bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I/II trial of autophagy inhibition in combination with neoadjuvant gemcitabine in patients with high-risk pancreatic adenocarcinoma: Safety, clinical response, and correlative studies.
Authors: Lotze Michael T. , Boone Brian A. , Zureikat Amer H. , Bahary Nathan , Lehman David , Liotta Lance A. , Zeh Herbert J. 
Published: February 2017

218 Background: Autophagy is a cell survival mechanism, upregulated in pancreatic ductal adenocarcinoma, correlating adversely with response to therapy and prognosis. The autophagy inhibitor hydroxychloroquine (HCQ) is a novel treatment. Methods: A Phase I/II trial examined pre-operative gemcitabine with HCQ in the treatment of pancreatic cancer patients. Eligibility was restricted to those predicted to have limited survival following surgical resection. Two doses of gemcitabine (1500mg/m2) were administered with oral HCQ (200-1200mg/day) for 31 days until operation in a Storer phase 1 design. Primary endpoint was the safety and tolerability of HCQ. Secondary endpoints were clinical response as assessed by CA 19-9 and R0 resection rates. LC3 and cleaved caspase 3 staining were assessed as biologic correlates to clinical response. Additional exploratory endpoints included serum levels of HMGB1, IL-6, and DNA DAMPs. Results: Thirty-five patients were enrolled in the safety phase of the trial. Two patients withdrew consent prior to treatment and two others were removed due to a stroke and allergic rash, resulting in 31 patients completing treatment. There were no dose limiting toxicities and no treatment delays. 14 patients (45%) had a decrease in CA19-9 of >50% following treatment. 29 patients (94%) underwent surgical resection with an R0 resection rate of 81%. There was one peri-operative mortality (3.2%) with significant morbidity (Grade 3/4) affecting 29% of patients. Increases in pancreatic LC3 staining were consistent with autophagy inhibition. There was a statistically non significant trend towards increased apoptosis with increasing doses of HCQ. Both mitochondrial and nuclear DNA (p = .09) decreased. During treatment, HMGB1 and IL-6 levels rose and then returned to normal levels. Conclusions: Pre-operative autophagy inhibition with HCQ in combination with gemcitabine is safe and tolerable and associated with biomarkers of response. This regimen has promise as a biologically active strategy and future trials will examine HCQ in combination with Nab-paclitaxol/Gemcitabine combinations. Clinical trial information: NCT01128296.
Phase Ib of anticancer stem cell antibody OMP-59R5 (anti-Notch2/3) in combination with nab-paclitaxel and gemcitabine (Nab-P+Gem) in patients (pts) with untreated metastatic pancreatic cancer (mPC).
Authors: O'Reilly Eileen Mary , Smith Lon S. , Bendell Johanna C. , Rangwala Fatima A. , Schmidt William , Stephenson Joe , Kapoun Ann , Xu Lu , Hill Dawn , Zhou Lei , Dupont Jakob , Cohn Allen Lee 
Published: February 2017

220 Background: OMP-59R5, a fully human IgG2 antibody, inhibits signaling of Notch2 and 3 receptors. Tumor regression was seen in Notch3 expressing patient-derived pancreatic cancer xenografts when OMP-59R5 was combined with Nab-P+Gem. The maximum tolerated dose (MTD) of single agent OMP-59R5 was 7.5 mg/kg every other week (Smith, EORTC 2012); the main dose limiting toxicity (DLT) was grade 3 diarrhea. This study is to determine the MTD, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of OMP-59R5 in combination with Nab-P+Gem in mPC. Methods: Cohorts of 3 to 6 pts were treated at each dose level of OMP-59R5. OMP-59R5 is given intravenously every other week (days 1 and 15) with GEM 1,000 mg/m2 alone (first two cohorts) or nab-P 125 mg/m2 and GEM 1,000 mg/m2 on days 1, 8, and 15 of every 28-day cycle. Results: By August 30, 2013, 24 pts were treated. No DLTs have occurred. Frequently reported (≥10%) OMP-59R5 treatment-related adverse events (AEs) were: diarrhea (44%), fatigue (44%), and nausea (16%); most were grade 1 or 2 and managed with supportive care. Frequent chemo-related AEs (≥10%) were cytopenia, fatigue, diarrhea, and nausea. GEM or Nab-P+Gem did not alter PK of OMP-59R5. See table for additional data. Conclusions: OMP-59R5 with Nab-P+ Gem is well tolerated. The MTD has not been reached. Encouraging anti-tumor activity is observed. Updated Safety, PK/PD, and efficacy data will be presented. Clinical trial information: NCT01647828. [Table: see text]
Analysis of the genomic profile of biphenotypic tumors compared to cholangiocarcinoma and hepatocellular carcinoma.
Authors: Keller Jesse W. , Doyle Maria Majella , Wang-Gillam Andrea , Brunt Elizabeth , Vachhajarani Neeta , Chapman William , Tan Benjamin R. 
Published: February 2017

226 Background: Biphenotypic (combined HCC/Cholangiocarcinoma) tumors represent a minority of primary liver cancers. While databases such as the Catalog of Somatic Mutations in Cancer (COSMIC) have genetic information on a large number of cases of HCC and Cholangiocarcinoma, there is little known about rarer Biphenotypic tumors. In this analysis we examine the results of targeted next-generation sequencing to assess genomic differences between these tumors. We utilize the COSMIC database for comparison. Methods: The database of theIRB-approved Washington University Hepatobiliary Registry identified patients with HCC, cholangiocarcinoma and biphenotypic tumors with specimens evaluated utilizing next generation sequencing via a Comprehensive Cancer Gene Set. Further data on corresponding genes was collected from the COSMIC database (v66) for comparison. Results: In this descriptive analysis 15 patients with biphenotypic tumors, 7 patients with HCC and 6 patients with cholangiocarcinoma are presented. The percent of samples with corresponding genetic mutations are outlined (table). These are compared to existing COSMIC data. Conclusions: Biphenotypic tumors had high levels of mutations in EGFR, P53 and Flt3. Mutations in MET, BRAF, CSF1, and MAPK1 were largely isolated to biphenotypic tumors. Mutations in CTNBB1 were isolated to cases of HCC. Notably, mutations in EGFR, Flt3 and FGFR4 were found in all three tumors in higher numbers than seen via review of COSMIC data. Overall, Biphenotypic tumors are genetically complex tumors that share many features of HCC and cholangiocarcinoma. [Table: see text]
Variability in immune infiltrates and HLA expression in cholangiocarcinoma.
Authors: Sabbatino Francesco , Milham Lucia , Deshpande Vikram , Konstantinidis Ioannis T. , Zhu Andrew X. , Santos Daniela Dias , Bardeesy Nabeel , Hong Theodore S. , Tanabe Kenneth , Ferrone Soldano , Lillemoe Keith , Ferrone Cristina 
Published: February 2017

230 Background: Cholangiocarcinoma continues to have a dismal prognosis. The lack of effective therapy prompted us to determine whether patients develop an immune response against their own tumors. The aim of this study is to evaluate the CD8 infiltrate and expression of HLA class I antigen processing machinery (APM) components in cholangiocarcinoma. The HLA class I antigen processing machinery (APM) components play a crucial role in expression of HLA class I tumor antigen derived peptide complexes. These complexes mediate the recognition of tumor cells by cognate T cells. Defects in the expression of HLA class I APM components by tumor cells suggests that the infiltrating lymphocytes impose selective pressure on tumor cells. This selective pressure would facilitate the outgrowth of tumors by escaping T cell recognition. Methods: Retrospective review of clinicopathologic factors was performed for 18 peripheral cholangiocarcinomas. Formalin fixed, paraffin embedded tumors were evaluated for the content of lymphocyte infiltrates and for the expression of HLA class I APM components. Results: Eighteen patients underwent a partial hepatectomy for peripheral cholangiocarcinoma of whom 10 were female. Median age was 63yo. The majority of patients had node negative tumors (10/12). All tumors had lymphocytic infiltration. Median number of lymphocytes in the fibrous septae between tumor lobules was 42 CD8 T cells per 10 high power field, but only 4 CD8 T cells within tumor lobules. HLA class I APM components was defective and not detected in three tumors, all of which were poorly differentiated. HLA expression was down regulated in 9 tumors. HLA expression was in normal range in the remaining 6 tumors. Median overall survival has not been reached. Conclusions: Lymphocytic infiltrates were seen in all resected cholangiocarcinoma specimens. The loss of HLA class I APM component expression in cholangiocarcinoma suggests that infiltrating lymphocytes reflect a patient’s immune response to his/her tumor. This information provides a sound rationale to consider immunotherapy in the treatment of cholangiocarcinoma, specifically with antibodies to check point molecules which enhance patients’ immune response against his own tumors.
Novel PAK4 inhibitors for pancreatic cancer therapy.
Authors: Azmi Asfar S. , Senapedis William , Baloglu Erkan , Landesman Yosef , Kalid Ori , Aboukameel Amro , Bao Bin , Shacham Sharon , Sarkar Fazlul H. , Kauffman Michael , Mohammad Ramzi M 
Published: February 2017

233 Background: Pancreatic cancer (PC) is a deadly disease in urgent need of novel molecularly targeted drugs. Gene copy number amplification studies in PC patient cohorts has shown amplification of the p21-activated kinase (PAK) family member PAK4. PAK4 acts as a key effector of the Rho family GTPases downstream of Ras signaling. Moreover, PAK4 protein is over-expressed in PC cell lines but not in normal human pancreatic ductal epithelial (HPDE) cells. Most importantly, RNA interference of PAK4 has been shown to suppress PC cell proliferation. These studies clearly make PAK4 an attractive therapeutic target especially because direct targeting of Kras has been a failure. Methods: We have identified a new class of PAK4 allosteric modulators that show anti-proliferative activity against several PC cell lines (IC50s <250nM) while sparing normal HPDE (IC50s5 fold higher). Results: Cell growth inhibition is concurrent with apoptosis induction and suppression of colony formation in the PC cell lines (and not in HPDE cells). Our small molecule PAK4 allosteric modulator, KPT-7189, suppresses PAK4 protein expression and caused reversal of anti-apoptotic signaling. PAK4 RNA interference enhances KPT-7189 activity, and co-immunoprecipitation experiments showed disruption of PAK4 binding partners. KPT-7189 also inhibited spheroid forming ability of highly resistant PC cells carrying markers of cancer stem cells (CSCs;triple positive for CD33+CD44+EpCAM+) consistent with epithelial-to-mesenchymal (EMT) phenotype. Molecular analyses of KPT-7189 treated CD33+CD44+EpCAM+ spheroids showed suppression of EMT and CSC markers with re-expression of epithelial phenotype markers. Another potent PAK allosteric modulator in the same series, KPT-7651 showing good oral bioavailability (%F = 95%) was well tolerated by mice with a maximum tolerated dose of 60 mg/kg following oral administration. Pre-clinical animal efficacy trial in sub-cutaneous, orthotopic and LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre transgenic mice model is currently under investigation. Conclusions: This is the first proof of concept study demonstrating the development of a PAK4-targeted drug for the treatment of PC, and thus further pre-clinical and clinical investigations are warranted.
In vitro activity of ABT-888 (A), 5-FU (F), and dacarbazine (D) in neuroendocrine tumors (NET).
Authors: Lubner Sam Joseph , Somnay Yash , Deming Dustin A. , Holen Kyle D. , Chen Herbert 
Published: February 2017

236 Background: Low-grade neuroendocrine tumors (NET) have few cytotoxic chemotherapy options. Data suggests that a combination of temozolomide and a fluoropyrimidine has clinical efficacy. ABT-888 is a novel poly-ADP ribose polymerase (PARP) inhibitor that has been tested in a phase 1 setting with temozolomide, with synergy demonstrated in preclinical models of other tumors. We proposed an in-vitro study of ABT-888 with varying concentrations of dacarbazine (D), and 5-FU (F) on human neuroendocrine cells (BON). Methods: BON cells were incubated with varying concentrations and combinations of ABT-888 (2.5, 5 and 10uM), F (25-100uM), and D (25-100uM) for 96 hours. After incubation, cell growth was measured by MTT rapid colorimetric assay with absorbance reported as mean % control. Western blot analysis was performed for chromogranin A, PARP, γH2AXand XIAP to assess for cell death and on-target effects for the population treated with 5-FU. Combination indices (CI) were calculated using the Chou-Talalay method using CompuSyn. CI’s below 1 signified synergy. Results: ABT-888 alone did not demonstrate any antitumor effect (103%). D alone had antitumor effect (74% at 50uM, 67% at 100uM) which was improved by adding ABT-888 (70% at 50uM D; CI 0.73; p=0.06, 60% at 100 uM D; CI 0.88; p=0.0003). F alone had antitumor effect (82% at 50uM and 71% at 100uM) which was improved by adding 2.5uM ABT-888 (71% at 50uM of F; CI=0.59, and 58% at 100uM of F; CI=0.74), and further enhanced with 5uM of concomitant ABT-888 (56% at 50uM of F; CI=0.68, and 49% at 100uM of F; CI=0.76). Western analysis of lysates showed markers of increased apoptosis, decreased PARP, and decreased expression of CgA. The combination of F+D did not demonstrate increased cytotoxicity with the addition of ABT-888 (58% with/without ABT-888 p=0.61). Conclusions: ABT-888 demonstrated in vitro synergy against BON cells with F or D. The combination of all three compounds (A+F+D) did not demonstrate synergy above F+D. Synergy was statistically significant with increasing doses of cytotoxic compounds which are achievable in vivo with current doses of A, F, and D. The combination of ABT-888 with temozolomide or a fluoropyrimidine merits further study in human clinical trials.
Mismatch repair protein loss and microsatellite instability in cholangiocarcinoma.
Authors: Goyal Lipika , Deshpande Vikram , Chung Daniel C , Groeschl Ryan Thomas , Gamblin T. Clark , Zhu Andrew X. 
Published: February 2017

237 Background: Hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch Syndrome, is an autosomal dominant syndrome characterized by mutations in genes involved in DNA mismatch repair (MMR) and consequent microsatellite instability (MSI). These genetic aberrations lead to an increased incidence of multiple malignancies including colorectal and endometrial cancer, among others. While an association between biliary tumors and HNPCC has been proposed, no published studies have documented MMR protein loss and MSI in a series of biliary tumor samples. After diagnosing cholangiocarcinoma (CCA) in two clinic patients known to have HNPCC and incidentally noting MMR protein loss and MSI in their tumor, we conducted an exploratory study to evaluate the frequency of MMR protein loss and MSI in patients with CCA. Methods: Discarded tissue samples from patients with CCA treated at the Massachusetts General Hospital (n=44) were evaluated for the loss of MLH1, PMS2, MSH2, and MSH6 with immunohistochemical staining. The results were correlated with clinicopathologic features, and the MSI status was collected from the medical record. Results: Four (9.1%) of 44 patients were found to have loss of at least two MMR proteins: 2 pts had MSH2/MSH6 loss, 1 had MLH1/PMS2 loss, and 1 had loss of all 4 proteins. Two patients had previously been tested for microsatellite instability and both were MSI-high. The clinicopathologic features of the 4 patients included: median age 54.5 yo; M:F 1:3; diagnosed with ≥ 1 HNPCC-related malignancy 1/4; family history of ≥ 2 HNPCC-related tumors 2/4, intrahepatic:extrahepatic CCA 3:1; moderately-poorly:poorly differentiated 2:2; T1:T2 3:1; ≥1 positive lymph node 1/4; lymphovascular invasion 2/3; perineural invasion 2/4. Conclusions: MMR protein loss was discovered in 9.1% of patients with CCA in this initial cohort. A second validation cohort from a different institution is currently being tested, and the results will be presented at the meeting. CCA may be an underappreciated co-morbid neoplasm in the spectrum of tumors for HNPCC. MMR protein loss should be further explored as a mechanism of oncogenesis in CCA, and clinicians should be aware of this malignancy in surveillance of patients with HNPCC.
Analysis of metabolic response (MR) by positron emission tomography (PET) compared with tumor response by computed tomography (CT) from MPACT, a phase III trial comparing nab-paclitaxel (nab-P) plus gemcitabine (G) versus G alone for patients (pts) with metastatic adenocarcinoma of the pancreas.
Authors: Ramanathan Ramesh K. , Von Hoff Daniel D. , Moore Malcolm J. , Teixeira Luis , Siena Salvatore , Tabernero Josep , Goldstein David , Wei Xinyu , Lu Brian 
Published: February 2017

254^ Background: In the MPACT trial, nab-P + G demonstrated superior efficacy vs G alone for the treatment of metastatic pancreatic cancer (PC). Pts with an MR (according to EORTC criteria) had a 5-month improvement in median overall survival (OS) vs those without an MR (13 vs 8 months for nab-P + G and 12 vs 7 months for G alone). This analysis examines the relationship between MR by PET and tumor response by CT. Methods: Previously untreated pts (N = 861) with metastatic PC were randomized 1:1 to receive nab-P 125 mg/m2 + G 1000 mg/m2 on days 1, 8, and 15 every 4 wk or G alone 1000 mg/m2 weekly for 7 wk followed by 1 wk of rest (cycle 1) and then days 1, 8, and 15 every 4 wk (cycle ≥ 2). Tumor responses were evaluated every 8 wk by CT using RECIST v1.0. CT-documented disease progression led to treatment discontinuation. PET scans were evaluated at baseline, wk 8, and wk 16. Results: In 257 pts with a PET scan at baseline, 252 (98%) had ≥ 2 PET-avid lesions. The rate of MR (complete [CMR] or partial [PMR]) was higher for nab-P + G vs G alone (63% vs 38%; P < 0.0001). The ORRs by CT (complete response + partial response [CR/PR]) in the same pts were 31% for nab-P + G vs 11% for G. In a pooled-treatment-arm analysis (n = 255), 130 pts (51%) had an MR by PET, and 54 (21%) had a CR or PR by CT. Among pts with an MR by PET, 32% had a CR or PR, 43% had stable disease, and 16% had progressive disease (PD) by CT. Pts who had an MR by PET in the absence of a CR or PR by CT (n = 88) had a median OS of 10 months (table). Conclusions: Rates of MR by PET in this trial were > 2-fold the response rates by CT, suggesting that PET may be a more sensitive marker of tumor response. Of the pts without a CR or PR by CT, those with an MR by PET had a longer median OS vs those without one. A set of pts who had PD by CT exhibited an MR by PET. Thus, PET may identify a set of pts who may benefit from continued treatment despite PD by CT. Further research is needed to explore the radiological and clinical characteristics of these pts. Clinical trial information: NCT00844649. [Table: see text]
Interim analysis of a phase II study of dose-modified FOLFIRINOX (mFOLFIRINOX) in locally advanced (LAPC) and metastatic pancreatic cancer (MPC).
Authors: James Edward Samuel , Yao Xiaopan , Cong Xiangyu , Stein Stacey , Kaley Kristin , Hahn Carol , Cha Charles , Salem Ronald R , Hochster Howard S. , Lacy Jill 
Published: February 2017

256 Background: Although FOLFIRINOX is superior to gemcitabine in MPC, the regimen is associated with significant toxicities (Conroy et al. N Engl J Med 2011;364:1817). In our prior retrospective analysis, efficacy was not compromised by dose attenuations of FOLFIRINOX (Gunturu et al. Med Oncol 2013;30:361). Based on this analysis, we are conducting a prospective phase II open label study to evaluate the efficacy & tolerability of mFOLFIRINOX in pts with advanced pancreatic cancer (PC). Methods: Previously untreated pts with MPC or LAPC received mFOLFIRINOX with 25% dose reductions of irinotecan & bolus 5-FU given every two wks until progression, unacceptable toxicity, or surgical resection. All pts received prophylactic pegfilgrastim. FDG-PET scans were obtained at baseline & after 2 cycles. CAT scans were obtained after every 4 cycles. Toxicities & response rate (RR) were compared to historical data reported by Conroy. Results: 53 pts with ECOG PS ≤1 have been enrolled to date between 11/11 and 08/13, Pt characteristics: LAPC 22; MPC 31; median age 62 yrs (range 46-86); male 30. Median # of cycles was 8 (range 1-21). Grade 3/4 toxicities were: anemia, febrile neutropenia (FN) & peripheral sensory neuropathy (PSN) – 3.8% each; ALT increased & thromboembolism – 5.7% each; diarrhea 7.5%; fatigue 11.3%; neutropenia 17%; thrombopenia 11.3% & vomiting 1.9%. Anemia ( p< 0.04), FN (p<0.04), PSN (p<0.04) and vomiting (p<0.02) were significantly decreased compared to historical data (Conroy). Response by RECIST (CR+PR) in 26 evaluable pts with MPC was 29% (0 CR, 9 PR, 14 SD, 3 PD) & similar to historical data (31.6%; p 0.85). 6/13 evaluable pts with LAPC underwent resection (46%).13/36 pts evaluable for PET response had a >50% decrease in SUV(max)(36%). Evaluation for OS & PFS is ongoing. Conclusions: Findings from our interim analysis suggests that mFOLFIRINOX, given along with prophylactic pegfilgrastim is associated with a similar RR and improved tolerability compared to full dose FOLFIRINOX in advanced PC. In pts with LAPC, neoadjuvant FOLFIRINOX appears to have substantial activity with 46% of evaluable pts undergoing resection. Accrual will continue to reach a goal of 70 pts. Clinical trial information: NCT01523457.
A phase II study of vismodegib, a hedgehog (Hh) pathway inhibitor, combined with gemcitabine and nab-paclitaxel (nab-P) in patients (pts) with untreated metastatic pancreatic ductal adenocarcinoma (PDA).
Authors: De Jesus-Acosta Ana , O'Dwyer Peter J. , Ramanathan Ramesh K. , Von Hoff Daniel D. , Maitra Anirban , Rasheed Zeshaan , Zheng Lei , Rajeshkumar N. V. , Le Dung T. , Hoering Antje , Bolejack Vanessa , Yabuuchi Shinichi , Laheru Daniel A. 
Published: February 2017

257 Background: The Hh pathway is overexpressed in PDA tumors. Pre-clinically, Hh inhibitors have demonstrated a reduction in pancreatic cancer stem cells (pCSC) and stroma. Vismodegib, an oral small-molecule antagonist of the Hh pathway, has previously been safely combined with Gemcitabine chemotherapy. Methods: Pts with untreated, metastatic PDA were treated with Gemcitabine (1000 mg/m2) + nab-P (125 mg/m2) on days 1, 8 and 15 of 28 days cycle. Vismodegib (150mg PO daily) was started on the second cycle. All drugs were continued until disease progression or unacceptable toxicities. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), response rate (RR), and toxicity. Pre and post treatment tumor biopsies were obtained from primary or metastatic lesions. Results: 59 patients have been enrolled at 3 sites. Median age 60 (range 42-86); ECOG PS 0/1: 23 (40%)/ 34 (60%); male/female 32 (54%)/ 27 (46%). Estimated median PFS and OS in ITT population was 5.5 and 10 mo respectively (95% CI: 5.2-5.9 / 7.3-11). Of the 49 pts evaluable for response to date, 1 (2%) had CR, 20 (41%) had PR, 21 (43%) had SD and 7 (14%) had PD. Common Gr ≥3 toxicities: neutropenia 37.5% (n=21), anemia 21.4% (n=12), neuropathy 16.1% (n=9) and fatigue 9.4% (n=5). All patients with partial response had response within the primary pancreatic tumor. CA19-9 declines of >70% occurred in 57% of patients with measurable levels. Conclusions: Addition of Vismodegib to Gemcitabine/nab-P is well tolerated in patients with untreated PDA. This trial is ongoing to complete 80 patients. Blood and tumor tissue biomarker analyses for stem cells, Hh signaling and stromal activity are ongoing and will be reported in ASCO GI 2014. Clinical trial information: NCT01088815.