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Background Targeted next-generation sequencing (NGS) is frequently obtained at the University of California, Los Angeles (UCLA) for clinical characterization of CNS tumors. In this study, we describe the diagnostic reliability of the Foundation Medicine (FM) targeted NGS platform and its ability to explore and identify tumor characteristics of prognostic significance in gliomas. Methods Neuro-oncology patients seen at UCLA who have received FM testing between August 2012 and March 2019 were included in this study, and all mutations from FM test reports were recorded. Initial tumor diagnoses and diagnostic markers found via standard clinical methods were obtained from pathology reports. With overall and progression-free survival data, elastic net regularized Cox regression and Cox proportional hazards models were used to determine whether any mutations of unknown significance detected by FM could predict patient outcome in glioblastoma (GBM). Results Six hundred and three samples tested by FM from 565 distinct patients were identified. Concordance of diagnostic markers was high between standard clinical testing methods and FM. Oligodendroglial markers detected via FM were highly correlated with 1p19q codeletion in IDH mutated gliomas. FM testing of multiple tumor samples from the same patient demonstrated temporal and spatial mutational heterogeneity. Mutations in BCORL1, ERBB4, and PALB2, which are mutations of unknown significance in GBM, were shown to be statistically significant in predicting patient outcome. Conclusions In our large cohort, we found that targeted NGS can both reliably and efficiently detect important diagnostic markers in CNS tumors.

2540 Background: Glioblastoma (GBM) in elderly patients differ molecularly as compared to younger patients, and may have increased angiogenic activity. Bevacizumab (BV) is an anti-angiogenic monoclonal antibody against vascular endothelial growth factor. We conducted a clinical trial to evaluate the efficacy and safety of BV and temozolomide (TMZ) for elderly patients with a new diagnosis of GBM, while deferring radiotherapy. Methods: This is a phase II, single-arm, multicenter, open label trial. Eligible patients have a tissue diagnosis of GBM with no treatment other than surgery, age ≥ 70, KPS ≥ 60, and adequate organ function. TMZ was initiated within 2 weeks of surgery and BV was initiated within 4 weeks thereafter. TMZ was administered at 150-200 mg/m2/day for 5 days every 4 weeks and BV at 10mg/kg every 2 weeks. A historical control group of 42 patients with similar criteria who received concurrent TMZ and RT followed by adjuvant TMZ, was derived for comparison from an institutional patient database. The primary endpoint is overall survival (OS) and secondary endpoints are progression-free-survival and safety. Results: 50 patients were enrolled from June 2010 to January 2016. Median age is 75 (range 70-87), and median KPS is 80 (range 60-100). 17 patients had a biopsy only, 26 patients have MGMT promoter methylation, and all patients are IDH wildtype. The study and control group are well matched in terms of age and molecular markers, however, the study patients had worse initial KPS and higher baseline tumor volume. At time of analysis, all but 2 patients were deceased. The median OS was 12.6 months for study patients (95% CI, 10.9-15.9 months) and 16.3 months for control patients (95% CI, 12.9-22.4 months). In a multivariate Cox analysis, baseline tumor volume (HR = 2.6, p = 0.0001) and MGMT promoter methylation (HR = 0.49, p = 0.004) were significant prognostic markers. Treatment type did not have a significant impact on OS (HR = 1.5, p = 0.14). Treatment-related serious adverse events included: pulmonary embolism (5), cerebral hemorrhage (3), pneumonia (1), intestinal perforation (1), deep venous thrombosis (6), hypertension (2), atrial fibrillation (1), congestive heart failure (1), cardio-respiratory arrest (1), lymphopenia (2), thrombocytopenia (8), and neutropenia (5). Conclusions: The results of this study suggest for patients with newly diagnosed GBM age ≥70 and KPS ≥60, treatment with BV and TMZ is equivalent to standard chemoradiotherapy, and has tolerable side effects. Complete endpoint analysis will be presented with the poster. Clinical trial information: NCT01149850 .

BACKGROUND: Primary CNS Lymphoma (PCNSL) is an aggressive form of diffuse large B-cell lymphoma (DLBCL). Lenalidomide is an immunomodulatory agent which has shown activity in relapsed or refractory CNS and non-CNS DLBCL. The ideal dosing, timing as consolidation therapy, and role in maintenance therapy remain unclear. METHODS: We describe 3 elderly patients with R/R PCNSL who were treated with lenalidomide. All patients had a pathological diagnosis of PCNSL, immunocompetent status, failed at least 2 previous therapies including methotrexate and rituximab. One patient had also failed autologous stem cell transplant. Lenalidomide was administered orally, 25mg/day on days 1–21 of a 28-day cycle. RESULTS: Median age was 68 (range 65–71). Median KPS was 70 (range 60–70). Patient 1 achieved complete response (CR) after cycle 4, 2 additional maintenance cycles (20mg; reduced for Grade 3–4 Thrombocytopenia), and is in remission after 11 months. Patient 2 achieved partial response (PR) after cycle 1, CR after cycle 8, and 2 additional maintenance cycles; dose reduced at cycle 6 (20mg) for Grade 3–4 Neutropenia, and is in remission after 14 months. Patient 3 achieved PR after cycle 1, mixed response after cycle 2, and died 15 weeks after start of treatment; of note, patient was also on rituximab. Molecular and immunologic correlates are pending and will be presented with the abstract. CONCLUSIONS: This case series shows lenalidomide has single agent activity in heavily pre-treated R/R PCNSL. All the patients had clinical and radiographic response to treatment. Hematologic toxicities occurred at higher dose, however even at reduced dose, lenalidomide was effective in maintaining remission. In elderly patients, using lenalidomide at relapse and deferring neurotoxic treatment options may have a role in preserving good performance status. Further prospective studies are warranted to determine the efficacy and optimal dose of lenalidomide in patients with newly diagnosed and R/R PCNSL.

Aim: Long-term survivors (LTS)after glioma recurrence while on bevacizumab (Bev)therapy are rarely reported in the current literature. The purpose of this case series is to confirm the existence of and describe a large cohort of recurrent glioma LTS treated with Bev (Bev-LTS). Patients & methods: We identified Bev-LTS as patients with post-Bev initiation survival times of ≥3 years among 1397 Bev treated recurrent glioma patients. Results: Among 962 grade-IV,221 grade III, and214 grade II Bev-treated glioma patients, we identified 28 (2.9%),14 (6.3%) and8(3.7%)Bev-LTS patients, respectively. 45Bev-LTS patients recurred on Bev, with 36 of those patients continuing therapy.Conclusion: Our study shows that a small portion of grade-IV, -III,and -II glioma patients can have long-term survival on Bev therapy even after Bev recurrence.

Introduction. Mild hypotension is a well-recognized complication of intravenous pentobarbital; however fulminant cardiopulmonary failure has not been previously reported.Case Report. A 28-year-old woman developed pentobarbital-induced cardiopulmonary failure that was successfully treated with maximal medical management including arteriovenous extracorporeal membrane oxygenation. She made an excellent cardiopulmonary and neurological recovery.Discussion and Conclusion. Pentobarbital is underrecognized as a potential cause of myocardial stunning. The mechanism involves direct myocardial depression and inhibition of autonomic neuroanatomical structures including the medulla and hypothalamus. Early recognition and implementation of aggressive cardiopulmonary support are essential to optimize the likelihood of a favorable outcome.

Sex differences in the structure and organization of the corpus callosum (CC) can be attributed to genetic, hormonal or environmental effects, or a combination of these factors. To address the role of gonadal hormones on axon myelination, functional axon conduction and immunohistochemistry analysis of the CC in intact, gonadectomized and hormone-replaced gonadectomized animals were used. These groups were subjected to cuprizone diet-induced demyelination followed by remyelination. The myelinated component of callosal compound action potential was significantly decreased in ovariectomized and castrated animals under normal myelinating condition. Compared to gonadally intact cohorts, both gonadectomized groups displayed more severe demyelination and inhibited remyelination. Castration in males was more deleterious than ovariectomy in females. Callosal conduction in estradiol-supplemented ovariectomized females was significantly increased during normal myelination, less attenuated during demyelination, and increased beyond placebo-treated ovariectomized or intact female levels during remyelination. In castrated males, the non-aromatizing steroid dihydrotestosterone was less efficient than testosterone and estradiol in restoring normal myelination/axon conduction and remyelination to levels of intact males. Furthermore, in both sexes, estradiol supplementation in gonadectomized groups increased the number of oligodendrocytes. These studies suggest an essential role of estradiol to promote efficient CC myelination and axon conduction in both sexes.