tbuckley/cabot-search huggingface dataset:
Sex hormone, insulin, and insulin-like growth factor signaling in recurrence of high stage endometrial cancer: Results from the NRG Oncology/Gynecologic Oncology Group 210 trial.
Authors: Gloria S. Huang, Melissa A. Merritt, Alan Hutson, Howard D. Strickler, Mark Einstein, Jurriaan Brouwer-Visser, Nilsa C. Ramirez, Heather A. Lankes, Mona El-Bahrawy, Xiaonan Xue, Herbert Yu, Robert S. Mannel, David M. O'Malley, David Gardner Mutch, Paul Disilvestro, Melissa Ann Geller, Saketh R Guntupalli, Michael J. Birrer, David S. Miller, Marc J. Gunter
Journal: Journal of Clinical Oncology (2019)

5509 Background: Sex hormone and insulin/insulin-like growth factor (IGF) axis signaling pathways play an important role in endometrial cancer development but their role in endometrial cancer recurrence is unknown. In this study GOG-8015 we evaluated these pathways in a prospective cohort of patients diagnosed with the most common type of endometrial cancer, endometrioid adenocarcinoma. Methods: Stage II-IV endometrioid endometrial adenocarcinoma patients (N = 816) enrolled in the GOG-210 study with pre-treatment specimens were tested for tumor mRNA and protein expression levels of IGF1, IGF2, IGF binding proteins ( IGFBP) -1and -3, the insulin (IR) and IGF-I receptors (IGF1R), and phosphorylated (activated) IR/IGF1R as well as estrogen (ER) and progesterone receptors (PR) using quantitative PCR and immunohistochemistry (IHC). Serum concentrations of insulin, IGF-I, IGFBP-3, estradiol, estrone and sex hormone binding globulin were measured using ELISAs. Hazard ratios (HR) and 95% confidence intervals (CI) for risk of recurrence were obtained from multivariable Cox proportional hazard’s models with adjustment for age, stage and grade. Results: Recurrence occurred in 280 (34%) cases during a mean of 5.4 years of follow-up. ER-positivity (HR 0.67, 95% CI 0.47-0.95), IR-positivity (HR 0.53, 95% CI 0.29-0.98) and serum IGF-I levels (highest versus lowest quartile, HR 0.66, 95% CI 0.47-0.92) were inversely associated with recurrence risk. Conversely, circulating estradiol (highest versus lowest tertile, HR 1.55, 95% CI 1.02-2.36) and insulin (per 10 uU/ml, HR 1.52, 95% CI 1.12-2.06) and phosphorylated IGF1R/pIR expression (HR 1.40, 95% CI 1.02-1.92) were associated with increased risk of recurrence. Conclusions: We identified novel sex hormone and insulin/IGF axis tissue and circulating biomarkers of recurrence in a prospective study of high stage endometrioid endometrial cancer. Circulating insulin and estradiol, and tissue phosphorylated (activated) IGR1R/IR were independently associated with recurrence. These findings support prioritizing studies to establish their clinical utility as prognostic biomarkers and to investigate new strategies that target these pathways for prevention and treatment of endometrial cancer recurrence.
Safety and enhanced immunostimulatory activity of the DRD2 antagonist ONC201 in advanced solid tumor patients with weekly oral administration
Authors: Mark N. Stein, Jyoti Malhotra, Rohinton S. Tarapore, Usha Malhotra, Ann W. Silk, Nancy Chan, Lorna Rodriguez, Joseph Aisner, Robert D. Aiken, Tina Mayer, Bruce G. Haffty, Jenna H. Newman, Salvatore M. Aspromonte, Praveen K. Bommareddy, Ricardo Estupinian, Charles B. Chesson, Evita T. Sadimin, Shengguo Li, Daniel J. Medina, Tracie Saunders, Melissa Frankel, Aparna Kareddula, Sherrie Damare, Elayne Wesolowsky, Christian Gabel, Wafik S. El-Deiry, Varun V. Prabhu, Joshua E. Allen, Martin Stogniew, Wolfgang Oster, Joseph R. Bertino, Steven K. Libutti, Janice M. Mehnert, Andrew Zloza
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> ONC201 is a small molecule antagonist of DRD2, a G protein-coupled receptor overexpressed in several malignancies, that has prolonged antitumor efficacy and immunomodulatory properties in preclinical models. The first-in-human trial of ONC201 previously established a recommended phase II dose (RP2D) of 625 mg once every three weeks. Here, we report the results of a phase I study that evaluated the safety, pharmacokinetics (PK), and pharmacodynamics&nbsp;(PD) of weekly ONC201. <h3>Methods</h3> Patients ≥ 18 years old with an advanced solid tumor refractory to standard treatment were enrolled. Dose escalation proceeded with a 3 + 3 design from 375 mg to 625 mg of ONC201. One cycle, also the dose-limiting toxicity (DLT) window, was 21 days. The primary endpoint was to determine the RP2D of weekly ONC201, which was confirmed in an 11-patient dose expansion cohort. <h3>Results</h3> Twenty patients were enrolled: three at 375 mg and 17 at 625 mg of ONC201. The RP2D was defined as 625 mg with no DLT, treatment discontinuation, or dose modifications due to drug-related toxicity. PK profiles were consistent with every-three-week dosing and similar between the first and fourth dose. Serum prolactin and caspase-cleaved cytokeratin-18 induction were detected, along with intratumoral integrated stress response activation and infiltration of granzyme B+ Natural Killer cells. Induction of immune cytokines and effectors was higher in patients who received ONC201 once weekly versus once every three weeks. Stable disease of &gt; 6 months was observed in several prostate and endometrial cancer patients. <h3>Conclusions</h3> Weekly, oral ONC201 is well-tolerated and results in enhanced immunostimulatory activity that warrants further investigation. <h3>Trial registration</h3> NCT02250781 (Oral ONC201 in Treating Patients With Advanced Solid Tumors), NCT02324621 (Continuation of Oral ONC201 in Treating Patients With Advanced Solid Tumors).
Prevalence of DNA damage response and repair, cellular signaling, tumor suppressor, and immune checkpoint gene mutations in gastrointestinal cancers.
Authors: Aidan M Burke, Petra Prins, Celine Yeh, Benjamin Adam Weinberg, Sunnie S. Kim, Aiwu Ruth He, Michael J. Pishvaian, John Marshall, Keith Robert Unger
Journal: Journal of Clinical Oncology (2019)

e15149 Background: The prevalence of genetic mutations in gastrointestinal (GI) cancers is not well characterized. Molecular targeted therapies have substantial potential to improve outcomes. As next-generation sequencing (NGS) has become more commercially available, there may be additional opportunities to find novel targets for therapy or identify predictors of response to chemotherapy and radiotherapy. Commercially available DNA sequencing was conducted on patients with GI cancers to identify novel therapeutic and prognostic factors. Methods: A total of 86 solid tumor biopsy specimens from GI cancers were submitted for molecular profiling with NGS. Tumor molecular profiles were reviewed to identify frequently occurring pathogenic mutations in DNA damage and repair (DDR), cell cycle (CC), tumor suppressor (TS) and immune checkpoint (IC) pathways. DDR genes included MGMT, MSH 2/6 and ERCC1. CC genes included cMET, EGFR and KRAS. TS genes included APC, PTEN and TP53. IC genes included PD-1 and PDL-1. The overall frequency of mutations as well as the frequency of mutations for each primary site was analyzed. Results: Samples from colorectal (CRC, n=36), gastroesophageal (GE, n=5), liver and bile duct (LBD, n=14), pancreatic (PC, n=26) and other (OC, n=5) GI cancers were analyzed. Overall 46.3% of samples had at least one DDR mutation and commonly occurred in PC (57.7%) and CRC (50.0%).The most commonly mutated DDR genes were MGMT, TOPO1 and TOP2A. 55.2% of samples had at least one CC mutation and were most common in PC (69.2%), CRC (61.1%) and LBD (42.9%). The most common CC mutations were PTEN, P53 and KRAS. 65.5% of samples had at least one TS mutation with TP52 and PTEN being the most common. TS mutations occurred commonly in CRC (80.6%) and GE (60.0%). Mutations in PD-1 and PD-L1 (IC) were present in 25.3% of samples and occurred most frequently in GE (80.0%) and LBD (28.6%). Conclusions: Mutations were commonly seen in DDR (46.3%), CC (55.2%), TS (65.5%) and IC (25.3%) genes in GI primaries, providing a path to explore the role of novel therapeutic agents and how these mutations might be used to predict clinical outcomes.
The influence of kinesin light chain-2 on the radiosensitivity of non-small cell lung cancer cells and the underlying mechanisms.
Authors: Shangbiao Li, Xiaoxia Zhu
Journal: Journal of Clinical Oncology (2019)

e14512 Background: Our previous study found upregulated kinesin light chain-2 (KLC2) in non-small cell lung cancer (NSCLC) cell lines and tissues, which is associated with a poor prognosis. KLC2 promotes the migration ability of lung cancer cells. However, the influence of KLC2 on radiosensitivity of NSCLC has not yet been reported. Methods: Sensitivity of lung cancer cells to radiation was analyzed by colony formation, γH2AX immunofluorescent staining assay and neutral comet assay in vitro and a xenograft tumor model in vivo. Gene set enrichment analysis (GSEA), qRT-PCR and western blot assay were performed to predict and validate the potential target genes of KLC2. Results: We found that down-regulation of KLC2 could significantly improve the radio-sensitivity of lung cancer cells, while the overexpression of KLC2 had the opposite effect. GSEA identified p53 signal pathway as differentially enriched with high KLC2 expression, which was validated by western blot assay. Using data from TCGA, we found a positive correlation between the mRNA level of KLC2 and that of HuR. The expression of KLC2 mRNA and protein in lung cancer cells was significantly reduced when downregulating HuR. Interestingly, the overexpression of KLC2 could also significantly decrease the expression of HuR. Conclusions: The above results indicated that HuR could upregulate the expression of KLC2, which might decrease the phosphorylation of p53 and thereby weakened the radio-sensitivity of NSCLC cells. KLC2 could also positively regulate the expression of HuR as a positive feedback. Support: 81572279, 2016J004, LC2016PY016, 2018CR033
Case 49-1989
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Charles J. Homcy, James F. Southern
Journal: New England Journal of Medicine (1989)

Case Records of the Massachusetts General Hospital from The New England Journal of Medicine — Case 49-1989 — A 71-Year-Old Man with Thrombocytopenia and Hypotension after Resection of a Colonic Carcinoma
Reply to Zeynep G. Gul, Alberto Martini, and Carl A. Olsson's Letter to the Editor re: Jacob A. Burns, Adam B. Weiner, William J. Catalona, et al. Inflammatory Bowel Disease and the Risk of Prostate Cancer. Eur Urol 2019;75:846–52
Authors: Jacob A. Burns, Adam B. Weiner, Shilajit Kundu
Journal: European Urology (2019)
Severe and malignant hypertension are common in primary atypical hemolytic uremic syndrome
Authors: Teresa Cavero, Emilia Arjona, Karina Soto, Fernando Caravaca-Fontán, Cristina Rabasco, Luis Bravo, Francisco de la Cerda, Nadia Martín, Miquel Blasco, Ana Ávila, Ana Huerta, Virginia Cabello, Ana Jarque, Concepción Alcázar, Xavier Fulladosa, Javier Carbayo, Sara Anaya, Carmen Cobelo, Natalia Ramos, Elena Iglesias, José Baltar, Rocío Martínez-Gallardo, Lourdes Pérez, Enrique Morales, Roberto González, Manuel Macía, Juliana Draibe, Luis Pallardó, Luis F. Quintana, Mario Espinosa, Xoana Barros, Fernando Pereira, Mercedes Cao, Juan Antonio Moreno, Santiago Rodríguez de Córdoba, Manuel Praga
Journal: Kidney International (2019)
A point-of-care neutrophil elastase activity assay identifies bronchiectasis severity, airway infection and risk of exacerbation
Authors: Amelia Shoemark, Erin Cant, Luis Carreto, Alexandria Smith, Martina Oriano, Holly R. Keir, Lidia Perea, Elisabet Canto, Leonardo Terranova, Silvia Vidal, Kelly Moffitt, Stefano Aliberti, Oriol Sibila, James D. Chalmers
Journal: European Respiratory Journal (2019)

Introduction Neutrophil elastase activity in sputum can identify patients at high risk of airway infection and exacerbations in bronchiectasis. Application of this biomarker in clinical practice is limited, because no point-of-care test is available. We tested whether a novel semi-quantitative lateral flow device (neutrophil elastase airway test stick – NEATstik®) can stratify bronchiectasis patients according to severity, airway infection and exacerbation risk. Methods Sputum samples from 124 patients with stable bronchiectasis enrolled in the UK and Spain were tested using the NEATstik®, which scores neutrophil elastase concentration from 0 (&lt;8 µg·mL −1 elastase activity) to 10 (maximum detectable neutrophil elastase activity). High neutrophil elastase activity was regarded as a NEATstik® grade &gt;6. Severity of disease, airway infection from sputum culture and exacerbations over the 12 months were recorded. An independent validation was conducted in 50 patients from Milan, Italy. Measurements and main results Patients had a median age of 69 years and forced expiratory volume in 1 s (FEV 1 ) 69%. High neutrophil elastase activity was associated with worse bronchiectasis severity using the bronchiectasis severity index (p=0.0007) and FEV 1 (p=0.02). A high NEATstik® grade was associated with a significant increase in exacerbation frequency, incident rate ratio 2.75 (95% CI 1.63–4.64, p&lt;0.001). The median time to next exacerbation for patients with a NEATstik® grade &gt;6 was 103 days compared to 278 days. The hazard ratio was 2.59 (95% CI 1.71–3.94, p&lt;0.001). Results were confirmed in the independent validation cohort. Conclusions A novel lateral flow device provides assessment of neutrophil elastase activity from sputum in minutes and identifies patients at increasing risk of airway infection and future exacerbations.
The association between gut microbiome and anthropometric measurements in Bangladesh
Authors: Gwendolyn Osborne, Fen Wu, Liying Yang, Dervla Kelly, Jiyuan Hu, Huilin Li, Farzana Jasmine, Muhammad G Kibriya, Faruque Parvez, Ishrat Shaheen, Golam Sarwar, Alauddin Ahmed, Mahbub Eunus, Tariqul Islam, Zhiheng Pei, Habibul Ahsan, Yu Chen
Journal: Gut Microbes (2019)

Our objective was to investigate the relationship between the gut microbiota and anthropometric measurements among 248 participants from the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh. Our cohort represents a unique population that allows for the investigation of the gut microbiota and anthropometric measurements in lean individuals. We measured height, weight, arm, thigh, hip, and waist circumferences, and collected fecal samples. Microbial DNA was extracted from the stool samples and sequenced by 16S rRNA gene sequencing. We examined associations between relative abundance of individual bacterial taxa from phylum to genus levels and anthropometric measurements. We found that higher BMI, mid-upper arm circumference, waist circumference, and waist-to-hip ratio were associated with a lower alpha diversity of fecal bacteria. Relative abundance of the genus Oscillospira and the family S24-7 were inversely related to all measurements after correction for multiple testing. Relative abundance of genus Acidaminococcus and family Ruminococcaceae were also associated with several measurements. The positive associations of the genus Acidaminococcus with BMI, as well as waist and hip circumferences, were stronger in women than in men. Our data in this lean Bangladeshi population found a correlation between Oscillospira and leanness, as measured using multiple anthropometric measures.
Patient (pt) characteristics, treatment patterns, outcomes and prognostic factors in plasmacytoid urothelial carcinoma (PUC).
Authors: Leonidas Nikolaos Diamantopoulos, Ali Raza Khaki, Funda Vakar-Lopez, Maria S. Tretiakova, John L. Gore, George R Schade, Sarah P. Psutka, Andrew Caleb Hsieh, John Kyung Lee, Todd Yezefski, Michael Thomas Schweizer, Heather H. Cheng, Evan Y. Yu, Petros Grivas, Robert B. Montgomery, Jonathan L. Wright
Journal: Journal of Clinical Oncology (2019)

e16007 Background: PUC is uncommon and highly aggressive, with limited data on treatment patterns, outcomes and prognostic factors. We hypothesized that PUC is associated with clinical under-staging, poor outcomes and lack of chemotherapy (CT) response. Methods: We conducted a retrospective review of pts with UC and plasmacytoid component (PUC), seen in our institution (2000 - 2018). Demographic and clinicopathologic data, treatment modalities, pathologic complete/partial response (pCR, pPR) to neoadjuvant CT (NAC), and overall survival (OS) from diagnosis and surgery (Sx) were captured. T-test, chi-square, and Cox-regression were used to explore potential prognostic associations. OS was estimated with KM method. Results: We identified 63 consecutive pts (51 men) with available data for analysis. Median age at diagnosis was 67 (44-89). During initial diagnostic workup, 32 (51%) pts had extravesical disease (cT3:24, cT4:8) and 23 (36.5%) hydronephrosis at imaging. Overall, 39 (62%) pts underwent Sx with curative intent, 25 (39.6%) were pre-treated with cisplatin-based NAC; adjuvant CT was given to 15 (24%). The remaining pts pursued bladder-sparing and/or palliative approaches. At time of Sx, 17/39 (43.6%) pts had pathologic upstaging, 10 (25.6%) had positive margins and 19 (48.7%) pN+ stage. In the NAC pt subset (25 pts), 5 (20%) had progression on scans, 19 (76%) had Sx; 2 pts had pCR (10.5%), 1 had pPR, 6 (31.5%) had pathologic upstaging. In the entire cohort, median follow-up was 8 months. Median OS was 20.7 months from diagnosis and 23.6 months from Sx. NAC was not significantly associated with longer OS (from Sx) (HR 1.53, 95%CI 0.16-15, p = 0.715) and the same was true for adjuvant CT (HR 0.64, 95%CI 0.1-4, p = 0.630). 15/39 pts recurred after Sx (38.4%), with 9/15 (60%) having peritoneal/retroperitoneal involvement. Conclusions: PUC frequently presented with advanced stage at diagnosis and demonstrated poor NAC response, frequent upstaging, positive margins and pN+ stage at Sx. More than half of patients who recurred after Sx, presented with (retro)peritoneal disease. Studies evaluating molecular biomarkers and drivers in PUC, and prospective clinical trials are being pursued.
Implementation of the VA Symptom Assessment Scale (VSAS): Five-year experience.
Authors: Daphne Ruth Friedman, Vikas Patil, Kelli Marie Rasmussen, Brian C Sauer, Michael J. Kelley, Ahmad Sami Halwani
Journal: Journal of Clinical Oncology (2019)

e23120 Background: Cancer patients experience symptoms which may precede diagnosis, occur during therapy, and persist into survivorship. Symptom assessments and patient reported outcomes have been shown to improve quality of life and extend survival in cancer patients. The Veterans Administration Symptom Assessment Scale (VSAS) is a clinical tool to document cancer-related symptoms. Here, we report VSAS adoption in five Veterans Health Administration (VHA) hematology-oncology sites during a five-year period. Methods: Data was collected from the Corporate Data Warehouse (CDW): VSAS data, date of birth, gender, race, ethnicity, vital status, year of cancer diagnosis, ICD-O-3, VHA facility, and clinic stop codes. Descriptive analyses of patient demographics, disease characteristics, and VSAS utilization was performed. VSAS is comprised of 13 symptoms, rated on a 0 to 10 scale. A VSAS visit was defined as the date the VSAS was administered to a patient. Results: From January 2013 through June 2018, there were 41,917 instances of VSAS administered to 9,409 unique patients at five VHA facilities: 8,512 (90.5%) were male; 5,241 (56%) were non-Hispanic White, 3,743 (40%) were Black, and 297 (3%) were other racial categories or not available. The median age at the first VSAS visit was 67 years. In patients whose oncologic diagnosis was recorded by a cancer registrar (4,536), the most common diagnoses were prostate cancer, lung cancer (all histologies), colon cancer, and multiple myeloma. The number of VSAS administrations increased annually, from 866 in 2013 to 12,775 in 2017, which may be attributed to increased adoption of VSAS across and within VHA facilities. Individual patients completed the VSAS 1-57 times (median 2). At the five VHA facilities utilizing VSAS in 2017, VSAS was administered at 56% of hematology-oncology clinic visits. Conclusions: VSAS is a tool to measure and document patient symptom burden, and has been successfully adopted in the last five years at select VHA facilities. Expanded use of VSAS throughout the VHA is an important step in improving the quality of life and extending survival of veterans with cancer and blood disorders.
Clinicopathological significance and prognostic value of intratumoral and peritumoral lymphocytes in endometrial cancer patients.
Authors: Martin Ore-Arce, Carmen Illueca Ballester, Raquel Lopez-Reig, Monica Parra-Grande, Ignacio Romero, Jose Antonio Lopez-Guerrero, Andres Poveda
Journal: Journal of Clinical Oncology (2019)

e17116 Background: The characterization and prognostic relevance of immune cells in the tumor microenvironment of endometrial cancer (EC) remain unknown. Our aims are to analyze the presence of tumor infiltrating lymphocytes (TIL) and peritumoral lymphocytes (PTL) in tumoral tissue of patients with EC, and to identify the correlation between TILs and PTLs subsets with clinicopathologic features and its prognostic value Methods: CD3, CD4, CD8, CD20, and FOXP-3 was determined by immunohistochemestry (IHQ). A 4-point score was defined based on TIL counts per highpowered field: (negative, low, moderate, and high). We used 10% positive peritumoral lymphocytes as a low-high cutoff value. POLE mutation was identified by Sanger sequencing of the exonuclease domain (exons 9-14). Analysis of mismatch repair expression and TP53 gene mutation status were assessed. Results from IHQ and analysis mutation were correlated with clinicopathological parameters and survival. Results: We recovered tumor samples from 68 FIGO stage I–IV EC patients. POLE mutations were identified in 5 of 44 (11.4%) EC analyzed. Microsatellite instability (MSI) and TP53 mutation were found in 45% and 25 % of cases respectively. According PTL, MSI tumors were significantly associated with low CD4+ (p = 0.01). High CD8+ was significantly associated with endometrioid grade 1-2 tumors (p = 0.04). Low FOXP3+ was significantly associated with endometrioid grade 1-2 (p = 0.02), MSS tumors (p &lt; 0.01), FIGO stage I-II (p &lt; 0.01), POLE WT (p &lt; 0.01), TP53 WT (p &lt; 0.01), and negative lymphovascular space invasion (p &lt; 0.01). Negative CD20+ TIL was associated with endometrioid grade 1-2 tumors (p &lt; 0.01) and ≥50% myometrial invasion (p = 0.03). Moderate CD8+ TIL was associated with lower tumor stage (p = 0.01). High CD8+ TIL was associated with better 5-year overall survival (OS) rate (high: 100 % vs. low: 53%; p = 0.003). No significant association was observed between POLE status, TP53 status, MMR expression and survival. Conclusions: Regulatory and cytotoxic T cells subsets differs in EC patients. High CD8+ TILs was significantly associated with better 5-year OS.