Orthopedia homeobox protein (OTP) in the diagnostic and prognostic workup of pulmonary carcinoid tumors.
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ABSTRACT:
SUBMITTER: Vesterinen T
PROVIDER: S-EPMC9903083 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
Publications
Orthopedia homeobox protein (OTP) in the diagnostic and prognostic workup of pulmonary carcinoid tumors.
Vesterinen Tiina T Arola Johanna J
Translational lung cancer research 20221226 1
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Project description:BackgroundOrthopedia homeobox (OTP) has shown to be a useful prognostic marker to predict outcome in pulmonary carcinoids, which is also supported by the World Health Organization. However, the discontinuation of the initially used polyclonal antibody and absence of a reliable routinely applicable monoclonal OTP antibody hampers implementation in routine diagnostics. Here, new monoclonal antibodies directed against OTP were developed and verified on formalin-fixed paraffin-embedded tissue of pulmonary neuroendocrine tumors (NETs) for clinical diagnostics.MethodsOTP specific monoclonal antibodies were produced from mice immunised with a recombinant human OTP protein fragment. Enzyme-linked immunosorbent assay (ELISA) positive hybridomas were evaluated using immunohistochemistry (IHC). Following epitope-mapping and isotyping, purified monoclonal antibodies were validated for IHC in formalin-fixed paraffin-embedded tissues, the optimal dilution was determined, and results were cross validated with the OTP polyclonal antibody (HPA039365, Atlas Antibodies). Staining protocols were optimized on two automated staining platforms and performance was harmonized using a tissue microarray (TMA).ResultsTwo clones (CL11222 and CL11225) were selected for purified monoclonal antibody (mAb) production. Intratumor heterogeneity assessment revealed similar performance for both clones. While clone CL11225 displayed a unique epitope compared to those present in the polyclonal antibody, this clone performed most similar to the polyclonal antibody. Cross-platform assessment revealed an excellent agreement for clone CL11225 while clone CL11222 showed somewhat discordant results on Dako.ConclusionsNew monoclonal OTP specific antibodies have been developed and verified on different automated immunohistochemical staining platforms. The OTP specific monoclonal antibodies showed excellent agreement with the often-used polyclonal antibody allowing application in routine diagnostics.
| S-EPMC9742615 | biostudies-literature
Project description:ObjectiveGenetic studies in obese rodents and humans can provide novel insights into the mechanisms involved in energy homeostasis.MethodsIn this study, we genetically mapped the chromosomal region underlying the development of severe obesity in a mouse line identified as part of a dominant N-ethyl-N-nitrosourea (ENU) mutagenesis screen. We characterized the metabolic and behavioral phenotype of obese mutant mice and examined changes in hypothalamic gene expression. In humans, we examined genetic data from people with severe early onset obesity.ResultsWe identified an obese mouse heterozygous for a missense mutation (pR108W) in orthopedia homeobox (Otp), a homeodomain containing transcription factor required for the development of neuroendocrine cell lineages in the hypothalamus, a region of the brain important in the regulation of energy homeostasis. OtpR108W/+ mice exhibit increased food intake, weight gain, and anxiety when in novel environments or singly housed, phenotypes that may be partially explained by reduced hypothalamic expression of oxytocin and arginine vasopressin. R108W affects the highly conserved homeodomain, impairs DNA binding, and alters transcriptional activity in cells. We sequenced OTP in 2548 people with severe early-onset obesity and found a rare heterozygous loss of function variant in the homeodomain (Q153R) in a patient who also had features of attention deficit disorder.ConclusionsOTP is involved in mammalian energy homeostasis and behavior and appears to be necessary for the development of hypothalamic neural circuits. Further studies will be needed to investigate the contribution of rare variants in OTP to human energy homeostasis.
| S-EPMC5681237 | biostudies-literature
Project description:Limited number of tumor types have been examined for Orthopedia Homeobox (OTP) expression. In pulmonary carcinoids, loss of expression is a strong indicator of poor prognosis. Here, we investigated OTP expression in 37 different tumor types, and the association between OTP expression and DNA methylation levels in lung neuroendocrine neoplasms. We analyzed publicly available multi-omics data (whole-exome-, whole-genome-, RNA sequencing and Epic 850K-methylation array) of 58 typical carcinoids, 27 atypical carcinoids, 69 large cell neuroendocrine carcinoma and 51 small cell lung cancer patients and TCGA (The Cancer Genome Atlas) data of 33 tumor types. 850K-methylation analysis was cross-validated using targeted pyrosequencing on 35 carcinoids. We report bimodality of OTP expression in carcinoids (OTPhigh vs OTPlow group, likelihood-ratio test P = 1.5 × 10-2 ), with the OTPhigh group specific to pulmonary carcinoids while absent from all other cohorts analyzed. Significantly different DNA methylation levels were observed between OTPhigh and OTPlow carcinoids in 12/34 OTP infinium probes (FDR < 0.05 and β-value effect size > .2). OTPlow carcinoids harbor high DNA methylation levels as compared to OTPhigh carcinoids. OTPlow carcinoids showed a significantly worse overall survival (log-rank test P = .0052). Gene set enrichment analysis for somatically mutated genes associated with hallmarks of cancer showed robust enrichment of three hallmarks in the OTPlow group, that is, sustaining proliferative signaling, evading growth suppressor and genome instability and mutation. Together our data suggest that high OTP expression is a unique feature of pulmonary carcinoids with a favorable prognosis and that in poor prognostic patients, OTP expression is lost, most likely due to changes in DNA methylation levels.
| S-EPMC9303689 | biostudies-literature
Project description:Evasion of innate immunity represents a frequently employed method by which tumor cells survive and thrive. Previously, the development of immunotherapeutic agents capable of overcoming this evasion has realized pronounced clinical utility across a variety of cancer types. More recently, immunological strategies have been investigated as potentially viable therapeutic and diagnostic modalities in the management of carcinoid tumors. Classic treatment options for carcinoid tumors rely upon surgical resection or non-immune pharmacology. Though surgical intervention can be curative, tumor characteristics, such as size, location, and spread, heavily limit success. Non-immune pharmacologic treatments can be similarly limited, and many demonstrate problematic side effects. Immunotherapy may be able to overcome these limitations and further improve clinical outcomes. Similarly, emerging immunologic carcinoid biomarkers may improve diagnostic capabilities. Recent developments in immunotherapeutic and diagnostic modalities of carcinoid management are summarized here.
| S-EPMC10004351 | biostudies-literature
Project description:ObjectivesThe optimal management of locally advanced and metastatic pulmonary carcinoid tumors remains to be determined.Materials and methodsA retrospective review was conducted on patients with typical and atypical pulmonary carcinoid tumors treated at our institutions between 1990 and 2012.Results300 patients were identified with pulmonary carcinoid, (80 patients with atypical carcinoid), of whom 29 presented with metastatic disease (16 atypical). Of evaluable patients, 26 (41%) with stages I-III atypical carcinoid tumors recurred at a median time of 3.7 years (range, 0.4-32), compared to 3 (1%) patients with typical carcinoid (range, 8-12.3). 39 patients were treated with chemotherapy, including 30 patients with metastatic disease (27 atypical), and 7 patients were treated with adjuvant platinum-etoposide chemoradiation (6 atypical, 1 typical, 6 stage IIIA, 1 stage IIB). At a median follow-up of 2 years there were 2 recurrences in the 7 patients receiving adjuvant treatment. Median survival after diagnosis of metastatic disease for patients with atypical pulmonary carcinoid was 3.3 years with a 5-year survival of 24%. Treatment regimens showing efficacy in pulmonary carcinoid include 15 patients treated with octreotide-based therapies (10% response rate (RR), 70% disease control rate (DCR), 15 month median progression-free survival (PFS)), 13 patients treated with etoposide+platinum (23% RR, 69% DCR, 7 month median PFS), and 14 patients treated with temozolomide-based therapies (14% RR, 57% DCR, 10 month median PFS). 8 of 10 patients with octreotide-avid disease treated with an octreotide-based regimen experienced disease control (1 partial response, 7 stable disease) for a median of 18 months (range 6-72 months).ConclusionsThese results support our previous finding that a subset of pulmonary carcinoid tumors are responsive to chemotherapy.
| S-EPMC4293119 | biostudies-literature
Project description:Pulmonary carcinoid tumors account for up to 5% of all lung malignancies in adults, comprise 30% of all carcinoid malignancies, and are defined histologically as typical carcinoid (TC) and atypical carcinoid (AC) tumors. The role of specific genomic alterations in the pathogenesis of pulmonary carcinoid tumors remains poorly understood. We sought to identify genomic alterations and pathways that are deregulated in these tumors to find novel therapeutic targets for pulmonary carcinoid tumors.We performed integrated genomic analysis of carcinoid tumors comprising whole genome and exome sequencing, mRNA expression profiling and SNP genotyping of specimens from normal lung, typical and atypical carcinoid, and small cell lung carcinoma (SCLC) to fully represent the lung neuroendocrine tumor spectrum. Pathway analysis of of CNV and gene expression data suggested deregulation of the NF-ĸB and MAPK/ERK pathways. This study identified mutated genes affecting cancer relevant pathways and biological processes that could provide opportunities for developing targeted therapies for pulmonary carcinoid tumors.
2018-01-26 | GSE108055 | GEO
Project description:BACKGROUND: Pulmonary neuroendocrine tumors (Pulmonary NETs) include a wide spectrum of tumors, from the low-grade typical carcinoid (TC) and the intermediate-grade atypical carcinoid (AC), to the high-grade large-cell neuroendocrine carcinoma (LCNEC) and the small-cell carcinoma (SCLC). Epithelial Mesenchymal Transition (EMT) is a process initially recognised during several critical stages of embryonic development, which has more recently been implicated in promoting carcinoma invasion and metastasis. The initial stage of the EMT process begins with the deregulation of adhesion molecules, such as E-cadherin, due to transcriptional repression carried out by factors such as Snail family members, Twist and Foxc2. METHODS: Immunohistochemistry for EMT markers and E-cadherin/ ?-catenin complex in 134 patients with pulmonary NETs between 1990 - 2009. Analysis of potential associations with clinicopathological variables and survival. RESULTS: Pulmonary NETs of high malignant potential (LCNEC and SCLC) had reduced expression of the adhesion molecules and high level expression of transcriptional repressors (Snail1, Snail2, Twist and Foxc2). Snail high expression levels and the loss of E-cadherin/?-catenin complex integrity had the strongest negative effect on the five-year survival rates. E-cadherin/?-catenin complex integrity loss independently predicted lymph node involvement and helped in Atypical Carcinoid (AC) vs Typical Carcinoid (TC) differential diagnosis. Importantly, among the TC group, the loss of E-cadherin/?-catenin complex integrity identified patients with an adverse clinical course despite favourable clinicopathological features. CONCLUSION: The immunohistochemical determination of E-cadherin/?-catenin complex integrity loss and EMT markers in the clinical setting might be a potential useful diagnostic and prognostic tool especially among the TC patients.
| S-EPMC4256901 | biostudies-other
Project description:BackgroundFor young borderline ovarian tumor (BOT) patients, preservation of the uterus was incorporated as an accepted option into treatment guidelines. For the endometrioid subtype (eBOT) however, adequate histological evaluation is challenging and might be associated with synchronous endometrial disorders or misinterpreted as spread from uterine primaries.Case presentationWe report the cases of two young patients with eBOT who underwent treatment according to current guidelines. In both cases, unexpected findings of invasive uterine carcinomas were established in final histopathological evaluation.ConclusionsThis constellation highlights the challenging diagnostic workup of BOT and underlines that uterine curettage is indispensable for eBOT to exclude uterine primary tumors when fertility preservation is planned. Accordingly, we suggest to include this procedure into recommendations for diagnostic workup and to state the potential risk in treatment guidelines.
| S-EPMC8265084 | biostudies-literature
Project description:Neuroendocrine tumors (NETs) are epithelial malignancies that can arise from multiple tissues. Gastrointestinal (GI) NETs are the most common; in this review of extra-abdominal carcinoid tumors, we focus our discussion on bronchial and thymic carcinoid tumors. Bronchial carcinoid tumors comprise a quarter of all NETs and less than 2% of all lung cancers. Thymic carcinoid tumors are extremely rare, accounting for 5% of thymic tumors. Both bronchial and thymic carcinoid tumors are histologically classified as either typical or atypical based on their mitotic rate (less than 2 or 2-10 mitoses per 10 high-powered fields (HPF), respectively). Both bronchial and thymic carcinoids can present with symptoms of obstruction and potentially carcinoid syndrome. The gold standard of management of bronchial and thymic carcinoid tumors is surgical resection. For patients with advanced disease, first-line systemic therapy is generally somatostatin analog monotherapy with octreotide or lanreotide. In patients with refractory disease, therapy generally involves peptide receptor radioligand therapy, everolimus, or cytotoxic chemotherapy. There are ongoing, prospective trials comparing the mainstays of systemic therapy for these patients, as well as ongoing evaluations of immune checkpoint inhibitors and multi-kinase inhibitors. Prognosis for both bronchial and thymic carcinoid tumors depends on histologic grade, local versus invasive disease, and extent of metastases. Herein we provide a summary of the pathophysiologic and clinical background, the current state of the field in diagnosis and management, and note of key ongoing prospective trials for patients with bronchial and thymic carcinoid tumors.
| S-EPMC10134339 | biostudies-literature
Project description:The aim of our study was to explore the value of the 8th edition TNM staging system on evaluating the prognosis of colorectal carcinoid. Colorectal carcinoid patients between 1988 and 2015 were selected in the Surveillance, Epidemiology, and End Results Program (SEER) database for analysis. About 4286 patients with colorectal carcinoid tumors were identified, of which were carcinoid tumor NOS (n = 1726), neuroendocrine carcinoma (NEC) (n = 1346) and other carcinoid tumor (OCT) (n = 591). Worsening 10-year CSS rates with increasing N status, M status, and SEER historic stage were demonstrated across all three above groups (all P < .05). In carcinoid tumor NOS, significant differences in CSS were found with increasing combined 8th AJCC stages (P < .001), except for that between stage II and stage III (10-year CSS rate: 82.6% vs 84.3%, P = .68). While combined 8th TNM stage in NEC and OTC exhibited greater separations in CSS despite on-going overlaps between groups. For carcinoid tumor NOS, stage II (HR = 3.37; 95% CI: 0.97-11.76), and stage III (HR = 2.09; 95% CI: 0.51-8.66) conferred no significant difference in CSS compared with stage I, while stage IV had an increasing HR of 5.09 (95% CI: 1.08-24.08). Although combined 8th AJCC stage had a good ability to distinguish 10-year CSS of patients with NEC or OCT, detailed 8th AJCC stage did not seem to be applicable. Detailed 8th AJCC categories of advanced stages in all the three groups conferred increased HRs with overlapping CIs. However, in the early and middle status, HRs did not increase with the increase of stages, or there was no difference in HRs between adjacent stages. Combined 8th TNM stage was not practical for judging the survival outcomes of colorectal carcinoid tumor NOS, especially in patients with stages II and III, but it provided useful prognostic information for NEC and OCT. However, for all carcinoid tumors, the prognostic values of detailed 8th AJCC stage were not enough accurate in the clinic. More optimized staging methods should be developed and validated in the future.
| S-EPMC7643648 | biostudies-literature