Takashi Imamoto

Neuroendocrine differentiation in the progression of prostate cancer

Neuroendocrine (NE) cells originally exist in the normal prostate acini and duct, regulating prostatic growth, differentiation and secretion. Clusters of malignant NE cells are found in most prostate cancer (PCa) cases. NE differentiation (NED) is the basic character of the prostate, either benign or malignant. NE cells hold certain peptide hormones or pro‐hormones, which affect the target cells by endocrine, paracrine, autocrine and neuroendocrine transmission in an androgen‐independent fashion due to the lack of androgen receptor. NED is accessed by immunohistochemical staining or measurement of serum levels of NE markers. The extent of NED is associated with progression and prognosis of PCa. Chromogranin A (CGA) is the most important NE marker. In metastatic PCa, pretreatment serum CGA levels can be a predictor for progression and survival after endocrine therapy. It is recommended to measure longitudinal change in serum CGA. The NE pathway can also be a therapeutic target.

The role of testosterone in the pathogenesis of prostate cancer

Abstract:  Relationships between androgenic hormones and prostatic tissue growth are complex. It is certainly true that the prostate will not develop without androgens and the gland will atrophy if androgen support is withdrawn. The hormonal hypothesis remains one of the most important hypotheses in the etiology of prostate cancer (PCa), and efforts are continuing to improve the understanding of androgen actions in PCa. Although evidence from epidemiological studies of associations between circulating levels of androgens and PCa risk has been inconsistent, the traditional view that higher testosterone (T) levels represent a risk factor for PCa appears to have little evidentiary support. Reinvestigation of the relationship between T and PCa seems important and necessary if a new, clinically and scientifically rewarding concept is to be constructed. The present review considers the metabolism and intraprostatic action of T, epidemiological evidence, and the association between T and PCa risk.

Development of a new nomogram for predicting the probability of a positive initial prostate biopsy in Japanese patients with serum PSA levels less than 10 ng/mL

Objectives:  Although several nomograms for prostate cancer detection have been developed for Western populations, the models constructed on Japanese data would be more useful for the Japanese population because of various differences between Western and Asian populations. We previously developed a model for predicting the probability of a positive initial prostate biopsy using clinical and laboratory data from Japanese males. In the present study, a predictive model for Japanese males with a prostate‐specific antigen (PSA) < 10 ng/mL was developed to guide decision‐making for prostate biopsies.

Molecular analysis of multifocal prostate cancer by comparative genomic hybridization.

Prostate cancer is often multifocal and shows histological heterogeneity among different tumor foci within the same prostate. We analyzed the origin and molecular basis of multifocal prostate cancer and genomic alterations associated with tumor progression.

Implications of Serum Bone Turnover Markers in Prostate Cancer Patients With Bone Metastasis

OBJECTIVES To assess the diagnostic accuracy of serum bone turnover markers for detection of bone metastasis in patients with prostate cancer (PCa) and to assess the usefulness of these markers as predictors of mortality from PCa. METHODS Serum total alkaline phosphatase, bone-specific alkaline phosphatase, carboxy-terminal pyridinoline cross-linked telopeptide parts of type-I collagen (1CTP), tartrate-resistant acid phosphatase type 5 b, and prostate-specific antigen (PSA) levels were measured in 222 patients (58 with bone metastasis, 57 with T2M0 PCa, 55 with T3M0 PCa, and 52 without PCa). Multivariate stepwise logistic regression analysis was used to identify independent predictors of bone metastasis. Correlation of serum marker levels with bone metastasis was assessed using receiver operating characteristics analysis. Multivariate Cox proportional hazards analysis was used to predict cause-specific survival in PCa patients with bone metastasis. RESULTS Serum total alkaline phosphatase, bone-specific alkaline phosphatase, 1CTP, tartrate-resistant acid phosphatase type 5 b, and PSA levels were significantly elevated in patients with bone metastasis, and correlated significantly with the extent of disease on bone scintigraphy. Multivariate stepwise logistic regression analysis demonstrated that serum PSA and 1CTP were significant predictors of bone metastasis. Receiver operating characteristics analyses showed that serum 1CTP level was the most reliable predictor of bone metastasis (area under the curve = 0.85). Multivariate Cox proportional hazards analysis revealed that only serum 1CTP was an independent prognostic factor for PCa-related death. CONCLUSIONS Serum 1CTP level was a more reliable marker than the others to detect bone metastatic spread and to predict survival probability in PCa patients with bone metastasis.

Neuroendocrine differentiation in stage D2 prostate cancers

Objectives:  Chromogranin A (CgA) and neuro‐specific enolase (NSE) are gaining acceptance as markers of several types of neuroendocrine tumors and the concentration of CgA and NSE have been reported to be elevated in relation to neuroendocrine differentiation of prostate cancer. The aim of the present study was to examine the correlation between the immunohistochemical (IHC) findings and serum value for CgA and NSE in untreated stage D2 prostate cancer patients.

FOXA1 promotes tumor progression in prostate cancer via the insulin-like growth factor binding protein 3 pathway.

Fork-head box protein A1 (FOXA1) is a “pioneer factor” that is known to bind to the androgen receptor (AR) and regulate the transcription of AR-specific genes. However, the precise role of FOXA1 in prostate cancer (PC) remains unknown. In this study, we report that FOXA1 plays a critical role in PC cell proliferation. The expression of FOXA1 was higher in PC than in normal prostate tissues (P = 0.0002), and, using immunohistochemical analysis, we found that FOXA1 was localized in the nucleus. FOXA1 expression levels were significantly correlated with both PSA and Gleason scores (P = 0.016 and P = 0.031, respectively). Moreover, FOXA1 up-regulation was a significant factor in PSA failure (P = 0.011). Depletion of FOXA1 in a prostate cancer cell line (LNCaP) using small interfering RNA (siRNA) significantly inhibited AR activity, led to cell-growth suppression, and induced G0/G1 arrest. The anti-proliferative effect of FOXA1 siRNA was mediated through insulin-like growth factor binding protein 3 (IGFBP-3). An increase in IGFBP-3, mediated by depletion of FOXA1, inhibited phosphorylation of MAPK and Akt, and increased expression of the cell cycle regulators p21 and p27. We also found that the anti-proliferative effect of FOXA1 depletion was significantly reversed by simultaneous siRNA depletion of IGFBP-3. These findings provide direct physiological and molecular evidence for a role of FOXA1 in controlling cell proliferation through the regulation of IGFBP-3 expression in PC.

Influence of visceral obesity on oncologic outcome in patients with renal cell carcinoma.

Objective: At present, computed tomography (CT) is used in almost all patients with renal tumors. We aimed to investigate the relationship between visceral adipose tissue (VAT), as assessed by CT, and various other factors in patients with renal cell carcinoma (RCC). Methods: We undertook an examination of VAT in 117 male patients undergoing nephrectomy or partial nephrectomy at Chiba University Hospital using software designed to detect VAT in the horizontal plane of the body cavity. Pathological stage, microvascular invasion, tumor grade, performance status, C-reactive protein, BMI, hypertension, hyperlipemia, hyperglycemia, history of smoking and cause-specific survival rate were examined in relation to VAT, and multivariate Cox regression analysis was used to determine significant predictors of cause-specific survival. Results: VAT in patients with stage I disease was significantly greater than that in patients with more advanced disease (p = 0.0219). VAT in patients with microvascular invasion was significantly smaller than in those without microvascular invasion (p = 0.0260). Patients with high VAT had significantly higher cumulative cause-specific survival when compared to patients with low VAT (p = 0.0257). Conclusion: VAT was associated with better clinical features in patients with RCC. Further study is necessary in order to clarify the role of VAT in RCC.

Does presence of prostate cancer affect serum testosterone levels in clinically localized prostate cancer patients

The relationships between serum level of testosterone (T) and prostate cancer (PCa) are complex. The present study evaluated whether presence of PCa alters serum T levels. Subjects were 125 patients with clinically localized PCa treated using radical prostatectomy (RP), for whom pretreatment T levels were recorded. We investigated clinical and pathological factors such as pretreatment serum T level, age, pretreatment prostate-specific antigen, Gleason score and pathological stage. Serum T and human luteinizing hormone (LH) levels before and after RP were then compared in 118 of the 125 patients. Mean pretreatment T level was significantly higher in patients with organ-confined PCa (pT2; 4.03±1.50 ng ml−1) than in patients with nonorgan-confined cancer (pT3; 3.42±1.06 ng ml−1; P=0.0438). No association existed between pretreatment serum T level and pathological Gleason score. After RP, serum T level (5.60±1.90 ng ml−1) was significantly elevated compared to preoperative level (3.89±1.43 ng ml−1; P<0.0001). In parallel, significant increases were seen in postoperative serum LH level (6.86±3.64 ng ml−1) compared to preoperative level (5.11±2.47 ng ml−1; P=0.0001). In contrast, differences in serum T levels according to pathological stage disappeared postoperatively (P=0.5513). Significant increases in serum T and LH levels were seen after RP, compared to preoperative levels in parallel. This study suggests that serum T levels are altered by the presence of PCa, supporting the possibility that PCa may inhibit serum T levels with negative feedback in the hypothalamic–pituitary axis.

High predictive accuracy of Aldosteronoma Resolution Score in Japanese patients with aldosterone-producing adenoma.

BACKGROUND Primary aldosteronism caused by aldosterone-producing adenoma is the most common curable cause of secondary hypertension, but despite resection, many patients continue to require antihypertensive medications to control their blood pressure postoperatively. The Aldosteronoma Resolution Score is a preoperative 4-item predictive model for the complete postoperative resolution of hypertension. Our aim was to validate the accuracy of this model in predicting postoperative resolution of hypertension in Japanese patients. METHODS The records of 91 Japanese patients who underwent unilateral adrenalectomy for aldosterone-producing adenoma were surveyed retrospectively. Patients were distributed into 2 groups according to whether blood pressure was normal without antihypertensive medications at 6 months postoperatively. Clinical and biochemical data were evaluated at baseline and after the 6-month follow-up. RESULTS At 6 months, blood pressure had normalized in 45% of the patients without antihypertensive medications. Multivariate logistic regression analysis revealed that patients who had complete resolution of hypertension were significantly more likely to have been taking ≤2 antihypertensive medications preoperatively, have a duration of hypertension of <6 years, and be female. The predictive accuracy of the Aldosteronoma Resolution Score was assessed using the area under the curve of receiver operator characteristics analysis. The value of the area under the curve was 0.81. CONCLUSION Our external validation revealed that the Aldosteronoma Resolution Score developed using Western data can identify accurately Japanese individuals with aldosterone-producing adenoma who are likely to have complete resolution of hypertension after adrenalectomy.