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Projetos de Pesquisa
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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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Agora exibindo 1 - 10 de 38
  • article 20 Citação(ões) na Scopus
    Could the Less-Than Subtotal Parathyroidectomy Be an Option for Treating Young Patients With Multiple Endocrine Neoplasia Type 1-Related Hyperparathyroidism?
    (2019) MONTENEGRO, Fabio Luiz de Menezes; BRESCIA, Manilla D'Elboux Guimaraes; JR, Delmar Muniz Lourenco; ARAP, Sergio Samir; D'ALESSANDRO, Andre Fernandes; SILVA FILHO, Gilberto de Britto e; TOLEDO, Sergio Pereira de Almeida
    Background: The surgical treatment of primary hyperparathyroidism (HPT) in patients with multiple endocrine neoplasia type 1 (MEN1) has evolved due the concern of permanent hypoparathyroidism. As the diagnosis has increased, the extent of operation has decreased. Most MEN1 patients requiring parathyroidectomy are younger than 50 years and they pose a difficult balance to achieve between persistent HPT and life-long hypoparathyroidism. The aim of the present study is to review our experience with a large series of patients with MEN1-related HPT (HPT/MEN1) treated at a single institution in order to find clues to a better treatment decision in these younger cases. Method: Retrospective analysis of consecutive HPT/MEN1 cases treated at a single institution with different operations: total parathyroidectomy and immediate forearm autograft (TPTX-AG), subtotal (STPTX), unintentional less than subtotal (U-LSTPTX) and intentional less than subtotal parathyroidectomy (I-LSTPTX). Results: Considering 84 initial cases operated on since 2011 (TPTX-AG, 39; STPTX, 22, U-LSTPTX, 13, and I-LSTPTX, 10), the rates of hypoparathyroidism were 30.8% (U-LSTPTX), 28.2% (TPTX-AG), 13.6% (STPTX), and 0% (I-LSTPTX). Two-thirds of them (68%; 57/84) were young (< 50 years) or asdolescents. MIBI scan was more sensitive to show parathyroid glands and bilateral disease. Considering the concordance of MIBI and ultrasound for the possibility of unilateral clearance, it would be suitable to 22.6% of the cases. Intra-operative parathormone showed a significant decay even after unilateral exploration, but longer follow up is necessary. Overall, there were seven (4%) adolescents in 161 cases treated from 1987 to 2018, three underwent TPTX-AG and four had U-LSTPTX. Five are euparathyroid, one had mild recurrence, and one required a reoperation after 8 years due to the residual gland. Conclusions: Young patients are the most frequent candidates to parathyroidectomy. Less extensive procedures may be planned only if carefully reviewed preoperative imaging studies suggest a localized disease. Patients and their relatives should be fully informed of the risks and benefits during consent process. Future research with larger cohorts and long-term results are necessary to clarify if less than I-LSPTX or unilateral clearance are really adequate in selected groups of patients with HPT/MEN1 presenting lower volume of disease detected by preoperative imaging studies.
  • bookPart
    Tumores neuroendócrinos
    (2013) LOURENçO JR., Delmar Muniz; TOLEDO, Rodrigo Almeida; TOLEDO, Sergio Pereira de Almeida
  • 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 24 Citação(ões) na Scopus
    Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study
    (2019) MACIEL, Rui M. B.; CAMACHO, Cleber P.; ASSUMPCAO, Ligia V. M.; BUFALO, Natassia E.; CARVALHO, Andre L.; CARVALHO, Gisah A. de; CASTRONEVES, Luciana A.; JR, Francisco M. de Castro; CEOLIN, Lucieli; CERUTTI, Janete M.; CORBO, Rossana; FERRAZ, Tania M. B. L.; V, Carla Ferreira; FRANCA, M. Inez C.; GALVAO, Henrique C. R.; GERMANO-NETO, Fausto; GRAF, Hans; JORGES, Alexander A. L.; KUNII, Ilda S.; LAURIA, Marcio W.; LEAL, Vera L. G.; LINDSEY, Susan C.; JR, Delmar M. Lourenco; MADER, Lea M. Z.; MAGALHAES, Patricia K. R.; MARTINS, Joao R. M.; MARTINS-COSTA, M. Cecilia; MAZETOR, Glaucia M. F. S.; IMPELLIZZERI, Anelise I.; NOGUEIRA, Celia R.; I, Edenir Palmero; PESSOA, Cencita H. C. N.; PRADA, Bibiana; SIQUEIRA, Debora R.; SOUSA, Maria Sharmila A.; TOLEDO, Rodrigo A.; VALENTE, Flavia O. F.; VAISMAN, Fernanda; WARD, Laura S.; WEBER, Shana S.; V, Rita Weiss; YANG, Ji H.; DIAS-DA-SILVA, Magnus R.; HOFF, Ana O.; TOLEDO, Sergio P. A.; MAIA, Ana L.
    Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant genetic disease caused by RET gene germline mutations that is characterized by medullary thyroid carcinoma (MTC) associated with other endocrine tumors. Several reports have demonstrated that the RET mutation profile may vary according to the geographical area. In this study, we collected clinical and molecular data from 554 patients with surgically confirmed MTC from 176 families with MEN2 in 18 different Brazili an centers to compare the type and prevalence of RET mutations with those from other countries. The most frequent mutations, classified by the number of families affected, occur in codon 634, exon 11 (76 families), followed by codon 918, exon 16 (34 families: 26 with M918T and 8 with M918V) and codon 804, exon 14 (22 families: 15 with V804M and 7 with V804L). When compared with other major published series from Europe, there are several similarities and some differences. While the mutations in codons C618, C620, C630, E768 and S891 present a similar prevalence, some mutations have a lower prevalence in Brazil, and others are found mainly in Brazil (G533C and M918V). These results reflect the singular proportion of European, Amerindian and African ancestries in the Brazilian mosaic genome.
  • 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.
  • bookPart
    Neoplasias endócrinas múltiplas
    (2013) HOFF, Ana Oliveira; LOURENçO JUNIOR, Delmar Muniz; TOLEDO, Rodrigo de Almeida; TOLEDO, Sergio P. A.
  • 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.