京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22368号 / 医博第4609号 / 新制||医||1043(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙折 晃史, 教授 松田 文彦, 教授 滝田 順子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Objective. To assess the acceptability of cervical screening using direct visual inspection after acetic acid application followed by immediate cryotherapy for cervical intraepithelial neoplasia among women in rural Guatemala. Materials and Methods. An unselected group of 1,052 women voluntarily registered to undergo cervical screening using direct visual inspection of the cervix after acetic acid application. Women with acetowhite changes consistent with cervical intraepithelial neoplasia were offered immediate cryotherapy. Results. Cervical screening was deferred in 80 (7.6%) registrants, and 18 (1.7%) refused to undergo an examination. Among the 954 registrants screened, 125 (13%) had findings consistent with cervical intraepithelial neoplasia. Cryotherapy was deferred in three patients. A total of 121 (99%) women agreed to immediate cryotherapy. Conclusion. Direct cervical visualization after acetic acid application followed by immediate cryotherapy for acetowhite changes consistent with cervical intraepithelial neoplasia would be a well-accepted method of cervical screening in rural Guatemala.

Cancer is a leading cause of mortality in the United States. Despite much research on specific carcinogens, the cause of many cancers remains unclear. The identification of novel causative agents offers the potential for cancer prevention. Diseases such as obesity and diabetes mellitus, characterized by hyperinsulinemia, are associated with increased risk of endometrial, colorectal, and breast carcinomas. There is increasing evidence that insulin is a growth factor for tumor formation. The mechanisms underlying insulin-mediated neoplasia may include enhanced DNA synthesis with resultant tumor cell growth, inhibition of apoptosis, and altered sex hormone milieu. The reduced insulin levels seen with physical activity, weight loss, and a high fiber diet may account for decreased cancer risk. The role of newer drugs that restore sensitivity to insulin, thereby reducing hyperinsulinemia, is an exciting potential area of cancer prevention. In this review, we discuss the potential role of insulin as a tumor growth factor.

Background/aims Conjunctival squamous cell carcinoma (CSCC) is the most frequent malignant tumour of the conjunctiva, with scarce recurrence and infrequent metastasis. The purpose of this study is to describe the clinical and pathological characteristics of this neoplasm and to identify the prognostic factors for recurrence and metastasis in a cancer hospital in Peru. Materials and method A longitudinal, retrospective study of 176 consecutive patients diagnosed with SCC of the conjunctiva. Sociodemographic and clinical characteristics were evaluated. In addition, Kaplan-Meier curves were performed, and Cox regression was used to determine prognostic factors for recurrence and metastasis over time. Result Only 12.5% presented tumour size ≤5 mm. The highest proportion according to the histopathological type was the well-differentiated infiltrative forms (40.9%), and according to tumour, node, metastases (TNM), stage T3 was the most frequent (31.3%). The most performed initial treatment was orbital exenteration (38.6%). The proportion of recurrence was 6.8% and 8.0% for metastasis. The annual survival rate was 7% and the annual metastasis rate was 6%; for recurrence after 5 years, the survival rate was 11% and the metastasis rate was 14%. No prognostic factor evaluated was significant. Conclusion This is the most extensive patient study in Latin America with CSCC, with a high proportion of advanced histopathological grade, TNM stages, and radical treatments such as exenteration. Recurrence rates on average are similar to other reported studies, and it describes the rates of metastasis that have been poorly described in the literature. / Revisión por pares

In the normal ectocervix, mitoses are rare and are usually confined to the basal layers. In contrast, they occur more frequently in cervical intraepithelial neoplasia (CIN) and are seen at higher levels, suggesting that CIN may be associated with a progressive dysfunction in proliferative activity of cervical cells. The objective of this study was to use proliferating cell nuclear antigen (PCNA) immunohistochemistry to examine the proliferative activity of cervical epithelial cells in CIN lesions. Sixty- eight cervical biopsies were examined; 20 were totally benign, 14 had CIN I, 21 CIN II, and 13 CIN III. In benign epithelia, PCNA staining was usually confined to the basal layers, whereas in CIN the staining was seen at progressively higher levels of the epithelium. There was a statistically significant correlation between the CIN grade and the highest level of PCNA staining (PCNA grade, r = 0.746, P < 0.001). In addition, the PCNA grade showed significant correlation with the highest level at which mitoses were seen (mitosis grade, r = 0.706, P < 0.001), and a strong direct correlation between the mitosis and CIN grades was also observed (r = 0.955, P < 0.001). These data demonstrate that (1) PCNA immunoreactivity in neoplastic cervical epithelium is different from that seen in the normal cervix, suggesting that CIN is associated with a dysfunctional proliferation of cervical epithelium, (2) that there is a significant correlation between the PCNA grade and CIN grades, and (3) the 'mitosis grades' have a strong correlation with the CIN grades.

INTRODUÇÃO: A imensa maioria dos casos com Neoplasia Endócrina Múltipla Tipo 2 (NEM2) é causada por uma única mutação germinativa no proto-oncogene RET. Entretanto, há alguns poucos casos descritos na literatura (~16) que apresentam duplas mutações/polimorfismos no gene RET, geralmente associados a fenótipos atípicos. OBJETIVOS: Os objetivos deste projeto são: a) caracterizar os aspectos clínicos de pacientes advindos de cinco famílias não relacionadas com diagnóstico de NEM2A, nas quais se documentou a presença de uma nova dupla mutação germinativa RET nos códons 634 e 791 e b) realizar rastreamento gênico familiar dos casos sob-risco com a finalidade de identificarmos possíveis casos com esta nova mutação. PACIENTES: Cinco casos-índice foram recentemente descobertos albergando a dupla mutação germinativa RET C634Y/Y791F. Nestas famílias há relato de 208 parentes, potencialmente, sob-risco (~50%) de serem portadores desta mutação. Dentre estes 208 indivíduos, 81 (38,9%) aceitaram participar do rastreamento gênico. MÉTODOS: O estudo foi realizado na Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. O DNA do sangue periférico dos pacientes e de seus parentes sob- risco foi obtido após a obtenção do consentimento livre e esclarecido. Após PCR, foi realizado o sequenciamento gênico direto (ABI 3130x/l Sequencer, Applied Biosystems), abrangendo todos os 20 éxons do RET. Foram investigados potenciais polimorfismos e mutações no RET. Os tumores NEM2-relacionados (carcinoma medular de tireoide, CMT; feocromocitoma, FEO; hiperparatireoidismo primário, HPT) foram estudados quanto a vários parâmetros clínicos, como: sinais/sintomas; dimensão, penetrância e agressividade dos tumores; porcentagem de remissão bioquímica do CMT, e recidiva ou persistência dos tumores. RESULTADOS: Dentre os 81 indivíduos que participaram do rastreamento gênico, documentamos 28 casos (34,5%) como portadores da dupla mutação RET C634Y/Y791F. Além disso, as mutações foram testadas in vitro e um gene de efeito fundador foi descartado. Observou-se que: a) os cinco casos-índice (100%) com mutação germinativa RET C634Y/Y791F apresentaram FEO com características tais como, tumores medindo acima de 5,0 cm, e quatro dentre os cinco casos (80%) tiveram o diagnóstico com idades inferiores a 35 anos. A frequência de FEO nos parentes adultos (a partir da terceira década) foi de 73% e eram bilaterais em 80%; b) as características do CMT nos afetados albergando a mutação RET 634/791 eram similares às que ocorrem em pacientes com a mutação 634 isolada. Adicionalmente, estudo in vitro desta dupla mutação revelou que o grau de fosforilação das células com a dupla mutação celular 634/791 era significativamente maior (p=0,04), quando comparada com a capacidade fosforilativa das mutações 634 e 791 avaliadas individualmente. CONCLUSÃO: Diante dos presentes achados, conclui-se que os pacientes com esta nova dupla mutação tenderam a apresentar FEO de maior agressividade (precocidade, tumores volumosos e bilaterais), enquanto que o CMT, nestes casos, apresentava características usuais aos portadores de mutação RET no códon 634. A nossa hipótese é que os achados relativos ao FEO, nos presentes pacientes, foram influenciados pela presença da segunda mutação RET Y791F, a qual teria atuado como fator modulador do fenótipo. Esta hipótese foi suportada pelos estudos in vitro. Além disso, a ausência de um efeito fundador levou-nos a prever que esta dupla mutação RET pode não ser rara, na área geográfica estudada. Ainda que estes achados devam ser validados, os presentes dados podem ser úteis no diagnóstico genético e no manejo clínico e terapêutico dos pacientes com NEM2A / INTRODUCTION: The vast majority of cases with multiple endocrine neoplasia type 2A (MEN2A) is caused by a single germline mutation in the RET proto-oncogene. However, some instances (~16) of double germline RET mutations have been reported, most frequently associated with atypical phenotypes. OBJECTIVES: The main goals of this project were: a) to characterize the phenotype of patients from five unrelated MEN2A families harboring a new RET double germline in codons 634 and 791; b) perform the genetic screening in at-risk family members attempting to search for new similarly affected cases. PATIENTS: Five affected index-cases were recently found with this new double RET mutation C634Y/Y791F. In these five families, 208 first-degree relatives were reported and they were at-risk (~50%) to develop this mutation. Eighty-one individuals out of the 208 at-risk relatives (38.9%) were available and signed the informed consent. METHODS: The present investigation was performed at the Department of Endocrinology, School of Medicine, University of São Paulo. DNA was obtained from the peripheral blood of patients and at-risk relatives, after obtaining the informed consent of all individuals. After PCR, the direct genetic sequence was performed (ABI 3130x/l Sequencer, Applied Biosystems), involving all 20 exons of the RET proto-oncogene. Potential mutations and polymorphisms were investigated. In addition, the mutations were tested in vitro and a potential founder effect was evaluated. The MEN2A- related tumors (medullary thyroid carcinoma, MTC; pheochromocytoma, PHEO; and primary hyperparathyroidism, HPT) were approached using several clinical parameters, as: signs and symptoms; age at the diagnosis; tumor size and aggressiveness; biochemical remission of MTC; tumor relapse or persistence; RESULTS: Within the 81 genetically screened individuals, 28 cases (34.5%) were documented harboring the RET C634Y/Y791F germline mutation. It was observed that: a) the five affected index-cases (100%) were presented with PHEOs with features such as tumors measuring more than 5.0cm, and four out of the five cases (80%) had this diagnosis under the age of 35 years old. The frequency of PHEO in the adult affected relatives was also high (73%), from the third decade on, and were bilateral in 80%; b) the features and outcome of MTC in the affected C634Y/Y791F cases were similar to those MEN2A cases harboring the RET 634 mutation only. In addition, in vitro studies verified that cells with the 634/791 mutation had a significantly higher capacity of phosphorylation than cells harboring each individual mutation (p=0.04). Also, a founding gene was ruled out in these families. CONCLUSION: Our present data indicated that the earlier and more aggressive PHEOs seen in the present cases were most probably due to a phenotype modulation of the second RET 791 mutation. This hypothesis was supported by data from in vitro studies. Also, the absence of a founding couple led us to predict that this double RET mutation may not be rare, in the studied geographic area. Although these findings need to be validated, the present data may be useful in the genetic diagnosis as well as in the clinical and therapeutic management of MEN2A

O cão é a única espécie, além do homem, em que o câncer de próstata (CP), a neoplasia intraepitelial prostática (PIN) e a hiperplasia prostática benigna (HPB) ocorrem espontaneamente, permitindo dessa forma que se realize estudo comparativo de afecções benignas e malignas da próstata. Acredita-se que a existência de stem cells malignas, localizadas na camada de células basais da próstata, seja um dos fatores responsáveis pelo insucesso da terapia por ablação androgênica que ocorre na maioria dos carcinomas prostáticos avançados. O objetivo deste estudo foi caracterizar a próstata canina quanto a aspectos envolvidos na evolução para o carcinoma prostático, tentando identificar a origem celular e as alterações das lesões pré-neoplásicas. Foram obtidas 44 próstatas na necrópsia. Amostras prostáticas foram fixadas em metacarne, embebidas em parafina e seccionadas a 5µm para a coloração com hematoxilina eosina (HE) e avaliadas em relação à presença de hiperplasia, prostatite, PIN e neoplasia. Além disso, cortes corados em HE representando cada afecção foram utilizados na determinação da área nuclear média por morfometria computadorizada. Cortes histológicos obtidos em lâminas silanizadas foram utilizados na imunoistoquímica para células basais (p63 e 34E-12), conexinas 32 e 43, receptor de andrógeno (AR) e antígeno nuclear de proliferação celular (PCNA). Amostras foram coletadas também em nitrogênio líquido e mantidas a 80o C para a realização do PCR quantitativo em tempo real, para a determinação da expressão do RNAm do AR, e para a realização do Western blot, para a determinação da expressão da conexina 43. As afecções mais freqüentes foram a prostatite e a hiperplasia prostática benigna. Foi observada uma maior porcentagem de células basais e um alto índice proliferativo, como demonstrado pela imunoistoquímica para o PCNA, na neoplasia intraepitelial prostática. Além disso, observou-se nessas lesões marcação nuclear heterogênea para o AR, menor em relação à dos ácinos benignos. Ao contrário do observado na próstata humana, não foi observada expressão das conexinas 32 e 43 na próstata canina (normal ou com PIN). A área nuclear média, obtida pela morfometria computadorizada, foi maior em células epiteliais de ácinos apresentando PIN e/ou neoplasia em relação à de células epiteliais de ácinos benignos. Observou-se expressão variável do RNAm para o AR nas PINs e neoplasias, utilizando-se o PCR em tempo real. Estes achados sugerem que células basais malignas desempenham papel na origem da neoplasia intraepitelial prostática e possuem capacidade de proliferar a despeito da expressão heterogênea do receptor de andrógeno. / Dogs are the only animal other than man to develop prostate cancer, prostatic intraepithelial neoplasia (PIN) and benign prostatic hyperplasia (HPB) spontaneously, allowing the comparison between benign and malignat affections of prostate. Malignant stem cells among the basal cell layer of the prostate are believed to play an important role in the failure of androgen-ablation therapy that occurs in most advanced prostate cancer. The goal of this study was to characterize the canine prostate in relation to evolution to prostatic carcinoma, trying to identify the cellular origin and the alterations of pre-neoplastic lesions. Forty-four canine prostates were obtained at necropsy. Prostatic samples were fixed in methacarn, embedded in paraffin wax and sectioned into 5µm-thick slices for hematoxylin eosin (HE) staining and evaluated for the presence of hyperplasia, prostatitis, PIN and neoplasia. Moreover, HE stained sections representing each affection were used to determine the mean nuclear area by computerized morphometry. Tissue sections obtained in silanized slides were used in immunohistochemical staining for basal cells (p63 and 34E-12), connexins 32 and 43, androgen receptor (AR) and proliferating-cell nuclear antigen (PCNA). Quantitative real-time PCR to determine the expression level of AR at the mRNA level and Western blot to protein levels of connexin 43 were examined in samples collected using liquid nitrogen and kept at 80o C. The most common lesions were prostatitis and benign prostatic hyperplasia. The prostatic intraepithelial neoplasia exhibited a higher percent of basal cells and was highly proliferative, as demonstrated by PCNA immunohistochemistry. Moreover, these lesions exhibited heterogeneous nuclear AR staining, lower in comparision with benign acini. In contrast to human prostate, the canine prostate (normal or harboring PIN) did not express the connexins 32 and 43. The mean nuclear area measured by computerized morphometry was greater in epithelial cells of PIN and neoplastic acini than that of benign acini. We found variable RNAm AR expression in prostatic intraepithelial neoplasia and neoplasia by real-time PCR. These findings suggest that malignant basal cells may play a role in the origin of PIN and can proliferate despite the heterogeneous AR expression.

Introdução: Além do catabolismo protéico acentuado, o paciente com câncer apresenta alterações no metabolismo lipídico. Objetivo: o objetivo do estudo foi avaliar as concentrações séricas de ácidos graxos (AG) antes, durante e após o tratamento oncológico de pacientes com neoplasia de estômago ou de esôfago. Casuística: O estudo prospectivo longitudinal foi conduzido com 14 pacientes com neoplasia de estômago ou de esôfago [62,1 anos (IC95% 55,6-68,6)], sob tratamento oncológico em unidade especializada. O estudo incluiu também 15 voluntários saudáveis [61,0 anos (IC95% 57,1-65,0)]. Métodos: Foram aplicados os questionários de ingestão alimentar (Recordatórios de 24h) e inquéritos relacionados com efeitos adversos e de toxicidade (CTCAE) que potencialmente interferem na ingestão alimentar e no estado nutricional. Foram feitas as medidas antropométricas, a impedância bioelétrica e coleta de sangue para os exames laboratoriais. Os AG foram determinados por cromatografia gasosa e expressos como porcentagem da área total. No Grupo Câncer, os procedimentos foram feitos antes do início, na metade e ao término do tratamento oncológico; o Grupo Controle foi submetido às mesmas avaliações em apenas uma ocasião. A análise estatística foi feita por meio do software Statistica 8.0, usando testes estatísticos não paramétricos. Resultados: As reações adversas relacionadas ao tratamento oncológico foram redução da ingestão de alimentos, saliva espessa com alteração no paladar e náuseas. Antes do início do tratamento, os pacientes com câncer já haviam perdido 17% do peso em relação ao usual; o peso corporal e o IMC reduziram entre a primeira e a terceira avaliação, mas não houve alteração na composição de massa corporal magra e gorda, na ingestão energética e da maioria dos macronutrientes no decorrer do estudo. Em relação ao Grupo Controle, o ácido nervônico foi maior enquanto que os ácidos gama-linolênico e alfalinolênico foram menores no Grupo Câncer. Na avaliação longitudinal, o ácido lignocérico reduziu durante o tratamento oncológico. Conclusão: os pacientes com câncer de esôfago e de estômago apresentam alteração discreta na concentração dos AG séricos em relação aos controles e o tratamento oncológico teve pouco impacto no perfil de AG circulantes / Introduction: In addition to enhanced protein catabolism, the cancer patient has alterations in lipid metabolism. Objective: The objective of the study was to evaluate serum concentrations of fatty acids (FA) before, during and after cancer treatment of patients with gastric or esophageal cancer. Subjects: The prospective longitudinal study was conducted with 14 patients with gastric or esophageal cancer [62.1 years (95% CI 55.6 to 68.6)], under cancer treatment in a specialized unit. The study also included 15 healthy volunteers [61.0 years (95% CI 57.1 to 65.0)]. Methods: The food intake questionnaires were applied (24-hour Dietary Recall) and inquiries related adverse effects and toxicity (CTCAE) that potentially interfere with food intake and nutritional status. Anthropometric measurements were made, the bioelectrical impedance and blood collection for laboratory tests. Gas chromatography determined the FA that was expressed as a percentage of the total area. In Cancer Group, the procedures were done before the start, the middle and at the end of cancer treatment; the control group underwent the same evaluations on only one occasion. Statistical analysis was performed using Statistica 8.0 software, using non-parametric statistical tests. Results: Adverse reactions related to cancer treatment have been reduced food intake, thick saliva with altered taste and nausea. Before the treatment, the patients with cancer had already lost 17% of weight with respect to the usual. Body weight and BMI reduced between the first and the third evaluation, but there was no change in the composition of lean and fat mass, energy intake and macronutrient most during the study. Compared to the control group, the nervonic acid was higher while the gamma-linolenic and alpha-linolenic acids were lower in the cancer group. In the longitudinal evaluation, the lignoceric acid reduced during cancer treatment. Conclusion: Patients with esophageal and stomach cancer have a mild change in the concentration of serum FA compared to controls and cancer treatment had little impact on the current FA profile

Introdução: Fadiga em mulheres com câncer de mama pode ser frequente, acentuada e levar a prejuízos na funcionalidade e sofrimento. No entanto, é pouco explorada na população brasileira. Objetivo: Estimar a prevalência de fadiga e analisar os fatores relacionados ao sintoma em mulheres com câncer de mama. Método: Estudo transversal com amostra não probabilística constituída por 163 mulheres com câncer de mama em acompanhamento ambulatorial (idade média de 51,7 anos, escolaridade média de 13,6 anos de estudo e, 23,4% apresentaram tumor em estádio IV). Os dados foram coletados na cidade de São Paulo, no período de julho de 2006 a abril de 2008, em três serviços de oncologia, sendo um público e dois privados. A fadiga, variável dependente do estudo, foi avaliada por meio da Escala de Fadiga de Piper Revisada (0-10). As variáveis independentes foram idade, escolaridade, situação marital, trabalho remunerado, renda familiar, estadiamento do câncer, tratamento atual para o câncer, níveis de hemoglobina, índice de massa corporal, depressão, capacidade funcional, presença e intensidade de dor e alteração do sono. Resultados: Fadiga foi definida como aquela com escore 4. A prevalência do sintoma foi de 31,9% [IC95%: 24,8 39,6] e a intensidade média foi 6,0 (DP=1,3). Na análise univariada,observou-se que cinco, das 18 variáveis independentes testadas, foram identificadas como fatores de risco para a fadiga em mulheres com câncer de mama: nível de hemoglobina, capacidade funcional, depressão, dor e prejuízo do sono. No entanto, na análise de regressão múltipla, apenas dor e depressão foram fatores independentemente associados à fadiga em mulheres com câncer de mama. As mulheres com dor apresentaram chance 12% maior de apresentar fadiga em comparação àquelas pacientes sem dor. As mulheres com depressão apresentaram chance 6% maior de ter fadiga em comparação às pacientes sem essa morbidade. Conclusão: A prevalência de fadiga foi elevada e, visto que se adotou critério rígido para se definir fadiga (aquela com escore 4), pode-se assumir que o sintoma era clinicamente relevante. Fadiga associou-se com prejuízo do sono, dor, depressão e capacidade funcional, mas apenas dor e depressão foram preditores independentes confirmando a complexidade do sintoma e a existência de um cluster de sintomas. O controle da fadiga é pouco conhecido, mas depressão e dor são sintomas passíveis de modificação na prática clínica. Assim, talvez seja possível algum alívio da fadiga por meio do tratamento da dor e da depressão. Esses resultados podem contribuir no manejo de sintomas prevalentes em pacientes com câncer de mama, visando minorar o desconforto, melhorar o bem estar e a qualidade de vida dessa população. / Introduction: Fatigue in women with breast cancer can be frequent, accentuated and lead to prejudices in the functionality and suffering. However, is little explored in the Brazilian population. Objective: To estimate the fatigue prevalence and analyze the factors related to the symptom in women with breast cancer. Method: Transversal study with sample non probabilistic constituted by 163 women with breast cancer in ambulatory follow-up (mean age of 51.7years, mean schooling of 13.6 years of study and, 23.4% presented tumor in IV stage). The data were collected at São Paulo city, in the period of July of 2006 to April of 2008, in three services of oncology, being one public and two private. The fatigue, dependent variable of the study, was evaluated by means of the Piper Fatigue Scale Reviewed (0-10). The independent variables were age, schooling, marital situation, remunerated work, familiar income, staging of the cancer, present treatment for cancer, levels of hemoglobin, body mass index, depression, functional capacity, presence and intensity of pain and sleep alteration. Results: Fatigue was defined as that with score 4. The prevalence of the symptom was 31.9% [IC95%: 24.8 39.6] and the mean intensity was 6.0 (DP=1.3). In the univariate analysis, it observed that five, of the 18 independent variables, were identified as risk factors for the fatigue in women with breast cancer: level of hemoglobin, functional capacity, depression, pain and sleep prejudice. However, in the multiple regression analysis, only pain and depression were factors independently associated to the fatigue in women with breast cancer. The women with pain presented chance 12% greater of presenting fatigue in comparison to those without pain. The women with depression presented chance 6% greater of having fatigue in comparison to the patients without this morbidity. Conclusion: The fatigue prevalence was elevated and, once it adopted rigid criteria to define fatigue (that with score 4), it can assume that the symptom was clinically relevant. Fatigue was associated with sleep prejudice, pain, depression and functional capacity, but only pain and depression were independent predictors confirming the symptom complexity and the existence of a cluster of symptoms. The fatigue control is little known, but depression and pain are symptoms susceptible to modification in the clinical practice. Thus, maybe it can be possible any fatigue relief by means of the pain and depression treatment. These results can contribute in the management of prevalent symptoms in patients with breast cancer, aiming at reducing the discomfort, improving wellbeing and life quality of this population.