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Sharma A, Muralitharan M, Ramage J, Clement D, Menon K, Srinivasan P, Elmasry M, Reed N, Seager M, Srirajaskanthan R. Current Management of Neuroendocrine Tumour Liver Metastases. Curr Oncol Rep 2024; 26:1070-1084. [PMID: 38869667 PMCID: PMC11416395 DOI: 10.1007/s11912-024-01559-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/22/2024] [Indexed: 06/14/2024]
Abstract
PURPOSE OF REVIEW This article aims to illustrate the current state of investigations and management of liver metastases in patients with Neuroendocrine Neoplasms. Neuroendocrine tumours (NETs) are rising in incidence globally and have become the second most prevalent gastrointestinal malignancy in UK and USA. Frequently, patients have metastatic disease at time of presentation. The liver is the most common site of metastases for gastro-enteropancreatic NETs. Characterisation of liver metastases with imaging is important to ensure disease is not under-staged. RECENT FINDINGS Magnetic resonance imaging and positron emission tomography are now becoming standard of care for imaging liver metastases. There is an increasing armamentarium of therapies available for management of NETs and loco-regional therapy for liver metastases. The data supporting surgical and loco-regional therapy is reviewed with focus on role of liver transplantation. It is important to use appropriate imaging and classification of NET liver metastases. It is key that decisions regarding approach to treatment is undertaken in a multidisciplinary team and that individualised approaches are considered for management of patients with metastatic NETs.
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Affiliation(s)
- Aditya Sharma
- Department of Gastroenterology, King's College Hospital, SE5 9RS, London, U.K
| | | | - John Ramage
- Neuroendocrine Tumour Unit, Institute of Liver Studies, King's College Hospital, SE5 9RS, London, U.K
| | - Dominique Clement
- Department of Gastroenterology, King's College Hospital, SE5 9RS, London, U.K
- Neuroendocrine Tumour Unit, Institute of Liver Studies, King's College Hospital, SE5 9RS, London, U.K
| | - Krishna Menon
- Institute of Liver Studies, King's College Hospital, SE5 9RS, London, U.K
| | - Parthi Srinivasan
- Institute of Liver Studies, King's College Hospital, SE5 9RS, London, U.K
| | - Mohamed Elmasry
- Institute of Liver Studies, King's College Hospital, SE5 9RS, London, U.K
| | - Nick Reed
- Department of Oncology, Beatson Centre, G12 0YN, Glasgow, U.K
| | - Matthew Seager
- Department of Radiology, King's College Hospital, SE5 9RS, London, U.K
| | - Rajaventhan Srirajaskanthan
- Department of Gastroenterology, King's College Hospital, SE5 9RS, London, U.K..
- Neuroendocrine Tumour Unit, Institute of Liver Studies, King's College Hospital, SE5 9RS, London, U.K..
- Neuroendocrine Tumour Unit Institute of liver studies, King's College Hospital, SE5 9RS, London, U.K..
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Konuparamban A, Nautiyal A, Jha AK, Mithun S, Srichandan T, Puranik A, Rangarajan V. Optimization of the number of post-therapeutic planar imaging time points for the most reliable organ and tumour dosimetry in peptide receptor radionuclide therapy. HEALTH AND TECHNOLOGY 2024; 14:799-815. [DOI: 10.1007/s12553-024-00867-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 04/09/2024] [Indexed: 01/06/2025]
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Han L, Li J, Liang C, Chu Y, Wang Y, Lv L, Liu D, Tan Y. Risk factors for positive resection margins after endoscopic resection for gastrointestinal neuroendocrine tumors. Surg Endosc 2024; 38:2041-2049. [PMID: 38429572 DOI: 10.1007/s00464-024-10706-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 01/18/2024] [Indexed: 03/03/2024]
Abstract
BACKGROUND In recent years, the incidence of gastrointestinal neuroendocrine tumors (GI-NETs) has remarkably increased due to the widespread use of screening gastrointestinal endoscopy. Currently, the most common treatments are surgery and endoscopic resection. Compared to surgery, endoscopic resection possesses a higher risk of resection margin residues for the treatment of GI-NETs. METHODS A total of 315 patients who underwent surgery or endoscopic resection for GI-NETs were included. We analyzed their resection modality (surgery, ESD, EMR), margin status, Preoperative marking and Prognosis. RESULTS Among 315 patients included, 175 cases underwent endoscopic resection and 140 cases underwent surgical treatment. A total of 43 (43/175, 24.57%) and 10 (10/140, 7.14%) patients exhibited positive resection margins after endoscopic resection and surgery, respectively. Multivariate regression analysis suggested that no preoperative marking and endoscopic treatment methods were risk factors for resection margin residues. Among the patients with positive margin residues after endoscopic resection, 5 patients underwent the radical surgical resection and 1 patient underwent additional ESD resection. The remaining 37 patients had no recurrence during a median follow-up of 36 months. CONCLUSIONS Compared with surgery, endoscopic therapy has a higher margin residual rate. During endoscopic resection, preoperative marking may reduce the rate of lateral margin residues, and endoscopic submucosal dissection may be preferred than endoscopic mucosal resection. Periodical follow-up may be an alternative method for patients with positive margin residues after endoscopic resection.
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Affiliation(s)
- Liu Han
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
- Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan, China
- Clinical Research Center for Digestive Diseases in Hunan Province, Changsha, 410011, Hunan, China
| | - Jianglei Li
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
- Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan, China
- Clinical Research Center for Digestive Diseases in Hunan Province, Changsha, 410011, Hunan, China
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410000, Hunan, China
| | - Chengbai Liang
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
- Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan, China
- Clinical Research Center for Digestive Diseases in Hunan Province, Changsha, 410011, Hunan, China
| | - Yi Chu
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
- Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan, China
- Clinical Research Center for Digestive Diseases in Hunan Province, Changsha, 410011, Hunan, China
| | - Yongjun Wang
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
- Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan, China
- Clinical Research Center for Digestive Diseases in Hunan Province, Changsha, 410011, Hunan, China
| | - Liang Lv
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
- Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan, China
- Clinical Research Center for Digestive Diseases in Hunan Province, Changsha, 410011, Hunan, China
| | - Deliang Liu
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
- Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan, China.
- Clinical Research Center for Digestive Diseases in Hunan Province, Changsha, 410011, Hunan, China.
| | - Yuyong Tan
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
- Research Center of Digestive Diseases, Central South University, Changsha, 410011, Hunan, China.
- Clinical Research Center for Digestive Diseases in Hunan Province, Changsha, 410011, Hunan, China.
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Valian H, Hassan Emami M, Heidari A, Amjadi E, Fahim A, Lalezarian A, Ali Ehsan Dehkordi S, Maghool F. Trend of the polyp and adenoma detection rate by sex and age in asymptomatic average-risk and high-risk individuals undergoing screening colonoscopy, 2012-2019. Prev Med Rep 2023; 36:102468. [PMID: 37869540 PMCID: PMC10587514 DOI: 10.1016/j.pmedr.2023.102468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 10/08/2023] [Accepted: 10/09/2023] [Indexed: 10/24/2023] Open
Abstract
Adenoma detection rate (ADR) is an imperative quality measure for colorectal cancer (CRC) screening. This retrospective observational study aimed to determine the trend of polyp detection rate (PDR) and ADR in asymptomatic average- and high-risk participants in different age groups who underwent screening colonoscopy over the seven years from April 2012 to March 2019 in a tertiary gastroenterology referral center of Iran. Of 1676 participants, 51.8 % were men (mean age 52.3 years). The overall PDR and ADR were 22.7 %, and 13.5 %, respectively. Both Polyps and adenomas were more common in age groups 51-59 and ≥60 years in high-risk patients than in the corresponding groups of average-risk patients (p < 0.05). Also, both PDR and ADR were more frequent in men than in women among all studied age groups, but it was statistically significant only for the youngest age group (16.8 % versus 10.5 %, p < 0.05) for PDR and the oldest age group (19.7 % versus 13 %, p < 0.05) for ADR, respectively. The trend of total ADR was upward over 7 years in both average-risk (6.7 % to 13.3 %) and high-risk (9.8 % to 27 %) groups and across all age groups in both sexes. Multivariable logistic regression revealed that high-risk individuals had an elevated risk of adenoma compared with average-risk patients (OR: 1.6, p = 0.006). Substantial variation in thresholds of polyp and adenoma detection by age, sex, and risk categories emphasizes the need for a risk-adapted approach to CRC screening and prevention programs.
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Affiliation(s)
- Hengameh Valian
- Poursina Hakim Digestive Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Hassan Emami
- Poursina Hakim Digestive Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Aida Heidari
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Sciences and Technologies, University of Isfahan, Isfahan, Iran
| | - Elham Amjadi
- Poursina Hakim Digestive Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Alireza Fahim
- Poursina Hakim Digestive Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Anasik Lalezarian
- Poursina Hakim Digestive Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Fatemeh Maghool
- Poursina Hakim Digestive Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Sciences and Technologies, University of Isfahan, Isfahan, Iran
- Department of Family Medicine, University of Debrecen, Debrecen, Hungary
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Ito T, Ueda K, Fujimori N, Jensen RT. Clinical Manifestation of Endocrine Tumors of the Pancreas. THE PANCREAS 2023:791-798. [DOI: 10.1002/9781119876007.ch102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Kupietzky A, Dover R, Mazeh H. Surgical aspects of small intestinal neuroendocrine tumors. World J Gastrointest Surg 2023; 15:566-577. [PMID: 37206065 PMCID: PMC10190731 DOI: 10.4240/wjgs.v15.i4.566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 02/25/2023] [Accepted: 03/27/2023] [Indexed: 04/22/2023] Open
Abstract
Small intestinal neuroendocrine tumors (NETs) are a heterogeneous group of epithelial tumors with a predominant neuroendocrine differentiation. Although NETs are usually considered rare neoplasms, small intestinal NETs are the most common primary malignancy of the small bowel, with an increasing prevalence worldwide during the course of the past few decades. The indolent nature of these tumors often leads to a delayed diagnosis, resulting in over one-third of patients presenting with synchronous metastases. Primary tumor resection remains the only curative option for this type of tumor. In this review article, the various surgical aspects for the excision of small intestinal NETs are discussed.
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Affiliation(s)
- Amram Kupietzky
- Department of Surgery, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91240, Israel
| | - Roi Dover
- Department of Surgery, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91240, Israel
| | - Haggi Mazeh
- Department of Surgery, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91240, Israel
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Marchese U, Gaillard M, Pellat A, Tzedakis S, Abou Ali E, Dohan A, Barat M, Soyer P, Fuks D, Coriat R. Multimodal Management of Grade 1 and 2 Pancreatic Neuroendocrine Tumors. Cancers (Basel) 2022; 14:433. [PMID: 35053593 PMCID: PMC8773540 DOI: 10.3390/cancers14020433] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/11/2022] [Accepted: 01/13/2022] [Indexed: 12/13/2022] Open
Abstract
Pancreatic neuroendocrine tumors (p-NETs) are rare tumors with a recent growing incidence. In the 2017 WHO classification, p-NETs are classified into well-differentiated (i.e., p-NETs grade 1 to 3) and poorly differentiated neuroendocrine carcinomas (i.e., p-NECs). P-NETs G1 and G2 are often non-functioning tumors, of which the prognosis depends on the metastatic status. In the localized setting, p-NETs should be surgically managed, as no benefit for adjuvant chemotherapy has been demonstrated. Parenchymal sparing resection, including both duodenum and pancreas, are safe procedures in selected patients with reduced endocrine and exocrine long-term dysfunction. When the p-NET is benign or borderline malignant, this surgical option is associated with low rates of severe postoperative morbidity and in-hospital mortality. This narrative review offers comments, tips, and tricks from reviewing the available literature on these different options in order to clarify their indications. We also sum up the overall current data on p-NETs G1 and G2 management.
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Affiliation(s)
- Ugo Marchese
- Department of Digestive, Hepatobiliary and Pancreatic Surgery, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (M.G.); (S.T.); (D.F.)
| | - Martin Gaillard
- Department of Digestive, Hepatobiliary and Pancreatic Surgery, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (M.G.); (S.T.); (D.F.)
| | - Anna Pellat
- Gastroenterology and Digestive Oncology Unit, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.P.); (E.A.A.); (R.C.)
| | - Stylianos Tzedakis
- Department of Digestive, Hepatobiliary and Pancreatic Surgery, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (M.G.); (S.T.); (D.F.)
| | - Einas Abou Ali
- Gastroenterology and Digestive Oncology Unit, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.P.); (E.A.A.); (R.C.)
| | - Anthony Dohan
- Department of Radiology, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.D.); (M.B.); (P.S.)
| | - Maxime Barat
- Department of Radiology, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.D.); (M.B.); (P.S.)
| | - Philippe Soyer
- Department of Radiology, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.D.); (M.B.); (P.S.)
| | - David Fuks
- Department of Digestive, Hepatobiliary and Pancreatic Surgery, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (M.G.); (S.T.); (D.F.)
| | - Romain Coriat
- Gastroenterology and Digestive Oncology Unit, Cochin Teaching Hospital, AP-HP, Université de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France; (A.P.); (E.A.A.); (R.C.)
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Zhang D, Lu L, Zhu HJ, Xiao Y, Han XL, Du SD, Xue HD, Liu QX, Zhu ZH, Hu MM, Zhai X, Xing XP, Lu ZL. Somatostatin Treatment for Ectopic ACTH Syndrome due to Pancreatic Neuroendocrine Tumors: Review of the Literature. Int J Endocrinol 2022; 2022:6283706. [PMID: 35265125 PMCID: PMC8901294 DOI: 10.1155/2022/6283706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 01/21/2022] [Accepted: 02/01/2022] [Indexed: 12/04/2022] Open
Abstract
OBJECTIVES To analyze and summarize the effect of SSA treatment on EAS due to p-NETs (EAS-p-NETs). METHODS Thirteen patients with EAS-p-NETs treated with SSAs at our center or described in the literature were included in this study. Clinical characteristics, laboratory data, imaging studies, histopathologic results, the effect of SSA treatment, and the prognosis of these EAS-p-NET patients were evaluated. RESULTS Four males and 9 females with an average age of 42.9 years were included in the study. The mean duration of follow-up was 38.8 ± 28.2 months. As one of the combined treatment measures, SSAs controlled the levels of ACTH and cortisol in 9 of the 13 patients (69.2%). Partial response was observed in 3 patients (23.1%), stable disease in 2 patients (15.4%), and progressive disease in 6 patients (46.2%). The median time to tumor progression was 24 months, and the median overall survival was 61 months. The side effects of SSA treatment included temporary mild abdominal pain, diarrhea, gallstones, and cholecystitis. CONCLUSIONS As a supplemental therapy, SSA treatment led to clinical and biochemical improvement with a good safety profile in patients exhibiting EAS-p-NET with metastasis. However, tumor progression was inhibited by SSA treatment in only a few patients. Combined with other treatments, SSAs may improve the prognosis of patients with EAS-p-NETs.
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Affiliation(s)
- Da Zhang
- Department of Endocrinology, Air Force Medical Center, People's Liberation Army, Beijing 100142, China
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Lin Lu
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Hui-Juan Zhu
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Yu Xiao
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Xian-Lin Han
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Shun-Da Du
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Hua-Dan Xue
- Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Qing-Xing Liu
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Zhao-Hui Zhu
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Ming-Ming Hu
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Xiao Zhai
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Xiao-Ping Xing
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Zhao-Lin Lu
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
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Pérez Ramírez A, Moreno Loro A, Mohigefer Barrera J, Herrera Justiniano JM. Ectopic ACTH syndrome in a patient with Crohn�s disease. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2022; 114:690-691. [DOI: 10.17235/reed.2022.8825/2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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10
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Shaib WL, Zakka K, Penley M, Jiang R, Akce M, Wu C, Maithel SK, Sarmiento JM, Kooby D, Behera M, Alese OB, El-Rayes BF. Role of Resection of the Primary in Metastatic Well-Differentiated Neuroendocrine Tumors. Pancreas 2021; 50:1382-1391. [PMID: 35041337 PMCID: PMC10848811 DOI: 10.1097/mpa.0000000000001936] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Resection of the primary (RP) in metastatic neuroendocrine tumor (NET) is controversial. The aim was to evaluate survival outcomes for RP in metastatic NET patients. METHODS Data were obtained from US hospitals at the National Cancer Database between 2004 and 2014. χ2, analysis of variance tests, univariate, and multivariate cox proportional hazards models were evaluated. Kaplan-Meier curves and log-rank tests conducted to compare the survival difference of patient characteristics. RESULTS A total of 2361 patients were identified. The mean age was 62.1 years (standard deviation, 13 years), male-to-female ratio 1:1; 33% were small intestine, 26.3% pancreas, and 24.4% lung; 69.6% were well-differentiated; and 42.5% underwent RP. The 5-year overall survival (OS) was significantly improved for patients who underwent RP in small intestine (5-year OS, 63.9% vs 44.2%), lung (5-year OS, 65.4% vs 20.2%), and pancreas tumors (5-year OS, 75.6% vs 30.6%). On multivariate analysis, RP (hazard ratio, 0.46; 95% confidence interval, 0.29-0.73; P < 0.001), female, year of diagnosis 2010-2014, margin, Charlson-Deyo score less than 2, and age less than 51 years, were associated with better OS. CONCLUSIONS Resection of the primary in metastatic well-differentiated NET is associated with improved OS compared with no RP.
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Affiliation(s)
- Walid L. Shaib
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Katerina Zakka
- Department of Internal Medicine, Wellstar Atlanta Medical Center, Atlanta, GA
| | - McKenna Penley
- Winship Research Informatics, Emory University, Atlanta, GA
| | - Renjian Jiang
- Winship Research Informatics, Emory University, Atlanta, GA
| | - Mehmet Akce
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Christina Wu
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Shishir K. Maithel
- Department of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | | | - David Kooby
- Department of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Madhusmita Behera
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
- Winship Research Informatics, Emory University, Atlanta, GA
| | - Olatunji B. Alese
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Bassel F. El-Rayes
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
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Koch C, Koca E, Filmann N, Husmann G, Bojunga J. Time from first tumor manifestation to diagnosis in patients with GEP-NET: Results from a large German tertiary referral center. Medicine (Baltimore) 2021; 100:e27276. [PMID: 34664885 PMCID: PMC8448036 DOI: 10.1097/md.0000000000027276] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 09/01/2021] [Indexed: 11/26/2022] Open
Abstract
Patients with neuroendocrine tumors (NET) often go through a long phase between onset of symptoms and initial diagnosis.Assessment of time to diagnosis and pre-clinical pathway in patients with gastroenteropancreatic NET (GEP-NET) with regard to metastases and symptoms.Retrospective analysis of patients with GEP-NET at a tertiary referral center from 1984 to 2019; inclusion criteria: Patients ≥18 years, diagnosis of GEP-NET; statistical analysis using non-parametrical methods.Four hundred eighty-six patients with 488 tumors were identified; median age at first diagnosis (478/486, 8 unknown) was 59 years; 52.9% male patients. Pancreatic NET: 143/488 tumors; 29.3%; small intestinal NET: 145/488 tumors, 29.7%. 128/303 patients (42.2%) showed NET specific and 122/486 (25%) patients other tumor-specific symptoms. 222/279 patients had distant metastases at initial diagnosis (187/222 liver metastases). 154/488 (31.6%) of GEP-NET were incidental findings. Median time from tumor manifestation (e.g., symptoms related to NET) to initial diagnosis across all entities was 19.5 (95% CI: 12-28) days. No significant difference in patients with or without distant metastases (median 73 vs 105 days, P = .42).A large proportion of GEP-NET are incidental findings and only about half of all patients are symptomatic at the time of diagnosis. We did not find a significant influence of the presence of metastases on time to diagnosis, which shows a large variability with a median of <30 days.
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Affiliation(s)
- Christine Koch
- Goethe University Frankfurt, University Hospital, Department of Gastroenterology, Hepatology and Endocrinology, Frankfurt, Germany
| | - Esra Koca
- Goethe University Frankfurt, University Hospital, Department of Gastroenterology, Hepatology and Endocrinology, Frankfurt, Germany
| | - Natalie Filmann
- Goethe University Frankfurt, Department of Biostatistics and Mathematical Modeling, Frankfurt, Germany
| | - Gabriele Husmann
- Goethe University Frankfurt, University Hospital, University Cancer Center, Tumor Documentation, Frankfurt, Germany
| | - Jörg Bojunga
- Goethe University Frankfurt, University Hospital, Department of Gastroenterology, Hepatology and Endocrinology, Frankfurt, Germany
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12
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Mineur L, Boustany R, Vazquez L. Paraneoplastic Cushing Syndrome in Gastrointestinal Neuroendocrine Tumour. Case Rep Oncol 2021; 14:1407-1413. [PMID: 34720949 PMCID: PMC8525292 DOI: 10.1159/000518316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 07/05/2021] [Indexed: 11/19/2022] Open
Abstract
Ectopic production of adrenocorticotropic hormone (ACTH) by gastrointestinal neuroendocrine tumours (NETs) is relatively uncommon. We report a rare case of a liver metastatic G1 low-grade NET of the intestine that induced hypercortisolism after surgical resection. A 50-year-old man was admitted for an intestinal obstruction caused by a tumour of the intestine. Paraneoplastic Cushing syndrome was diagnosed more than a year later following the appearance of cushingoid symptoms, despite stable disease according to RECIST criteria but chromogranin A increase. Ketoconazole and sandostatin medical treatment and liver chemoembolization never managed to control the hypercortisolism unlike the bilateral adrenalectomy. The identification and effective management of this uncommon statement of ectopic ACTH secretion is important to improve the patient's prognosis and quality of life.
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Affiliation(s)
| | | | - Léa Vazquez
- Institute Sainte Catherine, Gastrointestinal and Liver Cancer Unit, Avignon, France
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13
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Kaçmaz E, Sarasqueta AF, van Eeden S, Dreijerink KMA, Klümpen HJ, Tanis PJ, van Dijkum EJMN, Engelsman AF. Update on Incidence, Prevalence, Treatment and Survival of Patients with Small Bowel Neuroendocrine Neoplasms in the Netherlands. World J Surg 2021; 45:2482-2491. [PMID: 33895862 PMCID: PMC8236032 DOI: 10.1007/s00268-021-06119-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/03/2021] [Indexed: 01/28/2023]
Abstract
BACKGROUND Small bowel neuroendocrine neoplasms (SB-NEN) are rare cancers, population-based studies are needed to study this rare indolent disease. The aim of this study was to explore trends in epidemiology, treatment and survival outcomes of patients with SB-NEN based on Dutch nationwide data. PATIENTS AND METHODS Patients with grade 1 or 2 SB-NEN diagnosed between 2005 and 2015 were retrieved from the Netherlands Cancer Registry and linked to The Nationwide Network and Registry of Histo- and Cytopathology in the Netherlands. Age-adjusted incidence rates were calculated based using the direct standardization method. Survival analyses were performed with the Kaplan-Meier method. RESULTS A total of 1132 patients were included for epidemiological analyses. The age-adjusted incidence rate of SB-NEN increased from 0.52 to 0.81 per 100.000 person-years between 2005 and 2015. Incidence was higher for males than females (0.93 vs. 0.69 in 2015). Most patients had grade 1 tumours (83%). Surgery was performed in 86% of patients, with resection of the primary tumour in 99%. During the study period, administration of somatostatin analogues (SSAs) increased from 5 to 22% for stage III and from 27 to 63% for stage IV disease. Mean follow-up was 61 (standard deviation 38) months. Survival data were complete for 975/1132 patients and five-year overall survival was 75% for stage I-II, 75% for stage III and 57% for stage IV. CONCLUSIONS This study shows an increase in the incidence of SB-NEN in the Netherlands. A predominant role of surgery was found in all disease stages. Use of SSAs has increased over time.
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Affiliation(s)
- Enes Kaçmaz
- Department of Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.,Amsterdam Center for Endocrine and Neuroendocrine Tumours (ACcENT), Cancer Center Amsterdam, ENETS Center of Excellence, Amsterdam, The Netherlands
| | - Arantza Farina Sarasqueta
- Amsterdam Center for Endocrine and Neuroendocrine Tumours (ACcENT), Cancer Center Amsterdam, ENETS Center of Excellence, Amsterdam, The Netherlands.,Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Susanne van Eeden
- Amsterdam Center for Endocrine and Neuroendocrine Tumours (ACcENT), Cancer Center Amsterdam, ENETS Center of Excellence, Amsterdam, The Netherlands.,Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Koen M A Dreijerink
- Amsterdam Center for Endocrine and Neuroendocrine Tumours (ACcENT), Cancer Center Amsterdam, ENETS Center of Excellence, Amsterdam, The Netherlands.,Department of Endocrinology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Heinz-Josef Klümpen
- Amsterdam Center for Endocrine and Neuroendocrine Tumours (ACcENT), Cancer Center Amsterdam, ENETS Center of Excellence, Amsterdam, The Netherlands.,Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Pieter J Tanis
- Department of Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.,Amsterdam Center for Endocrine and Neuroendocrine Tumours (ACcENT), Cancer Center Amsterdam, ENETS Center of Excellence, Amsterdam, The Netherlands
| | - Els J M Nieveen van Dijkum
- Department of Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.,Amsterdam Center for Endocrine and Neuroendocrine Tumours (ACcENT), Cancer Center Amsterdam, ENETS Center of Excellence, Amsterdam, The Netherlands
| | - Anton F Engelsman
- Amsterdam Center for Endocrine and Neuroendocrine Tumours (ACcENT), Cancer Center Amsterdam, ENETS Center of Excellence, Amsterdam, The Netherlands. .,Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, de Boelelaan 1117, 1081HV, Amsterdam, The Netherlands.
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14
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Blažević A, Brabander T, Zandee WT, Hofland J, Franssen GJH, van Velthuysen MLF, Feelders RA, De Herder WW. Evolution of the Mesenteric Mass in Small Intestinal Neuroendocrine Tumours. Cancers (Basel) 2021; 13:cancers13030443. [PMID: 33503893 PMCID: PMC7865677 DOI: 10.3390/cancers13030443] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 01/10/2021] [Accepted: 01/15/2021] [Indexed: 11/27/2022] Open
Abstract
Simple Summary Around two-thirds of patients with small intestinal neuroendocrine tumours are present with a metastatic mesenteric mass. This mass is known to cause intestinal complications, however, little is known on its development over time in the era of targeted therapy. Therefore, we conducted a retrospective study to assess the growth and response to therapy. We found that the growth of the mesenteric mass was detectable in 13.5% over a median time of 3.4 years and peptide receptor radionuclide therapy resulted in size reduction in only 3.8%. This site-specific static growth behavior is important to note when assessing disease progression and therapeutic options. Abstract Background: A metastatic mesenteric mass is a hallmark of small intestinal neuroendocrine tumours (SI-NETs). However, little is known on its development over time. Therefore, we conducted a study to assess the evolution of a SI-NET-associated mesenteric mass over time. Methods: Retrospectively, 530 patients with proven SI-NET were included. The presence and growth of a mesenteric mass was assessed using RECIST 1.1 criteria on every consecutive CT-scan until the end of follow-up or resection. Results: At baseline, a mesenteric mass was present in 64% of the patients, of whom 13.5% showed growth of the mesenteric mass with a median time to growth of 40 months. Male gender was the only independent predictor of growth (OR 2.67). Of the patients without a mesenteric mass at the first evaluation, 2.6% developed a pathological mesenteric mass. Treatment with peptide receptor radionuclide therapy (PRRT; N = 132) resulted in an objective size reduction of the mesenteric mass in 3.8%. Conclusion: The metastatic mesenteric mass in SI-NETs has a static behavior over time. Therefore, site-specific growth behavior should be taken into account when selecting target lesions and assessing disease progression and therapeutic response. PRRT appears not to be effective for size reduction of the mesenteric mass.
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Affiliation(s)
- Anela Blažević
- Department of Internal Medicine, Sector Endocrinology, ENETS Center of Excellence, Erasmus University Medical Center and Erasmus MC Cancer Institute, 3015 GD Rotterdam, The Netherlands; (W.T.Z.); (J.H.); (R.A.F.); (W.W.D.H.)
- Correspondence: ; Tel.: +31-10-7040704; Fax: +31-10-7033268
| | - Tessa Brabander
- Department of Radiology & Nuclear Medicine, ENETS Center of Excellence, Erasmus University Medical Center and Erasmus MC Cancer Institute, 3015 GD Rotterdam, The Netherlands;
| | - Wouter T. Zandee
- Department of Internal Medicine, Sector Endocrinology, ENETS Center of Excellence, Erasmus University Medical Center and Erasmus MC Cancer Institute, 3015 GD Rotterdam, The Netherlands; (W.T.Z.); (J.H.); (R.A.F.); (W.W.D.H.)
- Department of Endocrinology, University Medical Center Groningen and University of Groningen, 9700 RB Groningen, The Netherlands
| | - Johannes Hofland
- Department of Internal Medicine, Sector Endocrinology, ENETS Center of Excellence, Erasmus University Medical Center and Erasmus MC Cancer Institute, 3015 GD Rotterdam, The Netherlands; (W.T.Z.); (J.H.); (R.A.F.); (W.W.D.H.)
| | - Gaston J. H. Franssen
- Department of Surgery, ENETS Center of Excellence, Erasmus University Medical Center and Erasmus MC Cancer Institute, 3015 GD Rotterdam, The Netherlands;
| | - Marie-Louise F. van Velthuysen
- Department of Pathology, ENETS Center of Excellence, Erasmus University Medical Center and Erasmus MC Cancer Institute, 3015 GD Rotterdam, The Netherlands;
| | - Richard A. Feelders
- Department of Internal Medicine, Sector Endocrinology, ENETS Center of Excellence, Erasmus University Medical Center and Erasmus MC Cancer Institute, 3015 GD Rotterdam, The Netherlands; (W.T.Z.); (J.H.); (R.A.F.); (W.W.D.H.)
| | - Wouter W. De Herder
- Department of Internal Medicine, Sector Endocrinology, ENETS Center of Excellence, Erasmus University Medical Center and Erasmus MC Cancer Institute, 3015 GD Rotterdam, The Netherlands; (W.T.Z.); (J.H.); (R.A.F.); (W.W.D.H.)
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15
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Limouris GS. Gastro-entero-pancreatic Neuroendocrine Tumors. LIVER INTRA-ARTERIAL PRRT WITH 111IN-OCTREOTIDE 2021:21-28. [DOI: 10.1007/978-3-030-70773-6_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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16
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Grimaldi F, Vescini F, Kara E. Treatment of NET-Related Symptoms. NEUROENDOCRINE NEOPLASIA MANAGEMENT 2021:101-111. [DOI: 10.1007/978-3-030-72830-4_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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17
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Haddad T, Fard-Esfahani A, Vali R. A review of pediatric neuroendocrine tumors, their detection, and treatment by radioisotopes. Nucl Med Commun 2021; 42:21-31. [PMID: 33044400 DOI: 10.1097/mnm.0000000000001305] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Neuroendocrine tumors (NETs) are rare in childhood. Neuroblastoma is the most common pediatric extracranial solid tumor, occurring >90% in children younger than 5 years of age. Pheochromocytoma and paraganglioma are rare NETs, causing hypertension in 0.5-2% of hypertensive children. Gastroenteropancreatic NETs can occur in children and are classified into carcinoids and pancreatic tumors. Nuclear medicine procedures have an essential role both in the diagnosis and treatment of NETs. Metaiodobenzylguanidine (MIBG) labeled with radioiodine has a well-established role in diagnosis as well as therapeutic management of the neuroblastoma group of diseases. During recent decades, establishing the abundant expression of somatostatin receptors by NETs first led to scintigraphy with somatostatin analogs (i.e. Tc/In-octreotide) and, later, with the emergence of positron-emitting labeled agents (i.e. Ga-DOTATATE/DOTATOC/DOTANOC) PET scans with significantly higher detection efficiency became available. Therapy with somatostatin analogs labeled with beta emitters such as Lu-177 and Y-90, known as peptide receptor radionuclide therapy, is a promising new option in the management of patients with inoperable or metastasized NETs. In this article, pediatric NETs are briefly reviewed and the role of radioactive agents in the detection and treatment of these tumors is discussed.
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Affiliation(s)
- Tara Haddad
- Diagnostic Imaging Department, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Armaghan Fard-Esfahani
- Research Center for Nuclear Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Vali
- Diagnostic Imaging Department, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
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18
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Si Y, Guan J, Xu Y, Chen K, Kim S, Zhou L, Jaskula-Sztul R, Liu XM. Dual-Targeted Extracellular Vesicles to Facilitate Combined Therapies for Neuroendocrine Cancer Treatment. Pharmaceutics 2020; 12:E1079. [PMID: 33187322 PMCID: PMC7696983 DOI: 10.3390/pharmaceutics12111079] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 10/28/2020] [Accepted: 11/09/2020] [Indexed: 12/18/2022] Open
Abstract
Neuroendocrine (NE) cancers arise from cells within the neuroendocrine system. Chemotherapies and endoradiotherapy have been developed, but their clinical efficacy is limited. The objective of this study was to develop a dual-targeted extracellular vesicles (EV)-delivered combined therapies to treat NE cancer. Specifically, we produced EV in stirred-tank bioreactors and surface tagged both anti-somatostatin receptor 2 (SSTR 2) monoclonal antibody (mAb) and anti-C-X-C motif chemokine receptor 4 (CXCR4) mAb to generate mAbs-EV. Both live-cell confocal microscopy imaging and In Vivo Imaging System (IVIS) imaging confirmed that mAbs-EV specifically targeted and accumulated in NE cancer cells and NE tumor xenografts. Then the highly potent natural cytotoxic marine compound verrucarin A (Ver-A) with IC50 of 2.2-2.8 nM and microtubule polymerization inhibitor mertansine (DM1) with IC50 of 3.1-4.2 nM were packed into mAbs-EV. The in vivo maximum tolerated dose study performed in non-tumor-bearing mice indicated minimal systemic toxicity of mAbs-EV-Ver-A/DM1. Finally, the in vivo anticancer efficacy study demonstrated that the SSTR2/CXCR4 dual-targeted EV-Ver-A/DM1 is more effective to inhibit NE tumor growth than the single targeting and single drug. The results from this study could expand the application of EV to targeting deliver the combined potent chemotherapies for cancer treatment.
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Affiliation(s)
- Yingnan Si
- Department of Biomedical Engineering, University of Alabama at Birmingham (UAB), 1825 University Blvd, Birmingham, AL 35294, USA; (Y.S.); (J.G.); (Y.X.); (K.C.); (S.K.)
| | - JiaShiung Guan
- Department of Biomedical Engineering, University of Alabama at Birmingham (UAB), 1825 University Blvd, Birmingham, AL 35294, USA; (Y.S.); (J.G.); (Y.X.); (K.C.); (S.K.)
| | - Yuanxin Xu
- Department of Biomedical Engineering, University of Alabama at Birmingham (UAB), 1825 University Blvd, Birmingham, AL 35294, USA; (Y.S.); (J.G.); (Y.X.); (K.C.); (S.K.)
| | - Kai Chen
- Department of Biomedical Engineering, University of Alabama at Birmingham (UAB), 1825 University Blvd, Birmingham, AL 35294, USA; (Y.S.); (J.G.); (Y.X.); (K.C.); (S.K.)
| | - Seulhee Kim
- Department of Biomedical Engineering, University of Alabama at Birmingham (UAB), 1825 University Blvd, Birmingham, AL 35294, USA; (Y.S.); (J.G.); (Y.X.); (K.C.); (S.K.)
| | - Lufang Zhou
- Department of Medicine, University of Alabama at Birmingham, 703 19th Street South, Birmingham, AL 35294, USA;
| | - Renata Jaskula-Sztul
- Department of Surgery, University of Alabama at Birmingham, 1808 7th Avenue South, Birmingham, AL 35294, USA;
| | - X. Margaret Liu
- Department of Biomedical Engineering, University of Alabama at Birmingham (UAB), 1825 University Blvd, Birmingham, AL 35294, USA; (Y.S.); (J.G.); (Y.X.); (K.C.); (S.K.)
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19
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Eto K, Yoshida N, Iwagami S, Iwatsuki M, Baba H. Surgical treatment for gastrointestinal neuroendocrine tumors. Ann Gastroenterol Surg 2020; 4:652-659. [PMID: 33319155 PMCID: PMC7726685 DOI: 10.1002/ags3.12396] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 07/05/2020] [Accepted: 07/27/2020] [Indexed: 12/13/2022] Open
Abstract
Neuroendocrine tumors (NETs) are rare neoplasms, with an estimated annual incidence of 6.9/100 000. They arise from cells of the diffuse endocrine system, which are mainly dispersed throughout the gastrointestinal (GI), pancreatic, and respiratory tracts. The incidence of GI-NETs has recently begun to show a steady increase. According to the Surveillance, Epidemiology, and End Results database, 53% of patients with NETs present with localized disease, 20% with locoregional disease, and 27% with distant metastases at the time of diagnosis. Surgery is the mainstay for the treatment of locoregional GI-NETs. Endoscopic resection is an option for well-differentiated early GI-NETs, which are thought to very rarely metastasize to lymph nodes. A lesion that is technically difficult to resect via endoscopy is an indication for local resection (partial resection without lymph node dissection). GI-NETs with possible lymph node metastasis is an indication for enterectomy with lymph node dissection. For NETs with metastatic lesions, cytoreduction surgery can control hormonal hypersecretion and alleviate symptoms; therefore, cytoreduction surgery is recommended. The indications for surgery vary and are based on the organ where the NET arose; therefore, an understanding of the patient's clinical state and individualized treatment that is based on the characteristics of the patient's GI-NET is needed. This review summarizes surgical treatments of GI-NETs in each organ.
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Affiliation(s)
- Kojiro Eto
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Naoya Yoshida
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Shiro Iwagami
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Masaaki Iwatsuki
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Hideo Baba
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
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20
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Costa RDD, Kemp R, Santos JSD, Costa DAPD, Ardengh JC, Ribas-Filho JM, Ribas CAPM. THE ROLE OF CONVENTIONAL ECHOENDOSCOPY (EUS) IN THERAPEUTIC DECISIONS IN PATIENTS WITH NEUROENDOCRINE GASTROINTESTINAL TUMORS. ACTA ACUST UNITED AC 2020; 33:e1512. [PMID: 32844878 PMCID: PMC7448866 DOI: 10.1590/0102-672020190001e1512] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 04/23/2020] [Indexed: 12/14/2022]
Abstract
Background:
Gastrointestinal neuroendocrine tumors are rare, usually presented as
subepithelial or polypoid tumors. Accurate diagnosis and indication of the
type of resection are still challenging.
Aim:
To determine the effectiveness of echoendoscopy in determining the depth of
the lesions (T) identified by endoscopy in order to evaluate surgical and/or
endoscopic indication, and to evaluate the results of endoscopic removal in
the medium term.
Methods:
Twenty-seven patients were included, all of whom underwent echoendoscopy for
TN tumor staging and the evaluation of possible endoscopic resection. The
parameters were: lesion size, origin layer, depth of involvement and
identified perilesional adenopathies. The inclusion criteria for endoscopic
resection were: 1) high surgical risk; 2) those with NET <2 cm; 3)
absence of impairment of the muscle itself; and 4) absence of perilesional
adenopathies in echoendoscopy and in others without distant metastases.
Exclusion criteria were TNE> 2 cm; those with infiltration of the muscle
itself; with perilesional adenopathies and distant metastases. The
techniques used were: resection with polypectomy loop; mucosectomy with
saline injection; and mucosectomy after ligation with an elastic band. The
anatomopathological study of the specimens included evaluation of the
margins and immunohistochemistry (chromogranin, synaptophysin and Ki 67) to
characterize the tumor. Follow-up was done at 1, 6 and 12 months.
Results:
Resections with polypectomy loop were performed in 15 patients; mucosectomy
in five; mucosectomy and ligation with elastic band in three and the
remaining four were referred for surgery. The anatomopathological specimens
and immunohistochemical analyzes showed positive chromogranin and
synaptophysin, while Ki 67 was less than 5% among all cases. The medium-term
follow-up revealed three recurrences. The average size of tumors in the
stomach was 7.6 mm and in the duodenum 7.2 mm. Well-demarcated, hypoechoic,
homogeneous lesions occurred in 75%; mucous layer in 80%; and the deep and
submucosal mucosa in 70%.
Conclusions:
Echoendoscopy proved to be a good method for the study of subepithelial
lesions, being able to identify the layer affected by the neoplasm, degree
of invasion, echogenicity, heterogeneity, size of the lesion and
perilesional lymph node involvement and better indicate the treatment
option.
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Affiliation(s)
- Rodrigo Dias da Costa
- Medical Research Institute, University Evangelical Hospital of Curitiba, Evangelical Faculty of Paraná, Curitiba, PR, Brazil
| | - Rafael Kemp
- Hospital das Clínicas, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - José Sebastião Dos Santos
- Hospital das Clínicas, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | | | - José Celso Ardengh
- Medical Research Institute, University Evangelical Hospital of Curitiba, Evangelical Faculty of Paraná, Curitiba, PR, Brazil
| | - Jurandir Marcondes Ribas-Filho
- Medical Research Institute, University Evangelical Hospital of Curitiba, Evangelical Faculty of Paraná, Curitiba, PR, Brazil
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21
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Ahmed M. Gastrointestinal neuroendocrine tumors in 2020. World J Gastrointest Oncol 2020; 12:791-807. [PMID: 32879660 PMCID: PMC7443843 DOI: 10.4251/wjgo.v12.i8.791] [Citation(s) in RCA: 121] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 05/26/2020] [Accepted: 07/19/2020] [Indexed: 02/05/2023] Open
Abstract
Gastrointestinal neuroendocrine tumors are rare slow-growing tumors with distinct histological, biological, and clinical characteristics that have increased in incidence and prevalence within the last few decades. They contain chromogranin A, synaptophysin and neuron-specific enolase which are necessary for making a diagnosis of neuroendocrine tumor. Ki-67 index and mitotic index correlate with cellular proliferation. Serum chromogranin A is the most commonly used biomarker to assess the bulk of disease and monitor treatment and is raised in both functioning and non-functioning neuroendocrine tumors. Most of the gastrointestinal neuroendocrine tumors are non-functional. World Health Organization updated the classification of neuroendocrine tumors in 2017 and renamed mixed adenoneuroendocrine carcinoma into mixed neuroendocrine neoplasm. Gastric neuroendocrine tumors arise from enterochromaffin like cells. They are classified into 4 types. Only type I and type II are gastrin dependent. Small intestinal neuroendocrine tumor is the most common small bowel malignancy. More than two-third of them occur in the terminal ileum within 60 cm of ileocecal valve. Patients with small intestinal neuroendrocrine tumors frequently show clinical symptoms and develop distant metastases more often than those with neuroendocrine tumors of other organs. Duodenal and jejuno-ileal neuroendocrine tumors are distinct biologically and clinically. Carcinoid syndrome generally occurs when jejuno-ileal neuroendocrine tumors metastasize to the liver. Appendiceal neuroendocrine tumors are generally detected after appendectomy. Colonic neuroendocrine tumors generally present as a large tumor with local or distant metastasis at the time of diagnosis. Rectal neuroendocrine tumors are increasingly being diagnosed since the implementation of screening colonoscopy in 2000. Gastrointestinal neuroendocrine tumors are diagnosed and staged by endoscopy with biopsy, endoscopic ultrasound, serology of biomarkers, imaging studies and functional somatostatin scans. Various treatment options are available for curative and palliative treatment of gastrointestinal neuroendocrine tumors.
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Affiliation(s)
- Monjur Ahmed
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Thomas Jefferson University, Philadelphia, PA 19107, United States
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22
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Gut P. Oncological management of advanced neuroendocrine tumours (Review). Mol Clin Oncol 2020; 13:8. [PMID: 32754322 DOI: 10.3892/mco.2020.2078] [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: 02/07/2020] [Accepted: 06/02/2020] [Indexed: 11/06/2022] Open
Abstract
The oncological principles of managing patients with gastroenteropancreatic neuroendocrine tumours (GEP-NETs) depends on a number of factors and requires a multidisciplinary approach. Recent data have provided additional therapeutic options, including biotherapy, traditional chemotherapy and novel targeted agents. Somatostatin analogues (SSAs) inhibit multiple cellular functions, including secretion, motility and proliferation. Interferon appears to act through several mechanisms, with antisecretory effects, immunomodulatory effects and antiproliferative functions, the latter inhibiting direct growth or attenuating angiogenesis. Opinions on when to commence chemotherapy for well differentiated GEP-NETs varies among experts. In previous years, reserving chemotherapy for patients with progressive disease (well differentiated, inoperable and/or metastatic GEP-NETs) was reasonably well argued for. Most well differentiated endocrine tumours are richly vascular and many express vascular endothelial growth factor (VEGF) receptors. In a xenograft model of a human carcinoid, treatment with an anti-VEGF monoclonal antibody was revealed to inhibit tumour growth and metastasis. As the role of angiogenesis and hypoxic-associated factors appears to be associated with tumour aggressiveness, strategies using agents which target angiogenesis have been developed. Mammalian target of rapamycin (mTOR) is a conserved serine-threonine kinase that regulates the cell cycle and metabolism in response to environmental factors. In addition, mTOR inhibition suppression was demonstrated to suppress NET growth. Each patient requires an individual approach to the choice of therapy, which should be selected depending on the severity of disease.
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Affiliation(s)
- Paweł Gut
- Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, Poznań 60-355, Poland
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23
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Rajaretnam NS, Meyer-Rochow GY. Surgical Management of Primary Small Bowel NET Presenting Acutely with Obstruction or Perforation. World J Surg 2020; 45:203-207. [PMID: 32696097 DOI: 10.1007/s00268-020-05689-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/01/2020] [Indexed: 11/30/2022]
Abstract
Up to 35% of small bowel neuroendocrine tumors (SBNETs) may present with an acute intra-abdominal complication including obstruction, perforation, bleeding or ischemia and may require emergency surgical treatment in centers not normally accustomed to managing patients with neuroendocrine tumors. These patients may have a known diagnosis of SBNET, be suspected as suffering from SBNET or have SBNET diagnosed as an incidental finding on presenting radiology or postoperative pathology. Perioperative priorities include obtaining both clinical and radiological staging with cross-sectional imaging and clinical examination, screening for the presence of carcinoid syndrome and right-sided cardiac disease and assessment of prognosis. Intraoperatively careful attention should be paid to noting the presence and location of multifocal primary and metastatic disease. Ideally, surgical resection with mesenteric lymph node dissection is the treatment of choice for obstructing and perforating lesions. Extended lymphadenectomy along the SMA, SMV and behind the pancreas should be primarily considered an elective procedure. In unwell patients with advanced disease surgical bypass (jejuno or ileocolic) or proximal defunctioning should be undertaken but, given the excellent long-term survivals in patients with stage IV disease, could be considered bridging procedures to elective resection following formal staging and multidisciplinary review.
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Affiliation(s)
- N S Rajaretnam
- Department of Surgery, Waikato Hospital, Private Bag 3200, Hamilton, 3204, New Zealand
| | - G Y Meyer-Rochow
- Department of Surgery, Waikato Hospital, Private Bag 3200, Hamilton, 3204, New Zealand.
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Narayan A, Yan Y, Lisok A, Brummet M, Pomper MG, Lesniak WG, Dannals RF, Merino VF, Azad BB. A side-by-side evaluation of [ 18F]FDOPA enantiomers for non-invasive detection of neuroendocrine tumors by positron emission tomography. Oncotarget 2019; 10:5731-5744. [PMID: 31645896 PMCID: PMC6791383 DOI: 10.18632/oncotarget.27184] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 08/05/2019] [Indexed: 12/11/2022] Open
Abstract
Neuroendocrine tumors (NETs) are an extremely heterogenous group of malignancies with variable clinical behavior. Molecular imaging of patients with NETs allows for effective patient stratification and treatment guidance and is crucial in selection of targeted therapies. Positron emission tomography (PET) with the radiotracer L-[18F]FDOPA is progressively being utilized for non-invasive in vivo visualization of NETs and pancreatic β-cell hyperplasia. While L-[18F]FDOPA-PET is a valuable tool for disease detection and management, it also exhibits significant diagnostic limitations owing to its inherent physiological uptake in off-target tissues. We hypothesized that the D-amino acid structural isomer of that clinical tracer, D-[18F]FDOPA, may exhibit superior clearance capabilities owing to a reduced in vivo enzymatic recognition and enzyme-mediated metabolism. Here, we report a side-by-side evaluation of D-[18F]FDOPA with its counterpart clinical tracer, L-[18F]FDOPA, for the non-invasive in vivo detection of NETs. In vitro evaluation in five NET cell lines, including invasive small intestinal neuroendocrine carcinomas (STC-1), insulinomas (TGP52 and TGP61), colorectal adenocarcinomas (COLO-320) and pheochromocytomas (PC12), generally indicated higher overall uptake levels of L-[18F]FDOPA, compared to D-[18F]FDOPA. While in vivo PET imaging and ex vivo biodistribution studies in PC12, STC-1 and COLO-320 mouse xenografts further supported our in vitro data, they also illustrated lower off-target retention and enhanced clearance of D-[18F]FDOPA from healthy tissues. Cumulatively our results indicate the potential diagnostic applications of D-[18F]FDOPA for malignancies where the utility of L-[18F]FDOPA-PET is limited by the physiological uptake of L-[18F]FDOPA, and suggest D-[18F]FDOPA as a viable PET imaging tracer for NETs.
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Affiliation(s)
- Athira Narayan
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Yu Yan
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Ala Lisok
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Mary Brummet
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Martin G Pomper
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Wojciech G Lesniak
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Robert F Dannals
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Vanessa F Merino
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Babak Behnam Azad
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD, USA
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Sansone A, Lauretta R, Vottari S, Chiefari A, Barnabei A, Romanelli F, Appetecchia M. Specific and Non-Specific Biomarkers in Neuroendocrine Gastroenteropancreatic Tumors. Cancers (Basel) 2019; 11:E1113. [PMID: 31382663 PMCID: PMC6721814 DOI: 10.3390/cancers11081113] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 07/31/2019] [Accepted: 08/02/2019] [Indexed: 12/11/2022] Open
Abstract
The diagnosis of neuroendocrine tumors (NETs) is a challenging task: Symptoms are rarely specific, and clinical manifestations are often evident only when metastases are already present. However, several bioactive substances secreted by NETs can be included for diagnostic, prognostic, and predictive purposes. Expression of these substances differs between different NETs according to the tumor hormone production. Gastroenteropancreatic (GEP) NETs originate from the diffuse neuroendocrine system of the gastrointestinal tract and pancreatic islets cells: These tumors may produce many non-specific and specific substances, such as chromogranin A, insulin, gastrin, glucagon, and serotonin, which shape the clinical manifestations of the NETs. To provide an up-to-date reference concerning the different biomarkers, as well as their main limitations, we reviewed and summarized existing literature.
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Affiliation(s)
- Andrea Sansone
- Section of Medical Pathophysiology, Food Science and Endocrinology, Dept. of Experimental Medicine, Sapienza University of Rome, 00165 Rome, Italy
| | - Rosa Lauretta
- Internal Medicine, Angioloni Hospital, San Piero in Bagno, 47026 Forlì-Cesena, Italy
| | - Sebastiano Vottari
- Endocrinology Unit, Regina Elena National Cancer Institute IRCCS, Rome 00144, Italy
| | - Alfonsina Chiefari
- Endocrinology Unit, Regina Elena National Cancer Institute IRCCS, Rome 00144, Italy
| | - Agnese Barnabei
- Endocrinology Unit, Regina Elena National Cancer Institute IRCCS, Rome 00144, Italy
| | - Francesco Romanelli
- Section of Medical Pathophysiology, Food Science and Endocrinology, Dept. of Experimental Medicine, Sapienza University of Rome, 00165 Rome, Italy
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Yoon SE, Kim JH, Lee SJ, Lee J, Park SH, Park JO, Lim HY, Kang WK, Park YS, Kim ST. The impact of primary tumor site on outcomes of treatment with etoposide and cisplatin in grade 3 gastroenteropancreatic neuroendocrine carcinoma. J Cancer 2019; 10:3140-3144. [PMID: 31289584 PMCID: PMC6603380 DOI: 10.7150/jca.30355] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 05/03/2019] [Indexed: 11/06/2022] Open
Abstract
Background: Gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) is a heterogeneous disease in terms of embryonic origin, aggressiveness, prognosis, and genomic profiling. Data regarding the efficacy of etoposide and cisplatin (EP) as a standard treatment of the primary tumor site in GEP-NEC are limited. Materials and Methods: We analyzed 64 patients with histopathologically confirmed metastatic GEP-NEC who received EP at Samsung Medical Center, Seoul, Korea, between January 2010 and January 2018. Based on primary tumor site, outcome of treatment with EP was evaluated. Results: Primary sites included 22 foregut-derived GEP-NECs (stomach, n = 6; duodenum, n = 4; pancreas, n = 12), 4 midgut-derived GEP-NECs, 5 hindgut-derived GEP-NECs of the rectum, 25 GEP-NECs originating from the hepatobiliary (HB) tract, and 12 GEP-NECs involving only intra-abdominal lymph nodes. No patient had a complete response (CR) and 17 had a partial response (PR), resulting in a 27.9% response rate (RR). When evaluating the efficacy of EP based on primary tumor site, the RR was most favorable in GEP-NECs involving only intra-abdominal lymph nodes, followed by GEP-NECs originating from foregut, midgut, HB, and hindgut. However, no statistically significant difference was observed for RR based on primary tumor site (P = 0.821). Similarly, no significant differences were found for progression-free survival (PFS) among patients with GEP-NECs arising from various primary tumor sites. Conclusion: Results from this study showed that RR and PFS associated with EP treatment were not different based on the primary tumor site in patients with advanced or metastatic GEP-NEC.
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Affiliation(s)
- Sang Eun Yoon
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jung Hoon Kim
- Division of Hematology/Oncology, Department of Internal Medicine, School of Medicine Gyeongsang National University, Jinju, Korea
| | - Su Jin Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Se Hoon Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joon Oh Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ho Yeong Lim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Won Ki Kang
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young Suk Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Patient Preferences Concerning Alternative Treatments for Neuroendocrine Tumors: Results of the "PIANO-Study". Int J Technol Assess Health Care 2019; 35:243-251. [PMID: 31044688 DOI: 10.1017/s0266462319000217] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECTIVES Neuroendocrine tumors (NETs) are rare, slow-growing malignant tumors. So far, there are no data on patient preferences regarding its therapy. This empirical study aimed to elicit patient preferences in the drug treatment of NET. METHODS Based on qualitative patient interviews and an analytic hierarchy process, six patient-relevant attributes were analyzed and weighted using a discrete-choice experiment. Patients were recruited with the help of a NET support group. An experimental 3*3 + 6*3 -MNL design was created using NGene. The design consisted of eighty-four choices, divided into seven blocks. Participants were randomly assigned to these blocks. The analysis included random parameter logit and latent class models. RESULTS A total of 275 participants (51.6 percent female; mean age, 58.4 years) were included. The preference analysis within the random parameter logit model, taking into account the 95 percent confidence interval, showed predominance for the attribute "overall survival." The attributes "response to treatment" and "stabilization of tumor growth" followed. The side effects "nausea/vomiting" and "diarrhea" were considered of relatively equal importance. Latent class analysis of possible subgroup differences revealed three preference patterns. CONCLUSIONS Preferences can influence therapeutic decisions. Preference analyses indicated that "overall survival" had the strongest influence, with participants clearly weighing outcome attributes higher than side effect attributes. In conclusion, mono-criterial decisions would not fully reflect patient perspectives.
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Mafficini A, Scarpa A. Genetics and Epigenetics of Gastroenteropancreatic Neuroendocrine Neoplasms. Endocr Rev 2019; 40:506-536. [PMID: 30657883 PMCID: PMC6534496 DOI: 10.1210/er.2018-00160] [Citation(s) in RCA: 131] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Accepted: 12/27/2018] [Indexed: 12/11/2022]
Abstract
Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are heterogeneous regarding site of origin, biological behavior, and malignant potential. There has been a rapid increase in data publication during the last 10 years, mainly driven by high-throughput studies on pancreatic and small intestinal neuroendocrine tumors (NETs). This review summarizes the present knowledge on genetic and epigenetic alterations. We integrated the available information from each compartment to give a pathway-based overview. This provided a summary of the critical alterations sustaining neoplastic cells. It also highlighted similarities and differences across anatomical locations and points that need further investigation. GEP-NENs include well-differentiated NETs and poorly differentiated neuroendocrine carcinomas (NECs). NENs are graded as G1, G2, or G3 based on mitotic count and/or Ki-67 labeling index, NECs are G3 by definition. The distinction between NETs and NECs is also linked to their genetic background, as TP53 and RB1 inactivation in NECs set them apart from NETs. A large number of genetic and epigenetic alterations have been reported. Recurrent changes have been traced back to a reduced number of core pathways, including DNA damage repair, cell cycle regulation, and phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling. In pancreatic tumors, chromatin remodeling/histone methylation and telomere alteration are also affected. However, also owing to the paucity of disease models, further research is necessary to fully integrate and functionalize data on deregulated pathways to recapitulate the large heterogeneity of behaviors displayed by these tumors. This is expected to impact diagnostics, prognostic stratification, and planning of personalized therapy.
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Affiliation(s)
- Andrea Mafficini
- ARC-Net Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.,Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Aldo Scarpa
- ARC-Net Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.,Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
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Papalampros A, Mpaili E, Moris D, Sarlanis H, Tsoli M, Felekouras E, Trafalis DT, Kontos M. A case report on metastatic ileal neuroendocrine neoplasm to the breast masquerading as primary breast cancer: A diagnostic challenge and management dilemma. Medicine (Baltimore) 2019; 98:e14989. [PMID: 31008928 PMCID: PMC6494217 DOI: 10.1097/md.0000000000014989] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
RATIONALE Metastatic neuroendocrine neoplasms (NENs) to the breast are very rare entities comprising only 1% to 2% of all metastatic breast tumors. In this article, we describe a case of a neuroendocrine ileal neoplasm metastatic to breast and liver, with breast metastatic tumor to be the initial manifestation of the disease. PATIENT CONCERNS We herein report a rare case of a female patient admitted to our department with a palpable painful mass on her left breast. DIAGNOSIS The surgical and histological investigation revealed a metastatic neuroendocrine neoplasm to the breast originated from terminal ileum. INTERVENTIONS A left lumpectomy, right hemicolectomy, cholecystectomy, left hepatectomy along with liver metastasectomies (V, VI, VIII) plus radiofrequency ablation of lesions to the right liver lobe plus standard lymphadenectomy was performed. OUTCOMES Considering the advanced stage of the disease, the patient received an adjuvant therapy of somatostatin analog plus everolimus. Under the guidance of oncological consultation, patients follow-up with CT and MRI scan and clinical re-evaluations in the first 3 and 6 months, substantiates no evidence of recurrence and she presents herself asymptomatic. LESSONS An appropriate level of suspicion and selective immunohistochemistry in these cases, particularly where no prior history of a known primary neuroendocrine neoplasm occurs, may help to diagnose a previously undetected neuroendocrine tumor elsewhere in the body and provide guidance for the appropriate treatment selection.
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Affiliation(s)
- Alexandros Papalampros
- 1st Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Eustratia Mpaili
- 1st Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Demetrios Moris
- Department of Surgery, Duke University Medical Center, Duke University, Durham, NC
| | | | - Marina Tsoli
- 1st Propaedeutic Department of Internal Medicine
| | - Evangelos Felekouras
- 1st Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios T. Trafalis
- Department of Pharmacology, Unit of Clinical Pharmacology and Therapeutic Oncology, Medical School, National and Kapodistrian University of Athens
| | - Michael Kontos
- 1st Department of Surgery, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
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30
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Zaidi MY, Lopez-Aguiar AG, Dillhoff M, Beal E, Poultsides G, Makris E, Rocha F, Crown A, Idrees K, Marincola Smith P, Nathan H, Beems M, Abbott D, Barrett JR, Fields RC, Davidson J, Cardona K, Maithel SK. Prognostic Role of Lymph Node Positivity and Number of Lymph Nodes Needed for Accurately Staging Small-Bowel Neuroendocrine Tumors. JAMA Surg 2019; 154:134-140. [PMID: 30383112 PMCID: PMC6439661 DOI: 10.1001/jamasurg.2018.3865] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Importance Little information is available regarding the minimum number of lymph nodes needed to accurately stage patients when performing a mesenteric lymphadenectomy for small-bowel neuroendocrine tumors. Objectives To determine the prognostic role of lymph node positivity and the ideal number of lymph nodes for accurately staging patients with small-bowel neuroendocrine tumors. Design, Setting, and Participants This case series from the US Neuroendocrine Tumor Study Group, a collaboration among 8 US-based, academic tertiary care referral centers, obtained demographic, perioperative, and pathologic data from the group's database, Social Security Death Index, and publicly available obituaries. All patients in these institutions with small-bowel neuroendocrine tumors who underwent curative-intent surgical resection of a primary tumor between January 1, 2000, and December 31, 2015, were included (n = 199). Patients with duodenal or ampullary tumors, other nonneuroendocrine concurrent malignant neoplasms, mortality of fewer than 30 days after the surgical procedure, and distant metastatic disease were excluded. Data analysis was conducted from September 1, 2017, to December 1, 2017. Main Outcomes and Measures Primary study outcome was recurrence-free survival. Hypothesis was generated after data collection and data entry into the US Neuroendocrine Tumor Study Group database. Results Of the 199 patients included, 112 (56.3%) were male and 87 (43.7%) female with a mean (SD) age of 60.3 (12.5) years and a mean (SD) body mass index of 29.5 (6.0). One hundred fifty-four patients (77.4%) had lymph node-positive disease. No difference in 3-year recurrence-free survival was found between patients with lymph node-positive and lymph node-negative disease. Patients with 4 positive lymph nodes had a worse 3-year recurrence-free survival compared with those with 1 to 3 or 0 positive lymph nodes (81.6% vs 91.4% vs 92.1%; P = .01). When examining patients with fewer than 8 resected lymph nodes, no difference in 3-year recurrence-free survival was observed among patients with 4 or more, 1 to 3, or 0 positive lymph nodes (100% vs 93.8% vs 91.7%; P = .87). Retrieval of 8 or more lymph nodes, however, accurately discriminated patients with 4 or more, 1 to 3, or 0 positive lymph nodes (3-year recurrence-free survival: 79.9% vs 89.6% vs 92.9%; P = .05). Conclusions and Relevance The findings from this study suggest that, for patients undergoing curative-intent resection of small-bowel neuroendocrine tumors, accurate lymph node staging requires a minimum of 8 lymph nodes for examination, and 4 or more positive lymph nodes are associated with decreased 3-year recurrence-free survival compared with 1 to 3 or 0 positive lymph nodes; a thorough regional lymphadenectomy may be critical for accurate staging and management of this disease.
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Affiliation(s)
- Mohammad Y. Zaidi
- Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, Georgia
| | - Alexandra G. Lopez-Aguiar
- Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, Georgia
| | - Mary Dillhoff
- Division of Surgical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus
| | - Eliza Beal
- Division of Surgical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus
| | - George Poultsides
- Department of Surgery, Stanford University Medical Center, Stanford, California
| | - Eleftherios Makris
- Department of Surgery, Stanford University Medical Center, Stanford, California
| | - Flavio Rocha
- Department of Surgery, Virginia Mason Medical Center, Seattle, Washington
| | - Angelena Crown
- Department of Surgery, Virginia Mason Medical Center, Seattle, Washington
| | - Kamran Idrees
- Division of Surgical Oncology, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Paula Marincola Smith
- Division of Surgical Oncology, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Hari Nathan
- Division of Hepatopancreatobiliary and Advanced Gastrointestinal Surgery, Department of Surgery, University of Michigan, Ann Arbor
| | - Megan Beems
- Division of Hepatopancreatobiliary and Advanced Gastrointestinal Surgery, Department of Surgery, University of Michigan, Ann Arbor
| | - Daniel Abbott
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison
| | - James R. Barrett
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison
| | - Ryan C. Fields
- Department of Surgery, Washington University School of Medicine in St Louis, St Louis, Missouri
| | - Jesse Davidson
- Department of Surgery, Washington University School of Medicine in St Louis, St Louis, Missouri
| | - Kenneth Cardona
- Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, Georgia
| | - Shishir K. Maithel
- Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, Georgia
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Fouché M, Bouffard Y, Le Goff MC, Prothet J, Malavieille F, Sagnard P, Christin F, Hayi-Slayman D, Pasquer A, Poncet G, Walter T, Rimmelé T. Intraoperative carcinoid syndrome during small-bowel neuroendocrine tumour surgery. Endocr Connect 2018; 7:1245-1250. [PMID: 30352418 PMCID: PMC6240144 DOI: 10.1530/ec-18-0324] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 10/04/2018] [Indexed: 11/11/2022]
Abstract
Only few descriptions of intraoperative carcinoid syndrome (ioCS) have been reported. The primary objective of this study was to describe ioCS. A second aim was to identify risk factors of ioCS. We retrospectively analysed patients operated for small-bowel neuroendocrine tumour in our institution between 2007 and 2015, and receiving our preventive local regimen of octreotide continuous administration. ioCS was defined as highly probable in case of rapid (<5 min) arterial blood pressure changes ≥40%, not explained by surgical/anaesthetic management and regressive ≥20% after octreotide bolus injection. Probable cases were ioCS which did not meet all criteria of highly-probable ioCS. Suspected ioCS were detected on the anaesthesia record by an injection of octreotide due to a manifestation which did not meet the criteria for highly-probable or probable ioCS. A total of 81 patients (liver metastases: 59, prior carcinoid syndrome: 49, carcinoid heart disease: 7) were included; 139 ioCS occurred in 45 patients: 45 highly probable, 67 probable and 27 suspected. ioCs was hypertensive (91%) and/or hypotensive (29%). There was no factor, including the use of vasopressors, significantly associated with the occurrence of an ioCS. All surgeries were completed and one patient died from cardiac failure 4 days after surgery. After preoperative octreotide continuous infusion, ioCS were mainly hypertensive. No ioCS risk factors, including vasopressor use, were identified. No intraoperative carcinoid crisis occurred, suggesting the clinical relevance of a standardized octreotide prophylaxis protocol.
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Affiliation(s)
- Myrtille Fouché
- Department of Anaesthesiology and Critical Care Medicine, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
- Correspondence should be addressed to M Fouché:
| | - Yves Bouffard
- Department of Anaesthesiology and Critical Care Medicine, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | - Mary-Charlotte Le Goff
- Department of Anaesthesiology and Critical Care Medicine, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | - Johanne Prothet
- Department of Anaesthesiology and Critical Care Medicine, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | - François Malavieille
- Department of Anaesthesiology and Critical Care Medicine, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | - Pierre Sagnard
- Department of Anaesthesiology and Critical Care Medicine, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | - Françoise Christin
- Department of Anaesthesiology and Critical Care Medicine, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | - Davy Hayi-Slayman
- Department of Anaesthesiology and Critical Care Medicine, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | - Arnaud Pasquer
- Department of Visceral Surgery, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | - Gilles Poncet
- Department of Visceral Surgery, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | - Thomas Walter
- Department of Hepatogastroenterology and Oncology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | - Thomas Rimmelé
- Department of Anaesthesiology and Critical Care Medicine, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
- EA 7426 Hospices Civils de Lyon-University Claude Bernard Lyon 1-Biomérieux ‘Pathophysiology of Injury-Induced Immunosuppression’ Pi3, Lyon, France
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32
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Health-Related Quality of Life After Surgery for Small Intestinal Neuroendocrine Tumours. World J Surg 2018; 42:3231-3239. [DOI: 10.1007/s00268-018-4638-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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33
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Wu L, Fu J, Wan L, Pan J, Lai S, Zhong J, Chung DC, Wang L. Survival outcomes and surgical intervention of small intestinal neuroendocrine tumors: a population based retrospective study. Oncotarget 2018; 8:4935-4947. [PMID: 27903960 PMCID: PMC5354882 DOI: 10.18632/oncotarget.13632] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Accepted: 11/08/2016] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Small intestinal neuroendocrine tumors (SiNETs) without distant metastasis typically behave in an indolent manner, but there can be heterogeneity. We aimed to define the survival outcomes and impacts of surgical intervention. METHODS A retrospective cohort study was conducted by using data from the Surveillance, Epidemiology, and End Results (SEER) database. Clinicopathologic features were analyzed in 4407 patients between 2000 and 2012. The cancer specific survival (CSS) was calculated by the Kaplan-Meier method. Multivariable Cox regression models with hazard ratios (HRs) were constructed to analyze survival outcomes and risk factors. RESULTS The adjusted incidence of early SiNETs is 1.3/100,000. Tumors are most commonly located in the ileum and are small (≤ 2 cm). The 5-year and 10-year CSS rates were 95.0% and 88.5%, respectively. Age > 50 years, large tumor size (> 2cm), poor differentiation, advanced T classification, and absence of surgical treatment were independent predictors of poor survival. Stratified analysis indicated that surgery significantly improved survival in patients that were white (HR, 0.45), > 50 years old (HR, 0.61), had duodenal tumors (HR, 0.43), large tumors (> 2cm) (HR, 0.32), advanced T classification (T3: HR, 0.29; T4: HR, 0.18) or well differentiation (HR, 0.55). There was no significant survival difference between local resection and radical resection (P =0.884). CONCLUSIONS Early SiNETs have a favorable prognosis. Surgical resection may improve outcomes, particularly in older patients and those with large tumors. More aggressive resections couldn't improve outcomes.
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Affiliation(s)
- Lunpo Wu
- Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.,Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Jianfei Fu
- Department of Oncology, Zhejiang University Jinhua Hospital, Jinhua, Zhejiang Province, China
| | - Li Wan
- Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.,Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Jie Pan
- Department of Endocrinology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Sanchuan Lai
- Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province, China.,Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Jing Zhong
- Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.,Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Daniel C Chung
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Liangjing Wang
- Department of Gastroenterology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.,Institution of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang Province, China
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Sporadic Gastroenteropancreatic Neuroendocrine Tumors. Updates Surg 2018. [DOI: 10.1007/978-88-470-3955-1_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Zandee WT, de Herder WW. The Evolution of Neuroendocrine Tumor Treatment Reflected by ENETS Guidelines. Neuroendocrinology 2018; 106:357-365. [PMID: 29320780 PMCID: PMC6067804 DOI: 10.1159/000486096] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 12/05/2017] [Indexed: 12/11/2022]
Abstract
In 2016, the third version of guidelines for the diagnosis and treatment of neuroendocrine tumors (NETs) has been published by the European Neuroendocrine Tumor Society (ENETS). These guidelines reflect the progress in treatment of NETs, and by comparing the newest guidelines with the first guidelines of 2001, this progress can be clearly recognized. Diagnostic accuracy has been increased by the introduction of PET-CT with Ga-labelled somatostatin analogs, and multiple new treatments and treatment schedules have been developed, like peptide receptor radiotherapy with radiolabeled somatostatin analogs, or targeted therapies. Evidence and indications for these therapies are discussed in the ENETS guidelines. In this review, we aim to show the progress in NET diagnosis and treatment on the basis of the advances in the guidelines, but also to discuss the unsolved questions and unmet needs which still remain.
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Affiliation(s)
- Wouter T. Zandee
- *Wouter T. Zandee, MD, Department of Internal Medicine, Endocrinology Sector, Erasmus Medical Center, ‘s-Gravendijkwal 230, NL–3015 CE Rotterdam (The Netherlands), E-Mail
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Petersenn S, Koch CA. Neuroendocrine neoplasms - still a challenge despite major advances in clinical care with the development of specialized guidelines. Rev Endocr Metab Disord 2017; 18:373-378. [PMID: 29480376 DOI: 10.1007/s11154-018-9442-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Stephan Petersenn
- ENDOC Center for Endocrine Tumors, Erik-Blumenfeld-Platz 27a, 22587, Hamburg, Germany.
| | - Christian A Koch
- Medicover Oldenburg MVZ, Oldenburg, Germany
- Department of Medicine III, Technical University of Dresden, Dresden, Germany
- University of Louisville, Louisville, KY, USA
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Oronsky B, Ma PC, Morgensztern D, Carter CA. Nothing But NET: A Review of Neuroendocrine Tumors and Carcinomas. Neoplasia 2017; 19:991-1002. [PMID: 29091800 PMCID: PMC5678742 DOI: 10.1016/j.neo.2017.09.002] [Citation(s) in RCA: 453] [Impact Index Per Article: 56.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 09/06/2017] [Accepted: 09/07/2017] [Indexed: 02/07/2023]
Abstract
This review covers the diverse topic of neuroendocrine neoplasms (NENs), a relatively rare and heterogeneous tumor type, comprising ~2% of all malignancies, with a prevalence of <200,000 in the United States, which makes it an orphan disease (Basu et al., 2010).1 For functional purposes, NENs are divided into two groups on the basis of clinical behavior, histology, and proliferation rate: well differentiated (low grade to intermediate grade) neuroendocrine tumors and poorly differentiated (high grade) neuroendocrine carcinoma (Bosman et al., 2010)2; this histological categorization/dichotomization is highly clinically relevant with respect to impact on treatment and prognosis even though it is not absolute since a subset of tumors with a low-grade appearance behaves similarly to high-grade lesions. Given the relative dearth of evidenced-based literature about this orphan disease as a whole (Modlin et al., 2008),3 since the focus of most articles is on particular anatomic subtypes of NENs (i.e., gastroenteropancreatic or pulmonary), the purpose of this review is to summarize the presentation, pathophysiology, staging, current standard of care treatments, and active areas of current research.
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Affiliation(s)
- Bryan Oronsky
- EpicentRx Inc, 4445 Eastgate Mall, Suite 200, San Diego, CA 92121, USA.
| | - Patrick C Ma
- West Virginia University, Mary Babb Randolph Cancer Center, 8901 Wisconsin Ave., PO Box 9162, Morgantown, WV 26506, USA
| | - Daniel Morgensztern
- Washington University School of Medicine, Division of Oncology, 660 S. Euclid, Box 8056, St. Louis, MO 63110, USA
| | - Corey A Carter
- Walter Reed National Military Medical Center, 8901 Wisconsin Ave., Bethesda, MD 20889, USA
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Manguso N, Johnson J, Harit A, Nissen N, Mirocha J, Hendifar A, Amersi F. Prognostic Factors Associated with Outcomes in Small Bowel Neuroendocrine Tumors. Am Surg 2017. [DOI: 10.1177/000313481708301033] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Small bowel neuroendocrine tumors (SBNET) account for most gastrointestinal neuroendocrine tumors. Patients often present with late-stage disease; however, there is little information regarding factors that contribute to recurrence. Database review identified 301 patients diagnosed with SBNET between 1990 and 2013. Univariate analysis included patients who underwent complete resection. Survival was estimated by the Kaplan–Meier method. A total of 147 patients met study criteria. Average age was 60 years (range 21–91); 49 per cent were male. Thirty-seven (25.3%) patients had laparoscopic resection, and 29 (19.9%) patients had only small bowel disease, whereas 108 (72.6%) had nodal metastasis. Five-year overall and disease-free survival were 97.5 and 73.5 per cent. Forty-seven (32%) patients had recurrence. The recurrence group was more likely to have an open operation (59.6 vs 32%, P < 0.01), mesenteric invasion, or lymphatic metastasis (87.2 vs 67%, P < 0.01) compared with the no-recurrence group. Cox regression analysis showed that variables associated with recurrence included nodal disease (HR 9.06, P = 0.03), lymphovascular invasion (LVI) (3.95, P < 0.01), perineural invasion (PNI) (3.48, P < 0.01), and mesenteric involvement (3.77, P = 0.03). Patients with SBNET presenting with nodal metastasis, mesenteric involvement, LVI, or PNI have a higher risk of recurrence. Closer surveillance should be considered after operative resection.
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Affiliation(s)
- Nicholas Manguso
- Division of Surgical Oncology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Jeffrey Johnson
- Division of Surgical Oncology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Attiya Harit
- Division of Surgical Oncology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Nicholas Nissen
- Division of Surgical Oncology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA
| | - James Mirocha
- Division of Surgical Oncology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Andrew Hendifar
- Division of Hematology Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Farin Amersi
- Division of Surgical Oncology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA
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Abstract
Intestinal neuroendocrine tumors (NETs) constitute a heterogeneous group with duodenal, small intestinal, colonic and rectal NETs. They constitute more than half of all NETs, with the highest frequencies in the rectum, small intestine, and colon. The tumor biology varies with the location of the primary tumor as well as with the grade and staging of the tumor. Small intestinal NETs usually present low proliferation and are treated in the first line with somatostatin analogs according to current guidelines. If progression occurs, one can add interferon alpha or change the treatment to everolimus. Peptide receptor radionuclide therapy (PRRT) with Lutetium177-DOTATATE can be an option in the future after registration of the compound. Rectal tumors are usually small when they metastasize; they can be treated with somatostatin analogs but more so with PRRT, while another option is of course everolimus. Colonic NETs are more aggressive than the rest of intestinal NETs and will be treated with everolimus, sometimes in combination with somatostatin analogs based on positive scintigraphy. Another option is a cytotoxic agent such as streptozotocin plus 5-fluorouracil (5-FU) or temozolomide plus capecitabine. The most aggressive tumors, i.e. neuroendocrine carcinoma G3, are treated with a platin-based therapy plus etoposide; if they present with a lower proliferation, i.e. <50%, temozolomide plus capecitabine plus bevacizumab can also be attempted. Duodenal NETs are mostly treated similar to pancreatic NETs, either with cytotoxic agents, streptozotocin plus 5-FU, or temozolomide plus capecitabine, or with targeted agents such as everolimus.
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Affiliation(s)
- Kjell Öberg
- Department of Endocrine Oncology, Uppsala University Hospital, Uppsala, Sweden
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Jang S, Jin H, Roy M, Ma AL, Gong S, Jaskula‐Sztul R, Chen H. Antineoplastic effects of histone deacetylase inhibitors in neuroendocrine cancer cells are mediated through transcriptional regulation of Notch1 by activator protein 1. Cancer Med 2017; 6:2142-2152. [PMID: 28776955 PMCID: PMC5603840 DOI: 10.1002/cam4.1151] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Revised: 06/23/2017] [Accepted: 07/03/2017] [Indexed: 01/19/2023] Open
Abstract
Notch signaling is minimally active in neuroendocrine (NE) cancer cells. While histone deacetylase inhibitors (HDACi) suppress NE cancer growth by inducing Notch, the molecular mechanism underlying this interplay has not yet been defined. NE cancer cell lines BON, H727, and MZ-CRC-1 were treated with known HDACi Thailadepsin-A (TDP-A) and valproic acid (VPA), and Notch1 mRNA expression was measured with RT-PCR. Truncated genomic fragments of the Notch1 promotor region fused with luciferase reporter were used to identify the potential transcription factor (TF) binding site. The key regulatory TF was identified with the electrophoretic mobility shift assay (EMSA). The effect of HDACi on Notch1 level was determined before and after silencing the TF. TDP-A and VPA induced Notch1 mRNA in a dose-dependent manner. A functional DNA motif at -80 to -52 from the Notch1 start codon responsible for the HDACi-dependent Notch1 induction was identified. Mutation of this core sequence failed to induce luciferase activity despite HDACi treatment. EMSA showed the greatest gel shift with AP-1 in nuclear extracts. Knockdown of AP-1 significantly attenuated the effect of HDACi on Notch1 induction. Interestingly, AP-1 transfection did not alter Notch1 level, suggesting that AP-1 is necessary but insufficient for HDACi activation of Notch1. Therefore, AP-1 is the TF that binds to a specific transcription-binding site within the Notch1 promotor region to trigger Notch1 transcription. Elucidating the HDACi activation mechanism may lead to the development of novel therapeutic options against NE cancers and facilitate the identification of clinical responders and prevent adverse effects.
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Affiliation(s)
- Samuel Jang
- Howard Hughes Medical InstituteBirminghamAlabama35233
- Department of SurgeryUniversity of Alabama at BirminghamBirminghamAlabama35233
| | - Haining Jin
- Department of SurgeryUniversity of Alabama at BirminghamBirminghamAlabama35233
| | - Madhuchhanda Roy
- Department of SurgeryUniversity of Alabama at BirminghamBirminghamAlabama35233
| | - Alice L. Ma
- Department of SurgeryUniversity of Alabama at BirminghamBirminghamAlabama35233
| | - Shaoqin Gong
- Department of Biomedical EngineeringUniversity of Wisconsin‐MadisonMadisonWI53715
| | | | - Herbert Chen
- Department of SurgeryUniversity of Alabama at BirminghamBirminghamAlabama35233
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Ma Z, Cai H, Cui Y. Progress in the treatment of esophageal neuroendocrine carcinoma. Tumour Biol 2017; 39:1010428317711313. [PMID: 28653897 DOI: 10.1177/1010428317711313] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Esophageal neuroendocrine neoplasms are rare. With the improvement and popularization of diagnostic methods, the morbidity statistics have increased annually in recent years. There are currently no treatment guidelines for esophageal neuroendocrine neoplasms, and surgery is the only cure. This usually involves radical surgery when the tumor is limited to the primary site or when only regional lymph node metastasis occurs. Surgical treatment is key to treating esophageal neuroendocrine neoplasms, but combined treatment with chemotherapy and radiotherapy can significantly improve patient survival. The effect of radiotherapy alone on this disease is poor. However, targeted endocrine therapy can improve endocrine hormone symptoms. The prognosis of patients with esophageal neuroendocrine neoplasms is mainly determined by the pathological stage. With the development of molecular biology techniques, the combination of targeted drugs and traditional chemotherapy is expected to provide novel ideas and directions for the treatment of esophageal neuroendocrine neoplasms in the coming years. In this article, the status of esophageal neuroendocrine tumor treatments was reviewed in detail.
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Affiliation(s)
- Zheng Ma
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Hongfei Cai
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Youbin Cui
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
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Lappano R, Maggiolini M. Pharmacotherapeutic Targeting of G Protein-Coupled Receptors in Oncology: Examples of Approved Therapies and Emerging Concepts. Drugs 2017; 77:951-965. [PMID: 28401445 DOI: 10.1007/s40265-017-0738-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
G protein-coupled receptors (GPCRs) are involved in numerous physio-pathological processes, including the stimulation of cancer progression. In this regard, it should be mentioned that although GPCRs may represent major pharmaceutical targets, only a few drugs acting as GPCR inhibitors are currently used in anti-tumor therapies. For instance, certain pro-malignancy effects mediated by GPCRs are actually counteracted by the use of small molecules and peptides that function as receptor antagonists or inverse agonists. Recently, humanized monoclonal antibodies targeting GPCRs have also been developed. Here, we review the current GPCR-targeted therapies for cancer treatment, summarizing the clinical studies that led to their official approval. We provide a broad overview of the mechanisms of action of the available anti-cancer drugs targeting gonadotropin-releasing hormone, somatostatin, chemokine, and Smoothened receptors. In addition, we discuss the anti-tumor potential of novel non-approved molecules and antibodies able to target some of the aforementioned GPCRs in different experimental models and clinical trials. Likewise, we focus on the repurposing in cancer patients of non-oncological GPCR-based drugs, elucidating the rationale behind this approach and providing clinical evidence on their safety and efficacy.
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Affiliation(s)
- Rosamaria Lappano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
| | - Marcello Maggiolini
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
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Cioppi F, Cianferotti L, Masi L, Giusti F, Brandi ML. The LARO-MEN1 study: a longitudinal clinical experience with octreotide Long-Acting Release in patients with Multiple Endocrine Neoplasia type 1 Syndrome. CLINICAL CASES IN MINERAL AND BONE METABOLISM : THE OFFICIAL JOURNAL OF THE ITALIAN SOCIETY OF OSTEOPOROSIS, MINERAL METABOLISM, AND SKELETAL DISEASES 2017; 14:123-130. [PMID: 29263719 PMCID: PMC5726195 DOI: 10.11138/ccmbm/2017.14.1.123] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary tumoral syndrome, featured by a combination of neoplasms of various endocrine and nonendocrine tissues. Approximately 33% of MEN1-related deaths are due to the malignant behaviour of well-differentiated neuroendocrine tumors (NETs), for which a preventive surgical treatment is not feasible. Somatostatin analogues (SSA) have been employed in the treatment of NETs in the stage of advanced or metastatic disease, in order to control the growth and secretion of tumor lesions. A longitudinal, open label study named "LARO-MEN1" was undertaken in order to assess whether early medical treatment with long-acting SSA could act as a preventive approach in small MEN1-related gastroenteropancreatic (GEP) NETs. Thirty consecutive patients affected by MEN1 were screened and 8 patients with small (<2 cm) NETs and abnormal laboratory values of at least one of the GEP hormones were administered octreotide acetate slow-release formulation (LAR) (10 mg i.m. every 28 days). Octreotide LAR was effective in decreasing GEP hormones and overall safe in the majority of patients up to six years of treatment, maintaining the disease stable also in terms of tumor size. The positive outcomes of this study in MEN1 patients reinforce the results obtained in advanced NETs on the use of SSA, opening to the opportunity for preventive use of octreotide LAR, aimed to delay or even avoid surgery in these patients.
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Affiliation(s)
- Federica Cioppi
- Bone and Mineral Metabolism Unit, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
| | - Luisella Cianferotti
- Bone and Mineral Metabolism Unit, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
| | - Laura Masi
- Bone and Mineral Metabolism Unit, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
| | - Francesca Giusti
- Bone and Mineral Metabolism Unit, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
| | - Maria Luisa Brandi
- Bone and Mineral Metabolism Unit, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
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The Impact of Radiological Response to Peptide Receptor Radionuclide Therapy on Overall Survival in Patients With Metastatic Midgut Neuroendocrine Tumors. Clin Nucl Med 2017; 42:e135-e141. [PMID: 27922860 DOI: 10.1097/rlu.0000000000001457] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Chen G, Jaskula-Sztul R, Esquibel CR, Lou I, Zheng Q, Dammalapati A, Harrison A, Eliceiri KW, Tang W, Chen H, Gong S. Neuroendocrine Tumor-Targeted Upconversion Nanoparticle-Based Micelles for Simultaneous NIR-Controlled Combination Chemotherapy and Photodynamic Therapy, and Fluorescence Imaging. ADVANCED FUNCTIONAL MATERIALS 2017; 27:1604671. [PMID: 28989337 PMCID: PMC5630134 DOI: 10.1002/adfm.201604671] [Citation(s) in RCA: 114] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
Although neuroendocrine tumors (NETs) are slow growing, they are frequently metastatic at the time of discovery and no longer amenable to curative surgery, emphasizing the need for the development of other treatments. In this study, multifunctional upconversion nanoparticle (UCNP)-based theranostic micelles are developed for NET-targeted and near-infrared (NIR)-controlled combination chemotherapy and photodynamic therapy (PDT), and bioimaging. The theranostic micelle is formed by individual UCNP functionalized with light-sensitive amphiphilic block copolymers poly(4,5-dimethoxy-2-nitrobenzyl methacrylate)-polyethylene glycol (PNBMA-PEG) and Rose Bengal (RB) photosensitizers. A hydrophobic anticancer drug, AB3, is loaded into the micelles. The NIR-activated UCNPs emit multiple luminescence bands, including UV, 540 nm, and 650 nm. The UV peaks overlap with the absorption peak of photocleavable hydrophobic PNBMA segments, triggering a rapid drug release due to the NIR-induced hydrophobic-to-hydrophilic transition of the micelle core and thus enabling NIR-controlled chemotherapy. RB molecules are activated via luminescence resonance energy transfer to generate 1O2 for NIR-induced PDT. Meanwhile, the 650 nm emission allows for efficient fluorescence imaging. KE108, a true pansomatostatin nonapeptide, as an NET-targeting ligand, drastically increases the tumoral uptake of the micelles. Intravenously injected AB3-loaded UCNP-based micelles conjugated with RB and KE108-enabling NET-targeted combination chemotherapy and PDT-induce the best antitumor efficacy.
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Affiliation(s)
- Guojun Chen
- Department of Materials Science and Engineering, University of Wisconsin-Madison, Madison, WI 53715, USA. Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA
| | - Renata Jaskula-Sztul
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Corinne R Esquibel
- Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Irene Lou
- Department of Surgery, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Qifeng Zheng
- Department of Materials Science and Engineering, University of Wisconsin-Madison, Madison, WI 53715, USA. Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA
| | - Ajitha Dammalapati
- Department of Surgery, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - April Harrison
- Department of Surgery, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Kevin W Eliceiri
- Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA. Department of Biomedical Engineering University of Wisconsin-Madison, Madison, WI 53706, USA. Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Weiping Tang
- School of Pharmacy, University of Wisconsin-Madison, WI 53705, USA
| | - Herbert Chen
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Shaoqin Gong
- Department of Materials Science and Engineering, University of Wisconsin-Madison, Madison, WI 53715, USA. Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA. Department of Biomedical Engineering University of Wisconsin-Madison Madison, WI 53706, USA
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Citterio D, Pusceddu S, Facciorusso A, Coppa J, Milione M, Buzzoni R, Bongini M, deBraud F, Mazzaferro V. Primary tumour resection may improve survival in functional well-differentiated neuroendocrine tumours metastatic to the liver. Eur J Surg Oncol 2017; 43:380-387. [PMID: 27956320 DOI: 10.1016/j.ejso.2016.10.031] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2016] [Revised: 10/14/2016] [Accepted: 10/18/2016] [Indexed: 01/09/2023] Open
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Cidon EU. New therapeutic approaches to metastatic gastroenteropancreatic neuroendocrine tumors: A glimpse into the future. World J Gastrointest Oncol 2017; 9:4-20. [PMID: 28144395 PMCID: PMC5241526 DOI: 10.4251/wjgo.v9.i1.4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 10/13/2016] [Accepted: 11/21/2016] [Indexed: 02/05/2023] Open
Abstract
Neuroendocrine (NE) gastroenteropancreatic tumors are a heterogeneous group of neoplasias arising from neuroendocrine cells of the embryological gut. Their incidence have increased significantly over the past 3 decades probably due to the improvements in imaging and diagnosis. The recent advances in molecular biology have translated into an expansion of therapeutic approaches to these patients. Somatostatin analogs, which initially were approved for control of hormonal syndromes, have recently been proven to inhibit tumor growth. Several new drugs such as antiangiogenics and others targeting mammalian target of rapamycin pathways have been approved to treat progressive pancreatic neuroendocrine tumors (NETs) although their role in non-pancreatic is still controversial. The treatment of NETs requires a coordinated multidisciplinary approach. The management of localized NETs primarily involves surgical resection followed by surveillance. However, the treatment of unresectable and/or metastatic disease may involve a combination of surgical resection, systemic therapy, and liver-directed therapies with the goal of alleviating symptoms of peptide release and controlling tumor growth. This article will review the current therapeutic strategies for metastatic gastroenteropancreatic NETs and will take a glimpse into the future approaches.
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Advances in the diagnosis and treatment of pancreatic neuroendocrine neoplasms in Japan. J Gastroenterol 2017; 52:9-18. [PMID: 27539256 DOI: 10.1007/s00535-016-1250-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 07/27/2016] [Indexed: 02/06/2023]
Abstract
Several new developments have occurred in the field of pancreatic neuroendocrine neoplasm (PNEN) recently in Japan. First, the utility of chromogranin A (CgA), useful for the diagnosis and monitoring of the treatment response of neuroendocrine neoplasm (NEN), has been demonstrated in Japan. For PNEN diagnosis and treatment, grading and correct histological diagnosis according to the WHO 2010 classification is important. Regarding the histological diagnosis, the advent of endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) has enabled correct pathological diagnosis and suitable treatment for the affected tissue. Furthermore, EUS-FNA has also facilitates the assessment of the presence or absence of gene mutations. In addition, patients who have a well-differentiated neuroendocrine tumor (NET) showing a Ki-67 index of higher than 20 % according to the WHO 2010 classification, have also been identified, and their responses to treatment were found to be different from those of patients with poorly differentiated neuroendocrine carcinoma (NEC). Therefore, the concept of NET G3 was proposed. Additionally, somatostatin receptor type 2 is expressed in several cases of NET, and somatostatin receptor scintigraphy (111In-octreoscan) has also been approved in Japan. This advancement will undoubtedly contribute to the localization diagnosis, the identification of remote metastasis, and assessments of the treatment responses of PNEN. Finally, regarding the treatment strategy for PNEN, the management of liver metastasis is important. The advent of novel molecular-targeted agents has dramatically improved the prognosis of advanced PNEN. Multimodality therapy that accounts for the tumor stage, degree of tumor differentiation, tumor volume, and speed of tumor growth is required.
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Pokuri VK, Fong MK, Iyer R. Octreotide and Lanreotide in Gastroenteropancreatic Neuroendocrine Tumors. Curr Oncol Rep 2016; 18:7. [PMID: 26743514 DOI: 10.1007/s11912-015-0492-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Neuroendocrine tumors are heterogeneous, rare malignancies that arise most commonly in the gastrointestinal tract and pancreas. They often secrete vasoactive substances resulting in carcinoid syndrome and the tumor cells exclusively express somatostatin receptors. Octreotide and lanreotide are the two synthetic somatostatin analogs used for the control of carcinoid symptoms and tumor progression in advanced inoperable disease. Recent pivotal trials (PROMID and CLARINET studies) established their antitumor activity. We discuss the available data to support their use as symptom controlling and antiproliferative agents. This article also reviews the guidelines (National Comprehensive Cancer Network and North American Neuro Endocrine Tumor Society), cost-analysis (suggesting the cost-effectiveness of lanreotide autogel compared to higher doses of octreotide long acting release formulation in refractory patients), and future directions of somatostatin analogs in the management of patients refractory to conventional doses of octreotide and lanreotide.
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Affiliation(s)
- Venkata K Pokuri
- Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Mei Ka Fong
- Department of Pharmacy, Carolinas Healthcare System, Levine Cancer Institute, Charlotte, NC, USA
| | - Renuka Iyer
- Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA.
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50
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Ileal “carcinoid” tumors—small size belies deadly intent: high rate of nodal metastasis in tumors ≤1 cm in size. Hum Pathol 2016; 56:123-7. [DOI: 10.1016/j.humpath.2016.05.023] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 05/13/2016] [Accepted: 05/27/2016] [Indexed: 01/13/2023]
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