bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exposure-response (E-R) relationship of ramucirumab (RAM) from two global, randomized, double-blind, phase 3 studies of patients (Pts) with advanced second-line gastric cancer.
Authors: Tabernero Josep , Ohtsu Atsushi , Muro Kei , Van Cutsem Eric , Oh Sang Cheul , Bodoky Gyorgy , Shimada Yasuhiro , Hironaka Shuichi , Ajani Jaffer A. , Tomasek Jiri , Safran Howard , Chandrawansa Kumari , Hsu Yanzhi , Heathman Michael , Khan Azhar Z , Ni Lan , Melemed Allen S. , Gao Ling , Ferry David , Fuchs Charles S. 
Published: February 2017

121 Background: We evaluated the E-R relationship of RAM in pts with advanced gastric cancer from the REGARD and RAINBOW trials. Methods: Pts received RAM (8 mg/kg) or placebo (PL) q2w in REGARD; or RAM (8 mg/kg) or PL q2w + paclitaxel (PAC) 80 mg/m2 on days 1, 8, and 15 (28-day cycle) in RAINBOW. Sparse pharmacokinetic (PK) samples were collected; a population PK analysis was conducted. A model-predicted minimum concentration after first RAM dose (Cmin,1) was used for correlation with efficacy and safety variables. Kaplan-Meier, Cox regression, and logistic regression analyses evaluated E-R relationships. Results: Analyses included 72 RAM and 35 PL pts from REGARD and 321 RAM+PAC and 335 PL+PAC pts from RAINBOW. Conclusions: Ram was safe and effective at 8 mg/kg q2w. Population PK suggests higher RAM exposures were associated with longer PFS and OS, better hazard ratios, and increased toxicity. Further studies to validate the PK model and evaluate RAM dosing are warranted. [Table: see text]
A phase II trial of 5-weekly S-1 plus cisplatin (CDDP) combination with trastuzumab (Tmab) for HER2-positive advanced gastric or esophagogastric junction (EGJ) cancer: WJOG7212G (T-SPACE) study.
Authors: Miura Yuji , Takano Toshimi , Sukawa Yasutaka , Nosho Katsuhiko , Hironaka Shuichi , Mori Misuzu , Nishikawa Kazuhiro , Tokunaga Shinya , Okuda Hiroyuki , Tsuda Masahiro , Taku Keisei , Nishikawa Kazuo , Moriwaki Toshikazu , Yoshimura Kenichi , Boku Narikazu , Hyodo Ichinosuke 
Published: February 2017

126 Background: Five-weekly schedule of S-1 plus CDDP (5-weekly SP) is the standard first-line chemotherapy for the patients (pts) with advanced gastric cancer (AGC) in Japan. Tmab with fluoropyrimidine plus CDDP chemotherapy has shown a survival benefit for pts with HER2-positive AGC and EGJ cancer. However, little information on the efficacy and safety of 5-weekly SP combined with Tmab is available. Methods: We conducted a prospective, single arm, multicenter, phase II trial of 5-weekly SP (S-1 40-60 mg bid for 21 days plus CDDP 60 mg/m2on day 8, every 5 weeks) combined with Tmab (8 mg/kg as a loading dose then 6 mg/kg, every 3 weeks) for pts with HER2-positive (IHC 3+ or IHC 2+ and FISH positive) AGC or EGJ cancer. Primary endpoint was response rate (RR) evaluated by independent review committee, using RECIST v1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. With power of 80% and one-sided alpha of 10%, thirty-five pts were required to reject 40% of RR under expected 60% RR. During the study, protocol was amended based on the favorable accrual rate. Pts were enrolled over 35 to improve precision, until pts enrollment up to 55 (power 85% and alpha 5%) or the end of predetermined accrual period, whichever came first. Results: Between August 2012 to January 2014, 44 pts were enrolled. Pts’ characteristics were: males 34 (77%), median age 62.6 years, PS 0-1 42 (95%), primary tumor site of stomach 37 (84%), histology of diffuse type 18 (41%). IHC 3+ was recorded in 32 (73%) pts. The RR was 64% (95% CI 48-78, one-sided p<0.001). The median PFS was 6.0 months (95% CI 5.1-10.9). The median OS was not reached. The toxicities in the first four courses were assessed. The most common grade 3 to 4 adverse events were anorexia (23%), diarrhea (11%), neutropenia (23%), anemia (16%), and thrombocytopenia (11%). One (2%) treatment-related death was reported. Conclusions: 5-weekly SP combined with Tmab showed a good efficacy with acceptable toxicities for pts with advanced AGC or EGJ cancer. Clinical trial information: UMIN000008389.
The prognostic value of signet ring cell histology in resected gastric cancer.
Authors: Postlewait Lauren McLendon , Squires Malcolm Hart , Kooby David A. , Poultsides George A. , Weber Sharon M. , Bloomston Mark , Fields Ryan C. , Pawlik Timothy M. , Votanopoulos Konstantinos Ioannis , Schmidt Carl Richard , Ejaz Aslam , Acher Alexandra W. , Worhunsky David J. , Saunders Neil , Swords Doug S. , Jin Linda X. , Cho Clifford Suhyun , Cardona Kenneth , Staley Charles A. , Maithel Shishir Kumar 
Published: February 2017

128 Background: Conflicting data exist on the prognostic implication of signet ring cell (SRC) histology in gastric adenocarcinoma (GAC). Our aim was to assess the association of SRC with recurrence and survival in patients undergoing resection of GAC. Methods: All pts who underwent curative intent resection for GAC from 2000 to 2012 at 7 academic institutions comprising the US Gastric Cancer Collaborative were included. 30-day mortalities were excluded. Survival analyses included Kaplan Meier log rank and multivariate Cox regression. Primary endpoints were recurrence-free survival (RFS) and overall survival (OS). Stage-specific analysis was performed. Results: Of 965 pts, 768 met inclusion criteria. SRC was present in 39.5% and was associated with female gender (52.9% vs 38.6%; p<0.001), younger age (61 vs 67 yrs; p<0.001), poor differentiation (94.8% vs 50.3%; p<0.001), perineural invasion (PNI: 41.4% vs 23%; p<0.001), distal location (82.2% vs 70.1%; p<0.001), receipt of adjuvant therapy (63% vs 51.2%; p=0.002), and more advanced stage (Stage 3: 55.2% vs 36.5%; p<0.001). SRC was associated with earlier recurrence (56.7mo vs median not reached (MNR); p=0.009) and decreased OS (33.7mo vs 46.6mo; p=0.011). When accounting for other adverse pathologic features, PNI (HR 1.57; p=0.016) and higher TNM stage (HR 2.63; p<0.001) were associated with decreased RFS, but SRC was not. PNI (HR 1.53; p=0.006), higher TNM Stage (HR 2.10; p<0.001), greater size (HR 1.05; p=0.014), and adjuvant therapy (HR 0.50; p<0.001) were associated with OS. SRC was not an independent predictor of OS. Stage-specific analysis showed no association between SRC and RFS or OS in Stage 1 or 3. In Stage 2, SRC was associated with earlier recurrence (38.1mo vs MNR; p=0.005) but not OS. The negative association of SRC with decreased RFS persisted in multivariate analysis (HR 3.11; p=0.015). Conclusions: Signet ring histology is associated with other adverse pathologic features including higher grade and higher TNM stage but is not independently associated with reduced RFS or OS. Identification of signet ring histology during preoperative evaluation should not, in isolation, dictate treatment strategy.
Doubling of 30-day mortality by 90 days after esophagectomy: A measure of outcomes for quality improvement.
Authors: In Haejin , Palis Bryan E. , Posner Mitchell , Ferguson Mark K. , Winchester David P , Pezzi Christopher M 
Published: February 2017

134 Background: Delivery of high-quality cancer care critically relies on the ability to measure and compare quality for continuous improvement. For esophageal cancer, operative mortality has traditionally been assessed at 30 days. Ninety-day mortality has been suggested as a more appropriate indicator of quality particularly after complex cancer surgery. Our objectives were to: 1) compare 30- and 90-day mortality rates after esophagectomy; 2) compare drivers of 30- and 90-day mortality; and 3) examine whether 90-day mortality affects hospital rankings. Methods: Esophagectomies for non-metastatic esophageal cancer patients diagnosed between 2007 and 2011 were identified in the National Cancer Data Base (NCDB). Mortality rates were examined by patient demographics, tumor characteristics and hospital procedural volume. Risk-adjusted hierarchical logistic regression models examined hospital performance for mortality. Results: 15,805 esophagectomy patients at 977 hospitals were available for analysis. Ninety-day overall mortality was more than double the 30-day mortality (8.9% vs 4.2%, p<0.0001). In multivariate analysis, while both 30- and 90-day mortality were associated with patient factors such as age, comorbidity and hospital volume, only 90-day mortality was influenced by tumor and management related variables such as stage, tumor location and receipt of neoadjuvant therapy. Hospital performance was examined as top 10%, middle 10-90% and lowest 10% as ranked using risk-adjusted odds of mortality. There was moderate correlation between ranking based on 30- and 90-day mortality [weighted kappa = 0.45 (95% CI 0.39 - 0.52)]. Compared to 30-day mortality rankings, nearly 20% of hospitals changed their ranking category when 90-day mortality rankings were used. Conclusions: Ninety-day mortality provides additional information for surgical risk assessment and has the potential to greatly enhance data for quality improvement efforts. Data provided for hospital quality improvement should include 90-day mortality, along with 30-day mortality and annual volume.
Comparison of efficacy and tolerance of first-line palliative chemotherapy EOX and mDCF regimens in patients with locally advanced inoperable or metastatic gastric or gastroesophageal junction adenocarcinoma without overexpression of HER2 receptors.
Authors: Ochenduszko Sebastian , Konopka Kamil , Puskulluoglu Miroslawa , Urbanczyk Katarzyna , Budzynski Andrzej , Matlok Maciej , Lazar Agata , Sinczak-Kuta Anna , Krzemieniecki Krzysztof 
Published: February 2017

135 Background: The aim of the study was to compare efficacy and tolerance of first-line palliative chemotherapy EOX (epirubicin/oxaliplatin/capecitabine) and mDCF (docetaxel/cisplatin/5FU/leucovorin) regimens in patients with locally advanced inoperable or metastatic gastric or gastroesophageal junction adenocarcinoma without overexpression of HER2 receptors. Methods: Each chemotherapy regimen was assigned with 21 patients. Planned treatment consisted of 12 every-two-weeks mDCF cycles (docetaxel 40 mg/m2 day 1, leucovorin 400 mg/m2 day 1, 5FU 400 mg/m2 bolus day 1, 5FU 1000 mg/m2/d days 1 and 2, cisplatin 40 mg/m2 day 3) or 8 every-three-weeks EOX cycles (epirubicin 50mg/m2 day 1, oxaliplatin 130mg/m2 day 1, capecitabine 1250mg/m2/d days 1 to 21). The primary endpoint was overall survival in all patients who commenced at least one chemotherapy cycle. Results: Median progression-free survival was 5.8 months in EOX group and 7.5 months in mDCF group (p=0.11), and median overall survival was 8.5 months and 12.0 months respectively (p=0.219). Due to toxicity, patients in the EOX arm had more frequent reductions of cytostatics doses (42.9% vs 5.0%; p=0.009) as well as delays in the administration of subsequent chemotherapy cycles (81.0% vs 65.0%; p=0.424). Rates of all grade 3 or 4 adverse events were comparable between both arms (76.19% in the EOX vs 70.0% in the mDCF; p=1.000). Toxicities that occurred more frequently in the EOX group compared to mDCF group were: nausea (28.6% vs 5.0%; p=0.093), thromboembolic events (19.0% vs 10%; p=0.663) and grade 3 or 4 neutropenia (71.4% vs 55.0%; p=0.443). Conclusions: In this patients population with locally advanced inoperable or metastatic gastric or gastroesophageal junction adenocarcinoma without overexpression of HER2 receptors treatment with mDCF regimen was associated with a statistically non-significant 3.5 month longer median overall survival without increase in toxicity. Updated data will be presented.
ACEIs/ARBs to improve survival in advanced gastric cancer patients receiving S-1 plus cisplatin.
Authors: Kumekawa Yosuke , Wakatsuki Takeru , Osumi Hiroki , MATSUSHIMA TOMOHIRO , Nakayama Izuma , Ogura Mariko , Ichimura Takashi , Takahari Daisuke , Ozaka Masato , Suenaga Mitsukuni , Shinozaki Eiji , Chin Keisho , Mizunuma Nobuyuki 
Published: February 2017

174 Background: Gastric cancer is heterogeneous disease and male predominant incidence is recognized across the world. Interactions between tumor cells and microenvironments, such as cancer-associated fibroblasts (CAFs) and M2 macrophage, play an important role in cancer progression and CAFs and M2 macrophage predict worse outcomes in several types of cancer. Angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) are widely used in cardiovascular disease because these drugs reduced cardiovascular events via inhibiting fibroblasts and inflammation. Moreover these drugs improved survival in advanced pancreatic cancer gemcitabine (Br J Cancer, Nakai, 2010). Given that CAFs and M2 macrophage are associated worse outcomes and ACEIs/ARBs may inhibit these factors, we hypothesized that these drugs may improve survival in advanced gastric cancer. Methods: Two-hundred and twenty advanced gastric cancer patients were enrolled between Jan. 2007 and Dec. 2011. These patients were received S-1 plus cisplatin (SP) as the first-line therapy in our institute. We retrospectively analyzed whether ACEIs/ARBs could predict better survival. Primary endpoint was overall survival (OS) and endpoint was estimated using by Kaplan-Meier methods and compared by the log-rank test. Results: Median age was 61 years old and 68.1% of the patients were male. Eighteen of 220 patients took ACEIs and/or ARBs. No significant difference was shown in patient characteristics between two groups. Median survival time (MST) of all patients was 416 days. There was marginal differences between two groups; MST in ACEI/ARB group was 763 days and 412 days in non-ACEI/ARB group, respectively (HR, 0.59 ; 95% CI 0.34-1.05 ; P=0.071). After analyzing according to gender, MST in male was 997 days in ACEI/ARB group vs. 412 days in non-ACEI/ARB group (HR, 0.42 ; 95% CI 0.18-0.97 ; P=0.037); however, no significant difference was found in female (HR, 0.84 ; 95% CI 0.38-1.86 ; P=0.67). Conclusions: ACEIs/ARBs may have a favorable effect in gastric cancer; however, gender difference may be involved in their efficacy. Further clinical validations and molecular correlation analyses are warranted.
Randomized phase II study of FOLFOX +/- MET inhibitor, onartuzumab (O), in advanced gastroesophageal adenocarcinoma (GEC).
Authors: Shah Manish A. , Cho Jae Yong , Huat Iain Tan Bee , Tebbutt Niall C. , Yen Chia-Jui , Kang Alice , Shames David S. , Bu Lilian , Kang Yoon-Koo 
Published: February 2017

2 Background: Aberrant up-regulation of the MET/HGF pathway is associated with poor prognosis in multiple malignancies, including GEC. Onartuzumab (O) is a fully humanized, monovalent anti-MET antibody that inhibits HGF binding and receptor activation. We examined the efficacy and safety of mFOLFOX6 and O in the first-line setting for metastatic, HER2-negative GEC. Methods: This was a double-blind, placebo controlled phase II study in which patients were randomized 1:1 to mFOLFOX6 + O 10 mg/kg. Eligibility included no prior treatment for metastatic disease, age >18, ECOG 0-1, retained organ function, HER2-negative, and evaluable disease. The primary objectives were to detect a meaningful improvement in progression free survival (PFS) in the ITT population or the MET-positive (≥ 50% of tumor with moderate-strong intensity staining by IHC based on central review) subgroup. With 120 patients enrolled and 84 PFS events observed, the target HR was 0.7 in the ITT population, and 0.6 in the MET-positive subgroup (estimated 50% of total). Results: 123 patients (83 Asia/Pacific, 40 US) from 25 sites were from 7/2012-5/2013. The treatment arms were well balanced: median age (57 placebo (P), 58.5 O), male (n=36 (59%) P, n=40 (65%) O), and MET-positive (n=19 (33%) P, n=16 (28%) O). Serious adverse events were more frequent with O (55%) vs placebo (40%). Selected grade 3-5 adverse events observed at least 5% more commonly with O included neutropenia (58% vs 45%), thrombocytopenia (10% vs 3%), peripheral edema (10% vs 0), and pulmonary embolism (7% vs 2%). At data cutoff (29 Jan 2014), 96 patients had PFS events (n=46 (74%) O, n=50 (82%) P), with median PFS of 6.77 and 6.97 months, respectively (HR 1.08, 95% CI 0.71-1.63). In the MET-positive subgroup, median PFS was 5.95 months for O and 6.8 months for placebo (HR 1.38 [0.60-3.20]). No difference in efficacy was noted with alternate MET-positive definitions (50% vs 90% MET staining, and 1, 2, or 3+ intensity). Conclusions: The addition of O to mFOLFOX6 in metastatic GEC did not improve PFS in either an unselected population or in MET-positive patients as defined by IHC. Additional biomarker analyses are ongoing to identify patients that may benefit from MET inhibition. Clinical trial information: NCT01662869.
Urinary metabolomics of gastric cancer.
Authors: Chan Angela W , Mercier Pascal , Schiller Dan E. , Eurich Dean , Broadhurst David , Sawyer Michael B. 
Published: February 2017

22 Background: Gastric cancer (GC) has 70-75% mortality, attributable to delayed diagnosis. There is no standard screening in North America. Metabolomics is a systems biology approach to measure low molecular weight chemicals (metabolites) in body fluids or tissues to provide a phenotypic “fingerprint” of disease etiology. In this preliminary study it was hypothesized that metabolic profiling of urine samples using 1H-NMR spectroscopy could discriminate between resectable gastric adenocarcinoma (GC), benign gastric disease (BN), and healthy (HE) patients (pts). Methods: Midstream urine samples were collected, processed, and biobanked at -80°C, from 30 BN, 30 HE and 16 of 29 GC pts visiting three Edmonton clinics from August 2013 – January 2014. Thirteen of 29 samples were retrieved from a 2009-13 GC biobank. Samples were matched on age, gender and BMI. Using a validated standard operating procedure each sample was analyzed using high resolution 1H-NMR spectroscopy. Resulting spectral traces were converted into annotated and quantified metabolite profiles of 58 metabolites. Univariate and multivariate statistical analysis uncovered a disease specific biomarker profile. Partial Least Squares Discriminant Analysis (PLS-DA) developed a GC vs. HE discriminative model. A Receiver Operator Characteristic (ROC) curve was constructed. Results: There was no significant difference in metabolite profiles between GC and BN pts. However, univariate analysis revealed 13 metabolites that differed significantly between GC and HE (p<0.05). Correlation analysis, followed by PLS-DA produced a discriminative model with an area under ROC curve of 0.996, such that for a specificity of 100% the corresponding sensitivity was 93%. Conclusions: GC pts have a distinct urinary metabolite profile compared to HE controls; however in this study metabolic profiling was unable to discriminate GC from BN pts. This was probably due to sample size and phenotypic heterogeneity of BN patients. This preliminary study shows clinical potential for metabolic profiling for early GC detection.
Phase II study of front-line dovitinib (TKI258) versus sorafenib in patients (Pts) with advanced hepatocellular carcinoma (HCC).
Authors: Cheng Ann-Lii , Thongprasert Sumitra , Lim Ho Yeong , Sukeepaisarnjaroen Wattana , Yang Tsai-Sheng , Wu Cheng-Chung , Chao Yee , Chan Stephen Lam , Kudo Masatoshi , Ikeda Masafumi , Kang Yoon-Koo , Pan Hongming , Numata Kazushi , Han Guohong , Balsara Binaifer , Zhang Yong , Rodriguez Ana-Maria , Zhang Yi , Wang Yongyu , Poon Ronnie Tung-Ping 
Published: February 2017

237 Background: HCC is a highly vascularized tumor, and inhibition of angiogenesis by sorafenib (Sor)—a VEGFR and PDGFR inhibitor—delays tumor progression. However, angiogenic escape from Sor may result from activation of the FGFR pathway, which also plays an important role in angiogenesis. Dovitinib (Dov) inhibits FGFR as well as VEGFR and PDGFR. Here, we study frontline Dov vs Sor in pts with advanced HCC. Methods: Eligible pts in this open-label study had ≥ 1 measurable lesion at baseline. All pts were ineligible for or had disease progression after surgical and/or locoregional therapies. Prior systemic HCC therapy was not allowed. Pts were randomized to receive Dov (500 mg/day, 5 days on/2 days off) or Sor (400 mg twice daily) until disease progression, unacceptable toxicity, or death. No treatment crossover was allowed. The primary endpoint was overall survival (OS). The key secondary endpoint was time to tumor progression (TTP) by local investigator’s assessment (per RECIST v1.1). Results: Pts received Dov (n = 82) or Sor (n = 83). Most pts—43 (52.4%) in the Dov arm and 60 (72.3%) in the Sor arm—discontinued treatment due to progressive disease. Median OS (95% CI) was 34.6 wk (28.6-39.4 wk) for Dov and 36.7 wk (23.3-49.3 wk) for Sor; Kaplan-Meier HR, 1.27; 95% CI, 0.89-1.80. Median TTP (95% CI) was 17.6 wk (12.3-18.4 wk) and 17.9 wk (12.3-18.9 wk), respectively. In pts who received ≥ 1 dose of study drug, median duration of exposure was 2.5 mo for Dov (n = 79) and 3.2 mo for Sor (n = 83). The most common adverse events, regardless of cause, were diarrhea (62.0%), decreased appetite (43.0%), nausea and vomiting (40.5% each), fatigue (35.4%), rash (34.2%), and pyrexia (30.4%) in the Dov arm and palmar-plantar erythrodysesthesia syndrome (66.3%), diarrhea (42.2%), and decreased appetite (31.3%) in the Sor arm. VEGFR1 and HGF baseline plasma levels appear to be associated with OS only in the Dov arm. Median OS in the lower biomarker group for both VEGFR1 and HGF was 11 mo while it was 5.6 and 5.9 mo for VEGFR1 and HGF, respectively, in the higher biomarker group. Conclusions: Activity of Dov was not greater than that of Sor in frontline HCC. The safety profile was similar to that observed in other single-agent Dov trials. Clinical trial information: NCT01232296.