bluuebunny/crossref_metadata_2025_split huggingface dataset:
Somatostatin receptor subtypes 1-5 gene expression in multiple sites in the same individual.
Authors: Hall Michael Anthony , Milosavljevic Tanja , Casey Peter , Anthony Catherine T. , Woltering Eugene 
Published: February 2017

182 Background: Metastatic tumors may be fundamentally different than the primary tumor. This phenomenon may partially explain resistance of metastatic disease to therapy. We evaluated the gene expression levels of somatostatin receptor subtypes 1-5 (SSTR 1-5) in patients with disseminated neuroendocrine tumors (NETS) undergoing cytoreduction of their primary tumor and its nodal and liver metastasis. Methods: We compared the gene expression levels for SSTR 1-5 in primary tumor and their nodal and liver metastasis. The small bowel primary (SB), a mesenteric lymph node (LN) and a liver metastasis and their normal tissue counterparts were evaluated in four patients. RNA samples from each tissue underwent gene expression analysis using a customized Real Time Quantitative PCR (RT-qPCR) gene array. Normal tissue gene expression was compared to that obtained from the tumor sample at each site. Results: SSTR 2 was overexpressed (four-fold or greater, p≤ 0.01) compared to control levels in 8/12 (67%) specimens; 4/4 (100%) of the liver specimens, 3/4 (75%) of the SB specimens, and 1/4 (25%) of the LN specimens. SSTR 2 gene overexpression was not observed in all three tumor sites in any patient. No tumor had SSTR 2 downregulation. SSTR 5 was overexpressed (four-fold or greater, p≤ 0.01) compared to control levels in 6/12 (50%) specimens; 3/4 (75%) of the liver specimens, 2/4 (50%) of the SB specimens, and 1/4 (25%) of the LN specimens. SSTR 5 gene expression was up-regulated in all three tumor sites in one individual. SSTR 5 was down-regulated (7-fold, p<0.01) in one LN specimen. Changes in gene expression levels of SSTR 3 and SSTR 4 showed inconsistency between tumor sites, whereas that of SSTR1 was observed only at the metastatic sites. Conclusions: These results explain the observed variability in somatostatin receptor expression seen in 111In pentetreotide scans in multiple tumor sites from the same individual. The observation that gene expression varies from metastasis to metastasis may also help explain the difficulty in designing therapies that cure patients rather than inducing partial remissions.
Use of the monoclonal antibody PAM4 to differentiate pancreatic ductal adenocarcinoma (PDAC) from chronic pancreatitis and benign nonmucinous cysts of the pancreas.
Authors: Shi Chanjuan , Goldenberg David M. , Gold David V. 
Published: February 2017

188 Background: Previous studies have demonstrated that anti-mucin monoclonal antibody (mAb) PAM4 is highly specific for PDAC and its precursor lesions. To investigate specificity further, we examined the expression of PAM4-reactive mucin in chronic pancreatitis and benign non-mucinous cystic lesions of the pancreas. Methods: A tissue microarray of PDAC (N=14), as well as surgical specimens from chronic pancreatitis (N=32) and benign non-mucinous cystic lesions of the pancreas (N=19), were assessed by immunohistochemistry for expression of the PAM4-reactive mucin, as well as MUC1 (mAb-MA5), MUC4 (mAb-8G7), and CEACAM6 (mAb-MN-15). Results: PAM4-reactive mucin, MUC1, MUC4 and CEACAM6 were expressed in 79% (11/14), 100% (14/14), 86% (12/14) and 100% (14/14) of invasive pancreatic adenocarcinoma. PAM4 only weakly labeled 6% (1/19) of benign non-mucinous cystic lesions, 1 of 15 serous cystadenomas (SCAs) and 0 of 4 cysts with squamous epithelial lining (2 lymphoepithelial cysts, and 2 retention cysts with squamous metaplasia). However, the expression of MUC1, MUC4 and CEACAM6 was detected in 53% (8/15), 0% (0/15) and 13% (2/15) of SCAs, and in 4, 3 and 3 of the 4 cysts with squamous epithelial lining, respectively. PAM4 labeled 19% (6/32) of chronic pancreatitis specimens; however, this PAM4 reactivity was restricted to the PanIN precursor lesions associated with chronic pancreatitis. Inflamed tissue was negative. The expression of MUC1, MUC4 and CEACAM6 was detected in 90% (27/30), 78% (25/32), and 97% (31/32) of chronic pancreatitis. In all of the positively-labeled specimens, the reactivity was present in non-neoplastic inflamed pancreatic tissue in addition to PanIN. Conclusions: The expression of PAM4 was detected in only 6% of benign non-mucinous cystic lesions and in the precursor lesions associated with chronic pancreatitis. These results suggest that PAM4, in contrast to MUC1, MUC4, and CEACAM6, may be useful to differentiate benign non-mucinous cystic lesions of the pancreas and chronic pancreatitis from PDAC. (Supported in part by NIH grant CA096924.)
Treating chronic hepatitis in Asian and Pacific Island populations: A comparison of program costs according to current treatment guidelines.
Authors: Robotin Monica Cristina , Patton Yumi , Kansil Melanie Q , George Jacob , Penman Andrew G 
Published: February 2017

193 Background: Hepatitis B (HBV) infection is endemic in many Asian and Pacific Island countries, with 25-40% of chronic hepatitis B (CHB) patients developing cirrhosis or hepatocellular cancer (HCC). Increased migration from high HBV prevalence countries leads to Vietnamese-born Americans and Australians 11-13 times more likely to develop HCC than other groups. As antiviral therapy is more cost-effective than HCC screening, we developed a program of hepatitis B screening, monitoring and treatment targeting high–risk populations in Sydney aged >35 years (the median age for HBeAg sero-conversion in Asian populations). Here we compare estimated program costs using guidelines for HBV treatment in hepatitis B e antigen negative populations. Methods: Using a Markov model, we modelled CHB disease progression and management costs using guidelines published by the American, European and Asian Pacific Associations for the Study of Liver Disease (AASLD, EASL and APASL) and algorithms created by US hepatology experts and our B Positive program, using different levels of alanine aminotransferase (ALT) for treatment initiation. We factored in costs for CHB screening and surveillance for liver damage provided by specialists and/or primary care providers, including CHB and HCC treatment, individualised by viral load and ALT levels. Costs were discounted by 5% and calculated in Australian dollars (AUD); incremental costs used AASLD guidelines as a baseline. Results: Assuming a 25% enrolment in our target population of patients with CHB in South West Sydney followed up for 50 years, total program costs would amount to 9,205,680 AUD. Using AASLD guidelines, estimated cost would amount to 6,344 AUD per patient. APASL guidelines lead to a 132% cost rise, the B Positive program costs 152% more, while the US algorithm and EASL are associated with a 221% cost increment to achieve the equivalent cost/QALY. Conclusions: While the AASLD guidelines appear to be the least costly, uncertainties about “ideal” ALT and viral load levels for treatment initiation and the extent of the benefit conferred in terms of HCC cases averted will need to be resolved to inform large-scale prevention programs.
Use of EGF A61G polymorphism to predict overall survival in a phase III study of gemcitabine plus cetuximab versus gemcitabine in patients with locally advanced or metastatic pancreatic adenocarcinoma (SWOG 0205).
Authors: Labonte Melissa Janae , Goldman Bryan H. , Zhang Wu , Blanke C. D. , Philip Philip Agop , Wong Ralph , O'Reilly Eileen Mary , Benedetti Jacqueline K. , Lenz Heinz-Josef 
Published: February 2017

203 Background: The SWOG 0205 phase III study failed to demonstrate an advantage from the addition of cetuximab to gemcitabine for overall survival (OS), progression-free survival (PFS) or objective response in advanced pancreatic cancer. Molecular markers may identify subgroups of pts who benefit from this regimen. This report summarizes the results of a pilot project aimed at screening germline single nucleotide polymorphisms (SNPs) in genes involved in gemcitabine metabolism pathway (CDA and RRM1) and EGFR signaling pathway (EGF, EGFR, IGF1, FCGR2A/3A, KRAS, IL8, COX-2, CCND1) to identify pts that may benefit from this treatment. Methods: Genomic DNA was extracted from 88 available serum samples for this molecular correlates pilot study. Sixteen SNPs were evaluated using PCR-based protocols. There were no differences in baseline characteristics or outcome between pts included in the analysis and the entire study population. Associations between genotype and OS were assessed using stratified Cox regression, with adjustment for treatment arm. Genotypes were parameterized as the number of dominant alleles. No p value adjustments were made for multiple comparisons. Results: Median age was 63.3 years (range: 29.6-85.0), and median OS (95% CI) was 5.7 months (mos) (range: 4.4-6.8) in this subset. There was a statistically significant association between EGF A61G SNP (rs4444903) genotype and OS (p=0.04). Among pts carrying the AA genotype, median OS was 8.4 mos (95% CI 4.9-15.0), as compared to 5.6 mos (95% CI 3.0-9.0) among those with the AG genotype and 5.3 mos. (95% CI 2.2-7.1) for the GG genotype. Evidence was weak for interaction between treatment arm and rs4444903 genotype (p=0.13). No significant associations between other SNPs and OS were observed. Conclusions: This exploratory study suggests that the EGF A61G polymorphism may be a useful molecular marker for predicting clinical outcomes in metastatic pancreatic adenocarcinoma pts treated with gemcitabine-based chemotherapy.
Inhibition of poly (ADP-ribose) polymerase-1 (PARP-1) to increase radiosensitivity of human pancreatic cancer (PAC) cell lines proficient in homology-directed repair (HDR).
Authors: Lowery Maeve A. , Vanoli Fabio , Yu Kenneth H. , Jasin Maria , O'Reilly Eileen Mary , Moynahan Mary Ellen 
Published: February 2017

204 Background: Radiation-induced single strand DNA breaks (SSBs) are primarily repaired by base excision repair, of which PARP1 is a key component. Unrepaired SSBs may cause collapse of stalled replication forks during DNA replication generating DNA double-strand breaks (DSBs). PARP inhibition has been shown to potentiate the effect of radiotherapy (RT) in a variety of human cancers in vitro and in vivo. We investigated the ability of the PARP inhibitor olaparib to radiosensitize BRCA1/2 wild-type human PAC cell lines and quantified repair capability of an induced DSB by HDR using the I-SceI-induced DSB DR-GFP assay. Methods: MiaPaCa -2 and ASPC-1 human PAC cells lines were exposed to RT administered in a single fraction by 157-gammacell irradiator at doses of 2, 4, 6 and 8 Gy in the presence or absence of olaparib at a dose of 500nM (4 hours pre and 20 hours post RT). Plates were incubated at 37C for 10-14 days and stained with Giemsa. Clonogenic survival assays following olaparib continuous exposure at concentrations up to 10 µM for 10-14 days were also performed. HDR of an induced DNA DSB was assessed in ASPC1 and MiaPaCa cell lines by co-transfection with an I-SceI expression vector and the DR-GFP reporter plasmid(Pierce et al., 1999), and in BRCA2 deficient CAPAN-1 cells harboring a stably integrated chromosomal DR-GFP gene (Moynahan et al. 2001). Results: Linear quadratic models were fitted to the data sets to generate survival curves. The half maximal inhibitory concentration (IC 50) of RT was 2Gy for both cell lines. The sensitivity enhancement ratio (SER) at 25% survival was 1.44 and 1.53 for MiaPaCa-2 and ASPC-1 cell lines respectively. Both cell lines were resistant to treatment with single agent olaparib to dose of 10µM and were proficient in HDR of DNA DSBs when compared to the BRCA2-deficient Capan-1 cell line. Conclusions: Inhibition of PARP increases radiosensitivity in human PAC cell lines proficient in HDR of DNA DSBs and resistant to treatment with single agent PARP inhibitor. Therapeutic strategies incorporating PARP inhibition and RT offer potential to improve clinical outcomes for patients presenting with localized sporadic and BRCA mutated PAC.
An analysis of ERCC1, hENT1, RRM1, and RRM2 expression in resected pancreas adenocarcinoma: Implications for adjuvant treatment.
Authors: Fisher Sarah B. , Patel Sameer H. , Bagci Pelin , Kooby David A. , El-Rayes Bassel F. , Staley Charles A. , Adsay Volkan , Maithel Shishir Kumar 
Published: February 2017

206 Background: Tumor overexpression of excision repair cross complementing gene 1 (ERCC1) was recently shown to be associated with decreased survival in patients with pancreas adenocarcinoma (PAC). Ribonucleotide reductase 1 and 2 (RRM) and human equilibrative nucleotide transporter 1 (hENT1) are integral to DNA synthesis and cellular transport and are implicated as poor prognostic factors in other malignancies. Their role in PAC is not well defined. Methods: A prospective database (n=220) was used to randomly select 95 pts who underwent pancreaticoduodenectomy for PAC between 1/00-10/08. IHC analysis was performed on tumor samples for RRM1 and 2, hENT1, and ERCC1. Main outcomes were recurrence-free (RFS) and overall survival (OS). Results: Median age was 63 yrs; median FU, RFS, and OS was 49, 10.6 and 15.5 mo. Median tumor size was 3cm, 26% had a positive margin, 34% were poorly differentiated, 61% had positive lymph nodes (LN), 88% had perineural invasion (PNI), and 45% had lymphovascular invasion (LVI). High expression of RRM1, RRM2, hENT1, and ERCC1 was present in 40%, 17%, 85%, and 16% of patients, respectively. High RRM2 was associated with reduced RFS (6.9 vs 16.0 mo; p<0.0001) and decreased OS (9.1 vs 18.4 mo; p<0.0001). High ERCC1 was associated with reduced RFS (6.1 vs 15 mo; p=0.04) and decreased OS (8.9 vs 18.1 mo; p=0.03). RRM1 and hENT1 were not associated with survival. After accounting for known adverse factors, high RRM2 and ERCC1 persisted as negative prognostic factors for RFS and OS (Table). A subset analysis of those who received adjuvant therapy (n=74) revealed the same negative effect of high RRM2 and ERCC1 on RFS and OS. Conclusions: High RRM2 and ERCC1 tumor expression are associated with reduced RFS and OS after resection of pancreas cancer. These biomarkers may help personalize adjuvant therapy. [Table: see text]
Significance of CEACAM6 expression in biliary tract carcinoma.
Authors: Rocha Flavio G. , Torres Javierra , Chou Joanne F. , Katabi Nora , Gönen Mithat , DeMatteo Ronald P. , Fong Yuman , Allen Peter J , D'Angelica Michael Ian , Klimstra David S. , Jarnagin William R. 
Published: February 2017

207 Background: The entire biliary tree is at risk for malignant change, but little is known about differences in molecular pathogenesis with respect to anatomic site. CEACAM6 is a membrane protein involved in cell adhesion and signaling that is overexpressed in pancreatic adenocarcinoma and associated with poor prognosis. This study examines CEACAM6 expression in the entire spectrum of biliary carcinomas and its relationship to outcome. Methods: Tissue microarrays containing triplicate cores of paraffin-embedded surgical specimens from patients with bile duct carcinoma (hilar, intrahepatic, distal) and control tissue were stained for CEACAM6 by immunohistochemistry. Clinical, pathologic and survival data were analyzed and correlated with CEACAM6 expression. Survival was estimated using the Kaplan-Meier method and compared with log rank test. Results: One hundred twenty cases of bile duct carcinomas from 1992-2007 were assembled in the tissue microarrays. Strong CEACAM6 signal was present in 30/60 (50%) of hilar tumors, 7/45 (16%) of intrahepatic tumors, 7/15 (47%) of distal tumors, and none of the control tissues. Overall median survival and follow-up were 36.4 months and 98.3 months, respectively. CEACAM6 staining did not correlate with sex, grade, positive lymph nodes, vascular invasion or metastases but was associated with age > 65 (p<0.05) and higher T stage (p<0.05). After R0 resection, CEACAM6 expression was associated with disease-specific survival (DSS) only in the subset of patients with intrahepatic cholangiocarcinoma (median DSS 78 months for negative and 16 months for positive, p<0.002). Vascular invasion was the sole independent predictor of survival on multivariate proportional hazards regression (HR=1.742 [1.048-2.895 95%CI], p<0.03) in the entire cohort. Conclusions: CEACAM6 may serve as a marker of poor outcome in patients with intrahepatic cholangiocarcinoma and should be further evaluated as a means of selecting patients for adjuvant therapy after resection.
Is the number of TACE treatments in HCC patients associated with improved survival? A SEER-Medicare population analysis.
Authors: Shaya Fadia T. , Breunig Ian Michael , Hanna Nader , Pandya Naimish B. , Chirikov Viktor , Seal Brian S. , Mullins C. Daniel 
Published: February 2017

210 Background: We examine treatment patterns and associated survival outcomes of TACE at all stages of Hepatocellular Carcinoma in SEER Medicare. Methods: Medicare enrollees, 65 and older, with a diagnosis of a primary HCC between 2000-07 who received treatment were followed through end of 2009 using the Surveillance, Epidemiology and End-Results Program (SEER) and linked Medicare databases, with claims from Medicare parts A and B. Using Cox proportional hazards models, we assessed the impact on mortality, of each additional TACE, systemic chemotherapy, SIRT, external beam radiation therapy, ablation and surgical resection, controlling for cancer stage, general health status, underlying liver disease (alcohol related, Hepatitis B and C, moderate/severe liver dysfunction), and demographics. We assessed overall and HCC-related mortality for all, then for TACE-only treated patients, and stratified outcomes by stage. Results: Out of 3322 treated non-transplant HCC patients, 1094 got TACE, 74% were Caucasian, 6% African American, 66% male, and 45% were at stage 1/2, 17% at stage 3 and 14% at stage 4. Most (56%) received 1, 23% 2, 11% 3 and 10% 4 or more TACEs. In the adjusted models, both overall and HCC mortality reduction were associated with treatment with up to 2 TACEs (HR=0.68, P=<0.001 and HR=0.73, P=<0.001, respectively). A third TACE, but not a fourth, provided a further decrease in overall mortality (0.46, <0.001) and HCC mortality (.45, <0.001). When stratified by stage, the second TACE had a significant marginal effect within Stage 3, and only the first TACE had benefit within Stage 4. No effects were found for TACE in early HCC. In the adjusted models, liver conditions were not associated with HCC mortality among TACE treated patients only. Conclusions: TACE provides a survival benefit for elderly HCC patients in clinical practice. However, the survival benefit may decrease beyond 3 TACE treatments and varies by stage. Additional TACE treatments may be confounded if 4+ TACE treatments are utilized mainly to treat biologically aggressive disease related to extensive tumor burden, advanced disease or recurrences. Treatment selection bias cannot be excluded and should be further explored.
Phase Ib study of ipilimumab alone or in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene (vaccine) in pancreatic cancer.
Authors: Le Dung Thi , Lutz Eric , Huang Lanqing , Onners Beth , Uram Jennifer , Solt Sara , Sugar Elizabeth , Zheng Lei , Jaffee Elizabeth M. , Laheru Dan 
Published: February 2017

211 Background: Ipilimumab (IPI) at 3mg/kg has been tested in pancreatic ductal adenocarcinoma (PDA) with a low but detectable response rate. This supports a role for immunotherapy in PDA. Melanoma (MEL) studies demonstrate a dose-response relationship with IPI. Preclinical studies show synergy between anti-CTLA-4 antibodies and GM-CSF cell-based vaccines. This study evaluated IPI 10mg/kg alone (Arm 1) versus IPI 10mg/kg + vaccine (Arm 2) in PDA. Methods: 30 subjects with previously treated, locally advanced or metastatic PDA were randomized (1:1) to Arm 1 or 2. Induction treatments were administered every 3 weeks (wk) X 4 doses. Subjects with stable disease (SD) or better between wk 14 and 22 were eligible for maintenance doses every 12 wks. Activity was assessed by response and overall survival (OS). IFN-g Elispots and ELISAs were used to detect induction of mesothelin-specific T cells and galectin-3 antibodies (Abs), respectively. Results: Baseline characteristics were similar (87% metastatic, 100% gemcitabine-treated) with the exception that Arm 1 had a lower % of subjects with > 1 prior therapies (60 vs 100%). Arm 1 had 2 SD (7 and 22 wks). Arm 2 had 3 SD (1 delayed regression starting at wk 14 and maintained until wk 31, 1 delayed stabilization starting at wk 22 and ongoing at wk 57, 1 SD ongoing at wk 64). Transient CA19-9 declines were seen only in Arm 2 (7/15). Median OS was 3.3 vs 5.5 months in Arm 1 vs Arm 2 (p=0.12) with a 12 month OS of 7 vs 27%. 73% (Arm 1) and 80% (Arm 2) of subjects experienced immune related adverse events (IRAE). 20% of subjects on both arms had Grade 3-4 IRAEs including rash (1), colitis (2), Guillain-Barre (1), nephritis (1), and pneumonitis (1). Rash was less frequent in Arm 1 (53 vs 73%). IRAEs (p=0.037), mesothelin T cell responses (p=0.012), and enhancement of the T cell repertoire (p=0.026) were associated with OS in both arms. Galectin-3 Ab responses were associated with OS in Arm 2 (p=0.002). Conclusions: Immunotherapy has potential even in advanced PDA. IRAEs in PDA are similar to IRAEs in MEL. Delayed responses suggest that standard RECIST criteria will underestimate activity and targeting a population with a longer life expectancy may improve efficacy.
Use of high-resolution fluorescence laparoscopy with fluorophore-conjugated tumor-specific antibodies for the detection of pancreatic cancer metastasis invisible with standard laparoscopy.
Authors: Metildi Cristiina A. , Kaushal Sharmeela , Tran Cao Hop S. , Snyder Cynthia S. , Talamini Mark A. , Luiken George A. , Hoffman Robert M. , Bouvet Michael 
Published: February 2017

212 Background: Standard laparoscopy for pancreatic cancer often leads to false negative results, causing understaging of the disease. Improved sensitivity and resolution are necessary. Methods: Orthotopic and carcinomatosis mouse models of human pancreatic cancer were established with red fluorescent protein (RFP)-expressing or non-fluorescent BxPC-3 human pancreatic cancer cells. The mice with orthotopic unlabeled pancreatic cancer were administered Alexa 488- or 555-conjugated anti-CEA by tail-vein injection 2-4 weeks after tumor implantation. Diagnostic laparoscopy was performed with a Stryker L9000 LED light source or X8000 xenon light source 24 hours later. Pancreatic tumors were detected and localized under each light mode. After laparoscopy, intravital images were obtained with the OV-100 and Maestro CRI Small Animal Imaging Systems as positive controls. Tumors were collected for histologic analysis. Results: Fluorescence laparoscopy (FL) with the use of 495-nm excitation filter and an LED light source enabled more rapid and accurate identification and localization of primary tumors and metastases than bright light laparoscopy (BL). The use of fluorescent conjugates antibody-labeled tumors improved the accuracy of staging laparoscopy, increasing the sensitivity from 40% in BL to 96% in FL (p<0.001). FL was sufficiently sensitive to detect sub-millimeter tumor deposits that went undetected under BL. With adjustments to the LED light source, we could simultaneously detect tumor lesions of different fluorescent colors and surrounding structures with minimal autofluorescence. Conclusions: The use of FL and fluorophore-labeled anti-CEA antibodies permits rapid detection and accurate localization of primary and metastatic CEA-expressing human pancreatic cancer, including tumors that were undetectable with BL. The introduction of an LED light source allows simultaneous identification of fluorescent tumor of different wavelengths without compromising background illumination. Further development of this technology for clinical use can improve the staging and treatment of pancreatic cancer.