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Ito T, Ramos-Alvarez I, Jensen RT. Successful Lifetime/Long-Term Medical Treatment of Acid Hypersecretion in Zollinger-Ellison Syndrome (ZES): Myth or Fact? Insights from an Analysis of Results of NIH Long-Term Prospective Studies of ZES. Cancers (Basel) 2023; 15:1377. [PMID: 36900170 PMCID: PMC10000208 DOI: 10.3390/cancers15051377] [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: 01/13/2023] [Revised: 02/09/2023] [Accepted: 02/15/2023] [Indexed: 02/24/2023] Open
Abstract
Analysis of the efficacy/pharmacology of long-term/lifetime medical treatment of acid hypersecretion in a large cohort of ZES patients in a prospective study. This study includes the results from all 303 patients with established ZES who were prospectively followed and received acid antisecretory treatment with either H2Rs or PPIs, with antisecretory doses individually titrated by the results of regular gastric acid testing. The study includes patients treated for short-term periods (<5 yrs), patients treated long-term (>5 yrs), and patients with lifetime treatment (30%) followed for up to 48 years (mean 14 yrs). Long-term/lifelong acid antisecretory treatment with H2Rs/PPIs can be successfully carried out in all patients with both uncomplicated and complicated ZES (i.e., with MEN1/ZES, previous Billroth 2, severe GERD). This is only possible if drug doses are individually set by assessing acid secretory control to establish proven criteria, with regular reassessments and readjustments. Frequent dose changes both upward and downward are needed, as well as regulation of the dosing frequency, and there is a primary reliance on the use of PPIs. Prognostic factors predicting patients with PPI dose changes are identified, which need to be studied prospectively to develop a useful predictive algorithm that could be clinically useful for tailored long-term/lifetime therapy in these patients.
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Affiliation(s)
- Tetsuhide Ito
- Neuroendocrine Tumor Centre, Fukuoka Sanno Hospital, International University of Health and Welfare, 3-6-45 Momochihama, Sawara-Ku, Fukuoka 814-0001, Japan
| | | | - Robert T. Jensen
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA
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Marcal LP, Chuang HH, Tran Cao HS, Halperin DM. Pancreatic Neuroendocrine Tumors. ONCOLOGIC IMAGING : A MULTIDISCIPLINARY APPROACH 2023:197-217. [DOI: 10.1016/b978-0-323-69538-1.00014-8] [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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3
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Carcinoid Crisis: A Misunderstood and Unrecognized Oncological Emergency. Cancers (Basel) 2022; 14:cancers14030662. [PMID: 35158931 PMCID: PMC8833591 DOI: 10.3390/cancers14030662] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/22/2022] [Accepted: 01/26/2022] [Indexed: 01/25/2023] Open
Abstract
Carcinoid Crisis represents a rare and extremely dangerous manifestation that can occur in patients with Neuroendocrine Tumors (NETs). It is characterized by a sudden onset of hemodynamic instability, sometimes associated with the classical symptoms of carcinoid syndrome, such as bronchospasm and flushing. Carcinoid Crisis seems to be caused by a massive release of vasoactive substances, typically produced by neuroendocrine cells, and can emerge after abdominal procedures, but also spontaneously in rare instances. To date, there are no empirically derived guidelines for the management of this cancer-related medical emergency, and the available evidence essentially comes from single-case reports or dated small retrospective series. A transfer to the Intensive Care Unit may be necessary during the acute setting, when the severe hypotension becomes unresponsive to standard practices, such as volemic filling and the infusion of vasopressor therapy. The only effective strategy is represented by prevention. The administration of octreotide, anxiolytic and antihistaminic agents represents the current treatment approach to avoid hormone release and prevent major complications. However, no standard protocols are available, resulting in great variability in terms of schedules, doses, ways of administration and timing of prophylactic treatments.
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Abstract
Carcinoid syndrome, a paraneoplastic condition linked with the release of multiple humoral factors, affects around 30-40% of patients with well-differentiated neuroendocrine tumours. Carcinoid syndrome has a major and unfavourable impact on patients' quality of life; it raises costs when compared to non-functioning neuroendocrine tumours; and it causes patients' lifestyles to alter, such as food, job, physical activity, and social life. Somatostatin analogues have been the first-line therapy for individuals with neuroendocrine tumours and carcinoid disease for decades. While these drugs give considerable relief from carcinoid syndrome symptoms, clinical progression is unavoidable, necessitating further research into newer treatment measures. Carcinoid tumours are sometimes difficult to diagnose because of their vague or nonspecific symptoms. There have been several advancements in all aspects of carcinoid syndrome, as well as novel therapeutics, in the previous few years. New epidemiological studies show that it is becoming more common; increasing insights into the pathogenesis of its various clinical manifestations and its natural history: definition of prognostic factors; new methods to verify its presence; the development of new drugs to treat its various manifestations, both initially and in somatostatin-refractory cases; and an increased understanding of the pathogenesis, natural history, and management of the disease. An all language literature search was conducted on MEDLINE, COCHRANE, EMBASE, and Google Scholar till November 2021. The following search strings and Medical Subject Headings (MeSH) terms were used: "Recent advances", "Carcinoid syndrome", "Neuroendocrine Neoplasms" and "Carcinoid heart disease". We comprehensively reviewed the literature on the pathogenesis, clinical features, and newer treatment modalities for Carcinoid Syndrome. Recent advancements in research and management have resulted from advances in our understanding of the aetiology of carcinoid syndrome. The development of molecular indicators of aggressiveness improved serum tumour markers, and the molecular aetiology of carcinoid heart disease are all possible because of advances in molecular biology. We conducted a comprehensive review to update knowledge regarding the pathophysiology, diagnostic protocols, and current and newer treatments for carcinoid syndrome, which presently requires a multidisciplinary approach, due to the complexity of the illness's aetiology, diagnosis, and therapy.
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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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Haddad T, Fard-Esfahani A, Vali R. A review of pediatric neuroendocrine tumors, their detection, and treatment by radioisotopes. Nucl Med Commun 2021; 42:21-31. [PMID: 33044400 DOI: 10.1097/mnm.0000000000001305] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Neuroendocrine tumors (NETs) are rare in childhood. Neuroblastoma is the most common pediatric extracranial solid tumor, occurring >90% in children younger than 5 years of age. Pheochromocytoma and paraganglioma are rare NETs, causing hypertension in 0.5-2% of hypertensive children. Gastroenteropancreatic NETs can occur in children and are classified into carcinoids and pancreatic tumors. Nuclear medicine procedures have an essential role both in the diagnosis and treatment of NETs. Metaiodobenzylguanidine (MIBG) labeled with radioiodine has a well-established role in diagnosis as well as therapeutic management of the neuroblastoma group of diseases. During recent decades, establishing the abundant expression of somatostatin receptors by NETs first led to scintigraphy with somatostatin analogs (i.e. Tc/In-octreotide) and, later, with the emergence of positron-emitting labeled agents (i.e. Ga-DOTATATE/DOTATOC/DOTANOC) PET scans with significantly higher detection efficiency became available. Therapy with somatostatin analogs labeled with beta emitters such as Lu-177 and Y-90, known as peptide receptor radionuclide therapy, is a promising new option in the management of patients with inoperable or metastasized NETs. In this article, pediatric NETs are briefly reviewed and the role of radioactive agents in the detection and treatment of these tumors is discussed.
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Affiliation(s)
- Tara Haddad
- Diagnostic Imaging Department, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Armaghan Fard-Esfahani
- Research Center for Nuclear Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Vali
- Diagnostic Imaging Department, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
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Fust K, Maschio M, Kohli M, Singh S, Pritchard DM, Marteau F, Myrenfors P, Feuilly M. A Budget Impact Model of the Addition of Telotristat Ethyl Treatment to the Standard of Care in Patients with Uncontrolled Carcinoid Syndrome. PHARMACOECONOMICS 2020; 38:607-618. [PMID: 32157590 DOI: 10.1007/s40273-020-00896-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
BACKGROUND Carcinoid syndrome, a rare condition in patients with neuroendocrine tumours, characterised by flushing and diarrhoea, severely affects patients' quality of life. The current carcinoid syndrome standard of care includes somatostatin analogues, but some patients experience uncontrolled symptoms despite somatostatin analogue therapy. Telotristat ethyl is a novel treatment approved by the European Medicines Agency (EMA) and US FDA that significantly reduces bowel movement frequency in patients with uncontrolled carcinoid syndrome. OBJECTIVE We developed a model to evaluate the 5-year budget impact of introducing telotristat ethyl to standard care in Swedish patients with uncontrolled carcinoid syndrome. METHODS Treatment response in the 12-week phase III TELESTAR trial (NCT01677910) informed telotristat ethyl efficacy; subsequently, health states were captured by a Markov model using 4-week cycles. TELESTAR open-label extension data informed telotristat ethyl discontinuation. The number of treatment-eligible patients was estimated from literature reviews reporting the prevalence, incidence and mortality of carcinoid syndrome. A Swedish database study informed real-world costs related to carcinoid syndrome and carcinoid heart disease costs. Telotristat ethyl market share was assumed to increase annually from 24% (year 1) to 70% (year 5). RESULTS Over the 5-year model horizon, 44 patients were expected to initiate telotristat ethyl treatment. The cumulative net budget impact of adding telotristat ethyl to current standard of care was €172,346; per-year costs decreased from €66,495 (year 1) to €29,818 (year 5). Increased drug costs from adding telotristat ethyl were offset by reduced costs elsewhere. CONCLUSIONS The expected budget impact of adding telotristat ethyl to the standard of care in Sweden was relatively low, largely because of the rarity of carcinoid syndrome.
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Affiliation(s)
- Kelly Fust
- Optum, 1325 Boylston Street, Boston, MA, 02215, USA
| | - Michael Maschio
- Formerly affiliated with Optum, 5500 North Service Road, Suite 501, Burlington, ON, L7L 6W6, Canada
| | - Michele Kohli
- Formerly affiliated with Optum, 5500 North Service Road, Suite 501, Burlington, ON, L7L 6W6, Canada
| | - Simron Singh
- Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada
| | - D Mark Pritchard
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool, L69 3BX, UK
| | - Florence Marteau
- Ipsen Pharma, 65 Quai Georges Gorse, 92100, Boulogne-Billancourt, France
| | | | - Marion Feuilly
- Ipsen Pharma, 65 Quai Georges Gorse, 92100, Boulogne-Billancourt, France.
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Rendell MS. The journey from gene knockout to clinical medicine: telotristat and sotagliflozin. DRUG DESIGN DEVELOPMENT AND THERAPY 2019; 13:817-824. [PMID: 30880915 PMCID: PMC6408923 DOI: 10.2147/dddt.s144556] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Gene knockout has been a powerful technique to evaluate the physiologic role of selected gene products. Lexicon pioneered high-throughput gene knockout technology and went further in designing agents to inhibit products of gene expression. Two agents have entered late-stage development. Telotristat is an inhibitor of tryptophan hydroxylase (TPH), preventing the production of serotonin. Although this agent blocks the two isoforms of TPH, it does not cross the blood–brain barrier, thus avoiding central neurologic manifestations. It inhibits the peripheral production of serotonin, and in particular prevents serotonin action in the intestines, resulting in decreased peristaltic action. Lexicon successfully developed telotristat to treat carcinoid syndrome not responding adequately to somatostatin inhibitors. Sotagliflozin development proceeded from the observation that dual inhibition of SGLT2 in the kidneys and SGLT1 in the intestines resulted in increased renal glucose excretion, reduced early-phase glucose absorption, as well as increased blood levels of GLP-1 and PYY. Initial development efforts focused on type 1 diabetes and have shown reduced postprandial glucose levels, less tendency to hypoglycemia, and lower HbA1c. Several other SGLT2 inhibitors have been associated with increased frequency of diabetic ketoacidosis (DKA). In the type 1 trials, sotagliflozin-treated individuals experienced DKA at a higher rate than placebo-treated patients. The sotagliflozin development program has now been extended to trials on type 2 diabetes. Long-term clinical trials will determine the benefits and risks of the agent in comparison to other currently marketed SGLT2 inhibitors.
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Affiliation(s)
- Marc S Rendell
- Association of Diabetes Investigators, Omaha, NE 68131, USA, .,Rose Salter Medical Research Foundation, Newport Coast, CA 92657, USA,
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Lesén E, Björstad Å, Björholt I, Marlow T, Bollano E, Feuilly M, Marteau F, Welin S, Elf AK, Johanson V. Real-world treatment patterns, resource use and costs of treating uncontrolled carcinoid syndrome and carcinoid heart disease: a retrospective Swedish study. Scand J Gastroenterol 2018; 53:1509-1518. [PMID: 30449217 DOI: 10.1080/00365521.2018.1531653] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES To quantify healthcare resource use (HRU) and costs in relation to carcinoid syndrome (CS) and carcinoid heart disease (CHD) in a real-world setting, and to provide perspective on treatment patterns. MATERIALS AND METHODS Patient data and HRU were collected retrospectively from three Swedish healthcare registers. Adult patients diagnosed with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) grade 1 or 2 and CS who purchased somatostatin analogs (SSAs), and experienced controlled (defined by SSAs use) and uncontrolled (defined by SSAs dose escalation) CS for ≥8 months during the study period were included. Patients diagnosed with CHD from the date of the GEP-NET diagnosis were included in the CHD study group. RESULTS Overall, total HRU cost increased with uncontrolled CS and CHD. Total resource cost was 15,500€/patient during controlled CS (8 months), rising to 21,700€/patient during uncontrolled CS (8 months), representing an increase of ∼40% (6200€/patient). Costs/patient were driven mainly by SSA use, tumor-related medical interventions and examinations. The total mean cost/year of disease was 1100€/patient without CHD, compared to 4600€/patient with CHD, a difference of 3500€/patient. Excluding SSA cost burden, the main drivers of increased cost in CHD patients were surgical interventions and echocardiography. CONCLUSIONS This study provides a comprehensive overview of the treatment patterns and burden of uncontrolled CS symptoms and CHD using Swedish national register data. Increases in medical interventions and examinations HRU and increased SSA use suggest that SSA dose escalation alone may not effectively control the symptoms associated with uncontrolled CS, highlighting an unmet treatment need in this patient group.
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Affiliation(s)
- Eva Lesén
- a PharmaLex, formerly Nordic Health Economics AB , Gothenburg , Sweden
| | - Åse Björstad
- a PharmaLex, formerly Nordic Health Economics AB , Gothenburg , Sweden
| | - Ingela Björholt
- a PharmaLex, formerly Nordic Health Economics AB , Gothenburg , Sweden
| | - Tom Marlow
- a PharmaLex, formerly Nordic Health Economics AB , Gothenburg , Sweden
| | - Entela Bollano
- b Department of Cardiology , Sahlgrenska University Hospital , Gothenburg , Sweden
| | | | | | - Staffan Welin
- d Department of Endocrine Oncology , Uppsala University Hospital , Uppsala , Sweden
| | - Anna-Karin Elf
- e Department of Surgery , Sahlgrenska University Hospital , Gothenburg , Sweden
| | - Viktor Johanson
- e Department of Surgery , Sahlgrenska University Hospital , Gothenburg , Sweden
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10
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Cella D, Beaumont JL, Hudgens S, Marteau F, Feuilly M, Houchard A, Lapuerta P, Ramage J, Pavel M, Hörsch D, Kulke MH. Relationship Between Symptoms and Health-related Quality-of-life Benefits in Patients With Carcinoid Syndrome: Post Hoc Analyses From TELESTAR. Clin Ther 2018; 40:2006-2020.e2. [PMID: 30477789 DOI: 10.1016/j.clinthera.2018.10.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 09/12/2018] [Accepted: 10/09/2018] [Indexed: 02/07/2023]
Abstract
PURPOSE Patients with metastatic neuroendocrine tumors and carcinoid syndrome (CS) may experience chronic, recurring symptoms despite somatostatin analogue therapy. Little is known about the relationship between bowel movement (BM) frequency, patient-reported symptoms and health-related quality of life (QoL). Data from the TELESTAR study were used in exploratory, post hoc analyses to understand the relationship between durable reductions in BM frequency, symptom relief, and health-related QoL. METHODS Patients with metastatic neuroendocrine tumors and CS in the Phase III TELESTAR study were randomized (1:1:1) to receive telotristat ethyl (TE) 250 mg, TE 500 mg, or placebo three times daily (TID) during a 12-week double-blind treatment period (DBTP). All patients received TE 500 mg TID in an open-label extension (OLE) to Week 48. Durable response was predefined. Analyses compared durable responders (DRs) and non-durable responders (NDRs), irrespective of treatment group, at Weeks 12, 24, and 48. FINDINGS At the start of the DBTP, 135 patients were randomized, 45 patients each to TE 250 mg, TE 500 mg, and placebo. After the 12-week DBTP, 48 of 135 patients were DRs (TE 250 mg, n = 20; TE 500 mg, n = 19; placebo, n = 9). Of the 115 patients who entered the OLE, 35 were DRs initially randomized to TE 250 mg (n = 18) or 500 mg (n = 17), 29 of whom maintained a durable response throughout the OLE. Of the 71 DBTP-NDRs (inclusive of patients initially randomized to placebo), 28 became OLE-DRs. There were 29 NDRs initially randomized to placebo who entered the OLE, 16 of whom became DRs when switched to TE 500 mg. DRs during the DBTP had greater symptom improvements in the DBTP; these improvements continued over the OLE. DBTP-DRs also maintained more meaningful QoL improvements in EORTC QLQ-C30 global health status, nausea and vomiting, pain, diarrhea, and EORTC QLQ-GINET21 gastrointestinal symptoms over the DBTP and OLE periods than DBTP-NDRs. IMPLICATIONS These results suggest that sustained improvements in BM frequency in patients with CS may have multifaceted, long-term effects on a patient's well-being. ClinicalTrials.gov identifiers: NCT01677910.
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Affiliation(s)
- David Cella
- Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
| | - Jennifer L Beaumont
- Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Terasaki Research Institute, Los Angeles, CA, USA
| | | | | | | | | | | | - John Ramage
- Hampshire Hospitals, Basingstoke, United Kingdom
| | - Marianne Pavel
- Universitatsklinikum Erlangen, Erlangen, Germany; Charité-Universitätsmedizin Berlin, Berlin, Germany
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Abstract
Neuroendocrine tumors, including carcinoids, are rare and insidiously growing tumors. Related to their site of origin, tumors can be functional, causing various forms of the carcinoid syndrome, owing to the overproduction of serotonin, histamine, or other bioactive substances. They often invade adjacent structures or metastasize to the liver and elsewhere. Treatment includes multimodal approaches, including cytoreductive surgery, locoregional embolization, cytotoxic therapy, peptide receptor radionuclide therapy, and various targeted therapies with goals of symptom relief and control of tumor growth. This article summarizes current and emerging approaches to management and reviews several promising future therapies.
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Affiliation(s)
- Paul Benjamin Loughrey
- Department of Ophthalmology, Royal Victoria Hospital, Belfast Trust, Grosvenor Road, Belfast, BT12 6BA, UK; Department of Endocrinology and Diabetes, Royal Victoria Hospital, Belfast Trust, Grosvenor Road, Belfast, BT12 6BA, UK
| | - Dongyun Zhang
- Department of Medicine, David Geffen School of Medicine, University of California, 700 Tiverton Avenue, Los Angeles, CA 90095, USA
| | - Anthony P Heaney
- Department of Medicine, David Geffen School of Medicine, University of California, 700 Tiverton Avenue, Los Angeles, CA 90095, USA; Department of Neurosurgery, David Geffen School of Medicine, University of California, 700 Tiverton Avenue, Los Angeles, CA 90095, USA.
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12
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Rastogi V, Singh D, Mazza JJ, Parajuli D, Yale SH. Flushing Disorders Associated with Gastrointestinal Symptoms: Part 1, Neuroendocrine Tumors, Mast Cell Disorders and Hyperbasophila. Clin Med Res 2018; 16:16-28. [PMID: 29650525 PMCID: PMC6108509 DOI: 10.3121/cmr.2017.1379a] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 11/30/2017] [Accepted: 12/21/2017] [Indexed: 02/08/2023]
Abstract
Flushing is the subjective sensation of warmth accompanied by visible cutaneous erythema occurring throughout the body with a predilection for the face, neck, pinnae, and upper trunk where the skin is thinnest and cutaneous vessels are superficially located and in greatest numbers. Flushing can be present in either a wet or dry form depending upon whether neural-mediated mechanisms are involved. Activation of the sympathetic nervous system results in wet flushing, accompanied by diaphoresis, due to concomitant stimulation of eccrine sweat glands. Wet flushing is caused by certain medications, panic disorder and paroxysmal extreme pain disorder (PEPD). Vasodilator mediated flushing due to the formation and release of a variety of biogenic amines, neuropeptides and phospholipid mediators such as histamine, serotonin and prostaglandins, respectively, typically presents as dry flushing where sweating is characteristically absent. Flushing occurring with neuroendocrine tumors accompanied by gastrointestinal symptoms is generally of the dry flushing variant, which may be an important clinical clue to the differential diagnosis. A number of primary diseases of the gastrointestinal tract cause flushing, and conversely extra-intestinal conditions are associated with flushing and gastrointestinal symptoms. Gastrointestinal findings vary and include one or more of the following non-specific symptoms such as abdominal pain, nausea, vomiting, diarrhea or constipation. The purpose of this review is to provide a focused comprehensive discussion on the presentation, pathophysiology, diagnostic evaluation and management of those diseases that arise from the gastrointestinal tract or other site that may cause gastrointestinal symptoms secondarily accompanied by flushing. This review is divided into two parts given the scope of conditions that cause flushing and affect the gastrointestinal tract: Part 1 covers neuroendocrine tumors (carcinoid, pheochromocytomas, vasoactive intestinal polypeptide, medullary carcinoma of the thyroid), polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS), and conditions involving mast cells and basophils; while Part 2 covers dumping syndrome, mesenteric traction syndrome, rosacea, hyperthyroidism and thyroid storm, anaphylaxis, panic disorders, paroxysmal extreme pain disorder, and food, alcohol and medications.
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Affiliation(s)
- Vaibhav Rastogi
- University of Central Florida College of Medicine/HCA Consortium Graduate Medical Education, North Florida Regional Medical Center, 6500 W Newberry Rd, Gainesville, FL 32605
- University of Central Florida College of Medicine, 6850 Lake Nona Blvd, Orlando, FL 32827
| | - Devina Singh
- Feinstein Institute for Medical Research, 350 Community Dr. Manhasset, NY 11030
| | - Joseph J Mazza
- Marshfield Clinic Research Institute, 1000 North Oak Avenue, Marshfield, WI 54449
| | - Dipendra Parajuli
- University of Louisville, Department of Medicine, Gastroenterology, Hepatology and Nutrition. Director, Fellowship Training Program, Director, Medical Procedure Unit Louisville VAMC 401 East Chestnut Street, Louisville, KY 40202
| | - Steven H Yale
- University of Central Florida College of Medicine/HCA Consortium Graduate Medical Education, North Florida Regional Medical Center, 6500 W Newberry Rd, Gainesville, FL 32605.
- University of Central Florida College of Medicine, 6850 Lake Nona Blvd, Orlando, FL 32827
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Tolliver S, Graham J, Kaffenberger BH. A review of cutaneous manifestations within glucagonoma syndrome: necrolytic migratory erythema. Int J Dermatol 2018; 57:642-645. [PMID: 29450880 DOI: 10.1111/ijd.13947] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 01/08/2018] [Accepted: 01/21/2018] [Indexed: 12/14/2022]
Abstract
Necrolytic migratory erythema (NME) is a rare skin disorder that is a cutaneous manifestation of the glucagonoma syndrome. It presents with annular eruptions of migrating erythematous papules and plaques with superficial epidermal necrosis, central flaccid bullae, and crusted erosions located primarily in the intertriginous areas. Treatment with the long-acting somatostatin analog Octreotide is a potential therapy to help ameliorate skin symptoms. We present a case of a patient with a 1-year history of a pancreatic glucagonoma that developed an ulcerated, plaque-like, weeping rash over multiple areas of their body despite current treatment with Octreotide and stable pancreatic tumor staging. The patient had a similar rash when initially diagnosed with a glucagonoma, and it quickly improved after Octreotide treatment. Clinical examination and biopsy were consistent with necrolytic migratory erythema due to an underlying glucagonoma. This rare case adds to our understanding of the clinical presentation of NME, as well as highlights the relapsing and remitting course, even if the underlying pancreatic tumor is stable and the patient is undergoing treatment.
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Affiliation(s)
- Starling Tolliver
- Division of Dermatology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Jaqueline Graham
- Division of Dermatology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Benjamin H Kaffenberger
- Division of Dermatology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA
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Sporadic Gastroenteropancreatic Neuroendocrine Tumors. Updates Surg 2018. [DOI: 10.1007/978-88-470-3955-1_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Marotta V, Zatelli MC, Sciammarella C, Ambrosio MR, Bondanelli M, Colao A, Faggiano A. Chromogranin A as circulating marker for diagnosis and management of neuroendocrine neoplasms: more flaws than fame. Endocr Relat Cancer 2018; 25:R11-R29. [PMID: 29066503 DOI: 10.1530/erc-17-0269] [Citation(s) in RCA: 110] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 10/24/2017] [Indexed: 12/13/2022]
Abstract
Owing to the heterogeneity of neuroendocrine neoplasms (NENs), the availability of reliable circulating markers is critical for improving diagnostics, prognostic stratification, follow-up and definition of treatment strategy. This review is focused on chromogranin A (CgA), a hydrophilic glycoprotein present in large dense core vesicles of neuroendocrine cells. Despite being long identified as the most useful NEN-related circulating marker, clinical application of CgA is controversial. CgA assays still lack standardization, thus hampering not only clinical management but also the comparison between different analyses. In the diagnostic setting, clinical utility of CgA is limited as hampered by (a) the variety of oncological and non-oncological conditions affecting marker levels, which impairs specificity; (b) the fact that 30-50% of NENs show normal CgA, which impairs sensitivity. Regarding the prognostic phase, there is prospective evidence which demonstrates that advanced NENs secreting CgA have poorer outcome, as compared with those showing non-elevated marker levels. Although the identification of cut-offs allowing a proper risk stratification of CgA-secreting patients has not been performed, this represents the most important clinical application of the marker. By contrast, based on prospective studies, the trend of elevated circulating CgA does not represent a valid indicator of morphological evolution and has therefore no utility for the follow-up phase. Ultimately, current knowledge about the role of the marker for the definition of treatment strategy is poor and is limited by the small number of available studies, their prevalent retrospective nature and the absence of control groups of untreated subjects.
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Affiliation(s)
- Vincenzo Marotta
- Department of Clinical Medicine and SurgeryFederico II University, Naples, Italy
| | - Maria Chiara Zatelli
- Section of Endocrinology and Internal MedicineDepartment of Medical Sciences, University of Ferrara, Ferrara, Italy
| | | | - Maria Rosaria Ambrosio
- Section of Endocrinology and Internal MedicineDepartment of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Marta Bondanelli
- Section of Endocrinology and Internal MedicineDepartment of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Annamaria Colao
- Department of Clinical Medicine and SurgeryFederico II University, Naples, Italy
| | - Antongiulio Faggiano
- Thyroid and Parathyroid Surgery UnitIstituto Nazionale per lo Studio e la Cura dei Tumori 'Fondazione G. Pascale' - IRCCS, Naples, Italy
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16
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Sadeghian A, Rouhana H, Oswald-Stumpf B, Boh E. Etiologies and management of cutaneous flushing. J Am Acad Dermatol 2017; 77:405-414. [PMID: 28807108 DOI: 10.1016/j.jaad.2016.12.032] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Revised: 12/07/2016] [Accepted: 12/18/2016] [Indexed: 12/31/2022]
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17
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Rogowski W, Wachuła E, Lewczuk A, Kolasińska-Ćwikła A, Iżycka-Świeszewska E, Sulżyc-Bielicka V, Ćwikła JB. Baseline chromogranin A and its dynamics are prognostic markers in gastroenteropancreatic neuroendocrine tumors. Future Oncol 2017; 13:1069-1079. [DOI: 10.2217/fon-2016-0455] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: This study assessed whether absolute chromogranin A (CgA) values at various stages of treatment have prognostic value in patients with pancreatic and midgut neuroendocrine tumors, subjected to peptide receptor radionuclide therapy with 90Y-[DOTA0, D-Phe1, Tyr3]-octreotate. Patients & methods: CgA was determined before peptide receptor radionuclide therapy, 6 weeks, 6, 12, 18 and 24 months after the last dose of 90Y-[DOTA0, D-Phe1, Tyr3]-octreotate. The primary end point was overall survival. Results: Elevated baseline CgA concentrations and their relative increase within the first year of observation were unfavorable predictors of overall survival, but not progression. Conclusion: Even a single baseline measurement of CgA can be useful in establishing prognosis in this group, if this parameter exceeds its upper normal limit more than tenfold.
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Affiliation(s)
- Wojciech Rogowski
- Clinical Department of Chemotherapy, Hospital Ministry of the Interior & Administration & Warmia & Mazury Oncology Centre, Olsztyn, Poland
- Department of Medical Science, University of Varmia & Masuria, Olsztyn, Poland
| | - Ewa Wachuła
- Clinical Department of Chemotherapy, Hospital Ministry of the Interior & Administration & Warmia & Mazury Oncology Centre, Olsztyn, Poland
| | - Anna Lewczuk
- Department of Endocrinology, Medical University of Gdańsk, Gdańsk, Poland
| | - Agnieszka Kolasińska-Ćwikła
- Department of Clinical Oncology, Maria-Skłodowska-Curie Memorial Cancer Center & Institute of Oncology, Warsaw, Poland
| | | | | | - Jarosław B Ćwikła
- Department of Medical Science, University of Varmia & Masuria, Olsztyn, Poland
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18
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Bonne L, Verslype C, Laenen A, Cornelissen S, Deroose CM, Prenen H, Vandecaveye V, Van Cutsem E, Maleux G. Safety and efficacy of doxorubicin-eluting superabsorbent polymer microspheres for the treatment of liver metastases from neuroendocrine tumours: preliminary results. Radiol Oncol 2017; 51:74-80. [PMID: 28265235 PMCID: PMC5330173 DOI: 10.1515/raon-2017-0007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 01/12/2017] [Indexed: 01/08/2023] Open
Abstract
Background The aim of the study was to retrospectively evaluate the symptom control, tumour response, and complication rate in patients with liver-predominant metastatic neuroendocrine tumours treated with transarterial chemoembolization using doxorubicin-eluting superabsorbent polymer (SAP) microspheres. Patients and methods Patients with neuroendocrine liver metastases who underwent hepatic transarterial chemoembolization using doxorubicin-eluting SAP-microspheres (50–100 μm Hepasphere/Quadrasphere Microsphere® particles, Merit Medical, South Jordan, Utah, USA) were included in this study. Pre-and post-procedure imaging studies were evaluated to assess short and intermediate-term tumour response using modified RECIST criteria. Symptom relief and procedure-related complications were evaluated. Results A total of 27 embolization procedures were performed on 17 patients. Twelve of 17 patients (70%) were symptomatic, including carcinoid syndrome (n = 8) and severe, uncontrollable hypoglycemia (n = 4). Eight of 12 patients (67%) had complete symptom relief, and the remaining 4 (33%) had partial relief. One patient developed ischemic cholecystitis (6%). No other hepatobiliary complications occurred. Short-term and intermediate-term imaging follow-up was available for 15/17 patients (88%) and 12/14 patients (86%) respectively. At short-term follow-up (< 3 months), 14 patients (93%) showed partial response and the remaining patient had progressive disease (7%). At intermediate-term imaging follow-up (> 3 months), partial response, stable disease and progressive disease were found respectively in 7 (58%), 3 (25%) and 2 (17%) patients. Conclusions Chemoembolization with doxorubicin-eluting SAP-microspheres is a safe and effective treatment option for neuroendocrine liver metastases and is associated with a low complication rate. In particular, no clinically evident liver necrosis or bile duct complications were encountered.
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Affiliation(s)
- Lawrence Bonne
- Department of Radiology, University Hospitals Leuven, Belgium
| | - Chris Verslype
- Department of Hepatology and Gastroenterology, University Hospitals Leuven, Belgium
| | - Annouschka Laenen
- Interuniversity Centre for Biostatistics and Statistical Bioinformatics, Catholic University of Leuven and University Hasselt, Belgium
| | | | | | - Hans Prenen
- Department of Hepatology and Gastroenterology, University Hospitals Leuven, Belgium
| | | | - Eric Van Cutsem
- Department of Hepatology and Gastroenterology, University Hospitals Leuven, Belgium
| | - Geert Maleux
- Department of Radiology, University Hospitals Leuven, Belgium
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19
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Kaltsas G, Caplin M, Davies P, Ferone D, Garcia-Carbonero R, Grozinsky-Glasberg S, Hörsch D, Tiensuu Janson E, Kianmanesh R, Kos-Kudla B, Pavel M, Rinke A, Falconi M, de Herder WW. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Pre- and Perioperative Therapy in Patients with Neuroendocrine Tumors. Neuroendocrinology 2017; 105:245-254. [PMID: 28253514 PMCID: PMC5637287 DOI: 10.1159/000461583] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 02/10/2017] [Indexed: 01/25/2023]
Abstract
Neuroendocrine tumors of the small intestine are the most common causes of the carcinoid syndrome. Carcinoid heart disease occurs in more than half of the patients with the carcinoid syndrome. Patients with carcinoid heart disease who need to undergo surgery should also undergo preoperative evaluation by an expert cardiologist. Treatment with long-acting somatostatin analogs aims at controlling the excessive hormonal output and symptoms related to the carcinoid syndrome and at preventing a carcinoid crisis during interventions. Patients with a gastrinoma require pre- and postoperative treatment with high doses of proton pump inhibitors. Patients with a glucagonoma require somatostatin analog treatment and nutritional supplementation. Patients with a VIPoma also require somatostatin analog treatment and intravenous fluid and electrolyte therapy. Insulinoma patients generally require intravenous glucose infusion prior to operation. In patients with localized operable insulinoma, somatostatin analog infusion should only be considered after the effect of this therapy has been electively studied.
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Affiliation(s)
- Gregory Kaltsas
- Endocrine Unit, Department of Pathophysiology, National and Kapodistrian University of Athens, Athens, Greece
- *Gregory Kaltsas, Sector of Endocrinology, Department of Pathophysiology, National and Kapodistrian University of Athens, Mikras Assias 75, Goudi, GR-11527 Athens (Greece), E-Mail
| | - Martyn Caplin
- Neuroendocrine Tumour Unit, Royal Free Hospital, London, UK
| | | | - Diego Ferone
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DiMI), Center of Excellence for Biomedical Research (CEBR), IRCCS AOU San Martino-IST, University of Genova, Genova, Italy
| | | | - Simona Grozinsky-Glasberg
- Neuroendocrine Unit, Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Dieter Hörsch
- Gastroenterology and Endocrinology Center for Neuroendocrine Tumors Bad Berka, Bad Berka, Germany
| | - Eva Tiensuu Janson
- Department of Endocrine Oncology, Uppsala University Hospital, Uppsala, Sweden
| | - Reza Kianmanesh
- Department of Digestive and Endocrine Surgery, Robert Debré Hospital, Reims, France
| | - Beata Kos-Kudla
- Department of Pathophysiology and Endocrinology, Division of Endocrinology, Medical University of Silesia, Katowice, Poland
| | - Marianne Pavel
- Department of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Berlin
| | - Anja Rinke
- Department of Gastroenterology, UKGM Marburg and Philipps University Marburg, Marburg, Germany
| | - Massimo Falconi
- Chirurgia del Pancreas, Pancreas Translational and Clinical Research Center, Ospedale San Raffaele, Università “Vita e Salute”, Milano, Italy
| | - Wouter W. de Herder
- ENETS Centre of Excellence, Erasmus MC Cancer Centre, Rotterdam, The Netherlands
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20
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Riihimäki M, Hemminki A, Sundquist K, Sundquist J, Hemminki K. The epidemiology of metastases in neuroendocrine tumors. Int J Cancer 2016; 139:2679-2686. [PMID: 27553864 DOI: 10.1002/ijc.30400] [Citation(s) in RCA: 221] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Revised: 07/17/2016] [Accepted: 07/20/2016] [Indexed: 12/13/2022]
Abstract
The epidemiology of metastases in neuroendocrine tumors (NETs) is virtually unknown. The present novel approach took use of two nationwide Swedish registers to assess the distribution of metastatic sites in comparison to adenocarcinoma. 7,334 patients with NET were identified from the Swedish Cancer Registry. Metastatic sites were identified from the National Patient and Cause of Death Registries. Sites of metastasis were investigated depending on the primary site of NET. The metastatic potential of NET was assessed. The liver was the most common site of metastasis (82% of patients with metastases), and the small intestine was the most common source of NET metastases. Of all patients with metastatic lung NETs, 66% had liver metastases, whereas the corresponding number for adenocarcinoma of lung was only 20%. The risk of metastasis was highest if the primary was in the small intestine or pancreatohepatobiliary tract, whereas it was lower with appendiceal and rectal NET. Men had more bone metastases compared to women. Patients with metastatic NET had worse prognosis if the primary site was unknown (11 months, 9% of NET patients) compared to those whose primary was known (19 months). The metastatic potential of NETs varies profoundly depending on the primary site. NETs show a clear preference to metastasize to the liver. Surveillance of liver metastases may enable earlier diagnosis and treatment. In liver metastases from NET, the small intestine should be suspected as the primary site, whereas the lung should be suspected in nervous system metastases of NET origin.
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Affiliation(s)
- Matias Riihimäki
- Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany. .,Center for Primary Health Care Research, Lund University, Malmö, Sweden.
| | - Akseli Hemminki
- Faculty of Medicine, Cancer Gene Therapy Group, University of Helsinki, Finland.,Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
| | | | - Jan Sundquist
- Center for Primary Health Care Research, Lund University, Malmö, Sweden
| | - Kari Hemminki
- Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.,Center for Primary Health Care Research, Lund University, Malmö, Sweden
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21
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Dimitriadis GK, Weickert MO, Randeva HS, Kaltsas G, Grossman A. Medical management of secretory syndromes related to gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer 2016; 23:R423-36. [PMID: 27461388 DOI: 10.1530/erc-16-0200] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 07/26/2016] [Indexed: 12/14/2022]
Abstract
Although recent epidemiological evidence indicates that the prevalence of non-functioning gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) is rising, a significant number of GEP-NETs still present with symptoms related to the secretion of biologically active substances leading to the development of distinct clinical syndromes. In the past, these syndromes were associated with substantial morbidity and mortality due to the lack of specific therapies; however, since the introduction of long-acting somatostatin analogues and medications such as proton pump inhibitors, their control has been greatly improved. As a result, nowadays, the main cause of morbidity and mortality in GEP-NETs is mostly directly related to tumour growth and the extent of metastatic disease. However, in some patients with functioning tumours and extensive disease, control of the secretory syndrome still remains problematic, necessitating the employment of several cytoreductive techniques, which may not always be sufficient. Recently, new agents directed against tumour growth, or exerting increased binding activity to receptors expressed in these tumours, or interfering with the synthetic pathway of some of the compounds secreted by these tumours, have been developed. Since there are no specific guidelines addressing the totality of the management of the secretory syndromes related to GEP-NETs, this review aims at critically analysing the medical management of previously recognised secretory syndromes; it also addresses areas of uncertainty, assesses the newer therapeutic developments and also addresses recently described but poorly characterised secretory syndromes related to GEP-NETs.
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Affiliation(s)
- Georgios K Dimitriadis
- The Arden NET CoEWarwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals of Coventry and Warwickshire NHS Trust, Coventry, UK Division of Translational and Experimental MedicineWarwick Medical School, University of Warwick, Coventry, UK Division of Endocrinology and Investigative MedicineImperial College London, Hammersmith Campus, London, UK
| | - Martin O Weickert
- The Arden NET CoEWarwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals of Coventry and Warwickshire NHS Trust, Coventry, UK Division of Translational and Experimental MedicineWarwick Medical School, University of Warwick, Coventry, UK Centre for Applied Biological and Exercise SciencesCoventry University, Coventry, UK
| | - Harpal S Randeva
- The Arden NET CoEWarwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals of Coventry and Warwickshire NHS Trust, Coventry, UK Division of Translational and Experimental MedicineWarwick Medical School, University of Warwick, Coventry, UK Centre for Applied Biological and Exercise SciencesCoventry University, Coventry, UK
| | - Gregory Kaltsas
- The Arden NET CoEWarwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals of Coventry and Warwickshire NHS Trust, Coventry, UK Division of PathophysiologyNational and Kapodistrian University of Athens Medical School, Athens, Greece Oxford Center for DiabetesEndocrinology and Metabolism, University of Oxford, Oxford, UK
| | - Ashley Grossman
- Oxford Center for DiabetesEndocrinology and Metabolism, University of Oxford, Oxford, UK
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22
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Abstract
Neuroendocrine tumors (NETs) are slow-growing neoplasms capable of storing and secreting different peptides and neuroamines. Some of these substances cause specific symptom complexes, whereas others are silent. They usually have episodic expression, and the diagnosis is often made at a late stage. Although considered rare, the incidence of NETs is increasing. For these reasons, a high index of suspicion is needed. In this article, the different clinical syndromes and the pathophysiology of each tumor as well as the new and emerging biochemical markers and imaging techniques that should be used to facilitate an early diagnosis, follow-up, and prognosis are reviewed.
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23
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Kuriry H, Swied AM. Large-Cell Neuroendocrine Carcinoma of the Esophagus: A Case from Saudi Arabia. Case Rep Gastroenterol 2015; 9:327-34. [PMID: 26600769 PMCID: PMC4649715 DOI: 10.1159/000441381] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Neuroendocrine carcinomas of the esophagus are very rare, and the majority are high grade (poorly differentiated). They occur most frequently in males in their sixth and seventh decades of life. There have been no concrete data published on clinical features or on prognosis. We report a case of large-cell neuroendocrine carcinoma of the esophagus in a 66-year-old Saudi female with progressive dysphagia and weight loss. Upper endoscopy revealed an esophageal ulcerated mass.
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Affiliation(s)
- Hadi Kuriry
- King Abdulaziz Medical City, Riyadh, Saudi Arabia
| | - Abdul Monem Swied
- King Saud bin Abdulaziz University for Health Science, Riyadh, Saudi Arabia
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24
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Grimaldi F, Fazio N, Attanasio R, Frasoldati A, Papini E, Angelini F, Baldelli R, Berretti D, Bianchetti S, Bizzarri G, Caputo M, Castello R, Cremonini N, Crescenzi A, Davì MV, D’Elia AV, Faggiano A, Pizzolitto S, Versari A, Zini M, Rindi G, Öberg K. Italian Association of Clinical Endocrinologists (AME) position statement: a stepwise clinical approach to the diagnosis of gastroenteropancreatic neuroendocrine neoplasms. J Endocrinol Invest 2014; 37:875-909. [PMID: 25038902 PMCID: PMC4159596 DOI: 10.1007/s40618-014-0119-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Accepted: 03/29/2014] [Indexed: 02/07/2023]
Affiliation(s)
- Franco Grimaldi
- Endocrinology and Metabolic Disease Unit, Azienda Ospedaliero-Universitaria “S. Maria della Misericordia”, P.le S.M. della Misericordia, 15-33100, Udine, Italy
| | - Nicola Fazio
- Unit of Gastrointestinal and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy
| | | | - Andrea Frasoldati
- Endocrinology Unit, Arcispedale S. Maria Nuova IRCCS, Reggio Emilia, Italy
| | - Enrico Papini
- Endocrinology Unit, Regina Apostolorum Hospital, Albano Laziale, Rome, Italy
| | - Francesco Angelini
- Oncology and Hematology Unit, Regina Apostolorum Hospital, Albano Laziale, Rome, Italy
| | - Roberto Baldelli
- Endocrinology Section, Regina Elena National Cancer Institute, Rome, Italy
| | - Debora Berretti
- Gastroenterology Unit, Azienda Ospedaliero-Universitaria “S. Maria della Misericordia”, Udine, Italy
| | - Sara Bianchetti
- Oncology and Hematology Unit, Regina Apostolorum Hospital, Albano Laziale, Rome, Italy
| | - Giancarlo Bizzarri
- Diagnostic Imaging Unit, Regina Apostolorum Hospital, Albano Laziale, Rome, Italy
| | - Marco Caputo
- Dipartimento Servizi di Diagnosi e Cura, AUSL 22 Regione Veneto, Bussolengo, VR Italy
| | - Roberto Castello
- Medicina Interna ad indirizzo Endocrinologico, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Nadia Cremonini
- Endocrinology Unit, Maggiore and Bellaria Hospital, Bologna, Italy
| | - Anna Crescenzi
- Pathology Unit, Regina Apostolorum Hospital, Albano Laziale, Rome, Italy
| | - Maria Vittoria Davì
- Medicina Interna D, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Angela Valentina D’Elia
- Genetic Service, Azienda Ospedaliero-Universitaria “S. Maria della Misericordia”, Udine, Italy
| | - Antongiulio Faggiano
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Stefano Pizzolitto
- Pathology Unit, Azienda Ospedaliero-Universitaria “S. Maria della Misericordia”, Udine, Italy
| | - Annibale Versari
- Nuclear Medicine Service, Arcispedale S. Maria Nuova IRCCS, Reggio Emilia, Italy
| | - Michele Zini
- Endocrinology Unit, Arcispedale S. Maria Nuova IRCCS, Reggio Emilia, Italy
| | - Guido Rindi
- Institute of Pathology, Policlinico A. Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Kjell Öberg
- Department of Endocrine Oncology, University Hospital, Uppsala, Sweden
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25
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Mistry M, Gupta M, Kaler M. Pregnancy in multiple endocrine neoplasia type 1 equals multiple complications. Obstet Med 2014; 7:123-5. [PMID: 27512437 DOI: 10.1177/1753495x14532634] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Multiple endocrine neoplasia type 1 (MEN 1) is a rare inherited disorder caused by mutations in the tumour suppressor gene MEN 1. It is characterised by a predisposition towards the development of parathyroid, anterior pituitary and entero-pancreatic tumours. Clinically, MEN 1 is defined following development of two out of these three tumours. There have been no published cases of the management of MEN 1 in pregnancy. We report the first case of a 31-year-old primigravida with a confirmed diagnosis of MEN 1 prior to conception. Due to the rare nature of MEN 1, there are no guidelines on how such women should be managed. The main issues were to assess and manage potential complications, such as hypercalcaemia, diabetes mellitus and the symptoms from a pituitary tumour as well the issues around a gastrinoma and monitor fetal well-being. A Caesarean section was performed at 35 weeks gestation for a growth-restricted fetus with raised umbilical artery Dopplers. The neonate was treated with intravenous calcium secondary to hypocalcaemia. The patient and neonate recovered well. We have demonstrated successful management of a woman with MEN 1 who completed her pregnancy with few complications and a healthy neonate. It is vital for such women to be managed in the context of a multidisciplinary team setting to optimise maternal and fetal outcomes.
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Affiliation(s)
- Megha Mistry
- Department of Obstetrics and Gynaecology, Barts Health, Whipps Cross University Hospital, London, UK
| | - Manish Gupta
- Department of Obstetrics and Gynaecology, Barts Health, Whipps Cross University Hospital, London, UK
| | - Mandeep Kaler
- Department of Obstetrics and Gynaecology, Barts Health, Whipps Cross University Hospital, London, UK
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Abstract
The term red face is reserved for lesions located exclusively or very predominantly on the face that result from changes in cutaneous blood flow triggered by multiple different conditions. Facial erythema may not only present clinically as a distinct entity, but can also be a sign of other diseases. Patients with a red face challenge clinicians to consider a broad differential diagnosis. Diagnosis is based on date and mode of appearance, characteristics of the erythema, functional signs, and associated systemic manifestations. In most cases, the cause is a benign disease such as rosacea, contact dermatitis, photodermatosis, and climacterium, and a thorough history and physical examination is enough to make a diagnosis; facial erythema may also present as a symptom of drug allergies, cardiac disease, carcinoid syndrome, pheochromocytoma, mastocytosis, and anaphylaxis, as well as some rare causes such as medullary carcinoma of the thyroid, pancreatic cell tumor, and renal carcinoma where further laboratory, radiologic, or histopathologic studies are required. In this review, the mechanisms of flushing, its clinical differential diagnosis, and management of various conditions that cause flushing are discussed.
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Affiliation(s)
- Güliz İkizoğlu
- Department of Dermatology, Mersin University, School of Medicine, Mersin, Turkey.
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27
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Comparative immunohistochemical analysis of pulmonary and thymic neuroendocrine carcinomas using PAX8 and TTF-1. Mod Pathol 2013; 26:1554-60. [PMID: 23787439 DOI: 10.1038/modpathol.2013.111] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Revised: 04/23/2013] [Accepted: 04/26/2013] [Indexed: 02/03/2023]
Abstract
PAX8 is expressed in thymic epithelial neoplasms and a subset of neuroendocrine carcinomas of gastrointestinal origin but not pulmonary neuroendocrine carcinomas. Thyroid transcription factor 1 (TTF-1) is known to be positive in pulmonary neuroendocrine carcinomas, but studies investigating its expression in thymic neuroendocrine carcinomas are lacking. To date, there are no comprehensive studies focusing on the comparative expression of PAX8 or TTF-1 in pulmonary and thymic neuroendocrine carcinoma. Twenty-five cases of low and intermediate grade neuroendocrine carcinomas of pulmonary and thymic origin, respectively, were selected for immunohistochemical studies using antibodies directed against PAX8 and TTF-1. The percentage of positive tumor cells as well as the intensity of staining were evaluated and scored. Twenty-one of the pulmonary neuroendocrine carcinomas were classified as low grade (typical carcinoid) and 4 as intermediate grade (atypical carcinoid) tumors; the thymic tumors consisted of 8 low grade and 17 intermediate grade neuroendocrine carcinomas. Only 2 (8%) of the pulmonary tumors showed nuclear expression of PAX8 while 19 (76%) expressed TTF-1. Of the thymic tumors, 8 (32%) were positive for PAX8 and 2 (8%) showed TTF-1 positivity. Primary neuroendocrine carcinomas of the thymus are rare neoplasms that display a more aggressive clinical course than pulmonary neuroendocrine carcinomas, highlighting the importance of the separation of these tumors. To date, there are no specific immunomarkers to distinguish between neuroendocrine carcinomas of pulmonary and thymic origin. The differential expression of PAX8 and TTF-1 may prove useful in this context as a PAX8+/TTF-1- immunophenotype appears to be more common in thymic neuroendocrine carcinomas, whereas the reverse (PAX8-/TTF-1+) is true for most pulmonary neuroendocrine carcinomas.
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Abstract
Pancreatic neuroendocrine neoplasms are uncommon but rising in incidence. There have been recent changes in the WHO nomenclature and a newly proposed American Joint Committee on Cancer TNM staging, which complement each other. These neoplasms are of great medical and radiological interest because of their diverse presenting features and imaging appearances. There is an increased role for both anatomic and functional imaging in the assessment of these neoplasms. A review of the nomenclature, staging, and imaging is presented in this paper.
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29
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Krausch M, Kroepil F, Lehwald N, Lachenmayer A, Schott M, Anlauf M, Cupisti K, Knoefel WT, Raffel A. Notch 1 tumor expression is lacking in highly proliferative pancreatic neuroendocrine tumors. Endocrine 2013; 44:182-6. [PMID: 23225326 DOI: 10.1007/s12020-012-9850-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2012] [Accepted: 11/28/2012] [Indexed: 12/22/2022]
Abstract
To date, very little is known about the development of benign organic hyperinsulinism and its metastatic potential. Typical morphologic, biochemical, or genetic differentiations for benign or malign tumor course of insulinomas do not exist. As signaling pathways may affect pancreatic cancer development and the maintenance of the neoplastic phenotype, the purpose of this study was to examine the role of Notch1 expression in organic hyperinsulinism. We examined 32 well-differentiated pancreatic endocrine tumors (wd PET); 11 wd PET of unknown behavior (wd PET ub); and 15 wd pancreatic endocrine cancer (wd PEC) for Notch1 expression by immunohistochemistry. Demographic data, clinical data, and follow-up of all patients were analyzed. Islets of the Langerhans show the strongest Notch1 staining in nearly 90 %. Positive Notch1 staining was absent in the acinar of the pancreas. In patients with a wd PET more than every second tumor (56.3 %/n = 18/32) demonstrated a negative Notch1 staining. The other 14 patients were positive for Notch1. Tumors of unknown behavior (wd PET ub) and malignant insulinomas had no signs of Notch expression in contrast to benign insulinomas. Considering the clinical and histomorphological tumor behavior, no correlation between Notch1 expression and clinical data was found. The missing Notch expression in the malignant tumor course might be used as a potential predictive marker, but further studies are needed to investigate the underlying molecular mechanism.
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Affiliation(s)
- Markus Krausch
- Department of General, Visceral and Pediatric Surgery, Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, 40225, Düsseldorf, Germany
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Vianna PM, Ferreira CR, de Campos FPF. Somatostatinoma syndrome: a challenging differential diagnosis among pancreatic tumors. AUTOPSY AND CASE REPORTS 2013; 3:29-37. [PMID: 31528595 PMCID: PMC6671881 DOI: 10.4322/acr.2013.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Accepted: 03/05/2013] [Indexed: 12/20/2022] Open
Abstract
Among the neuroendocrine neoplasia, the pancreatic somatostatin-producing tumors are very rare. Usually functional, these tumors produce the somatostatinoma syndrome, which encompasses diabetes mellitus, diarrhea/steatorrhoea, and cholelithiasis. Other symptoms may include dyspepsia, weight loss, anemia, and hypochlorhydria. All theses symptoms are explained by the inhibitory actions of the somatostatin released by tumoral cells originated from pancreatic delta cells or endocrine cells of the digestive tract. The diagnosis is easy to overlook since these symptoms are commonly observed in other more common syndromes. Besides the clinical features, diagnosis is based on serum determination of somatostatin, and imaging exams, such as ultrasound, computer tomography and positron emission tomography. Pathologic examination is characterized by the positivity of immunohistochemical reaction for synaptophysin, chromogranin, and somatostatin. These tumors can be classified according to tumor size, mitotic index, neural or vascular invasion, and distant metastases. The authors describe the case of a 61-year-old female patient who sought medical care because of a 6-month history of watery diarrhea, weight loss, and depression. She was diagnosed with diabetes mellitus 3 years ago. Imaging examination revealed a tumoral mass of 4 cm in its longest axis in the topography of the head of the pancreas and calculous cholecistopathy. The patient’s clinical status was unfavorable for a surgical approach. She died after 20 days of hospitalization. The definitive diagnosis was achieved with the autopsy findings, which disclosed a pancreatic somatostatinoma.
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Affiliation(s)
- Paula Martinez Vianna
- Department of Pathology - Faculdade de Medicina - Universidade de São Paulo, São Paulo/SP - Brazil
| | - Cristiane Rúbia Ferreira
- Anatomic Pathology Service - Hospital Universitário - Universidade de São Paulo, São Paulo/SP - Brazil
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Chou WC, Hung YS, Hsu JT, Chen JS, Lu CH, Hwang TL, Rau KM, Yeh KY, Chen TC, Sun CF. Chromogranin A is a reliable biomarker for gastroenteropancreatic neuroendocrine tumors in an Asian population of patients. Neuroendocrinology 2012; 95:344-50. [PMID: 22343505 DOI: 10.1159/000333853] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2011] [Accepted: 09/26/2011] [Indexed: 01/28/2023]
Abstract
PURPOSE To evaluate the significance of plasma chromogranin A (CgA) levels in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NET) in terms of disease status and treatment responses. MATERIALS AND METHODS Forty-four GEP-NET patients comprising 15 disease-free patients and 29 patients with active disease, as well as 26 healthy participants were enrolled in this study between April 2010 and April 2011. Clinicopathological factors were collected and serial plasma CgA levels were measured. RESULTS Plasma CgA levels were significantly higher in GEP-NET patients with active disease than in disease-free patients (p = 0.011) or healthy participants (p = 0.001). No difference in CgA levels was observed in terms of primary tumor location, tumor grade, and functional status in patients with active disease. CgA values at 94 U/l distinguished healthy individuals or disease-free patients from patients with active disease. Sensitivity and specificity rates were 86 and 88%, respectively. CgA levels at 110 U/l differentiated patients without recurrence from those with recurrence, with a sensitivity rate of 100% and a specificity rate of 80%. Patients (5/5, 100%) with stable disease and who showed partial response after treatment had a more than 20% decrease in CgA levels compared with the baseline values. Patients (6/6, 100%) with progressive disease showed a less than 20% decrease or increase in CgA levels. CONCLUSION The plasma CgA level is a reliable biomarker for GEP-NET. We conclude that changes in CgA levels are associated with disease status and treatment responses.
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Affiliation(s)
- Wen-Chi Chou
- Division of Hematology-Oncology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, No. 5 Fushing St., Kweishan Shiang, Taoyuan, Taiwan, ROC
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Significance of plasma chromogranin A determination in neuroendocrine tumour (NET) diagnosis. Folia Histochem Cytobiol 2011; 48:603-10. [DOI: 10.2478/v10042-010-0088-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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Lawrence B, Gustafsson BI, Kidd M, Pavel M, Svejda B, Modlin IM. The clinical relevance of chromogranin A as a biomarker for gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am 2011; 40:111-34, viii. [PMID: 21349414 DOI: 10.1016/j.ecl.2010.12.001] [Citation(s) in RCA: 111] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Chromogranin A, although it exhibits limitations, is currently the most useful general tumor biomarker available for use in the diagnosis and management of gastroenteropancreatic neuroendocrine tumors (NETs). The value of the chromogranin A lies in its universal cosecretion by the majority of neuroendocrine cells that persists after malignant transformation. Clinicians aware of the physiologic role of chromogranin A and its secretion in a variety of non-NET-related pathologic conditions can use this protein as a moderately effective tumor biomarker in the management of GEP-NETs.
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Affiliation(s)
- Ben Lawrence
- Gastrointestinal Pathobiology Research Group, Department of Surgery, Yale University School of Medicine, 310 Cedar Street, PO Box 208602, New Haven, CT 06520-8062, USA
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Aniq H, Campbell R, Vinjamuri S. Nuclear Medicine Techniques for Pain Management. Pain Manag 2011. [DOI: 10.1016/b978-1-4377-0721-2.00010-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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35
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Advances in the therapy of gastroenteropancreatic-neuroendocrine tumours (GEP-NETs). Clin Transl Oncol 2010; 12:481-92. [PMID: 20615825 DOI: 10.1007/s12094-010-0541-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Neuroendocrine tumours (NET) of the digestive tract comprise a broad range of malignancies. The therapeutic approach to these tumours has not evolved as it did in other tumour types in the last two decades. The deeper knowledge of the underlying molecular biology behind the growth of neuroendocrine cells has brought much information to light. We now know that somatostatin analogues may not only be considered as symptomatic treatment but also as antitumour agents. Sunitinib, a tyrosine kinase (TK) inhibitor with antiangiogenic and antitumoural properties, has been shown to induce significant improvement in progression-free survival in a randomised trial conducted in well-differentiated pancreatic islet-cell NETs. The relevance of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway seems to be crucial in gastroenteropancreatic (GEP)-NETs. In fact, mTOR inhibitors have shown activity in uncontrolled trials, and large, randomised trial results will be available shortly. In this article, we summarise the most recent available data on medical therapy for GEPNETs.
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Abstract
OBJECTIVES Patients with rare gastrointestinal (GI) malignancies can exhibit unique objective and subjective manifestations. This article is a primer for the fundamental understanding of some of these diseases, namely gastrointestinal stromal tumors (GIST) and gastroenteropancreatic neuroendocrine tumors (NET) and therapeutic strategies. DATA SOURCES Epidemiologic data, published research reports, national guidelines for oncology practice, and personal experience. CONCLUSION Despite the rarity of GIST, gastroenteropancreatic neuroendocrine tumors, gastric lymphoma, and adenocarcinoma of the small bowel, oncology nurses must be prepared to effectively assess, plan, and implement care strategies for these patients. IMPLICATIONS FOR NURSING PRACTICE Caring for patients with uncommon GI malignancies is challenging for oncology nurses whose experience with these tumors is limited. Fundamental knowledge and awareness of resources can help to ensure optimal patient care. Case vignettes illustrate patient presentation and formulation of treatment recommendations.
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Affiliation(s)
- Carolyn Grande
- Abramson Cancer Center, Hospital of the University of Pennsylvania, Division of Medicine, Department of Hematology-Oncology, Philadelphia, PA, USA.
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37
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Ardill JES. Circulating markers for endocrine tumours of the gastroenteropancreatic tract. Ann Clin Biochem 2009; 45:539-59. [PMID: 18941127 DOI: 10.1258/acb.2008.008039] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The diffuse endocrine system (DES) includes a wide range of secretory cells that may be the source of tumours. Gastroenteropancreatic endocrine (GEP) tumours arising within the DES secrete a variety of peptides and amines that are found in the circulation and are responsible for the syndromes associated with these tumours. In this review, the most common tumours of the GEP tract are outlined and the circulating products of these tumours identified. Where differential diagnosis is difficult these points are addressed. The peptides most commonly secreted by GEP neuroendocrine tumours are identified and described and their biological activities are discussed. Current methods available for measurement of these peptides are described. Attention is drawn towards molecular specificity where appropriate, as many pancreatic and gut peptides fall within families which show considerable homology, such as the tachykinin family or the glucagon family. Other peptides such as gastrin circulate in multiple molecular forms. This homology and diversity may cause difficulty in the interpretation of peptide measurements in the clinical situation if assays are not specific.
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Affiliation(s)
- Joy E S Ardill
- Regional Regulatory Peptide Laboratory, Department of Clinical Biochemistry, Royal Victoria Hospital and Queen's University, Belfast BT12 6BJ, UK.
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38
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Campbell-Thompson M, Dixon LR, Wasserfall C, Monroe M, McGuigan JM, Schatz D, Crawford JM, Atkinson MA. Pancreatic adenocarcinoma patients with localised chronic severe pancreatitis show an increased number of single beta cells, without alterations in fractional insulin area. Diabetologia 2009; 52:262-70. [PMID: 19002428 PMCID: PMC7321839 DOI: 10.1007/s00125-008-1200-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2008] [Accepted: 10/02/2008] [Indexed: 01/09/2023]
Abstract
AIMS/HYPOTHESIS Recent histological analysis of pancreases obtained from patients with long-standing type 1 diabetes identified chronic islet inflammation and limited evidence suggestive of beta cell replication. Studies in rodent models also suggest that beta cell replication can be induced by certain inflammatory cytokines and by gastrin. We therefore tested the hypothesis that beta cell replication is observed in non-autoimmune human pancreatic disorders in which localised inflammation or elevated gastrin levels are present. METHODS Resected operative pancreatic specimens were obtained from patients diagnosed with primary adenocarcinoma (with or without chronic severe pancreatitis) or gastrinoma. Additional pancreatic tissue was obtained from autopsy control patients. Immunohistochemistry was used to assess fractional insulin area, beta cell number and replication rate and differentiation factors relevant to beta cell development. RESULTS Fractional insulin area was similar among groups. Patients with pancreatic adenocarcinoma and localised chronic severe pancreatitis displayed significant increases in the number of single beta cells, as well as increased beta cell replication rate and levels of neurogenic differentiation 1 in islets. Patients with gastrinoma demonstrated significant increases in the number of single beta cells, but the beta cell replication rate and islet differentiation factor levels were similar to those in the control group. CONCLUSIONS/INTERPRETATION These findings indicate that chronic severe pancreatic inflammation can be associated with significant effects on beta cell number or replication rate, depending on the distribution of the cells. This information may prove useful for attempts seeking to design therapies aimed at inducing beta cell replication as a means of reversing diabetes.
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Affiliation(s)
- M Campbell-Thompson
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, 1600 SW Archer Road, PO Box 100275, Gainesville, FL 32610, USA.
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Halfdanarson TR, Rubin J, Farnell MB, Grant CS, Petersen GM. Pancreatic endocrine neoplasms: epidemiology and prognosis of pancreatic endocrine tumors. Endocr Relat Cancer 2008; 15:409-27. [PMID: 18508996 PMCID: PMC2693313 DOI: 10.1677/erc-07-0221] [Citation(s) in RCA: 268] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Pancreatic endocrine tumors (PETs) are uncommon tumors with an annual incidence <1 per 100 000 person-years in the general population. The PETs that produce hormones resulting in symptoms are designated as functional. The majority of PETs are non-functional. Of the functional tumors, insulinomas are the most common, followed by gastrinomas. The clinical course of patients with PETs is variable and depends on the extent of the disease and the treatment rendered. Patients with completely resected tumors generally have a good prognosis, and aggressive surgical therapy in patients with advanced disease may also prolong survival. The epidemiology, prognosis, and established and novel prognostic markers of PETs are reviewed.
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Affiliation(s)
- Thorvardur R Halfdanarson
- Division of Oncology, Department of Medical Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
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40
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Khanna G, O'Dorisio SM, Menda Y, Kirby P, Kao S, Sato Y. Gastroenteropancreatic neuroendocrine tumors in children and young adults. Pediatr Radiol 2008; 38:251-9, quiz 358-9. [PMID: 17906857 PMCID: PMC2292492 DOI: 10.1007/s00247-007-0564-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2007] [Revised: 05/31/2007] [Accepted: 06/14/2007] [Indexed: 12/01/2022]
Abstract
We review the imaging findings of pediatric gastroenteropancreatic neuroendocrine tumors (GEP-NETs) using contemporary anatomic and molecular imaging techniques. A low index of suspicion can result in significant delays in diagnosis of pediatric GEP-NETs. A multimodality imaging approach, using both anatomic and functional imaging, is essential in the diagnosis, staging, and surveillance of these potentially malignant tumors.
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Affiliation(s)
- Geetika Khanna
- Department of Radiology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, USA.
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41
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Diagnostic value of CDX-2 and TTF-1 expressions in separating metastatic neuroendocrine neoplasms of unknown origin. Appl Immunohistochem Mol Morphol 2008; 15:407-14. [PMID: 18091383 DOI: 10.1097/01.pai.0000210416.53493.0f] [Citation(s) in RCA: 101] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Histomorphologic features and routine endocrine immunohistochemical (IHC) markers do not differentiate neuroendocrine tumors (NETs) in relation to their location, making it difficult to establish the site of origin of a metastatic neoplasm. Site-specific markers would be useful, particularly when examining small biopsies. CDX-2 and thyroid transcription factor-1 (TTF-1) are transcription factors that have been recently proposed as IHC markers of intestinal and pulmonary adenocarcinomas, respectively. However, their expression in NETs has not been widely studied. The objective of this study is to evaluate the expression of TTF-1 and CDX-2 in NETs and their potential usefulness in distinguishing gastrointestinal and pulmonary NETs from other sites. We performed an IHC study on formalin-fixed, paraffin-embedded sections from 155 primary NETs, including 60 pulmonary, 60 gastrointestinal, 30 pancreatic, and 5 NETs from other sites. In addition, we evaluated 13 metastatic NETs, including 11 cases of gastrointestinal and 2 of pulmonary origin. In this study, CDX-2 was expressed in 28/60 (47%) of gastrointestinal NETs with the following results: 11/11 (100%) appendiceal, 12/14 (86%) small intestinal, 3/4 (75%) colonic, 2/11 (18%) rectal, and 0/20 (0%) gastric. TTF-1 was expressed in pulmonary carcinoid tumors in 13/30 (43%) and in 27/30 (90%) pulmonary small cell carcinomas. NETs of other origins (pancreas, skin, ovary, and thymus) were negative for both TTF-1 and CDX-2. Metastatic neuroendocrine neoplasms of intestinal origin were positive for CDX-2 and negative for TTF-1. In conclusion, CDX-2 expression is highly specific in identifying NETs of intestinal origin and TTF-1 expression is helpful in identifying NETs of pulmonary origin, which can be quite useful in the diagnosis of metastatic NETs of unknown origin.
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42
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Gur C, Lalazar G, Salmon A, Dubiner V, Gross DJ. Metastatic pancreatic neuroendocrine tumor presenting as a pituitary space occupying lesion: a case report. Pituitary 2008; 11:293-7. [PMID: 17638085 DOI: 10.1007/s11102-007-0053-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Neuroendocrine tumor metastases to the pituitary gland are very rare. There are few case reports of carcinoid tumor metastases to the pituitary, but no cases of pancreatic neuroendocrine pituitary metastases have been reported. In this report we present a 55-year-old female with a sellar mass, ophthalmoplegia and headaches initially thought to represent an invasive null cell pituitary adenoma. However a histological (trans-sphenoidal and liver biopsies) and systemic investigation proved it to be a metastasis of an undiagnosed pancreatic neuroendocrine tumor. Our patient was unique in respect to the location of the metastasis and the uncharacteristically high proliferative index of her tumor. She received conventional therapy consisting of Sandostatin, chemotherapy and radiotherapy as well as labeled somatostatin following an avid uptake on octreotide scanning. Despite a radiological improvement the patient suffered progressive clinical deterioration and died.
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Affiliation(s)
- Chamutal Gur
- Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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43
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Carcinoid syndrome and carcinoid crisis secondary to a metastatic carcinoid tumour of the lung: a therapeutic challenge. Eur J Gastroenterol Hepatol 2007; 19:1154-9. [PMID: 17998844 DOI: 10.1097/meg.0b013e3282294d88] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
We describe a 53-year-old male patient, with a known history of metastatic carcinoid tumour of the lung, who developed a variety of symptoms of the carcinoid syndrome and subsequently a carcinoid crisis. Although bronchial carcinoid tumours are very rarely associated with symptoms of the carcinoid syndrome, a subset may develop a severe hypersecretory syndrome and exhibit an aggressive behaviour. In cases with excessive tumour load and difficult-to-control hypersecretory syndrome, management by a specialized multidisciplinary team using evidence-based regimens is mandatory to deal with the life-threatening carcinoid crisis, to improve patients' outcome and quality of life.
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Moayedoddin B, Booya F, Wermers RA, Lloyd RV, Rubin J, Thompson GB, Fatourechi V. Spectrum of malignant somatostatin-producing neuroendocrine tumors. Endocr Pract 2006; 12:394-400. [PMID: 16901794 DOI: 10.4158/ep.12.4.394] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE To evaluate the clinical manifestations and outcome of patients with somatostatinomas--rare neuroendocrine tumors of pancreaticoduodenal origin. METHODS We searched the medical archives and tumor registry of our institution for somatostatinomas or somatostatin-staining tumors for the 12-year period from January 1990 to February 2002. In addition, we reviewed laboratory databases for patients who had an elevated serum somatostatin level. Patients with a neuroendocrine tumor and an elevated serum somatostatin level or somatostatin-positive tumor immunostaining were included in this study. RESULTS Eleven patients qualified (9 men and 2 women; median age at diagnosis, 45 years; age range, 22 to 73). The diagnosis of a somatostatinoma was made by immunostaining of the tumor in 9 patients and by finding elevated serum somatostatin levels in 2. Five primary tumors were of duodenal and 6 of pancreatic origin. Psammoma body formation and association with neurofibromatosis were seen only in the duodenal tumors. The known primary tumor sizes varied from 2 to 6 cm. Liver metastatic lesions were present in 6 patients, abdominal lymph node involvement was found in 10 patients, and lung, spleen, and ovarian metastatic involvement was noted in 1 patient each. Diabetes was present in 4 patients (36%) and cholelithiasis in 7 (64%). The presence of a mass led to the diagnosis in most patients with primary duodenal tumors, whereas patients with pancreatic tumors were more likely to have endocrine manifestations. A Whipple procedure was performed in 6 patients, distal pancreatectomy in 3, hepatic artery embolization or ligation in 3, and partial hepatectomy in 1. Cancer-related death occurred in 4 patients, 1 to 8 years after diagnosis (median, 4.5 years). At last follow-up, 2 patients were alive without evidence of disease (8 and 10 years after diagnosis), and 3 were alive with liver metastatic lesions. The status of 2 patients was unclear. CONCLUSION Somatostatinomas occurred with approximately equal frequency in the duodenum and the pancreas. The duodenal tumors were more likely to be pure somatostatinomas and have psammoma bodies. Pancreatic tumors were more likely to be multihormonal. Cholelithiasis and diabetes were seen in 64% and 36%, respectively, of the patients. Mass effect of the tumor was the usual manifestation leading to diagnosis. These tumors are slow growing, and long-term survival is possible.
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Mendoza-Guil F, Hernández-Jurado I, Burkhardt P, Linares J, Naranjo R. [Necrolytic migratory erythema associated with glucagonoma]. ACTAS DERMO-SIFILIOGRAFICAS 2006; 96:175-8. [PMID: 16476361 DOI: 10.1016/s0001-7310(05)73062-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Glucagonoma is a rare pancreatic tumor that is usually associated with a syndrome that includes diabetes, anemia, weight loss and skin lesions in the form of necrolytic migratory erythema. We present the case of a patient with malignant glucagonoma treated with surgery and octreotide, which manifested with skin lesions. The discussion will review the physiopathology, other causes of necrolytic erythema, diagnosis and differential diagnosis and treatment.
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Affiliation(s)
- Francisco Mendoza-Guil
- Servicio de Dermatología, Hospital Clínico San Cecilio, Pintor Zuloaga 14, 6.o H, 18005 Granada, Spain.
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Destri GL, Reggio E, Veroux M, Lanzafame S, Puleo S, Minutolo V. A Rare Cystic Non-Functioning Neuroendocrine Pancreatic Tumor with An Unusual Presentation. TUMORI JOURNAL 2006. [DOI: 10.1177/030089160609200316] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
This report describes a patient with a cystic non-functioning neuroendocrine glucagon cell pancreatic tumor presenting with demyelination of the optical nerve that had initially provoked marked monolateral reduced vision and had led to a suspected diagnosis of multiple sclerosis. Cystic degeneration is uncommon in endocrine pancreatic tumors due to their abundant vascular supply. Very few cases of cystic neuroendocrine non-functioning pancreatic tumors have been reported in the international literature. The presence of atypical neurological symptoms, such as sudden visual impairment, should be taken into account in the differential diagnosis for such tumors. The prognosis is poor, because most of these tumors are malignant and diagnosed at an advanced stage. The three-year disease-free survival of our patient, however, encourages the use of aggressive surgical treatment.
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Affiliation(s)
- Giovanni Li Destri
- Department of Surgical Sciences, Transplantation and Advanced Technologies, University Hospital, Catania, Italy
| | - Ester Reggio
- Department of Neurological Sciences, University Hospital, Catania, Italy
| | - Massimiliano Veroux
- Department of Surgical Sciences, Transplantation and Advanced Technologies, University Hospital, Catania, Italy
| | - Salvatore Lanzafame
- Department G.S. Ingrassia, Pathological Anatomy, University Hospital, Catania, Italy
| | - Stefano Puleo
- Department of Surgical Sciences, Transplantation and Advanced Technologies, University Hospital, Catania, Italy
| | - Vincenzo Minutolo
- Department of Surgical Sciences, Transplantation and Advanced Technologies, University Hospital, Catania, Italy
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47
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Kidd M, Modlin IM, Mane SM, Camp RL, Eick G, Latich I. The role of genetic markers--NAP1L1, MAGE-D2, and MTA1--in defining small-intestinal carcinoid neoplasia. Ann Surg Oncol 2006; 13:253-62. [PMID: 16424981 DOI: 10.1245/aso.2006.12.011] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2004] [Accepted: 08/22/2005] [Indexed: 11/18/2022]
Abstract
BACKGROUND Standard clinical and immunohistochemical methods cannot reliably determine whether a small intestinal carcinoid (SIC) is indolent or aggressive. We hypothesized that carcinoid malignancy could be defined by using quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) and immunohistochemical approaches that evaluate potential marker genes. METHODS Candidate marker gene expression (nucleosome assembly protein 1-like 1 [NAP1L1], melanoma antigen D2 [MAGE-D2], and metastasis-associated protein 1 [MTA1]) identified by Affymetrix transcriptional profiling was examined by QRT-PCR in SIC, liver, and lymph node (LN) metastases, colorectal carcinomas, and healthy tissues. Immunohistochemical expression levels of MTA1 were analyzed quantitatively by a novel automated quantitative analysis in a tissue microarray of 102 gastrointestinal carcinoids and in a breast/prostate carcinoma array. RESULTS Affymetrix transcriptional profiling identified three potentially useful malignancy-marker genes (out of 1709 significantly altered genes). By QRT-PCR, NAP1L1 was significantly (P < .03) overexpressed in SIC compared with colorectal carcinomas and healthy tissue. Increased levels (P < .05) were identified in both liver and LN metastases. Levels in colorectal carcinomas were the same as in healthy mucosa. MAGE-D2 and MTA1 were increased (P < .05) in primary tumors and metastases and overexpressed in carcinomas. Automated quantitative analysis demonstrated the highest levels of MTA1 immunostaining in malignant primary SICs and in metastases to the liver and LN. These were significantly increased (P < .02) compared with nonmetastatic primary tumors. MTA1 was overexpressed in breast and prostate carcinomas (P < .05). CONCLUSIONS SICs overexpress the neoplasia-related genes NAP1L1 (mitotic regulation), MAGE-D2 (adhesion), and MTA1 (estrogen antagonism). The ability to determine the malignant potential of these tumors and their propensity to metastasize provides a biological rationale for the management of carcinoids and may have prognostic utility.
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Affiliation(s)
- Mark Kidd
- Department of Surgery, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208062, New Haven, Connecticut 06520-8062, USA
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Davies AHG, Larsson G, Ardill J, Friend E, Jones L, Falconi M, Bettini R, Koller M, Sezer O, Fleissner C, Taal B, Blazeby JM, Ramage JK. Development of a disease-specific Quality of Life questionnaire module for patients with gastrointestinal neuroendocrine tumours. Eur J Cancer 2006; 42:477-84. [PMID: 16412628 DOI: 10.1016/j.ejca.2005.10.025] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2005] [Accepted: 10/31/2005] [Indexed: 12/19/2022]
Abstract
Quality of life (QoL) measurements are increasingly being used as an end point in cancer clinical trials. Standard generic QoL questionnaires may not assess symptoms produced by neuroendocrine tumours. Here we report the development of a disease-specific quality of life score questionnaire for patients with neuroendocrine tumours of the gut to supplement the EORTC core cancer questionnaire, the QLQ-C30. Phases 1-3 of the EORTC quality of life group guidelines for module development were used to design the new questionnaire. Forty-one relevant issues (questions) were generated after an extensive literature search. Following interviews of 15 health care workers and 35 patients, a 35 question provisional questionnaire was constructed. This was translated into seven European languages and pre-tested in 180 patients resulting in a 21-item module that will be validated in an international clinical trial. The EORTC QLQ-NET21 provides a site-specific module to supplement the QLQ-C30 for patients with neuroendocrine tumours.
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Affiliation(s)
- A H G Davies
- Institute of Liver Studies, Carcinoid Clinic, King's College Hospital, Denmark Hill, London SE5 9RS, UK.
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Kianmanesh R, O'toole D, Sauvanet A, Ruszniewski P, Belghiti J. [Surgical treatment of gastric, enteric, and pancreatic endocrine tumors Part 1. Treatment of primary endocrine tumors]. ACTA ACUST UNITED AC 2005; 142:132-49. [PMID: 16142076 DOI: 10.1016/s0021-7697(05)80881-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Endocrine tumors (ET) of the digestive tract (formerly called neuroendocrine tumors) are rare. They are classified into two principal types: gastrointestinal ET's (formerly called carcinoid tumors) which are the most common, and pancreaticoduodenal ET's. Functioning ET's secrete polypeptide hormones which cause characteristic hormonal syndromes. The management of ET is multidisciplinary. Poorly-differentiated ET's have a poor prognosis and are treated by chemotherapy. Surgical excision is the only curative treatment of well-differentiated ET's. The surgical goals are to: 1. prolong survival by resecting the primary tumor and any nodal or hepatic metastases, 2. control the symptoms related to hormonal secretion, 3. prevent or treat local complications. The most common sites of gastrointestinal ET's ( carcinoids) are the appendix and the rectum; these are often small (<1 cm), benign, and discovered fortuitously at the time of appendectomy or colonoscopic removal. Ileal ET's, even if small, are malignant, frequently multiple, and complicated in 30-50% of cases by bowel obstruction, mesenteric invasion, or bleeding. The carcinoid syndrome (consisting of abdominal pain, flushing, diarrhea, hypertension, bronchospasm, and right sided cardiac vegetations) is caused by the hypersecretion of serotonin into the systemic circulation; it occurs in 10% of cases and is usually associated with hepatic metastases. More than half of the cases of pancreatic ET are non-functional. They are usually malignant and of advanced stage at diagnosis presenting as a palpable or obstructing mass or as liver metastases. Insulinoma and gastrinoma (cause of the Zollinger-Ellison syndrome) are the most common functional ET's. 80% are sporadic; in these cases, tumor size, location, and malignant potential determine the type of resection which may vary from a simple enucleation to a formal pancreatectomy. In 10-20% of cases, pancreaticoduodenal ET presents in the setting of multiple endocrine neoplasia (NEM type I), an autosomal-dominant genetic disease with multifocal endocrine involvement of the pituitary, parathyroid, pancreas, and adrenal glands. For insulinoma with NEM-I, enucleation of lesions in the pancreatic head plus a caudal pancreatectomy is the most appropriate procedure. For gastrinoma with NEM-I, the benefit of surgical resection for tumors less than 2-3 cm in size is not clear. The lesions are frequently small, multiple, and widespread and recurrence is frequent after excision. The long-term prognosis is nevertheless fairly good. But the eventual development of liver metastases which are the most common cause of mortality still argues for an aggressive surgical approach in the early stages of the disease.
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Affiliation(s)
- R Kianmanesh
- Fédération d'Hépato-Gastroentérologie, Hôpital Beaujon, Clichy.
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Tomassetti P, Campana D, Piscitelli L, Mazzotta E, Brocchi E, Pezzilli R, Corinaldesi R. Treatment of Zollinger-Ellison Syndrome. World J Gastroenterol 2005; 11:5423-32. [PMID: 16222731 PMCID: PMC4320348 DOI: 10.3748/wjg.v11.i35.5423] [Citation(s) in RCA: 15] [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] [Indexed: 02/06/2023] Open
Abstract
In this article, we have reviewed the main therapeutic measures for the treatment of Zollinger-Ellison syndrome (ZES). Review of the literature was based on computer searches (Pub-Med, Index Medicus) and personal experiences. We have evaluated all the measures now available for treating patients with sporadic gastrinomas or gastrinomas associated with Multiple Endocrine Neoplasia Type 1, (MEN 1) including medical therapy such as antisecretory drugs and somatostatin analogs (SST), chemotherapy and chemoembolization, and surgical procedures. In ZES patients, the best therapeutic procedure is surgery which, if radical, can be curative. Medical treatment can be the best palliative therapy and should be used, when possible, in association with surgery, in a multimodal therapeutic approach.
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Affiliation(s)
- Paola Tomassetti
- Department of Internal Medicine and Gastroenterology, University of Bologna, Policlinico S.Orsola-Malpighi, Via Massarenti, 9, 40138, Bologna, Italy.
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