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
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conferenceObject A Lower Ki 67 Labelling Index (LI) Cut-Point Improves the Prognostic Assessment and Might Aid in the Diagnosis of Adult Adrenocortical Tumors(2018) MARTINS FILHO, Sebastiao N.; ALMEIDA, Madson Q.; SOARES, Ibere C.; WAKAMATSU, Alda; ALVES, Venancio; FRAGOSO, Maria C.; ZERBINI, Maria- 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.
- Genetic and clinical aspects of paediatric pheochromocytomas and paragangliomas(2021) PETENUCI, Janaina; GUIMARAES, Augusto G.; FAGUNDES, Gustavo F. C.; BENEDETTI, Anna Flavia F.; AFONSO, Ana Caroline F.; PEREIRA, Maria Adelaide A.; ZERBINI, Maria Claudia N.; SIQUEIRA, Sheila; YAMAUCHI, Fernando; SOARES, Silvia C.; SROUGI, Victor; TANNO, Fabio Y.; CHAMBO, Jose L.; I, Roberto Lopes; DENES, Francisco T.; HOFF, Ana O.; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; V, Maria Candida B. Fragoso; ALMEIDA, Madson Q.Objective Few and conflicting reports have characterized the genetics of paediatric pheochromocytomas and paragangliomas (PPGLs). This study aimed to investigate the clinical and genetic features of Brazilian children with PPGL. Patients and Methods This study included 25 children (52% girls) with PPGL. The median age at diagnosis was 15 years (4-19). The median time of follow-up was 145 months. The genetic investigation was performed by Sanger DNA sequencing, multiplex ligation-dependent probe amplification and/or target next-generation sequencing panel. Results Of the 25 children with PPGL, 11 (44%), 4 (16%), 2 (8%), 1 (4%) and 7 (28%) had germline VHL pathogenic variants, SDHB, SDHD, RET and negative genetic investigation, respectively. Children with germline VHL missense pathogenic variants were younger than those with SDHB or SDHD genetic defects [median (range), 12 (4-16) vs. 15.5 (14-19) years; P = .027]. Moreover, 10 of 11 cases with VHL pathogenic variants had bilateral pheochromocytoma (six asynchronous and four synchronous). All children with germline SDHB pathogenic variants presented with abdominal paraganglioma (one of them malignant). The two cases with SDHD pathogenic variants presented with head and neck paraganglioma. Among the cases without a genetic diagnosis, 6 and 2 had pheochromocytoma and paraganglioma, respectively. Furthermore, metastatic PPGL was diagnosed in four (16%) of 25 PPGL. Conclusions Most of the paediatric PPGL were hereditary and multifocal. The majority of the affected genes belong to pseudohypoxic cluster 1, with VHL being the most frequently mutated. Therefore, our findings impact surgical management and surveillance of children with PPGL.
- Internal validation and decision curve analysis of a preoperative nomogram predicting a postoperative complication in pheochromocytoma surgery: An international study(2020) PHILLIPS, John; BLOOM, Jonathan; YARLAGADDA, Vidhush; SCHULTZ, Luciana; GORDETSKY, Jennifer; TANNO, Fabio Y.; CHAMBO, Jose L.; ALMEIDA, Madson Q.; V, Maria C. B. Fragoso; SROUGI, Miguel; SROUGI, Victor; RAIS-BAHRAMI, SoroushObjectives To develop a preoperative nomogram that would predict the risk of a postoperative complication for pheochromocytoma patients undergoing adrenalectomy using an international database. Methods We retrospectively analyzed preoperative variables and postoperative outcomes in patients who underwent adrenalectomy for pheochromocytoma in three institutions from 2000 to 2017. Internal validation of a generated nomogram was carried out with receiver operating characteristics, calibration plots, and decision curve analyses. Results A total of 153 patients who had undergone 166 adrenalectomies were included in the study. Overall, post-adrenalectomy complications were seen in 30% of patients, whereas 9.6% of patients sustained a Clavien >= 3a complication. Independent predictors of a complication were a history of hypertension, body mass index, tumor size, and Charlson Comorbidity Index score. On internal validation, the multivariable model generated a nomogram that predicted a postoperative complication or clinically hemodynamic event with an area under the curve of 0.86, showed good calibration and had an overall net benefit. Conclusions An internally validated nomogram combining body mass index, Charlson Comorbidity Index score and tumor size can predict the probability of a post-adrenalectomy complication in those with and without hypertension. The model, the first of its kind in pheochromocytoma surgery, identifies patients at risk of a postoperative complication at the time of their presentation with pheochromocytoma.
- Amplification of the Insulin-Like Growth Factor 1 Receptor Gene Is a Rare Event in Adrenocortical Adenocarcinomas: Searching for Potential Mechanisms of Overexpression(2014) RIBEIRO, Tamaya Castro; JORGE, Alexander Augusto; ALMEIDA, Madson Q.; MARIANI, Beatriz Marinho de Paula; NISHI, Mirian Yumi; MENDONCA, Berenice Bilharinho; FRAGOSO, Maria Candida Barisson Villares; LATRONICO, Ana ClaudiaContext. IGF1R overexpression appears to be a prognostic biomarker of metastatic pediatric adrenocortical tumors. However, the molecular mechanisms that are implicated in its upregulation remain unknown. Aim. To investigate the potential mechanisms involved in IGF1R overexpression. Patients and Methods. We studied 64 adrenocortical tumors. IGF1R copy number variation was determined in all patients using MLPA and confirmed using real time PCR. In a subgroup of 32 patients, automatic sequencing was used to identify IGF1R allelic variants and the expression of microRNAs involved in IGF1R regulation by real time PCR. Results. IGF1R amplification was detected in an adrenocortical carcinoma that was diagnosed in a 46-year-old woman with Cushing's syndrome and virilization. IGF1R overexpression was demonstrated in this case. In addition, gene amplification of other loci was identified in this adrenocortical malignant tumor, but no IGF1R copy number variation was evidenced in the remaining cases. Automatic sequencing revealed three known polymorphisms but they did not correlate with its expression. Expression of miR-100, miR-145, miR-375, and miR-126 did not correlate with IGF1R expression. Conclusion. We demonstrated amplification and overexpression of IGF1R gene in only one adrenocortical carcinoma, suggesting that these combined events are uncommon. In addition, IGF1R polymorphisms and abnormal microRNA expression did not correlate with IGF1R upregulation in adrenocortical tumors.
- Retrospective Analysis of Prognostic Factors in Pediatric Patients with Adrenocortical Tumor from Unique Tertiary Center with Long-Term Follow-Up(2022) BACHEGA, Fernanda S.; V, Caio Suartz; ALMEIDA, Madson Q.; BRONDANI, Vania B.; CHARCHAR, Helaine L. S.; LACOMBE, Amanda M. F.; MARTINS-FILHO, Sebastiao N.; SOARES, Ibere C.; ZERBINI, Maria Claudia N.; DENES, Francisco T.; MENDONCA, Berenice; I, Roberto Lopes; LATRONICO, Ana Claudia; V, Maria Candida B. FragosoPediatric adrenocortical tumors (PACTs) represent rare causes of malignancies. However, the south/southeast regions of Brazil are known to have a high incidence of PACTs because of the founder effect associated with a germline pathogenic variant of tumor suppressor gene TP53. We aimed to retrospectively analyze the types of variables among hormone production, radiological imaging, tumor staging, histological and genetic features that were associated with the occurrence of malignancy in 95 patients (71% females) with PACTs from a unique center. The worst prognosis was associated with those aged > 3 years (p < 0.05), high serum levels of 11-desoxicortisol (p < 0.001), tumor weight >= 200 g (p < 0.001), tumor size >= 5 cm (p < 0.05), Weiss score >= 5 (p < 0.05), Wieneke index >= 3 (p < 0.001) and Ki67 >= 15% (p < 0.05). Furthermore, patients with MacFarlane stage IV had an overall survival rate almost two times shorter than patients with other stages (p < 0.001). Additionally, the subtractions of BUB1B-PINK1 (<6.95) expression (p < 0.05) and IGF-IR overexpression (p = 0.0001) were associated with malignant behavior. These results helped identify patients who are likely to have an aggressive course; further multicenter prospective studies are required to confirm our results. In conclusion, PACTs with these patterns of prognostic factors could be treated using an adjuvant approach that may improve the overall survival in such patients.
conferenceObject Metabolic Reprograming in Adrenocortical Tumors in Children: A Promising New Pathway in the Biology of This Disease(2016) ZERBINI, Maria; PINHEIRO, Celine; GRANJA, Sara; LONGATTO, Adhemar; FARIA, Andre M.; FRAGOSO, Maria C. V.; LOVISOLO, Silvana M.; LERARIO, Antonop M.; ALMEIDA, Madson Q.; BALTAZAR, Fatima- SDHB large deletions are associated with absence of MIBG uptake in metastatic lesions of malignant paragangliomas(2021) PETENUCI, Janaina; FAGUNDES, Gustavo F. C.; BENEDETTI, Anna Flavia F.; GUIMARAES, Augusto G.; AFONSO, Ana Caroline F.; MOTA, Flavia T.; MAGALHAES, Aurea Luiza F.; COURA-FILHO, George B.; ZERBINI, Maria Claudia N.; SIQUEIRA, Sheila; MONTENEGRO, Fabio L. M.; SROUGI, Victor; TANNO, Fabio Y.; CHAMBO, Jose Luis; FERRARI, Marcela S. S.; BEZERRA NETO, Joao Evangelista; PEREIRA, Maria Adelaide A.; LATRONICO, Ana Claudia; FRAGOSO, Maria Candida B. V.; MENDONCA, Berenice B.; HOFF, Ana O.; ALMEIDA, Madson Q.
- Comparison of Pheochromocytoma-Specific Morbidity and Mortality Among Adults With Bilateral Pheochromocytomas Undergoing Total Adrenalectomy vs Cortical-Sparing Adrenalectomy(2019) NEUMANN, Hartmut P. H.; TSOY, Uliana; BANCOS, Irina; AMODRU, Vincent; WALZ, Martin K.; TIROSH, Amit; KAUR, Ravinder Jeet; MCKENZIE, Travis; QI, Xiaoping; BANDGAR, Tushar; PETROV, Roman; YUKINA, Marina Y.; ROSLYAKOVA, Anna; HORST-SCHRIVERS, Anouk N. A. van der; BERENDS, Annika M. A.; HOFF, Ana O.; CASTRONEVES, Luciana Audi; FERRARA, Alfonso Massimiliano; RIZZATI, Silvia; MIAN, Caterina; DVORAKOVA, Sarka; HASSE-LAZAR, Kornelia; KVACHENYUK, Andrey; PECZKOWSKA, Mariola; LOLI, Paola; ERENLER, Feyza; KRAUSS, Tobias; ALMEIDA, Madson Q.; LIU, Longfei; ZHU, Feizhou; RECASENS, Monica; WOHLLK, Nelson; CORSSMIT, Eleonora P. M.; SHAFIGULLINA, Zulfiya; CALISSENDORFF, Jan; GROZINSKY-GLASBERG, Simona; KUNAVISARUT, Tada; SCHALIN-JANTTI, Camilla; CASTINETTI, Frederic; VLCEK, Petr; BELTSEVICH, Dmitry; I, Viacheslav Egorov; SCHIAVI, Francesca; LINKS, Thera P.; LECHAN, Ronald M.; BAUSCH, Birke; YOUNG JR., William F.; ENG, Charis; JAISWAL, Sanjeet Kumar; ZSCHIEDRICH, Stefan; V, Maria C. B. Fragoso; PEREIRA, Maria A. A.; LI, Minghao; COSTA, Josefina Biarnes; JUHLIN, Carl Christofer; GROSS, David; VIOLANTE, Alice H. D.; KOCJAN, Tomaz; NGEOW, Joanne; YOEL, Uri; FRAENKEL, Merav; SIMSIR, Ilgin Yildirim; UGURLU, M. Umit; ZIAGAKI, Athanasia; DIAZ, Luis Robles; KUDLAI, Inna Stepanovna; GIMM, Oliver; SCHERBAUM, Christina Rebecca; ABEBE-CAMPINO, Gadi; BARBON, Giovanni; TASCHIN, Elisa; MALINOC, Angelica; KHUDIAKOVA, Natalia Valeryevna; V, Nikita Ivanov; PFEIFER, Marija; ZOVATO, Stefania; PLOECKINGER, Ursula; MAKAY, Ozer; GRINEVA, Elena; JARZAB, Barbara; JANUSZEWICZ, Andrzej; SHAH, Nalini; SEUFERT, Jochen; OPOCHER, Giuseppe; LARSSON, CatharinaIMPORTANCE Large studies investigating long-term outcomes of patients with bilateral pheochromocytomas treated with either total or cortical-sparing adrenalectomies are needed to inform clinical management. OBJECTIVE To determine the association of total vs cortical-sparing adrenalectomy with pheochromocytoma-specific mortality, the burden of primary adrenal insufficiency after bilateral adrenalectomy, and the risk of pheochromocytoma recurrence. DESIGN, SETTING, AND PARTICIPANTS This cohort study used data from a multicenter consortium-based registry for 625 patients treated for bilateral pheochromocytomas between 1950 and 2018. Data were analyzed from September 1, 2018, to June 1, 2019. EXPOSURES Total or cortical-sparing adrenalectomy. MAIN OUTCOMES AND MEASURES Primary adrenal insufficiency, recurrent pheochromocytoma, and mortality. RESULTS Of 625 patients (300 [48%] female) with a median (interquartile range [IQR]) age of 30 (22-40) years at diagnosis, 401 (64%) were diagnosed with synchronous bilateral pheochromocytomas and 224 (36%) were diagnosed with metachronous pheochromocytomas (median [IQR] interval to second adrenalectomy, 6 [1-13] years). In 505 of 526 tested patients (96%), germline mutationswere detected in the genes RET (282 patients [54%]), VHL (184 patients [35%]), and other genes (39 patients [7%]). Of 849 adrenalectomies performed in 625 patients, 324 (52%) were planned as cortical sparing and were successful in 248 of 324 patients (76.5%). Primary adrenal insufficiency occurred in all patients treated with total adrenalectomy but only in 23.5% of patients treated with attempted cortical-sparing adrenalectomy. A third of patients with adrenal insufficiency developed complications, such as adrenal crisis or iatrogenic Cushing syndrome. Of 377 patients who became steroid dependent, 67 (18%) developed at least 1 adrenal crisis and 50 (13%) developed iatrogenic Cushing syndrome during median (IQR) follow-up of 8 (3-25) years. Two patients developed recurrent pheochromocytoma in the adrenal bed despite total adrenalectomy. In contrast, 33 patients (13%) treated with successful cortical-sparing adrenalectomy developed another pheochromocytoma within the remnant adrenal after a median (IQR) of 8 (4-13) years, all of which were successfully treated with another surgery. Cortical-sparing surgery was not associated with survival. Overall survivalwas associated with comorbidities unrelated to pheochromocytoma: of 63 patients who died, only 3 (5%) died of metastatic pheochromocytoma. CONCLUSIONS AND RELEVANCE Patients undergoing cortical-sparing adrenalectomy did not demonstrate decreased survival, despite development of recurrent pheochromocytoma in 13%. Cortical-sparing adrenalectomy should be considered in all patients with hereditary pheochromocytoma.