tbuckley/cabot-search huggingface dataset:
A systems biology approach to investigating the influence of exercise and fitness on the composition of leukocytes in peripheral blood
Authors: Michael P. Gustafson, Ara Celi DiCostanzo, Courtney M. Wheatley, Chul-Ho Kim, Svetlana Bornschlegl, Dennis A. Gastineau, Bruce D. Johnson, Allan B. Dietz
Journal: Journal for ImmunoTherapy of Cancer (2017)

<h3>Background</h3> Exercise immunology has become a growing field in the past 20 years, with an emphasis on understanding how different forms of exercise affect immune function. Mechanistic studies are beginning to shed light on how exercise may impair the development of cancer or be used to augment cancer treatment. The beneficial effects of exercise on the immune system may be exploited to improve patient responses to cancer immunotherapy. <h3>Methods</h3> We investigated the effects of acute exercise on the composition of peripheral blood leukocytes over time in a male population of varying fitness. Subjects performed a brief maximal intensity cycling regimen and a longer less intense cycling regimen at separate visits. Leukocytes were measured by multi-parameter flow cytometry of more than 50 immunophenotypes for each collection sample. <h3>Results</h3> We found a differential induction of leukocytosis dependent on exercise intensity and duration. Cytotoxic natural killer cells demonstrated the greatest increase (average of 5.6 fold) immediately post-maximal exercise whereas CD15<sup>+</sup> granulocytes demonstrated the largest increase at 3 h post-maximal exercise (1.6 fold). The longer, less intense endurance exercise resulted in an attenuated leukocytosis. Induction of leukocytosis did not differ in our limited study of active (<i>n</i> = 10) and sedentary (<i>n</i> = 5) subjects to exercise although we found that in baseline samples, sedentary individuals had elevated percentages of CD45RO<sup>+</sup> memory CD4<sup>+</sup> T cells and elevated proportions of CD4<sup>+</sup> T cells expressing the negative immune regulator programmed death-1 (PD-1). Finally, we identified several leukocytes whose presence correlated with obesity related fitness parameters. <h3>Conclusions</h3> Our data suggests that leukocytes subsets are differentially mobilized into the peripheral blood and dependent on the intensity and duration of exercise. Pre-existing compositional differences of leukocytes were associated with various fitness parameters.
Glutaminase and poly(ADP-ribose) polymerase inhibitors suppress pyrimidine synthesis and VHL-deficient renal cancers
Authors: Arimichi Okazaki, Paulo A. Gameiro, Danos Christodoulou, Laura Laviollette, Meike Schneider, Frances Chaves, Anat Stemmer-Rachamimov, Stephanie A. Yazinski, Richard Lee, Gregory Stephanopoulos, Lee Zou, Othon Iliopoulos
Journal: Journal of Clinical Investigation (2017)

Many cancer-associated mutations that deregulate cellular metabolic responses to hypoxia also reprogram carbon metabolism to promote utilization of glutamine. In renal cell carcinoma (RCC), cells deficient in the von Hippel–Lindau (VHL) tumor suppressor gene use glutamine to generate citrate and lipids through reductive carboxylation (RC) of α-ketoglutarate (αKG). Glutamine can also generate aspartate, the carbon source for pyrimidine biosynthesis, and glutathione for redox balance. Here we have shown that VHL–/– RCC cells rely on RC-derived aspartate to maintain de novo pyrimidine biosynthesis. Glutaminase 1 (GLS1) inhibitors depleted pyrimidines and increased ROS in VHL–/– cells but not in VHL+/+ cells, which utilized glucose oxidation for glutamate and aspartate production. GLS1 inhibitor–induced nucleoside depletion and ROS enhancement led to DNA replication stress and activation of an intra–S phase checkpoint, and suppressed the growth of VHL–/– RCC cells. These effects were rescued by administration of glutamate, αKG, or nucleobases with N-acetylcysteine. Further, we observed that the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib synergizes with GLS1 inhibitors to suppress the growth of VHL–/– cells in vitro and in vivo. This work describes a mechanism that explains the sensitivity of RCC tumor growth to GLS1 inhibitors and supports the development of therapeutic strategies for targeting VHL-deficient RCC.
Clinical trial subjects compared to "real world" patients: Generalizability of renal cell carcinoma trials.
Authors: Aaron Philip Mitchell, Michael Roger Harrison, Daniel J. George, Amy Pickar Abernethy, Mark S. Walker, Bradford Richard Hirsch
Journal: Journal of Clinical Oncology (2014)

6510 Background: While narrow eligibility criteria improve the internal validity of clinical trials, they threaten the generalizability of study findings to real-world populations. How similar is the population of patients receiving treatment for metastatic renal cell cancer (mRCC) to subjects enrolled in pivotal trials? Methods: A retrospective registry of academic (Duke University Health System) and community (ACORN Network) practices was used to compare real world mRCC patients to study subjects in the landmark phase III clinical trials of the new, targeted therapies. Patients were compared to subjects who were treated with the same agent. Results: Of 633 patients in the registry, 438 received sunitinib, sorafenib, temsirolimus, or pazopanib; everolimus and axitinib were not included due to small patient numbers. Registry patients were a mean of 4.6 years older than clinical trial subjects (p <0.0001). With the exception of temsirolimus-treated patients, registry patients had poorer risk disease by MSKCC model (poor: 7.4% vs 2.9%, p<0.0001; favorable: 30.6% vs 43.8%, p=0.0004) and were more likely to have impaired functional status (ECOG >1, 8.4% vs 0.6%, p<0.0001). Applying the eligibility criteria described in the clinical trial manuscripts, 40.0% of patients failed inclusion criteria for the phase III clinical trial testing the drug they received (Table), 9.9% due solely to non-clear cell histology. Conclusions: mRCC patients in “real world” clinical practice are older and sicker than those enrolled in pivotal clinical trials. Over one third of mRCC patients would not have met eligibility criteria for the phase III clinical trial that led to approval of the agent they received. Application of clinical trial findings to dissimilar populations may result in patient harm. Research of mRCC drugs in general populations is needed to guide real world clinical practice. Agent used to treat mRCC cohort patients N Clinical trial used for comparison Patients meeting exclusion criteria (%) Sunitinib 289 Motzer et al, NEJM 2007 98 (33.9) Sorafenib 59 Escudier et al, NEJM 2007 20 (33.9) Temsirolimus 59 Hudes et al, NEJM 2007 44 (74.6) Pazopanib 31 Sternberg et al, JCO 2010 13 (41.9) Total 438 175 (40.0)
Angiogenesis pathway gene polymorphisms associated with clinical outcome in recurrent ovarian cancer treated with low dose cyclophosphamide and bevacizumab: A California Consortium Trial
Authors: A. M. Schultheis, D. Yang, A. A. Garcia, R. Morgan, D. Gandara, S. Scudder, A. Oza, H. Hirte, G. Fleming, L. Roman, H. Lenz
Journal: Journal of Clinical Oncology (2006)

5017 Background: Despite advances in chemotherapy, ovarian cancer remains a major cause of cancer mortality worldwide. It has therefore become essential to identify novel therapeutic targets, such as angiogenesis which is a complex process regulated by the delicate balance between various local proangiogenic and antiangiogenic proteins. Bevacizumab, a monoclonal antibody binding to VEGF, has shown significant activity in colon, breast, lung and ovarian cancer. There are no established molecular markers to predict response or time to tumor progression for Bevacizumab based chemotherapy. The key enzymes of the VEGF pathway are: Vascular Endothelial Growth Factor (VEGF), VEGF Receptor (VEGFR), Hypoxia Inducible Factor1 (HIF α and β-subunit), Neuropilin1 (NRP), Interleukin-8 (IL-8), Adrenomedullin (AM) and Leptin. Methods: Seventy patients with refractory ovarian cancer were enrolled in a Phase II clinical trial and treated with Cyclophoshamide 50 mg po/Bevacizumab 10 mg/kg IV every 14 days. From 52 patients blood samples were available for gDNA extraction and PCR-RFLP assays. Results: 13 patients had a PR (25%) and 39 were non responders. 31 pts had progressed. Median follow-up of 8.3 months with a median progression-free survival of 6.6 months. Patients who were homozygous A/A or heterozygous A/T genotype at the −251 locus in the IL-8 gene had a lower response rate than those who were T/T (P = 0.047 Fisher’s exact test). Patients with Vegf936 C/C had a median TTP of 6.5 months, pts with any T (T/T, C/T) had a median TTP of 17.2 months. Pts carrying both AM 3’end alleles &lt;14 CA repeats had 3.4 months median TTP, patients with at least one allele &gt;14 showed a median TTP of 6.6 months; for both alleles &gt;14 patients showed 8.7 months of median TPP (P = 0.0006 Log-rank test) Conclusions: Our data suggest for the first time, that IL-8 may be a potential molecular predictor of response to Bevacizumab based chemotherapy. We also demonstrate that both VEGF 936 and the AM 3’ dinucleotide repeat polymorphisms are potential molecular markers for time to tumor progression. A larger prospective study is needed to validate and confirm our preliminary findings. This study was supported by NCI grant NO1 CM 17101. [Table: see text]
Impact of proximity to NCI- and NCCN-designated cancer centers on outcomes for patients with prostate cancer undergoing radical prostatectomy.
Authors: Cameron Ghaffary, Tamer Dafashy, Christopher David Kosarek, Zhigang Duan, Brian F. Chapin, Karim Chamie, Simon P. Kim, Justin Edwin Fang, Preston Kerr, Karen E. Hoffman, Sharon Hermes Giordano, Eduardo Orihuela, Stephen Bentley Williams
Journal: Journal of Clinical Oncology (2017)

14 Background: National Cancer Institute (NCI) and National Comprehensive Cancer Network (NCCN)-designated cancer centers (CCs) offer patients state-of-the-art treatment. We sought to identify whether proximity to NCI/NCCN CCs was associated with survival outcomes for prostate cancer patients who undergo radical prostatectomy (RP). Methods: A total of 12,478 total patients diagnosed with clinical stage T1 or T2 prostate cancer between 2004–2011 using linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data were included. Multivariable regression analyses were used to quantify overall survival and use of secondary therapies for RP patients according to proximity to NCI/NCCN CCs. Cox proportional hazards models were used to quantify the association between survival outcomes and access to NCI/NCCN CCs. Results: Patients with proximity to ≥ 2 NCI centers and those diagnosed in 2011 enjoyed a statistically significant overall survival advantage when compared to no access to an NCI center (Hazard Ratio (HR) 0.72; 95% confidence interval (CI) 0.57–0.92, p &lt; 0.01). Proximity to an NCCN CC, when compared with men who did not have access, was associated with improved overall survival (HR 0.76; 95% CI 0.61–0.95, p = 0.015). There was no significant difference in use of secondary therapies according to NCI or NCCN access. Conclusions: Patients who undergo RP with access to an NCI/NCCN CCs experienced improved overall survival with no significant difference in utilization of secondary therapies. Given the need for improved health quality measures in cancer care, these findings may support health policy implementation and regionalization of care to these centers.
Desmoid fibromatosis and pregnancy: A multi-institutional analysis of recurrence and obstetric risk.
Authors: Marco Fiore, Sara Coppola, Chiara Colombo, Monica M. Bertagnolli, Suzanne George, Axel Le Cesne, Paolo Giovanni Casali, Alessandro Gronchi, Sylvie Bonvalot, Chandrajit P. Raut
Journal: Journal of Clinical Oncology (2012)

10017 Background: Desmoid fibromatosis (DF) may be diagnosed during or after pregnancy (P). However, the risk of progression during P, or in women of child-bearing age with DF prior to P, is unknown. Furthermore, obstetric risks have not been well described. Methods: Institutional databases were reviewed at 3 sarcoma referral centers in Europe and US for women with sporadic DF from 1985 to 2011. Pregnancy and treatment data, outcomes, and obstetric complications were recorded. Results: Overall 75 women were identified. DF was diagnosed during P in 17 women (Group A) or within 6 mo after P in 10 (Group B), was in situ at the time of P in 29 women (Group C), or had been resected prior to P in 19 (Group D). Anatomic site, outcomes, and treatment for each group are in the Table. Among patients operated at diagnosis, 2/11 (18%) recurred (Group A+B). Among the entire cohort, 15 women (20%) recurred after definitive treatment and only 6 (8%) needed multiple treatments after P. Ten spontaneous regressions occurred after P (13%). Twelve women had further P following the DF-related one, and 3 (25%) needed treatment after the subsequent P. At a median follow up of 35 mo from P, 17 women did not receive any treatment (23%), and 39 remain disease-free (52%). Caesarean section was needed in 14 cases (19%), but only in 1 expressly due to DF. DF-related P was associated with abortion in 6 cases (4 spontaneous, 2 voluntary); in no case was it caused by the presence of DF. Conclusions: DF developing prior to or during P may progress during the course of P or thereafter. Spontaneous regression after P was also observed. When resected, P-related DF rarely recurs. Wait &amp; see is an option as well. DF history is not an indication for therapeutic abortion nor a contraindication against subsequent P. [Table: see text]
The incidence, risk factors and prognostic implications of venous thromboembolism in Asian patients with non-small cell lung cancer.
Authors: Yun-Gyoo Lee, Inho Kim, Eunyoung Lee, Soo-Mee Bang, Chang Hyun Kang, Young Tae Kim, Hak Jae Kim, Hong-Gyun Wu, Young Whan Kim, Tae Min Kim, Keun-Wook Lee, Se-Hoon Lee, Dong-Wan Kim, Dae Seog Heo
Journal: Journal of Clinical Oncology (2013)

1590 Background: The goal of this study was to describe the incidence, risk factors and prognostic implications of venous thromboembolism (VTE) in Asian patients with non-small cell lung cancer (NSCLC). The association between specific gene mutations and the risk of VTE was also evaluated. Methods: A total of 1998 consecutive patients with NSCLC were enrolled and analyzed retrospectively. To minimize potential confounding, we used propensity score-matching to compare overall survival between patients with and without VTE. Results: The 6-month and 2-year cumulative incidences of VTE were 4.2% and 6.4%, respectively. The risk of VTE increased 2.45-fold with each advancing stage in NSCLC (common hazard ratio [HR] 2.45; 95% CI 1.96–3.05; P&lt;0.001). In multivariate analyses, the effects of therapeutic variables including surgery, chemotherapy, and radiotherapy on the development of VTE were modified by NSCLC stage. Therefore, we calculated stratum-specific HRs by performing stratified analyses for each stage. The independent predictors of VTE were advanced age, pneumonectomy (vs. lobectomy) and palliative radiotherapy (vs. no radiotherapy) in localized NSCLC and no surgery (vs. lobectomy) and palliative radiotherapy (vs. no radiotherapy) in locally advanced NSCLC. Adenocarcinoma histology (vs. squamous cell carcinoma) was the only independent risk factor for increased risk of VTE in metastatic NSCLC. EGFR mutation was independently associated with a 47% lower risk of VTE in adenocarcinoma compared to wild type (HR 0.53; 95% CI 0.29–0.99; P=0.045). Among both the entire and propensity score-matched cohorts, a significant survival difference was observed between patients with and without VTE in localized NSCLC, but not in locally advanced or metastatic NSCLC. The strong association we observed between VTE and the increased rate of recurrence (risk ratio 2.0; 95% CI 1.28–3.12; P=0.009) can explain the significant difference in survival in localized NSCLC. Conclusions: Approximately 6.4% of Asian patients with NSCLC developed VTE during a 2-year period. The association between VTE and decreased survival was limited to localized NSCLC.
Minimally invasive complete mesocolic excision and central vascular ligation for right colon cancer: Defining the radicality of central lymphadenectomy.
Authors: Tarik Sammour, Songphol Malakorn, Rajesh Thampy, Harmeet Kaur, Brian Bednarski, Craig Messick, George J. Chang, Y. Nancy You
Journal: Journal of Clinical Oncology (2017)

715 Background: Complete mesocolic excision (CME) with central vascular ligation (CVL) has been advocated for right colon cancer (RC), but the radicality of lymphadenectomy remains controversial. Optimal D2 lymphadenectomy removes all intermediate nodes with high ligation (HL) of feeding vessels, while D3 lymphadenectomy additionally exposes and retrieves nodes along ventral superior mesenteric vessels (SMA/V). We aim to evaluate minimally invasive CME-CVL, explicitly defining the radicality of central lymphadenectomy. Methods: Patients who underwent minimally invasive resection for RC between 2008 and 2016 were identified from a prospective institutional database. CME was standard. The radicality of central lymphadenectomy was defined as high ligation (HL, optimal D2) vs central node dissection (CND, D3) after review of operative reports and/or videos. A blinded radiologist evaluated the pre- and post-operative CT scans for radiographically abnormal nodes. Results: Among 200 patients, 169 (84.5%) underwent laparoscopic and 31 (15.5%) robotic resection. Central lymphadenectomy was performed as HL in 58 (29%) and as CND in 142 (71%) patients. Preoperative imaging identified abnormal D2 nodes in 33.0% and D3 nodes in 2.6%. CND was performed in 73% of those with abnormal D2 and 100% of those with abnormal D3 nodes. Pathologically positive nodes were identified in 41% (37.9% of the HL and 42.3% of the CND, p=0.64). The median number of nodes retrieved was 27 and 32, respectively. No patient had residual abnormal node on post-operative imaging. The 30 day mortality rate was 0%, and morbidity rate was 15% (4% grade 3, 11% grades 1-2). After a median of 22 months, one (0.5%) patient recurred locally at the anastomosis. Conclusions: Minimally invasive CME-CVL can be safely performed with excellent nodal yield with both optimal D2 as well as D3 lymphadenectomy. With imperfect clinical nodal staging, the near-zero local recurrence rate observed supports CME with optimal D2 lymphadenectomy as a minimum standard and D3 lymphadenectomy when radiographically abnormal nodes are identified.
FDG PET predicts prognosis of patients with resectable metastatic colorectal cancer (CRC) treated with preoperative chemotherapy
Authors: P. Flamen, V. Huberty, C. Garcia, B. Vanderlinden, K. Muylle, H. Legendre, M. Paesmans, M. Van Den Eynde, A. Hendlisz
Journal: Journal of Clinical Oncology (2007)

14540 Background: Standard evaluation of response to chemotherapy in metastatic CRC is unsatisfactory. Metabolism based imaging using positron emission tomography and fluorodeoxyglucose (FDG-PET) is increasingly used to assess treatment efficacy. Aim: To evaluate the prognostic value of FDG-PET metabolic response to chemotherapy in resectable metastatic CRC. Methods: We reviewed retrospectively 382 patients with metastatic CRC between 7/2002 and 8/2006. Patients curatively operated from CRC metastases treated with preoperative chemotherapy and evaluated by FDG PET at baseline and before surgery were considered eligible for the study. Time to progression (TTP) was defined as the time between surgery and the first proof of recurrence of disease. Total Lesion Glycolysis (TLG) was used as the metabolic parameter. It represents the product of the mean standardised FDG uptake (SUV) of each lesion and its volume. The change of the sum of the TLG of all lesions was calculated. A cut-off of 30% was used to differentiate responders and non- responders. Results: 18 patients (median age 65 yrs) were included. 16 patients were operated from liver mets, and 2 from lung mets. Chemotherapy regimen was FOLFOX 4 in 10 patients, FOLFIRI in 7, and FOLFIRI-bevacizumab in 1 patient. Median number of lesions was 3 (1 to 10) before and 1 after chemotherapy. Median baseline TLG was 115.8 (6.8–841.8). Median post chemo TLG was 12.8 (0–1608.9). The distribution of the metabolic responses was CR 5, PR 9, SD 1, PD 3, with a response rate of 14/18 (78%, 95% CI : 52%-94%). Baseline TLG was not different between responders and non responders (p=0.88). Median follow-up was 422 days: 6 patients died, 15 had recurrent disease. Median TTP was 31 days for non responders, and 197 days for responders (p value not calculated because of the small number of non responding patients). After dichotomization of TLG values using their median as threshold, the post chemo TLG influenced significantly TTP (p=0.001, median TTP 86 days vs 263 days) along with the change of TLG (p=0.002, 107 days vs 263 days). Conclusions: Metabolic response assessment using PET allows a prognostic stratification after preoperative chemotherapy in resectable metastatic CRC. No significant financial relationships to disclose.
Development and validation of prognostic models in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib: A Greek-French collaboration.
Authors: Vasilios Karavasilis, Kimon Tzanis, Christina Bamia, Reza-Thierry Elaidi, Efthimios Kostouros, Antonios Visvikis, Dimosthenis-Vasilios Skarlos, Helena Linardou, Evangelia Razis, Michael Chrisofos, Kostas Stravodimos, George Lazaridis, Eleni Timotheadou, Constantinos Hatzimouratidis, Stephane Oudard, George Fountzilas, Meletios A. Dimopoulos, Aristotelis Bamias
Journal: Journal of Clinical Oncology (2012)

e15040 Background: The use of tyrosine kinase inhibitors (TKIs) in mRCC has improved prognosis but the individual outcome remains largely unpredictable. The MSKCC model, used to identify risk groups, was developed in cytokine-treated patients and has not been externally validated in the TKI era. It contains 3 laboratory factors (total 5), making its application to retrospective series somewhat problematic. Subsequently, a more complicated model, using 4 laboratory factors (total 6) has been described. The Hellenic Cooperative Oncology Group recently described a simpler model with only 3 clinical factors. We are describing the application and external validation of this model. Methods: 128 Greek patients with mRCC treated with 1 st line sunitinib were included. All had had nephrectomy. Previous interferon was allowed. Cox regression was used to develop a predictive model for overall survival (OS). Our model was compared to that of MSKCC and Heng’s using ROC curves and Harrell’s Concordance Index. Risk groups were defined by the calculated prognostic index and by clinical factors. External validation was done using a sample of 226 French patients. The Royston and Sauerbrei D statistic was used as a measure of discrimination of the survival model. Results: Time from diagnosis of RCC to start of sunitinib (&lt;12), PS (&gt;1) and number of metastatic sites (&gt;1) were independent adverse prognostic factors in the Greek dataset. The co-efficients for each factor were: 0.51, 0.97, 0.61, respectively. The 3 risk groups were defined by the 25 th and 75 th percentiles of the prognostic index values (Table 1). The model was of equal prognostic value to the MSKCC (p=.272) and Heng’s (p=.075). French had better survival than Greek patients especially in the high risk group (for all models). Validation of our model in the French data showed that it was applicable (R 2 D: 0.14, SE: 0.09), especially for the low/medium risk groups. Conclusions: Our model is the only one externally validated in TKI-treated patients. It may be considered as a simpler alternative to those currently applied. [Table: see text]