tbuckley/cabot-search huggingface dataset:
Exercise intolerance among survivors of childhood cancer exposed to cardiotoxic therapy: Identification of survivors at increased risk through myocardial strain and ejection fraction.
Authors: Kirsten K. Ness, Juan Carlos Plana Gomez, Vijaya Joshi, Russell V Luepker, Jean-Bernard Durand, Daniel M. Green, Robyn Partin, MS, Aimee Santucci, Deo Kumar Srivastava, Melissa M. Hudson, Leslie L. Robison, Gregory T. Armstrong
Journal: Journal of Clinical Oncology (2018)

10565 Background: Exercise intolerance is an established risk factor for heart failure and death in the general population. Exercise capacity and factors associated with intolerance have not been extensively studied in adult survivors of childhood cancer exposed to cardiotoxic therapy. Methods: Survivors exposed to cardiotoxic therapies, without clinical heart failure (N = 577, 52% male, mean age 35.8±8.2 years), and community controls (N = 286, 48% male, mean age 34.4±10.0 years) completed maximal cardiopulmonary exercise testing to determine exercise capacity (pkVO2; intolerance defined as < 20th %tile of age- and sex-specific predicted values) and echocardiography for EF and global longitudinal strain (GLS). EF < 50% and GLS ≥2 SD above age and sex normative values were evaluated for associations with exercise intolerance among survivors in models adjusted for race, pulmonary function, neuropathy, strength, physical activity and smoking. Results: Exercise intolerance (93.7%) and abnormal EF (7.6%) and GLS (27.6%) were common among survivors, differing significantly from controls: lower mean pkVO2 (25.8±8.0 vs. 32.9±9.4, p = 0.001) and EF (57.6±5.5 vs. 60.3±5.5, p < 0.001) and higher GLS (-19.6±2.6 vs. -20.4±3.2, p < 0.001). Conclusions: Survivors exposed to cardiotoxic agents have dose dependent impairment in exercise capacity. Abnormal GLS, but not EF, is associated with exercise intolerance among survivors, and should be considered in screening guidelines for survivors. pkVO2 EF GLS Control 32.9±9.4 60.3±5.5 -20.4±3.2 1-199 mg/m2 anthracyclines 28.7±6.4* 58.4±5.4* -20.2±2.8 200-349 mg/m2 anthracyclines 27.6±6.5* 58.4±5.4* -20.2±2.8 350+ mg/m2 anthracyclines 25.4±6.1* 57.2±4.9* -19.5±2.6* Chest RT, any anthracyclines 27.5±4.8* 57.0±3.9* -19.5±2.0* Chest RT, no anthracyclines 25.4±7.1* 58.2±6.0* -19.1±3.0* *p < 0.05 for comparison with control In adjusted models, EF < 50% was not (OR 2.2, 95% CI 0.4-11.1), but GLS ≥2 SD was (OR 3.0, 95% CI 1.1-8.2) associated with exercise intolerance among survivors. In models limited to survivors with EF > 50% GLS identified survivors with exercise intolerance (OR 3.7, 95% CI 1.1-13.0).
A Brief Report of Transformation From NSCLC to SCLC: Molecular and Therapeutic Characteristics
Authors: Léonie Ferrer, Matteo Giaj Levra, Marie Brevet, Martine Antoine, Julien Mazieres, Giulio Rossi, Rita Chiari, Virginie Westeel, Michel Poudenx, Jacques Letreut, Radj Gervais, Giorgia Osman, Nicolas Girard, Anne Claire Toffart, Silvia Novello, Denis Moro-Sibilot
Journal: Journal of Thoracic Oncology (2018)
A phase I, open-label dose-escalation trial of weekly (qw) BI 836880, a vascular endothelial growth factor (VEGF)/angiopoietin-2 (Ang-2)-blocking Nanobody, in patients (pts) with advanced/metastatic solid tumors.
Authors: Nicolas Isambert, Elena Elez, Sylvie Zanetta, Ignacio Matos, Serge Nazabadioko, Wenqiong Xue, Philippe Carrière, Josep Tabernero
Journal: Journal of Clinical Oncology (2018)

e24013 Background: VEGF and Ang-2 are often overexpressed in human cancers and the VEGF/VEGFR2 and Ang-2/Tie-2 pathways are established independent therapeutic targets. Given the crosstalk between the pathways there is rationale for dual inhibition. BI 836880, a humanized bispecific nanobody (engineered antibody fragment of variable antibody domains) inhibits VEGF and Ang-2 and has demonstrated preclinical activity in cancer models. Methods: Pts with solid tumors refractory after prior therapies/for whom no therapy existed received BI 836880 qw (IV; starting dose 40 mg). Dose escalation followed a Bayesian logistic regression model with overdose control. Maximum tolerated dose (MTD; primary endpoint) was evaluated based on dose-limiting toxicities (DLTs) in the first 21-day cycle. Treatment-related AEs (TRAEs) leading to dose reduction/discontinuation (secondary endpoint), PK/PD and best overall response were assessed. Results: 14 pts have so far been treated: median age 60 yrs; 79% female; most common primary tumor sites were colorectal (43%), ovarian/endometrial (29%). Median (range) duration of treatment: 33 days (1–483). Most common AEs (all grade/grade ≥3): asthenia 57%/7%, decreased appetite 29%/0%, vomiting 29%/0%, hypertension 21%/7%. 1 pt had an AE leading to dose reduction (LVEF decrease; TRAE). 5 pts had TRAEs leading to discontinuation; 3 pts who experienced DLTs (see table), 2 pts with non-DLTs (abdominal infection and fistula [n = 1]; pulmonary hemorrhage [n = 1]). 2 pts (endometrial/ovarian carcinoma [n = 1 each]) had confirmed partial responses. PK/PD analysis of 9 evaluable pts showed dose-proportional plasma kinetics of BI 836880. Conclusions: BI 836880 demonstrated a manageable safety profile and dose-proportional plasma kinetics. The 180 mg cohort is being expanded to confirm the MTD. In a parallel study of BI 836880 q3w, recommended phase 2 dose was determined as 720 mg. Clinical trial information: NCT02689505.Dose, mg Pts, n Pts with DLT, n 40 2 0 120 5 1: G2 proteinuria 150 2 0 180 2* 0 240 3 2: G3 proteinuria and G3 hypertension (n = 1); G3 LVEF decrease (n = 1) G = grade *Cohort being expanded to confirm MTD; Week 1 Cycle 2
Change of expression of estrogen-regulatory genes in uterine malignancies.
Authors: Denis S. Kutilin, Oleg Ivanovich Kit, Dmitry I. Vodolazhsky, Ivan Nikitin, Tatiana Moiseenko, Elena Mikhaylovna Frantsiyants
Journal: Journal of Clinical Oncology (2016)

e17126 Background: Uterine cancer ranks 6th among the most common cancers affecting women in developed countries. Hyperestrogenia plays a leading role in the pathogenesis of this disease. The purpose of this study was to investigate changes in expression of genes responsible for the reception of estrogen and steroids metabolism: CYP1A 1, CYP1A 2, CYP1B 1, CYP19A, ESR1, ESR2, GPER, STS, SULT1A and SULT1E1 in uterine malignancies to create a predictive biomarker of malignancy. Methods: This study used biopsies of conditionally healthy and tumor tissues of 27 patients aged 33-75 years with histologically confirmed diagnosis of uterine cancer. Relative expression of genes was determined by RT-qPCR (ACTB gene – reference). Total RNA was isolated from tissue by Chomczynski&Sacchi method. Reverta-L reagent kit (Russia, InterLabService) was used to synthesize cDNA library. Primers were designed using the NCBI GenBank database. RT-qPCR amplification was performed on Thermal Cycler Bio-Rad CFX96 (Bio-Rad, USA). Results: Tumor tissue in all groups of patients (median age 60 years) showed an increased expression of gene ESR1 by 124% (p < 0.05) as compared to healthy uterine tissue. Patients under 55 years showed an increased expression of gene SULT1E1 by 200% (p < 0.005), and patients over 55 years - an increased expression of gene ESR1 by 124% (p < 0.005) in the tumor tissue compared with healthy uterine tissue. Patients with uterine G1 adenocarcinoma (median age 63 years) showed significant (p < 0.005) increase in expression of genes CYP1A1, CYP1A2, CYP1B1, CYP19A, ESR1, ESR2, GPER, STS, SULT1A1 and SULT1E1 by 1820%, 845% , 420%, 737%, 198%, 174%, 54%, 746%, 309% and 412% in the tumor tissue compared to normal, patients with G2 adenocarcinoma (median age 59 years) did not have significant differences in gene expression, and patients with G3 adenocarcinoma (median age 58 years) showed a significant (p < 0.005) increase in expression of genes CYP1A2, CYP19A, ESR2, GPER, STS and SULT1E1 by 90%, 72%, 98%, 50%, 130% and 110%. Conclusions: Gene expression of CYP1A1, CYP1A2, CYP1B1, CYP19A, ESR1, ESR2, GPER, STS, SULT1A and SULT1E1 in tumor tissue of uterine varies depending on the degree of differentiation of tumor cells (G) and age of patients.
NHS makes good progress on sustainability, report shows
Authors: Jacqui Wise
Journal: BMJ (2018)

Over the past 10 years the health and social care system in England has reduced its carbon footprint by 18.5% at the same time as clinical activity has grown by 27.5%, according to a report from the Sustainable Development Unit for NHS England and Public Health England.1

Carbon emissions have fallen from 33.3 million tonnes in 2007 to 27.1 million tonnes in 2017—a reduction equivalent to the annual emissions from a small country such as Mauritius or Cyprus. The rate of reduction has sped up in the past two years but is still behind the trajectory to achieve the Climate Change Act 2020 target of 34%.

For the first time, the amount of water used directly and indirectly by any health and social care system in the world has been estimated. The total water footprint of the NHS in England fell by 21% over …
The influence of cisplatin de-escalation on survival outcomes in oropharyngeal head and neck squamous cell carcinoma (OPC).
Authors: Geoffrey David Peters, Robin Milne, Anne Bernard, Kate Elizabeth Roberts, Matthew C Foote, Benedict Panizza, Sandro Virgilio Porceddu, Jermaine Coward
Journal: Journal of Clinical Oncology (2017)

e17551 Background: Chemoradiotherapy (CRT) with 3 cycles (#) of high-dose cisplatin (HDC) (100mg/m2 weeks 1,4 &amp; 7) and 70Gy over 7 weeks is associated with improved overall survival (OS) compared with radiotherapy (RT) alone in locally advanced OPC. Human Papilloma Virus (HPV) related tumours have superior outcomes and de-escalating treatment is a contemporary issue. Our study objectives were to determine if 2# HDC were non-inferior to 3#, how this was influenced by prognostic factors including stage, smoking history and p16 status, and to explore toxicity attributed to HDC. Methods: A single centre, retrospective analysis was undertaken for OPC patients who received CRT with HDC between Oct 2009 -Dec 2012. Those with distant metastatic disease or receiving induction chemotherapy were excluded. Data extracted included HPV and smoking status, tumour stage by 7 th Ed AJCC TNM and ICON-S classification, # HDC completed, toxicity and OS. Log-rank test was used for OS analysis. Results: 63, 96 and 4 patients received 3, 2 and 1 # HDC respectively. Median RT dose was 70Gy (range 66-70). 110 (67.5%) were p16 +, 28 (17.2%) were p16 negative and 25 (15.3%) unknown. 52 had omission of #3 HDC predominantly due to neutropenia (33%), nephrotoxicity (23%) and ototoxicity (12%). 19 had delays in #2 HDC resulting in omission of #3 due to completion of RT. There was no difference in OS between 3 #(mean OS (yrs)+/- SEM: 6.05+/- 0.22) or 2# HDC (5.70+/- 0.21) in all comers (p = 0.255). For RTOG0129 low risk p16+ patients, there was no significant difference (p = 0.896) between 3# (6.33+/- 0.24; n = 24) and 2# (6.18+/- 0.25; n = 44) HDC. Similar results were evident for ICON-S stage I for 3# (6.36+/-0.19; n = 25) vs 2# (6.30+/- 0.19; n = 42) HDC (p = 0.932). For RTOG 0129 intermediate risk p16 + OPC there was a significant difference (p = 0.017) in OS favouring 3# (6.29+/-0.22; n = 20) versus 2# (4.81+/-0.67; n = 10) HDC. For p16 negative patients there was no difference (p = 0.265) in OS between 3# (4.06+/-0.94; n = 9) and 2# (5.17+/-0.48; n = 22) HDC. Conclusions: This data suggests that cisplatin de-escalation does not confer inferior OS in low risk HPV related OPC. Significant toxicities with HDC influenced the ability to complete prescribed treatment.
Corrigendum to “Alveolar echinococcosis: From a deadly disease to a well-controlled infection. Relative survival and economic analysis in Switzerland over the last 35 years” [J Hepatol 49 (2008) 72–77]
Authors: Paul R. Torgerson, Alexander Schweiger, Peter Deplazes, Maja Pohar, Jürg Reichen, Rudolf W. Ammann, Philip E. Tarr, Nermin Halkic, Beat Müllhaupt
Journal: Journal of Hepatology (2018)
Exosomal miR-1290 as a predictive biomarker for docetaxel response in metastatic castration resistant prostate cancer (mCRPC).
Authors: Niraj Konchady Shenoy, Liang Wang, Chiang-Ching Huang, Manish Kohli
Journal: Journal of Clinical Oncology (2016)

e16596 Background: Docetaxel is an approved and widely used chemotherapy for treating mCRPC. There are no validated predictive biomarkers for assessing docetaxel response. Extracellular microRNAs (miRNAs) have demonstrated promising potential as biomarkers in cancer and treatment outcomes. We evaluated candidate plasma exosomal miRNAs as biomarkers of response to docetaxel in mCRPC. Methods: RNA sequencing of cell free plasma RNA from mCRPC patients was performed to identify candidate exosomal miRNAs that demonstrated association with overall survival in a screening cohort of 23 mCRPC patients. Candidate miRNAs with prognostic associations were then evaluated in a separate second cohort of 42 mCRPC patients using quantitative real-time polymerase chain reaction, for association with response to docetaxel, (as assessed by the time period between the start of docetaxel and switch in systemic therapy because of disease progression). Cox regression and Kaplan-Meier analyses were used to evaluate progression-free survival association using candidate miRNAs. Results: PlasmaRNA sequencing in the screening cohort generated > 6.80 million mappable reads per patient sample. Of those with normalized read counts ≥ 5, 43% were mapped to miRNAs for a total of 375 known and 57 novel miRNAs. Cox regression analysis identified an association of miR-1290, -1246, and -375 prognostic for overall survival (false discover rate < 0.05). In evaluating the predictive value of the candidate miRNAs for response to docetaxel in mCRPC in a second cohort of 42 mCRPC patients treated with docetaxel chemotherapy, we observed that higher miR-1290 levels were associated with a shorter progression-free survival time (median PFS: 9 months vs 13 months, p = 0.14). Conclusions: Predictive biomarkers for docetaxel response based on miR evaluation revealed a single miR, miR-1290, as a promising candidate with higher plasma levels associated with poor response to docetaxel in mCRPC patients. A larger study is needed for validating these findings.
Treatment patterns and costs associated with axitinib and everolimus treatment for renal cell carcinoma: A retrospective health claims analysis.
Authors: Elizabeth A. MacLean, Joshua Brown, Timothy W. Smith, Laura A. Cisar, James Harnett
Journal: Journal of Clinical Oncology (2016)

e16089 Background: Real-world data may inform treatment decisions for metastatic renal cell carcinoma (mRCC). We compared treatment patterns and healthcare costs for mRCC patients initiating axitinib or everolimus as 2nd-line (2L) or later (3L+) therapy. Methods: This retrospective cohort study used Truven Marketscan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits Databases to identify patients age ≥ 20 years with mRCC newly initiating axitinib or everolimus between 5/1/2012 – 4/30/2014. Patients had continuous enrollment ≥ 12 months before and ≥ 6 months post-index, ≥ 2 index prescriptions and ≥ 1 prior line of mRCC therapy using all available claims history. We compared demographics, clinical characteristics and treatment patterns using Chi-square, Student t-test, and Wilcoxon signed-rank test (α = 0.05). Costs were compared using generalized linear modeling to adjust for demographic, clinical, and treatment variables. Results: Among 310 patients (50% receiving axitinib), cohorts were not significantly (NS) different in demographics or Charlson Comorbidity Index. Axitinib patients had higher mean [SD] days from earliest RCC diagnosis to index (784 [358] vs. 686 [391], p = 0.0231) and from earliest metastatic diagnosis to index (632 [342] vs. 518 [332], p = 0.0.0032), and higher mean [SD] prior lines of therapy (1.58 [0.87] vs 1.17 [0.46], p < 0.0001). More axitinib patients were persistent at six months (43.9% vs. 22.6%, p = 0.0001), and fewer switched within six months (31.6% vs. 43.2%, p = 0.0458). Mean [95%CI] RCC-related ($70,352 [$59,237 – $83,552] vs $65,165 [$54,719 – $77,605], p = 0.1920) and all-cause total costs ($83,659 [$69,473 – $100,742] vs $81,777 [$67,640 –$98,869], p = 0.7207) were NS different for axitinib and everolimus, respectively. Adjusted models also showed NS differences for all-cause and RCC-related total costs in the base model and when stratified by 2L/3L+ and age < 65/ ≥ 65. Conclusions: Although axitinib patients had more time from diagnosis to index and more prior therapy, treatment persistence was longer and total costs were NS different.
TCT-805 Temporal Trends and Outcomes of Percutaneous Ventricular Septal Rupture Closure in ST-elevation Myocardial Infarction in the United States
Authors: Srikanth Yandrapalli, Prakash Harikrishnan, Wilbert Aronow, William Frishman, Howard Cooper, Srihari Naidu
Journal: Journal of the American College of Cardiology (2018)
Prevalence of preexisting mental illness in SEER-Medicare breast cancer patients.
Authors: Cole Brandon Haskins, Bradley D. McDowell, Ryan Carnahan, Jess Fiedorowicz, Robert B. Wallace, Brian J. Smith, Elizabeth A. Chrischilles
Journal: Journal of Clinical Oncology (2018)

e13564 Background: Patients with mental illness (MI) existing before breast cancer (BC) may face varying diagnostic and treatment practices. However, studies have not explored the full range of preexisting MI. We described MI prevalence prior to BC diagnosis, and examined the impact of lookback period on reported MI prevalence in a broad national sample of patients from the SEER-Medicare linked cancer registry. Optimizing lookback improves the balance of sample size to misclassification risk. Methods: Included women were part of a study about preexisting MI and influence on endocrine therapy use, aged 68+ at their first BC diagnosed 2007-2013, excluding lobular carcinoma in situ. All patients had continuous Medicare parts A and B for 36+ months prior and 18+ months after BC diagnosis, 3+ months of continuous part D coverage prior and 18+ months after, and a record of surgery. MI was identified with one inpatient or two outpatient ICD-9 diagnoses occurring 30+ days apart. Results: Estimates of any MI prevalence increased with extended lookback: 6490 (24.2%) versus 3555 (13.3%) for 3 and 1-year intervals, respectively. Mood (11.1% at 3 years, 4.9% at 1 year), anxiety (9.5%, 4.2%), and psychotic disorders (5.0%, 3.0%) were most prevalent, followed by dementias (4.4%, 2.7%), drug use (4.2%, 1.8%), and bipolar disorders (1.2%, 0.8%). Less common were delirium (1.2%, 0.5%), adjustment (0.4%, 0.1%), alcohol (0.3%, 0.1%), and personality disorders (0.3%, 0.1%). Conclusions: As many as one-fourth of Medicare enrolled women have evidence of MI preceding BC diagnosis. Limiting lookback to a 1-year interval would allow for relaxed inclusion criteria, and increase sample size to 32,053 (16.4% larger). However, our 3-year lookback identified 10.9% more MI diagnoses than in our 1-year interval. The potential increase in sample size may not be worth the risk of MI misclassification. The 3-year cohort is well suited to detect MI and sufficiently robust to test most specific MI/cancer hypotheses.
Targeting mutant p53 with PK11007: A new approach for the treatment of patients with triple-negative breast cancer?
Authors: Naoise C Synnott, Matthias R Bauer, Stephen F. Madden, Alyson M. Murray, Rut Klinger, Norma O'Donovan, Darran O'Connor, William M. Gallagher, John Crown, Alan R Fersht, Michael J. Duffy
Journal: Journal of Clinical Oncology (2017)

e14099 Background:The identification of a targeted therapy for patients with triple-negative breast cancer (TNBC) is one of the most urgent needs in breast cancer therapeutics. Since the p53 gene is mutated in approximately 80% of TNBC patients, it is a potential therapeutic target for this form of breast cancer. PK11007 is a 2-sulfonypyrimidine that stabilizes and reactivates mutant p53 (Bauer et al, PNAS 2016). The compound recently was reported to preferentially decrease viability in p53-compromised cancer cells. The aim of this investigation was to evaluate PK11007 as a potential new treatment for TNBC. Methods: Cell viability was determined using the MTT assay. Apoptosis was detected using Annexin V Apoptosis Detection Kit. Migration was determined by Transwell migration assay. Knockdowns of p53 protein were carried out using predesigned Flexitube sequences (Qiagen). Results: IC 50 values for inhibition of proliferation by PK11007 in the panel of 17 breast cell lines ranged from 2.3 to 42.2 μM. There were significantly lower IC 50 values for TNBC than for non-TNBC cell lines (p = 0.03) and for p53-mutated cell lines compared with p53 WT cells (p = 0.003). Response to PK11007 however, was independent of ER or HER2 status of the cells. In addition, PK11007 induced apoptosis and inhibited migration in p53 mutant cell lines. Using RNAseq and gene ontogeny analysis, we found that PK11007 altered the expression of genes enriched in pathways involved in regulated cell death, regulation of apoptosis, signal transduction, protein refolding and locomotion. To establish if PK11007 acts by targeting mutant p53, we used siRNA to knockdown p53 in 3 p53-mutated TNBC cell lines. Reduction in p53 protein levels resulted in a significant decrease in the growth inhibitory effects of PK11007, in all 3 cell lines investigated, suggesting that PK11007 mediates growth inhibition via p53. The observations that PK11007 inhibited cell growth, induced apoptosis, blocked cell migration and altered genes involved in cell death, are all consistent with the ability of PK11007 to activate mutant p53. Conclusions: Based on our data, we conclude that targeting mutant p53 with PK11007 is a potential approach for treating p53-mutated TNBC.
TCT-492 Multimodality Management of Cardiogenic Shock in the United States: Insights from the Cardiogenic Shock Working Group Registry
Authors: Kevin Morine, Lena Jorde, Allen Razavi, Robert Pedicini, Shiva Annamalai, Michele Esposito, Kyle Gobeil, Jaime Hernandez-Montfort, Claudius Mahr, Arthur Reshad Garan, Navin Kapur
Journal: Journal of the American College of Cardiology (2018)