Decoding the puzzle: A multidisciplinary systematic review of adult brainstem glioma.

Adult brainstem gliomas (BSGs) are a group of rare central nervous system tumors with varying prognoses and controversial standard treatment strategies. To provide an overview of current trends, a systematic review using the PRISMA guidelines, Class of evidence (CE) and strength of recommendation (SR), was conducted. The review identified 27 studies. Surgery was found to have a positive impact on survival, particularly for focal lesions with CE II SR C. Stereotactic image-guided biopsy was recommended when resective surgery was not feasible with CE II and SR B. The role of systemic treatments remains unclear. Eight studies provided molecular biology data. This review gathers crucial literature on diagnosis and management of adult BSGs. It provides evidence-based guidance with updated recommendations for diagnosing and treating, taking into account recent molecular and genetic advancements. The importance of brain biopsy is emphasized to optimize treatment using emerging genetic-molecular findings and explore potential targeted therapies.

Present and Future of Immunotherapy in Patients With Glioblastoma: Limitations and Opportunities.

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor. Standard therapies, including surgical resection, chemoradiation, and tumor treating fields, have not resulted in major improvements in the survival outcomes of patients with GBM. The lack of effective strategies has led to an increasing interest in immunotherapic approaches, considering the success in other solid tumors. However, GBM is a highly immunosuppressive tumor, as documented by the presence of several mechanisms of immune escape, which may represent a reason why immunotherapy clinical trials failed in this kind of tumor. In this review, we examine the current landscape of immunotherapy strategies in GBM, focusing on the challenge of immunoresistance and potential mechanisms to overcome it. We discussed completed and ongoing clinical trials involving immune checkpoint inhibitors, oncolytic viruses, vaccines, and CAR T-cell therapies, to provide insights into the efficacy and outcomes of different immunotherapeutic interventions. We also explore the impact of radiotherapy on the immune system within the GBM microenvironment highlighting the complex interactions between radiation treatment and the immune response.

Spinal ependymoma in adults: from molecular advances to new treatment perspectives.

Ependymomas are rare glial tumors with clinical and biological heterogeneity, categorized into supratentorial ependymoma, posterior fossa ependymoma, and spinal cord ependymoma, according to anatomical localization. Spinal ependymoma comprises four different types: spinal ependymoma, spinal ependymoma MYCN-amplified, myxopapillary ependymoma, and subependymoma. The clinical onset largely depends on the spinal location of the tumor. Both non-specific and specific sensory and/or motor symptoms can be present. Owing to diverse features and the low incidence of spinal ependymomas, most of the current clinical management is derived from small retrospective studies, particularly in adults. Treatment involves primarily surgical resection, aiming at maximal safe resection. The use of radiotherapy remains controversial and the optimal dose has not been established; it is usually considered after subtotal resection for WHO grade 2 ependymoma and for WHO grade 3 ependymoma regardless of the extent of resection. There are limited systemic treatments available, with limited durable results and modest improvement in progression-free survival. Thus, chemotherapy is usually reserved for recurrent cases where resection and/or radiation is not feasible. Recently, a combination of temozolomide and lapatinib has shown modest results with a median progression-free survival (PFS) of 7.8 months in recurrent spinal ependymomas. Other studies have explored the use of temozolomide, platinum compounds, etoposide, and bevacizumab, but standard treatment options have not yet been defined. New treatment options with targeted treatments and immunotherapy are being investigated. Neurological and supportive care are crucial, even in the early stages. Post-surgical rehabilitation can improve the consequences of surgery and maintain a good quality of life, especially in young patients with long life expectancy. Here, we focus on the diagnosis and treatment recommendations for adults with spinal ependymoma, and discuss recent molecular advances and new treatment perspectives.

Actionable molecular alterations in newly diagnosed and recurrent IDH1/2 wild-type glioblastoma patients and therapeutic implications: a large mono-institutional experience using extensive next-generation sequencing analysis.

BACKGROUND: Next-generation sequencing (NGS) panels enable the identification of alterations in cancer-related genes. This may guide a molecularly targeted strategy for the treatment of glioblastoma (GBM). MATERIAL AND METHODS: We retrospectively analysed data obtained using FoundationOne®CDx in a large cohort of IDH1/2 wild-type GBM. We aimed to 1) identify potentially actionable molecular alterations at diagnosis and/or recurrence based on ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) defined categories of targetability, 2) understand the clinical implications of NGS in terms of access to and activity of targeted therapies. RESULTS: In 442 samples, an NGS profile was available in 98.2%. The median time from diagnosis to NGS profiling was 7.4 months (interquartile range (IQR): 3.4-13.2). Although about half of the patients had at least one actionable molecular alteration, only 3.4% of them were classified as ESCAT IB-IC and 6.7% as ESCAT IIB. Only 36 patients (10.5%) received personalised treatment in clinical trials or as off-label/compassionate use from second-line (median line 3). Most patients did not receive targeted therapy due to clinical deterioration/death (49.6%). Patients treated with dabrafenib/trametinib (9 patients) had the highest disease control rate of 77% and an objective response rate of 22%, with a median progression-free survival (PFS) of 5.2 months. No complete/partial responses were seen with the other regimens. 4/9 (44.4%) patients on anti-BRAF/anti-MEK, 2/4 patients (50%) on erdafitinib and 1/1 patient on capmatinib had a PFS ratio > 1.3. One recurrent GBM patient with ROS1-GOCP fusion maintained a complete response for 11.3 months on entrectinib. CONCLUSIONS: Our study demonstrated the feasibility of NGS in GBM samples. As the number of clinically relevant targets was limited and only a small group of GBM patients were treated with targeted therapy, NGS testing should be performed in the context of clinical trials. Our results support the activity of anti-BRAF/anti-MEK, while for the other agents prospective study results are needed to draw solid conclusions.

Association between thyroid function and regorafenib efficacy in patients with relapsed wild-type IDH glioblastoma: a large multicenter study.

PURPOSE: Regorafenib demonstrated encouraging results in recurrent glioblastoma patients. Some studies showed that changes in circulating thyroid hormones (fT3, fT4, fT3/fT4 ratio) can be considered as prognostic factors in patients with various types of tumors. We designed this study to investigate the relationship between baseline thyroid variables and outcome in IDH-wild type GBM patients who were treated with regorafenib. METHODS: This multicenter retrospective study included recurrent IDH-wild-type glioblastoma patients treated with regorafenib. Only patients with baseline thyroid function values (TSH, fT3, fT4, fT3/fT4 ratio) available were evaluated. RANO criteria were used to analyze neuroradiological response. Survival curves were estimated using the Kaplan-Meier method. The relationships between baseline thyroid variables (TSH, fT3, fT4, fT3/fT4) and survival (PFS, OS) were investigated with Cox regression models. RESULTS: From November 2015 to April 2022, 134 recurrent IDH-wildtype GBM patients were treated with regorafenib and 128 of these had information on baseline thyroid function value. Median follow-up was 8 months (IQR 4.7-14.0). Objective Response Rate was 9% and Disease Control Rate was 40.9%. Median PFS was 2.7 months (95%CI 2.2-3.6) and median OS was 10.0 months (95%CI 7.0-13.0). Lower baseline TSH value in the blood was correlated with a higher rate of disease progression to regorafenib (p = 0.04). Multivariable analyses suggested a non-linear relationship between PFS (p = 0.01) and OS (p = 0.03) with baseline fT3/fT4 ratio. CONCLUSION: In recurrent wild-type IDH glioblastoma patients, baseline fT3/fT4 ratio showed a non-linear relationship with survival, with different impacts across the spectrum of fT3/fT4 ratio. Moreover, baseline TSH may be a predictor of regorafenib activity.

The role of radiation therapy and systemic treatments in meningioma: The present and the future.

Meningiomas are the most prevalent tumors of the central nervous system. Their standard treatment is surgery, which can be curative. Adjuvant radiotherapy treatment is reserved for newly diagnosed cases of grade II and grade III meningiomas in cases of recurrent disease or when surgery is not radical or feasible. However, around 20% of these patients cannot undergo further surgical and/or radiotherapy treatment. Systemic oncological therapy can find its place in this setting. Several tyrosine kinase inhibitors have been tested (gefitinib, erlotinib, sunitinib) with unsatisfactory or negative results. Bevacizumab has shown encouraging results in these settings of patients. Immunotherapy with immune checkpoint inhibitors has reported interesting results with modest objective response rates. Several ongoing studies are assessing different target therapies and multimodal therapies; the results are to be disclosed. Not only a better understanding of the molecular characteristics in meningiomas has allowed the gathering of more information regarding pathogenesis and prognosis, but in addition, the availability of new target therapy, immunotherapy, and biological drugs has widened the scope of potentially effective treatments in this patient population. The aim of this review was to explore the radiotherapy and systemic treatments of meningioma with an analysis of ongoing trials and future therapeutic perspectives.

Knowing when to discontinue Temozolomide therapy in responding aggressive pituitary tumors and carcinomas: a systematic review and Padua (Italy) case series.

INTRODUCTION: Pituitary adenomas can show a tendency to grow, despite multimodal treatment. Temozolomide (TMZ) has been used in the last 15 years in patients with aggressive pituitary tumors. TMZ requires a careful balance of different expertise, especially for selection criteria. AREAS COVERED: We conducted: (1) a systematic review of the published literature from 2006 to 2022, collecting only cases with a complete description of patient follow-up after TMZ discontinuation; (2) a description of all patients with aggressive pituitary adenoma or carcinoma treated in Padua (Italy). EXPERT OPINION: There is considerable heterogeneity in the literature: TMZ cycles duration ranged from 3 to 47 months; the follow-up time after TMZ discontinuation ranged from 4 to 91 months (mean 24 months, median 18 months), at least a stable disease has been reported in 75% of patients after a mean 13 months (range 3-47 months, median 10 months). The Padua (Italy) cohort reflects the literature. Future directions to explore are to understand the pathophysiological mechanism of TMZ resistance escape, to develop predicting factors to TMZ treatment (especially through the delineation of the underlying transformation processes), and to further expand the therapeutic applications of TMZ (as neoadjuvant, combined with radiotherapy).

Impressive response to dabrafenib and trametinib plus silybin in a heavily pretreated IDH wild-type glioblastoma patient with BRAFV600E -mutant and SOX2 amplification.

Isocitrate dehydrogenase wild-type glioblastoma is the most frequent primary brain tumor in adult patients and its prognosis is still dismal with a median survival of about 1 year. BRAF V600E mutation, an important target for personalized therapy, has been identified in about 3% of these patients, but few data are available from prospective studies on the role of anti-BRAF drugs in adult glioblastoma patients. Moreover, SOX2 gene amplification and overexpression can represent an important mechanism of resistance to BRAF inhibitors by STAT3 gene activation. We present the case of a heavily pretreated 42-year-old man with BRAF V600E mutant and SOX2 amplification glioblastoma having a radiologic and metabolic [analyzed by a brain 18F-fluoro-ethyl-tyrosine([18F]FET) PET/MRI] complete response to the combination therapy with dabrafenib plus trametinib and silybin, a potent STAT3 inhibitor. The patient is currently undergoing treatment after a total of 24 months of continuation therapy with a good safety profile. In conclusion, we showed a promising activity of the personalized treatment of BRAF and MEK inhibitors in patient with BRAF V600E mutant glioblastoma; silybin can play an important role in decreasing drug resistance during BRAF inhibitor therapy, especially in patients with SOX2 amplification.

Efficacy and safety of chlorpromazine as an adjuvant therapy for glioblastoma in patients with unmethylated MGMT gene promoter: RACTAC, a phase II multicenter trial.

Introduction: Drug repurposing is a promising strategy to develop new treatments for glioblastoma. In this phase II clinical trial, we evaluated the addition of chlorpromazine to temozolomide in the adjuvant phase of the standard first-line therapeutic protocol in patients with unmethylated MGMT gene promoter. Methods: This was a multicenter phase II single-arm clinical trial. The experimental procedure involved the combination of CPZ with standard treatment with TMZ in the adjuvant phase of the Stupp protocol in newly-diagnosed GBM patients carrying an unmethylated MGMT gene promoter. Progression-free survival was the primary endpoint. Secondary endpoints were overall survival and toxicity. Results: Forty-one patients were evaluated. Twenty patients (48.7%) completed 6 cycles of treatment with TMZ+CPZ. At 6 months, 27 patients (65.8%) were without progression, achieving the primary endpoint. Median PFS was 8.0 months (95% CI: 7.0-9.0). Median OS was 15.0 months (95% CI: 13.1-16.9). Adverse events led to reduction or interruption of CPZ dosage in 4 patients (9.7%). Discussion: The addition of CPZ to standard TMZ in the first-line treatment of GBM patients with unmethylated MGMT gene promoter was safe and led to a longer PFS than expected in this population of patients. These findings provide proof-of-concept for the potential of adding CPZ to standard TMZ treatment in GBM patients with unmethylated MGMT gene promoter. Clinical trial registration: https://clinicaltrials.gov/study/NCT04224441, identifier NCT04224441.

Diagnosis and Treatment of Pineal Region Tumors in Adults: A EURACAN Overview.

Pineal region tumors are rare intracranial tumors, accounting for less than 1% of all adult intracranial tumor lesions. These lesions represent a histologically heterogeneous group of tumors. Among these tumors, pineal parenchymal tumors and germ cell tumors (GCT) represent the most frequent types of lesions. According to the new WHO 2021 classification, pineal parenchymal tumors include five distinct histotypes: pineocytoma (PC), pineal parenchymal tumors of intermediate differentiation (PPTID), papillary tumor of the pineal region (PTPR), pinealoblastoma (PB), and desmoplastic myxoid tumor of the pineal region, SMARCB1-mutant; GCTs include germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, mixed GCTs. Neuroradiological assessment has a pivotal role in the diagnostic work-up, surgical planning, and follow-up of patients with pineal masses. Surgery can represent the mainstay of treatment, ranging from biopsy to gross total resection, yet pineal region tumors associated with obstructive hydrocephalus may be surgically managed via ventricular internal shunt or endoscopic third ventriculostomy. Radiotherapy remains an essential component of the multidisciplinary treatment approach for most pineal region tumors; however, treatment volumes depend on the histological subtypes, grading, extent of disease, and the combination with chemotherapy. For localized germinoma, the current standard of care is chemotherapy followed by reduced-dose whole ventricular irradiation plus a boost to the primary tumor. For pinealoblastoma patients, postoperative radiation has been associated with higher overall survival. For the other pineal tumors, the role of radiotherapy remains poorly studied and it is usually reserved for aggressive (grade 3) or recurrent tumors. The use of systemic treatments mainly depends on histology and prognostic factors such as residual disease and metastases. For pinealoblastoma patients, chemotherapy protocols are based on various alkylating or platinum-based agents, vincristine, etoposide, cyclophosphamide and are used in association with radiotherapy. About GCTs, their chemosensitivity is well known and is based on cisplatin or carboplatin and may include etoposide, cyclophosphamide, or ifosfamide prior to irradiation. Similar regimens containing platinum derivatives are also used for non-germinomatous GCTs with very encouraging results. However, due to a greater understanding of the biology of the disease's various molecular subtypes, new agents based on targeted therapy are expected in the future. On behalf of the EURACAN domain 10 group, we reviewed the most important and recent developments in histopathological characteristics, neuro-radiological assessments, and treatments for pineal region tumors.

Newly Diagnosed Multifocal GBM: A Monocentric Experience and Literature Review.

Glioblastomas with multiple foci at presentation (mGBMs) account for 2-35% of all GBMs. mGBMs have limited existing data and no standardized treatment. This study aims to determine their incidence, demographic and clinical features, outcome, and prognostic factors in terms of overall survival. We performed a monocentric retrospective study, reviewing patients treated at the Istituto Oncologico Veneto. Inclusion criteria were: new diagnosis of GBM and presence of multiple lesions on pre-treatment MRI. ECOG PS was used to evaluate clinical condition, RANO criteria for radiological assessment, and CTCAE v5.0 for treatment-related adverse events. The incidence of newly diagnosed mGBM was 7.2% and the study population consisted of 98 patients. Median age was 63 years, M:F ratio of 1.8:1, and a surgical approach was undertaken in 73 patients (mostly partial resection). MGMT was methylated in 47.5%, and 82 patients received active oncological treatment (65.9% radiotherapy plus temozolomide (RT + TMZ)). The disease control rate with RT + TMZ was 63%. Median OS of the entire study population was 10.2 months (95% CI 6.6-13.8), and median PFS was 4.2 months (95% CI 3.2-5.2). The ECOG PS, the extent of resection, and the RT + TMZ were significant prognostic factors in the univariate analysis for OS, but only the RT + TMZ was a significant independent OS predictor in the multivariate analysis (HR = 3.1, 95% IC 1.3-7.7, p = 0.014). The incidence of mGBM is not rare. RT + TMZ is confirmed to be an independent prognostic factor for survival and a safe and effective treatment. When feasible, RT + TMZ should be considered as a possible first-line treatment. The role of the extent of resection is still unclear.

An Overview of Intracranial Ependymomas in Adults.

Ependymomas are rare primary central nervous system tumors. They can form anywhere along the neuraxis, but in adults, these tumors predominantly occur in the spine and less frequently intracranially. Ependymal tumors represent a heterogenous group of gliomas, and the WHO 2016 classification is based essentially on a grading system, with ependymomas classified as grade I, II (classic), or III (anaplastic). In adults, surgery is the primary initial treatment, while radiotherapy is employed as an adjuvant treatment in some cases of grade II and in all cases of anaplastic ependymoma; chemotherapy is reserved for recurrent cases. In recent years, important and interesting advances in the molecular characterization of ependymomas have been made, allowing for the identification of nine molecular subgroups of ependymal tumors and moving toward subgroup-specific patients with improved risk stratification for treatment-decisions and future prospective trials. New targeted agents or immunotherapies for ependymoma patients are being explored for recurrent disease. This review summarizes recent molecular advances in the diagnosis and treatment of intracranial ependymomas including surgery, radiation therapy and systemic therapies.

Regorafenib in Recurrent Glioblastoma Patients: A Large and Monocentric Real-Life Study.

Despite multimodal treatment with surgery and radiochemotherapy, the prognosis of glioblastoma remains poor, and practically all glioblastomas relapse. To date, no standard treatment exists for recurrent glioblastoma patients and traditional therapies have showed limited efficacy. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor showing encouraging benefits in recurrent GBM patients enrolled in the REGOMA trial. We performed a large study to investigate clinical outcomes and the safety of regorafenib in a real-life population of recurrent glioblastoma patients. Patients receiving regorafenib outside clinical trials at the Veneto Institute of Oncology were retrospectively reviewed. The major inclusion criteria were: histologically confirmed diagnosis of glioblastoma, prior first line therapy according to "Stupp protocol", Eastern Cooperative Oncology Group (ECOG) performance status score ≤1. According to the original schedule, patients received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle. The primary endpoints of the study were overall survival and safety. A total of 54 consecutive patients were enrolled. The median age was 56, MGMT methylated status was found in 28 out of 53 available patients (52.8%), IDH mutation in 5 (9.3%) and 22 patients were receiving steroids at baseline. The median overall survival was 10.2 months (95% CI, 6.4-13.9), the OS-12 was 43%. Age, MGMT methylation status and steroid use at baseline were not statistically significant on a multivariate analysis for OS. Patients reporting a disease control as best response to regorafenib demonstrated a significant longer survival (24.8 months vs. 6.2 months for patients with progressive disease, p = 0.0001). Grade 3 drug-related adverse events occurred in 10 patients (18%); 1 patient (2%) reported a grade 4 adverse event (rash maculo-papular). No death was considered to be drug-related. This study reported the first large "real-life" experience of regorafenib in recurrent glioblastoma. Overall, our results are close to the ones reported in the previous phase 2 study, despite the fact that we had a longer survival. We showed the encouraging activity and tolerability of this treatment in recurrent glioblastoma patients when used as a second-line treatment.

Depatuxizumab Mafodotin (Depatux-M) Plus Temozolomide in Recurrent Glioblastoma Patients: Real-World Experience from a Multicenter Study of Italian Association of Neuro-Oncology (AINO).

BACKGROUND: Depatuxizumab Mafodotin (Depatux-M; ABT-414) is an antibody-drug conjugate consisting of a specific antibody against activated EGFR and a cytotoxic agent with antimicrotubule activity. The INTELLANCE 2/EORTC 1410 phase 2 trial produced interesting results for the combination regimen of Depatux-M and temozolomide in EGFR-amplified glioblastoma patients at first recurrence. For the first time worldwide, our work investigated the clinical outcome and safety of this combination in a real-life population. MATERIALS AND METHODS: Patients were enrolled from seven AINO (Italian Association of Neuro-Oncology) Institutions. The major inclusion criteria were: histologically confirmed diagnosis of glioblastoma, EGFR-amplified, one or more prior systemic therapies and ECOG PS ≤ 2. According to the original schedule, patients received Depatux-M 1.25 mg/kg every 2 weeks combined with temozolomide. The primary endpoints of the study were overall survival and safety. RESULTS: A total of 36 patients were enrolled. The median age was 57 years, ECOG PS was 0-1 in 28 patients (88%), MGMT methylated status was found in 22 (64%), 15 patients (42%) received the combined treatment as second-line therapy. The median OS was 8.04 months (95% CI, 5.3-10.7), the 12 month-OS was 37%. On univariate and multivariate analyses, the MGMT methylation status was the only factor resulting significantly associated with survival. Grade 3 ocular toxicity occurred in 11% of patients; no grade 4 ocular toxicity was reported. No death was considered to be drug-related. CONCLUSIONS: The study reported the first "real world" experience of Depatux-M plus temozolomide in recurrent glioblastoma patients. Encouraging clinical benefits were demonstrated, even though most patients were treated beyond second-line therapy. Overall, the results are close to those reported in the previous phase 2 trial. Toxicity was moderate and manageable.

Recurrent Glioblastoma: From Molecular Landscape to New Treatment Perspectives.

Glioblastoma is the most frequent and aggressive form among malignant central nervous system primary tumors in adults. Standard treatment for newly diagnosed glioblastoma consists in maximal safe resection, if feasible, followed by radiochemotherapy and adjuvant chemotherapy with temozolomide; despite this multimodal treatment, virtually all glioblastomas relapse. Once tumors progress after first-line therapy, treatment options are limited and management of recurrent glioblastoma remains challenging. Loco-regional therapy with re-surgery or re-irradiation may be evaluated in selected cases, while traditional systemic therapy with nitrosoureas and temozolomide rechallenge showed limited efficacy. In recent years, new clinical trials using, for example, regorafenib or a combination of tyrosine kinase inhibitors and immunotherapy were performed with promising results. In particular, molecular targeted therapy could show efficacy in selected patients with specific gene mutations. Nonetheless, some molecular characteristics and genetic alterations could change during tumor progression, thus affecting the efficacy of precision medicine. We therefore reviewed the molecular and genomic landscape of recurrent glioblastoma, the strategy for clinical management and the major phase I-III clinical trials analyzing recent drugs and combination regimens in these patients.

Clinical Management of Diffuse Low-Grade Gliomas.

Diffuse low-grade gliomas (LGG) represent a heterogeneous group of primary brain tumors arising from supporting glial cells and usually affecting young adults. Advances in the knowledge of molecular profile of these tumors, including mutations in the isocitrate dehydrogenase genes, or 1p/19q codeletion, and in neuroradiological techniques have contributed to the diagnosis, prognostic stratification, and follow-up of these tumors. Optimal post-operative management of LGG is still controversial, though radiation therapy and chemotherapy remain the optimal treatments after surgical resection in selected patients. In this review, we report the most important and recent research on clinical and molecular features, new neuroradiological techniques, the different therapeutic modalities, and new opportunities for personalized targeted therapy and supportive care.