bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human equilibrative nucleoside transporter 1 (hENT1) in gemcitabine and FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin)-treated patients with metastatic pancreatic cancer: The randomized phase II PAN1 study.
Authors: Chua Yu Jo , Karapetis Christos Stelios , Gebski Val , O'Connell Rachel , Begbie Stephen , Nott Louise M. , Cronk Michelle F. , Underhill Craig , Abdi Ehtesham A. , Van Hagen Thomas , Wong Nicole , Hall Merryn , Ferraro Danielle Angela , Sjoquist Katrin Marie , Santos Cheryl , Mackey John Robert , Goldstein David 
Published: February 2017

228 Background: GEM-based treatment is a standard treatment for metastatic pancreas cancer. Monotherapy efficacy is only modest, and outcomes are improved by combination treatment or the non-GEM FOLFIRINOX triplet. There is a need for biomarkers to select between these divergent options. hENT1 is a potential predictive marker of benefit from GEM, but conflicting results have been observed in studies that have evaluated resected and metastatic pancreatic cancer. This principal objective of this study was to evaluate hENT1 prospectively as a predictive marker in GEM and non-GEM treated patients. Methods: Patients with previously untreated metastatic pancreatic adenocarcinoma and tumour tissue available for hENT1 testing were randomized between GEM (1,000 mg/m2 D1, 8, 15 Q4w) or FOLFOX (oxaliplatin 85 mg/m2, 5-fluorouracil (5FU) 400 mg/m2, leucovorin 400 mg/m2 D1 and 5FU 2,400 mg/m2over 46 hours D1-3) until disease progression or unacceptable toxicity. Tumor samples were tested prospectively for hENT1 by immunohistochemistry. The primary endpoint was progression-free survival (PFS). Results: The study was open from July 2011 to February 2013, but closed after 16 of the planned 80 patients were enrolled. 1 patient who died before treatment was excluded from the outcome analysis. 7/16 patients were hENT1 high (43.8%, 95%CI 23.1-66.8%). In the GEM arm (n=7), the 4 who were hENT1 high had longer PFS and overall survivals (OS) than those who were hENT1 low (median PFS 5.7 vs. 1.8 months; median OS 13.9 vs. 3.5 months), whereas outcomes were similar with FOLFOX for both hENT1 groups. There were no unexpected adverse events. Conclusions: This prospective study showed a longer survival in those patients with high hENT1 treated with GEM. There was no difference in survival according to hENT1 expression in patients treated with FOLFOX. Given the small sample size this may be due to chance, but supports the need for further research into the predictive value of hENT1. Clinical trial information: ACTRN12610001047088.[Table: see text]
mTOR/P70S6K signaling pathway as a potential target for advanced gallbladder cancer therapy.
Authors: Roa Juan Carlos , Leal Pamela , Weber Helga , Garcia Patricia , Sandoval Alejandra , Buchegger Kurt , Tapia Oscar , Nervi Bruno , Grez Manuel 
Published: February 2017

242 Background: Gallbladder cancer (GBC) is a highly malignant tumor usually diagnosed at advanced stages and characterized by a poor prognosis. Effective therapeutic strategies are urgently needed to improve the prognosis of GBC patients. Our objective was to analyze the expression of mTOR/p70S6K pathway in primary tumors and GBC cell lines, and to evaluate the effect of mTOR inhibitors in in vitro and in vivo models of GBC. Methods: The expression of mTOR/p70S6K signaling pathway components was examined by immunohistochemistry in primary tumors and chronic cholecystitis (CC), and by Western blot in eight GBC cell lines. The in vitro effect of mTOR inhibitors (LY294002, Rapamycin, Everolimus and AZD8055) on cell viability and migration was assessed by MTS and Transwell chamber assays. The therapeutic effect of Rapamycin was evaluated in subcutaneous tumor models (NOD/SCID mice). Treatment started when tumor volumes had reached 100mm3. Animals (G-415 and TGBC-2TKB xenografts) were randomly divided (n=5 per group) and treated with Polietilenglicol solution as vehicle and 10mg/kg of Rapamycin, daily IP injection (5 days/week for 3 weeks). Mice were sacrificed 30 days after treatment and tumors were dissected and measured. Tumor volume was calculated as π/6 × (large diameter) × (small diameter)2. Results: Our findings indicate that mTOR/p70S6K pathway is frequently activated in GBC (>60% of tumors showed high expression of phospho-mTOR and phospho-p70S6K, compared to CC). GBC patients whose tumors overexpressed phospho-mTOR had a poorer prognosis (p=0.02). G-415 and TGBC-2TKB cells showed a constitutive activation of this pathway and the treatment with different mTOR inhibitors significantly reduced their viability and migration capacity (p<0.001). In subcutaneous tumor models, treatment with Rapamycin significantly reduced the weight and tumor volume compared with the control group (p<0.001). Conclusions: mTOR/p70S6K signaling pathway is frequently activated in gallbladder cancer tissues and cells lines, which suggest that this pathway is a potential therapeutic target for the treatment of advanced GBC, using Rapamycin or other specific inhibitors. Supported by FONDECYT 1090171 and DIUFRO DI11-0039.
Loss of SMAD4 and effect on overall survival in resected gastrointestinal neuroendocrine tumors.
Authors: Roland Christina Lynn , Kang Ya'an , Chatterjee Deyali , Estrella Jeannelyn , Rashid Asif , Lee Jeffrey Edwin , Yao James C. , Fleming Jason B. 
Published: February 2017

250 Background: Studies by comparative genomic hybridization have demonstrated that the 18q chromosomal region is frequently lost in gastrointestinal neuroendocrine tumors (GI-NET). However, the impact of DPC/SMAD4 loss, which is located 18q21, in the pathogenesis of GI-NET remains controversial. In this study, we sought to determine the protein expression of SMAD4 in GI-NET and the impact on oncologic outcomes. Methods: To investigate the role of SMAD4 in GI-NET, a tissue microarray consisting of 33 GI-NET was constructed and analyzed by immunohistochemistry for SMAD4 expression. SMAD4 expression was classified as negative, SMAD4-low (≤10% cells +) or SMAD4-high (>10% cells+). Staining results were correlated clinicopathologic features and overall survival. Results: Of the 33 tumors examined, 93% were low- or intermediate-grade and 7% high-grade. 35% of GI-NET were negative for SMAD4, 45% were SMAD4-low and 15% SMAD4-high. Expression of Chromogranin was observed in 91% of all tumors, synaptophysin in 94%, CDX2 in 64%, and CK19 in 55%. We were unable to identify any association between loss of SMAD4 and stage or tumor grade. There was an inverse correlation between loss of SMAD4 and CK19 expression, whereby 75% of SMAD4-neg tumors expressed CK19 and only 32% of SMAD4+ expressed CK19 (p=0.01). At a median follow-up of 123 months, median overall survival was 203 months. Survival differences related to SMAD4 status resulted in clinically meaningful, although statistically non-significant, differences in overall survival (SMAD4-low: 132 months vs. SMAD4-high: 203 months, p=0.058). Conclusions: Differences in SMAD4 expression result in clinically important differences in overall survival, although this cohort may be underpowered to detect a statistically-significant difference. Future studies with larger patient populations may be critical to evaluate the importance of SMAD4 in the pathogenesis of GI-NET.
Investigation of metformin as a radiation sensitizer in pancreatic cancer.
Authors: Dorth Jennifer Anne , Ferris Gina , Zeng Johnathan , Welford Scott 
Published: February 2017

253 Background: Clinical study demonstrates that diabetic patients taking metformin while undergoing chemotherapy and/or radiation for localized pancreatic cancer have improved overall survival compared to diabetics not taking metformin or non-diabetic patients (Sadeghi, Clin Cancer Res 2012). Metformin may act as a radiosensitizer through direct effects on cancer cells and/or indirect effects on the host, such as the inhibition of hepatic gluconeogenesis or inflammation (Pollak, Clin Cancer Res 2012). In vitro study demonstrates that the direct effects of metformin include suppression of mTOR, G2/M cell cycle arrest, and toxicity to cancer stem cells with resultant increase in chemo and radiosensitivity, though some of these studies employed supra-physiologic doses of metformin (1-10mM) instead of physiologic doses (10uM) (Song, Sci Rep 2012; Sanli, IJROBP 2010). Methods: MiaPaCa-2 human pancreatic cancer cells were grown in physiologic (5mM) or supra-physiologic (25mM) glucose media. After exposure to metformin (10uM or 10mM) for 3-7 days in cell culture, phosphorylation of AMPK, a target of metformin, was measured by western blot and radiation survival was determined by clonogenic survival assay. Results: MiaPaCa-2 cells grown in 5mM glucose media with metformin have higher levels of AMPK phosphorylation than those grown in 25mM glucose media or without metformin. Radiation clonogenic survival was similar between cells exposed to any of the treatment conditions, including differences in glucose concentration and/or presence of metformin. Conclusions: MiaPaCa-2 pancreatic cancer cells do not demonstrate enhanced radiosensitivity to metformin in vitro. Future studies will investigate whether K-Ras wild-type cell lines exhibit enhanced radiosensitivity to metformin in vitro and whether metformin acts as a radiosensitizer in vivo.
Eligibility of metastatic pancreatic adenocarcinoma (MPA) patients for first-line palliative intent nab-paclitaxel plus gemcitabine (NG) versus FOLFIRINOX (FIO).
Authors: Peixoto Renata D'Alpino , Renouf Daniel John , Lim Howard John , Cheung Winson Y. 
Published: February 2017

259 Background: The ACCORD 11 and the MPACT trials recently showed superiority of FIO and NG over gemcitabine alone, respectively. However, both trials had strict inclusion criteria. The aim of this study was to determine the proportion of patients (pts) with MPA who would be potentially eligible for first-line palliative intent chemotherapy with FIO and NG in routine clinical practice. Methods: 473 consecutive pts who presented with MPA and initiated palliative chemotherapy with gemcitabine from 2000 to 2011 at the BC Cancer Agency were identified using the provincial pharmacy database. Clinicopathological variables and treatment outcomes were retrospectively collected and compared among groups. Eligibility criteria for each regimen were in accordance with the criteria as described in the respective pivotal phase III trials. Results: In total, median age was 66 years (range 34–89) and 258 (55%) were men. Only 24.7% of the pts would be eligible for FIO as compared to 45.2% for NG. The main reasons for ineligibility for FIO were ECOG performance status (PS) ≥ 2 (56.5%), age > 76 years (19.0%), and bilirubin > 1.5 times the upper limit of the normal range (ULN) (18.6%). The main reasons for ineligibility for NG were bilirubin > ULN (24.5%), ECOG PS ≥ 3 (14.6%), and cardiac dysfunction (13.8%). Median overall survival (OS) for the entire cohort treated with gemcitabine was 5.8 months (95% CI 5.4-6.2). On univariate analyses, eligible pts for FIO had longer median OS than ineligible pts (8.6 vs 4.7 months, p<0.001). Eligible pts for NG also had longer median OS than those deemed ineligible (6.7 vs 4.9 months, p=0.008). After accounting for ECOG PS in the multivariate model, eligibility for either FIO or NG no longered predicted for better OS. Conclusions: In ourpopulation-based analysis, almost twice as many pts would be eligible for NG when compared to FIO, mostly due to ECOG PS. The longer OS observed in the FIO-eligible population likely reflects the exclusion of ECOG PS 2 pts.
Association of ALDH-expressing cancer stem cells with survival in patients with resected pancreatic adenocarcinoma treated with adjuvant chemoradiation.
Authors: Kumar Rachit , Dholakia Avani Satish , Herman Joseph M. , Maitra Anirban , Matsui William H. , Hong Seung-Mo , Wolfgang Christopher Lee , Laheru Daniel A. , Iacobuzio-Donahue Christine A , Rasheed Zeshaan 
Published: February 2017

262 Background: We and others have identified aldehyde dehydrogenase (ALDH) activity as a marker of pancreatic cancer stem cells (or tumor-initiating cells). The presence of cancer stem cells (CSCs) has been associated with decreased survival and treatment resistance in pancreatic adenocarcinoma. We investigate the role of ALDH expression in predicting survival and patterns of disease recurrence in patients treated with chemoradiation (CRT) following pancreatectomy. Methods: Tissue microarrays using surgical specimens from 1998 to 2002 were stained for ALDH1 and scored as ALDH-positive or ALDH-negative by two expert pancreatic pathologists blinded to patient outcomes. Physician documentation and radiology reports were used to determine follow-up information. Time to local failure (TLF), time to distant metastases (TDM), progression-free survival (PFS), and overall survival (OS) were analyzed using SPSS software. Results: Previously we found that ALDH expression was associated with worse OS in a cohort of 269 patients with resected pancreatic adenocarcinoma (Rasheed, JNCI 2009). From this cohort, adjuvant treatment information was available for 87 patients with ALDH-negative tumors (48.6%) and 41 patients with ALDH-positive tumors (45.6%). In patients treated with adjuvant CRT, median overall survival was superior in the ALDH-negative cohort vs. the ALDH-positive cohort, 26.3 months vs. 18.2 months (p=0.011). Further, in patients treated with adjuvant CRT, ALDH-negative patients had statistically greater TLF, TDM, and PFS than their ALDH-positive counterparts (see table). On multivariate analysis, ALDH positive tumor staining (HR 1.94, p=0.004) and tumor grade (HR 1.54, p=0.041) predicted lower OS, and ALDH positive tumor staining (HR 1.83, p=0.008), tumor grade (HR 1.52, p=0.038), and tumor size >3 cm (HR 1.65, p=0.023) predicted decreased PFS. Conclusions: This study suggests that adjuvant CRT improves TLF, TDM, PFS, and OS in patients with localized pancreatic adenocarcinoma not enriched with ALDH-expressing CSCs. Laboratory studies will help elucidate the mechanisms of treatment resistance in ALDH expressing CSCs.
Prospective phase II study of inoperable pancreatic adenocarcinoma with neoadjuvant gemcitabine, docetaxel, and capecitabine (GTX).
Authors: Gulati Anthony Paul , Schreibman Stephen M. , Schrope Beth , Lee James A. , Allendorf John , Chabot John A. , Tsushima Dawn , Mowatt Kelley B. , Oprescu Anna , Chu Kyung , Sherman William H. , Ennis Ronald D. , Lee Yoomi , Fine Robert Lance 
Published: February 2017

274 Background: Chemoradiation (CRT) is used in unresectable pancreatic cancer (PC) to convert patients to a resectable state. Those who go to surgery can have a similar survival as those initially deemed resectable, with a mOS of 8.2-9 mo. We recently reported a prospective phase II trial of our synergistic regimen (GTX) for patients with metastatic PC with a mOS of 14.7 mo. Methods: 35 patients with ECOG PS 0-2 and completely unresectable advanced PC (localized to the pancreas, small bowel, stomach and/or encasing at least 2 vessels such as the SMA, CA, HA, PV, or SMV) were treated with GTX: Capecitabine (Xeloda) PO 1500mg/m2 divided into 2 doses daily on days 1-14, gemcitabine 750mg/m2 IV given over 75 min on days 4 & 11, docetaxel 30mg/m2 IV infusion over 30 minutes preceded by dexamethasone 10mg IV/PO on days 4 & 11, in a 21 day cycle. 3 cycles were given before evaluation. If eligible, a patient was allowed to proceed to surgery without radiation. Otherwise, starting on week 12, 5040 cGy of conformal radiation was given over 5-6 weeks (Mon-Fri) with weekly gemcitabine 250-300mg/m2 IV infusion over 30 min. No adjuvant treatment was given on protocol. Primary objective was conversion rate to operable status, and secondary objectives included RR (based upon RECIST), OS, and PFS. Results: Duration of neoadjuvant chemotherapy was 9 weeks and 0% showed POD during this time. 20 of 35 patients (57%) became eligible for surgery. Of all 35 patients, there was a 49% rate of negative margins at surgery (in 85% of those patients who underwent surgery). 23 patients (66%) underwent CRT, and 11 of them (48%) ultimately went to surgery and had clean margins. Median OS from initiation of chemotherapy for all patients was 17.4 mo and >22 mo if they went to surgery (20/35 pts, 1 alive). PFS of patients who underwent surgery was 13.2 mo. Grade 3/4 toxicities primarily included neutropenia (25%), leukopenia (11%), and diarrhea (6%). No deaths were attributed to GTX. Conclusions: Neoadjuvant GTX +/- radiation with gemcitabine can be used as an effective treatment for patients with truly unresectable PC. Clinical trial information: NCT00869258.
Open-label prospective study of safety and efficacy of glass-based Y-90 radioembolization for infiltrative HCC with PVT.
Authors: Kokabi Nima , Camacho Juan C. , Xing Minzhi , Kauh John S. , El-Rayes Bassel F. , Kim Hyun Sik 
Published: February 2017

276 Background: Safety and efficacy of Yttrium-90 (Y90) therapy for infiltrative unresectable hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) require further evaluation. Methods: A prospective single center, open-label, single arm safety and efficacy study recruited patients with unresectable (Barcelona Liver Cancer Stage C) infiltrative HCC with PVT. Safety was assessed according to Common Terminology Criteria for Adverse Events v.3.0 at 1 week and monthly thereafter for 6 months post therapy. Efficacy was assessed by overall survival (OS) as primary endpoint. Tumor response was assessed by dynamic contrast MRI according to Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST at 1, 3, and 6 months (secondary endpoint). To achieve 0.95 power (α=0.05) and predicting prolongation of mean OS by at least 50% over the best supportive care (4 months ± 2 months (SD)), the study was designed to recruit 30 patients. Survival analysis was performed using Kaplan-Meier estimation. Prognostic factors were tested using log-rank and univariate analysis. Results: Thirty (n=30) patients were enrolled and underwent Y90 therapy (median age 63). The median OS was 13 months (CI: 4.1-21.1 months). Six patients had transaminitis (70% grade 1, 30% grade 2) while 8 patients had biliary toxicity (50% grade 1, 10% grade 2, 40% grade 3). Grade 3 bilirubin toxicity occurred in the same 2 patients with grade 2 transaminase toxicity. Although all patients recovered from transient liver toxicities, grade ≥2 liver toxicity was found to be predictor of poor outcome with median OS of 3.6 months for patients with grade ≥2 toxicity vs. 13 months for those with grade 1 or no toxicity (p=0.004). Child-Pugh class B, INR ≥1.5, and grade ≥2 hepatobiliary toxicities were found to be poor prognostic factors by both log-rank and univariate analysis (p<0.05). Upon short-term imaging follow up (mean 34 days post Y90), 80% of patients were found to have complete (13%) or partial (67%) response according to targeted mRECIST criteria, with 93% stable disease according to targeted RECIST. Conclusions: In patients with unresectable infiltrative HCC and PVT, Y90 therapy is a viable and safe treatment option.
Effects of gemcitabine and stereotactic body radiotherapy on quality of life in locally advanced pancreatic cancer.
Authors: Dholakia Avani Satish , Chang Daniel Tandel , Goodman Karyn A. , Sugar Elizabeth , Hacker-Prietz Amy , Columbo Laurie Ann , Griffith Mary E , Wild Aaron Tyler , Moningi Shalini , Pawlik Timothy M. , Fisher George A. , Ellsworth Susannah G. , Koong Albert , Herman Joseph M. 
Published: February 2017

278 Background: Existing literature on the impact of radiation therapy for locally advanced pancreatic cancer (LAPC) on quality of life (QoL) is limited and is specific to standard chemoradiation. We prospectively investigated patient-reported QoL after treatment with fractionated stereotactic body radiation therapy (SBRT). Methods: Forty-nine patients with LAPC treated were prospectively enrolled in a clinical trial at 3 institutions. Participants received a total of 33 Gy in 6.6 Gy daily fractions using SBRT either upfront (N=5) or after a single induction cycle of gemcitabine (N=44), followed by post-SBRT gemcitabine until evidence of disease progression. Two validated questionnaires, the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and pancreatic cancer-specific QLQ-PAN26, were administered to patients prior to SBRT and at 4-weeks and 3 to 4-months following SBRT. Results: QoL questionnaires were available for 43 patients (88%) in the clinical trial at enrollment, of which 38 (88%) and 22 (51%) also had data at 4-weeks and 3 to 4-months following SBRT, respectively. There was no significant change in global QoL scores from enrollment at 4-weeks (p=0.682) and 4-months (p>0.999) following SBRT. Patients demonstrated a significant improvement in pancreatic pain (p=0.001), body image (p=0.007) and jaundice (p=0.001) scores from the pre-SBRT values at 4 weeks following SBRT. The initial 4-week results were similar when restricted to those patients with both 4-week and 4-month QoL data (p=0.020) and jaundice (p=0.004); however, these symptoms had returned to enrollment levels by the 4-month follow-up. An improvement in body image (p=0.016) and decline in role functioning (p=0.002) were observed in patients with 4-month follow-up QoL questionnaires. Conclusions: LAPC patients undergoing SBRT experience no impairment in global QoL and have short-term improvements in symptoms commonly bothersome to this population including pancreatic pain, body image, and jaundice. Patients also experience a delay in impaired role functioning several months after treatment. These results warrant further investigation of SBRT for LAPC. Clinical trial information: NCT01146054.
Role of adjuvant radiation therapy in ampullary carcinoma: Propensity-score matched SEER analysis.
Authors: Byun John , Grover Surbhi , Hertan Lauren Michelle , Apisarnthanarax Smith 
Published: February 2017

282 Background: Ampullary cancer outcomes have been reported to compare favorably with pancreatic and biliary malignancies. Consensus guidelines on the optimal adjuvant management after resection in these patients remain unclear. Propensity score matching was used to compare the outcomes of patients with ampullary cancer receiving or not receiving radiation therapy (RT) from the Surveillance, Epidemiology, and End Results (SEER) database. Methods: Patients with a diagnosis of ampulla of vater carcinoma who underwent curative intent surgery were identified within 17 SEER registries from 1998-2008. Patients with M1 disease or follow up less than 5 months were excluded. Data on patient characteristics such as age at diagnosis, race, tumor characteristics including TNM staging and histologic subtype, and survival outcomes were extracted and compared between patients who received adjuvant RT and those who did not. Propensity score matching was used to minimize treatment selection bias within the specified characteristics and estimate the impact of RT on median survival times (MST). Matching algorithms used validated Mahalanobis nearest neighbor methods based on conditional probabilities of receiving RT. Results: Of the 1782 patients identified, 490 (25%) were treated with adjuvant RT: 318 (65%) T3/4 and 333 (68%) N1. Cox regression with propensity score analysis for patients with RT showed an overall decrease in survival time by 3.67 months (p<0.05). Propensity score analysis showed slightly worse survival in patients who received RT compared to those who did not (MST 2.7 vs. 3.0 years, respectively, p=0.04). There was a trend towards a survival benefit with RT in a subgroup of patients over the age of 66 years with T2N0 tumors (MST 4.7 vs. 2.7 years, respectively, p=0.14). Survival outcomes analyzed by other T and N stages were not statistically significant. Conclusions: Adjuvant RT does not confer a survival benefit in resected ampullary cancers as studied in the propensity-score adjusted SEER patient population. Further studies should be conducted in order to elucidate the role of adjuvant RT for ampullary cancers.