tbuckley/cabot-search huggingface dataset:
An immune response-associated genomic model to predict early resistance to PD1/PD-L1 blockade among real-world TMB-high Chinese cancer patients.
Authors: Qiang Xu, Shichun Lu, Guan Wang, Jinwang Wei, Angela Wu, Chun Dai, Xin Cai, Ying Luo, Wending Sun
Journal: Journal of Clinical Oncology (2019)

e14167 Background: TMB-high was used as a favorable biomarker to predict the response to anti-PD-1/PD-L1 therapy, but a substantial portion of the TMB-high patients suffered from early resistance with limited clinical benefits but potential severe adverse effects. Methods: Whole-exome sequencing were performed in more than 200 advanced cancer patients, who received anti-PD-1 therapy alone or in combination with chemotherapy and targeted therapy across 20 provinces of China, with quarterly follow-ups. The genomic profiles of the patients with progressive disease (PD) and complete remission (CR) outcomes were individually analyzed and the potential resistance and hypersensitive biomarkers were identified. These biomarkers were formulated into an immune response-associated genomic (IRAG) model based on XGBoost algorithm to predict the sensitivity to PD-1 blockage and early resistance among TMB-high patients. Results: Non-synonymous somatic mutations (CTNNB1, B2M, PD-L1 and HLA class I genes), somatic gene amplifications (MDM2/4, CDK4, CCND1/FGF3/FGF4/FGF19, FLT3 and MYC), chromosome 9p21 deletion, and loss of heterozygosity in chromosome 6 HLA-I region were identified as potential resistance biomarkers in the PD group. TMB-high, microsatellite instability (MSI), TMB-low with indel-proportion high, POLE loss-of-function mutations, Epstein-Barr virus infection and DNA mismatch repair-deficient germline and somatic mutations were identified as potential hypersensitivity biomarkers in the CR group. By combining all genomic resistance and hypersensitivity biomarkers, we developed a quantitative IRAG model and separated the patients into three groups: TMB-low, TMB-high/IRAG-low and TMB-high/IRAG-high. The PFS in TMB-high/IRAG-low group was characterized with early clinical resistance, similar to the TMB-low group (median: 3.8 vs. 4.2 months, p = 0.22). The reanalysis of the patient set with known clinical outcomes showed that the TMB-high/IRAG-high group had a significantly longer PFS than the other two groups. (median: 10 vs. 3.8, 4.2 months, p &lt; 0.001). The TMB-high/IRAG-high group clearly showed higher chromosomal stability with fewer somatic copy number alterations. Conclusions: We developed a model based on one single genomic assay (whole-exome) to successfully identify those TMB-high patients who suffered from early resistance to PD-1 inhibitors. Larger cohort and independent analyses are necessary to verify the validity of these results.
A large subtype of squamous cell carcinoma enriched for TrkB-T1 mRNA.
Authors: Yalu Zhou, Joel L. Schwartz, Saurabh Sinha, Ardaman Shergill, Guy Adami
Journal: Journal of Clinical Oncology (2019)

e14751 Background: A large subtype of squamous cell carcinoma enriched for TrkB-T1 mRNA. Background The NTRK2 genetic locus encodes neurotrophin membrane receptors that play an important role in normal neural tissue plasticity, growth, and survival. One NTRK2-encoded protein is TrkB-FL, which can regulate multiple pathways relevant to cancer. A second NTRK2 gene mRNA isoform encodes TrkB-T1, a receptor that has a different cytoplasmic domain and is encoded in a mRNA with a unique 3’ terminal exon. Methods: Tumors from The Cancer Genome Atlas (TCGA) and other studies were classified according to the expression of a single form of NTRK2 mRNA that of TrkB-T1. Analysis of differentially expressed genes in TrkB-T1 high expressers was done to determine if tumors enriched for TrkB-T1 were a uniform group independent of anatomic site. Results: The mRNA for TrkB-T1 is the most abundant NTRK2 gene mRNA in all squamous cell carcinomas (SCCs). Comparison of oral SCC (OSCC) high TrkB-T1 RNA expressers to low expressers (n = 284) revealed gene expression differences consistent with the high TrkB-T1 tumors being more neural-like. The upregulated genes in the TrkB-T1 RNA high expressers also showed enrichment of pathways involved in retinol metabolism, hedgehog signaling, and the Nfe2l2 response, among other pathways. An examination of larynx, esophagus, and lung SCCs (n = 100, 100, 540) showed induction of the same pathways among the tumors that expressed high levels of TrkB-T1 mRNA.. Surprisingly, the relationship of high level TrkB-T1 expression to patient outcomes was SCC anatomic site specific. High TrkB-T1 mRNA levels in laryngeal SCC correlated with poor survival, but the opposite was true for lung SCC. This may be because pathways enriched in the TrkB high expressers, like those regulated by Nfe2l2, Pik3ca, and Sox2, are known to have SCC anatomic site-specific effects on progression. Conclusions: High level TrkB-T1 mRNA serves as a marker of a distinct SCC subtype. These tumors share the enrichment of at least 3 pathways relevant to tumor progression, Nfe2l2 response, retinol metabolism, and hedgehog signaling.
Plasma concentrations of dabrafenib and trametinib (PCD/T) monitoring in advanced <i>BRAFV600<sup>mut</sup></i> melanoma patients.
Authors: Elisa Funck-Brentano, Margot Raynal, Jean-Claude Alvarez, Alain Beauchet, Christian Funck-Brentano, Philippe Saiag
Journal: Journal of Clinical Oncology (2019)

9541 Background: Dabrafenib (D) and trametinib (T) are highly ative in BRAF V600mut melanoma pts. One previous study suggested high PCD to be associated with adverse effects (AE) but not with tumor response. We investigated the relationship between PCD/T and tumor control or AE. Methods: PCD/T were evaluated with high-performance liquid chromatography/mass spectrometry in D+T-treated metastatic melanoma patients. We analyzed results at steady state (≥2 d for D, 24 d for T after introduction or dose modification) and far from peak concentrations (8 to 14.5 h for D and 20-28 h for T). We collected data of tumor assessments (RECIST 1.1) prospectively stored in our database and AE (CTCAE 4.0) blinded to PCD/T results. Each AE was associated with the closest sample harvested to the beginning of AE, or in the absence of AE with the highest PCD/T level for each patient. Results: We analyzed 75 D and 58 T assays from 36 pts (19M/17F), treated with D+T for metastatic melanoma (Stage IV: N = 35), mostly in first line (69.4%). Initial D dose was 300 mg/d and 2 mg/d for T, reduced in 10 patients (27.7%) for AE: to 30% of D (N = 8) and 25% of T (N = 8). High interindividual variability of PCD (range: 4-945ng/mL, median 70.0) and of PCT (5-25ng/mL, median 8.6) was observed. No differences between mean PCD/T at the time of evaluations showing progressive disease (PD) compared to those without PD pts (146.6±111.6 and 9.3±2.1) and pts with complete (N = 11), partial (N = 1) or stable response (N = 1) (160.6±127.9, P = 0.81 and 10.6ng/mL±2.6, P = 0.29) were observed. No significant relationship was shown between PCD/T and body mass index (r = 0.22 and -0.31), age (p = 0.19 and 0.26), or between PCD/T and D (p = 0.11) or T (p = 0.17) doses, neither between elevated mean PCD/T and any most common AE. Conclusions: This study shows a high interindividual variability but failed to show a relationship between PCD or T and tumor response nor AE. One limit is we did not explore PC of D active metabolites (hydroxy-and desmethylD). It has been shown that there is an auto-induction of D; T inhibits P-gp, a D substrate, suggesting synergistic pharmacological interactions. Thus, D pharmacokinetic seems to be too complex to be easily monitored.
Identification and use of treatment (tx) options in patients (pts) with advanced non-small cell lung cancer (aNSCLC) after comprehensive genomic profiling (CGP): A real-world study.
Authors: Celine Mascaux, Lukas Bubendorf, Fabrice Barlesi, James W. Clendening, Qing Zhang, Kieran Mace, Adam Gondos, Stefan Foser, Lisa I. Wang, Luis G. Paz-Ares
Journal: Journal of Clinical Oncology (2019)

9076 Background: The number of targeted txs for NSCLC is increasing. By analyzing numerous molecular alterations, CGP may open more targeted tx options than single biomarker testing. Methods: We analyzed a database linking Flatiron Health electronic health record-based clinical and Foundation Medicine, Inc. (FMI) CGP genomic alteration (GA) data in US pts diagnosed from 1/2011 with aNSCLC, primarily from community practices, and with follow-up through 6/2018. We examined the prevalence and distribution of genomic findings, and agreement between tx received and CGP-directed tx options (approved for aNSCLC/other tumors) on the FMI report as a measure of clinical utility. The latter was evaluated in a subset of pts with sufficient tx and follow-up data after FMI testing. Results: Among 5112 FMI-tested pts (first test observed 8/2012), 49% had their FMI test before starting any line of tx, 97% had ≥ 1 GA with known/likely function (median = 5), and 85% had ≥ 1 potential tx option (52% had ≥ 1 option for aNSCLC and 33% had ≥ 1 for another tumor type only). In 1366 pts evaluable for tx agreement after FMI testing, 572 (42%) received a tx listed on the FMI report and 111 (8%) were enrolled in clinical trials. Pts with a tx option approved for aNSCLC were more likely to have a tx agreeing with an option on the FMI report (67% of 754) v pts with a tx option approved in another tumor type only (8% of 612). Among the 1366 pts, 14% had EGFR/ALK/ROS1/BRAF (EARB) tx options only. The remaining 1170 had a non-EARB tx option, either as their only option (1014; 87%), or in addition to an EARB tx option (156; 13%). The non-EARB tx options included 377 pts (32%) with a tumor mutational burden-associated tx option. In these 1170 pts, 341 (29%) had an agreeing tx besides EARB, and 100 (9%) were enrolled on trials. Conclusions: FMI CGP identified potential NSCLC-specific tx options/a clinical trial opportunity for 52% of pts with aNSCLC. Of the pts evaluated for tx agreement, almost ½ received a tx agreeing with an option on the FMI report and/or were enrolled in a clinical trial. FMI CGP adds value beyond single biomarker testing by identifying txs and trial options in a meaningful proportion of pts.
Depression and health care utilization and costs in patients diagnosed with cancer.
Authors: Jennifer Lynne Steel, Geena Richards, Timothy Billiar, Judith Procopio, Jessica Miceli, Carol Lynn Hecht, Barbara Kucinski, Allan Tsung, Emily Murphy, J. Wallis Marsh, Michael Antoni, Yoram Vodovotz, Mikhaila Layshock, Michael Spring, Ritambhara Pathak, Hannah Cheng, David A. Geller
Journal: Journal of Clinical Oncology (2019)

e23128 Background: The aims of this study were to examine the associations between depression and complications, health care utilization and costs in patients with cancer. Methods: Patients diagnosed with cancer were administered a battery of questionnaires, including the Center for Epidemiological Studies-Depression (CES-D) Scale. Health care utilization and costs for patients was collected for one year after the administration of the CES-D. Descriptive statistics, Chi-square and ANOVA, and ordered restricted inference analyses were performed. Results: Of the 100 patients, the mean age was 64.0 years (SD = 10.3), the majority of patients were male (51%), Caucasian (89%), diagnosed with hepatocellular or cholangiocarcinoma (47%) and stage III and IV cancer (60%), and 34% of patients had clinical levels of depressive symptoms (CES-D &gt; 16). No demographic or disease specific variables were associated with depressive symptoms or outcomes. Surgical patients with clinical levels of depression had a greater number of complications [Chi-square = 4.4, p = 0.036] and a greater severity of complications using Clavien-Dindo classification [Chi-square = 4.5, p = 0.033]. Patients undergoing chemotherapy, who reported depressive symptoms in the clinical range, were more likely to require medical intervention for chemotherapy side effects [Chi-square = 4.2, p = 0.04]. Patients with clinical levels of depressive symptoms also had a greater number of emergency room visits [F(1,99) = 8.4, p = 0.005]. Patients who reported clinical levels of depressive symptoms had significantly higher median costs associated with the loss of work force productivity (Median = $7154 versus $2104; p = 0.015), hospital costs (Median = $29,917 versus $8292, p = 0.019), and cost per registration (Median = $3324 versus $1247, p = 0.017) but lower physician costs (Median = $6171 versus $10,821; p = 0.026) than patients with non-clinical levels of depressive symptoms. Conclusions: Depressive symptoms are associated with increased complications and health care utilization and costs. There is an urgent need for effective and scalable interventions to reduce depressive symptoms in patients diagnosed with cancer to improve quality of life and reduce health care utilization and costs.
Advanced Volumetric 3-Dimensional Visualization of Surgical Anatomy—Are We There Yet?
Authors: Carla M. Pugh
Journal: JAMA Surgery (2019)

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Oncology precision medicine for hepatobiliary and pancreatic cancer: An institutional review.
Authors: Geoffrey Bellini, Jennifer Jo Godden, James L. Weese, Aaron Chevinsky, Wesley Allan Papenfuss, Michael A. Thompson
Journal: Journal of Clinical Oncology (2019)

e14626 Background: Hepatobiliary cancers - hepatocellular carcinoma (HCC), intra or extrahepatic cholangiocarcinoma (I/EC), and gallbladder carcinoma (GB) - and pancreatic adenocarcinoma (PC) remain a leading cause of death with little improvement in long-term outcome. Recent studies have suggested that these cancers harbor actionable mutations to varying degrees. The aim of our study was to examine the number of patients (Pts) with these primary tumors who underwent molecular testing in a large vertically integrated health system. Subsequently, we analyzed the percentage of that population who may be candidates for oncology precision medicine (OPM) directed therapy. Methods: We identified Pts with HCC, IC, EC, GB in an IRB reviewed OPM database of our system over a one year period. Pts who underwent molecular panel testing were selected out, and their molecular alterations were identified and stratified by cancer type. Results: 304 total Pts were identified. 61 (20%) underwent molecular testing broken down as follows: 17/132 (13%) I/EC and HCC, 3/11 (27%) GB, and 41/161 (25%) PC. Quantity not sufficient for testing was in 10/61 (16%), of which 5/10 (50%) were resubmitted and tested successfully. 6/61 (10%) were cancelled or deemed not appropriate. Test recommended potential actionability was 8/17 (47%) of I/EC and HCC, 2/3 (67%) of GB, and 25/41 (61%) of PC. Conclusions: OPM is a dynamic area of increasing testing and learning. We found 13-27% of hepatobiliary and pancreatic Pts had molecular testing, which suggests the potential to increase molecular screening for this difficult group of tumors. Total genetic alterations (TGA) and clinically relevant genomic alterations (CRGA) per patient are similar to Ross et al. ( http://ow.ly/k52a30nBMnU ) for GB. Final interpretation regarding pragmatic actionability (patient on drug) and clinical outcomes are still under investigation.[Table: see text]
BRCA tumor test in ovarian cancers: The changing role of molecular pathology in the era of PARP inhibitor (PARPi) therapy.
Authors: Caterina Fumagalli, Elena Guerini Rocco, Federica Tomao, Ilaria Betella, Alessandra Rappa, Giuseppe Viale, Fedro Peccatori, Nicoletta Colombo, Massimo Barberis
Journal: Journal of Clinical Oncology (2019)

5572 Background: The PARPi Olaparib has been approved in maintenance setting of recurrent platinum-sensitive and BRCA mutated, ovarian cancer (OC) patients. However, according to the striking results of SOLO 1 trial, it could be shortly proposed even to newly diagnosed BRCA mutated OC women. We report the results of the implementation of tumor BRCA test in diagnostic setting within the frame of institutional workflow for the management of OC patients. Methods: 223 women with OC were consecutively referred over 25 months to tumor BRCA test. The test was requested by gynecologic oncologist at the diagnosis of non-mucinous and non-borderline OC, upon discussion on the implications of the test result and written consent collected for each patient. Formalin-fixed paraffin embedded (FFPE) specimens of OC were tested using the automatized “Oncomine BRCA Research Assay” Next Generation Sequencing (NGS) panel. The tumor BRCA test was also performed on 5 archetypal cytological samples from ascites. Results: All the cases were considered adequate for the NGS analysis according to the tumor cell content (more than 10%) and the DNA yield extracted (more than 10 ng). The tumor BRCA test had a successful rate of 99.1% . The median Turn-Around Time (TAT) was 17 calendar days, from 33 days of the first trimester to 14 days of the last trimester of this analysis. Overall BRCA1 or BRCA2 pathogenic (P)/likely pathogenic (LP) mutations were found in 62 (28.1%) cases and variants of uncertain significance (VUS) in 25 (11.3%) cases, including 3 cases with a BRCA1 P variant and a concurrent BRCA2 VUS alteration. In detail, 47 P/LP variants and 16 VUS were identified in BRCA1 whereas 15 P/LP mutations and 9 VUS occurred in BRCA2. Complete concordance in tumor BRCA test results were seen between ascites cytological samples and matched tumors. Conclusions: The tumor BRCA test could be implemented in routine diagnostic setting, at diagnosis of non-mucinous and non-borderline OC. The test could be performed on FFPE specimens, had an high successful rate and a TAT compatible with clinical needs. The promising data on cytological samples will be confirmed in larger series.
Delay in time to adjuvant chemotherapy and its impact on outcome in completely resected advanced ovarian malignancies treated with CRS, CRS+IP and CRS +HIPEC.
Authors: Ashwin K Rajgopal, S.P. Somashekhar, Rohit Kumar C, Ramya Yethadka, Vijay Ahuja, Amit Rauthan, Poonam Patil
Journal: Journal of Clinical Oncology (2019)

e17051 Background: The relationship between initiation time of adjuvant chemotherapy in ovarian cancer and prognosis has remained controversial. This study was done to determine whether time from optimal cytoreductive surgery (CRS) to initiation of adjuvant chemotherapy impacts disease free &amp; overall survival in advanced ovarian carcinoma. Methods: Total of 185 patients with primary advanced epithelial ovarian carcinoma (Stage IIIc or selected Stage IV), underwent optimal cytoreduction (either as upfront or interval) &amp; adjuvant chemotherapy. The analysis of interval between day of surgery and start of adjuvant chemotherapy and its impact on outcome was done. Results: CRS with intraperitoneal (IP) chemotherapy either in the form of IP port or hyperthermic intraperitoneal chemotherapy (HIPEC) was done in 135patients (60+ 75) and CRS alone in 50 patients. The median delay in starting adjuvant chemotherapy was 35 days for the whole cohort (32 days in the CRS group, 34 days in CRS+ IP group and 41 days in CRS+ HIPEC group). Delay in chemotherapy, as defined by more than 42 days had significant impact on DFS in CRS alone group (36 months vs 17 months: p = 0.02) had some impact in patients receiving intraperitoneal chemotherapy (38 versus 28 months; p = 0.78) &amp; no impact on CRS+HIPEC group (35 vs 32 months; p = 0.17). In comparison to HIPEC vs non HIPEC group (CRS &amp; CRS+IP), there was a meaningful impact on DFS with reference to delay in non HIPEC group ( 38 vs 22 months p = .08 whereas in the HIPEC group delay didn’t have any impact(35vs 32 months p = 017). There was trend towards better OS (88 vs 71 months p = 0.49). Conclusions: Delay in starting adjuvant chemotherapy certainly had impact on outcome with respect to CRS &amp; CRS + IP arm (non HIPEC group) whereas the delay didn’t have an impact in the HIPEC group owing to the fact that single dose of chemotherapy during surgery in heated environment may substitute for the delay. However well designed clinical studies needs to be designed to evaluate the impact of single dose of intraperitoneal heated therapy &amp; its interplay in delay on starting adjuvant chemotherapy.
Exercise training prevents cardiac dysfunction and altered sarcoplasmic calcium reuptake in a genetic model of cardiomyopathy induced by sympathetic hyperactivity
Authors: Alessandra Medeiros, Natale P. Rolim, Kaleizu T. Rosa, Angelica M. Amanso, Carla R. Carvalho, Maria Cláudia Irigoyen, Eduardo M. Krieger, José E. Krieger, C. E. Negrão, Patricia C. Brum
Journal: Circulation (2004)
Von Hippel-Lindau Acts as a Metabolic Switch Controlling Nephron Progenitor Differentiation
Authors: Kasey Cargill, Shelby L. Hemker, Andrew Clugston, Anjana Murali, Elina Mukherjee, Jiao Liu, Daniel Bushnell, Andrew J. Bodnar, Zubaida Saifudeen, Jacqueline Ho, Carlton M. Bates, Dennis Kostka, Eric S. Goetzman, Sunder Sims-Lucas
Journal: Journal of the American Society of Nephrology (2019)

Nephron progenitors, the cell population that give rise to the functional unit of the kidney, are metabolically active and self-renew under glycolytic conditions. A switch from glycolysis to mitochondrial respiration drives these cells toward differentiation, but the mechanisms that control this switch are poorly defined. Studies have demonstrated that kidney formation is highly dependent on oxygen concentration, which is largely regulated by von Hippel-Lindau (VHL; a protein component of a ubiquitin ligase complex) and hypoxia-inducible factors (a family of transcription factors activated by hypoxia).To explore VHL as a regulator defining nephron progenitor self-renewal versus differentiation, we bred Six2-TGCtg mice with VHLlox/lox mice to generate mice with a conditional deletion of VHL from Six2+ nephron progenitors. We used histologic, immunofluorescence, RNA sequencing, and metabolic assays to characterize kidneys from these mice and controls during development and up to postnatal day 21.By embryonic day 15.5, kidneys of nephron progenitor cell-specific VHL knockout mice begin to exhibit reduced maturation of nephron progenitors. Compared with controls, VHL knockout kidneys are smaller and developmentally delayed by postnatal day 1, and have about half the number of glomeruli at postnatal day 21. VHL knockout nephron progenitors also exhibit persistent Six2 and Wt1 expression, as well as decreased mitochondrial respiration and prolonged reliance on glycolysis.Our findings identify a novel role for VHL in mediating nephron progenitor differentiation through metabolic regulation, and suggest that VHL is required for normal kidney development.