bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase IB/II randomized study of mFOLFIRINOX (mFFOX) + pegylated recombinant human hyaluronidase (PEGPH20) versus mFFOX alone in patients with good performance status metastatic pancreatic adenocarcinoma (mPC): SWOG S1313 (NCT #01959139).
Authors: Ramanathan Ramesh K. , McDonough Shannon , Philip Philip Agop , Hingorani Sunil R. , Lacy Jill , Kortmansky Jeremy S. , Thumar Jaykumar Ranchodbhai , Chiorean E. Gabriela , Shields Anthony Frank , Behl Deepti , Mehan Paul Tracy , Gaur Rakesh , Seery Tara Elisabeth , Guthrie Katherine , Hochster Howard S. 
Published: January 2019

208 Background: PEGPH20 degrades hyaluronan (HA), a major component of the stroma, increases delivery of gemcitabine and prolongs survival in preclinical models. We evaluated the activity of PEGPH20 in combination with mFFOX in mPC , unselected for tumor HA. Methods: Pertinent eligibility: untreated mPC, PS of 0-1 and adequate organ function. Standard FFOX was modified to add prophylactic growth factor support and omit bolus 5FU. Due to increased thromboembolic (TE) events with PEGPH20, an amendment instituted LMWH prophylaxis in the PEGPH20 arm only. Following a dose finding cohort of mFFOX + PEGPH20, the Phase II study randomized patients (1:1) to the combination arm or mFFOX alone (n = 138). The primary endpoint was overall survival (OS), with a null median OS of 10 mo and an alternative of 15 mo (1-sided type 1 error 0.1, 80% power). Results: PEGPH20 at 3 mcg/kg, q2 weeks was more tolerable than twice weekly dosing. The randomized phase II study began May 2015. The planned interim futility analysis when 35 deaths occurred gave a HR of 0.44 favoring the standard arm, thus the study was closed to accrual (March 2017). As of August 22, 2017 (n = 111), the estimated median OS in the mFFOX arm was 15.1 mo (95% CI 10.1-15.7) vs 7.6 mo (95% CI 4.6-9.2) in the PEGPH20 arm. Conclusions: OS in the mFFOX control arm (15.1 mo) is longest yet reported. Addition of PEGPH20 to mFFOX is not recommended for further study and appears to be detrimental (HR = 0.48). The impact of PEGPH20 on OS was unexpected and in contrast to favorable results reported for the combination of gemcitabine/nab-paclitaxel + PEGPH20 especially in the HA high cohort (Hingorani S et al. A 4008, ASCO 2017). PEGPH20 with mFFOX caused increased toxicity (mostly GI and TE events) and decreased treatment duration compared to mFFOX alone. Tumor HA content will be analyzed. Funding: NIH/NCI grants CA180888, CA180819; and in part by Halozyme Inc. Clinical trial information: 01959139. [Table: see text]
Chemotherapy use in the elderly for stage IV pancreatic cancer: An NCDB analysis.
Authors: Ahmed Aabra , Sitenga Jenna , Aird Gregory , Walters Ryan W , Silberstein Peter T. 
Published: January 2019

223 Background: Cancer incidence is higher in the elderly, yet these patients tend to be underrepresented in clinical trials and receive less treatment than their younger counterparts. This study seeks to elucidate the impact of chemotherapy in elderly patients with stage IV pancreatic cancer. Methods: We identified 68,044 patients with stage IV pancreatic cancer over the age of 65 diagnosed between the years 2004-2013. Between-chemotherapy survival differences were estimated by the Kaplan-Meier method and associated log-rank tests; Tukey-Kramer adjusted p < .05 indicated statistical significance. Results: Statistically significant differences in demographics of patients with and without chemotherapy included that patients given chemotherapy were more likely to live in an area with a median income of $63,000+ (34.9% vs 30.2%, respectively), receive treatment at an academic center (36.6% vs. 30.7% respectively), and have no comorbidities (66.9% vs. 59.4%, respectively) compared to those not given chemotherapy. Statistically significant survival differences were indicated between all chemotherapy groups (all adjusted p < 0.05), such that patients receiving chemotherapy survived longer than those without chemotherapy (median survival 5.5, 1.3 months, respectively). A larger proportion of patients receiving chemotherapy were alive at 6, 12, and 24 months relative to patients receiving no chemotherapy. Use of chemotherapy has increased over time for elderly stage IV pancreatic cancer patients, such that 37.9% of patients diagnosed in 2004 received chemotherapy, while 45.9% of patients diagnosed in 2013 received chemotherapy. Conclusions: To our knowledge, we are the largest trial to investigate treatment of stage IV pancreatic cancer in the elderly. Although the prognosis is overall poor, chemotherapy provided a mild survival benefit. Use of chemotherapy in these patients increased from 2004 to 2013, yet less than half of patients received chemotherapy. [Table: see text]
Single institutional analysis of pancreatic cancer survival trends based on BMI.
Authors: Wiisanen Jeff , McWilliams Robert R. , Bamlet William R 
Published: January 2019

234 Background: Body mass index (BMI) has been reported to determine risk for pancreatic cancer in addition to outcome, as those with higher BMI have decreased survival. Since May 2011, therapy for pancreatic cancer has improved with the addition of FOLFIRINOX. This study looks at overall survival in relation to BMI since the advent of the FOLFIRINOX. Methods: 2,277 patients with pancreatic adenocarcinoma were identified through the Mayo Clinic SPORE pancreatic cancer registry from 2000-14. Usual adult and BMI at time of enrollment were utilized as a binary variable ( < 30, ≥30 kg/m2). These were analyzed for association with survival using Kaplan-Meier curves and Cox proportional hazards regression. Results: For the 2000-11 and 2011-14 groups, stage distribution was 4.4%, 34.7%, 21.6%, 39.2% and 1.2%, 39%, 22.2%, 37.6%, respectively for stage 1-4. Since pancreatic cancer commonly causes weight loss, more patients were in the higher usual adult BMI (34.6%) compared to enrollment (17.1%). For the period 2000-11, 33.8% of patients had a usual adult BMI of 30+ vs 37.8% for the 2011-14 patients. As previously reported, there was a difference in survival by BMI for the period 2000-May 2011, however, this was not seen for the period June 2011-14. Conclusions: Based on this cohort of patients, the previously reported detrimental effect of elevated BMI on survival in pancreatic cancer patients is no longer seen. This corresponds with the time period of improvement in pancreatic cancer treatment with FOLFIRINOX. Further studies should be performed to confirm our findings and to identify the causality of this association. [Table: see text]
Prediction of overall survival for metastatic pancreatic cancer treated with gemcitabine monotherapy: Development and external validation of a prognostic nomogram with open clinical trial data.
Authors: Hang Junjie , Wu Lixia , Du Jiadi , Jiang Hua , Xu Kequn 
Published: January 2019

237 Background: There is a need for prognostic tools in metastatic pancreatic cancer (MPC) because they have the potential to optimize patients’ selection in clinical trail and guide treatment strategies. We address this issue by developing and validating a prognostic nomogram with open clinical trail data. Methods: Data from the comparator arm of three clinical trails (NCT00844649, NCT01124786 and NCT00574275) in MPC treated with gemcitabine as first-line chemotherapy were analyzed. The former two were taken as training cohort while NCT00574275 was used as validation cohort. Cox regression model was used to investigate prognostic factors from twenty-three baseline characteristics in training cohort. Based on these factors, a nomogram was developed and internally validated with Harrell’s Concordance index (C-index) and calibration plots. It was further externally validated in the validation cohort. Results: In the training cohort (n = 445), performance status, liver metastasis, CA19-9 log-value, neutrophil, platelet (PLT) and albumin were independent prognostic factors for overall survival (OS). A nomogram based on these factors was generated to predict OS and survival probabilities. The nomogram showed an acceptable discrimination ability (C-index: 0.683) and good calibration. The prognostic score based on nomogram could stratify patients into three-risk groups with median OS of 11.7, 7.0 and 3.7 months (P < 0.001). The nomogram was further externally validated in validation cohort (n = 273, C-index: 0.699); median OS of 10.6, 7.3 and 4.0 months for the three-risk groups (P < 0.001). Conclusions: The prognostic nomogram can accurately predict OS for MPC treated with gemcitabine as first-line chemotherapy. [Table: see text]
Palliative care intervention and aggressive care at end-of-life in patients with advanced pancreatic adenocarcinoma.
Authors: Lees Caitlin , Hopman Wilma M , Younis Tallal , Lamond Nathan William Dana , Ramjeesingh Ravi 
Published: January 2019

244 Background: Unresectable pancreatic cancer carries one of the worst prognoses amongst malignancies. For these patients, their treatment at end-of-life represents some of the most expensive care they will receive. Resource-intensive care at the end of life contrasts with the preferences of many patients and their family members. We have examined the intensity of end-of-life care in patients diagnosed with unresectable pancreatic adenocarcinoma using a previously published aggressiveness score. Methods: The surveillance and epidemiology unit of the program of care for cancer identified all patients diagnosed with unresectable pancreatic adenocarcinoma in Nova Scotia between January 1, 2011 and December 31, 2014. Charts were then reviewed for demographic data, Charlson Comorbidity Index, and consultation with Palliative Care. An aggressiveness of end-of-life care score, which has been previously described in the literature, was employed. Briefly, scores ranged from 0 to 6, with higher scores representing more aggressive care. One point was assigned for each of the following events in the last 30 days of life: two or more emergency department visits, two or more hospitalizations, 14 or more inpatient days, chemotherapy, intensive care unit admission, death in hospital. One-way ANOVA was then performed to determine factors associated with more aggressive end-of-life care. Results: In total, 264 patients met inclusion criteria. Mean aggressiveness of end-of-life care was 0.92 (95% CI 0.8 – 1.03). On average, patients seen by Palliative Care at any point in their illness had less aggressive treatment than those never seen by Palliative Care (0.83 vs 1.38, p = 0.001). Conclusions: In patients diagnosed with unresectable pancreatic cancer, less aggressive end-of-life care Further work, including prospective studies, is needed to identify a true association between palliative care intervention and less aggressive care at end-of-life. Such an association could lead to benefits for the patient and reduce costly resource-intensive care.
Preclinical study of antitumor activity of trastuzumab emtansine in HER2-positive biliary tract cancer.
Authors: Yamashita-Kashima Yoriko , Fujimura Takaaki , Shu Sei , Yanagisawa Mieko , Mochizuki Marie , Yorozu Keigo , Kouno Mirei , Furugaki Koh , Higuchi Ryota , Shoda Junichi , Harada Naoki , Yoshimura Yasushi 
Published: January 2019

256 Background: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate composed of trastuzumab and DM1 (an anti-microtubule agent derived from maytansine) that is approved for the treatment of HER2-positive metastatic breast cancer. HER2-overexpression rate in biliary tract cancer (BTC) is reported as approximately 10%, and HER2-targeted therapy may enhance therapeutic efficacy in HER2-positive BTC. In this study, we investigated the antitumor activity of T-DM1 in several BTC cell lines and xenograft models. Methods: HER2 expression was detected by flow cytometry and Western blotting in 17 BTC cell lines. The cell growth inhibition activity of T-DM1 and DM1 was examined by quantifying the DNA with Hoechst 33258 nucleic acid stain. In vivo antitumor activity of T-DM1 was evaluated in three xenograft mouse models using cell lines with different levels of HER2 expression. HER2 expression in xenografts was assessed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), according to gastric cancer criteria. Cell cycle was assessed by flow cytometry after staining with propidium iodide. Apoptosis was assessed by caspase 3/7 activity measurement. Results: In the 17 BTC cell lines, HER2 expression was high in KMCH-1, Mz-ChA-1, and TGBC-18-TKB. Although cell growth inhibition of DM1 was similar in all cell lines (50% inhibitory concentration (IC50): 0.79–7.2 nM), that of T-DM1 was HER2-expression-dependent, with IC50 values in KMCH-1, Mz-ChA-1, and KKU-100 (which has low HER2 expression) of 0.031, 1.3, and 4.3 μg/mL, respectively. In KMCH-1 and Mz-ChA-1 xenograft models, T-DM1 treatment once every 3 weeks for 6 weeks showed significant dose-dependent antitumor activity, and tumor growth inhibition 21 days after first dose at 20 mg/kg T-DM1 was 108% (KMCH-1) and 75% (Mz-ChA-1), whereas there was no significant efficacy in KKU-100 xenograft model. Values for HER2 status (IHC score/FISH ratio of HER2 to CEP17) in KMCH-1, Mz-ChA-1, and KKU-100 tumor tissues were 3+/3.5, 2+/4.7, and 0/1.1, respectively. In KMCH-1, T-DM1 induced M phase arrest and apoptosis, as is reported in HER2-positive breast cancer cells. Conclusions: T-DM1 could be an effective therapy for HER2-overexpressed BTC.
Automation of quantifying and mapping of stromal and malignant cells in pancreatic adenocarcinoma using deep learning.
Authors: Lee Sunyoung S. , Kim Jin Cheon , Dolan Jillian , Baird Andrew 
Published: January 2019

266 Background: The characteristic histological feature of pancreatic adenocarcinoma (PAD) is extensive desmoplasia alongside leukocytes and cancer-associated fibroblasts. Desmoplasia is a known barrier to the absorption and penetration of therapeutic drugs. Stromal cells are key elements for a clinical response to chemotherapy and immunotherapy, but few models exist to analyze the spatial and architectural elements that compose the complex tumor microenvironment in PAD. Methods: We created a deep learning algorithm to analyze images and quantify cells and fibrotic tissue. Histopathology slides of PAD patients (pts) were then used to automate the recognition and mapping of adenocarcinoma cells, leukocytes, fibroblasts, and degree of desmoplasia, defined as the ratio of the area of fibrosis to that of the tumor gland. This information was correlated with mutational burden, defined as mutations (mts) per megabase (mb) of each pt. Results: The histopathology slides (H&E stain) of 126 pts were obtained from The Cancer Genome Atlas (TCGA) and analyzed with the deep learning model. Pt with the largest mutational burden (733 mts/mb, n = 1 pt) showed the largest number of leukocytes (585/mm2). Those with the smallest mutational burden (0 mts/mb, n = 16 pts) showed the fewest leukocytes (median, 14/mm2). Mutational burden was linearly proportional to the number of leukocytes (R2 of 0.7772). The pt with a mutational burden of 733 was excluded as an outlier. No statistically significant difference in the number of fibroblasts, degree of desmoplasia, or thickness of the first fibrotic layer (the smooth muscle actin-rich layer outside of the tumor gland), was found among pts of varying mutational burden. The median distance from a tumor gland to a leukocyte was inversely proportional to the number of leukocytes in a box of 1 mm2 with a tumor gland at the center. Conclusions: A deep learning model enabled automated quantification and mapping of desmoplasia, stromal and malignant cells, revealing the spatial and architectural relationship of these cells in PAD pts with varying mutational burdens. Further biomarker driven studies in the context of immunotherapy and anti-fibrosis are warranted.
Comprehensive genomic profiling (CGP) in KRAS wild-type (WT) pancreatic ductal adenocarcinoma (PDAC).
Authors: George Ben , Greenbowe Joel R. , Hendifar Andrew Eugene , Golan Talia , Javle Milind M. , Maitra Anirban , Bahary Nathan , Schrock Alexa Betzig , Stephens Philip J. , Miller Vincent A. , Ross Jeffrey S. , Yakirevich Evgeny , Ritch Paul S. , Thomas James P. , Ali Siraj Mahamed , Singhi Aatur D. 
Published: January 2019

271 Background: Mutations in oncogenic KRAS have been widely accepted as the signature genomic alteration (GA) in sporadic PDAC, but therapeutic efforts aimed at targeting constitutively activated KRAS have been disappointing. We examined somatic GAs in KRAS WT PDAC utilizing a CGP platform to identify actionable targets. Methods: DNA was extracted from formalin fixed paraffin embedded (FFPE) PDAC clinical specimens and CGP was performed on hybrid-capture, adaptor ligation based libraries to a mean coverage depth of > 600 unique reads. Alterations in the RAS/ RAF/ MEK pathway genes ( KRAS, NRAS, HRAS, ARF, BRAF, EGFR, MAP2K2, MAP2K1, MAPK1) and DNA Damage Repair (DDR) pathway genes ( BRCA1/2, ATM, ATR, BRIP1, RAD50, RAD51, RAD52, PALB2, CHEK1, CHEK2) were examined. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. TMB was categorized based on mutations(m)/Mbp of DNA - high (H; > 20), Intermediate (I; 8-20) and low (L; < 8). Results: CGP was performed on 3426 PDAC specimens; 1815 (53%) were male, 390 (11.3%) were KRAS WT. GAs in the RAS/ RAF/ MEK pathway were identified in 90.6% of all cases, while 68 (17.4%) KRAS WT cases had one or more GAs in RAS/ RAF/ MEK pathway genes. DDR pathway GAs were identified in 1405 (41%) cases for a total of 2050 GAs, and 180 (46%) KRAS WT cases for a total of 285 GAs. DDR pathway alterations were common in KRAS WT PDAC compared to KRAS mutated PDAC (p = 0.028). Among the 842 (24.6%) cases with available TMB data, 5 (0.6%), 104 (12.3%) and 733 (87.1%) pts had H, I and L, TMB respectively. Among 88 (22.6%) KRAS WT cases with available TMB data, 2 (2.3%), 12 (13.6%) and 74 (84.1%) pts had H, I and L, TMB, respectively. MSI status was available in 2314 (67.5%) cases, 13 (0.6%) were MSI-high (MSI-H); among the KRAS WT cases, 222 (57%) had MSI status available, 3 (1.3%) were MSI-H. Conclusions: MSI-H status and high TMB are rare in PDAC, regardless of KRAS mutation status. GAs in the DDR pathway are relatively common in PDAC and may serve as predictive biomarkers for platinum chemotherapeutic agents and/or PARP inhibitors. Prospective validation of such predictive gene signatures will improve therapeutic efficacy and minimize toxicities.
Integrative whole exome, transcriptome, and clinical profiling of biliary tract cancers (BTCs).
Authors: Tran Nguyen H. , Vats Pankaj , Robinson Dan R. , Zalupski Mark , Hersberger Katherine E , Mendiratta-Lala Mishal , Kumar-Sinha Chandan , Wu Yi-Mi , Lonigro Robert J , Cao Xuhong , Chinnaiyan Arul , Sahai Vaibhav 
Published: January 2019

279 Background: BTC is clinically and genomically heterogeneous and next generation sequencing may identify disease subsets with distinct prognostic and therapeutic implications. Methods: Patients (pts) with BTC underwent whole exome and transcriptome sequencing via the Michigan Oncology Sequencing (MI-ONCOSEQ) platform between 09/2011 and 07/2017. Results: 53 pts (47.2% female) with median age 60 (range 17-72) years had 38 intrahepatic, 6 perihilar, and 4 extrahepatic distal cholangiocarcinoma (CCA) while 3 had gallbladder and 2 mixed CCA/hepatocellular carcinoma. Forty-one pts (77.3%) had advanced BTC at diagnosis and 40 (75.5%) received platinum doublet as first line therapy. The most frequent somatic mutations were TP53 (35.8%), BAP1 (18.9%), KRAS (17.0%), IDH1 (15.1%), PBRM1 (13.2%), ARID1A (11.3%), and SMAD4 (11.3%). Median overall survival (OS) in 8 pts with IDH1 mutation was 16.8 months (none received IDH1 inhibitor). Putative pathogenic germline variants were noted in 6 (11.3%) pts of which 4 were biallelic (MSH2, BRCA1, BRCA2 and MUTYH) and 2 monoallelic (ATM and FH). Germline mutation in FH has not been reported in BTC. Biallelic DNA damage repair pathway mutations were noted in 14 (26.4%; 11 somatic, 3 germline) pts and their median OS was 16.8 months. Of these 9 pts with advanced BTC received 1st line platinum therapy and had a median PFS of 9.3 months (4 PR, 3 SD). Nine (17%) pts had FGFR2 fusion (6 partners); median OS not yet reached (6 alive; 5 received FGFR inhibitor). Potentially targetable molecular alterations (IDH1, MSH2, BRCA1/2, PALB2, ATM, FGFR2, ERBB2) were identified in 27 (50.9%) pts. Copy number profile shows frequent loss of chr1p, chr3p, chr4, chr6q, chr8p, chr9, and gain of chr1q, chr7, and chr8q. Immune profiling & pathway analysis of BTCs with clinical correlation is ongoing. Conclusions: Integrative sequencing of BTCs with clinical profiling will lead to more precise treatment of pts with BTCs.
The role of HNF4A in GATA4-deficiency phenotypes of hepatocellular carcinoma.
Authors: Tan Yu Bin , Shuen Timothy , Toh Han Chong 
Published: January 2019

284 Background: Hepatocellular carcinoma (HCC) is the 2nd leading global cause of cancer death. Recently, we have discovered previously undescribed deletion and germline mutation of GATA4 and showed that GATA4 is a key differentiation driver and metabolic regulator in HCC. However, as GATA4 is mostly deleted in HCC, targeting GATA4-downstream molecules is ideal. In this study, proof-of-concept experiments were conducted to show that introduction of HNF4A, which is a GATA4-regulated downstream target, could partially rescue the impaired phenotypes in GATA4-deficient HCC cell line. Methods: Correlation analysis using gene expression microarray of human HCC samples was conducted to identify the genes that are positively correlated with GATA4. A transgenic mouse model with a liver-specific conditional GATA4 knockout was designed to identify liver morphology and gene expression changes which are correlated with the loss of Gata4 in the mouse liver. CRISPR-mediated knockout of GATA4 and lentiviral HNF4A overexpression was carried out in a GATA4-deficient HCC cell lines, PLC/PRF/5 and Hep3B, followed by proliferation, apoptosis, cell cycle and senescence functional assays. Results: Pearson correlation analysis from human HCC samples showed that expression of HNF4A is positively correlated with that of GATA4. Livers from conditional Gata4 knockout mice had lower Hnf4a gene expression when compared to age-matched control mice. Loss of function analysis by CRISPR-mediated GATA4 knockout further showed downregulation of HNF4A in GATA4-deficient PLC/PRF/5 cell line. Lentiviral HNF4A overexpression in PLC/PRF/5 and Hep3B demonstrated reduced proliferation and increased apoptosis while PLC/PRF/5 also showed cell cycle arrest at G2/M phase when compared to control. However, no senescence induction was detected in HNF4A-overexpressing cells. Conclusions: Transgenic mouse data, CRISPR-mediated knockout and analysis of HCC samples showed that HNF4A is a key GATA4-downstream target. HNF4A overexpression decreases proliferation, increases apoptosis and cell cycle arrest in GATA4-deficient HCC cell lines, thus representing a possible therapeutic target for HCC.