bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antitumor efficacy of M3814 as a radiation sensitizer in neuroendocrine tumor (NET) preclinical models.
Authors: Chauhan Aman , Rychahou Piotr , Izumi Tadahide , Arnold Susanne M. , Anthony Lowell Brian , Evers Mark , Kunos Charles 
Published: May 2019

e15699 Background: Recent FDA approval of peptide receptor radiotherapy paved the way for radiation-based treatment for gastroenteropancreatic neuroendocrine tumors (GEPNETs). M-3814, a DNA-dependent Protein Kinase Inhibitor (DNA-PKi), is known to potentiate the effects of radiation therapy in various solid tumor in vivo models. Currently there is no data evaluating anti-tumor efficacy of DNA-PK inhibitors in preclinical NET models. M-3814 inhibits DNA damage repair mechanism; antitumor efficacy of M-3814 in NETs is unknown. Methods: The efficacy of M-3814 in combination with radiation therapy (XRT) was evaluated in QGP-1 (pancreatic NET cell line) mouse model. Mice were injected with QGP-1 cells (5 mice) in 100 µL of PBS into the flank of mice with a 27-gauge needle. When tumor volumes reached average ~200 mm3, tumors were excised, separated into equal size tumor pieces and implanted subcutaneously into athymic nude mice. Next, mice were randomized into 4 groups for treatment with either placebo (n = 5), M-3814 (n = 5) alone (100 mg/Kg body weight (BW), XRT (n = 5) alone or in combination with M-3814 (n = 5). Treatment started when palpable tumors were established (200 mm3). Mice received M-3814 by gavage 30 minute prior to radiation therapy and irradiated with 4 daily doses of XRT at 2Gy per dose. Results: XRT and XRT+M-3814 treatment significantly decreased tumor size compared to control group. Combination treatment resulted in marked anti-tumor activity compared to both control group and XRT group. Tumors treated with XRT+M-3814 were also visibly less vascular. (Images will be provided in the poster). M-3814 alone had no effect on tumor growth as expected. Similar mouse weight changes were observed in both XRT and XRT+M-3814 treatment groups. Conclusions: M-3814 is a potent radiation sensitizer in preclinical neuroendocrine models. Strong antitumor activity was observed in QGP-1 xenograft model with marked reduction of tumor growth. Our enthusiasm for current project is driven not only by its inherent scientific importance, but also by its translational potential and the possibility to provide a more effective and less toxic radiation based treatment regimen for neuroendocrine tumors. [Table: see text]
Epidemiology, national trends and clinical associations of pancreatic adenocarcinoma in chronic pancreatitis patients: A nationwide inpatient sample (NIS) study.
Authors: Elkafrawy Ahmed , Asif Samia , Othman Hasan F. , Shrestha Anuj 
Published: May 2019

e15737 Background: Chronic pancreatitis (CP) is a known risk factor for pancreatic adenocarcinoma (PA). The aim of this study was to evaluate epidemiology, national trends and clinical associations of PA in hospitalized US patients with CP using the NIS database. Methods: ICD-9 CM codes were used to identify patients with CP and PA between 2002-2014. Age, gender, race, mortality, length of stay (LOS) and commonly associated comorbidities were correlated. Statistical analysis was done using SPSS 25. Results: We identified 1,677,517 patients with CP between 2002-2014. Patients with concurrent PA comprised 1.3 % (21,832) of total patients with CP. During the study period, the prevalence of PA in CP patients remained nearly steady (1.2% in 2002 and 1.3% in 2014). Median LOS was 8 days and decreased from 10 days in 2002 to 6 days in 2014. Overall mortality was 3.5% during hospitalization with the trend of mortality not showing a significant change in the study period (4.2% in 2002 and 4.1% in 2014). Median cost of total hospitalization for CP with PA was 52,116 USD, almost three-folds higher than for CP alone (18,797 USD) and increased from 42,241 USD in 2002 to 55,525 USD in 2014. For patients with CP and PA, 87.5% were above 50-years-old; 55.6% were males; Caucasians and African-Americans represented 72.2% and 12.6% of patients respectively. Interestingly, factors less associated with PA in CP included alcohol (OR 0.27, 95% CI 0.26-0.29, P < .0001), Diabetes Mellitus (DM) (OR 0.78, 95% CI 0.74-0.82, P < 0.0001), Chronic hepatitis C (OR 0.56, 95%CI 0.48-0.66, P < 0.0001) and pancreatic cysts and pseudocyst (OR 0.76, 95%, CI 0.69-0.83, P < 0.0001). Tobacco use, metabolic syndrome, Chronic hepatitis B and H. Pylori infection were not statistically associated with PA. Conclusions: In hospitalized patients with CP, 1.3% had PA. During the study duration, trends of prevalence and mortality did not show significant change, median LOS decreased and hospitalization cost of charge increased. Risk factors for PA like alcohol, DM, chronic hepatitis C, and pancreatic cysts were less associated with PA in patients with CP. Future studies are needed for early detection of PA in patients with CP.
Adjuvant nab-paclitaxel plus gemcitabine versus gemcitabine in resected pancreatic ductal adenocarcinoma: A Chinese single institution.
Authors: Yin Zhuzeng , Liu Rong 
Published: May 2019

e15740 Background: Adjuvant chemotherapy with gemcitabine (GEM) is standard care for resected pancreatic ductal adenocarcinoma (PDAC). Nab-paclitaxel plus gemcitabine (AG) vs gemcitabine (GEM) have shown better survival and tumor response with in advanced or metastatic PDAC. We aimed to determine the efficacy and safety of AG compared with GEM for resected PDAC. Methods: We retrospectively reviewed resectable PDAC patients (pts) who received AG or GEM as adjuvant chemotherapy from January 2013 to December 2016 at the Chinese PLA General Hospital, Bei Jing, China. Pts received nab-paclitaxel (125mg/m2) followed by GEM (1,000 mg/m2) on days 1, 8 every 3 weeks or GEM (1,000 mg/m2) alone on days 1, 8 every 3 weeks for 6 cycles unless disease progression or there was unacceptable level of adverse events. Disease free survival (DFS), overall survival (OS) and toxicity were analyzed. Results: Among 70 pts received AG or GEM as adjuvant chemotherapy, 10 pts were excluded due to the serious complication or R2 resection. The analysis was based on 30 pts in each group undergone complete macroscopic (R0 or R1) resection. Median DFS was 15.8 months (95% CI 13.1-18.5) in AG group (6 pts not arrived) compared with 12.2 months in GEM group (95% CI 9.6-14.8, P= 0.039, 3 pts not arrived). Median OS was 28.3 months (95% CI 21.9-34.6) in AG group (11 pts not arrived) as compared with 20.6 months in GEM group (95% CI 11.2-29.9, P= 0.028, 7 pts not arrived). The 2 years survival rate was 63.3% versus 43.3% in AG group versus GEM group. The most common adverse events of grade 3 or higher were leukopenia (32.3% in AG group vs. 20.7% in GEM group, P= 0.387), neutropenia (45.2% vs.31%, P= 0.298), G-CSF use (41.9% vs. 24.1%, P= 0.177), sensory peripheral neuropathy (51.6% vs. 24.1%, P= 0.036) and fatigue (3.2% vs. 3.4%, P= 0.737). Conclusions: Our results provide the first evidence that the adjuvant combination of nab-paclitaxel plus gemcitabine significantly improved DFS and OS of resected PDAC. Future RCTs with multi-center participation, particularly focused on adjuvant AG, can further provide information to confirm and strengthen these data.
Proton pump inhibitor (PPI) exposure and risk of pancreatic cancer (PC): Meta-analysis.
Authors: Al Khushaym Nasser Mubarak , Almutairi Abdulaali , Fallatah Saad , Althagafi Abdulhamid , Oh Mok , McBride Ali , Babiker Hani M. , Abraham Ivo 
Published: May 2019

e15755 Background: PPIs are widely used in the treatment of various acid related disorders. Observational studies have raised concern about an association of PPI use and PC but findings have been inconsistent. This meta-analysis aimed to estimate from published studies the pooled PC risk among subjects exposed and not exposed to PPIs. Methods: We searched PubMed, EMBASE, Scopus, Cochrane Library and clinicaltrials.gov to identify relevant studies on the association of PPI exposure and PC risk. Three reviewers independently screened search results for eligibility and extracted data from retained studies. Our primary analysis quantified PC risk among subjects exposed vs not exposed to PPI, expressed as the pooled (adjusted) odds ratio (OR/aOR) and 95% confidence interval (95%CI) as estimated in a random effect model. We performed similar secondary analyses in selected subgroups. Results: Of the 2683 reports yielded by the search 1 randomized trial, 2 cohort, and 9 case-control studies with 1,093,766 subjects (123,214 cases; 970,552 controls) were retained. Our main analysis (exposed vs non exposed) revealed a significant overall association between PPI exposure and PC risk (OR 1.77, 95%CI 1.14-2.74). Secondary analyses showed higher risk estimates from high quality (NOS > 7) studies (OR 2.04, 95%CI 1.03-4.02), observational studies (aOR, 1.70 95%CI 1.08-2.68), and studies with PPI use and PC risk as main outcome (aOR 2.01, 95%CI 1.06-3.83). Subgroup analyses by comorbidities showed an association with diabetes (aOR 1.98, 95%CI 1.02-3.82) but not pancreatitis (aOR 1.77, 95%CI 0.93-3.35). PC risk was not associated with duration of PPI use longer 1 (aOR 1.36 95%CI 0.81-2.28 and > 3 yrs (aOR 1.21 95%CI 0.73-2.02). In addition to the overall PPI class effect in the primary analysis, rabeprazole was singularly associated with PC risk (aOR 5.40 95%CI 1.98-14.70). Conclusions: Pooled risk estimates suggest that the class of PPIs is associated with a general 1.77 fold increase in PC risk, independent of duration of PPI exposure. Diabetic patients are at a significant incremental risk over the base risk.
Adjuvant therapy with gemcitabine and stereotactic body radiation therapy versus gemcitabine alone for resected stage II pancreatic cancer: A prospective, randomized, open label, single-center trial.
Authors: Ma Tao , Bai Xueli , Wei Qichun , Gao Shunliang , Huang Bingfeng , Chen Wei , Wang Ji , Liang Tingbo 
Published: May 2019

e15765 Background: Although adjuvant chemotherapy with gemcitabine has for years been the standard of care for resected pancreatic cancer, the role of adjuvant radiation is still debatable. We aimed to investigate the efficacy of gemcitabine combined with stereotactic body radiation therapy (SBRT) as adjuvant therapy for resected stage II pancreatic cancer. Methods: This single center randomized controlled trial was designed to enroll 512 patients with stage II pancreatic cancer that underwent curative-intended radical resection from a large-volume tertiary pancreatic center in China. Patients were randomly assigned to gemcitabine-alone adjuvant chemotherapy or adjuvant SBRT (25 Gray in 5 fractions) followed by gemcitabine chemotherapy. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints included locoregional recurrence-free survival (LRFS), overall survival (OS), and incidence of adverse events. Interim analysis was planned at the time of 2.5-years’ enrollment. Results: 40 patients were randomly assigned to treatment between Sep 1, 2015, and Mar 31, 2018 (21 to the gemcitabine group and 19 to the gemcitabine plus SBRT group). Of these, one was excluded because of ineligibility and one did not receive any treatment. The median RFS was 12.4 (9.3-15.6) months in the gemcitabine group and 14.7 (9.2-20.1) months in the gemcitabine plus SBRT group ( P= 0.753), with median LRFS of 18.2 (14.6-21.7) months in the gemcitabine group and 13.1 (9.1-16.8) months in the gemcitabine plus SBRT group ( P= 0.333). The median OS was 21.7 (19.5-24.0) months in the gemcitabine group and 16.9 (12.8-20.9) in the gemcitabine plus SBRT group ( P= 0.066). Grade 3 or 4 neutropenia, thrombocytopenia, nausea or vomiting, and liver dysfunction were all comparable between the two groups. Evaluation of data from the first 40 enrolled patients indicated that the addition of adjuvant SBRT was not associated with either better local disease control or recurrence free survival. And because of failure to achieve the accrual target, the trial was terminated prematurely. Conclusions: Adjuvant SBRT neither provided a survival benefit nor improved local disease control in resected stage II pancreatic cancer. Clinical trial information: NCT02461836.
Transducer array layout optimization for the treatment of pancreatic cancer using Tumor Treating Fields (TTFields) in the phase 3 PANOVA-3 trial.
Authors: Naveh Ariel , Hershkovich Hadas Sara , Kirson Eilon David , Weinberg Uri , Bomzon Zeev 
Published: May 2019

e15766 Background: TTFields is an antimitotic cancer treatment that utilizes low intensity (1-3 V/cm) alternating electric fields in the intermediate frequency (100-300 kHz), which are delivered in two orthogonal directions using 2 pairs of transducer arrays. Based on favorable results in a Phase 2 study in locally-advanced pancreatic cancer (LAPC), an ongoing Phase 3 PANOVA-3 trial [NCT03377491] is investigating the efficacy of adding TTFields to nab-paclitaxel and gemcitabine in LAPC. Preclinical studies show that the effect of TTFields is intensity-dependent with a therapeutic threshold of 1 V/cm. The field distribution within the body is known to changes with array placement. The current study was designed to develop clinical practice guidelines for optimizing the layout of arrays applied to patients participating in the TTFields arm of the PANOVA-3 study. Methods: Three realistic computerized models of a male, a female and an obese male were used to simulate delivery of TTFields to the abdomen. For each model, 6-8 different layouts utilizing combinations of arrays with either 13 or 20 disks per-array were tested. The arrays were placed over the upper 6 standard abdominopelvic regions, and field intensity distributions within these regions were evaluated. Results: In all simulations, the large arrays generated higher field intensities than the smaller arrays. However, models with lower BMI were almost covered entirely using large arrays, increasing the potential of skin toxicity from TTFields. However, these Low BMI models were able to receive TTFields at an anti-mitotic intensity with smaller arrays. The clinical guidelines were formulated based on the following principles: the target tumor region should be directly between the arrays, (b) the extent of disease as well as the anatomy of the patient determines the size of arrays determined using waist circumference measurements. Conclusions: A matrix for selecting between 8 individual array layouts was generated based on these principles. The clinical practice guidelines allow the optimization of TTFields delivery to individual patients treated in the PANOVA-3 Study.
Pancreatic cancer survival trends overall, by stage, and histologic sub-type: An analysis of Surveillance, Epidemiology and End Results (SEER) population-based data (2000-2015).
Authors: Karimi Parisa , Gordon-Dseagu Vanessa L , Chernyavskiy Pavel , Goggins Michael , Rosenberg Philip S. , Stolzenberg-Solomon Rachael 
Published: May 2019

e15772 Background: Pancreatic cancer (PC) is the third leading cause of cancer mortality in the United States, with an overall relative 5-year survival rate of 8.2%. We conducted a comprehensive evaluation of survival trends after PC diagnosis overall and by stage and histologic sub-type. Methods: We conducted a retrospective, population-based study of 91,234 PC cases using nationally representative data from the SEER program to evaluate 5-year survival trends by histologic sub-type from 2000 to 2015. Our model incorporated sub-type-specific random intercepts to effectively stabilize survival estimates by borrowing information across all sub-types. The estimation was performed in a fully Bayesian setting in R. Results: Adenocarcinoma, not otherwise specified (NOS) and ductal adenocarcinomas comprised 81% of PC. Cancer stage and histologic sub-type were both important factors in explaining variability in 5-year survival. We observed a consistent ordering of cancer stages within each histologic sub-type from highest to lowest survival for local, regional, and metastatic disease, respectively. Adenocarcinoma not otherwise specified, ductal adenocarcinoma, ductal specified as mucinous, and poorly specified type had the lowest 5-year survival with fitted ranges of 25-35% for localized, 5-19% for regional and < 4% for metastatic disease. Ductal arising from intraductal papillary mucinous neoplasm, ductal specified as cystic, acinar cell, other adenocarcinoma, and non-carcinomas had intermediate 5-year survival of 54-75%; while endocrine non-secretory or neuroendocrine, endocrine secretory, carcinoid, and solid pseudopapillary cancers had the best survival (87-98%). On average, across histologic sub-types, PC survival improved by 0.5% (90% credible interval 0.01%, 1.0%) per year, or 5.1% (0.1%, 10.0%) per decade. Some improvement in fitted survival occurred across all stages and histologic sub-types. Conclusions: Overall survival for patients with PC has improved by around 5% per decade from 2000 to 2015, with significant heterogeneity by histologic sub-type.
Defining the heterogeneity landscape of pancreatic cancer copy number alterations.
Authors: Baslan Timour , Wu Jie , Cheung Yee Him , Bermeo Jonathan , Dimitrova Nevenka 
Published: May 2019

e15776 Background: Pancreatic cancer (PDAC) is projected to become the second leading cause of cancer related mortality by 2030. Bulk whole genome sequencing studies of PDAC have characterized the landscape of clonal mutations and highlighted the prominence of copy number alterations (CNAs) in PDAC genomes. However, little is known with regards to the extent of sub-clonal heterogeneity of somatic CNAs and it is hypothesized that this heterogeneity is a contributing factor to the limited effectiveness of existing therapies. Methods: We retrieved absolute copy number information using bulk sparse whole genome sequencing of multi-region sampled PDAC samples as well as matching primary-metastasis tumor samples from over 100 patients. In addition, we analyzed copy number variations in a subset of these samples (n = 15) at single-cell resolution (~1000 cells in total). Results: We describe a detailed picture of sub-clonal CNAs genetic heterogeneity. Our results illustrate, among other findings, (1) extensive sub-clonal diversity of CNAs giving rise to many genetically unique sub-clonal cancer populations, (2) somatic mosaicism of chromosomal amplicons in single-cancer cells, (3) variation in the dosage of cancer genes, including the KRAS oncogene, in different tumor sub-clones and (4) somatic alterations, such as amplification of 8q11 containing the metastasis promoting gene IKBKB, associated with primary PDAC progression to liver metastasis. Conclusions: Our results offer an in-depth view of the sub-clonal heterogeneity of somatic CNAs in pancreatic cancer and illustrate ways in which such heterogeneity could lead to therapeutic resistance.
Profile of somatic mutations in young adults with pancreatic cancer.
Authors: Rodrigues Livia Munhoz , Maistro Simone , Katayama Maria Lucia Hirata , Roela Rosimeire Aparecida , Koike Folgueira Maria A. A. 
Published: May 2019

e15790 Background: Most pancreatic carcinomas (PC) occur in older people, however a few cases are detected in young adults. In this age group, the carcinogenic process is less well understood. Our goal was to identify and to characterize cancer driver genes in early age onset PC. Methods: Somatic variants of individuals affected by PC aged ≤45 years were searched in the COSMIC and CBioPortal databases. The variants were annotated using Oncotator, excluding the silent and intronic variants. Implication in cancer causality was evaluated in the Cancer Gene Census (CGC) and the Candidate Cancer Gene Database (CCGD). The most frequently mutated genes were identified and investigated to determine if they configured FrequentLy mutAted GeneS (FLAGs). Results: Whole genome (4) or exome (29) sequencing was available from 33 individuals (14 females and 19 males). A median of 31 (7-102) alterations per tumor, mainly represented by C > T substitutions (median 16, 2-71), was detected. A median of 3 (0-11) truncated alterations, 4 (1-13) genes cataloged as CGC and 8 (1-22) genes cataloged as CCGD rank A or B was identified per tumor. The most frequently affected genes were those characteristic of tumor promotion in pancreatic cancer carcinogenesis, such as KRAS (79%), TP53 (64%), SMAD4 (18%), followed by RYR1 (15%) and TTN (12%) genes, the latter two classified as FLAGs and, finally, HERC2, GREB1 and DMBT1 (9%). Seventeen samples presented variants in both TP53 and KRAS (17/33), 9 and 4 presented only KRAS or TP53 variants, respectively. Three samples with mutations in neither of these genes presented mutations in genes such as BCLAF1, DCC, BRAF, CDH11 and CDKN2A, both CGCs. Three out of 9 samples carrying KRAS but not TP53 mutations presented variants in DNA homologous repair (HHR) genes. Among all the altered genes, the main biological processes were cell adhesion (139 genes involved) and anatomical structure formation involved in morphogenesis (127), while the most enriched pathways were Wnt (45) and Cadherin (30). Conclusions: TP53 and KRAS are the somatic mutations most frequently detected in PC. 10% of the samples showed no change in these genes, but showed changes in other CGCs. HERC2, GREB1 and DMBT1 are potential cancer drivers in young adult PCs.
DNA repair deficiency association with prognosis in pancreatic cancer: A single-institution experience.
Authors: Bajwa Suhaib , Odeny Thomas A , Saeed Anwaar , Kasi Anup 
Published: May 2019

e15798 Background: Understanding survival outcomes of various pathogenic mutations helps guide treatment decision making for patients. Classic pancreatic cancer mutations such as KRAS and TP53 have well documented survival outcomes while other mutations leading to DNA repair deficiency do not have well understood survival outcomes. Methods: We retrospectively evaluated survival outcomes of 70 pancreatic cancer patients who had their cancers genetically profiled by NGS methods. Patients with DNA repair deficiency harbored mutations in genes such as BRCA1 (1 Pts), BRCA2 (8 Pts), ATM (5 Pts), NBN (1 Pt), and BRIP1 (1 Pt). We compared baseline characteristics, tumor stage and clinical outcomes between patients with DNA repair deficiency versus DNA repair proficient cancer patients. Comparative survival analysis between the two groups was performed using Kaplan-Meir methods. Results: Baseline characteristics for all patients are recorded in (Table). Median OS is 24 months for DNA repair proficient group and 20 months for DNA repair deficient group. A comparison of Kaplan-Meir survival curves between the two groups yielded a p-value of 0.72. This is most likely due to sample size and different chemotherapy regimens which make it hard to retrospectively compare patient groups. Conclusions: Patients with mutated DNA repair genes did not have significantly worse survival. We are designing a clinical trial utilizing a PARP inhibitor, for these patients in order to better control for all factors in order to better ascertain any survival differences between the two groups. PARP inhibitor will create multiple single strand breaks which cancer cells deficient in DNA repair genes cannot repair and thus trigger cancer cell death[Table: see text]