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Background High-dose methotrexate (HDMTX) is a mainstay of primary central nervous system lymphoma (PCNSL) treatment. Transient hepatotoxicity from HDMTX has been characterized in pediatric patients but not in adults. We sought to characterize hepatotoxicity in adult PCNSL patients undergoing HDMTX treatment. Methods Retrospective study of 65 PCNSL patients treated at the University of Virginia from 02/01/2002 to 04/01/2020 was performed. Hepatotoxicity was defined using National Cancer Institute Common Toxicity Criteria (CTC) for adverse events, fifth version. High-grade hepatotoxicity was defined as a bilirubin or aminotransferase CTC grade of 3 or 4. Relationships between clinical factors and hepatotoxicity were assessed with logistic regression. Results Most patients (90.8%) had a rise of at least one aminotransferase CTC grade during HDMTX treatment. 46.2% had high-grade hepatotoxicity based on aminotransferase CTC grade. No patients developed high-grade bilirubin CTC grades during chemotherapy. Liver enzyme test values decreased to low CTC grade or normal in 93.8% of patients after the conclusion of HDMTX treatment without treatment regimen changes. Prior ALT elevation (P = .0120) was a statistically significant predictor of high-grade hepatotoxicity during treatment. Prior history of hypertension was associated with increased risk of toxic serum methotrexate levels during any cycle (P = .0036). Conclusions Hepatotoxicity develops in the majority of HDMTX-treated PCNSL patients. Transaminase values decreased to low or normal CTC grades in almost all patients after treatment, without modification of MTX dosage. Prior ALT elevation may predict patients’ increased hepatotoxicity risk, and hypertension history may be a risk factor for delayed MTX excretion.

PURPOSE Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically driven phase II study in recurrent or progressive grade 1-3 meningiomas. PATIENTS AND METHODS Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy. RESULTS Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events. CONCLUSION GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2-mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.

In the United States, diagnosis of grade 3 or 4 glioma qualifies patients for Social Security disability benefits. Low-grade gliomas (LGGs) can be similarly debilitating, with at least 31% of patients presenting with cognitive deficits and 80% with tumor-related epilepsy. A diagnosis of LGG does not in and of itself qualify patients for disability benefits; the burden of proof is substantially higher. We outline the American healthcare system process of medical documentation to support disability benefits, Social Security Disability Insurance (SSDI) and Supplemental Security Income (SSI). We provide a template to assist providers in facilitating the application process for patients with LGG. The provider’s role is not to simply “declare” a patient disabled, but to provide comprehensive documentation regarding diagnosis, treatment, disease status, symptoms, and functional status in the medical record. As cognitive symptoms and seizures are 2 key sources of disability in LGG patients, selective referrals to neuropsychology and epileptology may improve patient care and bolster documentation of the patient’s symptoms in these domains. Likewise, connecting patients with social workers and disability claims representatives can assist them in navigating the complicated application process. We provide an extensive review for patient eligibility in the United States to receive disability. We map a comprehensive care process that may have relevance to multiple regions outside the United States. Providers are better able to help their patients navigate the disability application process when they understand how to address physical and cognitive changes for thorough care of their patient.

Treatment recommendations for grade 3 gliomas are guided by their histopathologic and molecular phenotype. In the 2021 WHO classification, these tumors are categorized into two types, grade 3 IDH mutant (IDHmt), 1p/19q codeleted oligodendroglioma and IDH mutant astrocytoma. Treatment consists of maximal safe surgery, followed by radiation therapy (RT) and alkylating agent-based chemotherapy. Based on the updated CATNON result, RT followed by temozolomide improves outcome in patients with non-codeleted grade 3 IDHmt astrocytoma. In patients with IDHmt, codeleted oligodendroglioma, the addition of procarbazine, CCNU, and vincristine regimen is the recommended treatment, based on large randomized controlled trials. These current treatments prolong the overall survival to up to 10 years in patients with grade 3 IDHmt astrocytoma and 14 years in grade 3 IDHmt codeleted oligodendroglioma. Treatment options at recurrence include re-resection, re-irradiation, and other cytotoxic chemotherapy; however, these are of limited benefit. Novel agents targeting IDH mutation and its metabolic effects are currently under investigation to improve the outcome of these patients.

Venous thromboembolism (VTE) and other vascular events are common in patients with brain tumors, but their optimal management is not firmly established, in large part due to the competing risk of intracranial hemorrhage (ICH) in this population.There is conflicting evidence on whether therapeutic anticoagulation increases the risk of ICH in patients with brain tumors, with several metanalysis and retrospective cohort studies showing an increased risk and others showing no differences. Current guidelines recommend anticoagulating brain tumors patients with VTE with either low-molecular weight heparin (LMWH) or direct oral anticoagulants (DOACs), and several retrospective studies have shown the risk of ICH with DOACs is similar or smaller than with LMWH.An increased risk of VTE exists in a variety of brain tumor types. Most patients with brain tumors and VTE should receive therapeutic anticoagulation, and recent retrospective evidence supports the use of both LMWH and DOACs as effective and relatively safe in this setting. Patients with brain tumors are also at increased risk of other vascular tumor- or treatment-related complications whose optimal management is unclear.

Patients with diffuse glioma are at high risk of developing venous thromboembolism (VTE) over the course of the disease, with up to 30% incidence in patients with glioblastoma (GBM) and a lower but nonnegligible risk in lower-grade gliomas. Recent and ongoing efforts to identify clinical and laboratory biomarkers of patients at increased risk offer promise, but to date, there is no proven role for prophylaxis outside of the perioperative period. Emerging data suggest a higher risk of VTE in patients with isocitrate dehydrogenase (IDH) wild-type glioma and the potential mechanistic role of IDH mutation in the suppression of production of the procoagulants tissue factor and podoplanin. According to published guidelines, therapeutic anticoagulation with low molecular weight heparin (LMWH) or alternatively, direct oral anticoagulants (DOACs) in patients without increased risk of gastrointestinal or genitourinary bleeding is recommended for VTE treatment. Due to the elevated risk of intracranial hemorrhage (ICH) in GBM, anticoagulation treatment remains challenging and at times fraught. There are conflicting data on the risk of ICH with LMWH in patients with glioma; small retrospective studies suggest DOACs may convey lower ICH risk than LMWH. Investigational anticoagulants that prevent thrombosis without impairing hemostasis, such as factor XI inhibitors, may carry a better therapeutic index and are expected to enter clinical trials for cancer-associated thrombosis.

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We previously showed the involvement of the tyrosine kinase receptor c-Met in medulloblastoma malignancy. The nonreceptor tyrosine kinases focal adhesion kinase (FAK) and Pyk2 are key players in the progression of different cancers. However, their role in medulloblastoma malignancy is not well understood. In this study, using a protein array approach, we found that c-Met induces FAK and Pyk2 phosphorylation in medulloblastoma cells. We therefore studied the interactions between c-Met and FAK/Pyk2 and their implications for medulloblastoma therapy. We found that c-Met activates FAK and Pyk2 in several medulloblastoma cell lines. We also found that FAK and Pyk2 mediate the malignant effects of c-Met on medulloblastoma cell proliferation, migration, and invasion. On the basis of these findings, we hypothesized that combined c-Met and FAK inhibitions would have additive effects on the inhibition of medulloblastoma malignancy. To test this hypothesis, we assessed the effects on medulloblastoma malignancy parameters of single or combined treatments of medulloblastoma cells with c-Met and FAK small-molecule kinase inhibitors. We found a significant increase in the inhibitory effect of both inhibitors on medulloblastoma cell migration and cell invasion as compared with single inhibitions (P < 0.05). In addition, oral gavage treatment with c-Met inhibitor of mice bearing medulloblastoma xenografts significantly reduced in vivo tumor growth. Therefore, combining c-Met inhibitors with FAK inhibitors constitutes a new potential strategy for medulloblastoma therapy. Altogether, our study describes a role for FAK and Pyk2 in medulloblastoma malignancy, uncovers new interactions between c-Met and FAK/Pyk2, and proposes for the first time combining anti-c-Met and anti-FAK inhibitors as a new strategy for medulloblastoma therapy. Mol Cancer Ther; 11(2); 288–97. ©2011 AACR.

Supplementary Figure S3. Maximum change from baseline in the sum of target lesions and treatment duration ("other tumor types", intrahepatic cholangiocarcinoma, glioblastoma).

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