bluuebunny/crossref_metadata_2025_split huggingface dataset:
Monitoring tumor specific mutations in plasma during systemic treatment of biliary tract cancer.
Authors: Jensen Lars Henrik , Andersen Rikke Fredslund , Jakobsen Anders Kristian Moeller 
Published: March 2017

318 Background: We have previously reported a rate of 23% RAS/RAF mutations in plasma from patients with KRAS exon 2 and 3 wild-type, non-resectable biliary tract tumors. We wanted to explore the changes in circulating tumor specific DNA (ctDNA) during systemic chemotherapy in these patients. Methods: Patients with non-resectable biliary tract cancer treated within a phase II trial were included if they had KRAS exon 2 and 3 wild-type tumor tissue, had quantifiable levels of tumor specific DNA in plasma and progressive disease on imaging. They received gemcitabine, oxaliplatin and capecitabine with either bevacizumab or panitumumab. Treatment continued for up to six months until progression. Blood sampling and evaluation according to RECIST 1.1 were done every 12 weeks. Droplet Digital PCR was performed on DNA isolated from 4 ml plasma. A pre-amplification step was done and adequate positive and negative controls were included. The extended RAS and BRAF mutation analysis covered 20 mutations in KRAS exons 3/4, NRAS exon 2/3, PIK3CA and BRAF V600E. The percentage of tumor specific DNA relative to total DNA was reported. Results: The inclusion criteria were met by 13 patients, 10 women and three men. The typical pattern was seen in eight cases, where the percentage of tumor specific DNA dropped at least half during therapy and rose at least two-fold at progression. In three patients, a baseline sample was not available or there was not an initial drop, but the ctDNA rose at progression. One patient had an initial drop, but not a rise a progression based on imaging. The last patient progressed rapidly. Conclusions: This exploratory analysis pointed toward changes in percentage of tumor specific mutations in plasma as a marker of effect and progression. Dynamics of liquid biopsies is a promising tool in monitoring biliary tract cancer patients during systemic therapy. Clinical trial information: NCT01206049.
The impact of SPARC expression in survival of pancreatic ductal adenocarcinoma patients after curative resection.
Authors: Murakawa Masaaki , Aoyama Toru , Miyagi Yohei , Atsumi Yousuke , Kazama Keisuke , Kobayashi Satoshi , Ueno Makoto , Morimoto Manabu , Yamamoto Naoto , Sato Tsutomu , Yoshikawa Takaki , Rino Yasushi , Masuda Munetaka , Morinaga Soichiro 
Published: March 2017

321 Background: The predictive roles of secreted protein acidic and rich in cysteine (SPARC) in resected pancreatic ductal adenocarcinoma (PDAC) patients have not been clarified. We investigated the correlations between the SPARC expression and the postoperative prognosis. Methods: We retrospectively analyzed the clinical data from consecutive patients who underwent curative resection for pancreatic cancer in our institution from 2005 to 2014. Stromal SPARC expression was analyzed by immunohistochemistry on tumor tissue microarrays (TMAs) from the patients. Results: 179 patients were enrolled to this study. The median follow-up period of the present study was 62.1 months. 70 patients had positive SPARC expression (39.1%). There were no significant difference between the positive SPARC expression group and negative group. In survival analysis, there was significant difference in the 5-year overall survival (OS) rates after surgery, which were 8.1% and 19.8% between the SPARC positive and negative groups, respectively (p = 0.0316). Univariate analysis showed SPARC expression, size of tumor, lymph node metastasis, and residual tumor as the possible prognostic factors. Multivariate analysis revealed SPARC expression (hazard ratio (HR) = 1.44 95%CI; 1.017-2.051), lymph node metastasis (HR = 2.019 95%CI; 1.318-3.091), and residual tumor (HR = 1.648 95%CI; 1.132-2.401)as the independent prognostic factor. Conclusions: Stromal SPARC expression in resectable pancreatic cancer patients might be useful as the predictive survival marker. The prognostic value of SPARC expression should be confirmed in another cohort or in a prospective multicenter-study.
Immune analysis of fibrolamellar hepatocellular carcinoma.
Authors: Akce Mehmet , Vence Luis M , Blando Jorge M , Sharma Padmanee , Hassan Manal , Kaseb Ahmed Omar 
Published: March 2017

324 Background: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare variant of hepatocellular carcinoma (HCC) with about 200 annual cases reported globally. Surgical resection is the main treatment. Although FLHCC develops in the absence of cirrhosis surrounding hepatic parenchyma may have mononuclear cell and lymphocyte infiltrates. Immunotherapy by targeting programmed death 1 (PD-1) has emerged as a potential therapy for HCC and multiple clinical trials are being conducted, however little is known about immunological features of FLHCC. We aimed to analyze tumor microenvironment by immunohistochemistry and flow cytometry. Methods: Surgical samples of two FLHCC cases, 23 year old woman (case 1) and 25 year old man (case 2) who underwent neoadjuvant chemotherapy with 5 Fluorouracil + Interferon followed by surgical resection were analyzed. Expression of CD4, CD8, PD-1, programmed death ligand 1(PD-L1), CD45RO, CD 57, CD68, OX 40, inducible costimulator (ICOS), FoxP3, Gr-B was evaluated by immunohistochemistry. Flow cytometry analysis of CD8, CD4 effector (Teff) and regulatory (Treg) T cells were performed. Immune monitoring studies were conducted by the Immunotherapy Platform at MD Anderson Cancer Center. Results: By immunohistochemistry,expression of PD-1 and PDL-1 in the tumor sampleswas asfollows:PD-1 (5.9%) and PDL-1 (4.1%) of total cells in case 1 versus PD-1 (6.3%) and PDL-1 (3.5%) in case 2. FoxP3 expression was 0.3% and 1%, whereas ICOS expression was 0.2% and 1% in case 1 and 2, respectively. By flow cytometry analysis, case 1 presented the following frequencies: CD8+CTLA4+ (40%), CD8+PD1+ (40%) of total CD8 T cells, CD4+TeffCTLA4+ (55%), CD4+TeffPD1+ (30%), CD4+TeffICOS+ (15%) of total CD4 Teff cells and CD4+TregCTLA+ (90%), CD4+TregPD1+ (30%), CD4+TregICOS+ (70%) of total CD4 Tregs. Similarly, in case 2 the percentages were CD8+CTLA-4+ (20%), CD8+PD1+ (40%), CD4+TeffCTLA4+ (25%), CD4+TeffPD1+ (65%), CD4+TeffICOS+ (30%), CD4+TregCTLA+ (90%), CD4+TregPD1+ (70%), CD4+TregICOS+ (80%). Conclusions: PD-1, PDL-1, CTLA-4 and ICOS expression in FLHCC might render support to consideration of potential utilization of antibodies against PD-1, PDL-1 and CTLA-4 for treatment for a devastating cancer with unmet need for treatment.
Effect of advanced age, elevated bilirubin, and disease extent on outcomes of unresectable pancreatic cancer (UPC) patients receiving first-line chemotherapy: A population-based study.
Authors: Cherniawsky Hannah Marie , Wang Ying , Ghosh Sunita , Cheung Winson Y. , Ho Maria Yi 
Published: March 2017

325 Background: Superiority of FOLFIRINOX (FFN) and nab-paclitaxel plus gemcitabine (NG) over standard gemcitabine (GEM) monotherapy for UPC was shown in the PRODIGE and MPACT trials, respectively. However, both trials either excluded or limited enrollment of patients with locally advanced disease, elevated bilirubin and advanced age. We sought to determine the impact of age, bilirubin and disease extent on treatment outcomes in the real-world setting. Methods: We identified all patients newly diagnosed with UPC who received palliative chemotherapy at any 1 of 6 British Columbia Cancer Centers and the Cross Cancer Institute in Alberta from January 2014 to April 2016. Receipt of at least one cycle of chemotherapy represented treatment with group assignment based on the initial regimen delivered. Outcomes were compared while adjusting for age, bilirubin, extent of disease, and other measured confounders. Results: A total of 292 consecutive patients were identified of whom 161 (55%) were aged > = 65 years, 164 (56%) were male, 74 (25%) had elevated bilirubin, and 205 (70%) had metastatic disease at the time of presentation. Patients who received FFN or NG had a longer median overall survival (OS) than those treated with GEM alone after adjusting for age, ECOG, bilirubin and extent of metastatic disease (11 vs 10 vs 4 months, respectively; FFN: HR 0.297, 95% CI 0.199-0.445, p < 0.0001, and NG: HR 0.338, 95% CI 0.236 – 0.485, p < 0.0001). Similarly, FFN and NG patients also had longer progression-free survival (PFS) in comparison to GEM alone (8.8 vs 6.9 vs 2.9 months, respectively; FFN: HR 0.33, 95% CI 0.22-0.499, p < 0.0001, and NG: HR 0.47, 95% CI 0.33 – 0.67, p < 0.0001). Advanced age and elevated bilirubin were not significantly associated with OS and PFS (p > 0.05). Conclusions: The efficacy of FFN and NG were superior when compared to GEM alone for patients with UPC in the real-world setting. This population-based study showed that the benefits of FFN and NG persisted regardless of advanced age and hyperbilirubinemia.
Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio as prognostic factors for locally advanced pancreatic cancer patients.
Authors: Lee Byung Min , Chung Seung Yeun , Chang Jee Suk , Lee Kyong Joo , Song Si Young , Seong Jinsil 
Published: March 2017

326 Background: It is well known that locally advanced pancreatic cancer patients have a poor prognosis. Recently, hematologic markers showing systemic inflammatory status such as neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) have aroused much attention due to its potential to predict patient survival. In this study, we investigated whether pre-treatment NLR and PLR independently and in combination would be significant prognostic factors for survival in locally advanced pancreatic cancer patients. Methods: A total of 497 locally advanced (borderline resectable and unresectable) pancreatic cancer patients who received neoadjuvant or definitive chemoradiotherapy (CCRT) between January 2005 and December 2015 were included in this study. NLR and PLR prior to the start of treatment within 2 weeks were defined as pre-treatment NLR and PLR. We divided the patients with the median values of pre-treatment NLR and PLR; NLR < 2.44 group (n = 248), NLR ≥ 2.44 group (n = 249), PLR < 149 group (n = 248) and PLR ≥ 149 (n = 249) group. Overall survival (OS) and progression-free survival (PFS) were compared between each group for NLR and PLR. Results: Median overall survival was 15.7 months (range, 2.3-128.5 months). For NLR, the OS, PFS rates were significantly lower in the NLR ≥ 2.44 group, with 1-year OS rates of 67.9% and 61.5% (p = 0.003) and 1-year PFS rates of 38.1% and 32.4% (p = 0.003), for NLR < 2.44 and ≥ 2.44 group, respectively. The PLR ≥ 149 group also showed significantly poorer OS and PFS than PLR < 149 group. The 1-year OS rates were 68.1% and 61.3% (p = 0.029) and 1-year PFS rates were 37.9% and 32.5% (p = 0.027), for PLR < 149 and ≥ 149 group, respectively. When multivariate analysis was performed, NLR ≥ 2.44 remained as a significant adverse factor for OS (p = 0.011) and PFS (p = 0.026). PLR > 149 also proved to be a significant factor for poorer OS (p = 0.003) and PFS (p = 0.021). Conclusions: Elevated pre-treatment NLR and PLR independently and in combination significantly predicted poor OS and PFS. Pre-treatment NLR and PLR are useful prognostic factors for OS and PFS in locally advanced pancreatic cancer patients.
Expression of exportin 1 (XPO1/CRM1) in pancreatic adenocarcinoma.
Authors: Saulino David M , Younes Pamela S , Biley Jennifer M , Younes Mamoun 
Published: March 2017

327 Background: Exportin 1 (XPO1/CRM1) is a nuclear export chaperone that mediates the nuclear export of several proteins that are essential to growth regulation and tumor suppression. It was found to be overexpressed in several types of human malignancies and overexpression was found to be associated with poor prognosis. Pancreatic adenocarcinoma (PAC) is associated with very poor survival and currently has no effective treatment. Selective inhibitors of nuclear export are currently undergoing phase I and II clinical trials in hematologic malignancies and solid tumors. The aim of this study was to determine the expression of XPO1/CRM1 in pancreatic adenocarcinoma (PAC) and its relation to survivin expression and proliferative activity as determined by the S-phase fraction (SPF). Methods: Sections of tissue microarray containing 77 formalin fixed and paraffin embedded human PAC were stained by immunohistochemistry (IHC) using monoclonal antibodies to XPO1/CRM1, survivin, and for Cyclin A. The levels of XPO1/CRM1 and survivin expression in tumor cells and the S-phase fraction (SPF) were determined using a quantitative digital image analysis solution (OTMIAS). Results: Sixty-six of the 77 (86%) cases were positive for XPO1/CRM1, with the mean expression value ranging from 0.3 to 53 units and the median ranging from 0.3 to 45 units. There was significant correlation between the mean and median expression values of XPO1/CRM1 in tumor cells with the mean and median values of expression of survivin (p < 0.001). Moreover, the mean and median XPO1/CRM1 expression levels in tumor cells correlated significantly with SPF (p = 0.005). Conclusions: XPO1/CRM1 is expressed in a significant proportion of PAC, and increased expression correlates with both survivin expression and increased proliferative activity, suggesting that selective inhibitors of nuclear export may be effective against PAC.
Identification of circulating microRNAs for the diagnosis of early-stage gastric cancer.
Authors: Brunet-Vega Anna , Ramírez-Lázaro María José , Lozano Juan José , Quílez María Elisa , Garcia-Martinez Lorena , Junquera Félix , Pericay Carles , Calvet Xavier , Lario Sergio 
Published: March 2017

33 Background: The development of gastric cancer (GC) is a stepwise progression from non-active gastritis (NAG), chronic active gastritis (CAG) and precursor lesions of GC (PLGC: atrophy, metaplasia). Early detection of GC improves survival rates. Recent evidence has proposed circulating microRNAs (c-miRNAs) as biomarkers. The aim was to explore the c-miRNA profile of a cohort of non-GC and GC patients in order to identify early biomarkers of GC. Methods: Thirty-eight patients were enrolled: ten with NAG, nine with H. pylori infected with CAG, eight with PLGC, and ten with GC. GC patients were at TNM stages I and II. As quality controls, synthetic RNA was added during the isolation, cDNA synthesis, and PCR steps. MiRNA profiling was performed using Exiqon Human Panel I. Exploratory significance was set at P<0.05 with fold change (FC)≥1.6. Results: Of the total of 372 miRNAs analyzed, 154 miRNAs were detected in all samples. miR-185-5p was used to normalize. Compared to NAG individuals, GC patients showed downregulation of three miRNAs. GC patients also showed reduced expression of miR-205 compared to H.pylori-infected patients with CAG. Five miRNAs were upregulated in GC patients compared to PLGC patients (miR-134, miR-204, miR-224, miR-409, miR-877). Finally, in comparison with non-GC, seven miRNAs were found to be deregulated in GC patients (miR-130b, miR-144, miR-205, miR-219a, miR-224, miR-451a, miR-501). Specificities calculated at 90% sensitivity were low and significant FC ranged from -3.2 to 2.8. Conclusions: Using miRNA qPCR quantification, we found a deregulation of c-miRNAs in early GC. However, our results also show low diagnostic accuracy for early GC due to the small FC observed and the overlap in the miRNA levels between non-GC and GC patients. Further validation in a larger cohort and a prospective study is needed to determine conclusively whether these miRNAs serve as biomarkers. In our opinion, new methods need to be developed in order to quantify c-miRNAs and improve their diagnostic accuracy. [Table: see text]
A phase II study of gemcitabine as adjuvant treatment for biliary tract cancer after surgical resection.
Authors: Woo Sang Myung , Yoon Kyong-Ah , Hong Eun Kyung , Park Weon Seo , Han Sung-Sik , Park Sang Jae , Joo Jungnam , Park Eun Young , Lee Ju Hee , Kim Yun-Hee , Kim Tae Hyun , Lee Woo Jin 
Published: March 2017

330 Background: The role of adjuvant therapy following resection of biliary tract cancer (BTC) remains unclear. We therefore evaluated the feasibility and toxicity of adjuvant gemcitabine in patients with BTC. Methods: This clinical phase II study was an open-label, single center, single-arm study. Within 8 weeks after gross complete resection of BTC, patents received gemcitabine 1000 mg/m2as an intravenous 30-min infusion on day 1, 8, and 15 for every 28 days. Intratumoral expression of cytidine deaminase (CDA), human equilibrative transporter-1 (hENT1), deoxycytidine kinase (dCK) and ribonucleotide reductase subunit 1 (RRM1) was measured by immunohistochemistry and eight SNPs in the CDA, hENT1, dCK, hCNT3 and RRM1 genes were evaluated. The relationship of each with patients’ clinical outcomes was assessed. Results: From January 2010 to July 2014, a total of 72 BTC patients (26 with gallbladder cancer, 33 with extrahepatic cholangiocarcinoma, and 13 with intrahepatic cholangiocarcinoma) were enrolled. At a median follow-up was 38.09 months (range: 4.14-68.29), 2-year recur- free survival (RFS) was 43% (95% CI, 33% to 57%). The most common grade 3 and 4 toxicity was neutropenia, which occurred in 8 patients (11%). There was one treatment-related death from pneumonitis. The Cox proportion hazard model was performed with the following nine variables; gross type, degree of tumor differentiation. pathologic T factor, N stage, vascular invasion, perineural invasion, lymphatic invasion, dosage, and each protein expression. In the multivariable model, DCK expression, vascular invasion, and lymph node metastasis, were significantly associated with RFS. None of the tested SNPs was significantly associated with RFS or with any hematologic or non-hematologic toxicity. Conclusions: Although the primary hypothesis of this study, defined as a 2-year RFS of 60%, was not met, intratumoral DCK expression was significantly associated with RFS in patients with resected BTC treated with postoperative gemcitabine chemotherapy. Future randomized controlled trials are warranted. Clinical trial information: NCT01043172.
Targeted pancreatic cancer drug-delivery utilizing sigma-2 ligand/receptor internalization is energy-dependent.
Authors: Jin Linda X , Vangveravong Suwanna , Cullinan Darren R , Goedegebuure Peter S. , Loza Andrew J , Mach Robert H , Spitzer Dirk , Hawkins William G. 
Published: March 2017

331 Background: Pancreatic cancer is a devastating disease that is poorly responsive to traditional systemic therapies. Cancer-selective drug delivery can improve survival and reduce systemic toxicities. We have developed a pancreatic cancer drug delivery platform based on sigma-2 receptor ligands conjugated to small molecule drug cargos, which improves delivery and efficacy through efficient drug internalization. However, the mechanism of drug internalization via the sigma-2 receptor/ligand interaction remains unclear. Methods: Uptake of fluorescently conjugated sigma-2 ligand SW120 was studied in ASPC-1 human pancreatic cancer cells. Uptake was measured at 37C, 4C, after competitive inhibition with sigma-2 ligand SW43, and after pretreatment with Pitstop 2 (Abcam), an inhibiter of clathrin-mediated endocytosis. Uptake was visualized using live-cell imaging using A1Rsi confocal laser scanning microscope (Nikon). Image analysis was performed using FIJI (NIH) and Matlab (Mathworks). Results: SW120 (10 nM) was rapidly internalized into ASPC-1 cells at 37C with maximal fluorescence at 12 minutes. As a negative control, incubation of ASPC-1 cells with the unconjugated flourophore NBD Cl demonstrated no uptake after 15 minutes, indicating that uptake of SW120 depends on the specific sigma-2 receptor/ligand interaction. Fluorescence at 15 minutes was reduced by 85% in ASPC-1 cells incubated at 4C, indicating uptake of SW120 into cells is an energy dependent process. Pretreatment of cells with Pitstop 2 decreased total flourescence at 15 minutes by 76%, suggesting an important role of clathrin-mediated endocytosis in sigma-2 receptor uptake, while pretreatment with competitive inhibitor SW43 reduced uptake by 84%, suggesting that sigma-2 ligands are internalized via a specific receptor capable of saturation. Conclusions: Sigma-2 receptor ligands are rapidly internalized into pancreatic cancer cells via a specific, targetable, energy-dependent pathway that appears to rely on clathrin-mediated endocytosis. Further understanding of sigma-2 mediated drug internalization can help optimize targeted drug development and delivery for pancreatic cancer patients.
The clinical significance of KRAS monitoring in tumor tissues and blood of patients with pancreatic tumor.
Authors: Watanabe Fumiaki , Suzuki Koichi , Ichida Kosuke , Takayama Yuji , Fukui Taro , Kakizawa Nao , Noda Hiroshi , Rikiyama Toshiki 
Published: March 2017

334 Background: Monitoring of gene alterations in blood to track circulating tumor DNAs has been attempted for a clinical application. For example, KRAS monitoring in colorectal cancer provides a valuable biomarker for diagnosis and prediction of treatment outcome. While half of of colon cancer has RAS mutation, 90% of pancreatic cancer shows KRAS mutation, suggesting that most of pancreatic cancer is a good candidate for KRAS monitoring. In this study, we elucidated the clinical significance of KRASmonitoring in patients with pancreatic tumor during treatments. Methods: KRAS mutation in tumor tissues was determined by Scorpion ARMS or RASKET methods in 39 patients with pancreatic tumors. KRASmutation in blood (G12D, G12V, G12C, G12A, G12S, G12R, G13D, Q61L, Q61H) were investigated by using droplet digital polymerase chain reaction (ddPCR) in 24 patients treated with chemotherapy. Results: KRAS assessment in tumor tissues showed 33 patients with mutation and 6 patients without mutation. Thirty-three patients with mutation showed significantly poor prognosis of 49% in three years overall survival (OS) as compared with 100% in 6 patients with mutation (p=0.02). KRAS assessment in blood revealed that KRAS mutation was detected in 14 patients, but no detection was seen in 10 patients. Patients harboring KRAS mutation in blood exhibited significantly poor treatment outcome, including 12 patients with progressive disease, as compared with 10 patients without detection of mutation, including 6 patients with any treatment responses (stable disease in 4 patients and partial response in 2 patients, p=0.03). Fourteen patients with mutation in blood displayed poor prognosis of 20% in three years overall survival (OS), comparing to 69% in 10 patients without mutation in blood (p=0.06). Conclusions: KRAS status in tumor tissues was involved in prognosis; in addition, KRAS status in blood was implicated in treatment response of chemotherapy in patients with pancreatic tumor. KRAS monitoring in tumor tissues and blood provides useful information for the treatment strategy including chemotherapy in patients with pancreatic tumor.