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1.
Int. braz. j. urol ; 45(3): 514-522, May-June 2019. tab
Artigo em Inglês | LILACS-Express | ID: biblio-1012319

RESUMO

ABSTRACT Purpose: To investigate risk factors for complications in patients undergoing adrenalectomy. Materials and Methods: A retrospective search of our institutional database was performed of patients who underwent adrenalectomy, between 2014 and 2018. Clinical parameters and adrenal disorder characteristics were assessed and correlated to intra and post-operative course. Complications were analyzed within 30-days after surgery. A logistic regression was performed in order to identify independent predictors of morbidity in patients after adrenalectomy. Results: The files of 154 patients were reviewed. Median age and Body Mass Index (BMI) were 52-years and 27.8kg/m2, respectively. Mean tumor size was 4.9±4cm. Median surgery duration and estimated blood loss were 140min and 50mL, respectively. There were six conversions to open surgery. Minor and major post-operative complications occurred in 17.5% and 8.4% of the patients. Intra-operative complications occurred in 26.6% of the patients. Four patients died. Mean hospitalization duration was 4-days (Interquartile Range: 3-8). Patients age (p=0.004), comorbidities (p=0.003) and pathological diagnosis (p=0.003) were independent predictors of post-operative complications. Tumor size (p<0.001) and BMI (p=0.009) were independent predictors of intra-operative complications. Pathological diagnosis (p<0.001) and Charlson score (p=0.013) were independent predictors of death. Conclusion: Diligent care is needed with older patients, with multiple comorbidities and harboring unfavorable adrenal disorders (adrenocortical carcinoma and pheocromocytoma), who have greater risk of post-operative complications. Patients with elevated BMI and larger tumors have higher risk of intra, but not of post-operative complications.

2.
Int Braz J Urol ; 45(3): 514-522, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31038857

RESUMO

PURPOSE: To investigate risk factors for complications in patients undergoing adrenalectomy. MATERIALS AND METHODS: A retrospective search of our institutional database was performed of patients who underwent adrenalectomy, between 2014 and 2018. Clinical parameters and adrenal disorder characteristics were assessed and correlated to intra and post-operative course. Complications were analyzed within 30-days after surgery. A logistic regression was performed in order to identify independent predictors of morbidity in patients after adrenalectomy. RESULTS: The files of 154 patients were reviewed. Median age and Body Mass Index (BMI) were 52-years and 27.8kg/m2, respectively. Mean tumor size was 4.9±4cm. Median surgery duration and estimated blood loss were 140min and 50mL, respectively. There were six conversions to open surgery. Minor and major post-operative complications occurred in 17.5% and 8.4% of the patients. Intra-operative complications occurred in 26.6% of the patients. Four patients died. Mean hospitalization duration was 4-days (Interquartile Range: 3-8). Patients age (p=0.004), comorbidities (p=0.003) and pathological diagnosis (p=0.003) were independent predictors of post-operative complications. Tumor size (p<0.001) and BMI (p=0.009) were independent predictors of intra-operative complications. Pathological diagnosis (p<0.001) and Charlson score (p=0.013) were independent predictors of death. CONCLUSION: Diligent care is needed with older patients, with multiple comorbidities and harboring unfavorable adrenal disorders (adrenocortical carcinoma and pheocromocytoma), who have greater risk of post-operative complications. Patients with elevated BMI and larger tumors have higher risk of intra, but not of post-operative complications.


Assuntos
Doenças das Glândulas Suprarrenais/cirurgia , Adrenalectomia/efeitos adversos , Complicações Intraoperatórias/etiologia , Complicações Pós-Operatórias/etiologia , Neoplasias do Córtex Suprarrenal/complicações , Neoplasias do Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/cirurgia , Doenças das Glândulas Suprarrenais/complicações , Doenças das Glândulas Suprarrenais/patologia , Carcinoma Adrenocortical/complicações , Carcinoma Adrenocortical/patologia , Carcinoma Adrenocortical/cirurgia , Adulto , Idoso , Análise de Variância , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Estatísticas não Paramétricas , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral
3.
Endocr Relat Cancer ; 25(9): 783-793, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29748190

RESUMO

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8 cm vs ≥2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.

4.
Eur J Endocrinol ; 178(1): 59-65, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28982703

RESUMO

OBJECTIVE: Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene are frequent in corticotroph tumors causing Cushing's disease (CD). Corticotroph tumor progression, the so-called Nelson's syndrome (NS), is a potentially life-threatening complication of bilateral adrenalectomy in patients with refractory CD that is caused by the development of an ACTH-secreting tumor of the pituitary gland. Whether USP8 alterations are also present in progressive Nelson's tumors has not been studied in detail so far. DESIGN AND METHODS: Retrospective, multicenter study involving tumors from 33 patients with progressive corticotroph tumors (29 females) and screening for somatic mutations on the mutational hotspot of the USP8 gene in the exon 14 with Sanger sequencing. RESULTS: Fifteen out of 33 tumors (45%) presented with a mutation in the exon 14 of USP8, with c.2159C>A (p.Pro720Gln) being the most frequent (9/33), followed by c.2155_2157delTCC (p.Ser718del, 4/33) and c.2152T>C (p.Ser718Pro, 2/33). This prevalence is similar to that previously reported for CD. Mutations were found exclusively in females. Other variables, such as age at diagnosis with NS, body mass index, hyperpigmentation, visual field defects, adenoma size or mortality, did not significantly differ between patients with wild-type and mutant tumors. Patients with USP8 mutant tumors exhibited higher levels of plasma ACTH after surgery (median: 640 vs 112 pg/mL, P = 0.03). No differences were observed in ACTH normalization (<50 pg/mL) and tumor control after surgery for Nelson's tumor. CONCLUSION: Somatic mutations in USP8 are common in Nelson's tumors, indicating that they do not drive the corticotroph tumor progression that leads to NS, and may be associated with a less favorable biochemical outcome after surgery for Nelson's tumor.


Assuntos
Carcinogênese/genética , Progressão da Doença , Endopeptidases/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Mutação/genética , Síndrome de Nelson/genética , Ubiquitina Tiolesterase/genética , Hormônio Adrenocorticotrópico/sangue , Adulto , Carcinogênese/metabolismo , Estudos de Coortes , Corticotrofos/fisiologia , Feminino , Humanos , Masculino , Síndrome de Nelson/sangue , Síndrome de Nelson/cirurgia , Estudos Retrospectivos , Adulto Jovem
5.
Oncotarget ; 8(38): 63835-63845, 2017 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-28969033

RESUMO

BACKGROUND: Discrimination between benign and malignant tumors is a challenging process in pediatric adrenocortical tumors. New insights in the metabolic profile of pediatric adrenocortical tumors may contribute to this distinction, predict prognosis, as well as identify new molecular targets for therapy. The aim of this work is to characterize the expression of the metabolism-related proteins MCT1, MCT2, MCT4, CD147, CD44, GLUT1 and CAIX in a series of pediatric adrenocortical tumors. METHODS: A total of 50 pediatric patients presenting adrenocortical tumors, including 41 clinically benign and 9 clinically malignant tumors, were included. Protein expression was evaluated using immunohistochemistry in samples arranged in tissue microarrays. RESULTS: The immunohistochemical analysis showed a significant increase in plasma membrane expression of GLUT1 in malignant lesions, when compared to benign lesions (p=0.004), being the expression of this protein associated with shorter overall and disease-free survival (p=0.004 and p=0.001, respectively). Although significant differences were not observed for proteins other than GLUT1, MCT1, MCT4 and CD147 were highly expressed in pediatric adrenocortical neoplasias (around 90%). CONCLUSION: GLUT1 expression was differentially expressed in pediatric adrenocortical tumors, with higher expression in clinically malignant tumors, and associated with shorter survival, suggesting a metabolic remodeling towards a hyperglycolytic phenotype in this malignancy.

6.
Int. braz. j. urol ; 43(5): 841-848, Sept.-Oct. 2017. tab, graf
Artigo em Inglês | LILACS-Express | ID: biblio-892887

RESUMO

ABSTRACT Purpose: To evaluate the role of ARDT after surgical resection of ACC. Materials and Methods: Records of patients from our institutional ACC database were retrospectively assessed. A paired comparison analysis was used to evaluate the oncological outcomes between patients treated with surgery followed by ARDT or surgery only (control). The endpoints were LRFS, RFS, and OS. A systematic review of the literature and meta-analysis was also performed to evaluate local recurrence of ACC when ARDT was used. Results: Ten patients were included in each Group. The median follow-up times were 32 months and 35 months for the ARDT and control Groups, respectively. The results for LRFS (p=0.11), RFS (p=0.92), and OS (p=0.47) were similar among subsets. The mean time to present with local recurrence was significantly longer in the ARDT group compared with the control Group (419±206 days vs. 181±86 days, respectively; p=0.03). ARDT was well tolerated by the patients; there were no reports of late toxicity. The meta-analysis, which included four retrospective series, revealed that ARDT had a protective effect on LRFS (HR=0.4; CI=0.17-0.94). Conclusions: ARDT may reduce the chance and prolong the time to ACC local recurrence. However, there were no benefits for disease recurrence control or overall survival for patients who underwent this complementary therapy.

7.
Int Braz J Urol ; 43(5): 841-848, 2017 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28727379

RESUMO

PURPOSE: To evaluate the role of ARDT after surgical resection of ACC. MATERIALS AND METHODS: Records of patients from our institutional ACC database were retrospectively assessed. A paired comparison analysis was used to evaluate the oncological outcomes between patients treated with surgery followed by ARDT or surgery only (control). The endpoints were LRFS, RFS, and OS. A systematic review of the literature and meta-analysis was also performed to evaluate local recurrence of ACC when ARDT was used. RESULTS: Ten patients were included in each Group. The median follow-up times were 32 months and 35 months for the ARDT and control Groups, respectively. The results for LRFS (p=0.11), RFS (p=0.92), and OS (p=0.47) were similar among subsets. The mean time to present with local recurrence was significantly longer in the ARDT group compared with the control Group (419±206 days vs. 181±86 days, respectively; p=0.03). ARDT was well tolerated by the patients; there were no reports of late toxicity. The meta-analysis, which included four retrospective series, revealed that ARDT had a protective effect on LRFS (HR=0.4; CI=0.17-0.94). CONCLUSIONS: ARDT may reduce the chance and prolong the time to ACC local recurrence. However, there were no benefits for disease recurrence control or overall survival for patients who underwent this complementary therapy.


Assuntos
Neoplasias do Córtex Suprarrenal/radioterapia , Carcinoma Adrenocortical/radioterapia , Neoplasias do Córtex Suprarrenal/cirurgia , Adrenalectomia , Carcinoma Adrenocortical/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Radioterapia Adjuvante/métodos , Estudos Retrospectivos , Adulto Jovem
8.
Int Braz J Urol ; 42(4): 671-7, 2016 Jul-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27564276

RESUMO

PURPOSE: To evaluate the presentation and early surgical outcomes of elderly patients undergoing adrenalectomy for phaeochromocytoma. PATIENTS AND METHODS: A retrospective search was performed of our adrenal disorders database for patients who underwent surgery for phaeochromocytoma or paraganglioma between 2009 and 2014. Patients >60 years old were classified as elderly. The clinical manifestations, intraoperative course, and early postoperative outcomes of elderly patients were compared to those of younger individuals (<60 years old). RESULTS: The mean (±standard deviation) age in the older (n=10) and younger (n=36) groups was 69.6±5.3 years and 34.0±12.9 years. Germ-line mutations were more common in younger patients (50.0% versus 0%; p=0.004), whereas incidental lesions were more common in the elderly (40.0% versus 5.3%; p=0.003). In both groups, surgery was most commonly performed by videolaparoscopy (90% in the elderly and 82% in the younger group), with similar intraoperative anesthetic and surgical outcomes. Postoperatively, the older group more commonly received vasoactive drugs (60.0% versus 10.5%; p<0.001) and had a longer intensive care unit stay (3.1±2.8 versus 1.4±1.0 days; p=0.014), more clinical complications (60% versus 18.9%; p=0.01), and longer hospital stay (10.2±8.4 versus 5.7±4.9 days; p=0.028). CONCLUSIONS: Although all patients received the same preoperative preparation, the elderly group exhibited a slower and more complicated recovery after adrenalectomy. Meticulous perioperative care should be used in the elderly when treating phaeochromocytoma; nevertheless, adrenalectomy is a relatively safe procedure in this patient population.


Assuntos
Neoplasias das Glândulas Suprarrenais/cirurgia , Adrenalectomia/normas , Feocromocitoma/cirurgia , Adulto , Fatores Etários , Idoso , Distribuição de Qui-Quadrado , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/classificação , Estudos Retrospectivos , Adulto Jovem
10.
Int. braz. j. urol ; 42(4): 671-677, July-Aug. 2016. tab
Artigo em Inglês | LILACS-Express | ID: lil-794685

RESUMO

ABSTRACT Purpose: To evaluate the presentation and early surgical outcomes of elderly patients undergoing adrenalectomy for phaeochromocytoma. Patients and Methods: A retrospective search was performed of our adrenal disorders database for patients who underwent surgery for phaeochromocytoma or paraganglioma between 2009 and 2014. Patients >60 years old were classified as elderly. The clinical manifestations, intraoperative course, and early postoperative outcomes of elderly patients were compared to those of younger individuals (<60 years old). Results: The mean (±standard deviation) age in the older (n=10) and younger (n=36) groups was 69.6±5.3 years and 34.0±12.9 years. Germ-line mutations were more common in younger patients (50.0% versus 0%; p=0.004), whereas incidental lesions were more common in the elderly (40.0% versus 5.3%; p=0.003). In both groups, surgery was most commonly performed by videolaparoscopy (90% in the elderly and 82% in the younger group), with similar intraoperative anesthetic and surgical outcomes. Postoperatively, the older group more commonly received vasoactive drugs (60.0% versus 10.5%; p<0.001) and had a longer intensive care unit stay (3.1±2.8 versus 1.4±1.0 days; p=0.014), more clinical complications (60% versus 18.9%; p=0.01), and longer hospital stay (10.2±8.4 versus 5.7±4.9 days; p=0.028). Conclusions: Although all patients received the same preoperative preparation, the elderly group exhibited a slower and more complicated recovery after adrenalectomy. Meticulous perioperative care should be used in the elderly when treating phaeochromocytoma; nevertheless, adrenalectomy is a relatively safe procedure in this patient population.

11.
Cancer Cell ; 29(5): 723-736, 2016 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-27165744

RESUMO

We describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs. Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/genética , Genoma Humano/genética , Genômica/métodos , Adolescente , Neoplasias do Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/terapia , Carcinoma Adrenocortical/patologia , Carcinoma Adrenocortical/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Metilação de DNA , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Avaliação de Resultados (Cuidados de Saúde) , Prognóstico , Adulto Jovem
12.
Minerva Endocrinol ; 41(3): 341-50, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26977888

RESUMO

Infertility is frequent in patients harboring pituitary adenomas. The mechanisms involved include hypogonadism secondary to hormonal hypersecretion (prolactin, growth hormone and cortisol), stalk disconnection and pituitary damage. With the improvement of clinical and surgical treatment, pregnancy in women harboring pituitary adenomas turned into a reality. Pituitary hormonal hyper- and hyposecretion influences pregnancy outcomes, as well as pregnancy can interfere on pituitary tumors, especially in prolactinomas. We review literature about specific follow-up and management in pregnant women harboring prolactinomas, acromegaly, or Cushings disease and the impact of clinical and surgical treatment on each condition.


Assuntos
Adenoma/tratamento farmacológico , Neoplasias Hipofisárias/tratamento farmacológico , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Adulto , Feminino , Humanos , Gravidez
13.
Urology ; 90: 217-20, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26775074

RESUMO

OBJECTIVE: To avoid hormonal replacement after partial adrenalectomy (PA), establishing the precise limit of an adrenal gland resection is essential. Herein, we evaluated the use of three-dimensional (3D) adrenal gland printing and volumetry measurement before PA to improve the determination of the remnant gland volume. METHODS: Concomitant total adrenalectomy and a contralateral PA were performed in a patient with primary macronodular adrenal hyperplasia that exhibited mild hypercortisolism, arterial hypertension, and diabetes. Before surgery, a 3D replica of the adrenal gland to be partially resected was printed and given to the surgeon. The volumetry of the gland was measured by computed tomography 3D image reconstruction. RESULTS: No postoperative complications were noted. Immediately after the surgery, the patient initiated corticosteroid replacement, which was interrupted 52 days later. At the 6-month follow-up, the patient stopped using medications for diabetes and reduced the number of antihypertensive medications from 5 to 1. The pre- and postoperative serum cortisol levels were, respectively, 28 and 8.7 mcg/dl (n 5-25 mcg/dl). The pre- and postoperative adrenocorticotropic hormone levels were, respectively, <5 and 88 pg/ml (n 7.2-63 pg/ml). The postoperative adrenal volume was 12% of the total preoperative adrenal volume. CONCLUSION: The use of 3D printing associated with adrenal volumetry might be a useful tool for the surgeon when performing PA, enabling an estimation of the remnant gland volume.


Assuntos
Doenças das Glândulas Suprarrenais/cirurgia , Glândulas Suprarrenais/patologia , Adrenalectomia/métodos , Impressão Tridimensional , Idoso , Humanos , Hiperplasia/cirurgia , Masculino , Tamanho do Órgão
14.
Oncotarget ; 6(42): 44403-21, 2015 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-26587828

RESUMO

Adrenocortical carcinomas (ACCs) are complex neoplasias that may present unexpected clinical behavior, being imperative to identify new biological markers that can predict patient prognosis and provide new therapeutic options. The main aim of the present study was to evaluate the prognostic value of metabolism-related key proteins in adrenocortical carcinoma. The immunohistochemical expression of MCT1, MCT2, MCT4, CD147, CD44, GLUT1 and CAIX was evaluated in a series of 154 adult patients with adrenocortical neoplasia and associated with patients' clinicopathological parameters. A significant increase in was found for membranous expression of MCT4, GLUT1 and CAIX in carcinomas, when compared to adenomas. Importantly MCT1, GLUT1 and CAIX expressions were significantly associated with poor prognostic variables, including high nuclear grade, high mitotic index, advanced tumor staging, presence of metastasis, as well as shorter overall and disease free survival. In opposition, MCT2 membranous expression was associated with favorable prognostic parameters. Importantly, cytoplasmic expression of CD147 was identified as an independent predictor of longer overall survival and cytoplasmic expression of CAIX as an independent predictor of longer disease-free survival. We provide evidence for a metabolic reprogramming in adrenocortical malignant tumors towards the hyperglycolytic and acid-resistant phenotype, which was associated with poor prognosis.


Assuntos
Neoplasias do Córtex Suprarrenal/química , Adenoma Adrenocortical/química , Carcinoma Adrenocortical/química , Biomarcadores Tumorais/análise , Metabolismo Energético , Adolescente , Neoplasias do Córtex Suprarrenal/mortalidade , Neoplasias do Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/terapia , Adenoma Adrenocortical/mortalidade , Adenoma Adrenocortical/patologia , Adenoma Adrenocortical/terapia , Carcinoma Adrenocortical/mortalidade , Carcinoma Adrenocortical/patologia , Carcinoma Adrenocortical/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/análise , Basigina/análise , Anidrase Carbônica IX , Anidrases Carbônicas/análise , Intervalo Livre de Doença , Feminino , Transportador de Glucose Tipo 1/análise , Humanos , Receptores de Hialuronatos/análise , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Índice Mitótico , Transportadores de Ácidos Monocarboxílicos/análise , Proteínas Musculares/análise , Gradação de Tumores , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Simportadores/análise , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
15.
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
16.
Clin Endocrinol (Oxf) ; 81(4): 503-10, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24717047

RESUMO

CONTEXT: The role of planar cell polarity (Wnt/PCP) and calcium-dependent (Wnt/Ca) noncanonical Wnt pathways in adrenocortical tumours (ACTs) is unknown. OBJECTIVES: To investigate the gene expression of Wnt/PCP and Wnt/Ca pathways and its association with TP53 p.R337H and CTNNB1 mutations in paediatric and adult ACTs and to correlate these findings with clinical outcome. PATIENTS: Expression of noncanonical Wnt-related genes was evaluated in 91 ACTs (66 children and 25 adults) by qPCR and the expression of beta-catenin, P53 and protein effectors of Wnt/Ca (NFAT) and Wnt/PCP (JNK) by immunohistochemistry. TP53 and CTNNB1 genes were sequenced. RESULTS: TP53 p.R337H mutation frequency was higher in children (86% vs 28%), while CTNNB1 mutation was higher in adults (32% vs 6%). Mortality was higher in adults harbouring TP53 p.R337H and in children with CTNNB1 mutations. Overexpression of WNT5A, Wnt/Ca ligand, was observed in children and adults. Overexpression of MAPK8 and underexpression of PRICKLE, Wnt/PCP mediators, were observed in paediatric but not in adult cases. Cytoplasmic/nuclear beta-catenin and P53 accumulation was observed in the majority of paediatric and adult ACTs as well as NFAT and JNK. Overexpression of MAPK8 and underexpression of PRICKLE were associated with mortality in children, while overexpression of WNT5A and underexpression of PRICKLE were associated with mortality in adults. CONCLUSIONS: In our study, TP53 p.R337H and CTNNB1 mutations correlated with poor prognosis in adults and children, respectively. We demonstrate, for the first time, the activation of Wnt/PCP and Wnt/Ca noncanonical pathway genes, and their association with poor outcome in children and adults, suggesting their putative involvement in ACTs aggressiveness.


Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Via de Sinalização Wnt/fisiologia , Adolescente , Neoplasias do Córtex Suprarrenal/genética , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Imuno-Histoquímica , Lactente , Masculino , Pessoa de Meia-Idade , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Via de Sinalização Wnt/genética , Adulto Jovem , beta Catenina/genética , beta Catenina/metabolismo
17.
J Clin Endocrinol Metab ; 99(7): E1209-16, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24712566

RESUMO

BACKGROUND: The sonic hedgehog (SHH) pathway plays a key role in rodent adrenal cortex development and is involved in tumorigenesis in several human tissues, but data in human adrenal glands are limited. OBJECTIVES: The objectives of the study were to analyze the involvement of the SHH pathway in human adrenal development and tumorigenesis and the effects of SHH inhibition on an adrenocortical tumor (ACT) cell line. PATIENTS AND METHODS: Expression of SHH pathway components was evaluated by immunohistochemistry in 51 normal adrenals (33 fetal) and 34 ACTs (23 pediatric) and by quantitative PCR in 81 ACTs (61 pediatric) and 19 controls (10 pediatric). The effects of SHH pathway inhibition on gene expression and cell viability in the NCI-H295A adrenocortical tumor cell line after cyclopamine treatment were analyzed. RESULTS: SHH pathway proteins were present in fetal and postnatal normal adrenals and showed distinct patterns of spatiotemporal expression throughout development. Adult adrenocortical carcinomas presented with higher expression of PTCH1, SMO, GLI3, and SUFU compared with normal adult adrenal cortices. Conversely, pediatric ACTs showed lower mRNA expression of SHH, PTCH1, SMO, GLI1, and GLI3 compared with normal pediatric adrenal cortices. In vitro treatment with cyclopamine resulted in decreased GLI3, SFRP1, and CTNNB1 mRNA expression and ß-catenin staining as well as decreased cell viability. CONCLUSIONS: The SHH pathway is active in human fetal and postnatal adrenals, up-regulated in adult adrenocortical carcinomas, and down-regulated in pediatric ACTs. SHH pathway antagonism impaired cell viability. The SHH pathway is deregulated in ACTs and might provide a new target therapy to be explored.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Córtex Suprarrenal/embriologia , Córtex Suprarrenal/crescimento & desenvolvimento , Carcinoma Adrenocortical/genética , Proteínas Hedgehog/genética , Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/metabolismo , Adulto , Estudos de Casos e Controles , Células Cultivadas , Criança , Desenvolvimento Embrionário/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Proteínas Hedgehog/metabolismo , Humanos , Recém-Nascido , Gravidez , Estudos Retrospectivos , Transdução de Sinais/genética
18.
Am J Pathol ; 181(3): 1017-33, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22800756

RESUMO

Dysregulation of the WNT and insulin-like growth factor 2 (IGF2) signaling pathways has been implicated in sporadic and syndromic forms of adrenocortical carcinoma (ACC). Abnormal ß-catenin staining and CTNNB1 mutations are reported to be common in both adrenocortical adenoma and ACC, whereas elevated IGF2 expression is associated primarily with ACC. To better understand the contribution of these pathways in the tumorigenesis of ACC, we examined clinicopathological and molecular data and used mouse models. Evaluation of adrenal tumors from 118 adult patients demonstrated an increase in CTNNB1 mutations and abnormal ß-catenin accumulation in both adrenocortical adenoma and ACC. In ACC, these features were adversely associated with survival. Mice with stabilized ß-catenin exhibited a temporal progression of increased adrenocortical hyperplasia, with subsequent microscopic and macroscopic adenoma formation. Elevated Igf2 expression alone did not cause hyperplasia. With the combination of stabilized ß-catenin and elevated Igf2 expression, adrenal glands were larger, displayed earlier onset of hyperplasia, and developed more frequent macroscopic adenomas (as well as one carcinoma). Our results are consistent with a model in which dysregulation of one pathway may result in adrenal hyperplasia, but accumulation of a second or multiple alterations is necessary for tumorigenesis.


Assuntos
Neoplasias do Córtex Suprarrenal/patologia , Transformação Celular Neoplásica/patologia , Progressão da Doença , Fator de Crescimento Insulin-Like II/metabolismo , beta Catenina/metabolismo , Proteína da Polipose Adenomatosa do Colo/metabolismo , Corticosteroides/metabolismo , Neoplasias do Córtex Suprarrenal/genética , Animais , Biomarcadores Tumorais/metabolismo , Transformação Celular Neoplásica/genética , Metilação de DNA/genética , Regulação Neoplásica da Expressão Gênica , Impressão Genômica , Humanos , Hiperplasia , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Camundongos , Camundongos Knockout , Análise Multivariada , Mutação/genética , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estabilidade Proteica , Transporte Proteico , Regulação para Cima/genética
20.
Pituitary ; 14(4): 400-4, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19655257

RESUMO

Nelson's syndrome (NS) is characterized by the appearance and/or progression of ACTH-secreting pituitary macroadenomas in patients who had previously undergone bilateral adrenalectomy for the treatment of Cushing's disease. Such corticotroph macroadenomas respond poorly to currently available therapeutic options which include surgery, radiotherapy and chemotherapy. P53 protein accumulation may be detected by immunohistochemistry in pituitary corticotroph adenomas and it has been suggested that it might be causally related to tumor development. Wild type P53 protein plays an important role in the cellular response to ionizing radiation and other DNA damaging agents and is mutated in many human tumors. In this study we report an adult male patient with NS who underwent both transsphenoidal and transcranial pituitary surgeries, conventional and stereotaxic radiotherapy and brachytherapy. Despite of the efforts to control tumor mass and growth, this macroadenoma displayed relentless growth and aggressive behavior. DNA extracted from the first two surgical samples, as well as DNA from peripheral blood leukocytes disclosed normal p53 sequence. DNA extracted from tumor samples obtained at surgeries performed after pituitary irradiation carried a somatic heterozygous mutation, consisting of a deletion of four cytosines between nucleotides 12,144-12,149 in exon 4 of the p53 gene. This frameshift mutation creates a stop codon in exon 4 excluding the expression of a functional protein from the defective allele. These data demonstrate a possible association between the P53 protein loss of function induced by radiotherapy and the aggressive course of the disease in this patient.


Assuntos
Adenoma Hipofisário Secretor de ACT/radioterapia , Adenoma/radioterapia , Genes p53/efeitos da radiação , Mutação , Síndrome de Nelson/radioterapia , Efeitos da Radiação , Adenoma Hipofisário Secretor de ACT/etiologia , Adenoma Hipofisário Secretor de ACT/genética , Adenoma/etiologia , Adenoma/genética , Adulto , Sequência de Bases , Análise Mutacional de DNA , Evolução Fatal , Humanos , Masculino , Síndrome de Nelson/complicações , Síndrome de Nelson/genética , Irradiação Hipofisária/efeitos adversos
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