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Pancreatic Neoplasms: HELP
Articles by Chanjuan Shi
Based on 40 articles published since 2010
(Why 40 articles?)
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Between 2010 and 2020, Chanjuan Shi wrote the following 40 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Pancreatic Neuroendocrine Tumors. 2016

Salaria, Safia N / Shi, Chanjuan. ·Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, 1161 21st Avenue South, C-3321 MCN, Nashville, TN 37232-2561, USA. · Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, 1161 21st Avenue South, C-3321 MCN, Nashville, TN 37232-2561, USA. Electronic address: Chanjuan.Shi@vanderbilt.edu. ·Surg Pathol Clin · Pubmed #27926362.

ABSTRACT: Pancreatic neuroendocrine neoplasms include well-differentiated pancreatic neuroendocrine tumors (PanNETs) and neuroendocrine carcinomas (NECs) with well-differentiated PanNETs accounting for most cases. Other pancreatic primaries and metastatic carcinomas from other sites can mimic pancreatic neuroendocrine neoplasms. Immunohistochemical studies can be used to aid in the differential diagnosis. However, no specific markers are available to differentiate PanNETs from NETs of other sites. Although NECs are uniformly deadly, PanNETs have variable prognosis. Morphology alone cannot predict the tumor behavior. Although some pathologic features are associated with an aggressive course, Ki67 is the only prognostic molecular marker routinely used in clinical practice.

2 Review The complexity of pancreatic ductal cancers and multidimensional strategies for therapeutic targeting. 2011

Kern, Scott E / Shi, Chanjuan / Hruban, Ralph H. ·Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA. sk@jhmi.edu ·J Pathol · Pubmed #21125682.

ABSTRACT: The directions of differentiation and the molecular features of ductal pancreatic cancer have by now been explored in reasonable detail. Already, diagnoses and therapeutic strategies benefit from observations distinguishing the major variant types of pancreatic cancer and the differing stages of disease at presentation. Additionally, individual patients differ within each variant type. In certain high-risk groups, this permits focused screening efforts. The tumorigenic influences that characterize individual patients are increasingly considered appropriate in defining clinical treatment plans. As a result, multiple variables affect success when individualizing screening or therapy. These competing variables often limit the potential for success: some variables dominate and should receive greater consideration than others. Simplistic expectations, often falsely optimistic, for individualized care may fail to 'pan out' in the real world. The development of individualized care will be efficient only when the full complexity of the disease is embraced.

3 Article Tobacco Carcinogen-Induced Production of GM-CSF Activates CREB to Promote Pancreatic Cancer. 2018

Srinivasan, Supriya / Totiger, Tulasigeri / Shi, Chanjuan / Castellanos, Jason / Lamichhane, Purushottam / Dosch, Austin R / Messaggio, Fanuel / Kashikar, Nilesh / Honnenahally, Kumaraswamy / Ban, Yuguang / Merchant, Nipun B / VanSaun, Michael / Nagathihalli, Nagaraj S. ·Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida. · Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee. · Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee. · Department of Pathology, University of Colorado, Denver, Colorado. · Department of Public Health, University of Miami Miller School of Medicine, Miami, Florida. · Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida. · Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida. nnagathihalli@med.miami.edu. ·Cancer Res · Pubmed #30232221.

ABSTRACT: Although smoking is a significant risk factor for pancreatic ductal adenocarcinoma (PDAC), the molecular mechanisms underlying PDAC development and progression in smokers are still unclear. Here, we show the role of cyclic AMP response element-binding protein (CREB) in the pathogenesis of smoking-induced PDAC. Smokers had significantly higher levels of activated CREB when compared with nonsmokers. Cell lines derived from normal pancreas and pancreatic intraepithelial neoplasm (PanIN) exhibited low baseline pCREB levels compared with PDAC cell lines. Furthermore, elevated CREB expression correlated with reduced survival in patients with PDAC. Depletion of CREB significantly reduced tumor burden after tobacco-specific nitrosamine 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) treatment, suggesting a CREB-dependent contribution to PDAC growth and progression in smokers. Conversely, NNK accelerated PanIN lesion and PDAC formation via GM-CSF-mediated activation of CREB in a PDAC mouse model. CREB inhibition (CREBi) in mice more effectively reduced primary tumor burden compared with control or GM-CSF blockade alone following NNK exposure. GM-CSF played a role in the recruitment of tumor-associated macrophages (TAM) and regulatory T cell (Treg) expansion and promotion, whereas CREBi significantly reduced TAM and Treg populations in NNK-exposed mice. Overall, these results suggest that NNK exposure leads to activation of CREB through GM-CSF, promoting inflammatory and Akt pathways. Direct inhibition of CREB, but not GM-CSF, effectively abrogates these effects and inhibits tumor progression, offering a viable therapeutic strategy for patients with PDAC.

4 Article Inverse Correlation of STAT3 and MEK Signaling Mediates Resistance to RAS Pathway Inhibition in Pancreatic Cancer. 2018

Nagathihalli, Nagaraj S / Castellanos, Jason A / Lamichhane, Purushottam / Messaggio, Fanuel / Shi, Chanjuan / Dai, Xizi / Rai, Priyamvada / Chen, Xi / VanSaun, Michael N / Merchant, Nipun B. ·Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida. · Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida. · Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee. · Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee. · Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida. · Department of Public Health, University of Miami Miller School of Medicine, Miami, Florida. · Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida. nmerchant@med.miami.edu. ·Cancer Res · Pubmed #30154150.

ABSTRACT: Major contributors to therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC) include

5 Article A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors. 2018

Alvarez, Mariano J / Subramaniam, Prem S / Tang, Laura H / Grunn, Adina / Aburi, Mahalaxmi / Rieckhof, Gabrielle / Komissarova, Elena V / Hagan, Elizabeth A / Bodei, Lisa / Clemons, Paul A / Dela Cruz, Filemon S / Dhall, Deepti / Diolaiti, Daniel / Fraker, Douglas A / Ghavami, Afshin / Kaemmerer, Daniel / Karan, Charles / Kidd, Mark / Kim, Kyoung M / Kim, Hee C / Kunju, Lakshmi P / Langel, Ülo / Li, Zhong / Lee, Jeeyun / Li, Hai / LiVolsi, Virginia / Pfragner, Roswitha / Rainey, Allison R / Realubit, Ronald B / Remotti, Helen / Regberg, Jakob / Roses, Robert / Rustgi, Anil / Sepulveda, Antonia R / Serra, Stefano / Shi, Chanjuan / Yuan, Xiaopu / Barberis, Massimo / Bergamaschi, Roberto / Chinnaiyan, Arul M / Detre, Tony / Ezzat, Shereen / Frilling, Andrea / Hommann, Merten / Jaeger, Dirk / Kim, Michelle K / Knudsen, Beatrice S / Kung, Andrew L / Leahy, Emer / Metz, David C / Milsom, Jeffrey W / Park, Young S / Reidy-Lagunes, Diane / Schreiber, Stuart / Washington, Kay / Wiedenmann, Bertram / Modlin, Irvin / Califano, Andrea. ·Department of Systems Biology, Columbia University, New York, NY, USA. · DarwinHealth Inc, New York, NY, USA. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Institute for Systems Genetics, New York University Langone Medical Center, New York, NY, USA. · Department of Urology, Columbia University, New York, NY, USA. · Division of Pathology, European Institute of Oncology, Milan, Italy. · Broad Institute of Harvard and MIT, Cambridge, MA, USA. · Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Cedars-Sinai Medical Center, Los Angeles, CA, USA. · Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. · PsychoGenics Inc., Tarrytown, NY, USA. · Department of General and Visceral Surgery, Zentralklinik, Bad Berka, Germany. · Sulzberger Columbia Genome Center, Columbia University, New York, NY, USA. · Wren Laboratories, Branford, CT, USA. · Division of Hematology Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. · Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. · Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. · Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA. · Department of Neurochemistry, the Arrhenius Laboratories for Nat. Sci., Stockholm University, Stockholm, Sweden. · Laboratory of Molecular Biotechnology, Institute of Technology, University of Tartu, Tartu, Estonia. · Falconwood Foundation, New York, NY, USA. · Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria. · Department of Pathology, Columbia University, New York, NY, USA. · Department of Pathology, University Health Network, University of Toronto, Toronto, Canada. · Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA. · Division of Colon and Rectal Surgery, State University of New York, Stony Brook, NY, USA. · Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI, USA. · Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA. · Imperial College London, London, UK. · Medical Oncology, National Center for Tumor Diseases Heidelberg, University Medical Center Heidelberg, Heidelberg, Germany. · Mount Sinai School of Medicine, New York, NY, USA. · Department of Surgery, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA. · Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA. · Department of Internal Medicine, Division of Gastroenterology, Charite, Universitätsmedizin Berlin, Berlin, Germany. · Emeritus Professor Gastrointestinal Surgery, School of Medicine, Yale University, New Haven, Connecticut, USA. imodlin@irvinmodlin.com. · Department of Systems Biology, Columbia University, New York, NY, USA. califano@cumc.columbia.edu. · Department of Biomedical Informatics, Columbia University, New York, NY, USA. califano@cumc.columbia.edu. · Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA. califano@cumc.columbia.edu. · J.P. Sulzberger Columbia Genome Center, Columbia University, New York, NY, USA. califano@cumc.columbia.edu. · Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA. califano@cumc.columbia.edu. ·Nat Genet · Pubmed #29915428.

ABSTRACT: We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology.

6 Article EUS and confocal endomicroscopic diagnosis of pancreatic acinar cell cystadenoma. 2018

Orr, Jordan / Lockwood, Robert / Roberts, Jordan / Shi, Chanjuan / Yachimski, Patrick. ·Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA. · Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. ·Gastrointest Endosc · Pubmed #29906415.

ABSTRACT: -- No abstract --

7 Article Hepatic micrometastases are associated with poor prognosis in patients with liver metastases from neuroendocrine tumors of the digestive tract. 2018

Gibson, William E / Gonzalez, Raul S / Cates, Justin M M / Liu, Eric / Shi, Chanjuan. ·Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37027. · Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642. · Department of Surgery, Rocky Mountain Cancer Centers, Denver, CO 80218. · Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37027. Electronic address: Chanjuan.Shi@vanderbilt.edu. ·Hum Pathol · Pubmed #29763717.

ABSTRACT: Pathologic examination of hepatic metastasectomies from patients with metastatic small intestinal or pancreatic neuroendocrine tumor frequently reveals micrometastases undetectable by radiologic or macroscopic gross examination. This finding raises the possibility that undetectable micrometastases remain in these patients after metastasectomy. Here we examined liver resections for micrometastases and assessed their impact on prognosis. Hepatic metastasectomies from 65 patients with neuroendocrine tumor of the small intestine (N = 43) or pancreas (N = 22) were reviewed for the presence of micrometastases, which were defined as microscopic tumor foci ≤1 mm in greatest dimension. Medical records were also reviewed for patient demographics, clinical history, and follow-up data. Micrometastasis was identified in 36 (55%) of 65 hepatic resection specimens. More hepatic micrometastases were seen in small intestinal cases than in pancreatic cases (29/43, 67%, versus 7/22, 32%; P < .01). They were typically present within portal tracts, sometimes with extension into the periportal region or sinusoidal spaces away from the portal tracts. Patients without hepatic micrometastases had fewer macrometastases or more R0 hepatic resections than those with micrometastases. The presence of hepatic micrometastases was associated with poor overall survival both before (hazard ratio [HR] 3.43; 95% CI 1.14-10.30; P = .03) and after accounting for confounding variables in stratified Cox regression (HR 4.82; 95% CI 1.0621.79; P = .04). In conclusion, hepatic micrometastases are common in patients with metastatic small intestinal or pancreatic neuroendocrine tumor and are independently associated with poor prognosis. These data suggest that surgical resection of hepatic metastases is likely not curative in these patients.

8 Article Development of Aggressive Pancreatic Ductal Adenocarcinomas Depends on Granulocyte Colony Stimulating Factor Secretion in Carcinoma Cells. 2017

Pickup, Michael W / Owens, Philip / Gorska, Agnieszka E / Chytil, Anna / Ye, Fei / Shi, Chanjuan / Weaver, Valerie M / Kalluri, Raghu / Moses, Harold L / Novitskiy, Sergey V. ·Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco (UCSF), San Francisco, California. · Department of Cancer Biology and the Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University, Nashville, Tennessee. · Division of Cancer Biostatistics, Department of Biostatistics, Vanderbilt University, Nashville, Tennessee. · Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee. · Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Cancer Biology and the Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University, Nashville, Tennessee. sergey.v.novitskiy@vanderbilt.edu. ·Cancer Immunol Res · Pubmed #28775207.

ABSTRACT: The survival rate for pancreatic ductal adenocarcinoma (PDAC) remains low. More therapeutic options to treat this disease are needed, for the current standard of care is ineffective. Using an animal model of aggressive PDAC (Kras/p48

9 Article Early onset pancreatic malignancies: Clinical characteristics and survival associations. 2016

Beeghly-Fadiel, Alicia / Luu, Hung N / Du, Liping / Shi, Chanjuan / McGavic, Dauphne P / Parikh, Alexander A / Raskin, Leon. ·Division of Epidemiology, School of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Comprehensive Cancer Center, Nashville, TN. · Department of Epidemiology and Biostatistics, College of Public Health, University of South Florida, Tampa, FL. · School of Medicine, Center for Quantitative Sciences, Vanderbilt University Medical Center and Vanderbilt Ingram Comprehensive Cancer Center, Nashville, TN. · Department of Pathology, School of Medicine, Vanderbilt University Medical Center, Nashville, TN. · Vanderbilt Cancer Registry, Vanderbilt University Medical Center and Vanderbilt Ingram Comprehensive Cancer Center, Nashville, TN. · Division of Surgical Oncology and Endocrine Surgery, School of Medicine, Vanderbilt University Medical Center, Nashville, TN. · Division of Epidemiology, School of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Comprehensive Cancer Center, Nashville, TN. leonid.raskin@vanderbilt.edu. ·Int J Cancer · Pubmed #27416564.

ABSTRACT: Diagnosed before age 50, early onset pancreatic malignancy (EOPM), is hypothesized to be a distinct subset of disease, although research is limited. To better characterize EOPM, and the effect of age at diagnosis on pancreatic cancer survival, we examined clinical characteristics and survival in EOPM and typical age-at-onset pancreatic malignancy (TOPM) cases. Vanderbilt University Medical Center (VUMC) Cancer Registry confirmed pancreatic adenocarcinomas (PDACs) and malignant pancreatic neuroendocrine tumors (PNETs) were evaluated. Clinical characteristics were compared using χ(2) tests. Overall survival was visualized with Kaplan-Meier functions; Cox proportional hazards regression was used to evaluate hazard ratios (HRs) and 95% confidence intervals (CIs). A total of 1,697 pancreatic malignancies were diagnosed at the VUMC between 1988 and 2013. Of 1,407 PDACs, 118 (8.4%) were EOPM, which was associated with significantly better survival (adjusted HR: 0.82, 95% CI: 0.67-1.00). EOPM and TOPM PDACs significantly differed with regard to having multiple malignancies; survival associations significantly differed by race, stage of disease, treatment and multiple malignancies. Of 190 PNETs, 63 (33.1%) were EOPM, which was not significantly associated with survival (adjusted HR: 0.80, 95% CI: 0.46-1.40). Malignant neuroendocrine EOPM and TOPM cases significantly differed by stage of disease and tumor location; survival associations significantly differed by family history of pancreatic cancer, stage of disease and multiple malignancies. Differences in clinical characteristics and associations with survival were identified, indicating that EOPM is distinct from TOPM, and exists among both pancreatic adenocarcinomas and malignant pancreatic neuroendocrine tumors.

10 Article Safety and Efficacy of 68Ga-DOTATATE PET/CT for Diagnosis, Staging, and Treatment Management of Neuroendocrine Tumors. 2016

Deppen, Stephen A / Liu, Eric / Blume, Jeffrey D / Clanton, Jeffrey / Shi, Chanjuan / Jones-Jackson, Laurie B / Lakhani, Vipul / Baum, Richard P / Berlin, Jordan / Smith, Gary T / Graham, Michael / Sandler, Martin P / Delbeke, Dominique / Walker, Ronald C. ·Veterans Affairs Hospital, Tennessee Valley VA Healthcare System, Nashville, Tennessee Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee. · Rocky Mountain Cancer Centers, Denver, Colorado. · Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee. · Oregon Medical Group, Springfield, Oregon. · THERANOSTICS Center for Molecular Radiotherapy and Molecular Imaging (PET/CT), ENETS Center of Excellence, Zentralklinik Bad Berka, Bad Berka, Germany. · Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; and. · Veterans Affairs Hospital, Tennessee Valley VA Healthcare System, Nashville, Tennessee Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Radiology, University of Iowa, Iowa City, Iowa. · Veterans Affairs Hospital, Tennessee Valley VA Healthcare System, Nashville, Tennessee Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; and ronald.walker@vanderbilt.edu. ·J Nucl Med · Pubmed #26769865.

ABSTRACT: METHODS: (68)Ga-DOTATATE PET/CT and (111)In-pentetreotide scans were obtained for 78 of 97 consecutively enrolled patients with known or suspected pulmonary or gastroenteropancreatic neuroendocrine tumors. Safety and toxicity were measured by comparing vital signs, serum chemistry values, or acquisition-related medical complications before and after (68)Ga-DOTATATE injection. Added value was determined by changes in treatment plan when (68)Ga-DOTATATE PET/CT results were added to all prior imaging, including (111)In-pentetreotide. Interobserver reproducibility of (68)Ga-DOTATATE PET/CT scan interpretation was measured between blinded and nonblinded interpreters. RESULTS: (68)Ga-DOTATATE PET/CT and (111)In-pentetreotide scans were significantly different in impact on treatment (P < 0.001). (68)Ga-DOTATATE PET/CT combined with CT or liver MRI changed care in 28 of 78 (36%) patients. Interobserver agreement between blinded and nonblinded interpreters was high. No participant had a trial-related event requiring treatment. Mild, transient events were tachycardia in 1, alanine transaminase elevation in 1, and hyperglycemia in 2 participants. No clinically significant arrhythmias occurred. (68)Ga-DOTATATE PET/CT correctly identified 3 patients for peptide-receptor radiotherapy incorrectly classified by (111)In-pentetreotide. CONCLUSION: (68)Ga-DOTATATE PET/CT was equivalent or superior to (111)In-pentetreotide imaging in all 78 patients. No adverse events requiring treatment were observed. (68)Ga-DOTATATE PET/CT changed treatment in 36% of participants. Given the lack of significant toxicity, lower radiation exposure, and improved accuracy compared with (111)In-pentetreotide, (68)Ga-DOTATATE imaging should be used instead of (111)In-pentetreotide imaging where available.

11 Article Expression of CD24, a Stem Cell Marker, in Pancreatic and Small Intestinal Neuroendocrine Tumors. 2015

Salaria, Safia / Means, Anna / Revetta, Frank / Idrees, Kamran / Liu, Eric / Shi, Chanjuan. ·From the Departments of Pathology, Microbiology, and Immunology; Safia.n.salaria@vanderbilt.edu. · Surgery; and. · From the Departments of Pathology, Microbiology, and Immunology; · Surgical Oncology, Vanderbilt University Hospital, Nashville, TN. ·Am J Clin Pathol · Pubmed #26386086.

ABSTRACT: OBJECTIVES: CD24 has been considered a normal and cancer stem cell marker. Potential intestinal stem cells weakly express CD24. In the pancreas, CD24 is a possible cancer stem cell marker for ductal adenocarcinoma. METHODS: Expression of CD24 in intestinal and pancreatic neuroendocrine tumors (NETs) was examined. Immunohistochemistry was performed on benign duodenum, ileum mucosa, and pancreas, as well as primary duodenal, primary and metastatic ileal, and pancreatic NETs. RESULTS: Scattered CD24-positive cells were noted in the duodenal and ileal crypts, most of which showed a strong subnuclear labeling pattern. Similar expression was observed in 41 (95%) of 43 primary ileal NETs but in only four (15%) of 26 duodenal NETs (P < .01). In addition, metastatic ileal NETs retained CD24 expression. Pancreatic islets did not express CD24, and only rare cells had subnuclear labeling of CD24 in the pancreatic ducts. Unlike ileal NETs, only five (5%) of 92 pancreatic NETs expressed CD24 in the subnuclear compartment (P < .01). All five NETs showed a unique morphology with prominent stromal fibrosis. CONCLUSIONS: CD24 expression was frequent in primary and metastatic midgut NETs but rare in pancreatic and duodenal NETs. Expression of CD24 in ileal NETs may have future diagnostic and therapeutic implications.

12 Article Signal Transducer and Activator of Transcription 3, Mediated Remodeling of the Tumor Microenvironment Results in Enhanced Tumor Drug Delivery in a Mouse Model of Pancreatic Cancer. 2015

Nagathihalli, Nagaraj S / Castellanos, Jason A / Shi, Chanjuan / Beesetty, Yugandhar / Reyzer, Michelle L / Caprioli, Richard / Chen, Xi / Walsh, Alex J / Skala, Melissa C / Moses, Harold L / Merchant, Nipun B. ·Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, Florida. · Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee. · Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee. · Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee. · Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee. · Department of Biomedical Engineering, Vanderbilt University School of Medicine, Nashville, Tennessee. · Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee. · Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, Florida. Electronic address: nmerchant@miami.edu. ·Gastroenterology · Pubmed #26255562.

ABSTRACT: BACKGROUND & AIMS: A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the presence of a dense desmoplastic reaction (stroma) that impedes drug delivery to the tumor. Attempts to deplete the tumor stroma have resulted in formation of more aggressive tumors. We have identified signal transducer and activator of transcription (STAT) 3 as a biomarker of resistance to cytotoxic and molecularly targeted therapy in PDAC. The purpose of this study is to investigate the effects of targeting STAT3 on the PDAC stroma and on therapeutic resistance. METHODS: Activated STAT3 protein expression was determined in human pancreatic tissues and tumor cell lines. In vivo effects of AZD1480, a JAK/STAT3 inhibitor, gemcitabine or the combination were determined in Ptf1a(cre/+);LSL-Kras(G12D/+);Tgfbr2(flox/flox) (PKT) mice and in orthotopic tumor xenografts. Drug delivery was analyzed by matrix-assisted laser desorption/ionization imaging mass spectrometry. Collagen second harmonic generation imaging quantified tumor collagen alignment and density. RESULTS: STAT3 activation correlates with decreased survival and advanced tumor stage in patients with PDAC. STAT3 inhibition combined with gemcitabine significantly inhibits tumor growth in both an orthotopic and the PKT mouse model of PDAC. This combined therapy attenuates in vivo expression of SPARC, increases microvessel density, and enhances drug delivery to the tumor without depletion of stromal collagen or hyaluronan. Instead, the PDAC tumors demonstrate vascular normalization, remodeling of the tumor stroma, and down-regulation of cytidine deaminase. CONCLUSIONS: Targeted inhibition of STAT3 combined with gemcitabine enhances in vivo drug delivery and therapeutic response in PDAC. These effects occur through tumor stromal remodeling and down-regulation of cytidine deaminase without depletion of tumor stromal content.

13 Article Cadherin 17 is frequently expressed by 'sclerosing variant' pancreatic neuroendocrine tumour. 2015

Johnson, Adam / Wright, Jesse P / Zhao, Zhiguo / Komaya, Tatsuki / Parikh, Alexander / Merchant, Nipun / Shi, Chanjuan. ·Department of Microbiology, Immunology and Pathology, Vanderbilt University Medical Center, Nashville, TN, USA. ·Histopathology · Pubmed #25307987.

ABSTRACT: AIMS: Recently, we described a series of pancreatic neuroendocrine tumours (PanNETs) featuring prominent stromal fibrosis, which we called sclerosing PanNETs. The aim of this study was to examine the pathological, immunophenotypic and clinical differences between sclerosing and non-sclerosing PanNETs. METHODS AND RESULTS: One hundred and six PanNETs were identified, of which 15 (14%) were sclerosing NETs. Tissue microarrays containing 44 non-sclerosing and five sclerosing PanNETs, as well as sections from 10 additional sclerosing tumours, were immunohistochemically labelled for serotonin, CDX2, CDH17, and islet 1. Sclerosing PanNETs were smaller (P = 0.045) and more likely to show an infiltrative growth pattern (P < 0.001) than non-sclerosing PanNETs. They were frequently associated with a large pancreatic duct, causing duct stenosis. Additionally, we found significantly increased expression of the small intestinal NET markers serotonin, CDX2 and CDH17 in sclerosing PanNETs (P < 0.001) as compared with non-sclerosing PanNETs. No difference in clinical outcome was found; however, more sclerosing PanNETs were stage IIB or above (P = 0.035), with lymph node metastasis being seen in three of nine sclerosing PanNETs with a tumour size of <20 mm. CONCLUSIONS: Sclerosing PanNETs have distinct pathological features and biomarker expression profiles. In addition, lymph node metastasis can be present even with small sclerosing PanNETs.

14 Article Pancreatic neuroendocrine tumors: pathologic and molecular characteristics. 2014

Shi, Chanjuan / Klimstra, David S. ·Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, New York 10065. Electronic address: klimstrd@mskcc.org. ·Semin Diagn Pathol · Pubmed #25441311.

ABSTRACT: Pancreatic neuroendocrine neoplasms include mainly well-differentiated neuroendocrine tumors but also rare poorly differentiated neuroendocrine carcinomas. Molecular mechanisms underlying pancreatic neuroendocrine tumorigenesis have recently been elucidated. While alterations in the chromatin remodeling and PI3K/Akt/mTOR pathways are present in most well-differentiated pancreatic neuroendocrine tumors, mutations in TP53 and RB may contribute to the development of pancreatic poorly differentiated neuroendocrine carcinomas. With these discoveries, new molecular targeted therapies have become available and show promise in some patients with pancreatic well-differentiated neuroendocrine tumor.

15 Article PI3K regulation of RAC1 is required for KRAS-induced pancreatic tumorigenesis in mice. 2014

Wu, Chia-Yen C / Carpenter, Eileen S / Takeuchi, Kenneth K / Halbrook, Christopher J / Peverley, Louise V / Bien, Harold / Hall, Jason C / DelGiorno, Kathleen E / Pal, Debjani / Song, Yan / Shi, Chanjuan / Lin, Richard Z / Crawford, Howard C. ·Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York. · Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York. · Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida. · Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida; Department of Chemistry, Stony Brook University, Stony Brook, New York. · Division of Hematology/Oncology, Stony Brook University, Stony Brook, New York. · Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York; Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida. · Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida; Molecular Genetics and Microbiology Graduate Program, Stony Brook University, Stony Brook, New York. · Molecular and Cellular Biology Graduate Program, Stony Brook University, Stony Brook, New York. · Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee. · Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York; Medical Service, Northport VA Medical Center, Northport, New York. Electronic address: richard.lin@stonybrook.edu. · Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York; Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida. Electronic address: crawford.howard@mayo.edu. ·Gastroenterology · Pubmed #25311989.

ABSTRACT: BACKGROUND & AIMS: New drug targets are urgently needed for the treatment of patients with pancreatic ductal adenocarcinoma (PDA). Nearly all PDAs contain oncogenic mutations in the KRAS gene. Pharmacological inhibition of KRAS has been unsuccessful, leading to a focus on downstream effectors that are more easily targeted with small molecule inhibitors. We investigated the contributions of phosphoinositide 3-kinase (PI3K) to KRAS-initiated tumorigenesis. METHODS: Tumorigenesis was measured in the Kras(G12D/+);Ptf1a(Cre/+) mouse model of PDA; these mice were crossed with mice with pancreas-specific disruption of genes encoding PI3K p110α (Pik3ca), p110β (Pik3cb), or RAC1 (Rac1). Pancreatitis was induced with 5 daily intraperitoneal injections of cerulein. Pancreata and primary acinar cells were isolated; acinar cells were incubated with an inhibitor of p110α (PIK75) followed by a broad-spectrum PI3K inhibitor (GDC0941). PDA cell lines (NB490 and MiaPaCa2) were incubated with PIK75 followed by GDC0941. Tissues and cells were analyzed by histology, immunohistochemistry, quantitative reverse-transcription polymerase chain reaction, and immunofluorescence analyses for factors involved in the PI3K signaling pathway. We also examined human pancreas tissue microarrays for levels of p110α and other PI3K pathway components. RESULTS: Pancreas-specific disruption of Pik3ca or Rac1, but not Pik3cb, prevented the development of pancreatic tumors in Kras(G12D/+);Ptf1a(Cre/+) mice. Loss of transformation was independent of AKT regulation. Preneoplastic ductal metaplasia developed in mice lacking pancreatic p110α but regressed. Levels of activated and total RAC1 were higher in pancreatic tissues from Kras(G12D/+);Ptf1a(Cre/+) mice compared with controls. Loss of p110α reduced RAC1 activity and expression in these tissues. p110α was required for the up-regulation and activity of RAC guanine exchange factors during tumorigenesis. Levels of p110α and RAC1 were increased in human pancreatic intraepithelial neoplasias and PDAs compared with healthy pancreata. CONCLUSIONS: KRAS signaling, via p110α to activate RAC1, is required for transformation in Kras(G12D/+);Ptf1a(Cre/+) mice.

16 Article Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes. 2014

Chmielecki, Juliann / Hutchinson, Katherine E / Frampton, Garrett M / Chalmers, Zachary R / Johnson, Adrienne / Shi, Chanjuan / Elvin, Julia / Ali, Siraj M / Ross, Jeffrey S / Basturk, Olca / Balasubramanian, Sohail / Lipson, Doron / Yelensky, Roman / Pao, William / Miller, Vincent A / Klimstra, David S / Stephens, Philip J. ·Foundation Medicine, Cambridge, Massachusetts. · Vanderbilt University Medical Center, Nashville, Tennessee. · Foundation Medicine, Cambridge, Massachusetts. Albany Medical College, Albany, New York. · Memorial Sloan Kettering Cancer Center, New York, New York. · Memorial Sloan Kettering Cancer Center, New York, New York. klimstrd@mskcc.org pstephens@foundationmedicine.com. · Foundation Medicine, Cambridge, Massachusetts. klimstrd@mskcc.org pstephens@foundationmedicine.com. ·Cancer Discov · Pubmed #25266736.

ABSTRACT: SIGNIFICANCE: PACC is genomically distinct from other pancreatic cancers. Fusions in RAF genes and mutually exclusive inactivation of DNA repair genes represent novel potential therapeutic targets that are altered in over two thirds of these tumors.

17 Article Loss of HNF6 expression correlates with human pancreatic cancer progression. 2014

Pekala, Kelly R / Ma, Xidi / Kropp, Peter A / Petersen, Christine P / Hudgens, Courtney W / Chung, Christine H / Shi, Chanjuan / Merchant, Nipun B / Maitra, Anirban / Means, Anna L / Gannon, Maureen A. ·Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. · Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, USA. · 1] Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA [2] VA Medical Center, Nashville, TN, USA. · Department of Oncology, Johns Hopkins University, Baltimore, MD, USA. · Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA. · Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA. · 1] Department of Oncology, Johns Hopkins University, Baltimore, MD, USA [2] Department of Pathology, Johns Hopkins University, Baltimore, MD, USA. · 1] Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA. · 1] Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, USA [3] VA Medical Center, Nashville, TN, USA [4] Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA. ·Lab Invest · Pubmed #24638272.

ABSTRACT: Normal pancreatic epithelium progresses through various stages of pancreatic intraepithelial neoplasms (PanINs) in the development of pancreatic ductal adenocarcinoma (PDAC). Transcriptional regulation of this progression is poorly understood. In mouse, the hepatic nuclear factor 6 (Hnf6) transcription factor is expressed in ductal cells and at lower levels in acinar cells of the adult pancreas, but not in mature endocrine cells. Hnf6 is critical for terminal differentiation of the ductal epithelium during embryonic development and for pancreatic endocrine cell specification. We previously showed that, in mice, loss of Hnf6 from the pancreatic epithelium during organogenesis results in increased duct proliferation and altered duct architecture, increased periductal fibrosis and acinar-to-ductal metaplasia. Here we show that decreased expression of HNF6 is strongly correlated with increased severity of PanIN lesions in samples of human pancreata and is absent from >90% of PDAC. Mouse models in which cancer progression can be analyzed from the earliest stages that are seldom accessible in humans support a role for Hnf6 loss in progression from early- to late-stage PanIN and PDAC. In addition, gene expression analyses of human pancreatic cancer reveal decreased expression of HNF6 and its direct and indirect target genes compared with normal tissue and upregulation of genes that act in opposition to HNF6 and its targets. The negative correlation between HNF6 expression and pancreatic cancer progression suggests that HNF6 maintains pancreatic epithelial homeostasis in humans, and that its loss contributes to the progression from PanIN to ductal adenocarcinoma. Insight on the role of HNF6 in pancreatic cancer development could lead to its use as a biomarker for early detection and prognosis.

18 Article Fibrogenesis in pancreatic cancer is a dynamic process regulated by macrophage-stellate cell interaction. 2014

Shi, Chanjuan / Washington, M Kay / Chaturvedi, Rupesh / Drosos, Yiannis / Revetta, Frank L / Weaver, Connie J / Buzhardt, Emily / Yull, Fiona E / Blackwell, Timothy S / Sosa-Pineda, Beatriz / Whitehead, Robert H / Beauchamp, R Daniel / Wilson, Keith T / Means, Anna L. ·Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. · Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. · Department of Genetics, St Jude Children's Research Hospital, Memphis, TN, USA. · Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA. · Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA. · 1] Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA. · 1] Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA [2] Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA [3] Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA [4] Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA. ·Lab Invest · Pubmed #24535260.

ABSTRACT: Pancreatic cancer occurs in the setting of a profound fibrotic microenvironment that often dwarfs the actual tumor. Although pancreatic fibrosis has been well studied in chronic pancreatitis, its development in pancreatic cancer is much less well understood. This article describes the dynamic remodeling that occurs from pancreatic precursors (pancreatic intraepithelial neoplasias (PanINs)) to pancreatic ductal adenocarcinoma, highlighting similarities and differences between benign and malignant disease. Although collagen matrix is a commonality throughout this process, early stage PanINs are virtually free of periostin while late stage PanIN and pancreatic cancer are surrounded by an increasing abundance of this extracellular matrix protein. Myofibroblasts also become increasingly abundant during progression from PanIN to cancer. From the earliest stages of fibrogenesis, macrophages are associated with this ongoing process. In vitro co-culture indicates there is cross-regulation between macrophages and pancreatic stellate cells (PaSCs), precursors to at least some of the fibrotic cell populations. When quiescent PaSCs were co-cultured with macrophage cell lines, the stellate cells became activated and the macrophages increased cytokine production. In summary, fibrosis in pancreatic cancer involves a complex interplay of cells and matrices that regulate not only the tumor epithelium but the composition of the microenvironment itself.

19 Article GNAS sequencing identifies IPMN-specific mutations in a subgroup of diminutive pancreatic cysts referred to as "incipient IPMNs". 2014

Matthaei, Hanno / Wu, Jian / Dal Molin, Marco / Shi, Chanjuan / Perner, Sven / Kristiansen, Glen / Lingohr, Philipp / Kalff, Jörg C / Wolfgang, Christopher L / Kinzler, Kenneth W / Vogelstein, Bert / Maitra, Anirban / Hruban, Ralph H. ·Departments of *Pathology ††Oncology #Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine ‡Ludwig Center for Cancer Genetics **Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD §Department of Pathology, Microbiology, Immunology, Vanderbilt University Medical Center, Nashville, TN Departments of †General, Visceral, Thoracic and Vascular Surgery ¶Prostate Cancer Research ∥Institute of Pathology, University of Bonn, Bonn, Germany. ·Am J Surg Pathol · Pubmed #24525507.

ABSTRACT: Incipient intraductal papillary mucinous neoplasms (IPMNs) are poorly described subcentimeter pancreatic cysts with papillae and mucin similar to IPMNs. They are larger than pancreatic intraepithelial neoplasia but do not meet the cutoff size for IPMNs (≥ 1 cm). GNAS codon 201 mutations are hallmark genetic alterations of IPMNs. Hence, we sought to determine the GNAS status of incipient IPMNs to better classify these lesions. Incipient IPMNs from 3 institutions were histologically reassessed, manually microdissected, and the genomic DNA was extracted. Using a sensitive digital ligation technique, the mutational status of KRAS at codon 12 and GNAS at codon 201 was determined. We included 21 incipient IPMNs from 7 male and 12 female patients with a median age of 63 years (range, 40 to 76 y). Most patients underwent surgery for pancreatic ductal adenocarcinoma (N = 8) or ampullary adenocarcinoma (N = 3). The median incipient IPMN size was 4 mm (range, 2 to 7 mm), and a majority had gastric-foveolar (N = 11) or intestinal (N = 5) differentiation. The maximum dysplasia observed was intermediate, and most of the lesions had intermediate-grade dysplasia. Mutational analysis revealed KRAS codon 12 mutations in all 21 incipient IPMNs, whereas 7 lesions (33%) in 7 individual patients harbored GNAS codon 201 mutations. The presence of GNAS 201 mutations in incipient IPMNs suggests that a fraction of these cysts are in fact small IPMNs. Morphologically, incipient IPMNs do not appear to be high-risk lesions. Additional studies in a larger cohort are needed to define the relationship of incipient IPMNs to larger IPMNs and, more importantly, to determine their clinical significance.

20 Article Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases. 2014

Basturk, Olca / Tang, Laura / Hruban, Ralph H / Adsay, Volkan / Yang, Zhaohai / Krasinskas, Alyssa M / Vakiani, Efsevia / La Rosa, Stefano / Jang, Kee-Taek / Frankel, Wendy L / Liu, Xiuli / Zhang, Lizhi / Giordano, Thomas J / Bellizzi, Andrew M / Chen, Jey-Hsin / Shi, Chanjuan / Allen, Peter / Reidy, Diane L / Wolfgang, Christopher L / Saka, Burcu / Rezaee, Neda / Deshpande, Vikram / Klimstra, David S. ·Departments of *Pathology ***Surgery †††Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY †Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center ‡‡‡Department of Surgery, Johns Hopkins University, Baltimore, MD ‡Department of Pathology, Emory University, Atlanta, GA §Department of Pathology, Penn State Hershey MC, Hershey ∥Department of Pathology, University of Pittsburgh, Pittsburgh, PA **Department of Pathology, Ohio State University, Columbus ††Department of Pathology, Cleveland Clinic, Cleveland, OH ‡‡Department of Pathology, Mayo Clinic, Rochester, MN §§Department of Pathology, University of Michigan, Ann Arbor, MI ∥∥Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA ¶¶Department of Pathology, Indiana University, Indianapolis, IN ##Department of Pathology, Vanderbilt University, Nashville, TN §§§Department of Pathology, Massachusetts General Hospital, Boston, MA ¶Department of Pathology, Ospedale di Circolo, Varese, Italy #Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. ·Am J Surg Pathol · Pubmed #24503751.

ABSTRACT: BACKGROUND: In the pancreas, poorly differentiated neuroendocrine carcinomas include small cell carcinoma and large cell neuroendocrine carcinoma and are rare; data regarding their pathologic and clinical features are very limited. DESIGN: A total of 107 pancreatic resections originally diagnosed as poorly differentiated neuroendocrine carcinomas were reassessed using the classification and grading (mitotic rate/Ki67 index) criteria put forth by the World Health Organization in 2010 for the gastroenteropancreatic system. Immunohistochemical labeling for neuroendocrine and acinar differentiation markers was performed. Sixty-three cases were reclassified, mostly as well-differentiated neuroendocrine tumor (NET) or acinar cell carcinoma, and eliminated. The clinicopathologic features and survival of the remaining 44 poorly differentiated neuroendocrine carcinomas were further assessed. RESULTS: The mean patient age was 59 years (range, 21 to 82 y), and the male/female ratio was 1.4. Twenty-seven tumors were located in the head of the pancreas, 3 in the body, and 11 in the tail. The median tumor size was 4 cm (range, 2 to 18 cm). Twenty-seven tumors were large cell neuroendocrine carcinomas, and 17 were small cell carcinomas (mean mitotic rate, 37/10 and 51/10 HPF; mean Ki67 index, 66% and 75%, respectively). Eight tumors had combined components, mostly adenocarcinomas. In addition, 2 tumors had components of well-differentiated NET. Eighty-eight percent of the patients had nodal or distant metastatic disease at presentation, and an additional 7% developed metastases subsequently. Follow-up information was available for 43 patients; 33 died of disease, with a median survival of 11 months (range, 0 to 104 mo); 8 were alive with disease, with a median follow-up of 19.5 months (range, 0 to 71 mo). The 2- and 5-year survival rates were 22.5% and 16.1%, respectively. CONCLUSIONS: Poorly differentiated neuroendocrine carcinoma of the pancreas is a highly aggressive neoplasm, with frequent metastases and poor survival. Most patients die within less than a year. Most (61%) are large cell neuroendocrine carcinomas. Well-differentiated NET and acinar cell carcinoma are often misdiagnosed as poorly differentiated neuroendocrine carcinoma, emphasizing that diagnostic criteria need to be clearly followed to ensure accurate diagnosis.

21 Article Differentiation of pancreatic ductal adenocarcinoma from chronic pancreatitis by PAM4 immunohistochemistry. 2014

Shi, Chanjuan / Merchant, Nipun / Newsome, Guy / Goldenberg, David M / Gold, David V. ·From the Departments of Pathology, Microbiology, and Immunology (Dr Shi) and Surgical Oncology (Dr Merchant), Vanderbilt University Medical Center, Nashville, Tennessee · and the Center for Molecular Medicine and Immunology, Garden State Cancer Center, Morris Plains, New Jersey (Mr Newsome and Drs Goldenberg and Gold). ·Arch Pathol Lab Med · Pubmed #24476519.

ABSTRACT: CONTEXT: PAM4 is a monoclonal antibody that shows high specificity for pancreatic ductal adenocarcinoma (PDAC) and its neoplastic precursor lesions. A PAM4-based serum immunoassay is able to detect 71% of early-stage patients and 91% with advanced disease. However, approximately 20% of patients diagnosed with chronic pancreatitis (CP) are also positive for circulating PAM4 antigen. The specificity of the PAM4 antibody is critical to the interpretation of the serum-based and immunohistochemical assays for detection of PDAC. OBJECTIVE: To determine whether PAM4 can differentiate PDAC from nonneoplastic lesions of the pancreas. DESIGN: Tissue microarrays of PDAC (N = 43) and surgical specimens from CP (N = 32) and benign cystic lesions (N = 19) were evaluated for expression of the PAM4 biomarker, MUC1, MUC4, CEACAM5/6, and CA19-9. RESULTS: PAM4 and monoclonal antibodies (MAbs) to MUC1, MUC4, CEACAM5/6, and CA19-9 were each reactive with the majority of PDAC cases; however, PAM4 was the only monoclonal antibody not to react with adjacent, nonneoplastic parenchyma. Although PAM4 labeled 19% (6 of 32) of CP specimens, reactivity was restricted to pancreatic intraepithelial neoplasia associated with CP; inflamed tissues were negative in all cases. In contrast, MUC1, MUC4, CEACAM5/6, and CA19-9 were detected in 90%, 78%, 97%, and 100% of CP, respectively, with reactivity also present in nonneoplastic inflamed tissue. CONCLUSIONS: PAM4 was the only monoclonal antibody able to differentiate PDAC (and pancreatic intraepithelial neoplasia precursor lesions) from benign, nonneoplastic tissues of the pancreas. These results suggest the use of PAM4 for evaluation of tissue specimens, and support its role as an immunoassay for detection of PDAC.

22 Article Epidermal growth factor receptor signaling pathway is frequently altered in ampullary carcinoma at protein and genetic levels. 2014

Mikhitarian, Kaidi / Pollen, Maressa / Zhao, Zhiguo / Shyr, Yu / Merchant, Nipun B / Parikh, Alexander / Revetta, Frank / Washington, M Kay / Vnencak-Jones, Cindy / Shi, Chanjuan. ·Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. · Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA. · Department of Surgery, Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN, USA. ·Mod Pathol · Pubmed #24186143.

ABSTRACT: Our objective was to explore alteration of the epidermal growth factor receptor (EGFR) signaling pathway in ampullary carcinoma. Immunohistochemical studies were employed to evaluate expression of amphiregulin as well as expression and activation of EGFR. A lab-developed assay was used to identify mutations in the EGFR pathway genes, including KRAS, BRAF, PIK3CA, PTEN, and AKT1. A total of 52 ampullary carcinomas were identified, including 25 intestinal-type and 24 pancreatobiliary-type tumors, with the intestinal type being associated with a younger age at diagnosis (P=0.03) and a better prognosis (P<0.01). Expression of amphiregulin correlated with better differentiation (P<0.01), but no difference was observed between two major histologic types. Expression and activation of EGFR was more commonly seen in the pancreatobiliary type (P<0.01). Mutations were detected in 50% of the pancreatobiliary type and 60% of the intestinal type. KRAS was the most common gene mutated in the pancreatobiliary type (42%) as well as the intestinal type (52%). Other mutations detected included PIK3CA, SMAD4 and BRAF. KRAS mutations at codons 12 and 13 did not adversely affect overall survival. In conclusion, EGFR expression and activation were different between intestinal- and pancreatobiliary-type ampullary carcinoma. KRAS mutation was common in both histologic types; however, the incidence appeared to be lower in the pancreatobiliary type compared with its pancreatic counterpart, pancreatic ductal adenocarcinoma. Mutational analysis of the EGFR pathway genes may provide important insights into personalized treatment for patients with ampullary carcinoma.

23 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.

24 Article Diagnostic and therapeutic implications of a novel immunohistochemical panel detecting duodenal mucosal invasion by pancreatic ductal adenocarcinoma. 2013

Sopha, Sabrina C / Gopal, Purva / Merchant, Nipun B / Revetta, Frank L / Gold, David V / Washington, Kay / Shi, Chanjuan. ·Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center Nashville, TN, USA. ·Int J Clin Exp Pathol · Pubmed #24228110.

ABSTRACT: BACKGROUND: We investigated a series of pancreaticoduodenectomy and duodenal biopsies with a panel of immunohistochemical markers to identify duodenal mucosal invasion by pancreatic ductal adenocarcinoma (PDAC), including markers of poor prognosis and targets of promising novel immunotherapies. MATERIALS AND METHODS: Eighteen consecutive pancreaticoduodenectomy specimens with duodenal mucosal invasion by PDAC were examined for expression of MUC1, MUC4, MUC5AC, MUC6, mesothelin, MUC2, CDX2, and DPC4 on formalin-fixed, paraffin-embedded sections of duodenal-ampullary-pancreatic junctions. Expression of all but MUC6 was also assessed in duodenal biopsies from 12 patients with duodenal mucosal invasion by PDAC. RESULTS: The duodenal mucosa expressed MUC1 (crypts), MUC2 (goblet cells), MUC6 (Brunner glands), CDX2, and DPC4. PDACs in the duodenal mucosa from the resection (n=16-18) and biopsy (n=12) specimens were marked as follows: MUC1 100% (30/30), MUC4 83% (24/29), MUC5AC 83% (25/30), mesothelin 82% (23/28), MUC2 7% (2/30), and CDX2 36% (10/28). Loss of DPC4 expression was seen in 16 of 29 (55%) cases. Reactive mucosa adjacent to PDAC expressed MUC4, MUC5AC and mesothelin in 65% (17/26), 19% (5/27), and 19% (5/26) of cases, respectively. While MUC5AC and mesothelin had high diagnostic accuracy for detection of PDAC, MUC2, CDX2 and DPC4 expression demonstrated negative correlation with PDAC, with absent expression being highly specific for PDAC. CONCLUSION: Immunohistochemical labeling for PDAC biomarkers may aid the diagnosis of PDAC in duodenal biopsy, especially in situations where diagnosis of a pancreatic mass is challenging.

25 Article Grading of well-differentiated pancreatic neuroendocrine tumors is improved by the inclusion of both Ki67 proliferative index and mitotic rate. 2013

McCall, Chad M / Shi, Chanjuan / Cornish, Toby C / Klimstra, David S / Tang, Laura H / Basturk, Olca / Mun, Liew Jun / Ellison, Trevor A / Wolfgang, Christopher L / Choti, Michael A / Schulick, Richard D / Edil, Barish H / Hruban, Ralph H. ·Departments of *Pathology §Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD †Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN ‡Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY ∥Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO. ·Am J Surg Pathol · Pubmed #24121170.

ABSTRACT: The grading system for pancreatic neuroendocrine tumors (PanNETs) adopted in 2010 by the World Health Organization (WHO) mandates the use of both mitotic rate and Ki67/MIB-1 index in defining the proliferative rate and assigning the grade. In cases when these measures are not concordant for grade, it is recommended to assign the higher grade, but specific data justifying this approach do not exist. Thus, we counted mitotic figures and immunolabeled, using the Ki67 antibody, 297 WHO mitotic grade 1 and 2 PanNETs surgically resected at a single institution. We quantified the Ki67 proliferative index by marking at least 500 cells in "hot spots" and by using digital image analysis software to count each marked positive/negative cell and then compared the results with histologic features and overall survival. Of 264 WHO mitotic grade 1 PanNETs, 33% were WHO grade 2 by Ki67 proliferative index. Compared with concordant grade 1 tumors, grade-discordant tumors were more likely to have metastases to lymph node (56% vs. 34%) (P<0.01) and to distant sites (46% vs. 12%) (P<0.01). Discordant mitotic grade 1 PanNETs also showed statistically significantly more infiltrative growth patterns, perineural invasion, and small vessel invasion. Overall survival was significantly different (P<0.01), with discordant mitotic grade 1 tumors showing a median survival of 12 years compared with 16.7 years for concordant grade 1 tumors. Conversely, mitotic grade 1/Ki67 grade 2 PanNETs showed few significant differences from tumors that were mitotic grade 2 and either Ki67 grade 1 or 2. Our data demonstrate that mitotic rate and Ki67-based grades of PanNETs are often discordant, and when the Ki67 grade is greater than the mitotic grade, clinical outcomes and histopathologic features are significantly worse than concordant grade 1 tumors. Patients with discordant mitotic grade 1/Ki67 grade 2 tumors have shorter overall survival and larger tumors with more metastases and more aggressive histologic features. These data strongly suggest that Ki67 labeling be performed on all PanNETs in addition to mitotic rate determination to define more accurately tumor grade and prognosis.

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