RESUMO
Major depressive disorder (MDD) is a common comorbidity in chronic obstructive pulmonary disease (COPD), affecting up to 57% of patients with COPD. Although the comorbidity of COPD and MDD is well established, the causal relationship between these two diseases is unclear. A large-scale electronic health record clinical biobank and genome-wide association study summary statistics for MDD and lung function traits were used to investigate potential shared underlying genetic susceptibility between COPD and MDD. Linkage disequilibrium score regression was used to estimate genetic correlation between phenotypes. Polygenic risk scores (PRS) for MDD and lung function traits were developed and used to perform a phenome-wide association study (PheWAS). Multi-trait-based conditional and joint analysis identified single-nucleotide polymorphisms (SNPs) influencing both lung function and MDD. We found genetic correlations between MDD and all lung function traits were small and not statistically significant. A PRS-MDD was significantly associated with an increased risk of COPD in a PheWAS [odds ratio (OR) = 1.12, 95% confidence interval (CI): 1.09-1.16] when adjusting for age, sex and genetic ancestry, but this relationship became attenuated when controlling for smoking history (OR = 1.08, 95% CI: 1.04-1.13). No significant associations were found between the lung function PRS and MDD. Multi-trait-based conditional and joint analysis identified three SNPs that may contribute to both traits, two of which were previously associated with mood disorders and COPD. Our findings suggest that the observed relationship between COPD and MDD may not be driven by a strong shared genetic architecture.
Assuntos
Transtorno Depressivo Maior/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/genética , Adulto , Idoso , Comorbidade , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/fisiopatologia , Feminino , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Herança Multifatorial/genética , Fenótipo , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fatores de Risco , Tennessee/epidemiologiaRESUMO
OBJECTIVES: From a genetic perspective, relatively little is known about how mass emigrations of African, European, and Asian peoples beginning in the 16th century affected Indigenous Caribbean populations. Therefore, we explored the impact of serial colonization on the genetic variation of the first Caribbean islanders. MATERIALS AND METHODS: Sixty-four members of St. Vincent's Garifuna Community and 36 members of Trinidad's Santa Rosa First People's Community (FPC) of Arima were characterized for mitochondrial DNA and Y-chromosome diversity via direct sequencing and targeted SNP and STR genotyping. A subset of 32 Garifuna and 18 FPC participants were genotyped using the GenoChip 2.0 microarray. The resulting data were used to examine genetic diversity, admixture, and sex biased gene flow in the study communities. RESULTS: The Garifuna were most genetically comparable to African descendant populations, whereas the FPC were more similar to admixed American groups. Both communities also exhibited moderate frequencies of Indigenous American matrilines and patrilines. Autosomal SNP analysis indicated modest Indigenous American ancestry in these populations, while both showed varying degrees of African, European, South Asian, and East Asian ancestry, with patterns of sex-biased gene flow differing between the island communities. DISCUSSION: These patterns of genetic variation are consistent with historical records of migration, forced, or voluntary, and suggest that different migration events shaped the genetic make-up of each island community. This genomic study is the highest resolution analysis yet conducted with these communities, and provides a fuller understanding of the complex bio-histories of Indigenous Caribbean peoples in the Lesser Antilles.
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Grupos Raciais/genética , Grupos Raciais/história , Adulto , Cromossomos Humanos Y/genética , DNA/genética , DNA Mitocondrial/genética , Feminino , Genética Populacional , História do Século XV , História do Século XVI , História do Século XVIII , História do Século XIX , História Antiga , Migração Humana/história , Humanos , Masculino , São Vicente e Granadinas , Trinidad e TobagoRESUMO
OBJECTIVE: Overall about 10 to 20% of pheochromocytomas/paragangliomas (PHEOs/PGLs) are metastatic, with higher metastatic potential observed in succinate dehydrogenase subunit B/fumarate hydratase (SDHB/FH)-related tumors. Due to the improved availability of biochemical and genetic testing and the frequent use of anatomical/functional imaging, there is currently a higher detection rate of metastatic PHEO/PGL. METHODS: A retrospective analysis of 132 patients (27 children, 105 adults) with metastatic PHEO/PGL diagnosed and treated from 2000 to 2014 was conducted. RESULTS: Seventy-seven (58%) males and 55 (42%) females were included; 39 (30%) have died, with no sex preference. Seventy-three (55%) patients had SDHB mutations; 59 (45%) patients had apparently sporadic tumors (AST). SDHB patients had an average age at primary tumor diagnosis of 31 ± 16 years compared to 40 ± 15 years in AST patients (P<.001). The average metastatic interval (MI) decreased with increasing age in both SDHB and AST patients (P = .013 for both). Only 16% of all primary tumors were smaller than 4.5 cm. Eleven percent of patients had biochemically silent disease, more with SDHB. Of SDHB patients, 23% had metastatic tumors at first diagnosis, compared to 15% of AST patients. Five- and 10-year survival rates were significantly better for metastatic AST than SDHB patients (P = .01). Overall survival was significantly different between children and adults (P = .037); this was mostly attributed to the SDHB patients, in whom children had statistically significantly longer survival than adults (P = .006). The deceased patients all died due to the PHEO/PGL and mainly had noradrenergic phenotypes. CONCLUSION: In children, metastatic PHEOs/PGLs are mainly due to SDHB mutations; in adults they are equally distributed between in SDHB mutations and AST, with better 5- and 10-year survival rates for ASTs. In SDHB patients, children survive longer than adults. Primary metastatic tumors, most presenting as noradrenergic PGLs, are larger than 4.5 cm in >80% of patients. The frequency of metastatic tumors from primary AST increases with age, including a decreased MI compared to SDHB tumors. These results support several recommendations that are summarized in the Discussion.
Assuntos
Neoplasias das Glândulas Suprarrenais/epidemiologia , Neoplasias das Glândulas Suprarrenais/patologia , Paraganglioma/epidemiologia , Paraganglioma/patologia , Feocromocitoma/epidemiologia , Feocromocitoma/patologia , Adolescente , Neoplasias das Glândulas Suprarrenais/genética , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , National Institutes of Health (U.S.) , Metástase Neoplásica , Paraganglioma/genética , Feocromocitoma/genética , Prognóstico , Estudos Retrospectivos , Succinato Desidrogenase/genética , Análise de Sobrevida , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Hereditary head and neck paragangliomas (HNPGLs) account for at least 35% of all HNPGLs, most commonly due to germline mutations in SDHx susceptibility genes. Several studies about sympathetic paragangliomas have shown that (18)F-FDG PET/CT was not only able to detect and localize tumours, but also to characterize tumours ((18)F-FDG uptake being linked to SDHx mutations). However, the data concerning (18)F-FDG uptake specifically in HNPGLs have not been addressed. The aim of this study was to evaluate the relationship between (18)F-FDG uptake and the SDHx mutation status in HNPGL patients. METHODS: (18)F-FDG PET/CT from sixty HNPGL patients were evaluated. For all lesions, we measured the maximum standardized uptake values (SUVmax), and the uptake ratio defined as HNPGL-SUVmax over pulmonary artery trunk SUVmean (SUVratio). Tumour sizes were assessed on radiological studies. RESULTS: Sixty patients (53.3% with SDHx mutations) were evaluated for a total of 106 HNPGLs. HNPGLs-SUVmax and SUVratio were highly dispersed (1.2-30.5 and 1.0-17.0, respectively). The HNPGL (18)F-FDG uptake was significantly higher in SDHx versus sporadic tumours on both univariate and multivariate analysis (P = 0.002). We developed two models for calculating the probability of a germline SDHx mutation. The first one, based on a per-lesion analysis, had an accuracy of 75.5%. The second model, based on a per-patient analysis, had an accuracy of 80.0%. CONCLUSIONS: (18)F-FDG uptake in HNPGL is strongly dependent on patient genotype. Thus, the degree of (18)F-FDG uptake in these tumours can be used clinically to help identify patients in whom SDHx mutations should be suspected.
Assuntos
Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Síndromes Neoplásicas Hereditárias/diagnóstico por imagem , Paraganglioma Extrassuprarrenal/diagnóstico por imagem , Succinato Desidrogenase/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Criança , Feminino , Fluordesoxiglucose F18 , Predisposição Genética para Doença , Genótipo , Neoplasias de Cabeça e Pescoço/genética , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas Mitocondriais/genética , Imagem Multimodal , Análise Multivariada , Síndromes Neoplásicas Hereditárias/genética , Paraganglioma Extrassuprarrenal/genética , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Tomografia Computadorizada por Raios X , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Adulto JovemRESUMO
BACKGROUND: Succinate dehydrogenase subunit B (SDHB) mutations are associated with aggressive pheochromocytoma (PHEO)/paraganglioma (PGL) behavior, often resulting in metastatic disease and fatal outcomes. These tumors are often larger, extra-adrenal, and contain lower catecholamine concentrations than other hereditary PHEOs/PGLs. This study evaluated the size and age at diagnosis of primary SDHB-related PHEOs/PGLs as independent predictors of their metastatic behavior and outcome (survival). METHODS: One hundred six patients with SDHB mutation-related PHEO/PGL were included in this retrospective study. The recorded largest diameters, locations, and patient ages at initial diagnosis of SDHB-related primary tumors were analyzed in the context of time to metastasis and patient survival. RESULTS: First, the development of metastatic disease in patients with primary tumors ≥4.5 cm was significantly earlier than in patients with smaller tumors (P = 0.003). Second, patients with primary tumors larger than 5.5 cm also had worse overall survival than patients with smaller tumors (P = 0.008). Third, age at initial diagnosis was found to be an independent predictor of patient survival (PHEOs: P = 0.041; PGLs: P < 0.001). Fourth, we did not observe a significant difference in survival based on the specific SDHB mutations or patient sex. CONCLUSION: Receiver operating characteristic curves established 4.5 cm as the best value to dichotomize the primary SDHB-related PHEO/PGL in order to evaluate the development of metastatic disease and 5.5 cm as the best value for survival prediction. Subsequently, the size of the primary tumor was found as an age-independent predictor of patient survival and metastases development in PGL. In both PHEO and PGL, age at diagnosis was found to be a size-independent predictor of patient survival. No significant difference was found in metastases development or patient survival between males and females or among specific SDHB mutations. This data further extends and supports previous recommendations that carriers with SDHB mutations must undergo early and regular evaluations to detect PHEO/PGL in order to achieve the best clinical outcome.
Assuntos
Neoplasias das Glândulas Suprarrenais/patologia , Metástase Neoplásica/patologia , Paraganglioma/patologia , Feocromocitoma/patologia , Succinato Desidrogenase/genética , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Adulto , Fatores Etários , Detecção Precoce de Câncer , Feminino , Humanos , Masculino , Metástase Neoplásica/genética , Paraganglioma/diagnóstico , Paraganglioma/genética , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Adulto JovemRESUMO
OBJECTIVE: Medullary thyroid carcinoma (MTC) and pheochromocytoma/paraganglioma (PHEO/PGL) are rare neuroendocrine tumors. Because of the increased metastatic rates in certain genetic backgrounds, early diagnosis and treatment are essential to improved patient outcomes. Our objective was to summarize recent findings related to the genetics, diagnosis, and management of MTC and PHEO/PGL. METHODS: A literature review was performed. RESULTS: MTC is primarily associated with mutations in the rearranged during transfection (RET) proto-oncogene. Determining the specific genetic mutation can guide patient management and screening. Early detection and appropriate surgical management of MTC is critical to prevent or limit metastatic spread, as treatment options for patients with metastatic disease are limited. PHEO/PGL also has a strong genetic component, with approximately 50% of cases linked to germline and somatic mutations in 15 genes. Although most PHEO/PGLs are benign, factors such as genetic background, size, tumor location, and high methoxytyramine levels are associated with higher rates of metastatic disease. The state-of-the-art diagnosis and localization of PHEO/PGLs is based on measurement of plasma metanephrines and methoxytyramine and functional imaging studies. For both PHEO/PGL and MTC, surgery is the only curative treatment. Treatment options for patients with metastatic disease are limited. CONCLUSION: As genetic testing becomes more widely available, the diagnosis of MTC and PHEO/PGL will be made earlier due to routine screening of at-risk patients. In addition, continued advances in basic science, diagnostic methods, and imaging techniques will improve understanding of the pathogenesis of these diseases and facilitate the introduction of novel treatment strategies for patients with metastatic disease.
Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Carcinoma Neuroendócrino/genética , Paraganglioma/genética , Feocromocitoma/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/terapia , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/terapia , Testes Genéticos , Humanos , Paraganglioma/diagnóstico , Paraganglioma/terapia , Feocromocitoma/diagnóstico , Feocromocitoma/terapia , Proto-Oncogene Mas , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/terapiaAssuntos
Autoimunidade , Proteínas/metabolismo , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Humanos , Modelos Logísticos , Fenótipo , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Proteínas/imunologia , Doença Pulmonar Obstrutiva Crônica/genética , População BrancaRESUMO
BACKGROUND: Pheochromocytomas (PCCs)/paragangliomas (PGLs) are neuroendocrine tumours that may cause arrhythmia and death if untreated. Treatment for patients with metastatic tumours is lacking. As new PCC/PGL susceptibility genes are discovered that are associated with the mTOR pathway, treatment targets focusing on this pathway are being intensively explored. DESIGN: Twenty-one human PCC/PGLs were analysed from two tertiary care centres. Immunohistochemistry (IHC) analysis was performed for phospho-mTOR (pmTOR), phospho-S6K (pS6K), phosphoinositide 3-kinase (PI3K), phospho-4EBP1 (p4EBP1), HIF1α and MIB-1 in 6 metastatic SDHB PCC/PGLs, 15 nonmetastatic PCC/PGLs, (including 1 TMEM127 PCC and 1 nonmetastatic SDHB PGL) and 6 normal adrenal medullas. The product of the intensity of stain and percentage of cells stained was calculated as an H score. RESULTS: Using a two-sample t-test and paired t-test, pmTOR and pS6K had significantly higher H scores in nonmetastatic PCC/PGLs than in metastatic SDHB PCC/PGLs. HIF1α had significantly higher H scores in metastatic SDHB PCC/PGLs compared with nonmetastatic PCC/PGLs and normal adrenal medulla. No difference in H scores was seen with p4EBP1, PI3K and MIB-1 when comparing metastatic SDHB PCC/PGLs and nonmetastatic PCC/PGLs. Significantly higher difference in pS6K was seen in normal adrenal medullas compared to nonmetastatic PCC/PGLs and metastatic SDHB PCC/PGLs. CONCLUSION: The present results suggest that the use of mTOR inhibitors alone for metastatic SDHB PCC/PGLs may not achieve good therapeutic efficacy in patients.
Assuntos
Paraganglioma/metabolismo , Succinato Desidrogenase/genética , Serina-Treonina Quinases TOR/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Medula Suprarrenal/metabolismo , Proteínas de Ciclo Celular , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Mutação/genética , Metástase Neoplásica , Paraganglioma/tratamento farmacológico , Paraganglioma/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Quinases S6 Ribossômicas/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Ubiquitina-Proteína Ligases/metabolismo , Regulação para CimaRESUMO
Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD). Little is known about the prevalence and clinical profiles of patients with COPD-PH. We report the clinical characteristics, hemodynamic profiles, and prognosis in a large population of patients with COPD referred for right heart catheterization (RHC). We extracted data from all patients referred for RHC between 1997 and 2017 in Vanderbilt's deidentified medical record. PH was defined as mean pulmonary artery pressure >20 mmHg. Pre- and postcapillary PH were defined according to contemporary guidelines. COPD was identified using a validated rules-based algorithm requiring international classification of diseases codes relevant to COPD. We identified 6065 patients referred for RHC, of whom 1509 (24.9%) had COPD and 1213 had COPD and PH. Patients with COPD-PH had a higher prevalence of diabetes, atrial fibrillation, and heart failure compared with COPD without PH. Approximately 55% of patients with COPD-PH had elevated left ventricle (LV) filling pressure. Pulmonary function testing data from individuals with COPD-PH revealed subtype differences, with precapillary COPD-PH having lower diffusion capacity of the lungs for carbon monoxide (DLCO) values than the other COPD-PH subtypes. Patients with COPD-PH had significantly increased mortality compared with COPD alone (hazard ratio [HR]: 1.70, 95% confidence interval [CI]: 1.28-2.26) with the highest mortality among the combined pre- and postcapillary COPD-PH subgroup (HR: 2.39; 95% CI: 1.64-3.47). PH is common among patients with COPD referred for RHC. The etiology of PH in patients with COPD is often mixed due to multimorbidity and is associated with high mortality, which may have implications for risk factor management.
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PURPOSE: Genetic differences in immunity may contribute to toxicity and outcomes with immune checkpoint inhibitor (CPI) therapy, but these relationships are poorly understood. We examined the genetics of thyroid immune-related adverse events (irAE). EXPERIMENTAL DESIGN: In patients with non-small cell lung cancer (NSCLC) treated with CPIs at Memorial Sloan Kettering (MSK) and Vanderbilt University Medical Center (VUMC), we evaluated thyroid irAEs. We typed germline DNA using genome-wide single-nucleotide polymorphism (SNP) arrays and imputed genotypes. Germline SNP imputation was also performed in an independent Dana-Farber Cancer Institute (DFCI) cohort. We developed and validated polygenic risk scores (PRS) for hypothyroidism in noncancer patients using the UK and VUMC BioVU biobanks. These PRSs were applied to thyroid irAEs and CPI response in patients with NSCLC at MSK, VUMC, and DFCI. RESULTS: Among 744 patients at MSK and VUMC, thyroid irAEs occurred in 13% and were associated with improved outcomes [progression-free survival adjusted HR (PFS aHR) = 0.68; 95% confidence interval (CI), 0.52-0.88]. The PRS for hypothyroidism developed from UK Biobank predicted hypothyroidism in the BioVU dataset in noncancer patients [OR per standard deviation (SD) = 1.33, 95% CI, 1.29-1.37; AUROC = 0.6]. The same PRS also predicted development of thyroid irAEs in both independent cohorts of patients treated with CPIs (HR per SD = 1.34; 95% CI, 1.08-1.66; AUROC = 0.6). The results were similar in the DFCI cohort. However, PRS for hypothyroidism did not predict CPI benefit. CONCLUSIONS: Thyroid irAEs were associated with response to anti-PD-1 therapy. Genetic risk for hypothyroidism was associated with risk of developing thyroid irAEs. Additional studies are needed to determine whether other irAEs also have shared genetic risk with known autoimmune disorders and the association with treatment response.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Doenças da Glândula Tireoide/induzido quimicamente , Doenças da Glândula Tireoide/genética , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Resultado do TratamentoAssuntos
Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/secundário , Paraganglioma/patologia , Tomografia por Emissão de Pósitrons , Idoso , Transporte Biológico , Neoplasias Ósseas/metabolismo , Didesoxinucleosídeos/metabolismo , Di-Hidroxifenilalanina/análogos & derivados , Di-Hidroxifenilalanina/metabolismo , Dopamina/análogos & derivados , Dopamina/metabolismo , Fluordesoxiglucose F18/metabolismo , Humanos , Masculino , Traçadores RadioativosRESUMO
PURPOSE: Succinate dehydrogenase subunit B (SDHB) gene mutations are associated with an aggressive clinical disease course of pheochromocytoma/paraganglioma (PHEO/PGL). Limited information is available concerning PHEO/PGL penetrance among SDHB mutation carriers with regards to primary tumor location, specific mutation type, and gender. We assessed PHEO/PGL penetrance in SDHB mutation carriers and described the clinical presentation and disease course. METHODS: Asymptomatic relatives (N = 611) of 103 index patients were tested for SDHB mutations. Mutation carriers (N = 328) were offered PHEO/PGL screening, of which 241 participated and were included in penetrance analysis. For additional disease outcome analysis, the 103 index patients and 40 screened individuals who developed PHEO/PGL were included. Clinical data were collected between October 2004 and June 2016. RESULTS: Forty (16.60%) of the 241 screened individuals developed PHEO/PGL during the study. The penetrance estimate in this population was 49.80% (95% CI 29-74.9) at 85 years. A significantly higher age-related penetrance of disease was observed in males compared to females, with 50% penetrance achieved at age 74 vs. not reached. Age-related penetrance analysis demonstrated 4 mutations (Ile127Ser, IVS1+1G>T, Exon 1 deletion, Arg90X) presenting with a slower rate of disease development (50% penetrance ages, respectively: not achieved, 70, 63, 61 years) compared to Arg46X and Val140Phe mutations (50% penetrance at 38 years). CONCLUSIONS: Here, we found a higher estimated penetrance compared to several other studies, and a striking difference in age-related penetrance between male and female SDHB mutation carriers with no association between mutation and gender or tumor location.
Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Paraganglioma/genética , Feocromocitoma/genética , Succinato Desidrogenase/genética , Adolescente , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Paraganglioma/patologia , Penetrância , Feocromocitoma/patologia , Adulto JovemRESUMO
Urinary bladder paraganglioma (paraganglioma) is a rare tumor of chromaffin cells of the sympathetic system of the urinary bladder wall. We studied 14 cases of this entity and investigated the usefulness of SDHB protein staining by immunohistochemistry (IHC) as a diagnostic tool to identify patients with bladder paragangliomas that could be associated with SDHB gene mutations, as these patients have a more aggressive disease. Eleven tumors from these patients were stained by IHC. Six of 11 tumors were negative for SDHB staining by IHC with no cytoplasmic staining in tumor cells when compared with normal tissues. Five of these 6 negative cases were confirmed to be positive for germline SDHB mutations. One case showed negative staining and no germline SDHB mutation; however, further investigation of the tumor revealed a somatic SDHB gene deletion. The remaining 5 cases showed strong cytoplasmic staining, but they were negative for the presence of SDHB mutation. They were found to be either sporadic tumors or part of von Hippel-Lindau syndrome. Staining for SDHA was positive in all cases. Our study confirms that there is very good correlation between the presence of an SDHB mutation, whether germline or sporadic, and negative SDHB IHC staining in urinary bladder paragangliomas, and this is the first study to demonstrate that somatic mutations can be recognized by IHC staining.
Assuntos
Biomarcadores Tumorais/genética , Análise Mutacional de DNA/métodos , Mutação em Linhagem Germinativa , Imuno-Histoquímica , Paraganglioma Extrassuprarrenal/genética , Succinato Desidrogenase/genética , Neoplasias da Bexiga Urinária/genética , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inclusão em Parafina , Paraganglioma Extrassuprarrenal/enzimologia , Paraganglioma Extrassuprarrenal/patologia , Valor Preditivo dos Testes , Fixação de Tecidos , Neoplasias da Bexiga Urinária/enzimologia , Neoplasias da Bexiga Urinária/patologia , Adulto JovemRESUMO
UNLABELLED: (18)F-FDG PET/CT has been proven to be a highly sensitive method for pheochromocytomas/paragangliomas (PHEOs/PGLs) associated with succinate dehydrogenase (SDH) mutations. This finding has been attributed to altered tumor cell metabolism resulting from these mutations and does not provide additional prognostic information to genotype. Therefore, identification of new biomarkers for aggressiveness is needed. A high Ki-67 index was proposed to be an additional prognostic factor. This pilot study aimed to evaluate 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET/CT, a PET proliferation tracer, as a potential imaging agent in a series of 12 PHEO/PGL patients with different genetic backgrounds, to compare (18)F-FLT uptake with (18)F-FDG PET/CT, and to evaluate classic factors of aggressiveness. METHODS: Twelve patients (7 metastatic and 5 nonmetastatic) were prospectively evaluated with (18)F-FDG and (18)F-FLT and followed for at least 2 y after the initial imaging work-up. Uptake was assessed at a lesion level, visually and quantitatively by maximum standardized uptake values (SUVmax) for both tracers. (18)F-FLT uptake was compared with risk factors known to be linked with a poor prognosis in PGLs (SDHB-mutated status, lesion size, dopaminergic phenotype) and with (18)F-FDG uptake. RESULTS: In 12 patients, 77 lesions were assessed. All lesions had low (18)F-FLT uptake (median SUVmax, 2.25; range, 0.7-4.5). There was no apparent superiority of (18)F-FLT uptake in progressive lesions, and most of the lesions showed a mismatch, with high (18)F-FDG uptake (median SUVmax, 10.8; range, 1.1-79.0) contrasting with low (18)F-FLT uptake. CONCLUSION: This study suggests that PHEOs/PGLs-even those that progress-do not exhibit intense (18)F-FLT uptake. It provides the first in vivo demonstration that proliferation may not be a major determinant of (18)F-FDG uptake in these tumors. These findings provide new insight into the biologic behavior of PGL and suggest that antiproliferative agents may be suboptimal for treatment of these tumors.
Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Didesoxinucleosídeos , Paraganglioma/diagnóstico por imagem , Feocromocitoma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idoso , Proliferação de Células , Dopamina , Feminino , Testes Genéticos , Glicólise , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Paraganglioma/genética , Feocromocitoma/genética , Feocromocitoma/patologia , Projetos Piloto , Prognóstico , Padrões de Referência , Fatores de Risco , Imagem Corporal TotalRESUMO
OBJECTIVE: Our primary goal was to examine the clinical characteristics of a series of patients with urinary bladder paragangliomas (UBPGLs), focusing particularly on their genetic backgrounds. MATERIALS AND METHODS: We analyzed the medical records of patients who presented to the National Institutes of Health with UBPGL from 2000 to 2013 to determine their clinical characteristics and outcomes, biochemical phenotype, tumor size, and genetic background. RESULTS: Of the 27 patients with UBPGLs who were identified, 17 (63%) had underlying genetic mutations. Overall, 14 (51.9%) patients had a germline mutation in the succinate dehydrogenase subunit B gene (SDHB), and 3 (11.1%) had mutations in the von Hippel-Lindau gene (VHL). Of the 21 patients who had biochemical data available before their first operation, 19 (90.5%) presented with a noradrenergic biochemical phenotype; 7 (33.3%) patients had tumors that also secreted dopamine. In addition, 1 patient (4.8%) had elevated metanephrine levels, and 2 (9.5%) had normal biochemical data. In total, 13 (48.1%) patients in the series were diagnosed with metastatic disease, at either first presentation or follow-up; 6 of these patients (46.1%) had SDHB mutations. CONCLUSIONS: UBPGLs typically present with a noradrenergic phenotype and are frequently associated with underlying germline mutations. Patients presenting with these rare neuroendocrine tumors should be screened for these mutations. In addition, patients with UBPGLs should be followed up closely for metastatic development regardless of genetic background, as almost half of the patients in this series presented with metastatic disease and less than half of them had SDHB mutations.
Assuntos
Mutação em Linhagem Germinativa , Paraganglioma Extrassuprarrenal/genética , Succinato Desidrogenase/genética , Neoplasias da Bexiga Urinária/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Adolescente , Adulto , Criança , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Paraganglioma Extrassuprarrenal/patologia , Neoplasias da Bexiga Urinária/patologia , Adulto JovemRESUMO
OBJECTIVE: Testing for succinate dehydrogenase subunit B (SDHB) mutations is recommended in all patients with metastatic phaeochromocytomas and paragangliomas (PPGLs), but may not be required when metastatic disease is accompanied by adrenaline production. This retrospective cohort study aimed to establish the prevalence of SDHB mutations among patients with metastatic PPGLs, characterised by production of adrenaline compared with those without production of adrenaline, and to establish genotypephenotype features of metastatic PPGLs according to underlying gene mutations. DESIGN AND METHODS: Presence of SDHB mutations or deletions was tested in 205 patients (114 males) aged 42+/-16 years (range 986 years) at diagnosis of metastatic PPGLs with and without adrenaline production. RESULTS: Twenty-three of the 205 patients (11%) with metastatic PPGLs had disease characterised by production of adrenaline, as defined by increased plasma concentrations of metanephrine larger than 5% of the combined increase in both normetanephrine and metanephrine. None of these 23 patients had SDHB mutations. Of the other 182 patients with no tumoural adrenaline production, 51% had SDHB mutations. Metastases in bone were 3641% more prevalent among patients with SDHB mutations or extra-adrenal primary tumours than those without mutations or with adrenal primary tumours. Liver metastases were 81% more prevalent among patients with adrenal than extra-adrenal primary tumours. CONCLUSION: SDHB mutation testing has no utility among patients with adrenaline-producing metastatic PPGLs, but is indicated in other patients with metastatic disease. Our study also reveals novel associations of metastatic spread with primary tumour location and presence of SDHB mutations.
Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Testes Genéticos/estatística & dados numéricos , Mutação/genética , Feocromocitoma/genética , Succinato Desidrogenase/genética , Adolescente , Neoplasias das Glândulas Suprarrenais/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Criança , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Feocromocitoma/diagnóstico , Análise de Componente Principal , Estudos Retrospectivos , Adulto JovemRESUMO
Pheochromocytomas and paragangliomas are chromaffin cell tumors arising from neuroendocrine cells. At least 1/3 of paragangliomas are related to germline mutations in 1 of 17 genes. Although these tumors can occur throughout the body, cardiac paragangliomas are very rare, accounting for <0.3% of mediastinal tumors. The purpose of this study was to determine the clinical characteristics of patients with cardiac paragangliomas, particularly focusing on their genetic backgrounds. A retrospective chart analysis of 15 patients with cardiac paragangliomas was performed to determine clinical presentation, genetic background, diagnostic workup, and outcomes. The average age at diagnosis was 41.9 years. Typical symptoms of paraganglioma (e.g., hypertension, sweating, palpitations, headache) were reported at initial presentation in 13 patients (86.7%); the remaining 2, as well as 4 symptomatic patients, initially presented with cardiac-specific symptoms (e.g., chest pain, dyspnea). Genetic testing was done in 13 patients (86.7%); 10 (76.9%) were positive for mutations in succinate dehydrogenase (SDHx) subunits B, C, or D. Thirteen patients (86.7%) underwent surgery to remove the paraganglioma with no intraoperative morbidity or mortality; 1 additional patient underwent surgical resection but experienced intraoperative complications after removal of the tumor due to co-morbidities and did not survive. SDHx mutations are known to be associated with mediastinal locations and malignant behavior of paragangliomas. In this report, the investigators extend the locations of predominantly SDHx-related paragangliomas to cardiac tumors. In conclusion, cardiac paragangliomas are frequently associated with underlying SDHx germline mutations, suggesting a need for genetic testing of all patients with this rare tumor.
Assuntos
Neoplasias Cardíacas/genética , Mutação/genética , Paraganglioma/metabolismo , Succinato Desidrogenase/genética , Adulto , Diagnóstico por Imagem , Feminino , Neoplasias Cardíacas/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Paraganglioma/diagnóstico , Estudos RetrospectivosRESUMO
PURPOSE: Paragangliomas (PGLs) are tumors that can metastasize and recur; therefore, lifelong imaging follow-up is required. Hybrid PET/CT is an essential tool to image PGLs. Novel hybrid PET/MRI scanners are currently being studied in clinical oncology. We studied the feasibility of simultaneous whole-body PET/MRI to evaluate patients with PGLs. METHODS: Fifty-three PGLs or PGL-related lesions from 8 patients were evaluated. All patients underwent a single-injection, dual-modality imaging protocol consisting of a PET/CT and a subsequent PET/MRI scan. Four patients were evaluated with F-FDG, 2 with F-fluorodihydroxyphenylalanine, and 2 with F-fluorodopamine. PET/MRI data were acquired using a hybrid whole-body 3-tesla integrated PET/MRI scanner. PET and MRI data (Dixon sequence for attenuation correction and T2-weighted sequences for anatomic allocation) were acquired simultaneously. Imaging workflow and imaging times were documented. PET/MRI and PET/CT data were visually assessed (blindly) in regards to image quality, lesion detection, and anatomic allocation and delineation of the PET findings. RESULTS: With hybrid PET/MRI, we obtained high-quality images in an acceptable acquisition time (median, 31 minutes; range, 25-40 minutes) with good patient compliance. A total of 53 lesions, located in the head and neck area (6 lesions), mediastinum (2 lesions), abdomen and pelvis (13 lesions), lungs (2 lesions), liver (4 lesions), and bones (26 lesions), were evaluated. Fifty-one lesions were detected with PET/MRI and confirmed by PET/CT. Two bone lesions (L4 body, 8 mm, and sacrum, 6 mm) were not detectable on an F-FDA scan PET/MRI, likely because F-FDA was washed out between PET/CT and PET/MRI acquisitions. Coregistered MRI tended to be superior to coregistered CT for head and neck, abdomen, pelvis, and liver lesions for anatomic allocation and delineation. CONCLUSIONS: Clinical PGL evaluation with hybrid PET/MRI is feasible with high-quality image and can be obtained in a reasonable time. It could be particularly beneficial for the pediatric population and for precise lesion definition in the head and neck, abdomen, pelvis, and liver.
Assuntos
Di-Hidroxifenilalanina/análogos & derivados , Dopamina/análogos & derivados , Fluordesoxiglucose F18 , Imageamento por Ressonância Magnética , Paraganglioma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Adulto , Feminino , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , National Institutes of Health (U.S.) , Estados Unidos , Imagem Corporal TotalRESUMO
Head and neck paragangliomas (HNPGLs) are rare neuroendocrine tumors belonging to the family of pheochromocytoma/paraganglioma neoplasms. Despite advances in understanding the pathogenesis of these tumors, the growth potential and clinical outcome of individual cases remains largely unpredictable. Over several decades, surgical resection has long been the treatment of choice for HNPGLs. However, increasing experience in various forms of radiosurgery has been reported to result in curative-like outcomes, even for tumors localized in the most inaccessible anatomical areas. The emergence of such new therapies challenges the traditional paradigm for the management of HNPGLs. This review will assist and guide physicians who encounter patients with such tumors, either from a diagnostic or therapeutic standpoint. This review will also particularly emphasize current and emerging knowledge in genetics, imaging, and therapeutic options as well as the health-related quality of life for patients with HNPGLs.
Assuntos
Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/terapia , Paraganglioma/diagnóstico , Paraganglioma/terapia , Neoplasias de Cabeça e Pescoço/etiologia , Humanos , Paraganglioma/etiologiaRESUMO
PURPOSE: Pheochromocytomas (PCCs) are neuroendocrine tumors arising from the adrenal medulla or as paraganglioma (PGL) from extra-adrenal sites. While usually benign, a small fraction is malignant. Multi-modality therapy is used in treating malignant disease; however, little data exist on the role of external beam radiation therapy (EBRT). In this retrospective review, we assessed response to EBRT in malignant PCCs or PGLs. METHODS AND MATERIALS: Records of patients treated at the National Institutes of Health who received EBRT between 1990 and 2012 were studied. Patients were assessed for symptomatic control, biochemical response, local and distant control by response evaluation criteria in solid tumors v1.1 or stable disease on imaging reports, toxicity by radiation therapy oncology group (RTOG) criteria, and survival. RESULTS: There were 24 patients treated who received EBRT to lesions of the abdomen (n = 3), central nervous system (n = 4), and bone (n = 40). Lesions were treated with 3D conformal EBRT to a mean dose of 31.8 Gy in 3.3 Gy fractions, or fractionated stereotactic radiosurgery to 21.9 Gy in 13.6 Gy fractions. Patients experienced acute (n = 15) and late (n = 2) RTOG toxicities; no patient experienced acute toxicity ≥4 or late toxicity ≥2. Symptomatic control was achieved in 81.1% of lesions. Stable radiographic response was achieved in 86.7% of lesions with progression in 13%. Distant progression was observed overall in 75% of patients and average survival was 52.4 months. CONCLUSION: Malignant PCC and PGL often do not respond well to current systemic therapies. In these cases, EBRT can be considered in patients with symptomatic, localized disease progression.