tbuckley/cabot-search huggingface dataset:
Recurrent versus de novo metastatic NSCLC: Impact on outcomes.
Authors: Sara Moore, Bonnie Leung, Jonn Wu, Aria Shokoohi, Cheryl Ho
Journal: Journal of Clinical Oncology (2017)

9045 Background: Metastatic non-small-cell lung (NSCLC) cancer has a poor prognosis, with a 5 year survival less than 5%. The majority of patients present with stage IV and many patients treated curatively with stage I-III will develop recurrent metastatic disease. It is unknown if the natural history differs between patients with recurrent versus de novo metastatic NSCLC. We hypothesized that de novo metastatic disease is associated with decreased overall survival compared to recurrent metastatic disease. Methods: A retrospective review was completed of all patients with NSCLC referred to the BC Cancer Agency from 2005-2012. Two cohorts were created; de novo metastatic disease and patients treated with curative intent (surgery or radiotherapy) that developed recurrent, metastatic disease. Information was collected on known prognostic and predictive factors. Overall survival was calculated from the date of diagnosis of metastatic disease. Results: A total of 9656 patients were referred, 5783 (60%) with de novo stage IV disease, and 3873 (40%) with stage I-III disease. Of patients with initial stage I-III, 1801 received curative therapy (751 surgery, 1050 radiotherapy) and 802 developed metastases. Patients in the de novo cohort were more likely to be male (52% vs 47%), have poorer performance status (ECOG≥2 50% vs 43%), and receive no palliative chemotherapy (67% vs 61%). The median overall survival in the de novo cohort was 4.7 m vs 6.9 m in the recurrent cohort (p &lt; 0.001). De novo status was associated with shorter overall survival and this remained significant in a multivariate model that incorporated gender, ECOG and lines of palliative chemotherapy (hazard ratio 1.228[95% confidence interval 1.134-1.330], p-value &lt; 0.001). Conclusions: In a large population based study of NSCLC, de novo metastatic status was independently associated with decreased overall survival from the time of metastatic disease diagnosis. De novo versus recurrent status should be used as a prognostic factor to inform patient decisions and ensure balanced stratification of patients in clinical trials.
Association of CDKN2A/2B deletion with homozygous deletion of TCR- γ gene in T-ALL.
Authors: Anita Chopra, Jay Singh, Deepak Verma, Nishi Rajput, Sameer Bakhshi, Amar Ranjan Singh, Rajive Kumar
Journal: Journal of Clinical Oncology (2017)

e18516 Background: T-lineage acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease that arises in a multistep fashion through acquisition of several genetic aberrations. Absence of biallelic deletion of TCR-γ (ABD), a marker of immaturity, and CDKN2A/2B deletion have been identified as poor predictors of outcome in T-ALL treated with contemporary protocols. The aim of this study was to determine the correlation between ABD and CDKN2A/2B in Indian T-ALL patients. Methods: A total of 31 cases of T-ALL, diagnosed on morphology, cytochemistry and immunophenotyping, were included in the study. The age of the patients ranged from 1-50 years. The patients were investigated for CDKN2A/2B deletion by multiplex ligation dependent probe amplification (MLPA) using the commercially available probe set P383 (MRC Holland). The status of the deletion of TCR- γ was determined using quantitative assay described by Gutierrez et al. 1 Results: Absence of biallelic deletion of TCR- γ gene were found in 14 (45.16%) patients. Homozygous deletion was seen in 13 (41.93%) patients while monoallelic deletion was seen in 5 (16.12%) patients. CDKN2A/2B deletions were found in (48.38%) patients. On correlation of CDKN2A/2B deletion and TCR- γ deletion, it was found that CDKN2A/2B deletion was found in 2/14 (14.28%) patients with ABD and 10/13 (76.92%) patients with homozygous deletion. Conclusions: CDKN2A/2B deletion are more common in patients with homozygous deletion of TCR- γ gene.
Combined effect of gemcitabine (GEM) and sapC-DOPS nanovesicles on pancreatic ductal adenocarcinoma (PDAC) in mice.
Authors: Xiaoyang Qi, Harold W. Davis, Zhengtao Chu, Subrahmanya D. Vallabhapurapu, Nida Hussain, Robert S. Franco, John Charles Morris, Angela N. Johnson, Olugbenga Olanrele Olowokure
Journal: Journal of Clinical Oncology (2018)

e16209 Background: Phosphatidylserine (PS) is an anionic phospholipid primarily localized on the inner plasma membrane of healthy cells. In contrast, PS is externally expressed on cancer cells and tumor-associated vascular cells. PS is further externalized by treatment with GEM, a drug commonly used to treat advanced PDAC, the fourth leading cause of cancer-related death. The efficacy of GEM in combination with PS-targeted cancer-selective protein-lipid nanovesicles (SapC-DOPS) was studied in vitro and in PDAC mouse models. Methods: MiaPaCa-2 subcutaneous PDAC tumors (100-300 mm3) were established in female athymic nude mice. Mice (12/group) were treated with GEM (40 mg/kg ip), SapC-DOPS (4.9 mg/kg iv), or both (GEM+SapC-DOPS) on day 26 and every 3 days thereafter. Tumor surface PS and size were analyzed at day 55. Orthotopic p53 2.1.1 tumors were generated in FVB/n mice and were confirmed by bioluminescence. 6 mice/group were treated with DOPS (1.9 mg/kg iv), GEM (10 mg/kg ip), SapC-DOPS (3 and 1.9 mg/kg iv), or GEM+SapC-DOPS 2x/week to day 55 and followed for survival. PS levels and cell death in vitro were confirmed by flow cytometry and MTT assay, respectively at 24-48 hr after GEM (10 nM-1 μM) in human AsPC-1, MiaPaCa-2, murine p53 2.1.1 PDAC, and immortalized human pancreatic duct epithelial cells. Results: Elevated PS surface expression on viable PDAC cells was confirmed 48 hr after GEM in vitro and in subcutaneous tumors. Cancer cell death was notably higher in GEM+SapC-DOPS treated mice compared to GEM or SapC-DOPS alone (75.5±2.1% vs. 25.0±1.5% and 17.3±5.1%, respectively). SapC-DOPS+GEM more effectively inhibited tumor growth in both subcutaneous and orthotopic xenograft models compared to GEM alone. SapC-DOPS+GEM improved survival vs. either drug alone. Conclusions: The combination of GEM and SapC-DOPS demonstrated enhanced antitumor activity in PDAC. This suggests that targeting externalized PS combined with chemotherapy is an effective means of selectively inducing tumor cell death, providing support for clinical study.
Effect of adoption of neoadjuvant chemotherapy for advanced ovarian cancer on all-cause mortality.
Authors: Alexander Melamed, Günther Fink, Alexi A. Wright, Nancy Lynn Keating, Allison Ann Gockley, Marcela G. del Carmen, John O. Schorge, Jose Alejandro Rauh-Hain
Journal: Journal of Clinical Oncology (2017)

5537 Background: Use of neoadjuvant chemotherapy followed by surgery for advanced epithelial ovarian cancer is controversial in the United States. Methods: Use of neoadjuvant chemotherapy for stage IIIC and IV ovarian cancer has increased gradually in the United States since 2007, but rates of adoption vary by region. Between 2011 and 2012, use of neoadjuvant chemotherapy increased by 27% in the New England and East South Central regions, but remained unchanged in three control regions (South Atlantic, West North Central, and East North Central regions). Employing prospectively collected data from Commission on Cancer-accredited cancer programs in the United States, we used this discontinuity in treatment approach to assess the causal impact of neoadjuvant chemotherapy on all-cause mortality in a quasi-experimental fuzzy regression discontinuity design. Kaplan-Meier curves and proportional hazard models were estimated to compare mortality differences between rapidly-adopting regions and controls. We also conducted a cross-sectional analysis of the relationship between regional use of neoadjuvant chemotherapy and survival. Results: We identified 1,156 women treated for advanced epithelial ovarian cancer during 2011 and 2012 in the two rapidly-adopting regions and 4,878 women in the three control regions. In the rapidly-adopting regions, patients treated in 2012 compared with 2011 had a mortality hazard ratio (HR) of 0.81 (95%CI=0.71-0.94) after adjusting for mortality time trends, while no difference was observed in control regions (HR=1.02, 95%CI=0.93-1.12). Compared with control regions, we observed larger declines in 90-day surgical mortality (7.0% to 4.0% versus 5.0 to 4.3%, p=0.01) and in the proportion of women not receiving surgery and chemotherapy (20.0% to 17.4% versus 19.0 to 19.5%, p=0.04) in rapidly adopting regions. Cross-sectional analysis confirmed that treatment in regions with greater use of neoadjuvant chemotherapy was associated was lower mortality (p=0.001). Conclusions: Adoption of neoadjuvant chemotherapy for advanced epithelial ovarian cancer in New England and East South Central regions led to a sizable reduction in mortality within three years after diagnosis.
Ensituximab (E) in patients (pts) with refractory metastatic colorectal cancer (mCRC): Results of a phase I/II clinical trial.
Authors: Richard D. Kim, Philip M. Arlen, Kwong Y. Tsang, Sharon Mavroukakis, Anjum Zaki, Karen Cui, Nilofer Saba Azad, Benjamin R. Tan, Elizabeth Poplin, Michael Morse, Muhammad Shaalan Beg
Journal: Journal of Clinical Oncology (2017)

3081 Background: E is an investigational, novel, chimeric monoclonal IgG1 antibody derived from an immunogenic neoantigen with sequence homology to MUC5AC that is preferentially expressed with exquisite specificity to pancreatic cancer and CRC. Its mechanism of action is via antibody-dependent cellular cytotoxicity (ADCC). The efficacy and safety of E was evaluated in a single-arm, open-label, phase 1/2 clinical trial of adult pts with refractory mCRC. Methods: Pts were selected based on &gt; 20% expression of tumor antigen, as measured by immunohistochemistry. Based on phase 1 results, E was administered 3 mg/kg IV every 2 weeks until unacceptable toxicity or disease progression. Primary endpoint was overall survival (OS). Serum cytokine levels were analyzed at baseline, day 4, and day 15. E-mediated ADCC of CD16 genotype V/V, V/F, and F/F pt PBMCs was measured with an IN-111 release assay using the E target-expressing ASPC-1 pancreatic cancer cell line. Results: Fifty-seven and 63 pts were evaluable for OS and safety, respectively. Median OS was significantly longer than historical control: 6.8 vs 5.0 months (mo); p = 0.007; 95% CI: 5.39,8.02. Three pts were alive at end of study (21, 21, and 24 mo); 21 pts survived ≥ 12 mo. Pts had a median of 4 prior therapies (range 2-9); 25% had received regorafenib. Forty-seven pts were evaluable by RECIST, and 20 (43%) had stable disease of target lesions at end of first course (day 57). E was well tolerated, with &lt; 2% grade 3 and no grade 4 toxicities. There were no trends in serum cytokine and chemokine levels. Analysis of 56 samples (8 V/V, 26 V/F, 17 F/F, and 5 undetermined) showed that V/V PBMCs had significantly higher E-mediated ADCC than PBMCs harboring other genotypes. No correlation between CD16 polymorphism and pt outcome was observed. Conclusions: E demonstrated excellent tolerability and encouraging OS in this heavily pretreated population. Correlative in vitro data suggest that E can mediate higher levels of ADCC activity in individuals with a V/V versus other genotypes. The lack of correlation between CD16 polymorphism and pt outcomes in this study suggests that other immune-related factors (under investigation) may impact the efficacy of E in vivo. Clinical trial information: NCT01040000.
Responses and durability in NSCLC treated with pegilodecakin and anti-PD-1.
Authors: Edward B. Garon, Jeffrey Gary Schneider, Deborah J.L. Wong, Raid Aljumaily, Wolfgang Michael Korn, Jeffrey R. Infante, Manish R. Patel, Karen A. Autio, Kyriakos P. Papadopoulos, Aung Naing, Nashat Y. Gabrail, Pamela N. Munster, Jonathan Wade Goldman, Annie Hung, Peter Van Vlasselaer, Joseph Leveque, Martin Oft, David R. Spigel
Journal: Journal of Clinical Oncology (2018)

9018 Background: Responses in NSCLC to agents targeting the PD-1/PD-L1 axis are correlated with PD-L1 expression by immunohistochemistry (IHC), tumor mutational burden (TMB), interferon associated mRNA Expression Profile (GEP) and the absence of liver metastases. Anti-PD-1 impedes the inhibition of T cells while pegilodecakin (AM0010) stimulates the survival, and expansion of intra-tumoral, antigen activated CD8+ T cells (Mumm et al., 2010). This provides a rationale for combining anti-PD-1 agents with pegilodecakin. Methods: Pretreated NSCLC subjects (n = 34), received pegilodecakin (10-20µg/kg QD, SC) with pembrolizumab (2mg/kg, q3wk IV; n = 5) or nivolumab (3mg/kg, q2wk IV; n = 29). Median follow-up is 31.2 months (range 28.3 to 33+) and 17.5 months (range 8.3 to 25.9+), respectively. Responses were assessed by irRC. Twenty subjects had sufficient tissue for PD-L1 testing with the 22C3 IHC assay (CLIA) and 10 subjects had sufficient tissue for TMB evaluation by whole exome sequencing (WES) and pre-treatment GEP by Nanostring. Results: In 26 subjects evaluable for response, the ORR was 41% (11 PRs). Another 12 subjects (46%) had SD as best response. As investigators were asked to preferentially enroll PD-L1 negative patients, PD-L1 expression was < 1% in 12 of 20 PD-L1 evaluable subjects with 4 achieving a PR. Ten subjects had sufficient tissue for TMB and GEP, including 6 PRs. Five of the 8 who tested low to intermediate for TMB (≤ 243 mut) had a PR as did 2 of 6 GEP negative subjects. In addition, 5 of 8 subjects with liver metastasis had a PR. The mPFS and mOS of the five NSCLC subjects (4/4 tested PD-L1 < 1%) treated with pegilodecakin + pembrolizumab was 10.9 and 32.2 months, respectively. The mPFS and mOS for the pegilodecakin + nivolumab cohort (8/16 PD-L1 < 1%) has not been reached. Conclusions: Pegilodecakin when added to anti-PD-1 therapy in advanced NSCLC patients was associated with response rates and durability of benefit greater than has been seen with anti-PD-1 alone. Responses were seen in settings in which anti-PD-1 therapy has demonstrated limited benefit, such as absent PD-L1 expression, low TMB and/or the presence of liver metastasis. These preliminary findings support further studies of pegilodecakin with anti-PD-1 therapies. Clinical trial information: NCT02009449.
Abstract 14463: Elevated Bone Marrow Derived Stromal Cell Derived Factor-1 Is Associated With Mortality in Heart Failure
Authors: Kateryna Sopova, Beatrice von Jeinsen, Lars Palapies, Konstantinos Stellos, Stephan Fichtlscherer, Florian Seeger, Stefanie Dimmeler, Birgit Assmus, Andreas Zeiher, Till Keller
Journal: Circulation (2016)

Background: Bone marrow-derived cells are functionally exhausted in patients with chronic heart failure. We hypothesized that chronic heart failure is associated with impairment of the bone marrow niche. Stromal cell derived factor-1 (SDF-1) is an essential regulator of bone marrow cell function. Therefore, we evaluated whether bone marrow derived SDF-1 is associated with prognosis in patients with chronic heart failure. Methods and Results: SDF-1 levels were determined in bone marrow plasma of 188 patients with chronic heart failure, who were enrolled in the Frankfurt Bone Marrow-Derived Cell Therapy Registry. Within a 5-year follow-up period 52 patients died. In a sub-cohort of 50 patients we further evaluated SDF-1 levels determined in peripheral blood samples. Bone marrow plasma and peripheral blood SDF-1 levels were closely correlated (r=0.6, p<0.001). SDF-1 levels in bone marrow plasma were almost twice as high as in peripheral blood. Bone marrow SDF-1 levels were inversely correlated with left vent...
Abstract 12308: Aortic Aneurysm Associated With Bicuspid Aortic Valve: Relation to Gender, Hemodynamics, and Valve Morphology: The NHLBI GenTAC Registry
Authors: Mary J Roman, Norma L Pugh, Joseph E Bavaria, Richard B Devereux, Kim A Eagle, Kathryn Holmes, Scott A LeMaire, Shaine A Morris, Reed Pyeritz, William J Ravekes, Federico M Asch
Journal: Circulation (2015)

Background: Aortic aneurysm phenotype in bicuspid aortic valve (BAV) may vary according to gender, hemodynamic alterations, and valve morphology (type of cusp fusion). To better understand these potential associations, BAV participants in the GenTAC Registry were analyzed. Methods: 973 patients with BAV were enrolled (76.3% male; mean age 44.5 years). At time of enrollment, 549 (56.4%; 76.9% male) had undergone valvular and/or aortic surgery. Imaging data were available on 424 unoperated or pre-operative participants. Results: Sinuses of Valsalva (SOV) diameter was larger in men than women (3.90 vs. 3.36 cm, p&lt;0.0001); Z score: 2.2±2.3 vs. 1.4±1.9, p=0.002), whereas ascending aortic (AscAo) diameters were comparable (4.01 vs. 3.89, p=0.22; Z score: 3.2±2.0 vs. 3.5±2.2, p=0.124). BAV function was normal in 15.0%, predominantly regurgitant (AR) in 38.9%, predominantly stenotic (AS) in 21.6%, and mixed AS/AR in 16.0%. AR was more common in men (43.8 vs. 25.0%, p=0.003) whereas AS was more common in women (30.0 vs. 18.6%, p=0.033). Moderate-severe AR was associated with larger SOV diameters than mild AS (p=0.01) or moderate-severe AS (p=0.0006) or normal function (p&lt;0.001). SOV diameters in mild AR were larger than those with normal function (p=0.012). Moderate-severe AS was associated with significantly larger AscAo diameter compared to normal function (p=0.002) but not compared to BAV with AR. AscAo diameters were larger in AR compared to normal function (both p&lt;0.001). Diameters of the SOV (3.70±0.67 vs. 3.36±0.56 cm, p=0.001) were larger in right-left fusion than in right-non fusion pattern whereas AscAo diameter was comparable. Conclusions: In the GenTAC Registry, SOV diameters were larger in males, even after adjustment for body size. AR was associated with both SOV and AscAo enlargement whereas moderate-severe AS was only associated with AscAo enlargement. Aortic diameters were larger in those with right-left cusp fusion independent of valve function.
TCT-538 Bleeding Outcomes in Patients Undergoing Combined TAVR/PCI: Time for an Adjustment to the CathPCI Bleeding Model?
Authors: Aakriti Gupta, Matthew Finn, Torsten Vahl, Tamim Nazif, Emily Smyth, Kathryn Fidlow, Martin Leon, Susheel Kodali, Ajay Jayant Kirtane
Journal: Journal of the American College of Cardiology (2018)
Statins don’t reduce cardiovascular disease or death in healthy over 75s, study finds
Authors: Gareth Iacobucci
Journal: BMJ (2018)

Statins are not associated with a reduction in cardiovascular disease (CVD) or death in healthy people aged over 75, a study1 published in The BMJ has found.

But in people with type 2 diabetes, statins were related to a reduction in CVD and death from any cause up to the age of 85 years, the authors reported.

Researchers at the University Institute for Primary Care Research Jordi Gol and the Girona Biomedical Research Institute aimed to assess whether treatment with statins is associated with a reduction in CVD and death in old (75 to 84 years) and very old (85 years and over) adults with and without …
Effects and moderators of exercise on muscle strength, muscle function and aerobic fitness in patients with cancer: a meta-analysis of individual patient data
Authors: Maike G Sweegers, Teatske M Altenburg, Johannes Brug, Anne M May, Jonna K van Vulpen, Neil K Aaronson, Gill Arbane, Martin Bohus, Kerry S Courneya, Amanda J Daley, Daniel A Galvao, Rachel Garrod, Kathleen A Griffith, Wim H Van Harten, Sandra C Hayes, Fernando Herrero-Román, Marie J Kersten, Alejandro Lucia, Alex McConnachie, Willem van Mechelen, Nanette Mutrie, Robert U Newton, Frans Nollet, Karin Potthoff, Martina E Schmidt, Kathryn H Schmitz, Karl Heinz Schulz, Gabe Sonke, Karen Steindorf, Martijn M Stuiver, Dennis R Taaffe, Lene Thorsen, Jos W Twisk, Miranda J Velthuis, Jennifer Wenzel, Kerri M Winters-Stone, Joachim Wiskemann, Mai J Chin A Paw, Laurien M Buffart
Journal: British Journal of Sports Medicine (2018)

Objective To optimally target exercise interventions for patients with cancer, it is important to identify which patients benefit from which interventions. Design We conducted an individual patient data meta-analysis to investigate demographic, clinical, intervention-related and exercise-related moderators of exercise intervention effects on physical fitness in patients with cancer. Data sources We identified relevant studies via systematic searches in electronic databases (PubMed, Embase, PsycINFO and CINAHL). Eligibility criteria We analysed data from 28 randomised controlled trials investigating the effects of exercise on upper body muscle strength (UBMS) and lower body muscle strength (LBMS), lower body muscle function (LBMF) and aerobic fitness in adult patients with cancer. Results Exercise significantly improved UBMS (β=0.20, 95% Confidence Interval (CI) 0.14 to 0.26), LBMS (β=0.29, 95% CI 0.23 to 0.35), LBMF (β=0.16, 95% CI 0.08 to 0.24) and aerobic fitness (β=0.28, 95% CI 0.23 to 0.34), with larger effects for supervised interventions. Exercise effects on UBMS were larger during treatment, when supervised interventions included ≥3 sessions per week, when resistance exercises were included and when session duration was &gt;60 min. Exercise effects on LBMS were larger for patients who were living alone, for supervised interventions including resistance exercise and when session duration was &gt;60 min. Exercise effects on aerobic fitness were larger for younger patients and when supervised interventions included aerobic exercise. Conclusion Exercise interventions during and following cancer treatment had small effects on UBMS, LBMS, LBMF and aerobic fitness. Demographic, intervention-related and exercise-related characteristics including age, marital status, intervention timing, delivery mode and frequency and type and time of exercise sessions moderated the exercise effect on UBMS, LBMS and aerobic fitness.