bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combination of the PAM4 and CA19-9 biomarkers to improve the detection of pancreatic adenocarcinoma.
Authors: Gold David V. , Gaedcke Jochen , Ghadimi B. Michael , Goggins Michael , Hruban Ralph H. , Liu Mengling , Newsome Guy , Goldenberg David M. 
Published: February 2017

164 Background: Pancreatic ductal adenocarcinoma (PDAC) is almost universally lethal, due mainly to the inability to detect early-stage disease. Thus, identification of biomarkers that can identify patients with early-stage PDAC may improve overall survival. Methods: In a blinded study, PAM4 and CA19-9 immunoassays were performed on sera from 480 patients, including those with confirmed PDAC (N=234), other cancers (N=84), benign diseases of the pancreas (N=89), and healthy adults (N=50). Results: Overall sensitivity for PDAC was similar, 74% and 77% for PAM4 and CA19-9, respectively. Sensitivity for detection of early, stage-1 disease (N=26), although somewhat higher for the PAM4-antigen, was also statistically similar, 65% and 58% for PAM4 and CA19-9, respectively (P = 0.5775). However, specificity was significantly lower for CA19-9, particularly with respect to chronic pancreatitis (CP): 68% vs.86% for the PAM4 assay (P = 0.014). Furthermore, CA19-9 results showed considerably higher detection rates for non-PDAC neoplasia, including patients with other cancers that metastasized to the pancreas. Thus, positive likelihood ratios (+LR) were lower for CA19-9 (+LR = 2.41) than for the PAM4 assay (+LR = 5.29). PAM4 and CA19-9 antigen levels in PDAC were independent of each other (r2 = 0.003, P=0.410); however, the positive and negative interpretations were concordant in 68% of the cases. Thus, we used a combined biomarker analysis that ultimately improved the overall PDAC detection rate (84%), without a significant decrease in specificity (83%). Comparison of the ROC curves for PDAC vs. CP and PDAC vs. benign disease demonstrated a statistically significant improvement for the combined immunoassay, as compared to either assay alone (P < 0.0001 in both comparisons), to detect and discriminate PDAC from benign disease. Conclusions: While the PAM4-immunoassay provides high sensitivity and specificity for detection and diagnosis of PDAC, inclusion of the CA19-9 biomarker significantly enhanced positive identification of PDAC patients, from 74% to 84%. Further studies are needed to confirm these results. (Supported in part by NIH grants CA096924, CA120432 and CA62924, and the Turpin Foundation.)
S100A4 as a biomarker of resistance to gemcitabine: A secondary analysis of RTOG 9704.
Authors: Tempero Margaret A. , Moughan Jennifer , Kim Grace E. , Kakar Sanjay , Hyun Teresa S. , Regine William , Mowat Rex B. , Charpentier Kevin , Small William , Guha Chandan , Chang David K. , Biankin Andrew Victor 
Published: February 2017

165 Background: Preclinical studies suggest that nuclear expression of the Ca++ binding protein S100A4 induces gemcitabine resistance in pancreatic cancer cell lines (Mahon et al, Cancer Research, 2007). As a consequence, we assessed the potential role of S100A4 protein expression as a clinical biomarker of gemcitabine resistance in the RTOG 9704 adjuvant trial, which compared gemcitabine to continuous infusion 5FU. Methods: Analyzable archival tissue samples were available for 184 patients on which the secondary analysis was based. Immunohistochemistry was used to detect S100A4 expression on a tissue microarray with triplicate samples from each specimen. Tissue was semiquantitatively scored for % labeled cells and intensity and dichotomized to negative or positive expression. DSS was estimated univariately with the Kaplan-Meier method and multivariate Cox proportional hazards models were used to determine if S100A4 expression correlated with DSS. Results: The analysis was based on 184 specimens; 97 from the 5FU arm and 87 from the gemcitabine arm (see table below). For S100A4 related DSS, the HR for negative vs. positive expression in the 5FU and gemcitabine treatment arms was 0.93 (95% C.I. = [0.53, 1.63], p=0.80) and 1.85 (95% C.I. = [0.96, 3.56], p=0.066), respectively. The 2-year DSS for S100A4-negative patients in the 5FU treatment arm was 26%, and 39% for S100A4-positive patients. In the gemcitabine treatment arm, 2-year DSS for S100A4-negative patients was 59% and 37% for S100A4-positive patients. Conclusions: The association with improvement in survival for S100A4-negative patients treated with gemcitabine, although not statistically significant, supports the hypothesis that S100A4 expression predicts for chemoresistance to gemcitabine. The small number of unique samples available from RTOG 9704, especially in subgroups of interest, was a limiting factor in this study. This project was supported by RTOG grant U10 CA21661, U24 CA114734, and CCOP grant U10 CA37422 from the National Cancer Institute (NCI) and the RTOG Translational Research Program. [Table: see text]
Is laparoscopy still needed for staging resectable pancreatic cancer?
Authors: Santoro Peter Michael , Abdel-Misih Raafat Z. , Petrelli Nicholas J. , Bennett Joseph J. 
Published: February 2017

168 Background: Imaging for pancreatic cancer has demonstrated increased accuracy in staging patients before resection. Many propose diagnostic laparoscopy is therefore unnecessary before laparotomy and resection. Pancreatic cancer still has a high incidence of peritoneal and liver metastases that may be radiographically occult. Our hypothesis is that laparoscopy is still necessary to detect occult disease and avoid non-curative laparotomy in cases of peri-pancreatic malignancy. Methods: Patient data were collected at a large, academic community-based tertiary care center with a specialized pancreatic team. Retrospective chart review was performed for patients surgically treated for peri-pancreatic neoplasms between the years 2005-2011. Patients with adenocarcinoma were the focus of this study. All patients had triple phase CT imaging for staging and to assess resectability. Patients who had laparoscopy (group 1) were identified and compared to those who did not (group 2). Results: Two hundred and two patients from 2005-2011 with pancreatic neoplasms were identified as radiographically resectable. Of these, 107 had pancreatic adenocarcinoma (53%). In the first group, 80 patients underwent diagnostic laparoscopy (75%) and metastatic disease was identified in 8 cases (10%). Laparotomy for resection was performed for the remaining 72 patients and 6 were found to have metastatic disease that was missed during laparoscopy. The overall prevalence of metastatic disease in this group was 17.5%. In the second group, 27 patients underwent laparotomy without laparoscopy. Four of these patients(15%) were found to have metastatic disease. The sensitivity of laparoscopy to detect radiographically occult metastases was 70%. Laparoscopy still missed 43% (6/14) of patients ultimately found to have metastatic disease in this group. Conclusions: Occult metastases were still found in 15%-17.5% of patients despite modern CT scan imaging. Even though laparoscopy missed some metastases when compared to laparotomy, our results show that 10% of patients were spared an unnecessary laparotomy. Laparoscopy should still play a role in staging patients with radiographically resectable pancreatic cancer.
Association of high histone H3K4 trimethylation level and prognosis of patients with low-TNM-stage hepatocellular carcinoma.
Authors: Xu Junyao , He Chuanchao , Zhang Jianlong , Wang Jie 
Published: February 2017

171 Background: Along with genetic events, tumor associated epigenetic alterations including DNA methylation and post-translational histone modifications are important determinants in the initiation and progression of hepatocellular cancer (HCC) and represent promising biomarkers and therapeutic targets. Locus-specific trimethylation of histone H3 lysine 4 (H3K4me) is a well-known modification linked to the enhanced transcriptional expression of many genes activated in HCC. However its expression and association with prognosis of HCC patients remain unclear. Our aim was to assess the cellular expression pattern of H3K4me3 in HCC and its association with clinicopathologic variables and outcome. Methods: Expression of H3K4me3 and the histone methyltransferase SMYD3 was studied by western blotting and immunohistochemistry in human HCC cell lines and tumor tissue micmicroarray, which is from a well–characterized series of HCC patients(n=168). Tissue staining were assessed using blinded semiquantitative scoring. The optimal cut-point of H3K4me3 expression for prognosis was determined by the X-tile program. The prognostic significance was evaluated using Kaplan-Meier survival estimates and log-rank tests. Tumor tissue micmicroarray from another independent HCC patients cohort(n=147) was used for validation studies. Results: Expression of H3K4me3 and the histone methyltransferase SMYD3 were enhanced in HCC cell lines.In clinical tumor specimens, enhanced expression of H3K4me3 was correlated with reduced overall survival (P < 0.0001), especially in early-stage HCC patients(TNM I/II).Furthermore,both univariate and multivariate analysis revealed that H3K4me3 level was a significant and independent predictor of poor survival (hazard ratio,3.592; 95% CI, 2.302-5.605). In addition, H3K4m3 expression was positively correlated with SMYD3 expression in both testing and validation cohorts (P<0.0001). Conclusions: H3K4me3 level defines previously unrecognized subsets of HCC patients with distinct epigenetic phenotype and clinical outcome, thus can be a novel predictor for poor prognosis of HCC patients, especially within TNM I/IIstage.
Pancreatic neuroendocrine tumors: Twenty years’ experience of 100 patients at a single center.
Authors: Shiba Satoshi , Morizane Chigusa , Kondo Shunsuke , Ueno Hideki , Ikeda Masafumi , Yamaguchi Tomohiro , Okusaka Takuji , Shimada Kazuaki , Kosuge Tomoo , Hiraoka Nobuyoshi 
Published: February 2017

179 Background: Pancreatic neuroendocrine tumors (NETs) are rare neoplasms that exhibit a variety of diverse morphological, functional and behavioral characteristics. However, only a few reports have evaluated large case series of pancreatic endocrine tumors. Methods: We conducted a retrospective review of 100 consecutive patients with pancreatic NETs diagnosed pathologically and treated at the National Cancer Center Hospital between 1991 and 2010. Results: The characteristics of the 100 patients were as follows: male, 49; female, 51; median age, 55 years. Fourteen patients gave a history of endocrine symptoms at the time of diagnosis. The primary tumors arose in the head, body and tail of the pancreas in 54, 25 and 21 patients, respectively. According to the 2010 grading classification of the World Health Organization, 11 patients were classified as having NET G1, 44 as having NET G2 and 29 as having NEC. The five-year survival rates of the patients with NET G1, NET G2 and NEC were 91%, 78% and 12%, respectively. The five-year survival rates of the patients with stage I, II and III, and IV disease classified according to the American Joint Committee on Cancer (AJCC) were 100%, 68% and 9%, respectively. Distant metastases occurred in 18% percent of the NET G1 patients, 39% of the NET G2 patients and 83% of the NEC patients. Treatment was undertaken by surgical resection in 82%, 59% and 24% of patients with NET G1, NET G2 and NEC, respectively. The five-year survival rates of the patients with NET G1, NET G2 and NEC after radical surgery were 100%, 91% and 36%, respectively. Among the 33 patients treated by systemic chemotherapy, the median survival period was 22.9 months in the patients with NET G1/G2 and 6.6 months in those with NEC. A multivariate analysis identified lower age, good performance status (PS) and lower histopathologic grade as independent favorable prognostic factors. Conclusions: Patients with NET G1, G2 treated by surgical resection had a good prognosis. Most patients with NEC exhibited distant metastases and had a poor prognosis. Histopathologic grade is an important factor for selecting the appropriate treatment strategy and predicting the prognosis in patients with pancreatic NETs.
Additional primary malignancies in patients with pancreatic cancer.
Authors: Allamaneni Shyam S. , Sharma Rohit , Miller Austin , Yendamuri Saikrishna S. , Gibbs John F. 
Published: February 2017

185 Background: Rates of second primary malignancy have been increasing with increased cancer survivorship. The published literature on second primaries in patients with pancreatic adenocarcinoma is sparse. We addressed this question utilizing the SEER database. Methods: 99,614 patients of primary pancreatic adenocarcinoma diagnosed between 1973-2006 were identified from SEER database. Of these, 8,889 (8.93%) had another primary diagnosed before pancreatic cancer (BPC) and 1813 (1.82%) a second primary diagnosed after pancreatic cancer (APC). SAS was used for statistical analysis and P-value <0.05 was determined to be significant. Results: The most common non-pancreatic primary identified were prostate, breast, lung, colorectal, and urinary bladder. The median age at presentation was 75 and 71 years in the BPC and APC groups respectively. APC patients had higher odds of developing primary cancers of embryonic gut origin (esophagus, stomach, small intestine, hepatobiliary, lung, and thyroid) compared to PBC patients (p<0.05). Patients of BPC compared to APC were more likely to be older than 70 yrs (70.5% vs. 65.3% p=0.01), less likely to undergo surgery for pancreatic cancer (11.2% vs.5.87% p=<0.05) and with decreased median survival (7 vs.3 months). With each passing decade, increasing second primaries were diagnosed, presumably reflecting better overall survival from cancer diagnosis. Conclusions: Approximately 11% of pancreatic adenocarcinoma patients have another cancer in their life time. Identifying common genetic and risk factors in these patients with multiple malignancies may provide the new therapeutic opportunities for patients with pancreatic cancer.
Methodology to screen and evaluate cost/survival of anticancer drugs in advanced/metastatic gastrointestinal cancers.
Authors: Guirgis Helmy M. 
Published: February 2017

196 Background: There is a paucity of methods to screen cost/survival of anticancer drugs in 1st-line advanced/metastatic (adv/met) gastrointestinal (GI) cancers. Methods: Average whole prices (AWP) in United States dollars (US $) of evaluated drugs for the entire course were divided by previously reported median survival gain in days. Generic drugs were given flat total costs of up to $750. A 100% crude score was assigned to cost/survival/day < $25 and 0% to cost/survival/day $750. Results were expressed as % scores of cost/progression-free-survival (cost/PFS) or cost/overall survival (cost/OS). Guidelines were suggested for corrections; lack of OS - 10%, adverse effects (AEs) - 0 -15%, Quality of life (QoL) - 0-10% and administration and preparation (A and P) - 0-10%. Results: Generic drugs scored 80%-90% in pancreatic and biliary followed by Trastuzumam 60% in gastric and Bevacizumab 0-40% in colon cancers (Table 1). Conclusions: Methodology based on limits on cost/survival/day was developed to screen anticancer drugs in GI cancers. Generic drugs in bilary and pancreatic cancers scored the highest. [Table: see text]
Phase I randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib as first-line treatment in patients with metastatic pancreatic cancer (SWOG-0727).
Authors: Philip Philip Agop , Goldman Bryan H. , Ramanathan Ramesh K. , Lenz Heinz-Josef , Lowy Andrew M. , Whitehead Robert P. , Iqbal Syma , Gaur Rakesh , Benedetti Jacqueline K. , Blanke C. D. 
Published: February 2017

198 Background: Targeting a single pathway in pancreatic adenocarcinoma (PAC) did not impact the natural history of this molecularly complex disease. Epidermal growth factor receptor (EGFR) targeting with erlotinib marginally improved the outcome of patients with advanced disease. We tested the hypothesis that if the EGFR and IGF-1R pathways are simultaneously blocked then progression free survival (PFS) would be significantly improved by abrogating reciprocal signaling. Methods: S0727 was a phase I/randomized phase II (RP2) study testing the anti-IGF-1R monoclonal antibody cixutumumab combined with erlotinib and gemcitabine in patients with metastatic PAC. The control arm was erlotinib plus gemcitabine. The primary endpoint of the RP2 portion of the study was PFS. Eligibility included patients with untreated metastatic disease, performance status 0/1, fasting blood glucose less than institutional upper limit of normal, and willingness to provide tissue and blood specimens for correlative studies. Results: In Phase I portion (n=10) safety of cixutumumab 6 mg/kg IV/wk, erlotinib 100 mg/day orally and gemcitabine 1000 mg/m2 IV D 1,8, and 15 of a 28-day cycle was established. In the RP2 portion (n=124) 114 eligible patients (median age 63) were included. On the cixutumumab arm, 59% of patients were female vs. 41% on control arm. Median PFS and overall survival were 4 and 7 months, respectively, in both arms. Four patients on cixutumumab remain on treatment; sensitivity analyses show no impact on the conclusions. Major grade 3 and 4 toxicities were (cixutumumab/control) elevation of transaminases (12%/6%), fatigue (24%/21%), gastrointestinal (35%/28%), and hematologic (53%/39%). Grade 3/4 hyperglycemia was seen in 27% of patients on cixutumumab. Grade 3 or 4 kin toxicity was similar in both arms of the study (< 5%). Five treatment-related deaths were reported: 2 cardiac on each arm, 1 pulmonary on cixutumumab. Conclusions: IGF-1R inhibitor cixutumumab did not improve the progression free or overall survival in patients with metastatic PAC treated with erlotinib and gemcitabine in a molecularly unselected population.
The prognostic significance of extra-intestinal tumor location for primary nonmetastatic gastrointestinal stromal tumors.
Authors: Guye Mary Lydon , Nelson Rebecca A. , Arrington Amanda Kathleen , Chen Steven L. , Chow Warren Allen , Kim Joseph 
Published: February 2017

2 Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm of the GI tract. Tumor size, tumor location, and mitotic index are established factors that risk stratify recurrence and survival. Extra-intestinal GISTs are infrequently observed and our objective was to investigate the outcomes of patients with primary GISTs found outside the GI tract. Methods: The Surveillance Epidemiology and End Results registry was used to identify patients with GIST treated with surgery between 1996 and 2008. Patients were evaluated by standard clinical and pathological indices including: age, primary tumor location (extra−intestinal vs. GI tract), tumor size, tumor grade, and extent of disease. Overall survival differences between primary site groups were assessed by Kaplan-Meier method. Univariate and stepwise multivariate Cox proportional hazards analyses were performed. Results: Of the 2812 patients with surgically treated GIST, 2489 (88.5%) had a primary tumor location in the GI tract and 323 (11.5%) were located in extra-intestinal sites. Comparison of patients by primary tumor location demonstrated more locally advanced cancers with lymph node involvement (40.2% vs. 18.4%; p<.0001) and a higher occurrence of distant metastatic disease (22.3% vs. 16.6%; p<.0001) among the extra-intestinal GISTs. When comparing overall survival, patients with extra-intestinal GISTs had significantly worse 5 year survival (62% vs. 70%, respectively; p=0.002) than patients with primary tumors within the GI tract. Stepwise multivariate analysis showed that non-intestinal site was an independent predictor of poorer survival (HR 1.29, 95% CI [1.05-1.59], p=0.015). Conclusions: Our data indicates that extra-intestinal location for primary non-metastatic GIST is an independent poor prognostic factor, with worse overall survival, compared to GISTs located within the GI tract. Risk stratification for prognosis should account for these rare GIST locations.
A novel xenograft model of gastrointestinal stromal tumors.
Authors: Sicklick Jason Keith , Leonard Stephanie Yvette , Mose Evangeline , French Randall P , Criscuoli Michele , Jaquish Dawn V , Maruyama Karly , Schwab Richard B. , Cheresh David , Lowy Andrew M. 
Published: February 2017

202 Background: GIST treatment with imatinib has served as the prototype for targeted molecular therapy. However, patients frequently acquire drug resistance to imatinib and this has prompted the development of additional multi-kinase inhibitors. To date, preclinical testing of novel agents has predominantly been performed using cell line based subcutaneous xenografts that may overestimate drug activity in the clinic. This suggests that novel in vivo models are needed to improve prediction of clinical efficacy. We hypothesized that human GISTs could be intra-peritoneally xenografted into immunodeficient mice in order to better recapitulate the microenvironment and biology of GIST. Methods: Tumor acquisition was performed under an IRB-approved protocol. Following tumor resection, we anesthetized NOD-scid (NS) or NS gamma (NSG) mice and performed a midline laparotomy. 2′2 mm tumor fragments were sutured into the abdominal viscera of NS (N=10) or NSG (N=15) mice. Tumors were imaged every 3-4 wks with ultrasound (US). 2 mice were also evaluated with PET scan. Results: We have xenografted GISTs from 3 patients into 25 mice with an 80% success rate and 4% perioperative mortality. We observed tumor progression in the liver (9/10), renal capsule (8/10), lesser sac (2/3), or gastric wall (1/2) of mice. This included 14 primary xenografts and 11 passaged xenografts. At 21-196 d (median 46 d), tumor size averaged 473±736 mm3 (median 104 mm3, range 2.2-2683 mm3) by US. In addition, 30% (6/20) of mice developed metastatic disease based upon US, necropsy, histology and/or KIT immunostaining. We also determined that 2/2 tumors were FDG-avid on PET. Conclusions: To our knowledge, we report the first intra-peritoneal xenograft model of human GIST using patient-derived tumor tissue. This novel in vivo approach is a reproducible model of human GIST that replicates the tumor microenvironment, heterogeneity, and metastatic potential of a human GI sarcoma. As compared to current research tools/models, this approach may allow researchers to better predict chemotherapeutic responses, further understand the tumor biology of GIST, and serve as a means to propagate additional tumor tissue for subsequent experimental analyses.