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Pancreatic Neoplasms: HELP
Articles by Francis Charles Brunicardi
Based on 24 articles published since 2009
(Why 24 articles?)
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Between 2009 and 2019, F. C. Brunicardi wrote the following 24 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Closing the Disparity in Pancreatic Cancer Outcomes: A Closer Look at Nonmodifiable Factors and Their Potential Use in Treatment. 2019

Vick, Alexis D / Hery, Danielle N / Markowiak, Stephen F / Brunicardi, F Charles. ·From the College of Medicine and Life Sciences, and. · Department of Surgery, College of Medicine and Life Sciences, University of Toledo, ProMedica Health System, Toledo, OH. ·Pancreas · Pubmed #30629027.

ABSTRACT: OBJECTIVES: African Americans (AAs) have disproportionately higher incidence and lower survival rates from pancreatic cancer compared with whites. Historically, this disparity has been attributed to modifiable risk factors. Recent studies suggest that nonmodifiable aspects may also play an important role. We review these new contributions as potential targets for closing the disparity. METHODS: A PubMed search was conducted to review studies of nonmodifiable elements contributing to pancreatic cancer disparities in AAs. RESULTS: Several nonmodifiable risks are associated with the racial disparity in pancreatic cancer. SSTR5 P335L, Kaiso, and KDM4/JMJD2A demonstrate differential racial expression, increasing their potential as therapeutic targets. Many social determinants of health and their associations with diabetes, obesity, and the microbiome are partially modifiable risk factors that significantly contribute to outcomes in minorities. Barriers to progress include the low minority inclusion in research studies. CONCLUSIONS: Genomics, epigenetics, the microbiome, and social determinants of health are components that contribute to the pancreatic cancer disparity in AAs. These factors can be researched, targeted, and modified to improve mortality rates. Closing the disparity in pancreatic cancer will require an integrated approach of personalized medicine, increased minority recruitment to studies, and advanced health care/education access.

2 Review Pancreatic cancer actionable genes in precision medicine and personalized surgery. 2017

Yu, Juehua / Liu, Shi-He / Sanchez, Robbi / Nemunaitis, John / Rozengurt, Enrique / Brunicardi, F Charles. ·Division of General Surgery, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, CA, USA. · Mary Crowley Cancer Research Center, Dallas, TX, USA. · Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, CA, USA. · Division of General Surgery, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, CA, USA. Electronic address: cbrunicardi@mednet.ucla.edu. ·Surgeon · Pubmed #27374183.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with an overall 5-year survival rate less than 5% due to the poor early diagnosis and lack of effective therapeutic options. The most effective therapy remains surgery, however post-operative survival could be enhanced with effective adjuvant therapy. The massive information gained from Omics techniques on PDAC at the beginning of the 21st century is a remarkable accomplishment. However, the information gained from the omics data, including next generation sequencing data, has yet to successfully affect care of patients suffering with PDAC. Therefore, we propose the development of an actionable genomic platform that matches a patient's PDAC clinically actionable genes with potential targeted adjuvant therapies. Using this platform, PDX1 has been identified as a potential actionable gene for PDAC, therefore, RNAi therapy, gene therapy and small inhibitory drugs, all targeting PDX1, serve as potential targeted adjuvant therapies. Preclinical studies support the hypothesis that identification of PDAC actionable genes could permit translation of a patient's genomic information into precision targeted adjuvant therapy for PDAC.

3 Review Vertically integrated translational studies of PDX1 as a therapeutic target for pancreatic cancer via a novel bifunctional RNAi platform. 2014

Wu, J / Liu, S / Yu, J / Zhou, G / Rao, D / Jay, C M / Kumar, P / Sanchez, R / Templeton, N / Senzer, N / Maples, P / Nemunaitis, J / Brunicardi, F C. ·Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. · Gradalis, Carrollton, TX, USA. · 1] Gradalis, Carrollton, TX, USA [2] Mary Crowley Cancer Research Center, Dallas, TX, USA. ·Cancer Gene Ther · Pubmed #24457987.

ABSTRACT: RNA interference (RNAi) represents a powerful, new tool for scientific investigation as well as a promising new form of targeted gene therapy, with applications currently in clinical trials. Bifunctional short hairpin RNA (shRNA) are synthetic RNAi molecules, engineered to utilize multiple endogenous RNAi pathways to specifically silence target genes. Pancreatic and duodenal homeobox 1 (PDX1) is a key regulator of pancreatic development, β-cell differentiation, normal β-cell function and pancreatic cancer. Our aim is to review the process of identifying PDX1 as a specific, potential RNAi target in pancreatic cancer, as well as the underlying mechanisms and various forms of RNAi, with subsequent testing and development of PDX1-targeted bifunctional shRNA therapy.

4 Review Defining the cancer master switch. 2011

Balentine, Courtney J / Berger, David H / Liu, Shi-He / Chen, Changyi / Nemunaitis, John / Brunicardi, F Charles. ·Michael E. DeBakey Veterans Affairs Hospital, Houston, TX, USA. ·World J Surg · Pubmed #21286716.

ABSTRACT: BACKGROUND: Recent research has focused on signaling cascades and their interactions yielding considerable insight into which genetic pathways are targeted and how they tend to be altered in tumors. Therapeutic interventions now can be designed based on the knowledge of pathways vital to tumor growth and survival. These critical targets for intervention, master switches for cancer, are termed so because the tumor attempts to "flip the switch" in a way that promotes its survival, whereas molecular therapy aims to "switch off" signals important for tumor-related processes. METHODS: Literature review. CONCLUSIONS: Defining useful targets for therapy depends on identifying pathways that are crucial for tumor growth, survival, and metastasis. Because not all signaling cascades are created equal, selecting master switches or targets for intervention needs to be done in a systematic fashion. This discussion proposes a set of criteria to define what it means to be a cancer master switch and provides examples to illustrate their application.

5 Review Value of pancreatic resection for cancer metastatic to the pancreas. 2010

Sweeney, Alex D / Fisher, William E / Wu, Meng-Fen / Hilsenbeck, Susan G / Brunicardi, F Charles. ·Michael E DeBakey Department of Surgery, Baylor College of Medicine, The Elkins Pancreas Center, Houston, Texas, USA. ·J Surg Res · Pubmed #20422750.

ABSTRACT: BACKGROUND: Cancer metastatic to the pancreas from other primary sites is uncommon, and it has been treated with an aggressive surgical approach in fit patients when the primary tumor is controlled and the pancreas is the only site of metastatic disease. The value of pancreatic resection in this setting is unclear. The purpose of this study was to review cases of cancer metastatic to the pancreas. METHODS: We reviewed our experience with cancer metastatic to the pancreas and the literature regarding resection of pancreatic metastases. Patient and tumor characteristics were summarized using descriptive statistics. RESULTS: A total of 220 patients with pancreatic metastasis were analyzed. Three patients were selected from our own experience, and 217 were selected from a literature review. In the 127 patients whose symptoms were recorded at the time of presentation, the most common presenting symptoms were jaundice (n = 32, 25.2%) and abdominal pain (n = 25, 19.7%). In the 189 patients for whom the location of the metastasis in the pancreas was revealed, the most common location was the head of the pancreas (n = 79, 41.8%). The primary tumor site was most commonly kidney (n = 155, 70.5%). Surgical resection was attempted in 177 of 220 patients; 135 patients suffering from RCC metastasis also underwent pancreatic resection. In the latter group, a median survival of 70 months was seen, as well as 78% and 65% 2- and 5-year survival rates, respectively. CONCLUSION: Survival after resection of RCC with isolated metastasis to the pancreas is favorable. However, a more detailed analysis considering outcomes without surgery for each primary tumor site is needed before the value of this aggressive surgical approach can be completely assessed in the general occurrence of pancreatic metastasis.

6 Article KRAS mutant allele-specific expression knockdown in pancreatic cancer model with systemically delivered bi-shRNA KRAS lipoplex. 2018

Rao, Donald D / Luo, Xiuquan / Wang, Zhaohui / Jay, Christopher M / Brunicardi, Francis C / Maltese, William / Manning, Luisa / Senzer, Neil / Nemunaitis, John. ·Strike Bio, Dallas, TX, United States of America. · University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States of America. · Gradalis, Inc., Dallas, TX, United States of America. ·PLoS One · Pubmed #29851957.

ABSTRACT: The KRAS oncogene, present in over 90% of pancreatic ductal adenocarcinomas, is most frequently the result of one of three gain-of-function substitution mutations of codon 12 glycine. Thus far, RAS mutations have been clinically refractory to both direct and selective inhibition by systemic therapeutics. This report presents the results of pre-clinical assessment of a lipoplex comprising a plasmid-encoded, modular bi-functional shRNA (bi-shRNA), which executes selective and multi-mutant allelic KRASG12mut gene silencing, encased within a fusogenic liposome systemic delivery vehicle. Using both a dual luciferase reporter system and a Restriction Fragment Length Polymorphism (RFLP) assay, selective discrimination of KRASG12mut from KRASwt was confirmed in vitro in PANC1 cells. Subsequently, systemic administration of the bi-shRNAKRAS fusogenic lipoplex into female athymic Nu/Nu mice bearing PANC1 xenografts demonstrated intratumoral plasmid delivery, KRASG12mut knockdown, and inhibition of tumor growth, without adverse effect. Clinical trials with the bi-shRNA lipoplex have been implemented.

7 Article A novel synthetic human insulin super promoter for targeting PDX-1-expressing pancreatic cancer. 2018

Liu, Shi-He / Yu, Juehua / Sanchez, Robbi / Liu, Xiaochen / Heidt, David / Willey, James / Nemunaitis, John / Brunicardi, Francis Charles. ·Department of Surgery, University of Toledo College of Medicine & Life Sciences, Toledo OH, USA. · Department of Surgery, University of California at Los Angeles, CA, USA. · Department of Medicine, University of Toledo College of Medicine & Life Sciences, Toledo OH, USA. · Department of Surgery, University of Toledo College of Medicine & Life Sciences, Toledo OH, USA. Electronic address: Francis.Brunicardi@UToledo.edu. ·Cancer Lett · Pubmed #29309817.

ABSTRACT: Our previous studies have shown that a rat insulin promoter II fragment (RIP) was used to effectively target pancreatic adenocarcinoma (PDAC) and insulinoma that over-express pancreatic and duodenal homeobox-1 (PDX-1). To enhance the activity and specificity of the human insulin promoter, we engineered a synthetic human insulin super-promoter (SHIP). Reporter assay demonstrated that SHIP1 was the most powerful promoter among all of the SHIPs and had far greater activity than the endogenous human insulin promoters and RIP in PDAC expressing PDX-1. Over-expression, knockdown and competitive inhibition of PDX-1 expression assay proved that PDX-1 is a critical transcript factor to regulate the activity of SHIP1. SHIP1-driven viral thymidine kinase followed by ganciclovir (SHIP1-TK/GCV) resulted in cytotoxicity to PDAC cells in vitro. Systemic delivery of SHIP1-TK/GCV in PDAC xenograft mice significantly suppressed PANC-1 tumor growth in vivo greater than RIP-TK/GCV and CMV-TK/GCV controls (p < .05). These preclinical data suggest that SHIP1 is a powerful novel promoter that can be used to target human PDAC expressing PDX-1 in clinical trials. Furthermore, this novel strategy of engineering synthetic super-promoters could be used for other cancer targets.

8 Article Metformin Restrains Pancreatic Duodenal Homeobox-1 (PDX-1) Function by Inhibiting ERK Signaling in Pancreatic Ductal Adenocarcinoma. 2016

Zhou, G / Yu, J / Wang, A / Liu, S-H / Sinnett-Smith, J / Wu, J / Sanchez, R / Nemunaitis, J / Ricordi, C / Rozengurt, E / Brunicardi, F C. ·Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, CA, USA. cbrunicardi@mednet.ucla.edu. ·Curr Mol Med · Pubmed #26695692.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most potent and perilous diseases known, with a median survival rate of 3-5 months due to the combination of only advanced stage diagnosis and ineffective therapeutic options. Metformin (1,1-Dimethylbiguanide hydrochloride), the leading drug used for type 2 diabetes mellitus, emerges as a potential therapy for PDAC and other human cancers. Metformin exerts its anticancer action via a variety of adenosine monophosphate (AMP)-activated protein kinase (AMPK)- dependent and/or AMPK-independent mechanisms. We present data here showing that metformin downregulated pancreatic transcription factor pancreatic duodenal homeobox-1 (PDX-1), suggesting a potential novel mechanism by which metformin exerts its anticancer action. Metformin inhibited PDX-1 expression at both protein and mRNA levels and PDX-1 transactivity as well in PDAC cells. Extracellular signal-regulated kinase (ERK) was identified as a PDX-1-interacting protein by antibody array screening in GFP-PDX-1 stable HEK293 cells. Co-transfection of ERK1 with PDX-1 resulted in an enhanced PDX-1 expression in HEK293 cells in a dose-dependent manner. Immunoprecipitation/Western blotting analysis confirmed the ERK-PDX-1 interaction in PANC-1 cells stimulated by epidermal growth factor (EGF). EGF induced an enhanced PDX-1 expression in PANC-1 cells and this stimulation was inhibited by MEK inhibitor PD0325901. Metformin inhibited EGF-stimulated PDX-1 expression with an accompanied inhibition of ERK kinase activation in PANC- 1 cells. Taken together, our studies show that PDX-1 is a potential novel target for metformin in PDAC cells and that metformin may exert its anticancer action in PDAC by down-regulating PDX-1 via a mechanism involving inhibition of ERK signaling.

9 Article Liposomal insulin promoter-thymidine kinase gene therapy followed by ganciclovir effectively ablates human pancreatic cancer in mice. 2015

Wu, James X / Liu, Shi-He / Nemunaitis, John J / Brunicardi, F Charles. ·David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. · Mary Crowley Cancer Research Centers, Dallas, TX, USA. · David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. Electronic address: CBrunicardi@mednet.ucla.edu. ·Cancer Lett · Pubmed #25596375.

ABSTRACT: PDX1 is overexpressed in pancreatic cancer, and activates the insulin promoter (IP). Adenoviral IP-thymidine kinase and ganciclovir (TK/GCV) suppresses human pancreatic ductal carcinoma (PDAC) in mice, but repeated doses carry significant toxicity. We hypothesized that multiple cycles of liposomal IP-TK/GCV ablate human PDAC in SCID mice with minimal toxicity compared to adenoviral IP-TK/GCV. SCID mice with intraperitoneal human pancreatic cancer PANC-1 tumor implants were given a single cycle of 35 µg iv L-IP-TK, or four cycles of 1, 10, 20, 30, or 35 µg iv L-IP-TK (n = 20 per group), followed by intraperitoneal GCV. Insulin and glucose levels were monitored in mice treated with four cycles of 35 µg iv L-IP-TK. We found that four cycles of 10-35 µg L-IP-TK/GCV ablated more PANC-1 tumor volume compared to a single cycle with 35 µg. Mice that received four cycles of 10 µg L-IP-TK demonstrated the longest survival (P < 0.05), with a median survival of 126 days. In comparison, mice that received a single cycle of 35 µg L-IP-TK/GCV or GCV alone survived a median of 92 days and 68.7 days, respectively. There were no significant changes in glucose or insulin levels following treatment. In conclusion, multiple cycles of liposomal IP-TK/GCV ablate human PDAC in SCID mice with minimal toxicity, suggesting non-viral vectors are superior to adenoviral vectors for IP-gene therapy.

10 Article A novel epigenetic CREB-miR-373 axis mediates ZIP4-induced pancreatic cancer growth. 2013

Zhang, Yuqing / Yang, Jingxuan / Cui, Xiaobo / Chen, Yong / Zhu, Vivian F / Hagan, John P / Wang, Huamin / Yu, Xianjun / Hodges, Sally E / Fang, Jing / Chiao, Paul J / Logsdon, Craig D / Fisher, William E / Brunicardi, F Charles / Chen, Changyi / Yao, Qizhi / Fernandez-Zapico, Martin E / Li, Min. ·Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA. ·EMBO Mol Med · Pubmed #23857777.

ABSTRACT: Changes in the intracellular levels of the essential micronutrient zinc have been implicated in multiple diseases including pancreatic cancer; however, the molecular mechanism is poorly understood. Here, we report a novel mechanism where increased zinc mediated by the zinc importer ZIP4 transcriptionally induces miR-373 in pancreatic cancer to promote tumour growth. Reporter, expression and chromatin immunoprecipitation assays demonstrate that ZIP4 activates the zinc-dependent transcription factor CREB and requires this transcription factor to increase miR-373 expression through the regulation of its promoter. miR-373 induction is necessary for efficient ZIP4-dependent enhancement of cell proliferation, invasion, and tumour growth. Further analysis of miR-373 in vivo oncogenic function reveals that it is mediated through its negative regulation of TP53INP1, LATS2 and CD44. These results define a novel ZIP4-CREB-miR-373 signalling axis promoting pancreatic cancer growth, providing mechanistic insights explaining in part how a zinc transporter functions in cancer cells and may have broader implications as inappropriate regulation of intracellular zinc levels plays an important role in many other diseases.

11 Article Gene profile identifies zinc transporters differentially expressed in normal human organs and human pancreatic cancer. 2013

Yang, J / Zhang, Y / Cui, X / Yao, W / Yu, X / Cen, P / Hodges, S E / Fisher, W E / Brunicardi, F C / Chen, C / Yao, Q / Li, M. ·Vivian L. Smith Department of Neurosurgery, University of Texas Medical School at Houston, 6431 Fannin Street, MSE R266, Houston, TX 77030, USA. ·Curr Mol Med · Pubmed #23331012.

ABSTRACT: Deregulated expression of zinc transporters was linked to several cancers. However, the detailed expression profile of all human zinc transporters in normal human organs and in human cancer, especially in pancreatic cancer is not available. The objectives of this study are to investigate the complete expression patterns of 14 ZIP and 10 ZnT transporters in a large number of normal human organs and in human pancreatic cancer tissues and cell lines. We examined the expression patterns of ZIP and ZnT transporters in 22 different human organs and tissues, 11 pairs of clinical human pancreatic cancer specimens and surrounding normal/benign tissues, as well as 10 established human pancreatic cancer cell lines plus normal human pancreatic ductal epithelium (HPDE) cells, using real time RT-PCR and immunohistochemistry. The results indicate that human zinc transporters have tissue specific expression patterns, and may play different roles in different organs or tissues. Almost all the ZIPs except for ZIP4, and most ZnTs were down-regulated in human pancreatic cancer tissues compared to the surrounding benign tissues. The expression patterns of individual ZIPs and ZnTs are similar among different pancreatic cancer lines. Those results and our previous studies suggest that ZIP4 is the only zinc transporter that is significantly up-regulated in human pancreatic cancer and might be the major zinc transporter that plays an important role in pancreatic cancer growth. ZIP4 might serve as a novel molecular target for pancreatic cancer diagnosis and therapy.

12 Article Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. 2012

Biankin, Andrew V / Waddell, Nicola / Kassahn, Karin S / Gingras, Marie-Claude / Muthuswamy, Lakshmi B / Johns, Amber L / Miller, David K / Wilson, Peter J / Patch, Ann-Marie / Wu, Jianmin / Chang, David K / Cowley, Mark J / Gardiner, Brooke B / Song, Sarah / Harliwong, Ivon / Idrisoglu, Senel / Nourse, Craig / Nourbakhsh, Ehsan / Manning, Suzanne / Wani, Shivangi / Gongora, Milena / Pajic, Marina / Scarlett, Christopher J / Gill, Anthony J / Pinho, Andreia V / Rooman, Ilse / Anderson, Matthew / Holmes, Oliver / Leonard, Conrad / Taylor, Darrin / Wood, Scott / Xu, Qinying / Nones, Katia / Fink, J Lynn / Christ, Angelika / Bruxner, Tim / Cloonan, Nicole / Kolle, Gabriel / Newell, Felicity / Pinese, Mark / Mead, R Scott / Humphris, Jeremy L / Kaplan, Warren / Jones, Marc D / Colvin, Emily K / Nagrial, Adnan M / Humphrey, Emily S / Chou, Angela / Chin, Venessa T / Chantrill, Lorraine A / Mawson, Amanda / Samra, Jaswinder S / Kench, James G / Lovell, Jessica A / Daly, Roger J / Merrett, Neil D / Toon, Christopher / Epari, Krishna / Nguyen, Nam Q / Barbour, Andrew / Zeps, Nikolajs / Anonymous1421514 / Kakkar, Nipun / Zhao, Fengmei / Wu, Yuan Qing / Wang, Min / Muzny, Donna M / Fisher, William E / Brunicardi, F Charles / Hodges, Sally E / Reid, Jeffrey G / Drummond, Jennifer / Chang, Kyle / Han, Yi / Lewis, Lora R / Dinh, Huyen / Buhay, Christian J / Beck, Timothy / Timms, Lee / Sam, Michelle / Begley, Kimberly / Brown, Andrew / Pai, Deepa / Panchal, Ami / Buchner, Nicholas / De Borja, Richard / Denroche, Robert E / Yung, Christina K / Serra, Stefano / Onetto, Nicole / Mukhopadhyay, Debabrata / Tsao, Ming-Sound / Shaw, Patricia A / Petersen, Gloria M / Gallinger, Steven / Hruban, Ralph H / Maitra, Anirban / Iacobuzio-Donahue, Christine A / Schulick, Richard D / Wolfgang, Christopher L / Morgan, Richard A / Lawlor, Rita T / Capelli, Paola / Corbo, Vincenzo / Scardoni, Maria / Tortora, Giampaolo / Tempero, Margaret A / Mann, Karen M / Jenkins, Nancy A / Perez-Mancera, Pedro A / Adams, David J / Largaespada, David A / Wessels, Lodewyk F A / Rust, Alistair G / Stein, Lincoln D / Tuveson, David A / Copeland, Neal G / Musgrove, Elizabeth A / Scarpa, Aldo / Eshleman, James R / Hudson, Thomas J / Sutherland, Robert L / Wheeler, David A / Pearson, John V / McPherson, John D / Gibbs, Richard A / Grimmond, Sean M. ·The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia. ·Nature · Pubmed #23103869.

ABSTRACT: Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

13 Article PDX-1 is a therapeutic target for pancreatic cancer, insulinoma and islet neoplasia using a novel RNA interference platform. 2012

Liu, Shi-He / Rao, Donald D / Nemunaitis, John / Senzer, Neil / Zhou, Guisheng / Dawson, David / Gingras, Marie-Claude / Wang, Zhaohui / Gibbs, Richard / Norman, Michael / Templeton, Nancy S / Demayo, Francesco J / O'Malley, Bert / Sanchez, Robbi / Fisher, William E / Brunicardi, F Charles. ·Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America. ·PLoS One · Pubmed #22905092.

ABSTRACT: Pancreatic and duodenal homeobox-1 (PDX-1) is a transcription factor that regulates insulin expression and islet maintenance in the adult pancreas. Our recent studies demonstrate that PDX-1 is an oncogene for pancreatic cancer and is overexpressed in pancreatic cancer. The purpose of this study was to demonstrate that PDX-1 is a therapeutic target for both hormonal symptoms and tumor volume in mouse models of pancreatic cancer, insulinoma and islet neoplasia. Immunohistochemistry of human pancreatic and islet neoplasia specimens revealed marked PDX-1 overexpression, suggesting PDX-1 as a "drugable" target within these diseases. To do so, a novel RNA interference effector platform, bifunctional shRNA(PDX-1), was developed and studied in mouse and human cell lines as well as in mouse models of pancreatic cancer, insulinoma and islet neoplasia. Systemic delivery of bi-shRNA(humanPDX-1) lipoplexes resulted in marked reduction of tumor volume and improved survival in a human pancreatic cancer xenograft mouse model. bi-shRNA(mousePDX-1) lipoplexes prevented death from hyperinsulinemia and hypoglycemia in an insulinoma mouse model. shRNA(mousePDX-1) lipoplexes reversed hyperinsulinemia and hypoglycemia in an immune-competent mouse model of islet neoplasia. PDX-1 was overexpressed in pancreatic neuroendocrine tumors and nesidioblastosis. These data demonstrate that PDX-1 RNAi therapy controls hormonal symptoms and tumor volume in mouse models of pancreatic cancer, insulinoma and islet neoplasia, therefore, PDX-1 is a potential therapeutic target for these pancreatic diseases.

14 Article Negative regulation of pancreatic and duodenal homeobox-1 by somatostatin receptor subtype 5. 2012

Zhou, Guisheng / Liu, Shi-He / Shahi, Kelly M / Wang, Hua / Duan, Xueyan / Lin, Xia / Feng, Xin-Hua / Li, Min / Fisher, William E / Demayo, Francesco J / Dawson, David / Brunicardi, F Charles. ·Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, California 90095, USA. ·Mol Endocrinol · Pubmed #22669743.

ABSTRACT: Somatostatin receptor subtype 5 (SSTR5) mediates the inhibitory effect of somatostatin and its analogs on insulin expression/secretion and islet cell proliferation. We provide biochemical and genetic evidence that SSTR5 exerted its physiological actions via down-regulating pancreatic and duodenal homeobox-1 (PDX-1), a β-cell-specific homeodomain-containing transcription factor. Cotransfection of SSTR5 with PDX-1 resulted in dose-dependent inhibition of PDX-1 expression in human embryonic kidney 293 cells. SSTR5 agonist RPL-1980 inhibited PDX-1 expression and abolished glucagon-like peptide 1-stimulated PDX-1 expression in mouse insulinoma β-TC-6 cells. SSTR5 knockdown by short hairpin RNA led to increased PDX-1 expression that was accompanied by enhanced insulin secretion stimulated by high glucose in β-TC6 cells and alternated expressions of cell cycle proteins that favor cell proliferation in mouse insulinoma MIN6 cells. Quantitative RT-PCR analysis showed that cotransfected SSTR5 inhibited PDX-1 mRNA expression, whereas knockdown of SSTR5 increased PDX-1 mRNA expression. In addition, we found that cotransfected wild-type SSTR5 increased PDX-1 ubiquitination in human embryonic kidney 293 cells, whereas SSTR5 P335L, a hypofunctional single nucleotide polymorphism of SSTR5, inhibited PDX-1 ubiquitination. SSTR5 knockout resulted in increased expression of PDX-1, insulin, and proliferating cell nuclear antigen in the islets of sstr(-/-) mice. Immunohistochemistry analysis showed that SSTR5 P335L was associated with elevated expression of PDX-1 in human pancreatic neuroendocrine tumor. Taken together, our studies demonstrated that SSTR5 is a negative regulator for PDX-1 expression and that SSTR5 may mediate the inhibitory effects of somatostatin and its analogs on insulin expression/secretion and cell proliferation via down-regulating PDX-1 at both transcriptional and posttranslational levels.

15 Article Genomic sequencing of key genes in mouse pancreatic cancer cells. 2012

Wang, Y / Zhang, Y / Yang, J / Ni, X / Liu, S / Li, Z / Hodges, S E / Fisher, W E / Brunicardi, F C / Gibbs, R A / Gingras, M-C / Li, M. ·Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China. ·Curr Mol Med · Pubmed #22208613.

ABSTRACT: Pancreatic cancer is a multiple genetic disorder with many mutations identified during the progression. Two mouse pancreatic cancer cell lines were established which showed different phenotype in vivo: a non-metastatic cell line, Panc02, and a highly metastatic cell line, Panc02-H7, a derivative of Panc02. In order to investigate whether the genetic mutations of key genes in pancreatic cancer such as KRAS, TP53 (p53), CDKN2A (p16), SMAD4, ZIP4, and PDX-1 contribute to the phenotypic difference of these two mouse pancreatic cancer cells, we sequenced the exonic regions of these key genes in both cell lines and in the normal syngeneic mouse pancreas and compared them with the reference mouse genome sequence. The exons of KRAS, SMAD4, CDKN2A (p16), TP53 (p53), ZIP4, and PDX-1 genes were amplified and the genotype of these genes was determined by Sanger sequencing. The sequences were analyzed with Sequencher software. A mutation in SMAD4 was identified in both cell lines. This homozygote G to T mutation in the first position of codon 174 (GAA) generated a stop codon resulting in the translation of a truncated protein. Further functional analysis indicates that different TGF-β/SMAD signaling pathways were involved in those two mouse cell lines, which may explain the phonotypic difference between the two cells. A single nucleotide polymorphism (SNP) in KRAS gene (TAT to TAC at codon 32) was also identified in the normal pancreas DNA of the syngenic mouse and in both derived tumoral Panc02 and Panc02-H7 cells. No mutation or SNP was found in CDKN2A (p16), TP53 (p53), ZIP4, and PDX-1 genes in these two cell lines. The absence of mutations in genes such as KRAS, TP53, and CDKN2A, which are considered as key genes in the development of human pancreatic cancer suggests that SMAD4 might play a central and decisive role in mouse pancreatic cancer. These results also suggest that other mechanisms are involved in the substantial phenotypic difference between these two mouse pancreatic cancer cell lines. Further studies are warranted to elucidate the molecular pathways that lead to the aggressive metastatic potential of Panc02-H7.

16 Article SSTR5 P335L monoclonal antibody differentiates pancreatic neuroendocrine neuroplasms with different SSTR5 genotypes. 2011

Zhou, Guisheng / Gingras, Marie-Claude / Liu, Shi-He / Sanchez, Robbi / Edwards, Dean / Dawson, David / Christensen, Kurt / Paganelli, Giovanni / Gibbs, Richard / Fisher, William / Brunicardi, Francis C. ·Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA. ·Surgery · Pubmed #22136833.

ABSTRACT: BACKGROUND: Somatostatin receptor type 5 (SSTR5) P335L is a hypofunctional, single nucleotide polymorphism of SSTR5 with implications in the diagnostics and therapy of pancreatic neuroendocrine neoplasms. The purpose of this study is to determine whether a SSTR5 P335L-specific monoclonal antibody could sufficiently differentiate pancreatic neuroendocrine neoplasms (PNENs) with different SSTR5 genotypes. METHODS: Cellular proliferation rate, SSTR5 mRNA level, and SSTR5 protein level were measured by performing MTS assay, a quantitative reverse transcription polymerase chain reaction study, Western blot analysis, and immunohistochemistry, respectively. SSTR5 genotype was determined with the TaqMan SNP Genotyping assay (Applied Biosystems, Foster City, CA). RESULTS: We found that the SSTR5 analogue RPL-1980 inhibited cellular proliferation of CAPAN-1 cells more than that of PANC-1 cells. Only PANC-1 (TT) cells, but not CAPAN-1 (CC) cells expressed SSTR5 P335L. In 29 white patients with PNENs, 38% had a TT genotype for SSTR5 P335L, 24% had a CC genotype for WT SSTR5, and 38% hada CT genotype for both SSTR5 P335L and WT SSTR5. Immunohistochemistry using SSTR5 P335L monoclonal antibody detected immunostaining signals only from the neuroendocrine specimens with TT and CT genotypes, but not those with CC genotypes. CONCLUSION: A SSTR5 P335L monoclonal antibody that specifically recognizes SSTR5 P335L but not WT SSTR5 could differentiate PNENs with different SSTR5 genotypes, thereby providing a potential tool for the clinical diagnosis of PNEN.

17 Article Association between somatostatin receptor 5 gene polymorphisms and pancreatic cancer risk and survival. 2011

Li, Donghui / Tanaka, Motofumi / Brunicardi, F Charles / Fisher, William E / Gibbs, Richard A / Gingras, Marie-Claude. ·Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. dli@mdanderson.org ·Cancer · Pubmed #21692047.

ABSTRACT: BACKGROUND: Somatostatin (SST) inhibited cell proliferation and negatively regulated the release of growth hormones by means of specific receptors (SSTR). Genetic variation in SSTR had been associated with risk of human cancers but had never been investigated in pancreatic cancer. METHODS: In this retrospective study the SSTR5 gene in paired tumor and blood samples from 33 pancreatic adenocarcinoma patients using the Sanger method were sequenced. Three single nucleotide polymorphisms (SNPs) in samples from 863 patients with pancreatic ductal adenocarcinoma and 876 healthy controls using the TaqMan method were analyzed. The associations between gene polymorphisms and pancreatic cancer risk and survival were analyzed by multivariate logistic regression and Cox proportional hazard models, respectively. RESULTS: No somatic mutations were identified, but 3 nonsynonymous SSTR5 SNPs (P109S, L48M, and P335L) in pancreatic tumors were identified. The SSTR5 P109S variant allele was associated with a 1.62-fold increased risk of pancreatic cancer (95% confidence interval [CI]: 1.08-2.43, P = 0.019). Furthermore, the SSTR5 L48M AC variant and smoking had a joint effect on pancreatic cancer risk (p(interaction) = 0.035). The odds ratios (95% confidence intervals) were 0.58 (0.34-0.97), 1.49 (1.18-1.89), and 2.27 (1.35-3.83) for the variant genotype alone, smoking alone, and both factors, respectively, compared with no factors. Finally, SSTR5 P335L CC and P109S CC combined were associated with lower overall survival durations in patients with resectable disease. CONCLUSIONS: These data suggest that SSTR5 genetic variants play a role in pancreatic cancer development and progression.

18 Article Multiple treatment cycles of liposome-encapsulated adenoviral RIP-TK gene therapy effectively ablate human pancreatic cancer cells in SCID mice. 2011

Liu, Shi-He / Smyth-Templeton, Nancy / Davis, Alan R / Davis, Elizabeth A / Ballian, Nikiforos / Li, Min / Liu, Hao / Fisher, William / Brunicardi, F Charles. ·Michael E. DeBakey Department of Surgery, Elkins Pancreas Center, Baylor College of Medicine, Houston, TX 77030, USA. ·Surgery · Pubmed #21295812.

ABSTRACT: BACKGROUND: Adenoviral gene therapy has been applied widely for cancer therapy; however, transient gene expression as result of humoral immunoneutralization response to adenovirus limits its effect. The purpose of this study is to determine whether DOTAP:cholesterol liposome could shield adenovirus from neutralizing antibody and permit the use of multiple cycles of intravenous liposome encapsulated serotype 5 adenoviral rat insulin promoter directed thymidine kinase (L-A-5-RIP-TK) with ganciclovir (GCV) to enhance its effect. METHODS: The effect of multiple cycles of systemic L-A-5-RIP-TK/GCV therapy was evaluated in grouped PANC-1 SCID mice treated with different numbers of cycles. Humoral immune response to A-5-RIP-TK or L-A-5-RIP-TK was assessed using C57/B6J mice challenged with adenovirus or liposome adenovirus complex. RESULTS: The minimal residual tumor burden (3.2 ± 0.6 mm(3)) and greatest survival time (153.0 ± 6 days) were obtained in the mice receiving 4 and 3 cycles of therapy, respectively. Toxicity to islet cells associated with RIP-TK/GCV therapy was observed after 4 cycles. DOTAP:chol-encapsulated adenovectors were able to protect adenovectors from the neutralization of high titer of anti-adenoviral antibodies induced by itself. CONCLUSION: Multiple treatment cycles of L-A-5-RIP-TK/GCV ablate human PANC-1 cells effectively in SCID mice; however, the mice become diabetic and have substantial mortality after the 4th cycle. Liposome-encapsulated adenovirus is functionally resistant to the neutralizing effects of anti-adenoviral antibodies, suggesting feasibility of multiple cycles of therapy. Liposome encapsulation of the adenovirus may be a promising strategy for repeated delivery of systemic adenoviral gene therapy.

19 Article The hypofunctional effect of P335L single nucleotide polymorphism on SSTR5 function. 2011

Zhou, Guisheng / Gingras, Marie-Claude / Liu, Shi-He / Li, Donghui / Li, Zhijun / Catania, Robbi L / Stehling, Kelly M / Li, Min / Paganelli, Giovanni / Gibbs, Richard A / Demayo, Francesco J / Fisher, William E / Brunicardi, F Charles. ·Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. ·World J Surg · Pubmed #21249361.

ABSTRACT: BACKGROUND: Somatostatin receptor subtype 5 (SSTR5) mediates the inhibitory effect of somatostatin on insulin expression/secretion and cell proliferation. A number of single nucleotide polymorphisms (SNPs) of SSTR5 have been identified, including P335L, a nonsynonymous SNP located in the protein C-terminal region and encrypted by the codon CCG (proline) or the codon CTG (leucine). In the present study we sought to determine the distribution of the SSTR5 P335L SNP in a cohort of pancreatic cancer patients and whether the P335L SNP affected cellular function of SSTR5 in human pancreatic cancer. METHODS: The P335L germline genotype of 246 patients with pancreatic cancer (213 Caucasians, 16 Hispanics, and 17 African Americans) and 17 human pancreatic cell lines was determined with the TaqMan SNP Genotyping assay. Human SSTR5 leucine variant (L335) was generated by performing site-directed mutagenesis using SSTR5 proline variant (P335) as a template. Transient transfections were performed in HEK293, Mia PaCa-2, and β-TC-6 cells using Lipofectamine 2000. The expression of SSTR5 L335 was determined with a mouse monoclonal anti-SSTR5 L335 antibody generated in our laboratory. The cell proliferation rate was measured by performing MTS assays. Insulin concentration was measured by performing ELISA assays. RESULTS: Genotyping of the patients' blood indicated that the frequency of the T allele (CT and TT genotypes) in codon 335 of SSTR5 in Caucasians, Hispanics, and African Americans was 52, 69, and 35%, respectively, which was race-dependent. Statistical analysis indicated that association between the frequency of the T allele and the existence of pancreatic cancer in each race missed significance perhaps due to limited sample size. In 17 tested human pancreatic cancer cell lines, 5 (Capan-2, HPAF-II, Panc03.27, Panc-1, and -3) were homozygous (TT genotype) and 9, including Mia PaCa-2, were heterozygous (CT genotype). Overexpression of SSTR5 L335 in Mia PaCa-2 cells enhanced cell proliferation compared to overexpression of SSTR5 P335. Overexpression of SSTR5 P335 enhanced the inhibitory effect of SSTR5 agonist RPL-1980 on cell proliferation of Mia PaCa-2 cells and glucose-stimulated insulin secretion from mouse insulinoma cells, while overexpression of SSTR5 L335 blocked the inhibitory effect of RPL-1980. Overexpression of SSTR5 L335 enhanced PDX-1 expression in Mia PaCa-2 cells. A specific monoclonal antibody was generated to detect SSTR5 P335L. CONCLUSION: SSTR5 P335L SNP widely exists in the human population, in patients with pancreatic cancer, and is race-dependent. The SNP is also present in selected human pancreatic cancer cell lines. In contrast to SSTR5 P335, overexpression of the SSTR5 L335 variant resulted in cellular proliferation and PDX-1 overexpression in human pancreatic cancer cells. Its overexpression blocked the inhibitory effect of an SSTR5-specific analog on human pancreatic cancer cell proliferation and on glucose-stimulated insulin secretion from mouse insulinoma cells. These data suggest that SSTR5 P335L is a hypofunctional protein with a potentially harmful effect on function, as well as potential latent effect, and therefore it could affect the clinical response to somatostatin analog therapy for patients with pancreatic cancer.

20 Article PDX-1: demonstration of oncogenic properties in pancreatic cancer. 2011

Liu, Shi-He / Patel, Sanjeet / Gingras, Marie-Claude / Nemunaitis, John / Zhou, Guisheng / Chen, Changyi / Li, Min / Fisher, William / Gibbs, Richard / Brunicardi, F Charles. ·Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA. ·Cancer · Pubmed #20886630.

ABSTRACT: BACKGROUND: Pancreatic-duodenal homeobox 1 (PDX-1) is a transcription factor that regulates embryologic pancreas development and insulin expression in the adult islet; however, it is overexpressed in many types of cancer, including pancreatic cancer. The purpose of this study was to investigate the role of PDX-1 in tumorigenesis in human cells. METHODS: In vitro cell proliferation, invasion, and transformation were performed in human embryonic kidney cell line (HEK 293), pancreatic cancer cell line MIA PaCa2, and human pancreatic ductal epithelial (HPDE) cells transiently or stably expressing PDX-1 or green fluorescent protein (GFP) PDX-1, with or without cotransfection of PDX-1 short hairpin RNA (shRNA). In vivo tumor formation was carried out in severe combined immunodeficiency (SCID) mice with subcutaneous injection of HEK 293 and MIA PaCa2 stably transfected cells. Cell cycle was analyzed by Western blot or immunostaining. Microarray of RNA from pancreatic adenocarcinoma cells with and without PDX-1 shRNA was performed and analyzed. RESULTS: Transient and stable expressing PDX-1 significantly increased cell proliferation and invasion in HEK 293, human pancreatic ductal epithelial (HPDE), and MIA PaCa2 cells versus controls (P < .05), human PDX-1 shRNA reversed these effects. Expression of PDX-1 significantly increased colony formation in HEK 293, HPDE, and MIA PaCa2 cells versus controls in vitro (P < .05). PDX-1 promoted HEK 293 and MIA PaCa2 tumor formation in SCID mice as compared with that of control (P < .05). PDX-1 overexpression disrupted cell cycles proteins. PDX-1 expression was confirmed by Western blot and tracked by viewing of GFP-PDX-1 expression. Microarray data support an oncogenic role of PDX-1 in pancreas cancer cells. CONCLUSIONS: PDX-1 induced increased cell proliferation, invasion, and colony formation in vitro, and resulted in markedly increased HEK 293 and MIA PaCa2 tumor formation in SCID mice. These data suggest that PDX-1 is a potential oncogene that regulates tumorigenesis.

21 Article A combinatorial approach for targeted delivery using small molecules and reversible masking to bypass nonspecific uptake in vivo. 2010

Shi, Q / Nguyen, A T / Angell, Y / Deng, D / Na, C-R / Burgess, K / Roberts, D D / Brunicardi, F C / Templeton, N S. ·Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA. ·Gene Ther · Pubmed #20463761.

ABSTRACT: We have developed a multi-disciplinary approach combining molecular biology, delivery technology, combinatorial chemistry and reversible masking to create improved systemic, targeted delivery of plasmid DNA while avoiding nonspecific uptake in vivo. We initially used a well-characterized model targeting the asialolglycoprotein receptor in the liver. Using our bilamellar invaginated vesicle (BIV) liposomal delivery system with reversible masking, we increased expression in the liver by 76-fold, nearly equaling expression in first-pass organs using non-targeted complexes, with no expression in other organs. The same technology was then applied to efficiently target delivery to a human tumor microenvironment model. We achieved efficient, targeted delivery by attachment of specific targeting ligands to the surface of our BIV complexes in conjunction with reversible masking to bypass nonspecific tissues and organs. We identified ligands that target a human tumor microenvironment created in vitro by co-culturing primary human endothelial cells with human lung or pancreatic cancer cells. The model was confirmed by increased expression of tumor endothelial phenotypes including CD31 and vascular endothelial growth factor-A, and prolonged survival of endothelial capillary-like structures. The co-cultures were used for high-throughput screening of a specialized small molecule library to identify ligands specific for human tumor-associated endothelial cells in vitro. We identified small molecules that enhanced the transfection efficiency of tumor-associated endothelial cells, but not normal human endothelial cells or cancer cells. Intravenous (i.v.) injection of our targeted, reversibly masked complexes into mice, bearing human pancreatic tumor and endothelial cells, specifically increased transfection to this tumor microenvironment approximately 200-fold. Efficacy studies using our optimized targeted delivery of a plasmid encoding thrombospondin-1 eliminated tumors completely after five i.v. injections administered once every week.

22 Article Down-regulation of ZIP4 by RNA interference inhibits pancreatic cancer growth and increases the survival of nude mice with pancreatic cancer xenografts. 2009

Li, Min / Zhang, Yuqing / Bharadwaj, Uddalak / Zhai, Qihui Jim / Ahern, Charlotte H / Fisher, William E / Brunicardi, F Charles / Logsdon, Craig D / Chen, Changyi / Yao, Qizhi. ·Molecular Surgeon Research Center, Elkins Pancreas Center, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA. minli@bcm.edu ·Clin Cancer Res · Pubmed #19755388.

ABSTRACT: PURPOSE: Zinc levels have been correlated with cancer risk, although the role of zinc and zinc transporters in cancer progression is largely unknown. We recently found that a zinc transporter, ZIP4, is overexpressed in pancreatic cancer. In this study, we further deciphered the role that ZIP4 plays in a pancreatic cancer mouse model by silencing ZIP4. EXPERIMENTAL DESIGN: ZIP4 stable silencing was established in pancreatic cancer cell lines ASPC-1 (ASPC-shZIP4) and BxPC-3 (BxPC-shZIP4) by short hairpin RNA using retrovirus vectors. The stable cells were characterized in vitro and in vivo using a nude mouse xenograft model. RESULTS: Silencing of ZIP4 was associated with decreased cell proliferation, migration, and invasion. Both ASPC-shZIP4 and BxPC-shZIP4 cells showed a significant reduction in tumor volume and weight in the s.c. model, and decreased primary tumor weight in the orthotopic model compared with the vector control cells (ASPC-shV and BxPC-shV). Silencing of ZIP4 also caused reduced incidence of tumor metastasis in the mice and downsized the tumor grade. More importantly, silencing of ZIP4 significantly increased the survival rate of nude mice with orthotopic xenografts (P = 0.005). All ASPC-shZIP4-injected mice (100%) remained alive up to 32 days after tumor implantation, whereas only 30% of the ASPC-shV mice were alive at the same time point. CyclinD1 expression was decreased in the ASPC-shZIP4 xenografts. CONCLUSIONS: These results identify a previously uncharacterized role of ZIP4 in pancreatic cancer progression, and indicate that knocking down ZIP4 by short hairpin RNA might be a novel treatment strategy for pancreatic cancers with ZIP4 overexpression.

23 Article Value of pancreatic resection for cancer metastatic to the pancreas. 2009

Sweeney, Alex D / Wu, Meng-Fen / Hilsenbeck, Susan G / Brunicardi, F Charles / Fisher, William E. ·The Elkins Pancreas Center, Dan L. Duncan Cancer Center, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA. ·J Surg Res · Pubmed #19375718.

ABSTRACT: BACKGROUND: Cancer metastatic to the pancreas from other primary sites is uncommon, and it has been treated with an aggressive surgical approach in fit patients when the primary tumor is controlled and the pancreas is the only site of metastatic disease. The value of pancreatic resection in this setting is unclear. The purpose of this study was to review cases of cancer metastatic to the pancreas. METHODS: We reviewed our experience with cancer metastatic to the pancreas and the literature regarding resection of pancreatic metastases. Patient and tumor characteristics were summarized using descriptive statistics. RESULTS: A total of 220 patients with pancreatic metastasis were analyzed. Three patients were selected from our own experience, and 217 were selected from a literature review. In the 127 patients whose symptoms were recorded at the time of presentation, the most common presenting symptoms were jaundice (n=32, 25.2%) and abdominal pain (n=25, 19.7%). In the 189 patients for whom the location of the metastasis in the pancreas was revealed, the most common location was the head of the pancreas (n=79, 41.8%). The primary tumor site was most commonly kidney (n=155, 70.5%). Surgical resection was attempted in 177 of 220 patients; 135 patients suffering from renal cell carcinoma (RCC) metastasis also underwent pancreatic resection. In the latter group, a median survival of 70 mo was seen, as well as 78% and 65% 2- and 5 y survival rates, respectively. CONCLUSION: Survival after resection of RCC with isolated metastasis to the pancreas is favorable. However, a more detailed analysis considering outcomes without surgery for each primary tumor site is needed before the value of this aggressive surgical approach can be completely assessed in the general occurrence of pancreatic metastasis.

24 Article Developing a tissue resource to characterize the genome of pancreatic cancer. 2009

Voidonikolas, Georgios / Gingras, Marie-Claude / Hodges, Sally / McGuire, Amy L / Chen, Changyi / Gibbs, Richard A / Brunicardi, F Charles / Fisher, William E. ·Michael E. DeBakey Department of Surgery, Baylor College of Medicine, 1709 Dryden, Suite 1500, Houston, TX 77030, USA. ·World J Surg · Pubmed #19137368.

ABSTRACT: With recent advances in DNA sequencing technology, medicine is entering an era in which a personalized genomic approach to diagnosis and treatment of disease is feasible. However, discovering the role of altered DNA sequences in various disease states will be a challenging task. The genomic approach offers great promise for diseases, such as pancreatic cancer, in which the effect of current diagnostic and treatment modalities is disappointing. To facilitate the characterization of the genome of pancreatic cancer, high-quality and well-annotated tissue repositories are needed. This article summarizes the basic principles that guide the creation of such a repository, including sample processing and preservation techniques, sample size and composition, and collection of clinical data elements.