bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early initiation of chemotherapy after histological diagnosis to improve the prognosis of metastatic pancreatic ductal adenocarcinoma.
Authors: Suzuki Rei , Takagi Tadayuki , Hikichi Takuto , Sato Ai , Watanabe Ko , Nakamura Jun , Konno Naoki , Waragai Yuichi , Kikuchi Hitomi , Obara Katsutoshi , Ohira Hiromasa 
Published: February 2017

273 Background: Since pancreatic ductal adenocarcinoma (PDAC) shows aggressive progression, we speculate that prolonged waiting time after detection of disease until initiation of treatment may relate to prognosis of patients with advanced diseases. Methods: We included patients diagnosed to have metastatic PDAC in Fukushima Medical University between September 2006 and January 2014. All patients underwent more than 2 cycles of gemcitabine treatment (1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle) after confirming histological diagnosis. We classified waiting time as Time A (detection-to-diagnosis waiting time) and Time B (diagnosis-to-treatment waiting time). Each period was further divided into 2 groups (shorter [-short] or longer [-long] waiting time than median length of each waiting time group). Kaplan-Meier methods, log-rank test and Cox proportional hazard methods were used to analyze overall survival (OS). Results: Twenty three patients were included. Median age was 64 (49-75) and length of waiting time was 19.5 days (4-78) in Time A and 9.0 days (2-34) in Time B. Regarding Time A, there was no significant difference in median OS between Time A-short and Time A-long (198.5 vs. 197.0 days; hazard ration [HR] 1.096; 95% confidential interval [CI] 0.4822-2.537; P=0.81). On the other hand, median OS was significantly better in Time B-short than Time B-long (median OS 290 vs. 160 days; HR, 0.381; 95% CI, 0.096-0.622; P= 0.0078). Conclusions: We foundthat waiting time between disease detection and diagnosis didn’t impact on prognosis of metastatic PDAC contrary to our speculation. However, patients with short waiting time (less than 9 days) after diagnosis until initiation of first chemotherapy had better prognosis than patients who had long waiting time. These findings suggest that early initiation of chemotherapy after histological diagnosis can improve the prognosis of metastatic PDAC.
Role of microbiota and Toll-like receptors in progression of esophageal adenocarcinoma (EAC) in a rat reflux model.
Authors: Kelly Lori A , Zaidi Ali H , Barlek Mark , Kreft Rachael , Omstead Ashten , Kosovec Juliann , Komatsu Yoshihiro , Jobe Blair A 
Published: February 2017

28 Background: The discovery of the link between H. pylori and gastric cancer may be the most direct proof that bacterial signaling and host response can result in carcinogenesis. Accumulating evidence supports that activation of the Toll-like receptor (TLR) signaling pathway by microbes is associated with the development of GI malignancies. Using the modified Levrat model of gastroduodenojejunal reflux which mimics the physiological and molecular sequence of human EAC in the rat, this study profiles the expression of genes central to TLR-mediated signal transduction as well as characterizes the esophageal microbiome across the spectrum of EAC development. Methods: Modified Levrat’s surgery induced chronic acid reflux in Sprague-Dawley’s with harvest of esophagus 40 weeks post-surgery. Macordissection of normal adjacent epithelium, Barrett’s esophagus (BE), dysplasia and EAC tumor was performed followed by RNA/DNA isolation. Five samples per group were selected for gene expression profiling on the Qiagen TLR Signaling Pathway PCR Array as well as microbiome analysis by IBIS technology. Validation of IBIS was performed by fluorescence in situ hybridization (FISH). Results: Gene expression analysis identified TLRs 1-3 and 6, 7, 9 as significantly upregulated in EAC compared to normal esophagus. TLR 1 and 5 were significantly upregulated in dysplasia. TLR 1 was significantly upregulated in BE and normal adjacent epithelium. Thirty seven genes involved in the TLR signaling pathway were dysregulated in EAC, 30 in dysplasia, 21 in BE and 23 in normal adjacent. IBIS analysis revealed a prevalence of E. coli in BE and EAC which was validated by FISH. Conclusions: Toll-like receptor (TLR) signaling pathway responses to E. coli may participate in the development of EAC. E. coli may be a potential risk factor for EAC requiring further clinical validation.
Next-generation sequencing: Profiling gallbladder cancer (GBC).
Authors: Chiu Joanne Wing-Yan , Serra Stefano , Kamel-Reid Suzanne , Zhang Tong , McNamara Mairead Geraldine , Bedard Philippe L. , Hedley David W. , Moore Malcolm J. , Dhani Neesha C. , Shek Tony , Kwong Yok-Lam , Yau Thomas Cheung , Doherty Mark , Knox Jennifer J. 
Published: February 2017

286 Background: Molecular profiling data of GBC is scant and it is often included with other biliary cancers for analysis, which may hinder advancing drug discovery. Methods: Archival formalin fixed paraffin embedded (FFPE) tissue of GBC from 2 research hospitals in Toronto (n=21) and Hong Kong (n=21) were analyzed by MassARRAY Sequenom panel (23 genes, 279 mutations), or by next general sequencing (NGS) using Proton or Illumina MiSeq TruSeq Amplicon Cancer Panel (48 genes, 212 amplicons, ≥500x coverage). Results of other biliary cancer and ampullary cancer from an ongoing profiling project were also reported. Results: Twelve biliary cancer samples first analyzed with Sequenom revealed no mutations. Reanalysis with NGS of these yielded mutations in 5. All subsequent samples were analyzed with NGS (n=57). Mutations were identified in 80% [53 mutations in 42 GBC, 8 mutations in 9 intrahepatic cholangiocarcinoma (IHC), 7 mutations in 6 hilar/distal bile duct cancers (DBD)]. The most frequent mutations in GBC were TP53 and SMAD4, and KRAS mutation was found in 7% (Table). PIK3CA mutation was found in 5% of GBC but not the other biliary cancers, and IDH1 mutation was exclusive for IHC, in agreement with published literature. TP53 mutations in GBC patients did not correlate with gender, tumor grade, survival, or treatment response to gemcitabine-based chemotherapy. There was no difference in mutation patterns in GBC between 2 institutions/countries. Conclusions: NGS can be utilized for molecular profiling of biliary cancer, detecting potentially actionable targets in the majority of cases. Our preliminary data suggests GBC may have its own molecular profile, deserving special consideration in trial design for biliary cancer. To our knowledge the current study is the biggest cohort of NGS analysis for GBC. [Table: see text]
Effects of neoadjuvant therapy on pancreatic cancer stem cells.
Authors: Miller Adam R. , Horsley Whitney H. , Sandusky George , Stanley Melissa , O'Neil Bert H. , Shahda Safi 
Published: February 2017

292 Background: Several factors are involved in pancreatic cancer’s (PC) resistance to therapy. Cancer Stem cells (CSCs) represent a small and unique population of cancer cells, that are resistant to chemotherapy and radiotherapy and have the capability to differentiate and produce further resistant clones. Our hypothesis was that stem cell frequency would differ in treated vs. untreated pancreatic cancers. Methods: Resected FFPE PC specimens were collected under IRB- approved protocols and were separated into two group categories: cases that received neoadjuvant therapy (NA) and matched control cases with no treatment prior to surgical resection (SU). Immunostaining with CD24 and ALDH1 was performed using the DAKO FLEX SYSTEM. Each slide was scanned using the Aperio Whole Digital Imaging System. The digital scans were analyzed using the standard positive pixel algorithm for immunostains (brown positive, blue negative) that gives a percent of positive pixels in the cross section of the tissue. Care was taken to exclude false-positive staining sections of intact physiologic acinar and islet cells. Positivity data was compared between the two groups using a two-sample t-test using unequal or equal variances where an F-test deemed each appropriate. Results: Twenty cases were examined (10 NA and 10 SU). Patients in the NA arm received the following treatments (4 FOLFIRINOX, 2 nab-Paclitaxel + gemcitabine, 2 treated with concurrent gemcitabine/radiotherapy and 2 patients’ details are not available). Using two-sample t-test analysis, we found a statistically significant difference of median expression (percent positive pixels) of CD24 (20.5% vs. 66.9% expression, P <0.01,) and ALDH1 (41.5% vs. 60.5%, P= 0.04) between NA vs. SU respectively. This small study demonstrates lower expression of CSCs markers in patients receiving NA therapy in comparison to SU treated patients, indicating an effect from neoadjuvant therapy on CSCs. Conclusions: This is the first analysis of CSCs markers in patients with PC receiving NA therapy compared to surgery. In this small group, CSCs markers reflecting CSCs numbers in patients’ tumors were lower in the group receiving NA therapy prior to surgery; suggesting that CSCs may in fact be sensitive to standard chemotherapy.
The association of epithelial expression of hENT1 and survival from adjuvant gemcitabine in pancreatic ductal adenocarcinoma (PDAC).
Authors: Renouf Daniel John , Karasinska Joanna , Kalloger Steve , Peixoto Renata D'Alpino , O'Connor Kate , Schaeffer David 
Published: February 2017

296 Background: Human equilibrative nucleoside transporter 1 (hENT1) mediates the cellular uptake of gemcitabine. Low tumour hENT1 expression has been associated with reduced survival from gemcitabine in some studies. We analyzed the prognostic effect of hENT1 expression in a cohort of PDAC patients (pts) who underwent surgical resection. Methods: A tissue microarray (TMA) composed of duplicate 0.6 mm cores from 261 resected PDACs was constructed from all available cases derived from the archives of Vancouver General Hospital between 1988 - 2013. TMA sections (4 µm) were stained with an antibody for hENT1 (SP120- Spring Biosciences) and scored using a four-tiered scoring system (negative, weak, moderate and strong staining). The expression of hENT1 in the epithelial component of PDAC was quantified and patient samples were divided into low (negative and weak staining) and high (moderate and strong staining) hENT1-expressing groups. Treatment and survival data were collected. Survival differences were quantified with Kaplan-Meier method and log-rank statistic. Results: Our cohort included pts who received no adjuvant chemotherapy (CT) (n=182) or gemcitabine (n=59). Cases treated with other regimens (n=20) were excluded. There was no significant difference in the median overall survival (OS) between pts with low (14.0 months, n=167) and high hENT1 expression (15.2 months, n=15) in the absence of adjuvant CT. Gemcitabine treated patients with low hENT1 expression (n=51) had a median OS of 20.9 months. Median OS was not reached in the group of pts with high hENT1 expression (n=8) who received gemcitabine, with only 2 deaths at the 24 month time point and 6 censorings (p = 0.045). Pts who received gemcitabine had an increased median OS (24.8 months) compared to pts who did not receive adjuvant CT (14.0 months) regardless of hENT1 expression (p<0.0001). Conclusions: Consistent with the ESPAC-3 data, in our analysis adjuvant gemcitabine was associated with increased OS in PDAC pts with high epithelial hENT1 expression (determined using the SP120 antibody) compared to pts with low hENT1 expression. Prospective evaluation of the predictive value of hENT1 expression in this setting is needed.
Relationship between PD-L1 expression and clinical outcomes in patients (Pts) with advanced gastric cancer treated with the anti-PD-1 monoclonal antibody pembrolizumab (Pembro; MK-3475) in KEYNOTE-012.
Authors: Muro Kei , Bang Yung-Jue , Shankaran Veena , Geva Ravit , Catenacci Daniel Virgil Thomas , Gupta Shilpa , Eder Joseph Paul , Berger Raanan , Gonzalez Edward J. , Ray Archana , Dolled-Filhart Marisa , Emancipator Kenneth , Pathiraja Kumudu , Lunceford Jared K. , Cheng Jonathan D. , Koshiji Minori , Chung Hyun Cheol 
Published: February 2017

3 Background: Tumors use the PD-1 pathway to evade immune surveillance. Pembrolizumab, an anti-PD-1 monoclonal antibody, has shown antitumor activity in advanced cancers. We assessed the safety and efficacy of pembrolizumab in patients with advanced gastric cancer in KEYNOTE-012 (Clinicaltrials.gov identifier NCT01848834). Methods: Archival tumor samples from patients from Asia-Pacific (AP) and rest of the world (ROW) with recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction were screened for PD-L1 expression using a prototype IHC assay with the 22C3 antibody. Only patients with distinctive stromal or ≥1% tumor nest cell PD-L1 staining were eligible. Patients received pembrolizumab 10 mg/kg every 2 weeks for up to 24 months or until complete response, progression, or unacceptable toxicity. Imaging was performed every 8 weeks. Primary efficacy end point is ORR assessed per RECIST v1.1 by independent central review. Secondary end points include duration of response, PFS, and OS. Results: Of the 162 patientts screened, 65 (40%) were PD-L1+. Of these 65 patients, 39 enrolled (19 from AP, 20 from ROW; median age, 63 years [range 33-78]). The number of prior therapies for advanced disease ranged from 0 to 5; 67% received ≥2 prior therapies. Median follow-up duration was 8.8 months (range 6.2-12.6); 13 patients (33%) remain on therapy. Four patients experienced 5 total grade 3-5 drug-related adverse events: peripheral sensory neuropathy, fatigue, decreased appetite, hypoxia, and pneumonitis (n = 1 each). There was 1 drug-related death (hypoxia). ORR was 22% (95% CI 10-39) by central review and 33% (95% CI 19-50) by investigator review. Median time to response was 8 weeks (range 7-16), with a median response duration of 24 weeks (range 8+ to 33+). PD-L1 expression level was associated with ORR (1-sided P = 0.10). The 6-month PFS rate was 24%. The 6-month OS rate was 69%. Conclusions: Pembrolizumab demonstrated manageable toxicity and promising antitumor activity in advanced gastric cancer. These results support the ongoing development of pembrolizumab for gastric cancer. Clinical trial information: NCT01848834.
Exploratory biomarker results from early investigation of PEGPH20 in combination with gemcitabine (Gem) in patients with pancreatic cancer (PDA).
Authors: Hingorani Sunil R. , Harris William Proctor , Beck Joseph Thaddeus , Berdov Boris A. , Wagner Stephanie Ann , Pshevlotsky Eduard M. , Tjulandin Sergei , Gladkov Oleg , Holcombe Randall F. , Jiang Ping , Maneval Daniel C. , Korn Ronald I , Shepard Harold Michael , Devoe Craig E. 
Published: February 2017

300 Background: PEGPH20 (PEG), a PEGylated recombinant human hyaluronidase, has anti-tumor activity as a single agent and in combination with chemotherapy in preclinical models. A Phase 1b study of PEG + Gem (P+G) in patients (pts) with advanced PDA showed good anti-tumor activity, particularly in pts with HAhigh tumors (ECCO 2013). In this study, we investigated pharmacodynamic (PD) markers including plasma(soluble) HA (sHA), dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and 18Fluorodeoxyglucose positron emission tomography (PET/CT) to explore additional correlates for PEG activity. Methods: 28 pts with stage IV PDA were treated with PEG at 1, 1.6, or 3µg/kg IV twice weekly for Wks 1-4 and Wks 5-7, followed by 1 wk rest, plus Gem at 1000 mg/m2 IV once weekly for Wks 1-7, then 1 wk rest. Thereafter, P+G was given once weekly for 3 wks in 4-wk cycles. Serial plasma samples were collected and analyzed in a quantitative assay for PEG and sHA. Exploratory imaging by DCE-MRI was performed on selection pts at baseline, 8hr, 24hr and end of cycle 1, PET/CT was performed at baseline and at the end of each cycle. Results: PEG pharmacokinetics was well-characterized by a 2-compartment PK model, peak plasma concentration increased in a dose-proportional manner after a single or repeat administration of PEG. Dose- and time-dependent increases in sHA were observed within 2-3 days after 1.0, 1.6, or 3.0 µg/kg of PEG administration. The median peak concentrations were 3,736; 48,150; and 74,950ng/mL, respectively, and increased with increasing doses. sHA reached steady state approximately 1 wk after repeated PEG administration, consistent with the expected hyaluronidase activity of PEG. Exploratory analysis with DCE-MRI from 6 pts showed an early increase (24hrs) in tumor perfusion (Ktrans) in target lesions. PET/CT from 5 pts showed an average reduction in the maximum standardized uptake value (SUVmax) of 37% at EOC1, and partial metabolic responses using EORTC criteria were achieved in 4 of 5 pts. These results suggest that P+G has measurable biological activity in metastatic PDA Conclusions: Plasma sHA concentration, DCE-MRI and PET/CT are PD markers for evaluation of P+G activity.
DNA repair inhibition by DT01 as an adjuvant therapy at each stage of hepatocellular cancer (HCC) treatment.
Authors: Devun Flavien , Herath Nirmitha , Denys Alban , Sun Jian-sheng , Dutreix Marie 
Published: February 2017

303 Background: Hepatocellular carcinoma (HCC) is the most common liver cancer. Radiofrequency ablation (RFA), transarterial chemoembolization (TACE) or chemotherapy (CT) can be considered at each stage of HCC. The efficacy of these DNA damage inducing treatments could be enhanced by DNA damage repair inhibition. DT01 inhibits the complete DNA double-strand break repair machinery. Here, we assess the combination of DT01 with RFA, TACE or CT in preclinical models. Methods: For association with RFA, mice bearing flank-grafted tumors were sham treated (n=18), treated by DT01 (n=22), RFA (n=21) or a combination of DT01 and RFA (n=19). Mice were either sacrificed for pathological study or followed for survival. For association with TACE, rabbits bearing VX2 hepatocellular carcinoma in liver were untreated (n=9), treated with TACE (n=13) or treated with TACE and DT01 (n=14). Tumor growth, vascularization, necrosis and metastases were assessed with ultrasound scanning, color Doppler, pathology and autopsy respectively. For association with CT, mice bearing orthotopic liver tumors were administered NaCl (n=7), CT (doxorubicin) (n=10), systemic DT01 treatment (n=7) or an association of DT01 and CT (n=10). Tumor growth and pathological studies were assessed. Results: Mice treated by RFA and DT01 have longer survival compared to RFA alone (median survival: 57 vs 40 days) with 54% of complete responses while RFA alone improved survival moderately (median survival: 40 vs 28 days for control). Rabbits treated with TACE and DT01, in comparison to CT alone, show efficient tumor growth control, an increase of tumor necrosis (61% vs 40%), a decrease of metastases (21 vs 54%) and an absence of neoangiogenesis rebound. Mice treated with CT in combination with DT01 show a significant decrease in tumor volume and tumor necrosis, compared to the mice treated with CT alone. In all models, DT01 addition to treatments did not add any toxicity. Conclusions: Our results show that the addition of DT01 to RFA, TACE or CT enhances their antitumor activities and provide an experimental basis for the use of DT01 as an adjuvant therapy at each stage of HCC treatment.
Effect of high expression of fatty acid binding protein 5 on prognosis and epithelial-mesenchymal transition in hepatocellular carcinoma.
Authors: Ohata Takanori , Yokoo Hideki , Kamiyama Toshiya , Aiyama Takeshi , Wakayama Kenji , Orimo Tatsuya , Kakisaka Tatsuhiko , Tsuruga Yousuke , Kamachi Hirofumi , Taketomi Akinobu 
Published: February 2017

310 Background: Hepatocellular carcinoma (HCC) is one of the cancer types with poor prognosis. The high expression of Fatty Acid Binding Protein 5 (FABP5) has been reported its malignant potential in several cancers. However, the function of FABP5 in HCC remains unknown. We analyzed the correlation between the expression of FABP5 and malignant behavior of HCC using HCC tissues and human HCC cell lines. Methods: A total of 231 HCC samples were obtained through our institute and subjected to immunohistochemical analysis. In vitro, protein expression of FABP5 in HCC cell lines was assessed by Western blot analysis. To the higher FABP5 expression cell lines, we performed proliferation assay, migration assay and invasion assay with or without genetic down-regulation of FABP5 by short hairpin RNA (shRNA). Results: The intensity of immunostaining in HCC tissues was determined comparing to immunoreactivity of Kupffer cells, and the patients were divided into a strong staining group (n=127) and a weak staining group (n=104) according to the intensity of immunostaining. In the strong staining group, 5-year overall survival rate was 58.3%, compared with 90.5% in the weak staining group (p<0.0001). In addition, 5-year relapse free survival rate in the strong staining group was 23.1%, compared with 46.9% in the weak staining group (p<0.0001). Moreover, the strong staining of FABP5 positively correlated with early recurrence, extrahepatic metastasis, AFP, AFP-L3%, PIVKA II, tumor size, poor differentiation, and micro/macro vascular invasion (P<0.05). In vitro, the knockdown of FABP5 significantly inhibited cell proliferation, migration and invasiveness. Additionally, the knockdown of FABP5 was associated with inhibition of epithelial-mesenchymal transition (EMT), including down-regulation of N-cadherin, and Snail converse to the activation of E-cadherin and ZO-1. Conclusions: FABP5 was closely related with the gain of malignant potential through the activation of EMT, and also behaved as a significant prognostic and recurrence factor. Therefore, FABP5 may serve as a new biomarker of HCC and a potential molecular target for the development of HCC therapies.
BRAF mutations in patients with well-differentiated pancreatic neuroendocrine tumors (WD pNETs).
Authors: Raj Nitya Prabhakar , Meyers Paul A. , Saltz Leonard , Reidy Diane Lauren 
Published: February 2017

321 Background: Whole exome sequencing in WD pNETs demonstrated an increased number of mutations in genes implicated in chromatin remodeling and in the PI3K/Akt/mTOR pathway. Next-generation sequencing (NGS) allows us to bring this technology to the clinic to better characterize WD pNETs and potentially offer tailored therapies. Methods: A NGS platform developed at Memorial Sloan Kettering Cancer Center (MSKCC) termed MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets) was used. This platform screens for 341 cancer genes commonly altered across tumor types. Thus far, 14 patients with WD pNETs have consented to MSK-IMPACT. Results: To date, mostpatients harbor no clinically validated or actionable mutations. Two patients, however, harbor different and potentially actionable BRAF mutations. The first patient is a 39 year-old woman with a BRAF V600E mutation. She presented with somatostatin receptor-negative, aggressive disease involving the liver, lymph nodes, adnexa, and peritoneum. She was initially diagnosed elsewhere as having a signet ring cell adenocarcinoma, and responded to FOLFOX and bevacizumab. Pathology review at MSKCC, however, identified the tumor as metastatic WD pNET. Upon disease progression, a repeat biopsy confirmed metastatic WD pNET. She is currently on capecitabine and temozolomide with clinical improvement. The second patient is a 22 year-old woman with metastatic WD pNET with a BRAF K601E mutation. Her tumor also has an aggressive behavior; she has progressed on all conventional and nonconventional therapies. Given the finding of a BRAF K601E mutation, she received trametinib and dabrafenib, but developed disease progression after 3 months. Conclusions: Two potentially actionable BRAF mutations were identified from NGS of WD pNETs. BRAF mutations have not been previously reported in pNETs. It is unclear whether BRAF mutations are oncogenic drivers, and whether BRAF-targeted treatments would be beneficial. Both patients show an atypical, aggressive presentation and course. Further testing is warranted to determine the role and clinical significance of BRAF in pNETs. Evaluation using pNET tissue microarrays is ongoing and will be reported at the meeting.