In der vorliegenden Arbeit wurden kognitive und psychische Veränderungen im Rahmen neurochirurgischer Interventionen bei Patienten mit erstmaligen intrakraniellen Meningeomen unter Berücksichtigung des Screening-Verfahrens MoCA® untersucht. Die prospektiv angelegte Studie wurde an einer anfallenden Patientenstichprobe (n=14) im Erhebungszeitraum 2013 – 2015 durchgeführt. Hierbei wurde umfangreich das präoperative kognitive Niveau mit zahlreichen standardisierten neuropsychologischen Testverfahren sowie auch das psychische Befinden mittels geeigneter Fragebögen untersucht. Die Ergebnisse wurden mit alters- und bildungsadäquaten gesunden Kontrollen (n=14) verglichen. Im Fokus der Studie stand die Evaluation des MoCA®, eines inzwischen weithin etablierten Screenings. Die Ergebnisse zeigten neben signifikant schlechteren Leistungen der Patienten im präoperativen MoCA® und zumindest tendenziell höherer Lernleistung, schnelleren Detektions- und Umstellzeiten, kürzeren Bearbeitungszeiten und höheren Produktionsmaßen bei den Gesunden in die gleiche Richtung einer eher globalen präoperativen Leistungsminderung. In Bezug auf das psychische Befinden zeigten Patienten vor der Operation gegenüber Gesunden eine deutlich höhere Angst, und zumindest nominal eine höhere Depressivität, die jedoch statistisch ebenfalls nicht bedeutsam war. Das psychische Befinden hatte statistisch keinen bedeutsamen Einfluss auf die präoperativen Testergebnisse im MoCA®. Symptomdauer, Tumorgröße oder Lateralität des Tumors zeigten keinen statistisch relevanten Einfluss auf die präoperativen Testergebnisse im MoCA® oder auf das präoperative psychische Befinden. Der Vergleich der prä- und postoperativen Ergebnisse der Patienten ergab für den MoCA® keine statistisch bedeutsame Änderung. Das psychische Befinden der Patienten änderte sich im Verlauf des postoperativen Jahres dagegen nicht, weder in Bezug auf die Ängstlichkeit noch hinsichtlich der Depressivität. Schließlich konnte für die operationsspezifischen Variablen (Schnitt-Naht-Zeit, Resektionsausmaß) kein relevanter Einfluss auf die postoperativen kognitiven Leistungen im MoCA® bzw. auf das postoperative psychische Befinden nachgewiesen werden. Die vorliegenden Ergebnisse weisen insgesamt darauf hin, dass Patienten mit erstmaligen intrakraniellen Meningeomen im präoperativen Leistungsbild durchaus schlechtere Ergebnisse erzielen als Gesunde und dass sich diese Leistungen im postoperativen Verlauf mehrheitlich zu erholen scheinen. Dies deckt sich mit den bisherigen Erkenntnissen. Schließlich bestätigt die bereits präoperativ erhöhte Schließlich bestätigt die bereits präoperativ erhöhte psychische Belastung der Patienten die bisherigen Erkenntnisse einer höheren Prävalenz von Stress, Depression, Angststörungen bzw. einer Kombination. Auch zeigt sich, dass das psychischen Befinden keinen nachweisbaren Einfluss auf das postoperative Leistungsbild zu haben scheint.:1 EINLEITUNG 2 THEORETISCHER HINTERGRUND 2.1 Hirntumoren – Ätiologie, Arten, WHO-Gradierung, Epidemiologie und Klinik 2.2 Meningeome – Ätiologie, Arten, WHO-Gradierung, Epidemiologie und Klinik 2.3 Meningeome - Diagnostik und Therapie 2.4 Allgemeine Aspekte kognitiver Diagnostik - Entwicklungen und Standards 2.5 Der MoCA® als kognitives Screening zur Verlaufskontrolle 2.6 Erkenntnisse kognitiver Diagnostik bei Hirntumoren im Allgemeinen 2.7 Erkenntnisse kognitiver Diagnostik bei Meningeomen im Speziellen 2.8 Psychisches Befinden und Lebensqualität bei Patienten mit Meningeomen 2.9 Zusammenfassung 2.10 Fragestellungen 2.10.1 Kognitive Leistungen vor und nach der Exstirpation 2.10.2 Psychisches Befinden vor und nach der Exstirpation 2.10.3 Einflussfaktoren auf die präoperative Situation 2.10.4 Einflussfaktoren auf die postoperative Situation 3 METHODEN 3.1 Zur Vorbereitung der Studie 3.2 Untersuchungsdesign 3.3 Fallzahlschätzung 3.4 Ein- und Ausschlusskriterien 3.5 Organisation und Rekrutierung 3.6 Stichprobe 3.7 Eingesetzte neuropsychologische Testverfahren 3.8 Eingesetzte klinisch-psychologische Fragebögen 3.9 Ablauf der Untersuchungen 3.10 Reduktion der Variablenanzahl für die Analyse 3.11 Statistische Analyse 4 ERGEBNISSE 4.1 Kognitive Leistungen vor und nach der Exstirpation 4.2 Psychisches Befinden vor und nach der Exstirpation 4.3 Einflussfaktoren auf die präoperative Situation 4.4 Einflussfaktoren auf die postoperative Situation 5 DISKUSSION 5.1 Kognitive Leistungen vor und nach der Exstirpation eines Meningeoms 5.2 Psychisches Befinden vor und nach der Exstirpation eines Meningeoms 5.3 Methodologische Würdigung 6 SCHLUSSFOLGERUNGEN UND AUSBLICK 7 ZUSAMMENFASSUNG 7.1 Theoretischer Hintergrund 7.2 Methoden 7.3 Ergebnisse 7.4 Schlussfolgerungen

Submitted by Cássio da Cruz Nogueira (cassionogueirakk@gmail.com) on 2017-03-27T13:49:49Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_AnaliseAlteracoesNumero.pdf: 1579411 bytes, checksum: 25990e97eda3beed8df2da4e15eaa1ad (MD5) / Approved for entry into archive by Edisangela Bastos (edisangela@ufpa.br) on 2017-04-05T14:46:17Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_AnaliseAlteracoesNumero.pdf: 1579411 bytes, checksum: 25990e97eda3beed8df2da4e15eaa1ad (MD5) / Made available in DSpace on 2017-04-05T14:46:17Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_AnaliseAlteracoesNumero.pdf: 1579411 bytes, checksum: 25990e97eda3beed8df2da4e15eaa1ad (MD5) Previous issue date: 2013-12-13 / CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico / Os meningiomas constituem o segundo tipo de tumor primários cerebral mais comum, originando-se nas meninges que revestem o cérebro e a medula espinhal. Possuem crescimento lento, sendo encontrados com maior freqüência no SNC. Na maioria dos casos são benignos, porém há também casos de meningiomas classificados como malignos. No nível citogenético, os meningiomas são os tumores mais bem estudados em humanos, e os resultados demonstraram que as alterações mais frequentes nesse tipo de tumor tem sido a perda de uma cópia do cromossomo 22 e a deleção do braço curto do cromossomo 1. Essas alterações têm sido associadas ao processo de gênese tumoral, por serem características de tumores de baixo grau, principalmente deleções envolvendo o cromossomo 22. Dessa forma, o objetivo do presente trabalho foi analisar a recorrência de alterações no número de cópias (CNAs) envolvendo os cromossomos 1p e 22 em meningiomas de grau I e II, além de averiguar a existência de outros rearranjos recorrentes, por meio da análise genômica comparativa de alta resolução (array-CGH). As amostras analisadas foram provenientes de oito pacientes. Todas as amostras apresentaram ganhos e perdas de diversos segmentos cromossômicos. Com exceção de um caso, todos os outros apresentaram em maior ou menor grau mais deleções do que amplificações. A perda de segmentos localizados em 1p foi observada em todas as amostras analisadas. Algumas CNAs apresentaram recorrência em até seis dos oito casos. O cromossomo 22 apresentou CNAs em todas as amostras, mas a monossomia total só foi observada em duas das oito amostras. A análise global de CNAs em todas as amostras demonstrou que, apesar de alterações em 1p e 22 serem as modificações mais observadas, como o esperado, outras regiões genômicas também se apresentaram modificadas em várias amostras, apontando para um possível envolvimento dessas modificações com o processo de tumorigênese e progressão tumoral. Algumas delas, como alterações nos pares 9, 12 e 17, já foram observadas em outros trabalhos e foram correlacionadas com meningiomas atípicos e anaplásicos. Dessa forma, os dados obtidos apontam para a existência de um número maior de alterações genômicas em meningiomas de baixo grau, refutando, em parte, a afirmação de que esses tumores são caracterizados por um pequeno número de alterações quando comparados com tumores de malignidade maior. No entanto, o fato desses tumores apresentarem as alterações que são clássicas dos meningiomas, mesmo os benignos, como as deleções em 1p e em 22q, pode ser um indício de que estas alterações devem estar ligadas com os eventos iniciais destes meningiomas, como já foi sugerido diversas vezes por outros autores. Concluindo, essas alterações permanecem como marcadores importantes em meningiomas, e as relações dessas e outras CNAs com a resposta a diferentes tratamentos e ocorrência de recidivas devem ser o próximo passo após a caracterização citogenômica baseada em array-CGH. / Meningiomas are the second most common type of primary brain tumor, originating in the meninges covering the brain and spinal cord. They show slow growth, and are found more often in the CNS, being benign in most case, although there are also cases of meningiomas classified as malignant. At the cytogenetic level, meningiomas are the most well studied tumors in humans: studies in CNS tumors have shown that most cases had chromosomal abnormalities, and the most common alterations in theis type of tumor are the loss of one copy of chromosome 22 and deletion of the short arm of chromosome 1. These alterations have been associated with the tumorigenesis process, because they are found mostly in low-grade tumors, particularly deletions involving chromosome 22. Thus, the aim of this study was to analyze the occurrence of copy number alterations (CNAs) involving chromosomes 1p and 22 meningiomas grade I and II, and in addition to verifying the existence of other recurrent rearrangements through the application of high resolution comparative genomic hybridization (array - CGH ). Tumor samples were collected from eight patients. All samples showed gains and losses of various chromosomal segments. Except for one case, all others showed, in different degrees though, more deletions than amplifications. Loss of 1p segments was observed in all samples. Some CNAs were recurrent, being found up to six out of the eight cases. Pair 22 showed CNV in all samples, but the total monosomy was observed in only two of the eight samples. The global analysis of CNAs in all samples showed that, although changes 1p and 22 were the most frequent observed alterations, as expected, other genomic regions had also alterations in various samples, indicating a possible involvement of these modifications in the process of tumorigenesis and tumor progression. For instance, alterations in pairs 9, 12 and 17, have been observed in other studies and were correlated with atypical and anaplastic meningiomas. Our data indicate the existence of a larger number of genomic alterations in low-grade meningiomas, disagreeing partly with the assumption that these tumors are characterized by a small number of changes, usually involving pair 22 and, less frquently, loss of 1p. However, the fact that these tumors present alterations that are classically found in meningiomas, even benign, such as deletions in 1p and 22q, may be an indication that these changes must be linked with the early events of origin in meningiomas, as already suggested several times by other authors . In conclusion, these alterations remain important markers in meningiomas, and the relationships of these and other CNAs with the response to different treatments and recurrences should be the next step after cytogenomic characterization based on array-CGH has been completed.

<p>Neurofibromatosis type-2 (NF2) is an autosomal dominant disorder with the clinical hallmark of bilateral eighth cranial nerve schwannomas. However, the diagnostic criterion is complicated by the presence of a variable phenotype, with the severe form presenting with additional tumors such as peripheral schwannoma, meningioma and ependymoma. We constructed a microarray spanning 11Mb of 22q, encompassing the <i>NF2 </i>gene, to detect deletions in schwannoma. Forty seven patients were analyzed and heterozygous deletions were detected in 45% of tumors. Using this array-based approach, we also detected genetic heterogeneity in a number of samples studied. Despite the high sensitivity and the comprehensive series of studied schwannomas, no homozygous deletions affecting the <i>NF2</i> gene were detected <b>(paper I)</b>. In order to detect more subtle deletions within the <i>NF2</i> locus, a higher-resolution gene-specific array was developed, for the detection of disease-causing<b> </b>deletions using a PCR-based non-redundant strategy. This novel approach for array construction significantly increased the reliability and resolution of deletion-detection within the <i>NF2 </i>locus <b>(paper II)</b>. To further expand the coverage of the 11 Mb microarray, we constructed the first comprehensive microarray representing a human chromosome for analysis of DNA copy number. This 22q array covers 34.7 Mb, representing 1.1% of the genome, with an average resolution of 75 kb <b>(paper III)</b>. Using this array, we analyzed sporadic and familial schwannomatosis samples, which revealed two commonly deleted regions within the immunoglobulin lambda locus and the <i>GSTT1/CABIN1</i> locus. These regions were further characterized using higher-resolution non-redundant arrays, bioinformatic tools, positional cloning and mutational screening. Missense mutations were detected in the <i>CABIN1</i> gene, which may contribute to the pathogenesis of schwannomatosis and therefore requires further study <b>(paper IV)</b>. Meningioma is the second most common NF2-associated tumor and loss of 1p has been previously established as a major genetic factor for disease initiation/progression and also correlates with increased morbidity. We analyzed 82 meningiomas using a chromosome 1 tiling-path genomic microarray. The distribution of aberrations detected supports the existence of at least four regions on chromosome 1, which are important for meningioma tumorigenesis <b>(paper V)</b>.</p>

<p>Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder with the clinical hallmark of bilateral vestibular schwannomas (VS). Patients affected by a severe NF2 phenotype also presents with peripheral schwannomas, meningiomas and ependymomas. The closely related disorder schwannomatosis also displays multiple schwannomas, but never VS. Mutation screening of the <i>NF2</i> gene in the above mentioned tumors did not identify mutations in numerous of cases. We analyzed the DNA sequence covering the <i>NF2</i> locus in order to identify evolutionarily conserved non-genic sequences (CNGs) with unknown regulatory function (paper I). The aim was to analyze CNGs for mutations in DNA derived from patients affected by NF2 associated tumors. During mutation analysis of the coding part of <i>NF2</i> and within the CNGs defined in paper I, were mutations detected in 39% of sporadic meningiomas (paper II). Two candidate regions were identified on 22q using array-CGH. Methylation profiling did not identify methylation of the <i>NF2</i> promoter in these tumors. Sporadic schwannomas were profiled for CNV using a 22q genomic array in the search for putative gene(s) that in addition to <i>NF2</i> could be involved in the development of schwannoma and/or schwannomatosis (paper III). The predominant aberration identified was monosomy 22. Terminal and interstitial deletions encompassing the <i>NF2</i> gene were detected in tumor DNA and eight loci affected by CNV in constitutional DNA. Some of these CNVs are unlikely to be phenotypically neutral, considering their size and gene content. Two schwannomatosis candidate regions were identified on 22q using array-CGH (paper IV). These regions were further characterized by a PCR-product based array with higher resolution. Rearrangements of the immunoglobulin lambda (<i>IGL</i>) locus detected were restricted to schwannomatosis patients. In the second candidate region spanning <i>GSTT1</i> and <i>CABIN1</i> genes, was frequent copy number polymorphism at the <i>GSTT1</i> locus identified. We further describe missense mutations in the <i>CABIN1 </i>gene, making this gene a plausible candidate which may contribute to the pathogenesis of these disorders. </p>

Neurofibromatosis type-2 (NF2) is an autosomal dominant disorder with the clinical hallmark of bilateral eighth cranial nerve schwannomas. However, the diagnostic criterion is complicated by the presence of a variable phenotype, with the severe form presenting with additional tumors such as peripheral schwannoma, meningioma and ependymoma. We constructed a microarray spanning 11Mb of 22q, encompassing the NF2 gene, to detect deletions in schwannoma. Forty seven patients were analyzed and heterozygous deletions were detected in 45% of tumors. Using this array-based approach, we also detected genetic heterogeneity in a number of samples studied. Despite the high sensitivity and the comprehensive series of studied schwannomas, no homozygous deletions affecting the NF2 gene were detected <b>(paper I)</b>. In order to detect more subtle deletions within the NF2 locus, a higher-resolution gene-specific array was developed, for the detection of disease-causing<b> </b>deletions using a PCR-based non-redundant strategy. This novel approach for array construction significantly increased the reliability and resolution of deletion-detection within the NF2 locus <b>(paper II)</b>. To further expand the coverage of the 11 Mb microarray, we constructed the first comprehensive microarray representing a human chromosome for analysis of DNA copy number. This 22q array covers 34.7 Mb, representing 1.1% of the genome, with an average resolution of 75 kb <b>(paper III)</b>. Using this array, we analyzed sporadic and familial schwannomatosis samples, which revealed two commonly deleted regions within the immunoglobulin lambda locus and the GSTT1/CABIN1 locus. These regions were further characterized using higher-resolution non-redundant arrays, bioinformatic tools, positional cloning and mutational screening. Missense mutations were detected in the CABIN1 gene, which may contribute to the pathogenesis of schwannomatosis and therefore requires further study <b>(paper IV)</b>. Meningioma is the second most common NF2-associated tumor and loss of 1p has been previously established as a major genetic factor for disease initiation/progression and also correlates with increased morbidity. We analyzed 82 meningiomas using a chromosome 1 tiling-path genomic microarray. The distribution of aberrations detected supports the existence of at least four regions on chromosome 1, which are important for meningioma tumorigenesis <b>(paper V)</b>.

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder with the clinical hallmark of bilateral vestibular schwannomas (VS). Patients affected by a severe NF2 phenotype also presents with peripheral schwannomas, meningiomas and ependymomas. The closely related disorder schwannomatosis also displays multiple schwannomas, but never VS. Mutation screening of the NF2 gene in the above mentioned tumors did not identify mutations in numerous of cases. We analyzed the DNA sequence covering the NF2 locus in order to identify evolutionarily conserved non-genic sequences (CNGs) with unknown regulatory function (paper I). The aim was to analyze CNGs for mutations in DNA derived from patients affected by NF2 associated tumors. During mutation analysis of the coding part of NF2 and within the CNGs defined in paper I, were mutations detected in 39% of sporadic meningiomas (paper II). Two candidate regions were identified on 22q using array-CGH. Methylation profiling did not identify methylation of the NF2 promoter in these tumors. Sporadic schwannomas were profiled for CNV using a 22q genomic array in the search for putative gene(s) that in addition to NF2 could be involved in the development of schwannoma and/or schwannomatosis (paper III). The predominant aberration identified was monosomy 22. Terminal and interstitial deletions encompassing the NF2 gene were detected in tumor DNA and eight loci affected by CNV in constitutional DNA. Some of these CNVs are unlikely to be phenotypically neutral, considering their size and gene content. Two schwannomatosis candidate regions were identified on 22q using array-CGH (paper IV). These regions were further characterized by a PCR-product based array with higher resolution. Rearrangements of the immunoglobulin lambda (IGL) locus detected were restricted to schwannomatosis patients. In the second candidate region spanning GSTT1 and CABIN1 genes, was frequent copy number polymorphism at the GSTT1 locus identified. We further describe missense mutations in the CABIN1 gene, making this gene a plausible candidate which may contribute to the pathogenesis of these disorders.

Abstract The purpose of the present study was to implement a unique low-field open magnetic resonance scanner for perioperative imaging in neurosurgery. A paradigm was created for joint intraoperative/interventional MRI, including premises, surgical practice and an operational model. The feasibility of the paradigm was tested in clinical work. The joint use of the facilities between the Departments of Neurosurgery and Diagnostic Radiology was found to enhance the economic rationale and provide for perioperative imaging. It was also found to be organizationally viable in the long run. Intraoperative MRI was implemented and studied in connection with neuronavigation and other intraoperative instruments, tools and imaging modalities. The unique shut down possibility of the magnet enabled staged operating-imaging practice, use of non-MRI-compatible instruments and devices, multimodal imaging with navigation, and avoidance of safety risks associated with operating in magnetic fringe fields. Two dynamic contrast enhanced MR imaging sequences, which used undersampled projection reconstruction, were implemented in the low-field scanner. The applicability of these imaging sequences to follow contrast enhancement of meningiomas was studied in laboratory experiments and in two patient cases. The laboratory experiments showed a nearly linear response in signal intensity to the concentration of gadopentetate dimeglumine in purified water up to 1.25 mM. The patient cases showed results consistent with an earlier study performed at high-field strength. The potential of low-field MRI study including dynamic contrast enhanced imaging to predict surgical and histopathologic characteristics of meningiomas was studied in a series of 21 patients. Dynamic contrast enhanced imaging could be used to evaluate microvessel densities of meningiomas. Surgical bleeding, blood loss during operation, progesterone receptor expression and collagen content were statistically best correlated to the relative intensity of meningioma on FLAIR images. Tissue hardness correlated best with relative intensity on T2-weighted images.

Le cancer du cerveau est associé à une morbidité importante et à un fardeau économique considérable pour les systèmes de santé, les patients et leur famille. Malheureusement, on en sait toujours très peu sur l’étiologie de cette maladie. Les métaux, les métalloïdes et les fumées de soudures constituent une grande famille de cancérogènes professionnels potentiels à laquelle des millions de travailleurs sont exposés. La littérature scientifique fournit certains éléments de preuve que l’exposition professionnelle à quelques composés métalliques pourrait augmenter le risque de cancer du cerveau, mais la plupart des études publiées étaient limitées dans leur taille d’échantillons et en leurs capacités de mesurer efficacement l’exposition professionnelle à vie. Cette thèse a pour objectif de fournir de nouveaux éléments de preuve concernant l’association entre l’exposition professionnelle à certains composés métalliques et les deux principaux sous-types histologiques du cancer du cerveau, le gliome et le méningiome. Deux projets existants constituent la base de cette thèse: INTEROCC, une grande étude internationale cas-témoins sur l’association entre l’exposition professionnelle et le cancer du cerveau, incluant 2 054 cas de gliome, 1 924 cas de méningiome et 5 601 témoins, ainsi que CANJEM, une nouvelle matrice emplois-exposition basée sur plus de 30 000 emplois. CANJEM est un tableau croisé de trois axes: un axe de codes professionnels, un axe de périodes de temps et un axe d’agents chimiques. CANJEM fournit diverses mesures d’exposition à des agents professionnels sélectionnés en fonction d’un titre occupationnel et d’une période de temps. CANJEM étant un outil complexe conçu pour offrir une flexibilité considérable à l’utilisateur, les deux premiers volets de cette thèse ont été consacrés à l’examen de certaines des considérations méthodologiques associées à l’utilisation de CANJEM dans le cadre d’une étude épidémiologique. Premièrement, nous avons examiné comment la modification de la résolution des axes de codes professionnels et de périodes de temps influençait la proportion d’emplois pouvant être liés à CANJEM dans l’étude INTEROCC. Nous avons ensuite comparé l’accord de paires de versions de CANJEM pour la probabilité d’exposition et la concentration pondérée par la fréquence d’exposition de 19 composés métalliques en utilisant le coefficient d’accord de Gwet (AC2). Nous avons observé que, selon la résolution utilisée, CANJEM pouvait lier entre 70,7% et 98,1% de l’ensemble des emplois disponibles dans l’étude INTEROCC. De plus, la modification de l’axe de code professionnel avait un impact plus important que la modification de l’axe de période de temps sur les mesures d’expositions. Deuxièmement, l’évaluation par des experts est généralement considérée comme l’étalon-or dans l’évaluation rétrospective de l’exposition professionnelle. Différents seuils peuvent être appliqués à la probabilité d’exposition fournie par CANJEM afin de distinguer «exposé» de «non exposé». Nous avons comparé les rapports de cotes (RC) obtenus à l’aide de plusieurs versions de variables d’exposition binaire et cumulative pour neuf cancérogènes potentiels du poumon avec des RC obtenus à l’aide de l’évaluation par des experts. Des modèles de régression logistique inconditionnels ont été utilisés pour examiner l’association entre chaque variable d’exposition et le cancer du poumon chez 1 200 cas de cancer du poumon et 1 505 témoin issus d’une étude cas-témoin basée à Montréal. La sensibilité de l’évaluation dérivée de CANJEM par rapport à l’évaluation par experts variait de 0,12 à 0,78, tandis que la spécificité variait de 0,84 à 0,99. Dans l’ensemble, CANJEM a été capable reproduire les associations obtenues avec l’évaluation par experts, l’utilisation de seuils de probabilité de 25% ou 50% fournissant généralement les meilleurs résultats. Finalement, nous avons examiné le lien entre l’exposition professionnelle à 21 composés métalliques et le gliome ainsi que le méningiome dans l’étude INTEROCC à l’aide de régressions logistiques conditionnelles. La stratégie analytique était basée sur les observations faites dans les deux premiers volets. Nous n’avons observé aucune preuve de la présence d’association entre les agents sélectionnés et le gliome, mais la présence d’associations positives entre ces agents et le méningiome a été suggérée. Des associations statistiquement significatives ont également été observées entre le méningiome et une exposition inférieure à 15 ans aux fumées de plomb (RC (intervalle de confiance de 95%)) (1,67 (1,02-2,74)), aux composés du zinc (2,14 (1,02-3,89)), aux fumées de soudure (1,80 (1,17-2,77)), aux fumées d’oxydes métalliques (1,51 (1,03-2,21)) et entre une faible exposition cumulée au chrome VI (1,99 (1,03-3,84)) et aux fumées de brasage (1,83 (1,17-2,87)). L’évaluation rétrospective de l’exposition constitue l’un des principaux défis de l’épidémiologie professionnelle. Dans cette thèse, nous avons constaté que CANJEM, bien qu’imparfaite, était une approche appropriée pour l’évaluation de l’exposition professionnelle dans les études épidémiologiques. Bien qu’il soit difficile de déterminer le rôle exact joué par chacun des agents examinés, nos résultats supportent la présence d’une association positive entre les composés métalliques et plus particulièrement les fumées métalliques et le méningiome. / Brain cancer is associated with substantial lifelong morbidity and considerable economic burden for public health systems, patients, and their families. Very little is known regarding the etiology of this disease. Metals, metalloids, and welding fumes are a large family of potential occupational carcinogens to which millions of workers are exposed. The literature provides some evidence that occupational exposure to a few metallic compounds could increase the risk of brain cancer, but most published studies were limited in sample size and ability to effectively measure lifetime occupational exposure. In this thesis, we aimed to provide new evidence concerning the association between occupational exposure to selected metallic compounds and glioma and meningioma, the two major histological subtypes of brain cancer. Two existing projects provided the basis for the thesis: INTEROCC, a large international pooled case-control study on the association between occupational exposures and brain cancer, including 2,054 glioma cases, 1,924 meningioma cases, and 5,601 controls; CANJEM a new job exposure matrix based on the expert assessment of > 30,000 jobs. CANJEM is a cross-tabulation of three axes: an occupation code axis, a time period axis, and a chemical agent axis that provides various metrics of exposure to selected occupational agents based on a job title and a time period. However, CANJEM is also a complex tool designed to offer considerable flexibility to the user. The first two components of this thesis focused on the examination of some of the methodological considerations associated with the use of CANJEM in the context of an epidemiological study. First we examined how changing the resolution of the occupational code and time period axes, affected the proportion of jobs in the INTEROCC study that could be linked to CANJEM. We then compared the agreement among pairs of versions of CANJEM for the probability and frequency weighted concentration of exposure to 19 metallic compounds using Gwet’s agreement coefficient (AC2). We observed that, depending on the resolution used, CANJEM could be linked to 70.7% to 98.1% of all jobs available in the INTEROCC study. Furthermore, we observed that varying the occupation code axis had a greater impact than varying the time period axis. Neither the metrics of exposure nor the linkage rate were strongly affected by other aspects of CANJEM examined. Second, expert assessment is usually considered the gold standard in retrospective occupational exposure assessment. Different cutpoints can be applied to the probability of exposure provided by CANJEM to distinguish “exposed” from “unexposed”. We compared odds ratios (ORs) obtained using multiple versions of a binary ever and a cumulative exposure variable for nine potential and known lung carcinogens with ORs obtained using expert assessment. Unconditional logistic regression models adjusted for potential confounders were used to examine the association between each exposure variable and lung cancer in 1,200 lung cancer cases and 1,505 controls from a Montreal based case-control study. Sensitivity of the CANJEM-derived assessment vs. the expert assessment ranged from 0.12 to 0.78 while Specificity ranged from 0.84 to 0.99. Overall, CANJEM was fairly successful in reproducing the associations obtained with the expert assessment method, with the use of probability thresholds of 25% or 50% generally providing the best results for both exposure variables. Finally, we examined the association between occupational exposure to 21 metallic compound and glioma and meningioma in the INTEROCC study using conditional logistic regression adjusted for potential confounders. The analytical strategy was based on the observations made in the two previous components. We observed no evidence of association between the selected agents and glioma, but there was evidence of positive associations between some of the agents and meningioma. Statistically significant associations with OR (95% confidence interval) were also observed between < 15 years of exposure to lead fumes (1.67 (1.02-2.74)), zinc compounds (2.14 (1.02-3.89)), soldering fumes (1.80 (1.17-2.77)), and metal oxide fumes (1.51 (1.03-2.21)) and low cumulative exposure to chromium VI (1.99 (1.03-3.84)) and soldering fumes (1.83 (1.17-2.87)) and meningioma. One of the main challenges in occupational cancer epidemiology is retrospective exposure assessment. In this thesis we found that, while imperfect, CANJEM was a cost-efficient approach to occupational exposure in epidemiological studies. Although it is difficult to determine the exact role played by individual agents examined, our results provide some support for the presence of a positive association between metallic compounds, and more particularly metallic fumes, and meningioma.

Objective The goal of this retrospective study is the evaluation of risk factors for postoperative neurological deficits after petroclival meningioma (PCM) surgery with special focus on standard craniotomies. Materials and methods One-hundred-fifty-eight patients were included in the study, of which 133 patients suffered from primary and 25 from recurrent PCM. All patients were operated on and evaluated concerning age, tumor size, histology, pre- and postoperative cranial nerve (CN) deficits, morbidity, mortality, and surgical complications. Tumor-specific features—e.g., consistency, surface, arachnoid cleavage, and location—were set in a four-grade classification system that was used to evaluate the risk of CN deficits and tumor resectability. Results After primary tumor resection, new CN deficits occurred in 27.3% of patients. Preoperative ataxia improved in 25%, whereas 10% developed new ataxia. Gross total resection (GTR) was achieved in 59.4%. The morbidity rate, including hemiparesis, shunt-dependence, postop-hemorrhage, and tracheostomy was 22.6% and the mortality rate was 2.3%. In recurrent PCM surgery, CN deficits occurred in 16%. GTR could be achieved in three cases. Minor complications occurred in 20%. By applying the proposed new classification system to patients operated via standard craniotomies, the best outcome was observed in type I tumor patients (soft tumor consistency, smooth surface, plane arachnoid cleavage, and unilateral localization) with GTR in 78.7% (p < 0.001) and 11.9% new CN deficits (p = 0.006). Conclusion Standard craniotomies as the retrosigmoid or subtemporal/pterional approaches are often used for the resection of PCMs. Whether these approaches are sufficient for GTR—and avoidance of new neurological deficits—depends mainly on the localization and intrinsic tumor-specific features.

Tesis por compendio / [ES] El cáncer constituye la segunda causa de muerte en España. El tromboembolismo venoso (TEV), una complicación del cáncer, conlleva gran gasto del presupuesto sanitario y representa la segunda causa de muerte en estos pacientes. Sin embargo, las herramientas actuales disponibles para la identificación de pacientes oncológicos con elevado riesgo trombótico son limitadas. Adicionalmente, no existen métodos simples, mínimamente invasivos y económicos de diagnóstico de cáncer vesical. Por este motivo, se utilizan técnicas dañinas como la tomografía computarizada la cual implica una elevada dosis de exposición a radiación y procedimientos invasivos como la cistoscopia. Además, un estado hipercoagulable parece tener una relación directa con una mayor carga tumoral y un peor pronóstico. El objetivo principal de la presente Tesis Doctoral es explorar la utilidad clínica de nuevos métodos diagnósticos y pronósticos para el cáncer y sus complicaciones trombóticas. En la primera parte de la Tesis, nos hemos centrado en el papel de miRNAs en orina como biomarcadores de cáncer vesical. Hemos identificado al miR-29c-3p como el miRNA más estable por lo que fue utilizado como normalizador. Hemos ajustado un modelo de regresión logística ordinal para el diagnóstico y estratificación de cáncer vesical utilizando la expresión de miRNAs en orina de pacientes y controles. Este modelo incluyó la expresión de 7 miRNAs: miR-221-3p, miR-93-5p, miR-362-3p, miR-191-5p, miR-200c-3p, miR-192-5p y miR-21-5p. En la segunda parte de la Tesis, nos centramos en el estudio de nuevos biomarcadores para la trombosis asociada a cáncer. Analizamos el potencial predictivo de los miRNAs y de marcadores de activación de neutrófilos en pacientes con cáncer pancreático y pacientes con glioma y meningioma. En cáncer pancreático, obtuvimos un perfil de 7 miRNAs (miR-486-5p, miR-106b-5p, let-7i-5p, let-7g-5p, miR-144-3p, miR-19a-3p y miR-103a-3p) capaz de estimar el riesgo de TEV al diagnóstico con dianas incluidas en las rutas pancreatic cancer y complement and coagulation cascades. En el estudio de los marcadores de activación de neutrófilos, obtuvimos un nuevo modelo predictivo de TEV con la calprotectina como variable predictora. Respecto al estudio de trombosis asociada a cáncer en tumores intracraneales, en pacientes con glioma, ajustamos y validamos un modelo predictivo de embolismo pulmonar (EP) postquirúrgico con 6 miRNAs: miR-363-3p, miR-93-3p, miR-22-5p, miR-451a, miR-222-3p y miR-140-3p y otro con cfDNA y mieloperoxidasa como predictores. Además, hemos combinado los dos tipos de marcadores y hemos obtenido un modelo con mayor capacidad predictiva que incluye a miR-140-3p y a la mieloperoxidasa como predictores. En pacientes con meningioma, ajustamos y validamos un modelo predictivo de EP postquirúrgico con 6 miRNAs: miR-29a-3p, miR-660-5p, miR-331-3p, miR-126-5p, miR-23a-3p y miR-23b-3p. En conclusión, proponemos diferentes perfiles de biomarcadores para el diagnóstico de cáncer de vejiga y para la identificación de pacientes oncológicos con elevado riesgo de trombosis. / [CA] El càncer constitueix la segona causa de mort a Espanya. El tromboembolisme venós (TEV), una complicació del càncer, representa la segona causa de mort en aquests pacients i comporta una gran despesa sanitària. No obstant això, les eines disponibles actualment per a la identificació de pacients oncològics amb elevat risc trombòtic són limitades. Actualment, no existeixen mètodes diagnòstics per al càncer de bufeta senzills, mínimament invasius i econòmics. Per aquest motiu, s'utilitzen tècniques nocives com la tomografia computada la qual implica una elevada dosi d'exposició a radiació i procediments invasius com la cistoscòpia. A més, un estat hipercoagulable sembla tindre una relació directa amb una major càrrega tumoral i un pitjor pronòstic. L'objectiu principal de la present Tesi Doctoral fou explorar la utilitat clínica de nous mètodes diagnòstics i pronòstics per al càncer i les seues complicacions trombòtiques. En la primera part de la Tesi, ens hem centrat en el paper dels microRNAs (miRNAs) en orina com biomarcadors de càncer de bufeta. Hem identificat al miR-29c-3p com el miRNA més estable per la qual cosa va ser utilitzat com a normalitzador. Hem ajustat un model de regressió logística ordinal per al diagnòstic i estratificació de càncer de bufeta utilitzant l'expressió de miRNAs en orina de pacients i controls. Aquest model va incloure l'expressió de 7 miRNAs: miR-221-3p, miR-93-5p, miR-362-3p, miR-191-5p, miR-200c-3p, miR-192-5p i miR-21-5p. En la segona part de la Tesi, ens centràrem en l'estudi de nous biomarcadors per a la trombosi associada a càncer. Analitzàrem el potencial predictiu dels miRNAs i de marcadors d'activació de neutròfils en pacients amb càncer pancreàtic i pacients amb glioma i meningioma. En càncer pancreàtic, vàrem obtindre un perfil de 7 miRNAs (miR-486-5p, miR-106b-5p, let-7i-5p, let-7g-5p, miR-144-3p, miR-19a-3p i miR-103a-3p) capaç d'estimar el risc de TEV al diagnostic dels pacients els quals tenen dianes incloses en les rutes biològiques pancreatic cancer y complement and coagulation cascades. En el estudi dels marcadors d¿activació de neutròfils, vàrem obtenir un altre model predictiu de TEV amb la calprotectina com a variable predictora. Respecte a l'estudi de trombosi associada a càncer en tumors intracranials, en pacients amb glioma, ajustàrem i validàrem un model predictiu d'embolisme pulmonar (EP) incidental postquirúrgic amb 6 miRNAs (miR-363-3p, miR-93-3p, miR-22-5p, miR-451a, miR-222-3p i miR-140-3p) i un altre amb cfDNA i mieloperoxidasa com a predictors. A més, vàrem combinar els dos tipus de marcadors i vàrem obtenir un model amb major capacitat predictiva que inclou al miR-140-3p i la mieloperoxidasa com a predictors. En pacients amb meningioma, ajustàrem i validàrem un model predictiu d¿EP incidental postquirúrgic amb 6 miRNAs: miR-29a-3p, miR-660-5p, miR-331-3p, miR-126-5p, miR-23a-3p i miR-23b-3p. En conclusió, proposem diferents perfils de biomarcadors per al diagnòstic de càncer de bufeta i per a la identificació de pacients oncològics amb elevat risc de trombosi. / [EN] Cancer is the second leading cause of death in Spain. Collaterally, venous thromboembolism (VTE), as a complication of cancer, consumes a great part of its healthcare budget and, more importantly, it is the second cause of death in these patients. However, limited tools are available to identify high risk patients. Additionally, a simple, minimally invasive and economical diagnostic methods for bladder cancer are also lacking. For that aim, harmful techniques are used like CT scan with high radiation exposure and invasive procedures like cystoscopy. Moreover, a hypercoagulable state seems directly related to a large tumor burden and poor prognosis. The overall aim of this Doctoral Thesis is to explore the clinical utility of novel diagnostic and prognostic methods for cancer and its thrombotic complications. In the first part of this Doctoral Thesis, we focused on the role of urine miRNAs as bladder cancer biomarkers. We identified miR-29c-3p as the most stable miRNA and was therefore used as normalizer. We adjusted an ordinal logistic regression model for the diagnosis and stratification of BC using the urine miRNA expression levels of patients and controls. This model included 7 miRNAs: miR-221-3p, miR-93-5p, miR-362-3p, miR-191-5p, miR-200c-3p, miR-192-5p and miR-21-5p. In the second part of this Doctoral Thesis, we focused on the study of novel biomarkers for cancer-associated thrombosis. We analyzed the predictive potential of miRNAs and neutrophil activation markers of thrombotic events in patients with pancreatic cancer and patients with glioma and meningioma. In pancreatic cancer, we obtained a profile of 7 miRNAs (miR-486-5p, miR-106b-5p, let-7i-5p, let-7g-5p, miR-144-3p, miR-19a-3p and miR-103a-3p) able to estimate the risk of potential VTE at diagnosis with targets involved in the pancreatic cancer and complement and coagulation cascades pathways. In the study of the neutrophil activation makers, we obtained a new predictive model of VTE with calprotectin as predictor. Regarding the study of cancer-associated thrombosis in intracranial tumors, in glioma patients, we adjusted and validated a predictive model for post-surgical pulmonary embolism (PE) with 6 miRNAs: miR-363-3p, miR-93-3p, miR-22-5p, miR-451a, miR-222-3p and miR-140-3p, and another with cfDNA and myeloperoxidase as predictors. Furthermore, we combined both types of biomarkers and obtained an improved model using myeloperoxidase and miR-140-3p as predictors. In meningioma patients we fitted and validated a predictive model with 6 miRNAs: miR-29a-3p, miR-660-5p, miR-331-3p, miR-126-5p, miR-23a-3p and miR-23b-3p. In conclusion, we propose several profiles of biomarkers for the diagnosis of bladder cancer and for the identification of oncologic patients at high risk of suffering a thrombotic event. / Oto Martínez, AJ. (2022). Novel Diagnostic and Prognostic Methods for Cancer and Cancer Associated Thrombosis [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/181510 / Compendio