OBJETIVO: Apresentar os resultados da técnica de derivação urinária continente descrita por Macedo, em relação à continência, achados operatórios e complicações cirúrgicas. MÉTODOS: De janeiro de 2006 a novembro de 2016, 29 pacientes foram submetidos à técnica de Macedo. Dados demográficos, tempo de hospitalização, tempo cirúrgico, tempo de seguimento, taxa de continência, capacidade do reservatório e complicações pós-operatórias foram avaliados. RESULTADOS: Sessenta e nove por cento eram masculinos e a mediana de idade foi de 16,9 anos. A etiologia principal foi meningomielocele (69,1%). A média do tempo cirúrgico foi 4,2 h (DP 0,9 2,9-6,3). A mediana do tempo de internação foi 10 dias (IIQ: 11,3; 5-51). A média de seguimento foi 3,3 anos (DP 2,2 0,3 – 9,8). Procedimento no colo vesical foi realizado em 12 pacientes (41,3%). A taxa de continência do conduto cateterizável foi de 82,8%. A capacidade do reservatório aumentou de 134,4 para 364,4 ml (p <0.0001). A taxa de continência melhorou significativamente (20 vs. 74%, p <0.0001). Não houve mudança na taxa de filtração glomerular a longo prazo (143.1 vs. 147 ml/min, p = 0.45). Taxa de morbidade foi 58% (25 complicações em 17 pacientes), 72% ocorreram nos primeiros 60 dias e 60% foram classificadas Clavien-Dindo I ou II. CONCLUSÃO: Nossos resultados em relação a taxas de continência, tempo cirúrgico e complicações demonstram que a enterocistoplastia de Macedo é viável, reprodutível e com bons resultados. / OBJECTIVE: To present the results of technique of continent urinary diversion, described by Macedo, in relation to continence, operative findings and postoperative complications. METHODS: From January 2006 to November 2016, 29 patients were underwent to urinary diversion by Macedo’s technique. Patients demographics, hospitalization time, surgical time, follow up, continence rate, reservoir capacity and postoperative complications were evaluated. RESULTS: Sixty nine percent were male and the median age was 16.9 years. The main etiology was meningomyelocele (69.1%). The mean surgical time was 4.2 hours (SD 0.9 range 2.9-6.3). The median length of hospital stay was 10 days (IQR: 11.3 range 5-51). The mean follow up was 3.3 years (SD 2.2 range 0.3 - 9.8). Procedure in the bladder neck was performed in 12 patients (41.3%). The continence rate of the catheterizable conduit was 82.8%. The reservoir capacity increased from 134.4 to 364.4 ml (p <0.0001). The continence rate improved significantly (20 vs. 74%, p <0.0001). There was no change in glomerular filtration rates in the long term (143.1 vs. 147 ml/min, p = 0.45). Morbidity rate was 58% (25 complications in 17 patients), 72% occurred within the first 60 days and 60% were classified as Clavien-Dindo I or II. CONCLUSION: Our results regarding continence rates, surgical time and complications demonstrated that Macedo’s enterocystoplasty is feasible, reproducible and with good result.

No description available.

Introdução: Apesar de recentes inovações e aprimoramentos no tratamento do Câncer de Bexiga (CaB) não músculo invasivo, o índice de progressão e recorrência continuam altos possivelmente devido a tumores residuais ou não evidenciados na ressecção transuretral de bexiga (RTU), o que profundamente afeta o prognóstico desta doença e evidencia a importância da qualidade desse procedimento padrão não só para o diagnóstico, mas também para o estadiamento e tratamento do tumor de bexiga. A presença de muscular própria no espécime é essencial para conduzir o tratamento, embora esta esteja presente apenas em cerca de 36-51% dos casos. Na sua ausência muitas vezes torna-se necessário um novo procedimento, vindo com isso a morbidade e os gastos de uma nova cirurgia. Dessa forma várias técnicas têm sido propostas com o intuito de melhorar a acurácia da RTUb, o que pode reduzir as ressecções incompletas e o subestadiamento. Objetivo: Avaliar a importância da biópsia de congelação do leito da lesão ressecada no que diz respeito ao estadiamento inicial e controle local da doença. Materiais e Métodos: Estudo prospectivo e randomizado dos pacientes com tumor de bexiga sem tratamento prévio que foram submetidos à RTUb no período de 09/2011 a 08/2013 em uma única instituição (Instituto do Câncer do Estado de São Paulo - ICESP). Esses pacientes foram submetidos à RTUb convencional, conforme o Guideline Europeu (EAU, 2011). No grupo 1, foi realizada biópsia de congelação do leito da lesão após a RTU, onde o cirurgião julgou esta ser possivelmente invasiva, aguardando análise do patologista quanto a presença de muscular própria, se caso esta não estivesse representada, era feita nova biópsia até sua representatividade. O grupo 2 são os controles não sendo submetidos à biópsia de congelação. Foram incluídos apenas os pacientes que tiveram critério e foram submetidos à re-RTUb. Um total de 150 pacientes foram randomizados, tornando-se elegíveis 131, sendo 64 no grupo 1 e 67 no grupo 2. Resultados: Comparando-se os grupos, não houve diferença em relação ao sexo, idade, quantidade e tamanho do tumor. No estudo anatomo-patológico da RTUb houve representatividade muscular em 100% x 58,5%, entre os grupos 1 e 2, respectivamente, com p < 0,001. Na Re-RTUb o índice de tumor residual foi 10,4% x 35,2%, entre os grupos 1 e 2, respectivamente, com p = 0,005. No grupo 1, 15 pacientes foram diagnosticados como pT2 com 100% do diagnóstico na primeira RTUb; no grupo 2, 6 pacientes tiveram diagnóstico de pT2 com apenas 33,3% na primeira RTUb, p=0,003. O tempo cirúrgico médio foi de 50 min no grupo 1 e 42min no grupo 2 (p= 0,037). Não houve diferença em relação à complicações (transfusão e perfuração vesical). Conclusão: A biópsia de congelação melhorou o correto estadiamento e controle local do câncer de bexiga, além de aumentar a acurácia do diagnóstico de doença pT2, podendo permitir o planejamento precoce do tratamento definitivo sem aumentar as complicações / Background and Purpose: Despite recent improvements of bladder cancer treatment, recurrence and progression rates are still high, possibly related to residual or overlooked tumors at the first transurethral resection (TUR), which strongly emphasizes the importance of the quality of this method. In order to improve the effectiveness of the procedure, we sought to evaluate the impact of frozen section during TUR, aiming on increasing muscular layer sample in the specimen, which may minimize incomplete resections and understaging. Patients and Methods: We prospectively included 150 consecutive patients assigned to TUR which were randomized to undergo either frozen section biopsy of the tumor bed during the TUR procedure until muscle was obtained or standard resection procedure (no frozen section). Nineteen patients were excluded after randomization, leaving 131 for analysis. All patients underwent a second TUR performed 4-6 weeks later. Frozen sections and final pathology reports were centralized and all performed by pathologists, the doubtful cases were reviewed by one uropathologist. Exclusion criteria: incomplete resection at first TUR, no criteria for second TUR according to EUA Guideline Update 2011 and previous bladder cancer treatment. (Group w/ biopsy, n = 64; Group control, n=67). Results: Both groups were comparable regarding age, gender, size and number of lesions. The majority of patients had high grade tumor in both groups. In the group where frozen section was obtained, muscle-invasive disease was higher (23% x 3%, p < 0,001). All patients in this group had muscle layer represented in the final pathology at the first TUR, while only 60% of patients in the control group (p < 0.001), including 40,5% of patients with pTa, 81,5% with pT1 e 100% with pT2 and Cis. Ninety percent of patients in the biopsy group had no residual tumor compared to 65% of the control group at second TUR (p=0,002). While all 15 patients in the frozen section group with T2 disease were diagnosed at first TUR, only 2 of 6 patients (33%) in the control group were diagnosed initially. The surgery duration was longer in the study group with mean of 50 min x 42 min (p=0,037) and there were no significant differences regarding complications (perforation and transfusion rates). Conclusion: Our results support the prove of principal that standard TUR with frozen section biopsy of bladder tumor bed increase the disease control and improve the diagnosis of T2 tumors, which may lead to reduced the number of patients in need a second TUR and avoid pT2 disease diagnosis delay, with no more complications

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Introdução: Apesar de recentes inovações e aprimoramentos no tratamento do Câncer de Bexiga (CaB) não músculo invasivo, o índice de progressão e recorrência continuam altos possivelmente devido a tumores residuais ou não evidenciados na ressecção transuretral de bexiga (RTU), o que profundamente afeta o prognóstico desta doença e evidencia a importância da qualidade desse procedimento padrão não só para o diagnóstico, mas também para o estadiamento e tratamento do tumor de bexiga. A presença de muscular própria no espécime é essencial para conduzir o tratamento, embora esta esteja presente apenas em cerca de 36-51% dos casos. Na sua ausência muitas vezes torna-se necessário um novo procedimento, vindo com isso a morbidade e os gastos de uma nova cirurgia. Dessa forma várias técnicas têm sido propostas com o intuito de melhorar a acurácia da RTUb, o que pode reduzir as ressecções incompletas e o subestadiamento. Objetivo: Avaliar a importância da biópsia de congelação do leito da lesão ressecada no que diz respeito ao estadiamento inicial e controle local da doença. Materiais e Métodos: Estudo prospectivo e randomizado dos pacientes com tumor de bexiga sem tratamento prévio que foram submetidos à RTUb no período de 09/2011 a 08/2013 em uma única instituição (Instituto do Câncer do Estado de São Paulo - ICESP). Esses pacientes foram submetidos à RTUb convencional, conforme o Guideline Europeu (EAU, 2011). No grupo 1, foi realizada biópsia de congelação do leito da lesão após a RTU, onde o cirurgião julgou esta ser possivelmente invasiva, aguardando análise do patologista quanto a presença de muscular própria, se caso esta não estivesse representada, era feita nova biópsia até sua representatividade. O grupo 2 são os controles não sendo submetidos à biópsia de congelação. Foram incluídos apenas os pacientes que tiveram critério e foram submetidos à re-RTUb. Um total de 150 pacientes foram randomizados, tornando-se elegíveis 131, sendo 64 no grupo 1 e 67 no grupo 2. Resultados: Comparando-se os grupos, não houve diferença em relação ao sexo, idade, quantidade e tamanho do tumor. No estudo anatomo-patológico da RTUb houve representatividade muscular em 100% x 58,5%, entre os grupos 1 e 2, respectivamente, com p < 0,001. Na Re-RTUb o índice de tumor residual foi 10,4% x 35,2%, entre os grupos 1 e 2, respectivamente, com p = 0,005. No grupo 1, 15 pacientes foram diagnosticados como pT2 com 100% do diagnóstico na primeira RTUb; no grupo 2, 6 pacientes tiveram diagnóstico de pT2 com apenas 33,3% na primeira RTUb, p=0,003. O tempo cirúrgico médio foi de 50 min no grupo 1 e 42min no grupo 2 (p= 0,037). Não houve diferença em relação à complicações (transfusão e perfuração vesical). Conclusão: A biópsia de congelação melhorou o correto estadiamento e controle local do câncer de bexiga, além de aumentar a acurácia do diagnóstico de doença pT2, podendo permitir o planejamento precoce do tratamento definitivo sem aumentar as complicações / Background and Purpose: Despite recent improvements of bladder cancer treatment, recurrence and progression rates are still high, possibly related to residual or overlooked tumors at the first transurethral resection (TUR), which strongly emphasizes the importance of the quality of this method. In order to improve the effectiveness of the procedure, we sought to evaluate the impact of frozen section during TUR, aiming on increasing muscular layer sample in the specimen, which may minimize incomplete resections and understaging. Patients and Methods: We prospectively included 150 consecutive patients assigned to TUR which were randomized to undergo either frozen section biopsy of the tumor bed during the TUR procedure until muscle was obtained or standard resection procedure (no frozen section). Nineteen patients were excluded after randomization, leaving 131 for analysis. All patients underwent a second TUR performed 4-6 weeks later. Frozen sections and final pathology reports were centralized and all performed by pathologists, the doubtful cases were reviewed by one uropathologist. Exclusion criteria: incomplete resection at first TUR, no criteria for second TUR according to EUA Guideline Update 2011 and previous bladder cancer treatment. (Group w/ biopsy, n = 64; Group control, n=67). Results: Both groups were comparable regarding age, gender, size and number of lesions. The majority of patients had high grade tumor in both groups. In the group where frozen section was obtained, muscle-invasive disease was higher (23% x 3%, p < 0,001). All patients in this group had muscle layer represented in the final pathology at the first TUR, while only 60% of patients in the control group (p < 0.001), including 40,5% of patients with pTa, 81,5% with pT1 e 100% with pT2 and Cis. Ninety percent of patients in the biopsy group had no residual tumor compared to 65% of the control group at second TUR (p=0,002). While all 15 patients in the frozen section group with T2 disease were diagnosed at first TUR, only 2 of 6 patients (33%) in the control group were diagnosed initially. The surgery duration was longer in the study group with mean of 50 min x 42 min (p=0,037) and there were no significant differences regarding complications (perforation and transfusion rates). Conclusion: Our results support the prove of principal that standard TUR with frozen section biopsy of bladder tumor bed increase the disease control and improve the diagnosis of T2 tumors, which may lead to reduced the number of patients in need a second TUR and avoid pT2 disease diagnosis delay, with no more complications

published_or_final_version / Pharmacology / Doctoral / Doctor of Philosophy

No description available.

Bladder obstruction (neurogenic or anatomic) induces strain injury in detrusor smooth muscle cells. Signaling via strain injury in other systems has been highly studied, while in bladder obstruction, it has been quite limited to a small number of pathways. In our study we have examined the effects of strain injury using a combination of in vivo, ex vivo and in vitro models, with the aim of understanding disease pathogenesis in the bladder. Using a combination of literature searches, phospho-protein screens and pathway analysis, we uncovered three pathways activated by mechanical strain, ERK, STAT3 and mTOR, with potential for changing not only the way we understand but also the way we treat obstructive myopathies of the bladder. We found that not only were these pathways activated in response to strain and distension injury of BSMC, but they were also responsible for proliferation and sometimes de-differentiation. Included herein are three chapters, published in 2006 and 2010, on the role of ERK, STAT3 and mTOR pathways in bladder smooth muscle cell proliferation and differentiation, 8 Appendices containing the first pages of other papers and reviews published during the course of my studies.

Urinary incontinence has already been identified worldwide for years as a health problem affecting essentially women, which can interfere with their overall quality of life. However in Rwanda, this problem has yet not been addressed adequately either because of lack of expertise, or because of cultural traditions associated with taboos among women. Social conditions of women facing this problem hinder them from seeking possibly adequate medical assistance. It is important that this problem be addressed because it may lead to disability, social seclusion, psychological stress and economic burdens. This study was a pioneer one, intended to diagnose the extent of the problem through determining the prevalence of urinary incontinence as well as its impact on the quality of life among women. The study will hopefully be followed by the promotion of physiotherapy to tackle the problem and therefore reduce the number of people suffering from urinary incontinence.

Diabetic cystopathy is a chronic and common complication of diabetes with a classical triad of symptoms; decreased bladder sensation, increased bladder capacity and impaired detrusor muscle contractility (Hunter and Moore, 2003). In animal models of diabetes such as streptozotocin-induced diabetes in the rat, abnormalities of bladder function have been reported (Longhurst and Belis, 1986). The prototypic TRPV channel, TRPV1, is activated by capsaicin, which has been shown to cause contraction of the rat bladder (Saitoh et al., 2007), and this is reduced in STZ-diabetic rat bladder (Pinna et al., 1994). Therefore we hypothesize that TRPV1 function will be reduced in the diabetic bladder. The aim of this study are the following: Firstly, to investigate the effect of the streptozotocin (STZ) model of diabetes on a range of TRP channel functions in the urinary bladder smooth muscle preparation using TRP channel agonists and antagonists and to study the neurotransmitters involved in the contractile or relaxant responses. Some studies were also performed on colon tissues. Secondly, to explore the involvement of cholesterol modudation in TRP channel signalling. Thirdly, to study the change in TRP channel response with time following the treatment with streptozotocin. The results showed that the contractile responses to the TRPV1 agonist capsaicin, TRPV4 agonist 4-α-PDD, and TRPA1 agonist allyl isothiocyanate were significantly reduced in diabetic bladder. The selective TRPV1 antagonist, SB-366791, inhibited the contractile responses to capsaicin confirming the involvement of TRPV1 channels. The effect of diabetes is unlikely to be at the level of contractile machinery since the contractile responses to muscarinic receptor agonist carbachol were not significantly reduced in diabetic tissues. It is reported for the first time that the combination of neurokinin 1 and 2 antagonists GR-205171 and SB-207164 inhibited the contractile responses to capsaicin suggesting that a neurokinin may be the neurotransmitter involved in the capsaicin responses. In addition, the reduction of the responses to capsaicin in STZ-induced diabetic tissues occurred not only in urinary bladder but also in colon. Cholesterol-PEG significantly lowered the maximal contractile responses to capsaicin of rat bladder strips. Methyl-β-cyclodextrin, α-cyclodextrin and β-cyclodextrin at the same concentrations enhanced the contractile responses to capsaicin in the control and diabetic rat bladder strips. These effects of cyclodextrin are specific to capsaicin activated contractions and not seen with TRPA1 activation, suggesting that the effects are not mediated downstream of channel activation. Since α-cyclodextrin does not sequester cholesterol, the enhanced responses to cyclodextrins may not be due to the cholesterol modulations. Instead, theses novel findings may possibly occur by changing the local membrane lipid environment of the TRPV1 channel. As early as 36 hours after induction of diabetes by STZ, the contractile responses to capsaicin were significantly reduced in comparison to those of the controls and this reduction persisted until the eight weeks time point. In contrast, responses to the TRPA1 agonist allyl isothiocyanate were not affected at early time points but were reduced one week after STZ treatment. This detailed time course analysis suggests that there are novel mechanisms of modulation of the TRPV1 channels in this STZ model. In conclusion, in the rat urinary bladder or colon preparations, diabetes mellitus using STZ animal model caused 1) the impairment of a number of TRP channel subfamily functions, TRPV1, TRPV4 and TRPA1 but not TRPM8. The combination of NK1 and NK2 antagonists significantly inhibited the responses to capsaicin. This may suggest the involvement of neurokinin in postsynaptic transmission in rat bladder following the activation of TRPV1 channel, 2) the impairment caused by STZ-induced diabetes occurred very early (within 36 hours after diabetes induction) in TRPV1 channel but not TRPA1 channel. There are specific early effects of STZ treatment on TRPV1 channel function at a time when other afferent nerve terminal channels (TRPA1) are functioning normally, suggesting that early onset of dysfunction in TRPV1 signalling may not merely be the consequence of nerve damage, 3) the mechanism of this impairment may not be the effect of neuropathy on neurotransmitter release or nerve damage. Improving the responsiveness of nerves of bladder in diabetic patients might be of therapeutic benefit. The present studies suggest that it is possible to enhance function using indirect modulators such as bradykinin which potentiated the TRPV1 channel function in diabetic rat bladders.