Distribution of Metastatic Nodes in N0-1 Patients with Tonsillar Squamous Cell Carcinoma and Its Implications for Selective Neck Dissection.

OBJECTIVE: We aimed to evaluate the pattern of neck metastasis in patients with primary tonsillar carcinoma treated by primary surgery and neck dissection. Impact of the extent of neck dissection and level of metastatic nodes on survival were also evaluated. METHODS: We evaluated 163 consecutive patients with tonsillar squamous cell carcinoma submitted for neck dissection and staged as cN0-1. Selective neck dissection was performed using a template encompassing levels I-III, whereas radical neck dissection led to the removal at levels I-V. For each patient, number of metastatic nodes, their distribution, and data regarding postoperative treatment and oncologic outcomes were analyzed. RESULTS: Occult neck metastasis at levels I, IV, and V were rare with two cases each. In the clinically negative (cN0) patients, there were no cases of metastasis at level V and two cases at level I or IV. The extent of neck dissection and level of metastatic nodes had no impact on disease-specific survival or neck recurrence. CONCLUSION: We conclude that in cN0 patients, removal at levels II and III is mandatory but levels I, IV, and V may be spared.

Relaxation of imprinting of IGFII gene in juvenile nasopharyngeal angiofibromas.

IGFII and H19 genes are expressed only from one allele due to genomic imprinting, biallelic expression (loss of imprinting) being associated with the tumorigenic process of different types of tumors. The mechanism responsible for genomic imprinting is not yet determined, although DNA methylation has been considered the main genetic event for an imprinted mark. In the current study, the authors analyzed the imprinting status and expression levels of the IGFII and H19 genes in 27 cases of Juvenile Nasopharyngeal Angiofibroma (JNA) using RFLPs, RT-PCR, and Southern and Northern Blots. The authors found that four out of eight informative cases (50%) for ApaI/IFGII polymorphism showed biallelic expression of IFGII whereas none of the nine informative cases for the polymorphism showed biallelic expression of the H19 gene. Overexpression of IFGII was observed in 8 out of 22 cases (36.4%), and 7 out of 19 cases (36.8%) showed H19 overexpression. Hypomethylation was found only in the H19 gene in six out of eight cases analyzed. Therefore, our results demonstrate that alterations in the IFGII/H19 imprinted region occur in JNA.

Markers of vascular differentiation, proliferation and tissue remodeling in juvenile nasopharyngeal angiofibromas.

Juvenile nasopharingeal angiofibroma (JNA) is a histologically benign locally aggressive tumor characterized by irregular vessels embedded in a fibrous stroma. Excessive vascularity results in bleeding complications, and the inhibition of angiogenesis is a promising strategy for managing extensive JNA tumors. To better characterize the endothelial components of JNA, we aimed to evaluate markers of vascular differentiation and proliferation, such as friend leukemia integration-1 (FLI-1) and endoglin, lymphatic markers, including podoplanin and vascular endothelial growth factor receptor 3 (VEGFR3) and its cognate ligand VEGFC, GLUT-1, a diagnostic marker that discriminates between hemangiomas and vascular malformations, and two markers of tissue remodeling, stromelysin 3 (ST3) and secreted acid protein rich in cysteine (SPARC). Antigens were assessed immunohistochemically in vessels and stromal cells of JNA archival cases (n=22). JNA endothelial cells were positive for endoglin, VEGFC and FLI-1, whereas podoplanin and VEGFR3 were negative in all cases. Both endothelial cells and fibroblasts stained for ST3 and SPARC. GLUT-1 was investigated in JNA cases, in infantile hemangiomas (n=123) and in vascular malformations (n=135) as controls. JNAs and vascular malformations were GLUT-1-negative, while hemangiomas showed positive staining. The presence of markers of endothelial differentiation and proliferation highlighted the hyper-proliferative state of JNA vessels. The absence of podoplanin and VEGFR3 underscores their blood endothelial cell characteristic. The absence of GLUT-1 discriminates JNAs from hemangiomas. ST3 and SPARC up-regulation in endothelial cells and fibroblasts may contribute to a compensatory signaling for controlling angiogenesis. Some of these markers may eventually serve as therapeutic targets. Our results may aid in the understanding of JNA pathophysiology.

Overexpression of Fos-related antigen-1 in head and neck squamous cell carcinoma.

The activating protein-1 (AP-1) family of transcription factors has been implicated in the control of proliferation and differentiation of keratinocytes, but its role in malignant transformation is not clear. The aim of this study is to assess the pattern of mRNA expression of jun-fos AP-1 family members in 45 samples of head and neck squamous cell carcinomas (HNSCC) and matched adjacent mucosa by means of Northern blot analysis. Transcripts of all family members were identified, except for JunB that was detected only by means of reverse transcription polymerase chain reaction. Neither c-Fos nor JunD or FosB mRNA differed between tumours and normal tissues. We observed a strong Fos-related antigen-1 (Fra-1) and Fra-2 expression, but only Fra-1 mRNA densitometric values were higher in tumour, compared to normal adjacent mucosa (t-test, P = 0.006). A direct relationship between the positive expression of Fra-1 mRNA, above tumour median, was associated with the presence of compromised lymph nodes (Fischer exact test, P = 0.006). In addition, Fra-1 protein staining was assessed in a collection of 180 tumours and 29 histologically normal samples adjacent to tumours in a tissue array. Weak reactivity, restricted to the basal cell layer, was detected in 79% of tumour adjacent normal tissues, opposed to the intense reactivity of cancer tissues. In the subgroup of oral cancers, we have observed a shift in Fra-1 immunoreactivity, as long as the number of patients in each category, cytoplasmic or nuclear/cytoplasmic staining, was analysed (Fischer exact test, P = 0.0005). Thus, Fra-1 gene induction and accumulation of Fra-1 protein may contribute to the neoplastic phenotype in HNSCC.

Increased mortality and inflammation in tumor necrosis factor-stimulated gene-14 transgenic mice after ischemia and reperfusion injury.

TSG-14/PTX3 is a gene inducible by tumor necrosis factor (TNF)-alpha, interleukin-1 beta, and lipopolysaccharide in fibroblasts, macrophages, and endothelial cells. It encodes a 42-kd secreted glycoprotein that belongs to the pentraxin family of acute-phase proteins. Recently, we demonstrated that TSG-14 transgenic mice (TSG-14tg) overexpressing the murine TSG-14 gene under control of its own promoter are more resistant to lipopolysaccharide-induced shock and to polymicrobial sepsis caused by cecal ligation and puncture. Here we show that after ischemia and reperfusion (I/R) injury, TSG-14tg mice have an impaired survival rate, which appeared secondary to a markedly increased inflammatory response, as assessed by the local (duodenum and ileum) and remote (lung) enhancement in vascular permeability, hemorrhage, and neutrophil accumulation. Moreover, tissue concentrations of TNF-alpha, interleukin-1 beta, KC, and MCP-1 were higher in TSG-14tg as compared to wild-type mice after I/R injury. Of note, elevated TNF-alpha concentrations in serum were only observed in TSG-14tg mice and blockage of TNF-alpha action prevented lethality of TSG-14tg mice. These results demonstrate that transgenic expression of TSG-14 induces an enhanced local and systemic injury and TNF-alpha-dependent lethality after I/R. Taken together, our data point to a critical role of TSG-14 in controlling acute inflammatory response in part via the modulation of TNF-alpha expression.

Vaccination against Fasciola hepatica infection using a Schistosoma mansoni defined recombinant antigen, Sm14.

Fasciola hepatica is the causative agent of fasciolosis in many areas in America, Europe, Africa, Asia and Australia. There is an urgent need for improved methods to control the parasite's transmission. We describe the use of an experimental vaccine based on a recombinant antigen cloned from another parasite, Schistosoma mansoni (Sm14), that induces high levels of cross protection in mice against both S. mansoni and F. hepatica. Sheep and mice vaccinated with Sm14 were significantly protected against challenge infection with metacercariae of Fasciola hepatica and were completely free of the histopathological hepatic damage related to liver fluke infection. The vaccine will provide a valuable new tool to aid in transmission control of this economically important disease.

In silico comparison of the transcriptome derived from purified normal breast cells and breast tumor cell lines reveals candidate upregulated genes in breast tumor cells.

Genes that are differentially expressed in tumor tissues are potential diagnostic markers and drug targets. The DNA sequence information available in the public databases can be used to identify transcripts differentially expressed in cancer. We report here the combined use of the ORESTES sequences generated in the FAPESP/LICR Human Cancer Genome Project and information available in the UniGene and SAGE databases to characterize the transcriptome of normal and breast tumor cells. We have identified 154 genes as candidates for overexpression in breast tumor cells. Among these, 28 genes have been shown by others to be overexpressed in breast or other tumors. Using RT-PCR, we tested 11 candidate genes and found that 9 were indeed overexpressed in breast tumor cells.

Assessment of control selection bias in a hospital-based case-control study of upper aero-digestive tract cancers.

BACKGROUND: Most of the evidence identifying determinants of UADT cancer risk comes from hospital-based case-control studies. However, such studies are thought to be influenced by selection bias given the extent of association of tobacco smoking and alcohol drinking with other diseases in the general population. We assessed the extent of selection bias due to inclusion of controls with tobacco or alcohol related diseases in a hospital-based case-control study of upper aero-digestive tract (UADT) cancers in Brazil. METHODS: Risk factor information was obtained from 784 cases and 1568 non-cancer controls. Causes of hospitalization for controls were scored according to their likelihood of association with tobacco and alcohol. Odds ratios (OR) were calculated by conditional logistic regression with and without exclusion of controls with tobacco or alcohol related diseases. RESULTS: The OR for smoking slightly increased after exclusion of controls with tobacco-related diseases, from 15.3 (95% confidence interval [CI]: 9.7, 24.2) among heaviest smokers (pack-years > 91) to 18.6 (95%CI: 11.4, 30.2). The OR for alcohol consumption remained unchanged after exclusion of controls with alcohol related diseases. Associations of low magnitude for some dietary variables (citric fruits, carotene-rich foods, spicy foods, maté tea) and wood stove use were not appreciably affected by the exclusion of controls. CONCLUSION: The bias introduced by controls with tobacco and alcohol related diseases is small, when these exposures are investigated as determinants, and almost negligible when considered as confounders of the association between other factors and UADT cancers.

Expressão do p53 no carcinoma epidermóide do lábio / P53 expression in squamous cell carcinoma of the lip

OBJETIVO: Verificar o valor da expressão do p53 no carcinoma epidermóide (CEC) de lábio. MÉTODO: O estudo imunohistoquímico foi feito em material fixo em formol e mantido em bloco de parafina, corado com anticorpos anti-p53, segundo técnica da Streptavidina-Biotina-Peroxidase. Para análise estatística, foi empregado o teste de Fisher para a diferenciação de grupos em relação às variáveis do estudo. RESULTADOS: A expressão do p53 foi positiva em 87,5 por cento do CEC bem diferenciado, 60 por cento no moderadamente diferenciado e 91,67 por cento no pouco diferenciado. Nas margens de ressecção cirúrgica foi negativa em 94,23 por cento e positiva em 5,77 por cento, havendo associação entre o grau de diferenciação e a expressão do p53 (p=0,05). CONCLUSÃO: A expressão do p53 foi positiva na lesão primária e negativa na margem de ressecção cirúrgica, mas não é determinante de mudanças no paradigma cirúrgico.

BACKGROUND: To assess the p53 expression in squamous cell carcinoma (SCC) of the lip. METHODS: Immunohystochemical study for samples fixed in formaline and paraphin in bloc stained with anti-p53 antibodies through Streptavidina-Biotina-Peroxidase. For statistical analysis the Fisher Test was employed for group differences (p<0.10). RESULTS: The p53 expression were positive in 87.50 percent of well differentiated SCC, 60.0 percent of moderately differentiated tumors, 91.67 percent of poorly differentiated; for surgical margins, 94.23 percent were negative and 5.77 percent positive, with an association between differentiation degree and p53 expression (p=0.05). CONCLUSION: The p53 expression was significant in SCC of the lip and negative for surgical margins, but it is not determinant of changing in surgical paradigm.

Looking Beyond Tobacco and Alcohol: The Role of Lifestyle and Other Environmental Risk Factors for Laryngeal Cancer

Laryngeal cancer incidence in São Paulo, Brazil, is one of the highest in the world. OBJECTIVE: This hospitalbasedcase-control study was designed to investigate exposure-disease relationship between larynx cancer andsmoking and drinking history, diet, occupational exposures and other characteristics. MATERIAL ANDMETHODS: The study was conducted in 3 metropolitan areas in Brazil: São Paulo (South-east), Curitiba (South)and Goiânia (Central-west). We have analyzed information on demographics, occupational history, environmental exposures, tobacco smoking and alcoholdrinking habits obtained from interviews with 194 cases and 804 controls (non-cancer inpatients) matched on 5-year age group, gender, hospital catchments area, and trimester of admission. RESULTS: Tobacco and alcohol consumption were the most important factors for prediction of laryngeal cancer. Other important riskfactors were indoor exposure to wood stove fumes (RR=2.6), woodworking (RR=1.9), family history of cancer(RR=2.1), and high consumption of coffee and “chimarrão”(a kind of maté tea ). There was a protective effect for the consumption of citric fruits and forcarotene-rich vegetables. CONCLUSION: regionally specific lifestyle (“chimarrão”, high consumption of woodworking, and family history of cancer may be responsible for a substantial proportion of incidentlaryngeal cancer cases.

P53 overexpression in epidermoid carcinoma of the head and neck

The theory of field cancerization in tumors of the head and neck reflects the complex oncogenesis that occurs in this region. The mechanisms that control cell proliferation at the molecular level in epidermoid carcinomas (ECs) of the upper aerodigestive tract are still unclear. Mutations in p53 are the genetic alterations most often detected in ECs of the head and neck and seem to contribute actively to the carcinogenic process triggered by p53 as a tumor-suppressor gene and to its association with tobacco. The objective of the present study was to investigate the expression of p53 protein in epidermoid head and neck carcinomas by immunohistochemistry and its immunohistochemical correlation with other prognostic factors. The study was conducted on 63 consecutive ECs cases not submitted to previous treatment. Specimens of the tumor and of the normal adjacent mucosa were collected during surgery and submitted to immunohistochemical reaction for the determination of the expression of anti-protein p53 antibody (M7001 DAKO A/S, Denmark). Anatomo-clinical and demographic data were not significantly correlated with the presence of lymph node metastases or p53 expression in the tumor or in the adjacent normal mucosa. Tumor localization in the larynx was significantly correlated with p53 expression. Histological grading as grades I,II,III and IV was correlated whith significant p53 expression (p = 0.025). Conclusions: 1) in the studied material obtained from 63 cases of head and neck ECs, we detected a 48 percent rate of immunohistochemically detectable p53 overexpression; 2) we did not detect a relationship between demographic patient data and p53 expression in the tumor or in the normal adjacent mucosa; 3) p53 overexpression was significantly more frequent in ECs material from the larynx; and 4) The presence of 12 cases with p53 overexpression in the normal adjacent mucosa and with a p53-negative tumor is in agreement with the theory of field concerization. Follow-up of this patient series for a longer period of time will permit a better analysis of these values.

Implantaçäo do registro hospitalar de câncer e a qualidade das informaçöes hospitalares - A. C. Camargo Säo Paulo / The imptementution of a hospital-based c&ncer registry and the qualitY of information

O presente artigo tem como objetivo descrever as diferentes fases do processo de implantação do registro de base hospitalar num centro de referência em oncologia, com os respectivos procedimentos para se assegurar a qualidade das informações. As análises preliminares foram realizadas com os primeiros 2.300 pacientes incluídos, com diagnóstico confirmado de neoplasia maligna, admitidos durante o ano de 1994. A confiabilidade das codificações foi avaliada através da recodificação de 15(por cento) dos casos de estudo piloto selecionados aleatoriamente. Nesta análise de concordância todos os ítens da ficha foram incluídos, porém com maior ênfase na topografia do tumor, no tipo histológico e no estadiamento. O estadiamento clínico, que se baseia na classificação TNM, teve uma concordância média de 82(por cento) entre a primeira e a segunda codificação, feita por diferentes codificadores. Os tumores de próstata, retina e cérebro foram as topografias que apresentaram codificações discordantes. A manutenção da qualidade das informações ocupou uma posição de destaque dentre os desafios enfrentados pelo RHCHACC durante a sua fase de implantação. Os seguintes aspectos mereceram cuidados maiores no decorrer deste processo: o estadiamento dos tumores pediátricos, a codificação dos linfomas devido à grande variedade de tipos histológicos, o estadiamento de tumores em que o TNM não pode ser aplicado, o treinamento e a supervisão de codificadores e a qualidade do prontuário médico

Frequency of the CCR5delta32 allele in Brazilians: a study in colorectal cancer and in HTLV-I infection

A observaçäo de que indivíduos homozigotos para uma deleçäo de 32 pares de base no gene que codifica para o receptor 5 de cc-quimiocinas apresentam um menor risco de contrair a infecçäo por HIV-1 levou à investigaçäo da freqüência deste polimorfismo em várias populaçöes mundiais. É importante investigar se o CCR5delta32 é um fator a ser considerado na epidemiologia do HIV em populaçöes individuais. Com estes pressupostos em mente nós estabelecemos a freqüência do CCR5delta32 em uma grande amostra (907 indivíduos näo-relacionados) da populaçäo urbana do sudeste brasileiro, estratificada da seguinte maneira: 322 indivíduos sadios, 354 pacientes com câncer colorretal e 229 doadores de sangue. Os três grupos apresentaram essencialmente a mesma freqüência alélica de CCR5delta32 e a comparaçäo par-a-par näo revelou diferenças significativas. Assim, os nossos resultados podem ser agrupados para fornecer uma estimativa confiável de 0,053 ñ 0,005 da freqüência alélica de CCR5delta32. Os doadores de sangue compreendiam 50 indivíduos soronegativos para HTLV-I, 115 indivíduos assintomáticos por ELISA mas com resultados indeterminados em Western blot, 49 indivíduos soropositivos para HTLV-I mas assintomáticos e 15 indivíduos soropositivos para HTLV-I sintomáticos com mielopatia. Foi observado um sugestivo gradiente decrescente da freqüência alélica de CCR5delta32 nestas categorias. Entretanto, quando aplicamos o teste exato de Fisher, näo emergiram diferenças significativas. Para uma melhor avaliaçäo da influência do alelo CCR5delta32 na probabilidade de infectar-se com HTLV-I ou de desenvolver doença clínica seräo necessários estudos com um maior número de doadores de sangue.

Exenteraçäo pélvica no câncer ginecológico: relato de 13 casos / Pelvic exenteration in gynecological cancer: report of 13 cases

Treze pacientes com câncer ginecológico avançado foram submetidas a exenteraçäo pélvica no Departamento de Ginecologia do hospital A. C. Camargo, no período de setembro de 1979 a março de 1987. O câncer de vulva se igualou com o do colo uterino na indicaçäo da cirurgia. A mortalidade operatória foi de 23 por cento. As complicaçöes cirúrgicas foram a deiscência na derivaçäo urétero-ileal e as fístulas intestinais e urinárias. As causas de morte cirúrgica foram embolia pulmonar, insuficiência cardíaca e septicemia. Os fatores clínico-patológicos limitantes da sobrevida foram o tamanho do tumor maior que 3,5 cm e o tempo de recorrência menor que 12 meses após o tratamento inicial. A sobrevida foi de 31 por cento há sete anos.

Doença de Paget da vulva: relato de três casos / Vulvar Paget's disease: report of 3 cases

Entre 1983-90 foram diagnosticados e tratados três casos de doença de Paget da vulva no Departamento de Ginecologia do Hospital A. C. Camardo da Fundaçäo Antonio Prudente. Uma das pacientes (caso 2) apresentava um arcinoma de mama concomitante. Uma outra paciente (caso 1) apresentou também um câncer de mama após a doença Paget vulvar. A vulvectomia simples foi o tratamento de escolha em dois casos e na 3ª paciente foi feita vulvectomia total com linfadenectomias inguinal e pélvica. Um caso acha-se vivo (caso 3) quatro anos após a cirurgia. Os outros dois casos sobreviveram seis e sete anos, vindo a falecer devido a acidente vascular cerebral e a infarto do miocárdio repentino, livres de neoplasia. Nos casos de doença de Paget da vulva há possibilidade de existirem outros tumores primários. O clínico deve estar sempre alerta quanto a esta possibilidade.