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1
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Shinozaki S, Osawa H, Miura Y, Nomoto H, Sakamoto H, Hayashi Y, Yano T, Despott EJ, Yamamoto H. Endoscopic findings and outcomes of gastric mucosal changes relating to potassium-competitive acid blocker and proton pump inhibitor therapy. DEN OPEN 2025; 5:e400. [PMID: 38919514 PMCID: PMC11196240 DOI: 10.1002/deo2.400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/27/2024] [Accepted: 06/03/2024] [Indexed: 06/27/2024]
Abstract
Gastric mucosal changes associated with long-term potassium-competitive acid blocker and proton pump inhibitor (PPI) therapy may raise concern. In contrast to that for PPIs, the evidence concerning the safety of long-term potassium-competitive acid blocker use is scant. Vonoprazan (VPZ) is a representative potassium-competitive acid blocker released in Japan in 2015. In order to shed some comparative light regarding the outcomes of gastric mucosal lesions associated with a long-term acid blockade, we have reviewed six representative gastric mucosal lesions: fundic gland polyps, gastric hyperplastic polyps, multiple white and flat elevated lesions, cobblestone-like gastric mucosal changes, gastric black spots, and stardust gastric mucosal changes. For these mucosal lesions, we have evaluated the association with the type of acid blockade, patient gender, Helicobacter pylori infection status, the degree of gastric atrophy, and serum gastrin levels. There is no concrete evidence to support a significant relationship between VPZ/PPI use and the development of neuroendocrine tumors. Current data also shows that the risk of gastric mucosal changes is similar for long-term VPZ and PPI use. Serum hypergastrinemia is not correlated with the development of some gastric mucosal lesions. Therefore, serum gastrin level is unhelpful for risk estimation and for decision-making relating to the cessation of these drugs in routine clinical practice. Given the confounding potential neoplastic risk relating to H. pylori infection, this should be eradicated before VPZ/PPI therapy is commenced. The evidence to date does not support the cessation of clinically appropriate VPZ/PPI therapy solely because of the presence of these associated gastric mucosal lesions.
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Affiliation(s)
- Satoshi Shinozaki
- Shinozaki Medical ClinicTochigiJapan
- Department of MedicineDivision of GastroenterologyJichi Medical UniversityTochigiJapan
| | - Hiroyuki Osawa
- Department of MedicineDivision of GastroenterologyJichi Medical UniversityTochigiJapan
| | - Yoshimasa Miura
- Department of MedicineDivision of GastroenterologyJichi Medical UniversityTochigiJapan
- Department of MedicineDivision of Gastroenterology and HepatologyNihon University School of MedicineTokyoJapan
| | - Hiroaki Nomoto
- Department of MedicineDivision of GastroenterologyJichi Medical UniversityTochigiJapan
| | - Hirotsugu Sakamoto
- Department of MedicineDivision of GastroenterologyJichi Medical UniversityTochigiJapan
| | - Yoshikazu Hayashi
- Department of MedicineDivision of GastroenterologyJichi Medical UniversityTochigiJapan
| | - Tomonori Yano
- Department of MedicineDivision of GastroenterologyJichi Medical UniversityTochigiJapan
| | - Edward J. Despott
- Royal Free Unit for EndoscopyThe Royal Free Hospital and UCL Institute for Liver and Digestive HealthLondonUK
| | - Hironori Yamamoto
- Department of MedicineDivision of GastroenterologyJichi Medical UniversityTochigiJapan
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2
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Acher AW, Hallet J. Advances in Management of Nonfunctional Pancreas Neuroendocrine Tumors. Surg Clin North Am 2024; 104:1095-1111. [PMID: 39237166 DOI: 10.1016/j.suc.2024.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/07/2024]
Abstract
This article presents updates in the surgical management of non-functional sporadic pancreas neuroendocrine tumors NET, including considerations for assessment of biologic behavior to support decision-making, indications for surgery, and surgical approaches tailored to the unique nature of neuroendocrine tumors.
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Affiliation(s)
- Alexandra W Acher
- Department of Surgery, University of Toronto, 2075 Bayview Avenue, Toronto, ON, Canada, M4N 3M5
| | - Julie Hallet
- Department of Surgery, University of Toronto, 2075 Bayview Avenue, Toronto, ON, Canada, M4N 3M5; Susan Leslie Clinic for Neuroendocrine Tumors, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
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3
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Kővári B, Carneiro F, Lauwers GY. Epithelial tumours of the stomach. MORSON AND DAWSON'S GASTROINTESTINAL PATHOLOGY 2024:227-286. [DOI: 10.1002/9781119423195.ch13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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4
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Lam SK, Lau GKK. Proton pump inhibitors are not associated with fundic gland polyps - a systematic review that takes into consideration all known confounders. Eur J Gastroenterol Hepatol 2024; 36:831-844. [PMID: 38829941 PMCID: PMC11146189 DOI: 10.1097/meg.0000000000002788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Accepted: 04/21/2024] [Indexed: 06/05/2024]
Abstract
Sporadic fundic gland polyps (FGPs) progress, albeit rarely, to dysplasia and cancer. Two meta-analyses, including 8 and 11 studies, concluded that proton pump inhibitors (PPIs) were associated with FGPs. Intervention is considered unnecessary when FGPs have a background of PPIs use. Both meta-analyses, however, disregarded known confounders: age, sex, endoscopy indications, study design (prospective or retrospective), duration of PPI use, and H. pylori infection. Confounders are known to invalidate meta-analyses. We followed PRIXMA guidelines and searched the literature for studies on FGPs in PPI-users and PPI-nonusers. In the 22 studies searched, we compared FGPs in PPI-users (n = 6534) and PPI-nonusers (n = 41 115). Heterogeneity was significant (Cochran Q = 277.8, P < 0.0001; I2 = 92.8%), annulling meta-analysis performed by blanket tallying. To offset the above confounders, we matched PPI-users and PPI-nonusers by (a) age and sex (n = 4300 and 29 307, respectively) and (b) their propensity scores derived from the confounders (n = 2950 and 4729, respectively). After both matching, FGPs were not significantly different between PPI-users and PPI-nonusers [odds ratio (OR) = 1.1, P = 0.3078; OR = 0.9, P = 0.3258, respectively]. Furthermore, FGP frequency did not correlate with increasing duration of PPI use (Pearson and Spearman correlation coefficients = 0.1162, 0.0386, P < 0.6064, 0.8646, respectively); it was not significantly different between any of the duration periods of observation, namely, <10, 10-20, 20-40, >40 months, nor was it significantly different between PPI-users and PPI-nonusers within each duration period (P > 0.05). We conclude that PPIs are not associated with FGPs, implying that a background history of PPI use is not a justification for nonintervention in the management of FGPs.
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Affiliation(s)
- Shiu Kum Lam
- Gastroenterology & Hepatology of The Humanity & Health Medical Centre
- Former Chair & Dean of Medicine, The University of Hong Kong
| | - George Ka Kit Lau
- Gastroenterology & Hepatology of The Humanity & Health Medical Centre, Hong Kong, Hong Kong
- Liver Diseases & Transplant Centre, The Fifth Medical Centre of Chinese PLA General Hospital, Beijing, China
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5
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Franchina M, Cavalcoli F, Falco O, La Milia M, Elvevi A, Massironi S. Biochemical Markers for Neuroendocrine Tumors: Traditional Circulating Markers and Recent Development-A Comprehensive Review. Diagnostics (Basel) 2024; 14:1289. [PMID: 38928704 PMCID: PMC11203125 DOI: 10.3390/diagnostics14121289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 06/13/2024] [Accepted: 06/15/2024] [Indexed: 06/28/2024] Open
Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms presenting unique challenges in diagnosis and management. Traditional markers such as chromogranin A (CgA), pancreatic polypeptide (PP), and neuron-specific enolase (NSE) have limitations in terms of specificity and sensitivity. Specific circulating markers such as serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) and various gastrointestinal hormones such as gastrin, glucagon, somatostatin, and vasoactive intestinal peptide (VIP) have a role in identifying functional NENs. Recent advances in molecular and biochemical markers, also accounting for novel genomic and proteomic markers, have significantly improved the landscape for the diagnosis and monitoring of NENs. This review discusses these developments, focusing on both traditional markers such as CgA and NSE, as well as specific hormones like gastrin, insulin, somatostatin, glucagon, and VIP. Additionally, it covers emerging genomic and proteomic markers that are shaping current research. The clinical applicability of these markers is highlighted, and their role in improving diagnostic accuracy, predicting surgical outcomes, and monitoring response to treatment is demonstrated. The review also highlights the need for further research, including validation of these markers in larger studies, development of standardized assays, and integration with imaging techniques. The evolving field of biochemical markers holds promise for improving patient outcomes in the treatment of NENs, although challenges in standardization and validation remain.
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Affiliation(s)
- Marianna Franchina
- Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
| | - Federica Cavalcoli
- Gastroenterology and Digestive Endoscopy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Olga Falco
- Department of Medicine and Surgery, University of Milano-Bicocca, 20126 Milan, Italy
| | - Marta La Milia
- Department of Medicine and Surgery, University of Milano-Bicocca, 20126 Milan, Italy
| | - Alessandra Elvevi
- Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
| | - Sara Massironi
- Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy
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6
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Hallet J, Clarke CN. ASO Practice Guidelines Series: Surgical Management of Gastrointestinal (Midgut) Neuroendocrine Neoplasms. Ann Surg Oncol 2024; 31:1704-1713. [PMID: 38167813 DOI: 10.1245/s10434-023-14802-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 12/06/2023] [Indexed: 01/05/2024]
Abstract
Gastrointestinal midgut neuroendocrine neoplasms (NENs) are a heterogeneous group of uncommon malignancies. For well-differentiated NENs, known as neuroendocrine tumors (NETs), surgery is a cornerstone of management in localized and metastatic disease. Because of heterogeneous tumor behaviour, association with endocrine syndrome, and prognosis, the management of NETs must be individualized to all these factors in addition to the primary site. With the fast pace of advancement in the field, both for therapies and understanding of tumoral etiology and behaviour, it is important for surgical oncologists to remain updated on guidelines recommendations and suggested treatment pathways. Those guidelines provide important guidance for management of NETs but are largely based on expert opinions and interpretation of retrospective evidence. This article reviews highlights of most recent practice guidelines for midgut (gastric, duodenal, small intestinal, and appendiceal) NETs.
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Affiliation(s)
- Julie Hallet
- Department of Surgery, University of Toronto, Toronto, ON, Canada.
- Susan Leslie Clinic for Neuroendocrine Tumors, Odette Cancer Centre - Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
| | - Callisia N Clarke
- Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
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Wetz C, Ruhwedel T, Schatka I, Grabowski J, Jann H, Metzger G, Galler M, Amthauer H, Rogasch JMM. Plasma Markers for Therapy Response Monitoring in Patients with Neuroendocrine Tumors Undergoing Peptide Receptor Radionuclide Therapy. Cancers (Basel) 2023; 15:5717. [PMID: 38136263 PMCID: PMC10741556 DOI: 10.3390/cancers15245717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 12/03/2023] [Accepted: 12/04/2023] [Indexed: 12/24/2023] Open
Abstract
BACKGROUND Pretherapeutic chromogranin A, alkaline phosphatase (ALP), or De Ritis ratio (aspartate aminotransferase/alanine aminotransferase) are prognostic factors in patients with metastatic neuroendocrine tumors (NET) undergoing peptide receptor radionuclide therapy (PRRT). However, their value for intratherapeutic monitoring remains unclear. We evaluated if changes in plasma markers during PRRT can help identify patients with unfavorable outcomes. METHODS A monocentric retrospective analysis of 141 patients with NET undergoing PRRT with [177Lu]Lu-DOTATOC was conducted. Changes in laboratory parameters were calculated by dividing the values determined immediately before each cycle of PRRT by the pretherapeutic value. Patients with low vs. high PFS were compared with the Wilcoxon rank-sum test. RESULTS Progression, relapse, or death after PRRT was observed in 103/141 patients. Patients with low PFS showed a significant relative ALP increase before the third (p = 0.014) and fourth (p = 0.039) cycles of PRRT. Kaplan-Meier analysis revealed a median PFS of 24.3 months (95% CI, 20.7-27.8 months) in patients with decreasing ALP values (Δ > 10%) during treatment, 12.5 months (95% CI, 9.2-15.8 months) in patients with increasing ALP values (Δ > 10%), and 17.7 months (95% CI, 13.6-21.8 months) with stable ALP values (Δ ± 10%). CONCLUSIONS Based on these exploratory data, a rise in plasma ALP might indicate disease progression and should be interpreted cautiously during therapy.
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Affiliation(s)
- Christoph Wetz
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (T.R.); (G.M.); (M.G.); (H.A.); (J.M.M.R.)
| | - Tristan Ruhwedel
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (T.R.); (G.M.); (M.G.); (H.A.); (J.M.M.R.)
| | - Imke Schatka
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (T.R.); (G.M.); (M.G.); (H.A.); (J.M.M.R.)
| | - Jane Grabowski
- Berlin Institute of Health at Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany;
| | - Henning Jann
- Department of Hepatology and Gastroenterology, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany;
| | - Giulia Metzger
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (T.R.); (G.M.); (M.G.); (H.A.); (J.M.M.R.)
| | - Markus Galler
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (T.R.); (G.M.); (M.G.); (H.A.); (J.M.M.R.)
| | - Holger Amthauer
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (T.R.); (G.M.); (M.G.); (H.A.); (J.M.M.R.)
| | - Julian M. M. Rogasch
- Department of Nuclear Medicine, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (T.R.); (G.M.); (M.G.); (H.A.); (J.M.M.R.)
- Berlin Institute of Health at Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany;
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8
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Alkhayat MJ, Davis K, Atkins SJ, Sheikh AA, Saif MW. Ten-Fold Elevation of Chromogranin A Level Unrelated to a Neuroendocrine Tumor: A Case Report of the Diagnostic Interference of Proton Pump Inhibitors. Cureus 2023; 15:e46862. [PMID: 37954718 PMCID: PMC10637770 DOI: 10.7759/cureus.46862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/11/2023] [Indexed: 11/14/2023] Open
Abstract
Chromogranin A (CgA) is a well-known biomarker for neuroendocrine tumors (NETs). However, due to its non-specificity, a proper assessment of CgA test results requires a detailed knowledge of the factors, conditions, and medications influencing its serum concentration. We describe a case of a 61-year-old patient presenting with a mass suspicious of a gastrointestinal NET and an exceedingly high level of serum CgA persistent after mass resection. Following a thorough review of patient's medical history and clinical presentation, along with radiographic and pathological findings, no evidence of a NET was detected. A trial of proton-pump inhibitor (PPI) withdrawal led to a dramatic normalization of CgA level, marking it as the culprit causing this tumor marker elevation. This case highlights the significant impact of PPI use on CgA level, and should incentivize clinicians to provide proper education to patients prior to testing.
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Affiliation(s)
- Maha J Alkhayat
- General Medicine, Alfaisal University College of Medicine, Riyadh, SAU
| | - Kaamela Davis
- Medical Oncology/Hematology, Orlando Health Cancer Institute, Orlando, USA
| | - Sarah J Atkins
- Medical Oncology/Hematology, Orlando Health Cancer Institute, Orlando, USA
| | - Asad A Sheikh
- Medical Oncology/Hematology, Orlando Health Cancer Institute, Orlando, USA
| | - Muhammad W Saif
- Medical Oncology/Hematology, Orlando Health Cancer Institute, Orlando, USA
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9
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Gastritis, Gastric Polyps and Gastric Cancer. Int J Mol Sci 2021; 22:ijms22126548. [PMID: 34207192 PMCID: PMC8234857 DOI: 10.3390/ijms22126548] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 06/08/2021] [Accepted: 06/14/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer is still an important disease causing many deaths worldwide, although there has been a marked reduction in prevalence during the last few decades. The decline in gastric cancer prevalence is due to a reduction in Helicobacter pylori infection which has occurred for at least 50 years. The most probable mechanism for the carcinogenic effect of H. pylori is hypergastrinemia since H. pylori infected individuals do not have increased risk of gastric cancer before the development of oxyntic atrophy. When atrophy has developed, the carcinogenic process continues independent of H. pylori. Autoimmune gastritis also induces oxyntic atrophy leading to marked hypergastrinemia and development of ECL cell neoplasia as well as adenocarcinoma. Similarly, long-term treatment with efficient inhibitors of acid secretion like the proton pump inhibitors (PPIs) predisposes to ECL cell neoplasia of a different degree of malignancy. Contrasting the colon where most cancers develop from polyps, most polyps in the stomach have a low malignant potential. Nevertheless, gastric polyps may also give rise to cancer and have some risk factors and mechanisms in common with gastric cancer. In this overview the most common gastric polyps, i.e., hyperplastic polyps, adenomatous polyps and fundic gland polyps will be discussed with respect to etiology and particularly use of PPIs and relation to gastric carcinogenesis.
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10
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Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) - A Helicobacter-opposite point. Best Pract Res Clin Gastroenterol 2021; 50-51:101728. [PMID: 33975682 DOI: 10.1016/j.bpg.2021.101728] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 02/08/2021] [Indexed: 01/31/2023]
Abstract
Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is a rare familial gastric cancer syndrome with an autosomal dominant pattern of inheritance. It is characterised by fundic gland polyposis of the gastric body and is associated with a significant risk of gastric adenocarcinoma. Unlike sporadic gastric cancer, Helicobacter pylori is usually absent in patients with GAPPS. This opposite-point finding has so far not been fully clarified. Prophylactic total gastrectomy is indicated in all cases of GAPPS with fundic gland polyposis and the presence of any dysplasia. If no dysplasia is found at histology, prophylactic gastrectomy is suggested at between 30 and 35 years of age, or at five years earlier than the age at which the youngest family member developed gastric cancer. Different phenotypes of GAPPS demand an individual approach to particular family members.
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11
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Tomita T. Significance of chromogranin A and synaptophysin in pancreatic neuroendocrine tumors. Bosn J Basic Med Sci 2020; 20:336-346. [PMID: 32020844 PMCID: PMC7416176 DOI: 10.17305/bjbms.2020.4632] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Accepted: 02/04/2020] [Indexed: 01/17/2023] Open
Abstract
The two most commonly used immunohistochemical markers for neuroendocrine cells and their tumors are chromogranin A (CgA) and synaptophysin (SPY). CgA is a marker for neuroendocrine secretory granules of four pancreatic hormones and gastrin while SPY is a marker for synaptic vesicles in neuroendocrine cells, which release classic neurotransmitters such as acetylcholine and others. CgA is involved in synthesis and secretion of peptide hormones through exocytosis while the function of SPY is elusive. Thirty-five pancreatic neuroendocrine tumors (Pan-NETs) were studied, consisting of 14 insulinomas, 8 gastrinomas, 2 glucagonomas, 6 pancreatic polypeptidomas and 5 non-functioning tumors, and were immunostained for four pancreatic hormones, gastrin, CgA, and SPY. Majority of Pan-NETs were less immunostained for the endocrine hormones and CgA than the normal pancreatic endocrine cells. CgA immunostaining mostly correlates with each hormone staining in non-β-cell tumors, while SPY immunostaining recognizes endocrine cells diffusely in the cytoplasm. CgA immunostaining is less in insulinomas than in non-β-cell tumors, and CgA immunostaining may distinguish CgA-weaker insulinomas from CgA-stronger non-β-cell tumors. CgA immunostaining may be used as an independent marker for biological aggressiveness in non-β-cell Pan-NETs. The serum CgA levels are higher in subjects harboring non-β-cell tumors than those harboring insulinomas, and the serum CgA elevates in parallel to the increasing metastatic tumor mass. Thus, CgA positive immunostaining in Pan-NETs correlates with the elevated serum levels of CgA for diagnosing CgA-positive non-β-cell Pan-NETs and the increasing serum CgA levels indicate increasing metastatic tumor mass.
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Affiliation(s)
- Tatsuo Tomita
- Departments of Integrative Biosciences and Pathology, Oregon Health and Science University, Portland, Oregon, USA
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12
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Re: Neuroendocrine differentiation markers guide treatment sequence selection in metastatic castration-resistant prostate cancer. The Prostate. 2019;1-7. Prostate 2019; 79:813-814. [PMID: 30995357 DOI: 10.1002/pros.23775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 01/22/2019] [Indexed: 11/07/2022]
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13
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Robbins HL, Symington M, Mosterman B, Tranter F, Davies L, Randeva HS, Penedo A, Ferreira C, Darby C, Grammatopoulos D, Kaltsas G, Weickert MO. Effects of intake of breakfast or caffeine-containing beverages on measurement of circulating chromogranin A in plasma. ACTA ACUST UNITED AC 2018. [DOI: 10.1002/ygh2.208] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Helen L. Robbins
- The ARDEN NET Centre, European Neuroendocrine Tumour Society (ENETS) Centre of Excellence (CoE); University Hospitals Coventry and Warwickshire NHS Trust; Coventry UK
| | - Megan Symington
- The ARDEN NET Centre, European Neuroendocrine Tumour Society (ENETS) Centre of Excellence (CoE); University Hospitals Coventry and Warwickshire NHS Trust; Coventry UK
| | - Barbara Mosterman
- The ARDEN NET Centre, European Neuroendocrine Tumour Society (ENETS) Centre of Excellence (CoE); University Hospitals Coventry and Warwickshire NHS Trust; Coventry UK
| | - Fiona Tranter
- The ARDEN NET Centre, European Neuroendocrine Tumour Society (ENETS) Centre of Excellence (CoE); University Hospitals Coventry and Warwickshire NHS Trust; Coventry UK
| | - Louise Davies
- The ARDEN NET Centre, European Neuroendocrine Tumour Society (ENETS) Centre of Excellence (CoE); University Hospitals Coventry and Warwickshire NHS Trust; Coventry UK
| | - Harpal S. Randeva
- The ARDEN NET Centre, European Neuroendocrine Tumour Society (ENETS) Centre of Excellence (CoE); University Hospitals Coventry and Warwickshire NHS Trust; Coventry UK
- Clinical Sciences Research Laboratories, Division of Translational Medicine, Warwick Medical School; University of Warwick, University Hospital; Coventry UK
- Coventry University; Centre for Applied Biological & Exercise Sciences; Coventry UK
| | - Ana Penedo
- Institute of Precision Diagnostics & Translational Medicine and Department of Clinical Biochemistry; University Hospitals Coventry and Warwickshire NHS Trust; Coventry UK
| | - Clara Ferreira
- Nuclear Medicine Department; University Hospitals Coventry and Warwickshire NHS Trust; Coventry UK
| | - Catherine Darby
- Institute of Precision Diagnostics & Translational Medicine and Department of Clinical Biochemistry; University Hospitals Coventry and Warwickshire NHS Trust; Coventry UK
| | - Dimitri Grammatopoulos
- Institute of Precision Diagnostics & Translational Medicine and Department of Clinical Biochemistry; University Hospitals Coventry and Warwickshire NHS Trust; Coventry UK
| | - Gregory Kaltsas
- The ARDEN NET Centre, European Neuroendocrine Tumour Society (ENETS) Centre of Excellence (CoE); University Hospitals Coventry and Warwickshire NHS Trust; Coventry UK
| | - Martin O. Weickert
- The ARDEN NET Centre, European Neuroendocrine Tumour Society (ENETS) Centre of Excellence (CoE); University Hospitals Coventry and Warwickshire NHS Trust; Coventry UK
- Clinical Sciences Research Laboratories, Division of Translational Medicine, Warwick Medical School; University of Warwick, University Hospital; Coventry UK
- Coventry University; Centre for Applied Biological & Exercise Sciences; Coventry UK
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14
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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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Sporadic Fundic Gland Polyps and Gastric Acid Suppression Level. Am J Med Sci 2017; 354:561-564. [PMID: 29208252 DOI: 10.1016/j.amjms.2017.07.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2017] [Accepted: 06/07/2017] [Indexed: 11/24/2022]
Abstract
BACKGROUND Fundic gland polyps (FGPs) are a common endoscopic finding and are known to be associated with proton pump inhibitors (PPIs) use. It is not known if their prevalence is affected by gastric acidity levels. This study aimed to assess whether there is a correlation between FGPs and gastric acidity levels as identified on 24-hour ambulatory impedance-pH studies in patients on PPI therapy. METHODS We performed a review of 402 consecutive patients who take at least once daily PPI and underwent esophagogastroduodenoscopy with combined impedance-pH studies in the same setting (time and place) between January 2010 and December 2014. Patients were classified into 2 groups based on the presence or absence of biopsy-confirmed FGPs during endoscopy. RESULTS Of the 402 patients, 30 (7%) had FGPs. One of these polyps was found with low-grade dysplasia. There was no significant difference of the distributions of the [H+] in the FGPs versus the nonpolyp groups (P = 0.741). There was no significant difference between the 2 groups regarding PPI dose frequency regimens (once and twice) (P = 0.074). However, we found weak ordinal association with PPI duration (P = 0.01) (Spearman = 0.1). CONCLUSIONS FGPs are common endoscopic lesions. Incidence of dysplasia in FGPs is not only rare, but also of unknown clinical significance. Although they seem to be associated with PPIs, the mechanism remains unclear, as we found no correlation between the presence of FGPs and gastric acid control or PPI dose. Future studies would be useful to elucidate an alternate mechanism.
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Kato K, Iwasaki Y, Taniguchi M, Onodera K, Kawakami T, Matsuda M, Higuchi M, Kato K, Kato Y, Tamakawa S, Furukawa H. Successful treatment of proton pump inhibitor induced sporadic fundic gland polyps with an argon plasma coagulator in a patient with polycythaemia vera. Int J Surg Case Rep 2017; 33:75-78. [PMID: 28284066 PMCID: PMC5345958 DOI: 10.1016/j.ijscr.2017.02.039] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 02/21/2017] [Accepted: 02/21/2017] [Indexed: 12/22/2022] Open
Abstract
INTRODUCTION Proton pump inhibitor (PPI) use is associated with the development of fundic gland polyps (FGPs); discontinuing PPIs is associated with regression of FGPs. Here, we report a rare case of non-respondent FGPs after discontinuation of PPI that were successfully treated using an argon plasma coagulator (APC). PRESENTATION OF CASE We present the case of a 68-year-old woman with a history of polycytheamia vera. She also had gastroesophageal reflux disease (GERD) and had been taking 10 mg of omeprazole daily for the past three years. Esophagogastroduedenoscopy (GF) revealed over 100 pedunculated polyps in the gastric body and fundus. Histological examination of the specimens showed dilated oxyntic glands with flattened parietal and mucous cells. Based on these findings and the clinical history, a diagnosis of FGPs was made. Omeprazole use was then discontinued. Repeat GF performed 6 months and 1 year later showed a significant increase in the number and size of the polyps. APC treatment was performed every 6 months for 3 years. Further GF showed a significant decrease in the number and size of the FGPs 4 years after discontinuing PPI. DISCUSSION We conclude that PPI use is a strong risk factor for the development of FGPs and discontinuing PPI is associated with regression of FGPs, but not in patients with polycythaemia vera. However, the mechanism involved in the interaction between FGP and polycytheamia vera remains unknown. CONCLUSION Non-respondent FGPs after discontinuation of PPI use may be successfully treated using APC.
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Affiliation(s)
- Kazuya Kato
- Department of Surgery, Pippu Clinic, 2-10, 1 chome Nakamachi, Pippu, Town Kamikawa-gun, Hokkaido, 078-0343, Japan.
| | - Yoshiaki Iwasaki
- Department of Gastroenterology and Hepatology, Okayama University, 2-5-1, Shikata town, Okayama city, Okayama, 700-8558, Japan
| | - Masahiko Taniguchi
- Department of Surgery, Saint Maria Hospital, 442 Fukumoto Town, Kurume City, Fukuoka, 830-8543, Japan
| | - Kazuhiko Onodera
- Department of Surgery, Sapporo Hokuyu Hospital, 5-1, 6-6 Higashi- Sapporo, Shiroishi-ku, Sapporo City, 003-0006, Japan
| | - Takako Kawakami
- Department of Surgery, Pippu Clinic, 2-10, 1 chome Nakamachi, Pippu, Town Kamikawa-gun, Hokkaido, 078-0343, Japan
| | - Minoru Matsuda
- Department of Surgery, Pippu Clinic, 2-10, 1 chome Nakamachi, Pippu, Town Kamikawa-gun, Hokkaido, 078-0343, Japan
| | - Mineko Higuchi
- Department of Surgery, Pippu Clinic, 2-10, 1 chome Nakamachi, Pippu, Town Kamikawa-gun, Hokkaido, 078-0343, Japan
| | - Kimitaka Kato
- Department of Surgery, Pippu Clinic, 2-10, 1 chome Nakamachi, Pippu, Town Kamikawa-gun, Hokkaido, 078-0343, Japan
| | - Yurina Kato
- Department of Surgery, Pippu Clinic, 2-10, 1 chome Nakamachi, Pippu, Town Kamikawa-gun, Hokkaido, 078-0343, Japan
| | - Susumu Tamakawa
- Department of Pathology, Asahikawa Medical Center, 4048 7 chome, Hanasaki-cho, Asahiwaka City, 070-8644, Japan
| | - Hiroyuki Furukawa
- Department of Surgery, Asahikawa Medical University, 1-1, 2-1 Midorigaoka, Asahikawa, 078-8510, Japan
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The gastrin receptor antagonist netazepide (YF476) in patients with type 1 gastric enterochromaffin-like cell neuroendocrine tumours: review of long-term treatment. Eur J Gastroenterol Hepatol 2016; 28:1345-1352. [PMID: 27682220 DOI: 10.1097/meg.0000000000000713] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Netazepide (YF476) is a recently developed, orally active gastrin receptor antagonist that, in short trials in patients with type 1 gastric enterochromaffin-like cell neuroendocrine tumours, has been shown to induce a significant reduction in the number and size of tumours as well as serum chromogranin A (CgA). The aim of this review is to evaluate the long-term effect and safety of netazepide. PATIENTS AND METHODS Five patients previously treated with netazepide in an open-label trial were offered continuous treatment with netazepide 25 mg once daily. Upper endoscopy was performed every 6 months. The tumours were counted and measured, and tissue samples were obtained from the flat corpus mucosa. Enterochromaffin-like cell hyperplasia was classified according to Solcia and colleagues and volume density of CgA immunoreactive (IR) cells was calculated. Fasting serum CgA and fasting serum gastrin were measured every 3 months. RESULTS All tumours regressed completely in three of five patients; time until total disappearance was 3, 9 and 12 months. In the other two patients, the number of tumours was reduced from 13 to 5 and from 14 to 3. Serum CgA showed a rapid and sustained decrease (P<0.001). The mean reduction in serum CgA was 4.1±0.5 nmol/l. Similarly, volume density of CgA IR cells in the flat corpus mucosa decreased (P<0.001), with the mean change being 2.0±0.4%. Serum gastrin and volume density of gastrin IR cells in the antral part of the stomach remained unchanged (P=0.2 and 0.7, respectively). CONCLUSION Long-term administration of netazepide is effective and safe.
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The first European family with gastric adenocarcinoma and proximal polyposis of the stomach: case report and review of the literature. Gastrointest Endosc 2016; 84:718-25. [PMID: 27343414 DOI: 10.1016/j.gie.2016.06.023] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Accepted: 06/07/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) has to date been recognized in only 8 families worldwide. Recently, different point mutations within the Ying Yang 1 (YY1) binding motif in promoter 1B of the APC gene were assigned as causal in 6 families with GAPPS. METHODS We diagnosed GAPPS across 3 generations in a Czech white family. RESULTS The proband's mother died of gastric cancer at 49 years of age. The proband died of gastric cancer at 56 years of age. All 3 of the proband's daughters inherited polyposis, involving exclusively the gastric fundus and body, with relative sparing of the lesser curve. The daughters have all been regularly surveyed endoscopically. Polyposis progressed rapidly with intestinal differentiated low-grade and high-grade dysplasia present on polypectomy specimens 5 years after the original diagnosis. On this basis, all 3 of the proband's daughters were scheduled for prophylactic total gastrectomy. Unfortunately, the middle daughter presented with generalized gastric adenocarcinoma and died at the age of 26 years. The other 2 daughters (aged 30 and 23 years) underwent total gastrectomy within 6 weeks of their sister's death; histology of surgical specimens showed gastric adenocarcinoma stage IA (pT1a, N0, M0) in both cases. Bi-directional Sanger sequencing of promoter 1B revealed a point mutation (c.-191 T>C) in all 3 daughters of the proband. CONCLUSIONS Atypical endoscopic progression of the fundic gland polyposis, with the presence of dysplasia on polypectomy specimens and genetic testing with recently discovered mutations in promoter 1B of the APC gene might help clinicians to decide whether prophylactic gastrectomy should be performed.
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Abstract
Chromogranin A (CgA) is an established plasma marker of neuroendocrine tumors and has been suggested to also have a role as biomarker in other diseases. Whether CgA has any role as biomarker in diabetes is, however, unresolved, but its widespread distribution in the secretory granules in endocrine tissues including β cells and α cells in pancreas, and the metabolic effects of its peptide fragments suggest that CgA may play a pathophysiological role in diabetes, and thus also be a potential diabetes biomarker. In this review, we summarize the available information on CgA and some of its functional post-translational cleavage products in diabetes, followed by a discussion of its potential as a plasma marker in diabetes and the methodological concerns involved.
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Affiliation(s)
- Kasper Broedbaek
- Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark
| | - Linda Hilsted
- Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark
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Gut P, Czarnywojtek A, Fischbach J, Bączyk M, Ziemnicka K, Wrotkowska E, Gryczyńska M, Ruchała M. Chromogranin A - unspecific neuroendocrine marker. Clinical utility and potential diagnostic pitfalls. Arch Med Sci 2016; 12:1-9. [PMID: 26925113 PMCID: PMC4754364 DOI: 10.5114/aoms.2016.57577] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Accepted: 05/20/2014] [Indexed: 12/13/2022] Open
Abstract
Chromogranin A, despite a number of limitations, is still the most valuable marker of neuroendocrine tumors (NETs). Granins belong to the family of acidic proteins that constitute a major component of secretory granules of various endocrine and neuroendocrine cells, which are components of both the classical endocrine glands and the diffuse neuroendocrine system. These cells are a potential source of transformation into neuroendocrine tumors. The awareness of potential causes influencing the false results of its concentrations simplifies diagnosis and treatment. One of the disadvantages of this marker is its non-specificity and the existence of a number of pathological processes leading to an increase in its concentration, which often results in confusion and diagnostic difficulties. The molecular structure is characterized by a number of sites susceptible to the proteolytic activity of enzymes, resulting in the formation of a number of biologically active peptides. Presumably they act as precursors of active proteins. Chromogranin expression correlates with the amount of secretory vesicles in neuroendocrine cells. The peptide chain during biochemical changes becomes a precursor of biologically active proteins with a wide range of activities. There are a number of commercially available kits for the determination of chromogranin A, which differ in methodology. We present the evaluation of chromogranin A as a marker of neuroendocrine tumors in clinical practice and the possible factors that may affect the outcome of its concentration.
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Affiliation(s)
- Paweł Gut
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Agata Czarnywojtek
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Jakub Fischbach
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Maciej Bączyk
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Katarzyna Ziemnicka
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Elżbieta Wrotkowska
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Maria Gryczyńska
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Marek Ruchała
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
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CAMILO SMP, ALMEIDA ÉCDS, MIRANZI BAS, SILVA JC, NOMELINI RS, ETCHEBEHERE RM. ENDOSCOPIC AND HISTOPATHOLOGIC GASTRIC CHANGES IN CHRONIC USERS OF PROTON-PUMP INHIBITORS. ARQUIVOS DE GASTROENTEROLOGIA 2015; 52:59-64. [DOI: 10.1590/s0004-28032015000100013] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Accepted: 10/07/2014] [Indexed: 03/14/2023]
Abstract
Background Proton-pump inhibitors have been used for at least two decades. They are among the most commonly sold drugs in the world. However, some controversy remains about the indications for their use and the consequences of their prolonged use. Objectives To evaluate and compare the endoscopic and histopathologic gastric changes in chronic users of proton-pump inhibitors to changes in non-users. Methods A prospective study performed at a tertiary Public Hospital involving 105 patients undergoing upper-gastrointestinal endoscopy. Subjects included 81 proton-pump inhibitor users and 24 non-users (control group). Biopsies of the antral-type mucosa, the antral-fundic transition, and the fundus were evaluated by the Sydney System. The presence of erosion or ulceration, lymphatic follicles, reactive gastropathy, and polypoid or epithelial hyperplasia was also determined. Serum levels of gastrin were measured. Results We found two polyps, one in each group, both of which were negative for Helicobacter pylori. There were two cases of parietal cell hyperplasia in users of proton-pump inhibitors. Gastrin was elevated in 28 users of proton-pump inhibitors and in four members of the control group. We did not find statistically significant differences in the endoscopic or histopathologic findings between the two groups. Conclusions Chronic use of proton-pump inhibitors for the duration examined was not associated with significant gastric changes. An interesting finding was that the 4 chronic users of proton-pump inhibitors who had serum gastrin levels above 500 pg/mL also had positive serology for Chagas disease.
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Modlin IM, Aslanian H, Bodei L, Drozdov I, Kidd M. A PCR blood test outperforms chromogranin A in carcinoid detection and is unaffected by proton pump inhibitors. Endocr Connect 2014; 3:215-23. [PMID: 25316294 PMCID: PMC8473957 DOI: 10.1530/ec-14-0100] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
A critical requirement in neuroendocrine tumor (NET) management is a blood biomarker test that is sensitive, specific and reproducible. We evaluated a PCR-based 51-transcript signature to detect tumors, compared it with chromogranin A (CgA) and examined the confounding effect of proton pump inhibitors (PPIs), which cause falsely elevated CgA levels. The multigene signature was evaluated in two groups. Group 1: 125 prospectively collected NETs: gastroenteropancreatic NETs (n=91, including 42 pancreatic and 40 small intestinal), carcinoids of unknown primary (n=18) and other sites (n=16). Group 2: prospectively collected non-NET patients receiving PPIs (>1 month; dyspepsia, n=19; GERD, n=6; and pancreatitis, n=4) and 50 controls. All samples were analyzed by PCR (marker genes) and ELISA (DAKO-CgA). Sensitivity comparisons included χ(2), non-parametric measurements, and receiver operating characteristic (ROC) curves. Group 1: 123 NETs were PCR-positive (98.4%) compared with 50 (40%) CgA-positive (χ(2)=97.3, P<10(-26)). Significant differences (P<0.001) were noted between pancreas: PCR 95% vs CgA 29.2% (P<10(-9)) and small intestine: 100 vs 58% (P<10(-4)). The multigene test was elevated in all grades (G1-G3), in both local and disseminated disease, and was not normalized by somatostatin analog therapy. It was also elevated in 97% of CgA normal NETs. Group 2: PPI administration increased CgA in 83% and CgA was elevated in 26% of controls. PCR values were not elevated in either group. PCR performance metrics were as follows: sensitivity 98.4%, specificity 100%, positive predictive value 100%, negative predictive value 97.8%, and the ROC-derived area under the curve (AUC) was 0.997. These were significantly better than CgA (all metrics <60%; AUC, 0.54; Z-statistic, 10.44, P<0.0001). A 51-panel multigene blood transcript analysis is significantly more sensitive than plasma CgA for NET detection and is unaffected by acid suppression therapy.
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Affiliation(s)
- Irvin M Modlin
- Wren Laboratories35 NE Industrial Road, Branford, Connecticut, USAYale University School of Medicine310 Cedar St, New Haven, Connecticut, USA
| | - Harry Aslanian
- Wren Laboratories35 NE Industrial Road, Branford, Connecticut, USAYale University School of Medicine310 Cedar St, New Haven, Connecticut, USA
| | - Lisa Bodei
- Wren Laboratories35 NE Industrial Road, Branford, Connecticut, USAYale University School of Medicine310 Cedar St, New Haven, Connecticut, USA Wren Laboratories35 NE Industrial Road, Branford, Connecticut, USAYale University School of Medicine310 Cedar St, New Haven, Connecticut, USA
| | - Ignat Drozdov
- Wren Laboratories35 NE Industrial Road, Branford, Connecticut, USAYale University School of Medicine310 Cedar St, New Haven, Connecticut, USA
| | - Mark Kidd
- Wren Laboratories35 NE Industrial Road, Branford, Connecticut, USAYale University School of Medicine310 Cedar St, New Haven, Connecticut, USA
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Abstract
OBJECTIVES The prevalence of fundic gland polyps (FGPs) is increasing. Some researchers consider this increase to be associated strongly with the long-term use of proton-pump inhibitors (PPIs); however, not all researchers share this belief. There are minimal data on the development of FGPs in China. Therefore, we aimed to investigate the prevalence of FGPs and risk factors associated with the development of this disease. MATERIALS AND METHODS We studied 10 904 consecutive patients who underwent gastroduodenal endoscopies at our digestive endoscopy center between February 2011 and January 2013. Information on sex, age, Helicobacter pylori infection, PPIs intake, and the pathological results of the polyps were collected in the FGPs group and in the control group. The use of PPIs, sex, and H. pylori infection were statistically evaluated as dichotomous variables using a χ-test; age was evaluated as a continuous variable using a t-test. Finally, these factors were evaluated using a multiple logistic regression analysis. RESULTS Gastric polyps were found in 759 (7.0%) patients, and 213 (2.0%) of these patients had FGPs. FGPs accounted for 28.1% of the gastric polyps. In the FGPs group, the percentage of H. pylori infection was 66.8% and the percentage of PPIs intake for at least 12 months was 23.1%. In the control group, the percentage of H. pylori infection was 77.4% and the percentage of PPIs intake for at least 12 months was 2.3%. The difference in the long-term use of PPIs was statistically significant between these two groups [χ=33.98, P<0.05, odds ratio (OR)=12.83, 95% confidence interval (CI): 4.47-36.80]. The results of the logistic regression were as follows: long-term use of PPIs (P<0.01, OR=14.11, 95% CI: 4.15-47.93); age (P<0.01, OR=1.69, 95% CI: 1.31-2.18). The P-values for sex and H. pylori infection were higher than 0.05. CONCLUSION Age and the long-term use of PPIs were risk factors for the presence of FGPs; the long-term use of PPIs was a particularly strong risk factor.
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Pedersen L, Nybo M. Preanalytical factors of importance for measurement of Chromogranin A. Clin Chim Acta 2014; 436:41-4. [DOI: 10.1016/j.cca.2014.04.026] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Revised: 04/28/2014] [Accepted: 04/28/2014] [Indexed: 12/01/2022]
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Karger S, Wiesner T, Kersting A, Braun M, Ebert T, Wurst U, Kratzsch J, Stumvoll M, Fasshauer M. Increased chromogranin a and carcinoid syndrome-like symptoms in a patient treated with duloxetine. Endocr Pract 2014; 20:e215-8. [PMID: 25100382 DOI: 10.4158/ep14162.cr] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE We report the case of a 50-year-old female patient who presented with symptoms suggestive of a serotonin-secreting neuroendocrine neoplasm. In addition, her serum chromogranin A (CA) level was elevated by more than 8-fold. METHODS We present a case report with review of the relevant literature. RESULTS No abnormalities could be detected in a complete conventional and functional morphological diagnostic work-up including a gallium-68-DOTA-d-Phe1-Tyr3-octreotide (Ga-68-DOTATOC) positron emission tomography-computed tomography (PET-CT) scan. These negative results prompted us to consider possible drug-related effects as the cause for these findings. The patient had started to take duloxetine, a second-generation antidepressant (SGA) and selective serotonin-norepinephrine reuptake inhibitor (SNRI), at a dose of 60 mg/day 2 months prior to her first visit at our department for pain relief. After withdrawal of duloxetine, her symptoms promptly ceased, and her CA levels fell to normal values within 7 weeks. CONCLUSION We conclude that selective serotonin-norepinephrine reuptake inhibitors (SNRIs) can cause symptoms suggestive of serotonin-secreting neuroendocrine neoplasms, as well as elevated CA levels leading to unnecessary and expensive diagnostic workups. To our knowledge, the association between SNRI treatment and increased CA levels has not been described in the literature and needs to be further evaluated in well-controlled prospective studies.
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Affiliation(s)
- Stefan Karger
- Department of Endocrinology and Nephrology, University of Leipzig
| | - Tobias Wiesner
- Department of Endocrinology and Nephrology, University of Leipzig
| | - Anette Kersting
- Clinic of Psychosomatic Medicine and Psychotherapy, University of Leipzig
| | - Miriam Braun
- Clinic of Psychosomatic Medicine and Psychotherapy, University of Leipzig
| | - Thomas Ebert
- Department of Endocrinology and Nephrology, University of Leipzig IFB Adiposity Diseases, University of Leipzig
| | - Ulrike Wurst
- Department of Endocrinology and Nephrology, University of Leipzig IFB Adiposity Diseases, University of Leipzig
| | - Juergen Kratzsch
- Institute for Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig
| | - Michael Stumvoll
- Department of Endocrinology and Nephrology, University of Leipzig
| | - Mathias Fasshauer
- Department of Endocrinology and Nephrology, University of Leipzig IFB Adiposity Diseases, University of Leipzig
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Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014; 3:1-17. [DOI: 10.5315/wjh.v3.i1] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
As recognition of mast cell (MC) involvement in a range of chronic inflammatory disorders has increased, diagnosticians’ suspicions of MC activation disease (MCAD) in their chronically mysteriously inflamed patients have similarly increased. It is now understood that the various forms of systemic mastocytosis - diseases of inappropriate activation and proliferation of MCs seemingly driven by a small set of rare, usually constitutively activating mutations in assorted MC regulatory elements - comprise merely the tip of the MCAD iceberg, whereas the far larger and far more clinically heterogeneous (and thus more difficult to recognize) bulk of the iceberg consists of assorted forms of MC activation syndrome (MCAS) which manifest little to no abnormal MC proliferation and may originate from a far more heterogeneous set of MC mutations. It is reasonable to suspect MCAD when symptoms and signs of MC activation are present and no other diagnosis better accounting for the full range of findings is present. Initial laboratory assessment should include not only routine blood counts and serum chemistries but also a serum total tryptase level, which helps direct further evaluation for mastocytosis vs MCAS. Appropriate tissue examinations are needed to diagnose mastocytosis, while elevated levels of relatively specific mast cell mediators are sought to support diagnosis of MCAS. Whether assessing for mastocytosis or MCAS, testing is fraught with potential pitfalls which can easily yield false negatives leading to erroneous rejection of diagnostic consideration of MCAD in spite of a clinical history highly consistent with MCAD. Efforts at accurate diagnosis of MCAD are worthwhile, as many patients then respond well to appropriately directed therapeutic efforts.
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Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014; 3:1-17. [DOI: 10.5315/wjh.v3.i1.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
As recognition of mast cell (MC) involvement in a range of chronic inflammatory disorders has increased, diagnosticians’ suspicions of MC activation disease (MCAD) in their chronically mysteriously inflamed patients have similarly increased. It is now understood that the various forms of systemic mastocytosis - diseases of inappropriate activation and proliferation of MCs seemingly driven by a small set of rare, usually constitutively activating mutations in assorted MC regulatory elements - comprise merely the tip of the MCAD iceberg, whereas the far larger and far more clinically heterogeneous (and thus more difficult to recognize) bulk of the iceberg consists of assorted forms of MC activation syndrome (MCAS) which manifest little to no abnormal MC proliferation and may originate from a far more heterogeneous set of MC mutations. It is reasonable to suspect MCAD when symptoms and signs of MC activation are present and no other diagnosis better accounting for the full range of findings is present. Initial laboratory assessment should include not only routine blood counts and serum chemistries but also a serum total tryptase level, which helps direct further evaluation for mastocytosis vs MCAS. Appropriate tissue examinations are needed to diagnose mastocytosis, while elevated levels of relatively specific mast cell mediators are sought to support diagnosis of MCAS. Whether assessing for mastocytosis or MCAS, testing is fraught with potential pitfalls which can easily yield false negatives leading to erroneous rejection of diagnostic consideration of MCAD in spite of a clinical history highly consistent with MCAD. Efforts at accurate diagnosis of MCAD are worthwhile, as many patients then respond well to appropriately directed therapeutic efforts.
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Goetze JP, Alehagen U, Flyvbjerg A, Rehfeld JF. Chromogranin A as a biomarker in cardiovascular disease. Biomark Med 2014; 8:133-40. [DOI: 10.2217/bmm.13.102] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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Management of gastric polyps: an endoscopy-based approach. Clin Gastroenterol Hepatol 2013; 11:1374-84. [PMID: 23583466 PMCID: PMC3962745 DOI: 10.1016/j.cgh.2013.03.019] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2013] [Revised: 03/19/2013] [Accepted: 03/19/2013] [Indexed: 02/07/2023]
Abstract
The endoscopic finding of a gastric polyp and the histopathologic report that follows may leave clinicians with questions that have not been addressed in formal guidelines: do all polyps need to be excised, or can they just be sampled for biopsy? If so, which ones and how many should be sampled? What follow-up evaluation is needed, if any? This review relies on the existing literature and our collective experience to provide practical answers to these questions. Fundic gland polyps, now the most frequent gastric polyps in Western countries because of widespread use of proton pump inhibitors, and hyperplastic polyps, the second most common polyps notable for their association with gastritis and their low but important potential for harboring dysplastic or neoplastic foci, are discussed in greater detail. Adenomas have had their name changed to raised intraepithelial neoplasia and are decreasing in parallel with Helicobacter pylori infection; however, they do retain their importance as harbingers of gastric cancer, particularly in East Asia. Gastrointestinal stromal tumors have low incidence and no known associations, but their malignant potential is high; early diagnosis and proper management are crucial. Although rare and benign, inflammatory fibroid polyps need to recognized, particularly by pathologists, to avoid misdiagnosis. Gastric neuroendocrine tumors (carcinoids) are important because of their association with either atrophic gastritis or the multiple endocrine neoplasia syndromes; those that do not arise in these backgrounds have high malignant potential and require aggressive management. The review concludes with some practical suggestions on how to approach gastric polyps detected at endoscopy.
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Bech PR, Martin NM, Ramachandran R, Bloom SR. The biochemical utility of chromogranin A, chromogranin B and cocaine- and amphetamine-regulated transcript for neuroendocrine neoplasia. Ann Clin Biochem 2013; 51:8-21. [DOI: 10.1177/0004563213489670] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Neuroendocrine neoplasia (NEN) is a heterogeneous group of tumours and often represents a therapeutic challenge to clinicians. The peptides chromogranin A (CgA), chromogranin B (CgB) and cocaine- and amphetamine-regulated transcript (CART) are widely distributed throughout the neuroendocrine system. CgA and CgB have been used as general NEN biomarkers for many years, while CART has only recently been identified. Of these biomarkers, CgA is the most commonly used. However, circulating CgA concentrations exhibit considerable intra-individual biological variation, are altered by proton pump inhibitors (PPIs) and somatostatin analogues and are elevated in non-NEN malignancies. Therefore, interpretation of CgA results must be in the context of these confounding factors. The effects of treatment and non-NEN conditions on circulating CgB and CART concentrations are less well understood. CgB is less affected by impaired renal function and PPIs than CgA; while, circulating CART concentrations lack a diurnal variation in humans and are more reliable markers of pancreatic NEN malignancy than CgA. The utility of circulating CgA measurements in NEN prognosis, surveillance and disease recurrence has been widely investigated. However, the utility of CgB and CART in NEN management is yet to be elucidated. Further studies are needed to establish whether CgB and CART are useful alternatives to CgA.
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Affiliation(s)
- PR Bech
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK
| | - NM Martin
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK
| | - R Ramachandran
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK
| | - SR Bloom
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London, UK
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Carneiro F, Lauwers GY. Epithelial Tumours of the Stomach. MORSON AND DAWSON'S GASTROINTESTINAL PATHOLOGY 2013:180-222. [DOI: 10.1002/9781118399668.ch13] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Fossmark R, Sørdal Ø, Jianu CS, Qvigstad G, Nordrum IS, Boyce M, Waldum HL. Treatment of gastric carcinoids type 1 with the gastrin receptor antagonist netazepide (YF476) results in regression of tumours and normalisation of serum chromogranin A. Aliment Pharmacol Ther 2012; 36:1067-75. [PMID: 23072686 DOI: 10.1111/apt.12090] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2012] [Revised: 09/23/2012] [Accepted: 09/27/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND Patients with chronic atrophic gastritis have long-term gastric hypoacidity, and secondary hypergastrinaemia. Some also develop gastric ECL cells carcinoids (type 1 GC). Most type 1 GC remain indolent, but some metastasise. Patients undergo surveillance, and some are treated with somatostatin analogues, endoscopic resection or surgery. Netazepide (YF476) is a highly selective, potent and orally active gastrin receptor antagonist, which has anti-tumour activity in various rodent models of gastric neoplasia driven by hypergastrinaemia. Netazepide has been studied in healthy volunteers. AIM To assess the effect of netazepide on type 1 GC. METHODS Eight patients with multiple type 1 GC received oral netazepide once daily for 12 weeks, with follow-up at 12 weeks in an open-label, pilot trial. Upper endoscopy was performed at 0, 6, 12 and 24 weeks, and carcinoids were counted and measured. Fasting serum gastrin and chromogranin A (CgA) and safety and tolerability were assessed at 0, 3, 6, 9, 12 and 24 weeks. RESULTS Netazepide was well tolerated. All patients had a reduction in the number and size of their largest carcinoid. CgA was reduced to normal levels at 3 weeks and remained so until 12 weeks, but had returned to pre-treatment levels at 24 weeks. Gastrin remained unchanged throughout treatment. CONCLUSIONS The gastrin receptor antagonist netazepide is a promising new medical treatment for type 1 gastric carcinoids, which appear to be gastrin-dependent. Controlled studies and long-term treatment are justified to find out whether netazepide treatment can eradicate type 1 gastric carcinoids.
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Affiliation(s)
- R Fossmark
- Department of Gastroenterology and Hepatology, St. Olavs Hospital, Trondheim, Norway.
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Fundic gland polyps and association with proton pump inhibitor intake: a prospective study in 1,780 endoscopies. Dig Dis Sci 2011; 56:1743-8. [PMID: 21127978 DOI: 10.1007/s10620-010-1493-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2010] [Accepted: 11/10/2010] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Fundic gland polyps (FGPs) are incidentally found when an endoscopy is performed for a non-related indication. Some authors suggested a relationship with proton pump inhibitor (PPI) intake. We aimed to determine their prevalence and association with PPI intake. METHODS We prospectively studied 1,780 patients who underwent a gastroduodenal endoscopy at our ambulatory care center between June 2007 and August 2008. PPI intake during a period of at least 12 months, female gender and age were statistically evaluated as risk factors for the presence of FGPs. Then, a multiple logistic regression analysis was applied to these variables. RESULTS Gastric polyps were found in 129 patients (7.2%) and 77 (4.33%) were FGPs. Five patients with no available histology were excluded for the assessment of risk factors. PPI intake was detected in 49 patients with FGPs (63.6%) and 264 without FGPs (15.5%) (P < 0.0001). Fifty-nine patients with FGPs (76.7%) and 987 without FGPs (58.1%) were women (P < 0.001). The mean age was 58.91 ± 11.82 years in patients with FGPs and 50.34 ± 15.04 years in patients without FGPs (P < 0.0001). The three variables remained significant in the multiple model: PPI intake: P < 0.0001, OR 9.00 (95% CI 5.44-14.89); female gender: P = 0.0001, OR 2.95 (95% CI 1.69-5.15); age: P = 0.001, OR 1.03 (95% CI 1.01-1.05). CONCLUSIONS In our population, the prevalence of FGPs was high. Although female gender and age were also significant, PPI intake was the strongest risk factor associated with the presence of FGPs.
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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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Malignant Range Elevation of Serum Chromogranin A due to Inadvertent Use of Proton Pump Inhibitor in a Subject with Pancreatic Incidentaloma. Case Rep Endocrinol 2011; 2011:342480. [PMID: 22937281 PMCID: PMC3420657 DOI: 10.1155/2011/342480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2011] [Accepted: 06/10/2011] [Indexed: 11/18/2022] Open
Abstract
We present a case of highly elevated tenfold rise of serum chromogranin A in a young, morbidly obese, hypertensive female being investigated for pancreatic mass, weight loss, and elevated ESR. Following extensive noninvasive investigations, an ultrasound-guided pancreatic biopsy confirmed benign haemorrhagic cyst. A clue to the etiology of the hyperchromogranin A was the elevated serum gastrin level leading to suspicion of proton pump inhibitor administration confirmed by admittance to its use. Withdrawal of the medication led to dramatic resolution of the neuroendocrine tumor marker.
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Gori G, Spinelli G, Spinelli C, Tuccori M, Blandizzi C, Del Tacca M. Esomeprazole-induced hyperchromograninemia in the absence of concomitant hypergastrinemia. Nat Rev Gastroenterol Hepatol 2010; 7:642-6. [PMID: 20938461 DOI: 10.1038/nrgastro.2010.152] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
BACKGROUND A 37-year-old female, who had a neuroendocrine pancreatic neoplasm, underwent duodeno-cephalo-pancreatectomy. In the 2 years following surgery, she had normal levels of serum chromogranin A (CgA), gastrin and other tumor markers. About 3 years after surgery, owing to the onset of reflux-like dyspeptic symptoms, the patient started treatment with the PPI esomeprazole. During PPI treatment, the patient's serum CgA level rose to more than three times the upper limit of normal, although her gastrin levels remained in the normal range. These findings were interpreted as being suggestive of neuroendocrine tumor relapse. INVESTIGATIONS Thoraco-abdominal CT, In¹¹¹-octreotide total body scan, CT of sella turcica, Tc(99m)-sestamibi neck scan, mutational analysis of chromosome 11q13 (site of multiple endocrine neoplasia type 1 [MEN1] gene). Discontinuation of, and rechallenge with, esomeprazole. DIAGNOSIS Esomeprazole-induced hyperchromograninemia in the absence of elevated levels of fasting serum gastrin. MANAGEMENT Discontinuation of acid-suppressive treatment and continuation of oncologic follow-up.
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Affiliation(s)
- Giovanni Gori
- Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, via Roma, 55-56126 Pisa, Italy
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Modlin IM, Gustafsson BI, Moss SF, Pavel M, Tsolakis AV, Kidd M. Chromogranin A--biological function and clinical utility in neuro endocrine tumor disease. Ann Surg Oncol 2010; 17:2427-2443. [PMID: 20217257 DOI: 10.1245/s10434-010-1006-3] [Citation(s) in RCA: 260] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2009] [Indexed: 02/06/2023]
Abstract
BACKGROUND Neuroendocrine tumors (NETs) are a form of cancer that differ from other neoplasia in that they synthesize, store, and secrete peptides, e.g., chromogranin A (CgA) and amines. A critical issue is late diagnosis due to failure to identify symptoms or to establish the biochemical diagnosis. We review here the utility of CgA measurement in NETs and describe its biological role and the clinical value of its measurement. METHODS Literature review and analysis of the utility of plasma/serum CgA measurements in NETs and other diseases. RESULTS CgA is a member of the chromogranin family; its transcription and peptide processing are well characterized, but its precise function remains unknown. Levels are detectable in the circulation but vary substantially (approximately 25%) depending on which assay is used. Serum and plasma measurements are concordant. CgA is elevated in approximately 90% of gut NETs and correlates with tumor burden and recurrence. Highest values are noted in ileal NETs and gastrointestinal NETs associated with multiple endocrine neoplasia type 1. Both functioning and nonfunctioning pancreatic NETs have elevated values. CgA is more frequently elevated in well-differentiated tumors compared to poorly differentiated NETs. Effective treatment is often associated with decrease in CgA levels. Proton pump inhibitors falsely increase CgA, but levels normalize with therapy cessation. CONCLUSIONS CgA is currently the best available biomarker for the diagnosis of NETs. It is critical to establish diagnosis and has some utility in predicting disease recurrence, outcome, and efficacy of therapy. Measurement of plasma CgA is mandatory for the effective diagnosis and management of NET disease.
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Affiliation(s)
- Irvin M Modlin
- Gastrointestinal Pathobiology Research Group, Yale University School of Medicine, New Haven, CT, USA.
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Bakkelund KE, Waldum HL, Nordrum IS, Hauso Ø, Fossmark R. Long-term gastric changes in achlorhydric H(+)/K(+)-ATPase beta subunit deficient mice. Scand J Gastroenterol 2010; 45:1042-7. [PMID: 20476858 DOI: 10.3109/00365521.2010.490952] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Hypergastrinemia is known to induce enterochromaffin-like (ECL) cell derived tumors in rodents and man. In this study, we have examined the effect of life-long gastric anacidity and secondary hypergastrinemia in H(+)/K(+)-ATPase beta subunit knockout (KO) mice. MATERIAL AND METHODS Female H(+)/K(+)-ATPase beta subunit KO mice and controls were followed up to 20 months before being sacrificed. At termination, intragastric acidity was measured and internal organs were examined for macroscopic and histological changes. Plasma gastrin and serum albumin were measured. RESULTS KO mice were anacidic and hypergastrinemic. The oxyntic mucosa was markedly, and with increase in age, hyperplastic with cystic dilatations resembling the changes seen in patients with Menetrier's disease. Serum albumin in KO mice did not differ from controls. KO mice had a marked ECL cell hyperplasia, but only one gastric carcinoma was found. CONCLUSION H(+)/K(+)-ATPase beta subunit KO mice develop Menetrier-like changes in the stomach, and may be useful in studying the pathogenesis and treatment of Menetrier's disease. The reason why only one KO mice developed gastric neoplasia whereas the histamine-2 blocker loxtidine has previously been found to regularly induce ECL cell carcinoids in mice is not known.
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Affiliation(s)
- Karin E Bakkelund
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
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Molina R, Alvarez E, Aniel-Quiroga A, Borque M, Candás B, Leon A, Poyatos RM, Gelabert M. Evaluation of chromogranin A determined by three different procedures in patients with benign diseases, neuroendocrine tumors and other malignancies. Tumour Biol 2010; 32:13-22. [PMID: 20730520 DOI: 10.1007/s13277-010-0085-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2010] [Accepted: 07/26/2010] [Indexed: 01/27/2023] Open
Abstract
UNLABELLED CgA is a tumor marker in NET's (neuroendocrine tumors) but different ranges of sensitivity and specificity according to the commercial assay kits used have been reported. Our aim was to compare three commercial available assay kits that use three different methodologies (IRMA, RIA and ELISA) to determine CgA, in a clinical setting: 52 healthy people, 98 patients with benign diseases, 94 patients with non-NET´s malignancies, 20 SCLC and in 79 patients with NET's. RESULTS Using a cut-off with a 100% specificity in healthy people (6 nmol/L, 60 ng/ml, and 90 ng/ml, for RIA, ELISA and IRMA, respectively), abnormal serum concentrations of CgA were found in a high proportion of patients with renal failure (76.7% ,86,7% and 93.3% with ELISA; IRMA and RIA, respectively) other benign diseases (excluding patients with creatinine concentrations > 1.5 mg/dl)(40,3%, 50% and 53,2% with ELISA, IRMA and RIA, respectively) or in patients with non-NET´s malignancies (excluding SCLC and patients with renal failure) (59,8% ELISA, 55,4%% IRMA, 37% RIA). The highest CgA sensitivity in SCLC was obtained with ELISA (100%) and in NET´s with ELISA (83.3%) and IRMA (80.3%) (RIA 65.2%). ROC curves comparing healthy people and NET´s or NET´s- benigns showed a significantly higher area under the curve (AUC) with ELISA (0.964 and 0.774), or IRMA (0.955 and 0.785), and smaller with RIA (0,806 and 0.691). CONCLUSIONS CgA is not a specific tumormarker and abnormal concentrations may be found in non-NET´s. The higher AUC, sensitivity and specificity obtained with the ELISA and IRMA indicates that these are the best techniques to determine CgA.
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Affiliation(s)
- Rafael Molina
- Oncobiology Unit, Laboratory of Biochemistry, Hospital Clinic of Barcelona, C/Villarroel 170, Barcelona, 08036, Spain.
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Jianu CS, Fossmark R, Syversen U, Hauso Ø, Waldum HL. A meal test improves the specificity of chromogranin A as a marker of neuroendocrine neoplasia. Tumour Biol 2010; 31:373-80. [PMID: 20480408 DOI: 10.1007/s13277-010-0045-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2009] [Accepted: 04/22/2010] [Indexed: 11/25/2022] Open
Abstract
Chromogranin A (CgA) is a neuroendocrine tumor (NET) marker. Modest CgA elevation is found in subjects with enterochromaffin-like (ECL) cell hyperplasia due to hypergastrinemia. Somatostatin analogs reduce CgA levels in patients with NET. Meals may affect serum CgA levels. The aims of the study were to investigate meal-induced CgA release and the short-term effect of octreotide on serum CgA levels. Four groups were studied: group A, seven patients with ECL cell hyperplasia secondary to use of proton pump inhibitors (PPIs); group B, six patients with gastric carcinoid type 1/ECL hyperplasia due to chronic atrophic gastritis (CAG); group C, six patients with nongastric NETs; group D, seven controls. The subjects were studied on three separate days with the use of three exposures: a test meal, pentagastrin subcutaneously (not group C), and octreotide intravenously. Serum CgA and gastrin were analyzed. A test meal induced a significant CgA increase in long-term PPI users and in healthy controls. The meal did not affect CgA levels in patients with gastric carcinoid type 1 or patients with NETs. The test meal increased gastrin levels in all groups except in those with CAG. Pentagastrin increased CgA levels in all groups tested except in those with CAG, while octreotide, reduced CgA and gastrin levels in all groups. Serum CgA should be determined in fasting individuals. A test meal may distinguish between increased CgA levels in PPI users from nongastric NET patients. Concomitant gastrin determination may help to discriminate between nongastric NETs and CAG. Intravenous octreotide rapidly reduces serum CgA.
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Affiliation(s)
- Constantin S Jianu
- Department of Gastroenterology and Hepatology, St. Olav's Hospital, Olav Kyrres gt. 17, 7006, Trondheim, Norway.
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Ally MR, Veerappan GR, Maydonovitch CL, Duncan TJ, Perry JL, Osgard EM, Wong RKH. Chronic proton pump inhibitor therapy associated with increased development of fundic gland polyps. Dig Dis Sci 2009; 54:2617-22. [PMID: 19830554 DOI: 10.1007/s10620-009-0993-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2009] [Accepted: 09/14/2009] [Indexed: 12/13/2022]
Abstract
BACKGROUND Fundic gland polyps (FGP) have been implicated with long-term proton pump inhibitor (PPI) use. AIMS We attempted to investigate the impact of length and dosage of PPI therapy on the development of FGP. METHODS A retrospective cohort study of all patients who had gastric polyps removed during elective upper endoscopy between March and September 2007 as part of a prior prospective study protocol was carried out. FGP were determined histologically. Prior to endoscopy, all patients completed a questionnaire regarding PPI use and length of therapy (no PPI use, 1-48 months, >48 months). The dosage of PPI was obtained via a thorough chart review of electronic medical records. RESULTS Three hundred and eighty-five patients completed upper endoscopy and a questionnaire reporting PPI use (252 [65.4%] patients on PPI). On endoscopy, 55 patients had polyps, with the majority (43/55, 78%) being FGP, resulting in an overall prevalence of 11.1% (43/385). On univariate analysis, FGP were associated with Caucasian race (15 vs. 6%; P=0.009) and chronic PPI therapy (>48 months) (31.9 vs. 7.5%, P<0.001). There was a significant linear-by-linear association between PPI dosage and FGP prevalence (no PPI use, 7.5%; once daily, 10.8%; twice daily 17.4%, P=0.026). On logistic regression, the only independent predictor of FGP was duration of PPI use >48 months (P=0.001, odds ratio [OR] 4.7 [2.0-12.9]). CONCLUSIONS The only independent predictor of FGP development in our study was duration of PPI therapy greater than 48 months. Increased dosage of therapy did not significantly impact the development of FGP.
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Affiliation(s)
- Mazer R Ally
- Gastroenterology Service, Department of Medicine, Walter Reed Army Medical Center, 6900 Georgia Avenue, NW, Washington, DC 20307-5001, USA
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Freston JW, Hisada M, Peura DA, Haber MM, Kovacs TO, Atkinson S, Hunt B. The clinical safety of long-term lansoprazole for the maintenance of healed erosive oesophagitis. Aliment Pharmacol Ther 2009; 29:1249-60. [PMID: 19416133 DOI: 10.1111/j.1365-2036.2009.03998.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND The clinical safety of long-term lansoprazole therapy for the maintenance of healed erosive oesophagitis has not been extensively studied in clinical trials. AIM To assess the long-term clinical safety of dose-titrated lansoprazole as maintenance therapy for up to 82 months in subjects with healed erosive oesophagitis. METHODS Clinical safety was assessed by monitoring adverse events (AEs), laboratory data including serum gastrin levels, and endoscopy. RESULTS Mean duration (+/- s.d.) of lansoprazole treatment during the titrated open-label period was 56 +/- 24 months (range <1-82 months). Overall, 189 of 195 (97%) subjects experienced a total of 2825 treatment-emergent AEs. Most AEs occurred during the first year of treatment, were mild-to-moderate in severity and resolved while on treatment. Of 155 serious AEs (in 74 subjects), only two (colitis and rectal haemorrhage in one subject) were considered treatment-related. Sixty-nine of 195 subjects (35%) experienced 187 treatment-related AEs, with diarrhoea (10%), headache (8%) and abdominal pain (6%) being the most common. Gastrin levels > or = 400 pg/mL were seen in 9% of subjects; hypergastrinemia was not associated with gastro-intestinal AEs or nodules/polyps. CONCLUSIONS Lansoprazole maintenance therapy for up to 6 years is safe and well tolerated in subjects with healed erosive oesophagitis.
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Affiliation(s)
- J W Freston
- Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA
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Burkitt MD, Varro A, Pritchard DM. Importance of gastrin in the pathogenesis and treatment of gastric tumors. World J Gastroenterol 2009; 15:1-16. [PMID: 19115463 PMCID: PMC2653300 DOI: 10.3748/wjg.15.1] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
In addition to regulating acid secretion, the gastric antral hormone gastrin regulates several important cellular processes in the gastric epithelium including proliferation, apoptosis, migration, invasion, tissue remodelling and angiogenesis. Elevated serum concentrations of this hormone are caused by many conditions, particularly hypochlorhydria (as a result of autoimmune or Helicobacter pylori (H pylori)-induced chronic atrophic gastritis or acid suppressing drugs) and gastrin producing tumors (gastrinomas). There is now accumulating evidence that altered local and plasma concentrations of gastrin may play a role during the development of various gastric tumors. In the absence of H pylori infection, marked hypergastrinemia frequently results in the development of gastric enterochromaffin cell-like neuroendocrine tumors and surgery to remove the cause of hypergastrinemia may lead to tumor resolution in this condition. In animal models such as transgenic INS-GAS mice, hypergastrinemia has also been shown to act as a cofactor with Helicobacter infection during gastric adenocarcinoma development. However, it is currently unclear as to what extent gastrin also modulates human gastric adenocarcinoma development. Therapeutic approaches targeting hypergastrinemia, such as immunization with G17DT, have been evaluated for the treatment of gastric adenocarcinoma, with some promising results. Although the mild hypergastrinemia associated with proton pump inhibitor drug use has been shown to cause ECL-cell hyperplasia and to increase H pylori-induced gastric atrophy, there is currently no convincing evidence that this class of agents contributes towards the development of gastric neuroendocrine tumors or gastric adenocarcinomas in human subjects.
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Juul-Hansen P, Rydning A. On-demand requirements of patients with endoscopy-negative gastro-oesophageal reflux disease: H2-blocker vs. proton pump inhibitor. Aliment Pharmacol Ther 2009; 29:207-12. [PMID: 19006541 DOI: 10.1111/j.1365-2036.2008.03877.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND It is questionable whether a symptomatic condition with few serious medical consequences requires proton pump inhibitor (PPI) treatment. If effective, a less-potent treatment may be preferable. AIM To compare an H2-blocker in an effervescent formulation with a PPI in on-demand treatment of endoscopy-negative gastro-oesophageal reflux disease (GERD). METHODS Included were patients with heartburn and/or acid regurgitation for at least 3 months duration, a negative endoscopy and a positive response to 7 days of lansoprazole 60 mg daily. Following pH-metry, the patients were randomized to receive either ranitidine effervescent tablets 75 mg or lansoprazole capsules 15 mg to a maximum of four per day on-demand. The numbers taken were registered monthly for 6 months. If treatment was unsuccessful (lack of efficacy or side effects), patients were registered as failures. RESULTS One hundred and three patients were included and 63 were considered for statistical analysis; 32 on lansoprazole and 31 on ranitidine. Seventeen (55%) on ranitidine and four (13%) on lansoprazole failed. The average number of tablets per day was 1.2 in the lansoprazole group and 3.1 in the ranitidine group. CONCLUSIONS On-demand treatment in patients with endoscopy-negative GERD gives a high success rate with a fairly low dose of PPI. The H2-blocker had significantly less success; nevertheless, almost half were satisfied with the treatment.
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Abstract
PURPOSE OF REVIEW This review summarizes the past year's literature regarding the regulation and assessment of gastric acid secretion. RECENT FINDINGS Gastric acid secretion is regulated by biologic agents produced and released by enteroendocrine cells and neurons as well as by exogenously administered substances and infection. Too much acid can lead to gastroesophageal reflux disease, peptic ulcer disease, and stress-related erosion/ulcer disease. Too little acid can interfere with the absorption of certain nutrients, predispose to enteric infection, and interfere with the absorption of some medications. Gastrin, histamine, gastrin-releasing peptide, ghrelin, orexin, and glucocorticoids stimulate whereas leptin, glucagon-like peptide 1, and Helicobacter pylori inhibit acid secretion. Helicobacter pylori inhibits the transcriptional activity of HK-ATPase, the proton pump of the parietal cell. SUMMARY A better understanding of the pathways and mechanisms regulating gastric acid secretion should lead to improved management of patients with acid-induced disorders as well as those who secrete too little acid.
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Abstract
Fundic gland polyps are now commonly recognized during endoscopy. These polyps are benign, often multiple and usually detected in the gastric body and fundus. In the past, these polyps were sometimes associated with familial adenomatous polyposis. In recent years, it has become evident that increasing numbers of these polyps are being detected during endoscopic studies, particularly in patients treated with proton pump inhibitors for prolonged periods. In some, dysplastic changes in these polyps have also been reported. Recent studies have suggested that there may be no increase in risk of colon cancer with long-term proton pump inhibitor therapy. While temporarily reassuring, ongoing vigilance, particularly in those genetically predisposed to colon cancer, is still warranted.
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