bluuebunny/crossref_metadata_2025_split huggingface dataset:
Is there a role for the quantification of RRM1 and ERCC1 expression in pancreatic ductal adenocarcinoma?
Authors: Valsecchi Matias Emanuel , Littman Susan Joy , Holdbrook Thomas , Leiby Benjamin , Mitchell Edith P. , Yeo Charles , Brody Jonathan Robert , Witkiewicz Agnieszka 
Published: February 2017

246 Background: RRM1 and ERCC1 overexpression has been extensively investigated as potential predictive markers of tumor sensitivity to conventional chemotherapy agents, most thoroughly in lung cancer. However, data in pancreatic cancer are scarce. Methods: We investigated the mRNA and protein expression of ERCC1 and RRM1 by RT-PCR and immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded pancreatic ductal carcinoma (PDA) tissues. The primary outcome investigated was the association between RRM1 and ERCC1 expression and overall survival (OS) or disease-free survival (DFS). Results: A total of 94 patients with resected PDA were included in this study. Most of them (87%) received gemcitabine based chemotherapy. Data for OS analysis was available in all cases but only 68% had enough information to estimate DFS. IHC analysis revealed information for 99% (93/94) and 100% of the cases for RRM1 and ERCC1 expression respectively. However, PCR data interpretation was possible in only 49 (52%) and 79 (84%) cases respectively. There was no significant association between high or low expression of either RRM1 or ERCC1, either in univariate or multivariate analyses, detected by IHC and OS (14.4 vs. 19.9 months; P = 0.5 and 17.1 vs. 19.9; P = 0.83 respectively) or PCR and OS (48.0 vs. 24.1 months; P = 0.21 and 22.0 vs. 16.0 months; P = 0.39 respectively) (Table 1). Similar results were obtained for DFS. Conclusions: RRM1 and ERCC1 expression does not seem to have a clear predictive or prognostic value in pancreatic cancer. Our data raise some questions regarding the real clinical and practical significance of analyzing these molecules as predictors of outcomes. [Table: see text]
Looking for synergy or additivity between 188Re and sorafenib on hepatoma cell lines.
Authors: Pracht Marc , Lepareur Nicolas , Edeline Julien , Lenoir Laurence , Ardisson Valerie , Clement Bruno , Raoul Jean Luc , Boucher Eveline , Garin Etienne 
Published: February 2017

247 Background: In case of non resectable HCC, radioembolization and sorafenib (S) are therapeutic options respectively for intermediate and advanced stages. In some other cancers, there is an increase of efficacy when external beam radiotherapy is done concomitantly with systemic chemotherapy or targeted therapies. So we wondered if there could be a synergistic or an additive activity when S is combined with a radionuclide. Methods: Hepatoma cell lines N1S1 (murine HCC), HepG2 (human hepatoblastoma) and HepaRG (human HCC) were treated with increasing concentrations of rhenium-188 (188Re) or S. On each cell line, we have studied the cellular toxicities of S and 188Re using Tetrazolium dye test, extra-cellular medium LDH level and morphologic analysis. This was done for different dosage of S and 188Re. We measured the lethal concentration killing 25% of cells (LC25) with the results of the Tetrazolium dye test. Secondly, we looked for synergy or additivity on cellular toxicity of these two compounds according to cell lines by combined treatment. Synergy or additivity was estimated with the combination index (CI) method (synergy if CI lower than 1, additivity if CI = 1, antagonism if CI upper to 1) based on the Tetrazolium dye test’s results. Results: Monotherapy dose-dependent toxicities were observed for all three cell lines with 188Re and for the N1S1 and HepG2 cell lines only with S. Combined treatment with 188Re and S showed synergy on HepaRG and N1S1 cell lines and additivity on the HepG2 cell line. Conclusions: The additive, and even synergistic, interest of a combined treatment with 188Re and S is demonstrated in vitro (for the first time to our knowledge) on hepatoma cell lines. This results, in particular for the HepaRG cell line (human HCC), could be explained by the down-regulation of the hepatic drug transporters which are responsible for the Sorafenib efflux in case of simultaneous DNA damages due to a radionuclide exposition. This promising approach now needs to be confirmed in vivo. [Table: see text]
Targeting hyaluronan (HA) in tumor stroma: Interim safety and translational evaluation of pegylated hyaluronidase (PEGPH20) in patients (pts) with advanced solid tumors—A focus on gastrointestinal malignancies.
Authors: Infante Jeffrey R. , Ramanathan Ramesh K. , Borad Mitesh J. , Rosen Lee S. , Korn Ronald , Dychter Samuel Simon , Shepard Harold Michael , Maneval Daniel C. , Jiang Ping , Carson Deborah , Von Hoff Daniel D. , Frost Gregory Ian 
Published: February 2017

249 Background: HA, a glycosaminoglycan in the tumor matrix, accumulates in 20-30% of solid tumors and ≥28%, ≥42% and ≥87% of colon, gastric and pancreatic ductal adenocarcinoma (PDA) tumors, respectively. Tumors that accumulate HA can develop high interstitial fluid pressure (IFP) and are resistant to chemotherapy. HA in human PDA is associated with disease progression and poor prognosis. In animal models, PEGPH20 reduced tumor-associated HA, tumor IFP and tumor growth, and increased efficacy of chemotherapy. Pharmacodynamic (PD) activity of PEGPH20 is being evaluated in Phase 1 (Ph1) trials. Methods: Two Ph1 studies in pts with advanced solid tumors refractory to prior therapy examined the safety, tolerability, PK, PD and MTD of single-agent IV PEGPH20. Dosing in Study 1 was 2x/wk and then reduced to q21d and in Study 2 is 1-2x/wk x 4wks and 1x/wk thereafter with dexamethasone pre-medication regimen. Biomarkers evaluated: Histochemistry to detect depletion of tumor HA, serum HA catabolites, Dynamic Contrast Enhanced (DCE)-MRI and FDG-PET. Results: In Study 1, the first 3 pts demonstrated musculoskeletal events (MSE; 2 pts dosed with 50 µg/kg 2x/wk, severe; 1 pt dosed with 0.5µg/kg 2x/wk, moderate) not predicted from GLP safety studies. The frequency of drug administration was reduced to q21d and the next 10 pts tolerated ≤1.5 µg/kg. In Study 2, dexamethasone pre-medication regimen was evaluated while dosing at 1-2x/wk. Nine pts were dosed ≤5.0 µg/kg. Doses ≤3.0 µg/kg administered 2x/wk were tolerated with intermittent Grade 1-2 MSE. Activity of PEGPH20 was reflected by increased HA serum catabolites. Pre- and post-dose biopsies from 2 colon pts demonstrated a 23-60% reduction in tumor HA after 4 wks of PEGPH20 dosing. DCE-MRI of PDA and FDG-PET of lung metastases increased tumor perfusion (Ktrans) and decreased metabolic activity 8 and 24hrs post-PEGPH20 dose and was still apparent after 4 wks of treatment with PEGPH20. Conclusions: Ongoing Ph1 studies have shown in vivo activity of PEGPH20 through HA plasma catabolites, tumor HA depletion, DCE-MRI and FDG-PET.
Randomized phase II trial of gemcitabine plus S-1 combination therapy versus S-1 in advanced biliary tract cancer: Results of the Japan Clinical Oncology Group study (JCOG0805).
Authors: Morizane Chigusa , Okusaka Takuji , Mizusawa Junki , Takashima Atsuo , Ueno Makoto , Ikeda Masafumi , Hamamoto Yasuo , Ishii Hiroshi , Boku Narikazu , Furuse Junji 
Published: February 2017

255 Background: Gemcitabine plus cisplatin combination (GC) therapy is the standard therapy for advanced biliary tract cancer (BTC). In previous trials, gemcitabine plus S-1 combination (GS) therapy and S-1 mono-therapy had shown considerable efficacy in patients with BTC. The aim of this trial is to evaluate the efficacy and safety of the two regimens and to determine which is more promising as a test arm regimen for a subsequent phase III trial. Methods: Chemotherapy-naive patients with recurrent or unresectable BTC (gallbladder [GB], intrahepatic biliary duct [IHBD], extrahepatic biliary duct [EHBD], ampulla of Vater [AV]), an ECOG PS of 0 - 1, and adequate organ function were randomly assigned to receive GS (gemcitabine: 1000 mg/m2, iv, days 1 and 8; S-1: 60 mg/m2, p.o., days 1 - 14, every 3 weeks) or S-1 (80 mg/m2, p.o., days 1 - 28, every 6 weeks). We assumed that %1-year survival of one regimen is 30% and that of the other regimen is more than 40%. To ensure at least 85% probability of correct selection, 98 eligible pts are required. The decision rule was that the regimen with higher %1-year survival will be considered as more promising regimen. Results: From February 2009 to April 2010, 101 pts (GB, n=38; IHBD, n=35; EHBD, n=20; AV, n=8) were randomized (GS, n=51; S-1, n=50). For the GS arm and S-1 arm, %1-year survivals were 52.9% and 40.0%, the median survival time were 12.5 and 9.0 months (hazard ratio 0.86 [95%CI 0.54-1.36]; p=0.52), and the median progression-free survival time were 7.1 and 4.2 months (0.44 [0.29-0.67]; p<0.0001). Grade 3/4 hematological toxicities were more frequent in the GS arm than in the S-1 arm, (percentage in GS/S-1 arms): neutropenia, 60.8/4.0; leukocytopenia, 29.4/2.0; hemoglobin, 11.8/4.0; and thrombocytopenia, 11.8/4.0; respectively. Although two treatment-related deaths occurred in the GS arm (pneumonitis, acute myocardial infarction), other grade 3/4 non-hematological toxicities were infrequent and reversible in both arms. Conclusions: The GS arm was superior in %1-year survival to S-1. Here we consider GS to be more promising as the test arm for a subsequent phase III trial comparing with GC.
Phase II trial of fixed-dose rate gemcitabine, bevacizumab, and concurrent 30 gy radiotherapy as preoperative treatment for potentially resectable pancreatic adenocarcinoma.
Authors: Van Buren George , Ramanathan Ramesh K. , Krasinskas Alyssa M , Smith Ryan , Abood Gerard J. , Shuai Yongli , Potter Douglas M. , Bahary Nathan , Lembersky Barry C. , Zureikat Amer H , Bartlett David L. , Zeh Herbert , Moser Arthur J 
Published: February 2017

258 Background: Effective multimodality treatment for localized pancreatic cancer is elusive. We hypothesized that preoperative fixed-dose rate (FDR) gemcitabine (GEM) combined with short-course radiotherapy (RT) and the angiogenesis inhibitor bevacizumab (BEV) would improve margin negative surgical outcomes and complete pathological response rates. Methods: Multisite phase II trial evaluating all potentially-resectable pancreatic adenocarcinoma without major arterial involvement or portal venous occlusion. Dual primary endpoints included complete pathological response and margin negative resection rates of 10% and 80%. Subjects received FDR GEM on days 1, 15, and 29 combined with BEV (10 mg/kg IV), followed on day 43 by BEV and concurrent 30 Gy RT (3 Gy/fraction) over 10 days. After restaging, subjects underwent laparoscopy and possible resection after day 85. Stopping criteria required continuous monitoring of serious wound complications. Results: 58 subjects enrolled, of which 29 (50%) had suspected venous involvement. 57 completed treatment without dose-limiting toxicity or delays in surgery. Two grade 4 (3.4%) and 17 grade 3 toxicities (28.8%) occurred. Four patients progressed before surgery. 54 subjects underwent laparoscopy; ten had unexpected carcinomatosis, and one was unresectable. 43 subjects were resected (74%; 33 pancreatico-duodenectomy, 8 distal pancreatectomy, 1 total pancreatectomy, 1 Appleby); 19 (44%) required portal vein resection. Margin negative outcome was achieved in 38 (88%, 95% CI: 75%-96%) with one complete pathological response (2.3%; 95% CI: 0.1%- 12%) and seven (6 grade 3; 1 grade 4) wound complications (13%). Median overall survival (OS) was 16.3 months (95% CI: 13.9 -22.1) and 21.3 months (95% CI: 15.0-32.9) after resection. Median progression-free survival (PFS) was 5.7 months (95% CI: 3.9-9.1) and 9.9 months (95% CI: 5.7 to 14.1) after resection, with 7 local and 21 distant recurrences. Conclusions: Combination therapy was well-tolerated and was within statistical design parameters for the primary endpoints despite a significant proportion of borderline tumors.
A phase II trial of gemcitabine and S-1 therapy in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer (JSAP-03).
Authors: Saiura Akio , Ueno Hideki , Kosuge Tomoo , Matsuyama Yutaka , Ishii Hiroshi , Nakao Akimasa , Doi Ryuichiro , Tanaka Masao 
Published: February 2017

263 Background: Although anti-tumor effect of gemcitabine (G) and S-1 (S) therapy is high for advanced pancreatic cancer (PC) patients, safety and effectiveness of postoperative GS adjuvant therapy has not been fully examined. Methods: Eligibility criteria included macroscopically curative resection of invasive ductal PC and no prior chemotherapy. Patients were recruited in 19 institutes. The primary endpoint was overall survival (OS). The patients received G (800 mg/m2/week) intravenously over 30 min on day 1 and S (60 mg/m2/day) orally twice daily from days 1 to 7 every 14 days for 12 cycles. Results: Fifty-five patients were enrolled in this study. One patient was excluded from the analysis due to no malignant pathology. Remaining 54 patients were analyzed. Deaths were observed in 17 patients (31.5%). Median overall survival was not reached. Estimated 1-year and 2-year OS were 88.9% (95% CI, 76.9-94.8) and 72.1% (95%CI, 58.1-82.2), respectively. Recurrences were observed in 31 patients (57.4%). Estimated 1-year and 2-year disease-free survival were 57.4% (95% CI, 43.2-69.3) and 44.4% (95%CI, 30.9-57.0), respectively. G3 febrile neutropenia was observed in 1.9 % of the patients, whereas the most common adverse reactions were neutropenia (G3/4: 59.2%, G4: 25.9%). There were no G4 adverse events except neutropenia and hyperkalemia (1.9%). G3 adverse events included anemia (3.7%), alanine aminotransferase elevation (3.6%), fatigue (1.9%), nausea (1.9%), vomiting (1.9%) and infection without neutropenia (1.9%). The protocol treatments could not finish in 6 patients due to adverse reactions. Conclusions: Our phase II results suggest that the postoperative GS therapy is a promising regimen that merits further investigation. Phase III trial of postoperative G versus GS therapy is now going on (JSAP-04).
The natural history and effect of adjuvant therapy on resected AJCC stage I-II lymph node-negative pancreatic cancer.
Authors: McKenzie Shaun , Huang Bin , Tucker Thomas , McGrath Patrick , Jones Dennie V. , Desimone Philip , Evers Mark 
Published: February 2017

264 Background: Previous investigation has suggested that early stage, lymph node negative pancreatic adenocarcinoma (PAC) has a relatively good prognosis and adjuvant therapy provides little benefit over surgery alone. The purpose of our trial was to evaluate patients with stage I-II PAC receiving surgical resection to determine their clinical characteristics, overall outcome, and the impact of adjuvant therapy on survival. Methods: Utilizing the population-based registry data from the Kentucky Cancer Registry (KCR) we identified patients with lymph node negative, AJCC I-II, PAC who underwent pancreatic resection during the years of 1995-2008. Patients were further stratified by receipt of surgery alone versus surgery with adjuvant chemotherapy or chemoradiation. Clinical and pathologic data included patient demographics, tumor characteristics, and lymph node status. Kaplan-Meier and Cox-regression survival analyses were performed. Results: During the study period, 203 patients meeting criteria were identified from the KCR. Median survival (MS) for the entire cohort was 21.7 months. The majority of patients were >70 years old, Caucasian, had well or moderately differentiated tumors and tumors <5cm. 46% (n=94) and 54% (n=109) of patients had stage I and II disease respectively. When stratified by surgery only (n=119, 59%) versus adjuvant therapy (n=84, 41%), only younger age predicted receipt of adjuvant therapy (p=0.002). Adjuvant therapy provided no benefit over surgery alone regardless of stage (stage I MS: 21.5 vs. 24.7 months, p=0.97 and stage II MS: 24.2 vs. 18.0, p=0.13, respectively). By multivariate analysis, only tumor size >5cm predicted worse survival (HR 2.32, CI 1.21-4.45, p=0.012). Age, stage, adjuvant therapy, differentiation, and lymph node retrieval had no impact on survival. Conclusions: Our data indicate that the survival for surgically resected early stage, lymph node negative pancreatic adenocarcinoma remains poor and is not improved by the addition of adjuvant chemotherapy. These findings should be considered when designing future adjuvant therapy trials for this deadly disease.
Second interim analysis of GIDEON (Global Investigation of Therapeutic Decisions in Unresectable HCC and of Its Treatment with Sorafenib): U.S. versus global perspective on patient and disease characteristics, treatment history, and sorafenib use.
Authors: Martin Robert C. G. , El-Khoueiry Anthony B. , Goldenberg Alec , Venook Alan Paul , Mantry Parvez , Gholam Pierre Michel , McGuire Brendan , Sanyal Arun , Geschwind Jeff H. , Marrero Jorge A. 
Published: February 2017

278 Background: GIDEON is a global, prospective, noninterventional study of patients (pts) treated with sorafenib (SOR) for unresectable hepatocellular carcinoma (uHCC). Regions evaluated included US, Europe, Japan, Asia Pacific, and Latin America. Detailed regional data were presented by Kudo et al (ILCA 2011, abstr 0-030). Data from the second US interim analysis are compared to global results. Methods: Eligible pts had uHCC and were treated with SOR. Demographics, disease etiology, treatment history, and SOR dosing were compared in a descriptive, preplanned subgroup analysis. Results: Global and US safety populations comprised 1571 and 313 pts, respectively. In the US, hepatitis B was less common (18% vs 37% global) whereas hepatitis C was more frequent (53% vs 32% global). Alcoholic liver disease etiology was higher in US pts (41% vs 29% global). US pts were diagnosed with later-stage disease, but fewer US pts had documented BCLC and Child-Pugh status. Fewer US pts had an ECOG PS 0 at start of SOR (28% vs 40% global). Rates of prior surgery and locoregional treatment were similar in US (11% and 49%, respectively) and global pts (19% and 55%, respectively). US pts treated with TACE (n = 116) underwent fewer TACE procedures (≥3: 13.8% vs 38.9% global); most (59%) TACE-treated pts in the US received 1 treatment. In US vs global pts, median time from prior surgery to start of SOR was 10 months (range 1-61) vs 14 months (range 1-181) and median time from last TACE to start of SOR was 3.2 months vs 3.1 months. Conclusions: Disease characteristics and treatment patterns for pts with uHCC in the US differ from those in the global population. US pts enrolled in GIDEON (ie, receiving SOR) have differing etiologies of liver disease and have a greater proportion of hepatic dysfunction, likely accounting for worse performance status. [Table: see text]
Smoking and binge drinking among cancer survivors: The forth Korean national health and nutrition examination surveys (KNHANES IV, 2007-2009).
Authors: Han Mi Ah , Oh Myeung Guen , Park Jong , Ryu So Yeon , Choi Seong Woo 
Published: February 2017

28 Background: This study aimed to describe the prevalence of smoking and binge drinking among cancer survivors in Korea, and to compare these rates with those of two control groups: individuals without a history of cancer but with other chronic diseases, and individuals without a history of cancer and without other chronic diseases. Methods: The study is a cross-sectional analysis of 37,878 adults ≥20 years old who participated in the Forth Korean National Health and Nutrition Examination Surveys (KNHANES IV, 2007-2009). The prevalence of smoking and binge drinking were assessed and compared to two control groups. Logistic regression analyses were performed to determine the likelihood and predictors of current smoking and binge drinking. Results: The prevalence of smoking and binge drinking were 9.6% and 6.6% among cancer survivors, respectively. Cancer survivors showed lower smoking rate compared with both control groups after adjusting gender, age, marital status, education, income and health insurance. Survivors’ smoking and binge drinking did not vary substantially by the clinical factors assessed. Conclusions: In our study, the smoking rate was significantly low in cancer survivor compared with both control groups. This result suggested that cancer survivors were more likely than individuals without a cancer history to obtain good health related behavior.
Use of probe-based confocal laser endomicroscopy (pCLE) in the diagnosis of cholangiocarcinoma.
Authors: Wysocki John D. , Newby Celeste , Joshi Virendra 
Published: February 2017

281 Background: Despite technologic advances in endoscopy and new cytologic techniques, cholangiocarcinoma is a challenging diagnosis for the endoscopist and oncologists. Current sampling techniques include cytology brushing, biopsy, and fine needle aspiration but are limited in their sensitivity. Confocal laser endomicroscopy (CLE) is a relatively new modality that offers in-vivo imaging of the gastrointestinal tract with microscopic detail in living cells. Methods: This was an observational study of 10 patients with indeterminate biliary strictures who were evaluated with ERCP, cholangioscopy, and CLE to determine the sensitivity and specificity of tissue biopsy compared to virtual biopsy using this new technology, CLE. All cases were confirmed to be cholangiocarcinoma by histopathology. Fluorescein 10% was used as a contrast agent. Results: The 10 ERCP cases that were reviewed demonstrated biliary strictures that were suspicious for malignancy based on history and clinical presentation. Nearly all initial brushings and traditional biopsies were inconclusive. Subsequent ERCP and cholangioscopy with CLE imaging was performed. The biliary architecture was concerning for malignancy according to the Miami Criteria. Images were reviewed by 2 independent physicians. Every case demonstrated thick bands >20 µm and dark clumps of glands. Bright vessels ( >20 µm) with tortuosity were visualized in seven cases. Other findings include reticular networks of dark bands and small, fine branching bands <20 µm, but these patterns were infrequent. Conclusions: 1.CLE is a novel tool to investigate indeterminate biliary strictures and potentially diagnose cholangiocarcinoma in conjunction with other diagnostic modalities during the initial ERCP and cholangioscopy. 2. Our early experience found sensitivity 90% , specificity of 100% , NPV 90% 3. CLE gives the opportunity to obtain en-vivo targeted biopsies during cholangioscopy as well as reduce repeat procedures and cost.