bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of mTOR and hypoxia pathway activation in promoting tumorigenesis of intrahepatic cholangiocarcinoma.
Authors: McRee A. J. , Chen S. , O'Neil B. H. , Rathmell K. 
Published: February 2017

218 Background: Cholangiocarcinoma (CC) is an aggressive malignancy that often presents in advanced stages with poor response rates to conventional chemotherapy. Recent studies of CC have uncovered several oncogenes and tumor suppressors implicated in the transition from biliary hyperplasia to malignancy. We have developed a mouse model of intrahepatic CC that results from deletion of the phosphatase and tensin homolog (PTEN) gene and the von Hippel Lindau (VHL) gene, a tumor suppressor that regulates hypoxia inducible factor (HIF) expression. Immunohistochemical (IHC) analysis of the liver tumors revealed strong staining of p-AKT and HIF-1α. This study aims to determine the expression of the same downstream targets p-AKT and HIF1α in a dataset of human CC tumors. Methods: Archived samples from 33 CC patients were sectioned and stained via IHC for p-AKT and HIF1α expression. Samples were evaluated using a proportion score (PS) for neoplastic cells on a scale of 0 to 5, and an intensity score (IS) expressed on a scale of 0 to 3. Normal liver samples were used as controls. Results: Using a combined score of at least 5 to determine positive expression, 18% of the 33 evaluated samples displayed positive p-AKT expression and 61% displayed positive HIF1α expression. 15% of cases displayed concomitant expression of both p-AKT and HIF1α, while 39% of evaluated samples had expression of neither protein. Conclusions: Delineating the molecular pathways that lead to CC formation is crucial in developing novel therapeutics for a disease in drastic need of more effective therapies. Our group has developed a mouse model of intrahepatic CC that suggests a synergistic role of PTEN and VHL in the tumorigenesis of CC with upregulation of p-AKT and HIF1α. A modest percentage of a cohort of human samples demonstrates a similar expression pattern, potentially defining a distinct molecular subtype of this cancer with implications for tumor behavior and response to treatment. Future studies will correlate these molecularly-defined subtypes to the clinicopathologic characteristics of the tumors with the ultimate aim of establishing biomarkers of disease prognosis as well as potential predictive indicators of treatment activity. No significant financial relationships to disclose.
Phase I/II study of PCI-27483, a coagulation factor VIIa (FVIIa) inhibitor in patients with advanced pancreatic cancer receiving treatment with gemcitabine.
Authors: Ramanathan R. K. , Gressler V. , Shah S. , Loury D. , Hamdy A. , Khorana A. A. 
Published: February 2017

221 Background: PCI-27483 is a selective inhibitor of FVIIa, a serine protease activated by interaction with tissue factor (TF). TF upregulation in tumor cells correlates with angiogenesis and a worsened prognosis. Hydrolysis of protease activated receptors by the TF:FVIIa complex induces up-regulation of IL-8 and VEGF. PCI-27483 inhibited the growth of human pancreatic tumors in animal models at a 2.5x to 3.0x change in prothrombin time. PK/INR relationships from a phase I study in healthy volunteers were used to select initial doses of PCI-27483 for the current study. Methods: Patients (pts) with locally advanced or metastatic pancreatic cancer, ECOG performance status 0-1, and normal coagulation were enrolled. All pts in phase I and II receive gemcitabine (G) as a 30-min IV infusion at a dose of 1000 mg/m2 on 3 out of every 4 wks. PCI-27483 is administered twice daily by SC injection. In phase I, doses of PCI-27483 were intra-patient escalated (0.8 to1.2 to1.5 mg/kg) over 4 to 8 wks. The targeted peak INR, measured 2 h postdose, was 3.0. In phase II, pts are being randomized to a control arm to receive G only or to a PCI-27483 arm to receive G plus PCI-27483. Phase I pts receiving 80% of planned doses during in first 6 wks were considered evaluable. Spiral CT scans are performed at 8-wk intervals. Study endpoints: adverse event profile, progression-free survival, venous thromboembolic events, and overall survival. Results: Phase I—8 pts enrolled, 5 pts evaluable. Highest dose of PCI- 27483 achieved was 0.8 mg/kg for 2 pts, 1.2 mg/kg for 3 pts and 1.5 mg/kg for 3 pts. Hematologic toxicity: grade 3 neutropenia (n= 1) or anemia (n = 2). Other grade 3 toxicities: elevated INR (n = 4) or elevated aPTT (n = 1). Dose-level-specific mean 2-h INR values were 2.2 at 0.8 mg/kg (CV=9%; n=7), 3.2 at 1.2 mg/kg (CV=33%; n=6) and 2.9 at 1.5 mg/kg (CV=16%; n=3). No VTEs occurred. Radiologic evaluations of 5 evaluable pts: 4 SD at 16 wks (1st pt SD for >40 wks; 5th pt SD at 8 wks, 16-wk scan pending). Conclusions: PCI-27483 is well tolerated at doses up to 1.5 mg/kg bid with G 1,000 mg/m2. Sustained SDs occurred and INRs were generally within the expected range. The randomized phase II study is ongoing at a dose of 1.2 mg/kg bid. [Table: see text]
Use of human equilibrative nucleoside transporter 1 to predict survival after adjuvant gemcitabine chemotherapy in resected pancreatic adenocarcinoma.
Authors: Morinaga S. , Yamamoto N. , Shiozawa M. , Tamagawa H. , Ueno M. , Nakamura Y. , Miyagi Y. , Ohkawa S. , Yoichi K. , Akaike M. 
Published: February 2017

224 Background: Gemcitabine is a promising adjuvant treatment for patients with resected pancreatic adenocarcinoma. Human equilibrative nucleoside transporter 1 (hENT1) is the major transporter responsible for 2′, 2′-difluoro-2deoxycytidine (gemcitabine) uptake into cells. The aim of this study was to determine the outcomes according to the expression of hENT1 in tumor cells in patients treated with adjuvant gemcitabine chemotherapy after curative resection. Methods: We studied 27 pancreatic adenocarcinoma patients treated with gemcitabine adjuvant chemotherapy after curative resection and 8 gemcitabine naïve patients between 2006 and 2008. The hENT expressions were assessed using immunohistochemistry. The staining intensity of hENT1 protein was assigned a score from 0 to 3 based on staining with 0: no staining, 1: weakly positive, 2: moderately positive, 3: strongly positive. The percentage of positive tumor cells was scored as follows, 0: no positive tumor cell; 1: < 50% positive cells, 2: 51-80% positive cells, 3: > 81% positive cells. The hENT1 score was obtained by calculating the sum of these two scores. Each patients received adjuvant chemotherapy by either protocols as follows; GEM 1,000 mg/m2biweekly × 12 (6 months) or GEM 1,000 mg/m2Days 1,8,15; every 4 weeks for 6 months. Results: 11 patients were assigned to low hENT1 expression group (hENT1 score <4) and 16 patients to high hENT1 group (hENT1 score 4,5,6). The median DFS was 7.3 months (95% CI, 3.6-11.1) in the low hENT1 group, and 9.3 months (95% CI, 4.2-14.5) in the high hENT1 group. The median OS was 11.8 months (95% CI, 6.9- 16.6) in the low hENT1 group, and 22.2 months (95% CI, 11.5-32.9). The high hENT1 group had significantly longer DFS (Log-rank, p=0.04) and OS (p=0.02). In the gemcitabine naïve patients after curative resection, neither DFS nor OS correlated with hENT1 expression. Conclusions: In the pancreatic cancer patients treated with adjuvant gemcitabine chemotherapy after curative resection, both DFS and OS correlated with hENT1 expression. The expression of hENT1 may provides prognostic information and predictive for benefit from gemcitabine in these patients. No significant financial relationships to disclose.
Prognostic factors for stage IV gastric cancer.
Authors: Chu K. , Chan S. 
Published: February 2017

23 Background: In general, the most significant prognostic factor for gastric cancer is tumor stage. In a patient with stage IV gastric cancer, other prognostic factors would be helpful to guide appropriate therapy and to avoid unnecessary suffering as well as fruitless and expensive therapy. Methods: Data of all patients with gastric cancer managed at the Department of Surgery of The University of Hong Kong are entered prospectively into a computer database. Between January 1996 and December 2007, 1,109 patients who have not received prior treatment for their gastric cancer are included in the present study. Factors correlated with tumor stage as well as factors associated with survival are studied with univariate analysis. Significant factors are then subjected to multivariate analysis. In patients with stage IV disease, significant factors associated with survival are then studied with univariate and multivariate Cox regression analysis. Results: 1,109 patients with age of 66 ± 14 years were included. There was a male predominance (M:F = 705:404). 18.1%, 10.3%, 28.3%, and 43.2% have stage I, II, III, and IV diseases, respectively. Spearman's rank correlation analysis identified haemoglobin, lymphocyte/WCC ratio (LWR), platelet count, albumin, CEA, CA19-9, and C-reactive protein (CRP) to be significantly correlated with tumor stage. Multivariate analysis identified LWR, platelet count, albumin, CA 19-9 and CRP as independent factors associated with tumor stage. On the other hand, CA19-9, CRP, LWR and tumor stage were found to be independent prognostic factors associated with overall survival. Among the group of patients with stage IV disease, ECOG status (OR 1.265, 95% CI 1.025 – 1.562), CA 19-9 (OR 1.0, 95% CI 1.0 – 1.0), CRP (OR 1.050, 95% CI 1.021 – 1.081) as well as LWR (OR 0.076, 95% CI 0.011 – 0.552) were found to be independent prognostic factors for survival. Conclusions: Within the group of patients with stage IV gastric cancer, ECOG status, lymphocyte/ WCC ratio, serum CA19.9 and C-reactive protein level were found to be independent prognostic factors for survival. No significant financial relationships to disclose.
Feasibility assessment of GI tumor stroma gene expression profiles with microarray technology in formalin-fixed, paraffin-embedded (FFPE) specimens.
Authors: Wang S. X. , Wang J. , Beg M. S. , Ozhegov E. , Qu A. X. , Bogdanov V. 
Published: February 2017

232 Background: Cancer stroma plays a critical role in tumorigenesis. Microarrays are widely used to study gene expression patterns in tumor frozen tissue to explore tumorigenesis and predict recurrence. Here we explored the feasibility of applying microarrays to tumor stroma using FFPE specimens. Methods: Ten samples were obtained from one colon and one pancreatic cancer specimen. Tumor stroma and normal stroma were microdissected. RNA was extracted, amplified, and labeled using Nugene FFPE kit, with array analysis using Affymetrix Human Gene 1.0. To assess reproducibility, each stroma sample was run twice in parallel. To test the reproducibility of sampling, the specimen was microdissected twice at a different stroma location. GenePattern software was used; correlation between parallel samples and the repeat dissection samples was calculated and ComparativeMarkerSelection program with two-sided T test was used to study gene profiles in pancreatic and colon stroma. To validate the array results, the profile differences were analyzed against public databases. Results: The correlation between the duplicate samples was in the range of 0.978-0.988. The correlation between the original versus the repeat dissection at a different stroma site was 0.953-0.967. 19,319 probes with gene annotation were examined, and pancreatic stroma was compared to colon stroma. We found that 90% of these genes were expressed at similar levels. Using a cutoff of 1.3, we identified 50 genes that were expressed greater than 30% in pancreatic stroma compared to colon stroma. We researched these 50 genes against GeneNote, GNF, Unigene and SAGE databases. Upregulation of 95% of these genes in pancreatic stroma is consistent with the public databases. Moreover, among these genes we identified PNLIP, CPB1 CPA2, PRSS1/PRSS2, AMY1A, AMY1B, AMY1C, and AMY2A, known to be highly expressed in pancreatic tissue. Conclusions: Gene expression microarray is a tool that can be effectively used to analyze normal and tumor stroma in GI cancer. FFPE tissue is suitable for such an analysis, as evidenced by high reproducibility and biologic consistency of the obtained data. No significant financial relationships to disclose.
Activity of fractionated radioimmunotherapy with clivatuzumab tetraxetan combined with low-dose gemcitabine (Gem) in advanced pancreatic cancer (APC).
Authors: Ocean A. J. , Guarino M. J. , Pennington K. L. , Montero A. J. , Bekaii-Saab T. , Gulec S. A. , Teoh N. , Gold D. V. , Wegener W. A. , Goldenberg D. M. 
Published: February 2017

240 Background: The90Y-labeled anti-mucin humanized mAb, clivatuzumab tetraxetan (90Y-hPAM4), is in clinical development in APC. A phase I/II trial of 90Y-hPAM4 with low-dose radiosensitizing Gem has now concluded 90Y-dose escalation. Methods: Pts with untreated, inoperable, stage 3-4 APC received 200 mg/m2 Gem once-weekly x 4 with 90Y-hPAM4 on wks 2-4, and with 90Y escalated in cohorts by 3+3 design. Tumor responses were assessed by CT, FDG/PET and serum CA19.9, with cycles repeated until progression or unacceptable toxicity. Results: Of 42 pts (40-87 yrs, ECOG PS 0-1, 36 stage 4), 4 withdrew early while 38 received weekly x 3 90Y doses of 6.5 (N=4), 9 (N=12), 12 (N=17) and 15 (N=5) mCi/m2. Treatment was well-tolerated with few non-hematologic side-effects, including 13 pts retreated with 1-3 additional cycles. CTCv3 grade 3-4 plts or ANC developed in 21/38 (55%) pts after cycle 1 and all (100%) retreated pts after last cycle. Escalation reached limits on radiation doses to the marrow, but hematologic suppression was reversible without major infections or bleeding events, except for 3 pts after repeated cycles, one with extensive marrow tumor infiltration. By CT, the overall disease control rate was 55%, including 6 pts (16%) with partial responses (PRs) by RECIST criteria and 15 pts (39%) with stabilization as best response. After cycle 1, 43% (10/23) improved by PET studies (negative or >25% reduced uptake), and 36% (9/25) with elevated CA19.9 levels had >50 decreases. With 26% (10/38) of pts still in follow-up, 55% (21/38) have now achieved survival of ≥ 6 months [18% (7/38) ≥ 1 yr]. Treatment outcome may increase with 90Y dose, since pts treated at 3 x ≥12 mCi/m2 vs ≤9 mCi/m2 had 19% vs 6% PRs by CT, 47% vs 22% CA19.9 decreases, 63% vs 25% PET improvement, and 64% vs. 44% survival ≥ 6 months. Anecdotally, PS and pain level improved, which needs validation. Updated survival will be presented at the meeting. Conclusions: Fractionated 90Y-hPAM4 plus low-dose Gem showed encouraging therapeutic activity with manageable hematological toxicity. The 12-mCi/m2 dose level was selected for continued dose exploration now underway, involving standard Gem doses and adding maintenance Gem. [Table: see text]
Clinical activity of the oral MEK1/MEK2 inhibitor GSK1120212 in pancreatic and colorectal cancer.
Authors: Messersmith W. A. , Falchook G. S. , Fecher L. A. , Gordon M. S. , Vogelzang N. J. , DeMarini D. J. , Peddareddigari V. G. , Xu Y. , Bendell J. C. , Infante J. R. 
Published: February 2017

246 Background: GSK1120212 is a reversible, highly selective allosteric inhibitor of MEK1/MEK2. The objectives of this phase I study are to define the maximum tolerated dose (MTD), and to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and response rate of GSK1120212 in advanced solid tumors. Cohorts of advanced chemoresistant pancreas (PC) and colorectal cancer (CRC) patients have been enrolled. Methods: GSK1120212 is given orally, once daily (QD). In this three-part study GSK1120212 was escalated to an MTD, was administered in selected tumor types to evaluate recommended phase II doses (RP2D), and was evaluated for minimum biological activity using PD assessments. Results: 202 patients (pts) have received ≥ 1 dose of GSK1120212, including 26 PC and 27 CRC pts. The MTD is 3 mg QD and the RP2D is 2 mg QD. Dose limiting toxicities are rash (N=2), diarrhea (N=1), central serous retinopathy (N=2) and are reversible. At 2 mg QD (N=68), the most common adverse events are rash (47% G1, 37% G2, 4% G3) and diarrhea (41% G1, 12% G2, 1% G3). There has been one event of retinal vein occlusion. GSK1120212 has a small peak:trough ratio of ∼ 2 and an effective half life of ∼ 4.5 days. Steady state is reached by ∼ day 15. In the 26 evaluable PC pts, 2 partial responses (PR) and 11 stable diseases (SD) have been observed. 1 PR is KRAS mutation positive and is ongoing at 28 weeks. Among the SD pts, 2 achieved ≥ 20% tumor reduction and at least 3 were on study for 16 weeks or longer. CA19-9 reduction ≥ 55% was observed in both PR and 3 SD pts, 1 of which remained on study for 40 weeks. Among the KRAS mutation positive CRC pts (n=12), 4 SD were observed. These pts were on study for 31, 28, 16, and 16 weeks. Among the KRAS mutation negative or status unknown pts (n=12), 2 SD were observed; no pt was on study for > 19 weeks. Among the B-RAF mutation positive pts (n=3), 2 SD were observed; both are still ongoing at >16 weeks. Conclusions: The RP2D is well tolerated. The long effective half life and small peak:trough ratio of GSK1120212 allow constant target inhibition within a narrow range of exposure. GSK1120212 demonstrates durable clinical activity in a subset of pts with PC or CRC. [Table: see text]
Evaluation of progression-free survival by blinded independent central review in patients with progressive, well-differentiated pancreatic neuroendocrine tumors treated with sunitinib or placebo.
Authors: Van Cutsem E. , Seitz J. F. , Raoul J. , Valle J. W. , Faivre S. J. , Patyna S. , Klademenos D. , Lu D. , Chao R. C. , Raymond E. 
Published: February 2017

249 Background: Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor with antiangiogenic activity. In a phase III, double-blind, placebo-controlled, randomized trial in patients with advanced, well-differentiated progressive pancreatic neuroendocrine tumors (NET), sunitinib 37.5 mg continuous daily dosing significantly improved investigator-assessed progression-free survival (PFS) compared with placebo (median, 11.4 months vs. 5.5 months; hazard ratio [HR] 0.418; 95% CI: 0.263, 0.662; P=0.0001). To evaluate the possibility that recognizable treatment- associated adverse events (AEs) might have impacted the efficacy results by unblinding the investigators, we conducted a retrospective blinded independent central review (BICR) of the tumor imaging scans. Methods: PFS was defined as the time from randomization to the first objective progression of disease or death due to any cause, whichever occurred first. Baseline and on-study CT/MRI scans were evaluated independently according to a two-reader, two-time point lock, followed by a sequential locked read, batch mode paradigm, by independent, third party radiologists. Reading radiologists were blinded to investigator tumor assessments and AEs; discrepancies were adjudicated by a similarly blinded and independent third radiologist. Results: Overall, 171 patients were randomized to treatment (sunitinib, n=86, placebo, n=85). Scans were collected retrospectively for 170 (99.4%) patients. Complete scan sets/time points were available for 160 patients (93.6%). Median PFS based on BICR of scans was 12.6 months for sunitinib and 5.8 months for placebo with an HR of 0.315 (95% CI: 0.181, 0.546; p=0.000015), consistent with the investigator- assessed PFS results. Conclusions: This BICR of tumor scans confirms the investigator-assessed, clinically meaningful PFS benefit of sunitinib in patients with pancreatic NET, and provides evidence against the presence of any systematic bias favoring sunitinib. [Table: see text]
Robotic-assisted pancreaticoduodenctomy at a high-volume pancreas center.
Authors: Zureikat A. H. , Bartlett D. L. , Steel J. L. , Moser A. J. , Zeh H. 
Published: February 2017

258 Background: Robotic-assisted pancreatic surgery is gaining momentum due to improved ergonomics, dexterity, and visualization compared to standard laparoscopy. These technical advantages in combination with experience and improved robotic technology may reduce the significant morbidity associated with pancreaticoduodenectomy (PD). Methods: Retrospective analysis of consecutive robotic-assisted PD performed for all indications. Patients with potentially resectable tumors were selected for robotic PD on the basis of our EUS/CT predictive model. We evaluated perioperative events, final pathology, and complications occurring within the first 30 days on an intention-to-treat basis. Results: 42 robotic-assisted PD (22 women) were attempted between October 2008 and June 2010. Mean age was 67 years (SD=16, range 27-85), with median BMI 26.5 (IQR=7.8). 52.4% of patients had an ASA score of III. Final pathology included 13 pancreatic ductal adenocarcinoma, 9 peri-ampullary adenocarcinoma, 8 pancreatic neuroendocrine tumors, 5 IPMN, 2 cholangiocarcinoma, 2 pseudo-papillary neoplasm, 1 serous cystadenoma, 1 mucinous cystic neoplasm, and 1 duodenal adenoma. The first 34 patients underwent classic PD, and the final 8 patients had pylorus-preserving PD. Conversion to open was necessary in 8 patients (19%). Mean operative time was 576 min (SD=327, range 327-848 min) with 400mL median estimated blood loss (IQR=475). For malignancies, the R0 resection rate was 88% (4/34) with mean lymph node harvest of 17 (SD=7.3, range 8-37). The pancreatic fistula rate was 21% with ISGPF Grades B and C leaks observed in 9.6%. 10 patients (23.8%) developed minor complications (Clavien grade 1/2), whereas 11 had major complications (26.2%). There was one late death (2.4%). Median length of stay was 10 days (IQR=5). Statistically significant reductions in estimated blood loss (643mL vs. 317mL, p=0.003) and conversion to open (7 vs. 1, p=0.02) were observed in the latter half of the series. Conclusions: Robotic-assisted PD can be performed safely with postoperative and oncologic outcomes comparable to open surgery. The learning curve continues to evolve after 40 cases. No significant financial relationships to disclose.