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2.
Eur J Endocrinol ; 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33166271

RESUMO

Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest of the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we therefore provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.

4.
Cancers (Basel) ; 12(9)2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32937772

RESUMO

Mitotane is widely used for the treatment of adrenocortical cancer (ACC), although the drug-related toxicity complicates its use. The aim of this study is to assess comprehensively the different endocrine and metabolic unwanted effects of the drug, and to provide data on the supportive therapies. We retrospectively analyzed 74 ACC patients adjuvantly treated with mitotane for ≥12 months. During the treatment period (40 months, 12-195), 32.4% of patients needed replacement therapy for mineralocorticoid deficit, 36.2% for hypothyroidism and 34.3% for male hypogonadism. In fertile women, hypogonadism was uncommon, while 65.4% of women developed ovarian cysts. Although no significant change in low-density lipoprotein (LDL) was observed, statins were started in 50% of patients for a significant increase in total cholesterol and triglycerides. Dyslipidemia occurred early, after a median time of 6 months from mitotane start. Conversely, testosterone replacement was usually started after >2 years. In many cases, ranging from 29.4% to 50% according to the side effect, toxicity occurred well before the achievement of the target mitotane concentrations. Supportive therapies were able to revert the biochemical alterations induced by mitotane, although higher doses were needed for a likely pharmacokinetic interaction of exogenous steroids and statins with mitotane. In conclusion, adjuvant mitotane therapy is associated with a spectrum of unwanted effects encompassing the function of different endocrine glands and requires a careful clinical and biochemical assessment associated with the therapeutic drug monitoring.

5.
Lancet Diabetes Endocrinol ; 8(9): 773-781, 2020 09.
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.


Assuntos
Neoplasias das Glândulas Suprarrenais/epidemiologia , Neoplasias das Glândulas Suprarrenais/urina , Metabolômica/métodos , Esteroides/urina , Neoplasias das Glândulas Suprarrenais/diagnóstico , Adulto , Idoso , Diagnóstico Diferencial , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Achados Incidentais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
6.
Eur Radiol ; 30(12): 6958-6964, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32621242

RESUMO

OBJECTIVES: To evaluate the impact of image-guided ablation of liver and lung metastases from adrenocortical carcinoma (ACC). METHODS: Patients with oligometastatic ACC (liver and lung metastases) who underwent image-guided ablation were retrospectively included in the study. Complete ablation (CA) at the first contrast-enhanced CT control, local tumor progression (LTP), local tumor progression-free survival (LTPFS), liver disease-free survival (LDFS), and overall survival (OS) were evaluated. Correlation between outcomes and other prognostic factors (including Ki67, hormonal secretion, and progression-free survival after primary tumor resection (PR-PFS)) was also analyzed. Kaplan-Meier methods, log-rank tests, and Spearman correlation models were applied. RESULTS: Thirty-two ACC metastases (4 lung and 28 liver) from 16 patients (10 females; mean age 41 years) were treated with RFA or MWA. A single major adverse event was observed (intrahepatic hematoma with subsequent right hemothorax). One patient (2 lesions) was lost to follow-up. CA was obtained in 97% (29/30). During follow-up, LTP was registered in 7/29 cases (24.1%), with a median LTPFS of 21 months (± 12.6). Metastasis size was significantly higher in case of LTP (20 mm vs. 34.5 mm; p = 0.009) and was an independent predictive factor of local tumor control with an AUC of 0.934 (p = 0.0009). Hepatic progression was observed in 66% of the cases, with a median LDFS of 25 months. Median OS was 48.6 months. PR-PFS and hormonal secretion were independent predictors of OS (p < 0.001 and p = 0.045, respectively). CONCLUSIONS: Image-guided ablation achieves adequate local tumor control of ACC liver and lung metastases, providing a safe and effective treatment option in the multidisciplinary management of the oligometastatic ACC. KEY POINTS: • Image-guided ablation allows adequate local tumor control in the oligometastatic adrenocortical carcinoma setting. • After percutaneous thermal ablation, complete ablation was achieved in 29 out of 30 lesions (97%). • Lesion size together with primary resection disease-free survival and hormonal secretion play a significant role in determining outcomes.

7.
Eur J Endocrinol ; 183(4): D1-D13, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32698136

RESUMO

The literature on an association between acromegaly and cancer is particularly abundant on either colorectal cancer or thyroid cancer, and an endless debate is ongoing whether patients with acromegaly should be submitted to specific oncology screening and surveillance protocols. The aim of the present work is to review the most recent data on the risk of either colorectal cancer or thyroid cancer in acromegaly and discuss the opportunity for specific screening in relation to the accepted procedures in the general population.


Assuntos
Acromegalia/complicações , Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer , Programas de Rastreamento , Monitorização Fisiológica , Neoplasias da Glândula Tireoide/diagnóstico , Acromegalia/diagnóstico , Acromegalia/epidemiologia , Acromegalia/terapia , Adenoma/complicações , Adenoma/diagnóstico , Adenoma/epidemiologia , Adenoma/terapia , Neoplasias Colorretais/complicações , Neoplasias Colorretais/epidemiologia , Detecção Precoce de Câncer/métodos , Detecção Precoce de Câncer/normas , Endocrinologia/métodos , Endocrinologia/normas , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Adenoma Hipofisário Secretor de Hormônio do Crescimento/diagnóstico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/epidemiologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/terapia , Humanos , Programas de Rastreamento/métodos , Programas de Rastreamento/normas , Oncologia/métodos , Oncologia/normas , Monitorização Fisiológica/métodos , Monitorização Fisiológica/normas , Vigilância da População/métodos , Guias de Prática Clínica como Assunto/normas , Neoplasias da Glândula Tireoide/complicações , Neoplasias da Glândula Tireoide/epidemiologia
8.
Best Pract Res Clin Endocrinol Metab ; 34(3): 101435, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32580879
9.
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.

10.
Cancers (Basel) ; 12(4)2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32290298

RESUMO

Etoposide, doxorubicin and cisplatin plus oral mitotane (EDP-M) comprise the reference regimen in the management of patients with adrenocortical carcinoma (ACC). In this paper, we described the outcome of 58 patients with advanced/metastatic ACC consecutively treated with EDP-M in a reference center for this rare disease in Italy. In this series, EDP-M obtained a partial response in 50% of patients; median progression free survival (PFS) and overall survival were 10.1 months (95% Confidence Interval [CI 95%] 8.1-12.8) and 18.7 months (95% CI: 14.6-22.8), respectively. EDP-M was not interrupted in five patients showing disease progression after two cycles without the appearance of new lesions and mitotane levels below the therapeutic range. In two of them, the disease remained stable at further imaging evaluations and the other three obtained a partial response. Twenty-six responding patients underwent surgery of residual disease and 13 of them became disease free. Surgery identified a pathological complete response (pCR) in four patients (7%) and Ki67 expression in post-chemotherapy tumor specimens, inferior to 15% (median value), was associated with better PFS and survival. In the present study, the EDP-M regimen is confirmed to have a limited efficacy. Early disease progression does not mean treatment inefficacy. Surgery of residual disease in partially responding patients allows for the detection of pCR in few of them and this condition is predictive of long-term survival. Ki67 expression of post-chemotherapy residual disease could be an additional prognostic factor that deserves to be studied further.

11.
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.

12.
Cancers (Basel) ; 12(4)2020 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-32283844

RESUMO

Mitotane is the only drug approved for the treatment of adrenocortical carcinoma (ACC). The regimen to be added to mitotane is a chemotherapy including etoposide, doxorubicin, and cisplatin. This pharmacological approach, however, has a limited efficacy and significant toxicity. Evidence indicates that ACC seems to be sensitive to alkylating agents. Trabectedin is an anti-tumor drug that acts as an alkylating agent with a complex mechanism of action. Here, we investigated whether trabectedin could exert a cytotoxic activity in in vitro cell models of ACC. Cell viability was evaluated by MTT assay on ACC cell lines and primary cell cultures. The gene expression was evaluated by q-RT-PCR, while protein expression and localization were studied by Western blot and immunocytochemistry. Combination experiments were performed to evaluate their interaction on ACC cell line viability. Trabectedin demonstrated high cytotoxicity at sub-nanomolar concentrations in ACC cell lines and patient-derived primary cell cultures. The drug was able to reduce /ß catenin nuclear localization, although it is unclear whether this effect is involved in the observed cytotoxicity. Trabectedin/mitotane combination exerted a synergic cytotoxic effect in NCI-H295R cells. Trabectedin has antineoplastic activity in ACC cells. The synergistic cytotoxic activity of trabectedin with mitotane provides the rationale for testing this combination in a clinical study.

13.
Cells ; 9(4)2020 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-32260362

RESUMO

Adrenocortical carcinoma (ACC) is a rare cancer with poor prognosis. Mitotane, the standard treatment for ACC, impairs adrenocortical steroid biosynthesis and cholesterol metabolism. In the H295R cell line, a standard ACC in vitro model, mitotane was previously reported to enhance the production of some oxysterols. To verify the possible mechanistic involvement of oxysterols in the anti-ACC effect of mitotane, a gas chromatography mass spectrometry (GC-MS) profiling of oxysterols and the main cholesterol precursors was carried out in H295R cells. Among the oxysterols detected in mitotane-treated cells, 27OHC was markedly produced, as well as lanosterol and lathosterol cholesterol precursors. In this cell model, mitotane was confirmed to affect mitochondrial transmembrane potential and induce apoptosis. Such cytotoxic effects were perfectly matched by H295R cell treatment with a single identical micromolar amount of 27OHC. The mitotane-dependent strong increase in 27OHC was confirmed in vivo, in the plasma of ACC patients under treatment with the drug. Moreover, lanosterol, lathosterol, desmosterol and, to a minor extent, 24-hydroxycholesterol and 25-hydroxycholesterol plasma levels were significantly increased in those patients. The cytotoxic effect of mitotane on ACC cells may be partly related to the increased intracellular level of 27OHC induced by the drug itself.

14.
Cancers (Basel) ; 12(3)2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32164326

RESUMO

Mitotane is a steroidogenesis inhibitor and adrenolytic drug used for treatment of adrenocortical cancer (ACC). Mitotane therapy causes adrenal insufficiency requiring glucocorticoid replacement in all patients. However, it is unclear whether chronic therapy with mitotane induces complete destruction of zona fasciculata and whether hypothalamic-pituitary-adrenal (HPA) axis can recover after treatment cessation. Our objective was to assess the HPA axis recovery in a cohort of patients after cessation of adjuvant mitotane therapy for ACC. We retrospectively reviewed patient files with stage I-II-III ACC in two referral centers in Canada and Italy. Data on demographics, tumor characteristics, hormonal profile, and HPA axis were collected. Data from 23 patients with pathologically proven ACC treated with adjuvant mitotane for a minimum of two years were analyzed. Eight patients were males and 15 were females and the median age was 41 years old (range 18 to 73). After mitotane cessation, 18/23 (78.3%) patients achieved a complete HPA axis recovery while 3/23 (13.0%) were unable to tolerate glucocorticoid withdrawal despite having normal hormonal test values and 2/23 (8.7%) never achieved recovery. The mean time interval between mitotane cessation and HPA axis recovery was 2.7 years. A high proportion of patients achieved HPA axis recovery following cessation of mitotane adjuvant therapy. However, complete recovery was often delayed up to 2.5 years and regular assessment of the hormonal profile is required.

15.
Endocrinol Metab (Seoul) ; 35(1): 26-35, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32207261

RESUMO

Adrenal masses are mainly detected unexpectedly by an imaging study performed for reasons unrelated to any suspect of adrenal diseases. Such masses are commonly defined as "adrenal incidentalomas" and represent a public health challenge because they are increasingly recognized in current medical practice. Management of adrenal incidentalomas is currently matter of debate. Although there is consensus on the need of a multidisciplinary expert team evaluation and surgical approach in patients with significant hormonal excess and/or radiological findings suspicious of malignancy demonstrated at the diagnosis or during follow-up, the inconsistency between official guidelines and the consequent diffuse uncertainty on management of small adrenal incidentalomas still represents a considerable problem in terms of clinical choices in real practice. The aim of the present work is to review the proposed strategies on how to manage patients with adrenal incidentalomas that are not candidates to immediate surgery. The recent European Society of Endocrinology/European Network for the Study of Adrenal Tumors guidelines have supported the view to avoid surveillance in patients with clear benign adrenal lesions <4 cm and/or without any hormonal secretion; however, newer prospective studies are needed to confirm safety of this strategy, in particular in younger patients.

16.
Cancers (Basel) ; 12(2)2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32033200

RESUMO

Mitotane is the only approved drug for advanced adrenocortical carcinoma (ACC) and no biomarkers are available to predict attainment of therapeutic plasma concentrations and clinical response. Aim of the study was to evaluate the suitability of cytochrome P450(CYP)2W1 and CYP2B6 single nucleotide polymorphisms (SNPs) as biomarkers. A multicenter cohort study including 182 ACC patients (F/M = 121/61) treated with mitotane monotherapy after radical resection (group A, n = 103) or in not completely resectable, recurrent or advanced disease (group B, n = 79) was performed. CYP2W1*2, CYP2W1*6, CYP2B6*6 and CYP2B6 rs4803419 were genotyped in germline DNA. Mitotane blood levels were measured regularly. Response to therapy was evaluated as time to progression (TTP) and disease control rate (DCR). Among investigated SNPs, CYP2W1*6 and CYP2B6*6 correlated with mitotane treatment only in group B. Patients with CYP2W1*6 (n = 21) achieved less frequently therapeutic mitotane levels (>14 mg/L) than those with wild type (WT) allele (76.2% vs 51.7%, p = 0.051) and experienced shorter TTP (HR = 2.10, p = 0.019) and lower DCR (chi-square = 6.948, p = 0.008). By contrast, 55% of patients with CYP2B6*6 vs. 28.2% WT (p = 0.016) achieved therapeutic range. Combined, a higher rate of patients with CYP2W1*6WT+CYP2B6*6 (60.6%) achieved mitotane therapeutic range (p = 0.034). In not completely resectable, recurrent or advanced ACC, CYP2W1*6 SNP was associated with a reduced probability to reach mitotane therapeutic range and lower response rates, whereas CYP2B6*6 correlated with higher mitotane levels. The association of these SNPs may predict individual response to mitotane.

17.
J Clin Endocrinol Metab ; 105(4)2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31900474

RESUMO

CONTEXT: The frequency of adrenal incidentalomas and their association with comorbid conditions have been assessed mostly in retrospective studies that may be prone to ascertainment bias. OBJECTIVE: The objective of this work is to evaluate the frequency of adrenal incidentalomas and their associated comorbid conditions. DESIGN: A prospective cohort study was conducted. SETTING: This study took place at a radiology department at a public hospital. PARTICIPANTS: Unselected outpatients who underwent an abdominal computed tomography (CT) from January 2017 to June 2018. Patients with known or suspected adrenal disease or malignancy were excluded. EXPOSURE: All abdominal CT scans were evaluated by an experienced radiologist. Hormonal workup including a 1-mg dexamethasone suppression test was performed in patients bearing adrenal incidentalomas. MAIN OUTCOME AND MEASURE: Frequency of adrenal incidentalomas in abdominal CT of unselected patients; frequency of comorbid conditions, and hormonal workup in patients bearing adrenal incidentalomas. RESULTS: We recruited 601 patients, and in 7.3% of them an adrenal tumor was found serendipitously. The patients bearing an adrenal incidentaloma had higher body mass index (P = .009) and waist circumference (P = .004) and were more frequently diabetic (P = .0038). At multivariable regression analysis, diabetes was significantly associated with the presence of adrenal incidentalomas (P = .003). Autonomous cortisol secretion was observed in 50% of patients who did not suppress cortisol less than 50 nmol/L after 1 mg dexamethasone. CONCLUSIONS: The frequency of adrenal incidentalomas is higher than previously reported. Moreover, adrenal incidentalomas are tied to increased risk of type 2 diabetes. This finding is free from ascertainment bias because patients with adrenal incidentalomas were drawn from a prospective cohort with the same risk of diabetes as the background population.

18.
Hypertens Res ; 43(6): 500-510, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31586159

RESUMO

The available data on the natural history of pheochromocytomas and paragangliomas after radical surgery are heterogeneous and discordant. The aim of our retrospective multicenter study was to find predictors of recurrence in patients with pheochromocytomas and sympathetic paragangliomas submitted to radical surgery in Piedmont (a region in northwest Italy). We collected data from 242 patients diagnosed between 1990 and 2016. Forty-two patients (17.4%) had disease recurrence. Multivariate analysis showed that genetic mutation (HR = 3.62; 95% CI 1.44-9.13; p = 0.006), younger age (HR = 0.97; 95% CI 0.95-0.99; p = 0.031) and larger tumor size (HR = 1.01; 95% CI 1.00-1.02; p = 0.015) were independently associated with a higher recurrence risk of pheochromocytoma and paraganglioma; in pheochromocytomas, genetic mutation (HR = 3.4; 95% CI 1.00-11.48; p = 0.049), younger age (HR = 0.97; 95% CI 0.94-0.99; p = 0.02), higher tumor size (HR = 1.01; 95% CI 1.00-1.03; p = 0.043) and PASS value (HR = 1.16; 95% CI 1.03-1.3; p = 0.011) were associated with recurrence. Moreover, tumor size was the only predictor of metastatic pheochromocytoma and paraganglioma (HR = 4.6; 95% CI 1.4-15.0; p = 0.012); tumor size (HR = 3.93; 95% CI 1.2-16.4; p = 0.026) and PASS value (HR = 1.27; 95% CI 1.06-1.53; p = 0.007) were predictors of metastatic pheochromocytoma. In conclusion, our findings suggest that the recurrence of pheochromocytoma and sympathetic paraganglioma develops more frequently in younger subjects, patients with a family history of chromaffin tissue neoplasms, mutations in susceptibility genes, larger tumors and higher values of PASS. We recommend genetic testing in all patients with PPGL and strict follow-up at least on an annual basis.

19.
J Clin Endocrinol Metab ; 105(3)2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31633759

RESUMO

CONTEXT: We investigated the role of Gallium 68 dodecanetetraacetic acid Tyr3-octreotide (68Ga-DOTATOC) positron emission tomography/computed tomography (PET/CT) in detecting somatostatin receptors (SSTRs) in 19 patients with metastatic adrenocortical carcinoma (ACC) and explored the activity of yttrium-90/lutetium-177 (90Y/177Lu-DOTATOC) peptide receptor radionuclide therapy (PRRT). CASE DESCRIPTION AND METHODS: 68Ga uptake in metastatic sites was scored in terms of intensity and anatomical uptake distribution of standard uptake value (SUV). Tissue expression of SSTR2A and SSTR5 was also evaluated by immunohistochemistry (IHC) on primary tumors. Eight (42%) patients displayed radiometabolic uptake of any-grade intensity with focal and limited distribution. Two (11%) patients displayed strong uptake in multiple lesions and were treated with PRRT. Both obtained an overall disease control lasting 4 and 12 months, respectively. CONCLUSIONS: ACC can express SSTRs as detected by IHC and 68Ga-DOTATOC PET. SSTRs-based PRRT may represent a potential treatment opportunity for a minority of patients with advanced ACC. This treatment modality deserves further investigation.


Assuntos
Neoplasias do Córtex Suprarrenal/radioterapia , Carcinoma Adrenocortical/radioterapia , Octreotida/análogos & derivados , Receptores de Somatostatina/metabolismo , Radioisótopos de Ítrio/uso terapêutico , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/patologia , Adulto , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Octreotida/uso terapêutico , Prognóstico , Estudos Prospectivos
20.
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.

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