria should be named with their specific contributions in an Acknowledgment in the manuscript.

Authors must obtain written permission to include the names of all individuals included in the Acknowledgment section, and the corresponding author must confirm that such permission has been obtained in the Authorship Form.

Authors should report the use of artificial intelligence, language models, machine learning, or similar technologies to create content or assist with writing or editing of manuscripts in the Acknowledgment section or the Methods section if this is part of formal research design or methods. This should include a description of the content that was created or edited and the name of the language model or tool, version and extension numbers, manufacturer, date(s) of use, and confirmation that the authors take responsibility for the integrity of the content generated. (Note: this does not include basic tools for checking grammar, spelling, references, etc.) See also Use of AI in Publication and Research and Statistical Analysis Subsection .

Requirements for Reporting

Authors of research articles should follow the EQUATOR Reporting Guidelines . See specific Study Types for detailed guidance on reporting.

Causal language (including use of terms such as effect and efficacy) should be used only for randomized clinical trials. For all other study designs (including meta-analyses of randomized clinical trials), methods and results should be described in terms of association or correlation and should avoid cause-and-effect wording. To read more about use of causal language, see the AMA Manual of Style .

Research reports should be timely and current and should be based on data collected as recently as possible. Manuscripts based on data from randomized clinical trials should be reported as soon as possible after the trial has ended, ideally within 1 year after follow-up has been completed.

For cohort studies, the date of final follow-up should be no more than 5 years before manuscript submission. Likewise, data used in case-control or cross-sectional studies should have been collected as recently as possible, but no more than 5 years before manuscript submission. Manuscripts in which the most recent data have been collected more than 5 years ago ordinarily will receive lower priority for publication; thus, authors of such manuscripts should provide a detailed explanation of the relevance of the information in light of current knowledge and medical practice as well as the most recent date(s) of analysis of the study.

General Considerations

Authors are encouraged to consult "Reporting Statistical Information in Medical Journal Articles." 1 In the Methods section, describe statistical methods with enough detail to enable a knowledgeable reader with access to the original data to reproduce the reported results. Such description should include appropriate references to the original literature, particularly for uncommon statistical methods. For more advanced or novel methods, provide a brief explanation of the methods and appropriate use in the text and consider providing a detailed description in an online supplement.

In the reporting of results, when possible, quantify findings and present them with appropriate indicators of measurement error or uncertainty, such as confidence intervals (see Reporting Standards and Data Presentation ). Avoid relying solely on statistical hypothesis testing, such as the use of P values, which fails to convey important quantitative information. For observational studies, provide the numbers of observations. For randomized trials, provide the numbers randomized. Report losses to observation or follow up (see Missing Data ). For multivariable models, report all variables included in models, and report model diagnostics and overall fit of the model when available (see Statistical Procedures ).

Define statistical terms, abbreviations, and symbols, if included. Avoid nontechnical uses of technical terms in statistics, such as correlation, normal, predictor, random, sample, significant, trend. Do not use inappropriate hedge terms such as marginal significance or trend toward significance for results that are not statistically significant. Causal language (including use of terms such as effect and efficacy) should be used only for randomized clinical trials. For all other study designs (including meta-analyses of randomized clinical trials), methods and results should be described in terms of association or correlation and should avoid cause-and-effect wording.

Sample Size Calculations

For randomized trials, a statement of the power or sample size calculation is required (see the EQUATOR Network CONSORT Guidelines ). For observational studies that use an established population, a power calculation is not generally required when the sample size is fixed. However, if the sample size was determined by the researchers, through any type of sampling or matching, then there should be some justification for the number sampled. In any case, describe power and sample size calculations at the beginning of the Statistical Methods section, following the general description of the study population.

Descriptive Statistics

It is generally not necessary to provide a detailed description of the methods used to generate summary statistics, but the tests should be briefly noted in the Methods section (eg, ANOVA or Fisher exact test).

Statistical Procedures

Identify regression models with more than 1 independent variable as multivariable and regression models with more than 1 dependent variable as multivariate. Report all variables included in models, as well as any mathematical transformations of those variables. Provide the scientific rationale (clinical, statistical, or otherwise) for including variables in regression models.

For regression models fit to dependent data (eg, clustered or longitudinal data), the models should account for the correlations that arise from clustering and/or repeated measures. Failure to account for such correlation will result in incorrect estimates of uncertainty (eg, confidence intervals). Describe how the model accounted for correlation. For example, for an analysis based on generalized estimating equations, identify the assumed correlation structure and whether robust (or, sandwich) variance estimators were used. Or, for an analysis based on mixed-effects models, identify the assumed structure for the random effects, such as the level of random intercepts and whether any random slopes were included. Fixed-effects estimation should be described as conditional likelihood. Avoid the term fixed effects for describing covariates.

Missing Data

Report losses to observation, such as dropouts from a clinical trial or those lost to follow-up or unavailable in an observational study. If some participants are excluded from analyses because of missing or incomplete data, provide a supplementary table that compares the observed characteristics between participants with complete and incomplete data. Consider multiple imputation methods to impute missing data and include an assessment of whether data were missing at random. Approaches based on "last observation carried forward" should not be used.

Primary Outcomes, Multiple Comparisons, and Post Hoc Comparisons

Both randomized and observational studies should identify the primary outcome(s) before the study began, as well as any prespecified secondary, subgroup, and/or sensitivity analyses. Comparisons arrived at during the course of the analysis or after the study was completed should be identified as post hoc. For analyses of more than 1 primary outcome, corrections for multiple testing should generally be used. For secondary outcomes, address multiple comparisons or consider such analyses as exploratory and interpret them as hypothesis-generating. The reporting of all outcomes should match that included in study protocols. For randomized clinical trials, protocols with complete statistical analysis plans should be cited in the Methods section and submitted as online supplementary content. Randomized clinical trials should be primarily analyzed according to the intention-to-treat approach. Deviations from strict intention-to-treat analysis should be described as "modified intention-to-treat," with the modifications clearly described.

Statistical Analysis Subsection

At the end of the Methods section, briefly describe the statistical tests used for the analysis. State any a priori levels of significance and whether hypothesis tests were 1- or 2-sided. Also include the statistical software used to perform the analysis, including the version and manufacturer, along with any extension packages (eg, the svy suite of commands in Stata or the survival package in R). Do not describe software commands (eg, SAS proc mixed was used to fit a linear mixed-effects model). If analysis code is included, it should be placed in the online supplementary content.

Reporting Standards and Data Presentation

Analyses should follow EQUATOR Reporting Guidelines and be consistent with the protocol and statistical analysis plan, or described as post hoc.

When possible, present numerical results (eg, absolute numbers and/or rates) with appropriate indicators of uncertainty, such as confidence intervals. Include absolute numbers and/or rates with any ratio measures and avoid redundant reporting of relative data (eg, % increase or decrease). Use means and standard deviations (SDs) for normally distributed data and medians and ranges or interquartile ranges (IQRs) for data that are not normally distributed. Avoid solely reporting the results of statistical hypothesis testing, such as P values, which fail to convey important quantitative information. For most studies, P values should follow the reporting of comparisons of absolute numbers or rates and measures of uncertainty (eg, 0.8%, 95% CI −0.2% to 1.8%; P  = .13). P values should never be presented alone without the data that are being compared. If P values are reported, follow standard conventions for decimal places: for P values less than .001, report as " P <.001"; for P values between .001 and .01, report the value to the nearest thousandth; for P values greater than or equal to .01, report the value to the nearest hundredth; and for P values greater than .99, report as " P >.99." For studies with exponentially small P values (eg, genetic association studies), P values may be reported with exponents (eg, P  = 1×10 −5 ). In general, there is no need to present the values of test statistics (eg, F statistics or χ² results) and degrees of freedom when reporting results.

For secondary and subgroup analyses, there should be a description of how the potential for type I error due to multiple comparisons was handled, for example, by adjustment of the significance threshold. In the absence of some approach, these analyses should generally be described and interpreted as exploratory, as should all post hoc analyses.

For randomized trials using parallel-group design, there is no validity in conducting hypothesis tests regarding the distribution of baseline covariates between groups; by definition, these differences are due to chance. Because of this, tables of baseline participant characteristics should not include P values or statements of statistical comparisons among randomized groups. Instead, report clinically meaningful imbalances between groups, along with potential adjustments for those imbalances in multivariable models. To read more about statistical tests and data presentation, see the AMA Manual of Style .

Researchers are encouraged to report studies that include diverse and representative participants and to indicate participant inclusion and exclusion criteria and how the findings generalize to the population(s) that are the focus of or are compatible with the research question. Aggregate, deidentified demographic information (eg, age, sex, race and ethnicity, and socioeconomic indicators) should be reported for all research reports along all prespecified outcomes. Demographic variables collected for a specific study should be reported in the Methods section. Demographic information assessed should be reported in the Results section, either in the main article or in an online supplement or both. If any demographic characteristics that were collected are not reported, the reason should be stated. Summary demographic information (eg, baseline characteristics of study participants) should be reported in the first line of the Results section of Abstracts.

Reporting Age

Study inclusion or exclusion criteria by age or age group should be defined in the Methods section. Stratification by age groups should be based on relevance to disease, condition, or population (eg, <5 or >65 years). The ages for study participants should be reported in aggregate (ie, mean and SD or median and IQR or range) in the Results section.

Reporting Sex and Gender

The term sex should be used when reporting biological factors and gender should be used when reporting gender identity or psychosocial/cultural factors. The methods used to obtain information on sex, gender, or both (eg, self-reported, investigator observed or classified, or laboratory test) should be explained in the Methods section. 12 The distribution of study participants or samples should be reported in the Results section, including for studies of humans, tissues, cells, or animals. All participants should be reported, not just the category that represents the majority of the sample. Studies that address pregnancy should follow these recommendations, and if the gender identity of participants was not assessed, use the terms "pregnant participants," "pregnant individuals," "pregnant patients," etc, as appropriate.

In research articles, sex or gender should be reported and defined, and how sex or gender was assessed should be described. Whenever possible, all main outcomes should be reported by sex (or gender if appropriate). In nonresearch reports, choose sex-neutral terms that avoid bias, suit the material under discussion, and do not intrude on the reader's attention.

Reporting Race and Ethnicity

The Methods section should include an explanation of who identified participant race and ethnicity and the source of the classifications used (eg, self-report or selection, investigator observed, database, electronic health record, survey instrument).

If race and ethnicity categories were collected for a study, the reasons that these were assessed also should be described in the Methods section. If collection of data on race and ethnicity was required by the funding agency, that should be noted.

Specific racial and ethnic categories are preferred over collective terms, when possible. Authors should report the specific categories used in their studies and recognize that these categories will differ based on the databases or surveys used, the requirements of funders, and the geographic location of data collection or study participants. Categories included in groups labeled as "other" should be defined.

Categories should be listed in alphabetical order in text and tables.

Race and ethnicity of the study population should be reported in the Results section.

For additional information, see " Updated Guidance on Reporting Race and Ethnicity in Medical and Science Journals " and the Summary Guide for Preferred Terms When Reporting Race and Ethnicity .

For all manuscripts reporting data from studies involving human participants or animals, formal review and approval, or formal review and waiver, by an appropriate institutional review board or ethics committee is required and should be described in the Methods section. 2(p226) For those investigators who do not have formal ethics review committees, the principles outlined in the Declaration of Helsinki should be followed. 13 For investigations of humans, state in the Methods section the manner in which informed consent was obtained from the study participants (ie, oral or written) and whether participants received a stipend. Authors of research studies involving humans should not make independent determinations of exemption or exclusion of IRB or ethical review; they should cite the institutional or regulatory policy for that determination and indicate if the data are deidentified and publicly available or protected by prior consent or privacy safeguards. Editors may request that authors provide documentation of the formal review and recommendation from the institutional review board or ethics committee responsible for oversight of the study.

A signed statement of informed consent to publish patient descriptions, photographs, video, and pedigrees should be obtained from all persons (parents or legal guardians for minors) who can be identified (including by the patients themselves) i/n such written descriptions, photographs, or pedigrees and should be submitted with the manuscript and indicated in the Acknowledgment section of the manuscript. Such persons should be offered the opportunity to see the manuscript before its submission. 2(pp229-232)

Omitting data or making data less specific to deidentify patients is acceptable, but changing any such data is not acceptable. Only those details essential for understanding and interpreting a specific case report or case series should be provided. Although the degree of specificity needed will depend on the context of what is being reported, specific ages, race/ethnicity, and other sociodemographic details should be presented only if clinically or scientifically relevant and important. 2 Cropping of photographs to remove identifiable personal features that are not essential to the clinical message may be permitted as long as the photographs are not otherwise altered. Please do not submit masked photographs of patients. Patients' initials or other personal identifiers must not appear in an image.

Patient Permission Form:

The Patient Permission form for publication of identifying material is available here . Translated versions in Arabic, Chinese, French, German, Hindi, Italian, Japanese, Portuguese, and Spanish are available on request.

AI Used in Manuscript Preparation

When traditional and generative AI technologies are used to create, review, revise, or edit any of the content in a manuscript, authors should report in the Acknowledgment section the following:

• Name of the AI software platform, program, or tool
• Version and extension numbers
• Manufacturer
• Date(s) of use
• A brief description of how the AI was used and on what portions of the manuscript or content
• Confirmation that the author(s) take responsibility for the integrity of the content generated

Note this guidance does not apply to basic tools for checking grammar, spelling, references, and similar.

AI Used in Research

When AI (eg, large language model [LLM] or natural language processing [NLP], supervised or unsupervised machine learning [ML] for predictive/prescriptive or clustering tasks, chatbots, or similar other technologies) is used as part of a scientific study, authors should:

• Follow relevant reporting guidelines for specific study designs when they exist and report each recommended guideline element with sufficient detail to enable reproducibility.
• Avoid inclusion of identifiable patient information in text, tables, and figures.
• Be aware of copyright and intellectual property concerns - if including content (text, images) generated by AI, and indicate rights or permissions to publish that content as determined by the AI service or owner.

Also address the following:

Methods Section

• Include the study design and, if a relevant reporting guideline exists, indicate how it was followed, with sufficient detail to enable reproducibility.
• Describe how AI was used for specific aspects of the study (eg, to generate or refine study hypotheses, assist in the generation of a list of adjustment variables, create graphs to show visual relationships).
• For studies using LLMs, provide the name of the platform or program, tool, version, and manufacturer; specify dates and prompt(s) used and their sequence and any revisions to prompts in response to initial outputs.
• For studies reporting ML and algorithm development, include details about data sets used for development, training, and validation. Clearly state if algorithms were trained and tested only on previously collected or existing data sets or if the study includes prospective deployment. Include the ML model and describe the variables and outcome(s) and selection of the fine-tuning parameters. Describe any assumptions involved (eg, log linearity, proportionality) and how these assumptions were tested.
• Indicate the metric used to evaluate the performance of the algorithms, including bias, discrimination, calibration, reclassification, and others as appropriate.
• Indicate the methods used to address missing data.
• Indicate institutional review board/ethics review, approval, waiver, or exemption.
• Describe methods or analyses included to address and manage AI-related methodologic bias and inaccuracy of AI-generated content.
• Indicate, when appropriate, if sensitivity analyses were performed to explore the performance of the AI model in vulnerable or underrepresented subgroups.
• Provide a data sharing statement, including if code will be shared.

Results Section

• When reporting comparisons, provide performance assessments (eg, against standard of care), include effect sizes and measures of uncertainty (eg, 95% CIs) and other measurements such as likelihood ratios, and include information about performance errors, inaccurate or missing data, and sufficient detail for others to reproduce the findings.
• Report the results of analyses to address methodologic bias and population representation.
• If examples of generated text or content are included in tables or figures, be sure to indicate the source and licensing information, as noted above.

Discussion Section

• Discuss the potential for AI-related bias and what was done to identify and mitigate such bias.
• Discuss the potential for inaccuracy of AI-generated content and what was done to identify and manage this.
• Discuss generalizability of findings across populations and results of analyses performed to explore the performance of the AI model in vulnerable or underrepresented subgroups.

A signed statement of permission should be included from each individual identified as a source of information in a personal communication or as a source for unpublished data, and the date of communication and whether the communication was written or oral should be specified. 2(p199) Personal communications should not be included in the list of references but added to the text parenthetically.

Authors and reviewers are expected to notify editors if a manuscript could be considered to report dual use research of concern (ie, research that could be misused by others to pose a threat to public health and safety, agriculture, plants, animals, the environment, or material). 14 The editor in chief will evaluate manuscripts that report potential dual use research of concern and, if necessary, consult additional reviewers.

Journal Policies

Final decisions regarding manuscript publication are made by the editor in chief or a designated editor who does not have any relevant conflicts of interest. The journal has a formal recusal process in place to help manage potential conflicts of interest of editors. In the event that an editor has a conflict of interest with a submitted manuscript or with the authors, the manuscript, review, and editorial decisions are managed by another designated editor without a conflict of interest related to the manuscript.

All authors are required to complete and submit a Publishing Agreement that is part of the journal's electronic Authorship Form. In this agreement, authors will transfer copyright or a publication license; or indicate that they are employed by a federal government; or indicate that they are an employee of an institution that considers the work in the manuscript a work for hire, in which case an authorized representative of that institution will assign copyright or a publication license on the author's behalf.

Published articles become the permanent property of the American Medical Association (AMA) and may not be published elsewhere without written permission. Unauthorized use of the journal's name, logo, or any content for commercial purposes or to promote commercial goods and services (in any format, including print, video, audio, and digital) is not permitted by the JAMA Network or the AMA.

1. Cummings P, Rivara FP. Reporting statistical information in medical journal articles. Arch Pediatr Adolesc Med . 2003;157(4):321-324. doi:10.1001/archpedi.157.4.321

2. Iverson C, Christiansen S, Flanagin A, et al. AMA Manual of Style: A Guide for Authors and Editors . 11th ed. Oxford University Press; 2020. http://www.amamanualofstyle.com

3. Golub RM. Correspondence course: tips for getting a letter published in JAMA . JAMA . 2008;300(1):98-99. doi:10.1001/jama.300.1.98

4. International Committee of Medical Journal Editors. Recommendations for the conduct, reporting, editing, and publication of scholarly work in medical journals. Updated May 2023. Accessed May 18, 2023. http://www.icmje.org/recommendations/

5. Fontanarosa PB, Flanagin A, DeAngelis CD. Update on JAMA 's policy on release of information to the public. JAMA . 2008;300(13):1585-1587. doi:10.1001/jama.300.13.1585

6. Fontanarosa P, Bauchner H, Flanagin A. Authorship and team science. JAMA . 2017;318(24):2433-2437. doi:10.1001/jama.2017.19341

7. Fontanarosa PB, Flanagin A, DeAngelis CD. Reporting conflicts of interest, financial aspects of research, and role of sponsors in funded studies. JAMA . 2005;294(1):110-111. doi:10.1001/jama.294.1.110

8. DeAngelis CD, Drazen JM, Frizelle FA, et al; International Committee of Medical Journal Editors. Clinical trial registration: a statement from the International Committee of Medical Journal Editors. JAMA . 2004;292(11):1363-1364. doi:10.1001/jamainternmed.2014.6933

9. DeAngelis CD, Drazen JM, Frizelle FA, et al; International Committee of Medical Journal Editors. Is this clinical trial fully registered? a statement from the International Committee of Medical Journal Editors. JAMA . 2005;293(23):2927-2929. doi:10.1001/jama.293.23.jed50037

10. The CONSORT Group. The CONSORT statement. Updated 2014. Accessed September 23, 2016. http://www.consort-statement.org/consort-2010

11. American Association for Public Opinion Research. Best practices for survey research. Accessed March 23, 2023. https://aapor.org/standards-and-ethics/best-practices/

12. Clayton JA, Tannenbaum C. Reporting sex, gender, or both in clinical research? JAMA . 2016;316(18):1863-1864. doi:10.1001/jama.2016.16405

13. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA . 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053

14. Journal Editors and Authors Group. Statement on scientific publication and security. Science . 2003;299(5610):1149. doi:10.1126/science.299.5610.1149 . Published correction appears in Science . 2003;299(5614):1845.

15. Christiansen S, Flanagin A. Correcting the medical literature: "to err is human, to correct divine." JAMA . 2017;318(9):804-805. doi:10.1001/jama.2017.11833

Last Updated: April 16, 2024

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• Author Guidelines

For 'Defining the role of authors and contributors', 'Disclosure of financial and non-financial relationships and activities, and conflicts of interest', and 'Responsibility in the submission and peer-review process' see Our Policies. For further information on copyright management, see About Haematologica .

1. JOURNAL SCOPE

Haematologica is the main tool through which the Ferrata-Storti Foundation, a non-profit organization, promotes the dissemination of new knowledge in the field of hematology. A high quality of articles, immediate free access to everything published and the lowest possible cost for authors are the principles that inspire Haematologica's management.

Haematologica considers for publication manuscripts on malignant and non-malignant hematologic diseases, including hemostasis defects. The subject area of clinical manuscripts can range from etiology to diagnostics, prognosis, prevention, and treatment. Clinical studies on drugs that modify the hemostatic process for antihemorrhagic or antithrombotic purposes fall within the field of interest of Haematologica. Basic studies on hematopoiesis, blood cells, hemostasis and blood banking that have the potential for clinical relevance are also considered for publication.

Haematologica does not publish the results of studies that have already been published, even partially, or are going to be published in any form, except for meeting abstracts and manuscripts released as a preprint before or during submission. Preprints are allowed under these conditions:

• Once published in Haematologica, the author is responsible for ensuring that the preprint record is updated with a publication reference, including the DOI and a URL link to the published version of the article on the Haematologica website.
• The preprint must not be modified while the manuscript is under evaluation and cannot be updated if the manuscript is accepted for publication in Haematologica.
• Preprints, as well as any related public comments, will be considered in the evaluation of the manuscript submitted to Haematologica.
• The existence of a preprint must be explicitly stated in the submission form and in the cover letter for the submission.

Haematologica does not consider for publication papers not reporting primary data (such as editorials, review articles, perspective articles, guidelines, position papers and similar articles) that pharmaceutical or medical device company employees and/or medical writers supported by a pharmaceutical or medical device company have had any role in drafting.

2. TYPES OF ARTICLES

Original articles. There is no limit to the number of authors, but this must be commensurate with the complexity of the study. The manuscript should be divided into sections under the following subheadings: Abstract, Introduction, Methods, Results, Discussion, and References.

• Abstract (unstructured), maximum 250 words. Articles reporting clinical trials should provide the trial registration number at the end of the abstract. Use abbreviations only for terms that occur at least twice. In this case, explain their meaning when they are first used.
• Main text (Introduction, Methods, Results, Discussion), maximum 4,000 words . The Methods and Results sections can be divided with specific subtitles. The Methods section (maximum 500 words) should include the most important methods that allow readers to understand the article content. When required, further information on methodology can be provided in the Supplementary data.
• References , maximum 50.
• Figure and Tables, maximum 8 items in total. Additional figures and tables can be published as Supplementary data.

Original articles reporting randomized trials must follow CONSORT recommendations , meta-analyses and guidelines EHA recommendations , observational studies STROBE recommendations , and studies of diagnostic accuracy STARD guidelines .

Review articles. As a rule, Reviews are by invitation. However, authoritative researchers can submit reviews on topics for which they have demonstrated competence. The maximum number of authors is usually limited to three. Review articles are a maximum 5,000 words long (excluding abstract, tables, figure legends and references) and do not have a specific structure. The reviews should contain an unstructured abstract of a maximum of 250 words (abbreviations only for terms that occur at least twice), and have a maximum of 100 references. Authors are encouraged to describe the methods used for locating, selecting, extracting, and synthesizing data; this is mandatory for systematic reviews (see PRISMA guidelines). The use of tables and figures is strongly encouraged (no limit to their number). When deemed appropriate by the publisher, a graphic artist will redesign submitted figures.

Spotlight Review articles. These brief reviews are by invitation only and are intended to discuss recent advances that have transformed or will transform the hematology field. They are a maximum 3,000 words long (excluding abstract, tables, figure legends and references), have an unstructured abstract of a maximum of 250 words, and a maximum of 40 references. The use of figures summarizing the topics discussed is very welcome.

Perspective articles. The format and editorial guidelines for this type of article are the same as for Reviews article. The perspective articles differ from Reviews articles because they do not require a systematic and exhaustive analysis of the literature, but allow authors to use literature data to freely express their personal opinion on topics and controversies relevant to hematology.

Editorials. Editorials that comment on Haematologica articles are by invitation and are published in the same issue as the commented paper. However, submission of Editorials by authoritative researchers on debated topics or important news is welcome. Editorials have a free structure (no abstract), contain about 1,500 words (excluding tables and references), up to 20 references and may contain two display items (figures and/or tables). No more than two authors are permitted. The use of a figure is strongly encouraged. When deemed appropriate by the publisher, a graphic artist will redesign the submitted figure.

Guideline articles . These should be produced by an international group of experts. These articles are up to 5,000 words long (excluding tables, figure legends and references), and the authors are free to give the text the structure that best suits their purposes. The articles should contain an unstructured abstract of maximum 250 words, can include all the figures and tables that the authors deem necessary, and have a maximum 100 references. We recommend following the PRISMA recommendations for this type of article.

Letters to the Editor. This type of article is dedicated to the publication of original data that can be reported and discussed in no more than 1,500 text words (excluding tables, figure legends and references). Letters have no abstract, no headings, a maximum of three tables and/or figures, and no more than 15 references. Letters should start with a paragraph summarizing the rationale for the study and the major conclusions. When appropriate, the reporting recommendations detailed for Original articles should be followed. Letters can be accompanied by three additional figures/tables/videos (three items overall) in an online supplementary. The use of text in online Supplementary data is not foreseen except for the legends of the figures and the titles of the tables (no Methods).

Case reports & Case series. Reports of special cases that contribute to a better understanding of hematologic diseases or to patients' care will be considered for publication. These reports need to be conclusive and must include insights into pathogenesis in addition to the description of the clinical case(s). Only a few Case reports can be published and a strict selection is in place. Case reports have no abstract, no headings, and a maximum of 1,500 words in the text (excluding tables, figure legends and references), a maximum of three tables and/or figures, and 15 references. Supplementary data cannot be used.

Comments . This format is used to discuss a recently published article in Haematologica, or cutting edge ideas or developments in the broad field of hematology. Papers containing new data cannot be published with this format. Comments have no abstract, a maximum of 1,000 words in the text and 10 essential references. Comments should not include figures or tables. Please start the comment with a paragraph summarizing the rationale for the comment, citing the article or articles that form the basis for the comment. No more than two authors are allowed.

3. DIFFERENT REQUIREMENTS FOR FIRST SUBMISSION AND REVISED MANUSCRIPTS

We are very flexible on the format of the first submission and the rules described in the following sections do not necessarily all have to be respected.

At initial submission , only two PDF files will be requested:

• One pdf file with the text, tables, and figures (please, make sure the file size is below 5 MB)
• One PDF file with all supplementary data

A revised manuscript must comply with all the editorial rules. The following files will be requested:

• One Word document with text and tables (indicate in color the changes that were made compared to the first submission)
• One high quality file for each figure
• One pdf file with all supplementary data
• In case of changes in the authorship, please fill in this form and submit it as supplementary file: Change of Authorship Form

4. MANUSCRIPT STYLE

Manuscripts should be prepared according to the Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals ( ICMJE Recommendations ) .

Manuscripts should be prepared using American English spelling . Scientific nomenclature should be used without the Saxon Genitive (for example: use 'Hodgkin Lymphoma' and not 'Hodgkin's Lymphoma').

Abbreviations and acronyms can be used when a term that includes multiple words is used more than once in the Abstract and more than three times in the Main text. The Abstract, Main Text and Figure legends should be considered as separate entities and abbreviations must be explained in full in each of these parts of the manuscript. Abbreviations and acronyms used in tables must be explained in a note below the table. Abbreviations should not be used in the title unless the abbreviation is better understood than the full designation, such as for DNA, which is more easily understood than Deoxyribonucleic acid. If this is the case, explain the abbreviation in the Abstract. Abbreviations should not be written in the plural form.

Units and measurements. Use the SI system of units. Authors who fail to use the SI system in the figures will be asked to redo the figures.

Drugs. Commercial names of drugs should be avoided. Drugs should be referred to by their generic names unless different proprietary versions are being discussed.

Genes and proteins. Use the official gene symbols when referring to genes, transcripts and proteins. (for example: Use ABL1, not ABL or c-ABL; use MYC, not c-Myc). Use this database as a reference: https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene . Human Genes: the names should be indicated in italics and capitals, Human Proteins: the names should be in capital letters. Mouse and Rat Genes: the names should be indicated in italics, with only the first letter in capital and the remaining letters in lowercase (Shh). Mouse and Rat Proteins: the names should be indicated only in capital letters (SHH). Zebrafish and Frog (xenopus sp.) Genes: the names should be indicated in italics and all in lowercase (shh). Zebrafish and Frog (xenopus sp.) Proteins: the names must have the first letter in capital and the remaining letters in lowercase.

5. STUDIES INVOLVING HUMANS OR ANIMALS

Protection of human individuals in research. When reporting studies (prospective or retrospective) involving people, medical records, and human tissues, authors should indicate whether the procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2013. Authors should also declare that any research involving people, medical records, and human tissues was approved by the relevant institutional review boards or ethics committees and that all human participants gave written informed consent (Haematologica reserves the right to ask the authors or the institution they indicated for a copy of the document). Patients have a right to privacy that should not be violated. Identifying information, including names, initials, or hospital numbers, should not be published. Photographs and any data that can lead to patient identification can be published only if this is essential for scientific purposes and the subject has signed a specific written informed consent.

Protection of animals in research. When performing experiments on animals or animal tissues, authors should seek approval from an institutional ethics committee and should strictly follow the institutional and national guidelines for the care and use of laboratory animals. Haematologica only considers manuscripts reporting on studies on animals or animal tissues if ethical committee approval of the study can be documented.

Clinical trials. We request, as a condition for publication, the registration of all clinical trials in a public trials registry. The ICMJE provides specific guidelines on this topic. The ICMJE defines a clinical trials as any research project that prospectively assigns human subjects to intervention or concurrent comparison or control groups to study the cause-and-effect relationship between a medical intervention and a health outcome. Medical interventions include drugs, surgical procedures, devices, behavioral treatments, process-of-care changes, and the like. Haematologica does not advocate one particular registry, but follows the ICMJE recommendations. Because it is critical that trial registries are independent of for-profit interests, the ICMJE policy requires registration in a WHO primary registry rather than solely in an associate registry, since for-profit entities manage some associate registries.

6. USE OF ARTIFICIAL INTELLIGENCE-ASSISTED TECHNOLOGIES

At submission of the manuscript, authors must disclose whether they used Artificial Intelligence (AI)-assisted technologies. If so, both the cover letter and the submitted paper should include a description of the technologies used and for what purposes they were employed.

7. ORGANIZATION OF MANUSCRIPTS

Manuscripts must have the following sequence of items:

• Figure legends

8. TITLE PAGE

Information provided on the title page should correspond exactly with the information provided in the online system for submission.

Title. The title should consist of a phrase or a sentence; question forms should be avoided. Capitalize the first letter of the sentence only, and try not to use abbreviations. In the event that abbreviations are used because they are very easily understood, they must be spelled out in the abstract. Abbreviation of study group names may be presented in the title if they are expanded in the abstract. All members’ names should be listed in an appendix and presented at the end of the main text. In this case, include a title page note that refers to that appendix.

Authors. Names of authors should be presented as full first name, initial of middle name (if applicable) and last name. Number authors’ affiliation in superscript. Do not include professional titles or abbreviations of qualifications or positions held. Haematologica does not limit the number of authors of original articles, letters, guidelines and case reports. However, it must be proportionate to the complexity of the data presented, and the editor will ask for a reduction of the number of authors if the list does not seem justified. See above Types of articles for the maximum number of authors for the other types of articles.

Authors' contributions. If more than one author contributed equally to the work as 'principal investigator' (first name) or 'senior' author (last name), a statement of equal contribution can be placed here . Use authors’ initials rather than full names, e.g. 'GGH and FS contributed equally as co-first authors'. In the list of authors, use an asterix ( * ) before the name of authors to indicate sharing the position of first author, a hash ( # ) for last position. An high number of authors contributing equally is discouraged. If 'equal contribution' as a principal investigator is attributed to more than three authors and 'senior author' to more than two people, please explain the reason for this anomaly in the accompanying letter. In the rare cases in which all authors contributed equally, their names must appear in alphabetical order. Information on contributions to the manuscript of each author should be provided during the online submission.

Affiliations. The authors’ affiliations should be provided on a new line immediately after the authors’ names with every affiliation on a new line. Provide only city, state (abbreviated for USA affiliations) and country. Do not give full address. Provide the postal code only in case it is required for the identification of the institution.

Running heads. Please provide a short title as running head wirh a maximum 50 characters. The use of acronyms and abbreviations is permitted.

Corresponding author. Indicate the name and email address of the author who is in charge of managing the correspondence.

Data-sharing statement. It is strongly recommended that authors make their original data and protocols available to other investigators without unreasonable restrictions. Authors should therefore indicate if and how these data can be obtained. This information will appear at the end of the manuscript.

Word count. Provide a separate word count for the abstract and the main text (= introduction + methods + results + discussion). Indicate how many tables and figures are present in the manuscript. Indicate how many supplementary files are associated with the manuscript (we request one PDF file for all supplementary data; only in specific circumstances, such as submission of movies or Excel tables, do we accept more than one PDF file).

Trial registration. Confirmation and details of trial registration should be given on the first page; please use the following form: ' ClinicalTrials.gov identifier: NCT00123456 '

Acknowledgments. If applicable, indicate secretarial and editorial assistance, technical and intellectual input and advice, etc.

Funding. For all types of financing (e.g., governmental, industrial, personal) it is recommended to report the identifiers and indicate which authors were the beneficiaries. For example, This investigation was supported by grant DKxxxx to AB from the National Institutes of Health, USA.

9. ABSTRACT

A summary (unstructured) of 250 words is required only for Original articles, Reviews, Perspectives, and Guidelines. Do not include references. See Manuscript style for abbreviations and acronyms.

10. MAIN TEXT

See above Types of articles for word limits and Manuscript style for other editorial requirements.

Subheadings. In the types of articles that require structuring of the main text into different sections, we discourage the use of more than one level of subheadings within each section. The style of the different subheadings levels must be consistent.

11. CITATIONS AND REFERENCES

Authors must take great care over the accuracy of citations in the text and corresponding references. Accuracy is very important because references will be linked to Medline and other online databases, and these links do not work if citation information is not completely accurate.

Every citation needs a reference, and every reference must correspond to a citation. Authors must take care that this also occurs in revised papers, in which references are often moved, added or deleted.

If you use citation software , please check carefully to ensure that it formats references according to the rules for Haematologica. You can download the reference style to be used by Endnote

11.1. Citations of bibliographic references must be numbered consecutively in the order in which they appear the first time in the text. Figures and tables do not have an independent numbering sequence but follow the logic of the reading sequence. So, the numbering of references appearing for the first time in tables and figures depends on where the diction Figure x or Table y is used for the first time in the main text.

In the text, cite references by inserting the superscripted reference number:

• Melick 5 reported IDH1 mutations in AML.
• Melick and Brown 5 reported IDH1 mutations in AML.
• Melick et al 5 reported IDH1 mutations in AML.
• Several groups reported the presence of IDH1 mutations in AML. 5-9
• Two studies reported IDH1 mutations in AML. 5,6
• Melik et al 5 identified IDH1 mutations in AML while Brown 10 did not.

Never refer to the number of the reference

• For a review, see Melick et al 11 (Not: For a review, see 11 )

11.2. Citation of Figures and Tables. References to tables and figures in the same article should be presented in brackets and should specify 'Table' or 'Figure' and the relevant identification number. When reference is made to more than one table or figure, please follow these examples: Figures 1 and 2; Tables 1 and 3; Figures 2-4 and 6; Tables 2, 4 and 6. References to figure panels and subpanels should be presented by adding a capital letter in alphabetic order immediately after the identification number (for example: Figure 1A, Figure 1B). When reference is made to more than one figure panel or subpanel, follow these examples: Figure 2B, C; Figure 3B-D). For references to Figures, Tables or Movies in the Supplementary data , add an S to the number of Figure-Table-Movie (e.g. Movie S1).

11.3. Citations only in the text. Any data or information not yet published in any way should not be referenced and should be mentioned in the text in parentheses. Written permission for the reference to be made must be obtained from the person concerned, a copy of which may be requested by the journal. Submitted papers follow the same rules. (Desmopressin reduced bleeding time in a mouse model of Scott syndrome. G. Rossi, University of Pavia, email, 20 August 2020).

11.4. Reference list. Each reference must allow the reader to reach the cited document easily. It is therefore not acceptable, for example, to cite a presentation at a congress in the References if the proceedings have not been published in a scientific journal or a website. Place References after the Main text. Haematologica adopted the recommendations of the International Committee of Medical Journal Editors (ICMJE) for the style of the references. So, the titles of journals should be abbreviated according to the style used for MEDLINE .

In short, follow these guidelines:

• Journal article with 6 or less than 6 authors : list all authors. Silvestri L, Pagani A, Nai A, De Domenico I, Kaplan J, Camaschella C. The serine protease matripase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Met. 2008;8(6):502-511.
• Journal article with more than 6 authors: list the first 3 authors followed by 'et al.' Diop F, Moia R, Favini C, et al. Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia. Haematologica. 2020;105(2):448-456.
• Journal article published online as Early view or Epub ahead of print: indicate the date on which the article was published online and report the DOI (digital object identifier).' Hermand P, Azouzi S, Gautier EF, et al. The proteome of neutrophils in sickle cell disease reveals an unexpected activation of interferon alpha signaling pathway. Haematologica. 2020 Mar 5. doi: 10.3324/haematol.2019.238295. [Epub ahead of print]
• Journal article in press: use the phrase 'In press.' instead of year, volume number, and page numbers. Hermand P, Azouzi S, Gautier EF, et al. The proteome of neutrophils in sickle cell disease reveals an unexpected activation of interferon alpha signaling pathway. Haematologica. In press.
• Personal communication, submitted article, unpublished data: see above paragraph 11.3. Citations only in the text.
• Book: indicate Author(s)/Editor(s), Title, Type of Medium, Edition, Editor, Place of Publication, Publisher, Date of Publication. See International Committee of Medical Journal Editors (ICMJE) for more details. Iverson C, Flanagin A, Fontanarosa PB, et al. American Medical Association manual of style. 9th ed. Baltimore (MD): Williams & Wilkins; 1998.
• Book chapter: indicate Author(s) of the chapter, Title of the chapter, Book Information. Whiteside TL, Heberman RB. Effectors of immunity and rationale for immunotherapy. In: Kufe DW, Pollock RE, Weichselbaum RR, Bast RC Jr, Gansler TS, Holland JF, Frei E 3rd, editors. Cancer medicine 6. Hamilton (ON): BC Decker Inc; 2003. p. 221-228.
• Published abstract: indicate Author(s), Title and indication of where the abstract was published. Manni S, Carrino M, Fregnani A, e al. Protein kinase CK1 alpha inhibition causes mantle cell lymphoma cell apoptosis. Haematologica 2018;103(s3):abstract 829.
• Online document: indicate the author(s) or any institutional author, document title, the URL, and the date on which it was accessed. Boyle-Lab. Blacklist/hg19-bla cklist.v2.bed.gz at master BoyleLab/Blacklist. https://github.com/Boyle-Lab/Blacklist Accessed November 27, 2021.
• Preprint: indicate the author(s), title, name of the online platform where the preprint has been posted, date on which the article was published online, DOI (digital object identifier), indication that it is a preprint and has not been peer reviewed. Zhai B, Clarke K, Bauer DL et al. SARS-CoV-2 antibody response is associated with age in convalescent outpatients. medRxiv. 2021 Nov 8. doi: 11.1101/2021.11.08.21265888 [preprint, not peer-reviewed]. If a DOI is not available, report the URL to reach the article. Yahya D, Miteva V, Micheva I, Ruseva T, Angelova L. Cytogenetic analysis of patients with hematological malignancies. Research Square. 2022 Oct 25. https://www.researchsquare.com/article/rs-953779/v1 [preprint, not peer-reviewed].

12. FIGURES AND TABLES

The maximum number of figures and tables is indicated above in Types of articles . The authors are strongly encouraged to present only the tables and figures that are essential to understand the meaning of their study in the main text, placing the other data (such as patients' characteristics and primer sequences) in the Supplementary data when this is allowed for that type of article.

For the first submission of the manuscript, it is only required that figures and tables are easy understandable. For subsequent submissions , however, figures and tables are required to comply exactly with all specific editorial rules. Failure to comply with these rules causes non-acceptance of the paper independently of its scientific merit.

12.1. Figures. Figures must be in JPG, PNG or PDF. Files of color figures should be submitted as RGB (red/green/blue; not CMYK).

The recommended resolution is 600 dpi.

Figures can be of two dimensions in terms of width:

• 8 cm (1920 pixels) for one column figures
• 16 cm (3840 pixels) for two column figures

12.1.2. Line art figures (graphs, scatter plots, diagnostic algorithms, flowcharts and other types of text-based figures). A common problem of these types of figures is that the text is written in characters that are too small and are difficult to read. Many readers of Haematologica use tablets or even smartphones to read the journal and, consequently, the optimal dimensions of writing are those that allow easy reading even on small screens. As a simple general rule, we suggest that Authors prepare their line art figures 8 cm (1920 pixels) wide or 16 cm wide (3840 pixels), and print them in their original size: the font sizes are correct if all the writing is easily legible. Even if differences in readability of different fonts prevent us from providing precise indications, we advise against the use of fonts smaller than 8 pt or larger than 12 pt. Make sure that the thickness of the lines is such as to make them easily visible when printing the figure. It is advisable to avoid pastel (light) colors for both lettering and lines because they may be poorly visible on some screens.

12.1.3. Images. Changes introduced to digital images to improve readability can result in incorrect information. It is therefore recommended that any type of image retouching is avoided. However, if the authors deem it essential to modify an image, the changes must be applied to the whole figure and not to single portions. Linear changes in contrast, brightness or color must be applied equally to all parts of the image. Contrast and brightness should not be increased to such an extent that parts of the image disappear. Authors must include scale bars in any microscopy images of cells or tissues. Staining techniques must be reported in legends.

Electrophoretic gels and blots shoshould have full tonal range to avoid loss of data and should contain molecular weight markers. If possible, avoid constructing a figure by assembling lanes from different sections of one or more gels. If this is unavoidable, borders must be easily identifiable or marked and the legend must explain how the figure was created. Authors may be asked to provide the original figures not retouched or cropped for review.

12.1.4. Complex, multipanel figures. Multi-paneled figures must be supplied as one file, with each panel clearly labeled. Avoid giving a header to each panel, but give this information in the figure legend. The size and style of letters and labels of different panels must be uniform within each figure and, whenever possible, between figures. See paragraphs 12.1.2 and 12.1.3 for additional technical details. The choice to reduce the number of figures by creating complex panels with a number of items is discouraged. We suggest that authors do not use more than six, simple panels for each figure. As a rule, the figures are to be published on a single page with vertical (portrait) orientation. Please take this into account when structuring your figures to avoid publishing delays resulting from our request to change them. Please, consider placing figures that are very large or do not fit on a single vertical page in the Supplementary data when this is allowed for the type of your article.

The figure below has only four panels, but it contains too many items, which are not always clearly indicated. The writing is too small and difficult to read even when the image is displayed as a full page on a large screen. Furthermore, different sizes and types of characters are used for similar writing. Figures of this type discourage the reader from reading (and therefore citing) the article.

The figure below also has 4 panels, but it is well organized, the writing is readable even on a small screen and each item is easily identifiable. This type of figure attracts readers.

12.1.5. Reproductions and adaptations. The author must obtain written permission for the reproduction and adaptation of material that has already been published. Permission should be obtained from the copyright holder or publisher. Before a manuscript is accepted, Haematologica will need to receive a copy of the written permission. All material presented from other sources should be identified and should be accompanied by a specific reference in the legend confirming that permission for its use had been obtained, for example: 'Adapted from Berger et al. Leukemia 2003, 17, 1820-1826; with permission.'

12.1.6. Legend to figures. Legends should contain a title (in bold) and sufficient details to make the figure easy to understand. When a figure contains multiple panels, the legend needs to start with a first sentence as an overall title for the entire figure and the rest of the text as the explanation of the figure panels. For the references that appear for the first time in a legend, see paragraph 10.1. Citations of Bibliographic references . All abbreviations, acronyms and symbols in each figure should be explained in the legend regardless of whether this was done in the main text.

12.1.7. Videos. We recommend the MP4 format. In case MP4 is not available, we accept MOV and AVI. Videos must be no larger than 10 MB. For optimal compatibility across operating systems and devices, please select H.264 compression when saving.

12.2. Tables. As for figures, consider the possibility of placing non essential tables in Supplementary data when this is allowed for the type of article being submitted. This is particular important for very large tables that take up more than one page or do not fit on a single page in a portrait orientation. Haematologica accepts any type of table formatting. However, we suggest using spreadsheet software programs (such as Microsoft Excel Tables or Microsoft Word Tables) that allow automatic transfer of data and reduce the risk of mistakes during manual transcription. Tables should have a short and clear title. Provide a legend (if needed) directly below the table. Explain all abbreviations, acronyms and symbols in the legend, regardless of whether this was done in the main text of the manuscript.

13. SUPPLEMENTARY DATA

Prepare one single PDF file containing all supplementary data (supplementary methods, supplementary results, supplementary figures, supplementary tables). The Supplementary data has its own reference list. Everything that is included in the Supplementary data must comply with editorial rules. Please consider that we will not modify in any way what is included in the PDF and that failure to comply with editorial rules does not allow us to publish the article. Whenever possible, keep the PDF size below 30 MB. Additional files that cannot be incorporated in the PDF file (such as videos, large excel tables running over several pages, etc.) should be provided separately. Please note that for technical reasons files not embedded in the pdf will not be visible when the paper appears online as Early view, but will be published after its inclusion in an issue.

14. SUBMISSION FEE AND PUBLICATION CHARGE

14.1. Submission fee. A nonrefundable fee of € 70 (including VAT) is due on submission for all uninvited papers with the only exception of Guidelines and Comments.

14.2. Publication charge.

• Guideline articles, Comments and all kinds of papers by invitation: Free of charge.
• Original articles, uninvited Reviews, uninvited Perspective articles and uninvited Editorials submitted before October 1, 2023: € 2,000 (plus VAT when needed) if authors choose to transfer the copyright to the Ferrata Storti Foundation, owner of the journal, under a Creative Commons license CC BY-NC (see section 17 ); € 3,000 (plus VAT when needed) if authors' institutions or funders require publication under a CC BY license (see section 17 ).
• Original articles, uninvited Reviews, uninvited Perspective articles and uninvited Editorials submitted starting from October 1, 2023: € 2,300 (plus VAT when needed) if authors choose to transfer the copyright to the Ferrata Storti Foundation, owner of the journal, under a CC BY-NC ; € 3,000 (plus VAT when needed) if authors' institutions or funders require publication under a CC BY license .
• Letters and Case reports submitted before October 1, 2023: € 400 (plus VAT when needed) if authors choose to transfer the copyright to the Ferrata Storti Foundation, owner of the journal, under a Creative Commons license CC BY-NC ; € 600 (plus VAT when needed) if authors' institutions or funders require publication under a CC BY license .
• Letters and Case reports submitted starting from October 1, 2023: € 600 (plus VAT when needed) if authors choose to transfer the copyright to the Ferrata Storti Foundation, owner of the journal, under a Creative Commons license CC BY-NC ; € 900 (plus VAT when needed) if authors' institutions or funders require publication under a CC BY license .
• No publication charge is required for authors from countries defined as low-income by the World Bank.

15. SUBMISSION PROCESS

During submission, authors are asked to disclose any potential conflicts of interest by filling in a form prepared by the International Committee of Medical Journal Editors. For information on conflicts of interest, see Disclosure of financial and non-financial relationship and activities, and conflicts of interest in Our Policies

Submitted articles undergo the regular revision process which, in the event the manuscript does not undergo a quick rejection and is subject to external review, allows a first response in 3-4 weeks. In rare cases, the Editor can accept the authors' request that the manuscript follows an accelerated procedure (see 15.2 Fast-track review).

15.1. Regular submission. Go to Submit a manuscript and follow the instructions.

Be ready to submit the files indicated in Section 3. Different requirements for first submission and revised manuscript . For Revised manuscripts , make sure that all changes are in color (do not use 'track changes'). Moreover, be ready to provide a detailed description of all changes made in the main manuscript in response to the questions/remarks of the reviewers. In order to prepare this document, copy and paste each question/remark of the reviewers and provide a short answer on how this question/remark has been addressed in the revised manuscript. The description of changes can be copied and pasted into a text box during online submission. If figures or tables need to be included in the answers to the reviewers, a PDF file with that information can be uploaded as a supplementary file.

Please consider that the authors' names and affiliations inserted in the online submission system will be those that will appear in PubMed soon after pre-publication. The Haematologica Journal staff is therefore not responsible for eventual inaccuracies or mistakes in the affiliations introduced during the submission process. Please, also note that the affiliations that will appear in PubMed after the final publication of the paper will be those indicated by the authors during the proofreading and they will replace the ones appeared in the pre-publication

Before resubmitting a manuscript that has been modified according to reviewers' suggestions, carefully check that all content, including Results, Tables and Figures, is correct. If accepted, your manuscript will be pre-published exactly as it is. Moreover, what is contained in the pre-published manuscript will be used for producing the final version of your article that will be included in an issue of the journal. Please, take note that the data cannot be changed during the production process and that their correction requires publication of an erratum in one of the following issues of the journal.

15.2. Fast-track review. Manuscripts (Original articles) reporting results that promise to substantially change clinical practice or the current view of biological processes associated with blood diseases can be selected for fast-track review. These papers will receive an initial decision within 1 week. We can only select a few articles for fast track, as this requires extra efforts by our reviewers and editors. Thus, these manuscripts will be selected by the editors. Authors can request fast-track review by e-mail: please send the manuscript as a PDF file with an accompanying explanation why rapid review should be considered to: [email protected]

16. REVIEW PROCESS

All manuscripts submitted to Haematologica are critically revised in accordance with the principles of Peer Review of JCMJE . Each paper is first evaluated by one or more editors, who will assess the overall quality and novelty of the work and the article's appropriateness for the scope of Haematologica. Articles that are not found to be relevant for Haematologica will not be sent out for external review and will be returned to the authors. The remaining articles are reviewed by external referees. We aim to provide feedback to the authors in less than 4 weeks after submission (1 week for Fast track articles).

17. COPYRIGHT

Authors can choose to publish their manuscripts in Haematologica under a Creative Commons license CC BY-NC or a Creative Commons license CC BY . For other types of copyright management, please contact the Editorial office .

According to both CC BY-NC and CC BY licenses , an article may be copied, displayed, distributed, republished or otherwise reused for non-commercial purposes. With the CC BY-NC license the authors transfer the copyright of the article to the Ferrata Storti Foundation, which becomes the only body authorized to use the article for commercial purposes. With the CC BY license, anyone can use the article even for commercial purposes. The latter license is required by some funding bodies or by some institutions to which authors belong. For more detail on this matter see: Right & Permissions

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Authors are instructed to follow the guidelines before submission of manuscript to Annals of Leukemia Research.

Peer Review : Annals of Leukemia Research follows double blinded peer review process where authors and reviewers donot know the identities of each other and kept confidential.

Publication Ethics : Articles published under Annals of Leukemia Research follow COPE-Community of Publication Ethics. Authors, reviewers and editors are instructed to follow publication ethics to maintain the journal integrity.

Plagiarism : Annals of Leukemia Research is committed to publish original material which is neither been published or under review in other journals or copying the content from the published articles. We use different software’s to check the plagiarism for the submitted manuscripts.

Duplicate Submission : Annals of Leukemia Research restrict publishing duplicate submissions i.e, the articles that are already published or under review with journals.

Improper Author Contribution : It is important for authors to mention all others authors list in the manuscript who has contributed their scientific work.

Conflict of Interest : Articles published under Annals of Leukemia Research must be accompanied by a conflict of interest disclosure. This includes financial and non financial interests, affiliations or any personal, racial and intellectual properties.

Manipulation : Annals of Leukemia Research donot encourage manipulation of data in Citations, figures and results.

We invite authors to submit original research, review, case reports, letter to the editor, editorials, mini reviews, etc..

• Manuscript Title
• Introduction
• Materials and methods
• Acknowledgment
• Conflict of interest if any

Review : Article should not contain more than 6000 words; abstract word limit should be 250 words.

Case Report : Article should not contain more than 3000 words; abstract word limit should be 250 words and with maximum of 30 references. Submitted case reports should be unique and the clinical observations to be made on one or more number of patients.

Editorial : Manuscript should not contain more than 1000 words and with maximum of 10 references. Editorial board members are invited to submit the editorials that are entitled to comment on recently published articles or highlight the ongoing research in the area of interest.

Mini Review : Article should not contain more than 3000 words; Abstract word limit should be 250 words with Maximum of 40 references. It is a concise review of a particular area where the references needs to be cited within past 5 years.

Letter to the Editor : Article should not contain more than 1000 words; and should have maximum of 10 references. In letter to the editor, authors can convey their thoughts and can raise their concerns on recently published articles.

Clinical Images : Clinical images are limited to 3 images with maximum of 250 words in case description or image description with 5 references.

Manuscript preparation Guidelines : Authors are requested to follow the guidelines before submission of manuscript

• Title : Manuscript title should not exceed more than 160 characters and should be in title case
• Authors : List the full names of all the authors along with their affiliations
• Affiliations : Author affiliation should be mentioned in order: Department, University/Institute, City, State, Country and Country, to identify different affiliations use superscript numbers.
• Corresponding Author : For further corresponding author has to provide their full name, affiliation, telephone number and email address.

Abstract : Abstracts are limited to 250 words that describe Aims, Methods, Results and Conclusion (for research article) of the study. Author need to summarize their findings. Donot include any citations in the abstract. Authors can even include keywords in the abstract.

Keywords : Authors can include maximum of five keywords, abbreviations should not be used in the keyword section.

Text : Text should include Introduction, Materials & Methods, Results, Discussion, Conclusion and Acknowledgement (If any). Use numbering for references in the body text.

Results : Results mentioned in the results section should not be repeated in the discussion section. Results should provide complete details of the experiment that should support the conclusion of the study. Tables and figures can be included in the results section.

Discussion : This section should be separate or can be combined with results (results and discussion) or can be mixed with conclusion (discussion and conclusion). Detailed interpretation of data should not be included in the results, it should be included in the discussion section. Donot repeat the details given in the introduction.

Acknowledgement : Authors can include funding sources and personal acknowledgement in this section. Authors are encouraged to list all the funding sources used for preparation of manuscript. Please provide the grant number and authors associated with specific funding sources.

Figures : Preferred formats are JPEG, TIFF, PNG, GIF and power point. This section includes Figures, their title and description. Figure legends should not be repeated in text. If a figure has been published elsewhere, then you need to get the permission from the copyright to reproduce the material at the time of submitting agreement form. Figures should be numbered in order (as per cited in the text part)

Tables : Tables should not be embedded with the text, but it can be cited in the text part. Each table should contain title and description. There is no limit for tables submitted. Tables should provide new information instead of duplicating the same given in the text. Do not use spaces while making tables. Table should be provided in word document, so that the text in the table can be copy editable as per journal format.

Supplementary Files : We do not limit the number of supplementary material items that author has to include in the manuscript. Supplementary materials should be named as S (Example Figure S1, Table S1, Video S1, etc..). Make sure that these supplementary items should be cited in the text.

References : Published and accepted articles should be included in the reference list. References should be numbered consecutively in order in which they are first cited in the text part. Author can also cite the references in the tables and figures apart from text part. In in-text references, authors surname and year should be included if publications are cited in the text.

Journal References : Author, A. (Publication Year). Article title. Periodical Title, Volume(Issue), pp.-pp. Nevin, A. (1990). The changing of teacher education special education.

Teacher Education and Special Education : The Journal of the Teacher Education Division of the Council for Exceptional Children, 13(3-4), 147-148.

Book References : Finney, J. (1970). Time and again. New York, NY: Simon and Schuster.

Website References : Author, A. (Year, Month Date of Publication). Article title. Retrieved from URL

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Leukaemia articles from across Nature Portfolio

Leukaemia is a type of blood cancer, which starts in blood-forming tissue, such as the bone marrow, and causes large numbers of immature blood cells to be produced and enter the bloodstream. Leukaemia is subdivided into different subtypes according to cellular maturity (acute or chronic) and cell type (lymphocytic or myeloid).

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Leukemia Research Reports: Guide for authors.

Leukemia Research Reports , 21 Nov 2012 , 1(1): A2-5 https://doi.org/10.1016/j.lrr.2012.11.002   PMID: 24371763  PMCID: PMC3787823

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Abstract 

Free full text , leukemia research reports : guide for authors.

Leukemia Research Reports is an open access, international journal which delivers timely information online to all health care professionals involved in basic and/or applied clinical research in leukemias, lymphomas, multiple myeloma and other hematologic malignancies. It does this by rapidly publishing a range of peer-reviewed short form papers, including brief communications, case reports, letters to the Editors, images, and debate articles. The Editors encourage the submission of articles relevant to normal and leukemic hemopoiesis, biochemistry, cell biology, immunology and molecular biology as well as epidemiologic and clinical studies. Leukemia Research Reports ' coverage encompasses the application of oncogenes, genomics (gene expression profiles and microRNAs), proteomics, growth factors, cell markers, cell cycle and differentiation agents, novel therapeutics and clinical trials in both the acute and chronic leukemias as well as the myelodysplastic syndromes. In addition articles are solicited on the rapidly growing specialty of marrow or stem cell reconstitution after high dose therapy with curative attempt in patients with a wide range of neoplasms.

Publishing policy —All articles will be peer reviewed and if accepted for publication in the Journal, Authors will be notified of this decision and at the same time requested to pay an Article Processing Fee of US$ 600/EUR 458/JPY 46,638 (exclusive of VAT/Sales Tax). Following payment of this fee, articles will be made universally available at no further charge through ScienceDirect and through the Journal's own website www.lrreports.com .

Submission of Manuscripts – All Manuscripts and Material should be submitted on-line via EES→ http://ees.elsevier.com/lrr/

Please refer to the ‘Tutorial for Authors’ located on the EES site for guidance on the electronic submission process.

All published papers containing research data are subject to peer-review. Submission of an article implies that the work described has not been published previously and will not be simultaneously submitted or published elsewhere (except in the form of an abstract or as part of a published lecture or academic thesis), that it is not under consideration for publication elsewhere, that its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted, it will not be published elsewhere in the same form, in English or in any other language, without the written consent of the Publisher.

These guidelines generally follow the ‘Uniform Requirements for Manuscripts Submitted to Biomedical Journals’. The complete document appears at → http://www.icmje.org .

Submitting an Article —Articles should be submitted online at → http://ees.elsevier.com/lrr/ and the instructions on the site should be closely followed. Authors may submit manuscripts and track their progress to final decision.

Types of Contribution —All articles are limited by word count and the number of references. Word count limits do not include the abstract, references, acknowledgment, figures or tables, or their captions.

Brief Communications include an abstract; the total word count should not exceed 1200 words, a maximum of 10 references and up to 4 figures and/or tables.

Case Reports include an abstract; they should not exceed 1200 words, a maximum of 10 references and an optional 1–2 figures and/or tables.

Letters to the Editor should clearly indicate the purpose of the letter by a brief striking title; they should include an abstract and should not exceed 1200 words, up to 5 references and an optional 1–2 figures and/or tables.

Debate and Controversies —the journal welcomes opinion pieces on research and clinical topics in leukemia. Debate & Controversies articles should include an abstract, should not exceed 1200 words, plus a maximum of 5 references and 1 figure or table.

Images —authors are encouraged to submit images for publication. These should be accompanied by a title and a caption that explains the significance of the image. In addition to ‘still life ‘ images, authors may submit video files. For full details of artwork formats see below.

Meeting Perspectives are reports on one or several sessions of Congress, Workshops or Symposia (also closed ones). Such papers should not exceed 1200 words, 5 references and up to 2 figures and/or tables.

Comments on Published Papers are comments on a prior published paper. Mention the title in both the Cover Letter and the References. This paper does not have an abstract and should not exceed 1200 words; limit 3 references and optional 1–2 figures and/or tables. Comments that seek to address an error in a previous paper are exempt from the Article Processing Fee if accepted for publication.

Preparation of Manuscripts

1. Covering letter : This is a letter stating that you wish to submit your paper to Leukemia Research Reports . Please include the title, and signature of corresponding author. Also include details of any previous version.

2. All contributions must be 1.5 spaced except the references which are single spaced with a space between each reference.

3. Manuscripts submitted for publication should be written concisely and clearly. Manuscripts will only be accepted when they are written in an acceptable standard of English (American or British usage is accepted, but not a mixture of these). Authors whose native language is not English are strongly advised to have their manuscripts be checked by an English-speaking colleague prior to submission or to submit them for language editing (see below for more details). Either the Concise Oxford Dictionary or Webster's New International Dictionary may be used as a standard for English spelling.

4. The manuscript should be organized in the following sequence: All manuscripts must have a title page which is Page 1 of your manuscript. Note the Title should be clear, descriptive and less than 20 words long. Avoid non-specific phrases such as ‘A study of…’ or ‘The effects of…’. Do not give the title a numbered subtitle or series number.

The title page is the first page of the paper and must contain the following: title name of authors (listed as, first name last name academic degree then superscript the institutional code); institutional has superscript code (1, 2, 3,…), Department of…, institution, city and country; the Corresponding Author. Note : No positions like Dr., Professor, or Faculty of, we use academic degrees only.

Role of Corresponding Author : Please note there is only one corresponding author of the manuscript. The corresponding author is the one that submits the manuscript and is displayed on the Title Page of the manuscript. They have the duty to ensure that all of the named authors have seen and approved the original manuscript and subsequent revisions. Each author should have participated sufficiently in the work to take public responsibility for the content. The corresponding author should also ensure that those who have contributed to the research are acknowledged appropriately either as a co-author or in the Acknowledgments. In addition, the corresponding author has the prime responsibility for ensuring the paper is correctly prepared according to the Guide for Authors. Submitted manuscripts not complying with the Guide for Authors may be returned to the authors for revision.

Word Count : does not include the references, acknowledgment, figures and tables.

Abstract : The abstract should be clear, descriptive and less than 100 words.

Keywords —Keywords are index terms or descriptions for information retrieval systems, and a maximum of five should be provided. Words selected should reflect the essential topics of the article and may be taken from both the title and the text.

Abbreviations and units : Generally, avoid abbreviations in the Title and abbreviating single words. Otherwise explain all abbreviations at first mention in the abstract and text, except for: DNA, RNA, AIDS, and HIV. Standard SI abbreviations for units do not need to be spelled out.

Brief Communications should include an Introduction, Materials and Methods, Results and Discussion sections. Case Reports and Letters to the Editor do not need to include these divisions.

Introduction : This should give the reasons for doing the work. As this is a specialist journal a detailed review of the literature is not necessary. The introduction should preferably conclude with a final paragraph stating concisely and clearly the aims and objectives of the investigation.

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Acknowledgments, a comprehensive landscape of transcription profiles and data resources for human leukemia.

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Mei Luo , Ya-Ru Miao , Ya-Juan Ke , An-Yuan Guo , Qiong Zhang; A comprehensive landscape of transcription profiles and data resources for human leukemia. Blood Adv 2023; 7 (14): 3435–3449. doi: https://doi.org/10.1182/bloodadvances.2022008410

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Comprehensive transcriptome analysis for 14 leukemia types and 53 leukemia cell lines.

LeukemiaDB: a comprehensive human leukemia transcriptome database.

Visual Abstract

As a heterogeneous group of hematologic malignancies, leukemia has been widely studied at the transcriptome level. However, a comprehensive transcriptomic landscape and resources for different leukemia subtypes are lacking. Thus, in this study, we integrated the RNA sequencing data sets of >3000 samples from 14 leukemia subtypes and 53 related cell lines via a unified analysis pipeline. We depicted the corresponding transcriptomic landscape and developed a user-friendly data portal LeukemiaDB. LeukemiaDB was designed with 5 main modules: protein-coding gene, long noncoding RNA (lncRNA), circular RNA, alternative splicing, and fusion gene modules. In LeukemiaDB, users can search and browse the expression level, regulatory modules, and molecular information across leukemia subtypes or cell lines. In addition, a comprehensive analysis of data in LeukemiaDB demonstrates that (1) different leukemia subtypes or cell lines have similar expression distribution of the protein-coding gene and lncRNA; (2) some alternative splicing events are shared among nearly all leukemia subtypes, for example, MYL6 in A3SS, MYB in A5SS, HMBS in retained intron, GTPBP10 in mutually exclusive exons, and POLL in skipped exon; (3) some leukemia-specific protein-coding genes, for example, ABCA6, ARHGAP44, WNT3, and BLACE, and fusion genes, for example, BCR-ABL1 and KMT2A-AFF1 are involved in leukemogenesis; (4) some highly correlated regulatory modules were also identified in different leukemia subtypes, for example, the HOXA9 module in acute myeloid leukemia and the NOTCH1 module in T-cell acute lymphoblastic leukemia. In summary, the developed LeukemiaDB provides valuable insights into oncogenesis and progression of leukemia and, to the best of our knowledge, is the most comprehensive transcriptome resource of human leukemia available to the research community.

Leukemia is the main type of hematologic cancer that arises from malignant proliferation and differentiation disorders of blood cells, resulting in abnormal hematopoietic function. 1 , 2 Generally, leukemia can be classified based on the differentiation stage and the origin of malignancies 2 ; for example, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and B-cell ALL (B-ALL). Different leukemia subtypes show distinct clinical characteristics and transcriptomic profiles, 3 , 4 indicating diverse mechanisms underlying their leukemogenesis at the transcription level. Thus, an integrated analysis of leukemia expression data can provide comprehensive insights for elucidating the common and specific regulatory mechanisms among different leukemia subtypes.

Previous studies on leukemia have demonstrated that abnormal gene expression, alternative splicing (AS), and gene fusion play critical roles in the initiation and progression of leukemia. 5 , 6 For example, the BCR-ABL1 fusion event encodes a continuously activated ABL kinase, which leads to disruptions of key cellular processes and leukemogenesis. 5 Classical AS of AML1 could produce proteins with different domain structures that regulate cell growth and/or differentiation in leukemogenesis, 7 and the circular RNA (circRNA) circMYBL2 (the back-splicing [BS] of MYBL2 ) could regulate FLT3 translation by recruiting PTBP1 to promote AML progression. 8 Besides, the aberrant expression of long noncoding RNAs (lncRNAs) has demonstrated strong associations with recurrent mutations, clinical features, and outcomes in AML. 9 Thus, systematic investigation of the expression profiles and alterations of RNA molecules in leukemia samples could improve the understanding of the dysregulated regulation underlying leukemogenesis and facilitate the characterization of the transcriptional features and biomarkers of different leukemia subtypes.

However, most previous leukemia studies focused on 1 specific leukemia subtype or a limited number of subtypes, resulting in massive independent datasets with batch effects, which formed barriers in terms of integrated investigation and systematic comparison of various leukemia subtypes. In addition, further use of these data is severely hampered by a lack of integrative tools for visualization and analysis. Although a few of resources were developed to address this problem, such as LeGenD and Leukemia Gene Atlas, 10 the chief limitations of these resources lie in the small sample size and out-of-date information. For example, the data of Leukemia Gene Atlas were based on gene expression from microarrays from before 2012, and this platform is currently unavailable because of maintenance, whereas the LeGenD database only has deposited information on 70 genes. Therefore, a comprehensive leukemia transcriptome data resource, which contains gene expression, AS events, and fusion profiles of various types of RNAs across leukemia subtypes, is indispensable and an urgent need of leukemia researchers.

Thus, in this study, we attempted to address this issue by developing the LeukemiaDB data repository ( http://bioinfo.life.hust.edu.cn/LeukemiaDB ) to curate a comprehensive transcription landscape of leukemia from large-scale RNA sequencing (RNA-seq) data (>3000 samples) of 14 subtypes and 53 related cell lines. In addition, we systematically investigated the expression characteristics and structure variants of RNA molecules across patients with, and cell lines of, different leukemia subtypes.

Collection and quality control of leukemia RNA-seq data

RNA-seq data were collected from the NCBI GEO and SRA databases using the keywords "leukemia AND Homo sapiens AND RNA-seq." The detailed metadata of samples were retrieved using crawler modules of Beautiful Soup 4.4.0 and urllib2 in Python. The disease information of samples was manually confirmed based on the metadata and related published papers, and irrelevant samples (eg, nonleukemia or ambiguous disease) were discarded. After these procedures, a total of 3504 samples were collected from public data portals. Transcriptome data were downloaded and unpacked through SRA Toolkit (version 2.9.0-ubuntu64), of which data from the non-Illumina platform were removed. Adapter sequence removal and reads trimming were accomplished via Trimmomatic 11 (version 0.32) with default parameters, and FastQC (version 0.11.5) was used for quality control. HISAT2 (version 2.0.4) 12 was used to quickly align clean reads to the human reference genome GRCh38. Samples with an alignment rate of <75% were excluded from our study.

Integration for putative lncRNA annotation files

To better estimate the abundance of lncRNAs, we merged the lncRNA annotations files of Ensembl version 84 and NONCODE version 6.0 by GffCompare (version 0.9.8) as previously described. 13 In brief, class codes from the output of GffCompare were used to explore relationships between lncRNAs of NONCODE and genes of Ensembl: (1) lncRNAs of NONCODE with class codes of “=” and “c” were deemed redundant transcripts from Ensembl, and their NONCODE IDs were replaced by Ensembl ones (their expression will be merged with Ensembl genes); (2) lncRNAs with other types of class codes were considered novel lncRNAs compared with those found in the Ensembl annotation. In addition, we inspected flanking genes around lncRNAs via a sliding window using bedtools (version 2.17). Finally, the merged GTF annotation file was used for abundance estimation of lncRNAs in further analysis.

Abundance estimation and analysis of protein-coding genes and lncRNAs

Raw counts of protein-coding genes and lncRNAs were obtained via featureCounts (version 2.0.3), 14 and the abundance was estimated via StringTie (version 1.3.0) using the GRCh38 and merged GTF annotation file mentioned earlier. Samples with a small amount of detected lncRNA (<1000) and coding gene (<3000) were excluded, with the aimed of ensuring that samples comparable and have enough molecule information for the further analysis. Finally, 3068 samples were included in LeukemiaDB. Moreover, to better integrate the expression data from different projects, batch effect removal (BER) was performed on protein-coding genes or lncRNAs via the R package ComBat function 15 for patient and cell line samples, respectively. Principal component analysis and uniform manifold approximation and projection (UMAP) were used to evaluate and visualize the power of the BER strategy. Principal component analysis was performed via R package FactoMineR and factoextra, whereas UMAP was implemented using R package umap with the “n_neighbors = 15” and “method = naive” parameters. The results of UMAP analysis for samples (the axes information in UAMP) were deposited in the supplemental Material 1.

Specifically expressed genes (SEGs) were detected via the SEGtool 16 using the sensitive mode (detect_mod = 1) for each cell line or leukemia subtype. Here, the average expression matrix of genes in all samples of the given condition (eg, the chronic myeloid leukemia [CML] disease) was used as input for SEG detection. The symbol SEG_high indicated that the gene was specifically expressed in a small number of leukemia subtypes, whereas SEG_low represented that the expression level of the gene was at the extremely low level in the given condition(s) when compared with that of other genes.

Quantification and analysis of circRNAs

To achieve reliable precision and balanced performance, CIRI2 (version 2.0.6), 17 CIRCexplorer2 (version 2.3.6), 18 and circRNA_finder 19 were combined to detect circRNAs. Firstly, samples with a number of BS reads <10 were excluded from circRNAs detection. Furthermore, circRNAs were retained if they fit these criteria: (1) circRNAs with BS reads ≥2; (2) circRNAs detected by at least 2 tools; and (3) circRNAs found in >10% of samples (at least 3 samples) in a certain leukemia subtype or cell line. In addition, circRNAs with ≤2 mismatches across 3 tools were deemed identical. The abundance of circRNAs was estimated by BS reads and normalized using reads-per-million mapped reads. We defined circRNA observed in only 1 leukemia subtype or cell line as a specific circRNA.

The coexpression and TF-target regulatory network analysis

Two types of coexpression pairs (messenger RNA [mRNA]-lncRNA and mRNA-circRNA) were identified. The candidate coexpression pairs were defined by a |Spearman correlation coefficient| (|R|) > 0.5 and a P value < .01. The detailed information of 1665 human transcription factors (TFs) and 1025 TF cofactors was obtained from AnimalTFDB 3.0, 20 and a number of 2 712 247 TF–target pairs were retrieved from the hTFtarget database. 21  

Detection of AS events

The rMATS (docker version: rMATS-docker 0.1beta) was used to detect 5 types of AS events 22 : (1) alternative 5′ donor sites (A5SS), shortened 5′ exons via internal splice sites; (2) alternative 3′ donor sites (A3SS), similar to A5SS but occurring in 3′ exons; (3) skipped exon (SE) means exon(s) excluded in the transcript; (4) retained intron (RI) means intron retained in transcripts; and (5) mutually exclusive exons, 1 exon is included whereas the other excluded compared with that in putative transcripts. 23 We also defined the splicing ratio of a AS event, which is the ratio of samples with this AS event to all samples of a cell line or leukemia subtype. AS events that met the following criteria were retained: (1) the AS events were detected in at least 3 samples and (2) occurred in >40% samples of a leukemia subtype or cell line. The percent splice in value (calculated by rMATS) and a Student t  test (adjusted P values using Benjamini Hochberg method) were used to assess the level and significance of AS events. AS events that occurred in only 1 leukemia subtype or cell line were defined as specific.

Identification of fusion genes in paired-end sequencing samples

Fusion genes were detected from paired-end RNA-seq data using EricScript 24 with GRCh38 reference, in which, R (version 3.4.3), Samtools (version 0.1.19), BWA (version 0.7.17), and Seqtk (version 1.3-r106) were used. The EricScore estimated using EricScript was identified as the fusion score (a range of ∼0-1), which was positively correlated to the reliability of fusion events. The occurrence rate for a fusion event was calculated as the number of fusion-detected samples divided by the total number of samples in a given leukemia subtype. The reliable fusion genes were retained based on the following criteria: (1) fusion genes with spanning reads ≥2, crossing reads ≥1, fusion score >0.7 and (2) occurred in at least 2% or 15% (the higher one) of samples of a leukemia subtype or cell line. Fusion events that occurred in only 1 leukemia subtype or cell line were considered specific.

Survival analysis and drug response analysis

The Kaplan-Meier survival analysis was carried out using R packages (survival and survminer), whereas the log-rank test was used to assess the statistical significance of the survival curves in 2 user-defined groups. The relationship between gene expression and drug response was evaluated using Spearman correlation coefficient of the 50% inhibitory concentration data and gene expression profiles, as we have previously used in GSCALite, 25 which were retrieved from cancer cell lines from the Genomics of Drug Sensitivity in Cancer (GDSC) 26 and the Cancer Therapeutics Response Portal (CTRP) databases. 27 Drug-gene pairs with |R| > .2 and a false discovery rate of <0.05 were curated in LeukemiaDB, and a gene with positive (or negative) Spearman correlation coefficient in a given drug-gene pair was defined as drug resistant (or sensitive) in that condition.

Database implementation

LeukemiaDB was constructed with Python Flask-RESTful API frameworks ( https://flask-restful.readthedocs.io/ ), AngularJS structural framework ( https://angularjs.org ), and Bootstrap (version v3.3.7, a free and open-source CSS/HTML front-end framework, https://getbootstrap.com/ ). A source-available and cross-platform NoSQL database program MongoDB (version linux-x86_64-3.3.6) ( https://www.mongodb.com/ ) was used for data deposition. The LeukemiaDB provides a stable and user-friendly service with the Apache HTTP Server.

Global pattern of transcriptome profiles in patients with leukemia and leukemia cell lines

In this study, we depicted the transcriptome profiles of 3036 samples from 187 public data sets, including 14 leukemia subtypes, 53 leukemia cell lines, and 92 normal samples ( Figure 1 A-B). The workflow of the transcriptome analysis is shown in Figure 1 C, and the workflow is described in detail in “Methods.” Previous studies demonstrated that batch effects, which often result in discrepancies in the statistical distributions across data from different data sets, may be the largest barrier to integration analysis for data from different studies. 28 Thus, the well-treated (BER) data are the basis of integration analysis, and all deposited data in our LeukemiaDB were processed with BER.

Statistics of all samples and workflow of transcriptomic analysis. (A) Sample distribution of leukemia cell lines in LeukemiaDB. (B) Sample statistics of each leukemia subtype in LeukemiaDB. (C) Schematic workflow of transcriptomic analysis in LeukemiaDB. aCML, atypical chronic myeloid leukemia; AML, acute myeloid leukemia; AMKL, acute megakaryoblastic leukemia; AMoL, acute monocytic leukemia; APL, acute promyelocytic leukemia; B-ALL, B cell acute lymphoblastic leukemia; CLL, chronic lymphocytic leukemia; Ery, erythroleukemia; MDS, myelodysplastic syndrome; PCL, plasma cell leukemia; T-ALL, T cell acute lymphoblastic leukemia.

After the BER procedure, we found that most samples were well clustered based on their disease subtypes (supplemental Figures 1A-B, 2A-B, and 3), especially for CML, acute monocytic leukemia, and acute megakaryoblastic leukemia, implying the success of our BER strategy. We investigated the expression profiles of protein-coding genes and lncRNAs for each leukemia subtype and cell line. Here, we detected ∼20 000 protein-coding genes in all samples from patients with leukemia or leukemia cell lines, of which nearly 5% were highly expressed with a transcripts per million (TPM) value of >100, and 25% to 35% were expressed at a low expression level (TPM, 0-1; Figure 2 A-B). In addition, ∼61 000 and ∼46 000 lncRNAs were detected in patients with leukemia and leukemia cell lines, respectively, of which ∼95% were expressed with a TPM value of <1 ( Figure 2 C-D). Different leukemia subtypes or cell lines (excluding atypical CML [aCML] and the ARH77 cell line) exhibited similar expression distribution, in which ∼5% of the protein-coding genes were highly expressed with TPM values of >100 (supplemental Figure 4A-B), and ∼95% lncRNAs were lowly expressed with TPM values <1 (supplemental Figure 4C-D).

Expression characterization in leukemia. (A-B) Distribution of the average expression level of protein-coding genes in (A) patients with leukemia and (B) leukemia cell lines. (C-D) Distribution of the average expression level of lncRNAs in (C) patients with leukemia and (D) leukemia cell lines. (E) Number of circNRAs detected by 3 tools in all samples (yellow labels show the number of circRNAs detected with at least 2 tools). (F) Number of retained circNRAs in patients and cell lines. (G) UpSet plots and distribution of 5 AS event types in leukemia. The pie chart shows the distribution of 5 AS events. (H-I) The number of fusion genes detected in (H) patients with leukemia and (I) leukemia cell lines.

In addition, high-quality circRNAs were identified for each leukemia subtype (see “Methods”). Although the numbers of detected circRNAs varied greatly among the 3 tools used ( Figure 2 E), we found that the distributions of circRNA total BS counts in all samples were similar (supplemental Figure 4E). In total, 128 138 circRNAs were identified by at least 2 tools, of which only 6.9% (n = 8882) were retained via rigorous strategies ( Figure 2 E). Most (n = 6105) of the 8882 circRNAs were derived from cell lines, of which 2527 circRNAs were shared with patients ( Figure 2 F). For each cell line and leukemia subtype, the number of detected circRNAs varied greatly, ranging from 0 to 4574 (supplemental Figure 4F) in cell lines and 0 to 2403 in leukemia subtypes (supplemental Figure 4G).

We also investigated the AS transcripts in leukemia samples. Here, we found that the SE event was the most prevalent AS event among 5 AS types (47.9%, n = 13 607), and the RI event was the least prevalent (9.9%, n = 2821; Figure 2 G). In addition, we found that 459 genes covered 5 AS types in all leukemia samples ( Figure 2 G), which may be prone to splicing genes in leukemia. Although the numbers of AS events varied greatly for different leukemia subtypes or cell lines (supplemental Figure 4H-I), the distribution of AS events in different leukemia subtypes or cell lines exhibited a similar tendency to the earlier description, that is, SE events accounted for nearly 50% of the total AS events (supplemental Figure 4J-K). Interestingly, we found that the AS profiles of the RS4;11 cell line differed from those of other cell lines, and the occurrence of the RI event accounted for ∼50% of the total AS events (supplemental Figure 4J).

Fusion genes were also investigated in paired-end sequencing samples from patients with leukemia and leukemia cell lines ( Figure 2 H-I). Here, we observed that 68 fusion genes were identified in patients with B-ALL, and there were <10 fusion genes in patients with AML and CML ( Figure 2 H). Notably, far more fusion genes were observed in the HL−60/S4 cell line compared with other cell lines ( Figure 2 I), which may be because of the characteristics of the samples; the HL−60/S4 samples were taken from a single study that had high sequencing depth, thus, more stable fusion genes were detected.

Comprehensive data resource to explore transcriptome profiles in human leukemia

We integrated the transcriptome profiles of functional RNAs in leukemia subtypes and cell lines as well as the TCGA-AML survival information and drug sensitivity data from GDSC and CTRP to develop the comprehensive LeukemiaDB. The LeukemiaDB data portal provides information about 5 types of molecules, that is, protein-coding genes, lncRNA, circRNA, fusion genes, and AS, by integrating expression abundance, coexpression modules, TF-target regulation, and leukemia-specific molecules in leukemia subtypes or cell lines ( Figure 3 A-B). In addition, detailed sample information is displayed by LeukemiaDB or linked to relevant websites, and LeukemiaDB also curates the relationships between gene expression and patient survival from TCGA-AML data as well as the associations between gene expression and drug resistance from GDSC and CTRP data. Three main sections are provided for searching, browsing, and data visualization. With the “browse by modules” section, users can click a diagram and access the molecules of interest directly. For example, the protein-coding gene module allows users to quickly search gene expression profiles via a gene symbol or Ensembl ID. The protein-coding gene module also allows users to browse the average expression of a target gene in 14 leukemia types ( Figure 3 B). With the “browse by subtypes” section, users can easily obtain all transcriptome profiles of a selected leukemia type, including the expression level and regulatory information of protein-coding genes, lncRNAs, and circRNAs as well as AS events, fusion genes, and subtype-specific molecular profiles ( Figure 3 B). Via this section, LeukemiaDB provides the aforementioned transcriptomic molecular features for a given cell line ( Figure 3 B).

LeukemiaDB website. (A) LeukemiaDB’s homepage. (B) Six LeukemiaDB modules (protein-coding genes, fusion genes, AS, LncRNA, circRNA, and TCGA-AML) for integrated analysis of public RNA-seq data.

Integrated analysis of protein-coding genes and noncoding RNAs

Further comparative analyses were performed to identify commonalities and differences among different leukemia subtypes and cell lines. Firstly, we detected SEGs in each leukemia subtype and cell line. In a previous study, we demonstrated that SEG_high genes may be crucial molecules in oncogenesis and serve as potential biomarkers for the diagnosis and prognosis of cancers. 29 Interestingly, in this study, we observed that the number of SEG_high genes was predominant both in cell lines and patient samples ( Figure 4 A-B), which may provide important clues for leukemia research. For example, NOTCH3 , as a major oncogenic driver in T-cell ALL (T-ALL), 30 was identified as a SEG_high gene in multiple T-ALL cell lines (supplemental Figure 5A), and several SEG_high genes were identified as potential markers in CLL, 31 for example, ABCA6 , ARHGAP44, and WNT3 (supplemental Figure 5B). Notably, B-ALL and pre–B-ALL shared 39 of 40 (97.5%) SEG_high genes, which suggests high similarity in the molecular characteristics and leukemogenesis between these 2 leukemia subtypes. In addition, BLACE , which is identified as the SEG_high gene in B-A (supplemental Figure 5C), was reported to be expressed exclusively in B-ALL but rarely expressed in other types of hematologic malignancies. 32 Note that additional SEGs were included in LeukemiaDB for further study.

Numbers of specifically expressed protein-coding genes and circRNAs in leukemia. (A) Number of SEGs in cell lines. (B) Number of SEGs in patients. (C-D) The number of specific circRNAs in samples of (C) different leukemia subtypes and (D) cell lines. Here, SEG_high and SEG_low means the gene was highly and lowly expressed, respectively, in that subtype.

Next, we explored specific circRNAs in leukemia subtypes or cell lines; however, the number of circRNAs varied greatly ( Figure 4 C-D). Nonetheless, some specific circRNAs have been reported to play important roles in leukemogenesis. For example, several T-ALL–specific circRNAs identified in our study, for example, TASP1 - and PSEN1 -derived circRNAs, have been reported to be dysregulated in T-ALL. 33 Notably, TASP1 -derived circRNA was identified as a specific circRNA in T-ALL cell lines, for example, CUTLL1 and HPB-ALL. In addition, the PVT1 -derived circRNA, which was previously reported to affect ALL cell growth and pose a potential therapeutic target, 34 was detected in T-ALL.

Regulatory network analysis of TF-target, mRNA-lncRNA, and mRNA-circRNA was performed to better elucidate the regulatory relationship of protein-coding genes, lncRNAs, circRNAs, and TFs. In patient samples, 2 297 453 to 21 289 406 highly correlated mRNA-mRNA coexpression pairs were detected (supplemental Figure 5D), and 3 994 844 to 37 707 656 pairs were found in cell lines (supplemental Figure 5E). In addition, we highlighted TF-target pairs with high correlation (|R| > .5; P value < .05) and kept 19 687 to 167 951 pairs in patients with leukemia and 43 876 to 325 966 pairs in cell lines ( Figure 5 A-B). The number of mRNA-lncRNA pairs varied from 1 400 200 to 71 435 444 in patients with leukemia (supplemental Figure 5F) and 243 373 to 277 991 449 in cell lines (supplemental Figure 5G). Notably, we identified fewer mRNA-circRNA pairs than other coexpression types, ranging from 0 to 234 in patients and 0 to 216 in cell lines ( Figure 5 C-D).

Molecular regulatory network in leukemia. (A-B) The number of TF-target pairs with high correlation (R > 0.05; P value < .01) in (A) leukemia subtypes and (B) cell lines. (C-D) The number of mRNA-circRNA pairs with high correlation (R > 0.05; P value < .01) in (C) patients with leukemia and (D) leukemia cell lines. (E) TF-target regulatory modules of HOXA9 in AML from LeukemiaDB data. (F) mRNA-lncRNA regulatory modules of NOTCH1 in T-ALL from LeukemiaDB data.

Previous studies have demonstrated the critical roles of mRNA-circRNA, mRNA-lncRNA, and TF-target pairs in leukemia progression. 35 , 36 In this study, we observed that the circRNA derived from DNAH14 was highly correlated to the host gene in T-ALL (R = 0.73; P value = .02), which implies the regulation by the circRNA of its host gene  DNAH14 (supplemental Figure 5H). In addition, a previous study showed that the circular isoform of DNAH14 may be involved in the regulation of tumor-associated pathways, 37 which may function by regulating the host gene. We also inspected the potential roles of coregulation modules in leukemia, and we found that several HOXA9 -related pairs formed a HOXA9 module ( Figure 5 E), in which the HOXA9/MEIS1 pair was frequently coexpressed in human myeloid leukemia 38 and related to leukemogenesis. 39 , 40 Another study reported that PBX3 , which is highly correlated with HOXA9 (R = 0.68; P value < 2.0 × 10 16 ), is an important cofactor of HOXA9 in AML. 41 In this study, we observed that a crucial driver gene, that is, NOTCH1 of T-ALL, was coexpressed with multiple lncRNAs, for example, NONHSAG114941.1 (R = 0.61; P value = 6.2 × 10 9 ) and NONHSAG103232.2 (R = 0.50; P value = 6.6 × 10 6 ), which has been reported to promote cell proliferation in T-ALL by interacting with NOTCH1 . 42 Note that the developed LeukemiaDB includes additional modules for the research community.

Analysis of AS events among leukemia subtypes and cell lines

To better elucidate the characteristics of AS events among patients with leukemia or leukemia cell lines, we first detected the aforementioned AS events, of which SE AS events with a high splicing ratio (>0.9) accounted for >50% ( Figure 6 A,C). In addition, specific AS events were identified, and the number of specific AS events varied from 7 (myelodysplastic syndrome) to 4551 (AML) in patients ( Figure 6 B) and from 1 (eg, Jurkat and MOLM-1) to 3293 (HL-60/S4) in cell lines ( Figure 6 D). The specific AS events may contribute to the progression of specific leukemia subtypes, for example, we found that the SE event of SLC38A9 was AML-specific and occurred in 49% of AML samples, which has been reported as a risk factor in AML. 43  

Landscape of AS events. (A-B) The number of AS events with a high splicing ratio (splicing ratio >0.9) in (A) patients with leukemia and (B) leukemia cell lines. (C-D) The number of specific AS events in (C) patients with leukemia and (D) leukemia cell lines. (E) Top 10 frequently spliced genes of each AS event in each leukemia subtype.

We also found that the AS of MYB and HNRNPH1 occurred frequently in all leukemia subtypes and several cell lines ( Figure 6 E; supplemental Figure 5A), which implies that the dysfunction of AS in these genes may play important roles or function as valuable biomarkers in leukemogenesis. MYB is considered a potential therapeutic target in leukemia, 44 and HNRNPH1 has been reported as a crucial regulator of cellular proliferation and disease progression in CML. 45 In addition, we identified the top 10 genes with the most AS events across leukemia subtypes. Here, we found that the AS of several genes appeared in most leukemia subtypes, for example, A3SS of MYL6 (supplemental Figure 6B), A5SS of MYB (supplemental Figure 6C), RI of HMBS (supplemental Figure 6D), mutually exclusive exons of GTPBP10 (supplemental Figure 6E), and SE of POLL (supplemental Figure 6F). These top genes may contribute to the progression and treatment of leukemia.

Landscape of fusion genes in leukemia subtypes and cell lines

Gene fusion, as a main driver event in leukemia, can serve as an important biomarker in the diagnostic therapy and prognosis of leukemia, for example, BCR-ABL in CML. 46 LeukemiaDB includes deposited comprehensive fusion events from patients with various leukemia subtypes and corresponding cell lines. Most of the fusion events mentioned in a previous study 47 can be found in our LeukemiaDB, both the common ( BCR-ABL1 , PML-RARA ) and rare (or defined as novel: EBF1-PDGFRB ) fusion events. Further analysis of fusion events demonstrated that 10 of 196 fusion events in all the patients with leukemia were shared among different leukemia subtypes, and 493 of 1694 in all cell lines samples were shared among different cell lines, whereas other fusion events are specific in different leukemia subtypes ( Figure 7 A-B). The occurrence rates of fusion genes ranged from 0.15 to 0.71 in patients with leukemia (supplemental Figure 7A) and 0.41 to 1.00 among cell lines (supplemental Figure 7B). Notably, we found that several specific fusion genes play important roles in the leukemogenesis of given leukemia subtypes. For example, as a driven event in CML, 46 , BCR-ABL1 was identified as a specific fusion gene in patients with CML ( Figure 7 C; occurrence rate = 0.71) and CML cell lines ( Figure 7 D; occurrence rate = 0.65-1.00). In addition, the fusion score of BCR-ABL1 in 10 of 14 patients with CML was >0.74 ( Figure 7 E), and its fusion score in most CML cell line samples was >0.90 ( Figure 7 F). The fusion gene KMT2A-AFF1 , which was previously reported to be related to poor prognosis of pro–B-ALL 48 and occurred in subtype 4 or subtype 5 AML, was detected in 22 of 28 (78.6%) of samples of SEM (pro–B-ALL cell line) and 9 of 16 (56.3%) of samples in MV4-11 (subtype 5 AML cell line; Figure 7 G). Notably, the average fusion scores of KMT2A-AFF1 were >0.9 in SEM and MV4-11 cell lines ( Figure 7 H-I).

Analysis of fusion genes in leukemia. (A-B) The number of specific fusion genes in (A) patients with leukemia and (B) leukemia cell lines. (C-D) the ratio of specific fusion genes in (C) patients with CML and (D) CML cell lines. (E) Fusion score of BCR-ABL1 in patients with CML. (F) The distribution of fusion scores of BCR-ABL1 in CML cell lines. (G) Occurrence rate of KMT2A-AFF1 in SEM or MV4-11 cell lines. The distribution of KMT2A-AFF1 fusion scores in (H) SEM and (I) MV4-11 cell lines.

Leukemia is the main group of hematopoietic malignancies with high histological and functional heterogeneity. Over the past decade, many studies have focused on different leukemia subtypes, resulting in vast amounts of transcriptome data. However, these data are dispersed among thousands of published studies and cannot be shared directly or repurposed in the research community because of technical barriers, such as batch effects and bioinformatic skills. Therefore, in this study, we systematically integrated and analyzed large-scale high-quality RNA-seq data of human leukemia and the information regarding the influence of genes on drug response and survival, and then we developed the comprehensive leukemia database LeukemiaDB, which allows users to investigate the important features of RNAs underlying different leukemia subtypes at the transcriptional level.

A systematic investigation of expression profiles of protein-coding genes and noncoding RNAs and the regulatory mechanisms across leukemia subtypes can help us better understand leukemogenesis and progression, thereby facilitating effective leukemia diagnosis and therapy. In this study, we detected ∼20 000 protein coding genes, 60 000 lncRNAs, 8882 circRNAs, 5 AS event types, and various fusion genes ( Figure 2 ). Our data have demonstrated that different leukemia subtypes or cell lines exhibit both specific and common characteristics. For example, aCML is a rare subtype of myelodysplastic/myeloproliferative neoplasm that shares clinical and laboratory features with CML. 49 The ARH77 cell line is derived from a patient with plasma cell leukemia; however, it exhibits the characteristics of a healthy B-lymphoblastoid and those of Epstein-Barr virus–transformed B-lymphoblastoid cell lines. 50 , 51 These particularities may cause aCML, and the ARH77 cell line shows great differences from patients with other leukemias and other leukemia cell lines. Note that the detected genes or AS events are dependent on the sequencing depth of the sample. For example, we observed that more fusion genes and AS events were identified in the HL-60/S4 cell line ( Figure 2 I; supplemental Figure 4I), which may be caused by samples with the highest sequencing depth. In addition, our results highlight the importance of lncRNAs, circRNAs, and TFs in the gene dysregulation and pathogenesis of leukemia, for example, HOXA9 in AML ( Figure 5 E) and NONHSAG114941.1, NONHSAG103232.2 ( Figure 5 F), and circDNAH14 in T-ALL. Massive regulatory pairs, including both reported and newly identified pairs, are provided to the research community in the developed LeukemiaDB data portal.

The structural and splicing alteration of RNAs as oncogenic drivers play important roles in leukemogenesis and progression. 43 , 46 Our integrated analysis of large-scale RNA-seq data provides comprehensive views for gene fusion and AS events in leukemia subtypes and cell lines. For example, fusion gene BCR-ABL1 , as the driven event and therapy target in CML, 46 was detected in 96% of the CML samples ( Figure 5 C). In addition, several specific fusion events with high occurrence rates and fusion scores were detected in pro–B-ALL cell lines, for example, KMT2A-AFF1 ( Figure 5 F). Furthermore, other recenty discovered fusion genes are included in LeukemiaDB, which may provide new insights into the mechanism of leukemogenesis in different leukemia subtypes.

In this study, we applied rigorous strategies to curate and integrate leukemia RNA-seq data from different studies; however, several limitations can be identified and discussed. Firstly, most of the considered data sets were generated using different library protocols and sequencing platforms, thereby representing technological limitations. The severe inhomogeneity of sequencing data can influence the detection sensitivity of RNAs and downstream analysis, for example, inefficient detection of circRNAs on poly-A–enriched RNA-seq data and the influence of read length on fusion gene detection. 52 Secondly, even for the same leukemia subtype or cell line, several factors, for example, different treatment conditions, genetic characteristics, and unavailable clinical features (representing biological limitations), can affect data integration from different studies. In some cases, batch effects, which may be the largest barrier to integration analysis for data from different studies, often result in discrepancies in the statistical distributions across data from different studies or laboratories. Although we used several well-known algorithms and tools to perform BER and different leukemia subtypes were grouped together in the UMAP plot, several batch effects could be observed as well, such as the CLL and CML (supplemental Figure 3). Moreover, we also observed that several samples were confounded with other subtypes of samples, for example, a few of T-ALL samples in CLL cluster (supplemental Figure 3) and pre–B-ALL samples mixed with B-ALL, which may be attributes of those samples (we rechecked their metadata) and a limitation of available BER methods. 53 Finally, the unbalanced sample sizes of different leukemia subtypes may influence the power of statistical analysis. For example, massive circRNAs were detected in K562 (supplemental Figure 4D), which may be caused by the large amount of public RNA-seq data for the K562 line. Besides, although we had carefully controlled batch effects during data integration from different studies, challenges remain in batch effects that require further investigation. In addition, because of the incomplete clinical metadata of public data sets, samples had not been further subdivided by cytogenetics, morphology, and immunophenotype profiles, which is a chief limitation of integration analysis from public data and further direct application of our data on precision medicine in Leukemia researchers. However, further use of these data is severely hampered by a lack of integrative tools for visualization and analysis, and this integrated resource in our study is the optimal solution.

Collectively, we have provided comprehensive and multidimensional transcriptome profiles (protein coding genes, lncRNAs, circRNAs, AS events, and fusion genes) of patients with leukemia and leukemia cell lines. In the future, we will plan to update the LeukemiaDB data portal along with the massive cohorts released, and further analysis will be performed to solve urgent problems in the field of leukemia research.

The authors are grateful to the laboratory members and the providers of public data for their contribution.

This work was supported by the National Key R&D Program of China (2021YFF0703704), the Natural Science Foundation for Distinguished Young Scholars of Hubei Province of China (2020CFA070), the Science, Technology and Innovation Commission of Shenzhen Municipality (JCYJ20210324141814037), the China Postdoctoral Science Foundation (2021M701793, 2021M824702, and 2022M713541), and the Science and Technology Project of Nantong City (MS22022109).

Contribution: A.-Y.G. and Q.Z. designed this project; M.L. and Q.Z. collected data and performed analysis; Y.J.K. worked on the fusion identification for leukemia subtypes; M.L. and Y.M. constructed the database; and A.-Y.G., M.L., and Q.Z. wrote and revised the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Qiong Zhang, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, China; e-mail: [email protected] ; and An-Yuan Guo, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China; e-mail: [email protected] .

Author notes

Data are available on request from the corresponding authors, Qiong Zhang ( [email protected] ) and An-Yuan Guo ( [email protected] ).

The full-text version of this article contains a data supplement.

Supplemental data

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Acute Myeloid Leukemia, Version 3.2023, NCCN Clinical Practice Guidelines in Oncology

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Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. Like AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a myeloid malignancy. It is a rare malignancy characterized by the aggressive proliferation of precursors of plasmacytoid dendritic cells that frequently involves the bone marrow, skin, central nervous system, and other organs and tissues. This discussion section focuses on the diagnosis and management of BPDCN as outlined in the NCCN Guidelines for AML.

• Management of Blastic Plasmacytoid Dendritic Cell Neoplasm

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare myeloid malignancy, representing only 0.44% of hematologic malignancies, with an incidence of 0.04 cases per 100,000 people in the United States. 1 , 2 BPDCN, which was formerly known as blastic natural killer cell lymphoma or granular CD4+/CD56+ hematodermic neoplasm, was renamed in the 2008 WHO classification with the evolving knowledge of its PDC origin. 3 , 4 In 2016, it was recognized as a unique myeloid malignancy. 5 The 2022 WHO classification system considers BPDCN to be a subtype of a group of malignancies known as plasmacytoid dendritic cell neoplasms. 6 Pathologically, it is characterized by aggressive proliferation of precursors of PDCs. 7 , 8 The etiology of BPDCN is unknown, but its association with myelodysplastic syndromes or chronic myelomonocytic leukemia in some cases may suggest a related pathogenesis. 7 , 9 BPDCN is associated with a poor prognosis, with a median overall survival (OS) of approximately 8 to 12 months when patients are treated with chemotherapy. 8 , 10 Median age of presentation is 65 to 67 years, with an approximate male-to-female ratio of 3:1. The most frequent clinical presentation of typical BPDCN cases is asymptomatic solitary or multiple skin lesions that can disseminate rapidly without therapy. 7 , 8 Peripheral blood and bone marrow involvement may be minimal at presentation, but tend to develop as the disease progresses. Additional sites of involvement can include lymph nodes, spleen, and other extramedullary organs. 4 , 7 , 11 Less commonly, patients may present with features of an acute leukemia without skin manifestations. 8 Central nervous system (CNS) involvement is not infrequent; approximately 10% of patients who present with neurologic symptoms at diagnosis have confirmed CNS involvement, 12 and rates of CNS involvement, both at diagnosis and at relapse, have been found to be in the range of 9% to 26% in several additional studies. 8 , 13 , 14

Evaluation and initial workup for suspected BPDCN consists of a comprehensive medical history and physical examination. Laboratory evaluations include a comprehensive metabolic panel and a complete blood cell (CBC) count including platelets and a differential of white blood cells. Analyses of peripheral blasts; bone marrow biopsy and aspirate; biopsy of skin lesions and, if suspected to be involved, lymph nodes; and other tissues are recommended. These analyses should include dendritic cell morphology assessment, immunohistochemistry, flow cytometry, cytogenetic analysis (including karyotyping and/or fluorescence in situ hybridization), and molecular analyses. Analysis of skin lesions often occurs in collaboration with dermatology. It is essential to differentiate the skin lesions of BPDCN from other neoplastic and nonneoplastic skin lesions and rashes, including leukemia cutis associated with acute myeloid leukemia (AML), and analysis by experienced hematopathologists is often required. 4 If extramedullary disease and/or lymphadenopathy is suspected, a PET/CT scan is recommended. A lumbar puncture is highly recommended at initial diagnosis to rule out CNS disease, and subsequent intrathecal prophylaxis is strongly encouraged even in the absence of known CNS disease. 4

Diagnosis of BPDCN can be difficult due to overlapping morphologic, immunophenotypic, and clinical features of other hematologic malignancies, such as AML. 4 This is particularly true when BPDCN presents as isolated cutaneous lesions, because biopsy specimens from cutaneous lesions may not yield sufficient cells for appropriate flow cytometric analysis. 4 A diagnosis of BPDCN requires expression of at least 4 of these 6 antigens on malignant cells: CD123 (also referred to as interleukin-3 receptor-alpha [IL3Rα]), CD4, CD56, TCL-1, CD2AP, and CD303/BDCA-2, in the absence of lineage-specific markers. 4 , 7 TCF4/CD123 coexpression has also been found to be a sensitive and specific diagnostic marker for BPDCN. 15 , 16 CD303 is emerging as another marker useful in the diagnosis of BPDCN and may serve as a potential marker for further directed therapy. 17 BPDCN must be distinguished from mature plasmacytoid dendritic cell proliferation in which PDCs are morphologically mature and CD56-negative. 7 In addition, recurrent mutations in the following genes have been described: ASXL1 , IDH1 , IDH2 , IKZF1 , IKZF2 , IKZF3 , NPM1 , NRAS , TET1 , TET2 , TP53 , U2AF1 , and ZEB2 . 4 , 7 , 18 , 19

Induction Therapy for Patients With BPDCN

Given the rarity of BPDCN, no standardized chemotherapy approach has been established. 8 Historically, therapeutic approaches have varied widely and have included irradiation for localized skin lesions, lymphoma- or leukemia-type chemotherapy regimens, and hematopoietic cell transplantation (HCT). 20 Despite good initial responses to chemotherapy, with response rates of 40% to 90%, 4 early relapse rates are high, even among those who achieve complete remission (CR). 4 , 8 , 20 CD123-targeted therapy with tagraxofusp-ersz has more recently emerged as the preferred treatment option in appropriate candidates.

• CD123-Targeted Therapy

CD123, or IL3Rα, overexpression is present in virtually all cases of BPDCN. 11 Tagraxofusp (formerly SL-401) is a recombinant fusion protein made up of the catalytic and translocation domains of diphtheria toxin fused to IL-3 that has shown activity against BPDCN.

The first prospective study of treatment of patients with BPDCN included 11 patients with recurrent or refractory (R/R) BPDCN or who were not candidates for chemotherapy who were treated with SL-401. 21 Each cycle of SL-401 treatment was comprised of a 12.5 µg/kg dose administered over a 15-minute infusion every day for up to 5 doses. Of 9 evaluable patients who received treatment, 5 had a CR and 2 had a partial response (PR) after one cycle of SL-401 treatment (78% overall response rate [ORR]). The median duration of response was 5 months (range, 1–20+ months), with responses occurring in all sites of disease, including skin, bone marrow, and lymph nodes. Acute infusion-related adverse effects such as fever, chills, and nausea were mild to moderate in severity and were most commonly seen within the first several hours after SL-401 infusion; however, these symptoms were occasionally noted up to 4 to 8 hours following infusion. Premedications including acetaminophen, diphenhydramine, methylprednisolone, and famotidine were given, likely mitigating these events. Resulting symptoms following infusion responded to additional dosing of acetaminophen, meperidine, antiemetics, and/or H1- and H2-histamine antagonists. These acute infusion-related events may be related to cytokine release from necrotic cells and damaged BPDCN blasts. Most patients experienced one or more symptoms suggestive of vascular or capillary leak syndrome (CLS), such as hypoalbuminemia, edema, hypotension, and hyponatremia. Hypoalbuminemia was the most consistent and early manifestation of CLS (grade 1 in 4 patients, grade 2 in 6 patients). Symptoms of CLS were managed by the administration of parenteral albumin and diuretics. Although several patients experienced grade 3 thrombocytopenia and neutropenia, myelosuppression was generally modest and reversible, potentially reflecting the minimal expression of IL3R on normal myeloid progenitors. Many patients experienced transaminitis without hyperbilirubinemia, with onset typically 5 to 10 days postinfusion and with full resolution typically 15 to 21 days following infusion.

In a multicohort study by Pemmaraju et al, 22 84 patients with untreated or relapsed BPDCN were treated with an intravenous infusion of tagraxofusp at a dose of 12 µg/kg on days 1 to 5 of each 21-day cycle. Treatment was given until disease progression or unacceptable adverse effects. Of the 84 patients, 65 received first-line treatment and 19 had received prior treatment. Among evaluable patients who received first-line treatment of tagraxofusp, the primary outcome (CR and clinical CR) was observed in 57% of patients, ORR was 75%, and median OS was 15.8 months. Of the patients who achieved CR or clinical CR following first-line treatment of tagraxofusp, 51% were successfully bridged to HCT (allogeneic HCT, n=13; autologous HCT, n=6) while in remission and the median OS in this subgroup was 38.4 months. Of the 18 patients who achieved CR or clinical CR following first-line treatment who did not proceed to HCT, 4 had duration of responses >6 months. Among the 19 patients who had received prior therapy, ORR was 58% with a median OS of 8.2 months. Among this subgroup, 1 patient was successfully bridged to HCT. Based on earlier data from this trial, 11 the FDA approved tagraxofusp-erzs for the treatment of BPDCN in adults and pediatric patients aged ≥2 years in 2018.

The most common adverse effects noted in the study by Pemmaraju et al 22 were increased levels of alanine aminotransferase and aspartate aminotransferase, hypoalbuminemia, fatigue, fever, thrombocytopenia, nausea, and peripheral edema. In addition, CLS was observed in 21% of patients (8 of which were grade ≥3 and 3 of which were grade 5 resulting in death), primarily in the first cycle of treatment. Median time to onset of CLS was 6 days (range, 3–51 days), with a median duration of 6 days (range, 3–69 days). CLS was managed by withholding further doses of tagraxofusp, administering intravenous albumin or glucocorticoids, and careful management of volume status.

• Chemotherapy

In a retrospective multicenter study, 41 patients with BPDCN received induction treatment with AML-type regimens (n=26) and acute lymphoblastic leukemia (ALL)/lymphoma-type regimens (n=15). 8 The AML-type treatment protocols included MEC (mitoxantrone/cytarabine/etoposide), ICE (idarubicin/cytarabine/etoposide), standard-dose cytarabine + anthracycline (7 + 3), FLAG (fludarabine/cytarabine/granulocyte colony-stimulating factor), and FLAG-IDA (FLAG + idarubicin). The ALL/lymphoma-type regimens included hyper-CVAD (alternative cycles of hyperfractionated cyclophosphamide/vincristine/doxorubicin/dexamethasone/methotrexate/cytarabine), GIMEMA ALL trial therapy (association of doxorubicin/vincristine/prednisone/asparaginase), CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone), and CHOEP (CHOP + etoposide). There were patients who required additional therapy based on extramedullary disease (4 received intrathecal chemotherapy for CNS involvement and 2 received radiation therapy for skin lesions); 14% of patients underwent allogeneic HCT at some point in their course of therapy. After induction, the overall CR rate was 41%, with 7 patients achieving CR after AML-type induction, and 10 patients achieving CR after ALL-type induction. Median OS was 8.7 months (range, 0.2–32.9 months), and patients who received ALL-type chemotherapy appeared to have longer OS compared with those treated with AML-type chemotherapy (12.3 vs 7.1 months, respectively; P =.02). In addition, the median OS of patients who received transplant was significantly higher than nontransplanted patients (22.7 vs 7.1 months, respectively; P =.03). Age was also noted to be a significant prognostic factor, with a median OS of 12.6 months in patients aged <65 years compared with 7.1 months for those aged >65 years ( P =.04). Relapses occurred in 35% of patients at a median of 9.1 months.

An additional retrospective study analyzed the impact of 4 different chemotherapeutic approaches: (1) local therapy or systemic regimens less aggressive than CHOP, (2) CHOP and CHOP-like regimens, (3) acute leukemia regimens, and (4) allogeneic or autologous HCT. 20 Therapies less intensive than CHOP were a heterogenous group, including local radiation, systemic steroids, and supportive care, but were mostly cyclophosphamide-based chemotherapy regimens. Although this group had a high ORR of 80% (68% CR), only 7% of patients had a sustained CR and the median OS for evaluable patients was 9 months. Patients in the CHOP and CHOP-like regimens arm had similar results despite therapy being more aggressive, with an ORR of 70% (55% CR) and only 1 case of sustained CR. Intensive acute leukemia regimens resulted in a CR rate of 94%, with approximately one-third of patients experiencing a sustained CR. There were 10 evaluable patients in the HCT arm (6 allogeneic, 4 autologous). Median OS was 38.5 months in the allogeneic arm compared with 16.5 months in the autologous arm. At the time of publication, all but one patient who had undergone allogeneic HCT in first remission remained disease-free.

Another retrospective study evaluated the diagnostic flow cytometry pattern and outcome of 9 patients with BPDCN after frontline treatment with hyper-CVAD. 23 In this group, 7 patients received induction treatment with hyper-CVAD and had a CR of 67% and ORR of 86%. Of the 6 patients whose disease responded to therapy, 5 received planned allogeneic HCT. With a median follow-up of 13.3 months, the 1-year disease-free survival (DFS) and OS rates for all patients were 56% and 67%, respectively. The 1-year DFS for those who received allogeneic HCT was 80%. The 1-year OS for patients who received allogeneic HCT was 80%, compared with 50% in those who received chemotherapy alone. Median OS was 7.9 months for those who received chemotherapy alone.

A more recent retrospective study compared outcomes of 100 patients with BPDCN treated with frontline hyper-CVAD–based therapy (n=35), tagraxofusp (n=37), or other therapies (n=28). 24 The highest CR rates were seen with hyper-CVAD–based therapy (80%), followed by tagraxofusp (59%), and finally other regimens (43%) ( P =.01), although there was no significant difference in OS (28.3 vs 13.7 vs 22.8 months, respectively; P =.41) or remission duration probability (38.6 months vs not reached vs 10.2 months, respectively; P =.24) noted between the 3 arms. In the hyper-CVAD–based group, 51% of patients were bridged to HCT, compared with 49% of patients in the tagraxofusp group and 38% in the other regimens group, respectively ( P =.455). This study suggests a continued role for hyper-CVAD–based regimens in the targeted-therapy era.

• Venetoclax-Based Regimens

The antiapoptotic protein B-cell leukemia/lymphoma-2 (BCL2) is overexpressed in a majority of patients with BPDCN. 25 Venetoclax is an oral selective BCL2 inhibitor approved in combination with azacitidine, decitabine, or low-dose cytarabine for the treatment of newly diagnosed AML in patients aged ≥75 years or for those who are otherwise not candidates for intensive remission induction therapy. 26 In vitro, BPDCN cells were found to be uniformly sensitive to venetoclax in a study that measured direct cytotoxicity, apoptosis assays, and dynamic BH3 profiling. 27

A retrospective study assessed the efficacy of venetoclax combinations in a total of 43 patients with R/R myeloid malignancies, including 2 patients with BPDCN. 25 The most common treatment regimens included venetoclax with decitabine (53%), azacitidine (19%), and low-dose cytarabine (19%). Patients had been previously treated with a median of 3 prior lines of therapy, including allogeneic HCT in 12%. Although ORR was seen in 21% of patients, neither of the 2 patients with BPDCN who were evaluated achieved a response by formal criteria, although one patient had a major response by PET/CT, bone marrow blast reduction of >50%, and improvement in cutaneous lesions. The other patient with BPDCN also had a significant improvement in cutaneous lesions. All patients who received venetoclax combination therapy experienced grade ≥3 neutropenia and 72% developed a grade ≥3 infection, most commonly pneumonia, bacteremia, cellulitis, invasive fungal infections, and urinary tract infections. All patients were given allopurinol for tumor lysis syndrome prophylaxis, and none developed hyperuricemia that required rasburicase. 25 Venetoclax in combination with hypomethylating agents appears to have efficacy in BPDCN, but larger and more formalized studies are necessary to confirm these observations.

• Hematopoietic Cell Transplantation

Due to the rarity of BPDCN, there have been limited established standardized therapeutic approaches. 28 HCT seems to generate durable remissions, especially if given in first CR, as indicated by the studies discussed in the chemotherapy section, as well as others. 3 , 8 , 20 , 23 , 28 , 29 However, it is worth noting that data are limited to small case series and retrospective registry studies, and larger prospective studies are needed to elucidate the role of HCT in BPDCN. 29

A retrospective analysis from the Japan Society for Hematopoietic Cell Transplantation aimed to clarify the role of allogeneic or autologous HCT in treating BPDCN. 3 In this analysis, 25 patients were identified, with 14 having undergone allogeneic HCT and 11 having undergone autologous HCT. All patients who underwent autologous HCT were in first CR, whereas 12 of the 14 patients who underwent allogeneic HCT were in first CR (2 were not in remission). With a median follow-up of 53.5 months, the OS rates at 4 years for patients who underwent autologous and allogeneic HCT were 82% and 53%, respectively ( P =.11) and the progression-free survival (PFS) rates were 73% and 48%, respectively ( P =.14). Data suggest that receiving autologous HCT in first CR may substantially enhance survival. OS outcomes in the allogeneic HCT subgroup did not differ significantly between myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) regimens.

A North American multicenter retrospective study analyzed the outcomes of BPDCN patients treated with allogeneic HCT (n=37) or autologous HCT (n=8). 29 Allogeneic HCT recipients had a 1-year and 3-year OS of 68% (95% CI, 49%–81%) and 58% (95% CI, 38%–75%), respectively. Receiving allogeneic HCT in first CR yielded improved 3-year OS versus allogeneic HCT not in first CR (74% [95% CI, 48%–89%] vs 0%; P <.0001), and outcomes were not impacted by conditioning type (MAC vs RIC). The 1-year OS for autologous HCT recipients was 11% (95% CI, 8%–50%).

A more recent retrospective study evaluated 162 adults with BPDCN who underwent first HCT (allogeneic HCT, n=146; autologous HCT, n=16), 78% of whom were in first CR. 30 Among the allogeneic HCT group, 54% received MAC, 46% received RIC, and 59% received in vivo T-cell depletion. Total body irradiation (TBI) was used in 61% of MAC transplants and 26% of RIC transplants. Comparable 1-year OS and PFS rates were seen following allogeneic and autologous HCT (OS, 66% vs 70%; PFS, 62% vs 66%). TBI as the conditioning backbone in allogeneic HCT led to significant improvements in OS and PFS compared with all other conditioning regimens. Adjusted 2-year PFS for MAC + TBI was 95% compared with 82% for MAC without TBI, 41% for RIC + TBI, and 60% for RIC without TBI, respectively.

• NCCN Recommendations

For patients who are candidates for intensive remission induction therapy, the panel recommends tagraxofusp-ersz as the preferred option, and other options include AML-type (standard-dose cytarabine + anthracycline using 7 + 3), ALL-type (hyper-CVAD), and lymphoma-type (CHOP) regimens. If CNS disease is documented at diagnosis, intrathecal chemotherapy should also be given. If CNS disease is not present at diagnosis, prophylactic intrathecal chemotherapy is strongly encouraged.

Tagraxofusp-ersz should be administered as an intravenous infusion at 12 µg/kg over 15 minutes once daily on days 1 to 5 of each 21-day cycle. Alternatively, 5 doses can be administered over a 10-day period, if needed for dose delays. It is important to note that patients must have a baseline serum albumin of ≥3.2 g/dL to be able to start treatment with this agent. The most serious adverse effect associated with tagraxofusp is CLS, which can occur during the first cycle of treatment and can be life-threatening. 11 A decrease in serum albumin during the first days of treatment seems to be the most consistent predictor of CLS. 11 Management includes delaying or withholding additional tagraxofusp doses, administering intravenous albumin according to prespecified measures, administering glucocorticoids, and close management of volume status. 11 The panel recommends replacing serum albumin if <3.5 g/dL or if there is a reduction of ≥0.5 g/dL from baseline. The panel also recommends premedication with an H1-histamine antagonist, acetaminophen, corticosteroid, and H2-histamine antagonist prior to each infusion to help reduce the risk of hypersensitivity reaction.

With all treatment options, if CR is observed, allogeneic or autologous HCT should be considered. If tagraxofusp-erzs was given as an initial treatment and HCT is not feasible, additional cycles of tagraxofusp-erzs should be continued until disease progression. If disease progresses or does not respond to induction therapy, patients should be considered for a clinical trial (preferred) or regimens used for R/R disease.

For patients with low performance and/or nutritional status (ie, serum albumin <3.2 g/dL) or for those who are not candidates for intensive remission induction therapy or tagraxofusp-ersz, treatment options are limited. If disease is localized or isolated to cutaneous involvement, palliative treatment options include surgical excision or focal radiation. If disease is systemic, palliative options include low-intensity therapy with venetoclax-based regimens, steroids, and supportive care.

• Postremission Surveillance for BPDCN

Following completion of consolidation therapy, it is recommended to monitor a CBC, including platelets, every 1 to 3 months for the first 2 years, then every 3 to 6 months thereafter for up to 5 years. Bone marrow evaluation should be performed only if cytopenias develop or if peripheral smear is abnormal, rather than as routine surveillance at fixed intervals, unless the bone marrow evaluation is being performed as part of a clinical research protocol. For patients with prior evidence of extramedullary disease, a repeat PET/CT scan is recommended. In addition, routine thorough skin examinations with a rebiopsy should occur for any suspicious skin or extramedullary lesions.

• Management of R/R BPDCN

Upon relapse, the NCCN AML Panel recommends evaluating for CNS disease and administering intrathecal chemotherapy prophylaxis. 12 Management options for R/R BPDCN include clinical trial (preferred), tagraxofusp-ersz (preferred, if not already used), 11 chemotherapy (if not already given), local radiation to isolated lesions, systemic steroids, or venetoclax-based regimens. 25 , 27 During administration of any treatment option, a donor search should also be started at first relapse in appropriate patients if no sibling donor has been identified.

BPDCN is a rare myeloid malignancy that often initially presents with asymptomatic skin lesions but with peripheral blood and bone marrow involvement developing as the disease progresses. Less commonly, patients present in a leukemic phase without skin manifestations. Prognosis is poor, with median OS of 8 to 12 months when treated with chemotherapy. 8 , 10 Decisions about diagnosis and management of BPDCN should involve multidisciplinary consultation at a high-volume center with use of appropriate interventions, and referral to an academic institution should be considered. For fit patients, current treatment options include the targeted therapy tagraxofusp-erzs and chemotherapy, whereas patients with low albumin and/or comorbidities should receive localized therapy or supportive care. For patients who achieve CR with tagraxofusp-erzs or chemotherapy, allogeneic or autologous HCT should be considered. Studies suggest that being in first remission during receipt of allogeneic HCT significantly enhances median OS. 8 , 23 , 28 Treatment options for R/R disease include clinical trial (preferred), tagraxofusp-ersz or chemotherapy if not already used, local radiation to isolated lesions, systemic steroids, and venetoclax-based therapies.

Despite the development of tagraxofusp-erzs and high ORRs, relapses are still common and outcomes for patients with R/R BPDCN remain dismal. Additional novel therapies, targeting both CD123 and other targets, are being actively investigated. In addition, a collaborative initiative, the North American BPDCN Consortium (NABC), made up of a group of experts from multiple areas of expertise, has been formed to define the current standard of care for management of BPDCN and to identify future areas of research. 31

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• NCCN CATEGORIES OF EVIDENCE AND CONSENSUS

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

PLEASE NOTE

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

The complete NCCN Guidelines for Acute Myeloid Leukemia are not printed in this issue of JNCCN but can be accessed online at NCCN.org .

© 2023, National Comprehensive Cancer Network® (NCCN®). All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

Disclosures for the NCCN Acute Myeloid Leukemia Panel

At the beginning of each NCCN Guidelines Panel meeting, panel members review all potential conflicts of interest. NCCN, in keeping with its commitment to public transparency, publishes these disclosures for panel members, staff, and NCCN itself.

Individual disclosures for the NCCN Acute Myeloid Leukemia Panel members can be found on page 513. (The most recent version of these guidelines and accompanying disclosures are available at NCCN.org .)

The complete and most recent version of these guidelines is available free of charge at NCCN.org .

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Current Guidelines and Treatment Algorithm of Chronic Myeloid Leukemia

• First Online: 28 September 2023

Cite this chapter

• Carol Cheung Yuk Man 3  

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Chronic myeloid leukemia is the prototype of precision medicine. With efficacious BCR::ABL1 tyrosine kinase inhibitors (TKIs), the prognosis of CML has remarkably improved. Several TKIs are approved for the treatment of newly diagnosed patients with CML in chronic phase (CP), and the choice of first-line agent is individualized and multifactorial. The importance of regular molecular monitoring by real-time quantitative PCR and pro-active management of drug-related adverse events cannot be over-emphasized. Patients who are in sustained deep molecular response might potentially be eligible for TKI discontinuation. Response to TKI should be closely monitored in high-risk patients and patients in accelerated phase. BCR::ABL1 kinase domain mutation analysis should be performed in patients who have suboptimal response to TKI. Failure of at least two TKIs should prompt referral for allogeneic hematopoietic stem cell transplantation (HSCT). Prognosis of CML blast phase remains poor; patients should be treated with a potent TKI with combination chemotherapy, followed by allogeneic HSCT once second CP is achieved.

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Cheung Yuk Man, C. (2023). Current Guidelines and Treatment Algorithm of Chronic Myeloid Leukemia. In: Gill, H., Kwong, YL. (eds) Pathogenesis and Treatment of Leukemia. Springer, Singapore. https://doi.org/10.1007/978-981-99-3810-0_48

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A British Society for Haematology Guideline on the diagnosis and management of chronic myeloid leukaemia

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• 1 St James's University Hospital, Leeds, UK.
• 2 Imperial College, London, UK.
• 3 University of Southampton, Southampton, UK.
• 4 University Hospital, Nottingham, UK.
• 5 University Hospital of Wales, Cardiff, UK.
• 6 Great Ormond Street Hospital, London, UK.
• 7 King's College Hospital NHS Foundation Trust, London, UK.
• 8 MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
• 9 Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK.
• 10 BSH Haemato-Oncology Task Force representative.
• 11 University of Glasgow, Glasgow, Scotland.
• PMID: 32734668
• DOI: 10.1111/bjh.16971

Keywords: BCR-ABL; CML; imatinib; tyrosine kinases.

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Acute myeloid leukemia.

Anusha Vakiti ; Prerna Mewawalla .

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Last Update: August 8, 2023 .

• Continuing Education Activity

Acute myeloid leukemia (AML) is the most common leukemia among the adult population and accounts for about 80% of all cases. It is characterized by clonal expansion of immature "blast cells" in the peripheral blood and bone marrow resulting in ineffective erythropoiesis and bone marrow failure. With recent advancements in the management guidelines, the cure rates have increased up to 15% in patients older than 60 years and about 40% in patients below 60 years of age. Despite advancements in therapeutic regimens, the prognosis remains very poor in the elderly population. This activity examines when this condition should be considered in the differential diagnosis and how to evaluate it properly. This activity highlights the role of the interprofessional team in caring for patients with this condition.

• Identify the epidemiology of acute myeloid leukemia.
• Describe the physical exam of a patient with acute myeloid leukemia,
• Review the management of acute myeloid leukemia.
• Explore modalities to improve care coordination among interprofessional team members in order to improve outcomes for patients affected by acute myeloid leukemia.
• Introduction

Acute myeloid leukemia (AML) is the most common leukemia among the adult population and accounts for about 80% of all cases. It is characterized by clonal expansion of immature “blast cells” in the peripheral blood and bone marrow resulting in ineffective erythropoiesis and bone marrow failure. With recent advancements in the management guidelines, the cure rates have increased up to 15% in patients older than 60 years and about 40% in patients below 60 years of age. Despite advancements in therapeutic regimens, the prognosis remains very poor in the elderly population. [1] [2] [3]

Depending upon the etiology, genetics, immune-phenotype, and morphology, there are different classification systems for AML. [4] [5]

The most common risk factor for AML is myelodysplastic syndrome. Other hematological disorders that increase the risk of AML include myelofibrosis and aplastic anemia.

Several congenital disorders like Down syndrome and Bloom syndrome also increase the risk of AML, which tends to present in the early 20s.

Environmental exposures like radiation, tobacco smoke and benzene are also risk factors for AML

Finally, previous exposure to chemotherapeutic agents is also a risk factor for AML.

• Epidemiology

The number of new cases among men and women per year is about 4.2 per 100,000 population. The incidence is over 20,000 cases per year in the United States. The average age at the time of diagnosis is about 65 years. It is more prevalent among non-Hispanic whites. Males have more predominance compared to females, with a ratio of 5:3.

• Pathophysiology

AML is characterized by mutations of the genes involved in hematopoiesis. These mutations result in a clonal expansion of undifferentiated myeloid precursors (blasts) in the peripheral blood and bone marrow resulting in ineffective erythropoiesis and bone marrow failure. Recent studies also revealed that it could arise from a series of recurrent hematopoietic stem cell genetic alterations which get accumulated with age. In most cases, AML appears as de novo in a previously healthy person. The exact cause of genetic mutations is unclear, but few risk factors include exposure to radiation, chemotherapeutic agents, and smoking. AML can also evolve from myeloproliferative disorders (MPD), myelodysplastic syndrome (MDS), paroxysmal nocturnal hemoglobinuria, and aplastic anemia. Familial causes of genetic mutations should also be considered.

AML is a highly heterogeneous disease with a variable prognosis. It can result from genetic mutations, chromosomal translocations, or changes in molecular levels. About 97% of the cases have been studied to have genetic mutations. Despite its heterogeneity, it can be categorized into favorable, intermediate, or adverse-risk groups based on cytogenetics. The prognosis within these categories varies widely. The chromosomal translocations t (8;21), t (15;17), or inv (16) have a favorable prognosis with 3-year overall survival (OS) rate of about 66% and 33% in patients younger than 60 and older than 60 years of age respectively. People with t (9;11), monosomy 5 or 7, and normal cytogenetics (CN-AML) have an intermediate risk. A high risk of treatment failure and death was noted in people with t (6;9), inv (3). or 11q changes. The presence of c-KIT mutations in patients with t (8;21) increases the risk of relapse and decreases the OS.

About 25% to 30% of AML patients have Nucleophosmin 1 ( NPM1 ) mutations. This is the most common mutation found in AML and has a female predominance. Clinically, the mutation has monocytic morphology and in the absence of FMS-like tyrosine kinase 3 or  FLT3-ITD , predicts favorable OS. NPM1  mutations are chemosensitive to intensive chemotherapy in both young and old patients. It is associated with other recurrent genetic abnormalities such as FLT3-ITD  (40%),  FLT3-TKD  (10% to 15%), and  IDH  mutations (25%).

FLT3 is strongly expressed in hematopoietic stem cells with important roles in cell survival and proliferation. Mutations involving the Internal tandem duplications (ITD) and the tyrosine kinase domain (TKD) of the FLT3 gene have been found in 20% of AML cases and 30% to 45% of CN-AML patients. Both the mutations activate FLT3 signaling, promoting blast proliferation. Patients with FLT3 mutations can have severe leukocytosis. FLT3-ITD mutations have been associated with an increased risk of relapse. Tyrosine kinase inhibitors (TKI) are being tested in FLT3 mutated AML patients. Unfortunately, when used alone, TKIs showed only a transient reduction of blasts, and even if initially effective, the subsequent acquisition of secondary mutations induces resistance over time.

Runt-related transcription factor ( RUNX1 ) is an essential component of hematopoiesis. It is also known as AML1 protein or core-binding factor subunit alpha-2 ( CBFA2 ). RUNX1  is located at chromosome 21 and is frequently translocated with the ETO (Eight Two One)/RUNX1T1  gene located on chromosome 8q22, creating an AML-ETO  or t(8;21)(q22;q22) AML which is seen in about 12% of AML cases. They are commonly associated with trisomy 13, trisomy 21 and show resistance to standard induction therapy.

Mutations in isocitrate dehydrogenase ( IDH) are oncogenic. They are seen in 15% to 20% of all AML cases and 25% to 30% of patients with CN-AML. More commonly seen in older individuals.

TP53 mutations are associated with very poor prognosis and are resistant to chemotherapy.

• History and Physical

Due to ineffective erythropoiesis and bone marrow failure, patients experience a variety of symptoms including recurrent infections, anemia, easy bruising, excessive bleeding, headaches, and bone pains. Depending on the degree of anemia, they can experience generalized weakness, fatigue, shortness of breath, and chest tightness. The physical examination can reveal bruises, pallor, hepatomegaly, and splenomegaly. Lymphadenopathy is rare. DIC is common in patients with AML. Signs of organ infiltration are not uncommon; they may include hepatosplenomegaly and lymphadenopathy. Sometimes a skin rash due to infiltration of leukemic cells will occur.

AML should be suspected in anyone with unexplained cytopenias (decreased cell count of white blood cells, hemoglobin, or platelets), the presence of circulating blast cells in the peripheral blood, easy bruising or bleeding or recurrent infections. In some cases, they can present with renal failure secondary to tumor lysis syndrome which is an oncologic emergency. [6] [7] [8] [9]

Some patients may have elevated LDH and hyperuricemia, suggesting tumor lysis syndrome, which is a medical emergency.

The blood smear will reveal circulating blasts and schistocytes if DIC is present.

The presence of at least 20% blasts in the bone marrow or peripheral blood is diagnostic of AML. It can be diagnosed with bone marrow aspiration and biopsy. Additional diagnostics include flow cytometry, cytogenetics, and fluorescence in situ hybridization (FISH). The presence of Auer rods (clumps of azurophilic granules resembling elongated needles) is diagnostic of AML. Auer rods can be seen in many subtypes of AML, but abundantly seen in APL.

Oncologic emergencies associated with AML include neurologic or respiratory distress due to leukostasis, APL-induced DIC, tumor lysis syndrome, and central nervous system (CNS) involvement. [10]

Other tests include a chest x-ray, MUGA scan to assess the heart, and ECG.

• Treatment / Management

Individuals who achieve complete remission (CR) with a blast count of less than 5% in the bone marrow after induction therapy tend to have increased survival. Despite induction therapy, there is still minimal residual disease for which consolidation therapy is initiated to prevent any risk of relapse by eliminating the residual disease. Despite many advances, the mainstay of therapy remains a combination of cytarabine-based and anthracycline-based regimens. For eligible candidates, allogeneic stem cell transplantation should be considered. [11] [12] [13] [14]

Induction Therapy

This is a standard of care for younger patients, elderly with a low risk of treatment-related mortality (TRM), and ones with favorable and intermediate-risk factors. The induction therapy is highly toxic to bone marrow, causing pancytopenias and bleeding complications, gastrointestinal system issues, kidney failure due to tumor lysis syndrome, and electrolyte disturbances. It may take up to 1 month for the cell counts to recover, and these patients need aggressive monitoring to manage any complications. Baseline cardiac function should be estimated before initiating the treatment, and the ejection fraction (EF) needs to be monitored carefully, as anthracyclines can cause significant cardiotoxicity. Studies have shown greater benefit with higher doses, but toxicities may limit its use. It consists of the "7+3" regimen that includes continuous infusion of cytarabine for seven days along with anthracycline on days 1 to 3. Patients with refractory disease have shown higher CR and similar overall survival (OS) by using higher doses of cytarabine or by using a combination of fludarabine, cytarabine, and idarubicin. Despite TRM in older patients, chemotherapy has shown to improve the survival rate among the elderly (older than 65 years). Decitabine, a methylating agent used in the treatment of MDS, has shown improvement in OS in the elderly population. The response should be evaluated by repeating the bone marrow aspirate and biopsy after 2 weeks of initiating the induction therapy. Reinduction can be done with high dose cytarabine or by combining with etoposide if there is persistent evidence of disease. About 60% to 80% de novo AML will achieve CR with induction therapy.

Even before the diagnosis, if APL is suspected, then the treatment should be initiated with all-trans retinoic acid (ATRA), as early use of ATRA decreases the risk of disseminated intravascular coagulation (DIC) and mortality associated with it.

Consolidation Therapy

After achieving CR with induction therapy, consolidation therapy is initiated with high dose cytarabine, called HiDAC, and hematopoietic cell transplantation (HCT). HCT is preferred in individuals less than 60 years of age with intermediate or unfavorable prognoses. If a donor is available, then allogeneic HCT is preferred over autologous HCT. They should be monitored for signs or symptoms of acute or chronic graft versus host disease (GVHD).

Novel Targets

Ongoing studies with Fms-like tyrosine kinase 3 (FLT3) inhibitors, IDH inhibitors, and immune therapies.

All blood products must be irradiated to prevent transfusion-related graft versus host disease, which is usually fatal.

IV antibiotics are given to febrile patients, and prophylactic antifungal therapy is recommended.

• Differential Diagnosis
• Acute Lymphoblastic Leukemia (ALL)
• Aplastic anemia
• B-cell lymphoma
• Bone marrow failure
• Chronic myelogenous leukemia (CML)
• Lymphoblastic lymphoma
• Myelodysplastic syndrome (MDS)
• Myelophthisic anemia
• Primary myelofibrosis

In the past, the French-American-British system classified AML into eight subtypes, FAB M0 to M7, which are as follows:

• M0: Undifferentiated AML
• M1: AML with minimal maturation
• M2: AML with maturation
• M3: Acute promyelocytic leukemia (APL)
• M4: Acute myelomonocytic leukemia
• M5: Acute monocytic leukemia
• M6: Acute erythroid leukemia
• M7: Acute megakaryocytic leukemia

In 2016, World Health Organization (WHO) revised the classification and categorized it into AML with recurrent genetic abnormalities, AML with myelodysplasia-related changes, therapy-related myeloid neoplasms, NOS, myeloid sarcoma, myeloid proliferations related to Down syndrome.

AML with recurrent genetic abnormalities includes- 

• AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1
• AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
• APL with t(15;17)(q22;q12); PML-RARA
• AML with t(9;11)(p21.3;q23.3); MLLT3-KMT2A
• AML with t(6;9)(p23;q24); DEK-NUP214
• AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM
• AML (megakaryoblastic) with t(1;22)(p13.3;q13.3); RBM15-MKL1
• AML with mutated NPM1
• AML with biallelic mutations CEBPA

 AML not otherwise specified (NOS) includes:

• AML with minimal differentiation
• AML without maturation
• AML with maturation
• Acute myelomonocytic leukemia
• Acute monoblastic/monocytic leukemia
• Pure erythroid leukemia
• Acute megakaryoblastic leukemia
• Acute basophilic leukemia
• Acute panmyelosis with myelofibrosis

Based on the etiology of the AML, it can be categorized into d e novo AML, Secondary AML (s-AML), which evolves from prior MPD or MDS, and Therapy related AML (t-AML) following exposure to chemotherapeutic agents or radiation therapy or toxins.

By assessing the prognostic factors, clinicians can decide whether a standard therapy or more intense therapy would be helpful in maintaining CR and OS rates. The prognostic factors are chromosomal abnormalities (favorable abnormalities include t(8;21), t(15;17), inversion of chromosome 16), genetic mutations ( NPM1 gene has a favorable prognosis, and FLT3 gene has unfavorable prognosis). Worse outcomes have been noted with older age, white blood cell count greater than 100,000 at the time of diagnosis, s-AML, t-AML, the presence of leukemic cells in the central nervous system (CNS).

Recent techniques such as PCR and flow cytometry can detect the presence of minimal residual disease among CR patients. Persistently elevated levels of RUNX1-RUNX1T1 despite induction therapy in patients with t(8;21) AML are associated with an increased incidence of relapse.

• Enhancing Healthcare Team Outcomes

AML is a common hematological malignancy in adults. Despite many advances, the malignancy still carries a poor prognosis. Hence, it is best managed by an interprofessional team that includes a hematologist, oncologist. internist, pathologist, and an intensivist. The key is to prevent more harm to the patient, and hence a universal treatment plan must be developed and carried out.

The pharmacist should educate the patient on the chemotherapeutic drugs, their benefits, and their adverse effects.  The oncology nurse is vital for treatment administration and monitoring for potential complications.

The nurse should educate the patient on infection prevention by washing hands, rinsing all fruits and vegetables, avoiding crowds, and seeking help at the first sign of fever.

The radiologist is essential for the placement of long-term venous catheters and other imaging studies. The primary care physician should educate the patient on personal hygiene, hand washing, and immunization. The dietitian should help manage nutrition, and the social worker should ensure that the patient has all the support to complete the treatment.

The only person who should make changes in medications is the oncologist. A conference should be held on a weekly basis, and all concerns attended to at that time. Patients should be provided with a realistic message about survival.

An interprofessional approach to evaluation and management will lead to the best outcomes. [Level 5] Overall, life expectancy has increased slightly, but most patients have a markedly shortened lifespan. [15] [16]

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Disclosure: Anusha Vakiti declares no relevant financial relationships with ineligible companies.

Disclosure: Prerna Mewawalla declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

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