bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessment of genomic alterations in adenosquamous carcinoma of the pancreas (ASCOP).
Authors: Jordan Emmet , Basturk Olca , Leach Steven D , Klimstra David S. , Allen Peter J. , Berger Michael F. , Askan Gokce , Yu Kenneth H. , O'Reilly Eileen Mary , Lowery Maeve Aine 
Published: February 2017

261 Background: ASCOP represents a rare subtype (1-4%) of exocrine pancreatic cancer for which the clinical and molecular features are not well defined. We reviewed clinical characteristics and performed comprehensive molecular profiling in a cohort of patients with ASCOP treated at MSKCC. Methods: Patients (pts) with ASCOP diagnosed from January 2000-July 2015 were identified from a prospectively maintained database, following IRB approval. Clinicopathological data including time to progression (TTP), recurrence-free interval (RFI) and overall survival (OS) were recorded. Samples were reviewed by a pancreas pathologist to optimally select the squamous component for molecular profiling using MSK-IMPACT platform. This is a hybridization capture based next generation sequencing assay for targeted deep sequencing of all exons and selected introns of 410 key cancer genes. Tumor and matched normal libraries (where available; n=9) were sequenced on an Illumina HiSeq 2500. Sequencing output was processed using a custom analysis pipeline to detect single nucleotide variants, short indels, copy number aberrations and structural rearrangements. Results: We identified 84 pts with ASCOP of whom 15 had sufficient tissue/consent for analysis. Median OS for resected pts was 17 months (mo) and 6 mo respectively. Median PFS on 1st line therapy (FLT) for stage IV disease was 3 mo. 53 pts underwent surgical resection, of whom 11 remain disease free at median follow up of 24 mo. 15/15 (100%) had KRAS mutations (mut). 11/15 (73%) had TP53 mut. 6/15 (40%) had SMAD4 mut [4 point mutations (PM), 2 frameshift deletions]. 6/15 (40%) had CDKN2A mut (4 deletions, 2 PM). Mut were also found in FAT 1 (3/15), JAK3 3 (3/15), TBX 3 (2/15) and FGFR amplification was found in 1 pt sample. Conclusions: ASCOP like conventional ductal adenocarcinoma has a poor prognosis with a comparable molecular signature in the most common alterations. Potential targets e.g., FGFR1 may allow novel agents in select pts. [Table: see text]
The mitochondrial metabolism inhibitor CPI-613 in combination with mFOLFIRINOX for pancreatic adenocarcinoma.
Authors: Alistar Angela Tatiana , Desnoyer Rodwige , D'Agostino Ralph 
Published: February 2017

264 Background: Stage IV pancreatic cancer is a lethal disease with limited treatment options. Current standard practice is combination chemotherapy with FOLFIRINOX or Gemcitabine + Abraxane. Despite these two new treatment options, the response rate and survival are limited in stage IV pancreatic cancer. The glycolic and mitochondrial metabolisms are aberrant in pancreatic cancer and translate into chemo-resistance. Inhibition of glutamine metabolism can potentially synergize with therapies that increase intracellular reactive oxygen species such as chemotherapy. CPI -613 is a novel anti-mitochondrial developed by Cornerstone Pharmaceuticals. Methods: A phase I clinical trial with mFOLFIRINOX+ CPI-613 in never treated for stage IV pancreatic cancer patients was initiated. The goals of this phase 1trial are: (1) To determine the Maximum Tolerated Dose (MTD) of CPI-613, when used in combination with mFOLFIRINOX, in patients with metastatic pancreatic cancer, (2) To assess the safety of CPI-613/ mFOLFIRINOX combination in patients with metastatic pancreatic cancer, and (3) To obtain preliminary data on efficacy of treatment with CPI-613/ mFOLFIRINOX Results: The MTD for CPI 613 was identified at 500mg/m2. The treatment combination is feasible and well-tolerated. The combination treatment was not found to have higher toxicity than FOLFIRINOX alone. The objective response rate was 53.9 % which is higher than FOLFIRINOX alone (reported as 31.6%). One patient has a complete radiologic and clinical response and two other patients have near complete responses. Conclusions: The preliminary efficacy data of this phase I clinical trial will inform a multi-institutional randomized phase II study of FOLFIRINOX vs. m FOLFIRINOX+ CPI613 in the near future. Clinical trial information: NCT01835041.
Preliminary observations of blood-based (BB) molecular testing in a subset of patients with pancreatic cancer (PDA) participating in the Know Your Tumor (KYT) initiative.
Authors: Pishvaian Michael J. , Matrisian Lynn , Hendifar Andrew Eugene , Engebretson Anitra , Rahib Lola , Hoos William Arthur , Mikhail Sameh , Chung Vincent M. , Picozzi Vincent J. , Heartwell Craig , Mason Kimberly , Varieur Katelyn , Madhavan Subha , Petricoin Emanuel , Brody Jonathan Robert 
Published: February 2017

268 Background: Obtaining an adequate tissue sample for molecular profiling to guide therapy selection for patients with advanced cancers can be clinically difficult, and/or patients may not want to undergo a biopsy. There has been a growing interest in the use of BB tests, including cell free DNA (cfDNA) and exosome/circulating tumor cell based-analyses as surrogates for tumor tissue (TT) testing. Validation of BB tests in PDA is possible because > 90% of PDAs harbor KRAS mutations – thus providing a reliable “internal control.” Methods: The Pancreatic Cancer Action Network (PanCAN) and Perthera initiated an IRB-approved registry trial for patients with pancreatic cancer wherein we facilitated commercially available, CLIA certified multi-Omic profiling including next generation DNA sequencing (NGS), immunohistochemistry, and phosphoproteomics on patient tumor samples. In a subset of these patients, we incorporated BB testing. Results: A KRAS mutation has been identified in 87% of KYT patients based on TT NGS in general. As of this report, 17 BB test results (cfDNA NGS) were available. In 8 patients we were able to compare the cfDNA NGS directly with TT NGS. BB testing identified a KRAS mutation in 1/8 compared to 8/8 from the tumor tissue. Of the 9/17 patients who did not have corresponding TT NGS, a KRAS mutation was found on BB testing in 3/9 samples. 4/17 BB cases overall revealed KRAS mutations, but when cases were filtered for patients with extensive metastatic disease and progressive disease at the time of blood sampling, the KRAS mutation rate increased to 2/5 overall. Actionable findings (i.e. linked to a specific therapeutic option) were identified in 6/17 cases, of which 3/17 had both an actionable mutation and a KRAS mutation. Conclusions: Although we are aware of the limitations of this study, we recommend that for patients who have biopsiable disease, a TT test should still be the gold standard for molecular profiling. For those without biopsiable disease, the KYT program presents an opportunity to determine the parameters that influence the probability of obtaining reliable molecular profiling information from a BB sample.
PANOVA: A pilot study of TTFields concomitant with gemcitabine for front-line therapy in patients with advanced pancreatic adenocarcinoma.
Authors: Rivera Fernando , Gallego Javier , Guillen Carmen , Benavides Manuel , Lopez-Martin Jose A. , Betticher Daniel C. , Kueng Marc 
Published: February 2017

269 Background: TTFields are alternating electric fields delivered to the region of the tumor by means of non-invasive transducer arrays. TTFields interfere with mitotic spindle formation, thus having an anti-mitotic activity. In pancreatic cancer, TTFields decreased proliferation and clonogenic potential in vitro, and reduced tumor volume in vivo. The PANOVA trial was designed to test TTFields, combined with chemotherapy, in pancreatic cancer. Methods: Twenty patients with advanced pancreatic adenocarcinoma were enrolled in a prospective, single arm study of TTFields at 150 kHz, concomitant with standard weekly gemcitabine. All patients had histologically-confirmed unresectable tumors, with an ECOG performance score of 0-1 and no prior chemotherapy or radiation therapy. The primary endpoint was incidence and severity of treatment emergent adverse events (AEs). Secondary endpoints included progression free survival (PFS), PFS rate at 6 months, overall survival (OS) and response rate. Results: The median age was 73 (range – 49-81) and 60% of the patients were females. Most patients (80%) had an ECOG score of 1. Twelve patients (60%) had distant metastases, while the others had locally advanced disease. Median compliance with TTFields was 78% (14 hours/day), with median duration of 5 months. Fourteen patients (70%) had serious (grade 3-5) AEs during the study period. Six patients (30%) had hematological, 45% gastrointestinal and 15% pulmonary AEs. Ten patients (50%) had treatment-related skin toxicity, of which only 2 were grade 3, both resolved with appropriate treatment. No TTFields-related serious AEs were reported. The median PFS was 8.3 months (95% CI 4.3, 10.3). PFS rate at 6 months was 56%. Of the evaluable tumors, 30% had partial response and another 30% stable disease. The median OS was 14.9 months and 1-year survival rate was 55%. Conclusions: TTFields concomitant to gemcitabine are tolerable and safe for advanced pancreatic cancer patients. The efficacy results are promising and support further research in this indication. An extension of the PANOVA protocol, including 20 additional patients who receive gemcitabine, nab-paclitaxel and TTFields is ongoing. Clinical trial information: NCT01971281.
Antitumor activity and immune reponse in CD40 immunotherapy with gemcitabine and nab-paclitaxel in an orthotopic pancreatic cancer mouse model.
Authors: Siolas Despina , Cullis Jane , Avanzi Antonina , Byrne Kate , Leichman Lawrence P. , Vonderheide Robert H. , Bar-Sagi Dafna 
Published: February 2017

271 Background: Pancreatic cancer is well known for its aggressive clinical course and resistance to chemotherapy. A Phase I trial of CD40 immunotherapy in combination with gemcitabine demonstrated the combination was safe and achieves tumor responses in patients with pancreatic ductal adenocarcinoma. We investigated the effectiveness of gemcitabine, albumin-bound paclitaxel and CD40 agonist immunotherapy in an orthotopic pancreatic mouse model. Methods: Pancreatic cells obtained from a KrasG12D;Trp53R172H (KPC) genetically engineered mouse were cultivated in cell culture and surgically implanted into the pancreata of immunocompetent syngeneic C57/Bl6 mice allowing for tumor formation in situ. Two weeks after KPC cell implantation, mice were treated with 120 mg/kg gemcitabine and 120 mg/kg nab-paclitaxel by intraperitoneal injection. Forty eight hours after chemotherapy administration, mice were treated with 100 ug of FGK45 CD40 immunotherapy. Mouse tumors and spleens were harvested from euthanized mice ten days after drug treatment. Tumor and spleens were analyzed histologically and by flow cytometry. Results: Mice treated with combination chemotherapy and immunotherapy had a significant reduction in tumor volume in comparison to vehicle treated mice. Combination chemotherapy did not cause a significant decrease in tumor volume. No changes were seen in stromal remodeling using trichrome histological staining. Mice treated with CD40 immunotherapy had an increase in spleen size indicating an immune response. Histological and flow cytometry analysis revealed an increase in CD45+ cells in the tumors of the CD40 immunotherapy treated samples in comparison to chemotherapy alone. Conclusions: CD40 immunotherapy in combination with gemcitabine and albumin-bound paclitaxel has significant antitumor activity in an orthotopic pancreatic cancer mouse model provoking an immune response in the tumors. Future experiments will focus on identifying immune mediators critical for drug efficacy.
Clinical and biomarker evaluations of sunitinib in patients (pts) with advanced well-differentiated grade 3 (G3) and poorly differentiated neuroendocrine neoplasms (PD-NEN).
Authors: Dreyer Chantal , Couvelard Anne , Walter Thomas , Lombard Bohas Catherine , Niccoli Patricia , Seitz Jean-François , Hentic Olivia , Pellat Anna , Andre Thierry , Couffignat Camille , Lobbe Nathalie , Mentre France , Bedossa Pierre , Hammel Pascal , Faivre Sandrine J. , Zappa Magalie , Ruszniewski Philippe B. , Raymond Eric 
Published: February 2017

274 Background: Angiogenesis is extensively developed in well-differentiated pancreatic neuroendocrine tumors (PNET) where sunitinib was showed to prolong progression-free survival leading to FDA and EMA approval. However, clinical experience in pts with well-differentiated G3 & PD-NEN remains limited. Methods: This prospective phase II trial evaluate potential biomarkers correlating with sunitinib activity in pts with advanced well differentiated G3 or PD-NEN. Sunitinib was given at the dose of 37.5 mg/d as a continuous daily dosing until progression or unacceptable toxicity. Evaluation of activity was based on RECIST1.1. Safety was evaluated according to NCI-CTCAEv4. Pharmacokinetics (PK) of sunitinib and SU12662 (main active metabolite) were evaluated. Tumor biomarkers (PDGFR-b, VEGFR2, Carbonic Anhydrase 9, Ki67 and p-AKT) were evaluated in tumor tissues, quantified in tumor cells and stroma (vessels, fibroblasts) using immunohistochemistry and correlated with response by RECIST. Results: Among 31 pts (M/F: 18/13, median age 61), 13 pancreatic, 5 gastric, 5 rectal, 4 colonic, and 4 other G3 & PD-NEN were entered. 27 pts had previous treatment with chemotherapy (mainly platinum/VP16). Among 26 pts evaluable for safety and activity, 7 pts (23%, 95%CI: 6.9%-39.3%), including 3 pts classified as well-differentiated G3 neoplasms) experienced partial responses and tumor stabilizations (clinical benefit). Safety and PK exposure to sunitinib and SU12662 in those pts was consistent with that experienced in PNET. Among the above evaluated tumor biomarkers, only Ki67 correlated with sunitinib activity. The median Ki67 was 20% and 77.5% in pts with CB versus non-responders (p=.002), respectively. ROC curves showed correlations between lower Ki67 in tumors and sunitinib activity (OR:0.9; IC95%:0.831-0.9, p=.039). With a threshold value of Ki67 of 47%, sensitivity and specificity were 80%, the predictive positive value was 67% and the negative predictive value was 86%. Conclusions: In pts with well-differentiated G3 & PD-NEN, sunitinib showed evidence of activity that was more pronounced in pts with Ki67<47%. Clinical trial information: NCT01215578.
DNA sequencing to identify potentially novel targets for therapy in pancreatic cancer.
Authors: Toll Jeffrey , Osipov Arsen , Khanuja Jasleen , Pan Dana , Patel Rishi , Zhou Jenny , Shinde Arvind Manohar , Annamalai Alagappan , Hendifar Andrew Eugene , Tuli Richard 
Published: February 2017

275 Background: Molecular differences in solid tumors have been shown to correlate with heterogeneity of response. Unfortunately, minimal data exists in pancreatic ductal adenocarcinoma (PDA). Next generation sequencing (NGS) may provide genetic signatures that allow prognostic stratification and predict response to targeted therapy. Methods: DNA was extracted from biopsy specimens of 64 patients (pts) with PDA at Cedars-Sinai Medical Center. DNA sequencing was performed for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X using the Illumina HiSeq 2000 platform (Foundation Medicine, Cambridge, MA). We report all genetic alterations including those classified as variants of unknown significance (VUS) as these may potentially be important for further study. Results: 94% of our patients had KRAS mutations, SMAD(39%) P53 (69%), and CDKN2A (48%). 17% of the pts had all 4 mutations. 4.6% had none. MLL and ARID genes, both involved in chromatin remodeling, were altered in (45%) and (35%) of the patients respectively. Alterations in MLL2 (22%) have been previously described. Interestingly, we also identified mutations in MLL3 (15%) and MLL (8%) of patients. We also identified an equal frequency of mutations in ARID1A mutations (17%) and ARID 1B (17%). ATM (19%) and ATR (11%) genes involved in double stranded DNA repair were mutated in a total of 30%. BRCA1 (12.5%) and BRCA2 (14%) were mutated in 26.5%, and PALB2 in another 2%. PMS2 (mismatch repair) was also mutated in 9% of patients. In total 67% of patients had alterations in one of these DNA repair pathways. There were a number of other genes noted to harbor mutations in greater than 10% of patients including BCOR, which is known to interact with MLL and seen in acute leukemia, FANC complex, GPR124 (angiogenesis), as well IRS2, PIK3A in the akt-PIK pathway. Conclusions: NGS in a cohort of advanced pancreatic cancer patients identified novel alterations in genes associated with chromatin modeling and DNA repair. These pathways may serve as potential avenues for targeted therapy in pancreatic cancer.
Effect of intratumoral CD3+ and NKp46+ cells on tumor progression in resected colorectal liver metastases treated with neoadjuvant chemotherapy.
Authors: Donadon Matteo , Cimino Matteo , Hudspeth Kelly , Di Tommaso Luca , Preti Max , Roncalli Massimo , Mavilio Domenico , Torzilli Guido 
Published: February 2017

281 Background: The long-term outcome of patients resected for colorectal liver metastases (CLM) after neoadjuvant chemotherapy (CHT) depends by several tumoral and non-tumoral factors, such as the immune response to the tumor and to the CHT. The aim of this study was to investigate the impact of the pathological and immunological response in patients undergoing liver resection for CLM after CHT in regards to the long-term outcome. Methods: The immunoreactivity to CD3+ and NKp46+ cells inside the tumor, at the border between the tumor and the normal liver, and inside the normal liver was tested by computer-assisted image analyses in 121 patients undergoing liver resection for CLM between 2005 and 2013 preoperatively treated with oxaliplatin or irinotecan with or without bevacizumab or cetuximab. The survival was assessed in relation to several prognostic factors and to that immunoreactivity. Results: At univariate analysis T1/T2- and N0-status of the primary tumor, metachronous CLM, the radiological response, and the higher density of intratumoral CD3+ ( > 1%) and of NKp46+ (mean > 1) were found to be significantly associated with prolonged survival, but only intratumoral CD3+ ( > 1%) and NKp46+ (mean > 1) were significant on multivariate analysis (P = 0.005 and P = 0.004 respectively). On logistic regression analysis the metachronous CLM (OR = 2.781; P = 0.002), the use of irinotecan and cetuximab (OR = 3.891; P = 0.001) and the radiological response (OR = 3.219; P = 0.001) were found to be associated with increasing density of intratumoral CD3+ and NKp46+ cells. No significant associations were found with CLM number or size, CEA, or number of CHT courses. Combining the intratumoral CD3+ and NKp46+ cells density we defined four stages of survival (P = 0.003): patients presenting intratumoral CD3+ ( > 1%) and NKp46+ (mean > 1) had 100% overall survival at 5 years. Conclusions: Intratumoral CD3+ and NKp46+ cells density is a crucial prognostic factor in patients undergoing hepatic resection for CLM after CHT, and the kind of CHT seems related to their density. Further external validations are required to confirm our promising findings.
Multi-Omic profiling (MoP) for patients (pts) with pancreatic cancer (PDA): Initial results of the Know Your Tumor (KYT) initiative.
Authors: Pishvaian Michael J. , Brody Jonathan Robert , Matrisian Lynn , Hendifar Andrew Eugene , Engebretson Anitra , Hoos William Arthur , Mikhail Sameh , Chung Vincent M. , Picozzi Vincent J. , Ramos Corinne , Heartwell Craig , Mason Kimberly , Varieur Katelyn , Rahib Lola , Petricoin Emanuel , Madhavan Subha 
Published: February 2017

282 Background: Emerging insights into the molecular biology of tumors and recent developments in MoP have led to the identification of targets that can be used for selecting treatment (tx) regimens. Multiple testing platforms are available, though most studies to date have used only next generation DNA sequencing (NGS). Methods: The Pancreatic Cancer Action Network (PanCAN) and Perthera have initiated an IRB-approved registry trial wherein we facilitate commercial MoP on tumor tissue from PDA patients. MoP includes NGS, immunohistochemistry (IHC), and phosphoproteomics (PHO). The results are reviewed by a team of PDA specialists in the context of the pt’s tx history. Tx options are prioritized based on the actionable molecular abnormalities. Pts are being followed longitudinally to assess physician acceptance of the tx options and track survival outcomes. Results: From 06/2014 to 09/2015, Perthera reports were delivered for 117 pts. 44% of the analyses were for second-line tx and 43% for ≥ third-line. Tumor based NGS and IHC were available for 75% and 90% of pts, respectively, and research use only PHO data was available for 20 pts. Actionable findings, defined based on a high response rate in pts with an identified molecular abnormality (in any cancer type), or based on a mechanism/pathway-defined implication of response to tx were identified in 43% of pts, primarily based on NGS. Incorporation of IHC refined and expanded chemotherapy tx options in all pts. PHO revealed pathway activation (e.g. mTOR, JAK-STAT, MET, RET, or EGFR) in 16/20 samples. Interestingly, only 45% of KRAS mutant samples had PHO-defined activation of the MEK-ERK pathway. Conclusions: MoP resulted in actionable findings in 43% of PDA pts using NGS and IHC. Incorporation of PHO data could have a significant impact on MoP-based therapy options. Analysis of the MoP in the context of patient history by a PDA specialist provided a service to treating oncologists in the community that was frequently incorporated into their treatment decisions. Survival outcomes will be presented. As additional testing platforms and results become available, the breadth and confidence of actionable markers is expected to increase.