bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genotyping of circulating tumor DNA in biliary tract cancer to reveal diagnostic and prognostic information.
Authors: Berger Andreas Wolfgang , Ettrich Thomas Jens , Schwerdel Daniel , Dolnik Anna , Beuter Florian , Blätte Tamara J. , Schmidt Stefan A. , Stanescu Nora , Steinacker Jochen , Marienfeld Ralf , Bullinger Lars , Seufferlein Thomas 
Published: January 2019

291 Background: Biliary tract cancer (BTC) shows increasing incidence and is associated with a high mortality. Diagnosis is difficult due to the frequently occurring inaccessibility of the tumor for biopsy. Noninvasive approaches for (i) assessing and (ii) monitoring the tumor-specific molecular setup are desirable. Characterization of circulating tumor DNA (ctDNA) may help to achieve this goal. Methods: Blood and tumor tissue samples from patients with locally advanced or metastatic BTC prior to and during palliative treatment were collected. Tumor tissue and corresponding ctDNA samples underwent targeted genotyping of the 15 most frequently mutated genes in BTC. Findings were correlated with clinical and imaging data. Results: 24 therapy naive patients with histologically confirmed BTC were included for analyses. The overall mutational concordance (blood/tissue) was 74% and 92% for intrahepatic tumors. The mean variant allele frequency (VAF) in tumor tissue of therapy naïve patients was significantly higher compared to the respective ctDNA (p = 0.0291). In turn, the sequencing depth for ctDNA was significantly deeper (p = 0.0001), enabling us to detect also rare variants. Mean ctDNA VAF at baseline significantly correlated with tumor load (Spearman, r = 0.4073, p = 0.0433) and, exclusively for intrahepatic tumors, also with progression-free survival (Spearman, r = -0.5878, p = 0.0386). During 1st line palliative treatment, we detected a change in the mutational landscape in 36% of cases, Moreover, we had access to ctDNA samples of 5 pretreated patients. While ctDNA samples of therapy naïve patients (n = 23) showed a mean of 0.78 mutations per patient, ctDNA samples of pretreated patients (n = 5) exhibited a mean of 0.4 mutations (p = 0.5519). Conclusions: The molecular landscape of BTC is depicted in ctDNA which may enable to adapt diagnostic and therapeutic strategies to the specific molecular setup present at a certain time. In contrast, the use of targeted resequencing is likely to be insufficient for a comprehensive assessment of treatment induced BTC evolution. For this purpose, we suggest a more extensive analysis of ctDNA by broader sequencing applications and the incorporation of epigenetics.
Phase II study of olaparib for BRCAness phenotype in pancreatic cancer.
Authors: Golan Talia , Varadhachary Gauri R. , Sela Tal , Fogelman David R. , Halperin Naama , Shroff Rachna T. , Halparin Sharon , Xiao Lianchun , Aderka Dan , Maitra Anirban , Ackerstein Aliza , Wolff Robert A. , Shacham-Shmueli Einat , Javle Milind M. 
Published: January 2019

297 Background: The subtype of pancreatic ductal adenocarcinoma cancer (PDAC) patients with DNA damage repair (DDR) deficiency from BRCA1/2 mutations has a favorable prognosis and is sensitive to platinum analogues and PARP inhibition. About 10-20% of PDAC patients have DDR deficiency without BRCA mutations (BRCA ness). The efficacy of olaparib in this population is unknown. Methods: Two parallel phases II trials (Israel and U.S.) are ongoing to determine the efficacy of olaparib in advanced PDAC with BRCA ness. Inclusion criteria: ≥ 1 prior systemic therapy for advanced PDAC, ECOG 0-1, germline BRCA 1/ 2 ( gBRCA) mutation negative, previously known DDR genetic aberrations (DDR-GA), family history of BRCA-associated cancers in ≥2 first-degree relatives (without DDR-GA), ATM loss by IHC (Israel only). Primary and secondary endpoints are objective response rate and PFS, respectively. With an type I error rate α of 0.1 and a β error rate of 0.2, and assuming P0 and P1 are 5% and 20%, respectively, study will enroll 24 patients at each site. Results: Thus far, 21 and 11 patients treated in Israel and U.S; respectively. DDR phenotype: Family history of BRCA cancer without DDR-GA (n = 14), DDR-GA (n = 12), ATM loss by IHC (n = 5). DDR-GAs were ATM (n = 6), PALB2 (n = 1), BRCA somatic (2), FANCB (1), PTEN (1) and CCNE1 (1). Efficacy data are in Table. Common toxicities were grade 1-2 anemia, fatigue and nausea. No responses were observed in platinum refractory cases. Conclusions: Olaparib was tolerated well in this study population. Olaparib showed encouraging initial antitumor activity in platinum-sensitive, gBRCA negative PDAC patients with DDR GA and in patients with family history of BRCA cancers (without identifiable DDR-GA). Clinical trial information: NCT02677038 ; NCT02511223. [Table: see text]
A translational effort to identify prognostic and predictive biomarkers in pancreatic cancer among RBM3-regulated genes.
Authors: Olsson Hau Sofie , Karnevi Emelie , Lundgren Sebastian , Li Bo , Lynch Seodhna , Elebro Jacob , Heby Margareta , Nodin Bjorn , Eberhard Jakob , Uhlen Mathias , Moran Bruce , Gallagher William M. , Jirstrom Karin 
Published: January 2019

305 Background: Pancreatic cancer has a dismal prognosis and clinical protocols are still lacking predictive biomarkers. RNA-binding motif protein 3 (RBM3) has emerged as a promising biomarker in several solid cancers, including pancreatic cancer. High RBM3 expression in human tumors has been associated with good response to chemotherapy, as well as to confer increased chemosensitivity in vitro. The aim of this study was to identify RBM3-regulated genes in pancreatic cells in vitro, and further interrogate their potential utility as prognostic and predictive biomarkers in a translational setting. Methods: Next generation RNA-sequencing was applied to compare gene expression between MIAPaCa-2 cells with siRNA-downregulated RBM3 and control cells. Single genes with the strongest association to RBM3 were further selected by gene set enrichment analysis, and their prognostic value in pancreatic cancer was examined in The Cancer Genome Atlas (TCGA). The most promising biomarker candidates with well-validated antibodies were then analyzed by immunohistochemistry in tissue microarrays with tumors from a consecutive, retrospective cohort of 175 patients with periampullary and pancreatic adenocarcinoma. Results: MIAPaCa-2 cells with downregulated RBM3 displayed 21 differentially expressed genes (p < 0.01). One of the top downregulated genes was PDS cohesion associated factor A (PDS5A) encoding a protein involved in sister chromatid cohesion. PDS5A protein expression was reduced in siRBM3-treated MIAPaCa-2 cells compared to control cells. High PDS5A mRNA expression was significantly associated with a reduced survival in pancreatic cancer in the TCGA (n = 176, p = 0.026). High PDS5A protein expression in the separate cohort was significantly associated with a poor prognosis but predictive of improved response to adjuvant chemotherapy in KRAS-mutated, but not wild-type, pancreatobiliary-type tumors (p for interaction = 0.043). Conclusions: Here, we provide the first report of the expression of PDS5A in pancreatic and periampullary cancer, suggesting its potential utility as a prognostic and predictive biomarker. Further studies to unravel the underlying mechanisms are encouraged.
Bioengineered microRNA-1291 effects on pancreatic cancer cell proliferation and xenograft tumor growth.
Authors: Tu Mei-Juan , Duan Zhijian , Zhang Qianyu , Qiu Jing-Xin , Gonzalez Frank J , Kim Edward Jae-hoon , Yu Aiming 
Published: January 2019

307 Background: MicroRNAs (miR) have proved to be vital regulators in the control of tumor progression. Our recent studies have revealed miR-1291 is downregulated in patient pancreatic cancer (PC) specimens and re-introduction of miR-1291 suppresses tumorigenesis of PC cells. We have developed a novel ncRNA bioengineering technology to produce a miR-1291 prodrug. In this study, we aimed to assess the effectiveness of this miR-1291 prodrug as a monotherapy, as well as in combination with chemotherapy, for treatment of PC. Methods: Sensitivity of PC cells to miR-1291 prodrug alone, gemcitabine plus nab-paclitaxel (Gem-nP) alone, and their combination was evaluated by CellTiter-Glo assay. Mature miR-1291 and ARID3B mRNA levels were determined by quantitative real-time PCR (q-PCR) assay. A luciferase reporter gene assay was used to validate interaction between miR-1291 and ARID3B 3’UTR. Target protein expression was examined by Western blot and immunofluorescence analyses. PANC-1 and PC patient-derived xenograft (PDX) mouse models were established and used to assess anti-tumor effects of miR-1291 monotherapy and combination therapy with Gem-nP. Results: Cytotoxicity assays showed that miR-1291 prodrug enhanced the sensitivity of PANC-1 and AsPC-1 cells to Gem-nP. Luciferase assays confirmed ARID3B as a target for miR-1291 as predicted by computational analysis. qPCR analysis demonstrated that miR-1291 prodrug was readily processed to mature miR-1291 and subsequently upregulated ARID3B mRNA levels. miR-1291 prodrug also elevated the protein levels of ARID3B. Co-administration of miR-1291 prodrug and Gem-nP increased caspase-3/7 and γH2AX levels in PC cells, compared to miR-1291 or Gem-nP treatment alone. In addition, systemic administration of in vivo-jet PEI formulated miR-1291 prodrug suppressed tumor growth in both a PANC-1 xenograft model and three PDX models, and largely enhanced the efficacy of Gem-nP. All treatments were well tolerated in mice in vivo. Conclusions: Our bioengineered miR-1291 prodrug has therapeutic potential as a monotherapy but also can act as a sensitizing agent to chemotherapy. This novel treatment approach should be further explored for PC.
Soluble urokinase plasminogen activator receptor (suPAR) as a novel serum biomarker for patients undergoing resection of colorectal liver metastases.
Authors: Loosen Sven H , Binneboesel Marcel , Klink Christian , Ulmer Tom Florian , Longerich Thomas , Trautwein Christian , Roderburg Christoph , Luedde Tom , Neumann Ulf Peter 
Published: January 2019

309 Background: In colorectal cancer (CRC), the liver is the most common site of metastasis. Surgical resection represents the standard potentially curative therapy for patients with colorectal liver metastases (CRLM). However, 5-year survival rates after resection do not exceed 50%, and despite existing preoperative stratification algorithms it is still not fully understood which patients benefit most from surgery. The soluble urokinase plasminogen activator receptor (suPAR) has recently evolved as a promising biomarker for distinct clinical conditions. Here, we examined a potential role of circulating suPAR as a biomarker in patients undergoing resection of CRLM. Methods: Expression levels of uPAR, the membrane-bound source of circulating suPAR, were analysed in tissue samples of CRLM using RT-PCR and IHC. SuPAR serum levels were measured by ELISA in 104 patients undergoing surgical resection of CRLM as well as 50 healthy controls. Results were correlated with clinical data. Results: In line with an upregulation of uPAR in the CRLM tissue, serum levels of suPAR were significantly elevated in patients with CRLM compared to healthy controls. Patients with preoperative suPAR serum levels above our defined ideal cut-off value of 4.83 ng/ml showed a strikingly reduced overall survival after resection of CRLM, which could be confirmed for right- and left-sided primary CRC. Importantly, none of these patients reached long-term survival compared to patients with preoperative suPAR serum concentrations below the cut-off value. Moreover, multivariate Cox-regression analysis revealed preoperative suPAR serum levels as an independent prognostic factor in this setting. Additionally, elevated preoperative suPAR but not creatinine levels were a predictor of acute kidney injury after CRLM resection, correlating with a longer postoperative hospitalization. Conclusions: Serum levels of suPAR represent a promising novel biomarker in patients with resectable CRLM that might help to guide preoperative treatment decisions with regards to patients’ outcome and the identification of patients particularly susceptible to postoperative acute kidney injury.
Clinico-pathological analyses of the relationship between SMAD4, TP53, CDKN2A mutations and recurrence and prognosis in patients with pancreatic cancer: A single institutional study.
Authors: Fukahori Masaru , Naito Yoshiki , Ishikawa Hiroto , Ushijima Tomoyuki , Nagasu Sachiko , Miwa Keisuke , Sakaue Takahiko , Takahashi Kenjirou , Nakayama Masamichi , Yasumoto Makiko , Ishida Yusuke , Okabe Yoshinobu , Okuda Kouji , Torimura Takuji 
Published: January 2019

319 Background: Gene mutations of SMAD4, TP53 and CDKN2A( p16) have been reported to be associated with poor prognosis and metastatic burden in advanced pancreatic cancer (PC). On the other hand, the association between these gene mutations and recurrence in PC is still unclear. The present study aimed to whether the 3 gene mutations were related to the recurrence and the prognosis in PC patients. Methods: Formalin-fixed paraffin-embedded tumor samples were gathered from patients with PC who underwent curative resection between January 2014 and December 2015. We retrospectively evaluated a relationship between the mutation status of SMAD4, TP53 and p16 and the recurrence and prognosis in patients with PC. Results: Totally, fifty-six samples of patients with PC (Stage I/ II/ III: 5/6/45 (UICC 7th)) were included in this analysis. Recurrence was seen in 32 patients (57.1%). Patients with PC both recurrence and advanced pathological stage showed poor prognosis. Each 3 gene mutation did not show a significant association with recurrence. TP53 and p16 single mutations did not show significant association with prognosis. However, the patients with PC who have SMAD4 mutation showed a significant poor prognosis (Overall survival: 18.6 vs. 34.5 months, p = 0.03). Multivariate analysis showed only recurrence was a significant prognostic factor (p = 0.01) Conclusions: The present study suggested that there was no association between SMAD4 and recurrence, whereas in case of recurrence, SMAD4 mutation may be associated with prognosis in PC patients.
Effect of a third-generation oncolytic herpes simplex virus on the growth of human hepatocellular carcinoma.
Authors: Nakatake Richi , Kaibori Masaki , Nakamura Yusuke , Matsushima Hideyuki , Okumura Tadayoshi , Inou Yasushi , Todo Tomoki , Kon Masanori 
Published: January 2019

321 Background: Multimodality therapies are used to manage patients with hepatocellular carcinoma (HCC), although advanced HCC is incurable. The third-generation oncolytic herpes simplex virus type 1 (HSV-1) T-01 replicates efficiently and selectively in tumor cells, kills tumor cells without damaging the surrounding normal tissues, and induces host immune responses specific to tumor cells. Here we investigated the antitumor effects of T-01 on HCC. Methods: The cytopathic activities of T-01 were tested at different multiplicities of infection in 14 human and one murine hepatoma cell lines in vitro. In mouse various xenograft models, HuH-7, KYN-2, PLC/PRF/5 and HepG2 human cells and Hepa1-6 murine cells were used to investigate the in vivo efficacy of T-01. Results: T-01 was cytotoxic to 13 cell lines (in vitro), including 10 human HCCs, two human hepatoblastomas, and one murine hepatoma. In mouse xenograft models of subcutaneous, orthotopic, and peritoneal tumor metastasis in athymic mice (BALB/c nu/nu), the growth of tumors formed by the HCC cell lines HuH-7, KYN-2, and PLC/PRF/5 as well as those formed by the hepatoblastoma cell line HepG2 was inhibited by T-01 compared with that of mock-inoculated tumors. In a bilateral Hepa1-6 subcutaneous tumor model in C57BL/6 mice, the growth of tumors inoculated with T-01 was inhibited and, in the contralateral tumors without T-01, T-01 also significantly reduced tumor growth compared with mock-infected tumors. T-01 infection significantly enhanced antitumor efficacy via T cell-mediated immune responses. Conclusions: These results demonstrate that a third-generation oncolytic HSV-1 may serve as a novel treatment for patients with HCC.
Effect of AdipoR agonist in cholangiocarcinoma.
Authors: Bui Khac Cuong , Nguyen Mai Ly Thi , Barat Samarpita , Chen Xi , Bhuria Vikas , Xing Jun , Nguyen Linh Toan , Le Huu Song , Velavan Thirumalaisamy P. , Wilkens Ludwig , Malek Nisar P , Bozko Przemyslaw , Plentz Ruben R 
Published: January 2019

323 Background: Adiponectin is the key adipokine, which plays an important role in health and disease such as obesity, diabetes, and cancer. Adiponectin is reduced in different tumor types, especially in obesity-related cancer, and recent studies showed that Adiponectin had a potential anti-cancer effect. Obesity is a risk factor for various tumor diseases including cholangiocarcinoma (CC), the second most common primary hepatic cancer. The aim of this study is to investigate for the first time the anti-cancer effect of AdipoR agonist in CC cell lines and a CC engineered mouse model. Methods: Human CC cell lines (TFK-1 and SZ-1) and CC engineered mice (Alb-Cre/KRASG12D/p53L/L) were used to investigate the anti-cancer effects of an AdipoR agonist (2-(4-Benzoylphenoxy)-N-[1-(phenylmethyl)-4-piperidinyl]-acetamide). Cell proliferation, migration, invasion, colony formation, apoptosis assay were applied to evaluate the effect of AdipoR agonist in vitro. In addition, important cancer signalling pathways and targets were analysed by Western Blot. Mice (n = 12) were treated with AdipoR or verhicle and tumor burden and survival were monitored. Results: AdipoR agonist suppressed proliferation, migration, invasion, colony formation and apoptosis in CC cells. AdipoR agonist regulated the expression of different proteins such as EMT markers, pAMPK, pSTAT3, and PARP, which have pivotal functions in cholangiocarcinogenesis. AdipoR agonist also prolonged survival time in a CC engineered mouse model. Conclusions: Our data revealed that AdipoR agonist inhibited successfully cell proliferation, migration, invasion, colony formation and apoptosis in vitro, and prolonged mice survival in vivo through regulation of crucial signaling pathways in cholangiocarcinogenesis. These results suggested that AdipoR agonist might become a new potential candidate for CC treatment in the future.
Chemotherapy choice in advanced pancreatic cancer: What patient and disease factors influence prescription patterns?
Authors: Raskin William , Guo Helen , Beca Jaclyn Marie , Isaranuwatchai Wanrudee , Qiao Lucy , Earle Craig , Berry Scott R. , Biagi James Joseph , Welch Stephen , Meyers Brandon Matthew , Mittmann Nicole , Coburn Natalie G. , Pardhan Aliya , Arias Jessica , Schwartz Deborah , Gavura Scott , Forbes Leta Marie , McLeod Robin , Kennedy Erin Diane , Chan Kelvin K. 
Published: January 2019

327 Background: FOLFIRINOX (FFX), gemcitabine+nab-paclitaxel (GnP) and gemcitabine monotherapy (Gem)) are universally funded as first-line chemotherapy regimens for advanced pancreatic cancer (APC) in Ontario, Canada. However, there is scarce real-world data on factors that may influence choice of chemotherapy regimens in APC. Methods: Patients who received first-line chemotherapy for APC between April 2015-March 2016 in Ontario were identified from CCO’s New Drug Funding Program database and linked to the Ontario Cancer Registry and other provincial databases to ascertain baseline factors. Multinomial logistic regressions were used to examine the associations between the prescribed chemotherapy regimen and baseline factors. Results: 546 patients were identified, with a mean age of 65 and 43.6% female. 9.9% and 9.7% had received adjuvant gemcitabine and radiation treatment respectively. 17.6% had previous pancreatic resection. 68.3% had zero Charlson score and 30.6% had ECOG performance status (PS) of 0. 72.7% had metastatic disease. The majority of the patients received FFX (52.4%) compared to GnP (35.7%) and Gem (11.9%). Age and ECOG PS were strongly associated with choice of chemotherapy regimens. (See Table) Conclusions: In Ontario, increased patient age and worse ECOG PS are strongly associated with choice of Gem compared to GnP and FFX. Previous treatments and stage of disease also impact chemotherapy choice. Understanding how providers choose chemotherapy in APC aids in comprehending our practices. Odds ratio (OR) and p value from multinomial logistic regressions. [Table: see text]
Adaptive versus non-adaptive MRI-guided radiation treatments for pancreatic cancer: A dosimetric study.
Authors: Spieler Benjamin Oren , El Bared Nancy , Padgett Kyle , Brown Karen Moya , Portelance Lorraine , Mellon Eric Albert 
Published: January 2019

336 Background: Combination MRI and radiation therapy systems enable magnetic resonance image guided radiation therapy (MR-IGRT). MR-IGRT allows clear visualization of the target and organs at risk (OARs) allowing for dose adaptation. Using adaptive MR-IGRT with Cobalt-60 for stereotactic body radiation therapy (SBRT) in locally advanced pancreatic cancer (LAPC), we hypothesized that MR-IGRT would improve dose to pancreatic tumor without increasing doses to OARs. Methods: Ten LAPC patients received five fraction SBRT with a total dose of 33-40 Gy. For each fraction, the original plan dose was compared to the dose that would be delivered if the original radiotherapy plan was applied to the anatomy that day (non-adaptive). An adaptive plan was then created for each fraction. The plan was re-optimized based on the anatomy as seen on the daily MRI and re-normalized so the volume of the PTV receiving 100% of the prescription (PTV100) would be 90%. Both the non-adaptive and adaptive doses to the target volume and the OARs were recorded to evaluate the value of adaptation. We used a paired t-test to compare PTV100 between the adaptive and non-adaptive techniques and Chi2 tests to compare the probability of dose constraint failures for OARs. Results: Adaptive MR-IGRT improved target coverage. Mean PTV100 for adaptive and non-adaptive techniques was 89.9% [88.4-90.4] and 78.4% [27.3-96.6] respectively, p = 0.0017. There were no statistically significant differences for violations of dose constraints of OARs using adaptive vs. non-adaptive techniques. Point maxima violations above 35 Gy to duodenum occurred in 6 adaptive fractions (renormalized to 90%) vs. 12 non-adaptive fractions (p = 0.118); to stomach in 8 adaptive fractions vs. 9 non-adaptive fractions (p = 0.790), and to bowel in 9 adaptive fractions vs. 6 non-adaptive fractions (p = 0.401). When adapting, attention must be paid to other OARs in the area: Spinal cord point maxima were violated in 4 adaptive fractions. Conclusions: This study demonstrates that adaptive techniques significantly increase SBRT dose delivered to LAPC without significantly increasing dose constraint violations to OARs. Adaptive MR-IGRT may allow for further SBRT dose escalations.