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Ribeiro FM, Encarnação PMCC, Silva ALM, Correia PMM, Pinto AX, Oliveira RG, Sereno J, Pais ML, Abrunhosa A, Castro IF, Santos AC, Veloso JFCA. First performance evaluation of easyPET.3D, a high-resolution and cost-effective benchtop preclinical PET scanner. EJNMMI Phys 2025; 12:48. [PMID: 40418258 DOI: 10.1186/s40658-025-00757-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Accepted: 04/18/2025] [Indexed: 05/27/2025] Open
Abstract
PURPOSE EasyPET.3D is a preclinical positron emission tomography (PET) scanner with a unique scanning method based on two face-to-face detector modules with two axes of motion. Its performance evaluation is presented using the NEMA NU-4 standards and an animal model. METHODS Each detector module consists of a 32 × 2 pixelated cerium-doped lutetium-yttrium oxyorthosilicate (LYSO:Ce) scintillator array with individual crystals of 2.0 × 2.0 × 30 mm3. The crystal arrays are coupled to 1.3 × 1.3 mm2 silicon photomultipliers (SiPMs). The transaxial field-of-view (FoV) is adjustable up to 48 mm in diameter, and the axial length is 73 mm. The performance characterization includes spatial resolution, sensitivity, count rate, scatter fraction (SF), and image quality (IQ) measurements. Furthermore, mice experiments were conducted to evaluate the in vivo imaging capability. RESULTS Spatial resolution at the FoV centre (CFoV) in radial, tangential, and axial directions was 0.98±0.08, 0.97±0.06 and 0.94±0.08 mm, respectively. An absolute sensitivity of 0.23% was measured at CFoV. The mouse-like phantom SF was 16% (913 cps at 18 MBq). Recovery coefficients in the IQ phantom varied from 21±34% to 85±50% (1 to 5 mm diameter rods, accordingly). The uniformity was 17.6%, and spill-over ratios for water-filled and air-filled chambers were 0.49 and 0.40, respectively. CONCLUSION EasyPET.3D geometry favours the reduction of parallax error, despite its low sensitivity. The system linearity is suitable for the low range of activities (7-8 MBq) used for mice imaging. The overall performance showed that easyPET.3D has potential for entry-level preclinical applications.
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Affiliation(s)
- Fabiana M Ribeiro
- Institute for Nanostructures, Nanomodelling and Nanofabrication (i3N), Physics Department (DFis), University of Aveiro (UA), Aveiro, 3810-193, Portugal.
| | - Pedro M C C Encarnação
- Institute for Nanostructures, Nanomodelling and Nanofabrication (i3N), Physics Department (DFis), University of Aveiro (UA), Aveiro, 3810-193, Portugal
| | - Ana L M Silva
- Institute for Nanostructures, Nanomodelling and Nanofabrication (i3N), Physics Department (DFis), University of Aveiro (UA), Aveiro, 3810-193, Portugal
| | - Pedro M M Correia
- Institute for Nanostructures, Nanomodelling and Nanofabrication (i3N), Physics Department (DFis), University of Aveiro (UA), Aveiro, 3810-193, Portugal
| | - Afonso X Pinto
- Institute for Nanostructures, Nanomodelling and Nanofabrication (i3N), Physics Department (DFis), University of Aveiro (UA), Aveiro, 3810-193, Portugal
| | - Regina G Oliveira
- Institute for Nanostructures, Nanomodelling and Nanofabrication (i3N), Physics Department (DFis), University of Aveiro (UA), Aveiro, 3810-193, Portugal
| | - José Sereno
- Institute for Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, Coimbra, 3000-548, Portugal
- Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), University of Coimbra, Coimbra, 3000-548, Portugal
| | - Mariana Lapo Pais
- Institute for Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, Coimbra, 3000-548, Portugal
- Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), University of Coimbra, Coimbra, 3000-548, Portugal
| | - Antero Abrunhosa
- Institute for Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, Coimbra, 3000-548, Portugal
- Coimbra Institute for Biomedical Imaging and Translational Research (CIBIT), University of Coimbra, Coimbra, 3000-548, Portugal
| | - Ismael F Castro
- Radiation Imaging Technologies Lda. (RI-TE), University of Aveiro Incubator, PCI- Creative Science Park, Ílhavo, 3830- 352, Portugal
| | - Ana C Santos
- Biophysics Institute, Faculty of Medicine (FMUC), Institute for Clinical and Biomedical Research (iCBR), Environment, Genetics and Oncobiology (CIMAGO), Center for Innovative Biomedicine and Biotechnology (CIBB), Centre for Mechanical Engineering, Materials and Processes (CEMMPRE), University of Coimbra, Coimbra, 3000- 548, Portugal
| | - João F C A Veloso
- Institute for Nanostructures, Nanomodelling and Nanofabrication (i3N), Physics Department (DFis), University of Aveiro (UA), Aveiro, 3810-193, Portugal
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Pedersen C, Aboian M, McConathy JE, Daldrup-Link H, Franceschi AM. PET/MRI in Pediatric Neuroimaging: Primer for Clinical Practice. AJNR Am J Neuroradiol 2022; 43:938-943. [PMID: 35512826 DOI: 10.3174/ajnr.a7464] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 12/13/2021] [Indexed: 11/07/2022]
Abstract
Modern pediatric imaging seeks to provide not only exceptional anatomic detail but also physiologic and metabolic information of the pathology in question with as little radiation penalty as possible. Hybrid PET/MR imaging combines exquisite soft-tissue information obtained by MR imaging with functional information provided by PET, including metabolic markers, receptor binding, perfusion, and neurotransmitter release data. In pediatric neuro-oncology, PET/MR imaging is, in many ways, ideal for follow-up compared with PET/CT, given the superiority of MR imaging in neuroimaging compared with CT and the lower radiation dose, which is relevant in serial imaging and long-term follow-up of pediatric patients. In addition, although MR imaging is the main imaging technique for the evaluation of spinal pathology, PET/MR imaging may provide useful information in several clinical scenarios, including tumor staging and follow-up, treatment response assessment of spinal malignancies, and vertebral osteomyelitis. This review article covers neuropediatric applications of PET/MR imaging in addition to considerations regarding radiopharmaceuticals, imaging protocols, and current challenges to clinical implementation.
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Affiliation(s)
- C Pedersen
- From the Department of Radiology (C.P., M.A.), Yale School of Medicine, New Haven, Connecticut
| | - M Aboian
- From the Department of Radiology (C.P., M.A.), Yale School of Medicine, New Haven, Connecticut
| | - J E McConathy
- Division of Molecular Imaging and Therapeutics (J.E.M.), Department of Radiology, University of Alabama at Birmingham, Birmingham, Alabama
| | - H Daldrup-Link
- Department of Radiology and Pediatrics (H.D.-L.), Stanford University School of Medicine, Palo Alto, California
| | - A M Franceschi
- Neuroradiology Division (A.M.F.), Department of Radiology, Northwell Health/Donald and Barbara Zucker School of Medicine, Lenox Hill Hospital, New York, New York
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Wakfie-Corieh C, Rodríguez Rey C, Ortega Candil A, Ávila Ramírez L, Pérez Rodríguez O, Carreras Delgado J. Forma focal de hiperinsulinismo congénito en una recién nacida diagnosticada con 18F-DOPA PET/TC, que permite el abordaje quirúrgico laparoscópico. Rev Esp Med Nucl Imagen Mol 2021. [DOI: 10.1016/j.remn.2020.06.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Wakfie-Corieh CG, Rodríguez Rey C, Ortega Candil A, Ávila Ramírez LF, Pérez Rodríguez O, Carreras Delgado JL. Focal form of congenital hyperinsulinism in a newborn diagnosed with 18F-DOPA PET/CT allows laparoscopic surgical approach. Rev Esp Med Nucl Imagen Mol 2021; 40:318-319. [PMID: 34305034 DOI: 10.1016/j.remnie.2020.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 06/23/2020] [Indexed: 11/28/2022]
Affiliation(s)
- C G Wakfie-Corieh
- Servicio de Medicina Nuclear, Hospital Clínico San Carlos, Madrid, Spain.
| | - C Rodríguez Rey
- Servicio de Medicina Nuclear, Hospital Clínico San Carlos, Madrid, Spain
| | - A Ortega Candil
- Servicio de Medicina Nuclear, Hospital Clínico San Carlos, Madrid, Spain
| | - L F Ávila Ramírez
- Servicio de Cirugía Pediátrica, Hospital Clínico San Carlos, Madrid, Spain
| | - O Pérez Rodríguez
- Unidad de Endocrinología Infantil, Hospital Clínico San Carlos, Madrid, Spain
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States LJ, Saade-Lemus S, De Leon DD. 18-F-L 3,4-Dihydroxyphenylalanine PET/Computed Tomography in the Management of Congenital Hyperinsulinism. PET Clin 2021; 15:349-359. [PMID: 32498990 DOI: 10.1016/j.cpet.2020.03.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in neonates and infants. Several genetic mutations have been identified and are associated with 2 distinct histopathologic forms of disease: diffuse and focal. Targeted clinical evaluation to distinguish medically treatable disease from disease requiring surgical management can prevent life-threatening complications. Detection and localization of a surgically curable focal lesion using PET imaging with 18-F-L 3,4-dihydroxyphenylalanine ([18F]-FDOPA) has become standard of care. This article provides guidelines for the selection of patients who can benefit from [18F]-FDOPA-PET/computed tomography and protocols and tips used to diagnose a focal lesion of HI.
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Affiliation(s)
- Lisa J States
- Section of Oncologic Imaging, Radiology Department, The Children's Hospital of Philadelphia, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA.
| | - Sandra Saade-Lemus
- Section of Oncologic Imaging, Radiology Department, The Children's Hospital of Philadelphia, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA; The Roberts Center for Pediatric Research, Room 8255, 2715 South Street, Philadelphia, PA 19146, USA
| | - Diva D De Leon
- Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA; Division of Endocrinology and Diabetes, Congenital Hyperinsulinism Center, The Children's Hospital of Philadelphia, 3500 Civic Center Boulevard, Philadelphia, PA 19104, USA
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Mitrofanova LB, Perminova AA, Ryzhkova DV, Sukhotskaya AA, Bairov VG, Nikitina IL. Differential Morphological Diagnosis of Various Forms of Congenital Hyperinsulinism in Children. Front Endocrinol (Lausanne) 2021; 12:710947. [PMID: 34497584 PMCID: PMC8419459 DOI: 10.3389/fendo.2021.710947] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 08/04/2021] [Indexed: 12/23/2022] Open
Abstract
INTRODUCTION Congenital hyperinsulinism (CHI) has diffuse (CHI-D), focal (CHI-F) and atypical (CHI-A) forms. Surgical management depends on preoperative [18F]-DOPA PET/CT and intraoperative morphological differential diagnosis of CHI forms. Objective: to improve differential diagnosis of CHI forms by comparative analysis [18F]-DOPA PET/CT data, as well as cytological, histological and immunohistochemical analysis (CHIA). MATERIALS AND METHODS The study included 35 CHI patients aged 3.2 ± 2.0 months; 10 patients who died from congenital heart disease at the age of 3.2 ± 2.9 months (control group). We used PET/CT, CHIA of pancreas with antibodies to ChrA, insulin, Isl1, Nkx2.2, SST, NeuroD1, SSTR2, SSTR5, DR1, DR2, DR5; fluorescence microscopy with NeuroD1/ChrA, Isl1/insulin, insulin/SSTR2, DR2/NeuroD1 cocktails. RESULTS Intraoperative examination of pancreatic smears showed the presence of large nuclei, on average, in: 14.5 ± 3.5 cells of CHI-F; 8.4 ± 1.1 of CHI-D; and 4.5 ± 0.7 of control group (from 10 fields of view, x400). The percentage of Isl1+ and NeuroD1+endocrinocytes significantly differed from that in the control for all forms of CHI. The percentage of NeuroD1+exocrinocytes was also significantly higher than in the control. The proportion of ChrA+ and DR2+endocrinocytes was higher in CHI-D than in CHI-F, while the proportion of insulin+cells was higher in CHI-A. The number of SST+cells was significantly higher in CHI-D and CHI-F than in CHI-A. CONCLUSION For intraoperative differential diagnosis of CHI forms, in addition to frozen sections, quantitative cytological analysis can be used. In quantitative immunohistochemistry, CHI forms differ in the expression of ChrA, insulin, SST and DR2. The development of a NeuroD1 inhibitor would be advisable for targeted therapy of CHI.
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Garg PK, Putegnat B, Truong L, Reynolds C, Sanchez I, Nedrelow JK, Uffman J, Lokitz SJ, Nazih R, Garg S, Thornton PS. Visual interpretation, not SUV ratios, is the ideal method to interpret 18F-DOPA PET scans to aid in the cure of patients with focal congenital hyperinsulinism. PLoS One 2020; 15:e0241243. [PMID: 33108363 PMCID: PMC7591017 DOI: 10.1371/journal.pone.0241243] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 10/11/2020] [Indexed: 11/18/2022] Open
Abstract
INTRODUCTION Congenital hyperinsulinism is characterized by abnormal regulation of insulin secretion from the pancreas causing profound hypoketotic hypoglycemia and is the leading cause of persistent hypoglycemia in infants and children. The main objective of this study is to highlight the different mechanisms to interpret the 18F-DOPA PET scans and how this can influence outcomes. MATERIALS AND METHODS After 18F-Fluoro-L-DOPA was injected intravenously into 50 subjects' arm at a dose of 2.96-5.92 MBq/kg, three to four single-bed position PET scans were acquired at 20, 30, 40 and 50-minute post injection. The radiologist interpreted the scans for focal and diffuse hyperinsulinism using a visual interpretation method, as well as determining the Standard Uptake Value ratios with varying cut-offs. RESULTS Visual interpretation had the combination of the best sensitivity and positive prediction values. CONCLUSIONS In patients with focal disease, SUV ratios are not as accurate in identifying the focal lesion as visual inspection, and cases of focal disease may be missed by those relying on SUV ratios, thereby denying the patients a chance of cure. We recommend treating patients with diazoxide-resistant hyperinsulinism in centers with dedicated multidisciplinary team comprising of at least a pediatric endocrinologist with a special interest in hyperinsulinism, a radiologist experienced in interpretation of 18F-Fluoro-L-DOPA PET/CT scans, a histopathologist with experience in frozen section analysis of the pancreas and a pancreatic surgeon experienced in partial pancreatectomies in patients with hyperinsulinism.
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Affiliation(s)
- Pradeep K. Garg
- Center for Molecular Imaging and Therapy, Biomedical Research Foundation, Shreveport, Louisiana, United States of America
- * E-mail:
| | - Burton Putegnat
- Cook Children’s Medical Center, Fort Worth, Texas, United States of America
| | - Lisa Truong
- Cook Children’s Medical Center, Fort Worth, Texas, United States of America
| | - Courtney Reynolds
- Cook Children’s Medical Center, Fort Worth, Texas, United States of America
| | - Irene Sanchez
- Cook Children’s Medical Center, Fort Worth, Texas, United States of America
| | | | - John Uffman
- Cook Children’s Medical Center, Fort Worth, Texas, United States of America
| | - Stephen J. Lokitz
- Center for Molecular Imaging and Therapy, Biomedical Research Foundation, Shreveport, Louisiana, United States of America
| | - Rachid Nazih
- Center for Molecular Imaging and Therapy, Biomedical Research Foundation, Shreveport, Louisiana, United States of America
| | - Sudha Garg
- Center for Molecular Imaging and Therapy, Biomedical Research Foundation, Shreveport, Louisiana, United States of America
| | - Paul S. Thornton
- Cook Children’s Medical Center, Fort Worth, Texas, United States of America
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Xu A, Cheng J, Sheng H, Wen Z, Lin Y, Zhou Z, Zeng C, Shao Y, Li C, Liu L, Li X. Clinical Management and Gene Mutation Analysis of Children with Congenital Hyperinsulinism in South China. J Clin Res Pediatr Endocrinol 2019; 11:400-409. [PMID: 31208162 PMCID: PMC6878346 DOI: 10.4274/jcrpe.galenos.2019.2019.0046] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
OBJECTIVE To explore the clinical presentation and molecular genetic characteristics of a cohort of congenital hyperinsulinism (CHI) patients from southern China and also to explore the most appropriate therapeutic approaches. METHODS We retrospectively reviewed a cohort of 65 children with CHI. Mutational analysis was performed for KCNJ11 and ABCC8 genes. The GLUD1 gene was sequenced in patients with hyperammonaemia. GCK gene sequencing was performed in those patients with no mutation identified in the ABCC8, KCNJ11 or GLUD1 genes. RESULTS ABCC8 mutations were identified in 16 (25%) of the cohort, GLUD1 mutations were identified in five children, and no KCNJ11 or GCK mutations were identified. Moreover, some unique features of ABCC8 gene mutations in southern Chinese CHI patients were found in this study. The most common mutation was a deletion/insertion mutation p.Thr1042GlnfsX75 was found in five unrelated patients, which possibly represents a relatively common mutation in southern China. Five novel ABCC8 mutations were detected. The mutations were p.Phe5SerfsX72, p.Gln273ArgfsX85, p.Leu724del, p.Asp1447Gly and IVS 25-1G>T. Five compound heterozygous mutations of ABCC8 gene were identified in this study, and three of these patients were diazoxide-responsive. Forty patients were diazoxide-responsive, 13 patients were diazoxide-unresponsive and 12 patients received dietary treatment only. A pancreatectomy was performed in 10 patients who were unresponsive to medical treatment. CONCLUSION To the best of our knowledge, this is the first study of CHI in south China. Mutations in ABCC8 are the most common causes of CHI in this cohort. Diazoxide and dietary treatment were effective in most patients. Multicentre studies are necessary to obtain the long-term follow-up characteristics of such patients at a national level.
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Affiliation(s)
- Aijing Xu
- Guangzhou Women and Children’s Medical Center, Clinic of Genetics and Endocrinology, Guangzhou, China,Contributed equally to this work
| | - Jing Cheng
- Guangzhou Women and Children’s Medical Center, Clinic of Genetics and Endocrinology, Guangzhou, China,Contributed equally to this work
| | - Huiying Sheng
- Guangzhou Women and Children’s Medical Center, Clinic of Genetics and Endocrinology, Guangzhou, China
| | - Zhe Wen
- Guangzhou Women and Children’s Medical Center, Clinic of Pediatric Surgery, Guangzhou, China
| | - Yunting Lin
- Guangzhou Women and Children’s Medical Center, Clinic of Genetics and Endocrinology, Guangzhou, China
| | - Zhihong Zhou
- Guangzhou Women and Children’s Medical Center, Clinic of Genetics and Endocrinology, Guangzhou, China
| | - Chunhua Zeng
- Guangzhou Women and Children’s Medical Center, Clinic of Genetics and Endocrinology, Guangzhou, China
| | - Yongxian Shao
- Guangzhou Women and Children’s Medical Center, Clinic of Genetics and Endocrinology, Guangzhou, China
| | - Cuiling Li
- Guangzhou Women and Children’s Medical Center, Clinic of Genetics and Endocrinology, Guangzhou, China
| | - Li Liu
- Guangzhou Women and Children’s Medical Center, Clinic of Genetics and Endocrinology, Guangzhou, China
| | - Xiuzhen Li
- Guangzhou Women and Children’s Medical Center, Clinic of Genetics and Endocrinology, Guangzhou, China,* Address for Correspondence: Guangzhou Women and Children’s Medical Center, Clinic of Genetics and Endocrinology, Guangzhou, China Phone: +86020-38076127 E-mail:
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Maines E, Giacomello L, D'Onofrio M, Salgarello M, Gaudino R, Baggio L, Bordugo A. Images from 18F-DOPA Scan in Congenital Hyperinsulinism: Not Always a Clue for Diagnosis. Nucl Med Mol Imaging 2017; 51:362-363. [PMID: 29242734 DOI: 10.1007/s13139-016-0434-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Revised: 06/19/2016] [Accepted: 06/27/2016] [Indexed: 11/28/2022] Open
Abstract
Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in childhood (Horm Res 70:65-72, 2008; J Clin Endocr Metab 93:869-875, 2008). 18-Fluoro-L-dihydroxy-phenylalanine (18F-DOPA) positron emission tomography (PET) can detect areas of increased activity in the pancreas and may differentiate focal from diffuse CHI (J Clin Endocr Metab 93:869-875, 2008; Radiology 253:216-222, 2009). We here report the case of a girl who complained of recurrent episodes of severe hypoglycaemia despite previous partial pancreatectomy. To evaluate the need for additional surgical intervention, we performed 18F-DOPA PET/computed tomography (CT), which showed a focal lesion corresponding to the anatomical region of the pancreatic tail. On the other hand, abdominal magnetic resonance imaging (MRI) clearly demonstrated that the 18F-DOPA uptake was in a loop of bowel occupying the previous surgical bed. Our case highlights that bowel uptake can be a possible pitfall in the interpretation of 18F-DOPA PET/CT in children affected by CHI, suggesting that when 18F-DOPA PET/CT results do not fit the clinical picture, magnetic resonance imaging (MRI) may allow a more accurate correlation of the radiotracer activity with the underlying anatomical or pathological structure.
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Affiliation(s)
- Evelina Maines
- Inherited Metabolic Diseases Unit, Department of Paediatrics, Regional Centre for Newborn Screening, Diagnosis and Treatment of Inherited Metabolic Diseases and Congenital Endocrine Diseases, Azienda Ospedaliera Universitaria Integrata, Piazzale Ludovico Antonio Scuro, 10, 37134 Verona, Italy
| | - Luca Giacomello
- Paediatric Surgery Unit, Department of Surgical Sciences, "Giambattista Rossi" Hospital, University of Verona, Verona, Italy
| | - Mirko D'Onofrio
- Department of Radiology, "Giambattista Rossi" Hospital, University of Verona, Verona, Italy
| | - Matteo Salgarello
- Department of Nuclear Medicine, Ospedale Sacro Cuore Don Calabria, Negrar, University of Verona, Verona, Italy
| | - Rossella Gaudino
- Division of Paediatric Endocrinology, Paediatric Clinic, Department of Life and Reproduction Sciences, "Giambattista Rossi" Hospital, University of Verona, Verona, Italy
| | - Laura Baggio
- Inherited Metabolic Diseases Unit, Department of Paediatrics, Regional Centre for Newborn Screening, Diagnosis and Treatment of Inherited Metabolic Diseases and Congenital Endocrine Diseases, Azienda Ospedaliera Universitaria Integrata, Piazzale Ludovico Antonio Scuro, 10, 37134 Verona, Italy
| | - Andrea Bordugo
- Inherited Metabolic Diseases Unit, Department of Paediatrics, Regional Centre for Newborn Screening, Diagnosis and Treatment of Inherited Metabolic Diseases and Congenital Endocrine Diseases, Azienda Ospedaliera Universitaria Integrata, Piazzale Ludovico Antonio Scuro, 10, 37134 Verona, Italy
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Abstract
Pancreatic β-cells are finely tuned to secrete insulin so that plasma glucose levels are maintained within a narrow physiological range (3.5-5.5 mmol/L). Hyperinsulinaemic hypoglycaemia (HH) is the inappropriate secretion of insulin in the presence of low plasma glucose levels and leads to severe and persistent hypoglycaemia in neonates and children. Mutations in 12 different key genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1 and PMM2) that are involved in the regulation of insulin secretion from pancreatic β-cells have been described to be responsible for the underlying molecular mechanisms leading to congenital HH. In HH due to the inhibitory effect of insulin on lipolysis and ketogenesis there is suppressed ketone body formation in the presence of hypoglycaemia thus leading to increased risk of hypoglycaemic brain injury. Therefore, a prompt diagnosis and immediate management of HH is essential to avoid hypoglycaemic brain injury and long-term neurological complications in children. Advances in molecular genetics, imaging techniques (18F-DOPA positron emission tomography/computed tomography scanning), medical therapy and surgical advances (laparoscopic and open pancreatectomy) have changed the management and improved the outcome of patients with HH. This review article provides an overview to the background, clinical presentation, diagnosis, molecular genetics and therapy in children with different forms of HH.
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Affiliation(s)
- Hüseyin Demirbilek
- Hacettepe University Faculty of Medicine, Department of Paediatric Endocrinology, Ankara, Turkey
| | - Khalid Hussain
- Sidra Medical and Research Center, Clinic of Paediatric Medicine, Doha, Qatar
,* Address for Correspondence: Sidra Medical and Research Center, Clinic of Paediatric Medicine, Doha, Qatar Phone: +974-30322007 E-mail:
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Michels N, Susi K, Marques-Vidal PM, Nydegger A, Puder JJ. Psychosocial Quality-of-Life, Lifestyle and Adiposity: A Longitudinal Study in Pre-schoolers (Ballabeina Study). Int J Behav Med 2017; 23:383-392. [PMID: 26809517 DOI: 10.1007/s12529-016-9537-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
PURPOSE In obesity prevention, understanding psychosocial influences in early life is pivotal. Reviews reported contradictory results and a lack of longitudinal studies focusing on underlying lifestyle factors. This study tested whether psychosocial Quality-Of-Life (QOL) was associated with pre-schoolers' lifestyle and adiposity changes over one school year and whether lifestyle moderated the latter. It was hypothesised that QOL might not impact adiposity in everybody but that this might depend on preceding lifestyle. METHOD Longitudinal data from 291 Swiss pre-schoolers (initially 3.9-6.3 years) was available. The following measures were used in longitudinal regressions: psychosocial QOL by PedsQL, adiposity (BMI z-score, waist, fat%), diet (food frequency), sedentary time and accelerometer-based activity. RESULTS Concerning lifestyle, low psychosocial QOL was only related to unfavourable changes in diet (less fruit β = 0.21 and more fat intake β = -0.28) and lower physical activity (β = 0.21). Longitudinal QOL-adiposity relations appeared only after moderation by lifestyle factors (beta-range 0.13-0.67). Low psychosocial QOL was associated with increased adiposity in children with an unhealthy diet intake or high sedentary time. By contrast, low psychosocial QOL was associated with decreasing adiposity in high fruit consumers or more physically active pre-schoolers. CONCLUSION Results emphasise the need for testing moderation in the QOL-adiposity relation. An unhealthy diet can be a vulnerability factor and high physical activity a protective factor in QOL-related adiposity. Consequently, QOL and lifestyle should be targeted concurrently in multi-factorial obesity prevention. The environment should be an 'activity encouraging, healthy food zone' that minimises opportunities for stress-induced eating. In addition, appropriate stress coping skills should be acquired.
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Affiliation(s)
- Nathalie Michels
- Department of Public Health, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 4K3, Ghent, B-9000, Belgium.
| | - Kriemler Susi
- Institute for Social and Preventive Medicine, University of Zürich, Zürich, Switzerland
| | - Pedro M Marques-Vidal
- Department of Internal Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Andreas Nydegger
- Department of Pediatrics, Pediatric Gastroenterology Unit, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Jardena J Puder
- Diabetes and Metabolism & Division of Pediatric Endocrinology, Service of Endocrinology, Diabetes and Obesity, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
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Demirbilek H, Rahman SA, Buyukyilmaz GG, Hussain K. Diagnosis and treatment of hyperinsulinaemic hypoglycaemia and its implications for paediatric endocrinology. INTERNATIONAL JOURNAL OF PEDIATRIC ENDOCRINOLOGY 2017; 2017:9. [PMID: 28855921 PMCID: PMC5575922 DOI: 10.1186/s13633-017-0048-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Accepted: 08/15/2017] [Indexed: 12/14/2022]
Abstract
Glucose homeostasis requires appropriate and synchronous coordination of metabolic events and hormonal activities to keep plasma glucose concentrations in a narrow range of 3.5–5.5 mmol/L. Insulin, the only glucose lowering hormone secreted from pancreatic β-cells, plays the key role in glucose homeostasis. Insulin release from pancreatic β-cells is mainly regulated by intracellular ATP-generating metabolic pathways. Hyperinsulinaemic hypoglycaemia (HH), the most common cause of severe and persistent hypoglycaemia in neonates and children, is the inappropriate secretion of insulin which occurs despite low plasma glucose levels leading to severe and persistent hypoketotic hypoglycaemia. Mutations in 12 different key genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1 and PMM2) constitute the underlying molecular mechanisms of congenital HH. Since insulin supressess ketogenesis, the alternative energy source to the brain, a prompt diagnosis and immediate management of HH is essential to avoid irreversible hypoglycaemic brain damage in children. Advances in molecular genetics, imaging methods (18F–DOPA PET-CT), medical therapy and surgical approach (laparoscopic and open pancreatectomy) have changed the management and improved the outcome of patients with HH. This up to date review article provides a background to the diagnosis, molecular genetics, recent advances and therapeutic options in the field of HH in children.
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Affiliation(s)
- Huseyin Demirbilek
- Department of Paediatric Endocrinology, Hacettepe University, Faculty of Medicine, Ankara, Turkey
| | - Sofia A Rahman
- Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine, University College London, 30 Guilford Street, London, WC1N 1EH UK
| | - Gonul Gulal Buyukyilmaz
- Department of Paediatric Endocrinology, Hacettepe University, Faculty of Medicine, Ankara, Turkey
| | - Khalid Hussain
- Department of Paediatric Medicine Sidra Medical & Research Center, OPC, C6-337, PO Box 26999, Doha, Qatar
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Yorifuji T, Horikawa R, Hasegawa T, Adachi M, Soneda S, Minagawa M, Ida S, Yonekura T, Kinoshita Y, Kanamori Y, Kitagawa H, Shinkai M, Sasaki H, Nio M. Clinical practice guidelines for congenital hyperinsulinism. Clin Pediatr Endocrinol 2017; 26:127-152. [PMID: 28804205 PMCID: PMC5537210 DOI: 10.1297/cpe.26.127] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 03/08/2017] [Indexed: 12/11/2022] Open
Abstract
Congenital hyperinsulinism is a rare condition, and following recent advances in
diagnosis and treatment, it was considered necessary to formulate evidence-based clinical
practice guidelines reflecting the most recent progress, to guide the practice of
neonatologists, pediatric endocrinologists, general pediatricians, and pediatric surgeons.
These guidelines cover a range of aspects, including general features of congenital
hyperinsulinism, diagnostic criteria and tools for diagnosis, first- and second-line
medical treatment, criteria for and details of surgical treatment, and future
perspectives. These guidelines were generated as a collaborative effort between The
Japanese Society for Pediatric Endocrinology and The Japanese Society of Pediatric
Surgeons, and followed the official procedures of guideline generation to identify
important clinical questions, perform a systematic literature review (April 2016), assess
the evidence level of each paper, formulate the guidelines, and obtain public
comments.
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Affiliation(s)
- Tohru Yorifuji
- Division of Pediatric Endocrinology and Metabolism, Children's Medical Center, Osaka City General Hospital, Osaka, Japan
| | - Reiko Horikawa
- Division of Endocrinology and Metabolism, National Center for Child Health and Development, Tokyo, Japan
| | | | - Masanori Adachi
- Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Kanagawa, Japan
| | - Shun Soneda
- Department of Pediatrics, St. Marianna University School of Medicine, Kanagawa, Japan
| | | | - Shinobu Ida
- Department of Pediatric Gastroenterology, Nutrition and Endocrinology, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan
| | - Takeo Yonekura
- Department of Pediatric Surgery, Nara Hospital, Kindai University Faculty of Medicine, Nara, Japan
| | - Yoshiaki Kinoshita
- Department of Pediatric Surgery, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yutaka Kanamori
- Department of Surgery, National Center for Child Health and Development, Tokyo, Japan
| | - Hiroaki Kitagawa
- Division of Pediatric Surgery, St. Marianna University School of Medicine, Kanagawa, Japan
| | - Masato Shinkai
- Department of Surgery, Kanagawa Children's Medical Center, Kanagawa, Japan
| | - Hideyuki Sasaki
- Department of Pediatric Surgery, Tohoku University, Miyagi, Japan
| | - Masaki Nio
- Department of Pediatric Surgery, Tohoku University, Miyagi, Japan
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14
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Signore A, Glaudemans AWJM, Gheysens O, Lauri C, Catalano OA. Nuclear Medicine Imaging in Pediatric Infection or Chronic Inflammatory Diseases. Semin Nucl Med 2017; 47:286-303. [PMID: 28417857 DOI: 10.1053/j.semnuclmed.2016.12.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
In this review article, we focus on the most recent applications of nuclear medicine techniques (mainly 99mTc/111In white blood cells (WBC) scan, [18F]-FDG-PET/CT, [18F]-FDG-PET/MRI, and 99mTc-IL-2 scintigraphy) in the study of children affected by peripheral bone osteomyelitis, fungal infections, inflammatory bowel diseases, and type 1 diabetes, owing to recent important published evidences of their role in the management of these diseases. For osteomyelitis in children, both bone scintigraphy and [18F]-FDG-PET have a major advantage of assessing the whole body in one imaging session to confirm or exclude multifocal involvement, whereas WBC scan has a limited role. In children with fungal infections, [18F]-FDG-PET can help in defining the best location for biopsy and can help in evaluating the extent of the infection and organs involved (also sites that were not yet clinically apparent), although its main role is for therapy monitoring. In inflammatory bowel diseases, and Crohn disease in particular, WBC scan has been successfully used for many years, but it is now used only in case of doubtful magnetic resonance (MR) or when MR cannot be performed and endoscopy is inconclusive. By contrast, there is an accumulating evidence of the role of [18F]-FDG-PET in management of children with Crohn disease, and PET/MR could be a versatile and innovative hybrid imaging technique that combines the metabolic information of PET with the high soft tissue resolution of MR, particularly for distinguishing fibrotic from active strictures. Finally, there are several new radiopharmaceuticals that specifically target inflammatory cells involved in the pathogenesis of insulitis aiming at developing new specific immunotherapies and to select children candidates to these treatments for improving their quality of life.
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Affiliation(s)
- Alberto Signore
- Nuclear Medicine Unit, Department of Medical-Surgical Sciences and Translational Medicine, "Sapienza" University of Rome, Rome, Italy.
| | - Andor W J M Glaudemans
- Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Olivier Gheysens
- Department of Nuclear Medicine and Molecular imaging, University Hospitals Leuven, Leuven, Belgium
| | - Chiara Lauri
- Nuclear Medicine Unit, Department of Medical-Surgical Sciences and Translational Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Onofrio A Catalano
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
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15
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Eriksson O, Laughlin M, Brom M, Nuutila P, Roden M, Hwa A, Bonadonna R, Gotthardt M. In vivo imaging of beta cells with radiotracers: state of the art, prospects and recommendations for development and use. Diabetologia 2016; 59:1340-1349. [PMID: 27094935 DOI: 10.1007/s00125-016-3959-7] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Accepted: 03/23/2016] [Indexed: 12/15/2022]
Abstract
Radiotracer imaging is characterised by high in vivo sensitivity, with a detection limit in the lower picomolar range. Therefore, radiotracers represent a valuable tool for imaging pancreatic beta cells. High demands are made of radiotracers for in vivo imaging of beta cells. Beta cells represent only a small fraction of the volume of the pancreas (usually 1-3%) and are scattered in the tiny islets of Langerhans throughout the organ. In order to be able to measure a beta cell-specific signal, one has to rely on highly specific tracer molecules because current in vivo imaging technologies do not allow the resolution of single islets in humans non-invasively. Currently, a considerable amount of preclinical data are available for several radiotracers and three are under clinical evaluation. We summarise the current status of the evaluation of these tracer molecules and put forward recommendations for their further evaluation.
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Affiliation(s)
- Olof Eriksson
- Preclinical PET Platform, Department of Medical Chemistry, Uppsala University, Dag Hammarskjölds väg 14C, 3tr, SE-751 83, Uppsala, Sweden.
- Turku PET Centre, University of Turku, Turku, Finland.
- Department of Biosciences, Åbo Akademi University, Turku, Finland.
| | - Maren Laughlin
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Maarten Brom
- Department of Radiology and Nuclear Medicine, Radboud university medical center, PO Box 9101, 6500HB, Nijmegen, the Netherlands
| | - Pirjo Nuutila
- Turku PET Centre, University of Turku, Turku, Finland
| | - Michael Roden
- Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany
| | - Albert Hwa
- JDRF, Discovery Research, New York, NY, USA
| | - Riccardo Bonadonna
- Division of Endocrinology, Department of Clinical and Experimental Medicine, University of Parma and AOU of Parma, Parma, Italy
| | - Martin Gotthardt
- Department of Radiology and Nuclear Medicine, Radboud university medical center, PO Box 9101, 6500HB, Nijmegen, the Netherlands.
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Han B, Newbould M, Batra G, Cheesman E, Craigie RJ, Mohamed Z, Rigby L, Padidela R, Skae M, Mironov A, Starborg T, Kadler KE, Cosgrove KE, Banerjee I, Dunne MJ. Enhanced Islet Cell Nucleomegaly Defines Diffuse Congenital Hyperinsulinism in Infancy but Not Other Forms of the Disease. Am J Clin Pathol 2016; 145:757-68. [PMID: 27334808 PMCID: PMC4922485 DOI: 10.1093/ajcp/aqw075] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
OBJECTIVES To quantify islet cell nucleomegaly in controls and tissues obtained from patients with congenital hyperinsulinism in infancy (CHI) and to examine the association of nucleomegaly with proliferation. METHODS High-content analysis of histologic sections and serial block-face scanning electron microscopy were used to quantify nucleomegaly. RESULTS Enlarged islet cell nuclear areas were 4.3-fold larger than unaffected nuclei, and the mean nuclear volume increased to approximately threefold. Nucleomegaly was a normal feature of pediatric islets and detected in the normal regions of the pancreas from patients with focal CHI. The incidence of nucleomegaly was highest in diffuse CHI (CHI-D), with more than 45% of islets containing two or more affected cells. While in CHI-D nucleomegaly was negatively correlated with cell proliferation, in all other cases, there was a positive correlation. CONCLUSIONS Increased incidence of nucleomegaly is pathognomonic for CHI-D, but these cells are nonproliferative, suggesting a novel role in the pathobiology of this condition.
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Affiliation(s)
- Bing Han
- From the Faculty of Life Sciences, University of Manchester, Manchester, UK
| | | | | | | | | | - Zainab Mohamed
- From the Faculty of Life Sciences, University of Manchester, Manchester, UK Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust (CMFT), Manchester, UK
| | - Lindsey Rigby
- Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust (CMFT), Manchester, UK
| | - Raja Padidela
- Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust (CMFT), Manchester, UK
| | - Mars Skae
- Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust (CMFT), Manchester, UK
| | - Aleksandr Mironov
- From the Faculty of Life Sciences, University of Manchester, Manchester, UK
| | - Tobias Starborg
- From the Faculty of Life Sciences, University of Manchester, Manchester, UK
| | - Karl E Kadler
- From the Faculty of Life Sciences, University of Manchester, Manchester, UK
| | - Karen E Cosgrove
- From the Faculty of Life Sciences, University of Manchester, Manchester, UK
| | - Indraneel Banerjee
- Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust (CMFT), Manchester, UK
| | - Mark J Dunne
- From the Faculty of Life Sciences, University of Manchester, Manchester, UK
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17
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Willekens SMA, van der Kroon I, Joosten L, Frielink C, Boerman OC, van den Broek SAMW, Brom M, Gotthardt M. SPECT of Transplanted Islets of Langerhans by Dopamine 2 Receptor Targeting in a Rat Model. Mol Pharm 2015; 13:85-91. [PMID: 26607139 DOI: 10.1021/acs.molpharmaceut.5b00518] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Pancreatic islet transplantation can be a more permanent treatment for type 1 diabetes compared to daily insulin administration. Quantitative and longitudinal noninvasive imaging of viable transplanted islets might help to further improve this novel therapy. Since islets express dopamine 2 (D2) receptors, they could be visualized by targeting this receptor. Therefore, the D2 receptor antagonist based tracer [(125/123)I][IBZM] was selected to visualize transplanted islets in a rat model. BZM was radioiodinated, and the labeling was optimized for position 3 of the aromatic ring. [(125)I]-3-IBZM was characterized in vitro using INS-1 cells and isolated islets. Subsequently, 1,000 islets were transplanted in the calf muscle of WAG/Rij rats and SPECT/CT images were acquired 6 weeks after transplantation. Finally, the graft containing muscle was dissected and analyzed immunohistochemically. Oxidative radioiodination resulted in 3 IBZM isomers with different receptor affinities. The use of 0.6 mg/mL chloramine-T hydrate resulted in high yield formation of predominantly [(125)I]-3-IBZM, the isomer harboring the highest receptor affinity. The tracer showed D2 receptor mediated binding to isolated islets in vitro. The transplant could be visualized by SPECT 6 weeks after transplantation. The transplants could be localized in the calf muscle and showed insulin and glucagon expression, indicating targeting of viable and functional islets in the transplant. Radioiodination was optimized to produce high yields of [(125)I]-3-IBZM, the isomer showing optimal D2R binding. Furthermore, [(123)I]IBZM specifically targets the D2 receptors on transplanted islets. In conclusion, this tracer shows potential for noninvasive in vivo detection of islets grafted in the muscle by D2 receptor targeting.
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Affiliation(s)
- Stefanie M A Willekens
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center , PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Inge van der Kroon
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center , PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Lieke Joosten
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center , PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Cathelijne Frielink
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center , PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Otto C Boerman
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center , PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | | | - Maarten Brom
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center , PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Martin Gotthardt
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center , PO Box 9101, 6500 HB Nijmegen, The Netherlands
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Kühnen P, Matthae R, Arya V, Hauptmann K, Rothe K, Wächter S, Singer M, Mohnike W, Eberhard T, Raile K, Lauffer LM, Iakoubov R, Hussain K, Blankenstein O. Occurrence of giant focal forms of congenital hyperinsulinism with incorrect visualization by (18) F DOPA-PET/CT scanning. Clin Endocrinol (Oxf) 2014; 81:847-54. [PMID: 24750227 DOI: 10.1111/cen.12473] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2013] [Revised: 01/09/2014] [Accepted: 04/14/2014] [Indexed: 11/29/2022]
Abstract
CONTEXT Congenital hyperinsulinism (CHI) is a rare disease characterized by severe hypoglycaemic episodes due to pathologically increased insulin secretion from the pancreatic beta cells. When untreated, CHI might result in irreversible brain damage and death. Currently, two major subtypes of CHI are known: a focal form, associated with local distribution of affected beta cells and a nonfocal form, affecting every single beta cell. The identification of focal forms is important, as the patients can be cured by limited surgery. (18) F DOPA-PET/CT is an established non-invasive approach to differentiate focal from nonfocal CHI. OBJECTIVE The purpose of this study was to identify possible limitations of (18) F DOPA-PET/CT scan in patients with focal forms nonfocal CHI. DESIGN A retrospective chart review of 32 patients (from 2008 through 2013) who underwent (18) F DOPA-PET/CT and partial pancreatectomy for focal CHI at the reference centres in Berlin, Germany and London, UK. RESULTS In most cases (n = 29, 90·7%), (18) F DOPA-PET/CT was sufficient to localize the complete focal lesion. However, in some patients (n = 3, 9·3%), (18) F DOPA-PET/CT wrongly visualized only a small portion of the focal lesion. In this group of patients, a so-called 'giant focus' was detected in histopathological analysis during the surgery. CONCLUSIONS Our data show that in most patients with focal CHI (18) F DOPA-PET/CT correctly predicts the size and anatomical localisation of the lesion. However, in those patients with a 'giant focal' lesion (18) F DOPA-PET/CT is unreliable for correct identification of 'giant focus' cases.
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Affiliation(s)
- Peter Kühnen
- Institut für experimentelle pädiatrische Endokrinologie, Charité Universitätsmedizin, Berlin, Germany
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Petraitienė I, Barauskas G, Gulbinas A, Malcius D, Hussain K, Verkauskas G, Verkauskienė R. Congenital hyperinsulinism. MEDICINA (KAUNAS, LITHUANIA) 2014; 50:190-195. [PMID: 25323548 DOI: 10.1016/j.medici.2014.08.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Accepted: 06/03/2014] [Indexed: 11/27/2022]
Abstract
Hyperinsulinism is the most common cause of hypoglycemia in infants. In many cases conservative treatment is not effective and surgical intervention is required. Differentiation between diffuse and focal forms and localization of focal lesions are the most important issues in preoperative management. We present a case of persistent infancy hyperinsulinism. Clinical presentation, conservative treatment modalities, diagnostic possibilities of focal and diffuse forms, and surgical treatment, which led to total recovery, are discussed.
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Affiliation(s)
- Indrė Petraitienė
- Institute of Endocrinology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania.
| | - Giedrius Barauskas
- Department of Surgery, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Antanas Gulbinas
- Department of Surgery, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania; Institute for Digestive Research, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Dalius Malcius
- Department of Pediatric Surgery, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Khalid Hussain
- Great Ormond Street Hospital for Children NHS Trust and Institute of Child Health, University College London, London, UK
| | - Gilvydas Verkauskas
- Children's Hospital, Vilnius University Hospital Santariskiu Klinikos, Vilnius, Lithuania
| | - Rasa Verkauskienė
- Institute of Endocrinology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
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Gopal-Kothandapani JS, Hussain K. Congenital hyperinsulinism: Role of fluorine-18L-3, 4 hydroxyphenylalanine positron emission tomography scanning. World J Radiol 2014; 6:252-260. [PMID: 24976928 PMCID: PMC4072812 DOI: 10.4329/wjr.v6.i6.252] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Revised: 03/19/2014] [Accepted: 05/19/2014] [Indexed: 02/06/2023] Open
Abstract
Congenital hyperinsulinism (CHI) is a rare but complex heterogeneous disorder caused by unregulated secretion of insulin from the β-cells of the pancreas leading to severe hypoglycaemia and neuroglycopaenia. Swift diagnosis and institution of appropriate management is crucial to prevent or minimise adverse neurodevelopmental outcome in children with CHI. Histologically there are two major subtypes of CHI, diffuse and focal disease and the management approach will significantly differ depending on the type of the lesion. Patients with medically unresponsive diffuse disease require a near total pancreatectomy, which then leads on to the development of iatrogenic diabetes mellitus and pancreatic exocrine insufficiency. However patients with focal disease only require a limited pancreatectomy to remove only the focal lesion thus providing complete cure to the patient. Hence the preoperative differentiation of the histological subtypes of CHI becomes paramount in the management of CHI. Fluorine-18L-3, 4-hydroxyphenylalanine positron emission tomography (18F-DOPA-PET) is now the gold standard for pre-operative differentiation of focal from diffuse disease and localisation of the focal lesion. The aim of this review article is to give a clinical overview of CHI, then review the role of dopamine in β-cell physiology and finally discuss the role of 18F-DOPA-PET imaging in the management of CHI.
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22
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Abstract
Dihydroxyphenylalanine (DOPA) is a neutral amino acid that resembles natural l-dopa (dopamine precursor). It enters the catecholamine metabolic pathway of endogenous l-DOPA in the brain and peripheral tissues. It is amenable to labeling with fluorine-18 (18F) for PET imaging and was originally used in patients with Parkinson’s disease to assess the integrity of the striatal dopaminergic system. The recent introduction and use of hybrid PET/CT scanners has contributed significantly to the management of a series of other pathologies including neuroendocrine tumors, brain tumors, and pancreatic cell hyperplasia. These pathologic entities present an increased activity of l-DOPA decarboxylase and therefore demonstrate high uptake of 18F-DOPA. Despite these potentially promising applications in several clinical fields, the role of 18F-DOPA has not been elucidated completely yet because of associated difficulties in synthesis and availability. Unfortunately, the available literature does not provide recommendations for procedures or administered activity, acquisition timing, and premedication with carbidopa. The aim of this paper is to outline the physiological biodistribution and normal variants, including possible pitfalls that may lead to misinterpretations of the scans in various clinical settings.
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Abstract
18F-DOPA is a radiopharmaceutical with interesting clinical applications and promising performances in the evaluation of the integrity of dopaminergic pathways, brain tumors, NETs (especially MTCs, paragangliomas, and pheochromocytomas), and congenital hyperinsulinism. 18F-DOPA traces a very specific metabolic pathway and has a very precise biodistribution pattern. As for any radiopharmaceutical, the knowledge of the normal distribution of 18F-DOPA, its physiologic variants, and its possible pitfalls is essential for the correct interpretation of PET scans. Moreover, it is important to be aware of the potential false-positive and false-negative episodes that can occur in the various clinical settings.
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Affiliation(s)
- Sotirios Chondrogiannis
- Department of Nuclear Medicine, PET/CT Centre, Santa Maria della Misericordia Hospital, Viale Tre Martiri 140, Rovigo 45100, Italy
| | - Maria Cristina Marzola
- Department of Nuclear Medicine, PET/CT Centre, Santa Maria della Misericordia Hospital, Viale Tre Martiri 140, Rovigo 45100, Italy
| | - Domenico Rubello
- Department of Nuclear Medicine, PET/CT Centre, Santa Maria della Misericordia Hospital, Viale Tre Martiri 140, Rovigo 45100, Italy.
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Diagnostic role of 18F-dihydroxyphenylalanine positron emission tomography in patients with congenital hyperinsulinism: a meta-analysis. Nucl Med Commun 2013; 34:347-53. [PMID: 23376859 DOI: 10.1097/mnm.0b013e32835e6ac6] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES Studies have reported the applications of F-dihydroxyphenylalanine (F-DOPA) PET in patients with congenital hyperinsulinism (CHI). The aim of this study was to systematically review and perform a meta-analysis of published data on the diagnostic role of F-DOPA PET in patients with CHI. MATERIALS AND METHODS A comprehensive computer literature search of studies on F-DOPA PET or PET/computed tomography (CT) in patients with CHI was conducted. The pooled sensitivity and specificity of F-DOPA PET or PET/CT in patients with CHI were calculated. The area under the receiver-operating characteristic curve was calculated to measure the accuracy of F-DOPA PET or PET/CT in patients with CHI. RESULTS Ten studies comprising 181 patients with CHI were included in this meta-analysis. The pooled sensitivity of F-DOPA PET and PET/CT in detecting CHI was 88% on a per-patient-based analysis. The pooled specificity of F-DOPA PET and PET/CT in demonstrating CHI was 79%. The area under the receiver-operating characteristic curve was 0.92 on a per-patient-based analysis. CONCLUSION In patients with CHI, F-DOPA PET or PET/CT demonstrated high sensitivity and specificity. F-DOPA PET and PET/CT are accurate methods for the diagnosis of CHI. Nevertheless, possible sources of false-positive and false-negative results should be kept in mind.
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26
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Calton EA, Temple IK, Mackay DJ, Lever M, Ellard S, Flanagan SE, Davies JH, Hussain K, Gray JC. Hepatoblastoma in a child with a paternally-inherited ABCC8 mutation and mosaic paternal uniparental disomy 11p causing focal congenital hyperinsulinism. Eur J Med Genet 2013; 56:114-7. [DOI: 10.1016/j.ejmg.2012.12.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2012] [Accepted: 12/09/2012] [Indexed: 01/19/2023]
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27
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Haldorsen IS, Ræder H, Vesterhus M, Molven A, Njølstad PR. The role of pancreatic imaging in monogenic diabetes mellitus. Nat Rev Endocrinol 2011; 8:148-59. [PMID: 22124438 DOI: 10.1038/nrendo.2011.197] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
In neonatal diabetes mellitus resulting from mutations in EIF2AK3, PTF1A, HNF1B, PDX1 or RFX6, pancreatic aplasia or hypoplasia is typical. In maturity-onset diabetes mellitus of the young (MODY), mutations in HNF1B result in aplasia of pancreatic body and tail, and mutations in CEL lead to lipomatosis. The pancreas is not readily accessible for histopathological investigations and pancreatic imaging might, therefore, prove important for diagnosis, treatment, and research into these β-cell diseases. Advanced imaging techniques can identify the pancreatic features that are characteristic of inherited diabetes subtypes, including alterations in organ size (diffuse atrophy and complete or partial pancreatic agenesis), lipomatosis and calcifications. Consequently, in patients with suspected monogenic diabetes mellitus, the results of pancreatic imaging could help guide the molecular and genetic investigation. Imaging findings also highlight the critical roles of specific genes in normal pancreatic development and differentiation and provide new insight into alterations in pancreatic structure that are relevant for β-cell disease.
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Affiliation(s)
- Ingfrid S Haldorsen
- Department of Radiology, Haukeland University Hospital, N-5021 Bergen, Norway
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Abstract
Congenital hyperinsulinism of infancy (CHI) is characterized by inappropriate insulin secretion resulting in persistent hypoglycemia, which can lead to irreversible severe neurological damage in the infant. Many patients with CHI will respond to medical therapy, but surgery is necessary in those that do not. There are 2 main histologic subtypes, diffuse and focal, both of which may require different surgical strategies. Near-total pancreatectomy is the procedure of choice for diffuse CHI, whereas a localized resection is curative in focal CHI. Open surgery is the traditional approach to pancreatic resection. However, laparoscopy is increasingly used, particularly in localized resection for focal disease. We describe both methods of pancreatectomy.
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Affiliation(s)
- Agostino Pierro
- Department of Paediatric Surgery, UCL Insitute of Child Health and Great Ormond Street Hospital for Children, London, United Kingdom.
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Zani A, Nah SA, Ron O, Totonelli G, Ismail D, Smith VV, Ashworth M, Blankenstein O, Mohnike W, De Coppi P, Eaton S, Hussain K, Pierro A. The predictive value of preoperative fluorine-18-L-3,4-dihydroxyphenylalanine positron emission tomography-computed tomography scans in children with congenital hyperinsulinism of infancy. J Pediatr Surg 2011; 46:204-8. [PMID: 21238668 DOI: 10.1016/j.jpedsurg.2010.09.093] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2010] [Accepted: 09/30/2010] [Indexed: 12/21/2022]
Abstract
BACKGROUND/PURPOSE In congenital hyperinsulinism (CHI) of infancy, the use of preoperative fluorine-18-L-3,4-dihydroxyphenylalanine-positron emission tomography-computed tomography ((18)F-DOPA-PET-CT) scan has recently been reported. The aim of this study was to evaluate the accuracy of this technique in discriminating between diffuse and focal CHI and the anatomical localization of focal lesions. METHODS Between 2006 and 2010, (18)F-DOPA-PET scan was performed in 19 children with CHI (median age, 2 months; range, 1-12 months) who were not responding to medical therapy and underwent laparoscopic or open surgery. The findings of (18)F-DOPA-PET scan were correlated with histology. RESULTS In 5 children, (18)F-DOPA-PET scan showed diffuse pancreatic uptake, confirmed at histology and supporting the genetic suspicion of diffuse disease. In 14 children, (18)F-DOPA-PET scan indicated focal pancreatic uptake, which corresponded to histology. However, in 5 patients (36%), (18)F-DOPA-PET scan was inaccurate in defining the location of the lesion (n = 3), size of the lesion (n = 1), or both location and size (n = 1), leading to an inaccurate pancreatic resection. CONCLUSIONS Fluorine-18-L-3,4-dihydroxyphenylalanine-positron emission tomography-computed tomography scan discriminates between diffuse and focal forms of CHI. In focal forms, (18)F-DOPA-PET scan is useful in 2/3 of patients in defining the site and dimension of the focal lesion. Intraoperative histologic confirmation of complete focal lesion resection is needed.
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Affiliation(s)
- Augusto Zani
- Department of Paediatric Surgery, Institute of Child Health and Great Ormond Street Hospital for Children, Great Ormond Street, London, United Kingdom
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Castillo Meleán J, Ermert J, Coenen HH. Efficient synthesis of fluorobenzyloxoimidazolidinone derivatives: precursors for the radiosynthesis of [18F]fluorophenylamino acids. Tetrahedron 2010. [DOI: 10.1016/j.tet.2010.10.036] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Abstract
Congenital hyperinsulinism is a leading cause of severe hypoglycaemia in the newborn period. There are two (diffuse and focal) histological subtypes of congenital hyperinsulinism. The diffuse form affects the entire pancreas and if medically unresponsive will require a near total (95%-98%) pancreatectomy. The focal form affects only a small region of the pancreas (with the rest of the pancreas being normal in endocrine and exocrine function) and only requires a limited pancreatectomy. This limited section of the focal lesion has the potential for curing the patient. Thus the pre-operative differentiation of these two subgroups is extremely important. Recent advances in Fluorine-18-L-dihydroxyphenylalanine positron emission tomography ((18)F-DOPA PET/CT) have radically changed the clinical approach to patient with congenital hyperinsulinism. In most patients this novel imaging technique is able to offer precise pre-operative localisation of the focal lesion, thus guiding the extent of surgical resection.
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Affiliation(s)
- Dunia Ismail
- Clinical and Molecular Genetics Unit, The Developmental Endocrinology Research Group, Institute of Child Health, University College London, Great Ormond Street Hospital for Children NHS Trust, 30 Guilford Street, London, WC1N 1EH, UK
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32
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Abstract
In both type 1 and type 2 diabetes mellitus, beta-cell mass (BCM), which exclusively produces insulin, is lost. Various therapeutic strategies are being developed that target BCM to restore its function by promoting beta-cell neogenesis and regeneration or by preventing its apoptosis. To this end, it is essential to identify biomarkers of BCM. Of the various imaging platforms, radionuclide-based imaging methods using radioligands that directly target BCM appear promising. In particular, the vesicular monoamine transporter type 2 (VMAT2), which is expressed almost exclusively by beta-cells and found in close association with insulin, can be noninvasively imaged with PET and (11)C-dihydrotetrabenazine or its derivatives. Despite the major limitation that beta-cells are low in abundance (1%-2%) and dispersed throughout the pancreas, VMAT2 PET is sensitive enough to detect VMAT2 signal and to allow kinetic model-based quantification of VMAT2 binding within the pancreas. However, these techniques are still in early stages, and careful further evaluations and technical developments are needed before they can be clinically used as a valid biomarker of BCM.
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Affiliation(s)
- Masanori Ichise
- Department of Radiology, Columbia University Medical College, New York, New York 11032, USA.
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Abstract
Insulinomas are rare causes of hypoglycemia. After having ruled out non insulinomatous causes of hypoglycemia in a patient in whom Whipple's triad is documented, hyperinsulinism must be demonstrated biochemically, either during a spontaneous hypoglycemic episode or, more often, during a supervised fast which may be prolonged up to 72 h. A mixed-meal test may also help to diagnose the very rare cases of postprandial hypoglycemia related to non insulinoma pancreatogenic hypoglycemic syndrome (NIPHS) or to some rare insulinomas. Only when diagnosis of hypoglycemic hyperinsulinism is made, the tumor localization process may be initiated. This may be difficult due to the small size of insulinomas (generally < 1 cm). Multimodal approach is necessary. The association of endoscopic ultrasound and CT-scan or MRI seems optimal. Octreoscan will be also performed. First results with a very new technique, the GLP-1 receptor imaging, are promising for localizing very small tumors. This localization aims to allow a sparing surgery; enucleation of benign tumors, if possible, allows a pancreatic tissue preservation in patients with quite normal survival.
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Affiliation(s)
- L Cazabat
- Hôpitaux de Paris, Service d'Endocrinologie et des Maladies de la Reproduction, Hôpital de Bicêtre et Faculté de Médicine Paris-Sud, Université Paris Sud 11, 78, rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France.
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Abstract
Although 6-(18)F-fluoro-L-dopa ((18)F-FDOPA) has been available to study the striatal dopaminergic system for more than 2 decades, the full potential of the tracer was not realized before the introduction of (18)F-FDOPA PET and PET/CT to image a variety of neuroendocrine tumors (NETs) and pancreatic beta-cell hyperplasia. Together with receptor-based imaging, (18)F-FDOPA offers a formerly unforeseen means to assist in the management of NETs and infants with persistent hyperinsulinemic hyperplasia. Institutions with special expertise in surgical, oncologic, and radiologic therapeutic modalities for NETs derive the highest benefit from (18)F-FDOPA PET/CT. (18)F-FDOPA-guided therapy may add to NET control by ensuring maximal cytoreduction.
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Affiliation(s)
- Heikki Minn
- Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland.
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Capito C, Khen-Dunlop N, Ribeiro MJ, Brunelle F, Aigrain Y, Crétolle C, Jaubert F, De Lonlay P, Nihoul-Fékété C. Value of18F–fluoro-l-dopa PET in the Preoperative Localization of Focal Lesions in Congenital Hyperinsulinism. Radiology 2009; 253:216-22. [DOI: 10.1148/radiol.2532081445] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Abstract
Congenital hyperinsulinism is the principle cause of hypoglycemia during infancy but successful treatment is difficult and persistent hypoglycemia carries the risk of neurologic damage. Focal and diffuse abnormalities are the common forms of hyperinsulinism. Identification and localization of focal hyperinsulinism can be cured by partial pancreatectomy. It has been shown that affected pancreatic areas utilize LDOPA in a higher rate than normal pancreatic tissue and, thus, labeling L-DOPA with fluorine-18 (FDOPA) allows functional mapping of hyperinsulinism using PET. This article presents a fundamental overview of the genetics background, pathology, management, and the role of FDOPA-PET imaging in hyperinsulinism.
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Molecular imaging with positron emission tomography in paediatric oncology--FDG and beyond. Pediatr Radiol 2009; 39 Suppl 3:450-5. [PMID: 19440765 DOI: 10.1007/s00247-009-1231-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Kapoor RR, James C, Hussain K. Advances in the diagnosis and management of hyperinsulinemic hypoglycemia. ACTA ACUST UNITED AC 2009; 5:101-12. [PMID: 19165222 DOI: 10.1038/ncpendmet1046] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2008] [Accepted: 11/12/2008] [Indexed: 12/16/2022]
Abstract
Hyperinsulinemic hypoglycemia (HH) is a consequence of unregulated insulin secretion by pancreatic beta-cells and is a major cause of hypoglycemic brain injury and mental retardation. Congenital HH is caused by mutations in genes involved in regulation of insulin secretion, seven of which have been identified (ABCC8, KCNJ11, GLUD1, CGK, HADH, SLC16A1 and HNF4A). Severe forms of congenital HH are caused by mutations in ABCC8 and KCNJ11, which encode the two components of the pancreatic beta-cell ATP-sensitive potassium channel. Mutations in HNF4A, GLUD1, CGK, and HADH lead to transient or persistent HH, whereas mutations in SLC16A1 cause exercise-induced HH. Rapid genetic analysis combined with an understanding of the histological features (focal or diffuse disease) of congenital HH and the introduction of (18)F-L-3,4-dihydroxyphenylalanine PET-CT to guide laparoscopic surgery have totally transformed the clinical approach to this complex disease. Adult-onset HH is mostly caused by an insulinoma; however, it has also been reported to present as postprandial HH in patients with noninsulinoma pancreatogenous hypoglycemia syndrome, in those who have undergone gastric-bypass surgery for morbid obesity, and in those with mutations in the insulin-receptor gene.
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Affiliation(s)
- Ritika R Kapoor
- Institute of Child Health, University College London and Great Ormond Street Hospital for Children National Health Services Trust, London, UK
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