26 results on '"Conlon, Kevin"'
Search Results
2. Contributors
- Author
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Abdalla, Eddie K., primary, Abou-Alfa, Ghassan K., additional, Adams, Reid B., additional, Adsay, N. Volkan, additional, Ahluwalia, Jatinder P., additional, Akhurst, Timothy, additional, Atwell, Thomas D., additional, Austin, Mary T., additional, Bassi, Claudio, additional, Becker, Christoph D., additional, Beckingham, Ian J., additional, Belghiti, Jacques, additional, Berne, Thomas V., additional, Bilchik, Anton J., additional, Binmoeller, Kenneth F., additional, Bismuth, Henri, additional, Blomley, Martin J.K., additional, Blumgart, Leslie H., additional, Bornman, P.C., additional, Brody, Lynn, additional, Broelsch, Christoph E., additional, Brown, Carlos V.R., additional, Brown, Karen T., additional, Brown, Melissa L., additional, Bruix, Jordi, additional, Brunt, Elizabeth M., additional, Büchler, Markus W., additional, Burroughs (Hon), Andrew K., additional, Butturini, Giovanni, additional, Cameron, Iain C., additional, Carloni, Alessio, additional, Carr-Locke, David L., additional, Cha, Charles, additional, Chapman, William C., additional, Chung, Jin Wook, additional, Cioni, Dania, additional, Conlon, Kevin C., additional, Correia, Mauro M., additional, Corvera, Carlos U., additional, Cosgrove, David O., additional, Covey, Anne M., additional, Angelica, Michael D', additional, Darcy, Michael, additional, Davison, Brian D., additional, DeCorato, Douglas R., additional, DeMatteo, Ronald P., additional, Demetriades, Demetrios, additional, Demetriou, Achilles A., additional, Desai, Niraj M., additional, Dhanireddy, Kiran K., additional, Diamond, Thomas, additional, Di Mola, Fabio F., additional, Di Sebastiano, Pierluigi, additional, Doyle, Majella, additional, Eckersley, Robert J., additional, Joseph Espat, N., additional, Fan, Sheung-Tat, additional, Farges, Olivier, additional, Castillo, Carlos Fernández-Del, additional, Fischer, Mary, additional, Fong, Yuman, additional, Friess, Helmut, additional, Fuster, Josep, additional, Garg, Nisha, additional, Gerdes, Hans, additional, Gertsch, Philippe, additional, Getradjman, George, additional, Gittes, George K., additional, Glasgow, Sean C., additional, Gondolesi, Gabriel E., additional, Goulis, John, additional, Gouma, Dirk J., additional, Halpern, Neil A., additional, Hann, Lucy E., additional, Hartwig, Werner, additional, Heffernan, Nancy, additional, Helton, William Scott, additional, Hemming, Alan W., additional, Henderson, J. Michael, additional, Ho, Choon-Kiat, additional, Ichai, Philippe, additional, Imamura, Hiroshi, additional, Imrie, C.W., additional, Jackson, James, additional, Janicki, Piotr K., additional, Jarnagin, William R., additional, Jenkins, Roger L., additional, Kahl, Stefan, additional, Kamiya, Junichi, additional, Kayaalp, Cuneyt, additional, Kelly, Colleen R., additional, Kemeny, Nancy E., additional, Kirk, Allan D., additional, Kitagawa, Yuichi, additional, Kleeff, Jörg, additional, Klimstra, David S., additional, Knechtle, Stuart J., additional, Kobayashi, Hiroyuki, additional, Kotru, Anil, additional, Krige, Jake E.J., additional, Ku, Yonson, additional, Kurtz, Robert C., additional, LaBrecque, Douglas R., additional, Lang, Hauke, additional, La Quaglia, Michael P., additional, Larusso, Nicholas F., additional, Lazaridis, K.N., additional, Lee, L.S., additional, Lencioni, Riccardo, additional, Liau, Kui Hin, additional, Lightdale, Charles J., additional, Lillemoe, Keith D., additional, Lin, James, additional, Linehan, David C., additional, Lipsett, Pamela A., additional, Llovett, Josep M., additional, Lowell, Jeffrey A., additional, Madoff, David C., additional, Maitra, Anirban, additional, Majeed, Ali W., additional, Makuuchi, Masatoshi, additional, Malfertheiner, Peter, additional, Marcos, Amadeo, additional, Markmann, James F., additional, Mathie, Robert T., additional, McAuliffe, Priscilla F., additional, McKay, Colin J., additional, Melendez, Jose A., additional, Moldawer, Lyle L., additional, Mole, Damian J., additional, Mönkemüller, Klaus, additional, Nagino, Masato, additional, Nagle, Alexander, additional, Nagorney, David M., additional, Nakakura, Eric K., additional, Nakeeb, Attila, additional, Neuberger, James, additional, Nimura, Yuji, additional, Nunes, Quentin M., additional, O'Grady, John G., additional, O'Laoide, Risteard, additional, Olthoff, Kim M., additional, Ong, Evan S., additional, Orloff, Marshall J., additional, Orloff, Mark S., additional, Orloff, Susan L., additional, Paradis, Valérie, additional, Passik, Steven D., additional, Peitgen, Heinz-Otto, additional, Pillarisetty, Venu, additional, Wright Pinson, C., additional, Pitt, Henry A., additional, Pomposelli, James J., additional, Poon, Ronnie T., additional, Prinz, Richard A., additional, Que, Florencia G., additional, Rikkers, Layton F., additional, Rowlands, Brian J., additional, Sala, Margarita, additional, Saldinger, Pierre F., additional, Salim, Ali, additional, Saltz, Leonard B., additional, Samonakis, Dimitrios N., additional, Samuel, Didier, additional, Sano, Tsuyoshi, additional, Sarmiento, Juan M., additional, Scatton, O., additional, Schattner, Mark, additional, Schmidt, Christian Max, additional, Schulick, Richard D., additional, Schwartz, Lawrence H., additional, Schwartz, Myron E., additional, Shepherd, Ross W., additional, Siddiqi, Nasir H., additional, Sigal, Samuel H., additional, Smajda, C., additional, Small, Aaron J., additional, Smith, Andrew M., additional, Soehendra, Nib, additional, Soper, Nathaniel J., additional, Starzl, Thomas E., additional, Steer, Michael, additional, Stevens, Peter D., additional, Strong, Russell W., additional, Stubbs, Richard S., additional, Takayama, Tadatoshi, additional, Taylor, Rebecca, additional, Teitcher, Jerrold, additional, Terpstra, Onno T., additional, Terraz, Sylvain, additional, Thomas, Philip G., additional, Thomas, William E.G., additional, Toouli, James, additional, Triantos, Christos K., additional, Tseng, Jennifer F., additional, Van Sonnenberg, Eric, additional, Varela, Maria, additional, Varma, Deepak, additional, Vauthey, Jean-Nicholas, additional, Verna, Elizabeth C., additional, Vilgrain, V., additional, Voigt, Louis, additional, Wagman, Raquel, additional, Wands, Jack R., additional, Wang, Han Lin, additional, Warshaw, Andrew L., additional, Weber, Kaare J., additional, Weber, Sharon, additional, Weitz, Jürgen, additional, Werner, Jens, additional, Wheatley, Anthony M., additional, Winston, Corinne, additional, Wizorek, Joseph J., additional, Wong, John, additional, Yeo, Charles J., additional, Yoon, Chang Jin, additional, Zimmerman, Arthur, additional, and Zogakis, Theresa G., additional
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- 2007
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3. RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation
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Walsh, Naomi, Larkin, Anne-Marie, Swan, Niall, Conlon, Kevin, Dowling, Paul, McDermott, Ray, Clynes, Martin, Walsh, Naomi, Larkin, Anne-Marie, Swan, Niall, Conlon, Kevin, Dowling, Paul, McDermott, Ray, and Clynes, Martin
- Abstract
We previously identified Hop as over expressed in invasive pancreatic cancer cell lines and malignant tissues of pancreatic cancer patients, suggesting an important role for Hop in the biology of invasive pancreatic cancer. Hop is a co-chaperone protein that binds to both Hsp70/Hsp90. We hypothesised that by targeting Hop, signalling pathways modulating invasion and client protein stabilisation involving Hsp90-dependent complexes may be altered. In this study, we show that Hop knockdown by small interfering (si)RNA reduces the invasion of pancreatic cancer cells, resulting in decreased expression of the downstream target gene, matrix metalloproteinases-2 (MMP-2). Hop in conditioned media co-immunoprecipitates with MMP-2, implicating a possible extracellular function for Hop. Knockdown of Hop expression also reduced expression levels of Hsp90 client proteins, HER2, Bcr-Abl, c-MET and v-Src. Furthermore, Hop is strongly expressed in high grade PanINs compared to lower PanIN grades, displaying differential localisation in invasive ductal pancreatic cancer, indicating that the localisation of Hop is an important factor in pancreatic tumours. Our data suggests that the attenuation of Hop expression inactivates key signal transduction proteins which may decrease the invasiveness of pancreatic cancer cells possibly through the modulation of Hsp90 activity. Therefore, targeting Hop in pancreatic cancer may constitute a viable strategy for targeted cancer therapy.
- Published
- 2011
4. Development of a clinical score to estimate pancreatitis-related hospital admissions in patients with a new diagnosis of chronic pancreatitis: the trinity score.
- Author
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Keaskin L, Egan SM, Almirall-Sanchez A, Tewatia V, Jorba R, Ferreres J, Belén Ballesté, Memba R, Ridgway PF, O'Connor DB, Duggan SN, and Conlon KC
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- Humans, Retrospective Studies, Hospitalization, Hospitals, Pancreatitis, Chronic complications, Pancreatitis, Chronic diagnosis, Pancreatitis, Chronic therapy
- Abstract
Background: The clinical course of chronic pancreatitis is unpredictable and there is no globally accepted score to predict the disease course. We developed a clinical score to estimate pancreatitis-related hospitalisation in patients with newly diagnosed chronic pancreatitis., Methods: We conducted a retrospective cohort study using two clinical chronic pancreatitis databases held in tertiary referral centres in Dublin, Ireland, and in Tarragona, Spain. Individuals diagnosed with chronic pancreatitis between 2007 and 2014 were eligible for inclusion. Candidate predictors included aetiology, body mass index, exocrine dysfunction, smoking and alcohol history. We used multivariable logistic regression to develop the model., Results: We analysed data from 154 patients with newly diagnosed chronic pancreatitis. Of these, 105 patients (68%) had at least one hospital admission for pancreatitis-related reasons in the 6 years following diagnosis. Aetiology of chronic pancreatitis, body mass index, use of pain medications and gender were found to be predictive of more pancreatic-related hospital admissions. These predictors were used to develop a clinical score which showed acceptable discrimination (area under the ROC curve = 0.70)., Discussion: We developed a clinical score based on easily accessible clinical parameters to predict pancreatitis-related hospitalisation in patients with newly diagnosed chronic pancreatitis., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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5. Physical activity for chronic pancreatitis: a systematic review.
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Monaghan B, Monaghan A, Mockler D, Ul Ain Q, Duggan SN, Conlon KC, and Gormley J
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- Chronic Disease, Exercise, Humans, Pancreas, Pancreatitis, Chronic complications, Pancreatitis, Chronic diagnosis, Pancreatitis, Chronic therapy, Sarcopenia diagnosis, Sarcopenia etiology
- Abstract
Background: Chronic pancreatitis (CP) is a progressive inflammatory disorder of the pancreas. Sarcopenia is a degenerative loss of skeletal muscle mass, quality, and strength and is commonly associated with chronic pancreatitis. Regular physical activity and adequate functional fitness have been found to ameliorate the risk and effects of sarcopenia in other chronic diseases. The objective of this systematic review was to collate all the published evidence which has examined any type of physical activity as an intervention in the chronic pancreatitis patient population., Methods: This systematic review was conducted in accordance with the PRISMA guidelines. The search strategy was designed by the medical librarian (DM) for Embase and then modified for the other search platforms. Two of the researchers (BM) and (AM) then performed the literature search using the databases Embase, Medline, CINAHL, and Web of Science., Results: An electronic identified a total of 571 references imported to Covidence as 420 when the duplicates (151) were removed. 420 titles were screened and 390 were removed as not relevant from their titles. 30 full text papers were selected and from these, only one full text paper was deemed suitable for inclusion., Conclusions: There is currently insufficient evidence to advise physical activity in the chronic pancreatitis population. However, given the evidence to support physical activity in many other chronic diseases this review highlights the need for urgent investigation of physical activity as an intervention on this specific patient population., (Copyright © 2022 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)
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- 2022
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6. External validation of postoperative pancreatic fistula prediction scores in pancreatoduodenectomy: a systematic review and meta-analysis.
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Pande R, Halle-Smith JM, Phelan L, Thorne T, Panikkar M, Hodson J, Roberts KJ, Arshad A, Connor S, Conlon KC, Dickson EJ, Giovinazzo F, Harrison E, de Liguori Carino N, Hore T, Knight SR, Loveday B, Magill L, Mirza D, Pandanaboyana S, Perry RJ, Pinkney T, Siriwardena AK, Satoi S, Skipworth J, Stättner S, Sutcliffe RP, and Tingstedt B
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- Humans, Pancreas surgery, Postoperative Complications diagnosis, Postoperative Complications etiology, Postoperative Complications surgery, Retrospective Studies, Risk Assessment, Risk Factors, Pancreatic Fistula diagnosis, Pancreatic Fistula etiology, Pancreatic Fistula surgery, Pancreaticoduodenectomy adverse effects
- Abstract
Background: Multiple risk scores claim to predict the probability of postoperative pancreatic fistula (POPF) after pancreatoduodenectomy. It is unclear which scores have undergone external validation and are the most accurate. The aim of this study was to identify risk scores for POPF, and assess the clinical validity of these scores., Methods: Areas under receiving operator characteristic curve (AUROCs) were extracted from studies that performed external validation of POPF risk scores. These were pooled for each risk score, using intercept-only random-effects meta-regression models., Results: Systematic review identified 34 risk scores, of which six had been subjected to external validation, and so included in the meta-analysis, (Tokyo (N=2 validation studies), Birmingham (N=5), FRS (N=19), a-FRS (N=12), m-FRS (N=3) and ua-FRS (N=3) scores). Overall predictive accuracies were similar for all six scores, with pooled AUROCs of 0.61, 0.70, 0.71, 0.70, 0.70 and 0.72, respectively. Considerably heterogeneity was observed, with I2 statistics ranging from 52.1-88.6%., Conclusion: Most risk scores lack external validation; where this was performed, risk scores were found to have limited predictive accuracy. . Consensus is needed for which score to use in clinical practice. Due to the limited predictive accuracy, future studies to derive a more accurate risk score are warranted., (Copyright © 2021. Published by Elsevier Ltd.)
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- 2022
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7. A high prevalence of genetic polymorphisms in idiopathic and alcohol-associated chronic pancreatitis patients in Ireland.
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Ní Chonchubhair HM, Duggan SN, Egan SM, Kenyon M, O'Toole D, McManus R, and Conlon KC
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- Chronic Disease, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Genetic Predisposition to Disease, Humans, Ireland epidemiology, Mutation, Polymorphism, Genetic, Prevalence, Trypsin genetics, Alcoholism complications, Pancreatitis, Chronic diagnosis, Pancreatitis, Chronic epidemiology, Pancreatitis, Chronic genetics, Trypsin Inhibitor, Kazal Pancreatic genetics
- Abstract
Background: Individual genetic architecture is considered central to susceptibility and progression of disease in chronic pancreatitis. The study aimed to evaluate the presence of common pancreatic gene mutations in a defined cohort of idiopathic and alcohol-induced chronic pancreatitis patients in Ireland., Methods: The study comprised patients with idiopathic and alcohol-induced chronic pancreatitis and historic controls. Variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, cationic trypsinogen (PRSS1) gene and serine protease inhibitor kazal type-1 (SPINK1) gene, were assessed by Taqman© genotyping assay., Results: Of n = 126 patients and n = 167 controls, mutations were detected in 23 (20%) and in 10 (6%) respectively (P < 0.001). The majority of mutations found were in the SPINK1 gene variant N34S (13%) which increased disease risk almost six-fold (OR 5.9). Neither CFTR severe mutation (F508del) (P = 0.649) nor mild variant (R117H) (P = 0.327) were over-represented amongst patients compared to control subjects. PRSS1 variants were not detected in either patient or control subjects., Conclusion: There was a significant prevalence of chronic pancreatitis-associated gene mutations in this well-phenotyped cohort. In patients with alcohol-related or idiopathic chronic pancreatitis, the possibility of genetic mutations in the SPINK 1 gene should be considered as a contributing aetiology factor., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)
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- 2021
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8. Imaging of genetically-mediated pancreatitis.
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O'Brien CM, O'Brien AC, Gleeson L, Conlon K, Feeney J, and Malone DE
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- Adult, Aged, Carrier Proteins genetics, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Female, Genotype, Humans, Male, Middle Aged, Mutation, Pancreatic Neoplasms, Pancreatitis therapy, Pancreatitis, Chronic genetics, Pancreatitis, Chronic surgery, Retrospective Studies, Trypsin genetics, Trypsin Inhibitor, Kazal Pancreatic genetics, Young Adult, Pancreatitis diagnostic imaging
- Abstract
Objectives: To review the imaging of patients with Genetically-Mediated Pancreatitis (GMP), identify common imaging findings in this cohort and assess phenotypical characteristics of specific genotypes., Materials and Methods: Retrospective review of the databases of the Irish National Surgical Centre for Pancreatic Cancer (NSCPC) and Cystic Fibrosis (CF) from November 2010 to January 2018. Retrospective imaging and chart review for the patients with positive genetics for GMP., Results: The NSCPC database contained 699 patients; the CF database included 352 patients. Of these 1051, 14 were identified as having GMP (age range: 20-65, M:F ratio of 1:1). 14 of 1051 patients from the database had positive genetics for GMP. 10 had imaging to support a diagnosis of hereditary pancreatitis or familial recurrent pancreatitis (1.3%) and 4 had imaging to support a diagnosis of CF-related pancreatitis. Imaging findings were considered in 3 categories, determined by genotype - PRSS1 hereditary pancreatitis, SPINK 1 autosomal recessive pancreatitis and those for CFTR - cystic fibrosis related pancreatitis. Imaging findings in PRSS1 hereditary pancreatitis patients included: pancreatic atrophy, calcification and main pancreatic duct (MPD) dilatation, referred to as the PRSS1 imaging triad. Patients with the SPINK1 gene mutation had less severe imaging manifestations (pancreatic atrophy 33%, MPD dilatation 33%, pancreatic calcification 33%). CFTR patients with imaging findings had pancreatic atrophy (100%)., Conclusion: GMP should be suspected when the features of 'chronic pancreatitis' are seen in young adults with no history of excess alcohol intake. Genetic testing, endocrinology review and long-term imaging follow-up for pancreatic carcinoma are indicated., (Copyright © 2020 Elsevier Inc. All rights reserved.)
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- 2020
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9. Delivery of hepato-pancreato-biliary surgery during the COVID-19 pandemic: an European-African Hepato-Pancreato-Biliary Association (E-AHPBA) cross-sectional survey.
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Balakrishnan A, Lesurtel M, Siriwardena AK, Heinrich S, Serrablo A, Besselink MGH, Erkan M, Andersson B, Polak WG, Laurenzi A, Olde Damink SWM, Berrevoet F, Frigerio I, Ramia JM, Gallagher TK, Warner S, Shrikhande SV, Adam R, Smith MD, and Conlon KC
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- Africa epidemiology, Biliary Tract Neoplasms complications, COVID-19, Coronavirus Infections epidemiology, Cross-Sectional Studies, Delivery of Health Care methods, Europe epidemiology, Female, Humans, Liver Neoplasms complications, Male, Pancreatic Neoplasms complications, Pandemics, Pneumonia, Viral epidemiology, SARS-CoV-2, Societies, Medical, Betacoronavirus, Biliary Tract Neoplasms surgery, Coronavirus Infections complications, Digestive System Surgical Procedures methods, Liver Neoplasms surgery, Pancreatic Neoplasms surgery, Pneumonia, Viral complications
- Abstract
Background: The extent of the COVID-19 pandemic and the resulting response has varied globally. The European and African Hepato-Pancreato-Biliary Association (E-AHPBA), the premier representative body for practicing HPB surgeons in Europe and Africa, conducted this survey to assess the impact of COVID-19 on HPB surgery., Methods: An online survey was disseminated to all E-AHPBA members to assess the effects of the pandemic on unit capacity, management of HPB cancers, use of COVID-19 screening and other aspects of service delivery., Results: Overall, 145 (25%) members responded. Most units, particularly in COVID-high countries (>100,000 cases) reported insufficient critical care capacity and reduced HPB operating sessions compared to COVID-low countries. Delayed access to cancer surgery necessitated alternatives including increased neoadjuvant chemotherapy for pancreatic cancer and colorectal liver metastases, and locoregional treatments for hepatocellular carcinoma. Other aspects of service delivery including COVID-19 screening and personal protective equipment varied between units and countries., Conclusion: This study demonstrates that the COVID-19 pandemic has had a profound adverse impact on the delivery of HPB cancer care across the continents of Europe and Africa. The findings illustrate the need for safe resumption of cancer surgery in a "new" normal world with screening of patients and staff for COVID-19., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)
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- 2020
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10. Rapid progression of adult T-cell leukemia/lymphoma as tumor-infiltrating Tregs after PD-1 blockade.
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Rauch DA, Conlon KC, Janakiram M, Brammer JE, Harding JC, Ye BH, Zang X, Ren X, Olson S, Cheng X, Miljkovic MD, Sundaramoorthi H, Joseph A, Skidmore ZL, Griffith O, Griffith M, Waldmann TA, and Ratner L
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- Adult, Animals, Disease Progression, Gene Expression Regulation, Leukemic drug effects, Humans, Leukemia-Lymphoma, Adult T-Cell genetics, Leukemia-Lymphoma, Adult T-Cell pathology, Mice, T-Lymphocytes, Regulatory drug effects, T-Lymphocytes, Regulatory metabolism, Tumor Cells, Cultured, Antineoplastic Agents, Immunological therapeutic use, Leukemia-Lymphoma, Adult T-Cell drug therapy, Nivolumab therapeutic use, Programmed Cell Death 1 Receptor antagonists & inhibitors, T-Lymphocytes, Regulatory pathology
- Abstract
Immune checkpoint inhibitors are a powerful new tool in the treatment of cancer, with prolonged responses in multiple diseases, including hematologic malignancies, such as Hodgkin lymphoma. However, in a recent report, we demonstrated that the PD-1 inhibitor nivolumab led to rapid progression in patients with adult T-cell leukemia/lymphoma (ATLL) (NCT02631746). We obtained primary cells from these patients to determine the cause of this hyperprogression. Analyses of clonality, somatic mutations, and gene expression in the malignant cells confirmed the report of rapid clonal expansion after PD-1 blockade in these patients, revealed a previously unappreciated origin of these malignant cells, identified a novel connection between ATLL cells and tumor-resident regulatory T cells (Tregs), and exposed a tumor-suppressive role for PD-1 in ATLL. Identifying the mechanisms driving this alarming outcome in nivolumab-treated ATLL may be broadly informative for the growing problem of rapid progression with immune checkpoint therapies.
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- 2019
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11. The predictive value of C-reactive protein (CRP) in acute pancreatitis - is interval change in CRP an additional indicator of severity?
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Stirling AD, Moran NR, Kelly ME, Ridgway PF, and Conlon KC
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- Acute Disease, Adolescent, Adult, Aged, Aged, 80 and over, Area Under Curve, Biomarkers blood, Child, Databases, Factual, Female, Humans, Male, Middle Aged, Pancreatitis diagnosis, Patient Admission, Predictive Value of Tests, Prognosis, ROC Curve, Reproducibility of Results, Retrospective Studies, Severity of Illness Index, Time Factors, Young Adult, C-Reactive Protein metabolism, Pancreatitis blood
- Abstract
Background: Using revised Atlanta classification defined outcomes, we compare absolute values in C-reactive protein (CRP), with interval changes in CRP, for severity stratification in acute pancreatitis (AP)., Methods: A retrospective study of all first incidence AP was conducted over a 5-year period. Interval change in CRP values from admission to day 1, 2 and 3 was compared against the absolute values. Receiver-operator characteristic (ROC) curve and likelihood ratios (LRs) were used to compare ability to predict severe and mild disease., Results: 337 cases of first incidence AP were included in our analysis. ROC curve analysis demonstrated the second day as the most useful time for repeat CRP measurement. A CRP interval change >90 mg/dL at 48 h (+LR 2.15, -LR 0.26) was equivalent to an absolute value of >150 mg/dL within 48 h (+LR 2.32, -LR 0.25). The optimal cut-off for absolute CRP based on new, more stringent definition of severity was >190 mg/dL (+LR 2.72, -LR 0.24)., Conclusion: Interval change in CRP is a comparable measure to absolute CRP in the prognostication of AP severity. This study suggests a rise of >90 mg/dL from admission or an absolute value of >190 mg/dL at 48 h predicts severe disease with the greatest accuracy., (Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)
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- 2017
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12. Proceedings of the first international state-of-the-art conference on minimally-invasive pancreatic resection (MIPR).
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Vollmer CM, Asbun HJ, Barkun J, Besselink MG, Boggi U, Conlon KC, Han HS, Hansen PD, Kendrick ML, Montagnini AL, Palanivelu C, Røsok BI, Shrikhande SV, Wakabayashi G, Zeh HJ, and Kooby DA
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- Education, Medical methods, Health Care Costs, Humans, Pancreatectomy adverse effects, Pancreatectomy economics, Pancreatectomy education, Pancreaticoduodenectomy adverse effects, Pancreaticoduodenectomy economics, Pancreaticoduodenectomy education, Postoperative Complications etiology, Risk Factors, Treatment Outcome, Laparoscopy adverse effects, Laparoscopy economics, Laparoscopy education, Pancreatectomy methods, Pancreaticoduodenectomy methods, Robotic Surgical Procedures adverse effects, Robotic Surgical Procedures economics, Robotic Surgical Procedures education
- Abstract
The application of minimally-invasive techniques to major pancreatic resection (MIPR) has occurred steadily, but slowly, over the last two decades. Questions linger regarding its safety, efficacy, and broad applicability. On April 20th, 2016, the first International State-of-the-Art Conference on Minimally Invasive Pancreatic Resection convened in Sao Paulo, Brazil in conjunction with the International Hepato-Pancreato-Biliary Association's (IHPBA) 10th World Congress. This report describes the genesis, preparation, execution and output from this seminal event. Major themes explored include: (i) scrutiny of best-level evidence outcomes of both MIPR Distal Pancreatectomy (DP) and pancreatoduodenectomy (PD), (ii) Cost/Value/Quality of Life assessment of MIPR, (iii) topics in training, education and credentialing, and (iv) development of best approaches to analyze results of MIPR - including clinical trial design and registry development. Results of a worldwide survey of over 400 surgeons on the practice of MIPR were presented. The proceedings of this event serve as a platform for understanding the role of MIPR in pancreatic resection. Data and concepts presented at this meeting form the basis for further study, application and dissemination of MIPR., (Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)
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- 2017
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13. Minimally invasive pancreatic resections: cost and value perspectives.
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Conlon KC, de Rooij T, van Hilst J, Abu Hidal M, Fleshman J, Talamonti M, Vanounou T, Garfinkle R, Velanovich V, Kooby D, and Vollmer CM
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- Cost-Benefit Analysis, Hospital Costs, Humans, Laparoscopy adverse effects, Models, Economic, Pancreatectomy adverse effects, Pancreaticoduodenectomy adverse effects, Quality of Life, Robotic Surgical Procedures adverse effects, Treatment Outcome, Health Care Costs, Laparoscopy economics, Pancreatectomy economics, Pancreaticoduodenectomy economics, Robotic Surgical Procedures economics
- Abstract
Background: The number of minimally invasive pancreatic resections (MIPR) performed for benign or malignant disease, have increased in recent years. However, there is limited information regarding cost/value implications., Methods: An international conference evaluating MIPR was held during the 12th Bi-Annual International Hepato-Pancreato-Biliary Association (IHPBA) World Congress in Sao Paulo, Brazil, on April 20th, 2016. This manuscript summarizes the presentations that reviewed current topics in cost and value as they pertain to MIPR., Results: Compared to the open approach, MIPR's are associated with higher operative costs but lower postoperative costs. However, measurements of patient value (defined as improvement in both quantity and quality of life) and financial value (using incremental cost-effectiveness ratio) are required to determine the true value at societal level., Conclusion: Challenges remain as to how the potential benefits, both to the patient and the healthcare system as a whole, are measured. Research comparing MIPR versus other techniques for pancreatectomy will require appropriate and valid measurement tools, some of which are yet to be refined. Nonetheless, the experience to date would support the continued development of MIPR by experienced surgeons in high-volume pancreatic centers, married with appropriate review and recalibration., (Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)
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- 2017
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14. Standardizing terminology for minimally invasive pancreatic resection.
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Montagnini AL, Røsok BI, Asbun HJ, Barkun J, Besselink MG, Boggi U, Conlon KC, Fingerhut A, Han HS, Hansen PD, Hogg ME, Kendrick ML, Palanivelu C, Shrikhande SV, Wakabayashi G, Zeh H, Vollmer CM, and Kooby DA
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- Consensus, Humans, Delphi Technique, Laparoscopy classification, Pancreatectomy classification, Pancreaticoduodenectomy classification, Robotic Surgical Procedures classification, Terminology as Topic
- Abstract
Background: There is a growing body of literature pertaining to minimally invasive pancreatic resection (MIPR). Heterogeneity in MIPR terminology, leads to confusion and inconsistency. The Organizing Committee of the State of the Art Conference on MIPR collaborated to standardize MIPR terminology., Methods: After formal literature review for "minimally invasive pancreatic surgery" term, key terminology elements were identified. A questionnaire was created assessing the type of resection, the approach, completion, and conversion. Delphi process was used to identify the level of agreement among the experts., Results: A systematic terminology template was developed based on combining the approach and resection taking into account the completion. For a solitary approach the term should combine "approach + resection" (e.g. "laparoscopic pancreatoduodenectomy); for combined approaches the term must combine "first approach + resection" with "second approach + reconstruction" (e.g. "laparoscopic central pancreatectomy" with "open pancreaticojejunostomy") and where conversion has resulted the recommended term is "first approach" + "converted to" + "second approach" + "resection" (e.g. "robot-assisted" "converted to open" "pancreatoduodenectomy") CONCLUSIONS: The guidelines presented are geared towards standardizing terminology for MIPR, establishing a basis for comparative analyses and registries and allow incorporating future surgical and technological advances in MIPR., (Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)
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- 2017
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15. Worldwide survey on opinions and use of minimally invasive pancreatic resection.
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van Hilst J, de Rooij T, Abu Hilal M, Asbun HJ, Barkun J, Boggi U, Busch OR, Conlon KC, Dijkgraaf MG, Han HS, Hansen PD, Kendrick ML, Montagnini AL, Palanivelu C, Røsok BI, Shrikhande SV, Wakabayashi G, Zeh HJ, Vollmer CM, Kooby DA, and Besselink MG
- Subjects
- Adult, Attitude of Health Personnel, Clinical Competence, Education, Medical, Continuing, Education, Medical, Graduate, Health Care Surveys, Health Knowledge, Attitudes, Practice, Humans, Laparoscopy education, Middle Aged, Pancreatectomy education, Pancreaticoduodenectomy education, Robotic Surgical Procedures education, Surgeons psychology, Laparoscopy trends, Pancreatectomy trends, Pancreaticoduodenectomy trends, Practice Patterns, Physicians' trends, Robotic Surgical Procedures trends, Surgeons trends
- Abstract
Background: The introduction of minimally invasive pancreatic resection (MIPR) into surgical practice has been slow. The worldwide utilization of MIPR and attitude towards future perspectives of MIPR remains unknown., Methods: An anonymous survey on MIPR was sent to the members of six international associations of Hepato-Pancreato-Biliary (HPB) surgery., Results: The survey was completed by 435 surgeons from 50 countries, with each surgeon performing a median of 22 (IQR 12-40) pancreatic resections annually. Minimally invasive distal pancreatectomy (MIDP) was performed by 345 (79%) surgeons and minimally invasive pancreatoduodenectomy (MIPD) by 124 (29%). The median total personal experience was 20 (IQR 10-50) MIDPs and 12 (IQR 4-40) MIPDs. Current superiority for MIDP was claimed by 304 (70%) and for MIPD by 44 (10%) surgeons. The most frequently mentioned reason for not performing MIDP (54/90 (60%)) and MIPD (193/311 (62%)) was lack of specific training. Most surgeons (394/435 (90%)) would consider participating in an international registry on MIPR., Discussion: This worldwide survey showed that most participating HPB surgeons value MIPR as a useful development, especially for MIDP, but the role and implementation of MIPD requires further assessment. Most HPB surgeons would welcome specific training in MIPR and the establishment of an international registry., (Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2017
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16. Evaluation of a "Subintern" Role: Action Over Observation For Final-Year Medical Students in Surgery.
- Author
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Morris MC, Hennessy M, Conlon KC, and Ridgway PF
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- Internship and Residency, Personal Satisfaction, Physician-Patient Relations, Students, Medical psychology, Education, Medical, Undergraduate methods, General Surgery education
- Abstract
Background: This study sought to investigate the potential of a subinternship apprentice role as a structured experiential learning opportunity by enabling final-year medical students to learn through action rather than observation., Methods: A convenience sample of 65 final-year medical students was allocated to "intern shadow" (control group) or "subintern" (research group) for 2 weeks during the first clinical attachment of their final year. "Intern shadow" involved direct observation of the intern role, whereas "subintern" involved a fully immersive performance of the intern role under direct supervision by the surgical team. All students completed an evaluation form that was devised in-house and based on course learning objectives. This consisted of Likert scales and free text., Results: Wilcoxon rank sum test results showed that students participating in the "subintern" group had a statistically significantly better clinical experience than the "intern-shadow" group regarding role modeling (p = 0.0002), learning and teaching (p = 0.0021), organization and support (p = 0.0219), and patient interaction (p = 0.0063)., Conclusion: The "subintern" apprentice role shows strong potential for enabling final-year students to learn on the job by actually performing the intern role rather than merely observing an intern at work. Subinterns reported feeling valued within the team structure and expressed a desire to emulate expert practice directly experienced through close collaboration with consultant surgeons., (Copyright © 2015 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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17. Does EUS-FNA molecular analysis carry additional value when compared to cytology in the diagnosis of pancreatic cystic neoplasm? A systematic review.
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Gillis A, Cipollone I, Cousins G, and Conlon K
- Subjects
- DNA analysis, DNA Mutational Analysis, Genes, ras genetics, Humans, Pancreas diagnostic imaging, Pancreatic Cyst genetics, Endoscopic Ultrasound-Guided Fine Needle Aspiration methods, Molecular Diagnostic Techniques methods, Pancreas pathology, Pancreatic Cyst diagnosis
- Abstract
Background: Endoscopic ultrasonography with fine needle aspiration (EUS-FNA) has become an integral tool in the diagnosis of pancreatic cystic lesions (PCLs) and the analysis of molecular/DNA abnormalities might improve the accuracy of pre-operative diagnosis. A review was conducted of all studies using EUS-FNA aspirates of PCLs to assess the accuracy and added benefit that molecular analysis provides to cytological analysis., Methods: A systematic review of the literature was conducted using PRISMA guidelines and electronic databases: PubMed/SCOPUS/EMBASE/Cochrane/CINAHL. Surgical pathology was used as the definitive reference standard. The QUADAS-2 tool was used for quality assessment., Results: In total, 162 articles were identified; 12 articles met inclusion/exclusion criteria. Ten studies reported on cytology and 8 studies reported k-ras mutational analysis. 362 patients (of 1115 total) had surgical pathology available. The sensitivity and specificity of cytology was 0.42 and 0.99; the sensitivity and specificity of k-ras was 0.39 and 0.95; and the sensitivity and specificity of the combined test of cytology and k-ras was 0.71 and 0.88, respectively., Conclusions: k-ras mutational analysis used as an individual screening test has a poor diagnostic accuracy, as does cytology when used alone. The benefit comes with utilization in a combined fashion. More studies are needed to evaluate the correct sequence and utility of these tests for cyst differentiation., (© 2014 International Hepato-Pancreato-Biliary Association.)
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- 2015
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18. An alternative certification examination ("ACE") in surgery.
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Morris MC, Gillis AE, Smoothey CO, Hennessy M, Conlon KC, and Ridgway PF
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- Clinical Competence, Communication, Cooperative Behavior, Humans, Ireland, Patient Safety, Physician-Patient Relations, Reproducibility of Results, Certification, Educational Measurement methods, General Surgery education
- Abstract
Background: Medical graduates are required to be competent in many domains of professional practice when joining the health care workforce. Current undergraduate examination methods robustly assess up to 5 of these 8 required skills. This study sought to evaluate an alternative certification examination ("ACE") in assessing all of the 8 required domains in surgical cases., Methods: A total of 143 final-year medical students were invited to participate in an "ACE" in February 2013. In total, 137 students, 95.8% of the class, agreed to participate. The "ACE" format consisted of 4 sequential patient encounters observed by 2 independent examiners. It assessed all the 8 required domains of professional practice. The examiners and the students evaluated this examination format using a Likert scale and free-text comments., Results: The "ACE" assessed all the 8 domains. The inclusion of a patient safety measure to avoid an egregious error in the pass criteria resulted in 27 (18.9%) students failing to meet them. The correlation of grades between the independent examiners in the "ACE" was strong at a Cronbach α of 0.907 (CI: 0.766-1). The "ACE" format was reported as an acceptable examination methodology by the examiners for formative or summative assessment of surgical cases at the end of a primary medical degree., Conclusion: The "ACE" format is standardized, is integrative, and has excellent interrater reliability. Inclusion of a patient safety measure as pass criteria appears to increase specificity. The "ACE" shows potential as an alternative examination to the traditional long case examination and objective structured clinical examination in assessing all the 8 domains of professional practice., (Copyright © 2014 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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19. Incidence and risk factors of delirium in patients post pancreaticoduodenectomy.
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Gallagher TK, McErlean S, O'Farrell A, Hoti E, Maguire D, Traynor OJ, Conlon KC, and Geoghegan JG
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- Adult, Age Factors, Aged, Aged, 80 and over, Chi-Square Distribution, Databases, Factual, Delirium diagnosis, Female, Hospitals, University, Humans, Incidence, Ireland, Length of Stay, Male, Middle Aged, Multivariate Analysis, Odds Ratio, Retrospective Studies, Risk Factors, Time Factors, Treatment Outcome, Delirium epidemiology, Pancreaticoduodenectomy adverse effects
- Abstract
Background: Post-operative delirium is an important and common complication of major abdominal surgery characterized by acute confusion with fluctuating consciousness. The aim of this study was to establish the incidence of post-operative delirium in patients undergoing a pancreaticoduodenectomy and to determine the risk factors for its development., Methods: From a prospectively maintained database, a retrospective cohort analysis was performed of 50 consecutive patients who underwent a pancreaticoduodenectomy at the National Surgical Centre for Pancreatic Cancer in St. Vincent's University Hospital, Dublin and whose entire post-operative stay was in this institution, between July 2011 and December 2012. Two independent medical practitioners assessed all data and delirium was diagnosed according to criteria of the Diagnostic and Statistical Manual Disorder (DSM), fourth edition. Univariate and multivariate analyses were performed., Results: Seven patients (14%) developed post-operative delirium. The median onset was on the second post-operative day. Older age was predictive of an increased risk of delirium post-operatively. Those who developed delirium had a significantly increased length of stay (LOS) as well as a significantly increased risk of developing at least a grade 3 complication (Clavien-Dindo classification)., Conclusion: This study demonstrates that post-operative delirium is associated with a more complicated recovery after a pancreaticoduodenectomy and that older age is independently predictive of its development. Focused screening may allow targeted preventative strategies to be used in the peri-operative period to reduce complications and costs associated with delirium., (© 2014 International Hepato-Pancreato-Biliary Association.)
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- 2014
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20. Global phosphoproteomic profiling reveals distinct signatures in B-cell non-Hodgkin lymphomas.
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Rolland D, Basrur V, Conlon K, Wolfe T, Fermin D, Nesvizhskii AI, Lim MS, and Elenitoba-Johnson KS
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Antigens, Neoplasm immunology, Cell Line, Tumor, Cell Proliferation, Cluster Analysis, Gene Knockdown Techniques, Germinal Center metabolism, Germinal Center pathology, Humans, Lymphoma, B-Cell diagnosis, Lymphoma, Non-Hodgkin diagnosis, Membrane Proteins metabolism, Models, Biological, Phosphopeptides metabolism, Phosphorylation, Signal Transduction, src-Family Kinases metabolism, Lymphoma, B-Cell metabolism, Lymphoma, Non-Hodgkin metabolism, Phosphoproteins metabolism, Proteomics methods
- Abstract
Deregulation of signaling pathways controlled by protein phosphorylation underlies the pathogenesis of hematological malignancies; however, the extent to which deregulated phosphorylation may be involved in B-cell non-Hodgkin lymphoma (B-NHL) pathogenesis is largely unknown. To identify phosphorylation events important in B-NHLs, we performed mass spectrometry-based, label-free, semiquantitative phosphoproteomic profiling of 11 cell lines derived from three B-NHL categories: Burkitt lymphoma, follicular lymphoma, and mantle-cell lymphoma. In all, 6579 unique phosphopeptides, corresponding to 1701 unique phosphorylated proteins, were identified and quantified. The data are available via ProteomeXchange with identifier PXD000658. Hierarchical clustering highlighted distinct phosphoproteomic signatures associated with each lymphoma subtype. Interestingly, germinal center-derived B-NHL cell lines were characterized by phosphorylation of proteins involved in the B-cell receptor signaling. Of these proteins, phosphoprotein associated with glycosphingolipid-enriched microdomains 1 (PAG1) was identified with the most phosphorylated tyrosine peptides in Burkitt lymphoma and follicular lymphoma. PAG1 knockdown resulted in perturbation of the tyrosine phosphosignature of B-cell receptor signaling components. Significantly, PAG1 knockdown increased cell proliferation and response to antigen stimulation of these germinal center-derived B-NHLs. These data provide a detailed annotation of phosphorylated proteins in human lymphoid cancer. Overall, our study revealed the utility of unbiased phosphoproteome interrogation in characterizing signaling networks that may provide insights into pathogenesis mechanisms in B-cell lymphomas., (Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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21. Integrated phosphoproteomic and metabolomic profiling reveals NPM-ALK-mediated phosphorylation of PKM2 and metabolic reprogramming in anaplastic large cell lymphoma.
- Author
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McDonnell SR, Hwang SR, Rolland D, Murga-Zamalloa C, Basrur V, Conlon KP, Fermin D, Wolfe T, Raskind A, Ruan C, Jiang JK, Thomas CJ, Hogaboam CM, Burant CF, Elenitoba-Johnson KS, and Lim MS
- Subjects
- Animals, Antineoplastic Agents pharmacology, Cell Line, Tumor, Cell Proliferation, Humans, Metabolomics, Mice, Mice, SCID, Neoplasm Transplantation, Phosphorylation, Proteomics, Substrate Specificity, Thyroid Hormone-Binding Proteins, Carrier Proteins metabolism, Gene Expression Regulation, Neoplastic, Lymphoma, Large-Cell, Anaplastic metabolism, Membrane Proteins metabolism, Protein-Tyrosine Kinases metabolism, Thyroid Hormones metabolism
- Abstract
The mechanisms underlying the pathogenesis of the constitutively active tyrosine kinase nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) expressing anaplastic large cell lymphoma are not completely understood. Here we show using an integrated phosphoproteomic and metabolomic strategy that NPM-ALK induces a metabolic shift toward aerobic glycolysis, increased lactate production, and biomass production. The metabolic shift is mediated through the anaplastic lymphoma kinase (ALK) phosphorylation of the tumor-specific isoform of pyruvate kinase (PKM2) at Y105, resulting in decreased enzymatic activity. Small molecule activation of PKM2 or expression of Y105F PKM2 mutant leads to reversal of the metabolic switch with increased oxidative phosphorylation and reduced lactate production coincident with increased cell death, decreased colony formation, and reduced tumor growth in an in vivo xenograft model. This study provides comprehensive profiling of the phosphoproteomic and metabolomic consequences of NPM-ALK expression and reveals a novel role of ALK in the regulation of multiple components of cellular metabolism. Our studies show that PKM2 is a novel substrate of ALK and plays a critical role in mediating the metabolic shift toward biomass production and tumorigenesis.
- Published
- 2013
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22. Markedly additive antitumor activity with the combination of a selective survivin suppressant YM155 and alemtuzumab in adult T-cell leukemia.
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Chen J, Pise-Masison CA, Shih JH, Morris JC, Janik JE, Conlon KC, Keating A, and Waldmann TA
- Subjects
- Adult, Alemtuzumab, Animals, Antibodies, Monoclonal, Humanized pharmacology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Cells, Cultured, Drug Synergism, Humans, Imidazoles pharmacology, Inhibitor of Apoptosis Proteins antagonists & inhibitors, Inhibitor of Apoptosis Proteins genetics, Leukemia-Lymphoma, Adult T-Cell genetics, Leukemia-Lymphoma, Adult T-Cell pathology, Mice, Mice, Inbred NOD, Mice, SCID, Naphthoquinones pharmacology, Substrate Specificity, Survivin, Xenograft Model Antitumor Assays, Antibodies, Monoclonal, Humanized administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Imidazoles administration & dosage, Leukemia-Lymphoma, Adult T-Cell drug therapy, Naphthoquinones administration & dosage
- Abstract
Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4(+)CD25(+) lymphocytes caused by human T-cell lymphotropic virus type 1. Currently, there is no accepted curative therapy for ATL. In gene expression profiling, the antiapoptotic protein survivin (BIRC5) demonstrated a striking increase in ATL, and its expression was increased in patient ATL cells resistant to the anti-CD52 monoclonal antibody alemtuzumab (Campath-1H). In this study, we investigated the antitumor activity of a small-molecule survivin suppressant YM155 alone and in combination with alemtuzumab in a murine model of human ATL (MET-1). Both YM155 alone and its combination with alemtuzumab demonstrated therapeutic efficacy by lowering serum soluble IL-2Rα (sIL-2Rα) levels (P < .001) and prolonged the survival of tumor-bearing mice (P < .0001). Moreover, the combination of YM155 with alemtuzumab demonstrated markedly additive antitumor activity by significantly lowering serum sIL-2Rα levels and improving the survival of leukemia-bearing mice compared with monotherapy with either YM155 (P < .001) or alemtuzumab (P < .05). More significantly, all mice that received the combination therapy survived and were tumor free >6 months after treatment. Our data support a clinical trial of the combination of YM155 with alemtuzumab in ATL. This trial was registered at www.clinicaltrials.gov as #NCT00061048.
- Published
- 2013
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23. Phase 1 trial of IL-15 trans presentation blockade using humanized Mikβ1 mAb in patients with T-cell large granular lymphocytic leukemia.
- Author
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Waldmann TA, Conlon KC, Stewart DM, Worthy TA, Janik JE, Fleisher TA, Albert PS, Figg WD, Spencer SD, Raffeld M, Decker JR, Goldman CK, Bryant BR, Petrus MN, Creekmore SP, and Morris JC
- Subjects
- Aged, Aged, 80 and over, Animals, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal immunology, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Monoclonal, Humanized immunology, Cell Division immunology, Cell Line, Tumor, Female, Humans, Injections, Intravenous, Interleukin Receptor Common gamma Subunit immunology, Interleukin-15 genetics, Interleukin-15 immunology, Interleukin-2 Receptor beta Subunit genetics, Macaca fascicularis, Male, Mice, Middle Aged, RNA, Messenger metabolism, Treatment Outcome, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal, Humanized administration & dosage, Interleukin-2 Receptor beta Subunit immunology, Leukemia, Large Granular Lymphocytic immunology, Leukemia, Large Granular Lymphocytic therapy
- Abstract
In the present study, Hu-Mikβ1, a humanized mAb directed at the shared IL-2/IL-15Rβ subunit (CD122) was evaluated in patients with T-cell large granular lymphocytic (T-LGL) leukemia. Hu-Mikβ1 blocked the trans presentation of IL-15 to T cells expressing IL-2/IL-15Rβ and the common γ-chain (CD132), but did not block IL-15 action in cells that expressed the heterotrimeric IL-15 receptor in cis. There was no significant toxicity associated with Hu-Mikβ1 administration in patients with T-LGL leukemia, but no major clinical responses were observed. One patient who had previously received murine Mikβ1 developed a measurable Ab response to the infused Ab. Nevertheless, the safety profile of this first in-human study of the humanized mAb to IL-2/IL-15Rβ (CD122) supports its evaluation in disorders such as refractory celiac disease, in which IL-15 and its receptor have been proposed to play a critical role in the pathogenesis and maintenance of disease activity.
- Published
- 2013
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24. Radiation therapy for the management of patients with HTLV-1-associated adult T-cell leukemia/lymphoma.
- Author
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Simone CB 2nd, Morris JC, Stewart DM, Urquhart NE, Janik JE, Kreitman RJ, Lita E, Conlon K, Wharfe G, Waldmann TA, and Kaushal A
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Combined Modality Therapy, Female, HTLV-I Infections virology, Humans, Leukemia-Lymphoma, Adult T-Cell complications, Leukemia-Lymphoma, Adult T-Cell drug therapy, Male, Middle Aged, Mucositis etiology, Radiotherapy adverse effects, Radiotherapy Dosage, Retrospective Studies, Skin Diseases etiology, Survival Analysis, Treatment Outcome, HTLV-I Infections complications, Human T-lymphotropic virus 1, Leukemia-Lymphoma, Adult T-Cell radiotherapy, Radiotherapy methods
- Abstract
Human T-cell leukemia virus type 1-associated adult T-cell leukemia/lymphoma (ATL) typically has survivals measured in months with chemotherapy. One prior published series (1983-1991) assessed local radiotherapy for ATL. Ten consecutive patients with pathologically confirmed ATL treated with radiotherapy were reviewed. Subtypes included acute (n = 7), smoldering (n = 2), and lymphomatous (n = 1). Patients received an average of 2.5 systemic therapy regimens before radiotherapy. Twenty lesions (cutaneous = 10, nodal = 8, extranodal = 2) were treated to a mean of 35.4 Gy/2-3 Gy (range, 12-60 Gy). At 9.0-month mean follow-up (range, 0.1-42.0 months), all lesions symptomatically and radiographically responded, with in-field complete responses in 40.0% (nodal 37.5% vs. cutaneous 50.0%; P = .62). No patient experienced in-field progression. Nine patients developed new/progressive out-of-field disease. Median survival was 17.0 months (3-year survival, 30.0%). No Radiation Therapy Oncology Group acute grade ≥ 3 or any late toxicity was noted. This report is the first to use modern radiotherapy techniques and finds effective local control across ATL subtypes. Radiotherapy should be considered for symptomatic local progression of ATL.
- Published
- 2012
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25. Solid-pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor beta-catenin mutations.
- Author
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Abraham SC, Klimstra DS, Wilentz RE, Yeo CJ, Conlon K, Brennan M, Cameron JL, Wu TT, and Hruban RH
- Subjects
- Adolescent, Adult, Aged, Base Sequence genetics, Cystadenoma, Papillary pathology, Female, Gene Expression, Genes, p53, Genes, ras, Humans, Male, Middle Aged, Molecular Sequence Data, Pancreatic Neoplasms pathology, beta Catenin, Carcinoma, Ductal, Breast genetics, Cystadenoma, Papillary genetics, Cytoskeletal Proteins genetics, Mutation physiology, Pancreatic Neoplasms genetics, Trans-Activators
- Abstract
Solid-pseudopapillary tumors (SPTs) are unusual pancreatic neoplasms of low malignant potential that most frequently affect young women. Genetic events contributing to the development of SPTs are unknown. Whereas the more common ductal adenocarcinomas of the pancreas essentially never harbor beta-catenin or APC gene mutations, we have recently identified alterations of the APC/beta-catenin pathway in other nonductal pancreatic neoplasms including pancreatoblastomas and acinar cell carcinomas. We analyzed a series of 20 SPTs for somatic alterations of the APC/beta-catenin pathway using immunohistochemistry for beta-catenin protein accumulation, direct DNA sequencing of beta-catenin exon 3, and direct DNA sequencing of the mutation cluster region in exon 15 of the APC gene in those SPTs that did not harbor beta-catenin mutations. Immunohistochemical labeling for cyclin D1 was performed to evaluate the overexpression of this cell-cycle protein as one of the putative downstream effectors of beta-catenin dysregulation. In addition, we analyzed the SPTs for genetic alterations commonly found in pancreatic ductal adenocarcinomas, including mutations in the K-ras oncogene and p53 and DPC4 tumor suppressor genes, using direct DNA sequencing of K-ras and immunostaining for p53 and Dpc4. Almost all SPTs harbored alterations in the APC/beta-catenin pathway. Nuclear accumulation of beta-catenin protein was present in 95% (19 of 20), and activating beta-catenin oncogene mutations were identified in 90% (18 of 20) of the SPTs. Seventy-four percent (14 of 19) showed overexpression of cyclin D1, ranging from 10 to 70% of tumor nuclei. In contrast, no K-ras mutations were present in any of the 20 SPTs, and Dpc4 expression was intact in all 16 SPTs for which immunohistochemical labeling was successful. Overexpression of p53 was limited to only 3 of 19 (15.8%) SPTs. These results emphasize the two distinct, divergent genetic pathways of neoplastic progression in pancreatic ductal and nonductal neoplasms.
- Published
- 2002
- Full Text
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26. Genetic and immunohistochemical analysis of pancreatic acinar cell carcinoma: frequent allelic loss on chromosome 11p and alterations in the APC/beta-catenin pathway.
- Author
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Abraham SC, Wu TT, Hruban RH, Lee JH, Yeo CJ, Conlon K, Brennan M, Cameron JL, and Klimstra DS
- Subjects
- Adenomatous Polyposis Coli Protein metabolism, Adolescent, Adult, Aged, Carcinoma, Acinar Cell metabolism, Child, Preschool, Chromosomes, Human, Pair 5, Cytoskeletal Proteins metabolism, Female, Genes, Tumor Suppressor, Humans, Immunohistochemistry, Male, Middle Aged, Mutation, Pancreatic Neoplasms metabolism, Signal Transduction genetics, beta Catenin, Adenomatous Polyposis Coli Protein genetics, Carcinoma, Acinar Cell genetics, Chromosomes, Human, Pair 11, Cytoskeletal Proteins genetics, Loss of Heterozygosity, Pancreatic Neoplasms genetics, Trans-Activators
- Abstract
Acinar cell carcinomas (ACCs) are rare malignant tumors of the exocrine pancreas. The specific molecular alterations that characterize ACCs have not yet been elucidated. ACCs are morphologically and genetically distinct from the more common pancreatic ductal adenocarcinomas. Instead, the morphological, immunohistochemical, and clinical features of ACCs overlap with those of another rare pancreatic neoplasm, pancreatoblastoma. We have recently demonstrated a high frequency of allelic loss on chromosome arm 11p and mutations in the APC/beta-catenin pathway in pancreatoblastomas, suggesting that similar alterations might also play a role in the pathogenesis of some ACCs. We analyzed a series of 21 ACCs for somatic alterations in the APC/beta-catenin pathway and for allelic loss on chromosome 11p. In addition, we evaluated the ACCs for alterations in p53 and Dpc4 expression using immunohistochemistry, and for microsatellite instability (MSI) using polymerase chain amplification of a panel of microsatellite markers. Allelic loss on chromosome 11p was the most common genetic alteration in ACCs, present in 50% (6 of 12 informative cases). Molecular alterations in the APC/beta-catenin pathway were detected in 23.5% (4 of 17) of the carcinomas, including one ACC with an activating mutation of the beta-catenin oncogene and three ACCs with truncating APC mutations. One ACC (1 of 13, 7.6%) showed allelic shifts in four of the five markers tested (MSI-high), two (15.4%) showed an allelic shift in only one of the five markers tested (MSI-low), and no shifts were detected in the remaining 10 cases. The MSI-high ACC showed medullary histological features. In contrast, no loss of Dpc4 protein expression or p53 accumulation was detected. These results indicate that ACCs are genetically distinct from pancreatic ductal adenocarcinomas, but some cases contain genetic alterations common to histologically similar pancreatoblastomas.
- Published
- 2002
- Full Text
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