tbuckley/cabot-search huggingface dataset:
Association between hospital volume, treatment patterns and overall survival (OS) of patients with intrahepatic cholangiocarcinoma (IHCC).
Authors: Sri Harsha Tella, Anuhya Kommalapati, Gaurav Goyal, Mitesh J. Borad, Amit Mahipal
Journal: Journal of Clinical Oncology (2018)

e16118 Background: IHCC is a rare cancer with poor OS. The purpose of this study is to determine the association between the number of patients with IHCC treated annually at a treatment facility (volume) and different risk-adjusted survival outcomes. Methods: Patients with IHCC diagnosed between 2004 & 2015 were included. We classified facilities by tertiles (T; mean patients with IHCC treated per year): T1: < 2.56; T2: 2.57 – 5.39 and T3: ≥5.40. We used SPSS to account for clustering of patients within centers (based on the volumes: lower, middle & higher 1/3rd of the cases) and Cox regression to determine the volume-outcome relationship, adjusting for covariates-patient demographics, tumor characteristics, insurance & therapy. Kaplan Meier estimates of 1-, 3-yr OS were compared with log-rank tests. Results: Total of 11344 IHCC patients treated at 1106 facilities. The median age at diagnosis was 65 years (range, 11-90). The median annual facility volume was 2 patients per year (r, 1-92). Multivariable analysis showed that facility volume was independently associated with all-cause mortality (p < 0.0001). The unadjusted median OS by facility volume was: T1: 5 months (m), T2: 8.1 m, and T3: 13.1 m (p < .0001). Compared with patients treated at T3 facilities, patients treated at lower-tertile facilities had significantly higher risk of death [T2 hazard ratio (HR), 1.12 (95% CI, 1.05- 1.23); T1 HR, 1.21 (CI, 1.11 - 1.33)]. Stage-wise sub-group analysis showed that patients treated at high volume centers are more likely to get surgery (34.6 vs 13.1%) and adjuvant chemo and radiation therapy. Chemo and radiation therapy patterns were similar among facilities. Receipt of surgical therapy was independently associated with prolonged OS. Conclusions: Patients who were treated for IHCC at high-volume centers were more likely to receive surgery and adjuvant therapy and had a significant improvement in survival compared to that of patients treated at low- volume facilities. Therapy received (%) OS (%) Stage 1 Stage 2 Stage 3 Stage 4 Surgery Chemo Radiation 1 yr 3 yr 1 yr 3 yr 1 yr 3 yr 1 yr 3 yr T1 (33.6%) 13.1 32 4 54.5 31 40 14 35 9 25 6 T2 (22.8%) 23.2 32 3 60 38 50 22 37 13 30 7 T3 (43.6%) 34.6 31 4 73.5 47 62 31 53 17 41 9
A multicenter, randomized, open-label, phase II trial of erlotinib versus etoposide plus cisplatin with concurrent radiotherapy in unresectable stage III non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) activating mutation.
Authors: Ligang Xing, Gang Wu, Lvhua Wang, Jian-Cheng Li, Jianhua Wang, Zhiyong Yuan, Ming Chen, Yaping Xu, Zhengfei Zhu, You Lu, Chun Han, Tingyi Xia, Conghua Xie, Guang Li, Jinming Yu
Journal: Journal of Clinical Oncology (2017)

8531 Background: Concurrent chemoradiotherapy is the standard treatment for patients(pts) with unresectable stage IIIA/IIIB NSCLC. In EGFR mutant pts, tyrosine kinase inhibitor(TKI) exhibits clinical benefits over chemotherapy regimens in terms of efficacy and safety as well as specific enhancement of radiation effects. This multicenter, randomized, open-label, phase II trial aimed to compare the erlotinib and etoposide/cisplatin with concurrent radiotherapy (RT) in pts with EGFR-mutant. Methods: Histopathology/cytology confirmed stage IIIA/B unresectable NSCLC pts (age 18-75) with ECOG PS 0-1 and EGFR exon 19 or 21 mutation were included and randomized (1:1) into two arms: erlotinib (E) and etoposide/cisplatin (EP). E arm was treated with oral erlotinib (150mg/day for 2 years or till either disease progression or intolerable toxicities) and RT (200cGy/day, 5 days/week for 6 weeks from first day erlotinib). EP arm was treated with sequential etoposide (50 mg/m 2 IV days 1-5, 29-33) and cisplatin (50mg/m 2 IV day 1,8, 29,36) and RT (from first day drug). Primary endpoint is progress free survival (PFS). Secondary endpoints are objective response rate(ORR), local control rate(LCR), overall survival(OS), quality of life(QoL) and safety. Results: 252 pts were screened, and 41 were enrolled into E(n=20) and EP(n=21) arms. Characteristics of age, sex, histologic type, N2, EGFR 19 and 21 mutation were well balanced in each arm. Comparing with EP, median PFS of E arm was significantly improved (27.86 vs 6.41 months; HR 0.053, 95% CI: 0.006-0.463; P&lt;0.001). ORR and DCR were 60.0% vs. 38.1%( P=0.217), and 65% vs. 47.6%( P=0.350), respectively. Two arms had same incidence of adverse effects (CTCAE Grade≥1, 86.7%[13/15]), and most common sAE(Grade≥3) was rash (20%, 3/15) and hematological toxicity(26.7%, 4/15), respectively. Conclusions: In unresectable stage III EGFR mutant NSCLC pts, concurrent erlotinib/RT provides a statistically significant PFS improvement with well tolerability. These results warrant a phase III study to confirm. (RECEL, NCT01714908). Clinical trial information: NCT01714908.
Clinical utility of a novel circulating tumor DNA test in guiding targeted therapy selection.
Authors: Tsai Ming Hung, Hung-Chih Lai, Alex Atkins, Si-Hong Lu, Wen-Tsung Huang, Tony Tzeng, Chia-Hsun Hsieh, Yu-lin Lin, Su-Peng Yeh, Shih-En Chang, Mana Javey, Rui Mei
Journal: Journal of Clinical Oncology (2018)

e24082 Background: Circulating tumor DNA (ctDNA) based companion diagnostics have been valuable in identifying matched targeted therapy options in lung cancer. Cellmax Life’s 73-gene pan-cancer OncoLBx panel analyzes ctDNA for all genes and classes of alterations in NCCN treatment guidelines for targeted therapy selection. Here we evaluated the clinical utility of the panel in Taiwanese patients. Methods: A novel variant identification platform, SMSEQ, was utilized to identify SNV, indels, rearrangements and CNVs in the tumor DNA derived from blood, cerebral spinal fluid (CSF), and tissue with allele fractions as low as 0.1% with 99.999% specificity. Results: More than 250 Taiwanese patients, predominantly with colorectal (24%), breast (23%), lung (9%), ovarian (6%), liver (5%), and pancreatic (5%) cancer were tested. Clinically relevant somatic variants (KRAS, ERBB2, EGFR, APC, PIK3CA, PTEN, CDKN2A, MPL, JAK2) were identified in > 81% of patients. Eight consenting patients who shared their medical history before and after testing were managed according to the test-result based recommendations. Two patients, one with cancer of unknown primary and metastatic brain lesions, and the other with prior diagnosis of breast cancer, were found to have ERBB2 amplification in CSF and plasma respectively, and responded to anti-HER2 combination therapy. Successful treatment with mTOR inhibitors was noted in three different patients with carcinomas of breast and adrenal gland, harboring PIK3CA and PTEN mutations. Pazopanib therapy yielded good clinical response in the patient with head and neck squamous cell carcinoma with PDGFR VUS found in plasma. In addition to solid tumors, OncoLBx aided in the management of two diffuse large B cell lymphoma (DLBCL) patients. One DLBCL patient benefitted from the Ruxolitinib administration based on JAK2 amplification, while in the other patient liquid biopsy was utilized as a monitoring tool for minimal residual disease detection, enabling an oncologist to provide the most suitable care. Conclusions: The CellMax 73-gene NCCN-complete pan-cancer liquid biopsy has demonstrated clinical utility in terms of treatment response and recurrence monitoring.
Pathogenic variants in DNA damage response (DDR) genes in patients with advanced solid tumors.
Authors: Ecaterina Elena Ileana Dumbrava, Lauren Brusco, Molly S Daniels, Chetna Wathoo, Kenna Rael Shaw, Karen H. Lu, Xiaofeng Zheng, Louise C. Strong, Jennifer Keating Litton, Banu Arun, Agda Karina Eterovic, Sarina Anne Piha-Paul, Vivek Subbiah, David S. Hong, Scott Eric Woodman, John Mendelsohn, Timothy Anthony Yap, Gordon B. Mills, Ken Chen, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2017)

11567 Background: Deleterious mutations in DDR genes are frequently associated with response to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum chemotherapy. However, much remains unknown about their association with specific molecular signaling pathways. We report the prevalence of pathogenic variants in DDR genes and their co-alteration with other somatic variants. Methods: Targeted exome sequencing of 201 genes was performed in 1,189 patients (pts) with advanced solid tumors enrolled in a molecular testing protocol (NCT01772771), using matched normal and tumor DNA. We assessed germline and somatic alterations in 15 cancer-related DDR genes, their co-occuring genomic alterations and the tumor mutation burden (TMB), defined as number of somatic non-synonymous mutations. Results: A total of 124 pathogenic or likely pathogenic variants in DDR genes were identified in 111/1189 (9%) pts with 57% of these alterations being somatic. These variants were found in the following genes: ATM 17 pts (1.4%); BAP1 5 pts (0.4%); BRCA1 18 pts (1.5%); BRCA2 17pts (1.4%); CHEK1 8 pts (0.7%); CHEK2 16 pts (1.3%); ERCC3 4 pts (0.3%); ERCC4 2 pts (0.2%); ERCC5 3 pts (0.2%); MLH1 4pts (0.3%); MSH2 8 pts (0.7%); MSH6 6 pts (0.5%); PALB2 3 pts (0.2%) and RAD51 1pt (0.1%). DDR alterations were found more frequently in the following tumor types tested: breast 14%, colorectal 12%, melanoma 8%, glioblastoma 6% and ovarian 6%. The most relevant somatic co-alterations with DDR mutations were activation of the PI3K/AKT/mTOR pathway through mutations or copy-number variations in AKT1, MTOR, NF1, PIK3CA, PIK3R1, PTEN, TSC1 and TSC2 (p = 0.008). Patients with deleterious variants in mismatch excision repair genes (MLH1, MSH2 or MSH6) had a significantly higher TMB than all other patients enrolled (median TMB = 62 vs 5, p = 0.002). Patients with somatic pathogenic DDR variants had a significantly higher TMB (median = 13) compared to patients with germline DDR variants (median = 5) (p = 0.004). Conclusions: The association of DNA repair mutations with alterations in signaling pathways provide rationale for novel therapeutic combinations. Variations in TMB based on distinct types of DDR gene alterations may have implications for immunotherapy.
TCT-851 Histopathological and Scanning Electron Microscopy Thrombus Findings in Patients Undergoing Primary vs. Rescue Percutaneous Coronary Intervention
Authors: Stella Marinelli Pedrini, Jamil Cade, Paula Gomes, Marco Tulio Souza, Francisco Fonseca, None Antonio Carvalho, Carlos Campos, Rita Sinigaglia-COimbra, Fabiana Rached, Marcelo Franken, Adriano Caixeta
Journal: Journal of the American College of Cardiology (2018)
Abstract 17624: Life's Simple 7s of Cardiovascular Health Among Hispanic/Latinos: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL)
Authors: Hector M González, Wassim Tarraf, Thomas Mosley, Clinton Wright, Tatjana Rundek, Pamela L Lutsey, Natalia Gouskova, Ellen Grober, Amber Pirzada, Martha Daviglus
Journal: Circulation (2012)

OBJECTIVES: To estimate current prevalence of cardiovascular health among various Hispanic/Latino ethnicities. BACKGROUND: Recently, the American Heart Association established a goal to improve the...
A designer bow-tie combination therapeutic platform: An approach to resistant cancer treatment by simultaneous delivery of cytotoxic and anti-inflammatory agents and radiation
Authors: Rakesh K. Pathak, Uttara Basu, Anis Ahmad, Shrita Sarkar, Anil Kumar, Bapurao Surnar, Saba Ansari, Katarzyna Wilczek, Michael E. Ivan, Brian Marples, Nagesh Kolishetti, Shanta Dhar
Journal: Biomaterials (2018)
First-in-class phase I study evaluating MP0250, a VEGF and HGF neutralizing DARPIN molecule, in patients with advanced solid tumors.
Authors: Analia Azaro, Jordi Rodon, Mark R. Middleton, Richard D. Baird, Richard Herrmann, Ulrike Fiedler, Jutta Haunschild, Micha Häuptle, Frank Jurgen Hermann, Sabrina Schreiner, Andreas Harstrick, Keith M. Dawson, Aurelius Gabriel Omlin
Journal: Journal of Clinical Oncology (2018)

2520 Background: The VEGF/VEGFR and HGF/c-MET pathways are key mediators of the growth of solid tumours. MP0250 is a first-in-class, tri-specific DARPin compound neutralizing VEGF-A and HGF as well as binding to human serum albumin to increase plasma half-life and potentially enhance tumour penetration. Methods: Patients with advanced solid tumours were enrolled in a 3+3 dose escalation part (cohorts 1-5) and then in a single-arm dose expansion part (cohorts 6-7) (NCT02194426). The primary objectives were to evaluate safety, tolerability, the recommended biological dose, the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs) and the pharmacokinetics of MP0250. The secondary objective was to characterize the immunogenicity of MP0250. Results: From August 2014 until January 2018, 45 patients were enrolled in 7 different cohorts: cohort 1 to 5 (3 hr infusion, q2w): 0.5 mg/kg; 1.5 mg/kg; 4 mg/kg; 8 mg/kg, and 12 mg/kg; dose expansion cohorts: cohort 6 (1 hr infusion, q2w): 8 mg/kg and cohort 7 (1 hr infusion, q3w): 12 mg/kg. Patients were heavily pre-treated with a median of 3.6 lines of previous treatment (1-13). Median number of MP0250 infusions were 6.5 (1-31). Most common any-grade TEAEs were: hypertension 67% (grade 3: 37%), proteinuria 49% (grade 3: 4.4%), diarrhoea 36% (grade 3: 2.2 %), nausea 36% and fatigue 31% (grade 3: 2.2%). Two out of 5 patients in the 12 mg/kg q2w had a DLT (hypertension, nephrotic syndrome, GI bleeding). Additional DLTs (1 patient per cohort) occurred at 4 mg/kg q2w (left ventricular failure), 8 mg/kg q2w (creatinine and urea increase and thrombocytopenia), 8 mg/kg 1 hr infusion q2w (nephrotic syndrome) and 12 mg/kg q3w (nephrotic syndrome). Based on these data, the MTD for MP0250 was determined to be 8 mg/kg q2w or 12 mg/kg q3w. Two patients achieved a partial response, 44 % of patients were on MP0250 treatment for 3 months, 9 % for 6 months and 1 patient for over 1 year. Conclusions: In this FIH study, MP0250 was well tolerated with most AEs being consistent with profound inhibition of the VEGF pathway. Signs of single agent antitumour activity were observed and MP0250 is being further developed in lung cancer and multiple myeloma. Clinical trial information: NCT02194426.
Prognostic benefit of taking statin and/or metformin in elderly patients with advanced non-small cell lung cancer: A nationwide population-based epidemiologic study.
Authors: Yun-Gyoo Lee, Ju Hyun Lee, Joung Soon Jang, Jee Hyun Kim
Journal: Journal of Clinical Oncology (2018)

10045 Background: Comorbidities including dyslipidemia, diabetes and coronary heart disease are frequently found in elderly patients with advanced non-small cell lung cancer (NSCLC). Taking statin and/or metformin attenuates chronic inflammations, and could affect cancer outcomes. We aimed to evaluate prognostic impact of taking statin and/or metformin on survival in elderly patients with advanced NSCLC. Methods: Patients ≥ 70 years with advanced NSCLC incident from 2007 to 2012 were identified using reimbursement claims from Korea’s National Health Insurance Service Database, and exposures to statin and/or metformin were also documented. Cox proportional-hazards model and propensity score matched analysis were used to estimate the impact of drug exposures on overall survival (OS). Results: Excluding 976 treated by upfront anti-EGFR, 7298 receiving palliative chemotherapy were included: statin preparations were taken in 13.0%, metformin preparations in 13.8%, both in 3.5%, and neither in 76.6%, respectively. Median OS of statin + / metformin +, statin + / metformin –, statin - / metformin +, and statin - / metformin – users was 14.5, 12.9, 11.4 and 9.9 months respectively. By multivariate analyses, metformin was not statistically significantly associated with improved OS in statin non-user (HR 0.99; 95% CI 0.91-1.08; p= 0.819) and statin user (HR 0.99; 95% CI 0.85-1.16; p= 0.898) group. However, use of statin, regardless of metformin, was associated with improved OS (HR 0.80; 95% CI 0.74-0.86; p< 0.001). In propensity-matched cohort, survival benefit was noted not by use of metformin (HR 0.97; 95%CI 0.85-1.11; p= 0.661), but by use of statin (HR 0.83; 95%CI 0.73-0.95; p= 0.007). There was no significant effect modifier. Conclusions: We found that the about one-quarter of elderly NSCLC patients were taking statin and/or metformin. Exposures to statin could be the independent prognostic factor for better survival in elderly advanced NSCLC patients.
Abstract 19882: The Effect of High Functional Aerobic Capacity on Cardiovascular Mortality in Patients With Diabetes Undergoing a Symptom-Limited Exercise Stress Test: A Long-Term Follow-up Study
Authors: Jose R Medina-Inojosa, Manuel Jimenez Navarro, Juan Pablo Rodriguez, Virend Somers, Allison Thomas, Ray Squires, Francisco Lopez-Jimenez
Journal: Circulation (2016)

Introduction: High Functional Aerobic Capacity (FAC) measured during symptom-limited treadmill ECG stress testing (TMET) has been associated with lower cardiovascular (CV) mortality, but little is ...
Risks, Benefits, and What Matters to the Patient
Authors: Nancy E. Lundebjerg
Journal: JAMA Cardiology (2018)

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PARADIGM study: A multicenter, randomized, phase III study of mFOLFOX6 plus panitumumab or bevacizumab as first-line treatment in patients with <i>RAS</i> (<i>KRAS/NRAS</i>) wild-type metastatic colorectal cancer.
Authors: Takayuki Yoshino, Hiroyuki Uetake, Katsuya Tsuchihara, Kohei Shitara, Kentaro Yamazaki, Jun Watanabe, Eiji Oki, Takeo Sato, Takeshi Naitoh, Yoshito Komatsu, Takeshi Kato, Ikuo Mori, Kazunori Yamanaka, Masamitsu Hihara, Junpei Soeda, Takeharu Yamanaka, Kiwamu Akagi, Atsushi Ochiai, Kei Muro
Journal: Journal of Clinical Oncology (2021)

85 Background: The optimal choice of monoclonal antibodies (mAbs) for first-line treatment in patients (pts) with RAS ( KRAS/NRAS) wild-type metastatic colorectal cancer (mCRC) remains controversial. The meta-analyses of subgroup analyses in phase III studies of pts with KRAS exon 2 wild-type mCRC suggested a longer overall survival (OS) with an anti-EGFR mAb over bevacizumab in pts with RAS wild-type mCRC or with left-sided primary tumors. However, there has been no prospective study comparing the two mAbs in these pt populations. This randomized phase III study was originally designed to demonstrate the superiority of panitumumab versus bevacizumab, both in combination with mFOLFOX6, for RAS wild-type mCRC, but we have revised the protocol to analyze efficacy in pts with a left-sided primary tumor as the primary (final) analysis. Methods: Eligible pts are aged 20-79 years with histologically/cytologically confirmed RAS wild-type chemotherapy-naive mCRC, and ECOG performance status 0-1. Between May 29, 2015 and Jun 8, 2017, 823 pts were randomized 1:1 to panitumumab plus mFOLFOX6 or bevacizumab plus mFOLFOX6 by the minimization method and the randomisation was stratified by institution, age (20-64 vs. 65-79 years), and liver metastases (present vs. absent). The primary analysis was revised to adopt a hierarchical testing procedure; we first compare OS between the two arms in left-sided primary tumor population, and only if there is statistically significant difference, then ITT population analysis will be performed. In this revised plan, the expected number of deaths is 420 in the left-sided population to provide 80% power to detect an OS hazard ratio of 0.74 at a one-sided significance level of 0.02101 determined on the alpha spending function approach after one interim analysis. A large-scale exploratory biomarker substudy to identify potential biomarker candidates using tumor tissue and circulating tumor DNA is also underway (Clinical trial no.: NCT02394834). The data cut off for the primary analysis is expected to be during 1Q 2021. Results: Results are expected in 2021. Conclusions: Results are expected in 2021. Clinical trial information: NCT0239475.
Multi-platform characterization of cutaneous melanoma from patients treated with immune checkpoint inhibitors.
Authors: Dan Moldoveanu, Mathieu Lajoie, Xiu Huang, Maria Lvova, Julie Y Tse, Stephen Lyle, Alexei Protopopov, Meaghan Russel, Matthew Dankner, Sonia Del Rincon, Leon Van Kempen, Alan Spatz, Wilson H. Miller, Kevin Petrecca, Beatrice Wang, Sarkis H. Meterissian, Kevin Watters, Catalin Liviu Dragos Mihalcioiu, Dana Vuzman, Ian Watson
Journal: Journal of Clinical Oncology (2018)

e15071 Background: Therapeutics targeting inhibitory immune checkpoints have revolutionized the treatment of advanced and metastatic melanoma. Clinical trials of dual treatment with anti-CTLA4 and anti-PD-1 monoclonal antibodies observed up to 57.6% response rates with 11.5% of patients achieving complete response and 13.1% having stable disease for over 12 months of follow-up (Larkin et al. 2015). However, side effects continue to be a major problem with over 40% of patients reporting a severe adverse event. A number of groups have identified that tumour mutation burden, gene expression signatures and tumor aneuploidy are predictors of immunotherapy response (reviewed in Sharma et al. 2017). A significant knowledge gap remains regarding which combination of factors best predict a priori response to immune checkpoint inhibitors. Methods: We performed a multi-platform integrative analysis of 42 regional metastatic melanoma samples from patients treated with immune checkpoint inhibitors. Platforms included in this study were focused sequencing of >400 cancer-associated genes using the CANCERPLEX platform from Kew Group Inc., DNA copy number, 7-colour immunofluorescence of immune infiltration markers, and analysis of peripheral blood. Results: Our focused sequencing gene panel was shown to predict tumour mutation burden and to accurately identify known melanoma driver mutations. Tumour lymphocyte infiltration predicted immune checkpoint response, and highly infiltrated tumours had improved survival (p<0.05). Furthermore, elevated pre-treatment eosinophil and basophil counts were associated with improved treatment response, while high lactate dehydrogenase levels were associated with poor survival and decreased response rates. Conclusions: This study adds to a growing body of knowledge to understand the molecular determinants of response to immune checkpoint inhibitors to further personalize melanoma care.