京都大学 / 新制・論文博士 / 博士(医学) / 乙第13421号 / 論医博第2229号 / 新制||医||1052(附属図書館) / (主査)教授 伊達 洋至, 教授 大鶴 繁, 教授 中山 健夫 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Introdução: A Síndrome HELLP é uma complicação das formas graves de préeclampsia caracterizada por hemólise, elevação das enzimas hepáticas e plaquetopenia. O tratamento gera discussão principalmente nos casos abaixo de 34 semanas. Objetivos: Caracterizar a população internada com diagnóstico de Síndrome HELLP no HCFMUSP entre 2001 a 2011. Associar os parâmetros clínicos e laboratoriais maternos como preditores de complicações maternas e perinatais. Caracterizar os resultados perinatais e complicações maternas na conduta conservadora. Método: Estudo retrospectivo observacional e analítico. Resultados: Foram internadas 51 pacientes. A idade média foi de 27,48 anos, a maioria foi da cor branca (47%) e com pelo menos mais de 1 gestação (62,75%). Apenas 15,69% apresentavam hipertensão arterial crônica. A idade Gestacional média foi 30,94 semanas. Os sintomas clínicos e exames laboratoriais maternos não apresentaram relação com as complicações maternas e resultados perinatais. As complicações maternas não apresentaram relação com resultados perinatais, exceto a Idade gestacional. A conduta conservadora foi possível em 16 pacientes com ganho médio de 12,94 dias na gestação. As complicações maternas foram insuficiência renal aguda em 3 casos, descolamento de placenta em 2 casos e iminência de eclampsia em 1 caso. As complicações perinatais foram sepse em 10 casos, angústia respiratória em 10 casos, hemorragia intracraniana em 2 casos, enterocolite necrosante em 2 casos, Apgar < 7 no 5° min. em 2 casos e óbito neonatal tardio em 2 casos, permanência no berçário em média de 41,47 ± 21,75 dias. A idade gestacional média no parto foi de 30,56 ± 3,41 semanas. O peso médio dos recém-nascidos foi 1.116,64 ± 393,52 g. A conduta resolutiva foi necessária em 19 pacientes e as complicações maternas observadas foram insuficiência renal aguda em 5 casos, descolamento de placenta em 1 caso, iminência de eclampsia em 4 casos e eclampsia em 4 casos. As complicações perinatais foram sepse em 12 casos, angústia respiratória em 10 casos, hemorragia intracraniana em 4 casos, Apgar < 7 no 5° min. em 3 casos e óbito neonatal tardio em 2 casos, permanência no berçário em média de 58 ± 23 dias. A idade gestacional média no parto foi de 28,93 ± 2,11 semanas. O peso médio dos recém-nascidos foi 1.090 ± 307,49 g. Conclusão: Não há relação direta entre a gravidade da doença materna e resultados perinatais adversos. A Idade gestacional foi a única variável determinante para os resultados perinatais. Na conduta conservadora houve ganho de 2 semanas na gestação e 17 dias a menos de permanência no berçário / Introduction: The HELLP syndrome is a complication of severe forms of preeclampsia characterized by hemolysis, elevated liver enzymes and thrombocytopenia. The treatment is questioned especially in cases before 34 weeks. Objectives: This study aims to characterize the population of hospitalized patients with HELLP Syndrome at HCFMUSP 2001-2011. To associate maternal clinical and laboratory parameters as predictives for maternal complications and adverse perinatal outcomes. Other aim is to charaterize maternal and perinatal outcomes in the expectant management. Methods: This is a retrospective observational and analytical study. Results: There were 51 patients hospitalized. The mean age was 27.48 years, most were white (47%) and had at least one pregnancy (62.75%). Only 15.69% had chronic arterial hypertension. The average gestational age was 30.94 weeks. The maternal clinical symptoms and laboratory tests did not correlate with maternal complications and perinatal outcomes. Maternal complications were not associated with perinatal outcomes except gestational age. Expectant management was possible in 16 patients with in average gain of 12.94 days of pregnancy. Maternal complications were acute renal failure in 3 cases, placental abruption in 2 cases and imminent eclampsia in 1 case. Perinatal complications were neonatal sepsis in 9 cases, respiratory distress syndrome in 10 cases, intracranial hemorrhage in 1 case, Apgar score less than 7 at 5° minute in 2 cases and neonatal late death in 2 cases, period of hospitalization in average of 41.47 ± 21.75 days. The gestational age at delivery was in average 30.8 ± 3.41 weeks. The weight of the newborns was in average 1116.64 ± 393.52 in average. Immediate interruption was need in 19 patients and the maternal complications were acute renal failure in 5 cases, placental abruption in 1 case and imminent eclampsia in 3 cases, eclampsia in 4 cases; Perinatal complications were: neonatal sepsis in 12 cases, respiratory distress syndrome in 14 cases, intracranial hemorrhage in 4 cases, necrotizing enterocolitis in 1 case, Apgar score less than 7 at 5° minute in 3 cases and neonatal late death in 1 case, period of hospitalization in average of 58 ± 23 days. The gestational age at delivery was in average 29.4 ± 2.4 weeks. The weight of the newborns was in average 1090 ± 307.49 in average. Conclusion: There is no direct relationship between the severity of maternal disease and adverse perinatal outcomes. The gestational age of delivery was crucial to perinatal outcomes. There were gain of 2 weeks of gestational age between hospitalization and delivery and 17 days less of hospitalization for newborns in the expectant management

Introdução: A Síndrome HELLP é uma complicação das formas graves de préeclampsia caracterizada por hemólise, elevação das enzimas hepáticas e plaquetopenia. O tratamento gera discussão principalmente nos casos abaixo de 34 semanas. Objetivos: Caracterizar a população internada com diagnóstico de Síndrome HELLP no HCFMUSP entre 2001 a 2011. Associar os parâmetros clínicos e laboratoriais maternos como preditores de complicações maternas e perinatais. Caracterizar os resultados perinatais e complicações maternas na conduta conservadora. Método: Estudo retrospectivo observacional e analítico. Resultados: Foram internadas 51 pacientes. A idade média foi de 27,48 anos, a maioria foi da cor branca (47%) e com pelo menos mais de 1 gestação (62,75%). Apenas 15,69% apresentavam hipertensão arterial crônica. A idade Gestacional média foi 30,94 semanas. Os sintomas clínicos e exames laboratoriais maternos não apresentaram relação com as complicações maternas e resultados perinatais. As complicações maternas não apresentaram relação com resultados perinatais, exceto a Idade gestacional. A conduta conservadora foi possível em 16 pacientes com ganho médio de 12,94 dias na gestação. As complicações maternas foram insuficiência renal aguda em 3 casos, descolamento de placenta em 2 casos e iminência de eclampsia em 1 caso. As complicações perinatais foram sepse em 10 casos, angústia respiratória em 10 casos, hemorragia intracraniana em 2 casos, enterocolite necrosante em 2 casos, Apgar < 7 no 5° min. em 2 casos e óbito neonatal tardio em 2 casos, permanência no berçário em média de 41,47 ± 21,75 dias. A idade gestacional média no parto foi de 30,56 ± 3,41 semanas. O peso médio dos recém-nascidos foi 1.116,64 ± 393,52 g. A conduta resolutiva foi necessária em 19 pacientes e as complicações maternas observadas foram insuficiência renal aguda em 5 casos, descolamento de placenta em 1 caso, iminência de eclampsia em 4 casos e eclampsia em 4 casos. As complicações perinatais foram sepse em 12 casos, angústia respiratória em 10 casos, hemorragia intracraniana em 4 casos, Apgar < 7 no 5° min. em 3 casos e óbito neonatal tardio em 2 casos, permanência no berçário em média de 58 ± 23 dias. A idade gestacional média no parto foi de 28,93 ± 2,11 semanas. O peso médio dos recém-nascidos foi 1.090 ± 307,49 g. Conclusão: Não há relação direta entre a gravidade da doença materna e resultados perinatais adversos. A Idade gestacional foi a única variável determinante para os resultados perinatais. Na conduta conservadora houve ganho de 2 semanas na gestação e 17 dias a menos de permanência no berçário / Introduction: The HELLP syndrome is a complication of severe forms of preeclampsia characterized by hemolysis, elevated liver enzymes and thrombocytopenia. The treatment is questioned especially in cases before 34 weeks. Objectives: This study aims to characterize the population of hospitalized patients with HELLP Syndrome at HCFMUSP 2001-2011. To associate maternal clinical and laboratory parameters as predictives for maternal complications and adverse perinatal outcomes. Other aim is to charaterize maternal and perinatal outcomes in the expectant management. Methods: This is a retrospective observational and analytical study. Results: There were 51 patients hospitalized. The mean age was 27.48 years, most were white (47%) and had at least one pregnancy (62.75%). Only 15.69% had chronic arterial hypertension. The average gestational age was 30.94 weeks. The maternal clinical symptoms and laboratory tests did not correlate with maternal complications and perinatal outcomes. Maternal complications were not associated with perinatal outcomes except gestational age. Expectant management was possible in 16 patients with in average gain of 12.94 days of pregnancy. Maternal complications were acute renal failure in 3 cases, placental abruption in 2 cases and imminent eclampsia in 1 case. Perinatal complications were neonatal sepsis in 9 cases, respiratory distress syndrome in 10 cases, intracranial hemorrhage in 1 case, Apgar score less than 7 at 5° minute in 2 cases and neonatal late death in 2 cases, period of hospitalization in average of 41.47 ± 21.75 days. The gestational age at delivery was in average 30.8 ± 3.41 weeks. The weight of the newborns was in average 1116.64 ± 393.52 in average. Immediate interruption was need in 19 patients and the maternal complications were acute renal failure in 5 cases, placental abruption in 1 case and imminent eclampsia in 3 cases, eclampsia in 4 cases; Perinatal complications were: neonatal sepsis in 12 cases, respiratory distress syndrome in 14 cases, intracranial hemorrhage in 4 cases, necrotizing enterocolitis in 1 case, Apgar score less than 7 at 5° minute in 3 cases and neonatal late death in 1 case, period of hospitalization in average of 58 ± 23 days. The gestational age at delivery was in average 29.4 ± 2.4 weeks. The weight of the newborns was in average 1090 ± 307.49 in average. Conclusion: There is no direct relationship between the severity of maternal disease and adverse perinatal outcomes. The gestational age of delivery was crucial to perinatal outcomes. There were gain of 2 weeks of gestational age between hospitalization and delivery and 17 days less of hospitalization for newborns in the expectant management

Adjuvant hormonal therapy has been demonstrated to be able to delay disease progression in nonmetastatic prostate cancer. To date, however, a favorable impact on survival has only been demonstrated in lymph-node-positive disease and in external-beam radiotherapy series with locally advanced and probably mainly micrometastatic tumors. The Bicalutamide Early Prostate Cancer Program is the largest study under way to define the role of adjuvant treatment in early prostate cancer and identify subgroups of patients likely to benefit from immediate hormonal therapy. At the time of the most recently published analysis, the risk of objective clinical progression was significantly reduced in the bicalutamide arm (hazards ratio 0.58, 95% confidence interval 0.51–0.66, p < 0.0001). However, further maturation of data is needed to see whether this difference will lead to a survival advantage. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

The treatment of clinically locally advanced prostate carcinoma (stage cT3) remains controversial. One of the main reasons for this controversy results from the substantial staging error attached to the clinical diagnosis cT3 with overstaged T2 tumors and understaged node-positive cases. Treatment options in this situation include radical prostatectomy, external beam radiotherapy, immediate or delayed androgen deprivation treatment and the so-called ‘watchful waiting’. Acceptable and often surprisingly good tumor-specific survival rates have been reported for radical prostatectomy in pT3 series – based on good clinical case selection – approaching those of pT2 series. In lymph node-positive pT3 cases, adjuvant hormone deprivation seems to prolong survival which it does not in lymph node-negative pT3 disease. A benefit of adjuvant external beam radiotherapy after radical prostatectomy for pT3 cases in prolonging overall survival has not been shown, despite the fact that it can prevent or delay biochemical and local recurrence. External beam radiotherapy as the only treatment for cT3 disease results in unfavorable tumor-specific survival rates, which can be significantly improved with adjuvant hormonal treatment with LHRH agonists. If, in case of advanced age and/or significant comorbidity, primary hormonal treatment is chosen, early hormonal deprivation therapy seems to offer marginal benefits in survival compared to delayed treatment. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Quality-of-life and functional outcomes are important in the choice of treatment for men with localized prostate cancer. These issues were investigated in the present thesis. All living 400 men randomized to radical prostatectomy or watchful waiting from 1989 to 1999 in the Scandinavian Prostate Cancer Group Number 4 (SPCG-4) were included. An additional 281 men compromised an age-matched control group. Physical symptoms, symptom-induced stress, sense of well-being and self-assessed quality of life were evaluated by a study-specific questionnaire. Results showed that prostate cancer men, regardless if they were allocated to radical prostatectomy or watchful waiting were suffering of long term adverse effects, mainly erectile dysfunction, urinary leakage and voiding symptoms. In the prostatectomy group, erectile dysfunction and urinary leakage were often consequences of surgery; in the watchful waiting group the side-effects could be caused by tumor progression. The quality of life deteriorated over time. High self-assessed quality of life was reported by 35 % in the radical, 34 % in watchful-waiting, and 43 % in the control groups after a median follow-up time of 12.2 years. The SPCG-4 men significantly more often reported anxiety than did controls. Erectile dysfunction was associated with the most negative influence on quality of life in both SPCG-4 groups. Men in the prostatectomy group were more distressed by erectile dysfunction than watchful waiting. Androgen deprivation therapy had negative effects on all psychological parameters, including quality of life, for the watchful waiting but not for the prostatectomy group. Information about the prostate-cancer disease was significantly higher in the radical-prostatectomy group than in watchful waiting. Check-ups were associated with worry, especially for those on androgen deprivation therapy. Open radical prostatectomy led to an increased rate of inguinal hernia compared with robot-assisted technique. In conclusion, the data of this thesis emphasize that it takes more than a decade to understand the patterns of adverse effects and time dimension of their occurrence for each treatment. Consideration of quality of life has a high priority to aid the ageing man through the shifting scenarios of localized prostate cancer.

Background: Prostate Cancer (PC) is a common and highly variable disease. Using current diagnostic methods, the prostate specific antigen (PSA) blood test and histological grading of prostate tissue needle biopsies, it is often difficult to evaluate whether the patient has a PC that requires active treatment or not. The absolute majority of all 10,000 cases of PCs diagnosed annually in Sweden have tumours graded as Gleason score (GS) 6-7 and a PSA value in blood below 10. Many of these are harmless and can be left without active treatment and hence spared problematic post-therapy side-effects, others are highly malignant and require early diagnosis and treatment. Better prognostic markers are needed and the aim of this study was to evaluate prognostic markers and to test if these markers could identify patients with indolent tumours. Methods: We have studied tumour material from 419 men consecutively diagnosed with PC at transurethral resection (1975-1990). The majority of these patients (295) had no metastasis at diagnosis and was not given any curative treatment and only hormonal treatment upon symptoms from metastatic progression. Standard histological sections and tissue microarrays (TMA) from these tumours and surrounding normal prostate tissue were stained and evaluated for cell proliferation (Ki67), blood vessels (endoglin and von Willebrand factor, vWf) and the extracellular matrix component hyaluronan (HA). An orthotopic rat PC model was used to explore hyaluronan staining, hyaluronic acid synthase (HAS)-1 mRNA levels and the effect of local HA treatment on tumour growth. Results: Tumour cell proliferation (Ki67) and the density of intra-tumoural endoglin stained blood vessels were independent prognostic markers (i.e. they added prognostic information to the conventional prognostic markers; clinical stage and GS). None of the GS 6 patients with low staining for both Ki67 and endoglin died of PC within 15 years of follow-up. High HA staining in the tumour epithelium and stroma was a negative prognostic marker of cancer specific survival but they were not independent of GS. High HA staining and high vascular density in the stroma of the surrounding morphologically normal prostate were prognostic for short cancer specific survival. Implantation of tumour cells in the normal rat prostate resulted in an increase in HA and HAS-1 mRNA levels in the prostate tissue surrounding prostate tumours. Concurrently intra-prostatic injection of HA also stimulated tumour growth. Conclusions: By evaluating both tumour cell proliferation (Ki67) and vascular density, it is possible to identify patients with very low risk of cancer specific death in the absence of active treatment. Prostate tumours influence the surrounding non-malignant prostate tissue, for example they cause an increased angiogenesis and synthesis of hyaluronan. Such responses can possibly be used to diagnose PC and to evaluate PC aggressiveness.

Adjuvant hormonal therapy has been demonstrated to be able to delay disease progression in nonmetastatic prostate cancer. To date, however, a favorable impact on survival has only been demonstrated in lymph-node-positive disease and in external-beam radiotherapy series with locally advanced and probably mainly micrometastatic tumors. The Bicalutamide Early Prostate Cancer Program is the largest study under way to define the role of adjuvant treatment in early prostate cancer and identify subgroups of patients likely to benefit from immediate hormonal therapy. At the time of the most recently published analysis, the risk of objective clinical progression was significantly reduced in the bicalutamide arm (hazards ratio 0.58, 95% confidence interval 0.51–0.66, p < 0.0001). However, further maturation of data is needed to see whether this difference will lead to a survival advantage. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

The treatment of clinically locally advanced prostate carcinoma (stage cT3) remains controversial. One of the main reasons for this controversy results from the substantial staging error attached to the clinical diagnosis cT3 with overstaged T2 tumors and understaged node-positive cases. Treatment options in this situation include radical prostatectomy, external beam radiotherapy, immediate or delayed androgen deprivation treatment and the so-called ‘watchful waiting’. Acceptable and often surprisingly good tumor-specific survival rates have been reported for radical prostatectomy in pT3 series – based on good clinical case selection – approaching those of pT2 series. In lymph node-positive pT3 cases, adjuvant hormone deprivation seems to prolong survival which it does not in lymph node-negative pT3 disease. A benefit of adjuvant external beam radiotherapy after radical prostatectomy for pT3 cases in prolonging overall survival has not been shown, despite the fact that it can prevent or delay biochemical and local recurrence. External beam radiotherapy as the only treatment for cT3 disease results in unfavorable tumor-specific survival rates, which can be significantly improved with adjuvant hormonal treatment with LHRH agonists. If, in case of advanced age and/or significant comorbidity, primary hormonal treatment is chosen, early hormonal deprivation therapy seems to offer marginal benefits in survival compared to delayed treatment. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.