First application of GammaTile cesium-131 brachytherapy with maximal safe resection of a glioma in a patient with limited scleroderma.

The purpose of this report is to present the first documented application of GammaTile to an intra-cranial tumor of a patient with a symptomatic radiosensitive connective tissue disorder, a case where there were significant concerns with standard oncologic strategies. We hypothesized that GammaTile® (GT Medical Technologies, Tempe, Arizona, USA) would also be advantageous in the application of intra-cranial tumors in patients with conditions of increased radiosensitivity. We generated a standard external beam radiation therapy (EBRT) plan consisting of an overall 1.5 cm expansion to 59.4 Gy in 1.8 Gy fractions. Also, we developed a CyberKnife (Accuray, Sunnyvale, CA, USA) plan with a 5 mm expansion on the surgical cavity prescribed to 60 Gy in 30 fractions, to make an EBRT comparison using the same prescription volume as GammaTile. We report the first published application of GammaTile® brachytherapy to an intra-cranial malignancy in a patient with limited scleroderma. The dose delivered by GammaTile was compared to the dose that would be delivered with both typical volumes and small volumes of EBRT. The maximum dose delivered to the scar and scalp by GammaTile was reduced to half of that from other external beam techniques (~25 Gy vs. ~55 Gy). MRI imaging at 6 months and 12 months post-resection demonstrated no evidence of disease recurrence nor radiation necrosis. At the 12-month follow-up visit, the surgical scar was well-healed with no skin changes to the surrounding scalp. Dosimetrically and clinically, this report highlights the successful application of GammaTile to an intra-cranial tumor bed in a patient with scleroderma.

Epidemiology, biology, and management of venous thromboembolism in gliomas: An interdisciplinary review.

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.

Current Considerations in the Treatment of Grade 3 Gliomas.

OPINION STATEMENT: 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 Thrombotic Events and Anticoagulation in Brain Tumor Patients.

PURPOSE OF REVIEW: Brain tumor patients have a 20-30% risk of venous thromboembolism (VTE), with management complicated by risk of intracranial hemorrhage (ICH). Here we review the epidemiology, pathogenesis, and recommended management of VTE in brain tumors. RECENT FINDINGS: New risk factors and molecular mechanisms of VTE in brain tumor patients have emerged, including the protective effect of IDH mutation in gliomas and the potential role of podoplanin-mediated platelet aggregation in thrombogenesis in these tumors. Recent studies show that the risk of ICH is not significantly higher in brain tumor patients receiving anticoagulation. Based on systemic cancer trials, direct oral anticoagulants (DOACs) may be a suitable alternative to traditional heparin treatment, but the applicability of these findings to brain tumors is unclear. Anticoagulation is indicated in the treatment of VTE for brain tumor patients, and appears to be reasonably safe; based on retrospective evidence, DOACs may be a reasonable agent.

Surveillance imaging frequency in adult patients with lower-grade (WHO Grade 2 and 3) gliomas.

With improved outcome following aggressive treatment in patients with grade 2 and 3 IDH-mutant (IDHmt), 1p/19q codeleted oligodendroglioma and IDHmt, non-codeleted astrocytoma, prolonged surveillance is desirable for early detection of tumor growth and malignant transformation. Current National Comprehensive Cancer Network (NCCN) guidelines provide imaging follow-up recommendations based on molecular classification of lower-grade gliomas, although individualized imaging guidelines based on treatments received and after tumor recurrence are not clearly specified. Other available guidelines have yet to incorporate the molecular biomarkers that inform the WHO classification of gliomas, and in some cases do not adequately consider current knowledge on IDHmt glioma growth rate and recurrence patterns. Moreover, these guidelines also do not provide specific recommendations for concerning clinical symptoms or radiographic findings warranting imaging studies out of prespecified intervals. Focusing on molecularly defined grade 2 and 3 IDHmt astrocytomas and oligodendrogliomas, we review current knowledge of tumor growth rates and time to tumor progression for each tumor type and propose a range of recommended MRI surveillance intervals for both the newly diagnosed and recurrent tumor setting. Additionally, we summarize situations in which imaging is advisable outside of these intervals.

Central Nervous System Complications Among Oncology Patients.

Cancer treatment related injury to the central nervous system (CNS) is well-recognized in the setting of brain-directed radiation therapies and conventional and novel systemic anticancer therapies. Late-delayed treatment-induced CNS complications frequently result in permanent neurologic disability. Therapeutic options are supportive with limited clinical benefit, whereby alteration or discontinuation of the overall antineoplastic treatment plan is frequently necessary to prevent further neurologic injury. Better identification of patients at high risk for developing late CNS toxicities, neuroprotective strategies with modification of existing antineoplastic treatment regimens, and research efforts directed at earlier recognition and improved treatment of central neurologic complications are paramount.

Management of venous thromboembolism in high-grade glioma: Does low molecular weight heparin increase intracranial bleeding risk?

BACKGROUND: Venous thromboembolism (VTE) occurs in up to 30% of patients with high-grade glioma (HGG). Concern for increased risk of intracranial hemorrhage (ICH) with therapeutic anticoagulation (AC) complicates VTE treatment. Some retrospective studies have reported an increased risk of ICH associated with therapeutic AC; however, effective alternatives to AC are lacking. The aim of our study is to assess the risk of ICH in HGG patients with VTE on low molecular weight heparin (LMWH). METHODS: We performed a retrospective matched cohort study of HGG patients from January 2005 to August 2016. Blinded review of neuroimaging for ICH was performed. For analysis of the primary endpoint, estimates of cumulative incidence (CI) of ICH were calculated using competing risk analysis with death as competing risk; significance testing was performed using the Gray's test. Median survival was estimated using the Kaplan-Meier method. RESULTS: Two hundred twenty patients were included, 88 (40%) with VTE treated with LMWH, 22 (10%) with VTE, not on AC, and 110 (50%) without VTE. A total of 43 measurable ICH was recorded: 19 (26%) in LMWH, 3 (14%) in VTE not on AC, and 21 (19%) in non-VTE cohort. No significant difference was observed in the 1-year CI of ICH in the LMWH cohort and non-AC with VTE group (17% vs 9%; Gray's test, P = .36). Among patients without VTE, the 1-year CI of ICH was 13%. Median survival was similar among all 3 cohorts. CONCLUSIONS: Our data suggest that therapeutic LMWH is not associated with substantially increased risk of ICH in HGG patients.

Proliferating CD8+ T Cell Infiltrates Are Associated with Improved Survival in Glioblastoma.

BACKGROUND: tumor-infiltrating lymphocytes are prognostic in many human cancers. However, the prognostic value of lymphocytes infiltrating glioblastoma (GBM), and roles in tumor control or progression are unclear. We hypothesized that B and T cell density, and markers of their activity, proliferation, differentiation, or function, would have favorable prognostic significance for patients with GBM. METHODS: initial resection specimens from 77 patients with IDH1/2 wild type GBM who received standard-of-care treatment were evaluated with multiplex immunofluorescence histology (mIFH), for the distribution, density, differentiation, and proliferation of T cells and B cells, as well as for the presence of tertiary lymphoid structures (TLS), and IFNγ expression. Immune infiltrates were evaluated for associations with overall survival (OS) by univariate and multivariate Cox proportional hazards modeling. RESULTS: in univariate analyses, improved OS was associated with high densities of proliferating (Ki67+) CD8+ cells (HR 0.36, p = 0.001) and CD20+ cells (HR 0.51, p = 0.008), as well as CD8+Tbet+ cells (HR 0.46, p = 0.004), and RORγt+ cells (HR 0.56, p = 0.04). Conversely, IFNγ intensity was associated with diminished OS (HR 0.59, p = 0.036). In multivariable analyses, adjusting for clinical variables, including age, resection extent, Karnofsky Performance Status (KPS), and MGMT methylation status, improved OS was associated with high densities of proliferating (Ki67+) CD8+ cells (HR 0.15, p < 0.001), and higher ratios of CD8+ cells to CD4+ cells (HR 0.31, p = 0.005). Diminished OS was associated with increases in patient age (HR 1.21, p = 0.005) and higher mean intensities of IFNγ (HR 2.13, p = 0.027). CONCLUSIONS: intratumoral densities of proliferating CD8 T cells and higher CD8/CD4 ratios are independent predictors of OS in patients with GBM. Paradoxically, higher mean intensities of IFNγ in the tumors were associated with shorter OS. These findings suggest that survival may be enhanced by increasing proliferation of tumor-reactive CD8+ T cells and that approaches may be needed to promote CD8+ T cell dominance in GBM, and to interfere with the immunoregulatory effects of IFNγ in the tumor microenvironment.

Predictors of early, recurrent, and intractable seizures in low-grade glioma.

BACKGROUND: Seizures are common among patients with low-grade glioma (LGG) and can significantly affect morbidity. We sought to determine the association between the clinical and molecular factors with seizure incidence and refractoriness in LGG patients. METHODS: We conducted a retrospective review at the University of Virginia in patients with LGG (World Health Organization, WHO Grade II) evaluated between 2002 and 2015. Descriptive statistics were calculated for variables of interest, and the Kaplan-Meier method was used to estimate survival curves, which were compared with the log-rank test. RESULTS: A total of 291 patients were included; 254 had molecular testing performed for presence of an isocitrate dehydrogenase (IDH) mutation and/or 1p/19q codeletion. Sixty-eight percent of patients developed seizures prior to LGG diagnosis; 41% of all patients had intractable seizures. Using WHO 2016 integrated classification, there was no significant difference in seizure frequency during preoperative and postoperative periods or in developing intractable seizures, though a trend toward increased preoperative seizure incidence among patients with the IDH mutation was identified (P = .09). Male sex was significantly associated with higher seizure incidence during preoperative (P < .001) and postoperative periods (P < .001); men were also more likely to develop intractable seizures (P = .01). CONCLUSIONS: Seizures are common among patients with LGG. Differences in preoperative or postoperative and intractable seizure rates by WHO 2016 classification were not detected. Our data showed a trend toward higher seizure incidence preoperatively in patients with IDH-mutant LGG. We describe a unique association between male sex and seizure incidence and intractability that warrants further study.

Risk of Venous Thromboembolism in Grade II-IV Gliomas as a Function of Molecular Subtype.

OBJECTIVE: To determine the incidence of venous thromboembolism (VTE) in lower-grade gliomas (LGGs, WHO grades II-III) and to stratify the risk of VTE by molecular subtype in gliomas grade II-IV, we performed a retrospective review of a large cohort of patients with glioma. METHODS: We performed a retrospective analysis of a cohort of 635 adult patients with glioma with molecular testing seen at the University of Virginia with a diagnosis of diffuse glioma established from January 2005 to August 2017. Estimates of cumulative incidence of VTE were calculated with death as competing risk; significance was determined using the Fine and Gray model. RESULTS: Of 256 patients with LGG, 81 were isocitrate dehydrogenase (IDH) wild-type; 113 IDH mutant, 1p/19q codeleted; and 62 IDH mutant, 1p/19q intact. With a median follow-up of 17.9 months, the overall cumulative incidence of VTE was 8.2% for grade II (147 patients), 9.2% for grade III (109 patients), and 30.5% for grade IV (334 patients). In grade II-IV patients, absence of an IDH mutation was associated with a threefold increase in VTE risk when compared to IDH-mutant patients (hazard ratio 3.06, 95% confidence interval 2.03-4.64). In patients with glioblastoma, there was no difference in VTE incidence according to O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. CONCLUSION: Patients with LGG have a higher VTE risk compared to the general population, which is decreased, but not eliminated, in the presence of an IDH mutation. MGMT promoter methylation in glioblastoma does not affect the incidence of VTE.

Antiangiogenic Therapy of High-Grade Gliomas.

Angiogenesis plays a critical pathologic role in malignant gliomas. In the past few years, numerous studies using bevacizumab (BEV), a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), have been conducted in patients with brain tumors. Current evidence suggests that such treatment produces favorable results in patients with recurrent glioblastoma multiforme (GBM), but is not associated with any benefits in newly diagnosed GBM and recurrent WHO grade III gliomas. Initial experience using BEV for management of central nervous system radiation necrosis demonstrated radiographic improvement in the majority of cases, but optimal dose and treatment duration in such cases still remain in question. The results of clinical trials on other antiangiogenic agents in patients with malignant gliomas were generally disappointing. Future therapeutic approaches should include strategies that targets different angiogenic pathways, block tumor invasiveness, and inhibit GBM stem cells. Evaluation of validated biomarkers and novel imaging parameters may eventually allow better selection of patients who will likely benefit from treatment with VEGF inhibitors.

Effect of neoadjuvant temozolomide upon volume reduction and resection of diffuse low-grade glioma.

Maximal safe resection is associated with prolonged survival in patients with low-grade glioma (LGG). It has been suggested that neoadjuvant temozolomide may provide sufficient tumor shrinkage to facilitate aggressive surgical debulking. We examined the impact of temozolomide upon volume reduction and resectability of LGG. We retrospectively identified 20 adult patients with biopsy-proven, deemed not totally resectable LGGs, treated initially with temozolomide. Volumetric 3D (calculated from serial FLAIR images) and 2D tumor measurements were obtained prior to treatment and at 3 months post-treatment. The anticipated extent of resection (EOR) at the 2 time points was measured based on anatomical limitations, calculated as: [(total tumor volume - unresectable tumor volume)/total tumor volume] ×100. Eloquent cortex, deep structures and corpus callosum were considered unresectable. Mean tumor volume was 68.4 cm(3) pre-treatment and 49.5 cm(3) at 3 months post-treatment. The mean change from baseline to 3 months after treatment was -32.5 % (p < 0.001). Mean 2D pre-treatment area was 28.6 and 23.3 cm(2) at 3 months post-treatment. The 2D change was also significant, with mean change of -17% (p < 0.001). 5% had partial response; 40% minor response; 45% stable disease; and 10% progressive disease by RANO criteria. Mean pre-treatment anticipated EOR was 67.2 and 71.5% at 3 months post-treatment. The mean change from baseline was 4.3% (p = 0.10). Our findings demonstrate significant volumetric and 2D reduction of LGG with temozolomide. Although this tumor shrinkage might facilitate radical surgical resection in some cases, our data failed to show statistically significant improvement in anticipated EOR.

Thrombosis in brain tumors.

Venous thromboembolism (VTE) is common in patients with brain tumors, occurring in up to 30% of patients with high-grade glioma and up to 20% of those with brain metastasis and primary central nervous system (CNS) lymphoma. The risk is correlated with higher grade malignancies and is directly associated with the production of the potent procoagulant, tissue factor (TF). Upregulation of TF influences both the coagulation pathway and oncogenic signaling mechanisms important for cancer progression. The risk of intracranial hemorrhage with the use of anticoagulants complicates the management of VTE in patients with brain tumor. We discuss the recommended anticoagulants used for initial and long-term treatment of established VTE, including unfractionated heparin, low-molecular-weight heparin (LMWH), and warfarin. Therapeutic anticoagulation, particularly LMWH followed by secondary prophylaxis, is generally safe and effective in the treatment of VTE, including patients on antiangiogenic agents. Anticoagulation also reduces the risk of VTE during the perioperative period. However, despite the high risk of VTE throughout the course of disease, present data do not support routine thromboprophylaxis in brain tumor patients. Further investigation regarding the mechanisms underlying the hypercoagulable state of patients with brain tumors and the potential role of the factors and products of thrombogenesis as biomarkers for risk stratification will be useful in identification and management of patients at risk of developing VTE. Novel oral anticoagulants that directly inhibit thrombin such as dabigatran or factor Xa, including rivaroxaban and apixaban have several potential advantages; however, due to limited data in the cancer population, the use of these newer oral anticoagulants is not currently recommended for patients with malignancy and VTE. Recent studies have explored the role of anticoagulants as anticancer agents, which may contribute to cancer treatment in the future.

Angiogenic inhibition in high-grade gliomas: past, present and future.

High-grade gliomas, especially glioblastoma (GBM), are among the most aggressive and vascularized tumors. Angiogenesis plays a significant role in tumor growth and survival, and thus offers a target for anticancer treatment. Bevacizumab, a humanized monoclonal antibody against VEGF, was approved by the US FDA as a single agent for the treatment of recurrent glioblastoma. Significant radiographic response and progression-free survival were seen with bevacizumab treatment. However, benefits to overall survival remain undetermined. Other antiangiogenic strategies targeting VEGF, VEGF receptor (VEGFR) and other angiogenic factors have also been examined. Tumor progression after antiangiogenic treatment is inevitable, and effective salvage therapy is yet to be identified. Mechanisms of resistance to antiangiogenic therapy include activation of alternative proangiogenic pathways and increased tumor invasion. Strategies targeting these escape mechanisms are currently being investigated. The use of antiangiogenic drugs is generally well tolerated, although rare and potentially life-threatening adverse effects have been identified. With the striking antipermeability effect of anti-VEGF inhibitors, assessment of true tumor response has become a challenge. The Response Assessment in Neuro-Oncology Working Group has developed new criteria for clinical trials in patients with high-grade glioma. Identification of neuroimaging advances and biologic markers will greatly enhance treatment strategies for these patients.