bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of SLC15A2 genomic variation with the response to sorafenib treatment: Whole-genome analysis in patients with hepatocellular carcinoma.
Authors: Kim Bo Hyun , Lee Yeon-Su , Kim Byung Chul , Shin Aesun , Kim Jin Sook , Hong Seung-Hyun , Hwang Jung-Ah , Lee Jung Ahn , Nam Seungyoon , Lee Sung Hoon , Bhak Jong , Park Joong-Won 
Published: February 2017

308 Background: Reliable biomarkers are required to predict patient response to sorafenib. We attempted to investigate genomic variations associated with responsiveness to sorafenib treatment in patients with unresectable hepatocellular carcinoma (HCC) and their functional relevance. Methods: We obtained blood samples from 4 strong and 3 poor responders to sorafenib treatment and subjected these samples to whole-genome analysis. Next, we performed validation tests for candidate single-nucleotide polymorphisms (SNPs) in the samples of 174 HCC patients who were treated with sorafenib, followed by in vitro functional analysis and in silico analyses of candidate SNPs. Results: On average, 90 gigabases/sample was generated at ~34X sequencing depth. In total, 1813 genomic variations were perfectly matched to sorafenib responses in the clinical data; 708 were located within regions for sorafenib-target genes or drug absorption, distribution, metabolism, and excretion (ADME)-related genes—36 within the coding regions and 6 identified as non-synonymous single-nucleotide variants from 4 ADME-related genes (ABCB1, FMO3, MUSK, and SLC15A2), which potentially cause functional alterations. Validation tests of 174 patients confirmed sequencing results and revealed that patients with the C/C genotype for rs2257212 in SCL15A2 displayed higher risk for cancer progression than did patients with C/T or T/T genotypes (HR: 2.18; 95% CI, 1.15–4.15; P = 0.018). In vitro functional analysis revealed that cells harboring C/C genotype for this SNP displayed lower response to sorafenib treatment than did cells harboring the T/T genotype. Structural prediction analysis revealed change in protein phosphorylation levels, potentially affecting sorafenib-associated enzymatic activity. Conclusions: SLC15A2 could be a robust biomarker of response to sorafenib treatment in HCC patients.
Challenges with genomic testing in pancreaticobiliary cancers: Results of a prospective cohort study.
Authors: Sohal Davendra , Rini Brian I. , Estfan Bassam N. , Shepard Dale Randall , McNamara Michael J. , Dreicer Robert , Bolwell Brian James , Khorana Alok A. 
Published: February 2017

314 Background: Therapeutic options for advanced pancreaticobiliary (PB) malignancies may be improved by genomics-driven therapies. We conducted a prospective cohort study of outpatient genomic testing to identify prevalence of actionable alterations and therapeutic impact of such testing in PB cancers. Methods: Eligibility requirements included confirmed pathologic diagnosis of select solid tumor malignancies without a known curative option, age ≥ 18 years, and an ECOG performance status of 0-2. Data for the PB cancer subgroup are presented here. Tumor samples were sequenced for up to 315 candidate genes in collaboration with Foundation Medicine, Inc. (Cambridge, MA). Results were discussed at the Cleveland Clinic Genomics Tumor Board that made therapeutic recommendations to treating physicians. Results: From Aug 2013 to Aug 2014, samples from 228 patients were analyzed; 24 (11%) had PB cancers. For the latter subgroup, median age was 60 years; 14 (58%) were male; 20 (83%) were white. Twelve (50%) tumors were pancreatic, 11 (46%) from biliary tract/gallbladder, and 1 (4%) periampullary. Median time from consent to result was 24 (range, 3-84) days. Eight (33%) samples had inadequate tissue compared with 6/174 (3%) non-PB samples (p<0.001). Among patients with adequate tissue (n=16), a median of 3 (1-7) mutations were detected per sample; TP53 (50%), CDKN2A/p16 (44%) and KRAS (38%) were most common. A targeted therapy was recommended in 7 (44%) patients. Of these, 78% of recommendations were for specific clinical trials. To date, no patient with PB cancer has received a targeted therapy, compared with 6/45 (13%) patients with colorectal cancer (p=0.18). The most common reason for non-receipt of recommended targeted therapy was non-availability of clinical trials. Conclusions: Compared with other common solid tumors, genomic profiling in pancreaticobiliary cancers is challenged by paucity of diagnostic tissue collected during routine clinical care. Targeted therapy options (on-study or off-label) are few at this time. Precision oncology in pancreaticobiliary cancers will remain under-utilized until access to clinical trials is enhanced.
Tumor c-Met expression and prognosis of advanced hepatocellular carcinoma patients treated with sorafenib.
Authors: Shao Yu Yun , Hsiao Chi-Huang , Lee Ray , Puig Oscar , Chan Soa-Yu , Li Yong-Shi , Hsu Chih-Hung 
Published: February 2017

317 Background: Overexpression of c-Met signaling has been associated with development and progression of hepatocellular carcinoma (HCC). We explored the prognostic role of tumor c-Met expression in patients with advanced HCC. Methods: Patients who had received sorafenib alone as first-line therapy for advanced HCC and had available archival tumor tissues were enrolled. Expression of total c-Met was determined by immunohistochemical staining using CONFIRM anti-total c-MET (SP44) rabbit monoclonal primary antibody (Ventana) on the BenchMark ULTRA staining platform. We evaluated c-Met expression by H scores and by a clinical score as defined in the table. Results: The study enrolled 62 patients, all with Child-Pugh class A status. The HCC etiology was hepatitis B in 48 patients, and hepatitis C in 12 patents; 57 had BCLC disease; 40 had extrahepatic metastasis, and 37 had macrovascular invasion. Clinical scores of c-Met were 0 in 30 (48%) patients, 1 in 31 (50%) patients, 2 in 1 (2%) patients, and 3 in 0 patients. Patients with different clinical scores of c-Met had similar PFS (p = 0.821) or OS (p = 0.533). The median membranous H score and cytoplasmic score were 32.5 and 5, respectively. Patients with higher (≥ median) and lower c-Met membranous H scores or cytoplasmic H scores also had similar PFS and OS. Conclusions: High c-Met expression was rare in this advanced HCC cohort. Tumor expression of c-Met had no obvious associations with the prognosis of advanced HCC. (This study was supported by National Science Council, Taiwan (NSC-102-2314-B-002-120, NSC-103-2314-B-002-181-MY2, NSC-103-2314-B-002-092)). [Table: see text]
Oncologic impact of monocarboxylate transporter 4 (MCT4) in pancreatic cancer.
Authors: Lee Sung Hwan , Kang Chang Moo , Hwang Ho Kyoung , Lee Woo Jung 
Published: February 2017

319 Background: Transporters for monocarboxylate play an integral role in cancer metabolism in terms of the regulation of intracellular pH. The aim of our study is to check the oncologic impact of Monocarboxylate Transporter 4 (MCT4) expression in pancreatic cancer. Methods: To identify oncologic impact of MCT4 in pancreatic cancer, we performed immunohistochemical (IHC) stains for MCT4 in paraffin embedded block of resected pancreatic cancer tissue. MCT4 expression was correlated with short-term and long-term oncologic outcomes. Results: Fifty patients were enrolled to this study and formalin-fixed, paraffin-embedded (FFPE) tissue block of surgically resected pancreatic cancer and survival data were used for identify the oncologic impact of MCT4. Overall expression of MCT4 in pancreatic cancer was observed (84.5% above intensity grade 1) compared to normal pancreatic tissue in immunohistochemical stain. High expression of MCT4 was observed in twenty-two patients (44%). There were no statistical difference regarding tumor size, T-stage, N-stage, perineural invasion, lymphovascular invasion, tumor grade, R0 resection, and postoperative adjuvant treatment between high and low MCT4 expression group (p>0.05). However, high MCT4 expression group showed significantly poorer cancer-specific survivals than low expression group (median survival; 15 vs. 32 months, p=0.001). Conclusions: The expression of monocarboxylate transporter 4 (MCT4) was identified as poor prognostic factor in pancreatic cancer. Further study to identify the possibility of MCT4 as a potential therapeutic target for treating pancreatic cancer is mandatory.
Effect of neoadjuvant treatment with gemcitabine with nab-paclitaxel on SPARC and Ki-67 in patients with resectable pancreatic adenocarcinoma.
Authors: Sliesoraitis Sarunas , Collinsworth Amy L. , Trevino Jose Gilberto , Zlotecki Robert , Lu Xiaomin , Lightsey Judith L. , Allegra Carmen Joseph , Alkhasawneh Ahmad , Dang Long H. , Daily Karen Colleen , Behrns Kevin , Liu Chen , Hughes Steven J. , Ivey Alison Marguerite , Chauhan Shailendra , Desai Neelam Vijay , George Thomas J. 
Published: February 2017

322 Background: Nab-paclitaxel (nab-P) and gemcitabine (Gem) improve survival in metastatic pancreatic cancer (PCa). We sought to determine the impact of nab-P and Gem on the primary tumor and associated microenvironment in neoadjuvant treatment (NAT). Methods: All patients in the GAIN-1 study (NCT01470417) received NAT with nab-P and Gem with or without radiation depending on risk status. A comparator group without NAT was matched for age, sex, race, resection status, smoking, primary tumor site, and tumor size. Surgical specimens of tumor, associated stroma and lymph nodes were analyzed. Routine immunohistochemistry (IHC) for Ki-67 and TUNEL was performed. Immunolabeling was assessed using anti-SPARC antibody (Invitrogen) with scoring consistent with prior reports: Negative = intensity absent to weak (+) with extent <10%; Positive = intensity moderate (++) to strong (+++) with extent ≥ 10%. For Ki-67 and TUNEL, the percentage of positive tumor cells was averaged over four HPF/specimen. Study was conducted with IRB approval. Results: A total of 30 unique patients were included in this analysis, 8 NAT cases and 22 matched controls. Clinical outcomes have been previously reported. Minimal to no SPARC expression was noted in either group of tumor cells. However, stromal SPARC expression was markedly reduced in NAT group (mean 2.88 ± 0.69%) compared to controls (28.43 ± 5.80%; p = 0.0002). Ki-67 was reduced in NAT group compared to controls (10.5 ± 2.83% vs. 36.76 ± 4.32%; p = 0.0004). TUNEL stain revealed a trend toward lower levels in NAT group (mean 1.13 ± 0.30% vs. 1.62 ± 0.31%; p = 0.574). SPARC, Ki-67 and TUNEL did not correlate with survival. Conclusions: SPARC expression in pCa primary tumors is low. Neoadjuvant nab-P and Gem significantly decreased stromal SPARC and tumor Ki-67. There was no change in TUNEL expression, indicating a population of residual viable cells. Additional stromal microenvironment change analysis in response to treatment is ongoing.
RAS mutations and their correlation with survival of patients with advanced pancreatic adenocarcinoma.
Authors: Almeida Thiago Lins , Gomes Jessica Ribeiro , Machado Marcel Cerqueira Cesar , Buzaid Antonio C. , Maluf Fernando C. 
Published: February 2017

325 Background: The prognosis of pancreatic adenocarcinoma (PA) remains poor despite FOLFIRINOX and nab-paclitaxel-gemcitabine based chemotherapy. The epidermal growth factor receptor (EGFR) has a major role in pancreatic cancer carcinogenesis.The RAS status showed to be a predictive factor for response to anti-EGFR therapy in colon cancer. We aim to analyze the K-RAS and N-RAS status in PA and its prognostic impact. Methods: Retrospective analysis included 24 patients with metastatic (67%) or locally advanced (29%) PA at diagnosis (AEMOC, Brazil). K-RAS and N-RAS profile were performed by polymerase chain reaction and bidirectional sequencing (codons 12, 13, 61, 117, 146). The results were then analyzed in regards to overall survival (OS) and progression-free survival (PFS) in PA. Results: The sample showed: median age of 63 years (28-86), 62.5% male, 45.8% smoker, head site (67%), ductal (68%), and mild differentiation features (45%). The first-line therapy was FOLFIRINOX (62.5%) and gemcitabine (33.3%). The median PFS and OS were 6.5 and 13 months (mo), respectively. Nineteen patients (79.1%) presented mutation in K-RAS: four c.35G>A (G12D), four c.34G>C (G12R), four c.35G>T (G12V), three c.35G>C (G12A), one c.437C>T (A146V), and one c.34G>T (G12C). Mutation in N-RAS (c.38G>A (G13D) was detected in only one patient (4%). The only independent factor for survival was K-RAS status: the c.35G>A (G12D) polymorphism yielded worse PFS and OS when compared to non-c.35G>A (G12D) mutation: 3 vs 7 mo [HR 0.25, 95% CI, (0.04–1.63)] for PFS (p<0,0043) and 3.5 vs13 mo [HR 0.17, 95% CI, 0.01-1.58)] for OS (p<0,0001), respectively. Conclusions: K-RAS was the only prognostic factor for PFS and OS, with the polymorphism c.35G>A (G12D) being related to a worse prognostic. Further studies are necessary to better evaluate whether K-RAS and N-RAS status is prognostic and/or predictive factor.
Impact of preoperative neutrophil to lymphocyte ratio on long-term survival in patients with esophageal squamous cell carcinoma.
Authors: Kamachi Kenichi , Ozawa Soji , Kazuno Akihito , Makuuchi Hiroyasu , Oguma Junya , Yamasaki Yasusi , Ninomiya Yamato 
Published: February 2017

33 Background: Elevated neutrophil to lymphocyte ratio (NLR) reflects patients’ inflammation status and closely relates to tumor progression. The aim of this study was to evaluate the clinical significance of the preoperative NLR in patients who undergo an esophagectomy for esophageal squamous cell carcinoma. Methods: A total of 340 patients who underwent an esophagectomy for esophageal squamous cell carcinoma between 2003 and 2008 were retrospectively reviewed. The NLR ≥ 3 was considered to be elevated and the patients were divided into two groups. The overall and disease-free survival curves of the two NLR groups were determined using the Kaplan-Meier method and were compared using a log-rank test. A cox proportional hazards regression analysis was used for the univariate and multivariate analyses. Results: The study included 306 males and 34 females. Seventy-two patients (21%) had an elevated NLR. The 5-year overall survival for patients with high NLR was significantly worse than that for patients with normal NLR (41% vs 69%, p < 0.001). The 5-year disease-free survival for patients with high NLR was significantly worse than that for patients with normal NLR (41% vs 59%, p < 0.001). In multivariate analysis, a high NLR (HR 1.76, 95% CI 1.19-2.60, p = 0.005), an upper tumor location (HR 1.97, 95% CI 1.18-3.30, p = 0.010), an advanced T stage (HR 2.71, 95% CI 1.70-4.31, p < 0.001), and a larger number of metastatic lymph nodes (HR 4.38, 95% CI 1.18-3.30, p < 0.001) were independent predictors of poor overall survival. Conclusions: Our results suggested that the elevated preoperative NLR predicts poor overall and disease-free survival after an esophagectomy for esophageal squamous cell carcinoma.
Metachronous pancreatic cancer originating from disseminated founder pancreatic intraductal neoplasias.
Authors: Ono Yusuke , Karasaki Hidenori , Imai Koji , Sasajima Junpei , Chiba Shin-ichi , Funakoshi Hiroshi , Muraki Miho , Hanaoka Hideki , Furukawa Takahisa , Furukawa Hiroyuki , Kono Toru , Nagashima Kazuo , Mizukami Yusuke 
Published: February 2017

330 Background: Clonal populations originated from benign-looking “founder cells” may spread widely within pancreas instead of being localized in situ before frank pancreatic ductal adenocarcinoma (PDA) can be detected. Metachronous PDA is not common event, and we here sought to define potent origin of multiple PDAs developed in a woman by using advanced genetics technologies. Methods: In addition to precise pathological assessment, genetic approaches such as deep sequencing of multiplex PCR amplicons of cancer-associated genes (Ion Torrent PGM platform) and digital PCR were employed. Results: Curative resection of pancreatic head tumor was performed; however, “recurrent” lesions in the remnant pancreas were found 3.5-years later and total pancreatectomy was subsequently performed. The metachronous lesions were morphologically similar to the primary PDA. All 3 PDAs were shown to possess rare somatic mutations in KRAS (p.T58I and p.Q61H). Curiously, identical KRAS mutations were found in low-grade “intraepithelial” lesions, which localized in normal area of the pancreas and one of them possessed p53mutation, which was also found in the PDAs. Conclusions: Rare KRAS haplotype was identified in the metachronous PDAs in the current case. Surprisingly, the identical somatic mutations were also found in independent low-grade “intraepithelial” lesions with and without additional mutation in p53. The footprint of the tumor evolution marked by mutational profiling supports a human correlate to the mouse models of “dissemination” occurring at the earliest stages of pancreatic neoplasia.
Efficacy and safety of nintedanib versus sorafenib in Asian patients with advanced hepatocellular carcinoma (HCC): A randomized phase II trial.
Authors: Cheng Ann-Lii , Yen Chia-Jui , Kim Tae-You , Feng Yin-Hsun , Chao Yee , Lin Deng-Yn , Loembe Arsene-Bienvenu , Hocke Julia , Choi Caren , Ryoo Baek-Yeol 
Published: February 2017

339 Background: Nintedanib (N) is an oral, triple angiokinase inhibitor of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptors. This randomized, multicenter, open-label, Phase II study (NCT00987935; 1199.39) evaluated the efficacy and safety of N versus sorafenib (S) in Asian patients with advanced HCC. Preliminary analysis showed similar time to progression (TTP) by independent central review (ICR). Methods: Asian patients with unresectable advanced HCC, Child–Pugh score 5–6, ECOG-PS ≤2, and alanine/aspartate aminotransferase (ALT/AST) ≤2× upper limit of normal were enrolled. Patients were randomized 2:1 to N 200 mg bid or S 400 mg bid continuously in 28-day cycles, until intolerable adverse events (AEs) or disease progression (PD); treatment beyond PD was allowed if clinical benefit was perceived. Primary endpoint was TTP by ICR (RECIST 1.0) and secondary endpoints were overall survival (OS) and investigator-assessed (IA) TTP. Results: Patients (N=95) were randomized to receive N (n=63) or S (n=32); arms were balanced except for macroscopic vascular invasion (48% vs 31%). At the final cutoff date (16 Jul 14), 88% of patients had a TTP event, and 86% had an OS event; 1 patient was on treatment beyond PD. N and S had comparable IA TTP (median 2.8 vs 3.0 months; HR 1.39 [95% CI: 0.87–2.23]) and OS (median 10.2 vs 10.7 months; HR 0.94 [95% CI: 0.59–1.49]). ICR TTP data are pending. All but 1 patient reported an AE (CTCAE 3.0). More S-treated patients had Grade ≥3 AEs (56% vs 84%), serious AEs (46% vs 56%), and AEs leading to dose reduction (19% vs 59%) and drug discontinuation (24% vs 34%). Class-specific AEs of tyrosine kinase inhibitors in >15% of S-treated patients were hypertension, hand-foot skin reaction, and thrombocytopenia; only anemia was higher with N. AEs previously observed and higher with N were vomiting and nausea; ALT/AST increases and diarrhea were higher with S. Rash was reported in >15% of patients only with S. Conclusions: N shows similar efficacy to S for TTP and OS. N was better tolerated than S and AEs were generally manageable. Further studies of N in Asian patients with advanced HCC are warranted. Clinical trial information: NCT00987935.
A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer.
Authors: Scott Aaron James , O'Neil Bert H. , Gomes Christina , Baranda Joaquina Celebre , Cohen Steven J. , Tejani Mohamedtaki Abdulaziz , Maguire Robert T. , Wilhelm Francois , Maniar Manoj , Cohen Deirdre Jill , Ma Wen Wee , Aisner Dara , Cho Jonathan K. , Olowokure Olugbenga Olanrele , Coveler Andrew L. , Menter Alex R. , Rubin Peter , Cusnir Mike , Messersmith Wells A. 
Published: February 2017

342 Background: Rigosertib (ON 01910.Na), a dual non-ATP inhibitor of polo-like kinase 1 (Plk1) and phosphoinositide 3-kinase (PI3K) pathways, was assessed in patients with treatment-naïve metastatic pancreatic adenocarcinoma. Methods: Patients with metastatic adenocarcinoma of the pancreas were randomized in a 2:1 fashion to gemcitabine 1000 mg/m2 weekly for 3 weeks of a 4-week cycle plus rigosertib 1800mg/m2 via 2-hr CIV infusions given twice weekly for 3 weeks of a 4-week cycle versus gemcitabine 1000mg/m2 weekly for 3 weeks in a 4-week cycle. Results: A total of 160 patients were enrolled globally and randomly assigned to rigosertib plus gemcitabine (106 patients) or gemcitabine (54). The most common grade 3 or higher adverse events were neutropenia (8% in the rigosertib plus gemcitabine group vs. 6% in the gemcitabine group), hyponatremia (17% vs. 4%), and anemia (8% vs. 4%). The primary outcome of the study, median OS, was 6.1 months in the gemcitabine plus rigosertib arm versus 6.4 months with gemcitabine alone (hazard ratio (HR), 1.24; 95% confidence interval [CI], 0.85-1.81). The median PFS was 3.4 months for both groups (HR, 0.96; 95% CI, 0.68-1.36). The overall best response between arms were partial response rates of 19% versus 13% and stable disease in 50% versus 56% in the gemcitabine plus rigosertib versus gemcitabine alone, respectively. Of 64 tumor samples sent for molecular analysis, 47 were adequate for multiplex genetic testing and 41 were positive for mutations. The majority of cases had KRAS gene mutations (40/47, 85%), which included c.35G>T, p.G12V (12 cases), c.35G>A, p.G12D (21 cases), c.34G>C, p.G12R (4 cases), c.34G>T, p.G12C (1 case) and c.183C>A, p.Q61H (2 cases). Other mutations detected included TP53 (13 cases) and PIK3CA(1 case). No correlation between mutational status and efficacy was detected. Conclusions: The combination of rigosertib plus gemcitabine failed to demonstrate an improvement in survival or response compared to gemcitabine alone in metastatic pancreatic adenocarcinoma. Clinical trial information: NCT01360853.