bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation of KRAS mutational state with the expression of the hedgehog pathway in patients with pancreatic ductal adenocarcinoma.
Authors: Santoni Matteo , Bittoni Alessandro , Andrikou Kalliopi , Lanese Andrea , Loretelli Cristian , Conti Alessandro , d'Arenzo Marco , Mandolesi Alessandra , Bearzi Italo , Cascinu Stefano 
Published: February 2017

227 Background: Pancreatic ductal adenocarcinoma (PDAC) is commonly associated with mutations in the KRAS gene. However, how KRAS mutations promote pancreatic carcinogenesis has not been fully established. Here we examine the association between KRAS mutational state and the expression of different tumor markers in PDAC samples. Methods: Immunohistochemical analysis was performed on PDAC specimens to identify the levels of expression of 28 surface and nuclear proteins: BRCA1, BRCA2, NOTCH1, SPARC, SHH, DHH, IHH, SMO, PTCH1, PTCH2, ALCAM, OCT3.4, PROM1, CD44, CD24, LGR5, BMP4, KDR, FLT1, PDGFRB, VEGFA, VEGFB, PGF, CDKN2A, SMAD4, MET, HGF, MUC6. All samples were also tested for identification of KRAS isoforms (wild type (WT) vs mutated type (MT)) expression by means of RT-PCR. Levels of mRNA expression were matched with a common standard tissue marker. Expression levels of PDAC markers were compared between MT and WT KRAS groups. Differences between groups were tested using Mann-Whitney U test for unpaired samples. Exploratory univariate logistic regression was also performed to evaluate possible correlations between increasing levels of each marker and KRAS mutational state. Results: 110 samples were collected. Of them, data on KRAS were provided for 86 samples; 40 and 46 samples expressed the WT and MT KRAS isofo rms, respectively. Preliminary analysis showed that the expression of SHH and IHH resulted significantly higher in KRAS MT samples (U=1097 p= 0.013 and U=1072 p= 0.028 respectively), whereas higher levels of SMAD4 (U=634, p= 0.012) and HGF (U= 655, p= 0.03) were expressed in the KRAS WT group. A weak difference between groups was found for the MUC6 pathway (U= 666, p= 0.056). No differences of VEGFA, VEGFB and VEGFRB expression were found between MT and WT groups. At univariate logistic regression we found that increased levels of SHH correlated with the expression of KRAS MT phenotype (OR 57.5, p= 0.011), while IHH showed only a weaker significance level (OR 13.1, p= 0.069). Conclusions: These results indicate that oncogenic KRAS is directly associated with SHH expression in PDAC tissues. They also mark Hedgehog pathway components as relevant therapeutic targets for KRAS-mutant patients.
A phase I study of the anti-IGF-1R monoclonal antibody (MoAb), IMC-A12 (I), and everolimus (E) in well-differentiated neuroendocrine tumors (WD NET).
Authors: Dasari Arvind , Phan Alexandria , Gupta Sanjay , Hess Kenneth R. , Culotta Kirk Salvatore , Rashid Asif , Yeung S. J. , Chen Helen X. , Dong Mei , Halperin Daniel M. , Subbiah Ishwaria Mohan , Meric-Bernstam Funda , Yao James C. 
Published: February 2017

232 Background: Octreotide LAR (LAR) and E have well known anti-cancer effects in WD NETs. Preclinical data also show that inhibition of the insulin like growth factor receptor (IGF-1R) may sensitize NETs to mTOR inhibitors such as E. Methods: Patients (pts) with WD NETs, ECOG performance status ≤ 2 and adequate organ function were treated with LAR 20 mg IM q 21days (d), E 10 mg po daily and escalating doses of I iv q 21 d in 21 d cycles in cohorts of 6 until maximum tolerated dose (MTD). Recommended phase II dose (RP2D) was defined as dose level below MTD. An expansion cohort of 9 pts was planned at RP2D. Plasma samples for everolimus pharmacokinetics (PK), IGF, mTOR pathway pharmacodynamics (PD) in addition to paired tissue biopsies were obtained. Results: 19 pts with previously treated (median prior systemic therapy, 1, range 0-3) WDNET (4 pancreatic NET, 11 carcinoid, 4 unknown primary) were enrolled in this single institution study. Ten pts in dose escalation and 9 in expansion phases received a median of 8.5 cycles (range, 3-19+). Dose limiting toxicities (DLTs) were grade (g) 3 mucositis in 2 pts at 2nddose level of I 15 mg/m2 q 21 d. Most frequent adverse events (AEs) observed while on study were fatigue, hyperlipidemia, weight loss (74%), dysguesia (68%), hyperglycemia and mucositis (63%). Most common g3 AEs were fatigue (21%), mucositis, transaminitis and electrolyte disturbances (all 11%). Other g 3 AEs included anorexia, anemia, injury, retinal detachment, dehydration and thromboembolism. One g 4 AE of hyperglycemia was noted during the expansion phase. One pt with pancreatic NET had confirmed partial response and 17 had stable disease as best response. The median progression free survival was 34+ weeks. Conclusions: The RP2D of this combination is I 10 mg/m2, LAR 20 mg IM q 21 d, E 10 mg po daily. PK, PD and other correlative analyses are ongoing and will be presented at the meeting. Although adequate safety and a sign of activity were noted in this study, these will need to be reconciled with data from larger studies of anti-IGF-1R MoAb in NET and other cancers that have been disappointing. Clinical trial information: NCT01204476.
ERCC1 mRNA levels as a useful prognostic biomarker for extrahepatic cholangiocarcinoma with R0 resection.
Authors: Uemura Shuichiro , Kuramochi Hidekazu , Nakajima Go , Sato Yasuto , Higuchi Ryota , Yamamoto Masakazu 
Published: February 2017

239 Background: To date, no prognostic biomarker for biliary tract carcinoma has been identified. In previous studies of biliary tract carcinoma, no reliable data was found due to the varying composition of the cancer type (gallbladder, cholangiocarcinoma, and ampullary carcinoma), differences in tumor location, a mixture of curative and non-curative operations, and differences in operative methods. Methods: Fifty extrahepatic cholangiocarcinoma patients who underwent a pancreatoduodenectomy with R0 resection at the Tokyo Women’s Medical University Hospital were examined. All patients were pathologically diagnosed as having papillary or tubular adenocarcinoma. T-RNA was extracted from FFPE samples, and mRNA expression levels were measured by real-time RT-PCR. Results: In the preliminary analysis, 10 patients who have survived more than 5 years (LS group) and 10 patients who had a relapse within 2 years (SS group) were selected. EGFR, AREG, EREG, MMP-9, CDH-1, PARP1, and ERCC1 mRNA expression were examined; only the ERCC1 mRNA levels showed a significant difference between the LS and SS groups (median ERCC1: LS 26.5 vs. SS 9.7, p=0.0073). The median survival time (MST) of the patients with high ERCC1 levels was significantly higher than that in patients with a low ERCC1 level (MST: not reached vs. 16M). Then, 30 more patients with the same backgrounds were added to the study, and ERCC1 mRNA levels were measured in all 50 patients. The patients with high ERCC1 mRNA levels had a significantly greater overall survival rate compared with those with low ERCC1 levels (MST: not reached vs. 12.5M, 5-year survival rate: 92% vs 51%; p=0.04). In multivariate analysis, no lymph node metastases or high ERCC1 expression were significantly associated with better overall survival. Conclusions: ERCC1 mRNA expression seemed to be a useful prognostic biomarker for extrahepatic cholangiocarcinoma with R0 resection.
Survival benefits of adjuvant radiotherapy and lymph node dissection in pancreatic cancer treated with surgery and chemotherapy.
Authors: Mellon Eric Albert , Springett Gregory M. , Hoffe Sarah E. , Hodul Pamela Joy , Malafa Mokenge Peter , Meredith Kenneth , Fulp William J. , Zhao Xiuhua , Weber Jill , Shridhar Ravi 
Published: February 2017

263 Background: Prior SEER analyses of the benefit of radiotherapy in surgically resected pancreatic cancer could not analyze chemotherapy recipients due to limited database information. Recent updates permit us to determine the effects of postoperative radiation therapy (PORT) and lymph node resection (LNR) on overall survival (OS) in pancreatic cancer among patients treated with both surgery and chemotherapy. Methods: An analysis of surgically resected pancreatic cancer patients receiving chemotherapy from the SEER database between 2004-2008 was performed. Survival was calculated by Kaplan-Meier method and log-rank analysis. Multivariate analysis (MVA) was by the Cox proportional hazard model. Results: We identified 2,966 patients who met inclusion criteria. PORT significantly improved OS in pancreatic cancer patients treated with surgery and chemotherapy (p=0.02). Median survival (MS), 1-year OS, and 3-year OS was 21 months, 77%, and 28% with PORT (n=1842) versus 20 months, 70%, and 25% without radiation (n=1124). On subset analysis, the benefit of PORT was limited to node positive patients. In N1 patients (n=2043) MS, 1-year OS, and 3-year OS was 19 months, 73%, and 25% with PORT versus 18 months, 67%, and 20% without PORT (p<0.01). For N0 patients (n=923) MS, 1-year OS, and 3-year OS was 26 months, 85%, and 36% with PORT versus 25 months, 79%, and 38% without PORT (p=0.87). Increasing nodal count on LNR correlated with improved OS on MVA for all and N1 patients (each p<0.001). Significant cut points for OS based on LNR in N1 patients were found for greater than 8, 10, 12, 15, 20, and 30 nodes resected (p<0.05 for all). Prognostic factors on MVA include receipt of radiation, age, female sex, well differentiated grade, N0 status, and disease contained within the pancreas (p < 0.03 for all). In N1 patients (n=2043), these factors remained significant except patient age. In N0 patients (n=923), only pancreas-confined disease and less than high grade tumor were associated with survival benefit. Conclusions: PORT and degree of LNR are both correlated with improved OS in pancreatic cancer patients treated with surgery and chemotherapy. Benefit of PORT and LNR seems limited to node positive patients.
Impact of ROS1, ALK, and/or MET expression level on the therapeutic efficacy of GEMOX with and without cetuximab in ABTC: A post hoc analysis of a randomized phase II trial.
Authors: Chiang Nai-Jung , Hsu Chiun , Chen Jen-Shi , Tsou Hiso-Hui , Chao Yee , Shan Yang-Shen , Huang Shiu-Feng , Chiu Chang-Fang , Lee Kuan-Der , Chen Li-Tzong 
Published: February 2017

267 Background: Our randomized phase II trial showed adding cetuximab to GEMOX marginally improved the ORR and median PFS in ABTC patients regardless their KRAS mutation status. Recently, MET overexpression was noted in 11.7% to 16.2% of BTC, and associated with poor OS. ROS1 kinase fusion has also been detected in 8.6% of IHCC.The aim of the study is to evaluate the impact of ROS1, ALK and/or MET (RAM) overexpression on the clinical outcomes of ABTC patients. Methods: FFPE tissue sections that were prospectively collected for biomarker study from all 122 patients were subjected for determining the expression of ROS1, ALK and MET by IHC in a central laboratory. Results: Of 110 patients with enough tissue section for IHC of all three markers, 18 tumors were found to over-express ROS1 (in 9), ALK (in 5) and/or MET (in 6). One tumor over-expressed all three biomarkers. As compared with RAMlow tumors, the 18 RAMhigh tumors were significantly more of IHCC and without prior surgery, and with more frequent concurrent KRAS mutation. RAMhigh tumors was associated with significant inferior median OS than RAMlow tumors, 5.7 vs 11.8 months (p=0.04). Of the latter 92 patients, adding cetuximab improved the therapeutic efficacy of GEMOX in ABTC, with ORR of 31.8% vs 10.4% (p=0.02), DCR of 61.4% vs 37.5% (p=0.04) and median PFS of 7.0 vs 4.5 months (p=0.02). OS was only marginally affected, with median OS of 12.5 vs 10.4 months (p=0.36). The ORR in KRASwt and KRASmut patients receiving C-GEMOX and GEMOX was 34.5% vs 11.8% (p=0.04) and 26.7% vs 7.1% (p=0.33), respectively; whiles the DCR was 65.5% vs 50.0% (p=0.31) and 53.3% vs 7.1% (p=0.01), respectively, and the median PFS was 7.1 vs 5.8 months (p=0.07) and 7.0 vs 1.9 months (p=0.05), respectively. The results suggest that, the presence of KRAS mutation did not preclude the benefit of adding cetuximab to GEMOX in RAMlowsubpopulation. Conclusions: ROS1/ALK/METhigh ABTC had poor survival after C-GEMOX/GEMOX; while C-GEMOX significantly improved the ORR, DCR and PFS as compared to GEMOX alone in patients with ROS1/ALK/METlow tumors regardless their KRAS mutation status. Biomarker-driven design is warranted for future ABTC trials.
ELECT: A phase 3 study of efficacy and safety of lanreotide autogel/depot (LAN) treatment for carcinoid syndrome in patients with neuroendocrine tumors (NETs).
Authors: Vinik Aaron , Wolin Edward M. , Audry Helene , Gomez-Panzani Edda L. ,   ELECT Study Group
Published: February 2017

268 Background: Somatostatin analogs (SSAs) are the mainstay treatment for carcinoid syndrome. LAN is a long-acting SSA approved for this indication in >50 countries, but not yet in the US. ELECT is a large multinational phase 3 study evaluating rescue therapy use as a novel alternate endpoint for carcinoid symptom control with LAN. Methods: Eligible patients were age ≥ 18 years with histologically-confirmed NET and a history of carcinoid syndrome, and naïve to SSA treatment or responsive to conventional doses of octreotide LAR (≤ 30 mg/4 weeks) or short acting (≤ 600 µg/day SC). Design: a 16-week, randomized (LAN 120 mg [n=59] vs placebo [n=56] every 4 weeks) double-blind phase, followed by a 32-week long-term open label phase on LAN. Patients had access to short acting octreotide as rescue for breakthrough symptoms throughout the study. Primary endpoint: % of days the patient used rescue octreotide during the double-blind phase. The study was designed to have 90% power to detect a treatment difference of 30%. NCT00774930. Results: Among thestudy population, 83 (72%) had symptoms for ≥ 1 year, and51 (44%)had no prior SSA therapy. Mean [95% CI] % of days with rescue medication use was statistically lower with LAN (34% [25, 42%]) vs placebo (49% [40, 57%]), absolute difference –15% [–27, –3%], p=0.02; however, the pre-defined difference was not met. Complete/partial success (≤3 days use) rather than failure (> 3 days use) was more likely with LAN than placebo (OR 2.4 [95% CI 1.1, 5.3]; p=0.04). Treatment emergent AEs: 15 (26%) LAN patients vs 11 (19%) placebo patients; few AEs were serious (2 [3%] vs 5 [9%]) or led to study withdrawal (1 [2%] vs 1 [2%]). Most frequent AEs were GI disorders, 9 (16%) on LAN vs 5 (9%) on placebo. Conclusions: In the ELECT study, LAN significantly reduced need for short acting SSA use with a favorable safety/tolerability profile. This confirms LAN’s positive benefit-risk profile, which is consistent with experience from previous trials and many years of clinical practice in many countries around the world. Clinical trial information: NCT00774930.
Novel Kras-directed therapy in combination with chemotherapy for locally advanced pancreatic adenocarcinoma.
Authors: Golan Talia , Hubert Ayala , Shemi Amotz , Segal Amiel , Khvalevsky Elina Zorde , Domb Avi , Ben-David Eliel , Raskin Stephen , Goldes Yuri , Lahav Maor , Dancour Alan , Galun Eithan 
Published: February 2017

270 Background: K-Ras mutation G12D is most prevalent in pancreatic adenocarcinoma (PDAC). siRNA against the K-RasG12D(siG12D) mutant had showed significant preclinical anti-tumor effects. siG12D LODER - is a miniature biodegradable polymeric matrix that encompasses anti K-RasG12D siRNA drug, designed to release the drug regionally along 4 months. The siG12D LODER is placed with Endoscopic US biopsy. Methods: Open label phase I study of patients with locally advanced non-operable PDAC in the first-line setting. Patients were assigned to receive siG12D LODERs in a dose escalation, dose cohorts were: 0.025mg, 0.75mg and 3.0mg. Gemcitabine 1000 mg/m2IV was given on a weekly basis, following the siG12D LODER insertion, until disease progression. The RP2D (recommended phase II dose) was further examined in highest dose cohort in combination with modified Folfirinox (Oxaliplatin 85mg/m2, Irinotecan 150mg/m2 followed by a Fluorouracil continuous IV infusion 2,400mg/m2 46 hours every 2 weeks). Follow up period was 8 weeks and survival follow up until death. Primary study objectives were to determine the dose-limiting toxicities (DLT) and maximum tolerated doses (MTD). Results: 15 patients with locally advanced PDAC have been enrolled. Two patients were omitted from study but followed for safety due to metastatic disease detected on day 1 post siG12D LODER implant imaging. Median age = 70 (range 52-85); male:female =8:7. Among 13 treated patients, the most frequent adverse events observed in the study were typically grade 1- 2 in severity; 4 patients experienced serious adverse events (SAE). No DLTs were observed. CT performed 8-12 weeks following the procedure showed tumor regression in 66% (8 of the first 12 patients, 7/8 from 2nd and 3rd cohorts).Reduction in tumor marker CA 19-9 was observed in 64% (7/11) of patients. Median overall survival was 16.26 months, 14.01 months and 15.11 months in the 0.025 mg, 0.75 mg and the 3 mg treatment groups respectively. Conclusions: The combination of siG12D LODER and chemotherapy is well tolerated. The combination has demonstrated promising efficacy in locally advanced pancreatic cancer with durable responses. NCT01188785. Clinical trial information: NCT01188785.
Surgical strategy for borderline resectable pancreatic body cancer.
Authors: Yamaue Hiroki , Okada Ken-Ichi , Tani Masaji , Kawai Manabu , Hirono Seiko , Miyazawa Motoki , Shimizu Atsushi 
Published: February 2017

271 Background: The indications for distal pancreatectomy with en-bloc celiac axis resection (DP-CAR) in pancreatic carcinoma remain controversial. Moreover, the incidence of delayed gastric emptying (DGE) is high in patients undergoing distal pancreatectomy with DP-CAR. Methods: Fifty-two consecutive patients with pancreatic cancer who underwent distal pancreatectomy, including 36 standard distal pancreatectomies (standard DP) and 16 DP-CAR were reviewed. To determine the incidence of DGE, 37 consecutive patients who underwent DP-CAR were evaluated for the incidence of DGE, including 23 patients with left gastric artery (LGA)-resecting DP-CAR (conventional DP-CAR) and compared it with 14 patients who underwent distal pancreatectomy with preservation of the LGA (modified DP-CAR). Results: The estimated overall 1- and 2-year survival rates after standard DP / DP-CAR were 81/81% and 52/53%, and the median survival times were 32/25 months, respectively, with no significant difference comparing standard DP. There were no differences in the mortality rates and the incidence of each complication between the two groups except for delayed gastric emptying. In the conventional DP-CAR group, the LGA were involved in 20 patients (87.0%). The ISGPS grades were: no DGE = 43%, grade A = 26%, B = 13% and C = 17% in the conventional DP-CAR group, and no DGE = 93%, grade A = 7%, grade B/C = 0% in the modified DP-CAR group. The R0 rate was higher in the modified DP-CAR group (79%) compared to the conventional DP-CAR group (43%) (p=0.048). On multivariate analysis, resection of the LGA was an independent risk factor for increased incidence of DGE. Conclusions: DP-CAR was a feasible and safe procedure, similar to standard DP. Modified DP-CAR significantly reduced the incidence of DGE in comparison to conventional DP-CAR.
Harvesting lymph nodes in gastric cancer surgery: A prospective randomized controlled study.
Authors: Aoyama Toru , Fujikawa Hirohito , Shirai Junya , Yoichi Kameda , Cho Haruhiko , Hayashi Tsutomu , Rino Yasushi , Hasegawa Shinichi , Oshima Takashi , Masuda Munetaka , Oba Mari Saito , Morita Satoshi , Yoshikawa Takaki 
Published: February 2017

28 Background: Harvesting lymph node (LN) after gastrectomy is essential for accurate staging. Conventional method (CONV) to retrieve LN immediately after surgery is accepted in Japan but its efficacy and quality highly depends on the case and examiners. Another method is to retrieve LN stained by methylene blue dye (MBD), by which the physicians may easily pick up blue LN. This trial evaluated the efficiency and quality of both methods in randomized fashion. Methods: Key eligible criteria are as follows. (i) Histologically proven adenocarcinoma of the stomach, (ii) Clinical stage I-III, (iii) R0 resection is planned by gastrectomy with D1+ or D2 lymphadenectomy. Examiners for harvesting LN are qualified based on the experience. After curative surgery, LNs are harvested from the specimen immediately after surgery in the CONV group and from the specimens who had been fixed with 10% buffered formalin with methylene blue for 48 hours in the MBD group. The primary endpoint is the ratio of the pathological number of the harvested LNs per time (minutes) as an efficacy measure. The secondary endpoint is the pathological number of harvested LNs as a quality measure. The sample size was determined to be 60 considering the primary measurement as 40 LNs / 30 minutes in CONV and 40 LNs / 22.5 minutes in MBD with two-sided alpha error of 5% and statistical power of 80%. Results: Between August 2012 and December 2012, 60 patients were assigned to CONV (n=29) and MBD (n=31). Total/subtotal gastrectomy was 12/17 in CONV and 12/19 in MBD, respectively. D1+/D2 was 17/12 in CONV and 15/16 in MBD, respectively. Baseline demographics were well balanced between the both. The number of pathological harvesting LNs (median, range) was 32 (11-57) in CONV and 41 (17-79) in MBD (P=0.005). The time per case for harvesting LN (median, range) was 33 (15-58) minutes in CONV and 25 (13-102) minutes in MBD (p=0.743). The ratio of the number of the harvested LNs per time (median, range) was 1.12 (0.42-2.07) in CONV and 1.42 (0.50-3.07) in MBD (p=0.01). Conclusions: When harvesting LN in gastric cancer surgery, methylene blue dye-assisted technique is superior in the efficacy and quality as compared with conventional method. Clinical trial information: UMIN000008624.