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Potievskiy MB, Nekrasova LA, Korobov IV, Bykova EA, Moshurov RI, Sokolov PV, Shatalov PA, Falaleeva NA, Petrov LO, Trifanov VS, Ivanov SA, Shegai PV, Kaprin AD. Prognostic Impact of Phenotypic and Genetic Features of Pancreatic Malignancies. Life (Basel) 2025; 15:635. [PMID: 40283189 PMCID: PMC12028913 DOI: 10.3390/life15040635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 03/28/2025] [Accepted: 04/06/2025] [Indexed: 04/29/2025] Open
Abstract
Pancreatic cancer is a tumor with a poor prognosis, and improving its survival outcomes remains a formidable challenge, requiring a multidisciplinary approach that integrates innovative surgical and pharmacological strategies, guided by molecular and genetic insights. The pathomorphological and genetic characteristics of pancreatic cancer, reflected in morphological, immunohistochemical, and serological marker expression, reveal key patterns of tumor genotypic changes during carcinogenesis, aiding in prognostic evaluation and clinical strategy development. The mutational profile of pancreatic tumors is quite heterogeneous and diverse in terms of mutated genes, including in relation to morphological subtypes, but certain patterns have been identified as a result of studies. Pancreatic adenocarcinoma, for instance, is frequently driven by mutations regulating cell division (KRAS). The disease prognosis often depends on the morphological subtype and tumor microenvironment. Neuroendocrine tumors of the pancreas are characterized by a number of pathogenetic features that distinguish them from adenocarcinomas. Thus, neuroendocrine tumors are characterized by mutations of the MENIN protein, which prevents cells from entering the mitosis phase by stimulating the expression of cell cycle regulators. Thus, epithelial and neuroendocrine malignancies of the pancreas differ in immunohistochemical and genetic features, but there are similar mechanisms of pathogenesis, such as BRCA1 and BRCA2 gene mutations, impaired expression of p53 antioncogene, and HIF-2α and mTOR receptor mutations. The predictive impact of serological markers, such as CA 19-9 and CEA, offers insights into tumor metastasis and long-term outcomes, emphasizing the need for personalized therapeutic strategies. Tailoring treatments based on individual molecular profiles holds promise for improving prognosis, as the genetic landscape of pancreatic tumors varies significantly between patients. This underscores the importance of a systematic, patient-specific approach that addresses tumor heterogeneity, resistance mechanisms, and the molecular underpinnings of carcinogenesis.
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Affiliation(s)
- Mikhail B. Potievskiy
- FSBI National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 249036 Obninsk, Russia; (L.A.N.); (I.V.K.); (E.A.B.); (R.I.M.); (P.V.S.); (P.A.S.); (N.A.F.); (L.O.P.); (V.S.T.); (S.A.I.); (P.V.S.); (A.D.K.)
| | - Lidia A. Nekrasova
- FSBI National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 249036 Obninsk, Russia; (L.A.N.); (I.V.K.); (E.A.B.); (R.I.M.); (P.V.S.); (P.A.S.); (N.A.F.); (L.O.P.); (V.S.T.); (S.A.I.); (P.V.S.); (A.D.K.)
| | - Ivan V. Korobov
- FSBI National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 249036 Obninsk, Russia; (L.A.N.); (I.V.K.); (E.A.B.); (R.I.M.); (P.V.S.); (P.A.S.); (N.A.F.); (L.O.P.); (V.S.T.); (S.A.I.); (P.V.S.); (A.D.K.)
| | - Ekaterina A. Bykova
- FSBI National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 249036 Obninsk, Russia; (L.A.N.); (I.V.K.); (E.A.B.); (R.I.M.); (P.V.S.); (P.A.S.); (N.A.F.); (L.O.P.); (V.S.T.); (S.A.I.); (P.V.S.); (A.D.K.)
| | - Ruslan I. Moshurov
- FSBI National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 249036 Obninsk, Russia; (L.A.N.); (I.V.K.); (E.A.B.); (R.I.M.); (P.V.S.); (P.A.S.); (N.A.F.); (L.O.P.); (V.S.T.); (S.A.I.); (P.V.S.); (A.D.K.)
| | - Pavel V. Sokolov
- FSBI National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 249036 Obninsk, Russia; (L.A.N.); (I.V.K.); (E.A.B.); (R.I.M.); (P.V.S.); (P.A.S.); (N.A.F.); (L.O.P.); (V.S.T.); (S.A.I.); (P.V.S.); (A.D.K.)
| | - Peter A. Shatalov
- FSBI National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 249036 Obninsk, Russia; (L.A.N.); (I.V.K.); (E.A.B.); (R.I.M.); (P.V.S.); (P.A.S.); (N.A.F.); (L.O.P.); (V.S.T.); (S.A.I.); (P.V.S.); (A.D.K.)
| | - Natalia A. Falaleeva
- FSBI National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 249036 Obninsk, Russia; (L.A.N.); (I.V.K.); (E.A.B.); (R.I.M.); (P.V.S.); (P.A.S.); (N.A.F.); (L.O.P.); (V.S.T.); (S.A.I.); (P.V.S.); (A.D.K.)
| | - Leonid O. Petrov
- FSBI National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 249036 Obninsk, Russia; (L.A.N.); (I.V.K.); (E.A.B.); (R.I.M.); (P.V.S.); (P.A.S.); (N.A.F.); (L.O.P.); (V.S.T.); (S.A.I.); (P.V.S.); (A.D.K.)
| | - Vladimir S. Trifanov
- FSBI National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 249036 Obninsk, Russia; (L.A.N.); (I.V.K.); (E.A.B.); (R.I.M.); (P.V.S.); (P.A.S.); (N.A.F.); (L.O.P.); (V.S.T.); (S.A.I.); (P.V.S.); (A.D.K.)
| | - Sergey A. Ivanov
- FSBI National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 249036 Obninsk, Russia; (L.A.N.); (I.V.K.); (E.A.B.); (R.I.M.); (P.V.S.); (P.A.S.); (N.A.F.); (L.O.P.); (V.S.T.); (S.A.I.); (P.V.S.); (A.D.K.)
| | - Peter V. Shegai
- FSBI National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 249036 Obninsk, Russia; (L.A.N.); (I.V.K.); (E.A.B.); (R.I.M.); (P.V.S.); (P.A.S.); (N.A.F.); (L.O.P.); (V.S.T.); (S.A.I.); (P.V.S.); (A.D.K.)
| | - Andrei D. Kaprin
- FSBI National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, 249036 Obninsk, Russia; (L.A.N.); (I.V.K.); (E.A.B.); (R.I.M.); (P.V.S.); (P.A.S.); (N.A.F.); (L.O.P.); (V.S.T.); (S.A.I.); (P.V.S.); (A.D.K.)
- Department of Oncology and Radiology, Institute of Medicine, Peoples’ Friendship University of Russia—RUDN University, 6 Miklukho-Maklaya Street, 117198 Moscow, Russia
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Alférez MD, Corda A, de Blas I, Gago L, Fernandes T, Rodríguez-Piza I, Balañá B, Corda F, Gómez Ochoa P. Percutaneous Ultrasound-Guided Radiofrequency Ablation as a Therapeutic Approach for the Management of Insulinomas and Associated Metastases in Dogs. Animals (Basel) 2024; 14:3301. [PMID: 39595353 PMCID: PMC11591051 DOI: 10.3390/ani14223301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 11/11/2024] [Accepted: 11/13/2024] [Indexed: 11/28/2024] Open
Abstract
Insulinomas are the most common neoplasms of the endocrine pancreas in dogs, leading to persistent hypoglycemia due to inappropriate insulin secretion. The standard treatment is surgical resection, but it carries significant risks, including pancreatitis and diabetes mellitus. This study investigates the efficacy and safety of percutaneous ultrasound-guided radiofrequency ablation (RFA) as an alternative to surgery. A total of 29 dogs diagnosed with insulinoma were treated with RFA, targeting both primary pancreatic tumors and metastases in regional lymph nodes or the liver. Blood glucose levels and tumor size were monitored before and after the procedure. RFA led to a significant increase in blood glucose levels and a reduction in tumor size in all patients, with minimal postoperative complications. The results suggest that RFA is a feasible and effective treatment option for insulinomas in dogs.
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Affiliation(s)
| | - Andrea Corda
- Department of Veterinary Medicine, University of Sassari, 07100 Sassari, Italy;
| | - Ignacio de Blas
- Department of Animal Pathology, University of Zaragoza, 50013 Zaragoza, Spain;
| | - Lucas Gago
- Department of Mathematics and Computer Science, University of Barcelona, 08007 Barcelona, Spain;
| | - Telmo Fernandes
- Imaginologia Veterinaria do Porto, 4490-479 Porto, Portugal;
| | | | | | - Francesca Corda
- Department of Veterinary Medicine, University of Sassari, 07100 Sassari, Italy;
| | - Pablo Gómez Ochoa
- VetCorner Unavets, 50012 Zaragoza, Spain; (M.D.A.); (P.G.O.)
- Department of Animal Pathology, University of Zaragoza, 50013 Zaragoza, Spain;
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Park YM, Seo HI, Noh BG, Kim S, Hong SB, Lee NK, Kim DU, Han SY. Clinicopathological characteristics of extrahepatic biliary neuroendocrine neoplasms in the gallbladder, extrahepatic biliary tract, and ampulla of Vater: A single-center cross-sectional study. Ann Hepatobiliary Pancreat Surg 2023; 27:380-387. [PMID: 37840317 PMCID: PMC10700941 DOI: 10.14701/ahbps.23-045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/05/2023] [Accepted: 06/06/2023] [Indexed: 10/17/2023] Open
Abstract
Backgrounds/Aims In 2019, the grading and staging system for neuroendocrine neoplasms (NENs) was significantly changed. In this study, we report the clinicopathological characteristics and surgical outcomes of patients with extrahepatic biliary NENs who underwent curative resection with or without adjuvant treatment. Methods We retrospectively reviewed a database of 16 patients who developed NENs, neuroendocrine carcinoma (NEC), and mixed endocrine non-endocrine neoplasms (MiNENs) after curative resection. Among them, eight patients had ampulla of Vater (AoV) tumors, and eight patients had non-AoV tumors. Results G1 and G2 were more frequently observed in the AoV group than in the non-AoV group (12.5% and 62.5%, respectively). In contrast, NEC and MiNEN were more common in the non-AoV group (50.0%). High Ki-67 index (> 20%) and perineural invasion (PNI) were more frequently observed in the non-AoV group. Advanced age (> 65 years), mitotic count > 20 per 2 mm2, and Ki-67 index > 20% were strongly correlated with patient survival (p = 0.018, 0.009, and 0.044, respectively). Advanced age (> 65 years) and mitotic count > 20 per 2 mm2 were significantly correlated with disease recurrence (p = 0.033 and 0.010, respectively). Conclusions AoV and non-AoV tumors had significant differences in the histologic grade, Ki67, and PNI. Patients with non-AoV tumors had an increased risk for survival and recurrence than those in the AoV group. For extrahepatic biliary NENs, early detection of tumors, adequate surgery, and aggressive adjuvant treatment for high-risk patients are important to achieve long-term survival and prevent disease recurrence.
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Affiliation(s)
- Young Mok Park
- Department of Surgery, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Hyung Il Seo
- Department of Surgery, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Byeong Gwan Noh
- Department of Surgery, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Suk Kim
- Department of Radiology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Seung Baek Hong
- Department of Radiology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Nam Kyung Lee
- Department of Radiology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Dong Uk Kim
- Department of Internal Medicine, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Sung Yong Han
- Department of Internal Medicine, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
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Magi L, Marasco M, Rinzivillo M, Faggiano A, Panzuto F. Management of Functional Pancreatic Neuroendocrine Neoplasms. Curr Treat Options Oncol 2023; 24:725-741. [PMID: 37103745 PMCID: PMC10272249 DOI: 10.1007/s11864-023-01085-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/20/2023] [Indexed: 04/28/2023]
Abstract
OPINION STATEMENT Functional pancreatic neuroendocrine neoplasms (pNENs) are rare and heterogeneous diseases in terms of both clinical and pathological aspects. These tumors secrete hormones or peptides, which may cause a wide variety of symptoms related to a clinical syndrome. The management of functional pNENs is still challenging for clinicians due to the need to control both tumor growth and specific symptoms. Surgery remains the cornerstone in the management of local disease because it can definitively cure the patient. However, when the disease is not resectable, a broad spectrum of therapeutic options, including locoregional therapy, somatostatin analogs (SSAs), targeted therapies, peptide-receptor radionuclide therapy (PRRT), and chemotherapy, are available. The present review summarizes the main key issues regarding the clinical management of these tumors, providing a specific highlight on their therapeutic approach.
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Affiliation(s)
- Ludovica Magi
- Digestive Disease Unit, Sant'Andrea University Hospital, ENETS Center of Excellence, Via di Grottarossa 1035, 00189, Rome, Italy
| | - Matteo Marasco
- Digestive Disease Unit, Sant'Andrea University Hospital, ENETS Center of Excellence, Via di Grottarossa 1035, 00189, Rome, Italy
| | - Maria Rinzivillo
- Digestive Disease Unit, Sant'Andrea University Hospital, ENETS Center of Excellence, Via di Grottarossa 1035, 00189, Rome, Italy
| | - Antongiulio Faggiano
- Endocrinology Unit, Sant'Andrea University Hospital, ENETS Center of Excellence, Rome, Italy
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Via Di Grottarrossa 1035, 00189, Rome, Italy
| | - Francesco Panzuto
- Digestive Disease Unit, Sant'Andrea University Hospital, ENETS Center of Excellence, Via di Grottarossa 1035, 00189, Rome, Italy.
- Department of Medical-Surgical Sciences and Translational Medicine, Sapienza University of Rome, Via di Grottarossa 1035, 00189, Rome, Italy.
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Muttillo EM, Mazzarella G, Picardi B, Rossi S, Cinelli L, Diana M, Baiocchini A, Felli E, Pessaux P, Felli E, Muttillo IA. Treatment strategies for neuroendocrine liver metastases: a systematic review. HPB (Oxford) 2022; 24:1832-1843. [PMID: 35794053 DOI: 10.1016/j.hpb.2022.06.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 03/19/2022] [Accepted: 06/15/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Gastroenteropancreatic neuroendocrine tumors are often diagnosed when metastatic. The liver is the main site of metastases. Unfortunately, optimal management of neuroendocrine liver metastases remains a topic of debate. The aim of this study was to make a systematic review of the current literature about the results of the different treatments of neuroendocrine liver metastases. METHODS A systematic review was conducted for English language publications from 1995 to 2021. Outcomes were analyzed according to survival, disease-free survival, and in the case of systemic therapies, progression-free survival. RESULTS 5509 patients were analyzed in the review. 67% of patients underwent surgery achieving 5 years overall survival despite only 30% percent without a recurrence. 60% of patients that had received a transplant reached 5 years survival with a low disease-free survival rate (20%). Five-year survival rate was 36.2% for patients undergoing loco-regional therapies. CONCLUSION Surgical resection is the best treatment when metastases are resectable, with the highest rate of survival, although liver transplantation shows good results for patients not eligible for surgery. Loco-regional therapies may be useful when surgical resection is contraindicated, or selectively used as a bridge to surgery or transplantation. Systemic therapies are indicated in patients for whom curative treatment cannot be obtained.
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Affiliation(s)
- Edoardo M Muttillo
- Department of Surgical Sciences, Sapienza University of Rome, Rome, Italy; Research Institute Against Digestive Cancer (IRCAD), Strasbourg, France
| | - Gennaro Mazzarella
- Department of General and Emergency Surgery, Ospedale San Filippo Neri, Rome, Italy
| | - Biagio Picardi
- Department of General and Emergency Surgery, Ospedale San Filippo Neri, Rome, Italy
| | - Stefano Rossi
- Department of General and Emergency Surgery, Ospedale San Filippo Neri, Rome, Italy
| | | | - Michele Diana
- Research Institute Against Digestive Cancer (IRCAD), Strasbourg, France
| | | | - Eric Felli
- Hepatology, Department of Biomedical Research, Inselspital, University of Bern, Bern, Switzerland
| | - Patrick Pessaux
- Research Institute Against Digestive Cancer (IRCAD), Strasbourg, France; HPB Unit, Digestive Surgery Department, Nouvel Hopital Civil, University of Strasbourg, Strasbourg, France
| | - Emanuele Felli
- Research Institute Against Digestive Cancer (IRCAD), Strasbourg, France; Service Chirurgie Digestive et Transplantation Hépatique Hopital Trousseau CHU Tours, France
| | - Irnerio A Muttillo
- Department of General and Emergency Surgery, Ospedale San Filippo Neri, Rome, Italy.
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Noh BG, Seo HI, Park YM, Kim S, Hong SB, Lee SJ. Complete resection of large-cell neuroendocrine and hepatocellular carcinoma of the liver: A case report. World J Clin Cases 2022; 10:8277-8283. [PMID: 36159537 PMCID: PMC9403669 DOI: 10.12998/wjcc.v10.i23.8277] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 06/07/2022] [Accepted: 07/11/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Combined tumors comprising large-cell neuroendocrine carcinoma and hepatocellular carcinoma have been rarely reported in the literature.
CASE SUMMARY We report a case of a 73-year-old woman with chronic hepatitis B suspected to have a malignant hepatic mass (segment 3; size, 4.5 cm) and lymph node metastasis based on computed tomography and magnetic resonance imaging. Despite being Child-Pugh class A, esophageal varices were present. She underwent left lateral sectionectomy and lymph node dissection. Pathological examination revealed a collision tumor consisting of large-cell neuroendocrine (90%) and hepatocellular (10%) carcinomas. The combined carcinoma had metastasized to one of the three lymph nodes excised. The patient recovered without any postoperative complications and was discharged in good condition on postoperative day 13. Adjuvant chemotherapy was not performed. No recurrence occurred during a follow-up period of 24 mo.
CONCLUSION To improve the therapeutic management of combined tumors in the liver, it is necessary to discuss each clinical experience and consider an appropriate method for the preoperative diagnosis and treatment.
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Affiliation(s)
- Byeong Gwan Noh
- Division of HBP Surgery and Transplantation, Department of Surgery, Pusan National University School of Medicine, Biomedical Research Institute, Pusan National University Hospital, Busan 49241, South Korea
| | - Hyung-Il Seo
- Division of HBP Surgery and Transplantation, Department of Surgery, Pusan National University School of Medicine, Biomedical Research Institute, Pusan National University Hospital, Busan 49241, South Korea
| | - Young Mok Park
- Division of HBP Surgery and Transplantation, Department of Surgery, Pusan National University School of Medicine, Biomedical Research Institute, Pusan National University Hospital, Busan 49241, South Korea
| | - Suk Kim
- Department of Radiology, Pusan National University School of Medicine, Biomedical Research Institute, Pusan National University Hospital, Busan 49241, South Korea
| | - Seung Baek Hong
- Department of Radiology, Pusan National University School of Medicine, Biomedical Research Institute, Pusan National University Hospital, Busan 49241, South Korea
| | - So Jeong Lee
- Department of Pathology, Pusan National University School of Medicine, Biomedical Research Institute, Pusan National University Hospital, Busan 49241, South Korea
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Faleiro I, Roberto VP, Demirkol Canli S, Fraunhoffer NA, Iovanna J, Gure AO, Link W, Castelo-Branco P. DNA Methylation of PI3K/AKT Pathway-Related Genes Predicts Outcome in Patients with Pancreatic Cancer: A Comprehensive Bioinformatics-Based Study. Cancers (Basel) 2021; 13:cancers13246354. [PMID: 34944974 PMCID: PMC8699150 DOI: 10.3390/cancers13246354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/02/2021] [Accepted: 12/07/2021] [Indexed: 11/19/2022] Open
Abstract
Simple Summary Pancreatic cancer is a highly lethal malignancy. Dysregulation of epigenetic mechanisms leads to abnormal patterns of gene expression contributing to the development and progression of cancer. We explored the ability of DNA methylation of PI3K-related genes to differentiate between malignant and healthy pancreatic tissue using distinct pancreatic cancer cohorts, and found that the methylation levels of the ITGA4, SFN, ITGA2, and PIK3R1 genes are altered in tumour samples since the early stages of malignant transformation and could serve as new diagnostic tools. We also demonstrate that these alterations correlate with overall survival and recurrence-free survival of the patients suggesting that its assessment can serve as independent prognostic indicators of patients’ survival with higher sensitivity and specificity than the currently implemented biomarkers. Therefore, the methylation profile of genes involved in this pathway may be an alternative method for predicting cell malignancy and help doctors’ decisions on patient care. Abstract Pancreatic cancer (PCA) is one of the most lethal malignancies worldwide with a 5-year survival rate of 9%. Despite the advances in the field, the need for an earlier detection and effective therapies is paramount. PCA high heterogeneity suggests that epigenetic alterations play a key role in tumour development. However, only few epigenetic biomarkers or therapeutic targets have been identified so far. Here we explored the potential of distinct DNA methylation signatures as biomarkers for early detection and prognosis of PCA. PI3K/AKT-related genes differentially expressed in PCA were identified using the Pancreatic Expression Database (n = 153). Methylation data from PCA patients was obtained from The Cancer Genome Atlas (n = 183), crossed with clinical data to evaluate the biomarker potential of the epigenetic signatures identified and validated in independent cohorts. The majority of selected genes presented higher expression and hypomethylation in tumour tissue. The methylation signatures of specific genes in the PI3K/AKT pathway could distinguish normal from malignant tissue at initial disease stages with AUC > 0.8, revealing their potential as PCA diagnostic tools. ITGA4, SFN, ITGA2, and PIK3R1 methylation levels could be independent prognostic indicators of patients’ survival. Methylation status of SFN and PIK3R1 were also associated with disease recurrence. Our study reveals that the methylation levels of PIK3/AKT genes involved in PCA could be used to diagnose and predict patients’ clinical outcome with high sensitivity and specificity. These results provide new evidence of the potential of epigenetic alterations as biomarkers for disease screening and management and highlight possible therapeutic targets.
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Affiliation(s)
- Inês Faleiro
- Faculty of Medicine and Biomedical Sciences (FMCB), Campus de Gambelas, University of Algarve, 8005-139 Faro, Portugal;
- Algarve Biomedical Center Research Institute (ABC-RI), 8005-139 Faro, Portugal
- Instituto de Medicina Molecular João Lobo Antunes (IMM), Faculty of Medicine, University of Lisbon, 1649-028 Lisbon, Portugal
| | - Vânia Palma Roberto
- Faculty of Medicine and Biomedical Sciences (FMCB), Campus de Gambelas, University of Algarve, 8005-139 Faro, Portugal;
- Algarve Biomedical Center Research Institute (ABC-RI), 8005-139 Faro, Portugal
- Champalimaud Research Program, Champalimaud Center for the Unknown, 1400-038 Lisbon, Portugal
- Centre of Marine Sciences (CCMAR), University of Algarve, 8005-139 Faro, Portugal
- Correspondence: (V.P.R.); (P.C.-B.)
| | - Secil Demirkol Canli
- Molecular Pathology Application and Research Center, Hacettepe University, 06100 Ankara, Turkey;
| | - Nicolas A. Fraunhoffer
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix-Marseille Université, Parc Scientifique et Technologique de Luminy, 13288 Marseille, France; (N.A.F.); (J.I.)
| | - Juan Iovanna
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix-Marseille Université, Parc Scientifique et Technologique de Luminy, 13288 Marseille, France; (N.A.F.); (J.I.)
| | - Ali Osmay Gure
- Department of Medical Biology, Acibadem University, 34684 Istanbul, Turkey;
| | - Wolfgang Link
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain;
| | - Pedro Castelo-Branco
- Faculty of Medicine and Biomedical Sciences (FMCB), Campus de Gambelas, University of Algarve, 8005-139 Faro, Portugal;
- Algarve Biomedical Center Research Institute (ABC-RI), 8005-139 Faro, Portugal
- Champalimaud Research Program, Champalimaud Center for the Unknown, 1400-038 Lisbon, Portugal
- Correspondence: (V.P.R.); (P.C.-B.)
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Mollinedo F, Gajate C. Direct Endoplasmic Reticulum Targeting by the Selective Alkylphospholipid Analog and Antitumor Ether Lipid Edelfosine as a Therapeutic Approach in Pancreatic Cancer. Cancers (Basel) 2021; 13:4173. [PMID: 34439330 PMCID: PMC8394177 DOI: 10.3390/cancers13164173] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/11/2021] [Accepted: 08/15/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, shows a dismal and grim overall prognosis and survival rate, which have remained virtually unchanged for over half a century. PDAC is the most lethal of all cancers, with the highest mortality-to-incidence ratio. PDAC responds poorly to current therapies and remains an incurable malignancy. Therefore, novel therapeutic targets and drugs are urgently needed for pancreatic cancer treatment. Selective induction of apoptosis in cancer cells is an appealing approach in cancer therapy. Apoptotic cell death is highly regulated by different signaling routes that involve a variety of subcellular organelles. Endoplasmic reticulum (ER) stress acts as a double-edged sword at the interface of cell survival and death. Pancreatic cells exhibit high hormone and enzyme secretory functions, and thereby show a highly developed ER. Thus, pancreatic cancer cells display a prominent ER. Solid tumors have to cope with adverse situations in which hypoxia, lack of certain nutrients, and the action of certain antitumor agents lead to a complex interplay and crosstalk between ER stress and autophagy-the latter acting as an adaptive survival response. ER stress also mediates cell death induced by a number of anticancer drugs and experimental conditions, highlighting the pivotal role of ER stress in modulating cell fate. The alkylphospholipid analog prototype edelfosine is selectively taken up by tumor cells, accumulates in the ER of a number of human solid tumor cells-including pancreatic cancer cells-and promotes apoptosis through a persistent ER-stress-mediated mechanism both in vitro and in vivo. Here, we discuss and propose that direct ER targeting may be a promising approach in the therapy of pancreatic cancer, opening up a new avenue for the treatment of this currently incurable and deadly cancer. Furthermore, because autophagy acts as a cytoprotective response to ER stress, potentiation of the triggering of a persistent ER response by combination therapy, together with the use of autophagy blockers, could improve the current gloomy expectations for finding a cure for this type of cancer.
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Affiliation(s)
- Faustino Mollinedo
- Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, C/Ramiro de Maeztu 9, E-28040 Madrid, Spain;
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Pancreatic Neuroendocrine Tumor with Benign Serous Cystadenoma: A Rare Entity. Case Rep Oncol Med 2021; 2021:9979998. [PMID: 34395004 PMCID: PMC8360748 DOI: 10.1155/2021/9979998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 07/19/2021] [Indexed: 11/18/2022] Open
Abstract
Mixed serous-neuroendocrine neoplasm constitutes pancreatic serous cystic neoplasms and pancreatic neuroendocrine tumor, two tumor components with different underlying pathologies. The differentiation of these tumors is important as the management and prognosis depend on the pancreatic neuroendocrine tumor component. We report a case of mixed serous-neuroendocrine neoplasm in a 47-year-old female who presented with epigastric pain abdomen for two years. Imaging studies, tumor markers, thorough systemic evaluation, surgical resection, histopathological examination, and timely follow-up constituted our management approach. A 4 cm × 4 cm mass in the distal pancreas with multiple cysts in the pancreatic parenchyma containing serous fluid on distal pancreatectomy and splenectomy was found. The histopathological examination revealed combined benign serous cystadenoma and neuroendocrine tumor. She did not have any recurrence or metastasis by four years of follow-up.
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10
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Abstract
AbstractPituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with widespread occurrence and diverse functions. PACAP binds to specific PAC1 and non-specific VPAC1/2 receptors. PACAP is considered as a growth factor, as it plays important roles during development and participates in reparative processes. Highest concentrations are found in the nervous system and endocrine glands, where several functions are known, including actions in tissue growth, differentiation and tumour development. Therefore, we have investigated expression of PACAP and its receptors in different tumours, including those of endocrine glands. We showed earlier that PACAP and PAC1 receptor staining intensity decreased in pancreatic ductal adenocarcinoma. In the present study we aimed to investigate alterations of PACAP and PAC1 receptor in human insulinoma and compared the immunostaining pattern with samples from chronic pancreatitis patients. We collected perioperative and histological data of patients who underwent operation because of insulinoma or chronic pancreatitis over a five-year-long period. Histology showed chronic pancreatitis with severe scar formation in pancreatitis patients, while tumour samples evidenced Grade 1 or 2 insulinoma. PACAP and PAC1 receptor expression was studied using immunohistochemistry. Staining intensity was very strong in the Langerhans islets of normal tissue and discernible staining was also observed in the exocrine pancreas. Immunostaining intensity for both PACAP and PAC1 receptor was markedly weaker in insulinoma samples, and disappeared from chronic pancreatitis samples except for intact islets. These findings show that PAC1 receptor/PACAP signalling is altered in insulinoma and this suggests a possible involvement of this system in tumour growth or differentiation.
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11
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Tudela-Lerma M, Orcajo-Rincón J, Ramón-Botella E, Álvarez-Luque A, Gonzalez-Leyte M, Rotger-Regi A, Velasco-Sánchez E, Colón-Rodriguez A. Efficacy and safety of Yttrium-90 radioembolization in the treatment of neuroendocrine liver metastases. Long-term monitoring and impact on survival. Rev Esp Med Nucl Imagen Mol 2021. [DOI: 10.1016/j.remnie.2021.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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12
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Tudela-Lerma M, Orcajo-Rincón J, Ramón-Botella E, Álvarez-Luque A, González-Leyte M, Rotger-Regi A, Velasco-Sánchez E, Colón-Rodríguez A. Efficacy and safety of Yttrium-90 radioembolization in the treatment of neuroendocrine liver metastases. Long-term monitoring and impact on survival. Rev Esp Med Nucl Imagen Mol 2020; 40:82-90. [PMID: 33239249 DOI: 10.1016/j.remn.2020.09.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 09/27/2020] [Accepted: 09/28/2020] [Indexed: 10/22/2022]
Abstract
INTRODUCTION AND OBJECTIVE Neuroendocrine tumors (NETs) debut in 75% of cases with liver metastases (LMNETs), whose therapeutic approach includes surgical resection and liver transplantation, while liver radioembolization with 90 Y-microspheres (TARE) is reserved for non-operable patients usually due to high tumor burden. We present the accumulated experience of 10 years in TARE treatment of LMNETs in order to describe the safety and the effectiveness of the oncological response in terms of survival, as well as to detect the prognostic factors involved. MATERIAL AND METHODS Of 136 TARE procedures, performed between January 2006 and December 2016, 30 LMNETs (11.1%) were retrospectively analyzed. The study variables were: Tumor response, time to liver progression, survival at 3 and 5 years, overall mortality and mortality associated with TARE. The radiological response assessment was assessed using RECIST 1.1 and mRECIST criteria. RESULTS An average activity of 2.4 ± 1.3 GBq of 90 Y was administered. No patient presented postembolization syndrome or carcinoid syndrome. There were also no vascular complications associated with the procedure. According to RECIST 1.1 criteria at 6 months, 78.6% presented partial response and 21.4% stable disease, there was no progression or complete response (1 by mRECIST). Survival at 3 and 5 years was 73% in both cases. CONCLUSION TARE treatment with 90 Y-microspheres in LMNETs, applied within a multidisciplinary approach, is a safe procedure, with low morbidity, capable of achieving a high rate of radiological response and achieving lasting tumor responses.
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Affiliation(s)
- M Tudela-Lerma
- Servicio de Cirugía, Hospital General Universitario Gregorio Marañón, Madrid, España
| | - J Orcajo-Rincón
- Servicio de Medicina Nuclear, Hospital General Universitario Gregorio Marañón, Madrid, España.
| | - E Ramón-Botella
- Servicio de Radiología, Hospital General Universitario Gregorio Marañón, Madrid, España
| | - A Álvarez-Luque
- Servicio de Radiología Vascular e Intervencionista, Hospital General Universitario Gregorio Marañón, Madrid, España
| | - M González-Leyte
- Servicio de Radiología Vascular e Intervencionista, Hospital General Universitario Gregorio Marañón, Madrid, España
| | - A Rotger-Regi
- Servicio de Medicina Nuclear, Hospital General Universitario Gregorio Marañón, Madrid, España
| | - E Velasco-Sánchez
- Servicio de Cirugía, Hospital General Universitario Gregorio Marañón, Madrid, España
| | - A Colón-Rodríguez
- Servicio de Cirugía, Hospital General Universitario Gregorio Marañón, Madrid, España
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Mpilla GB, Philip PA, El-Rayes B, Azmi AS. Pancreatic neuroendocrine tumors: Therapeutic challenges and research limitations. World J Gastroenterol 2020; 26:4036-4054. [PMID: 32821069 PMCID: PMC7403797 DOI: 10.3748/wjg.v26.i28.4036] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/10/2020] [Accepted: 07/16/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic neuroendocrine tumors (PNETs) are known to be the second most common epithelial malignancy of the pancreas. PNETs can be listed among the slowest growing as well as the fastest growing human cancers. The prevalence of PNETs is deceptively low; however, its incidence has significantly increased over the past decades. According to the American Cancer Society's estimate, about 4032 (> 7% of all pancreatic malignancies) individuals will be diagnosed with PNETs in 2020. PNETs often cause severe morbidity due to excessive secretion of hormones (such as serotonin) and/or overall tumor mass. Patients can live for many years (except for those patients with poorly differentiated G3 neuroendocrine tumors); thus, the prevalence of the tumors that is the number of patients actually dealing with the disease at any given time is fairly high because the survival is much longer than pancreatic ductal adenocarcinoma. Due to significant heterogeneity, the management of PNETs is very complex and remains an unmet clinical challenge. In terms of research studies, modest improvements have been made over the past decades in the identification of potential oncogenic drivers in order to enhance the quality of life and increase survival for this growing population of patients. Unfortunately, the majority of systematic therapies approved for the management of advanced stage PNETs lack objective response or at most result in modest benefits in survival. In this review, we aim to discuss the broad challenges associated with the management and the study of PNETs.
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Affiliation(s)
- Gabriel Benyomo Mpilla
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States
| | - Philip Agop Philip
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States
| | - Bassel El-Rayes
- Department of Hematology Oncology, Emory Winship Institute, Atlanta, GA 30322, United States
| | - Asfar Sohail Azmi
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, United States
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Takahashi D, Kojima M, Morisue R, Sugimoto M, Kobayashi S, Takahashi S, Konishi M, Gotohda N, Ikeda M, Ochiai A. Comparison of morphological features in lymph node metastasis between pancreatic neuroendocrine neoplasms and pancreatic ductal adenocarcinomas. Pancreatology 2020; 20:936-943. [PMID: 32553561 DOI: 10.1016/j.pan.2020.05.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 05/04/2020] [Accepted: 05/19/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Various studies have reported inconsistent results regarding the use of lymph node size for the prediction of metastasis in pancreatic cancer. Further, there is even less information in pNENs. Thus, the clinical accuracy and utility of using lymph node size to predict lymph node metastasis in pNENs has not been fully elucidated OBJECTIVES: This study aimed to examine differences in lymph node morphology between pancreatic neuroendocrine neoplasms (pNENs) and pancreatic ductal adenocarcinomas (PDACs) to create more accurate diagnostic criteria for lymph node metastasis. METHODS We assessed 2139 lymph nodes, 773 from pNEN specimens and 1366 from PDAC specimens, surgically resected at our institute between 1994 and 2016. We evaluated the number, shape, size, and presence of metastasis. RESULTS Sixty-eight lymph nodes from 16 pNEN patients and 109 lymph nodes from 33 PDAC patients were metastatic. There were more lymph nodes sampled per case in the PDAC group than in the pNEN group (31.8 vs. 18.0). Metastatic lymph nodes in pNEN patients were larger and rounder than those in PDAC patients (minor axis: 5.15 mm vs. 3.11 mm; minor axis/major axis ratio: 0.701 vs. 0.626). The correlation between lymph node size and metastasis was stronger in pNENs (r = 0.974) than in PDACs (r = 0.439). CONCLUSIONS Lymph node status and morphology are affected by differences in tumor histology. The lymph node minor axis is a reliable parameter for the prediction of lymph node metastasis and has more utility as a predictive marker in pNENs than in PDACs.
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Affiliation(s)
- Daigoro Takahashi
- Division of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Motohiro Kojima
- Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
| | - Ryo Morisue
- Division of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Motokazu Sugimoto
- Division of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shin Kobayashi
- Division of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shinichiro Takahashi
- Division of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Masaru Konishi
- Division of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Naoto Gotohda
- Division of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Atsushi Ochiai
- Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Japan
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15
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Zhang Z, Liu M, Ji S, Luo G, Xu W, Liu W, Hu Q, Sun Q, Ye Z, Qin Y, Fan G, Yu X, Xu X. Prognostic Value and Clinical Predictors of Lymph Node Metastases in Pancreatic Neuroendocrine Tumors. Pancreas 2020; 49:381-386. [PMID: 32132507 DOI: 10.1097/mpa.0000000000001493] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES To investigate the correlation between lymph node metastasis (LNM) and various clinicopathological features of pancreatic neuroendocrine tumors (pNETs) and its impact on prognosis. METHODS We searched the Surveillance Epidemiology and End Results database (2004-2015) for patients with surgically treated pNETs. Factors correlated with LNMs were analyzed by logistic regression and by Cox analysis. RESULTS For tumors of 1 to 4 cm, age (P < 0.001, P = 0.014), grade (P < 0.001, P < 0.001), LNMs (P = 0.008, P < 0.001), and size (P = 0.038, P = 0.002) predicted overall survival (OS) and disease-specific survival (DSS). For tumor greater than 4 cm, age (P < 0.001, P = 0.001) and grade (P = 0.011, P = 0.048) were independent prognostic factors of OS and DSS. Lymph node metastasis modestly predicted DSS (P = 0.028) but not OS (P = 0.218). CONCLUSIONS In pNETs greater than 4 cm, LNM is not a predictor of OS and modestly predicts DSS, and lymphadenectomy may be unhelpful in these patients. For pNETs 1 to 4 cm, LNM predicts poor OS and DSS, which supports lymphadenectomy in these patients. Pancreas-sparing resection with only limited peripancreatic node sampling needs to be questioned.
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Affiliation(s)
- Zheng Zhang
- From the Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University; Shanghai Pancreatic Cancer Institute; and Pancreatic Cancer Institute, Fudan University, Shanghai, China
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Xiao Y, Yang Y, Wang Y, Li X, Wang W. Five Novel Genes Related to the Pathogenesis and Progression of Pancreatic Neuroendocrine Tumors by Bioinformatics Analysis With RT-qPCR Verification. Front Neurosci 2019; 13:937. [PMID: 31607839 PMCID: PMC6771308 DOI: 10.3389/fnins.2019.00937] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 08/21/2019] [Indexed: 12/17/2022] Open
Abstract
Objective To explore novel related genes and potential biomarkers of pancreatic neuroendocrine tumors (PanNETs). Materials and Methods Two data sets from ICGC and two from the NCBI GEO database were used to identify the differentially expressed genes (DEGs) in PanNETs. The common DEGs among the four sources were analyzed; furthermore, the relationship of these gene expression patterns with different PanNET grades, their mutation status and corresponding impact on prognosis, the interaction network, and the relationship with three known PanNET genes (ATRX, DAXX, and MEN1) were analyzed by two other GEO data and cBioPortal database. Finally, the expressions of novel DEGs were validated in Chinese PanNET tissues by RT-qPCR. Results Five new DEGs (ABCC8, PCSK2, IL13RA2, KLKB1, and PART1) and one confirmed DEG-ISL1 were identified. The mutation counts of DEGs increased with the tumor grade increasing from G1 to G3, and PanNET patients present vascular invasion or are deceased. These DEG expression patterns in PanNETs are quite different from that of pancreatic ductal adenocarcinoma and are related to A–D–M (ATRX–DAXX–MEN1) mutation. ABCC8 and KLKB1 are co-occurrence with the A–D–M axis in PanNETs. Importantly, patients with DEG mutations have a lower survival rate. RT-qPCR verification results of KLKB1 (P < 0.01), IL13RA2 (P < 0.01), ABCC8 (P < 0.01), and PART1 (P < 0.0001) expressions in Chinese PanNET tissues are consistent with our database analysis, which were significantly up-regulated. However, the expression of PCSK2 (P < 0.01) was contrary to our bioinformatics analysis, which was significantly down-regulated, suggesting that the expression trend of PCSK2 may be different among different races. These results indicated that these five genes may play an important role in the occurrence and progression of PanNETs. Conclusion Five novel common DEGs identified are related to the development and prognosis of PanNETs and may serve as specific biomarkers and therapeutic targets.
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Affiliation(s)
- Yu Xiao
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuemei Yang
- Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yanfeng Wang
- Department of Pathology, Heilongjiang Province Land Reclamation Headquarters General Hospital, Harbin, China
| | - Xiaoou Li
- Department of Pathology, DaXing Hospital Affiliated to Capital Medical University, Beijing, China
| | - Wenze Wang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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17
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Natale F, Vivo M, Falco G, Angrisano T. Deciphering DNA methylation signatures of pancreatic cancer and pancreatitis. Clin Epigenetics 2019; 11:132. [PMID: 31492175 PMCID: PMC6729090 DOI: 10.1186/s13148-019-0728-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 08/16/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Chronic pancreatitis presents a high risk of inflammation-related progression to pancreatic cancer. Pancreatic cancer is the fourth leading cause of cancer-related death worldwide. The high mortality rate is directly related to the difficulty in promptly diagnosing the disease, which often presents as overt and advanced. Hence, early diagnosis for pancreatic cancer becomes crucial, propelling research into the molecular and epigenetic landscape of the disease. MAIN BODY Recent studies have shown that cell-free DNA methylation profiles from inflammatory diseases or cancer can vary, thus opening a new venue for the development of biomarkers for early diagnosis. In particular, cell-free DNA methylation could be employed in the identification of pre-neoplastic signatures in individuals with suspected pancreatic conditions, representing a specific and non-invasive method of early diagnosis of pancreatic cancer. In this review, we describe the molecular determinants of pancreatic cancer and how these are related to chronic pancreatitis. We will then present an overview of differential methylated genes in the two conditions, highlighting their diagnostic or prognostic potential. CONCLUSION Exploiting the relation between abnormally methylated cell-free DNA and pre-neoplastic lesions or chronic pancreatitis may become a game-changing approach for the development of tools for the early diagnosis of pancreatic cancer.
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Affiliation(s)
- Francesco Natale
- Department of Biology, University of Naples Federico II, 80126, Naples, Italy.
| | - Maria Vivo
- Department of Biology, University of Naples Federico II, 80126, Naples, Italy
| | - Geppino Falco
- Department of Biology, University of Naples Federico II, 80126, Naples, Italy.,Biogem Scarl, Istituto di Ricerche Genetiche "Gaetano Salvatore", 83031, Ariano Irpino, Italy
| | - Tiziana Angrisano
- Department of Biology, University of Naples Federico II, 80126, Naples, Italy.
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Diagnostic and Management Challenges in Vasoactive Intestinal Peptide Secreting Tumors: A Series of 15 Patients. Pancreas 2019; 48:934-942. [PMID: 31268974 DOI: 10.1097/mpa.0000000000001347] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVES Vasoactive intestinal peptide-secreting tumors (VIPomas) are rare functioning neuroendocrine tumors often characterized by a difficult-to-control secretory syndrome and high potential to develop metastases. We hereby present the characteristics of 15 cases of VIPomas and provide a recent literature review. METHODS This was a retrospective data analysis of 15 patients with VIPoma from 3 different centers and literature research through PubMed database during the last 10 years. RESULTS Fifteen patients with VIPomas (9 with hepatic metastases at diagnosis) with watery diarrhea and raised VIP levels were studied. Ten patients (67%) had grade 2 tumors, 6 of 15 had localized disease and underwent potentially curative surgery, whereas the remaining 9 received multiple systemic therapies; 3 patients died during follow-up. The median overall survival was 71 months (range, 41-154 months). Patients who were treated with curative surgery (n = 7) had longer median overall survival compared with patients who were treated with other therapeutic modalities (44 vs 33 months). CONCLUSIONS The management of VIPomas is challenging requiring the application of multiple treatment modalities. Patients who underwent surgical treatment with curative intent appear to have higher survival rate. Central registration and larger prospective studies are required to evaluate the effect of currently employed therapies in these patients.
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Chen X, Wang Z. The Differences Between Pancreatic Neuroendocrine Tumors Grade 2 and Grade 3-Letter. Clin Cancer Res 2019; 25:4580. [PMID: 31308051 DOI: 10.1158/1078-0432.ccr-19-0518] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 05/17/2019] [Accepted: 05/17/2019] [Indexed: 11/16/2022]
Affiliation(s)
- Xiao Chen
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
| | - Zhongqiu Wang
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
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Kaeppeli SAM, Schibli R, Mindt TL, Behe M. Comparison of desferrioxamine and NODAGA for the gallium-68 labeling of exendin-4. EJNMMI Radiopharm Chem 2019; 4:9. [PMID: 31659487 PMCID: PMC6522624 DOI: 10.1186/s41181-019-0060-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 05/02/2019] [Indexed: 12/25/2022] Open
Abstract
INTRODUCTION Radiolabeled exendin-4 (Ex4) derivatives are used to target the glucagon-like peptide-1 receptor (GLP-1R) for the clinical diagnosis of insulinomas, a rare type of neuroendocrine tumor. Gallium-68 is an ideal diagnostic nuclide for this application and a study evaluating an exendin-4-NODAGA conjugate is currently underway. However, in complexion with the chelator DFO, its in vivo stability has been a matter of dispute. The aim of this work was to directly compare [68Ga]Ga-Ex4NOD with [68Ga]Ga-Ex4DFO in vitro and in vivo. METHODS In our approach, we directly compared N'-[5-(acetyl-hydroxy-amino)pentyl]-N-[5-[3-(5-aminopentyl-hydroxy-carbamoyl)propanoylamino]pentyl]-N-hydroxy-butane diamide (desferriox-amine B, DFO) and 2-(4,7-bis (carboxymethyl)-1,4,7-triazonan-1-yl) pentanedioic acid (NODAGA) conjugated to exendin-4 in vitro and in vivo. We radiolabeled the peptides with gallium-68, followed by HPLC quality control. In vitro characterization was performed in CHL cells overexpressing the GLP-1R and in vivo studies were conducted with CD1 nu/nu mice carrying tumors derived from these cells. RESULTS We found that both peptides could be radiolabeled with a molar activity of about 9.33 MBq/nmol without further purification. They internalized equally well into GLP-1R-expressing cells and their IC50 was similar with 15.6 ± 7.8 nM and 18.4 ± 3.0 nM for [natGa]Ga-Ex4NOD and [natGa]Ga-Ex4DFO, respectively. In vivo, [68Ga]Ga-Ex4NOD accumulated more in all tissue, while [68Ga]Ga-Ex4DFO exhibited a more favorable target-to-kidney ratio. CONCLUSION AND RELEVANCE DFO is a suitable chelator for the radiolabeling of exendin-4 derivatives with gallium-68 for in vitro and preclinical in vivo studies. DFO performed better in vivo due to its significantly lower kidney accumulation (p < 0.0001). It was also found to be stable in vivo in mice, contrary to earlier reports. Based on our results, the DFO chelating system in combination with exendin-4 would be an interesting option for clinical imaging of insulinomas.
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Affiliation(s)
- Simon A M Kaeppeli
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, OIPA/102, Forschungsstrasse 111, 5232, Villigen-PSI, Switzerland
| | - Roger Schibli
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, OIPA/102, Forschungsstrasse 111, 5232, Villigen-PSI, Switzerland.,Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093, Zurich, Switzerland
| | - Thomas L Mindt
- Ludwig Boltzmann Institute Applied Diagnostics, General Hospital Vienna (AKH), c/o Sekretariat Nuklearmedizin Währinger Gürtel 18-20, Vienna, Austria.,Department of Biomedical Imaging and Image Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
| | - Martin Behe
- Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, OIPA/102, Forschungsstrasse 111, 5232, Villigen-PSI, Switzerland.
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Wu J, Sun C, Li E, Wang J, He X, Yuan R, Yi C, Liao W, Wu L. Non-functional pancreatic neuroendocrine tumours: emerging trends in incidence and mortality. BMC Cancer 2019; 19:334. [PMID: 30961556 PMCID: PMC6454719 DOI: 10.1186/s12885-019-5543-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 03/28/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Our aim was to determine the epidemiology and recent changes in the trends of non-functional pancreatic neuroendocrine tumours (NF-pNETs) at the population level. In addition, we explored the risk factors that are associated with survival duration. METHODS Cases were identified form the Surveillance, Epidemiology, and End Results (SEER) Programme database from 2000 to 2014. Data on incidence and incidence-based (IB) mortality for NF-pNET were obtained from this database. Secular trends in age-adjusted incidence and IB mortality were determined by using the Joinpoint Regression program. Data analyses were performed using chi-square tests, Kaplan-Meier curves and Cox proportional hazards regression. RESULTS Overall, 4766 patients diagnosed with NF-pNET with a median age of 59 years were identified through our descriptive criteria. Caucasian patients accounted for the majority of the study population, and the proportion of patients with distant disease significantly decreased during our study period. Overall, there was an increase in incidence and IB mortality for NF-pNET; however, the rate of increase decreased during the recent years. In addition, the incidence trends of NF-pNET located in the pancreatic head significantly increased, and rates fo increase in IB mortality for NF-pNET in the pancreatic tail decreased in recent years. Additionally, the 1-, 5-, and 10-year survival rates were 79.0, 51.8, 38.1%, respectively. Furthermore, patient age, tumour grade, stage at diagnosis, tumour size, tumour site and resection were associated with mortality. CONCLUSION Despite increases in incidence and IB mortality, the rate of change in IB mortality for NF-pNET has decreased in recent years. Survival duration displayed a secular increase during the overall period, and the prognosis and survival duration of patients were closely related to the time of diagnosis, age of the patients and size and location of the tumour. Appropriate treatment adjustments based on tumour stage may thus facilitate improvements in patient outcomes.
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Affiliation(s)
- Junjun Wu
- Department of General Surgery, Second Affiliated Hospital of Nanchang University, No.1 Minde Load, Nanchang, 330006, China
| | - Chi Sun
- Department of Nursing, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Enliang Li
- Department of General Surgery, Jiangxi Province Pediatric Hospital, Nanchang, China
| | - Jiakun Wang
- Department of General Surgery, Second Affiliated Hospital of Nanchang University, No.1 Minde Load, Nanchang, 330006, China
| | - Xianping He
- Department of General Surgery, Second Affiliated Hospital of Nanchang University, No.1 Minde Load, Nanchang, 330006, China
| | - Rongfa Yuan
- Department of General Surgery, Second Affiliated Hospital of Nanchang University, No.1 Minde Load, Nanchang, 330006, China
| | - Chenghao Yi
- Department of Breast Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Wenjun Liao
- Department of General Surgery, Second Affiliated Hospital of Nanchang University, No.1 Minde Load, Nanchang, 330006, China.
| | - Linquan Wu
- Department of General Surgery, Second Affiliated Hospital of Nanchang University, No.1 Minde Load, Nanchang, 330006, China.
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Textural analysis on contrast-enhanced CT in pancreatic neuroendocrine neoplasms: association with WHO grade. Abdom Radiol (NY) 2019; 44:576-585. [PMID: 30182253 DOI: 10.1007/s00261-018-1763-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE Grades of pancreatic neuroendocrine neoplasms (PNENs) are associated with the choice of treatment strategies. Texture analysis has been used in tumor diagnosis and staging evaluation. In this study, we aim to evaluate the potential ability of texture parameters in differentiation of PNENs grades. MATERIALS AND METHODS 37 patients with histologically proven PNENs and underwent pretreatment dynamic contrast-enhanced computed tomography examinations were retrospectively analyzed. Imaging features and texture features at contrast-enhanced images were evaluated. Receiver operating characteristic curves were used to determine the cut-off values and the sensitivity and specificity of prediction. RESULTS There were significant differences in tumor margin, pancreatic duct dilatation, lymph nodes invasion, size, portal enhancement ratio (PER), arterial enhancement ratio (AER), mean grey-level intensity, kurtosis, entropy, and uniformity among G1, G2, and pancreatic neuroendocrine carcinoma (PNEC) G3 (p < 0.01). Similar results were found between pancreatic neuroendocrine tumors (PNETs) G1/G2 and PNEC G3. AER and PER showed the best sensitivity (0.86-0.94) and specificity (0.92-1.0) for differentiating PNEC G3 from PNETs G1/G2. Mean grey-level intensity, entropy, and uniformity also showed acceptable sensitivity (0.73-0.91) and specificity (0.85-1.0). Mean grey-level intensity was also showed acceptable sensitivity (91% to 100%) and specificity (82% to 91%) in differentiating PNET G1 from PNET G2. CONCLUSIONS Our data indicated that texture parameters have potential in grading PNENs, in particular in differentiating PNEC G3 from PNETs G1/G2.
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Pradhan R, George N, Mandal K, Agarwal A, Gupta SK. Endocrine Manifestations of Von Hippel-Landau Disease. Indian J Endocrinol Metab 2019; 23:159-164. [PMID: 31016171 PMCID: PMC6446673 DOI: 10.4103/ijem.ijem_252_18] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder characterized by various endocrine, nonendocrine, benign, and malignant tumors in various organs. VHL tumor suppressor gene, located on short arm of chromosome 3 is responsible for this. Pheochromocytoma (PCC) is one of the important endocrine manifestations that needs to be ruled out in case of VHL suspicion. In this review, we summarize the endocrine manifestations of VHL disease and their management while giving case history of five such cases.
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Affiliation(s)
- Roma Pradhan
- Department of Endocrine Surgery, Dr. RMLIMS, Lucknow, Uttar Pradesh, India
| | - Nelson George
- Department of Endocrine Surgery, SGPGIMS, Lucknow, Uttar Pradesh, India
| | - Kaushik Mandal
- Department of Genetics, SGPGIMS, Lucknow, Uttar Pradesh, India
| | - Amit Agarwal
- Department of Endocrine Surgery, SGPGIMS, Lucknow, Uttar Pradesh, India
| | - Sushil K. Gupta
- Department of Endocrinology, SGPGIMS, Lucknow, Uttar Pradesh, India
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24
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Neoplasms of the Neuroendocrine Pancreas: An Update in the Classification, Definition, and Molecular Genetic Advances. Adv Anat Pathol 2019; 26:13-30. [PMID: 29912000 DOI: 10.1097/pap.0000000000000201] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
This review focuses on discussing the main modifications of the recently published 2017 WHO Classification of Neoplasms of the Neuroendocrine Pancreas (panNEN). Recent updates separate pancreatic neuroendocrine tumors into 2 broad categories: well-differentiated pancreatic neuroendocrine tumors (panNET) and poorly differentiated pancreatic neuroendocrine carcinoma (panNEC), and incorporates a new subcategory of "well-differentiated high-grade NET (G3)" to the well-differentiated NET category. This new classification algorithm aims to improve the prediction of clinical outcomes and survival and help clinicians select better therapeutic strategies for patient care and management. In addition, these neuroendocrine neoplasms are capable of producing large quantity of hormones leading to clinical hormone hypersecretion syndromes. These functioning tumors include, insulinomas, glucagonomas, somatostatinomas, gastrinomas, VIPomas, serotonin-producing tumors, and ACTH-producing tumors. Although most panNENs arise as sporadic diseases, a subset of these heterogeneous tumors present as parts on inherited genetic syndromes, such as multiple endocrine neoplasia type 1, von Hippel-Lindau, neurofibromatosis type 1, tuberous sclerosis, and glucagon cell hyperplasia and neoplasia syndromes. Characteristic clinical and morphologic findings for certain functioning and syndromic panNENs should alert both pathologists and clinicians as appropriate patient management and possible genetic counseling may be necessary.
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25
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Choe J, Kim KW, Kim HJ, Kim DW, Kim KP, Hong SM, Ryu JS, Tirumani SH, Krajewski K, Ramaiya N. What Is New in the 2017 World Health Organization Classification and 8th American Joint Committee on Cancer Staging System for Pancreatic Neuroendocrine Neoplasms? Korean J Radiol 2018; 20:5-17. [PMID: 30627018 PMCID: PMC6315069 DOI: 10.3348/kjr.2018.0040] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Accepted: 07/09/2018] [Indexed: 12/12/2022] Open
Abstract
The diagnosis and management of pancreatic neuroendocrine neoplasms (NENs) have evolved significantly in recent years. There are several diagnostic and therapeutic challenges and controversies regarding the management of these lesions. In this review, we focus on the recent significant changes and controversial issues regarding the diagnosis and management of NENs and discuss the role of imaging in the multidisciplinary team approach.
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Affiliation(s)
- Jooae Choe
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Kyung Won Kim
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Hyoung Jung Kim
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Dong Wook Kim
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Kyu Pyo Kim
- Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Seung-Mo Hong
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Jin-Sook Ryu
- Department of Nuclear Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Sree Harsha Tirumani
- Department of Imaging, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Katherine Krajewski
- Department of Imaging, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Nikhil Ramaiya
- Department of Imaging, UH Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA
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26
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Grosse C, Noack P, Silye R. Accuracy of grading pancreatic neuroendocrine neoplasms with Ki-67 index in fine-needle aspiration cellblock material. Cytopathology 2018; 30:187-193. [PMID: 30303569 DOI: 10.1111/cyt.12643] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Revised: 09/10/2018] [Accepted: 09/17/2018] [Indexed: 12/16/2022]
Abstract
OBJECTIVE The aim of this study was to assess the preoperative tumour grade of pancreatic neuroendocrine neoplasms (panNENs) by determining the Ki-67 index in endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) material and to correlate the preoperative tumour grade with the postoperative tumour grade in surgical specimens. METHODS We performed a retrospective review of the institutional pathology database over a 10-year period (2007-2017) to identify all cases of panNENs with corresponding preoperative EUS-FNA cytological material and surgical specimens. Fifteen cases with adequate EUS-FNA material (more than 400 tumour cells on cellblock) were identified. The cytological and histological samples were graded based on the mitotic rate and the Ki-67 index in accordance with the 2017 World Health Organisation grading system for panNENs. The tumour grades determined on EUS-FNA cellblock material were compared with the histological tumour grades. RESULTS Mean age at diagnosis was 64.8 ± 12.7 years (range, 38-85 years). The grading scores assigned to the cytological and histological samples were concordant in all 15 (100%) cases. Of those, two (13%) cases were scored as grade 1, nine (60%) cases as grade 2 and four (27%) cases as grade 3 tumours. CONCLUSION Our study shows that tumour grade in patients with PanNENs can be reliably determined by assessing the Ki-67 index in EUS-FNA specimens based on the 2017 World Health Organisation classification and grading system.
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Affiliation(s)
- Claudia Grosse
- Department of Pathology, Kepler University Hospital, Linz, Austria
| | - Petar Noack
- Department of Pathology, Kepler University Hospital, Linz, Austria
| | - Rene Silye
- Department of Pathology, Kepler University Hospital, Linz, Austria
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27
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Multiple Endocrine Neoplasia Type 1: A Case Report With Review of Imaging Findings. Ochsner J 2018; 18:170-175. [PMID: 30258300 DOI: 10.31486/toj.17.0019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Background Multiple endocrine neoplasia type 1 (MEN1) is a rare, autosomal dominant inherited syndrome caused by mutations in the MEN1 tumor suppressor gene. The diagnosis is defined clinically by the presence of 2 or more primary MEN1 tumors (parathyroid, anterior pituitary, and pancreatic islet). We describe the case of a patient who presented with classic history and imaging findings for MEN1. Case Report A male in his early thirties with a history of hyperparathyroidism and a transsphenoidal prolactinoma resection presented years later with abdominal symptoms concerning for Zollinger-Ellison syndrome: worsening epigastric abdominal pain, nausea, vomiting, and diarrhea. Contrast-enhanced computed tomography (CT) of the abdomen revealed hyperenhancing pancreatic lesions and duodenal inflammation, suggesting pancreatic neuroendocrine tumor (gastrinoma) with secondary duodenitis. Bilateral indeterminate hypoattenuating adrenal nodules were also seen on contrast-enhanced CT, and follow-up magnetic resonance imaging confirmed benign adrenal adenomas. Furthermore, thyroid ultrasound and sestamibi scintigraphy revealed a parathyroid adenoma. With confirmatory imaging findings, history, and presenting symptoms, the patient was clinically diagnosed with MEN1 syndrome and underwent surgical and medical management. Conclusion This case exhibits the classic history with corresponding imaging findings of MEN1 syndrome, including pancreatic neuroendocrine tumors, parathyroid adenoma, and adrenal adenomas. High clinical suspicion for MEN1 should lead to endocrinology evaluation with appropriate laboratory workup and targeted imaging evaluation of the typical endocrine organs as described for this patient.
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28
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Lo GC, Kambadakone A. MR Imaging of Pancreatic Neuroendocrine Tumors. Magn Reson Imaging Clin N Am 2018; 26:391-403. [DOI: 10.1016/j.mric.2018.03.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Ierardi AM, Biondetti P, Padovano B, Magenta Biasina A, Bongini M, Carrafiello G. Intra-caval Percutaneous Radiofrequency Ablation for a Neuroendocrine Tumor (NET) Metastasis in Transplanted Liver. Cardiovasc Intervent Radiol 2018; 41:1962-1967. [PMID: 30014252 DOI: 10.1007/s00270-018-2032-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Accepted: 07/09/2018] [Indexed: 12/20/2022]
Abstract
Less than 1% of patients with liver metastases from neuroendocrine tumors (NETs) are susceptible to liver transplantation. We report a case of a patient transplanted 13 years ago for NET metastases, with a lesion histologically proved for NET metastasis located at the cava vein anastomosis. He was treated with percutaneous radiofrequency ablation (RFA) after a first failed attempt of endovascular approach. The vascular heat sink, which RFA is susceptible to, was considered an advantage in this case, since it restricted the propagation of heat only to the tissue located in the very proximity of the RFA antenna, protecting the inferior vena cava vessel walls. This positive result may suggest an additional use of RFA in selected challenging cases.
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Affiliation(s)
- Anna Maria Ierardi
- Diagnostic and Interventional Radiology Department, ASST Santi Paolo e Carlo, San Paolo Hospital, University of Milan, Via A di Rudinì 8, 20142, Milan, IT, Italy
| | - Pierpaolo Biondetti
- Diagnostic and Interventional Radiology Department, ASST Santi Paolo e Carlo, San Paolo Hospital, University of Milan, Via A di Rudinì 8, 20142, Milan, IT, Italy
| | - Barbara Padovano
- Nuclear Medicine Department, IRCCS Istituto Nazionale dei Tumori, Milan, IT, Italy
| | - Alberto Magenta Biasina
- Diagnostic and Interventional Radiology Department, ASST Santi Paolo e Carlo, San Paolo Hospital, University of Milan, Via A di Rudinì 8, 20142, Milan, IT, Italy
| | - Marco Bongini
- Gastrointestinal Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori, University of Milan, 20133, Milan, Italy
| | - Gianpaolo Carrafiello
- Diagnostic and Interventional Radiology Department, ASST Santi Paolo e Carlo, San Paolo Hospital, University of Milan, Via A di Rudinì 8, 20142, Milan, IT, Italy.
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30
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Tseng CM, Cheng TY, Chen TB, Tien YW, Chen CC, Lin JT, Wang HP. Low accuracy of chromogranin A for diagnosing early-stage pancreatic neuroendocrine tumors. Oncol Lett 2018; 15:8951-8958. [PMID: 29805630 PMCID: PMC5958764 DOI: 10.3892/ol.2018.8472] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 08/08/2017] [Indexed: 11/30/2022] Open
Abstract
The aim of the present study was to evaluate the clinical utility of plasma chromogranin A (CgA) in patients diagnosed with early-stage pancreatic neuroendocrine tumors (PNETs) in terms of diagnostic value and treatment response. A total of 35 patients with PNETs were prospectively enrolled from August 2010 to April 2014. Demographic and clinicopathological data were collected, and serial plasma CgA levels were measured. Tumor responses were defined by the Response Evaluation Criteria In Solid Tumors criteria. Pearson's χ2 test was used for the analysis of the association between the plasma CgA level and various factors. Plasma CgA level was significantly associated with the size (P=0.03), metastasis (P=0.02) and tumor stage (P=0.03) of the PNETs. Using 126 U/l as the optimal cutoff value, the sensitivity and specificity were 87.5 and 81.5%, respectively. For localized tumors, the sensitivity of CgA for diagnosing PNETs was relatively low, even following a lowering of the cutoff values (29.6–51.9%). Plasma CgA level was correlated with therapeutic response in those patients with high baseline CgA levels (P=0.025), but not in the patients with low baseline CgA levels (P=0.587). In conclusion, plasma CgA level was associated with tumor size, metastasis and tumor stage in patients with PNET. For early-stage PNETs, CgA exhibited a limited role in diagnosis and treatment response evaluation in the population of the present study.
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Affiliation(s)
- Chao-Ming Tseng
- Department of Internal Medicine, E-Da Cancer Hospital/I-Shou University, Kaohsiung 824, Taiwan, R.O.C
| | - Tsu-Yao Cheng
- Department of Laboratory Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10002, Taiwan, R.O.C.,Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10002, Taiwan, R.O.C
| | - Tai-Been Chen
- Department of Medical Imaging and Radiological Sciences, I-Shou University, Kaohsiung 824, Taiwan, R.O.C
| | - Yu-Wen Tien
- Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10002, Taiwan, R.O.C
| | - Chien-Chuan Chen
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10002, Taiwan, R.O.C
| | - Jaw-Town Lin
- School of Medicine, Fu Jen Catholic University, New Taipei City 10002, Taiwan, R.O.C
| | - Hsiu-Po Wang
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10002, Taiwan, R.O.C
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31
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Vatsadze SZ, Eremina OE, Veselova IA, Kalmykov SN, Nenajdenko VG. 18F-Labelled catecholamine type radiopharmaceuticals in the diagnosis of neurodegenerative diseases and neuroendocrine tumours: approaches to synthesis and development prospects. RUSSIAN CHEMICAL REVIEWS 2018. [DOI: 10.1070/rcr4752] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Lopez-Aguiar AG, Ethun CG, Postlewait LM, Zhelnin K, Krasinskas A, El-Rayes BF, Russell MC, Sarmiento JM, Kooby DA, Staley CA, Maithel SK, Cardona K. Redefining the Ki-67 Index Stratification for Low-Grade Pancreatic Neuroendocrine Tumors: Improving Its Prognostic Value for Recurrence of Disease. Ann Surg Oncol 2017; 25:290-298. [PMID: 29079920 DOI: 10.1245/s10434-017-6140-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Indexed: 01/03/2023]
Abstract
BACKGROUND The Ki-67 index is an established prognostic marker for recurrence after resection of pancreatic neuroendocrine tumors (PanNETs) that groups tumors into three categories: low grade (< 3%), intermediate grade (3-20%), and high grade (> 20%). Given that the majority of resected PanNETs have a Ki-67 less than 3%, this study aimed to stratify this group further to predict disease recurrence more accurately. METHODS The Ki-67 index was pathologically re-reviewed and scored by a pathologist blinded to all other clinicopathologic variables using tissue microarray blocks made in triplicate. All patients who underwent curative-intent resection of non-metastatic PanNETs at a single institution from 2000 to 2013 were included in the study. The primary outcome was recurrence-free survival (RFS). RESULTS Of 113 patients with well-differentiated PanNETs resected, 83 had tissue available for pathologic re-review. The Ki-67 index was lower than 3% for 72 tumors (87%) and between 3 and 20% for 11 tumors (13%). Considering only Ki-67 less than 3%, the tumors were further stratified by Ki-67 into three groups: group A (< 1%, n = 43), group B (1-1.99%, n = 23), and group C (2-2.99%, n = 6). Compared with group A, groups B and C more frequently had advanced T stage (T3: 44% and 67% vs 12%; p = 0.003) and lymphovascular invasion (50% and 83% vs 23%; p = 0.007). Groups B and C had similar 1- and 3-year RFS, both less than group A. After combining groups B and C, a Ki-67 of 1-2.99% was associated with decreased RFS compared with group A (< 1%). This persisted in the multivariable analysis (hazard ratio [HR] 8.6; 95% confidence interval [CI] 1.0-70.7; p = 0.045), with control used for tumor size, margin-positivity, lymph node involvement, and advanced T stage. CONCLUSIONS PanNETs with a Ki-67 of 1-2.99% exhibit distinct biologic behavior and earlier disease recurrence than those with a Ki-67 lower than 1%. This new stratification scheme, if externally validated, should be incorporated into future grading systems to guide both surveillance protocols and treatment strategies.
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Affiliation(s)
| | - Cecilia G Ethun
- Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Lauren M Postlewait
- Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Kristen Zhelnin
- Department of Pathology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Alyssa Krasinskas
- Department of Pathology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Bassel F El-Rayes
- Department of Hematology Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Maria C Russell
- Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Juan M Sarmiento
- Department of General Surgery, Emory University, Atlanta, GA, USA
| | - David A Kooby
- Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Charles A Staley
- Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Shishir K Maithel
- Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Kenneth Cardona
- Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
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33
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Chen X, Wang Z. Differences between Grades G1 and G2 Hypovascular Pancreatic Neuroendocrine Tumors and Pancreatic Neuroendocrine Carcinoma. Radiology 2017; 285:331-332. [PMID: 28926309 DOI: 10.1148/radiol.2017171126] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Xiao Chen
- Department of Radiology, the Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Rd, Nanjing 210029, China
| | - Zhongqiu Wang
- Department of Radiology, the Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Rd, Nanjing 210029, China
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Computed Tomography Features Predictive of Lymph Node Involvement in Patients With a Nonfunctioning Pancreatic Neuroendocrine Tumor. Pancreas 2017; 46:1056-1063. [PMID: 28787330 DOI: 10.1097/mpa.0000000000000888] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES This study aims to identify the computed tomography (CT) features that may differentiate nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs) with lymph node (LN) metastasis from NF-PanNETs without lymph node metastasis. METHODS We retrospectively analyzed 166 NF-PanNETs in 166 patients who had undergone surgical resection (median age, 53). Two radiologists evaluated the qualitative and quantitative CT findings. Through univariate and multivariate logistic regression analyses, we determined independent significant findings for differentiating NF-PanNETs with LN metastasis from NF-PanNETs without LN metastasis. Recurrence-free survival (RFS) and overall survival (OS) were compared between the 2 groups using Kaplan-Meier analysis and log-rank testing. RESULTS Of the 166 NF-PanNETs, 24 (14.5%) tumors demonstrated LN metastasis. Three CT findings, radiologic LN enlargement (adjusted odds ratio [OR], 11.76; P = 0.001), liver metastasis (OR, 10.31; P = 0.027), and portal enhancement ratio of <1.238 (OR, 3.58; P = 0.033), were independently significant for differentiating NF-PanNETs with LN metastasis from NF-PanNETs without LN metastasis. Tumor size greater than 2 cm also showed a statistically marginal significance (OR, 8.47; P = 0.050). The median RFS and OS in NF-PanNETs with LN metastasis were significantly shorter than NF-PanNETs without LN metastasis (23.7 months vs 33.2 months, P < 0.001; 33.7 months vs 54.8 months, P < 0.001). CONCLUSIONS Four CT findings can be useful to differentiate NF-PanNETs with LN metastasis and NF-PanNETs without LN metastasis.
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Moschovis D, Gazouli M, Tzouvala M, Vezakis A, Karamanolis G. Long non-coding RNA in pancreatic adenocarcinoma and pancreatic neuroendocrine tumors. Ann Gastroenterol 2017; 30:622-628. [PMID: 29118556 PMCID: PMC5670281 DOI: 10.20524/aog.2017.0185] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2017] [Accepted: 07/05/2017] [Indexed: 12/21/2022] Open
Abstract
Interest in non-coding regions of DNA has been increasing since the mapping of the human genome revealed that human DNA contains far fewer genes encoding proteins than previously expected. However, analysis of the derivatives of DNA transcription (transcriptomics) revealed that the majority of the genetic material is transcribed into non-coding RNA (ncRNA), indicating that these molecules probably provide the functional diversity and complexity of the physiology of the human body that cannot be attributed to the proteins. Of these ncRNA, long ncRNA (lncRNA) have a length greater than 200 nucleotides and share many common components with the coding messenger RNA (mRNA): They are transcribed by RNA polymerase II, comprised of multiple exons and subjected to normal RNA splicing giving RNA products of several kilobases. Scientific data reveal the regulatory role of lncRNA in the control of gene expression during cell development and homeostasis. However, to date, very few lncRNAs have been characterized in depth, and lncRNAs are thought to have a wide range of functions in cellular and developmental processes. These molecules will have the possibility to be used as biomarkers and contribute to the development of targeted therapies. Concerning pancreatic cancer, there are limited data in the literature that correlate the growth of these tumors with deregulation of various lncRNA. We herein review the literature regarding the role of lncRNA as a diagnostic and prognostic biomarker and possible therapeutic target in the neoplasms of the pancreas, particularly pancreatic adenocarcinoma and pancreatic neuroendocrine tumors.
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Affiliation(s)
- Dimitrios Moschovis
- Department of Gastroenterology, Agios Panteleimon General Hospital, Nikea (Dimitrios Moschovis, Maria Tzouvala), Greece
| | - Maria Gazouli
- Department of Basic Medical Sciences, Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens (Maria Gazouli), Greece
| | - Maria Tzouvala
- Department of Gastroenterology, Agios Panteleimon General Hospital, Nikea (Dimitrios Moschovis, Maria Tzouvala), Greece
| | - Antonios Vezakis
- 2 Department of Surgery, Aretaieion University Hospital, National and Kapodistrian University of Athens (Antonios Vezakis), Greece
| | - George Karamanolis
- Gastroenterology Unit, 2 Department of Surgery, Aretaieio University Hospital, National and Kapodistrian University of Athens (George Karamanolis), Greece
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Abstract
Pancreatic neuroendocrine tumors (PanNETs) manifest with a range of symptoms and pose a therapeutic challenge. A team approach, in which many specialists come together, is necessary in the quest for the best patient-tailored treatment. Disciplines such as oncology, surgery, basic science, endocrinology, radiology, and nuclear medicine need to work side by side, equally contributing to patient care and to advancing our better understanding of this fascinating disease.
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Affiliation(s)
| | - Christos Dervenis
- Department of Surgical Oncology and HPB Surgery, Metropolitan Hospital, Athens, Greece
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Hu J, Hu Q, Hu H. Characterization of single lesion nonfunctioning pancreatic neuroendocrine carcinoma via computed tomography. Oncol Lett 2017; 13:2186-2190. [PMID: 28454379 PMCID: PMC5403290 DOI: 10.3892/ol.2017.5729] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 10/24/2016] [Indexed: 11/17/2022] Open
Abstract
Nonfunctioning pancreatic neuroendocrine carcinoma (NPNEC) is a poorly differentiated neuroendocrine carcinoma and a rare type of pancreatic cancer. Computed tomography (CT)-based imaging is currently the most effective method for diagnosing and classifying NPNEC. The present study investigated the clinical features and CT manifestations of this disease. The CT manifestations and clinical data of 13 patients with NPNEC, confirmed by surgery or needle biopsy, were retrospectively analyzed. None of the 13 patients exhibited endocrine-related symptoms and a single lesion with a variable position in the pancreatic was observed in all patients. The tumors were generally round or irregular, with inhomogeneous density and an average diameter of 7.45±3.92 cm (range, 4.0–16.0 cm). Cystic necrosis zones were observed in 5 patients and calcification was observed in 2. A total of 4 patients exhibited intrahepatic metastases, and 2 patients demonstrated spleen and colon invasion. Enhanced scanning indicated that tumors were markedly enhanced. There were 11 cases of middle or high-grade enhancement (84.6%) and 2 cases of mild enhancement (15.4%). Marked envelope enhancement was observed in 3/11 patients with high-grade enhancement. In conclusion, the majority of patients with NPNEC lacked characteristic manifestations. While the CT examination revealed certain characteristics, histological analysis was necessary to confirm diagnoses.
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Affiliation(s)
- Jibo Hu
- Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Qunhui Hu
- Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Hongjie Hu
- Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
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Jiang Y, Jin JB, Zhan Q, Deng XX, Shen BY. Impact and Clinical Predictors of Lymph Node Metastases in Nonfunctional Pancreatic Neuroendocrine Tumors. Chin Med J (Engl) 2016; 128:3335-44. [PMID: 26668149 PMCID: PMC4797510 DOI: 10.4103/0366-6999.171427] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background: The optimal surgical management of nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) is still controversial. Here, we evaluated the impact of lymph node status on postoperative recurrence in patients with NF-PNET and the potential of preoperative variables for predicting lymph node metastasis (LNM). Methods: In this mono-institutional retrospective cohort study conducted in 100 consecutive patients who underwent NF-PNET resection between January 2004 and December 2014, we evaluated risk factors for survival using the Kaplan–Meier method and the Cox regression model. Predictors of LNM were evaluated using the logistic regression model, and the power of predictive models was evaluated using receiver operating characteristic curve analysis. Results: Five-year disease-free survival of resected NF-PNET was 64.1%. LNM was independently associated with postoperative recurrence (hazard ratio = 3.995, P = 0.003). Multivariate analysis revealed tumor grade as an independent factor associated with LNM (G2 vs. G1: odds ratio [OR] =6.287, P = 0.008; G3 vs. G1: OR = 12.407, P = 0.001). When tumor grade was excluded, radiological tumor diameter >2.5 cm (OR = 5.430, P = 0.013) and presence of symptoms (OR = 3.366, P = 0.039) were significantly associated with LNM. Compared to neoplasms with radiological diameter >2.5 cm (32.1%), tumors ≤2.5 cm had an obviously lower risk of LNM (7.7%), indicating the reliability of this parameter in predicting LNM (area under the curve, 0.693). Incidentally discovered NF-PNETs ≤2.5 cm were associated with a low-risk of LNM and excellent survival. Conclusions: LNM is significantly associated with postoperative recurrence. Radiological tumor diameter is a reliable predictor of LNM in NF-PNETs. Our results indicate that lymphadenectomy in small (≤2.5 cm) NF-PNETs is not routinely necessary.
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Affiliation(s)
| | | | | | | | - Bai-Yong Shen
- Department of General Surgery, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
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Jin M, Roth R, Gayetsky V, Niederberger N, Lehman A, Wakely PE. Grading pancreatic neuroendocrine neoplasms by Ki-67 staining on cytology cell blocks: manual count and digital image analysis of 58 cases. J Am Soc Cytopathol 2016; 5:286-295. [PMID: 31042505 DOI: 10.1016/j.jasc.2016.03.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 03/24/2016] [Accepted: 03/24/2016] [Indexed: 06/09/2023]
Abstract
INTRODUCTION Controversy remains as to whether Ki-67 labeling on endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) cell blocks (CBs) can be used to grade pancreatic neuroendocrine neoplasms (PanNENs) reliably and what would be the best methodology for doing so. MATERIALS AND METHODS A retrospective search identified cases with both EUS-FNA and correlating surgical pathology (SP) available. 58 CBs (>100 tumor cells) were identified. Ki-67 labeling on CB was counted using both manual count (MC) and digital image analysis (DIA, ImmunoRatio software). The grades determined on CB were compared with those on corresponding SP reports (kappa statistics). The correct grading rates between MC and DIA were compared (McNemar's test). Total tumor cell number (TTCN, cutoffs: 500 and 2000) was used as a stratification factor (chi-square tests for trend). RESULTS Of 58 cases, the SP grade distribution was 31 grade 1, 23 grade 2, and 4 grade 3. Overall, the grading concordance of CB MC and SP was higher than that of CB DIA and SP (McNemar's P-value = 0.022). Compared with SP, CB MC correctly graded 69% (40 of 58) [κ = 0.44 (95% CI: 0.21, 0.66)]; CB DIA correctly graded 55% (32 of 58) [κ = 0.19 (95% CI: 0.04, 0.42)]. Grade 1 tumors had the highest concordance. Although the correct grading rate improved as TTCN increased, no statistical significance was found. CONCLUSION Although Ki-67 labeling on CB can be used to grade PanNENs, limitation exists, particularly for grade 2 tumors. The method of counting makes a difference: MC is more accurate than DIA. The major reasons of discordance include non-tumor cell contamination and insufficient sampling.
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Affiliation(s)
- Ming Jin
- Department of Pathology, The Ohio State University Wexner Medical Center, S305B Rhodes Hall, 450 W. 10th Avenue, Columbus, Ohio, 43210.
| | - Rachel Roth
- Department of Pathology, Bethesda North Hospital, Cincinnati, Ohio
| | - Vera Gayetsky
- Department of Pathology, The Ohio State University Wexner Medical Center, S305B Rhodes Hall, 450 W. 10th Avenue, Columbus, Ohio, 43210
| | - Nicholas Niederberger
- Department of Pathology, The Ohio State University Wexner Medical Center, S305B Rhodes Hall, 450 W. 10th Avenue, Columbus, Ohio, 43210
| | - Amy Lehman
- Center for Biostatistics, The Ohio State University, Columbus, Ohio
| | - Paul E Wakely
- Department of Pathology, The Ohio State University Wexner Medical Center, S305B Rhodes Hall, 450 W. 10th Avenue, Columbus, Ohio, 43210
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Li Y, Dai M, Chang X, Hu W, Chen J, Guo J, Wu W, Zhang T, Liao Q, Liu Z, Hu Y, Zhao Y. Mixed serous neuroendocrine neoplasm of the pancreas: Case report and literature review. Medicine (Baltimore) 2016; 95:e4205. [PMID: 27559942 PMCID: PMC5400308 DOI: 10.1097/md.0000000000004205] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
INTRODUCTION The aim of this study was to report a new case of mixed serous neuroendocrine neoplasm (MSNN) and review the literature concerning this type of lesion, which was added to the World Health Organization classification of pancreatic tumors in 2010. RESULTS A 73-year-old woman presented with a pancreatic mass. The lesion was an intriguing combination of serous cystic neoplasm (SCN) and pancreatic neuroendocrine tumor (PanNET), in which the PanNET component grew into the wall of the serous oligocystic adenoma. We searched different databases for studies that had investigated MSNN. A total of 15 patients (age, 28-78), including the patient in the present study, were evaluated. We discuss these cases in detail especially regarding morphology and pathology; our case was the only one involving a collision type combination. CONCLUSION Although MSNN is recognized as a variant of SCN, it is quite different from SCN or PanNET. A new morphological analysis of MSNN may help in elucidating its histogenesis and prognosis.
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Affiliation(s)
| | - Menghua Dai
- Department of General Surgery
- Correspondence: Menghua Dai, Department of General Surgery, Peking Union Medical College Hospital, 100730 Beijing, P.R. China (e-mail: ); Yupei Zhao, Department of General Surgery, Peking Union Medical College Hospital, 100730 Beijing, P.R. China (e-mail: )
| | - Xiaoyan Chang
- Department of Pathology, Peking Union Medical College Hospital, Beijing
| | - Wendi Hu
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, P.R. China
| | - Jie Chen
- Department of Pathology, Peking Union Medical College Hospital, Beijing
| | | | | | | | | | | | - Ya Hu
- Department of General Surgery
| | - Yupei Zhao
- Department of General Surgery
- Correspondence: Menghua Dai, Department of General Surgery, Peking Union Medical College Hospital, 100730 Beijing, P.R. China (e-mail: ); Yupei Zhao, Department of General Surgery, Peking Union Medical College Hospital, 100730 Beijing, P.R. China (e-mail: )
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Dréanic J, Lepère C, El Hajjam M, Gouya H, Rougier P, Coriat R. Emergency therapy for liver metastases from advanced VIPoma: surgery or transarterial chemoembolization? Ther Adv Med Oncol 2016; 8:383-7. [PMID: 27583030 DOI: 10.1177/1758834016656495] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
VIPoma is a rare neuroendocrine tumor (NET) with a high potential to develop hepatic metastases and poor prognosis. The primitive tumor is nonsymptomatic and usually localized within the pancreas. Liver metastasis drives the prognosis and induces profuse watery diarrhea or renal failure. We herein present severe renal failure or diarrhea in two patients hospitalized in intensive care justifying emergency treatment of liver metastasis. The two patients experienced severe diarrhea due to a hypersecretion of vasoactive intestinal peptide (VIP) from liver metastasis released into the blood circulation. Therapeutic management was discussed and liver transarterial chemoembolization (TACE) was performed with chemotherapy-loaded embospheres, which cause necrosis of tumor lesions. TACE controlled the hormonal syndrome and made patients eligible for curative surgery. Tumor necrosis occurred and VIP levels collapsed. Surgery was performed in one of the two cases after TACE and the patient was considered in remission. Both patients were still alive after 3 years of follow up. Thus, TACE is feasible and appears to be an effective emergency treatment in patients with a VIP-hormonal syndrome due to liver metastases. Despite the biological disorder due to the hormonal secretion, an aggressive approach is warranted in VIP liver metastasis.
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Affiliation(s)
- Johann Dréanic
- Gastroenterology and Endoscopy Unit, Hôpital Cochin, 27, Rue du Faubourg, Saint Jacques F75014, Paris, France
| | - Céline Lepère
- Department of Digestive Oncology, Hôpital Européen Georges Pompidou, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, AP-HP, Paris, France
| | - Mostafa El Hajjam
- Department of Radiology, Hôpital Ambroise Paré, Université Paris Ouest Versailles, AP-HP, Boulogne, France
| | - Hervé Gouya
- Department of Radiology, Hôpital Cochin, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, AP-HP, Paris, France
| | - Philippe Rougier
- Department of Digestive Oncology, Hôpital Européen Georges Pompidou, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, AP-HP, Paris, France
| | - Romain Coriat
- Department of Gastroenterology and Endoscopy, Hôpital Cochin, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, AP-HP, Paris, France
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Evaluation and management of pancreatic lesions in patients with von Hippel–Lindau disease. Nat Rev Clin Oncol 2016; 13:537-49. [PMID: 27030075 DOI: 10.1038/nrclinonc.2016.37] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Onesti JK, Shirley LA, Saunders ND, Davidson GW, Dillhoff ME, Khabiri H, Guy GE, Dowell JD, Schmidt CR, Shah MH, Bloomston M. Elevated Alkaline Phosphatase Prior to Transarterial Chemoembolization for Neuroendocrine Tumors Predicts Worse Outcomes. J Gastrointest Surg 2016; 20:580-6. [PMID: 26489743 DOI: 10.1007/s11605-015-2998-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2015] [Accepted: 10/14/2015] [Indexed: 01/31/2023]
Abstract
INTRODUCTION We hypothesized that an elevated preoperative alkaline phosphatase (AP) predicted worse outcomes for patients undergoing transarterial chemoembolization (TACE) for neuroendocrine tumor (NET) liver metastases. METHODS We reviewed all patients who underwent TACE for metastatic NET between 2009 and 2013. Survival was evaluated using preprocedure variables. RESULTS One hundred and nine patients underwent 210 TACE procedures. The average age was 57.7 years (range 20-78). Primary sites included pancreas (N = 20), other gastrointestinal (N = 52), lung (N = 9), and unknown (N = 28). The tumor was grade 1 in 68 (62 %), grade 2 in 21 (19 %), and grade 3 in 3 (3 %). Extrahepatic disease was present in 54 (50 %) and greater than 50 % hepatic tumor burden by imaging in 63 (58 %). Elevated bilirubin occurred in 8 (7 %), elevated AP in 22 (20 %), elevated ALT in 21 (19 %), and elevated AST in 41 (38 %). Univariate predictors included tumor grade (43 vs 27 vs 21 months, p = 0.015), hepatic tumor burden (59 vs 37 months, p = 0.009), and elevated AP (59 vs 23 months, p < 0.001). On multivariate analysis, only elevated AP (p = 0.001) predicted worse survival. CONCLUSIONS Elevated AP prior to TACE for metastatic NET portends a worse survival outcome, even more so than tumor grade or extent of hepatic disease.
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Affiliation(s)
- Jill K Onesti
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center, 250 Cherry St, Grand Rapids, MI, 49503, USA.
| | - Lawrence A Shirley
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center, 250 Cherry St, Grand Rapids, MI, 49503, USA
| | - Neil D Saunders
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center, 250 Cherry St, Grand Rapids, MI, 49503, USA
| | - Gail W Davidson
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center, 250 Cherry St, Grand Rapids, MI, 49503, USA
| | - Mary E Dillhoff
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center, 250 Cherry St, Grand Rapids, MI, 49503, USA
| | - Hooman Khabiri
- Division of Interventional Radiology, The Ohio State University Wexner Medical Center, 250 Cherry St, Grand Rapids, MI, 49503, USA
| | - Gregory E Guy
- Division of Interventional Radiology, The Ohio State University Wexner Medical Center, 250 Cherry St, Grand Rapids, MI, 49503, USA
| | - Joshua D Dowell
- Division of Interventional Radiology, The Ohio State University Wexner Medical Center, 250 Cherry St, Grand Rapids, MI, 49503, USA
| | - Carl R Schmidt
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center, 250 Cherry St, Grand Rapids, MI, 49503, USA
| | - Manisha H Shah
- Division of Medical Oncology, The Ohio State University Wexner Medical Center, 250 Cherry St, Grand Rapids, MI, 49503, USA
| | - Mark Bloomston
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center, 250 Cherry St, Grand Rapids, MI, 49503, USA
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Role of Locoregional and Systemic Approaches for the Treatment of Patients with Metastatic Neuroendocrine Tumors. J Gastrointest Surg 2015; 19:2273-82. [PMID: 26341823 DOI: 10.1007/s11605-015-2931-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 08/20/2015] [Indexed: 01/31/2023]
Abstract
Although gastroenteropancreatic neuroendocrine tumors are often perceived as being indolent tumors, more than half of the patients will harbor liver metastases at the time of diagnosis. Gastroenteropancreatic neuroendocrine tumors have the potential to be aggressive and resistant to therapy, making the integration of both locoregional and systemic therapy even more critical in the treatment of patients with locally advanced or metastatic lesions. Over the last several years, significant advancements have been made in the surgical treatment, liver-directed therapy, and medical management of gastroenteropancreatic neuroendocrine tumors. While surgical resection is the cornerstone of therapy, cytoreductive surgery, orthotopic liver transplantation, local ablation, and intra-arterial therapy all improve the prognosis of patients suffering with locally advanced or metastatic disease. In addition, great strides have been made in the medical management of gastroenteropancreatic neuroendocrine tumors, particularly with the evolution of novel molecular targeted therapy, such as everolimus and sunitinib. Hence, gastroenteropancreatic neuroendocrine tumor is becoming a disease process requiring more of a multi-disciplinary approach with the integration of both locoregional and systemic therapies for improved outcomes.
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Al-Hawary MM, Francis IR, Anderson MA. Pancreatic Solid and Cystic Neoplasms: Diagnostic Evaluation and Intervention. Radiol Clin North Am 2015; 53:1037-48. [PMID: 26321452 DOI: 10.1016/j.rcl.2015.05.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
High-resolution imaging modalities, such as multi-detector computed tomography, MR imaging, and endoscopic ultrasound, are frequently used alone or in combination to characterize focal solid and cystic pancreatic neoplasms. Imaging in solid pancreatic neoplasms, typically adenocarcinoma and neuroendocrine tumors, is primarily used to detect and stage the extent of the tumor and to determine if complete surgical resection for cure is feasible. In cystic pancreatic masses, imaging aims to differentiate benign nonmucinous cystic lesions from potentially or frankly malignant mucin-producing cysts. Several noninvasive and invasive treatment options can be performed if surgical resection is not possible or contraindicated.
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Affiliation(s)
- Mahmoud M Al-Hawary
- Division of Abdominal Imaging, Department of Radiology, University of Michigan Hospitals, 1500 East Medical Center Drive, Room B1 D502, Ann Arbor, MI 48109, USA.
| | - Isaac R Francis
- Division of Abdominal Imaging, Department of Radiology, University of Michigan Hospitals, 1500 East Medical Center Drive, Room B1 D540, Ann Arbor, MI 48109, USA
| | - Michelle A Anderson
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Hospitals, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
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Martin AK, Zhou Z. Endoscopic ultrasound-guided fine-needle aspiration for the diagnosis of pancreatic cysts by combined cytopathology and cystic content analysis. World J Gastrointest Endosc 2015; 7:1157-1169. [PMID: 26504505 PMCID: PMC4613805 DOI: 10.4253/wjge.v7.i15.1157] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 08/03/2015] [Accepted: 09/08/2015] [Indexed: 02/05/2023] Open
Abstract
Recent advances in imaging technology have resulted in an increase in incidental discoveries of pancreatic cystic lesions. Pancreatic cysts comprise a wide variety of lesions and include non-neoplastic cysts and neoplastic cysts. Because some pancreatic cysts have more of a malignant potential than others, it is absolutely essential that an accurate diagnosis is rendered so that effective care can be given to each patient. In many centers, endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) has emerged as the modality of choice that enables one to distinguish between mucinous and non-mucinous lesion, diagnose malignancy and collect cyst fluid for further diagnostic studies, such as pancreatic enzyme levels, molecular analysis and other tumor biomarkers. The current review will focus on EUS-guided FNA and the cytological diagnosis for pancreatic cysts.
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Abstract
von Hippel-Lindau (VHL) disease is an autosomal dominant disorder caused by heterozygous mutations in the VHL tumor suppressor gene that is characterized by the occurrence of multiple endocrine and nonendocrine lesions. This review focuses on the endocrine manifestations of VHL disease. Pancreatic neuroendocrine proliferations (ductuloinsular complexes, islet dysplasia, endocrine microadenoma, and neuroendocrine tumors), pheochromocytomas, and extra-adrenal paragangliomas are important endocrine manifestations of VHL disease. They frequently display characteristic clinical, biochemical, and histopathologic features that, although not pathognomonic, can be helpful in suggesting VHL disease as the underlying etiology and distinguishing these tumors from sporadic cases. Recent improvements in treatment and outcomes of renal cell carcinomas have allowed pancreatic neuroendocrine tumors to emerge as a significant source of metastatic disease, making the accurate recognition and classification of these neoplasms by the pathologist of utmost importance to determine prognosis, treatment, and follow-up strategies for affected patients.
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Affiliation(s)
- Clarissa Cassol
- From the Department of Pathology, University Health Network, Toronto, Ontario, Canada, and the Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada
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Intravoxel incoherent motion diffusion-weighted imaging of pancreatic neuroendocrine tumors: prediction of the histologic grade using pure diffusion coefficient and tumor size. Invest Radiol 2015; 49:396-402. [PMID: 24500090 DOI: 10.1097/rli.0000000000000028] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE The purpose of this study was to assess the value of intravoxel incoherent motion and diffusion-weighted imaging for predicting the histologic grade of pancreatic neuroendocrine tumors (PNETs). MATERIALS AND METHODS Forty patients with surgically diagnosed PNETs who underwent preoperative magnetic resonance imaging, including diffusion-weighted imaging with a series of 10 b values (0-1000 s/mm(2), were included in this institutional review board-approved retrospective study. The apparent diffusion coefficient (ADC(total)), the intravoxel incoherent motion parameters (pure diffusion coefficient [D], pseudodiffusion coefficient [D(*)], and perfusion fraction [f]) were measured on the tumors. Histologic grading was performed on the basis of the World Health Organization 2010 classification system. Logistic regression analysis and receiver operating curve analysis were performed to identify the significant factors predicting the histologic grades. RESULTS Grades 2 and 3 tumors were significantly larger than grade 1 tumors (average 3.62 cm vs 2.17 cm in diameter; P=0.001). Grades 2 and 3 tumors showed significantly lower D values than did grade 1 tumors (0.95 vs 1.21×10(-3) mm(2)/s; P=0.009), although the ADC(total) showed no significant difference. When any of the following 2 criteria was used, (a) tumor size smaller than 2.0 cm in diameter and (b) D value greater than 1.2×10(-3) mm(2)/s, the sensitivity, specificity, and positive predictive value for diagnosing grade 1 PNETs were 76.92%, 100%, and 100%, respectively. CONCLUSIONS Pure diffusion coefficient (D) is possibly a better marker than ADC(total) is for differentiating grade 1 from grade 2 or 3 PNET and, combined with tumor size, can predict grade 1 PNET with a high specificity.
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Gebauer N, Schmidt-Werthern C, Bernard V, Feller AC, Keck T, Begum N, Rades D, Lehnert H, Brabant G, Thorns C. Genomic landscape of pancreatic neuroendocrine tumors. World J Gastroenterol 2014; 20:17498-17506. [PMID: 25516664 PMCID: PMC4265611 DOI: 10.3748/wjg.v20.i46.17498] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2014] [Revised: 05/03/2014] [Accepted: 07/25/2014] [Indexed: 02/07/2023] Open
Abstract
AIM: To investigate the prognostic role of genomic stability and copy number alterations (CNAs) pancreatic neuroendocrine tumors (PanNETs).
METHODS: A high-resolution array-based comparative genomic hybridization approach was utilized in order to investigate and quantify chromosomal aberrations in a panel of 37 primary PanNET and 11 metastatic samples. DNA samples were extracted from formalin-fixed and paraffin-embedded tumor specimen. Genomic findings were correlated with histopathological and immunohistochemical data. Moreover, the dataset was subjected to employing an unsupervised hierarchical clustering analysis approach utilizing Euclidean distance and average linkage and associations between genomically defined tumor groups and recurrent CNAs or clinicopathological features of the study group were assessed.
RESULTS: Numerous chromosomal aberrations were recurrently detected in both, primary tumor samples and metastases. Copy number gains were most frequently observed at 06p22.2-p22.1 (27.1%), 17p13.1 (20.8%), 07p21.3-p21.2 (18.8%), 09q34.11 (18.8%). Genomic losses were significantly less frequent and the only recurrent aberration affected 08q24.3 (6.3%). Moreover, we detected a high degree of genomic heterogeneity between primary tumors and metastatic lesions. Unsupervised hierarchical clustering of loci affected by CNAs in more than 3 primary tumor samples revealed two genetically distinct tumor groups as well as two chromosomal clusters of genomic imbalances indicating a small subset of tumors with common molecular features (13.5%). Aberrations affecting 6p22.2-22.1, 8q24.3, 9q34.11 and 17p13.1 (P = 0.011; 0.003; 0.003; 0.001), were significantly associated with a poorer survival prognosis.
CONCLUSION: This study suggests that several frequent CNAs in numerous candidate regions are involved in the pathogenesis and metastatic progression of PanNET.
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Dy BM, Que FG, Thompson GB, Young WF, Rowse P, Strajina V, Richards ML. Metastasectomy of neuroendocrine tumors in patients with multiple endocrine neoplasia type 1. Am J Surg 2014; 208:1047-53; discussion 1052-3. [DOI: 10.1016/j.amjsurg.2014.08.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Revised: 08/11/2014] [Accepted: 08/13/2014] [Indexed: 12/12/2022]
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