Abstract¡G Activating point mutations of the BRAF gene have been recently reported to be restricted to papillary thyroid carcinomas (PTCs) and anaplastic thyroid carcinomas (ATCs) arising from PTCs among various benign and malignant thyroid tumors. A thymine-to-adenine transversion at nucleotide 1799 (T1799A), formerly designated as T1796A, in exon 15 resulting in a valine to glutamate substitution at residue 600 (V600E), formerly designated as V599E, was the only mutational site reported in thyroid cancer. We have previously shown that BRAFV600E mutations were detected in 49 of 105 (47%) PTCs but not in 5 follicular thyroid carcinomas (FTCs), 10 follicular adenomas, 3 Hürthle cell adenomas and 10 nodular goiters. In contrast to PTC, to date only few studies have been published concerning the frequency of BRAFV600E in ATCs and their coexisting differentiated thyroid carcinomas. In addition, there is no report concerning the BRAF status in multiple PTCs. In this study, paraffin-embedded tumor tissues of 25 patients with thyroid cancer (15 ATCs and 10 PTCs) were obtained from the Department of Pathology of Chang Gung Memorial Hospital-Kaohsiung. Nine ATCs were found to contain a coexisting differentiated carcinoma, including three follicular and six papillary carcinomas. Ten cases of PTC with multiple tumor foci were selected from a cohort of 105 PTCs as previously reported. Paraffin blocks containing tumor were sectioned followed by microdissection to obtain tissue for DNA extraction. Mutational hot spot in exon 15 (codon 600) of the BRAF gene were amplified by PCR and sequenced with an automatic sequencer. BRAFV600E mutations were detected in 3 of 15 (20%) ATCs. In the 9 coexisting differentiated carcinomas, 2 out of 6 PTCs harbored BRAF mutations but not in the three follicular carcinomas. In none of 3 ATCs with coexisting PTCs were mutations detectable in both tumor types. Among the ten cases of PTCs with multiple tumor foci, 5 cases demonstrated the same BRAF status in each tumor foci whereas 5 cases showed distinct BRAF status in different tumor foci. We conclude that the distinct BRAF status in anaplastic carcinoma and its coexisting differentiated carcinoma suggests that anaplastic carcinoma might not arise from differentiated carcinoma.The distinct BRAF status in different tumor foci of multiple papillary carcinomas suggests that multifocal tumors might not be formed through intrathyroidal lymphatic metastasis.

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A eosinofilia tecidual associada a tumores (TATE) tem sido descrita, entre outras localizações, nas neoplasias malignas da região de cabeça e pescoço. O mecanismo de atração dos eosinófilos e seu papel nos tumores ainda não foram definidos, sendo correlacionados tanto com um prognóstico favorável, como desfavorável, ou mesmo não apresentando qualquer relação com a evolução dos pacientes. Com o objetivo de verificar a influência da TATE no prognóstico de carcinomas espinocelulares localizados na língua, assoalho bucal, área retromolar e gengiva inferior com estadiamento clínico II e III foram analisados 125 pacientes quanto às características clínicas, tratamento e evolução, bem como os aspectos microscópicos relativos à morfologia e invasão tumoral e presença do infiltrado inflamatório, destacando-se a eosinofilia tecidual, quantificada por meio de análise morfométrica. O número de eosinófilos obtidos nos carcinomas espinocelulares de boca variou de 0 a 392 por milímetro quadrado. A TATE foi classificada em discreta (0 a 26 EOS/mm2), moderada (27 a 83 EOS/mm2) e intensa (84 EOS/mm2 ou mais) e apresentou uma correlação estatisticamente significativa com a intensidade do infiltrado inflamatório mononuclear e com a localização do infiltrado inflamatório eosinofílico. A análise da eosinofilia tecidual como fator prognóstico feita pelo estimador produto-limite de Kaplan-Meier e pelo modelo de riscos proporcionais de Cox demonstrou que a eosinofilia tecidual intensa constitui um fator de prognóstico favorável independente nos carcinomas espinocelulares com estadiamento clínico II e III localizados na língua, assoalho bucal, área retromolar e gengiva inferior. Estes resultados sugerem uma função antitumoral dos eosinófilos cujos mecanismos devem ser melhor investigados. / Tumor-associated tissue eosinophilia (TATE) has been described in many sites, including head and neck. The mechanism of eosinophil attraction, and its role in tumors is not defined yet, and its presence has been related to a favorable as well as unfavorable prognosis, or even with no influence on patients outcome. Intending to verify the influence of TATE on the prognosis of squamous cell carcinomas of the tongue, oral floor, retromolar area and inferior gingiva with TNM stages II and III, 125 patients were analyzed with respect to the clinical characteristics, treatment and evolution, as well as microscopic features related to tumor morphology and invasion and the presence of the inflammatory infiltrate, with special emphasis to tissue eosinophilia, quantified through morphometrical analysis. The eosinophil count of oral squamous cell carcinomas varied from 0 to 392 per square millimeter. TATE was classified as discrete (0 to 26 EOS/mm2), moderate (27 a 83 EOS/mm2) and intense (84 EOS/mm2 or more) and correlated with the intensity of the mononuclear inflammatory infiltrate and with the location of the eosinophilic inflammatory infiltrate. The analysis of TATE performed by the Kaplan-Meier product-limit actuarial method and Cox proportional hazards regression model demonstrated that intense tissue eosinophilia is an independent favorable prognostic factor for squamous cell carcinomas with TNM stages II and III, located on the tongue, oral floor, retromolar area and inferior gingiva. These findings suggest a antitumoral role of eosinophils which mechanisms should be better investigated.

A eosinofilia tecidual associada a tumores (TATE) tem sido descrita, entre outras localizações, nas neoplasias malignas da região de cabeça e pescoço. O mecanismo de atração dos eosinófilos e seu papel nos tumores ainda não foram definidos, sendo correlacionados tanto com um prognóstico favorável, como desfavorável, ou mesmo não apresentando qualquer relação com a evolução dos pacientes. Com o objetivo de verificar a influência da TATE no prognóstico de carcinomas espinocelulares localizados na língua, assoalho bucal, área retromolar e gengiva inferior com estadiamento clínico II e III foram analisados 125 pacientes quanto às características clínicas, tratamento e evolução, bem como os aspectos microscópicos relativos à morfologia e invasão tumoral e presença do infiltrado inflamatório, destacando-se a eosinofilia tecidual, quantificada por meio de análise morfométrica. O número de eosinófilos obtidos nos carcinomas espinocelulares de boca variou de 0 a 392 por milímetro quadrado. A TATE foi classificada em discreta (0 a 26 EOS/mm2), moderada (27 a 83 EOS/mm2) e intensa (84 EOS/mm2 ou mais) e apresentou uma correlação estatisticamente significativa com a intensidade do infiltrado inflamatório mononuclear e com a localização do infiltrado inflamatório eosinofílico. A análise da eosinofilia tecidual como fator prognóstico feita pelo estimador produto-limite de Kaplan-Meier e pelo modelo de riscos proporcionais de Cox demonstrou que a eosinofilia tecidual intensa constitui um fator de prognóstico favorável independente nos carcinomas espinocelulares com estadiamento clínico II e III localizados na língua, assoalho bucal, área retromolar e gengiva inferior. Estes resultados sugerem uma função antitumoral dos eosinófilos cujos mecanismos devem ser melhor investigados. / Tumor-associated tissue eosinophilia (TATE) has been described in many sites, including head and neck. The mechanism of eosinophil attraction, and its role in tumors is not defined yet, and its presence has been related to a favorable as well as unfavorable prognosis, or even with no influence on patients outcome. Intending to verify the influence of TATE on the prognosis of squamous cell carcinomas of the tongue, oral floor, retromolar area and inferior gingiva with TNM stages II and III, 125 patients were analyzed with respect to the clinical characteristics, treatment and evolution, as well as microscopic features related to tumor morphology and invasion and the presence of the inflammatory infiltrate, with special emphasis to tissue eosinophilia, quantified through morphometrical analysis. The eosinophil count of oral squamous cell carcinomas varied from 0 to 392 per square millimeter. TATE was classified as discrete (0 to 26 EOS/mm2), moderate (27 a 83 EOS/mm2) and intense (84 EOS/mm2 or more) and correlated with the intensity of the mononuclear inflammatory infiltrate and with the location of the eosinophilic inflammatory infiltrate. The analysis of TATE performed by the Kaplan-Meier product-limit actuarial method and Cox proportional hazards regression model demonstrated that intense tissue eosinophilia is an independent favorable prognostic factor for squamous cell carcinomas with TNM stages II and III, located on the tongue, oral floor, retromolar area and inferior gingiva. These findings suggest a antitumoral role of eosinophils which mechanisms should be better investigated.

Nos connaissances sur les mécanismes étiopathogéniques des cancers utérins (endomètre et col) sont en constante amélioration. Cependant, le dépistage précoce des lésions précancéreuses a été réalisé, jusqu'à présent, avec plus de succès pour le col que pour le corps utérin. En outre, un diagnostic histopathologique précis est obligatoire pour adopter la stratégie thérapeutique la plus appropriée. L'objectif général de ce travail a été de valider des marqueurs diagnostiques potentiels des cancers utérins en utilisant la technologie des « Tissus Puces» ou «Tissue Microarray» (TMA) qui permet l'examen uniforme et simultané d'un grand nombre d'échantillons déposés sur une même lame. Grâce à cette technologie, nous avons montré que la détection d'une série de marqueurs (ADN de papillomavirus humain, protéine p16, involucrine et antigène Ki67) peut améliorer le diagnostic histopathologique des différentes lésions (pré)néoplasiques cervicales. En outre, ces biomarqueurs pourraient aider à mieux comprendre la biologie des lésions épithéliales cervicales en les reliant à des critères morphologiques précis. Nous avons également évalué l'intérêt de marqueurs diagnostiques basés sur la méthylation de l'ADN dans la carcinogenèse endométriale. Notre démonstration d'une hyperméthylation des promoteurs de deux gènes suppresseurs de tumeur (RASSF1A et RARB2) au cours de la carcinogenèse endométriale et dans les tissus normaux adjacents aux tumeurs suggère un rôle important de la méthylation de l'ADN dans linitiation et la progression des lésions (pré) cancéreuses de lendomètre.

Epithelial adhesion molecule, E-cadherin plays important role in maintaining structural integrity of epithelial tissue. Altered expression of E-cadherin might result in the loss of contact inhibition growth property, abnormal cell growth and differentiation, hence the oncogenic transformation. To explore the role of E-cadherin in the tumor progression, we have investigate the expression pattern of E-cadherin in invasive cervical carcinomas. 77 paraffin embedded specimen with FIGO staging Ia¡]N=15¡^, Ib¡]N=19¡^, Ib meta¡]N=13¡^ IIa¡]N=17¡^, IIb¡]N=13¡^were included in immunohistochemical study, 18 surgical removed tumor tissues of Ib stage and its normal counter parts were used for semi-quantitative RT-PCR analysis. The results indicated that no significant correlation between E-cadherin expression level and tumor metasis, patient prognosis. However, E-cadherin immunostainimg intensity was significanty inverse correlated with tumor size¡]p < 0.001¡^. Notably, loss of membranes E-cadherin expression might be a significant factor that correlated with tumor metasis¡]p = 0.001,< 0.005¡^.

Summary of the Doctoral Dissertation Biomedical Science, Medicine (07 B) The doctoral dissertation has been prepared at Kaunas University of Medicine during the period of 2000-2004. Scientific Supervisor: Prof. Dr. Romualdas Gailys (Kaunas University of Medicine, Biomedical Sciences, Medicine – 07 B) The dissertation will be defended at the Medical Research Council of Kaunas University of Medicine. Chair: Prof. Habil. Dr. Dalia Pangonytė (Kaunas University of Medicine, Biomedical Sciences, Medicine – 07 B) Members: Prof. Habil. Dr. Vaiva Lesauskaitė (Kaunas University of Medicine, Biomedical Sciences, Medicine – 07 B) Prof. Habil. Dr. Laima Griciūtė (Vilnius University, Biomedical Sciences, Medicine – 07 B) Assoc. Prof. Dr. Antanas Sederevičius (Lithuanian Veterinary Academy, Biomedical Sciences, Veterinary Medicine – 12 B) Dr. Rimantas Žalinkevičius (Kaunas University of Medicine, Biomedical Sciences, Medicine – 07 B) Official opponents: Dr. Birutė Žilaitienė (Kaunas University of Medicine, Biomedical Sciences, Medicine – 07B) Assoc. Prof. Dr. Arvydas Laurinavičius (Vilnius University, Biomedical Sciences, Medicine – 07B) The dissertation will be defended at the open session of the Medical Research Council on the July 1st, 2005 in the auditorium of the Clinic of Pathology at Kaunas University of Medicine. Address: Eivenių str. 2, LT- 50009 Kaunas, Lithuania. The summary of the Doctoral Dissertation was sent out on May 31st, 2005. The Dissertation is available in the... [to full text]

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