京都大学 / 新制・課程博士 / 博士(医学) / 甲第24085号 / 医博第4861号 / 新制||医||1059(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 生田 宏一, 教授 金子 新 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Glioblastoma (GBM) remains the most aggressive and prevalent malignant primary brain tumor in adults. Unchanged since 2005, standard of care (SoC) consists of surgical resection, followed by radiation therapy (RT) with concurrent and adjuvant chemotherapy with temozolomide (TMZ). Despite these therapeutic efforts, patients succumb to recurrent disease with a median overall survival of 14.6 months and a five-year survival rate of 5.5-6.8%. Therapeutic failure is largely explained by ITH and the presence of treatment-resistant GBM stem-like cells (GSCs). Given the lack of understanding of recurrent GBM and absence of second line therapies patients, I hypothesize that genome-scale functional genetic interrogation will unravel recurrent GBM-specific tumor biology and inform development of novel therapeutics. First, I compared primary and recurrent GBM at the genetic, transcriptomic, proteomic and functional genetic levels. These analyses map a multilayered genetic response to drive tumor recurrence, identifying protein tyrosine phosphatase 4A2 (PTP4A2) as a novel modulator of self-renewal, proliferation and tumorigenicity at GBM recurrence. Mechanistically, genetic perturbation and a small molecule inhibitor of PTP4A2 repress axon guidance activity through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1) and exploit a genetic dependency on ROBO signaling. Importantly, engineered anti-ROBO1 single-domain antibodies also mimic the effects of PTP4A2 inhibition. Given the genetic dependency on ROBO signaling and enrichment of ROBO1 expression in GBM tissues, I undertook a campaign to evaluate ROBO1 as a therapeutic target in recurrent GBM and develop anti-ROBO1 chimeric antigen receptor T (CAR-T) cells using camelid single-domain antibodies targeting human ROBO1. I optimized the design of anti-ROBO1 CAR-T cells and tested the anti-tumor activity of these modalities in in vitro using patient-derived recurrent GBM lines and orthotopic patient-derived xenograft models. I present data to expand the repertoire of GBM-enriched antigens suitable for effective CAR-T cell therapy. Given that resistance to SoC and disease relapse are inevitable for GBM patients, pre-clinical and clinical advancement of immunotherapeutic modalities, combined with recent insights into the tumor immune microenvironment, are poised to improve clinical outcomes for this patient population. / Thesis / Doctor of Philosophy (PhD) / Glioblastoma remains the most lethal and prevalent primary brain tumor in adults. Standard of care for patients remains unchanged since 2005, consisting of surgery to remove visible tumor at diagnosis (primary tumor), followed by radiation therapy and chemotherapy to treat remaining tumor cells. Despite these therapeutic efforts, tumor relapse (recurrent tumor) is inevitable with no standardized second-line therapy. Patients succumb to recurrent disease with a median overall survival of 14.6 months and only 5.5-6.8% of patients survive five years post diagnosis. Therapy failure and tumor relapse are explained by immense diversity among tumor cells at the DNA and protein levels, giving rise to a subset of tumor cells with abilities to resist therapy and seed the recurrent tumor. Previous studies have presented evolution of tumor cells through therapy, with recurrent tumor cells harboring novel changes at the DNA and protein levels. However, the impact of these changes on tumor cell function has not been evaluated. In this thesis, we developed and applied a genetic screening technique to determine the functional role of thousands of genes in primary and recurrent tumor cells from the same patient. This analysis revealed numerous genes that exhibit differential effects on survival of primary and recurrent tumor cells, including genes that drive recurrent tumor cell growth but are dispensable in primary tumor cells. Functional remodeling of these genes and pathways revealed a new functional role of multiple proteins belonging to a process called axonal guidance in recurrent tumor cells. To evaluate the therapeutic potential of these findings, we deeply interrogated the mechanism by which axonal guidance drives recurrent tumor cells and targeted crucial molecular players using chemical and immunological therapies. Using models that predict clinical effectiveness, we engineered and tested a novel therapy that redirects immune cells to target recurrent tumor cells driven by dysfunctional axonal guidance activity. The goal of this thesis was to discover the functional differences between primary and recurrent tumor cells, thereby leveraging this information to engineer candidate therapies for treatment of recurrent glioblastoma.

Welche Ursachen führen bei Keimzelltumoren zu Spätrezidiven? Sind es ungünstige Tumorkonstellationen, Behandlungsfehler oder individuelle Faktoren, die zu Spätrezidiven von Keimzelltumoren (KZT) führen? Ziel der Untersuchung war es, diese Fragen zu beantworten, um Patienten zu identifizieren, für die sich daraus Konsequenzen in der Therapie und Verlaufskontrolle ergeben. Indem wir Spätrezidive nach 4 Jahren auswerteten, wollten wir die besonderen Merkmale dieser Patientengruppe herausarbeiten. Unter 759 erfassten Patienten sahen wir 165 Frührezidive (< 2 Jahre), 92 Rezidive nach 2 Jahren und 73 Spätrezidive mehr als 4 Jahre nach der Initialdiagnose. Unsere statistische Auswertung bezieht sich auf die Spätrezidive mit einer mittleren Beobachtungszeit von 143 Monaten. Die initiale Konstellation der Tumormarker spielt eine bedeutende Rolle. 66% der Patienten hatten sowohl AFP als auch ß-HCG erhöht (gegenüber 47% bei den Frührezidiven und 33% im Gesamtkollektiv). Das gonadal reine Embryonalzellkarzinom (EZK) führt häufiger zu Spätrezidiven als andere Keimzelltumoren. Risikobehaftet sind höhere Stadien, von denen sich unter den Spätrezidiven 85% fanden; initial aber nur 57%. Demgegenüber ist poor-prognosis nach IGCCCG kein Risikofaktor. Mehr als die Hälfte der spätrezidivierten Patienten hatte bereits vorher mindestens ein Rezidiv gehabt. Eine initial von der heutigen Leitlinie abweichende Behandlung war bei 40% der Spätrezidive zu finden. Gründe hierfür waren eine falsche Histologie, die ungenaue Stadienzuordnung oder eine fehlende bzw. inkomplette Residualtumorresektion. Eine günstige Prognose haben die Patienten, bei denen eine Metastasenresektion vorgenommen werden kann. Die Heilungsrate (NED) war bei den operierten Spätrezidiven (70%) deutlich hoher als denjenigen, die zusätzlich chemotherapiert (46%) oder lediglich mit Chemotherapie behandelt worden waren (36%). Als Grund hierfür, ist die Früherkennung und noch vorhandene Operabilität des Befundes anzunehmen. Alle Seminom-Spätrezidive mit initialer Radiatio haben von der Chemotherapie profitiert. Bis auf einen Todesfall in der Chemotherapie wurden alle geheilt. Spätrezidive von KZT sollten als besondere Entität definiert werden. Krankheitsverlauf, Behandlung und Nachsorge weichen von dem üblichen Muster ab. Nur Seminome oder chemonaive Patienten sind zytostatisch zu behandeln. Bei den Nichtseminomen, die bereits initial oder im Frührezidiv eine Chemotherapie erhalten haben, sollte wenn möglich, eine operative Behandlung erwogen werden. Patienten mit initial erhöhten Tumormarkern (AFP + ß-HCG), reinem gonadalem EZK, höheren Krankheitsstadien oder einem Rezidiv innerhalb der ersten 4 Jahre haben eine ungünstige Prognose und erfordern eine jährliche lebenslange spezielle Nachsorge. Die Nachsorge sollte neben der klinischen Untersuchung und AFP-Bestimmung ein Schnittbildverfahren des Thorax und Retroperitoneums beinhalten. / What are the reasons for late relapse of testicular germ cell tumor? Do unfavourable tumor constellations, mismanaged treatment or individual factors; lead to the late relapse of testicular germ cell tumor? The aim of this investigation was to find an answer to this question and to identify the patients, who would benefit from modified treatments and follow-up modalities. By researching the late relapses diagnosed at least 4 years later, we wanted to identify the special characteristics of this group of patients. Among the 759 patients with testis cancer we found 165 early relapses (

Mycket finns skrivet i ämnet frivård och återfall, varför det finns anledning att ytterligare se på hur frivårdens stödinsatser uppfattas av före detta kriminella, frivårdsanställda samt kamratorganisationen Kriminellas Revansch i Samhället, vilken frivården samarbetar med. Frivården har en tämligen hög återfallsstatistik hos de före detta kriminella som frivården fått i uppdrag att återanpassa till ett laglydigt liv. Särskilt hög är återfallsstatistiken hos de individer som haft kontakt med frivården mer än en gång efter att mer än en gång blivit lagförd för brott. Denna undersökning har sökt svar på hur frivårdens insatser uppfattas för att se på vad som eventuellt kan göras bättre i dagsläget. Frivårdsanställda och före detta kriminella, varav några medlemmar i KRIS, har intervjuats för att på så vis få en nyanserad bild av verklighetens uppfattningar. Resultatet visade att frivårdens stödverksamhet tycks sakna verktyg för att hjälpa till synes omotiverade individer. Det framkom också att i de fall de före detta kriminella kände sig negativt stämplade av handläggarna fungerade stödinsatserna sämre. Detta eftersom ett personligt bemötande enligt informanterna, ansetts viktigt för stödinsatsernas verkan. Personligt bemötande påverkar inte huruvida handläggare på frivården kan kontrollera brottsbelastningen fysiskt hos den stödbehövande, men har likväl upplevts som ett stöd av före detta kriminella individer. Lekmannaövervakare synes vara en insats väl värd att satsa på, visar denna undersökning.

Despite the fact that a lot of information exist in the literature regarding factors leading to drug abuse, consequences of drug abuse for adolescents; little exists that focuses on family support for adolescents after rehabilitation. The purpose of this study was to explore family support for adolescents after rehabilitation for drug abuse. The study was based on semi-structured interview based qualitative research. Findings during interviews was that the families have no clear understanding or are not skilled as to how to continue supporting the adolescents after they are discharged from the rehabilitation centre. What was also interesting according to the participants was that even in the rehabilitation centres families are not made part of or involved during the rehabilitation process. There is a need to make the rehabilitation centres aware that families need to be involved during the rehabilitation process of the adolescent so that it becomes easy for the families to continue supporting the adolescents after they have completed the rehabilitation process. / Health Studies / M.A. (Health Studies)

No contexto da Oncologia, define-se recidiva como o reaparecimento do câncer após um período de remissão da doença, o que acarreta menor possibilidade de cura e necessidade de reorganização do paciente e de sua família para lidarem com a situação de tratamento. Considerando o elevado nível de ansiedade associado ao diagnóstico de recidiva e o reduzido número de investigações disponíveis na literatura nacional e internacional sobre seus aspectos psicossociais no âmbito da Oncologia Pediátrica, o presente estudo teve como objetivo compreender as vivências de crianças e de seus cuidadores-familiares diante dessa fase do tratamento. Participaram da pesquisa crianças com idades entre cinco e 12 anos incompletos, em tratamento de recidiva de câncer em um centro de referencia brasileiro para atenção em onco-hematologia infantil, e seus cuidadores principais. Trata-se de um estudo descritivo e exploratório, com enfoque na abordagem clinico-qualitativa. A fim de atender aos objetivos propostos, foi realizada uma entrevista, guiada por um roteiro semiestruturado, com o familiar responsável pelo cuidado do paciente e duas sessões de aplicação do procedimento de Desenhos-Estórias com a criança. As verbalizações foram audiogravadas mediante o consentimento dos participantes. Os relatos extraídos das entrevistas e as narrativas obtidas nas sessões com as crianças foram transcritos na integra e literalmente e, posteriormente, submetidos a analise de conteúdo temática, sendo os conjuntos de Desenhos-Estórias analisados de acordo com as recomendações da literatura. Os resultados mostraram que o diagnostico de recidiva remeteu os participantes ao período inicial de investigação e diagnóstico, porém com maior mobilização e intensidade afetiva. Emergiram sentimentos de frustração em relação as expectativas de cura, vivências de ameaça e perda de controle diante do adoecer e do prognóstico, favorecendo o confronto com a possibilidade da morte. Tal situação prejudicou a projeção para a temporalidade da cura, de forma a trazer implicações para a atribuição de sentidos da existência. A necessidade de recomeço do tratamento foi acompanhada pela necessidade de reorganização da dinâmica familiar e pelo fortalecimento afetivo para enfrentamento das vicissitudes do cotidiano terapêutico. Observaram-se relações entre as vivências parental e infantil, abrangendo questões como a comunicação e os significados atribuídos ao adoecer. A religiosidade e a busca de senso de controle foram recursos importantes utilizados pelos cuidadores para o enfrentamento das situações desafiadoras, ao passo que as crianças buscaram manter a proximidade afetiva com os cuidadores e fortalecer o sentimento de segurança. Compreender as vivências da criança e de seu cuidador-familiar pode oferecer subsídios para o planejamento de intervenções psicológicas que favoreçam o enfrentamento das peculiaridades da situação de adoecimento introduzidas pelo diagnóstico de recidiva do câncer infantil, contribuindo para a implementação dos cuidados paliativos. / In the context of Oncology, relapse is defined as the reappearance of cancer after a remission period of the disease, which entails a lesser possibility of cure and the need for patients and families to get reorganized in order to cope with the treatment situation. In view of the high level of anxiety associated with the relapse diagnosis and the limited number of studies available in Brazilian and international literature about its psychosocial aspects in the Pediatric Oncology context, the aim in this research was to understand the experiences of children and their family caregivers in view of this treatment phase. The research participants were children between five and 12 incomplete years of age, undergoing cancer relapse treatment at a Brazilian referral center for childhood onco-hematology, as well as their primary caregivers. A descriptive and exploratory research with a clinical-qualitative approach was carried out. To achieve the objectives, an interview was held with the relative responsible for patient care, guided by a semistructured script, and two application sessions of the Drawing-And-Story Procedure with the child. The interviews were audio-recorded with the participants consent. The reports taken from the interviews and the narratives collected during the sessions with the children were fully and literally transcribed and then submitted to thematic content analysis, while the Drawings-Histories were analyzed in accordance with literature recommendations. The results showed that the relapse diagnosis returned the participants to the initial investigation and diagnosis period, but accompanied by greater mobilization and affective intensity. Feelings of frustration emerged with regard to the cure expectations, feelings of threat and loss of control in view of the disease and prognosis, favoring the confrontation with the possibility of death. This situation negatively affected the projected timing of cure, influencing the attribution of meanings to existence. The need to restart the treatment was accompanied by the need to reorganize the family dynamics and the need for affective strengthening to cope with the vicissitudes of daily treatment. Relations between parents and childrens experiences were observed, comprising issues like communication and the meanings attributed to the disease. Religiosity and the search for a sense of control were important resources the caregivers use to cope with these challenging situations, while the children attempted to maintain their affective proximity with the caregivers and strengthen their feeling of security. Understanding the experiences of the children and their family caregivers can support the planning of psychological interventions that favor coping with the peculiarities of the disease situation introduced by the relapse diagnosis of child cancer, contributing to the implementation of palliative care.

O objetivo deste estudo retrospectivo foi comparar cefalométricamente a estabilidade das alterações decorrentes do tratamento da má oclusão de Classe II completa, realizada com extração de dois e de quatro pré-molares, após um período médio de 9,42 anos pós-tratamento. Para tanto, foram selecionados 60 pacientes que apresentavam inicialmente má oclusão de Classe II completa e que foram tratados com um dos protocolos propostos. A amostra foi divida em dois grupos. O grupo 1 foi composto por 30 pacientes, tratados com extração de dois pré-molares superiores, sendo 17 do gênero masculino e 13 do gênero feminino, com idade inicial média de 12,87 anos que apresentavam má oclusão de Classe II completa. O grupo 2 foi constituído por 30 pacientes, 14 do gênero masculino e 16 do gênero feminino com idade inicial média de 13,64 anos tratados com extrações de dois pré-molares superiores e dois inferiores. Ambos os grupos foram tratados com aparelho fixo, utilizando a mecânica edgewise simplificada. As telerradiografias foram obtidas e avaliadas em três estágios: inicial (T1), final (T2) e pós-tratamento (T3), também se realizou a avaliação das alterações ocorridas nos períodos de tratamento (T2 - T1) e pós-tratamento (T3 -T2). O teste t dependente e a fórmula de Dalhberg foram utilizados para a avaliação dos erros sistemáticos e casuais respectivamente. A compatibilidade dos grupos quanto à proporção dos gêneros, tipo de má oclusão e proporção de pacientes com contenção 3x3 foi avaliada pelo teste do qui-quadrado. As variáveis diretamente relacionadas à estabilidade foram comparadas por médio do teste t independente. Os resultados demonstraram que houve uma maior recidiva da protrusão de incisivos superiores e da relação molar no grupo tratado com extrações de quatro pré-molares. O padrão de crescimento vertical, a redução do ângulo SNB e a recidiva da correção da relação maxilomandibular apresentaram uma correlação significante com a recidiva da relação molar. Em ambos os grupos a recidiva do trespasse horizontal, vertical e da relação de caninos mostraram uma correlação estatisticamente significante e diretamente proporcional a sua correção. / The aim of this retrospective study was to compare cephalometrically the stability of the alterations originated from the treatment of the complete Class II malocclusion, carried out by extracting two and four premolars, after an average period of 9.42 post-treatment years. For this reason, 60 patients were selected and they initially presented complete Class II malocclusion. Such patients were treated by means of one of the proposed protocols. The sample was divided into two groups. Group 1 consisted of 30 patients treated with the extraction of two superior premolars, being 17 male patients and 13 female, at an initial average age of 12.87 years old, presenting full Class II malocclusion. Group 2 consisted of 30 patients, 14 male and 16 female, at an initial average age of 13.64 years old, treated with extractions of two superior and two inferior premolars. Both groups were treated with fixed appliance, by using the simplified edgewise mechanics. The teleradiographies were then obtained and evaluated at three stages: initial (T1), final (T2) and post-treatment (T3). The evaluation of the alterations which occurred in the treatment periods (T2 - T1) and post-treatment periods (T3 -T2) was also carried out. The dependent t test and the Dalhberg?s formula were used in order to evaluate the systematic and casual errors, respectively. The compatibility of the groups regarding gender ratio, malocclusion type and patient ratio with 3x3 contention was evaluated by the qui-square test. The variables directly related with the stability were compared by means of the independent t test. The results demonstrated that there was a significant relapse of superior incisive teeth protrusion and of molar relationship in the group treated with extractions of four premolars. The vertical growth pattern, the reduction of the SNB angle and the recurrence of the maxillomandibular relationship correction presented a significant correlation with the relapse of the molar relationship. In both groups, the relapse of the overjet and overbite and of the canine relationship showed a statistically significant and directly proportional relationship with their correction.

Com o objetivo de contribuir com a literatura acerca da prevalência e etiologia da reabertura de espaços de extrações após o tratamento ortodôntico, o presente trabalho se propôs a: verificar a prevalência em casos de má oclusão de Classe I tratados com extrações de quatro primeiros pré-molares; identificar o arco de maior ocorrência; avaliar o comportamento desses espaços no período de 1 e 5 anos póstratamento; verificar a associação com fatores como a quantidade de apinhamento anteroinferior, quantidade de retração dos incisivos inferiores e angulação entre coroas de caninos e segundos pré-molares ao final do tratamento. A amostra deste estudo longitudinal foi composta por documentações ortodônticas de 54 indivíduos tratados na clínica de Ortodontia da Faculdade de Odontologia de Bauru, Universidade de São Paulo. A amostra foi dividida em dois grupos: Grupo 1, composto por casos em que houve a reabertura de espaços de extração no período pós-tratamento; e Grupo 2, composto por casos em que não houve a reabertura de espaços. Os modelos foram digitalizados mediante um scanner 3Shape R700 3D (3Shape A/S,Copenhagen, Dinamarca), e mensurados através do software OrthoAnalyzerTM 3D. A mensuração da quantidade de retração dos incisivos inferiores durante o tratamento foi realizada através das telerradiografias inicias e finais, utilizando o programa Dolphin®Imaging 11.5 (Chatsworth, CA, EUA). As alterações interfases dos espaços foram avaliadas por meio do teste de Friedman e o teste de McNemar. O teste t independente foi utilizado para a comparação intergrupos. Todos os testes estatísticos utilizaram o nível de significância de p<0,05. Os resultados mostraram que 33,33% da amostra apresentou reabertura de espaços de extração, com prevalência maior no arco superior. Houve tendência de fechamento dos espaços no período de 5 anos pós-tratamento. O grupo com reabertura apresentou menor apinhamento inicial e maior quantidade de retração dos incisivos inferiores durante o tratamento. Não houve diferença entre os grupos quanto à angulação final de caninos e segundos pré-molares. / In order to contribute with orthodontic literature upon extraction space reopening prevalence and etiology, this studys aim is: to verify the prevalence of extraction space reopening after orthodontic treatment of Class I malocclusion with four first premolar extractions; to identify the arch with higher occurrence; to evaluate the space changes in 1 and 5 years after treatment; to seek for associations with other clinical aspects such as initial mandibular crowding, amount of mandibular incisors retraction during treatment and angulation between canines and second premolars crowns. The sample of this long-term study comprised orthodontic records of 54 patients, who were treated in the clinic of Orthodontics of Bauru Dental School University of Sao Paulo. This sample was divided into two groups: Group 1, consisted of at least one extraction space reopening and group 2, without space reopening. The casts were digitalized by a 3D 3Shape R700 scanner (3Shape A/S,Copenhagen, Denmark) and measured on OrthoAnalyzerTM 3D software. Initial and final cephalometric radiographs were analyzed using Dolphin®Imaging 11.5 (Chatsworth, CA, USA) to measure the amount of mandibular incisors retraction during treatment. Quantitative changes of extraction sites over time were compared by Friedmans test and qualitative changes by McNemars test. T tests were used to compare the groups. The significance level for all statistics tests was p <0.05. Results showed that 33.33% of the complete sample demonstrated space reopening in the posttreatment period, with higher prevalence in the maxillary arch. The amount and frequency of the spaces tended to decrease 5 years after the end of treatment. Patients with space reopening had less initial anterior crowding and an increased amount of mandibular incisor retraction during treatment. Final neighboring tooth angulations were similar in both groups.

O carcinoma basocelular (CBC) é malignidade de incidência elevada e crescente na população caucasiana, e sua expressiva prevalência nos serviços de saúde remete à necessidade de avaliação dos índices de cura. O presente estudo analisou marcadores clínicos preditivos do comprometimento das margens cirúrgicas do CBC, em conjunto com um painel de marcadores imuno-histoquímicos (IHQ). Analisou-se 1294 laudos histopatológicos de CBC, emitidos durante 2011, e incluídos 674 casos de excisão cirúrgica completa realizada por diferentes especialidades em hospital terciário. Foram selecionados 40 casos dos diferentes subtipos histológicos para realização de IHQ para os marcadores Ber-EP4, MNF116, E-Caderina e VEGF, analisados por sistema digital de captação de imagens e programa de computador. Na amostra, houve predomínio de homens (60,4%) com idade média de 68 anos, da localização cefálica (71%) e do subtipo nodular (61%); da ulceração (p= 0,003) e do diâmetro médio superior dos CBC nos homens (307,41 mm2 x 190,74 mm2; p< 0,001); do subtipo superficial de localização no tronco (p< 0,001) e em mais jovens (<73 anos; p= 0,001); do subtipo nodular (p< 0,001) e ulcerado (p= 0,05) no segmento cefálico. A especialidade Dermatologia foi responsável pela maioria das cirurgias (78%), cuja dimensão média e índice de margens cirúrgicas livres dos CBC excisados foram respectivamente 274 mm2 e 95%, seguida por 279 mm2 e 89% na Cirurgia Plástica, 218 mm2 e 60% na Cirurgia de Cabeça e Pescoço (CCP), 87 mm2 e 49% na Oftalmologia. O risco para desfecho em margens cirúrgicas comprometidas foi determinado para: subtipo micronodular (OR 3,41; IC 95% 1,71 6,80; p= 0,001); localização cefálica (OR 8,33 IC 95% 1,05 50; p= 0,045); excisões realizadas pelas especialidades Oftalmologia (OR 10,12; IC 95% 4,40 23,27; p= 0,001) e CCP (OR 9,67; IC 95% 5,14 18,21; p= 0,001). A imunomarcação pelo Ber-EP4, MNF116 e ECaderina foi homogênea e de intensidade moderada a acentuada nas células neoplásicas em todos os subtipos; os valores de intensidade da marcação, percentual de área e escore para o MNF116 discriminaram os CBC agressivos (esclerodermiforme e micronodular) daqueles não agressivos (nodular e superficial); e foram superiores para ECaderina no subtipo superficial; o percentual de células marcadas pelo VEGF foi superior nos tumores agressivos (p< 0,001). O segmento cefálico e o subtipo micronodular, seguido do esclerodermiforme, implicam em riscos elevados para o comprometimento das margens e merecem atenção quanto ao manuseio cirúrgico. A imunomarcação por Ber-EP4, MNF116 e E-Caderina pode auxiliar na identificação de ninhos tumorais multifocais no subtipo superficial, ou em meio ao processo inflamatório nos subtipos agressivos. A marcação da E-Caderina pode representar o padrão menos agressivo e de crescimento radial do subtipo superficial; e a do VEGF, nos tumores mais agressivos, ser indicativa do papel desta proteína no comportamento mais invasivo. A especialidade Dermatologia tem expressiva participação institucional e níveis de resolubilidade superiores, representada pelas maiores frequências de excisão de CBC e de margens cirúrgicas livres. O reconhecimento de fatores preditivos para desfecho em margens cirúrgicas comprometidas é de fundamental relevância para o planejamento cirúrgico e obtenção das mais elevadas taxas de cura. / Basal cell carcinoma (BCC) is the most common human malignancy and it is increasing its incidence in the Caucasian population. The significant prevalence of cases in specialized health services indicates the need of assessment of cure rates. The present study analyzed clinical predictive markers of compromised surgical margins in BCC in association with a panel of Immunohistochemistry (IHC) markers. We analyzed 1294 BCC histopathological reports during 2011, and 674 cases of complete surgical excision performed by different specialties in a tertiary hospital were included. From the sample, 40 cases of different histological subtypes were selected to perform IHC markers Ber-EP4, MNF116, E-cadherin and VEGF, which were analyzed by digital image capture system and computer program. There was male predominance (60.4%) with mean age of 68 years, location at cephalic segment (71%) and nodular subtype (61%); ulceration (p= 0.003) and higher average size of CBC in men (307.41 mm2 x 190.74 mm2; p< 0.001); superficial subtype was more frequent on trunk (p< 0.001) and in younger than 73 years (p< 0.001); nodular subtype (p< 0.001) and ulceration (p= 0.05) at cephalic segment. The specialty Dermatology performed the majority of surgeries (78%), and the average size and the index of free surgical margins were 274 mm2 and 95% in Dermatology, 279 mm2 and 89% in Plastic Surgery, 218 mm2 and 60% in Head and Neck Surgery (HNS), 87 mm2 and 49% in Ophthalmology. The risk for compromised surgical margins was determined for: micronodular subtype (OR 3.41; 95% CI 1.71 6.80; p= 0.001); location at cephalic segment (OR 8.33; 95% CI 1.05 50; p= 0.045); excisions performed by Ophthalmology (OR 10.12; 95% CI 4.40 23.27; p= 0.001) and HNS (OR 9.67; 95% CI 5.14-18.21; p= 0.001). Immunostaining by Ber-EP4, MNF116 and E-cadherin was homogeneous and moderate to high intensity within the neoplastic cells in all BCC subtypes; values obtained from staining intensity, percentage of area and score for the MNF116 showed difference between aggressive BCC (morpheaform and micronodular) and non-aggressive (superficial nodular); and were higher for E-cadherin in superficial BCC; the percentage of marked cells by VEGF was higher in aggressive tumors (p< 0.001). The cephalic segment and micronodular subtype, followed by the morpheaform, imply high risks for compromised margins and deserve attention during the surgical treatment by trained experts. The immunohistochemistry markers Ber-EP4, MNF116 and E-cadherin may help the identification of multifocal tumor nests in superficial subtype or amid the inflammatory process in the aggressive subtypes. E-cadherin staining may represent the least aggressive and radial pattern of growth of superficial subtype. VEGF staining in peritumoral inflammatory cells of aggressive tumors may be indicative of the role of this protein in more invasive behavior of these subtypes of the BCC. Dermatology has significant institutional participation with highest resolution, represented by higher frequency of BCC excision and less compromised surgical margins. Knowing the predictive factors for compromised surgical margins is important for planning surgical treatment and obtaining the highest cure rates.

O objetivo deste estudo retrospectivo foi comparar cefalométricamente a estabilidade das alterações decorrentes do tratamento da má oclusão de Classe II completa, realizada com extração de dois e de quatro pré-molares, após um período médio de 9,42 anos pós-tratamento. Para tanto, foram selecionados 60 pacientes que apresentavam inicialmente má oclusão de Classe II completa e que foram tratados com um dos protocolos propostos. A amostra foi divida em dois grupos. O grupo 1 foi composto por 30 pacientes, tratados com extração de dois pré-molares superiores, sendo 17 do gênero masculino e 13 do gênero feminino, com idade inicial média de 12,87 anos que apresentavam má oclusão de Classe II completa. O grupo 2 foi constituído por 30 pacientes, 14 do gênero masculino e 16 do gênero feminino com idade inicial média de 13,64 anos tratados com extrações de dois pré-molares superiores e dois inferiores. Ambos os grupos foram tratados com aparelho fixo, utilizando a mecânica edgewise simplificada. As telerradiografias foram obtidas e avaliadas em três estágios: inicial (T1), final (T2) e pós-tratamento (T3), também se realizou a avaliação das alterações ocorridas nos períodos de tratamento (T2 - T1) e pós-tratamento (T3 -T2). O teste t dependente e a fórmula de Dalhberg foram utilizados para a avaliação dos erros sistemáticos e casuais respectivamente. A compatibilidade dos grupos quanto à proporção dos gêneros, tipo de má oclusão e proporção de pacientes com contenção 3x3 foi avaliada pelo teste do qui-quadrado. As variáveis diretamente relacionadas à estabilidade foram comparadas por médio do teste t independente. Os resultados demonstraram que houve uma maior recidiva da protrusão de incisivos superiores e da relação molar no grupo tratado com extrações de quatro pré-molares. O padrão de crescimento vertical, a redução do ângulo SNB e a recidiva da correção da relação maxilomandibular apresentaram uma correlação significante com a recidiva da relação molar. Em ambos os grupos a recidiva do trespasse horizontal, vertical e da relação de caninos mostraram uma correlação estatisticamente significante e diretamente proporcional a sua correção. / The aim of this retrospective study was to compare cephalometrically the stability of the alterations originated from the treatment of the complete Class II malocclusion, carried out by extracting two and four premolars, after an average period of 9.42 post-treatment years. For this reason, 60 patients were selected and they initially presented complete Class II malocclusion. Such patients were treated by means of one of the proposed protocols. The sample was divided into two groups. Group 1 consisted of 30 patients treated with the extraction of two superior premolars, being 17 male patients and 13 female, at an initial average age of 12.87 years old, presenting full Class II malocclusion. Group 2 consisted of 30 patients, 14 male and 16 female, at an initial average age of 13.64 years old, treated with extractions of two superior and two inferior premolars. Both groups were treated with fixed appliance, by using the simplified edgewise mechanics. The teleradiographies were then obtained and evaluated at three stages: initial (T1), final (T2) and post-treatment (T3). The evaluation of the alterations which occurred in the treatment periods (T2 - T1) and post-treatment periods (T3 -T2) was also carried out. The dependent t test and the Dalhberg?s formula were used in order to evaluate the systematic and casual errors, respectively. The compatibility of the groups regarding gender ratio, malocclusion type and patient ratio with 3x3 contention was evaluated by the qui-square test. The variables directly related with the stability were compared by means of the independent t test. The results demonstrated that there was a significant relapse of superior incisive teeth protrusion and of molar relationship in the group treated with extractions of four premolars. The vertical growth pattern, the reduction of the SNB angle and the recurrence of the maxillomandibular relationship correction presented a significant correlation with the relapse of the molar relationship. In both groups, the relapse of the overjet and overbite and of the canine relationship showed a statistically significant and directly proportional relationship with their correction.