Naoto Kamiya

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.

CHROMOGRANIN A CONCENTRATION AS A SERUM MARKER TO PREDICT PROGNOSIS AFTER ENDOCRINE THERAPY FOR PROSTATE CANCER

PURPOSE Chromogranin A is gaining acceptance as a serum marker of neuroendocrine tumors and the concentration is thought to be elevated in relation to neuroendocrine differentiation of prostate cancer. We examined the significance of the chromogranin A level as a serum marker for prostate cancer. MATERIALS AND METHODS Serum chromogranin A values were determined by monoclonal immunoradiometric assay in 108 patients with prostate cancer before treatment and in 66 with benign prostatic hyperplasia. In those with prostate cancer clinicopathological parameters, the response to endocrine therapy and the prognosis were evaluated in relation to serum chromogranin A. RESULTS Mean serum chromogranin A plus or minus standard deviation in prostate cancer and benign prostatic hyperplasia cases was 59.4 +/- 52.5 and 59.3 +/- 44.3 ng./ml., respectively (not significant). Poorly differentiated adenocarcinoma was associated with higher chromogranin A than well differentiated disease (p = 0.044). Of the stage D cases with a median prostate specific antigen (PSA) of 172.1 ng./ml. or less those with higher chromogranin A had a poorer prognosis than those with lower chromogranin A. In contrast, in stage D cases with a PSA of greater than 172.1 ng./ml. there was no difference in the prognosis between the higher and lower chromogranin A groups. CONCLUSIONS Serum chromogranin A tends to be elevated in patients with high grade prostate cancer. When combined with PSA, this marker may effectively predict a poor prognosis after endocrine therapy.

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.

Pretreatment Serum Level of Neuron Specific Enolase (NSE) as a Prognostic Factor in Metastatic Prostate Cancer Patients Treated with Endocrine Therapy

OBJECTIVE The serum level of neuron specific enolase (NSE) is gaining acceptance as a marker of neuroendocrine tumors. To clarify the role of NSE in prostate cancer progression, we examined the relationship of NSE to clinicopathological parameters. METHODS The pretreatment serum NSE level was measured in 104 patients with histologically confirmed prostatic adenocarcinoma (PCa) and 59 patients in whom prostate cancer was not detected (non-PCa). PCa patients consisted of 5 T1N0M0, 20 T2N0M0, 31 T3N0M0, 7 TxN1M0 and 41 TxNxM1 cases. RESULTS Non-PCa patients had significantly higher serum NSE than PCa patients. Serum NSE in metastatic PCa patients was significantly higher than that in non-metastatic patients, while NSE did not significantly differ with regard to histological grade, or prostate specific antigen (PSA) response to endocrine therapy. In PCa patients, serum NSE was not correlated to serum PSA nor chromogranin A. In metastatic patients who underwent endocrine therapy, the higher NSE group had significantly poorer cause-specific survival. CONCLUSION The pretreatment serum level of NSE can predict survival of metastatic PCa patients treated with endocrine therapy.

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.

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.

Clinical evaluation of transrectal power doppler imaging in the detection of prostate cancer.

To evaluate the clinical usefulness of power Doppler imaging (PDI) compared to gray-scale transrectal ultrasound (TRUS) in the detection of prostate cancer. A total of 101 men with abnormally high serum prostate specific antigen (PSA) levels and/or abnormal digital rectal examination (DRE) findings were assessed using TRUS and PDI. Random systematic sextant and bilateral far lateral prostate biopsies were performed in all cases. In addition, when TRUS revealed a hypoechoic lesion or PDI revealed a hypervascular lesion (HVL), these lesions were directly biopsied. Of the 101 patients, 48 (47.5%), 42 (41.5%) and 42 (41.5%) were suspicious of having prostate cancer by DRE, TRUS and PDI, respectively. Prostate needle biopsy revealed prostate cancer in 39 patients (38.6%) and benign prostatic diseases in 62 patients (61.4%). If prostate needle biopsy was avoided when PDI was negative, then PDI eliminated the need for biopsy in 59 of the 101 patients (rate of biopsy procedures saved: 58.4%) and missed only 8 (13.6%) prostate cancers. Moreover, in 63 patients with intermediate PSA (3–10 ng/ml), the rate of biopsy procedures saved by DRE, TRUS, and PDI was 60.3%, 65.1%, and 68.3%, respectively, and the rate of cancers missed was 26.3%, 19.5%, and 14.0%, respectively. In a total of 826 specimens of TRUS-guided prostate biopsy, 126 (15.3%) specimens had adenocarcinoma. Site by site based analysis of the present series revealed 34.1% of prostate cancer sites were isoechoic and hypervascular. On a site by site basis, PDI had better sensitivity, specificity, positive predictive value and negative predictive value than TRUS. In 48 patients without abnormal DRE findings, on a site by site basis, the sensitivities of TRUS and PDI were 22.9% and 34.4%, respectively. Gleason score was associated with a positive rate of PDI on both a patient basis and site by site basis. From these results, on a patient basis, we conclude that PDI was helpful in the indication for prostate biopsy for all patients or patients with intermediate PSA level. On a site by site basis, PDI may be able to select prostate cancer sites at biopsy, in particular inpatients without abnormal DRE findings.