bluuebunny/crossref_metadata_2025_split huggingface dataset:
A prospective study of repeat endoscopic biopsy to identify HER2-positive tumors following an initial HER2-negative biopsy in unresectable or metastatic gastric cancer: Gasther-1.
Authors: Kang Yoon-Koo , Park Sook Ryun , Park Young Soo , Lee Jeong Hoon , Ryoo Baek-Yeol , Woo Chang Gok , Lee Gin Hyug , Jung Hwoon-Yong , Ryu Min-Hee 
Published: February 2017

27 Background: The intratumoral heterogeneity of HER2 expression in gastric cancer (GC) is a major challenge for identifying patients (pts) who would benefit from anti-HER2 therapy. The aim of this study is to evaluate the significance of re-evaluation of the HER2 status by repeat endoscopic biopsy in pts with HER2-negative GC on initial endoscopic biopsy. Methods: Pts with unresectable or metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma who would receive 1st line chemotherapy were eligible if the HER2 was negative on the initial endoscopic biopsy. HER2 positivity was defined as IHC 3+ or IHC 2+/FISH+ using the GC scoring system. A repeat endoscopic biopsy was performed in ≥6 different primary tumor sites immediately after obtaining initial HER2-negative results. Results: From May 2011 to April 2013, a total of 183 pts were enrolled. Baseline characteristics at the time of the initial biopsy were as follows: tumor location, GEJ~fundus/body~antrum/diffuse stomach = 22 (12.0%)/115 (62.9%)/46 (25.1%); Lauren classification, intestinal/diffuse/mixed = 53 (29.0%)/111 (60.7%)/19 (10.4%); and HER2 IHC score, 0/1/2 = 149 (81.4%)/26 (14.2%)/8 (4.4%). The median number of biopsy pieces was 5 (range, 1-15) and 10 (1-15) in the initial and repeat biopsy, respectively (p<0.0001). As HER2 positive tumor was identified in 16 pts, HER2 positivity rate on repeat biopsy was 8.7% (95% CI 4.6-12.8%). The detection of HER2 positivity on repeat biopsy was associated with tumor location (diffuse stomach vs others = 0% vs 11.7%, p=0.013), Bormann type (IV vs others = 0% vs 11.7%, p=0.013), and the HER2 IHC score on the initial biopsy (0 vs 1/2 = 6.7% vs 18.2%, p=0.045). In multivariate analysis, the HER2 IHC score (1/2 vs 0, OR = 3.30; p=0.041) was an independent predictor of HER2 positivity in repeat biopsy. Conclusions: In pts with metastatic or unresectable GC, repeat endoscopic biopsy could detect HER2-positive GC which initial biopsy had missed. As anti-HER2 therapy improves the survival of pts with HER2 positive GC, in pts who showed HER2 negativity on initial biopsy, repeat biopsy should be considered subsequently.
A phase 1b study of the anticancer stem cell agent demcizumab (DEM) and gemcitabine (GEM) with or without paclitaxel protein bound particles (nab-paclitaxel) in patients with pancreatic cancer.
Authors: Gracian Antonio Cubillo , Jameson Michael B. , Grande Enrique , Cooray Prasad , Parnis Francis , Grimison Peter , Jeffery Mark , Stagg Robert J. , Dupont Jakob , Tebbutt Niall C. 
Published: February 2017

279 Background: Delta-like ligand 4 (DLL4) is a ligand that activates the Notch pathway. DEM is a humanized IgG2anti-DLL4 antibody that inhibits tumor growth and decreases cancer stem cell (CSC) frequency in minimally passaged human xenograft models. In addition, DEM has been shown to have an antiangiogenic effect and showed synergistic activity when combined with GEM and nab-paclitaxel in human pancreatic tumor-derived xenograft models. Methods: Pts with 1st line stage pancreatic cancer received DEM (2.5 every 2 or 4 wks or 5 mg/kg every 4 wks) and GEM 1000 mg/m27 of 8 wks, then 3 of every 4 wks. The primary objective was to determine the MTD of DEM. Other objectives were safety, efficacy, immunogenicity, PK and biomarkers of Notch signaling and CSCs. Results: Twenty four pts were enrolled; 8 received 2.5 mg/kg every 2 wks, 8 received 2.5 mg/kg every 4 wks & 8 received 5 mg/kg every 4 wks of DEM. Three (12.5%) and 21 (87.5%) pts had stage III and IV disease, respectively. Related AEs (all grades) in > 15% of pts were: fatigue (29%), hypertension (29%), vomiting (29%), nausea (25%), thrombocytopenia (21%) and decreased appetite (21%). The hypertension was managed with oral anti-hypertensives. Increased BNP values appear to be an early indicator of the cardiac effects of DEM and mildly elevated values are being used to initiate cardioprotective therapy with an ACE inhibitor or carvedilol. One pt who received 5 mg/kg developed reversible pulmonary hypertension and heart failure on study day 143. As a result, the duration of DEM will be limited to 70 days in subsequent cohorts. Four of 16 (25%) pts had a RECIST partial response and 7 had stable disease. The median PFS for the 5 mg/kg cohort was 5.9 months. The PK and immunogenicity data will also be presented. Conclusions: DEM plus GEM were generally well tolerated with fatigue, hypertension, and vomiting being the most common drug related AEs. Encouraging early clinical activity was observed. The duration of DEM is being limited to 70 days and nab-paclitaxel is also being given in subsequent cohorts. The first cohort of pts receiving GEM, nab-paclitaxel, and DEM has been enrolled and > 100 days of follow-up on these pts will be presented. Clinical trial information: NCT01189929.
Neoadjuvant chemotherapy with gemcitabine and S-1 for resectable and borderline pancreatic ductal adenocarcinoma: A prospective, multi-institutional, phase II trial.
Authors: Mizuma Masamichi , Motoi Fuyuhiko , Ishida Kazuyuki , Fujishima Fumiyoshi , Ottomo Shigeru , Oikawa Masaya , Okada Takaho , Shimamura Hiromune , Takemura Shinichi , Ono Fuminori , Akada Masanori , Nakagawa Kei , Katayose Yu , Egawa Shinichi , Unno Michiaki 
Published: February 2017

283 Background: Although surgical resection is the only curative treatment for pancreatic ductal adenocarcinoma (PDAC), recurrence rates are very high even if complete resection is performed. Accordingly, a new therapeutic strategy against PDAC is needed. Combination with gemcitabine and S-1 (GS) as first line chemotherapy is promising. The purpose of this study is to evaluate the feasibility and efficacy of GS for resectable and borderline PDAC in the neoadjuvant chemotherapy (NAC). Methods: This study is a prospective, multi-institutional, single-arm, phase II trial. Neoadjuvant chemotherapy with gemcitabine and S-1(NAC-GS) for resectable and borderline PDAC was performed as follows. Gemcitabine was given at a dose of 1,000 mg/m2 on days 1 and 8 of each cycle. S-1 was administered orally at a dose of 40 mg/m2 twice daily for the first 14 consecutive days followed by a 7-day rest. Each cycle was repeated every 21 days. The primary endpoint was the 2-year survival rate. Secondary endpoints were feasibility, resection rate, pathological effect, recurrence-free survival and tumor marker status. Results: 36 patients were enrolled between 2008 and 2010. 35 were eligible for participation in this trial. The most common toxicity was neutropenia in response to 90% of the relative dose intensity. Radiological tumor shrinkage and decreases of CA19-9 levels were seen in 69% and 89%, respectively. R0 resection rate was 87%, and the morbidity rate (40%) was acceptable. The 2-year survival rate of the total cohort was 45.7%. Patients undergoing surgical resection without distant metastases after NAC-GS (n=27) showed an increased median overall survival (34.7 months), compared with 10.0 months for resection with distant metastases or non-resection (p=0.0017). Conclusions: NAC-GS is safe and well tolerated in a multi-institutional setting. NAC-GS is encouraging patients with resectable and borderline PDAC because of better outcomes. Clinical trial information: UMIN-000001504.
Multicenter phase I trial of sorafenib (S) in high-risk hepatocellular carcinoma (HCC) patients after liver transplantation (LT).
Authors: Siegel Abby B. , El-Khoueiry Anthony B. , Finn Richard S. , Goyal Abhishek , Blanke Charles David , Brown Robert S. 
Published: February 2017

285 Background: LT offers excellent long-term survival for HCC patients within the Milan criteria. For those outside Milan, recurrence rates are higher. No known treatments have been shown to decrease risk of recurrence post-transplant. Methods: Subjects had pathologically proven HCC that was outside Milan (pre- or post-transplant), was poorly differentiated, or had vascular invasion. We used a standard 3+3 design, beginning drug between 4 and 16 weeks after LT, with planned duration of treatment of 24 weeks. Cohort dosages were: 1) 200 mg q day, 2) 200 mg BID, 3) 200 mg/400 mg q day. Correlative studies included circulating endothelial cells (CECs-Veridex) and plasma biomarkers (VEGF, sVEGFR1, sVEGFR2, IL-6 and HGF) collected prior to treatment, at 1 month, and at recurrence. Results: We enrolled 14 patients; 93% were men. Median age was 63; 71% had underlying HCV, 21% HBV, and 21% ETOH. 57% were outside Milan on preoperative imaging. On explant, 29% had poorly-differentiated tumors, and 36% had vascular invasion. MTD was 200 mg BID; only 43% of patients received >80% of planned dose. DLTs included liver function abnormalities (1), transplant rejection leading to death (1), and grade 3 hypertension (1). Grade 3-4 toxicities seen in >10% of subjects included: leukopenia (29%), LFT abnormalities (21%), hypertension (14%), hand-foot syndrome (14%) and diarrhea (14%). Over a median follow-up of 836 days, 1 patient died and 4 recurred (median time to recurrence=716 days). Two recurrences were in subjects with limited exposure to S. Median CEC number at baseline was 16 cells/4 ml for those who recurred, and 42 cells/4 ml for those who did not (p=0.10). Median sVEGFR2 levels decreased after 1 month on S (p=0.09), but did not predict recurrence. Conclusions: To our knowledge, this is the first multicenter phase I trial of S completed in the post-transplant setting for high-risk HCC. MTD of S was 200 mg PO BID. Post-transplant S was feasible. Exploratory biomarker data suggest that low CECs at baseline were potentially associated with a higher recurrence rate. Time to recurrence was promising compared with historic controls, but needs to be further explored and validated in a larger study. Clinical trial information: NCT00997022.
A phase I trial of cixutumumab (C) (IMC-A12) and sorafenib (S) for treatment of advanced hepatocellular carcinoma (HCC).
Authors: El-Khoueiry Anthony B. , O'Donnell Robert , Mack Philip C , Blanchard Suzette , Bahary Nathan , Jiang Yixing , Yen Yun , Wright John Joseph , Chen Helen , Lenz Heinz-Josef , Gandara David R. 
Published: February 2017

293 Background: The insulin growth factor (IGF) pathway is activated in hepatocarcinogenesis. C is a monoclonal antibody against human insulin-like growth factor-1 receptor (IGF-1R). In vivo HCC models show activated IGF signaling and antitumor effects due to C. Given the cross-talk between the IGF and VEGF pathways, the combination of C and S was chosen for study. Methods: This study evaluated the safety of C (2, 4 or 6 mg/kg) IV weekly with standard doses of S (400 mg po bid) in patients (pts) with HCC without standard curative options. Eligibility criteria included: no prior systemic therapy, Child-Pugh score of A or B7, ECOG 0 or 1, platelets > 75,000/mm3, and albumin > 2.8 g/dl. The study used a standard 3+3 design. One cycle was 28 days. Results: A total of 21 pts (17 males and 4 females) were enrolled; mean age was 63 years (43-85); 10 Asian, 4 Hispanic, 5 White, 1 Black, and 1 Native American. There were 3 dose limiting toxicities (DLTs); grade 3 hyperglycemia, grade 3 hypophosphatemia, and grade 5 peritonitis (table). The maximum tolerated dose (MTD) was C 4 mg/Kg and S 400 mg BID. Eighteen of 21 (86%) pts had ≥ grade 3 toxicities attributable to treatment. Grade 3 adverse events that occurred in ≥ 2 pts were: diarrhea (4; 19%), hypertension (4; 19%), thrombocytopenia (3; 14%), palmar-plantar erythrodysesthesia (2; 10%), hyperglycemia (2; 10%), and fatigue (2; 10%). There was one grade 4 colonic perforation and one grade 5 peritoneal infection in the same pt. The median number of cycles completed was 4 (0-19 cycles). Sixteen of the 21 pts completed 2 cycles and were evaluated for response. Thirteen of the sixteen (81%) (95% CI: 54%-96%) achieved stable disease. The median event-free survival was 3.8 months (95%CI: 1.9, 11.3). The median OS was 13.1 months (95% CI: 7.6, undefined). Conclusions: The majority of adverse events in pts treated with the combination of C and S were typical of sorafenib toxicity. There was preliminary evidence of efficacy as seen in the median OS. Analysis of biomarker correlative data is on-going. Clinical trial information: NCT01008566. [Table: see text]
Neoadjuvant chemoradiotherapy with S-1 in patients with borderline resectable pancreatic cancer.
Authors: Hattori Masashi , Fujii Tsutomu , Suenaga Masaya , Yamada Suguru , Kanda Mitsuro , Iwata Naoki , Kobayashi Daisuke , Tanaka Chie , Nakayama Goro , Sugimoto Hiroyuki , Koike Masahiko , Nomoto Shuji , Fujiwara Michitaka , Kodera Yasuhiro 
Published: February 2017

302 Background: The aim of this study was to investigate the efficacy and safety of neoadjuvant chemoradiotherapy (NACRT) with S-1 (oral fluoropyrimidine) followed by surgery for the treatment of borderline resectable pancreatic cancer that involved the major visceral artery or the portal venous system. Methods: Twenty-eight patients with pancreatic cancers that abutted the SMA in 10, the CHA in 7, the both SMA and CHA in 1, and occluded the SMV/PV in 10 were treated with NACRT at a single institution. Radiation therapy was delivered at a total dose of 50.4 Gy in 28 fractions. S-1 was administered orally at a dose of 80 mg/m(2)/day for 14 consecutive days followed by a 7-day rest period during radiation therapy. After radiotherapy and 2 courses of S-1, restaging was done to evaluate secondary resectability. Results: Of the all patients, 25 underwent a full course of NACRT, and NACRT terminated in 3 patients because of grade 3 leukopenia in 2 and tumor bleeding in 1. Partial response was achieved in 3 patients and stable disease in 22. Twenty-four patients (86%) underwent surgical resection, and all had margin-negative (R0) resections. Only two patients (8%) had major morbidity as Clavien-Dindo’s classification III or more, and there was no operative or in-hospital mortality. Pathological examination revealed that more than 50% of tumor cells had disappeared in 14 cases and all cases achieved Evans’ score IIa and more. Conclusions: Neoadjuvant chemoradiation with S-1 was feasible and promising therapy for borderline resectable pancreatic cancer that involves the major artery or the portal venous system.
Effects of valproic acid as a histone deacetylase inhibitor in combination with S-1 on advanced pancreatobiliary tract cancers: Clinical study phases I and II.
Authors: Iwahashi Shuichi , Shimada Mitsuo , Utsunomiya Toru , Morine Yuji , Imura Satoru , Ikemoto Tetsuya , Arakawa Yusuke , Kanamoto Mami , Saito Yu 
Published: February 2017

306 Background: Pancreatobiliary tract cancers are the most aggressive of human cancers. Histone deacetylase (HDAC) is well known to be associated with tumori-genesis through epigenetic regulation, and its inhibitors (HDACIs) induce differentiation and apoptosis of tumor cells. We are conducting a clinical trial of combination therapy using valproic acid (VPA, a HDACI) and S-1, that is an oral fluoropyrimidine derivative consisting of 5-fluorouracil. Methods: Patients with advanced pancreatobiliary tract cancers were eligible for this clinical trial. The 12 patients, in whom a curative operation was not feasible, were enrolled in this study. Patients received S-1 orally at 80 mg/m2 total daily dose on days 1 to 28, followed by a 14 day recovery period. They also received VPA orally at 15 mg/m2 total daily dose, twice daily. Results: One patient had partial response (PR); ten patients were recorded as stable disease (SD); and one patient showed progressive disease (PD). Eight patients had clinically significant drug-related adverse events. The most frequent adverse events were platelet depletion and fatigue. Grade 3/4 adverse events, including anemia and platelet depletion, were observed. Significant increases in the blood concentrations of VPA were confirmed two and four weeks after VPA administration. Conclusions: This clinical study suggests that the combination therapy of VPA and S-1 for the patients with pancreatobiliary tract cancers had a manageable safety profile and preliminary antitumor activity. Clinical trial information: 000004525.
Survival trends in unresectable hepatocellular carcinoma and the effect of DEB-TACE: SEER versus tertiary cancer center.
Authors: Xing Minzhi , Prajapati Hasmukh J. , Kokabi Nima , Camacho Juan C. , El-Rayes Bassel F. , Kim Hyun Sik 
Published: February 2017

308 Background: Long-term survival in patients with advanced unresectable hepatocellular carcinoma (HCC) treated with drug-eluting bead transarterial chemoembolization (DEB-TACE) vs. best supportive care has not been investigated in large-scale population studies. Methods: Under IRB approval, our institute’s cancer registry was queried for patients with advanced unresectable HCC diagnosed from Sept 2005 to Dec 2010, treated with DEB-TACE. Eighteen registries of the U.S. Surveillance, Epidemiology and End Results (SEER) database were queried for patients with advanced HCC not amenable to surgery/radiation diagnosed in the same time period. Baseline characteristics, median overall survival (OS) from HCC diagnosis and median OS from first DEB-TACE were stratified by national/state cohorts. Survival analysis and 95% confidence intervals (CI) were calculated using Kaplan-Meier estimation. Results: A total of 231 patients who underwent DEB-TACE for unresectable HCC (Group A) and 20,897 patients with unresectable HCC who received neither radiation nor cancer-directed surgery (Group B) were included. Both groups were similar for mean age at diagnosis, gender, race, bilobar disease, portal vein thrombosis and mean largest tumor size (p>0.05). Median OS from HCC diagnosis was 21.8 months (Group A; 95% CI, 18.1-25.4) and 4.0 months (Group B; 95% CI, 3.9-4.1), p<0.001. Median OS from first DEB-TACE was 15.0 months (Group A; 95% CI, 9.6-20.4). Interval survival rates from HCC diagnosis for Group A vs. B were: 99% vs. 65% (1 month), 92% vs. 49% (3 months), 75% vs. 36% (6 months), 58% vs. 35% (1 year), 36% vs. 9% (2 years), and 20% vs. 4% (3 years). Conclusions: DEB-TACE in patients with unresectable HCC demonstrated significantly greater median OS and favorable long-term survival rates compared to best supportive care in a population-based study. [Table: see text]
Relationship of ethnicity and overall survival (OS) in Asian patients (pts) on sorafenib for advanced hepatocellular carcinoma (HCC) in British Columbia, Canada.
Authors: Peixoto Renata D'Alpino , Renouf Daniel John , Gill Sharlene , Cheung Winson Y. , Kennecke Hagen F. , Lim Howard John 
Published: February 2017

311 Background: Although both the SHARP and the Asian-Pacific trials showed improved OS for sorafenib when compared to placebo, the magnitude of benefit was substantially less for Asian pts, who have a higher prevalence of hepatitis B (HBV) infection. Whether the worse prognosis is related to ethnicity or to the etiology of HCC remains unclear. BC has a sizeable Asian population that can provide a good comparison to Caucasian pts with HCC. The aim of this study was to identify prognostic factors among pts with HCC who received sorafenib. Methods: 257 consecutive pts with advanced HCC who initiated sorafenib from January 2008 to February 2013 were identified using our pharmacy database. Clinicopathological variables and outcomes were retrospectively collected. Prognostic factors were assessed by univariate (Kaplan-Meier curves and log-rank tests) and multivariate analyses (Cox proportional hazards models). Results: Median age was 62 years (range 22-93), 80.5% were men, and 37.7% were Asian. Among them, 34.2% had HBV and 29.6% had hepatitis C (HCV). In addition, 68.4% had cirrhosis and 46.3% had liver-limited disease. Median progression-free survival (PFS) was 3.7 months (95% CI 3.2-4.1). Median OS from initiation of sorafenib to death was 7.4 months (95% CI 5.7-9.1). On univariate analysis, good ECOG PS, AFP < 250 and history of HCV were associated with better OS (p < 0.001, 0.002 and 0.025, respectively). Ethnicity, age, gender, HBV, cirrhosis and extra-hepatic metastases were not significantly associated with OS. On multivariate analysis, good ECOG PS, AFP < 250 and HCV positivity correlated with better OS (p < 0.001, 0.001 and 0.006, respectively), while ethnicity did not. Conclusions: When treated with sorafenib at the same institution, Asians and Caucasians with advanced HCC had similar OS. ECOG PS, AFP and HCV were the only significant prognostic factors. A higher proportion of HCVpositivity might explain why the SHARP trial achieved better OS when compared to the Asian-Pacific trial.
Fifteen-year experience of all patients (pts) with small bowel adenocarcinoma (SBA), treated in a specialized gastrointestinal (GI) oncology unit: Royal Marsden (RM) experience.
Authors: Khan Khurum Hayat , Peckitt Clare , Sclafani Francesco , Trivedi Sachin , Jain Vikram Kumar , Stanway Susannah Jane , Cunningham David , Chau Ian 
Published: February 2017

316 Background: Small bowel adenocarcinoma (SBA) is a rare tumour with poor prognosis. There is paucity of published literature due to rarity of disease; we conducted this retrospective study to determine the clinical course and outcome along with prognostic factors in both early and later stage SBA. Methods: Clinical characteristics and outcomes of all pts treated consecutively in the GI Unit RM, 1996-2011 were recorded. The study endpoints were relapse free survival (RFS), progression free survival (PFS), and overall survival (OS), in early stage pts (G1) and in pts with advanced disease (presentation or relapse with un-resectable disease=G2). In G2 response rate (RR) to chemotherapy was determined. In both groups association to baseline prognostic factors were sought by performing Cox regression univariate analysis (UVA). Results: Eighty four pts with SBA were treated 1996-2011. A total of 48 presented with early stage disease (G1). In G1 (58.3% males; mean age, 57 years), 44/48 pts underwent R0 resection; 21 received adjuvant chemotherapy. RFS, PFS and OS in this group were 29.6 [95% confidence interval (CI) 3.3-55.9], 31.1 (CI=8.0-54.3) and 42.9 (CI=0-94.9) months (m), with median follow up of 76.4 m. Poor histological differentiation (p=0.025), abnormal CEA at presentation (P=0.082), and lymphovascular invasion (p=0.003) were prognostic of OS. G2 comprised of 36 pts with un-resectable disease along with 23 from G1 who subsequently relapsed [G2 (n=59); 52.5% males; mean age, 59 years]; 54 pts with metastatic and 5 with locally advanced disease; 78% received first-line chemotherapy. Overall RR of pts who received chemotherapy was 50%. OS and PFS were 12.8 (CI =8.4-17.2) and 8.8 (CI=5.5-12.3) m respectively; 1-year survival was 60.9% vs. 27.3% (no chemotherapy) (p=0.042). Abnormal albumin (0.041), platelet count (p=0.007) and CEA (p=0.025) were prognostic of OS in the chemotherapy group; doublet (18/41) versus triplet (23/41) chemotherapy were not prognostic (p=0.185). Conclusions: Pts with SBA and metastatic disease may derive benefit from systemic chemotherapy; prospective clinical trials are required to evaluate this further.