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Pancreatic Neoplasms: HELP
Articles by Ana M. C. De Jesus-Acosta
Based on 21 articles published since 2010
(Why 21 articles?)
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Between 2010 and 2020, A. De Jesus-Acosta wrote the following 21 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review The Molecular and Clinical Landscape of Pancreatic Neuroendocrine Tumors. 2019

Batukbhai, Bhavina D O / De Jesus-Acosta, Ana. ·Department of Oncology, Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD. ·Pancreas · Pubmed #30531241.

ABSTRACT: Pancreatic neuroendocrine tumors are rare tumors of the pancreas originating from the islets of the Langerhans. These tumors comprise 1% to 3% of all newly diagnosed pancreatic cancers every year and have a unique heterogeneity in clinical presentation. Whole-genome sequencing has led to an increased understanding of the molecular biology of these tumors. In this review, we will summarize the current knowledge of the signaling pathways involved in the tumorigenesis of pancreatic neuroendocrine tumors as well as the major studies targeting these pathways at preclinical and clinical levels.

2 Review Pancreatic neuroendocrine tumors: Challenges in an underestimated disease. 2016

Viúdez, A / De Jesus-Acosta, A / Carvalho, F L / Vera, R / Martín-Algarra, S / Ramírez, N. ·Department of Medical Oncology, Complejo Hospitalario de Navarra, IdiSNA Navarra Institute for Health Research, Navarra Public Health System, Pamplona, Navarra, Spain. Electronic address: antoniovb76@gmail.com. · Department of Medical Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. · Department of Urology, Georgetown University Hospital, Washington DC, USA. · Department of Medical Oncology, Complejo Hospitalario de Navarra, IdiSNA Navarra Institute for Health Research, Navarra Public Health System, Pamplona, Navarra, Spain. · Department of Medical Oncology, University Clinic of Navarra, University of Navarra, IdiSNA Navarra Institute for Health Research, Pamplona, Spain. · Oncohematology Research Group, Navarrabiomed-Miguel Servet Foundation, IdiSNA Navarra Institute for Health Research, Navarra Public Health System, Pamplona, Navarra, Spain. Electronic address: nramireh@cfnavarra.es. ·Crit Rev Oncol Hematol · Pubmed #27021395.

ABSTRACT: Pancreatic neuroendocrine tumours (PanNETs) are considered a relatively unusual oncologic entity. Due to its relative good prognosis, surgery remains the goal standard therapy not only in localized disease but also in the setting of locally or metastatic disease. Most of the patients are diagnosed in metastatic scenario, where multidisciplinary approach based on surgery, chemotherapies, liver-directed and/or molecular targeted therapies are commonly used. Owing to a deeper molecular knowledge of this disease, these targeted therapies are nowadays widely implemented, being the likely discovery of predictive biomarkers that would allow its use in other settings. This review is focused on describing the different classifications, etiology, prognostic biomarkers and multidisciplinary approaches that are typically used in PanNET.

3 Clinical Trial The Role of Stereotactic Body Radiation Therapy for Pancreatic Cancer: A Single-Institution Experience. 2015

Moningi, Shalini / Dholakia, Avani S / Raman, Siva P / Blackford, Amanda / Cameron, John L / Le, Dung T / De Jesus-Acosta, Ana M C / Hacker-Prietz, Amy / Rosati, Lauren M / Assadi, Ryan K / Dipasquale, Shirl / Pawlik, Timothy M / Zheng, Lei / Weiss, Matthew J / Laheru, Daniel A / Wolfgang, Christopher L / Herman, Joseph M. ·Department of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ·Ann Surg Oncol · Pubmed #25564157.

ABSTRACT: BACKGROUND: Stereotactic body radiation therapy (SBRT) is a promising option for patients with pancreatic cancer (PCA); however, limited data support its efficacy. This study reviews our institutional experience of SBRT in the treatment of locally advanced (LAPC) and borderline resectable (BRPC) PCA. METHODS: Charts of all PCA patients receiving SBRT at our institution from 2010 to 2014 were reviewed. Most patients received pre-SBRT chemotherapy. Primary endpoints included overall survival (OS) and local progression-free survival (LPFS). Patients received a total dose of 25-33 Gy in five fractions. RESULTS: A total of 88 patients were included in the analysis, 74 with LAPC and 14 with BRPC. The median age at diagnosis was 67.2 years, and median follow-up from date of diagnosis for LAPC and BRPC patients was 14.5 and 10.3 months, respectively. Median OS from date of diagnosis was 18.4 months (LAPC, 18.4 mo; BRPC, 14.4 mo) and median PFS was 9.8 months (95 % CI 8.0-12.3). Acute toxicity was minimal with only three patients (3.4 %) experiencing acute grade ≥3 toxicity. Late grade ≥2 gastrointestinal toxicity was seen in five patients (5.7 %). Of the 19 patients (21.6 %) who underwent surgery, 79 % were LAPC patients and 84 % had margin-negative resections. CONCLUSIONS: Chemotherapy followed by SBRT in patients with LAPC and BRPC resulted in minimal acute and late toxicity. A large proportion of patients underwent surgical resection despite limited radiographic response to therapy. Further refinements in the integration of chemotherapy, SBRT, and surgery might offer additional advancements toward optimizing patient outcomes.

4 Clinical Trial A phase II study of the gamma secretase inhibitor RO4929097 in patients with previously treated metastatic pancreatic adenocarcinoma. 2014

De Jesus-Acosta, Ana / Laheru, Daniel / Maitra, Anirban / Arcaroli, John / Rudek, Michelle A / Dasari, Arvind / Blatchford, Patrick J / Quackenbush, Kevin / Messersmith, Wells. ·Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St. CRB1-4M08, Baltimore, MD, 21287, USA, adejesu1@jhmi.edu. ·Invest New Drugs · Pubmed #24668033.

ABSTRACT: PURPOSE: The notch pathway is overexpressed in pancreatic adenocarcinoma. RO4929097, an oral inhibitor of the γ-secretase enzyme has been safely given as a single agent in patients with advanced solid tumors. We aimed to evaluate the efficacy of RO4929097 in patients with pancreatic adenocarcinoma (PDA). METHODS: A two-stage, single-arm Phase II trial was conducted in patients with previously treated metastatic PDA. RO4929097 was administered at a dose of 20 mg daily on days 1-3, 8-10 and 15-17 of 21-day cycles. The primary endpoint was survival at 6 months. Secondary endpoints included overall survival (OS), response rate, toxicities, pharmacokinetic and pharmacodynamic analyses. RESULTS: Eighteen patients were recruited, 17 in the first stage and one in the 2nd stage. It was decided to stop further enrollment after RO4929097 was discontinued by the sponsor and was no longer a development candidate. Three (25 %) of 12 evaluable patients achieved stable disease. The 6-month survival rate was 27.8 % (95 % CI 9.7-53.5). The median OS was 4.1 months (95 % CI 2.7-5.8 months) and median progression-free survival was 1.5 months (95 % CI 1.3-1.6 months). Pharmacokinetic properties of RO4929097 in patients (n = 5) with PDA was similar to that previously reported in other patient populations. There was a trend towards a decrease in HeyL (p = 0.08) gene expression in three patients following study drug administration. CONCLUSIONS: RO4929097 was well-tolerated in patients with previously treated PDA. Development of RO4929097 has been discontinued, but development of other notch-targeting agents in pancreatic cancer is continuing.

5 Clinical Trial Phase 2 study of erlotinib combined with adjuvant chemoradiation and chemotherapy in patients with resectable pancreatic cancer. 2013

Herman, Joseph M / Fan, Katherine Y / Wild, Aaron T / Hacker-Prietz, Amy / Wood, Laura D / Blackford, Amanda L / Ellsworth, Susannah / Zheng, Lei / Le, Dung T / De Jesus-Acosta, Ana / Hidalgo, Manuel / Donehower, Ross C / Schulick, Richard D / Edil, Barish H / Choti, Michael A / Hruban, Ralph H / Pawlik, Timothy M / Cameron, John L / Laheru, Daniel A / Wolfgang, Christopher L. ·Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland 21231, USA. jherma15@jhmi.edu ·Int J Radiat Oncol Biol Phys · Pubmed #23773391.

ABSTRACT: PURPOSE: Long-term survival rates for patients with resected pancreatic ductal adenocarcinoma (PDAC) have stagnated at 20% for more than a decade, demonstrating the need to develop novel adjuvant therapies. Gemcitabine-erlotinib therapy has demonstrated a survival benefit for patients with metastatic PDAC. Here we report the first phase 2 study of erlotinib in combination with adjuvant chemoradiation and chemotherapy for resected PDAC. METHODS AND MATERIALS: Forty-eight patients with resected PDAC received adjuvant erlotinib (100 mg daily) and capecitabine (800 mg/m(2) twice daily Monday-Friday) concurrently with intensity modulated radiation therapy (IMRT), 50.4 Gy over 28 fractions followed by 4 cycles of gemcitabine (1000 mg/m(2) on days 1, 8, and 15 every 28 days) and erlotinib (100 mg daily). The primary endpoint was recurrence-free survival (RFS). RESULTS: The median follow-up time was 18.2 months (interquartile range, 13.8-27.1). Lymph nodes were positive in 85% of patients, and margins were positive in 17%. The median RFS was 15.6 months (95% confidence interval [CI], 13.4-17.9), and the median overall survival (OS) was 24.4 months (95% CI, 18.9-29.7). Multivariate analysis with adjustment for known prognostic factors showed that tumor diameter >3 cm was predictive for inferior RFS (hazard ratio, 4.01; P=.001) and OS (HR, 4.98; P=.02), and the development of dermatitis was associated with improved RFS (HR, 0.27; P=.009). During CRT and post-CRT chemotherapy, the rates of grade 3/4 toxicity were 31%/2% and 35%/8%, respectively. CONCLUSION: Erlotinib can be safely administered with adjuvant IMRT-based CRT and chemotherapy. The efficacy of this regimen appears comparable to that of existing adjuvant regimens. Radiation Therapy Oncology Group 0848 will ultimately determine whether erlotinib produces a survival benefit in patients with resected pancreatic cancer.

6 Clinical Trial Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer. 2011

Villarroel, Maria C / Rajeshkumar, N V / Garrido-Laguna, Ignacio / De Jesus-Acosta, Ana / Jones, Siân / Maitra, Anirban / Hruban, Ralph H / Eshleman, James R / Klein, Alison / Laheru, Daniel / Donehower, Ross / Hidalgo, Manuel. ·Corresponding Author: Manuel Hidalgo, Clinical Research Program, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro, 3, 28029, Madrid, Spain. ·Mol Cancer Ther · Pubmed #21135251.

ABSTRACT: Metastasis and drug resistance are the major causes of mortality in patients with pancreatic cancer. Once developed, the progression of pancreatic cancer metastasis is virtually unstoppable with current therapies. Here, we report the remarkable clinical outcome of a patient with advanced, gemcitabine-resistant, pancreatic cancer who was later treated with DNA damaging agents, on the basis of the observation of significant activity of this class of drugs against a personalized xenograft generated from the patient's surgically resected tumor. Mitomycin C treatment, selected on the basis of its robust preclinical activity in a personalized xenograft generated from the patient's tumor, resulted in long-lasting (36+ months) tumor response. Global genomic sequencing revealed biallelic inactivation of the gene encoding PalB2 protein in this patient's cancer; the mutation is predicted to disrupt BRCA1 and BRCA2 interactions critical to DNA double-strand break repair. This work suggests that inactivation of the PALB2 gene is a determinant of response to DNA damage in pancreatic cancer and a new target for personalizing cancer treatment. Integrating personalized xenografts with unbiased exomic sequencing led to customized therapy, tailored to the genetic environment of the patient's tumor, and identification of a new biomarker of drug response in a lethal cancer.

7 Article The Significance of Ascites in Patients With Pancreatic Ductal Adenocarcinoma: A Case-Control Study. 2019

Baretti, Marina / Pulluri, Bhargavi / Tsai, Hua-Ling / Blackford, Amanda L / Wolfgang, Christopher L / Laheru, Daniel / Zheng, Lei / Herman, Joseph / Le, Dung T / Narang, Amol K / de Jesus-Acosta, Ana. ·Department of Medicine, The University of Vermont Medical Center, Burlington, VT. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, The Johns Hopkins Biostatistics Center. · Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD. · Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. · Departments of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, MD. ·Pancreas · Pubmed #30817723.

ABSTRACT: OBJECTIVE: Limited data exist on the impact of ascites in pancreatic ductal adenocarcinoma (PDAC). We evaluated the survival outcomes of patients with PDAC and ascites. METHODS: Retrospective, single-institution, case-control study including patients with newly diagnosed PDAC from 2007 to 2016. One hundred fifty-four patients with ascites at diagnosis (case group) and 154 controls were matched on age, sex, stage, Eastern Cooperative Oncology Group performance, surgical treatment, lymph node, and margin status. Ascites was defined as computed tomography-detected fluid in the pelvic/peritoneal cavity. Overall survival was compared between groups via Cox proportional hazards models with a gamma frailty term to account for the correlation between matched pairs on entire cohort and by disease stages for subgroup analysis. RESULTS: The 154 matched cases included 24 resectable, 19 borderline resectable, 51 locally advanced, and 60 metastatic disease. Patients with ascites had higher risk of death compared with those without (conditional hazard ratio, 1.58; 95% confidence interval, 1.23-2.03; P < 0.001). Stratified analysis showed a significant association between ascites and poor prognosis in patients with localized disease (conditional hazard ratio, 1.62; 95% confidence interval, 1.18-2.24; P = 0.003). CONCLUSIONS: Radiographic ascites is a poor prognostic factor in PDAC. Our findings may aid physicians in considering systemic therapy prior to attempting local treatments.

8 Article Multiplex Proximity Ligation Assay to Identify Potential Prognostic Biomarkers for Improved Survival in Locally Advanced Pancreatic Cancer Patients Treated With Stereotactic Body Radiation Therapy. 2018

Rao, Avani D / Liu, Yufei / von Eyben, Rie / Hsu, Charles C / Hu, Chen / Rosati, Lauren M / Parekh, Arti / Ng, Kendall / Hacker-Prietz, Amy / Zheng, Lei / Pawlik, Timothy M / Laheru, Daniel A / Jaffee, Elizabeth M / Weiss, Matthew J / Le, Dung T / Hruban, Ralph H / De Jesus-Acosta, Ana / Wolfgang, Christopher L / Narang, Amol K / Chang, Daniel T / Koong, Albert C / Herman, Joseph M. ·Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address: avani.rao@jhmi.edu. · Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California. · Department of Radiation Oncology, University of Arizona Cancer Center, Tucson, Arizona. · Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Division of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Division of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. ·Int J Radiat Oncol Biol Phys · Pubmed #29157747.

ABSTRACT: PURPOSE: To explore seromarker levels for associations with outcomes in locally advanced pancreatic cancer (LAPC) patients who received chemotherapy and stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: Serum from LAPC patients in 2 prospective trials of hypofractionated SBRT (5-6.6 Gy × 5) was collected before SBRT. Proximity ligation assay quantified the expression levels of 36 pancreatic cancer-specific candidate seromarkers: Axl, BMP2, CA 125, CA 19-9, CEA, CXCL-1/6/9/10, EGFR, Gas6, Her2, IGF-2, IGFBP-2/3/7, IL-6/6Ra/7/8/12, mesothelin, MMP-1/2/3/7, osteopontin, PDGFRa, PDK1, PF4, RegIV, SPARC, TGF-β, VEGF-A/D, and YKL40. Seromarker values were log transformed owing to log-normal distribution of the values, and Cox regression analysis was performed to assess for any association with overall survival. The Benjamini-Hochberg method was used to control for a false discovery rate (FDR) of only 10%. RESULTS: Sixty-four patients with LAPC were included. No clinical factors (including surgical resection, receipt of pre-SBRT chemotherapy, receipt of post-SBRT chemotherapy, performance status, and age) or potential biomarkers in the panel were associated with improved survival in this cohort after application of the FDR correction. Potential prognostic factors for improved survival for future investigation included surgical resection (P=.007, adjusted P=.153) and the serum expression of IL-8 (P=.006, adjusted P=.153), CA 19-9 (P=.031, adjusted P=.377), and MMP-1 (P=.036, adjusted P=.377). CONCLUSIONS: These data explore the expression of a panel of proteins in pre-SBRT serum of LAPC patients in the context of a conservative FDR correction. None of the clinical factors or expression levels of the serum proteins were found to be associated with survival; however, IL-8, CA 19-9, and MMP-1 were highlighted as possible candidates warranting inclusion in future seromarker studies in the ongoing efforts to identify tools for risk stratification and treatment allocation in LAPC.

9 Article Long-term survival benefit of upfront chemotherapy in patients with newly diagnosed borderline resectable pancreatic cancer. 2017

Shrestha, Bikram / Sun, Yifei / Faisal, Farzana / Kim, Victoria / Soares, Kevin / Blair, Alex / Herman, Joseph M / Narang, Amol / Dholakia, Avani S / Rosati, Lauren / Hacker-Prietz, Amy / Chen, Linda / Laheru, Daniel A / De Jesus-Acosta, Ana / Le, Dung T / Donehower, Ross / Azad, Nilofar / Diaz, Luis A / Murphy, Adrian / Lee, Valerie / Fishman, Elliot K / Hruban, Ralph H / Liang, Tingbo / Cameron, John L / Makary, Martin / Weiss, Matthew J / Ahuja, Nita / He, Jin / Wolfgang, Christopher L / Huang, Chiung-Yu / Zheng, Lei. ·Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. · Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Radiation Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Radiation Oncology, M.D. Anderson Cancer Center, Houston, Texas. · Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland. · The Second Affiliated Hospital of Zhejiang University, Hangzhou, China. ·Cancer Med · Pubmed #28639410.

ABSTRACT: The use of neoadjuvant chemotherapy or radiation for borderline resectable pancreatic adenocarcinoma (BL-PDAC) is increasing. However, the impact of neoadjuvant chemotherapy and radiation therapy on the outcome of BL-PDAC remains to be elucidated. We performed a retrospective analysis of 93 consecutive patients who were diagnosed with BL-PDAC and primarily followed at Johns Hopkins Hospital between February 2007 and December 2012. Among 93 patients, 62% received upfront neoadjuvant chemotherapy followed by chemoradiation, whereas 20% received neoadjuvant chemoradiation alone and 15% neoadjuvant chemotherapy alone. Resectability following all neoadjuvant therapy was 44%. Patients who underwent resection with a curative intent had a median overall survival (mOS) of 25.8 months, whereas those who did not undergo surgery had a mOS of 11.9 months. However, resectability and overall survival were not significantly different between the three types of neoadjuvant therapy. Nevertheless, 22% (95% CI, 0.13-0.36) of the 58 patients who received upfront chemotherapy followed by chemoradiation remained alive for a minimum of 48 months compared to none of the 19 patients who received upfront chemoradiation. Among patients who underwent curative surgical resection, 32% (95% CI, 0.19-0.55) of those who received upfront chemotherapy remained disease free at least 48 months following surgical resection, whereas none of the eight patients who received upfront chemoradiation remained disease free beyond 24 months following surgical resection. Neoadjuvant therapy with upfront chemotherapy may result in long-term survival in a subpopulation of patients with BL-PDAC.

10 Article Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer. 2017

Yarchoan, Mark / Myzak, Melinda C / Johnson, Burles A / De Jesus-Acosta, Ana / Le, Dung T / Jaffee, Elizabeth M / Azad, Nilofer S / Donehower, Ross C / Zheng, Lei / Oberstein, Paul E / Fine, Robert L / Laheru, Daniel A / Goggins, Michael. ·The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA. · Columbia University Medical Center, New York, NY, USA. ·Oncotarget · Pubmed #28454122.

ABSTRACT: BACKGROUND: Olaparib is an oral inhibitor of polyadenosine 5'-diphosphoribose polymerization (PARP) that has previously shown signs of activity in patients with BRCA mutations and pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: In this phase 1 dose-escalation trial in patients with unresectable PDAC, we determined the maximum tolerated dose (MTD) of olaparib (tablet formulation) in combination with irinotecan 70 mg/m2 on days 1 and 8 and cisplatin 25 mg/m2 on days 1 and 8 of a 28-day cycle (olaparib plus IC). We then studied the safety and tolerability of adding mitomycin C 5 mg/m2 on day 1 to this regimen (olaparib plus ICM). RESULTS: 18 patients with unresectable PDAC were enrolled. The MTD of olaparib plus IC was olaparib 100 mg twice-daily on days 1 and 8. The addition of mitomycin C to this dose level was not tolerated. Grade ≥3 drug-related adverse events (AEs) were encountered in 16 patients (89%). The most common grade ≥3 drug-related toxicities included neutropenia (89%), lymphopenia (72%), and anemia (22%). Two patients (11%), both of whom had remained on study for more than 12 cycles, developed drug-related myelodysplastic syndrome (MDS). The objective response rate (ORR) for all evaluable patients was 23%. One patient who carried a deleterious germline BRCA2 mutation had a durable clinical response lasting more than four years, but died from complications of treatment-related MDS. CONCLUSIONS: Olaparib had substantial toxicity when combined with IC or ICM in patients with PDAC, and this treatment combination did not have an acceptable risk/benefit profile for further study. However, durable clinical responses were observed in a subset of patients and further clinical investigation of PARP inhibitors in PDAC is warranted. TRIAL REGISTRATION: This clinical trial was registered on ClinicalTrials.gov as NCT01296763.

11 Article A new immunohistochemistry prognostic score (IPS) for recurrence and survival in resected pancreatic neuroendocrine tumors (PanNET). 2016

Viúdez, Antonio / Carvalho, Filipe L F / Maleki, Zahra / Zahurak, Marianna / Laheru, Daniel / Stark, Alejandro / Azad, Nilofer S / Wolfgang, Christopher L / Baylin, Stephen / Herman, James G / De Jesus-Acosta, Ana. ·Department of Medical Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. · Department of Medical Oncology, Complejo Hospitalario de Navarra-Instituto de Investigaciones Sanitarias de Navarra-IDISNA, Pamplona, Navarra, Spain. · Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. · The Division of Biostatistics and Bioinformatics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ·Oncotarget · Pubmed #26894863.

ABSTRACT: Pancreatic neuroendocrine tumor (PanNET) is a neoplastic entity in which few prognostic factors are well-known. Here, we aimed to evaluate the prognostic significance of N-myc downstream-regulated gen-1 (NDRG-1), O6-methylguanine DNA methyltransferase (MGMT) and Pleckstrin homology-like domain family A member 3 (PHLDA-3) by immunohistochemistry (IHC) and methylation analysis in 92 patients with resected PanNET and follow-up longer than 24 months. In multivariate analyses, ki-67 and our immunohistochemistry prognostic score (IPS-based on MGMT, NDRG-1 and PHLDA-3 IHC expression) were independent prognostic factors for disease-free-survival (DFS), while age and IPS were independent prognostic factors for overall survival (OS). Our IPS could be a useful prognostic biomarker for recurrence and survival in patients following resection for PanNET.

12 Article Longer Course of Induction Chemotherapy Followed by Chemoradiation Favors Better Survival Outcomes for Patients With Locally Advanced Pancreatic Cancer. 2016

Faisal, Farzana / Tsai, Hua-Ling / Blackford, Amanda / Olino, Kelly / Xia, Chang / De Jesus-Acosta, Ana / Le, Dung T / Cosgrove, David / Azad, Nilofer / Rasheed, Zeshaan / Diaz, Luis A / Donehower, Ross / Laheru, Daniel / Hruban, Ralph H / Fishman, Elliot K / Edil, Barish H / Schulick, Richard / Wolfgang, Christopher / Herman, Joseph / Zheng, Lei. ·*Departments of Oncology, Surgery, and Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD †Department of Surgery, University of Colorado School of Medicine, Denver, CO. ·Am J Clin Oncol · Pubmed #24351782.

ABSTRACT: OBJECTIVES: At diagnosis, 30% of patients with pancreatic cancer are unresectable stage 3 locally advanced. The standard treatment for locally advanced pancreatic cancer (LAPC) is not defined. The current study was conducted to assess the roles of chemotherapy and chemoradiation for LAPC treatment. MATERIALS AND METHODS: Between June 2006 and March 2011, 100 patients with LAPC were treated at the Johns Hopkins Hospital. Retrospective analysis was performed to compare cumulative incidence of progression (CIP) and overall survival (OS) among different subgroups. RESULTS: For the 100 patients, the median OS was 15.8 months and the median CIP was 8.4 months. The combination of chemotherapy and chemoradiation before disease progression was significantly associated with improved CIP (P=0.001) and improved OS when compared with chemoradiation alone (median OS: 16.4 vs. 11.1 mo, P=0.03). Among patients receiving combination treatment, patients who received chemotherapy first followed by chemoradiation had a trend toward lower CIP (P=0.09) and improved OS (median OS: 18.1 vs. 11.0 mo, P=0.09). Patients who received >2 cycles of chemotherapy before chemoradiation had a significantly decreased CIP (P=0.008) and a trend toward better OS (median OS: 19.4 vs. 15.7 mo, P=0.10). On multivariate analysis, receiving >2 cycles of chemotherapy before chemoradiation was associated with improved CIP. CONCLUSIONS: Although combination chemotherapy and chemoradiation is favored in the treatment of LAPC, longer induction chemotherapy may play a more important role in sensitization of tumors to subsequent chemoradiation. Our results support treating patients with induction chemotherapy for at least 3 cycles followed by consolidative chemoradiation. These results merit further validation by a prospective study.

13 Article Resected pancreatic ductal adenocarcinomas with recurrence limited in lung have a significantly better prognosis than those with other recurrence patterns. 2015

Wangjam, Tamna / Zhang, Zhe / Zhou, Xian Chong / Lyer, Laxmi / Faisal, Farzana / Soares, Kevin C / Fishman, Elliott / Hruban, Ralph H / Herman, Joseph M / Laheru, Daniel / Weiss, Matthew / Li, Min / De Jesus-Acosta, Ana / Wolfgang, Christopher L / Zheng, Lei. ·Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Division of Hematology and Oncology, University of Texas Health Science Center, San Antonio, TX, USA. · The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Division of Hematology and Oncology, University of Maryland School of Medicine, Baltimore, MD, USA. · Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · The Skip Viragh Center for Pancreatic Cancer, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · University of Oklahoma Health Science Center, Oklahoma City, OK, USA. ·Oncotarget · Pubmed #26372811.

ABSTRACT: The majority of patients with curative resection of pancreatic ductal adenocarcinoma recur within 5 years of resection. However, the prognosis associated with different patterns of recurrence has not been well studied. A retrospective review of patients who underwent curative surgical resection of pancreatic cancer was performed. Of the 209 patients, 174 patients developed recurrent disease. Of these 174, 28(16.1%) had recurrent disease limited to lung metastases, 20(11.5%) had recurrence in the lung plus one or more other sites excluding the liver, 73(42.0%) had liver metastasis alone or liver metastasis with any other site except lung, 28(16.1%) local recurrence only, and 25(14.3%) peritoneal recurrence alone or together with local recurrence. Patients with recurrence limited to lung had a 8.5 months(Mo) median survival from recurrence to death, which was significantly better than the survival associated with recurrence in the liver(5.1Mo), in the peritoneum(2.3Mo) or locally(5.1Mo) in multivariable analyses. Among all groups, the time from surgery to the diagnosis of recurrence in patients who recurred in only in the lung was also the longest. However, 75% of patients were found to have indeterminate lung nodules on their surveillance CT scans prior to the diagnosis of recurrence in lung. This delayed diagnosis of lung recurrence may have a negative impact on survival after recurrence. In conclusion, pancreatic cancer with lung recurrence has a significantly better prognosis than recurrence in other sites. Further studies are needed to investigate how different diagnostic and treatment modalities affect the survival of this unique subpopulation of pancreatic cancer patients.

14 Article Efficacy of platinum chemotherapy agents in the adjuvant setting for adenosquamous carcinoma of the pancreas. 2015

Wild, Aaron T / Dholakia, Avani S / Fan, Katherine Y / Kumar, Rachit / Moningi, Shalini / Rosati, Lauren M / Laheru, Daniel A / Zheng, Lei / De Jesus-Acosta, Ana / Ellsworth, Susannah G / Hacker-Prietz, Amy / Voong, Khinh R / Tran, Phuoc T / Hruban, Ralph H / Pawlik, Timothy M / Wolfgang, Christopher L / Herman, Joseph M. ·The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. ·J Gastrointest Oncol · Pubmed #25830031.

ABSTRACT: BACKGROUND: Pancreatic adenosquamous carcinoma (PASC) accounts for only 1-4% of all exocrine pancreatic cancers and carries a particularly poor prognosis. This retrospective study was performed to determine whether inclusion of a platinum agent as part of adjuvant therapy is associated with improved survival in patients with resected PASC. METHODS: Records of all patients who underwent pancreatic resection at Johns Hopkins Hospital from 1986 to 2012 were reviewed to identify those with PASC. Multivariable Cox proportional hazards modeling was used to assess for significant associations between patient characteristics and survival. RESULTS: In total, 62 patients (1.1%) with resected PASC were identified among 5,627 cases. Median age was 68 [interquartile range (IQR), 57-77] and 44% were female. Multivariate analysis revealed that, among all patients (n=62), the following factors were independently predictive of poor survival: lack of adjuvant therapy [hazard ratio (HR) =3.6; 95% confidence interval (CI), 1.8-7.0; P<0.001], margin-positive resection (HR =3.5; 95% CI, 1.8-6.8; P<0.001), lymph node involvement (HR =3.5; 95% CI, 1.5-8.2; P=0.004), and age (HR =1.0; 95% CI, 1.0-1.1; P=0.035). There were no significant differences between patients who did and did not receive adjuvant therapy following resection (all P>0.05). A second multivariable model included only those patients who received adjuvant therapy (n=39). Lack of inclusion of a platinum agent in the adjuvant regimen (HR =2.4; 95% CI, 1.0-5.8; P=0.040) and larger tumor diameter (HR =1.3; 95% CI, 1.0-1.6; P=0.047) were independent predictors of inferior survival. CONCLUSIONS: Addition of a platinum agent to adjuvant regimens for resected PASC may improve survival among these high-risk patients, though collaborative prospective investigation is needed.

15 Article The prognostic value of stroma in pancreatic cancer in patients receiving adjuvant therapy. 2015

Bever, Katherine M / Sugar, Elizabeth A / Bigelow, Elaine / Sharma, Rajni / Laheru, Daniel / Wolfgang, Christopher L / Jaffee, Elizabeth M / Anders, Robert A / De Jesus-Acosta, Ana / Zheng, Lei. ·Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ·HPB (Oxford) · Pubmed #25250696.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is comprised of a prominent desmoplastic stromal compartment and only 10-40% of the tumour consists of PDA cells. However, how stromal components should be assessed and how the characteristics of the stromal compartment determine clinical outcomes in PDA patients remain unknown. METHOD: A cohort of 66 consecutive patients who underwent pancreaticoduodenectomy and were primarily followed at Johns Hopkins Hospital between 1998 and 2004, and treated with adjuvant therapy, were included in a retrospective analysis. Resected PDA blocks with good tissue preservation were available for all patients. A new, computer-aided, quantitative method was developed to assess the density and activity of stroma in PDAs and the associations of these characteristics with clinical outcomes. RESULTS: High stromal density in resected PDA was found to be significantly associated with longer disease-free [adjusted hazard ratio (aHR) 0.39; P = 0.001] and overall (aHR 0.44; P = 0.004) survival after adjusting for the use of pancreatic cancer vaccine therapy, as well as gender and resection margin positivity. Stromal activity, representing activated pancreatic stellate cells in PDAs, was not significantly associated with the prognosis of resected PDAs. CONCLUSIONS: These results illustrate the complexity of the role of stroma in PDAs. Further exploration of the prognostic ability of the characteristics of stroma is warranted.

16 Article PAK1 mediates pancreatic cancer cell migration and resistance to MET inhibition. 2014

Zhou, Wei / Jubb, Adrian M / Lyle, Karen / Xiao, Qian / Ong, Christy C / Desai, Rupal / Fu, Ling / Gnad, Florian / Song, Qinghua / Haverty, Peter M / Aust, Daniela / Grützmann, Robert / Romero, Mally / Totpal, Klara / Neve, Richard M / Yan, Yibing / Forrest, William F / Wang, Yulei / Raja, Rajiv / Pilarsky, Christian / de Jesus-Acosta, Ana / Belvin, Marcia / Friedman, Lori S / Merchant, Mark / Jaffee, Elizabeth M / Zheng, Lei / Koeppen, Hartmut / Hoeflich, Klaus P. ·Department of Translational Oncology, Genentech, Inc, South San Francisco, CA 94080, USA. ·J Pathol · Pubmed #25074413.

ABSTRACT: Pancreatic adenocarcinoma (PDAC) is a major unmet medical need and a deeper understanding of molecular drivers is needed to advance therapeutic options for patients. We report here that p21-activated kinase 1 (PAK1) is a central node in PDAC cells downstream of multiple growth factor signalling pathways, including hepatocyte growth factor (HGF) and MET receptor tyrosine kinase. PAK1 inhibition blocks signalling to cytoskeletal effectors and tumour cell motility driven by HGF/MET. MET antagonists, such as onartuzumab and crizotinib, are currently in clinical development. Given that even highly effective therapies have resistance mechanisms, we show that combination with PAK1 inhibition overcomes potential resistance mechanisms mediated either by activation of parallel growth factor pathways or by direct amplification of PAK1. Inhibition of PAK1 attenuated in vivo tumour growth and metastasis in a model of pancreatic adenocarcinoma. In human tissues, PAK1 is highly expressed in a proportion of PDACs (33% IHC score 2 or 3; n = 304) and its expression is significantly associated with MET positivity (p < 0.0001) and linked to a widespread metastatic pattern in patients (p = 0.067). Taken together, our results provide evidence for a functional role of MET/PAK1 signalling in pancreatic adenocarcinoma and support further characterization of therapeutic inhibitors in this indication.

17 Article Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. 2014

Özdemir, Berna C / Pentcheva-Hoang, Tsvetelina / Carstens, Julienne L / Zheng, Xiaofeng / Wu, Chia-Chin / Simpson, Tyler R / Laklai, Hanane / Sugimoto, Hikaru / Kahlert, Christoph / Novitskiy, Sergey V / De Jesus-Acosta, Ana / Sharma, Padmanee / Heidari, Pedram / Mahmood, Umar / Chin, Lynda / Moses, Harold L / Weaver, Valerie M / Maitra, Anirban / Allison, James P / LeBleu, Valerie S / Kalluri, Raghu. ·Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA. · Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. · Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. · Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. · Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA. · Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. · Department of Medical Oncology, Johns Hopkins Hospital, Baltimore, MD 21287, USA. · Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA. · Departments of Pathology and Translational Molecular Pathology, Ahmad Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA. Electronic address: rkalluri@mdanderson.org. ·Cancer Cell · Pubmed #24856586.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal myofibroblasts, but their functional contribution remains unknown. Transgenic mice with the ability to delete αSMA(+) myofibroblasts in pancreatic cancer were generated. Depletion starting at either noninvasive precursor (pancreatic intraepithelial neoplasia) or the PDAC stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-mesenchymal transition, and cancer stem cells, with diminished animal survival. In PDAC patients, fewer myofibroblasts in their tumors also correlated with reduced survival. Suppressed immune surveillance with increased CD4(+)Foxp3(+) Tregs was observed in myofibroblast-depleted mouse tumors. Although myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival. This study underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC.

18 Article Baseline hemoglobin-A1c impacts clinical outcomes in patients with pancreatic cancer. 2014

Fan, Katherine Y / Dholakia, Avani S / Wild, Aaron T / Su, Zheng / Hacker-Prietz, Amy / Kumar, Rachit / Hodgin, Mary / Hsu, Charles C / Le, Dung T / De Jesus-Acosta, Ana / Diaz, Luis A / Laheru, Daniel A / Hruban, Ralph H / Fishman, Elliot K / Brown, Todd D / Pawlik, Timothy M / Wolfgang, Christopher L / Tran, Phuoc T / Herman, Joseph M. ·From the aDepartment of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; bDepartment of Statistics, Stanford University, Palo Alto, California; cDepartment of Radiation Oncology, University of California San Francisco, San Francisco, California; and dDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, eDepartment of Pathology, The Sol Goldman Pancreatic Cancer Research Center, fRussell H. Morgan Department of Radiology and Radiological Sciences, gDivision of Endocrinology and Metabolism, Department of Internal Medicine, and hDepartment of Surgery, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. ·J Natl Compr Canc Netw · Pubmed #24453292.

ABSTRACT: An association between diabetes mellitus and pancreatic ductal adenocarcinoma (PDA) has long been recognized. This article assesses the effect of the baseline hemoglobin-A1c (HbA1c) value on the clinical outcomes of patients with PDA. HbA1c values were prospectively collected on 656 consecutive patients presenting to a pancreas multidisciplinary cancer clinic from 2009 to 2012. Patients were diagnosed with benign pancreatic disease (BPD) or biopsy-confirmed resectable (R), borderline/locally advanced (BL), or metastatic (M) PDA. Excluded were those with prior treatment for PDA or a history of chronic diabetes mellitus (>1-year or unknown duration), resulting in a final cohort of 284 patients. Of 284 patients, 44 had benign disease, 62 had R-PDA, 115 had BL-PDA, and 63 had M-PDA. Patients with malignant disease (R-, BL-, and M-PDA) collectively had a higher average HbA1c value than patients with BPD (6.1% vs 5.6%; P<.001). Among patients with PDA (n=240), HbA1c values of 6.5% or greater were significantly associated with inferior overall survival (OS) compared with patients with HbA1c values less than 6.5% (hazard ratio [HR], 1.74; OS, 10.2 vs 13.0 months; P=.007), along with other known prognostic factors, such as age of 65 years or older, ECOG performance status of 1 or greater, carbohydrate antigen 19-9 level greater than 90, tumor size larger than 3 cm, and disease stage. HbA1c values of 6.5% or greater remained in the final predictive model using backward elimination (HR, 1.46; P=.097), indicating that HbA1c values of 6.5% or greater influence OS of patients with PDA even when accounting for other known prognostic factors. HbA1c level at presentation is significantly higher in patients with PDA than patients with BPD and seems to affect survival.

19 Article Resection of borderline resectable pancreatic cancer after neoadjuvant chemoradiation does not depend on improved radiographic appearance of tumor-vessel relationships. 2013

Dholakia, Avani S / Hacker-Prietz, Amy / Wild, Aaron T / Raman, Siva P / Wood, Laura D / Huang, Peng / Laheru, Daniel A / Zheng, Lei / De Jesus-Acosta, Ana / Le, Dung T / Schulick, Richard / Edil, Barish / Ellsworth, Susannah / Pawlik, Timothy M / Iacobuzio-Donahue, Christine A / Hruban, Ralph H / Cameron, John L / Fishman, Elliot K / Wolfgang, Christopher L / Herman, Joseph M. ·Department of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, 401 N. Broadway, Weinberg Suite 1440, Baltimore, MD 21231, USA. · Department of Radiology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 601 N. Broadway, Baltimore, MD 21231, USA. · Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 401 N. Broadway, Weinberg Suite 2242, Baltimore, MD 21231, USA. · Department of Oncology Biostatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 550 N. Broadway, Suite 1103, Baltimore, MD 21205, USA. · Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St., Baltimore, MD 21287, USA. · Department of Surgery, University of Colorado, 12631 E. 17th Avenue, Suite 6117, Aurora, CO 80045, USA. · Department of Surgery, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287, USA. ·J Radiat Oncol · Pubmed #25755849.

ABSTRACT: OBJECTIVE: Neoadjuvant therapy increases rates of margin-negative resection of borderline resectable pancreatic ductal adenocarcinoma (BL-PDAC). Criteria for BL-PDAC resection following neoadjuvant chemotherapy and radiation therapy (NCRT) have not been clearly defined. METHODS: Fifty consecutive patients with BL-PDAC who received NCRT from 2007 to 2012 were identified. Computed tomography (CT) scans pre- and post-treatment were centrally reviewed. RESULTS: Twenty-nine patients (58 %) underwent resection following NCRT, while 21 (42 %) remained unresected. Patients selected for and successfully undergoing resection were more likely to have better performance status and absence of the following features on pre- and post-treatment CT: superior mesenteric vein/portal vein encasement, superior mesenteric artery involvement, tumor involvement of two or more vessels, and questionable/overt metastases (all CONCLUSION: Apparent radiographic extent of vascular involvement does not change significantly after NCRT. Patients without metastatic disease should be chosen for surgical exploration based on adequate performance status and lack of disease progression.

20 Article Molecular determinants of retinoic acid sensitivity in pancreatic cancer. 2012

Gupta, Sonal / Pramanik, Dipankar / Mukherjee, Radha / Campbell, Nathaniel R / Elumalai, Sathyanarayanan / de Wilde, Roeland F / Hong, Seung-Mo / Goggins, Michael G / De Jesus-Acosta, Ana / Laheru, Daniel / Maitra, Anirban. ·Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ·Clin Cancer Res · Pubmed #22010213.

ABSTRACT: PURPOSE: To identify a predictive molecular "signature" for sensitivity to retinoic acid in pancreatic cancer. EXPERIMENTAL DESIGN: Fourteen patient-derived, low-passage pancreatic ductal adenocarcinoma (PDAC) lines with varied expression of fatty acid-binding protein 5 (FABP5) and cellular retinoic acid-binding protein 2 (CRABP2) were used to evaluate the response to all-trans retinoic acid (ATRA). Cell proliferation, apoptosis, and migration/invasion assays were used to measure the in vitro response. Tumor growth was monitored in subcutaneous xenografts in athymic nude mice for 4 weeks. RESULTS: Response to ATRA was observed to be dependent upon differential expression of FABP5 versus CRABP2. Thus, elevated FABP5 expression was associated with minimal cytotoxicity and tumor growth inhibition and a paradoxical increase in migration and invasion. Conversely, CRABP2 expression in the absence of FABP5 was associated with significant tumor growth inhibition with ATRA, even in gemcitabine-resistant tumors. The ATRA-resistant phenotype of FABP5(high)CRABP2(null) cells could be circumvented by ectopic expression of CRABP2. Alternatively, reexpression of endogenous CRABP2 could be enabled in FABP5(high)CRABP2(null) PDAC lines by exposure to decitabine and trichostatin A, thereby relieving epigenetic silencing of the CRABP2 gene promoter. Immunohistochemical staining for FABP5 in archival human tissue microarrays identifies a subset of cases (13 of 63, ~20%) which are negative for FABP5 expression and might be candidates for ATRA therapy. CONCLUSIONS: The widely used agent ATRA deserves a "second look" in PDAC, but needs to be targeted to patient subsets with biopsy-proven FABP5-negative tumors, or be combined with a chromatin-modifying agent to reexpress endogenous CRABP2.

21 Article A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma. 2012

De Jesus-Acosta, Ana / Oliver, George R / Blackford, Amanda / Kinsman, Katharine / Flores, Edna I / Wilfong, Lalan S / Zheng, Lei / Donehower, Ross C / Cosgrove, David / Laheru, Daniel / Le, Dung T / Chung, Ki / Diaz, Luis A. ·Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, CRB I, Room 590, Baltimore, MD 21231, USA. ·Cancer Chemother Pharmacol · Pubmed #21800112.

ABSTRACT: PURPOSE: Studies treating adenocarcinoma of the pancreas with gemcitabine alone or in combination with a doublet have demonstrated modest improvements in survival. Recent reports have suggested that using the triple-drug regimen FOLFIRINOX can substantially extend survival in patients with metastatic disease. We were interested in determining the clinical benefit of another three-drug regimen of gemcitabine, docetaxel and capecitabine (GTX) in patients with advanced pancreatic adenocarcinoma. PATIENTS AND METHODS: The cases of 154 patients, who received treatment with GTX chemotherapy with histologically confirmed locally advanced or metastatic pancreatic adenocarcinoma, were retrospectively reviewed. All demographic and clinical data were captured including prior therapy, adverse events, treatment response and survival. RESULTS: One hundred and seventeen metastatic and 37 locally advanced cases of adenocarcinoma of the pancreas were reviewed. Partial responses were noted in 11% of cases, and stable disease was observed in 62% of patients. Responses significantly correlated with toxicity (neutropenia, ALT elevation and hospitalizations). Grade 3 or greater hematologic and non-hematologic toxicities were noted in 41% and 9% of cases, respectively. Overall median survival was 11.6 months. Chemotherapy naïve patients with metastatic and locally advanced disease achieved a median survival of 11.3 and 25.0 months, respectively. CONCLUSIONS: We observe a substantial survival benefit with GTX chemotherapy in our cohort of patients with advanced pancreatic cancer. These findings warrant further investigation of this combination in this patient population.