bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aspirin and statin use and the risk of gallbladder cancer.
Authors: Prasai Kritika , Mady Mohamed , Yadav Siddhartha , Hassan Mohamed Abdelrahim Muddathir , Roberts Lewis R. , Mahipal Amit 
Published: January 2019

243 Background: The risk factors for gallbladder cancer (GBC) are poorly understood and preventive therapeutic options have not been identified. The use of aspirin (ASA) and/or statin has been associated with reduced risk of several gastrointestinal cancers. In this study, we explore if the use of ASA or statin is associated with a reduced risk of GBC. Methods: We identified patients with GBC diagnosed between the years 2000 and 2016 at Mayo Clinic. We identified matched controls in 2:1 fashion for age, gender and country of residence from patients who underwent cholecystectomy at Mayo Clinic. We collected information on co-morbidities and use of statins or ASA by retrospective chart review. We compared baseline characteristics between cases and controls using Fisher’s exact test for categorical variables and Mann-Whitney U test for continuous variables. We used binomial logistic regression to calculate the odds ratio (OR) and 95% confidence intervals (CI) to estimate the association of ASA or statin use with GBC. The logistic regression model included history of cholelithiasis, diabetes, hypercholesterolemia (HCL), hypertension (HTN), hyperthyroidism, hypothyroidism, primary sclerosing cholangitis (PSC), inflammatory bowel disease (IBD), cirrhosis and statin or ASA use as covariates. Results: 633 cases and 1,266 controls were included in our final analysis. The median age at diagnosis of cases and controls was 67 years. The control group had a significantly (p < 0.05) higher proportion of patients with cholelithiasis, HCL, HTN, hypothyroidism and liver cirrhosis compared to the cases. The case group,contrarily, had a significantly higher proportion of patients with PSC and IBD. In univariate analysis, ASA (OR: 0.41; 95% CI: 0.33-0.52) or statin (OR: 0.48; 95% CI: 0.38-0.60) use was associated with a lower risk of GBC (p < 0.001). However, in multivariate analysis, ASA use was associated with a lower risk of GBC (OR: 0.52; 95% CI: 0.41-0.67, p < 0.001) whereas statin use was not (OR: 0.76; 95% CI: 0.56-1.03, p = 0.08). Conclusions: Our study demonstrates that aspirin use is associated with a reduced risk of GBC, whereas statin use is not. Further studies on GBC are needed to confirm these results and to elucidate mechanisms that explain the risk reduction with aspirin.
Epidemiological trends of small bowel tumors and changing incidence in Utah.
Authors: Thota Ramya , Herget Kim , Sause William T. , Curtin Karen , Sweeney Carol , Neklason Deborah Wood 
Published: January 2019

245 Background: The incidence and prevalence of small bowel tumors in particular adenocarcinomas are thought to be rising but updated epidemiological data is lacking. Therefore, in this study we explored the evolving epidemiology of small bowel tumors. Methods: This is a retrospective population based study using Utah Cancer Registry (UCR) and Surveillance Epidemiology, and End Results program (SEER) conducted between 1973-2015. The age adjusted incidence and prevalence was determined. The incidence and prevalence rates were compared to other SEER residents diagnosed with invasive small bowel tumors using ICD codes C17.0 – C17.9). Results: The small bowel tumors have steadily increased from 1990 to 2015. In the UCR, the highest incidence of and small bowel tumors was reported 1.7 per 100,000 in 2015. The prevalence of small bowel tumors in the state of Utah from 1973 – 2014 was 616 including 41 adenocarcinomas, 327 with carcinoid tumors and 248 with other histology’s. There was 1.67% increase in incidence of small bowel tumors in SEER while in Utah we noted 2.81 % annual increase of incidence from 1990 to 2015. Especially, for small bowel adenocarcinomas, Utah has an annual increase of 2.43% from 1990-2015, and SEER had a smaller increase of 0.71% per year over the same time frame. Conclusions: The incidence of small bowel adenocarcinomas between 1995 and 2015 show a steady increase in both UCR and SEER databases. Despite the rarity of these tumors rising incidence warrants increasing awareness and need for better treatments to improve the survival outcomes of these under-studied tumors.
Dissecting the spatial heterogeneity of single circulating tumor cells reveals immune evasion through MAX regulated CCL5 overexpression in hepatocellular carcinoma.
Authors: Sun Yun-Fan , Yang Xin-Rong , Jia Fan 
Published: January 2019

246 Background: The transcriptional heterogeneity and immune evasion mechanisms of CTCs during systemic circulation are not well defined. Methods: Blood was drawn from 4 different vascular sites, including hepatic vein (HV), peripheral artery (PA), peripheral vein (PV) and portal vein (PoV) of 10 localized HCC patients. Single CTCs were isolated by negative enrichment and robotic micromanipulator, followed by single-cell RNA-sequencing (sc-RNAseq). After filtering, 113 CTCs with qualified data remained were subjected to further bioinformatics analysis. The scRNA-seq results were further validated in three independent cohorts of HCC patients. Results: Our scRNA-seq data revealed remarkable intra- and inter-vascular heterogeneity among CTCs from four vascular sites. We determined CTC transcriptional dynamics during transportation through consecutive vascular compartments and revealed their adaptation mechanisms under biomechanical stress during circulation. We further classified CTCs from different vascular sites into two subsets, namely dormant CTCs and activated CTCs. Dormant CTCs were associated with a non-cycling state and upregulation of EMT/angiogenic signatures and showed stronger prognostic ability for early recurrence than activated CTCs did. Furthermore, we discovered an immune escape mechanism by which CTCs recruited regulatory T cells (Tregs) via expression of CCL5, consequently promoting the formation of an immunosuppressive microenvironment favorable for their survival in the bloodstream and seeding in secondary organs. We proved that MAX, activated through the p38 pathway, was the key transcriptional factor regulating CCL5 overexpression, which was validated by ChIP, luciferase reporter gene and in vitro/vivo knockdown assays. And we further determined that Tregs-derived TGF-β1 can heighten MAX expression, thus amplifying the CCL5 expression. Conclusions: Collectively, our results reveal a previously unappreciated spatial heterogeneity of CTCs and a CTC immune-escape mechanism, which may aid in designing new anti-metastasis therapeutic strategies in HCC.
Soluble urokinase plasminogen activator receptor (suPAR) as a novel biomarker in patients undergoing resection of pancreatic adenocarcinoma.
Authors: Loosen Sven H , Binnebösel Marcel , Longerich Thomas , Roderburg Christoph , Trautwein Christian , Neumann Ulf Peter , Luedde Tom 
Published: January 2019

248 Background: Surgical resection represents the only potentially curative therapy for patients with pancreatic adenocarcinoma (PDAC), an aggressive malignancy with a very limited 5-year survival rate. However, even after successful R0 tumor resection, some patients are still facing an unfavourable prognosis underlining the need for better preoperative stratification algorithms. The soluble urokinase plasminogen activator receptor (suPAR) was recently described as a promising new biomarker for different clinical conditions including cancer. Here, we evaluated the potential role of circulating suPAR as a biomarker in patients undergoing resection of PDAC. Methods: Expression levels of uPAR, the membrane-bound source of circulating suPAR, were analysed in PDAC tissue samples using IHC. Serum levels of suPAR were measured by ELISA in an exploratory as well as a validation cohort comprising a total of 127 PDAC patients and 75 healthy controls. Results were correlated with clinical data. Results: Correlating with a high immunohistochemical expression of uPAR in PDAC tissue samples, serum levels of suPAR were significantly elevated in PDAC patients compared to healthy controls. Importantly, patients with high preoperative suPAR levels above a calculated cut-off value of 5.956 ng/ml showed a significantly reduced overall survival after tumor resection. The prognostic role of suPAR was further corroborated by uni- and multivariate Cox-regression analyses including parameters of systemic inflammation, liver and kidney function as well as clinico-pathological patients’ characteristics. Moreover, high baseline suPAR levels identified those patients particularly susceptible to acute kidney injury after surgery. Conclusions: Our data suggest that circulating suPAR represents a novel prognostic marker in PDAC patients undergoing tumor resection that might be a useful addition to existing preoperative stratification algorithms for identifying patients that particularly benefit from extended tumor resection.
Association of socioeconomic status with incidence and outcomes of gastric cancer in a Michigan cohort.
Authors: Karapetyan Lilit , Wang Ling , Gardiner Joseph , Laird-Fick Heather 
Published: January 2019

25 Background: The purpose of this study is to examine the association between socioeconomic factors and gastric cancer (GC) outcome in a cohort of patients in Michigan. Methods: We reviewed data for patients enrolled in the Michigan Cancer Surveillance Program, with diagnosis between 1990 and 2014 and follow up through 2016. Data extracted were age and stage at diagnosis, gender, race, zip code (as a proxy for family income), receipt of treatments, and survival status at last follow up. The poverty level (PL) was defined as average income by zip code < $24,600. Statistical comparisons were assessed by chi-square tests in contingency tables, by the log-rank test for survival, and Poisson regression for incidence rate comparisons. Results: We identified 10,828 GC patients (22.39% below PL, 64.64% between PL and 200% PL, 12.98% above 200% PL) with complete data for analysis. By race/ethnicity, 68.12% non-Hispanic blacks, 21.05% American Indian/Alaska Natives, 8.59% Asian/Pacific Islanders, 23.83% Hispanics, and 12.63% non-Hispanic whites lived in areas with average income below PL. The socioeconomic status by race among GC patients was significantly different (p < 0.0001). There was significant association of socioeconomic status and receipt of treatments. Patients living in areas below PL tended to have less information available about treatment received: unknown compared to no radiation (OR = 1.45, 95% CI 1.30-1.63), unknown compared to no chemotherapy (OR = 1.39, 95% CI 1.23-1.57), unknown compared to no surgery (OR = 1.49, 95% CI = 1.32-1.69). There was no significant relationship between stage at diagnosis and socioeconomic status (p = 0.153). The Poisson regression results showed that as average income increased in $10,000 increments in the area, incidence of gastric cancer is expected to decrease by 0.0642 (p < 0.0001). As income in the area increases by $10,000, risk of death is expected to decrease (HR 0.977, p = 0.0025). Conclusions: In Michigan, socioeconomic factors are associated with race, incidence of GC, receipt of treatments, and survival, but not stage at diagnosis.
Using novel real-time tracking to monitor postoperative recovery in a comprehensive cancer center.
Authors: Dong Sharlene , Barkley Rachel , Clark Clancy 
Published: January 2019

250 Background: Early mobilization is thought to be a key component of postoperative care following surgery. However, the benefit of early ambulation is not well studied. Normal and abnormal ambulatory patterns for postoperative cancer patients remains unknown. The aim of the current study is to characterize the postoperative movement patterns of the patients recovering from surgery at Comprehensive Cancer Center using an objective novel real-time location system (RTLS). Methods: In this retrospective cohort study, patient ambulatory movements were captured using RTLS. Clinical data was extracted from the medical record. A custom algorithm was created to measure postoperative ambulation and an ambulatory mobility event was defined as movement in and out of the patient’s room on the postoperative ward lasting from three to 60 minutes. Mobility data was analyzed to determine predictors of postoperative ambulation. Results: 358 postoperative patients (39.7% female, median age 62) were identified for inclusion in this study. 272 (76.0%) patients had a postoperative mobility event. Median number of walks 1.2 (IQR 0.7-2.2) per day was 6.7 (IQR) with median duration of 6.7 (IQR4.6-10.8) minutes. Time to first ambulatory event after surgery was 1.2 (IQR 0.9-2.0) days. Time to first ambulatory events varied by surgical service with Thoracic Surgery having the most patients ambulating on postoperative day zero (43.3%). In univariate analysis, young age, shorter operation length, and surgical service were predictors of early first ambulatory event (all p < 0.05). In multiple variable analysis, young age and surgical service were predictors of early first ambulatory event (all p < 0.05). Conclusions: The current study demonstrates the feasible application of RTLS to passively monitor the recovery of postoperative cancer patients In addition, this technology provides a novel opportunity to correlating patient movement with clinical outcomes, such as morbidity, mortality, and length of stay.
Clinical significance of monitoring KRAS in tissue and plasma of pancreatic cancer patients.
Authors: Watanabe Fumiaki , Suzuki Koichi , Endo Yuhei , Ishikawa Hideki , Kakizawa Nao , Noda Hiroshi , Rikiyama Toshiki 
Published: January 2019

254 Background: KRAS mutation is observed in 90% of pancreatic cancer patients. Therefore, investigating tumor DNA in plasma by KRAS monitoring may be even more valuable in pancreatic cancer patients. Methods: We collected the tissue and plasma of 78 pancreatic cancer patients (surgery group; 39, non-surgery group; 39). KRAS mutation in the tissue and mutated circulating tumor DNA (MctDNA) in plasma was detected by digital polymerase chain reaction in 78 patients. Identical KRAS mutation detected in tissue (ex. 12D, 12V) was monitored in plasma. Results: KRAS mutation in the tissue was detected in 65 of 73 patients. KRAS assessment in the tissue was not performed in 5 patients, because of tissues small amounts of tissue materials by biopsy. These 65 patients with KRAS mutation in tissue showed poorer prognosis (3 years OS; 23.4%) than 8 patients without mutation (3 years; 66.7%). MctDNA in plasma of surgery group was seen in 14 of 39 patients. Thirteen in 14 patients with MctDNA showed recurrence and 12 patients were dead. These 14 patients with MctDNA in plasma showed significantly poorer prognosis (2 years OS; 16.3%) than 25 patients without mutation (3 years; 71.6%) (p = 0.00). Univariate analysis revealed that poor differentiation and the detection of MctDNA were independent factors to predict poor survival in surgery group. The detection of MctDNA was confirmed to be an independent factor in multivariate analysis (Hazard ratio; 31.25). MctDNA in plasma of non-surgery group was seen in 28 of 39 patients. But, MctDNA in 6 patients was disappeared in clinical course. These 6 patients and 11 patients without MctDNA displayed better prognosis (2 years OS; 72.1%) than 22 patients with MctDNA (2 years OS; 12.1%) with significance (p = 0.0001). Univariate and multivariate analysis revealed that no treatment and the detection of MctDNA were independent factors to predict poor survival in non-surgery group. (Hazard ratio; 8.78, 4.76, respectively). Conclusions: KRAS monitoring in plasma reflects tumor dynamics. The appearance of MctDNA during KRAS monitoring provides important information for the treatment of pancreatic cancer patients.
The prognostic role of soluble transforming growth factor-β (sTGFb) and soluble programmed death-ligand 1 (sPDL1) in biliary tract cancer patients treated with binimetinib and capecitabine.
Authors: Kim Jin Won , Lee Kyung-Hun , Kim Ji-Won , Suh Koung Jin , Nam Ah-Rong , Bang Ju-Hee , Bang Yung-Jue , Oh Do-Youn 
Published: January 2019

257 Background: Transforming growth factor (TGF) -β signaling is important for tumor growth and metastasis in biliary tract cancer (BTC). TGF-β attenuates tumor response to programmed death-ligand 1 (PD-L1) blockade. This study aimed to evaluate a correlation between soluble TGF-β (s TGF-β) and soluble PD-L1 (sPD-L1) and its prognostic role in BTC. Methods: Study population consisted of 34 patients enrolled in phase Ib clinical trial of binimetinib (MEK inhibitor) with capecitabine in gemcitabine-pretreated BTC (ClinicalTrials.gov: NCT02773459). Blood samples at screening, after first cycle, after second cycle, and at disease progression were prospectively collected. Plasma sTGF-β and sPD-L1 values were measured by using an enzyme-linked immunosorbent assay. Results: In total 34 patients, 25 (73.5%) and 9 patients (26.5%) were second-line and third-line setting, respectively. Median progression-free survival (PFS) and overall survival (OS) were 4.1 and 7.8 months. The mean baseline sTGF-β and sPD-L1 were 18.7 ng/ml and 3.1 ng/ml. There was a positive correlation between sTGF-β and sPD-L1 value (pearson correlation = 0.596, p < 0.001). Mean baseline value was likely to be higher in best response of progressive disease, followed by stable disease and partial response. Similarly, higher baseline sTGF-β showed significantly shorter PFS (3.4 vs 5.1 months (m), p = 0.047) and OS (5.4 vs 9.7 m, p = 0.042). Higher baseline sPD-L1 also had a trend for poor PFS and OS (PFS: 3.0 vs 4.3 m, p = 0.220; OS: 6.4 vs 9.7 m, p = 0.140). Regarding changes from baseline to after first cycle, sTGF-β change of > 3.6 ng/ml demonstrated significantly shorter OS (5.9 vs 10.8 m, p = 0.020), although PFS did not differ according to sTGF-β change (p = 0.210). In contrast, OS did not differ according to sPD-L1 change (p = 0.190). sPD-L1 change > -1.7 ng/ml even had longer PFS (5.1 vs 2.2 m, p = 0.005). Conclusions: In BTC patients with binimetinib and capecitabine, there is a positive correlation between sTGF-β and sPD-L1 value and higher baseline sTGF-β and sPD-L1 indicate a worse prognosis. The early change of sTGF-β and sPD-L1 during treatment could predict the survival.
Gastrin vaccine and immune checkpoint antibody therapy for pancreatic cancer.
Authors: Smith Jill P , Osborne Nicholas , Sundseth Rebecca , Burks Julian , Cao Hong , Liu Xunxian H , Kroemer Alexander H , Sutton Lynda Youngpeter , Cato Allen 
Published: January 2019

259 Background: Pancreatic cancer is poorly responsive to therapy due to fibrosis in the tumor microenvironment and nonspecificity of treatments. The peptide gastrin stimulates growth of pancreatic cancer in an autocrine fashion. Polyclonal Antibody Stimulator (PAS) is a gastrin vaccine that in clinical trials prolongs survival of patients who develop neutralizing gastrin antibodies. We hypothesized that PAS also elicits a memory and T-cell response that would improve effectiveness of immune checkpoint antibodies. Methods: C57BL/6 mice were injected sc with syngeneic mT3 murine pancreatic cancer cells. After 1 week (tumors evident), groups were treated with PBS (control); PAS (100 μg or 250 μg); PD-1 antibody (150 μg); or combined therapy with PAS100/PD-1. PAS was given ip at weeks 0, 1 and 3. Anti-PD-1 was given on days 0, 4, 8, 15 and 21. On day 31 spleens were collected for T-cell surface analysis and cytokine activation by flow cytometry. Tumors were stained for fibrosis and with immunohistochemical stains for CD8+ and FoxP3+ tumor infiltrating lymphocytes (TILs). Results: PAS resulted in T-cell activation; however, the portion of terminally differentiated effector memory double negative T-cells (CD4- CD8-) in CD3+cells from mice treated with the combination PAS100/PD-1 was two-fold higher than those portions from mice treated with PBS, PD-1 or PAS100. Lymphocytes from PAS-treated mice elicited cytokine release (Interferon-γ, granzyme, perforin, and TNF-α) upon re-stimulation with gastrin in vitro, whereas PAS100/PD-1-treated mice show the highest endogenous cytokines levels. PAS250 monotherapy decreased tumor growth. Neither PAS100 nor anti-PD-1 monotherapy decreased tumor size, but combination PAS100/PD-1 antibody tumors were smaller, had less fibrosis, fewer T-regulatory lymphocytes, and increased CD8+ TILs. Conclusions: In addition to eliciting a B-cell response, PAS activates T-lymphocytes rendering tumors susceptible to immune checkpoint antibody treatment. Smaller tumors with combined therapy may be due to the anti-fibrotic effect of PAS on the tumor microenvironment and changes in CD8+ TILs. This study supports that PAS is an important immunotherapy that elicits both B- and T-cell anti-cancer responses.
T-cell–inflamed gene expression profile (GEP) and PD-L1 expression in patients (pts) with esophageal cancer (EC).
Authors: Steiniche Torben , Rha Sun Young , Chung Hyun Cheol , Georgsen Jeanette Bæhr , Ladekarl Morten , Nordsmark Marianne , Jespersen Marie Louise , Kim Hyo Song , Kim Hyunki , Fein Carly , Wu Ting , Savage Mary J. , Marton Matthew John , Kang S. Peter , Peter Senaka A. , Kelsen David Paul , Ku Geoffrey Yuyat 
Published: January 2019

26 Background: GEP and PD-L1 expression have been associated with anti–PD-1/PD-L1 therapy. In this retrospective observational study we explored the prognostic value of GEP and PD-L1 expression in pts with EC receiving standard-of-care therapy (SOC). Methods: Tumor tissue samples collected from 2005 to 2017 were procured from Yonsei Cancer Center (South Korea), Memorial Sloan Kettering Cancer Center (USA) and Aarhus University Hospital (Denmark). GEP score was derived from an 18-gene signature using extracted tumor RNA analyzed by NanoString nCounter; GEP high/intermediate (GEP-H/I) and low were defined by a cutoff of –1.540, consistent with pembrolizumab clinical trials. PD-L1 expression was assessed by PD-L1 IHC 22C3 pharmDx assay (Agilent); positive was defined as combined positive score (CPS) ≥ 10, where CPS is the the number of PD-L1–positive cells (tumor cells, lymphocytes and macrophages) divided by the total number of viable tumor cells, multiplied by 100. Associations of GEP score and PD-L1 expression with clinicopathologic variables were analyzed by chi-square test and multiple logistic regression models. Overall survival (OS) from diagnosis date to death date/last follow-up was analyzed using Cox proportional hazards models adjusting for age, sex, stage, region and ECOG performance status (PS). Results: 294 samples with both PD-L1 and GEP data were analyzed. Median age was 65 y (range 33-88); 85% were from men, 58% were stage IV, 63% were esophageal adenocarcinoma (EAC) and 37% were esophageal squamous cell carcinoma (ESCC). Overall 36% of tumors were GEP-H/I: 46% in EAC vs 18% in ESCC. GEP was not associated with OS overall (adjusted hazard ratio [aHR] –0.90; 95% CI 0.68-1.18) or in pts with EAC (aHR 0.93; 95% CI 0.68-1.27) or ESCC (aHR 0.76; 95% CI 0.40-1.44). 21% of tumors were PD-L1-CPS ≥ 10: 18% in EAC and 26% in ESCC. PD-L1 expression was associated with ECOG PS (adjusted odds ratio 0.520; 95% CI 0.309-0.875; P = 0.014) but was not associated with OS overall (aHR 0.89; 95% CI 0.64-1.24) or in pts with EAC (aHR 0.97; 95% CI 0.63-1.49) or ESCC (aHR 1.31; 95% CI 0.73-2.34). Conclusions: Our results suggest that T-cell–inflamed GEP and PD-L1 expression may not be prognostic in pts with EC who received SOC.