Rodent Brain Tumor Models for Studies Focusing on Boron Neutron Capture Therapy.

Rodent brain tumor models have been very useful in advancing the treatment of glioblastomas. This review focuses on the four most widely used rodent brain tumor models: the C6, 9L, and F98 rat gliomas, and the GL261 murine glioma. All of these have been used in studies relating to boron neutron capture therapy. The most important of these studies were those using the 9L gliosarcoma, which led to the clinical use of boronophenylalanine, and the F98 glioma, which has been used for the preclinical evaluation of new boron delivery agents and methods of optimizing their delivery.

Rat and Mouse Brain Tumor Models for Experimental Neuro-Oncology Research.

Rodent brain tumor models have been useful for developing effective therapies for glioblastomas (GBMs). In this review, we first discuss the 3 most commonly used rat brain tumor models, the C6, 9L, and F98 gliomas, which are all induced by repeated injections of nitrosourea to adult rats. The C6 glioma arose in an outbred Wistar rat and its potential to evoke an alloimmune response is a serious limitation. The 9L gliosarcoma arose in a Fischer rat and is strongly immunogenic, which must be taken into consideration when using it for therapy studies. The F98 glioma may be the best of the 3 but it does not fully recapitulate human GBMs because it is weakly immunogenic. Next, we discuss a number of mouse models. The first are human patient-derived xenograft gliomas in immunodeficient mice. These have failed to reproduce the tumor-host interactions and microenvironment of human GBMs. Genetically engineered mouse models recapitulate the molecular alterations of GBMs in an immunocompetent environment and "humanized" mouse models repopulate with human immune cells. While the latter are rarely isogenic, expensive to produce, and challenging to use, they represent an important advance. The advantages and limitations of each of these brain tumor models are discussed. This information will assist investigators in selecting the most appropriate model for the specific focus of their research.

A Comparison of the Clinical, Viral, Pathologic, and Immunologic Features of Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and Coronavirus 2019 (COVID-19) Diseases.

CONTEXT.­: The purpose of this review was to compare 3 coronavirus diseases, including severe acute respiratory syndrome, Middle East respiratory syndrome, and COVID-19 caused by SARS-CoV, MERS-CoV, and SARS-CoV-2 viruses, respectively. OBJECTIVE.­: To cover the following topics: clinical considerations, viral characteristics, pathology, immune response, pathogenesis, and the prognosis associated with each coronavirus disease in humans. DATA SOURCES.­: Clinically, flu-like symptoms are usual at the time of presentation for all 3 diseases, but these vary from asymptomatic to severe multisystem involvement. The pathology associated with symptomatic severe acute respiratory syndrome and COVID-19 has been well described, the most prominent of which is diffuse alveolar damage. The immune response to each of these viruses is highly complex and includes both humoral and cellular components that can have a significant impact on prognosis. In severe cases of COVID-19, a dysregulated innate host immune system can initiate a hyperinflammatory syndrome dominated by endothelial dysfunction that can lead to a hypercoagulable state with microthrombi, resulting in a systemic microvascular and macrovascular disease. CONCLUSIONS.­: The severe acute respiratory syndrome and Middle East respiratory syndrome epidemics have been limited, involving approximately 8000 and 2500 individuals, respectively. In contrast, COVID-19 has resulted in a worldwide pandemic with more than 177 million cases and 3.9 million deaths as of June 15, 2021, and fatality rates ranging from less than 0.1% to approximately 10% depending upon the country. Ending on a positive note, the development of a number of vaccines, at least 6 of which now are in clinical use, should mitigate and eventually control the devastating COVID-19 pandemic.

The illness and death of King George VI of England: the pathologists' reassessment.

The illness and death of King George VI has received renewed attention based on the events portrayed in the Netflix blockbuster series, The Crown. The King, a heavy smoker, underwent a left total pneumonectomy in September 1951 for what euphemistically was called "structural abnormalities" of his left lung, but what in reality was a carcinoma. His physicians withheld this diagnosis from him, the public, and the medical profession. The continuation of hemoptysis following surgery suggested that his cancer had spread to his right lung. Although he made a slow and uneventful recovery from his surgery, King George VI died suddenly and unexpectedly in his sleep on February 6, 1952, at the age of 56. Since the King had a history of peripheral vascular disease, it was assumed that the cause of death was a "coronary thrombosis." In this report, we explore the cardiovascular and oncologic findings relating to his illness and death and consider an alternative explanation for his demise, namely, that he may have died of complications from a carcinoma that had originated in his left lung and spread to his right lung, as evidenced by continued hemoptysis. We suggest that this possibly could have led to his sudden death due to either a pulmonary embolus or a massive intra-thoracic hemorrhage rather than a "coronary thrombosis."

An unexpected paradox: wall shear stress in the aorta is less in patients with severe atherosclerosis regardless of obesity.

BACKGROUND: Obesity is a widespread condition that is more prevalent in Western countries compared to others. Aortic atherosclerosis (AA) is a condition that frequently has been associated with obesity. An obesity paradox, where morbidly obese decedents had either no or minimal AA compared to nonobese decedents, recently has been described by some of us. The explanation for this almost counterintuitive paradox has yet to be determined, but a number of hypotheses were advanced, including hemodynamic factors producing aortic wall shear stress (WSS). The purpose of the present study was to determine if there was a relationship between AA and WSS, as determined by postmortem measurement of aortic wall diameters. METHODS: Circumferences of the aorta at the levels of the ascending, thoracic and abdominal aorta were measured in 274 consecutive autopsies over 2-year period of time. AA was assessed using a previously described grading scale as either mild or severe. Circumferences were mathematically converted to diameters and WSS was calculated using the Hagen-Poiseuille formula. Two different methods to estimate cardiac output were used, both based on literature methods, one of which was body mass index (BMI) dependent, and the other BMI independent. Univariate and multivariable analyses of the relationship between WSS, age, BMI, gender, race and severity of AA were performed. RESULTS: Of the 274 decedents, 140 had mild and 134 had moderate to severe AA. BMI <35 was associated with moderate to severe AA. WSS was inversely correlated with AA in all these segments of the aorta in each BMI subgroup with the exception of the ascending aorta for decedents with BMI ≤35 kg/m2. Contrary to what we had hypothesized, WSS was not a determinant of the obesity paradox. However, among all the variables analyzed, a history of hypertension, diabetes mellitus and age were significant factors for developing AA (relative risk [RR] 0.35, P = .039; RR 1.51, P = .0006, RR 1.19, P = .0001, respectively). CONCLUSIONS: Our data demonstrate that WSS was unexpectedly lower in decedents with moderate and severe AA as compared to those with mild AA. This observation, which requires further investigations, was seen in all BMI ranges and was confirmed by 2 methods to calculate WSS.

Phase I trial of intracerebral convection-enhanced delivery of carboplatin for treatment of recurrent high-grade gliomas.

BACKGROUND: Carboplatin is a potent cytoreductive agent for a variety of solid tumors. However, when delivered systemically, clinical efficacy for the treatment of high grade gliomas is poor due to limited penetration across the blood-brain barrier (BBB). Direct intracerebral (IC) convection-enhanced delivery (CED) of carboplatin has been used to bypass the BBB and successfully treat the F98 rat glioma. Based on these studies, we initiated a Phase I clinical trial. OBJECTIVE: This Phase I clinical trial was conducted to establish the maximum tolerated dose and define the toxicity profile of carboplatin delivered intracerebrally via convection enhanced delivery (CED) for patients with high grade glial neoplasms. METHODS: Cohorts of 3 patients with recurrent WHO grade III or IV gliomas were treated with escalating doses of CED carboplatin (1-4 µg in 54mL over 72 hours) delivered via catheters placed at the time of recurrent tumor resection. The primary outcome measure was determination of the maximum tolerated dose (MTD). Secondary outcome measures included overall survival (OS), progression-free survival (PFS), and radiographic correlation. RESULTS: A total of 10 patients have completed treatment with infusion doses of carboplatin of 1µg, 2µg, and 4µg. The total planned volume of infusion was 54mL for each patient. All patients had previously received surgery and chemoradiation. Histology at treatment include GBM (n = 9) and anaplastic oligodendroglioma (n = 1). Median KPS was 90 (range, 70 to 100) at time of treatment. Median PFS and OS were 2.1 and 9.6 months after completion of CED, respectively. A single adverse event possibly related to treatment was noted (generalized seizure). CONCLUSIONS: IC CED of carboplatin as a potential therapy for recurrent malignant glioma is feasible and safe at doses up to 4µg in 54mL over 72 hours. Further studies are needed to determine the maximum tolerated dose and potential efficacy.

Radiation therapy combined with intracerebral convection-enhanced delivery of cisplatin or carboplatin for treatment of the F98 rat glioma.

BACKGROUND: The purpose of this review is to summarize our own experimental studies carried out over a 13-year period of time using the F98 rat glioma as model for high grade gliomas. We evaluated a binary chemo-radiotherapeutic modality that combines either cisplatin (CDDP) or carboplatin, administered intracerebrally (i.c.) by means of convection-enhanced delivery (CED) or osmotic pumps, in combination with either synchrotron or conventional X-irradiation. METHODS: F98 glioma cells were implanted stereotactically into the brains of syngeneic Fischer rats. Approximately 14 days later, either CDDP or carboplatin was administered i.c. by CED, followed 24 h later by radiotherapy using either a synchrotron or, subsequently, megavoltage linear accelerators (LINAC). RESULTS: CDDP was administered at a dose of 3 µg in 5 µL, followed 24 h later with an irradiation dose of 15 Gy or carboplatin at a dose of 20 µg in 10 µL, followed 24 h later with 3 fractions of 8 Gy each, at the source at the European Synchrotron Radiation Facility (ESRF). This resulted in a median survival time (MeST) > 180 days with 33% long term survivors (LTS) for CDDP and a MeST > 60 days with 8 to 22% LTS, for carboplatin. Subsequently it became apparent that comparable survival data could be obtained with megavoltage X-irradiation using a LINAC source. The best survival data were obtained with a dose of 72 µg of carboplatin administered by means of Alzet® osmotic pumps over 7 days. This resulted in a MeST of > 180 days, with 55% LTS. Histopathologic examination of all the brains of the surviving rats revealed no residual tumor cells or evidence of significant radiation related effects. CONCLUSIONS: The results obtained using this combination therapy has, to the best of our knowledge, yielded the most promising survival data ever reported using the F98 glioma model.

Boron neutron capture therapy at the crossroads - Where do we go from here?

As elegant as is the concept upon which Boron Neutron Capture Therapy (BNCT) is based, unfortunately it has not gained widespread acceptance by the physicians who are treating cancer patients on a daily basis. The question is why? Very simply put, the clinical results obtained in treating patients with high grade gliomas and recurrent tumors of the head and neck region have not been convincing enough to produce more interest in BNCT as a cancer treatment modality. There are a variety of reasons for this, one of the most important of which has been its dependency on nuclear reactors as neutron sources. With the advent of accelerator based neutron sources (ABNS), this hopefully will be addressed. If the results obtained from ongoing and soon to be initiated clinical trials can at least demonstrate equivalency to those obtained with nuclear reactors, this should address the first problem. The second problem relates to boron delivery agents, and despite the considerable efforts of chemists and biologists over the past 50 years, there are only two drugs that currently are being used clinically, sodium borocaptate (BSH) and boronophenylalanine (BPA). It is widely recognized that these two drugs are less than ideal. Perhaps new and more effective boron delivery agents will finally appear on the scene, but barring that, we will address the question of what can be done now to make BNCT a more effective cancer treatment modality.

Clinicopathological complexity in the application of the universal definition of myocardial infarction.

A universal definition of myocardial infarction (UDMI) has been established, periodically updated, and refined over the past twenty years. The primary purpose of the UDMI is to bring uniformity and accuracy to clinical diagnosis. Herein, a review and analysis of the UDMI is presented with emphasis on clinicopathological correlation. Determination of the presence of myocardial injury is based on the detection of abnormal serum cardiac biomarkers, particularly cardiac troponin (cTn), and in the current fourth iteration of the UDMI, high sensitivity (hs)-cTn. Differentiation of myocardial infarction from other causes of myocardial injury requires the documentation of clinical evidence of myocardial ischemia. In this review, difficulties in applying the UDMI in actual practice are discussed, based on the experience and perspective of those of us who face these problems as part of our own practice of pathology. The complexity in application of the UDMI is highlighted by the presentation of five illustrative cases involving the differential diagnosis of myocardial injury and myocardial infarction due to atherothrombotic and nonatherothrombotic coronary artery disease. The cases include myocardial infarction due to severe coronary atherosclerosis, supply-demand mismatch, coronary artery dissection associated with an eosinophilic coronary periarteritis, and coronary thromboembolism, and a case with a differential diagnosis of myocarditis and myocardial infarction. These cases illustrate how pathological findings can contribute to more accurate application of the UDMI and how, when critically applied, the UDMI can be used to better characterize myocardial infarcts in clinical practice.

What did Joseph Stalin really die of? A reappraisal of his illness, death, and autopsy findings.

Joseph Stalin was one of the most important world leaders during the first half of the 20th century. He died suddenly in early March 1953 after a short illness, which was described in a series of medical bulletins in the Soviet newspaper Pravda. Based on both the clinical history and autopsy findings, it was concluded that Stalin had died of a massive hemorrhagic stroke involving his left cerebral hemisphere. However, almost 50 years later, a counter-narrative developed suggesting a more nefarious explanation for his sudden death, namely, that a "poison," warfarin, a potent anticoagulant, had been administered surreptitiously by one or more of his close associates during the early morning hours prior to the onset of his stroke. In the present report, we will examine this counter-narrative and suggest that his death was not due to the administration of warfarin but rather to a hypertension-related cerebrovascular accident resulting in a massive hemorrhagic stroke involving his left cerebral hemisphere. The counter-narrative was based on the misunderstanding of certain specific autopsy findings, namely, the presence of focal myocardial and petechial hemorrhages in the gastric and intestinal mucosa, which could be attributed to the extracranial pathophysiologic changes that can occur as a consequence of a stroke rather than the highly speculative counter-narrative that Stalin was "poisoned" by the administration of warfarin.

The Importance of the Autopsy in Medicine: Perspectives of Pathology Colleagues.

This article presents a perspective on the importance of the autopsy in medical practice and science based on experiences of the authors as physician-scientists involved in autopsy practice. Our perspectives are presented on the seminal contributions of the autopsy in the areas of cardiovascular disease, including congenital heart disease, atherosclerosis, coronary artery disease, and myocardial infarction, and infectious disease, including tuberculosis and viral infections. On the positive side of the future of the autopsy, we discuss the tremendous opportunities for important research to be done by application of advanced molecular biological techniques to formalin-fixed, paraffin-embedded tissue blocks obtained at autopsy. We also note with concern the countervailing forces impacting the influence of pathology in education and clinical practice at our academic medical centers, which also present impediments to increasing autopsy rates. Our challenge as academic pathologists, whose careers have been molded by involvement in the autopsy, is to counter these trends. The challenges are great but the benefits for medicine and society are enormous.

Genomic Analysis of an Obesity Paradox: A Microarray Study of the Aortas of Morbidly Obese Decedents With Mild and Severe Atherosclerosis.

BACKGROUND: Atherosclerosis of the aorta and coronary arteries is still one of the major causes of death. We recently reported obesity paradox between body mass index and atherosclerosis of the aortas (AA) in morbidly obese decedent patients. The cause of this obesity paradox is unknown. The aim of the present study was to carry out genomic microarray analysis to determine gene expression profiles in the aortas of morbidly obese decedents with either mild or severe atherosclerosis of the aorta. METHODS: Microarray studies using Affymetrix GeneChips Clariom D Human array chips were performed on the aortas obtained from 6 morbidly obese decedents, 3 of whom had minimal AA and 3 who had severe disease. RESULTS: Group 1 (severe AA) and group 2 (mild AA) included 3 patients each. The patients were matched by age and body mass index. There were significant (P<0.005) differences in the expressions of 1067 genes between groups 1 and 2, including 602 upregulated and 465 downregulated genes. CONCLUSIONS: Our data show significantly different gene signatures between morbidly obese decedents who have mild or severe AA, suggesting that genetic factors may be important contributors to the obesity paradox as it relates to aortic atherosclerosis. Further studies are warranted to define differences in protein expression in the aortas of these 2 groups to further elucidate the cause of this obesity paradox.

Boron delivery agents for neutron capture therapy of cancer.

Boron neutron capture therapy (BNCT) is a binary radiotherapeutic modality based on the nuclear capture and fission reactions that occur when the stable isotope, boron-10, is irradiated with neutrons to produce high energy alpha particles. This review will focus on tumor-targeting boron delivery agents that are an essential component of this binary system. Two low molecular weight boron-containing drugs currently are being used clinically, boronophenylalanine (BPA) and sodium borocaptate (BSH). Although they are far from being ideal, their therapeutic efficacy has been demonstrated in patients with high grade gliomas, recurrent tumors of the head and neck region, and a much smaller number with cutaneous and extra-cutaneous melanomas. Because of their limitations, great effort has been expended over the past 40 years to develop new boron delivery agents that have more favorable biodistribution and uptake for clinical use. These include boron-containing porphyrins, amino acids, polyamines, nucleosides, peptides, monoclonal antibodies, liposomes, nanoparticles of various types, boron cluster compounds and co-polymers. Currently, however, none of these have reached the stage where there is enough convincing data to warrant clinical biodistribution studies. Therefore, at present the best way to further improve the clinical efficacy of BNCT would be to optimize the dosing paradigms and delivery of BPA and BSH, either alone or in combination, with the hope that future research will identify new and better boron delivery agents for clinical use.

Boron neutron capture therapy for vulvar melanoma and genital extramammary Paget's disease with curative responses.

BACKGROUND: Although the most commonly recommended treatment for melanoma and extramammary Paget's disease (EMPD) of the genital region is wide surgical excision of the lesion, the procedure is highly invasive and can lead to functional and sexual problems. Alternative treatments have been used for local control when wide local excision was not feasible. Here, we describe four patients with genital malignancies who were treated with boron neutron capture therapy (BNCT). METHODS: The four patients included one patient with vulvar melanoma (VM) and three with genital EMPD. They underwent BNCT at the Kyoto University Research Reactor between 2005 and 2014 using para-boronophenylalanine as the boron delivery agent. They were irradiated with an epithermal neutron beam between the curative tumor dose and the tolerable skin/mucosal doses. RESULTS: All patients showed similar tumor and normal tissue responses following BNCT and achieved complete responses within 6 months. The most severe normal tissue response was moderate skin erosion during the first 2 months, which diminished gradually thereafter. Dysuria or contact pain persisted for 2 months and resolved completely by 4 months. CONCLUSIONS: Treating VM and EMPD with BNCT resulted in complete local tumor control. Based on our clinical experience, we conclude that BNCT is a promising treatment for primary VM and EMPD of the genital region. Trial registration numbers UMIN000005124.

A realistic appraisal of boron neutron capture therapy as a cancer treatment modality.

Boron neutron capture therapy (BNCT) is a binary therapeutic modality based on the nuclear capture and fission reactions that occur when the stable isotope boron-10 is irradiated with neutrons to produce high-energy alpha particles and recoiling lithium-7 nuclei. In this Commentary we will focus on a number of papers that were presented at a Symposium entitled "Current Clinical Status of Boron Neutron Capture Therapy and Paths to the Future", which was held in September 2017 at the China National Convention Center in Beijing. Results were presented by clinicians from Japan, Finland, the United States, the China mainland and Taiwan, China who have been working in the multiple disciplines that are required for carrying out clinical BNCT. The main focus was on the treatment of patients with malignant brain tumors, recurrent tumors of the head and neck region, and cutaneous melanomas. The results obtained in treating these patients were reported in detail and, although most of the patients with brain tumors and head and neck cancer were not cured, there was evidence of some clinical efficacy. Although there are a number of problems that must be addressed, further clinical studies to evaluate the efficacy of BNCT are warranted. First, despite considerable effort by numerous investigators over the past 40 years, there still are only two boron-containing drugs in clinical use, L-boronophenylalanine (BPA) and sodium borocaptate (BSH). Therefore, until new and more effective boron delivery agents are developed, efforts should be directed to improving the dosing and delivery of BPA and BSH. Second, due to a variety of reasons, nuclear reactor-based BNCT has ended except for its use in the China mainland and Taiwan. Therefore, the future of BNCT depends upon the results of the ongoing Phase II clinical trials that are being carried out in Japan and the soon to be initiated trials that will be carried out in Finland. If the results obtained from these clinical trials are sufficiently promising, then BNCT will have a clear path to the future, especially for patients with the therapeutically challenging malignancies that in the past have been treated with reactor-based BNCT.

Assessment of atherosclerotic luminal narrowing of coronary arteries based on morphometrically generated visual guides.

BACKGROUND AND AIMS: Determination of the degree of stenosis of atherosclerotic coronary arteries is an important part of postmortem examination of the heart, but, unfortunately, estimation of the degree of luminal narrowing can be imprecise and tends to be approximations. Visual guides can be useful to assess this, but earlier attempts to develop such guides did not employ digital technology. Using this approach, we have developed two computer-generated morphometric guides to estimate the degree of luminal narrowing of atherosclerotic coronary arteries. The first is based on symmetric or eccentric circular or crescentic narrowing of the vessel lumen and the second on either slit-like or irregularly shaped narrowing of the vessel lumens. METHODS: Using the Aperio ScanScope XT at a magnification of 20× we created digital whole-slide images of 20 representative microscopic cross sections of the left anterior descending (LAD) coronary artery, stained with either hematoxylin and eosin (H&E) or Movat's pentachrome stain. These cross sections illustrated a variety of luminal profiles and degrees of stenosis. Three representative types of images were selected and a visual guide was constructed with Adobe Photoshop CS5. Using the "Scale" and "Measurement" tools, we created a series of representations of stenosis with luminal cross sections depicting 20%, 40%, 60%, 70%, 80%, and 90% occlusion of the LAD branch. Four pathologists independently reviewed and scored the degree of atherosclerotic luminal narrowing based on our visual guides. In addition, digital technology was employed to determine the degree of narrowing by measuring the cross-sectional area of the 20 microscopic sections of the vessels, first assuming no narrowing and then comparing this to the percent of narrowing determined by precise measurement. RESULTS: Two of the observers were very experienced general autopsy pathologists, one was a first-year pathology resident on his first rotation on the autopsy service, and the fourth observer was a highly experienced cardiovascular pathologist. Interobserver reliability was assessed by determination of the intraclass correlation coefficient. The degrees of agreement for two H&E- and Movat-stained sections of the LADs from each of 10 decedents were 0.874 and 0.899, respectively, indicating strong interobserver agreement. On the average, the mean visual scores were ~8% less than the morphometric assessment (52.7 vs. 60.2), respectively. CONCLUSIONS: The visual guides that we have generated for scoring atherosclerotic luminal narrowing of coronary arteries should be helpful for a broad group of pathologists, from beginning pathology residents to experienced cardiovascular pathologists.

An Obesity Paradox: Increased Body Mass Index Is Associated with Decreased Aortic Atherosclerosis.

Brodsky et al. (Cardiovasc Pathol 25(6), 515-520, 2016) recently have reported that there was an unexpected and highly significant inverse correlation between body mass index (BMI) and atherosclerosis of the aortas of morbidly obese decedents (BMI >40 kg/m2). In a series of 304 decedents, 65 of whom were morbidly obese, minimal or no atherosclerosis was seen in 46 of them (70%) versus 20 (30%) who had severe atherosclerosis (P = 0.008). This obesity paradox was unexpected and raises important questions about the etiology and pathogenesis of atherosclerosis, which will be the subject of this commentary. The concept of healthy versus unhealthy adiposity may in part provide an explanation for the "obesity paradox." Another factor that will be considered is the possible role of adipokines and their genetic determinants that may significantly reduce the risk of developing aortic atherosclerosis in morbidly obese individuals. Considering the marked variability in the pattern and extent of atherosclerosis of the aorta, hemodynamic factors and endothelial cell shear stress may be the most important determinants that might explain the obesity paradox that we have observed. Finally, the possible role of gut microbiota and inflammation as factors in the etiopathogenesis of atherosclerosis will be considered, but their importance is less clear than that of hemodynamic factors. We conclude with the remarkable finding that a 5300-year-old, well-preserved mummy of the "Iceman," Ötzi had atherosclerotic disease of a number of major arteries and the interesting questions that this raises.

Cerebrospinal fluid dissemination of high-grade gliomas following boron neutron capture therapy occurs more frequently in the small cell subtype of IDH1R132H mutation-negative glioblastoma.

We have used boron neutron capture therapy (BNCT) to treat patients in Japan with newly diagnosed or recurrent high-grade gliomas and have observed a significant increase in median survival time following BNCT. Although cerebrospinal fluid dissemination (CSFD) is not usually seen with the current standard therapy of patients with glioblastoma (GBM), here we report that subarachnoid or intraventricular CSFD was the most frequent cause of death for a cohort of our patients with high-grade gliomas who had been treated with BNCT. The study population consisted of 87 patients with supratentorial high-grade gliomas; 41 had newly diagnosed tumors and 46 had recurrent tumors. Thirty of 87 patients who were treated between January 2002 and July 2013 developed CSFD. Tumor histology before BNCT and immunohistochemical staining for two molecular markers, Ki-67 and IDH1R132H, were evaluated for 20 of the 30 patients for whom pathology slides were available. Fluorescence in situ hybridization (FISH) was performed on 3 IDH1R132H-positive and 1 control IDH1R132H-negative tumors in order to determine chromosome 1p and 19q status. Histopathologic evaluation revealed that 10 of the 20 patients' tumors were IDH1R132H-negative small cell GBMs. The remaining patients had tumors consisting of other IDH1R132H-negative GBM variants, an IDH1R132H-positive GBM and two anaplastic oligodendrogliomas. Ki-67 immunopositivity ranged from 2 to 75%. In summary, IDH1R132H-negative GBMs, especially small cell GBMs, accounted for a disproportionately large number of patients who had CSF dissemination. This suggests that these tumor types had an increased propensity to disseminate via the CSF following BNCT and that these patients are at high risk for this clinically serious event.