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Adrenocortical carcinoma (ACC) is a rare malignancy that is associated with a dismal prognosis. Pan-genomic studies have demonstrated the involvement of ATRX and ZNRF3 genes in adrenocortical tumorigenesis. Our aims were to evaluate the protein expression of ATRX and ZNRF3 in a cohort of 82 adults with ACC and to establish their prognostic value. Two pathologists analyzed immuno-stained slides of a tissue microarray. The low protein expression of ATRX and ZNRF3 was associated with a decrease in overall survival (OS) (p = 0.045, p = 0.012, respectively). The Cox regression for ATRX protein expression of >1.5 showed a hazard ratio (HR) for OS of 0.521 (95% CI 0.273–0.997; p = 0.049) when compared with ≤1.5; for ZNRF3 expression >2, the HR for OS was 0.441 (95% CI, 0.229–0.852; p = 0.015) when compared with ≤2. High ATRX and ZNRF3 protein expressions were associated with optimistic recurrence-free survival (RFS) (p = 0.027 and p = 0.005, respectively). The Cox regression of RFS showed an HR of 0.332 (95%CI, 0.111–0.932) for ATRX expression >2.7 (p = 0.037), and an HR of 0.333 (95%CI, 0.140–0.790) for ZNRF3 expression >2 (p = 0.013). In conclusion, low protein expression of ATRX and ZNRF3 are negative prognostic markers of ACC; however, different cohorts should be evaluated to validate these findings.

INTRODUÇÃO: A hiperplasia macronodular adrenal primaria (HMAP) e uma doenca rara, caracterizada pela presenca de macronodulos nas adrenais e por uma producao aumentada, autonoma e sustentada de cortisol. Constitui uma causa incomum de sindrome de Cushing. O tratamento cirurgico e indicado visando o controle do hipecortisolismo e de suas consequencias. Estudamos uma nova abordagem cirurgica, a cirurgia poupadora de adrenal (adrenalectomia total laparoscopica do lado de maior volume/ atividade metabolica com adrenalectomia parcial laparoscopica contralateral), no tratamento da HMAP com o objetivo de possibilitar o controle do hipercortisolismo sem a necessidade de reposicao hormonal. OBJETIVOS: Os objetivos do estudo foram: 1) avaliar a efetividade e seguranca da cirurgia poupadora de adrenal e como foi a evolucao dos pacientes operados, do ponto de vista metabolico e clinico; 2) definir quais os fatores que influenciaram no tempo de recuperacao da funcao do eixo hipotalamo-hipofise-adrenal no pos-operatorio; 3) avaliar correlacao entre o volume das adrenais e a captacao de radioisotopo na tomografia por emissao de positrons com fluorodesoxiglicose marcada (18F-FDGPET/ CT). MÉTODOS: Dezessete pacientes com diagnostico de HMAP submetidos a cirurgia poupadora de adrenal, com pelo menos 12 meses de seguimento (mediana de seguimento de 41 meses), foram incluidos no estudo. A mediana da idade no momento da indicacao da cirurgia foi de 50 anos (41-69), e a mediana do IMC de 29 kg/m2, sendo 5 homens (29,5%) e 12 mulheres (70,5%). A adrenalectomia total foi realizada no lado com maior volume nos estudos de tomografia e maior atividade na 18F-FDGPET/ CT. O desfecho primario avaliado foi a recuperacao do eixo hipotalamo-hipofiseadrenal associada ao controle do hipercortisolismo, bem como a evolucao dos parametros clinicos e metabolicos no periodo pos-operatorio. Os desfechos secundarios incluiram a identificacao de fatores que influenciaram na recuperacao da funcao hormonal, juntamente com o estudo da correlacao entre o volume das adrenais e atividade glicolitica das glandulas. Utilizou-se tomografia com 3 meses de posoperatorio para avaliar a volumetria da adrenal remanescente. RESULTADOS: O tempo cirurgico medio foi de 199 } 39 minutos (variacao de 160-300); o tempo anestesico medio foi de 322}72 minutos (210-510). Nao ocorreram complicacoes intra-operatorias. Doze pacientes (70,5%) recuperaram a funcao da adrenal para producao de cortisol, enquanto os demais 5 (29,5%) permanecem dependentes de reposicao hormonal. O tempo medio de recuperacao da funcao da adrenal foi de 32 meses. O volume medio de glandula adrenal remanescente foi de 4,1 cm3. O nivel serico de ACTH mensuravel se mostrou um fator preditivo de menor tempo de recuperacao da funcao hormonal (p=0,003). Os pacientes operados apresentaram melhora significante do peso (88 para 82kg), da pressao arterial sistolica (145 para 121mmHg), da pressao arterial diastolica (91 para 78mmHg) e no numero de medicamentos para hipertensao arterial (2,8 para1,1). Por fim, foi confirmada a correlacao entre volume da adrenal e a captacao desta em SUV no exame de 18F-FDGPET/ CT (p=0,024). CONCLUSÕES: A cirurgia poupadora de adrenal se mostrou uma opcao segura no tratamento da HMAP, com bons resultados no controle do hipercortisolismo e na recuperacao da funcao hormonal. A cirurgia contribuiu para a melhora no peso, pressao arterial sistolica, pressao arterial diastolica e numero de medicamentos para hipertensao. Pacientes com ACTH mensuravel apresentaram melhor chance de recuperacao da funcao hormonal. Na HMAP, adrenais de maior volume tendem a apresentar maior atividade glicolitica na 18F-FDG-PET/CT INTRODUCTION: Primary macronodular adrenal hyperplasia (PMAH) is a rare disease characterized by adrenal macronodules and increased, autonomous and sustained cortisol production. This condition is an uncommon cause of Cushing\'s syndrome. The objective of surgical treatment is the control of excessive hormonal production and its consequences. We studied a new surgical approach that we called adrenal sparing surgery (total laparoscopic adrenalectomy of the adrenal gland with larger volume/higher metabolic activity associated with contralateral partial laparoscopic adrenalectomy), in order to achieve control of hypercortisolism without lifetime hormonal reposition disadvantages. OBJECTIVES: The objectives of this study: 1) evaluate the effectiveness and safety of adrenal sparing surgery and how was the evolution of operated patients, with clinical and metabolic parameters; 2) define which aspects influence in the time to recover the hypothalamus-pituitary-adrenal axis function in post-operative period; 3) evaluate the correlation between adrenal volume and SUV capitation on 18F-FDG-PET/CT. METHODS: Seventeen patients with diagnosed PMAH submitted to adrenal sparing surgery and, at least 12 months follow up were include in this study (median follow up of 41 months). In the moment the surgical treatment was indicated, the median age was 53 years-old (range 41- 69), median BMI was 29 kg/m2, including 5 male (29.5%) and 12 female (70.5%) patients. Total adrenalectomy was performed in the larger gland in CT and higher metabolic activity in 18F-FDG-PET/CT. The primary endpoint was the recovery of hypothalamus-pituitary-adrenal axis associated to hypercortisolism control, as well as the evolution of clinical and metabolic parameters in post-operative period. The secondary endpoints were the identification of factors that may have influenced the recovery of hormonal function, besides the study of the correlation between adrenal volume and radioisotope uptake by the glands. We used CT three months after surgery to evaluate remaining adrenal volume. RESULTS: Average surgical time was 199 } 39 minutes (range160-300); average anesthesia time was 322}72 minutes (range 210-510). There were no intra-operative complications. Twelve patients (70.5%) recovered adrenal function in cortisol production, while the other 5 remained in adrenal insufficiency The average time to adrenal function recovery was 32 months. In post-operative CT the average adrenal volume was 4.1 cm3. Measurable ACTH level (not suppressed) was associated with a better chance to recover hormonal function (p=0.003). Operated patients showed significant improvement in clinical parameters: weight reduction (88 to 82kg); reduction of both systolic (145 to 141 mmHg) and diastolic (91 to 78mmHg) blood pressures and in the number of hypertension medications (2.8 to 1.1). Finally, a correlation between adrenal volume and glycolytic uptake in 18F-FDG-PET/CT was confirmed (p=0.024). CONCLUSIONS: Adrenal sparing surgery is a safe and effective option in PMAH surgical treatment, providing high rate of hypercortisolism control and hormonal function recovery. The surgery contributed to weight reduction and improvement in hypertension and number of medications. In PMAH, larger adrenals tend to present a higher glycolytic uptake in 18F-FDG-PET/CT

Objective: Germline ARMC5 mutations are considered to be the main genetic cause of primary macronodular adrenal hyperplasia (PMAH). PMAH is associated with high variability of cortisol secretion caused from subclinical hypercortisolism to overt Cushing's syndrome (CS), in general due to bilateral adrenal nodules and rarely could also be due to non-synchronic unilateral adrenal nodules. The frequency of adrenal incidentalomas (AI) associated with PMAH is unknown. This study evaluated germline allelic variants of ARMC5 in patients with bilateral and unilateral AI and in patients with overt CS associated with bilateral adrenal nodules. Methods: We performed a retrospective multicenter study involving 123 patients with AI (64 bilateral; 59 unilateral). We also analyzed 20 patients with ACTH pituitary independent overt CS associated with bilateral adrenal nodules. All patients underwent germline genotyping analysis of ARMC5; abdominal CT and were classified as normal, possible or autonomous cortisol secretion, according to the low doses of dexamethasone suppression test. Results: We identified only one pathogenic allelic variant among the patients with bilateral AI. We did not identify any pathogenic allelic variants of ARMC5 in patients with unilateral AI. Thirteen out of 20 patients (65%) with overt CS and bilateral adrenal nodules were carriers of pathogenic germline ARMC5 allelic variants, all previously described. The germline ARMC5 mutation was observed in only one patient with bilateral AI; it was associated with autonomous cortisol secretion and showed to be a familial form. Conclusion: The rarity of germline ARMC5 mutations in AI points to other molecular mechanisms involved in this common adrenal disorder and should be investigated. In contrast, patients with overt Cushing's syndrome and bilateral adrenal nodules had the presence of ARMC5 mutations that were with high prevalence and similar to the literature. Therefore, we recommend the genetic analysis of ARMC5 for patients with established Cushing's syndrome and bilateral adrenal nodules rather than patients with unilateral AI.

Introdução: Postula-se que o aumento do metabolismo das proteínas da matriz extracelular está associado à fibrose tecidual no contexto de estenose de junção ureteropélvica (EJUP). O manejo ideal da EJUP permanece discutível. Este estudo casocontrole prospectivo teve como objetivo investigar se os níveis urinários de proteínas da matriz extracelular são úteis para discernir os pacientes com hidronefrose obstrutiva daqueles com hidronefrose não obstrutiva em crianças com hidronefrose unilateral secundária à obstrução ao nível da junção pieloureteral. Métodos: Setenta e quatro pacientes foram incluídos no estudo. Concentrações urinárias de metaloproteinases de matriz extracelular (MMP) -1, -2, -9 e -10 e os inibidores de metaloproteinases (TIMP) -1 e -2, valores absolutos e normalizados pela creatinina (Cr) urinária, bem como as características clínicas (grau de hidronefrose, função renal diferencial e t1 / 2) foram registradas nos seguintes grupos de pacientes de mesma idade: 26 crianças com hidronefrose obstrutiva no diagnóstico inicial e durante o pós-operatório da correção cirúrgica (grupo hidronefrose obstrutiva); 22 crianças com hidronefrose não obstrutiva no momento do diagnóstico e após seis meses de observação (grupo hidronefrose não obstrutiva); e 26 crianças sem qualquer condição do trato urinário (grupo controle). Os resultados foram avaliados estatisticamente usando para grupos homogêneos, uma análise de variância unilateral (ANOVA) e para grupos não paramétricos, teste de Mann-Whitney ou teste de Kruskal-Wallis. Resultados: Comparando as amostras iniciais, MMP-1, MMP-2, MMP-10 TIMP-1 e TIMP-2 apresentaram maior concentração no grupo hidronefrose obstrutiva e menor concentração no grupo controle. Os níveis de MMP-9 foram menores no grupo controle, mas maiores no hidronefrose não obstrutiva. A análise das curvas ROC mostrou um perfil diagnóstico melhor para a detecção de hidronefrose obstrutiva para MMP-2/Cr (área sob a curva ASC - de 0,655), TIMP-1/Cr (ASC - de 0,692) e TIMP-2/Cr (ASC de 0,678). A avaliação dos parâmetros no grupo hidronefrose obstrutiva, no pré e pós-operatório apresentou queda na concentração urinária de TIMP-1 e TIMP-2 e aumento na concentração urinária de MMP-1, MMP- 2, MMP-9 e MMP-10. Todas as proteínas analisadas permaneceram estáveis no grupo hidronefrose não obstrutiva no momento do diagnóstico e após seis meses de observação. Conclusão: Demonstramos que os pacientes pediátricos com hidronefrose obstrutiva apresentam concentrações significativamente maiores de MMP-2, TIMP-1 e TIMP-2. Particularmente, os níveis de TIMP-2 foram correlacionados à gravidade da obstrução e, portanto, pode ser um biomarcador urinário útil para alocar corretamente as crianças com EJUP entre o tratamento cirúrgico e o seguimento conservador. Após a pieloplastia, TIMP-1 e TIMP-2 apresentaram diminuição progressiva no pós-operatório, o que também é altamente desejável para marcadores urinários. Introduction: Extracellular matrix proteins have been found to be associated with tissue fibrosis in the setting of ureteropelvic junction obstruction (UPJO). The ideal management of UPJO remains debatable. This prospective case-control study aimed to investigate whether urinary levels of extracellular matrix proteins (associated to tissue fibrosis) are useful to discriminate the severity of urinary obstruction in children with unilateral ureteropelvic junction obstruction (UPJO). Methods: Seventy-four patients were enrolled in the study. Urinary matrix metalloproteinases (MMP) -1, -2, -9, -10 and metalloproteinase inhibitors (TIMP) -1 and -2 as well as clinical characteristics (hydronephrosis grade, differential renal function and t1/2) were measured in the following age-matched groups: 26 children with obstructive hydronephroses HN at initial diagnosis and during six months after dismembered pyeloplasty; 22 children with non-obstructive HN at diagnosis and after six months of observation; and 26 children without any urinary tract condition, as the control group. Results were assessed statistically using for homogenous groups, a one-way analysis of variances (ANOVA) and for nonparametric groups, MannWhitney test or Kruskal Wallis test was performed. Results: Comparing the initial samples, uMMP-1/Cr, uMMP-2/Cr, uMMP-10/Cr uTIMP-1/Cr and u-TIMP-2/Cr had higher concentration in obstructive HN group and lower concentration in control group. The uMMP-9/Cr levels were lower in control group, but higher in non-obstructive HN group. The ROC curves analysis showed a promising diagnostic profile for the detection of obstructive HN for uMMP-2/Cr (area under the curve AUC of 0.655), uTIMP-1/Cr (AUC of 0.692) and uTIMP-2/Cr (AUC of 0.678). The follow-up evaluation in the obstructive HN group, pre- and postoperatively depicted fall in urinary concentration of uTIMP-1/Cr and uTIMP-2/Cr and increase in urinary concentration of uMMP-1/Cr, uMMP-2/Cr, uMMP-9/Cr and uMMP-10/Cr. All analyzed proteins were stable in non-obstructive HN at diagnosis and after six months of observation. Conclusion: We demonstrated that pediatric patients with obstructive HN have significantly higher uMMP-2, uTIMP-1 and uTIMP-2 concentrations. Particularly, uTIMP-2 levels were correlated to severity of the obstruction and therefore, it might be a useful urinary biomarker to correctly allocate children with HN between surgical management vs follow-up. After pyeloplasty, uTIMP-1 and uTIMP-2 presented a progressive decrease postoperatively, which is also highly desirable for urinary markers.