bluuebunny/crossref_metadata_2025_split huggingface dataset:
Benefit of early-phase targeted, basket, and immune-based trials for patients with chemorefractory gastrointestinal (GI) cancers.
Authors: Agarwal Rajiv , Cangemi Nicholas Anthony , Epstein Andrew S. , Harding James J. , Segal Neil Howard , Reidy Diane Lauren , Hyman David Michael , Saltz Leonard B. 
Published: May 2019

e15700 Background: Historically, phase I trials were designed to establish phase II tolerable doses of new drugs. Efficacy concerns were secondary. In the modern era of targeted and immune-based therapies, investigator and patient expectations of efficacy in such trials have increased. Patients (pts) who have exhausted standard treatment options often seek participation in phase I drug development or phase II basket studies, with hope for therapeutic benefit. We assessed the benefit to pts with chemorefractory GI cancers from investigational early drug development trials at our institution. Methods: We reviewed the referral records of our Early Drug Development and Immunotherapy Services to identify pts referred from our GI Oncology Service in 2018. As pts are typically not referred unless with performance status 0-1, and normal liver, renal, and marrow function, those requesting early phase studies but not meeting these criteria were excluded from this analysis. End points were enrollment on a trial, 3 and 6-month PFS, and tumor shrinkage. Results: Of 245 GI Oncology pts referred in 2018, 26 (11%) were accrued to a trial: 14 to immune-based (1 withdrew before treatment) and 12 to targeted (3 to phase II basket): median age 53 (range 23-76); 15 female. GI cancer types included: colon (7), pancreas (7), cholangiocarcinoma (4), rectal (3), and appendiceal, peritoneal mesothelioma, small bowel, unknown primary, and gastric (1). Most common reasons for non-accrual were lack of available treatment spots and failure to meet eligibility criteria for specific trials. Of 22 pts with adequate follow up at time of analysis, none achieved 6-month PFS; one (5%) met 3-month PFS with tumor growth below RECIST criteria at 3 months and came off study for progression at 4 months. No pts achieved any degree of tumor shrinkage while receiving trial drugs. Conclusions: Phase I and phase II basket options for chemorefractory GI cancers were limited relative to demand. Benefit from investigational treatment in this patient population was limited; expectations may be overstated. Further research is underway to evaluate pts’ expectations for therapeutic benefit from early phase targeted and immune-based trials.
Alpha-1-acid glycoprotein 1 (AGP1) as a novel biomarker for pancreatic cancer.
Authors: Zhou Qimin , Andersson Roland , Hu Dingyuan , Bauden Monika , Sasor Agata , Bygott Thomas , Pawłowski Krzysztof , Pla_Parada Indira , Marko-Varga György , Ansari Daniel 
Published: May 2019

e15708 Background: Pancreatic cancer is a heterogeneous disease with an aggressive clinical course. Most patients are detected late due to the insidious onset of symptoms and lack of effective molecular markers. The purpose of this study was to develop protein markers for improved prognostication and non-invasive diagnosis. Methods: A mass spectrometry (MS)-based discovery approach was applied to pancreatic cancer tissues and healthy pancreas. In the verification phase, extracellular proteins with differential expression were further quantified in targeted mode using parallel reaction monitoring (PRM). Next, a tissue microarray (TMA) cohort including 140 pancreatic cancer resection specimens was constructed, in order to validate protein expression status and investigate potential prognostic implications. The levels of protein candidates were finally assessed in a panel of 80 serum samples with ELISA. Results: Protein sequencing with nano-liquid chromatography tandem MS (nano-LC-MS/MS) and targeted PRM identified alpha-1-acid glycoprotein 1 (AGP1) as a potential pancreatic cancer biomarker. Using TMA and immunohistochemistry, AGP1 expression was significantly associated with shorter overall survival (HR = 2.217; 95% CI 1.296-3.794, p = 0.004). Multivariable analysis confirmed the results (HR = 1.867; 95% CI 1.078-3.235, p = 0.026). Circulating levels of AGP1 yielded an area under the curve (AUC) of 0.85 for the discrimination of resectable pancreatic cancer and IPMN from healthy controls. Combining AGP1 with CA 19-9 displayed an AUC of 0.98 with an overall sensitivity of 96% at 90% specificity. Conclusions: This study suggests that AGP1 is a valid biomarker for pancreatic cancer.
Patient and physician preferences for NIH PROMIS patient-reported outcome (PRO) domains in pancreatic ductal adenocarcinoma (PDA).
Authors: Guan Michelle , Gresham Gillian , Shinde Arvind Manohar , Placencio-Hickok Veronica , Gong Jun , Tuli Richard , Hendifar Andrew Eugene 
Published: May 2019

e15721 Background: PDA is associated with high symptom burden. However, treatment and palliation decisions currently weigh on physician interpretation of clinical parameters and may not consider patient values and preferences. The NIH PROMIS tool was created to capture various health domains through PROs. The objective of this study was to identify the most important PROMIS domains to PDA pts and physician providers. Methods: Using the 31 domains in NIH’s PROMIS, we conducted online surveys with PDA pts and PDA physicians from 17 academic centers. These domains are categorized into mental, physical, and social health. Values for the PRO domains were quantified using Maximum Differences Scaling (Sawtooth Software). Results: A total of 116 PDA pts (55% males, 45% females; median age: 68 years, range 42-95) and 33 physicians (78% males, 22% females; median years of experience: 15) completed the surveys. The top five domains identified by pts and providers are listed in the table. Physical functioning (PF), ability to perform activities of daily living (ADLs) and symptom management were among the top domains for both pts and physicians regardless of age, gender, resection status, or years of physician experience. However, social domains such as ability to do things for yourself, family, and friends, and interactions with family/friends were ranked significantly higher by pts versus pain, anxiety, and depression by physicians (p < 0.01). Conclusions: Our findings suggest PDA pts value PF and engaging in work and social activities while physicians focus more on pain, depression, and symptom management. PROs need to become more important endpoints in clinical trials to better inform treatment decisions and develop therapies that address the health priorities of pts. [Table: see text]
Efficacy and safety of FOLFIRINOX in elderly patients with advanced pancreatic adenocarcinoma.
Authors: Jung Jae Hyup , Kang Jingu , Lee Jong-Chan , Hwang Jin-Hyeok 
Published: May 2019

e15729 Background: Although FOLFIRINOX showed improved efficacy in advanced pancreatic ductal adenocarcinoma (PDA), physicians still hesitate to administrate FOLFIRINOX in elderly patients despite of being in a good performance status. We investigated the efficacy and toxicity of FOLFIRINOX in elderly patients with advanced PDA. Methods: We retrospectively reviewed electronic medical records of advanced PDA patients administrated a first-line FOLFIRINOX from January 2012 to July 2017 in a single tertiary teaching hospital. All the patients were divided into two groups: non-elderly group A (age < 70) and elderly group B (age≥70). Overall survival (OS), progression free survival (PFS) and toxicities were compared between two groups using Cox proportional hazard model. Results: A total of 214 patients (Group A 176; B 38) met the eligible criteria. Median age was 61 years old (29-80, group A 59; B 73) and median cycle of FOLFIRINOX was 7.0 (1–75, group A and B 7.0). Median OS and PFS did not differ between group A and B (OS, 11.8 vs 12.0 months, hazard ratio [HR] 1.165, 95% confidence interval [CI] 0.785–1.728; PFS 6.5 vs 7.3 months, HR 1.003, 95% CI 0.694–1.451, respectively). When we analyzed OS according to tumor stage (locally advanced and metastatic), group A and B showed comparable median OS (15.8 vs 13.5 months in locally advanced PDA; 8.6 vs 9.8 months in metastatic PDA, respectively) There were no significant differences in terms of hematologic toxicities except Gr 3 or 4 thrombocytopenia (Group A 3.4%; B 13.2%, P = 0.028). Fatigue and diarrhea were observed more often in Group B than in group A (47.4% vs 10.2%, P = 0.000; 18.4% vs 4.5%, P = 0.010, respectively), all of which were manageable. More patients in group B received dose adjusted FOLFIRINOX than in group A, although there was no statitical significance. Conclusions: FOLFIRINOX could be considered as the first-line chemotherapy for elderly patients with advanced PDA as well as non-elderly patients when dosage modified appropriately, given comparable efficacies and acceptable and manageable toxicities. More studies are warranted to confirm this issue.
Prognostic value of lymph node positivity and number of lymph nodes required for accurate staging of pancreatic neuroendocrine tumors.
Authors: Hua Jie , Shi Si , Wei Miaoyan , Zhang Yiyin , Liang Chen , Meng Qingcai , Liu Jiang , Zhang Bo , Xu Jin , Yu Xianjun 
Published: May 2019

e15736 Background: The prognostic role of the number of positive lymph nodes (PLNs), as well as the minimum number of lymph nodes needed to accurately stage patients with pancreatic neuroendocrine tumors (pNETs), remain controversial. The aim of this study was to assess the effect of the number of PLNs on prognosis in pNETs and to determine the ideal number of examined lymph nodes (ELNs) for accurate staging of pNETs. Methods: The SEER database was reviewed from 2004 to 2014 for pts with surgically resected, pathologically confirmed pNETs. Pts with missing data for pathological stage, tumor size, ELNs or PLNs were excluded. Kaplan-Meier survival analysis was used to evaluate the association between lymph node involvement and disease-specific survival (DSS). The optimal number of ELNs was identified using the log odds of positive lymph nodes (LODDS). A large single institutional cohort with 203 patients was used for validation. Results: Of the 1,813 patients included, 686 (37.8%) had lymph node-positive disease. Patients with lymph node-positive disease had a significantly worse DSS than those with lymph node-negative disease (Log-rank P < 0.001). Patients with 4 or more positive lymph nodes had a worse DSS compared with those with 1 to 3 positive lymph nodes (Log-rank P < 0.001). In order to capture 95% of pNETs with PLNs at the time of surgery, 12 lymph nodes need to be examined (LODDS: -2.344). Findings were reproducible with the validation cohort. Conclusions: The number of PLNs leads to better prognostic discrimination of lymph node-positive patients with pNETs. The current staging systems may include an N-stage that distinguishes lymph node-positive disease into N1 (1 to 3 PLNs) and N2 (4 or more PLNs) categories. The minimum number of ELNs for accurate staging of pNETs is 12. [Table: see text]
Microbiome signature of bile from pancreatic and biliary tract cancer patients: A pilot study.
Authors: Poudel Shyam K. , Padmanabhan Roshan , Chahal Prabhleen , Sanaka Madhusudhan , Stevens Tyler , Guinta Kathryn , Khorana Alok A. , Sohal Davendra , Eng Charis 
Published: May 2019

e15744 Background: Recent studies especially in murine models have linked meta-organismal pathways in the gut microbial community to cancers of the pancreas and the biliary tract. However, data on microbiome in the biliary pool in patients to establish models for oncogenesis in the pancreatobiliary (PB) habitat have been limited. We analyzed bile collected from a pilot series of patients to identify microbiome signatures associated with malignancy. Methods: We collected bile samples from patients during routine endoscopic retrograde cholangiopancreatography in this study approved by the Cleveland Clinic Institutional Review Board for Human Subjects’ Protection. Of 10 patients, there were 5 with pancreatic ductal adenocarcinoma (PDA), 3 with cholangiocarcinoma (CC), 1 with ampullary adenocarcinoma, and 1 with gallstone pancreatitis. DNA was extracted from bile specimens using PowerViral RNA/DNA Isolation kit. Bacterial 16S rRNA gene amplification and library construction were performed according to the 16S Metagenomic Sequencing Library Preparation guide from Illumina. Post-sequencing analysis was done using QIIME (Quantitative Insights Into Microbial Ecology) and MICCA (MICrobial Community Analysis). Results: Most reads were from phyla Firmicutes (57.9%) and Proteobacteria (14.9%). One benign specimen (pancreatitis) separated clearly from the rest showing 98.9% of reads from Clostridium sensu stricto (phylum Firmicutes). Analysis of beta diversity showed six samples clustering tightly. Of these, 5 were PDA and 1 was CC. A second cluster included remaining 3 samples, 2 with CC and 1 with PDA; this latter had higher abundance of phyla Fusobacteria (90.6%) and Verrucomicrobia (92.9%). Conclusions: Select bacteria are differentially increased in malignant and benign PB diseases. Furthermore, distinct microbiome signatures may be associated with cancer in the pancreatic and biliary habitats. We intend to evaluate these findings in larger sample sizes and determine associations with clinical outcomes and response to treatment.
Exposure-response (E-R) analysis of efficacy of pegvorhyaluronidase alfa (PEGPH20) in combination with nab-paclitaxel + gemcitabine (AG) in patients (Pts) with metastatic pancreatic ductal adenocarcinoma.
Authors: Liu Yong , Bullock Andrea J. , Passarell Julie , Bihorel Sebastien , Fiedler-Kelly Jill , Heineman Thomas C , Sekulovich Rose E. 
Published: May 2019

e15746 Background: PEGPH20 depolymerizes extracellular matrix hyaluronan (HA) and is an investigational agent for the treatment of pts with HA-accumulating tumors. HALO-109-202 (260 pts) was conducted to evaluate the effect of PEGPH20 + AG in pts with mPDA. Methods: E-R models were developed to evaluate the relationship between PEGPH20 exposure and efficacy, including time to PFS, time to OS, and overall response (OR). Results: The final E-R PFS model was a Cox proportional hazards model that included effects of PEGPH20 Cmax and baseline tumor biopsy HA (high or low). Higher PEGPH20 Cmax was associated with a lower risk of radiological progression. Pts with baseline HA≥ 50% (HA-high) tumor biopsy were at a lower risk of radiological progression with PEGPH20 treatment. A similar E-R model evaluated the effect of PEGPH20 on OS, including effects of dose-adjusted PEGPH20 concentration 7 days postdose (D7 Conc), liver metastases, and baseline tumor burden. The model-predicted influence of PEGPH20 D7 Conc on risk of death indicated that with increasing PEGPH20 D7 Conc, the predicted risk of death decreases. Pts with liver metastases and higher baseline tumor burden were predicted to have a higher risk of death. The final E-R efficacy model for OR probability was a linear function of dose-adjusted PEGPH20 AUC in Cycle 1, where increasing exposure was related to a higher predicted OR probability. Conclusions: The E-R analyses demonstrate that improvements in PFS and OS with PEGPH20 + AG is PEGPH20 exposure-dependent, supporting 3 µg/kg as an appropriate dose for further development and emphasizing the need for sufficient PEGPH20 exposure for improved therapeutic effect. Clinical trial information: NCT01839487. [Table: see text]
Effect of neoantigen reactive T cells combined with chemotherapy and radiation on survival in advanced pancreatic cancer.
Authors: Liu Qin , Zou Zhengyun , Liu Baorui , Kong Weiwei , Chen Fangjun , Shao Jie 
Published: May 2019

e15756 Background: Pancreatic cancer (PC) is one of the most aggressive and death-relating malignancy. Gemcitabine (GEM) is the key agent in the first-line standard regimen for advanced PC, which is mostly diagnosed at advanced stage and unsuitable for curative resection. The objective responsive rate (ORR) and medium progression free survival (PFS) of various GEM-based regimens are still unsatisfied. Therefore, development of new therapeutic modalities, including immunotherapy, is needed. This study is to investigate the efficacy, safety and clinical beneficial of combination neoantigen based immunotherapy with GEM and radiotherapy in locally advanced and metastatic PC patients. Methods: Three locally advanced unresectable and seven metastatic PC patients received at least two cycles of GEM (1000mg/m2 on day 1 and day 6), radiotherapy combing with neoantigen induced DC vaccination on day 7 and cytotoxic T lymphocyte transfer from day 12 to 15 (repeated every 21 days). The locally advanced unresectable PC patients received stereotactic body radiotherapy (SBRT) with a total amount of 50-66Gy during the first cycle. For metastatic patients, their partial lesions received a low dose radiation (0.5Gy bid*2days ) on day 10 and 11 in each cycle. Results: Two cases were observed with partial remission (PR), five with stable disease (sd), and three with progressive disease (PD). The disease control rate (DCR) was 70%. Median progression free survival (PFS) was 6.4 months. After the first treatment cycle, the total effectiveness for pain easement and increasing appetite are 100% (8/8)and 66.7%, respectively. Haematotoxicities with a 40% incidence rate were the most common adverse drug reactions. Two patients had grade 1 to 2 neutropenia, two with grade 3 to 4 thrombocytopenia. Three patients suffered grade 1 to 2 gemcitabine-induced skin rash. No treatment-related mortality occurred. Conclusions: Neoantigen reactive T cells combined chemoradiotherapy demonstrated an acceptable response and safety in advanced pancreatic cancer patients.
Effect of ARK5 on the anti-tumour activity of OSI-027 via regulation of epithelial-mesenchymal transition in pancreatic cancer.
Authors: Zhi Xiao , Liang Tingbo 
Published: May 2019

e15758 Background: Pancreatic cancer (PC) is one of the most common lethal malignancies,OSI-027, a selective inhibitor of mTOR, has anti-tumour activity in PC and is currently in phase II clinical trials. According to the results of our previous study, OSI-027 sensitivity varies across pancreatic cancer cell lines; however, the underlying mechanisms are unclear. Methods: In this study,We sought to investigate the regulatory mechanisms underlying OSI-027 resistance in PC under both in vitro and in vivo conditions. Results: We demonstrated that in PC, sensitivity to OSI-027 was negatively correlated with ARK5 expression, and ARK5 knockdown could enhance OSI-027 sensitivity. Further, the mechanistic experiments showed that ARK5 inhibition could reverse EMT induced by OSI-027. Suppression of EMT by Twist siRNA could sensitize pancreatic cancer cells to OSI-027, but the combination of Twist siRNA and ARK5 siRNA did not enhance the anti-tumour effect of OSI-027. Moreover, under hypoxia-induced EMT, the cancer cells were less sensitive to OSI-027, but ARK5 siRNA could block the EMT process. The in vivo experiments showed that the combination of ARK5 and Twist siRNAs could enhance the anti-tumour effect of OSI-027 and restrain OSI-027-induced EMT. Conclusions: The results indicate that ARK5 plays a role in the resistance of pancreatic cancer cells to OSI-027 by regulating EMT and lay the groundwork for future clinical studies.
Effect of LAT2 on glutamine-dependent mTOR activation to promote glycolysis and chemoresistance in pancreatic cancer.
Authors: Qiu Jiangdong , Feng Mengyu , Cao Zhe , Yang Gang , Liu Yueze , Zhang Taiping 
Published: May 2019

e15759 Background: Reprogrammed energy metabolism has become the characteristic of cancer recently. Transporters act as amino acid sensors involved in mTOR recruitment and activation, which is crucial for the growth of both normal and tumor cells. L-type amino acid transporter 2 (LAT2), a Na+ -independent neutral amino acid transporter, is encoded by the SLC7A8 gene and responsible for transporting neutral amino acids, including a mTOR activator, glutamine. LAT2 was reported to be overexpressed in gemcitabine-resistant pancreatic cancer cells. However, the role of LAT2 in chemoresistance in pancreatic cancer remains unclear. Methods: The effects of LAT2 on biological behaviors of pancreatic cancer cells were analyzed. LAT2 and LDHB levels in tissues were detected, and the clinical value was evaluated. Results: We demonstrated that LAT2 played an oncogenic role and decreased the gemcitabine sensitivity of pancreatic cancer cells in vitro and in vivo. Survival analysis indicated that high expression of both LAT2 and LDHB was related to a poor prognosis in patients with pancreatic cancer. Furthermore, we found that LAT2 could promote proliferation, inhibit apoptosis, activate glycolysis and alter glutamine metabolism to activate mTOR in vitro and in vivo. Next, the combination of gemcitabine with an mTOR inhibitor (RAD001) could reverse the decrease in chemosensitivity caused by LAT2 overexpression in pancreatic cancer cells. Mechanistically, LAT2 promoted glycolysis and decreased gemcitabine sensitivity via regulating two glutamine-dependent positive feedback loops (the LAT2/p-mTORSer2448 loop and the glutamine/p-mTORSer2448/glutamine synthetase loop) in pancreatic cancer. Conclusions: Our data indicates that LAT2 functions as an oncogenic protein and could regulate glutamine-dependent mTOR activation to promote glycolysis and decrease gemcitabine sensitivity in pancreatic cancer. The LAT2-mTOR-LDHB pathway might be a promising therapeutic target in pancreatic cancer.