SERGIO PEREIRA DE ALMEIDA TOLEDO

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Departamento de Clínica Médica, Faculdade de Medicina - Docente
LIM/25 - Laboratório de Endocrinologia Celular e Molecular, Hospital das Clínicas, Faculdade de Medicina

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  • article 2 Citação(ões) na Scopus
    Assessing the emerging oncogene protein kinase C epsilon as a candidate gene in families with Carney complex-2
    (2012) TOLEDO, Rodrigo A.; SEKIYA, Tomoko; HORVATH, Anelia; FAUCZ, Fabio; FRAGOSO, Maria C. B. V.; LONGUINI, Viviane C.; LOURENCO JR., Delmar M.; TOLEDO, Sergio P. A.; STRATAKIS, Constantine A.
  • article 50 Citação(ões) na Scopus
    Penetrance of Functioning and Nonfunctioning Pancreatic Neuroendocrine Tumors in Multiple Endocrine Neoplasia Type 1 in the Second Decade of Life
    (2014) GONCALVES, Tatiana D.; TOLEDO, Rodrigo A.; SEKIYA, Tomoko; MATUGUMA, Sergio E.; MALUF FILHO, Fauze; ROCHA, Manoel S.; SIQUEIRA, Sheila A. C.; GLEZER, Andrea; BRONSTEIN, Marcelo D.; PEREIRA, Maria A. A.; JUREIDINI, Ricardo; BACCHELLA, Telesforo; MACHADO, Marcel C. C.; TOLEDO, Sergio P. A.; LOURENCO JR., Delmar M.
    Context: Data are scarce on the penetrance of multiple endocrine neoplasia type 1 (MEN1)-related nonfunctioning pancreatic neuroendocrine tumors (NF-PETs) and insulinomas in young MEN1 patients. Apotential positive correlation between tumor size and malignancy (2-3 cm, 18%; >3 cm, 43%) has greatly influenced the management of MEN1 adults with NF-PETs. Objective: The aim of the study was to estimate the penetrance of NF-PETs, insulinomas, and gastrinomas in young MEN1 carriers. Design: The data were obtained from a screening program (1996-2012) involving 113 MEN1 patients in a tertiary academic reference center. Patients: Nineteen MEN1 patients (aged 12-20 y; 16 patients aged 15-20 y and 3 patients aged 12-14 y) were screened for NF-PETs, insulinomas, and gastrinomas. Methods: Magnetic resonance imaging/computed tomography and endoscopic ultrasound (EUS) were performed on 10 MEN1 carriers, magnetic resonance imaging/computed tomography was performed on five patients, and four other patients underwent an EUS. Results: The overall penetrance of PETs during the second decade of life was42%(8 of 19). All eight PET patients had NF-PETs, and half of those tumors were multicentric. One-fifth of the screened patients (21%; 4 of 19) harbored at least one large tumor (>2.0 cm). Insulinoma was detected in two NF-PET patients (11%) at the initial screening; gastrinoma was not present in any cases. Six of the 11 (54%) screened patients aged 15-20 years who underwent an EUS had NF-PETs. Potential false-positive EUS results were excluded based on EUS-guided biopsy results, the reproducibility of the NF-PET findings, or the observation of increased tumor size during follow-up. Distal pancreatectomy and the nodule enucleation of pancreatic head tumors were conducted on three patients with large tumors (>2.0 cm; T2N0M0) that were classified as grade 1 neuroendocrine tumors (Ki-67 < 2%). Conclusions: Our data demonstrated high penetrance of NF-PETs in 15- to 20-year-old MEN1 patients. The high percentage of the patients presenting consensus criteria for surgery for NF-PET alone or NF-PET/insulinoma suggests a potential benefit for the periodic surveillance of these tumors in this age group.
  • article 14 Citação(ões) na Scopus
    Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing
    (2018) CARVALHO, Rafael A.; URTREMARI, Betsaida; JORGE, Alexander A. L.; SANTANA, Lucas S.; QUEDAS, Elisangela P. S.; SEKIYA, Tomoko; LONGUINI, Viviane C.; MONTENEGRO, Fabio L. M.; LERARIO, Antonio M.; TOLEDO, Sergio P. A.; MARX, Stephen J.; TOLEDO, Rodrigo A.; JR, Delmar M. Lourenco
    Background: Loss-of-function germline MEN1 gene mutations account for 75-95% of patients with multiple endocrine neoplasia type 1 (MEN1). It has been postulated that mutations in non-coding regions of MEN1 might occur in some of the remaining patients; however, this hypothesis has not yet been fully investigated. Objective: To sequence for the entire MEN1 including promoter, exons and introns in a large MEN1 cohort and determine the mutation profile. Methods and patients: A target next-generation sequencing (tNGS) assay comprising 7.2 kb of the full MEN1 was developed to investigate germline mutations in 76 unrelated MEN1 probands (49 familial, 27 sporadic). tNGS results were validated by Sanger sequencing (SS), and multiplex ligation-dependent probe amplification (MLPA) assay was applied when no mutations were identifiable by both tNGS and SS. Results: Germline MEN1 variants were verified in coding region and splicing sites of 57/76 patients (74%) by both tNGS and SS (100% reproducibility). Thirty-eight different pathogenic or likely pathogenic variants were identified, including 13 new and six recurrent variants. Three large deletions were detected by MLPA only. No mutation was detected in 16 patients. In untranslated, regulatory or in deep intronic MEN1 regions of the 76 MEN1 cases, no point or short indel pathogenic variants were found in untranslated, although 33 benign/likely benign and three new VUS variants were detected. Conclusions: Our study documents that point or short indel mutations in non-coding regions of MEN1 are very rare events. Also, tNGS proved to be a highly effective technology for routine genetic MEN1 testing.
  • conferenceObject
    Maxillary myxomas associated with MEN1 syndrome
    (2014) LOURENCO, D. M.; TOLEDO, R. A.; SEKIYA, T.; MORAES, M. B.; SANTANA, L. S.; TOLEDO, S. P. A.
  • conferenceObject
    Clinical Features and Penetrance of Pheochromocytoma in a Large Family with a Germline TMEM127 Mutation
    (2014) LOURENCO, Delmar Muniz; TOLEDO, Rodrigo A.; SEKIYA, Tomoko; LUCON, Marmo; CASTRO, C. C.; BORTOLOTTO, L. A.; TOLEDO, Sergio P. A.; DAHIA, Patricia L.
  • article 2 Citação(ões) na Scopus
    RET haplotype, not linked to the C620R activating mutation, associated with Hirschsprung disease in a novel MEN2 family
    (2012) QUEDAS, Elisangela P. S.; LONGUINI, Viviane C.; SEKIYA, Tomoko; COUTINHO, Flavia L.; TOLEDO, Sergio P. A.; TANNURI, Uenis; TOLEDO, Rodrigo A.
    Hirschsprung disease is a congenital form of aganglionic megacolon that results from cristopathy. Hirschsprung disease usually occurs as a sporadic disease, although it may be associated with several inherited conditions, such as multiple endocrine neoplasia type 2. The rearranged during transfection (RET) proto-oncogene is the major susceptibility gene for Hirschsprung disease, and germline mutations in RET have been reported in up to 50% of the inherited forms of Hirschsprung disease and in 15-20% of sporadic cases of Hirschsprung disease. The prevalence of Hirschsprung disease in multiple endocrine neoplasia type 2 cases was recently determined to be 7.5% and the co-occurrence of Hirschsprung disease and multiple endocrine neoplasia type 2 has been reported in at least 22 families so far. It was initially thought that Hirschsprung disease could be due to disturbances in apoptosis or due to a tendency of the mutated RET receptor to be retained in the Golgi apparatus. Presently, there is strong evidence favoring the hypothesis that specific inactivating haplotypes play a key role in the fetal development of congenital megacolon/Hirschsprung disease. In the present study, we report the genetic findings in a novel family with multiple endocrine neoplasia type 2: a specific RET haplotype was documented in patients with Hirschsprung disease associated with medullary thyroid carcinoma, but it was absent in patients with only medullary thyroid carcinoma. Despite the limited number of cases, the present data favor the hypothesis that specific haplotypes not linked to RET germline mutations are the genetic causes of Hirschsprung disease.
  • article 113 Citação(ões) na Scopus
    Risk Profiles and Penetrance Estimations in Multiple Endocrine Neoplasia Type 2A Caused by Germline RET Mutations Located in Exon 10
    (2011) FRANK-RAUE, Karin; RYBICKI, Lisa A.; ERLIC, Zoran; SCHWEIZER, Heiko; WINTER, Aurelia; MILOS, Ioana; TOLEDO, Sergio P. A.; TOLEDO, Rodrigo A.; TAVARES, Marcos R.; ALEVIZAKI, Maria; MIAN, Caterina; SIGGELKOW, Heide; HUEFNER, Michael; WOHLLK, Nelson; OPOCHER, Giuseppe; DVORAKOVA, Sarka; BENDLOVA, Bela; CZETWERTYNSKA, Malgorzata; SKASKO, Elzbieta; BARONTINI, Marta; SANSO, Gabriela; VORLAENDER, Christian; MAIA, Ana Luiza; PATOCS, Attila; LINKS, Thera P.; GROOT, Jan Willem de; KERSTENS, Michiel N.; VALK, Gerlof D.; MIEHLE, Konstanze; MUSHOLT, Thomas J.; BIARNES, Josefina; DAMJANOVIC, Svetozar; MURESAN, Mihaela; WUESTER, Christian; FASSNACHT, Martin; PECZKOWSKA, Mariola; FAUTH, Christine; GOLCHER, Henriette; WALTER, Martin A.; PICHL, Josef; RAUE, Friedhelm; ENG, Charis; NEUMANN, Hartmut P. H.
    Multiple endocrine neoplasia type 2 is characterized by germline mutations in RET. For exon 10, comprehensive molecular and corresponding phenotypic data are scarce. The International RET Exon 10 Consortium, comprising 27 centers from 15 countries, analyzed patients with RET exon 10 mutations for clinical-risk profiles. Presentation, age-dependent penetrance, and stage at presentation of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism were studied. A total of 340 subjects from 103 families, age 4-86, were registered. There were 21 distinct single nucleotide germline mutations located in codons 609 (45 subjects), 611 (50), 618 (94), and 620 (151). MTC was present in 263 registrants, pheochromocytoma in 54, and hyperparathyroidism in 8 subjects. Of the patients with MTC, 53% were detected when asymptomatic, and among those with pheochromocytoma, 54%. Penetrance for MTC was 4% by age 10, 25% by 25, and 80% by 50. Codon-associated penetrance by age 50 ranged from 60% (codon 611) to 86% (620). More advanced stage and increasing risk of metastases correlated with mutation in codon position (609-620) near the juxtamembrane domain. Our data provide rigorous bases for timing of premorbid diagnosis and personalized treatment/prophylactic procedure decisions depending on specific RET exon 10 codons affected. Hum Mutat 32:51-58, 2011. (C) 2010 Wiley-Liss, Inc.
  • article 17 Citação(ões) na Scopus
    Lymph node distribution in the central compartment of the neck: An anatomic study
    (2014) TAVARES, Marcos Roberto; CRUZ, Jose Arnaldo Shiomi da; WAISBERG, Daniel Reis; TOLEDO, Sergio Pereira de Almeida; TAKEDA, Flavio Roberto; CERNEA, Claudio Roberto; CAPELOZZI, Vera Luiza; BRANDAO, Lenine Garcia
    Background. Dissection of the central compartment of the neck (CCN) is performed for proven or suspected lymph node metastases of thyroid carcinoma. During this procedure, the recurrent laryngeal nerves and the parathyroid glands are at risk. The purpose of this study was to determine the anatomic distribution of the lymph nodes in the CCN. Methods. The anatomic distribution of the lymph nodes in the CCN was studied by dissection of 30 fresh cadavers. The soft tissue between the cricoid cartilage and the innominate vein, carotid arteries, and prevertebral fascia was removed and divided according to CCN sublevels. Nodules were identified by palpation in the specimen and sent for pathological examination. Results. Three to 44 (18.5 +/- 10.29) nodules were identified macroscopically. Two to 42 nodules were confirmed as lymph nodes after microscopic examination. The lymph node distribution was as follows: precricoid: 0 to 2 (0.9 +/- 0.72); pretracheal: 1 of 35 (12.4 +/- 8.19); lateral to the right recurrent laryngeal nerve (RLN): 0 to 11 (3.4 +/- 2.34); and lateral to the left: 0 to 4 (1.7 +/- 1.30). Twenty-six parathyroid glands were removed by 14 dissections. The innominate vein was found at 15 mm above the superior border of the clavicles to 35 mm below on the left side of the neck and 5 to 45 mm on the right side. Conclusion. The number of confirmed lymph nodes in the central neck varied from 2 to 42. Sixty-seven percent of the lymph nodes were in the pretracheal sublevel. There was no division between level VI and VII lymph nodes. Additionally, the innominate vein was found to be from 15 mm above the superior border of the clavicles to 35 mm below on the left side of the neck and 5 to 45 mm on the right side. Parathyroid glands were identified to be far away from the thyroid gland. (C) 2014 Wiley Periodicals, Inc.
  • article 20 Citação(ões) na Scopus
    Assessment of Depression, Anxiety, Quality of Life, and Coping in Long-Standing Multiple Endocrine Neoplasia Type 2 Patients
    (2017) RODRIGUES, Karine C.; TOLEDO, Rodrigo A.; COUTINHO, Flavia L.; NUNES, Adriana B.; MACIEL, Rui M. B.; HOFF, Ana O.; TAVARES, Marcos C.; TOLEDO, Sergio P. A.; LOURENCO JR., Delmar M.
    Background: Data on psychological harm in multiple endocrine neoplasia type 2 (MEN2) are scarce. Objectives: The aim of this study was to assess anxiety, depression, quality of life, and coping in long-standing MEN2 patients. Patients and Methods: Patients were 43 adults (age >= 18 years) with clinical and genetic diagnosis of MEN2 and long-term follow-up (10.6 +/- 8.2 years; range 1-33 years). This was a cross-sectional study with qualitative and quantitative psychological assessment using semi-directed interviews and HADS, EORTC QLQ C30, and MINI-MAC scales. Adopting clinical criteria from 2015 ATA Guidelines on MEN2, biochemical cure (39%; 16/41), persistence/recurrence (61%; 25/41), and stable chronic disease (22/41) of medullary thyroid carcinoma (MTC) were scored. Pheochromocytoma affected 19 (44%) patients, with previous adrenalectomy in 17 of them. Results: Overall, anxiety (42%; mean score 11 +/- 2.9; range 8-18; anxiety is defined as a score >= 8) and depression (26%; mean score 11 +/- 3.8; range 8-20; depression is defined as a score >= 8) symptoms were frequent. Patients who transmitted RET mutations to a child had higher scores for weakness-discouragement/anxious preoccupation and lower scores for cognitive, emotional, and physical functioning (p < 0.05). Feelings of guilt were present in 35% of patients with mutation-positive children. Lower mean score values for depression and anxiety and higher scores for role, cognitive, and emotional functioning were noticed in 33 patients who were well-informed about their disease (p < 0.05). Fighting spirit was more frequently found in patients with multiple surgical procedures (p = 0.019) and controlled chronic adrenal insufficiency (p = 0.024). Patients with MEN2-elated stress-inducing factors had lower scores for fighting spirit and cognitive functioning and higher scores for insomnia and dyspnea (p < 0.05). Eleven patients required sustained psychotherapeutic treatment. Mean global health status was relatively good in MEN2 cases (68.1 +/- 22.3), and the cured group had higher physical functioning (p = 0.021). Conclusions: Psychological distress is likely chronic in MEN2 patients. This study identified diverse MEN2-related factors (degree of information on disease, mutation-positive children, number of surgeries, comorbidities, stress-inducing factors, and cure) interfering positively or negatively with the results of the psychometrics scales. The active investigation of these factors and the applied psychological assessment protocol are useful to identify MEN2 patients requiring psychological assistance.
  • conferenceObject
    Penetrance of TMEM127-related pheochromocytoma in a six-generation family
    (2014) TOLEDO, S. P. A.; LOURENCO JR., D. M.; SEKIYA, T.; LUCON, A. M.; BAENA, R. C.; CASTRO, C. C.; BORTOLOTTO, L. A.; ZERBINI, M. C. N.; SIQUEIRA, S. A. C.; TOLEDO, R. A.; DAHIA, P. L. M.