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Glutathione S-transferase pi 1 (GSTP1) is lowly expressed in normal prostate luminal cells and becomes induced in most proliferative inflammatory atrophy (PIA) lesions. GSTP1 becomes silenced in prostatic intraepithelial neoplasia (PIN) and prostate adenocarcinoma (CaP) via cytosine-phospho-guanine (CpG) island promoter hypermethylation. However, GSTP1 methylation patterns in PIA and PIN, and their relationship to patterns in CaP are poorly understood. We used bisulfite genomic sequencing to examine patterns of GSTP1 promoter CpG island methylation in laser capture microdissected benign, PIA, PIN, and CaP regions from 32 subjects that underwent radical prostatectomy. We analyzed 908 sequence clones across 24 normal epithelium, 37 PIA, 18 PIN, and 23 CaP regions, allowing assessment of 34,863 CpG sites with allelic phasing. Normal and PIA lesions were mostly unmethylated with 0.52 and 1.3% of total CpG sites methylated, respectively. PIN and CaP lesions had greater methylation with 24% and 51% of total CpG sites methylated, respectively. The degree of GSTP1 methylation showed progression from PIA << PIN < CaP. PIN lesions showed more partial methylation compared with CaP lesions. Partially methylated lesions were enriched for methylation changes at AP1 and SP1 transcription factor binding sites. These results demonstrate that methylation density in the GSTP1 CpG island in PIN was intermediate relative to that in normal prostate epithelium/PIA and CaP lesions. These results are consistent with gradual spreading of DNA methylation centered at the SP1/AP1 transcription factor binding sites in precursor lesions, with subsequent spreading of methylation across the entire CpG island in transition to CaP., Prevention Relevance: DNA hypermethylation at the GSTP1 promoter progressively spreads from being unmethylated in normal prostate to intermediate levels in precursor lesions to extensive methylation in cancer. This molecular progression of GSTP1 promoter methylation patterns in early prostate carcinogenesis could be useful for identification and interception of prostate cancer precursors., (©2023 American Association for Cancer Research.)

A 73-year-old man was referred to our hospital because of a high prostate specific antigen (PSA) level. The PSA level at our hospital was 63.5 ng/ml. Pelvic magnetic resonance imaging (MRI) showed findings strongly suggestive of multiple pelvic bone metastases, but no obvious malignant findings in the prostate. A 12-core prostate biopsy was performed and no cancer was detected. Computed tomography and bone scintigraphy showed findings suspicious of bone metastases in the sternum, thoracolumbar spine, pelvic bone, and sacrum. Spine MRI revealed a mass in the vertebral body from the eighth thoracic vertebra to the first lumbar vertebra. A biopsy of the right iliac crest showed adenocarcinoma and was positive for PSA staining, leading to the diagnosis of multiple bone metastases of prostate cancer. Abiraterone acetate in combination with androgen deprivation was started. He received medication and radiation therapy to his sternum for pain relief. Spine MRI after 4 months showed decreased vertebral body weights and serum PSA levels were ＜0.003 ng/ml after 5 months. Seventeen months after treatment, PSA remains below 0.003 ng/ml, and the patient is currently pain-free.

A 77-year-old man was seen at our hospital with the chief complaint of pollakisuria. Magnetic resonance imaging (MRI) showed a 25 mm cystic tumor with solid components behind the prostate. A transrectal biopsy for the prostate showed no evidence of malignancy. Two years later, he complained of weak urinary stream, and the MRI diagnosis demonstrated an increase of the tumor size to 67 mm. Since prostatic sarcoma was diagnosed by the transrectal biopsy for the prostate, a tumor resection and prostatectomy were performed. At 19 months after the operation, there was no evidence of metastasis or recurrence, and he has had no dysuria. The final pathological diagnosis was of a prostatic STUMP.

Background: This study was undertaken to investigate if the prostate-specific antigen (PSA) level measured 3 months after radical prostatectomy (RP) is a predictor of biochemical recurrence (BCR)-free survival., Methods: We retrospectively reviewed the clinicopathologic data of 174 patients with a follow-up of at least 3 years after RP for clinically localized prostate cancer. None of the patients received neoadjuvant/adjuvant therapy. Subjects were categorized according to PSA level 3 months after RP (3M-PSA): <0.010 ng/mL (group 1; n = 119) or 0.010-0.100 ng/mL (group 2; n = 55). BCR was defined as two consecutive rises in PSA level ≥0.2 ng/mL., Results: At a median follow-up of 69.5 months (range 36-113 months), 32 (18.4 %) patients experienced BCR. The median time to BCR was 16 months (range 4-98 months) after RP. The 5-year BCR-free survival rate was 92.6 and 57.4 % in groups 1 and 2, respectively. Patients in group 1 had a significantly higher BCR-free survival rate than those in group 2 (log-rank P < 0.001). According to the Cox proportional hazards model, patients with a 3M-PSA level of <0.010 ng/mL were at lower risk for BCR (P < 0.001), along with pathologic Gleason sum 6 (P = 0.028). PSA nadir level after RP was also a risk factor for BCR (log-rank P < 0.001). Area under the receiver operating characteristic curve for 3M-PSA to predict BCR was almost equivalent to that for the PSA nadir level (0.855 vs. 0.849)., Conclusions: 3M-PSA is an independent predictor of BCR-free survival. Our findings might be used for a risk-adjusted follow-up protocol.

We aimed to analyse late toxicity associated with external beam radiation therapy (EBRT) for prostate cancer using uniform dose-fractionation and beam arrangement, with the focus on the effect of 3D (CT) simulation and portal field size. We collected data concerning patients with localized prostate adenocarcinoma who had been treated with EBRT at five institutions in Osaka, Japan, between 1998 and 2006. All had been treated with 70 Gy in 35 fractions, using the classical 4-field technique with gantry angles of 0°, 90°, 180° and 270°. Late toxicity was evaluated strictly in terms of the Common Terminology Criteria for Adverse Events Version 4.0. In total, 362 patients were analysed, with a median follow-up of 4.5 years (range 1.0-11.6). The 5-year overall and cause-specific survival rates were 93% and 96%, respectively. The mean ± SD portal field size in the right-left, superior-inferior, and anterior-posterior directions was, respectively, 10.8 ± 1.1, 10.2 ± 1.0 and 8.8 ± 0.9 cm for 2D simulation, and 8.4 ± 1.2, 8.2 ± 1.0 and 7.7 ± 1.0 cm for 3D simulation (P < 0.001). No Grade 4 or 5 late toxicity was observed. The actuarial 5-year Grade 2-3 genitourinary and gastrointestinal (GI) late toxicity rates were 6% and 14%, respectively, while the corresponding late rectal bleeding rate was 23% for 2D simulation and 7% for 3D simulation (P < 0.001). With a uniform setting of classical 4-field 70 Gy/35 fractions, the use of CT simulation and the resultant reduction in portal field size were significantly associated with reduced late GI toxicity, especially with less rectal bleeding.

Alternative Antiandrogen Therapy with Flutamide in Patients with Castration-Resistant Prostate Cancer : A Single Center Experience We analyzed the clinical effects of flutamide (FLT) as a second-line agent for maximum androgen blockade (MAB) in patients with castration-resistant prostate cancer who received bicalutamide (BCL) as the first-line MAB agent. This study included 44 cases with progressive prostate cancer who had relapsed after first-line MAB, with BCL at 80 mg/day. After checking for antiandrogen withdrawal syndrome (AWS), they were given FLT at 375 mg/day as second-line MAB. A partial response (prostate-specific antigen [PSA] decline ≧50%) and no change (PSA decline of 0-50% or increase ＜25%) by second-line MAB with FLT were achieved in 34.1% (15/44) and 25.0% (11/44), respectively. The median duration of PSA response was 8.2＋/-4.5 months. In multivariate analysis, Gleason score (≦7 vs ≧8), the first-line response (CR vs PR＋NC), and the second-line response (PR＋NC vs PD) were significantly predictive of cause-specific survival from first-line hormonal therapy relapse to cancer death. Our results confirm previous findings that alternative antiandrogen therapy is effective as a second-line hormonal therapy.

We report a case of primary malignant lymphoma of the prostate. An 84-year-old man was referred to our hospital with a chief complaint of urinary retention. Magnetic resonance imaging showed a large mass below the bladder and in front of the rectum. Histological and immunocytochemical studies of transperineal biopsy of the prostate showed diffuse large B-cell non-Hogkin's lymphoma. Radiological assessment of the disease confirmed stage IV according to the Ann Arbor classification. Although the tumor was markedly reduced in size after four cycles of combination chemotherapy with cyclophosphamide, adriamycin, vincristine, and prednisolone, he died with brain metastasis 4 months after the diagnosis.

Purpose: Since 2003, screening with prostate specific antigen (PSA) has been conducted to detect prostate cancer. We investigated the results between 2003 and 2007., Patients and Methods: Screening with PSA alone was performed for males aged over 50 years who desired prostate cancer screening. We used a PSA cutoff value of 4.00 ng per milliliter., Results: In 2003, there were 18,161 males aged over 50 years in Ikeda City. 3,738, 3,905, 4,129, 4,410, and 4,515 of the males underwent PSA screening in 2003, 2004, 2005, 2006, and 2007. The rate of elevated PSA levels was 7.9%-9.8% (median 9.1%). 161, 81, 70, 75 and 60 of the males visited us for secondary screening, and prostate biopsy was performed in 130 (80.7%), 57 (70.4%), 45 (64.3%), 38 (50.7%), and 42 (70.0%). Prostate cancer was detected in 91, 33, 29, 20 and 25 males, respectively. These values corresponded to 2.43%, 0.85%, 0.70%, 0.45% and 0.55% of the males who underwent primary screening. The incidence of prostate cancer was 0.96% during the 5 years. Clinical stage was B in 137 (69.2%), C in 52 (26.3%), D in 7 (3.5%), and unknown in 2. Surgery was performed in 87 (43.9%), endocrine therapy in 61 (30.8%), irradiation in 37 (18.7%), and follow up without treatment in 7 (3.5%). Treatment for 6 (3.0%) is unknown because they desired treatment at another hospital., Conclusions: 198 males were diagnosed with prostate cancer between 2003 and 2007. The clinical stage B was present in 137 (69.2%), and the early treatment was achieved. This may lead to a future decrease in the mortality rate.

Purpose: In this retrospective study we reported the results of salvage external beam radiotherapy for patients with biochemical recurrence after radical prostatectomy., Materials and Methods: A total of 28 patients with biochemical recurrence after radical prostatectomy underwent salvage radiotherapy with (n=16) or without (n=12) hormonal therapy. Median radiation dose was 60 Gy. Biochemical recurrence after radiotherapy was defined as a single prostate-specific antigen (PSA) of at least 0.1 ng/ml. Potential risk factors were evaluated for significant associations with biochemical recurrence., Results: The median follow-up period after salvage radiotherapy was 42 months. The actuarial biochemical recurrence free survival rate at 3 and 5 years was 81% and 74%, respectively. Addition of hormonal therapy to salvage radiotherapy did not alter biochemical recurrence rate (P = 0.56). Univariate analysis revealed that Gleason score of 8 to 10 (P = 0.026) and PSA before salvage therapy greater than 0.24 ng/ml (P = 0.0016) were significant risk factors for biochemical recurrence. On multivariate analysis, PSA before salvage therapy greater than 0.24 ng/ml (P = 0.017) maintained statistical significance. Of 28 patients 3 (11%) experienced late grade 3 toxicity of hematuria., Conclusion: Our data suggest that early use of salvage radiotherapy is beneficial for patients with biochemical recurrence after radical prostatectomy.

The present study was undertaken to test the effects of prostate cancer cell lines (LNCaP, DU145, PC3, and MDA PCa 2b) on osteoclastogenesis. Crude conditioned medium (CM) from all four prostate cancer cell lines enhanced expression of the mRNA for receptor activator of NF-kappaB ligand (RANKL) in a mouse osteoblast cell line, MC3T3-E1; however, CM had no effect on expression of osteoprotegerin (OPG) mRNA. Coculture of MC3T3-E1 with prostate cancer cells yielded similar results. The number of mature osteoclasts induced by soluble RANKL increased significantly when osteoclast precursor cells were cultured with CM from LNCaP and DU145 cells. CM from LNCaP and DU145 cells also induced maturation from precursor in the absence of soluble RANKL, and this effect was not blocked by OPG. Addition of CM from DU145 cells increased expression of MMP-9 mRNA by osteoclast precursors. Our findings indicate that prostate cancer mediates osteoclastogenesis through induction of RANKL expression by osteoblasts and through direct actions on osteoclast precursors mediated by some factors other than RANKL.

To our knowledge, no standard chemotherapy for patients with hormone-refractory prostate cancer (HRPC) has been established. Since most patients with HRPC are elderly and have bone metastasis, cytotoxic chemotherapy causes them to be at high risk for myelosuppression. Therefore, chemotherapeutic agents with low toxicity and good compliance should be elected. We conducted three regimens for HRPC on an outpatient basis. Eligibility criteria were defined as serial rising PSA values on 3 or more occasions at least 2 weeks apart or radiological new or extensive lesions under hormonal therapy. The first regimen is comprised of cyclophosphamide (CPM), 100 mg/day, UFT, 400 mg/day, and estramustine phosphate (EMP), 560 mg/day in two daily fractions. The second regimen is comprised of an oral administration of dexamethasone (DEX) (0.5-2 mg/day). The third regimen is comprised of DEX, 1 mg/day, cyclophosphamide, 100 mg/day and UFT, 400 mg/day in two daily fractions. Post-therapy prostate-specific antigen (PSA) level in serum, objective response on bone scan or measurable disease, and symptomatic response on bone pain were assessed. All regimens showed clinical efficacy with mild toxicity. Indications and limitations of these regimens are discussed. Further, the combination trials of taxane and EMP in patients with HRPC are reviewed.