tbuckley/cabot-search huggingface dataset:
FDA analysis of pembrolizumab trials in multiple myeloma: Immune related adverse events (irAEs) and response.
Authors: Aviva C Krauss, Flora Mulkey, Yuan-Li Shen, Amy Rosenberg, Barry Miller, Theresa Carioti, Kimberly Scott, Nicole Gormley, Marc Robert Theoret, Rajeshwari Sridhara, Ann T. Farrell, Richard Pazdur
Journal: Journal of Clinical Oncology (2018)

8008 Background: Development of irAEs with checkpoint inhibition may be associated with response in some disease settings. Methods: We evaluated overall survival (OS), safety and objective response rates (ORR) among patients who developed irAEs and those who did not in two trials of pembro in MM. KEYNOTE 183 (KN183) evaluated pomalidomide and dexamethasone (PomDex) with or without pembro in patients with relapsed/refractory (RR) MM, and KEYNOTE 185 (KN185) evaluated lenalidomide and dexamethasone (LenDex) with or without pembro in patients with newly diagnosed (ND) MM ineligible for autologous stem cell transplant. FDA placed both trials on clinical hold in July 2017 due to worse OS in the pembro-containing arms. Results: Using a June 2, 2017 data cut-off: median follow-up on KN183 was 8.1 months, 249 patients were randomized. There were 29 deaths in the pembro arm and 21 in the control arm, for an OS hazard ratio (HR) of 1.61 (95% CI: 0.91, 2.85). ORR was 34% in the pembro arm and 40% in the control arm. Median follow-up on KN185 was 6.6 months, 301 patients were randomized. There were 19 deaths in the pembro arm and 9 in the control arm, for an OS HR of 2.06 (95% CI: 0.93, 4.55). ORR was 64% in the pembro arm and 62% in the control arm. Neither trial showed a difference in time-to-progression between arms. In KN183, 58% of patients on the pembro arm developed an irAE, with an ORR of 37%, not significantly different than the 31% in those without an irAE. A trend was noted for improved ORR (49%) in those on the control arm (PomDex) with an irAE, compared to 33% in those without an irAE. In contrast, ORR in patients with NDMM in KN185 who developed an irAE were higher than in those who did not. Conclusions: The utility of immunotherapy in patients unable to mount adequate immune responses merits further study, as does the worse OS observed in both trials. KN183 KN185 Pembro+PomDex PomDex Pembro+LenDex LenDex ITT pop, N 125 124 151 150 Deaths 23% 17% 13% 6% ORR 34% 40% 64% 62% Safety Pop, N 120 121 149 145 Pts with irAE 58% 45% 68% 44% G≥3 irAE 18% 13% 36% 8% ORR in pts with No irAE 31% 33% 45% 53% irAE 37% 49% 73% 73% G≥3 irAE 29% 50% 70% 67%
Association of ovarian cancer (OC) risk with mutations detected by multiple-gene germline sequencing in 95,561 women.
Authors: Allison W. Kurian, Elisha Hughes, Elizabeth Handorf, Alexander Gutin, Brian Allen, Anne-Renee Hartman, Michael J. Hall
Journal: Journal of Clinical Oncology (2016)

5510 Background: Multiple-gene germline sequencing panels are increasingly used to assess hereditary cancer risk, yet the magnitude of OC risk is not well defined for many genes on clinically available panels. Methods: 95,561 women were tested clinically for hereditary cancer risk with a panel of 25 genes: APC, ATM, BARD1, BMPR1A, BRCA1/2, BRIP1, CDH1, CDK4, CHEK2, MLH2, MSH2, MSH6, MYH, NBN, P14ARF, P16, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, and TP53. Patients who had single- or founder-site testing, or prior BRCA1/2 testing, were excluded. Multivariable regression analysis was used to examine the association between pathogenic/suspected pathogenic mutations and personal OC history (Hx) (dependent variable). Independent variables were age, personal/family cancer Hx, and ancestry. Odds ratios (OR) with 95% confidence intervals (CI) excluding 1.0 were considered significant. Results: Mutations were detected in 6,775/95,561 (7%) patients, of which 3,007 (44%) were in BRCA1/2 and 3,768 (56%) in other genes. A significant association with personal OC Hx was found for ATM, BRCA1, BRCA2, BRIP1, MLH1, MSH2, MSH6, NBN, STK11, RAD51C and RAD51D (Table). Conclusions: Among nearly 100,000 women tested clinically for hereditary cancer risk, multiple-gene sequencing detected OC-associated mutations in 11 genes. Gene-specific estimates ranged from two (ATM, BRIP1, NBN, MSH2, MSH6) to > 10 (BRCA1, STK11) fold elevation in OC risk. These results inform the estimation of OC risk with mutations in 25 clinically tested genes. Gene OR (95%CI) for OC STK11 41.9 (5.55, 315) BRCA1 11.8 (9.99, 14.0) BRCA2 5.26 (4.38, 6.31) RAD51C 4.98 (3.09, 8.04) RAD51D 4.78 (2.13, 10.7) MLH1 3.11 (1.47, 6.59) BRIP1 2.62 (1.72, 3.98) MSH2 2.04 (1.08, 3.84) MSH6 1.92 (1.19, 3.10) NBN 1.85 (1.05, 3.24) ATM 1.69 (1.19, 2.40) PALB2 1.60 (0.98, 2.60) PMS2 1.57 (0.94, 2.60) CHEK2 0.86 (0.56, 1.33) TP53 0.66 (0.05, 8.68) CDH1 0.63 (0.08, 4.93) BARD1 0.59 (0.21, 1.68) P16 0.56 (0.12, 2.53) APC 0.36 (0.05, 2.77) MYH 0.40 (0.05, 3.26) BMPR1A * CDK4 * P14ARF * PTEN * SMAD4 * *Could not be estimated
Prognostic value of plasma fibrinogen level and cervical nodal necrosis in stage IVA/B nasopharyngeal carcinoma patients who had positive cervical nodal metastasis.
Authors: Mei Lan, Ying Huang, Chun-yan Chen, Zhijun Duan, Shao-xiong Wu, Lie Zheng, Li Tian, Junfang Liao, Fei Han, Tongyu Lin, Taixiang Lu
Journal: Journal of Clinical Oncology (2016)

6039 Background: Effective prognostic factors for stage IVA/B nasopharyngeal carcinoma (NPC) patients are limited. Fibrinolysis activation and cervical nodal necrosis (CNN) have been observed with a higher risk of progression and metastasis in head and neck cancers. The objective of this study was to investigate the prognostic value of plasma fibrinogen (FIB) level and CNN in stage IVA/B NPC patients who had positive cervical nodal metastasis. Methods: This was an institutional review board-approved retrospective study of 702 patients with newly diagnosed T4N1-2 or T1-4N3 NPC who were treated with definitive radiation therapy±chemotherapy, between January 2008 and December 2011. Coagulation tests including FIB, activated partial thromboplastin time were measured in all patients before treatment. Patients were also categorized into CNN group and non-CNN group. Disease-specific survival (DSS), disease-free survival (DFS) and distant metastasis-free survival (DMFS) were calculated using the Kaplan-Meier method, and differences were compared with log-rank test. Results: The death risk of patients with FIB > 4g/L was over 3-fold compared to patients with FIB ≤ 4 g/L. The 5-year DSS, DFS and DMFS rates for patients with FIB > 4 g/L and FIB ≤ 4 g/L were 60.3% and 75.4%, 56.6% and 69.0%, 55.3% and 68.2%, respectively (P < 0.001 for all). Further subgroup analysis demonstrated that survival decreased according to a gradual increase of FIB. The 5-year DSS, DFS and DMFS rates of the CNN and non-CNN groups were 62.1% and 82.5%, 44.7% and 81.0%, 48.9% and 81.2%, respectively (P < 0.004 for all). The distant metastasis risk of patients with both FIB > 4 g/L and CNN was over 7-fold compared with those without FIB increase or CNN. Multiple analysis showed that only FIB > 4 g/L, CNN were independent negative prognostic factors for DSS, DFS and DMFS. EBV-DNA was not an independent prognostic factor in multivariate analysis. Conclusions: Plasma FIB level and CNN presented to be stronger independent prognostic factors than EBV-DNA for stage IVA/B NPC patients who had positive cervical nodal metastasis. Studies about the mechanisms of how FIB and CNN affect survival are warranted.
Comparison of long-term survival outcomes between laparoscopic and open surgery for mid or low rectal cancer treated with preoperative chemoradiotherapy: 7-year follow-up of COREAN trial.
Authors: Ji Won Park, Seung-Yong Jeong, Sung-Bum Kang, Jungnam Joo, Mi Kyung Song, Seok-Byung Lim, Hyo Seong Choi, Duck-Woo Kim, Hee Jin Chang, Dae Yong Kim, Kyung Hae Jung, Tae-You Kim, Gyeong Hoon Kang, Eui Kyu Chie, Sun Young Kim, Dae Kyung Sohn, Jae-Sung Kim, Hye-Seung Lee, Jee Hyun Kim, Jae Hwan Oh
Journal: Journal of Clinical Oncology (2017)

3518 Background: Laparoscopic surgery for rectal cancer has been used widely. However, recent two randomized trials raised concerns about short-term oncologic safety of laparoscopic surgery for rectal cancer. The aim of this study was to evaluate the long-term oncologic safety of laparoscopic surgery for rectal cancer based on 7-year data from the Comparison of Open versus laparoscopic surgery for mid or low REctal cancer After Neoadjuvant chemoradiotherapy (COREAN) trial. Methods: COREAN trial was a non-inferiority, randomized controlled trial. Between April, 2006, and Aug, 2009, eligible participants with mid or low rectal cancer treated with preoperative chemoradiotherapy were randomly assigned (1:1) to laparoscopic (n = 170) or open surgery (n = 170). Seven-year outcomes included overall and disease-free survival, and local recurrence. Log-rank test and stratified Cox regression analysis were used for survival analysis. Analysis was by intention to treat. Results: The median follow-up times were 84 months (IQR: 61.5-97.0). No differences were found between laparoscopic and open surgery group in terms of overall and disease-free survival, and local recurrence (7-year overall survival: 83.2% [laparoscopic] vs 77.3% [open], p = 0.48; 7-year disease-free survival: 71.6% [laparoscopic] vs 64.3% [open], p = 0.20; 7-year local recurrence: 3.3% [laparoscopic] vs 7.9% [open], p = 0.08). Stratified Cox regression analysis adjusted for ypT, ypN and tumor regression grade showed no significant difference between groups in terms of overall and disease-free survival, and local recurrence. The hazard ratios for overall survival, disease-free survival and local recurrence (open vs laparoscopic surgery) were 0.96 (95% CI = 0.58-1.57), 1.03 (95% CI = 0.70-1.53), and 2.28 (95% CI = 0.82-7.16), respectively. Conclusions: The 7-year analysis confirm the long-term oncological safety of laparoscopic surgery for rectal cancer treated with preoperative chemoradiotherapy. The use of laparoscopic surgery does not compromise the long-term survival outcomes in rectal cancer. Clinical trial information: NCT00470951.
Prospective assessment of psychosocial outcomes of contralateral prophylactic mastectomy.
Authors: Abenaa M. Brewster, Susan K. Peterson, Isabelle Bedrosian, Alastair Mark Thompson, Dalliah MaShon Black, Jonathan Nelson, Robert Cook, Sarah Marie DeSnyder, Kelly Hunt, Scott B. Cantor, Robert Joseph Volk, Wenli Dong, Patricia A. Parker
Journal: Journal of Clinical Oncology (2017)

6569 Background: Increasing numbers of women are choosing contralateral prophylactic mastectomy (CPM) despite the lack of knowledge about its effect on long-term psychosocial adjustment. The objective of the study was to examine patient-centered psychosocial outcomes of women with breast cancer who have CPM versus those who do not in order to enhance shared surgical decision making. Methods: We enrolled 308 women with newly diagnosed, non-hereditary breast cancer prior to surgery (CPM or no CPM) at MD Anderson Cancer Center and Kelsey-Seybold Clinic between 2012 and 2015. Women completed validated questionnaires assessing psychosocial factors including quality of life (QOL), body image concerns, cancer distress, trust in physician and decision satisfaction pre-surgery and at 1, 6 and 12-months post-surgery. Repeated measures models were fitted to assess the association between psychosocial outcomes measured at each time point and CPM status adjusting for time effect. Results: Among 252 women (mean age 56) who completed pre and post-surgery questionnaires, 60% were non-Hispanic white, 16% non-Hispanic black, 16% Hispanic, 8% mixed race and 17% had CPM. Women who had CPM had higher scores for cancer distress and body image concerns and lower scores for QOL than women who did not have CPM at pre-surgery (p = 0.04, p &lt; 0.01, p = 0.20, respectively), and at 1 month (p = 0.42, p &lt; 0.001, p &lt; 0.01, respectively), 6 months (p = 0.03, p &lt; 0.001, p = 0.05, respectively) and 12 months (p = 0.01, p &lt; 0.001, p = 0.01, respectively) post-surgery. After adjusting for time effect, women who had CPM had higher post-surgery scores for cancer distress (p = 0.03), body image concerns (p &lt; 0.0001), QOL (p &lt; 0.01) and lower trust in physician (p = 0.03) than women who did not have CPM. There was no statistically significant difference by CPM status for cancer knowledge or decision satisfaction. Conclusions: This is the first study to demonstrate that psychosocial factors such as cancer distress, QOL and body image concerns are not improved by having CPM. The results highlight the importance of evaluating psychosocial factors pre- and post- surgery and the need to incorporate psychosocial assessment and counseling in the CPM decision making process.
National coverage analyses for NCI clinical trials: A pilot project to reduce participation barriers.
Authors: Andrea Denicoff, Grace Mishkin, Marjorie J. Good, Lucille Patrichuk, Lawrence Ragard, Kathleen R Hurtado, Kelly Willenberg, Connie M. Szczepanek, Casey Dawson, Morgen Alexander-Young, Debra L Strandberg, Julie Kardell, Sara McCartney, Mary Beth Sullivan, Michael Kelly, Michael Montello, Worta J. McCaskill-Stevens, Jeffrey S. Abrams, Margaret M. Mooney
Journal: Journal of Clinical Oncology (2017)

6542 Background: Since the implementation of the ACA, many insurers have followed Medicare’s lead in covering routine care costs associated with clinical trials (CTs). However, questions remain on how to distinguish routine care from non-billable research costs, and this has important financial implications for both sites and patients. As a result, many sites individually conduct coverage analyses (CAs) prior to opening CTs to determine billable routine costs. This is a significant duplication of effort for NCI network CTs that are open at hundreds of sites. A 2015 ASCO-NCI initiative identified the centralized creation of CAs for national CTs as a potential solution to reduce site burden, increase CT transparency and billing compliance, and ultimately reduce barriers to CT participation. We provide initial findings from the resulting NCI pilot program. Methods: NCI set up a Coverage Analysis Working Group (CAWG) made up of representatives from NCI’s Cancer Trials Support Unit (CTSU), network groups, NCI, and billing compliance consultants. CAWG created a CA template and development process for NCI network trials. CAWG will survey site users in April 2017 to evaluate the first year of the pilot project. Results: CAs for 7 CTs were first posted to the CTSU website on 4/20/16. As of January 2017, CAs have been posted for 22 CTs: 17 NCTN and 5 NCORP. This represents 14.6% of the 150 large, later-phase network trials available on the CTSU. These CAs had been posted for a mean of 219 days (median 238) as of 1/31/17. In this time, CAs were downloaded an average of 319 times (median 301), for a total of 7,007 downloads. An additional 26 CAs have been posted for MATCH (n = 20) and LUNG-MAP (n = 6) sub-studies and downloaded 7,035 times. Survey results evaluating this CA pilot will be presented in June 2017. Conclusions: Providing centralized CAs to NCI’s national network trials is feasible and well received with sites reporting that this pilot is reducing the time and effort of opening CTs and improving CT funding transparency. Collaboration is needed with CMS and third party payers to enhance clarity around CT coverage policy and billing compliance, along with continued feedback to make further improvements to reduce trial barriers.
Changes in body composition and prognostic importance of sarcopenia in patients receiving CTRT for oropharyngeal cancer.
Authors: Shrujal S. Baxi, Lee Jones, Anne Eaton, Stephanie Gandelman, Darragh Halpenny, Jasmyne Jackson, Rachel Kurtzman, Sean Matthew McBride, Andrew Plodkowski, David G. Pfister
Journal: Journal of Clinical Oncology (2016)

6077 Background: Concurrent chemoradiation (CTRT) improves outcomes in oropharyngeal cancer (OPC) but causes toxicities that alter body composition. In other cancers, loss of lean body mass (sarcopenia) is associated with poor prognosis. Changes in body composition in OPC, and the clinical importance of these alterations, have not been studied. Methods: Using a retrospective design, 234 OPC patients (mean age, 58 years (range 27 to 83); mean BMI, 29 kg/m2) receiving definitive CTRT were studied. Skeletal muscle cross-sectional area (CSA) at the third lumbar vertebra (L3) and thigh were assessed by CT-scan prior to and after completion of CTRT (median: 13.5 wks; range 2-27) and normalized to stature to obtain skeletal muscle index (cm2/m2). Sarcopenia was defined using previously published cutoffs. Cox models were used to assess the relationship between sarcopenia and recurrence-free survival (RFS) and overall survival (OS). Wilcoxon rank-sum tests were used to assess changes in percent loss in weight and L3 and thigh muscle CSA in patients hospitalized post-CTRT. Results: Prior to CTRT, 68% of patients were classified as sarcopenic. HPV-testing was completed in 168 (72%); 149 were positive. Post-CTRT, body mass (kg) decreased a median of 13.8% (IQR: 10.1% to 18.7%, p < .001) while muscle CSA at L3 and thigh decreased by 11.2% (IQR: 6.9% to 16.8%, p < .001) and 13.6% (IQR: 5.5% to 21.2%, p < .001), respectively; 89% were classified as sarcopenic. Older age and male were significant baseline predictors of sarcopenia post-CTRT (p's < 0.05). Fifty-eight (25%) patients were hospitalized within 3 months of CTRT. Median follow-up was 34 months; in this period, 26 recurrences and 19 deaths were observed. Greater percent weight loss and thigh muscle CSA loss were positively associated with risk of hospitalization (p's < 0.01); baseline or post-treatment sarcopenia were not associated with RFS or OS (p's > 0.05). Conclusions: A significant proportion of OPC patients present with clinical sarcopenia, while CTRT increases the proportion of subjects with this condition.Decreases in body and muscle mass are associated with hospitalization. The long-term clinical impact of these losses remains to be determined.
SMO mutations do not seem to drive multifocal relapse of locally advanced basal cell carcinoma after vismodegib discontinuation.
Authors: Nicole Basset Seguin, Meriem Ighilahriz, Meriem Benfodda, Nadem Soufir, Samia Mourah, Nicolas Dumaz, Maxime Battistella, Fanny Bouquet, Ariel Savina
Journal: Journal of Clinical Oncology (2018)

e21559 Background: Vismodegib , a selective Hh pathway inhibitor that targets Smoothened (SMO) is a major therapeutic breakthrough for locally advanced (la) or metastatic BCC. During treatment some patients can experience tumor regrowth due to selection of SMO mutant cells. In this work we have studied if SMO mutations were also implicated in multifocal tumor relapse after treatment discontinuation of patients having achieved complete remission (CR). Methods: Tumor tissue of 3 patients having achieved clinical complete remission of their laBCC with vismodegib who relapsed after treatment discontinuation were studied. All patients gave their written informed consent for the study. Frozen or formalin-fixed paraffin-embedded (FFPE) tumor tissues at baseline and after relapse were processed for DNA and RNA extraction (All prep DNA, RNA mini kit, QIAGEN). RNAs were evaluated by qRT-PCR for GLI1 and PTCH1 expression to evaluate Hh pathway activation. Results: All tumor samples studied showed elevated GLI1 and PTCH1 expression upon progression, indicating Hh pathway reactivation. Comparative genomic analysis of somatic mutations involving Hh pathway genes showed a similar pattern of gene mutations and no selection of new SMO mutants in the relapsing tumors. Two patients had PTCH1 mutations and the third one had a SMO activating driver mutation that were present at baseline and following relapse. One patient acquired a PTCH2 mutation in the relapsing tumor compared to baseline. P53 inactivating mutations were found in all 3 patients both at baseline and in the relapsing tumor. Conclusions: Our work shows that SMO mutations do not seem to be implicated in multifocal relapse following treatment discontinuation. The somatic mutational patterns appear rather stable from baseline to relapse, indicating that the tumor should maintain its sensitivity to vismodegib treatment. Indeed 2 of our 3 patients experienced tumor shrinkage after vismodegib rechallenge.
Abstract 13638: Endothelial-Mesenchymal Transition in Human Atrial Fibrillation
Authors: Takeshi Kato, Akiko Sekiguchi, Kouichi Sagara, Masayuki Takamura, Shuichi Kaneko, Tadanori Aizawa, Long-Tai Fu, Takeshi Yamashita
Journal: Circulation (2014)

Background: Atrial fibrosis is a hallmark of atrial structural remodeling leading to persistence of AF. Although fibroblasts are known to play a major role in atrial fibrosis, their source in the adult atrium is unclear. Here we tested the hypothesis that endothelial cells contribute to fibroblasts accumulation through an endothelial-mesenchymal transition (EndMT) in the human atrium during the progression of AF. Methods and Results: The study group consisted of patients with valvular disease or atrial septal defect who underwent cardiac surgery (n [[Unable to Display Character:  ]]=[[Unable to Display Character:  ]] 38). Atrial tissue was obtained from the left atrial appendage during cardiac surgery. The amount of fibrotic depositions in Masson Trichrome staining of the left atrium (LA) was positively correlated with left atrial dimension (LAD) (y = 0.3004x - 4.395, R2 = 0.3809, P < 0.0001). Also snail and S100A4, indicative of EndMT, in LA quantified by Western blotting showed statistically...
Relationship of RRM1 compared to ERCC1 gene in peripheral blood to the efficacy of the gemictable chemotherapy in advanced non-small cell lung cancer.
Authors: Xue-Lin Zou, Zhu-Ling Liu, Zhenyu Ding
Journal: Journal of Clinical Oncology (2016)

e23092 Background: Predicative biomarkers for chemotherapy in lung cancer are lacking. Controversies remain as to the biomarkers such as ERCC1 (for platinum) or RRM1 (for gemcitabine). Recently, plasma concentration of chemotherapy reagents has been proposed as novel biomarkers. In this study, we prospectively evaluated the capability of these biomarkers in predicating the efficacy of the first-line gemcitabine doublet chemotherapy. Methods: The blood from patients with metastatic non-small cell lung cancer who were prescribed with gemcitabine doublet chemotherapy was collected just following the administration of gemcitabine. The expression of ERCC1 and RRM1 was determined by real-time PCR. The concentration of gemcitabine was measured by high-performance liquid chromatography. The demographic features of the patients and the outcome of the chemotherapy were recorded. Results: Totally 59 patients were enrolled in this study. Median mRNA expression levels, relative to the housekeeping gene β-actin, were 11.05×10-3 (range 0.089×10-3–590.50×10-3) for ERCC1 and 1.20×10-3 (range 0.015×10-3–702.22×10-3) for RRM1 . The plasma concentrations of gemcitabine were 8.19 mg/ml (0-50.81mg/ml).None of these biomarkers were associated with the demographic features, nor did they have any association among each. Gemcitabine concentration could not predict the efficacy or toxicities of chemotherapy. Neither could the expression of ERCC1 and RRM1. However this study found the expression of RRM1 but not ERCC1 was correlated with the PFS of the chemotherapy. Conclusions: These results suggested that further studies are needed to evaluate the expression of the RRM1, ERCC1 and the plasma concentration of gemcitabine as predictive biomarkers for sensitivity to platinum agents and gemcitabine. Clinical trial information: ChiCTR-POC-15007228.