bluuebunny/crossref_metadata_2025_split huggingface dataset:
The prognostic value of neuroendocrine differentiation in patients with undifferentiated-type gastric adenocarcinoma.
Authors: Makuuchi Rie , Tokunaga Masanori , Goto Hironobu , Tanizawa Yutaka , Bando Etsuro , Kawamura Taiichi , Nakajima Takashi , Terashima Masanori 
Published: February 2017

20 Background: Neuroendocrine carcinoma (NEC) of the stomach is defined as carcinoma having prominent (>70%) neuroendocrine differentiation (NED), and is well known to be highly malignant tumor with extremely poor overall survival time. However the biological meaning of less NED in gastric adenocarcinoma is still unclear. The aim of this study is to identify the prevalence of NED in undifferentiated type gastric adenocarcinoma (UDGA) and to clarify the prognostic value of NED. Methods: A total of 112 patients with advanced UDGA who underwent curative resection at Shizuoka Cancer Center between January 2004 and December 2006 were included. We performed immunohistochemical analysis for neuroendocrine markers, and classified patients into four groups according to the result of the immunohistochemical study as follows: NEC group (n=6), NED > 70%; MANEC (mixed adenoneuroendocrine carcinoma ) group (n=0), 30-70%; NED+ group (n=46), 1-30%; NED- group (n=60), NED < 1%. In the present study, clinicopathological features were compared between the NED+ and NED- groups and independent prognostic factors were identified. Results: The patients in the NED+ group were significantly younger (61y) than the NED- group (63y, p=0.035). There were no differences in sex, tumor depth, lymph node metastasis, macroscopic type, tumor size, and histological type between the two groups. The five-year survival rates of the NED+ and the NED- groups were 75.7% and 56.5%, respectively. Overall survival was significantly better in the NED+ group than in the NED- group (p=0.030). Cox-proportional hazard model revealed that tumor invasion deeper than T3 (HR, 2.387; 95% CI, 1.114-5.114; p=0.025), lymph node involvement (HR, 3.000; 95% CI, 1.346-9.685; p=0.007) and presence of NED (HR, 0.478; 95% CI, 0.236-0.969; p=0.041) were selected as independent prognostic factors. Conclusions: The frequency of NED in UDGA was 41.1%. The long-term outcome in the NED+ group was better than that in the NED- group. Therefore, UDGA with NED might be clinicopathologically different from the NEC of the stomach and further large scale study should be warranted to determine the biological behavior and to estimate the proper treatment strategy.
Locally advanced or metastatic pancreatic tumors: Molecular biology may help to know it and to select the optimal treatment.
Authors: Faloppi Luca , Andrikou Kalliopi , Loretelli Cristian , Mandolesi Alessandra , Bianconi Maristella , Scartozzi Mario , Berardi Rossana , Bearzi Italo , Cascinu Stefano 
Published: February 2017

201 Background: Pancreatic cancer have a multi step progression model with successive mutations like activation of KRAS and inactivation of SMAD 4. Various studies demonstrated that loss of SMAD 4 cooperate with an activating KRAS mutation to promote progression, leading to dysregulation of TGFb pathway. This plays a pivotal role in the formation of desmoplastic reaction by the activation of stellate cells. Stromal cells synthesize and secrete multiple proteins like SPARC which has been associated with worst prognosis. Early data have suggested that the identification of cancer stem cells in primary tumors is associated with shorter OS, resistance to therapy and metastatic potential. Emerging evidence suggest that the activation of the NOTCH 1 pathway is associated with molecular characteristics of stem cells. The aim of our study is to investigate the relationship and the potential prognostic role of these biomarkers. Methods: In 110 histological samples of pancreatic ductal adenocarcinoma were performed immunohistochemical evaluations of KRAS, and molecular biology assessment of NOTCH 1 CD133, OCT3/4, SMAD 4, SPARC. Results: Preliminary analysis showed lower rate of KRAS mutations (54%) and higher expression of NOTCH 1 in KRAS WT patients (57% vs 41%). Different expression of OCT3/4 and CD133 was found according to NOTCH1 expression. In patients with NOTCH1 overexpression, OCT3/4 is found overexpressed (59% vs 45%). Instead in patients with lower NOTCH1 expression CD133 is overexpressed (59% vs 42%). Furthermore KRAS WT compared to MT patients showed higher expression of SMAD4 (66% vs 37%) and lower expression of SPARC (44% vs 59%). Conclusions: Our data indicate that KRAS status can differentiate two prognostic categories of pancreatic tumors: one (KRAS MT) probably more aggressive and characterized by early metastatization, associated to desmoplastic reaction and stemness (higher SPARC and CD133), the other (KRAS WT) with a more favourable behavior, correlated with a prevalent local invasiveness, with lower desmoplasia and stemness profile (lower SPARC and higher OCT3/4). These data suggest that the latter tumors are good candidates to radiotherapy as a part of combinated treatment.
The role of tumor vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptors (VEGFR) polymorphisms in the prediction of clinical outcome for advanced hepatocellular carcinoma receiving sorafenib.
Authors: Faloppi Luca , Scartozzi Mario , Loretelli Cristian , Bianconi Maristella , Giampieri Riccardo , Bittoni Alessandro , Del Prete Michela , Mandolesi Alessandra , Bearzi Italo , Cascinu Stefano 
Published: February 2017

208 Background: HCC still represents a medical challenge in cancer therapy. The introduction of new therapies has radically changed the approach to the disease and patients outcome. Currently the therapeutic stronghold is a TKIs directed against the VEGF family sorafenib. Polymorphisms of VEGF and its receptor genes are involved in regulating angiogenesis and lymphangiogenesis and thus in growth tumor control. The aim of our study is to evaluate the potential predictive and prognostic role of VEGF and VEGFR polymorphisms in determining the clinical outcome of HCC patients receiving sorafenib. Methods: 142 histologic samples (biopsies and surgical specimens) of HCC patients receiving sorafenib were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients time to progression (TTP) and overall survival (OS) were analysed. Results: VEGF-A rs25648 polymorphism was statistically significant in OS (15.0 mo for C vs 9.4 for T p=0.025). VEGF-A rs10434 was statistically significant for TTP (4.1 mo for G vs 1.2 for A p=0.0076) and OS (14.2 mo for G vs 1.7 for A p<0.0001). VEGF-C rs7664413 was significant in TTP (13.4 mo for C vs 2.0 for T p=0.0125) and OS (14.7 mo for C vs 5.6 for T p=0.0007). VEGFR2 rs1870377 was significant in TTP (19.9 mo for A vs 3.0 for T p=0.0271) and OS (29.6 mo for A vs 11.9 for T p=0.0096). At multivariate analysis VEGF-C rs7664413 has been confirmed as an independent factor for TTP (HR=0,61) and OS (HR=0,65). Conclusions: In our analysis patients with G polymorphism at rs10434, C polymorphism at rs7664413 and A polymorphism at rs1870377 have a better response (PFS and OS) during treatment with sorafenib. Patients with C polymorphism of rs7664413 and A polymorphism of rs1870377 show a favourable impact in this setting. Notably, VEGFR polymorphism result closely related to the treatment response and the specific signalling of sorafenib. Thus analysis of VEGF and its receptor genes polymorphisms represents a clinical tool to identify patients with favourable response to sorafenib presumably related to a more efficient control of tumor growth.
Imaging approaches to assess mechanism-of-action and response in patients with advanced hepatocellular carcinoma treated with the novel oncolytic poxvirus JX-594.
Authors: Patt Richard H. , Kirn David H. , Breitbach Caroline , Burke James M. , Lencioni Riccardo 
Published: February 2017

210 Background: The novel oncolytic virus JX-595 has demonstrated anti-cancer mechanisms of action, as defined in preclinical models, which includes cytolysis, intra-tumoral vascular disruption, and immune-mediated tumor targeting. Methods: To determine whether mechanism(s) of action (MOA) of the novel anti-cancer oncolytic virus JX-594 could be demonstrated by MRI imaging in patients with advanced hepatocellular carcinoma (HCC), dynamic contrast-enhanced MRI of the liver was performed at baseline, day 5, and week 8 following intra-tumoral injection. Images were evaluated by a central reviewer blinded to treatment and dose using both modified RECIST and Choi response criteria. 17/30 subjects underwent day 5 (D5) post-treatment imaging; 28/30 had week 8 (W8) imaging. Results: Choi responses correlated more reliably than RECIST with JX-594 MOA. Evidence of intra-tumoral vascular shutdown, manifest by areas of reduced or non-enhancement (Choi response), was observed in 6 of 17 subjects on D5 5 MRI scans. Day 5 Choi responses were a predictor of week 8 Choi responses in all but 1 subject. Of the 11/17 D5 Choi non-responders, 3 were Choi responders at 8 weeks. Increase in size at D5 of small lesions present at baseline (“unmasking”) is compatible with oncolytic flare due to intra-tumoral edema contributed to by cell lysis and immune infiltration. RECIST criteria tumor measurements did not identify MOA of JX-594, and resulted in the appearance of pseudoprogression at D5 in some subjects. Conclusions: Hyperacute MRI post-therapy can be used to detect activity of the JX-594, a novel oncolytic anti-cancer therapy. Day 5 Choi responses were a predictor of subsequent response at week 8. Clinical trial information: NCT00554372.
Investigating the prognostic value of a panel of biomarkers after curative intent resection of pancreatic ductal adenocarcinoma.
Authors: Johnson Benny , Khalil Maged F. , Blansfield Joseph , Lin Fan , Zhu Shaobo , Kirchner Lester 
Published: February 2017

211 Background: Pancreatic adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality in the United States. 80% of tumors are discovered with distant metastasis upon presentation. Of patients eligible for curative intent surgery, the 5-year survival rate is only 20%. Identification of a panel of biomarkers correlated with patient specific prognosis upon diagnosis can serve as a way to individualize treatment options. Methods: A retrospective cohort study analyzing pathology of patients who underwent curative intent surgery at our institution from 1998-2011 to identify whether the expression patterns of six biomarkers:S100P, Maspin, KOC, CEA, p53, and Ki-67 can be predicative of patient specific prognosis. Tissue microarrays of specimens were assessed by immunohistochemistry. Results: A total of 62 patients are included. Comparisons between groups on overall survival (OS) and progression free survival (PFS) are estimated using the Kaplan-Meier method and the log-rank test. Each biomarker was represented as low and high expression by categorizing the expression score at >4, based on intensity and extent of cells stained. 40 deaths occurred in the sample. Distant metastasis and differentiation (well/moderate vs. poor) were borderline related to OS (p=0.0120, p=0.0086). Interestingly, patients with a poor differentiation were less likely to die due to any cause (HR=0.41, 95% CI: 0.21, 0.82). 29 patients progressed in their disease. High/low KOC expression were significantly related to progression free survival (p=0.0556). Incorporating previously reported data on KOC, patients with a high KOC expression were more than 2 times more likely to progress compared to those with a low KOC expression (HR=2.04, 95% CI: 0.97, 4.29). Conclusions: In our study S100P, Maspin, CEA, p53 and Ki-67 expression patterns were not statistically significant in identifying PFS or OS in PDAC patients. However, our data is suggestive of KOC being a useful prognostic biomarker for identifying those patients with PDAC who have a high risk for early progression and distant metastasis. Larger studies are needed to determine whether KOC can be a therapeutic target in the treatment of pancreatic cancer.
Expression of programmed death ligand 1 (PD-L1) in malignant and nonmalignant pancreatic tissue.
Authors: Razzaque Saqib , Ashraf Noman , Chavez Julio C. , Malafa Mokenge Peter , Coppola Domenico , Springett Gregory M. , Helm James , Kim Richard D. 
Published: February 2017

215 Background: Programmed death 1 (PD-1) protein and its ligands (PD-L1 & L2) play a key role in the evasion of the host immune system by tumor cells via inhibition of T-cells. It is of therapeutic interest that a number of tumor types selectively over-express PD-L1, since antibodies directed against PD-L1 have recently been shown to induce durable tumor regression. Methods: In this study we evaluated the expression of PD-L1 in pancreatic tissue obtained from 145 patients with localized pancreatic adenocarcinoma who underwent curative resection at our institution (stage IA – IIB). Of the 145 patients, 44 had paired pancreatic tissue samples of the tumor and adjacent non-malignant pancreatic tissue. These paired samples were used to compare expression of PD-L1 in malignant and nonmalignant tissue. Immunohistochemical staining was performed using rabbit primary antibody against PD-L1 (CD274/B7-H1) on formalin-fixed, paraffin-embedded core sections in tissue microarrays. Immunostain intensity and percentage cells stained were each scored on a scale of 0 to 3, with 3 being maximal. The product of intensity and percentage was used as a semi-quantitative measure of PD-L1 expression. Only patients with a product score greater than 0 on either the malignant or non-malignant tissue were included in this study. Results: PD-L1 expression (product score) was higher in 81% (36/44) of the malignant tissue samples than in paired non-malignant samples, equal in 7% (3/44) and lower in 11% (5/44). PD-L1 expression in malignant tissue (mean product score = 4.23) was significantly higher than the non-malignant pancreatic tissue (mean product score = 1.73) (p < 0.0001). The median product score was also statistically significantly higher for malignant versus non-malignant (4 vs. 2) tissue. Conclusions: Pancreatic adenocarcinoma tumor cells express PD-L1 at a higher level than their non-malignant counterparts. Future trials should evaluate drugs targeting the PD-1/PD-L pathway in the treatment of pancreatic cancer.
Conditional survival in gastric cancer: Does race influence prognosis in long-term survivors?
Authors: Luyimbazi David , Nelson Rebecca A. , Chen Steven L. , Kim Joseph 
Published: February 2017

22 Background: Conditional survival (CS) estimates of gastric cancer patients have used standard clinical and pathologic factors to predict prognosis during the follow-up period. However, there are known racial disparities in gastric cancer outcomes that have not been previously considered in these CS estimates. Therefore our objective was to evaluate the role of race in CS of gastric cancer patients. Methods: Data from SEER was used to identify gastric cancer patients who underwent curative surgical intervention from 1988-2006. 3-year relative conditional survival (RCS) was computed for patients who had survived 1, 2 and 3 years from diagnosis. RCS was calculated by dividing observed survival by expected survival using an age-, sex-, and race-matched standard population. Results were compared across time and across select racial groups (white, black and Asian/Pacific Islander [API]) using the z test statistic. Results: Of 25,728 patients, 67% were white, 20% API and 13% black. Each racial group had increased RCS over all time periods (p<0.05). For 3-year survivors, we observed a trend towards equivalence of RCS values for all racial groups. This trend is supported by the highest percent improvement in RCS from diagnosis for both white and black patients, with 89% and 95% respectively (p<0.05). In contrast, API patients had a 62% improvement from diagnosis. Conclusions: Our study shows that although pronounced at diagnosis, disparities in RCS values decrease over time as patients approach 3 years after diagnosis. Therefore, while race is a significant prognostic indicator at diagnosis of gastric cancer, it has less impact the longer patients survive. [Table: see text]
Rates of pathologic complete or near complete response following neoadjuvant chemotherapy and stereotactic body radiation therapy for borderline resectable pancreatic cancer.
Authors: Chuong Michael , Mellon Eric Albert , Hoffe Sarah , Shridhar Ravi , Springett Gregory M. , Hodul Pamela Joy , Malafa Mokenge Peter , Figura Nicholas , Centeno Barbara 
Published: February 2017

221 Background: While the clinical response from induction chemotherapy followed by stereotactic body radiation therapy (SBRT) has been reported for borderline resectable pancreatic cancer (BRPC) patients, response from a histopathologic standpoint has not been described. Methods: This single-institution retrospective review evaluated BRPC patients who completed induction gemcitabine-based chemotherapy followed by 5-fraction SBRT. All patients were restaged and underwent resection. A pathologist (B.C.) specializing in pancreatic cancer reviewed each surgical specimen and assigned two Tumor Regression Grade (TRG) scores, one from the College of American Pathologists (CAP) and one from the MD Anderson Cancer Center (MDACC). Overall survival (OS) and progression free survival (PFS) were correlated to TRG score using the Kaplan-Meier method. Results: This study evaluated 35 resected BRPC patients with a median follow up of 13.8 months (range, 6.1-24.8). All received induction gemcitabine-based chemotherapy, most commonly GTX (gemcitabine, docetaxel, capecitabine) (82%), followed by 5-fraction SBRT with a median 35 Gy (range, 30-40). TRG scores according to the CAP were as follows, from best to worst response: 0 (n=3), 1 (n=13), 2 (n=15), and 3 (n=4). TRG scores according to MDACC were as follows, from best to worst response: IV (n=3), III(M) (n=6), IIB (n=11), IIA (n=10), and I (n=5). Any neoadjuvant treatment effect according to MDACC scoring (IIA-IV vs. I) was associated with improved OS and PFS (both p=0.019). Conclusions: This study demonstrated a significant pathologic response with a gemcitabine based neoadjuvant regimen containing SBRT and suggests a survival benefit based on response as measured by the MDACC scoring system.
Emerging concepts in combination chemotherapy for metastatic pancreatic cancer: A systematic review of randomized controlled trials.
Authors: Njei Basile M. , Ditah Ivo C. , Shimanovsky Alexei , Owusu Priscilla , Birk John W 
Published: February 2017

228 Background: Even though gemcitabine monotherapy is commonly used as first-line treatment for metastatic pancreatic cancer, many novel treatment approaches have focused on combination chemotherapy. FOLFIRINOX, a combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin, has recently been shown to improve survival compared to gemcitabine. However, it is unclear whether survival benefits are counterbalanced by a poor quality of life due to the adverse effects. The aim of this study was to review emerging strategies that enhance treatment of patients with metastatic pancreatic cancer. Methods: Two authors independently conducted a comprehensive search of the Cochrane library PUBMED, and published proceedings from major oncologic and gastrointestinal cancer meetings from January 1980 to July 2012. Only published randomized controlled trials were eligible for inclusion. Our primary outcome measures were: progression-free survival (PFS), overall survival (OS) and serious adverse events (grade 3 or 4). Results: Thirty-one studies involving 7,957 patients were included in the analysis. There was an overall statistically significant increase in OS (RR 1.10, 95% CI 1.03-1.30) and PFS (RR 1.27, 95% CI 1.14-1.46) for the gemcitabine-based combination therapy group versus the gemcitabine monotherapy group. Subgroup analysis showed that only patients with fluoropyrimidine and platinum containing regimens showed prolonged survival: RR 1.33, 95% CI 1.04-1.76 and RR 1.38, 95% CI 1.08-1.76, respectively. The most common severe adverse event (neutropenia) was found in 45% of patients treated with FOLFIRINOX. Conclusions: Overall, gemcitabine in combination with fluoropyrimidine or platinum containing regimens can improve overall survival in patients with metastatic pancreatic cancer compared to gemcitabine alone. Even though, FOLFIRINOX therapy is associated with better survival outcomes than gemcitabine, the prolonged survival comes at the cost of poorer quality of life due to a higher incidence of adverse events. More data is needed from studies involving novel combination therapy such as hedgehog pathway inhibitors and radio-immunotherapy.
Reduction of interobserver variability (IOV) by FDG-PET–based tumor volume delineation (TVD) in radiotherapy planning for pancreatic cancer.
Authors: Branagan Jennifer Mary Rose , Halle Charlotte , Falk Stephen , Radhakrishna Ganesh , Roy Rajarshi , Crosby Thomas , Hurt Chris , Brunner Thomas B. , Mukherjee Somnath 
Published: February 2017

229 Background: Wide IOV has been reported for CT-based TVD during radiotherapy planning for pancreatic cancer (Yamazaki, Anticancer Research 27: 2965-2972, 2007). PET-CT has been successfully incorporated into treatment planning in other tumour sites and has been shown to reduce IOV, but no study has looked at its role in pancreatic radiotherapy. Methods: Six radiation oncologists from 6 oncology centers in the UK were asked to outline GTVs in two cases with pancreatic head tumors. DICOM data set of planning CT, diagnostic CT and FDG-PET-CT scans were made available. GTV was first outlined using the information on the diagnostic CT scan alone, without access to PET scans (GTV_CT). The GTVs were then re-outlined using additional information from the PET scan (GTV_PET). A PTV was grown from the GTV, using a margin of 2cm sup-inf and 1.5cm radially from the GTV, as per standard UK practice. Results: A total of 48 countours (24 GTV contours and 24 PTV contours) were analysed, and the results are presented below (Table). Conclusions: The incorporation of PET scan resulted in a prominent reduction in standard deviation around tumor volumes, smaller largest:smallest GTV ratios and a larger percentage of overlap between investigator volumes, suggesting a reduction in Inter-Observer Variability. PET based RT planning should be considered in multicenter radiotherapy trials in pancreatic cancer to reduce IOV. [Table: see text]