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Abstract Purpose Differentiating between glioblastoma (GB) with multiple foci (mGB) and multifocal central nervous system lymphoma (mCNSL) can be challenging because these cancers share several features at first appearance on magnetic resonance imaging (MRI). The aim of this study was to explore morphological differences in MRI findings for mGB versus mCNSL and to develop an interpretation algorithm with high diagnostic accuracy. Methods In this retrospective study, MRI characteristics were compared between 50 patients with mGB and 50 patients with mCNSL treated between 2015 and 2020. The following parameters were evaluated: size, morphology, lesion location and distribution, connections between the lesions on the fluid-attenuated inversion recovery sequence, patterns of contrast enhancement, and apparent diffusion coefficient (ADC) values within the tumor and the surrounding edema, as well as MR perfusion and susceptibility weighted imaging (SWI) whenever available. Results A total of 187 mCNSL lesions and 181 mGB lesions were analyzed. The mCNSL lesions demonstrated frequently a solid morphology compared to mGB lesions, which showed more often a cystic, mixed cystic/solid morphology and a cortical infiltration. The mean measured diameter was significantly smaller for mCNSL than mGB lesions (p

Purpose: Differentiating between glioblastoma (GB) with multiple foci (mGB) and multifocal central nervous system lymphoma (mCNSL) can be challenging because these cancers share several features at first appearance on magnetic resonance imaging (MRI). The aim of this study was to explore morphological differences in MRI findings for mGB versus mCNSL and to develop an interpretation algorithm with high diagnostic accuracy. Methods: In this retrospective study, MRI characteristics were compared between 50 patients with mGB and 50 patients with mCNSL treated between 2015 and 2020. The following parameters were evaluated: size, morphology, lesion location and distribution, connections between the lesions on the fluid-attenuated inversion recovery sequence, patterns of contrast enhancement, and apparent diffusion coefficient (ADC) values within the tumor and the surrounding edema, as well as MR perfusion and susceptibility weighted imaging (SWI) whenever available. Results: A total of 187 mCNSL lesions and 181 mGB lesions were analyzed. The mCNSL lesions demonstrated frequently a solid morphology compared to mGB lesions, which showed more often a cystic, mixed cystic/solid morphology and a cortical infiltration. The mean measured diameter was significantly smaller for mCNSL than mGB lesions (p < 0.001). Tumor ADC ratios were significantly smaller in mCNSL than in mGB (0.89 ± 0.36 vs. 1.05 ± 0.35, p < 0.001). The ADC ratio of perilesional edema was significantly higher (p < 0.001) in mCNSL than in mGB. In SWI / T2*-weighted imaging, tumor-associated susceptibility artifacts were more often found in mCNSL than in mGB (p < 0.001). Conclusion: The lesion size, ADC ratios of the lesions and the adjacent tissue as well as the vascularization of the lesions in the MR-perfusion were found to be significant distinctive patterns of mCNSL and mGB allowing a radiological differentiation of these two entities on initial MRI. A diagnostic algorithm based on these parameters merits a prospective validation. [ABSTRACT FROM AUTHOR]

Introduction: The prognosis for glioblastoma multiforme (GBM), a malignant brain tumor, is poor despite recent advancements in treatments. Suicide gene therapy is a therapeutic strategy for cancer that requires a gene to encode a prodrug-activating enzyme which is then transduced into a vector, such as mesenchymal stem cells (MSCs). The vector is then injected into the tumor tissue and exerts its antitumor effects. Case presentation: A 37-year-old man presented to our department with two evident foci of glioblastoma multiforme at the left frontal and left parietal lobes. The patient received an injection of bone marrow-derived MSCs delivering the herpes simplex virus thymidine kinase (HSV-tk) gene to the frontal focus of the tumor, followed by ganciclovir administration as a prodrug for 14 days. For follow-up, the patient was periodically assessed using magnetic resonance imaging (MRI). The growth and recurrence patterns of the foci were assessed. After the injection on 09 February 2019, the patient’s follow-up appointment on 19 December 2019 MRI revealed a recurrence of parietal focus. However, the frontal focus had a slight and unremarkable enhancement. On the last follow-up (18 March 2020), the left frontal focus had no prominent recurrence; however, the size of the left parietal focus increased and extended to the contralateral hemisphere through the corpus callosum. Eventually, the patient passed away on 16 July 2020 (progression-free survival (PFS) = 293 days, overall survival (OS) = 513 days). Conclusion: The gliomatous focus (frontal) treated with bone marrow-derived MSCs carrying the HSV-TK gene had a different pattern of growth and recurrence compared with the non-treated one (parietal). [ABSTRACT FROM AUTHOR]

IntroductionThe prognosis for glioblastoma multiforme (GBM), a malignant brain tumor, is poor despite recent advancements in treatments. Suicide gene therapy is a therapeutic strategy for cancer that requires a gene to encode a prodrug-activating enzyme which is then transduced into a vector, such as mesenchymal stem cells (MSCs). The vector is then injected into the tumor tissue and exerts its antitumor effects.Case presentationA 37-year-old man presented to our department with two evident foci of glioblastoma multiforme at the left frontal and left parietal lobes. The patient received an injection of bone marrow-derived MSCs delivering the herpes simplex virus thymidine kinase (HSV-tk) gene to the frontal focus of the tumor, followed by ganciclovir administration as a prodrug for 14 days. For follow-up, the patient was periodically assessed using magnetic resonance imaging (MRI). The growth and recurrence patterns of the foci were assessed. After the injection on 09 February 2019, the patient's follow-up appointment on 19 December 2019 MRI revealed a recurrence of parietal focus. However, the frontal focus had a slight and unremarkable enhancement. On the last follow-up (18 March 2020), the left frontal focus had no prominent recurrence; however, the size of the left parietal focus increased and extended to the contralateral hemisphere through the corpus callosum. Eventually, the patient passed away on 16 July 2020 (progression-free survival (PFS) = 293 days, overall survival (OS) = 513 days).ConclusionThe gliomatous focus (frontal) treated with bone marrow-derived MSCs carrying the HSV-TK gene had a different pattern of growth and recurrence compared with the non-treated one (parietal).Trial registrationIRCT20200502047277N2. Registered 10 May 2020—Retrospectively registered, https://eng.irct.ir/trial/48110.

Primary glioblastoma (GBM), IDH-wildtype, especially with multifocal appearance/growth (mGBM), is associated with very poor prognosis. Several clinical parameters have been identified to provide prognostic value in both unifocal GBM (uGBM) and mGBM, but information about the influence of radiological parameters on survival for mGBM cohorts is scarce. This study evaluated the prognostic value of several volumetric parameters derived from magnetic resonance imaging (MRI). Data from the Department of Neurosurgery, Leipzig University Hospital, were retrospectively analyzed. Patients treated between 2014 and 2019, aged older than 18 years and with adequate peri-operative MRI were included. Volumetric assessment was performed manually. One hundred and eighty-three patients were included. Survival of patients with mGBM was significantly shorter (p < 0.0001). Univariate analysis revealed extent of resection, adjuvant therapy regimen, residual tumor volume, tumor necrosis volume and ratio of tumor necrosis to initial volume as statistically significant for overall survival. In multivariate Cox regression, however, only EOR (for uGBM and the entire cohort) and adjuvant therapy were independently significant for survival. Decreased ratio of tumor necrosis to initial tumor volume and extent of resection were associated with prolonged survival in mGBM but failed to achieve statistical significance in multivariate analysis.

Abstract Background Multifocal glioblastoma is a rare type of glioblastoma with worse prognosis. In this article, we aimed to report two cases of classical multifocal glioblastoma. Case presentation In case 1, a 47-year-old male presented with dizziness, and once had a sudden loss of consciousness accompanied by convulsion of limbs. Contrast-enhanced MRI showed multiple lesions with heterogeneously ring-enhanced characters in the left hemisphere, diagnosed as multifocal glioblastoma. He underwent a craniotomy of all lesions, concurrent radiotherapy and chemotherapy as well as additional chemotherapy of temozolomide. After 2 cycles, repeat MRI showed that the new lesions already occurred and progressed. Eventually, he abandoned the chemotherapy after the 2 cycles and died 1 year later. In case 2, a 71-year-old male presented with a history of headache, left limb weakness, and numbness. Discontinuous convulsion of limbs once occurred. Contrast-enhanced MRI showed multiple lesions located in the right hemisphere, diagnosed as multifocal glioblastoma. He underwent a right frontoparietal craniotomy of the main lesion. Hemorrhage of the residual tumor and pulmonary artery embolism occurred synchronously. Eventually, his family decided not to pursue any further treatment and opted for hospice care and he passed away within 11 days of surgery. Conclusions We reported two cases of typical multifocal glioblastoma. Valid diagnosis is crucial; then, resection of multiple lesions and canonical radio-chemotherapy probably bring survival benefits.

Caroline Sander,1 Vera Reuschel,2 Christian Eisenlöffel,3 Ulf Nestler,1 Jürgen Meixensberger11Department of Neurosurgery, University Hospital Leipzig, Leipzig 04103, Germany; 2Department of Neuroradiology, University Hospital Leipzig, Leipzig 04103, Germany; 3Institute of Neuropathology, University Hospital Leipzig, Leipzig 04103, GermanyPurpose: Familial glioblastoma multiforme (gbm) has been described in children with hereditary tumor syndromes. The occurrence of gbm in adult members of the same family and in the absence of tumor syndromes is extremely rare. We describe the cases of a brother and a sister with multifocal gbm diagnosed at the age of 63 years. We discuss three further paired gbm in adult patients from the literature.Patients and results: The sister was diagnosed with multifocal primary gbm in 2014 at the age of 63 years and 6 months. In 2018, her younger brother had to be operated on for a multifocal primary gbm at the age of 63 years and 9 months. Extended neuropathological examination revealed most markers to be similar, except for the percentage of O6,-methylguanine-DNA methyltransferase promotor methylation, the presence of intratumoral immune cells and the immunohistochemical expression of C12ORF75. Comparison with further published cases of familial adult GBM reveals that most of these patients are male, about 65 years old and the tumor is localized predominantly in the left temporal lobe.Conclusion: Paired adult familial gbm occurs mainly in the elderly male patient with an integrative diagnosis of primary gbm. Whereas a statistical coincidence seems to be most likely in these rare cases, supplementary and improved genetic studies may identify pathogenetic causes of gbm.Keywords: multifocal glioblastoma, familial tumor clustering, IDH-1 wildtype, tumor syndrome

Glioblastomas are malignant, poorly differentiated tumours of glial origin. They are the most common primary brain tumours, occurring in 2 to 3 per 100 000 adults. Published data on glioblastomas in Africa are scarce; however, the incidence has been found to be lower in people of African origin. In 0.5% to 15% of all cases, glioblastomas manifest as multiple lesions. In this report, we describe 4 patients with multifocal glioblastoma managed at our institution. There were 47 patients diagnosed with glioblastoma between 1 January and 31 December 2019, among whom we identified 4 (3 men and 1 woman) with multifocal glioblastoma and analysed their data. The median age at diagnosis was 50.5 years (range, 31-55 years). The median overall survival in our series was 8 months (range, 2-13 months). Two of our patients underwent excision of a single lesion, and the other 2 underwent biopsy only. One patient in our series received chemotherapy and radiotherapy after surgery. We found that multifocal glioblastoma is a rare presentation associated with poor outcomes. [ABSTRACT FROM AUTHOR]

Primary glioblastoma (GBM), IDH-wildtype, especially with multifocal appearance/growth (mGBM), is associated with very poor prognosis. Several clinical parameters have been identified to provide prognostic value in both unifocal GBM (uGBM) and mGBM, but information about the influence of radiological parameters on survival for mGBM cohorts is scarce. This study evaluated the prognostic value of several volumetric parameters derived from magnetic resonance imaging (MRI). Data from the Department of Neurosurgery, Leipzig University Hospital, were retrospectively analyzed. Patients treated between 2014 and 2019, aged older than 18 years and with adequate peri-operative MRI were included. Volumetric assessment was performed manually. One hundred and eighty-three patients were included. Survival of patients with mGBM was significantly shorter (p < 0.0001). Univariate analysis revealed extent of resection, adjuvant therapy regimen, residual tumor volume, tumor necrosis volume and ratio of tumor necrosis to initial volume as statistically significant for overall survival. In multivariate Cox regression, however, only EOR (for uGBM and the entire cohort) and adjuvant therapy were independently significant for survival. Decreased ratio of tumor necrosis to initial tumor volume and extent of resection were associated with prolonged survival in mGBM but failed to achieve statistical significance in multivariate analysis. [ABSTRACT FROM AUTHOR]

Introduction: Glioblastomas (GBMs) usually occur as a solitary lesion; however, about 0.5–35% present with multiple lesions (M-GBM). The genetic landscape of GBMs have been thoroughly investigated; nevertheless, differences between M-GBM and single-foci GBM (S-GBM) remains unclear. The present study aimed to determine differences in clinical and molecular characteristics between M-GBM and S-GBM. Methods: A retrospective review of multifocal/multicentric infiltrative gliomas (M-IG) from our institutional database was performed. Demographics, clinical, radiological, and genetic features were obtained and compared between M-GBM IDH-wild type (IDH-WT) vs 193 S-GBM IDH-WT. Mutations were examined by a targeted next-generation sequencing assay interrogating 315 genes. Results: 33M-IG were identified from which 94% were diagnosed as M-GBM IDH-WT, the remaining 6% were diagnosed as astrocytomas IDH-mutant. M-GBM and S-GBM comparison revealed that EGFR alterations were more frequent in M-GBM (65% vs 42% p = 0.019). Furthermore, concomitant EGFR/PTEN alterations were more common in M-GBM vs. S-GBM (36% vs 19%) as well as compared to TCGA (21%). No statistically significant differences in overall survival were observed between M-GBM and S-GBM; however, within the M-GBM cohort, patients harboring KDR alterations had a worse survival (KDR-altered 6.7 vs KDR-WT 16.6 months, p = 0.038). Conclusions: The results of the present study demonstrate that M-GBM genetically resembles S-GBM, however, M-GBM harbor higher frequency of EGFR alterations and co-occurrence of EGFR/PTEN alterations, which may account for their highly malignant and invasive phenotype. Further study of genetic alterations including differences between multifocal and multicentric GBMs are warranted, which may identify potential targets for this aggressive tumor. [ABSTRACT FROM AUTHOR]

Multifocal high-grade gliomas constitute an uncommon clinical entity that poses diagnostic and treatment dilemmas. Here we describe the approach to these central nervous system tumors and the management of a series of four clinical cases. We emphasize the necessity for biopsy soon after symptom onset, to differentiate multifocal gliomas from brain metastases and thus plan individualized treatment. As imaging accuracy increases, so does the reported incidence of diagnosed multifocal lesions. We review the current pathogenetic hypotheses and the clinical characteristics and problems arising from these tumors. [ABSTRACT FROM AUTHOR]

Adult cerebellar glioblastomas (cGBM) are rare and their characteristics remain to be fully described. We analyzed the characteristics of 17 adult patients with cGBM and compared them to a series of 103 patients presenting a supra-tentorial glioblastoma (stGBM). The mean age at GBMc diagnosis was 53.4 years (range 28–77). A history of neurofibromatosis type I was noted in 3 patients. cGBM were hemispheric in 10 patients (58.8%), only vermian in 4 patients (23.5%), and both vermian and hemispheric in 3 patients (17.7%). A H3 K27M mutation was identified in 3/14 patients, a TERT promoter mutation in 3/14 patients and a methylated MGMT promoter in 3/14 patients. None of the patients (0/14) harbored an EGFR amplification, an IDH or a BRAF mutation. Association with neurofibromatosis type I and H3K27M mutations were mutually exclusive. Compared with stGBM, cGBM occurred in younger patients (53.4 vs. 63.2, p = 0.02), were more frequently associated with neurofibromatosis type I (18 vs. 1%, p = 0.009) and with a H3 K27M mutation (21 vs. 3%, p = 0.02). They also tended to have a more frequent multifocal presentation at diagnosis (21 vs. 4.3%, p = 0.06), more frequently resulted in leptomeningeal or intra-axial metastasis (44.5 vs. 5%, p = 0.002) and were associated with a shorter median overall survival (5.9 vs. 14.2 months, p = 0.004). The present study suggests that adult cGBM differ from their supra-tentorial counterpart and constitute a heterogeneous group of IDH wild-type gliomas with at least two subgroups, one associated with H3K27M mutations and the other with neurofibromatosis type I. [ABSTRACT FROM AUTHOR]

Multifocal and multicentric glioblastoma (GBM) or collectively, m-GBM, is an imaging diagnosis present in up to 34% of patients with GBM. Compared to unifocal disease, patients with m-GBM have worse outcomes owing to the enhanced aggressive nature of the disease and its resistance to currently available treatments. To improve the understanding of its complex behavior, many associations have been established between the radiologic findings of m-GBM and its gross histology, genetic composition, and patterns of spread. Additionally, the holistic knowledge of the exact mechanisms of m-GBM genesis and progression is crucial for identifying potential targets permitting enhanced diagnosis and treatment. In this review, we aim to provide a comprehensive summary of the cumulative knowledge of the unique molecular biology and behavior of m-GBM and the association of these features with neuroimaging.

Background: Multifocal glioblastoma is an uncommon and refractory subtype of high-grade glioma since the burden of masses could not be eliminated simply by operation, and it is getting even harder to control if some deep structures, like thalamus and pineal region, are involved. Case presentation: Here we report a case of a 30-year-old male with multifocal glioblastoma affected his right thalamus, left lateral ventricle, and pineal region. Clinical manifestations include operation, concurrent radiochemotherapy, and a 12-cycle adjuvant temozolomide administration. The masses of this patient nearly disappeared after 15 months from the primary diagnosis, and no severe adverse event or neurological sequel occurred. Conclusions: Long-term temozolomide might be an optimal choice for patients with multifocal glioblastoma, especially with deep-seated structure involvement. [ABSTRACT FROM AUTHOR]

Background. New approaches are needed for patients newly diagnosed with bulky glioblastoma (GB) and/or with severe neurological impairment that cannot benefit from first line temozolomide (TMZ)-based chemoradiotherapy. Bevacizumab (BEV), an antiangiogenic anti-VEGF-R monoclonal antibody, has a rapid impact on tumor-related brain edema in recurrent GB. The present study reports the feasibility and efficacy of an induction treatment with TMZ and BEV to alleviate the initial neurological impairment and/or to reduce the tumor volume before a delayed chemoradiotherapy. Methods. We retrospectively analyzed tumor and target volumes and clinical neurological status in 39 patients with bulky GB and/or with severe neurological impairment after an induction treatment combining TMZ and BEV. Neurological and radiological responses were assessed according to RANO criteria. Calculating gross tumor and clinical target volumes (GTV and CTV) was done at diagnosis and before radiotherapy. Progression-free survival (PFS) and overall survival (OS) were determined by Kaplan Meier methods. Safety was reported according to NCTCAE. Results. A cohort of 39 patients was analyzed between December 2010 and April 2014. Upfront standard TMZ-based chemoradiotherapy was recused due either to tumor volume or impairment of neurological status and/or performance status. After TMZ/BEV induction (median time of 3 months), 6 (15%) patients achieved a partial response (PR), and 17 (44%) had a stable disease. 24 patients (62%) received a radical-intent chemoradiotherapy. TMZ-BEV induced median reduction of the clinical target volume (CTV) was 25.9% [-84.4%; - 4.8%]. The median PFS and OS were 8.4 months [95% CI: (6.6 - 9.9)] and 11.0 months [95% CI: (9.3 - 13.7)] , respectively in the whole cohort and 10.8 [95% CI: (9.3 - 12.9)] and 15.0 [95% CI: (13.2 - 17.8)] for irradiated patients. Induction treatment led to corticosteroid dose reduction or cessation in 21 patients (54%). KPS improvement was observed in 38% of patients . Toxicity was mild with only 7/39 (18%) grade III-IV toxicity, including 1 digestive bleeding and 1 epistaxis. Conclusion. TMZ-BEV induction led to CTV reduction allowing for optimal chemoradiotherapy in a majority (62%) of patients for which radiotherapy was initially recused. A clinical benefit was obtained with improved KPS and a decrease in steroid dose., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Background: The evolution of primary glioblastoma (GBM) is poorly understood. Multifocal GBM (ie, multiple synchronous lesions in one patient) could elucidate GBM development., Methods: We present the first comprehensive study of 12 GBM foci from 6 patients using array-CGH, spectral karyotyping, gene expression arrays, and next-generation sequencing., Results: Multifocal GBMs genetically resemble primary GBMs. Comparing foci from the same patient proved their monoclonal origin. All tumors harbored alterations in the 3 GBM core pathways: RTK/PI3K, p53, and RB regulatory pathways with aberrations of EGFR and CDKN2A/B in all (100%) patients. This unexpected high frequency reflects a distinct genetic signature of multifocal GBMs and might account for their highly malignant and invasive phenotype. Surprisingly, the types of mutations in these genes/pathways were different in tumor foci from the same patients. For example, we found distinct mutations/aberrations in PTEN, TP53, EGFR, and CDKN2A/B, which therefore must have occurred independently and late during tumor development. We also identified chromothripsis as a late event and in tumors with wild-type TP53. Only 2 events were found to be early in all patients: single copy loss of PTEN and TERT promoter point mutations., Conclusions: Multifocal GBMs develop through parallel genetic evolution. The high frequency of alterations in 3 main pathways suggests that these are essential steps in GBM evolution; however, their late occurrence indicates that they are not founder events but rather subclonal drivers. This might account for the marked genetic heterogeneity seen in primary GBM and therefore has important implications for GBM therapy., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)