Haruo Ito

The Role of Epigenetic Modifications in Retinoic Acid Receptor β2 Gene Expression in Human Prostate Cancers

The retinoic acid receptor (RAR) β gene is a putative tumor suppressor gene on chromosome 3p24, where a high incidence of loss of heterozygosity is detected in many types of tumors. Retinoic acid suppresses cancer cell growth through binding to RARs, especially RARβ, indicating a critical role in mediating anticancer effects. Selective loss or down-regulation of RARβ mRNA and protein has been reported in prostate cancers (PCas), although the mechanisms remain unclear. We investigated the role of epigenetic modification in RARβ2 gene silencing. Aberrant methylation was detected in 11 of 14 (79%) primary PCas, 9 of 10 (90%) hormone-refractory PCas, and 2 of 4 (50%) PCa cell lines, but not in any normal prostate samples. Chromatin immunoprecipitation assay showed that all RARβ2-negative cells (LNCaP, PC3, and DU145) were hypoacetylated at both histones H3 and H4. After exposure to 5-aza-2prime;-deoxycytidine treatment, Trichostatin A and all-trans retinoic acid induced partial demethylation, increased accumulation of acetylated histones, and markedly restored the expression of RARβ2 in RARβ2-negative cells. These data suggest that the RARβ2 gene may be one of the frequently silenced genes by epigenetic modifications in PCa.

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.

Clinical significance of pulmonary metastases in stage D2 prostate cancer patients.

Several prognostic factors such as the extent of bone metastases (EOD) in advanced prostate cancer (PCa) have been reported. Metastasis of the lung is rarely a significant clinical factor in the management of prostate cancer. The present study evaluates the clinical significance of lung metastases. We retrospectively reviewed the PCa database to identify patients with pulmonary metastases at initial diagnosis. The medical records of the patients were examined with respect to age, histologic grade, EOD score, marker response to endocrine therapy and clinical outcome. We then compared several potential clinical factors between patients with and without pulmonary metastases. Next, we retrospectively reviewed autopsy records of 60 Japanese patients who died of hormone-refractory metastatic PCa with particular focus upon metastatic profiles. A comparative study of stage D2 patients with (n=20) and without (n=77) pulmonary metastases found no significant differences in EOD score, performance status, marker response and survival. Only tumor grade was better in the group with, than without pulmonary metastases (P=0.0120, chi-square analysis). In the series of autopsies, we found pulmonary metastases in 38 cases (63%), following metastases of the bone (57 cases, 95%) and lymph nodes (52 cases, 87%). A retrospective analysis of survival showed that patients with bone or lymph node metastases had a positive relative risk. In contrast, lung metastasis could be a positive prognostic indicator, although the findings were not statistically significant. These data suggest that the presence of pulmonary metastasis has no ominous impact on clinical course and disease outcome even in patients with disseminated prostate cancer.

Clinical Characteristics of Prostate Cancer in Elderly Japanese Patients 80 Years of Age or Older

OBJECTIVE Prostate adenocarcinoma is predominantly a disease of elderly men. This study retrospectively examined prostate adenocarcinoma in Japanese patients 80 years of age or older to determine the natural history and prognosis of this malignancy in the elderly population. METHODS The medical records of 593 patients were reviewed, with respect to age, histologic grade, clinical and pathological stage, treatment modality and clinical outcome. A variety of possible clinical factors were compared between patient groups > or = 80 and < 80 years old. RESULTS No significant difference in clinical stage, tumor grade, and performance status (PS) was found between two age groups of patients with prostate cancer. A significant stage migration between pre-PSA era and PSA era was found only in the group < 80 years old. In the series of stage D2 cancer patients, while there was no significant difference in cause-specific and progression-free survival rates between the two groups, the younger group < 80 years old had a better marker response at 3 months from the start of endocrine therapy compared with the older group (P = 0.0048, chi2 analysis). CONCLUSION These data suggest that patients > or = 80 years with prostate cancer present with similar histologic grade and disease stage as younger patients, although the younger group with stage D2 had a better marker response to endocrine therapy.