Orientador : Prof. Dr. Roberto Pontarolo / Co-orientador : Prof. Dr. Bonald C. Figueiredo / Tese (doutorado) - Universidade Federal do Paraná, Setor de Ciências da Saúde, Programa de Pós-Graduação em Ciências Farmacêuticas. Defesa: Curitiba, 06/06/2011 / Bibliografia: fls. 101-110 / Área de concentração: Análises Clínicas / Resumo: Introdução. A incidência do tumor de córtex adrenal (TCA) é marcadamente alta no Estado do Paraná, onde mais de 95% dos pacientes herdaram a mutação germinativa R337H TP53 de um dos pais. O desconhecimento da existência da mutação impede uma ação preventiva contra o TCA avançado, assim como a falta de dados sobre o risco para outros tipos de câncer em crianças e adultos dificulta o planejamento epidemiológico e o aconselhamento genético. O presente trabalho foi proposto com o objetivo de esclarecer estes questionamentos. Métodos: Esta pesquisa foi aprovada pelo Comitê de Ética em Pesquisa em seres humanos do Hospital de Clínicas da UFPR, do Hospital Pequeno Príncipe e pela CONEP em 2005 e em 2009 (com novos objetivos). Foram coletadas amostras de sangue periférico para a identificação da mutação R337H TP53 por meio da técnica de PCRRFLP. A confirmação da mutação foi feita por meio do sequenciamento do exon 10 do gene TP53 e pelo achado da mesma mutação em outras pessoas da família. O acompanhamento ambulatorial das crianças com a mutação R337H se baseou nos exames periódicos médicos, em ecografias abdominais e concentrações plasmáticas de hormônios adrenocorticais. Os resultados preliminares de heredogramas das famílias com a mutação R337H revelaram casos de carcinoma de plexo coroide (CPC) com a mutação, o que motivou a pesquisa para esclarecer se há incidência aumentada de CPC no Paraná. Resultados: De dezembro de 2005 a março de 2010, 171.649 RN, de um total de 180.000, participaram do rastreamento da mutação R337H TP53. Foram identificados 461 RN (0,27%) com a mutação. Dezenove casos de TCA foram diagnosticados no grupo de RN (n=13) ou no grupo de parentes abaixo de 15 anos de idade (n=6) durante esta coorte. Além disso, 34 casos de TCA foram revelados (31 crianças e 3 adultos) no histórico sobre câncer das famílias avaliadas (n=343 famílias). Das crianças que participaram do protocolo de vigilância ambulatorial, oito (2,4%) desenvolveram o TCA. Das crianças restantes portadoras da mutação e que não participaram do protocolo de vigilância, nove (2,5%) desenvolveram o TCA. As crianças com diagnóstico de TCA a partir do protocolo de vigilância ambulatorial apresentaram média de tamanho de tumores estatisticamente menor (apenas no estadio I) do que as que não participaram do protocolo (7 casos nos estadios II ou III, incluindo um óbito). Em 63,3% (14/22) dos pacientes com CPC foi identificada a mutação R337H. Ao contrário, dos 100% de LOH identificado em casos de TCA, o mesmo percentual não aconteceu nos casos de CPC. Conclusões. Este estudo demonstra a viabilidade do rastreamento neonatal para a detecção da mutação R337H e tratamento precoce de crianças com TCA, o que sugere que tal procedimento deveria ser incluído no Programa de Triagem Neonatal existente nos Estados brasileiros com uma frequência da mutação semelhante à da população do Paraná (1/371). Esta mutação é responsável por mais de 60% dos casos de CPC, sugerindo uma incidência pelo menos duas vezes maior desta neoplasia no Estado do Paraná do que em outras regiões onde não ocorre a mutação R337H. / Abstract: Introduction. The incidence of adrenocortical tumor (ACT) is remarkably high in Parana State (Southern Brazil), where over 95% of patients inherited the germline R337H TP53 mutation from a parent. Lack of knowledge about the mutation prevents a preventive action against advanced ACT. Likewise, lack of data on the risk for other types of cancer in children hamper the epidemiological monitoring and genetic counsling. This study was proposed to clarify these questions. Methods. This study was approved by the Ethics Committee for Research in Humans from the Hospital de Clínicas from UFPR, from the Pequeno Príncipe Hospital, and by CONEP in 2005 and 2009 (with new goals). Peripheral blood samples were collected for DNA analysis of the R337H mutation of the TP53 gene using the PCR-RFLP assay. Confirmation of the mutation was performed by sequencing of the TP53 exon 10 and by the identification of the same mutation in other family members. Outpatient Children with the R337H mutation was based on periodic medical examination, abdominal ultrasound and plasma concentrations of adrenocortical hormones. Preliminary analysis of the pedigrees of the families revealed cases of choroid plexus carcinoma (CPC) with the mutation and encouraged further study to verify whether there is increased incidence of CPC in Paraná state. Results. From December 2005 to March 2010, 171.649 newborns from a total of 180.000 were recruited for the screening of the R337H TP53 mutation. We identified 461 infants (0.27%) with this mutation. Nineteen cases of ACT were diagnosed in the group of newborns (n = 13) or in the group of relatives under 15 years of age (n = 6) in this cohort. In addition, 34 cases of ACT (31 children and 3 adults) were identified through the family history of cancer (n=353 families). Of the newborns who have participated of the surveillance program, eight (2.4%) developed TCA. Of the remaining newborns with the mutation who were not in the surveillance program, nine (2.5%) developed ACT. Children diagnosed with ACT through the surveillance program presented tumors with average size statistically smaller (only stage I) than those who did not attend the surveillance program (7 cases in stages II or III, including one deceased child). In 63.3% (14/22) of the patients with CPC was identified the germline R337H mutation. Unlike the ACT with 100% LOH, a lower percentage of LOH was found in CPC. Conclusions. This study demonstrates the feasibility of the neonatal screening to detect and treat precociously the ACT from children with the R337H mutation, suggesting that the neonatal screening for the R337H mutation should be included in the neonatal screening program in the Brazilian states with a similar frequency of mutation found in Paraná state (1/371). This mutation is responsible for more than 60% of the CPC cases in children, suggesting an incidence at least twice higher in Paraná than in other regions without the mutation R337H.

Introdução/Objetivo: Existem evidências indicando que a resposta virológica sustentada (RVS) ao tratamento com interferon pode estar associada com menor incidência de carcinoma hepatocelular (CHC) em pacientes com cirrose causada pelo vírus da hepatite C (VHC). O objetivo do presente estudo foi comparar a incidência de CHC em cirróticos com RVS versus sem RVS. Métodos: Foram selecionados 85 pacientes com cirrose compensada (Child A) secundária ao VHC, confirmada por biópsia, sem quaisquer outras causas de doença hepática. Todos foram submetidos a tratamento com interferon ± ribavirina por pelo menos 24 semanas. Antes do tratamento nenhum paciente apresentava evidência de CHC à ultrassonografia abdominal (US). RVS foi definida como RNA do VHC negativo (PCR qualitativo com limite de detecção de 50 UI/ml) 24 semanas após o final do tratamento. Foram incluídos apenas pacientes com seguimento semestral com US e alfa-fetoproteína e anual com PCR por mais de 12 meses após o final do tratamento. O CHC foi diagnosticado por biópsia ou achados coincidentes de lesão focal com diâmetro superior a 2cm na US e tomografia computadorizada helicoidal trifásica com sinais de hipervascularização arterial. Resultados: Dos 85 pacientes, 38 (45%) alcançaram RVS e 47 (55%) não. A média do seguimento em pacientes com RVS versus sem RVS foi de 32,1 ± 20 meses (variação: 12-84 meses) e 28,2 ± 18 meses (variação: 12-96 meses), respectivamente (P=0,51). O CHC foi diagnosticado em 1 (3%) dos 38 pacientes com RVS e 8 (17%) dos 47 pacientes sem RVS (P=0,02; Razão de chance: 0,13; Intervalo de confiança de 95%: 0,006-0,9). As características pré-tratamento foram semelhantes entre os pacientes com e sem RVS, tanto demográficas (idade e sexo) quanto clínicas (Child A, média da dose total de interferon e tempo de seguimento). Além da ocorrência de CHC, a única outra variável com diferença significativa encontrada entre os grupos com e sem RVS foi o percentual de pacientes com genótipo 1 (13% versus 35%, respectivamente; P = 0,04). Comparando-se os pacientes com e sem CHC, a única variável com diferença estatisticamente significativa encontrada foi o percentual de RVS (11% versus 49%, respectivamente; P = 0,03). Conclusões: Pacientes com cirrose pelo VHC que atingem RVS têm menor incidência de CHC quando comparados àqueles sem RVS. A única diferença entre os grupos com e sem CHC foi a ocorrência de RVS. Este achado indica que a ausência do VHC pode tanto representar fator protetor direto contra o CHC, quanto servir como marcador indireto para identificar cirróticos com menor probabilidade de desenvolver CHC. / Background/Aim: There is strong evidence that sustained virologic response (SVR) to interferon treatment has an impact on the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HVC) related cirrhosis. The aim of this study was to compare the rate of HCC among HCV cirrhotics with vs without SVR. Methods: Eighty five biopsy proven cirrhotic patients with HCV infection (PCR positive), without any other form of liver disease were included. All were treated with interferon (IFN) ± ribavirin (RBV) for at least 24 weeks. Before treatment, all patients were compensated (Child A) and had no evidence of HCC on abdominal ultrasound (US). None had previous hepatic decompensation. SVR was defined as negative HCV-RNA (qualitative PCR with a limit of detection of 50 IU/ml) 24 weeks after end of treatment. Patients followed every 6 months with US and alpha-fetoprotein (AFP) for > 12 months after end of therapy were included. HCC was diagnosed by liver biopsy and/or coincident findings of focal lesion > 2 cm on US and spiral CT with arterial hypervascularization. Results: Thirty eight (45%) were SVRs and 47 (55%) were not. Mean follow-up was 32,1 ± 20 months (range:12-84 months) in SVRs vs 28,2 ± 18 months (range:12-96 months) in no-SVRs (P=0.51). HCC was diagnosed in 1 (3%) of 38 SVRs vs 8 (17%) of 47 patients without SVR (P=0.02; OR:0.13, 95% CI:0.006-0.9). All had similar pre-treatment characteristics (age, sex, liver function, Child A, total interferon dose and follow-up time). Besides HCC incidence, the only significant difference between SVRs and no-SVRs was the rate of genotype 1 (13% vs 35%, respectively, P = 0.04). Comparing patients with and without HCC, the only significant difference was found in the rate of SVR (11% vs 49%, respectively; P = 0,03). Conclusion: HCV cirrhotics with SVR have a lower incidence of HCC compared to those without SVR. The only difference between the groups with and without HCC was the rate of SVR. This finding may indicate that either absence of HCV-RNA truly protects against HCC, or acts as surrogate marker to identify cirrhotics that have a low probability of HCC development on long-term follow-up.

Carcinoma medular da tiroide (CMT), tumor maligno originário de células C ou parafoliculares tireoidianas, representa cerca de 4% de todos os tumores malignos dessa glândula. O CMT ocorre principalmente na forma esporádica (75%), mas também pode ocorrer como parte de uma doença hereditária transmitida de forma autossômica dominante, com 100% de penetrância, chamada neoplasia endócrina múltipla tipo 2 (NEM 2). A síndrome NEM 2 é classificada em três subtipos clínicos distintos: NEM tipo 2A (NEM 2A); NEM tipo 2B (NEM 2B) e câncer medular de tireoide familiar (CMTF). O protooncogene RET (REarranged during Transfection) é o gene de susceptibilidade para CMT hereditário e mutações somáticas nesse gene são descritas em aproximadamente 50% dos casos CMT esporádicos. Polimorfismos de nucleotídeo único (SNPs) do proto-oncogene RET têm sido implicados na patogênese e progressão do carcinoma medular da tireoide. A presença da variante genética silenciosa S836S tem sido associada com o risco de desenvolver ou modificar o curso clínico do CMT. No entanto, o mecanismo exato com que esse polimorfismo exerce seu efeito ainda é pouco compreendido. Uma das hipóteses propostas sugere que outras variantes funcionais do RET possam estar em desequilíbrio de ligação (DL) com o polimorfismo S836S, sendo essas capazes de modular a expressão gênica. Na doença de Hirschsprung, a variante S836S está em DL com polimorfismos da região 3’UTR do RET e associada ao desenvolvimento da doença. Nesse estudo, nós investigamos a frequência dos polimorfismos rs76759170 e rs3026785 da região 3’UTR do proto-oncogene RET em pacientes com CMT e verificamos a presença de desequilíbrio de ligação entre essas variantes e o polimorfismo S836S. De forma interessante, observamos que as variantes 3’UTR podem afetar a estrutura e a flexibilidade do mRNA do RET, o que sugere um envolvimento funcional dessas variantes sobre a estrutura secundária do mRNA desse gene. Além disso, o haplótipo contendo os alelos polimórficos S836S e 3’UTR foi associado ao desenvolvimento de doença metastática em pacientes com CMT. / Medullary thyroid carcinoma (MTC), a malignant tumor originating in parafollicular C cells of the thyroid, represents about 4% of all thyroid cancers. MTC is mainly sporadic (75%), but may also be part of an inherited disorder transmitted as an autosomal dominant trait with 100% penetrance, referred as multiple endocrine neoplasia type 2 (MEN 2). The MEN 2 syndrome is classified into three distinct clinical subtypes: MEN type 2A (MEN 2A); MEN type 2B (MEN 2B) and familial MTC (FMTC). The RET (REarranged during Transfection) proto-oncogene is the susceptibility gene for hereditary MTC and somatic RET point mutations are described in approximately 50% of MTC cases. The RET single nucleotide polymorphisms (SNPs) have been implicated in the pathogenesis and progression of MTC. The presence of S836S neutral variant might modify disease susceptibility and clinical phenotype in MTC. However, the exact mechanism by which this polymorphism modulates the MTC pathogenesis is still poorly understood. One of the proposed mechanisms suggests that the S383S neutral variant might be in linkage disequilibrium (LD) with unknown functional variants; these might be modulating gene expression. In patients with Hirschsprung's disease, strong LD between S836S and RET 3'UTR variants has been reported. Here, we evaluated the frequency of rs76759170 and rs3026785 3'UTR polymorphisms in patients with MTC and observed strong LD between these variants and S836S polymorphism. Interestingly, we demonstrated that the 3’UTR variants may affect the RET mRNA structure and flexibility, supporting the hypothesis of a functional involvement of the 3’UTR variant allele on secondary structure of RET mRNA. Furthermore, the haplotype harboring these variants was associated with development of metastatic disease in individuals with MTC.

Made available in DSpace on 2015-12-06T23:02:54Z (GMT). No. of bitstreams: 0 Previous issue date: 2003 / O carcinoma da papila duodenal maior e classificado como uma neoplasia da regiao periampular. Sua incidencia varia entre 0,06 a 0,21 por cento nos achados de autopsia e corresponde a 5 por cento de todos os tumores malignos do trato gastrintestinal. Seu diagnostico preciso e precoce e fundamental para a decisao terapeutica, principalmente por apresentar o prognostico mais favoravel comparado as outras neoplasias periampulares. No entanto, o diagnostico obtido pela duodenoscopia nem sempre e confirmado pelo exame da biopsia endoscopica, em razao da dificuldade de diferenciar lesoes nao invasivas de carcinomas, mesmo por patologistas experientes. O objetivo deste trabalho foi avaliar o valor e a limitacao da duodenoscopia e da biopsia endoscopica no diagnostico do cancer de papila duodenal maior. Analisou-se retrospectivamente 30 doentes com suspeita de carcinoma de papila, sendo 11 do sexo feminino e 19 do sexo masculino; a idade variou de 39 a 71 anos, sendo a media de 55,7 anos. Todos os doentes foram submetidos a duodenopancreatectomia parcial, sendo o exame da peca operatoria o padrao ouro para a analise do valor dos testes. A acuracia e a sensibilidade da duodenoscopia para malignidade foram de 83,3 por cento e 86,2 por cento respectivamente, enquanto a acuracia e a sensibilidade da biopsia endoscopica foi de 66,6 por cento e 65,5 por cento. Ao comparar os metodos de diagnostico, nao houve diferenca significante entre a concordancia e a discordancia da duodenoscopia e da biopsia endoscopica / Carcinoma of the papilla of Vater is classified as periampullary cancer; 5% of all gastrointestinal tract malignant. Early and accurate diagnosis is important for those patients with tumor of the papilla as the prognosis is more favorable than others periampulary neoplasms. Endoscopically obtained biopsies from suspicious papillas can establish an early and immediate preoperative diagnosis, although even for skilled pathologists it is difficult to distinguish carcinomas from non-invasive lesions on the basis of forceps biopsies. The purpose of this study was to asses the preoperative diagnostic accuracy of duodenoscopy appearance and biopsy in all suspicious of tumor. Thirty patients with suspicious of carcinoma of the papilla of Vater and with final diagnosis established by Whipple’s procedure were included in this retrospectively study. In each case, a comparison was made between endoscopic biopsy and duodenoscopy appearance. A final diagnosis was established by surgical specimen. After surgery the resected tumors of the papilla of Vater were definitely diagnosed as adenocarcinomas in 96.7% (29 patients) and inflammatory non-neoplastic lesion in 3.3% (01 patient). Duodenoscopic appearance accuracy for malignancy was 83,32%. One case was diagnosed falsely as positive by duodenoscopy appearence. Endoscopic biopsy accuracy was 66,6%. When we compared both methods, we noticed that concordance value was 50%. / BV UNIFESP: Teses e dissertações

Hyperactive Wnt signaling is the seminal event in colorectal cancer (CRC) pathogenesis, where β-catenin serves as a key Wnt mediator enhancing CRC cell proliferation and survival. c-Cbl is a unique E3 ligase, which degrades both mutant and active (tumorigenic) β-catenin. c-Cbl phosphorylation at tyrosine 731 (Y731) regulates its binding and down regulation of β-catenin specifically in the presence of Wnt ligand (Wnt-on state). Since aberrant Wnt signaling activation is found in almost all cases of human CRC, it would be critical to understand the influence of c-Cbl phosphorylation on CRC cell survival. We hypothesized that c-Cbl phosphorylation regulates CRC cell survival in a Wnt dependent manner, a state that is mediated through mutations in β-catenin or adenomatosis polyposis coli (APC). Cbl phosphorylation was examined in a panel of Wnt-off cells with wild-type β-catenin and APC CRC cell line (RKO cell line) and Wnt-on cell lines with mutant APC (Wnt-on- DLD1, HCT15 cell line) or mutant β-catenin (HCT116) using phospho-specific antibodies to c-Cbl tyrosine residues at 700 (Y700), 731 and 774 (Y774) positions. Biological significance of specific phosphorylation sites was evaluated with phospho-inactive mutants of c-Cbl (Y700F, Y731F and Y774F) using both the MTT cell proliferation assay and the non-adherent colony formation assay. Potential meditators of c-Cbl were examined using immunoblotting. Here we show that c-Cbl was phosphorylated at all three major phosphorylation sites (Y700, Y731 and Y774) in both Wnt-off and Wnt-on CRC cell lines. However, the amount of phosphorylation was reduced in Wnt-on CRC cell lines (DLD1, HCT116 and HCT15) compared to Wnt-off (RKO) cell line. Wild-type c-Cbl significantly enhanced survival in RKO cell lines and reduced survivability in DLD1 cell lines. In contrast to the effect of wild-type c-Cbl, Y731F increased CRC cell survival and non-adherent colony forming units. Our preliminary data suggests that c-Cbl Y731 mutation regulates CRC survival through β-catenin. c-Cbl is heavily phosphorylated in CRC cell lines, where wild-type c-Cbl significantly inhibits cell survival in Wnt-on and enhances cell survival in Wnt-off CRC cell lines. Furthermore, our data indicates that Y731 influences CRC survival and colony formation only in Wnt-on cell lines. Though further validation is required, this dichotomy in the effect of c-Cbl phosphorylation on CRC survival being mediated by Wnt status can be further explored as a potentially novel therapeutic target in mutant CRC tumors, which represent more than 90% of CRC cases in humans.

Perineural invasion (PNI) in cutaneous squamous cell carcinoma (cSCC) and desmoplastic melanoma (DM) may be a negative prognostic finding, and likely contributes to increased rates of local recurrence. The biological mechanisms underlying PNI remain unclear, although several lines of evidence implicate neurotrophins and their receptors. Expression of the high affinity nerve growth factor (NGF) receptor TrkA has been shown to be associated with PNI in numerous malignancies, although literature in cutaneous neoplasms is sparse. Given this, we sought to ascertain the incidence of PNI in a cohort cSCCs using double immunostaining (DIS), and to investigate PNI's relationship with TrkA expression and established histopathologic prognosticators. In DMs we investigated the relationship between TrkA and PNI. In DM we additionally analyzed expression of the low affinity NGF receptor (p75NGFR) and the presence of a functional polymorphism in the glial cell line-derived neurotrophic factor (GDNF) receptor RET (RETp) as they relate to PNI. In this IRB approved study, cSCCs from the head and neck (H&N) and 53 from non-H&N areas were immunohistochemically analyzed for PNI (DIS with S100 and p63) and TrkA expression. For DM, 43 cases were immunohistochemically evaluated for TrkA and p75NGFR expression while RETp was detected by direct DNA sequencing. The presence of each was correlated with histologically observed PNI. In cSCCs, comparing H&N versus non-H&N areas; using hemotoxylin and eosin (H&E) PNI was detected in 11% versus 6% of cases respectively and using DIS, in 23% versus 15% respectively, with significant disagreement between both methods (𝜅=0.47, p=0.002). There was a 2.33 fold increase in PNI detection with DIS compared to H&E (95%CI: 1.12-4.87; p=0.02). TrkA expression was 2.9 times more frequently observed in cSCCs from the H&N compared to those from non-H&N areas (p=0.01). Regardless of site, TrkA expression was associated with decreased degree of differentiation (OR=6.46, p=0.0006) and high-risk morphologic variants (OR = 6.53, p=0.002). TrkA expression was not significantly associated with PNI (p=0.33). In DM, PNI was present in 67% of cases. On univariate analysis; p75NGFR was associated with PNI (expression detected in 79% of PNI-positive cases compared to 36% of PNI-negative cases, p=0.005), increased Breslow's depth and greater Clark's Level (p= 0.007 and p= 0.01 respectively). RETp was noted in 28% of cases but was not significantly associated with PNI (p=0.27) or other histopathologic variables. TrkA expression was absent in all cases. PNI was associated with increased Breslow's depth and Clark's Level (p=0.01 and p=0.009 respectively). Controlling for the association between p75NGFR and depth, p75NGFR remained associated with an increased propensity for PNI (OR=4.68, p=0.04). In conclusion, increased PNI detection with DIS in cSCCs underscores the adjunctive utility of immunohistochemistry in microstaging. Although unlikely to play a role in the development of PNI, TrkA's association with cSCCs from H&N and select histopathologic parameters suggests a role for the NGF-TrKA axis in tumorogenesis while its absent expression in DM suggests that expression is lineage-related. Lastly, In DM, p75NGFR expression is significantly associated with PNI and a more locally aggressive phenotype.

PURPOSE: HCC is a complicated disease with high mortality rates and limited treatment options. No universal clinical or molecular classification established to inform better treatment options. There has been very limited success in determining a molecular profile that represent valid drivers in HCC patients and thus no targeted agents have obtained marketing approval. However, emerging data suggest the FGF19-pathway as a HCC driver and a potential therapeutic target. This research study aims to investigate whether the HCC prognostic risk factor, serum AFP, is predictive of FGF19 protein expression as assessed by immunohistochemistry in advanced HCC patients. METHODS: A cross-sectional analysis was performed from baseline data collected in a Phase 1 study conducted at various centers across the US, EU, and Asia. Only advanced HCC patients with adequate liver function were eligible for enrollment. Demographic data, detailed history of HCC, and any prior treatments or surgeries were recorded. Baseline laboratory values and prognostic factors including performance status (ECOG), lab values (i.e. bilirubin, albumin), and the number, size and biomarker status of the tumor(s) were collected. Differences between groups were assessed by t test, or Chi-square test, as appropriate. Multivariate logistic stepwise regression analyses were performed including all parameters with highly significant correlations in the multivariate analysis. RESULTS: Only AFP, metastatic disease, and prior surgery met the criteria to be incorporated into the final model. Results indicated that high AFP had a statistically significant (p-value = .01) positive association (Wald chi-square statistic = 6.601) with positive FGF19 IHC status. The odds ratio for being FGF19 IHC+ was 12.216 among the high AFP subjects as compared to low AFP subjects, and also statistically significant but had a very wide 95% confidence interval (1.811, 82.79). CONCLUSIONS: The results indicated that HCC patients with high serum AFP levels have a twelve fold higher chance of having a positive FGF19 IHC status than those with low AFP levels. Further studies are warranted in order to replicate the data in a larger sample size to understand future clinical implications once treatment options become available for FGF19 IHC positive patients.

Trabajo de Investigación Requisito para optar al Título de Cirujano Dentista / Autor no autoriza el acceso a texto completo de su documento / El carcinoma oral de células escamosas (COCE) es la neoplasia maligna más frecuente de cavidad oral. La presentación de COCE en individuos sin los factores de riesgo más fuertemente asociados, como el tabaquismo y consumo de alcohol, ha estimulado la búsqueda de nuevos elementos desencadenantes. Estudios recientes han descrito un posible rol etiológico del virus papiloma humano (VPH) en cánceres de cabeza y cuello. En carcinomas orales este rol aún es controversial. COCE se caracteriza por alta tasa de invasión y metástasis, describiéndose que tanto el aumento de la vascularización del tumor como la expresión de factores proangiogénicos estarían asociados a mal pronóstico. Las metaloproteinasas de matriz (MMP) están implicadas en este proceso. Estudios señalan MMP-9, como un factor clave dentro del proceso de angiogénesis. Se cree que proteínas virales del VPH interactuarían directamente con el gen promotor de MMP-9, aumentando su expresión y por tanto, favoreciendo el crecimiento tumoral. El objetivo de este estudio fue determinar una posible asociación entre la presencia de VPH y la sobreexpresión de MMP-9 en células neoplásicas de COCE. Se seleccionaron 50 casos de COCE registrados en el Servicio de Anatomía Patológica de la Facultad de Odontología de la Universidad de Chile y del Instituto Nacional del Cáncer. La presencia de VPH fue detectada a través de PCR convencional y la detección de MMP-9 mediante inmunohistoquímica. Los análisis estadísticos se realizaron mediante el software Stata 11.0. De un total de 50 casos analizados, 10 (20%) resultaron positivos en la detección de VPH. La inmunomarcación positiva para MMP-9 estuvo presente en los 50 casos de COCE evaluados (100%), con un porcentaje de marcación promedio de 79,8%. La prevalencia del VPH en muestras de COCE fue similar a lo reportado en la literatura, al igual que el promedio de inmunomarcación para MMP-9. No hubo asociación entre COCE VPH positivo con mayor inmunotinción para MMP-9, sin embargo, las muestras COCE VPH negativas presentaron una asociación estadísticamente significativa con una menor inmunomarcación para MMP-9. Nuestros resultados sugieren que la ausencia de VPH disminuiría la expresión de MMP-9 en COCE.

Magister Scientiae Dentium - MSc(Dent) / Background: Recent epidemiological reports established that there is an increase in the incidence of oral squamous cell carcinoma in young patients. Some report this to be in the absence of contributing habits such as smoking and alcohol use. Few reports of such a nature have reported a similar trend in South Africa. Aim: Describe the epidemiological pattern of oral squamous cell carcinoma seen at the Tygerberg academic complex. Method: Histopathological biopsy reports of patients diagnosed by the oral pathology department of Tygerberg hospital from 1996 to 2013 were electronically retrieved and included. Patients were grouped by age into two groups, one included patients 40 years and younger, the other included patients older than 40 years. Descriptive analysis was performed for age, sex, smoking and alcohol habits and oral site of tumor. Frequency of OSCC patients was calculated manually from the total number of oral biopsies. Chi- square or Fisher’s exact tests were used as appropriate. Probabilities of less than 0.05 were regarded as significant. Results: The total number of OSCC patients over the 18-year period was 2220. The mean age was 57.6years.The male to female ratio was 2.9:1 for all age groups and 2.2:1 for young patients. The majority of patients (96%) were above 40 years old. Smoking and alcohol were commonly reported for all age groups (91.3%) and (83.8%) for young patients. The tongue was the commonest site for all age groups (30.8%) followed by oropharynx (27.3%) while in younger patients, the oropharynx was the commonest site (30.3%) followed by tongue (29.2%). Conclusion: The study confirmed that OSCC is still an affliction of people older than 40 years and males are predominantly affected. Smoking and alcohol are strong risk factors for OSCC irrespective of patient's age. OSCC among people older than 40 years may have no great difference from the same disease affecting younger ones in terms of sex, oral habits and tumor site.

O carcinoma medular de tireóide (CMT) é uma neoplasia maligna rara, ocorrendo na forma esporádica ou hereditária. Mutações germinativas no protooncogene RET são responsáveis pelo CMT hereditário. No entanto, a maioria dos casos de CMT ocorre em indivíduos sem história familiar, na qual a patogênese da doença ainda é pouco compreendida. Os polimorfismos do gene RET são descritos na população geral assim como em pacientes com CMT. Embora, estas variações alélicas aparentemente não confiram qualquer atividade transformadora no receptor RET, estudos sugerem que essas alterações genéticas podem modificar a suscetibilidade à doença e o fenótipo clínico em pacientes com CMT esporádico ou hereditário. Uma maior freqüência dos polimorfismos localizados nos exons 11 (G691S), 13 (L769L), 14 (S836S) e 15 (S904) é descrita em pacientes com CMT provenientes de países Americanos e Europeus. Na presente revisão, analisamos criticamente os resultados obtidos nos diferentes estudos e descrevemos a freqüência dos polimorfismos do RET em pacientes Brasileiros com CMT esporádico. / Medullary thyroid carcinoma (MTC) is a rare malignant neoplasia, which may occur on sporadic form or on a hereditary basis. Germ line mutations in the RET proto-oncogene is responsible for hereditary MTC. However, most MTC occur in individuals without family history where the pathogenesis is still unclear. Single nucleotide polymorphisms (SNPs) of the RET gene have been described in the general population as well as in patients with MTC. Even though these allelic variants do not seem to confer any transforming activity to the tyrosine kinase domain of the RET protein, cumulative studies suggest that they could modify disease susceptibility and clinical phenotype in patients with sporadic or hereditary MTC. Polymorphisms located in exon 11 (G691S) 13 (L769L), 14 (S836S) and 15 (S904S) seem to be over-represented in sporadic MTC patients from American and European countries. Here, we discuss the results obtained in different studies as well as describe the frequency of RET polymorphisms in Brazilian patients with sporadic MTC.