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Pancreatic Neoplasms: HELP
Articles by Luis A. Diaz
Based on 15 articles published since 2010
(Why 15 articles?)
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Between 2010 and 2020, Luis A. Diaz wrote the following 15 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review The early detection of pancreatic cancer: what will it take to diagnose and treat curable pancreatic neoplasia? 2014

Lennon, Anne Marie / Wolfgang, Christopher L / Canto, Marcia Irene / Klein, Alison P / Herman, Joseph M / Goggins, Michael / Fishman, Elliot K / Kamel, Ihab / Weiss, Matthew J / Diaz, Luis A / Papadopoulos, Nickolas / Kinzler, Kenneth W / Vogelstein, Bert / Hruban, Ralph H. ·Authors' Affiliations: Departments of Medicine; Surgery; · Surgery; Pathology; Oncology; · Authors' Affiliations: Departments of Medicine; · Pathology; Oncology; Department of Epidemiology, the Bloomberg School of Public Health, Baltimore, Maryland. · Oncology; Radiation Oncology; and. · Authors' Affiliations: Departments of Medicine; Pathology; Oncology; · Radiology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine; and. · Surgery; · Oncology; · Pathology; Oncology; · Pathology; Oncology; rhruban@jhmi.edu. ·Cancer Res · Pubmed #24924775.

ABSTRACT: Pancreatic cancer is the deadliest of all solid malignancies. Early detection offers the best hope for a cure, but characteristics of this disease, such as the lack of early clinical symptoms, make the early detection difficult. Recent genetic mapping of the molecular evolution of pancreatic cancer suggests that a large window of opportunity exists for the early detection of pancreatic neoplasia, and developments in cancer genetics offer new, potentially highly specific approaches for screening of curable pancreatic neoplasia. We review the challenges of screening for early pancreatic neoplasia, as well as opportunities presented by incorporating molecular genetics into these efforts.

2 Review The clinical utility of biomarkers in the management of pancreatic adenocarcinoma. 2014

Jazieh, Khalid A / Foote, Michael B / Diaz, Luis A. ·The Swim Across America Laboratory, The Ludwig Center for Cancer Genetics and Therapeutics, Baltimore, MD; The Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD. ·Semin Radiat Oncol · Pubmed #24635863.

ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States and survival rates have seen minimal improvement over the past few decades. Although results are poor, surgical resection is considered the only curative therapeutic intervention for pancreatic cancer, thereby emphasizing the significance of effective diagnostic and prognostic tools to improve outcomes. As such, biomarkers play a promising role in the development of personalized treatments for patients with pancreatic cancer. Prognostic biomarkers, such as serum carbohydrate antigen 19-9 in particular, as well as cancer stem cell markers, provide valuable insight into the biological processes of an individual and their likely course of disease. This, consequently, allows for the assessment of optimal therapeutic intervention. Furthermore, current efforts target putative predictive biomarkers such as BRCA2, PALB2, and SPARC so as to determine their influence on tumor response on targeted therapies. As research progresses, more evidence will provide clinicians with guidelines on the utilization of biomarkers to accurately stage and tailor personalized treatment to the needs of specific patients with pancreatic cancer.

3 Clinical Trial Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. 2013

Le, Dung T / Lutz, Eric / Uram, Jennifer N / Sugar, Elizabeth A / Onners, Beth / Solt, Sara / Zheng, Lei / Diaz, Luis A / Donehower, Ross C / Jaffee, Elizabeth M / Laheru, Daniel A. ·The Sidney Kimmel Cancer Center, the Skip Viragh Center for Pancreatic Cancer, Research and Clinical Care, and the Sol Goldman Pancreatic Cancer Center at Johns Hopkins, Baltimore, MD, USA. dle2@jhmi.edu ·J Immunother · Pubmed #23924790.

ABSTRACT: Preclinical reports support the concept of synergy between cancer vaccines and immune checkpoint blockade in nonimmunogenic tumors. In particular, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibodies have been successfully combined with GM-CSF cell-based vaccines (GVAX). Ipilimumab (anti-CTLA-4) has been tested as a single agent in patients with pancreatic ductal adenocarcinoma (PDA) resulting in a delayed response at a dose of 3 mg/kg. Our study evaluated ipilimumab 10 mg/kg (arm 1) and ipilimumab 10 mg/kg + GVAX (arm 2). A total of 30 patients with previously treated advanced PDA were randomized (1:1). Induction doses were administered every 3 weeks for a total of 4 doses followed by maintenance dosing every 12 weeks. Two patients in arm 1 showed evidence of stable disease (7 and 22 wk) but none demonstrated CA19-9 biochemical responses. In contrast, 3 patients in arm 2 had evidence of prolonged disease stabilization (31, 71, and 81 wk) and 7 patients experienced CA19-9 declines. In 2 of these patients, disease stabilization occurred after an initial period of progression. The median overall survival (OS) (3.6 vs. 5.7 mo, hazards ratio: 0.51, P = 0.072) and 1 year OS (7 vs. 27%) favored arm 2. Similar to prior ipilimumab studies, 20% of patients in each arm had grade 3/4 immune-related adverse events. Among patients with OS > 4.3 months, there was an increase in the peak mesothelin-specific T cells (P = 0.014) and enhancement of the T-cell repertoire (P = 0.031). In conclusion, checkpoint blockade in combination with GVAX has the potential for clinical benefit and should be evaluated in a larger study.

4 Article Acquired resistance to immunotherapy in MMR-D pancreatic cancer. 2018

Hu, Zishuo Ian / Hellmann, Matthew D / Wolchok, Jedd D / Vyas, Monika / Shia, Jinru / Stadler, Zsofia K / Diaz, Luis A / O'Reilly, Eileen M. ·Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Division of Solid Tumor Oncology, New York, NY, USA. · Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering, New York, NY, USA. · Department of Medicine, Weill Cornell Medical College, New York, NY, USA. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA. · Department of Pathology, Weill Cornell Medical College, New York, NY, USA. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. oreillye@mskcc.org. · Division of Solid Tumor Oncology, New York, NY, USA. oreillye@mskcc.org. · Department of Medicine, Weill Cornell Medical College, New York, NY, USA. oreillye@mskcc.org. · David M. Rubenstein Center for Pancreatic Cancer Research, New York, NY, USA. oreillye@mskcc.org. ·J Immunother Cancer · Pubmed #30458888.

ABSTRACT: BACKGROUND: MMR-D pancreatic cancer have been reported to respond to checkpoint inhibitor therapy. Here, we report the first case of acquired resistance to immunotherapy in MMR-D pancreatic cancer. CASE PRESENTATION: A 45-year-old woman with unresectable MMR-D pancreatic cancer was initially treated with FOLFIRINOX, FOLFIRI, and stereotactic body radiation with stable disease burden. After 3 months, imaging showed progression of disease with an increase in CA19-9. She was subsequently enrolled in a clinical trial of an anti-PD-L1 antibody in combination with an IDO1 inhibitor. She demonstrated a partial response to therapy by RECIST 1.1 criteria with declining tumor markers. Twenty-two months after beginning immunotherapy, imaging revealed an increasing left ovarian cystic mass. There were no other sites of progressive disease. The patient underwent a total hysterectomy and bilateral salpingo-oophorectomy, appendectomy, omentectomy and pelvic lymphadenopathy. Pathology was consistent with a metastasis from the pancreas involving the endometrium and left ovary. Thereafter, the patient continued with PD-1 blockade therapy off protocol with no further progressive disease. Immune profiling showed high levels of CD8+ T cells and PD-1 positive immune cells infiltrating the tumor, with a moderate level of PD-L1 expression in both the immune cells and the tumor cells. Next generation sequencing found only the KRAS G12D and RNF43 G659Vfs*41 mutations were retained from the pre-treatment tumor in the treatment-resistant tumor. CONCLUSIONS: This is the first report describing acquired resistance to immunotherapy in MMR-D pancreatic cancer with accompanying genomic and immune profiling. This case of oligoprogression in the setting of immunotherapy demonstrates the feasibility of localized treatment followed by continuation of immunotherapy to sustain ongoing response.

5 Article Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations. 2018

Hu, Zishuo I / Shia, Jinru / Stadler, Zsofia K / Varghese, Anna M / Capanu, Marinela / Salo-Mullen, Erin / Lowery, Maeve A / Diaz, Luis A / Mandelker, Diana / Yu, Kenneth H / Zervoudakis, Alice / Kelsen, David P / Iacobuzio-Donahue, Christine A / Klimstra, David S / Saltz, Leonard B / Sahin, Ibrahim H / O'Reilly, Eileen M. ·Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Pathology, Weill Cornell Medical College, New York, New York. · Department of Medicine, Weill Cornell Medical College, New York, New York. · David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York. · Trinity College, Dublin, Ireland. · Emory University School of Medicine, Atlanta, Georgia. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. oreillye@mskcc.org. ·Clin Cancer Res · Pubmed #29367431.

ABSTRACT:

6 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.

7 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.

8 Article Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients. 2015

Sausen, Mark / Phallen, Jillian / Adleff, Vilmos / Jones, Siân / Leary, Rebecca J / Barrett, Michael T / Anagnostou, Valsamo / Parpart-Li, Sonya / Murphy, Derek / Kay Li, Qing / Hruban, Carolyn A / Scharpf, Rob / White, James R / O'Dwyer, Peter J / Allen, Peter J / Eshleman, James R / Thompson, Craig B / Klimstra, David S / Linehan, David C / Maitra, Anirban / Hruban, Ralph H / Diaz, Luis A / Von Hoff, Daniel D / Johansen, Julia S / Drebin, Jeffrey A / Velculescu, Victor E. ·The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. · Personal Genome Diagnostics Inc., Baltimore, Maryland 21224, USA. · The Translational Genomics Research Institute, Scottsdale, Arizona 85004, USA. · Mayo Clinic Arizona, Scottsdale, Arizona 85054, USA. · Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA. · Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. · Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. · School of Medicine and Dentistry, University of Rochester, Rochester, New York, 14642, USA. · Virginia Piper Cancer Center, Scottsdale Healthcare, Scottsdale, Arizona 85258, USA. · Department of Oncology and Medicine, Herlev Hospital, University of Copenhagen, Copenhagen 2730, Denmark. · Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ·Nat Commun · Pubmed #26154128.

ABSTRACT: Pancreatic adenocarcinoma has the worst mortality of any solid cancer. In this study, to evaluate the clinical implications of genomic alterations in this tumour type, we perform whole-exome analyses of 24 tumours, targeted genomic analyses of 77 tumours, and use non-invasive approaches to examine tumour-specific mutations in the circulation of these patients. These analyses reveal somatic mutations in chromatin-regulating genes MLL, MLL2, MLL3 and ARID1A in 20% of patients that are associated with improved survival. We observe alterations in genes with potential therapeutic utility in over a third of cases. Liquid biopsy analyses demonstrate that 43% of patients with localized disease have detectable circulating tumour DNA (ctDNA) at diagnosis. Detection of ctDNA after resection predicts clinical relapse and poor outcome, with recurrence by ctDNA detected 6.5 months earlier than with CT imaging. These observations provide genetic predictors of outcome in pancreatic cancer and have implications for new avenues of therapeutic intervention.

9 Article Family history as a marker of platinum sensitivity in pancreatic adenocarcinoma. 2015

Fogelman, David / Sugar, Elizabeth A / Oliver, George / Shah, Neeraj / Klein, Alison / Alewine, Christine / Wang, Huamin / Javle, Milind / Shroff, Rachna / Wolff, Robert A / Abbruzzese, James L / Laheru, Daniel / Diaz, Luis A. ·Department of G.I. Medical Oncology, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 426, Houston, TX 77030, USA. · University of Texas/M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 426, Houston, TX 77096, USA. · Sidney Kimmel Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA. · Departments of Biostatistics and Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA. · Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Room E3537, Baltimore, MD 21205, USA. · 6300 Harry Hines Blvd. Ste 265, Dallas, TX 75235, USA. · Staten Island University Hospital, 475 Seaview Avenue, Staten Island, NY 10305, USA. · Departments of Pathology and Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA. · Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 1650 Orleans St., Rm G89, Baltimore, MD 21231-1000, USA. · Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, USA. · Johns Hopkins Bloomberg School of Public Health, 1650 Orleans Street, CRB I Room 590, Baltimore, MD 21231, USA. · Department of Medical Oncology, NCI-National Cancer Institute, 10 Center Dr, Bldg 10/12N226, Bethesda, MD 20892, USA. · 1515 Holcombe Blvd., Unit 0085, Houston, TX 77030, USA. · Division of Medical Oncology, Duke University, 10 Searle Drive, 445 Seeley G Mudd Building, Durham, NC 27710, USA. · Swim Across America Laboratory, Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins, 1650 Orleans Street, CRB I Room 590, Baltimore, MD 21231, USA. ·Cancer Chemother Pharmacol · Pubmed #26126726.

ABSTRACT: PURPOSE: Metastatic pancreatic adenocarcinoma is considered a uniformly fatal disease with a median survival of 1 year with modern chemotherapy. While a subset of patients achieve prolonged survival, few of the factors that define this group of patients are known. METHODS: For the determination of overall survival (OS), 549 patients with histologically confirmed metastatic pancreatic adenocarcinoma were evaluated. Emphasis was placed on treatment history and family history of breast, ovarian, and pancreatic cancers. To ensure a uniform metastatic population, patients treated with prior locoregional therapies (i.e., surgery or radiotherapy) were excluded as were patients with a prior history of stage I-III disease. RESULTS: Patients with family history or pedigree history of cancer had superior OS. This was especially true in patients with three or more relatives with either breast, ovarian, or pancreatic cancers [hazard ratio (HR) 0.49, 95 % confidence interval (CI) 0.30-0.80, p = 0.003]. First-line platinum chemotherapy was associated with a poor survival (hazard ratio for death 1.74, 95% CI 1.12-2.71, p = 0.01) for patients without a family history of these cancers but not for those without such a history (p = 0.31). In fact, as the number of relatives with these cancers increased, the OS survival improved for individuals receiving first-line platinum therapy (HR 0.76, 95 % CI 0.65-0.89, p = 0.0004), which was not the case for those receiving other therapies (p = 0.98). CONCLUSIONS: Treatment with platinum chemotherapy in patients with a family history of breast, ovarian, or pancreatic cancers was associated with a longer survival, whereas platinum use in patients without such a family history of cancer was associated with poor survival. These findings suggest that family history may serve as a predictive marker for platinum use in patients with metastatic pancreatic adenocarcinoma.

10 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.

11 Article A single institution's 26-year experience with nonfunctional pancreatic neuroendocrine tumors: a validation of current staging systems and a new prognostic nomogram. 2014

Ellison, Trevor A / Wolfgang, Christopher L / Shi, Chanjuan / Cameron, John L / Murakami, Peter / Mun, Liew Jun / Singhi, Aatur D / Cornish, Toby C / Olino, Kelly / Meriden, Zina / Choti, Michael / Diaz, Luis A / Pawlik, Timothy M / Schulick, Richard D / Hruban, Ralph H / Edil, Barish H. ·Departments of *Surgery †Pathology ‡Oncology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD §Vanderbilt University Medical Center, Department of Pathology, Microbiology and Immunology, Nashville, TN ¶The Johns Hopkins Bloomberg School of Public Health, Department of Biostatistics, Baltimore, MD; and ∥The University of Colorado, Department of Surgery, Aurora, CO. ·Ann Surg · Pubmed #23673766.

ABSTRACT: OBJECTIVE: To validate the 2010 American Joint Committee on Cancer (AJCC) and 2006 European Neuroendocrine Tumor Society (ENETS) tumor staging systems for pancreatic neuroendocrine tumors (PanNETs) using the largest, single-institution series of surgically resected patients in the literature. BACKGROUND: The natural history and prognosis of PanNETs have been poorly defined because of the rarity and heterogeneity of these neoplasms. Currently, there are 2 main staging systems for PanNETs, which can complicate comparisons of reports in the literature and thereby hinder progress against this disease. METHODS: Univariate and multivariate analyses were conducted on the prognostic factors of survival using 326 sporadic, nonfunctional, surgically resected PanNET patients who were cared for at our institution between 1984 and 2011. Current and proposed models were tested for survival prognostication validity as measured by discrimination (Harrel's c-index, HCI) and calibration. RESULTS: Five-year overall-survival rates for AJCC stages I, II, and IV are 93% (88%-99%), 74% (65%-83%), and 56% (42%-73%), respectively, whereas ENETS stages I, II, III, and IV are 97% (92%-100%), 87% (80%-95%), 73% (63%-84%), and 56% (42%-73%), respectively. Each model has an HCI of 0.68, and they are no different in their ability to predict survival. We developed a simple prognostic tool just using grade, as measured by continuous Ki-67 labeling, sex, and binary age that has an HCI of 0.74. CONCLUSIONS: Both the AJCC and ENETS staging systems are valid and indistinguishable in their survival prognostication. A new, simpler prognostic tool can be used to predict survival and decrease interinstitutional mistakes and uncertainties regarding these neoplasms.

12 Article Genetically defined subsets of human pancreatic cancer show unique in vitro chemosensitivity. 2012

Cui, Yunfeng / Brosnan, Jacqueline A / Blackford, Amanda L / Sur, Surojit / Hruban, Ralph H / Kinzler, Kenneth W / Vogelstein, Bert / Maitra, Anirban / Diaz, Luis A / Iacobuzio-Donahue, Christine A / Eshleman, James R. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA. ·Clin Cancer Res · Pubmed #22753594.

ABSTRACT: PURPOSE: Pancreatic cancer is the fourth cause of death from cancer in the western world. Majority of patients present with advanced unresectable disease responding poorly to most chemotherapeutic agents. Chemotherapy for pancreatic cancer might be improved by adjusting it to individual genetic profiles. We attempt to identify genetic predictors of chemosensitivity to broad classes of anticancer drugs. EXPERIMENTAL DESIGN: Using a panel of genetically defined human pancreatic cancer cell lines, we tested gemcitabine (antimetabolite), docetaxel (antimicrotubule), mitomycin C (MMC; alkylating), irinotecan (topoisomerase I inhibitor), cisplatin (crosslinking), KU0058948 (Parp1 inhibitor), triptolide (terpenoid drug), and artemisinin (control). RESULTS: All pancreatic cancer cell lines were sensitive to triptolide and docetaxel. Most pancreatic cancer cells were also sensitive to gemcitabine and MMC. The vast majority of pancreatic cancer cell lines were insensitive to cisplatin, irinotecan, and a Parp1 inhibitor. However, individual cell lines were often sensitive to these compounds in unique ways. We found that DPC4/SMAD4 inactivation sensitized pancreatic cancer cells to cisplatin and irinotecan by 2- to 4-fold, but they were modestly less sensitive to gemcitabine. Pancreatic cancer cells were all sensitive to triptolide and 18% were sensitive to the Parp1 inhibitor. P16/CDKN2A-inactivated pancreatic cancer cells were 3- to 4-fold less sensitive to gemcitabine and MMC. CONCLUSIONS: Chemosensitivity of pancreatic cancer cells correlated with some specific genetic profiles. These results support the hypothesis that genetic subsets of pancreatic cancer exist, and these genetic backgrounds may permit one to personalize the chemotherapy of pancreatic cancer in the future. Further work will need to confirm these responses and determine their magnitude in vivo.

13 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.

14 Article Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. 2011

Wu, Jian / Matthaei, Hanno / Maitra, Anirban / Dal Molin, Marco / Wood, Laura D / Eshleman, James R / Goggins, Michael / Canto, Marcia I / Schulick, Richard D / Edil, Barish H / Wolfgang, Christopher L / Klein, Alison P / Diaz, Luis A / Allen, Peter J / Schmidt, C Max / Kinzler, Kenneth W / Papadopoulos, Nickolas / Hruban, Ralph H / Vogelstein, Bert. ·Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA. ·Sci Transl Med · Pubmed #21775669.

ABSTRACT: More than 2% of the adult U.S. population harbors a pancreatic cyst. These often pose a difficult management problem because conventional criteria cannot always distinguish cysts with malignant potential from those that are innocuous. One of the most common cystic neoplasms of the pancreas, and a bona fide precursor to invasive adenocarcinoma, is called intraductal papillary mucinous neoplasm (IPMN). To help reveal the pathogenesis of these lesions, we purified the DNA from IPMN cyst fluids from 19 patients and searched for mutations in 169 genes commonly altered in human cancers. In addition to the expected KRAS mutations, we identified recurrent mutations at codon 201 of GNAS. A larger number (113) of additional IPMNs were then analyzed to determine the prevalence of KRAS and GNAS mutations. In total, we found that GNAS mutations were present in 66% of IPMNs and that either KRAS or GNAS mutations could be identified in 96%. In eight cases, we could investigate invasive adenocarcinomas that developed in association with IPMNs containing GNAS mutations. In seven of these eight cases, the GNAS mutations present in the IPMNs were also found in the invasive lesion. GNAS mutations were not found in other types of cystic neoplasms of the pancreas or in invasive adenocarcinomas not associated with IPMNs. In addition to defining a new pathway for pancreatic neoplasia, these data suggest that GNAS mutations can inform the diagnosis and management of patients with cystic pancreatic lesions.

15 Article DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. 2011

Jiao, Yuchen / Shi, Chanjuan / Edil, Barish H / de Wilde, Roeland F / Klimstra, David S / Maitra, Anirban / Schulick, Richard D / Tang, Laura H / Wolfgang, Christopher L / Choti, Michael A / Velculescu, Victor E / Diaz, Luis A / Vogelstein, Bert / Kinzler, Kenneth W / Hruban, Ralph H / Papadopoulos, Nickolas. ·Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA. ·Science · Pubmed #21252315.

ABSTRACT: Pancreatic neuroendocrine tumors (PanNETs) are a rare but clinically important form of pancreatic neoplasia. To explore the genetic basis of PanNETs, we determined the exomic sequences of 10 nonfamilial PanNETs and then screened the most commonly mutated genes in 58 additional PanNETs. The most frequently mutated genes specify proteins implicated in chromatin remodeling: 44% of the tumors had somatic inactivating mutations in MEN1, which encodes menin, a component of a histone methyltransferase complex, and 43% had mutations in genes encoding either of the two subunits of a transcription/chromatin remodeling complex consisting of DAXX (death-domain-associated protein) and ATRX (α thalassemia/mental retardation syndrome X-linked). Clinically, mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis. We also found mutations in genes in the mTOR (mammalian target of rapamycin) pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for treatment with mTOR inhibitors.