Citations

3612 Background: The RAS/RAF/MEK signal transduction pathway is critical to the development of colorectal cancer, and tumors harboring KRAS, NRAS, and BRAF mutations were shown to be resistant to radiation. Thus, we conducted a phase I study of trametinib, a potent MEK1/2 inhibitor, in combination with CRT in patients with LARC. Methods: Phase I trial for patients with Stage II/III rectal cancers with a 3+3 design, and an expansion cohort of 12 patients at the maximum tolerated dose (MTD). Trametinib is given orally at 3 dose levels: 0.5mg, 1mg, and 2mg (Mon-Fri). CRT regimen is infusional 5-flourouracil (5FU) 225mg/m2/day (Mon-Fri) and daily fractions of 1.8 Gy (total 50.4Gy). There is a 5-day trametinib lead-in followed by trametinib and CRT. Six to 10 weeks after completion of CRT, patients then proceed to their surgery and adjuvant therapy. The primary endpoint is to identify the MTD and recommended phase 2 dose of trametinib with CRT. Immunohistochemistry staining for phosphorylated –ERK (pERK) and genomic profiling is performed on the tumor samples. Results: Enrollment is complete at all dose levels with18 patients, and 15 patients evaluable for toxicity and response as of Feb 6. One dose-limiting toxicity of diarrhea was observed at the 2mg dose. Grade 3 and most common toxicities are shown in Table 1. No grade 4/5 toxicities have been observed. At 2mg dose level, 3/9 (33%) patients had pathological complete response (pCR) and 2/9 (22%) had a near pCR. Correlative studies confirm decrease in pERK levels with increasing doses of trametinib. Correlation of genomic mutational status with toxicity, response, and outcomes is being analyzed. Conclusions: The combination of trametinib with 5FU CRT is tolerable with promising preliminary activity. Final results will be presented at the meeting. Toxicities. Clinical trial information: NCT01740648. [Table: see text]

Purpose To determine baseline individual and school-related factors associated with increased risk of developing depression symptoms by year four (Y4) of medical school, and to develop a prognostic index that stratifies risk of developing depression symptoms (Depression-PI) among medical students. Method The authors analyzed data from 3,743 students (79% of 4,732) attending 49 U.S. medical schools who completed baseline (2010) and Y4 (2014) surveys. Surveys included validated scales measuring depression, stress, coping, and social support. The authors collected demographics and school characteristics and conducted multivariate analysis to identify baseline factors independently associated with Y4 depression symptoms. They used these factors to create a prognostic index for developing depression. They randomly divided the data into discovery (n = 2,455) and replication (n = 1,288) datasets and calculated c statistics ( c ). Results The authors identified eight independent prognostic factors for experiencing depression symptoms during training within the discovery dataset: age; race; ethnicity; tuition; and baseline depression symptoms, stress, coping behaviors, and social support. The Depression-PI stratified four risk groups. Compared with the low risk group, those in the intermediate, high, and very high risk groups had an odds ratio of developing depression of, respectively, 1.75, 3.98, and 9.19 ( c = 0.71). The replication dataset confirmed the risk groups. Conclusions Demographics; tuition; and baseline depression symptoms, stress, coping behaviors, and social support are independently associated with risk of developing depression during training among U.S. medical students. By stratifying students into four risk groups, the Depression-PI may allow for a tiered primary prevention approach.

Abstract Objectives: To investigate the antitumor potential of the widely used anticholesterol drug Atorvastatin (ATV) alone, in combination with Carboplatin (CBPT) and with the glycolytic inhibitor PFK158 (PFKi) in ovarian cancer (OC). Methods: MTT assay and the Chou-Talalay methodology were used to test anticancer activity in vitro; half maximal inhibitory concentration (IC50) and combination index (CI) were calculated. Cellular changes were studied with transmission electron microscopy (TEM). ATV was combined with PFKi as we previously showed that PFKi, in addition to glycolysis, inhibits lipid metabolism by targeting PLA2G3. PLA2G3 expression was studied by western blot given that downregulation in OVCAR8 using two shRNAs (sh33, sh35) induced autophagy, a prodeath condition in OC, and was associated with chemosensitization compared to nontargeted controls (NTC) (unpublished data). A random sample of 10 patient-derived OC xenografts (PDX) was studied by TEM. Results: OVCAR8 exhibited a dose dependent proliferation inhibition when treated with ATV (IC50 8μM). PFKi and CBPT IC50 were 4μM and 78μM. PFKi treatment combined with 4μM and 8μM of ATV resulted in ATV sensitizing cells to PFKi by shifting PFKi IC50 down to 2.7μM and 0.4μM, respectively. When ATV was combined in constant ratio with CBPT, CIs were >1.1 indicating antagonism. Combination of ATV 4μM with PFKi 2μM resulted in greater decrease in PLA2G3 and p62 and greater increase in cleaved PARP compared to PFKi alone suggesting higher levels of autophagy and apoptosis. ATV and combination treatment resulted in increased caveolin-1 levels, previously shown to be associated with apoptotic cell death. TEM analysis of ATV and PFKi treated cells showed greater number of lipid rich multilamellar bodies (MLB) compared to controls. PLA2G3 knockdowns exhibited higher MBL formation, lower p62, and when treated with statin and with PFKi, cleaved PARP was significantly higher compared to NTCs. TEM showed that PDXs clustered in low and high MLB groups suggesting a distinct novel phenotype. Conclusions: ATV could enhance PFKi antitumor activity by jointly targeting PLA2G3 leading to metabolic reprogramming of OC. Importantly, ATV antagonized CBPT. Additional studies are in progress to explore the mechanistic pathway of ATV and characterize the significance of MLB in OC as a prodeath phenotype and biomarker of response. Citation Format: Eleftheria Kalogera, Debarshi Roy, Jamie N. Bakkum-Gamez, William A. Cliby, Sean C. Dowdy, Viji Shridhar. Atorvastatin antagonizes carboplatin, synergizes with the glycolytic inhibitor PFK-158, and induces lipid laden multilamellar bodies in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5821.

Abstract Introduction: Mitochondria are intracellular organelles that play an important role in energy metabolism, reactive oxygen species generation, and apoptosis. They possess their own haploid genome distinct from nuclear DNA, and mutations in mitochondrial DNA (mtDNA) have previously been linked to cancer risk, disease progression, and treatment response for multiple tumor types. However, the spectrum of mtDNA variation in epithelial ovarian carcinoma (EOC) and associations with clinical characteristics have not been fully explored. Methods: We extracted mtDNA from fresh frozen EOC tumors of women diagnosed with primary invasive epithelial ovarian, fallopian tube, or peritoneal carcinoma, and performed targeted sequencing using the Illumina MiSeq Reporter mtDNA workflow. Homoplasmic and heteroplasmic SNVs and indels were called using an in-house bioinformatics pipeline. We estimated mtDNA haplogroup using Haplogrep and compared to results from available germline mtDNA SNP genotyping. We derived regional weighted variant burden scores based on mtDNA functional domains, accounting for underlying haplogroup, heteroplasmic fraction, and predicted functional impact. To assess potential differences in variant burden by histotype, we compared burden scores using Kruskal-Wallis testing. Among high-grade serous tubo-ovarian cases, we explored associations with overall survival (OS) using Cox proportional hazards regression. After quality control filtering, 389 mitochondrial genomes were analyzed, including those from 320 tubo-ovarian high-grade serous tumors, 42 endometrioid tumors, and 18 clear cell tumors. Results: Accounting for predicted haplogroup, we identified a median count of two global private heteroplasmies per tumor (range: 0-9). Elevated mutation rates were identified in the regulatory control region as well as among the various mt-tRNAs (>3 per 10kb per sample) relative to the remainder of the mtDNA. The majority of recurrent variants across tumors were also identified in the mtDNA control region. We did not observe an association with overall mtDNA variant burden and patient age at diagnosis. Regional mtDNA burden scores revealed a significant association with histotype (P<0.001) for the oxidative phosphorylation complex IV genes, with higher burden in tubo-ovarian high-grade serous and clear-cell tumors relative to endometrioid tumors. For patients with tubo-ovarian high-grade serous tumors, increased variant burden in MT-CO1 (cytochrome C oxidase I) was associated with improved OS (HR = 0.32; 95% CI = [0.14,0.70], LRT P = 0.001) after adjustment for age, stage, and debulking status. Conclusions: We demonstrate a wide range of tumor mtDNA variant patterns in the largest known collection of EOC patients. This work provides the first extensive evaluation of mtDNA variation in these diseases and highlights the potential prognostic relevance of mitochondrial dysfunction. Citation Format: Nicholas B. Larson, Stacey J. Winham, Chen Wang, Jared M. Evans, Sebastian M. Armasu, Bryan M. McCauley, Sean J. Yoder, Lan Min Zhang, Catherine M. Phelan, Ellen L. Goode. Targeted deep sequencing of mitochondrial DNA in epithelial ovarian carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 420.

The clinical phenotype of leucine‐rich glioma‐inactivated protein 1 (LGI1) and contactin‐associated proteinlike 2 (CASPR2) autoimmunity is well defined in adults. Data for children are limited (<10 cases). Among 13,319 pediatric patients serologically tested for autoimmune neurological disorders (2010–2017), 264 were seropositive for voltage‐gated potassium channel‐complex–IgG (radioimmunoprecipitation). Only 13 (4.9%) were positive by transfected cell‐binding assay for LGI1‐IgG (n = 7), CASPR2‐IgG (n = 3), or both (n = 3). This is significantly less than in adults. Encephalopathy, seizures, and peripheral nerve hyperexcitability were common, as was coexisting autoimmunity. No faciobrachial dystonic seizures or cancers were identified. Functional neurologic disorders were frequently the initial diagnosis, and immunotherapy appeared beneficial. Ann Neurol 2018;84:473–480