tbuckley/cabot-search huggingface dataset:
Phase II trial of everolimus and erlotinib in patients with platinum-resistant recurrent and/or metastatic head and neck squamous cell carcinoma.
Authors: Erminia Massarelli, Lawrence E. Ginsberg, Heather Lin, Hai T. Tran, J. Jack Lee, Michelle D. Williams, George R. Blumenschein, Charles Lu, Merrill S. Kies, Vassiliki Papadimitrakopoulou
Journal: Journal of Clinical Oncology (2013)

6067 Background: Head and neck squamous cell carcinoma (HNSCC) is characterized by epidermal growth factor receptor (EGFR) overexpression but treatments targeting EGFR have met with limited clinical success. We hypothesized that everolimus (EV), an mTOR inhibitor, potentiates the activity of erlotinib (ER), an EGFR tyrosine kinase inhibitor, in platinum-resistant recurrent and/or metastatic HNSCC. Methods: This single-arm two-stage phase II clinical trial evaluated EV 5 mg and ER 150 mg orally daily in patients (pts) with platinum-resistant recurrent and/or metastatic HNSCC. Primary endpoints were response rate and 12-week progression-free survival (PFS). Plasma biomarkers by multianalyte profiling (Luminex Corp) and ELISA at baseline (20 pts), 4 weeks (18 pts) and 12 weeks (16 pts) as well as p16 expression in baseline tumor tissue (29 pts) were assessed in correlation with clinical results. Results: Of the 36 evaluable pts (median age 61 years, 29 males, 19 with oropharynx primaries, 15 with ≥2 lines of chemotherapy, 17 with prior cetuximab), 3 (8%) achieved partial response at 4 weeks, one of which was confirmed at 12 weeks, while 27 (75%) pts achieved disease stabilization at 4 weeks, 11 of which were confirmed at 12 weeks. The 12-week PFS was 49%, median PFS was 11.9 weeks and median overall survival (OS) was 10.25 months. Grade 3 toxicities included mucositis (17%), fatigue (14%), skin (8%), diarrhea (8%), and 5 pts withdrew from trial secondary to toxicity. High neutrophil gelatinase-associated lipocalin(NGAL) levels at baseline were associated with worse OS (HR 4.59; 95%CI 1.36, 15.46; p=0.014) and at 4 weeks with worse PFS (HR=12.29; 95% CI 1.26, 119.87; p=0.03) and OS (HR=6.21; 95% CI 0.95, 40.62; p=0.057). High carbonic anhydrase-9 (CA-9) levels at 4 weeks were associated with worse OS (HR=1.18; 95% CI 1.001, 1.41; p=0.049), while decreased CA-9 levels at 4 weeks were associated with better PFS (p=0.77). Conclusions: Efficacy for the combination ofEV and ER is reasonable however plasma markers of tumor invasion and hypoxia are associated with worse outcomes, and further biomarker analysis may define subsets of pts with significant therapeutic benefit. Clinical trial information: NCT00942734.
Addressing the Opioid Epidemic in the United States
Authors: Walid F. Gellad, Chester B. Good, David J. Shulkin
Journal: JAMA Internal Medicine (2017)

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Is conventional chemotherapy effective in advanced sarcomatoid lung cancers?
Authors: Thibault Vieira, Aurelie Cazes, Bonnette Pierre, Leila Zemoura, Isabelle Monnet, Hubert De Cremoux, Christos Chouaid, Michael Duruisseaux, Etienne Giroux Leprieur, Laure Belmont, Armelle Lavole, Jacques Cadranel, Marie Wislez
Journal: Journal of Clinical Oncology (2012)

e18102 Background: Sarcomatoid lung cancers (SC) are associated with poor prognosis. A few studies suggest that these tumors are resistant to platinum-based chemotherapy. Methods: Between January 1994 and October 2011, all consecutive patients with SC were screened from six French centers. Patients with advanced disease and treated with first-line chemotherapy were included in this study. Clinical data, staging (TNM 2009 classification), drugs and response to chemotherapy (RECIST 1.1) at first tumor assessment were reported. Factors associated with progressive disease (PD) in univariate (p&lt;0.2) were included in multivariate analysis. Results: 111 patients with SC were screened. 51 had advanced stage and were treated by a first-line chemotherapy. Among them, 27 (53%) had initial advanced disease and 24 (47%) had relapse after radical surgery or radiotherapy. Patients were 60.7±3 years old, 69% were male, 86% smokers and 86% were symptomatic. PS was 0 (57%), 1 (39%) 2 (4%). Stages at the diagnosis were I (15.5%), II (13.5%), IIIA (20%), IIIB (6%), IV (45%). Histological subtype were pleomorphic (70%), pure sarcoma-like (20%) unspecified (6%), carcino-sarcoma (4%). 38 (75%) received a platinum based-combination and 13 (25%) a monotherapy. Drug given alone or combined with platin were gemcitabine (23%), navelbine (16%), placlitaxel (16%), docetaxel (12%), pemetrexed (9.8%), ifosfamide (9.8%), vepeside (4%) and others (11%). At first tumor assessment, PD and disease control rates were 71% and 29%, respectively. Median progression free survival was 2 months IC 95% [1.3, 2.7]. Median overall survival was 6 months [3.2, 8.8]. In univariate analysis, age, gender, smoking status, numbers of metastatic locations, histological subtypes, monotherapy vs platin-based combinations, relapse after radical treatment vs initial advanced disease were not associated with PD. In multivariate analysis, initial advanced disease was the only independent factor of PD (OR 4.59 [1.17, 18] p=0.03). Conclusions: Our series confirm that advanced SC are refractory to conventional chemotherapy. Molecular characterizations are needed to improve therapeutic strategy.
Analysis of treatment duration and safety of adjuvant erlotinib (E) versus placebo (P) after surgery in patients (pts) with non-small cell lung cancer (NSCLC): RADIANT trial.
Authors: Mary E.R. O'Brien, Wilfried Ernst Erich Eberhardt, Nasser K. Altorki, David R. Spigel, Lucio Crino, Chun-Ming Tsai, Eun Kyung Cho, Joo-Hang Kim, Aleksandra Szczesna, Philip C. Hoffman, Otto Burghuber, Shaf Keshavjee, Sergey Orlov, Piotr Serwatowski, Jiuzhou Wang, Margaret A. Foley, Julie D. Horan, Jung Wook Park, Frances A. Shepherd, Karen Kelly
Journal: Journal of Clinical Oncology (2014)

7535 Background: We describe treatment duration and safety in the safety full analysis set (sFAS) and in the subset of pts with EGFR del19 and L858R mutations (EGFR M+). Methods: RADIANT was a randomized trial of adjuvant E v P in pts with stage IB-IIIA NSCLC following complete tumor resection w/ or w/o adjuvant chemotherapy. Pts were randomized (2:1) to receive up to 2 years of E 150mg/day or P. AEs were graded with NCI CTCAE v3.0. Dose reductions to 100mg and then 50mg were allowed; pts not tolerating 50mg/day were discontinued. Results: The sFAS included 954 pts, of whom 159 (16.7%) were EGFR M+. AEs led to treatment termination in 33.6% of pts on E versus 8.5% on P in sFAS, and 30% versus 5.1% in the EGFR M+ subset. In sFAS, 22.6% of E pts had Gr ≥3 skin disorders (rash, dermatitis acneiform, pruritus, etc.) and 6.2% had Gr ≥3 diarrhoea. The figures were similar for EGFR M+ pts. In sFAS, pts received 11.9 versus 21.9 m (median) of E versus P, and 27% v 46% were treated for >22 m. For EGFR M+ pts median treatment duration was 21-22 m in both arms and 34% versus 40.7% (E vs P) received >22 m of therapy. In sFAS, 26.7% versus 10.8% (E vs P) pts in received <3 m of therapy, as did 21% versus 8.5% EGFR M+ pts. AEs led to dose interruption, reduction, or both in 18.5, 24.5, 25.5% in sFAS; the figures were generally similar for EGFR M+ pts. Conclusions: The safety profile of E was consistent with that in advanced disease, although Gr ≥3 skin disorders was more frequent than previously reported in advanced NSCLC (9-14%). For E, AE frequency was similar between sFAS and EGFR M+ subset. While treatment duration was longer in the EGFR M+ subset than sFAS, frequency of AE leading to treatment termination was similar. Further investigation of E in EGFR M+ is warranted. Clinical trial information: NCT00373425. sFAS EGFR M+ E P E P N 611 343 100 59 AEs leading to treatment termination % Any 33.6 8.5 30 5.1 Drug-related 26.7 2.3 25 0 AEs leading to dose Interruption 18.5 6.7 22 6.8 Reduction 24.5 2.6 22 1.7 Both % 25.5 1.5 34 1.7 Gr≥3 skin disorder % 22.6 0.3 20 0 Gr≥3 diarrhea % 6.2 0.3 5 0 Median treatment duration (m) 11.9 21.9 21.2 21.9 >22m of treatment % 27.5 45.8 34 40.7
Heritable interleukin-17F (IL17F) gene variation and overall survival (OS) in pancreatic cancer patients (pts): Results from a genome-wide association study (GWAS) in CALGB 80303
Authors: F. Innocenti, K. Owzar, N. Cox, P. Evans, M. Kubo, D. Hollis, T. Mushiroda, H. L. Kindler, Y. Nakamura, M. J. Ratain
Journal: Journal of Clinical Oncology (2009)

4531 Background: CALGB 80303 was a randomized, phase III study in 602 advanced pancreatic cancer (PC) pts treated with gemcitabine plus either bevacizumab or placebo. No difference in OS was observed between the two arms (Kindler, ASCO 2007). As part of the study, we prospectively collected germline DNA for pharmacogenetic studies, originally focusing on the association of candidate genes with OS and toxicity. We subsequently amended the study to conduct a GWAS in order to identify other associations. Methods: Germline DNA was isolated from peripheral blood on 352 pts, and was typed for more than 550,000 SNPs using the Illumina550 platform. The associations between OS and SNPs were investigated using the log-rank test. A review of the clinical data and ancestry genomic analysis identified 294 pts who were clinically eligible and determined to be genetically European, and this subset was used for the primary analysis. Results: For the analysis of OS, pts in both arms were pooled, and two SNPs were associated with OS using genome-wide criteria (p≤10–7). This included an intergenic SNP on chromosome 15 (rs7174643), and a nonsynonymous SNP in the IL17F gene ( rs763780 ) with an allelic frequency of 3.9% (H161R, p&lt;2.7x10–8). Median OS was significantly shorter for the H/R heterozygotes (3.1 months, 95% CI 2.3–4.3, n=23), as compared to the H/H homozygotes (6.8 months, 95% CI 5.8–7.3, n=271). This association remained highly significant when the analysis was stratified by extent of disease or previous radiotherapy. There was no evidence of an interaction with bevacizumab, suggesting that this SNP is prognostic rather than predictive. Conclusions: Heritable variation in IL17F may be a prognostic marker for PC. Wildtype (161H) IL17F is a pro-inflammatory, anti-angiogenic cytokine (Starnes, J Immunol 2001). The 161R mutant IL17F antagonizes wildtype IL17F (Kawaguchi, J Allergy Clin Immunol, 2006), potentially resulting in a pro-angiogenic effect. Replication studies in PC and other solid tumors are indicated. [Table: see text]
Cardiac Regeneration
Authors: Francisco X. Galdos, Yuxuan Guo, Sharon L. Paige, Nathan J. VanDusen, Sean M. Wu, William T. Pu
Journal: Circulation Research (2017)

Palliative surgery for congenital heart disease has allowed patients with previously lethal heart malformations to survive and, in most cases, to thrive. However, these procedures often place pressure and volume loads on the heart, and over time, these chronic loads can cause heart failure. Current therapeutic options for initial surgery and chronic heart failure that results from failed palliation are limited, in part, by the mammalian heart’s low inherent capacity to form new cardiomyocytes. Surmounting the heart regeneration barrier would transform the treatment of congenital, as well as acquired, heart disease and likewise would enable development of personalized, in vitro cardiac disease models. Although these remain distant goals, studies of heart development are illuminating the path forward and suggest unique opportunities for heart regeneration, particularly in fetal and neonatal periods. Here, we review major lessons from heart development that inform current and future studies directed at enhancing cardiac regeneration.
Accelerating the clinical trial start-up process for early-phase cancer studies: A test of process change to support rapid activation in an academic medical center.
Authors: Sheilah K Hurley, Therica M Miller, Rebecca Flores Stella, Keren Dunn, Ryan Schroeder, Mahendra Yatawara, Robert A. Figlin, Monica M. Mita, Howard Mark Sandler, Steven Piantadosi
Journal: Journal of Clinical Oncology (2013)

e17507 Background: Clinical trial sponsors have strong scientific, financial, and regulatory interests in rapidly activating studies at participating sites. Academic medical centers have difficulty activating trials within a few weeks of sponsor agreement because, among other inefficiencies, they engage the necessary committee reviews, regulatory approvals, contracting, and budgeting in serial fashion. Incremental revisions in such workflows do not result in strong improvements. Methods: We redesigned our institutional workflow to complete clinical trial activation tasks within six weeks. Historical procedures were replaced rather than scrutinized. A high level leadership committee was required to change and integrate procedures across the medical center, and engage sponsors to improve their turnaround times. A web-based collaborative workflow tracking tool was created to help coordinate the necessary tasks and measure performance. Six clinical trials from the Cancer Center portfolio were used to test and improve the new workflow. Results: Clinical trial activation redesign took one year. For the six studies used as tests of change, the activation times were 49, 54, 78, 58, 62, and 32 days. Times in excess of 6 weeks were largely due to sponsor delays. Conclusions: Considerable effort is required to significantly alter a complex workflow like clinical trial activation. Appropriate priorities, leadership, staffing, and tools are required. Markedly shortened study activation for a small series of cancer trials taught our academic medical center lessons that will be useful for improving the process for all clinical trials, and will make us a better partner for pharmaceutical and academic sponsors as well as for investigator initiated research. [Table: see text]
THE ASSOCIATION OF ISCHEMIA ON SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY-MYOCARDIAL PERFUSION IMAGE AND FRACTIONAL FLOW RESERVE BY CORONARY COMPUTED TOMOGRAPHIC ANGIOGRAPHY
Authors: Rine Nakanishi, Kazuhiro Osawa, Indre Ceponiene, Glenn Huth, Jason Cole, Michael Kim, Negin Nezarat, Sina Rahmani, Dong Li, Christopher Dailing, Matthew Budoff
Journal: Journal of the American College of Cardiology (2017)
CORONARY ARTERY CALCIUM IN THE ELDERLY: PREVALENCE, SEVERITY, AND ASSOCIATION WITH ALL-CAUSE MORTALITY
Authors: Yoav Arnson, Alan Rozanski, Heidi Gransar, Sean Hayes, Yuka Otaki, Mhairi Doris, Frances Wang, John Friedman, Louise Thomson, Balaji Tamarappoo, Piotr Slomka, Damini Dey, Daniel Berman
Journal: Journal of the American College of Cardiology (2017)
Use of gene expression profiling to identify fibronectin 1 and MIG as candidate biomarkers for breast cancer screening
Authors: E. B. Ruiz-Garcia, V. Scott, C. Machavoine, J. M. Bidart, L. Lacroix, S. Delaloge, F. Andre
Journal: Journal of Clinical Oncology (2009)

e22034 Background: There is a need to develop blood-based bioassays for breast cancer screening. We used differential gene expression between breast cancer samples and benign tumors to identify candidate biomarkers for blood-based screening Methods: 3 candidate proteins (Fibronectin 1, CXCL9, Complement Factor B) were identified from a gene expression dataset that included 120 breast cancer samples and 45 benign lesions. Proteins selection was done with these criteria: differential gene expression between cancer and benign lesion, protein released in the extracellular medium (SwissProt), commercially available ELISAkit, accuracy of the ELISA assay in a feasibility study (n=23). Proteins concentrations were determined in blood samples by ELISA. Blood samples were from normal volunteers blood donors (n=119) and early breast cancer patients (n=133). Results: 73% of the patients were cT1-T2 tumour. CA15.3 was within normal range (&lt;30 IU/ml) in 114 patients (86%). Blood concentrations of CXCL9 and Fibronectin 1 were higher in cancer patients as compared to normal volunteers, mean concentration for CXCL9 was 851pg/ml (range 121- 3941) and 635 pg/ml (range 12–4327) in cancer patients and normal volunteers respectively (p=0.013). CXCL9 concentration was significantly higher in patients with ER-negative breast cancer (mean: 999 pg/ml) as compared to normal volunteers (p=0.003), data consistent with gene expression profile. Fibronectin 1 mean concentration was 190 μg/ml (range 11–326) for cancer patients and 125 μg/ml (range 58–212) for normal volunteers (p&lt;0.001). AUC for breast cancer diagnosis were 0.78 and 0.62 for Fibronectin 1 and CXCL9 respectively. A combined score including Fibronectin 1 and CXCL9 dosages presented a sensitivity of 53% and a 98% specificity. Similar performances were observed for ER-negative tumors Conclusions: This study suggests that Fibronectin 1/CXCL9 dosage in serum could screen a significant rate of breast cancer, including ER-negative breast cancer. These data suggest that analysis of differential gene expression is a good approach to select candidate biomarker to set-up blood assays cancer screening. Prospective validation of the combined score, and development of in house ELISA assay for 25 additional proteins are ongoing. No significant financial relationships to disclose.
U2AF1 Mutation Variants and Their Phenotypic and Prognostic Relevance in Primary Myelofibrosis
Authors: Ayalew Tefferi, Daniela Barraco, Terra L. Lasho, Christy Finke, Sahrish Shah, Curtis A. Hanson, Rhett P. Ketterling, Animesh Pardanani
Journal: Blood (2016)
THE EFFECT OF PROPROTEIN CONVERTASE SUBTILISIN-KEXIN TYPE 9 INHIBITORS ON CLINICAL OUTCOMES IN PATIENTS WITH HYPERCHOLESTEROLEMIA: A META-ANALYSIS OF 16,721 PATIENTS FROM 33 RANDOMIZED CLINICAL TRIALS
Authors: Aris Karatasakis, Barbara Danek, Judit Karacsonyi, Bavana Rangan, Michele Roesle, Amy Atwell, Erica Resendes, Thomas Knickelbine, Michael Miedema, Shuaib Abdullah, Houman Khalili, Subhash Banerjee, Emmanouil Brilakis
Journal: Journal of the American College of Cardiology (2017)
Aggregates of Reticulocytes, Monocytes and Platelets Exist in Whole Blood of Sickle Cell Patients: Roles for Plasma Fibronectin, α4 Integrins and PSGL-1.
Authors: Julia E. Brittain, Shantres C. Clark, Kenneth I. Ataga, Eugene P. Orringer, Leslie V. Parise
Journal: Blood (2005)
DEFICIENCY OF LONG NONCODING RNA MALAT1 CAUSES IMMUNE SYSTEM DEREGULATION AND ACCELERATED ATHEROSCLEROSIS IN APO E-/- MICE
Authors: Wolfgang Poller, Martina Gast, Bernhard Rauch, Shinichi Nakagawa, Kannanganattu Prasanth, Andrea Stroux, Jan Haas, Benjamin Meder, Carsten Skurk, Ursula Rauch-Kröhnert, Ulf Landmesser
Journal: Journal of the American College of Cardiology (2017)
Continuation of sunitinib following RECIST progression on first-line sunitinib.
Authors: Mauricio Emmanuel Burotto Pichun, Julia Wilkerson, Wilfred Donald Stein, Robert John Motzer, Susan Elaine Bates, Tito Fojo
Journal: Journal of Clinical Oncology (2013)

4585 Background: In the last seven years the FDA and the EMA have approved seven agents for treatment of RCC. Five of these target the VEGF pathway. Methods: We conducted a detailed analysis of data from the sunitinib registration trial examining the growth and regression rate constants and the stability of the growth rate as measures of effectiveness and to understand development of resistance. Results: Sufficient data was available for the analysis of 350/374 patients enrolled. Statistically valid data was obtained in 321(91.7%). The median regression rate constant was 0.0048 days -1 , and in 59 patients no evidence of growth was recorded while on study, only regression. The median growth rate was 0.00082 days -1 and this rate was stable a median of 267 days, remaining stable beyond 300 days in 172 patients, beyond 600 days in 95 patients, and beyond 900 days in 49 pts. A suggestion of a possible increase of the growth rate while sunitinib was administered could be discerned in only 15/321 pts. With a median growth rate 0.00082 days -1 the estimated time to progression were sunitinib discontinued and then re-started would have been a minimum of 7.3 months. Thus a meaningful outcome could be achieved provided continued sunitinib is tolerable. Finally with an estimated 47%, 27% and 13% of tumor still sensitive to sunitinib 100, 200 and 300 days after starting therapy, shrinkage with a new TKI in patients who discontinue sunitinib before day 300 for toxicity may not be a sign of non-cross resistance, but of residual sensitive tumor. Conclusions: Prolonged stability of the growth rate of RCC on sunitinib is consistent with intrinsic and not acquired resistance. Baring toxicity, continued sunitinib beyond RECIST criteria for progression may provide a beneficial outcome and can be considered a treatment alternative in selected patients. Randomized trials to assess the value of VEGF TKI’s in patients whose disease has “progressed” on sunitinib should consider including an arm that continues sunitinib to test this hypothesis.