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Popa SG, Golli AL, Matei CF, Sonei AN, Vere C, Cimpeanu R, Munteanu M, Munteanu A. Pancreatic Neuroendocrine Tumors-Diagnostic Pitfalls of Non-Diabetic Severe Hypoglycemia: Literature Review and Case Report. Diagnostics (Basel) 2025; 15:337. [PMID: 39941267 PMCID: PMC11816404 DOI: 10.3390/diagnostics15030337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/23/2025] [Accepted: 01/27/2025] [Indexed: 02/16/2025] Open
Abstract
Background: Hypoglycemia in the case of persons without diabetes is a rare event, being usually, initially misinterpreted based on the symptoms that can mimic various diseases, especially of a neuro-psychiatric nature. In the case of the identification of insulin-mediated hypoglycemia, the evaluation of pancreatic neuroendocrine tumors, which represent the most common and worrisome causes of non-diabetic insulin-mediated hypoglycemia, must be considered. Case Report: We present the case of a 57-year-old patient, hospitalized for a history of approximately one month of recurrent episodes of symptoms suggestive for severe hypoglycemia. The biological evaluation performed during an episode of hypoglycemia showed a plasma glucose value of 44 mg/dL, insulinemia 16.3 µU/mL, C peptide 3.72 ng/mL, HbA1c 4.99%, absence of urinary ketone bodies and anti-insulin antibodies <0.03 U/mL. The CT and MRI examination showed a 15.3/15 mm rounded tumor in the pancreatic corporeo-caudal region. The pancreatic tumor formation was enucleated and the histopathological and immunohistochemical analysis confirmed the diagnosis of the pancreatic neuroendocrine tumor with a positive reaction for chromogranin A, synaptophysin and insulin, without malignancy features (Ki 67 positive in 1% of the tumor cells). The postoperative evolution was favorable, without episodes of hypoglycemia, the fasting insulinemia one day after surgery being 4.1 µU/mL and HbA1c at three weeks postoperatively being 5.51%. Conclusions: The management of patients with hyperinsulinemic hypoglycemia secondary to insulinoma involves multidisciplinary collaboration with an important role in recognizing symptoms suggestive of hypoglycemia in a person without diabetes, initiating biological and imaging evaluation, establishing the optimal therapeutic option and histopathological confirmation.
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Affiliation(s)
- Simona Georgiana Popa
- Department of Diabetes, Nutrition and Metabolic Diseases, University of Medicine and Pharmacy, 200349 Craiova, Romania;
| | - Andreea Loredana Golli
- Department of Public Health and Healthcare Management, University of Medicine and Pharmacy, 200349 Craiova, Romania
| | - Cristina Florentina Matei
- Department of Diabetes, Nutrition and Metabolic Diseases, Emergency County Hospital, 200642 Craiova, Romania; (C.F.M.); (A.N.S.)
| | - Alexandra Nicoleta Sonei
- Department of Diabetes, Nutrition and Metabolic Diseases, Emergency County Hospital, 200642 Craiova, Romania; (C.F.M.); (A.N.S.)
| | - Cristin Vere
- Department of Gastroenterology, University of Medicine and Pharmacy, 200349 Craiova, Romania; (C.V.); (R.C.)
| | - Radu Cimpeanu
- Department of Gastroenterology, University of Medicine and Pharmacy, 200349 Craiova, Romania; (C.V.); (R.C.)
| | - Marian Munteanu
- Department of Surgery, University of Medicine and Pharmacy, 200349 Craiova, Romania; (M.M.); (A.M.)
| | - Alexandru Munteanu
- Department of Surgery, University of Medicine and Pharmacy, 200349 Craiova, Romania; (M.M.); (A.M.)
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Li W, Cheng Y, Ma Q, Wu Z, Wang Z. Clinical characteristics and treatment outcomes of patients with insulinoma-a single center's experience of 76 cases over a 10-year period. Heliyon 2025; 11:e41799. [PMID: 39897806 PMCID: PMC11782979 DOI: 10.1016/j.heliyon.2025.e41799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 12/25/2024] [Accepted: 01/07/2025] [Indexed: 02/04/2025] Open
Abstract
Objective Insulinoma is a rare pancreatic neuroendocrine neoplasm caused by pancreatic beta cell tumor or beta cell proliferation resulting in excessive insulin secretion. Due to its rarity, surgical analysis and summary studies on patients with insulinoma are few and the sample size is limited. Methods In this study, we retrospective the cumulative experiences including demographics, clinical characteristics, detailed surgical reports and postoperative outcome of 76 patients diagnosed with insulinoma from 2010 to 2020 at the First Affiliated Hospital of Xi'an Jiaotong University. Results Our cohort consisted of 48 females and 28 males with an average diagnosis age of 52 years. Loss of consciousness (68 %), sweating (59 %), vertigo (56 %) are three most shown symptoms. The average time from symptom onset to diagnosis of insulinoma was 33.4 month. When CT combined with MRI was used, the diagnostic rate was as high as 96.87 %. Of the 76 patients, 48.68 % of preoperative tumors were in the head/neck, and the remaining 51.32 % were in the body/tail. Most of the patients received surgery for enucleation (65.79 %). The duration of surgery was 216 ± 105 min. The incidence of postoperative pancreatic fistula was 53.95 %. Postoperative pancreatic hemorrhage occurred in 6 patients (7.89 %), all of whom were pancreatic head/neck surgery patients. The incidence of pancreatic fistula, bleeding and major complications after the operation of pancreatic head/neck insulinoma was higher than that of pancreatic body/tail insulinoma. Conclusion CT combined with MRI can localize insulinoma in most patients. As a parenchyma-sparing pancreatectomy, enucleation is the procedure of choice if possible. The incidence of postoperative hemorrhage should be more vigilant after the surgery of pancreatic head/neck insulinoma. The intraoperative suture of high-risk vessels prone to bleeding should be performed if necessary.
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Affiliation(s)
| | | | - Qingyong Ma
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China
| | - Zheng Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China
| | - Zheng Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China
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Bahou K, Achour Y, Ilahiane M, Sekkat H, Bakali Y, Mhamdi Alaoui M, Raiss M, Sabbah F, Hrora A. Diagnosis and management of benign secreting pancreatic insulinoma: What's new? 4 case report. Rare Tumors 2025; 17:20363613241313409. [PMID: 39790868 PMCID: PMC11713962 DOI: 10.1177/20363613241313409] [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: 09/28/2024] [Accepted: 12/19/2024] [Indexed: 01/12/2025] Open
Abstract
Introduction and importance: Even though insulinoma is the most frequent neuroendocrine tumor, it represents only 2% of pancreatic 2% of all pancreatic neoplasms. Diagnosis is relatively simple, and surgery after accurate determination of the tumors location within the pancreas is the cornerstone of its treatment. Case presentation: We herein report 4 patients undergoing various surgeries for benign secreting insulinomas, after extensive radiological and endoscopic exploration. Clinical discussion: Diagnosis is relatively simple relying on clinical and biological criteria, it must be followed by an extensive and accurate preoperative determination of the tumors localization. The laparoscopic tumoral enucleation is the treatment of choice for small isolated tumors, but open surgery still has its indications. Conclusion: Pancreatic insulinoma is a rare neuroendocrine tumor that can be life-threatening due to hypoglycemic manifestations. The diagnosis is based on clinical and biological criteria. echo endoscopy and to a lesser extent radiological exploration can precisely determine the tumors location. Laparoscopic surgical enucleation of the tumor remains the preferred curative treatment.
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Affiliation(s)
- Khawla Bahou
- Digestive Surgical Department C, Ibn Sina University Hospital, Rabat, Morocco
- Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat, Morocco
| | - Youssef Achour
- Digestive Surgical Department C, Ibn Sina University Hospital, Rabat, Morocco
- Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat, Morocco
| | - Mehdi Ilahiane
- Digestive Surgical Department C, Ibn Sina University Hospital, Rabat, Morocco
- Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat, Morocco
| | - Hamza Sekkat
- Digestive Surgical Department C, Ibn Sina University Hospital, Rabat, Morocco
- Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat, Morocco
| | - Younes Bakali
- Digestive Surgical Department C, Ibn Sina University Hospital, Rabat, Morocco
- Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat, Morocco
| | - Mouna Mhamdi Alaoui
- Digestive Surgical Department C, Ibn Sina University Hospital, Rabat, Morocco
- Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat, Morocco
| | - Mohammed Raiss
- Digestive Surgical Department C, Ibn Sina University Hospital, Rabat, Morocco
- Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat, Morocco
| | - Farid Sabbah
- Digestive Surgical Department C, Ibn Sina University Hospital, Rabat, Morocco
- Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat, Morocco
| | - Abdelmalek Hrora
- Digestive Surgical Department C, Ibn Sina University Hospital, Rabat, Morocco
- Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat, Morocco
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Vaezi MA, Nekoufar S, Robati AK, Salimi V, Tavakoli-Yaraki M. Therapeutic potential of β-hydroxybutyrate in the management of pancreatic neoplasms: exploring novel diagnostic and treatment strategies. Lipids Health Dis 2024; 23:376. [PMID: 39543582 PMCID: PMC11562866 DOI: 10.1186/s12944-024-02368-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 11/09/2024] [Indexed: 11/17/2024] Open
Abstract
Pancreatic neoplasm, a highly aggressive and often fatal cancer, poses challenges due to late detection and nonspecific symptoms. Therefore, both early diagnosis and appropriate therapeutic approaches are necessary to augment the condition of these patients. Cancer cells undergo metabolic deregulation, which enables their proliferation, survival, and invasion. As a result, it is crucial to focus on the metabolic pathways in prevalent cancers and explore treatment strategies that target these pathways to control tumor growth effectively. This is particularly relevant in cancers like pancreatic cancer, which undergo numerous metabolic alterations. The ketogenic regimen, characterized by low carbohydrate and protein contents and high-fat sources, does not involve caloric restriction. This allows for the induction of ketogenesis and an increase in ketone bodies, while insulin and glucose levels remain low even after meals. This unique metabolic state may influence the tumor microenvironment. Given the lack of unanimous agreement on the precise role and mechanism of the ketogenic diet, this review aims to clarify the diagnostic value and accuracy of ketone bodies in various types of pancreatic tumors and explore the potential anti-cancer effects of the ketogenic diet when used alone or in conjunction with chemotherapy, also to determine the potential of the ketogenic diet to be used as adjuvant therapy. The outcomes of this study are instrumental in enhancing our understanding of the benefits and drawbacks associated with employing this diet for the management and diagnosis of pancreatic cancer.
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Affiliation(s)
- Mohammad Amin Vaezi
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, P.O. Box: 1449614535, Tehran, Iran
| | - Samira Nekoufar
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, P.O. Box: 1449614535, Tehran, Iran
| | - Ali Karami Robati
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, P.O. Box: 1449614535, Tehran, Iran
| | - Vahid Salimi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoumeh Tavakoli-Yaraki
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, P.O. Box: 1449614535, Tehran, Iran.
- Finetech in Medicine Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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Mahaldar EA, Khan K, Khan M, Shahbuddin MI. Insulinoma: Unraveling the Mystery of a Stealthy Culprit. Cureus 2024; 16:e74364. [PMID: 39723310 PMCID: PMC11669375 DOI: 10.7759/cureus.74364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/23/2024] [Indexed: 12/28/2024] Open
Abstract
Insulinoma, a rare pancreatic neuroendocrine tumor, stealthily lurks within the pancreas, often evading detection until its distinctive symptom, recurrent hypoglycemia, comes to the surface. This case report aims to highlight the significance of a multidisciplinary approach in the management of this uncommon neuroendocrine tumor by discussing the diagnostic, therapeutic, and follow-up difficulties encountered in an older adult presenting with atypical symptoms of insulinoma.
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Affiliation(s)
- Eram A Mahaldar
- Internal Medicine, Nottingham University Hospitals National Health Service (NHS) Trust, Nottingham, GBR
| | - Kulsum Khan
- Internal Medicine, Nottingham University Hospitals National Health Service (NHS) Trust, Nottingham, GBR
| | - Mustafa Khan
- Internal Medicine, Nottingham University Hospitals National Health Service (NHS) Trust, Nottingham, GBR
| | - Mohammed I Shahbuddin
- Endocrinology and Diabetes, Nottingham University Hospitals National Health Service (NHS) Trust, Nottingham, GBR
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Şahin R, Rakıcı İT, Baloğlu MC, Şahin ÖF, Çermik TF. 68Ga-NODAGA-Exendin-4 PET/CT Findings in a Case of Metastatic Insulinoma With Refractory Hypoglycemia Controlled by 90Y Transarterial Radioembolization. Clin Nucl Med 2024; 49:e392-e393. [PMID: 38967509 DOI: 10.1097/rlu.0000000000005266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/06/2024]
Abstract
ABSTRACT Metastatic insulinomas can cause recurrent hypoglycemia requiring continuous IV glucose infusion. Various medical and chemotherapeutic treatment options are used to reduce the patient's risk of death due to hypoglycemia. Treatment-resistant hepatic metastatic insulinomas may benefit clinically from 90Y transarterial radioembolization therapy. In this case, we present a case of liver metastatic insulinoma that achieved clinical improvement after 2 cycles of 90Y microspheres transarterial radioembolization, and the presence of active metastases was demonstrated with 68Ga-NODAGA-exendin-4 PET/CT imaging.
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Namysl-Kaletka A, Wydmanski J, Debosz-Suwinska I, Kaszuba M, Gabrys D, Roch-Zniszczol A, Handkiewicz-Junak D. Stereotactic Body Radiation Therapy for Symptomatic Pancreatic Insulinoma: Two-Case Report and Literature Review. Curr Oncol 2024; 31:4123-4132. [PMID: 39057179 PMCID: PMC11275479 DOI: 10.3390/curroncol31070307] [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: 06/03/2024] [Revised: 07/14/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
Insulinoma is the most common functional neuroendocrine tumor of the pancreas, with the main clinical symptom being hypoglycemia. The standard treatment is surgery, but some patients are not eligible for surgery, while in those operated on, the risk of perioperative complications is up to 30%. Diazoxide treatment to prevent hypoglycemia is effective only in 50% of patients. To prevent tumor growth and hormonal excess, stereotactic radiotherapy may be an alternative to surgical treatment. In our paper, we present two cases of patients with insulinoma treated successfully with stereotactic body radiation therapy (SBRT).
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Affiliation(s)
- Agnieszka Namysl-Kaletka
- Radiotherapy Department, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland
| | - Jerzy Wydmanski
- Radiotherapy Department, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland
| | - Iwona Debosz-Suwinska
- Radiotherapy Department, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland
| | - Malgorzata Kaszuba
- Radiology and Diagnostic Imaging Department, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland
| | - Dorota Gabrys
- Radiotherapy Department, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland
| | - Agata Roch-Zniszczol
- Radiotherapy Department, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland
| | - Daria Handkiewicz-Junak
- Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, 44-102 Gliwice, Poland
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8
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Xiao D, Zhu L, Xiong S, Yan X, Jiang Q, Wang A, Jia Y. Outcomes of endoscopic ultrasound-guided ablation and minimally invasive surgery in the treatment of pancreatic insulinoma: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 2024; 15:1367068. [PMID: 38645424 PMCID: PMC11026617 DOI: 10.3389/fendo.2024.1367068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 03/25/2024] [Indexed: 04/23/2024] Open
Abstract
Background and aims Most pancreatic insulinomas can be treated by minimally invasive modalities. The aim of this meta-analysis was to assess the clinical outcomes of endoscopic ultrasound (EUS)-guided ablation and minimally invasive surgery (MIS) in the treatment of pancreatic insulinoma. Materials and methods Online databases were searched for relevant studies. The primary aim was to compare the rates of adverse events (AEs) and the secondary aims were to compare the clinical and technical success rates, length of hospital stays, and symptom recurrence rates between EUS and MIS approaches. Results Eight studies with 150 patients were identified that reported EUS-guided ablation outcomes, forming the EUS group, and 9 studies with 236 patients reported MIS outcomes, forming the MIS group. The pooled median age of the included patients in the EUS group was greater than that of the MIS group (64.06 vs. 44.98 years old, p < 0.001). Also, the technical success rate was significantly higher in the EUS group (100% vs. 96.6%, p = 0.025), while the clinical success was significantly higher (6%) in the MIS group (94% vs. 98.7%, p = 0.021). The AE rates (18.7% vs. 31.1%, p = 0.012) and severe AE rates (1.3% vs. 7.9%, p = 0.011) were significantly lower in the EUS group. The median length of hospital stay in the EUS group (2.68 days, 95% CI: 1.88-3.48, I2 = 60.3%) was significantly shorter than in the MIS group (7.40 days, 95% CI: 6.22-8.58, I2 = 42.2%, p < 0.001). The recurrence rate was significantly higher in the EUS group (15.3% vs. 1.3%, p < 0.001). Conclusions EUS-guided ablation is associated with a lower AE rate and a shorter length of hospital stay, but a higher recurrence rate for the treatment of insulinoma compared with MIS. The EUS approach may be an alternative, even first-line, treatment for poor surgery candidates.
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Affiliation(s)
- Dan Xiao
- Department of Gastroenterology, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, Hubei, China
| | - Li Zhu
- Gastrointestinal Surgery, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, Hubei, China
| | - Si Xiong
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, Hubei, China
| | - Xu Yan
- Internal Medicine Department, University Hospital, Wuhan Institute of Technology, Wuhan, Hubei, China
| | - Qin Jiang
- Department of Gastroenterology, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, Hubei, China
| | - Ao Wang
- Department of Gastroenterology, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, Hubei, China
| | - Yegui Jia
- Department of Gastroenterology, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, Hubei, China
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Gao R, Yin B, Jin J, Tian X, Zhang Y, Wei J, Cao F, Wang Z, Ma Z, Wang M, Gou S, Cong L, Xu Q, Wu W, Zhao Y. Preoperative pancreatic stent placement before the enucleation of insulinoma located in the head and neck of the pancreas in proximity to the main pancreatic duct: study protocol for a multicentre randomised clinical trial in Chinese tertiary medical centres. BMJ Open 2024; 14:e078516. [PMID: 38569703 PMCID: PMC10989159 DOI: 10.1136/bmjopen-2023-078516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 02/27/2024] [Indexed: 04/05/2024] Open
Abstract
INTRODUCTION The surgical intervention approach to insulinomas in proximity to the main pancreatic duct remains controversial. Standard pancreatic resection is recommended by several guidelines; however, enucleation (EN) still attracts surgeons with less risk of late exocrine/endocrine insufficiency, despite a higher postoperative pancreatic fistula (POPF) rate. Recently, the efficacy and safety of preoperative pancreatic stent placement before the EN have been demonstrated. Thus, a multicentre open-label study is being conducted to evaluate the efficacy and safety of stent placement in improving the outcome of EN of insulinomas in proximity to the main pancreatic duct. METHODS AND ANALYSIS This is a prospective, randomised, open-label, superiority clinical trial conducted at multiple tertiary centres in China. The major eligibility criterion is the presence of insulinoma located in the head and neck of the pancreas in proximity (≤2 mm) to the main pancreatic duct. Blocked randomisation will be performed to allocate patients into the stent EN group and the direct EN group. Patients in the stent EN group will go through stent placement by the endoscopist within 24 hours before the EN surgery, whereas other patients will receive EN surgery directly. The primary outcome is the assessment of the superiority of stent placement in reducing POPF rate measured by the International Study Group of Pancreatic Surgery standard. Both interventions will be performed in an inpatient setting and regular follow-up will be performed. The primary outcome (POPF rate) will be tested for superiority with the Χ2 test. The difference in secondary outcomes between the two groups will be analysed using appropriate tests. ETHICS AND DISSEMINATION The study has been approved by the Peking Union Medical College Hospital Institutional Review Board (K23C0195), Ruijin Hospital Ethics Committee (2023-314), Peking University First Hospital Ethics Committee (2024033-001), Institutional Review Board of Xuanwu Hospital of Capital Medical University (2023223-002), Ethics Committee of the First Affiliated Hospital of Xi'an Jiaotong University (XJTU1AF2023LSK-473), Institutional Review Board of Tongji Medical College Tongji Hospital (TJ-IRB202402059), Ethics Committee of Tongji Medical College Union Hospital (2023-0929) and Shanghai Cancer Center Institutional Review Board (2309282-16). The results of the study will be published in an international peer-reviewed journal. TRIAL REGISTRATION NUMBER NCT05523778.
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Affiliation(s)
- Ruichen Gao
- Peking Union Medical College, Beijing, People's Republic of China
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, People's Republic of China
| | - Bohui Yin
- Peking Union Medical College, Beijing, People's Republic of China
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, People's Republic of China
| | - Jiabin Jin
- Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- Research Institute of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
- Department of General Surgery, Ruijin-Hainan Hospital, Shanghai Jiao Tong University School of Medicine, Hainan, People's Republic of China
| | - Xiaodong Tian
- Department of Hapatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, People's Republic of China
| | - Yuhua Zhang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, People's Republic of China
| | - Jishu Wei
- Pancreas Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
| | - Feng Cao
- Xuanwu Hospital, Beijing, People's Republic of China
| | - Zheng Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Zhijun Ma
- Panjin People's Hospital, Panjin, Liaoning, People's Republic of China
| | - Min Wang
- Department of Biliary-Pancreatic Surgery, Huazhong University of Science and Technology Tongji Medical College Tongji Hospital, Wuhan, Hubei, People's Republic of China
| | - Shanmiao Gou
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Lin Cong
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, People's Republic of China
| | - Qiang Xu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, People's Republic of China
| | - Wenming Wu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, People's Republic of China
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, People's Republic of China
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Silvestris N, Franchina T, Gallo M, Argentiero A, Avogaro A, Cirino G, Colao A, Danesi R, Di Cianni G, D'Oronzo S, Faggiano A, Fogli S, Giuffrida D, Gori S, Marrano N, Mazzilli R, Monami M, Montagnani M, Morviducci L, Natalicchio A, Ragni A, Renzelli V, Russo A, Sciacca L, Tuveri E, Zatelli MC, Giorgino F, Cinieri S. Diabetes management in cancer patients. An Italian Association of Medical Oncology, Italian Association of Medical Diabetologists, Italian Society of Diabetology, Italian Society of Endocrinology and Italian Society of Pharmacology multidisciplinary consensus position paper. ESMO Open 2023; 8:102062. [PMID: 38070434 PMCID: PMC10714217 DOI: 10.1016/j.esmoop.2023.102062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 10/07/2023] [Accepted: 10/11/2023] [Indexed: 12/31/2023] Open
Abstract
Cancer management has significantly evolved in recent years, focusing on a multidisciplinary team approach to provide the best possible patient care and address the various comorbidities, toxicities, and complications that may arise during the patient's treatment journey. The co-occurrence of diabetes and cancer presents a significant challenge for health care professionals worldwide. Management of these conditions requires a holistic approach to improve patients' overall health, treatment outcomes, and quality of life, preventing diabetes complications and cancer treatment side-effects. In this article, a multidisciplinary panel of experts from different Italian scientific societies provide a critical overview of the co-management of cancer and diabetes, with an increasing focus on identifying a novel specialty field, 'diabeto-oncology', and suggest new co-management models of cancer patients with diabetes to improve their care. To better support cancer patients with diabetes and ensure high levels of coordinated care between oncologists and diabetologists, 'diabeto-oncology' could represent a new specialized field that combines specific expertise, skills, and training.
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Affiliation(s)
- N Silvestris
- Medical Oncology Unit, Department of Human Pathology "G. Barresi", University of Messina, Messina.
| | - T Franchina
- Medical Oncology Unit, Department of Human Pathology "G. Barresi", University of Messina, Messina
| | - M Gallo
- Endocrinology and Metabolic Diseases Unit, AO SS Antonio e Biagio e Cesare Arrigo of Alessandria, Alessandria
| | - A Argentiero
- Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari
| | - A Avogaro
- Department of Medicine, University of Padova, Padua
| | - G Cirino
- Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples
| | - A Colao
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples; UNESCO Chair, Education for Health and Sustainable Development, Federico II University, Naples
| | - R Danesi
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa
| | | | - S D'Oronzo
- Interdisciplinary Department of Medicine, University of Bari Aldo Moro, Bari
| | - A Faggiano
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, ENETS Center of Excellence, Sapienza University of Rome, Rome
| | - S Fogli
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa
| | - D Giuffrida
- Department of Oncology, Istituto Oncologico del Mediterraneo, Viagrande, Catania
| | - S Gori
- Oncologia Medica, IRCCS Ospedale Don Calabria-Sacro Cuore di Negrar, Verona
| | - N Marrano
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari
| | - R Mazzilli
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, ENETS Center of Excellence, Sapienza University of Rome, Rome
| | - M Monami
- Diabetology, Careggi Hospital and University of Florence, Firenze
| | - M Montagnani
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Pharmacology, Medical School, University of Bari Aldo Moro, Bari
| | - L Morviducci
- Diabetology and Nutrition Unit, Department of Medical Specialties, ASL Roma 1 - S, Spirito Hospital, Rome
| | - A Natalicchio
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari
| | - A Ragni
- Endocrinology and Metabolic Diseases Unit, AO SS Antonio e Biagio e Cesare Arrigo of Alessandria, Alessandria
| | - V Renzelli
- Diabetologist and Endocrinologist, Italian Association of Medical Diabetologists, Rome
| | - A Russo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo
| | - L Sciacca
- Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania, Catania
| | - E Tuveri
- Diabetology, Endocrinology and Metabolic Diseases Service, ASL-Sulcis, Carbonia
| | - M C Zatelli
- Section of Endocrinology, Geriatrics, and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara
| | - F Giorgino
- Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari
| | - S Cinieri
- Medical Oncology Division and Breast Unit, Senatore Antonio Perrino Hospital, ASL Brindisi, Brindisi, Italy
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Ekanayake AB, Stubbs H, Broutin D, Karasik O, Kinaan M. Not Just an Accident: A Case of Insulinoma. Cureus 2023; 15:e48514. [PMID: 38074057 PMCID: PMC10708470 DOI: 10.7759/cureus.48514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 11/07/2023] [Indexed: 10/16/2024] Open
Abstract
Insulinomas are a rare cause of recurrent hypoglycemia in non-diabetic patients. Diagnosis requires hypoglycemia (plasma glucose <50 mg/dL), neuroglycopenic symptoms, and prompt relief of symptoms following the administration of glucose, known as Whipple's triad. The gold standard diagnostic tests are measuring insulin, C-peptide, and glucose during a 72-hour fast. In the preoperative period and in patients with unresectable or metastatic tumors, medical management with diazoxide and octreotide can be considered for recurrent hypoglycemia. We present a case of insulinoma in a 37-year-old woman who initially presented after a seizure-related motor vehicle accident. Upon admission, her initial glucose level was 32 mg/dL, indicating a likely hypoglycemic seizure. During her hospitalization, she had recurrent episodes of fasting and postprandial hypoglycemia, ranging from 32-70 mg/dL. She exhibited the characteristics of Whipple's triad when values dropped below 50 mg/dL. These episodes necessitated continuous infusions of 10% dextrose. Tests for insulin autoantibodies, sulfonylurea screens, and thyroid function yielded unremarkable results. A 72-hour fasting test was initiated to investigate potential endogenous causes of excessive insulin production. Laboratory results from a venous glucose level of 46 mg/dL indicated a notable rise in C peptide and insulin levels, alongside beta hydroxybutyrate suppression, all of which fulfilled the diagnostic criteria for insulinoma. An abdominal magnetic resonance imaging (MRI) unveiled a 1.3 cm mass in the pancreatic tail. This case emphasizes the importance of employing a focused approach when evaluating non-diabetic individuals displaying hypoglycemia with positive Whipple's triad. This targeted method not only enables early detection of this rare condition but also assists in eliminating other common causes of recurrent hypoglycemia in non-diabetic individuals. Moreover, in addition to this diagnosis being rare, it is important to note that patients with insulinomas typically do not exhibit a glucose level low enough to induce seizures during their initial presentation.
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Affiliation(s)
- Asanka B Ekanayake
- Internal Medicine, HCA Florida Osceola Hospital, Kissimmee, USA
- Internal Medicine, University of Central Florida College of Medicine, Orlando, USA
| | - Harrison Stubbs
- Internal Medicine, HCA Florida Osceola Hospital, Kissimmee, USA
| | | | - Olga Karasik
- Internal Medicine, HCA Florida Osceola Hospital, Kissimmee, USA
| | - Mustafa Kinaan
- Endocrinology, HCA Florida Osceola Hospital, Kissimmee, USA
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12
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Crinò SF, Napoleon B, Facciorusso A, Lakhtakia S, Borbath I, Caillol F, Do-Cong Pham K, Rizzatti G, Forti E, Palazzo L, Belle A, Vilmann P, van Laethem JL, Mohamadnejad M, Godat S, Hindryckx P, Benson A, Tacelli M, De Nucci G, Binda C, Kovacevic B, Jacob H, Partelli S, Falconi M, Salvia R, Landoni L, Larghi A. Endoscopic Ultrasound-guided Radiofrequency Ablation Versus Surgical Resection for Treatment of Pancreatic Insulinoma. Clin Gastroenterol Hepatol 2023; 21:2834-2843.e2. [PMID: 36871765 DOI: 10.1016/j.cgh.2023.02.022] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 02/14/2023] [Accepted: 02/21/2023] [Indexed: 03/07/2023]
Abstract
BACKGROUND & AIMS Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is emerging as a safe and effective treatment for pancreatic neuroendocrine tumors. We aimed to compare EUS-RFA and surgical resection for the treatment of pancreatic insulinoma (PI). METHODS Patients with sporadic PI who underwent EUS-RFA at 23 centers or surgical resection at 8 high-volume pancreatic surgery institutions between 2014 and 2022 were retrospectively identified and outcomes compared using a propensity-matching analysis. Primary outcome was safety. Secondary outcomes were clinical efficacy, hospital stay, and recurrence rate after EUS-RFA. RESULTS Using propensity score matching, 89 patients were allocated in each group (1:1), and were evenly distributed in terms of age, sex, Charlson comorbidity index, American Society of Anesthesiologists score, body mass index, distance between lesion and main pancreatic duct, lesion site, size, and grade. Adverse event (AE) rate was 18.0% and 61.8% after EUS-RFA and surgery, respectively (P < .001). No severe AEs were observed in the EUS-RFA group compared with 15.7% after surgery (P < .0001). Clinical efficacy was 100% after surgery and 95.5% after EUS-RFA (P = .160). However, the mean duration of follow-up time was shorter in the EUS-RFA group (median, 23 months; interquartile range, 14-31 months vs 37 months; interquartile range, 17.5-67 months in the surgical group; P < .0001). Hospital stay was significantly longer in the surgical group (11.1 ± 9.7 vs 3.0 ± 2.5 days in the EUS-RFA group; P < .0001). Fifteen lesions (16.9%) recurred after EUS-RFA and underwent a successful repeat EUS-RFA (11 patients) or surgical resection (4 patients). CONCLUSION EUS-RFA is safer than surgery and highly effective for the treatment of PI. If confirmed in a randomized study, EUS-RFA treatment can become first-line therapy for sporadic PI.
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Affiliation(s)
- Stefano Francesco Crinò
- Digestive Endoscopy Unit, The Pancreas Institute, University Hospital of Verona, Verona, Italy.
| | - Bertrand Napoleon
- Service de Gastroentérologie, Hôpital Privé Jean Mermoz, Ramsay Générale de Santé, Lyon, France
| | - Antonio Facciorusso
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | | | - Ivan Borbath
- Department of Hepato-gastroenterology, Cliniques Universitaires St Luc, Brussels, Belgium
| | - Fabrice Caillol
- Endoscopy Unit, Paoli Calmettes Institute, Marseille, France
| | | | - Gianenrico Rizzatti
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Edoardo Forti
- Digestive and Interventional Endoscopy Unit, ASST Niguarda, Milan, Italy
| | | | - Arthur Belle
- Department of Gastroenterology, Cochin Hospital, Paris, France
| | - Peter Vilmann
- Department of Gastroenterology, Herlev-Gentofte Hospital, Herlev, Denmark
| | - Jean-Luc van Laethem
- Hepato-Gastroenterology, Hôpital Erasme, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Mehdi Mohamadnejad
- Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Sebastien Godat
- Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Pieter Hindryckx
- Department of Gastroenterology, University of Ghent, Ghent, Belgium
| | - Ariel Benson
- Institute of Gastroenterology and Hepatology, Hadassah Medical Center, Jerusalem, Israel and Faculty of Medicine, Hebrew University of Jerusalem, Israel
| | - Matteo Tacelli
- Pancreato-biliary Endoscopy and EUS Division, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Germana De Nucci
- Gastroenterology and Endoscopy Unit, ASST Rhodense, Garbagnate Milanese, Milan, Italy
| | - Cecilia Binda
- Gastroenterology and Digestive Endoscopy Unit, Ospedale Morgagni-Pierantoni, AUSL Romagna, Forlì, Italy
| | - Bojan Kovacevic
- Department of Gastroenterology, Herlev-Gentofte Hospital, Herlev, Denmark
| | - Harold Jacob
- Institute of Gastroenterology and Hepatology, Hadassah Medical Center, Jerusalem, Israel and Faculty of Medicine, Hebrew University of Jerusalem, Israel
| | - Stefano Partelli
- Pancreatic and Transplant Surgery Unit, Pancreas Translational and Clinical Research Centre, San Raffaele IRCCS, Università Vita-Salute, Milan, Italy
| | - Massimo Falconi
- Pancreatic and Transplant Surgery Unit, Pancreas Translational and Clinical Research Centre, San Raffaele IRCCS, Università Vita-Salute, Milan, Italy
| | - Roberto Salvia
- General and Pancreatic Surgery Department, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
| | - Luca Landoni
- General and Pancreatic Surgery Department, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
| | - Alberto Larghi
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
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13
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Crinò SF, Partelli S, Napoleon B, Conti Bellocchi MC, Facciorusso A, Salvia R, Forti E, Cintolo M, Mazzola M, Ferrari G, Carrara S, Repici A, Zerbi A, Lania A, Tacelli M, Arcidiacono PG, Falconi M, Larghi A, Rizzatti G, Alfieri S, Panzuto F, Hindryckx P, Berrevoet F, Lapauw B, Lakhtakia S, Sundaram S, Samanta J, Rastogi A, Landoni L. Study protocol for a multicenter randomized controlled trial to compare radiofrequency ablation with surgical resection for treatment of pancreatic insulinoma. Dig Liver Dis 2023; 55:1187-1193. [PMID: 37407318 DOI: 10.1016/j.dld.2023.06.021] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 06/19/2023] [Accepted: 06/21/2023] [Indexed: 07/07/2023]
Abstract
BACKGROUND Insulinoma is the most common functional pancreatic neuroendocrine tumor and treatment is required to address symptoms associated with insulin hypersecretion. Surgical resection is effective but burdened by high rate of adverse events (AEs). Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) demonstrated encouraging results in terms of safety and efficacy for the management of these tumors. However, studies comparing surgery and EUS-RFA are lacking. AIMS The primary aim is to compare EUS-RFA with surgery in term of safety (overall rate of AEs). Secondary endpoints include: (a) severe AEs rate; (b) clinical effectiveness; (c) patient's quality of life; (d) length of hospital stay; (e) rate of local/distance recurrence; (f) need of reintervention; (g) rate of endocrine and exocrine pancreatic insufficiency; (h) factors associated with EUS-RFA related AEs and clinical effectiveness. METHODS ERASIN-RCT is an international randomized superiority ongoing trial in four countries. Sixty patients will be randomized in two arms (EUS-RFA vs surgery) and outcomes compared. Two EUS-RFA sessions will be allowed to achieve symptoms resolution. Randomization and data collection will be performed online. DISCUSSION This study will ascertain if EUS-RFA can become the first-line therapy for management of small, sporadic, pancreatic insulinoma and be included in a step-up approach in case of clinical failure.
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Affiliation(s)
- Stefano Francesco Crinò
- Digestive Endoscopy Unit, The Pancreas Institute, G. B. Rossi University Hospital, University Hospital of Verona, P.le L.A. Scuro 10, Verona 37134, Italy.
| | - Stefano Partelli
- Pancreatic and Transplant Surgery Unit, Pancreas Translational and Clinical Research Centre, San Raffaele IRCCS, Università Vita-Salute, Milan, Italy
| | - Bertrand Napoleon
- Service de Gastroentérologie, Hôpital Privé Jean Mermoz, Ramsay Générale de Santé, Lyon, France
| | - Maria Cristina Conti Bellocchi
- Digestive Endoscopy Unit, The Pancreas Institute, G. B. Rossi University Hospital, University Hospital of Verona, P.le L.A. Scuro 10, Verona 37134, Italy
| | - Antonio Facciorusso
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Roberto Salvia
- General and Pancreatic Surgery Department, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
| | - Edoardo Forti
- Digestive and Interventional Endoscopy Unit, ASST Niguarda, Milan, Italy
| | - Marcello Cintolo
- Digestive and Interventional Endoscopy Unit, ASST Niguarda, Milan, Italy
| | - Michele Mazzola
- Division of Minimally-Invasive Surgical Oncology, ASST Niguarda, Milan, Italy
| | - Giovanni Ferrari
- Division of Minimally-Invasive Surgical Oncology, ASST Niguarda, Milan, Italy
| | - Silvia Carrara
- Division of Gastroenterology and Digestive Endoscopy, Humanitas Research Hospital-IRCCS, Rozzano, MI, Italy
| | - Alessandro Repici
- Division of Gastroenterology and Digestive Endoscopy, Humanitas Research Hospital-IRCCS, Rozzano, MI, Italy
| | - Alessandro Zerbi
- Pancreatic Unit, Humanitas Research Hospital-IRCCS, Rozzano, MI, Italy
| | - Andrea Lania
- Endocrinology, Diabetology and Medical Andrology Unit, Humanitas Research Hospital-IRCCS, Rozzano (MI), Italy
| | - Matteo Tacelli
- Pancreato-Biliary Endoscopy and EUS Division, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Paolo Giorgio Arcidiacono
- Pancreato-Biliary Endoscopy and EUS Division, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Massimo Falconi
- Pancreatic and Transplant Surgery Unit, Pancreas Translational and Clinical Research Centre, San Raffaele IRCCS, Università Vita-Salute, Milan, Italy
| | - Alberto Larghi
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Gianenrico Rizzatti
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Sergio Alfieri
- Pancreatic Surgery Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Francesco Panzuto
- Department of Medical-Surgical Sciences and Translational Medicine, Digestive Disease Unit, ENETS Center of Excellence, Sant'Andrea University Hospital, Sapienza University of Rome, Rome, Italy
| | - Pieter Hindryckx
- Department of Gastroenterology, University of Ghent, Ghent, Belgium
| | - Frederik Berrevoet
- Department of Hepatobiliopancreatic Surgery, University of Ghent, Ghent, Belgium
| | - Bruno Lapauw
- Department of Endocrinology, University of Ghent, Ghent, Belgium
| | | | - Sridhar Sundaram
- Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Mumbai, India
| | - Jayanta Samanta
- Departments of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashu Rastogi
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Luca Landoni
- General and Pancreatic Surgery Department, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
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14
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Borrelli de Andreis F, Boškoski I, Mascagni P, Schepis T, Bianchi A, Schinzari G, Annicchiarico BE, Quero G, Tortora G, Alfieri S, Gasbarrini A, Costamagna G, Spada C, Attili F. Safety and efficacy of endoscopic ultrasound-guided radiofrequency ablation for pancreatic insulinoma: A single-center experience. Pancreatology 2023; 23:543-549. [PMID: 37236853 DOI: 10.1016/j.pan.2023.05.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 04/28/2023] [Accepted: 05/13/2023] [Indexed: 05/28/2023]
Abstract
BACKGROUND/OBJECTIVES Insulinomas are rare, functioning pancreatic neuroendocrine neoplasms (pNEN), whose gold standard therapy is surgical resection. Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is a recent technique that has emerged as a minimally invasive therapeutic option for patients with pancreatic lesions not eligible for surgery. In this study, we aimed to describe a series of patients with unresectable pancreatic insulinoma treated with EUS-RFA. METHODS This is a single-center, retrospective study including all consecutive patients with functioning pancreatic insulinoma undergoing EUS-RFA for surgical unfitness or surgery refusal, between March 2017 and September 2021. Technical success (i.e., complete mass ablation), adverse event rate and severity, clinical and radiologic outcomes (i.e., symptom remission with a normal concentration of blood glucose, and the presence of intralesional necrosis), and post-procedural follow-up were assessed. RESULTS A total of 10 patients (mean age: 67.1 ± 10.1years; F:M 7:3) were included. The mean size of insulinoma was 11.9 ± 3.3 mm. Technical success and clinical remission were achieved in 100% of patients. Only one (10%) patient was successfully treated with two RFA sessions. Two procedure-related early adverse events occurred, including two (20%) cases of mild abdominal pain. No major complications were observed. The complete radiologic response within 3 months after EUS-RFA was observed in all patients (100%). After a median follow-up of 19.5 (range12-59) months, symptom remission and persistent euglycemia were assessed in all the patients. CONCLUSIONS Data from this case series suggest that EUS-RFA is a feasible and safe therapeutic approach for pancreatic insulinomas in patients unwilling or unable to undergo surgery with medium-term efficacy.
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Affiliation(s)
| | - Ivo Boškoski
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Centre for Endoscopic Research Therapeutics and Training (CERTT), Università Cattolica Del Sacro Cuore di Roma, Italy
| | - Pietro Mascagni
- Digestive Surgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Institute of Image-Guided Surgery, IHU-Strasbourg, France
| | - Tommaso Schepis
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Antonio Bianchi
- Endocrinology and Diabetology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Giovanni Schinzari
- Comprehensive Cancer Center, Medical Oncology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | | | - Giuseppe Quero
- Digestive Surgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Giampaolo Tortora
- Comprehensive Cancer Center, Medical Oncology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Sergio Alfieri
- Digestive Surgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Guido Costamagna
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Centre for Endoscopic Research Therapeutics and Training (CERTT), Università Cattolica Del Sacro Cuore di Roma, Italy
| | - Cristiano Spada
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Fabia Attili
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
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15
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Piscopo L, Zampella E, Pellegrino S, Volpe F, Nappi C, Gaudieri V, Fonti R, Vecchio SD, Cuocolo A, Klain M. Diagnosis, Management and Theragnostic Approach of Gastro-Entero-Pancreatic Neuroendocrine Neoplasms. Cancers (Basel) 2023; 15:3483. [PMID: 37444593 DOI: 10.3390/cancers15133483] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/23/2023] [Accepted: 06/30/2023] [Indexed: 07/15/2023] Open
Abstract
Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) constitute an ideal target for radiolabeled somatostatin analogs. The theragnostic approach is able to combine diagnosis and therapy by the identification of a molecular target that can be diagnosed and treated with the same radiolabeled compound. During the last years, advances in functional imaging with the introduction of somatostatin analogs and peptide receptor radionuclide therapy, have improved the diagnosis and treatment of GEP-NENs. Moreover, PET/CT imaging with 18F-FDG represents a complementary tool for prognostic evaluation of patients with GEP-NENs. In the field of personalized medicine, the theragnostic approach has emerged as a promising tool in diagnosis and management of patients with GEP-NENs. The aim of this review is to summarize the current evidence on diagnosis and management of patients with GEP-NENs, focusing on the theragnostic approach.
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Affiliation(s)
- Leandra Piscopo
- Department of Advanced Biomedical Sciences, University of Naples, Federico II, 80131 Naples, Italy
| | - Emilia Zampella
- Department of Advanced Biomedical Sciences, University of Naples, Federico II, 80131 Naples, Italy
| | - Sara Pellegrino
- Department of Advanced Biomedical Sciences, University of Naples, Federico II, 80131 Naples, Italy
| | - Fabio Volpe
- Department of Advanced Biomedical Sciences, University of Naples, Federico II, 80131 Naples, Italy
| | - Carmela Nappi
- Department of Advanced Biomedical Sciences, University of Naples, Federico II, 80131 Naples, Italy
| | - Valeria Gaudieri
- Department of Advanced Biomedical Sciences, University of Naples, Federico II, 80131 Naples, Italy
| | - Rosa Fonti
- Department of Advanced Biomedical Sciences, University of Naples, Federico II, 80131 Naples, Italy
| | - Silvana Del Vecchio
- Department of Advanced Biomedical Sciences, University of Naples, Federico II, 80131 Naples, Italy
| | - Alberto Cuocolo
- Department of Advanced Biomedical Sciences, University of Naples, Federico II, 80131 Naples, Italy
| | - Michele Klain
- Department of Advanced Biomedical Sciences, University of Naples, Federico II, 80131 Naples, Italy
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16
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Zhang J, Jiang R, Hong X, Wu H, Han X, Wu W. Metastatic insulinoma: exploration from clinicopathological signatures and genetic characteristics. Front Oncol 2023; 13:1109330. [PMID: 37251916 PMCID: PMC10213277 DOI: 10.3389/fonc.2023.1109330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Accepted: 04/27/2023] [Indexed: 05/31/2023] Open
Abstract
Background Insulinoma is a rare type of pancreatic neuroendocrine tumor with low incidence and low-malignant features. While very few insulinomas present with malignant behaviours, such as lymph node and liver metastasis, only a few studies have focused on this field owing to the limitation of samples. Existing evidence suggests that metastatic insulinoma largely derive from non-functional pancreatic neuroendocrine tumor. However, we found a portion of metastatic insulinomas may derive from non-metastatic insulinomas and explored their clinicopathological signatures and genetic characteristics. Methods Four metastatic insulinoma patients with synchronous liver metastasis or lymph node metastasis at the Peking Union Medical College Hospital between October 2016 and December 2018 were enrolled, and whole exon and genome sequencing were performed on fresh frozen tissues and peripheral blood samples. Clinicopathological information and genomic sequencing results were collected and matched to explore the characteristics of the metastatic insulinomas. Results These four metastatic insulinoma patients underwent surgery or interventional therapy, and their blood glucose levels immediately increased and maintained within standard range after treatment. For these four patients, the proinsulin/insulin molar ratio <1 and primary tumors were all present as PDX1+, ARX-, and insulin+, which were similar to non-metastatic insulinomas. However, the liver metastasis showed PDX1+ and ARX+, insulin+. Meanwhile, genomic sequencing data showed no recurrently mutations and typical CNV patterns. However, one patient harboured the YY1 T372R mutation, a recurrently mutated gene in non-metastatic insulinomas. Conclusions A portion of metastatic insulinomas were largely derived from non-metastatic insulinomas in hormone secretion and ARX/PDX1 expression patterns. Meanwhile, the accumulation of ARX expression may be involved in the progression of metastatic insulinomas.
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Affiliation(s)
- Jingcheng Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Rui Jiang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Xiafei Hong
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Huanwen Wu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Xianlin Han
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Wenming Wu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
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17
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Qiu L, Lan L, Cai L, Chen L, Chen Y. 68Ga-DOTA-Exendin-4 PET/CT Demonstrated a Higher Detection Efficacy for Double-Primary Insulinomas Than MRI: A Case Report. Clin Nucl Med 2023; 48:286-287. [PMID: 36723891 DOI: 10.1097/rlu.0000000000004508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
ABSTRACT We presented a 20-year-old woman with gradually increasing lethargy and multiple episodes of dizziness for 5 months. The laboratory examination revealed decreasing level of blood glucose and elevated levels of fasting plasma insulin and C-peptide. The MRI identified a focal nodule in the tail of the pancreas. 68Ga-DOTA-exendin-4 PET/CT revealed 2 intense focal tracer uptakes in the tail of the pancreas, one of which corresponded to the lesion revealed on MRI. The immunohistochemical results of resected samples confirmed the diagnosis of double-primary insulinomas. 68Ga-DOTA-exendin-4 PET/CT demonstrated excellent localization and characterization for double-primary insulinomas in the tail of the pancreas.
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18
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Melikyan M, Gubaeva D, Shadrina A, Bolmasova A, Kareva M, Tiulpakov A, Efremenkov A, Sokolov Y, Brusgaard K, Christesen HT, Andersen K, Stepanov A, Averyanova J, Makarov S, Gurevich L. Insulinoma in childhood: a retrospective review of 22 patients from one referral centre. Front Endocrinol (Lausanne) 2023; 14:1127173. [PMID: 37152923 PMCID: PMC10155867 DOI: 10.3389/fendo.2023.1127173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 03/27/2023] [Indexed: 05/09/2023] Open
Abstract
Background Insulinomas are very rare in childhood with sparse knowledge on the clinical aspects and the presence of Multiple Endocrine Neoplasia type 1 (MEN1). Methods We conducted a retrospective review of patients diagnosed with insulinoma between 1995 and 2021, presenting to one referral centre in Russia. Clinical, biochemical, genetic, imaging and histological data were collected. In addition, follow-up and family data were obtained. Results A total of twenty-two children aged 5 to 16 years were identified. The median (range) gap between the first hypoglycaemia symptoms and diagnosis was 10 (1-46) months. Twelve children (55%) were misdiagnosed to have epilepsy and were treated with anticonvulsants before hypoglycemia was revealed. Contrast enhanced MRI and/or CT were accurate to localize the lesion in 82% (n=18). Five patients (23%) had multiple pancreatic lesions. All children underwent surgical treatment. The median (range) diameter of removed tumors was 1.5 (0.3-6) cm. Histopathological studies confirmed the presence of insulinoma in all cases. Immunohistochemical studies revealed G2 differentiation grade in 10 out of 17 cases. Two patients were diagnosed with metastatic insulinoma. One of them had metastases at the time of insulinoma diagnosis, while the other was diagnosed with liver metastases eight years after the surgery. Eight children (36%) were found to carry MEN1 mutations, inherited n=5, de novo n=1, no data, n=2. Children with MEN1 had significantly higher number of pancreatic tumors compared to sporadic cases. All of them developed additional MEN1 symptoms during the following 2-13 years. In the five patients with inherited MEN1, seven family members had hitherto undiscovered MEN1 manifestations. Conclusions In this large cohort of children with rare pediatric insulinomas, MEN1 syndrome and G2 tumors were frequent, as well as hitherto undiscovered MEN1 manifestations in family members. Our data emphasize the need of genetic testing in all children with insulinoma and their relatives, even in the absence of any other features, as well as the importance of a prolonged follow-up observation.
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Affiliation(s)
- Maria Melikyan
- Department of Pediatric Endocrinology, Endocrinology Research Center, Moscow, Russia
- Department of Endocrinology, Yerevan State Medical University, Yerevan, Armenia
- Department of pediatrics, Center of Medical Genetics and Primary Health Care, Yerevan, Armenia
- *Correspondence: Maria Melikyan,
| | - Diliara Gubaeva
- Department of Pediatric Endocrinology, Endocrinology Research Center, Moscow, Russia
- Department of Pediatric Endocrinology, Alder Hey Children’s Hospital, Liverpool, United Kingdom
| | - Anna Shadrina
- Department of Pediatric Endocrinology, Endocrinology Research Center, Moscow, Russia
| | - Anna Bolmasova
- Department of Pediatric Endocrinology, Endocrinology Research Center, Moscow, Russia
| | - Maria Kareva
- Department of Pediatric Endocrinology, Endocrinology Research Center, Moscow, Russia
| | - Anatoly Tiulpakov
- Department of Pediatric Endocrinology, Endocrinology Research Center, Moscow, Russia
- Department of Endocrinology, Federal State Budgetary Scientific Institution Research Centre for Medical Genetics (RCMG), Moscow, Russia
| | - Artem Efremenkov
- Department of Pediatric Surgery, Central Clinical Hospital, Moscow, Russia
| | - Yuri Sokolov
- Department of Pediatric Surgery, Endocrinology Research Center, Moscow, Russia
| | - Klaus Brusgaard
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
- Odense Pancreas Center OPAC and Steno Diabetes Center Odense, Odense, Denmark
- Department of Endocrinology, Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark
| | - Henrik T. Christesen
- Odense Pancreas Center OPAC and Steno Diabetes Center Odense, Odense, Denmark
- Department of Endocrinology, Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | - Kirstine Andersen
- Odense Pancreas Center OPAC and Steno Diabetes Center Odense, Odense, Denmark
- Department of Endocrinology, Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | - Alexey Stepanov
- Department of Abdominal Surgery, Russian Children's Clinical Hospital, Moscow, Russia
| | - Julia Averyanova
- Department of Abdominal Surgery, Russian Children's Clinical Hospital, Moscow, Russia
| | - Sergey Makarov
- Department of Abdominal Surgery, Russian Children's Clinical Hospital, Moscow, Russia
| | - Larisa Gurevich
- Morphological Department of Oncology, State Budget Health Agency Moscow Region Moscow Regional Research Clinical Institute, Moscow, Russia
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19
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Walker MP, Shenoy V, Metz DC, Stanley CA, Fraker D, Chandrasekhara V, Amaro A. Case presentation of 8-year follow up of recurrent malignant duodenal Insulinoma and lymph node metastases and literature review of malignant Insulinoma management. BMC Endocr Disord 2022; 22:310. [PMID: 36494838 PMCID: PMC9733155 DOI: 10.1186/s12902-022-01219-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 11/04/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Insulinoma is an uncommon insulin-secreting neuroendocrine tumor that presents with severe recurrent hypoglycemia. Although cases of extrapancreatic insulinomas have been reported, the majority of insulinomas occur in the pancreas. The number of reported cases of ectopic insulinomas with follow-up assessments is limited and they do not report disease recurrence. The current report presents the first documented case of recurrent extrapancreatic insulinoma with 8 years of follow-up, provides relevant literature review, and proposes surveillance and treatment strategies. CASE PRESENTATION We describe an insulinoma localized in the duodenal wall of a 36-year-old female who presented in 2013 with weight gain and Whipple's triad and was successfully managed with duodenotomy and enucleation. She presented again in 2017 with recurrent Whipple's triad and was found to have metastatic disease localized exclusively to peripancreatic lymph nodes. Primary pancreatic insulinoma was not evident and her hypoglycemia resolved following lymph node dissection. Eight years after initial presentation continuous glucose monitoring (CGM) showed a trend for euglycemia, and PET-CT Gallium 68 DOTATATE scan evaluation indicated absence of recurrent disease. CONCLUSION Insulinomas are rare clinical entities and extrapancreatic insulinomas are particularly uncommon. Follow-up evaluation and treatment strategies for ectopic insulinoma recurrence presents a significant clinical challenge as the condition has hitherto remained undescribed in the literature. Available evidence in the literature indicates that lymph node metastases of intrapancreatic insulinomas likely do not change prognosis. Given the absence of long-term data informing the management and monitoring of patients with extrapancreatic insulinoma, we suggest patient education for hypoglycemic symptoms, monitoring for hypoglycemia with CGM, annual imaging, and a discussion with patients regarding treatment with octreotide or alternative somatostatin receptor analog therapies.
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Affiliation(s)
- Michelle P Walker
- Department of Endocrinology, University of Pennsylvania, 3400 Civic Center Boulevard, West Pavilion, 4th Floor, Philadelphia, PA, 19104, USA.
| | - Vikram Shenoy
- Department of Endocrinology, Christiana Care, 4735 Ogletown Stanton Road, Suite MAP2, Newark, DE, 19713, USA
| | - David C Metz
- Department of Gastroenterology, University of Pennsylvania, 3400 Civic Center Boulevard, South Pavilion, 4th Floor, Philadelphia, PA, 19104, USA
| | - Charles A Stanley
- Department of Endocrinology and Metabolism, Children's Hospital of Philadelphia, 3516 Civic Center Boulevard #802, Philadelphia, PA, 19104, USA
| | - Douglas Fraker
- Department of Endocrine and Oncologic Surgery, University of Pennsylvania, 3400 Civic Center Boulevard, West Pavilion, 3rd Floor, Philadelphia, PA, 19104, USA
| | - Vinay Chandrasekhara
- Department of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street. SW, Rochester, MN, 55905, USA
| | - Anastassia Amaro
- Department of Endocrinology, University of Pennsylvania, 3400 Civic Center Boulevard, West Pavilion, 4th Floor, Philadelphia, PA, 19104, USA
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20
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Henker R, Lincke T, Hoffmeister A. Case report - Selective internal radiation therapy (SIRT) in a patient with hyperinsulinemic hypoglycemia due to a metastatic insulinoma with late onset of endocrine activity. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:1332-1334. [PMID: 35042268 DOI: 10.1055/a-1690-8018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Insulinomas are the most common functioning pancreatic neuroendocrine tumors (NET), which can lead to hyperinsulinemic hypoglycemia. In advanced metastatic stages of the disease, the prognosis is poor. Patients with hormonally active insulinomas primarily present with features of neuroglycopenia. Transformation from a nonfunctional to a functional NET is rare. Here, we present a case of a 59-year-old male adult with a metastatic insulinoma and late onset of endocrine activity. Besides medical treatment with Diazoxide and small frequent feedings, continuous intravenous glucose application was eventually required to avoid hypoglycemia. Furthermore, we show that selective internal radiation therapy (SIRT) can be an effective therapeutic approach for symptom reduction in advanced metastatic disease.
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Affiliation(s)
- Robert Henker
- Medizinische Klinik 2, Universitatsklinikum Leipzig, Leipzig, Germany
| | - Thomas Lincke
- Klinik und Poliklinik für Nuklearmedizin, Universitätsklinikum Leipzig, Leipzig, Germany
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21
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Wang F, Yang Z, Chen X, Peng Y, Jiang H, Qin S. A novel diagnostic model for insulinoma. Discov Oncol 2022; 13:68. [PMID: 35916979 PMCID: PMC9346017 DOI: 10.1007/s12672-022-00534-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 07/27/2022] [Indexed: 11/28/2022] Open
Abstract
The aim is to describe a simple and feasible model for the diagnosis of insulinoma. This retrospective study enrolled 37 patients with insulinoma and 44 patients with hypoglycemia not due to insulinoma at the First Affiliated Hospital of Guangxi Medical University. General demographic and clinical characteristics; hemoglobin A1c (HbA1c), insulin and C-peptide concentrations; and the results of 2-h oral glucose tolerance tests (OGTT) were recorded, and a logistic regression model predictive of insulinoma was determined. Body mass index (BMI), HbA1c concentration, 0-h C-peptide concentration, and 0-h and 1-h plasma glucose concentrations (P < 0.05 each) were independently associated with insulinoma. A regression prediction model was established through multivariate logistics regression analysis: Logit p = 7.399+(0.310 × BMI) - (1.851 × HbA1c) - (1.467 × 0-h plasma glucose) + (1.963 × 0-h C-peptide) - (0.612 × 1-h plasma glucose). Using this index to draw a receiver operating characteristic (ROC) curve, the area under the curve (AUC) was found to be 0.957. The optimal cut-off value was - 0.17, which had a sensitivity of 89.2% and a specificity of 86.4%. Logit P ≥ - 0.17 can be used as a diagnostic marker for predicting insulinoma in patients with hypoglycemia.
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Affiliation(s)
- Feng Wang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Zhe Yang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - XiuBing Chen
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Yiling Peng
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - HaiXing Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China.
| | - ShanYu Qin
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China.
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22
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Adelmeyer J, Göbel F, Kann PH. Is the Size of Insulinoma Predictive for its Endocrine Behavior? An Endoscopic Ultrasound Study. Exp Clin Endocrinol Diabetes 2022; 130:687-692. [PMID: 35500603 DOI: 10.1055/a-1840-7492] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
OBJECTIVE Insulinoma is a rare tumor of the pancreas that can lead to spontaneous hypoglycemia due to excessive insulin secretion. Seventy-two-hour fast is the gold standard for finding the correct diagnosis. Endoscopic ultrasound (EUS) is an established examination method to identify the suspicious lesion. Previous studies correlate the measured size of insulinoma and their endocrine behavior. This study was designed to find a relation between these variables. METHODS We took the data of patients who had a histologically confirmed insulinoma after receiving an endoscopic ultrasound in our department. Size and echogenicity were correlated with the endpoint of the 72-hour fast and hormone levels. RESULTS A total of 45 patients were identified. Most insulinomas were small with a volume of<2 cm3 (median 1.15 cm3). There was no correlation between the duration of fasting, hormone levels, and the size of the insulinoma. In addition, in a subgroup analysis, no connection could be established between the size of the insulinoma and the amount of insulin released after oral glucose exposure. We found that homogeneous tumors were significantly smaller and had a lower Ki-67 index. Furthermore, there was a tendency towards a shorter duration for the 72-hour fast for the small tumors. DISCUSSION This data suggests that the measured size of insulinoma by EUS is not related to the time until termination of the 72-hour fast and measured hormone levels. The echogenicity seems more important, showing that homogenous tumors are an indicator of a higher differentiation, which can result in a shorter duration of the fasting period. The differences in the secretion behavior of the insulinomas could complicate the correlation of size and the 72-hour fast period.
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Affiliation(s)
- Jan Adelmeyer
- Center for Endocrinology, Diabetology & Osteology of Philipps-University Marburg 35037 Marburg, Germany
| | - Franziska Göbel
- Center for Endocrinology, Diabetology & Osteology of Philipps-University Marburg 35037 Marburg, Germany
| | - Peter Herbert Kann
- Center for Endocrinology, Diabetology & Osteology of Philipps-University Marburg 35037 Marburg, Germany
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23
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Karanth JB, Pai V, Maribashetti K. Pancreatic neuroendocrine tumour-insulinoma masquerading as a psychiatric illness. BMJ Case Rep 2022; 15:e249698. [PMID: 35701018 PMCID: PMC9198684 DOI: 10.1136/bcr-2022-249698] [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: 06/06/2022] [Indexed: 11/03/2022] Open
Abstract
A female patient in her early sixties had problems of recurrent syncopal attacks and panic attacks over the last 5 years. She had been initially managed for an anxiety disorder with psychiatric medications. During one of those episodes, she was brought to our hospital in an unconscious state with a low blood sugar level of 43 mg/dL. She was suspected to have a neuroendocrine tumour and diagnosis was established by supervised fasting up to 72 hours and imaging. Her recorded blood sugar during fasting was 37 mg/dL. She underwent surgery and presently remains asymptomatic. Physicians should have a high suspicion of insulinoma in patients presenting with repeated episodes of hypoglycaemic symptoms in the absence of any cognizable cause.
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Affiliation(s)
| | - Vishwas Pai
- Oncosurgery, Shripad Hegde Institute of Medical Sciences, Sirsi, Karnataka, India
| | - Kiran Maribashetti
- Internal Medicine, Army Hospital Research and Referral, New Delhi, India
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24
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Sharma A, Varshney P, Kasliwal R, Nagar A, Venkatatelikicherla K, Sarin S, Choubey RP, Kapoor VK. Insulinoma—Accurate Preoperative Localization Is the Key to Management: An Initial Experience. Indian J Surg Oncol 2022; 13:403-411. [DOI: 10.1007/s13193-022-01534-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 04/19/2022] [Indexed: 11/30/2022] Open
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25
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McComb K, Roulston G, Armstrong L. Insulinoma: an uncommon cause of delirium. Age Ageing 2022; 51:6550830. [PMID: 35305086 DOI: 10.1093/ageing/afac055] [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: 08/01/2021] [Indexed: 11/13/2022] Open
Abstract
We present the case of an 83-year-old woman with recurrent episodes of delirium occurring overnight, associated with hypoglycaemia. Other causes for delirium were excluded. Laboratory findings were in keeping with endogenous insulin production. Computerised tomography imaging revealed a small mass in the pancreas supporting a presumed diagnosis of an insulinoma. Given the patient's frailty and cognitive impairment, a conservative management approach was taken. Diazoxide was commenced with resolution of episodes of delirium. This case highlights hypoglycaemia, and insulinoma, as a rare, but treatable cause of delirium. It demonstrates the importance of blood sugar screening in delirium. It emphasises the holistic modifications to management, which must be taken to ensure patient-centred care when caring for an older adult living with frailty, who may have cognitive impairment.
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Affiliation(s)
- Katie McComb
- Lagan Valley Hospital, South Eastern Health and Social Care Trust, Lisburn BT28 1JP, UK
| | - Gary Roulston
- Lagan Valley Hospital, South Eastern Health and Social Care Trust, Lisburn BT28 1JP, UK
| | - Lynne Armstrong
- Lagan Valley Hospital, South Eastern Health and Social Care Trust, Lisburn BT28 1JP, UK
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26
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Yang Y, Shi J, Zhu J. Diagnostic performance of noninvasive imaging modalities for localization of insulinoma: A meta-analysis. Eur J Radiol 2021; 145:110016. [PMID: 34763145 DOI: 10.1016/j.ejrad.2021.110016] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/25/2021] [Accepted: 10/31/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Insulinoma is the most common functional neuroendocrine tumor found only in the pancreas. The early detection of insulinoma is of importance. Studies comparing the performance of noninvasive modalities were limited by sample size and heterogeneity between studies. The aim of this meta-analysis was to evaluate the diagnostic performance of PET/CT, SPECT/CT, CT and MRI for the localization of insulinoma, and to provide evidence for clinical practice. METHODS PubMed, Embase, Cochrane Library, Wanfang Data and China National Knowledge Infrastructure were searched from inception to May 31, 2021. Pooled sensitivity, specificity, positive Likelihood Ratio (+LR) and negative Likelihood Ratio (-LR), diagnostic odds ratio (DOR), and concordance rate were calculated. RESULTS A total of 19 studies including 708 patients of insulinoma reached the inclusion criteria. PET/CT imaging demonstrated a pooled sensitivity of 0.79 (95% CI: 0.54-0.92) and a pooled specificity of 0.84 (95% CI: 0.20-0.99). The pooled sensitivity and specificity of SPECT/CT were 0.77 (95% CI: 0.46-0.93) and 0.45 (95% CI: 0.22-0.70). CT showed an overall sensitivity of 0.54 (95% CI: 0.35-0.72) and specificity of 0.75 (95% CI: 0.54-0.88). The pooled sensitivity and specificity for MRI were 0.54 (95% CI: 0.31-0.75) and 0.65 (95% CI: 0.39-0.84), respectively. The concordance rates of PET, SPECT, CT, and MRI were 78% (95% CI: 66-90%), 74% (95% CI: 52-97%), 56% (95% CI: 41-72%), and 53% (95% CI: 33-73%), respectively. CONCLUSION Results of this study indicate that PET/CT demonstrated superior performance than SPECT/CT, CT and MRI for the localization of insulinoma. GLP-1R based PET/CT manifested better diagnostic performance in comparison with SSTR based PET/CT imaging modality.
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Affiliation(s)
- Yi Yang
- Department of Nuclear Medicine, The Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medical University, Suzhou, Jiangsu Province, PR China
| | - Jian Shi
- Department of Radiology, Suzhou Integrative Traditional Chinese and Western Medicine Hospital, Suzhou, Jiangsu Province, PR China
| | - Jianbing Zhu
- Department of Radiology, The Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medical University, Suzhou, Jiangsu Province, PR China.
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Diagnostic and Interventional Role of Endoscopic Ultrasonography for the Management of Pancreatic Neuroendocrine Neoplasms. J Clin Med 2021; 10:jcm10122638. [PMID: 34203922 PMCID: PMC8232656 DOI: 10.3390/jcm10122638] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 05/28/2021] [Accepted: 06/07/2021] [Indexed: 12/11/2022] Open
Abstract
Pancreatic neuroendocrine neoplasms (PanNENs) are relatively rare, but their incidence has increased significantly in the last decades. Precise diagnosis and prognostic stratification are crucial for proper patient management. Endoscopic ultrasound (EUS) is the modality of choice for diagnosis of solid pancreatic tumors, showing a higher tumor detection rate than other imaging modalities, especially for small size lesions. EUS also serves as a guide for preoperative sampling and other interventions. EUS-tissue acquisition is a safe and highly accurate technique for cyto/histological diagnosis of PanNENs with a well-demonstrated correlation between Ki-67 proliferation index values and tumor grading on EUS and surgical specimens according to the WHO 2017 classification. Furthermore, the possibility of a preoperative EUS-guided fine needle tattooing or fiducial markers placement may help the surgeon to locate small and deep tumors, thus avoiding formal pancreatic resections in favor of parenchymal-sparing surgery. Finally, locoregional ablative treatments using either ethanol injection or radiofrequency ablation have been proposed in recent studies with promising results in order to control symptoms or reduce tumor burden in selected patients unfit for surgery with functioning or non-functioning PanNENs. This article review highlights the current role of EUS in PanNENs management, focusing on the present and future applications of EUS-guided interventions.
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28
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Spada F, Rossi RE, Kara E, Laffi A, Massironi S, Rubino M, Grimaldi F, Bhoori S, Fazio N. Carcinoid Syndrome and Hyperinsulinemic Hypoglycemia Associated with Neuroendocrine Neoplasms: A Critical Review on Clinical and Pharmacological Management. Pharmaceuticals (Basel) 2021; 14:ph14060539. [PMID: 34199977 PMCID: PMC8228616 DOI: 10.3390/ph14060539] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 05/31/2021] [Accepted: 06/01/2021] [Indexed: 02/05/2023] Open
Abstract
The carcinoid syndrome (CS) and hyperinsulinemic hypoglycemia (HH) represent two of the most common clinical syndromes associated with neuroendocrine neoplasms (NENs). The former is mainly related to the serotonin secretion by a small bowel NEN, whereas the latter depends on an insulin hypersecretion by a pancreatic insulinoma. Both syndromes/conditions can affect prognosis and quality of life of patients with NENs. They are often diagnosed late when patients become strongly symptomatic. Therefore, their early detection and management are a critical step in the clinical management of NEN patients. A dedicated and experienced multidisciplinary team with appropriate therapeutic strategies is needed and should be encouraged to optimize clinical outcomes. This review aims to critically analyze clinical features, evidence and treatment options of CS and HH and therefore to improve their management.
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Affiliation(s)
- Francesca Spada
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO) IRCCS, via G. Ripamonti 435, 20141 Milano, Italy; (F.S.); (A.L.); (M.R.)
| | - Roberta E. Rossi
- Hepatology and Hepato-Pancreatic-Biliary Surgery and Liver Transplantation, Fondazione IRCCS, Istituto Nazionale Tumori (INT), via G. Venezian 1, 20133 Milano, Italy; (R.E.R.); (S.B.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, via Festa del Perdono 7, 20122 Milano, Italy
| | - Elda Kara
- Endocrinology and Metabolism Unit, University Hospital S. Maria della Misericordia, Piazzale Santa Maria della Misericordia, 15, 33100 Udine, Italy; (E.K.); (F.G.)
| | - Alice Laffi
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO) IRCCS, via G. Ripamonti 435, 20141 Milano, Italy; (F.S.); (A.L.); (M.R.)
| | - Sara Massironi
- Division of Gastroenterology, San Gerardo Hospital, Bicocca School of Medicine, University of Milano Bicocca, 20126 Milano, Italy;
| | - Manila Rubino
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO) IRCCS, via G. Ripamonti 435, 20141 Milano, Italy; (F.S.); (A.L.); (M.R.)
| | - Franco Grimaldi
- Endocrinology and Metabolism Unit, University Hospital S. Maria della Misericordia, Piazzale Santa Maria della Misericordia, 15, 33100 Udine, Italy; (E.K.); (F.G.)
| | - Sherrie Bhoori
- Hepatology and Hepato-Pancreatic-Biliary Surgery and Liver Transplantation, Fondazione IRCCS, Istituto Nazionale Tumori (INT), via G. Venezian 1, 20133 Milano, Italy; (R.E.R.); (S.B.)
| | - Nicola Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO) IRCCS, via G. Ripamonti 435, 20141 Milano, Italy; (F.S.); (A.L.); (M.R.)
- Correspondence: ; Tel.: +39-025-748-9258
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Effraimidis G, Knigge U, Rossing M, Oturai P, Rasmussen ÅK, Feldt-Rasmussen U. Multiple endocrine neoplasia type 1 (MEN-1) and neuroendocrine neoplasms (NENs). Semin Cancer Biol 2021; 79:141-162. [PMID: 33905872 DOI: 10.1016/j.semcancer.2021.04.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 01/03/2021] [Accepted: 04/16/2021] [Indexed: 12/14/2022]
Abstract
Neuroendocrine neoplasms (NENs) are relatively rare neoplasms with 6.4-times increasing age-adjusted annual incidence during the last four decades. NENs arise from neuroendocrine cells, which release hormones in response to neuronal stimuli and they are distributed into organs and tissues. The presentation and biological behaviour of the NENs are highly heterogeneous, depending on the organ. The increased incidence is mainly due to increased awareness and improved detection methods both in the majority of sporadic NENs (non-inherited), but also the inherited groups of neoplasms appearing in at least ten genetic syndromes. The most important one is multiple endocrine neoplasia type 1 (MEN-1), caused by mutations in the tumour suppressor gene MEN1. MEN-1 has been associated with different tumour manifestations of NENs e.g. pancreas, gastrointestinal tract, lungs, thymus and pituitary. Pancreatic NENs tend to be less aggressive when arising in the setting of MEN-1 compared to sporadic pancreatic NENs. There have been very important improvements over the past years in both genotyping, genetic counselling and family screening, introduction and validation of various relevant biomarkers, as well as newer imaging modalities. Alongside this development, both medical, surgical and radionuclide treatments have also advanced and improved morbidity, quality of life and mortality in many of these patients. Despite this progress, there is still space for improving insight into the genetic and epigenetic factors in relation to the biological mechanisms determining NENs as part of MEN-1. This review gives a comprehensive update of current evidence for co-occurrence, diagnosis and treatment of MEN-1 and neuroendocrine neoplasms and highlight the important progress now finding its way to international guidelines in order to improve the global management of these patients.
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Affiliation(s)
- Grigoris Effraimidis
- ENETS Neuroendocrine Tumor Centre of Excellence, Rigshospitalet, Copenhagen University Hospital, Denmark; Department of Medical Endocrinology and Metabolism, Rigshospitalet, Copenhagen University Hospital, Denmark
| | - Ulrich Knigge
- ENETS Neuroendocrine Tumor Centre of Excellence, Rigshospitalet, Copenhagen University Hospital, Denmark; Department of Medical Endocrinology and Metabolism, Rigshospitalet, Copenhagen University Hospital, Denmark; Department of Surgery and Transplantation, Rigshospitalet, Copenhagen University Hospital, Denmark
| | - Maria Rossing
- Centre for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Denmark
| | - Peter Oturai
- Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Copenhagen University Hospital, Denmark
| | - Åse Krogh Rasmussen
- ENETS Neuroendocrine Tumor Centre of Excellence, Rigshospitalet, Copenhagen University Hospital, Denmark; Department of Medical Endocrinology and Metabolism, Rigshospitalet, Copenhagen University Hospital, Denmark
| | - Ulla Feldt-Rasmussen
- ENETS Neuroendocrine Tumor Centre of Excellence, Rigshospitalet, Copenhagen University Hospital, Denmark; Department of Medical Endocrinology and Metabolism, Rigshospitalet, Copenhagen University Hospital, Denmark; Institute of Clinical Medicine, Faculty of Health Sciences, Copenhagen University, Denmark.
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Dobrindt EM, Mogl M, Goretzki PE, Pratschke J, Dukaczewska AK. Insulinoma in pregnancy (a case presentation and systematic review of the literature). Rare Tumors 2021; 13:2036361320986647. [PMID: 33613925 PMCID: PMC7874339 DOI: 10.1177/2036361320986647] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 12/17/2020] [Indexed: 12/05/2022] Open
Abstract
Insulinomas are rare, benign and functional tumors that coincidentally may become overt during pregnancy or in the post-partum period. As the general symptoms of a pregnancy might cover the clinical presentation, diagnosing remains challenging. We present one additional case of a post-partum insulinoma, combined with a systematic review of the literature to sum up relevant details in diagnosis and treatment. A systematic request of Pubmed/Medline was conducted using the following terms: "insulinoma AND pregnancy" and "insulinoma" for a second request of ClinicalTrials.gov. All publications concerning pregnant or post-partum women with insulinoma were included. Thirty-six cases could be identified for analysis. Each publication was reviewed for demographic, diagnostic and therapeutic data. The most frequent clinical signs were unconsciousness and neurological symptoms. 64.9% were diagnosed during early pregnancy and 35.1% post-partum. 91.9% underwent surgery with a third resected during pregnancy without severe influence on fetal or maternal outcome. Three patients died of metastatic disease or misdiagnosing, two of them miscarried. Insulinoma in pregnancy is rare but should be considered in case of unclear hyperinsulinemic hypoglycemia. Surgery can be performed during the second trimester or post-partum with promising outcome.
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Affiliation(s)
- Eva M Dobrindt
- Department of Surgery, Campus Charité Mitte|Campus Virchow-Klinikum, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin
| | - Martina Mogl
- Department of Surgery, Campus Charité Mitte|Campus Virchow-Klinikum, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin
| | - Peter E Goretzki
- Department of Surgery, Campus Charité Mitte|Campus Virchow-Klinikum, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte|Campus Virchow-Klinikum, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin
| | - Agata K Dukaczewska
- Department of Surgery, Campus Charité Mitte|Campus Virchow-Klinikum, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin
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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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Cavalcoli F, Rossi RE, Massironi S. Circulating Biochemical Markers of Gastro-Entero-Pancreatic (GEP) Neuroendocrine Neoplasms (NENs). NEUROENDOCRINE NEOPLASIA MANAGEMENT 2021:55-74. [DOI: 10.1007/978-3-030-72830-4_5] [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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Niederle B, Selberherr A, Bartsch DK, Brandi ML, Doherty GM, Falconi M, Goudet P, Halfdanarson TR, Ito T, Jensen RT, Larghi A, Lee L, Öberg K, Pavel M, Perren A, Sadowski SM, Tonelli F, Triponez F, Valk GD, O'Toole D, Scott-Coombes D, Thakker RV, Thompson GB, Treglia G, Wiedenmann B. Multiple Endocrine Neoplasia Type 1 and the Pancreas: Diagnosis and Treatment of Functioning and Non-Functioning Pancreatic and Duodenal Neuroendocrine Neoplasia within the MEN1 Syndrome - An International Consensus Statement. Neuroendocrinology 2021; 111:609-630. [PMID: 32971521 DOI: 10.1159/000511791] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 09/18/2020] [Indexed: 11/19/2022]
Abstract
The better understanding of the biological behavior of multiple endocrine neoplasia type 1 (MEN1) organ manifestations and the increase in clinical experience warrant a revision of previously published guidelines. Duodenopancreatic neuroendocrine neoplasias (DP-NENs) are still the second most common manifestation in MEN1 and, besides NENs of the thymus, remain a leading cause of death. DP-NENs are thus of main interest in the effort to reevaluate recommendations for their diagnosis and treatment. Especially over the last 2 years, more clinical experience has documented the follow-up of treated and untreated (natural-course) DP-NENs. It was the aim of the international consortium of experts in endocrinology, genetics, radiology, surgery, gastroenterology, and oncology to systematically review the literature and to present a consensus statement based on the highest levels of evidence. Reviewing the literature published over the past decade, the focus was on the diagnosis of F- and NF-DP-NENs within the MEN1 syndrome in an effort to further standardize and improve treatment and follow-up, as well as to establish a "logbook" for the diagnosis and treatment of DP-NENs. This shall help further reduce complications and improve long-term treatment results in these rare tumors. The following international consensus statement builds upon the previously published guidelines of 2001 and 2012 and attempts to supplement the recommendations issued by various national and international societies.
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Affiliation(s)
- Bruno Niederle
- Department of Surgery, Medical University of Vienna, Vienna, Austria,
| | | | - Detlef K Bartsch
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Maria L Brandi
- Firmo Lab, Fondazione F.I.R.M.O. and University Florence, Florence, Italy
| | - Gerard M Doherty
- Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Massimo Falconi
- Pancreatic Surgery, San Raffaele Scientific Institute, "Vita-Salute" University, Milan, Italy
| | - Pierre Goudet
- Service de Chirurgie Viscérale et Endocrinienne, Centre Hospitalier Universitaire François Mitterand, Dijon, France
| | | | - Tetsuhide Ito
- Neuroendocrine Tumor Centre, Fukuoka Sanno Hospital and Department of Gastroenterology, Graduate School of Medical Sciences, International University of Health and Welfare, Sawara-ku, Fukuoka, Japan
| | - Robert T Jensen
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Alberto Larghi
- Digestive Endoscopy Unit, Fondazione Policlinico A. Gemelli IRCCS and Center for Endoscopic Research, Therapeutics and Training, Catholic University, Rome, Italy
| | - Lingaku Lee
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Kjell Öberg
- Endocrine Oncology, Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden
| | - Marianne Pavel
- Endocrinology and Diabetology, Department of Medicine 1, University Clinic of Erlangen, Erlangen, Germany
| | - Aurel Perren
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Samira M Sadowski
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Francesco Tonelli
- Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
| | - Frédéric Triponez
- Thoracic and Endocrine Surgery, University Hospital of Geneva, Geneva, Switzerland
| | - Gerlof D Valk
- Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Dermot O'Toole
- Department of Clinical Medicine, St. James's Hospital and St Vincent's University Hospital and Trinity College, Dublin, Ireland
| | - David Scott-Coombes
- Department of Endocrine Surgery, University Hospital of Wales, Cardiff, United Kingdom
| | - Rajesh V Thakker
- Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, United Kingdom
| | - Geoffrey B Thompson
- Section of Endocrine Surgery, Department of Gastroenterologic and General Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Giorgio Treglia
- Imaging Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
| | - Bertram Wiedenmann
- Department of Gastroenterology and Hepatology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany
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Prídavková D, Samoš M, Kyčina R, Adamicová K, Kalman M, Belicová M, Mokáň M. Insulinoma presenting with postprandial hypoglycemia and a low body mass index: A case report. World J Clin Cases 2020; 8:4169-4176. [PMID: 33024775 PMCID: PMC7520770 DOI: 10.12998/wjcc.v8.i18.4169] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/23/2020] [Accepted: 08/21/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Insulinomas are the most common type of functioning endocrine neoplasms of the pancreas presenting hypoglycemic symptoms. Patients characteristically develop symptoms while fasting, but some patients have reported symptoms only in the postprandial state. Repeated and prolonged hypoglycemic episodes can reduce the awareness of adrenergic symptoms, and patients may have amnesia, which delays diagnosis.
CASE SUMMARY We describe a case of a 24-year-old underweight patient who showed hypoglycemic symptoms for almost 6 years. Although patients with insulinoma characteristically develop symptoms while fasting, this young man had hypoglycemic symptoms up to one hour postprandially, especially after high-sugar meals and after physical activity. The fasting tests and imaging methods performed at local hospitals were evaluated as negative for abnormal results. However, brown adipose tissue exhibited increased metabolic activity, and some muscle groups had histological changes as indicated by positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography. Glycogen deficiency was also histologically confirmed. The patient’s symptoms progressed over the years and occurred more frequently, i.e., several times a month, and the patient had reduced awareness of adrenergic symptoms. The follow-up fasting test was positive, and the imaging results showed a tumor in the head of the pancreas. The patient underwent laparotomy with enucleation of the insulinoma.
CONCLUSION Weight gain and fasting hypoglycemia are not necessarily characteristics of insulinoma. In prolonged cases, adrenergic symptoms can be suppressed.
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Affiliation(s)
- Dana Prídavková
- Clinic of Internal Medicine I, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Martin 03601, Slovakia
| | - Matej Samoš
- Clinic of Internal Medicine I, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Martin 03601, Slovakia
| | - Roman Kyčina
- Clinic of Surgery and Transplant Center, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Martin 03601, Slovakia
| | - Katarína Adamicová
- Department of Pathological Anatomy, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Martin 03601, Slovakia
| | - Michal Kalman
- Department of Pathological Anatomy, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Martin 03601, Slovakia
| | - Margita Belicová
- Clinic of Internal Medicine I, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Martin 03601, Slovakia
| | - Marián Mokáň
- Clinic of Internal Medicine I, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Martin 03601, Slovakia
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Ravens S, Scheit L. [Intermittent disturbances of perception during fasting in a 46-year-old female patient]. Internist (Berl) 2020; 61:964-968. [PMID: 32734334 DOI: 10.1007/s00108-020-00830-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
BACKGROUND We report the case of a 46-year-old female patient who presented in the emergency department with intermittent disturbances of perception when fasting. DIAGNOSTICS In the diagnostic fasting test, a hyperinsulinemic hypoglycemia already occurred after 7h. A sonographic examination was inconspicuous, therefore, a Ga 68-HA-DOTATATE positron emission tomography computed tomography (PET-CT) was carried out. The results were indicative of a neuroendocrine neoplasm, which gave rise to the suspicion of an insulinoma. CLINICAL COURSE For surgical treatment the patient was transferred to an external hospital. Following surgery, the patient was free of symptoms. CONCLUSION If multiple symptoms of hypoglycemia are present, an insulinoma as the cause must be considered in the differential diagnostics.
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Affiliation(s)
- S Ravens
- Klinik I Innere Medizin, Bundeswehrkrankenhaus Hamburg, Lesserstraße 180, 22049, Hamburg, Deutschland
| | - L Scheit
- Klinik I Innere Medizin, Bundeswehrkrankenhaus Hamburg, Lesserstraße 180, 22049, Hamburg, Deutschland.
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Hasanov R, Samadov E, Bayramov N, Ünlü A, Petrone P. Surgical management of insulinomas at the Azerbaijan Medical University: a retrospective study of 21 cases over a 10-year period. Turk J Med Sci 2020; 50:1262-1269. [PMID: 32394681 PMCID: PMC7491297 DOI: 10.3906/sag-2001-150] [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: 01/20/2020] [Accepted: 05/05/2020] [Indexed: 11/27/2022] Open
Abstract
Background/aim This study represents the first report that evaluates the experience gathered from diagnosis, surgical treatment and outcome of insulinoma patients from Azerbaijan. Materials and methods We retrospectively review of insulinoma patients for a 10-year period. Collected data included patient demographics, laboratory and imaging tests, detailed surgical reports, histopathological examination of resected specimens, and clinical follow-up. Results Twenty-one insulinoma patients were identified. Male patients comprised 52.4%; mean age was 44 years. Mean time to diagnosis was 14 months; 61% patients had ≥3 medical referrals due to hypoglycemia-related symptoms. Diagnosis sensitivity of CT, MRI and US was 85%, 80%, and 55%, respectively. The mean glucose, insulin, C-peptide levels were 35.7 ± 9.5 mg/dL, 33.5 ± 21.9 µU/mL, and 3.74 ± 1.88 ng/mL, respectively. Pancreatic head and tail were the most frequent tumor locations; mean tumor size was 1.5 ± 0.7 cm. No statistical association was found between the tumor size and preoperative glucose, C-peptide and insulin levels. Distal pancreatectomy and enucleation were the most common surgical procedures. Local tumor recurrence rate was 14%. There was no mortality. Conclusions To prevent delayed diagnoses, physicians should be familiar with the typical symptoms of these rare tumors.
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Affiliation(s)
- Rovshan Hasanov
- Endocrinology Clinic, Leyla Medical Center; Baku, Azerbaijan
| | - Elgun Samadov
- General Surgery Clinic, Leyla Medical Center; Baku, Azerbaijan
| | - Nuru Bayramov
- General Surgery Department, Azerbaijan Medical University; Baku, Azerbaijan
| | - Aytekin Ünlü
- Department of General Surgery, University of Medical Sciences, Gulhane Medical University; Ankara, Turkey
| | - Patrizio Petrone
- Department of Surgery, NYU Langone Health – NYU Winthrop Hospital; NYU Long Island School of Medicine; Mineola, NY USA
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Chen HY, Zhou YL, Chen YH, Wang X, Zhang H, Ke NW, Liu XB, Tan CL. Functionality is not an independent prognostic factor for pancreatic neuroendocrine tumors. World J Gastroenterol 2020; 26:3638-3649. [PMID: 32742132 PMCID: PMC7366052 DOI: 10.3748/wjg.v26.i25.3638] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 05/08/2020] [Accepted: 06/09/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pancreatic neuroendocrine neoplasms (pNENs) that produce hormones leading to symptoms are classified as functional tumors, while others are classified as nonfunctional tumors. The traditional view is that functionality is a factor that affects the prognosis of pNEN patients. However, as the sample sizes of studies have increased, researches in recent years have proposed new viewpoints. AIM To assess whether functionality is an independent factor for predicting the prognosis of pNEN patients. METHODS From January 2004 to December 2016, data of patients who underwent surgery at the primary site for the treatment of pNENs from the Surveillance, Epidemiology, and End Results (SEER) database and West China Hospital database were retrospectively analyzed. RESULTS Contemporaneous data from the two databases were analyzed separately as two cohorts and then merged as the third cohort to create a large sample that was suitable for multivariate analysis. From the SEER database, age (P = 0.006) and T stage (P < 0.001) were independent risk factors affecting the survival. From the West China Hospital database, independent prognostic factors were age (P = 0.034), sex (P = 0.032), and grade (P = 0.039). The result of the cohort consisting of the combined populations from the two databases showed that race (P = 0.015), age (P = 0.002), sex (P = 0.032) and T stage (P < 0.001) were independent prognostic factors. In the West China Hospital database and in the total population, nonfunctional pNETs and other functional pNETs tended to have poorer prognoses than insulinoma. However, functionality was not associated with the survival time of patients with pNETs in the multivariate analysis. CONCLUSION Functionality is not associated with prognosis. Race, age, sex, and T stage are independent factors for predicting the survival of patients with pNETs.
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Affiliation(s)
- Hong-Yu Chen
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Ya-Liang Zhou
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yong-Hua Chen
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xing Wang
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Hao Zhang
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Neng-Wen Ke
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xu-Bao Liu
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Chun-Lu Tan
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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Tachibana T, Kasajima A, Aoki T, Tabata T, McNamara K, Yazdani S, Satoko S, Fujishima F, Motoi F, Unno M, Sasano H. Progesteron receptor expression in insulin producing cells of neuroendocrine neoplasms. J Steroid Biochem Mol Biol 2020; 201:105694. [PMID: 32437964 DOI: 10.1016/j.jsbmb.2020.105694] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Revised: 05/02/2020] [Accepted: 05/04/2020] [Indexed: 12/15/2022]
Abstract
Progesterone receptor (PgR) inhibits cell proliferation in pancreatic neuroendocrine neoplasms (PanNEN). In non-neoplastic pancreas, loss of PgR induces β-cell proliferation and insulin production. However, detailed association between PgR and insulin producing PanNENs is poorly understood. Insulin, proinsulin, and PgR were immunolocalized in 82 PanNENs (54 non-functioning PanNENs: NF-PanNENs and 28 insulinomas). The status of immunoreactivity was compared to the clinicopathological factors of the patients. Immunoreactivity was also confirmed by employing the double-immunohistochemistry. These results were also compared with those in non-neoplastic Langerhans islets. PgR immunoreactivity was significantly higher in insulinomas than that in NF-PanNENs (p < 0.001). Insulin and proinsulin immunoreactivity was also detected in 20 (37 %) of (single cell) insulin positive NFs (Inspos-NF-PanNEN), in which PgR expression was higher than in insulin negative NF-PanNENs (Insneg-NF-PanNEN, p = 0.03). The ratio of PgR-insulin double positive cells to overall insulin positive cells, as well as PgR-proinsulin double positive cells to proinsulin positive cells, was detected to the same degree in insulinoma (PgR-insulin 70 %, PgR-proinsulin 66 %), Inspos-NF-PanNENs (PgR-insulin 65 %, PgR-proinsulin 68 %) and normal islet (PgR-insulin 80 %, PgR-proinsulin 72 %). PgR and insulin expressing cells colocalize in tumor cells of the PanNENs regardless of the hormone-related symptoms of the patients. Inhibitory effect of PgR on tumor cells might be associated with the favourable clinical outcome of insulinoma patients.
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Affiliation(s)
- Tomoyoshi Tachibana
- Department of Pathology, Tohoku University Graduate School of Medicine, Miyagi, Japan; Department of Surgery, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Atsuko Kasajima
- Department of Pathology, Tohoku University Graduate School of Medicine, Miyagi, Japan; Technical University Munich, School of Medicine, Klinikum rechts der Isar, Department of Pathology, Munich, Germany; Member of the German Cancer Consortium (DKTK), Germany.
| | - Takeshi Aoki
- Department of Surgery, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Tomoaki Tabata
- Department of Pathology, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Keely McNamara
- Department of Pathology, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Samaneh Yazdani
- Department of Pathology, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Sato Satoko
- Department of Pathology, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Fumiyoshi Fujishima
- Department of Pathology, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Fuyuhiko Motoi
- Department of Surgery, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Hironobu Sasano
- Department of Pathology, Tohoku University Graduate School of Medicine, Miyagi, Japan
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Bocchini M, Nicolini F, Severi S, Bongiovanni A, Ibrahim T, Simonetti G, Grassi I, Mazza M. Biomarkers for Pancreatic Neuroendocrine Neoplasms (PanNENs) Management-An Updated Review. Front Oncol 2020; 10:831. [PMID: 32537434 PMCID: PMC7267066 DOI: 10.3389/fonc.2020.00831] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 04/28/2020] [Indexed: 12/14/2022] Open
Abstract
Pancreatic neuroendocrine tumors (PanNENs) are rare sporadic cancers or develop as part of hereditary syndromes. PanNENs can be both functioning and non-functioning based on whether they produce bioactive peptides. Some PanNENs are well differentiated while others-poorly. Symptoms, thus, depend on both oncological and hormonal causes. PanNEN diagnosis and treatment benefit from and in some instances are guided by biomarker monitoring. However, plasmatic monoanalytes are only suggestive of PanNEN pathological status and their positivity is typically followed by deepen diagnostic analyses through imaging techniques. There is a strong need for new biomarkers and follow-up modalities aimed to improve the outcome of PanNEN patients. Liquid biopsy follow-up, i.e., sequential analysis on tumor biomarkers in body fluids offers a great potential, that need to be substantiated by additional studies focusing on the specific markers and the timing of the analyses. This review provides the most updated panorama on PanNEN biomarkers.
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Affiliation(s)
- Martine Bocchini
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Fabio Nicolini
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Stefano Severi
- Nuclear Medicine and Radiometabolic Units, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Alberto Bongiovanni
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Toni Ibrahim
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Giorgia Simonetti
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Ilaria Grassi
- Nuclear Medicine and Radiometabolic Units, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Massimiliano Mazza
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
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Hofland J, Kaltsas G, de Herder WW. Advances in the Diagnosis and Management of Well-Differentiated Neuroendocrine Neoplasms. Endocr Rev 2020; 41:bnz004. [PMID: 31555796 PMCID: PMC7080342 DOI: 10.1210/endrev/bnz004] [Citation(s) in RCA: 120] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 02/28/2020] [Indexed: 02/07/2023]
Abstract
Neuroendocrine neoplasms constitute a diverse group of tumors that derive from the sensory and secretory neuroendocrine cells and predominantly arise within the pulmonary and gastrointestinal tracts. The majority of these neoplasms have a well-differentiated grade and are termed neuroendocrine tumors (NETs). This subgroup is characterized by limited proliferation and patients affected by these tumors carry a good to moderate prognosis. A substantial subset of patients presenting with a NET suffer from the consequences of endocrine syndromes as a result of the excessive secretion of amines or peptide hormones, which can impair their quality of life and prognosis. Over the past 15 years, critical developments in tumor grading, diagnostic biomarkers, radionuclide imaging, randomized controlled drug trials, evidence-based guidelines, and superior prognostic outcomes have substantially altered the field of NET care. Here, we review the relevant advances to clinical practice that have significantly upgraded our approach to NET patients, both in diagnostic and in therapeutic options.
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Affiliation(s)
- Johannes Hofland
- ENETS Center of Excellence, Section of Endocrinology, Department of Internal Medicine, Erasmus MC Cancer Center, Erasmus MC, Rotterdam, The Netherlands
| | - Gregory Kaltsas
- 1st Department of Propaupedic Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Wouter W de Herder
- ENETS Center of Excellence, Section of Endocrinology, Department of Internal Medicine, Erasmus MC Cancer Center, Erasmus MC, Rotterdam, The Netherlands
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Majid Z, Tahir F, Haider SA. Long-standing Sporadic Pancreatic Insulinoma: Report of a Rare Case. Cureus 2020; 12:e6947. [PMID: 32190498 PMCID: PMC7067366 DOI: 10.7759/cureus.6947] [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] [Indexed: 12/05/2022] Open
Abstract
Insulinomas are rare, functional pancreatic neuroendocrine tumors arising from the pancreatic multipotent stem cells or neuroendocrine islet, occurring with a higher proportion in females. Majority of insulinomas have a sporadic etiology; however, only 5%-10% develop as a part of multiple endocrine neoplasm type 1 syndrome. They usually present with symptoms of hypoglycemia including disturbance in orientation, tremors, diaphoresis, altered mental state, seizures and visual changes among others. The diagnosis is based on appreciation of the classic Whipple triad, i.e. neuroglycopenic symptoms and sympathetic drive along with low serum glucose levels (<50 mg/dL) and a complete reversibility of these symptoms with prompt administration of glucose. The gold standard treatment for insulinoma involves complete surgical excision (i.e. enucleation), which is curative in 90% of the patients. Health care physicians should have a high index of suspicion for this tumor in patients presenting with neurological and sympathetic symptoms, particularly if they are resolved after eating. Here, we report the case of a 48-year-old female with the history of multiple episodes of hypoglycemic symptoms for the past two years which improved on glucose intake. Furthermore, we also summarized the discussion regarding diagnosis and management of pancreatic insulinoma.
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Affiliation(s)
- Zainab Majid
- Internal Medicine, Dow University of Health Sciences, Karachi, PAK
| | - Faryal Tahir
- Internal Medicine, Dow University of Health Sciences, Karachi, PAK
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Maggio I, Mollica V, Brighi N, Lamberti G, Manuzzi L, Ricci AD, Campana D. The functioning side of the pancreas: a review on insulinomas. J Endocrinol Invest 2020; 43:139-148. [PMID: 31368049 DOI: 10.1007/s40618-019-01091-w] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 07/24/2019] [Indexed: 12/19/2022]
Abstract
PURPOSE Insulinomas are a rare type of neuroendocrine tumors, originating in the pancreas, difficult to diagnose and to treat. Due to its rarity, insulinomas are a not well-known pathological entity; thus, the diagnostic process is frequently a medical challenge with many possible differential diagnoses. The diagnostic process varies between non-invasive procedures, such as the fasting test or imaging techniques, and invasive ones. Insulinomas are rarely malignant, but the glycemic imbalance correlated with this tumor can frequently alter the quality of life of the patients and the consequent hypoglycemia can be extremely dangerous. Moreover, insulinomas can be associated with different genetic syndromes, such as Multiple Endocrine Neoplasia 1, accompanied by other specific symptoms. There are many different treatment strategies, depending on the need to control symptoms or control diseases progression, the only curative one being surgery. METHODS AND RESULTS We reviewed the evidences present in the literature on insulinomas and reported its main clinical characteristics and management strategies. CONCLUSION The aim of this review of the literature is to present the current knowledge on insulinomas, exploring the main clinical characteristics, the diagnostic tools, and the therapeutic strategies.
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Affiliation(s)
- I Maggio
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - V Mollica
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - N Brighi
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
- NET Team Bologna ENETS Center of Excellence, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - G Lamberti
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - L Manuzzi
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - A D Ricci
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - D Campana
- NET Team Bologna ENETS Center of Excellence, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy.
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy.
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Hofland J, de Herder WW, Kann PH. Turning Up the Heat: Endoscopic Ablation of Pancreatic Neuroendocrine Neoplasms. J Clin Endocrinol Metab 2019; 104:5053-5055. [PMID: 31058975 DOI: 10.1210/jc.2019-00954] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Accepted: 04/30/2019] [Indexed: 12/27/2022]
Affiliation(s)
- Johannes Hofland
- ENETS Center of Excellence, Section of Endocrinology, Department of Internal Medicine, Erasmus Cancer Institute, Erasmus Medical Center, GE Rotterdam, Netherlands
| | - Wouter W de Herder
- ENETS Center of Excellence, Section of Endocrinology, Department of Internal Medicine, Erasmus Cancer Institute, Erasmus Medical Center, GE Rotterdam, Netherlands
| | - Peter H Kann
- Centre for Endocrinology, Diabetology and Osteology, Phillipps University Marburg, Marburg, Germany
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Abstract
Neuroendocrine tumors (NETs) originate from the neuroendocrine cell system in the bronchial and gastrointestinal tract and can produce hormones leading to distinct clinical syndromes. Systemic treatment of patients with unresectable NETs aims to control symptoms related to hormonal overproduction and tumor growth. In the last decades prognosis has improved as a result of increased detection of early stage disease and the introduction of somatostatin analogs (SSAs) as well as several new therapeutic options. SSAs are the first-line medical treatment of NETs and can control hormonal production and tumor growth. The development of next-generation multireceptor targeted and radiolabelled somatostatin analogs, as well as target-directed therapies (as second-line treatment options) further improve progression-free survival in NET patients. To date, however, a significant prolongation of overall survival with systemic treatment in NET has not been convincingly demonstrated. Several new medical options and treatment combinations will become available in the upcoming years, and although preliminary results of preclinical and clinical trials are encouraging, large, preferrably randomized clinical studies are required to provide definitive evidence of their effect on survival and symptom control.
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Dai H, Chen H, Hong X, Han X, Xu Q, Pang H, Yuan J, Wang X, Xu P, Jiang J, Jiang R, Zhuang Z, Zhao Y, Wu W. Early detection of cognitive impairment in patients with insulinoma. Endocrine 2019; 65:524-530. [PMID: 31292840 DOI: 10.1007/s12020-019-01994-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 06/23/2019] [Indexed: 10/26/2022]
Abstract
PURPOSE Long-standing hypoglycemia can cause cognitive impairment, and whether recurrent severe hypoglycemia impacts cognitive function in patients with insulinoma has not been studied. This study focused on exploring the cognitive function in patients with insulinoma. METHODS A prospective study was conducted to assess cognitive function in patients with insulinoma by administering the Montreal Cognitive Assessment (MoCA) questionnaire between January 2016 and July 2017, and patients with cognitive impairment were followed up to undergo the MoCA test 1 year after surgery. The MoCA scores after surgery were compared with the scores before surgery, and the associations between cognitive impairment and relevant factors were further evaluated by multiple linear regression analysis. RESULTS Eighteen out of thirty-four patients (53%) with insulinoma were screened positive for cognitive impairment as defined by a MoCA score <26. Performance in certain cognitive domains, including visuospatial and executive functions, delayed memory, attention, language, and abstraction, was significantly worse in patients with cognitive impairment. Multivariate analysis indicated that MoCA scores correlated significantly with tumor grade and years of education. Eight patients with cognitive impairment were lost to follow-up. The remaining ten patients with cognitive impairment showed improvements 1 year postoperatively, and seven patients recovered to normal cognitive function. CONCLUSIONS Cognitive impairment was found in patients with insulinoma and was reversible in some patients 1 year after surgery. More studies are needed to explore the underlying mechanisms of the existence and reversibility of cognitive impairment in patients with insulinoma.
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Affiliation(s)
- Hongmei Dai
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hao Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiafei Hong
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xianlin Han
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qiang Xu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haiyu Pang
- Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jing Yuan
- Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xianze Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Peiran Xu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jialin Jiang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Rui Jiang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhe Zhuang
- School of Medicine, Tsinghua University, Beijing, China
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Wenming Wu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Egorov AV, Lezhinskiy DV, Vasilyev IA, Musaev GK, Parnova VA. [Choice of surgical approach to insulin-producing pancreatic tumors]. Khirurgiia (Mosk) 2019:41-45. [PMID: 31464273 DOI: 10.17116/hirurgia201908141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
AIM To determine the optimal surgical approach to insulin-producing pancreatic tumors via an analysis of early postoperative results. MATERIAL AND METHODS There were 134 patients with insulin-producing pancreatic tumors followed by organic hyperinsulinism who have undergone surgery in the faculty-based surgical clinic of the Sechenov First Moscow State Medical University for the period 1990-2017. Patients were divided into three groups depending on type of surgical intervention. Surgical procedure was determined after comprehensive preoperative and intraoperative examination including intraoperative ultrasound. RESULTS Incidence of postoperative complications was 32.8%. Ten (7.5%) patients required redo surgical interventions. Overall postoperative mortality was 4.5%. The best immediate results were observed in patients undergoing distal pancreatectomy. There was a correlation between incidence of early postoperative complications and tumor location depth in the enucleation group. CONCLUSION Enucleation is advisable for insulinoma of pancreatic head or uncinated process, as well as superficial tumors of the left half of the pancreas. Distal pancreatectomy is indicated for deep tumors of the left half of the pancreas. Indications for pancreatoduodenectomy are individual.
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Affiliation(s)
- A V Egorov
- Sechenov First Moscow State Medical University, Moscow, Russia
| | - D V Lezhinskiy
- Sechenov First Moscow State Medical University, Moscow, Russia
| | - I A Vasilyev
- Sechenov First Moscow State Medical University, Moscow, Russia
| | - G Kh Musaev
- Sechenov First Moscow State Medical University, Moscow, Russia
| | - V A Parnova
- Sechenov First Moscow State Medical University, Moscow, Russia
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Abstract
Persistent hyperinsulinemic hypoglycemia in adults is most commonly caused by insulinomas, which pose a diagnostic challenge to physicians, surgeons, and radiologists and require multimodality imaging for precise localization and staging. PET tracers such as F-FDOPA and glucagon-like peptide 1 receptor analogs have been used for imaging insulinomas. Glucagon-like peptide 1 receptor analogs have recently shown promising results in preoperative localization of these tumors, as all insulinomas express glucagon-like peptide 1 receptors. Ga-DOTA-Exendin PET and MRI done in the present case helped in precise localization and management of the culprit lesion, whereas contrast-enhanced CT and F-FDOPA PET failed to do so.
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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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Dauben L, Simon MC, Strassburger K, Burkart V, Weber KS, Schinner S, Roden M, Müssig K. Comparison of the diagnostic accuracy of the current guidelines for detecting insulinoma. Eur J Endocrinol 2019; 180:381-386. [PMID: 30991361 DOI: 10.1530/eje-18-0879] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 04/16/2019] [Indexed: 12/24/2022]
Abstract
Objective Insulinomas are rare pancreatic endocrine tumors characterized by hypoglycemia. Guidelines by the Endocrine Society (ES), the European (ENETS) and the North American (NANETS) Neuroendocrine Tumor Societies provide divergent diagnostic criteria. This study compared the diagnostic accuracy of these different criteria during the 72-h fasting test. Design Retrospective cohort study. Methods From 2000 to 2014, 64 patients with a suspected insulinoma underwent a 72-h fasting test and were included in the analysis. This study assessed the diagnostic sensitivity, specificity and accuracy based on venous blood glucose and corresponding insulin levels measured by electrochemiluminescence immunoassay (ECLIA). Results Based on 64 individuals (18 with, 46 without insulinoma), the ES criteria provided a diagnostic sensitivity of 0.94 (0.73-1.00), specificity of 0.89 (0.76-0.96) and accuracy of 0.91 (0.81-0.96). ENETS/NANETS criteria reached a diagnostic sensitivity of 0.78 (0.52-0.94), specificity of 1.00 (0.92-1.00) and accuracy of 0.94 (0.85-0.98). Conclusions These results point to a higher diagnostic sensitivity with less specificity for diagnosing insulinoma using ES criteria and a higher specificity at lower sensitivity by using ENETS/NANETS criteria. Before considering these results when applying the different criteria in clinical practice, the results should be confirmed in further studies comprising larger cohorts.
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Affiliation(s)
- Laura Dauben
- Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Marie-Christine Simon
- Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Klaus Strassburger
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- Institute for Biometrics and Epidemiology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany
| | - Volker Burkart
- Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Katharina S Weber
- Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Sven Schinner
- Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Michael Roden
- Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Karsten Müssig
- Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
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Akahori H. Clinical remission of an inoperable malignant insulinoma by the combination treatment with octreotide and everolimus. J Gen Fam Med 2019; 20:107-110. [PMID: 31065475 PMCID: PMC6498131 DOI: 10.1002/jgf2.235] [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: 04/17/2018] [Revised: 11/20/2018] [Accepted: 12/16/2018] [Indexed: 12/31/2022] Open
Abstract
We report a 52-year-old woman with inoperable malignant insulinoma with multiple liver metastases. Histological examination of biopsy specimens from the pancreatic and hepatic lesions revealed pancreatic neuroendocrine tumor (pNET), G2. The tumor cells were positive for somatostatin receptor (SSTR) 2, 5, and the mammalian target of rapamycin (mTOR). Monthly intramuscular administration of octreotide LAR and once-daily oral administration of everolimus combination treatment markedly reduced the sizes of liver metastases, and hypoglycemia was well controlled. Combination treatment with somatostatin analog and mTOR inhibitor may be another effective approach in inoperable metastatic malignant insulinoma.
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Affiliation(s)
- Hiroshi Akahori
- Department of Internal Medicine (Endocrinology and Metabolism)Toyama Prefectural Central HospitalToyama‐cityToyamaJapan
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