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1.
J Clin Endocrinol Metab ; 105(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31665449

RESUMO

CONTEXT: Urine steroid metabolomics, combining mass spectrometry-based steroid profiling and machine learning, has been described as a novel diagnostic tool for detection of adrenocortical carcinoma (ACC). OBJECTIVE, DESIGN, SETTING: This proof-of-concept study evaluated the performance of urine steroid metabolomics as a tool for postoperative recurrence detection after microscopically complete (R0) resection of ACC. PATIENTS AND METHODS: 135 patients from 14 clinical centers provided postoperative urine samples, which were analyzed by gas chromatography-mass spectrometry. We assessed the utility of these urine steroid profiles in detecting ACC recurrence, either when interpreted by expert clinicians or when analyzed by random forest, a machine learning-based classifier. Radiological recurrence detection served as the reference standard. RESULTS: Imaging detected recurrent disease in 42 of 135 patients; 32 had provided pre- and post-recurrence urine samples. 39 patients remained disease-free for ≥3 years. The urine "steroid fingerprint" at recurrence resembled that observed before R0 resection in the majority of cases. Review of longitudinally collected urine steroid profiles by 3 blinded experts detected recurrence by the time of radiological diagnosis in 50% to 72% of cases, improving to 69% to 92%, if a preoperative urine steroid result was available. Recurrence detection by steroid profiling preceded detection by imaging by more than 2 months in 22% to 39% of patients. Specificities varied considerably, ranging from 61% to 97%. The computational classifier detected ACC recurrence with superior accuracy (sensitivity = specificity = 81%). CONCLUSION: Urine steroid metabolomics is a promising tool for postoperative recurrence detection in ACC; availability of a preoperative urine considerably improves the ability to detect ACC recurrence.

2.
J Clin Endocrinol Metab ; 100(12): 4604-11, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26461265

RESUMO

CONTEXT: Adrenocortical carcinomas (ACCs) are rare, aggressive tumors, of which some express receptors for estradiol, progesterone, and/or human chorionic gonadotoropin. Because this disease is encountered frequently in young women, pregnancy is a relevant issue. OBJECTIVE: to evaluate the impact of pregnancy on outcome of patients previously treated for ACC. DESIGN/SETTING: retrospective observational multicenter study of the European Network for the Study of Adrenal Tumors. PATIENTS: Seventeen ACC patients (21 pregnancies), becoming pregnant at least 3 months after the initial treatment, were compared with 247 nonpregnant ACC patients less than 47 years old. A control group of 34 patients matched for age, sex, and tumor stage was used for survival analysis. MAIN OUTCOME MEASURE(S): Overall survival, tumors characteristics at diagnosis, pregnancy outcome. RESULTS: All 17 patients with pregnancies had localized ACC. The median time between surgery and conception was 4 years (0.3-12 y). Two pregnancies were terminated at 8 weeks. Sixteen women gave birth to 19 live infants. With exception of 1 (presumably unrelated) cardiac malformation, no severe fetal or maternal complication was observed. After a median follow-up time of 8.36 years and 5.26 years after the first conception, 1 of the 17 patients had died and 5 had experienced a recurrence, among whom 3 occurred before conception. Overall survival was not significantly different between the "pregnancy group" and the matched controls. CONCLUSION: Pregnancy in patients previously treated for ACC seems to not be associated with worse clinical outcome, although a "healthy mother effect" cannot be excluded.


Assuntos
Neoplasias do Córtex Suprarrenal/terapia , Carcinoma Adrenocortical/terapia , Gravidez , Adolescente , Neoplasias do Córtex Suprarrenal/complicações , Neoplasias do Córtex Suprarrenal/cirurgia , Adrenalectomia , Carcinoma Adrenocortical/complicações , Carcinoma Adrenocortical/cirurgia , Adulto , Fatores Etários , Anormalidades Congênitas/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Complicações na Gravidez/epidemiologia , Resultado da Gravidez , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
3.
Mod Pathol ; 28(6): 807-21, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25720320

RESUMO

Despite the established role of SDHB/SDHA immunohistochemistry as a valuable tool to identify patients at risk for familial succinate dehydrogenase-related pheochromocytoma/paraganglioma syndromes, the reproducibility of the assessment methods has not as yet been determined. The aim of this study was to investigate interobserver variability among seven expert endocrine pathologists using a web-based virtual microscopy approach in a large multicenter pheochromocytoma/paraganglioma cohort (n=351): (1) 73 SDH mutated, (2) 105 non-SDH mutated, (3) 128 samples without identified SDH-x mutations, and (4) 45 with incomplete SDH molecular genetic analysis. Substantial agreement among all the reviewers was observed either with a two-tiered classification (SDHB κ=0.7338; SDHA κ=0.6707) or a three-tiered classification approach (SDHB κ=0.6543; SDHA κ=0.7516). Consensus was achieved in 315 cases (89.74%) for SDHB immunohistochemistry and in 348 cases (99.15%) for SDHA immunohistochemistry. Among the concordant cases, 62 of 69 (~90%) SDHB-/C-/D-/AF2-mutated cases displayed SDHB immunonegativity and SDHA immunopositivity, 3 of 4 (75%) with SDHA mutations showed loss of SDHA/SDHB protein expression, whereas 98 of 105 (93%) non-SDH-x-mutated counterparts demonstrated retention of SDHA/SDHB protein expression. Two SDHD-mutated extra-adrenal paragangliomas were scored as SDHB immunopositive, whereas 9 of 128 (7%) tumors without identified SDH-x mutations, 6 of 37 (~16%) VHL-mutated, as well as 1 of 21 (~5%) NF1-mutated tumors were evaluated as SDHB immunonegative. Although 14 out of those 16 SDHB-immunonegative cases were nonmetastatic, an overall significant correlation between SDHB immunonegativity and malignancy was observed (P=0.00019). We conclude that SDHB/SDHA immunohistochemistry is a reliable tool to identify patients with SDH-x mutations with an additional value in the assessment of genetic variants of unknown significance. If SDH molecular genetic analysis fails to detect a mutation in SDHB-immunonegative tumor, SDHC promoter methylation and/or VHL/NF1 testing with the use of targeted next-generation sequencing is advisable.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Complexo II de Transporte de Elétrons/análise , Imuno-Histoquímica/normas , Paraganglioma/genética , Feocromocitoma/genética , Succinato Desidrogenase/análise , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Complexo II de Transporte de Elétrons/genética , Humanos , Microscopia/métodos , Mutação , Variações Dependentes do Observador , Succinato Desidrogenase/genética , Telepatologia/métodos
4.
J Clin Endocrinol Metab ; 100(3): 841-9, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25559399

RESUMO

BACKGROUND: Recurrence of adrenocortical carcinoma (ACC) even after complete (R0) resection occurs frequently. OBJECTIVE: The aim of this study was to identify markers with prognostic value for patients in this clinical setting. DESIGN, SETTING, AND PARTICIPANTS: From the German ACC registry, 319 patients with the European Network for the Study of Adrenal Tumors stage I-III were identified. As an independent validation cohort, 250 patients from three European countries were included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinical, histological, and immunohistochemical markers were correlated with recurrence-free (RFS) and overall survival (OS). RESULTS: Although univariable analysis within the German cohort suggested several factors with potential prognostic power, upon multivariable adjustment only a few including age, tumor size, venous tumor thrombus (VTT), and the proliferation marker Ki67 retained significance. Among these, Ki67 provided the single best prognostic value for RFS (hazard ratio [HR] for recurrence, 1.042 per 1% increase; P < .0001) and OS (HR for death, 1.051; P < .0001) which was confirmed in the validation cohort. Accordingly, clinical outcome differed significantly between patients with Ki67 <10%, 10-19%, and ≥20% (for the German cohort: median RFS, 53.2 vs 31.6 vs 9.4 mo; median OS, 180.5 vs 113.5 vs 42.0 mo). Using the combined cohort prognostic scores including tumor size, VTT, and Ki67 were established. Although these scores discriminated slightly better between subgroups, there was no clinically meaningful advantage in comparison with Ki67 alone. CONCLUSION: This largest study on prognostic markers in localized ACC identified Ki67 as the single most important factor predicting recurrence in patients following R0 resection. Thus, evaluation of Ki67 indices should be introduced as standard grading in all pathology reports of patients with ACC.


Assuntos
Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/cirurgia , Carcinoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/cirurgia , Biomarcadores Tumorais/metabolismo , Antígeno Ki-67/metabolismo , Adolescente , Neoplasias do Córtex Suprarrenal/mortalidade , Adrenalectomia , Carcinoma Adrenocortical/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
5.
Int J Cancer ; 135(11): 2711-20, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-24752622

RESUMO

Cyclophosphamide-dacarbazine-vincristine regimen is recommended for the treatment of malignant pheochromocytoma and paraganglioma (MPP); however, dacarbazine is the only recognized active drug in neuroendocrine tumours. We investigated the therapeutic benefit of temozolomide (TMZ), an oral alternative to dacarbazine, in patients with MPP. This is a retrospective study of consecutive patients with documented progressive MPP. We examined the correlation between Succinate dehydrogenase B (SDHB) mutation and O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation and MGMT expression in the French nation-wide independent cohort of 190 pheochromocytomas or paragangliomas (PP). Progression-free survival (PFS) according to RECIST 1.1 and PERCIST 1.0 criteria was the primary end point. Fifteen consecutive patients with MPP were enrolled; ten (67%) carried a mutation in SDHB. The mean dose intensity of TMZ was 172 mg/m(2) /d for 5 days every 28 days. Median PFS was 13.3 months after a median follow-up of 35 months. There were five partial responses (33%), seven stable (47%) and three progressive diseases (20%). Grade 3 toxicities were lymphopenia in two patients and hypertension in one. Partial responses were observed only in patients with mutation in SDHB. MGMT immunohistochemistry was negative in tumour samples from four patients who responded to treatment. SDHB germline mutation was associated with hypermethylation of the MGMT promoter and low expression of MGMT in 190 samples of the French nation-wide independent cohort. This study demonstrates that TMZ is an effective antitumour agent in patients with SDHB-related MPP. The silencing of MGMT expression as a consequence of MGMT promoter hypermethylation in SDHB-mutated tumours may explain this finding.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Neoplasias Encefálicas/genética , Dacarbazina/análogos & derivados , Mutação/genética , Paraganglioma/genética , Feocromocitoma/genética , Succinato Desidrogenase/genética , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/mortalidade , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Dacarbazina/uso terapêutico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Paraganglioma/tratamento farmacológico , Paraganglioma/mortalidade , Paraganglioma/secundário , Feocromocitoma/tratamento farmacológico , Feocromocitoma/mortalidade , Feocromocitoma/secundário , Reação em Cadeia da Polimerase , Prognóstico , Regiões Promotoras Genéticas/genética , Estudos Retrospectivos , Taxa de Sobrevida , Temozolomida , Proteínas Supressoras de Tumor/genética
6.
Hum Mutat ; 31(4): 369-79, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20358582

RESUMO

PRKAR1A encodes the regulatory subunit type 1-alpha (RIalpha) of the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA). Inactivating PRKAR1A mutations are known to be responsible for the multiple neoplasia and lentiginosis syndrome Carney complex (CNC). To date, at least 117 pathogenic variants in PRKAR1A have been identified (online database: http://prkar1a.nichd.nih.gov). The majority are subject to nonsense mediated mRNA decay (NMD), leading to RIalpha haploinsufficiency and, as a result, activated cAMP signaling. Recently, it became apparent that CNC may be caused not only by RIalpha haploinsufficiency, but also by the expression of altered RIalpha protein, as proven by analysis of expressed mutations in the gene, consisting of amino acid substitutions and in-frame genetic alterations. In addition, a new subgroup of mutations that potentially escape NMD and result in CNC through altered (rather than missing) protein has been analyzed-these are frame-shifts in the 3' end of the coding sequence that shift the stop codon downstream of the normal one. The mutation detection rate in CNC patients is recently estimated at above 60%; PRKAR1A mutation-negative CNC patients are characterized by significant phenotypic heterogeneity. In this report, we present a comprehensive analysis of all presently known PRKAR1A sequence variations and discuss their molecular context and clinical phenotype.


Assuntos
Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Processamento Alternativo/genética , Complexo de Carney/diagnóstico , Complexo de Carney/enzimologia , Complexo de Carney/genética , Mutação da Fase de Leitura/genética , Estudos de Associação Genética , Humanos , Penetrância , Deleção de Sequência/genética
7.
PLoS One ; 4(9): e7094, 2009 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-19763184

RESUMO

The Warburg effect describes how cancer cells down-regulate their aerobic respiration and preferentially use glycolysis to generate energy. To evaluate the link between hypoxia and Warburg effect, we studied mitochondrial electron transport, angiogenesis and glycolysis in pheochromocytomas induced by germ-line mutations in VHL, RET, NF1 and SDH genes. SDH and VHL gene mutations have been shown to lead to the activation of hypoxic response, even in normoxic conditions, a process now referred to as pseudohypoxia. We observed a decrease in electron transport protein expression and activity, associated with increased angiogenesis in SDH- and VHL-related, pseudohypoxic tumors, while stimulation of glycolysis was solely observed in VHL tumors. Moreover, microarray analyses revealed that expression of genes involved in these metabolic pathways is an efficient tool for classification of pheochromocytomas in accordance with the predisposition gene mutated. Our data suggest an unexpected association between pseudohypoxia and loss of p53, which leads to a distinct Warburg effect in VHL-related pheochromocytomas.


Assuntos
Feocromocitoma/genética , Feocromocitoma/fisiopatologia , Adolescente , Adulto , Idoso , Criança , Transporte de Elétrons , Feminino , Genes p53/genética , Mutação em Linhagem Germinativa , Glicólise , Humanos , Hipóxia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Neovascularização Patológica , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação Oxidativa
8.
J Clin Endocrinol Metab ; 94(6): 2085-91, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19293268

RESUMO

BACKGROUND: The "complex of myxomas, spotty skin pigmentation, and endocrine overactivity," or "Carney complex" (CNC), is caused by inactivating mutations of the regulatory subunit type 1A of the cAMP-dependent protein kinase (PRKAR1A) gene and as yet unknown defect(s) in other gene(s). Delineation of a genotype-phenotype correlation for CNC patients is essential for understanding PRKAR1A function and providing counseling and preventive care. METHODS: A transatlantic consortium studied the molecular genotype and clinical phenotype of 353 patients (221 females and 132 males, age 34 +/- 19 yr) who carried a germline PRKAR1A mutation or were diagnosed with CNC and/or primary pigmented nodular adrenocortical disease. RESULTS: A total of 258 patients (73%) carried 80 different PRKAR1A mutations; 114 (62%) of the index cases had a PRKAR1A mutation. Most PRKAR1A mutations (82%) led to lack of detectable mutant protein (nonexpressed mutations) because of nonsense mRNA mediated decay. Patients with a PRKAR1A mutation were more likely to have pigmented skin lesions, myxomas, and thyroid and gonadal tumors; they also presented earlier with these tumors. Primary pigmented nodular adrenocortical disease occurred earlier, was more frequent in females, and was the only manifestation of CNC with a gender predilection. Mutations located in exons were more often associated with acromegaly, myxomas, lentigines, and schwannomas, whereas the frequent c.491-492delTG mutation was commonly associated with lentigines, cardiac myxomas, and thyroid tumors. Overall, nonexpressed PRKAR1A mutations were associated with less severe disease. CONCLUSION: CNC is genetically and clinically heterogeneous. Certain tumors are more frequent, with specific mutations providing some genotype-phenotype correlation for PRKAR1A mutations.


Assuntos
Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Mutação , Adolescente , Doenças do Córtex Suprarrenal/complicações , Doenças do Córtex Suprarrenal/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação/fisiologia , Mixoma/complicações , Mixoma/genética , Fenótipo , Adulto Jovem
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