bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final analysis of a phase IB/randomized phase II study of gemcitabine (G) plus placebo (P) or vismodegib (V), a hedgehog (Hh) pathway inhibitor, in patients (pts) with metastatic pancreatic cancer (PC): A University of Chicago phase II consortium study.
Authors: Catenacci Daniel Virgil Thomas , Bahary Nathan , Nattam Sreenivasa R. , Marsh Robert de Wilton , Wallace James Alfred , Rajdev Lakshmi , Cohen Deirdre Jill , Sleckman Bethany G. , Lenz Heinz-Josef , Stiff Patrick J. , Thomas Sachdev P. , Xu Peng , Henderson Les , Horiba Margit Naomi , Vannier Michael , Karrison Theodore , Stadler Walter Michael , Kindler Hedy Lee 
Published: March 2020

4012 Background: Sonic Hh (SHh), the ligand for the Hh pathway, is over-expressed in >80% of PC. V had activity in preclinical murine PC models leading to increased tumor perfusion, enhanced tumor delivery of G, and an improvement in survival. Methods: We conducted a placebo-controlled, phase IB/randomized phase II trial of GV or GP. Eligible pts, KPS 80-100, had untreated metastatic PC, or had completed adjuvant therapy > 6 months (mo) prior. Primary endpoint: progression-free survival (PFS). Correlatives: serial SHh serum levels; serial perfusion CT imaging. All pts received G 1000mg/m2over 30 minutes, days (D) 1, 8, 15, Q28D. A lead-in phase IB was performed. Pts, stratified by KPS (80 v 90/100), and disease status (newly diagnosed/recurrent), were randomized to V (150 mg PO daily) or P. For pts on P, cross-over was allowed at progression. Assuming a mPFS of 3.5 months for GP and 5.7 months for GV (HR=0.61), a sample size of 106 subjects (53 per group) provided 85% power to detect this difference, using a one-sided test at the 0.10 significance level. Results: No safety issues were identified in 7 pts enrolled in the phase IB study. The phase II study enrolled 106 evaluable pts (V/P 53/53) at 13 sites 2/10-6/12. Pt characteristics: median age 65/64 (range 52-82/39-83); KPS (% pts) 80: 38/30; 90: 26/38; 100: 36/32; newly diagnosed 91%/91%; recurrent: 9%/9%. Grade 3/4 toxicity (V/P, % pts, >5% in either arm): neutropenia 32/28; lymphopenia 4/15; thrombocytopenia 9/11; anemia 9/23; hyponatremia 4/15; fatigue 13/8; hyperglycemia 23/19; elevated ALT 13/9; hyperbilirubinemia 11/6; nausea 11/11. Response (%): CR 0/2, PR 8/11, SD 51/38. mPFS: 4.0/2.5 mo (95% CI: 2.5-5.3/1.9-3.8; HR 0.81 [0.54-1.21], p=0.30). 22 pts (42%) on GP crossed over to GV at progression. mOS: 6.9/6.1 mo (95% CI:5.8-8.0/5.0-8.0, HR 1.04, [0.69-1.58], p=0.84). Updated laboratory/radiological correlatives will be presented. Conclusions: Toxicity between the groups was similar. The addition of V to G in an unselected cohort does not improve response, PFS, or OS in pts with metastatic PC. Funding NCI N01-CM-62201. Clinical trial information: NCT01064622.
Use of pharmacogenomic modeling in pancreatic cancer for prediction of chemotherapy response and resistance.
Authors: Yu Kenneth H. , Sangar Vineet , Ricigliano Mark , Hidalgo Manuel , Abou-Alfa Ghassan K. , Lowery Maeve Aine , Saltz Leonard , Crotty Joseph F. , Gary Kristen , Yin Jing , Choi Eun Yong , O'Reilly Eileen Mary 
Published: March 2020

4017 Background: Pancreatic adenocarcinoma (PDAC) is uniformly lethal and is the 4th leading cause of cancer mortality. Despite this, modern cytotoxics (C) can induce tumor responses and extend life. Xenograft models have shown that pharmacogenomic (PGx) modeling of C can predict efficacy. Chemo-sensitivity and gene expression profiling of circulating tumor and invasive cells (CTICs) isolated from peripheral blood may predict tumor response, progression and resistance. Methods: A prospective MSKCC study has completed planned accrual of 50 patients. 10 mL of peripheral blood is collected from patients with unresectable PDAC prior to C and at disease progression. Clinical data is prospectively collected. CTICs are isolated (Vita-Cap, Vitatex Inc.), total RNA is extracted and gene-expression analysis is performed. PGx models for twelve chemotherapy drug combinations used in PDAC were created from the GI50 data obtained from the NCI-60 cell lines (CellPath Therapeutics, Inc., Baltimore, MD). Expression data were normalized through GCRMA then probed to identify expression differences between patients with short v long TTP and within patients at baseline v at time of progression. The analysis was performed at the pathway and individual gene level. Results: CTICs were isolated, and gene expression and chemo-sensitivity patterns were obtained in all 50 patients prior to initiating C and in 20 patients at 1st line disease progression. Preliminary analysis demonstrates clinical benefit for patients treated with C predicted to be effective versus ineffective (TTP 7.3 mo v 3.7 mo, p=0.017, HR 0.30). Changes in chemo-sensitivity patterns were evident at disease progression, reflecting treatment resistance. Pathway analysis revealed that E2F1 and NFκB pathways are associated with prognosis, PLC and RB1 pathways become disrupted with disease progression. Conclusions: Isolation and gene expression profiling of CTICs can be performed reliably in unresectable PDAC. Preliminary analysis suggests that C profiling can predict response. Repeat PGx profiling identifies key pathways associated with treatment resistance. Clinical trial information: NCT01474564.
KRAS mutation status-stratified randomized phase II trial of GEMOX with and without cetuximab in advanced biliary tract cancer (ABTC): The TCOG T1210 trial.
Authors: Chen Li-Tzong , Chen Jen-Shi , Chao Yee , Tsai Chang-Sung , Shan Yan-Shen , Hsu Chiun , Huang Shiu-Feng , Tsou Hsiao-Hui , Lee Kuan-Der , Chiu Chang-Fang , Rau Kun-Ming , Ho Ching-Liang , Yu Ming-Sun ,   Taiwan Cooperative Oncology Group
Published: March 2020

4018 Background: Gemcitabine/platinum combination is considered as globally acceptable standard care in patients with ABTC. Two recently published randomized trials showed adding EGFR antagonist, either erlotinib or cetuximab, does not further improve the clinical outcomes of gemcitabine/oxaliplatin (GEMOX)-treated ABTC patients. However, the impact of KRAS mutation status on the results of both studies was not properly addressed. Methods: A prospective, multicenter randomized, phase II trial to evaluate the therapeutic efficacies of adding cetuximab to GEMOX in patients with ABTC, in which eligible patients were stratified by status of KRAS mutation and ECOG PS, and tumor location then randomized to receive either GEMOX (gemcitabine 800 mg/m2, fixed-rate infusion and oxaliplatin 85 mg/m2, i.v., Q 2 weeks) or GEMOX plus cetuximab (500 mg/m2, i.v., Q 2 weeks, C-GEMOX). The primary endpoint was overall response rate (ORR). As an exploratory trial, 120 (60 per arm) patients was estimated to detect a two-tailed 10% difference in ORR (20% in GEMOX and 30% in C-GEMOX) with a significant level of a=0.2 and b=0.5. Results: Between Nov 2010 and May 2012, a total of 122 patients were accrued. The demography was male: 47.5%, median age: 60 y/o, ECOG PS 0/1: 28.7%/71.3%, IHCC/EHCC/GBC: 71.3%/16.4%/12.3%, KRAS mutation: 36.1%, with locally advanced/metastatic diseases: 32.0%/68.0%, and prior surgical resection: 41.8%. On intent-to-treat analysis, the ORR and DCR in the C-GEMOX (N=62) and GEMOX (N-60) arms was 27.3% vs 15.0% (p=0.1223) and 82.2% vs 60.0% (p=0.0090), respectively (Fisher’s exact test); while the median PFS was 7.1 vs 4.0 months (p= 0.0069) and median OS was 10.3 vs 8.8 months (p=0.4057), respectively (log-rank test). Planned subgroup analysis showed the 43 patients with KRAS mutated tumors benefited more from cetuximab therapy, with a DCR of 78.3% vs 38.1% (p=0.0132), median PFS of 7.0 vs 1.9 months (p=0.0351) and median OS of 10.3 vs 6.6 months (p=0.6924). Conclusions: Adding cetuximab significant improves the DCR and PFS of GEMOX in ABTC patients, notably in subpopulation with KRAS mutated tumors. Larger-scale phase III trial is warranted. Clinical trial information: NCT01267344.
MAGIC trial gene expression profiling study.
Authors: Smyth Elizabeth Catherine , Tan Iain BeeHuat , Cunningham David , Wotherspoon Andrew , Lin Suling Joyce , Okines Alicia Frances Clare , Langley Ruth E. , Nankivell Matthew , Stenning Sally P. , Tan Patrick 
Published: March 2020

4020 Background: The MRC MAGIC trial established perioperative epirubicin, cisplatin and 5FU (ECF) chemotherapy as a standard of care for patients (pts) with operable oesophagogastric (OG) cancer (Cunningham NEJM 2006). We performed transcriptomic profiling of archival MAGIC tissue to evaluate an existing intrinsic gastric cancer (GC) gene signature, to describe expression patterns of biologically informative genes and to identify prognostic or predictive markers. Methods: RNA was extracted from formalin fixed paraffin embedded (FFPE) resections and analysed with the NanoString nCounter system. Our panel comprised 151 genes including intrinsic GC (G-INT and G-DIFF) signature genes (Tan Gastroenterology 2011), and genes amplified/deleted in GC including the therapeutic targets FGFR2, EGFR, ERBB2 and c-MET (Deng Gut 2012). Data was preprocessed using nsolver analysis software with 2-step normalisation and log2 transformed. G-INT and G-DIFF subtype classification used the nearest template prediction algorithm; these were then correlated with pt characteristics and survival. The overexpression threshold was defined as deviation above the normal quantile-quantile plot. Results: Sufficient RNA for analysis was available for 209 resected pts. A pilot study (n=23) confirmed RNA quality and correlation between NanoString and Affymetrix results. RNA was more often available for pts with GC (p<0.001) and pts in the surgery alone arm (p=0.049). 70% of pts were classified into G-INT or G-DIFF intrinsic signature subtype (false discovery rate (FDR) <0.05); 61 (30%) were ambiguous. Predominantly mutually exclusive overexpression of receptor tyrosine kinase (RTK) targets EGFR, ERBB2, FGFR, and c-MET was seen in 5%, 12%, 9% and 6% of pts respectively. Conclusions: Although bias may exist in tissue availability for chemosensitive pts, transcriptomic profiling of archival FFPE from this mature phase 3 study provides powerful insight into the molecular heterogeneity of OG cancer. 70% of evaluable MAGIC pts were classified unambiguously into intrinsic GC subtypes. Mutually exclusive overexpression of targetable RTKs supports a personalized approach in OG cancer evaluating targeted drugs in relevant biological subgroups. Survival analyses are ongoing.
Randomized phase II trial of extended versus standard neoadjuvant therapy for esophageal cancer, NCCTG (Alliance) trial N0849.
Authors: Alberts Steven R. , Soori Gamini S. , Shi Qian , Wigle Dennis A. , Sticca Robert P. , Miller Robert Clell , Leenstra James L. , Peller Patrick J. , Wu Tsung-Teh , Yoon Harry H. , Drevyanko Timothy F. , Ko Stephen , Mattar Bassam Ibrahim , Nikcevich Daniel A. , Behrens Robert J. , Khalil Maged F. , Kim George P. 
Published: March 2020

4026 Background: Patients (pts) with locally advanced esophageal or gastroesophageal junction (GEJ) adenocarcinoma commonly receive neoadjuvant chemoradiotherapy (chemo-RT). Despite this approach the rate of recurrence remains high. Given the difficulties of postoperative therapy, the efficacy of extended neoadjuvant therapy was assessed. Methods: Eligibility criteria included T3-4,N0 – Tany,N(+) disease amenable to radiation and surgery. Pts were randomized to either arm A (docetaxel 60 mg/m2 day 1 , oxaliplatin [Oxal] 85 mg/m2 day 1, and capecitabine 1250 mg/m2/day days 1-14 x 2 cycles [DOC] followed by 5-FU 180 mg/m2/day continuous IV through radiation + Oxal 85 mg/m2 days 1,15,29 + 50.4 Gy radiation (chemo-RT)) or arm B (chemo-RT alone). Randomization was stratified by ECOG PS (0/1 vs 2) and stage (II vs III/IVA). Primary endpoint was pathologic complete response (PCR) rate, defined as no gross or microscopic tumor identified in the surgical specimen. Interim analysis assessed efficacy and futility of the experimental intervention. Wilcoxon rank sum and Fisher’s exact tests were used to compare clinical/pathologic factors between arms. Results: Baseline and stratification factors were well balanced between arms. Of 42 pts included in the interim analysis (86% male; age [median 63, range 38-88], 100% PS 0/1; 71% stage III; 55% esophagus, 40% GEJ; 36% measurable disease), 4 and 1 pts in arms A and B, respectively, did not have surgery due to death (A, 2), progressive disease (A, 1), alternative treatment (A, 1) or adverse event (B, 1). Among 21 arm A pts, 21, 20, and 19 pts started 1st cycle of DOC, 2nd cycle of DOC and chemo-RT, respectively. All arm B pts received chemo-RT. 33% (7/21) of arm A and 48% (10/21) of arm B pts achieved PCR (p=0.53). Among pts undergoing surgery, 94% (16/17) and 100% (20/20) of arm A and B pts had complete resection (p=0.46). 38% and 24% of arm A and B pts experienced at least one grade 4+ adverse event at least possibly related to treatment (p=0.51). Conclusions: Extended neoadjuvant therapy in pts with locally advanced esophageal or GEJ adenocarcinoma failed to improve the PCR rate. Follow-up in regard to survival and rate of recurrence is ongoing. Clinical trial information: NCT00938470.
The impact of diabetes on HCC.
Authors: Graef Suzanne , Berhane Sarah , Teng Mabel Joey , Skowronska Anna , Johnson Philip James 
Published: March 2020

4029 Background: The incidence of hepatocellular carcinoma (HCC) in the UK has increased by 40% over the last 20 years, with a corresponding increase in mortality rate. The rising incidence of obesity and type II diabetes are believed to be contributing factors due to the association with non-alcoholic fatty liver and steatohepatitis. We aimed to examine if diabetes was as an independent risk factor for the development of HCC and to assess the impact of diabetes on overall survival (OS). Methods: Data from 724 patients with HCC and a control group comprising 340 patients with chronic liver disease were collected prospectively between 2007 and 2012. The odds ratio (OR) for HCC in diabetic versus non-diabetic patients was calculated. Univariate and multivariate analysis was performed using logistic regression. Cox proportional hazards analysis was used to estimate hazard ratio (HR) for death for HCC patients, with and without diabetes and for the impact of variation in diabetic treatments. Results: The prevalence of diabetes was 39% within the HCC population and 10.3% within the chronic liver disease group. Univariate analysis demonstrated increased risk of HCC associated with age, sex, diabetes, haemochromatosis, cirrhosis, alcohol abuse and Child’s score. In patients with diabetes OR for HCC was 5.74 (CI 3.9-8.3; p<0.001). Age, sex, cirrhosis, Child’s score, diabetes and diabetes treatment with insulin, retained significance as independent risk factors in multivariate analysis. There was no survival difference for HCC patients with and without diabetes. In diabetic patients with HCC, treatment of diabetes with metformin, compared against other diabetic treatment options, was associated with a significantly longer OS (31 versus 24 months, p = 0.016; HR 0.74, p = 0.027). Conclusions: This study has demonstrated that diabetes is an independent risk factor for the development of HCC in a high risk population and that treatment with insulin appears to confer further independent risk. Diabetes has no effect on survival following the development of HCC but treatment of diabetes with metformin is associated with prolonged survival. In considering the optimal treatment for diabetes in chronic liver disease the beneficial effects of metformin on OS, if HCC develops, should be taken into account.
DOCOX: A phase II trial with docetaxel and oxaliplatin as a second-line systemic therapy for patients with advanced and/or metastatic adenocarcinoma of the pancreas.
Authors: Ettrich Thomas Jens , von Wichert Goetz , Gress Thomas M. , Michl Patrick , Geissler Michael , Hebart Holger Frithjof , Berger Andreas W. , Porzner Marc , Danner Bettina , Muche Rainer , Seufferlein Thomas 
Published: March 2020

4034 Background: In Europe and the USA, pancreatic ductal adenocarcinoma (PDAC) is the fifth most common cause of cancer-related death. For patients with metastatic disease, palliative cytostatic systemic treatment is the only option. There is no established standard for 2nd-line treatment. Fluoropyrimidines either alone or in combination with Oxaliplatin or other chemotherapeutic agents are increasingly used. There are interesting data regarding the combination of Gemcitabine with Oxaliplatin or Docetaxel with respect to progression free survival (PFS) and tumor response in 1st-line. For the first time, the DocOx-trial investigates the combination of Oxaliplatin with Docetaxel as 2nd-line treatment after progression under palliative first-line systemic treatment with Gemcitabine. Methods: Prospective, single arm, non-randomized, multicenter, Simon´s two stage phase II trial using Docetaxel (75 mg/m2, 60 min, d 1) plus Oxaliplatin (80 mg/m2, 120 min, d 2, qd 22). Duration of the trial is scheduled up to 8 cycles. Primary endpoint: tumor response (RR) according to RECIST 1.0. Secondary endpoints: PFS, OS, safety/toxicity, QoL/clinical benefit. Results: Here we present the data on response rate (RR), median progression free survival (mPFS) and median overall survival (mOS) as of February 4th, 2013. Data represents the Intention to treat-analysis of the 44 patients included between 2009 and 2012. 5 patients did not obtain any treatment. RR was 16% (7 partial remissions, no complete remission) with a disease control rate (DCR) of 48% after the first two treatment cycles. Median PFS was 7 weeks ( 95%-CI: 6-16 w.) and median OS after start of 2nd-line therapy was 36 weeks ( 95%-CI: 19-55 w.). Conclusions: In this single-arm 2nd-line trial for the treatment of PDAC, the combination of Doxcetaxel and Oxaliplatin shows very promising results compared to other 2nd-line-protocols such as OFF. Some patients seem to benefit particularly as indicated by long periods of treatment in this setting. Even after 8 cycles of treatment with DocOx, partial response was observed in 2 patients and stable disease in another 6 patients corresponding a disease control rate of 18%. Clinical trial information: NCT00690300.
A pilot phase II multicenter study of nab-paclitaxel (Nab-P) and gemcitabine (G) as preoperative therapy for potentially resectable pancreatic cancer (PC).
Authors: MacKenzie Shawn , Zeh Herbert , McCahill Laurence E. , Sielaff Timothy D. , Bahary Nathan , Gribbin Thomas Edward , Seng John E. , Leach Joseph W. , Harmon Jocelyn , Demeure Michael J. , Von Hoff Daniel D. , Moser A Jim , Ramanathan Ramesh K. ,   PCRT
Published: March 2020

4038 Background: Nab-P plus G is a new option for advanced PC. This combination was evaluated as a preoperative regimen for potentially resectable PC. Methods: Patients (pts, n=25) with resectable PC (NCCN criteria) were treated with 3 cycles of Nab-P (125mg/m2) & G (1000mg/m2) on day 1, 8, and 15, followed by surgical resection. The chosen endpoint was Grade III/IV histological changes (Arch Surg.127:1335-39:1992) in > 30% of resected tumor specimens. Results: Accrual is complete with 25 pts (median age 65, 10 F:15 M), 14/25 completed 3 cycles of treatment. Early drug discontinuation or drug interruption prior to the completion of 3 cycles occurred in 11 pts due to azotemia, cholangitis, pneumonia, catheter infection and pt decision. One pt had a fatal (grade 5) non-neutropenic aspergillus pneumonia. There was one episode of neutropenic fever (4%), and 3 episodes of cholangitis (12%) due to biliary stent malfunction. Other adverse events (grade 3/4) include neutropenia 64%, anemia 20%, dehydration 12%, nausea 12% and thrombocytopenia 12%. Dose reductions due to AEs were required in 5 pts, (3-neutropenia, 2-rash). Surgical resection was successful in 20/25 pts: 12- Pancreaticoduodenectomy, 8- Distal Pancreatectomy, 19/20 pts underwent an R0 resection. Surgical resection was not done in 5/25 pts due to: pre-operatively identified metastatic disease (2), blood vessel involvement at surgery (1), pt declined (1) and a pre-operative death (1).Post-operative tumor staging identified a complete response (n=1); stage IA (n=1); stage IIA (n=6); and stage IIB (n=12). Radiological partial response (PR) was documented in 4 pts prior to surgery. CA19-9 levels decreased from baseline by > 50% in 60% (n=15) of pts and by > 90% in 16% (n=4). Post-operative > 90% histological tumor response (Grade 3/4) was seen in 6 of 20 (30%) resected specimens. Conclusions: Preoperative therapy with Nab-P plus G is feasible with evidence of activity by radiological (PR in 16%), CA19-9 (decrease > 50% in 60% of pts) and pathological down staging (Grade 3/4 in 30% in resected tumor specimens). A larger study is warranted. Supported by Abraxis/Celgene Pharmaceuticals and the TGen foundation. Clinical trial information: NCT01298011.
Whole-transcriptome paired-end sequencing and the pancreatic cancer genetic landscape.
Authors: Macchini Marina , Astolfi Annalisa , Indio Valentina , Vecchiarelli Silvia , Grassi Elisa , Serra Carla , Casadei Riccardo , Santini Donatella , D'Ambra Marielda , Ricci Claudio , Minni Francesco , Biasco Guido , Di Marco Mariacristina 
Published: March 2020

4048 Background: A deeper knowledge of the pancreatic cancer (PDAC) biology is needed to improve the prognosis of the disease. Methods: 17 PDAC samples were collected by ultrasound-guided biopsy used for DNA and RNA extraction. 14 samples were analyzed by high resolution copy number analysis (CNA) on Affymetrix SNP array 6.0 and with segmentation algorithm against a reference of 270 Ceu HapMap individuals (Partek Genomic Suite). 17 samples were analyzed by whole transcriptome massively parallel sequencing, performed at 75x2 bp on a HiScanSQ Illumina platform. An average of 7, 3x107 reads per sample were generated, with a mean read depth of 50X. Single nucleotide variants (SNVs) were detected with SNVMix2 and compared with genetic variation databases (dbSNP, 1000genomes, Cosmic). Non-synonimous SNVs were analyzed with the predictors SNPs and GO and PROVEAN. Results: CNA results in 9/14 samples exhibited both macroscopic and cryptic cytogenetic alterations, with a mean of 10 CNA per patient. Most frequent gains were observed in 18q11.2 involving GATA6 (3/14) and 19q13 targeting AKT2 (3/14) while hotspot deletions were found on 18q21 (7/14), 17p13 (6/14), 9p21.3 (6/14), 15q (5/14) and 1q35 (4/14). RNAseq showed that samples exhibited a mean of 145 (range: 61-240) non-synonimous SNVs, of which 16 on average are potentially disease-related. Merging copy number and RNAseq data we highlighted the major oncogenic hits of PDAC, confirming the prevalence (14/17) of KRAS mutations, in one case also NRAS (G13D), and the three oncosuppressor CDKN2A (mutated in 3 cases and deleted in 6 cases, in hetero- or homozygosity), SMAD4 (altered by point mutation or gene deletion in 7/14), and TP53 (lost in 6/14 and mutated in 5/17). The signaling pathways affected were: KRAS/MAPK, TGFbeta and integrin signaling, proliferation and apoptosis, DNA damage response, and epithelial to mesenchymal transition. Moreover we found new oncogenic alterations, such as HMGCR, that displayed mutations in 17% of the analyzed patients (3/17). Conclusions: NGS combined with high resolution cytogenetic analysis can improve the understanding of pancreatic carcinogenesis.