Como em diversos tumores sólidos, no câncer de cabeça e pescoço (HNSCC) a presença de metástases é um importante fator de mal prognóstico. Até o momento, estudos indicam que, no microambiente inflamatório tumoral, a estimulação com o Fator de Necrose Tumoral Alpha (TNF-?) leva à ativação de diferentes vias moleculares, como a via do Fator Nuclear Kappa-B (NF-kB) e PI3K/AKT, que inibem GSK3? e consequentemente, promovem a estabilização e translocação nuclear de SNAIL e betacatenina. De um modo geral, em diversos tipos de câncer, enquanto beta-catenina tem ação em promover a proliferação celular, membros da família SNAIL são capazes de induzir o processo de transição epitélio-mesenquimal (EMT). Sabe-se que os eventos de EMT estão envolvidos tanto na iniciação de metástases quanto na geração de célulastronco tumorais (CSCs), que por sua vez estão associadas à falha terapêutica e recidiva, devido à características que lhe conferem resistência aos tratamentos convencionais. Ao silenciar a expressão gênica de modo pós-transcricional, microRNAs (miRs) tem sido associados à regulação tanto da EMT quanto da geração de CSCs. Com uso da abordagem de High-Content Screening (HCS, análise celular multiparamétrica quantitativa por microscopia automatizada), buscamos investigar a capacidade de um grupo de 30 miRs humanos, muitos deles envolvidos em vias inflamatórias e na pluripotência, em modular aspectos relacionados a sobrevivência celular e EMT, em uma linhagem celular derivada de HNSCC (FADU) sob estímulo inflamatório. Inicialmente, avaliamos o potencial do TNF-? em modular parâmetros morfométricos, bem como a presença/localização de proteínas relacionadas com a EMT e capacidade migratória. Posteriormente, avaliamos o efeito de moléculas miméticas dos miRs em suprimir ou potencializar a sobrevivência celular e EMT em células estimuladas com TNF-?, seguido da identificação de transcritos alvos preditos (bem como das vias de sinalização enriquecidas para estes alvos) comumente alvejados por grupos de miRs que levaram a alterações multiparamétricas similares. De modo geral, miRs que alvejaram RELA e AKT2/AKT3 foram responsáveis pela redução na proliferação celular e EMT, enquanto o oposto foi observado em miRs que alvejaram GSK3B e ARHGAP5 (inibidor de RhoA). O silenciamento por siRNAs específicos contra RELA e CTNNB1, causou à redução na sobrevivência celular, enquanto que o silenciamento de AKT1 e CTNNB1 levou à redução na expressão proteica de SNAIL/SLUG. Finalmente, o silenciamento de RELA, AKT1, GSK3B e CTNNB1 levou a redução na sobrevivência celular e indução a apoptose mesmo na ausência de estimulação com TNF-?. Como um todo, nós demonstramos que a abordagem de HCS permitiu a identificação de miRs com efeitos fenotípicos similares (no contexto de proliferação e EMT) e que, a predição de alvos compartilhados por estes miRs, levou à identificação de alvos e vias de sinalização relevantes do ponto de vista terapêutico. / Like many solid cancers, in head and neck cancer (HNC) the presence of metastases is an important factor of poor prognosis. To date, studies indicate that, in the tumor inflammatory microenvironment, stimulation with Tumor Necrosis Factor Alpha (TNF-?) leads to the activation of different molecular pathways, such as the Nuclear Factor-Kappa B (NF-kB) and PI3K/AKT pathway, inhibiting GSK3? and the degradation of SNAIL and beta-catenin, stabilizing them promoting their nuclear translocation. In general, in several types of cancer, while beta-catenin acts to promote cell proliferation, members of the SNAIL family induce the epithelial-mesenchymal (EMT) transition process. It is known that EMT events are involved both in the initiation of metastases and generation of cancer stem cells (CSCs), which in turn are associated with therapeutic failure and relapse, due to its properties that confer resistance to conventional treatments. By silencing gene expression in a post-transcriptional fashion, microRNAs (miRs) have been associated with the regulation of both EMT and CSCs generation. Using the HighContent Screening (HCS) approach, we sought to investigate the ability of a group of 30 human miRs, many of them involved in inflammatory pathways and pluripotency, to modulate aspects related to cell survival and EMT, in a HNSCC-derived cell line (FADU) under inflammatory stimuli. Initially, we evaluated the potential of TNF-? in modulating morphometric parameters, as well as the presence/location of EMT-related proteins and migratory capacity. Subsequently, we evaluated the effect of miRs mimetic molecules on suppressing or potentiating cell survival and EMT in TNF-?-stimulated cells, followed by the identification of predicted target transcripts (as well as signaling pathways enriched for these targets) commonly targeted by groups of miRs that led to similar multiparametric changes. Overall, miRs that targeted RELA and AKT2/AKT3 were responsible for the reduction in cell proliferation and EMT, while the opposite was observed in miRs that targeted GSK3B and ARHGAP5 (RhoA inhibitor). Gene silencing by specific siRNAs against RELA and CTNNB1 caused a reduction in cell survival, while silencing of AKT1 and CTNNB1 led to reduced protein expression of SNAIL/SLUG. Finally, the silencing of RELA, AKT1, GSK3B and CTNNB1 led to a reduction in cell survival and induction of apoptosis even in the absence of TNF-? stimulation. As a whole, we demonstrated that the HCS approach allowed the identification of miRs with similar phenotypic effects (in the context of proliferation and EMT) and that the prediction of targets shared by these miRs led to the identification of relevant targets and signaling pathways from the therapeutic point of view.

INTRODUÇÃO: Osteopontina (OPN) é uma glicoproteína presente em tecidos e fluidos orgânicos e envolvida em vários processos patológicos que incluem inflamação, proliferação celular, invasão da matriz extracelular, progressão tumoral e metástase. Em pacientes (pts) portadores de carcinoma epidermóide de cabeça e pescoço (CECCP), OPN tem sido associada a uma maior agressividade tumoral e empregada como marcador prognóstico. Nós investigamos o valor prognóstico e preditivo da OPN sérica em pacientes portadores de CECCP tratados de forma uniforme. MÉTODOS: Estudo longitudinal prospectivo de 47 pts portadores de CECCP localmente avançado e irressecável submetidos à quimioterapia e radioterapia. OPN sérica foi determinada pelo método ELISA (kit 1 com17 pts e kit 2 com 30 pts) com coleta realizada antes e após o término do tratamento e estudada a relação entre OPN, categorizada como alta ou baixa em relação ao valor mediano, e as características clínico-patológicas, resposta ao tratamento, sobrevida global (SG) e sobrevida livre de progressão (SLP). RESULTADOS: A OPN sérica mediana dos pacientes determinada pelo kit 1 (em ng/ml) foi de 2,1 e 1,9 pré e pós-tratamento, respectivamente; no kit 2 (em ng/ml) foi de 69,5 e 87,9 pré e pós-tratamento, respectivamente. Pacientes portadores de tumores de orofaringe foram mais freqüentemente associados a baixos níveis séricos de OPN pós-tratamento, em comparação com outros sub-sítios (p=0,03). Observada tendência à associação entre os valores séricos baixos de osteopontina pós-tratamento e a resposta tratamento (p=0,06). Houve associação entre os valores elevados da osteopontina pós-tratamento e menor SLP (p=0,09, log rank), com medianas de 11,9 meses e 14,5 meses, conforme valores séricos de OPN pós-tratamento altos e baixos, respectivamente. Não houve associação dos valores séricos de OPN pré e pós-tratamento e a SG (p=0,19 e p= 0,10, respectivamente). CONCLUSÃO: Neste grupo de pacientes portadores de CECCP, sugere-se que OPN sérica baixa após a quimioradioterapia associa-se à resposta ao tratamento e melhor SLP. / INTRODUCTION: Osteopontin (OPN) is a glycoprotein present in tissues and body fluids involved in several pathological processes that include inflammation, cell proliferation, invasion of the extracellular matrix, tumor progression and metastasis. In head and neck squamous cell carcinoma (HNSCC) patients, OPN has been associated with greater tumor aggressiveness and used as a prognostic marker. We investigated the prognostic and predictive value of plasma OPN in homogeneously treated (HNSCC) patients. METHODS: Longitudinal prospective study of 47 patients with locally advanced and inoperable HNSCC treated with exclusive platin based concomitant chemoradiotherapy. Plasma OPN was determined by ELISA (n=14 kit I, n=32 kit II) pre and postreatment and correlated with tumor response, overall survival (OS) and progression-free survival (PFS). RESULTS: Median OPN levels in ng/ml were 2,1 and 1,9 pre and postreatment, respectively, by kit I and 69,5 and 87,9 by kit II. Patients were categorized as OPN low or high, using the median as a cut-off point. Patients with oropharynx tumors, as compared to other subsites, were more frequently categorized as low OPN (p = 0,03). A low postreatment OPN level was associated with tumor response (p = 0,06) and a high postreatment OPN level was associated with poor PFS, 11.9 vs. 14.5 months (p=0.09, log rank). Mean OS was 16.2 and 13.7 months in low and high postreatment OPN pts, respectively (p=0.10, log rank). CONCLUSIONS: In this group of HNSCC patients, it is suggested that a low plasma OPN after chemoradiotherapy is associated with a lower response rate and a worse PFS.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-03-29T12:06:37Z No. of bitstreams: 1 renatajacobdanielsalomaodecampos.pdf: 4531760 bytes, checksum: 6dd9d17faef4a3f61ca6cdf234689f94 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-03-30T11:19:07Z (GMT) No. of bitstreams: 1 renatajacobdanielsalomaodecampos.pdf: 4531760 bytes, checksum: 6dd9d17faef4a3f61ca6cdf234689f94 (MD5) / Made available in DSpace on 2017-03-30T11:19:07Z (GMT). No. of bitstreams: 1 renatajacobdanielsalomaodecampos.pdf: 4531760 bytes, checksum: 6dd9d17faef4a3f61ca6cdf234689f94 (MD5) Previous issue date: 2009-07-27 / O câncer de cabeça e pescoço é uma doença que tem alta prevalência e morbidade. O tratamento radioterápico tem mostrado bons resultados, mas nem sempre a função é preservada completamente. O presente estudo teve o objetivo de investigar a ocorrência de queixa vocal após o tratamento radioterápico e/ou quimioterápico, mensurando de maneira subjetiva e objetiva a qualidade vocal e a qualidade de vida dos pacientes com câncer de cabeça e pescoço. A proposta metodológica é de um estudo transversal, baseado na seleção de casos diagnosticados e tratados no Setor de Radioterapia do Instituto Oncológico de Juiz de Fora, no período de 2000 a 2006. Foram realizadas avaliações da qualidade vocal de forma subjetiva e objetiva e protocolo de qualidade de vida. Para o estudo foram selecionados pacientes portadores de tumores de cavidade oral, faringe e laringe submetidos a tratamento, com estádio I, II, III, IV (neste último, que recusaram tratamento cirúrgico) e com proposta terapêutica de radioterapia exclusiva ou concomitante à quimioterapia. Foram excluídos, para tanto, os pacientes submetidos a tratamento cirúrgico na região de cabeça e pescoço (em decorrência do câncer) combinado ou não a outra conduta, história de alterações neurológicas, alterações de ordem física, motora e/ou emocional que impedem ao paciente de participar e os que recusaram. Os dados foram analisados no programa SPSS 15.0, sendo que as proporções entre os grupos analisados, segundo localização anatômica, sexo, padrão de intervenção terapêutica foram realizadas através do teste χ2. Variáveis contínuas tiveram suas médias e foram analisadas pelo teste t de Student. A comparação de variáveis de natureza ordinal com desfechos nominais foi feita através do teste Kruskal Wallis. O nível de significância estatística foi fixado em 5%. Os principais resultados obtidos indicam predomínio do sexo masculino (76%), tabagistas (80%) e etilistas (76%). O tipo histológico carcinoma epidermoide foi identificado em 76%. O estádio II foi encontrado em 32%, e a combinação de tratamento por radioterapia e quimioterapia aconteceu em 56%. Após o tratamento, 40% apresentaram queixa de rouquidão e 47,6% com disfonia moderada. Quanto à qualidade de vida, os pesquisados apresentaram desvantagem leve seja no aspecto físico, funcional e emocional, porém 80% referem dificuldade em ser entendido no uso da voz em conversação diária. Conclui-se que a fonoaudiologia tem importante papel na equipe multidisciplinar, visto que algumas sequelas estão presentes após o tratamento dos cânceres de cabeça e pescoço e assim contribui para a reintegração do paciente ao convívio social de forma saudável e para sua qualidade de vida. / Head and neck cancer has high prevalence and morbidity. Although radiotherapy has shown good results, function is not always fully preserved. This study aimed to investigate the occurrence of voice complaints after radiotherapy and/or chemotherapy, with subjective and objective assessments of voice quality and quality of life of head and neck cancer patients. This cross-sectional study selected subjects diagnosed and treated at the Radiotherapy Division of the Instituto Oncológico, Juiz de Fora, Minas Gerais, Brazil, during the period from 2000 through 2006. Voice quality was assessed through subjective and objective analyses, while quality of life was assessed through a protocol. Patients with stages I, II, III and IV oral, pharyngeal and laryngeal cancer, undergoing treatment with radiotherapy only or chemotherapy-concomitant radiotherapy, were enrolled. Stage IV patients refusing surgery were also included. Exclusion criteria were: cancer-related head and neck surgery, alone or combined with another therapy; history of neurological disorders; physical, motor or emotional changes precluding participation; and refusal to participate. The SPSS 14.0 software was used for data analysis, with the χ2 test being used to calculate the proportions among the groups, according to anatomical location, sex and therapy modality. Continuous variables had their means analyzed by Student`s t test. Comparison of ordinal variables with nominal outcomes was made by Kruskal Wallis`s test. The statistical significance level was set at 5%. The main results indicated a predominance of males (76%), smokers (80%) and alcoholusers (76%). Squamous cell carcinoma was the histological type identified in 76%. Stage II was found in 32%, and combined radiotherapy/chemotherapy was undergone by 56%. After treatment, 40% complained oh hoarseness and 47.6% of moderate dysphonia. As for quality of life, those interviewed were mildly handicapped concerning their physical, functional and emotional status. Yet, 80% reported difficulty to have their voice understood on daily conversation. In conclusion, speech therapy plays an important role in the multidisciplinary team, once some sequelae are present after therapy for head and neck cancer. Speech therapy thus contributes to bringing the patient back to society, restoring health and improving the quality of life.

L’objectif principal de notre travail était d’évaluer deux nouvelles technologies, l’arcthérapie par la technique Rapid’Arc de chez Varian Medical System® et l’irradiation hélicoïdale avec Tomotherapy Hi-Art de chez Accuray® dans les tumeurs des Voies Aéro-Digestives Supérieures. Dans un premier temps, nous avons montré que ces 2 techniques étaient équivalentes du point de vue de la délivrance de la dose à partir de cas théoriques (30 cas) mais également in vivo à partir d’une population de patients analysée de façon prospective dans le cadre de l’étude nationale ARTORL (115 cas). Puis, nous avons cherché à augmenter le ratio thérapeutique en combinant l’une de ces 2 techniques avec des nouvelles techniques d’irradiation en conditions stéréotaxiques (Cyberknife d’Accuray® et Vero de Brainlab®). Nous avons étudié ensuite la toxicité radio-induite la plus fréquente dans notre population, à savoir la xérostomie. Aucun facteur prédictif de toxicités n’a pu être mis en évidence. Toutefois, nous avons pu créer un modèle prédictif de la fonction de récupération de la glande sous maxillaire, celles-ci étant souvent moins bien protégées. L’ensemble de ces résultats confirme les capacités « conformationnelles » de ces 2 nouvelles techniques innovantes et de leurs équivalences d’un point de vue dosimétrique et surtout clinique. Par ailleurs, cette équivalence dosimétrique de ces deux machines a également été retrouvée dans l’irradiation de tumeur pelvienne, dans le cadre de l’étude prospective ARTPELVIS. Le suivi ultérieur de ces populations permettra de confirmer l’équivalence clinique de ces 2 techniques d’un point de vue carcinologique. / The main objectif of our work was to assess two new technologies, arctherapy by Rapid'Arc technology from Varian Medical System® and helical irradiation with Tomotherapy Hi-Art, Accuray® in Head and Neck cancer. First, we showed that these 2 techniques were equivalent in terms of dose delivery from theoretical cases (30 cases), but also in vivo from a population of patients analyzed prospectively included in the national study ARTORL (115 cases). Then, we tried to increase the therapeutic ratio by combining one of these 2 techniques with new techniques for stereotactic irradiation (Cyberknife of Accuray® and Vero Brainlab®). We then studied the most common toxicity in our population, ie xerostomia. No predictif factor could be highlighted. However, we were able to create a predictive model of the recovery function of the sub-mandibular gland, they tend to be less well protected. All these results confirm the "conformational" capacity of these two new innovative techniques, their equivalences dosimetric and especially clinically. These results were confirmed in an another location in the prospective study ARTPELVIS. Subsequent monitoring of these populations will confirm the clinical equivalence of these new technologies.

Abstract The prognosis of patients with head and neck squamous cell carcinoma has improved only little during the last decades. Clinical markers for the biological aggressiveness of the cancer are few. The most reliable prognostic indicator is the stage of the disease. Research of the significance of the TP53 tumor suppressor gene as a predictive marker for prognosis and response to treatment in head and neck cancer has given discrepant results. One reason is probably the attempt to use p53 immunohistochemistry as a surrogate for TP53 mutations. However, in immunohistochemistry the protein is analyzed and thus the result does not usually correlate with TP53 mutations. The marker for prognosis of the response to treatment has to be reliable, and the analytical method needs to be both sensitive and specific. In addition to a sensitive method for TP53 mutation analysis the localization and quality of the mutations have to be analyzed to reveal the significance of the mutation on the function of the p53 protein. In this study, TP53 mutations were analyzed, using a sensitive PCR-SSCP method, in the tumors of patients with head and neck squamous cell carcinoma. The quality and localization of mutations were analyzed by sequencing. The frequency of the TP53 mutations and the effect on the function of the p53 protein were studied using IARC TP53 mutation database and literature. Correlation of TP53 mutations with chemical exposure and their significance on prognosis and response to radiation treatment was studied. In addition, the significance of cell cycle regulators cyclin D1, p16, p21 as potential markers of biological aggressiveness of tumors was studied. The results of this study showed that the patients carrying in their tumor TP53 mutations in the DNA binding region of the gene had been exposed to chemicals more than patients with no mutation or other types of mutations. These mutations also correlated with biological aggressiveness and prognosis and the response to radiation treatment. It was also shown that a combination of cyclin D1 and p16 analyzed by immunohistochemistry correlated with worse prognosis in head and neck cancer. / Tiivistelmä Pään ja kaulan alueen levyepiteelisyöpää sairastavien potilaiden ennuste ei ole juurikaan parantunut viime vuosikymmeninä. Syövän biologista aggressiivisuutta kuvaavia ennustetekijöitä on vähän, luotettavimpana niistä taudin levinneisyys. Tutkimustulokset TP53-kasvunrajoitegeenin merkityksestä prognostisena ja hoitovastetta kuvaavana, prediktiivisenä merkkiaineena pään ja kaulan alueen syövissä ovat ristiriitaisia. Tämä johtuu muun muassa siitä, että p53-immunohistokemiaa on yritetty käyttää TP53-mutaatioiden analysoimiseen. Immunohistokemiassa analysoidaan proteiinia, eikä tulos siksi yleensä korreloi TP53-mutaatioiden esiintymiseen. Prognostisen tai hoitovastetta ennustavan merkkiaineen tulee mitata haluttua asiaa luotettavasti, ja sen analysoimiseen tulee käyttää herkkää ja spesifistä menetelmää. Herkän mutaatioanalyysimenetelmän lisäksi mutaatioiden paikan ja laadun tarkempi analysoiminen on välttämätöntä, jotta saadaan selville mutaation merkitys p53 proteiinin toiminnalle. Tässä työssä tutkittiin pään ja kaulan alueen levyepiteelisyöpää sairastavien potilaiden kasvaimista TP53- mutaatioiden esiintymistä validoidulla, herkällä PCR-SSCP-menetelmällä. Mutaatioiden laatu ja sijainti geenissä analysoitiin sekvensoimalla. IARC:n TP53-mutaatiotietopankin ja kirjallisuuden tietojen avulla selvitettiin mutaatioiden yleisyys ja niiden vaikutus p53-proteiinin toimintaan. Tutkimuksessa selvitettiin TP53-mutaatioiden korrelaatiota kemialliseen altistumiseen ja niiden merkitystä potilaan ennusteeseen ja sädehoitovasteeseen. Lisäksi tutkittiin solusyklin säätelijöiden sykliini D1-, p16- ja p21-proteiinien merkitystä taudin biologiseen aggressiivisuuteen. Väitöskirjatutkimuksen tulokset osoittivat, että potilaat, joiden kasvaimessa oli TP53-mutaatio DNA-sitoutumisalueella, olivat altistuneet kemikaaleille enemmän kuin potilaat, joiden kasvaimissa oli toisenlaisia mutaatioita tai ei mutaatiota ollenkaan. Tutkimuksessa havaitut mutaatiot liittyivät taudin biologiseen aggressiivisuuteen ja huonoon ennusteeseen sekä heikompaan sädehoitovasteeseen. Lisäksi havaittiin, että sykliini D1- ja p16-proteiinin yhdistelmä immunohistokemiallisesti analysoituna korreloi huonoon ennusteeseen pään ja kaulan syövissä.

Der Hedgehog Signaltransduktionsweg (HhP) ist in der Embryologie und für die Tumor-entstehung bedeutsam und kann durch den spezifischen Antagonisten Cyclopamin (Cyc) inhibiert werden. Simvastatin (Sim) kann die für den HhP essentielle Cholesterolsynthese blockieren. Die therapeutische Unterdrückung des HhP in Kopf-Hals-Plattenepithel-karzinomen (HNSCC) zu untersuchen erschien nach verschiedenen Literaturhinweisen lohnend. In den Experimenten, deren Ergebnisse bereits in Artikeln publiziert wurden, konnten antineoplastische Effekte von Cyc bzw. Sim allein und in Kombination mit den Leitlinientherapeutika Cisplatin (Cis) oder Docetaxel (DTX) an der epithelialen Zelllinie KB, den Kopf-Hals-Zelllinien FaDu und HN-5, sowie an primären HNSCC ex vivo nachgewiesen werden. Biopsien von 49 HNSCC wurden im FLAVINO-Assay mit Cyc bzw. Sim in steigenden Konzentrationen allein und kombiniert mit Cis oder DTX untersucht. In die Auswertung konnten gemäß den Einschlusskriterien (histopathologisch bestätigtes HNSCC und suffiziente Koloniebildung im FLAVINO-Assay) 18 HNSCC einbezogen werden. Bei den Voruntersuchungen führten sowohl Cyc als auch Sim zu einer signifikanten Zeit- und Dosis-abhängigen Reduktion der Lebensfähigkeit von KB, FaDu und HN-5. Ebenso unterdrückten sowohl Cyc als auch Sim die Koloniebildung epithelialer Zellen im FLAVINO-Assay hochsignifikant. Auch tolerierbare Cis- und DTX-Konzentrationen zeigten eine signifikante Wachstumshemmung. In der Analyse des Interaktionsmodus wurde in den untersuchten Kombinationen (Sim+Cis, Sim+DTX, Cyc+Cis und Cyc+DTX) in allen Fällen Additivität als prädominanter Interaktionstyp ermittelt. Die Ergebnisse dieser Arbeit weisen den HhP als potentielles Target in HNSCC aus. Potentere und human besser verträgliche HhP-Blocker sollten unsere Ergebnisse bestätigen und in klinischen Studien getestet werden. Auch die Wirksamkeit von Sim auf HNSCC sollte in prospektiven klinischen Studien weiter analysiert und bestätigt werden. Möglicherweise vermag Sim bzw. die HhP-Blockade zukünftig einen Beitrag zur Therapie von HNSCC im Rahmen multimodaler Therapiekonzepte zu leisten.

Erst seit 2010 sind kombinierte Positronenemissionstomographie- Magnetresonanztomographie-Geräte (PET/MRT) zur hybriden Bildgebung verfügbar. Die mit der Entwicklung der Geräte verbundenen Hoffnungen bezüglich der onkologischen Diagnostik lagen zunächst auf einer verbesserten Genauigkeit in der Tumordetektion im Vergleich zur PET/CT. Rasch wurde jedoch deutlich, dass insbesondere die Möglichkeit der non-invasiven, multiparametrischen Charakterisierung von Tumorerkrankungen einen wesentlichen Vorteil der PET/MRT gegenüber der PET/CT darstellt. Der im Universitätsklinikum Leipzig AöR 2011 installierte PET/MRT-Scanner war einer der ersten weltweit und in dieser Habilitationsschrift sind die ersten Erfahrungen mit dieser Methode auf dem Gebiet der onkologischen Diagnostik zusammengefasst. Schwerpunkt ist dabei die Diagnostik von Kopf-Hals-Tumoren, da in diesem Bereich die CT aufgrund des im Vergleich zur MRT schlechteren Weichteilkontrastes Einschränkungen aufweist. In dieser Schrift werden zunächst die unterschiedlichen Konzepte im Gerätedesign der PET/MRT und die Besonderheiten der PET/MRT im Vergleich zur PET/CT erläutert. Auch die kritischen Punkte, die bei der Implementierung eines PET/MRT-Scanners zu beachten sind, werden detailliert dargestellt. Hierbei werden besonders die baulichen und organisatorischen Aspekte berücksichtigt, es werden aber auch Hinweise zur Qualitätskontrolle und zur Entwicklung von Untersuchungsprotokollen gegeben. In der ersten klinischen Studie zur Anwendung der PET/MRT mit 18F-Fluorodesoxyglucose (18F-FDG) bei Patienten mit Kopf-Hals-Tumoren konnten wir hinsichtlich Sensitivität und Spezifität noch keine Unterschiede zur PET/CT nachweisen. Allerdings war hier die untersuchte Patientengruppe heterogen und enthielt sowohl Primär- als auch Rezidivtumore. Aktuell konzentriert sich die onkologische Forschung am PET/MRT auf die Möglichkeiten der multiparametrischen Bildgebung zur Detektion und vor allem Charakterisierung von Tumorerkrankungen. Hier konnten wir signifikante Korrelationen von Glukosestoffwechsel und verschiedenen Perfusionsparametern bei Patienten mit Kopf-Hals-Tumoren nachweisen. Bei Patientinnen mit Zervixkarzinom konnte ein inverser Zusammenhang zwischen Glukosestoffwechsel und Diffusionsrestriktion nachgewiesen werden. Die letzte aufgeführte Arbeit zeigt die Korrelationen zwischen der bildgebenden Tumorcharakterisierung und histopathologischen Ergebnissen bei Kopf-Hals-Tumoren, wo wir Zusammenhänge von Kernfläche und dem Proliferationsmarker Ki-67 mit Diffusionseigenschaften bzw. Glukosestoffwechsel im Tumorgewebe nachweisen konnten.:Inhalt 1. Einführung in die Thematik 1.1. Entwicklung der hybriden Bildgebung 1.2. Technische Konzepte zur Kombination von PET und MRT 1.2.1. Separate Geräte – räumlich getrennt 1.2.2. Separate Geräte - in einem Raum kombiniert 1.2.3. Integrierte Geräte 1.3. Schwächungskorrektur 1.4. Einsatzgebiete 1.5. Untersuchungsprotokoll am PET/MRT 1.5.1. Allgemeine Überlegungen zum Untersuchungsablauf 1.5.2. MRT-Sequenzen 1.5.3. PET-Tracer 1.6. Eigene Studien 2. Originalarbeiten 2.1. Physikalische und organisatorische Maßnahmen für Installation, regulatorische Anforderungen und Implementierung eines simultanen hybriden PET/MR-Bildgebungssystems in Forschung und klinischer Versorgung 2.2. Ergebnisse der simultanen 18F-FDG PET/MRT im Vergleich zur 18F-FDG PET/CT bei Patienten mit Kopf-Hals-Tumoren 2.3. In vivo Korrelation von Glukosemetabolismus, Zelldichte und mikrozirkulatorischen Parametern bei Patienten mit Kopf-Hals-Tumoren: erste Ergebnisse von Untersuchungen mittels simultaner PET/MRT 2.4. Simultane 18F-FDG PET/MRT: Korrelation von scheinbarem Diffusionskoeffizient (ADC) und standardisiertem Aufnahmewert (SUV) beim primären und rezidivierten Zervixkarzinom 2.5. Simultane 18F-FDG PET/MRT: Assoziationen zwischen Diffusion, Glukosemetabolismus und histopathologischen Parametern bei Patienten mit Plattenepithelkarzinomen der Kopf-Hals- Region 3. Ausblick mit Übersichtsartikel „Molekulare Bildgebung bei Kopf-Hals-Tumoren“ 4. Literaturverzeichnis 5. Erklärung über die eigenständige Anfertigung der Arbeit und Kenntlichmachung der benutzten Hilfsmittel bzw. Hilfen 6. Lebenslauf 7. Danksagung

A studies carries for the last twenty years accumulated data that show two different etiology of head and neck squamous cell carcinoma. Tumors located in the oral cavity are often independent of the viral infection and is associated with tobacco and alcohol use. Approximately 26 % of all HNC and more than 50 % of tonsillar cancers are associated with the presence of high risk human papillomavirus (HR HPV). The purpose of this study was to determine whether changes in HPV DNA prevalence in oral rinses and/ or HPV - specific antibody levels in sera of patients with head and neck carcinoma (HNC) have prognostic significance. Patients with HNC were enrolled (N=142). The presence of HPV DNA was assayed in tumor tissue and oral rinses, and HPV-specific antibodies were assessed in sera. Sera were drawn one month and one year after the end of treatment. One year after treatment, oral rinses were collected. Altogether, 59.2 % tumors were HPV positive. Initially, the presence of HPV DNA in the tumors strongly correlated with HPV DNA positivity in oral rinses as well as with the presence of HPV- specific antibodies in sera. Out of 66 patients with HPV positive oral rinses at enrollment, 84.8 % became negative at one-year follow up. The mean titres of HPV 16 E6 and E7 antibodies at follow- up were lower in...

Die vorliegende retrospektive Studie zur postoperativen Radiochemothera-pie bei fortgeschrittenen Kopf-Hals-Tumoren sollte die eigenen Ergebnisse mit den prospektiv-randomisierten Studien vergleichend darlegen und dabei den Nutzen einer Radiochemotherapie überprüfen. Insgesamt wurden 155 Patienten in der retrospektiven Analyse eingeschlossen. Die Überlebens- und Rezidivraten des Patientengutes konnten anlehnend zu den publizier-ten Studien reproduziert werden. Ein Vorteil der Radiochemotherapie in Bezug nehmend auf den posttherapeutischen Verlauf konnte hierbei nicht festgestellt werden. Es traten signifikant vermehrt höhergradige Akutne-benwirkungen nach Applizierung der simultanen, systemischen Therapie auf. Die Arbeit konnte zeigen, dass sich durch die Reduzierung der Gesamt-behandungszeit als auch des Intervalls zwischen Operation und Beginn der adjuvanten Therapie das Gesamtüberleben sowie die lokoregionäre Rezidiv-rate signifikant verbessern ließen. Insgesamt scheinen die Fernmetastasie-rungen und die lokoregionären Rezidive maßgebend für die immer noch un-befriedigenden Überlebensraten zu sein. Gegenstand weiterer Untersu-chungen sollte daher die Optimierung der prätherapeutischen Diagnostik sowie der adjuvanten Therapie sein.

Magister Chirurgiae Dentium (MChD) / Oral Squamous Cell Carcinoma (OSCC) patients suffer from the terrible consequences of the disease and its treatment modalities, and as a result, their Quality of Life (QoL) and Oral Health-related Quality of Life (OHRQoL) is badly affected, especially due to functional limitation, physical disability and psychological disability that they encounter before, during and after treatment. There is a need for more research on OHRQoL of OSCC patients at various treatment intervals. The present study focused on investigating OHRQoL of OSCC patients at the post-treatment phase.