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Pancreatic Neoplasms: HELP
Articles by Stephen M. Hewitt
Based on 7 articles published since 2010
(Why 7 articles?)
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Between 2010 and 2020, Stephen M. Hewitt wrote the following 7 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Clinical Trial Phase IIA trial testing erlotinib as an intervention against intraductal pancreatic mucinous neoplasms. 2011

Lipkin, Steven / Lee, John / Imagawa, David / Hewitt, Stephen M / Tucker, Chris / Zell, Jason A / Wong, Vanessa / Garcia, Angela / Gonzalez, Rachel / Della Zanna, Gary / Richmond, Ellen / Rodriguez, L M / Bigg, M / Schnoll-Sussmans, F / Meyskens, Frank. ·Department of Medicine and Chao Family NCI Designated Comprehensive Cancer Center, University of California Irvine, Irvine, California, USA. stl2012@med.cornell.edu ·Cancer Prev Res (Phila) · Pubmed #21464031.

ABSTRACT: Intraductal papillary mucinous neoplasms (IPMN) are a distinct type of precursor lesions that cause about 5% of pancreatic adenocarcinoma (1, 2). Four-year survival rates of 40% to 75% are reported (3-7). There is currently no chemotherapy specifically approved for treating IPMNs. The number of IPMN cases has significantly increased over the last decade (8).

2 Article Expression of the scaffold connector enhancer of kinase suppressor of Ras 1 (CNKSR1) is correlated with clinical outcome in pancreatic cancer. 2017

Quadri, Humair S / Aiken, Taylor J / Allgaeuer, Michael / Moravec, Radim / Altekruse, Sean / Hussain, S Perwez / Miettinen, Markku M / Hewitt, Stephen M / Rudloff, Udo. ·Thoracic and Gastrointestinal Oncology Branch, Gastrointestinal Oncology Section, Investigator Center for Cancer Research, National Cancer Institute, Building 10 - Hatfield CRC, Room 4-5950, Bethesda, MD, 20892, USA. · Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA. · Surveillance Informatics Branch, National Cancer Institute, Bethesda, MD, USA. · Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD, USA. · Experimental Pathology Laboratory, Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA. · Thoracic and Gastrointestinal Oncology Branch, Gastrointestinal Oncology Section, Investigator Center for Cancer Research, National Cancer Institute, Building 10 - Hatfield CRC, Room 4-5950, Bethesda, MD, 20892, USA. rudloffu@mail.nih.gov. ·BMC Cancer · Pubmed #28732488.

ABSTRACT: BACKGROUND: Despite the near universal occurrence of activating codon 12 KRAS somatic variants in pancreatic cancer, there is considerable heterogeneity in the molecular make-up, MAPK/ERK pathway activation states, and clinical outcome in this disease. We analyzed the expression levels of CNKSR1, a scaffold that influences MAPK/ERK pathway activity, in clinical pancreas cancer specimens and their impact on survival of patients with pancreatic cancer. METHODS: Immunohistochemical staining for CNKSR1 expression was performed on 120 specimens from three independent pancreatic cancer tissue registries, phospho-ERK levels were measured in 86 samples. Expression was divided into CNKSR1 low and CNKSR1 high and correlated with clinicopathological variables including overall survival using multivariate Cox proportional hazard ratio models. RESULTS: CNKSR1 expression was increased in tumors compared to matched normal uninvolved resection specimens (p = 0.004). 28.3% (34/120) of patient specimens stained as CNKSR1 low compared to 71.7% (86/120) of specimens which stained as CNKSR1 high. High CNKSR1 expression was more prevalent in low grade tumors (p = 0.04). In multivariate analysis, low CNKSR1 expression status was independently correlated with decreased overall survival (HR = 2.146; 95% CI 1.34 to 3.43). When stratifying primary, non-metastatic tumor biopsies by CNKSR1 expression, resection was associated with improved survival in patients with high CNKSR1 expression (p < 0.0001) but not low CNKSR1 expression (p = 0.3666). Pancreatic tumors with nuclear in addition to cytoplasmic CNKSR1 staining (32/107) showed increased nuclear phospho-ERK expression compared to tumor with cytoplasmic CNKSR1 staining only (p = 0.017). CONCLUSION: CNKSR1 expression is increased in pancreatic tissue specimens and was found to be an independent prognostic marker of overall survival. CNKSR1 may help to identify patient subgroups with unfavorable tumor biology in order to improve risk stratification and treatment selection. Cellular distribution of CNKSR1 was correlated with nuclear pERK expression.

3 Article Pancreatic adenocarcinoma up-regulated factor expression is associated with disease-specific survival in cervical cancer patients. 2015

Choi, Chel Hun / Chung, Joon-Yong / Park, Ho-Seop / Jun, Minsik / Lee, Yoo-Young / Kim, Byung-Gie / Hewitt, Stephen M. ·Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA; Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 135-710, Republic of Korea. · Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. · Department of Pathology, Asan Medical Center, University of Ulsan School of Medicine, Seoul, 138-736, Republic of Korea. · Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 135-710, Republic of Korea. · Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 135-710, Republic of Korea. Electronic address: bksong.kim@samsung.com. · Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. Electronic address: genejock@helix.nih.gov. ·Hum Pathol · Pubmed #25870121.

ABSTRACT: Pancreatic adenocarcinoma up-regulated factor (PAUF) is a novel soluble protein involved in tumor development and metastases. This study was to investigate the PAUF expression and its prognostic value in cervical cancer patients. The expression of PAUF was immunohistochemically determined in 345 formalin-fixed, paraffin-embedded cervical cancer tissues and 107 normal cervical epitheliums. Subsequently, its associations with clinicopathological characteristics and patient survival were assessed. PAUF protein was expressed both in cytoplasm and nucleus, and cytoplasmic expression was more frequent in cancers than normal tissues (32% versus 17%, P = .002), and the difference was prominent in glandular cells. Notably, the expression was more frequent in adenocarcinoma than in squamous cell carcinoma (57% versus 25%, respectively; P < .001), and the differential expression was also seen at the messenger RNA level (P = .014). Cox regression analysis showed that the cytoplasmic expression of PAUF protein was independently associated with poor disease-free (hazard ratio = 2.3; 95% confidence interval, 1.2-4.3; P = .008) and overall survival (hazard ratio = 2.9; 95% confidence interval, 1.2-7.5; P = .020). Detection of PAUF expression may aid current evaluation of prognosis in cervical adenocarcinoma.

4 Article CLPTM1L promotes growth and enhances aneuploidy in pancreatic cancer cells. 2014

Jia, Jinping / Bosley, Allen D / Thompson, Abbey / Hoskins, Jason W / Cheuk, Adam / Collins, Irene / Parikh, Hemang / Xiao, Zhen / Ylaya, Kris / Dzyadyk, Marta / Cozen, Wendy / Hernandez, Brenda Y / Lynch, Charles F / Loncarek, Jadranka / Altekruse, Sean F / Zhang, Lizhi / Westlake, Christopher J / Factor, Valentina M / Thorgeirsson, Snorri / Bamlet, William R / Hewitt, Stephen M / Petersen, Gloria M / Andresson, Thorkell / Amundadottir, Laufey T. ·Authors' Affiliations: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics; Pediatric Oncology Branch; Laboratory of Pathology; Division of Cancer Control and Population Sciences; Laboratory of Experimental Carcinogenesis, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda; Laboratory of Proteomics and Analytical Technologies, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research; Laboratory of Protein Dynamics and Signaling and Laboratory of Cell & Developmental Signaling, NCI-Frederick, Frederick, Maryland; Keck School of Medicine, University of Southern California, Los Angeles, California; University of Hawaii Cancer Center, Honolulu, Hawaii; Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa; and Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. · Authors' Affiliations: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics; Pediatric Oncology Branch; Laboratory of Pathology; Division of Cancer Control and Population Sciences; Laboratory of Experimental Carcinogenesis, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda; Laboratory of Proteomics and Analytical Technologies, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research; Laboratory of Protein Dynamics and Signaling and Laboratory of Cell & Developmental Signaling, NCI-Frederick, Frederick, Maryland; Keck School of Medicine, University of Southern California, Los Angeles, California; University of Hawaii Cancer Center, Honolulu, Hawaii; Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa; and Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota amundadottirl@mail.nih.gov. ·Cancer Res · Pubmed #24648346.

ABSTRACT: Genome-wide association studies (GWAS) of 10 different cancers have identified pleiotropic cancer predisposition loci across a region of chromosome 5p15.33 that includes the TERT and CLPTM1L genes. Of these, susceptibility alleles for pancreatic cancer have mapped to the CLPTM1L gene, thus prompting an investigation of the function of CLPTM1L in the pancreas. Immunofluorescence analysis indicated that CLPTM1L localized to the endoplasmic reticulum where it is likely embedded in the membrane, in accord with multiple predicted transmembrane domains. Overexpression of CLPTM1L enhanced growth of pancreatic cancer cells in vitro (1.3-1.5-fold; PDAY7 < 0.003) and in vivo (3.46-fold; PDAY68 = 0.039), suggesting a role in tumor growth; this effect was abrogated by deletion of two hydrophilic domains. Affinity purification followed by mass spectrometry identified an interaction between CLPTM1L and non-muscle myosin II (NMM-II), a protein involved in maintaining cell shape, migration, and cytokinesis. The two proteins colocalized in the cytoplasm and, after treatment with a DNA-damaging agent, at the centrosomes. Overexpression of CLPTM1L and depletion of NMM-II induced aneuploidy, indicating that CLPTM1L may interfere with normal NMM-II function in regulating cytokinesis. Immunohistochemical analysis revealed enhanced staining of CLPTM1L in human pancreatic ductal adenocarcinoma (n = 378) as compared with normal pancreatic tissue samples (n = 17; P = 1.7 × 10(-4)). Our results suggest that CLPTM1L functions as a growth-promoting gene in the pancreas and that overexpression may lead to an abrogation of normal cytokinesis, indicating that it should be considered as a plausible candidate gene that could explain the effect of pancreatic cancer susceptibility alleles on chr5p15.33.

5 Article Functional activity and tumor-specific expression of dual oxidase 2 in pancreatic cancer cells and human malignancies characterized with a novel monoclonal antibody. 2013

Wu, Yonghzong / Antony, Smitha / Hewitt, Stephen M / Jiang, Guojian / Yang, Sherry X / Meitzler, Jennifer L / Juhasz, Agnes / Lu, Jiamo / Liu, Han / Doroshow, James H / Roy, Krishnendu. ·Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. ·Int J Oncol · Pubmed #23404210.

ABSTRACT: Dual oxidase 2 (Duox2), one of the seven members of the NADPH oxidase gene family, plays a critical role in generating H2O2 for thyroid hormone biosynthesis and as an integral part of the host defense system of the respiratory epithelium and the gastrointestinal tract. Recent evidence suggests that the regulation of Duox2 expression is under the control of pro-inflammatory cytokines and that Duox2-induced reactive oxygen species (ROS) contribute to the inflammation-related tissue injury that occurs in two pre-malignant, inflammatory conditions: chronic pancreatitis and inflammatory bowel disease. Because no reliable Duox antibodies are commercially available, we report the development of a murine monoclonal antibody (MAb) to Duox2 (clone Duox S-12) and its use for the characterization of Duox2 expression in human tumors, tumor cell lines and normal tissues. Duox S-12 specifically detected both endogenously- and ectopically-expressed Duox2 protein by immunoblotting, immunofluorescence microscopy and immunohistochemistry (where both membranous and cytoplasmic staining were present). Duox2 expression detected by Duox S-12 was functionally coupled to the generation of H(2)O(2) in pancreatic cancer cells that expressed Duox2 and its cognate maturation factor DuoxA2. Although Duox S-12 recognizes ectopically expressed Duox1 protein because of the extensive amino acid homology between Duox1 and Duox2, the lack of substantial Duox1 mRNA expression in human tumors (except thyroid cancer) allowed us to evaluate Duox2 expression across a wide range of normal and malignant tissues by immuno-histochemistry. Duox2 was expressed at elevated levels in many human cancers, most notably tumors of the prostate, lung, colon and breast while brain tumors and lymphomas demonstrated the lowest frequency of expression. The Duox-specific monoclonal antibody described here provides a promising tool for the further examination of the role of Duox-dependent reactive oxygen production in inflammation-related carcinogenesis, where alterations in oxidant tone play a critical role in cell growth and proliferation.

6 Article Association of prion protein expression with pancreatic adenocarcinoma survival in the SEER residual tissue repository. 2011

Sy, Man-Sun / Altekruse, Sean F / Li, Chaoyang / Lynch, Charles F / Goodman, Marc T / Hernandez, Brenda Y / Zhou, Lan / Saber, Maria Sibug / Hewitt, Stephen M / Xin, Wei. ·Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA. ·Cancer Biomark · Pubmed #22820080.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an important cause of cancer death with no clear prognostic biomarker. Expression of prion (PrP) has been reported to be a marker of poor prognosis in a series of Caucasian PDAC cases. We determined the prognostic value of PrP in a racially and geographically diverse population-based series of PDAC cases. PrP expression was examined in 142 PDAC cases from three cancer registries. Cases included 71 Caucasian, 54 Asian/Pacific Islanders and 17 Blacks diagnosed from 1983-2000, and followed through 2008. Hazard ratios (HR) and 95% confidence intervals (CIs) for the association of PrP expression with survival were computed after adjustment for case attributes. The risk of death was about four times higher (HR=3.8; 95% PDAC cases with PrP(+) tumors (median survival 5 months) compared to the 34 cases with PrP(-) tumors (median survival 20 months). Of 51 cases with resected, localized PDAC median survival was 74 months for 17 cases with PrP(-) tumors versus 14 months for 34 cases with PrP(+) tumors (HR=6.7; 95% CI: 2.6, 17.4). All 6 surviving cases had PrP(-) negative tumors (median survival, > 10 years). PrP may have potential as a prognostic biomarker in PDAC patient management.

7 Article Multiple endocrine neoplasia type 1 deletion in pancreatic alpha-cells leads to development of insulinomas in mice. 2010

Shen, H-C Jennifer / Ylaya, Kris / Pechhold, Klaus / Wilson, Arianne / Adem, Asha / Hewitt, Stephen M / Libutti, Steven K. ·Tissue Array Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-8322, USA. ·Endocrinology · Pubmed #20555035.

ABSTRACT: The pancreatic alpha- and beta-cells are critical components in regulating blood glucose homeostasis via secretion of glucagon and insulin, respectively. Both cell types are typically localized in the islets of Langerhans. However, little is known about the roles of paracrine interactions that contribute to their physiological functions. The lack of suitable cell lines to study alpha- and beta-cells interactions have led us to develop an alpha-cell-specific Cre-expressing transgenic line utilizing a glucagon promoter sequence, the Glu-Cre transgenic mouse. Here, we demonstrate that the Glu-Cre could specifically and efficiently excise floxed target genes in adult islet alpha-cells. We further showed that deletion of the tumor suppressor gene, multiple endocrine neoplasia type 1 (Men1), in alpha-cells led to tumorigenesis. However, to our surprise, the lack of Men1 in alpha-cells did not result in glucagonomas but rather beta-cell insulinomas. Because deletion of the Men1 alleles was only present in alpha-cells, our data suggested that cross communication between alpha- and beta-cells contributes to tumorigenesis in the absence of Men1. Together, we believed that the new model systems described here will allow future studies to decipher cellular interactions between islet alpha- and beta-cells in a physiological context.