bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of body mass index (BMI) on outcomes after surgical resection and adjuvant therapy for pancreatic cancer patients.
Authors: Khawaja M. R. , Zyromski N. , Yu M. , Cardenes H. R. , Schmidt C. M. , Sandusky G. , Howard T. J. , Chiorean E. G.
Published: February 2017

185

Background: Obesity is one of the factors commonly associated with pancreatic cancer risk, but its prognostic role for survival is debatable. This study aimed to determine the role of BMI in treatment outcomes of pancreatic cancer patients (pts) undergoing surgical resection followed by adjuvant therapy.

Methods: We retrospectively reviewed 165 consecutive pts with pancreatic cancer undergoing pancreaticoduodenectomy at Indiana University Hospital between 2004 and 2008. Fifty-three pts who received adjuvant treatment [gemcitabine alone (C-group): n=19; gemcitabine + radiotherapy (CRT-group): n=34] at our institution were included in the analysis. The Kaplan-Meier method was used to estimate the disease-free survival (DFS) and overall survival (OS); log-rank test was used to compare these outcomes between BMI groups (normal 18.5-24.99 kg/m2 vs. overweight/obese ≥ 25 kg/m2).

Results: The sample comprised 53 pts (28 males; median age 62 yrs) with a median follow-up of 18.6 months (mos). Thirty pts (56.6%) had their BMIs recorded before the date of surgery, and 23 pts prior to starting adjuvant therapy. Two (3.8%) pts were underweight, 21 (39.6%) had a normal BMI and 30 (56.6%) were overweight/obese. There was no statistically significant difference in the median DFS of obese/overweight and normal BMI pts irrespective of adjuvant therapy (C or CRT) (14.47 vs. 11.80 mos; p= 0.111). Obese/overweight pts had a better median OS [25.2 vs. 14.6 mos; p=0.045 overall (25.7 vs. 16.9 mos; p= 0.143 for the CRT-group and 17.3 vs. 13.4 mos; p= 0.050 for the C-group)], 1-year survival [96.7% vs. 61.9%; p < 0.0001 overall (95% vs. 64.3%; p= 0.001 for the CRT-group, and 90% vs. 57.1%; p=0.016 with C)], and 2-year survival [52.6% vs. 25.4%; p < 0.0001 overall (60.0% vs. 30.0%; p=0.0001 for the CRT-group and 37.5% vs. 14.3%; p=0.0002 for the C-group)] than patients with normal BMI.

Conclusions: In our experience, overweight/obese pts undergoing surgery followed by adjuvant therapy have better survival rates than patients with normal BMI.

[Table: see text]

No significant financial relationships to disclose.
Extrapancreatic tumors in intraductal papillary mucinous neoplasm of the pancreas.
Authors: Park Y. J. , Lee S.
Published: February 2017

189

Background: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas has a favorable prognosis, but seems to be associated with a high incidence of extrapancreatic tumors. The purpose of this study was to evaluate the incidence and clinicopathologic features of extrapancreatic tumors associated with IPMN compared with pancreas cancer.

Methods: Thirty-seven patients with IPMN of the pancreas and eighty-four patients with pancreas cancer, confirmed by surgical resection and typical findings of endoscopic ultrasonography and CT imaging between October 1, 1998, and August 31, 2009, were included. All pancreas cancers were diagnosed with surgical resection and biopsy. These patients were examined for the development of extrapancreatic tumors.

Results: Of 37 patients with IPMN, 14 (38%) had 18 extrapancreatic tumors, and 10 (27%) had 13 extrapancreatic malignancies. Five, six, and two extrapancreatic malignancies had been diagnosed before, during, and after the diagnosis of IPMN. Gastric adenocarcinoma (3 patients, 23%) and colorectal carcinoma (3 patients, 23%) were the most common neoplasms. Other extrapancreatic tumors included lung cancer (n=2), prostatic cancer (n=1), renal cell carcinoma (n=1), cholangiocellular carcinoma (n=1), urinary bladder cancer (n=1), and gallbladder cancer (n=1), respectively. As benign tumor, there were two gallbladder adenoma, one gastric adenoma, one colonic adenoma and one benign ovarian cystic neoplasm, respectively. On the other side, of 84 patients with pancreas cancer, 9 (10%) had 9 extrapancreatic tumors and 2 (2%) had extrapancreatic malignancies which were stomach cancer (n=1, 1%) and breast cancer (n=1, 1%) respectively. As benign tumor, there were colon adenoma (n=3), hepatic hemangioma (n=2), gastric adenoma (n=1), and uterine myoma (n=1).

Conclusions: IPMN is associated with high incidence of extrapancreatic tumors, particularly gastric and colorectal neoplasm but pancreas cancer did not show associations with extrapancreatic tumor. Upper gastrointestinal endoscopy and colonoscopy should be done, and systemic surveillance for the possible occurrence of other tumors may allow early detection of extrapancreatic tumor in patients with IPMN.

No significant financial relationships to disclose.
An engineered anti-CA19-9 cys-diabody for PET imaging of pancreas cancer and targeting of polymerized liposomal nanoparticles.
Authors: Girgis M. D. , McCabe K. , Olafsen T. , Bergara F. , Kenanova V. , Federman N. , Wu A. , Tomlinson J. S.
Published: February 2017

198

Background: Antibody-based therapeutics is a rapidly growing field. Small engineered antibody fragments, such as the cys-diabody demonstrate similar antigen affinity compared to the parental antibody but have a shorter serum half-life (4hrs) and possess the ability to be conjugated to nanoparticles. Our goal was to engineer an anti-CA19-9 cys-diabody fragment in hopes of imaging and targeting pancreatic cancer.

Methods: The anti-CA19-9 cys-diabody was created by cloning the variable region of the parental antibody, engineering a C-terminus cysteine, expressing in NS0 cells followed by protein purification utilizing HPLC. Maleimide chemistry was used to conjugate the cys-diabody to PLNs through the engineered cysteine residues. Immunofluorescence and flow cytometry were used to evaluate targeting of cys-diabody and diabody conjugated PLNs to human pancreatic cancer cell lines. The cys-diabody was evaluated in a mouse xenograft model harboring CA19-9 positive (BxPC3) and negative (MiaPaca) tumors. The cys-diabody was radiolabeled with a positron emitter (I-124) and microPET/CT were performed after tail vein injection. Percent of injected dose per gram (%ID/g) of radioactivity was measured in blood and tumor to provide objective confirmation of the microPET images.

Results: Immunofluorescence and flow cytometry showed specific binding of the anti-CA19-9 cys- diabody. Tumor xenograft imaging of the anti-CA19-9 cys-diabody demonstrated an average tumor:blood (%ID/g) ratio of 3.3 and positive:negative tumor ratio of 7.4. Successful conjugation of the cys-diabody to PLNs was indicated by immunofluorescence showing specific targeting of PLN-cys- diabody conjugate to human pancreatic cancer cells in vitro.

Conclusions: Our results show that the anti-CA19.9 cys- diabody targets pancreatic cancer providing specific molecular imaging in tumor xenograft models. Furthermore, the PLN-cys-diabody conjugate targets human pancreatic cancer cells with the potential to deliver targeted treatment. Further studies evaluating the in vivo ability of the PLN-cys-diabody conjugate to target pancreatic cancer need to be performed.

No significant financial relationships to disclose.
Association of excision repair cross-complementation group 1 (ERCC1) gene expression (GE) with outcome in stage II-III esophageal adenocarcinoma (EA) patients treated with preoperative platinum-based chemoradiation (CRT) in a phase II cooperative study (SWOG 0356).
Authors: Bohanes P. O. , Goldman B. H. , Benedetti J. , Blanke C. D. , Leichman L. P. , Iqbal S. , Thomas C. R. , Corless C. L. , Gold P. J. , Lenz H.
Published: February 2017

2

Background: Preoperative platinum-based CRT for operable esophageal cancer has improved overall survival (OS) compared to surgery alone. The phase II SWOG 0356 trial designed to test oxaliplatin (OXP) plus infusion 5-fluorouracil (5-FU) and external beam radiation prior to surgery for potentially curable EA has produced promising centrally confirmed complete pathologic response (pCR) rate (28.3%). After surgery patients were given a second cycle of OXP and 5FU. 2-year OS was 54.2%. However, treatment efficacy may be significantly compromised as a result of interindividual variations. We tested whether intratumoral GE levels in drug metabolism (DPD, GSTPi, TS and TP) and DNA repair (ERCC1 and XPD) predicted clinical outcome (CO). We also tested whether specific pattern of 12 polymorphisms in 8 genes (drug metabolism (GSTP, MTHFR and TS) and DNA repair (ERCC1, RAD51, XPD, XRCC1 and XRCC3)) predicted CO.

Methods: A total of 90 patients from the SWOG 0356 study were eligible for the molecular correlative study. mRNA was extracted from laser-capture-microdissected tumor tissue. After cDNA was prepared by reverse transcription, quantitation of the candidate genes and an internal reference gene (ß-actin) was performed using a fluorescence-based real-time detection method (TaqMan). Established GE cutoffs were tested (ERCC1 <1.7 x 10-3; TS <4.0 x 10-3). DNA was extracted from blood and genotyped using PCR-RFLP techniques.

Results: In univariate analysis, we found ERCC1 GE levels to be significantly associated with progression-free survival (PFS) and OS. Patients with high ERCC1 GE levels had worse 2-year PFS (17 vs 67%, p=0.004) and 2-year OS (37 vs 72%, p=0.04) compared to low GE levels. ERCC1 GE levels were not associated with pCR. All the other GE levels tested did not show significant association with CO. None of the tested polymorphisms showed any association with CO.

Conclusions: Our data suggest that GE levels of ERCC1 may help to identify patients with stage II-III EA likely to experience longer survival when treated with preoperative OXP-based CRT.

No significant financial relationships to disclose.
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.
In vitro sensitivity to 5-FU and gemcitabine in pancreatic cancer.
Authors: Franko J. , Bilimoria M. M. , Chalikonda S. , Iannitti D. A.
Published: February 2017

312

Background: Gemcitabine and 5-fluorouracil (5-FU) represent the mainstay of chemotherapeutic options for pancreatic cancer. Currently, approximately 40% of patients with pancreatic cancer receive chemotherapy. Relapse is common after resection and adjuvant therapy, and response rates are low in patients with advanced/metastatic disease. The purpose of this study was to describe the prevalence of in vitro drug sensitivity or resistance to these agents in pancreatic cancer and explore the clinical implication of in vitro assessment.

Methods: From August 2006 to January 2010, 74 specimens from patients with primary/metastatic pancreatic cancer were tested for response to gemcitabine, 5-FU, and their combination using an in vitro chemosensitivity assay (ChemoFx, Precision Therapeutics, Pittsburgh, PA). Tumors were classified as sensitive or resistant based on in vitro dose response curves.

Results: Thirty-four of the 74 tumor specimens (46%) exhibited in vitro chemosensitivity to gemcitabine, 5-FU, or their combination. Fourteen tumors (19%) were sensitive to gemcitabine, and 12 (16%) to 5-FU. Of the 60 patient specimens resistant to gemcitabine, 4 (7%) were sensitive to 5-FU. Conversely, of the 62 specimens resistant to 5-FU, 6 (10%) were sensitive to gemcitabine. Eight of the 74 specimens (11%) were sensitive to both gemcitabine and 5-FU and 56 (76%) were resistant to both agents. Of these 56 specimens, 16 (29%) showed sensitivity to the gemcitabine/5-FU combination.

Conclusions: The ChemoFx data indicates a high (76%) in vitro resistance rate to traditional chemotherapy. In vitro chemosensitivity to gemcitabine only partially overlaps with that of 5-FU and the gemcitabine/5-FU combination. Thus, tumors resistant to one drug, were not necessarily resistant to the other and vice versa. Further correlation with clinical outcomes is needed to determine the clinical efficacy of the ChemoFx assay.

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Epidermal growth factor receptor overexpression in resected pancreatic cancer.
Authors: Mahipal A. , McDonald M. J. , Witkiewicz A. , Carr B. I.
Published: February 2017

317

Background: The effect of overexpression of epidermal growth factor receptor (EGFR) in pancreatic carcinoma is uncertain. In this study, we examine the association between EGFR overexpression (membrane and cytoplasmic) and histopathologic features and clinical outcomes in patients post resection.

Methods: Seventy three patients underwent curative resection for pancreatic cancer from 4/08 to 4/10. Tumor EGFR expression was determined immunohistochemically using EGFR pharmDxTM kit. Cytoplasmic overexpression was considered positive if EGFR expression was seen in the cytoplasm in ≥10% of cells. Cell membrane staining scores were assigned: 0 (no membrane staining), 1+ (incomplete membrane staining in ≥ 10% of cells, 2+ (complete weak/moderate membrane staining in ≥ 10% of cells) and 3+ (complete heavy staining in ≥ 10% of cells). A score of 2+ and 3+ were considered as membrane overexpression. Comparisons between EGFR overexpression and clinicopathologic features were assessed by chi-square test with p-value < 0.05 as statistically significant. Proportional hazard regression was used to estimate progression free survival and overall survival.

Results: Out of 73 patients, 43 (59%) and 50 (68%) patients had membrane and cytoplasmic EGFR overexpression respectively. AJCC stages were: stage I: 8, stage II: 63, stage III: 1 and stage IV: 1 patient. There was statistically significant correlation between cell membrane EGFR overexpression and lymph node positivity (p=0.04). Membrane EGFR overexpression was not significantly associated with local invasion, margin positivity, vascular invasion, perineural invasion, histologic grade or stage. Cytoplasmic EFGR overexpression was significantly associated with margin positivity (p=0.01) only. The hazard ratios (95% CI) for PFS and OS in patients with membrane EGFR overexpression was 1.37 (0.72-2.60) and 1.27 (0.62-2.61) respectively. The corresponding values for patients with cytoplasmic overexpression were 1.65 (0.80-3.37) and 1.25 (0.58-2.71) respectively.

Conclusions: Membrane EGFR overexpression was associated with lymph node status and cytoplasmic EFGR overexpression with margin positivity. There was no association of EFGR expression and clinical outcomes.

No significant financial relationships to disclose.
Resected pancreatic neuroendocrine tumors: Patterns of failure and disease-related outcomes with or without radiotherapy.
Authors: Zagar T. M. , White R. R. , Willett C. G. , Papavassiliou P. , Tyler D. S. , Papalezova K. , Guy C. , Clough R. , Czito B. G.
Published: February 2017

325

Background: Pancreatic neuroendocrine tumors (NET) are rare with improved prognosis compared to adenocarcinomas. Surgical resection remains the standard of care although many patients present with unresectable/metastatic disease. While many resected patients will fail distantly, little is known regarding the use of adjuvant radiotherapy. To define this and establish specific patterns of failure, an analysis of resected patients from a single institution was performed.

Methods: From 1994 to 2009, 33 patients with NET of the pancreatic head underwent resection with curative intent at Duke University. Sixteen patients were treated with surgical resection alone, and an additional 17 underwent resection with adjuvant (n=10) or neoadjuvant (n=7) radiation therapy, usually with concurrent fluoropyrimidine-based chemotherapy (CMT). Median radiation dose was 50.4 Gy and median follow-up 28 months.

Results: Patients receiving radiation therapy were more likely to have involved nodes (47% vs 19%, p=0.09), more mitoses per high power field (p=0.10) and involved margins (47% vs 31%, p=0.20) compared to surgery alone patients. Median survival for the whole cohort was 52 months. Two-year survival was 68% for the CMT group and 93% for the surgery alone group (p=0.03). Two-year local control was 85% for the CMT and 90% for the surgery group (p=0.49). Two-year metastasis-free survival was 45% and 69% for the CMT and surgery patients, respectively (p=0.02).

Conclusions: Patients receiving CMT were more likely to have adverse pathologic features compared to surgery-alone patients. Survival outcomes were high in both groups, although less so in the CMT group. Distant metastasis development dominated patterns of failure. Local failure following resection of NETs is uncommon, and the role of adjuvant radiotherapy in this setting remains unclear.

No significant financial relationships to disclose.
Concurrent chemoradiotherapy for unresectable hilar choloangiocarcinoma: A single-institution experience.
Authors: Hunag P. , Chao Y. , Li C. , Lee R. , Wang L. , Yen S.
Published: February 2017

326

Background: Hilar cholangiocarinoma (Klatskin tumor) is a rare malignancy which is best managed with surgical resection. The majority of patients, however, is unresectable at the time of diagnosis and generally has a poor outcome. The purpose of this study was to retrospectively evaluate the role of chemoradiotherapy (CCRT) for patients with unresectable hilar choloangiocarcinoma at a single institution.

Methods: Between 2001 and 2008, a total of 33 patients with unresectable, nonmetastatic hilar cholangiocarcinoma treated at Taipei Veterans General Hospital were reviewed. All patients were to receive 3D-CRT with a median dose of 50.4 Gy (range, 39.6- 60) at 1.8-2 Gy per fraction per day. Sixteen patients also received bolus 5-fluorouracil (5-FU) CCRT (500 mg/m2/d for 3 days repeated every 2 weeks during radiotherapy for 6 weeks). Survivals were estimated by the Kaplan-Meier method and compared by log-rank test.

Results: There were 21 males and 12 females, with a median age of 71 years (range, 29 - 81). The median follow-up time was 10.4 months (range, 1 – 42.3) for all patients with the 1- and 2-year survival rates of 45% and 12%, respectively. The median overall survival (OS) and progression-free survival (PFS) were 13.5 months and 10.2 months for the CCRT group, and 10.4 months and 6.5 months for the RT alone group (p = 0.36 and p = 0.28, respectively). Adverse events were similar in thetwo groups with 14 patients (42%) developed grade 1-2 gastrointestinal toxicity during RT. Locoregional progression was observed in 26 patients (79%) and distant metastases in 9 patients (27%). All patients experienced disease progression and had died at time of analysis.

Conclusions: The outcome remains poor for unresectable hilar cholangiocarcinoma despite aggressive combined modality treatment. Although not statistically significant, our data showed CCRT provides longer OS and PFS in patients with unresectable hilar cholangiocarcinoma compared to RT alone. Locoregional progression is the main problem for this disease and the efficacy of adding chemotherapy or biologic agents needs to be further investigated.

No significant financial relationships to disclose.
Is pancreaticoduodenectomy performed at a comprehensive community cancer center comparable to tertiary centers' results?
Authors: Cheng C. , Duppler D. , Koczon-Jaremko B.
Published: February 2017

334

Background: We maintained a prospective database covering the period from 2001 to 2010. Outcome data are analyzed. We believe that the outcome achieved at a small cancer center is comparable to a tertiary cancer center.

Methods: Our study measures the outcome of pancreaticoduodenectomy. Data were compared to the published literature.

Results: There are 62 patients with histology-proven pancreatic cancer; ampullary adenocarcinoma and other histology types were included in the study. PPPD was performed in 41 patients. Twenty patients had classic PD. Three patients had portal venorrhaphy. Fifty patients had malignancy, whereas 11 had a benign histology. One case had dual histology (ductal carcinoma and neuroendocrine). The average age of patients was 63. Mean preoperative CA19-9 for exocrine pancreatic malignancies was 638, whereas for benign lesions and endocrine tumors it was 122. Average operative time is 6 hours 25 minutes for surgeries before 2005 and 5 hrs 48 minutes for surgeries performed after 2005. Blood transfusion was rare with 15 patients received blood product. There was one perioperative death due to ischemic bowel (4.3%). Average length of stay in the hospital was 15 days (range 0-87 days). There was no pancreatic leak among any of the patients. Two bile leaks were identified, one controlled with the drainage tube and the other one required repeat surgery. 30 days mortality rate was calculated at 10%. To date, 27 patients have died, with two from causes unrelated to carcinoma. Mean survival during our study period is 30.6 months. In comparison to published literature, the mortality, morbidity, and survival are similar. In the literature five year survival for pancreatic cancer patients treated with pancreaticoduodenectomy ranges from 10% to 29%.

Conclusions: In our study 5-yr survival was 45%. Despite overall poor outcome for patients with pancreatic and biliary malignancies, surgery can be performed in community hospitals with special interest in treating pancreatic disorder, offering patients prolonged survival and quality of life. Pancreaticoduodenectomy is effective and safe with low hospital mortality and with acceptable complication rates.

No significant financial relationships to disclose.
Prognostic implication of intraoperative radiotherapy for unresectable pancreatic cancer.
Authors: Fujii T. , Nagai S. , Kodera Y. , Kanda M. , Sahin T. T. , Sugimoto H. , Nomoto S. , Takeda S. , Morita S. , Nakao A.
Published: February 2017

346

Background: There is no established treatment strategy for unresectable pancreatic cancer, and the prognostic effect of intraoperative radiotherapy (IORT) is considered to be limited.

Methods: We reviewed 614 surgical cases of pancreatic cancer and selected 198 cases that did not undergo pancreatectomy because of distant metastasis or locally advanced disease, at the Department of Surgery II, between July 1981 and June 2009. Liver metastasis was observed in 70 patients and peritoneal metastasis in 44. Treatment for those who were feasible consisted of IORT and/or postoperative chemotherapy. Overall survival and prognostic factors were evaluated for all patients and for each pattern of disease spread.

Results: IORT was performed in 120 patients (61%), and chemotherapy was indicated in 80 (40%). Overall survival in the non-treatment group was significantly inferior to that for IORT alone and IORT plus gemcitabine (GEM)-based chemotherapy (median survival time: 3.2 months vs. 6.1 and 7.9 months; P = 0.0001 and <0.0001, respectively). After multivariate analysis, IORT and GEM-based chemotherapy were identified as independent prognostic factors [hazard ratio (HR) = 0.51, P < 0.001; HR = 0.43, P < 0.001]. IORT was an independent prognostic determinant for patients with peritoneal metastasis (HR = 0.24, P = 0.011), whereas it was not for those with liver metastasis (HR = 0.78, P = 0.381).

Conclusions: The prognostic value of IORT is most prominent in the peritoneal disease. IORT followed by GEM-based chemotherapy is possibly one of the most recommended treatment strategies in unresectable pancreatic cancer.

No significant financial relationships to disclose.
Percutaneous transhepatic biliary drainage (PTBD) and endoscopic retrograde cholangiopancreatography (ERCP) for malignant obstructive jaundice (OJ) in advanced digestive cancers.
Authors: Iruarrizaga E. , Azkona E. , Martinez M. , Iza E. , Lopez-Vivanco G. , Munoz Llarena A. , Ferreiro J. , Ballesteros D. , Fernandez R. , Rubio I.
Published: February 2017

348

Background: OJ is a relatively frequent complication in patients with advanced malignancies that usually causes refractory symptoms and can make chemotherapy (CT) treatment difficult. In the last years, the use of different non-surgical techniques, such as PTBD or ERCP, is increasing.

Methods: From Sep-05 to Aug-10, patients with OJ due to advanced digestive cancers who underwent ERCP or PTBD were included. Baseline characteristics, acute and late complications and outcome were retrospectively collected. Jaundice resolution was recognized if bilirubin value decreased to at least grade 1, after the procedure. Overall survival (OS) was calculated from the date of the technique to the date of death or last follow-up.

Results: Seventy-six consecutive patients were collected. Male/Female: 52p/24p; Mean age 63.5 y-o (range: 33-85); ECOG performance status 0/1/2/3: 1/37/27/11; Primary tumour: pancreas 30, biliary tract 18, colorectal 16, gastric 7, and gall bladder 5, and of them, 13% were unresectable locally advanced and 87% metastatic. ERCP was used in 59% of the patients and PTBD in 49% and the proportion of intrahepatic and extrahepatic causes were 1:1. Mean hospital stay was 11.3 days (95% CI 1-21). Twenty- six patients (32%) suffered a complication during the hospital stay: 9 cholangitis, 7 catheter obstruction, 2 bleeding, 2 acute pancreatitis and 6 other, and 8 died of procedure-related adverse event. After hospital discharge there were 34% infections, 17% catheter obstruction and 8% other. After the technique OJ was solved (bilirubin nadir) in 49% of the patients and 55% underwent palliative CT. Median OS was 30 weeks (95% CI: 17-42).

Conclusions: PTBD and ERCP are appropriate techniques in patients with malignant OJ and can resolve an absolute contraindication for palliative CT. However, major complications are frequent and a relatively high mortality rate should be expected. Therefore an adequate patient selection is crucial to prevent adverse events.

No significant financial relationships to disclose.