bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of inhibition of poly-(ADP ribose) polymerase on gemcitabine and radiation-induced cytotoxicity of pancreatic cancer cells.
Authors: Tuli R. , Surmak A. , Blackford A. , Leubner A. , Jaffee E. M. , DeWeese T. L. , Herman J. M. 
Published: February 2017

203 Background: Poly-(ADP ribose) polymerases (PARPs) are DNA-binding proteins involved in DNA repair. PARP inhibition has resulted in excellent antitumor activity when used with other cytotoxic therapies. ABT-888 is a promising PARP inhibitor with excellent potency against the PARP-1/2 enzymes and good oral bioavailability. We attempt to determine whether PARP-1/2 inhibition alone, or in combination with gemcitabine, will enhance the effects of irradiation (RT) of pancreatic cancer cells. Methods: The pancreatic carcinoma cell lines, MiaPaCa-2 and Panc02, were treated with ABT-888, gemcitabine, RT, or combinations thereof. RT was delivered with a 137-Cs Gammacell in a single fraction. Cells were pre-treated once with ABT-888 and/or gemcitabine 30 minutes prior to RT. Viability was assessed through reduction of resazurin into fluorescent resorufin. Levels of apoptosis were determined by measuring caspase-3/7 activity using a luminescent assay. PARP activity was determined using a chemiluminescent PAR elisa. Results: The half maximal inhibitory concentration (IC50) of RT was 5 Gy; IC10 for ABT-888 and gemcitabine were 10 uM and 5 nM, respectively. Treatment with ABT-888 (10 uM), gemcitabine (5 nM), or combinations of the two with RT led to increasingly higher rates of cell death 8 days after treatment (p<0.001). RT dose enhancement factors were 1.5, 1.82 and 2.36 for 1, 10 and 100 uM ABT-888, respectively. Minimal cytotoxicity was noted when cells were treated with ABT-888 alone up to 100 uM. Caspase activity was not significantly increased when treated with ABT-888 (10 uM) alone (1.28 fold, p=0.077), but became significant when RT (2 Gy) was added (2.03 fold, p=0.006). This difference was further enhanced by the addition of gemcitabine (2.95 fold, p=0.004). Conclusions: ABT-888 is a potent radiosensitizer of pancreatic cancer cells with minimal cytotoxicity when used alone. Cell death is further potentiated by cotreatment with gemcitabine. Radiation-induced apoptosis was significantly enhanced by ABT-888 and gemcitabine, suggesting a synergistic mechanism of interference with DNA repair. These data are currently being validated in an orthotopic pancreatic cancer mouse model. No significant financial relationships to disclose.
Early-onset gastric cancer: A distinct clinical entity with a different prognosis?
Authors: Santos Sousa H. , Bouca-Machado T. , Lima-da-costa E. , Pinto-de-Sousa J. , Preto J. , Sousa-Rodrigues J. , Costa-Maia J. 
Published: February 2017

22 Background: This study aimed to evaluate the early onset gastric cancer (EOGC), considered as gastric cancer in a patient younger than 45 years, as a distinct entity with a different prognosis. Methods: This study is related to 1,256 patients admitted with gastric or gastroesophageal junction carcinoma in our department between January 1988 and December 2008. There were 10.59% (133 cases) of EOGC in our series. The following clinical, pathological and staging parameters were studied: age, gender, tumor location, ressecability, type of resection surgery, type of resection, type of lymphadenectomy (Siewert and Japanese classifications), number of lymph nodes studied, tumor dimensions, macroscopic form, histological classification (Lauren and Ming), venous invasion, lymphatic permeation, perineural invasion, depth wall invasion (T), lymph node metastases (N) – TNM and Japanese classification and lymph node ratio – distance metastases (M) and stage. Results: Significant differences were observed in the type of resection surgery (p<0.001) and type of lymphadenectomy (p=0.008), with more radical surgery performed in EOGC patients. Some tumor characteristics also showed significant differences: tumor dimensions (p=0.004), with EOGC usually smaller; diffuse type according to Lauren's classification (p<0.001); infiltrative type according to Ming's classification (p=0.001); less venous invasion (p=0.005); less lymphatic permeation (p=0.029). There were no significant differences in the staging parameters. There were significant differences in the survival rate (p<0.001), with 5-year survival rate of 44% in patients with EOGC compared with 31% in older patients. Cox-regression analysis revealed that age was an independent prognostic factor (HR 2,166, 1,133-4,139 CI 95%, p = 0.019), as well as depth wall invasion (T) and lymph node ratio. Conclusions: In this study, EOGC revealed to be a distinct clinical entity that presented differences in various clinico-pathological parameters. Despite EOGC presented more aggressive pathological characteristics, there was a better survival in this group, probably because the physical status of younger patients which allowed a more aggressive treatment. No significant financial relationships to disclose.
Pattern of in vitro chemotherapy response in pancreatic cancer and its clinical implication.
Authors: Franko J. , Bilimoria M. M. , Chalikonda S. , Iannitti D. A. 
Published: February 2017

229 Background: Gemcitabine and 5-fluorouracil (5-FU) with or without oxaliplatin are used to manage advanced or recurrent pancreatic cancer. Options are limited for patients who do not respond to these agents. This study determined the pattern of response to alternative agents using an in vitro chemotherapy assessment. Methods: From August 2006 to January 2010, 113 tumor specimens from pancreatic cancer patients were tested for response to gemcitabine, 5-FU, oxaliplatin, docetaxel, or irinotecan using an in vitro chemosensitivity assay (ChemoFx, Precision Therapeutics, Inc., Pittsburgh PA). Tumors were classified as sensitive or resistant based on in vitro dose response curves. Results: Thirty-five percent of tumors exhibited in vitro chemosensitivity to irinotecan, 23% to gemcitabine, 19% to 5-FU, 9% to oxaliplatin, and 8% to docetaxel. For tumors resistant to gemcitabine, 23% were sensitive to irinotecan, 6% (4/72) to 5-FU, 3% (2/68) to oxaliplatin, and 2% (1/64) to docetaxel (Table). Of the 68 tumors resistant to both gemcitabine and 5-FU, 11/59 (19%) were sensitive to irinotecan, 2/61 (3%) to oxaliplatin, and 0/57 (0%) to docetaxel. Forty-nine tumors were resistant to all tested agents. Conclusions: ChemoFx analysis of pancreatic cancer patient specimens indicates a high resistance rate to gemcitabine and 5-FU. The sensitivity of 19% of the gemcitabine/5-FU resistant specimens to irinotecan suggests that some patients who do not respond to standard therapy may respond to irinotecan. The potential of ChemoFx to identify the potentially most effective therapy in pancreatic cancer patients will be examined in future studies. [Table: see text] [Table: see text]
Effect of a histone deacetylase inhibitor on antitumor effect of gemcitabine to focus the gene network of ingenuity pathways analysis.
Authors: Iwahashi S. , Shimada M. , Utsunomiya T. , Imura S. , Morine Y. , Ikemoto T. , Mori H. , Hanaoka J. , Saito Y. 
Published: February 2017

230 Background: Histone deacetylase (HDAC) is strongly associated with epigenetic regulation and carcinogenesis, and its inhibitors induce the differentiation or apoptosis of cancer cells. Valproic acid (VPA) is one of the clinically available HDAC inhibitors. We previously showed that VPA augmented antitumor effect of GEM in choalngiocarcinoma cell line (2010 GI Symposium); this time, we performed microarray analysis and Ingenuity Pathways Analysis (IPA) to identify the systematic mechanism of the augmentative effect of VPA. Methods: Human cholangiocarcinoma cell line (HuCCT1) was used. The anticancer effects of VPA or gemcitabine (GEM), and the effects of VPA combined with GEM were studied by MTT assay. We divided the following four groups: control group, VPA group, GEM group, VPA plus GEM combination group. The gene expressions of p21, HDAC, VEGF, and HIF-1 were evaluated by RT-PCR. And, the microarray analysis was performed, the genes were picked up using Gene Spring GX10, and then IPA was performed. Results: In GEM alone group, no effect of GEM was observed in dose of 5 mm, and 16% of proliferation-inhibitory effects were observed in dose of 10 nm. In VPA alone group, no effect of VPA was observed in dose of 0.5 mm, and 12%, 35%, and 67% of proliferation-inhibitory effects were observed in dose of 1.0, 5.0, and 10mm, respectively. GEM (5 nm) and VPA (0.5 mm) reduced by 23%, which significantly augmented the anticancer effect of GEM alone or VPA alone (p<0.01). Furthermore, GEM combined with VPA upregulated the p21 expression compared with single agent (p<0.05). And, in regard to microarray analysis, we analyzed in 28,869 genes. The 24 genes were picked up with the comparison between VPA group and VPA plus GEM combination group using Gene Spring GX10, and the gene network of the cellular development containing the gene relevant to the differentiation of cancer cell, HLA-DR, was formed with IPA. Conclusions: VPA augmented the effects of anticancer agents in a cholangiocarcinoma cell line. Such effects may be owing to the gene network of the cellular development. HDAC inhibitor may have the effect of the differentiation of cancer cell. No significant financial relationships to disclose.
Randomized phase II trial of panitumumab (P), erlotinib (E), and gemcitabine (G) versus erlotinib-gemcitabine in patients with untreated, metastatic pancreatic adenocarcinoma.
Authors: Kim G. P. , Foster N. R. , Salim M. , Flynn P. J. , Moore D. F. , Zon R. , Mowat R. B. , McCullough A. , Meyers J. P. , Alberts S. R. 
Published: February 2017

238 Background: Dual inhibition of the EGFR pathway using erlotinib and the monoclonal antibody panitumumab results in greater antitumor activity in preclinical pancreatic cancer models. A trial evaluating this approach was conducted. Methods: A safety analysis was initially performed with 6 patients at P 4 mg/kg every two weeks, E 100 mg daily, G 1000 mg/m2 weekly of a 28-day cycle. PGE was well tolerated with a grade 3 fatigue as only dose-limiting toxicity. Patients (pts) were then randomized to either PGE or GE alone. Eligibility included: no prior chemo, ECOG PS 0-1, bilirubin <2x UL, AST <2.5x UL. CT scans every 2 cycles. Results: 93 pts (46-GE; 47-PGE) were randomized from January to August, 2010. Median age 61 years and 65% male. ECOG PS 0 (51%) and PS 1 (49%). No significant differences in baseline characteristics observed between treatment arms. 81 pts evaluable for AEs; 37 (46%) had a maximum grade 3 (at least possibly related to treatment), and 12 (15%) maximum grade 4 or 5. Treatment arms similar with respect to the overall AEs with exception grade 1-3 acneiform rash, GE (65%) vs. PGE (85%). Commonly occurring grade 4 AEs (at least possibly related) consisted of thrombosis (3 pts) and thrombocytopenia (2 pts). Two grade 5 events occurred in PGE arm—duodenal hemorrhage (possibly related) and pancolitis with multisystem failure (unlikely). An additional PGE pt died 30 days off study (grade 5 CHF, possibly). 54 patients (67%; 31-GE, 23-PGE) ended treatment; 38 (70%) for disease progression (24-GE; 14-PGE). Other reasons for treatment discontinuation: AEs (9; 17%), pt refusal (4; 7%), death on study (2; 4%), other (1). In 81 pts with at least 1 cycle of chemotherapy, the median PFS for GE 2.0 months and 3.3 months for PGE. Accrual for the study was recently completed and overall and 6-month survival data will be presented. Conclusions: This study involved an initial run-in design to define tolerable doses of dual EGFR inhibitors, PGE, in pancreatic cancer patients. Although preliminary, the randomized phase II portion has been completed and differences between GE and PGE in terms of relevant clinical outcomes, PFS, are observed. No significant financial relationships to disclose.
Carcinoma of the ampulla of Vater: Patterns of failure after resection and benefit of adjuvant radiotherapy.
Authors: Palta M. , Willett C. G. , Patel P. , Tyler D. S. , Uronis H. E. , Czito B. G. 
Published: February 2017

254 Background: Ampullary carcinoma is a rare malignancy. Despite radical resection, survival rates remain low with high rates of local failure. To define the role of radiation therapy and chemotherapy with surgery, we performed a single institution analysis of treatment- related outcomes. Methods: A retrospective analysis was performed of all patients undergoing potentially curative therapy for adenocarcinoma of the ampulla of Vater at Duke University Hospitals between 1975 and 2009. Local control (LC), overall survival (OS), disease-free survival (DFS), and metastases-free survival (MFS) were estimated using the Kaplan-Meier Method. Results: One hundred thirty-seven patients with ampullary carcinoma underwent potentially curative pancreaticoduodenectomy. Sixty-one patients undergoing resection received adjuvant (n= 43) or neoadjuvant (n=18) radiation therapy with concurrent chemotherapy (CRT). Patients receiving radiotherapy were more likely to have poorly differentiated tumors. Median radiation dose was 50 Gy. Median follow up was 8.8 years. Of patients receiving neoadjuvant therapy, 67% were downstaged on final pathology with 28% achieving pathologic complete response. Three-year local control was significantly improved in patients receiving CRT (88% vs. 55% p= 0.001) with trend toward a 3-year OS benefit in patients receiving CRT (62% vs. 46% p=0.074). Despite this, there was no significant difference in 3-year DFS (66% CRT vs 48% surgery alone p=0.09) or MFS (69% CRT vs 63% surgery alone p=0.337). Conclusions: Long term survival rates are low. Local failure rates are high following radical resection alone and improved with CRT. Despite more adverse pathologic features in patients receiving CRT, survival outcomes were at least equivalent with a trend toward statistical significance. Given the patterns of relapse with surgery alone and local control benefit in patients receiving CRT, the use of chemoradiotherapy in selected patients should be considered. No significant financial relationships to disclose.
Stage at presentation for medically underserved gastric cancer patients.
Authors: Alattar M. , Hahn K. , Wray C. J. 
Published: February 2017

26 Background: Survival disparities in the United States exist for nearly all malignancies. The relationship between stage at presentation and outcome is not well understood. Our hypothesis is that medically un- and underinsured gastric cancer (GC) patients present at advanced stage leading to worse outcomes. Methods: Institutional review board approved review of the departmental gastrointestinal cancer database from 04/08/2000 to 11/18/2008. All patients diagnosed with gastric adenocarcinoma were included; clinicopathologic, treatment and outcome data was recorded. Statistical analysis was performed using STATA 10. Results: A total of 185 patients (108 male, 77 female) were included in this study. Mean age at diagnosis for all patients was 55.3 yrs. The mean age at diagnosis was lower for Hispanics (52.4 years) when compared to other races (ANOVA p = 0.00). The majority of Hispanic patients presented with stage IV disease (55%, chi square p = 0.01). The age range and minimum age at diagnosis was different for Hispanics. Median survival for the entire cohort was 12.3 mo. Although not significant (log rank p = NS), median survival was lowest for African Americans (AA) and Asians. Cox proportional hazards model demonstrated surgical resection and adjuvant therapy (chemoradiation) to be independent predictors of survival. Conclusions: Hispanic patients in medically un- and underinsured populations showed significantly younger age at presentation and more advanced stage of GC. However, median survival for Hispanic GC patients was not significantly shortened compared to other races in this cohort. Survival for AA and Asian patients in a public safety net hospital remains poor and investigation into factors contributing to such disparities is ongoing. [Table: see text] No significant financial relationships to disclose.
Phase II study of fixed-dose-rate infusion of gemcitabine and UFT combination chemotherapy in patients with advanced bile duct cancer: Daegu Gyeoungbuk Oncology Group.
Authors: Ryoo H. , Bae S. , Kim M. , Lee K. H. , Song H. , Chae Y. , Lee W. , Baek J. 
Published: February 2017

280 Background: This phase II study evaluated efficacy of fixed dose rate (FDR) infusion of gemcitabine (10mg/m2/min) and UFT combination in chemo-naïve patients with advanced bile duct cancer. Methods: This was an open-label, single-arm, multicenter, phase II study with a Simon two-stage minimax design. Patients received the FDR gemcitabine 1,000mg/m2 for 3 consecutive weeks and UFT 400 mg/m2 on days 1-21. The cycle was repeated every 28 days. The primary end point was Response Evaluation Criteria in Solid Tumors (RECIST) -defined objective response rate. Secondary end points included clinical benefit response (CBR), safety, progression-free survival (PFS), and overall survival (OS). Clinical characteristics including four single nucleotide polymorphisms in DNA repair genes (RecQ1, RAD54L, XRCC1, ATM) were evaluated whether these influence the overall survival. Results: Between December 2006 and February 2008, fifty-one patients were enrolled, with a median age of 58 years. The majority of patients (76%) had intra-hepatic disease. Fourteen patients (27%) had a RECIST investigator-assessed, partial response (PR); disease control rate (PR + stable disease) was 55%. CBR was 14% among 37 evaluable patients. Hematologic toxicity was main grade 3 or 4 treatment-related adverse events. Median PFS was 4.0 months (95% CI, 2.9 to 5.1 months). Median OS was 7.0 months (95% CI, 3.5 to 10.5 months). Intrahepatic disease, poor performance, and, XRCC1 R194W C/C type were predictive markers of poor overall survival. Conclusions: FDR gemcitabine and UFT demonstrated apparent activity in patients with advanced bile duct cancer. However, this activity did not translate to prolong survival. The location of disease, performance status, and, polymorphic variants of DNA repair genes may affect clinical outcome of patients with advanced bile duct cancer. No significant financial relationships to disclose.
Augmenting chemotherapy response through EMAP II combination in experimental pancreatic cancer.
Authors: Awasthi N. , Schwarz M. A. , Yen P. L. , Schwarz R. 
Published: February 2017

294 Background: Gemcitabine (Gem), the most active drug for locally advanced, non-operable and metastatic PDAC, has limited benefits as single agent or in combination. Endothelial monocyte activating polypeptide II (EMAP, E) enhances Gem effects in PDAC. We evaluated the antitumor activities of EMAP in combination with doxorubicin (Dox) or docetaxel (DT) in PDAC. Methods: In vitro cell proliferation, protein expression and apoptosis were analyzed by WST-1 assay, Western blotting and FACS analysis. In vivo local tumor growth and animal survival experiments were performed in murine xenografts. Results: In vitro PDAC cell proliferation was not affected by EMAP, compared to a small inhibition by Dox, DT and Gem. EMAP combination to these agents did not increase the antiproliferative effects. In endothelial cells (ECs), EMAP, Dox, DT and Gem all inhibited proliferation (59, 79, 96 and 85% at 10 μM, respectively); addition of EMAP caused additive antiproliferative effects. In PDAC cells, no agent caused measurable apoptosis, but in ECs all agents either alone or in combination increased the apoptosis. In vivo, Dox, DT, Gem and EMAP all decreased local tumor growth, and addition of EMAP enhanced inhibitory effects of DT and Gem, but not of Dox (92, 63, 60, 42, 73, 85 and 68 % inhibition after Dox, DT, Gem, E, Dox+E, DT+E and Gem+E, respectively); DT followed by Gem led to 72% inhibition without EMAP, and to 99% with EMAP (p=0.001). Inhibition of intra-tumoral proliferative activity and increase of apoptotic index were enhanced in all EMAP combination groups. Compared to controls (median survival: 21 days), EMAP (20 d) had no, but Dox (31 d) and DT (35 d) had extended survival benefit. EMAP enhanced the DT effect (44 d, p=0.009) but not that of Dox (31 d, p=0.04). In a sequential therapy experiment, median survival after controls, Gem, DT, Gem followed by DT, DT followed by Gem, Gem+E, DT+E, Gem/DT+E and DT/Gem+E was 17, 25, 29, 39, 39, 28, 35, 34 and 41 days, respectively. Conclusions: The antiendothelial agent EMAP enhances antitumor effects of not just gemcitabine. Therefore, combination approaches with EMAP-like agents could render other drugs such as taxanes or their doublets sufficiently effective for clinical applications in PDAC therapy. No significant financial relationships to disclose.
Impact of adjuvant chemotherapy on time to relapse in cholangiocarcinoma.
Authors: Di Girolamo S. , Nobili E. , Derenzini E. , de Rosa F. , Agostini V. , Ercolani G. , Corbelli J. , Pinna A. , Biasco G. , Brandi G. 
Published: February 2017

299 Background: Biliary tract cancer is a rare malignancy with poor prognosis. Surgery is the only potential curative approach, but even if surgical intervention is performed correctly the relapse risk remains very high. In adjuvant setting only few randomized trials using no standard treatments and producing controversial data are reported in literature. Methods: This is a retrospective analysis on 144 consecutive biliary tract cancer patients (pts), undergone potentially curative resection in our institution (109 pts with R0 surgery and 31 pts with R1 surgery). The series included 57 intrahepatic cholangiocarcinomas (ICC), 68 extrahepatic cholangiocarcinomas (ECC), 19 gallbladder cancers (GBC) (Table). Median age was 63, 80 pts were males and 64 pts were females. 80 (60 R0 and 20 R1) out of 144 pts received adjuvant chemotherapy and the remaining 64 pts (49 R0 and 15 R1) started a follow-up program. Adjuvant chemotherapy schedule was gemcitabine 1000 mg/m2 at day 1, 8, 15 every 28, for six months. Results: Median time to relapse (TTR) in the treatment group and in the follow-up group were 18 months and 11 months respectively (p=0.038). No grade 3-4 chemotherapy-related adverse events were observed and only grade 1-2 thrombocytopenia occurred. This hematologic toxicity did not affect treatment dose intensity. Conclusions: Our preliminary retrospective analysis suggests a significant advantage of adjuvant treatment on TTR in radically resected biliary tract cancer patients, although further placebo-controlled double blind trials are required. [Table: see text] No significant financial relationships to disclose.