219 results on '"Irvin M."'
Search Results
2. The Search for More Effective Methods of Teaching High School Biology to Slow Learners Through Interaction Analysis, Part I. The Effects of Varying Teaching Patterns
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Citron, Irvin M. and Barnes, Cyrus W.
- Abstract
Presents the procedures, results, and conclusions of a study designed to determine which of several varying patterns of teaching was best for the achievement of the slow learner in a high school biology course (LC)
- Published
- 1970
3. The Search for More Effective Methods of Teaching High-School Biology to Slow Learners Through Interaction Analysis, Part II. The Effects of Various Constant Teaching Patterns
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Citron, Irvin M. and Barnes, Cyrus W.
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Presents the procedures, results, and conclusions of a study designed to determine whether constant patterns of teaching of various kinds over an extended period could affect concept formation, problem solving, and total achievement of slow learners in a high school biology course. (LC)
- Published
- 1970
4. A novel liquid biopsy (NETest) identifies paragangliomas and pheochromocytomas with high accuracy
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Karel Pacak, Mark Kidd, Leah Meuter, and Irvin M. Modlin
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Cancer Research ,medicine.medical_specialty ,biology ,Receiver operating characteristic ,business.industry ,Endocrinology, Diabetes and Metabolism ,Neuroendocrine tumors ,medicine.disease ,biology.organism_classification ,Gastroenterology ,Pheochromocytoma ,Pheos ,Endocrinology ,Oncology ,Paraganglioma ,Internal medicine ,Blood assay ,medicine ,Biomarker (medicine) ,Liquid biopsy ,business - Abstract
Pheochromocytomas and paragangliomas (PHEOs/PGLs) represent diagnostically challenging and complex neuroendocrine tumors (NETs). Current biomarker tests for PHEOs/PGLs are technically complex or limited. We assessed the diagnostic utility of a NET-specific 51-marker gene blood assay (NETest) in patients with PHEOs/PGLs (n = 81), including ten pediatric patients, and age-/gender-matched controls (n = 142) using a prospective case:control (1:2) analysis. mRNA was measured (qPCR), and results were scaled from 0 to 100 (upper limit of normal < 20). Receiver operating curve (ROC) and non-parametric (Mann–Whitney) tests were used for analyses (two-tailed). All data are presented as mean ± s.e.m. NETest accuracy for PHEO/PGL diagnosis was 100%. PHEO/PGL scores were 70 ± 3 vs 8.5 ± 1 in controls (P < 0.0001), and ROC analysis was 0.99 ± 0.004 (P < 0.0001). Diagnostic metrics were 94% accurate, 100% sensitive, and 92% specific. Imaging correlation with 68Ga-PET-SSA was 100%. NETest levels in PHEOs (n = 26) were significantly (P < 0.0001) elevated (83 ± 4) vs 66 ± 4 in PGLs (n = 40) and mixed PHEOs/PGLs (n = 5: 37 ± 3). Adrenal-derived tumors (n = 30) exhibited higher scores (76 ± 5) than extra-adrenal-derived tumors (66 ± 4, P < 0.05). Cluster 2 tumors exhibited significantly (P = 0.034) elevated NETest levels (n = 4: 92 ± 2) vs cluster 1 tumors (n = 35: 69 ± 4). Regulatory pathway analysis identified elevated RAS-RAF, metastatic, pluripotential, neural and secretory gene cluster levels (P < 0.05) in PHEOs compared to PGLs. Cluster 2 PPGLs exhibited elevated (P = 0.046) levels of growth factor signaling genes compared to cluster 1. The PHEOs/PGLs in the pediatric cohort (n = 10) were all NETest-positive (81 ± 8) and exhibited a gene expression profile spectrum analogous to adults. Circulating NET transcript analysis identifies PHEOs/PGLs with 100% efficacy and is likely to have clinical utility in the diagnosis and management of PHEO/PGL patients.
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- 2021
5. Circulating biomarkers of gastroenteropancreatic and lung neuroendocrine neoplasms: 'The times they are a changin'
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Mark Kidd, Irvin M. Modlin, Kjell Öberg, Lisa Bodei, Alexandra Kitz, and Anna Malczewska
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Lung ,biology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Chromogranin A ,030209 endocrinology & metabolism ,Disease ,Neuroendocrine tumors ,medicine.disease ,03 medical and health sciences ,Tumor Status ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Internal medicine ,Radionuclide therapy ,medicine ,biology.protein ,Liquid biopsy ,business ,Progressive disease - Abstract
Biomarkers that are secretory monoanalyte products of gastroenteropancreatic and bronchopulmonary or lung neuroendocrine tumors (NETs) have significant limitations in clinical utility. The assessment of secretory activity provides little information in regard to tumor biology. Furthermore, ∼50% of NETs have measurable secretory products. Molecular genomic identification in blood (NETest liquid biopsy) of the regulators of tumor biology provide multianalyte, real-time assessment of tumor status. These data represent the assessment of ∼2000 NETs over 5 years and demonstrate the NETest has ∼95% accuracy in GEP-NET andbronchopulmonary neuroendocrine tumor diagnosis, is >90% concordant with imaging, and is 90% accurate in differentiating stable from progressive disease. The comparable metrics for Chromogranin A are all ∼50%. In addition, the NETest identifies complete surgical resection in 100% and has a 98% efficacy in monitoring peptide receptor radionuclide therapy efficacy. Real-time liquid biopsy assessment of NET disease provides a noninvasive, accurate strategy to define the NET patient journey. “The times they are a changin”….
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- 2021
6. An Assessment of Circulating Chromogranin A as a Biomarker of Bronchopulmonary Neuroendocrine Neoplasia: A Systematic Review and Meta-Analysis
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Anna Malczewska, Somer Matar, Beata Kos-Kudła, Kjell Öberg, Irvin M Modlin, Lisa Bodei, and Mark Kidd
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Oncology ,endocrine system ,medicine.medical_specialty ,Lung Neoplasms ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Neuroendocrine tumors ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Biomarkers, Tumor ,Humans ,Medicine ,Lung cancer ,Prospective cohort study ,biology ,Endocrine and Autonomic Systems ,business.industry ,Chromogranin A ,Retrospective cohort study ,medicine.disease ,Neuroendocrine Tumors ,Systematic review ,Meta-analysis ,biology.protein ,Biomarker (medicine) ,business - Abstract
Background: Management of bronchopulmonary neuroendocrine neoplasia (NEN; pulmonary carcinoids [PCs], small-cell lung cancer [SCLC], and large cell neuroendocrine carcinoma) is hampered by the paucity of biomarkers. Chromogranin A (CgA), the default neuroendocrine tumor biomarker, has undergone wide assessment in gastroenteropancreatic neuroendocrine tumors. Objectives: To evaluate CgA in lung NEN, define its clinical utility as a biomarker, assess its diagnostic, prognostic, and predictive efficacy, as well as its accuracy in the identification of disease recurrence. Methods: A systematic review of PubMed was undertaken using the preferred reporting items for systematic reviews and meta-analyses guidelines. No language restrictions were applied. Overall, 33 original scientific papers and 3 case reports, which met inclusion criteria, were included in qualitative analysis, and meta-analysis thereafter. All studies, except 2, were retrospective. Meta-analysis statistical assessment by generic inverse variance methodology. Results: Ten different CgA assay types were reported, without consistency in the upper limit of normal (ULN). For PCs (n = 16 studies; median patient inclusion 21 [range 1–200, total: 591 patients]), the CgA diagnostic sensitivity was 34.5 ± 2.7% with a specificity of 93.8 ± 4.7. CgA metrics were not available separately for typical or atypical carcinoids. CgA >100 ng/mL (2.7 × ULN) and >600 ng/mL (ULN unspecified) were anecdotally prognostic for overall survival (n = 2 retrospective studies). No evidence was presented for predicting treatment response or identifying post-surgery residual disease. For SCLC (n = 19 studies; median patient inclusion 23 [range 5–251, total: 1,241 patients]), the mean diagnostic sensitivity was 59.9 ± 6.8% and specificity 79.4 ± 3.1. Extensive disease typically exhibited higher CgA levels (diagnostic accuracy: 61 ± 2.5%). An elevated CgA was prognostic for overall survival (n = 4 retrospective studies). No prospective studies evaluating predictive benefit or prognostic utility were identified. Conclusion: The available data are scarce. An assessment of all published data showed that CgA exhibits major limitations as an effective and accurate biomarker for either PC or SCLC. Its utility especially for localized PC/limited SCLC (when surgery is potentially curative), is limited. The clinical value of CgA remains to be determined. This requires validated, well-constructed, multicenter, prospective, randomized studies. An assessment of all published data indicates that CgA does not exhibit the minimum required metrics to function as a clinically useful biomarker for lung NENs.
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- 2019
7. Blood Chromogranin A Is Not Effective as a Biomarker for Diagnosis or Management of Bronchopulmonary Neuroendocrine Tumors/Neoplasms
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Matteo Roffinella, Agnieszka Kolasińska-Ćwikła, Lisa Bodei, Beata Kos-Kudła, Anna Malczewska, Anna Lewczuk-Myślicka, Somer Matar, Pier Luigi Filosso, Irvin M. Modlin, Alejandro L Suarez, Ignat Drozdov, Jarosław B. Ćwikła, Mark Kidd, Harry R. Aslanian, and Kjell Öberg
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Adult ,Male ,endocrine system ,medicine.medical_specialty ,Lung Neoplasms ,Adolescent ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Carcinoid Tumor ,Disease ,Neuroendocrine tumors ,Gastroenterology ,Article ,030218 nuclear medicine & medical imaging ,Young Adult ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Idiopathic pulmonary fibrosis ,0302 clinical medicine ,Endocrinology ,Stable Disease ,Internal medicine ,Biomarkers, Tumor ,Humans ,Medicine ,Aged ,Aged, 80 and over ,Lung ,biology ,Receiver operating characteristic ,Endocrine and Autonomic Systems ,business.industry ,Chromogranin A ,Middle Aged ,Prognosis ,medicine.disease ,Neuroendocrine Tumors ,medicine.anatomical_structure ,biology.protein ,Biomarker (medicine) ,Female ,business - Abstract
Background: Identification of circulating tumor markers for clinical management in bronchopulmonary (BP) neuroendocrine tumors/neoplasms (NET/NEN) is of considerable clinical interest. Chromogranin A (CgA), a “universal” NET biomarker, is considered controversial as a circulating biomarker of BPNEN. Aim: Assess utility of CgA in the diagnosis and management of BPNEN in a multicentric study. Material and Methods: CgA diagnostic metrics were assessed in lung NET/NENs (n = 200) and controls (n = 140), randomly assigned to a Training and Test set (100 BPC and 70 controls in each). Assay specificity was evaluated in neoplastic lung disease (n = 137) and nonneoplastic lung disease (n = 77). CgA efficacy in predicting clinical status was evaluated in the combined set of 200 NET/NENs. CgA levels in bronchopulmonary neuroendocrine tumor (BPNET) subtypes (atypical [AC] vs. typical [TC]) and grade was examined. The clinical utility of an alteration of CgA levels (±25%) was evaluated in a subset of 49 BPNET over 12 months. CgA measurement was by NEOLISATM kit (EuroDiagnostica). Results: Sensitivity and specificity in the training set were 41/98%, respectively. Test set data were 42/87%. Training set area under receiver operator characteristic analysis differentiated BPC from control area under the curve (AUC) 0.61 ± 0.05 p = 0.015. Test set the data were AUC 0.58 ± 0.05, p = 0.076. In the combined set (n = 200), 67% BPNET/NEN (n = 134) had normal CgA levels. CgA levels did not distinguish histological subtypes (TC vs. AC, AUC 0.56 ± 0.04, p = 0.21), grade (p = 0.45–0.72), or progressive from stable disease (AUC 0.53 ± 0.05 p = 0.47). There was no correlation of CgA with Ki-67 index (Pearson r = 0.143, p = 0.14). For nonneoplastic diseases (chronic obstructive pulmonary disorder and idiopathic pulmonary fibrosis), CgA was elevated in 26–37%. For neoplastic disease (NSCLC, squamous cell carcinoma), CgA was elevated in 11–16%. The neuroendocrine SCLC also exhibited elevated CgA (50%). Elevated CgA was not useful for differentiating BPNET/NEN from these other pathologies. Monitoring BPNET/NEN over a 12-month period identified neither CgA levels per se nor changes in CgA were reflective of somatostatin analog treatment outcome/efficacy or the natural history of the disease (progression). Conclusions: Blood CgA levels are not clinically useful as a biomarker for lung BPNET/NEN. The low specificity and elevations in both nonneoplastic as well as other common neoplastic lung diseases identified limited clinical utility for this biomarker.
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- 2019
8. Treatment of advanced gastroenteropancreatic neuroendocrine neoplasia, are we on the way to personalised medicine?
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Rita T. Lawlor, Marianne Pavel, Christoph J. Auernhammer, Halfdan Sorbye, Aldo Scarpa, Thomas M. Gress, Matthias M. Weber, Lisa Bodei, Irvin M. Modlin, Sebastian Krug, Anja Rinke, Mark Kidd, Ilaria Marinoni, and Aurel Perren
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0301 basic medicine ,medicine.medical_treatment ,cancer genetics ,Neuroendocrine tumors ,Bioinformatics ,chemotherapy ,Molecular oncology ,Epigenesis, Genetic ,03 medical and health sciences ,0302 clinical medicine ,molecular oncology ,Stomach Neoplasms ,Intestinal Neoplasms ,Biomarkers, Tumor ,medicine ,Humans ,immunotherapy ,neuroendocrine tumors ,Epigenetics ,Precision Medicine ,610 Medicine & health ,business.industry ,Gastroenterology ,Immunotherapy ,medicine.disease ,Pancreatic Neoplasms ,Radiation therapy ,Clinical trial ,030104 developmental biology ,Targeted drug delivery ,030220 oncology & carcinogenesis ,570 Life sciences ,biology ,Identification (biology) ,business - Abstract
Gastroenteropancreatic neuroendocrine neoplasia (GEPNEN) comprises clinically as well as prognostically diverse tumour entities often diagnosed at late stage. Current classification provides a uniform terminology and a Ki67-based grading system, thereby facilitating management. Advances in the study of genomic and epigenetic landscapes have amplified knowledge of tumour biology and enhanced identification of prognostic and potentially predictive treatment subgroups. Translation of this genomic and mechanistic biology into advanced GEPNEN management is limited. ‘Targeted’ treatments such as somatostatin analogues, peptide receptor radiotherapy, tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors are treatment options but predictive tools are lacking. The inability to identify clonal heterogeneity and define critical oncoregulatory pathways prior to therapy, restrict therapeutic efficacy as does the inability to monitor disease status in real time. Chemotherapy in the poor prognosis NEN G3 group, though associated with acceptable response rates, only leads to short-term tumour control and their molecular biology requires delineation to provide new and more specific treatment options.The future requires an exploration of the NEN tumour genome, its microenvironment and an identification of critical oncologic checkpoints for precise drug targeting. In the advance to personalised medical treatment of patients with GEPNEN, clinical trials need to be based on mechanistic and multidimensional characterisation of each tumour in order to identify the therapeutic agent effective for the individual tumour.This review surveys advances in NEN research and delineates the current status of translation with a view to laying the basis for a genome-based personalised medicine management of advanced GEPNEN.
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- 2021
9. OMIC gene cluster evaluation amplifies the prognostic accuracy of the NETest
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Irvin M. Modlin, Ignat Drozdov, Mark Kidd, and Alexandra Kitz
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Gene cluster ,Computational biology ,Biology - Published
- 2020
10. Neuroendocrine Tumor Omic Gene Cluster Analysis Amplifies the Prognostic Accuracy of the NETest
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Mark Kidd, Ignat Drozdov, Alexandra Kitz, and Irvin M Modlin
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Oncology ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Neuroendocrine tumors ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Endocrinology ,Predictive Value of Tests ,Internal medicine ,medicine ,Metabolome ,Biomarkers, Tumor ,Cluster Analysis ,Humans ,Survival analysis ,biology ,Endocrine and Autonomic Systems ,Cancer ,Epigenome ,medicine.disease ,Omics ,Prognosis ,Neuroendocrine Tumors ,Ki-67 ,biology.protein ,Biological Assay ,Transcriptome ,Progressive disease ,Follow-Up Studies - Abstract
Background: The NETest is a multigene assay comprising 51 circulating neuroendocrine tumor (NET)-specific transcripts. The quotient of the 51-gene assay is based upon an ensemble of machine learning algorithms. Eight cancer hallmarks or “omes” (apoptome, epigenome, growth factor signalome, metabolome, proliferome, plurome, secretome, SSTRome) represent 29 genes. The NETest is an accurate diagnostic (>90%) test, but its prognostic utility has not been assessed. In this study, we describe the expansion of the NETest omic cluster components and demonstrate that integration amplifies NETest prognostic accuracy. Methods: Group 1: n = 222; including stable disease (SD, n = 146), progressive disease (PD, n = 76), and controls (n = 139). Group 2: NET Registry NCT02270567; n = 88; prospective samples (SD, n = 54; PD, n = 34) with up to 24 months follow-up. We used PubMed literature review, interactomic analysis, nonparametric testing, Kaplan-Meier survival curves, and χ2 analyses to inform and define the prognostic significance of NET genomic “hallmarks.” Results: 2020 analyses: In-depth analyses of 47 NETest genes identified a further six omes: fibrosome, inflammasome, metastasome, NEDome, neurome, and TFome. Group 1 analysis: Twelve omes, excluding the inflammasome and apoptome, were significantly (p < 0.05, 2.1- to 8.2-fold) elevated compared to controls. In the PD group, seven omes (proliferome, NEDome, epigenome, SSTRome, neurome, metastasome, and fibrosome) were elevated (both expression levels and fold change >2) versus SD. Group 2 analysis: All these seven omes were upregulated. In PD, they were significantly more elevated (p < 0.02) than in SD. The septet omic expression exhibited a 69% prognostic accuracy. The NETest alone was 70.5% accurate. A low NETest (≤40) integrated with epigenome/metastasome levels was an accurate prognostic for PD (90%). A high NETest (>40) including the fibrosome/NEDome predicted PD development within 3 months (100%). Using decision tree analysis to integrate the four omes (epigenome, metastasome, fibrosome, and NEDome) with the NETest score generated an overall prognostic accuracy of 93%. Conclusions: Examination of NETest omic gene cluster analysis identified five additional clinically relevant cancer hallmarks. Identification of seven omic clusters (septet) provides a molecular pathological signature of disease progression. The integration of the quartet (epigenome, fibrosome, metastasome, NEDome) and the NETest score yielded a 93% accuracy in the prediction of future disease status.
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- 2020
11. [Untitled]
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Mark Kidd, Anna Malczewska, Somer Matar, Irvin M. Modlin, Ignat Drozdov, Kyung-Min Chung, and Lisa Bodei
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Oncology ,medicine.medical_specialty ,biology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Chromogranin A ,030209 endocrinology & metabolism ,Diagnostic accuracy ,Neuroendocrine tumors ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,030220 oncology & carcinogenesis ,Internal medicine ,Therapeutic assessment ,medicine ,biology.protein ,Biomarker (medicine) ,Clinical registry ,Liquid biopsy ,business - Abstract
The neuroendocrine neoplasms test (NETest) is a multianalyte liquid biopsy that measures neuroendocrine tumor gene expression in blood. This unique signature precisely defines the biological activity of an individual tumor in real time. The assay meets the 3 critical requirements of an optimal biomarker: diagnostic accuracy, prognostic value, and predictive therapeutic assessment. NETest performance metrics are sensitivity and specificity and in head-to-head comparison are 4-fold to 10-fold more accurate than chromogranin A. NETest accurately identifies completeness of surgery and response to somatostatin analogs. Clinical registry data demonstrate significant clinical utility in watch/wait programs.
- Published
- 2018
12. Measurement of circulating transcript levels (NETest) to detect disease recurrence and improve follow-up after curative surgical resection of well-differentiated pancreatic neuroendocrine tumors
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Irvin M. Modlin, Ignat Drozdov, Cansu Guney Genc, Els J. M. Nieveen van Dijkum, Anna Malczewska, Heinz-Josef Klümpen, Anneke P. J. Jilesen, Casper H.J. van Eijck, Mark Kidd, Surgery, AGEM - Digestive immunity, CCA - Imaging and biomarkers, Oncology, and AGEM - Endocrinology, metabolism and nutrition
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Male ,medicine.medical_specialty ,030209 endocrinology & metabolism ,Neuroendocrine tumors ,Logistic regression ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Biomarkers, Tumor ,Blood test ,Humans ,Lymph node ,Aged ,Retrospective Studies ,medicine.diagnostic_test ,Receiver operating characteristic ,biology ,business.industry ,Area under the curve ,Chromogranin A ,Cell Differentiation ,General Medicine ,Middle Aged ,medicine.disease ,Pancreatic Neoplasms ,Neuroendocrine Tumors ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Surgery ,Female ,Neoplasm Recurrence, Local ,business ,Pancreas - Abstract
Background: Recurrence of pancreatic neuroendocrine tumors (pNET) after surgery is common. Strategies to detect recurrence have limitations. We investigated the role of clinical criteria and the multigene polymerase chain reaction–based NETest during post-operative follow-up of pNET. Methods: We studied 3 groups of resections: R0 with no recurrence (n = 11), R0 with recurrence (n = 12), and R1 with no recurrence (n = 12). NETest levels (>40%) were compared with chromogranin A (CgA) and clinicopathological criteria (CC; grade, lymph node metastases, size). Nonparametric, receiver operating characteristics, logistic regression, and predictive feature importance analyses were performed. Results: NETest was higher in R0 with recurrence (56 ± 8%) compared with R1 with no recurrence (39 ± 6%) and R0 with no recurrence (28 ± 6%, P
- Published
- 2018
13. Molecular strategies in the management of bronchopulmonary and thymic neuroendocrine neoplasms
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Mark Kidd, Irvin M. Modlin, Margot E T Tesselaar, Ignat Drozdov, Kyung-Min Chung, Matteo Roffinella, Agnieska Kolasinska-Cwikla, Jarosław B. Ćwikła, Anna Lewczuk, Lisa Bodei, and Pier Luigi Filosso
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,biology ,business.industry ,Somatostatin receptor ,medicine.medical_treatment ,Cell of origin ,Chromogranin A ,Review Article ,Bioinformatics ,Targeted therapy ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Enterochromaffin cell ,biology.protein ,medicine ,Biomarker (medicine) ,Epigenetics ,business ,Survival rate - Abstract
Thoracic NETs [bronchopulmonary NETs (BPNETs) and thymic NETs (TNET)] share a common anatomic primary location, likely a common cell of origin, the “Kulchitsky cell” and presumably, a common etiopathogenesis. Although they are similarly grouped into well-differentiated [typical carcinoids (TC) and atypical carcinoids (AC)] and poorly differentiated neoplasms and both express somatostatin receptors, they exhibit a wide variation in clinical behavior. TNETs are more aggressive, are frequently metastatic, and have a lower 5-year survival rate (~50% vs. ~80%) than BPNETs. They are typically symptomatic, most often secreting ACTH (40% of tumors) but both tumor groups share secretion of common biomarkers including chromogranin A and 5-HIAA. Consistently effective and accurate circulating biomarkers are, however, currently unavailable. Surgery is the primary therapeutic tool for both BPNET and TNETs but there remains little consensus about later interventions e.g., targeted therapy, or how these can be monitored. Genetic analyses have identified different topographies (e.g., significant alterations in chromatin and epigenetic remodeling in BPNETs versus frequent chromosomal abnormalities in TNETs) but there is an absence of clinically actionable mutations in both tumor groups. Liquid biopsies, tools that can measure neoplastic signatures in peripheral blood, can potentially be leveraged to detect disease early i.e., recurrence, predict tumors that may respond to specific therapies and serve as real-time monitors for treatment responses. Recent studies have identified that mRNA transcript analysis in blood effectively identifies both BPNET and TNETs. The clinical utility of this gene expression assay includes use as a diagnostic, confirmation of completeness of surgical resection and use as a molecular management tool to monitor efficacy of PRRT and other therapeutic strategies.
- Published
- 2017
14. The clinical utility of circulating neuroendocrine gene transcript analysis in well-differentiated paragangliomas and pheochromocytomas
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Aleksander Prejbisz, Mark Kidd, Ilona Michałowska, Irvin M. Modlin, Lisa Bodei, Anna Lewczuk, Joseph Chiarelli, Andrzej Januszewicz, Mariola Pęczkowska, Agnieska Kolasinska-Cwikla, Dawid Niec, and Jarosław B. Ćwikła
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Adult ,Oncology ,medicine.medical_specialty ,Multivariate analysis ,Adolescent ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Context (language use) ,Pheochromocytoma ,Lanreotide ,Malignancy ,Paraganglioma ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Pregnancy ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Prospective Studies ,Receptors, Somatostatin ,Child ,Prospective cohort study ,biology ,business.industry ,Chromogranin A ,General Medicine ,Middle Aged ,medicine.disease ,Neuroendocrine Tumors ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,Female ,Histopathology ,business ,Progressive disease - 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 P P P 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.
- Published
- 2017
15. Chromogranin A
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Irvin M. Modlin, Lisa Bodei, and Mark Kidd
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Oncology ,endocrine system ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Neuroendocrine tumors ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Biomarkers, Tumor ,Internal Medicine ,medicine ,Humans ,Nutrition and Dietetics ,biology ,business.industry ,Chromogranin A ,medicine.disease ,Neuroendocrine Tumors ,Circulating biomarkers ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Biomarker (medicine) ,030211 gastroenterology & hepatology ,business - Abstract
The review summarizes the utility and limitations of chromogranin A (CgA) as a circulating biomarker for neuroendocrine tumors (NETs).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).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.
- Published
- 2016
16. Blood measurement of neuroendocrine gene transcripts defines the effectiveness of operative resection and ablation strategies
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Ronald R. Salem, Daniele Alaimo, Lei Weng, Stephen Callahan, Lisa Bodei, Irvin M Modlin, Nancy S. Teixeira, Omar Faiz, Panagiotis Drymousis, Mark Kidd, Andrea Frilling, Ignat Drozdov, and Harpreet Wasan
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Adult ,Male ,medicine.medical_specialty ,Transcription, Genetic ,medicine.medical_treatment ,030209 endocrinology & metabolism ,Neuroendocrine tumors ,Polymerase Chain Reaction ,Gastroenterology ,Resection ,Disease activity ,03 medical and health sciences ,0302 clinical medicine ,Stomach Neoplasms ,Cytoreduction Surgical Procedures ,Internal medicine ,Intestinal Neoplasms ,Biomarkers, Tumor ,medicine ,Humans ,Embolization ,Gene transcript ,Aged ,Aged, 80 and over ,biology ,business.industry ,Chromogranin A ,Middle Aged ,medicine.disease ,Ablation ,Surgery ,Pancreatic Neoplasms ,Neuroendocrine Tumors ,Curative treatment ,030220 oncology & carcinogenesis ,biology.protein ,Female ,Neoplasm Recurrence, Local ,business ,After treatment ,Genes, Neoplasm - Abstract
Surgery is the only curative treatment for gastroenteropancreatic neuroendocrine tumors (GEP-NETs), but the prediction of residual disease/recurrence is limited in the absence of optimal biomarkers. We examined whether a blood-based multianalyte neuroendocrine gene transcript assay (NETest) would define tumor cytoreduction and therapeutic efficacy.The NETest is a polymerase chain reaction-based analysis of 51 genes. Disease activity is scaled 0-100%; minimal14%, low 14-47%, and high47%. A total of 35 GEP-NETs in 2 groups were evaluated. I: after surgery (R0, n = 15; residual, n = 12); II: nonsurgery (n = 8: embolization with gel-foam alone [bland: n = 3]), transarterial chemoembolization (n = 2), and radiofrequency embolization (n = 3). Measurement (quantitative real-time-polymerase chain reaction) and chromogranin A (CgA; enzyme-linked immunosorbent assay) were undertaken preoperatively and 1 month after treatment.NETest score was increased in 35 (100%) preoperatively; 14 (40%) had increased CgA (χ(2) = 30, P2 × 10(-8)). Resection reduced NETest from 80 ± 5% to 29% ± 5, (P.0001). CgA decrease was insignificant (14.3 ± 1.6 U/L to 12.2 ± 1.7 U/L). NETest decreases correlated with diminished tumor volume (R(2) = 0.29, P = .03). Cytoreduction significantly reduced NETest from 82 ± 3% to 41% ± 6, P.0001). CgA was not decreased (21.4 ± 5.5 U/L to 18.4 ± 10.1 U/L). Four (36%) of 11 R0s with increased NETest at 1 month developed positive imaging (sensitivity 100%, specificity 20%). One hundred percent (ablated group) were transcript- and image-positive.Blood NET transcripts delineate surgical resection/cytoreduction and facilitate identification of residual disease.
- Published
- 2016
17. Measurement of circulating transcripts and gene cluster analysis predicts and defines therapeutic efficacy of peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors
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Richard P. Baum, Mark Kidd, Stefano Severi, Sylvia Nicolini, Eric P. Krenning, Lisa Bodei, Irvin M. Modlin, Giovanni Paganelli, Ignat Drozdov, Dik J. Kwekkeboom, and Radiology & Nuclear Medicine
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Male ,Oncology ,Pathology ,Octreotide ,Neuroendocrine tumors ,0302 clinical medicine ,68Ga-PET ,Nuclear Medicine and Imaging ,Gene cluster ,NETest ,Cluster Analysis ,Gene Regulatory Networks ,Chromogranin ,Gene transcripts ,Neuroendocrine tumor ,PRRT ,Radiology, Nuclear Medicine and Imaging ,Aged, 80 and over ,biology ,Somatostatin receptor ,Chromogranin A ,General Medicine ,Middle Aged ,Neuroendocrine Tumors ,Treatment Outcome ,030220 oncology & carcinogenesis ,Metabolome ,Female ,Radiology ,medicine.drug ,Adult ,medicine.medical_specialty ,Receptors, Peptide ,030209 endocrinology & metabolism ,NO ,03 medical and health sciences ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,RNA, Messenger ,Grading (tumors) ,Aged ,Receiver operating characteristic ,business.industry ,medicine.disease ,Radionuclide therapy ,biology.protein ,Radiopharmaceuticals ,business - Abstract
Background Peptide receptor radionuclide therapy (PRRT) is an effective method for treating neuroendocrine tumors (NETs). It is limited, however, in the prediction of individual tumor response and the precise and early identification of changes in tumor size. Currently, response prediction is based on somatostatin receptor expression and efficacy by morphological imaging and/or chromogranin A (CgA) measurement. The aim of this study was to assess the accuracy of circulating NET transcripts as a measure of PRRT efficacy, and moreover to identify prognostic gene clusters in pretreatment blood that could be interpolated with relevant clinical features in order to define a biological index for the tumor and a predictive quotient for PRRT efficacy. Methods NET patients (n = 54), M: F 37:17, median age 66, bronchial: n = 13, GEP-NET: n = 35, CUP: n = 6 were treated with Lu-177-based-PRRT (cumulative activity: 6.5-27.8 GBq, median 18.5). At baseline: 47/54 low-grade (G1/G2; bronchial typical/atypical), 31/49 (18)FDG positive and 39/54 progressive. Disease status was assessed by RECIST1.1. Transcripts were measured by real-time quantitative reverse transcription PCR (qRT-PCR) and multianalyte algorithmic analysis (NETest); CgA by enzyme-linked immunosorbent assay (ELISA). Gene cluster (GC) derivations: regulatory network, protein:protein interactome analyses. Statistical analyses: chi-square, non-parametric measurements, multiple regression, receiver operating characteristic and Kaplan-Meier survival. Results The disease control rate was 72 %. Median PFS was not achieved (follow-up: 1-33 months, median: 16). Only grading was associated with response (p < 0.01). At baseline, 94 % of patients were NETest-positive, while CgA was elevated in 59 %. NETest accurately (89 %, chi(2) = 27.4; p = 1.2 x 10(-7)) correlated with treatment response, while CgA was 24 % accurate. Gene cluster expression (growth-factor signalome and metabolome) had an AUC of 0.74 +/- 0.08 (z-statistic = 2.92, p < 0.004) for predicting response (76 % accuracy). Combination with grading reached an AUC: 0.90 +/- 0.07, irrespective of tumor origin. Circulating transcripts correlated accurately (94 %) with PRRT responders (SD+PR+CR; 97 %) vs. non-responders (91 %). Conclusions Blood NET transcript levels and the predictive quotient (circulating gene clusters+grading) accurately predicted PRRT efficacy. CgA was non-informative.
- Published
- 2015
18. Circulating Transcript Analysis (NETest) in GEP-NETs Treated With Somatostatin Analogs Defines Therapy
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Mark Kidd, Lisa Bodei, Irvin M. Modlin, Artur Sankowski, Agnieszka Kolasińska-Ćwikła, and Jarosław B. Ćwikła
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Adult ,Male ,medicine.medical_specialty ,Antineoplastic Agents, Hormonal ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Octreotide ,Context (language use) ,Neuroendocrine tumors ,Digestive System Neoplasms ,Biochemistry ,Cohort Studies ,Endocrinology ,Internal medicine ,Biomarkers, Tumor ,Humans ,Medicine ,Prospective Studies ,Progression-free survival ,Prospective cohort study ,Aged ,Neoplasm Staging ,Aged, 80 and over ,biology ,business.industry ,Biochemistry (medical) ,Chromogranin A ,Middle Aged ,medicine.disease ,Survival Analysis ,Tumor Burden ,Neuroendocrine Tumors ,Cross-Sectional Studies ,Somatostatin ,Response Evaluation Criteria in Solid Tumors ,biology.protein ,Female ,Drug Monitoring ,Neoplasm Grading ,business ,Follow-Up Studies ,medicine.drug - 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 (99mTc-[HYNIC, Tyr3]-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; χ2 = 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.
- Published
- 2015
19. Inefficacy of chromogranin a assays as neuroendocrine tumor diagnostic tools compared to the NETest
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Irvin M. Modlin, Alexandra Kitz, Beata Kos-Kudła, Mark Kidd, and Anna Malczewska
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Oncology ,Cancer Research ,medicine.medical_specialty ,biology ,business.industry ,Chromogranin A ,Disease ,Diagnostic tools ,Internal medicine ,medicine ,biology.protein ,business ,Monitoring tool - Abstract
4612 Background: Chromogranin A (CgA) remains a commonly used diagnostic and monitoring tool for neuroendocrine tumor disease despite NCCN guidelines identifying it as a category 3 (major concerns about utility) biomarker. Several commercial assays have been developed to measure this protein (or its fragments) and are available both at CLIA-certified laboratories (USA) as well as in NET Centres of Excellence (CoEs - Europe). CgA is typically reimbursed by insurance companies and appears in several guidelines (e.g., ENETS). We sought to directly evaluate the accuracy of detecting NET disease using two different CgA assays, one in the USA (NEOLISA, EuroDiagnostica, IBL-America, CLIA-certified laboratory) and one in an ENETS CoE (CgA ELISA, Demeditec Diagnostics, Germany). We compared the results to the NETest, a circulating mRNA assay, recently validated as an IVD for NETs. Methods: Patients: NETs ( n=258) including lung: n=43; duodenum n=9; gastric: n=44; pancreas: n=67; small bowel: n=40; appendix: n=10; rectum: n=45. No image-evidence of disease ( n=122) (IND) and image-positive disease (IPD) ( n=136). CgA assays (plasma): NEOLISA, ULN >108ng/ml, DD: ULN>99ng/ml. Data mean±SEM. NETest (whole blood): qRT-PCR - multianalyte algorithmic analyses, CLIA-laboratory. All samples de-identified and assessed blinded. Statistics: Mann-Whitney U-test, Pearson correlation & McNemar-test. Results: In the entire group ( n=258), NEOLISA assay CgA levels were significantly ( p2=15.04, p
- Published
- 2020
20. A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors
- Author
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Shereen Ezzat, Anil K. Rustgi, Stuart L. Schreiber, Kay Washington, Arul M. Chinnaiyan, Andrew L. Kung, Elena V. Komissarova, Charles Karan, Beatrice S. Knudsen, Diane Reidy-Lagunes, Daniel Diolaiti, Zhong Li, Irvin M. Modlin, Roberto Bergamaschi, Andrea Frilling, Jakob Regberg, David C. Metz, Filemon S. Dela Cruz, Deepti Dhall, Douglas A. Fraker, Emer Leahy, Ülo Langel, Ronald Realubit, Laura H. Tang, Stefano Serra, Afshin Ghavami, Prem S. Subramaniam, Antonia R. Sepulveda, Tony Detre, Lisa Bodei, Jeffrey W. Milsom, Xiaopu Yuan, Mark Kidd, Andrea Califano, Daniel Kaemmerer, Kyoung Mi Kim, Young Suk Park, Mariano J. Alvarez, Paul A. Clemons, Elizabeth A. Hagan, Robert E. Roses, Helen Remotti, Jeeyun Lee, Hai Li, Roswitha Pfragner, Massimo Barberis, Merten Hommann, Virginia A. LiVolsi, Allison R. Rainey, Michelle K. Kim, Adina Grunn, Gabrielle E. Rieckhof, Chanjuan Shi, Bertram Wiedenmann, Hee C. Kim, Dirk Jaeger, Lakshmi P. Kunju, Mahalaxmi Aburi, and Dr. Heinz-Horst Deichmann Stiftung
- Subjects
0301 basic medicine ,Pyridines ,Antineoplastic Agents ,Neuroendocrine tumors ,Biology ,Malignancy ,Histone Deacetylases ,Article ,Transcriptome ,Cohort Studies ,03 medical and health sciences ,chemistry.chemical_compound ,In vivo ,Stomach Neoplasms ,Cell Line, Tumor ,Intestinal Neoplasms ,Genetics ,medicine ,Humans ,Precision Medicine ,Pancreas ,Progenitor ,Entinostat ,11 Medical And Health Sciences ,06 Biological Sciences ,medicine.disease ,Gastrointestinal Tract ,Histone Deacetylase Inhibitors ,Pancreatic Neoplasms ,Neuroendocrine Tumors ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Cell culture ,Benzamides ,Cancer research ,Developmental Biology - Abstract
We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology.
- Published
- 2018
21. Blood measurements of Neuroendocrine Tumor (NET) transcripts and gene cluster analysis predict efficacy of PRRT
- Author
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Mark Kidd, Lisa Bodei, Richard P. Baum, Irvin M. Modlin, der Zwaan Wouter van, Ignat Drozdov, Eric Krenning, and Dik Kwekkeboom
- Subjects
Gene cluster ,Computational biology ,Biology - Published
- 2017
22. Gene transcript analysis blood values correlate with Ga-68-DOTA-somatostatin analog (SSA) PET/CT imaging in neuroendocrine tumors and can define disease status
- Author
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Dik J. Kwekkeboom, Valentina Ambrosini, Lisa Bodei, Stefano Severi, Giovanni Paganelli, Mark Kidd, Eric P. Krenning, Irvin M. Modlin, Ignat Drozdov, Vikas Prasad, Richard A. Baum, Bodei, L., Kidd, M., Modlin, I.M., Prasad, V., Severi, S., Ambrosini, V., Kwekkeboom, D.J., Krenning, E.P., Baum, R.P., Paganelli, G., Drozdov, I., and Radiology & Nuclear Medicine
- Subjects
Oncology ,endocrine system ,medicine.medical_specialty ,Concordance ,Standardized uptake value ,68Ga-SSA PET ,Chromogranin A ,Gene transcripts ,MORF4L2 ,NETest ,Neuroendocrine ,Radiology, Nuclear Medicine and Imaging ,Medicine (all) ,Neuroendocrine tumors ,NO ,Nuclear Medicine and Imaging ,Internal medicine ,medicine ,Radiology, Nuclear Medicine and imaging ,biology ,medicine.diagnostic_test ,business.industry ,General Medicine ,medicine.disease ,Gene transcript ,Positron emission tomography ,Radionuclide therapy ,biology.protein ,Biomarker (medicine) ,Radiology ,business ,Nuclear medicine ,Progressive disease - Abstract
Purpose Precise determination of neuroendocrine tumor (NET) disease status and response to therapy remains a rate-limiting concern for disease management. This reflects limitations in biomarker specificity and resolution capacity of imaging. In order to evaluate biomarker precision and identify if combinatorial blood molecular markers and imaging could provide added diagnostic value, we assessed the concordance between Ga-68-somatostatin analog (SSA) positron emission tomography (PET), circulating NET gene transcripts (NETest), chromogranin A (CgA), and Ki-67 in NETs. Methods We utilized two independent patient groups with positive Ga-68-SSA PET: data set 1 (Ga-68-SSA PETs undertaken for peptide receptor radionuclide therapy (PRRT), as primary or salvage treatment, n = 27) and data set 2 (Ga-68-SSA PETs performed in patients referred for initial disease staging or restaging after various therapies, n = 22). We examined the maximum standardized uptake value (SUVmax), circulating gene transcripts, CgA levels, and baseline Ki-67. Regression analyses, generalized linear modeling, and receiver-operating characteristic (ROC) analyses were undertaken to determine the strength of the relationships. Results SUVmax measured in two centers were mathematically evaluated (regression modeling) and determined to be comparable. Of 49 patients, 47 (96 %) exhibited a positive NETest. Twenty-six (54 %) had elevated CgA (chi(2) = 20.1, p < 2.5x10(-6)). The majority (78 %) had Ki-67 < 20 %. Gene transcript scores were predictive of imaging with > 95 % concordance and significantly correlated with SUVmax (R (2) = 0.31, root-mean-square error = 9.4). The genes MORF4L2 and somatostatin receptors SSTR1, 3, and 5 exhibited the highest correlation with SUVmax. Progressive disease was identified by elevated levels of a quotient of MORF4L2 expression and SUVmax [ROC-derived AUC (R (2) = 0.7, p < 0.05)]. No statistical relationship was identified between CgA and Ki-67 and no relationship with imaging parameters was evident. Conclusion Ga-68-SSA PET imaging parameters (SUVmax) correlated with a circulating NET transcript signature. Disease status could be predicted by an elevated quotient of gene expression (MORF4L2) and SUVmax. These observations provide the basis for further exploration of strategies that combine imaging parameters and disease-specific molecular data for the improvement of NET management.
- Published
- 2015
23. 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
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Irvin M. Modlin, Margot E T Tesselaar, Alberto Oliaro, Ignat Drozdov, Riccardo Carlo Cristofori, Agnieszka Kolasińska-Ćwikła, Anna Malczewska, Kyung-Min Chung, Monica Boita, Anna Lowczak, Francesco Guerrera, Valentina Zunino, Anna Lewczuk, Jarosław B. Ćwikła, Maria Graziella Catalano, Mauro Papotti, Lisa Bodei, Emanuela Arvat, Matteo Roffinella, Wieneke A. Buikhuisen, Mark Kidd, Pier Luigi Filosso, Anna Doboszyńska, and Beata Kos-Kudła
- Subjects
Male ,Pathology ,Lung Neoplasms ,Thoracic ,Gastroenterology ,0302 clinical medicine ,Lung surgery ,Aged, 80 and over ,medicine.diagnostic_test ,biology ,Area under the curve ,Chromogranin A ,General Medicine ,Middle Aged ,Neuroendocrine Tumors ,medicine.anatomical_structure ,Bronchopulmonary neuroendocrine tumours ,Carcinoid ,Neuroendocrine tumour multigene blood test ,Surgery ,Pulmonary and Respiratory Medicine ,Cardiology and Cardiovascular Medicine ,030220 oncology & carcinogenesis ,Disease Progression ,Adenocarcinoma ,Female ,Adult ,medicine.medical_specialty ,030209 endocrinology & metabolism ,03 medical and health sciences ,Young Adult ,Predictive Value of Tests ,Internal medicine ,medicine ,Carcinoma ,Biomarkers, Tumor ,Blood test ,Humans ,RNA, Messenger ,Aged ,Retrospective Studies ,Lung ,business.industry ,medicine.disease ,biology.protein ,business ,Progressive disease ,Blood sampling - Abstract
OBJECTIVES The management of bronchopulmonary neuroendocrine tumours (BPNETs) is difficult, since imaging, histology and biomarkers have a limited value in diagnosis, predicting outcome and defining therapeutic efficacy. We evaluated a NET multigene blood test (NETest) to diagnose BPNETs, assess disease status and evaluate surgical resection. METHODS (i) Diagnostic cohort: BP carcinoids (n = 118)-typical carcinoid, n = 67 and atypical carcinoid, n = 51; other lung NEN (large-cell neuroendocrine carcinoma and small-cell lung carcinoma, n = 13); adenocarcinoma, (n = 26); squamous cell carcinoma (n = 23); controls (n = 90) and chronic obstructive pulmonary disease (n = 18). (ii) Surgical cohort, n = 28: BP carcinoids (n = 16: typical carcinoid 12; atypical carcinoid 4); large-cell neuroendocrine carcinoma, n = 3; lung adenocarcinoma, n = 8 and squamous cell carcinoma, n = 1. Blood sampling was performed presurgery and 30 days post-surgery. Transcript levels measured by quantitative polymerase chain reaction were calculated as activity scores (0-100% scale: normal
- Published
- 2017
24. A multianalyte PCR blood test outperforms single analyte ELISAs (chromogranin A, pancreastatin, neurokinin A) for neuroendocrine tumor detection
- Author
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Stephen Callahan, Mark Kidd, Daniele Alaimo, Irvin M. Modlin, Ignat Drozdov, Lisa Bodei, and Nancy Teixiera
- Subjects
Adult ,Male ,Cancer Research ,Analyte ,medicine.medical_specialty ,Neurokinin A ,Endocrinology, Diabetes and Metabolism ,Enzyme-Linked Immunosorbent Assay ,Polymerase Chain Reaction ,Gastroenterology ,Pancreastatin ,chemistry.chemical_compound ,Endocrinology ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Blood test ,Aged ,Hematologic Tests ,biology ,medicine.diagnostic_test ,Receiver operating characteristic ,business.industry ,Reproducibility of Results ,Chromogranin A ,Middle Aged ,Pancreatic Hormones ,Neuroendocrine Tumors ,Tumor detection ,Oncology ,chemistry ,biology.protein ,Biomarker (medicine) ,Female ,business - 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 includedχ2, 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,P95% 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.
- Published
- 2014
25. Utility of a ready-to-use PCR system for neuroendocrine tumor diagnosis
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Irvin M Modlin, Nicholas J. Ferranti, Lisa Bodei, Mark Kidd, Nicole Gurunlian, Philip Bennett, Anna Malczewska, Somer Matar, and Ignat Drozdov
- Subjects
0301 basic medicine ,Oncology ,Physiology ,Gene Expression ,Pilot Projects ,Artificial Gene Amplification and Extension ,Squamous Cell Lung Carcinoma ,Neuroendocrine tumors ,Polymerase Chain Reaction ,Lung and Intrathoracic Tumors ,Mathematical and Statistical Techniques ,0302 clinical medicine ,Adenocarcinomas ,Gene expression ,Medicine and Health Sciences ,Medicine ,Prospective Studies ,Multidisciplinary ,Adenocarcinoma of the Lung ,biology ,Statistics ,Squamous Cell Carcinomas ,Chromogranin A ,Clinical Laboratory Sciences ,Body Fluids ,Neuroendocrine Tumors ,Clinical Laboratories ,Blood ,Research Design ,030220 oncology & carcinogenesis ,Physical Sciences ,Anatomy ,Algorithms ,Research Article ,medicine.medical_specialty ,Science ,Research and Analysis Methods ,Carcinomas ,03 medical and health sciences ,Diagnostic Medicine ,Internal medicine ,Biomarkers, Tumor ,Genetics ,Humans ,Statistical Methods ,Molecular Biology Techniques ,Molecular Biology ,Reproducibility ,business.industry ,Reproducibility of Results ,Biology and Life Sciences ,Cancers and Neoplasms ,Pilot Studies ,Molecular diagnostics ,medicine.disease ,Tumor tissue ,030104 developmental biology ,Increased risk ,Case-Control Studies ,biology.protein ,RNA ,Ready to use ,business ,Mathematics ,Forecasting - Abstract
Background Multigene-based PCR tests are time-consuming and limiting aspects of the protocol include increased risk of operator-based variation. In addition, such protocols are complex to transfer and reproduce between laboratories. Aims Evaluate the clinical utility of a pre-spotted PCR plate (PSP) for a novel multigene (n = 51) blood-based gene expression diagnostic assay for neuroendocrine tumors (NETs). Methods A pilot study (n = 44; 8 controls and 36 NETs) was undertaken to compare CQ, normalized gene expression and algorithm-based output (NETest score). Gene expression was then evaluated between matched blood:tumor tissue samples (n = 7). Thereafter, two prospective sets (diagnostic: n = 167; clinical validation: n = 48, respectively) were evaluated for diagnostic and clinical utility value. Two independent molecular diagnostics facilities were used to assess assay reproducibility and inter-laboratory metrics. Samples were collected (per CLIA protocol) processed to mRNA and cDNA and then either run per standard assay (liquid primers) or on PSPs. Separately, matching plasma samples were analyzed for chromogranin A (CgA). Statistics included non-parametric testing, Pearson-concordance, Predictive Modeling and AUROC analyses. Results In the pilot study (n = 44), CQ values were highly concordant (r: 0.82, p96%) scores and was significantly better (p96%) NETest results. Moreover, it functions significantly more accurately than CgA.
- Published
- 2019
26. Gut neuroendocrine tumor blood qPCR fingerprint assay: characteristics and reproducibility
- Author
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Irvin M. Modlin, Ignat Drozdov, and Mark Kidd
- Subjects
Male ,Oncology ,medicine.medical_specialty ,Time Factors ,Clinical Biochemistry ,Cell ,CD59 ,Biology ,Real-Time Polymerase Chain Reaction ,Marker gene ,Eating ,Sex Factors ,Limit of Detection ,Stomach Neoplasms ,Internal medicine ,Intestinal Neoplasms ,Biomarkers, Tumor ,medicine ,Humans ,Gene ,Messenger RNA ,Reproducibility ,Biochemistry (medical) ,Age Factors ,Reproducibility of Results ,Proton Pump Inhibitors ,General Medicine ,Gold standard (test) ,Pancreatic Neoplasms ,Neuroendocrine Tumors ,medicine.anatomical_structure ,Endocrinology ,Female ,Sample collection ,Artifacts - Abstract
Background: We have developed a PCR-based tool that measures a 51-gene panel for identification of gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) in peripheral blood. This manuscript assesses the robustness (performance metrics) of this tool with a specific focus on the effects of individual parameters including collection, storage, acid suppressive medication [proton pump inhibitor (PPI)], age, sex, race and food on accuracy. Methods: Performance metrics were evaluated using a gold standard (mRNA derived from three individual human neuroendocrine tumor cell lines) and clinical samples using qPCR. Results: One hundred percent of the 51 transcripts were amplified in the gold standard (NEN cell line-derived mRNA) (CQALG9, was robust [low variation, low M-value, high (99.5%) PCR efficiency] and unaffected by sample processing. Test meals, long-term PPI use (>1 year), age, sex and ethnicity had no effect on the signature. Expression of two genes, ALP2 and CD59 correlated strongly with RNA integrity (R=0.72, p Conclusions: The 51 marker gene signature was robust and reproducible, exhibiting acceptable inter- and intra-assay metrics (APLP2 and CD59 are effective surrogate markers of proper sample collection and processing.
- Published
- 2013
27. Neuroendocrine tumor biomarkers: From monoanalytes to transcripts and algorithms
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Irvin M. Modlin, Lisa Bodei, and Mark Kidd
- Subjects
0301 basic medicine ,Endocrinology, Diabetes and Metabolism ,Disease ,Neuroendocrine tumors ,Biology ,Bioinformatics ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Circulating tumor cell ,medicine ,Biomarkers, Tumor ,Humans ,Early Detection of Cancer ,Tumor microenvironment ,Cancer ,Chromogranin A ,medicine.disease ,MicroRNAs ,Neuroendocrine Tumors ,030104 developmental biology ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Biomarker (medicine) ,Identification (biology) ,Algorithms - 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.
- Published
- 2016
28. NET Blood Transcript Analysis Defines the Crossing of the Clinical Rubicon: When Stable Disease Becomes Progressive
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Mark Kidd, Vikas Prasad, Irvin M. Modlin, Marianne Pavel, Ignat Drozdov, and Henning Jann
- Subjects
Adult ,Male ,medicine.medical_specialty ,Disease free survival ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Neuroendocrine tumors ,Biology ,Real-Time Polymerase Chain Reaction ,Disease-Free Survival ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Endocrinology ,Stable Disease ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,Aged ,Gastrointestinal Neoplasms ,Aged, 80 and over ,Endocrine and Autonomic Systems ,Disease progression ,Follow up studies ,Transcript analysis ,Middle Aged ,medicine.disease ,Pancreatic Neoplasms ,Neuroendocrine Tumors ,030220 oncology & carcinogenesis ,Disease Progression ,Biomarker (medicine) ,Female ,Neoplasm Grading ,Follow-Up Studies - Abstract
Background/Aims: A key issue in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is early identification and prediction of disease progression. Clinical evaluation and imaging are limited due to the lack of sensitivity and disease indolence. We assessed the NETest as a predictive and prognostic marker of progression in a long-term follow-up study. Methods: GEP-NETs (n = 34) followed for a median 4 years (2.2-5.4) were evaluated. WHO tumor grade/stage grade 1: n = 17, grade 2: n = 14, grade 3: n = 1 (for 2, no grade was available); 31 (91%) were stage IV. Baseline and longitudinal imaging and blood biomarkers were available in all, and progression was defined per standard clinical protocols (RECIST 1.0). The NETest was measured by quantitative PCR of blood and multianalyte algorithmic analysis (disease activity scaled 0-100% with low 80%); chromogranin A (CgA) was measured by radioimmunoassay (normal Results: At baseline, 100% were NETest positive, and CgA was elevated in 50%. The only baseline variable (Cox modeling) associated with PFS was NETest (hazard ratio = 1.022, 95% confidence interval = 1.005-1.04; p < 0.012). Using Kaplan-Meier analyses, the baseline NETest (>80%) was significantly associated (p = 0.01) with disease progression (median PFS 0.68 vs. 2.78 years with >25%) in consistently predicting disease alterations (40%, p < 2 × 10-5, χ2 = 18). The NETest had an earlier time point change than imaging (1.02 ± 0.15 years). Baseline NETest levels >40% in stable disease were 100% prognostic of disease progression versus CgA (χ2 = 5, p < 0.03). Baseline NETest values 2 = 3.8 vs. CgA). Conclusion: The NETest correlated with a well-differentiated GEP-NET clinical status. The NETest has predictive and prognostic utility for GEP-NETs identifying clinically actionable alterations ∼1 year before image-based evidence of progression.
- Published
- 2016
29. Ultrastructure of ECL cells in Mastomys after long-term treatment with H2 receptor antagonist loxtidine
- Author
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Reidar Alexander Vigen, Irvin M. Modlin, Duan Chen, Mark Kidd, and Chun-Mei Zhao
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Male ,endocrine system ,medicine.medical_specialty ,Enterochromaffin-like Cells ,Carcinoid Tumor ,Lipofuscin ,Pathology and Forensic Medicine ,Rats, Sprague-Dawley ,Mice ,Microscopy, Electron, Transmission ,Histamine H2 receptor ,Stomach Neoplasms ,Internal medicine ,Autophagy ,medicine ,Animals ,Enterochromaffin-like cell ,Molecular Biology ,Omeprazole ,Gastrin ,Inclusion Bodies ,Mice, Knockout ,Hyperplasia ,biology ,General Medicine ,Triazoles ,Anti-Ulcer Agents ,biology.organism_classification ,medicine.disease ,Receptor, Cholecystokinin B ,Rats ,Endocrinology ,Histamine H2 Antagonists ,Mastomys ,Vacuoles ,Ultrastructure ,Female ,Murinae ,medicine.drug - Abstract
Gastric ECL-cell hyperplasia and carcinoids (ECLoma) develop after 1 year in rats treated with omeprazole or 2 months in Mastomys treated with loxtidine. The aim of this study was to examine the ultrastructure of ECL cells in Mastomys after loxtidine treatment with an attempt to evaluate whether an impairment of autophagy was involved in the tumorigenesis. Mastomys were given loxtidine for 8 or 27 weeks. Morphological analysis of ECL cells showed that (1) cell size was not increased after 8 or 27 weeks; (2) secretory vesicles, a hallmark feature of welldifferentiated ECL cells, were unchanged after 8 weeks but reduced after 27 weeks; (3) granules were reduced after 8 or 27 weeks; (4) microvesicles were unchanged after the treatment; and (5) vacuoles and lipofuscin bodies were found occasionally after 8 weeks but not at 27 weeks. In addition, the appearance of ECL-cell ultrastructure differed between loxtidine-treated Mastomys and rats treated with omeprazole or subjected to antrectomy, but was similar between Mastomys treated with loxtidine for 27 weeks and mice deficient in CCK(2) receptor. We suggest that the ultrastructure of ECL cells in Mastomys after long-term treatment with loxtidine displayed an impaired formation of vacuoles and lipofuscin bodies, markers of the autophagic pathway.
- Published
- 2012
30. The role of mechanical forces and adenosine in the regulation of intestinal enterochromaffin cell serotonin secretion
- Author
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Bauer E. Sumpio, Mark Kidd, Atle van Beelen Granlund, Bernhard Svejda, Arne K. Sandvik, Andrew T. Timberlake, Bjorn I. Gustafsson, Alexander L. Chin, Irvin M. Modlin, and Roswitha Pfragner
- Subjects
Male ,Adenosine ,Physiology ,Receptor expression ,MAP Kinase Kinase 1 ,Gene Expression ,Hormones and Signaling ,Adenosine-5'-(N-ethylcarboxamide) ,Tryptophan Hydroxylase ,Vesicular monoamine transporter 1 ,Mechanotransduction, Cellular ,Serotonin secretion ,chemistry.chemical_compound ,Crohn Disease ,Acetamides ,Cyclic AMP ,Phosphorylation ,Cyclic AMP Response Element-Binding Protein ,Receptor ,Cells, Cultured ,TPH1 ,Gastroenterology ,Middle Aged ,Adenosine A2 Receptor Antagonists ,Enterochromaffin cell ,Female ,Signal Transduction ,medicine.drug ,Adult ,Serotonin ,medicine.medical_specialty ,Adenosine A2 Receptor Agonists ,Receptor, Adenosine A2A ,Colon ,MAP Kinase Signaling System ,Biology ,Receptor, Adenosine A2B ,Cell Line, Tumor ,Physiology (medical) ,Internal medicine ,Enterochromaffin Cells ,medicine ,Humans ,Aged ,Hepatology ,Receptor, Adenosine A1 ,Receptor, Adenosine A3 ,Cyclic AMP-Dependent Protein Kinases ,Endocrinology ,chemistry ,Purines ,Vesicular Monoamine Transport Proteins ,Stress, Mechanical ,Proto-Oncogene Proteins c-akt ,Adenosine A2B receptor - Abstract
Enterochromaffin (EC) cells of the diffuse neuroendocrine cell system secrete serotonin (5-HT) with activation of gut motility, secretion, and pain. These cells express adenosine (ADORA) receptors and are considered to function as mechanosensors. Physiological pathways mediating mechanosensitivity and adenosine responsiveness remain to be fully elucidated, as do their roles in inflammatory bowel disease (IBD) and neoplasia. Pure (98–99%) FACS-sorted normal and IBD human EC cells and neoplastic EC cells (KRJ-I) were studied. IBD-EC cells and KRJ-I overexpressed ADORA2B. NECA, a general ADORA receptor agonist, stimulated, whereas the A2B receptor antagonist MRS1754 inhibited, 5-HT release (EC50 = 1.8 × 10−6 M; IC50 = 3.7 × 10−8 M), which was associated with corresponding alterations in intracellular cAMP levels and pCREB (Ser133). Mechanical stimulation using a rhythmic flex model induced transcription and activation of Tph1 (tryptophan hydroxylase) and VMAT1 (vesicular monoamine transporter 1) and the release of 5-HT, which could be inhibited by MRS1754 and amplified by NECA. Secretion was also inhibited by H-89 (PKA inhibitor) while Tph1 and VMAT1 transcription was regulated by PKA/MAPK and PI3K-mediated signaling. Normal and IBD-EC cells also responded to NECA and mechanical stimulation with PKA activation, cAMP production, and 5-HT release, effects reversible by MRS1754. EC cells express stimulatory ADORA2B, and rhythmic stretch induces A2B activation, PKA/MAPK/IP3-dependent transcription, and PKA-dependent secretion of 5-HT synthesis and secretion. Receptor expression is amplified in IBD and neoplasia, and 5-HT release is increased. Determination of factors that regulate EC cell function are necessary for understanding its role as a mechanosensory cell and to facilitate the development of agents that can selectively target cell function in EC cell-associated disease.
- Published
- 2012
31. The clinical implications and biologic relevance of neurofilament expression in gastroenteropancreatic neuroendocrine neoplasms
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Hubertus Schmitz-Winnenthal, Irvin M. Modlin, Lars Fischer, Mark Kidd, Daniele Alaimo, Simon Schimmack, Ben Lawrence, Bernhard Svejda, and Markus W. Büchler
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,biology ,Chromogranin A ,Neuroendocrine tumors ,medicine.disease ,Metastasis ,medicine.anatomical_structure ,Oncology ,Internexin ,Ki-67 ,biology.protein ,medicine ,Enterochromaffin cell ,Cancer research ,Pancreas ,Neuroendocrine cell - Abstract
BACKGROUND: Although gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) exhibit widely divergent behavior, limited biologic information (apart from Ki-67) is available to characterize malignancy. Therefore, the identification of alternative biomarkers is a key unmet need. Given the role of internexin alpha (INA) in neuronal development, the authors assessed its function in neuroendocrine cell systems and the clinical implications of its expression as a GEP-NEN biomarker. METHODS: Functional assays were undertaken to investigate the mechanistic role of INA in the pancreatic BON cell line. Expression levels of INA were investigated in 50 pancreatic NENs (43 primaries, 7 metastases), 43 small intestinal NENs (25 primaries, 18 metastases), normal pancreas (n = 10), small intestinal mucosa (n = 16), normal enterochromaffin (EC) cells (n = 9), mouse xenografts (n = 4) and NEN cell lines (n = 6) using quantitative polymerase chain reaction, Western blot, and immunostaining analyses. RESULTS: In BON cells, decreased levels of INA messenger RNA and protein were associated with the inhibition of both proliferation and mitogen-activated protein kinase (MAPK) signaling. INA was not expressed in normal neuroendocrine cells but was overexpressed (from 2-fold to 42-fold) in NEN cell lines and murine xenografts. In pancreatic NENs, INA was overexpressed compared with pancreatic adenocarcinomas and normal pancreas (27-fold [P = .0001], and 9-fold [P = .02], respectively). INA transcripts were correlated positively with Ki-67 (correlation coefficient [r] = 0.5; P < .0001) and chromogranin A (r = 0.59; P < .0001). INA distinguished between primary tumors and metastases (P = .02), and its expression was correlated with tumor size, infiltration, and grade (P < .05). CONCLUSIONS: INA is a novel NEN biomarker, and its expression was associated with MAPK signaling and proliferation. In clinical samples, elevated INA was correlated with Ki-67 and identified malignancy. INA may provide additional biologic information relevant to delineation of both pancreatic NEN tumor phenotypes and clinical behavior. Cancer 2011. © 2011 American Cancer Society.
- Published
- 2011
32. Limitations in small intestinal neuroendocrine tumor therapy by mTor kinase inhibition reflect growth factor-mediated PI3K feedback loop activation via ERK1/2 and AKT
- Author
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Ben Lawrence, Irvin M. Modlin, Mark Kidd, Bernhard Svejda, Roswitha Pfragner, and Alexander Kazberouk
- Subjects
MAPK/ERK pathway ,Cancer Research ,medicine.medical_specialty ,Cell Survival ,AKT1 ,Biology ,Octreotide ,Phosphatidylinositol 3-Kinases ,Cell Line, Tumor ,Internal medicine ,Intestinal Neoplasms ,Intestine, Small ,medicine ,Humans ,Everolimus ,Viability assay ,Phosphorylation ,Protein Kinase Inhibitors ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Mitogen-Activated Protein Kinase 1 ,Sirolimus ,Mitogen-Activated Protein Kinase 3 ,Kinase ,TOR Serine-Threonine Kinases ,RPTOR ,Neuroendocrine Tumors ,Endocrinology ,Somatostatin ,Oncology ,Cancer research ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
BACKGROUND: Treatment of small intestinal neuroendocrine tumors (SINETs) with mammalian target of rapamycin (mTOR) inhibitors alone or with somatostatin analogs has been proposed as effective therapy, because both agents have been reported to exhibit antiproliferative activity. Because adenocarcinomas escape mTOR inhibition, we examined whether the escape phenomenon occurred in SINETs and whether usage of somatostatin analogs with mTOR inhibitors surmounted loss of inhibition. METHODS: The effects of the somatostatin analog octreotide (OCT), the mTOR inhibitor RAD001 (RAD), or the combination were evaluated in SINET cell lines (KRJ-I, H-STS) using cell viability assays, western blotting, enzyme-linked immunosorbent assay, and reverse-transcription polymerase chain reaction to assess antiproliferative signaling pathways and feedback regulation. RESULTS: RAD (10 � 9 M) incompletely decreased cell viability (� 40% to þ15%); growth escape (P < .001) was noted at 72 hours in both cell lines. Phosphorylated (p)mTOR/mTOR and pp70S6K/p70S6K ratios were decreased but were associated with increases in phosphorylated extracellular signal-regulated kinase (pERK)/ERK and pAKT/AKT in both cell lines, whereas phosphorylated insulin-like growth factor 1 receptor (pIGF-1R)/IGF-1R levels were elevated only in H-STS cells. Increased (P < .05) transcript levels for AKT1, MAPK, mTOR, IGF-1R, IGF-1, and TGFb1 were evident. OCT (10 � 6 M) itself had no significant effect on growth signaling in either cell line. An antiproliferative effect (66 � 5%) using OCTþRAD was only noted in the KRJ-I cells (P < .05). CONCLUSIONS: SINET treatment with the mTOR inhibitor RAD had no antiproliferative effect based on activation of pAKT and pERK1/2. A combinatorial approach using OCT and RAD failed to overcome this escape phenomenon. However, differences in RAD response rates in individual NET cell lines suggested that pretreatment identification of different tumor sensitivity to mTOR inhibitors could provide the basis for individualized treatment. Cancer 2011;117:4141–54. V C 2011 American Cancer Society.
- Published
- 2011
33. Parietal cell activation by arborization of ECL cell cytoplasmic projections is likely the mechanism for histamine induced secretion of hydrochloric acid
- Author
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Ingunn Bakke, Irvin M. Modlin, Bjorn I. Gustafsson, Øyvind Hauso, Helge L. Waldum, Eiliv Brenna, Reidar Fossmark, and Mark Kidd
- Subjects
endocrine system ,Enterochromaffin-like Cells ,Histamine secretion ,Cell Communication ,Biology ,Histamine Release ,Gastric Acid ,Rats, Sprague-Dawley ,Parietal Cells, Gastric ,Gastric glands ,medicine ,Gastric mucosa ,Animals ,Sigmodontinae ,Enterochromaffin-like cell ,Parietal cell ,Gastrin ,Gastroenterology ,Molecular biology ,Rats ,Foveolar cell ,Intercellular Junctions ,medicine.anatomical_structure ,Biochemistry ,Gastric Mucosa ,Female ,G cell - Abstract
Background and aims. Enterochromaffin-like (ECL) cells are central in the regulation of acid secretion. G cells release gastrin and activate ECL cell histamine secretion which stimulates parietal cell H2 receptors initiating acid secretion. It is unclear whether histamine-mediated parietal cell activation is via a vascular or paracrine pathway. To assess this, we utilized immunohistochemistry (IHC) and electron microscopy to examine gastric tissue and used visualization of formalin fixed dispersed gastric cells and glands to investigate and define the anatomical relationship between ECL and parietal cells. Material and methods. Sprague–Dawley rat stomachs were instilled with formalin. Thereafter fixed mucosal cells and whole gastric glands were dispersed by mechanical and chemical dissolution and enzymatic digestion. Smears with fixed isolated cells and whole glands were stained by IHC with histidine decarboxylase (HDC) and H + /K + -ATPase antibodies. Whole tissue samples of Sprague–Dawley and cotton rat oxyntic mucosa were investigated with IHC using HDC, VMAT2 and H + /K + -ATPase antibodies, and electron microscopy was performed to further delineate the precise anatomic relationship between ECL cells and parietal cells. Results. Each ECL cell generated a network of HDC- and VMAT2-positive dendriticlike elongations that were in direct contact with several parietal cells. Thus, ECL cells at the base of the gland were in communication with parietal cells in the middle of the gland. Electron microscopy confirmed that the cytoplasmic ECL cell elongations containing secretory vesicles were in direct juxtaposition to parietal cells. Conclusions. These findings indicate that ECL cells directly regulate parietal cell function in a neurocrine manner via slender neuron-like elongations.
- Published
- 2011
34. Short Communication: Human Blood Dendritic Cells Are Infected Separately from Monocytes in HIV Type 1 Patients
- Author
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Maria Colon, Manuel Vázquez, Sharilyn Almodovar, Irvin M. Maldonado, Carlos A. Lopez, Eric Lorenzo, and Martin D. Hill
- Subjects
Glycosylation ,Time Factors ,Myeloid ,Molecular Sequence Data ,Immunology ,HIV Infections ,Pathogenesis ,Biology ,Monocytes ,Blood cell ,chemistry.chemical_compound ,Virology ,medicine ,Humans ,Gene ,Phylogeny ,Sequence Analysis, RNA ,Monocyte ,env Gene Products, Human Immunodeficiency Virus ,Cell Differentiation ,Dendritic Cells ,Dendritic cell ,Infectious Diseases ,medicine.anatomical_structure ,chemistry ,DNA, Viral ,HIV-1 ,Interleukin 19 ,Viral disease - Abstract
Monocytes serve as a systemic reservoir of myeloid precursors for the renewal of tissue macrophages and dendritic cells (DCs). Both monocytes and dendritic cells can be infected with HIV-1. Circulating DCs are believed to be derived from a common precursor of monocytes, or, in the case of inflammatory challenge, from monocytes directly. Because there are fewer infected blood monocytes than infected cells after differentiation, we hypothesized that the majority of HIV-1 infection in circulating DCs occurs via direct viral binding to their CD4 and coreceptors after differentiation. We isolated monocytes at one time point and circulating dendritic cells at a second time point from the blood of HIV-1-infected patients. Proviral DNA was isolated from DCs and monocytes, and the C2-V4 region of the HIV-1 env gene was cloned and sequenced. Phylogeny, nucleotide distances, and glycosylation patterns of the env gene were performed. The phylogenetic trees revealed that viral forms from the monocytes clustered distantly from the quasispecies derived from circulating DCs. The nucleotide distances and differing glycosylation patterns suggest that the infection of DCs is independent of the infection of the monocytes.
- Published
- 2010
35. Chromogranin A—Biological Function and Clinical Utility in Neuro Endocrine Tumor Disease
- Author
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Steven F. Moss, Irvin M. Modlin, Bjorn I. Gustafsson, Mark Kidd, Marianne Pavel, and Apostolos V. Tsolakis
- Subjects
Oncology ,endocrine system ,medicine.medical_specialty ,Pathology ,Disease ,Neuroendocrine tumors ,Surgical oncology ,Internal medicine ,Biomarkers, Tumor ,medicine ,Carcinoid Heart Disease ,Humans ,Endocrine Tumors ,Multiple endocrine neoplasia ,biology ,business.industry ,Cancer ,Chromogranin A ,Prognosis ,medicine.disease ,Neuroendocrine Tumors ,biology.protein ,Biomarker (medicine) ,Surgery ,business - Abstract
Neuroendocrine tumors (NETs) are a form of cancer that differ from other neoplasia in that they synthesize, store, and secrete peptides, e.g., chromogranin A (CgA) and amines. A critical issue is late diagnosis due to failure to identify symptoms or to establish the biochemical diagnosis. We review here the utility of CgA measurement in NETs and describe its biological role and the clinical value of its measurement.Literature review and analysis of the utility of plasma/serum CgA measurements in NETs and other diseases.CgA is a member of the chromogranin family; its transcription and peptide processing are well characterized, but its precise function remains unknown. Levels are detectable in the circulation but vary substantially (approximately 25%) depending on which assay is used. Serum and plasma measurements are concordant. CgA is elevated in approximately 90% of gut NETs and correlates with tumor burden and recurrence. Highest values are noted in ileal NETs and gastrointestinal NETs associated with multiple endocrine neoplasia type 1. Both functioning and nonfunctioning pancreatic NETs have elevated values. CgA is more frequently elevated in well-differentiated tumors compared to poorly differentiated NETs. Effective treatment is often associated with decrease in CgA levels. Proton pump inhibitors falsely increase CgA, but levels normalize with therapy cessation.CgA is currently the best available biomarker for the diagnosis of NETs. It is critical to establish diagnosis and has some utility in predicting disease recurrence, outcome, and efficacy of therapy. Measurement of plasma CgA is mandatory for the effective diagnosis and management of NET disease.
- Published
- 2010
36. IL1β- and LPS-induced serotonin secretion is increased in EC cells derived from Crohn’s disease
- Author
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Mark Kidd, Bjorn I. Gustafsson, Irvin M. Modlin, and Ignat Drozdov
- Subjects
Lipopolysaccharides ,Serotonin ,medicine.medical_specialty ,Lipopolysaccharide ,Physiology ,Interleukin-1beta ,Enzyme-Linked Immunosorbent Assay ,Biology ,Inflammatory bowel disease ,Article ,Serotonin secretion ,chemistry.chemical_compound ,Crohn Disease ,Internal medicine ,Enterochromaffin Cells ,Escherichia coli ,medicine ,Humans ,Secretion ,Phosphorylation ,Reverse Transcriptase Polymerase Chain Reaction ,Endocrine and Autonomic Systems ,Toll-Like Receptors ,NF-kappa B ,Gastroenterology ,Interleukin ,Flow Cytometry ,medicine.disease ,Molecular biology ,Endocrinology ,Somatostatin ,chemistry ,Enterochromaffin cell ,TLR4 ,Mitogen-Activated Protein Kinases ,Signal Transduction - Abstract
Gut mucosal enterochromaffin (EC) cells are regarded as key regulators of intestinal motility and fluid secretion via secretion of serotonin (5HT), are increased in numbers in mucosal inflammation and located in close proximity to immune cells. We examined whether interleukin (IL)1beta and Escherichia coli lipopolysaccharide (LPS) induced EC cell 5HT release through Toll-like/IL-1 (TIL) receptor activation, nuclear factor kappa B (NFkappaB) and mitogen-activated protein kinase (MAPK) phosphorylation and evaluated whether somatostatin could inhibit this phenomenon. Pure (>98%) human intestinal EC cells were isolated by fluorescent activated cell sorting from preparations of normal (n = 5) and Crohn's colitis (n = 6) mucosa. 5HT release was measured (ELISA), and NFkappaB and ERK phosphorylation quantitated (ELISA) in response to IL1beta and LPS. 5HT secretion was increased by both E. coli LPS (EC(50) = 5 ng mL(-1)) and IL1beta (EC(50) = 0.05 pmol L(-1)) >2-fold (P < 0.05) in Crohn's EC cells compared with normal EC cells. Secretion was reversible by the TLR4 antagonist, E. coli K12 LPS (IC(50) = 12 ng mL(-1)) and the IL1beta receptor antagonist (ILRA; IC(50) = 3.4 ng mL(-1)). IL1beta caused significant (P < 0.05) NFkappaB and MAPK phosphorylation (40-55%). The somatostatin analogue, lanreotide inhibited IL1beta-stimulated secretion in Crohn's (IC(50) = 0.61 nmol L(-1)) and normal EC cells (IC(50) = 1.8 nmol L(-1)). Interleukins (IL1beta) and bacterial products (E. coli LPS) stimulated 5HT secretion from Crohn's EC cells via TIL receptor activation (TLR4 and IL1beta). Immune-mediated alterations in EC cell secretion of 5HT may represent a component of the pathogenesis of abnormal bowel function in Crohn's disease. Inhibition of EC cell-mediated 5HT secretion may be an alternative therapeutic strategy in the amelioration of inflammatory bowel disease symptomatology.
- Published
- 2009
37. Principal Component Analysis, Hierarchical Clustering, and Decision Tree Assessment of Plasma mRNA and Hormone Levels as an Early Detection Strategy for Small Intestinal Neuroendocrine (Carcinoid) Tumors
- Author
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Irvin M. Modlin, Roswitha Pfragner, Boaz Nadler, Ignat Drozdov, Bjorn I. Gustafsson, and Mark Kidd
- Subjects
Adult ,Male ,medicine.medical_specialty ,Carcinoid tumors ,medicine.medical_treatment ,Connective tissue ,Enzyme-Linked Immunosorbent Assay ,Carcinoid Tumor ,Biology ,Neuroendocrine tumors ,Sensitivity and Specificity ,Marker gene ,Internal medicine ,Intestinal Neoplasms ,Intestine, Small ,Biomarkers, Tumor ,medicine ,Cluster Analysis ,Humans ,RNA, Messenger ,RNA, Neoplasm ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Principal Component Analysis ,Reverse Transcriptase Polymerase Chain Reaction ,Growth factor ,Decision Trees ,Connective Tissue Growth Factor ,Middle Aged ,Prognosis ,medicine.disease ,CTGF ,Early Diagnosis ,Endocrinology ,medicine.anatomical_structure ,Oncology ,Case-Control Studies ,Chromogranin A ,Female ,Surgery ,Ghrelin ,Hormone - Abstract
Incidence of neuroendocrine tumors (NETs) is increasing (approximately 6%/year), but clinical presentation is nonspecific, resulting in delays in diagnosis (5-7 years; approximately 70% have metastases). This reflects absence of a sensitive plasma marker. The aim of this study is to investigate whether detection of circulating messenger RNA (mRNA) alone or in combination with circulating NET-related hormones and growth factors can detect gastrointestinal NET disease. The small intestinal (SI) NET cell line KRJ-I was used to define the sensitivity of real-time polymerase chain reaction (PCR) for mRNA detection in blood. NSE, Tph-1, and VMAT2 transcripts were identified from one KRJ-I cell/ml blood. mRNA from the tissue and plasma of SI-NETs (n = 12) and gastric NETs (n = 7), and plasma from healthy controls (n = 9) was isolated and real-time PCR performed. Tph-1 was a specific marker of SI-NETs (58%, p \ 0.03) whereas CgA transcripts did not differentiate tumors from controls. Patients with metastatic disease expressed more marker transcripts than localized tumors (75% versus 18%, p \ 0.02). Plasma 5-hydroxytryptamine (5-HT), chro- mogranin A (CgA), ghrelin, and connective tissue growth factor (CTGF) fragments were measured, combined with mRNA levels, and a predictive mathematical model for NET diagnosis developed using decision trees. The sensi- tivity and specificity to diagnose SI-NETs and gastric NETs were 81.2% and 100%, and 71.4% and 55.6%, respectively. We conclude that mRNA from one NET cell/ ml blood can be detected. Circulating plasma Tph-1 is a promising marker gene for SI-NET disease (specificity 100%) while an increased number of marker transcripts ((2) correlated with disease spread. Including NET-related circulating hormones and growth factors in the algorithm increased the sensitivity of detection of SI-NETs from 58 to 82%.
- Published
- 2008
38. From Leningrad to London: The Saga of Kulchitsky and the Legacy of the Enterochromaffin Cell
- Author
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Irvin M. Modlin, Ignat Drozdov, Viktor V. Goloubinov, and Mark Kidd
- Subjects
musculoskeletal diseases ,medicine.medical_specialty ,Endocrine and Autonomic Systems ,Endocrinology, Diabetes and Metabolism ,education ,Subject (philosophy) ,Biology ,stomatognathic diseases ,Cellular and Molecular Neuroscience ,Endocrinology ,Internal medicine ,Enterochromaffin cell ,medicine ,skin and connective tissue diseases ,health care economics and organizations - Abstract
By the end of the 19th century, the subject of internal secretion and the consequences of its perturbations had been explored in considerable depth but with little clear understanding. Despite the anatomic delineation of the majority of the glands and tissues that comprised the gross endocrine system, the cellular basis and the interactions between the ‘internal glands’ and the nervous system had not been clearly delineated. Prominent early investigators in the field included Rudolf Peter Heidenhain (1834–1897), who described a novel class of clear cells (1868), Paul Langerhans (1847–1888), who identified pancreatic islets in 1869, and M.C. Ciacco (1877–1956), who coined the term ‘enterochromaffin’ (1906). Their contributions facilitated the description of the diffuse neuroendocrine system (DNES) by F. Feyrter (1938) which allowed for the understanding of a syncytial regulatory system that consisted of both endocrine and neural components. This rich developmental history often reveals the name of Kulchitsky, but little recognition has been given to his seminal contributions. Indeed the Russian, Nikolai Konstantinovich Kulchitsky (1856–1925), both due to his modest and unassuming nature and the tragic events of his life, was little recognized and has been relegated to a mere eponymous attribution. In reality, his life bears legacy to rich scientific contributions spanning a great teaching and scientific career at Kharkov University, to responsibilities as the Imperial Minister of Education for all of Russia. He identified the Kulchitsky cell, trained and mentored numerous professors of histopathology, was incarcerated by the Bolsheviks and worked in a soap factory to save his life. He and his family finally fled on a British battleship with the remnants of the Russian Royal family to England where he secured a position with Bayliss and Starling at University College, London (UCL). His mysterious demise in a lift-shaft accident on his 69th birthday tragically terminated a life of great service to science and teaching. He excelled as a histopathologist and was responsible for the early description of tonsillar and gut epithelial leucocytes as well as defining components of the Ascaris life cycle. At UCL, his contributions to the anatomic delineation of muscle nerve endings were highly regarded and widely admired. It is, however, his identification of the enterochromaffin cell in 1897 for which he is most remembered since this observation formed the basis for the subsequent delineation of the DNES and provided the cellular framework on which the discipline of gut neuroendocrinology would be established.
- Published
- 2008
39. Inhibition of proliferation of small intestinal and bronchopulmonary neuroendocrine cell lines by using peptide analogs targeting receptors
- Author
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Irvin M. Modlin, Andrew V. Schally, Maximillian V. Malfertheiner, Mark Kidd, and Roswitha Pfragner
- Subjects
Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Apoptosis ,Caspase 3 ,Carcinoid Tumor ,Growth Hormone-Releasing Hormone ,Gonadotropin-Releasing Hormone ,chemistry.chemical_compound ,Internal medicine ,Intestinal Neoplasms ,Intestine, Small ,Tumor Cells, Cultured ,medicine ,Humans ,Cytotoxic T cell ,Pyrroles ,RNA, Messenger ,Receptors, Somatostatin ,Receptor ,Caspase ,Cell Proliferation ,biology ,Cytotoxins ,Reverse Transcriptase Polymerase Chain Reaction ,Cell growth ,Bronchial Neoplasms ,Cell Cycle ,Cell cycle ,Flow Cytometry ,Ki-67 Antigen ,Somatostatin ,Endocrinology ,Oncology ,chemistry ,Doxorubicin ,Cancer research ,biology.protein ,Growth inhibition ,Receptors, LHRH - Abstract
BACKGROUND. Currently, no consistently effective therapy is available to inhibit cell proliferation or metastasis of neuroendocrine tumor (NET) disease. The effects of 4 novel peptides were analyzed: a targeted cytotoxic analog of luteinizing hormone-releasing hormone (LH-RH) analog (AN-152), a targeted cytotoxic analog of somatostatin (AN-238), and 2 antagonists of growth hormone-releasing hormone (GH-RH) on 3 NET (carcinoid) cell lines that expressed respective peptide receptors. METHODS. The effects of the compounds were evaluated on cell proliferation in vitro using MTT uptake and Ki67 expression, apoptosis (caspase 3 expression and activity), and cell cycle parameters (DNA distribution). RESULTS. Proliferation of the LH-RH receptor-expressing lung NET, NCI-H720 line, was inhibited 2-fold by AN-152 containing doxorubicin compared with the chemotherapy alone (IC50 of 9.1 nM vs 24 nM). This was associated with a reduction in Ki67 transcript and an increase in both caspase 3 mRNA levels and activity. Proliferation of the GH-RH receptor expressing lung NET, NCI-H727 line, was inhibited by both GH-RH antagonists, the effects being mediated through changes in Ki67 expression, but not in caspase 3-mediated apoptosis. The small intestinal NET, KRJ-I line, was 8× more sensitive to inhibition by AN-238 than to 2-pyrolino-doxorubicin, reflected by increased caspase 3 transcript as well as activity. AN-238-mediated growth inhibition culminated in complete G1 arrest. CONCLUSIONS. The data demonstrate GH-RH antagonists or peptide-linked antineoplastic agents such as AN-152 and AN-238 are effective inhibitors of NET proliferation in vitro. Because peptide receptors such as those for GH-RH, LH-RH, and SST subtypes are commonly expressed by NETs, the development of antineoplastic agents targeted to specific tumor receptors may provide a more efficacious strategy than systemic chemotherapeutic agents currently in use. Cancer 2008. © 2008 American Cancer Society.
- Published
- 2008
40. Molecular mechanisms in therapy of acid-related diseases
- Author
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Irvin M. Modlin, Jai Moo Shin, Olga Vagin, Gary S. Sachs, Keith Munson, and M. Kidd
- Subjects
Peptic Ulcer ,Hydrogen potassium ATPase ,ATPase ,Pharmacology ,Peptic ulceration ,Article ,Gastric Acid ,H(+)-K(+)-Exchanging ATPase ,Cellular and Molecular Neuroscience ,Histamine H2 receptor ,medicine ,Humans ,Secretion ,Dyspepsia ,Molecular Biology ,Parietal cell ,biology ,Chemistry ,Proton Pump Inhibitors ,Cell Biology ,medicine.disease ,medicine.anatomical_structure ,Biochemistry ,Peptic ulcer ,Gastroesophageal Reflux ,biology.protein ,Molecular Medicine ,Gastric acid - Abstract
Inhibition of gastric acid secretion is the mainstay of the treatment of gastroesophageal reflux disease and peptic ulceration; therapies to inhibit acid are among the best-selling drugs worldwide. Highly effective agents targeting the histamine H2 receptor were first identified in the 1970s. These were followed by the development of irreversible inhibitors of the parietal cell hydrogen-potassium ATPase (the proton pump inhibitors) that inhibit acid secretion much more effectively. Reviewed here are the chemistry, biological targets and pharmacology of these drugs, with reference to their current and evolving clinical utilities. Future directions in the development of acid inhibitory drugs include modifications of current agents and the emergence of a novel class of agents, the acid pump antagonists.
- Published
- 2007
41. GeneChip, geNorm, and gastrointestinal tumors: novel reference genes for real-time PCR
- Author
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Shrikant Mane, Boaz Nadler, Geeta N. Eick, Irvin M. Modlin, Manish C. Champaneria, Maximillian V. Malfertheiner, Mark Kidd, and Roswitha Pfragner
- Subjects
Microarray ,Physiology ,Adenocarcinoma ,Biology ,Reference genes ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Genetics ,medicine ,Humans ,Gene ,Gastrointestinal Neoplasms ,Oligonucleotide Array Sequence Analysis ,Regulation of gene expression ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,medicine.disease ,Molecular biology ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,Real-time polymerase chain reaction ,Calibration ,Gene chip analysis ,Genes, Neoplasm - Abstract
Accurate quantitation of target genes depends on correct normalization. Use of genes with variable tissue transcription ( GAPDH) is problematic, particularly in clinical samples, which are derived from different tissue sources. Using a large-scale gene database (Affymetrix U133A) data set of 36 gastrointestinal (GI) tumors and normal tissues, we identified 8 candidate reference genes and established expression levels by real-time RT-PCR in an independent data set ( n = 42). A geometric averaging method (geNorm) identified ALG9, TFCP2, and ZNF410 as the most robustly expressed control genes. Examination of raw CTvalues demonstrated that these genes were tightly correlated between themselves ( R2> 0.86, P < 0.0001), with low variability [coefficient of variation (CV) 2< 0.4), and was considered the least stable gene. To illustrate the importance of correct normalization, the target gene, MTA1, was significantly overexpressed ( P = 0.0006) in primary GI neuroendocrine tumor (NET) samples (vs. normal GI samples) when normalized by geNormATZbut not when normalized using GAPDH. The geNormATZapproach was, in addition, applicable to adenocarcinomas; MTA1 was overexpressed ( P < 0.04) in malignant colon, pancreas, and breast tumors compared with normal tissues. We provide a robust basis for the establishment of a reference gene set using GeneChip data and provide evidence for the utility of normalizing a malignancy-associated gene ( MTA1) using novel reference genes and the geNorm approach in GI NETs as well as in adenocarcinomas and breast tumors.
- Published
- 2007
42. Small bowel carcinoid (enterochromaffin cell) neoplasia exhibits transforming growth factor–β1-mediated regulatory abnormalities including up-regulation of C-Myc and MTA1
- Author
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Manish C. Champaneria, Geeta N. Eick, Anthony K. C. Chan, Robert L. Camp, Mark Kidd, Irvin M. Modlin, Roswitha Pfragner, and Shrikant M. Mane
- Subjects
Cyclin-Dependent Kinase Inhibitor p21 ,MAPK/ERK pathway ,Cancer Research ,Blotting, Western ,Cell ,Smad Proteins ,Carcinoid Tumor ,Biology ,Histone Deacetylases ,Metastasis ,Proto-Oncogene Proteins c-myc ,Transforming Growth Factor beta1 ,chemistry.chemical_compound ,Intestinal Neoplasms ,Enterochromaffin Cells ,Tumor Cells, Cultured ,medicine ,Humans ,Phosphorylation ,Cells, Cultured ,Cell Proliferation ,Mitogen-Activated Protein Kinase 1 ,Mitogen-Activated Protein Kinase 3 ,Cell growth ,Cadherins ,medicine.disease ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Repressor Proteins ,medicine.anatomical_structure ,Oncology ,chemistry ,Cell culture ,Trans-Activators ,Enterochromaffin cell ,Cancer research ,Growth inhibition ,Signal Transduction ,Transforming growth factor - Abstract
Although it is known that small intestinal carcinoids are derived from enterochromaffin (EC) cells, these cells remain poorly characterized and little is known of the growth regulatory mechanisms of these neuroendocrine cells. Down-regulation or loss of the transforming growth factor-beta1 (TGFbeta1) cytostatic program and activation of TGFbeta-mediated transcriptional networks is associated with uncontrolled growth and metastasis in other neural tumors, glioblastomas. Whether this phenomenon is common to small intestinal carcinoid tumors was investigated.The effects of TGFbeta1 on cultured normal EC cells (isolated by FACS sorting) and the neoplastic EC cell line, KRJ-I, was assessed using the MTT assay. The TGFbetaRII transcript and protein were identified in tumor cells and the effects of TGFbeta1 on SMAD2 phosphorylation and nuclear translocation quantified. The time-dependent response of SMAD4, SMAD7, c-Myc, and P21(WAF1/CIP1) protein expression and c-Myc and p21(WAF1/CIP1) transcript was measured in response to TGFbeta1 and the transcript expression of candidate downstream targets, MTA1 and E-cadherin, were assessed.TGFbeta1 inhibited normal EC cell proliferation (IC(50) = 17 pM) but stimulated neoplastic EC cell proliferation (EC(50) = 22 pM). In tumor cells, significantly decreased transcript (P.01) of TGFbetaRII was identified, but no receptor mutations were identified and protein expression was evident. TGFbeta1 (1 ng/mL) resulted in SMAD2 phosphorylation and7% nuclear expression compared with 93% in normal EC cells. In neoplastic cells, TGFbeta1 (1 ng/mL) caused a decrease in SMAD4 (16%, P.05), whereas SMAD7 and c-Myc transcript and protein were respectively increased21% (P.05) and approximately 40% (P.002). TGFbeta1 (1 ng/mL) also decreased p21(WAF1/CIP1) transcript by 60% (P.001) and protein that was undetectable at 24 hours. Expression of the downstream targets of the c-Myc pathway, MTA1, was increased (20%) and E-cadherin decreased (30%).The neoplastic EC cell is characterized by loss of TGFbeta-1-mediated growth inhibition and, similar to glioblastomas, utilizes the TGFbeta system to induce gene responses associated with growth promotion (c-Myc and the ERK pathway), invasion (E-cadherin), and metastasis (MTA1).
- Published
- 2007
43. Further delineation of the continuous human neoplastic enterochromaffin cell line, KRJ-I, and the inhibitory effects of lanreotide and rapamycin
- Author
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Geeta N. Eick, Irvin M. Modlin, Roswitha Pfragner, Manish C. Champaneria, John R. Murren, and Mark Kidd
- Subjects
Sirolimus ,medicine.medical_specialty ,TPH1 ,biology ,Chromogranin A ,Neurosecretory Systems ,Peptides, Cyclic ,Molecular biology ,Endocrinology ,Somatostatin ,Cell culture ,Cell Line, Tumor ,Internal medicine ,Enterochromaffin Cells ,medicine ,Enterochromaffin cell ,biology.protein ,Humans ,Serotonin ,Receptor ,Molecular Biology ,Intracellular - Abstract
Small intestinal carcinoids (SICs) are the most prevalent gastrointestinal carcinoid and characterized by local invasion metastasis and protean symptomatology. The proliferative and secretory regulation of the cell of origin, the enterochromaffin (EC) cell has not been characterized. The absence of either a pure preparation of normal EC cells or human EC carcinoid cell lines has hindered the development of therapeutic agents. We therefore further characterized the neoplastic SIC cell line, KRJ-I by assessing its secretory (serotonin (5-HT)) and proliferative responses and defining its log growth phase transcriptome. Electron microscopy demonstrated oval, lobulated nuclei and substance P, and 5-HT-positive cytoplasmic vesicles. RT-PCR detected transcripts for chromogranin A (CHGA), VMAT1 (SLC18A1), tryptophan hydroxylase (TPH1), substance P (TAC1), guanylin (GUCA2A), and SERT (SLC6A4). By immunohistochemistry, all cells were positive for CHGA, SERT, VMAT1, and TPH1. Transcriptome analysis (Affymetrix U133 Plus chips) identified somatostatin SSTR2/3, adrenergic α1C and β1, dopamine D2, nicotinic-type cholinergic A5, A6, B1, muscarinic acetylcholine M4, and 5-HT-2A receptors. The presence of transcripts for SSTR1, SSTR2, and SSTR3 receptors was confirmed by RT-PCR and sequencing. Isoproterenol (ISO) resulted in a dose-dependent increase in intracellular cAMP (EC50=340 nM) and 5-HT (EC50=81 nM) which was completely inhibited by the cAMP antagonist 2′,5′-dideoxyadenosine (10 μM). Preincubation with a SSTR agonist, lanreotide, inhibited Ip-stimulated 5-HT secretion (IC50=420 nM). Both lanreotide (10 nM) and rapamycin (50 nM) inhibited proliferation (20±12 and 35±5% respectively) in serum-free medium whereas gefitinib (1 nM–10 μM) inhibited proliferation at micromolar concentrations. KRJ-I is a neoplastic EC cell line that can be used as an in vitro model of SICs as it will allow elucidation and clarification of the secretory and proliferative mechanism(s) of neoplastic EC cells and the molecular signatures that characterize each of these responses.
- Published
- 2007
44. Role of CCN2/CTGF in the proliferation of Mastomys enterochromaffin-like cells and gastric carcinoid development
- Author
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Shrikant Mane, Irvin M. Modlin, Mark Kidd, Robert L. Camp, and Geeta N. Eick
- Subjects
endocrine system ,medicine.medical_specialty ,Physiology ,medicine.medical_treatment ,Carcinoid Tumor ,Polymerase Chain Reaction ,Immediate-Early Proteins ,Stomach Neoplasms ,Physiology (medical) ,Internal medicine ,Enterochromaffin Cells ,medicine ,Animals ,Enterochromaffin-like cell ,Oligonucleotide Array Sequence Analysis ,Gastrin ,Hyperplasia ,integumentary system ,Hepatology ,biology ,Cell growth ,Growth factor ,Connective Tissue Growth Factor ,Gastroenterology ,biology.organism_classification ,medicine.disease ,CTGF ,Endocrinology ,Gastric Mucosa ,Mastomys ,Enterochromaffin cell ,Intercellular Signaling Peptides and Proteins ,Murinae ,Cell Division - Abstract
Mastomys enterochromaffin-like (ECL) cell proliferation is initially gastrin driven, but once neoplasia develops, cells become gastrin autonomous. We hypothesized that CCN2 (CTGF), a mitogenic growth factor, may regulate ECL cell proliferation. A Mastomys GeneChip database was examined (dCHIP) to identify CCN2 expression levels. CCN2 in normal and tumor ECL cell preparations obtained using FACS (100 nM acridine orange) was examined by real-time PCR. CCN2 protein was identified in mucosal and ECL cell preparations by immunohistochemistry. Short-term cultured cells were stimulated with either CCN2 or CCN2 + EGF, and proliferation was measured (MTT assay). The ERK1/2 inhibitor PD-98059 (0.1–100 μM) was assessed in terms of CCN2 (1 ng/ml)-mediated proliferation and ERK1/2 phosphorylation. CCN2 transcript and protein was then examined in clinical gastric carcinoids. The ccn2 transcript was upregulated in tumor samples compared with the normal mucosa (+2.36-fold, P < 0.01). PCR demonstrated that ccn2 was not expressed in FACS-prepared (>98% pure) normal ECL cells but was elevated in tumor ECL cell fractions (41.3 ± 10.7-fold). Immunostaining of the Mastomys gastric mucosa and FACS preparations confirmed that CCN2 protein was present in ECL tumors but not in normal ECL cells. Neither CCN2 nor CCN2 + EGF stimulated normal ECL cell proliferation. CCN2 stimulated tumor proliferation (EC50 ∼0.01 ng/ml); EGF significantly augmented ( P < 0.01) CCN2-induced tumor cell proliferation (EC50 = 20 pg/ml). PD-98059 inhibited CCN2-induced proliferation (−12 ± 3%, P < 0.05) and ERK1/2 phosphorylation (−34 ± 5%, P < 0.05) in tumor cells. In clinical samples, both CCN2 transcript and protein were elevated in gastrin-autonomous carcinoids ( P < 0.02) compared with the normal mucosa. In conclusion, CCN2 may be a proliferative regulator of Mastomys ECL neoplastic proliferation once these cells become autonomous of gastrin regulation. Identification of CCN2 in gastric carcinoid tissue may be useful both as an indicator of ECL cell transformation and may define gastrin autonomy, a criteria of gastric carcinoid malignancy.
- Published
- 2007
45. Consensus on biomarkers for neuroendocrine tumour disease
- Author
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Tim Meyer, Irvin M. Modlin, David C. Metz, Kay Washington, Marianne Pavel, Eric Liu, Steven F. Moss, Jonathan R. Strosberg, Wouter W. de Herder, Edward M. Wolin, Andrea Frilling, Anthony P. Heaney, Kjell Öberg, Dik J. Kwekkeboom, David S. Klimstra, James R. Goldenring, Internal Medicine, and Radiology & Nuclear Medicine
- Subjects
Oncology ,medicine.medical_specialty ,Delphi Technique ,NEURON-SPECIFIC ENOLASE ,Carcinoid tumors ,Disease ,Neuroendocrine tumors ,CHROMOGRANIN-A ,GUIDELINES ,Article ,Breast cancer ,Internal medicine ,PROGASTRIN-RELEASING PEPTIDE ,medicine ,PROGNOSTIC MARKERS ,Biomarkers, Tumor ,BREAST-CANCER ,Humans ,Oncology & Carcinogenesis ,CARCINOID-TUMORS ,Science & Technology ,biology ,PLASMA ,business.industry ,Chromogranin A ,Cancer ,PANCREATIC ENDOCRINE TUMORS ,medicine.disease ,Neoplastic Cells, Circulating ,Prognosis ,National Cancer Institute (U.S.) ,United States ,Neuroendocrine tumour ,MicroRNAs ,Neuroendocrine Tumors ,Immunology ,biology.protein ,Biomarker (medicine) ,business ,Life Sciences & Biomedicine ,PANCREASTATIN ,1112 Oncology And Carcinogenesis - 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.
- Published
- 2015
46. Blood and tissue neuroendocrine tumor gene cluster analysis correlate, define hallmarks and predict disease status
- Author
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Mark Kidd, Irvin M. Modlin, and Ignat Drozdov
- Subjects
Adult ,Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Neuroendocrine tumors ,Transcriptome ,Young Adult ,Endocrinology ,Gene cluster ,medicine ,Biomarkers, Tumor ,Cluster Analysis ,Humans ,Aged ,Aged, 80 and over ,biology ,Receiver operating characteristic ,Middle Aged ,medicine.disease ,Fold change ,Neuroendocrine Tumors ,Oncology ,Ki-67 ,Multigene Family ,biology.protein ,Disease Progression ,Biomarker (medicine) ,Female ,Progressive disease ,Algorithms - Abstract
A multianalyte algorithmic assay (MAAA) identifies circulating neuroendocrine tumor (NET) transcripts (n=51) with a sensitivity/specificity of 98%/97%. We evaluated whether blood measurements correlated with tumor tissue transcript analysis. The latter were segregated into gene clusters (GC) that defined clinical ‘hallmarks’ of neoplasia. A MAAA/cluster integrated algorithm (CIA) was developed as a predictive activity index to define tumor behavior and outcome. We evaluated three groups. Group 1: publically available NET transcriptome databases (n=15; GeneProfiler). Group 2: prospectively collected tumors and matched blood samples (n=22; qRT-PCR). Group 3: prospective clinical blood samples,n=159: stable disease (SD):n=111 and progressive disease (PD):n=48. Regulatory network analysis, linear modeling, principal component analysis (PCA), and receiver operating characteristic analyses were used to delineate neoplasia ‘hallmarks’ and assess GC predictive utility. Our results demonstrated: group 1: NET transcriptomes identified (92%) genes elevated. Group 2: 98% genes elevated by qPCR (fold change >2,PR2=0.7,PP92%. Blood transcript measurement predicts NET activity.
- Published
- 2015
47. Glucagon receptor gene mutations with hyperglucagonemia but without the glucagonoma syndrome
- Author
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Günter Klöppel, Andrea Frilling, Roberto Dina, Irvin M Modlin, Panagiotis Vlavianos, Panagiotis Drymousis, Helen C Miller, Patrizia Cohen, and Mark Kidd
- Subjects
Pathology ,medicine.medical_specialty ,endocrine system ,Case Report ,Gene mutation ,Hyperglucagonemia ,Glucagon ,Alpha cell ,Internal medicine ,Medicine ,Pancreas ,biology ,business.industry ,Chromogranin A ,Glucagon receptor gene ,Hyperplasia ,medicine.disease ,medicine.anatomical_structure ,Endocrinology ,Mutation ,biology.protein ,business ,Glucagon receptor ,Adenomatosis - Abstract
Pancreatic neoplasms producing exclusively glucagon associated with glucagon cell hyperplasia of the islets and not related to hereditary endocrine syndromes have been recently described. They represent a novel entity within the panel of non-syndromic disorders associated with hyperglucagonemia. This case report describes a 36-year-old female with a 10 years history of non-specific abdominal pain. No underlying cause was evident despite extensive diagnostic work-up. More recently she was diagnosed with gall bladder stones. Abdominal ultrasound, computerised tomography and magnetic resonance imaging revealed no pathologic findings apart from cholelithiasis. Endoscopic ultrasound revealed a 5.5 mm pancreatic lesion. Fine needle aspiration showed cells focally expressing chromogranin, suggestive but not diagnostic of a low grade neuroendocrine tumor. OctreoScan(®) was negative. Serum glucagon was elevated to 66 pmol/L (normal: 0-50 pmol/L). Other gut hormones, chromogranin A and chromogranin B were normal. Cholecystectomy and enucleation of the pancreatic lesion were undertaken. Postoperatively, abdominal symptoms resolved and serum glucagon dropped to 7 pmol/L. Although H and E staining confirmed normal pancreatic tissue, immunohistochemistry was initially thought to be suggestive of alpha cell hyperplasia. A count of glucagon positive cells from 5 islets, compared to 5 islets from 5 normal pancreata indicated that islet size and glucagon cell ratios were increased, however still within the wide range of normal physiological findings. Glucagon receptor gene (GCGR) sequencing revealed a heterozygous deletion, K349_G359del and 4 missense mutations. This case may potentially represent a progenitor stage of glucagon cell adenomatosis with hyperglucagonemia in the absence of glucagonoma syndrome. The identification of novel GCGR mutations suggests that these may represent the underlying cause of this condition.
- Published
- 2015
48. GNA15 expression in small intestinal neuroendocrine neoplasia: functional and signalling pathway analyses
- Author
-
Ben Lawrence, Mark Kidd, Irvin M. Modlin, Claudio Bassi, Daniele Alaimo, Roswitha Pfragner, Sara Zanini, and Francesco Giovinazzo
- Subjects
MAPK/ERK pathway ,MAP Kinase Signaling System ,Cells ,Biology ,Small ,GNA15 ,Cell Line ,Stomach Neoplasms ,Cell Line, Tumor ,Intestine, Small ,Intestinal Neoplasms ,medicine ,Humans ,KRJ-I cell line ,Pancreas ,Cells, Cultured ,PI3K/AKT/mTOR pathway ,Neuroendocrine cell ,Gq-G11 ,Neoplastic ,Tumor ,Cultured ,Stomach ,NF-kappa B ,G protein ,Cell Biology ,Hedgehog signaling pathway ,GTP-Binding Protein alpha Subunits ,Intestine ,Gene Expression Regulation, Neoplastic ,ß(1) adrenergic receptor ,Pancreatic Neoplasms ,Haematopoiesis ,Neuroendocrine Tumors ,Real-time polymerase chain reaction ,medicine.anatomical_structure ,Gene Expression Regulation ,Gastric Mucosa ,Small intestinal neuroendocrine neoplasia ,Immunology ,Gα15 ,GTP-Binding Protein alpha Subunits, Gq-G11 ,Proto-Oncogene Proteins c-akt ,Signal Transduction ,Cancer research ,Immunohistochemistry ,Stem cell - Abstract
Gastroenteropancreatic neuroendocrine neoplasia (GEP-NEN) comprises a heterogeneous group of tumours that exhibit widely divergent biological behaviour. The identification of new targetable GPCR-pathways involved in regulating cell function could help to identify new therapeutic strategies. We assessed the function of a haematopoietic stem cell heterotrimeric G-protein, Gα15, in gut neuroendocrine cell models and examined the clinical implications of its over expression. Functional assays were undertaken to define the role of GNA15 in the small intestinal NEN cell line KRJ-I and in clinical samples from small intestinal NENs using quantitative polymerase chain reaction, western blot, proliferation and apoptosis assays, immunoprecipitation, immunohistochemistry (IHC) and automated quantitative analysis (AQUA). GNA15 was not expressed in normal neuroendocrine cells but was overexpressed in GEP-NEN cell lines. In KRJ-I cells, decreased expression of GNA15 was associated with inhibition of proliferation, activation of apoptosis and differential effects on pro-proliferative ERK, NFκB and Akt pathway signalling. Moreover, Gα15 was demonstrated to couple to the ß1 adrenergic receptor and modulated proliferative signals through this GPCR. Transcript and protein levels of GNA15 were significantly elevated in primary and metastatic tumours compared to normal mucosa and were particularly increased in low Ki-67 expressing tumours. IHC and AQUA revealed that a higher Gα15 expression was associated with a poorer survival. GNA15 may have a pathobiological role in SI-NENs. Targeting this signalling mediator could provide an opportunity for the development of new therapeutic strategies for this tumour type.
- Published
- 2015
49. Utility of molecular genetic signatures in the delineation of gastric neoplasia
- Author
-
Geeta N. Eick, Robert L. Camp, Michelle N. Zikusoka, Shrikant Mane, Igor Latich, Irvin M. Modlin, and Mark Kidd
- Subjects
Adult ,Genetic Markers ,Male ,endocrine system ,Cancer Research ,Pathology ,medicine.medical_specialty ,Carcinoid Tumor ,Adenocarcinoma ,Histone Deacetylases ,Metastasis ,Diagnosis, Differential ,Antigens, Neoplasm ,Stomach Neoplasms ,Chromogranins ,medicine ,Humans ,Neoplasm Invasiveness ,Adaptor Proteins, Signal Transducing ,Aged ,Oligonucleotide Array Sequence Analysis ,Tissue microarray ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Stomach ,Chromogranin A ,Cancer ,Middle Aged ,medicine.disease ,Immunohistochemistry ,digestive system diseases ,Repressor Proteins ,Gene expression profiling ,Phenotype ,medicine.anatomical_structure ,Oncology ,Trans-Activators ,Cancer research ,biology.protein ,Female ,Gastric Neoplasm - Abstract
Current techniques to define gastric neoplasia are limited but molecular genetic signatures can categorize tumors and provide biological rationale for predicting clinical behavior. We identified three gene signatures: Chromogranin A (CgA), MAGE-D2 (adhesion), and MTA1 (metastasis) that define gastrointestinal (GI) carcinoids and hypothesize that their expression can delineate gastric neoplasia. This strategy provides a molecular basis to define neuroendocrine gastric carcinoids (GCs), neuronal stromal tumors (GISTs), or epithelial cell (gastric adenocarcinomas [GCAs])-derived tumors.Total RNA was isolated from 38 GCs: Type I/II (n = 7), Type III/IV (n = 6), GISTs (n = 12), GCAs (n = 13), and normal mucosa (n = 12). Quantitative reverse transcriptase polymerase chain reaction (Q RT-PCR) gene expression was quantified against glyseraldehyde-3-phosphate dehydrogenase (GAPDH) and CgA and MTA1 protein expression levels were analyzed by immunohistochemical analyses of a gastric neoplasia microarray.CgA was elevated in Type I/II (10-fold; P.01) and Type III/IV (100-fold, P.005), decreased in GISTs (100-fold, P.03), and unchanged in GCAs. MAGE-D2 was 5-10-fold elevated (P.05) in Type III/IV, GISTs, and GCAs but not in Type I/II tumors. MTA1 (5-fold, P.01) was elevated in GCs (Type III/IVI/II, P.05), in GISTs (4-fold, P.05), and GCAs. CgA protein levels were elevated in GCs (P.005) but not in GISTs and GCAs. MTA1 levels were elevated in all tumors (P.02) compared with normal, and especially with tumor invasion (P.05).CgA discriminates GCs from other gastric neoplasms; overexpression of MAGE-D2 and MTA1 differentiate Type III/IV from Type I/II GCs. GISTs share similar expression patterns with Type III/IV GCs but have decreased CgA. MTA1 is a marker of tumor invasion.
- Published
- 2006
50. Current Status of Gastrointestinal Carcinoids
- Author
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Michelle N. Zikusoka, Irvin M. Modlin, Igor Latich, Mark Kidd, and Michael D. Shapiro
- Subjects
Pathology ,medicine.medical_specialty ,Hepatology ,medicine.medical_treatment ,Gastroenterology ,Rectum ,Carcinoid Tumor ,Somatostatinoma ,Neuroendocrine tumors ,Biology ,medicine.disease ,digestive system diseases ,Appendix ,Transplantation ,Radiation therapy ,medicine.anatomical_structure ,Carcinoembryonic antigen ,Internal medicine ,medicine ,biology.protein ,Humans ,Embolization ,Gastrointestinal Neoplasms - Abstract
Gastrointestinal (GI) carcinoids are ill-understood, enigmatic malignancies, which, although slow growing compared with adenocarcinomas, can behave aggressively. Carcinoids are classified based on organ site and cell of origin and occur most frequently in the GI (67%) where they are most common in small intestine (25%), appendix (12%), and rectum (14%). Local manifestations--mass, bleeding, obstruction, or perforation--reflect invasion or tumor-induced fibrosis and often result in incidental detection at emergency surgery. Symptoms are protean (flushing, sweating, diarrhea, bronchospasm), usually misdiagnosed, and reflect secretion of diverse amines and peptides. Biochemical diagnosis is established by elevation of plasma chromogranin A (CgA), serotonin, or urinary 5-hydroxyindoleacetic acid (5-HIAA), while topographic localization is by Octreoscan, computerized axial tomography (CAT) scan, or endoscopy/ultrasound. Histological identification is confirmed by CgA and synaptophysin immunohistochemistry. Primary therapy is surgical excision to avert local manifestations and decrease hormone secretion. Hepatic metastases may be amenable to cytoreduction, radiofrequency ablation, embolization alone, or with cytotoxics. Hepatic transplantation may rarely be beneficial. Chemotherapy and radiotherapy have minimal efficacy and substantially decrease quality of life. Intravenously administered receptor-targeted radiolabeled somatostatin analogs are of use in disseminated disease. Local endoscopic excision for gastric (type I and II) and rectal carcinoids may be adequate. Somatostatin analogues provide the most effective symptomatic therapy, although interferon has some utility. Overall 5-year survival for carcinoids of the appendix is 98%, gastric (types I/II) is 81%, rectum is 87%, small intestinal is 60%, colonic carcinoids is 62%, and gastric type III/IV is 33%.
- Published
- 2005
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