bluuebunny/crossref_metadata_2025_split huggingface dataset:
The expression of versican and its role in pancreatic neuroendocrine tumors.
Authors: Sun Zhao , Gao Heli , Gu Junjie , Cheng Yuejuan , Chen Yuanjia , Bai Chunmei 
Published: January 2019

254 Background: Pancreatic neuroendocrine tumor (pNET) is a group of rare and heterogeneous tumor. Prognostic biomarkers are essential to better predict patients’ prognosis and approve individualized chemotherapy. According to references, Versican(VCAN) expression plays an important role in the development of various tumors.Our previous study found VCAN had a tumor-specific expression in pNET tissues. Therefore, further study is performed to investigate the relationship between VCAN expression in pNET tissues and patients’ prognosis. Methods: Clinicopathological data of pNET patients who underwent surgery between 2005 and 2010 were collected, followed up and evaluated. VCAN expression was assessed by immunohistochemical (IHC) staining. The relationship between VCAN expression and clinicopathological characteristics of patients were analyzed by Chi square. The expression between VCAN expression and disease-free survival (DFS) of patients were analyzed by Kaplan-Meier. The relationship between patients’ DFS and relative clinicopathological characters were analyzed by Cox regression. Results: 174 pNET patients were enrolled in our research. Among them, 124 patients were VCAN positive and 50 were VCAN negative. VCAN expression was significantly associated with tumor stage. Better disease-free survival (DFS) was observed in patients with VCAN positive compared to those with VCAN negative (124.1±75.71m,99.35±12.14,respectively, p = 0.003).Multivariate analysis demonstrated that VCAN expression, Grade, tumor size were independent prognostic predictor for patients’ prognosis(p = 0.01,0.000,0.001,respectively). Subgroup analysis revealed that VCAN positive predicted a better DFS in patients with Grade 2, Tumor size > 2cm, and Non-functional tumor(p = 0.04,0.002,0.01,respectively). Conclusions: pNET patients with VCAN positive had a longer DFS.
A study of the combination of oxaliplatin, capecitabine, and trastuzumab and chemo-radiotherapy in the adjuvant setting in operated patients with HER2+ gastric or gastroesophageal junction cancer (TOXAG study).
Authors: Abali Huseyin , Yalcin Suayib , Onal Cem , Dane Faysal , Oksuzoglu Berna , Ozdemir Nuriye , Mertsoylu Huseyin , Artac Mehmet , Camci Celaletdin , Karabulut Bulent , Basal Fatma Bugdaycı , Budakoglu Burcin , Sendur Mehmet Ali Nahit , Goktas Burce , Ozdener Fatih , Baygul Arzu 
Published: January 2019

26 Background: We evaluated the safety and tolerability of trastuzumab (T) in combination with oxaliplatin (O), capecitabine (C) and chemo-radiotherapy in the adjuvant setting in operated, HER-2 positive gastric or gastroesophageal junction adenocarcinoma patients. Methods: We have screened 212 and enrolled 34 patients who were curatively resected (R0, R1 with partial or total gastrectomy, with D2 lymph node dissection) and were HER2-positive (IHC 2+/FISH+ or IHC 3+). The primary objectives were safety and tolerability of the treatment combination and secondary objectives were disease-free and overall survival rates. Patients received T 8 mg/kg intravenously (iv) on Day 1 of cycle 1 and 6 mg/kg iv on day 1 of every following 3-weekly cycle for 1 year as 17 cycles, O 100 mg/m2 iv on Day 1 of cycles 1-3 and C 850 mg/m2 orally twice daily on days 1-14 of cycles 1-3 and 5 days per week during chemo-radiotherapy. Radiotherapy was given at a total dose of 45 Gy divided into 25 doses 5 treatment days per week for 5 weeks starting from the 1st day of cycle 4. Results: The median age was 57 years and 73.5% were male, 97.0% had an ECOG PS score ≤ 1,33, 97.0% had D2 lymph node resection. Staging was 3A or higher at the time of diagnosis in 76.4% of patients. Patients had high rate of tolerability to the combination regimen (90.3%) and successfully completed 3 cycles of O+C+T plus chemoradiotherapy followed by continuation with T, achieving the primary goal of the study by showing a better tolerability rate as compared to tolerability reported for INT0116 study (p = 0.0068). After 25 months of follow-up confirmed through a telephone visit, 59.8% patients were still alive and median overall survival was not yet reached. Twelve patients died secondary to disease progression. There were no deaths due to toxicity and 6 dose reductions overall (1 for T, 2 for O and 3 for C). T was stopped in one patient; C was temporarily interrupted 11 times (mostly during radiotherapy) and stopped in 1 patient. Conclusions: T in combination with C, O and radiotherapy in the adjuvant setting for gastric or gastroesophageal junction adenocarcinoma seems safe and tolerable. Clinical trial information: NCT01748773.
Pancreatic adenocarcinoma in young adults (≤45 years old): Characteristics and clinical outcomes from a Canadian center.
Authors: Desilets Antoine , Aubin Francine , Amireault Carl , Ayoub Jean-Pierre M. , Letourneau Richard , Tehfe Mustapha 
Published: January 2019

260 Background: Clinical data concerning pancreatic adenocarcinoma (PAC) in young adults is restricted. Limited evidence might suggest a worse prognosis in terms of overall survival (OS) and progression-free survival (PFS), when compared to an older population. Methods: The studied population included adults ≤45 diagnosed with a PAC (stages I to IV) between January 2006 and December 2016 at University of Montreal Health Center (CHUM), a tertiary care referral center in Canada. Clinical data was retrospectively extracted from chart review. The Kaplan Meier estimator was used for survival analyses. Results: 36 patients were identified in the study (median age 41.6, 56% males). Most patients (61%) had localized disease at diagnosis, with 22% presenting with metastases. The head of the pancreas was the primary site involved in 75% of cases. Most patients (63%) had a positive smoking history, with a median number of pack-years of 15. A personal history of cancer was present in 20% (n = 7) and 14% had a positive family history of PAC. Surgery was performed in 58% of individuals and systemic chemotherapy was offered to 89%. First-line agents included gemcitabine-based treatments (72%), FOLFIRINOX (19%) and 5-FU (9%). Despite treatment, 33% showed evidence of disease progression on initial follow-up imaging. Second-line chemotherapy was ultimately offered to 18 patients, and third-line treatments to 5. Survival data is described in the table below. Conclusions: According to our results, young patients with localized PAC may benefit from prolonged OS when compared to the literature. This could be attributed to a favourable comorbidity profile and increased surgical eligibility. Advanced stages however demonstrated a worse prognosis, with shorter OS. Young patients with PAC may also harbor a specific genetic profile, based on increased prevalence of personal and familial cancers. [Table: see text]
Impact of the T and N stage in the American Joint Committee on Cancer (AJCC) 8th edition staging system for pancreatic cancer with curative resection.
Authors: Todaka Akiko , Fukutomi Akira , Furuta Mitsuhiro , Shirasu Hiromichi , Kawahira Masahiro , Kawakami Takeshi , Yoshida Yukio , Kawai Sadayuki , Hamauchi Satoshi , Tsushima Takahiro , Yokota Tomoya , Machida Nozomu , Yamazaki Kentaro , Onozawa Yusuke , Yasui Hirofumi 
Published: January 2019

261 Background: The 8th edition of the AJCC staging system for pancreatic cancer contains several changes. T and N classification incorporate tumor size and number of positive lymph node (LN). The aim of this study was to evaluate the impact on the outcomes of the new classification for the patients who underwent curative resection and received adjuvant treatment with S-1. Methods: We retrospectively reviewed 96 patients who underwent curative resection for pancreatic ductal adenocarcinoma and received adjuvant treatment with S-1 (40, 50, or 60 mg according to body-surface area, orally administered twice a day for 28 days followed by a 14-day rest, every 6 weeks [one cycle], for up to four cycles) at our institution between January 2007 and December 2015. Inclusion criteria were as follows: PS0/1, adequate-organ functions, no critical complication, start of adjuvant therapy within 10 weeks after resection, and no active concomitant malignancy. Results: 66 patients were satisfied with these criteria. Patients characteristics were as follows: median age 67 years (range, 43-83), male 40 (61%), Pancreatoduodenectomy / Distal / Total pancreatectomy 50/14/2, combined portal vein or superior mesenteric vein resection 25 (38%), no postoperative complication 25 (38%), Well/Moderately/Poorly differentiated type 23/41/2, the median tumor size 30mm (range, 13-130), the median number of dissected LN 25 (range, 10-60), the median number of positive LN 2 (range, 0-8), and the resection margin status (R0/1) 62/4. The distribution in the 8th edition (1A/1B/2A/2B/3) was 6(9%) / 10(15%) / 5(8%) / 36(54%) / 9(14%), respectively. 2-year overall survival (OS) and relapse-free survival (RFS) were 70% and 52%. In the 8th edition staging system (1A/1B/2A/2B/3), 2-year OS and RFS were 100/90/80/66/40% and 83/70/53/49/22%, respectively. 2-year OS and RFS by T classification according to AJCC 8th edition were 100/68/56% and 90/39/56% (T1/2/3), while those by N classification were 90/66/40% and 70/49/22% (N0/1/2), respectively. Conclusions: The survival was poor with progress of the stage in the new classification. Especially at N stage, it might be suggested an association with prognosis.
Variations in DNA repair genomic alterations and tumor mutation burden in biliary tract cancer (BTC) subtypes.
Authors: Abdel-Wahab Reham , Ali Siraj Mahamed , Borad Mitesh J. , Shroff Rachna T. , Kwong Lawrence , Vauthey Jean-Nicolas , Koay Eugene Jon , Zuo Mingxin , Rashid Asif , Schrock Alexa Betzig , Ross Jeffrey S. , Bekaii-Saab Tanios S. , Javle Milind M. 
Published: January 2019

263 Background: DNA repair genomic alterations (GAs) have been identified in 12% of Intrahepatic cholangiocarcinoma (IHCCA), 26% of extrahepatic CCA (EHCCA) and 8% of gallbladder cancer (GBC) patients (pts) ( Cancer 2016;122:3838–3847). Recently, the Cancer Genome Atlas (TCGA) has described more than 20 mutated DNA repair genes, many of which were not previously represented in prior reports. DNA repair GAs including MSI are associated with higher tumor mutational burden (TMB). Our study aim is to identify variations in the frequency of DNA repair GAs in IHCCA, EHCCA, and GBC. Methods: Hybrid capture-based next-generation sequencing of 422 fixed formalin paraffin embedded (FFPE) tissue blocks of BTC including; 270 IHCCA, 60 EHCCA, and 92 GBC was performed. We included 20 DNA repair genes and classified them as "direct" DNA repair genes ( ATM, ATR, BRCA1, BRCA2, FANCA, FANCD2, MLH1, MSH2, MSH6, PALB2, POLD1, POLE, PRKDC, RAD50, SLX4) and "caretaker" genes that induce genomic instability ( BAP1, CDK12, MLL3, TP53, BLM). We calculated TMB on 1.1 Mb of sequenced DNA in 205 tissue specimens [138 IHCCA, 23 EHCCA, and 44 GBC] and classified into three groups; high (TMB-H; ≥ 20 mut/Mb), intermediate (TMB-I; 6-19mut/Mb) and low (TMB-L; < 6mut/Mb). Results: A distinct pattern of DNA repair GAs in each tumor type was detected. (Table 1). DNA repair GAs were more commonly noted in both EHCCA and GB (63%) as compared with IHCAA (45.2%) (p= .002). Direct DNA repair GAs were highest within EHCCA (25%), while indirect DNA GAs were predominant in GBC (59.8%) (p= 0.04 and 0.001, respectively). The frequency of TMB-H and TMB-I differed significantly between BTC subtypes. Pts with EHCCA and GBC had significantly higher TMB-H and TMB-I versus IHCCA. Conclusions: The frequency of DNA repair GA’s is higher in EHCCA and GBC as compared with IHCCA. These results may have implications for clinical trials with DNA repair inhibitors and immune checkpoint blockers. [Table: see text]
First prospective study evaluating effect of metformin (M) on disease control (DC) and activation of AMP-activated protein kinase (AMPKα) in patients (pts) with GI malignancies.
Authors: Godara Amandeep , Siddiqui Nauman S , Hachem Hilal , Martell Robert E. , Saif Wasif M. 
Published: January 2019

264 Background: Observational studies have demonstrated association of M with reduced cancer incidence and mortality in multiple cancer types, including GI. Anti-neoplastic effects of M are believed through many mechanisms including activation of AMP-activated protein kinase, which controls mammalian target of rapamycin (mTOR) growth regulatory pathway. Methods: In a pilot, delayed-start randomized study, non-diabetic pts with GI cancers were randomized to 2 arms, Stage 1: concurrent M (500mg twice daily) plus chemotherapy (M+C) vs. Chemo alone (C) followed by cross over to M+C arm in Stage 2, while adverse events (DLT) were assessed by CTCAE v.3.0. As a translational correlate, we used phosphorylation of AMPKα at Thr172 to measure AMPK activation by western blot technique in PBMCs isolated from pts before and after receiving M. These levels were correlated with radiological (RECIST 1.1) and tumor marker outcomes by descriptive analysis. Results: 41 pts with GI cancers (CRC: 22, PC: 12, GE: 4, BD: 2, others: 1) were treated in this trial. Mean duration of M therapy was 85 days (range: 9-443). There was no significant difference in grade 3 or above DLT in M+C vs. C arm (14% vs. 12% respectively). Gel band density analysis on 19 pts showed that 63% pts had increased phosphorylation of AMPKα after M (ratio of phospho-AMPKα after M to before M > 1) with mean = 1.227 (± 0.134). RECIST 1.1 restaging showed DC in 55% pts and 45% pts had decline in tumor markers. 8 of 12 pts with APC showed DC at the completion of study. Of note, 60% of pts with DC also showed increase in phosphorylation of AMKα. Conclusions: Our study is the first human study that prospectively demonstrates the impact of M on AMPKα phosphorylation, thus implying a potential role of M both as a chemopreventive and chemotherapeutic agent in GI cancers. Our study also shows the safety of M across various chemoregimens, providing a platform and justification for future studies. Potential benefits of M in preventive and treatment settings warrant further investigation in adequately powered prospective studies. We aim to perform a dose-escalation of M in our next study with additional metabolomics correlates. Clinical trial information: NCT01442870.
Prognostic value of serum interleukin-6 and YKL-40 and systemic inflammatory response in patients with unresectable pancreatic cancer.
Authors: Chen Inna , Dehlendorff Christian , Jensen Benny Vittrup , Pfeiffer Per , Bjerregaard Jon K. , Johansen Astrid Zedlitz , Nielsen Svend Erik , Andersen Fahimeh , Hollander Niels Henrik , Yilmaz Mette K. N. , Rasmussen Louise Skau , Johansen Julia S. 
Published: January 2019

267 Background: Interleukin-6 (IL-6) and YKL-40 (CHI3L1) are produced by pancreatic cancer (PC) cells and macrophages and activate inflammation. The aim of this prospective-retrospective biomarker study was to determine the prognostic value of serum IL-6 and YKL-40 and systemic inflammatory response in patients with PC receiving palliative chemotherapy. Methods: 625 patients with PC (M/F: 283/342; age <70 vs. ≥70: 395/230; ECOG PS of 0/1/2/3: 214/315/92/4; stage 3 vs. 4: 129/496; treated with gemcitabine n=437, FOLFIRINOX n=117, gemcitabine and nab-Paclitaxel n=54 or other n=17) were included in the BIOPAC biomarker study from 5 hospitals in Denmark. Pretreatment serum values of IL-6 (R&D Systems), YKL-40 (Quidel), and CA 19-9 (Siemens) were determined. Patients were grouped as low vs. high, dichotomized using cut-off for IL-6 > 4.92 pg/ml, for CA19-9 > 2183 U/ml and for YKL-40 > 95% age-corrected percentile. The main outcome was overall survival (OS) and hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were computed using Cox proportional hazards regression. Results: 598 (95.7%) patients died during follow-up. In univariate analysis elevated IL-6 (HR 1.93, 95% CI 1.63-2.28) and elevated YKL-40 (HR 1.74, 95% CI 1.47-2.05) were associated with short OS. Similar results were found if IL-6 and YKL-40 were included as continuous log2-transformed variables. Multivariable analysis showed that elevated IL-6 (HR 1.61, 95% CI 1.33-1.94), elevated YKL-40 (HR 1.36, 95% CI 1.13-1.64), elevated CA19-9 (HR 1.30, 95% CI 1.09-1.56), higher PS (1 vs. 0; HR 1.46, 95% CI 1.21-1.77 and PS 2 vs. 0; HR 2.73, 95% CI 2.08-3.58) and stage 4 vs. 3 (HR 1.79, 95% CI 1.44-2.24) were independently associated with a poor OS. In a subgroup of 386 patients with available laboratory data, higher C-reactive protein (HR 1.20, 95% CI 1.13-1.26), white blood cells (HR 1.41, 1.17-1.71) and absolute neutrophils count (HR 1.35, 95% CI 1.15-1.59) log2-transformed and adjusted for age, sex, PS, CA 19-9 and stage were associated with short OS. Conclusions: Serum IL-6, YKL-40 and CA19-9 along with CRP, WBC and ANC are independent prognostic biomarkers in patients with unresectable PC.
Expression of PD-L1 in periampullary adenocarcinoma: Relationship with morphological type, the immune microenvironment and prognosis.
Authors: Rastegar Nezhad Bahar Matilda , Heby Margareta , Lundgren Sebastian , Nodin Bjorn , Leandersson Karin , Elebro Jacob , Karnevi Emelie , Jirstrom Karin 
Published: January 2019

268 Background: Overall survival for patients with periampullary adenocarcinoma, including pancreatic cancer, continues to be poor. Pancreatic cancer is characterized by a largely immunosuppressive microenvironment, but blockade of the programmed death ligand 1 (PD-L1) pathway has still not been effective. Reports on the prognostic value of PD-L1 expression in pancreatic and in particular periampullary cancer are sparse. The aim of this study was therefore to analyze PD-L1 expression in periampullary adenocarcinoma, with specific reference to morphological type, tumor-infiltrating immune cells, and survival. Methods: PD-L1 expression in tumor cells (TC) and immune cells (IC) was assessed by immunohistochemistry on tissue microarrays with primary tumors from a retrospective consecutive cohort of 175 patients with resected periampullary adenocarcinoma, 65 of intestinal(I)-type and 110 of pancreatobiliary(PB)-type. Correlations with various immune cells were calculated with non-parametric tests. Cox proportional hazards models were applied to calculate hazard ratios (HR) and 95% confidence intervals (CI) for death. Results: TC PD-L1 expression was not associated with any clinicopathological factors nor with survival. IC PD-L1 ( > 10%) expression was higher in I-type than in PB-type tumors (p < 0.001), and correlated with defect mismatch repair (p = 0.012) and lymph node negativity (p = 0.016). IC PD-L1 was not prognostic in PB-type tumors. High IC PD-L1 was associated with a prolonged survival in the entire cohort (HR = 0.59, CI 0.40-0.88), and in I-type tumors (HR = 0.38, CI 0.18-0.81), but not after adjustment for other prognostic factors. In I-type tumors, high IC PD-L1 correlated with high density of T cells (CD3+, CD8+, FoxP3+), but not with B cell or macrophage density. There were no significant associations between IC PD-L1 expression and any other immune cells in PB-type tumors. Conclusions: High PD-L1 expression in IC is associated with a T cell dense tumor microenvironment and a prolonged survival in I-type, but not in PB-type, periampullary adenocarcinoma, thus indicating that the effect of immune-modulating therapies may differ by morphological type.
Mismatch repair deficiency in cholangiocarcinoma.
Authors: Kunk Paul Raymond , Obeid Joseph Mounir , Winters Kevin , Pramoonjago Patcharin , Brockstedt Dirk G. , Giobbie-Hurder Anita , Stelow Edward B , Bauer Todd W. , Slingluff Craig L. , Rahma Osama E. 
Published: January 2019

269 Background: Cholangiocarcinoma (CC) is a fatal malignancy with an unmet treatment need. With the approval of immunotherapy for solid tumors with mismatch repair (MMR) deficiency, there is a renewed interest in MMR testing. Little is known about the incidence of MMR deficiency in CC or its correlation to survival, immune cell infiltration, PD-L1 and other proteins expressed in CC such as mesothelin. Methods: CC tumors were identified from patients treated at the University of Virginia from 2000-2014. Tissue microarrays (TMAs) were constructed of 3-4 cores from each tumor and were stained by immunohistochemistry for MMR genes (MLH1, PMS2, MSH2, MSH6), mesothelin, PD-L1 and immune cells. TMAs were scanned using the Leica SCN400 and analyzed using the Digital Image Hub software. Stain intensity thresholds for defining positive cells were determined by two users and recorded as an average of all cores from each tumor. Mesothelin and PD-L1 expression were measured as a percentage of positive tumor cells. Correlation with overall survival was assessed using log-rank tests and classification and regression trees, with p values < 0.05 considered significant. Results: Ninety-one tumors were analyzed: 24 intrahepatic, 33 hilar, and 34 distal. MMR deficiency was found in 20 tumors (22%). None of the MMR deficient tumors co-expressed PD-L1 (>1%), which was found in 15% of the remaining tumors. T cell infiltration (CD4, CD8 and FoxP3) did not differ between MMR deficient or proficient tumors. Patients with MMR deficiency had a trend towards worse survival compared to those with proficiency (median OS: 19.2 vs. 28.1 months, p = 0.07). MMR deficient tumors showed a lower mesothelin expression compared to MMR proficient tumors, median 8 vs. 129 positive cells per TMA (p = 0.08). Patients with MMR deficiency and low mesothelin expression had a worse outcome compared to patients with MMR proficiency and high mesothelin expression (median OS: 14.5 vs. 30.0 months, p = 0.05). Conclusions: Given the high rate of MMR deficiency, all CC tumors should be tested and may benefit from anti-PD-1 therapy. The poor prognosis of MMR deficient CC may be independent of T-cell infiltration and additional studies are needed to better characterize the genetic and molecular landscape of this subset of tumors.