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1.
Int. braz. j. urol ; 45(3): 503-513, May-June 2019. tab, graf
Artigo em Inglês | LILACS-Express | ID: biblio-1012320

RESUMO

ABSTRACT Purpose: The purposes of the present study were to evaluate growth rate of nonfunctioning adrenal incidentalomas (AIs) and their development to hormonal hypersecretion on follow-up. Materials and methods: A retrospective study was conducted from the electronic medical records. A total of 314 patients were diagnosed with adrenal tumors between 2000 and 2016. After excluding patients who had overt adrenal endocrine disorders or whose adrenal tumors were clinically diagnosed as metastatic malignancies, we investigated 108 patients with nonfunctioning AIs including characteristics, the treatment, the way of follow-up and pathology. Results: Fifteen patients received immediate adrenalectomy because of the initial tumor size or patient's preference. Pathological examination revealed malignancy in 2 patients. In the remaining 93 patients, radiological examinations were performed periodically. Tumor enlargement of ≥ 1.0cm was observed in 8.6% of the patients who were followed up as nonfunctioning AIs with a median follow-up period of 61.5 months (range: 4-192). Eleven patients underwent adrenalectomy. On the pathological examinations, all of the tumors, which showed a size increase, were diagnosed as benign tumors. Regarding the followed up patients without adrenalectomy, only 2.4% of the patients had tumor enlargement during the prolonged follow-up. Furthermore, none of the patients developed hormonal hypersecretion or clinical signs such as obesity, glucose intolerance or poorly controlled hypertension. Conclusions: Tumor enlargement of AIs did not correlate with malignancy. The value of repeat radiological and hormonal examinations may be limited in the long-term follow-up of patients whose AIs are not enlarged.

2.
Int Braz J Urol ; 45(3): 503-513, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30785700

RESUMO

PURPOSE: The purposes of the present study were to evaluate growth rate of nonfunctioning adrenal incidentalomas (AIs) and their development to hormonal hypersecretion on follow-up. MATERIALS AND METHODS: A retrospective study was conducted from the electronic medical records. A total of 314 patients were diagnosed with adrenal tumors between 2000 and 2016. After excluding patients who had overt adrenal endocrine disorders or whose adrenal tumors were clinically diagnosed as metastatic malignancies, we investigated 108 patients with nonfunctioning AIs including characteristics, the treatment, the way of follow-up and pathology. RESULTS: Fifteen patients received immediate adrenalectomy because of the initial tumor size or patient's preference. Pathological examination revealed malignancy in 2 patients. In the remaining 93 patients, radiological examinations were performed periodically. Tumor enlargement of ≥ 1.0cm was observed in 8.6% of the patients who were followed up as nonfunctioning AIs with a median follow-up period of 61.5 months (range: 4-192). Eleven patients underwent adrenalectomy. On the pathological examinations, all of the tumors, which showed a size increase, were diagnosed as benign tumors. Regarding the followed up patients without adrenalectomy, only 2.4% of the patients had tumor enlargement during the prolonged follow-up. Furthermore, none of the patients developed hormonal hypersecretion or clinical signs such as obesity, glucose intolerance or poorly controlled hypertension. CONCLUSIONS: Tumor enlargement of AIs did not correlate with malignancy. The value of repeat radiological and hormonal examinations may be limited in the long-term follow-up of patients whose AIs are not enlarged.


Assuntos
Corticosteroides/sangue , Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Neoplasias das Glândulas Suprarrenais/metabolismo , Hormônio Adrenocorticotrópico/sangue , Neoplasias das Glândulas Suprarrenais/patologia , Adrenalectomia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Valores de Referência , Estudos Retrospectivos , Estatísticas não Paramétricas , Fatores de Tempo , Tomografia Computadorizada por Raios X , Carga Tumoral
3.
Prostate ; 78(3): 222-232, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29194690

RESUMO

BACKGROUND: Clarifying the mechanisms underlying prostate cancer (PC) progression and resistance to androgen deprivation therapy (ADT) is an urgent clinical issue. ADT influences steroidal metabolism in patients with PC and promotes the accumulation of carbon 21 steroids (C21s), such as progestin. Because the enzymes responsible for C21s metabolism are similar to those for androgen metabolism, PC cells may be able to metabolize C21s intracellularly. Therefore, there is a possibility that intracrine C21s are implicated in PC progression and resistance to ADT, and the influence of C21s on PC cells is yet to be elucidated. In the present study, we focused on 20ß-hydroxy-5α-dihydroprogesterone (20ß-OHDHP), a C21s metabolized from progestin, and showed that 20ß-OHDHP is synthesized in PC cells and is able to directly stimulate the androgen receptor (AR). METHODS: LNCaP, VCaP, and DU145 cells, which express a mutant AR (mAR), wild-type AR (wAR), and glucocorticoid receptor (GR), respectively, were incubated in the presence of several agents. After incubation, cell growth was determined by the MTS assay. PSA levels were determined by an enzyme immunoassay, and C21s and androgen levels were measured using liquid chromatography-mass spectrometry. Gene expression was analyzed by quantitative real-time polymerase chain reaction, and steroidal-receptor-related signaling was determined by a reporter assay. RESULTS: We affirmed that 20ß-OHDHP was synthesized from pregnenolone intracellularly in LNCaP and VCaP cells, and 20ß-OHDHP significantly promoted the growth of both cell lines without androgen conversion. 20ß-OHDHP directly stimulated both mAR and wAR. The presence of 20ß-OHDHP was sufficient for the proliferation and survival of LNCaP or VCaP cells, and 20ß-OHDHP promoted cell growth even in the presence of abiraterone. Using DU145 cells, we affirmed that 20ß-OHDHP did not stimulate GR, which has a potential to bypass AR signaling in PC cells promote PC cell growth. CONCLUSIONS: Under ADT, 20ß-OHDHP synthesized intracellularly from accumulated progestin in PC cells may accelerate cell growth via stimulation of both wAR and mAR. This pathway may represent an interesting candidate for targeted therapy.


Assuntos
20-alfa-Di-Hidroprogesterona/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Linhagem Celular Tumoral , Humanos , Masculino
4.
Nihon Hinyokika Gakkai Zasshi ; 108(4): 210-214, 2017.
Artigo em Japonês | MEDLINE | ID: mdl-30333444

RESUMO

A 56-year-old woman had complained of two year's consecutive left-side abdominal pain. Retroperitoneal tumor was diagnosed and the patient was referred to our institute in December 2014. Laboratory data including endocrinological activity and serological markers were within the normal ranges. Imaging studies showed that the solid tumor measuring 5 cm in diameter was uncovered in the retroperitoneum, between the abdominal aorta and left kidney. The patient underwent surgical removal of the tumor with the left kidney because the mass was highly adhesive to the left ovarian vessels and left renal vein. Histological examination showed proliferating spindle cells in the tumor, and immunoreactivity for desmin and alfa-smooth muscle actin in tumor cells confirmed the diagnosis of leiomyosarcoma originated in left ovarian vein with left renal vein invasion. The patient has been free of disease 21 months after the surgery. Ovarian vein leiomyosarcoma is extremely rare and we have found 18 cases in literature. Furthermore, only three cases of leiomyosarcoma arising from the ovarian vein with the renal vein invasion were reported including our case.

5.
Sci Rep ; 6: 32198, 2016 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-27561382

RESUMO

Intratumoural dihydrotestosterone (DHT) synthesis could be an explanation for castration resistance in prostate cancer (PC). By using liquid chromatography-mass spectrometry, we evaluated the intratumoral DHT synthesis from 5α-androstane-3ß,17ß-diol (3ß-diol), which is inactive androgen metabolized from DHT. 3ß-diol had biochemical potential to be converted to DHT via three metabolic pathways and could stimulate PC cell growth. Especially, 3ß-diol was not only converted back to upstream androgens such as dehydroepiandrosterone (DHEA) or Δ5-androstenediol but also converted directly to DHT which is the main pathway from 3ß-diol to DHT. Abiraterone had a significant influence on the metabolism of DHEA, epiandrosterone and 3ß-diol, by the inhibition of the intratumoural 3ß-hydroxysteroid dehydrogenase (3ß-HSD) activities which is one of key catalysts in androgen metabolic pathway. The direct-conversion of 3ß-diol to DHT was catalysed by 3ß-HSD and abiraterone could inhibit this activity of 3ß-HSD. These results suggest that PC had a mechanism of intratumoural androgen metabolism to return inactive androgen to active androgen and intratumoural DHT synthesis from 3ß-diol is important as one of the mechanisms of castration resistance in PC. Additionally, the inhibition of intratumoural 3ß-HSD activity could be a new approach to castration-resistant prostate cancer treatment.


Assuntos
3-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Androstano-3,17-diol/metabolismo , Androstenos/farmacologia , Di-Hidrotestosterona/metabolismo , Inibidores Enzimáticos/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias da Próstata/metabolismo , 3-Hidroxiesteroide Desidrogenases/genética , 3-Hidroxiesteroide Desidrogenases/metabolismo , Linhagem Celular Tumoral , Humanos , Masculino , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia
6.
Jpn J Clin Oncol ; 45(8): 774-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25981621

RESUMO

OBJECTIVE: Abiraterone acetate and docetaxel are promising treatment options for metastatic castration-resistant prostate cancer patients. However, the optimal sequencing of these agents is unclear, and no previous reports discuss Japanese metastatic castration-resistant prostate cancer patients. The purpose of this analysis is to reveal the outcomes of Japanese metastatic castration-resistant prostate cancer patients treated with abiraterone acetate followed by docetaxel. METHODS: We retrospectively reviewed Japanese Phase 1 and Phase 2 trials of metastatic castration-resistant prostate cancer patients treated with abiraterone acetate until disease progression and subsequently treated with docetaxel. The primary outcome measure was the rates of prostate-specific antigen declines ≧30 and ≧50%, respectively, with docetaxel. Secondary outcome measures included progression-free survival with docetaxel, and overall survival after initiation of abiraterone acetate and docetaxel. We performed correlation analysis between previous prostate-specific antigen response to abiraterone acetate and subsequent prostate-specific antigen response to docetaxel. RESULTS: We identified 15 patients had experienced disease progression with abiraterone acetate and subsequently were treated with docetaxel. Prostate-specific antigen declines ≧30 and ≧50% with docetaxel were observed in five patients (33%) and two patients (13%), respectively. The median progression-free survival with docetaxel was 3.7 months (95% confidence interval: 2.9-4.6). The median overall survival from initiation of docetaxel and abiraterone acetate were 14.4 months (95% confidence interval: 6.3-22.4), and 25.7 months (95% confidence interval: 20.1-30.7), respectively. No significant correlation was observed between these prostate-specific antigen responses (Pearson r = 0.206, P = 0.46). CONCLUSION: The efficacy of docetaxel in Japanese mCRPC patients that was resistant to abiraterone acetate was modest. The prostate-specific antigen response to previous abiraterone acetate could not predict the efficacy of subsequent docetaxel. Larger prospective trials are needed to validate these findings.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Acetato de Abiraterona , Idoso , Androstenos/administração & dosagem , Progressão da Doença , Intervalo Livre de Doença , Docetaxel , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Estudos Retrospectivos , Taxoides/administração & dosagem , Resultado do Tratamento
7.
Oncotarget ; 6(2): 604-16, 2015 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-25436982

RESUMO

While high doses of estrogen, in combination with androgens, can initiate prostate cancer (PCa) via activation of the estrogen receptor α (ERα), the role of ERα in PCa cells within established tumors is largely unknown. Here we show that expression of ERα is increased in high grade human PCa. Similarly, ERα is elevated in mouse models of aggressive PCa driven by MYC overexpression or deletion of PTEN. Within the prostate of PTEN-deficient mice, there is a progressive pattern of ERα expression: low in benign glands, moderate in tumors within the dorsal, lateral and ventral lobes, and high in tumors within the anterior prostate. This expression significantly correlates with the proliferation marker Ki67. Furthermore, in vitro knockdown of ERα in cells derived from PTEN-deficient tumors causes a significant and sustained decrease in proliferation. Depletion of ERα also reduces the activity of the PI3K and MAPK pathways, both downstream targets of non-genomic ERα action. Finally, ERα knockdown reduces the levels of the MYC protein and lowers the sensitivity of cellular proliferation to glucose withdrawal, which correlates with decreased expression of the glucose transporter GLUT1. Collectively, these results demonstrate that ERα orchestrates proliferation and metabolism to promote the neoplastic growth of PCa cells.


Assuntos
Receptor alfa de Estrogênio/biossíntese , PTEN Fosfo-Hidrolase/deficiência , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-myc/biossíntese , Animais , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Receptor alfa de Estrogênio/genética , Técnicas de Silenciamento de Genes , Genes myc , Glucose/metabolismo , Glucose/farmacologia , Humanos , Células MCF-7 , Masculino , Camundongos , Camundongos Transgênicos , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias da Próstata/genética , Proteínas Proto-Oncogênicas c-myc/genética , Transdução de Sinais , Análise de Sobrevida
8.
Sci Rep ; 3: 1528, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23524847

RESUMO

Intratumoral synthesis of dihydrotestosterone (DHT) from precursors cannot completely explain the castration resistance of prostate cancer. We showed that DHT was intratumorally synthesized from the inactive androgen metabolites 5α-androstane-3α/ß,17ß-diol (3α/ß-diol) in prostate cancer cells via different pathways in a concentration-dependent manner. Additionally, long-term culture in androgen-deprived media increased transcriptomic expression of 17ß-hydroxysteroid dehydrogenase type 6 (HSD17B6), a key enzyme of oxidative 3α-HSD that catalyzes the conversion of 3α-diol to DHT in prostate cancer cells. Correspondingly, the score for HSD17B6 in tissues of 42 prostate cancer patients undergoing androgen deprivation therapy (ADT) was about 2-fold higher than that in tissues of 100 untreated individuals. In men receiving ADT, patients showing biochemical progression had a higher HSD17B6 score than those without progression. These results suggested that 3α/ß-diol also represent potential precursors of DHT, and the back conversion of DHT from androgen derivatives can be a promising target for combination hormone therapy.


Assuntos
17-Hidroxiesteroide Desidrogenases/metabolismo , Androgênios/metabolismo , Androstano-3,17-diol/metabolismo , Di-Hidrotestosterona/metabolismo , Neoplasias da Próstata/metabolismo , 17-Hidroxiesteroide Desidrogenases/genética , Idoso , Androgênios/química , Androgênios/deficiência , Linhagem Celular Tumoral , Desidroepiandrosterona/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/enzimologia , Interferência de RNA , RNA Interferente Pequeno
9.
Diagn Pathol ; 7: 68, 2012 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-22697234

RESUMO

BACKGROUND: The prediction of pathological outcomes prior to surgery remains a challenging problem for the appropriate surgical indication of prostate cancer. This study was performed to identify preoperative values predictive of pathological and oncological outcomes based on standardized extended prostate biopsies with core histological results diagrammed/mapped in patients receiving radical prostatectomy for prostate cancer clinically diagnosed as localized or locally advanced disease. METHODS: In 124 patients with clinically localized or locally advanced prostate cancer (cT1c-cT3a) without prior treatment, pathological outcomes on the surgical specimen including seminal vesicle involvement (SVI), positive surgical margin (PSM), and perineural invasion (PNI) were studied in comparison with clinical parameters based on the results of 14-core prostate biopsies comprising sextant, laterally-directed sextant, and bilateral transition zone (TZ) sampling. RESULTS: Concerning the association of pathological outcomes with oncological outcomes, patients with PSM and PNI on surgical specimens had poorer biochemical-progression-free survival than those without PSM (logrank p = 0.002) and PNI (p = 0.003); it was also poorer concerning SVI, although the difference was not significant (p = 0.120). Concerning the impact of clinical parameters on these pathological outcomes, positive TZ and multiple positive biopsy cores in the prostatic middle were independent values predictive of SVI with multivariate analyses (p = 0.020 and p = 0.025, respectively); both positive TZ and multiple positive prostatic middle biopsies were associated with larger tumor volume (p < 0.001 in both). The percentage of positive biopsy cores (%positive cores) and biopsy Gleason score were independent values predictive of PSM (p = 0.001) and PNI (p = 0.001), respectively. Multiple positive cores in the prostatic base were associated with proximal/bladder-side PSM (p < 0.001), and also linked to poorer biochemical-progression-free survival (p = 0.004). Clinical T stage had no association with these pathological outcomes. CONCLUSIONS: %positive cores and Gleason score in extended biopsies were independent values predictive of PSM and PNI in prostate cancer clinically diagnosed as localized or locally advanced disease, respectively, which were associated with poorer oncological outcomes. When diagramming biopsy-core results, extended biopsy may provide additional information for predicting oncological and pathological outcomes including SVI in patients clinically diagnosed as having localized or locally advanced disease. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8790262771042628.


Assuntos
Biópsia com Agulha de Grande Calibre , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Adulto , Idoso , Intervalo Livre de Doença , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Prostatectomia , Neoplasias da Próstata/cirurgia , Resultado do Tratamento
10.
Growth Horm IGF Res ; 22(3-4): 122-8, 2012 Jun-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22579549

RESUMO

OBJECTIVE: This study was performed to elucidate the mechanism of high bone turnover during androgen deprivation therapy (ADT) in terms of osteogenic endocrine activity by testosterone, adrenal androgens, and insulin-like growth factor-1 (IGF-I), and to identify markers reflecting the bone mineral density (BMD) during ADT. DESIGN: BMD and samples of blood and urine were studied before and after 6months of ADT in 70 patients with localized prostate cancer. RESULTS: Before ADT, serum free-testosterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, and IGF-I levels were correlated with BMD (rs=0.344, p=0.004; rs=0.264, p=0.027; rs=0.329, p=0.005; rs=0.300, p=0.012, respectively). The serum IGF-I level was independently correlated with the pretreatment BMD (Multivariate p=0.001). These relationships disappeared after ADT (p=0.519, 0.316, 0.116, and 0.597, respectively). After ADT, serum levels of free-testosterone decreased (7.9 to 0.2pg/mL), and DHEA-S and androstenedione were also reduced (3.6 to 2.3µmol/L and 5.6 to 2.9nmol/L, respectively) (p<0.001 in all). In contrast, IGF-I levels were elevated after ADT by 11.6% (19.9 to 22.3nmol/L, p<0.001). Delta-values of IGF-I (post- minus pretreatment levels, mean: +2.2, ranged between -7.1 and +15.3) were inversely correlated with the pretreatment (rs=-0.333 p=0.005) and post-treatment (rs=-0.408, p=0.001) BMD. After ADT, the serum IGF-I level was closely correlated with the serum level of the bone formation marker bone-specific alkaline phosphatase (BAP) (rs=0.328, p=0.006), and delta-IGF-I and delta-BAP showed a close positive correlation (rs=0.388, p=0.001). The post-treatment BMD was correlated only with the urine deoxypyridinoline (DPD) concentration (rs=-0.302, p=0.024) among the bone formation/resorption markers including serum/urine N-telopeptide. CONCLUSIONS: Serum IGF-I levels increased during ADT in men with a low BMD. Coupled with reduced androgen levels, elevated IGF-I levels, which were positively correlated with BAP during ADT, possibly explain the mechanism of ADT-related high bone turnover. The increase of IGF-I is more prominent in men whose BMD is already low at the baseline, and urine DPD might be a marker that reflects BMD during ADT.


Assuntos
Androgênios/uso terapêutico , Osso e Ossos/fisiologia , Fator de Crescimento Insulin-Like I/genética , Neoplasias da Próstata/tratamento farmacológico , Regulação para Cima , Idoso , Antagonistas de Androgênios/uso terapêutico , Androgênios/deficiência , Antineoplásicos Hormonais/uso terapêutico , Densidade Óssea , Reabsorção Óssea , Sulfato de Desidroepiandrosterona/sangue , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/metabolismo , Testosterona/sangue
11.
Prostate ; 72(11): 1207-13, 2012 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-22213519

RESUMO

BACKGROUND: Interleukin-6 produced in adipose tissue plays a role in lipid metabolism, and also interacts with sex steroids. This study was performed to elucidate the mechanism of lipid metabolism disorder during androgen deprivation therapy (ADT) in terms of the association of interleukin-6 with sex steroids. METHODS: Seventy-two patients with localized prostate cancer were prospectively studied based on their body-composition and blood samples before and after ADT for 6 months. RESULTS: Before ADT, serum interleukin-6 levels were inversely correlated with serum total-testosterone (rs = -0.305, P = 0.009) and dihydrotestosterone (rs = -0.380, P = 0.006) concentrations, but not correlated with adrenal androgen or estradiol levels. Pretreatment interleukin-6 levels were positively correlated with %body fat (rs = 0.349, P = 0.003) and %visceral fat (rs = 0.384, P = 0.001). After ADT, %body fat increased (P < 0.001) and lean body mass decreased (P = 0.036). After ADT, in contrast to the pretreatment relationship, interleukin-6 levels were positively correlated with total-testosterone concentrations (rs = 0.343, P = 0.003), and were positively correlated also with levels of androstenedione (rs = 0.351, P = 0.002) and estoradiol (rs = 0.335, P = 0.004). Interleukin-6 levels were equivalent between before and after ADT (2.02 vs. 2.16 pg/ml, P = 0.205), but the positive correlation between interleukin-6 levels and %body or %visceral fat noted before ADT disappeared after ADT. CONCLUSIONS: Posttreatment interleukin-6 levels had a strong positive correlation with total-testosterone, androstenedione, and estradiol levels, suggesting that a regulation loop may emerge between these sex steroids and interleukin-6 during ADT. The altered association between interleukin-6 and sex steroids is possibly involved in ADT-related lipid metabolism disorder with unchanged interleukin-6 levels despite increased %body fat.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Hormônios Esteroides Gonadais/metabolismo , Interleucina-6/metabolismo , Transtornos do Metabolismo dos Lipídeos/metabolismo , Neoplasias da Próstata/metabolismo , Idoso , Composição Corporal , Hormônios Esteroides Gonadais/sangue , Humanos , Transtornos do Metabolismo dos Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/sangue , Neoplasias da Próstata/tratamento farmacológico , Fator de Necrose Tumoral alfa/metabolismo
12.
Urol Oncol ; 30(5): 596-601, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21458314

RESUMO

BACKGROUND: Luteinizing hormone (LH) during androgen-deprivation therapy (ADT) with gonadotropin-releasing hormone analogues (GnRHa) has been thought to be biologically inactive, and the regulation of LH during ADT with GnRHa is thus unknown. Insulin-like growth factor-1 (IGF-1) is involved in the regulation of cell proliferation and differentiation, and IGF-1 production in the liver is dependent on growth hormone (GH) secretion from the anterior pituitary. Despite the presence of IGF-1 receptors in the gonadotroph, associations between the GH/IGF-1 and pituitary-gonadal axes, e.g., whether IGF-1 elicits the LH secretion, remain unclear. METHODS: Seventy-one patients with localized prostate cancer, who received ADT with GnRHa, were prospectively studied based on their blood samples before treatment and after ADT for 6 months. We employed highly sensitive assays for measurement of serum testosterone (electrochemiluminescence immunoassay), GH/IGF-1 (radioimmunoassay), adrenocorticotropic hormone (ACTH: immunoradiometric assay), LH (chemiluminescent immunoassay), and dehydroepiandrosterone sulfate (DHEA-S: chemiluminescent enzyme immunoassay). RESULTS: No correlation was noted between the pretreatment LH and IGF-1 levels; after ADT, the serum LH level was closely correlated with the IGF-1 concentration [Spearman's correlation coefficient (rs) = 0.370, P = 0.001]. The serum levels of androgens and gonadotropins reduced following ADT (P < 0.001 in all). The serum IGF-1 level increased (22 ± 6 nmol/L) compared with that at the baseline (19 ± 5 nmol/L) (P < 0.001), but no change was observed in the serum GH concentration between before and after ADT (1.4 ± 2.3 vs. 0.9 ± 0.9 µg/L, respectively, P = 0.691). The serum testosterone level was not correlated with the LH level either before or after ADT. The testosterone and DHEA-S levels after ADT were correlated with ACTH concentration (rs = 0.367, P = 0.002 and rs = 0.354, P = 0.002, respectively). We did not identify any correlations between the serum IGF-1 concentration and Gleason score, PSA value, or androgen levels. CONCLUSIONS: During ADT with GnRHa, IGF-1 possibly promotes LH production, although its role is unclear. Associations among pituitary-gonadal, pituitary-adrenal, and GH/IGF-1 axes represented by IGF-1-mediated LH secretion and ACTH-mediated androgen synthesis are of interest, since both prostate epithelium proliferation and male anabolic activity are involved in these 3 axes. Assessment of oncologic outcomes is warranted for their significance in patients with prostate cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fator de Crescimento Insulin-Like I/metabolismo , Hormônio Luteinizante/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/tratamento farmacológico , Hormônio Adrenocorticotrópico/sangue , Idoso , Antagonistas de Androgênios/administração & dosagem , Antagonistas de Androgênios/efeitos adversos , Antineoplásicos Hormonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Sulfato de Desidroepiandrosterona/sangue , Flutamida/administração & dosagem , Flutamida/efeitos adversos , Gosserrelina/administração & dosagem , Hormônio do Crescimento Humano/sangue , Humanos , Imunoensaio/métodos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Avaliação de Resultados (Cuidados de Saúde) , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/patologia , Testosterona/sangue
13.
Jpn J Clin Oncol ; 41(11): 1259-64, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21940731

RESUMO

OBJECTIVE: In 2005, the University of California, San Francisco developed the Cancer of the Prostate Risk Assessment (UCSF-CAPRA) score as a new risk stratification tool. The UCSF-CAPRA, which ranges from 0 to 10 points, consists of five clinical variables, prostate-specific antigen, Gleason score, T stage, percent of positive biopsies and age. The aim of this study was to validate the UCSF-CAPRA score for Japanese prostate cancer patients receiving radical prostatectomy using the contemporary Gleason grading. METHODS: From 1999 to 2010, 211 men who underwent radical prostatectomy were used for validation. Biochemical progression-free survival was calculated using the Kaplan-Meier method and the UCSF-CAPRA and D'Amico risk categories were compared using the log-rank method. The concordance index (c-index) for the UCSF-CAPRA and D'Amico risk classification was calculated. RESULTS: Using the UCSF-CAPRA score, 85 (40.3%), 106 (50.2%) and 20 (9.5%) subjects were stratified as 0-2 points (low risk), 3-5 points (intermediate risk) and 6-10 points (high risk). Using the D'Amico risk criteria, 66 (31.3%), 89 (42.2%) and 56 (26.5%) were stratified as low-, intermediate- and high-risk groups, respectively. The Kaplan-Meier analysis showed that the UCSF-CAPRA divided the patients significantly into each risk category. There was no significant difference between low and intermediate in the D'Amico risk classification. The c-index of the UCSF-CAPRA and D'Amico classification was 0.755 and 0.713, respectively. CONCLUSION: The UCSF-CAPRA is an acceptable risk category tool comparable to that of the D'Amico risk classification for Japanese prostate cancer patients receiving radical prostatectomy in the contemporary Gleason grading era.


Assuntos
Recidiva Local de Neoplasia/diagnóstico , Prostatectomia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Grupo com Ancestrais do Continente Asiático , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Prognóstico , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , São Francisco , Taxa de Sobrevida
14.
J Urol ; 184(5): 1971-6, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20884032

RESUMO

PURPOSE: We elucidated the regulatory mechanism of adrenal androgen synthesis and examined the influence of pituitary-adrenal axis activity on prostate specific antigen during androgen deprivation therapy. MATERIALS AND METHODS: A total of 72 patients with localized prostate cancer were prospectively studied based on blood samples before and after androgen deprivation therapy for 6 months. Serum pituitary hormones, androgens and prostate specific antigen were measured using highly sensitive assays. RESULTS: After androgen deprivation therapy serum levels of luteinizing hormone, follicle-stimulating hormone, testosterone, dehydroepiandrosterone sulfate, androstenedione and prostate specific antigen decreased compared with those at the baseline (all values p <0.001). No difference was noted between serum levels before and after androgen deprivation therapy in growth hormone (p = 0.098) and adrenocorticotropic hormone (p = 0.101). Each serum level of luteinizing hormone, follicle-stimulating hormone and growth hormone after androgen deprivation therapy was not correlated with the serum levels of androgens or prostate specific antigen. The serum adrenocorticotropic hormone level after androgen deprivation therapy was correlated with the serum levels of testosterone (p = 0.002), dehydroepiandrosterone sulfate (p = 0.002), androstenedione (p = 0.006) and prostate specific antigen (p <0.001). Serum dehydroepiandrosterone sulfate and androstenedione levels were also correlated with serum prostate specific antigen (p <0.001 and p = 0.002, respectively). CONCLUSIONS: In patients treated with androgen deprivation therapy the pituitary-adrenal axis mediated by adrenocorticotropic hormone has a central role in the regulation of androgen synthesis. Serum adrenocorticotropic hormone and adrenal androgen concentrations were correlated with the posttreatment prostate specific antigen. Adrenocorticotropic hormone mediated androgen synthesis is a potential target for advanced androgen deprivation therapy.


Assuntos
Hormônio Adrenocorticotrópico/fisiologia , Antagonistas de Androgênios/uso terapêutico , Androgênios/biossíntese , Antineoplásicos Hormonais/uso terapêutico , Flutamida/uso terapêutico , Gosserrelina/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
15.
Cancer Lett ; 297(2): 226-30, 2010 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-20831980

RESUMO

The intracellular androgen metabolism and cell activity in prostate cancer cells with mutated (LNCaP-FGC) or wild-type (VCaP) androgen receptors in the presence of trilostane, an inhibitor of 3ß-hydroxysteroid dehydrogenase, were examined. Trilostane suppressed the intracellular production of androstenedione, testosterone, and dihydrotestosterone from dehydroepiandrosterone in LNCaP-FGC cells. In both LNCaP-FGC and VCaP cell types, the prostate-specific antigen (PSA) levels in media were increased by trilostane alone in a concentration-dependent manner. Both cells pretreated with trilostane showed a dose-dependent decrease in PSA production with bicalutamide (P<0.001). Trilostane should be used with particular concern when treating prostate cancer.


Assuntos
3-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Androgênios , Di-Hidrotestosterona/análogos & derivados , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Androgênios/biossíntese , Linhagem Celular Tumoral , Cromatografia Líquida , Desidroepiandrosterona/metabolismo , Di-Hidrotestosterona/farmacologia , Inibidores Enzimáticos/farmacologia , Humanos , Masculino , Espectrometria de Massas , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Testosterona/metabolismo
16.
Prostate ; 70(13): 1395-401, 2010 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-20687212

RESUMO

BACKGROUND: Although androgen deprivation therapy (ADT) has a marked impact on the androgen milieu in vivo and outcomes of prostate cancer (PCa), it remains unclear which parameters reflect the androgen milieu during ADT or whether the milieu is associated with PCa aggressiveness. METHODS: Seventy-two patients with localized PCa were prospectively studied based on their blood samples before and after ADT for 6 months. Serum androgens and related values were measured. RESULTS: Before ADT, there was no correlation between the serum prostate-specific antigen (PSA) and androgen levels. After ADT, the serum PSA levels were correlated with each level of serum testosterone, dihydrotestosterone, androstenedione, dehydroepiandrosterone-sulfate (DHEA-S), and 3alpha-diol G (P < 0.010 in all). Before ADT, patients with Gleason score of > or = 8 were likely to have lower serum testosterone levels than those with Gleason score of < or = 6 (P = 0.058). After ADT, conversely, the testosterone levels in patients with Gleason score of > or = 8 appeared to be higher than in those with Gleason score of < or = 6 (P = 0.060). The serum DHEA-S level was correlated with Gleason score before and after ADT (P = 0.050 and P = 0.040, respectively). CONCLUSIONS: The serum PSA levels well reflect the androgen milieu in localized PCa patients receiving ADT, which can be explained by the Saturation Model and disease control. The androgen milieu in men with high Gleason score PCa is probably less affected by conventional ADT than that in men with low score cancer, which was suggested to be associated with adrenal androgen levels.


Assuntos
Androgênios/sangue , Flutamida/uso terapêutico , Gosserrelina/uso terapêutico , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/tratamento farmacológico , Idoso , Antineoplásicos Hormonais/uso terapêutico , Distribuição de Qui-Quadrado , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento
17.
Urology ; 75(6): 1441-5, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20110105

RESUMO

OBJECTIVES: To elucidate the mechanism of blood hemoglobin loss in patients with prostate cancer during androgen deprivation therapy (ADT), and to examine the activity of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis during ADT, which plays an important role in hematopoiesis. METHODS: A total of 83 patients with localized prostate cancer, who received ADT, were prospectively studied on the basis of their blood samples at the baseline and after ADT for 6 months. RESULTS: Before ADT, the IGF-1 level was correlated with the red blood cell (RBC) count (Spearman's rank correlation coefficient analysis [rs]=0.315, P=.011), hemoglobin (rs=0.278, P=.018), and mean corpuscular volume (rs=0.266, P=.020), but such relationships disappeared after ADT. After ADT, the serum IGF-1 level increased compared with that at the baseline (21+/-6 vs 18+/-5 nmol/L, respectively, P<.001), but no change was observed in the serum GH level (P=.691). There was no difference between erythropoietin and interleukin-6 concentrations before and after ADT (P=.852 and P=.208, respectively). The hemoglobin concentration and RBC count declined after ADT compared with those before treatment (P<.001 for each). Although the mean corpuscular volume declined after ADT (P=.002), the mean cell hemoglobin was comparable between before and after ADT (P=.676). CONCLUSIONS: Despite the unaffected GH, erythropoietin, and interleukin-6 levels, the serum IGF-1 concentration was elevated by ADT. Even with the increased IGF-1 level, the RBC count and hemoglobin concentration declined after ADT. IGF-1 in the bone marrow erythroid progenitor cells might be functionally inactivated during ADT.


Assuntos
Antagonistas de Androgênios/efeitos adversos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/tratamento farmacológico , Somatomedinas/análise , Idoso , Antagonistas de Androgênios/uso terapêutico , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Biomarcadores/sangue , Biópsia por Agulha , Estudos de Coortes , Contagem de Eritrócitos , Eritropoese/efeitos dos fármacos , Seguimentos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Probabilidade , Estudos Prospectivos , Neoplasias da Próstata/patologia , Medição de Risco , Estatísticas não Paramétricas , Resultado do Tratamento
18.
Prostate ; 70(2): 155-61, 2010 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-19760629

RESUMO

BACKGROUND: Although androgen deprivation therapy (ADT) has been associated with bone loss in patients with prostate cancer, its mechanism remains unclear. The growth hormone (GH)/insulin-like growth factor-1 (IGF-1)/parathyroid hormone (PTH) axis plays a critical role in bone synthesis, but its activity during ADT is also unknown. METHODS: Seventy-one patients with localized prostate cancer, who received ADT, were prospectively studied based on their bone mineral density (BMD) and blood and urine samples at the baseline and after ADT for 6 months. RESULTS: The IGF-1 level was correlated with BMD before ADT (rs = 0.325, P = 0.007), but such a relationship disappeared after ADT (P = 0.565). Following ADT, the serum IGF-1 level increased compared with that at the baseline (22 +/- 6 nmol/L vs. 19 +/- 5 nmol/L, respectively, P < 0.001). The serum PTH level was reduced after ADT (41 +/- 33 ng/L) compared with the baseline (55 +/- 44 ng/L) (P < 0.001), but no change was observed in the serum GH level (P = 0.691). Bone resorption markers such as blood N-telopeptide (NTx), urinary NTx, calcium, and inorganic phosphorus levels increased after ADT (P < 0.001 in all). The ratio of the IGF-1 level after ADT/before ADT was associated with the ratio of the value after ADT/before ADT of alkaline phosphatase (rs = 0.266, P = 0.025) and calcium (rs = 0.242, P = 0.042). CONCLUSION: Despite the unaffected GH and upregulated bone resorption, the serum IGF-1 level was elevated by ADT. The IGF-1 level was correlated with BMD before ADT, but the relationship was disrupted after ADT. IGF-1 or its receptor in the bone may be functionally inactivated during ADT.


Assuntos
Antagonistas de Androgênios/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Doenças Ósseas Metabólicas/metabolismo , Flutamida/uso terapêutico , Orquiectomia/efeitos adversos , Neoplasias da Próstata/terapia , Idoso , Densidade Óssea , Doenças Ósseas Metabólicas/sangue , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/urina , Gosserrelina/uso terapêutico , Hormônio do Crescimento Humano/análise , Humanos , Fator de Crescimento Insulin-Like I/análise , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/análise , Estudos Prospectivos , Neoplasias da Próstata/sangue , Neoplasias da Próstata/urina
19.
Asian J Androl ; 11(3): 283-90, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19349948

RESUMO

Health-related quality-of-life (HRQOL) after a radical prostatectomy (RP) or external beam radiation therapy (EBRT) has not been studied in conjunction with oncological outcomes in relation to disease risk stratification. Moreover, the long-term outcomes of these treatment approaches have not been studied. We retrospectively analyzed oncological outcomes between consecutive patients receiving RP (n=86) and EBRT (n=76) for localized prostate cancer. HRQOL and functional outcomes could be assessed in 62 RP (79%) and 54 EBRT (79%) patients over a 3-year follow-up period (median: 41 months) using the Medical Outcomes Study Short Form-36 (SF-36) and the University of California Los Angeles Prostate Cancer Index (UCLA PCI). The 5-year biochemical progression-free survival did not differ between the RP and EBRT groups for low-risk (74.6% vs. 75.0%, P=0.931) and intermediate-risk (61.3% vs. 71.1%, P=0.691) patients. For high-risk patients, progression-free survival was lower in the RP group (45.1%) than in the EBRT group (79.7%) (P=0.002). The general HRQOL was comparable between the two groups. Regarding functional outcomes, the RP group reported lower scores on urinary function and less urinary bother and sexual bother than the EBRT group (P<0.001, P<0.05 and P<0.001, respectively). With risk stratification, the low- and intermediate-risk patients in the RP group reported poorer urinary function than patients in the EBRT group (P<0.001 for each). The sexual function of the high-risk patients in the EBRT group was better than that of the same risk RP patients (P<0.001). Biochemical recurrence was not associated with the UCLA PCI score in either group. In conclusion, low- to intermediate-risk patients treated with an RP may report relatively decreased urinary function during long-term follow-up. The patient's HRQOL after treatment did not depend on biochemical recurrence.


Assuntos
Prostatectomia/métodos , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/cirurgia , Qualidade de Vida , Radioterapia/métodos , Idoso , Intervalo Livre de Doença , Seguimentos , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
20.
Urol Oncol ; 26(3): 254-9, 2008 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18452815

RESUMO

BACKGROUND: Solitary fibrous tumor (SFT) is an infrequent but distinct neoplasm, which generally arises from submesothelial connective tissue in the pleura. SFT is rarely recognized in extrathoracic sites, and histologically identical conditions have also been reported in the retroperitoneum, although their pathophysiology has not been extensively investigated. METHODS: We present four cases of primary SFT in the retroperitoneum, and review 37 similar cases in the previous literature. RESULTS: About 40% of patients were asymptomatic, and 19.2% and 15.4% presented with an abdominal mass and urinary symptoms, respectively. The tumor size ranged between 2 and 26 (mean 9.1) cm. Sixty-three percent of tumors showed nonspecific development with haphazard distribution of bland short spindle or polygonal cells with or without collagenous bundles and stromal hyalinization. In 22.0%, hemangiopericytomatous appearance was seen. About 15% of cases showed histologically malignant characteristics. The tumor cells were immunoreactive for vimentin in all cases, CD34 in 91% and Bcl-2 in 86%. All tumors were excised, and in 85.4% of cases, tumors did not recur postoperatively for 6 to 48 months. No significant difference was found between the recurrence rate of histologically benign and malignant cases. Cases positive for both CD34 and Bcl-2 had no recurrence. CONCLUSIONS: The identification of SFT in the retroperitoneum is of importance because histopathological indicators of malignancy are not necessarily associated with clinical malignant potential in many cases of retroperitoneal SFT. Retroperitoneal SFT showing typical pathological features with expression of CD34 and Bcl-2 is associated with a favorable outcome following excision.


Assuntos
Neoplasias Retroperitoneais/patologia , Tumores Fibrosos Solitários/patologia , Adolescente , Adulto , Idoso , Antígenos CD34/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Cintilografia , Neoplasias Retroperitoneais/diagnóstico por imagem , Neoplasias Retroperitoneais/metabolismo , Neoplasias Retroperitoneais/cirurgia , Tumores Fibrosos Solitários/diagnóstico por imagem , Tumores Fibrosos Solitários/metabolismo , Tumores Fibrosos Solitários/cirurgia
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