Tetsuya Shindo

A Role for Preoperative Systemic Chemotherapy in Node-positive Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy

OBJECTIVE There are few reports investigating the potential benefits of preoperative systemic chemotherapy for patients with node-positive upper tract urothelial carcinoma. The purpose of this study was to examine the impact of preoperative systemic chemotherapy on the clinical outcomes of patients with node-positive upper tract urothelial carcinoma treated by radical nephroureterectomy. METHODS Data were collected on 195 consecutive patients with upper tract urothelial carcinoma treated by radical nephroureterectomy between 1995 and 2010 at a single institute. Of these, 29 patients with node-positive disease but no visceral metastasis were retrospectively evaluated. In patients who underwent preoperative systemic chemotherapy, tumor response, post-therapy pathological downstaging to either residual disease at radical nephroureterectomy or no residual lymph node metastasis (pN0) and toxicity were the endpoints of interest. Overall survival was compared between two groups: those with and without preoperative chemotherapy. RESULTS All patients underwent regional lymphadenectomy. Overall, 15 patients (52%) underwent preoperative systemic chemotherapy. Pathological downstaging was achieved in 47%, including pN0, but there was no pathological complete response. Eighty-six percent of the patients with pathological downstaging had no evidence of recurrence. The median overall survivals were 38 and 9 months for patients with and without preoperative systemic chemotherapy, respectively (hazard ratio: 0.26, P = 0.015, log-rank test). There was no significant difference in operative morbidity between the two groups, and no operations were delayed because of preoperative chemotherapy. CONCLUSIONS The survival of patients who undergo preoperative systemic chemotherapy following radical nephroureterectomy seems to be superior to that of those undergoing radical nephroureterectomy alone. However, to confirm this, prospective randomized studies are needed.

Long‐term outcome of small, organ‐confined renal cell carcinoma (RCC) is not always favourable

Small, organ‐confined renal cell carcinoma (RCC) generally has favourable pathological characteristics and a good prognosis. However, late recurrence is a known characteristic of the biological behaviour of RCC and no consensus has been established for surveillance protocols from 5 years after radical or partial nephrectomy. In the present study with long‐term follow‐up of patients with small RCCs, 18 of 172 patients (10.5%) with pT1a RCC developed recurrence and eight of these (4.7%) died from cancer. Patients with microvascular invasion had a higher risk for cancer death than those without (P < 0.001, Log‐rank test). Therefore long‐term follow‐up is required after surgery, particularly when the disease has microvascular invasion.

Influence of Body Mass Index and Total Testosterone Level on Biochemical Recurrence Following Radical Prostatectomy

OBJECTIVE A high body mass index (BMI) and a low testosterone level were recently reported to be prognostic factors for prostate-specific antigen (PSA) recurrence following radical prostatectomy (RP). The goal of this study was to clarify their relationship and influences on biochemical recurrence after RP. METHODS We analysed 126 patients whose data, including the pre-operative BMI and pre-operative serum total testosterone level, were available. All patients underwent RP at our institution between March 1998 and April 2006 without any adjuvant therapy or pelvic lymph node metastasis. The Cox proportional hazards model was used for the multivariate analysis regarding PSA recurrence for the variables of age, operation period, BMI, clinical stage, PSA, Gleasons sum, pre-operative serum total testosterone level and margin status. RESULTS There were no internal correlations among the parameters we used, even between BMI and the total testosterone level. The total testosterone level was not different between two BMI groups (BMI <26.4 and >/=26.4 kg/m(2): the cut-off is the mean + 1 SD). BMI, PSA and Gleasons sum were found to be independent predictors for PSA recurrence through the multivariate analysis. PSA recurrence-free survival rates at 2 years were 77% for BMI <26.4 kg/m(2), and 31% for BMI >/=26.4 kg/m(2) (P = 0.002, log-rank test, 95% CI: 1.489-7.726). CONCLUSIONS The current study suggests that high BMI independently contributes to PSA recurrence but that the total testosterone level does not. Although the mechanism by which obesity promotes PSA recurrence in RP patients has not been established, careful observation is needed for patients with high BMI.

Peritoneal dissemination of prostate cancer due to laparoscopic radical prostatectomy: a case report.

IntroductionPeritoneal dissemination with no further metastases of prostate cancer is very rare, with only three cases reported in the available literature. We report the first case of iatrogenic peritoneal dissemination due to laparoscopic radical prostatectomy.Case PresentationA 59-year-old Japanese man underwent laparoscopic radical prostatectomy for clinical T2bN0M0 prostate cancer, and the pathological diagnosis was pT3aN0 Gleason 3+4 adenocarcinoma with a negative surgical margin. Salvage radiation therapy was performed since his serum prostate-specific antigen remained at a measurable value. After the radiation, he underwent castration, followed by combined androgen blockade with estramustine phosphate and dexamethasone as each treatment was effective for only a few months to a year. Nine years after the laparoscopic radical prostatectomy, computed tomography revealed a peritoneal tumor, although no other organ metastasis had been identified until then. He died six months after the appearance of peritoneal metastasis. An autopsy demonstrated peritoneal dissemination of the prostate cancer without any other metastasis.ConclusionPhysicians should take into account metastasis to unexpected sites. Furthermore, we suggest that meticulous care be taken not to disseminate cancer cells to the peritoneum during laparoscopic radical prostatectomy.

Is T1G3 Bladder Cancer Having a Definite Muscle Layer in TUR Specimens a Highly Progressive Disease

OBJECTIVE Patients with T1G3 bladder cancer are at high risk of progression to muscle-invasive cancer, and early cystectomy is considered as a treatment option in this particular situation. On the other hand, understaging of T1G3 bladder cancer has been gradually proven as second or repeat transurethral resection (TUR) has been widely applied. To evaluate the real rate of progression, we investigated the prognosis of T1G3 bladder cancer in which a muscle layer was histologically confirmed in the TUR specimens. METHODS We retrospectively reviewed 48 patients with primary T1G3 bladder cancer in which a muscle layer in the TUR specimens was confirmed between 1990 and 2006 in our institute. We investigated recurrence and progression in 45 patients, excluding 3 who were immediately treated with radical cystectomy. Fifteen and 12 patients received intravesical treatment with bacillus Calmette-Guérin (BCG) and anticancer agents just after TUR, respectively. The remaining 18 did not have any such treatment. RESULTS Recurrence and progression were observed in 21 (47%) and 3 patients (6.7%), respectively, during a median follow-up period of 42.1 months. The 3-year recurrence-free and progression-free survival rates were 54% and 91%, respectively. No significant differences were observed in the rates between the patients with and without BCG treatment in the study. CONCLUSIONS There is a possibility that the progression rate in patients with T1G3 bladder cancer is not as high as previously reported when only patients whose muscle layer was histologically confirmed were analyzed. An adequate technique for TUR that unmistakably collects the muscle layer may be important to predict the outcome accurately.

The primary local stage at diagnosis predicts regional symptoms caused by local progression in patients with castration-resistant prostate cancer.

OBJECTIVE To identify the characteristics that predict occurrence of local progression-related events (LPREs) in patients with castration-resistant prostate cancer (CRPC) to adjust its management. METHODS We retrospectively reviewed the medical records of 39 patients with CRPC. LPREs were defined as regional symptoms caused by local progression and categorized into urinary events and rectal events. Urinary events were defined as ureteral obstruction, acute urinary retention, or hematuria requiring treatment, and rectal events were rectal obstruction or rectal bleeding caused by tumor invasion. RESULTS The median prostate-specific antigen level at diagnosis was 185 ng/mL. During the median follow-up period of 4.4 years, 10 patients (25.6%) had LPREs. Urinary events were observed in 8 patients (20.5%) and rectal events in 2 (5.1%). The proportion of T4 in patients with LPREs was higher than in those without LPREs (70.0% vs. 10.3%; P <.001). Stage T4 at diagnosis was an independent factor to predict LPREs in multivariate analysis (hazard ratio, 8.62; P = .004). The 5-year cumulative incidence of LPREs in patients with stage T4 was 70.0%, whereas in those with stage ≤T3, they were 3.6% (P <.001). CONCLUSION Patients with stage T4 at diagnosis are more likely to have a risk of LPREs than those with stage ≤T3. These results indicate that patients with locally advanced prostate cancer on androgen deprivation therapy need to be closely monitored for early diagnosis of CRPC and treated with the appropriate intervention for LPREs at the appropriate time.

Epigenetic silencing of miR-200b is associated with cisplatin resistance in bladder cancer

In this study, we identified microRNAs (miRNAs) involved in cisplatin (CDDP) resistance in bladder cancer (BCa). After establishing CDDP-resistant BCa cell lines (T24RC and EJ138RC), TaqMan arrays revealed that members of the miR-200 family (miR-200b, miR-200a and miR-429) were downregulated in T24RC as compared to parental T24 cells. miR-200b was associated with CDDP sensitivity in BCa cells, and its downregulation was associated with CpG island hypermethylation. Pharmacological demethylation using 5-aza-2’-deoxycytidine restored miR-200b expression, and the combination of 5-aza-2’-deoxycytidine + CDDP strongly inhibited T24RC cell proliferation. Microarray analysis revealed that miR-200b + CDDP induced genes involved in CDDP sensitivity or cytotoxicity, including IGFBP3, ICAM1 and TNFSF10, in the resistant cells. Expression and DNA methylation of miR-200b were inversely associated in primary BCa, and low expression/high methylation was associated with poor overall survival. These results suggest downregulation of miR-200b is associated with CDDP resistance in BCa. Epigenetic silencing of miR-200b may be a marker of CDDP resistance and a useful therapeutic target for overcoming CDDP resistance in BCa.

MP98-02 A POTENTIAL ROLE OF ABERRANT DNA METHYLATION IN THE CHEMORESISTANCE IN BLADDER CANCER CELLS. DNA METHYLATION INHIBITORS COULD RE-SENSITIZE DRUG-RESISTANCE BLADDER CANCER CELLS.

INTRODUCTION AND OBJECTIVES: Aberrant DNA methylation is one of the well-known epigenetic changes in cancer, although its involvement in the chemoresistance remains to be elucidated. In this study, we aimed to unravel the roles played by DNA methylation in chemoresistance in bladder cancer (BCa). METHODS: We established gemcitabine (GEM)-resistant (T24RG and UMUC3-RG) or cisplatin (CDDP)-resistant (T24-RC and UNUC3-RC) BCa cell lines by continuously treating their parental cells. Genome-wide DNA methylation was assessed by Infinium HumanMethylation450 BeadChip (HM450). To assess the chromatin accessibilities, cells were treated with a CpG methyltransferase M.SssI, after which DNA methylation was analyzed by HM450. To evaluate whether treatment with epigenetic drugs could overcome the chemoresistance in BCa, cells were treated with a DNA methyltransferase (DNMT) inhibitor 5-aza-2’-deoxycytidine (5-Aza-CdR) and/or a histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA), after which they were treated with or without GEM or CDDP. RESULTS: HM450 assays revealed increased levels of methylation at a number of CpG sites in the resistant cells as compared the parental cells (730 sites in T24-RC and 3856 sites in UMUC3-RC, respectively), however, a number of CpG sites remained unmethylated but loss chromatin accessibility in the resistant cells (1391 sites in T24RG and 1322 sites in UMUC3-RG, respectively. In CDDP-resistant BCa cells, a combination treatment with 5-Aza-CdR and CDDP synergistically suppressed cell proliferation, suggesting that 5-Aza-CdR restored CDDP-sensitivity (Figure A, B). In contrast, 5-Aza-CdR didn’t show any growth inhibitory effects in GEM-resistant cells (Figure C, D). Moreover, a treatment with SAHA with or without 5-Aza-CdR also failed to restore GEM-resistance in BCa cells (Figure E, F). CONCLUSIONS: Our results suggest that epigenetic alteration may be one of key factors for drug resistance, drug resistance cells could be desensitized by DNA methylation inhibitors especially in the CDDP-resistance in BCa cells.

Significance of intraprostatic architecture and regrowth velocity for considering discontinuation of dutasteride after combination therapy with an alpha blocker: A prospective, pilot study

Purpose We conducted a prospective single-center study to evaluate the possibility of discontinuation of dutasteride after combination therapy with an alpha blocker for benign prostatic hyperplasia (BPH). Materials and Methods We prospectively treated BPH patients with an alpha blocker and dutasteride (0.5 mg/d). Patients who had been treated with alpha blockers against BPH for more than 2 months were eligible, and 20 patients were included in the study. After 6 months of combination therapy, dutasteride was discontinued. Patients were followed for 12 months after cessation. Prostate volume, intraprostatic architecture determined by transrectal ultrasound, peak urinary flow rate, postvoid residual urine volume, and the serum prostate-specific antigen level were evaluated every 6 months, and the International Prostate Symptom Score and overactive bladder symptom score (OABSS) every 3 months. Patients were allowed to restart dutasteride during the follow-up period according to their desire. Results Twelve patients (12/20, 60%) restarted the combination therapy from 6 to 12 months into the follow-up period. For patients who restarted dutasteride, the prostate volume and OABSS had increased and worsened after discontinuation, respectively. A visible transition zone with a clear border on transrectal ultrasound at baseline and regrowth of the prostate after discontinuation of dutasteride were risk factors for restarting the therapy (Mann-Whitney U test: p=0.008, p=0.017). Conclusions Prostatic enlargement after discontinuation of dutasteride differs among patients. Rapid regrowth of the prostate leads to deterioration of storage symptoms and a tendency to restart dutasteride. Baseline intraprostatic architecture may be a predictive factor for whether the patient is a good candidate for discontinuation.

Bacillus Calmette-Guérin may have clinical benefit for glandular or squamous differentiation in non-muscle invasive bladder cancer patients: retrospective multicenter study

Objectives To clarify the efficacy of intravesical Bacillus Calmette-Guérin (BCG) instillation for non-muscle invasive bladder (NMIBC) cancer with variant histology, especially glandular differentiation or squamous differentiation. Materials and methods From May 1991 through June 2016, 53 patients were diagnosed retrospectively as having NMIBC with variant histology. Among these patients, 47 NMIBC patients with squamous differentiation or glandular differentiation were analyzed for this study. The median follow-up interval from diagnosis of NMIBC with variant histology was 28.9 months (1.5-168.8). Results Of these patients, 38 (80.9%) and 9 (19.1%) were diagnosed as having glandular differentiation and squamous differentiation, respectively. Radical cystectomy was conducted for six (12.8%) immediately after the diagnosis of NMIBC with variant histology. Of the 41 patients with bladder preservation, 20 (48.8%), 3 (7.3%), 3 (7.3%) and 15 (36.6%) underwent BCG, THP, MMC and no additional treatment, respectively. There were significant differences between BCG and other treatments or no additional treatment for recurrence (P = 0.034), progression (P = 0.004) and cancer-specific survival (P = 0.014). Conclusion Overall, our results show that intravesical BCG instillation for variant histology in NMIBC leads to a better prognosis with regard to progression and cause-specific survival than other intravesical treatments or no additional treatment. BCG treatment may also have a clinical benefit for variant histology in non-muscle invasive bladder cancer patients.