bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of weekly intraperitoneal paclitaxel combined with S-1 and oxaliplatin for gastric cancer with peritoneal metastasis.
Authors: Ishigami Hironori , Kaisaki Shoichi , Yamaguchi Hironori , Yamashita Hiroharu , Emoto Shigenobu , Kitayama Joji 
Published: February 2017

146 Background: Intraperitoneal (IP) chemotherapy is a promising treatment option for gastric cancer with peritoneal metastasis. We previously verified the safety and efficacy of IP paclitaxel (PTX) combined with S-1 and intravenous PTX in phase I and phase II studies. S-1 plus oxaliplatin (SOX) demonstrated efficacy in a phase II study, and is regarded as a candidate for the next-generation standard regimen for gastric cancer. We designed a new regimen combining weekly IP PTX with SOX in order to maximize systemic effects as well as local effects in the peritoneal cavity. A dose-escalation study of IP PTX in combination with fixed doses of SOX was carried out to determine the maximum-tolerated dose (MTD) and recommended dose (RD). Methods: PTX was administered intraperitoneally on days 1 and 8 with an initial dose of 20 mg/m2 (level 1), stepped up to 30 mg/m2 (level 2) or 40 mg/m2 (level 3) depending on observed toxicity. S-1 was administered orally at a dose of 80 mg/m2/day (b.i.d.) for 14 days followed by a 7-day rest. Oxaliplatin was administered intravenously at a dose of 100 mg/m2 on day 1. This treatment was repeated every 3 weeks. Toxicity was graded according to CTCAE v4.0. Dose-limiting toxicities (DLTs) were defined as grade 4 leukopenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, and grade 3 non-hematological toxicity. The MTD was defined as the dose level at which 2 or more of 3 or 6 patients developed DLTs during two courses of treatment. The RD was defined as one dose level under the MTD. Results: A total of 12 gastric cancer patients with peritoneal metastasis were enrolled. No DLTs were observed at all dose levels. Neutropenia in one patient at dose level 3 was the only grade 3 toxicity observed. Grade 2/3 leukopenia, neutropenia and thrombocytopenia were observed only in 2 patients at dose level 3. Regarding grade 2 non-hematological toxicities, anorexia, fatigue and nausea were observed in 6, 4 and 2 patients, respectively, independent of dose levels. Consequently, the MTD was not reached, and the RD of IP PTX was determined to be 40 mg/m2 (level 3). Conclusions: Combination chemotherapy of IP PTX with SOX was shown to be a safe regimen that should be further explored in clinical trials.
Detection of early-stage pancreatic ductal adenocarcinoma (PDAC): Sensitivity, specificity, and discriminatory properties of the serum-based PAM4-immunoassay.
Authors: Gold David V. , Gaedcke Jochen , Ghadimi B. Michael , Goggins Michael , Hruban Ralph H. , Liu Mengling , Newsome Guy , Goldenberg David M. 
Published: February 2017

151 Background: We recently reported that a serum-based enzyme immunoassay employing the PAM4 antibody was able to correctly identify 82% of patients with known PDAC and, importantly, that this assay had promising sensitivity for detecting early-stage disease. We now extend these findings in a much larger patient population that includes over 600 sera from both malignant and benign diseases of the pancreas and surrounding tissues. Methods: In a blinded analysis, sera from patients with confirmed PDAC (N=298), other cancers (N=99), benign disease of the pancreas (N=126), and healthy adults (N=79) were evaluated by enzyme immunoassay for concentration of PAM4-antigen levels. Results: Overall sensitivity for detection of PDAC was 76%, with 64% of stage-1 patients testing positive and a higher sensitivity (85%) for advanced disease. For the most part, sera from patients with neuroendocrine tumors of the pancreas or cancers of other origin (squamous, GIST, etc.) did not have elevated levels of the PAM4-antigen. Approximately half of the patients with ampullary (48%) and extrahepatic biliary (50%) adenocarcinomas had positive levels of circulating PAM4-antigen. Of 126 patients diagnosed with benign conditions of the pancreas, only 24 (19%) were positive and, in particular, 18 of 80 (23%) patients with chronic pancreatitis (CP) were positive. ROC curve analysis demonstrated a statistically significant difference between the PDAC and CP groups (P < 0.0001), with an area under the curve of 0.84 ± 0.02 (95% CI: 0.79 – 0.89). The positive- and negative-likelihood ratios for differentiating PDAC from benign conditions of the pancreas were 4.00 and 0.30, respectively. Conclusions: The PAM4-immunoassay detects nearly two-thirds of stage-1 PDAC patients, and does so with high discriminatory power with respect to benign pancreatic disease. Our results provide a rationale for longitudinal surveillance of patients considered at high-risk for PDAC (e.g., familial pancreatic cancer, new-onset diabetes, etc.) with the PAM4 assay. (Supported in part by NIH grants CA096924, CA120432 and CA62924, and the Turpin Foundation.)
Detection of resectable pancreatic cancer with SOMAmer proteomic technology.
Authors: Brand Randall , Buchholz Malte , Mehan Mike , Whitcomb David C. , Zeh Herbert , Moser Arthur J , Gress Thomas M , Williams Steve , dela Cruz Maria , Ostroff Rachel ,   European MolDiag-Paca Consortium
Published: February 2017

162 Background: To improve the current dismal 5-year survival rates for pancreatic adenocarcinoma (PC) it is essential to develop strategies focused on detection in high-risk populations. This study employed a unique SOMAmer proteomics platform to identify a biomarker panel that discriminates between pancreatic cancer and control patients. A secondary goal was to compare the panel with CA 19-9. Methods: Plasma samples (total < 20 ul) were analyzed for 825-proteins using a SOMAmer proteomics platform on training set of 100 cases and 69 controls from a single institution. The control group contained individuals with GI symptoms, including acute and chronic pancreatitis, and normal controls. An independent blinded validation set from another center consisted of 43 PC patients and 47 controls. About two thirds (96/143) of the study cases were in resectable stages I-IIb. Biomarkers were identified by Random Forest backwards selection, using a false-discovery-rate corrected value of p<0.001. CA19-9 levels were available on a subset of the patients from the training set (87 PC and 29 controls). A CA 19-9 level of > 40 U/ml was defined as positive. Results: In the training set, 37 markers were significantly different between case and controls. A 10 marker Random Forests classifier had an AUC of 0.91 for training and 0.90 for the independent validation set. Comparison of the SOMAmer results with CA 19-9 levels are shown in the table. There was 78% agreement between the two tests. One could maximize sensitivity with some sacrifice of specificity by combining either test positive (95% and 66%, respectively) or conversely maximize specificity (97%) with lower sensitivity of 77% if both tests must be positive. Conclusions: 1) The 10 marker SOMAmer biomarker panel is promising for the detection of resectable pancreatic cancer with an AUC of 0.91 on a training set, which was confirmed on an independent validation set. 2) Preliminary data suggests that this test is complementary to CA 19-9 with improved combined sensitivity of up to 95%. 3) Studies to assess further applications of these panels, including for risk assessment in individuals with a family history of pancreatic cancer, are underway. [Table: see text]
A population-based analysis of prognostic factors in patients with advanced hepatocellular carcinoma treated with sorafenib.
Authors: Smith Alan D. , Cheung Winson Y. 
Published: February 2017

163 Background: Available clinical prognostic scoring systems for advanced hepatocellular carcinoma (HCC) were developed in the era of conventional chemotherapy. In 2008, the molecularly targeted agent sorafenib became the new standard of care for advanced HCC due to its survival benefit. The utility of these prognostic models in the setting of sorafenib is unclear. Our aims were to assess for new prognostic factors in patients treated with sorafenib and compare these with known prognostic systems. Methods: All patients diagnosed with advanced HCC from 2008 to 2010 in British Columbia, Canada and treated with sorafenib at any 1 of 5 regional cancer centers were eligible. Based on the established Okuda, CLIP, Barcelona, and French staging systems, we collected baseline demographic and disease characteristics of patients prior to receipt of sorafenib. Multivariate logistic regression models were constructed to examine for associations between these clinical factors and overall survival. Results: Of 183 patients identified, 152 were evaluable: median age was 63 years, 78% were men, average number of sorafenib treatment was 5.3 cycles, and median overall survival was 9.6 months. The prevalence of hepatitis B, hepatitis C, and alcohol-related liver disease were 32%, 15%, and 11%, respectively. Univariate analyses showed that poor performance status, presence of clinical ascites, as well as elevated serum AST, GGT, ALP, bilirubin and platelet levels were each associated with worse overall survival (all p<0.05). In multivariate analyses, however, none of these clinical factors continued to be independently predictive of outcome (all p>0.05). Conclusions: Traditional clinical prognostic factors developed in the era of conventional chemotherapy do not appear to have the same prognostic utility in this contemporary Western cohort of advanced HCC patients treated with sorafenib. This observation underscores the need to identify molecular biomarkers that provide better prognostic information.
Blinded independent central response assessment using RECIST, mRECIST, and CHOI criteria in patients treated with sorafenib for advanced hepatocellular carcinoma (HCC).
Authors: Bouattour Mohamed , Wassermann Johanna , Bruno Onorina , Dreyer Chantal , Larroque Beatrice , Castera Laurent , Vilgrain Valérie , Belghiti Jacques , Raymond Eric , Faivre Sandrine J. 
Published: February 2017

172 Background: Despite survival benefit in patients with advanced HCC, sorafenib has been infrequently associated with changes in tumors dimensions, challenging standard RECIST criteria. Experts have suggested new response criteria based on changes in tumor vascularization and density (mRECIST and Choi). Aim is to evaluate response in patients treated with sorafenib using three different methods and their correlation with overall survival (OS) Methods: Radiological evaluations were performed from consecutive patients treated with sorafenib from January 2007 to February 2009. Patients were considered evaluable if CT scans were performed within 6 weeks before sorafenib and in the three months following treatment initiation at the first evaluation. A radiologist blinded for clinical data performed tumor evaluations according to RECIST, mRECIST, and Choi criteria. Best response was correlated with OS Results: Among 82 patients, 60 were evaluable (median age 63, male/female 52/8). The majority of patients were Child A (80%). Tumor staging showed BCLC stage B and C in 33% and 67%, respectively. The median duration of treatment with sorafenib was 6.6 months (range 1.2-16.5). Tumor evaluations by CT scan were performed in a median of 2.1 months (range 1.5-3.2). For the entire cohort, median OS was 9.9 months, and survival rates at 6, 12, and 24 months were 69%, 39% and 22%, respectively. The table summarizes the best responses measured using RECIST, mRECIST, and Choi criteria. Conclusions: Better OS was observed in patients with complete/partial response than in patients with stable disease and progression, regardless the type of radiological criteria. However, mRECIST and Choi criteria identified more adequately than RECIST subgroups of patients with complete/partial response who also experienced longer survival [Table: see text]
Baseline demographics of patients with neuroendocrine tumors presenting to seven National Comprehensive Cancer Network (NCCN) institutions: Development of a multi-institutional outcomes database.
Authors: Choti Michael A. , Mayorga Margaret A. , Bobiak Sarah , Kulke Matthew , Yao James C. , Bergsland Emily K. , Nakakura Eric K. , Bloomston Mark , Benson Al Bowen , Shah Manisha H. , Strosberg Jonathan R. 
Published: February 2017

187 Background: Diagnostic strategies, management paradigms, and clinical outcomes of patients with neuroendocrine tumors (NETs) are diverse and poorly characterized. The National Comprehensive Cancer Network (NCCN) created a comprehensive longitudinal database to characterize patients treated for NETs at seven participating institutions. Preliminary results from the database are reported. Methods: Member IRB approval was obtained to identify patients at least 18 years of age presenting to each of seven NCCN institutions between 2004 and 2007 with pathologically confirmed newly or previously diagnosed NETs via hospital medical records. Eligible patients included those with carcinoid (any site); goblet cell or adenocarcinoid; composite carcinoid; poorly differentiated gastrointestinal small cell tumor; pancreatic NET; NET of unknown primary site; pheochromocytoma; and paraganglioma. Baseline demographic characteristics were summarized for this analysis. Results: Among the 2,542 patients identified with a NET diagnosis, patients most frequently presented with carcinoid tumor (51%), pancreatic NET (27%) and NET of unknown primary site (8%). Median age at diagnosis was 55 (SD=13) and median age at first presentation to the NCCN was 57 (SD=13). Fifty-three percent of patients were female. Most (88%) were Caucasian and 8% were African American. Forty percent of patients were diagnosed with NET before presenting to the NCCN. Among these, the median time between initial NET diagnosis and presentation to the NCCN was 2 years (SD=6). Significant differences in provider specialty referral patterns were observed between institutions. Conclusions: The baseline demographic characteristics of NET patients in this new database are consistent with those previously reported in population-based registries. The NCCN database will provide a valuable resource for further exploration of patterns of diagnosis, treatment, consistency with established guidelines, as well as clinical outcomes in patients with this condition. Existing differences among institutions in referral patterns will be further explored.
Symptom changes that predict disease control by systemic chemotherapy in patients with advanced pancreatic cancer.
Authors: Kuwahara Akiko , Mitsunaga Shuichi , Ohno Izumi , Shimizu Satoshi , Takahashi Hideaki , Okuyama Hiroyuki , Okusaka Takuji , Ueno Hideki , Morizane Chigusa , Kondo Shunsuke , Ikeda Masafumi 
Published: February 2017

195 Background: Alleviation of symptoms is related to good tumor control in patients undergoing systemic chemotherapy for pancreatic cancer (PC). The predictive value of symptom change has not been fully understood. The aim of this study was to identify symptom changes that predicted disease control by systemic chemotherapy in PC patients. Methods: Patients with unresectable PC who had not received any anti-cancer therapy for PC were eligible for inclusion in this study. Patients with obvious infectious conditions were excluded. Symptoms were scored from 0 to 10 using the Japanese version of the MD Anderson Symptom Inventory before the start of chemotherapy and one month later. The response of the tumor was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) vs. 1.0. Disease control was defined as CR, PR, or SD. An attempt was made to identify symptom changes that predicted disease control, and their impact on progression-free survival (PFS) was assessed. Results: The symptoms of 87 patients (male/female: 46/41, Karnofsky performance status (KPS): 100/90/80/70-50: 32/29/17/9, median age: 66 years) were prospectively assessed. Gemcitabine monotherapy (GEM), a GEM-based regimen, and S-1 monotherapy were performed in 42, 41, and 4 patients, respectively. Disease control was observed in 31 patients. The pain scores (P=0.047) and sleep disturbance scores (P=0.052) one month later were lower than before treatment in patients with disease control. Patients without deterioration of pain or sleep disturbance had a higher frequency of disease control (P=0.098 and P=0.004, respectively) and a longer PFS (P=0.021 and P<0.001, respectively) than patients whose pain or sleep disturbance became more severe. Conclusions: Improvements in pain and sleep disturbance scores at one month predict disease control by systemic chemotherapy in patients with advanced PC.
Transforming growth factor (TGF) beta pathway and clinical outcome of pancreatic cancer.
Authors: Javle Milind M. , Tan Dongfeng , Li Yanan , Kar Siddhartha P. , Baladandayuthapani Veera , Dong Xiaoqun , Weatherly Jacqueline , Krishnan Sunil , Huang Tzu-chuan Jane , Fogelman David R. , Abbruzzese James L. , Wolff Robert A. , Li Donghui 
Published: February 2017

201 Background: TGF-beta acts both as a tumor suppressor or tumor promoter depending upon cellular context and stage of tumor progression. TGF-β exerts its effects through the TGF-beta-R1/ R2 receptors and the SMAD transcription regulators. We investigated the prognostic value of TGFβ signaling biomarkers in pancreatic cancer. Methods: We measured plasma TGF-beta-1 level using Meso Scale Discovery Multi-array Human TGF-beta-1 Assay in 643 pancreatic cancer patients. TGF-beta-R2 and SMAD4 protein expression were measured in 86 biopsies using immunohistochemisty (IHC). IHC intensity was scored 0-3. Percentage IHC-positive cancer cells were 0-3 (0: 0%+, 1: 1-10%+, 2: 10-25%+, 3: >25%+). Final IHC score was measured as intensity x percentage. We also genotyped 3 SNPs of TGFB1 gene using the Taqman assay. Kaplan-Meier and log-rank tests were used to analyze overall survival (OS) by TGFβ1 level. Multivariate Cox proportional hazards models with relevant clinical covariates were used to assess the relationship between IHC score and OS. Results: In patients with locally advanced and metastatic disease (n = 355), there was a significant association of plasma TGF-beta-1 with overall survival (OS). OS of the top quartile of TGF-beta-1 levels (>19.05 ng/mL) vs. those with low level was 27.7 weeks vs. 40 weeks, respectively [log-rank p = 0.0125, adjusted for baseline CA 19-9 and performance status (PS)]. No significant association between plasma TGF-beta-1 and OS was noted in surgical patients (n=288). In the multivariate Cox model, after adjusting for baseline stage, CA 19-9, PS, age and TGF-beta-R2 expression, complete loss of SMAD4 expression (IHC score 0) was significantly associated with lower OS (HR: 1.85, 95% CI: 1.06-3.23; p = 0.03). Progressive disease on gemcitabine-based therapy was more likely in SMAD4 IHC 0 group as compared with higher score (46.5% vs. 38.1% progressed; chi square p = 0.069). TGFB1 -1346T>C CT/TT genotype correlated with shorter OS [HR (95% CI): 1.21 (1.02-1.45), p=0.03] after adjusting for clinical variables. Conclusions: This large retrospective study suggests an important stage-dependant role of the TGF-beta pathway in pancreatic cancer. Targeting this pathway in advanced pancreatic cancer may have therapeutic relevance.
Staging of advanced hepatocellular carcinoma patients in the targeted therapy era.
Authors: Shah Neeraj Nailesh , Hassan Manal , Xiao Lianchun , Abbruzzese James L. , Morris Jeffrey , Kaseb Ahmed Omar 
Published: February 2017

209 Background: Several hepatocellular carcinoma (HCC) staging systems are currently available. However, they were all developed before the targeted therapy era prevailed in the last decade which has changed the natural history of the disease. Our study goal was to test the performance of different HCC staging systems in patients with HCC who were treated at our institution during the last decade. Methods: We prospectively enrolled 438 patients from early 2000 to late 2009. Baseline clinicopathologic parameters and staging were available, including the TNM, Cancer of the Liver Italian Program (CLIP), Barcelona Clinic Liver Cancer (BCLC), Okuda, and Chinese University Prognostic Index (CUPI). We performed survival and cox-regression analyses, and compared the staging systems’ predictive ability using Harrell's C-index. Finally, we performed a subgroup analysis of 3 independent cohorts based on whether or not they received sorafenib, whether or not they had hepatitis, and whether or not they had cirrhosis. Results: The overall survival was 13.9 months. Overall, CLIP score was the most predictive staging system with a C-index of 0.71. 187 patients were treated with targeted therapies and 138 were treated with sorafenib after it was approved in 2007. CLIP score was the most predictive staging system with a C-index of 0.71 in the no sorafenib group, and 0.74 in the sorafenib group. In hepatitis patients, CLIP topped amongst all staging systems with a C-index of 0.75, and in patients without hepatitis, despite all staging systems having a poor predictive ability, CLIP score still had the highest C-index of 0.67. Similarly, CLIP score had the best predictive ability in patients with and without pre-existing liver cirrhosis, with C-indices of 0.73 and 0.68 respectively. There was no statistically significant interaction between CLIP score and hepatitis status, and CLIP score and liver cirrhosis. Thus, overall the CLIP score was the best predictive system in all cohorts. Conclusions: Our results suggest that the CLIP score has the highest stratification ability in our advanced HCC patient population, including several subgroups. Our study confirms the utility of the CLIP score to stratify advanced HCC patients in clinical trials.
An integrated cross-species approach for the discovery of serum-based diagnostic biomarkers of PDAC using a genetically engineered murine model (GEMM).
Authors: Skoulidis Ferdinandos , Schiess Ralph , Aebersold Ruedi , Venkitaraman Ashok R. 
Published: February 2017

218 Background: The development of sensitive and specific biomarkers for the early diagnosis of human pancreatic ductal adenocarcinoma (PDAC) represents a major unmet clinical need. GEMMs that faithfully recapitulate the clinical, histological and molecular features of PDAC and capture its genomic complexity (including that triggered by a truncating germline Brca2 mutation) coupled with state of the art proteomic technologies can overcome some of the challenges associated with the analysis of a heterogeneous human disease. We have conducted a large scale screen for differentially expressed glycoproteins in pancreatic tissue and serum from mice with PDAC, pancreatic intra-epithelial neoplasia (PanIN) and matched healthy controls, using the well validated KPCB model of PDAC. Methods: Tryptic digests of protein extracts from snap frozen PDAC, pre-malignant and normal pancreata were subjected to solid-phase extraction of N-glycopeptides and the samples were analysed on a LTQ Orbitrap XL mass spectrometer. LC-MS feature maps were compared employing SuperHirn software and used for the label-free quantification of corresponding proteins. Primary mPDAC cell lines and their supernatants were also analysed. Selected candidate proteins were then quantified in mouse serum by SRM-based targeted proteomics. Results: 146 glycoproteins were identified as overexpressed by >2 fold (p<0.05, Student’s t test) in PDAC compared to normal pancreas and 60 were prioritised for targeted identification in mouse serum. 12 proteins were significantly upregulated (p<0.01, Mann-Whitney U test ) in the serum of tumour-bearing mice with PDAC compared to controls. Conclusions: Using a state of the art GEMM of PDAC, we have successfully applied a two-stage strategy for the tissue-based identification followed by quantification in murine serum of a panel of glycoproteins that are consistently over-expressed during mPDAC development. Validation in serum collections from patients with PDAC, chronic pancreatitis and healthy controls is underway and updated results will be presented at the conference.