Yes / Patients' pharmacogenetic data could be used to improve adherence to antipsychotic medication by increasing the likelihood of therapeutic response and reducing the prevalence of adverse drug reactions.

No description available.

Introdução: A depressão é uma condição frequente, de curso crônico e recorrente, usualmente associada à incapacitação funcional e comprometimento significativo no desempenho das atividades diárias. Assim, o desempenho ocupacional do paciente depressivo pode ser prejudicado, ocorrendo desorganização da rotina diária, dificuldades para desempenhar papéis ocupacionais, sociais e tarefas que possuem como objetivo a automanutenção, a produtividade e o lazer. Estudos estimam que 30 a 50% dos pacientes depressivos não apresentam resposta terapêutica adequada aos tratamentos antidepressivos disponíveis atualmente, sendo estes considerados pacientes depressivos resistentes ao tratamento. Além disso, investigações científicas indicam que pacientes com estresse precoce (EP) possuem risco aumentado de desenvolver episódio depressivo recorrente e resistente, sintomas mais graves, mais tentativas de suicídio e maior probabilidade de apresentar comorbidades psiquiátricas associadas, o que dificultaria a resposta terapêutica. Objetivos: O primeiro estudo objetivou examinar a influência do EP na resposta terapêutica de pacientes depressivos, bem como, identificar qual a melhor abordagem terapêutica para esses pacientes a partir dos achados da literatura. O segundo estudo teve como objetivo analisar a relação entre os subtipos de EP de pacientes psiquiátricos adultos tratados em um programa de semiinternação psiquiátrica em Hospital Dia (HD), além de investigar as chances de ocorrência de depressão de acordo com as características sociodemográficas e clínicas desta amostra. O terceiro estudo objetivou avaliar o impacto do EP na gravidade dos sintomas psiquiátricos e no desempenho ocupacional de pacientes depressivos adultos. O quarto estudo teve como propósito avaliar a influência de fatores sociodemográficos, clínicos, do EP e do desempenho ocupacional na resposta terapêutica de pacientes depressivos adultos tratados em um programa de semi-internação psiquiátrica em HD. E o quinto estudo objetivou descrever uma intervenção grupal de terapia ocupacional para pacientes depressivos adultos com EP inseridos em um programa de semi-internação psiquiátrica em HD. Métodos: O primeiro estudo foi desenvolvido por meio de uma revisão sistemática da literatura, utilizando as palavras chaves: early life stress, childhood maltreatment, child abuse childhood trauma, childhood neglect, depression, major depression, depressive, treatment response, treatment outcome, prediction nas seguintes bases de dados: PubMed, WEB OF KNOWLEDGE, PsycINFO e Scopus, publicados em inglês, sem limitação de tempo. O segundo estudo foi desenvolvido com a avaliação de n=81 pacientes psiquiátricos divididos em duas amostras: com EP (n=58) e sem EP (n=23) no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto. Nesta avaliação foram utilizados os seguintes instrumentos: Mini Entrevista Neuropsiquiátrica Internacional (MINI-PLUS) para avaliação do diagnóstico psiquiátrico; Questionário Sobre Traumas na Infância (CTQ) para avaliação do EP; Inventário de Depressão de Beck II (BDI-II), Inventário de Ansiedade de Beck (BAI), Escala Hospitalar de Ansiedade e Depressão (HAD), Escala de Ideação Suicida de Beck (BSI), Escala de Desesperança de Beck (BHS), Escala de Impulsividade de Barratt (BIS-11), para avaliação dos sintomas psiquiátricos, além de uma ficha sóciodemográfica e clínica para coleta de dados do paciente. O terceiro estudo foi desenvolvido com n=91 pacientes em episódio depressivo atual divididos em duas amostras: com EP (n=62) e sem EP (n=25) em regime de semiinternação psiquiátrica na mesma instituição. Os participantes também responderam os questionários citados anteriormente, além da Escala de Avaliação de Depressão GRID de Hamilton (GRID-HAM-D21) para avaliação da gravidade da sintomatologia depressiva e a Medida Canadense do Desempenho Ocupacional (COPM) para avaliação da auto-percepção do cliente sobre o desempenho ocupacional. O quarto estudo foi desenvolvido com n=73 pacientes em episódio depressivo atual divididos em dois grupos de acordo com a resposta terapêutica na Escala de Avaliação para Depressão de Montgomery-Asberg (MADRS): respondedores (n=40) e não respondedores ao tratamento (n=33), em regime de semiinternação psiquiátrica na mesma instituição. Além dos questionários já citados anteriormente, os participantes também responderam a MADRS para avaliação da resposta terapêutica. Vale mencionar que o protocolo de avaliação psicométrica foi aplicado na admissão hospitalar e 60 dias após. O quinto estudo foi desenvolvido com 10 pacientes em episódio depressivo atual submetidos a um protocolo de 8 sessões de grupo de Terapia Ocupacional, utilizando-se de atividades expressivas e reflexivas para ressignificação das histórias de EP. Resultados: Na revisão sistemática foram incluídos 21 estudos sobre a temática estudada, sendo que a maioria dos estudos aponta que os diferentes subtipos de EP podem desencadear psicopatologias mais graves e mais incapacitantes no adulto, como a depressão. Além disso, o EP influencia no curso clínico e na resposta terapêutica de pacientes depressivos crônicos. Não há consenso na literatura sobre a abordagem terapêutica que apresenta maior eficácia para o paciente depressivo com EP, embora abordagens combinadas demonstrem eficácia superior. No segundo estudo foi evidenciado que a ocorrência de depressão na idade adulta está relacionada à situações de abuso emocional e sexual e negligência física na infância. Pacientes com abuso emocional na infância possuem uma prevalência 4.38 maior de depressão em comparação com aqueles sem história de EP. Os resultados do terceiro estudo indicaram que na amostra avaliada, 70.4% dos pacientes depressivos sofreram algum tipo grave de EP, comparados a 29.6% sem EP. Além disso, os pacientes depressivos com EP apresentaram maior impulsividade do que os sem EP. Foram observadas ainda correlações significativas entre a gravidade do EP e os sintomas depressivos, ansiosos e ideação suicida no grupo com EP. Os pacientes com EP apresentaram pior desempenho ocupacional quando comparados com os sem EP, apresentando prejuízos principalmente no trabalho. Os resultados do quarto estudo indicam que 45.3% dos pacientes depressivos não responderam ao tratamento, comparados a 54.7% respondedores ao tratamento. Verificamos ainda que o EP desempenhou um papel importante na resposta terapêutica dos pacientes depressivos, sendo que 60 dias após o tratamento pacientes depressivos com EP apresentaram sintomas graves de ideação suicida quando comparados aos sem EP 60 dias após a admissão. Os resultados do estudo cinco indicaram que o grupo dentro dos princípios da Terapia Ocupacional é uma estratégia importante para ressignificação das histórias traumáticas na infância e adolescência de pacientes em episódio depressivo atual. As atividades terapêuticas forneceram subsídios para o paciente exteriorizar e reelaborar as vivências do EP. Conclusões: A integração destes dados destaca a importância da influência do EP no desencadeamento de transtornos psiquiátricos, de modo especial na depressão, no seu curso clínico e resposta terapêutica, além da necessidade de novas formas de intervenções terapêuticas, como às desenvolvidas pela Terapia Ocupacional para a ressignificação das vivências de EP. Ressalta-se a necessidade de novos estudos para o aprimoramento da compreensão dos efeitos nocivos do EP nas psicopatologias depressivas no adulto. / Introduction: Depression is a common condition, chronic and recurrent course, usually associated with functional impairment and significant depletion in performing daily activities. Thus, the occupational performance of the depressive patient may be impaired, occurring disruption of daily routine, difficulty of playing occupational roles, and social tasks, which aims are self-maintenance, productivity and leisure. Studies estimate that 30 to 50% of the depressed patients don\'t have adequate therapeutic response to antidepressant treatments currently available, which are considered depressed patients resistant to treatment. Moreover, scientific research indicates that patients with early life stress (ELS) present increased risk of developing recurrent and resistant depressive episodes, more severe symptoms, more suicide attempts and are more likely to have associated psychiatric comorbidities, which would hinder the therapeutic response. Aims: The first study aimed to examine the influence of ELS in therapeutic response of depressed patients, as well as identify the best therapeutic approach for these patients from the literature findings. The second study aimed to analyze the relationship between ELS subtypes in adult psychiatric patients from psychiatric semihospitalization program in Day Hospital (DH), and to investigate the chances of occurrence of depression according to the sociodemographic and clinical characteristics of this sample. The third study aimed to evaluate the impact of the ELS on the severity of psychiatric symptoms and occupational performance in depressed adults. The fourth study aimed to evaluate the influence of sociodemographic and clinical factors, ELS and occupational performance in the treatment of adult patient\'s depressive response treated in a psychiatric semi-hospitalization program in DH. The fifth study aimed to describe an intervention group of occupational therapy for depressive adult patients with ELS treated in a psychiatric semi-hospitalization program in DH. Methods: The first study was developed through a systematic review of literature using the key words: early life stress, childhood maltreatment, child abuse childhood trauma, childhood neglect, depression, major depression, depressive, treatment response, treatment outcome, prediction, in the following databases: PubMed, WEB OF KNOWLEDGE, PsycINFO e Scopus, published in English, without time limitation. The second study was developed with the assessment of n= 81 psychiatric patients divided into two samples: with ELS (n= 58) and without ELS (n= 23), at the Clinics Hospital of Medical School of Ribeirão Preto. In this evaluation, the following instruments were applied: Mini International Neuropsychiatric Interview (MINI-Plus) for evaluation of psychiatric diagnosis; Childhood Trauma Questionnaire (CTQ) for evaluation of ELS; Beck Depression Inventory II (BDI-II), Beck Anxiety Inventory (BAI), Beck Hopelessness Scale (BHS), Beck Scale for Suicidal Ideation (BSI), Barratt Impulsiveness Scale (BIS-11), Hospital Anxiety and Depression Scale (HAD), for evaluation of psychiatric symptoms, as well as a social record for collecting demografic and clinic patients\' data. The third study was conducted with n=91 patients with current depressive episode divided in two samples: with ELS (n=62) and without ELS (n=25), in psychiatric semi-hospitalization regime at the same institution. Participants also answered the questionnaires mentioned previously, as well as GRID Hamilton Depression Rating Scale (GRID-HAM-D21) to assess the severity of depressive symptoms and the Canadian Occupational Performance Measure to evaluate the selfperception of the customer about his/her occupational performance. The fourth study was conducted with n= 73 patients with current depressive episode divided into two groups according to the therapeutic response for Montgomery-Asberg Depression Rating Scale (MADRS): responders (n=40) and non-responders to treatment (n=33) in psychiatric semihospitalization regime at the same institution. In addition to the questionnaires previously mentioned, participants also answered MADRS for evaluation of therapeutic response. It is worth mentioning that the psychometric assessment protocol was applied at admission and 60 days later. The fifth study was conducted with n=10 patients with current depressive episode submitted to a protocol of 8 Occupational Therapy group sessions, using expressive and reflective activities to reframe the stories of ELS. Results: Systematic review included 21 trials on the subject matter, and most studies indicate that different subtypes of ELS can trigger more severe and disabling psychopathologies in adults, such as depression. Furthermore, ELS influences the clinical course and in therapeutic response in chronic depressive patients. There is no consensus in the literature on therapeutic approach that is more effective for depressed patients with ELS, although combined approaches demonstrate superior effectiveness. In the second study, it was shown that the occurrence of depression in adulthood is related to situations of emotional abuse, sexual and physical neglect in childhood. Patients with history of emotional abuse in childhood have 4.38 times higher prevalence of depression when compared to those without ELS. The third study results indicated that from the sample studied, 70.4% of depressive patients experienced a severe type of ELS, compared to 29.6% without ELS. Furthermore, depressive patients with ELS presented greater impulsivity than those without ELS. Significant correlations were observed between the severity of ELS and depressive symptoms, anxiety and suicidal ideation in the group with ELS. Patients with ELS showed worse occupational performance when compared to those without ELS, especially at work. The results of fourth study indicate that 45.3% of depressed patients don\'t respond to treatment, compared to 54.7% that responds to treatment also we found that ELS performed an important role in therapeutic response of depressive patients, as after 60 days depressed patients with ELS showed severe symptoms of suicidal ideation compared to without ELS 60 days after admission. The results of the fifth study indicated that the group of occupational therapeutic approach is an important strategy to reframe the stories of traumatic childhood and adolescence in patients with current depressive episode. Therapeutic activities provided resources to patient for externalizing and reworking experiences of ELS.Conclusions: The integration of these data highlights the importance of the influence of ELS in the onset of psychiatric disorders, especially depression, in its clinical course and therapeutic answer, and the need for new forms of therapeutic interventions, such as those developed by the Occupational Therapy for reframing experiences of ELS. It is noteworthy the need for further studies to improve understanding of the harmful effects of ELS in depressive disorders in adults.

Introdução: A depressão é uma condição frequente, de curso crônico e recorrente, usualmente associada à incapacitação funcional e comprometimento significativo no desempenho das atividades diárias. Assim, o desempenho ocupacional do paciente depressivo pode ser prejudicado, ocorrendo desorganização da rotina diária, dificuldades para desempenhar papéis ocupacionais, sociais e tarefas que possuem como objetivo a automanutenção, a produtividade e o lazer. Estudos estimam que 30 a 50% dos pacientes depressivos não apresentam resposta terapêutica adequada aos tratamentos antidepressivos disponíveis atualmente, sendo estes considerados pacientes depressivos resistentes ao tratamento. Além disso, investigações científicas indicam que pacientes com estresse precoce (EP) possuem risco aumentado de desenvolver episódio depressivo recorrente e resistente, sintomas mais graves, mais tentativas de suicídio e maior probabilidade de apresentar comorbidades psiquiátricas associadas, o que dificultaria a resposta terapêutica. Objetivos: O primeiro estudo objetivou examinar a influência do EP na resposta terapêutica de pacientes depressivos, bem como, identificar qual a melhor abordagem terapêutica para esses pacientes a partir dos achados da literatura. O segundo estudo teve como objetivo analisar a relação entre os subtipos de EP de pacientes psiquiátricos adultos tratados em um programa de semiinternação psiquiátrica em Hospital Dia (HD), além de investigar as chances de ocorrência de depressão de acordo com as características sociodemográficas e clínicas desta amostra. O terceiro estudo objetivou avaliar o impacto do EP na gravidade dos sintomas psiquiátricos e no desempenho ocupacional de pacientes depressivos adultos. O quarto estudo teve como propósito avaliar a influência de fatores sociodemográficos, clínicos, do EP e do desempenho ocupacional na resposta terapêutica de pacientes depressivos adultos tratados em um programa de semi-internação psiquiátrica em HD. E o quinto estudo objetivou descrever uma intervenção grupal de terapia ocupacional para pacientes depressivos adultos com EP inseridos em um programa de semi-internação psiquiátrica em HD. Métodos: O primeiro estudo foi desenvolvido por meio de uma revisão sistemática da literatura, utilizando as palavras chaves: early life stress, childhood maltreatment, child abuse childhood trauma, childhood neglect, depression, major depression, depressive, treatment response, treatment outcome, prediction nas seguintes bases de dados: PubMed, WEB OF KNOWLEDGE, PsycINFO e Scopus, publicados em inglês, sem limitação de tempo. O segundo estudo foi desenvolvido com a avaliação de n=81 pacientes psiquiátricos divididos em duas amostras: com EP (n=58) e sem EP (n=23) no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto. Nesta avaliação foram utilizados os seguintes instrumentos: Mini Entrevista Neuropsiquiátrica Internacional (MINI-PLUS) para avaliação do diagnóstico psiquiátrico; Questionário Sobre Traumas na Infância (CTQ) para avaliação do EP; Inventário de Depressão de Beck II (BDI-II), Inventário de Ansiedade de Beck (BAI), Escala Hospitalar de Ansiedade e Depressão (HAD), Escala de Ideação Suicida de Beck (BSI), Escala de Desesperança de Beck (BHS), Escala de Impulsividade de Barratt (BIS-11), para avaliação dos sintomas psiquiátricos, além de uma ficha sóciodemográfica e clínica para coleta de dados do paciente. O terceiro estudo foi desenvolvido com n=91 pacientes em episódio depressivo atual divididos em duas amostras: com EP (n=62) e sem EP (n=25) em regime de semiinternação psiquiátrica na mesma instituição. Os participantes também responderam os questionários citados anteriormente, além da Escala de Avaliação de Depressão GRID de Hamilton (GRID-HAM-D21) para avaliação da gravidade da sintomatologia depressiva e a Medida Canadense do Desempenho Ocupacional (COPM) para avaliação da auto-percepção do cliente sobre o desempenho ocupacional. O quarto estudo foi desenvolvido com n=73 pacientes em episódio depressivo atual divididos em dois grupos de acordo com a resposta terapêutica na Escala de Avaliação para Depressão de Montgomery-Asberg (MADRS): respondedores (n=40) e não respondedores ao tratamento (n=33), em regime de semiinternação psiquiátrica na mesma instituição. Além dos questionários já citados anteriormente, os participantes também responderam a MADRS para avaliação da resposta terapêutica. Vale mencionar que o protocolo de avaliação psicométrica foi aplicado na admissão hospitalar e 60 dias após. O quinto estudo foi desenvolvido com 10 pacientes em episódio depressivo atual submetidos a um protocolo de 8 sessões de grupo de Terapia Ocupacional, utilizando-se de atividades expressivas e reflexivas para ressignificação das histórias de EP. Resultados: Na revisão sistemática foram incluídos 21 estudos sobre a temática estudada, sendo que a maioria dos estudos aponta que os diferentes subtipos de EP podem desencadear psicopatologias mais graves e mais incapacitantes no adulto, como a depressão. Além disso, o EP influencia no curso clínico e na resposta terapêutica de pacientes depressivos crônicos. Não há consenso na literatura sobre a abordagem terapêutica que apresenta maior eficácia para o paciente depressivo com EP, embora abordagens combinadas demonstrem eficácia superior. No segundo estudo foi evidenciado que a ocorrência de depressão na idade adulta está relacionada à situações de abuso emocional e sexual e negligência física na infância. Pacientes com abuso emocional na infância possuem uma prevalência 4.38 maior de depressão em comparação com aqueles sem história de EP. Os resultados do terceiro estudo indicaram que na amostra avaliada, 70.4% dos pacientes depressivos sofreram algum tipo grave de EP, comparados a 29.6% sem EP. Além disso, os pacientes depressivos com EP apresentaram maior impulsividade do que os sem EP. Foram observadas ainda correlações significativas entre a gravidade do EP e os sintomas depressivos, ansiosos e ideação suicida no grupo com EP. Os pacientes com EP apresentaram pior desempenho ocupacional quando comparados com os sem EP, apresentando prejuízos principalmente no trabalho. Os resultados do quarto estudo indicam que 45.3% dos pacientes depressivos não responderam ao tratamento, comparados a 54.7% respondedores ao tratamento. Verificamos ainda que o EP desempenhou um papel importante na resposta terapêutica dos pacientes depressivos, sendo que 60 dias após o tratamento pacientes depressivos com EP apresentaram sintomas graves de ideação suicida quando comparados aos sem EP 60 dias após a admissão. Os resultados do estudo cinco indicaram que o grupo dentro dos princípios da Terapia Ocupacional é uma estratégia importante para ressignificação das histórias traumáticas na infância e adolescência de pacientes em episódio depressivo atual. As atividades terapêuticas forneceram subsídios para o paciente exteriorizar e reelaborar as vivências do EP. Conclusões: A integração destes dados destaca a importância da influência do EP no desencadeamento de transtornos psiquiátricos, de modo especial na depressão, no seu curso clínico e resposta terapêutica, além da necessidade de novas formas de intervenções terapêuticas, como às desenvolvidas pela Terapia Ocupacional para a ressignificação das vivências de EP. Ressalta-se a necessidade de novos estudos para o aprimoramento da compreensão dos efeitos nocivos do EP nas psicopatologias depressivas no adulto. / Introduction: Depression is a common condition, chronic and recurrent course, usually associated with functional impairment and significant depletion in performing daily activities. Thus, the occupational performance of the depressive patient may be impaired, occurring disruption of daily routine, difficulty of playing occupational roles, and social tasks, which aims are self-maintenance, productivity and leisure. Studies estimate that 30 to 50% of the depressed patients don\'t have adequate therapeutic response to antidepressant treatments currently available, which are considered depressed patients resistant to treatment. Moreover, scientific research indicates that patients with early life stress (ELS) present increased risk of developing recurrent and resistant depressive episodes, more severe symptoms, more suicide attempts and are more likely to have associated psychiatric comorbidities, which would hinder the therapeutic response. Aims: The first study aimed to examine the influence of ELS in therapeutic response of depressed patients, as well as identify the best therapeutic approach for these patients from the literature findings. The second study aimed to analyze the relationship between ELS subtypes in adult psychiatric patients from psychiatric semihospitalization program in Day Hospital (DH), and to investigate the chances of occurrence of depression according to the sociodemographic and clinical characteristics of this sample. The third study aimed to evaluate the impact of the ELS on the severity of psychiatric symptoms and occupational performance in depressed adults. The fourth study aimed to evaluate the influence of sociodemographic and clinical factors, ELS and occupational performance in the treatment of adult patient\'s depressive response treated in a psychiatric semi-hospitalization program in DH. The fifth study aimed to describe an intervention group of occupational therapy for depressive adult patients with ELS treated in a psychiatric semi-hospitalization program in DH. Methods: The first study was developed through a systematic review of literature using the key words: early life stress, childhood maltreatment, child abuse childhood trauma, childhood neglect, depression, major depression, depressive, treatment response, treatment outcome, prediction, in the following databases: PubMed, WEB OF KNOWLEDGE, PsycINFO e Scopus, published in English, without time limitation. The second study was developed with the assessment of n= 81 psychiatric patients divided into two samples: with ELS (n= 58) and without ELS (n= 23), at the Clinics Hospital of Medical School of Ribeirão Preto. In this evaluation, the following instruments were applied: Mini International Neuropsychiatric Interview (MINI-Plus) for evaluation of psychiatric diagnosis; Childhood Trauma Questionnaire (CTQ) for evaluation of ELS; Beck Depression Inventory II (BDI-II), Beck Anxiety Inventory (BAI), Beck Hopelessness Scale (BHS), Beck Scale for Suicidal Ideation (BSI), Barratt Impulsiveness Scale (BIS-11), Hospital Anxiety and Depression Scale (HAD), for evaluation of psychiatric symptoms, as well as a social record for collecting demografic and clinic patients\' data. The third study was conducted with n=91 patients with current depressive episode divided in two samples: with ELS (n=62) and without ELS (n=25), in psychiatric semi-hospitalization regime at the same institution. Participants also answered the questionnaires mentioned previously, as well as GRID Hamilton Depression Rating Scale (GRID-HAM-D21) to assess the severity of depressive symptoms and the Canadian Occupational Performance Measure to evaluate the selfperception of the customer about his/her occupational performance. The fourth study was conducted with n= 73 patients with current depressive episode divided into two groups according to the therapeutic response for Montgomery-Asberg Depression Rating Scale (MADRS): responders (n=40) and non-responders to treatment (n=33) in psychiatric semihospitalization regime at the same institution. In addition to the questionnaires previously mentioned, participants also answered MADRS for evaluation of therapeutic response. It is worth mentioning that the psychometric assessment protocol was applied at admission and 60 days later. The fifth study was conducted with n=10 patients with current depressive episode submitted to a protocol of 8 Occupational Therapy group sessions, using expressive and reflective activities to reframe the stories of ELS. Results: Systematic review included 21 trials on the subject matter, and most studies indicate that different subtypes of ELS can trigger more severe and disabling psychopathologies in adults, such as depression. Furthermore, ELS influences the clinical course and in therapeutic response in chronic depressive patients. There is no consensus in the literature on therapeutic approach that is more effective for depressed patients with ELS, although combined approaches demonstrate superior effectiveness. In the second study, it was shown that the occurrence of depression in adulthood is related to situations of emotional abuse, sexual and physical neglect in childhood. Patients with history of emotional abuse in childhood have 4.38 times higher prevalence of depression when compared to those without ELS. The third study results indicated that from the sample studied, 70.4% of depressive patients experienced a severe type of ELS, compared to 29.6% without ELS. Furthermore, depressive patients with ELS presented greater impulsivity than those without ELS. Significant correlations were observed between the severity of ELS and depressive symptoms, anxiety and suicidal ideation in the group with ELS. Patients with ELS showed worse occupational performance when compared to those without ELS, especially at work. The results of fourth study indicate that 45.3% of depressed patients don\'t respond to treatment, compared to 54.7% that responds to treatment also we found that ELS performed an important role in therapeutic response of depressive patients, as after 60 days depressed patients with ELS showed severe symptoms of suicidal ideation compared to without ELS 60 days after admission. The results of the fifth study indicated that the group of occupational therapeutic approach is an important strategy to reframe the stories of traumatic childhood and adolescence in patients with current depressive episode. Therapeutic activities provided resources to patient for externalizing and reworking experiences of ELS.Conclusions: The integration of these data highlights the importance of the influence of ELS in the onset of psychiatric disorders, especially depression, in its clinical course and therapeutic answer, and the need for new forms of therapeutic interventions, such as those developed by the Occupational Therapy for reframing experiences of ELS. It is noteworthy the need for further studies to improve understanding of the harmful effects of ELS in depressive disorders in adults.

Submitted by admin tede (tede@pucgoias.edu.br) on 2017-10-02T12:52:56Z No. of bitstreams: 1 JOSÉ ANTONIO VIANA DE MORAIS 3.pdf: 4387158 bytes, checksum: 813e3206f05ae2289634baf546698b46 (MD5) / Made available in DSpace on 2017-10-02T12:52:57Z (GMT). No. of bitstreams: 1 JOSÉ ANTONIO VIANA DE MORAIS 3.pdf: 4387158 bytes, checksum: 813e3206f05ae2289634baf546698b46 (MD5) Previous issue date: 2010-05-26 / Human papillomavirus (HPV) is one of the infections through sexual intercourse more often disseminated throughout the world. In Brazil it is estimated that there are around 3 to 6 million cases of HPV. There are few studies about HPV in men. This study examined the therapeutic response of patients men infected with HPV and treated topic with a solution of 90% trichloroacetic acid (ATA 90%). Were treated between January 2007 and December 2008, at the Hospital for Tropical Diseases in Araguaina (TO) 1056 patients undergoing clinical analysis by means of physical examination and penioscopia. The records of these patients were analyzed and found that 589 (55.8%) were diagnosed with HPV. Of these, 529 were selected for study as these met the following inclusion criteria: patients with macroscopic and penioscópico of HPV, which did not undergo any treatment before consultation, which were treated only with ATA 90% before and monitored for any recurrence, at least twelve months. After collecting data it was found that only 68 (12,8%) patients treated with ATA 90% had recurrence of lesions. The age of initial and final of HPV ranged from 18 to 73 years. The average age of patients with recurrence was 34.9 years, coinciding with the peak of sexual activity and the presence of multiple parters. About 80% of cases of recurrence occurred in the first six months. The association with other sexual diseases was recorded and the most prevalent pathologies: balanoposthistis (31,3%), genital herpes (9,2%), gonococal urethritis (2,8%) and no-gonococcal urethritis (0,9%). We found that the presence of other STDs contributes to treatment failure, whereas 75% of cases had tumor recurrence ATA 90% occurred in patients with an STD associated with HPV. Regarding the location of the lesions, it was found that 61.1% occurred at the distal end of the male phallus. The number of lesions detected per patient ranged from 1 to 9, with the majority (82.3%) patients had 2-5 lesions. In this study, we identified that the prevalence of HPV infection in men, STD clinic with urological monitoring was high. The therapeutic efficacy of ATA 90% was higher than the values commonly found in the literature and the recurrence rate of patients was low. We suggest that monitoring of patients with HPV after treatment with ATA is 90% done with routine queries for up to twenty-four months and quarterly consultations with the cases of recurrence. We emphasize the need for a focus on serving the man aiming to prevent controllable diseases evolve into malignancies. / O papilomavírus humano (HPV) é uma das infecções por via sexual mais frequentemente disseminadas em todo o mundo. No Brasil estima-se que existam em torno de 3 a 6 milhões de casos de HPV. Há poucos estudos sobre o HPV em homens. Este trabalho analisou a resposta terapêutica de pacientes do sexo masculino infectados HPV e tratados topicamente com solução de ácido tricloroacético à 90% (ATA 90%). Foram atendidos entre janeiro de 2007 e dezembro de 2008, no ambulatório do Hospital de Doenças Tropicais de Araguaína (TO), 1056 pacientes submetidos a analise clínica por meio do exame físico minucioso e penioscopia. Os prontuários desses pacientes foram analisados e verificou-se que 589 (55,8%) apresentaram diagnóstico de HPV. Destes, 529 foram selecionados para o estudo por atenderem aos seguintes critérios de inclusão: pacientes com diagnóstico macroscópico e penioscópico de HPV, que não realizaram qualquer tratamento antes da consulta, que foram tratados exclusivamente com ATA 90% antes de qualquer recidiva e monitorados por, no mínimo, doze meses. Após coleta de dados verificou-se que apenas 68 (12,8%) pacientes que realizaram tratamento com ATA 90% apresentaram recidiva das lesões. A faixa etária de acometimento do HPV variou de 18 a 73 anos. A idade média dos pacientes com recidiva foi de 34,9 anos, coincidente com o pico de atividade sexual e a presença de múltiplos parceiros. Cerca de 80% dos casos de recidiva ocorreram nos seis primeiros meses. A associação com outras DSTs foi observada, sendo as patologias mais prevalentes: a balanopostite (31,3%), o herpes genital (9,2%), a uretrite gonocócica (2,8%) e a uretrite não gonocócica (0,9%). Verificamos que a presença de outra DST contribui para o insucesso terapêutico, visto que 75% dos casos de recidiva pós ATA 90% ocorreram em pacientes portadores de alguma DST associada ao HPV. Em relação à localização das lesões, verificou-se que 61,1% ocorreram na extremidade distal do falo masculino. O número de lesões encontradas por paciente variou de 1 a 9, sendo que a maioria (82,3%) dos pacientes apresentou de 2 a 5 lesões. Neste estudo, identificamos que a prevalência da infecção por HPV em homens, em ambulatório de DST com acompanhamento urológico foi elevada. A eficácia terapêutica do ATA 90% mostrou-se maior que os valores comumente encontrados na literatura e o índice de recidiva dos pacientes foi baixo. Sugerimos que o acompanhamento dos pacientes com HPV após o tratamento com ATA 90% seja realizado com consultas rotineiras por até vinte e quatro meses e com consultas trimestrais para os casos de recidiva. Reforçamos a necessidade de um enfoque no atendimento do homem com intuito de evitar que doenças controláveis evoluam para doenças oncológicas.

Die Rheumatoide Arthritis (RA) ist eine der häufigsten Autoimmunerkrankungen des Menschen. Sie ist durch einen chronischen Verlauf mit Allgemeinsymptomen und erosiven Gelenkentzündungen gekennzeichnet. Die klinischen Beschwerden reichen von Morgensteifigkeit der Gelenke bis zu deren Funktionsverlust mit Deformationen. Extraartikuläre Manifestationen, vor allem das kardiovaskuläre System betreffend, erschweren den Krankheitsverlauf und verkürzen die Lebenserwartung. In der Pathogenese der RA steht die Synovitis, die Entzündung der Gelenkinnenhaut, im Mittelpunkt. Die Ansammlung von Lymphozyten und Monozyten in der Synovialmembran und sezernierte proinflammatorische Zytokine bewirken eine Aufrechterhaltung des Entzündungsgeschehens. Das hauptsächlich von Monozyten produzierte Zytokin Tumornekrosefaktor (TNF) spielt eine entscheidende Rolle in diesem Immunprozess. TNF stimuliert Fibroblasten zur Sezernierung destruktiver Enzyme und regt zur Produktion weiterer, proinflammatorischer Botenstoffe an. Klassischerweise wirkt TNF in seiner löslichen Form und bindet an TNF-Rezeptoren auf nahezu allen Körperzellen. Ein weiterer Wirkmechanismus ist die retrograde Signaltransduktion über membranständiges TNF (tmTNF). Die Funktion von tmTNF, als Rezeptor Signale in die tmTNF-tragende Zelle zu vermitteln, wird als Reverse Signaling bezeichnet. Es ist bekannt, dass Reverse Signaling via tmTNF in Monozyten von RA-Patienten Apoptose auslöst und in weiteren komplexen Immunprozessen involviert ist. Die Bedeutung von TNF für die Rheumatoide Arthritis wird nicht zuletzt dadurch unterstrichen, dass die anti-TNF-Therapie einen sehr wirksamen Therapieansatz darstellt. Die Behandlung führt bei ca. zwei Drittel der Patienten zu einer Reduktion der entzündlichen und schmerzhaften Gelenkschwellung und zu einem Sistieren der Gelenkdestruktion. Es ist jedoch bekannt, dass ein Teil der Patienten schlecht auf die Therapie anspricht. Das dadurch verzögerte Erreichen eines guten Therapieerfolgs führt zu einer Verlängerung des Leidens und zu unnötigen, zum Teil schwerwiegenden Nebenwirkungen. Gesundheitsökonomisch ist dies ebenfalls kritisch zu sehen, da mit hohen Behandlungskosten zu rechnen ist. Eine Vorhersage des Therapieansprechens ist jedoch aktuell nicht möglich. Ziel dieser Studie war es, einen prädiktiven Marker für das anti-TNF-Therapieansprechen bei Patienten mit RA zu finden. Dabei galt der Bedeutung des Reverse Signaling via tmTNF großes Interesse. In der Studie wurden 20 Patienten mit Rheumatoider Arthritis vor und während einer Therapie mit dem TNF-Antagonist Etanercept insgesamt 24 Wochen betreut. Die Erhebung klinischer Daten, wie die Anzahl der druckschmerzhaften und geschwollenen Gelenke, die Einschätzung der Krankheitsaktivität durch den Patienten auf einer visuellen Analogskala (VAS) und die Untersuchung der Entzündungsaktivität mit CRP und BSG, erfolgte einmalig vor und alle vier Wochen unter Therapie. Zur Einschätzung der Krankheitsaktivität wurde der Disease Activity Score (DAS) genutzt. Das Therapieansprechen wurde entsprechend einer Klassifikation und der Veränderung der einzelnen klinischen Parameter im Therapieverlauf gewertet. Auf der Suche nach einem prädiktiven Faktor wurden ebenfalls einmalig vor und alle vier Wochen während der Therapie mit Etanercept laborchemische Experimente durchgeführt. Dazu wurden aus dem Blut der RA-Patienten die Monozyten mit Hilfe einer Dichtegradientenzentrifugation und einer Magnetseparation isoliert. Diese wurden hinsichtlich ihrer Expression von tmTNF sowie TNFR1 und TNFR2 nach Inkubation mit entsprechenden Antikörpern durchflusszytometrisch untersucht. Weiterhin wurden die RA-Monozyten mit Etanercept bzw. einer Negativkontrolle inkubiert. Im Anschluss wurde die Apoptose der Monozyten mittels Durchflusszytometrie und Färbung mit Propidiumiodid bzw. Annexin V quantifiziert. Entsprechend den EULAR-Kriterien kam es bei 10 Patienten (53%) zu einem guten, bei 7 Patienten (37%) zu einem mittleren und bei 2 Patienten (10%) zu einem schlechten Ansprechen. Aufgrund der klinischer Beurteilung erfolgte eine Einteilung in zwei Gruppen, sodass unter den Patienten 10 Responder (53%) und 9 (47%) Non-Responder waren. Die Monozyten der RA-Patienten exprimierten tmTNF mit einer mittleren Fluoreszenzintensität (MFI) von 14,23 ± 3,04. Es wurde eine MFI für TNFR1 mit 31,84 ± 12,99 und für TNFR2 mit 30,02 ± 8,9 gemessen. Die Inkubation der RA-Monozyten mit Etanercept bzw. mit der Negativkontrolle ergab unterschiedliche Resultate innerhalb der Patientengruppe. Dabei wurde die Apoptose der Monozyten in Spontanapoptose (Negativkontrolle) und in Reverse Signaling induzierte Apoptose eingeteilt. Vor Beginn der anti-TNF-Therapie zeigte ein Teil der Patienten eine niedrige Spontanapoptose und eine erhöhte Reverse Signaling induzierte Apoptose. Die Monozyten der anderen RA-Patienten zeigten umgekehrt eine hohe Spontanapoptose und eine niedrige Reverse Signaling induzierte Apoptose. Im Folgenden wurde der Einfluss der Etanercept-Therapie auf die Apoptose der Monozyten untersucht. Es wurde ein Anstieg der niedrigen Spontanapoptose bzw. Reverse Signaling induzierte Apoptose und ein Abfall der hohen Spontanapoptose bzw. Reverse Signaling induzierte Apoptose gesehen. Bezieht man in die Analyse das Therapieansprechen mit ein, so ergibt sich für Responder eine initial hohe Spontanapoptose, die unter Therapie signifikant sinkt. Non-Responder hingegen haben vor Therapie eine niedrige Spontanapoptose, die unter einer Therapie mit Etanercept ansteigt. Für den Verlauf der Reverse Signaling induzierte Apoptose unter der anti-TNF-Therapie gab es keine signifikanten Unterschiede hinsichtlich des Therapieansprechens. Im Fisher-Exact-Test zeigte sich eine deutliche Tendenz (p=0,07), dass Patienten mit niedriger Spontanapoptose bzw. hoher Reverse Signaling induzierter Apoptose zu Studienbeginn schlecht auf die Therapie ansprechen. Dieses Ergebnis konnte mit Einzelparametern verifiziert werden. Die Studie kam zu dem Schluss, dass RA-Patienten, deren Monozyten eine niedrige Reverse Signaling induzierte Apoptose bzw. eine hohe Spontanapoptose aufwiesen, besser auf eine anti-TNF-Therapie mit Etanercept ansprachen. Dieses Ergebnis kann hilfreich für die Entwicklung einer entscheidenden Diagnostik vor Therapieeinstellung sein und leistet einen Beitrag für die Vorhersage des Therapieansprechens.

Therapeutic response assessment is a key component in adaptive image-guided radiotherapy. Conventional anatomic measures of response offer little information about the spatial distribution of tumor change. Recently developed voxel-wise response assessment methods operating on functional and biological imaging are better capable of evaluating the heterogeneity of response within the tumor, and thus may yield greater sensitivity than conventional approaches. However, voxel-wise analyses are limited by local registration uncertainties inherent to longitudinal imaging of tumors with changing morphology. A multi-resolution local histogram (LH) moment-based measure of voxel similarity was developed for the purpose of assessing the strength of correspondence between voxels of serial tumor images. This measure was first benchmarked through a series of experiments designed to establish robustness to image intensity variation and sensitivity to alterations in tissue structure through application of simulated deformations. The LH similarity method was subsequently developed as a means of mapping the spatial extent of structural change in tumors through the incorporation of an estimate of image complexity. The change maps were applied to a voxel-wise analysis of diffusion-weighted magnetic resonance imaging of patients with glioblastoma, acquired pre- and post-chemoradiotherapy. The sensitivity of the voxel-wise analysis in differentiating responding/stable patients from non-responding/progressing patients was improved by stratifying the analysis voxels according to regions of interest (ROI) based on the LH similarity-based estimate of tumor change. Meaningful correspondence relationships between evaluated voxels are essential for accurate image-based quantification of tumor structure and function with voxel-wise analysis techniques. The LH similarity methods developed here can robustly evaluate the quality of spatial and temporal voxel correspondence relationships and provide an automated tool for ROI selection and voxel change stratification. It is readily extendable to the analysis of the wide array of anatomic, functional and biological imaging currently used to characterize tumors, guide therapy and assess response.

Therapeutic response assessment is a key component in adaptive image-guided radiotherapy. Conventional anatomic measures of response offer little information about the spatial distribution of tumor change. Recently developed voxel-wise response assessment methods operating on functional and biological imaging are better capable of evaluating the heterogeneity of response within the tumor, and thus may yield greater sensitivity than conventional approaches. However, voxel-wise analyses are limited by local registration uncertainties inherent to longitudinal imaging of tumors with changing morphology. A multi-resolution local histogram (LH) moment-based measure of voxel similarity was developed for the purpose of assessing the strength of correspondence between voxels of serial tumor images. This measure was first benchmarked through a series of experiments designed to establish robustness to image intensity variation and sensitivity to alterations in tissue structure through application of simulated deformations. The LH similarity method was subsequently developed as a means of mapping the spatial extent of structural change in tumors through the incorporation of an estimate of image complexity. The change maps were applied to a voxel-wise analysis of diffusion-weighted magnetic resonance imaging of patients with glioblastoma, acquired pre- and post-chemoradiotherapy. The sensitivity of the voxel-wise analysis in differentiating responding/stable patients from non-responding/progressing patients was improved by stratifying the analysis voxels according to regions of interest (ROI) based on the LH similarity-based estimate of tumor change. Meaningful correspondence relationships between evaluated voxels are essential for accurate image-based quantification of tumor structure and function with voxel-wise analysis techniques. The LH similarity methods developed here can robustly evaluate the quality of spatial and temporal voxel correspondence relationships and provide an automated tool for ROI selection and voxel change stratification. It is readily extendable to the analysis of the wide array of anatomic, functional and biological imaging currently used to characterize tumors, guide therapy and assess response.

Le cancer médullaire de la thyroïde (CMT), qui représente 5 à 8% des cancers de la thyroïde, est issu de la transformation maligne des cellules C du parenchyme thyroïdien. Ce cancer, sporadique dans 70 à 80% des cas et familial pour les 20 à 30% restants, est essentiellement lié à des anomalies du proto-oncogène RET, codant un récepteur à activité tyrosine kinase. La fréquence élevée des mutations activatrices de RET ont permis d’identifier ce récepteur comme une cible thérapeutique majeure. Si la chirurgie est le traitement de référence pour les formes localisées, les formes localement avancées ou métastatiques, de pronostic plus péjoratif étaient avant le développement des thérapies moléculaires ciblées, dans une impasse thérapeutique. La meilleure compréhension de la biologie des tumeurs a permis le développement de ces thérapies plus rationnelles et plus spécifiques, en particulier des inhibiteurs d’activité tyrosine kinase (ITK). L’optimisation de leur utilisation en clinique nécessite de mieux comprendre leurs mécanismes d’action.Dans ce contexte, les objectifs de cette thèse ont été à la fois cognitifs et cliniques, visant à améliorer la compréhension de la réponse moléculaire à deux ITKs, le sunitinib et la vandetanib,dans le CMT, et à identifier de nouveaux biomarqueurs de suivi thérapeutique. Dans un premier temps, nous avons montré les effets antiprolifératifs, antitumoraux et antiangiogéniques du sunitinib et du vandetanib dans un modèle de CMT muté RETC634W, mettant en évidence des profils d’activité proches entre les deux inhibiteurs. Puis, les principales voies de signalisation mises en jeu lors de la réponse à ces ITKs ont été explorées par Reverse-Phase Protein Array(RPPA). Par une approche transcriptomique haut-débit menée sur des modèles précliniques, les principales fonctions cellulaires impliquées dans la réponse au sunitinib et au vandetanib ont été identifiées. Le rôle de gènes participant à l’invasion tissulaire et au pouvoir métastatique a été mis en évidence. De nouveaux biomarqueurs potentiels de réponse au vandetanib et au sunitinib, tels que l’IL-8 et le TGF-2 dont les taux sériques sont significativement plus élevés chez les patients atteints de CMT, ont été identifiés. Enfin, l’intérêt de trois approches méthodologiques dans lesuivi de la réponse antitumorale chez les patients a été évalué. Ainsi, le développement d’une méthode de dosage du vandetanib par spectrométrie de masse a permis de suggérer un lien entre des taux sériques élevés et l’apparition de toxicités sévères. L’évaluation de biomarqueurs dans le sérum de patients traités par le vandetanib a souligné l’intérêt de l’IL-8 comme marqueur pronostic potentiel dans cette pathologie. Enfin les résultats préliminaires, évaluant la réponse au sunitinib par échographie doppler sur un modèle préclinique de souris xénogreffées, ont confirmé l’intérêt de l’imagerie fonctionnelle dans ce domaine. / Medullary thyroid carcinoma (MTC) accounts for 5-8% of all thyroid cancers and occurs as either a sporadic form or in a familial context (25% of cases). Mutations which activate the RET proto-oncogene, encoding a tyrosine kinase receptor, are responsible for familial forms and are also detected in one-third of sporadic tumors. MTC patients with local disease may be cured after initial surgery, but persistent or recurrent disease occurs in half of cases, and distant metastases are the major cause of tumor related death. Up to now there is no effective systemic treatment and new therapeutic strategies are needed for locally advanced or metastatic MTC patients. The constitutive activation of RET is crucial in MTC pathogenesis and led to the development of small compounds targeting its tyrosine kinase activity (TKI). Gaining an understanding of how cancer cells respond to drugs is challenging to improve clinical use of these new therapeutic agents. In this context, we aimed to characterize molecular mechanisms of action of sunitinib and vandetanib, two TKIs currently evaluated in MTC patients. Our results, in in vitro as well as in vivo MTC models based on the RETC634W TT cell line, demonstrate that sunitinib and vandetanib has similar antiproliferative, antitumoral and antiangiogenic properties. Using the Reverse Phase Protein Array (RPPA) large-scale technology, we identified major signalling pathways inhibited after TKIs’ treatment. Expression microarrays allowed us to investigate signaling pathways modified after sunitinib and vandetanib treatment and to show that TKIs’ treatment induced major changes in the expression of genes involved in tissue invasion and metastasis. We identified encoding secreted proteins as candidate soluble biomarkers of response and, among them, we demonstrated that metastatic MTC patients presented increased serum levels of IL-8 and TGF-2. Three modalities for determining early responses to targeted agents in MTC patients were evaluated. First, a sensitive mass spectrometry assay was developed for the quantitation of vandetanib, and applied in MTC patients, showing a potential relationship between toxic side-effects and vandetanib serum levels and suggesting that therapeutic drug monitoring may be a useful tool for MTC patients’ follow-up. Then, candidate biomarkers were investigated in MTC patients underlying the potential use of IL-8 as prognostic marker. Finally, using doppler imaging in xenografted mice model, we confirmed the utility of imaging techniques in clinical evaluation of TKI’s response.

Background: Drugs targeting angiogenic pathway remain the mainstay of treatment for metastatic renal cell carcinoma (mRCC). Tyrosine Kinase Inhibitors (TKI) as Sunitinib, Pazopanib as single agents and humanised monoclonal antibody bevacizumab (Bev) in combination with Interferon- α2a (IFN) have established as the first-line therapy for mRCC. Despite improvements in treatment, there are multiple questions which remain unanswered. In the combination of Bev and IFN, the respective role of each drug and whether any additional anti-angiogenic activity is gained by adding IFN to Bev remains unknown. As the clinical benefit obtained with these cytostatic agents does not always correlate with the conventional response assessment techniques as RECIST, it is necessary to reconsider the methods by which we assess benefit from these therapies. In this thesis, I report three studies aiming to answer these questions. Methods: With the clinical trial reported here, I explore whether Bev induced changes in vascular parameters measured by Dynamic Contrast Enhanced MRI (DCE-MRI) is significantly enhanced by the addition of IFN. In a phase II, randomised, open labelled, multicentre trial, treatment naïve mRCC patients were randomised to receive Bev on its own or in combination with a low dose (3MU) or standard dose (9MU) IFN. DCE-MRI was used to assess the changes in vascularity with the primary endpoint being, changes in transfer coefficient (Ktrans) after six weeks of treatment. I also report two retrospective imaging-based studies, using contrast-enhanced CT scans, performed to improve the methodology of response assessment for these antiangiogenic therapeutics. Here I explore the use of a) combining changes in size and arterial phase contrast enhancement measured using CT scan and b) changes in CT texture as methods of therapeutic response assessment in mRCC patients treated with TKI. Results: With the phase 2 clinical trial, we faced significant difficulty in recruitment as a result of restrictions in access to treatment in NHS, other competing studies and restrictions proposed by the DCE-MRI inclusion criteria. With slow recruitment, an unplanned analysis was performed after 21 patients were recruited. Analysis of primary endpoint showed no trend in the difference between arms with no correlation found between change in Ktrans and addition of IFN to bevacizumab. Effect size analysis performed due to the small numbers recruited failed to show any significance in the observed difference in Ktrans. Change in Ktrans and Kep may identify a group of patients likely to have PFS > 6 months, but this observation needs to evaluation in a larger sample size. Measuring size and change in arterial phase enhancement retrospectively using CT, a new criterion "modified" Choi, which prerequisite a combination of a decrease in arterial phase density by 15% and a decrease in size by 10% for response was proposed. Response assessment was measured with RECIST, Choi and modified Choi individually in 20 evaluable patients retrospectively and clinical benefit compared with Kaplan-Meier statistics and Log-Rank test. Response assessment as defined by the modified Choi criteria successfully identified patients who received clinical benefit from the treatment. Time to progression (TTP) was 448 days for the partial response and 89 days for stable disease as per the new criteria which were statistically significant with a p-value of 0.002. The second retrospective analysis explored the textural changes in enhanced CT scan. Performed in collaboration with researchers from Brighton University who developed the software algorithm used to assess changes in entropy and uniformity, 87 metastases from 39 patients with mRCC were analysed at baseline and after two cycles of TKI treatment. Textural parameters and response assessment criteria were correlated with TTP. After two cycles of TKI, the decrease in tumour entropy was 3%-45%, and increase in uniformity was 5%-21%. At a threshold change of -2% with uniformity, on a coarse scale of 2.5, the textural change was able to separate responders from non-responders. With Kaplan-Meier analysis comparing all four criteria, the percentage change in uniformity was statistically more significant than for RECIST, Choi, and Modified Choi criteria. Cox regression analysis showed that texture uniformity was an independent predictor of time to progression. Discussion: With the studies reported here, I was able to demonstrate the importance of improving the methodology in assessment of therapeutic response to targeted anti-angiogenic therapy in metastatic renal cell carcinoma. Even though the clinical trial, terminated early due to slow recruitment, did not reach its primary endpoint, changes in other vascular parameters as Kep combined with changes Ktrans showed tendency towards identifying a group of patients who derived clinical benefit of >6months with these therapies. This is particularly exciting as given the vascular stabilisation effect proposed for bevacizumab, the effusion parameter Kep may be a better tool in assessing response rather than Ktrans and warrants further assessment in a larger cohort. Modified choi criterion and textural analysis are two important methodological improvements in response assessment of cytostatic anti-angiogenic therapy. In the analyses reported here, both techniques have shown superiority over RECIST in response assessment and differentiating mRCC patients who is likely to gain clinical benefit by TKI therapy. Validation of these criteria on a larger patient cohort is important. As these criterions are assessed on standard enhanced CT scans, incorporating these criteria, especially modified choi criterion, as part of standard CT assessment could be performed and will provide a real world validation. Retrospective assessment using larger cohort of patients from previous phase 3 trials or inclusion of these parameters prospectively in phase 3 trials would also help us in evaluating these modalities further.