RESUMO
BACKGROUND: Gonadotropin releasing hormone (GnRH) antagonists suppress follicle-stimulating hormone (FSH) to lower levels than GnRH agonists. This may partially explain the differences between these agents on prostate cancer outcomes. In this post-hoc analysis, FSH and prostate specific antigen (PSA) responses and the impact of cross-over from leuprolide to degarelix were evaluated from a 1-year comparative study (CS21) and its extension study (CS21A). MATERIALS AND METHODS: Overall, 610 patients were enrolled in CS21, wherein PSA and FSH levels were evaluated monthly. CS21A evaluated 386 patients, including those previously treated with degarelix (n = 251) who continued to receive degarelix, and those previously treated with leuprolide (n = 135) who crossed-over to receive degarelix. PSA and FSH levels were evaluated in CS21A for 3 months after cross-over. The associations between measurements were assessed using Spearman's correlation coefficient. The impact of class variables on FSH suppression were evaluated using Analysis of Variance. RESULTS: Rapid PSA and FSH suppression was observed and maintained in the degarelix arm (CS21 and CS21A), while patients on leuprolide experienced rising PSA during CS21. Patients crossed-over from leuprolide to degarelix achieved a suppression of FSH and a significant PSA decrease. PSA and FSH levels were significantly (p < .05) correlated at months 1, 3, 6, 12 and 13 in the degarelix arm. CONCLUSIONS: Significant FSH suppression with GnRH antagonists may explain its advantage over GnRH agonists in terms of better prostate cancer control. The effect of profound FSH suppression is analogous to the need for profound testosterone suppression for tumor control.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Hormônio Foliculoestimulante/metabolismo , Hormônio Liberador de Gonadotropina/agonistas , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Leuprolida/uso terapêutico , Oligopeptídeos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Idoso , Substituição de Medicamentos , Humanos , Calicreínas/metabolismo , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/metabolismoRESUMO
Tasquinimod is a small molecule with pleiotropic effects on the tumour microenvironment. Tasquinimod inhibits the growth and metastasis of tumour cells in vitro and in vivo. It targets the tumour microenvironment, enhancing the host immune response and inhibiting the angiogenic response. Tasquinimod influences infiltrating myeloid cells in the tumour milieu shifting the balance towards a less immunosuppressive phenotype. Myeloid-derived suppressor cells and tumour-associated macrophages are major components of the immunosuppressive microenvironment and as a result promote tumour growth and favour angiogenesis and metastasis formation. Growing evidence indicates that tasquinimod targets these myeloid cells and modulates local tumour immunity by blocking the interaction between the multifunctional protein S100A9 and its ligands receptor of advanced glycation end products and Toll-like receptor 4. Its anti-angiogenic effects are achieved at least in part through these effects on regulatory myeloid cells and also potentially through inactivating histone deacetylase-4 and reducing expression of hypoxia-inducible factor 1-controlled genes. The aim is to comprehensively review the mode of action of tasquinimod as a novel oral anti-cancer agent. Based on its unique combination of effects, tasquinimod is a novel agent with clinical therapeutic potential in various solid tumours, both alone and as part of rational combination therapy.
Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Quinolinas/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Animais , Humanos , Sistema Imunitário/fisiologia , Neoplasias/irrigação sanguínea , QuinolonasRESUMO
PURPOSE: Tasquinimod (Active Biotech) is an oral immunomodulatory, anti-angiogenic, and anti-metastatic agent that delayed metastatic disease progression in a randomized placebo-controlled phase II trial in men with metastatic castration-resistant prostate cancer (mCRPC). Here, we report long-term survival with biomarker correlates from this trial. EXPERIMENTAL DESIGN: Two hundred and one (134 tasquinimod and 67 placebo) men with mCRPC were evaluated. Forty-one men randomized to placebo crossed over to tasquinimod. Survival data were collected with a median follow-up time of 37 months. Exploratory biomarker studies at baseline and over time were collected to evaluate potential mechanism-based correlates with tasquinimod efficacy including progression-free survival (PFS) and overall survival (OS). RESULTS: With 111 mortality events, median OS was 33.4 months for tasquinimod versus 30.4 months for placebo overall, and 34.2 versus 27.1 months in men with bone metastases (n = 136), respectively. Multivariable analysis demonstrated an adjusted HR of 0.52 [95% confidence interval (CI), 0.35-0.78; P = 0.001] for PFS and 0.64 (95% CI, 0.42-0.97; P = 0.034) for OS, favoring tasquinimod. Time-to-symptomatic progression was improved with tasquinimod (P = 0.039, HR = 0.42). Toxicities tended to be mild in nature and improved over time. Biomarker analyses suggested a favorable impact on bone alkaline phosphatase and lactate dehydrogenase (LDH) over time and a transient induction of inflammatory biomarkers, VEGF-A, and thrombospondin-1 levels with tasquinimod. Baseline levels of thrombospondin-1 less than the median were predictive of treatment benefit. CONCLUSIONS: The survival observed in this trial of men with minimally symptomatic mCRPC suggests that the prolongation in PFS with tasquinimod may lead to a survival advantage in this setting, particularly among men with skeletal metastases, and has a favorable risk:benefit ratio.
Assuntos
Biomarcadores Tumorais/genética , Intervalo Livre de Doença , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Quinolinas/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Proteína C-Reativa/genética , Humanos , L-Lactato Desidrogenase/genética , Masculino , Metástase Neoplásica , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Quinolonas , Análise de Sobrevida , Fator A de Crescimento do Endotélio VascularRESUMO
A higher insulin level has been linked to the risk of prostate cancer promotion. However, several reports claim that there is no association between a higher insulin level and the risk of incident prostate cancer. In the present report, the insulin hypothesis was tested once more prospectively in men with a benign prostatic disorder. Three hundred and eighty-nine consecutive patients referred with lower urinary tract symptoms without clinical prostate cancer were included during 1994-2002. Follow-up was performed in 2006. Data were obtained from the Swedish National Cancer Register and the Regional Cancer Register, Oncological Centre, Göteborg, Sweden. At this follow-up, 44 of the patients included had developed prostate cancer. Men with prostate cancer diagnosis had a higher systolic (P<0.001) and diastolic blood pressure (P<0.000), were more obese as measured by BMI (P=0.010), waist (P=0.007) and hip measurements (P=0.041) than men who did not have prostate cancer diagnosis at follow-up. These men also had a higher uric acid level (P=0.040), and a higher fasting serum insulin level (P=0.023) than men who did not have prostate cancer diagnosis at follow-up. Following exclusion of T1a/b prostate cancer cases, the difference of the fasting serum insulin level between the groups was still significant (P=0.038). Our data support the hypothesis that a higher insulin level is a promoter of prostate cancer. Moreover, our data suggest that the insulin level could be used as a marker of the risk of developing prostate cancer. The present findings also seem to confirm that prostate cancer is a component of the metabolic syndrome. Finally, our data generate the hypothesis that the metabolic syndrome conceals early prostate cancer.
Assuntos
Insulina/sangue , Neoplasias da Próstata/sangue , Idoso , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Hipertensão/sangue , Hipertensão/epidemiologia , Masculino , Estadiamento de Neoplasias , Estudos Prospectivos , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Suécia/epidemiologiaRESUMO
BACKGROUND: Tasquinimod is a quinoline-3-carboxamide derivative with anti-angiogenic activity. Two open-label phase I clinical trials in patients were conducted to evaluate the safety and tolerability of tasquinimod, with additional pharmacokinetic and efficacy assessments. METHODS: Patients with castration-resistant prostate cancer with no previous chemotherapy were enrolled in this study. The patients received tasquinimod up to 1 year either at fixed doses of 0.5 or 1.0 mg per day or at an initial dose of 0.25 mg per day that escalated to 1.0 mg per day. RESULTS: A total of 32 patients were enrolled; 21 patients were maintained for >or=4 months. The maximum tolerated dose was determined to be 0.5 mg per day; but when using stepwise intra-patient dose escalation, a dose of 1.0 mg per day was well tolerated. The dose-limiting toxicity was sinus tachycardia and asymptomatic elevation in amylase. Common treatment-emergent adverse events included transient laboratory abnormalities, anaemia, nausea, fatigue, myalgia and pain. A serum prostate-specific antigen (PSA) decline of >or=50% was noted in two patients. The median time to PSA progression (>25%) was 19 weeks. Only 3 out of 15 patients (median time on study: 34 weeks) developed new bone lesions. CONCLUSION: Long-term continuous oral administration of tasquinimod seems to be safe, and the overall efficacy results indicate that tasquinimod might delay disease progression.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Orquiectomia , Neoplasias da Próstata/tratamento farmacológico , Quinolinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Quinolinas/efeitos adversos , Quinolinas/farmacocinética , QuinolonasRESUMO
The aetiology of benign prostatic hyperplasia (BPH) remains unclear. The objective of the present study was to test the insulin, oestradiol and metabolic syndrome hypotheses as promoters of BPH. The design was a risk factor analysis of BPH in which the total prostate gland volume was related to endocrine and anthropometric factors. The participants studied were 184 representative men, aged 72-76 years, residing in Göteborg, Sweden. Using a multivariate analysis, BPH as measured by the total prostate gland volume correlated statistically significantly with fasting serum insulin (beta=0.200, P=0.028), free oestradiol (beta=0.233, P=0.008) and lean body mass (beta=0.257, P=0.034). Insulin and free oestradiol appear to be independent risk factors for BPH, confirming both the insulin and the oestradiol hypotheses. Our findings also seem to confirm the metabolic syndrome hypothesis. The metabolic syndrome and its major endocrine aberration, hyperinsulinaemia, are possible primary events in BPH.
Assuntos
Estradiol/sangue , Insulina/sangue , Síndrome Metabólica/complicações , Hiperplasia Prostática/sangue , Hiperplasia Prostática/etiologia , Idoso , Humanos , Masculino , Fatores de RiscoRESUMO
Androgen-independent prostate cancer is an aggressive disease with high angiogenic and metastatic potential. Increased microvessel density and altered invasion properties have previously been described in LNCaP-19, an androgen-independent subline to LNCaP. To characterize the differences in angiogenesis and invasion, the vessels of these tumour xenografts were investigated with immunohistochemistry, and the influence of tumour cells on endothelial cell migration, proliferation and tube formation was studied in vitro. The blood vessels of LNCaP were found to be stabilized by pericytes more frequently than vessels in LNCaP-19. Further, tumour cell invasion was decreased in pericyte-covered blood vessels in both the tumour types. LNCaP-19 displayed an increased potential to induce endothelial cell migration in vitro. In conclusion, pericyte coverage seems to be important for the invasion of tumour cells into blood vessels. Further, LNCaP-19 has lower pericyte coverage and an increased potential to induce endothelial cell migration, which reflects its high microvessel density.
Assuntos
Invasividade Neoplásica/patologia , Neovascularização Patológica/patologia , Pericitos/patologia , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/patologia , Animais , Movimento Celular/fisiologia , Proliferação de Células , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Nus , Neovascularização Patológica/metabolismo , Pericitos/metabolismo , Neoplasias da Próstata/metabolismo , Transplante HeterólogoRESUMO
Developing germ cells may be sensitive to even moderate reductions in blood flow. Surprisingly, however, experimental evidence suggests that the rat testis may be unable to maintain its blood flow during a decrease in systemic blood pressure. This study was therefore performed in order to answer the following questions: Is the testis able to maintain its blood flow during moderate to major reductions in blood pressure and, if so, at which level of the testicular vasculature (main artery or microcirculation) does this compensatory response take place? Moderate (-20%) and major (-40%) reductions in blood pressure were induced in anaesthetized rats by haemorrhage and the effects on testicular microvascular blood flow and subcapsular testicular artery diameter were examined by using laser Doppler flowmetry and in vivo video-microscopy respectively. Haemorrhagic hypotension led to decreased local testicular blood flow, but the relative reductions in flow were generally only half as large as the reductions in blood pressure. Hypotension also decreased the diameter of the main subcapsular testicular artery. During large reductions in blood pressure the subcapsular testicular artery constricts and testicular blood flow decreases. However, blood flow is reduced proportionally less than the mean arterial pressure, suggesting that local regulatory mechanisms are present in the testicular microvasculature, which may prevent blood flow from falling below a critical level.
Assuntos
Hemorragia/fisiopatologia , Hipotensão/fisiopatologia , Testículo/irrigação sanguínea , Testículo/fisiopatologia , Adaptação Fisiológica/fisiologia , Animais , Artérias/fisiopatologia , Pressão Sanguínea , Hemorragia/complicações , Hipotensão/etiologia , Fluxometria por Laser-Doppler , Masculino , Microcirculação/fisiologia , Microscopia de Vídeo , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/fisiologia , Vasodilatação/fisiologiaRESUMO
OBJECTIVE: To evaluate the immunohistochemical expression of thrombospondin (TSP), a potent inhibitor of angiogenesis, in human benign prostatic hyperplasia (BPH) and prostate cancer. MATERIALS AND METHODS: The expression of TSP-1, TSP-2 and CD36 receptor was assessed in 73 tissue specimens using immunohistochemistry; specimens were from 32 patients with BPH, seven with prostatic intraepithelial neoplasia (PIN) and 34 with cancer. RESULTS: Immunohistochemistry showed that all 39 patients with BPH and PIN had TSP-1-positive glands. In contrast, none of the 34 patients with cancer had positive TSP-1 staining in the cancer tissue. All 73 patients were positive for TSP receptor CD36 and negative for TSP-2. CONCLUSIONS: TSP is expressed in BPH, down-regulated in PIN and absent in prostate cancer tissue. This may indicate that TSP is important in prostate cancer progression. Further studies are needed to understand the significance of these findings for the malignant transformation of the prostate gland.
Assuntos
Proteínas de Neoplasias/metabolismo , Hiperplasia Prostática/metabolismo , Neoplasia Prostática Intraepitelial/metabolismo , Neoplasias da Próstata/metabolismo , Trombospondina 1/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Neoplasia Prostática Intraepitelial/diagnóstico , Neoplasias da Próstata/diagnósticoRESUMO
Within the last decade prostate cancer mortality rates have started to decrease in some countries. Although it is tempting to assume that these trends are a result of earlier diagnosis and aggressive therapeutic intervention, as a consequence of prostate-specific antigen screening, definitive results from randomized trials of screening will not be available for several years. Moreover, there is mounting evidence that the effects of screening cannot be entirely responsible for this reduction in mortality rates. This review explores the possibility that other factors, particularly the increased uptake of early hormonal therapy, are contributing to the observed changes in mortality.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Humanos , Masculino , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/mortalidade , Análise de Sobrevida , Taxa de SobrevidaRESUMO
OBJECTIVES: To examine the development of antiandrogen-induced gynecomastia and breast tenderness in the first 253 patients in a randomized Scandinavian trial (SPCG-7/SFUO-3) with a 12-month complete follow-up evaluation performed by both doctors and patients. METHODS: In this study, the treating doctor and patient decided whether prophylactic irradiation (RT) of the breast should be given to prevent antiandrogen-induced gynecomastia. At each visit, the doctor evaluated the occurrence of gynecomastia and breast tenderness. Questions about gynecomastia and breast tenderness were also included in the study quality-of-life questionnaire (Prostate Cancer Symptom Scale). RESULTS: Mammary RT with mostly single fraction (12 to 15 Gy) electrons was given to 174 (69%) of the 253 evaluated patients. At the 1-year follow-up visit, the doctor evaluations indicated some form of gynecomastia in 71% and 28% (P <0.001) of the nonirradiated (no-RT) and irradiated (RT) patients, respectively. The patient evaluations at 1 year showed some form of breast enlargement in 78% and 44% (P <0.001) of the no-RT and RT patients, respectively. The doctors reported some form of breast tenderness at 1 year in 75% and 43% (P <0.001) of the no-RT and RT patients, respectively. The patient evaluations of breast tenderness show an expected significant increase in the RT arm at the 3-month follow-up, which was probably due to skin reactions. At 1 year, significantly more patients who marked "very much" on the Prostate Cancer Symptom Scale were seen in the no-RT group. A weak correlation between the doctors' and patients' detection of breast problems was observed. CONCLUSIONS: The results show that, with high significance, prophylactic RT of the breast decreases the risk of antiandrogen-induced gynecomastia and breast tenderness.
Assuntos
Antagonistas de Androgênios/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Mama/efeitos da radiação , Ginecomastia/induzido quimicamente , Ginecomastia/prevenção & controle , Neoplasias da Próstata/tratamento farmacológico , Antagonistas de Androgênios/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Doenças Mamárias/prevenção & controle , Seguimentos , Ginecomastia/diagnóstico , Nível de Saúde , Humanos , Masculino , Dor/prevenção & controle , Estudos Prospectivos , Qualidade de Vida , Radioterapia , Países Escandinavos e Nórdicos , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: To examine the effects of castration and continuous gonadotrophin releasing-hormone (GnRH) agonist and antagonist therapy on the expression of GnRH-receptors type I (GnRH-RI) in rat ventral prostate (VP) and pituitary tissue, and to compare the effects on prostate morphology. MATERIAL AND METHODS: Mature Sprague-Dawley rats were assigned to four treatment groups: group 1, vehicle only; group 2, GnRH agonist goserelin (100 microg/rat/day); group 3, GnRH antagonist cetrorelix (100 microg/rat/day); and group 4, orchidectomy. After 4 weeks the body weights were recorded and VP and pituitary tissue analysed for GnRH-RI expression using a competitive reverse transcriptase-polymerase chain reaction and immunohistochemistry. RESULTS: GnRH antagonist and orchidectomy decreased testosterone secretion and VP volume similarly, but the effects were not identical. The involution of the glandular lumina was more pronounced after orchidectomy while the antagonist therapy was more effective in suppressing epithelial cell proliferation. In the VP, GnRH-RI mRNA levels were increased after GnRH analogue therapy, but were unaffected by orchidectomy. In the pituitary, GnRH-RI mRNA expression was higher in response to orchidectomy and decreased after GnRH analogue treatment. CONCLUSION: Treatment with a GnRH antagonist for 4 weeks is more effective than an agonist in suppressing testosterone and inducing VP involution. The GnRH antagonist was more effective in suppressing VP epithelial cell proliferation than was castration, suggesting that it induces reduced proliferation by interfering with effects of locally produced GnRH. These results suggest that different regulatory mechanisms may operate in the rat VP than in the pituitary to control GnRH-RI mRNA expression.
Assuntos
Hormônio Liberador de Gonadotropina/farmacologia , Orquiectomia , Próstata/efeitos dos fármacos , Receptores LHRH/efeitos dos fármacos , Animais , Imuno-Histoquímica , Masculino , Hipófise/efeitos dos fármacos , Próstata/química , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Receptores LHRH/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodosRESUMO
OBJECTIVE: Finasteride has been shown to reduce prostate bleeding in patients with benign prostatic hyperplasia (BPH). The mechanisms behind this are not known, but it has been suggested that finasteride reduces bleeding by inhibiting angiogenesis in the prostate. Studies in animals have shown that castration rapidly induces involution of the prostate vasculature, and androgen-stimulated prostate growth may be angiogenesis dependent. The objective of this study was to explore the response to finasteride on the vasculature and the expression of vascular endothelial growth factor (VEGF), a potent regulatory factor of angiogenesis in human prostate tissue. MATERIAL AND METHODS: Patients with BPH were randomly assigned to 3 months of treatment either with finasteride (5 mg/day) or placebo before undergoing transurethral resection of the prostate (TURP). Prostate tissue VEGF expression was quantified by Western blot and the vascular density determined in Factor VIII immunostained tissue sections. Serum concentrations of VEGF were measured with ELISA technique. RESULTS: Patients treated with finasteride (n = 15) showed a decrease in prostate tissue VEGF(165) expression compared with placebo (n = 13) treated patients (p < 0.05), but the vascular density and the serum VEGF levels were unaffected. CONCLUSIONS: This study shows that finasteride treatment decreases VEGF expression in the human prostate.
Assuntos
Inibidores de 5-alfa Redutase , Fatores de Crescimento Endotelial/metabolismo , Inibidores Enzimáticos/farmacologia , Finasterida/farmacologia , Linfocinas/metabolismo , Próstata/metabolismo , Hiperplasia Prostática/tratamento farmacológico , Western Blotting , Finasterida/uso terapêutico , Humanos , Imuno-Histoquímica , Masculino , Microcirculação/efeitos dos fármacos , Estudos Prospectivos , Próstata/irrigação sanguínea , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/cirurgia , Ressecção Transuretral da Próstata , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
OBJECTIVE: Previous studies have shown a relationship between serum prostate-specific antigen (PSA) level and prostate tumour volume. Reports based on selected case series have also indicated that serum PSA may be used for staging, although a varying prevalence of metastasizing tumours complicates the interpretation of these studies. In order to determine the accuracy of the serum level of PSA in predicting the presence of metastases we performed a prospective cohort study of a geographically defined population of men with prostate cancer. METHODS: Serum level of PSA and the results of investigations for regional lymph node and distant metastases were recorded for all 8328 men with prostate cancer registered in the Swedish National Prostate Cancer Register 1996-1997. RESULTS: The prevalence of lymph node metastases among men who had undergone lymph node exploration was 4%, 16% and 33% for well, moderately and poorly differentiated tumours. The corresponding prevalence of distant metastases was 12%, 30% and 48%. With serum PSA <20 ng/ml as a cut-off point the negative likelihood ratios for well and moderately differentiated tumours were found to be 0.47 and 0.45 for lymph node metastases and 0.24 and 0.18 for distant metastases, resulting in post-test probabilities >92% for the exclusion of metastases. In men with poorly differentiated tumours, the negative likelihood ratio would need to be even lower to safely exclude disseminated disease. CONCLUSION: For well to moderately differentiated tumours, further investigations to assess the presence of metastases may be omitted with no great risk for understaging if serum PSA <20 ng/ml.
Assuntos
Linfonodos/patologia , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/patologia , Sistema de Registros , Idoso , Humanos , Excisão de Linfonodo , Metástase Linfática , Masculino , Estadiamento de Neoplasias , Prevalência , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: To evaluate how serum prostate-specific antigen (PSA) levels in a population-based cohort of men with prostate cancer vary with age and intensity in the diagnostic activity and to describe the treatment selection processes associated with PSA level. MATERIAL AND METHODS: All men in the Swedish National Prostate Cancer Register diagnosed during 1996-1997 were included. In 1996 the register included 19 counties, covering 61% of the Swedish male population, and in 1997 21 counties with 79% of the Swedish male population. RESULTS: A total of 8328 men were registered. PSA levels were missing in 341 cases. With increasing PSA there was a shift towards more advanced and poorly differentiated tumours. PSA at diagnosis increased with age, with the exception of patients younger than 50 years who had higher PSA values. The mean logarithm of PSA correlated negatively with the percentage of localized tumours (p < 0.005) and the age-adjusted incidence (p < 0.05) in each respective county in 1997. PSA was higher in men receiving radiotherapy compared with those treated with radical prostatectomy as well as in the group treated with bilateral orchiectomy compared with those receiving GnRH-analogues. CONCLUSIONS: If PSA is used as a surrogate measure of extent of tumour volume in a population of prostate cancer patients, our findings indicate that age distribution and differences in incidence (possibly due to variation in diagnostic activity) should be taken into account. In our cohort there was a selection process, probably in part guided by PSA level, when choosing type of curative or palliative treatment.
Assuntos
Antígeno Prostático Específico/sangue , Neoplasias da Próstata/diagnóstico , Sistema de Registros , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias da Próstata/epidemiologiaRESUMO
PURPOSE: Hereditary prostate cancer accounts for 5% to 10% of all prostate cancer cases. We assessed clinical characteristics and survival in patients with hereditary prostate cancer MATERIALS AND METHODS: The study comprised 201 patients from 62 Swedish hereditary prostate cancer families and 402 controls with prostate cancer who were matched for age and calendar year at diagnosis, and the hospital where the diagnosis was made. Clinical data were obtained from the National Cancer Registry, Causes of Death Registry and medical records. RESULTS: Median age at the diagnosis of hereditary prostate cancer was 68 years, which was 6 years less than in patients with prostate cancer in the general population in Sweden. Distributions of tumor grade, symptoms at diagnosis and initial therapy were similar in hereditary prostate cancer cases and controls. More controls were classified with localized disease but it may have been due to methodological problems. Overall and cancer specific survival was similar in patients with hereditary prostate cancer and controls as well as in subgroup analyses including those with early onset and those diagnosed before 1990. Prostate cancer was the cause of death in 75% of patients with hereditary prostate cancer, in contrast to 55% with prostate cancer in the Swedish population. This difference was completely explained by the earlier age at the diagnosis of hereditary prostate cancer. CONCLUSIONS: Hereditary prostate cancer has an earlier onset than sporadic prostate cancer but this study did not indicate any other important difference in clinical characteristics or survival in patients with hereditary prostate cancer and those with sporadic prostate cancer. However, it cannot be excluded that individual hereditary prostate cancer genes may have specific biological characteristics.
Assuntos
Neoplasias da Próstata/genética , Idade de Início , Idoso , Estudos de Casos e Controles , Humanos , Masculino , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Taxa de SobrevidaRESUMO
BACKGROUND: Treatment of localized prostate carcinoma (LPC) using radiotherapy (RT) can induce disturbances in a patient's quality of life (QOL) and urinary and intestinal function. Late symptoms and QOL were evaluated in a randomized trial between RT and deferred treatment (DT). METHODS: Quality of life was evaluated with European Organization for Research and Treatment of Cancer's QLQ-C30 (+3) formula. Urinary and intestinal problems were evaluated with a validated symptom specific self-assessment questionnaire, QUFW94. The questionnaires were sent to 108 randomized patients with LPC and to an age-matched control group (n = 68). Mean age was 72 years. Mean total dose was 65 grays (Gy; 62.3-70 Gy). The median follow-up time from randomization was 40.6 months for the RT group and 30.4 months for the DT group. RESULTS: Social functioning was the only QOL scale in which a significant difference was found between the two patient groups and compared with the control group. Multivariate regression analysis showed that hematuria, incontinence, mucus, and planning of daily activities in response to intestinal problems caused this decrease in QOL in the RT group. A significant increase of intestinal problems was observed in the RT versus DT groups regarding mucus, stool leakage, intestinal blood, and planning of daily activity in response to intestinal problems. CONCLUSIONS: The RT patients showed increased levels of minor intestinal side effects compared with the DT patients and the controls, but the RT patients reported no decreased QOL except for decreased social functioning. This could be because this group developed coping skills or because of a low magnitude of side effects to influence the QOL.
Assuntos
Neoplasias da Próstata/radioterapia , Qualidade de Vida , Radioterapia/efeitos adversos , Comportamento Social , Adaptação Psicológica , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Gastroenteropatias/etiologia , Hematúria/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Regressão , Incontinência Urinária/etiologiaRESUMO
The aim of this study was to evaluate different strategies to increase the tumour radiation dose for experimental radioimmunotherapy using 125I-labelled monoclonal antibody (MAb) E4 in a nude mice model xenografted with DU-145 tumours. The effects from a single injection of the 125I-labelled MAb E4, the same total amount of radiolabelled MAb E4 divided into three repeated injections, and the effect of pre-targeting with non-labelled MAb E4 for reducing the amount of shed antigen were investigated. Based on repetitive quantitative radioimmunoscintigraphies, calculation of the tumour radiation dose delivered from the 125I-nuclide was performed for each strategy. The single injection strategy without pretargeting rendered the highest mean tumour radiation dose, i.e. 0.23 Gy/MBq. Pretargeting with non-labelled MAb E4 before a single injection of [125I]E4 resulted in a slightly lower mean tumour radiation dose, i.e. 0.19 Gy/MBq, compared to the single injection alone. An even lower mean tumour radiation dose, i.e. 0.14 Gy/MBq, was obtained when the same total administered amount of activity was divided into three separate injections given in 10-day intervals. We concluded that the single injection strategy is the most efficient when using MAb E4 in this tumour model. The tumour radiation doses were not increased by dividing the same amount of activity into three injections or by pretargeting with non-labelled MAb E4.
Assuntos
Anticorpos Monoclonais , Radioisótopos do Iodo/farmacocinética , Neoplasias da Próstata/diagnóstico por imagem , Radioimunodetecção , Animais , Masculino , Camundongos , Camundongos Nus , Próstata/imunologia , Neoplasias da Próstata/imunologia , RadiometriaRESUMO
OBJECTIVE: To determine the role of vascular response in the castration-induced regression of benign and malignant human prostate tissue, as recent studies show that castration rapidly decreases blood flow and induces endothelial cell death, which may be important for subsequent epithelial cell death and involution of the glandular tissue of the prostate. MATERIALS AND METHODS: The expression of vascular endothelial growth factor (VEGF) and its receptors was analysed using the quantitative reverse transcriptase-polymerase chain reaction, in benign and tumour areas of core biopsies taken before, and approximately 1 week after castration therapy. The castration-induced VEGF response was related to therapy-induced changes in tumour cell apoptotic index and subsequent response in serum prostate-specific antigen (PSA). In another set of patients, serum VEGF was quantified by enzyme-linked immunosorbent assay before, and at 3--6 months after castration therapy. RESULTS: VEGF mRNA was down-regulated after castration in benign prostate tissue (P < or = 0.05), whereas in tumour tissue, VEGF levels were reduced in some of the patients but unchanged or increased in others. In most patients whose tumour tissue responded with VEGF reduction, there was a corresponding increase in tumour cell apoptosis. Serum VEGF levels were not significantly changed after castration. Almost all patients responded with a substantial reduction in serum PSA after castration. CONCLUSION: Castration reduces VEGF mRNA expression in benign prostate tissue and generally in those prostate tumours where castration also induces tumour cell apoptosis. This suggests that a therapy-induced down-regulation of VEGF could be important for tumour cell death.
Assuntos
Castração , Fatores de Crescimento Endotelial/metabolismo , Linfocinas/metabolismo , Neoplasias da Próstata/metabolismo , Apoptose , Biópsia/métodos , Humanos , Masculino , Neoplasias da Próstata/patologia , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
BACKGROUND: Inhibitory effects of gonadotropin-releasing hormone (GnRH) analogs on prostate cancer cell proliferation, both in vivo and in vitro, indicate the presence of specific binding sites for GnRH on prostate cancer cells. To investigate this issue further, we examined the expression of GnRH receptor (GnRH-R) mRNA and protein in human prostate biopsies as well as in other extrapituitary tissues. METHODS: The relative quantity of GnRH-R mRNA was determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) in human prostate biopsies. Extrapituitary GnRH-R levels were determined by a semiquantitative PCR reaction. RESULTS: Using PCR, a relatively high expression level of GnRH-R mRNA was found in prostate tumor tissue followed by normal prostate, thymus, and kidney expression levels. The levels showed by heart, brain, placenta, lung, liver, skeletal muscle, pancreas, colon, ovary, small intestine, spleen, and testis were low but detectable, whereas peripheral blood leukocyte showed no demonstrable product. GnRH-R immunoreactivity was localized in both luminal and basal epithelial cells in benign and malignant prostate tissue, and GnRH-R were also observed in intraprostatic lymphocytes. The relative GnRH-R mRNA levels in prostate biopsies from 16 patients showed a wide range of individual differences, but these differences were not related to histological grade. Castration therapy did not significantly influence GnRH-R mRNA expression in normal and malignant prostate tissue. CONCLUSIONS: These results suggest that epithelial cells and infiltrating lymphocytes are targets for GnRH action in the human prostate. Comparative data show relatively high GnRH-R expression in human prostate tissue compared to other human tissues.