tbuckley/cabot-search huggingface dataset:
The association between patient comorbidity and breast cancer survival.
Authors: Jaihong Han, Han-Byoel Lee, Young Joon Kang, Yumi Kim, Tae-Kyung Yoo, Hyeong-Gon Moon, Wonshik Han, Dong-Young Noh
Journal: Journal of Clinical Oncology (2016)

e12047 Background: There are studies suggesting significant association between the patient comorbidity and perioperative outcomes. In breast cancer, patient comorbidity can also influence the oncologic outcome by affecting the decisions regarding adjuvant treatments. In this study, we examined the long term oncologic outcome in breast cancer patients who underwent curative surgery according to the comorbid conditions. Methods: The medical records of 2,502 patients who underwent surgery for primary breast cancer from June 2006 to June 2010 were retrospectively reviewed. The patients were classified into three groups (ASA I, II, III) according to preoperative ASA status determined by the anesthesiologists. Clinico-pathologic characteristics of the patients were compared among the groups by chi-square test. Recurrence free survival (RFS) and overall survival (OS) were analyzed by performing Kaplan-Meier analysis and Cox regression. Results: The median follow-up period was 71 months. There were 1,792 (71.6%), 666 (26.6%), and 44 (1.8%) patients in ASA I. II, and III, respectively. Total 96 (3.8%) deaths and 269 (10.8%) recurrences (loco-regional and distant) occurred in follow-up period. With regard to the mortality, patients with high comorbidity showed significantly higher rate of death (51 (53.1%), 39 (40.6%) and 6 (6.3%) deaths in ASA I, II and III group, respectively, p < 0.001). The ASA III patients also showed significantly higher rate of breast cancer recurrence when compared to other groups (179 (66.5%), 81 (30.1%) and 9 (3.3%) in ASA I, II and III, respectively, p = 0.034). Cox multivariate analysis demonstrated that high ASA score was an independent prognostic factor in DFS and OS (95% confidence interval [CI], 1.067-1.839; p = 0.015 and 1.250-2.787; p = 0.002). Conclusions: In this study, high comorbidity was related to higher rates of mortality and recurrence in breast cancer patients.
Abstract 19913: Oxygen Concentration Modulates Human Cardiac Stem Cell Proliferation and Migration
Authors: Michael A Bellio, Claudia O Rodrigues, Ana Marie Landin, Konstantinos E Hatzistergos, Krystalenia Valasaki, Aisha Khan, Joshua M Hare, Ivonne H Schulman
Journal: Circulation (2016)

Introduction:  Cardiac Stem cells (CSCs) are currently being tested for their efficacy in the treatment of heart failure (HF). However, numerous factors are known to cause significant impairment to the exogenously delivered cell’s survival and regenerative capabilities. Hypoxia is one such stress that is known to contribute to inadequate tissue repair. Here, we test the hypothesis that hypoxia impairs cell proliferation, survival, and migration of human CSCs.   Methods and Results:  CSCs were expanded from endomyocardial biopsies from patients and selected for CD117 expression. Cultured at standard room air (21% O 2 ), CSCs were transferred to either physiologic (5%) or hypoxic (0.5%) conditions to assess the effect on cell proliferation, survival, and migration. Compared to both room air and hypoxia, the physiological O 2  elevated both proliferation (P 2  to a level comparable to physiologic migration (2-fold, P 2  (1.4-fold, P 2  concentration.   Conclusions:  Relative to hyperoxia and hypoxia, physiological O 2  concentration promotes cell proliferation and migration. This study provides novel insights into the modulatory effects of O 2  concentration on CSC biology and hasve important implications for refining stem cell therapies.
Efficacy, safety, tolerability, and pharmacokinetics of EPI-506 (ralaniten acetate), a novel androgen receptor (AR) N-terminal domain (NTD) inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC) progressing after enzalutamide and/or abiraterone.
Authors: Kim N. Chi, Ulka N. Vaishampayan, Michael S. Gordon, David C. Smith, Erin Rudsinski, Angela De Haas-Amatsaleh, Neil Thapar, Frank Perabo, Robert B. Montgomery
Journal: Journal of Clinical Oncology (2017)

5032 Background: EPI-506 (ralaniten acetate) is a first-in-class small molecule transcription inhibitor of the AR NTD. Nonclinical studies demonstrated activity against both full length and resistance-related AR species, including AR-v7. Methods: Open-label, single-arm, Phase 1/2 study evaluating EPI-506 administered orally once-daily. The Phase 1 is a 3+3 design to establish the safety, pharmacokinetic (PK) profile, and recommended phase 2 dose of EPI-506. Anti-tumor activity is also evaluated. Inclusion criteria included: mCRPC with progression after ≥1 line of hormonal therapy or chemotherapy, and progression on enzalutamide and/or abiraterone. Results: Eighteen patients (pts) have been enrolled in the dose escalation phase over 5 dose levels (80, 160, 320, 640, 1280 mg). Median age was 71 (range 58-87). Prior treatments included enzalutamide only (N = 7), abiraterone only (N = 2) or both (N = 9). Six pts have had prior chemotherapy. Seven pts have discontinued due to disease progression and 2 pts due to adverse events (AEs): Grade 4 elevated amylase (related) and Grade 4 gastrointestinal bleeding (unrelated). Median exposure was 98.5 days (range 26-338). Most frequently reported treatment emergent AEs were diarrhea (N = 7), nausea (N = 5) and fatigue (N = 3). One Grade 3 AE (AST elevation) at 1280 mg and one Grade 4 AE (increased amylase) at 640 mg were reported. PK data demonstrate a dose-proportional profile for C max and AUC coupled with an initial negative food effect up to 640 mg. At week 4 of continuous dosing, 3 of 18 evaluable pts demonstrated PSA declines ranging from 9 to 18% receiving doses ≥640 mg. Conclusions: EPI-506 is well-tolerated with a favorable safety profile. PK indicates dose-proportionality. PSA declines have been observed at doses associated with sub-therapeutic exposure in preclinical studies. This study is the first to evaluate targeting the AR NTD, a region critical for transcriptional function of all known AR species. Clinical trial information: NCT02606123.
Letter by Barakat et al Regarding Article, “Implantable Cardioverter-Defibrillator for Nonischemic Cardiomyopathy: An Updated Meta-Analysis”
Authors: Amr F. Barakat, Marwan Saad, Islam Y. Elgendy
Journal: Circulation (2017)

We read with great interest the meta-analysis by Golwala et al 1 that aimed to assess the benefits of an implantable cardioverter-defibrillator (ICD) for the primary prevention of mortality in patients with nonischemic cardiomyopathy.Their primary analysis demonstrated a 23% risk reduction in all-cause mortality in favor of ICD (hazard ratio, 0.77; 95% confidence interval, 0.64-0.91).They performed a subgroup analysis of the 2 trials that, according to the authors, compared ICD plus cardiac resynchronization therapy (CRT-D) plus optimal medical therapy with CRT-pacemaker plus optimal medical therapy, namely the COMPANION trial (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) 2 and the CRT subgroup of the DANISH trial (Danish Study to Assess the Efficacy of ICDs in Patients With Non-Ischemic Systolic Heart Failure on Mortality). 3 This subgroup analysis showed a trend toward mortality prevention with ICD but did not reach statistical significance (hazard ratio, 0.70; 95% confidence interval, 0.39-1.26).In both the primary and subgroup analyses, the authors used a hazard ratio of 0.50 (95% confidence interval, 0.29-0.88) in favor of ICD use when referring to the COMPANION trial.However, the above-mentioned hazard ratio (95% confidence interval) was reported in the COMPANION trial for the comparison between CRT-D and pharmacological therapy in the nonischemic cardiomyopathy subgroup, not for CRT-D versus CRT-pacemaker. 2 The trial never reported any separate statistical data for the comparison between CRT-D and CRT-pacemaker in the patients with nonischemic cardiomyopathy.Therefore, the inclusion of COMPANION in the primary analysis could be misleading given the imbalanced use of CRT, which has been shown to improve mortality in patients with heart failure regardless of ICD placement, 4,5 exclusively in the ICD arm and not in the control arm.Moreover, the subgroup analysis of "CRT only" trials included 1 trial that compared CRT-D with CRT-pacemaker (CRT subgroup of DANISH) 3 and a trial that compared CRT-D with medical therapy (COMPANION), 2 which makes the conclusion "that ICD may still reduce all-cause mortality in patients who are also candidates for CRT therapy" not supported by the data that the authors analyzed.In summary, the findings of this meta-analysis continue to support the notion of primary prevention ICD in patients with nonischemic cardiomyopathy, which is an important finding in view of the neutral results from the recent DANISH trial. 3However, accurate treatment summary estimates depend on correct selection of trials for analysis.
Preliminary outcomes of a primary care-based skin cancer screening program.
Authors: Laura Ferris, Melissa Saul, Yan Lin, Martin A. Weinstock, Alan Geller, Francis Solano, Erica Bromberg Neuren, John M. Kirkwood
Journal: Journal of Clinical Oncology (2016)

1508 Background: Screening for melanoma has the potential to save lives through early detection. However, few studies of organized screening programs have been reported in the United States. Methods: Primary care providers (PCPs) who are part of UPMC, a large health care system in western Pennsylvania, were offered online training in skin cancer screening (using the validated INFORMED module) and asked to provide an annual skin examination to patients age 35 years and older who presented for routine care. Demographics of screened patients, screening rate by PCP completion of training, and depth of melanomas diagnosed in screened vs. unscreened patients for the first 12 months of this initiative are presented. Results: In 2014, 333,788 screen-eligible patients were seen at UPMC and 51,772 (15.5%) were screened for skin cancer; the remaining patients made up the unscreened cohort. Patients seen by a PCP who completed the online training were more likely to be screened (24.7% of eligible patients vs. 12.6% with a PCP who did not complete training, p<0.001). The median age of screened patients was 60 years and the ratio of women to men screened was 1.3. 90.5% of screened individuals reported their race as white. Using hospital records and cancer registry data, we identified 48 incident melanomas in the screened group and 99 in the unscreened group. In the screened group, melanomas were diagnosed more frequently (1 per 1,078 in the screened group vs. 1 per 2,849 in the unscreened group, p<0.001), thinner (mean Breslow depth of 0.32 mm vs. 0.87 mm, in the unscreened group, p = 0.023), and more likely to be in situ, although this did not achieve statistical significance (39.6% in screened group vs. 28.3% in the unscreened group, p =0.168). Conclusions: Physician education and population-based screening for melanoma results in detection of thinner melanomas. Since melanoma thickness is predictive of mortality, physician education and patient screening has the potential to reduce melanoma mortality, although further studies will be needed to determine this. This approach also resulted in higher rates of screening of men, who are at highest risk of death from melanoma but have much lower screening rates than women, than other initiatives reported in the literature.
Controversies in the Management of Low-Risk Differentiated Thyroid Cancer
Authors: Megan R Haymart, Nazanene H Esfandiari, Michael T Stang, Julia Ann Sosa
Journal: Endocrine Reviews (2017)

Controversy exists over optimal management of low-risk differentiated thyroid cancer. This controversy occurs in all aspects of management, including surgery, use of radioactive iodine for remnant ablation, thyroid hormone supplementation, and long-term surveillance. Limited and conflicting data, treatment paradigm shifts, and differences in physician perceptions contribute to the controversy. This lack of physician consensus results in wide variation in patient care, with some patients at risk for over- or undertreatment. To reduce patient harm and unnecessary worry, there is a need to design and implement studies to address current knowledge gaps.
Re: Declan G. Murphy, Christopher J. Sweeney, Bertrand Tombal. “Gotta Catch 'em All” or Do We? Pokemet Approach to Metastatic Prostate Cancer. Eur Urol 2017;72:1–3.
Authors: Alison C. Tree, Shankar Siva, Piet Ost
Journal: European Urology (2017)
A phase I study of continuous (Con) and intermittent (Int) AZD2014 plus fulvestrant (F) in patients (pts) with estrogen receptor (ER+) metastatic breast cancer (BC).
Authors: Erika Paige Hamilton, Manish R. Patel, W Larry Gluck, Amy M. Weise, Shubham Pant, Suzanne Fields Jones, Patricia LoRusso, Muaiad Kittaneh, Sabina Cosulich, Elizabeth A. Harrington, Gillian Littlewood, Elisabeth Maria Oelmann, Howard A. Burris
Journal: Journal of Clinical Oncology (2016)

563 Background: Preclinical and clinical data suggest that pts with ER+ BC lose sensitivity to hormonal therapy and increase dependency on the mTOR pathway. AZD2014 is a selective dual mTORC1/2 inhibitor offering additional benefit vs other mTOR-Is through inhibition of TORC2 and short t1/2. This trial assesses the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of AZD2014 administered on either a Con or Int schedule in combination with F. Methods: Pts with ER+ BC (prior F progression allowed) were given Con or Int AZD2014 with 500mg F IM on day 1 (d14 load) of each 28 day cycle. Results: 99 pts (50 w/ prior F) were enrolled w/ a median of 6 prior Txs (range 1-26): 43 pts on Con (50mg BD, 35mg BD, 100mg QD, 75mgQD); 56 pts on Int (170mg, 125mg BD 2/7). Overall response rate (confirmed and unconfirmed) in Con was 23.3% and 20.5% in Int; 15 pts had PRs (9 confirmed [cPR], 6 unconfirmed). Clinical benefit rate (CBR = CR+PR+SD > 24 wks) was 40%. The median duration of cPRs was 9.1 months (95% CI; 3.9 to 16.0 months). Of those with prior F progression, 6 patients (12%) had cPRs, 52% were progression free for ≥ 5 cycles, and 24% for ≥ 10 cycles. mTORC1 and 2 expression was decreased in tumor and surrogate tissue. On Con, dose limiting toxicities (DLTs) were rash/stomatitis, hyperglycemia, fatigue, stomatitis, and rash (all 1 pt each); no DLTs were seen on Int. Discontinuation at RP2Ds due to AEs was 3% at Int (125mg BD) and 31% at Con (50mg BD). All grade treatment-related toxicity include: nausea (49% Con; 68% Int), fatigue (56% Con; 48% Int), stomatitis (58% Con; 34% Int), rash (33% Con, 13% Int) and diarrhea (42% Con; 41% Int). Nausea improved w/ prophylactic antiemetics. PK demonstrated no impact of F on AZD2014 exposure. RP2Ds are 50 mg BD Con and 125 mg BD Int. Conclusions: Both Con and Int dosing of AZD2014 with F is tolerable with clinical benefit observed. The activity and duration on trial seen in the setting of prior F progression is very encouraging. Toxicities and discontinuation rate, particularly on the Int schedule, compare favorably to observed rates in other trials with mTOR-I's. A randomized phase II trial of the combination is ongoing. Clinical trial information: NCT01597388.
A History of Asthma From Childhood and Left Ventricular Mass in Asymptomatic Young Adults
Authors: Dianjianyi Sun, Tiange Wang, Yoriko Heianza, Jun Lv, Liyuan Han, Felicia Rabito, Tanika Kelly, Shengxu Li, Jiang He, Lydia Bazzano, Wei Chen, Lu Qi
Journal: JACC Heart Failure (2017)

This study aimed to examine whether a history of asthma from childhood is associated with left ventricular (LV) mass in adulthood.Asthma has been related to various cardiovascular risk factors affecting LV hypertrophy. The authors saw a need for a prospective study to analyze the relationship between a history of asthma from childhood and markers of LV mass among asymptomatic young adults.Prospective analyses were performed among 1,118 Bogalusa Heart Study participants (average age at follow-up 36.7 ± 5.1 years), with a baseline history of self-reported asthma collected since childhood (average age at baseline 26.8 ± 10.1 years). LV mass (g) was assessed using 2-dimensional guided M-mode echocardiography and was indexed for body height (m2.7) as LV mass index (LVMI; g/m2.7). A multivariate linear mixed model was fitted for the repeated measures.After an average of 10.4 ± 7.5 years of follow-up, participants with a history of asthma from childhood had a greater LV mass (167.6 vs. 156.9; p = 0.01) and LVMI (40.7 vs. 37.7; p < 0.01) with adjustment for age, sex, race, smoking status, antihypertensive medication, heart rate, and systolic blood pressure (SBP). The difference of LVMI between group with asthma and the group without asthma remained significant after additional adjustment for body mass index (39.0 vs. 37.1; p = 0.03) and high-sensitivity C-reactive protein (38.4 vs. 36.6; p = 0.04). In addition, the authors found significant interactions between SBP and asthma on LV mass and LVMI (p for interaction <0.01, respectively). The associations between asthma and LV measures appeared to be stronger among pre-hypertensive and hypertensive participants (SBP ≥130 mm Hg) compared with participants with normal SBP (<130 mm Hg) (regression coefficient: 39.5 vs. 2.3 for LV mass and 9.0 vs. 0.9 for LVMI).The findings of this study indicate that a history of asthma is associated with higher LVMI, and this association is stronger among participants with pre-hypertension and hypertension.
Bronchial Provocation Testing Can Be Improved by Using Dry Powder Adenosine Instead of Nebulized Adenosine Monophosphate
Authors: Anne J. Lexmond, Ilse M. Boudewijn, Paul Hagedoorn, Siebrig Schokker, Claire A. Cox, Judith M. Vonk, Nick H. T. ten Hacken, Henderik W. Frijlink, Sebastiaan J. Vroegop, Maarten van den Berge
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Nivolumab combined with hypofractionated stereotactic irradiation (HFSRT) for patients with recurrent high grade gliomas: A phase I trial (NCT02829931).
Authors: Solmaz Sahebjam, Peter A. J. Forsyth, John Arrington, Nam D. Tran, Michael Vishal Jaglal, Sepideh Mokhtari, Wendy Long, Robert J Macaulay, Melissa Wicklund, Ali Drury-Sibiga, Tyra Gatewood, Timothy J. Robinson, Raju R. Raval, Michael Yu
Journal: Journal of Clinical Oncology (2017)

TPS2084 Background: Nivolumab is an IgG4 monoclonal antibody that targets the PD-1 immune checkpoint pathway and prevents binding of PD-1 with PD-L1 and PD-L2. Expression of PD-1 and PD-L1 is found in the microenvironment of high grade gliomas and correlates with worse outcome providing a rationale for investigating nivolumab in this group of patients (pts) with very limited treatment options. Nivolumab monotherapy is well tolerated in recurrent glioblastoma pts. Preclinical studies have demonstrated that radiotherapy synergizes with anti PD-1/PD-L1 blockade and produces tumor regression and long-term survival in orthotopic murine models of glioma. This report describes an ongoing phase I trial of nivolumab in combination with HFSRT in pts with recurrent WHO grade III or IV gliomas. Methods: This phase I study includes a safety cohort of 6 pts followed by dose expansion cohort of 20 pts (NCT02829931). Pts with bevacizumab naïve recurrent WHO grade III or IV gliomas (maximum diameter of enhancing brain lesion ≤ 4 cm) are eligible. An interval of at least 6 months after the end of prior radiation therapy is required unless there is a new recurrence outside of the previous radiotherapy treatment field. Eligible patients will be treated with HFSRT to the recurrent tumor (30 Gy delivered in 5 fractions). Nivolumab will be started 5 days after HFSRT. It will be administered intravenously every 2 weeks (at 240 mg flat dose) for 4 months. After 4 months, nivolumab will be administered every 4 weeks at 480 mg flat dose. The primary study objectives are to determine safety and tolerability of nivolumab administered in combination with HFSRT to recurrent high grade gliomas. Secondary endpoints include determination of the preliminary antitumor activity (response rate, 6-months survival and 9-months survival rates), and exploring tissue and imaging biomarkers. Study Progress: At deadline for abstract submission, 5 patients have been treated on this study. Clinical trial information: NCT02829931.
Detection of tumor-derived DNA mutations in cerebrospinal fluid of patients with primary or metastatic brain tumors.
Authors: Jianfei Wang, Wenbo Han, Chen Tian, Ying Hu, Yanhui Chen, Xiangru Li, Ruihan Guo, Haibo Wang, Henghui Zhang
Journal: Journal of Clinical Oncology (2017)

2070 Background: Because detecting tumor-derived cell free DNA (cfDNA) in the blood of patients with primary or metastatic brain tumors is challenging, here we studied whether cerebrospinal fluid (CSF) could be serve as an alternative “liquid biopsy” by enabling measurement of circulating DNA within CSF to characterize tumor specific mutations. Methods: The paired cfDNA in CSF and plasma were collected from 20 patients with brain tumors and was subjected to enrichment for a 1.15M size panel cover exon regions from 1,086 genes. Followed by next generation sequencing on an Illumina X10 platform, the captured sequencing data was further processed using bioinformatics analysis to identify somatic mutations, including single nucleotide variants (SNV) and short insertions/deletions (indels). Results: The mutation profiles of 48 tumor associated genes in cfDNA were compared between the CSF and plasma. Our results showed that both average somatic mutation number and frequency identified in the cerebrospinal fluid was much higher than that in the corresponding plasma samples (25 vs. 18 &amp; 1.39% vs. 0.55%). Among the twenty cases, one more potential actionable mutation, EGFR exon 19 deletion mutation with a 25.38% allele frequency variation, was only detected in the CSF cfDNA of a patient with brain metastasis lung cancer. Conclusions: Tumor mutations were detectable in CSF cfDNA of patients with different primary and metastatic brain tumors. Thus cerebrospinal fluid cell free DNA analysis could be a potential alternative analysis for patients with primary or metastatic brain tumors.
Multinational case-control study of risk factors for the development of late invasive pulmonary aspergillosis following kidney transplantation
Authors: F. López-Medrano, M. Fernández-Ruiz, J.T. Silva, P.L. Carver, C. van Delden, E. Merino, M.J. Pérez-Saez, M. Montero, J. Coussement, M. de Abreu Mazzolin, C. Cervera, L. Santos, N. Sabé, A. Scemla, E. Cordero, L. Cruzado-Vega, P.L. Martín-Moreno, Ó. Len, E. Rudas, A. Ponce de León, M. Arriola, R. Lauzurica, M.D. David, C. González-Rico, F. Henríquez-Palop, J. Fortún, M. Nucci, O. Manuel, J.R. Paño-Pardo, M. Montejo, A. Vena, B. Sánchez-Sobrino, A. Mazuecos, J. Pascual, J.P. Horcajada, T. Lecompte, A. Moreno, J. Carratalà, M. Blanes, D. Hernández, E.A. Hernández-Méndez, M.C. Fariñas, M. Perelló-Carrascosa, P. Muñoz, A. Andrés, J.M. Aguado
Journal: Clinical Microbiology and Infection (2017)