Usefulness of Alternative Therapy with Hydrocortisone in the Postoperative Management of Severe Primary Aldosteronism.

Mineralocorticoid deficiency (MD) with hyperkalemia is an important complication of adrenalectomy in patients with primary aldosteronism (PA). We herein report a 52-year-old man with refractory hypertension, hypokalemia, and severe renal dysfunction due to PA caused by a right adrenal adenoma. His estimated glomerular filtration rate (eGFR) transiently increased immediately after adrenalectomy but then gradually declined, and he developed hyperkalemia. A postoperative endocrine examination revealed MD. Considering the patient's hypertension and severe renal dysfunction, we administered hydrocortisone instead of fludrocortisone, which improved the hyperkalemia and stopped the decline in the eGFR. Alternative therapy with hydrocortisone may be useful in such patients with MD.

Subclassification of pT3 upper tract urothelial carcinoma: a multicenter retrospective study.

PURPOSE: The prognosis of patients with pT3 upper tract urothelial carcinoma (UTUC) varies. The current study aimed to further classify patients with pT3 UTUC into different survival outcome groups based on tumor location and site of invasion. METHODS: This retrospective study included 323 patients with pT3 UTUC who underwent nephroureterectomy at 11 hospitals in Japan. Histological and clinical data were obtained via a chart review. Univariate and multivariate Cox proportional hazards analyses showed the effect of different variables on recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: The median age of the patients was 72 years. Patients with pT3 UTUCs were divided into two groups: those with renal parenchymal invasion only (pT3a, n = 95) and those with peripelvic or periureteral fat invasion (pT3b, n = 228). pT3b UTUC was significantly associated with hydronephrosis, low preoperative estimated glomerular filtration rate (eGFR), histological nodal metastasis, nuclear grade 3, lymphovascular invasion (LVI), carcinoma in situ, and positive surgical margin. Based on the univariate analyses, patients with pT3b UTUC had a significantly lower 5-year RFS (42.4% vs. 70.1%, p < 0.0001), 5-year CSS (54.3% vs. 80.0%, p = 0.0002), and 5-year OS (47.8% vs. 76.8%, p < 0.0001) than those with pT3a UTUC. According to the multivariate analyses, nodal metastasis, LVI, adjuvant chemotherapy, preoperative eGFR, nuclear grade (RFS only), surgical margin (RFS only), and Charlson comorbidity index (OS only), but not pT3b stage, were associated with survival. CONCLUSION: Compared with pT3a UTUC, pT3b UTUC was significantly associated with worse histological features, consequently resulting in unsatisfactory survival outcomes.

Renal hyperparathyroidism.

The number of the patients with chronic kidney disease is now increasing in the world. The pathophysiology of renal hyperparathyroidism is closely associated with Klotho-FGF-endocrine axes, which must be solved definitively as early as possible. It was revealed that the expression of fgf23 is activated by calciprotein particles, which induces vascular ossification. And it is well known that phosphorus overload directly increases parathyroid hormone and hyperparathyroid bone disease develops in those subjects. On the other hand, low turnover bone disease is often recently. Both the patients with chronic kidney disease suffering from hyperparathyroid bone disease or low turnover bone disease are associated with increased fracture risk. Micropetrosis may be one of the causes of increased fracture risk in the subjects with low turnover bone disease. In this chapter, we now describe the diagnosis, pathophysiology and treatments of renal hyperparathyroidism.

Micropetrosis in hemodialysis patients.

Micropetrosis develops as a result of stagnation of calcium, phosphorus and bone fluid, which appears as highly mineralized bone area in the osteocytic perilacunar/canalicular system regardless of bone turnover of the patients. And microcracks are predisposed to increase in these areas, which leads to increased bone fragility. However, micropetrosis of hemodialysis (HD) patients has not been discussed at all. Micropetrosis area per bone area (Mp.Ar/B·Ar) and osteocyte number per micropetrosis area (Ot.N/Mp.Ar) were measured in nine HD patients with renal hyperparathyroidism (Group I), twelve patients with hypoparathyroidism within 1 year after the treatment of renal hyperparathyroidism (Group II) and seven patients suffering from hypoparathyroidism for over two years (Group III). And bone mineral density (BMD) and tissue mineral density (TMD) were calculated using µCT to evaluate bone mineral content of iliac bone of the patients. These parameters were compared among the three groups. Only Mp.Ar/B·Ar was statistically greater in Group II and III compared to Group I in the parameters of bone mineral content and micropetrosis. However, the other parameters were not statistically different among the three groups. In long-term HD patients, BMD and TMD may be modified by the causes of renal insufficiency and the treatment of renal bone disease. We concluded that Mp.Ar/B·Ar was greater in patients with long-term hypoparathyroidism than both those with short-term hypoparathyroidism and with renal hyperparathyroidism. Special attention should be paid to avoid long-term hypoparathyroidism of the patients from the view point of increased fracture risk caused by increased micropetrosis area.

Smaller decline of renal function after nephroureterectomy predicts poorer prognosis of upper tract urothelial carcinoma: a multicentre retrospective study.

PURPOSE: Renal function is frequently impaired in the patients with upper tract urothelial carcinoma. We aimed to evaluate the impact of renal function and its change after surgery on survival rates in patients with upper tract urothelial carcinoma after nephroureterectomy. METHODS: The study cohort comprised 755 patients with upper tract urothelial carcinoma who underwent nephroureterectomy between 1995 and 2016 at nine hospitals in Japan. Estimated glomerular filtration rate was calculated using the three-variable Japanese equation for glomerular filtration rate estimation from serum creatinine level and age. Outcomes were recurrence-free, cancer-specific and overall survivals. Univariate and multivariate Cox proportional hazards regression analyses were used. RESULTS: Median patients' age was 72 years old. Pre- and post-surgical median estimated glomerular filtration rate were 55.5 and 42.9 ml/min/1.73 m2, respectively. Median estimated glomerular filtration rate decline after surgery, which represents function of the affected side kidney, was 13.1 ml/min/1.73 m2. The 5-year recurrence-free, cancer-specific and overall survivals were 68.3, 79.4 and 74.0%, respectively. Multivariate analysis indicated that lower preoperative estimated glomerular filtration rate and estimated glomerular filtration rate decline were associated with poorer recurrence-free, cancer-specific and overall survivals, but post-operative estimated glomerular filtration rate was not. Estimated glomerular filtration rate decline was more significant poor-prognosticator than preoperative estimated glomerular filtration rate. Proportions of the patients with estimated glomerular filtration rate <60 ml/min/1.73 m2 before surgery were 50.6 and 73.2% in organ-confined disease and locally advanced disease, respectively (P < 0.0001). After surgery, they were 91.6 and 89.8%, respectively (P = 0.3896). CONCLUSIONS: Lower preoperative renal function, especially of the affected side kidney, was significantly associated with poor prognosis after nephroureterectomy for upper tract urothelial carcinoma. Many patients with locally advanced disease have reduced renal function at diagnosis and even more after surgery.

Continence Status and Presence of Pressure Skin Injury among Special Elderly Nursing Home Residents in Japan: A Nationwide Cross-Sectional Survey.

Urinary and fecal incontinence as well as skin pressure injury are common healthcare problems in nursing homes; however, the prevalence and related risk factors were not well understood in the Japanese special elderly nursing home settings. We surveyed the prevalence of urinary, fecal and double incontinence, and skin pressure injury among the elderly living in special elderly nursing homes in Japan. A nationwide cross-sectional epidemiological survey was conducted with a total of 4881 residents. The prevalence of urinary, fecal and double incontinence was 82.9%, 68.9% and 64.9%, respectively. Skin pressure injury was found in 283 residents (283/4881, 5.8%). Age, Care-Needs level, loss of voiding desire, and fecal incontinence were significant risk factors for urinary incontinence. Residential period, Care-Needs level, loss of voiding and defecation desires, and urinary incontinence were significant risk factors for fecal incontinence. Only male sex was a significant risk factor for skin pressure injury. Our study revealed continence status and the prevalence of pressure skin injury among older adult residents who receive end-of-life care in special elderly nursing homes in Japan. Further studies should be conducted to examine whether recovery of urinary and fecal sensations improves continence status.

Nationwide survey of continence status among older adult residents living in long-term care facilities in Japan: The prevalence and associated risk factors of incontinence and effect of comprehensive care on continence status.

AIM: This study aimed to identify the prevalence of urinary, fecal and double incontinence among Japanese residents aged ≥65 years living in long-term care facilities. Furthermore, the association between baseline characteristics and changes in toileting activity after a 3-month comprehensive care among older individuals was investigated. METHODS: We examined the prevalence of incontinence and its significant predictors. The association between the Functional Independence Measure score at baseline and each type of incontinence (urinary, fecal or double incontinence) was examined using a logistic regression model. Similarly, the association between the Functional Independence Measure score at baseline and improvement in toileting activity after a 3-month comprehensive care was examined. RESULTS: In total, 2517 residents (670 men and 1847 women) were recruited. The prevalence rates of urinary, fecal and double incontinence were 66.9%, 42.8% and 41.1%, respectively. In multivariate analysis, the sum of the motor subscales after removing four continence items and the sum of the cognitive subscales of the Functional Independence Measure score at baseline were significantly associated with all types of incontinence. The sum of the motor subscales after removing four continence items of the Functional Independence Measure score was associated with improved toileting activity. CONCLUSIONS: This study presented the prevalence of urinary, fecal and double incontinence among residents living in long-term care facilities in Japan. The Functional Independence Measure items at baseline were associated with not only continence status, but also improved toileting activity after 3-month comprehensive care. Geriatr Gerontol Int 2020; 20: 285-290.

Detection rate of clinically significant prostate cancer in magnetic resonance imaging and ultrasonography-fusion transperineal targeted biopsy for lesions with a prostate imaging reporting and data system version 2 score of 3-5.

OBJECTIVES: To evaluate the detection rates of clinically significant prostate cancer classified according to the prostate imaging reporting and data system scoring system using magnetic resonance imaging/ultrasound rigid fusion targeted biopsy. METHODS: A total of 339 patients underwent transperineal magnetic resonance imaging/ultrasound rigid fusion targeted biopsy in our institution between January 2015 and July 2017. Patients with prostate imaging reporting and data system category 1 or 2 and those with a pre-biopsy prostate-specific antigen value of >30 ng/mL were excluded from this study. Finally, 310 patients were recruited. RESULTS: The detection rates of clinically significant prostate cancer with prostate imaging reporting and data system category 3, 4, and 5 were 1.0% (1/98), 35.1% (47/134) and 73.1% (57/78), respectively. The factors affecting the detection of clinically significant prostate cancer with prostate imaging reporting and data system categories 4 and 5 were: (i) prostate imaging reporting and data system category 5; (ii) prostate volume <40 cc; (iii) no previous biopsy; (iv) lesion located in the peripheral zone; and (v) prostate-specific antigen density >0.35 ng/mL/mL. CONCLUSIONS: The detection rate of clinically significant prostate cancer on magnetic resonance imaging/ultrasound rigid fusion targeted biopsy is very low in patients with prostate imaging reporting and data system category 3; therefore, patients with this classification should not undergo targeted biopsy. Prostate-specific antigen density, prostate volume, locations of suspected cancer and history of biopsy should be considered to predict the detection rate of clinically significant prostate cancer with prostate imaging reporting and data system categories 4 and 5.

Gastric neuroendocrine carcinoma with positive staining for prostate cancer markers including prostate-specific antigen and alpha-methylacyl-CoA racemase.

We report a case with prostate cancer and gastric neuroendocrine carcinoma. A 72-year old male presented with a gastric lesion 5 months after radical prostatectomy. The lesion was immunohistochemically positive for PSA, alpha-methylacyl-CoA racemase, synaptophysin, and chromogranin A, but negative for androgen receptor (AR). Differentiating gastric neuroendocrine carcinoma from gastric metastasis of prostate cancer is difficult, as both lesions exhibit similar acinar cell proliferation with prominent nucleoli.1 We discuss the diagnostic process of this case and how AR was a useful specific marker for diagnosing primary gastric neuroendocrine carcinoma.

A prospective study of magnetic resonance imaging and ultrasonography (MRI/US)-fusion targeted biopsy and concurrent systematic transperineal biopsy with the average of 18-cores to detect clinically significant prostate cancer.

BACKGROUND: This study compared the detection rates for clinically significant prostate cancer (CSPC) between magnetic resonance imaging and ultrasonography (MRI/US)-fusion-targeted biopsy (TB), systematic biopsy (SB) and combination of TB and SB. METHODS: This prospective study evaluated simultaneous TB and SB for consecutive patients with suspicious lesions that were detected using pre-biopsy multiparametric MRI. A commercially available real-time virtual sonography system was used to perform the MRI/US-fusion TB with the transperineal technique. The prostate imaging reporting and data system version 2 (PI-RADS v2) was assigned to categorize the suspicious lesions. RESULTS: A total of 177 patients were included in this study. The detection rate for CSPC was higher using SB, compared to TB (57.1% vs 48.0%, p = 0.0886). The detection rate for CSPC was higher using the combination of TB and SB, compared to only SB (63.3% vs 57.1%, p = 0.2324). Multivariate analysis revealed that PIRADS v2 category 4 and an age of <65 years were independent predictors for TB upgrading (vs. the SB result). CONCLUSIONS: PI-RADS v2 category 4 and an age of <65 years were predictive factors of upgrading the Gleason score by MRI/US-fusion TB. Thus, MRI/US-fusion TB may be appropriate for patients with those characteristics. TRIAL REGISTRATION: This study was retrospectively registered at the University Hospital Medical Information Network ( UMINID000025911 ) in Jan 30, 2017.

Abhydrolase domain containing 2, an androgen target gene, promotes prostate cancer cell proliferation and migration.

BACKGROUND: The androgen receptor (AR) plays a key role in the development of prostate cancer. AR signalling mediates the expression of androgen-responsive genes, which are involved in prostate cancer development and progression. Our previous chromatin immunoprecipitation study showed that the region of abhydrolase domain containing 2 (ABHD2) includes a functional androgen receptor binding site. In this study, we demonstrated that ABHD2 is a novel androgen-responsive gene that is overexpressed in human prostate cancer tissues. METHODS: The expression levels of ABHD2 in androgen-sensitive cells were evaluated by quantitative reverse transcription polymerase chain reaction and western-blot analyses. LNCaP and VCaP cells with ABHD2 overexpression or short interfering RNA (siRNA) knockdown were used for functional analyses. ABHD2 expression was examined in clinical samples of prostate cancer by immunohistochemistry. RESULTS: We showed that ABHD2 expression is increased by androgen in LNCaP and VCaP cells. This androgen-induced ABHD2 expression was diminished by bicalutamide. While stable expression of ABHD2 affected the enhancement of LNCaP cell proliferation and migration, siRNA-mediated ABHD2 knockdown suppressed cell proliferation and migration. In addition, the siRNA treatment significantly repressed the tumour growth derived from LNCaP cells in athymic mice. Immunohistochemical analysis of ABHD2 expression in tumour specimens showed a positive correlation of ABHD2 immunoreactivity with high Gleason score and pathological N stage. Moreover, patients with high immunoreactivity of ABHD2 showed low cancer-specific survival rates and a resistance to docetaxel-based chemotherapy. CONCLUSION: ABHD2 is a novel androgen-regulated gene that can promote prostate cancer growth and resistance to chemotherapy, and is a novel target for diagnosis and treatment of prostate cancer.

[LEIOMYOSARCOMA ARISING FROM OVARIAN VEIN WITH RIGHT HYDRONEPHROSIS: A CASE REPORT].

The patient was a 37-year-old woman who had suffered from repeated pyelonephritis. Computed tomography (CT) of the abdomen revealed a 1.9 cm retroperitoneal mass with compression of the right ureter and hydronephrosis. The patient visited our medical center and admitted. The patient underwent a simple total excision of the mass and end-to-end ureteral anastomosis. The tumor involved right ovarian vein and right ureter. Histopathological diagnosis was leiomyosarcoma of the ovarian vein. At 12 months after operation, local recurrence of surroundings tissue of the right ureter and gallbladder, and inferior vena cava invasion is found. Thus, the patient underwent a right nephroureterectomy with partly resection of the inferior vena cava and en block excision of the gallbladder. While CT revealed no recurrence three months after the operation, adjuvant postoperative combination chemotherapy with gemcitabine and docetaxel was administered. Nine cases of this leiomyosarcoma arising from ovarian vein have been reported in the literature. Leiomyosarcoma arising from ovarian vein with hydronephrosis is a second example.

Clinical significance of amyloid precursor protein in patients with testicular germ cell tumor.

Introduction. The biological role of amyloid precursor protein (APP) is not well understood, especially in testicular germ cell tumors (TGCTs). Therefore, we aimed to investigate the immunoreactivity (IR) and expression of APP in TGCTs and evaluated its clinical relevance. Materials and Methods. We performed an analysis of immunohistochemistry and mRNA expression of APP in 64 testicular specimens and 21 snap-frozen samples obtained from 1985 to 2004. We then evaluated the association between APP expression and clinicopathological status in TGCTs. Results. Positive APP IR was observed in 9.8% (4/41) of seminomatous germ cell tumors (SGCTs) and 39.1% (9/23) of nonseminomatous germ cell tumors (NGCTs). NGCTs showed significantly more cases of positive IR (P = 0.00870) and a higher mRNA expression level compared with those of SGCTs (P = 0.0140). Positive APP IR was also significantly associated with α -fetoprotein ( α FP) elevation (P = 0.00870) and venous invasion (P = 0.0414). Conclusion. We observed an elevated APP expression in TGCTs, especially in NGCTs. APP may be associated with a more aggressive cancer in TGCTs.

14-3-3ζ, a novel androgen-responsive gene, is upregulated in prostate cancer and promotes prostate cancer cell proliferation and survival.

PURPOSE: Androgen receptor is an essential transcriptional factor that contributes to the development and progression of prostate cancer. In this study, we investigated the androgen regulation and functional analysis of 14-3-3ζ in prostate cancer. EXPERIMENTAL DESIGN: Using chromatin immunoprecipitation (ChIP) combined with DNA microarray (ChIP-chip) analysis in LNCaP cells, we identified a functional androgen receptor-binding site in the downstream region of the 14-3-3ζ gene. Androgen regulation was examined by quantitative reverse transcription PCR and Western blot analysis. Prostate cancer cells stably expressing 14-3-3ζ and siRNA knockdown were used for functional analyses. We further examined 14-3-3ζ expression in clinical samples of prostate cancer by immunohistochemistry and quantitative reverse transcription PCR. RESULTS: Androgen-dependent upregulation of 14-3-3ζ was validated at the mRNA and protein levels. The 14-3-3ζ gene is favorable for cancer-cell survival, as its ectopic expression in LNCaP cells contributes to cell proliferation and the acquired resistance to etoposide-induced apoptosis. 14-3-3ζ expression was associated with androgen receptor transcriptional activity and prostate-specific antigen (PSA) mRNA expression. Immunoprecipitation indicated that 14-3-3ζ was associated with androgen receptor in the nucleus. Clinicopathologic studies further support the relevance of 14-3-3ζ in prostate cancers, as its higher expression is associated with malignancy and lymph node metastasis. CONCLUSIONS: 14-3-3ζ is a novel androgen-responsive gene that activates proliferation, cell survival, and androgen receptor transcriptional activity. 14-3-3ζ may facilitate the progression of prostate cancer.

Oct1 regulates cell growth of LNCaP cells and is a prognostic factor for prostate cancer.

The androgen receptor (AR) plays a critical role in the development and the progression of prostate cancer. Alterations in the expression of AR coregulators lead to AR hypersensitivity, which is one of the mechanisms underlying the progression of prostate cancer into a castrate-resistant state. Octamer transcription factor 1 (Oct1) is a ubiquitous member of the POU-homeodomain family that functions as a coregulator of AR. In our study, the contribution of Oct1 to prostate cancer development was examined. Immunocytochemistry analysis showed that Oct1 is expressed in the nuclei of LNCaP cells. siRNA-mediated silencing of Oct1 expression inhibited LNCaP cell proliferation. Immunohistochemical analysis of Oct1 expression in tumor specimens obtained from 102 patients with prostate cancer showed a positive correlation of Oct1 immunoreactivity with a high Gleason score and AR immunoreactivity (p = 0.0042 and p < 0.0001, respectively). Moreover, patients with high immunoreactivity of Oct1 showed a low cancer-specific survival rate, and those patients with high immunoreactivities of both Oct1 and AR exhibited poorer cancer-specific prognosis. Multivariate hazard analysis revealed a significant correlation between high Oct1 immunoreactivity and poor cancer-specific survival (p = 0.012). These results demonstrate that Oct1 can be a prognostic factor in prostate cancer as a coregulator of AR and may lead to the development of a new therapeutic intervention for prostate cancer.

ARFGAP3, an androgen target gene, promotes prostate cancer cell proliferation and migration.

ADP ribosylation factor GTPase-activating protein 3 (ARFGAP3) is a GTPase-activating protein that associates with the Golgi apparatus and regulates the vesicular trafficking pathway. In the present study, we examined the contribution of ARFGAP3 to prostate cancer cell biology. We showed that ARFGAP3 expression was induced by 100 nM of dihydrotestosterone (DHT) at both the mRNA and protein levels in androgen-sensitive LNCaP cells. We generated stable transfectants of LNCaP cells with FLAG-tagged ARFGAP3 or a control empty vector and showed that ARFGAP3 overexpression promoted cell proliferation and migration compared with control cells. We found that ARFGAP3 interacted with paxillin, a focal adhesion adaptor protein that is important for cell mobility and migration. Small interfering RNA (siRNA)-mediated knockdown of ARFGAP3 showed that ARFGAP3 siRNA markedly reduced LNCaP cell growth. Androgen receptor (AR)-dependent transactivation activity on prostate-specific antigen (PSA) enhancer was synergistically promoted by exogenous ARFGAP3 and paxillin expression, as shown by luciferase assay in LNCaP cells. Thus, our results suggest that ARFGAP3 is a novel androgen-regulated gene that can promote prostate cancer cell proliferation and migration in collaboration with paxillin.

Clinical significance of steroid and xenobiotic receptor and its targeted gene CYP3A4 in human prostate cancer.

The steroid and xenobiotic receptor (SXR) regulates cytochrome P450 (CYP) enzymes, which are key inactivators of testosterone in the liver and prostate. In the present study, we investigated SXR expression in human prostate tissues. We determined SXR immunoreactivity using an anti-SXR antibody in benign (n = 78) and cancerous (n = 106) tissues obtained by radical prostatectomy. Stained slides were evaluated for the proportion and staining intensity of immunoreactive cells. Total immunoreactivity (IR) scores (range: 0-8) were calculated as the sum of the proportion and intensity scores. Associations between the clinicopathological features of the patients, SXR status, and CYP3A4 immunoreactivity were analyzed. Western blot analyses validated the specificity of the anti-SXR antibody in 293T cells transfected with pcDNA-FLAG-SXR. Positive (IR score: ≥ 2) nuclear SXR staining was observed in 91% (71/78) of benign foci and 47% (50/106) of cancerous lesions. Immunoreactivity scores were significantly lower in the cancerous lesions than in the benign foci (P < 0.0001). Clinicopathological analyses showed that cancer-specific survival in patients with high SXR IR scores (≥ 4) was significantly increased (P = 0.046). Combined data of present and previous studies showed that high IR scores for both the SXR and CYP3A4 correlated with significantly better cancer-specific survival rates in multivariate regression analyses (hazard ratio: 2.15, 95% confidence interval: 1.25-3.55, P = 0.007). We showed differential SXR expression in human prostate tissues. The high expression of the SXR and CYP3A4 is a strong prognostic indicator of favorable outcomes in prostate cancer, and could be a therapeutic target.

Differential expression of estrogen-related receptors beta and gamma (ERRbeta and ERRgamma) and their clinical significance in human prostate cancer.

Estrogen-related receptor (ERR) is a nuclear receptor that modulates the estrogen-signaling pathway. Here, we investigated the expression of both ERRbeta and ERRgamma in human prostate tissues. Using original rabbit polyclonal anti-ERRbeta and anti-ERRgamma antibodies, the expression of ERRbeta and ERRgamma was evaluated by immunohistochemical analysis of cancerous lesions (n = 107) and benign foci (n = 92), obtained by radical prostatectomy. Stained slides were evaluated for the proportion of immunoreactive cells and their staining intensity. Total immunoreactivity scores (IR scores; range, 0-8) were calculated as the sum of the proportion and intensity scores. The relationship between the clinicopathological characteristics of the patients and the expression of the three ERRs (ERRalpha, ERR beta, and ERR gamma) was evaluated. IR scores for ERRbeta and ERRgamma were significantly lower in cancerous lesions than that in benign foci (P < 0.0001, for both). Clinicopathological analyses revealed that the patients with low ERRgamma IR scores (

Expression of cytochrome P450 3A4 and its clinical significance in human prostate cancer.

OBJECTIVES: To evaluate CYP3A4 expression in human prostrate cancer (PCa) tissues. Enzymes of the cytochrome P450 (CYP) family are key inactivators of testosterone in the liver and prostate. We previously reported that CYP2B6 is a growth-inhibitory and prognostic factor in human PCa; however, the status of CYP3A4 in PCa remains unclear. METHODS: We used immunohistochemistry to analyze CYP3A4 expression in 107 human PCa specimens obtained by radical prostatectomy. Stained slides were evaluated for the proportion and staining intensity of positively stained cells. Total immunoreactivity scores (0-8) were obtained as the sum of the proportion and intensity scores. In addition, we estimated the relationship between CYP3A4 status and clinicopathologic features. RESULTS: CYP3A4 immunoreactivity was identified in the cytoplasm of prostate cells. The CYP3A4 immunoreactive PCa score (3.6+/-2.6) was significantly lower than that of benign epithelium (4.5+/-2.1; P < .0001). In addition, CYP3A4 immunoreactivity correlated inversely with the Gleason score (P < .0001). Decreased CYP3A4 immunoreactivity was significantly related to a poor prognosis in human PCa (P = .0175). CONCLUSIONS: We demonstrated differential CYP3A4 expression in prostatic tissues, indicating that decreased CYP3A4 expression may contribute to the development of PCa.