S-phase fraction and ploidy as predictive markers in primary disease and recurrence of papillary thyroid carcinoma.

OBJECTIVE: To investigate the prognostic influence of DNA ploidy and S-phase fraction (SPF) on disease-free (DFS) and overall survival (OS) of patients with primary disease and loco-regional lymph node recurrence of papillary thyroid carcinoma (PTC). DESIGN: A large prospective study with long-term follow-up (median, 117 months). PATIENTS: Two series of patients with primary PTC (n = 305) and lymph node recurrence metastasis (LNM) (n = 39) were involved in the study. MEASUREMENTS: Patient's age and gender, histological variant, pathological tumour-node-metastasis (pTNM) staging, extrathyroidal extension, vascular and lymphatic invasion and tumour bilateral growth were the clinical and pathological characteristics evaluated. DNA flow cytometry was performed on fresh/frozen surgical tumour samples. Cox regression models were estimated for prognostic analyses. RESULTS: Seventeen (5·6%) primary tumours and five (12·8%) LNMs were aneuploid, while mean SPF was 2·7% and 3·7%, respectively (P = 0·022). High SPF was significantly associated with lymphatic invasion and tall cell and diffuse sclerosing variants. In univariate analysis, all the clinico-pathological variables, but tumour bilateral growth and gender, were significantly correlated with survival. SPF showed borderline significance (P = 0·051) in relation to OS. In multivariate analysis, older age (≥48 years), lymph node spread and high SPF were significantly adverse prognostic factors. Extrathyroidal extension and distant metastasis for OS, as well as tumour size for DFS, were also found as unfavourable prognostic features. In LNM, the Kaplan-Meier curves showed significant differences for older age and DNA aneuploidy (recurrence; P = 0·011). CONCLUSION: The results indicate that SPF and ploidy can provide additional predictive information in patients with PTC.

Expression of iodine metabolism genes in human thyroid tissues: evidence for age and BRAFV600E mutation dependency.

CONTEXT: Children present a higher susceptibility to developing thyroid cancer after radioiodine exposure and also a higher frequency of functional metastases than adults. OBJECTIVE: To assess the mRNA expression of the sodium/iodide (Na(+)/I(-)) symporter (NIS), the Pendred syndrome gene (PDS), thyroperoxidase (TPO), thyroglobulin (Tg) and TSH receptor (TSH-R) in normal thyroid tissues (NTTs) and papillary thyroid carcinomas (PTCs) among different age groups. METHODS: Analysis included 59 samples: 21 NTTs and 38 PTCs, of which 21 were the classic type (CPTC) and 17 the follicular variant (FVPTC). Patients were divided into three age groups: I (n = 16) 5-21 years, II (n = 13) 22-59 years, and III (n = 10) 60-91 years. The relative mRNA expression of the five target genes was determinate by quantitative reverse transcription polymerase chain reaction (QRT-PCR). RESULTS: Expression of all genes was significantly higher in NTTs than in PTCs, and it was not age dependent in the NTT group. Among PTCs, the mean expression of PDS, TPO and TSH-R was significantly lower in group II than in group I. PDS, TPO and Tg expression was significantly lower in classic PTCs than in FVPTCs. The difference was related to a higher frequency of the BRAF(V600E) mutation in the former group. CONCLUSIONS: The finding of higher PDS, TPO and TSH-R mRNA expression in paediatric vs. adult primary tumour tissues supports the hypothesis that this might contribute to the increased functional activity of metastases in the paediatric group. The finding that mRNA expression of the target genes in NTT was not age dependent does not provide an explanation for the higher susceptibility in the paediatric group.

Mutation analysis of the RET proto-oncogene and early thyroidectomy: results of a Portuguese cancer centre.

BACKGROUND: Evidence that germline mutations in the RET proto-oncogene are the underlying cause of the familial form of medullary thyroid carcinoma (MTC) made it possible to identify gene carriers with a very high degree of accuracy. Aiming to define the mutational profile observed in our patients and to assess gene carriers' compliance with an early surgery, we reviewed results of molecular analysis of RET performed at our institution since 1994. METHODS: One hundred fifty-eight individuals were screened for germline mutations of the RET proto-oncogene. Seventy-seven patients had apparently sporadic MTC; 8 patients had both MTC and pheochromocytoma or MTC and clinical features of multiple endocrine neoplasia type 2B despite a negative family history; 8 patients were known to belong to affected kindreds; and 65 individuals were at-risk individuals to develop MTC. RESULTS: A germline mutation in RET was identified in 4% of apparently sporadic MTC patients, in 100% of patients with MTC and pheochromocytoma or MTC and clinical features of multiple endocrine neoplasia type 2B, and in 100% of probands of clinically established kindreds. The most affected codon was 634 (58%) followed by codon 804 (16%). Among at-risk individuals, 49% were identified as gene carriers. Seven individuals were submitted to prophylactic thyroidectomy (mean age, 17.7 +/- 12.5 years; range: 3-42 years), and all but 1 had MTC. CONCLUSIONS: RET mutational spectrum observed in the present population disclosed a higher frequency of codon 804 mutations than expected. Compliance with an early prophylactic surgery seemed to be influenced not only by medical advice and cultural factors but also by the aggressiveness of disease in gene carriers' families.

A multinodular goiter as the initial presentation of a renal cell carcinoma harbouring a novel VHL mutation.

BACKGROUND: Secondary involvement of the thyroid gland is rare. Often the origin of the tumor is difficult to identify from the material obtained by fine-needle aspiration cytology. Renal cell carcinoma of the clear-cell type is one of the more common carcinomas to metastasize to the thyroid gland. Somatic mutations of the von Hippel-Lindau tumor suppressor gene are associated with the sporadic form of this tumor. We aimed to illustrate the potential utility of DNA based technologies to search for specific molecular markers in order to establish the anatomic site of origin. CASE PRESENTATION: A 54-yr-old Caucasian male complaining of a rapidly increasing neck tumor was diagnosed as having a clear-cell tumor by fine-needle aspiration cytology. A positive staining for cytokeratin as well as for vimentin and CD10 in the absence of staining for thyroglobulin, calcitonin and TTF1 suggested a renal origin confirmed by computed tomography. Using frozen RNA, obtained from cells left inside the needle used for fine needle aspiration cytology, it was possible to identify a somatic mutation (680 delA) in the VHL gene. CONCLUSION: In the presence of a clear-cell tumor of the thyroid gland, screening for somatic mutations in the VHL gene in material derived from thyroid aspirates might provide additional information to immunocytochemical studies and therefore plays a contributory role to establish the final diagnosis. Moreover, in a near future, this piece of information might be useful to define a targeted therapy.

Germline MUTYH (MYH) mutations in Portuguese individuals with multiple colorectal adenomas.

Germinal mutations in the base excision repair (BER) gene MUTYH (MYH) have recently been described in association with predisposition to multiple colorectal adenomas and cancer. In contrast to the classic dominant condition of familial adenomatous polyposis (FAP) due to germinal mutations in the APC gene, the MYH polyposis is an autosomal recessive disease. The identification of individuals affected by MYH polyposis brings new and important implications for the diagnostic, screening, genetic counseling, follow up and therapeutic options in these patients. In this study, screening for germinal mutations in the MYH gene was performed in 53 Portuguese individuals with multiple colorectal adenomas or classic adenomatous polyposis, in whom no mutation had been identified in the APC gene. The results revealed the presence of biallelic germline MYH mutations in 21 patients. In addition, we here report 3 mutations (c.340T>C [p.Y114H]; c.503G>A [p.R168H]; and c.1186_1187insGG [p.E396fsX437]) which, to our knowledge, have not been previously described.

Immunostaining and RT-PCR: different approaches to search for RET rearrangements in patients with papillary thyroid carcinoma.

Different techniques of molecular biology have been used to screen for RET rearrangements. More recently, immunohistochemistry has been used, assuming that RET is not expressed in normal thyroid follicular cells. The present study was designed to define the prevalence of RET expression in patients with papillary thyroid carcinoma, by immunohistochemistry and by RT-PCR; to search specifically for RET/PTC-1; -2; -3 rearrangements using RT-PCR, and to compare results obtained by immunohistochemistry with those obtained by RT-PCR. Immunohistochemistry was performed using a polyclonal antibody against tyrosine kinase domain of Ret protein. Screening for RET/PTC1-3 was performed using RT-PCR and specific primers for each rearrangement; complementarily, a subset of cases were tested using RET exon 10/11 primers designed to detect the expression of the wild-type RET. Positive staining was observed in 30 of 39 (77%) tumours. RET/PTC1-3 rearrangements were detected in 8 of 32 (25%) cases. Ten of 15 (67%) cases expressed the wild-type RET. Two tumours characterised by positive immunostaining, absence of RET 5' expression and absence of RET/PTC1-3 expression were considered as expressing a RET rearrangement different from RET/PTC-1, -2, or -3. In 3 of 10 tumours, expression of the wild-type RET coexisted with the expression of a RET rearrangement. Positive staining does not necessarily mean the presence of a rearrangement; it may correspond to the expression of the wild-type RET, RET rearrangement or both. On the contrary, positive staining without evidence for the expression of the extracellular domain of RET is highly suggestive of a RET rearrangement independently of the type. Refinement of diagnosis depends on RT-PCR with specific primers.

Relationship between squamous cell carcinoma of the anterior two thirds of the tongue and removable denture use: a pioneer study in a Portuguese population.

The aim of the study was to determine whether there is any relationship between the presence of removable dentures and squamous cell carcinoma of the anterior two thirds of the tongue in a Portuguese population. A retrospective cross-sectional study was conducted on patients with a biopsy-proven diagnosis of squamous cell carcinoma of the tongue, who were seen and treated at the Department of Head and Neck Surgery of the Portuguese Institute of Oncology 'Francisco Gentil', Lisbon, Portugal, during a 3-year period. Several factors were examined: gender, use of removable dentures, age, location of the lesion, and alcohol and tobacco consumption. One hundred and six cases were selected from the initial 151 cases, with a male:female ratio of 3:1 and the lateral borders being the most commonly affected site. The prevalence in both genders was between the sixth and seventh decade of life. Men were more likely to consume alcohol and tobacco than women, and no relationship was observed between denture use and presence of carcinoma of the tongue. In light of the data obtained, it may be considered that female use of a denture plays an important role, but it cannot be identified as a remarkable etiologic factor.

Oral tongue squamous cell carcinoma (OTSCC): alcohol and tobacco consumption versus non-consumption. A study in a Portuguese population.

There has been an increase in the incidence of carcinoma of the tongue, particularly among alcohol and tobacco non-users. However, the number of studies that would allow a better understanding of etiological factors and clinical features, particularly in the Portuguese population, is very limited. This study was based on patients with squamous cell carcinoma of the anterior two thirds of the tongue that were treated at the Department of Head and Neck Surgery of the "Instituto Portugues de Oncologia de Lisboa - Francisco Gentil" (IPOLFG) in Lisbon, Portugal, between January 1, 2001 and December 31, 2009. The patients were divided in alcohol and tobacco users and non-users in order to evaluate the differences between these 2 groups based on gender, age, tumor location, denture use, and tumor size, metastasis and stage. Of the 354 cases, 208 were users and 146 were non-users. The main location in both groups was the lateral border of the tongue. Denture use showed no significant effect in both study groups. It was possible to conclude that patients who did not drink or smoke were older and presented with smaller tumor size, lower incidence of ganglion metastasis and lower tumor stage compared with alcohol and tobacco users.

Identification of de novo germline mutations in the HRPT2 gene in two apparently sporadic cases with challenging parathyroid tumor diagnoses.

The diagnosis of parathyroid carcinomas is often difficult. HRPT2 mutations have been identified in familial [hyperparathyroidism-jaw tumor (HPT-JT) syndrome] and sporadic parathyroid carcinomas, supporting that HRPT2 mutations may confer a malignant potential to parathyroid tumors. In this study, we report the clinical, histopathological, and genetic investigation of two unrelated cases, whom had apparently sporadic malignant parathyroid tumors, initially diagnosed as adenomas. In one case, the differential diagnosis was complicated by cervical seeding of parathyroid tumor cells. Genetic studies identified de novo HRPT2 germline mutations in cases 1 (c.518_521delTGTC [p.Ser174LysfsX27]) and 2 (c.226 C > T [p.Arg76X]), unveiling the hereditary HPT-JT syndrome in both patients. Furthermore, the identification of somatic mutations in the patients? parathyroid tumors provided evidence for complete inactivation of the HRPT2 gene, which was consistent with the tumor malignant features. The sensitivity of parafibromin immunostaining to detect HRPT2 mutations was limited. The present data suggests that patients with apparently sporadic parathyroid carcinomas, or parathyroid tumors with atypical histological features, should undergo molecular genetic testing, as it may detect germline HRPT2 mutations. Establishing the diagnosis of hereditary HPT-JT syndrome is relevant for clinical counseling and management of the carriers and their relatives.

[Weber-Christian disease: unknown etiology systemic panniculitis]. / Doença de Weber-Christian: paniculite sistémica de etiologia desconhecida.

Panniculitis is an inflammation occurring within adipose tissue. This process is often associated with auto-immune diseases, infections, malignancy and others diseases of unknown cause. We report a 16-year-old woman with constitutional symptoms and relapsing nonsuppurative nodular panniculitis. The etiological study didn't identify any associated disease, on admission or in 2,5 years of follow-up. This is a case of Weber-Christian disease with a favourable corticosteroid therapy result. The authors present a Weber-Christian disease bibliographic revision.

[The network of methotrexate toxicity]. / A teia de toxicidade do metotrexato.

INTRODUCTION: Methotrexate is a folic acid antagonist recognised as one of the most important DMARD's in the rheumatoid arthritis treatment. Although the indisputable efficacy and the good tolerance profile, the broad toxicity spectrum is very variable with respect both to symptoms and intensity. The side effects vary from malaise and asthenia to pneumonitis or pancytopenia, which can be fatal. OBJECTIVES: To review the adverse effects of methotrexate in the treatment of rheumatoid arthritis. MATERIALS AND METHODS: Literature review, using Medline as a starting point, searching with the keywords "methotrexate", "toxic effects", "adverse effects", "rheumatoid arthritis". The relevant papers and selected references found therein were used. RESULTS: The gastrointestinal symptoms are the most frequent, but myelossupression and pneumonitis are the most feared ones. Elevation of transaminases could indicate hepatic toxicity, placing the risk of cirrhosis. Cutaneous lesions, neurologic symptoms, changes in the bone metabolism, teratogenecity and hyperhomocysteinemia are other examples of the adverse effects of methotrexate. The post-dosing reactions are still not well known. The folate supplementation is important in the prevention of folate metabolism dependent symptoms. The farmacogenomics may help to identify patients in greater risk for multiple side effects. CONCLUSIONS: Knowing and monitoring the methotrexate side effects is extremely important and should be carefully considered in order to prevent both therapeutic withdrawals due to toxicity as well as fatal outcomes.

Primera experiencia cubana del empleo de los modelos pedfusor y dómino para tiva-tci en pediatría / The first Cuban experience in the use of Pedfusor models and Dòmino for TIVA-TCI in Pediatrics

Introducción: La anestesia total intravenosa es aún poco usada en el paciente pediátrico tanto menos en su modo de infusión controlada por computadora. Objetivos: Caracterizar el empleo de los modelos Pedfusor y Dòmino para TIVA-TCI en pediatría. Material y método: Se realizó estudio descriptivo, longitudinal y prospectivo en 5 pacientes pediátricos programados para cirugía ortopédica, en la Clínica Central Cira García Reyes en el período comprendido entre agosto-septiembre de 2009. La variables estudiadas fueron concentraciones plasmáticas promedio de Propofol en función del índice de estado cerebral, estabilidad hemodinámica, duración del acto anestésico, tiempo para el despertar y presencia de complicaciones. Los datos se descargaron directamente del programa Anestfusor y se procesaron a través de la estadística básica de Microsoft Excel 2007. La información se presentó en tablas y gráficos confeccionados en Word, y los resultados se analizaron de forma porcentual a partir de las variables definidas anteriormente. Resultados: Las concentraciones plasmáticas promedio de propofol empleadas tanto para el plasma como para el sitio efecto oscilaron entre 2,9±1,87 µ?ml-1 y 4,70±0,93 µml-1 y entre 2,90±1,87 µml-1 y 4,65±0,92 µml-1respectivamente, la estabilidad hemodinámica fue buena en 100 por ciento de los casos, el acto anestésico fue de duración intermedia y prolongada en 80 por cientoy 20 por ciento de los niños respectivamente, el tiempo para despertar promedio fue 6,32 ±2,05 minutos y osciló entre 3,5 y 8,8 minutos después de detenidas las infusiones. No se reportaron complicaciones. Conclusiones: el empleo de los modelos Pedfusor y Dòmino para TIVA-TCI en pediatría resultó clínicamente útil y seguro(AU

Introduction: The intravenous total anesthesia has still not much used in pediatric patient and much less in its computer-guided infusion way. Objectives: To characterize the use of the Pedfusor and Dòmino models for TIVA-TCI in Pediatrics. Material and Methods: A prospective, longitudinal and descriptive study was conducted in 5 pediatric patients programmed for orthopedic surgery in the Cira García Reyes Central Clinic over Aaugust-September, 2009. The study variables were the average plasma concentrations of Propofol depending of the brain state rate, hemodynamic stability, anesthetic act length, time to wake up and presence of complications. Data were directly collected from the Anestfusor program and processed using the basic statistics of Microsoft Excel 2007. The information was showed in tables and charts drawn up in Word and results were analyzed in a percentage way from the above mentioned variables.Results: The mean plasma concentrations of Propofol used for plasma and for effect site fluctuated from 2,9 ± 1,87 µ.ml-1 and 4,70 ± 0,93 u,ml-1 and 4,65 ± 0,92 u.ml-1, respectively, the hemodynamic stability was good in the 100 por ciento of cases; the anesthetic act had an intermediate and long length of 80 por ciento and 20 por ciento in the children, respectively, the mean time to wake up was of 6,32 ± 2,05 min and fluctuated from 3,5 to 8,8 min after infusion stopping. There were not complications. Conclusions: The use of Pedfusor and Dòmino models for TIVA-TCI in Pediatrics was clinically useful and safe(AU)

Relationship between squamous cell carcinoma of the anterior two thirds of the tongue and removable denture use: a pioneer study in a Portuguese population

The aim of the study was to determine whether there is any relationship between the presence of removable dentures and squamous cell carcinoma of the anterior two thirds of the tongue in a Portuguese population. A retrospective cross-sectional study was conducted on patients with a biopsy-proven diagnosis of squamous cell carcinoma of the tongue, who were seen and treated at the Department of Head and Neck Surgery of the Portuguese Institute of Oncology 'Francisco Gentil', Lisbon, Portugal, during a 3-year period. Several factors were examined: gender, use of removable dentures, age, location of the lesion, and alcohol and tobacco consumption. One hundred and six cases were selected from the initial 151 cases, with a male:female ratio of 3:1 and the lateral borders being the most commonly affected site. The prevalence in both genders was between the sixth and seventh decade of life. Men were more likely to consume alcohol and tobacco than women, and no relationship was observed between denture use and presence of carcinoma of the tongue. In light of the data obtained, it may be considered that female use of a denture plays an important role, but it cannot be identified as a remarkable etiologic factor.

O objetivo deste estudo foi determinar se existe alguma relação entre o uso de prótese removível e o carcinoma escamoso dos dois terços anteriores na população portuguesa estudada. Um estudo retrospectivo foi conduzido em paciente com diagnóstico anatomopatologico de carcinoma escamoso dos dois terços anteriores, diagnosticados no Instituto Português de Oncologia, Francisco Gentil, Lisboa desde 1 de Janeiro de 2001 até 31 de Dezembro de 2003. Diferentes fatores foram analisados: o gênero, uso de prótese removível, idade, localização, álcool e tabaco. Dos 151 casos iniciais de carcinoma, foram selecionados 106 casos mostrando numa proporção de 3:1 (masculino/feminino). Os bordos laterais foram a localização mais comum e a prevalência em ambos os sexos sitou-se entre a sexta e a sétima década. A presença de álcool e tabaco foi significativamente mais comum nos homens não se observando relação entre o uso de prótese e a presença do carcinoma na língua. Não se observou relação estatística entre o uso de prótese removível e o carcinoma escomoso dos dois terços anteriores da língua. Face aos resultados, o uso de prótese no sexo feminino desempenha um papel importante ainda que não possa ser considerado um fator etiológico significativo.

Oral tongue squamous cell carcinoma (OTSCC): alcohol and tobacco consumption versus non-consumption. A study in a Portuguese population

There has been an increase in the incidence of carcinoma of the tongue, particularly among alcohol and tobacco non-users. However, the number of studies that would allow a better understanding of etiological factors and clinical features, particularly in the Portuguese population, is very limited. This study was based on patients with squamous cell carcinoma of the anterior two thirds of the tongue that were treated at the Department of Head and Neck Surgery of the “Instituto Portugues de Oncologia de Lisboa - Francisco Gentil” (IPOLFG) in Lisbon, Portugal, between January 1, 2001 and December 31, 2009. The patients were divided in alcohol and tobacco users and non-users in order to evaluate the differences between these 2 groups based on gender, age, tumor location, denture use, and tumor size, metastasis and stage. Of the 354 cases, 208 were users and 146 were non-users. The main location in both groups was the lateral border of the tongue. Denture use showed no significant effect in both study groups. It was possible to conclude that patients who did not drink or smoke were older and presented with smaller tumor size, lower incidence of ganglion metastasis and lower tumor stage compared with alcohol and tobacco users.

Um aumento do carcinoma da língua, particularmente entre os não consumidores de álcool e tabaco tem se verificado recentemente. No entanto, o número de estudos que permitam uma melhor compreensão dos fatores etiológicos e características clínicas, particularmente na população Portuguesa, é muito limitado. Este estudo foi baseado em pacientes com carcinoma de dois terços anteriores da lingual que foram atendidos e tratados no Departamento de Cabeça e Pescoço do “Instituto Portugues de Oncologia de Lisboa, Francisco Gentil” (IPOLFG), Portugal, entre 1 de janeiro de 2001 e 31 de dezembro de 2009. Eles foram divididos em usuários de álcool e tabaco e não usuários, a fim de avaliar as diferenças entre estes 2 grupos com base no sexo, idade, localização do tumor, o uso de prótese dentária, tamanho do tumor, metástase e estágio. Dos 354 casos estudados, 208 eram usuários de álcool e tabaco e 146 eram não-usuários. A localização principal, em ambos os grupos, foram a bordos laterais da língua. O uso de prótese dentária mostrou não ter um efeito significativo em ambos os grupos de estudo. Pode-se concluir que os não-usuários de álcool e tabaco eram mais velhos e apresentaram carcinoma de menores dimensões, menor incidência de metástases ganglionares e um estágio mais inicial da doença do que os etilistas e fumantes.

Preoperative diagnosis of medullary thyroid carcinoma: fine needle aspiration cytology as compared with serum calcitonin measurement.

BACKGROUND AND OBJECTIVES: Preoperative diagnosis of sporadic medullary thyroid carcinoma (MTC) has mainly relied on fine needle aspiration cytology (FNAC). The present study aimed to compare the sensitivity of this technique with serum calcitonin (CT) measurement and to assess the therapeutic implications of an inadequate preoperative diagnosis. METHODS: We reviewed the clinical records of 91 MTC patients treated and/or followed at our institution between January 1990 and December 2003. RESULTS: After revision of clinical records, 77 individuals were considered eligible for the study. FNAC was performed in 67 patients (87%) with a sensitivity of 63%; serum CT was measured in 56 patients (73%) with a sensitivity of 98%. Both FNAC and serum CT were assessed in 51 patients (66%). FNAC detected only 74.5% of MTCs suspected by elevated serum CT. Among patients with a cytological diagnosis of MTC, total thyroidectomy (TT) was performed in 95% of patients. Among patients without a cytological diagnosis of MTC, TT was performed in 83% of patients in whom serum CT was evaluated prior to surgery whereas it was performed in only 46% of patients in whom CT evaluation was lacking. CONCLUSIONS: Despite the higher sensitivity of serum CT measurement, as compared with FNAC to diagnose MTC (98% vs. 63%), only 9% of patients might have escaped to surgery based on FNAC results. However, indication for surgery based on suspicious FNAC may not alert the surgeon for the need of a TT and exploration of nodes at least in the central compartment.

Complicaçöes da cirurgia larìngea / Complications of larynx surgery

Os autores apresentam uma atualizaçäo sobre o assunto