tbuckley/cabot-search huggingface dataset:
Anamorelin in cachectic patients with non-small cell lung cancer (NSCLC) and low BMI (&lt; 20 kg/m<sup>2</sup>): A pooled efficacy data analysis of two phase 3 studies.
Authors: David Christopher Currow, Jennifer S. Temel, Ruben Giorgino, Amy Pickar Abernethy, John Friend, Kenneth Fearon
Journal: Journal of Clinical Oncology (2016)

10119 Background: Cancer cachexia can be characterized by weight loss or low BMI, and is associated with increased morbidity and reduced survival. ROMANA 1 [NCT01387269; N = 484] and ROMANA 2 [NCT01387282; N = 495]) were randomized, double-blind, phase 3 trials of anamorelin, an oral ghrelin receptor agonist, in NSCLC patients with cachexia. The main outcomes have previously been reported; briefly, over 12 weeks anamorelin was well tolerated and compared with placebo, significantly increased lean and fat mass and improved anorexia/cachexia symptoms, while changes of handgrip strength (HGS) and fatigue were not different. The aim of this analysis was to assess the response to anamorelin specifically in patients with BMI below 20 kg/m2. Methods: Stage III/IV NSCLC patients with cachexia ( ≥ 5% weight loss during prior 6 months or BMI < 20 kg/m2) were randomly assigned (2:1) to daily oral 100 mg anamorelin or placebo for 12 weeks. A post-hoc pooled analysis of efficacy data from both trials was conducted in patients with BMI < 20 kg/m2 (N = 182) and with BMI ≥ 20 kg/m2(N = 647). Endpoints included changes in lean body mass (LBM), fat mass (FM), HGS, and changes in self-reported anorexia/cachexia concerns and fatigue. Results: Compared with placebo, anamorelin significantly increased LBM both in patients with low BMI (treatment difference: 1.71 kg [95% CI 0.88 – 2.54]) and in those with normal/high BMI (1.47 kg [1.00 - 1.94]) (p < 0.001). Greater increases in FM were observed in the BMI < 20 kg/m2 (1.66 kg [0.86 – 2.46], p < 0.001) than in the BMI ≥ 20 kg/m2 subgroup (0.79 kg [0.30 - 1.28], p = 0.002). There were no treatment differences in HGS. In patients with low BMI, anamorelin significantly improved vs placebo anorexia/cachexia symptoms (5.27 [2.11 - 8.43], p = 0.001) and fatigue (3.94 [0.56 – 7-32], p = 0.023), while these were not significant in patients with BMI ≥ 20 kg/m2(anorexia/cachexia symptoms: 0.91 [(-0.56) - 2.37], p = 0.224; fatigue: (-0.42) [(-2.07) – 1.23], p = 0.616). Conclusions: Anamorelin increased lean and fat mass while improving anorexia/cachexia and fatigue patient-reported outcomes measures in NSCLC patients with cachexia and BMI < 20 kg/m2. Clinical trial information: NCT01387269 and NCT01387282.
Circulating biomarkers and outcomes in advanced non-small cell lung cancer patients treated with anti-PD1 (program death 1 receptor) monoclonal antibodies.
Authors: Mary J. Fidler, Marta Batus, Imad Tarhoni, Selina Sayidine, Cristina L. Fhied, Sanjib Basu, Philip Bonomi, Jeffrey Allen Borgia
Journal: Journal of Clinical Oncology (2017)

e20592 Background: Current evaluation of immunohistochemical expression of PDL-1 (program death receptor 1 ligand) can select some non-small cell lung cancer (NSCLC) patients who may benefit from anti-PD1 directed therapy. It is an imperfect marker and there is little information about systemic modulation of the immune system on therapy. In this study we explored the prognostic value of baseline circulating immune checkpoint and inflammatory molecules in advanced non-small cell lung cancer (NSCLC) patients receiving anti-PD1 therapy. Methods: Prospectively collected serum from advanced NSCLC patients receiving nivolumab or pembrolizumab were evaluated with the MILLIPLEX Human High Sensitivity T-cell (17-plex) and ProcartaPlex Human Immuno-Oncology Checkpoint (14-plex) panels on our Luminex FlexMAP 3D. Biomarker level cutoffs were optimized and evaluated against progression-free survival (PFS) and overall survival (OS) using log-rank analysis. Results: 21 cases were enrolled in this pilot study: 72% Caucasian, 61% female, 24% never-smokers. IL-10 was found to have a significant association with both PFS (p = 0.0055) and OS (p = 0.024), with levels below 3.32 pg/mL being associated with a superior clinical outcome. We also found IL-2 and IL-6 to have significant associations with PFS (p = 0.033 and 0.040, respectively), again, with low levels being associated with a superior outcome. Neither of these had significant associations with OS. Low circulating levels of the T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) protein were associated with superior PFS (p = 0.036), and a weak trend (p = 0.19) for OS. Conclusions: In this small exploratory pilot study we identified several circulating molecules associated with inflammation and immune system regulation that may have prognostic value for anti-PD-1 therapy. Notably, TIM-3 is a Th1-specific protein associated with macrophage activation and is also a component of T-cell exhaustion along with LAG3 and PD-1. Additional studies to follow up on these findings in larger cohorts are underway.
TCT-529 Evaluation of the impact of a chronic total coronary occlusion on ventricular arrhythmias and long-term mortality in patients with ischemic cardiomyopathy and an implantable cardioverter-device (the eCTOpy-in-ICD study)
Authors: Ivo M. van Dongen, Dilek Yilmaz, Joelle Elias, Bimmer Claessen, Ronak Delewi, None Reinoud Knops, Arthur Wilde, Lieselot van Erven, Martin Schalij, Jose PS. Henriques
Journal: Journal of the American College of Cardiology (2018)
A randomized phase III trial on the role of esophagectomy in complete responders to preoperative chemoradiotherapy (CRT) for esophageal squamous cell carcinoma (ESCC).
Authors: Sook Ryun Park, Dok Hyun Yoon, Jong Hoon Kim, Yong-hee Kim, Hyeong Ryul Kim, Hyun Joo Lee, Hwoon-Yong Jung, Gin-Hyug Lee, Ho June Song, Do Hoon Kim, Kee Don Choi, Jeong Hoon Lee, Jin-Sook Ryu, Kyung-Ja Cho, Sung-Bae Kim
Journal: Journal of Clinical Oncology (2017)

4020 Background: To investigate the role of esophagectomy in pts who achieved clinical complete response (cCR) with CRT for locally advanced ESCC. Methods: Pts with resectable cT3-T4a anyN M0 or anyT N+ M0 thoracic ESCC, 20-75 yrs, and ECOG PS ≤2 received 2 cycles of induction XP (capecitabine 1000 mg/m 2 bid D1-14 + cisplatin 60 mg/m 2 D1 q3w) followed by CRT (50.4 Gy/28 fx, X 800 mg/m 2 bid x 5 d/w and P 30 mg/m 2 weekly). Pts with cCR were randomized to surgery (S) or observation (O). The primary endpoint was disease-free survival (DFS). Results: From Nov 2012 to March 2016, 86 pts (17.7% of the target number) were enrolled. The slow accrual caused early closure of the study. 81 pts completed CRT, and 38 pts (44.2%) achieved cCR among whom 37 pts were randomized to S (n=19) or O (n=18). The compliance rates differed between the allocated arms (68.4% in the S arm vs 100% in the O arm; P=0.020). In both Intent-to-treat (ITT) and as-treated analysis, there were no significant differences in DFS, PFS, TTP, and OS in both arms although the S arm tended to have better DFS, PFS and TTP than the O arm (Table 1). In the as-treated analysis, the relapse rate was 23.1% (3/13) in the S arm and 45.8% (11/24) in the O arm ( P=0.288). All 10 locoregional only relapse in the O arm were considered resectable, of whom 8 pts underwent surgery (n=7) or endoscopic dissection (n=1). In the as-treated analysis, the S arm had a higher R0 resection rate (92.3% vs 42.9%; P=0.031) and lower pTNM stages ( P=0.0005) than the O arm. Conclusions: Watchful waiting might be a valuable option in pts with thoracic ESCC who have cCR to CRT. Further large-scale studies are necessary to confirm our results and to optimize treatment decision in the individual pt. Clinical trial information: NCT01740375. [Table: see text]
Safety and efficacy of autologous stem cell transplantation in lymphoma patients in their 70s.
Authors: Lova Sun, Shuli Li, Phillippe Armand, Yi-Bin Albert Chen, Zachariah DeFilipp
Journal: Journal of Clinical Oncology (2017)

e19003 Background: High-dose chemotherapy and autologous stem cell transplantation (ASCT) can offer durable remission in many patients with relapsed or high-risk lymphoma. Elderly patients, who make up an increasing proportion of lymphoma patients, are often not considered candidates due to concern for excess toxicity and mortality. However, preliminary reports suggest that ASCT in carefully selected elderly patients can be feasible, safe, and effective. Methods: We identified patients ≥70 years of age with Hodgkin or non-Hodgkin lymphoma who underwent ASCT between 2000 and 2016 at two partner institutions. We recorded clinical characteristics, lymphoma diagnosis, conditioning regimen; and outcomes regarding engraftment, treatment toxicities, and relapse. Kaplan-Meier survival analysis for overall and relapse-free survival was performed. Results: 119 elderly patients with lymphoma who were treated with ASCT were identified. Median age at transplant was 72 (range, 70-79). The most common lymphoma subtype was diffuse large B-cell (n=75, 63%); others were T-cell (n=19), mantle cell (n=12), follicular (n=7), and Hodgkin (n=6). Conditioning regimens included BEAM (BCNU, etoposide, Ara-C, melphalan), CBV (cyclophosphamide, BCNU, etoposide), and Bu/Cy (busulfan/cyclophosphamide). Median time to neutrophil recovery (ANC&gt;500) and platelet recovery (&gt;20,000) were 10 and 12 days, respectively. Three patients had early mortality (within 100 days) from rapid disease progression (n=1) or treatment toxicity (n=2). Median follow up for survivors was 23 months (range, 0-157). Two-year progression-free survival and overall survival were 58% (95%CI, 48-67%) and 66% (95%CI, 55-74%), respectively. The leading cause of treatment failure was disease relapse, which occurred in 33% of patients (n=39). Two-year estimate for non-relapse mortality was 7% (95%CI, 3-14%). Conclusions: ASCT is safe and feasible in selected elderly lymphoma patients, although relapse and non-relapse mortality may be higher than in younger patients. Eligibility for ASCT should be an individualized decision, and age should not be an absolute barrier to ASCT referral in healthy elderly patients with lymphoma.
Clinical utilization of a CLIA-certified cell-free DNA (cfDNA) blood test for identification of targetable molecular alterations in patients with non-small cell lung cancer (NSCLC).
Authors: Hai T. Tran, Yasir Elamin, George R. Simon, George R. Blumenschein, Anne S. Tsao, Vassiliki Papadimitrakopoulou, Don Lynn Gibbons, Frank V. Fossella, Richard Burnham Lanman, Kimberly C. Banks, Lauren Averett Byers, Jianjun Zhang, John Heymach
Journal: Journal of Clinical Oncology (2016)

e23064 Background: The availability to have tumor genomic information from simple blood collection can significantly impact patient care. We report the clinical utility of a CLIA-certified cfDNA next generation sequencing (NGS) blood test in our patients (pts) with NSCLC. Methods: From April 2015 to January 2016, blood samples from 50 NSCLC pts were analyzed using cfDNA NGS with a panel of 70 cancer-related genes at a CLIA-certified lab (Guardant360, Guardant Health, Redwood City, CA) with reported sensitivity of 0.1% mutant allele fraction with high specificity ( > 99.9999%) (PLoS One, 10(10), 2015). Results: Fifty-three Guardant360 tests were completed in 50 pts (28/F:22/M); histology: adenocarcinoma(47), squamous(2) and sarcomatoid(1). Rationale for blood tests: insufficient tissue(32%), addition to tissue analysis(32%), alternative to tissue biopsy(13%), treatment evaluation/resistant(20.7%), no documentation(1.8%). Based on Guardant360 results, 37 pt samples demonstrated either no alterations(n = 8) or alterations that were not targetable(n = 29); concordance with at least 1 genomic alteration from paired tissue analysis in 8 pt samples and new genomic alterations dictating change in therapies in another 8 pts included: EGFR-T790M(n = 4), EML4-ALK fusion(n = 2), EGFR-e19del(n = 1), multikinase targets(n = 1). Serial testing was done in 2 cases, one had no targetable molecular alterations, with confirmation from tissue at second testing. The other pt had 3 serial tests over a 8-month period; while on erlotinib-based therapy, 1st test revealed EGFR-e19del at 0.31%, decreasing to 0.18% 4 months later; then, at progression, showed increased to 0.54% with appearance of EGFR-T790M (0.23%). At which time osimertinib was initiated. Complete clinical outcomes will be updated. Conclusions: Molecular testing of cfDNA is a simple, minimally invasive test when tissue sample is not available or inadequate for molecular analysis. It is particularly useful in the long-term management of patients for monitoring of emergence and confirmation of resistance-associated molecular alterations; such as EGFR-T790M.
Abstract MP42: Subfractions of High-density Lipoprotein Cholesterol and Carotid Intima-media Thickness
Authors: Eduard Tiozzo, Hannah Gardener, Barry I Hudson, Chuanhui Dong, David Della-Morte, Milita Crisby, Ronald B Goldberg, Mitchell S Elkind, Ying K Cheung, Clinton B Wright, Ralph L Sacco, Tatjana Rundek, Moise Desvarieux
Journal: Circulation (2016)

Background and Purpose: Recent drug trials have challenged the “HDL-cholesterol anti-atherosclerotic hypothesis”, suggesting that total levels of HDL-C may not be best target for intervention. HDL-cholesterol (HDL-C) subfractions may be better markers of vascular risk than total levels of HDL-C. The objective of this cross-sectional study was to investigate the relation between HDL2-C and HDL3-C fractions and carotid intima-media thickness (cIMT) in the population-based Northern Manhattan Study. Methods: We evaluated 988 stroke-free participants (mean age 66±8 years; 60% women; 66% Hispanic, and 34% Non-Hispanic) with available data on HDL-C subfractions using precipitation method and cIMT assessed by a high-resolution carotid ultrasound. The associations between HDL-C subfractions and cIMT were analyzed by multiple linear regression models. Results: The mean HDL2-C was 14 ± 8 mg/dl, HDL3-C 32 ± 8 mg/dl, and the mean total HDL-C was 46 ±14 mg/dl. The mean cIMT was 0.90 ± 0.08 mm. After controlling for demographics and vascular risk factors, HDL2-C and total HDL-C were inversely associated with cIMT (per 2SDs, beta= -0.012, p=0.03 and beta= -0.012, p=0.04, respectively). The same inverse association was more pronounced among those with diabetes (per 2SDs, HDL2-C: beta= -0.036, p=0.04; HDL-C: beta= -0.032, p=0.04). HDL3-C was inversely associated with cIMT but the association was not significant (per 2SDs, beta= -0.008, p=0.13) after adjustment. Conclusions: HDL2-C had greater effect on cIMT then HDL3-C in this urban population. This effect was especially pronounced among individuals with diabetes. More research in needed to determine anti-atherosclerotic effects of HDL-C subfractions and clinical relevance of raising their levels.
Outcomes by prior lines of therapy (LoT) in ZUMA-1, the pivotal phase 2 study of axicabtagene ciloleucel (Axi-Cel) in patients (Pts) with refractory large B cell lymphoma.
Authors: Frederick Lundry Locke, Armin Ghobadi, Lazaros J. Lekakis, David Bernard Miklos, Caron A. Jacobson, Eric D. Jacobsen, Ira Braunschweig, Olalekan O. Oluwole, Tanya Siddiqi, Yi Lin, Patrick Michael Reagan, Umar Farooq, Abhinav Deol, Adrian Bot, John M. Rossi, Yizhou Jiang, Allen Xue, William Y. Go, Sattva Swarup Neelapu
Journal: Journal of Clinical Oncology (2018)

3039 Background: In ZUMA-1 (NCT02348216), axi-cel, an anti-CD19 chimeric antigen receptor (CAR) T cell therapy, demonstrated significant benefit in patients (pts) with refractory large B cell lymphoma with an objective response rate (ORR) of 82% (complete response [CR] 58%; Neelapu & Locke et al. NEJM. 2017). These results supported the recent approval of axi-cel by the US FDA for the treatment of adult pts with relapsed or refractory large B cell lymphoma after ≥ 2 prior lines of systemic therapy. Here, we assessed outcomes of axi-cel by prior lines of therapy (LoT) in pts from Phases 1 and 2 of ZUMA-1. Methods: Pts with refractory large B cell lymphoma were leukapheresed and received 2 × 106 CAR T cells/kg after low-dose conditioning (Neelapu & Locke et al. NEJM 2017). Pts were evaluated by number of prior LoT: 2 – 3 vs ≥ 4. Autologous stem cell transplant (ASCT) was considered a prior LoT. Results: As of 8/11/17, median follow-up was 15.4 mo for the 108 pts treated with axi-cel. Sixty-two (57%) pts had 2 – 3 prior LoT and 43 (40%) had ≥ 4. Pts with 2 – 3 and ≥ 4 prior LoT had median ages of 60 and 55 y, 65% and 47% of pts had ECOG performance status 1, 18% and 42% had prior ASCT, and 76% and 93% had disease stage III/IV, respectively. ORRs were 94% and 67% for pts with 2 – 3 and ≥ 4 prior LoT, respectively, with CR rates of 65% and 53%; 44% and 42% of pts had ongoing responses as of the data cutoff (Table). Overall survival (OS) at 12 mo was 65% and 51% for pts with 2 – 3 and ≥ 4 prior LoT, respectively. Grade ≥ 3 treatment-emergent adverse events were reported for nearly all (100% and 93%) pts with 2 – 3 and ≥ 4 LoT, with similar rates of Grade ≥ 3 cytokine release syndrome (11% and 12%) and neurologic events (32% and 30%). There were 1 and 3 Grade 5 AEs unrelated to disease progression in the 2 – 3 and ≥ 4 LoT groups, respectively. Conclusions: Axi-cel demonstrated long-term clinical benefit for pts with refractory large B cell lymphoma regardless of the number of prior LoT. Drs Locke and Neelapu contributed equally. Clinical trial information: NCT02348216.Response, % (95% CI) LoT 2 – 3 (n = 62) ≥ 4 (n = 43) ORR 94 (84 – 98) 67 (51 – 81) CR rate 65 (51 – 76) 53 (38 – 69) Ongoing ORR 44 (31 – 57) 42 (27 – 58) 6-mo PFSa 49 (36 – 61) 51 (35 – 65) 12-mo OSa 65 (51 – 75) 51 (35 – 65) aKM estimate
The clinical impact of serum C-reactive protein levels in metastatic renal-cell carcinoma patients treated by second-line molecular targeted therapies.
Authors: Kimiharu Takamatsu, Ryuichi Mizuno, Nozomi Hayakawa, Takeo Kosaka, Eiji Kikuchi, Shuji Mikami, Mototsugu Oya
Journal: Journal of Clinical Oncology (2018)

e16572 Background: Molecular targeted therapies (TT) had been standard treatment for metastatic renal-cell carcinoma (mRCC) in this decade, but the appearance of immunoinhibitory drugs (Immuno-oncology: IO drugs) give us the new treatment option especially in second-line setting. Today, we need a new predictive biomarker of second-line treatment for the best treatment strategy. The aim of this study is evaluating the clinical effect of serum C-reactive protein (CRP) levels on prognosis after second-line treatment for mRCC. Methods: We reviewed 227 mRCC patients treated by TT. We evaluated the correlation between high serum CRP levels ( > 0.5ng/ml) before second-line treatment as well as other clinicopathological indices including age (≥70), number of metastatic sites (≥2), pathology (non-clear cell RCC), body mass index (≥25), estimated glomerular filtration ratio (≤60), MSKCC category before first-line and second-line TT (poor + int. vs. fav.), toxicity related first-line treatment discontinue and short duration of first-line TT (≤ 6months) and overall survival (OS) from second-line treatment initiation. Results: Of 126 patients who was treated by second-line TT, the median OS from second-line treatment was 14.3 months in all cohorts, 16.8 months in favorable (51 cases, 40.5%), 14.1 months in intermediate (66 cases, 52.3%) and 3.5 months in poor (9 cases, 7.1%) risk group by the MSKCC classification model. 45 patients (35.7%) were categorized in high CRP group. By univariate analysis, high-CRP group (p < 0.001), non-clear cell carcinoma (p = 0.001), MSKCC classification (intermediate or worse) before second-line treatment (p = 0.024) and short duration of first-line treatment (p = 0.029) were significantly correlated with shorter OS. By multivariate analysis, the elevated CRP was the independent prognostic factor for OS (hazard ratio = 2.70, 95% confidential interval = 1.45-5.00, p = 0.002). Conclusions: The baseline CRP levels before second-line treatment could be an easily evaluated and cost effectively predictive factor for second-line TT.
Omega-3 Fatty Acids and Genome-Wide Interaction Analyses Reveal <i>DPP10–</i>Pulmonary Function Association
Authors: Jiayi Xu, Nathan C. Gaddis, Traci M. Bartz, Ruixue Hou, Ani W. Manichaikul, Nathan Pankratz, Albert V. Smith, Fangui Sun, Natalie Terzikhan, Christina A. Markunas, Bonnie K. Patchen, Matthew Schu, May A. Beydoun, Guy G. Brusselle, Gudny Eiriksdottir, Xia Zhou, Alexis C. Wood, Mariaelisa Graff, Tamara B. Harris, M. Arfan Ikram, David R. Jacobs, Lenore J. Launer, Rozenn N. Lemaitre, George T. O’Connor, Elizabeth C. Oelsner, Bruce M. Psaty, Ramachandran S. Vasan, Rebecca R. Rohde, Stephen S. Rich, Jerome I. Rotter, Sudha Seshadri, Lewis J. Smith, Henning Tiemeier, Michael Y. Tsai, André G. Uitterlinden, V. Saroja Voruganti, Hanfei Xu, Nuno R. Zilhão, Myriam Fornage, M. Carola Zillikens, Stephanie J. London, R. Graham Barr, Josée Dupuis, Sina A. Gharib, Vilmundur Gudnason, Lies Lahousse, Kari E. North, Lyn M. Steffen, Patricia A. Cassano, Dana B. Hancock
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Rationale: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health.Objective: To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility.Methods: Associations of n-3 PUFA biomarkers (α-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (FEV1, FVC, and FEV1/FVC) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N = 16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N = 11,962) and replicated in one cohort (N = 1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of SNP associations and their interactions with n-3 PUFAs.Results: DPA and DHA were positively associated with FEV1 and FVC (P < 0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320—an intronic DPP10 SNP—with FVC when incorporating an interaction with DHA, and the finding was replicated (P2df = 9.4 × 10−9 across discovery and replication cohorts). The rs11693320-A allele (frequency, ∼80%) was associated with lower FVC (PSNP = 2.1 × 10−9; βSNP = −161.0 ml), and the association was attenuated by higher DHA levels (PSNP×DHA interaction = 2.1 × 10−7; βSNP×DHA interaction = 36.2 ml).Conclusions: We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction.