case study of a brain tumor patient

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• v.19(5); 2014 Sep

Case presentation – A five-year survival of the patient with glioblastoma brain tumor

Hubert urbańczyk.

a Centrum Onkologii, Instytut im. Marii Skłodowskiej-Curie, Oddział w Gliwicach, Zakład Radioterapii, Poland

Anita Strączyńska-Niemiec

b Centrum Onkologii, Instytut im. Marii Skłodowskiej-Curie, Oddział w Gliwicach, Zakład Patologii Nowotworów, Poland

Grzegorz Głowacki

Dariusz lange, leszek miszczyk.

This paper presents an atypical case of a patient with brain tumor of the glioblastoma multiforme (GBM) type who achieved a 5-year survival. Some general information is provided including epidemiology, diagnostic and treatment procedures (surgery and radio-chemo-therapy), and prognosis of survival related to GBM. The course of the disease, including its main symptoms, individual reasons for the delay of adjuvant treatment, after the primary surgical treatment, 37-month period of the decease free survival, as well as comprehensive management after the tumor recurrence are also presented. Histopathology confirming the clinical diagnosis is discussed in a separate chapter.

1. Background

Primary brain tumors account for about 2% of all malignant neoplasms in adults. Approximately a half of them represent gliomas, derived from neuroepithelial cells, among which glioblastoma (GBM) is the most common type.

GBM cases represent about 20% of all primary brain tumors in the adult population, and about 75% of all the anaplastic gliomas. 1 The prevalence of GBM is about 2–4 cases per 100,000. It is more common in men than in women, and its incidence increases with age. 2 Only sporadically, GBM can be found in individuals younger than 20 years of age, and its frequency rapidly increases, starting from the 5-th decade of life.

The treatment results of patients diagnosed with GBM are often unsatisfactory, and the outcome is usually poor. Currently, the main standard therapeutic methods include a radical surgical procedure, combined with radio-chemo-therapy. Some innovative methods of radiotherapy based on the application of novel radiosensitizers of corpuscular irradiation or radio-immune-therapy are now being investigated. A median survival time of patients diagnosed with GBM, treated only with the use of neurosurgical procedures are 3–5 months. The application of conventional adjuvant radiotherapy prolongs this average time about 3-fold, with a three-year survival for only about 6% of patients.

The post-treatment survival time depends on many clinical factors, such as general patient condition, age, and histopathological type of the tumor. Simson et al. demonstrated statistically significant longer survival periods among patients in whom the primary tumor location was in the frontal lobe, in comparison to the ones in whom it was located in the parietal or temporal cerebral region (11.4 months vs. 9.6 months vs. 9.1 months, respectively; p  = 0.01). 3 Severity of neurological symptoms, limits of the performed surgical procedures, and response to the applied therapy, based on imaging tests, also represent prognostic factors.

Etiology of malignant neoplasms of the central nervous system (CNS) is still unknown. The most common of many probable carcinogens include: nitrosamines, pesticides, herbicides, petrochemical substances, polyvinyl chloride, and electromagnetic irradiation. However, the role of these pro-carcinogenic factors has not been unequivocally proven. 4,5 In contrast, it has been documented that patients exposed to ionizing irradiation have an increased risk of the CNS malignant gliomas. According to the current state of knowledge in the field of molecular biology and genetics of these malignancies, two main hypotheses related to their development have been proposed. The first one includes de novo creation which is related to the loss of heterozygotic properties in chromosomes 9p, 10, 17p, and with the amplification of genes for the EGFR and CDK4 (this type of malignant growth occurs more often in older patients). The second one involves the creation of anaplastic gliomas, through the progression of gliomas with a lower malignancy grade (encountered more often in younger patients). 6,7

Currently, a required standard of therapy for patients with GBM is a combined treatment, including tumor resection, with following concomitant radio-chemo-therapy, and adjuvant chemo-therapy, based on Temozolomide. In patients who undergo non-radical surgery, or who are not treated surgically, the palliative whole brain radiotherapy (WBRT), stereotactic radiation surgery (SRS), or combination of both of these therapeutic methods are used. Also, the application of palliative chemotherapy and symptomatic treatment remain important. In addition, alternatively fractionated radiotherapy, brachytherapy, targeted molecular therapy, radio-immune-therapy, hadrone therapy, or radio-sensitizers can be considered in individual cases.

In 2005, Stupp et al. presented results of a randomized study conducted by EORTC ( European Organization for Research and Treatment of Cancer ) and NCIC ( National Cancer Institute of Canada ), comparing the application of combined radio-chemo-therapy based on Temozolomide and radical radiotherapy alone. The combined management in a statistically significant manner prolonged the total survival time from 12.1 to 14.6 months, and the rate of 2-year survival was 26.5%, compared to 10.4% for radiotherapy alone. 8 The follow-up results, after a longer period of observation, confirmed the previous reports. The 2-, 3-, and 4-year survival rates were 27.3%, 16.7%, and 12.9%, respectively ( p  < 0.0001) in the patients’ group treated with a combined therapy, and 11.2%, 4.3%, and 3.8%, in the patients’ group treated with radiotherapy only. 9

Unfortunately, despite the use of Temozolomide, the results are unsatisfactory. The reason for this therapeutic failure is the GBM resistance to most chemotherapeutic agents or rapid development of the GBM as a result of genetic transformations within the tumor cells. The main mechanism of the GBM resistance to alkylating agents, such as temozolomide, procarbazine, or nitrogen mustard derivatives, is the repair of damages caused by these drugs with involvement of protein coded by MGMT ( O 6 -methyl-guanine-DNA methyl-transferase ) gene.

A degree of methylation of the promoter's region of MGMT gene appears to be closely correlated with a therapeutic response of the glioma cells. Hypermethylation of this part of the gene significantly increases treatment efficacy among patients treated with Temozolomide, 10 influencing their survival period, as well. 9

2. Case presentation

The patient is a 38 year old Caucasian male, smoker (about 10–15 cigarettes per day for 20 years), without other relevant family or personal risk factors for neoplasic disease who had suffered from severe headaches and nausea (his first disease symptoms) since August of 2005. He did not seek any medical help until November of 2005, when he presented to his doctor, due to exacerbation of those symptoms. No abnormalities on both physical and neurological examinations were detected at that time.

On December 30th of 2005, the CT scan of his brain was remarkable for the following findings: “An expansive lesion of approximately 5 cm × 3 cm in size, located in the right temporal lobe, with nonhomogenic, post-contrast signal amplification. A large edema surrounding the lesion. A compression of the occipital corner of the right lateral ventricle. A slight enlargement of the supratentorial ventricular system, shifting to the left.”

On January 25th of 2006, the patient underwent surgical therapy, including right temporal craniotomy, with total resection of the tumor. On February 7th of 2006, a histopathology examination (identification number 475,958; Info-Pat, Poznań, Poland), confirmed a diagnosis of the GBM IV stage (according to WHO classification). Microscopic images of the tumor are presented ( Figs. 1–5 ).

Microscopic image of patient's tumor.

After the surgery, the patient was referred to the Institute of Radiation Oncology in Gliwice, Poland, for the post-operative radiotherapy. Although the patient was qualified for this treatment, he did not arrive to the Institute of Radiation Oncology on the day of the scheduled preparatory procedures. The reason for his absence was a simultaneous diagnostic finding of the left lung's tumor, for which the patient underwent a thoracotomy with the wedge tumor resection (for diagnostic purposes). On June 12th of 2006, based on the histopathological examination results, which showed post-tuberculosis lesions, the patient's pulmonary treatment was completed.

In February 2007, approximately 13 months after his brain tumor surgery, the patient again presented to the Institute of Oncology, and according to the follow-up diagnostic work-up, no brain tumor recurrence was found. Due to the absence of tumor, no radiotherapy was considered, and “watchful waiting” was recommended including brain imaging studies (CT or MRI) to be repeated every 3 months. In the face of the atypical disease course, an additional verification of the histopathological diagnosis was also performed, confirming the original findings of the GBM. The patient had remained under close control until February 2009 (37 months from his initial brain tumor surgery), and at that time the brain tumor recurrence was found. His recurrent tumor was located in the primary tumor's bed, and its size was 4 cm × 5.3 cm × 3.5 cm ( Fig. 6 ). However, those findings were not associated with any particular symptoms or abnormalities on subsequent physical or neurological examinations of the patient. On March 16th 2009, the patient underwent another craniotomy with the subtotal tumor resection. (MRI scans after the second craniotomy are shown in Figs. 7 and 8 .) The histopathology examination was again consistent with GBM. During the period from May 11th to June 19th of 2009, the patient received the radiotherapy dose of 60 Gy/30 fractions to the tumor lodge, including the residual tumor, with 2.5 cm of tissue margin. Due to the lack of the patient's consent, no chemotherapy was implemented. During the irradiation period, he had the first seizure episode, and was started on antiepileptic therapy (Depakine 200 mg a day). He continued this therapy for the rest of his life. After the radiotherapy, diagnostic follow-up examinations were conducted every 3 months. At the beginning of March 2010, another recurrence was found, and the tumor was localized in an upper part of the tumor bed, within the previously irradiated area (its size was 3.7 cm × 2.6 cm × 2.3 cm). Surprisingly, the patient had not experienced any symptoms, and his physical and neurological examinations were unremarkable. On March 13th of 2010, the stereotactic radiotherapy, using a single dose of 8 Gy applied to the area of recurrent tumor was performed. Unfortunately, on the control examination, on July 6th of 2010, further progression of the GBM was found. The patient expired on November 15th of 2010, in the local hospital (Zawiercie, Poland), due to the tumor expansion, resulting in cerebral edema, herniation, and multi-organ failure.

CT scan of recurrence tumor.

MRI scan after the second craniotomy.

3. Histopathology examination

On a histopathology specimen, the large areas of thrombotic necrosis, most probably caused by a large tumor size (5 cm × 3 cm) were found. In contrast, no “palisade” necrosis (with the characteristic palisade-like cell arrangements), typical for this type of tumor, was found.

Within vital tumor structures, a high cellular polymorphism was found. Besides some small calls (with hyperchromatic nucleus and scarce amount of cytoplasm), mostly atypical cells (giant, multisided or oval, with numerous nuclei with abnormal shapes, and visible nucleoli) were present. The cells revealed a strongly positive GFAP reaction that can be indicative of their glioma-type origin. Also, some distinctive GBM features, including proliferation of vascular endothelium (focal areas of numerous mitotic figures, in high power field – HPF), were visible. The described microscopic images are presented in Figs. 1–5 (the images of primary and recurrent tumors appear identical).

In this paper, we presented a remarkably long survival period (63 months since the initial onset of symptoms, and 58 months since the primary surgical treatment) of the GBM patient. An important message from our case study that could be useful in the management of many other GBM cases is that the initial complete resection suggests a beneficial role of radical neurosurgery in the early GBM treatment and potential survival period.

Unfortunately, we are unable to indicate the specific reasons for such a long survival of our relatively asymptomatic patient who experienced some disadvantages, including the second malignancy, which caused the delay in the application of his radiotherapy.

Nevertheless, it should be emphasized that personalized, patient-centered approach, using comprehensive diagnostic and therapeutic strategies, as well as vigilant, multi-level follow-up care, should be helpful in explaining different factors, contributing to overall survival. In addition, our single case presentation illustrates several challenges that are common to many GBM patients, and merit further, more individualized research on this devastating disease.

Conflict of interest

None declared.

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PERSPECTIVE article

Case report: end-stage recurrent glioblastoma treated with a new noninvasive non-contact oncomagnetic device.

• 1 Kenneth R. Peak Brain and Pituitary Tumor Treatment Center, Department of Neurosurgery, Houston Methodist Neurological Institute, Houston, TX, United States
• 2 Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, United States
• 3 Department of Neurosurgery, Weill Cornell Medical College, New York, NY, United States

Alternating electric field therapy has been approved for glioblastoma (GBM). We have preclinical evidence for anticancer effects in GBM cell cultures and mouse xenografts with an oscillating magnetic field (OMF) generating device. Here we report OMF treatment of end-stage recurrent glioblastoma in a 53-year-old man who had undergone radical surgical excision and chemoradiotherapy, and experimental gene therapy for a left frontal tumor. He experienced tumor recurrence and progressive enlargement with leptomeningeal involvement. OMF for 5 weeks was well tolerated, with 31% reduction of contrast-enhanced tumor volume and reduction in abnormal T2-weighted Fluid-Attenuated Inversion Recovery volume. Tumor shrinkage appeared to correlate with treatment dose. These findings suggest a powerful new noninvasive therapy for glioblastoma.

Introduction

For glioblastoma (GBM), the most common malignant tumor of the brain in adults, treatment outcome remains dismal. In over 40 years median survival has only shown modest improvement ( 1 ), and standard of care treatment often has negative impact on quality of life ( 2 ). Treatment including radiation and chemotherapy takes a heavy toll. Frequently patients cannot tolerate the completion of the prescribed chemotherapy cycles. Thus, there is a great unmet need for a completely different therapeutic approach with better outcome and less toxicity.

A new FDA-approved treatment involving electric fields alternating at 200 kHz called Optune™ therapy is now available for recurrent GBM as monotherapy and in combination with temozolomide for newly diagnosed GBM ( 3 , 4 ). It is also being tested in clinical trials for other cancers. Its hypothesized mechanism of action involves disruption of tubulin dimers, mitotic spindles, and cell division by electric field-induced dipole alignment and dielectrophoresis ( 5 ). It has a modest effect on survival, increasing median overall survival by 0.6 month in recurrent GBM ( 3 ), and in newly diagnosed GBM by 31% ( 4 ). Even this modest effect is encouraging for patients.

It has been shown that electromagnetic fields (EMF) produce anticancer effects in vitro ( 6 , 7 ). We have conducted preclinical experiments with a new noninvasive wearable device known as an Oncomagnetic device that generates oscillating magnetic fields (OMF) by rotating strong permanent magnets ( 8 , 9 ). The OMF generating components (oncoscillators) of the device can be attached to a helmet and treatment with the device does not require shaving the head. Using the oncoscillators of the device and specially devised patterns of magnet rotations we have produced strong selective anticancer effects in patient derived GBM and xenografted mouse models without causing adverse effects on cultured normal cells and normal mice ( 10 – 12 ). The mechanism of action of OMF differs from Optune™ and involves disruption of the electron transport in the mitochondrial respiratory chain causing elevation of reactive oxygen species and caspase-dependent cancer cell death ( 10 – 12 ).

Here we report evidence of treatment response in the first patient to ever receive this therapy with an untreatable left frontal GBM, treated with a wearable Oncomagnetic device in an FDA-approved Expanded Access Program.

Case Description

The patient is a 53-year-old man who first presented with altered mental status in May 2018. Imaging studies documented a large tumor in the left frontal lobe extending across the midline into the right frontal lobe, with diffuse and extensive infiltration through the corpus callosum. There was mass effect and severe edema. He was taken to the operating room on June 4, 2018, where he underwent left frontal craniotomy and radical excision of the tumor. The tumor was histopathologically confirmed as GBM. At the time of the surgery, the excision extended across the midline into the right frontal lobe. He was enrolled in a herpes simplex virus-thymidine kinase gene therapy program and received viral injection during surgery per protocol. In addition, per protocol, and as standard of care, he received concomitant radiation therapy and chemotherapy with temozolomide.

In August 2019, the patient presented with an area of contrast enhancement on MRI scan along the left ventricle. At first this was thought to be a treatment effect. This area progressively enlarged. Evaluations done before OMF treatment initiation on January 16, March 3, and April 15, 2020, demonstrated a clear recurrence. The tumor abutted the ventricle and there was evidence of leptomeningeal spread. The patient had already had radiation therapy and chemotherapy and the tumor was now progressing. The presence of leptomeningeal disease portends poor outcome, with median survival of 3.5 to 3.9 months ( 13 ).

Because of inadequacy of any standard of care options he was enrolled in an FDA-approved Expanded Access Program (EAP) for compassionate use treatment with the Oncomagnetic device. He signed an informed consent on April 15, 2020. The EAP study was carried out under a protocol approved by the Houston Methodist Research Institute Institutional Review Board.

Oncomagnetic Device

The Oncomagnetic device consists of 3 oncoscillators securely attached to an acrylonitrile butadiene styrene helmet and connected to a microprocessor-based electronic controller operated by a rechargeable battery ( Figure 1 ). Further details regarding the device are given in the Supplementary Appendix . Based on a finite element model-based calculation of the spread of the field and the size and magnetization of the rotated diametrically magnetized neodymium magnets, we estimated that the combined effective field (at least 1 mT in strength) of the 3 oncoscillators covered the entire brain, including the upper part of the brain stem.

Figure 1 Oncomagnetic Device. (A) Device helmet with 3 oncoscillators securely attached to it. The oncoscillators are connected to a controller box powered by a rechargeable battery. (B) The patient wearing the device helmet with three oncoscillators attached.

Oscillating Magnetic Field Treatment

The treatment consists of intermittent application of an OMF that needs to be generated by rotating permanent magnets in a specific frequency profile and timing pattern to be effective. The patient received this treatment initially in the Peak Center clinic under the supervision of the treating physician and the Principal Investigator (DSB) of this study for the first 3 days. The dose was escalated over this period as follows. On the first day, the treatment was for 2 hours with a 5-min break between the first and the second hour. On the second and third days, it was increased to 2 and 3 2-hour sessions, respectively, with 1-hour breaks between the sessions. The patient’s spouse was trained in the use and care of the device on these days. After this initial supervised phase, the treatment was continued at home unsupervised with the same regimen as on the third day, above. The spouse was instructed to maintain a daily log of the conduct and progress of treatment, and any observed treatment and adverse effects.

Clinical Evaluations and Neuroimaging

The patient was evaluated clinically by the treating physician on each of the 3 days that he received treatment in the clinic and 7, 16, 30 and 44 days after initiation of treatment. Magnetic Resonance Imaging (MRI) scans were done on Days 1, 3, 7, 16, 30 and 44. The Day 1 scan was done before initiation of treatment. All other scans were done after treatment initiation. The treatment was paused on Day 37 because of an unfortunate but unrelated severe closed head injury (CHI). MRI scans were done on a Siemens Magnetom Terra 7T scanner. MRI scans included T1 magnetization prepared rapid gradient echo scans with and without gadolinium contrast, and T2-weighted Fluid-Attenuated Inversion Recovery (FLAIR), T2-weighted Turbo Spin Echo, Diffusion Weighted Imaging, Susceptibility Weighted Imaging, proton Magnetic Resonance spectroscopy and Diffusion Tensor Imaging scans. Treatment effect on contrast-enhanced tumor (CET) was evaluated according to the response assessment in neuro-oncology (RANO) criteria for clinical trials ( 14 ). In addition, an automated software-based method developed in house was used to objectively calculate the CET volume (see below and Supplementary Appendix ).

Data Analysis

Post-contrast T1 anatomical and T2-FLAIR MRI scans at each of the 6 time points were used to determine changes in contrast-enhanced tumor (CET) volume and non-enhanced tumor infiltration, respectively, before and after initiation of treatment. Information on image processing, data normalization and plotting are given in the Supplementary Appendix . Values obtained from pre-treatment clinical scans taken at 2 time points over 3 months before enrollment of the patient were also plotted on the same graph. Because this is a single patient case report, we could not perform any meaningful statistical analysis. However, to obtain a semi-quantitative assessment of the significance of the trend seen with treatment, we analyzed the changes in CET volume using Bayesian logic, given the observed increasing trend at two pre-treatment time points. Accordingly, we assumed that the chance of increase, decrease and no change in the rate of tumor growth was the same at each time point after treatment initiation to calculate the probability of a decrease at each post-treatment initiation time point.

The patient received OMF treatment with the Oncomagnetic device for 36 days. The treatment regimen was changed at various times during this period based on the caregiver reports and clinical findings, as described below.

Clinical Findings

After the initial 3 days of supervised treatment, the patient was seen again by the treating physician in the outpatient clinic on Day 7 from the start of treatment. Because of inattention at baseline, the patient was having difficulty with the length of treatment sessions. They were reduced to 2 hours/day Monday through Friday with Saturday and Sunday off. The Day 16 clinical examination revealed that he was tolerating the treatment sessions well, so they were increased to a total of 3 hours/day (in one-hour increments with 5 min breaks) Monday through Friday and the weekends off. On Day 30 visit, the patient reported headaches related to transient hypertension for which he was taking medication. The treating physician increased blood pressure medication (Valsartan) with improvement. The treatment was paused on Day 36 because of a closed head injury from a fall. Whether the fall was related to the treatment in any way is uncertain. It is worth noting, however, that the patient had experienced several falls before initiation of treatment. At the last follow-up on Day 44 the patient was admitted to the inpatient unit for evaluation of closed head injury and underwent detailed assessment. There were no serious adverse events reported during treatment. The patient’s caregivers reported subjective improvement in speech and cognitive function.

MRI Findings

Evaluation of the T1 post-contrast clinical MRI scans obtained before initiation of treatment showed progression in accordance with the RANO criteria ( Figure 2A ). All scans acquired during treatment showed stable disease, according to these criteria ( Figure 2A ). To obtain an objective quantitative assessment of the CET volume we used an automated MATLAB software-based script. This analysis showed marked changes in CET volume with treatment. Figure 2B shows a plot of the CET volume as a function of time before and after initiation of treatment. It reveals that there was substantial growth of the tumor volume over the 3 months before the treatment. Within the first 3 days of treatment the trend is reversed with the volume steeply decreasing by ~10% on Day 7 and then less steeply by 31% on Day 30. Based on a Bayesian-type assessment of the probability of a decrease in CET volume at each post-treatment initiation time point, the decrease at Day 30 is statistically significant at P = 0.036. The treatment was paused on Day 37. After the pause we see another trend reversal and an increase in CET volume on Day 44.

Figure 2 Change in Contrast-Enhanced Tumor Volume. (A) T1-weighted axial post-contrast scans showing the contrast-enhanced tumor (CET) highlighted with an overlayed automated computer program-generated light-yellow mask at different time points (B) Left – A graph showing the change in CET volume over time. The treatment times and durations are shown as red bars and light-yellow highlights. The long pause in treatment is shown as a light-blue highlight. Right – T1-weighted axial post-contrast scans showing CET at two levels along the dorso-ventral axis at Day 1 before treatment and Day 30 of treatment.

The T2-FLAIR data in Figure 3A show changes in enhanced intensity volume of 1 – 11% over time. The decreases in volume are greater after a 3-day pause in treatment on Day 7 and after an 8-day pause on Day 44. These decreases are likely due to reduction in treatment-related cerebral edema and/or reduction in non-contrast enhancing tumor infiltration. The patient died ~3 months after cessation of treatment from the CHI. A brain only autopsy showed a resection cavity in the left frontal lobe (6.0 x 5.0 x 3.5 cm) and recurrent/residual glioblastoma with associated treatment effect (see Figures 3B–E ). Residual/recurrent high-grade glioma was present, including foci of densely cellular tumor, focal microvascular proliferation, and necrosis ( Figure 3C ). In addition, there was prominent treatment effect with pallor and rarefaction of white matter ( Figure 3D ), reactive astrocytosis, infarct-like necrosis ( Figure 3E ) and bizarre nuclear atypia within residual tumor cells. Additional features of treatment effect included dystrophic calcifications ( Figure 3E ).

Figure 3 Variation in Enhanced Intensity Volumes in T2-FLAIR MRI Scans and Autopsy Findings. (A) Top – Bar plots of the volumes of T2-FLAIR intensity enhancement in the whole brain at different time points. Overall, there was up to 11% decrease in T2 FLAIR volume over the course of treatment. Bottom – Representative T2-FLAIR images are shown. (B) Left hemisphere of the brain, examined grossly, showing no tumor mass. (C) Photomicrographs of the left cortex showing bland necrosis, residual tumor, and microvascular proliferation with thick-walled vessels. (D) Top left – Microscopic field of the left cingulate cortex showing a focus of rarefied, perivascular inflammation. Bottom left – Cortical field showing rarefied parenchyma and residual tumor cells, enlarged with treatment-type effect that can be seen in GBM. Top right – Micrographic field of the corpus callosum showing thinned, rarefied white matter tract. Bottom right – Field showing relatively uninvolved contralateral (right) cortex. (E) Top – Micrographic field in the left cortex showing infarct-like necrosis (left), tumor (right), and fibrin thrombus (lower right). Bottom – Left cortical field showing necrotic tissue with dystrophic calcification.

The findings of this study indicate that Oncomagnetic device-based OMF therapy is well tolerated by a patient who has end-stage recurrent GBM with leptomeningeal involvement and has no other available effective treatment options. They also demonstrate a clinically significant reduction in CET volume with reductions in non-enhanced tumor volume and/or edema in T2-FLAIR scans. The temporal profile of changes in CET volume also suggests a correlation with the treatment dose and the presence or absence of treatment. When the treatment dose was higher (6 hours/day for 4 days) we see a tumor volume reduction rate of 2.32 cm 3 /day. When it was lower (2 hours/day for 9 days and 3 hours/day for 18 days) the reduction is 1.03 cm 3 /day. Moreover, when the treatment was paused for 8 days the decreasing trend reversed and the CET volume increased, instead. Assuming that the ~1.03 cm 3 /day decreasing trend had continued until the treatment was paused, we can estimate that the CET volume grew at the rate of 1.26 cm 3 /day during the pause. Despite the apparent correlation it is possible that the treatment response is independent of the short-term changes in the treatment dose.

To our knowledge, there is no report in the literature of a noninvasive treatment-related shrinkage of CET volume of GBM at a rate comparable to that seen in this study. One published report on Optune™ therapy has reported that the time course of change in tumor volume in MRI scans shows a ~15% reduction over ~3 months ( 15 ). Besides Optune™, the other type of treatment approved by the FDA and recommended as a standard in National Comprehensive Cancer Network guidelines for recurrent GBM is the anti-vascular endothelial growth factor (VEGF) monoclonal antibody, Bevacizumab ( 16 , 17 ). Bevacizumab treatment response of reduction in tumor volume on MRI scans has been reported to be lower than is observed in the present study ( 18 ). Furthermore, while anti-VEGF drugs in general have mild toxicity profiles and two Phase II trials have shown anti-tumor efficacy ( 19 , 20 ), a subsequent Phase III trial did not show a significant increase in overall survival ( 21 – 23 ).

Noninvasive Oncomagnetic device based OMF therapy appears to be a safe and efficacious new modality of treatment against GBM that potentially has many advantages over existing treatments. The present report has the limitation of the treatment being conducted in only a single patient so far. Extending it to more patients in research studies would provide additional information regarding safety and efficacy.

Data Availability Statement

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

Ethics Statement

The studies involving human participants were reviewed and approved by Houston Methodist Research Institute Institutional Review Board. The patient/participant provided their written informed consent to participate in this study. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.

Author Contributions

SH and DB designed the study and drafted the manuscript. SH designed the device used in the study, supervised its construction and testing and quantitively analyzed the imaging data. DB provided medical care to the study subject, supervised the delivery of device treatment, and conducted his clinical assessments. SH, MS, and DB designed the device treatment protocol and interpreted the findings. LN constructed and tested the device and provided device treatment to the study subject. All authors contributed to the article and approved the submitted version.

This work was supported by a grant from the Translational Research Initiative of the Houston Methodist Research Institute to SH and DB, and by Donna and Kenneth Peak, the Kenneth R. Peak Foundation, the John S. Dunn Foundation, the Taub Foundation, the Blanche Green Fund of the Pauline Sterne Wolff Memorial Foundation, the Kelly Kicking Cancer Foundation, the Gary and Marlee Swarz Foundation, the Methodist Hospital Foundation, and the Veralan Foundation. The John S. Dunn Foundation also supports the Distinguished Professorship of MS.

Conflict of Interest

SH, MS, and DB are listed as inventors on a U.S. patent application filed by Houston Methodist Hospital for the device used in this report.

The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

The authors thank the patient for graciously volunteering to be a research subject in this study and the rest of his family for supporting him. We appreciate the assistance of Dr. Matthew Cykowski, MD, Department of Pathology and Genomic Medicine, who provided pathologic description and images. We thank Blessy S. John and Alvin Saldon for aiding in device construction.

Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.708017/full#supplementary-material

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7. Jimenez H, Blackman C, Lesser G, Debinski W, Chan M, Sharma S, et al. Use of non-Ionizing Electromagnetic Fields for the Treatment of Cancer. Front Biosci (Landmark Ed) (2018) 23:284–97. doi: 10.2741/4591

8. Helekar SA, Convento S, Nguyen L, John BS, Patel A, Yau JM, et al. The Strength and Spread of the Electric Field Induced by Transcranial Rotating Permanent Magnet Stimulation in Comparison With Conventional Transcranial Magnetic Stimulation. J Neurosci Methods (2018) 309:153–60. doi: 10.1016/j.jneumeth.2018.09.002

9. Helekar SA, Voss HU. Transcranial Brain Stimulation With Rapidly Spinning High-Field Permanent Magnets. IEEE Access (2016) 4:2520–8. doi: 10.1109/ACCESS.2016.2568739

10. Helekar S, Sharpe M, Pichumani K, Ijare O, Nguyen L, Baskin D. CTNI-48. Novel Treatment of End Stage Recurrent Glioblastoma Treated With a Noninvasive Oncomagnetic Device Using Oscillating Magnetic Fields – a New and Powerful Noninvasive Therapy. Neuro-Oncol (2020) 22:ii53–3. doi: 10.1093/neuonc/noaa215.214

11. Helekar S, Hambarde S, Baskin D, Sharpe M. EXTH-13. Potent Anticancer Effects of a New Wearable Noninvasive Oncomagnetic Device: Cellular Mechanisms of Action. Neuro-Oncol (2020) 22:ii89–9. doi: 10.1093/neuonc/noaa215.367

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13. Andersen BM, Miranda C, Hatzoglou V, DeAngelis LM, Miller AM. Leptomeningeal Metastases in Glioma: The Memorial Sloan Kettering Cancer Center Experience. Neurology (2019) 92:e2483–91. doi: 10.1212/WNL.0000000000007529

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16. Kreisl TN, Zhang W, Odia Y, Shih JH, Butman JA, Hammoud D, et al. A Phase II Trial of Single-Agent Bevacizumab in Patients With Recurrent Anaplastic Glioma. Neuro Oncol (2011) 13:1143–50. doi: 10.1093/neuonc/nor091

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18. Daniels D, Guez D, Last D, Hoffmann C, Nass D, Talianski A, et al. Early Biomarkers From Conventional and Delayed-Contrast Mri to Predict the Response to Bevacizumab in Recurrent High-Grade Gliomas. AJNR Am J Neuroradiol (2016) 37:2003–9. doi: 10.3174/ajnr.A4866

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Keywords: magnetic resonance imaging, contrast enhanced tumor, compassionate use treatment, radiation-type tumor necrosis 2, oscillating magnetic fields

Citation: Baskin DS, Sharpe MA, Nguyen L and Helekar SA (2021) Case Report: End-Stage Recurrent Glioblastoma Treated With a New Noninvasive Non-Contact Oncomagnetic Device. Front. Oncol. 11:708017. doi: 10.3389/fonc.2021.708017

Received: 11 May 2021; Accepted: 21 June 2021; Published: 22 July 2021.

Reviewed by:

Copyright © 2021 Baskin, Sharpe, Nguyen and Helekar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: David S. Baskin, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Clinical Presentation

Statement of ethics, disclosure statement, a 58-year-old woman with left-sided weakness and a history of a pediatric brain tumor: a case report.

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Shaakir Hasan , Michael J. Gigliotti , Melvin Deutsch , Stacey L. Reed , Rodney E. Wegner; A 58-Year-Old Woman with Left-Sided Weakness and a History of a Pediatric Brain Tumor: A Case Report. Case Rep Oncol 7 May 2018; 11 (1): 131–137. https://doi.org/10.1159/000487430

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Background: An uncommon but well-established complication of cranial irradiation is secondary neoplasm. This case presentation documents a radiation-induced malignant glioma 55 years after being diagnosed with “cerebral sarcoma,” now defined as atypical meningioma. This not only represents the longest reported latency period for a patient initially receiving over 30 Gy, but also provides a valuable historical perspective of neuro-oncology. Clinical Presentation: A 58-year-old female presenting with progressive left-sided upper and lower extremity weakness with a past medical history significant for “cerebral sarcoma” was diagnosed with glioblastoma multiforme. This patient had previously been treated with resection and adjuvant radiation therapy via a 280-kVP orthovoltage machine and received 3,390 rad to the posterior three-quarters of the skull for “cerebral sarcoma.” Conclusion: A comprehensive investigation of the past medical history helped uncover a mysterious pediatric diagnosis, helped drive the management 5 decades later, and serves as a reminder that seemingly safe interventions may still cause harm.

“Cerebral sarcoma” was defined in the literature as a neoplasm of the meninges prior to 1979, when the World Health Organization classified several subtypes of typical (grade I), atypical (grade II), and anaplastic (grade III) meningioma [ 1 ]. Given long-term toxicity risks, the utilization of radiotherapy in meningiomas remains controversial while postoperative radiotherapy is no longer indicated in pediatric populations [ 2 ].

This is largely because an uncommon but well-established complication of cranial irradiation is a secondary neoplasm [ 3, 4 ]. Notably, 1.3% of glioblastoma cases are associated with a previous exposure to radiation, with a median latency period of 9 years [ 5, 6 ]. Some studies suggest that doses greater than 30 Gy puts the patient at higher risk for malignancy compared to lower doses (less than 18 Gy), although others suggest that there is no threshold dose [ 3, 5 ].

We present the case of a radiation-induced glioblastoma multiforme (GBM) in a 58-year-old female who was treated for a “cerebral sarcoma” 55 years earlier, for which the original records were obtained.

Past Medical History

An otherwise healthy 58-year-old female revealed that in 1962 as a 3-year-old child she had been treated for a “cerebral sarcoma” with surgery and radiation. At the time, she presented with a headache and was diagnosed with an intracranial tumor via a ventriculogram. Excision of the lesion was described as “completely or nearly completely resected,” and per the pathology report was described as a “cerebral sarcoma or meningiosarcoma.” Adjuvant radiotherapy was requested by the neurosurgeon and the administering radiologist reluctantly agreed, noting that “meningiomas are not ordinarily treated with radiotherapy although some may respond, and sarcomas are certainly not radioresponsive. However, careful radiation therapy cannot do any harm and probably may do some good” (Fig.  1 ).

Assessment and plan of the treating radiologist from 1962.

The patient was treated with a 280-kVP orthovoltage machine with 2 lateral fields, prescribed to 14 cm depth on the right and 6 cm depth on the left. She ultimately received 3,390 of a planned 4,000 rad for 39 days in 1962 to the posterior three-fourths of the entire skull. Treatment was discontinued due to an intensely erythematous scalp, although no other toxicities or neurologic deficits were noted.

Examination

The patient presented with a 1-week history of progressively worsening left-sided upper and lower extremity weakness, described as an inability to hold objects in her left hand and frequent falls secondary to a left foot drop. The weakness eventually culminated in an episode where the patient fell out of bed and could not get up. Physical examination demonstrated stable vital signs, diffuse 3/5 strength in the left upper and lower extremities, and a right frontal craniotomy scar with surrounding soft tissue fibrosis (Karnofsky performance status 70).

Pathological Findings

A contrast-enhanced brain MRI demonstrated a 3 × 3 cm right frontoparietal resection cavity surrounded by a 5 × 4 cm area of heterogeneous contrast enhancement extending to the right corona radiata and periventricular white matter with associated cerebral edema (Fig.  2 ). The mass was not technically resectable due to location and biopsy was consistent with GBM, wild-type isocitrate dehydrogenase and unmethylated O 6 -methylguanine DNA methyltransferase (MGMT), with an MIB-1 index of 50% (Fig.  3 ).

T1-weighted brain MRI with contrast at the time of diagnosis of radiation-induced glioblastoma multiforme.

Radiation-induced glioblastoma multiforme demonstrating increased cellularity with marked nuclear atypia, necrosis, and vascular endothelialization.

It was determined that further maximal safe resection would not provide a beneficial therapeutic value, therefore definitive full-dose chemoradiation was recommended. Citing a declining performance status and discontent with the role radiation played in causing her malignancy, the patient ultimately declined treatment. Since identifying information was not used in the context of this case, informed consent for this case presentation was not required.

“Meningiosarcoma” or “cerebral sarcoma” are no longer considered histopathological diagnoses, but our patient likely had a variant of meningioma, which would have an approximately 90% chance of local control in such a scenario [ 7 ]. To this day, the role of radiotherapy in the management of typical and atypical meningiomas remains controversial, although several treatment paradigms have been established since the patient originally presented in 1962 [ 8 ]. For instance, there is virtually no indication for postoperative radiotherapy for meningioma in the pediatric population given the long-term toxicity risks [ 2 ]. As was the case for most radiation therapy in that era, the dose was limited by developing erythema of the scalp, an acute toxicity of little consequence, unlike the late and at that time unknown effect of secondary malignancy.

Cahan et al. [ 9 ] defined parameters of radiation-induced malignant gliomas (RIGMs) as follows: tumors localizing to where radiotherapy was applied, an adequate latency period measured in years, a histology different than that of the original tumor, and the patient should not have an underlying pathology favoring the growth of tumors. In this case, all four parameters were met. Although 80% of patients have a typical latency period within 15 years prior to the development of a secondary malignancy, the longest reported latency period includes a female who was treated for tinea capitis, presumably at a small dose, 61 years preceding the onset of a secondary malignancy [ 5, 10 ]. Prior to this case, the longest latency period between exposure of at least 30 Gy and induction of high-grade glioma was 37 years [ 11 ].

Histologically, radiation-induced GBMs are no different than de novo GBMs; however, there have been conflicting reports of whether RIMGs have greater homogeneity of gene expression [ 3, 12, 13 ]. With a median survival of 11 months, the prognosis for radiation-induced glioblastomas is comparable to that of GBMs with the unmethylated MGMT promoter gene, suggesting that perhaps they are associated with less favorable tumor biology [ 14, 15 ]. It should be noted that the vast majority of reported RIMGs were published before MGMT status testing became commonplace and before adjuvant temozolamide was established as the standard of care [ 16 ]. However, the median survival of RIMGs since 2007 was still 11.5 months [ 5 ].

The ideal management for de novo or secondary GBM in a medically fit patient includes gross total resection followed by adjuvant chemoradiation at a total dose of 6,000 cGy in 30 fractions with concurrent and adjuvant temozolomide [ 16 ]. The risk of neurotoxicity such as brain necrosis theoretically increases in the setting of reirradiation, which may be why only approximately 40% of patients with radiation-induced GBMs received reirradiation as part of their treatment [ 15 ]. Nevertheless, the risk of radionecrosis is minimal with reirradiation to the brain so long as the cumulative dose is less than 100 Gy at 2 Gy per fraction [ 17-19 ]. Furthermore, Paulino et al. [ 15 ] demonstrated that among 85 cases of RIMGs, the 35 patients who underwent reirradiation at a median dose of 50 Gy (range 30–76 Gy) had a median survival of 13 months compared to 8 months of those who were not reirradiated, without additional toxicity. It should be mentioned that potential long-term toxicity of reirradiation to the brain may not have been observed because most patients do not survive long enough to develop it.

This case illustrates how past medical history, going back even 50 years, is instrumental to workup and management. Two uncommon and valuable pieces of information include the patient’s knowledge of her pathology as a 3-year-old and medical records dating back to 1962, both of which helped determine the diagnosis and treatment. The medical records also provide a rare window as to how medicine was practiced 5 decades ago and how it has evolved since then. Importantly, they serve as a humble reminder that there are many aspects of medicine still unknown to clinicians, including the possibility that a seemingly safe therapeutic intervention can still cause harm.

We ensure the accuracy, quality, and integrity of this case report. No identifying patient information was disclosed.

The authors of this paper would like to disclose that they have no financial or other conflicts of interest in relation to this case study and publication.

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Progress to Advance Care, Treatments, and Outcomes for Brain Tumor Patients

April 25, 2022 , by Brittany Cordeiro, NCI-CONNECT Program Manager

Neuro-Oncologist Dr. Jing Wu reviews brain tumor scans

Read about our advances in care, treatments, and patient outcomes for brain and other central nervous systems tumors in honor of Brain Tumor Awareness Month. 

An estimated 700,000 people in the United States are living with a brain tumor. Over 25,000 more will be diagnosed with a cancerous brain or other central nervous system (CNS) tumor this year. The causes are not known. And, while males are slightly more likely to develop brain cancer than females, brain tumors do not discriminate.

In May, the brain tumor community joins together to raise awareness about brain tumors through education. By sharing the rarity and uniqueness of brain and other CNS tumors— 1.3 percent of all new cancers cases and over 130 different types—we can inspire research and clinical studies to improve diagnosis and standardize care.

We also hope to champion progress by sharing the work that NCI-CONNECT and the NCI Center for Cancer Research's Neuro-Oncology Branch (NOB) have completed over the last year to advance care, treatments, and patient outcomes.

Investigating New Therapies and Methods to Improve Outcomes

Nci-connect clinical studies expansion.

In 2021, NCI-CONNECT expanded two clinical studies—an immunotherapy drug trial and a tumor tissue repository study—to its national network of collaborative institutions to reach more people with rare brain and spine tumors and help researchers advance their knowledge of the diseases faster.

The first-of-its-kind immunotherapy drug trial is designed to test whether stimulating the immune system using nivolumab is effective and can shrink (or control the growth or spread of) specific types of recurrent rare brain and spine tumors. The trial first launched in 2017 at the NOB. Now, the trial is being led by NOB Associate Research Physician Marta Penas-Prado, M.D. It is also testing the changes that nivolumab induces in immune cells in peripheral blood during treatment—and whether nivolumab can improve the symptoms of people with these tumors.

The new multi-institutional Tissue Outcomes Study collects tumor tissue and comprehensive clinical data from deceased patients with rare brain and spine tumors, and people who were pregnant at diagnosis (or became pregnant after diagnosis). The study is breaking silos by working across the NCI-CONNECT national network. It is led by Dr. Penas-Prado.

NCI-CONNECT First-in-Human Study

In other firsts, NCI-CONNECT launched a first-in-human phase 1 clinical trial for people with recurrent rare brain and spine tumors. Led by Brett Theeler, M.D., neurologist and neuro-oncologist in the United States Army Medical Corps and NCI-CONNECT clinical collaborator, the trial is studying ONC206, an oral cancer therapy. The trial tests the dosing and safety in adult patients.

NOB Immunotherapy and Glioblastoma Trial

Glioblastoma is the most common type of primary brain cancer. People with this disease or a variant called gliosarcoma have poor long-term outcomes. NOB Chief and NCI-CONNECT Co-Leader Mark Gilbert, M.D., is leading a new clinical trial testing an immunotherapy treatment to slow or stop the spread of cancer cells in people with glioblastoma and gliosarcoma. The trial will also evaluate a test that may help determine who is likely to get an immune response.

We designed the study based on quality science and built-in cutting-edge techniques. The study results should be a very important contribution to the field.

Mark Gilbert, M.D., NOB Chief and NCI-CONNECT Co-Leader

Outcomes Intervention Studies

Under the leadership of NOB Deputy Chief and NCI-CONNECT Co-Leader Terri Armstrong, Ph.D., NCI-CONNECT also launched three studies in 2021 to measure if an intervention helps improve outcomes. Led by Amanda King, Ph.D., an iCURE postdoctoral fellow in the Patient Outcomes Program, a virtual reality study for patients with brain cancer investigates if using a virtual reality headset to deliver relaxation techniques helps to reduce the distress and anxiety that people experience ahead of their magnetic resonance imaging (MRI) scans and clinical appointments.  

Led by assistant investigator Dorela Shuboni-Mulligan, Ph.D., CRTA postdoctoral fellow in the Patient Outcomes Program, a sleep observation study measures daytime sleepiness and activity patterns using a smart wearable device. This will provide insight into the impact of sleep disturbance on those with brain cancers. 

Led by assistant investigator Alvina Acquaye, psychosocial behavioral specialist for NCI-CONNECT, the CALM therapy intervention study uses individualized therapy to address negative feelings and improve a person’s mood and the way they feel. This study will determine if using the CALM intervention helps to reduce depressive symptoms in people with brain cancer.

Bringing the Community Together to Advance Science and Patient Care

Virtual educational webinars were held to join experts across disciplines with advocates—and provide forums for thoughtful discussion about challenges and solutions.

Targeting CNS Tumor Metabolism

To advance the field of CNS tumor metabolism, NOB Investigator Mioara Larion, Ph.D., and Dr. Gilbert co-led a virtual symposium with the Society for Neuro-Oncology (SNO) on April 6-7, 2021. It was the first conference entirely dedicated to education and research on brain tumor metabolism . Over 500 people registered to attend. The conference brought together clinicians, researchers, trainees, patients, and experts in the field of metabolism. 

Survivorship Care in Neuro-Oncology Symposium

NOB Assistant Research Physician Heather Leeper, M.D., and Dr. Armstrong co-led the Survivorship Care in Neuro-Oncology Symposium on June 21-22, 2021. The symposium brought together neuro-oncology providers, researchers, advocates, patients, and care partners virtually to learn, discuss the challenges experienced by people living with brain and spine tumors, and develop survivorship care guidelines. Over 250 people attended the symposium.

Introduction to Career Pathways in Neuro-Oncology

On January 11, 2022, the NOB partnered with SNO to offer trainees of all disciplines the opportunity to learn about neuro-oncology careers in basic science, clinical care, and research. The free virtual event offered insights, opportunities, and strategies shared by world-renowned neuro-oncology professionals to expand a neuro-oncology career. There was also a post-session panel discussion for attendees to share their thoughts with experts.

NIH Tumor Boards and Journal Clubs

To encourage referrals and further collaboration, in 2020 we expanded our virtual journal club and weekly multidisciplinary NIH Neuro-Oncology Tumor Board live sessions to include investigators and cases from participating NCI-CONNECT consortium sites. As of November 2021, 28 providers had presented 41 cases at 24 tumor board meetings with 60 to 70 participants.

Awarding and Recognizing Pioneering Work

National research awards.

In 2021, Lasker Clinical Research Scholar and NOB Investigator Jing Wu, M.D., Ph.D., was accepted into the NExT (NCI Experimental Therapeutics) Program , which provides resources for projects focused on developing therapies for unmet needs. Dr. Wu leads the NOB Translational Research Program, which is dedicated to developing clinical trials for people living with brain and spine tumors. Her work combines both clinical and laboratory research and is making a difference in the field. 

Dr. Penas-Prado received an Award for Excellence in Rare CNS Disease at the 2021 SNO Annual Meeting for her abstract on the interim analysis of the immune checkpoint inhibitor nivolumab for people with rare CNS cancers trial. As of March 10, 2021, the interim analysis of the clinical trial determined that the disease control rate exceeded the minimum required to pass the interim analysis in the heavily pretreated cohort and continue the trial. 

Ultimately, this multicenter study should advance our understanding of these tumors, set the foundation for future trials, and provide better treatment options.

Marta Penas-Prado, M.D., NOB Associate Research Physician

Dr. Penas-Prado also received the 2022 Center for Cancer Research Staff Clinician Leadership Merit Award for leading our rare CNS tumor clinic and clinical trials, a national tumor board, and an international symposium. 

Dr. Leeper received an Award for Excellence in Survivorship at the 2021 SNO Annual Meeting for her abstract with the NOB Patient Outcomes Program on whether economic strain and mood disturbance during the COVID-19 pandemic may have additional impacts on patients’ symptoms and function. Dr. Leeper concluded that worse financial toxicity scores were strongly associated with worse overall symptom burden, worse anxiety and depression scores, and worse overall health-related quality of life scores. 

Trainee and Mentor Awards

Postbaccalaureate Research Fellow Yeonju Kim was selected as the Outstanding Post-Graduate Trainee at the 22nd Annual Center for Cancer Research Fellows and Young Investigators Colloquium, where she gave an oral presentation. Kim is mentored by NOB Staff Scientist Orieta Celiku, Ph.D., Dr. Gilbert, and Dr. Armstrong. Her colloquium abstract was titled, "ACROSS: Accrual and Access to Neuro-Oncology trials in the United States. "

Dr. Celiku received the 2022 NCI Staff Scientists and Staff Clinicians Outstanding Mentor Award for her exemplary mentorship in developing the next generation of cancer researchers.  

Sharing Progress to Raise Awareness

The NOB and NCI-CONNECT published over 80 abstracts that were presented at national meetings, one journal supplement, and 10 manuscripts. Our work modified two National Comprehensive Cancer Network (NCCN) guidelines for rare CNS tumors in 2020 and 2021. Our progress is made possible by the participation of patients and their care partners in our programs.

To continue our efforts in brain and spine tumor care, treatment, and research—and to improve survival and quality of life for people living with the disease—we encourage you to join us for Brain Tumor Awareness Month in May and share these advances. Educating those living with (or not yet diagnosed with) a brain or spine tumor can make an impact.

A case study of a long-term glioblastoma survivor with unmethylated MGMT and hypermutated genotype

Affiliations.

• 1 Cure Brain Cancer Biomarkers and Translational Research Group, Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
• 2 Neurospine Clinic, Prince of Wales Hospital, Randwick, New South Wales 2031, Australia.
• 3 University of New South Wales, Sydney, New South Wales 2031, Australia.
• 4 Department of Medical Oncology, Nelune Comprehensive Cancer Centre, Prince of Wales, Hospital, Randwick, New South Wales 2031, Australia.
• PMID: 31160353
• PMCID: PMC6549560
• DOI: 10.1101/mcs.a003251

Effective treatments that extend survival of malignant brain tumor glioblastoma (GBM) have not changed in more than a decade; however, there exists a minority patient group (<5%) whose survival is longer than 3 yr. We herein present a case report of a long-term surviving 51-yr-old female diagnosed with a MGMT unmethylated GBM. The patient was progression-free for 23 mo. Fresh primary and recurrent tumor samples were collected and processed for patient-derived model development. Whole-genome sequencing (WGS) was performed concurrently with additional standard of care diagnostics. WGS revealed a hypermutated genotype in the germline tissue and in both the primary and recurrent tumor samples. Specific to the matched tumors, an average of 30 cancer driver genes were mutated. Noteworthy was the identification of a nonsynonymous mutation in the POLE gene. As a possible instigator of the hypermutational genotype observed in the tumors, we identified nonsynonymous germline mutations within the mismatch repair genes, MLH1 and PMS2 Mutations within these genes are often indicative of the pan-cancer phenotype known as Lynch syndrome; however, their pathogenicity remains unreported. We performed a drug screen of 165 compounds, which identified one compound, YM155, an experimental survivin inhibitor, that showed effectivity to the patient-derived cell lines of both tumors. Treatment selection based on a patient's genome to individualize treatment for GBM patients could potentially be useful in the clinic. This is a promising avenue for further translational research, with larger databases and integrated platforms to increase the efficiency of analyzing and interpreting the individual genomic data of GBM.

Keywords: glioblastoma; glioma.

© 2019 Jue et al.; Published by Cold Spring Harbor Laboratory Press.

Publication types

• Case Reports
• Research Support, Non-U.S. Gov't
• Brain Neoplasms / diagnostic imaging
• Brain Neoplasms / drug therapy
• Brain Neoplasms / genetics*
• DNA Mismatch Repair / genetics
• Drug Screening Assays, Antitumor
• Gene Regulatory Networks
• Germ-Line Mutation
• Glioblastoma / diagnostic imaging
• Glioblastoma / drug therapy
• Glioblastoma / genetics*
• Imidazoles / pharmacology*
• Middle Aged
• Naphthoquinones / pharmacology*
• Neoplasm Recurrence, Local
• Whole Genome Sequencing
• Naphthoquinones
• sepantronium

Brain Tumor and Neuro-Oncology Research

Innovations in brain tumor and neuro-oncology.

• Laser Interstitial Thermotherapy with real-time MRI using the Monteris AutoLitt System
• Brain mapping with functional MRI (fMRI), Diffusion Tensor Imaging (DTI) and/or magnetoencephalography (MEG) to optimize identification of brain tumors and surrounding normal tissues
• Intraoperative MRI to maximize safety and completeness of tumor removal
• New techniques for optical and fluorescence imaging to better identify infiltrating tumor
• Convection Enhanced Delivery (CED): A technology to improve delivery of small anti-tumor molecules and chemotherapy to brain tumors
• Stereotactic Radiosurgery using Gamma Knife or CyberKnife®

Current Clinical Trials

UH provides both standard and advanced nonoperative treatments for patients with brain tumors through our advanced and extensive clinical trials. Many of these are offered in collaboration with the NCI-funded Adult Brain Tumor Consortium (ABTC), a group of 15 elite “Brain Tumor Centers of Excellence” which collaborate to offer the most innovative treatments to patients with brain tumors. Clinical trial offers change frequently, but current offers include:

• Tumor vaccines (immunotherapy) to teach the patient’s own immune system to fight their tumor
• New drugs specifically targeting brain tumor “stem cells” which are resistant to current therapies
• Gene therapy for brain tumors
• New agents targeting “angio-genesis,” the need for tumors to acquire a new blood supply
• Convection Enhanced Deliver (CED). New ways to deliver drugs and immunotoxins specifically to the tumor while avoiding toxicity from the normal brain.
• Innovative combinations of chemotherapeutic agents which are more powerful together than apart

Specific trials include:

• ABTC 0603 – A Phase I/II Trial of Hydroxychloroquine in conjunction with Radiation therapy and concurrent and Adjuvant Temozolomide in Patients with Newly diagnosed Glioblastoma Multiforme (Version 01/08/09)
• ABTC 0703 – Phase I/II study of the poly (ADP-ribose) polymerase-1(PARP-1) inhibitor BSI-201 in patients with newly diagnosed malignant glioma (version 02/06/09)
• ABTC 0904 – A Biomarker and Phase II Study of GDC-0449 in Patients with Recurrent Glioblastoma Multiforme
• ABTC 0901 – An Open Label, Phase 2 Study Evaluating the Safety and Efficacy of IMC-3G3 or IMC-1121B in Patients with Recurrent Glioblastoma Multiforme

How Common Is a Brain Tumor

Have you ever wondered how common brain tumors are? A brain tumor is an abnormal growth of cells within the brain or surrounding areas, and these growths can be either benign (non-cancerous) or malignant (cancerous). 

Brain tumors are rare, and less than 1 percent of the population is diagnosed with a malignant brain tumor during their lifetime.

Our aim is to provide comprehensive research on brain tumors, their prevalence, development factors, and the crucial role of early detection and treatment. Let’s take a closer look at brain tumors and their commonality.

Understanding Brain Tumors

A brain tumor is an abnormal growth of cells within the brain or the central spinal canal. It can originate in the brain itself (primary tumors) or spread from other parts of the body (secondary or metastatic tumors). Brain tumors can vary in their growth rates and potential to cause harm.

Types of Brain Tumors

Brain tumors are generally classified into two main categories: benign and malignant.

• Benign tumors : These non-cancerous growths typically grow slowly and do not spread to other body parts. While they can still cause significant health issues by pressing on sensitive brain areas, they are generally less aggressive than malignant tumors.
• Malignant tumors : These are cancerous growths that tend to grow rapidly and invade nearby tissues. Malignant brain tumors can be life-threatening and often require aggressive treatment.

Some common types of brain tumors include gliomas , meningiomas, pituitary adenomas, and schwannomas. Each type has unique characteristics and treatment options.

Symptoms and Diagnosis

The symptoms of brain tumors can vary widely depending on the tumor's size, type, and location within the brain. Common symptoms include headaches, seizures, vision or hearing changes, balance or coordination changes, and cognitive or personality changes.

Diagnosis typically involves a combination of neurological exams, imaging studies (like MRI or CT scans), and biopsy procedures to determine the tumor type and guide treatment planning.

Statistical Overview

With statistics, researchers and healthcare professionals can better understand the scope of the brain tumor challenge and work towards more effective solutions for patients across the globe. Let’s take a look at some statistical trends involving brain tumors: 

How Common Are Brain Tumors Globally?

Brain tumors are quite rare when compared to other types of cancer. Globally, the incidence rate of brain and other central nervous system (CNS) tumors is approximately 6.2 per 100,000 people per year. This figure represents both malignant and benign tumors.

Prevalence Rates in Different Age Groups

The prevalence of brain tumors varies across different age groups. In children, brain tumors are the second most common type of cancer after leukemia. For adults, the risk of developing a brain tumor increases with age, with the highest incidence rates observed in individuals over the age of 65. 

Gender Differences in Brain Tumor Occurrence

Gender also plays a role in the prevalence of brain tumors. Studies indicate that men are generally more likely to develop brain tumors compared to women. However, certain types of brain tumors, such as meningiomas, are more frequently diagnosed in women. 

Brain Tumors in Children vs Adults

Brain tumors are the second most common type of cancer in children, following leukemia. Approximately 20% of all childhood cancers are brain tumors, with around 4,000 new cases diagnosed annually in the United States alone. The most common types of brain tumors in children include medulloblastomas, gliomas, and ependymomas. These tumors can significantly impact a child's development and quality of life, making early diagnosis and treatment essential​ 

Common Types of Brain Tumors in Children

• Medulloblastomas : These are the most common malignant brain tumors in children and typically show up in the cerebellum. They can spread to other parts of the brain and spinal cord.
• Gliomas : These include a variety of tumors such as astrocytomas and glioblastomas, which can range from low-grade (slow-growing) to high-grade (fast-growing and more aggressive).
• Ependymomas : These tumors develop from the ependymal cells lining the ventricles of the brain and the center of the spinal cord. They can happen at any age but are more common in children.

Comparison with Adult Brain Tumor Statistics

Adults with brain tumors account for about 1.4% of all cancers. The incidence of brain tumors increases with age, and the types of tumors commonly seen in adults differ from those in children. 

For example, glioblastomas are the most common type of malignant brain tumor in adults, while meningiomas, which are typically benign, are also frequently diagnosed. The prognosis and treatment options for brain tumors can vary significantly between children and adults, highlighting the need for age-specific research and therapeutic approaches.

Support and Resources

Dealing with a brain tumor diagnosis can be overwhelming for both patients and their families. Support groups and resources help provide emotional support, practical advice, and a sense of community. 

Resources at Duke University's Tisch Brain Tumor Center

Duke University's Tisch Brain Tumor Center provides a comprehensive range of resources for patients and their families. These include:

• Patient Care and Support Services : The center offers multidisciplinary care teams that include neurologists, oncologists, surgeons, and support staff dedicated to providing personalized treatment plans and ongoing support​.
• Educational Materials : Duke University provides extensive educational resources to help patients and families understand their diagnosis, treatment options, and what to expect during the treatment process​​.
• Clinical Trials and Research : The Tisch Brain Tumor Center is involved in cutting-edge research and clinical trials to develop new and more effective treatments for brain tumors. Patients can participate in these trials, gain access to the latest therapies, and contribute to advancing medical knowledge.

Discover the Best Treatment Options Today

If you’re considering undergoing treatment for a brain tumor, visit our website to request an appointment with one of our leading physicians. Established in 1937, Duke University’s Tisch Brain Tumor Center provides hope and empowerment to anyone facing a brain tumor diagnosis. Passionately leading the pursuit to conquer brain cancer , we hope to be a beacon of hope to all those fighting this ongoing battle.

If you are considering treatment for brain cancer, visit our website to request an appointment with one of our leading physicians. 

Interested in joining the team of world-leading Neuro-Oncology doctors and practitioners? Visit our education & training page to learn more. You can also support the clinic by donating funds directly to patient care, research, education, and treatment for brain tumors. 

Related readings:

• What Is The Most Common Type of Brain Tumor in Kids?
• How Long Can You Have a Brain Tumor Without Knowing?
• How Active Can You Be with a Brain Cancer Diagnosis?

Frequently Asked Questions About Brain Tumors

What are the chances I have a brain tumor?

The chances of having a brain tumor depend on various factors, including age, genetics, and environmental exposures. Overall, brain and other central nervous system (CNS) tumors are relatively rare, with an incidence rate of approximately 6.2 per 100,000 people per year. The risk increases with age and is higher in individuals with certain hereditary conditions or a family history of brain tumors.

Can you live a full life with a brain tumor?

Many people with benign brain tumors can live full, productive lives, especially if the tumor is slow-growing and does not affect critical brain functions. Even for those with malignant tumors, advances in treatment options, including surgery, radiation, and chemotherapy , have improved survival rates and quality of life.

How common are brain tumors by age?

Brain tumors are more common in certain age groups. They are the second most common type of cancer in children, with approximately 4,000 new cases diagnosed annually in the U.S. For adults, the incidence of brain tumors increases with age, particularly in those over 65. 

What are the first signs of a brain tumor?

The first signs of a brain tumor can vary widely depending on the tumor's size, type, and location. Common first symptoms include persistent headaches, seizures, changes in vision or hearing, difficulty with balance or coordination, and cognitive or personality changes

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New research platform assesses brain cancer mutations during surgery

Lynda De Widt

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JACKSONVILLE, Fla. — Brain cancer is difficult to treat when it starts growing, and a prevalent type, known as a glioma , has a poor five-year survival rate. In a new study published in Proceedings of the National Academy of Sciences, Mayo Clinic researchers report on a new surgical platform used during surgery that informs critical decision-making about tumor treatment within minutes. Time is of the utmost importance when dealing with aggressive malignant tumors.

The platform uses mass spectrometry to identify a key gene mutation in brain cancer, known as isocitrate dehydrogenase (IDH) mutations, in real time. Mass spectrometry is a sensitive technique used to analyze substances in tissue samples, including those altered in cancer.

The study involved more than 240 small tissue biopsies from patients undergoing asleep and awake brain surgery for suspected glioma at Mayo Clinic between 2021 and 2023, and an additional 137 biopsies from an international collaborator. Neurosurgeons collected biopsy samples from the core of the tumor to identify the mutations, as well as from areas around it, to assess if the tumor had spread.

Each tissue sample was placed on a glass slide steps away from the patients during ongoing surgery. The samples were analyzed through the mass spectrometer, which allowed researchers to rapidly assess — within two minutes — whether an IDH mutation was present.

The researchers say that, in addition to enabling real-time diagnosis, the platform allows surgeons to determine a patient's prognosis and perform tumor resection to improve patient outcomes. In the future, the new platform will help surgeons take advantage of the window of opportunity in the operating room to tailor treatment to the molecular features of a tumor, a more personalized approach to medicine.

Researchers hope new therapies developed to target IDH mutations can be delivered in the operating room at the time of surgery.

"The ability to identify this mutation during brain surgery means that one day in the future we may be able to treat patients with this specific mutation locally before they leave the operating room," says the study's senior author, Alfredo Quiñones-Hinojosa, M.D. , dean of research and chair of the Department of Neurosurgery at Mayo Clinic in Florida.

"Therefore, we will be able to bring the fight against cancer to the operating room, before chemotherapy and radiation treatments begin, and before the disease has progressed and invaded further." Dr. Quiñones-Hinojosa is also director of the Brain Tumor Stem Cell Research Laboratory .

In the study, researchers were able to diagnose IDH gene mutations with 100% accuracy. They are conducting more research to find other signatures in tumors where the mutation is absent. In addition, they plan to broaden their discoveries to include other types of brain cancers.

This study was supported in part by the National Cancer Institute of the National Institutes of Health under award number R33CA240181. For a full list of authors, funding and disclosures, see the paper .

About Mayo Clinic Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the  Mayo Clinic News Network  for additional Mayo Clinic news.

Media contact:

• Kelley Luckstein, Mayo Clinic Communications, [email protected]
• Mayo Clinic Minute: No ‘lesser evil’ when it comes to tobacco use A Mayo Clinic virologist explains FLiRT and why you may need a new COVID-19 vaccination 

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Article Contents

Clinical case presentation, initial supportive care, initial diagnostic imaging, epidemiology, standard-of-care treatment, follow-up imaging, prognosis and survivorship.

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Case-Based Review : newly diagnosed glioblastoma

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Derek R. Johnson, Shannon E. Fogh, Caterina Giannini, Timothy J. Kaufmann, Aditya Raghunathan, Philip V. Theodosopoulos, Jennifer L. Clarke, Case-Based Review : newly diagnosed glioblastoma, Neuro-Oncology Practice , Volume 2, Issue 3, September 2015, Pages 106–121, https://doi.org/10.1093/nop/npv020

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Glioblastoma (WHO grade IV astrocytoma) is the most common and most aggressive primary brain tumor in adults. Optimal treatment of a patient with glioblastoma requires collaborative care across numerous specialties. The diagnosis of glioblastoma may be suggested by the symptomatic presentation and imaging, but it must be pathologically confirmed via surgery, which can have dual diagnostic and therapeutic roles. Standard of care postsurgical treatment for newly diagnosed patients involves radiation therapy and oral temozolomide chemotherapy. Despite numerous recent trials of novel therapeutic approaches, this standard of care has not changed in over a decade. Treatment options under active investigation include molecularly targeted therapies, immunotherapeutic approaches, and the use of alternating electrical field to disrupt tumor cell division. These trials may be aided by new insights into glioblastoma heterogeneity, allowing for focused evaluation of new treatments in the patient subpopulations most likely to benefit from them. Because glioblastoma is incurable by current therapies, frequent clinical and radiographic assessment is needed after initial treatment to allow for early intervention upon progressive tumor when it occurs.

A 73-year-old man presented to his local emergency department after experiencing a generalized seizure. He had moderate left-sided weakness in the initial postictal period which quickly resolved. In retrospect, the patient had noted subjective left-hand “clumsiness” for a month prior to the seizure, but had not reported it to his family or physician. A CT scan was obtained in the emergency room and was followed shortly by an MRI (Fig.  1 ). The patient was then referred to our institution for further care.

(A) Unenhanced CT, (B) T2-weighted FLAIR, (C) gradient echo T1-weighted, and (D) post-gadolinium spin echo T1-weighted images depict a relatively circumscribed mass in the left superior temporal lobe with both solid, enhancing components and some cystic or necrotic areas. Moderate edema signal surrounds a portion of the mass.

The presentation of high-grade glioma is variable, depending on the location of the lesion within the brain. Headaches, seizures, and subacutely progressive neurological deficits are all common presenting symptoms.

Antiepileptic Therapy

Patients who present with seizure should be treated with antiepileptic drug (AED) therapy. An optimum AED choice would have rapid efficacy, few side effects, and no drug–drug interactions. In clinical practice, levetiracetam is often chosen as the first-line agent in this setting. 1 Studies have suggested that some AEDs may have direct antitumor effects. For example, valproic acid is a histone deacetylase (HDAC) inhibitor, 2 while levetiracetam is an MGMT inhibitor. 3 However, no impact of AED choice on survival has been proven, so AED choice should be based on efficacy and tolerability.

In patients with high-grade glioma who have not had a seizure, there is no proven role for long-term prophylactic AED therapy, and the American Academy of Neurology recommends against the routine use of prophylactic AEDs outside of the immediate perioperative period. 4 As previous studies of prophylactic AED therapy evaluated older agents in mixed patient populations, some experts question their applicability to current practice. A large trial of lacosamide vs placebo for seizure prophylaxis in patients with high-grade gliomas is ongoing to address this issue. 5

Corticosteroid Therapy

In patients presenting with headaches or focal neurological deficits, symptoms may be due to peritumoral vasogenic edema, which may respond to corticosteroid therapy. Dexamethasone is often started at 16 mg daily in 4 divided doses, and tapered down to the lowest effective dose or discontinued altogether. While this dosing schedule is widely used based on the short pharmacologic half-life of dexamethasone, the biological half-life is in excess of 36 hours, and daily or twice-daily dosing is effective and more convenient for maintenance therapy in most patients. Gastrointestinal prophylaxis and pneumocystis prophylaxis should be considered in patients in whom long-term corticosteroid treatment is anticipated.

Clinical Case Relevance

The patient was started on antiepileptic therapy at the time of his original emergency department visit. He had no further seizures. His exam was pertinent for a Karnofsky Performance Score of 90, and subtle left-sided pronator drift and slowing of rapid hand and foot movements on the left side were his only findings on physical exam. Dexamethasone was not initiated as he did not have symptoms of elevated intracranial pressure, such as headache or papilledema.

Because the symptomatic presentation of brain tumors is nonspecific, the presumptive diagnosis of brain tumor is often made only after imaging. Glioblastoma may be initially imaged with CT, particularly in the emergency department setting, but MRI provides more diagnostic information.

The typical CT appearance of glioblastoma is a mass lesion, often iso- to hyperattenuating (bright) in comparison to normal gray matter, with surrounding hypoattenuation due to infiltrating tumor and vasogenic edema. Contrast-enhanced CT classically reveals a centrally necrotic enhancing mass. Given that vascular proliferation is a hallmark of glioblastoma, intratumoral hemorrhage is common and may be visualized on CT, though it is more frequently identified as microhemorrhages on MR susceptibility-weighted imaging (SWI). Calcification is uncommon in glioblastoma, but can occasionally be seen.

On MRI, nearly all glioblastomas enhance with gadolinium contrast, usually showing a thick, irregular rind of tumor surrounding a necrotic cavity. Heterogeneity of signal intensity and contrast enhancement within glioblastomas and irregularity in shape are expected. Vascular hyperpermeability contributes to surrounding vasogenic edema visible as high signal intensity on T2-weighted images. Hemorrhage may complicate the appearance of glioblastoma, with acute and early subacute hemorrhage appearing hypointense on T2-weighted images and iso- to hyperintense on T1-weighted images. This intrinsic T1 hyperintensity of blood is similar in appearance to gadolinium enhancement, so it is crucial to always compare T1-weighted postcontrast images with T1-weighted precontrast images to ensure accurate judgment of enhancement.

The infiltrative nature of glioblastoma is generally more apparent on MRI than on CT. Mass-like signal abnormality infiltrating along white matter tracts is suggestive of glioma as opposed to other entities. However, distinguishing between nonenhancing infiltrative glial tumor with edema and vasogenic edema from any other etiology can be difficult or impossible. Frequently, glial infiltration and thickening of the cerebral cortex can be appreciated on T2-weighted and T2-weighted FLAIR images, which may help to distinguish gliomas from other neoplasms. Multifocality, distant, or diffuse disease may be seen initially in approximately 13% of glioblastoma cases, with some areas sometimes looking less aggressive than the primary mass. 6 It is also well established that microscopic glial tumor cell infiltration is expected to extend beyond visualized signal abnormality on MRI.

The differential diagnosis of glioblastoma often includes metastasis and CNS lymphoma. Generally speaking, glioblastoma tends to be more irregularly shaped than metastases because of its predilection for spread along white matter tracts, 7 but there is overlap at least in qualitative analysis. Primary CNS lymphoma (PCNSL) in the immunocompetent patient is most often homogeneous in signal intensity and enhancement, though exceptions do occur; while heterogeneity and central necrosis are more common in CNS lymphoma in the immunocompromised.

Advanced MRI techniques including perfusion imaging techniques such as dynamic susceptibility contrast (DSC) imaging, diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), SWI, and MR spectroscopy may help to distinguish glioblastoma from other tumors. Given the histological hallmark of neovascularity in glioblastoma, increased blood volume (often expressed as rCBV, or relative cerebral blood volume) is expected within at least portions of a glioblastoma. 8–10 On MR spectroscopy, glioblastoma typically has the nonspecific findings of elevated choline and decreased N-acetylaspartate (NAA) and may have elevated lipid and lactate resonances. Generally speaking, the choline:NAA ratio increases with astrocytoma grade. 11 Due to the infiltrative nature of glioblastoma relative to metastases, one may expect greater CBV 12 , 13 and greater choline:creatine 14 , 15 in the peritumoral areas of glioblastoma relative to metastases. rCBV also tends to be greater in enhancing tumor and peritumoral areas of glioblastoma than in CNS lymphoma. 12 Apparent diffusion coefficient tends to be lower in CNS lymphoma than in glioblastoma, given the great hypercellularity of lymphoma. 12 Microhemorrhages on SWI are found in most glioblastomas but rarely in CNS lymphoma. 16 , 17 Differentiation of glioblastoma and lymphoma using multiparametric advanced MRI has also been suggested. 18 Imaging genomic mapping is a burgeoning area of research that has begun to discover associations between MRI features and glioblastoma genotypes and clinical phenotypes. 19

Many published reports using advanced MRI techniques have relied on quantitative analyses, which are currently difficult to standardize across imaging platforms and institutions. For example, with perfusion imaging, there exists great variability in all steps from IV gadolinium bolus injection to scanner platforms used to MRI scan parameters chosen to post-processing software and analysis techniques used. 20 Given the technical variabilities of advanced MR techniques and expected glioblastoma heterogeneity, there are limits to the sensitivity and specificity of these techniques. The standardization of advanced MRI is well recognized as a pressing clinical and research need.

The initial imaging obtained for this patient included a CT and contrast-enhanced MRI, shown in Fig.  1 . Both of these images, and the MRI in particular, were concerning for glioblastoma, and metastasis and non-neuroplastic entities such as infection or demyelination were thought to be significantly less likely.

Surgical resection is the primary treatment for glioblastomas. The goals of surgery are tissue diagnosis, including molecular and genetic tumor analysis, as well as cytoreduction for alleviation of presenting symptoms and improved tumor control. As previously discussed, in the appropriate context imaging can be very suggestive of glioblastoma. However, tissue diagnosis is the standard of care and only in cases of truly inaccessible tumors (such as brainstem lesions) or grave infirmity of the patient, precluding surgical candidacy, should treatment be undertaken without pathological confirmation of disease.

The surgical approach of choice is maximal safe resection. Over the past several years, significant data have accumulated supporting the idea that maximizing the extent of tumor resection positively impacts survival for patients with newly diagnosed glioblastoma. 21 , 22 In a single institution study of 949 patients with high-grade gliomas, more than half of whom were operated on for the first time, the extent of resection was shown to be an independent predictor (gross total resection [GTR] vs near total resection [NTR], NTR vs subtotal resection [STR]) of prolonged survival (median OS 11 months GTR, 9 months NTR, and 5 months STR). 23

The association between extent of resection and survival benefit holds true even for tumors that are difficult to resect. In a study of multicentric high-grade glioma, resection of a dominant lesion was strongly predictive of improved overall survival when compared with biopsy only (12 months vs 4 months). 24 In the setting of insular high-grade gliomas, one of the most technically difficult eloquent cortical areas to access surgically, extent of resection ≥90% of the tumor provided 2-year overall survival of 91% compared with 75% for volumetric resection <90% of the tumor, in addition to improved progression-free survival. 25 The beneficial effect of maximal resection has also been suggested to extend to elderly patients without an increase in mortality or complications. 26

Several technical intraoperative adjuncts have been developed in an effort to maximize the extent of safe resection. 27 , 28 Use of frameless stereotactic guidance, which allows for optimal patient positioning, accurate tailoring of the craniotomy, and safe access trajectory to the tumor, has become standard for resection of glioblastomas. Recent advances have made it possible for intraoperative guidance to integrate imaging tools such as tractography, which allows for identification of motor, speech, and visual pathways, as well as MR spectroscopy to facilitate accurate targeting of presumed higher-grade areas within a heterogeneous tumor. 29 In cases where only a biopsy is planned, such imaging integration allows targeting of regions likely to optimize diagnostic yield and accuracy.

Direct cortical mapping allows identification of motor pathways and, when combined with awake craniotomy used for mapping of language areas, is an important adjunct to surgical resection of lesions in eloquent cortex. 25 , 30 A systematic review of the literature showed that direct cortical mapping decreases late severe neurological deficits from 8.25% to 3.4% and increases the rate of GTR from 58% to 75%. 31

Intraoperative MRI has been used in an attempt to maximize extent of surgical resection and identification of residual resectable tumor. 32 In a study including both high-grade and low-grade tumors, use of intraoperative MRI increased the volumetric extent of resection from 76% to 96%. 33 However, the high installation cost of an intraoperative magnet as well as the complexities involved in its intraoperative use have led to research into alternate ways to identify residual tumor during surgical resection. The utilization of fluorescence guidance has been recently advocated. The use of fluorophores such as 5-aminolevulenic acid (5-ALA) or fluorescein, which accumulate in areas of blood brain disruption, can be a powerful adjunct that allows for the accurate identification of tumor borders and possible residual disease at the time of resection. 34–36 In a systematic review of 10 studies, patients who underwent surgery utilizing 5-ALA for maximizing resection had improved 6-month progression-free survival and overall survival. 37 A multicenter, randomized, phase III trial of 5-ALA-guided surgery found higher rates of gross total resection and 6-month progression-free survival in the 5-ALA group without any increase in adverse events. 38

Following the initial multicenter, randomized trial of implantable carmustine polymer wafers in the treatment of recurrent high-grade glioma, Attenello et al reported their experience with their use during surgery for newly diagnosed high-grade gliomas and found an overall median survival of 13.5 months without any increased incidence of complications. 39 , 40 Although the use of chemotherapy implants appears to be safe in the setting of primary glioblastoma, the relative lack of improved survival and the fact that much of the data regarding the use of chemotherapy wafer implants predates the use of temozolomide (TMZ), has limited enthusiasm for this approach.

Surgery for high-grade gliomas is in general associated with relatively low rates of major complications. In an analysis of the patients in the Glioma Outcomes Project, an overall complication rate of 24% was reported for surgical treatment of newly diagnosed high-grade gliomas. In decreasing frequency, major complications included: depression (11%), worsened neurological status (8.1%), seizures (7.5%), adverse drug reaction (5.2%), DVT (4.2%), intracranial bleeding (1.6%), and pulmonary embolism and wound infection (0.5% each). Perioperative mortality was reported as 1.5%. 41 These results were similar to an earlier study that reported 13% major complications and 1.7% mortality in patient undergoing craniotomy for intraparenchymal tumors. 42 In an analysis of the California Inpatient Database, Marcus et al reported a 30-day readmission rate of 13.2% for patients who underwent surgical treatment for a glioma who were originally discharged home. The most common presentations at readmission were seizures (20.9%) and surgical infection (14.5%). 43

In summary, surgery remains the first and very important treatment modality for a newly diagnosed glioblastoma. Its effectiveness for optimizing overall survival is related to the extent of resection and its safety is dependent on various intraoperative adjuncts that allow for accurate localization of the tumor as well as eloquent cortical areas.

The patient underwent resection of his tumor without use of awake craniotomy or intraoperative MRI. Following surgery, his left-sided weakness was transiently worse but it then improved back to the presurgical baseline. His extensive resection placed him in a more favorable prognostic group than biopsy alone would have. Preoperative and postoperative MRI images are displayed in Fig.  2 .

Post-gadolinium spin echo T1-weighted images (A) before and (B) after surgery.

The histological diagnosis in this case was WHO grade IV astrocytoma (glioblastoma). It was an infiltrative astrocytoma showing areas of high cellularity and brisk mitotic activity (Fig.  3 A), tumor necrosis (Fig.  3 B), and microvascular proliferation (Fig.  3 C). The diagnostic criteria from the WHO (2007) include presence of cytological atypia, mitotic activity, microvascular proliferation, and/or tumor necrosis. 44 Briefly, an infiltrative astrocytoma exhibiting cytological atypia alone, including elongated, irregular and hyperchromatic nuclei, is considered WHO grade II (diffuse astrocytoma). The presence of increased cellularity, nuclear atypia, and mitotic activity warrant a WHO grade III (anaplastic astrocytoma) designation. Tumors that additionally show microvascular proliferation and/or necrosis are WHO grade IV (glioblastoma). Classic microvascular proliferation has the appearance of “glomeruloid tufts,” consisting of multilayered, mitotically active endothelial cells admixed with smooth muscle cells/pericytes (as represented in Fig.  3 C). Although necrosis surrounded by pseudopalisading tumor cells is most characteristic of glioblastoma (Fig. 3 B), both geographic and pseudopalisading tumor necrosis can be present and are associated with similarly dismal prognoses. Astrocytoma grading is based on the highest histological grade. Since infiltrative astrocytomas can have considerable regional heterogeneity, especially toward their infiltrative border into surrounding parenchyma, it is important to assess whether a biopsy sample is representative of the entire tumor by correlating histological, clinical, and radiological findings. A biopsy taken at the periphery of a ring-enhancing mass could well show a low to moderately cellular tumor (as seen in Fig.  3 D) with/without mitoses, prompting an inaccurate diagnosis of diffuse or anaplastic astrocytoma (WHO grade II or III) rather than glioblastoma (WHO grade IV).

The biopsies demonstrated an infiltrating population of atypical astrocytic cells, showing (A) brisk mitotic activity, (B) tumor necrosis, and (C) microvascular proliferation, consistent with a diagnosis of glioblastoma. A biopsy from the periphery of this mass may show (D) a low-to-moderately cellular tumor, with or without mitoses, corresponding to a lower histological grade. In images (A) and (C), photographed at 400× magnification, the scale bars on the bottom right represent 20 µm. In images (B) and (D), photographed at 200× magnification, the scale bars represent 50 µm.

(A) The first MRI following chemoradiotherapy and (B) MRI evidence of tumor progression approximately 2 years later. Both are post-gadolinium spin echo T1-weighted images.

Historically, glioblastomas have been distinguished based on their clinical presentation as primary (de novo) or secondary glioblastomas that develop in progression from a lower grade astrocytoma. Primary glioblastomas, the most common (>90%), develop with a short clinical history without clinical or pathological evidence of a lower grade precursor, and are typically seen in older patients. There are no definite histological features to distinguish primary and secondary glioblastomas. With advancing molecular information, however, it is clear that primary and secondary glioblastoma are two different diseases.

Mutation of isocitrate dehydrogenase (IDH) is frequently seen in low-grade glioma, and is also found in approximately 12% of glioblastomas. 45 The presence of IDH mutation within a glioblastoma is suggestive of secondary glioblastoma, regardless of any previous history of low-grade glioma. 46–50 In glioblastoma, mutations almost exclusively involve residue 132 (R132) of IDH1 resulting in the substitution of arginine. 46 , 51 The presence of IDH1 mutation in glioblastoma has been associated with younger age and relatively longer survival. 52–56 Alterations in receptor tyrosine kinase pathways have also been frequently identified in glioblastomas. 57 Epidermal growth factor receptor (EGFR) activation, either by amplification of wild-type EGFR or by deletion of exons 2–7 that encode the extracellular domain (the variant III mutation) resulting in ligand-independent constitutive activation of EGFR, 47–49 is more commonly seen among primary glioblastomas. Mutations of the TP53 gene are frequent in, but not exclusive of, secondary glioblastomas. 50 , 58 , 59 On the other hand, mutations in the promoter region of the telomerase reverse transcriptase ( TERT ) gene are predominantly found in primary glioblastomas that lack IDH1 mutations, and appear to be associated with worse prognosis. 49 ,60–62

The gene for the DNA-repair enzyme O(6)-methylguanine-DNA methyltransferase ( MGMT ) has a promoter region that is rich in CG dinucleotide (CpG) sites that are normally unmethylated. However, in glioblastomas, the cytosine in these CpG sites may become methylated, resulting in transcriptional silencing of MGMT and subsequent impairment of the DNA-repair process. 63–65 Glioblastomas with MGMT -promoter hypermethylation are unable to repair the DNA damage caused by alkylating agents (such as TMZ), and carry a more favorable prognosis than tumors without methylation of MGMT . 66–69 Tumors with IDH mutation frequently have MGMT promoter methylation. 70

Integrated genomic analysis has revealed subsets of high-grade astrocytomas based on the differential expression of prognostic markers. 71 , 72 Three to four major subgroups are generally well recognized, and their distinction appears to be relatively robust on meta-analysis. 73 At one end of the spectrum is the proneural subgroup, characterized by alterations in markers associated with neurogenesis, strongly associated with IDH1 mutations, and tending to have more favorable outcomes. The mesenchymal subgroup is at the other end of the spectrum, expressing markers usually associated with mesenchymal tissue and increased angiogenesis, associated with loss and/or mutation of the NF1 gene, and tending to have relatively worse outcomes. These expression-based subgroups were also distinguished by their CpG island methylation status. 74 Glioblastomas in the proneural subgroup were more frequently found to show widespread CpG island hypermethylation, termed a glioma CpG island methylator phenotype (G-CIMP), which was not usually seen in tumors of the mesenchymal subgroup.

At present, the diagnosis of glioblastomas per the 2007 WHO guidelines is based on well-established histological features. However, testing for MGMT status is becoming accepted as a standard of care for newly diagnosed glioblastomas, as is screening for IDH1 mutations. As newer therapeutic modalities emerge, there is increasing recognition for the need to communicate the status of prognostically and therapeutically relevant genomic markers to help guide clinical decisions for patient management. In a preliminary attempt to address this, consensus guidelines suggested at an international meeting of neuropathologists recommended that pathologists to provide an integrated diagnosis that incorporates the histological diagnosis and relevant molecular information. 75 For example, the diagnosis of glioblastoma, WHO grade IV, might also include the results of the IDH1 mutation status, MGMT status, and other relevant markers.

Pathology revealed glioblastoma, MGMT methylated. The MGMT methylation status is prognostic of better survival, relative to patients with unmethylated MGMT , and it also may predict response to treatment in some situations, to be discussed later.

Glioblastoma is the most common primary brain tumor in adults. In the United States, the age-adjusted incidence rate is 3.19 (95% confidence interval 3.16–3.21) per 100 000 persons. 76 The lifetime risk of being diagnosed with an invasive cancer of the nervous system, most of which are either glioblastoma or glioblastoma precursors, is approximately 1 in 161, with the risk of dying from an invasive cancer of the nervous system being approximately 1 in 222. 77 Thus, while glioblastoma remains a relatively rare tumor, many patients will be aware of one or more acquaintances or relatives with this condition purely by chance, sometimes raising concern of clustering of tumors by geography or within a family.

Glioblastoma is more common in men than women, as are all infiltrating gliomas. Incidence rises with age, peaking in the 75–84 age range. Thus, though the overall age-adjusted incidence rate of glioblastoma does not appear to be rising, the raw number of tumors diagnosed each year is expected to climb in coming decades due to aging of the population at large. In the United States, glioblastoma is more common amongst non-Hispanic whites than in black, Asian/Pacific Islander, or American Indian/Alaskan native groups.

Ionizing radiation remains the only proven exposure risk factor for glioblastoma. Typically, radiation-induced glioblastoma is seen years after therapeutic radiation for another tumor or medical condition. Diagnostic radiation, for example from CT scanning or even dental X-rays may theoretically confer increased risk of glioma, but this has not yet been confirmed in large-scale epidemiological studies. Nonionizing radiation, specifically related to the use of cellular telephones, has not been convincingly linked to glioma incidence, but this is an area of active investigation. Asthma and atopic disease are associated with lower risk of glioblastoma in multiple studies, with one meta-analysis showing a reduction in glioma risk of 40% in patients with allergies. 78

Many patients with glioblastoma are concerned about possible genetic risk factors, and ask about the advisability of screening for relatives. A heritable component to glioblastoma risk has long been demonstrated by the association between glioblastoma and Mendelian cancer syndromes including the Lynch and Li-Fraumeni syndromes. Recently, genome-wide association studies have revealed single nucleotide polymorphisms (SNPs) associated with glioblastoma risk. These SNPs have been identified within the candidate genes TERT (chromosome 5p15.33), EGFR (7p11.2), CDKN2B (9p21.3), TP53 (17p13.1), and RTEL1 (20q13.33). 79 Other SNP associations such as those within CCDC26 (8q24.21) and PHLDB1 (11q23.3) are mainly associated with IDH-mutant tumors and thus risk of secondary glioblastoma. Most of the currently identified risk SNPs confer only a modest increase in risk of glioma, and thus the absolute risk of glioma remains low even in individuals carrying the risk SNPs.

The patient came from a large family with a history of a number of different tumor types, but no first or second degree relatives with primary brain tumors. He was reassured that his family members were at low risk of primary brain tumor, and no screening studies were recommended.

Glioblastoma is an infiltrative tumor, with residual disease present after surgery, even in cases of radiographic gross total resection. Additional treatment to address this residual tumor is thus necessary as soon as the operative site has healed appropriately. This additional treatment may take the form radiation therapy (RT), chemotherapy, or both, depending on the clinical scenario.

Current Standard-of-Care Therapy

The current standard-of-care treatment for newly diagnosed glioblastoma was established by a landmark trial conducted by the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada Trials Group (NCIC). 80 In this trial patients were randomized to RT alone (the previous standard of care) vs RT with concurrent and adjuvant oral TMZ chemotherapy. In this trial, median survival was 12.1 months in the radiation-only arm and 14.6 months in the TMZ arm. More importantly, combined chemoradiotherapy significantly increased the proportion of relatively long-term survivors from 10.9% to 27.2% at two years and from 1.9% to 9.8% at five years. Patients whose tumors had methylation of the promoter for the MGMT gene ( MGMT methylated) had greater benefit from the addition of TMZ (46% 2-year survival vs 27% for the MGMT unmethylated patients), but MGMT unmethylated patients still had incremental benefit from the addition of TMZ (14% 2-year survival vs <2%). 69

Numerous studies have indicated a benefit to using RT in the treatment of gliomas. 81 , 82 A dose of 60 Gy in 2 Gy fractions is the recommended dose based on prior studies indicating that doses up to but not exceeding 60 Gy impact survival. 83 , 84 Despite agreement of a standard dose recommended in both clinical trials and practice, there is tremendous variability in the volume of tissue irradiated. A common approach endorsed by the Radiation Therapy Oncology Group and other cooperative groups is to target the tumor edema with a 2.5-cm margin to a dose of 46 Gy followed by a cone down to the resection cavity and contrast-enhancing tumor with similar margin to a dose of 60 Gy. 85 Other cooperative groups also recommend a staged approach initially including tumor edema with a cone down to the enhancing tumor, but only add a 1-cm margin. Additional strategies include treating the enhancing tumor and resection cavity with a 2–3-cm margin to a total dose of 60 Gy without a staged volume reduction. 80 The volume of brain irradiated in each of these scenarios is substantially different. While studies have demonstrated comparable outcomes comparing conformal radiation to whole brain irradiation, similar comparisons have not been made between these varied radiation approaches. 86

Typically, TMZ is given daily during RT at a dose of 75 mg per square meter of surface area each day, followed by a rest period of approximately a month at the end of radiation. TMZ is then resumed at the dose of 150 mg per square meter on days 1–5 of a single 28-day cycle, and subsequent 28-day cycles are dosed at 200 mg per square meter on days 1–5 if the first adjuvant cycle was well tolerated. In the clinical trial that proved the efficacy of this approach, a total of 6 adjuvant cycles were given. 80 In practice, some physicians recommend more than 6 cycles, though there is currently no definitive data demonstrating that more prolonged regimens are associated with superior survival.

Side Effect Management

The most common symptomatic side effects of treatment are mild fatigue, nausea, and constipation. All patients receiving TMZ should be provided with antiemetic therapy, both to take prior to each TMZ dose to prevent nausea and also for as-needed use. Antiemetics of the serotonin 5-HT3 receptor antagonist class, such as ondansetron and granisetron, are often used for this purpose. TMZ often causes mild thrombocytopenia, but severe thrombocytopenia, neutropenia, and anemia are much less common. Asymptomatic leukopenia is very common in patients on TMZ. Prophylaxis against Pneumocystis jiroveci pneumonia with trimethoprim/sulfamethoxazole or an alternative agent is recommended for the full duration of TMZ therapy.

Common acute radiation side effects include headaches, nausea, exacerbation of presenting symptoms, hair loss, skin reaction at the site of radiation, and fatigue. Less common acute side effects can include dry mouth or altered taste, hearing impairment or seizures. Possible late side effects of radiation include decreased pituitary hormonal production, cataract formation, secondary cancers, and nerve damage. Radiation necrosis can occur and cause symptoms similar to tumor recurrence or stroke. Necrosis is initially managed with steroids but may require more intensive options such as surgery or bevacizumab therapy. 87

Neurocognition can be altered during initial therapy secondary to inflammation, anxiety, and medications, but radiation can also cause cognitive impairment months to years after it is completed, even in the absence of tumor progression. Learning and memory are the most commonly impaired cognitive domains. The extent of impairment may be related to patient-specific factors, but also related to volume of tissue irradiated and location of the radiation field. For example, dose to hippocampal structures has been found to influence extent of neurocognitive dysfunction. 88–90

Elderly Patients and Patients with Poor Performance Status

The pivotal trial that demonstrated the efficacy of TMZ for newly diagnosed glioblastoma did not include patients over the age of 70, leaving unanswered the question of whether this regimen is effective and well tolerated in elderly patients. 80 Moreover, a number of trials have been conducted that suggest, at least in some circumstances, abbreviated or less intensive treatments may be effective in older patients. In a randomized, phase III trial conducted by the Nordic Clinical Brain Tumor Study Group, patients age 60 or older with glioblastoma were randomized to the typical 6 weeks of RT, 2 weeks of hypofractionated RT, or TMZ without RT. 91 The trial demonstrated that both the hypofractionated RT and TMZ monotherapy were superior to 6 weeks of RT with respect to overall survival. Similarly, in the German NOA-08 trial, patients over 65 years of age were randomized to dose-dense TMZ or standard 6-week RT, with similar outcomes in each group. 92 Both the Nordic and NOA-08 trials demonstrated that MGMT methylation was predictive of response to TMZ therapy. Patients whose tumors demonstrated methylation of MGMT had better survival when treated with regimens that contained TMZ, whereas patients with unmethylated MGMT did better when treated with RT. Although both these studies were randomized phase III studies, there are significant limitations in interpreting the data. Notably, 6 weeks of RT with concurrent and adjuvant TMZ was not an arm in either study, so direct comparisons of these alternative approaches to the current standard of care are not possible. In addition, the definition of elderly varied across these trials and across other, retrospective analyses.

Currently, as no therapy has been proven superior or equivalent to standard combined chemoradiotherapy in elderly patients, this therapy is a reasonable option for patients of any age with good performance status who are felt likely to tolerate intensive treatment. In patients with poor performance status or those in whom treatment tolerability is a concern, treatment choice should be informed by MGMT methylation testing. In patients with MGMT methylation, TMZ monotherapy is reasonable, whereas RT monotherapy is an option for patients without MGMT methylation. Given the results of the Nordic trial, as well as a previous trial that demonstrated that abbreviated RT was not inferior to 6-week RT, hypofractionated RT is preferable to the standard six-week schedule in this patient group if not combined with chemotherapy. 93

Optune (NovoTTF-100A)

Recently released information, in the form of a press release and a presentation at a neuro-oncology specialty meeting, suggests that the addition of therapy with alternating electric fields via the Optune device (NovoCure) may prolong both progression-free and overall survival by several months when combined with standard chemoradiotherapy for newly diagnosed glioblastoma. 94 In the trial for which data were presented, Optune therapy was initiated at the time of initiation of adjuvant TMZ therapy and continued until tumor progression. While this result is cause for optimism, the results presented were from an interim data analysis, and publication of the full trial data in a peer-reviewed journal will be necessary before Optune therapy can be critically evaluated for possible inclusion in a new standard of care for glioblastoma.

Recent Clinical Trial Results

After combined chemoradiotherapy became the standard of care, more aggressive dosing of TMZ was tested in hopes that it might provide additional efficacy. RTOG 0525, a large phase III study, compared a dose-dense schedule of TMZ after RT with the standard 5-day schedule. No difference in survival was noted in either MGMT methylated or MGMT unmethylated patients. 85 Cilengitide, a targeted drug that inhibits integrins, was added to standard RT and TMZ in two separate clinical trials, a phase III study in MGMT methylated patients 95 and a phase II study in MGMT unmethylated patients, 96 but did not show improvement in survival in either case. The addition of the antiangiogenic agent bevacizumab, an antibody against VEGF, to standard RT and TMZ was tested in two large phase III trials. While there was some improvement in progression-free survival, no improvement in overall survival was noted in either of these trials. 97 , 98 As such, bevacizumab has not at this time been approved for use in initial treatment of glioblastoma.

Important Ongoing Clinical Trials

There are numerous phase I and II trials around the world testing the addition of other drugs to standard therapy, including targeted agents, cytotoxic agents, and a variety of immune-targeting approaches. In addition, there are trials in progress testing alternative radiation techniques such as proton therapy or imaging-guided radiation dose escalation, and trials testing metabolic approaches against cancer such as variations on the ketogenic diet.

With regard to phase III trials, a randomized, placebo-controlled trial is currently ongoing that tests the addition of an autologous vaccine made from a patient's own tumor and their own dendritic cells (DCVax-L) to initial adjuvant TMZ. 99 Another glioblastoma immunotherapy approach, using the EGFRvIII-targeted experimental cancer vaccine rindopepimut (CDX-110), is being evaluated in the ACT IV trial. 100 Within the elderly population specifically, a randomized, phase III trial comparing hypofractionated RT alone or in combination with TMZ has completed accrual in Canada, Europe, and Japan 101 ; the results are eagerly awaited to further inform whether combination therapy is effective in this patient population.

The patient had excellent performance status and was felt to be a candidate for standard chemoradiotherapy, despite his age of 73. He developed mild nausea and moderate fatigue during chemoradiotherapy, but no life-threatening toxicities. He likewise tolerated adjuvant TMZ well from a symptomatic standpoint, though several cycles had to be briefly delayed due to mild thrombocytopenia. He discontinued TMZ therapy and moved to an observational phase following the sixth adjuvant cycle. Had he not been judged a good candidate for standard therapy, a TMZ-only approach, sparing radiation, would have been an acceptable alternative for an elderly man with an MGMT -methylated tumor.

Initial Postoperative Imaging

Postoperative imaging is strongly recommended within the first 48 hours following surgical resection in order to establish a postoperative baseline. If MRI is obtained, it is important to compare precontrast T1-weighted images with post-contrast T1-weighted images in order to detect true residual enhancement, as blood products in or around the surgical bed are usually present and may cause T1 shortening on both pre-gadolinium and post-gadolinium images. It is also crucial to perform DWI in order to detect any perioperative infarction, which may subsequently gain enhancement in the subacute phase, lose restricted diffusion, and present as a troubling, new enhancing lesion on subsequent MRI follow-ups. 102

Long-term Follow-up

Generally, patients undergo monthly clinical evaluation and blood work during adjuvant TMZ, with MRI every other month. After the completion of TMZ, imaging is recommended every 2 to 3 months until 2 years from the end of treatment. After this time, MRI can be performed less often, provided the patient and physician are comfortable with this approach. Regardless of duration of disease-free survival, clinical evaluation and imaging should take place on at least an annual basis.

It is expected that the imaging appearance of a treated glioblastoma will evolve over time. One hopes for tumor regression after chemoradiation, but a temporary worsening of imaging findings, including increased contrast enhancement and edema signal with mass effect, is very common as a reaction to treated and dying tumor. This phenomenon is known as pseudoprogression, named so because the MRI appearance may be identical to tumor progression when, in fact, subsequent follow-up examinations with no change in therapy show regression of these imaging findings. 103 There is, unfortunately, often no basis on which to discriminate post-treatment related enhancement from enhancement related to viable tumor using standard morphological MRI.

Pseudoprogression may be more common with the combined use of TMZ with RT, it is more common in those with MGMT promoter methylation, and it has been associated with an improved clinical outcome in some cohorts. 104 , 105 The incidence of pseudoprogression is on the order of 30%, 106 depending on how it is judged, and most pseudoprogression occurs within 3 months of the end of RT. However, pseudoprogression occurring after this 3-month period but within the first year is not uncommon, particularly in those with MGMT promoter methylation. 107

The Macdonald criteria has been used as a framework for judging glioblastoma progression or regression, relying mainly upon 2-dimensional maximal diameters of contrast-enhancing lesions. 108 In 2010, the Response Assessment in Neurooncology (RANO) criteria were published, updating the Macdonald criteria in several important ways, while maintaining a reliance upon the product of perpendicular diameters of contrast-enhancing lesions as an indicator of tumor size and status. 109 One very important caveat in the RANO criteria is that, because of the common occurrence of pseudoprogression with modern chemoradiation therapy, a radiographic diagnosis of tumor progression cannot be made within the first 3 months of the end of chemoradiation if an enlarging, enhancing lesion is within the high-dose field of RT. Any apparent tumor progression within the first 3 months after radiation must be closely followed to differentiate early tumor progression from pseudoprogression. Because pseudoprogression occasionally occurs beyond 3 months from the end of radiotherapy, some would advocate early follow-up scans to confirm or deny pseudoprogression if there is apparent radiographic progression occurring even beyond the 3-month window after radiotherapy. RANO also allows for the determination of progression when there is nonenhancing tumoral progression, as nonenhancing tumor progression is not uncommon. 6 New, discrete, masslike abnormalities or new cortical expansion with T2 lengthening suggest nonenhancing tumor progression per RANO criteria. Unfortunately, distinguishing nonenhancing tumor from other treatment-related effects and edema is often difficult or impossible.

Given the complexity of MRI interpretation, other means of glioblastoma treatment response assessment are needed. Estimates of tumor cell proliferation rates and invasion have been made through the analysis of MRI coupled with computational modeling as a means to monitor treated glioblastomas over time. 110 , 111 Physiologic or mechanistic imaging techniques such as dynamic susceptibility contrast (DSC) perfusion imaging, dynamic contrast enhanced perfusion imaging (DCE), DWI, spectroscopy, and PET with various tracers also may aid in distinguishing progressing tumor from treatment-related changes such as pseudoprogression and radiation necrosis, but their implementation has to date been so variable site-to-site that these techniques have not been included in the RANO criteria.

Generally speaking, it is expected that CBV will be elevated with viable high-grade glioma but not radiation necrosis, and possibly not elevated with pseudoprogression, though data for pseudoprogression are as yet less clear. 112–119 However, the variability in perfusion imaging has already been mentioned, there is often overlap between CBV in viable glioblastoma and radiation-induced changes, there is frequently an admixture of viable tumor and radiation-induced changes, and leakage of gadolinium into the interstitium breaks tracer-kinetic modeling assumptions and presents a challenge to accurate determination of CBV. In order to optimize CBV measurement, the use of a leakage-correction option is advised during image postprocessing. Many experts also recommend the use of a gadolinium preload prior to the acquisition of DSC images. Histogram and voxel-wise analyses of perfusion data hold promise for improving the differentiation between viable tumor and treatment-related changes, but they are postprocessing intensive. 120 , 121 Given the frequent admixture of residual glioma and radiation-related changes, determination of a residual/recurrent tumor fraction would be desirable and such a metric using CBV has been shown to correlate with overall survival. 122 Importantly, the relative change in lesion CBV over time may be crucial in judging tumoral stability or progression, 123 though it bears stating explicitly that uniformity in perfusion technique between time points is mandatory for the best chance at fair comparisons.

DCE perfusion imaging, which is generally more technically demanding than DSC perfusion imaging, also holds promise for differentiating recurrent glioblastoma from treatment-related changes, using metrics such as the volume transfer coefficient k trans and initial area under the curve. 118 ,124–126 MR spectroscopy can be technically challenging to perform well and interpret, but after therapy choline and lipid and lactate levels have been shown to correlate with glioma outcomes. 119 , 127 More data on the value of MR spectroscopy in the glioblastoma post-treatment setting is needed. ADC values from DWI imaging, particularly when using advanced analysis techniques such as histogram analysis and functional diffusion maps (fDMs), 128–133 may also help to differentiate recurrent tumor from treatment-related changes. Amino acid PET may also aid in this discrimination better than with FDG PET but these techniques need further evaluation. 134–138 Finally, it is likely that multiparametric approaches with advanced MRI techniques will add to assessment of glioblastoma treatment response. 119

The first MRI following the completion of chemoradiotherapy, shown in Fig.  4 A, demonstrated a rim of contrast enhancement around the resection cavity that had not been visible on the initial postoperative imaging (Fig.  2 B). The patient was asymptomatic, the changes were suspected to be treatment-related, and no change of plan was recommended. He remained clinically and radiographically stable for nearly 2 years until he had tumor progression along the medial margin of his resection cavity, as shown in Fig.  4 B. His KPS at the time of progression was 80, due to increased left-sided weakness, but he was still able to live independently with his wife. After discussing options including continuing to focus on aggressive tumor treatment, potentially at the cost of short-term quality of life, vs prioritizing quality of life and supportive care with hospice, he chose to pursue salvage chemotherapy, the details of which are beyond the scope of this review.

Overall Survival

Survival after diagnosis of glioblastoma has been steadily improving over the course of the last decade, for reasons both known and unknown. The widespread adoption of TMZ for newly diagnosed glioblastoma in and after 2005 was associated with in an increase in population-level survival. 139 Likewise, though a survival benefit has yet to be demonstrated in a randomized prospective trial, population-based data suggest that survival also improved after the FDA approval of bevacizumab for recurrent glioblastoma. 140 Additional improvements in the survival of patients with glioblastoma may be due to incremental improvement in surgery, radiation, and supportive care.

The median survival figure of 14.6 months from the pivotal TMZ trial is often shared with patients with newly diagnosed glioblastoma, but clinical trial median survival numbers have little relevance when predicting the specific prognosis of an individual patient. Many factors can significantly impact survival, including but not limited to age at diagnosis, performance status, extent of resection, MGMT methylation status, and IDH mutation status. Median survival by MGMT methylation status in recent phase III trials is shown in Table  1 . A number of survival prognostication systems have been published, but again these are more relevant to cohorts than patients as individuals. In the long-term follow-up of the pivotal phase III TMZ trial, among patients treated with radiation and TMZ, 27.2% were still alive at 2 years, 16.0% at 3 years, 12.1% at 4 years, and 9.8% at 5 years. 141 Survival to 10 years or longer is very rare.

Survival by MGMT methylation status in recent phase III trials for newly diagnosed glioblastoma

a OS statistics from Stupp Lancet Oncology 2009; PFS statistics from Hegi NEJM 2005. All statistics regard the RT + TMZ trial arm.

Abbreviations: MGMT, O(6)-methylguanine-DNA methyltransferase; OS, overall survival; PFS, progression-free survival; EORTC, European Organisation for Research and Treatment of Cancer; NCIC, National Cancer Institute of Canada; RTOG, Radiation Therapy Oncology Group.

Because glioblastoma is an intrinsically fatal diagnosis, and treatment can cause significant side effects, most tumor treatment plans require the sacrifice of some quality of life in the short term in the hope of gaining duration of life in the longer term. Early in the course of disease, this is a trade-off that most patients readily accept, though some choose to forgo aggressive therapy. With each successive treatment, the expected duration of benefit tends to decrease and toxicity may increase, so the merits of focusing purely on quality of life should be readdressed regularly, for example at the time of clinical or radiographic progression. When the service is available, patients may benefit from speaking with a palliative care physician early in the course of their disease, and maintaining the relationship until the end of their lives. While death may occur precipitously as the result of a pulmonary embolism or intracerebral hemorrhage, most patients die after weeks or rarely months of progressive decline following the decision to discontinue aggressive tumor therapy, and hospice services can be extremely valuable to patients and their families in this situation.

Supportive Care (Long-term)

Most patients with glioblastoma who have experienced a seizure require lifelong AED therapy, particularly if seizures occur during or after initial tumor therapy. There is variability in practice regarding patients who experienced seizure at initial presentation and are seizure-free on anti-epileptic therapy following tumor treatment. Many neuro-oncologists recommend lifelong AED therapy in this situation as well, whereas others will consider tapering patients off of antiepileptic therapy after 1 to 2 years if he patient is interested in doing so and electroencephalogram (EEG) at that time does not demonstrate epileptiform discharges. Of course, freedom from seizures cannot be guaranteed, with or without continuation of antiepileptic therapy. Patients electing to attempt to discontinue AEDs should be counseled about seizure safety and avoiding high-risk activities.

Anticoagulation

Patients with glioblastoma are at significant risk of venous thromboembolism and related complications. There is no proven role for prophylactic anticoagulant therapy to prevent deep venous thrombosis (DVT). 142 Instead, patients should be educated about the symptoms of DVT and pulmonary embolism (PE), and physicians should have a low threshold for obtaining confirmatory testing if these symptoms occur. The diagnosis of glioblastoma is not a contraindication for treatment with systemic anticoagulation if a DVT/PE occurs, even in the setting of antiangiogenic therapy. 143 Treatment with low molecular weight heparin products has been shown to be more effective that oral anticoagulation with warfarin in patients with cancer. 144

Psychological and Emotional Well-being

Symptoms of depression and anxiety are common and undertreated in patients with glioblastoma. Many factors may contribute to depression in patients with glioblastoma, including loss of independence and function, the adjustment to the idea of a significantly shortened life, and possibly a direct biological effect of the tumor on neurotransmitter signaling. 145 Many patients and their families find cancer support groups, or ideally brain-tumor-specific support groups, very beneficial both for practical advice and the knowledge that they are not alone in facing this diagnosis. Antidepressant therapy and/or referral to a mental health professional should be considered for patients with symptoms that extend beyond the range of normal adjustment and negatively impact the quality of their lives.

Despite recent progress, glioblastoma remains an incurable tumor with survival under a year and a half for most patients. Multidisciplinary care is necessary to maximize survival time and preserve quality of life. In appropriately selected patients, aggressive surgery may relieve symptoms and prolong survival. Medical oncologists, radiation oncologists, and neurologists work as a team to design and deliver the initial treatment plan, typically involving the combination of RT and TMZ chemotherapy. Radiologists with expertise in the complexities of glioblastoma imaging help make the initial diagnosis and monitor response to therapy.

For glioblastoma survival to continue to improve, advances in each of these specialties and collaboration between specialties will be required. Advances in neurosurgical technique aided by advanced imaging modalities will allow for more extensive safe tumor resection at time of diagnosis and at time of recurrence. Ongoing clinical trials may help refine the long-recognized role of RT for the treatment of newly diagnosed glioblastoma in general and also define its role relative to that of TMZ in elderly patients. Novel therapeutic strategies, recently with an emphasis on molecularly targeted therapies and immunotherapeutic approaches, also hold the potential to significantly change the care of glioblastoma.

Conflict of interest statement . No conflicts of interest are reported for any author.

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• chemotherapy regimen
• glioblastoma
• surgical procedures, operative
• diagnostic imaging
• temozolomide
• standard of care

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Brain tumour detection using machine and deep learning: a systematic review

• Published: 23 May 2024

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• Novsheena Rasool   ORCID: orcid.org/0000-0001-6405-6415 1 &
• Javaid Iqbal Bhat 1  

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Brain tumors rank as the 1oth leading cause of mortality worldwide, accounting for 85% to 95% of all primary nervous system malignancies. The prevalence of this life-threatening disease is steadily increasing worldwide, highlighting the urgent need for an early and precise diagnosis. Timely identification is critical for initiating effective treatment and improving patient survival chances. Delayed diagnosis significantly elevates the risk of mortality. However, the heterogeneous nature of tumor cells poses challenges for radiologists, making manual diagnosis from magnetic resonance imaging (MRI) images time-consuming and complex. Machine learning (ML) and deep learning (DL) have become useful tools in medical image analysis. These techniques facilitate the automated extraction of intricate patterns and features from MRI images, thereby facilitating a more accurate and efficient tumor diagnosis. Furthermore, these algorithms have demonstrated the capability to handle the intricacy and variability of brain tumor characteristics, thereby improving the diagnostic process. A range of deep learning-based algorithms have been utilized to detect brain tumors, yielding impressive results. The purpose of this paper is to provide an exhaustive examination of the latest techniques used for diagnosing brain tumors from MRI imaging, utilizing machine and deep learning technologies. Moreover, it seeks to outline potential avenues for future exploration within this field. The profound insights gleaned from this comprehensive review are poised to offer invaluable guidance and support to both researchers and medical professionals in the healthcare industry.

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Machine learning and deep learning approach for medical image analysis: diagnosis to detection

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Rasool, N., Bhat, J.I. Brain tumour detection using machine and deep learning: a systematic review. Multimed Tools Appl (2024). https://doi.org/10.1007/s11042-024-19333-2

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Risk factors for secondary thyroid cancer in patients with breast cancer: a propensity‑matched SEER analysis

• Yizhuo Diao 1 ,
• Ruiqi Wang 1   na1 ,
• Jiaxue Cui 1   na1 ,
• Chenxin Jin 1 ,
• Yongxing Chen 1 &
• Xiaofeng Li 1  

Scientific Reports volume  14 , Article number:  12679 ( 2024 ) Cite this article

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• Cancer epidemiology
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With the rapid development of imaging technology and comprehensive treatment in modern medicine, the early diagnosis rate of breast cancer is constantly improving, and the prognosis is also improving; As breast cancer patients survive longer, the risk of developing second primary cancers increases. Since both breast and thyroid are Hormone receptor sensitive organs, which are regulated by hypothalamus pituitary target gland endocrine axis, changes in body endocrine status may lead to the occurrence of these two diseases in succession or simultaneously. This study extracted clinical data and survival outcomes of breast cancer patients registered in the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2019. After matching the case and controls with propensity scores, the selected patients were randomly split into training and test datasets at a ratio of 7:3. Univariate and multivariate COX proportional regression analysis is used to determine independent risk factors for secondary thyroid cancer and construct a column chart prediction model. Age, ethnicity, whether radiotherapy, tumor primary location, N stage, M stage were identified by Cox regression as independent factors affecting secondary thyroid cancer in patients with breast cancer patients, and a risk factor nomogram was established to predict patients’ 3 and 5 year survival probabilities. The AUC values for 3 and 5 years in the training set were 0.713, 0.707, and the c-index was 0.693 (95% CI 0.67144, 0.71456), and the AUC values for 3 and 5 years in the validation set were 0.681, 0.681, and the c-index was 0.673 (95% CI 0.64164, 0.70436), respectively.

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Impact of thyroid hormone replacement on the risk of second cancer after thyroidectomy: a Korean National Cohort Study

Introduction.

Breast cancer is a malignant tumor that occurs in the Epithelium of the breast gland 1 . It is the “No. 1 public enemy” that threatens the physical and mental health of women around the world today 2 . It ranks first in the incidence and death of cancer among women in most countries around the world 3 . According to the data of the 2023 American Cancer Statistical Report, breast cancer is still one of the three most common cancers among women 4 ,occupying the first place in expected new cases among women; With the rapid development of imaging technology and comprehensive treatment in modern medicine 5 , the early diagnosis rate of breast cancer continues to improve, and the prognosis also improves 6 .The disease-free survival rate and overall survival rate of breast cancer patients have significantly improved; With the prolongation of the survival period of breast cancer patients, the risk of second primary cancer (SPC) may increase 7 ; Thyroid cancer is a malignant tumor originating from thyroid follicular epithelium 8 . It is considered to be an inert tumor 9 and the most common malignant tumor in the Endocrine system and head and neck tumors 10 ; Since both breast and thyroid are Hormone receptor sensitive organs, which are regulated by hypothalamus pituitary target gland endocrine axis, changes in body endocrine status may lead to the occurrence of these two diseases in succession or simultaneously.

Materials and methods

Data sources.

The SEER database containing 13 registry centers prepared by the National Cancer Institute was selected for the data of this study, and a total of 692,555 patients diagnosed with breast cancer from 2010 to 2019 were extracted from the database using the SEER*Stat software program, and a total of 393,722 patients were screened according to the inclusion and exclusion criteria.

Inclusion and exclusion criteria

Inclusion criteria.

(1) Patients diagnosed with breast cancer as the first tumor from 2010 to 2019 (2) Patients with no more than 2 tumors and the second type of tumor is thyroid cancer (3) Female patients (4) Patients with complete clinical data(Includes time of diagnosis, age at diagnosis, marital status at diagnosis, site of origin, mode of diagnostic confirmation, mode of case report, chemotherapy or not, radiotherapy or not, molecular typing, Progesterone Receptor, Estrogen Receptor, T,N, and M typing, type of secondary second tumor, interval between secondary second tumors, survival time, survival status)

Exclusion criteria

(1) Those with benign tumors (2) Proven only at autopsy or death (3) Patients with thyroid cancer occurring within 3 months of breast cancer diagnosis

Independent variables

The study data were converted to categorical variables in order to make the study more intuitive and standardized. Race was categorized as black, white, and other; marital status was categorized as married, unmarried; radiation and chemotherapy status was categorized as yes, no; primary tumor location was categorized as mid-breast, quadrant I, quadrant II, quadrant III, quadrant IV, and other; estrogen receptor (ER), and progesterone receptor (PR) status was categorized as estrogen receptor (ER) and progesterone receptor (PR) status positive and negative; and molecular staging included LuminalA, LuminalB, HER2 overexpression and triple-negative; T staging as T0T1, T2, T3 and T4; N staging as N0, N1, N2 and N3; M staging as M0 and M1; and secondary thyroid cancer status as yes or no.

Statistical methods

R4.2.3 statistical software was used for analysis. Patient standardized incidence rates (SIR) were calculated using the Multiple Principal Standardized Incidence Rates (MP-SIR) module of SEER Stat 8.4.1 software. Due to the large difference in sample sizes between the case and control groups in this study, in order to equalize the distribution of covariates between the groups, equalize confounders, and reduce selection bias, we introduced the propensity score matching (PSM) method 11 , in which the two groups of patients were matched in a ratio of 1:4 12 . Using the R software package MatchIt , the PSM method was used to match the case and control groups according to the year of diagnosis in a 1:4 ratio, and a total of 392,803 patients with unilateral breast cancer were included as controls, and a 1:4 matching of the case and control groups was accomplished based on the year of diagnosis of breast cancer in the 919 case group of thyroid cancer secondary to breast cancer. Patients served as controls. To ensure that the 919 cases were matched to the 3676 controls, caliper distances were chosen to be as small as possible. Propensity scores were calculated using a logistic regression model, and for better matching, the final matching caliper distance was 0.1. The standardized mean difference (SMD) was used to assess the balance of baseline information between the case and control groups after PSM. We considered SMD less than or equal to 0.1 to indicate a good match 11 .

Further univariate and multivariate analyses were performed using the COX proportional risk model to determine the risk factors for secondary thyroid cancer in breast cancer patients. R-studio software was used to randomly divide all the data into training and validation sets in the ratio of 7:3, and χ 2 test and t-test were performed on different variables in the training and validation sets, and then univariate and multivariate Cox regression analyses were carried out on the data in the training set in order to train the model, and the validation set was used to validate the model 13 . A nomogram was created using the R packages rms , foreign and survival for the final filtered variables and the ROC curves were used to create the nomograms under the ROC curves. The area under the ROC curve (AUC value) and C-index were used to evaluate the accuracy of the model, the AUC and C-index range from 0 to 1, the closer to 1 indicates that the model is more accurate, and it is usually considered that the model has a better predictive ability when the AUC reaches more than 0.7; the calibration curve was used to evaluate the degree of calibration of the model, and the closer the calibration curve is to the standard curve, the stronger the predictive ability of the model. Variables with a univariate COX regression of P < 0.1 were included in the multifactor analysis, and the multifactor analysis was included in the final model with the criterion that the difference was considered statistically significant at P < 0.05 14 .

Ethical approval and consent to participate

Not applicable. Data is available in a public database, ethics approval is not applicable.

Standardized incidence rate

The SEER Stat 8.4.1 analysis yielded a SIR result of 14.89 with a 95% CI of 14.02–15.79 for the period 2010–2019, a predicted number of people of 74.16, and a 10 year actual number of people of 1104, with an incidence rate of 159.41/100,000, which leads to the conclusion that patients who already have breast cancer are more likely to develop thyroid cancer than healthy people.

Propensity score matching

919 patients with thyroid cancer secondary to breast cancer after screening as case group and 392,803 patients with solitary breast cancer as control group were included in the propensity score matching, according to the year of diagnosis according to the PSM method to achieve 1:4 matching, and finally a total of 919 cases in the case group and 3676 cases in the control group were obtained, and the results are shown in Table 1 . The R language tableone package automatically uses analysis of variance for continuous variables, which is equivalent to t-test since this data is only divided into two groups. The result before matching was P < 0.001 and the result after matching was P = 1, SMD < 0.001, which can be considered as well balanced between the matched case group and the control group.

Baseline information

The 919 patients with thyroid cancer secondary to breast cancer and the 3676 patients only with breast cancer obtained after propensity score matching, for a total of 4595 patients, were included in subsequent model analyses. The baseline data of the 4595 patients are shown in Table 2 .

Comparison of baseline characteristics

The 4594 patients obtained after propensity score matching were randomly divided into training set and validation set according to the ratio of 7:3, 3219 patients in the training set and 1376 patients in the validation set. t-test was used for continuous variables, and chi-square test was used for categorical variables to characterize the intergroup differences between the training set and the validation set, and the p-values were all greater than 0.05, which proved that there were no intergroup differences in the results of the randomized splitting, and the results are shown in Table 3 .

Results of univariate and multivariate cox regressions

The training set patient data were included in univariate Cox regression analysis for each of the 12 variables. To avoid omission of important variables, 11 variables with P < 0.1 in the univariate Cox regression were included in the multivariate Cox regression. We included the variables with p < 0.1 in the univariate Cox regression analysis to the multivariate Cox model to examine the independent risk factors for second thyroid cancer; when P < 0.05 in multivariate Cox regression analysis, the factor was an independent risk factor affecting patients’ secondary thyroid cancer. The results of this univariate Cox regression showed that age, ethnicity, marital status, primary tumor location, molecular typing, PR status, ER status, whether radiotherapy, whether chemotherapy, T stage, N stage, M stage were the factors affecting the secondary thyroid cancer in breast cancer patients; while the results of multivariate Cox regression showed that age, race, whether radiotherapy, primary tumor location, N-stage, and M-stage were independent risk factors affecting the development of thyroid cancer in patients with breast cancer, and the results are shown in Table 4 .

Creation of nomogram

Variables screened in the multifactorial Cox regression analysis (P < 0.05) were included in the cox proportional risk model, and nomograms were created using R-studio software. Each variable was projected upward for breast cancer patients, and then each score on the scale was summed to obtain a total score, based on which the risk of secondary thyroid cancer in breast cancer patients at 3 and 5 years could be predicted, and the higher the total score the higher the risk, the prediction results are shown in Fig. 1 . Patients with breast cancer who were younger, received radiotherapy, had N1 staging, M1 staging, were white and other race, and had a primary in the inner lower quadrant were at greater risk of secondary thyroid cancer.

The nomogram of the COX proportional risk model.

Validation of nomogram

Using the ROC curve AUC value and c-index to evaluate the differentiation of the model, we found that, in the Cox proportional risk regression model, the AUC values of three and five years for the patients in the training set (Fig. 2 ) were 0.713, 0.707, and the c -index was 0.693 (95% CI 0.67144, 0.71456), respectively, and the AUC of three and five years for the patients in the validation set (Fig. 3 ) values were 0.681, 0.681,c-index was 0.673 (95% CI 0.64164, 0.70436 respectively), we can consider the model as having moderate predictive power. The calibration plots were plotted using the data from the validation set to evaluate the fit of the established model, and the results showed that in the Cox proportional risk regression model, the calibration curves of 3 and 5 years were close to the dotted line with a 45 ° inclination in the middle, which indicated that the model fit was better.The calibration curves of 3 and 5 years are shown in Fig. 4 .

Three and Five year ROC curves for patients in the training center.

Three and Five year ROC curves for patients in the validation set.

The calibration curves of 3 and 5 years.

Utility and discussion

Breast cancer is known as the world’s number one “red face killer”, according to the latest cancer data released by the World Health Organization, the number of new cases of breast cancer (2.26 million) has exceeded that of lung cancer (2.2 million), and has become the most prevalent cancer in the world 4 . In recent years, more and more general hospitals have set up thyroid breast surgery departments, mainly because it is generally recognized that both the thyroid and the breast are target organs for hormone regulation by the hypothalamic-pituitary endocrine axis, and there are some common pathogenic factors in the two. Therefore, the use of a combination of clinical diagnostics and intelligent means to determine the risk factors for secondary thyroid cancer in breast cancer patients is important for both doctors and patients, and it can guide breast cancer patients for follow-up screening and help clinicians develop treatment plans for the general population and breast cancer survivors.

Although the number of breast cancer patients has been increasing year by year, the low incidence of dual primary cancers, the fact that patients with second primary cancer may be seen in different hospitals, the difficulty of data collection and the long time required for follow-up make the collection of data for the study of dual primary cancers of the breast still difficult. Therefore, this study chooses the U.S. National Cancer Database (SEER), which covers about 30% of the U.S. population, updates patient data in March to April every year, and has a large number of patients with a long follow-up period, making it a more ideal source of data for the study of dual primary cancers.

A total of 692,555 patients diagnosed with breast cancer in the SEER database from 2010 to 2019 were included in this study, and the SEERSTATA software was used to calculate the SIR > 1 for thyroid cancer secondary to breast cancer, and it can be assumed that patients with breast cancer are more likely to develop thyroid cancer compared to cancer-free populations, which is consistent with the findings of previous literature. Due to the large difference in sample size between the case and control groups, in order to minimize bias, we matched 919 patients with thyroid cancer secondary to breast cancer as the case group and 393,722 patients with solitary breast cancer as the control group using propensity score matching. Because the diagnostic criteria, examination instruments, and staging criteria may differ between years, we performed 1:4 propensity score matching according to the year of diagnosis to minimize confounding bias and to include as many control cases as possible to ensure representativeness 12 . The matched 4595 patients were randomly divided into training set and validation set in the ratio of 7:3, and the obtained training set was used to train the cox regression model, and the validation set was used to verify the stability of the model 15 , 16 . The results of univariate cox regression showed that the 11 factors included except ER were independent factors for secondary thyroid cancer in breast cancer patients, and the results of multivariate cox regression showed that age, ethnicity, location of primary tumor, whether or not to have radiotherapy, N-stage, and M-stage were independent factors for secondary thyroid cancer in breast cancer patients.

Contrary to the general impression that age, as a continuous variable with an OR value of less than 1, is considered a protective factor against secondary thyroid cancer from breast cancer, the younger the age, the more likely it is to be secondary thyroid cancer, and previous studies by other scholars have also demonstrated that patients with secondary thyroid cancer after breast cancer were younger compared with those who had breast cancer only 17 , which we believe may be related to the recent years of rejuvenation of the incidence of breast cancer, the early diagnosis and early treatment that makes the breast cancer patient. We believe that this may be related to the recent rejuvenation of breast cancer incidence, prolonged survival due to early diagnosis and early treatment, and the modern lifestyle, where a good prognosis increases the likelihood of a secondary second tumor. However, in some scholars’ studies, age is a risk factor for survival in patients with thyroid cancer secondary to breast cancer relative to patients with solitary breast cancer, and older patients are more likely to have lower survival rates 18 . In conclusion, age is an extremely important factor affecting breast cancer patients with secondary thyroid cancer and warrants further study.

In terms of race, the SEER database has more white profiles due to region, and multivariate cox results show that whiteness and other ethnicities are independent risk factors for secondary thyroid cancers in patients with breast cancer. This may be related to the level of medical care, conditions, and other factors that were co-incorporated into the study, with genetic susceptibility playing a different role in different factors. Mariotto A.B. et al. suggest that the higher incidence of second primary cancers among white women is due to the higher overall survival and screening rates among white women compared to black female populations, and that more comprehensive medical coverage and higher levels of medical care make it easier to diagnose the disease, which would inevitably lead to an increase in the number of diagnoses if these cancers were diagnosed at an earlier stage, which would be consistent with the results of the present study 19 . If these cancers were diagnosed at an early stage, this would inevitably lead to an increase in the number of diagnoses. However the study by Shuting Li et al. suggests that black women with breast cancer should be given attention 13 . However, in a study by Karan Seegobin et al., it was found that there was no significant difference in the incidence of secondary breast and gynecologic cancers between Caucasians and Blacks 20 ,which may be due to the different target second primary cancer disease types in the study, and further research is needed in the future.

Breast cancer patients who receive radiation therapy are more likely to develop secondary thyroid cancers compared to those who do not, a finding that is generally consistent with current clinical opinion that radiation therapy can affect thyroid hormone secretion and thyroid function 21 . The relationship between radiation therapy and the risk of second primary cancers has long been recognized, and it has been demonstrated that radiation therapy is associated with an increased risk of second primary malignancies after exposure 21 . In several observational studies of breast cancer follow-up, the incidence of subsequent secondary acute myeloid leukemia was increased in patients with breast cancer, which may be related to the dose intensity of chemotherapy, the use of adjuvant radiotherapy, and the use of granulocyte colony-stimulating factor (GCSF) 22 . Data from the DBCG (The Danish Breast Cancer Cooperative Group) registry estimate that the proportion of second primary cancers after breast cancer associated with radiation therapy is about 9%. This is consistent with the results from the US SEER database registry 23 . However Grantzau’s analysis found that breast cancer radiotherapy was associated with a small but significant increase in the risk of second cancers for lung, esophageal, and soft tissue cancers, but was not significantly associated with second cancers for thyroid cancer 24 . Another study on the health of the population in Taiwan compared the risk of TC in BC patients who received radiotherapy and those who did not, and the risk of TC in women who received radiotherapy was not significantly higher than that in women who did not receive radiotherapy. This may be related to the selection of data from different ethnic groups in different regions.

In addition, some researchers have suggested that the ER/PR signaling pathway may be a common etiology of breast and thyroid carcinogenesis, and studies of its mechanisms, including the ER pathway and CHEK2 gene mutations in thyroid tissues. In our study, only PR receptor status was an independent factor for secondary thyroid cancer in breast cancer patients. Some researchers have suggested that patients with secondary thyroid cancer have a higher rate of both ER and PR positivity than patients with breast cancer only 25 , 26 .ER has two isoforms, Erα and Erβ, and overexpression of ERα in thyroid cancer tissues and lack of expression of ERβ in peripheral tissues was reported in 2011 27 , and under-expression or deletion of ER can be considered a hallmark of thyroid cancer 28 . Undifferentiated thyroid stem and progenitor cells express lower levels of ERβ compared to differentiated human thyroid cells 29 . Therefore, low levels of ER expression may suggest dedifferentiation of thyroid cancer 27 , 30 . The fact that this paper did not conclude that ER has an effect on secondary thyroid cancer in breast cancer patients may be related to the fact that gene-related variables were not included in this study, and that the SEER database contains only baseline and treatment information and no genetic data, which is a limitation that exists in this study 31 , 32 , 33 .

In AJCC staging, T stage represents the size and extent of the tumor, N stage represents lymph node metastasis, and M stage represents distant spread, with more stages representing more seriousness and worse prognosis. In this study, it was concluded that in N staging, breast cancer patients with N1 stage were more likely to develop secondary thyroid cancer compared to other stages, which may be related to the survival period, and we believe that only if the survival period is long enough, there is a possibility of developing a second primary tumor, while patients with N1 stage had lymph node metastasis, but it was not as serious as N2, N3, and N4 stage, so they were more likely to have a longer survival period; while patients with N0 stage had not No lymph node metastasis has occurred, and from the perspective of disease development, the possibility of secondary cancer is less than that of stage N1.In M stage, M0 stage represents no distant metastasis, and M1 stage represents distant metastasis, and we generally know that tumors with metastases are more likely to cause other cancers.

To summarize, in this study, univariate and multivariate cox analyses were used to screen the influencing factors of secondary thyroid cancer in breast cancer patients, respectively, and a column-line diagram was successfully established, and the calibration curves of the training and validation sets were well fitted, and the AUC and c-index reached significance. It is suggested that the column-line diagram has good predictive ability for the risk of secondary thyroid cancer in breast cancer patients 3 and 5 years after the onset of the disease. However, since the data were obtained from the United States, more studies are needed to verify whether the results obtained by applying this data can be applied to the Chinese population, and the results of this study can provide some references for clinicians 14 .

This study also has some limitations; first, this is a retrospective study, and selection bias due to incomplete data is inevitable. Although we used PSM to avoid selection bias, potential confounders cannot be excluded. Secondly, the Cox model fits well, but the AUC of the validation set is less than 0.7, which represents that the predictive ability of the model is still lacking, which may be related to the fact that breast cancer patients have a good prognosis and a long survival period, while only ten years of data have been observed in the present study, so in the future, we need more follow-up data to improve the model. Because the SEER database itself provides a limited amount of information and the database does not provide any information about genes, we were unable to study the genetic correlation of breast cancer secondary to thyroid cancer at the genetic level. The database has not been updated with data on tumor grading since 2017, so it is not possible to analyze the grading situation, which deserves further study in the future.

Conclusions

In summary, our study suggests that breast cancer patients are more likely to develop thyroid cancer compared to the general population. Among them, age, ethnicity, marital status, primary tumor location, molecular typing, PR status, ER status, whether or not radiotherapy, whether or not chemotherapy, T stage, N stage, and M stage are the factors affecting the secondary thyroid cancer in breast cancer patients; age, ethnicity, whether or not radiotherapy was performed, primary location of the tumor, N stage, and M stage are the independent factors affecting the secondary thyroid cancer in patients with breast cancer patients: the younger the age, the whiter the ethnicity, the whites and the other ethnicities, undergoing radiotherapy, internal lower quadrant and other locations, N1 stage, and M1 stage are more likely to develop thyroid cancer in breast cancer patients.

Data availability

The datasets analyzed during the current study are available in the SEER*Stat software (version 8.4.2, download from https://seer.cancer.gov/data/options.html ). A registration form needs to be completed before using and filtercriteria need to be added. The datasets are also available from the corresponding author on reasonable request.

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Acknowledgements

We would like to thank Editage for English language editing.

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These authors contributed equally: Ruiqi Wang and Jiaxue Cui.

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Department of Epidemiology and Health Statistics, Dalian Medical University, 9 Lvshun South Road, Dalian, 116044, Liaoning, China

Yizhuo Diao, Ruiqi Wang, Jiaxue Cui, Chenxin Jin, Yongxing Chen & Xiaofeng Li

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Y.D. (first author): design, original draft preparation, software analysis, data analysis and interpretation, manuscript writing, final approval of manuscript. R.W.: data interpretation, final approval of manuscript. J.C: collection data, final approval of manuscript. C.J.: methodology, final approval of manuscript. Y.C.: methodology, final approval of manuscript. X.L.: corresponding author, guide the revision of the article, final approval of manuscript.

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Diao, Y., Wang, R., Cui, J. et al. Risk factors for secondary thyroid cancer in patients with breast cancer: a propensity‑matched SEER analysis. Sci Rep 14 , 12679 (2024). https://doi.org/10.1038/s41598-024-59209-x

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DOI : https://doi.org/10.1038/s41598-024-59209-x

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