tbuckley/cabot-search huggingface dataset:
Kinetics of HE4 and CA125 markers in metastatic ovarian cancer: The META4 study.
Authors: Pierre-Jean Lamy, Célia Touraine, Caroline Mollevi, Sylvie Roques, Catherine Viglianti, Frederic Montels, Anne Floquet, Isabelle Laure Ray-Coquard, Michel Fabbro
Journal: Journal of Clinical Oncology (2017)

e17059 Background: HE4 is a new marker that could improve the detection of ovarian cancer (OC). The objective of the present study was to compare the prognostic value of the HE4 and CA125 markers in patients (pts) with metastatic epithelial OC, considering the progression-free survival (PFS). Methods: 101 pts, treated with 2 nd /3 rd line of chemotherapy, were included in 3 cancer centers between 2010 and 2014. Serums were prospectively collected before the 1 st chemotherapy cycle, during chemotherapy and every 3 months until disease progression. The primary endpoint was HE4 and CA125 marker level evolution under treatment. Secondary endpoints were the markers’ main kinetic parameters: initial concentration, nadir, time to nadir, time to normalisation, half-life, doubling time and time to exceed the clinical threshold (CA125≥35UI/L; HE4≥75pM) (NCT01768156). Results: 89 pts were included in the final analysis. Median age was 65 (34-83). Histological sub-types were mainly serous (88%). The median PFS was 45 weeks (95%CI: 33.4-52). At baseline, median CA125 and HE4 levels were 210UI/L (7-10310) and 184pM (31-4836), respectively. Among 12 pts (13%) CA125- (with CA125 &lt; 35UI/L), 8 were HE4+ (with HE4≥75pM) and among 16 pts (18%) HE4-, 12 were CA125+. The median nadir was 31UI/L (3-8744) for CA125 and 75pM (20-4836) for HE4. Median time to nadir was 14 (0-130) and 12 weeks (0-52) for CA125 and HE4, respectively. The median time to normalization was 17 (3-247) and 17 weeks (2-203) for CA125 and HE4, and the median half-life was 8 (1-193) and 12 weeks (2-166), respectively. The median doubling time and the time to exceed the clinical threshold were respectively of 13.5 and 40.2 weeks for CA125, and 23 and 23.6 weeks for HE4. In multivariate analysis, the CA125 nadir ( &lt; 35 vs ≥35: HR = 3.13; 95%CI: 1.75-5.58), CA125 time to nadir ( &lt; 14 vs ≥14: HR = 0.46, 95%CI: 0.28-0.76), HE4 nadir ( &lt; 75 vs ≥75: HR = 1.95; 95%CI 1.16-3.27), and HE4 time to nadir ( &lt; 12 vs≥12: HR = 0.39; 95%CI: 0.23-0.67) were found significant prognostic factors for PFS. Conclusions: Nadir and time to nadir were significant for both HE4 and CA125 markers in multivariate analysis. Further investigations on HE4 kinetic could be helpful for monitoring pts presenting no variation of CA125. Clinical trial information: NCT01768156.
Improving outcomes with brentuximab vedotin (BV) plus chemotherapy in patients with newly diagnosed advanced stage Hodgkin lymphoma.
Authors: David J. Straus, Graham P. Collins, Jan Andrzej Walewski, Pier Luigi Zinzani, Andrew Grigg, Anna M. Sureda, Árpád Illés, Tae Min Kim, Sergiy Alekseev, Lena Specht, Valeria Buccheri, Anas Younes, Joseph M. Connors, Ashish Gautam, Indra Purevjal, Keenan Fenton, Gerald Engley, Andrea Gallamini
Journal: Journal of Clinical Oncology (2018)

7534 Background: ECHELON-1 is a phase 3 study of BV plus doxorubicin, vinblastine, and dacarbazine (A+AVD) vs ABVD as frontline therapy in untreated advanced HL (NCT01712490). G-CSF primary prophylaxis (G-PP) was administered at the investigators’ discretion, and during the study was formally recommended by an independent data monitoring committee (IDMC) for patients (pts) receiving A+AVD. For pts receiving A+AVD, G-PP was associated with fewer infections and ≥ Grade 3 AEs, including neutropenia (70% without vs 29% with G-PP) and febrile neutropenia (21% vs 11%). Methods: Exploratory analyses assessing outcomes and exposure in pts who received G-PP on the A+AVD arm compared with those who did not were conducted. G-PP was defined as use of G-CSF by Day 5 of treatment (tx); non-G-PP pts included pts who received G-CSF secondary prophylaxis. Results: 1334 pts with advanced HL were randomized 1:1 to receive A+AVD or ABVD. In 662 pts treated with A+AVD, G-PP was given to 42 of 499 pts who started tx prior to, and 41 of 163 pts who started tx after the IDMC recommendation. Across tx arms, baseline characteristics were similar between the subgroups. G-PP, compared with no G-PP, was associated with a lower rate of BV dose delays (35% vs 49%) and dose reductions (20% vs 26%), and decreased hospitalization rates (pts with at least 1 hospitalization 29% vs 38%). Of the 7 neutropenia-associated deaths during A+AVD tx, none occurred in pts who received G-CSF prior to the onset of neutropenia. A+AVD with G-PP was associated with a decreased risk of a modified progression free survival event (mPFS; Connors, 2018) by 25% compared to A+AVD without G-PP and by 42% compared to ABVD. Clinical trial information: NCT01712490. Conclusions: Concomitant administration of G-PP with A+AVD in pts with advanced HL reduced AEs and frequency of tx delays. Though the sample size is small, G-PP with A+AVD may be associated with improved efficacy and a decrease in early, neutropenia-associated deaths; a prospective clinical trial to further assess the safety and efficacy in pts receiving G-PP with A+AVD is planned. A+AVD ABVD With G-PP Without G-PP N 83 581 670 2-year mPFS % 84.6 81.7 77.2 95% CI 73.7, 91.3 78.1, 84.8 73.7, 80.4 Hazard ratio vs ABVD 0.58 0.79 - 95% CI 0.31, 1.07 0.62, 1.02
Progression free survival (PFS) as a surrogate endpoint for overall survival (OS) in first-line advanced ovarian cancer (AOC) therapy: A Gynecologic Cancer InterGroup individual (GCIG) patient-level (IPD) analysis of multiple randomized trials.
Authors: Xavier Paoletti, Liz-Anne Lewsley, Gennaro Daniele, Adrian David Cook, Nozomu Yanaihara, Anna Tinker, Gunnar Kristensen, Petronella B Ottevanger, Gerasimos Aravantinos, Ingrid A. Boere, Robert Fruscio, Anna K.L. Reyners, Eric Pujade-Lauraine, Andrea Harkin, Sandro Pignata, Tatsuo Kagimura, Stephen Welch, Karamouza Eleni, Rosalind Margaret Glasspool
Journal: Journal of Clinical Oncology (2018)

5576 Background: OS is considered the gold standard endpoint for controlled clinical trials but it requires extended follow-up (median OS > 40 months for first line therapy) and large sample sizes. Our objective was to evaluate whether PFS based on CA125 measurements confirmed by radiological exam or on combined GCIG criteria is a surrogate endpoint for OS in AOC. Methods: Using the meta-analytic approach on trials published after 2000, correlations between PFS and OS at the individual level, and between treatment effects on PFS and on OS at the trial level, were estimated using Kendall’ tau and copula bivariate (R2Copula) models respectively. Criteria for PFS surrogacy required R2Copula ≥ 0.80. Results: We analyzed IPD from 8,973 patients enrolled in 15 randomized first line trials of standard (n = 7), intensification (n = 5) and maintenance (n = 3) chemotherapies or targeted treatments. No heterogeneity in the treatment effects across trials was detected. High correlations were found at the individual level (tau = 0.69) but low correlation at the trial level (R2Copula = 0.03). Sub-group analyses led to similar results. Conclusions: This large IPD meta-analysis did not establish PFS as a surrogate endpoint for OS in first line treatment of AOC, but the analysis was limited by the narrow range of treatment effects observed and post study treatment. Additional trials are being collected that will enable us to refine the sub-groups analyses. Table of results Endpoint / Trial type Trials N (pts) taua R2Copulaa Overall 15 (8973) 0.69 0.03 CA125 confirmed by radiological exam 9 (5126) 0.67 0.16 GCIG criteria 4 (2548) 0.7 0.14 Carbo-Tax as control 9 (5807) 0.72 0.05 Standard or intensification 12 (7703) 0.71 0.10 Maintenance 3 (1270) 0.64 0.14 atau and R2 values range from 0 (no association) to 1 (perfect correlation).
Weight Management in Adults With Obesity
Authors: Susan Z. Yanovski
Journal: JAMA (2018)

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The impact of pricing strategy on the cost of oral anti-cancer drugs during dose reductions.
Authors: Judy Truong, Kelvin K. Chan, Helen Mai, Alexandra Chambers, Mona Sabharwal, Maureen E. Trudeau, Matthew C. Cheung
Journal: Journal of Clinical Oncology (2017)

e18312 Background: The pricing strategy of oral medications can affect their costs. The strategy of flat pricing per tablet may increase drug costs in the event of dose reductions requiring more tablets, as there is a single price for different tablet strengths, but the impact is largely unknown. With the strategy of linear pricing, the tablet price increases with its strength. We sought to determine the impact of pricing strategy on the cost of oral anti-cancer drugs during dose reductions. Methods: Oral anti-cancer drugs reviewed by the pan-Canadian Oncology Drug Review were identified between July 2011 to January 2015. The pricing strategy of these drugs was reviewed. We examined the percentage change in cost per mg and cost per 28 days as a result of dose reduction from dose level 0 to -1 and -2 for each drug. Results: Seventeen drugs for use in 20 indications were included in the analysis. There were 3 drugs for hematological malignancies and 14 drugs for solid cancers. Fifty-nine percent (10/17) of these drugs were available in multiple strengths; five of them utilized fixed pricing per tablet strategy and the other 5 utilized linear pricing. The remaining drugs (7/17) were available in a single strength tablet. Dose reductions generally increased the cost per mg for drugs using flat pricing per tablet, with a mean increase of 82% (range: 25%-200%) at dose level -1 and 100% (range: 0%-200%) at dose level -2. Dose reduction had no effect on the cost per mg of drug for drugs using linear pricing apart from lenalidomide, which had increased costs due to minimal price variation between the highest and lowest tablet strengths. In general, dose reduction did not decrease the cost per 28 days of drug for drugs using flat pricing per tablet, but was proportionally reduced in drugs using linear pricing. Conclusions: While there is a general expectation that the cost of drugs should decrease with dose reduction, oral anti-cancer drugs using flat pricing per tablet have increased cost per mg and no decrease in cost per 28 days despite dose reduction. Future economic evaluations should account for the impact of dose reductions for oral drugs using the flat pricing per tablet strategy on cost-effectiveness and budget.
<i>BRAF</i> V600E Mutation as a Negative Prognostic Determinant in Resected Colorectal Liver Metastases
Authors: Roberto Moretto, Chiara Cremolini, Alfredo Falcone
Journal: JAMA Surgery (2018)

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Functional profiling of a glioblastoma (GBM) patient-derived cell line (PDCL) panel to identify cell-intrinsic differential radiation response.
Authors: Mai Anh Huynh, Cecile L. Maire, Mohamed Abazeed, Fred C. Lam, Drew Adams, Kristine Pelton, Nancy Pinnell, David C. Knoff, Houari Korideck, Paul Van Hummelen, Aaron Thorner, Patrick Y. Wen, Azra Ligon, Scott R. Floyd, Stuart L. Schreiber, Matthew Meyerson, Keith L. Ligon, Brian Alexander
Journal: Journal of Clinical Oncology (2016)

2069 Background: It is not known whether GBM responds differently to radiation based on tumor cell-intrinsic factors. Newly developed PDCLs of GBM have potential to illuminate individual patient functional response to treatment at a scale not previously possible. We therefore assessed whether intrinsic differences in radiosensitivity are present in a large panel of clinically and genomically annotated GBM PDCLs. Methods: PDCLs were established from newly diagnosed (n = 25) and recurrent (n = 10) GBM patients. Whole exome sequencing and whole genome array comparative genomic hybridization was performed on the PDCLs, and patient outcomes data was collected. High-throughput functional radiation screening was performed across all patients at varying doses. Response was calculated at 9 days after treatment based on ATP measurement using Cell Titer Glo to assess growth and recovery. Proliferation was integrated as a function of dose for each cell line (AUC). AUC was correlated with genomic candidate factors and clinical outcomes. Cell cycle phase and activation of DNA damage repair was assessed in a subset of PDCLs. Results: Mean AUC values were normally distributed across patient models (p = 0.67 Shapiro-Wilk). The mean AUC for p53 mutant lines was 4.3 vs. 2.9 for p53 intact lines (p = 0.03). Whereas p53 mutant tumors were generally relatively resistant, p53 wild-type tumors showed significant variability in radiosensitivity. Radioresistant lines displayed higher levels of 53BP1 and phospho-γH2ax foci. There was no difference in radiosensitivity between tumors derived from treatment-naïve or recurrent tumors (p = NS). There was also no correlation of intrinsic radiosensitivity with patient outcome, though the analysis was limited by sample size and significant variability related to clinical prognostic factors. Conclusions: GBM PDCLs suggest the existence of tumor cell-intrinsic differences in radiosensitivity across patients that correlate with p53 mutation status and may relate to differences in the capacity for DNA repair. Further studies are needed to validate this in vivo and to determine whether PDCL may be useful functional indicators of clinical response.
Abstract 372: MicroRNA-9 Inhibits Hyperglycemia-induced Cardiac Pyroptosis by Targeting ELAVL1
Authors: Prince Jeyabal, Rajarajan A Thandavarayan, Darukeshwara Joladarashi, Sahana Suresh Babu, Shashirekha Krishnamurthy, Arvind Bhimaraj, Keith A Youker, Raj Kishore, Prasanna Krishnamurthy*
Journal: Circulation Research (2016)

Diabetic cardiomyopathy is a common complication in patients with diabetes and is associated with underlying chronic inflammation and cardiac cell death, subsequently leading to left ventricular dysfunction and heart failure. ELAV-like protein 1 (ELAVL1, mRNA stabilizing protein) and NLRP3 activation (inflammasome complex protein)-mediated IL-1beta synthesis play a critical role in the progression of heart failure. However, ELAVL1 regulation of pyroptosis (caspase-1-mediated programmed apoptosis) and associated IL-1beta release in cardiomyocytes, especially under diabetic condition, remains elusive. Human diabetic, non-diabetic heart tissues, human ventricular cardiomyocytes and rat cardiomyoblasts exposed to high glucose (HG) were used for our studies. Our data demonstrates that human ventricular cardiomyocytes exposed to high glucose condition showed significant increase in ELAVL1 and NLRP3 expression with a concomitant increase in caspase-1 and IL-1 beta expression. Furthermore, human cardiac tissue from diabetic patients showed increased ELAVL1, caspase-1 and NLRP3 expression as compared to non-diabetic hearts. Intriguingly, ELAVL1 knockdown abrogates TNF-α induced canonical pyroptosis via NLRP3, caspase-1 and IL-1beta suppression. Interestingly, miRNA-9 expression significantly reduces in high glucose treated cardiomyocytes and in human diabetic hearts. Bioinformatics analysis and target validation assays showed that miR-9 directly targets ELAVL1. Inhibition of miR-9 up regulates ELAVL1 expression and activates caspase-1. Alternatively, miR-9 mimics attenuate hyperglycemia-induced ELAVL1 and inhibit cardiomyocyte pyroptosis. To our knowledge, this is the first report to demonstrate the role of miR-9/ELAVL1 in hyperglycemia-induced cardiac pyroptosis. Taken together our study highlights the potential therapeutic implications in preventing cardiomyocyte cell loss in human diabetic failing heart.
Introducing first year medical students to oncology care through an elective seminar series.
Authors: Ryan Patrick McKillip, Olwen Mary Hahn, Nanna Helen Sulai, Olufunmilayo I. Olopade, Vineet M Arora, Daniel William Golden
Journal: Journal of Clinical Oncology (2016)

e18193 Background: Advancing the quality of cancer care requires that physicians be educated in oncology and its various disciplines. An oncology seminar series was designed and implemented for first year medical students (MS1s) to improve their knowledge of oncologic disciplines by educating them about these disciplines from both a research and clinical perspective. Methods: MS1s at a single United States medical school were invited to participate in the Scholars in Oncology-Associated Research (SOAR) summer program, which included a series of 10 lectures to demonstrate how clinical care, basic sciences, and social sciences apply to oncology as a multidisciplinary specialty. Lectures included topics specific to cancer genetics, medical, surgical, and radiation oncology, hospice/palliative medicine, and survivorship care. The MS1s attended a multidisciplinary tumor board and had the opportunity to shadow a pharmacist, radiation therapist, or palliative care advanced practice nurse. The MS1s completed self-assessments of their understanding of oncology and its disciplines before and after SOAR. Likert-type scores were 1 = not at all, 2 = somewhat, 3 = moderately, 4 = quite, and 5 = extremely and are reported as median [interquartile range]. Results: Eighteen MS1s successfully completed SOAR out of 21 who enrolled. Twenty pre- and 17 post-assessments were completed. The number of MS1s who indicated an intent to pursue an oncology-related specialty was 13 on both pre- and post-assessments. Self-reported understanding of oncology as a clinical discipline (2[2-3] vs. 4[4-4] p < .01) and research discipline (3[2-3] vs. 4[4-4] p < .01) improved after SOAR. Additionally, as clinical/research disciplines, self-reported understanding of cancer genetics (2[2-3] vs. 3[3-4] p < .01)/(2[2-3] vs. 4[3-4] p < .01), and medical oncology (2[1-2] vs. 4[4-4] p < .01)/(1[1-2] vs. 4[3-4] p < .01) improved after SOAR. Participants would recommend SOAR to future MS1s (4[4-5]). Conclusions: A structured didactic introduction to oncology, SOAR, was successfully piloted. MS1s report improved understanding of oncology and its distinct clinical and research disciplines. Future work will focus on expanding SOAR to a larger audience.
Celiac plexus radiosurgery: A new palliative modality for upper gastrointestinal malignancies—Final results of a proof-of-concept clinical trial.
Authors: Yaacov Richard Lawrence, Liat Hammer, Ofir Morag, Maoz Ben-Ailan, Dror Alezra, Ofer Margalit, Naama Halpern, Ben Boursi, Einat Shacham Shmueli, Galia Jacobson, Uri Amit, Tamar Katzman, Kinneret Shefer, Ilana Weiss, Inessa Yanovsky, Adam Dicker, Talia Golan, David Hausner, Zvi Symon
Journal: Journal of Clinical Oncology (2018)

10098 Background: Many patients with upper-abdominal malignancies suffer from severe lower back pain radiating to the epigastrium, caused by infiltration of the celiac plexus. The celiac plexus is a network of nociceptive nerves, located along the aorta. Contemporary approaches (opioids, celiac plexus chemical neurolysis, systemic chemotherapy) are often inadequate. The celiac plexus has not previously been targeted using radiation. We hypothesized that ablative radiation targeted to the celiac plexus would alleviate pain. Methods: We conducted a single arm prospective clinical trial. Eligible patients had celiac-pain > 4/10 on Numerical Rating Scale (NRS), ECOG ≤ 3, no previous abdominal RT, and were evaluable if they completed treatment per protocol with at least one post-treatment visit. The celiac plexus was irradiated from D12 to L2. Radiation was given as either five fractions of 9 Gy or a single-fraction 25 Gy. The primary endpoint was NRS pain 3 weeks post-treatment. Secondary endpoints were toxicity, pain at 6w, analgesic use, and pain interference with daily activities as evaluated by ‘Brief Pain Inventory’ before and after radiation. Results: 21 patients were evaluable: 2 received fractionated treatment, 19 received 25Gy single fraction. The median age of the study population was 63 yr with a median ECOG of 1, 86% had pancreatic cancer. Patients were a median of 8 months out from diagnosis, and had received a median of one systemic treatment. Toxicity was limited to grade 1-2. All patients reported decreased celiac pain: median baseline pain was 6/10 (IQR 5-7.7), was reduced to 2.3/10 (IQR 0.9-3.9) (p < 0.0005) at 3w, and to 1.8/10 (IQR 0-3.2) (p < 0.0005) at 6w post-treatment. Seven patients reported their celiac pain had been eliminated entirely. Median morphine consumption decreased (NS). Improvement was seen in multiple quality of life measures, includ. total wellbeing (p = 0.0001), daily activity (p = 0.005) and sleep quality (p = 0.002). Conclusions: Celiac plexus radiosurgery alleviates pain, and improves quality of life among patients with advanced upper-GI cancer. An international multi-center phase II trial is accruing. Clinical trial information: NCT02356406.