Vitamin D should be considered as a targeted therapy in glioblastoma cases

Objective: The aim of this study is to evaluate the demographic, radiological and histopathological findings, tumoral biomarkers, and survival rates of patients who underwent a stereotactic brain biopsy and those diagnosed with glioblastoma, metastasis, and lymphoma, and the changes in the diagnosis distribution over the years. Materials and Methods: The patients who underwent stereotactic biopsy in our clinic between 2012 and 2020 were evaluated retrospectively. Metastasis, glioblastoma, and lymphoma cases were evaluated as three main groups and the others were excluded. P53 gene expression, isocitrate dehydrogenase (IDH) mutation, and Ki-67 values in glioblastoma cases and Bcl-2, Bcl-6 proteins, and Ki-67 values in lymphomas and their relationship with survival were evaluated. Results: High p53 expression was observed in 27.5% cases diagnosed with glioblastoma. IDH mutation was negative in all glioblastoma cases. Presence of Bcl-2 and Bcl-6 proteins was not associated with survival in lymphomas. Survival rate was significantly higher in cases diagnosed with lymphoma (26.9%) compared to those diagnosed with glioblastoma. A statistically significant increase was determined in patients diagnosed with lymphoma considering the distribution of diseases and incidence and in the distribution of other diagnoses over the years ( p < 0.05). Conclusion: As per the distribution of the disease in recent times, it has been observed that there is an increase in lymphoma cases. Histopathology and biomarkers have great importance in the diagnosis and treatment of cerebral lesions. We think that our findings will be supported by studies in which larger patient population and detailed biomarkers will be studied.

A case of multicentric glioblastoma with the clinical and histopathological findings is presented in which three lesions are located above and below the tnetorium. Multicentric glioblastomas are those which have no macroscopic or microscopic connection.

Glioblastoma sometimes develops with acute onset due to intracerebral hemorrhage. Although it is sometimes difficult to diagnose patients with hemorrhagic-onset glioblastoma at the acute phase of intracerebral hemorrhage (ICH), the progressive enlargement of perifocal edema or the development of contrast-enhanced lesion triggers the diagnosis of glioblastoma within six months. Herein, we present a rare case of glioblastoma in which the diagnosis was delayed as long as 17 months after ICH. A 62-year-old man presented with a headache and aphasia. Computed tomography revealed ICH in the left temporal lobe. Magnetic resonance (MR) images revealed that the hematoma had a mix of isointense and surrounding hypointense lesions on T1-weighted MR images and gadolinium-enhanced lesions at the wall and the septum of the hematoma. An endoscopic evacuation of the hematoma was performed. No causative lesions were found during intraoperative and histological examinations. After seven months, abnormal signals were completely resolved on MR images, except for the small and stable enhanced lesion on three-dimensional gadolinium-enhanced T1-weighted MR imaging (3D Gd-T1WI) at the base of the hematoma, which did not change in size for seven months. However, a large gadolinium-enhanced lesion at the left temporal lobe developed 17 months after ICH. He underwent total resection of the lesion and was diagnosed with glioblastoma. He received radiation therapy and temozolomide but died of disseminated recurrence 31 months after ICH. In conclusion, this report presents a didactic case of glioblastoma in which the diagnosis of glioblastoma was delayed 17 months after ICH whereas hemorrhagic-onset glioblastoma was previously considered ruled out in cases in which six months or more have passed after ICH. In order not to overlook these cases, follow-up with 3D Gd-T1WI is essential in the case of suspected tumor-related ICH and close follow-up is recommended when the enhanced lesion does not resolve after a long period even if it does not grow.

Glioblastomas express a notable heterogeneity in both the histological and cell patterns with glial astrocytic differentiation. Primary glioblastoma, which is the most frequent presentation (90-95%), occurs mainly in older patients and arises de novo, without any clinical or histological evidence of a less malignant precursor lesion. EGFR amplification has been identified as a genetic hallmark of primary glioblastomas and occurs in 40-60% of cases. However, there exist primary glioblastomas without EGFR amplification/overexpression. The purpose of this study was to stabilize the association between cases with and without EGFR gene amplification with clinical and genetic parameters in 45 cases of primary glioblastomas. EGFR amplification was observed in 24 cases (53%), while in the remaining 21 cases (47%) this alteration was not displayed. And whereas EGFR was overexpressed in 79% of cases with EGFR amplification, only 33% of the cases without EGFR amplification showed overexpression. The amplification of EGFR was associated with amplifications in MDM2 and CDK4 and a higher percentage of cases with promoter methylation of INK4a. Only one case of glioblastoma with EGFR amplification presented TP53 mutation simultaneously. Seven remaining cases with TP53 mutations were glioblastomas without EGFR amplification. The INK4a, INK4b and ARF deletions were similar in the two groups. Primary glioblastomas with and without EGFR amplification did not show any significant differences in average survival. The genetic studies suggest the existence of molecular subtypes within primary glioblastoma that may, when fully defined, contribute toward the development of drugs that specifically target tumors with divergent genetic profiles.

Glioblastoma, isocitrate dehydrogenase (IDH) wild type, is an aggressive primary brain malignancy with a poor prognosis, despite treatment including surgery, chemotherapy, and radiation therapy. Few patients with glioblastoma develop metastasis outside the neuroaxis, likely due to disease progression in the brain prior to extraneural dissemination. The driving mutations of tumors in patients with extraneural metastases are not well described. In this case, we present a severe case of extraneural metastatic glioblastoma, as well as the genetic mutations of the tumor.

An unusual case of glioblastoma with adenoid structures arising in a 30-year-old Japanese woman with neurofibromatosis type-1 (NF1) is reported. The patient was admitted to University of Miyazaki Hospital, complaining of headache, nausea and vomiting. From the neuroradiological findings the patient was diagnosed as having glioblastoma, and the tumor was surgically resected. Histologically, the tumor consisted mainly of dark basophilic cells showing prominent tubular or glandular structures surrounded by large eosinophilic cells, in addition to the typical glioblastoma features in the periphery of the tumor. Both cells showed strong stainability with glial fibrillary acidic protein (GFAP) and S-100 protein immunohistochemically, so that the tumor was classified as adenoid glioblastoma. Several cases of glioblastoma have been reported to reveal the adenoid or epithelioid differentiation. The patients with NF1 are prone to develop malignant tumors including glioblastoma, but no cases representing adenoid glioblastoma associated with NF1 have been reported. This report is considered to be the first case of adenoid glioblastoma arising in a patient with NF1. The recognition of the existence of epithelial features of glioblastoma would be important in differential diagnosis of epithelioid tumors of the brain including metastatic carcinomas.

CASESWe report about 41 cases of malignant brain tumor which were treated with operation, irradiation, chemotherapy during past 62 months. 34 cases of glioblastoma, 2 cases of malignant glioma(WHO grade III), 2 cases of medulloblastoma, 1 case of germ cell tumor, 1 case of malignant neurocytoma, and 1 case of malignant ependymoma were included in 41 cases. Two cases of glioblastoma survived over than 25 years, but the median survival of dead 11 glioblastoma cases was 22 months. 4 cases were expired among another 7 cases.RESULTS6 cases showed mutation in ATRX and one case had mutation of IDH-1 among 34 cases of glioblastoma. One case showed mutation in ATRX and IDH-1 among 2 cases of malignant glioma. But the mutation in ATRX and IDH-1 had no correlation with convulsion. The initial symptom was epilepsy in 3 cases of glioblastoma and another 3 cases of glioblastoma showed convulsive seizure thereafter. One case of glioblastoma showed rapid aggravation of symptom after convulsion. The initial symptom was epilepsy in 1 case of malignant glioma. One case of malignant ependymoma and one case of medulloblastoma showed rapid aggravation of symptom after convulsion.DISCUSSIONNine cases showed convulsion among our 41 cases. Convulsion happened as initial symptom in 4 cases but it happened during treatment in 5 cases. Three cases among these 5 cases showed rapid aggravation of symptom after convulsion. So pre- and post-operative anti-epileptic treatment seems to be necessary.

Development of molecular diagnostics that can reliably differentiate amongst different subtypes of brain tumors is an important unmet clinical need in postgenomics medicine and clinical oncology. A simple linear formula derived from gene expression values of four genes (GFAP, PTPRZ1, GPM6B, and PRELP) measured from cDNA microarrays (n = 35) have distinguished glioblastoma and meningioma cases in a previous study. We herein extend this work further and report that the above predictor formula showed its robustness when applied to Affymetrix microarray data acquired prospectively in our laboratory (n = 80) as well as publicly available data (n = 98). Importantly, GFAP and GPM6B were both retained as being significant in the predictive model upon using the Affymetrix data obtained in our laboratory, whereas the other two predictor genes were SFRP2 and SLC6A2. These results collectively indicate the importance of the expression values of GFAP and GPM6B genes sampled from the two types of microarray technologies tested. The high prediction accuracy obtained in these instances demonstrates the robustness of the predictors across microarray platforms used. This result would require further validation with a larger population of meningioma and glioblastoma cases. At any rate, this study paves the way for further application of gene signatures to more stringent biopsy discrimination challenges.

The objective of this study was to determine if volumetric modulated arc therapy (VMAT) offers advantages over intensity modulated radiotherapy (IMRT) for complex brain gliomas and evaluate the role of an additional partial arc. Twelve patients with glioma involving critical organs at risk (OAR) were selected [six low grade brainstem glioma (BG) and six glioblastoma (GB) cases]. BGs were prescribed 54 Gy/30 fractions (frx), and GB treated to 50 Gy/30 frx to a lower dose PTV (PTV50) with a simultaneous integrated boost delivering a total dose of 60 Gy/30 frx to a higher dose PTV (PTV60). VMAT was planned with a single arc (VMAT1) and with an additional coplanar partial arc spanning 90° (VMAT2). We observed VMATI improving the PTV equivalent uniform dose (EUD) for BG cases (p=0.027), improving the V95 for the PTV50 in GB cases (p=0.026) and resulting in more conformal GB plans (p=0.008) as compare to IMRT. However, for the GB PTV60, IMRT achieved favorable V95 over VMAT1 and VMAT2 (0.0046 and 0.008, respectively). The GB total integral dose (ID) was significantly lower with VMAT1 and VMAT2 (p=0.049 and p=0.006, respectively). Both VMAT1 and VMAT2 reduced the ID, however, only at the 5 Gy threshold for BG cases (p=0.011 and 0.005, respectively). VMAT achieved a lower spinal cord maximum dose and EUD for BG cases and higher optic nerve doses, otherwise no significant differences were observed. VMAT1 yielded the fastest treatment times and least MU. We conclude that VMAT offers faster treatment delivery for complex brain tumors while maintaining similar dosimetric qualities to IMRT. Selective dosimetric advantages in terms of spinal cord sparing and lowering the ID are observed favoring the use of an additional coplanar partial arc.

Gliosarcoma (GS) is an uncommon malignant tumor of the brain, consisting of malignant glial, usually a glioblastoma (GB), as well as sarcomatous component; the latter is usually in the form of fibrosarcoma. We report a series of 10 GSs with prominent smooth muscle component, which is a rare occurrence. Out of a series of 225 cases of GB admitted in our hospital, 10 were diagnosed as GS with prominent smooth muscle component, gliomyosarcoma (GMS). This is an observational study based on the experience with 225 cases of GB, encountered between 1995 and 2008, in our hospital. The tumors showing prominent spindle cell component were stained with reticulin and 20 with strongly positive reticulin stain were diagnosed as GS. They were further studied by immunohistochemical staining for glial fibrillary acidic protein (GFAP), smooth muscle actin (SMA), desmin and factor VIII antigen. Out of 225 cases of GB, 20 were diagnosed as GS. Ten of these showed prominent smooth muscle component and were diagnosed as GMS. They revealed varying degrees of SMA and factor VIII Ag positivity. In the sarcomatous component, SMA and factor VIII positive cells were seen close to the vessel walls as well as away from them. GMS containing prominent smooth muscle component may not be as rare as has been reported in the literature. Both GS and GMS appear to arise from the vessel wall at least in some cases, suggesting their possible vascular origin.

Glioblastoma is a malignant brain tumor that occurs in all age groups and corresponds to WHO°IV. Based on genetics, global gene expression, and methylation patterns, glioblastoma may be categorized in different molecular subgroups. Among these subgroups “IDH” glioblastomas, which carry mutations within IDH1 or IDH2, as well as the “K27” and “G34” subgroups, which are characterized by distinct mutations within the H3F3A gene, can be clearly identified by sequencing methods and are particularly often found in younger patients below 30 years of age. We aimed to analyze the histomorphology of glioblastomas found in patients ≤30 years with the following assigned molecular subgroups: IDH (n = 12), H3F3A K27M (n = 21), H3F3A G34R (n = 12) or no IDH/H3F3A mutations (n = 24). Assessment of histomorphological characteristics was done blinded. IDH mutated cases displayed moderate cell densities and nuclear pleomorphism, showed an astroglial morphology and often harbored microcystic features or gemistocytic tumor cells. H3F3A K27M mutated cases more often showed necroses and displayed higher cell densities and pronounced nuclear pleomorphism. A fraction of these cases was additionally characterized by tumor giant cells. Glioblastoma cases carrying H3F3A G34R mutations predominantly displayed an undifferentiated/PNET-like morphology with densely packed cells and high nuclear pleomorphism. Tumor cell foci with epithelial appearance were specifically found in glioblastoma cases without IDH or H3F3A mutations. Moreover, a fraction of glioblastoma cases without IDH/H3F3A mutations exhibited tumor giant cells. Thus, molecular glioblastoma subgroups are characterized by distinct histomorphological features that can be detected by routine histology. Both IDH mutated cases and H3F3A G34R glioblastoma cases presented histomorphologically as a quite homogenous group. In contrast, H3F3A K27M cases and glioblastomas without IDH/H3F3A mutations displayed disparities of histomorphology, that might imply a more heterogeneous molecular picture. Our study underlines the diversity of glioblastoma and suggests that distinct morphological features reflect the underlying molecular characteristics.

To evaluate possible roles of matrix metalloproteinase (MMP)-1, -2, tissue inhibitor of metalloproteinase (TIMP)-1, -2 and membrane-type-1 matrix metalloproteinase (MT1-MMP) in invasion of human gliomas, expressions of these proteins were investigated in ten cases of human glioma and two meningioma tissues and eight human glioma cell lines. In gelatin zymography, MMP-2 activities of glioblastomas were higher than astrocytomas. The activated form of MMP-2 was seen in five of six cases of glioblastomas, but not in astrocytomas. MMP-9 activity was detected in all cases of malignant astrocytomas but the reactivity of MMP-9 was weaker than that of MMP-2. MT1-MMP mRNA expression in glioblastomas was higher than that in astrocytomas. Five cases of glioblastomas with activated form of MMP-2 had MT1-MMP expressions. In vitro, human glioma cell lines with high expression of MT1-MMP also showed high MMP-2 activity. TIMP-1 transcripts were constitutively present in almost all glioma tissues and cell lines, whereas TIMP-2 mRNA were weak especially in malignant gliomas. Imbalance of TIMP-2/MMP-2 was observed using immunoprecipitation analysis in a glioma cell line. High expression of MMP-2 and MT1-MMP is possibly involved in invasiveness of malignant glioma.

INTRODUCTION Li Fraumeni Syndrome (LFS) is a rare autosomal dominant tumor predisposition syndrome caused by germline alterations of the TP53. Brain tumors are included in LFS core cancers. Choroid plexus carcinomas and medulloblastomas tend to occur in pediatric LFS patients, while gliomas tend to occur in adult LFS patients. There are few previous reports about gliomas arising in the setting of LFS. Here, we report clinical and molecular features of three cases of glioblastoma, IDH-wildtype arising in the setting of LFS. RESULTS Mean age at diagnosis was 40 years (range: 32-45). Two patients were male. Two patients had medical history of multiple tumors and family history of brain tumors. Magnetic resonance imaging of each patients revealed a left cerebellar peduncle lesion with faint contrast-enhancement, a right parietal lobe lesion with nodular contrast-enhancement and two lesions in the pons (no enhancement) and right parietal lobe (ring enhancement), respectively. All patients underwent chemotherapy including temozolomide and/or bevacizumab combined with radiation therapy (60Gy) after surgery. Mean progression free survival was 10.4 months (range: 5.1-17.0). All patients were admitted to palliative care mean 17.3 months (range: 14.4-21.4) after diagnosis. All patients harbored heterozygous germline mutations of TP53. Whole exome sequencing and copy number analysis of tumor tissues revealed TP53 mutation and PDGFRA amplification in all patients. However, EGFR amplification, the combination of gain of chromosome 7 and loss of chromosome 10 (7+/10-) and mutations of IDH, H3F3A, BRAF and TERT promoter were not detected in all tissues. CONCLUSION We experienced three cases of glioblastoma, IDH-wildtype arising in the setting of LFS. Although tumor locations and radiographic features were varied, all clinical courses were poor. Notably, all tumor tissues harbored TP53 mutation and PDGFRA amplification, while no tumor tissues harbored TERT promoter mutation, EGFR amplification and 7+/10-.

BACKGROUND AND OBJECTIVESComprehensive Genome Profiling (CGP) has been covered by insurance since June 2019. This advancement has enabled the identification of therapeutic target gene mutations, improving access to drugs through clinical trials and patient-requested therapy programs. However, it has been noted that the number of cases that actually lead to treatment remains low. This study aims to examine the current status of CGP for brain and spinal cord tumor patients, assessing its utility and challenges. METHODSWe investigated 46 cases of central nervous system tumors that underwent CGP by April 2024. The focus was on the detection of MSI-H, TMB-H, NTRK fusion genes, and BRAF gene mutations, as well as the genetic mutations associated with recommended drugs, and examined the cases that led to actual treatment. RESULTSThe median age of the patients was 50 years. The breakdown included 26 cases of adult-type diffuse glioma, 5 cases of diffuse midline glioma with H3 K27M alteration, 1 case of pilomyxoid astrocytoma, 2 cases of ependymal tumors, 3 cases of atypical teratoid/rhabdoid tumor (AT/RT), 3 cases of anaplastic meningioma, and 6 other cases. MSI-H and TMB-H were found in 1 case of glioblastoma, TMB-H alone in 3 cases, NTRK fusion gene in 1 case of spinal glioma, and BRAF V600E mutation in 1 case of glioblastoma. Thirty cases (65%) received some form of recommendation, with 6 cases (13%) receiving drug treatment. Only the spinal glioma with the NTRK fusion gene showed significant improvement with entrectinib. CONCLUSIONWhile CGP is useful for identifying genetic abnormalities, its connection to actual treatment is limited. Future efforts should focus on developing new therapies and enhancing clinical trials, as well as exploring high-precision biomarkers and detailed analyses of the relationship between treatment history, clinical information, and genetic abnormalities.

Thirty-nine glial tumours (28 glioblastomas (GB) and 11 low-grade gliomas) were investigated with DNA microarrays to reveal a possible specific gene expression profile. Unsupervised classification through hierarchical cluster analysis identified two groups of tumours, the first composed of low-grade gliomas and the second mainly composed of GB. Nine genes were identified as most informative: seven were over-expressed in low-grade gliomas and under-expressed in GB; on the contrary, two genes, insulin-like growth factor binding protein 2 (IGFBP-2) and cell division cycle 20 homologue (CDC20), were over-expressed in GB and under-expressed in low-grade tumours. This same genetic profile was confirmed by reverse transcriptase polymerase chain reaction. Immunohistochemistry for IGFBP-2 was positive in 88.8% of the cases of GB and in only one low-grade glioma, whilst CDC20 immunostained 74.1% of the cases of GB and none low-grade glioma. This was confirmed in an additional series of cases studied with immunohistochemistry only. In conclusion, over-expression of mRNA levels of IGFBP-2 and CDC20 is highly related to GB, IGFBP-2 and CDC-20 gene and protein expressions are strongly correlated, and IGFBP-2 and CDC20 immunopositivity can be useful for the identification of GB in small biopsies.