Koichiro Akakura

Codon 877 mutation in the androgen receptor gene in advanced prostate cancer : Relation to antiandrogen withdrawal syndrome

The growth of prostate cancer is androgen responsive, and androgen receptor (AR) is thought to play an important role in the development of this cancer. Recently, some reports demonstrated that AR gene mutations were detected in human prostate cancer tissues. We have previously reported that one of eight endocrine therapy‐resistant prostate cancer cases showed AR gene mutation [Suzuki] et al: J Steroid Biochem Mol Biol46:759‐76, 19931. To further investigate structural abnormality of the AR in a large number of human prostate cancers, exons E H encoding DNA‐ and hormone‐binding domains were examined by single‐strand conformation polymorphism analysis of polymerase chain reaction products and direct sequencing. Tissues surgically removed from 30 cases of stage B or C prostate cancer and from 22 cases of endocrine therapy‐resistant cancers obtained at autopsy were used in the study. Three out of 22 cancer death cases (14%) revealed AR gene mutations, one of which contained two different mutations‐exon D in cancerous prostate and exon H in metastatic tissues. In the other two cases, AR gene mutations in exon H were found in metastatic tissues. All three cases in metastatic tissues showed the same mutation at codon 877 (877Thr + Ala). In stage B or C cancer tissues and the other cancer death samples, no AR mutation was detected. The mutation in exon H was identical to that reported in a human prostate cancer cell line, LNCaP. These results indicate that AR gene mutation scarcely occurs in the early stage of prostate cancer and that the mutation is found in relation to endocrine therapy resistance. Two patients with an AR gene mutation at codon 877 revealed a remarkable fall in prostate‐specific antigen after withdrawal of antiandrogen. Data on the other case were not available. These results indicate that a codon 877 mutation in the AR gene in advanced prostate cancer evokes the antiandrogen withdrawal syndrome. To our knowledge, this report is the first description of relationship between an AR mutation at codon 877 and the antiandrogen withdrawal syndrome.

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.

Long-term results of a randomized trial for the treatment of stages B2 and C prostate cancer: radical prostatectomy versus external beam radiation therapy with a common endocrine therapy in both modalities

OBJECTIVES To improve the treatment of locally advanced prostate cancer (Stages B2 and C), a prospective randomized trial was conducted to compare radical prostatectomy versus external beam radiotherapy with the combination of endocrine therapy in both modalities. METHODS One hundred patients were enrolled and 95 were evaluated. Forty-six patients underwent radical prostatectomy with pelvic lymph node dissection, and 49 were treated with radiation by linear accelerator with 40 to 50 Gy to the whole pelvis and a 20-Gy boost to the prostatic area. For all patients, endocrine therapy was initiated 8 weeks before surgery or radiation, and continued thereafter. The living patients were asked to respond to a quality-of-life questionnaire. RESULTS The follow-up period ranged from 6.0 to 94.4 months (median 58.5). The progression-free and cause-specific survival rates at 5 years were 90.5% and 96.6% in the surgery group and 81.2% and 84.6% in the radiation group, respectively. The surgery group had better progression-free and cause-specific survival rates (P = 0.044 and 0.024, respectively). More patients in the surgery group complained of urinary incontinence. The questionnaire revealed that quality of life was less disturbed in the radiation group. CONCLUSIONS Radical prostatectomy combined with endocrine therapy may contribute to the survival benefit of patients with locally advanced prostate cancer. External beam radiotherapy in combination with endocrine therapy can be used in selected patients because of its low morbidity.

Characterization of 5α-reductase gene expression in stroma and epithelium of human prostate

The expression of 5alpha-reductase type 1 and type 2 isoenzymes in hyperplastic human prostate tissue and several human prostate cell lines was investigated by Northern blot analyses, reverse transcription-polymerase chain reaction (RT-PCR), and enzyme activity. Separation of stroma and epithelium was confirmed histologically and only preparations with no apparent contamination were employed in the subsequent studies. Poly(A)+ RNA was isolated from stromal and epithelial fractions and analysed by Northern blot and RT-PCR. Inhibition of epithelial and stromal 5alpha-reductase activities by 17beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5alpha-androstan- 3-one (4MA) was assessed using a range of concentrations between 10(-13) and 10(-5) M. Results from Northern blot analyses and RT-PCR showed that the prostate stroma expressed 5alpha-reductase type 1 and type 2 isoenzymes, whereas the prostate epithelium only expressed 5alpha-reductase type 1. This was consistent with biphasic inhibition of 5alpha-reductase activity by 4MA in stroma and monophasic inhibition in epithelium. Cultured epithelial cells derived from human prostate only expressed 5alpha-reductase type 1 and had Vmax and Km values that approximated the lower end of the range reported for surgically removed prostate epithelium. The foregoing data explains the disparate activities of 5alpha-reductase, previously reported, in stroma and epithelium. The differential localization of these isoenzymes in the prostate suggests that future therapy of androgen-sensitive disease may be more successful through the use of selective inhibitors of the different 5alpha-reductase isoenzymes.

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.

Updated Japanese Urological Association Guidelines on prostate-specific antigen-based screening for prostate cancer in 2010

The exposure rate of screening for prostate cancer using prostate‐specific antigen (PSA) in Japan is still very low compared with that in the USA or western Europe. The mortality rate of prostate cancer will increase in the future and in 2020 it will be 2.8‐fold higher than in 2000. Therefore, there is an urgent need to determine the best available countermeasures to decrease the rate of prostate cancer death. PSA screening, which can reduce the risk of death as a result of prostate cancer, should be offered to all men at risk of developing prostate cancer with fact sheets showing updated benefits and drawbacks of screening for prostate cancer.

Identification of a 1‐cM region of common deletion on 13q14 associated with human prostate cancer

Frequent allelic losses on chromosome arm 13q are observed in carcinomas of the head and neck, breast, ovary, and pituitary gland. We analyzed 59 primary prostate tumors (stage B, 18 patients; C, 12 patients; D1, 4 patients; and endocrine therapy‐resistant cancer death, 25 patients), as well as 18 metastatic tissues from 14 of the 25 cancer death patients for loss of heterozygosity (LOH) using 35 microsatellite markers on chromosome arm 13q. Of the 59 primary tumors, 31 (53%) showed LOH involving at least one locus. Detailed deletion mapping identified a distinct commonly deleted region in the 1‐cM interval flanked by D13S153 and D13S273 on 13q14 and this region overlapped a part of the RB1 gene. Paired DNAs were available from both primary and metastatic tumors in the 14 cases of cancer death; among those pairs, we detected LOH on 13q in seven (50%) primary tumors, and in all metastatic foci (P = 0.0029). Moreover, the regions lost in metastatic tissues were more extensive than those seen in the corresponding primary tumors. These results suggest that inactivation of a putative tumor suppressor gene(s) including the RB1 gene on 13q14 plays an important role in human prostate cancer. Genes Chromosomes Cancer 24:183–190, 1999.

Dendritic Cell-Based Immunotherapy of Renal Cell Carcinoma

Dendritic cells potently stimulate antigen-specific immune responses and recent data indicate that they are also capable of eliciting antitumor immune responses. We are performing a pilot study which tests the safety and efficacy of antigen-loaded, cultured blood dendritic cells in patients with metastatic renal cell carcinoma. Dendritic cells are simultaneously pulsed with lysate from autologous tumor cells and with the immunogenic protein keyhole limpet hemocyanin. During the pulse, the cells are activated with a combination of tumor necrosis factor-alpha and prostaglandin E2. Patients receive 5-10 X 10(6) dendritic cells per intravenous infusion and up to six infusions at monthly intervals. The first results demonstrate that this treatment modality is very well tolerated and can be associated with strong immunological and clinical responses. The present article discusses the importance of dendritic cell maturation and the role of helper antigens in dendritic cell-based immunotherapy.

Antiandrogen withdrawal syndrome in prostate cancer after treatment with steroidal antiandrogen chlormadinone acetate

OBJECTIVES A case report is presented of 2 patients whose levels of serum prostate-specific antigen (PSA) improved after the withdrawal of a steroidal antiandrogen. METHODS Two cases with prostate cancer had been treated with surgical castration and the steroidal antiandrogen chlormadinone acetate (CMA), and, on disease progression, the administration of CMA was terminated. RESULTS Following withdrawal of CMA, a fall in PSA levels and remarkable clinical improvement were observed in both cases. One patient revealed a decrease and the other an increase in serum prostate acid phosphatase after the discontinuation of CMA. Serum levels of testosterone, prolactin, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione were not significantly elevated after CMA withdrawal. CONCLUSIONS Withdrawal of the steroidal antiandrogen CMA resulted in a decline in PSA levels and clinical improvement in prostate cancer patients with disease progression. Changes in testosterone, prolactin, or adrenal androgens were not a cause of the antiandrogen withdrawal syndrome.

Tumor marker doubling time in patients with prostate cancer : determination of prostate-specific antigen and prostatic acid phosphatase doubling time

To estimate the growth rate of prostate cancer, the doubling times of prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) were determined in 51 patients: 44 were refractory to endocrine therapy, and 7 were in an untreated state. Since an exponential increase in PSA and PAP was observed in all patients, the doubling time was calculated from a semilogarithmic plot of the respective markers. PSA doubling time was almost identical with that of PAP. The tumor marker doubling time in untreated patients was approximately 10 times greater than that in the patients who were refractory to endocrine therapy. In endocrine refractory patients, the tumor marker doubling time in patients who showed deterioration of bone lesions was less than that in patients with local regrowth and/or lymph node metastasis. The prognosis of endocrine refractory patients from the time showing tumor marker failure was examined. The group showing the longest time (> 80 days) had better prognosis than that shown by the other groups with shorter doubling times. It is concluded that the determination of tumor marker doubling time is of value for measuring the growth rates of prostate cancer, and for assessing prognosis after relapse.