MARIA CANDIDA BARISSON VILLARES FRAGOSO
Projetos de Pesquisa
Unidades Organizacionais
Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina - Médico
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
14 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 14
- Pregnancy in Women Previously Treated for an Adrenocortical Carcinoma(2015) CORBIERE, Pauline de; RITZEL, Katrin; CAZABAT, Laure; ROPERS, Jacques; SCHOTT, Matthias; LIBE, Rosella; KOSCHKER, Ann-Cathrin; LEBOULLEUX, Sophie; DEUTSCHBEIN, Timo; CAO, Christine Do; HAHNER, Stefanie; DRUI, Delphine; MIEHLE, Konstanze; CARON, Philippe; WALDMANN, Jens; CHABRE, Olivier; QUINKLER, Marcus; TOURAINE, Philippe; FRAGOSO, Maria C. Villares; BERTHERAT, Jerome; BERTAGNA, Xavier; FASSNACHT, Martin; RAFFIN-SANSON, Marie-LaureContext: 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 forACCseems to not be associated with worse clinical outcome, although a ""healthy mother effect"" cannot be excluded.
- Cytoreductive Surgery of the Primary Tumor in Metastatic Adrenocortical Carcinoma: Impact on Patients' Survival(2022) SROUGI, Victor; BANCOS, Irina; DAHER, Marilyne; LEE, Jeffrey E.; GRAHAM, Paul H.; KARAM, Jose A.; HENRIQUEZ, Andres; MCKENZIE, Travis J.; SADA, Alaa; BOURDEAU, Isabelle; POIRIER, Jonathan; VAIDYA, Anand; ABBONDANZA, Tiffany; KIERNAN, Colleen M.; RAO, Sarika N.; HAMIDI, Oksana; SACHITHANANDAN, Nirupa; HOFF, Ana O.; CHAMBO, Jose L.; ALMEIDA, Madson Q.; HABRA, Mouhammed Amir; V, Maria C. B. FragosoContext The role of cytoreduction of adrenocortical carcinoma (ACC) remains poorly understood. Objective To analyze the impact of cytoreductive surgery of the primary tumor in patients with metastatic ACC. Design and Setting We performed a multicentric, retrospective paired cohort study comparing the overall survival (OS) in patients with metastatic ACC who were treated either with cytoreductive surgery (CR group) or without cytoreductive surgery (no-CR group) of the primary tumor. Data were retrieved from 9 referral centers in the American-Australian-Asian Adrenal Alliance collaborative research group. Patients Patients aged >= 18 years with metastatic ACC at initial presentation who were treated between January 1, 1995, and May 31, 2019. Intervention Performance (or not) of cytoreductive surgery of the primary tumor. Main outcome and measures A propensity score match was done using age and the number of organs with metastasis (<= 2 or >2). The main outcome was OS, determined from the date of diagnosis until death or until last follow-up for living patients. Results Of 339 patients pooled, 239 were paired and included: 128 in the CR group and 111 in the no-CR group. The mean follow-up was 67 months. Patients in the no-CR group had greater risk of death than did patients in the CR group (hazard ratio [HR] = 3.18; 95% CI, 2.34-4.32). Independent predictors of survival included age (HR = 1.02; 95% CI, 1.00-1.03), hormone excess (HR = 2.56; 95% CI, 1.66-3.92), and local metastasis therapy (HR = 0.41; 95% CI, 0.47-0.65). Conclusion Cytoreductive surgery of the primary tumor in patients with metastatic ACC is associated with prolonged survival.
- KCNJ5 Somatic Mutation Is a Predictor of Hypertension Remission After Adrenalectomy for Unilateral Primary Aldosteronism(2019) VILELA, Leticia A. P.; RASSI-CRUZ, Marcela; GUIMARAES, Augusto G.; MOISES, Caio C. S.; FREITAS, Thais C.; ALENCAR, Natalia P.; PETENUCI, Janaina; GOLDBAUM, Tatiana S.; MACIEL, Ana Alice W.; PEREIRA, Maria Adelaide A.; V, Giovanio Silva; PIO-ABREU, Andrea; ZERBINI, Maria Claudia N.; CAVALCANTE, Aline C. B. S.; CARNEVALE, Francisco C.; PILAN, Bruna; YAMAUCHI, Fernando; SROUGI, Vitor; TANNO, Fabio Y.; CHAMBO, Jose L.; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; V, Maria Candida B. Fragoso; BORTOLOTTO, Luiz A.; DRAGER, Luciano F.; ALMEIDA, Madson Q.Context: Primary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). HT remission (defined as blood pressure <140/90 mm Hg without antihypertensive drugs) has been reported in approximately 50% of patients with unilateral PA after adrenalectomy. HT duration and severity are predictors of blood pressure response, but the prognostic role of somatic KCNJ5 mutations is unclear. Objective: To determine clinical and molecular features associated with HT remission after adrenalectomy in patients with unilateral PA. Methods: We retrospectively evaluated 100 patients with PA (60 women; median age at diagnosis 48 years with a median follow-up of 26 months). Anatomopathological analysis revealed 90 aldosterone-producing adenomas, 1 carcinoma, and 9 unilateral adrenal hyperplasias. All patients had biochemical cure after unilateral adrenalectomy. KCNJ5 gene was sequenced in 76 cases. Results: KCNJ5 mutations were identified in 33 of 76 (43.4%) tumors: p.Gly151Arg (n = 17), p.Leu168Arg (n = 15), and p.GIu145GIn (n = 1). HT remission was reported in 37 of 100 (37%) patients. Among patients with HT remission, 73% were women (P = 0.04), 48.6% used more than three antihypertensive medications (P= 0.0001), and 64.9% had HT duration <10 years (P= 0.0015) compared with those without HT remission. Somatic KCNJ5 mutations were associated with female sex (P = 0.004), larger nodules (P = 0.001), and HT remission (P = 0.0001). In multivariate analysis, only a somatic KCNJ5 mutation was an independent predictor of HT remission after adrenalectomy (P = 0.004). Conclusion: The presence of a KCNJ5 somatic mutation is an independent predictor of HT remission after unilateral adrenalectomy in patients with unilateral PA.
- Evidence for a Founder Effect of SDHB Exon 1 Deletion in Brazilian Patients With Paraganglioma(2023) FAGUNDES, Gustavo F. C.; FREITAS-CASTRO, Felipe; SANTANA, Lucas S.; AFONSO, Ana Caroline F.; PETENUCI, Janaina; FUNARI, Mariana F. A.; GUIMARAES, Augusto G.; LEDESMA, Felipe L.; PEREIRA, Maria Adelaide A.; VICTOR, Carolina R.; FERRARI, Marcela S. M.; COELHO, Fernando M. A.; SROUGI, Victor; TANNO, Fabio Y.; CHAMBO, Jose L.; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; V, Maria Candida B. Fragoso; HOFF, Ana O.; ALMEIDA, Madson Q.Context Limited information is available concerning the genetic spectrum of pheochromocytoma and paraganglioma (PPGL) patients in South America. Germline SDHB large deletions are very rare worldwide, but most of the individuals harboring the SDHB exon 1 deletion originated from the Iberian Peninsula. Objective Our aim was to investigate the spectrum of SDHB genetic defects in a large cohort of Brazilian patients with PPGLs. Methods Genetic investigation of 155 index PPGL patients was performed by Sanger DNA sequencing, multiplex ligation-dependent probe amplification, and/or target next-generation sequencing panel. Common ancestrality was investigated by microsatellite genotyping with haplotype reconstruction, and analysis of deletion breakpoint. Results Among 155 index patients, heterozygous germline SDHB pathogenic or likely pathogenic variants were identified in 22 cases (14.2%). The heterozygous SDHB exon 1 complete deletion was the most frequent genetic defect in SDHB, identified in 8 out of 22 (36%) of patients. Haplotype analysis of 5 SDHB flanking microsatellite markers demonstrated a significant difference in haplotype frequencies in a case-control permutation test (P = 0.03). More precisely, 3 closer/informative microsatellites were shared by 6 out of 8 apparently unrelated cases (75%) (SDHB-GATA29A05-D1S2826-D1S2644 | SDHB-186-130-213), which was observed in only 1 chromosome (1/42) without SDHB exon 1 deletion (X-2 = 29.43; P < 0.001). Moreover, all cases with SDHB exon 1 deletion had the same gene breakpoint pattern of a 15 678 bp deletion previously described in the Iberian Peninsula, indicating a common origin. Conclusion The germline heterozygous SDHB exon 1 deletion was the most frequent genetic defect in the Brazilian PPGL cohort. Our findings demonstrated a founder effect for the SDHB exon 1 deletion in Brazilian patients with paragangliomas.
- Response to Letter to the Editor from de Ponthaud et al: ""Cytoreductive Surgery of the Primary Tumor in Metastatic Adrenocortical Carcinoma: Impact on Patients' Survival"" (Feb, 10.1210/clinem/dgac097, 2022)(2022) SROUGI, V; HABRA, M. A.; V, M. C. B. Fragoso
- Expression of SOAT1 in Adrenocortical Carcinoma and Response to Mitotane Monotherapy: An ENSAT Multicenter Study(2020) WEIGAND, Isabel; ALTIERI, Barbara; LACOMBE, Amanda M. F.; BASILE, Vittoria; KIRCHER, Stefan; LANDWEHR, Laura-Sophie; SCHREINER, Jochen; ZERBINI, Maria C. N.; RONCHI, Cristina L.; MEGERLE, Felix; BERRUTI, Alfredo; CANU, Letizia; VOLANTE, Marco; PAIVA, Isabel; CASA, Silvia Della; SBIERA, Silviu; FASSNACHT, Martin; V, Maria Candida B. Fragoso; TERZOLO, Massimo; KROISS, MatthiasContext: 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.
- F-18-FDG-PET/CT Imaging of ACTH-Independent Macronodular Adrenocortical Hyperplasia (AIMAH) Demonstrating Increased F-18-FDG Uptake(2011) ALENCAR, Guilherme Asmar; FRAGOSO, Maria Candida Barisson Villares; YAMAGA, Lilian Yuri Itaya; LERARIO, Antonio Marcondes; MENDONCA, Berenice Bilharinho
- Primary Adrenal Insufficiency Due to Bilateral Adrenal Infarction in COVID-19(2022) MACHADO, Iza F. R.; MENEZES, Isabel Q.; FIGUEIREDO, Sabrina R.; COELHO, Fernando M. A.; TERRABUIO, Debora R. B.; V, Davi Ramos; FAGUNDES, Gustavo F. C.; MACIEL, Ana Alice W.; LATRONICO, Ana Claudia; V, Maria Candida B. Fragoso; CANCADO, Eduardo L. R.; MENDONCA, Berenice B.; ALMEIDA, Madson Q.Context: Coronavirus disease 2019 (COVID-19) is a proinflammatory and prothrombotic condition, but its impact on adrenal function has not been adequately evaluated. Case report: A 46-year-old woman presented with abdominal pain, hypotension, and skin hyperpigmentation after COVID-19 infection. The patient had hyponatremia, serum cortisol <1.0 mu g/dL, adrenocorticotropin (ACTH) of 807 pg/mL, and aldosterone <3 ng/dL. Computed tomography (CT) findings of adrenal enlargement with no parenchymal and minimal peripheral capsular enhancement after contrast were consistent with bilateral adrenal infarction. The patient had autoimmune hepatitis and positive antiphospholipid antibodies, but no previous thrombotic events. The patient was treated with intravenous hydrocortisone, followed by oral hydrocortisone and fludrocortisone. Discussion: We identified 9 articles, including case reports, of new-onset adrenal insufficiency and/or adrenal hemorrhage/infarction on CT in COVID-19. Adrenal insufficiency was hormonally diagnosed in 5 cases, but ACTH levels were measured in only 3 cases (high in 1 case and normal/low in other 2 cases). Bilateral adrenal nonhemorrhagic or hemorrhagic infarction was identified in 5 reports (2 had adrenal insufficiency, 2 had normal cortisol levels, and 1 case had no data). Interestingly, the only case with well-characterized new-onset acute primary adrenal insufficiency after COVID-19 had a previous diagnosis of antiphospholipid syndrome. In our case, antiphospholipid syndrome diagnosis was established only after the adrenal infarction triggered by COVID-19. Conclusion: Our findings support the association between bilateral adrenal infarction and antiphospholipid syndrome triggered by COVID-19. Therefore, patients with positive antiphospholipid antibodies should be closely monitored for symptoms or signs of acute adrenal insufficiency during COVID-19.
- Sonic Hedgehog Signaling Is Active in Human Adrenal Cortex Development and Deregulated in Adrenocortical Tumors(2014) GOMES, Debora C.; LEAL, Leticia F.; MERMEJO, Livia M.; SCRIDELI, Carlos A.; MARTINELLI JR., Carlos E.; FRAGOSO, Maria C. B. V.; LATRONICO, Ana C.; TONE, Luis G.; TUCCI, Silvio; YUNES, Jose A.; CARDINALLI, Izilda A.; MASTELLARO, Maria J.; BRANDALISE, Silvia R.; RAMALHO, Fernando; MOREIRA, Ayrton C.; RAMALHO, Leandra N.; CASTRO, Margaret de; ANTONINI, Sonir R. R.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 beta-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.
- Intra-individual Variability of Serum Aldosterone and Implications for Primary Aldosteronism Screening(2023) MACIEL, Ana Alice W.; FREITAS, Thais C.; FAGUNDES, Gustavo F. C.; PETENUCI, Janaina; VILELA, Leticia A. P.; BRITO, Luciana P.; GOLDBAUM, Tatiana S.; ZERBINI, Maria Claudia N.; LEDESMA, Felipe L.; TANNO, Fabio Y.; SROUGI, Victor; CHAMBO, Jose L.; PEREIRA, Maria Adelaide A.; COELHO, Fernando M. A.; CAVALCANTE, Aline C. B. S.; CARNEVALE, Francisco C.; PILAN, Bruna; PIO-ABREU, Andrea; V, Joao Silveira; CONSOLIM-COLOMBO, Fernanda M.; BORTOLOTTO, Luiz A.; LATRONICO, Ana Claudia; V, Maria Candida B. Fragoso; DRAGER, Luciano F.; MENDONCA, Berenice B.; ALMEIDA, Madson Q.Context Primary aldosteronism (PA) screening relies on an elevated aldosterone to renin ratio with a minimum aldosterone level, which varies from 10 to 15 ng/dL (277-415.5 pmol/L) using immunoassay. Objective To evaluate intra-individual coefficient of variation (CV) of aldosterone and aldosterone to direct renin concentration ratio (A/DRC) and its impact on PA screening. Methods A total of 671 aldosterone and DRC measurements were performed by the same chemiluminescence assays in a large cohort of 216 patients with confirmed PA and at least 2 screenings. Results The median intra-individual CV of aldosterone and A/DRC was 26.8% and 26.7%. Almost 40% of the patients had at least one aldosterone level <15 ng/dL, 19.9% had at least 2 aldosterone levels <15 ng/dL, and 16.2% had mean aldosterone levels <15 ng/dL. A lower cutoff of 10 ng/dL was associated with false negative rates for PA screening of 14.3% for a single aldosterone measurement, 4.6% for 2 aldosterone measurements, and only 2.3% for mean aldosterone levels. Considering the minimum aldosterone, true positive rate of aldosterone thresholds was 85.7% for 10 ng/dL and 61.6% for 15 ng/dL. An A/DRC >2 ng/dL/mu IU/mL had a true positive rate for PA diagnosis of 94.4% and 98.4% when based on 1 or 2 assessments, respectively. CV of aldosterone and A/DRC were not affected by sex, use of interfering antihypertensive medications, PA lateralization, hypokalemia, age, and number of hormone measurements. Conclusion Aldosterone concentrations had a high CV in PA patients, which results in an elevated rate of false negatives in a single screening for PA. Therefore, PA screening should be based on at least 2 screenings with concomitant aldosterone and renin measurements.