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1.
Artigo em Inglês | MEDLINE | ID: mdl-32711725

RESUMO

BACKGROUND: Cross-sectional imaging regularly results in incidental discovery of adrenal tumours, requiring exclusion of adrenocortical carcinoma (ACC). However, differentiation is hampered by poor specificity of imaging characteristics. We aimed to validate a urine steroid metabolomics approach, using steroid profiling as the diagnostic basis for ACC. METHODS: We did a prospective multicentre study in adult participants (age ≥18 years) with newly diagnosed adrenal masses. We assessed the accuracy of diagnostic imaging strategies based on maximum tumour diameter (≥4 cm vs <4 cm), imaging characteristics (positive vs negative), and urine steroid metabolomics (low, medium, or high risk of ACC), separately and in combination, using a reference standard of histopathology and follow-up investigations. With respect to imaging characteristics, we also assessed the diagnostic utility of increasing the unenhanced CT tumour attenuation threshold from the recommended 10 Hounsfield units (HU) to 20 HU. FINDINGS: Of 2169 participants recruited between Jan 17, 2011, and July 15, 2016, we included 2017 from 14 specialist centres in 11 countries in the final analysis. 98 (4·9%) had histopathologically or clinically and biochemically confirmed ACC. Tumours with diameters of 4 cm or larger were identified in 488 participants (24·2%), including 96 of the 98 with ACC (positive predictive value [PPV] 19·7%, 95% CI 16·2-23·5). For imaging characteristics, increasing the unenhanced CT tumour attenuation threshold to 20 HU from the recommended 10 HU increased specificity for ACC (80·0% [95% CI 77·9-82·0] vs 64·0% [61·4-66.4]) while maintaining sensitivity (99·0% [94·4-100·0] vs 100·0% [96·3-100·0]; PPV 19·7%, 16·3-23·5). A urine steroid metabolomics result indicating high risk of ACC had a PPV of 34·6% (95% CI 28·6-41·0). When the three tests were combined, in the order of tumour diameter, positive imaging characteristics, and urine steroid metabolomics, 106 (5·3%) participants had the result maximum tumour diameter of 4 cm or larger, positive imaging characteristics (with the 20 HU cutoff), and urine steroid metabolomics indicating high risk of ACC, for which the PPV was 76·4% (95% CI 67·2-84·1). 70 (3·5%) were classified as being at moderate risk of ACC and 1841 (91·3%) at low risk (negative predictive value 99·7%, 99·4-100·0). INTERPRETATION: An unenhanced CT tumour attenuation cutoff of 20 HU should replace that of 10 HU for exclusion of ACC. A triple test strategy of tumour diameter, imaging characteristics, and urine steroid metabolomics improves detection of ACC, which could shorten time to surgery for patients with ACC and help to avoid unnecessary surgery in patients with benign tumours. FUNDING: European Commission, UK Medical Research Council, Wellcome Trust, and UK National Institute for Health Research, US National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research.

3.
J Clin Endocrinol Metab ; 105(8)2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32449514

RESUMO

CONTEXT: Objective response rate to mitotane in advanced adrenocortical carcinoma (ACC) is approximately 20%, and adverse drug effects are frequent. To date, there is no marker established that predicts treatment response. Mitotane has been shown to inhibit sterol-O-acyl transferase 1 (SOAT1), which leads to endoplasmic reticulum stress and cell death in ACC cells. OBJECTIVE: To investigate SOAT1 protein expression as a marker of treatment response to mitotane. PATIENTS: A total of 231 ACC patients treated with single-agent mitotane as adjuvant (n = 158) or advanced disease therapy (n = 73) from 12 ENSAT centers were included. SOAT1 protein expression was determined by immunohistochemistry on formalin-fixed paraffin-embedded specimens. SETTING: Retrospective study at 12 ACC referral centers. MAIN OUTCOME MEASURE: Recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS). RESULTS: Sixty-one of 135 patients (45%) with adjuvant mitotane treatment had recurrences and 45/68 patients (66%) with mitotane treatment for advanced disease had progressive disease. After multivariate adjustment for sex, age, hormone secretion, tumor stage, and Ki67 index, RFS (hazard ratio [HR] = 1.07; 95% confidence interval [CI], 0.61-1.85; P = 0.82), and DSS (HR = 1.30; 95% CI, 0.58-2.93; P = 0.53) in adjuvantly treated ACC patients did not differ significantly between tumors with high and low SOAT1 expression. Similarly, in the advanced stage setting, PFS (HR = 1.34; 95% CI, 0.63-2.84; P = 0.45) and DSS (HR = 0.72; 95% CI, 0.31-1.70; P = 0.45) were comparable and response rates not significantly different. CONCLUSIONS: SOAT1 expression was not correlated with clinical endpoints RFS, PFS, and DSS in ACC patients with mitotane monotherapy. Other factors appear to be relevant for mitotane treatment response and ACC patient survival.

4.
Cancers (Basel) ; 12(3)2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32245135

RESUMO

Mitotane is the main option of treatment for advanced adrenocortical carcinoma (ACC). However, limited evidence is available regarding the impact of plasma mitotane levels on patient outcome. To address this question, we retrospectively analyzed patients with advanced ACC treated with mitotane for ≥3 months, with ≥3 measurements of plasma mitotane reported in the Lysosafe Online® database (HRA Pharma, France), followed at 12 tertiary centers in Italy from 2005 to 2017. We identified 80 patients, initially treated with mitotane alone (56.2%) or plus chemotherapy (43.8%). The preference toward combination therapy was given to de novo stage IV ACC and younger patients. After the first line of treatment, 25% of valid cases experienced clinical benefit (14.5% objective response, 10.5% stabilization of disease) and 75% progression, without differences between the groups of treatment. Patients with progression had a lower time in the target range (TTR) of plasma mitotane and an unfavorable outcome. Death occurred in 76.2% of cases and multivariate analysis showed that clinical benefit after first treatment and longer TTR were favorable predictors of overall survival (OS). In conclusion, the present findings support the importance of mitotane monitoring and strengthen the concept of a therapeutic window for mitotane.

5.
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.

6.
J Clin Med ; 8(11)2019 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-31684071

RESUMO

Mitotane is used as a post-operative adjuvant treatment for patients with adrenocortical carcinoma. Monitoring of plasma mitotane concentrations is recommended, but we do not know what impact target concentrations have on patient outcome. To answer this question, we retrospectively analyzed patient records in the Lysosafe Online® database (HRA Pharma, France) for patients who were treated for ≥6 months and who had ≥3 measurements of plasma mitotane levels during follow-ups at 11 tertiary centers in Italy from 2005 to 2017. We identified 110 patients treated with adjuvant mitotane for a median of 46 months (IQR, interquartile range, 28-62) with a median maintenance dose of 2.0 g/day (IQR 1.5-2.5). Achievement of target mitotane concentrations (≥14 mg/L) required a median of 8 months (IQR 5-19). Female sex was associated inversely with the dose, while body mass index (BMI) was correlated positively. Multivariate analysis showed that the Ki67 index and time to achieve the target range of plasma mitotane were independent predictors of recurrence-free survival (RFS). In a separate multivariate model, considering only the maintenance phase (month 7 to month 36, M7-M36) of treatment, the time in the target range of plasma mitotane was associated with a significantly lower risk of recurrence (Hazard Ratio, HR = 0.93; 0.88-0.98, p < 0.01). The prognostic implications of the time in target range and the time needed to reach target mitotane concentrations support the use of mitotane monitoring and may inform practice.

7.
Theranostics ; 9(17): 4946-4958, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31410193

RESUMO

Rationale: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that present variable outcomes. To date, no effective therapies or reliable prognostic markers are available for patients who develop metastatic PPGL (mPPGL). Our aim was to discover robust prognostic markers validated through in vitro models, and define specific therapeutic options according to tumor genomic features. Methods: We analyzed three PPGL miRNome datasets (n=443), validated candidate markers and assessed them in serum samples (n=36) to find a metastatic miRNA signature. An integrative study of miRNome, transcriptome and proteome was performed to find miRNA targets, which were further characterized in vitro. Results: A signature of six miRNAs (miR-21-3p, miR-183-5p, miR-182-5p, miR-96-5p, miR-551b-3p, and miR-202-5p) was associated with metastatic risk and time to progression. A higher expression of five of these miRNAs was also detected in PPGL patients' liquid biopsies compared with controls. The combined expression of miR-21-3p/miR-183-5p showed the best power to predict metastasis (AUC=0.804, P=4.67·10-18), and was found associated in vitro with pro-metastatic features, such as neuroendocrine-mesenchymal transition phenotype, and increased cell migration rate. A pan-cancer multi-omic integrative study correlated miR-21-3p levels with TSC2 expression, mTOR pathway activation, and a predictive signature for mTOR inhibitor-sensitivity in PPGLs and other cancers. Likewise, we demonstrated in vitro a TSC2 repression and an enhanced rapamycin sensitivity upon miR-21-3p expression. Conclusions: Our findings support the assessment of miR-21-3p/miR-183-5p, in tumors and liquid biopsies, as biomarkers for risk stratification to improve the PPGL patients' management. We propose miR-21-3p to select mPPGL patients who may benefit from mTOR inhibitors.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31214117

RESUMO

Chromaffin tumors are included among the causes of secondary hypertension because of the release of catecholamines. Nevertheless, the clinical, cardiovascular, and hypertensive picture of patients affected by pheochromocytomas/paragangliomas (PPGL) is extremely variable, due to the different quantitative and qualitative releasing activity of these tumors. A consistent percentage of these patients, about 20%, is normotensive and not affected by the characteristic symptomatic crises due to sudden release of catecholamines. The factors causing such wide clinical variability are many and probably not all known. It is well known that many of these tumors are genetically determined and that the genetic profile influences the biochemical characteristics and the biology of the tumors as well as the clinical presentation of the affected patients. The number of asymptomatic or poorly symptomatic patients is increased after the introduction of genetic screening and the early diagnosis in mutation carriers. In this paper we can review the genotype-phenotype correlation of PPGLs with a focus on the cardiovascular picture.

9.
Cancers (Basel) ; 11(6)2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31212687

RESUMO

Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors with a strong hereditary background and a large genetic heterogeneity. Identification of the underlying genetic cause is crucial for the management of patients and their families as it aids differentiation between hereditary and sporadic cases. To improve diagnostics and clinical management we tailored an enrichment based comprehensive multi-gene next generation sequencing panel applicable to both analyses of tumor tissue and blood samples. We applied this panel to tumor samples and compared its performance to our current routine diagnostic approach. Routine diagnostic sequencing of 11 PPGL susceptibility genes was applied to blood samples of 65 unselected PPGL patients at a single center in Dresden, Germany. Predisposing germline mutations were identified in 19 (29.2%) patients. Analyses of 28 PPGL tumor tissues using the dedicated PPGL panel revealed pathogenic or likely pathogenic variants in known PPGL susceptibility genes in 21 (75%) cases, including mutations in IDH2, ATRX and HRAS. These mutations suggest sporadic tumor development. Our results imply a diagnostic benefit from extended molecular tumor testing of PPGLs and consequent improvement of patient management. The approach is promising for determination of prognostic biomarkers that support therapeutic decision-making.

11.
Artigo em Inglês | MEDLINE | ID: mdl-30822354

RESUMO

CONTEXT: Cross sectional imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is regarded as a first-choice modality for tumor localization in patients with pheochromocytoma and paraganglioma (PPGL). 123I-labeled metaiodobenzylguanidine (123I-MIBG) is widely used for functional imaging but the added diagnostic value is controversial. OBJECTIVE: To establish the virtual impact of adding 123I-MIBG scintigraphy to CT or MRI on diagnosis and treatment of PPGL. DESIGN: International multicenter retrospective study. INTERVENTION: None. PATIENTS: 236 unilateral adrenal, 18 bilateral adrenal, 48 unifocal extra-adrenal, 12 multifocal and 26 metastatic PPGL. MAIN OUTCOME MEASURES: Patients underwent both anatomical imaging (CT and/or MRI) and 123I-MIBG scintigraphy. Local imaging reports were analyzed centrally by two independent observers who were blinded to the diagnosis. Imaging-based diagnoses determined by CT/MRI only, 123I-MIBG only, and CT/MRI combined with 123I-MIBG scintigraphy were compared with the correct diagnoses. RESULTS: The rates of correct imaging-based diagnoses determined by CT/MRI only versus CT/MRI plus 123I-MIBG scintigraphy were similar: 89.4 versus 88.8%, respectively, (P=0.50). Adding 123I-MIBG scintigraphy to CT/MRI resulted in a correct change in the imaging-based diagnosis and ensuing virtual treatment in four cases (1.2%: two metastatic instead of non-metastatic, one multifocal instead of single, one unilateral instead of bilateral adrenal) at the cost of an incorrect change in seven cases (2.1%: four metastatic instead of non-metastatic, two multifocal instead of unifocal and one bilateral instead of unilateral adrenal). CONCLUSIONS: For the initial localization of PPGL, the addition of 123I-MIBG scintigraphy to CT/MRI rarely improves the diagnostic accuracy at the cost of incorrect interpretation in others, even when 123I-MIBG scintigraphy is restricted to patients who are at risk for metastatic disease. In this setting, the impact of 123I-MIBG scintigraphy on clinical decision-making appears very limited.

12.
J Clin Endocrinol Metab ; 104(6): 2367-2374, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30715419

RESUMO

BACKGROUND: Malignant pheochromocytoma and paraganglioma (MPP) are characterized by prognostic heterogeneity. Our objective was to look for prognostic parameters of overall survival (OS) in MPP patients. PATIENTS AND METHODS: Retrospective multicenter study of MPP characterized by a neck-thoraco-abdomino-pelvic CT or MRI at the time of malignancy diagnosis in European centers between 1998 and 2010. RESULTS: One hundred sixty-nine patients from 18 European centers were included. Main characteristics of patients with MPP were: primary pheochromocytoma in 53% of patients; tumor- or hormone-related symptoms in 57% or 58% of cases; positive plasma or urine hormones in 81% of patients; identification of a mutation in SDHB in 42% of cases. Metastatic sites included bone (64%), lymph node (40%), lung (29%), and liver (26%); mean time between initial and malignancy diagnosis was 43 months (range, 0 to 614). Median follow-up was 68 months and median survival 6.7 years. Using univariate analysis, better survival was associated with head and neck paraganglioma, age <40 years, metanephrines less than fivefold the upper limits of the normal range, and low proliferative index. In multivariate analysis, hypersecretion [hazard ratio 3.02 (1.65 to 5.55); P = 0.0004] was identified as an independent significant prognostic factor of worst OS. CONCLUSIONS: Our results do not confirm SDHB mutations as a major prognostic parameter in MPP and suggest additional key molecular events involved in MPP tumor progression. Aside from SDHB mutation, the biology of aggressive MPP remains to be understood.


Assuntos
Neoplasias das Glândulas Suprarrenais/mortalidade , Paraganglioma/mortalidade , Feocromocitoma/mortalidade , Neoplasias das Glândulas Suprarrenais/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Paraganglioma/genética , Feocromocitoma/genética , Prognóstico , Estudos Retrospectivos , Succinato Desidrogenase/genética
13.
Lancet Diabetes Endocrinol ; 7(3): 213-220, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30660595

RESUMO

BACKGROUND: Multiple endocrine neoplasia type 2B is a rare syndrome caused mainly by Met918Thr germline RET mutation, and characterised by medullary thyroid carcinoma, phaeochromocytoma, and extra-endocrine features. Data are scarce on the natural history of multiple endocrine neoplasia type 2B. We aimed to advance understanding of the phenotype and natural history of multiple endocrine neoplasia type 2B, to increase awareness and improve detection. METHODS: This study was a retrospective, multicentre, international study in patients carrying the Met918Thr RET variant with no age restrictions. The study was done with registry data from 48 centres globally. Data from patients followed-up from 1970 to 2016 were retrieved from May 1, 2016, to May 31, 2018. Our primary objectives were to determine overall survival, and medullary thyroid carcinoma-specific survival based on whether the patient had undergone early thyroidectomy before the age of 1 year. We also assessed remission of medullary thyroid carcinoma, incidence and treatment of phaeochromocytoma, and the penetrance of extra-endocrine features. FINDINGS: 345 patients were included, of whom 338 (98%) had a thyroidectomy. 71 patients (21%) of the total cohort died at a median age of 25 years (range <1-59). Thyroidectomy was done before the age of 1 year in 20 patients, which led to long-term remission (ie, undetectable calcitonin level) in 15 (83%) of 18 individuals (2 patients died of causes unrelated to medullary thyroid carcinoma). Medullary thyroid carcinoma-specific survival curves did not show any significant difference between patients who had thyroidectomy before or after 1 year (comparison of survival curves by log-rank test: p=0·2; hazard ratio 0·35; 95% CI 0.07-1.74). However, there was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). There was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). In the other 318 patients who underwent thyroidectomy after 1 year of age, biochemical and structural remission was obtained in 47 (15%) of 318 individuals. Bilateral phaeochromocytoma was diagnosed in 156 (50%) of 313 patients by 28 years of age. Adrenal-sparing surgery was done in 31 patients: three (10%) of 31 patients had long-term recurrence, while normal adrenal function was obtained in 16 (62%) patients. All patients with available data (n=287) had at least one extra-endocrine feature, including 106 (56%) of 190 patients showing marfanoid body habitus, mucosal neuromas, and gastrointestinal signs. INTERPRETATION: Thyroidectomy done at no later than 1 year of age is associated with a high probability of cure. The reality is that the majority of children with the syndrome will be diagnosed after this recommended age. Adrenal-sparing surgery is feasible in multiple endocrine neoplasia type 2B and affords a good chance for normal adrenal function. To improve the prognosis of such patients, it is imperative that every health-care provider be aware of the extra-endocrine signs and the natural history of this rare syndrome. The implications of this research include increasing awareness of the extra-endocrine symptoms and also recommendations for thyroidectomy before the age of 1 year. FUNDING: None.

14.
J Clin Endocrinol Metab ; 104(5): 1712-1724, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30476173

RESUMO

CONTEXT: Novel tumor markers are urgently needed to better stratify adrenocortical cancer (ACC) patients and improve therapies for this aggressive neoplasm. OBJECTIVE: To assess the diagnostic and prognostic value of the actin-bundling protein fascin-1 (FSCN1) in adrenocortical tumors. DESIGN, SETTING AND PARTICIPANTS: A local series of 37 malignant/37 benign adrenocortical tumors at Careggi University Hospital and two independent validation ACC cohorts (Cochin, TCGA) from the European Network for the Study of Adrenal Tumors were studied. MAIN OUTCOME MEASURES: FSCN1 expression was quantified by immunohistochemistry, Western blot and quantitative RT-PCR in ACC specimens; overall and disease-free survival associated with FSCN1 expression were assessed by Kaplan-Meier analysis and compared with that of Ki67 labeling index and tumor stage. RESULTS: Despite the low diagnostic power, in the Florence ACC series, FSCN1 immunohistochemical detection appeared as an independent prognostic factor, also refining results obtained with staging and Ki67 labeling index. The robust prognostic power of FSCN1 levels was further confirmed in two independent ACC cohorts. A positive correlation was found between FSCN1 and steroidogenic factor-1 (SF-1), with a substantially higher expression of both factors in ACCs at advanced stages and with at least one of the three Weiss score parameters associated with invasiveness. Moreover, we demonstrated FSCN1 role in promoting cell invasion in a human ACC cell line only in the case of increased SF-1 dosage. CONCLUSIONS: These findings show that FSCN1 is a novel independent prognostic marker in ACC and may serve as a potential therapeutic target to block tumor spread.


Assuntos
Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Biomarcadores Tumorais/metabolismo , Proteínas de Transporte/metabolismo , Proteínas dos Microfilamentos/metabolismo , Adolescente , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/cirurgia , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Proteínas de Transporte/genética , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Proteínas dos Microfilamentos/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Adulto Jovem
15.
J Clin Endocrinol Metab ; 104(2): 312-318, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30383267

RESUMO

Background: Up to 7% of all adrenal incidentalomas (AIs) are pheochromocytomas (PCCs). In the evaluation of AI, it is generally recommended that PCC be excluded by measurement of plasma-free or 24-hour urinary fractionated metanephrines. However, recent studies suggest that biochemical exclusion of PCC not be performed for lesions with CT characteristics of an adrenocortical adenoma (ACA). Aim: To determine the proportion of PCCs with ACA-like attenuation or contrast washout on CT. Methods: For this multicenter retrospective study, two central investigators independently analyzed the CT reports of 533 patients with 548 histologically confirmed PCCs. Data on tumor size, unenhanced Hounsfield units (HU), absolute percentage washout (APW), and relative percentage washout (RPW) were collected in addition to clinical parameters. Results: Among the 376 PCCs for which unenhanced attenuation data were available, 374 had an attenuation of >10 HU (99.5%). In the two exceptions (0.5%), unenhanced attenuation was exactly 10 HU, which lies just within the range of ≤10 HU that would suggest a diagnosis of ACA. Of 76 PCCs with unenhanced HU > 10 and available washout data, 22 (28.9%) had a high APW and/or RPW, suggestive of ACA. Conclusion: Based on the lack of PCCs with an unenhanced attenuation of <10 HU and the low proportion (0.5%) of PCCs with an attenuation of 10 HU, it seems reasonable to abstain from biochemical testing for PCC in AIs with an unenhanced attenuation of ≤10 HU. The assessment of contrast washout, however, is unreliable for ruling out PCC.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Feocromocitoma/diagnóstico por imagem , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idoso , Meios de Contraste , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Feocromocitoma/patologia , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos
16.
Eur J Endocrinol ; 178(5): 431-437, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29467230

RESUMO

BACKGROUND: A substantial proportion of all pheochromocytomas is currently detected during the evaluation of an adrenal incidentaloma. Recently, it has been suggested that biochemical testing to rule out pheochromocytoma is unnecessary in case of an adrenal incidentaloma with an unenhanced attenuation value ≤10 Hounsfield Units (HU) at computed tomography (CT). OBJECTIVES: We aimed to determine the sensitivity of the 10 HU threshold value to exclude a pheochromocytoma. METHODS: Retrospective multicenter study with systematic reassessment of preoperative unenhanced CT scans performed in patients in whom a histopathologically proven pheochromocytoma had been diagnosed. Unenhanced attenuation values were determined independently by two experienced radiologists. Sensitivity of the 10 HU threshold was calculated, and interobserver consistency was assessed using the intraclass correlation coefficient (ICC). RESULTS: 214 patients were identified harboring a total number of 222 pheochromocytomas. Maximum tumor diameter was 51 (39-74) mm. The mean attenuation value within the region of interest was 36 ± 10 HU. Only one pheochromocytoma demonstrated an attenuation value ≤10 HU, resulting in a sensitivity of 99.6% (95% CI: 97.5-99.9). ICC was 0.81 (95% CI: 0.75-0.86) with a standard error of measurement of 7.3 HU between observers. CONCLUSION: The likelihood of a pheochromocytoma with an unenhanced attenuation value ≤10 HU on CT is very low. The interobserver consistency in attenuation measurement is excellent. Our study supports the recommendation that in patients with an adrenal incidentaloma biochemical testing for ruling out pheochromocytoma is only indicated in adrenal tumors with an unenhanced attenuation value >10 HU.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Glândulas Suprarrenais/diagnóstico por imagem , Feocromocitoma/diagnóstico por imagem , Centros Médicos Acadêmicos , Neoplasias das Glândulas Suprarrenais/patologia , Glândulas Suprarrenais/patologia , Adulto , Idoso , Diagnóstico Diferencial , Reações Falso-Negativas , Feminino , Hospitais de Ensino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Variações Dependentes do Observador , Feocromocitoma/patologia , Estudos Retrospectivos , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X , Carga Tumoral
17.
Endocrine ; 59(2): 280-287, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29299796

RESUMO

PURPOSE: Circulating microRNAs (miRNA) have been described in patients with adrenocortical tumors, but the expression of miRNAs in non-functioning and cortisol-producing tumors has not been yet compared. Therefore, the objective of this study was to evaluate the expression of plasma extracellular vesicle (EV)-associated microRNAs in patients with non-functioning adrenocortical adenoma (NFA), cortisol-producing adrenocortical adenoma (CPA) and cortisol-producing adrenocortical carcinoma (CP-ACC). METHODS: Preoperative plasma EV samples of 13 NFAs, 13 CPAs and 9 CP-ACCs were subjected to extracellular vesicle isolation. miRNAs were investigated by targeted quantitative real-time PCR normalized to cel-miR-39 as reference. Five miRNAs have been selected for this analysis based on the previous studies including hsa-miR-22-3p, hsa-miR-27a-3p, hsa-miR-210-3p, hsa-miR-320b and hsa-miR-375. RESULTS: We have observed significant overrepresentation of three miRNAs in both CPA and CP-ACC relative to NFA: hsa-miR-22-3p (p < 0.01 and p < 0.0001, respectively), hsa-miR-27a-3p (p < 0.05 in both comparisons) and hsa-miR-320b (p < 0.05 and p < 0.0001, respectively). Hsa-miR-320b has been significantly overrepresented in CP-ACC relative to CPA (p < 0.01). Hsa-miR-210-3p turned out to be significantly overrepresented only in CP-ACC compared to NFA (p < 0.05). Significant correlation was revealed between circulating miRNA concentrations and urinary free cortisol values for hsa-miR-22-3p, hsa-miR-27a-3p and hsa-miR-320b (p < 0.0001 for all) and cortisol after low-dose dexamethasone test for hsa-miR-22-3p and hsa-miR-320b (p < 0.05). Hsa-miR-27a-3p has been significantly stimulated by low-dose dexamethasone test (p < 0.05). CONCLUSIONS: EV-associated miRNAs are differentially expressed in different non-functioning and cortisol-producing adrenocortical tumors.


Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/metabolismo , MicroRNA Circulante/metabolismo , Vesículas Extracelulares/metabolismo , Hidrocortisona/metabolismo , Neoplasias do Córtex Suprarrenal/genética , Adenoma Adrenocortical/genética , Carcinoma Adrenocortical/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , MicroRNA Circulante/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
Eur J Endocrinol ; 178(1): R11-R17, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28924001

RESUMO

Mutations in one of the five genes encoding the succinate dehydrogenase (SDHx) or mitochondrial complex II cause the corresponding family syndromes characterized by the occurrence of pheochromocytomas (PHEO) and paragangliomas (PGL). Recently, other solid growths, such as gastrointestinal stromal tumors (GISTs), renal cell carcinomas (RCCs) and pituitary adenomas (PAs) have been associated with these syndromes. In the absence of prospective studies assessing their frequency, at present, their occurrence seems too infrequent to suggest systematic screening for SDHx mutation carriers. However, SDHB immunohistochemistry (IHC) on tumor tissues or SDHx genetic testing on blood or tumor samples should be performed in patients affected by GISTs, RCCs or PAs with clinicopathologic phenotypes suggesting an etiologic role of SDHx genes.


Assuntos
Doenças do Sistema Endócrino/diagnóstico , Doenças do Sistema Endócrino/genética , Paraganglioma/diagnóstico , Paraganglioma/genética , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Succinato Desidrogenase/genética , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/genética , Humanos , Mutação/genética , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/genética
19.
Oncotarget ; 8(39): 65525-65533, 2017 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-29029450

RESUMO

Adrenocortical cancer (ACC) is a rare aggressive malignancy. Recent ACC integrated genomics analysis contributed to redefine the risk groups on molecular basis, including tumor microRNAs (miRs), detectable also in the bloodstream. We developed a quantitative real-time (RT) assay for the measurement of miR483 and miR483-5p absolute levels in plasma samples. miR483/miR483-5p levels were evaluated in plasma samples of 27 patients with ACC before surgery and at follow-up. Statistically significant differences in miR483-5p and miR483 levels were found between stage 1/2 and stage 3/4 ACCs in pre-surgery and post-surgery samples. ROC curve analysis of miR483-5p levels gave a prediction of the clinical stage (accuracy 0.917±0.084), with the best cut-off value of 0.221 ng/ml, prognosticating overall and recurrence-free survival. In a multivariate Cox analysis (HR 16.2, 95%CI[1.39-188.6, P<0.026]), miR483-5p was the only variable that significantly predicted recurrence, but not overall survival. In addition, miR483 and miR483-5p levels correlated with the number of circulating tumor cells (CTCs) detected in the same blood samples, independently of the timing of sampling. In conclusion, we demonstrated that miR483-5p absolute plasma levels in ACC patients are powerful molecular markers that may help in the follow-up of patients after surgery and chemotherapy, and contribute to more accurately classify and predict tumor progression.

20.
Endocr Relat Cancer ; 24(10): 555-564, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28830936

RESUMO

Pheochromocytomas (Pheos) and paragangliomas (PGLs) are neuroendocrine tumors. Approximately 30-40% of Pheos/PGLs are due to germline mutations in one of the susceptibility genes, including those encoding the succinate dehydrogenase subunits A-D (SDHA-D). Up to 2/3 of patients affected by SDHB mutated Pheo/PGL develop metastatic disease with no successful cure at present. Here, for the first time, we evaluated the effects of SDHB silencing in a three dimension (3D) culture using spheroids of a mouse Pheo cell line silenced or not (wild type/wt/control) for the SDHB subunit. We investigated the role of the microenvironment on spheroid growth and migration/invasion by co-culturing SDHB-silenced or wt spheroids with primary cancer-activated fibroblasts (CAFs). When spheroids were co-cultured with fibroblasts, SDHB-silenced cells showed a significant increase in matrigel invasion as demonstrated by the computation of the migratory areas (P < 0.001). Moreover, cells detaching from the SDHB-silenced spheroids moved collectively, unlike the cells of wt spheroids that moved individually. Additionally, SDHB-silenced spheroids developed long filamentous formations along which clusters of cells migrated far away from the spheroid, whereas these structures were not present in wt spheroids. We found that lactate, largely secreted by CAFs, plays a specific role in promoting migration only of SDHB-silenced cells. In this study, we demonstrated that SDHB silencing per se increases tumor cell migration/invasion and that microenvironment, as represented by CAFs, plays a pivotal role in enhancing collective migration/invasion in Pheo SDHB-silenced tumor cells, suggesting their role in increasing the tumor metastasizing potential.


Assuntos
Succinato Desidrogenase/metabolismo , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Animais , Movimento Celular , Feminino , Humanos , Camundongos , Feocromocitoma/genética , Feocromocitoma/patologia , Microambiente Tumoral
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