bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of microRNA (MiRNA) expression profiles between opisthorchis viverrini-associated cholangiocarcinoma (OV-CCA) and non-opisthorchis viverrini-associated cholangiocarcinoma (non-OV CCA).
Authors: Tanasanvimon Suebpong , Rashid Asif , Wongkham Sopit , Churi Chaitanya , Tong Zhimin , Fogelman David R. , Silsirivanit Atit , Blechacz Boris , Klaikaew Naruemon , Bhudhisawasdi Vajarabhongsa , Vauthey Jean-Nicolas , Javle Milind M. 
Published: February 2017

206 Background: Cholangiocarcinoma in Thailand and Laos is associated with the liver fluke Opisthorchis viverrini (OV). Molecular differences between OV-CCA and Non-OV CCA remain to be defined. MiRNAs are regulators of mRNA that result in transcriptional repression or gene silencing. MiRNA profiles of OV vs. non-OV CCA have not yet been studied. Methods: 50 OV-CCA and 16 non-OV CCA pathological samples were obtained from Liver Fluke and Cholangiocarcinoma Center, Khonkaen University, Thailand and University of Texas, MD Anderson Cancer Center (MDACC), USA, respectively. Macrodissected common bile duct samples from MDACC were used as control groups. Global miRNA expression profiling was performed using the miRCURY LNA microRNA Array (Exiqon).qRT-PCR and in situ hybridization (ISH) were used to validate the miRNAs noted to be significant on the microRNA array. Results: Ten samples of OV and non-OV CCA were analyzed for global miRNA expression; 46 were used for validation. MiRNA microarray identified 71 miRNAs that were differentially expressed between OV-CCA and non-OV CCA (p<0.05). Of the 25 miRNAs with increased expression in OV-CCA, miR-141 and miR-200c were highly significant (p<0.01). These were overexpressed in OV-CCA as compared to control bile duct samples. The validation set on qRT-PCR showed significant miR-200c overexpression in 12 OV-CCA samples (p=0.02) and under expression in four non-OV CCA samples (p=0.006). ISH demonstrated miR-200c overexpression in 32 of 45 (71.1%) OV-CCA samples and 2 of 8 (25%) non-OV CCA samples. There was a trend toward better survival in OV-CCA patients with high miR-200c expression (9.5 vs 5.2 months, p=.08). Conclusions: MiRNA expression profiles differ between OV-CCA and non-OV CCA. MiR-200c was overexpressed in OV-CCA but under expressed in non-OV CCA. MiR-200C is known to repress epithelial-mesenchymal transition and its overexpression in OV-CCA may provide important insight into the distinct pathogenesis and prognosis of OV-CCA.
Combination therapy of intra-arterial 5-fluorouracil and systemic pegylated interferon alpha-2b for advanced hepatocellular carcinoma.
Authors: Kasai Kazuhiro , Sawara Kei , Suzuki Kazuyuki 
Published: February 2017

216 Background: Two recent phase III clinical trials have shown that sorafenib improves the survival in patients with advanced hepatocellular carcinoma (HCC). However, patients with HCC and portal vein tumor thrombosis (PVTT) usually have very short survival even when treated with sorafenib. On the other hand, recent advances in implantable drug delivery systems have made it possible to administer repeated hepatic arterial infusion chemotherapy (HAIC) agent. Since 2006, we have treated the patients displaying advanced HCC with PVTT by combined HAIC of 5-fluorouracil (5-FU) and systemic pegylated interferon (PEG-IFN)α-2b, and reported favorable results. In this article, we evaluated the efficacy of combined 5-FU and PEG-IFN α-2b, and compared outcomes between advanced HCC patients with PVTT treated using sorafenib. Methods: Forty patients with HCC and PVTT were enrolled. Of these, 21 patients were treated using subcutaneous administration of PEG-IFNα-2b and intra-arterial infusion of 5-FU [5-FU / PEG-IFN group], 19 patients were treated using continuous oral treatment with 400-800 mg of sorafenib [Sorafenib group]. We compared the early response to the therapy and the cumulative survival rate between these two groups. Results: The objective early response rate in the 5-FU / PEG-IFN group was significantly higher than that in the Sorafenib group (71.4 vs. 10.5%, P<0.01). The cumulative survival rates at 6, 12, 18, and 24 months, respectively, were 83.8, 77.8, 55.6, and 55.6% in the 5FU / PEG-IFN group, and 68.4, 37.7, 16.2, and 16.2% in the Sorafenib group. The cumulative survival rates was significantly higher in the 5FU / PEG-IFN group than in the Sorafenib group (P=0.03). Serious complications and treatment-related deaths were not observed in the 5FU / PEG-IFN group. On the other hand, the rate of discontinuation of treatment due to adverse events was 36.8% of the patients who were treated sorafenib. Conclusions: Based on our findings, this newly developed combination therapy may be useful for patients with advanced HCC, although a large-scale randomized controlled study by comparison with sorafenib is needed.
Pancreaticoduodenectomy versus radiosurgery for octogenarians with pancreatic head adenocarcinoma.
Authors: Hogg Melissa Ellen , Kim Carolyn H , Boone Brian A. , Lee Kenneth K , Moser Arthur J. , Bartlett David L , Heron Dwight Earl , Burton Steven A. , Zeh Herbert J. , Zureikat Amer H. 
Published: February 2017

220 Background: Recent reports have justified pancreaticoduodenectomy (PD) in octogenarians. Given the morbidity of PD and the increasing availability of stereotactic body radiosurgery (SBRT) we compared survival and morbidity of PD vs SBRT in octogenarians. Methods: A retrospective chart review was performed on all octogenarians with pancreatic head adenocarcinoma (PDA) who underwent open PD or SBRT from 2002-2011. Results: Twenty-six patients underwent PD, 17 (65%) resectable and 9 (35%) borderline, and 14 patients underwent SBRT, 10 (71%) resectable and 4 (29%) borderline (p=NS). All PD pts underwent R0/R1 resection. The groups differed in mean age (PD=83 vs SBRT=86 years, p=.01) and sex [males: PD=16 (62%) vs. SBRT=4 (29%)], but had the same BMI, Charlson Comorbidity Index, Karnofsky Performance Status, tumor size, and nodal status (p=NS). Of the SBRT group, 8 (57%) refused surgery; females were more likely to refuse surgery than males (8 (80%) vs 0, p=.0063). Compared to PD, SBRT patients took longer to intervention (26 vs 68 days, p=.0001). Twelve (46%) PD and 5 (36%) SBRT patients received chemotherapy (p=NS).Compared to the PD group, SBRT patients had no treatment related 90 day mortalities (0 vs 2 (8%), p=0.29), no complications (0 vs 14 (54%), p=.0007), and reduced length of hospital stay (0 vs 18.5 days, p=.0001). PD complications included pancreatic fistula and delayed gastric emptying in 3 (12%) and 4 (15%) patients respectively, and disposition was home=8 (31%), rehab=12 (46%), Skilled Nursing Facility =5 (19%), and Long Term Acute Care 1=(4%). Median time to metastasis was similar (PD=8.7 vs SBRT=7.3 months, p=NS). Median overall survival (PD=10.4 vs SBRT=10.2, p=NS) was the same in both groups. Four (15%) PD patients, stage II, are still alive (42-58 months); however, no SBRT patients are alive or have survived greater than 17 months. Conclusions: Octogenarians tolerated SBRT without morbidity, mortality, admission, or loss of independence compared to PD. Within this small series, disease specific survival and disease progression were not different between SBRT and PD raising a provocative question when counseling octogenarians about treatment strategy for head PDA.
Phase II study of induction therapy with gemcitabine and nab-paclitaxel followed by consolidation with mFOLFIRINOX in patients with metastatic pancreatic cancer.
Authors: Ramanathan Ramesh K. , Lee Peter , Leach Joseph W. , Anthony Stephen Patrick , Weiss Glen J. , Rosen Peter J. , Picozzi Vincent J. , Sachdev Jasgit C. , Larson Tim , Korn Ronald , Hu Chengcheng , Jameson Gayle S. , Stoll Amy C. , Von Hoff Daniel D. , Seng John E. 
Published: February 2017

233 Background: We designed a phase II study to evaluate the efficacy, toxicity and feasibility of administering nab-paclitaxel/gemcitabine (NabP-Gem) followed by mFOLFIRINOX in MPC. Methods: Eligible patients had evidence of untreated MPC with performance status of ECOG 0-1 and adequate organ function. Induction therapy was with Nab-P (125 mg/m2) and Gem (1000 mg/ m2) weekly x 3 every 4 weeks for a maximum of 6 months (6 cycles). mFOLFIRINOX every 2 weeks (Consolidation regimen) was initiated after 6 cycles of the Induction regimen, or earlier in case of progression, and given upto 6 months (12 cycles). The FOLFIRINOX regimen (NEJM,364:1817-25: 2011) was modified to omit the bolus 5FU and requires addition of granulocyte growth factor prophylaxis. A primary endpoint is to increase 1 year survival (n=30) to >70%, (95% confidence intervals for one year survival rate is +/- 20%). Results: As of 9/1/2012, 26 of 30 subjects have been accrued. M/F ratio is 58%/42%, median is 65 years. In 20 patients treated on the induction phase, 75% have a > 90% decrease in CA 19-9 levels. The partial response rate (PR) in the first 19 patients who have completed 4 cycles is 50%. Early image analysis on 9 subjects with concurrent CT and PET showed 44% PR (RECIST 1.1) but 89% by CHOI and PET criteria. A novel approach to interrogate tumor texture composition demonstrated substantial change in lesion texture following induction therapy. To date selected Grade > 3 adverse events are neutropenia (n=8), fatigue (n=5), thromboembolic events (n=4), peripheral neuropathy (n=3), dehydration (n=2), anemia (n=3), thrombocytopenia (n=2), febrile neutropenia (n=2) and myalgias (n=2). Among 26 patients who have received at least one cycle of NabP-Gem, ten dose reductions and four dose delays were seen. To date, 11 patients have begun the Consolidation regimen with mFOLFIRINOX. Conclusions: The induction NabP-Gem regimen shows preliminary evidence of substantial activity similar to published reports (JCO.29:4548-54: 2011). Study will now evaluate the safety, efficacy and feasibilty of the Consolidation regimen with mFOLFIRINOX. Supported by the Seena Magowitz Foundation. Clinical trial information: NCT01488552.
Patterns of recurrence and outcomes in pancreatic cancer.
Authors: Chen Kathryn Tzung-Kai , Singla Smit , Papavasiliou Pavlos , Arrangoiz Rodrigo , Gaughan John P. , Hoffman John Parker 
Published: February 2017

234 Background: There is limited evidence supporting improved overall survival in patients with pancreatic cancer with isolated lung metastases compared to other metastatic sites. We reviewed our experience with patterns of metastases and outcomes in pancreatic cancer. Methods: A retrospective review of 378 patients who underwent potentially curative pancreatic resection for pancreatic adenocarcinoma at a tertiary care cancer center between 1997-2010. All patients were restaged in accordance with AJCC 7th edition guidelines. Kaplan-Meier analysis with log-rank test and Cox regression was used to compare median overall and disease-free survival (OS and DFS). Results: Patients were divided into 8 groups based upon site of first recurrence. 40% of patients were without evidence of recurrence at time of last follow up (n=165). Sites of first recurrence are as follow: liver (n=93, 24.6%), lung (n=37, 9.8%), locoregional (n=49, 13%), peritoneum (n=17, 4.5%), bone (n=6, 1.6%), and distant (n=2, 0.5%). 23 patients (6.1%) presented with multiple sites as first recurrence. Patients with isolated lung metastases had longest median OS while those with liver metastases had the shortest median OS (32 months vs. 17 months, p<0.001). Time to recurrence for lung vs. liver metastases was 14.9 vs. 7.4 months (p<0.005). Patients with liver metastases uniformly had significantly worse median OS as compared to other sites of recurrence. Finally, with respect to isolated lung recurrences, only CA19-9 was a significant prognostic factor. Those patients with a CA19-9 at diagnosis >185 had a 5-fold greater risk of death in our length of follow-up. Conclusions: Pancreatic cancer patients with isolated lung metastases as the site of first recurrence have improved OS compared to other sites, while patients with liver metastases have worse OS. CA19-9 >185 at time of diagnosis among patients with isolated lung recurrences was predictive for worse outcomes.
A phase I study of GC33 in Japanese patients with advanced hepatocellular carcinoma (HCC).
Authors: Okusaka Takuji , Ikeda Masafumi , Ohkawa Shinichi , Yamamoto Shunsuke , Suzuki Ikue , Furuse Junji 
Published: February 2017

235 Background: Glypican-3 (GPC3) belongs to a family of cell-surface heparan sulfate proteoglycans and is specifically expressed in HCC. In this phase I study, we examined the safety, tolerability, and pharmacokinetics of GC33, a recombinant, humanized monoclonal antibody against GPC3, in Japanese patients (pts) with advanced HCC. Methods: This study was a 3+3 design for dose escalation to determine the maximum tolerated dose (MTD) of GC33 given intravenously at 5, 10, and 20 mg/kg weekly. Key eligibility criteria included histological or cytological confirmation of HCC, ECOG PS ≤ 1, Child-Pugh A or B, adequate organ function, and tumor tissues available for GPC3 immunohistochemistry. Results: Thirteen pts were enrolled at 3 dose levels: median age=65 years (range 48-78), M/F=12/1, ECOG PS 0/1=9/4, HBV/HCV=4/8, liver cirrhosis +/-=8/5, Child-Pugh A (5-6)/B (7) =10/3. All pts received prior systemic therapy including sorafenib. Treatment was well tolerated at all dose levels without DLT, and MTD was not reached. The most common AEs were lymphocyte count decrease (77%), Natural Killer cell count decrease (77%), C-reactive protein increase (69%) and pyrexia (62%). Grade 3 AEs (≥ 2 pts) were lymphocyte count decrease (23%), blood pressure increase (23%) and platelet count decrease (15%). Infusion reactions were seen in 62% of pts and medically manageable. Anti-GC33 antibody was not detected in any of the patients. PK analysis of GC33 showed a half-life of 4 to 7 days and dose proportional for AUC after the first dose. Trough concentrations reached a steady state after 4 to 6 doses. Twelve out of 13 biopsied tumor specimens showed immunoreactivity with mouse GC33 antibody. There was no CR or PR, but 7 SD and 3 of them had SD for more than 5 months before progression (all with GPC3 expression). Conclusions: GC33 was well-tolerated up to 20 mg/kg weekly in Japanese HCC pts with Child-Pugh A or B liver cirrhosis and potentially beneficial to GPC3+ HCC. A randomized phase II study of GC33 monotherapy as 2nd line therapy in advanced HCC pts is currently ongoing. Clinical trial information: JapicCTI-101255.
Activity observed in a phase I dose escalation trial of the hypoxia-activated, NO prodrug, RRx001.
Authors: Reid Tony R. , Infante Jeffrey R. , Burris Howard A. , Scribner Curtis , Knox Susan Jane , Oronsky Bryan , Stephens Janet L. , Scicinski Jan 
Published: February 2017

241 Background: RRx-001, the first member of a new class of anticancer compounds sourced from the defense industry, is a hypoxia-selective, nitrite reductase-activated prodrug of nitric oxide (NO). The active metabolites selectively enhance oxidative and nitrosative stress in cancer cells through glutathione depletion, ROS formation, and the generation of high local concentrations of NO. The objectives of this Phase 1 dose-escalation trial were to investigate safety, dose-limiting toxicities (DLTs), pharmacodynamics and pharmacokinetics (PK) of RRx-001. Methods: Eligible patients had advanced solid tumor malignancies; ECOG PS 0-2; adequate bone marrow function. In a 3+3 escalation design, RRx-001 was administered intravenously (IV) over 2-3 hours once weekly for 8 weeks to patients with advanced cancer in successive dose-escalating cohorts. PK was collected on days 1 and 50, and tumor blood flow, assessed by CEUS or DCE/DWI-MRI, was performed on days 1 and 8. Tumor response was determined every 8 weeks. Results: To date 12 patients have been dosed across 3 successive cohorts (10, 16.7, and 24.6 mg/m2). Tumor types included pancreas (3), colorectal (5), head and neck (2), melanoma (1), and cholangiocarcinoma (1). No DLTs or treatment-associated SAEs were observed. Transient infusion site pain was reported in 10/12 patients, grade 1 (9/10) or grade 2 (1/10), generally managed by lengthening the infusion duration and using peripheral venous access. No relevant treatment-related changes in laboratory values were observed. Seven patients were evaluable for response, with 1 partial response (parotid tumor). Three patients had stable disease ≥ 2 months (2 pancreas, 1 colorectal with treatment duration 10+ months, exceeding the response to his previous chemo regimen). One pancreas patient with an increase in tumor size due to treatment-related central necrosis was diagnosed with pseudoprogression and remained on study for 4 months. Conclusions: RRx-001, an anticancer agent with a novel structure and mechanism of action, is well tolerated with mild infusion-site pain. PK and PD data will be presented. Escalation is ongoing, but preliminary evidence of anti-tumor activity is promising. Clinical trial information: NCT01359982.
A retrospective review of chemotherapy for patients with small bowel adenocarcinoma in British Columbia.
Authors: Duerr Donat , Ellard Susan , Cormier Eric , Taylor Marianne , Rao Sanjay C. 
Published: February 2017

242 Background: Small bowel adenocarcinoma (SBA) can be associated with a poor prognosis. Randomized phase III trials of chemotherapy are not available due to the rarity of the disease. The Provincial Cancer Registry of the British Columbia Cancer Agency (BCCA) contains data on patients with SBA. Therefore we analyzed the outcome of patients with SBA diagnosed between 1990 and 2008. Methods: Individual charts of 150 patients with a histological diagnosis of SBA were retrospectively analyzed. Epidemiological data as well as information on chemotherapy administered were collected. DFS, PFS and OS were estimated by the Kaplan-Meyer method. Cox proportional hazards regression was performed to model the dependence on different parameters and model selection was done to determine their significance. Results: The baseline characteristics of patients, such as median age at diagnosis (65 years), tumor stage (I-II 33%, III-IV 58%, unknown 9%), and tumor location (duodenum 48%, jejunum 31%, ileum 21%) were consistent with data published in the literature. 55% of our patients had a positive family history of cancer; 29% developed a second tumor. CEA was elevated in 84% of stage IV patients, while it was normal in 85% of stage I-III patients. The DFS of 28 patients treated with adjuvant chemotherapy was identical to that of 47 patients without. However prognostic factors such as nodal status were not well balanced in the two groups. In the palliative setting patients treated with polychemotherapy (20 patients) had a statistically better OS than patients treated with monochemotherapy (12 patients) (p= 9.31e-06). Conclusions: Our study suggests a survival benefit for advanced-stage SBA patients treated with poly- versus monochemotherapy. However it should be taken in account that this is a retrospective analysis with several potential confounders. Nevertheless our study adds support to the body of evidence that chemotherapy may be beneficial for patients suffering from SBA, at least in the palliative setting.
Should all patients (pts) with advanced biliary cancers receive first-line treatment with cisplatin and gemcitabine (GC)?
Authors: Miranda Vanessa Costa , Dib-Faria Luiza , Braghiroli Maria Ignez Freitas Melro , Sabbaga Jorge , Saragiotto Daniel Fernandes , Castro Gilberto , Hoff Paulo M. , Riechelmann Rachel 
Published: February 2017

244 Background: GC is considered the standard of care for pts with advanced biliary tract cancer (BTC), providing median survival of nearly one year. (Valle J et al. NEJM 2010) Nevertheless, many pts experience poor outcomes, leading to a growing interest to identify pts who might benefit from such treatment. Here we aimed to investigate clinical and laboratory factors associated with poor survival among BTC pts treated with GC. Methods: We retrospectively evaluated all consecutive pts with advanced/metastatic BTC who received first line GC at the Instituto do Cancer do Estado de Sao Paulo, Brazil, in a 2 year-period. Clinical and laboratory variables that could influence pts’ outcomes were gathered from medical charts. Cox regression proportional hazard model was used to investigate the following prognostic factors for death: pre-treatment biliary deobstruction, baseline Ca 19.9, any GC interruptions or dose reductions, baseline ECOG status, Charlson Comorbidity Index (CCI) and age. P values < 0.05 in multivariable analysis were considered significant. Results: From January/2009 to July/2011, 72 pts were identified. The median age was 60 years (range 30-80 years), 45 pts (62.5%) were female and 50 (69.4%) presented baseline ECOG 0-1. The median number of cycles of CG was 4 (range 1-9). Grade 3 /4 neutropenia and thrombocytopenia occurred in 16.6% and 12.5% of pts, respectively. Median survival of the whole cohort was 9.53 months (95% CI: 6.2 - 11.4). Median survival in pts with ECOG 0/1 was 13.5 months (95% CI: 9,5 – NR) and among pts with ECOG 2/3 3,5 months (95% CI: 1-7). In the Cox multivariable model, ECOG 2 /3 versus 0/1 (HR: 8.4, 95% CI: 3.4 to 20.7; p<0.001) and CCI score ≥ 2 (HR: 9.5 95% CI: 1.6 to 55.3; p= 0.012) significantly predicted for poor survival. There was a trend for improved survival among pts who had biliary drainage before starting GC (HR: 2.3 95% CI: 1.0 - 5.3; p= 0.051). Conclusions: In this retrospective cohort of unselected pts with advanced BTC treated with first line GC, poor performance status and multiple comorbid illnesses were associated with dismal prognosis. Treatment with GC should be carefully discussed before being offered to these pts.
Phase II consortium (P2C) study of gemcitabine and tanespimycin (17AAG) for metastatic pancreatic cancer.
Authors: McWilliams Robert R. , Foster Nathan R. , Wang-Gillam Andrea , Erlichman Charles , Kim George P. 
Published: February 2017

245 Background: Gemcitabine (GEM) monotherapy for PDA has modest activity. 17-N-Allylamino-17-demthoxygeldanamycin (Tanespimycin/17AAG), is an HSP90 inhibitor, which results in degradation of a number of client proteins such as RAF and Akt. Arlander et al (J Biol Chem. 2003 278:52572-7) have demonstrated that 17AAG targeting of HSP90 leads to Chk1 degradation. Chk1 is upregulated with GEM treatment which affects cell survival (Karnitz et al. Mol Pharmacol. 2005 68:1636-44). In vitro, the combination demonstrated in vitro synergy. Thus the potential clinical activity in pancreatic cancer of the combination was explored. Methods: A phase II multicenter prospective study was performed using GEM 750 mg/m2 d1,8 and 17AAG 154 mg/m2 d2,9 on a 21 day cycle, as defined in a previous phase I trial. Patients with stage IV PDA, with adequate liver, kidney function and counts, ECOG 0-2 and no prior therapy for metastatic disease were eligible. The primary endpoint of 60% overall survival at 6 months was considered of clinical interest. Sixty-six patients were planned for accrual, and an interim analysis was planned after 25 evaluable patients. Informed, written consent was obtained from all pts. Results: Due to lack of drug availability and failure to achieve the planned endpoint, accrual was halted at 21 pts, enrolled from 5/08 to 9/10, of which 20 were evaluable (1 cancelled prior to treatment). Median age was 61.5 yrs., 55% were male, PS 0 (50%), 1 (45%), 2 (5%); 95% were non-Hispanic white, 1 was African American. Two had received adjuvant therapy for PDA. Tolerability was moderate, with 13 pts (65%) having > grade 3 adverse event (AE), with 15% gr 4 AEs and 0% gr 5. Nausea (20%), vomiting (20%), constipation (15%), dehydration (15%), and anorexia (10%), were the most common non-heme AEs. Lymphopenia (15%), leukopenia (10%) and neutropenia (10%) were common grade 3 hematologic AEs. No complete or partial responses were seen. 40% of patients were alive at 6 months, with a median OS of 5.4 months. Conclusions: HSP 90 inhibitor 17AAG in combination with GEM does not show activity for treatment of PDA. Further trials should not be pursued with this combination. Supported by N01-CM-62205. Clinical trial information: NCT00577889.