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Tacelli M, Gentiluomo M, Biamonte P, Castano JP, Berković MC, Cives M, Kapitanović S, Marinoni I, Marinovic S, Nikas I, Nosáková L, Pedraza-Arevalo S, Pellè E, Perren A, Strosberg J, Campa D, Capurso G. Pancreatic neuroendocrine neoplasms (pNENs): Genetic and environmental biomarkers for risk of occurrence and prognosis. Semin Cancer Biol 2025; 112:112-125. [PMID: 40158764 DOI: 10.1016/j.semcancer.2025.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 03/07/2025] [Accepted: 03/19/2025] [Indexed: 04/02/2025]
Abstract
Pancreatic neuroendocrine neoplasms (pNENs) are rare and heterogeneous tumors arising from neuroendocrine cells, representing approximately 10 % of all Gastro-Entero-Pancreatic neuroendocrine neoplasms. While most pNENs are sporadic, a subset is associated with genetic syndromes such as multiple endocrine neoplasia type 1 (MEN1) or von Hippel-Lindau disease (VHL). pNENs are further classified into functioning and non-functioning tumors, with distinct clinical behaviors, prognoses, and treatment approaches. This review explores genetic and environmental biomarkers that influence the risk, prognosis, and therapeutic responses in pNENs. The epidemiology of pNENs reveals an increasing incidence, primarily due to advancements in imaging techniques. Genetic factors play a pivotal role, with germline mutations in MEN1, VHL, and other genes contributing to familial pNENs. Somatic mutations, including alterations in the mTOR pathway and DNA maintenance genes such as DAXX and ATRX, are critical in sporadic pNENs. These mutations, along with epigenetic dysregulation and transcriptomic alterations, underpin the diverse clinical and molecular phenotypes of pNENs. Emerging evidence suggests that epigenetic changes, including DNA methylation profiles, can stratify pNEN subtypes and predict disease progression. Environmental and lifestyle factors, such as diabetes, smoking, and chronic pancreatitis, have been linked to an increased risk of sporadic pNENs. While the association between these factors and tumor progression is still under investigation, their potential role in influencing therapeutic outcomes warrants further study. Advances in systemic therapies, including somatostatin analogs, mTOR inhibitors, and tyrosine kinase inhibitors, have improved disease management. Biomarkers such as Ki-67, somatostatin receptor expression, and O6-methylguanine-DNA methyltransferase (MGMT) status are being evaluated for their predictive value. Novel approaches, including the use of circulating biomarkers (NETest, circulating tumor cells, and ctDNA) and polygenic risk scores, offer promising avenues for non-invasive diagnosis and monitoring. Despite these advancements, challenges remain, including the need for large, well-annotated datasets and validated biomarkers. Future research should integrate multi-omics approaches and leverage liquid biopsy technologies to refine diagnostic, prognostic, and therapeutic strategies. Interdisciplinary collaborations and global consortia are crucial for overcoming current limitations and translating research findings into clinical practice. These insights hold promise for improving prevention, early detection, and tailored treatments, ultimately enhancing patient outcomes.
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Affiliation(s)
- Matteo Tacelli
- Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | | | - Paolo Biamonte
- Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Justo P Castano
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain; Reina Sofia University Hospital, Córdoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain
| | - Maja Cigrovski Berković
- Department for Sport and Exercise Medicine, Faculty of Kinesiology University of Zagreb, Zagreb 10000, Croatia
| | - Mauro Cives
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy; Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy
| | - Sanja Kapitanović
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb 10000, Croatia
| | - Ilaria Marinoni
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - Sonja Marinovic
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb 10000, Croatia
| | - Ilias Nikas
- Medical School, University of Cyprus, Nicosia, Cyprus
| | - Lenka Nosáková
- Clinic of Internal Medicine - Gastroenterology, JFM CU, Jessenius Faculty of Medicine in Martin (JFM CU), Comenius University in Bratislava, Bratislava, Slovakia
| | - Sergio Pedraza-Arevalo
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain; Reina Sofia University Hospital, Córdoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain
| | - Eleonora Pellè
- Department of GI Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Aurel Perren
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - Jonathan Strosberg
- Department of GI Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Daniele Campa
- Department of Biology, University of Pisa, Pisa, Italy
| | - Gabriele Capurso
- Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, IRCCS Ospedale San Raffaele, Milan, Italy.
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Lyubimova NV, Timofeev YS, Markovich AA, Lebedeva AV, Karamisheva EI, Delektorskaya VV, Kushlinskii NE. Chromogranin B in blood serum of patients with neuroendocrine tumors. Klin Lab Diagn 2022; 67:440-443. [PMID: 36095079 DOI: 10.51620/0869-2084-2022-67-8-440-443] [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: 06/15/2023]
Abstract
Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms from cells of the diffuse neuroendocrine system. Chromogranin B (CgB) is an acidic protein of the granin family, which can be used to detect the tumours of neuroendocrine nature. Analysis of levels and evaluation of the diagnostic efficiency of CgB in the blood serum of patients with NETs of various localizations. Patients with NETs (n=121) without specific treatment were examined. In the study were presented next localizations: 74 - pancreas, 20 - stomach, 12 - large intestine, 15 - other localizations (lungs, mammary gland, prostate gland, NETs with unidentified primary). 54 practically healthy donors were examined as control group. The determination of CgB in blood serum was performed with ELISA method on BEP 2000 analyzer using a standardized test system Human Chromogranin B (USCN, China). CgB levels in common NET group (median 18.9 ng/mL) were statistically significantly higher than in the control group (8.8 ng/mL). The highest median was obtained in group of intestinal NETs (21.2 ng/ml), which exceeded the median of the control group by more than 2.4 times. According to ROC analysis in the common NET group relative to the control group, the area under the curve AUC was 0.88 (95% CI 0.83-0.929). According to cut-off level of CgB - 15.8 ng/ml, the diagnostic sensitivity was 69.4%, with a specificity of 96.3%. The highest diagnostic sensitivity was in the group of the intestinal NETs (75.0%) and pancreas (71.2%). The study showed the significance of CgB as a potential biochemical marker of NETs with various localizations, alternative to CgA.
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Affiliation(s)
| | - Yu S Timofeev
- N.N. Blokhin National Medical Research Center of Oncology
| | - A A Markovich
- N.N. Blokhin National Medical Research Center of Oncology
| | - A V Lebedeva
- N.N. Blokhin National Medical Research Center of Oncology
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Performance Evaluation of the KRYPTOR Compact PLUS Analyzer-Based B.R.A.H.M.S. CgA Ⅱ KRYPTOR Assay for Chromogranin A Measurement. Diagnostics (Basel) 2021; 11:diagnostics11122400. [PMID: 34943638 PMCID: PMC8700334 DOI: 10.3390/diagnostics11122400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/14/2021] [Accepted: 12/17/2021] [Indexed: 12/04/2022] Open
Abstract
Numerous immunoassays have been developed to measure the levels of chromogranin A (CgA), a useful biomarker for diagnosing and monitoring generally heterogeneous neuroendocrine tumors (NETs). Here, we evaluated the imprecision and linearity of three such assays: KRYPTOR (ThermoFisher Scientific), NEOLISA (EuroDiagnostica), and CgA-RIA (CisBio), using 123 samples for each assay. The correlation coefficients between the assays were 0.932 (CgA-RIA versus NEOLISA), 0.956 (KRYPTOR versus CgA-RIA), and 0.873 (NEOLISA versus KRYPTOR). KRYPTOR showed good precision, with percent coefficients of variation less than 5% for low and high concentration quality controls. Linearity was maintained over a wide concentration range. Comparison of CgA levels from three disease entities (NETs, non-NET pancreatic tumors, and prostate cancer) and healthy controls showed that patients with NETs had significantly higher CgA levels (n = 57, mean: 1.82 ± 0.43 log ng/mL) than healthy individuals (n = 20, mean: 1.51 ± 0.23 log ng/mL; p = 0.018). No other significant differences between groups were observed. All three immunoassays showed strong correlations in measured CgA levels. Because KRYPTOR operation uses a fully automated random-access system and requires shorter incubation times and smaller sample volumes, the KRYPTOR assay may improve laboratory workflow while maintaining satisfactory analytical performance.
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Ciobanu OA, Martin S, Fica S. Perspectives on the diagnostic, predictive and prognostic markers of neuroendocrine neoplasms (Review). Exp Ther Med 2021; 22:1479. [PMID: 34765020 PMCID: PMC8576627 DOI: 10.3892/etm.2021.10914] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 09/23/2021] [Indexed: 12/15/2022] Open
Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of rare tumors with different types of physiology and prognosis. Therefore, prognostic information, including morphological differentiation, grade, tumor stage and primary location, are invaluable and contribute to the formulation of treatment decisions. Biomarkers that are currently used, including chromogranin A (CgA), serotonin and neuron-specific enolase, are singular parameters that cannot be used to accurately predict variables associated with tumor growth, including proliferation, metabolic rate and metastatic potential. In addition, site-specific biomarkers, such as insulin and gastrin, cannot be applied to all types of NENs. The clinical application of broad-spectrum markers, as it is the case for CgA, remains controversial despite being widely used. Due to limitations of the currently available mono-analyte biomarkers, recent studies were conducted to explore novel parameters for NEN diagnosis, prognosis, therapy stratification and evaluation of treatment response. Identification of prognostic factors for predicting NEN outcome is a critical requirement for the planning of adequate clinical management. Advances in ‘liquid’ biopsies and genomic analysis techniques, including microRNA, circulating tumor DNA or circulating tumor cells and sophisticated biomathematical analysis techniques, such as NETest or molecular image-based biomarkers, are currently under investigation as potentially novel tools for the management of NENs in the future. Despite these recent findings yielding promising observations, further research is necessary. The present review therefore summarizes the existing knowledge and recent advancements in the exploration of biochemical markers for NENs, with focus on gastroenteropancreatic-neuroendocrine tumors.
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Affiliation(s)
- Oana Alexandra Ciobanu
- Department of Endocrinology and Diabetes, Elias Hospital, 011461 Bucharest, Romania.,Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, 20021 Bucharest, Romania
| | - Sorina Martin
- Department of Endocrinology and Diabetes, Elias Hospital, 011461 Bucharest, Romania.,Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, 20021 Bucharest, Romania
| | - Simona Fica
- Department of Endocrinology and Diabetes, Elias Hospital, 011461 Bucharest, Romania.,Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, 20021 Bucharest, Romania
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Öberg K. Molecular Genomic Blood Biomarkers for Neuroendocrine Tumors: The Long and Winding Road from Berzelius and Bence Jones to a Neuroendocrine Destination. Neuroendocrinology 2021; 111:297-303. [PMID: 32380502 DOI: 10.1159/000508488] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Accepted: 05/06/2020] [Indexed: 12/13/2022]
Affiliation(s)
- Kjell Öberg
- Department of Endocrine Oncology, University Hospital, Uppsala, Sweden,
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Goetz TI, Lang EW, Prante O, Maier A, Cordes M, Kuwert T, Ritt P, Schmidkonz C. Three-dimensional Monte Carlo-based voxel-wise tumor dosimetry in patients with neuroendocrine tumors who underwent 177Lu-DOTATOC therapy. Ann Nucl Med 2020; 34:244-253. [PMID: 32114682 PMCID: PMC7101301 DOI: 10.1007/s12149-020-01440-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 01/20/2020] [Indexed: 01/09/2023]
Abstract
Background Patients with advanced neuroendocrine tumors (NETs) of the midgut are suitable candidates for 177Lu-DOTATOC therapy. Integrated SPECT/CT systems have the potential to help improve the accuracy of patient-specific tumor dosimetry. Dose estimations to target organs are generally performed using the Medical Internal Radiation Dose scheme. We present a novel Monte Carlo-based voxel-wise dosimetry approach to determine organ- and tumor-specific total tumor doses (TTD). Methods A cohort of 14 patients with histologically confirmed metastasized NETs of the midgut (11 men, 3 women, 62.3 ± 11.0 years of age) underwent a total of 39 cycles of 177Lu-DOTATOC therapy (mean 2.8 cycles, SD ± 1 cycle). After the first cycle of therapy, regions of interest were defined manually on the SPECT/CT images for the kidneys, the spleen, and all 198 tracer-positive tumor lesions in the field of view. Four SPECT images, taken at 4 h, 24 h, 48 h and 72 h after injection of the radiopharmaceutical, were used to determine their effective half-lives in the structures of interest. The absorbed doses were calculated by a three-dimensional dosimetry method based on Monte Carlo simulations. TTD was calculated as the sum of all products of single tumor doses with single tumor volumes divided by the sum of all tumor volumes. Results The average dose values per cycle were 3.41 ± 1.28 Gy (1.91–6.22 Gy) for the kidneys, 4.40 ± 2.90 Gy (1.14–11.22 Gy) for the spleen, and 9.70 ± 8.96 Gy (1.47–39.49 Gy) for all 177Lu-DOTATOC-positive tumor lesions. Low- and intermediate-grade tumors (G 1–2) absorbed a higher TTD compared to high-grade tumors (G 3) (signed-rank test, p = < 0.05). The pre-therapeutic chromogranin A (CgA) value and the TTD correlated significantly (Pearson correlation: = 0.67, p = 0.01). Higher TTD resulted in a significant decrease of CgA after therapy. Conclusion These results suggest that Monte Carlo-based voxel-wise dosimetry is a very promising tool for predicting the absorbed TTD based on histological and clinical parameters.
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Affiliation(s)
- Th I Goetz
- Department of Nuclear Medicine, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.,Pattern Recognition Lab, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.,Biophysics, University of Regensburg, Regensburg, Germany
| | - E W Lang
- Biophysics, University of Regensburg, Regensburg, Germany
| | - O Prante
- Department of Nuclear Medicine, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - A Maier
- Pattern Recognition Lab, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - M Cordes
- Department of Nuclear Medicine, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - T Kuwert
- Department of Nuclear Medicine, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - P Ritt
- Department of Nuclear Medicine, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Christian Schmidkonz
- Department of Nuclear Medicine, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany. .,Clinic of Nuclear Medicine, University of Erlangen-Nuremberg, Ulmenweg 18, 91054, Erlangen, Germany.
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Adu-Gyamfi KO, Gyamfi R, Patri S. An unusual case of proton pump inhibitor induced hyperchromograninemia. J Community Hosp Intern Med Perspect 2020; 9:511-514. [PMID: 32002161 PMCID: PMC6968679 DOI: 10.1080/20009666.2019.1682748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 09/18/2019] [Indexed: 11/24/2022] Open
Abstract
Objective: To describe an unusual case of symptomatic hyperchromograninemia associated with proton pump inhibitor (PPI) use. Case Summary: A 55-year-old man with stage 1 follicular lymphoma and GERD on omeprazole presented with symptoms suggesting carcinoid syndrome. The only positive finding on workup was a markedly elevated level of chromogranin A and no carcinoid tumor was identified. Omeprazole was discontinued, following which his symptoms resolved and chromogranin A levels returned to normal. To the best of our knowledge, no symptoms have been previously reported in association with PPI-induced hyperchromograninemia. Discussion: The reliability of chromogranin A as a marker for neuroendocrine tumors is of growing concern. The reasons for the associated symptomatology in this case are unclear but could involve physiologic effects of chromogranin A breakdown products. The role of pharmacogenomics in PPI metabolism is discussed as a potential explanation for the significant hyperchromograninemia. Conclusion: The phenomenon of PPI-induced hyperchromograninemia is highlighted for providers especially in the context of neuroendocrine tumor diagnosis and surveillance. The need for more research into chromogranins is proposed.
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Affiliation(s)
| | | | - Sandeep Patri
- Department of Hospitalist Medicine, HSHS St. Vincent Hospital, Green Bay, WI, USA
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Molecular Profiling of Pheochromocytoma and Abdominal Paraganglioma Stratified by the PASS Algorithm Reveals Chromogranin B as Associated With Histologic Prediction of Malignant Behavior. Am J Surg Pathol 2020; 43:409-421. [PMID: 30451732 DOI: 10.1097/pas.0000000000001190] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Pheochromocytomas (PCCs) and abdominal paragangliomas (PGLs), collectively abbreviated PPGL, are believed to exhibit malignant potential-but only subsets of cases will display full-blown malignant properties. The Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) algorithm is a proposed histologic system to detect potential for aggressive behavior, but little is known regarding the coupling to underlying molecular genetics. In this study, a total of 92 PPGLs, previously characterized for susceptibility gene status and mRNA expressional profiles, were histologically assessed using the PASS criteria. A total of 32/92 PPGLs (35%) exhibited a PASS score ≥4, including all 8 cases with malignant behavior (7 with known metastases and 1 with extensively infiltrative local recurrence). Statistical analyzes between expressional data and clinical parameters as well as individual PASS criteria yielded significant associations to Chromogranin B (CHGB), BRCA2, HIST1H3B, BUB1B, and RET to name a few, and CHGB had the strongest correlation to both PASS and metastasis/local recurrence of all analyzed genes. Evident CHGB downregulation was observed in PPGLs with high PASS and overtly malignant behavior, and was also associated with shorter disease-related survival. This finding was validated using quantitative real-time polymerase chain reaction, in which CHGB expression correlated with both PASS and metastasis/local recurrence with consistent findings obtained in the TCGA cohort. Moreover, immunohistochemical analyses of subsets of tumors showed a correlation between high PASS scores and negative or weak CHGB protein expression. Patients with PPGLs obtaining high PASS scores postoperatively, also exhibited low preoperative plasma levels of CHGB. These data collectively point out CHGB as a possible preoperative and postoperative marker for PPGLs with potential for aggressive behavior.
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Shulman RJ, Öhman L, Stridsberg M, Cain K, Simrén M, Heitkemper M. Evidence of increased fecal granins in children with irritable bowel syndrome and correlates with symptoms. Neurogastroenterol Motil 2019; 31:e13486. [PMID: 30298961 PMCID: PMC6296885 DOI: 10.1111/nmo.13486] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 07/30/2018] [Accepted: 09/07/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND Granins have been implicated in the pathophysiology of irritable bowel syndrome (IBS) in adults. We sought to determine whether fecal granins are altered in children with IBS and associated with symptoms. METHODS Children (7-12 years of age) with IBS and healthy controls (HC) kept daily pain and stool diaries for 2 weeks. Stool samples were analyzed for chromogranins A and B (CgA, CgB) and secretogranins II and III (SgII, SgIII). Children also completed psychological measures to assess anxiety, depression, somatization, and internalizing symptoms. KEY RESULTS Fecal CgB and SgIII concentrations were higher in all the boys (IBS plus HC, n = 48) than in all the girls (IBS plus HC, n = 75) (P = 0.02 and P = 0.046, respectively). CgA and SgIII were greater in children with IBS (n = 52) vs HC (n = 69) (P = 0.01, P = 0.017, respectively). CgB and SgII did not differ between groups. In children with IBS, the number of pain episodes per week and mean daily pain rating correlated positively with all four granins. The number of stools per day correlated positively with CgB and SgII, and the percent of diarrheal stools (6 or 7 on the Bristol Scale) correlated inversely with all four granins in boys but not in girls. Fecal granins did not correlate with psychological measures. CONCLUSIONS AND INFERENCES As measured by fecal granins, there is evidence of neuroimmune activation in children with IBS. Granins are related to abdominal pain symptoms, stooling frequency, and stool form in children with IBS. Sex influences the fecal concentration of CgB and SgIII.
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Affiliation(s)
- Robert J. Shulman
- Children’s Nutrition Research Center, Baylor College of Medicine, Department of Pediatrics, Houston, TX
| | - Lena Öhman
- University of Gothenburg, Göteborg, Sweden
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Fecal chromogranins and secretogranins are linked to the fecal and mucosal intestinal bacterial composition of IBS patients and healthy subjects. Sci Rep 2018; 8:16821. [PMID: 30429499 PMCID: PMC6235916 DOI: 10.1038/s41598-018-35241-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 11/01/2018] [Indexed: 12/22/2022] Open
Abstract
Altered fecal levels of chromogranins (Cg) and secretogranins (Sg) are demonstrated in irritable bowel syndrome (IBS), but their role in IBS pathophysiology remains unknown. This study aimed to determine if granins are associated with bacterial composition, immune activation and IBS symptoms. Protein levels of fecal granins (CgA, CgB, SgII and SgIII) were analysed with immunoassays. Mucosal mRNA expression of granins, TPH1 and immune markers were evaluated with RT-qPCR. 16S rRNA gene sequencing was performed on fecal and mucosal bacteria. The intestinal granin profile, based on fecal protein levels and mucosal mRNA expression, could not discriminate between IBS patients (n = 88) and healthy subjects (HS, n = 33). IBS patients dominated by high fecal or mucosal granin levels, respectively, did not differ in symptom or immune profiles. Fecal-dominated and mucosal-dominated granin clusters of IBS patients and HS, demonstrated separate fecal and mucosal bacterial profiles and high fecal abundance of granins were associated with a less diverse bacterial composition and the Bacteroides enterotype. The intestinal granin profiles of IBS patients and HS are linked to the intestinal bacterial composition, diversity and enterotypes. These findings suggest that granins may be one of several host-produced factors regulating the microbiota composition of the intestine.
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Abstract
Neuroendocrine tumours (NETs) are neoplasms that arise from neuroendocrine cells. Neuroendocrine cells and their tumours can secrete a wide range of amines and polypeptide hormones into the systemic circulation. This feature has triggered widespread investigation into circulating biomarkers for the diagnosis of NETs as well as for the prediction of the biological behaviour of tumour cells. Classic examples of circulating biomarkers for gastroenteropancreatic NETs include chromogranin A, neuron-specific enolase and pancreatic polypeptide as well as hormones that elicit clinical syndromes, such as serotonin and its metabolites, insulin, glucagon and gastrin. Biomarker metrics of general markers for diagnosing all gastroenteropancreatic NET subtypes are limited, but specific hormonal measurements can be of diagnostic value in select cases. In the past decade, methods for detecting circulating transcripts and tumour cells have been developed to improve the diagnosis of patients with NETs. Concurrently, modern scanning techniques and superior radiotracers for functional imaging have markedly expanded the options for clinicians dealing with NETs. Here, we review the latest research on biomarkers in the NET field to provide clinicians with a comprehensive overview of relevant diagnostic biomarkers that can be implemented in dedicated situations.
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Affiliation(s)
- Johannes Hofland
- ENETS Center of Excellence, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, Netherlands.
| | - Wouter T Zandee
- ENETS Center of Excellence, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, Netherlands
| | - Wouter W de Herder
- ENETS Center of Excellence, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, Netherlands
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van Treijen MJC, van Beek DJ, van Leeuwaarde RS, Vriens MR, Valk GD. Diagnosing Nonfunctional Pancreatic NETs in MEN1: The Evidence Base. J Endocr Soc 2018; 2:1067-1088. [PMID: 30202829 PMCID: PMC6125714 DOI: 10.1210/js.2018-00087] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 07/26/2018] [Indexed: 02/07/2023] Open
Abstract
In multiple endocrine neoplasia type 1 (MEN1), nonfunctional pancreatic neuroendocrine tumors (NF-pNETs) are the most frequently diagnosed NETs and a leading cause of MEN1-related death. The high prevalence and malignant potential of NF-pNETs outline the need for an evidence-based screening program, as early diagnosis and timely intervention could reduce morbidity and mortality. Controversies exist regarding the value of several diagnostic tests. This systematic review aims to evaluate current literature and amplify an up-to-date evidence-based approach to NF-pNET diagnosis in MEN1. Three databases were systematically searched on the diagnostic value of biomarkers and imaging modalities. Twenty-seven studies were included and critically appraised (modified Quality Assessment of Diagnostic Accuracy Studies). Another 12 studies, providing data on age-related penetrance and tumor growth, were included to assess the optimal frequency and timing of screening. Based on current literature, biomarkers should no longer play a role in the diagnostic process for NF-pNETs, as accuracies are too low. Studies evaluating the diagnostic value of imaging modalities are heterogeneous with varying risks of bias. For the detection of NF-pNETs, endoscopic ultrasound (EUS) has the highest sensitivity. A combined strategy of EUS and MRI seems to be the most useful. Gallium 68 octreotate-DOTA positron emission tomography-CT could be added if NF-pNETs are diagnosed to identify metastasis. Reported growth rates were generally low, and two distinct phenotypes were observed. Surveillance programs should focus on and be adapted to the presence of substantial growth in NF-pNETs. The optimal age to start screening must yet be determined, as insufficient evidence for an evidence-based recommendation was available.
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Affiliation(s)
- Mark J C van Treijen
- Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Dirk-Jan van Beek
- Department of Endocrine Surgical Oncology, University Medical Center Utrecht, Utrecht, Netherlands
| | | | - Menno R Vriens
- Department of Endocrine Surgical Oncology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Gerlof D Valk
- Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, Netherlands
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13
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Corsello A, Di Filippo L, Massironi S, Sileo F, Dolcetta Capuzzo A, Gemma M, Carlucci C, Cusini C, Colombo B, Dallatomasina A, Franchi GM, Corti A, Manzoni MF. Vasostatin-1: A novel circulating biomarker for ileal and pancreatic neuroendocrine neoplasms. PLoS One 2018; 13:e0196858. [PMID: 29723285 PMCID: PMC5933774 DOI: 10.1371/journal.pone.0196858] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 04/20/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Chromogranin A (CgA) is a plasma biomarker widely used in the follow-up of patients with neuroendocrine neoplasms (NENs). However, its accuracy as a tumor biomarker is relatively low because plasma CgA can increase also in patients with other diseases or in subjects treated with proton-pump inhibitors (PPIs), a class of widely-used drugs. METHODS In the attempt to identify a more reliable biomarker for NENs, we investigated, by ELISA, the circulating levels of full-length CgA (CgA1-439) and of various CgA-derived fragments in 17 patients with ileal or pancreatic NENs, 10 healthy controls, and 21 healthy volunteers before and after treatment with PPIs. RESULTS Patients with ileal or pancreatic NENs showed increased plasma levels of total-CgA and CgA1-76 fragment (vasostatin-1, VS-1) compared to controls [median (25th-75th-percentiles); total-CgA: 1.85 nM (1.01-4.28) vs 0.75 nM (0.52-0.89), p = 0.004; VS-1: 2.76 nM (1.09-7.10) vs 0.29 nM (0.26-0.32), p<0.001, respectively], but not of CgA1-439 or CgA1-373 fragment. VS-1 positively correlated with total-CgA (r = 0.65, p<0.001). The Receiver Operating Characteristic area under the curve was 0.9935 for VS-1 and 0.8824 for total-CgA (p = 0.067). Treatment of patients with somatostatin analogues decreased both total-CgA and VS-1. In contrast, administration of PPIs increased the plasma levels of total-CgA, but not of VS-1. CONCLUSION These findings suggest that plasma VS-1 is a novel biomarker for ileal and pancreatic NENs. Considering that VS-1 is a well-defined fragment not induced by proton-pump inhibitors, this polypeptide might represent a biomarker for NENs diagnosis and follow-up more accurate and easier to standardize than CgA.
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Affiliation(s)
- Andrea Corsello
- Department of General Medicine and Endocrine Tumor Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Luigi Di Filippo
- Department of General Medicine and Endocrine Tumor Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Sara Massironi
- Department of Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Federica Sileo
- Department of General Medicine and Endocrine Tumor Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Anna Dolcetta Capuzzo
- Department of General Medicine and Endocrine Tumor Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Marco Gemma
- Department of Neurointensive Care, San Raffaele Scientific Institute, Milan, Italy
| | - Claudia Carlucci
- Clinical study & Data Management Unit, Haematology Project Foundation, Vicenza, Italy
| | - Claudio Cusini
- Department of General Medicine and Endocrine Tumor Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Barbara Colombo
- Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy
| | - Alice Dallatomasina
- Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy
| | - Giulia Maria Franchi
- Department of General Medicine and Endocrine Tumor Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Angelo Corti
- Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy
- San Raffaele Vita-Salute University, Milan, Italy
| | - Marco Federico Manzoni
- Department of General Medicine and Endocrine Tumor Unit, San Raffaele Scientific Institute, Milan, Italy
- San Raffaele Vita-Salute University, Milan, Italy
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14
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Affiliation(s)
- Arturo Chiti
- Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano
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15
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Georgantzi K, Sköldenberg EG, Stridsberg M, Kogner P, Jakobson Å, Janson ET, Christofferson RHB. Chromogranin A and neuron-specific enolase in neuroblastoma: Correlation to stage and prognostic factors. Pediatr Hematol Oncol 2018; 35:156-165. [PMID: 29737901 DOI: 10.1080/08880018.2018.1464087] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Chromogranin A (CgA) and neuron specific enolase (NSE) are important markers in adult neuroendocrine tumors (NET). Neuroblastoma (NB) has certain neuroendocrine properties. The aim of this study was to correlate blood concentrations of CgA, chromogranin B (CgB), and NSE to prognostic factors and outcome in children with NB. Blood samples from 92 patients with NB, 12 patients with benign ganglioneuroma (GN), 21 patients with non-NB solid tumors, 10 patients with acute leukemias, and 69 healthy children, were analyzed. CgA concentrations were higher in neonates vs. children older than one month in the control group (p < 0.0001), and in neonates with NB vs. the control group (p < 0.01). CgA and NSE concentrations were higher in patients with stages 3 and 4 disease (p < 0.05 and p < 0.05), in patients having tumors with amplification of MYCN (p < 0.05 and p < 0.001), or chromosome 1 p deletion (p < 0.05 and p < 0.05). NSE correlated to the tumor size at diagnosis (p < 0.001) and to tumor related death (p < 0.01) in NB. CgA and NSE concentrations were elevated in patients with NB and especially in those with advanced disease. Both CgA and NSE correlated to genetic markers, while only NSE correlated to primary tumor size and outcome in NB. We found that CgA and NSE are clinically valuable tumor markers in NB and they merit prospective clinical evaluations as such.
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Affiliation(s)
- Kleopatra Georgantzi
- a Department of Women's and Children's Health , Section of Pediatrics, University Children's Hospital , Uppsala , Sweden
| | - Erik G Sköldenberg
- b Department of Women's and Children's Health , Section of Pediatric Surgery, University Children's Hospital , Uppsala , Sweden
| | - Mats Stridsberg
- c Department of Clinical Chemistry , University Hospital , Uppsala , Sweden
| | - Per Kogner
- d Department of Women´s and Children´s Health , Karolinska University Hospital , Solna, Stockholm , Sweden
| | - Åke Jakobson
- a Department of Women's and Children's Health , Section of Pediatrics, University Children's Hospital , Uppsala , Sweden
| | - Eva Tiensuu Janson
- e Department of Medical Sciences , Uppsala University , Uppsala , Sweden
| | - Rolf H B Christofferson
- b Department of Women's and Children's Health , Section of Pediatric Surgery, University Children's Hospital , Uppsala , Sweden
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16
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Ferrari L, Seregni E, Lucignani G, Bajetta E, Martinetti A, Aliberti G, Pallotti F, Procopio G, Torre SD, Luksch R, Bombardieri E. Accuracy and Clinical Correlates of Two Different Methods for Chromogranin A Assay in Neuroendocrine Tumors. Int J Biol Markers 2018. [DOI: 10.1177/172460080401900407] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Measurement of chromogranin A (CgA) plays a major role in the management of neuroendocrine tumors (NET); however, reliable assaying of CgA is made difficult by the rapid hydrolysis following its release into the bloodstream. This study was aimed at the assessment of two assays for CgA in NET patients. CgA was measured in 93 patients by means of an enzyme-linked immunosorbent assay (ELISA) and an immunoradiometric assay (IRMA). The specificity and sensitivity of CgA were evaluated in relation to tumor histology. The clinical accuracy of the two assays was evaluated by receiver-operating characteristic (ROC) curve analysis. Regression analysis demonstrated different immunoreactivity for CgA of the antibodies used in the two kits (r=0.61). The two assays had different accuracy also in classifying patients according to their clinical condition (91% vs 64% specificity and 79% vs 79% sensitivity for the ELISA and IRMA assay, respectively) and tumor histology (81% vs 85% sensitivity for the ELISA and IRMA assays, respectively, in carcinoids; 92% vs 67% sensitivity for the ELISA and IRMA assays, respectively, in pancreatic islet cell tumors). The different clinical accuracy of the two assays was confirmed by the ROC analysis (AUC=0.90 vs AUC=0.87 for the ELISA and IRMA assays, respectively). In conclusion, because of the poor standardization of the commercially available measurement tools the clinical accuracy of CgA measurement depends on the assay used. This makes it difficult to compare CgA values measured with different kits and affects the clinical accuracy of the different assays for CgA.
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Affiliation(s)
- L. Ferrari
- Nuclear Medicine Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan
| | - E. Seregni
- Nuclear Medicine Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan
| | - G. Lucignani
- Institute of Radiological Sciences, University of Milan and Unit of Molecular Imaging, Division of Radiation Therapy, European Institute of Oncology, Milan - Italy
| | - E. Bajetta
- Medical Oncology Unit 2, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan
| | - A. Martinetti
- Nuclear Medicine Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan
| | - G. Aliberti
- Nuclear Medicine Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan
| | - F. Pallotti
- Nuclear Medicine Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan
| | - G. Procopio
- Institute of Radiological Sciences, University of Milan and Unit of Molecular Imaging, Division of Radiation Therapy, European Institute of Oncology, Milan - Italy
| | - S. Della Torre
- Medical Oncology Unit 2, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan
| | - R. Luksch
- Pediatric Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan
| | - E. Bombardieri
- Nuclear Medicine Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan
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17
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Rossi RE, Ciafardini C, Sciola V, Conte D, Massironi S. Chromogranin A in the Follow-up of Gastroenteropancreatic Neuroendocrine Neoplasms: Is It Really Game Over? A Systematic Review and Meta-analysis. Pancreas 2018; 47:1249-1255. [PMID: 30325865 DOI: 10.1097/mpa.0000000000001184] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVES Little is known about chromogranin A (CgA) during follow-up of gastroenteropancreatic neuroendocrine neoplasms. We hypothesized that serial CgA monitoring might be useful for the assessment of tumor progression, and we performed a systematic review of the literature and meta-analysis. METHODS A bibliographical search was performed in PubMed using "chromogranin A" and "neuroendocrine tumors" and "follow-up" and "biomarker" to identify all pertinent articles published in the last 10 years. RESULTS Eight studies were included in current meta-analysis. Chromogranin A as a follow-up marker shows sensitivity between 46% and 100% and specificity between 68% and 90%. The meta-analysis results showed an overall accuracy of 84% (95% confidence interval [CI], 81-86.6), a cumulative sensitivity of 74.6% (95% CI, 61.9-85.4), and a cumulative specificity of 84.7% (95% CI, 81.3-87.7). These data indicate that circulating CgA has a better overall accuracy in the follow-up setting; it can be used to rule the diagnosis of recurrence/progression in, rather than to rule it out. CONCLUSIONS Chromogranin A is more reliable when used to monitor disease progression and response to treatment and for the early detection of recurrence after treatment rather than in the diagnostic setting. It is more sensible to use this marker in those cases where the initial values were impaired.
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Affiliation(s)
- Roberta Elisa Rossi
- From the Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Department of Pathofisiology and Transplantation, Università degli Studi di Milano, Milan, Italy
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18
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Filosso PL, Kidd M, Roffinella M, Lewczuk A, Chung KM, Kolasinska-Cwikla A, Cwikla J, Lowczak A, Doboszynska A, Malczewska A, Catalano M, Zunino V, Boita M, Arvat E, Cristofori R, Guerrera F, Oliaro A, Tesselaar M, Buikhuisen W, Kos-Kudla B, Papotti M, Bodei L, Drozdov I, Modlin I. The utility of blood neuroendocrine gene transcript measurement in the diagnosis of bronchopulmonary neuroendocrine tumours and as a tool to evaluate surgical resection and disease progression†. Eur J Cardiothorac Surg 2017; 53:631-639. [DOI: 10.1093/ejcts/ezx386] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 09/30/2017] [Indexed: 01/04/2023] Open
Affiliation(s)
- Pier Luigi Filosso
- Department of Thoracic Surgery and Department of Oncology, University of Torino, Torino, Italy
| | - Mark Kidd
- Wren Laboratories, Branford, CT, USA
| | - Matteo Roffinella
- Department of Thoracic Surgery and Department of Oncology, University of Torino, Torino, Italy
| | - Anna Lewczuk
- Department of Endocrinology, Medical University of Gdansk, Gdansk, Poland
| | | | | | - Jaroslaw Cwikla
- Department of Radiology, University of Warmia and Mazury, Olsztyn, Poland
| | - Anna Lowczak
- Department of Radiology, University of Warmia and Mazury, Olsztyn, Poland
| | - Anna Doboszynska
- Department of Radiology, University of Warmia and Mazury, Olsztyn, Poland
| | - Anna Malczewska
- Department of Endocrinology, Medical University of Silesia, Katowice, Poland
| | - Maria Catalano
- Department of Thoracic Surgery and Department of Oncology, University of Torino, Torino, Italy
| | - Valentina Zunino
- Department of Thoracic Surgery and Department of Oncology, University of Torino, Torino, Italy
| | - Monica Boita
- Department of Thoracic Surgery and Department of Oncology, University of Torino, Torino, Italy
| | - Emanuela Arvat
- Department of Thoracic Surgery and Department of Oncology, University of Torino, Torino, Italy
| | - Riccardo Cristofori
- Department of Thoracic Surgery and Department of Oncology, University of Torino, Torino, Italy
| | - Francesco Guerrera
- Department of Thoracic Surgery and Department of Oncology, University of Torino, Torino, Italy
| | - Alberto Oliaro
- Department of Thoracic Surgery and Department of Oncology, University of Torino, Torino, Italy
| | - Margot Tesselaar
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Wieneke Buikhuisen
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Beata Kos-Kudla
- Department of Endocrinology, Medical University of Silesia, Katowice, Poland
| | - Mauro Papotti
- Department of Thoracic Surgery and Department of Oncology, University of Torino, Torino, Italy
| | - Lisa Bodei
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Irvin Modlin
- Department of Surgery, Yale University School of Medicine, New Haven, CT, USA
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19
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Abstract
Neuroendocrine cells are widely distributed throughout the body. They can produce, store, and secrete peptides and biogenic amines. Neuroendocrine tumors (NETs) are rare, but most are found in the intestine, pancreas, and lung. NETs may cause specific hormonal symptoms (eg, carcinoid syndrome) or appear nonfunctional. Blood or urine concentrations of tumor-secreted amines and peptides have been used as biomarkers in the diagnosis and management of NETs. This article focuses on currently available biochemical testing of blood or urine for gastroenteropancreatic and lung NETs and discusses the limitations of these tests and the potential role of newer multianalyte markers for NET management.
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Affiliation(s)
- Vidya Aluri
- Division of Endocrinology, University of Iowa, 200 Hawkins Drive, Iowa City, Iowa 52242,
| | - Joseph S. Dillon
- Division of Endocrinology, University of Iowa, 200 Hawkins Drive, Iowa City, Iowa 52242,
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20
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Prognostic and predictive biomarkers in neuroendocrine tumours. Crit Rev Oncol Hematol 2017; 113:268-282. [PMID: 28427516 DOI: 10.1016/j.critrevonc.2017.03.017] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 03/11/2017] [Indexed: 12/19/2022] Open
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21
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Pęczkowska M, Cwikla J, Kidd M, Lewczuk A, Kolasinska-Ćwikła A, Niec D, Michałowska I, Prejbisz A, Januszewicz A, Chiarelli J, Bodei L, Modlin I. The clinical utility of circulating neuroendocrine gene transcript analysis in well-differentiated paragangliomas and pheochromocytomas. Eur J Endocrinol 2017; 176:143-157. [PMID: 27913608 DOI: 10.1530/eje-16-0727] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 10/18/2016] [Accepted: 11/08/2016] [Indexed: 12/18/2022]
Abstract
CONTEXT Paragangliomas and pheochromocytomas (PPGLs) exhibit variable malignancy, which is difficult to determine by histopathology, amine measurements or tissue genetic analyses. OBJECTIVE To evaluate whether a 51-neuroendocrine gene blood analysis has clinical utility as a diagnostic and prognostic marker. DESIGN Prospective cohort study. Well-differentiated PPGLs (n = 32), metastatic (n = 4); SDHx mutation (n = 25); 12 biochemically active, Lanreotide treated (n = 4). Nine patients had multiple sampling. Age- and gender-matched controls and GEP-NETs (comparators). METHODS Circulating neuroendocrine tumor mRNA measured (qPCR) with multianalyte algorithmic analysis. Metabolic, epigenomic and proliferative genes as well as somatostatin receptor expression were assessed (averaged, normalized gene expression: mean ± s.e.m.). Amines were measured by HPLC and chromogranin A by ELISA. Analyses (2-tailed): Fisher's test, non-parametric (Mann-Whitney), receiver-operator curve (ROC) and multivariate analysis (MVA). All data are presented as mean ± s.e.m. RESULTS PPGL were NETest positive (100%). All exhibited higher scores than controls (55 ± 5% vs 8 ± 1%, P = 0.0001), similar to GEP-NETs (47 ± 5%). ROC analysis area under curve was 0.98 for differentiating PPGLs/controls (cut-off for normal: 26.7%). Mutation status was not directly linked to NETest. Genetic and molecular clustering was associated (P < 0.04) with NETest scores. Metastatic (80 ± 9%) and multicentric (64 ± 9%) disease had significantly (P < 0.04) higher scores than localized disease (43 ± 7%). Progressive disease (PD) had the highest scores (86 ± 2%) vs stable (SD, 41 ± 2%) (P < 0.0001). The area under the curve for PD from SD was 0.93 (cut-off for PD: 53%). Proliferation, epigenetic and somatostatin receptor gene expression was elevated (P < 0.03) in PD. Metabolic gene expression was decreased in SDHx mutations. Repeat NETest measurements defined clinical status in the 9 patients (6 SD and 3 PD). Amine measurement was non-informative. Multivariate analysis identified NETest >53% as an independent prognostic factor. CONCLUSION Circulating NET transcript analysis is positive (100% diagnostic) in well-differentiated PCC/PGL, scores were elevated in progressive disease irrespective of mutation or biochemical activity and elevated levels were prognostic.
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Affiliation(s)
| | - J Cwikla
- University of Warmia and MazuryThe Faculty of Medical Sciences, Olsztyn, Poland
| | - M Kidd
- Wren LaboratoriesBranford, Connecticut, USA
| | - A Lewczuk
- Medical University of GdanskGdansk, Poland
| | | | - D Niec
- Institute of CardiologyWarsaw, Poland
| | | | | | | | | | - L Bodei
- Memorial Sloan Kettering Cancer CenterNew York, USA
| | - I Modlin
- Yale University School of MedicineNew Haven, Connecticut, USA
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22
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Clinicopathological Features and Prognostic Factors of Colorectal Neuroendocrine Neoplasms. Gastroenterol Res Pract 2017; 2017:4206172. [PMID: 28194176 PMCID: PMC5282436 DOI: 10.1155/2017/4206172] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 11/10/2016] [Indexed: 12/20/2022] Open
Abstract
Background. Limited research is available regarding colorectal NENs and the prognostic factors remain controversial. Materials and Methods. A total of 68 patients with colorectal NENs were studied retrospectively. Clinical characteristics and prognosis between colonic and rectal NENs were compared. The Cox regression models were used to evaluate the predictive capacity. Results. Of the 68 colorectal NENs patients, 43 (63.2%) had rectal NENs, and 25 (36.8%) had colonic NENs. Compared with rectal NENs, colonic NENs more frequently exhibited larger tumor size (P < 0.0001) and distant metastasis (P < 0.0001). Colonic NENs had a worse prognosis (P = 0.027), with 5-year overall survival rates of 66.7% versus 88.1%. NET, NEC, and MANEC were noted in 61.8%, 23.5%, and 14.7% of patients, respectively. Multivariate analyses revealed that tumor location was not an independent prognostic factor (P = 0.081), but tumor size (P = 0.037) and pathological classification (P = 0.012) were independent prognostic factors. Conclusion. Significant differences exist between colonic and rectal NENs. Multivariate analysis indicated that tumor size and pathological classification were associated with prognosis. Tumor location was not an independent factor. The worse outcome of colonic NENs observed in clinical practice might be due not only to the biological differences, but also to larger tumor size in colonic NENs caused by the delayed diagnosis.
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23
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Pisani LF, Tontini GE, Marinoni B, Villanacci V, Bruni B, Vecchi M, Pastorelli L. Biomarkers and Microscopic Colitis: An Unmet Need in Clinical Practice. Front Med (Lausanne) 2017; 4:54. [PMID: 28540290 PMCID: PMC5423903 DOI: 10.3389/fmed.2017.00054] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Accepted: 04/21/2017] [Indexed: 12/19/2022] Open
Abstract
One of the most common causes of chronic diarrhea is ascribed to microscopic colitis (MC). MC is classified in subtypes: collagenous colitis (CC) and lymphocytic colitis (LC). Patients with MC report watery, non-bloody diarrhea of chronic course, abdominal pain, weight loss, and fatigue that may impair patient's health-related quality of life. A greater awareness, and concomitantly an increasing number of diagnoses over the last years, has demonstrated that the incidence and prevalence of MC are on the rise. To date, colonoscopy with histological analysis on multiple biopsies collected along the colon represents the unique accepted procedure used to assess the diagnosis of active MC and to evaluate the response to medical therapy. Therefore, the emerging need for less-invasive procedures that are also rapid, convenient, standardized, and reproducible, has encouraged scientists to turn their attention to the identification of inflammatory markers and other molecules in blood or feces and within the colonic tissue that can confirm a MC diagnosis. This review gives an update on the biomarkers that are potentially available for the identification of inflammatory activity, related to CC and LC.
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Affiliation(s)
- Laura Francesca Pisani
- Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Gian Eugenio Tontini
- Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Beatrice Marinoni
- Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | | | - Barbara Bruni
- Pathology and Cytodiagnostic Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Maurizio Vecchi
- Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Luca Pastorelli
- Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
- *Correspondence: Luca Pastorelli,
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24
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Valdiglesias V, Maseda A, Lorenzo-López L, Pásaro E, Millán-Calenti JC, Laffon B. Is Salivary Chromogranin A a Valid Psychological Stress Biomarker During Sensory Stimulation in People with Advanced Dementia? J Alzheimers Dis 2016; 55:1509-1517. [DOI: 10.3233/jad-160893] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Vanessa Valdiglesias
- Universidade da Coruña, DICOMOSA Group, Department of Psychology, Area of Psychobiology, A Coruña, Spain
| | - Ana Maseda
- Universidade da Coruña, Gerontology Research Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), SERGAS, A Coruña, Spain
| | - Laura Lorenzo-López
- Universidade da Coruña, Gerontology Research Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), SERGAS, A Coruña, Spain
| | - Eduardo Pásaro
- Universidade da Coruña, DICOMOSA Group, Department of Psychology, Area of Psychobiology, A Coruña, Spain
| | - José C. Millán-Calenti
- Universidade da Coruña, Gerontology Research Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), SERGAS, A Coruña, Spain
| | - Blanca Laffon
- Universidade da Coruña, DICOMOSA Group, Department of Psychology, Area of Psychobiology, A Coruña, Spain
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Abstract
OBJECTIVE Small intestinal neuroendocrine tumors (SI-NETs) are often detected after they have become metastatic. Using a novel protein array, we identified pathways important in SI-NET metastasis development in surgically resected patients. METHODS Paired primary tumors and liver metastases from 25 patients undergoing surgical resection for metastatic SI-NETs were harvested. Extracted proteins were separated by sodium dodecyl sulfate gel and multiplex immunoblots were performed with 136 antibodies. Significant Analysis of Microarray was used to select for differentially expressed proteins. A tissue microarray was constructed from 27 archived specimens and stained by immunohistochemistry. RESULTS Comparing primary SI-NETs with matched normal small-bowel mucosa, 9 proteins were upregulated and cyclin E was downregulated. The SI-NET liver metastases demonstrated upregulation of P-ERK and p27 but downregulation of CDK2 and CDC25B. When comparing primary SI-NET with their paired liver metastases, cyclin E demonstrated a significant upregulation in the liver metastasis. Tissue microarray demonstrated higher p38 expression and lower Cdc 25b expression in SI-NETs versus liver metastases and confirmed higher expression of p27 in liver metastases versus normal liver. CONCLUSIONS Few studies have compared protein expression in paired primary and metastatic SI-NETs. Our findings reveal changes in a limited number of proteins, suggesting that these may be targets for therapy.
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von Hardenberg J, Schwartz M, Werner T, Fuxius S, Müller M, Bolenz C, Weiß C, Heinrich E. Influence of abiraterone acetate on circulating neuromediators in chemotherapy-naïve castration-resistant prostate cancer. Prostate 2016; 76:613-9. [PMID: 26779767 DOI: 10.1002/pros.23152] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2015] [Accepted: 12/31/2015] [Indexed: 01/10/2023]
Abstract
BACKGROUND Abiraterone Acetate (AA) represents a highly effective androgen-receptor (AR) axis targeted agent. Treatment with AA in castration-resistant prostate cancer (CRPC) may partly mediate neuroendocrine differentiation (NED) as an escape mechanism, which may have implications for the choice of sequential therapy in CRPC. We evaluated how treatment with AA influences circulating neuromediators chromogranin A (CGA), neuron-specific enolase (NSE), and pro-gastrin-releasing peptide (Pro-GRP) in chemotherapy-naïve CRPC patients. METHODS We conducted an analysis in chemotherapy-naïve CRPC patients with clinical or radiographic progression of disease. A total of 35 patients were included at five institutions between February 2013 and December 2014. Sixteen of them had received AA. Serum samples were obtained before a docetaxel-based chemotherapy and analyzed in a reference laboratory. Univariable and multivariable analyses were performed to test the influence of AA treatment, its duration of treatment, and other clinicopathological variables on circulating neuromediators. RESULTS CGA and NSE levels were above the upper limit of normal (ULN) in n = 20 (57.1%) and n = 13 (37.1%), respectively. Treatment with AA and duration of treatment were not associated with levels above the ULN (CGA and NSE) or higher levels (Pro-GRP) of neuromediators. CGA levels were associated with age (P = 0.092), lymph node metastasis (P = 0.014), duration of androgen deprivation therapy (ADT; P = 0.083), and intake of proton pump inhibitors (P = 0.069). Pro-GRP levels were significantly associated with PSA levels (P = 0.002). On multivariate analysis, CGA levels above the ULN were significantly correlated with ADT (P = 0.01) and intake of proton pump inhibitors (P = 0.03). CONCLUSIONS Circulating neuromediators in chemotherapy-naïve CRPC patients were elevated in a high percentage of patients. ADT was found to be a relevant NED driver in this cohort. Our results may imply that patients with CRPC after first-line treatment with AA in CRPC are not at a higher risk for developing NED. The major limitation of the study represents the one-time analysis of neuromediators. Larger studies with serial blood measurements or biopsy analysis before and after treatment are needed to confirm our results.
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Affiliation(s)
- Jost von Hardenberg
- Department of Urology, Mannheim Medical Center, University of Heidelberg, Mannheim, Germany
| | - Maike Schwartz
- Department of Urology, Mannheim Medical Center, University of Heidelberg, Mannheim, Germany
| | | | - Stefan Fuxius
- Outpatient Oncology Practice Heidelberg, Heidelberg, Germany
| | - Markus Müller
- Department of Urology, Hospital Ludwigshafen, Ludwigshafen, Germany
| | - Christian Bolenz
- Department of Urology, Mannheim Medical Center, University of Heidelberg, Mannheim, Germany
| | - Christel Weiß
- Department of Medical Statistics, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Elmar Heinrich
- Department of Urology, University Hospital Goettingen, Goettingen, Germany
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Monaghan PJ, Lamarca A, Valle JW, Hubner RA, Mansoor W, Trainer PJ, Darby D. Routine measurement of plasma chromogranin B has limited clinical utility in the management of patients with neuroendocrine tumours. Clin Endocrinol (Oxf) 2016; 84:348-52. [PMID: 26608723 DOI: 10.1111/cen.12985] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 10/16/2015] [Accepted: 11/18/2015] [Indexed: 11/29/2022]
Abstract
OBJECTIVE Chromogranin A (CgA) and B (CgB) are markers for monitoring disease status in patients with gastroenteropancreatic neuroendocrine tumours (NETs). These are specialized diagnostic tests often necessitating referral of specimens to a supraregional assay service (SAS) laboratory for analysis. The aim of this audit was to assess whether measurement of either plasma CgA or CgB alone provides sufficient clinical information in comparison with the current practice of measuring both markers together. DESIGN A retrospective analysis was undertaken for all chromogranin tests requested for patients with a known NET diagnosis. Results were categorized based on whether plasma concentrations were elevated for one or both CgA and CgB. RESULTS A total of 325 sequential patients with a NET diagnosis had plasma chromogranin levels measured during the period of review. Baseline CgA was elevated in 60·9% of patients. Isolated elevations in CgA (with normal CgB) were found in 44·9% of patients, whilst combined elevations in both CgA and CgB were found in 16% of patients. Combined CgA and CgB concentrations within the normal range were observed for 38·5% of patients. Only two patients (0·6%) had an isolated elevation in CgB at baseline. Both patients had a diagnosis of pancreatic NET and were radiologically stable. Plasma CgA and CgB corresponded with disease stage (localized vs metastatic). CgB in addition to CgA did not provide any significant improvement in diagnostic performance for identification of metastatic disease compared to CgA alone. CONCLUSIONS Based on this NET population and specific assay performance characteristics, CgA alone provides sufficient information for the management of NET patients; the routine estimation of CgB in all patients is not informative in clinical practice.
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Affiliation(s)
- P J Monaghan
- The Christie Pathology Partnership, The Christie NHS Foundation Trust, Manchester, UK
| | - A Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust and ENETS Centre of Excellence, Manchester, UK
| | - J W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust and ENETS Centre of Excellence, Manchester, UK
- Institute of Cancer Sciences, University of Manchester, Manchester, UK
| | - R A Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust and ENETS Centre of Excellence, Manchester, UK
| | - W Mansoor
- Department of Medical Oncology, The Christie NHS Foundation Trust and ENETS Centre of Excellence, Manchester, UK
| | - P J Trainer
- Department of Endocrinology, The Christie NHS Foundation Trust, Manchester, UK
- Centre for Endocrinology & Diabetes, Institute of Human Development, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - D Darby
- Department of Clinical Biochemistry, Salford Royal Hospital, Salford, UK
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Abstract
PURPOSE OF REVIEW The review summarizes the utility and limitations of chromogranin A (CgA) as a circulating biomarker for neuroendocrine tumors (NETs). RECENT FINDINGS Blood CgA measurement has numerous clinical limitations including poor assay reproducibility, low sensitivity (meta-analysis: 73%, 95% confidence interval: 0.71-0.76), and a paucity of prospective validation studies. A recent study noted elevation in 27% of NETs with a predictive value of 50% for metastases. These findings are consistent with its efficacy primarily as a monoanalyte secretory rather than multidimensional neoplastic marker. An automated CgA assay (KRYPTOR) exhibits similar metrics to the DAKO assay but is only useful in serum and routine storage diminishes its accuracy. Current studies indicate that CgA is more effective as a biomarker for cardiac disease. Given the diverse limitations of CgA, NET biomarker focus has evolved toward measurement of multiple analytes, for example, transcripts. Multianalyte algorithmic analyses perform significantly better as diagnostic (>95%) and prognostic markers (>90%) than CgA (30-74 and ∼50%, respectively) since they delineate different aspects of the biological behavior of NETs, (e.g., proliferome and metabolome). SUMMARY CgA is neither a reliable nor robust NET biomarker. As a monoanalyte, it is restricted by poor metrics and has limited predictive value. Its current clinical utility appears optimal in cardiovascular disease. The significance of CgA in NET disease is diminishing as other analytical approaches, particularly transcript multianalyte assays or other strategies, evolve to supersede it.
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Affiliation(s)
- Mark Kidd
- aWren Laboratories, Branford, Connecticut, USA bDivision of Nuclear Medicine, European Institute of Oncology, Milan, Italy cSchool of Medicine, Yale University, New Haven, Connecticut, USA
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Salivary function impairment in type 2 Diabetes patients associated with concentration and genetic polymorphisms of chromogranin A. Clin Oral Investig 2016; 20:2083-2095. [PMID: 26750135 DOI: 10.1007/s00784-015-1705-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 12/29/2015] [Indexed: 01/17/2023]
Abstract
OBJECTIVES The purpose of this study was to evaluate the effect of type 2 diabetes mellitus (T2DM) on salivary function impairments according to glycemic control status and subsequently compare the concentration of chromogranin A (CHGA) with its genetic profile. MATERIALS AND METHODS Thirty-six patients with controlled T2DM, 36 with poorly controlled T2DM, and 38 nondiabetic subjects underwent salivary flow rate measurements by means of unstimulated labial (ULS), unstimulated whole (UWS), and stimulated whole saliva (SWS) collections. CHGA concentrations were determined in saliva and plasma with ELISA, and two CHGA polymorphisms (T-415C and Glu264Asp) were analyzed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS T2DM patients presented significantly lower ULS and UWS flow rates regardless of glycemic control status compared to controls (P = 0.002 and P = 0.027, respectively). The SWS flow rate in the poorly controlled T2DM was the lowest among the groups (P = 0.026). Significantly higher plasma and salivary CHGA levels were found in T2DM groups (P = 0.019 and P < 0.001, respectively). CHGA gene variants (T-415C and Glu264Asp) revealed significant differences between diabetics and control subjects when associated with lower salivary flow and higher salivary CHGA production (P < 0.05). CONCLUSIONS T2DM causes abnormalities in the function of salivary glands. However, poorly controlled T2DM has the most influence on SWS flow rates. Our findings indicate an association between plasma and salivary CHGA levels and T2DM patients. Furthermore, the results suggest that CGHA polymorphisms might be associated with salivary gland hypofunction and higher salivary CHGA production in T2DM patients. Nevertheless, further epidemiological studies are required to elucidate this clinical implication. CLINICAL RELEVANCE Salivary impairments and high levels of CHGA are associated with T2DM patients. In addition, CGHA polymorphisms might be associated with salivary gland hypofunction and higher salivary CHGA production in T2DM patients. This could be a significant insight to establish a role for salivary CHGA as a potential clinical biomarker to T2DM.
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Modlin IM, Bodei L, Kidd M. Neuroendocrine tumor biomarkers: From monoanalytes to transcripts and algorithms. Best Pract Res Clin Endocrinol Metab 2016; 30:59-77. [PMID: 26971844 DOI: 10.1016/j.beem.2016.01.002] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The management of neuroendocrine neoplasia remains a perplexing problem because of the lack of knowledge of the biology of the disease, its late presentation, the relative insensitivity of imaging modalities and a paucity of predictably effective treatment options. A critical limitation is posed by the lack of accurate biomarkers to guide management, monitor the efficacy of therapy and provide a prognostic assessment of disease progress. Currently utilized monoanalyte biomarkers (e.g. chromogranin, serotonin, pancreastatin etc.) exhibit variable metrics, poor sensitivity, specificity, and predictive ability and are rarely used to guide clinical decision making. A National Cancer Institute Neuroendocrine Tumor summit conference held in 2007 noted biomarker limitations to be a crucial unmet need in the management of neuroendocrine tumors. Nevertheless little progress has been made in this field until recently with the consideration of blood transcript analysis, circulating tumor cells and miRNA measurement. Given the complexity and multidimensionality of the neoplastic process itself, the heterogeneity of neuroendocrine tumors (NET) as well as the interaction of the tumor microenvironment, it is not unexpected that no single (monoanalyte) biomarker has proven to be effective. This deduction reflects the growing recognition that use of a monoanalyte to define a multidimensional disease process has inherent flaws. Logic dictates that no single measured parameter can capture the pathobiological diversity of neoplasia and monoanalytes cannot define the multiple variables (proliferation, metabolic activity, invasive potential and metastatic propensity) that constitute tumor growth. Thus far, most biomarkers whether in tissue or blood/urine have been single analytes with varying degrees of sensitivity and specificity and in general have failed to exhibit robust metrics or lacked methodological rigor. Neuroendocrine (NE) disease represents an area of biomarker paucity since the individual biomarkers (gastrin, insulin etc) are not widely applicable to the diverse types of NE neoplasia (NEN). Broad spectrum markers such as CgA have limitations in sensitivity, specificity and reproducibility. This review serves to provide a general background of the evolution of NET biomarkers. It provides an assessment of their current and past usage and limitations in assessing their diagnostic, pathologic and prognostic aspects in respect of NET. It provides a view of the changing methodology of biomarker development and the application of biomathematical analyses to redefining detection and treatment. Finally, it presents a description and consensus on current advances in transcript analysis, miRNA measurement and circulating tumor cell identification.
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Affiliation(s)
- Irvin M Modlin
- Emeritus Professor Gastroenterological Surgery, Yale University, School of Medicine, USA.
| | - Lisa Bodei
- Division of Nuclear Medicine, European Institute of Oncology, Milan, Italy
| | - Mark Kidd
- Wren Laboratories, 35 NE Industrial Road, Branford, CT 06405, USA
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Ćwikła JB, Bodei L, Kolasinska-Ćwikła A, Sankowski A, Modlin IM, Kidd M. Circulating Transcript Analysis (NETest) in GEP-NETs Treated With Somatostatin Analogs Defines Therapy. J Clin Endocrinol Metab 2015; 100:E1437-45. [PMID: 26348352 DOI: 10.1210/jc.2015-2792] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
CONTEXT Early and precise delineation of therapeutic responses are key issues in neuroendocrine neoplasm/tumor management. Imaging is currently used but exhibits limitations in sensitivity and specificity. The utility of biomarkers is unclear. objective, setting, and design: This prospective cohort study (11 mo) sought to determine whether measurements of circulating neuroendocrine tumor transcripts (NETest) predict responses to somatostatin analogs (SSAs). PATIENTS The test set consisted of 35 SSA-treated gastroenteropancreatic-NETs (RECISTevaluated). The prospective set consisted of 28 SSA-treated Grade 1-Grade 2 GEP-NETs. INTERVENTION(S) Whole blood for transcript analysis (NETest) and plasma for Chromogranin A (CgA) (baseline), were collected every 4 weeks (prior to SSA injection). Morphologic (multidetector computed tomography/MRI) and functional imaging ((99m)Tc-[HYNIC, Tyr(3)]-Octreotide) was undertaken at entry and 6-month intervals until progression (RECIST 1.0). MAIN OUTCOME MEASURE(S) Treatment response. RESULTS Test set: NETest (≥80%; scale, 0-100%) differentiated stable (SD) and progressive (PD) disease (P < .0001). Prospective set: 28 patients (26/28 SD) undergoing standard SSA. Grading: 12 G1, 16 G2. SSA Response: progression-free survival: 315 days: 14 (50%) SD, 14 (50%) PD. NETest: Twenty had elevated (≥80%) values; 14 developed PD; six, SD. CgA: Twelve of 28 exhibited elevated baseline values and/or subsequent >25% increase; eight developed PD; four, SD. NETest (P = .002) and grade (P = .054) were the only factors associated with treatment response. Multiple regression analysis established that the NETest could predict disease progression (P = .0002). NETest changes occurred significantly earlier (146 d prior to progression vs 56 d CgA; P < .0001; χ(2) = 19) and in more patients (100 vs 57%; P < .02). CONCLUSIONS NETest values (80-100%) were more accurate and occurred at a significantly earlier time point than CgA and predicted SSA treatment response.
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Affiliation(s)
- Jarosław B Ćwikła
- Department of Radiology, Faculty of Medical Sciences (J.Ć.), University of Warmia and Mazury, Olsztyn 10-558, Poland; Division of Nuclear Medicine (L.B.), European Institute of Oncology, Milan 20141, Italy; Department of Oncology (A.K.-Ć.), Maria Skłodowska-Curie Memorial Cancer Center, Institute of Oncology, Warsaw 44-101, Poland; Department of Radiology (A.S.), Hospital Ministry of Internal Affairs, Warsaw 02-507, Poland; Keewaydin Consulting, Inc. (I.M.M.), Woodbridge, Connecticut 06525; and Wren Laboratories (M.K.), Branford, Connecticut 06405
| | - Lisa Bodei
- Department of Radiology, Faculty of Medical Sciences (J.Ć.), University of Warmia and Mazury, Olsztyn 10-558, Poland; Division of Nuclear Medicine (L.B.), European Institute of Oncology, Milan 20141, Italy; Department of Oncology (A.K.-Ć.), Maria Skłodowska-Curie Memorial Cancer Center, Institute of Oncology, Warsaw 44-101, Poland; Department of Radiology (A.S.), Hospital Ministry of Internal Affairs, Warsaw 02-507, Poland; Keewaydin Consulting, Inc. (I.M.M.), Woodbridge, Connecticut 06525; and Wren Laboratories (M.K.), Branford, Connecticut 06405
| | - Agnieszka Kolasinska-Ćwikła
- Department of Radiology, Faculty of Medical Sciences (J.Ć.), University of Warmia and Mazury, Olsztyn 10-558, Poland; Division of Nuclear Medicine (L.B.), European Institute of Oncology, Milan 20141, Italy; Department of Oncology (A.K.-Ć.), Maria Skłodowska-Curie Memorial Cancer Center, Institute of Oncology, Warsaw 44-101, Poland; Department of Radiology (A.S.), Hospital Ministry of Internal Affairs, Warsaw 02-507, Poland; Keewaydin Consulting, Inc. (I.M.M.), Woodbridge, Connecticut 06525; and Wren Laboratories (M.K.), Branford, Connecticut 06405
| | - Artur Sankowski
- Department of Radiology, Faculty of Medical Sciences (J.Ć.), University of Warmia and Mazury, Olsztyn 10-558, Poland; Division of Nuclear Medicine (L.B.), European Institute of Oncology, Milan 20141, Italy; Department of Oncology (A.K.-Ć.), Maria Skłodowska-Curie Memorial Cancer Center, Institute of Oncology, Warsaw 44-101, Poland; Department of Radiology (A.S.), Hospital Ministry of Internal Affairs, Warsaw 02-507, Poland; Keewaydin Consulting, Inc. (I.M.M.), Woodbridge, Connecticut 06525; and Wren Laboratories (M.K.), Branford, Connecticut 06405
| | - Irvin M Modlin
- Department of Radiology, Faculty of Medical Sciences (J.Ć.), University of Warmia and Mazury, Olsztyn 10-558, Poland; Division of Nuclear Medicine (L.B.), European Institute of Oncology, Milan 20141, Italy; Department of Oncology (A.K.-Ć.), Maria Skłodowska-Curie Memorial Cancer Center, Institute of Oncology, Warsaw 44-101, Poland; Department of Radiology (A.S.), Hospital Ministry of Internal Affairs, Warsaw 02-507, Poland; Keewaydin Consulting, Inc. (I.M.M.), Woodbridge, Connecticut 06525; and Wren Laboratories (M.K.), Branford, Connecticut 06405
| | - Mark Kidd
- Department of Radiology, Faculty of Medical Sciences (J.Ć.), University of Warmia and Mazury, Olsztyn 10-558, Poland; Division of Nuclear Medicine (L.B.), European Institute of Oncology, Milan 20141, Italy; Department of Oncology (A.K.-Ć.), Maria Skłodowska-Curie Memorial Cancer Center, Institute of Oncology, Warsaw 44-101, Poland; Department of Radiology (A.S.), Hospital Ministry of Internal Affairs, Warsaw 02-507, Poland; Keewaydin Consulting, Inc. (I.M.M.), Woodbridge, Connecticut 06525; and Wren Laboratories (M.K.), Branford, Connecticut 06405
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Oberg K, Modlin IM, De Herder W, Pavel M, Klimstra D, Frilling A, Metz DC, Heaney A, Kwekkeboom D, Strosberg J, Meyer T, Moss SF, Washington K, Wolin E, Liu E, Goldenring J. Consensus on biomarkers for neuroendocrine tumour disease. Lancet Oncol 2015; 16:e435-e446. [PMID: 26370353 PMCID: PMC5023063 DOI: 10.1016/s1470-2045(15)00186-2] [Citation(s) in RCA: 211] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Revised: 03/24/2015] [Accepted: 03/26/2015] [Indexed: 02/06/2023]
Abstract
Management of neuroendocrine neoplasia represents a clinical challenge because of its late presentation, lack of treatment options, and limitations in present imaging modalities and biomarkers to guide management. Monoanalyte biomarkers have poor sensitivity, specificity, and predictive ability. A National Cancer Institute summit, held in 2007, on neuroendocrine tumours noted biomarker limitations to be a crucial unmet need in the management of neuroendocrine tumours. A multinational consensus meeting of multidisciplinary experts in neuroendocrine tumours assessed the use of current biomarkers and defined the perquisites for novel biomarkers via the Delphi method. Consensus (at >75%) was achieved for 88 (82%) of 107 assessment questions. The panel concluded that circulating multianalyte biomarkers provide the highest sensitivity and specificity necessary for minimum disease detection and that this type of biomarker had sufficient information to predict treatment effectiveness and prognosis. The panel also concluded that no monoanalyte biomarker of neuroendocrine tumours has yet fulfilled these criteria and there is insufficient information to support the clinical use of miRNA or circulating tumour cells as useful prognostic markers for this disease. The panel considered that trials measuring multianalytes (eg, neuroendocrine gene transcripts) should also identify how such information can optimise the management of patients with neuroendocrine tumours.
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Affiliation(s)
- Kjell Oberg
- Department of Medical Sciences, Endocrine Oncology, Uppsala University, Uppsala, Sweden
| | | | - Wouter De Herder
- Section of Endocrinology, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, Netherlands
| | | | - David Klimstra
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - David C Metz
- Division of Gastroenterology, University of Pennsylvania Health System, Philadelphia, PA, USA
| | - Anthony Heaney
- Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Dik Kwekkeboom
- Department of Nuclear Medicine, Erasmus Medical Centre, Rotterdam, Netherlands
| | | | - Timothy Meyer
- University College London Cancer Institute, London, UK
| | - Steven F Moss
- Brown University, Liver Research Center, Providence, RI, USA
| | - Kay Washington
- Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Edward Wolin
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
| | - Eric Liu
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - James Goldenring
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA
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Modlin IM, Kidd M, Bodei L, Drozdov I, Aslanian H. The clinical utility of a novel blood-based multi-transcriptome assay for the diagnosis of neuroendocrine tumors of the gastrointestinal tract. Am J Gastroenterol 2015; 110:1223-32. [PMID: 26032155 DOI: 10.1038/ajg.2015.160] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 04/16/2015] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Current monoanalyte blood-based biomarkers for the diagnosis and follow-up of neuroendocrine tumors (NETs) do not achieve satisfactory metrics of sensitivity and specificity. We report the sensitivity and selectivity of the PCR-based test, the NETest, to detect tumors with reference to other benign and malignant gastrointestinal diseases. METHODS A total of 179 cases (gastrointestinal tumors: n=81; pancreatic disease: n=98) were prospectively collected and assessed using the NETest or chromogranin A (CgA) to determine metrics for detecting small intestinal and pancreatic NETs. RESULTS For intestinal carcinoids, the accuracy of the NETest was 93% (all NETs positive and 3 (12%) colorectal tumors were positive). CgA was positive in 80%, but 29% (n=7) of colorectal cancers were CgA positive. For pancreatic disease, the NETest accuracy was 94% (96% NETs positive, 2 (6%) of intraductal papillary mucinous neoplasms (IPMNs) were positive). The accuracy of CgA was 56% (29% of pancreatic NETs were CgA positive). Overall, the NETest was significantly more sensitive than CgA for the detection of small intestinal (area under the curve 0.98 vs. 0.75 P<0.0001) and pancreatic NETs (0.94 vs. 0.52, P<0.0001). NETest scores were elevated (P<0.05) in extensive disease and were more accurate (76-80%) than CgA levels (20-32%). The metrics of the multianalyte NETest met the performance criteria proposed by the National Institutes of Health for biomarkers, whereas CgA measurement did not. CONCLUSIONS This study demonstrates that a blood-based multianalyte NET gene transcript measurement of well-differentiated small intestinal and pancreatic neuroendocrine tumor disease is sensitive and specific and outperforms the current monoanalyte diagnostic strategy of plasma CgA measurement.
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Affiliation(s)
- I M Modlin
- 1] Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, USA [2] Wren Laboratories, Branford, Connecticut, USA
| | - M Kidd
- Wren Laboratories, Branford, Connecticut, USA
| | - L Bodei
- Division of Nuclear Medicine, European Institute of Oncology (IEO), Milan, Italy
| | - I Drozdov
- Wren Laboratories, Branford, Connecticut, USA
| | - H Aslanian
- Section of Digestive Diseases, Yale University, New Haven, Connecticut, USA
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Yang X, Yang Y, Li Z, Cheng C, Yang T, Wang C, Liu L, Liu S. Diagnostic value of circulating chromogranin a for neuroendocrine tumors: a systematic review and meta-analysis. PLoS One 2015; 10:e0124884. [PMID: 25894842 PMCID: PMC4403810 DOI: 10.1371/journal.pone.0124884] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Accepted: 03/18/2015] [Indexed: 02/07/2023] Open
Abstract
Background In previous decades, chromogranin A (CgA) has been demonstrated to be the most promising biomarker for the diagnosis of neuroendocrine tumors (NETs), but its diagnostic value is still controversial. This meta-analysis aimed to estimate the potential diagnostic value of circulating CgA for NETs. Methods We collected relevant studies from several electronic databases as well as from reference lists. Diagnostic indices of CgA were pooled with random effects models. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and summary receiver operating characteristic (SROC) curves for the diagnosis of NETs were used to estimate the overall diagnostic efficiency. Results Through a search strategy, 13 studies met the inclusion criteria and were included. These studies contained 1260 patients with NETs and 967 healthy controls in the total sample. As a result, the overall sensitivity, specificity and diagnostic odds ratio (DOR) were 0.73 (95% CI: 0.71 to 0.76), 0.95 (95% CI: 0.93 to 0.96) and 56.29 (95% CI: 25.27 to 125.38), respectively, while the summary positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 14.56 (95% CI: 6.62 to 32.02) and 0.26 (95% CI: 0.18 to 0.38), respectively. In addition, the area under the curve (AUC) of the circulating CgA in the diagnosis of NETs was 0.8962. Conclusions These data demonstrate that circulating CgA is an efficient biomarker for the diagnosis of NETs with high sensitivity and specificity, which indicates that it may be helpful for the clinical management of NETs. However, further studies are needed to clarify this issue.
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Affiliation(s)
- Xin Yang
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuan Yang
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhilu Li
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Chen Cheng
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ting Yang
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Cheng Wang
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lin Liu
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shengchun Liu
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- * E-mail:
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Jilesen APJ, Busch ORC, van Gulik TM, Gouma DJ, Nieveen van Dijkum EJM. Standard pre- and postoperative determination of chromogranin a in resectable non-functioning pancreatic neuroendocrine tumors--diagnostic accuracy: NF-pNET and low tumor burden. Dig Surg 2015; 31:407-14. [PMID: 25572908 DOI: 10.1159/000370007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Accepted: 11/16/2014] [Indexed: 01/15/2023]
Abstract
BACKGROUND Chromogranin A (CgA) is often used in metastatic patients with nonfunctioning pancreatic neuroendocrine tumors (NF-pNET). The aim of this study is to assess the diagnostic accuracy of CgA in patients with low tumor burden. METHODS Resectable patients with NF-pNET without metastases at time of diagnosis were included between 2002 and 2013 in the Academic Medical Center of Amsterdam. CgA was determined at time of diagnosis and during follow-up according to a standardized method. The upper reference range was 94 µg/l. RESULTS Overall, 47 patients were included in this study. CgA was elevated preoperatively in only 10 patients (27%). In the detection of metastases during follow-up, the positive predictive value for CgA was 50% and negative predictive value was 81%. In 50% of the patients with an elevated CgA during follow-up, this test result was false-positive. CONCLUSIONS The diagnostic accuracy of CgA was low preoperatively in patients with resectable NF-pNET and low tumor burden. In the detection of recurrent disease after curative resection of NF-pNET, the diagnostic accuracy of CgA was moderate (50%). We conclude that the routine measurement of CgA at time of diagnosis or during follow-up after curative resection had limited value in patients with resectable NF-pNET.
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Kim MK, Warner RRP, Ward SC, Harpaz N, Roayaie S, Schwartz ME, Itzkowitz S, Wisnivesky J. Prognostic significance of lymph node metastases in small intestinal neuroendocrine tumors. Neuroendocrinology 2015; 101:58-65. [PMID: 25572143 PMCID: PMC4403253 DOI: 10.1159/000371807] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Accepted: 12/25/2014] [Indexed: 01/16/2023]
Abstract
BACKGROUND/AIMS Current staging guidelines for small intestinal neuroendocrine tumors (SI-NETs) differentiate between the presence (N1) and absence (N0) of lymph node (LN) metastases. However, the prognostic significance of the extent of LN involvement remains unknown. In this study, we used data from a population-based cancer registry to examine whether involvement of a higher number of LNs is associated with worse survival. METHODS We used the Surveillance, Epidemiology, and End Results (SEER) database to identify patients with histologically confirmed, surgically resected SI-NETS diagnosed between 1988 and 2010. Patients were classified into three groups by the LN ratio (number of positive LNs/number of total LNs examined, LNR): ≤0.2, >0.2-0.5, and >0.5. We used the Kaplan-Meier method and Cox models to assess NET cancer-specific survival differences (up to 10 years from diagnosis) according to LNR status. RESULTS We identified 2,984 surgically resected patients with stage IIIb (N1, M0) SI-NETs with detailed LN data. More than half of the NETs were located in the ileum. A higher LNR was significantly associated with worse NET cancer-specific survival (p < 0.0001). Ten-year NET-specific survival was 85, 77, and 74% for patients in the ≤0.2, >0.2-0.5, and >0.5 LNR groups, respectively. In stratified analyses, higher LNR groups had worse survival only in early tumor (T1, T2) disease (p < 0.0001). CONCLUSIONS The extent of LN involvement provides independent prognostic information on patients with LN-positive SI-NETs. This information may be used to identify patients at high risk of recurrence and inform decisions about the use of adjuvant therapy.
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Affiliation(s)
- Michelle Kang Kim
- Division of Gastroenterology, Department of Medicine, Mount Sinai School of Medicine, New York, N.Y., USA
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Landry CS, Cavaness K, Celinski S, Preskitt J. Biochemical prognostic indicators for pancreatic neuroendocrine tumors and small bowel neuroendocrine tumors. Gland Surg 2014; 3:215-8. [PMID: 25493250 DOI: 10.3978/j.issn.2227-684x.2014.10.01] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Accepted: 10/09/2014] [Indexed: 11/14/2022]
Abstract
Pancreatic neuroendocrine tumors (PNETs) and small bowel neuroendocrine tumors (SBNETs) are rare tumors that are frequently diagnosed late in the course of the disease. Several biomarkers have been proposed in the literature as prognostic factors for patients with these tumors. This article discusses a recent publication in Annals of Surgical Oncology from the University of Iowa analyzing the effect of different biomarkers on survival in patients with PNETs and SBNETs.
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Affiliation(s)
- Christine S Landry
- Department of Surgical Oncology, Baylor University Medical Center, 3410 Worth Street, Suite 235, Dallas, Texas 75246, USA
| | - Keith Cavaness
- Department of Surgical Oncology, Baylor University Medical Center, 3410 Worth Street, Suite 235, Dallas, Texas 75246, USA
| | - Scott Celinski
- Department of Surgical Oncology, Baylor University Medical Center, 3410 Worth Street, Suite 235, Dallas, Texas 75246, USA
| | - John Preskitt
- Department of Surgical Oncology, Baylor University Medical Center, 3410 Worth Street, Suite 235, Dallas, Texas 75246, USA
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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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Grimaldi F, Fazio N, Attanasio R, Frasoldati A, Papini E, Angelini F, Baldelli R, Berretti D, Bianchetti S, Bizzarri G, Caputo M, Castello R, Cremonini N, Crescenzi A, Davì MV, D’Elia AV, Faggiano A, Pizzolitto S, Versari A, Zini M, Rindi G, Öberg K. Italian Association of Clinical Endocrinologists (AME) position statement: a stepwise clinical approach to the diagnosis of gastroenteropancreatic neuroendocrine neoplasms. J Endocrinol Invest 2014; 37:875-909. [PMID: 25038902 PMCID: PMC4159596 DOI: 10.1007/s40618-014-0119-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Accepted: 03/29/2014] [Indexed: 02/07/2023]
Affiliation(s)
- Franco Grimaldi
- Endocrinology and Metabolic Disease Unit, Azienda Ospedaliero-Universitaria “S. Maria della Misericordia”, P.le S.M. della Misericordia, 15-33100, Udine, Italy
| | - Nicola Fazio
- Unit of Gastrointestinal and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy
| | | | - Andrea Frasoldati
- Endocrinology Unit, Arcispedale S. Maria Nuova IRCCS, Reggio Emilia, Italy
| | - Enrico Papini
- Endocrinology Unit, Regina Apostolorum Hospital, Albano Laziale, Rome, Italy
| | - Francesco Angelini
- Oncology and Hematology Unit, Regina Apostolorum Hospital, Albano Laziale, Rome, Italy
| | - Roberto Baldelli
- Endocrinology Section, Regina Elena National Cancer Institute, Rome, Italy
| | - Debora Berretti
- Gastroenterology Unit, Azienda Ospedaliero-Universitaria “S. Maria della Misericordia”, Udine, Italy
| | - Sara Bianchetti
- Oncology and Hematology Unit, Regina Apostolorum Hospital, Albano Laziale, Rome, Italy
| | - Giancarlo Bizzarri
- Diagnostic Imaging Unit, Regina Apostolorum Hospital, Albano Laziale, Rome, Italy
| | - Marco Caputo
- Dipartimento Servizi di Diagnosi e Cura, AUSL 22 Regione Veneto, Bussolengo, VR Italy
| | - Roberto Castello
- Medicina Interna ad indirizzo Endocrinologico, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Nadia Cremonini
- Endocrinology Unit, Maggiore and Bellaria Hospital, Bologna, Italy
| | - Anna Crescenzi
- Pathology Unit, Regina Apostolorum Hospital, Albano Laziale, Rome, Italy
| | - Maria Vittoria Davì
- Medicina Interna D, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Angela Valentina D’Elia
- Genetic Service, Azienda Ospedaliero-Universitaria “S. Maria della Misericordia”, Udine, Italy
| | - Antongiulio Faggiano
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Stefano Pizzolitto
- Pathology Unit, Azienda Ospedaliero-Universitaria “S. Maria della Misericordia”, Udine, Italy
| | - Annibale Versari
- Nuclear Medicine Service, Arcispedale S. Maria Nuova IRCCS, Reggio Emilia, Italy
| | - Michele Zini
- Endocrinology Unit, Arcispedale S. Maria Nuova IRCCS, Reggio Emilia, Italy
| | - Guido Rindi
- Institute of Pathology, Policlinico A. Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Kjell Öberg
- Department of Endocrine Oncology, University Hospital, Uppsala, Sweden
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Modlin IM, Drozdov I, Alaimo D, Callahan S, Teixiera N, Bodei L, Kidd M. A multianalyte PCR blood test outperforms single analyte ELISAs (chromogranin A, pancreastatin, neurokinin A) for neuroendocrine tumor detection. Endocr Relat Cancer 2014; 21:615-28. [PMID: 25015994 DOI: 10.1530/erc-14-0190] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
A critical requirement in neuroendocrine tumor (NET) management is a sensitive, specific and reproducible blood biomarker test. We evaluated a PCR-based 51 transcript signature (NETest) and compared it to chromogranin A (CgA), pancreastatin (PST) and neurokinin A (NKA). The multigene signature was evaluated in two groups: i) a validation set of 40 NETs and controls and ii) a prospectively collected group of NETs (n=41, 61% small intestinal, 50% metastatic, 44% currently treated and 41 age-sex matched controls). Samples were analyzed by a two-step PCR (51 marker genes) protocol and ELISAs for CgA, PST and NKA. Sensitivity comparisons included χ(2), non-parametric measurements, ROC curves and predictive feature importance (PFAI) analyses. NETest identified 38 of 41 NETs. Performance metrics were: sensitivity 92.8%, specificity 92.8%, positive predictive value 92.8% and negative predictive value 92.8%. Single analyte ELISA metrics were: CgA 76, 59, 65, and 71%; PST 63, 56, 59, and 61% and NKA 39, 93, 84, and 60%. The AUCs (ROC analysis) were: NETest: 0.96±0.025, CgA: 0.67±0.06, PST 0.56±0.06, NKA: 0.66±0.06. NETest significantly outperformed single analyte tests (area differences: 0.284-0.403, Z-statistic 4.85-5.9, P<0.0001). PFAI analysis determined NETest had most value (69%) in diagnosis (CgA (13%), PST (9%), and NKA (9%)). Test data were consistent with the validation set (NETest >95% sensitivity and specificity, AUC =0.98 vs single analytes: 59-67% sensitivity, AUCs: 0.58-0.63). The NETest is significantly more sensitive and efficient (>93%) than single analyte assays (CgA, PST or NKA) in NET diagnosis. Blood-based multigene analytic measurement will facilitate early detection of disease recurrence and can predict therapeutic efficacy.
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Affiliation(s)
- Irvin M Modlin
- Wren Laboratories35 NE Industrial Road, Branford, Connecticut 06405, USA
| | - Ignat Drozdov
- Wren Laboratories35 NE Industrial Road, Branford, Connecticut 06405, USA
| | - Daniele Alaimo
- Wren Laboratories35 NE Industrial Road, Branford, Connecticut 06405, USA
| | - Stephen Callahan
- Wren Laboratories35 NE Industrial Road, Branford, Connecticut 06405, USA
| | - Nancy Teixiera
- Wren Laboratories35 NE Industrial Road, Branford, Connecticut 06405, USA
| | - Lisa Bodei
- Wren Laboratories35 NE Industrial Road, Branford, Connecticut 06405, USA
| | - Mark Kidd
- Wren Laboratories35 NE Industrial Road, Branford, Connecticut 06405, USA
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Guillemot J, Guérin M, Thouënnon E, Montéro-Hadjadje M, Leprince J, Lefebvre H, Klein M, Muresan M, Anouar Y, Yon L. Characterization and plasma measurement of the WE-14 peptide in patients with pheochromocytoma. PLoS One 2014; 9:e88698. [PMID: 24523932 PMCID: PMC3921219 DOI: 10.1371/journal.pone.0088698] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2013] [Accepted: 01/09/2014] [Indexed: 02/04/2023] Open
Abstract
Granins and their derived peptides are valuable circulating biological markers of neuroendocrine tumors. The aim of the present study was to investigate the tumoral chromogranin A (CgA)-derived peptide WE-14 and the potential advantage to combine plasma WE-14 detection with the EM66 assay and the existing current CgA assay for the diagnosis of pheochromocytoma. Compared to healthy volunteers, plasma WE-14 levels were 5.4-fold higher in patients with pheochromocytoma, but returned to normal values after surgical resection of the tumor. Determination of plasma CgA and EM66 concentrations in the same group of patients revealed that the test assays for these markers had an overall 84% diagnostic sensitivity, which is identical to that determined for WE-14. However, we found that WE-14 measurement improved the diagnostic sensitivity when combined with the results of CgA or EM66 assays. By combining the results of the three assays, the sensitivity for the diagnosis of pheochromocytoma was increased to 95%. In fact, the combination of WE-14 with either CgA or EM66 test assays achieved 100% sensitivity for the diagnosis of paragangliomas and sporadic or malignant pheochromocytomas if taken separately to account for the heterogeneity of the tumor. These data indicate that WE-14 is produced in pheochromocytoma and secreted into the general circulation, and that elevated plasma WE-14 levels are correlated with the occurrence of this chromaffin cell tumor. In addition, in association with other biological markers, such as CgA and/or EM66, WE-14 measurement systematically improves the diagnostic sensitivity for pheochromocytoma. These findings support the notion that granin-processing products may represent complementary tools for the diagnosis of neuroendocrine tumors.
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Affiliation(s)
- Johann Guillemot
- Institut National de la Santé et de la Recherche Médicale (INSERM), U982, Mont-Saint-Aignan, France
- Normandy University, Normandy, France
- Rouen University, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine (IRIB), Mont-Saint-Aignan, France
- Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada
| | - Marlène Guérin
- Institut National de la Santé et de la Recherche Médicale (INSERM), U982, Mont-Saint-Aignan, France
- Normandy University, Normandy, France
- Rouen University, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine (IRIB), Mont-Saint-Aignan, France
| | - Erwan Thouënnon
- Institut National de la Santé et de la Recherche Médicale (INSERM), U982, Mont-Saint-Aignan, France
- Normandy University, Normandy, France
- Rouen University, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine (IRIB), Mont-Saint-Aignan, France
| | - Maité Montéro-Hadjadje
- Institut National de la Santé et de la Recherche Médicale (INSERM), U982, Mont-Saint-Aignan, France
- Normandy University, Normandy, France
- Rouen University, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine (IRIB), Mont-Saint-Aignan, France
| | - Jérôme Leprince
- Institut National de la Santé et de la Recherche Médicale (INSERM), U982, Mont-Saint-Aignan, France
- Normandy University, Normandy, France
- Rouen University, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine (IRIB), Mont-Saint-Aignan, France
| | - Hervé Lefebvre
- Institut National de la Santé et de la Recherche Médicale (INSERM), U982, Mont-Saint-Aignan, France
- Normandy University, Normandy, France
- Rouen University, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine (IRIB), Mont-Saint-Aignan, France
- Department of Endocrinology, Diabetes and Metabolic Diseases, Rouen University Hospital, Bois-Guillaume, France
| | - Marc Klein
- Department of Endocrinology, Hôpital de Brabois, University of Nancy, Nancy, France
| | - Mihaela Muresan
- Unit of Endocrinology, Hôpital Notre-Dame de Bon Secours, Metz, France
| | - Youssef Anouar
- Institut National de la Santé et de la Recherche Médicale (INSERM), U982, Mont-Saint-Aignan, France
- Normandy University, Normandy, France
- Rouen University, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine (IRIB), Mont-Saint-Aignan, France
| | - Laurent Yon
- Institut National de la Santé et de la Recherche Médicale (INSERM), U982, Mont-Saint-Aignan, France
- Normandy University, Normandy, France
- Rouen University, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine (IRIB), Mont-Saint-Aignan, France
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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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Modlin IM, Oberg K, Taylor A, Drozdov I, Bodei L, Kidd M. Neuroendocrine tumor biomarkers: current status and perspectives. Neuroendocrinology 2014; 100:265-77. [PMID: 25300695 DOI: 10.1159/000368363] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 09/10/2014] [Indexed: 12/20/2022]
Abstract
The identification of accurate harbingers of disease status and therapeutic efficacy are critical requirements in precise diagnosis and effective management. Initially, tissue analysis was regarded as ideal but invasive strategies represent risk compared with peripheral blood sampling. Thus far, most biomarkers, whether in tissue or blood/urine, have been single analytes with varying degrees of sensitivity and specificity. Some analytes have not exhibited robust metrics or have lacked methodological rigor. Neuroendocrine disease represents an area of dire biomarker paucity since the individual biomarkers (gastrin, insulin, etc.) are not widely applicable to the diverse types of neuroendocrine neoplasia. Broad-spectrum markers such as chromogranin A have limitations in sensitivity, specificity and reproducibility. Monoanalytes cannot define the multiple variables (proliferation, metabolic activity, invasive potential, metastatic propensity) that constitute tumor growth. The restricted status of the neuroendocrine neoplasia field has resulted in a lack of comprehensive knowledge of the molecular and cellular biology of the disease, with tardy application of innovative technology. This overview examines limitations in current practice and describes contemporary viable strategies under evaluation, including the identification of novel analytes (gene transcripts, microRNA), circulating tumor cells and metabolic imaging agents that identify disease. Novel requirements are necessary to develop biomathematical algorithms for synchronous calibration of multiple molecular markers and predictive nomograms that interface biological variables to delineate disease progress or treatment efficacy. Optimally, the application of novel techniques and amalgamations of multianalyte assessment will provide a personalized molecular disease signature extrapolative of neuroendocrine neoplasia status and likelihood of progression and predictive of therapeutic opportunity.
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Strid H, Simrén M, Lasson A, Isaksson S, Stridsberg M, Öhman L. Fecal chromogranins and secretogranins are increased in patients with ulcerative colitis but are not associated with disease activity. J Crohns Colitis 2013; 7:e615-22. [PMID: 23694857 DOI: 10.1016/j.crohns.2013.04.019] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Revised: 04/23/2013] [Accepted: 04/23/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Little is known of the importance of chromogranins (Cg) and secretogranins (Sg) in ulcerative colitis (UC). We therefore investigated fecal levels of CgA, CgB, SgII and SgIII, and their association with inflammatory activity, disease duration and medical therapy in UC. METHODS Analyses of CgA, CgB, SgII, SgIII and calprotectin in stool samples from 41 UC patients and 29 healthy controls were performed. Two stool samples, during relapse and remission, respectively, were obtained from each UC patient. RESULTS The levels of fecal CgA and SgII were higher in UC patients with active disease as compared to healthy controls. CgB and SgII were positively correlated with disease duration, but none of the granins were positively correlated with calprotectin, Mayo score, CRP or serum concentrations of TNF in UC patients with active disease. Also UC patients in remission had higher levels of CgA, CgB, SgII, and SgIII as compared to healthy controls. However, levels of fecal CgA, CgB, SgII and SgIII were lower during active disease relative to remission. Moreover, fecal levels of CgA and SgII were higher in UC patients in remission treated with thiopurines than in thiopurine-naïve patients in remission. CONCLUSION Fecal chromogranins and secretogranins are increased in UC but are not associated with disease activity, but seem to increase with duration of the disease. Thus, fecal granins might reflect structural changes associated with chronicity of disease, or medical therapy.
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Affiliation(s)
- Hans Strid
- Dept. of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Sweden
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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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Boškoski I, Volkanovska A, Tringali A, Bove V, Familiari P, Perri V, Costamagna G. Endoscopic resection for gastrointestinal neuroendocrine tumors. Expert Rev Gastroenterol Hepatol 2013; 7:559-69. [PMID: 23985005 DOI: 10.1586/17474124.2013.816117] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Gastrointestinal (GI) and neuroendocrine tumors (NETs) can be treated by mini-invasive endoscopic resection when localized in the superficial layers of the bowel wall and their size is <20 mm. Endoscopic diagnosis of NETs is usually incidental or suspected after clinical, laboratory or imaging findings. Endoscopic mucosal resection is the most commonly used technique for NET removal, endoscopic submucosal dissection is indicated in selected cases, while papillectomy is feasible for ampullary lesions. Histopathologic assessment of the resection margin (circumferential and deep) is important for staging. Incidence of endoscopic mucosal resection-/endoscopic submucosal dissection-related complications for removal of GI NETs are similar to those reported for other GI lesions. Endoscopic follow-up is based on histopathologic characteristics of the resected NETs and its site. NETs >20 mm in size, with penetration of the muscle layer and/or serosa are at high risk for metastases and surgical approach is recommended when feasible.
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Affiliation(s)
- Ivo Boškoski
- Digestive Endoscopy Unit, Gemelli University Hospital, Università Cattolica del Sacro Cuore, Rome, Italy
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Rustagi S, Warner RRP, Divino CM. Serum pancreastatin: the next predictive neuroendocrine tumor marker. J Surg Oncol 2013; 108:126-8. [PMID: 23775817 DOI: 10.1002/jso.23359] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Accepted: 05/14/2013] [Indexed: 01/15/2023]
Abstract
BACKGROUND AND OBJECTIVES Pancreastatin is a derived peptide of chromogranin A (CgA). Pancreastatin has the potential to be a diagnostic and predictive tumor marker in detecting NETs. METHODS Radioimmunoassay tests of pancreastatin and CgA were performed on 103 patient specimens collected at Mount Sinai Medical Center between 1/2010 and 7/2012. Patient demographics, diagnostic tests, surgical procedures, pathologic findings, adjuvant treatments, and survival were retrospectively reviewed. Statistical analysis utilized SPSS v20 software. RESULTS Mean pancreastatin levels were significantly higher in the 92 NETs patients than in the 11 non-NETs patients (227.261 vs. 59.727, P < 0.05). Twenty-seven of the 92 patients with elevated pancreastatin levels (mean = 240.67), had normal CgA levels (mean = 4.65). Pancreastatin had sensitivity and specificity of 64% (59/92), and 100% (11/11). CgA had lower sensitivity and specificity of 43% (40/92), and 64% (7/11). In all 27 instances the pancreastatin concentration was found to be sole indicator of NET disease. When controlling for the level of CgA for the entire sample, a statistically significant difference was not found in the mean pancreastatin levels between both patient groups (P = 0.139, R = 0.484). CONCLUSION Pancreastatin has greater sensitivity and specificity in diagnosing NETs than CgA. Further investigation of pancreastatin's diagnostic and predictive value is warranted.
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Affiliation(s)
- Sapna Rustagi
- Department of Surgery, The Mount Sinai Hospital New York, New York, NY 10029, USA
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Modlin IM, Drozdov I, Kidd M. The identification of gut neuroendocrine tumor disease by multiple synchronous transcript analysis in blood. PLoS One 2013; 8:e63364. [PMID: 23691035 PMCID: PMC3655166 DOI: 10.1371/journal.pone.0063364] [Citation(s) in RCA: 122] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2013] [Accepted: 04/01/2013] [Indexed: 12/21/2022] Open
Abstract
Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are increasing in both incidence and prevalence. A delay in correct diagnosis is common for these lesions. This reflects the absence of specific blood biomarkers to detect NENs. Measurement of the neuroendocrine secretory peptide Chromogranin A (CgA) is used, but is a single value, is non-specific and assay data are highly variable. To facilitate tumor detection, we developed a multi-transcript molecular signature for PCR-based blood analysis. NEN transcripts were identified by computational analysis of 3 microarray datasets: NEN tissue (n = 15), NEN peripheral blood (n = 7), and adenocarcinoma (n = 363 tumors). The candidate gene signature was examined in 130 blood samples (NENs: n = 63) and validated in two independent sets (Set 1 [n = 115, NENs: n = 72]; Set 2 [n = 120, NENs: n = 58]). Comparison with CgA (ELISA) was undertaken in 176 samples (NENs: n = 81). 51 significantly elevated transcript markers were identified. Gene-based classifiers detected NENs in independent sets with high sensitivity (85–98%), specificity (93–97%), PPV (95–96%) and NPV (87–98%). The AUC for the NEN gene-based classifiers was 0.95–0.98 compared to 0.64 for CgA (Z-statistic 6.97–11.42, p<0.0001). Overall, the gene-based classifier was significantly (χ2 = 12.3, p<0.0005) more accurate than CgA. In a sub-analysis, pancreatic NENs and gastrointestinal NENs could be identified with similar efficacy (79–88% sensitivity, 94% specificity), as could metastases (85%). In patients with low CgA, 91% exhibited elevated transcript markers. A panel of 51 marker genes differentiates NENs from controls with a high PPV and NPV (>90%), identifies pancreatic and gastrointestinal NENs with similar efficacy, and confirms GEP-NENs when CgA levels are low. The panel is significantly more accurate than the CgA assay. This reflects its utility to identify multiple diverse biological components of NENs. Application of this sensitive and specific PCR-based blood test to NENs will allow accurate detection of disease, and potentially define disease progress enabling monitoring of treatment efficacy.
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Affiliation(s)
- Irvin M Modlin
- Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, United States of America.
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Wagner M, Stridsberg M, Peterson CGB, Sangfelt P, Lampinen M, Carlson M. Increased Fecal Levels of Chromogranin A, Chromogranin B, and Secretoneurin in Collagenous Colitis. Inflammation 2013; 36:855-61. [DOI: 10.1007/s10753-013-9612-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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[Chromogranin A and neuroendocrine tumors]. ACTA ACUST UNITED AC 2012; 60:386-95. [PMID: 23271036 DOI: 10.1016/j.endonu.2012.10.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Revised: 10/20/2012] [Accepted: 10/23/2012] [Indexed: 11/21/2022]
Abstract
Chromogranin A (CgA) is the most abundant granin in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). As a tumor marker is moderately sensitive and nonspecific. Despite the limitations of testing methods, which require careful interpretation, especially in the case of gastrinomas, patients treated with somatostatin analogues, and poorly differentiated tumors, it is the best tumor marker in GEP-NETs and may be of value in other tumors with neuroendocrine differentiation. CgA may be used as a marker in blood or tissue samples through immunohistochemical techniques. CgA levels correlate with tumor burden and extension and may be used for diagnosis and monitoring of GEP-NETs, especially midgut carcinoids and endocrine pancreatic tumors. It is also useful as a prognostic marker for detection of recurrence and monitoring of response to different treatments.
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