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Genetic alterations help predict the clinical behavior of diffuse gliomas, but some variability remains uncorrelated. Here, we demonstrate that haploinsufficient deletions of chromatin-bound tumor suppressor NFKB inhibitor alpha (NFKBIA) display distinct patterns of occurrence in relation to other genetic markers and are disproportionately present at recurrence. NFKBIA haploinsufficiency is associated with unfavorable patient outcomes, independent of genetic and clinicopathologic predictors. NFKBIA deletions reshape the DNA and histone methylome antipodal to the IDH mutation and induce a transcriptome landscape partly reminiscent of H3K27M mutant pediatric gliomas. In IDH mutant gliomas, NFKBIA deletions are common in tumors with a clinical course similar to that of IDH wild-type tumors. An externally validated nomogram model for estimating individual patient survival in IDH mutant gliomas confirms that NFKBIA deletions predict comparatively brief survival. Thus, NFKBIA haploinsufficiency aligns with distinct epigenome changes, portends a poor prognosis, and should be incorporated into models predicting the disease fate of diffuse gliomas.

BackgroundWe sought to determine the maximum tolerated dose (MTD) of 5-fraction stereotactic radiosurgery (SRS) with 5-mm margins delivered with concurrent temozolomide in newly diagnosed glioblastoma (GBM).MethodsWe enrolled adult patients with newly diagnosed glioblastoma to 5 days of SRS in a 3 + 3 design on 4 escalating dose levels: 25, 30, 35, and 40 Gy. Dose limiting toxicity (DLT) was defined as Common Terminology Criteria for Adverse Events grades 3-5 acute or late CNS toxicity, including adverse radiation effect (ARE), the imaging correlate of radiation necrosis.ResultsFrom 2010 to 2015, thirty patients were enrolled. The median age was 66 years (range, 51-86 y). The median target volume was 60 cm3 (range, 14.7-137.3 cm3). DLT occurred in 2 patients: one for posttreatment cerebral edema and progressive disease at 3 weeks (grade 4, dose 40 Gy); another patient died 1.5 weeks following SRS from postoperative complications (grade 5, dose 40 Gy). Late grades 1-2 ARE occurred in 8 patients at a median of 7.6 months (range 3.2-12.6 mo). No grades 3-5 ARE occurred. With a median follow-up of 13.8 months (range 1.7-64.4 mo), the median survival times were: progression-free survival, 8.2 months (95% CI: 4.6-10.5); overall survival, 14.8 months (95% CI: 10.9-19.9); O6-methylguanine-DNA methyltransferase hypermethylated, 19.9 months (95% CI: 10.5-33.5) versus 11.3 months (95% CI: 8.9-17.6) for no/unknown hypermethylation (P = 0.03), and 27.2 months (95% CI: 11.2-48.3) if late ARE occurred versus 11.7 months (95% CI: 8.9-17.6) for no ARE (P = 0.08).ConclusionsThe per-protocol MTD of 5-fraction SRS with 5-mm margins with concurrent temozolomide was 40 Gy in 5 fractions. ARE was limited to grades 1-2 and did not statistically impact survival.

An estimated 20% of all patients with cancer will develop brain metastases, with the majority of brain metastases occurring in those with lung, breast and colorectal cancers, melanoma or renal cell carcinoma. Brain metastases are thought to occur via seeding of circulating tumour cells into the brain microvasculature; within this unique microenvironment, tumour growth is promoted and the penetration of systemic medical therapies is limited. Development of brain metastases remains a substantial contributor to overall cancer mortality in patients with advanced-stage cancer because prognosis remains poor despite multimodal treatments and advances in systemic therapies, which include a combination of surgery, radiotherapy, chemotherapy, immunotherapy and targeted therapies. Thus, interest abounds in understanding the mechanisms that drive brain metastases so that they can be targeted with preventive therapeutic strategies and in understanding the molecular characteristics of brain metastases relative to the primary tumour so that they can inform targeted therapy selection. Increased molecular understanding of the disease will also drive continued development of novel immunotherapies and targeted therapies that have higher bioavailability beyond the blood-tumour barrier and drive advances in radiotherapies and minimally invasive surgical techniques. As these discoveries and innovations move from the realm of basic science to preclinical and clinical applications, future outcomes for patients with brain metastases are almost certain to improve.

IntroductionMaximizing extent of surgical resection with the least morbidity remains critical for survival in glioblastoma patients, and we hypothesize that it can be improved by enhancements in intraoperative tumor detection. In a clinical study, we determined if therapeutic antibodies could be repurposed for intraoperative imaging during resection.MethodsFluorescently labeled cetuximab-IRDye800 was systemically administered to three patients 2 days prior to surgery. Near-infrared fluorescence imaging of tumor and histologically negative peri-tumoral tissue was performed intraoperatively and ex vivo. Fluorescence was measured as mean fluorescence intensity (MFI), and tumor-to-background ratios (TBRs) were calculated by comparing MFIs of tumor and histologically uninvolved tissue.ResultsThe mean TBR was significantly higher in tumor tissue of contrast-enhancing (CE) tumors on preoperative imaging (4.0 ± 0.5) compared to non-CE tumors (1.2 ± 0.3; p = 0.02). The TBR was higher at a 100 mg dose than at 50 mg (4.3 vs. 3.6). The smallest detectable tumor volume in a closed-field setting was 70 mg with 50 mg of dye and 10 mg with 100 mg. On sections of paraffin embedded tissues, fluorescence positively correlated with histological evidence of tumor. Sensitivity and specificity of tumor fluorescence for viable tumor detection was calculated and fluorescence was found to be highly sensitive (73.0% for 50 mg dose, 98.2% for 100 mg dose) and specific (66.3% for 50 mg dose, 69.8% for 100 mg dose) for viable tumor tissue in CE tumors while normal peri-tumoral tissue showed minimal fluorescence.ConclusionThis first-in-human study demonstrates the feasibility and safety of antibody based imaging for CE glioblastomas.

Objectives  Pituitary adenoma (PA), among the most commonly encountered sellar pathologies, accounts for 10% of primary intracranial tumors. The reported incidence of postoperative diabetes insipidus (DI) is highly variable. In this study, we report our experience with DI following endoscopic transsphenoidal surgery (TSS) for PAs, elucidating the risk factors of postoperative DI, the likelihood of long-term DI, and the impact of DI on the length of stay (LOS). Methods  The study included 178 patients who underwent endoscopic resection of PAs. Early DI was defined as that occurring within the first postoperative week. The mean follow-up was 36 months. Long-term DI was considered as DI apparent in the last follow-up visit. Results  Of the 178 patients included in the study, 77% of the tumors were macroadenomas. Forty-seven patients (26%) developed early DI. Long-term DI was observed in 18 (10.1%) of the full cohort. Age younger than 50 years was significantly associated with a higher incidence of long-term DI ( p  = 0.02). Macroadenoma and gross total resection were significantly associated with higher incidence of early DI ( p  = 0.05 and p  = 0.04, respectively). The mean LOS was 4 days for patients with early postoperative DI and 3 days for those without it. Conclusion  The reported incidence of postoperative DI is significantly variable. We identified age younger than 50 years a risk factor for developing long-term postoperative DI. Gross total surgical resection and tumor size (> 1 cm) were associated with development of early DI. Early DI increased the LOS on average by 1 day.

BackgroundPatient stratification to identify subtypes with different disease manifestations, severity, and expected survival time is a critical task in cancer diagnosis and treatment. While stratification approaches using various biomarkers (including high-throughput gene expression measurements) for patient-to-patient comparisons have been successful in elucidating previously unseen subtypes, there remains an untapped potential of incorporating various genotypic and phenotypic data to discover novel or improved groupings.MethodsHere, we present HOCUS, a unified analytical framework for patient stratification that uses a community detection technique to extract subtypes out of sparse patient measurements. HOCUS constructs a patient-to-patient network from similarities in the data and iteratively groups and reconstructs the network into higher order clusters. We investigate the merits of using higher-order correlations to cluster samples of cancer patients in terms of their associations with survival outcomes.ResultsIn an initial test of the method, the approach identifies cancer subtypes in mutation data of glioblastoma, ovarian, breast, prostate, and bladder cancers. In several cases, HOCUS provides an improvement over using the molecular features directly to compare samples. Application of HOCUS to glioblastoma images reveals a size and location classification of tumors that improves over human expert-based stratification.ConclusionsSubtypes based on higher order features can reveal comparable or distinct groupings. The distinct solutions can provide biologically- and treatment-relevant solutions that are just as significant as solutions based on the original data.

Patients with refractory metastatic triple-negative breast cancer (mTNBC) and symptomatic brain metastases have poor prognosis and are challenging to treat. The addition of an programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitor (pembrolizumab or atezolizumab) to first line chemotherapy has prolonged survivals in mTNBC patients with PD-L1-positive tumor and/or tumor-infiltrating immune cells. The clinical efficacy of the chemoimmunotherapy combination in patients with refractory mTNBC, especially brain metastasis, is unknown. Co-amplification of PD-L1, PD-L2, and Janus kinase 2 (PD-L1/PD-L2/JAK2) genes (PDJ amplification) is associated with high PD-L1 protein expression and a 65-87% response rate to PD-1/PD-L1 inhibitors in patients with lymphomas. But the utility of PDJ amplification as a biomarker predictive of response to PD-1/PD-L1 inhibitors is unknown for mTNBC patients. Here, we report a 46-year-old woman who had rapid tumor progression in the brain and lung within 3 months after chemotherapy, neurosurgery, and gamma knife stereotactic radiosurgery for brain metastasis. Next-generation sequencing of her brain metastasis specimen revealed 9 copies of PDJ amplification and a tumor mutational burden of 5 mutations per megabase. Although high PDJ mRNA expression levels were detected, PD-L1 protein expression was negative on tumor cells and 10% on tumor-associated immune cells. After the debulking brain tumor resection, she received pembrolizumab monotherapy, whole brain radiation, and then atezolizumab and nab-paclitaxel with good intracranial and extracranial responses for >16 months. To the best of our knowledge, this is the first report that PDJ amplification is associated with durable clinical response to the PD-1/PD-L1 inhibitor-containing, multidisciplinary management in a patient with refractory, PD-L1 protein-negative, PDJ-amplified mTNBC. Further study is warranted to understand the underlying mechanism and validate PDJ amplification as a biomarker for clinical response to PD-1/PD-L1 inhibitor-containing therapy in patients with mTNBC.

Teaching computer information systems via distance education is a challenge for both student and faculty. Much research work has been performed on methods of teaching via distance education. Today we are faced with a variety of options for course delivery. Asynchronous delivery via online or lesson instruction still remains most common. But alternative synchronous delivery methods such as Adobe Connect, Skype, and Eluminate Live are increasingly used as alternatives in a variety of situations and for a variety of purposes and classes. Our study reviews the use of synchronous distance course delivery and reports on specific experiences and results from two computer information systems courses over the past year. Post-class surveys from the students of these courses reveal interesting and useful insights into the acceptance and challenges of synchronous distance delivery methods including emphasis on technical stability and interaction.

PurposeTo determine the maximum tolerated dose (MTD) of vorinostat, a histone deacetylase inhibitor, given concurrently with stereotactic radiosurgery (SRS) to treat non-small cell lung cancer (NSCLC) brain metastases. Secondary objectives were to determine toxicity, local failure, distant intracranial failure, and overall survival rates.Materials and methodsIn this multicenter study, patients with 1 to 4 NSCLC brain metastases, each ≤2 cm, were enrolled in a phase 1, 3 + 3 dose escalation trial. Vorinostat dose levels were 200, 300, and 400 mg orally once daily for 14 days. Single-fraction SRS was delivered on day 3. A dose-limiting toxicity (DLT) was defined as any Common Terminology Criteria for Adverse Events version 3.0 grade 3 to 5 acute nonhematologic adverse event related to vorinostat or SRS occurring within 30 days.ResultsFrom 2009 to 2014, 17 patients were enrolled and 12 patients completed study treatment. Because no DLTs were observed, the MTD was established as 400 mg. Acute adverse events were reported by 10 patients (59%). Five patients discontinued vorinostat early and withdrew from the study. The most common reasons for withdrawal were dyspnea (n=2), nausea (n=1), and fatigue (n=2). With a median follow-up of 12 months (range, 1-64 months), Kaplan-Meier overall survival was 13 months. There were no local failures. One patient (8%) at the 400-mg dose level with a 2.0-cm metastasis developed histologically confirmed grade 4 radiation necrosis 2 months after SRS.ConclusionsThe MTD of vorinostat with concurrent SRS was established as 400 mg. Although no DLTs were observed, 5 patients withdrew before completing the treatment course, a result that emphasizes the need for supportive care during vorinostat administration. There were no local failures. A larger, randomized trial may evaluate both the tolerability and potential local control benefit of vorinostat concurrent with SRS for brain metastases.

BackgroundIn previous clinical trials, antiangiogenic therapies such as bevacizumab did not show efficacy in patients with newly diagnosed glioblastoma (GBM). This may be a result of the heterogeneity of GBM, which has a variety of imaging-based phenotypes and gene expression patterns. In this study, we sought to identify a phenotypic subtype of GBM patients who have distinct tumor-image features and molecular activities and who may benefit from antiangiogenic therapies.MethodsQuantitative image features characterizing subregions of tumors and the whole tumor were extracted from preoperative and pretherapy perfusion magnetic resonance (MR) images of 117 GBM patients in 2 independent cohorts. Unsupervised consensus clustering was performed to identify robust clusters of GBM in each cohort. Cox survival and gene set enrichment analyses were conducted to characterize the clinical significance and molecular pathway activities of the clusters. The differential treatment efficacy of antiangiogenic therapy between the clusters was evaluated.ResultsA subgroup of patients with elevated perfusion features was identified and was significantly associated with poor patient survival after accounting for other clinical covariates (P values 3) consistently found in both cohorts. Angiogenesis and hypoxia pathways were enriched in this subgroup of patients, suggesting the potential efficacy of antiangiogenic therapy. Patients of the angiogenic subgroups pooled from both cohorts, who had chemotherapy information available, had significantly longer survival when treated with antiangiogenic therapy (log-rank P=.022).ConclusionsOur findings suggest that an angiogenic subtype of GBM patients may benefit from antiangiogenic therapy with improved overall survival.