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Constitutional mismatch repair deficiency (CMMRD) is a rare autosomal recessive hereditary cancer syndrome due to biallelic germline mutation involving one of the four DNA mismatch repair genes. Here we present a case of a young female with CMMRD, homozygous for the c.2002A>G mutation in the PMS2 gene. She developed an early stage adenocarcinoma of the colon at the age of 14. Surveillance MRI of the brain at age 18 resulted in the detection of an asymptomatic brain cancer. On resection, this was diagnosed as an anaplastic astrocytoma. Due to emerging literature suggesting benefit of immunotherapy in this patient population, she was treated with adjuvant dual immune checkpoint inhibition, avoiding radiation. The patient remains stable with no evidence of progression 20 months after resection. The patient’s clinical course, as well as the rational for considering adjuvant immunotherapy in patients with CMMRD are discussed in this report.

Objective. The aim of this work was to obtain the primary cell lines of brain malignant tumors using the explant method. Materials and methods. Thirteen patients of both sexes, aged 22 to 66, were recruited. The tumor material of the patients was fragmented and placed in flasks with complete nutrient medium for glial tumor cells. Subsequently, the material was photographed at various stages of cultivation, the cell morphology was determined, and the rate of monolayer formation at the zero and first passages was assessed. Results. As a result, thirteen primary human cell lines of glial tumors were obtained: six glioblastoma lines, two glioblastoma lines with anaplastic astrocytoma, one anaplastic oligodendroglioma line, one diffuse astrocytoma line, one oligoastrocytoma line and one diffuse protoplasmic astrocytoma line, one anaplastic astrocytoma line. In the culture of diffuse astrocytoma, there were observed the cells forming a network at the bottom of the flask. In the culture of anaplastic astrocytoma at a confluence of 3050 %, fibroblast-like cells were presented, and at a confluence of 100 %, a monolayer was formed with cells intimately adjacent to each other. In the culture of oligoastrocytoma, both fibroblast-like cells and islets of closely intertwined fusiform cells were observed. The same was typical for the cells of diffuse protoplasmic astrocytoma. Anaplastic oligodendroglioma during the first week of cultivation was represented mainly by round cells with a contrast agent, which subsequently attached and actively proliferated. At a confluence of 3080 %, fibroblast-like cells were observed, and at 100 %, spindle-shaped cells closely adjacent to each other. In cultures of glioblastomas, no specific character of cell growth was revealed: spindle-shaped, fibroblast-like cells and cells with long processes forming a network were encountered. Glioblastoma cultures against the background of anaplastic astrocytoma were represented by a network of cells with long processes. At the zero passage, the rate of formation of a 100 % confluence monolayer ranged from 22 to 85 days. At the first passage, the cells reached a full monolayer within 4 to 25 days. At the zero passage, the longest time among all the samples to form the monolayer with a 100 % confluence needed glioblastoma lines on average 59 days. The shortest time to reach a 100 % confluence was required for cells of diffuse astrocytoma, anaplastic oligodendroglioma and glioblastoma against the background of anaplastic astrocytoma 2224 days. Conclusions. In our work, it was shown that the explant method ensures the production of viable cells of glial tumors and the possibility of their further cultivation.

Gliomas represent about 80% of primary brain tumours and about 30% of malignant ones, which today don’t have a resolution therapy because of their variability. A valid model for the study of new personalized therapies can be represented by primary cultures from patient’s tumour biopsies. In this study we consider 12 novel cell lines established from patients’ gliomas and immunohistochemically and molecularly characterized according to the newly updated 2016 CNS Tumour WHO classification. Eight of these lines were glioblastoma cells, two grade III glioma cells (anaplastic astrocytoma and oligo astrocytoma) and two low grade glioma cells (grade II astrocytoma and oligodendroglioma). All cell lines were analysed by immunohistochemistry for specific glioma markers, respectively VIMENTIN, GFAP, IDH1R132, and ATRX. The methylation status of the MGMT gene promoter was also determined in all lines. The comparison of the immunohistochemical characteristics and of the MGMT methylation status of the lines with the tissues of origin shows that the cells in culture maintain the same characteristics. Human cancer cell lines represent a support in the knowledge of tumour biology and in drug discovery through its facile experimental manipulation. NCT 04180046.

Temozolomide is an orally administered chemotherapeutic drug that has become a standard treatment for malignant gliomas. Severe toxicity of temozolomide is rare, especially shortly after administration. We report a 37-year-old male patient diagnosed with anaplastic astrocytoma following tumor resection. He was treated postoperatively with cranial radiation and adjuvant temozolomide 150 mg/m2 for six planned cycles. However, 3 days after finishing the first cycle of temozolomide, the patient's condition deteriorated. Laboratory results showed thrombocytopenia and lymphopenia, and chest X-ray revealed an infiltrate in the right segment of the lung, suggesting pneumonia. These conditions were thought to be caused by temozolomide. Although temozolomide is generally well tolerated by glioma patients, several adverse effects have been reported. In addition, malignancy, corticosteroids, and chemotherapy are known to increase the risk of immunosuppression. Close monitoring of patients treated with temozolomide is warranted, especially brain tumor patients, due to the risk of myelosuppression and severe infection. The work was approved by the Health Research Ethics Committee of DR Mohammad Hoesin Hospital (No. 130/kepkrsmh/2020) on December 15, 2020.

Introduction: Malignant gliomas refer to grade III or IV brain tumors defined according to the World Health Organization (WHO) classification. They are a heterogeneous group of pathologies and represent a serious health problem by their frequency, severity and treatment difficulties. The prognosis of malignant gliomas remains poor despite all the medical advances. Materials and Methods: It is a retrospective study included 20 cases of malignant glial tumors treated at the medical oncology department, Fattouma Bourguiba hospital in Monastir between 2012 and 2016, according to the STUPP protocol. Results: These were 12 men and 8 women with a median age of 43. Clinical signs were not very specific, dominated by intracranial hypertension and deficit signs. Imagery referred to the diagnosis of malignant gliomas in 1st intention. Surgery consisted of a macroscopically complete exeresis in (15%) cases, a partial exeresis in (50%), the rest of the patients had a stereotactic biopsy. Histology found GBM in 16 patients (80%), 2 cases of Grade III anaplastic astrocytoma (10%), 1 case of anaplastic oligodendroglioma (5%), and 1 case of Grade III anaplastic eppendymoma (5%). Most of our patients received concurrent radio-chemotherapy and adjuvant TMZ chemotherapy was administered in 15 patients, 7 of whom received the full 6 scheduled cures. A relapse treatment was decided in only one of the 12 patients who relapsed. 6 patients are still alive. The median survival is 11.27 months. In our series, overall survival was related to histological type (p = 0.006) and neurological status assessed at the end of RT-CT (p = 0.001). While age, general condition score, type of surgery, and post-therapeutic development did not show a statistically significant relationship, although survival rates were consistent with the criteria assessed. Conclusion: Malignant gliomas are rare tumors, bad prognosis, aggravated in Tunisia by a diagnostic delay. The creation of a multidisciplinary neuro-oncology group can help to improve management.

Objective To describe treatment toxicities and polypharmacy in older patients with malignant gliomas (MG). Background Advanced age in cancer patients is associated with increased treatment-related toxicities, acute care utilization and functional decline. Most patients with MG are over age 65, yet treatment patterns and toxicities are poorly defined. Methods A retrospective chart review of 125 patients with MG age 65 or older at the University of Rochester from January 2012 to December 2018. Results 115 patients with glioblastoma and 10 with anaplastic astrocytoma had a median age of 71 (range 65–89) at diagnosis and median overall survival (OS) of 10.3 months. Radiotherapy (RT) was offered and completed in 79% (fractionated, n = 69, hypofractionated, n = 30). 24% of the 98 patients treated with concurrent temozolomide (TMZ) experienced treatment delays (n = 24). Median of 4 cycles of adjuvant TMZ were taken by 61% (n = 76). Delays and dose reductions occurred in 55% during treatment with adjuvant TMZ, most commonly due to thrombocytopenia (n = 29) and fatigue (n = 15). 16/98 patients required transfusions during treatment with concurrent or adjuvant TMZ. At baseline, patients were prescribed a median of 11 medications. OS was longer in patients prescribed less than 8 medications vs. 8 or more (14 vs. 8.6 months, p = .0738). 96% experienced a non-elective hospital admission and 64% reported at least one fall. Conclusion Older patients with MG experience significant polypharmacy, treatment toxicities and falls. Studies incorporating geriatric assessment tools may better determine associations between geriatric syndromes and survival. Clinical trials in older patients should also include non-survival outcomes.

Background: Glioma is the most commonly occurring malignant brain tumor that varies by age, sex, race or ethnicity. A very few number of records on CNS tumors are available in Bangladesh. National Institute of Neurosciences and Hospital (NINS), Dhaka has a good number of CNS surgeries. Regularly both tumorous and non-tumorous ICSOL samples are examined here. Objective: The aim of the study was to see the subtypes, frequency and topography of Astrocytic tumors at NINS setting. Methodology: Data from the department of Neuropathology department of NINS since January 2013 to June 2019 were evaluated. Tissue were fixed in formalin, paraffin embedded, stained with H&E. Histomorphology and WHO 2007 CNS tumor classification were used. Result: From 3945 routine sample 567 cases were sorted out as Astrocytic tumor. Total male were 61% (346) and female 39% (221), male to female ratio was 1.6:1. The mean age was 32.64 and ranged from 1 to 80 years. Sixty six percent (66%) tumors were in supratentorial compartment, 15% infratentorial, 6.3% spinal and 9.7% in midline areas like thalamus, hypothalamus and seller region. In this study 34.6% (196) cases were Glioblastoma, followed by Anaplastic Astrocytoma 8.3%(47), Diffuse Astrocytoma 29% (165), Pilocytic Astrocytoma 26.6% (151), Pilomyxoid Astrocytoma 0.4% (2), Subependymal giant cell Astrocytoma 0.9% (5) and Pleomorphic Xanthoastrocytoma 0.1 (0.1). Topographically 66% glial tumors are supratentorial. Among the glial tumors 34.6% is Glioblastoma, 8.3% Anaplastic Astrocytoma, 29% Diffuse Astrocytoma and 26.6% Pilocytic astrocytoma. Common age group of Glioblastoma is 41-60 (52%) years, diffuse astrocytoma is 21-40 years 60.60 and Pilocytic Astrocytoma is 1-20 years (66.88). Glioblastoma, Anaplastic Astrocytoma and Diffuse astrocytoma are more common in male than female. Conclusion: There is no gender difference in case of Pilocytic Astrocytoma. Journal of National Institute of Neurosciences Bangladesh, 2020;6(2): 91-95

BACKGROUND: Although newly diagnosed high-grade glioma patients in Japan can receive bevacizumab (BEV) as first-line chemotherapy. randomized clinical trials have not shown a survival benefit for BEV for these patients. In this study, we investigated whether selective add-on BEV for patients with newly diagnosed glioblastoma (GBM) and anaplastic astrocytoma (AA) improves prognosis, in cases where tumors were continuously growing during radiotherapy concomitant with temozolomide (TMZ). METHODS: We conducted a retrospective survey of the overall survival (OS) of patients with GBM;AAs who were treated in our institution between 2006 and 2016. Patients whose tumors were continuously growing regardless of radiotherapy were categorized as the "progressive" group; remaining patients were categorized as the "non-progressive" group. Since 2013, patients in the "progressive" group received add-on BEV therapy with the Stupp regimen during or just after radiotherapy. RESULTS: Of 151 GBM/AA patients, 34 (22.5%) were categorized in the "progressive" group. Median OSs of the "progressive" and "nonprogressive" groups were 13.2 months and 25.3 months, respectively (P

OBJECTIVETumors of the CNS are the main causes of childhood cancer and have an incidence that exceeds that of leukemia. In addition, they are the leading causes of cancer-related death in childhood. High-grade gliomas account for 11% of such neoplasms and are characterized by aggressive clinical behavior and high morbidity and mortality. There is a lack of studies focusing on the factors that can prolong survival in these patients or guide therapeutic interventions. The authors aimed to investigate the factors related to longer survival durations, with a focus on reoperation for gross-total resection (GTR).METHODSIn this retrospective cohort study, the authors analyzed 78 patients diagnosed with high-grade gliomas occurring across all CNS locations except diffuse intrinsic pontine gliomas. Patients 0 to < 19 years of age were followed up at the Pediatric Oncology Institute. Overall survival (OS) and progression-free survival (PFS) were analyzed in the context of various prognostic factors, such as age, sex, histology, extent of tumor resection, reoperation for GTR, adjuvant treatment, and treatment initiation from 2010 onward.RESULTSWith a mean age at diagnosis of 8.7 years, 50% of the patients were female and approximately 39% underwent GTR at some point, which was already achieved in approximately 46% of them in the first surgery. The median OS was 17 months, and PFS was 10 months. In terms of median OS, the authors found no significant difference between those with reoperation for GTR and patients without GTR during treatment. Significant differences were observed in the OS in terms of the extent of resection in the first surgery, age, sex, Ki-67 expression, adjuvant treatment, and treatment initiation from 2010 onward. Furthermore, the PFS values significantly differed between those with GTR in the first surgery and Ki-67 expression ≥ 50%.CONCLUSIONSThis study demonstrates the importance of GTR for these neoplasms, highlights the role of surgeons in its achievement in the first attempt, and questions the role of reoperation for this purpose. Finally, this study further supports the use of combined adjuvant treatment for the improvement of OS and PFS.

BACKGROUND: Brain tumor incidence continues to increase during the last decade in several countries. Determining the response of intracranial tumors to treatment remains a major challenge in the field of neuro-oncology. Karnofsky Performance Status Scale (KPS) is a widely used method for assessing the functional status of a patient. AIM: This study aims to determine the relationship between stadium and histopathological features with clinical outcomes in patients with glioma tumors. METHODS: This was an observational analytic study with a retrospective approach at the H. Adam Malik General Hospital in Medan from September 2019 to September 2020. The study population was glioma patients. The research sample was 36 subjects taken consecutively. The independent variables of the study were stage and histopathological features, while the dependent variable of the study was KPS. Statistical analysis with Gamma test. RESULTS: Mean age was 38.11 ± 13.86 years. Most subjects were male, amounting to 20 subjects (55.6%). The most common type of glioma tumor was anaplastic astrocytoma, amounting to 8 subjects (22.2%). The highest tumor stage was a high-grade glioma, amounting to 19 subjects (52.8%), and the most histopathological features based on WHO criteria were WHO grade 3, totaling 13 subjects (36.1%). Most KPS is 80–100 with 19 subjects (52.8%). There is a significant correlation between the stage and histopathological features with KPS with a moderate correlation strength (p = 0.036; r = 0.598) (p = 0.024; r = 0.508) CONCLUSION: There is a significant correlation between stage and histopathological features with KPS with moderate correlation strength

Myeloid cells are an inherent part of the microenvironment of glioblastoma multiforme (GBM). There is growing evidence for their participation in mechanisms of tumor escape, especially in the development of resistance following initially promising anti-VEGF/VEGFR treatment. Thus, we sought to define the capability of myeloid cells to contribute to the expression of proangiogenic molecules in human GBM. We investigated GBM specimens in comparison with anaplastic astrocytoma (WHO grade III) and epilepsy patient samples freshly obtained from surgery. Flow cytometric analyses revealed two distinct CD11b+ CD45+ cell populations in GBM tissues, which were identified as microglia/macrophages and granulocytes. Due to varied granulocyte influx, GBM samples were subdivided into groups with low (GBM-lPMNL) and high (GBM-hPMNL) numbers of granulocytes (polymorphonuclear leukocytes; PMNL), which were related to activation of the microglia/macrophage population. Microglia/macrophages of the GBM-lPMNL group were similar to those of astrocytoma specimens, but those of GBM-hPMNL tissues revealed an altered phenotype by expressing high levels of CD163, TIE2, HIF1α, VEGF, CXCL2 and CD13. Although microglia/macrophages represented the main source of alternative proangiogenic factors, additionally granulocytes participated by production of IL8 and CD13. Moreover, microglia/macrophages of the GBM-hPMNL specimens were highly associated with tumor blood vessels, accompanied by remodeling of the vascular structure. Our data emphasize that tumor-infiltrating myeloid cells might play a crucial role for limited efficacy of anti-angiogenic therapy bypassing VEGF-mediated pathways through expression of alternative proangiogenic factors. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Background Radiotherapy may synergize with programmed cell death 1 (PD1)/PD1 ligand (PD-L1) blockade. The purpose of this study was to determine the recommended phase II dose, safety/tolerability, and preliminary efficacy of combining pembrolizumab, an anti-PD1 monoclonal antibody, with hypofractionated stereotactic irradiation (HFSRT) and bevacizumab in patients with recurrent high-grade gliomas (HGGs). Methods Eligible subjects with recurrent glioblastoma or anaplastic astrocytoma were treated with pembrolizumab (100 or 200 mg based on dose level Q3W) concurrently with HFSRT (30 Gy in 5 fractions) and bevacizumab 10 mg/kg Q2W. Results Thirty-two patients were enrolled (bevacizumab-naïve, n = 24; bevacizumab-resistant, n = 8). The most common treatment-related adverse events (TRAEs) were proteinuria (40.6%), fatigue (25%), increased alanine aminotransferase (25%), and hypertension (25%). TRAEs leading to discontinuation occurred in 1 patient who experienced a grade 3 elevation of aspartate aminotransferase. In the bevacizumab-naïve cohort, 20 patients (83%) had a complete response or partial response. The median overall survival (OS) and progression-free survival (PFS) were 13.45 months (95% CI: 9.46–18.46) and 7.92 months (95% CI: 6.31–12.45), respectively. In the bevacizumab-resistant cohort, PR was achieved in 5 patients (62%). Median OS was 9.3 months (95% CI: 8.97–18.86) with a median PFS of 6.54 months (95% CI: 5.95–18.86). The majority of patients (n = 20/26; 77%) had tumor-cell/tumor-microenvironment PD-L1 expression Conclusions The combination of HFSRT with pembrolizumab and bevacizumab in patients with recurrent HGG is generally safe and well tolerated. These findings merit further investigation of HFSRT with immunotherapy in HGGs.

Introduction It is common practice to prescribe prophylactic antiepileptic drugs (AED) to high-grade glioma (HGG) patients without a history of seizures, yet with limited evidence supporting its use. Ideally, the effectiveness of prophylactic anticonvulsants must outweigh the occurrence of adverse effects and interactions related to AED. The authors conducted a systematic review and metanalysis of longitudinal studies regarding the effectiveness of prophylactic AED in seizure-naive HGG patients. Materials and methods PubMed/MEDLINE, Cochrane Central Register of Controlled trials, Embase and clinicaltrials.gov databases were systematically searched. Of the initial 1773 studies identified, 15 were finally selected for data extraction and analysis. Heterogeneity among studies, pooled hazard ratios, publication bias and sensitivity analyses were performed separately for a 15-study group (HGG patients within larger series of brain tumors) and a 6-study group (exclusively HGG patients). Results AED prophylaxis did not significantly reduce the incidence of postoperative seizures compared with controls, both in the 15-study group (Mantel-Haenszel random-effects pooled OR 1.08, 95% CI 0.82–1.43, 2123 patients) and in the 6-study group (pooled OR 1.22, 95% CI 0.77–1.92, 540 patients). However, some issues (paucity of prospective trials, overall moderate-risk of bias, and few studies addressing HGG patients exclusively) preclude firm conclusions against routine prophylactic AED prescription. Reported adverse effects attributable to AED were acceptable in the majority of studies. Conclusions Within the limitations of this review, the results of this metanalysis do not support the routine administration of prophylactic AED to HGG patients without a history of seizures.

Background An optimal radiological surveillance plan is crucial for high-grade glioma (HGG) patients, which is determined arbitrarily in daily clinical practice. We propose the radiological assessment schedule using a parametric model of standardized progression-free survival (PFS) curves. Methods A total of 277 HGG patients (178 glioblastoma [GBM] and 99 anaplastic astrocytoma [AA]) from a single institute who completed the standard treatment protocol were enrolled in this cohort study and retrospectively analyzed. The patients were stratified into each layered risk group by genetic signatures and residual mass or through recursive partitioning analysis. PFS curves were estimated using the piecewise exponential survival model. The criterion of a 10% progression rate among the remaining patients at each observation period was used to determine the optimal radiological assessment time point. Results The optimal follow-up intervals for MRI evaluations of isocitrate dehydrogenase (IDH) wild-type GBM was every 7.4 weeks until 120 weeks after the end of standard treatment, followed by a 22-week inflection period and every 27.6 weeks thereafter. For the IDH mutated GBM, scans every 13.2 weeks until 151 weeks are recommended. The optimal follow-up intervals were every 22.8 weeks for IDH wild-type AA, and 41.2 weeks for IDH mutated AA until 241 weeks. Tailored radiological assessment schedules were suggested for each layered risk group of the GBM and the AA patients. Conclusions The optimal schedule of radiological assessments for each layered risk group of patients with HGG could be determined from the parametric model of PFS.

Temozolomide is an alkylating agent approved by the U.S. Food and Drug Administration in 1999 for the treatment of patients with primary brain tumors. The aim of this study was to confirm the bioequivalence and safety of two strengths (20–100 mg) of generic temozolomide in the form of TOZ039 and Temodal® capsules administered to brain tumor patients. An open-label, randomized, two-phase, two-period, crossover pharmacokinetic study was performed in a single institution. The reference and test drugs were prescribed at a dose of 150 mg/m2 daily from days 1 to 5 of a 28-day cycle in the first phase; in the second phase, either a 150- or 200-mg/m2 dose was prescribed, depending on patient tolerance. On days 1 and 2 of each phase, a fixed 200-mg dose was administered either as ten 20-mg capsules in the first cycle or two 100-mg capsules in the second cycle. Drug administration in the first two days was randomized, i.e., if TOZ309 was administered on day 1, Temodal® was administered on day 2, and vice versa. The rest of the prescribed dose was administered in the form of Temodal® and spread equally over days 3–5. Blood samples were obtained for pharmacokinetic evaluation on days 1 and 2. Bioequivalence was demonstrated if the geometric means ratio of the three main pharmacokinetic parameters (mean maximum plasma concentration (Cmax), area under the concentration–time curve (AUC) 0-t, AUC 0-∞) fell within the equivalence boundary of 80–125%. Twenty-nine glioblastoma multiforme or anaplastic astrocytoma patients were enrolled and dosed with the test and reference formulations under fasting conditions. The 90% confidence interval of the geometric means ratio for Cmax (91.08%, 106.18%), AUC0-t (98.62%,102.18%), and AUC0-∞ (98.65%, 102.21%) was well within the 80%–125% range for the 20-mg capsule, as was the Cmax (90.49%, 113.32%), AUC0-t (99.89%, 104.63%) and AUC0-∞ (99.99%, 104.67%) for the 100-mg capsule drug product. Additionally, all the secondary pharmacokinetic parameters were not significantly different. After two cycles of treatment, there was no mortality among the 29 patients, treatment-related severe adverse events, or events that would require study discontinuation; however, one significant adverse effect (life-threatening seizures) occurred and was related to disease progression. Adverse events were reported in 82.8% (24/29) patients, and treatment emergent adverse events were reported in 72.4% (21/29) patients. It can be concluded that 20-mg and 100-mg capsules of TOZ309 are bioequivalent to Temodal® capsules of the same strength under fasting conditions. https://www.chinadrugtrials.org.cn/index.html , CTR2017 0122.

Aim. The problem of anaplastic astrocytomas is quite relevant today. The WHO classification distinguishes IDH1 / IDH2 mutant anaplastic astrocytomas, anaplastic astrocytomas without IDH1 / IDH2 mutations, and anaplastic astrocytomas not otherwise specified. The aim of this work was to cluster IDH1 -mutant anaplastic astrocytomas based on their cytogenetic profile to select prognostically significant molecular subgroups, which can have both clinical and fundamental scientific value. Materials and methods . In this work, we performed a cluster analysis of anaplastic astrocytomas according to their cytogenetic profiles based on available genetic databases of tumors and large cohort studies, as well as a comparison of Kaplan – Meyer survival curves for various molecular subgroups of patients. Results. We studied the main genetic features of the inter-tumor heterogeneity of anaplastic astrocytomas and distinguished seven molecular subgroups based on the cytogenetic profile: embryo-like, inflammatory-like, deletion, matrix, cyclin, GATA3 -dependent and tyrosine kinase. Moreover, each of these subgroups has not only distinctive molecular characteristics, but also important clinical features. Conclusion. A detailed study of the molecular properties of anaplastic astrocytomas will not only optimize the process for predicting treatment outcomes, but also create innovative formats for targeted therapy within the framework of the concept of personalized medicine.

Temozolomide (TMZ) is an oral alkylating agent that is considered the standard therapy in primary intracranial malignancies. The medication is well tolerated with a most common side effect of bone marrow suppression that is encountered in a small proportion of patients, often reversible with medication discontinuation and supportive treatment. Rarely, aplastic anemia can develop during treatment with TMZ. Here, we present a case of a patient who developed aplastic anemia following treatment with TMZ. We offer a review of the existing literature to have a better understanding of the causative effect and to examine the characteristics and outcomes when aplastic anemia develops during treatment with TMZ.

The patients with glial tumors of varying degrees of anaplasia represent an imbalance in the composition of different subpopulations of immune cells, which leads to both specific immunosuppression and stimulation of the tumor process. For a comprehensive clinical assessment of the state of immunity in the blood, it is recommended to determine the ratio of the absolute level of immune cells, which integrally reflects the violation of certain indicators of innate and acquired immunity. Objective: To determine the relationship between the absolute number of lymphocytes, neutrophils, and platelets in the peripheral blood in glial tumors of varying degrees of anaplasia and at the stages of surgical treatment. Materials and methods. The case histories of 95 patients with glial tumors before surgery, on the 5 th –7 th day after surgery and before reoperation were studied. There were 71 patients initially operated for glial tumors of varying degrees of anaplasia, 40 patients with glioblastomas, 15 patients with anaplastic, and 16 patients with diffuse astrocytomas. Twenty-four patients were re-operated. The comparison group (control) consisted of 28 patients with non-cancerous diseases of the CNS. The age of patients with brain tumors and the comparison group ranged from 35 to 65 years. To analyze blood immunologic parameters, hematologic analyzer Mindray 3000 plus was used to identify the absolute number of platelets, neutrophils, and lymphocytes as well as the ratio index of the absolute number of neutrophils to the absolute number of lymphocytes (n/l), the absolute number of platelets to the absolute content of lymphocytes (p/l), the ratio of the absolute number of platelets to the absolute content of neutrophils (p/n). Results. In malignant glial tumors (glioblastomas and anaplastic astrocytomas), the level of n/l is significantly increased compared to the diffuse astrocytomas, the stimulation of neutrophil production and inhibition of lymphocyte formation are identified. On the 5 th –7 th days after surgery, there is no recovery of subpopulations of immune cells in the peripheral blood. The recurrences of glial tumors are accompanied by the imbalance in the structure of immune cells in peripheral blood that does not depend on the degree of tumors anaplasia. Conclusions. Determining the ratio of the absolute content of immune cells in the peripheral blood can serve as an informative indicator of the direction of disorders in congenital and acquired immune systems, which should be taken into account in the treatment of tumors.

BACKGROUND AND PURPOSE: DSC-PWI has demonstrated promising results in the presurgical diagnosis of brain tumors. While most studies analyze specific parameters derived from time-intensity curves, very few have directly analyzed the whole curves. The aims of this study were the following: 1) to design a new method of postprocessing time-intensity curves, which renders normalized curves, and 2) to test its feasibility and performance on the diagnosis of primary central nervous system lymphoma. MATERIALS AND METHODS: Diagnostic MR imaging of patients with histologically confirmed primary central nervous system lymphoma were retrospectively reviewed. Correlative cases of glioblastoma, anaplastic astrocytoma, metastasis, and meningioma, matched by date and number, were retrieved for comparison. Time-intensity curves of enhancing tumor and normal-appearing white matter were obtained for each case. Enhancing tumor curves were normalized relative to normal-appearing white matter. We performed pair-wise comparisons for primary central nervous system lymphoma against the other tumor type. The best discriminatory time points of the curves were obtained through a stepwise selection. Logistic binary regression was applied to obtain prediction models. The generated algorithms were applied in a test subset. RESULTS: A total of 233 patients were included in the study: 47 primary central nervous system lymphomas, 48 glioblastomas, 39 anaplastic astrocytomas, 49 metastases, and 50 meningiomas. The classifiers satisfactorily performed all bilateral comparisons in the test subset (primary central nervous system lymphoma versus glioblastoma, area under the curve = 0.96 and accuracy = 93%; versus anaplastic astrocytoma, 0.83 and 71%; versus metastases, 0.95 and 93%; versus meningioma, 0.93 and 96%). CONCLUSIONS: The proposed method for DSC-PWI time-intensity curve normalization renders comparable curves beyond technical and patient variability. Normalized time-intensity curves performed satisfactorily for the presurgical identification of primary central nervous system lymphoma.

Introduction and objective αB-crystallin belongs to the ubiquitous family of small heat-shock proteins. It was discovered as a physiological protein of the eye lens, maintaining its liquid-like property. Furthermore, αB-crystallin was proved to playa bipolar role in both physiological and pathophysiological conditions. This review discusses current knowledge about the biology and genetics of αB-crystallin, and summarizes recent advances in understanding its role in ophthalmic and neurological disorders, as well as breast cancer, renal cancer and other malignancies. State of knowledge α-crystallins are established as important elements of the protein quality control network, and consequently their defects are related to multiple human diseases. New studies highlight αB-crystallin's involvement in proliferative diabetic retinopathy angiogenesis and point out its therapeutic potential in age-related macular degeneration. αB-crystallin is thought to be associated with the disease-causing protein aggregates, leading to its connection with such neurological disturbances as anaplastic astrocytoma, Parkinson disease, aging deficits in the peripheral nervous system and multiple sclerosis. In breast cancer, it was proven to be a marker of aggressive behaviur and cerebral metastases. Strong expression of αB-crystallin promoted growth and migration of clear cell renal cell carcinoma cells and was correlated with lower overall survival rate. Considering other malignancies, its various roles were established in colorectal and gastric cancers, head and neck squamous cell carcinomas and osteosarcomas. Conclusions Further studies concerning αB-crystallin seem to be enormously promising, as they might improve our understanding of common human pathologies as well as contemporary diagnostics and treatment.

OBJECTIVE Anaplastic gliomas (AGs) are an extremely heterogeneous group of primary brain tumors. More recently, new discoveries have indicated that isocitrate dehydrogenase (IDH) mutation status is the most important parameter predicting survival. The primary aim of the present analysis was to identify prognostic factors, other than IDH status, that eventually impact survival. METHODS Patients with available clinical, imaging, and molecular profile data who were amenable to resection were evaluated. The extent of resection (EOR) was defined as gross-total resection (GTR), near-total resection (NTR), subtotal resection (STR), or partial resection (PR). Residual tumor volume (RTV) was quantified. Following surgery, patients received adjuvant chemotherapy alone, radiation therapy plus concomitant and adjuvant temozolomide (TMZ), or sequential radio-chemotherapy. Clinical outcome was evaluated by neurological examination and MRI 1 month after treatment and every 4 months thereafter. Tumor progression was defined according to the Response Assessment in Neuro-Oncology (RANO) working group. RESULTS Among 402 patients referred to the authors’ institution for AG, 142 were included in the present analysis. Eighty-eight (62%) were male and 54 (38%) were female, with a median age of 43 years (range 19–70 years). At admission, most patients had a Karnofsky Performance Scale score of 90–100 (84.5%) and were symptomatic (93.7%). Forty-eight (33.8%) patients had newly diagnosed anaplastic oligodendrogliomas (AOs), and 94 (66.2%) had anaplastic astrocytomas (AAs). Most of them had mutant IDH tumors (67.6%) and methylated O 6-methylguanine-DNA-methyltransferase (MGMT) promoter status (71.8%). GTR was performed in more than half of the patients (56.3%). RTV was detected in 83 (58.5%) patients. Following surgery, 72 (50.7%) patients received radiotherapy with concomitant and adjuvant TMZ, 48 (33.8%) received sequential radio-chemotherapy, and 22 (15.5%) received adjuvant chemotherapy alone. The median follow-up time was 40 months (range 16–146 months). The median PFS time and the 1-, 3-, and 5-year PFS rates were 35 months (95% CI 27–76) and 78.9% ± 3.4%, 49.7% ± 4.6%, and 42.7% ± 5.4%, respectively. The median OS time and the 1-, 3-, and 5-year OS rates were 91 months (95% CI 66–95) and 90.1% ± 2.5%, 70.9% ± 4.2%, and 61.8% ± 4.9%, respectively. Prognostic factors predicting survival other than molecular profile were the EOR and the RTV (p < 0.0001). Sequential radio-chemotherapy was the more effective treatment administered. CONCLUSIONS In addition to IDH status, EOR and the RTV have proved to statistically impact survival. The pivotal role of adjuvant radiotherapy has been recorded in all AG patients, regardless of tumor features.

Background Surgical options for patients with thalamic brain tumors are limited. Traditional surgical resection is associated with a high degree of morbidity and mortality. Laser interstitial thermal therapy (LITT) utilizes a stereotactically placed laser probe to induce thermal damage to tumor tissue. LITT provides a surgical cytoreduction option for this challenging patient population. We present our experience treating thalamic brain tumors with LITT. Objective To describe our experience and outcomes using LITT on patients with thalamic tumors. Methods We analyzed 13 consecutive patients treated with LITT for thalamic tumors from 2012 to 2017. Radiographic, clinical characteristics, and outcome data were collected via review of electronic medical records. Results Thirteen patients with thalamic tumors were treated with LITT. Most had high-grade gliomas, including glioblastoma (n = 9) and anaplastic astrocytoma (n = 2). The average tumor volume was 12.0 cc and shrank by 42.9% at 3 mo. The average hospital stay was 3.0 d. Median ablation coverage as calculated by thermal damage threshold (TDT) lines was 98% and 95% for yellow (>43°C for >2 min) or blue (>10 min), respectively. Median disease-specific progression-free survival calculated for 8 patients in our cohort was 6.1 mo (range: 1.1-15.1 mo). There were 6 patients with perioperative morbidity and 2 perioperative deaths because of intracerebral hematoma. Conclusion LITT is a feasible treatment for patients with thalamic tumors. LITT offers a cytoreduction option in this challenging population. Patient selection is key. Close attention should be paid to lesion size to minimize morbidity. More studies comparing treatment modalities of thalamic tumors need to be performed.

Treatment of recurrent gliomas is especially challenging, as many of these patients have previously been treated with extensive surgery, radiation, or systemic therapy. Due to this, the optimum therapy for patients with recurrent glioma is controversial, with widely variable practice patterns. In this opinion piece, a multidisciplinary panel of experts provides rationale for their treatment approach in a patient with recurrent glioma following subtotal resection with adjuvant chemoradiation for an anaplastic astrocytoma. In summary, the consensus of the panel was to recommend re-resection if possible with hypofractionated radiotherapy schedules, with re-irradiation and systemic therapy as directed by a multidisciplinary team through repeat analysis of the tumor specimen for an updated mutational burden.

The study objectiveis to assess the possibilities of magnetic resonance imaging (MRI) in SWI (susceptibility weighted imaging) in the differential diagnosis of glial brain tumors and primary brain lymphomas.Materials and methods.Fifty-four patients with brain tumors were studied (men – 27 (50 %), women – 27 (50 %)). Average age 57.9 years. Histological examination of the surgical material revealed the glial nature of tumors in 41 patients (26 of them with glioblastoma, anaplastic astrocytomas – 15), primary brain lymphomas – in 13 patients. Brain MRI was performed using tomographs with a magnetic field of 3 and 1.5 T. A semi-quantitative assessment of the data obtained in the SWI mode based on the classification of ITSS (intratumoral susceptibility signals), reflecting the severity of interstitial vascular architectonics and microbleeding.Results.The degree of ITSS was 3 in glioblastomas (G4 ) in 26 (100 %) cases, in the structure of gliomas (G3 ) the ITSS values were 3 in 3 (20 %) cases, in the remaining 12 (80 %) cases – ITSS 2. In the group of primary brain lymphomas, the ITSS 1 was in 4 (30.7 %) cases, ITSS 0 was in 9 (69.3 %) cases.Conclusion.MRI in SWI mode is a promising technique that allows one to quantify the degree of pathological changes in tumor vascular architectonics and intratumoral hemorrhages and has shown high specificity in the differential diagnosis of malignant gliomas and lymphomas of the brain, accompanied by active accumulation of contrast medium.

Purpose: If routine diagnostics are inconclusive, neurologic deterioration and death of patients with brain cancer are attributed to tumor or therapy. Therefore, diagnosing symptoms of encephalopathy caused by human cytomegalovirus (HCMV) reactivation remains uncommon. We investigated the role of HCMV reactivation in neurologic decline and clinical outcome after the start of radiochemotherapy. Experimental Design: HCMV analyses and extended MRI studies including additional independent retrospective neuroradiologic evaluation were performed at predetermined intervals and in case of sudden neurologic decline for 118 adult patients: 63 histologically proven high-grade gliomas, 55 with brain metastases. Immunophenotyping from simultaneously taken whole-blood samples was carried out to detect immune cells serving as prognostic marker for HCMV-associated complications. Symptomatic viremia and overall survival (OS) were the endpoints. Results: Twenty-four percent (28/118) of all patients (12/44 glioblastoma, 3/13 anaplastic astrocytoma; 8/31 non–small cell lung cancer (NSCLC), 13/24 other brain metastases) developed HCMV-viremia during or within 4 weeks after radiotherapy; 21 of 28 patients experienced concurrent major neurologic decline, reversible by antiviral treatment. Identified by immunophenotyping, pretherapeutically low basophil counts predicted a high-risk for HCMV-associated encephalopathy (glioblastoma: P = 0.002, NSCLC: P = 0.02). Median OS was substantially reduced after HCMV-associated encephalopathy without MRI signs of tumor progression [glioblastoma: 99 vs. 570 days (calculated 1-year OS: 22% vs. 69%; P = 0.01) and NSCLC: 47 vs. 219 days (calculated 1-year OS: 0% vs. 32%; P = 0.02)]. Conclusions: For patients with brain cancer, HCMV reactivation after the start of radiochemotherapy is a frequent risk for cognitively detrimental but treatable encephalopathy and premature death. Routinely performed HCMV diagnostics, assessing basophil counts and study-based anti-viral regimens, are necessary to combat this hidden threat. See related commentary by Lawler et al., p. 3077

Aim. To study the role of CT perfusion in the differential diagnosis of histological subtypes of supratentorial malignant gliomas and to determine the degree of their malignancy. Materials and methods. The study included 34 patients (20 men and 14 women, with an average age of 52 years) with newly detected supratenorial glial tumors, who subsequently underwent neurosurgical treatment in the NMIC of neurosurgery with histological verification of the diagnosis. Depending on the histological diagnosis, three groups of patients were identified: 1) anaplastic astrocytomas, 2) glioblastomas, 3) anaplastic oligodendrogliomas. The CT-perfusion protocol was performed on a 64-slice Optima 660 (GE) scanner and consisted of three separate parts: a low-dose axial CT of the brain with a slice thickness of 5 mm (90 kV), a perfusion protocol performed according to a prolonged scheme, with two consecutive continuous series of scans, and a post-contrast series of CT images in a spiral scanning mode. In addition, all patients underwent an MRI examination (using a Signa Hdxt 3.0 T (GE) MR scanner, in T2, T2-FLAIR, SWAN, DWI, and T1 modes before and after contrast enhancement).Results. The study demonstrated that anaplastic astrocytomas are characterized by significantly low absolute and normalized hemodynamics parameters (BF, BV, PS) when compared with glioblastomas, and significantly low absolute maximum values of blood flow (BF) and blood volume (BV) when compared with the group of anaplastic oligodendrogliomas. CT perfusion using the normalized permeability index (PS) can reliably differentiate glioblastomas and anaplastic oligodendrogliomas. Perfusion parameters, both absolute and normalized, did not show statistically significant differences in the differential diagnosis of various molecular and genetic subtypes of anaplastic astrocytomas.Conclusion. CT perfusion using all hemodynamic parameters demonstrated high reliability and efficacy in distinguishing between glioblastomas and anaplastic astrocytomas. Further research is required to evaluate the effectiveness of the method in distinguishing glioblastomas from anaplastic oligodendrogliomas.

High grade gliomas are associated with poor prognosis and high mortality. Conventional treatments and management of high grade gliomas have shown little improvement in 5-year overall survival. This phase I trial evaluated the safety, immunogenicity, and potential synergy of surgical resection with Gliadel Wafer implantation, followed by autologous tumor lysate-pulsed dendritic cell (DC) vaccine in patients with malignant glioma. Primary end points of this study were safety and surrogate markers of immunogenicity, overall survival, and progression free survival. Following surgical resection, Gliadel Wafers were placed along the resection cavity. Patients subsequently received intradermal injections of autologous tumor lysate-pulsed DC vaccines 3 times at 2 week intervals. Treatment response was evaluated clinically and through MRI at regular intervals. Twenty-eight patients received Gliadel Wafers and DC vaccination: 11 newly diagnosed (8 glioblastoma [GBM], 2 anaplastic astrocytoma [AA], and 1 anaplastic oligodendroglioma [AO]) and 17 recurrent (15 GBMs, 1 AA, and 1 AO) high grade gliomas. Immunogenicity data was collected for 20 of the 28 patients. Five of 20 patients showed elevated IFN-γ responses following vaccination. Median progression-free survival and overall survival for all GBM patients in the trial from the start of vaccination were 3.6 months and 16.9 months respectively. Comparisons between vaccine responders and non-vaccine responders were not statistically significant. Adjuvant autologous dendritic cells pulsed with tumor-lysate following resection and Gliadel Wafer placement is safe, elicits modest immunogenicity and shows similar clinical outcomes in patients who had DC vaccination in previous studies.

Coffin-Siris syndrome (CSS) is a rare congenital disorder with variable clinical phenotype consisting of developmental delay and characteristic facial features. It is caused by mutations in the chromatin remodeling switch/sucrose nonfermenting complex. Although SWI/SNF genes are widely implicated in tumorigenesis, only 8 cases of neoplasm have been reported in patients with CSS. We report a case of anaplastic astrocytoma (WHO grade III) in an 18-month-old child with CSS due to a de novo germline missense SMARCE1 mutation. Additional molecular features of the tumor are described as well. The role of missense SMARCE1 mutations in tumor predisposition in children with CSS should be further investigated to better inform genetic counselling.

Purpose Malignant glioma (MG) is the most deadly primary brain cancer. Signaling though the PI3K/AKT/mTOR axis is activated in most MGs and therefore a potential therapeutic target. The mTOR inhibitor temsirolimus and the AKT inhibitor perifosine are each well‐tolerated as single agents but with limited activity reclinical data demonstrate synergistic anti‐tumor effects from combined treatment. Therefore, we initiated a phase I trial of combined therapy in recurrent MGs to determine safety and a recommended phase II dose. Methods Adults with recurrent MG, Karnofsky Performance Status ≥ 60 were enrolled, with no limit on the number of prior therapies. Temsirolimus dose was escalated using standard 3 + 3 design from 15 mg to 170 mg administered once weekly. Perifosine was fixed as a 600 mg load on day 1 followed by 100 mg nightly (single agent MTD) until dose level 7 when the load increased to 900 mg. Results We treated 35 patients with with glioblastoma (17) or other MGs (18; including nine anaplastic astrocytoma, nine anaplastic oligodendroglioma, one anaplastic oligoastrocytoma, and two low grade astrocytomas with radiographic transformation to MG). We observed five dose‐limiting toxicities (DLTs): one at dose level 3 (50mg temsirolimus), then two at dose level 7 expansion (170 mg temsirolimus), and then two more at dose level 6 expansion (170 mg temsirolimus). DLTs included thrombocytopenia (n = 3), intracerebral hemorrhage (n = 1) and lung infection (n = 1). Conclusion Combining the mTOR inhibitor temsirolimus dosed at 115 mg weekly and the AKT inhibitor perifosine dosed at 100 mg daily (following 600 mg load) is tolerable in heavily pretreated adults with recurrent MGs.