Explore the vast range of titles available.

Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor predisposition syndrome that affects children and adults. Individuals with NF1 are at high risk for central nervous system neoplasms including gliomas. The purpose of this review is to discuss the spectrum of intracranial gliomas arising in individuals with NF1 with a focus on recent preclinical and clinical data. In this review, possible mechanisms of gliomagenesis are discussed, including the contribution of different signaling pathways and tumor microenvironment. Furthermore, we discuss the recent notable advances in the developing therapeutic landscape for NF1-associated gliomas including clinical trials and collaborative efforts.

Background High-dose methotrexate (HD-MTX) has broad use in the treatment of central nervous system (CNS) malignancies but confers significant toxicity without inpatient hydration and monitoring. Glucarpidase is a bacterial recombinant enzyme dosed at 50 units (u)/kg, resulting in rapid systemic MTX clearance. The aim of this study was to demonstrate feasibility of low-dose glucarpidase to facilitate MTX clearance in patients with CNS lymphoma (CNSL). Methods Eight CNSL patients received HD-MTX 3 or 6 g/m 2 and glucarpidase 2000 or 1000u 24 h later. Treatments repeated every 2 weeks up to 8 cycles. Results Fifty-five treatments were administered. Glucarpidase 2000u yielded > 95% reduction in plasma MTX within 15 min following 33/34 doses (97.1%) and glucarpidase 1000u yielded > 95% reduction following 15/20 doses (75%). Anti-glucarpidase antibodies developed in 4 patients and were associated with MTX rebound. In CSF, glucarpidase was not detected and MTX levels remained cytotoxic after 1 (3299.5 nmol/L, n  = 8) and 6 h (1254.7 nmol/L, n  = 7). Treatment was safe and well-tolerated. Radiographic responses in 6 of 8 patients (75%) were as expected following MTX-based therapy. Conclusions This study demonstrates feasibility of planned-use low-dose glucarpidase for MTX clearance and supports the hypothesis that glucarpidase does not impact MTX efficacy in the CNS. Clinical trial registration NCT03684980 (Registration date 26/09/2018).

BackgroundDrug Resistant Immunotherapy (DRI) combines an alkylating chemotherapy such as temozolomide (TMZ) to force the upregulation of tumor stress-associated NKG2D ligands while simultaneously treating with gamma-delta (γδ) T cells that are genetically engineered to express O-6-methylguanine-DNA methyltransferase (MGMT) to convey TMZ resistance. We present biologic correlative findings for our ongoing study NCT04165941, a Phase 1 trial assessing the safety of autologous DRI.MethodsAdult newly diagnosed GBM patients undergo resection, apheresis, chemoradiotherapy, and up to six cycles of maintenance-phase TMZ. Cohorts (C) 1, 2 and 3 each receive 1, 3 or 6 intracavitary doses of 1 x 107 DRI γδ T cells concomitantly with 150 mg/m2 of TMZ intravenously on day (D) 1 of each 28-day maintenance cycle. Peripheral blood is obtained for immunophenotyping and cytokine analysis at apheresis and at 30, 60, 90, 180, and 365 days following the first infusion. Peripheral blood RCL is assessed at 30, 90, 180 and 365 days following first infusion.ResultsResected primary tumors showed scarce immune cell infiltration with occasional perivascular cuffing. A small resected recurrent tumor from a C1 patient 148D following DRI γδ T cell treatment revealed widespread infiltration of immune cells, including γδ T cells and 60% necrosis. Infused cellular products contained >70–95% γδ T cells. TMZ-based lymphodepletion is evidenced throughout maintenance phase as peripheral T, B, and NK lymphocyte subsets remained near or below published normal ranges for as long as 365 days. CD8+ T cells predominately expressed a naïve (CD45RA+CD27+) phenotype at the beginning of each cycle. IFN-γ was initially upregulated to initiation of maintenance phase and through Day +365 consistent with lymphodepleting chemotherapy, . IL-17A and TNF-a also decrease while other cytokines remain at normal serum concentrations throughout treatment. Evaluable C1 patients surpassed expected median PFS at 8.3, 11.9, 7.4 months and OS of 15.6, 17.7 and 9.6 months respectively. Two C2 patients remain alive and progression free at 24.8 and 20.7 months. Two additional C2 patients died of unrelated cardiovascular events at 5.1 and 8.7 months respectively without progression. One C3 patient has completed 5/6 doses without DLT. Cytokine release syndrome (CRS), or neurotoxicity (ICANS) were not observed.ConclusionsData demonstrates that single and repeat doses of DRI γδ T cells manufactured and transduced in this protocol show manageable toxicity with continued encouraging trend in PFS. Immunophenotyping and Th1/Th2/Th17 cytokine analysis show maintenance of peripheral lymphodepletion throughout the treatment phase.Trial RegistrationClinical Trials Registration number NCT04165941 at www.clinicaltrials.comEthics ApprovalThe trial has been approved by the WCG study #1265787, IRB Tracking Number 20192345. Sponsor is the University of Alabama at Birmingham Neuro-Oncology Program, Sponsor Study Number UAB 1773, Principal Investigator Louis B. Nabors, MD.

Intraventricular melanoma is a very rare and highly malignant disease. Safe resection is the mainstay of treatment, but no standard guidelines exist for adjuvant therapy. Early histologic and molecular diagnosis is key for improved survival. Intraventricular melanoma is a very rare and highly malignant disease. Safe resection is the mainstay of treatment, but no standard guidelines exist for adjuvant therapy. Early histologic and molecular diagnosis is key for improved survival.

Leptomeningeal metastasis is extremely rare in patients with ovarian cancer, but should be considered in patients presenting with neurologic deficits such as cauda equine syndrome. Given its poor prognosis and lack of data currently on management, additional studies are needed to optimize treatment regimens and improve outcomes. Leptomeningeal metastasis is extremely rare in patients with ovarian cancer, but should be considered in patients presenting with neurologic deficits such as cauda equine syndrome. Given its poor prognosis and lack of data currently on management, additional studies are needed to optimize treatment regimens and improve outcomes.

PurposeSeizures are a common clinical occurrence in high-grade glioma (HGG). While many studies have explored seizure incidence and prevalence in HGG, limited studies have examined the prognostic effect of seizures occurring in the post-diagnosis setting. This study aims to assess the impact of seizure presentation on HGG survival outcomes.MethodsSingle-center retrospective review identified 950 patients with histologically-confirmed high-grade glioma. Seizure presentation was determined by clinical history and classified as early onset (occurring within 30 days of HGG presentation) or late onset (first seizure occurring after beginning HGG treatment). The primary outcome, hazard ratios for overall survival and progression-free survival, was assessed with multivariable Cox proportional-hazards models. IDH1 mutation status (assessed through immunohistochemistry) was only consistently available beginning in 2015; subgroup analyses were performed in the subset of patients with known IDH1 status.ResultsEpileptic activity before (HR = 0.81, 95% CI = 0.68–0.96, P = 0.017) or after (HR = 0.74, 95% CI = 0.60–0.91, P = 0.005) HGG diagnosis associated with improved overall survival. Additionally, late seizure onset significantly associated with lower odds of achieving partial (OR = 0.25, 95% CI = 0.12–0.53, P = < 0.001) or complete (OR = 0.30, 95% CI = 0.18–0.50, P < 0.001) seizure control than patients with early seizure onset.ConclusionsClinical seizures both at the time of diagnosis and later during the HGG treatment course are associated with improved overall survival. This association potentially persists for both IDH1-wildtype and IDH1-mutant patients, but further study is required.

Purpose: Gliomas are the most common primary brain tumor in adults in the US with an annual age-adjusted incidence rate of 4.67 to 5.73 per 100,000 persons. Exposure to ionizing radiation is the only established risk factor for non-hereditary glioma risk. There are several sources of carcinogenic contaminants in northeast Alabama and western Georgia with the Coosa River serving as the region’s primary water source. In this study, we aimed to examine the incidence rate of glioma in northeast Alabama compared to the rest of the state as well as the association of possible environmental exposure on disease risk and outcomes.Methods: This is a retrospective cohort study that included adult patients (≥20 years at diagnosis) from Alabama with a histopathological diagnosis of glioma, who presented to our institution between January 2015 and December 2019. We calculated the annual age-adjusted incidence rate (AAA-IR) among residents in counties intersected by the Coosa River in northeast Alabama (exposed group) and compared to the AAA-IR in the rest of the state (non-exposed group). The electronic medical records of the participants were reviewed for patient demographics, socioeconomic status, tumor characteristics, and vital status. The overall survival was assessed using both univariable and multivariable analyses.Results: A total of 660 patients were included in this study (528 non-exposed, and 132 exposed). The AAA-IR of glioma in Alabama was 3.2 per 100,000 persons. The AAA-IR of glioma in the exposed group was 4.76 per 100,000 persons vs 3.14 per 100,000 persons in the non-exposed group with a 50 % higher incidence rate of glioma in the exposed group (RR = 1.50; 95% CI, 1.22-1.89). There was no statistically significant difference between the two groups with respect to tumor characteristics or overall survival.Conclusions: Our findings indicate a significantly higher incidence of glioma in northeast Alabama compared to the rest of the state, which could be associated with environmental exposure. Future geospatial and prospective studies are needed to identify possible environmental risk factors in northeast Alabama and examine temporal sequence and also explore glioma incidence in other areas exposed to the same environmental pollutant(s) if a causal relationship is confirmed.

[...]glioblastoma tumors often display intrinsic resistance to chemotherapy and radiation therapy, necessitating the identification of alternative treatment strategies to overcome resistance mechanisms. Jennifer Yu, MD, is leading a study with in-depth intraoperative recording of tumor electrical activity. [...]the study aims to determine the impact of high electrical activity and pattern of activity on tumor invasion, and mechanistic basis of its regulation and functional consequences. Furthermore, this trial design allows for the rapid evaluation of novel therapeutic agents or drug combinations, facilitating the identification of promising candidates for further clinical development.

Purpose The impact of pain on functional status and mental health among older adults with cancer is a relevant, yet understudied. We sought to identify the prevalence of pain at diagnosis in older adults with gastrointestinal (GI) malignancies and evaluate the association of pain with functional status limitations, cognition, and mental health. Methods This prospective cross-sectional study included older adults (age ≥ 60) with GI cancers enrolled in the CARE Registry. Pain measured in numeric rating scale from 0 to 10. We utilized the literature based cutoff for moderate-severe as ≥ 4. Logistic regression used to assess differences in functional status, falls, cognitive complaints, and depression/anxiety associated with moderate/severe pain, adjusted for sex, race, education, ethnicity, marital status, cancer type/stage, and treatment phase. Results Our cohort included 714 older adults with an average mean age of 70 years and 59% male. Common diagnoses included colorectal (27.9%) and pancreatic (18%). A total of 43.3% reported moderate/severe pain. After multivariate adjusting for covariates, participants with self-reported moderate/severe pain were more likely to report limitations in instrumental activities of daily living (adjusted odds ratio [ aOR ] 4.3 95% confidence interval [ CI ] 3.1–6.1, p  < .001), limitation in activities of daily living ( aOR 3.2 95% CI 2.0–5.1, p  < .001), cognitive complaints ( aOR 2.9 95% CI 1.4–6.0, p  < .004), anxiety ( aOR 2.2 95% CI 1.4–3.4, p  < 0.01), and depression ( aOR 3.7 95% CI 2.2–6.5, p  < .001). Conclusions Pain is common among older adults with GI cancers and is associated with functional status limitations, cognitive complaints, and depression/anxiety. Strategies to reduce pain and minimize its potential impact on function and mental health warrant future research.

Purpose Primary Central Nervous System Lymphoma (PCNSL) is an aggressive tumor that is confined to the CNS. Although the provision of high-dose methotrexate (HD-MTX) has remarkably improved outcomes in PCNSL patients, the optimal treatment regimens and standard MTX dose for induction therapy have been largely controversial. Herein, we sought to explore the impact of adjuvant rituximab and different dosages of induction HD-MTX on survival outcomes of immunocompetent patients with PCNSL. Methods In this study, we examined patients with PCNSL treated at a single NCI-designated comprehensive cancer center to evaluate their survival outcomes. We conducted a retrospective analysis of 51 immunocompetent patients with PCNSL who received their induction chemotherapy at the University of Alabama at Birmingham (UAB) between 2001 and 2019. Only adult patients with a confirmed diagnosis of PCNSL who had either HD-MTX alone or in combination with rituximab were included. Patients’ demographics, clinical characteristics, and survival data were collected and analyzed. Results There is no significant difference in survival among patients who received MTX alone versus MTX plus rituximab (HR = 0.996 (95% CI: 0.398–2.493), p  = 0.994). Lower doses of MTX were associated with worse survival outcomes (HR = 0.680 (95% CI: 0.530–0.872), p  = 0.002); however, this difference in survival was not significant when adjusted to age (HR = 0.797 (95% CI: 0.584–1.088), p  = 0.153). Conclusion Our experience challenges the role of rituximab in PCNSL during induction therapy. Our study also highlights the shorter survival in elderly patients with PCNSL which can be related, to some extent, to the relatively lower doses of HD-MTX. There is an unmet need to establish a consensus on the most effective upfront regimen in PCNSL through prospective studies.