tbuckley/cabot-search huggingface dataset:
Abstract 18537: Aortic Valve Repair Improves Mid-term Outcomes versus Replacement for Aortic Insufficiency: A Propensity Matched Study
Authors: Jessica Kapralik, Kathryn McLean, Vincent Chan, Benjamin Sohmer, Marc Ruel, Thierry Mesana, Munir Boodhwani
Journal: Circulation (2015)

Objectives: Aortic valve (AV) repair has emerged as a feasible and attractive alternative to AV replacement in patients with aortic insufficiency (AI). However, little data exists comparing outcomes following repair versus replacement. We performed a single-center comparative study in patients undergoing AV repair or replacement for AI. Methods: Patients undergoing AV replacement (n=263) or repair (n=153) for AI between 2000 and 2014 were included. Patients ineligible for both repair and replacement surgeries and patients lacking perioperative data were excluded (n=155). To adjust for baseline differences, non-parsimonious logistic regression models were used to generate propensity scores. A 1:1 greedy matching algorithm was used to create 70 propensity matched pairs. Peri-operative and long-term clinical and echocardiographic outcomes were assessed, focusing on survival and valve-related events, and analyzed using Kaplan-Meier techniques. Primary endpoints included late mortality, myocardial infarction, stroke, and AV reoperation. Total follow-up exceeded 1100 patient-years in the entire cohort and 800 patient-years in the matched cohort. Results: The matched pairs were similar in baseline attributes including age (57±14 vs. 56±15, p=0.75), sex (Female: 17% vs. 25%, p=0.22), incidence of LV dysfunction (27% vs. 24%, p=0.38), severe AI (67% vs. 74%, p=0.42) and presence of cardiac risk factors. Replacements consisted of 53% mechanical, 41% bioprosthetic, and 6% homograft valves. Repairs included 61% valve-sparing root replacements, 70% cusp repairs with 43% bicuspid AVs. In hospital mortality (1% vs. 4%, repair vs. replacement, p=0.62) and perioperative outcomes were similar between groups. Four-year survival was 97±2% and 87±4% in repair vs. replacement groups (p=0.11). A total of 5 vs. 17 valve-related events occurred in repair vs. replacement groups. Freedom from primary endpoints at 4 years was 97±2% and 82±8% in the repair vs. replacement groups (p=0.03). Conclusions: In a propensity matched cohort, AV repair for AI was associated with a mid-term reduction in death and serious valve related complications compared to AV replacement. AV repair should be considered, when technically feasible, as the preferred treatment of AI.
ECOG 1808: Randomized phase II trial of sunitinib with or without gemcitabine in advanced kidney cancer with sarcomatoid features.
Authors: Naomi B. Haas, Maneka Puligandla, David F. McDermott, Janice P. Dutcher, Judith Manola, Michael Pins, Michael Anthony Carducci, Jacqueline Vuky, Bradley Curtis Carthon, Elizabeth R. Plimack, Leonard Joseph Appleman, Henry C. Pitot, Timothy Kuzel, Robert S. DiPaola
Journal: Journal of Clinical Oncology (2016)

4511 Background: Patients (pts) with RCC with sarcomatoid (sarc) features have poorer outcomes than those with non-sarc RCC. Sarc RCC demonstrated a 15.4% response rate (RR) to doxorubicin + gemcitabine (G) in E8802. A phase I trial of combined sunitinib/gemcitabine (SG) suggests activity in RCC with sarc. We sought to evaluate the effectiveness of SG and sunitinib alone (S) in sarc RCC. Methods: Pts were randomized 1:1 to each arm using a two-stage design. RCC pts with any sarc change and ≤ 1 prior non-vascular endothelial growth factor tyrosine kinase inhibitor were stratified into prognostic groups: good (clear cell, < 20% sarc, PS 0), intermediate (20-50% sarc, PS 0), and poor (non-clear cell or > 50% sarc or PS 1). The primary endpoint was RR. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. For SG, the null RR was 15% and a 30% RR was of interest. For S alone, a 20% RR was of interest vs. a 5% null rate. Success is defined as 10 of 43 SG pts or 4 of 37 S pts. Accrual goals were 45 pts in the SG arm and 40 in the S arm. Results: Both arms met protocol criteria for continuing to stage 2 of accrual. 47 pts were randomized to SG and 40 to S alone. 3 pts withdrew before treatment, 1 of whom was ineligible. The analyzable set includes eligible treated pts registered before June 2015. RR, PFS and OS are shown in the table. The most common adverse events were anemia, nausea, fatigue, hypertension, and decreased neutrophil count. Grade ≥ 3 events were experienced by 29 in the SG arm and 17 in the S arm. Conclusions: This is the largest and first randomized trial for sarc RCC. The RR on S alone meets protocol criteria for success. For SG, we await results from recently enrolled pts (expected by the ASCO meeting). Though preliminary, the results suggest a role for the addition of chemotherapy in this difficult to treat subset of RCC. Clinical trial information: NCT01164228. SG S Randomized 47 40 Assessable as of 1/23/16 35 36 Response Rate 7/35 = 20.0% 4/36 = 11.1% 2-stage Exact 90% CI 10.1 – 34.9% 5.1 – 34.0% Median PFS 23 weeks 13 weeks 90% CI 13-25 weeks 12-25 weeks Median OS 41 weeks 33 weeks 90% CI 32-90 weeks 29-59 weeks Median cycles received 3 2 Good Prognosis 5 (14.3%) 7 (19.4%) Intermediate Prognosis 6 (17.1%) 7 (19.4%) Poor Prognosis 24 (68.6%) 22 (61.1%)
Differential expression proteins in lung adenocarcinoma with bone metastasis: Correlation of ALDH2 and ENO1 with prognosis.
Authors: Mengdi Yang, Jing Sun, Zhiyu Wang, Rui Zhang, YIfeng Gu, Hui Zhao
Journal: Journal of Clinical Oncology (2017)

e20534 Background: The prognosis of lung adenocarcinoma (LUAD) with bone metastases (BM) is still poor. It is increasingly demanded to find key proteins to solve the problem. Methods: First, we collected three groups of bone tissues: normal, osteosarcoma, and LUAD with BM from Shanghai Sixth People's Hospital. Each group had five patients. Two-dimensional gel electrophoresis (2D-E) was used to find proteins with significant differences, then Maldi-tof-tof mass spectrometry was used to identify the proteins. Second, immunohistochemical (IHC) was used to check the expression of proteins in 28 BM patients and 9 LUAD patients. Real-Time PCR (QPCR), western boltting (WB) were further used to check the expression of para-LUAD, LUAD and BM. Last, we downloaded RNA-seq and clinical datas from the Cancer Genome Atlas(TCGA) database to further verify differentially expressed genes using ‘DESeq’ package and explored their relationship with survival using ‘survival’ package in R. Kaplan-Meier survival plot and the hazard ratio and logrankp was calculated (www.kmplot.com/lung). Results: We got 26 matched proteins from 2D-E, then selected Aldehyde Dehydrogenase 2 Family (Mitochondrial) (ALDH2) and Enolase-1 (ENO1). In IHC analysis, strong-stained ALDH2 showed OR = 0.568 (95 % confidence interval [CI], 0.317-1.019), p= 0.036, strong-stained ENO1 OR = 1.929 (95% CI, 0.915-4.066), p= 0.023, were associated with bone metastastic incidences in LUAD with statistically significantly difference. QPCR, WB validated that ALDH2 had lowest expression in BM, followed by LUAD samples, and para-LUAD highest. However, ENO1 displayed the opposite tendency . In TCGA LUAD RNA-seq, ALDH2 had low expression ( p= 3.83E-12, log2Foldchange = 1.158), and ENO1 was up-regulated ( p= 0.0004, log2Foldchange = 1.210 ). ALDH2 is correlated with better survival (HR = 0.47, 95% CI (0.37-0.61), logrankP = 6.5E-10), while ENO1 was inversely associated with better prognosis (HR = 1.67,95% CI (1.32-2.12), logrankP = 1.9E-05) in K-M Plotter. Conclusions: In this study, we discovered new differential expression and prognosis related proteins, ALDH2 and ENO1, and they are worthy of further exploration into the underlying mechanism.
Risk of hematological malignancies in patients treated with x-rays for benign lesions in the locomotor system: A retrospective analysis at a single institution.
Authors: Rebecca Buecker, Ulrich Schafer
Journal: Journal of Clinical Oncology (2018)

e13568 Background: To investigate the rate of hematological malignancies, i.e. leukemia, non-Hodgkin’s lymphoma, Hodgkin’s disease and myeloma in patients after low dose x-rays Treatment. Methods: A cohort of 3017 such patients (mean age 67 years, range 20 - 97 years), treated from 1995 -2007 at the General Hospital of Lippe (northern Germany) was analyzed with regard to the risk of hematologic malignancies suspected of emanating from red bone marrow. Therapy was applied on a conventional radiotherapy treatment with 200 kV orthovoltage x-rays in single fraction of 1 Gy to a total dose of 6 Gy in 6 fractions. Depending on the treated region, the absorbed red marrow dose was determined to be almost zero (elbow, hand, knee, foot; n = 1839), intermediate (shoulder; n = 930), and high (mostly trochanteric bursa and hip, occasionally spine and sacroiliac joint; n = 248). The endpoints (hematological malignancies) were searched for by computer linkage with the hospital information system (the General Hospital of Lippe is the only oncological center for more than 350 0000 people). The rate of hematological malignancies has been assigned to the different dose groups. Results: Median follow up was 8.8 years (range: 0 - 22.7 years). In the zero dose group, the rates for all hematological malignancies, only leukemia, and only leukemia except chronic lymphocytic leukemia were 4 / 1839 (0.8%), 5 / 1839 (0.3%), and 4 / 1839 (0.2%). In the intermediate dose group (n = 929), the corresponding values were 11 / 930 (1.2%), 3 / 930 (0.3%), and 2 / 930 (0.2%). In the highest dose group (n = 248), corresponding values were 4 / 248 (1.6%), 2 / 248 (0.8%), and 1 / 248 (0.4%). The differences between the dose groups were not significantly different (chi-squared test). Conclusions: No statistical evidence was provided in this cohort that a higher x-ray dose in the red bone marrow increases hematologic malignancies after low-dose radiotherapy of benign disease in middle-aged and older adults. However, in a larger number of patients, the differences between the dosage groups could reach the level of significance. Therefore, the extension of the cohort will be continued.
CCGD-ESCC: A Comprehensive Database for Genetic Variants Associated with Esophageal Squamous Cell Carcinoma in Chinese Population
Authors: Linna Peng, Sijin Cheng, Yuan Lin, Qionghua Cui, Yingying Luo, Jiahui Chu, Mingming Shao, Wenyi Fan, Yamei Chen, Ai Lin, Yiyi Xi, Yanxia Sun, Lei Zhang, Chao Zhang, Wen Tan, Ge Gao, Chen Wu, Dongxin Lin
Journal: Genomics Proteomics & Bioinformatics (2018)

Abstract Esophageal squamous-cell carcinoma (ESCC) is one of the most lethal malignancies in the world and occurs at particularly higher frequency in China. While several genome-wide association studies (GWAS) of germline variants and whole-genome or whole-exome sequencing studies of somatic mutations in ESCC have been published, there is no comprehensive database publically available for this cancer. Here, we developed the Chinese Cancer Genomic Database-Esophageal Squamous Cell Carcinoma (CCGD-ESCC) database, which contains the associations of 69,593 single nucleotide polymorphisms (SNPs) with ESCC risk in 2022 cases and 2039 controls, survival time of 1006 ESCC patients (survival GWAS) and gene expression (expression quantitative trait loci, eQTL) in 94 ESCC patients. Moreover, this database also provides the associations between 8833 somatic mutations and survival time in 675 ESCC patients. Our user-friendly database is a resource useful for biologists and oncologists not only in identifying the associations of genetic variants or somatic mutations with the development and progression of ESCC but also in studying the underlying mechanisms for tumorigenesis of the cancer. CCGD-ESCC is freely accessible at http://db.cbi.pku.edu.cn/ccgd/ESCCdb.
Phase 2 trial of the IDO pathway inhibitor indoximod plus gemcitabine / nab-paclitaxel for the treatment of patients with metastatic pancreas cancer.
Authors: Nathan Bahary, Andrea Wang-Gillam, Sigurdis Haraldsdottir, Bradley G. Somer, Jin S. Lee, Mark Allen O'Rourke, Asha Nayak-Kapoor, Gregory Lawrence Beatty, Mingen Liu, Devora Delman, Gabriela R. Rossi, Eugene Paul Kennedy, Nicholas N. Vahanian, Charles J. Link, Ignacio Garrido-Laguna
Journal: Journal of Clinical Oncology (2018)

4015 Background: The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that is exploited by tumors to prevent and evade anti-tumor immunity. Inhibitors of the IDO pathway, such as indoximod, are an increasingly validated class of potential cancer therapeutics. The combination of gemcitabine (G) and nab-paclitaxel (N) is a current SOC for metastatic pancreas cancer (MPC). Pre-clinical models have demonstrated synergy between indoximod and chemotherapy. Methods: Single arm study with indoximod (1200mg BID continuous) plus G / N (1000mg/m2 / 125mg/m2 q week x3 per 4-week cycle). Patients had treatment naïve MPC or 1st line therapy after previous resection and adjuvant therapy. Treatment continued until disease progression or toxicity. Primary endpoint was an improvement in median overall survival (mOS) from a historical 8.5 months for G / N to 12.1 months (hazard ratio (HR) of 0.70). Secondary endpoints included overall response rate (ORR) by site review RECIST 1.1. An expansion cohort enrolled patients undergoing pre and on-treatment (end Cycle 2) tumor biopsies. Results: A total of 135 patients initiated treatment in Phase 2 including 36 in the biopsy group. 104 were efficacy evaluable (EE) per the pre-specified definition of completing one cycle of therapy with one on-treatment imaging study. The ORR in the EE was 46.2% (48/104) with 1% CR (1/104) and 45.2% PR (47/104). The mOS in the EE was 10.9 months. Combination was generally well tolerated with fatigue, nausea, and anemia being the most commonly observed adverse events. Immunologic data by immunohistochemistry from biopsy samples (n = 11) indicate responders have increased intra-tumoral CD8 density after 2 cycles of therapy compared to non-responders (p = 0.030). Conclusions: EE patients had a mOS of 10.9 months and ORR of 46.2%; responding patients had an increased intra-tumoral CD8 density. The study did not meet the pre-specified primary goal of a 30% reduction in HR. However, the combination demonstrated activity with a promising ORR and immunologic correlation with response. These data support the continued development of combination indoximod immuno-chemotherapy for MPC. Clinical trial information: NCT02077881.
Phase 1 study to evaluate safety and efficacy of ipilimumab + nivolumab + external beam radiotherapy in patients with metastatic melanoma.
Authors: Michael Andrew Postow, Susan Jane Knox, Danielle McCabe, Mary J. Macri, Paul Schwarzenberger, Toni Ricciardi, Aileen Ryan, Ralph Rudolph Venhaus, Christopher Andrew Barker
Journal: Journal of Clinical Oncology (2017)

TPS9591 Background: Immunotherapy (IMT) with checkpoint blocking antibodies has led to progress in metastatic melanoma with 3 FDA-approved drugs, including the combination of ipilimumab (IPI), a CTLA-4 antibody, and nivolumab (NIVO), a PD-1 antibody. Although radiotherapy (RT) is primarily used as local palliative therapy in metastatic melanoma, it also possibly affects systemic antitumor immunity. Preclinical data suggest RT alters the tumor microenvironment and renders tumor cells more susceptible to immunologically-mediated disease regression. These preclinical immunologic effects of RT have been shown to vary by RT dose and fractionation. We are now conducting the first clinical trial in patients to evaluate the triple combination of IPI + NIVO + RT using 2 different dose/fractionation schemes of RT. Methods: This ongoing Phase 1, open-label, multicenter study (NCT02659540) evaluates safety, efficacy, and immunologic effects of IPI + NIVO + RT in 18 patients with unresectable stage IV melanoma. Patients must have 1 melanoma metastasis that can be safely irradiated for palliative purposes and at least 1 measurable lesion that will not be irradiated. Patients receive concurrent IPI (3 mg/kg) and NIVO (1 mg/kg) every 3 weeks (Q3W) x 4, followed by NIVO monotherapy (240 mg Q2W), with RT initiated between the first and second doses of IPI + NIVO. In Cohort A, the irradiated metastasis receives a conventionally fractionated low dose of 30 Gy in 10 fractions of 3 Gy each over 2 weeks. If ≤7 of 9 patients (78%) in Cohort A have Grade 3/4 drug- or radiation-related adverse events, safety is deemed acceptable and Cohort B enrollment opens. In Cohort B, the irradiated metastasis receives a hypofractionated high dose of 27 Gy in 3 fractions of 9 Gy each over 2 weeks. The primary endpoint is safety. Secondary endpoints are objective response rate and disease control rate by RECIST and immune-related RECIST measured at Weeks 12 and 18, duration of response, progression-free survival, and overall survival. Exploratory endpoints include correlative studies of immunological effects. Enrollment opened on 05 Aug 2016. As of 31 Dec 2016, 4 patients are enrolled in Cohort A; enrollment is ongoing. Clinical trial information: NCT02659540.
A phase 2, multicenter, open-label study to evaluate the efficacy and safety of CDX-3379 in combination with cetuximab in patients with advanced head and neck squamous cell carcinoma (HNSCC).
Authors: Julie E. Bauman, Nabil F. Saba, Douglas Adkins, Ying Wang, Yi He, Elsa Paradise, Roger B. Cohen
Journal: Journal of Clinical Oncology (2018)

TPS6091 Background: ErbB3 (HER3) and its ligand, neuregulin-1 (NRG1), are widely expressed in HNSCC and associated with tumor progression. ErbB3 may provide a key mechanism of resistance to therapies targeting EGFR and HER2. HPV− tumors, typified by poorer prognosis, have shown favorable response to ErbB3-targeted therapy. CDX-3379, an anti-ErbB3 monoclonal antibody with a half-life-extending Fc region YTE mutation, binds a unique epitope, locks ErbB3 in an inactive form, and blocks all ErbB3-dependent downstream signaling. CDX-3379 enhances antitumor activity of targeted therapies in preclinical models (Falchook ASCO 2016). In a phase (ph) 1 trial, CDX-3379 was well-tolerated alone and in combination with targeted agents. A patient (pt) with cetuximab-refractory HNSCC experienced a durable complete response to CDX-3379 + cetuximab, while 2 pts with BRAF-mutant non-small cell lung cancer, one dabrafenib-resistant, experienced partial responses to CDX-3379 + vemurafenib (Falchook ASCO 2016). A newly-initiated trial evaluates CDX-3379 + cetuximab in pts with HPV− cetuximab-resistant advanced HNSCC. Methods: A ph 2, multicenter, open-label clinical trial (NCT03254927) is enrolling ≤30 pts with advanced refractory HNSCC. Eligibility requires: screening biopsy; HPV−; RECIST 1.1 measurable disease; cetuximab resistance (progression within 6 months); prior PD-1-targeted check-point inhibition (if a candidate); no active brain metastases; and no nasal, paranasal sinus, or nasopharyngeal WHO Type III carcinoma. Pts receive CDX-3379 (initial dose 12 mg/kg IV q 21 days) + cetuximab (loading dose 400 mg/m2; 250 mg/m2 IV weekly) until progression/toxicity. Tumor assessments occur at 6-week intervals. Endpoints include objective response rate (ORR; primary), progression-free and overall survival, safety, pharmacokinetics, immunogenicity, and biomarkers (NRG, EGFR ligands). It is hypothesized that CDX-3379 + cetuximab will achieve ORR of 20%, with 80% power and a null hypothesis of ORR ≤5% and α = 0.05 based on a Simon’s 2-stage design. Three US sites are actively recruiting pts, with additional sites planned. Clinical trial information: NCT03254927.
Intratumoral G100 to induce systemic immune responses and abscopal tumor regression in patients with follicular lymphoma.
Authors: Christopher Flowers, Iris Isufi, Alex Francisco Herrera, Craig Okada, Elizabeth H. Cull, Bela Kis, Jorge Chaves, Nancy L. Bartlett, Locke Johnson Bryan, Roch Houot, Weiyun Z. Ai, Ian Chau, Kim Linton, Javier Briones, Luis de la Cruz Merino, Carlos Panizo, Gottfried Raffael Von Keudell, Hailing Lu, Frank J. Hsu, Ahmad Sami Halwani
Journal: Journal of Clinical Oncology (2017)

7537 Background: Follicular lymphoma (FL) is an incurable malignancy with patients (pts) ultimately relapsing following standard therapies. Active immunotherapy has the potential to induce life-long host anti-tumor immunity and disease control. G100 consists of glucopyranosyl lipid-A (GLA), a TLR-4 agonist in a specific formulation. Preclinically, G100 activates dendritic cells, T cells and NK cells, and triggers systemic anti-tumor immunity. In Merkel Cell carcinoma pts, G100 administered intratumorally (IT) induced tumor inflammation and responses including a CR after G100 alone. This is the first study of G100 IT in pts with NHL. Methods: Previously treated or naïve pts with FL with an injectable tumor site and distal sites of disease were eligible. In Part 1, G100 cohorts of 5 or 10µg were enrolled in a 3+3 design, followed by a large tumor ( &gt; 4cm) cohort at 20µg. Pts received 6-9 doses of G100 IT ~qwk after radiation (RT, 2 Gy x2 doses) to the lesion. A 2 nd course of G100 could be given without RT to an additional site. Results: As of 31Dec16, all 9 pts in Part 1 dose escalation (3 pts each at 5, 10, or 20 µg/dose) were evaluable for safety and efficacy. An additional 13 pts at 10µg/dose were included in the safety analysis only. No G100-related DLTs or SAEs were observed at any dose level. Of 22 safety pts, all G100 related AEs were grade 1/2 and none occurred in &gt; 2 pts. Tumor biopsies following G100 demonstrated diffuse infiltration of CD8+ T cells in 5/5 pts and T cell repertoire analyses indicated an increased frequency of clonal tumor infiltrating lymphocytes (TILs). Best responses include: 4 PRs (45%), 3 SDs (33%) and 2 pending (22%). Of the 4 PR pts, tumor regression ranged 58-89% including up to 56% shrinkage of abscopal (distal) sites. Conclusions: G100 IT was safe, well-tolerated, induced CD8+ T cell infiltration and expansion of TIL clones. G100/RT treated and abscopal lesion regressions were observed signifying the induction or boosting of systemic anti-tumor immunity. The induction of immune responses, favorable safety profile and clinical activity indicate that G100 IT is an active agent that warrants further investigation. Part 2 enrollment continues with randomization to G100/RT ± pembrolizumab. Clinical trial information: NCT02501473.