bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II trial of cabozantinib (XL-184) in patients with advanced cholangiocarcinoma.
Authors: Goyal Lipika , Yurgelun Matthew B. , Abrams Thomas Adam , Kwak Eunice Lee , Cleary James M. , Knowles Michelle , Regan Eileen , Gisondi Amy , Sheehan Susan , Zheng Hui , Zhu Andrew X. 
Published: February 2017

800 Background: Cholangiocarcinoma (CCA) carries a poor prognosis in advanced stages, and no standard treatment exists beyond the first line gemcitabine/platinum based combination regimen. Based on preclinical evidence of dysregulation of the VEGF and c-MET pathways in CCA, we performed a single arm phase II study of the dual VEGF receptor and c-MET small molecule inhibitor cabozantinib in patients with advanced CCA. Methods: All eligible pts had histologically confirmed unresectable or metastatic CCA and had progressed after 1 or 2 lines of systemic therapy. Pts were treated with cabozantinib 60mg orally daily continuously for 28 day cycles. Tumor assessments were obtained radiologically every 8 weeks. The primary endpoint was progression free survival (PFS). A Simon two stage design was used, and 9 of 20 pts had to be progression free at 16 weeks in order to proceed to the second stage. Results: Nineteen pts (male 32%; median age 67 years old; intrahepatic vs extrahepatic CCA, 95 vs 5%; 1 vs 2 previous lines of systemic therapy, 53% vs 47%%) were enrolled and all received at least one dose of study drug. After 12 pts failed to be progression free at 16 weeks, the study was terminated as it was determined that the criterion for proceeding to stage 2 could not be met. The median follow-up was 4.07 months (mos). No objective responses were seen. The median PFS was 1.77 mos (95% CI, 1.63-5.37), and the median overall survival was 5.20 mos (95% CI, 2.70-8.17). Eleven (58%) patients required dose reductions. Grade 3 and 4 adverse events occurred in 79% of pts and included neutropenia, epistaxis, hyperbilirubinemia, alkaline phosphatemia, AST/ALT elevation, anemia, lipasemia, and hypertension. One pt had a bowel perforation and another developed an enterocutaneous fistula while on the study drug. VEGF and c-MET pathway-related biomarker analysis is ongoing. Conclusions: Cabozantinib demonstrated limited antitumor activity in an unselected population of pts with advanced CCA. Despite close monitoring, a high rate of > grade 3 toxicities was observed at 60 mg daily dosing. This pt population may be more sensitive to drug doses tolerated by other solid tumor patient populations, and therefore, close monitoring remains critical for these pts in early phase clinical trials. Clinical trial information: NCT01954745.
Preoperative serum VEGF-A levels to predict survival for Caucasian and Asian patients undergoing resection for gastric adenocarcinoma.
Authors: Park Do Joong , Yoon Changhwan , Ku Geoffrey Yuyat , Coit Daniel G. , Strong Vivian E. , Yang Han-Kwang , Kim Hyung-Ho , Suh Yun-Suhk , Yoon Sam S. 
Published: February 2017

81 Background: Clinical trials in gastric adenocarcinoma (GC) patients of vascular endothelial growth factor A (VEGF-A) targeted therapies have suggested these therapies may be more effective in Caucasians (CA) than in Asians (AS). Methods: Levels of VEGF-A in serum were measured in CA and AS treated at two institutions prior to potentially curative surgical resection for GC, and levels were correlated with overall survival (OS). Results: There were significant differences in CA (n=118) and AS (n=115) in terms of age (median 66 vs. 59), use of neoadjuvant (52% vs. 14%) and adjuvant therapy (27% vs. 18%), tumor location (58% upper/GE junction vs. 80% distal/middle), Lauren classification (57% vs. 46% intestinal), and TNM status (65% stage II or III vs. 55% stage I). CA had a median VEGF-A levels that was 95% higher than that of AS as well as a much higher standard deviation (88.1 + 6206 vs. 45.2 + 76.3 pg/ml, p<0.001). CA with proximal/nondiffuse tumors had significantly higher VEGF-A levels than those with distal/nondiffuse or diffuse tumors (median 120 vs. 71 and 50 pg/ml; p=0.016). The 5-year OS for CA with low vs. high VEGF-A levels was 72.4% vs. 43.4% (p=0.001). In AS, there was no significant difference in 5-year OS according to VEGF-A level (77.4%% vs.85.6%, p=0.236). On multivariate analysis, tumor size, location, grade, N stage, and serum VEGF-A level were independent predictors of OS in CA. Conclusions: In patients with resectable GC, higher circulating VEGF-A levels are independently associated with decreased OS in CA but AS, suggesting varying importance of this angiogenic factor in GC progression among different races.
Her2 expression in gastroesophageal cancer (GEC) FFPE tissue using mass spectrometry (MS) and correlation with HER2 gene amplification.
Authors: Catenacci Daniel Virgil Thomas , Zhao Lei , Whitcomb Emma , Henderson Les , O'Day Emily , Xu Peng , Xiao Shu-Yuan , Lee Sang Mee , Liao Wei-Li , Thyparambil Sheeno P , Uzzell Jamar , Darfler Marlene , Krizman David , Burrows Jon , Hembrough Todd A. 
Published: February 2017

82 Background: HER2+ GEC derived benefit from trastuzumab. Her2 IHC is semi-quantitative, subjective, and sensitive to antigen instability; HER2 FISH is laborious, expensive, and subjective. False positivity/negativity have been described. Also, these are low throughput assays; there is known molecular heterogeneity, with several putative biomarkers, and only scarce tissue to assess for each. We sought to evaluate the association of Her2 MS expression with HER2 FISH, along with other markers within the ‘GEC-plex’. Methods: We utilized a previously described unique Her2 peptide and quantification method (Hembrough et al J Clin Oncol 32,2014(suppl 3;abstr17)). The assay was run on 27 cell lines, in parallel with HER2:CEP17 FISH. Her2 expression thresholds were established for HER2 amplification using ROC curves. We adjusted for Her3, Egfr, and Met MS expression levels and sample HER2:CEP17 ratio heterogeneity in a multiple linear regression model. The model/cut-offs were then validated prospectively on GEC tissues (n=142). Results: Her2 MS on cell lines revealed concordance with FISH (HER2:CEP17) ratio (R2=0.75), which improved by adjusting for Her3 MS, Egfr MS, Met MS and HER2:CEP17 heterogeneity (R2>0.98), with significant interactions. IHC correlation with HER2:CEP17 ratio was poor (R2=0.12). A wide range of expression was noted within IHC3+ patients (<150-24671amol/ug). Her2 MS expression (>150 amol/ug) was seen in 72.9% (102/142) of tissues (range <150-24671amol/ug); 9.9% (14/142) had Her2 > 750 amol/ug - all were HER2 FISH amplified. 6/142 (4%) cases <500 amol/ug were clinically ‘HER2amplified’. IHC/FISH results for cases with 550-750 amol/ug demonstrated an ‘equivocal’ zone, not unlike ‘IHC 2+’, but less frequent (8/142, 5.6% vs 46/142 32.4%). Conclusions: The MS HER2 assay can be multiplexed with other GEC biomarkers. A robust model was developed that showed strong correlation of Her2 MS with HER2:CEP17 ratio, particularly when adjusting for covariates Egfr MS, Met MS, Her3 MS, and HER2 FISH heterogeneity. Future analysis will assess the established model as a tool for better prediction of therapeutic benefit from anti-Her2 therapy compared to current methods.
Frequency of c-Met, HGF, and HER-2 expression and evaluation of their association with clinicopathologic and prognostic factors in gastric cancer.
Authors: Yalcin Suayib , Yildiz Yetkin , Sokmensuer Cenk 
Published: February 2017

88 Background: Met and HER-2 are protoonkogenes encoding receptor tyrosin kinases c-Met and HER-2 respectively. HGF is c-Met’s ligand. We aimed to determine the frequency of c-Met, HGF and HER-2 overexpression in gastric cancer and investigated their association with clinicopathological factors and prognosis. Methods: Patients withstage 1-4 disease were analyzed. Overexpressions of c-Met, HGF and HER-2 were carried out with immunohistochemistry. Results: A total of 143 patients, 97 male 46 female were enrolled. C-Met score was 3(+) in 31.5%, 2(+) in 27.3% and 1 (+) in 10.5% of the patients. There was no statistically significant difference in age, sex, tumor location, differentiation, Lauren classification, TNM staging, presence of distant metastasis, depth of tumor invasion (T), lymphovascular invasion, and survival between c-Met subgroups. HGF positivity was 20.6%. HER-2 was 3(+) in 9.1%, 2(+) in 9.8%, and 1(+) in 16.1% of the patients. HER-2 overexpression was associated with better differentiation, intestinal subtype and advanced stage. C-Met overexpression was 84.6% in HER-2 overexpression positive group and 56,2% in HER-2 overexpression negative group. There was no statistically significant difference in survival between the c-Met overexpression positive and negative stage 3 and 4 patients and there was no statistically significant differences in survival between the HGF positive and negative groups. The median survival was 11.6±6.3 months in HER-2 overexpression positive stage 4 group and 11.9±6.8 months in HER-2 overexpression negative stage 4 group. There was no statistically significant differences in survival between the two groups. Conclusions: C-Met was not associated with any negative prognostic factors in gastric cancer. HER2 was associated with better differentiation, intestinal subtype, advanced stage and c-met overexpression. HGF expression was not asscociated with any clinicopathological factor.
INTEGRATE: A randomized phase II double-blind placebo-controlled study of regorafenib in refractory advanced oesophagogastric cancer (AOGC)—A study by the Australasian Gastrointestinal Trials Group (AGITG), first results.
Authors: Pavlakis Nick , Sjoquist Katrin Marie , Tsobanis Eric , Martin Andrew , Kang Yoon-Koo , Bang Yung-Jue , O'Callaghan Christopher J. , Tebbutt Niall C. , Rha Sun Young , Lee Jeeyun , Cho Jae Yong , Lipton Lara Rachel , Burnell Margot J. , Alcindor Thierry , Strickland Andrew , Wong Mark , Kim Jin Won , Simes John , Zalcberg John Raymond , Goldstein David 
Published: February 2017

9 Background: Advanced Oesophago-Gastric Carcinoma (AOGC) has limited options following failure of first or second line chemotherapy (CT). Regorafenib (REG) is an oral multi-kinase inhibitor of kinases involved in angiogenesis, tumor microenvironment, and oncogenesis. This study examined whether REG has sufficient activity and safety for further evaluation. Methods: International (Australia & New Zealand (ANZ), Korea, Canada (NCIC CTG)) randomised phase II trial with 2:1 randomisation and stratification by: (1) Lines of prior CT for advanced disease (1 vs. 2) and (2) Region. Eligible patients received best supportive care plus 160mg REG or matching PBO orally on days 1-21 each 28-day cycle until disease progression or prohibitive adverse events. Primary endpoint was progression free survival (PFS) in the REG arm, assuming median 8 weeks (wks) in PBO arm, aiming for 13.2 wks with REG to be of interest. Results: From Nov 2012 to Feb 2014, 152 patients were enrolled, 147 evaluable [pre-specified primary analysis population]: (REG n=97: PBO n=50); well matched for key baseline prognostic indicators; male:female (118:29); primary location: OG Junction (56), stomach (85); lines of prior therapy: 1 (63), 2 (84); ECOG 0 (62): 1 (85). Time on treatment: Median: 7.9 (REG) v 4 (PBO) wks. In the evaluable population median PFS was 11.1 wks (95% CI: 7.7 - 12.3) (REG) and 3.9 wks (95% CI: 3.7 - 4.0) (PBO), log-rank p <0.0001; HR 0.41 (95% CI: 0.28 to 0.59). PFS results were maintained for secondary analysis including all randomized patients (n = 152). REG was well tolerated, with the spectrum of toxicity in keeping with previous reports. Conclusions: PFS was clearly significantly longer with REG than PBO, though PBO PFS was less than anticipated. The pre-specified exploratory comparisons provide compelling evidence that REG has sufficient activity with acceptable tolerability in refractory AOGC to warrant phase III evaluation. Mature OS results will be presented at the meeting. Clinical trial information: 12612000239864.
Effect of renal function on continuation of S-1 adjuvant chemotherapy in gastric cancer patients.
Authors: Makihara Katsuya , Azuma Sayaka , Ueno Hiroyuki , Nakata Izumi , Yamamoto Kazuyoshi , Nishikawa Kazuhiro , Hirao Motohiro , Fujitani Kazumasa , Tsujinaka Toshimasa 
Published: February 2017

90 Background: The results of ACTS-GC study showed that postoperative adjuvant chemotherapy with S-1 is the standard treatment for patients with stage II and stage III gastric cancer (GC) in Japan. In addition, completion of 12 months of S-1 treatment and a high relative performance (RP) value were reported to be related to improved survival. The plasma 5-fluorouracil concentration in patients receiving S-1 treatment is known to be significantly higher in patients with 50 ≤ Ccr < 80 mL/ min than in those with Ccr ≥ 80 mL/ min. The aim of this study was to investigate the association of the dose of S-1 based on renal function and compliance with S-1 treatment. Methods: This study is retrospective cohort study, included GC patients who were administered S-1 adjuvant chemotherapy at the Osaka National Hospital in Japan between August 2006 and August 2013. Cohort A comprised patients with Ccr ≥ 80 mL/min, those with 50 ≤ Ccr < 80 mL/min and dose reduction by one level, and those with Ccr < 50 mL/min and dose reduction by two levels. Cohort B included patients with Ccr < 50mL and dose reduction by one level. We compared the completion rate of 12 months of S-1 treatment and the RP value between cohorts A and B. Results: In total, 103 patients were included in this study: cohort A included 53 patients, and cohort B included 50 patients. The completion rate of 12 months of S-1 treatment was significantly higher in cohort A at 83% than in cohort B at 56% (OR: 3.8 [95% CI: 1.6–9.9], p = 0.003). The median RP value was significantly higher in cohort A at 93.8% than in cohort B at 74% (p = 0.007). In the subgroup analysis, no difference was found in the completion rate among patients with S-1 dose < 65 mg/m². Conclusions: Renal function was found to be an important factor for compliance with S-1 treatment as adjuvant chemotherapy for GC. The results of the present study suggest the need for dose reduction by one level in patients with Ccr < 80 mL/min.
The treatment of esophageal cancer by vascular-targeted photodynamic therapy (VTP) using orthotopic rat model.
Authors: Uzana Ronny , Preise Dina , Agemy Lilach , Elmoalem Rachel , Brandis Alexander , Belkin Varda , Salomon Yoram , Scherz Avigdor 
Published: February 2017

91 Background: Vascular targeted photodynamic therapy (VTP) based on local sensitization of circulating WST11, a water-soluble derivative of Pd-bacteriochlorophyll, enables effective focal ablation of solid tumors. Highly toxic oxygen radicals are produced in the vascular lumen upon illumination with near infra-red light (755nm), leading to irreversible occlusion of tumor feeding arteries and veins. WST11 clears rapidly from the circulation and does not accumulate in the body, providing high level of safety and minimizing adverse effects. WST11-VTP completed Phase II clinical trials in USA and Phase III in Europe for the treatment of early localized prostate cancer as a first line monotherapy with above 80% complete response rate. Here we evaluate its’ safety and efficacy for the treatment of esophageal cancer aiming at development of clinically translatable treatment protocol. Methods: We developed an orthotopic model in which esophageal cancer cells are implanted in the mid esophagus using endoscopy guided procedure. Established tumors are illuminated with cylindrical diffuser deployed through the custom built endoscopy guided system following infusion of WST11. For assessment of treatment safety and tissue recovery normal esophagus tissue was subjected to WST11-VTP using the same treatment set up. Selectivity and efficacy were evaluated histologically by examining sections of treated tumors and normal esophageal tissues under various treatment conditions. Results: Safety control VTP procedures on healthy esophageal tissues have shown a confined destruction only at the illuminated zone while collateral damage to neighboring tissues was not observed. The impact runs as deep as the muscularis propria without signs of perforation or death as a result of the procedure. The VTP protocol was able to ablate implanted and established tumors as opposed to the control group with light illumination alone without the sensitizer (WST11). Conclusions: VTP could be safely applied to treat esophageal tumors, with transient and mild adverse effects. Importantly, VTP effectively eradicated established esophageal tumors in tested set up that could be translated into a clinical treatment protocol.
Association between intratumoral HER2 heterogeneity (IHH) and trastuzumab (T-mab) efficacy in HER2 positive–gastric cancer (GC).
Authors: Wakatsuki Takeru , Yamamoto Noriko , Chin Keisho , Ogura Mariko , Shinozaki Eiji , Suenaga Mitsukuni , Ozaka Masato , Matsusaka Satoshi , Takahari Daisuke , Ichimura Takashi , Kumekawa Yosuke , Nakayama Izuma , MATSUSHIMA TOMOHIRO , Mizunuma Nobuyuki , Sano Takeshi , Yamaguchi Toshiharu , Ishikawa Yuichi 
Published: February 2017

92 Background: ToGA study showed superiority of adding T-mab to standard chemotherapy and a positive correlation between HER2 expression levels and the T-mab efficacy. In gastric cancer IHH is frequently recognized but its clinical impact on T-mab efficacy is unclear. Methods: Patients who were treated with T-mab and had surgical specimens available for IHC test were retrospectively examined. When all tumor cells overexpressed HER2 protein by IHC, the tumor was defined as non-HER2-heterogeneous. The others were defined as HER2-heterogeneous. Progression-free survival (PFS) and overall survival (OS) were estimated using by Kaplan-Meier methods and compared by the log-rank test. The level of significance was set to p<0.05 and all statistical tests were two-sided. Results: 23 patients were enrolled. Their median age was 68 years and 83% were male. PS 0, GEJ cancer, intestinal type histology, visceral metastasis (lung or liver), and previous chemotherapy were found in 57%, 35%, 83%, 57%, and 57% of them, respectively. After a median follow-up of 11.3 months, the median OS, PFS, and overall response rate were 14.4 months, 10.8 months, and 62.5%, respectively. All tumors were IHC3+, and 13 were non-HER2-heterogeneous and 10 were HER2-heterogeneous. There was no significant difference in clinicopathological features between the two groups. Median PFS in non-HER2-heterogeneous group (21.9 months) was significantly longer than that in HER2-heterogeneous group (8.6 months), (HR: 0.24 [0.06-0.91], P=0.024). Median OS in non-HER2-heterogeneous group was not reached while that in HER2-heterogeneous group was 12.9 months (HR: 0.29 [0.06-1.42], P=0.102). A higher rate of response to T-mab was seen in non-HER2-heterogeneous group than in HER2-heterogeneous group, though the difference was not statistically significant (75% vs. 50%, p=0.608). Conclusions: IHH might have robust clinical impact on T-mab efficacy for HER2 positive GC. These findings should be validated by independent large cohorts and further molecular correlative analyses are warranted.
Potential of PAR1 to be involved in the acquisition of drug resistance in human gastric cancer cell.
Authors: Fujimoto Daisuke , Ueda Yuki , Hirono Yasuo , Goi Takanori , Yamaguchi Akio 
Published: February 2017

94 Background: Side Population (SP) is a FCM term to define cell clusters with strong ability to efflux DNA dye Hoechst 33342 by ABC transporters. In some cases, cancer stem-like cells (CSLCs) were identified using the FCM-based SP technique and SP cells had ability of drug resistance because SP cells were expressed ABC transporter. CSLCs may generate tumors through the stem cell processes of self-renewal and differentiation into multiple cell types. Such cells are proposed to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. We had showed PAR1 had an intimate involved in gastric cancer metastasis. And PAR1 contributed to leukemic stem cell maintenance. So we studied PAR1 induced SP cells acquired the ability of drug resistance in gastric cancer. Methods: MKN45 cells stably expressing PAR1 (45-PAR1) were generated in our laboratory. siRNA against PAR1 was synthesized. We studied the change in fraction of SP cell, when PAR1-expressing cell (45-PAR1 and MKN74), PAR1-null expressing cell MKN45 and inhibited PAR1-expressing MKN74 by PAR1 siRNA (74-PAR1siRNA) were treated with PAR1 agonist TFLLR-NH2 or TFLLR-NH2 plus PAR1 selective antagonist SCH79797. And, we compared the drug resistance using paclitaxel, cisplatin and 5-FU and researched ABC transporter expression in MKN45, 45-PAR1 and MKN74 with TFLLR-NH2 or SCH79797 or PAR1 siRNA. Results: We showed the fraction of SP cells in 45-PAR1 and MKN74 achieved dramatic increases by TFLLR-NH2. But, the fraction of SP cells in MKN45 and 74-PAR1siRNA remained about the same by TFLLR-NH2. When treated with SCH79797, the fraction of SP cells remained about the same, too. As for drug resistance assay, 45-PAR1 and MKN74 achieved the same strong resistance of the SP cells by TFLLR-NH2. But, MKN45 and 74-PAR1siRNA were not able to obtain the drug resistance. When treated with TFLLR-NH2, 45-PAR1 and MKN74 showed the high expression of ABCG1 and MRP1, that proteins are ABC transporters, compared to MKN45 and 74-PAR1siRNA. These expression levels in 45-PAR1 and MKN74 with TFLLR-NH2 were equal to the SP cells. Conclusions: PAR1 is closely-involved in that gastric cancer cells achieved the drug resistance and were led to SP enriched in CSLCs.
Multiomics profiling for gastric cancer using high-tech omics-based patient evaluation (HOPE).
Authors: Terashima Masanori , Oshima Keiichi , Kusuhara Masatoshi , Urakami Kennichi , Tokunaga Masanori , Tanizawa Yutaka , Bando Etsuro , Kawamura Taiichi , Makuuchi Rie , Miki Yuichiro , Hatakeyama Keiichi , Yamaguchi Ken 
Published: February 2017

95 Background: The Project HOPE (High-tech Omics-based Patient Evaluation) is an ongoing comprehensive platform that analyzes genome and transcriptome of fresh surgical specimens and blood samples obtained from cancer patients using whole-exome sequencing (WES, AmpliSeq Exome kit, Life Technology) and gene expression profiling (GEP, DNA microarray, Agilent Technologies). The research plan was approved by institutional review board (IRB) in Shizuoka Cancer Center, and total number of patients evaluated in this plan was about 3000 during the 3-year period of the research. Here, we focused on gastric cancer to investigate its characteristic profile. Methods: Tumor sample and peripheral blood was obtained from a total of 19 gastric cancer patients. At the initial stage of the study, the known mutation sites were analyzed by the WES, and expression level of cancer-related genes was evaluated by GEP. Results: Fourteen patients out of 19 patients (74 %) were categorized as advanced gastric cancer. The patients with single nucleotide variations (SNVs) in tumor protein P53 (TP53) accounted for 37% (7/19), and 21% (4/19) of patients had multiple SNVs in the known mutation sites. Furthermore, in two patients with gene amplification of ERBB2 or EGFR, mRNA expression corresponding these genes was markedly up-regulated. Conclusions: WES and GEP analyses may play an important role in interpretation of genetic changes of cancer tissues and personalized medicine.