Yes / Malignant pleural mesothelioma (MPM) is associated with an extremely poor prognosis, and most patients initially are or rapidly become unresponsive to platinum-based chemotherapy. MicroRNA-31 (miR-31) is encoded on a genomic fragile site, 9p21.3, which is reportedly lost in many MPM tumors. Based on previous findings in a variety of other cancers, we hypothesized that miR-31 alters chemosensitivity and that miR-31 reconstitution may influence sensitivity to chemotherapeutics in MPM. Reintroduction of miR-31 into miR-31 null NCI-H2452 cells significantly enhanced clonogenic resistance to cisplatin and carboplatin. Although miR-31 re-expression increased chemoresistance, paradoxically, a higher relative intracellular accumulation of platinum was detected. This was coupled to a significantly decreased intranuclear concentration of platinum. Linked with a downregulation of OCT1, a bipotential transcriptional regulator with multiple miR-31 target binding sites, we subsequently identified an indirect miR-31-mediated upregulation of ABCB9, a transporter associated with drug accumulation in lysosomes, and increased uptake of platinum to lysosomes. However, when overexpressed directly, ABCB9 promoted cellular chemosensitivity, suggesting that miR-31 promotes chemoresistance largely via an ABCB9-independent mechanism. Overall, our data suggest that miR-31 loss from MPM tumors promotes chemosensitivity and may be prognostically beneficial in the context of therapeutic sensitivity.

La rhéologie et la photonique de divers systèmes biologiques complexes allant des protéines jusqu'aux bactéries et cellules ont été étudiées dans cette thèse. Ces travaux se basent sur deux grands thèmes, où le premier traite la modification des surfaces solides avec des molécules biologiques tandis que le second se concentre sur l'étude des effets des différentes drogues sur des cellules malignes, et non malignes par des techniques microscopiques complémentaires. Dans ce travail, des matrices orientées de films de polyélectrolytes/membrane pourpre ont été produites et étudiées en fonction de différentes conditions physico-chimiques. Des peptides spécifiques présentant de propriétés de reconnaissance de surface pour le ZnSe et le Si ont été isolées par la technologie de Phage Display. Le peptide de Si a été utilisé dans la détection des molécules avec une microcavité de silicium poreux, et ceci a montré un meilleur seuil de détection comparé à celui des autres méthodes classiques de fonctionnalisation. Le peptide spécifique de ZnSe a été utilisé afin de démontrer son utilité pour la préservation de l'activité et structure secondaire native des biomolécules adsorbées. Concernant les cellules, une différence de réponse, entre deux types de cellules épithéliales mammaires malignes MCF-7 et non-malignes HMEC184A1, sous traitement avec la curcumine, a été démontrée sur les cellules vivantes et fixées. Après, une évaluation des forces d'interaction entre un agent clinique anticancéreux cetuximab (CET) et EGFR (Epidermal Growth Factor Receptor) sur la surface des cellules de carcinome épithéliales A431 a été réalisé via la microscopie à force atomique en mode force. Une différence sur l'élasticité des cellules et sur les forces de liaison EGFR-CET a été notée quand le CET a été combiné avec d'autres drogues thérapeutiques. Les résultats de nos études d'imagerie fonctionnelle pourraient ouvrir de nouvelles voies dans la recherche de traitements contre le cancer. / The rheology and photonics of various complex biological systems ranging from proteins to bacteria and cells have been studied in this thesis. The work is organized around two major themes where the first one deals with surface modifications for adsorption of biological molecules while the second one focuses on comparative studies of non-malignant and cancerous cells under the effect of various drugs, using complementary microscopic techniques. In this work, oriented polyelectrolyte/purple membrane matrices have been produced and studied under different physico-chemical conditions. Peptides with surface recognition properties for the ZnSe and Si semiconductors have been isolated by Phage Display technology. The Si specific peptide has been used in detection of molecules with a porous silicon microcavity, providing a considerably enhanced detection resolution compared to traditional functionalization methods. The specific peptide of ZnSe has been used to demonstrate its utility in preservation of activity and native secondary structure of biomolecules in their adsorbed form. In the second part of my work concerning the cells, a different response (in morphology and elasticity) under treatment with curcumin, for two types of malignant MCF-7 and non-malignant HMEC184A1 mammary epithelial cells was demonstrated on living and fixed cells. Then, an evaluation of binding interactions between a clinical anticancer agent Cetuximab (CET) and the Epidermal Growth Factor Receptor (EGFR) on the surface of epithelial carcinoma A431 cells was performed via force mode atomic force microscopy. A difference was noted on the elasticity of cells and also on the EGFR-CET binding forces when CET was combined with other therapeutic drugs. The results of our functional imaging studies might open new avenues in the research for treatments against cancer.

Retinoblastoma (Rb) é o tumor ocular mais frequente na infância e cada grande Centro deve conhecer o perfil dos seus pacientes. Foi realizado um estudo do tipo coorte retrospectivo e incluiu pacientes com Rb atendidos entre 1983 e 2012 nos Serviços de Oncologia Pediátrica, Oftalmologia e Genética Médica do Hospital de Clínicas de Porto Alegre (HCPA). De um total de 165 registros no período foram efetivamente incluídos 140 pacientes, sendo 95,0% destes provenientes de municípios do Rio Grande do Sul. Os sinais mais frequentes ao diagnóstico foram: leucocoria (73,6%) e estrabismo (20,7%). Identificamos a seguinte distribuição: doença unilateral (65,0%), bilateral (32,9%) sendo 80,4% com doença multifocal (p=0,015), trilateral (2,1%). A idade média dos pacientes por ocasião dos primeiros sinais e sintomas foi de 18,1 meses [mediana=12,0] e a idade média ao diagnóstico foi 23,5 meses [mediana=16,5]. Cinquenta pacientes (35,7%) foram diagnosticados no 1º ano de vida. O tempo de diagnóstico médio da coorte foi 5,4 meses [mediana=3,0], (amplitude=0-77,0). A idade média aos primeiros sinais e sintomas do grupo com critérios de hereditariedade foi de 12,3 meses enquanto a do grupo não hereditário foi de 21,6 meses (p=0,001), enquanto a idade média ao diagnóstico foi de 15,9 meses vs. 28 meses, respectivamente (p<0,001). Entretanto não houve diferença na sobrevida entre esses subgrupos. O estadiamento ocular dos pacientes ao diagnóstico na sua maioria foi avançado (classificação de Reese V em 76,5%, Internacional D ou E em 78,1%), sendo que 35,2% dos unilaterais e 34,8% dos bilaterais já apresentavam doença extraocular em pelo menos um olho ao diagnóstico. Quinze pacientes (10,7%) tinham doença metastática ao diagnóstico. Em relação ao tratamento, diferentes modalidades foram utilizadas, sendo a maioria dos pacientes submetidos à cirurgia, sendo esta enucleação em 88,1% e exenteração em 11,9%. Uma parcela significativa dos pacientes foi tratada com quimioterapia sistêmica (57,1%) e/ou radioterapia (37,1%). Do total de pacientes recrutados, 131 (93,6%) permaneceram vinculados ao hospital até 2012 ou até o óbito. Destes, 32 (22,9%) recidivaram, resultando em 19 óbitos com 84,2% por progressão do Rb. Uma segunda neoplasia primária esteve presente em 4,3% (N=6) e dentre esses, um paciente teve uma terceira neoplasia primária. O tempo de seguimento médio foi 323,2 meses [300,3; 346,1]. As sobrevidas nos diferentes subgrupos foram as seguintes: sobrevida global 86,4%; no não metastático 92,0%; no metastático 40,0%; entre os intraoculares 94,0%; entre os extraoculares 68,5%; entre os unilaterais e bilaterais ambos com cerca de 88,0%; entre os trilaterais (N=3) todos foram a óbito; entre os unilaterais intraoculares 94,9% e extraoculares 75,0% e entre os bilaterais intraoculares 94,5% e extraoculares 68,4%. No nosso meio, o diagnóstico de Rb ainda é feito predominantemente em estadios avançados o que reduz a sobrevida dos pacientes e o índice de preservação do olho e da visão, além de aumentar a intensidade dos tratamentos realizados e consequentemente, toxicidade e efeitos tardios destes. Avaliações clínicas e oftalmológicas periódicas nos primeiros anos de vida da criança oferecem maior oportunidade de um diagnóstico precoce e o encaminhamento rápido à um Centro de Referência multidisciplinar que contemple cuidados terciários em Oftalmologia e Oncologia Pediátrica é fundamental. Existe grande necessidade de investimentos regionais que facilitem o acesso ao diagnóstico e tratamento do Rb, o tumor ocular mais frequente na infância. / Retinoblastoma (Rb) is the most frequent ocular tumor diagnosed in children and every pediatric hospital must be familiar with its clinical presentation and patient characteristics. A retrospective cohort study was undertaken, with patients diagnosed with retinoblastoma from 1983 until 2012, treated at the Pediatric Oncology Unit, Ophthalmology Unit, and Medical Genetics Unit of the Hospital de Clínicas de Porto Alegre (HCPA). Of a total of 165 registries during this time frame, 140 patients were included in this study, with 95% of them from the state of Rio Grande do Sul. The most frequent signs and symptoms at diagnosis were: leukocoria (73.6%) and strabismus (20.7%). The following distribution was identified: unilateral disease (65.0%), bilateral disease (32.9%), being 80.4% with multifocal disease, (P=0,015), and trilateral disease (2.1%). The average age of patients at the appearance of the first sign or symptom was 18.1 months [median=12.0] and the average age at diagnosis was 23.5 months [median=16.5]. Fifty patients (35.7%) were diagnosed during their first year of age. The average time to diagnosis was of 5.4 months [median=3.0], (amplitude=0-77.0). In the hereditary retinoblastoma group, the average age at the appearance of the first sign or symptom was 12.3 months, whereas the non-hereditary group presented the first sign or symptom on average at 21.6 months (P=0,001). The average age at diagnosis was 15.9 months vs. 28 months for the hereditary and non-hereditary patients, respectively (P<0.001). However, no significant difference in overall survival was found when both groups were compared. Ocular staging at diagnosis was, for the most part, advanced disease, (Reese V classification: 76.5%, Internacional Classification of Retinoblastoma D or E in 78.1% patients), being that 35.2% of cases were comprised of unilateral disease and 34.8% of patients with bilateral disease already presented with extraocular lesions in at least one eye at diagnosis. Fifteen patients (10.7%) presented with metastasis at diagnosis. With regards to treatment, differnet modalities were employed, being that most patients underwent surgery with enucleation in 88.1% and e exenteration in 11.9%. A significant number of patients received systemic chemotherapy (57.1%) and/or radiotherapy (37.1%). Of all patients included, 131 (93.6%) remained in follow up at the hospital until 2012 or until their demise. Of these patients, 32 (22.9%) relapsed, leading to 19 deaths, 84.2% of them due to disease progression. Secondary malignancies were present in 6 patients (4.3%) and, of these, one patient presented with two different secondary malignancies. The average time of patient follow up was 323.2 months [300.3; 346.1]. Overall survival was of 86.4%, with the following time frames among the different patient subgroups: 92.0% for non-metastatic patients, 40.0% for metastatic patients, intraoculares 94.0% for patients with intraocular disease, and 68.5% for patients with extraocular lesions. With regards to unilateral or bilateral disease, overall survival was of 88.0%; for patients with trilateral disease, (N=3) all patients expired. Survival of patients with unilateral and intraocular disease was of 94.9%; patients with unilateral and extraocular disease presented a overall survival of 75.0%. Patients with bilateral intraocular lesions overall survival was of 94.5%, whereas patients with bilateral and extraocular disease had an overall survival of 68.4%. In our setting, Rb diagnosis still occurs when the patients already manifest advanced disease, which reduces considerably their overall survival and preservation of the ocular globe and vision. Moreover, late diagnosis requires more agressive treatments, and consequently leads to more frequent toxicities and late side effects. Periodic clinical and ophthalmologic evaluations during the first years of a child's life offer a greater chance of early diagnosis and referral to a multidisciplinary pediatric oncology center, which is crucial for the patient’s well being. There is much need of further investments which facilitate patient access to diagnosis and treatment for Rb, which is the most common ocular tumor in children.

Retinoblastoma (Rb) é o tumor ocular mais frequente na infância e cada grande Centro deve conhecer o perfil dos seus pacientes. Foi realizado um estudo do tipo coorte retrospectivo e incluiu pacientes com Rb atendidos entre 1983 e 2012 nos Serviços de Oncologia Pediátrica, Oftalmologia e Genética Médica do Hospital de Clínicas de Porto Alegre (HCPA). De um total de 165 registros no período foram efetivamente incluídos 140 pacientes, sendo 95,0% destes provenientes de municípios do Rio Grande do Sul. Os sinais mais frequentes ao diagnóstico foram: leucocoria (73,6%) e estrabismo (20,7%). Identificamos a seguinte distribuição: doença unilateral (65,0%), bilateral (32,9%) sendo 80,4% com doença multifocal (p=0,015), trilateral (2,1%). A idade média dos pacientes por ocasião dos primeiros sinais e sintomas foi de 18,1 meses [mediana=12,0] e a idade média ao diagnóstico foi 23,5 meses [mediana=16,5]. Cinquenta pacientes (35,7%) foram diagnosticados no 1º ano de vida. O tempo de diagnóstico médio da coorte foi 5,4 meses [mediana=3,0], (amplitude=0-77,0). A idade média aos primeiros sinais e sintomas do grupo com critérios de hereditariedade foi de 12,3 meses enquanto a do grupo não hereditário foi de 21,6 meses (p=0,001), enquanto a idade média ao diagnóstico foi de 15,9 meses vs. 28 meses, respectivamente (p<0,001). Entretanto não houve diferença na sobrevida entre esses subgrupos. O estadiamento ocular dos pacientes ao diagnóstico na sua maioria foi avançado (classificação de Reese V em 76,5%, Internacional D ou E em 78,1%), sendo que 35,2% dos unilaterais e 34,8% dos bilaterais já apresentavam doença extraocular em pelo menos um olho ao diagnóstico. Quinze pacientes (10,7%) tinham doença metastática ao diagnóstico. Em relação ao tratamento, diferentes modalidades foram utilizadas, sendo a maioria dos pacientes submetidos à cirurgia, sendo esta enucleação em 88,1% e exenteração em 11,9%. Uma parcela significativa dos pacientes foi tratada com quimioterapia sistêmica (57,1%) e/ou radioterapia (37,1%). Do total de pacientes recrutados, 131 (93,6%) permaneceram vinculados ao hospital até 2012 ou até o óbito. Destes, 32 (22,9%) recidivaram, resultando em 19 óbitos com 84,2% por progressão do Rb. Uma segunda neoplasia primária esteve presente em 4,3% (N=6) e dentre esses, um paciente teve uma terceira neoplasia primária. O tempo de seguimento médio foi 323,2 meses [300,3; 346,1]. As sobrevidas nos diferentes subgrupos foram as seguintes: sobrevida global 86,4%; no não metastático 92,0%; no metastático 40,0%; entre os intraoculares 94,0%; entre os extraoculares 68,5%; entre os unilaterais e bilaterais ambos com cerca de 88,0%; entre os trilaterais (N=3) todos foram a óbito; entre os unilaterais intraoculares 94,9% e extraoculares 75,0% e entre os bilaterais intraoculares 94,5% e extraoculares 68,4%. No nosso meio, o diagnóstico de Rb ainda é feito predominantemente em estadios avançados o que reduz a sobrevida dos pacientes e o índice de preservação do olho e da visão, além de aumentar a intensidade dos tratamentos realizados e consequentemente, toxicidade e efeitos tardios destes. Avaliações clínicas e oftalmológicas periódicas nos primeiros anos de vida da criança oferecem maior oportunidade de um diagnóstico precoce e o encaminhamento rápido à um Centro de Referência multidisciplinar que contemple cuidados terciários em Oftalmologia e Oncologia Pediátrica é fundamental. Existe grande necessidade de investimentos regionais que facilitem o acesso ao diagnóstico e tratamento do Rb, o tumor ocular mais frequente na infância. / Retinoblastoma (Rb) is the most frequent ocular tumor diagnosed in children and every pediatric hospital must be familiar with its clinical presentation and patient characteristics. A retrospective cohort study was undertaken, with patients diagnosed with retinoblastoma from 1983 until 2012, treated at the Pediatric Oncology Unit, Ophthalmology Unit, and Medical Genetics Unit of the Hospital de Clínicas de Porto Alegre (HCPA). Of a total of 165 registries during this time frame, 140 patients were included in this study, with 95% of them from the state of Rio Grande do Sul. The most frequent signs and symptoms at diagnosis were: leukocoria (73.6%) and strabismus (20.7%). The following distribution was identified: unilateral disease (65.0%), bilateral disease (32.9%), being 80.4% with multifocal disease, (P=0,015), and trilateral disease (2.1%). The average age of patients at the appearance of the first sign or symptom was 18.1 months [median=12.0] and the average age at diagnosis was 23.5 months [median=16.5]. Fifty patients (35.7%) were diagnosed during their first year of age. The average time to diagnosis was of 5.4 months [median=3.0], (amplitude=0-77.0). In the hereditary retinoblastoma group, the average age at the appearance of the first sign or symptom was 12.3 months, whereas the non-hereditary group presented the first sign or symptom on average at 21.6 months (P=0,001). The average age at diagnosis was 15.9 months vs. 28 months for the hereditary and non-hereditary patients, respectively (P<0.001). However, no significant difference in overall survival was found when both groups were compared. Ocular staging at diagnosis was, for the most part, advanced disease, (Reese V classification: 76.5%, Internacional Classification of Retinoblastoma D or E in 78.1% patients), being that 35.2% of cases were comprised of unilateral disease and 34.8% of patients with bilateral disease already presented with extraocular lesions in at least one eye at diagnosis. Fifteen patients (10.7%) presented with metastasis at diagnosis. With regards to treatment, differnet modalities were employed, being that most patients underwent surgery with enucleation in 88.1% and e exenteration in 11.9%. A significant number of patients received systemic chemotherapy (57.1%) and/or radiotherapy (37.1%). Of all patients included, 131 (93.6%) remained in follow up at the hospital until 2012 or until their demise. Of these patients, 32 (22.9%) relapsed, leading to 19 deaths, 84.2% of them due to disease progression. Secondary malignancies were present in 6 patients (4.3%) and, of these, one patient presented with two different secondary malignancies. The average time of patient follow up was 323.2 months [300.3; 346.1]. Overall survival was of 86.4%, with the following time frames among the different patient subgroups: 92.0% for non-metastatic patients, 40.0% for metastatic patients, intraoculares 94.0% for patients with intraocular disease, and 68.5% for patients with extraocular lesions. With regards to unilateral or bilateral disease, overall survival was of 88.0%; for patients with trilateral disease, (N=3) all patients expired. Survival of patients with unilateral and intraocular disease was of 94.9%; patients with unilateral and extraocular disease presented a overall survival of 75.0%. Patients with bilateral intraocular lesions overall survival was of 94.5%, whereas patients with bilateral and extraocular disease had an overall survival of 68.4%. In our setting, Rb diagnosis still occurs when the patients already manifest advanced disease, which reduces considerably their overall survival and preservation of the ocular globe and vision. Moreover, late diagnosis requires more agressive treatments, and consequently leads to more frequent toxicities and late side effects. Periodic clinical and ophthalmologic evaluations during the first years of a child's life offer a greater chance of early diagnosis and referral to a multidisciplinary pediatric oncology center, which is crucial for the patient’s well being. There is much need of further investments which facilitate patient access to diagnosis and treatment for Rb, which is the most common ocular tumor in children.

Retinoblastoma (Rb) é o tumor ocular mais frequente na infância e cada grande Centro deve conhecer o perfil dos seus pacientes. Foi realizado um estudo do tipo coorte retrospectivo e incluiu pacientes com Rb atendidos entre 1983 e 2012 nos Serviços de Oncologia Pediátrica, Oftalmologia e Genética Médica do Hospital de Clínicas de Porto Alegre (HCPA). De um total de 165 registros no período foram efetivamente incluídos 140 pacientes, sendo 95,0% destes provenientes de municípios do Rio Grande do Sul. Os sinais mais frequentes ao diagnóstico foram: leucocoria (73,6%) e estrabismo (20,7%). Identificamos a seguinte distribuição: doença unilateral (65,0%), bilateral (32,9%) sendo 80,4% com doença multifocal (p=0,015), trilateral (2,1%). A idade média dos pacientes por ocasião dos primeiros sinais e sintomas foi de 18,1 meses [mediana=12,0] e a idade média ao diagnóstico foi 23,5 meses [mediana=16,5]. Cinquenta pacientes (35,7%) foram diagnosticados no 1º ano de vida. O tempo de diagnóstico médio da coorte foi 5,4 meses [mediana=3,0], (amplitude=0-77,0). A idade média aos primeiros sinais e sintomas do grupo com critérios de hereditariedade foi de 12,3 meses enquanto a do grupo não hereditário foi de 21,6 meses (p=0,001), enquanto a idade média ao diagnóstico foi de 15,9 meses vs. 28 meses, respectivamente (p<0,001). Entretanto não houve diferença na sobrevida entre esses subgrupos. O estadiamento ocular dos pacientes ao diagnóstico na sua maioria foi avançado (classificação de Reese V em 76,5%, Internacional D ou E em 78,1%), sendo que 35,2% dos unilaterais e 34,8% dos bilaterais já apresentavam doença extraocular em pelo menos um olho ao diagnóstico. Quinze pacientes (10,7%) tinham doença metastática ao diagnóstico. Em relação ao tratamento, diferentes modalidades foram utilizadas, sendo a maioria dos pacientes submetidos à cirurgia, sendo esta enucleação em 88,1% e exenteração em 11,9%. Uma parcela significativa dos pacientes foi tratada com quimioterapia sistêmica (57,1%) e/ou radioterapia (37,1%). Do total de pacientes recrutados, 131 (93,6%) permaneceram vinculados ao hospital até 2012 ou até o óbito. Destes, 32 (22,9%) recidivaram, resultando em 19 óbitos com 84,2% por progressão do Rb. Uma segunda neoplasia primária esteve presente em 4,3% (N=6) e dentre esses, um paciente teve uma terceira neoplasia primária. O tempo de seguimento médio foi 323,2 meses [300,3; 346,1]. As sobrevidas nos diferentes subgrupos foram as seguintes: sobrevida global 86,4%; no não metastático 92,0%; no metastático 40,0%; entre os intraoculares 94,0%; entre os extraoculares 68,5%; entre os unilaterais e bilaterais ambos com cerca de 88,0%; entre os trilaterais (N=3) todos foram a óbito; entre os unilaterais intraoculares 94,9% e extraoculares 75,0% e entre os bilaterais intraoculares 94,5% e extraoculares 68,4%. No nosso meio, o diagnóstico de Rb ainda é feito predominantemente em estadios avançados o que reduz a sobrevida dos pacientes e o índice de preservação do olho e da visão, além de aumentar a intensidade dos tratamentos realizados e consequentemente, toxicidade e efeitos tardios destes. Avaliações clínicas e oftalmológicas periódicas nos primeiros anos de vida da criança oferecem maior oportunidade de um diagnóstico precoce e o encaminhamento rápido à um Centro de Referência multidisciplinar que contemple cuidados terciários em Oftalmologia e Oncologia Pediátrica é fundamental. Existe grande necessidade de investimentos regionais que facilitem o acesso ao diagnóstico e tratamento do Rb, o tumor ocular mais frequente na infância. / Retinoblastoma (Rb) is the most frequent ocular tumor diagnosed in children and every pediatric hospital must be familiar with its clinical presentation and patient characteristics. A retrospective cohort study was undertaken, with patients diagnosed with retinoblastoma from 1983 until 2012, treated at the Pediatric Oncology Unit, Ophthalmology Unit, and Medical Genetics Unit of the Hospital de Clínicas de Porto Alegre (HCPA). Of a total of 165 registries during this time frame, 140 patients were included in this study, with 95% of them from the state of Rio Grande do Sul. The most frequent signs and symptoms at diagnosis were: leukocoria (73.6%) and strabismus (20.7%). The following distribution was identified: unilateral disease (65.0%), bilateral disease (32.9%), being 80.4% with multifocal disease, (P=0,015), and trilateral disease (2.1%). The average age of patients at the appearance of the first sign or symptom was 18.1 months [median=12.0] and the average age at diagnosis was 23.5 months [median=16.5]. Fifty patients (35.7%) were diagnosed during their first year of age. The average time to diagnosis was of 5.4 months [median=3.0], (amplitude=0-77.0). In the hereditary retinoblastoma group, the average age at the appearance of the first sign or symptom was 12.3 months, whereas the non-hereditary group presented the first sign or symptom on average at 21.6 months (P=0,001). The average age at diagnosis was 15.9 months vs. 28 months for the hereditary and non-hereditary patients, respectively (P<0.001). However, no significant difference in overall survival was found when both groups were compared. Ocular staging at diagnosis was, for the most part, advanced disease, (Reese V classification: 76.5%, Internacional Classification of Retinoblastoma D or E in 78.1% patients), being that 35.2% of cases were comprised of unilateral disease and 34.8% of patients with bilateral disease already presented with extraocular lesions in at least one eye at diagnosis. Fifteen patients (10.7%) presented with metastasis at diagnosis. With regards to treatment, differnet modalities were employed, being that most patients underwent surgery with enucleation in 88.1% and e exenteration in 11.9%. A significant number of patients received systemic chemotherapy (57.1%) and/or radiotherapy (37.1%). Of all patients included, 131 (93.6%) remained in follow up at the hospital until 2012 or until their demise. Of these patients, 32 (22.9%) relapsed, leading to 19 deaths, 84.2% of them due to disease progression. Secondary malignancies were present in 6 patients (4.3%) and, of these, one patient presented with two different secondary malignancies. The average time of patient follow up was 323.2 months [300.3; 346.1]. Overall survival was of 86.4%, with the following time frames among the different patient subgroups: 92.0% for non-metastatic patients, 40.0% for metastatic patients, intraoculares 94.0% for patients with intraocular disease, and 68.5% for patients with extraocular lesions. With regards to unilateral or bilateral disease, overall survival was of 88.0%; for patients with trilateral disease, (N=3) all patients expired. Survival of patients with unilateral and intraocular disease was of 94.9%; patients with unilateral and extraocular disease presented a overall survival of 75.0%. Patients with bilateral intraocular lesions overall survival was of 94.5%, whereas patients with bilateral and extraocular disease had an overall survival of 68.4%. In our setting, Rb diagnosis still occurs when the patients already manifest advanced disease, which reduces considerably their overall survival and preservation of the ocular globe and vision. Moreover, late diagnosis requires more agressive treatments, and consequently leads to more frequent toxicities and late side effects. Periodic clinical and ophthalmologic evaluations during the first years of a child's life offer a greater chance of early diagnosis and referral to a multidisciplinary pediatric oncology center, which is crucial for the patient’s well being. There is much need of further investments which facilitate patient access to diagnosis and treatment for Rb, which is the most common ocular tumor in children.

Inledning:Oral cancer är ett allvarligt tillstånd med hög dödlighet, särskilt vid sen diagnostisering. Brasilien är ett av de länder i världen som har högst prevalens och dödlighet i oral cancer och det är den femte vanligaste cancerformen I landet. Ett hjälpmedel för tidig diagnostisering är önskvärd.Syfte:Att utvärdera skillnaden i diagnostisk tillförlitlighet mellan konventionell oral undersökning och användning av multispektralt ljus (Identafi®) som en metod för tidig upptäckt av potentiellt maligna och maligna lesioner i munslemhinnan i en brasiliansk befolkning.Material och metod:Screening av en befolkning med förhöjd risk för att utveckla oral cancer i Goiânia, Goiás, Brasilien, för att upptäcka potentiellt maligna (PML) eller maligna lesioner (ML). Patienter med misstänkta PML eller ML upptäckta under screeningen undersöktes med multispektralt ljus (Identafi®). Tre oberoende observatörer genomförde bedömning med Identafi® och slutgiltig beslut avseende PML/ML togs i konsensus. Biopsier användes som diagnostisk referensstandard. Interobservatörs överensstämmelse beräknades som procentuell överensstämmelse och kappa-värde (κ).Resultat:Undersökning med Identafi® genererade tolv biopsier. Resultaten blev tre sant positiva, fem falskt positiva, två sant negativa och noll falskt negativa. Sensitiviteten beräknades till 0,29. Specificiteten var inte möjlig att beräkna, då det inte fanns några falska negativa resultat. Interobservatörs överensstämmelse för par av observatörer varierade mellan 78-86% och κ-värden mellan 0,46-0,60.Slutsats:Slutsatsen är att multispektralt ljus, Identafi® inte har inga fördelar jämfört med konventionell klinisk undersökning i fråga om diagnostisk träffsäkerhet för PML eller ML. Dock kan det vara till hjälp för en tandläkare eller oral kirurg som stöd i sitt beslutsfattande. Det kan också hjälpa kirurgen att ta en biopsi från det mest misstänkta delen av lesionen. Det finns inte tillräckligt publicerade studier som tyder på att Identafi® kan skilja mellan normal slemhinna och PML eller ML och denna studie bekräftar detta. Användning av Identafi® som ett hjälpmedel vid screening och undersökning för PML eller ML behöver utredas ytterligare, men baserat på denna studie kan Identafi® inte rekommenderas. / Introduction: Oral cancer is a severe condition with high mortality rate, in particular if diagnosed late. Brazil is one of the countries in the world with high prevalence and mortality from oral cancer and it is the fifth most common cancer there. An aid in early detection of oral cancer as an adjunct to health promotion is desirable.Purpose:The aim of this study was to evaluate the diagnostic accuracy of conventional oral examination and the use of multi spectral light (Identafi®) as an approach for early detection of potentially malignant or malignant lesions in the oral mucosa in a Brazilian population.Material and method:Screening of high-risk population in Goiania, Goias, Brazil, for oral potentially malignant lesions (PML) or malignant lesions (ML) as a selection phase. Patients collected from the screening were examined with multi spectral light (Identafi®) to evaluate diagnostic accuracy. Three observers independently assessed all lesions with Identafi® and the final decision if a lesion was present was taken in consensus. Inter observer agreement was calculated as overall agreement and as kappa value (κ). Biopsies were used as diagnostic reference standard.Results:Identafi® generated, from twelve biopsies, three true positive, five false positive, two true negative and zero false negative. Sensitivity was calculated to 0.29 and specificity was not possible to calculate since there were no false negative results.Inter observer agreement for the use of Identafi® was calculated as overall agreement and as kappa value (κ). The overall agreement for the three pairs of observers varied between 78-86% and κ-values between 0.46 and 0.60.Conclusion:The conclusion of this study is that Identafi® does not have any benefits over conventional oral examination in diagnostic accuracy for potentially malignant or malignant lesions in the oral mucosa. It might, however, be an aid for a dentists or oral surgeons that are unsure whether to take a biopsy or not. It can also aid the surgeon when taking a biopsy to take the most suspicious part of the lesion. There are not enough published evidence that Identafi® can discriminate between normal mucosa and PML or ML, and this study confirms previous results. The use of Identafi® as an aid in screening and examination for PML or ML needs further investigation.

Följande kandidatuppsats undersöker hur en elektronisk hälsoapplikation kan utformasför att öka medvetenheten om den personliga dagliga hälsan, fokuserat på huden och atthålla den frisk. Det sker genom att en prototyp har utformats där användaren genombilder samt text får instruktioner för att utföra en självkontroll. Prototypen innehållerockså en bildregistrering där användaren kan ladda upp bilder på en leverfläck ochgenom registreringen kan om leverfläcken utvecklas över tid. Syftet med prototypen äratt undersöka om en elektronisk hälsoapplikation utformad med fokus på återkopplingkan göra det möjligt för en person som inte är utbildad inom ämnet att undersöka sinhud samt se och följa förändring i en leverfläck genom bildanalys. Detta undersöktesgenom två tester. Ett frågeformulär där svarspersonen fick försöka avgöra om enleverfläck var frisk eller inte. Ett användartest där testpersonen fick testa bildanalysen,det som testades var om personen kunde ladda upp en bild samt se skillnad i bildernagenom bildregistreringen.Resultatet visar att majoriteten av enkätsvaren var korrekta svar, närmare bestämt 76,9procent. Personerna kunde identifiera om leverfläcken var frisk eller sjuk med hjälp avinformationen som tilldelades. Resultatet av användartesten visade att personerna kundeladda upp en bild på webbplatsen och sedan förstå bildanalysen. / This bachelor thesis examins how a electronic health application can be made toincrease awareness about personal daily health, with focus on individual skin andkeeping it healthy. This was made by creating a prototype where the user get usefulinformation on how to perform a self examination through text and images. Theprototype also contains functionality that allows the user to upload images of a moleand by an image registration follow possible changes over long periods of time. Thepurpose of the prototype is to investigate if an electronic health application with focuson feedback can make it possible for a person who is not educated in this area to examinthe skin and also discover possible changes over time with the image registration. Twotests were made to examin if this was possible. The first test was an questionnaire wherethe respondet tried to determine if a mole was healthy or not. The second test was a usertest where the test person got to try out the functionality with image registration in theprototype. The person got to upload an image and see the differences through the imageregistration.The results showed that the majority of the collected repsonses from the quetsionnairewas correct, with a percentage of 76,9 correct answers. The respondent could identify ifthe mole was healthy or not through the information that was presented. The results ofthe user test showed that all test persons could perform and understand the functionalityof uploading an image and then analyze the results throgh image registration.

Background: Psoas abscess is a rare clinical disease of various origins. Most common causes include hematogenous spread of bacteria from a different primary source, spondylodiscitis or perforated intestinal organs. But rarely some abscesses are related to malignant metastatic disease. Case presentation: In this case report we present the case of a patient with known squamous cell carcinoma of the cervix treated with radio-chemotherapy three years prior. She now presented with a psoas abscess and subsequent complete inferior vena cava thrombosis, as well as duodenal and vertebral infiltration. The abscess was drained over a prolonged period of time and later was found to be a complication caused by metastases of the cervical carcinoma. Due to the massive extent of the metastases a Whipple procedure was performed to successfully control the local progress of the metastasis. Conclusion: As psoas abscess is an unspecific disease which presents with non-specific symptoms adequate therapy may be delayed due to lack of early diagnostic results. This case report highlights the difficulties of managing a malignant abscess and demonstrates some diagnostic pitfalls that might be encountered. It stresses the necessity of adequate diagnostics to initiate successful therapy. Reports on psoas abscesses that are related to cervix carcinoma are scarce, probably due to the rarity of this event, and are limited to very few case reports. We are the first to report a case in which an extensive and complex abdominal procedure was needed for local control to improve quality of life.

La plaie tumorale est une infiltration par des cellules tumorales du tissu cutané, des vaisseaux sanguins et/ou lymphatiques. Ces plaies peuvent se présenter sous des aspects très différents accompagnés de symptômes variés. Outre les risques d'infection locale, les odeurs nauséabondes posent des problèmes récurrents d'isolement social, de difficultés conjugales et entrainent une sensation de dégout, de pourriture, voire de mort imminente. Elles influencent même le comportement médical. La colonisation bactérienne, les odeurs et les risques infectieux semblent intimement liés chez ces patients porteurs de plaie, dont l'immunité est le plus souvent affaiblie par l'administration de traitements anticancéreux. Ce projet a consisté à : 1) créer un fichier dynamique de données et prélever les patients porteurs de plaies tumorales, dans le cadre d'un travail de recherche clinique, 2) par une approche expérimentale personnelle et collaborative: caractériser la flore microbienne, la présence éventuelle de biofilm et les composés volatils des plaies, 3) analyser l'ensemble des données en mettant en évidence, si elles existent, les corrélations entre résultats des prélèvements et observations cliniques, 4) proposer de premières hypothèses, des pistes de solution, une adaptation des pratiques de soins.Une flore mixte composée de 54 bactéries différentes a été retrouvée sur les plaies et la présence de biofilm mise en évidence dans 35% des cas. 91 composés volatils ont été identifiés. Aucune infection n'a été relevée durant la période d'évaluation. Les conséquences de l'interactivité entre les bactéries, le biofilm et les composés volatils nous amènent à penser qu'il serait nécessaire de: 1) développer de nouvelles stratégies et topiques, 2) poursuivre les travaux sur le biofilm, 3) construire des projets en liens avec des psycho-oncologues et neuropsychiatres, 4) progresser vers la conception d'outils diagnostics et l'identification de biomarqueurs. / The malignant wound is an infiltration by tumoral cells of the cutaneous tissue, the blood and/or lymphatic vessels. These wounds can appear in different forms and and be accompagnied by various symptoms. Independently of the septic risk, the presence of nauseating odors induces social, family and conjugal difficulties, expressed mostly by disgust, a sensation of dirt or decay. It influences the medical behavior.Bacterial colonisation, odors and septic risks seem to be connected and mainly occur in patients who have a chronic wound and are immunodepressed by the anticancer therapies. This projetc [was] consisted in: 1) create a case report form and sample the malignant wound (clinical research), 2) characterize the microbial flora, the biofilm, and the volatile compounds with an experimental and collaborative approach, 3) analyse the results and the potential correlation between [the] laboratory's results and the clinical aspect of the wound, 4), propose potential solutions, hypothetis, and improvements of the clinical practice.A mixed flora, composed of 54 different bacterial types was identified; a biofilm was caracterized in 35% of cases. 91 volatile compounds were identified. No infection occurred during the evaluation period. The consequences of the interactivity of the bacteria, the biofilm and the volatils compounds suggest to: 1) develop new strategies and topics, 2) continue the research on the biofilm, 3) propose a research program with psycho-oncologists and neuropsychiatrics, 4) progress toward diagnostic tests conception and biomarkers identification.

Objetivo: Avaliar por meio da Tomografia Computadorizada singleslice, alterações nas estruturas do espaço mastigador, por disseminação loco-regional das neoplasias malignas originárias da loja tonsilar, trígono retromolar, seio maxilar e nasofaringe; correlacionar a presença de trismo com os achados tomográficos e dimensões do tumor. Material e métodos: foram selecionados prontuários de pacientes portadores de tumores malignos envolvendo as 4 regiões a serem estudadas, junto aos arquivos do Hospital Heliópolis. Foram excluídos os pacientes submetidos a terapêutica antineoplásica prévia ou com doenças inflamatórias ou infeciosas locais. Os prontuários foram revisados por um único examinador, onde foram coletadas informações relativas a idade, gênero, localização do tumor primário, tempo de evolução da doença, estadiamento do tumor e presença ou ausência de trismo. Após a administração do meio de contraste iodado, o protocolo de aquisição de imagens tomográficas foi de cortes axiais de 3mm de espessura, aquisições coronais foram feitas quando necessário. A análise das imagens foi feita por dois examinadores médicos, residentes do 3° de Radiologia médica, em momentos distintos, sem o conhecimento prévio das informações clínicas. Na avaliação do EM, os achados foram transcritos para uma planilha específica, considerando a presença ou ausência dos seguintes itens: simetria com o EM contralateral, obliteração do plano gorduroso, do trígono retromolar e do espaço faríngeo, edema e/ou atrofia dos músculos pterigoideos medial e lateral, destruição do ramo da mandíbula. Resultados: O trismo esteve presente em 10 pacientes estudados. Na associação entre dimensão do tumor e trismo, observamos que 90% dos pacientes apresentam tamanho T4, enquanto essa porcentagem é de 43% nos pacientes sem trismo. Analisando-se em termos de razão de chances, verificou-se que pacientes com tumores T4 apresentam uma chance de trismo de 11,6 vezes maior que as demais dimensões (T0 a T3). As neoplasias da loja tonsilar e trígono retromolar perfizeram 95% das neoplasias avaliadas. Foram encontrados apenas 3 casos de neoplasia da nasofaringe, e em nenhum deles observamos a presença de trismo, e não foi encontrado nenhum caso de neoplasia de seio maxilar. Relacionando os achados tomográficos com o grupo de pacientes com trismo, observamos que 60% dos pacientes com trismo apresentaram edema e/ou atrofia dos músculos pterigoideos na TC, enquanto que essa porcentagem foi de 21,8% nos pacientes sem trismo. Em relação às dimensões do tumor e sua relação com os achados das imagens observamos associação apenas entre tumores T4 e detecção de edema e/ou atrofia dos músculos pterigoideos, neste item pacientes com edema e/ou atrofia dos músculos pterigoideos apresentam 5,4 vezes ais chance de apresentarem trismo. Conclusões: Observamos na TC as seguintes alterações no EM: obliteração do plano gorduroso em 69,2 % dos pacientes, assimetria em 27,7%, edema/atrofia em 26,2 % dos pacientes e destruição óssea em 20%. Os graus de concordância inter examinadores foram variáveis. Encontramos associação apenas entre pacientes com trismo e edema/atrofia dos músculos pterigoideos. Neste mesmo item foi observado associação com tumores de dimensão T4. Não encontramos associação do trismo com os demais itens avaliados na TC. / Objective: Evaluate by computed tomography (CT) singleslice changes in the structures of the masticator space, for loco-regional dissemination of malignancies originating in the tonsil, retromolar area, maxillary sinus and nasopharynx to correlate the CT findings with trismus and the tumor dimensions. Material and Methods: The medical records of patients with malignant tumors involving the four regions to be studied were selected from the archives of the Heliopolis Hospital. Patients submited previously to antineoplastic therapy or with local inflammatory or infectious diseases were excluded. The medical records were reviewed by a single examiner, where information was collected on age, gender, tumor location, disease evolution, tumor stage, and the presence or absence of trismus. After administration of iodinated contrast media, the protocol the image acquisition was axial slices 3mm, coronal acquisitions were made when necessary. The image analysis of the MS by two medical examiner residents in their 3rd year of Medical Radiology, at distinct moments , without prior knowledge of the clinical information. In the evaluation of the MS, the findings were transcribed to a specific worksheet, considering the presence or absence of the following items: symmetry with the contralateral MS, obliteration of the fat plane of the retromolar trigone and the pharyngeal space, edema, and/or the atrophy of the medial and lateral pterygoid muscles, and destruction of the mandibular ramus. Results: According to the adopted criteria for trismus in this study, the presence of trismus was observed in 10 patients. The association between tumor size and trismus shows that 90% of patients present size T4, while this percentage is 43% in patients without trismus. Analyzing in terms of odds ratios, the study showed that patients with T4 sized tumors had a chance of developing trismus 11.6 times greater than patients with T0 to T3 sized tumors. The neoplasms of tonsillar crypts and retromolar trigone aggregated 95% of the neoplasms evaluated. Only 5% of the cases accounted for neoplasms of nasopharynx, in which none of them presented the existence of trismus. No cases of neoplasm of maxillary sinus was found. Correlating the CT findings with the group of patients with trismus, the observation was made that 60% of patients with trismus showed edema and/or pterygoid muscle atrophy on CT, whereas this percentage was 21.8% in patients without trismus. Regarding the dimensions of the tumor and its relationship with the image findings, the detection of edema and/or atrophy of the pterygoid muscles was observed only in association with T4 sized tumors. In this instance, patients with edema and/or atrophy of the pterygoid muscles present a 5,4 times greater chance of having trismus. Conclusions: Observed in the following changes in TC IN: obliteration of fat plane in 69.2% of patients, 27.7% asymmetry, edema / atrophy in 26.2% of patients and 20% in bone destruction. The degree of inter examiners were variable. Association was found only among patients with trismus and edema / atrophy of the pterygoid muscles. In this same item was observed association with tumor size T4. We found no association of trismus with other items valued at TC.