Single versus multiple reoperations for recurrent intracranial meningiomas.

PURPOSE: To identify the risk factors and management of the multiple recurrences and reoperations for intracranial meningiomas. METHODS: Data of a neurosurgical series of 35 patients reoperated on for recurrent intracranial meningiomas were reviewed. Analyzed factors include patient age and sex, tumor location, extent of resection, WHO grade, Ki67-MIB1 and PR expression at initial diagnosis, time to recurrence; pattern of regrowth, extent of resection, WHO grade and Ki67-MIB1 at first recurrence were also analyzed. All these factors were stratified into two groups based on single (Group A) and multiple reoperations (Group B). RESULTS: Twenty-four patients (69%) belonged to group A and 11 (31%) to group B. The age < 65 years, male sex, incomplete resection at both initial surgery and first reoperation, and multicentric-diffuse pattern of regrowth at first recurrence are risk factors for multiple recurrences and reoperations. In group B, the WHO grade and Ki67-MIB1 increased in further recurrences in 54% and 64%, respectively. The time to recurrence was short in 7 cases (64%), whereas 4 patients (36%) further recurred after many years. Eight patients (73%) are still alive after 7 to 22 years and 2 to 4 reoperations. CONCLUSION: The extent of resection and the multicentric-diffuse pattern of regrowth at first recurrence are the main risk factors for multiple recurrences and reoperations. Repeated reoperations might be considered even in patients with extensive recurrent tumors before the anaplastic transformation occurs. In such cases, even partial tumor resections followed by radiation therapy may allow long survival in good clinical conditions.

Malignant intraventricular meningioma: literature review and case report.

Malignant intraventricular meningiomas (IVMs) are very rare with only a few reported cases. A midline search up to December 2020 selected 40 articles for a total of 65 patients. The inclusion criteria were series and case reports in English language, as well as papers written in other languages, but with abstracts written in English. Malignant IVMs at the first diagnosis (group A, 50 patients) and those with anaplastic transformation from previous WHO grades I and II tumors (group B, 15 patients) were separately analyzed. The unique personal case among 1285 meningiomas (0.078%) is also added. Malignant IVMs mainly occur in women (61%) with a median age of 45 years and are mainly located in the lateral ventricle (93%) and trigonal region (74%), with no cases in the fourth ventricle. Irregular borders (80%), heterogeneous enhancement (83%), and perilesional edema (76%) are the most frequent radiological findings. The histology was mainly pure anaplastic (85%), whereas papillary (7%), rhabdoid (5%), and mixed forms (3%) are very rare. The CSF spread was found in 60% of the cases. The prognosis is very dismal, with an overall median survival of 17.5 months after surgery for the anaplastic forms. Malignant IVMs at initial diagnosis (group A) show better overall survival (25 months) than those occurring from anaplastic transformation of lower grade tumors (group B) (10.1 months).

MGMT and Whole-Genome DNA Methylation Impacts on Diagnosis, Prognosis and Therapy of Glioblastoma Multiforme.

Epigenetic changes in DNA methylation contribute to the development of many diseases, including cancer. In glioblastoma multiforme, the most prevalent primary brain cancer and an incurable tumor with a median survival time of 15 months, a single epigenetic modification, the methylation of the O6-Methylguanine-DNA Methyltransferase (MGMT) gene, is a valid biomarker for predicting response to therapy with alkylating agents and also, independently, prognosis. More recently, the progress from single gene to whole-genome analysis of DNA methylation has allowed a better subclassification of glioblastomas. Here, we review the clinically relevant information that can be obtained by studying MGMT gene and whole-genome DNA methylation changes in glioblastomas, also highlighting benefits, including those of liquid biopsy, and pitfalls of the different detection methods. Finally, we discuss how changes in DNA methylation, especially in glioblastomas bearing mutations in the Isocitrate Dehydrogenase (IDH) 1 and 2 genes, can be exploited as targets for tailoring therapy.

Recurrence of spinal meningiomas: analysis of the risk factors.

Objective: Spinal meningiomas are slow-growing tumors with low recurrence rate after complete resection. The aim of this study is to investigate the risk factors correlated to the recurrence.Material and Methods: Six patients with spinal WHO grade I meningiomas which recurred after complete resection were reviewed and compared to 50 patients with no recurrence; the data were also compared with those of 50 intracranial meningiomas which recurred and 50 which did not recur after complete resection. The investigated factors included age and sex, tumor location and size, type of arachnoid interface, entity of resection (Simpson I or II), tumor consistency and vascularity, histological type, Ki-67 MIB-1, progesterone receptor (PR) and estrogen receptor (ER) expression. The data were statistically analyzed with the Kaplan-Meier method.Results: The statistical analysis showed that the presence of arachnoidal invasion (p = 0.023) and higher Ki-67 LI (p < 0.0001) were the only two significant risk factors for recurrence for both spinal and intracranial meningiomas. Large tumor size (p = 0.012), Simpson grade II resection (p = 0.03) and the absence of PR expression (p < 0.0001) were significant risk factors for recurrence of intracranial but not spinal meningiomas. Finally, age and sex, tumor location, consistency and vascularity, histological type, and ER expression were not correlated to recurrence for both localizations.Conclusions: The proliferation index Ki-67 and the arachnoid invasion are the risk factors for recurrence of spinal meningiomas, whereas tumor size, dural resection and PR expression are not significant. The small tumor size and the limited dural invasion may contribute to explain the lower recurrence rate.

Multicentric and diffuse recurrences of meningiomas.

Background: Meningiomas recur with a rate of 10-32% at 10 years. Several features influence the risk of recurrence.Objective: To define the pathological and surgical features at risk of multicentric-diffuse versus local-peripheral recurrence.Methods: Thirty-three patients operated on for intracranial meningiomas who experienced multicentric-diffuse recurrence were retrospectively analyzed. The data of these patients were compared to those of 50 patients who experienced local-peripheral recurrence. The analyzed factors included age and sex, tumor location and shape, brain-tumor interface, entity of resection, WHO grade, Ki67 MIB1, progesterone receptor (PR) expression, number of reoperations, progression of WHO grade, and outcome.Results: Meningiomas which recurred in multicentric-diffuse pattern showed at initial surgery a significantly higher rate of flat-shaped tumors (p = .0008) and of cases with Ki67 Li ≥ 4% (p = .037) than those which recurred in localized-peripheral pattern, whereas other factors did not significantly differ. Among patients with multicentric-diffuse recurrences, 25 underwent one to three reoperations; 17 among them (66%) are alive with local tumor control or slow progression 2-25 years after the initial surgery versus only 2 out of 8 who did not undergo surgery.Conclusions: Flat-shaped meningiomas and those with Ki67 Li ≥ 4% are at higher risk of multicentric-diffuse recurrence. Multiple reoperations over a period of several years may obtain rather long survivals in selected patients with prevalent intradural, not anaplastic tumors and not too extensive dural infiltration.

WHO grade, proliferation index, and progesterone receptor expression are different according to the location of meningioma.

BACKGROUND: Meningiomas may show a different WHO grade and variable biological and clinical behaviors. The aim of the present study is to assess whether WHO grade, proliferation index, progesterone receptor (PR) expression, histological subtype, neuroradiological features, and the recurrence rate differ depending on the tumor location. METHODS: Three hundred meningiomas operated on from 2006 to 2016 were reviewed. The WHO grade (2007 classification), Ki67-MIB1, progesterone receptor expression, and histological subtype were reexamined and correlated to the meningioma location, classified as medial skull base, lateral skull base, non-skull base, and spinal. RESULTS: Non-skull base and lateral skull base meningiomas showed significantly higher rates of atypical WHO II forms (34% and 25.5% respectively) than medial skull base (12.5%) and spinal ones (7%) (p = 0.0003) and also higher rates of tumors with Ki67-Li > 4% (42% and 38% vs 22% and 14%) (p = 0.0031). The rate of meningiomas with PR expression ≤ 50% was significantly lower in medial skull base (25%) than in non-skull base (48%) (p = 0.009). Meningothelial and transitional meningiomas were more frequent at the skull base (68.5% and 54.5%, respectively), the fibroblastic subtype at the non-skull base (48.5%), and the psammomatous at the spinal canal (50%) (p < 0.00001). Medial skull base and spinal meningiomas showed significantly lower size (p < 0.00001), lower rates of cases with lost arachnoid interface (p = 0.0022), and significantly lower recurrence rates (p = 0.0035) than lateral skull base and non-skull base meningiomas. CONCLUSION: Medial skull base meningiomas show lower size, lower rate of atypical forms, lower Ki67-Li values, and significantly higher PR expression than those at the lateral skull base and non-skull base. This corresponds to lesser aggressiveness and lower recurrence rates.

Anti-Apoptotic and Anti-Oxidant Proteins in Glioblastomas: Immunohistochemical Expression of Beclin and DJ-1 and Its Correlation with Prognosis.

DJ-1 deglycase is a protein with anti-oxidative and anti-apoptotic properties and its role in oncogenesis is controversial. Indeed in primary breast cancer and non-small-cell lung carcinoma, its higher expression was shown in more aggressive tumors while in other neoplasms (e.g., pancreatic adenocarcinoma), higher expression was related to better prognosis. Beclin has a relevant role in autophagy and cellular death regulation, processes that are well known to be impaired in neoplastic cells. DJ-1 shows the ability to modulate signal transduction. It can modulate autophagy through many signaling pathways, a process that can mediate either cell survival or cell death depending on the circumstances. Previously, it has been suggested that the involvement of DJ-1 in autophagy regulation may play a role in tumorigenesis. The aim of our study was to investigate the link between DJ-1 and Beclin-1 in glioblastoma through the immunohistochemical expression of such proteins and to correlate the data obtained with prognosis. Protein expression was assessed by immunohistochemistry and the immunoscores were correlated with clinicopathologic parameters. Kaplan-Meier survival curves were generated. A statistically significant association between DJ-1 score and recurrence (p = 0.0189) and between the former and Isocitrate Dehydrogenase 1 (IDH1) mutation (p = 0.0072) was observed. Kaplan-Meier survival curve analysis revealed that a higher DJ-1 score was associated with longer overall survival (p = 0.0253, ĸ2 = 5.005). Furthermore, an unexpected direct correlation (p = 0.0424, r = 0.4009) between DJ-1 and Beclin score was evident. The most significant result of the present study was the evidence of high DJ-1 expression in IDH-mutant tumors and in cases with longer overall survival. This finding could aid, together with IDH1, in the identification of glioblastomas with better prognosis.

ATM and p53 combined analysis predicts survival in glioblastoma multiforme patients: A clinicopathologic study.

Glioblastoma is one of the most malignant cancers, with a distinguishing dismal prognosis: surgery followed by chemo- and radiotherapy represents the current standard of care, and chemo- and radioresistance underlie disease recurrence and short overall survival of patients suffering from this malignancy. ATM is a kinase activated by autophosphorylation upon DNA doublestrand breaks arising from errors during replication, byproducts of metabolism, chemotherapy or ionizing radiations; TP53 is one of the most popular tumor suppressor, with a preeminent role in DNA damage response and repair. To study the effects of the immunohistochemical expression of p-ATM and p53 in glioblastoma patients, 21 cases were retrospectively examined. In normal brain tissue, p-ATM was expressed only in neurons; conversely, in tumors cells, the protein showed a variable cytoplasmic expression (score: +,++,+++), with being completely undetectable in three cases. Statistical analysis revealed that high p-ATM score (++/+++) strongly correlated to shorter survival (P = 0.022). No difference in overall survival was registered between p53 normally expressed (NE) and overexpressed (OE) glioblastoma patients (P = 0.669). Survival analysis performed on the results from combined assessment of the two proteins showed that patients with NE p53 /low pATM score had longer overall survival than the NE p53/ high pATM score counterpart. Cox-regression analysis confirmed this finding (HR = 0.025; CI 95% = 0.002-0.284; P = 0.003). Our study outlined the immunohistochemical expression of p-ATM/p53 in glioblastomas and provided data on their possible prognostic/predictive of response role. A "non-oncogene addiction" to ATM for NEp53 glioblastoma could be postulated, strengthening the rationale for development of ATM inhibiting drugs.

Role of Macrophages in Brain Tumor Growth and Progression.

The role of macrophages in the growth and the progression of tumors has been extensively studied in recent years. A large body of data demonstrates that macrophage polarization plays an essential role in the growth and progression of brain tumors, such as gliomas, meningiomas, and medulloblastomas. The brain neoplasm cells have the ability to influence the polarization state of the tumor associated macrophages. In turn, innate immunity cells have a decisive role through regulation of the acquired immune response, but also through humoral cross-talking with cancer cells in the tumor microenvironment. Neoangiogenesis, which is an essential element in glial tumor progression, is even regulated by the tumor associated macrophages, whose activity is linked to other factors, such as hypoxia. In addition, macrophages play a decisive role in establishing the entry into the bloodstream of cancer cells. As is well known, the latter phenomenon is also present in brain tumors, even if they only rarely metastasize. Looking ahead in the future, we can imagine that characterizing the relationships between tumor and tumor associated macrophage, as well as the study of circulating tumor cells, could give us useful tools in prognostic evaluation and therapy. More generally, the study of innate immunity in brain tumors can boost the development of new forms of immunotherapy.

Evaluation of matrix metalloproteinase type IV-collagenases in serum of patients with tumors of the central nervous system.

The basement membrane collagen IV-degrading matrix metalloproteinases -2 and -9 (MMPs) are most often linked to the malignant phenotype of tumor cells by playing a critical role in invasion, metastasis, angiogenesis, and vasculogenesis. We verified the activity of these two MMPs in the sera of patients affected by brain tumors (20 gliomas, 28 meningiomas and 20 metastasis) by zymography. The sera of 25 healthy volunteers with no concomitant illnesses were used for controls. Zymography showed four dominant gelatinolytic bands of 240, 130, 92 (MMP-9) and 72 (MMP-2) kDa. No statistically significant variations of MMP-2 proteolytic activity between patients and healthy individuals were observed. On the contrary, MMP-9 (both monomeric and multimeric forms) lytic activities were significantly higher in tumors specimens compared to healthy controls (p < 0.001). Moreover, MMP-9 immunohistochemistry revealed: (1) a strong reactivity in neoplastic vessels of high-grade gliomas showing an inverse correlation with serum multimeric gelatinolytic activity; (2) a cytoplasmatic reactivity in meningiomas with a significantly increase in atypical meningioma compared with low-grade ones (p = 0.036); (3) a positive correlation between MMP-9 and Ki-67 (Sperman Rho coefficient r = 0.418 and p = 0.034). Our results suggest that serum and tissue MMP-9 might provide clinicians additional objective information in intracranial neoplasms. Finally, it should be possible to use MMP-9 as a target for new forms of therapy. Nevertheless, due to the small number of patients included in the study, the conclusion may not be transferable to the general population and therefore further evaluations are needed.

Atypical pituitary adenomas: clinical characteristics and role of ki-67 and p53 in prognostic and therapeutic evaluation. A series of 50 patients.

The aim of the study was to assess incidence rate, hormonal activity, and local invasiveness and evaluate outcomes of so-diagnosed atypical pituitary adenomas that underwent endoscopic endonasal surgery at the Division of Neurosurgery of Università degli Studi di Napoli Federico II. According to the 2004 WHO classification, atypical pituitary adenomas are defined by an invasive growth, Ki-67/MIB-1 proliferative index greater than 3 %, high p53 immunoreactivity, and increased mitotic activity. A retrospective analysis of a series of 434 pituitary adenomas that underwent endoscopic endonasal surgery at our department between March 2007 and February 2013 was performed. Fifty adenomas (11.5 %) met the criteria of diagnosis of atypical lesions; 10 (21.6 %) of the 50 patients were recurrent tumors with a previous transsphenoidal surgery. Forty-one (82 %) were macroadenomas, and 21/50 (42 %) showed a clear invasion of the cavernous sinus. Histotype of atypical adenomas figured out to be nonfunctioning in 23 cases (46 %), PRL secreting in 10 cases (20 %), ACTH secreting and GH secreting each apart in 8 patients (16 %), and in a single case a GH/PRL secreting adenoma (2 %). The Ki-67 labeling index ranged from 3.5 to 22.5 % (mean 5.6 %). Tumor recurrence was observed in six cases (12 %) after a mean time of 18 months (range 9-24 months). Mean follow-up was 36.5 months (range 2-80 months). Atypical pituitary adenomas account for ca. 10 % of all pituitary adenomas; these lesions have peculiar features. It should be considered that a strong immunopositivity of p53 and higher Ki-67 LI could predict an increased risk of tumor recurrence, but more studies and larger series are expected to confirm and enlarge the diagnostic and therapeutic management process of these lesions.

Expression of p40 (∆Np63) protein in meningiomas, an unexpected finding: immunohistochemical study and evaluation of its possible prognostic role.

According to the 2007 WHO (World Health Organization) Classification, meningiomas are divided into three grades of malignancy, with different recurrence rate, based exclusively on histopathological parameters. Loss/reduction of PgR (Progesterone Receptor) expression and increased Ki67 L.I. (Labeling Index) have been proven as possible prognostic factors able to predict the relapse of the disease. However, they sometimes result unreliable, especially when discordant. p40 is the short form of the p53 homologue gene p63, also named ∆Np63, and its antibody has recently been introduced as a highly specific diagnostic marker of the squamous cell carcinoma of the lung. Nevertheless its expression has been found in many other unconventional sites (e.g. placenta, urotheluim, etc). Herein we assessed the immuno-expression of p40 protein in a series of 72 meningiomas (35 grade I and 37 grade II) and analyzed its correlation with clinicopathological parameters, overall survival and recurrence free interval. We found that a high p40 score correlated with high histological grade, presence of recurrence, increased Ki67 L.I. and loss/reduction of PgR signal. Moreover, a higher expression of p40 was shown to be a significant prognostic factor for the development of recurrences and resulted a prognostic independent variable in multivariate analysis. Overall, for the first time, we investigated the expression of p40 protein in meningiomas and explored its usefulness as prognostic marker in addition to PgR and Ki67 L.I.

Essential role of ultrastructural examination for spindle cell oncocytoma: Case report of a rare neoplasm and review of the literature.

Spindle cell oncocytoma (SCO) is an extremely rare neoplasm of the sellar region recognized as a distinct benign histopathological subtype of pituitary tumors in the 2007 World Health Organization classification of tumors of the central nervous system. The morphology of its neoplastic cells (spindle cells and granular eosinophilic cytoplasm) is common to several other lesions so that immunohistochemistry, together with ultrastructural examination, becomes essential in solving this differential diagnosis. Despite being labeled as benign, recurrence is described. Herein, we report a case of SCO in a 77-year-old man and discuss the diagnostic difficulties, ultrastructural aspects, and prognostic factors.

Time to Recurrence of Intracranial Meningiomas from a Monoinstitutional Surgical Series.

BACKGROUND: Meningiomas show variable tendency to recur. While risk factors of recurrence have been largely investigated in literature, a paucity of data is available on the time to recurrence. Our purpose was to identify main factors affecting the time to recurrence to assist preoperative treatment decision-making strategy and to define a tailored clinical and neuroradiological follow-up. METHODS: Data of 35 patients with intracranial meningioma recurrences have been retrospectively reviewed. Demographic (patient age at initial diagnosis and sex), radiologic (meningioma location, pattern of regrowth and topography of recurrences at first reoperation), pathologic (WHO grade and Ki67-MIB1 at initial surgery and at first reoperation, progesterone receptor [PR] expression), and surgical (extent of resection at initial surgery according to Simpsons grading system, number of reoperations) factors were analyzed. RESULTS: Time to recurrence ranged from 20 to 120 months. Extent of resection at initial surgery was Simpson grade I in 7 patients (20%), grade II in 10 (28.5%), grade III in 14 (40%), and grade IV in 4 (11.5%). Longer median time to recurrence was observed for skull base localization (P < 0.01), Simpson grades I and II versus grades III (P = 0.01) and IV (P = 0.02), values of Ki67-MIB1 ≤ 4% (P = 0.001), and PR > 60% (P = 0.03); conversely, sex, age, number of reoperations, unchanged/progression of Ki67, and/or World Health Organization grade between first surgery and reoperation did not correlate in statistically significant way with time to recurrence. CONCLUSIONS: The extent of resection and the Ki67-MIB1 represent the most important factors predicting shorter recurrence time of intracranial meningiomas. Patients with incomplete (Simpson grades III and IV) resection and high Ki67-MIB1 values, especially at non-skull base localization and with low PR values, require a closer short-term clinical and radiologic follow-up in the first years after surgery.

Update on the Diagnosis and Management of Meningiomas.

This series of five articles (one original article and four reviews) focuses on the most recent and interesting research studies on the biomolecular and radiological diagnosis and the surgical and medical management of meningiomas [...].

WHO grade and pathological markers of meningiomas: Clinical and prognostic role.

In recent years, WHO grading criteria have emerged as an inaccurate tool to correctly predict the risk of progression/recurrence for meningioma patients. Therefore, great efforts were made to find further prognostic factors that could predict the clinical course of meningiomas. Why morphological criteria are not able alone to correctly predict outcome in all patients? What are the biological parameters underlying a more aggressive behavior? Are there any molecular markers can be integrated in the risk assessment? Could new technologies, such as methylome profiling, contribute to provide additional tools in patients prognostic evaluation? We performed a literature review to find answers to these questions. Meningiomas have been demonstrated to be extremely heterogeneous neoplasms, also from the genetic and epigenetic standpoints. However, WHO Classification of Tumours of the central Nervous System 5th edition introduced only CDKN2A/B deletion and TERT promoter mutations as poor prognostic, grade 3 defining parameters. The different proposals of integrated grading, taking into account cytogenetic alterations and study of methylation profile, have not yet been incorporated in WHO grading criteria. Work in progress: this is the summary of current knowledge. Further studies are needed to expand the diagnostic and prognostic equipment to be integrated into clinical practice.

Intracranial Meningiomas in Patients Aged ≥80 Years: Pathological Features and Surgical Problems.

BACKGROUND: Patients aged >80 years frequently have intracranial meningiomas. In the present study, we have discussed the pathological features, comorbidities, and surgical complications for this age group from a surgical series and literature review. METHODS: In the present study, we reviewed a surgical series of 354 intracranial meningiomas and compared the oldest age group (age, ≥80 years) of 17 patients with 73 patients aged 70-79 years and 264 patients aged <70 years. From a literature review, we selected 10 studies of meningiomas in patients aged ≥80 years. The analyzed factors included sex, meningioma location, World Health Organization grade, Ki-67 MIB1, progesterone receptor expression, comorbidities, American Society of Anesthesiologists class, Karnofsky performance scale score, postoperative complications, and death. RESULTS: Patients aged ≥80 years had had higher rates of World Health Organization grade II meningioma, higher rates of Ki-67 expression of >4% and <20%, and progesterone receptor expression <15%. Of the postoperative complications, only neurological deficits and acute bronchopneumonia were significantly more frequent in patients aged ≥80 years. The incidence of intracerebral hematoma, lung embolism, acute heart ischemia, and death were not significantly different between the patients aged ≥80 years and those aged 70-79 years and <70 years. CONCLUSIONS: Patients aged ≥80 years must be considered a true elderly group with higher rates of comorbidities. The very old age is not a limitation to surgery; however, careful patient selection is necessary. In addition, for the oldest age group, the surgical decision should not be delayed because of advancing age.

Atypical Teratoid/Rhabdoid Tumor of the Nervous System in Adults: Location-Related Features and Outcome.

BACKGROUND: Atypical teratoid/rhabdoid tumor (AT/RT) of the nervous system is a rare and highly malignant neoplasm, mainly affecting children, first recognized as a pathologic entity in 1996 and added to the World Health Organization Classification of the Tumors of the Central Nervous System in 2000. AT/RT is even rarer among adults and is associated with a worse prognosis. The aim of the present study was to analyze the different tumor features according to the location in adults. METHODS: A comprehensive and detailed literature review of AT/RTs in adults was made. The demographic, management, and outcome data associated with tumor location were analyzed and compared; histopathologic and molecular features were also discussed. Furthermore, we added our personal case with brain hemispheric localization and reported a progression-free survival of 103 months after gross total resection and adjuvant radiotherapy showing a peculiar histopathologic pattern. RESULTS: Female sex is mainly affected by AT/RT on median localizations, both intracranial and spinal, and by all sellar region cases. Gross total resection is mainly achieved among lateral compared with median localizations. Combined radiotherapy and chemotherapy is the most adopted adjuvant treatment in all tumor localizations and is related to better outcome. Postoperative death is reported only among sellar region localizations, whereas brain hemispheric cases show the best overall survival. CONCLUSIONS: AT/RTs show different and peculiar features according to their location, which significantly affects the outcome; precise knowledge of them helps the neurosurgeon in planning the best strategy for treatment.

Targeted inhibition of the methyltransferase SETD8 synergizes with the Wee1 inhibitor adavosertib in restraining glioblastoma growth.

Despite intense research efforts, glioblastoma remains an incurable brain tumor with a dismal median survival time of 15 months. Thus, identifying new therapeutic targets is an urgent need. Here, we show that the lysine methyltransferase SETD8 is overexpressed in 50% of high-grade gliomas. The small molecule SETD8 inhibitor UNC0379, as well as siRNA-mediated inhibition of SETD8, blocked glioblastoma cell proliferation, by inducing DNA damage and activating cell cycle checkpoints. Specifically, in p53-proficient glioblastoma cells, SETD8 inhibition and DNA damage induced p21 accumulation and G1/S arrest whereas, in p53-deficient glioblastoma cells, DNA damage induced by SETD8 inhibition resulted in G2/M arrest mediated by Chk1 activation. Checkpoint abrogation, by the Wee1 kinase inhibitor adavosertib, induced glioblastoma cell lines and primary cells, DNA-damaged by UNC0379, to progress to mitosis where they died by mitotic catastrophe. Finally, UNC0379 and adavosertib synergized in restraining glioblastoma growth in a murine xenograft model, providing a strong rationale to further explore this novel pharmacological approach for adjuvant glioblastoma treatment.