bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of liposomal irinotecan (nal-IRI) + 5-fluorouracil and leucovorin (5-FU/LV) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) who previously received gemcitabine (gem)-based therapy: Post-hoc analysis of the NAPOLI-1 trial.
Authors: Chen Li-Tzong , Wang-Gillam Andrea , Yanshen Shan , Macarulla Teresa , Blanc Jean-Frédéric , Hubner Richard , Chiu Chang-Fang , Schwartsmann Gilberto , Siveke Jens T. , Pipas J. Marc , Belanger Bruce , de Jong Floris , Mamlouk Khalid , Von Hoff Daniel D. 
Published: March 2017

303 Background: nal-IRI+5-FU/LV is approved in the United States and Taiwan for pts with mPDAC previously treated with gem-based therapy based on the NAPOLI-1 study which showed that nal-IRI+5-FU/LV improved overall survival (OS) vs 5-FU/LV (6.1 vs 4.2 mo; HR, 0.67; 95% CI, 0.49-0.92; P = 0.012; Wang-Gillam et al, Lancet. 2016). This post hoc analysis evaluated the efficacy and safety of nal-IRI+5-FU/LV in subgroups of pts defined by prior gem regimen including gem monotherapy and gem combinations (combo). Methods: This analysis (data cutoff, Nov 2015) focuses on the 236 pts assigned to nal-IRI+5-FU/LV q2w (n = 117) or 5-FU/LV qw for weeks 1-4 q6w cycle (n = 119). Pts previously received gem-based therapy in a neoadjuvant, adjuvant, locally advanced, or metastatic setting. Results: Of 117 pts in the nal-IRI+5-FU/LV arm, 53 (45%) previously received gem monotherapy and 64 (55%) previously received gem combo including erlotinib (n = 9) or nab-paclitaxel (n = 20). Of the 119 pts in the 5-FU/LV arm, 55 (46%) previously received gem monotherapy and 64 (54%) previously received gem combo including erlotinib (n = 17) or nab-paclitaxel (n = 11). Nal-IRI+5-FU/LV improved median OS, median PFS, and ORR vs 5-FU/LV, regardless of prior therapy (Table). Grade ≥3 treatment-emergent adverse events were not influenced by prior treatment. Clinical trial information: NCT01494506. Conclusions: These resultsshow consistent benefit of nal-IRI+5-FU/LV treatment across subgroups of pts who previously received gem therapy and support the ASCO guidelines recommending nal-IRI+5-FU/LV for this pt population. These analyses may be limited by the small sample size of treatment arms.[Table: see text]
A phase I study of ADH-1 with cisplatin (Cisp) and gemcitabine (Gem) in patients (Pts) with unresectable or metastatic pancreatic and biliary tract cancers.
Authors: Berim Lyudmyla Derby , Kos Beth M , Evande Ruby , Meza Jane L , Shostrom Valerie , Schwarz James K. , Grem Jean L. 
Published: March 2017

306 Background: Pancreatic cancer cells in vitro undergo epithelial to mesenchymal transformation (EMT) by up-regulating mesenchymal markers, including N-cadherin. The EMT leads to increased motility & invasiveness with collagen exposure in a pancreatic cancer mouse model, which can be inhibited by N-cadherin knockdown. ADH-1 is a small, cyclic pentapeptide with inhibitory effects on stromal & endothelial cells expressing N-cadherin. Methods: Escalating doses of ADH-1 were given twice weekly for 3 wk (1,000, 2,000 & 4,000 mg) with Cisp 25 mg/m2 & Gem1000 mg/m2/100 min days 1 & 8 of a 3 wk cycle in pts with pancreaticobiliary cancers with ECOG PS 0-2 & adequate bone marrow, renal & hepatic function. Standard 3 + 3 dose escalation was used. Peripheral blood was collected for biomarkers prior to each dose of ADH-1 during cycle 1. Due to limited drug supply, ADH-1 was given for the 1st 3 cycles. Results: Between 05/2013 - 04/2015, 17 pts were enrolled, received at least 1 dose of therapy, and were evaluable for toxicity: m 13/F 4; median 60 yr (range 37-81); pancreas 9 /biliary 8. 3 pts had prior adjuvant therapy. The number pts with dose-limiting toxicity during cycle 1 of ADH-1 (mg) were 0/4 at 1,000; 1/7 at 2,000 (gr 4 ANC, platelet); 2/6 pts 4,000 mg (1 pt: gr 3 pulmonary embolus and gr 4 plt; 1: gr 4 cholangitis/sepsis/multiorgan failure). 5 of 8 pts who had ≥ 6 cycles were taken off study due to cumulative toxicities rather than PD. 14 pts had ≥ 3 cycles of therapy and were evaluable for response: SD in 9 subjects; PD in 5. The median number cycles was 5.5 (range 1-30). Median time to treatment failure (TTF) for all patients was 113 days (range 7-724). Median OS was 218 days (7-853+). Pts with biliary cancer had a longer TTF and OS vs pancreatic cancer (TTF 217 vs 93 days; OS 305 vs 180 days). 6 pts survived > 12 months (biliary 4, pancreas 2). Biomarker analysis (ICAM 1; E selectin; VEGF, Soluble VEGF-R 2 and 3, FGF basic) is ongoing. Conclusions: The phase II dose of ADH1 given with Cisp/Gem is 2,000 mg IV twice weekly. ADH-1 was relatively well tolerated. Most pts ultimately required dose delays or reductions due to cumulative toxicity with Cisp/Gem. Clinical trial information: NCT01825603.
Detection of circulating tumor cells (CTC) using a non-EpCAM-based, high-definition, single-cell assay in advanced hepatocellular carcinoma (HCC) for patients enrolled on phase I and II trials of sorafenib plus temsirolimus.
Authors: Kelley Robin Kate , Rodriguez Lee Mariam , Hwang Jimmy , Gordan John Dozier , Nimeiri Halla Sayed , Bocobo Andrea Grace , Kircher Sheetal Mehta , Kanakamedala Advaita , Mulcahy Mary Frances , Benson Al Bowen , Kuhn Peter , Venook Alan P. 
Published: March 2017

311 Background: Noninvasive biomarkers are needed for diagnosis, prognosis, and molecular profiling of HCC due to scarcity of tumor tissue and heterogeneous tumor biology. CTC are detectable in metastatic HCC using methods which enrich for expression of the cell adhesion molecule, EpCAM. Because a subset of HCC does not express EpCAM, however, non-EpCAM enrichment methods are needed for CTC studies in HCC. Methods: This CTC cohort was derived from patients enrolled on multicenter phase 1 and 2 trials of the combination of sorafenib plus temsirolimus in advanced HCC (NCT01008917, NCT01687673) with approval and funding from the National Comprehensive Cancer Network (NCCN) Oncology Research Program. Eligibility required histologic diagnosis of incurable HCC with no prior systemic therapy. All patients in the cohort were treated at the recommended phase 2 dose of sorafenib 200 mg PO BID and temsirolimus 10 mg IV weekly. Whole blood samples were collected at baseline and on treatment. CTC were enumerated and analyzed cytomorphologically using a high-definition, single cell assay without EpCAM enrichment and blinded to clinical outcomes. Results: The CTC cohort was comprised of 36 patients (phase 1 n = 9, phase 2 n = 27). Characteristics: male 89%; white 64%, Asian/PI 28%, black 6%; HBsAg+ 31%, HCV+ 44%; Child Pugh A 92%, B7 8%; BCLC C 83%; tumor vascular invasion 47%; median AFP 74 ng/mL. Median OS from start of treatment was 392 days (95% CI: 214, 569). CTC ≥ 1/mL were detectable at baseline in 23/36 (64%) overall (95% CI: 47%, 80%), with similar findings in the phase 1 (56%) and phase 2 (67%) subsets. There was no significant relationship between baseline CTC values ≥ 1, 2, or 5/mL and overall survival (OS) on univariate analysis. Analyses of CTC relationship to clinical characteristics and time to progression, changes on treatment, and multivariable analysis for relationship to OS will be presented. Conclusions: CTC were detected in over 60% of patients in this advanced HCC clinical trial cohort using a non-EpCAM, high-definition single cell assay, suggesting future potential for noninvasive molecular profiling of HCC.
Germline mutations in seemingly sporadic pancreatic cancer.
Authors: Wong Cavin , Cuggia Adeline , Borgida Ayelet , Holter Spring , Hall Anita , Connor Ashton , Akbari Mohammad R , Gallinger Steven , Zogopoulos George 
Published: March 2017

312 Background: Genetic predisposition underlies approximately 10% of pancreatic cancer (PC). Germline mutations in BRCA1, BRCA2, PALB2, ATM, TP53, MLH1, MSH2, MSH6, PMS2, PRSS1, APC, BMPR1A, STK11, CDKN2A, and SMAD4 are associated with PC susceptibility. Since young onset is not a hallmark of hereditary PC, we have hypothesized that seemingly sporadic cases may carry germline mutations in these genes. Methods: To investigate the prevalence of germline mutations in these 15 genes among sporadic PC cases, we analyzed lymphocyte DNA next generation sequencing data from 296 PC cases ascertained over 1 year from two PC referral centers in Toronto and Montreal. Results: We identified 21 mutations in 5 of the 15 genes (10 in BRCA2, 2 in BRCA1, 5 in ATM, 1 in p16, 3 in PRSS1) in 19 individuals. One individual carried two BRCA2 mutations that are usually observed together, and another individual carried both a PRSS1 and ATM mutation, however, in the absence of pancreatitis, PRSS1 mutations are not known to increase risk of PC. Incidences of 1.7% and 4.1% in ATM and BRCA-1 or -2 were observed. Approximately half of these mutations (4/9 for BRCA2, 1/2 for BRCA1, and 1/1 for p16) were known founder mutations in the French Canadian, Ashkenazi Jewish, Dutch or Asian populations. Since the role of ATMin PC predisposition remains under investigation, we obtained further evidence by testing for loss of the wild-type allele in cases with available tumor tissue. We observed loss of the wild-type allele in the 2 cases tested. Interestingly, the final pathology for the resected specimen from one of these two cases favored an ampullary cancer rather than a PC diagnosis. Conclusions: Since there are screening implications for the relatives of carriers and potentially treatment considerations for patients using therapies targeting DNA repair defects, these findings suggest a role for reflex testing of incident cases for at least population-specific recurrent mutations. Our findings also suggest that ATM germline mutations may give rise to ampullary cancer, underlie 1.4% of incident PC cases and imply broader testing considerations. For patients, testing may direct therapy choices if these tumors are targetable using agents that exploit DNA repair defects.
Tremelimumab: A monoclonal antibody against CTLA-4—In combination with radiofrequency ablation (RFA) in patients with biliary tract carcinoma (BTC).
Authors: Duffy Austin G. , Pratt Drew , Kleiner David E , Mabry Donna , Fioravanti Suzanne , Walker Melissa , Figg William Douglas , Steinberg Seth M. , Anderson Victoria , Krishnasamy Venkatesh , Wood Bradford J. , Greten Tim F. 
Published: March 2017

316 Background: Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and results in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. Radiofrequency ablation (RFA) has been shown to induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment. Methods: Patients with refractory BTC were enrolled in a study of monthly Tremelimumab (10mg/kg, 6 doses) combined with RFA (to one lesion) performed on week 6. Tumor biopsies were performed at time of RFA with regular PBMC collection for intensive immunemontoring. Results: 17 pts enrolled. Characteristics: M:F 8:9; Median age 57(range 36-67); BTC subtype - intrahepatic/exrahepatic: 12/5. 13/17 had metastatic disease. All pts were chemorefractory with 12/17 having received at least 2 regimens. While on study, 6 pts had early PD within 6 weeks; 11 were able to undergo RFA. No DLT encountered. Most common toxicity was pruritus. There were no objective responses. Of evaluable pts N = 6 (55%) had stable disease as a best response. Conclusions: Tremelimumab in combination with subtotal RFA in patients with advanced BTC is safe and feasible. No objective responses have so far been seen in this predominantly primary intrahepatic BTC population. Full efficacy and immune monitoring data will be presented. Clinical trial information: NCT01853618.
Population pharmacokinetics (popPK) to evaluate the effect of intrinsic and extrinsic factors on regorafenib (REG) exposure in REG studies including patients with hepatocellular carcinoma (HCC).
Authors: Ploeger Bart , Cleton Adriaan , Keunecke Anne , Bruix Jordi , Meinhardt Gerold 
Published: March 2017

320 Background: REG is approved for refractory metastatic colorectal cancer (CRC) and gastrointestinal stromal tumors (GIST). In the phase 3 RESORCE trial (N = 573), REG (160 mg QD, 3 weeks on/1 week off) significantly (P < 0.001) improved overall survival (OS) vs placebo in HCC patients who progressed on sorafenib (HR 0.63; 95% CI 0.50‒0.79). We evaluated REG PK in RESORCE using a popPK model and the influence of intrinsic and extrinsic factors (covariates) on REG PK. Methods: The average concentrations of REG and its pharmacologically active metabolites (M-2, M-5) were estimated based on sparse PK sampling in cycles 1–2. A covariate analysis was conducted using exposure and covariate data in 16 clinical REG trials in CRC, GIST, and HCC (1337 subjects) using a graphical and generalized additive modeling (GAM) approach. Results: eGFR, total plasma protein, hematocrit, total bilirubin, AST, ALP, and Asians vs non-Asians did not significantly (p > 0.05) influence exposure, whereas covariates significantly (p < 0.05) influencing exposure in 16 studies including RESORCE were: being a healthy volunteer vs a patient, sex, age, hemoglobin at baseline, plasma albumin at baseline, BMI, and body weight. The identified covariate effects were considered small compared with observed overall variability in exposure. Visual comparison of the exposure estimates in RESORCE showed these were comparable to those in phase 3 studies in CRC and GIST. Exposure in Asians was comparable to that in the rest of the world (ROW) and there was no apparent difference in exposure between Japanese, Chinese, and ROW and between patients with mild/moderate hepatic impairment vs normal hepatic function. Only small numerical differences in exposure across different age categories were observed, with a tendency towards higher exposure in patients ≥ 65 years of age. Conclusions: The RESORCE data confirm previous observations that the identified covariates that significantly (P < 0.05) correlated with exposure only describe a small fraction ( < 10%) of the overall variability in exposure and, thus, are not expected to have a clinically relevant impact on REG exposure. Clinical trial information: NCT01774344.
Expression of GRP78 protein in pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasm.
Authors: Dhanarajan Asha R. , Hill Reginald , Pappas Sam G. , Abood Gerard J. , Gnerlich Jennifer Lynn , Ding Xianzhong 
Published: March 2017

323 Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis due to late detection, aggressive biology and resistance to chemotherapy. Markers for early detection of PDAC and mediators of chemoresistance are poorly understood. GRP78 is a major endoplasmic reticulum (ER) chaperone protein critical for protein quality control of the ER. Increased GRP78 expression promotes in vitro cancer cell survival, progression, and chemoresistance. This study aims to examine expression of GRP78 protein in PDAC and intraductal papillary mucinous neoplasm (IPMN) compared to normal pancreatic ducts using immunohistochemistry (IHC). Methods: The expression of GRP78 was assessed using IHC in 93 sections of formalin-fixed paraffin-embedded tissue: normal ducts (38), low grade IPMN (IPMN-LG, 26), high grade IPMN (IPMN-HG, 9), and PDAC (20). Immunostaining intensity of GRP78 protein was categorized as no or weak staining (0-1+) and strong staining (2-3+). Fisher’s exact test with two tails was performed using the GraphPad statistical software. Results: GRP78 expression was identified in the cytoplasm of normal pancreatic ducts, IPMN and PDAC with a fine granular pattern. All PDAC and IPMN-HG showed strong expression of GRP78 while the normal ductal cells showed only minimal expression of GRP78. 73% of IPMN-LG expresses GRP78 strongly. Statistical analysis revealed a significant difference in GRP78 expression level between normal ductal cells and all three pathological conditions including PDCA, IPMN-HG and IPMN-LG (all p < 0.0001). Conclusions: This study shows that the expression level of GRP78 is significantly increased in PDAC, IPMN-HG and IPMN-LG compared to normal ductal cells. There appears to be a progressive increase in GRP78 expression from IPMN-LG to IPMN-HG and invasive PDAC. Increased GRP78 expression may be a marker for those at risk of developing PDAC. Changes in GRP78 expression over time and its role in PDAC chemoresistance should be further assessed. [Table: see text]
Result of Arid1a deletion on intraductal papillary mucinous neoplasm formation.
Authors: Wang Sam C. 
Published: March 2017

328 Background: ARID1A, a member of the SWI/SNF chromatin-remodeling complex, is mutated in up to 30% of pancreatic ductal adenocarcinoma (PDAC). Here, we studied the effect of Arid1a loss in pancreatic tumorigenesis in the setting of a constitutively activated Kras allele ( KrasG12D), which is the basis of a well-established mouse model of pancreas cancer. Methods: Arid1a was deleted during embryogenesis in acinar, duct, and islet cells in Ptf1a-Cre; Arid1af/f (CA) and KrasG12D; Ptf1a-Cre; Arid1a f/f (KCA) mice. Arid1a was inducibly deleted in adult mice specifically in duct or acinar cells with KrasG12D; Sox9-CreER; Arid1a f/f (KSERA), and KrasG12D; Ptf1a-CreER; Arid1a f/f (KPERA) mice, respectively. Tamoxifen was given at 4 weeks of age. Results: Genotyping of CA mice toes and pancreata showed Arid1a loss only in the latter confirming pancreas-specific recombination. Western blot confirmed decreased protein expression and immunohistochemistry (IHC) demonstrated Arid1a loss in most of the acini and half of the ducts. ~35% of CA mice developed benign appearing cysts by 4 months. KCA mice had macroscopic cysts by 3 weeks. The cyst fluid was thick and amylase rich. These cysts resembled intraductal papillary mucinous neoplasm (IPMN) as they had papillary features and stained for Alcian blue, confirming the presence of mucin. Muc protein staining pattern was consistent with pancreaticobiliary type IPMN. The stroma was negative for estrogen and progesterone receptors. KSERA mice developed large mucin producing ductal lesions by 12 weeks while only pancreatic intraepithelial neoplasias were seen in KPERA mice. Conclusions: Arid1a loss in the pancreas leads to pancreaticobiliary IPMN that appear to arise from the duct cells. Future directions include aging studies to determine if these cysts transform to frank PDAC, determining the status of ARID1A in human IPMN, and elucidating the mechanisms for cyst formation. Finally, this model may be useful as a platform to test therapeutic interventions to treat IPMN.
The effects of pioglitazone treatment on pancreatic cancer-related insulin resistance.
Authors: Stern Jennifer , Arriaga Yull Edwin , Gupta Arjun , Verma Udit , Karri Sirisha , Syed Samira K. , Khosama Leticia , Mansour John C. , Scherer Philipp , Beg Muhammad Shaalan 
Published: March 2017

329 Background: Insulin resistance (IR) in pancreatic cancer (PC) patients is associated with cachexia and poor outcome. Pioglitazone (PIO) improves insulin sensitivity via activation of peroxisome proliferator-activated receptor (PPAR gamma). Effects of PIO on insulin sensitivity, glucose homeostasis, and circulating adipokine levels in PC have not been examined. Methods: Patients with metastatic PC were administered PIO 45mg/day orally for 8 weeks concurrent with chemotherapy. Patients with known DM at enrollment were identified Fasting plasma was collected at baseline, weeks 2, 4, 6, 8 of pioglitazone treatment and at 2 weeks-post treatment. The primary objective was to describe changes in indicators of IR, including glucoregulatory hormone levels, glucose tolerance, and inflammatory cytokines. Results: Fourteen patients (age 64y), with a mean BMI of 28 were enrolled. Mean adiponectin increased from baseline to week 8 of treatment (14.2± 3.3 and 46.9±11.4µg/ml, respectively, P ≤ 0.01), and returned to baseline levels at 2 weeks post-treatment (15.1±1.9 µg/ml). Markers of IR (serum glucose, insulin, glucagon, and response to an oral glucose bolus) did not correlate with tumor size, inflammatory cytokine levels, GM-CSF, or CA19-9. A dichotomous response to PIO treatment was observed between non-diabetic and T2DM patients. Fasting insulin increased 70.6±31.3% from baseline to treatment week 8 in patients with T2DM. In contrast, treatment of non-diabetic patients decreased fasting insulin by 40.2±6.3%, demonstrating a significant, P ≤ 0.01, difference in treatment response between PC patients with or without T2DM. Conclusions: We have demonstrated that PC patients respond to 8 weeks of PIO treatment with a significant rise in the insulin sensitizing adipokine, Adiponectin, with a complete wash-out after 2 weeks of cessation. PIO results in opposing fasting insulin responses in non-diabetic and DM patients suggests that diabetes status plays a significant role in the glucoregulatory effects of PIO treatment in PC patients. Clinical trial information: NCT01838317.
Preclinical antitumor activity of nanoliposomal irinotecan (Nal-IRI, MM-398) and utilization as a foundation of front-line pancreatic cancer regimens.
Authors: Gaddy Daniel F. , Lee Helen , Paz Nancy , Leonard Shannon C. , Kalra Ashish , Straubinger Ninfa L. , Straubinger Robert M , Gillard Bryan M. , Moser Michael T. , Foster Barbara A. , Drummond Daryl C. , Klinz Stephan G. , Hendriks Bart , Fitzgerald Jonathan B. 
Published: March 2017

336 Background: Nanoliposomal irinotecan (nal-IRI, MM-398) recently gained approval in combination with 5-fluorouracil/leucovorin (5-FU/LV) in post-gemcitabine metastatic pancreatic ductal adenocarcinoma (PDAC) based on the extended survival and manageable safety profile observed in the Phase 3 NAPOLI-1 trial. Preclinically, we have previously demonstrated the anti-tumor activity of nal-IRI with 5-FU and oxaliplatin, standard of care agents in first-line PDAC, and are currently investigating this combination in patients with previously untreated metastatic PDAC in a Phase 2 clinical trial (NCT02551991). Herein, we further evaluate nal-IRI as a potential backbone of first-line metastatic PDAC by assessing the preclinical anti-tumor activity of nal-IRI relative to, and in combination with, gemcitabine and nanoparticle albumin-bound-paclitaxel (nab-P). Methods: Nal-IRI tumor metabolite (CPT-11 and SN-38) levels were measured in mice treated with nal-IRI in combination with gemcitabine or nab-P. Anti-tumor activity and tolerability of nal-IRI, 5-FU, gemcitabine and nab-P monotherapies and combinations were evaluated using pancreatic cancer cell line (ASPC-1 and CFPAC-1)-derived xenograft models, as well as a panel of five patient-derived xenograft models. Results: Administration of gemcitabine or nab-P prior to or simultaneously with nal-IRI resulted in unchanged or increased nal-IRI deposition, as measured by tumor CPT-11 and SN-38 levels at 24 hours post-injection. Moreover, in both cell line-derived and patient-derived xenograft models of PDAC, nal-IRI monotherapy demonstrated comparable or improved anti-tumor activity relative to gemcitabine or nab-P monotherapies. Further, nal-IRI consistently improved tumor growth inhibition and survival when used in combination with either 5-FU, gemcitabine and/or nab-P, relative to the combination of gemcitabine plus nab-P. All treatments were well-tolerated in these preclinical models. Conclusions: These findings illustrate the compatibility and therapeutic potential of nal-IRI as a foundation of first-line PDAC combination regimens, and warrant clinical evaluation.