tbuckley/cabot-search huggingface dataset:
Scaling Up Testing for Human Immunodeficiency Virus Infection Among Contacts of Index Patients — 20 Countries, 2016–2018
Authors: Arielle Lasry, Amy Medley, Stephanie Behel, Mohammed I. Mujawar, Meagan Cain, Shane T. Diekman, Jacqueline Rurangirwa, Eduardo Valverde, Robert Nelson, Simon Agolory, Achamyeleh Alebachew, Andrew F. Auld, Shirish Balachandra, Sudhir Bunga, Thato Chidarikire, Vinh Q. Dao, Jacob Dee, L.E. Nicole Doumatey, Edington Dzinotyiweyi, Eric J. Dziuban, K. Alexandre Ekra, William B. Fuller, Amy Herman-Roloff, Nely B. Honwana, Nompumelelo Khanyile, Evelyn J. Kim, S. Francois Kitenge, Romel S. Lacson, Peter Loeto, Samuel S. Malamba, André H. Mbayiha, Alemayehu Mekonnen, Mirtie G. Meselu, Leigh Ann Miller, Goabaone P. Mogomotsi, Mary K. Mugambi, Lloyd Mulenga, Jane W. Mwangi, Jonathan Mwangi, Amassanh A. Nicoué, Mtemwa K. Nyangulu, Ismelda C. Pietersen, Puleng Ramphalla, Chanie Temesgen, Alfredo E. Vergara, Stanley Wei
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

In 2017, the Joint United Nations Programme on HIV/AIDS (UNAIDS) estimated that worldwide, 36.9 million persons were living with human immunodeficiency virus (HIV) infection, the virus infection that causes acquired immunodeficiency syndrome (AIDS). Among persons with HIV infection, approximately 75% were aware of their HIV status, leaving 9.4 million persons with undiagnosed infection (1). Index testing, also known as partner notification or contact tracing, is an effective case-finding strategy that targets the exposed contacts of HIV-positive persons for HIV testing services. This report summarizes data from HIV tests using index testing in 20 countries supported by CDC through the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) during October 1, 2016-March 31, 2018. During this 18-month period, 1,700,998 HIV tests with 99,201 (5.8%) positive results were reported using index testing. The positivity rate for index testing was 9.8% among persons aged ≥15 years and 1.5% among persons aged <15 years. During the reporting period, HIV positivity increased 64% among persons aged ≥15 years (from 7.6% to 12.5%) and 67% among persons aged <15 years (from 1.2% to 2.0%). Expanding index testing services could help increase the number of persons with HIV infection who know their status, are initiated onto antiretroviral treatment, and consequently reduce the number of persons who can transmit the virus.
Abstract 2930: Dantrolene, A Therapeutic Agent For Malignant Hyperthermia, Inhibits Catecholaminergic Polymorphic Ventricular Tachycardia: Insights From A RyR2 R2474S/+ Knock-in Mouse Model
Authors: Shigeki Kobayashi, Masafumi Yano, Hitoshi Uchinoumi, Xiaojuan Xu, Makoto Ohno, Hiroki Tateishi, Takeshi Yamamoto, Masunori Matsuzaki
Journal: Circulation (2007)

The N-terminal (1– 600) and central (2000 –2500) domains of the ryanodine receptor (RyR), harbor many mutations associated with malignant hyperthermia (MH), catecholaminergic polymorphic ventricula...
Universal endometrial cancer tumor typing: How much has immunohistochemistry, microsatellite instability, and MLH1 methylation improved the diagnosis of Lynch syndrome across the population?
Authors: Ryan Kahn, Sushmita Gordhandas, Brandon Paul Maddy, Becky Baltich Nelson, Gulce Askin, Paul J. Christos, Thomas A. Caputo, Eloise Chapman-Davis, Kevin Holcomb, Melissa Kristen Frey
Journal: Journal of Clinical Oncology (2019)

e17119 Background: Universal tumor testing for defective DNA mismatch repair (MMR) is recommended for all women diagnosed with endometrial cancer (EC) to identify those with underlying Lynch syndrome (LS). However, since its implementation in 2013, the effectiveness of this screening method on identifying individuals with LS across the population has not been well studied. The aim of this study was to evaluate outcomes of MMR immunohistochemistry (IHC), MLH1 methylation, and microsatellite instability (MSI) analysis among EC patients. Methods: We conducted a complete systematic search of online databases PubMed, Embase, Medline, and Cochrane Library between 1990-2018. A DerSimonian–Laird random-effects model meta-analysis was utilized to estimate the weighted prevalence of LS diagnoses. Results: The comprehensive search produced 3,427 publications. 29 peer-review studies met the inclusion criteria. 6,649 EC patients were identified, 206 (3%) were confirmed to have LS following positive universal tumor molecular screening.5,917 patients underwent tumor IHC, 28% had abnormal staining. 3,140 patients underwent MSI analysis, 31% had MSI instability. Among EC patients with deficient IHC staining or positive MSI analysis, the weighted prevalence of LS was 15% and 19% respectively. 1159 patients exhibited loss of MLH1 staining, 143 (13.7%) were found to be MLH1 methylation negative, 32 demonstrated a germline MLH1 mutation (2.8% of all MLH1 absent staining; 22.4% of all MLH1 methylation negative). 43% of EC patients diagnosed with LS via tumor typing would have been missed by family history-based screening alone. Conclusions: Despite widespread implementation of universal tumor testing in EC, data regarding results have previously been limited. For the first time, this study provides large-scale predictive values that will help practitioners evaluate abnormal results in the context of LS and aid in patient counseling. [Table: see text]
Mean Nocturnal Baseline Impedance Correlates With Symptom Outcome When Acid Exposure Time Is Inconclusive on Esophageal Reflux Monitoring
Authors: Arvind Rengarajan, Edoardo Savarino, Marco Della Coletta, Matteo Ghisa, Amit Patel, C. Prakash Gyawali
Journal: Clinical Gastroenterology and Hepatology (2019)
Office-Related COPD
Authors: Bridget Kuehn
Journal: JAMA (2019)

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Sensitivity of treatment-free survival (TFS), a novel outcome, to subgroup analyses of patients (pts) with advanced melanoma (MEL) treated with immune checkpoint inhibitors (ICI).
Authors: Charlene Mantia, Lillian Werner, Sumati Rao, Corey Ritchings, Ahmad A. Tarhini, Michael B. Atkins, David F. McDermott, Meredith M. Regan
Journal: Journal of Clinical Oncology (2019)

9550 Background: Many pts treated with ICIs can discontinue treatment and experience ongoing disease control and toxicity. We previously proposed a novel outcome, TFS, as the time between ICI therapy cessation and subsequent therapy initiation or death, with integrated graphical analysis to better characterize the unique effects of ICIs (ASCO 2018 #9531). In the CheckMate 067 and 069 trials of ipilimumab (IPI) and nivolumab (NIVO) alone or in combination (NIVO+IPI) in pts with MEL, the 36-month restricted mean TFS was 8.7, 4.6 and 11.1 mo, respectively. We explored the sensitivity of TFS to be informative of overall survival (OS) differences through subgroup analysis. Methods: Data from MEL pts in the CheckMate 067 and 069 trials were pooled and analyzed. TFS was defined as the area between the Kaplan-Meier curves for two endpoints, from randomization: (A) time to ICI therapy cessation; and (B) time to subsequent therapy initiation or death. TFS was estimated by restricted mean survival time until 36 mo since randomization. Differences in restricted mean TFS between subgroups of pts (such as PD-L1 status, lactate dehydrogenase [LDH], performance status [PS], gender) were calculated with bootstrapped 95% CIs. OS from randomization was also estimated. Results: Among 407 pts treated with NIVO+IPI, restricted mean TFS ranged from 8-13 mo across subgroups (Table). Subgroup differences in mean TFS were larger for prognostic factors LDH and PS and smaller in non-prognostic PD-L1 status and gender subgroups. Conclusions: Clinically meaningful TFS was seen across all subgroups. TFS was sensitive to prognostic subgroup differences. These results provide further support for TFS as a relevant clinical endpoint. Additional subgroups and comparisons with single agent NIVO and IPI arms will be presented at the meeting. [Table: see text]
XENERA-1: A phase II trial of xentuzumab (Xe) in combination with everolimus (Ev) and exemestane (Ex) in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) and non-visceral involvement.
Authors: Peter Schmid, Hope S. Rugo, Javier Cortes, Chin-Lun Huang, Kate Crossley, Dan Massey, Howard A. Burris
Journal: Journal of Clinical Oncology (2019)

TPS1103 Background: The mTOR inhibitor Ev, combined with Ex, is a mainstay in the treatment of post-menopausal women with advanced HR+/HER2- BC. However, the activity of Ev is limited by counter-regulatory feedback mechanisms in cancer cells, involving reactivation of insulin-like growth factor (IGF)/mTOR survival signaling. Combining Ev with the humanized IGF-1 and IGF-2 ligand-blocking antibody Xe abrogates this feedback, thus intensifying inhibition of tumor growth; this leads to a pronounced effect in patients with non-visceral (e.g., bone and lymph node) metastases. The phase II XENERA-1 trial evaluates the combination of Xe with Ev and Ex in post-menopausal women with HR+/HER2- BC. Methods: XENERA-1 (NCT03659136) is a double-blind, placebo-controlled, randomized study to assess the efficacy and safety of Xe in combination with Ev and Ex, in post-menopausal women with HR+/HER2- locally advanced/mBC and non-visceral disease. The population comprises post-menopausal mBC patients who have progressed on ≤1 previous line of a non-steroidal aromatase inhibitor, with or without a CDK 4/6 inhibitor, who may have received fulvestrant. Other inclusion criteria are: an Eastern Cooperative Oncology Group Performance Status of 0 or 1; adequate organ function; and non-visceral disease (absence of brain, liver, lung, peritoneal or pleural metastases). Patients are randomized (1:1) to receive Xe (1000 mg/week, iv) or placebo (weekly, iv), in combination with Ev (10 mg/day) and Ex (25 mg/day). Treatment will continue until disease progression, unacceptable toxicity or other reasons. The primary endpoint is progression-free survival according to RECIST 1.1 criteria, by independent review. Secondary endpoints are: overall survival; disease control; duration of disease control; objective response; and time to progression of pain/intensification of palliation. Safety and pharmacokinetic endpoints, and exploratory biomarkers will also be evaluated. The first patient was enrolled in January 2019; target enrollment is 80 patients in 12 countries. Clinical trial information: NCT03659136.
Neoadjuvant chemotherapy in advanced epithelial ovarian cancer: An institutional experience.
Authors: Kavitha Jain, Arun Chaturvedi, Sanjeev Misra, Vijay Kumar, Sameer Gupta, Manikandan Lakshmanan, Sudeep Garg
Journal: Journal of Clinical Oncology (2019)

e17044 Background: Epithelial ovarian cancer is the second most common gynecological malignancy among Indian women. Primary debulking surgery remains the standard of care in advanced operable ovarian cancer patients, but is associated with morbidity. Neoadjuvant chemotherapy followed by delayed primary cytoreductive surgery maybe a better treatment strategy in advanced ovarian cancer. We present our experience of neoadjuvant chemotherapy in advanced ovarian cancer with special emphasis on treatment outcomes. Methods: A retrospective analysis of advanced epithelial ovarian carcinoma (Stage IIIc and IV) patients treated at the Department of Surgical Oncology at King George’s Medical University, Lucknow between 2012 and 2017 was done. Results: A total of 151 patients with advanced ovarian carcinoma were treated during this period. Median age at diagnosis was 46 years. Among these patients, 137 underwent surgery, of which 59.1% were optimally cytoreduced. Papillary serous adenocarcinoma was the most common histological subtype (76.1%). Recurrence was seen in 79.3% patients, with a median time to recurrence 17 months (range 6.5 - 39 months). They were managed with second line chemotherapy and surgery. Median overall survival in this study for optimally cytoreduced stage III patients was 39 months and 18 months for optimally cytoreduced stage IV patients. Median progression free survival for stage III was 12 months and stage IV was 6 months. Conclusions: Neoadjuvant chemotherapy facilitates surgery in advanced ovarian cancer and helps in assessing chemotherapy responsiveness. It provides an opportunity to modify systemic treatment if there no response to therapy or disease progression.
Randomized, double-blind, phase 3 trial of first-line pembrolizumab + platinum doublet chemotherapy (chemo) ± lenvatinib in patients (pts) with metastatic nonsquamous non–small-cell lung cancer (NSCLC): LEAP-006.
Authors: Rina Hui, Makoto Nishio, Martin Reck, Delvys Rodriguez-Abreu, Tamer M. Fouad, Doreen Flaim, Lina Yin, Thao Dang, Roy S. Herbst
Journal: Journal of Clinical Oncology (2019)

TPS9118 Background: Lenvatinib (multiple-receptor tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1–3, fibroblast growth factor receptors 1–4, platelet-derived growth factor receptors α, c-kit, and RET) has antitumor activity in combination with pembrolizumab (anti–PD-1 inhibitor) or with chemo in advanced NSCLC. LEAP-006 (NCT03829319) evaluates first-line lenvatinib with pembrolizumab + chemo for metastatic nonsquamous NSCLC. Methods: This randomized, double-blind, 2-part, phase 3 study enrolls pts ≥18 years with histologically/cytologically confirmed metastatic, nonsquamous, treatment-naive NSCLC without sensitizing genetic aberrations. Pts receive lenvatinib 8 mg daily or matching placebo + pembrolizumab 200 mg + pemetrexed 500 mg/m 2 + carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m 2 Q3W (4 cycles) followed by maintenance pembrolizumab (35 cycles) + lenvatinib/placebo + pemetrexed (no limit). In part 1 (open-label safety run-in), ~12 pts receive lenvatinib + pembrolizumab + chemo (n ≥6 in each chemo arm). If &lt; 3 dose-limiting toxicities (DLTs; select prespecified AEs) occur in 6 pts in each arm in cycle 1, part 2 will begin enrolling. If ≥3 DLTs occur in 6 pts in each arm, enrollment in part 1 may continue with advisement by the study oversight committee. In part 2, pts are randomized 1:1 to lenvatinib or placebo + pembrolizumab + chemo, stratified by PD-L1 tumor proportion score ( &lt; 50%/≥50%), geographic site (East Asian/other), and ECOG PS (0/1). Tumor imaging occurs at baseline and Q6W until wk 18; then Q9W until wk 54; then Q12W until verified PD, initiation of new cancer therapy, study withdrawal, or death. AEs are graded by NCI CTCAE v4.0. The primary endpoint in part 1 is safety. The primary endpoints in part 2 are PFS (RECIST v1.1 by BICR) and OS, analyzed by Kaplan-Meier method and stratified log-rank test. Secondary endpoints in part 2 are ORR and DOR (RECIST v1.1 by BICR), safety, and quality of life. Enrollment into part 1 will begin in March 2019. For part 2, approximately 714 pts will enroll in 160 sites in 17 countries. Clinical trial information: NCT03829319.
NRG GY012: A randomized phase II study comparing single-agent olaparib, single agent cediranib, and the combination of cediranib/olaparib in women with recurrent, persistent or metastatic endometrial cancer.
Authors: Helen Mackay, Bj Rimel, David Bender
Journal: Journal of Clinical Oncology (2019)

TPS5609 Background: The Cancer Genome Atlas and others identified genomic events suggesting that endometrial cancer (EC) should be susceptible to DNA repair inhibition. Mutations in classical homologous recombination genes occur in 22% of EC, ARID1A 41% and PTEN loss occurs in 55% of EC. Data from pre-clinical models suggest poly ADP-ribose polymerase (PARP) inhibitors alone or in combination may be an effective therapeutic strategy in EC (Hansen 2016). Combinations of angiogenic inhibitors and PARP inhibitors have demonstrated synergistic effects and have been well tolerated in other tumor types. This study has been designed to compare 2 experimental arms exploring DNA repair inhibition versus cediranib alone which has previously shown promising activity in GOG 229J (Bender 2015). Methods: This is a multicenter randomized three arm study for patients with recurrent, metastatic or persistent EC. Patients are randomized 1:1:1 to cediranib PO 30 mg OD; olaparib 300 mg PO BID or the combination of cediranib 20 mg PO OD with olaparib 300 mg PO BID. All treatment cycles are 28 days. Primary endpoint is progression free survival (PFS). The study is powered to detect an increase in median PFS from 3.6 (based on cediranib alone) to 7.2 months with 90% power, using a one-sided test with α = 0.05 per comparison. Forty patients will be enrolled per arm, with an interim futility analysis planned. Eligibility includes endometroid, serous, and mixed histology EC; at least 1 prior line of chemotherapy (no more than 2 lines for metastatic disease), prior endocrine or immunotherapy is allowed; ECOG PS ≤ 2; adequate hepatic, bone marrow, coagulation and renal function. Archival tumor tissue and blood samples are being collected for translational studies. The study is open across the NRG network; 24 patients are enrolled to date . Amendments are planned to include additional arms investigating combination strategies targeting DNA repair and angiogenesis. Clinical trial information: 03660826.
Consolidation with Bortezomib, Lenalidomide and Dexamethasone Upgrades the Complete Remission Rate after Autologous Hematopoietic Cell Transplantation in Patients with Multiple Myeloma
Authors: Iman Aboudalle, Basel Haffar, Radwan Massoud, Ali Bazarbachi, Jean Elcheikh
Journal: Blood (2017)
Safety and efficacy of repeated intra-hepatic artery and intravenous infusion of ET140202, a novel anti-AFP/MHC complex T-cell, in advanced hepatocellular carcinoma.
Authors: Min Peng, Na Li, Chelsea Chang, Yi Yao, Bin Xu, Yu Zhang, Hong Liu, Bijan Nejadnik, Qibin Song, Cheng Liu
Journal: Journal of Clinical Oncology (2019)

e14013 Background: Despite the success in hematological malignancies, immunotherapy of solid tumors using redirected T cells such as CAR-T remains challenging due to the lack of a unique tumor antigen, inefficient trafficking of CAR T cells to tumor sites and the presence of immunosuppressive tumor microenvironment. ET140202 is a novel T-cell platform that targets AFP/MHC complex with GPC3-guided co-stimulation aiming to improve the specificity and efficacy. Herein we report a case study of ET140202 for a subject with AFP+ recurrent HCC previous treated with surgery and 2 TACE therapies. Baseline imaging showed multiple nodules on segment 7 of right lobe with enlarged lymph nodes in hepatic hilar region. Methods: From 9/25/18 to 1/29/19 the subject first received 2 intra-hepatic artery infusions (i.a.) of ET140202 T cells at the dose of 3×10 6 cells/kg followed by 4 i.v. infusions at the dose of 6×10 6 cells/kg. No lymphodepleting chemotherapy was given prior to T-cell infusion. Vital signs, blood cell count, and blood chemistry were monitored on Days 1, 3, 7, and 14. Clinical responses were assessed at Month 1, 2, 3, 4, 6, 9, 12 and 24. Results: Vital signs are normal after each infusion. No treatment-related Grade 2 or higher AEs observed. Grade 1 events that were possibly attributable to therapy included transient elevation of AST and bilirubin 58 days post the 1 st infusion. Both events resolved in 4 days without treatment. The subject did not experience any clinical signs of CRS or neurotoxicity. Month 1, 2, and 3 follow-ups showed that the number and size of the liver nodules slowly increased overtime. Month 4 follow-up showed that the size of liver nodules decreased more than 50% of baseline and resulted in PR based on RECIST criteria. The AFP level elevated in the subject after infusion and reached the peak of 2097 ng/mL 55 days post 1 st infusion, gradually dropped to 905 ng/mL on day 67, elevated to the 2 nd peak of 2660 ng/mL and gradually decreased to 1235 ng/mL at the last follow-up on day 130. Conclusions: Repeated infusion of ET140202 T cells via i.a. and i.v. routes is safe and shows early sign of efficacy 4 months post initiation of the treatment in AFP+/HLA-A2+ HCC subject.
Correlates of overall survival (OS) in metastatic uveal melanoma (mUM) and a randomized trial of cabozantinib (cabo) versus chemotherapy (chemo).
Authors: Daniel Olson, Riyue Bao, Jacob B Allred, Carrie Strand, Yuanyuan Zha, Timothy C. Carll, Brian Labadie, Bruno R. Bastos, Marcus O. Butler, Pamela N. Munster, Gary K. Schwartz, Jason J. Luke
Journal: Journal of Clinical Oncology (2019)

9506 Background: Survival is poor in mUM and treatment options are limited. MET kinase is over-expressed on UM and the MET inhibitor cabo showed activity in an early trial. Methods: A091201 was a 2:1 randomized phase II study testing progression-free survival (PFS) of cabo (60 mg daily) vs chemo (DTIC/TMZ). We studied baseline metastatic tumor samples (n = 19; 1 lung, 18 liver) by whole exome sequencing (WES) and RNAseq. We correlated data with OS and made comparisons for mUM vs. primary tumors from TCGA (n = 80). Results: 46 patients were accrued with 96% and 63% with liver metastases and elevated LDH, respectively. Toxicities were similar to prior reports of cabo and chemo. The trial stopped at interim analysis due to no difference in PFS (p = 0.964; HR = 0.99) or OS (p = 0.580; HR = 1.21). WES showed tumor mutational burden of 46±4 (mean±SEM) and did not separate OS at 1 year (p = 0.14, two-sided Wilcoxon rank sum test) in A091201. Recurrent known mutations included GNAQ/11, SF3B1, BAP1; novel mutations included GOLGA6L10, PKD1L3, and FAM228B. Gene expression signatures differed significantly between A091201 and TCGA cohorts including MET signaling (p = 7.87e-22), T cell-inflamed (p = 0.004), homologous recombination deficiency (p = 0.004), proliferation (p = 0.009) and hypoxia (p = 5.2e-10) (two-sided Student’s t-test). Tumor immune cell enrichment analysis revealed significant differences with lower M1:M2 macrophage (p = 1.2e-10) and higher T regs (p = 6.0E-21) in mUM relative to TCGA (two-sided Wilcoxon rank sum test). Epithelial-mesenchymal transition gene expression signature was significantly associated with worse OS in A091201 (p = 0.02) with angiogenesis signature trending toward significance (p = 0.21) (log-rank test). OS separated by differentially expressed genes with OS ≤ 1 year associating with increased expression of the angiogenesis/immune-associated molecule neuropilin 1. Conclusions: These results provide insights between primary and mUM indicating potential novel therapeutic approaches. Support: U10CA180821, U10CA180882, T32GM007019, Exelixis. https://acknowledgments.alliancefound.org ; Clinical trial information: NCT01835145.