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Pancreatic Neoplasms: HELP
Articles by Andrew M. Bellizzi
Based on 21 articles published since 2010
(Why 21 articles?)
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Between 2010 and 2020, Andrew Bellizzi wrote the following 21 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Serous Cystadenocarcinoma of the Pancreas: Clinical Features and Management of a Rare Tumor. 2016

Van Dyke, Timothy J / Johlin, Frederick C / Bellizzi, Andrew M / Howe, James R. ·Department of Surgery, University of Iowa Carver College of Medicine, Iowa, USA. ·Dig Surg · Pubmed #26998825.

ABSTRACT: BACKGROUND/AIMS: The vast majority of serous cystic neoplasms of the pancreas are benign, and small, asymptomatic lesions, which are generally managed with observation. However, some of these tumors may attain a large size and occasionally metastasize. METHODS: In this study, we present a 78-year-old man with serous cystadenocarcinoma of the pancreas with liver metastases treated by distal pancreatectomy and liver ablation, who went on to develop new liver metastases 5 years after the initial operation. We perform a literature review to determine the number of these malignant neoplasms previously reported and to identify features associated with malignant lesions. RESULTS: Literature reveals that metastatic serous cystadenocarcinomas of the pancreas are rare tumors, occurring in less than 3% of cases of serous cystic neoplasms. All malignant cases reported have been in tumors >4 cm in size. CONCLUSIONS: Serous cystic neoplasms of the pancreas >4 cm have malignant potential and therefore should be considered for surgical management.

2 Review Elevated pancreatic polypeptide levels in pancreatic neuroendocrine tumors and diabetes mellitus: causation or association? 2014

Maxwell, Jessica E / O'Dorisio, Thomas M / Bellizzi, Andrew M / Howe, James R. ·From the Departments of *Surgery, †Internal Medicine, and ‡Pathology, University of Iowa College of Medicine, Iowa City, IA. ·Pancreas · Pubmed #24713673.

ABSTRACT: Pancreatic neuroendocrine tumors (PNETs) that secrete primarily pancreatic polypeptide (PP) are rare and usually nonfunctional. There are approximately 2 dozen reports of PP-secreting PNETs, 3 of which have been associated with diabetes mellitus (DM). None suggest a mechanism for the association between PP-secreting PNETs and DM. We describe 5 patients with PP-producing tumors who were diagnosed with DM at the same time as their PNETs, review the literature on PP, and consider its role in the pathophysiology of DM. The cases discussed were extracted from our surgical neuroendocrine tumor database. We examined all patients with PP-predominant PNETs--both with DM (n = 5) and without (n = 8). The 5 patients with DM at the time of PNET diagnosis demonstrated improvement or resolution of their DM postoperatively. In the patients with PP-secreting PNETs but no diagnosis of DM preoperatively, 1 became hypoglycemic postoperatively, and 2 others developed postoperative DM. The 5 cases discussed in detail raise the question of whether the hypersecretion of PP in PNETs might be an important event leading to the development of DM. Although the literature does not provide a mechanism for this association, it may be related to the role of PP in hepatic glucose regulation.

3 Article The Pancreas as a Site of Metastasis or Second Primary in Patients with Small Bowel Neuroendocrine Tumors. 2019

Scott, Aaron T / Pelletier, Daniel / Maxwell, Jessica E / Sherman, Scott K / Keck, Kendall J / Li, Guiying / Dillon, Joseph S / O'Dorisio, Thomas M / Bellizzi, Andrew M / Howe, James R. ·Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA. · Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA. · Department of Surgery, University of Chicago, Chicago, IL, USA. · Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA. · Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA. james-howe@uiowa.edu. ·Ann Surg Oncol · Pubmed #31011904.

ABSTRACT: BACKGROUND: The small bowel and pancreas are the most common primary sites of neuroendocrine tumors (NETs) giving rise to metastatic disease. Some patients with small bowel NETs (SBNETs) present with synchronous or metachronous pancreatic NETs (PNETs), and it is unclear whether these are separate primaries or metastases from one site to the other. METHODS: A surgical NET database including patients undergoing operations for SBNETs or PNETs was reviewed. Patients with synchronous or metachronous tumors in both the small bowel and pancreas were identified, and available tissues from primary tumors and metastases were examined using a 4-gene quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC) panel developed for evaluating NETs of unknown primary. RESULTS: Of 338 patients undergoing exploration, 11 had NETs in both the small bowel and pancreas. Tissues from 11 small bowel tumors, 9 pancreatic tumors, and 10 metastases were analyzed. qPCR and IHC data revealed that three patients had separate SBNET and PNET primaries, and five patients had SBNETs that metastasized to the pancreas. Pancreatic tissue was unavailable in two patients, and qPCR and IHC gave discrepant results in one patient. CONCLUSIONS: NETs in both the small bowel and pancreas were found in 3% of our patients. In nearly two-thirds of evaluable patients, the pancreatic tumor was a metastasis from the SBNET primary, while in the remaining one-third of patients it represented a separate primary. Determining the origin of these tumors can help guide the choice of systemic therapy and surgical management.

4 Article Nicotinamide phosphoribosyltransferase expression and clinical outcome of resected stage I/II pancreatic ductal adenocarcinoma. 2019

Davis, Katelynn / Dunseth, Craig D / Mott, Sarah L / Cramer-Morales, Kimberly L / Miller, Ann M / Ear, Po Hien / Mezhir, James J / Bellizzi, Andrew M / Chan, Carlos H F. ·Department of Surgery, University of Iowa, Iowa City, IA, United States of America. · Department of Pathology, University of Iowa, Iowa City, IA, United States of America. · Holden Comprehensive Cancer Center, Iowa City, IA, United States of America. · Department of Biochemistry, University of Iowa, Iowa City, IA, United States of America. ·PLoS One · Pubmed #30856230.

ABSTRACT: BACKGROUND: Nicotinamide phosphoribosyltransferase (NAMPT) plays a key role in the biosynthesis of nicotinamide adenine dinucleotide (NAD+), which is a vital cofactor in redox reactions and a substrate for NAD+ consuming enzymes including CD38, PARPs and sirtuins. NAMPT over-expression has been shown in various cancers and its inhibition decreases cancer cell growth, making it an attractive therapeutic target. Here we examine the NAMPT expression in a large cohort of resected stage I/II pancreatic ductal adenocarcinomas (PDAs) and correlate its expression with clinical outcomes and pathologic features. METHODS: A retrospective review of patients with PDAs was conducted at a single institution. Tissue microarrays (TMAs) containing primary PDAs and their metastatic lymph nodes (mLNs) were constructed and stained for NAMPT expression. Each TMA core was evaluated for staining intensity of cancer cells (0 = no staining, 1+ = weak, 2+ = moderate, 3+ = strong) and a mean score was calculated for each case with at least two evaluable cores. NAMPT expression was correlated with clinicopathological variables using chi-squared or Fisher's exact test, and t-tests for categorical and continuous variables, respectively. Survival probabilities were estimated and plotted using the Kaplan-Meier method. Cox proportional hazards regression was used to assess the effects of NAMPT staining values on recurrence-free survival (RFS) and overall survival (OS). This study was conducted under an approved IRB protocol. RESULTS: 173 primary PDAs had at least 2 TMA cores with identifiable cancer cells. The mean IHC score was 0.55 (range: 0 to 2.33). The mean IHC score of mLNs was 0.39 (range: 0-2), which was not significantly different from their primary tumors (mean IHC score = 0.47, P = 0.38). Sixty-four percent (111/173) of PDAs were positive for NAMPT staining. Stage II tumors were more likely to be positive (68% of 151 vs 41% of 22; P = 0.01). Non-obese non-diabetic patients were more likely to have NAMPT+ tumors (43.7% vs. 27.9%, P = 0.04). While RFS and OS were not statistically different between NAMPT+ vs. NAMPT- PDAs, patients with NAMPT- tumors tended to have a longer median OS (26.0 vs. 20.4 months, P = 0.34). CONCLUSION: NAMPT expression was detected in 64% of stage I/II PDAs and up to 72% in non-obese non-diabetic patients. Frequency of NAMPT expression correlated with pathological stage, consistent with published literature regarding its role in cancer progression. While RFS and OS were not statistically significantly different, patients with NAMPT+ PDAs tended to have a shorter survival. Thus, NAMPT inhibition may prove beneficial in clinical trials.

5 Article Effective cytoreduction can be achieved in patients with numerous neuroendocrine tumor liver metastases (NETLMs). 2019

Scott, Aaron T / Breheny, Patrick J / Keck, Kendall J / Bellizzi, Andrew M / Dillon, Joseph S / O'Dorisio, Thomas M / Howe, James R. ·Department of Surgery, University of Iowa Carver College of Medicine, Iowa City. · Department of Biostatistics, University of Iowa College of Public Health, Iowa City. · Department of Pathology, University of Iowa Carver College of Medicine, Iowa City. · Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City. · Department of Surgery, University of Iowa Carver College of Medicine, Iowa City. Electronic address: james-howe@uiowa.edu. ·Surgery · Pubmed #30343949.

ABSTRACT: BACKGROUND: Cytoreductive surgery for neuroendocrine tumor liver metastases improves survival and symptomatic control. However, the feasibility of adequate cytoreduction in patients with many liver metastases remains uncertain. We compared patient outcomes based on the number of lesions treated to better define the efficacy of cytoreductive surgery for numerous neuroendocrine tumor liver metastases. METHODS: Patients undergoing hepatic cytoreductive surgery for gastroenteropancreatic neuroendocrine tumors were identified in our institutional surgical neuroendocrine tumor database. Imaging studies were reviewed to determine the liver tumor burden and percent cytoreduced. Overall survival and progression-free survival were compared, using the number of lesions treated, percent tumor debulked, and additional clinicopathologic characteristics. RESULTS: A total of 188 hepatic cytoreductive procedures were identified and stratified into groups according to the number of metastases treated: 1-5, 6-10, and >10. Median overall survival and progression-free survival were 89.4 and 22.5 months, respectively, and did not differ significantly between groups. Greater than 70% cytoreduction was associated with significantly better overall survival than <70% cytoreduction (134 months versus 38 months). CONCLUSION: In patients with gastroenteropancreatic neuroendocrine tumors and liver metastases, >70% cytoreduction led to improved overall survival and progression-free survival and was achieved reliably in patients undergoing debulking of >10 lesions. These data support an aggressive approach to patients with numerous neuroendocrine tumor liver metastases to achieve >70% cytoreduction.

6 Article The Distal Predilection of Small Bowel Neuroendocrine Tumors. 2018

Keck, Kendall J / Maxwell, Jessica E / Utria, Alan F / Bellizzi, Andrew M / Dillon, Joseph S / O'Dorisio, Thomas M / Howe, James R. ·Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA. · Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA. · Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA. · Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA. james-howe@uiowa.edu. ·Ann Surg Oncol · Pubmed #30054825.

ABSTRACT: BACKGROUND: The small bowel (SB) is the most common site of neuroendocrine tumors (NETs) of the GI tract. These are described as being predominantly jejunoileal, but their exact locations within the SB have not been well defined. We sought to determine prospectively the spectrum of SBNET locations. METHODS: Patients undergoing exploration for SBNET primaries had measurement of bowel length, tumor locations, and resection length recorded. Correlations of clinicopathologic factors were performed, and analysis done utilizing Welch's t test, Chi square test, and the Kaplan-Meier method. RESULTS: Measurements were recorded in 123 patients, 107 of whom had complete information. Multifocal tumors (MTs) were found in 69 (56%) and unifocal (UTs) in 54 (44%) patients. Only 1 of 107 patients had a tumor within 100 cm of the ligament of Treitz (LT), whereas 77 of 107 (72%) had tumors within 100 cm of the ileocecal valve (ICV). No MTs were found within 100 cm of LT, whereas 41 of 60 (68%) patients had all (10) or at least one tumor (31) located within 100 cm of the ICV. MTs required a mean resection length of 108 versus 59 cm for UTs (p < 0.01). Seventy-seven percent of UTs (36/47) were within 100 cm of ICV. Tumors occurring only between > 100 cm from the LT and ICV were seen in 29 of 107 (27%) patients. CONCLUSIONS: SBNETs are frequently multifocal and most commonly located within 100 cm of the ICV. SBNETs are less prevalent proximally in the small bowel, which may result from anatomic differences in enterochromaffin cell density, hormonal factors, or environmental exposures in the distal SB.

7 Article Increased Grade in Neuroendocrine Tumor Metastases Negatively Impacts Survival. 2017

Keck, Kendall J / Choi, Allen / Maxwell, Jessica E / Li, Guiying / O'Dorisio, Thomas M / Breheny, Patrick / Bellizzi, Andrew M / Howe, James R. ·Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA. · Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA. · Department of Biostatistics, University of Iowa College of Public Health, Iowa City, IA, USA. · Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA. · Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA. james-howe@uiowa.edu. ·Ann Surg Oncol · Pubmed #28560597.

ABSTRACT: BACKGROUND: Tumor grade is an important predictor of survival in gastroenteropancreatic (GEP) neuroendocrine tumors (NETs), as determined by Ki-67 expression and mitotic rate. NETs generally grow indolently, but some cells may acquire traits facilitating metastasis. It is unclear how frequently metastases differ in grade from their primary tumors, and whether increasing grade in metastases affects prognosis. METHODS: Ki-67 immunohistochemistry was performed on resected GEPNET specimens and cases with results for both primary tumors and concurrent metastases were identified. Grade was determined using a modified World Health Organization classification (Ki-67: G1 = 0-2%; G2 > 2-20%; G3 > 20%). RESULTS: Ki-67 was performed on both the primary tumor and metastases in 103 patients. Tumor grade was higher in metastases from 25 (24%) patients, 24 increased from G1 to G2, and 1 increased from G2 to G3; 68 (66%) patients had no change in grade (42 G1 and 26 G2), and 10 (10%) decreased from G2 to G1. No clinicopathologic factors were predictive of higher grade in metastases. The 5-year progression-free survival (PFS) was 55% for patients with stable grade versus 8% of patients with increased grade, while 5-year overall survival (OS) was 92 and 54%, respectively. The 5-year OS of patients who had stable grade with G1 and G2 primaries was 92 and 64%, respectively. CONCLUSIONS: Nearly one-third of patients had metastases with a different grade than their primary, and, when grade increased, both PFS and OS significantly decreased. Determining the grade in both the primary tumor and a metastasis is important for estimating prognosis and to help inform decisions regarding additional therapies.

8 Article Identification of primary tumors in patients presenting with metastatic gastroenteropancreatic neuroendocrine tumors. 2017

Keck, Kendall J / Maxwell, Jessica E / Menda, Yusuf / Bellizzi, Andrew / Dillon, Joseph / O'Dorisio, Thomas M / Howe, James R. ·Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA. · Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, IA. · Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA. · Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA. · Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA. Electronic address: james-howe@uiowa.edu. ·Surgery · Pubmed #27863780.

ABSTRACT: BACKGROUND: Patients with gastroenteropancreatic neuroendocrine tumors often present with metastases. Identification of the primary tumor is important for operative management, and therefore we sought to determine our success at identifying primary tumors with diagnostic testing and operative exploration. METHODS: A clinical neuroendocrine tumor database was reviewed to identify patients presenting with metastases and primary tumor in situ. Results of radiologic, endoscopic, and operative procedures were evaluated to determine which correctly identified the primary tumor. RESULTS: There were 197 patients presenting with metastases and unresected primaries, 134 who had an operation and 63 managed nonoperatively. Primaries were identified preoperatively in 168 (84%), at operative exploration in 7, and were not found in 22 patients. Computed tomography found 150/197 primary tumors, somatostatin-receptor scintigraphy 88/155, and endoscopy 43/107. The sensitivity of computed tomography surpassed scintigraphy (76% vs 57%, P < .01). The primary was removed in 130/134 (97%) patients, and hepatic debulking was performed in 67%. Median survival for operative patients with small bowel and pancreatic tumors was 145 and 71 months, respectively. CONCLUSION: Imaging and endoscopy identified the primary tumor in most patients, and the majority of the others were found at exploration. Preoperative testing facilitated operative planning, allowing for resection of the primary and hepatic debulking in most patients.

9 Article Liver-directed surgery of neuroendocrine metastases: What is the optimal strategy? 2016

Maxwell, Jessica E / Sherman, Scott K / O'Dorisio, Thomas M / Bellizzi, Andrew M / Howe, James R. ·Department of General Surgery, University of Iowa Carver College of Medicine, Iowa City, IA. · Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA. · Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA. · Department of General Surgery, University of Iowa Carver College of Medicine, Iowa City, IA. Electronic address: james-howe@uiowa.edu. ·Surgery · Pubmed #26454679.

ABSTRACT: INTRODUCTION: Neuroendocrine tumors (NETs) frequently metastasize to the liver. Operative debulking offers symptomatic relief and improved survival; however, the frequent presence of multifocal, bilobar disease and high recurrence rates introduces doubt regarding their optimal management. Parenchyma-sparing debulking (PSD) procedures (ablation, enucleation, wedge resections) may offer similar survival improvements as resection while minimizing morbidity and preserving functional liver tissue. METHODS: Clinicopathologic variables from 228 patients with small bowel or pancreatic NETs managed operatively at one institution were collected. Liver-directed surgery was carried out when substantial debulking was deemed feasible. Survival was assessed by use of the Kaplan-Meier method. RESULTS: A total of 108 patients with pancreatic NET or small bowel NET underwent liver-directed surgery with primarily PSD procedures. Nearly two-thirds of patients achieved 70% cytoreduction and 84% had concurrent resection of their primary. The median number of lesions treated was 6 (range, 1-36). There were no 30-day operative mortalities. The 30-day major complication rate was 13.0%. Patients who achieved 70% cytoreduction enjoyed improved progression free (median 3.2 years) and overall survival (median not reached). CONCLUSION: PSD procedures are safe and can achieve significant cytoreduction, which is associated with improved survival. Lowering the debulking target threshold to 70% may benefit NET patients by increasing eligibility for cytoreduction.

10 Article Non-hyperfunctioning pancreatic endocrine tumors: multimodality imaging features with histopathological correlation. 2015

Humphrey, Peter E / Alessandrino, Francesco / Bellizzi, Andrew M / Mortele, Koenraad J. ·Northwest Imaging, Kalispell Regional Medical Center, Kalispell, MT, 59901, USA. · Division of Abdominal Imaging and Intervention, Department of Radiology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. · Division of Body MRI, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Ansin 224, Boston, MA, 02215, USA. · Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA. · Department of Surgical Pathology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. · Division of Abdominal Imaging and Intervention, Department of Radiology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. kmortele@bidmc.harvard.edu. · Division of Body MRI, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Ansin 224, Boston, MA, 02215, USA. kmortele@bidmc.harvard.edu. ·Abdom Imaging · Pubmed #25989932.

ABSTRACT: PURPOSE: To evaluate the multimodality imaging features of non-hyperfunctioning pancreatic endocrine tumors (NF-PNET) with histopathological correlation. METHODS: Preoperative imaging (CT: n = 23; MRI: n = 14; (111)In-octreotide: n = 8) of 28 patients (17 female; mean age 55 years) with resected NF-PNET were evaluated for tumor location, size, morphology, attenuation/signal intensity, (111)In-octreotide uptake, cystic degeneration, and enhancement. Tissue specimens were assessed for the extent of stromal fibrosis, vascular density, presence of a fibrous pseudocapsule, and tumor grading. Correlation between imaging and histopathology was made using the Fisher-Freeman-Halton exact test. RESULTS: NF-PNET arose from the pancreatic head/neck (n = 10), body (n = 7), and tail (n = 11). On CT, NF-PNET (mean largest diameter: 4.4 cm) appeared predominantly solid (69.6%), well defined (91.3%), and oval (47.8%) in shape. In the late arterial phase, NF-PNET appeared mainly hypovascular (55.5%). Septations (30.4%) and calcifications (21.7%) were relatively uncommon. On MRI, NF-PNET (mean size: 2.6 cm) appeared most commonly as solid (57.1%), encapsulated (71.4%), oval (64.2%) lesions that were hyperintense on T2-WI (64.3%), and hypo- or isovascular to pancreas (66.7%) during the late arterial phase. Cystic NF-PNET (3.8 cm) were not significantly larger than solid (3.5 cm) NF-PNET (CT, p = 0.758; MRI, p = 0.451). (111)In-octreotide uptake was demonstrated in 5/8 (62.5%) patients. At histopathology, NF-PNET were predominantly encapsulated (69.2%); stromal fibrosis comprised <33% of the tumor (69.2%), and vascular density was average (46.1%). A significant association was demonstrated between the degree of fibrosis and hypointensity on T2-WI (p = 0.003). Vascular density, tumor grade, and degree of fibrosis did not significantly relate to the pattern of enhancement. CONCLUSIONS: NF-PNETs have variable imaging appearances but are most commonly oval shaped, solid, and well-defined/encapsulated masses, and hypovascular on late arterial and portal venous phase. Cystic degeneration in NF-PNET appears independent of tumor size. Low signal intensity on T2-WI correlates with extensive intratumoral fibrosis.

11 Article Loss of SOD3 (EcSOD) Expression Promotes an Aggressive Phenotype in Human Pancreatic Ductal Adenocarcinoma. 2015

O'Leary, Brianne R / Fath, Melissa A / Bellizzi, Andrew M / Hrabe, Jennifer E / Button, Anna M / Allen, Bryan G / Case, Adam J / Altekruse, Sean / Wagner, Brett A / Buettner, Garry R / Lynch, Charles F / Hernandez, Brenda Y / Cozen, Wendy / Beardsley, Robert A / Keene, Jeffery / Henry, Michael D / Domann, Frederick E / Spitz, Douglas R / Mezhir, James J. ·Department of Surgery, University of Iowa, Iowa City, Iowa. · Department of Radiation Oncology, University of Iowa, Iowa City, Iowa. · Department of Pathology, University of Iowa, Iowa City, Iowa. · Department of Biostatistics, University of Iowa, Iowa City, Iowa. · National Cancer Institute, Bethesda, Maryland. · Department of Epidemiology, University of Iowa, Iowa City, Iowa. · University of Hawaii Cancer Center, Honolulu, Hawaii. · University of Southern California, Los Angeles, California. · Galera Therapeutics, Malvern, Pennsylvania. · Department of Microbiology, University of Iowa, Iowa City, Iowa. · Department of Surgery, University of Iowa, Iowa City, Iowa. Department of Radiation Oncology, University of Iowa, Iowa City, Iowa. james-mezhir@uiowa.edu. ·Clin Cancer Res · Pubmed #25634994.

ABSTRACT: PURPOSE: Pancreatic ductal adenocarcinoma (PDA) cells are known to produce excessive amounts of reactive oxygen species (ROS), particularly superoxide, which may contribute to the aggressive and refractory nature of this disease. Extracellular superoxide dismutase (EcSOD) is an antioxidant enzyme that catalyzes the dismutation of superoxide in the extracellular environment. This study tests the hypothesis that EcSOD modulates PDA growth and invasion by modifying the redox balance in PDA. EXPERIMENTAL DESIGN: We evaluated the prognostic significance of EcSOD in a human tissue microarray (TMA) of patients with PDA. EcSOD overexpression was performed in PDA cell lines and animal models of disease. The impact of EcSOD on PDA cell lines was evaluated with Matrigel invasion in combination with a superoxide-specific SOD mimic and a nitric oxide synthase (NOS) inhibitor to determine the mechanism of action of EcSOD in PDA. RESULTS: Loss of EcSOD expression is a common event in PDA, which correlated with worse disease biology. Overexpression of EcSOD in PDA cell lines resulted in decreased invasiveness that appeared to be related to reactions of superoxide with nitric oxide. Pancreatic cancer xenografts overexpressing EcSOD also demonstrated slower growth and peritoneal metastasis. Overexpression of EcSOD or treatment with a superoxide-specific SOD mimic caused significant decreases in PDA cell invasive capacity. CONCLUSIONS: These results support the hypothesis that loss of EcSOD leads to increased reactions of superoxide with nitric oxide, which contributes to the invasive phenotype. These results allow for the speculation that superoxide dismutase mimetics might inhibit PDA progression in human clinical disease.

12 Article A practical method to determine the site of unknown primary in metastatic neuroendocrine tumors. 2014

Maxwell, Jessica E / Sherman, Scott K / Stashek, Kristen M / O'Dorisio, Thomas M / Bellizzi, Andrew M / Howe, James R. ·Department of General Surgery, University of Iowa Carver College of Medicine, Iowa City, IA. · Department of Pathology, University of Pennsylvania, Philadelphia, PA. · Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA. · Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA. · Department of General Surgery, University of Iowa Carver College of Medicine, Iowa City, IA. Electronic address: james-howe@uiowa.edu. ·Surgery · Pubmed #25456909.

ABSTRACT: INTRODUCTION: The site of a primary neuroendocrine tumor (NET) tumor is unknown before treatment in approximately 20% of small bowel (SBNET) and pancreatic (PNET) cases despite extensive workup. It can be difficult to discern a PNET from an SBNET on hematoxylin and eosin stains, and thus, more focused diagnostic tests are required. Immunohistochemistry (IHC) and gene expression profiling are two methods used to identify the tissue of origin from biopsied metastases. METHODS: Tissue microarrays were created from operative specimens and stained with up to seven antibodies used in the NET-specific IHC algorithm. Expression of four genes for differentiating between PNETs and SBNETs was determined by quantitative polymerase chain reaction and then used in a previously validated gene expression classifier (GEC) algorithm designed to determine the primary site from gastrointestinal NET metastases. RESULTS: The accuracy of the IHC algorithm in identifying the primary tumor site from a set of 37 metastases was 89%, with only one incorrect call. Three other samples were indeterminate as the result of pan-negative staining. The GEC's accuracy in a set of 136 metastases was 94%. The algorithm identified the primary tumor site in all cases in which IHC failed. CONCLUSION: Performing IHC, followed by GEC for indeterminate cases, identifies accurately the primary site in SBNET and PNET metastases in virtually all patients.

13 Article RABL6A promotes G1-S phase progression and pancreatic neuroendocrine tumor cell proliferation in an Rb1-dependent manner. 2014

Hagen, Jussara / Muniz, Viviane P / Falls, Kelly C / Reed, Sara M / Taghiyev, Agshin F / Quelle, Frederick W / Gourronc, Francoise A / Klingelhutz, Aloysius J / Major, Heather J / Askeland, Ryan W / Sherman, Scott K / O'Dorisio, Thomas M / Bellizzi, Andrew M / Howe, James R / Darbro, Benjamin W / Quelle, Dawn E. ·Department of Pharmacology, University of Iowa, Iowa City, Iowa. · Department of Pharmacology, University of Iowa, Iowa City, Iowa. Molecular and Cellular Biology Graduate Program, University of Iowa, Iowa City, Iowa. · Medical Scientist Training Program, University of Iowa, Iowa City, Iowa. · Department of Pharmacology, University of Iowa, Iowa City, Iowa. Medical Scientist Training Program, University of Iowa, Iowa City, Iowa. · Department of Pediatrics, College of Medicine, University of Iowa, Iowa City, Iowa. · Department of Pharmacology, University of Iowa, Iowa City, Iowa. The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. · Department of Microbiology, College of Medicine, University of Iowa, Iowa City, Iowa. · Molecular and Cellular Biology Graduate Program, University of Iowa, Iowa City, Iowa. The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. Department of Microbiology, College of Medicine, University of Iowa, Iowa City, Iowa. · Department of Pathology, College of Medicine, University of Iowa, Iowa City, Iowa. · Department of Surgery, College of Medicine, University of Iowa, Iowa City, Iowa. · The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. Department of Internal Medicine, College of Medicine, University of Iowa, Iowa City, Iowa. · The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. Department of Pathology, College of Medicine, University of Iowa, Iowa City, Iowa. · The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. Department of Surgery, College of Medicine, University of Iowa, Iowa City, Iowa. · Department of Pediatrics, College of Medicine, University of Iowa, Iowa City, Iowa. The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. · Department of Pharmacology, University of Iowa, Iowa City, Iowa. Molecular and Cellular Biology Graduate Program, University of Iowa, Iowa City, Iowa. Medical Scientist Training Program, University of Iowa, Iowa City, Iowa. The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. Department of Pathology, College of Medicine, University of Iowa, Iowa City, Iowa. dawn-quelle@uiowa.edu. ·Cancer Res · Pubmed #25273089.

ABSTRACT: Mechanisms of neuroendocrine tumor (NET) proliferation are poorly understood, and therapies that effectively control NET progression and metastatic disease are limited. We found amplification of a putative oncogene, RABL6A, in primary human pancreatic NETs (PNET) that correlated with high-level RABL6A protein expression. Consistent with those results, stable silencing of RABL6A in cultured BON-1 PNET cells revealed that it is essential for their proliferation and survival. Cells lacking RABL6A predominantly arrested in G1 phase with a moderate mitotic block. Pathway analysis of microarray data suggested activation of the p53 and retinoblastoma (Rb1) tumor-suppressor pathways in the arrested cells. Loss of p53 had no effect on the RABL6A knockdown phenotype, indicating that RABL6A functions independent of p53 in this setting. By comparison, Rb1 inactivation partially restored G1 to S phase progression in RABL6A-knockdown cells, although it was insufficient to override the mitotic arrest and cell death caused by RABL6A loss. Thus, RABL6A promotes G1 progression in PNET cells by inactivating Rb1, an established suppressor of PNET proliferation and development. This work identifies RABL6A as a novel negative regulator of Rb1 that is essential for PNET proliferation and survival. We suggest RABL6A is a new potential biomarker and target for anticancer therapy in PNET patients.

14 Article Gene expression accurately distinguishes liver metastases of small bowel and pancreas neuroendocrine tumors. 2014

Sherman, Scott K / Maxwell, Jessica E / Carr, Jennifer C / Wang, Donghong / Bellizzi, Andrew M / Sue O'Dorisio, M / O'Dorisio, Thomas M / Howe, James R. ·Department of Surgery, The University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, 52242-1086, USA. ·Clin Exp Metastasis · Pubmed #25241033.

ABSTRACT: Small bowel (SBNETs) and pancreatic neuroendocrine tumors (PNETs) often present with liver metastases. Although liver biopsy establishes a neuroendocrine diagnosis, the primary tumor site is frequently unknown without exploratory surgery. Gene expression differences in metastases may distinguish primary SBNETs and PNETs. This study sought to determine expression differences of four genes in neuroendocrine metastases and to create a gene expression algorithm to distinguish the primary site. Nodal and liver metastases from SBNETs and PNETs (n = 136) were collected at surgery under an Institutional Review Board-approved protocol. Quantitative PCR measured expression of bombesin-like receptor-3, opioid receptor kappa-1, oxytocin receptor, and secretin receptor in metastases. Logistic regression models defined an algorithm predicting the primary tumor site. Models were developed on a training set of 21 nodal metastases and performance was validated on an independent set of nodal and liver metastases. Expression of all four genes was significantly different in SBNET compared to PNET metastases. The optimal model employed expression of bombesin-like receptor-3 and opioid receptor kappa-1. When these genes did not amplify, the algorithm used oxytocin receptor and secretin receptor expression, which allowed classification of all 136 metastases with 94.1 % accuracy. In the independent liver metastasis validation set, 52/56 (92.9 %) were correctly classified. Positive predictive values were 92.5 % for SBNETs and 93.8 % for PNETs. This validated algorithm accurately distinguishes SBNET and PNET metastases based on their expression of four genes. High accuracy in liver metastases demonstrates applicability to the clinical setting. Studies assessing this algorithm's utility in prospective clinical decision-making are warranted.

15 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.

16 Article Utility of commercial DNA analysis in detecting malignancy within pancreatic cysts. 2013

Lee, Linda S / Wu, Bechien U / Banks, Peter A / Kadiyala, Vivek / Mehta, Shivani / Saltzman, John R / Thompson, Christopher C / Bellizzi, Andrew M. ·Center for Pancreatic Disease, Brigham and Women's Hospital. Boston, MA, USA. lslee@partners.org. ·JOP · Pubmed #24618422.

ABSTRACT: CONTEXT: Pancreatic cysts raise concern because of their malignant potential. Our aims were to assess accuracy of DNA analysis in detecting malignant pancreatic cysts at EUS-FNA and to determine whether DNA analysis added to imaging and cyst fluid studies enhanced International Association of Pancreatology (IAP) guidelines for resection of pancreatic cysts. METHODS: This is a retrospective study including pancreatic cysts undergoing EUS-FNA and DNA analysis with k-ras and loss of heterozygosity testing. Diagnostic models of 2006 and 2012 IAP guidelines, DNA analysis alone, and DNA combined with 2012 IAP guidelines were developed, and area under receiver operator characteristic curves (AUC) compared to determine the added value of DNA for detecting malignant cysts at the time of EUS-FNA. RESULTS: Two-hundreds and fifty-seven patients were included with 8 (3.1%) malignant cysts. Solid component (P<0.001), main pancreatic duct dilation (P=0.012), suspicious or malignant cytology (P=0.001), and high DNA quantity (P<0.001) were associated with malignancy. Concurrent high amplitude k-ras with loss of heterozygosity mutations was highly specific (98.4%) though insensitive (12.5%) for malignancy. The 2012 IAP guideline (AUC=0.87; 95% CI: 0.82-0.91) was superior to 2006 IAP guideline (AUC=0.54; 95% CI: 0.47-0.60) and DNA analysis alone (AUC=0.60; 95% CI: 0.53-0.66) for detecting malignant cysts (P=0.004 and P=0.002, respectively). Addition of DNA did not improve performance of the 2012 IAP guideline (AUC=0.84; 95% CI: 0.79-0.88). CONCLUSIONS: Commercial DNA analysis does not add useful information beyond imaging and cytology for detection of malignant pancreatic cysts. The 2012 IAP guideline better predicted malignant cysts than the 2006 IAP guideline.

17 Article Overexpression of membrane proteins in primary and metastatic gastrointestinal neuroendocrine tumors. 2013

Carr, Jennifer C / Sherman, Scott K / Wang, Donghong / Dahdaleh, Fadi S / Bellizzi, Andrew M / O'Dorisio, M Sue / O'Dorisio, Thomas M / Howe, James R. ·Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA. · Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA. · Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA. · Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA. ·Ann Surg Oncol · Pubmed #24114056.

ABSTRACT: BACKGROUND: Small bowel and pancreatic neuroendocrine tumors (SBNETs and PNETs) are rare tumors whose incidence is increasing. Drugs targeting the somatostatin receptor are beneficial in these tumors. To identify additional cell-surface targets, we recently found receptors and membrane proteins with gene expression significantly different from adjacent normal tissues in a small number of primary SBNETs and PNETs. We set out to validate these expression differences in a large group of primary neuroendocrine tumors and to determine whether they are present in corresponding liver and lymph node metastases. METHODS: Primary SBNETs and PNETs, normal tissue, nodal, and liver metastases were collected and mRNA expression of six target genes was determined by quantitative PCR. Expression was normalized to GAPDH and POLR2A internal controls, and differences as compared to normal tissue were assessed by Welch's t test. RESULTS: Gene expression was determined in 45 primary PNETs with 20 nodal and 17 liver metastases, and 51 SBNETs with 50 nodal and 29 liver metastases. Compared to normal tissue, the oxytocin receptor (OXTR) showed significant overexpression in both primary and metastatic SBNETs and PNETs. Significant overexpression was observed for MUC13 and MEP1B in PNET primary tumors, and for GPR113 in primary SBNETs and their metastases. SCTR and ADORA1 were significantly underexpressed in PNETs and their metastases. OXTR protein expression was confirmed by immunohistochemistry. CONCLUSIONS: OXTR is significantly overexpressed relative to normal tissue in primary SBNETs and PNETs, and this overexpression is present in their liver and lymph node metastases, making OXTR a promising target for imaging and therapeutic interventions.

18 Article Prognosis of minimally invasive carcinoma arising in mucinous cystic neoplasms of the pancreas. 2013

Lewis, Gloria H / Wang, Huamin / Bellizzi, Andrew M / Klein, Alison P / Askin, Frederic B / Schwartz, Lauren Ende / Schulick, Richard D / Wolfgang, Christopher L / Cameron, John L / O'Reilly, Eileen M / Yu, Kenneth H / Hruban, Ralph H. ·Departments of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. ·Am J Surg Pathol · Pubmed #23388125.

ABSTRACT: Although patients with surgically resected noninvasive mucinous cystic neoplasms (MCNs) of the pancreas are cured, the behavior of surgically resected minimally invasive adenocarcinomas arising in MCN has not been well established. We report 16 surgically resected MCNs with minimal invasion defined as unifocal or multifocal microscopic invasive adenocarcinoma confined to the ovarian stroma of the MCN without capsular or pancreatic parenchymal invasion. Pathologic findings were correlated with patient demographics, type of surgery, and long-term follow-up. Our study included 15 women and 1 man ranging in age from 25 to 66 years. The patients were followed up for a mean of 48.6 months (range, 12 to 148 mo). The MCNs ranged in size from 3.5 to 25 cm and were all located in the body/tail of the gland. Lymphovascular invasion was not identified in any of the cases, and all lymph nodes were negative for tumor. Ten neoplasms had unifocal invasion, whereas 6 had multifocal invasion. Twelve of the neoplasms were partially submitted for microscopic examination, whereas 4 were submitted entirely. Only 1 of the 16 minimally invasive MCNs recurred, and that tumor had been lighlty sampled pathologically. Our study demonstrates that the majority of patients with minimally invasive adenocarcinoma arising in MCNs are cured by surgery, particularly if the neoplasms are completely examined histologically.

19 Article Inflammatory protein profiling of pancreatic cyst fluid using EUS-FNA in tandem with cytokine microarray differentiates between branch duct IPMN and inflammatory cysts. 2012

Lee, Linda S / Banks, Peter A / Bellizzi, Andrew M / Sainani, Nisha I / Kadiyala, Vivek / Suleiman, Shadeah / Conwell, Darwin L / Paulo, Joao A. ·Center for Pancreatic Disease, Division of Gastroenterology Hepatology and Endoscopy, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, MA. · Center for Pancreatic Disease, Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, MA. · Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA. · Department of Radiology, Brigham and Women's Hospital, Boston, MA. · Department of Pathology, Children's Hospital Boston, Boston, MA Proteomics Center at Children's Hospital Boston, Boston, MA Center for Pancreatic Disease, Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, MA. ·J Immunol Methods · Pubmed #22683544.

ABSTRACT: BACKGROUND: Diagnosis of pancreatic cystic neoplasms remains problematic. We hypothesize that inflammatory mediator proteins in pancreatic cyst fluid can differentiate branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) and pancreatic inflammatory cysts. We aim to 1) detect inflammatory mediator proteins (IMPs) using a multiplexed IMP-targeted microarray in pancreatic cyst fluid obtained during endoscopic ultrasound fine needle aspiration (EUS-FNA) and 2) compare IMP profiles in pancreatic cyst fluid from BD-IPMNs and inflammatory cysts. Pancreatic cyst fluid from ten patients (5 BD-IPMN and 5 inflammatory cysts) was obtained by EUS-FNA and analyzed directly with a multiplexed microarray assay to determine concentrations of 89 IMPs. Statistical analysis was performed using non-parametric methods. RESULTS: Eighty-three of the 89 assayed IMPs were detected in at least one of the 10 patient samples. Seven IMPs were detected in BD-IPMN but not inflammatory cysts, while eleven IMPs were identified in inflammatory cysts but not BD-IPMN. Notably, granulocyte-macrophage colony-stimulating factor (GM-CSF) expression was present in all five inflammatory cyst samples. Hepatocyte growth factor (HGF) was present in significantly higher concentrations in inflammatory cysts compared to BD-IPMN. CONCLUSION: Our exploratory analysis reveals that GM-CSF and HGF in EUS-FNA-collected pancreatic cyst fluid can distinguish between BD-IPMN and inflammatory cyst. Coupling microarray molecular techniques to EUS-FNA may represent a major step forward to our understanding complex pancreatic disease.

20 Article Locally advanced anaplastic pancreatic adenocarcinoma with initial response to FOLFIRINOX and rapid progression after five months. 2012

Shinagare, Atul B / Ramaiya, Nikhil H / Bellizzi, Andrew M / Mayer, Robert J. ·Department of Imaging, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. ashinagare@partners.org ·Pancreatology · Pubmed #22487471.

ABSTRACT: Anaplastic pancreatic carcinoma (APC) is a rare, aggressive variant of pancreatic ductal adenocarcinoma. Surgery is the preferred treatment whenever possible, however APC is often unresectable at presentation and prognosis remains poor. We present a case of APC which showed a marked initial response to FOLFIRINOX with decreased size and increased cystic change, however then rapidly progressed with innumerable hepatic metastases after five months of FOLFIRINOX treatment. Although there is limited data on use of FOLFIRINOX in locally advanced pancreatic adenocarcinoma, it remains an attractive option in comparison to radiotherapy and 5-fluorouracil.

21 Article The mTOR pathway is frequently activated in pancreatic ductal adenocarcinoma and chronic pancreatitis. 2010

Bellizzi, Andrew M / Bloomston, Mark / Zhou, Xiao-Ping / Iwenofu, Obiajulu Hans / Frankel, Wendy L. ·Departments of Pathology, The Ohio State University Medical Center, Columbus, OH 43210-1218, USA. ·Appl Immunohistochem Mol Morphol · Pubmed #20661135.

ABSTRACT: INTRODUCTION: Mammalian target of rapamycin (mTOR) is a serine/threonine kinase critical to cell growth and proliferation through its effects on protein translation. Activation of the phosphatidylinositol 3-kinase/Akt/mTOR pathway has been described in various tumor types. Earlier studies have demonstrated loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function in some pancreatic ductal adenocarcinomas (PDAs). We performed immunohistochemistry for PTEN and p-RPS6 (major downstream mTOR effector) in a group of PDAs. An assessment of chronic pancreatitis (CP) and normal pancreas (NL) was performed in parallel. MATERIALS AND METHODS: Tissue microarrays were constructed from 49 PDA, 27 CP, and 12 NL. Cases were scored as follows: PTEN (intact: ≥ 5% staining and lost: < 5%) and p-RPS6 (0, 1+: modest intensity in ≥ 5% of cells and 2+: strong intensity ≥ 5% of cells). RESULTS: Forty-one percent of PDAs demonstrated loss of PTEN, and 75% demonstrated p-RPS6 immunoreactivity (1+ in 22 and 2+ in 3). PTEN was uniformly intact in NL and CP. Although p-RPS6 immunoreactivity was only noted in 1 NL control (8%), 1+ positivity was observed in 62% of CP. CONCLUSIONS: mTOR pathway activation, as evidenced by p-RPS6 immunoreactivity, is frequent in PDA. p-RPS6 expression was also frequent in CP, highlighting the importance of this pathway in both neoplastic and inflammatory processes. Given evidence of pathway activation and the existence of specific anti-mTOR therapeutics, mTOR represents a logical target for directed biologic therapy.