Toshiaki Shinojima

Decreased Acetylation of Histone H3 in Renal Cell Carcinoma: A Potential Target of Histone Deacetylase Inhibitors

PURPOSE Recent studies suggest that alterations in chromatin structure by histone acetylation may have an important role in the neoplastic process. We evaluated histone H3 acetylation in renal cell carcinoma and the effects of a histone deacetylase inhibitor on renal cancer cell lines. MATERIALS AND METHODS The expression of acetylated histone H3 (Lys9) in renal cell carcinoma and corresponding nonneoplastic tissue specimens was evaluated. We next assessed immunohistologically the relationships between acetylated histone H3 expression and clinicopathological parameters in 44 cases of renal cell carcinoma. Furthermore, we evaluated the effects of the histone deacetylase inhibitor depsipeptide on the renal cancer cell lines Caki-1, ACHN, 769P and 786O (ATCC). RESULTS Acetylated histone H3 expression was decreased in 85.0% of renal cell carcinomas compared to levels in nonneoplastic tissue. Decreased expression was related to high nuclear tumor grade and advanced pathological tumor stage (p = 0.048 and 0.032, respectively). Depsipeptide inhibited cell line proliferation in a time and dose dependent manner. Depsipeptide induced apoptosis in Caki-1, ACHN and 786O, and induced G2 cell cycle arrest in 769P. Concomitantly depsipeptide increased acetylated histone H3 and p21(WAF/CIP1) expression, and induced Bcl-2 phosphorylation. CONCLUSIONS These results suggest that the decreased acetylation of histone H3 is a common alteration in a malignant phenotype of renal cell carcinoma. Increasing the amount of acetylated histone H3 might be a therapeutic option for renal cell carcinoma.

Efficacy of 3-D computed tomographic reconstruction in evaluating anatomical relationships of colovesical fistula

A case of colovesical fistula is reported. The anatomy of the pelvis was determined preoperatively with 3‐D computed tomography (CT), and the fistula, including adjacent structures, could clearly be seen. Compared with conventional axial CT imaging, 3‐D CT provided better and more complete visualization of the anatomical relationships, which facilitated the surgical procedure and provided a good outcome.

Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal cell carcinoma and is associated with poor prognosis and cigarette smoke

Although exposure to environmental pollutants is one of the risk factors for renal cell carcinoma (RCC), its relationship with carcinogenesis and the progression of RCC remains unknown. The present study was designed to elucidate the role of the aryl hydrocarbon receptor (AhR), a major mediator of carcinogenesis caused by environmental pollutants, in the progression of RCC. The expression of AhR was investigated in 120 patients with RCC using immunohistochemistry, and its relationship with clinicopathological parameters and prognoses was statistically analyzed. RCC cell lines were exposed to indirubin or 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD), AhR ligands, to activate the AhR pathway, or were transfected with small interfering RNA (siRNA) for AhR. The expression of the AhR target genes CYP1A1 and CYP1B1, matrix metalloproteinases (MMPs), and invasion through MatrigelTM were then examined. AhR was predominantly expressed in the nuclei of high‐grade clear cell RCC (ccRCC) and tumor‐infiltrating lymphocytes (TILs), and its expression levels in cancer cells and TILs correlated with the pathological tumor stage and histological grade. A multivariate Cox analysis revealed that the strong expression of AhR in cancer cells was a significant and independent predictor of disease‐specific survival. AhR ligands up‐regulated the expression of AhR and CYPs and promoted invasion by up‐regulating MMPs. Furthermore, siRNA for AhR down‐regulated CYPs, and inhibited cancer cell invasion together with the down‐regulation of MMPs. These results suggest that AhR regulates the invasion of ccRCC and may be involved in tumor immunity. Therefore, inhibiting the activation of AhR may represent a potentially attractive therapeutic target for ccRCC patients.

Solifenacin or mirabegron could improve persistent overactive bladder symptoms after dutasteride treatment in patients with benign prostatic hyperplasia.

OBJECTIVE To evaluate the clinical response and adverse events (AEs) of solifenacin (SOL) or mirabegron (MIR) in benign prostatic hyperplasia patients with persistent overactive bladder (OAB) symptoms after dutasteride (DUT) treatment. METHODS Fifty cases with residual OAB symptom score (OABSS) ≥ 5 and OABSS Q3 ≥ 2 after at least 6 months treatment of DUT were included in this study. Patients were administered 5 mg/d of SOL (N = 25) or 50 mg/d of MIR (N = 25), and International Prostate Symptom Score (IPSS) and OABSS were prospectively collected at 4 and 12 weeks. The safety was evaluated by changes in postvoided residual urine volume and the incidence of AEs. RESULTS After DUT administration, the mean prostate volume, IPSS, and OABSS were 39.0 mL, 17.6, and 8.1, respectively. SOL 5 mg significantly reduced the IPSS, OABSS, and OABSS Q3 at 4 and at 12 weeks (-3.1, -2.7, -1.3; P <.05); however, 4 patients could not continue the SOL treatment owing to AEs. All patients could continue the 12 weeks of MIR treatment, and MIR 50 mg reduced IPSS and OABSS at 4 weeks and reduced IPSS, OABSS, and the OABSS Q3 (-3.0, -2.5, -0.9; P <.05) at 12 weeks. Postvoided residual urine volume increased by ≥ 100 mL after treatment in 2 cases in the SOL group but not in any patient in the MIR group. CONCLUSION Additional SOL or MIR might result in amelioration of the persistent OAB symptom after DUT treatment in patients with an enlarged prostate.

Should We Try Antiandrogen Withdrawal in Castration-Resistant Prostate Cancer Patients? Insights From a Retrospective Study.

BACKGROUND It remains uncertain whether those with response to antiandrogen withdrawal (AAW) have a better prognosis. We investigated the predictors of a better response to AAW and overall survival after acquiring resistance to first-line androgen deprivation therapy inpatients with castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS We retrospectively reviewed the medical records of 87 CRPC patients treated at Keio University Hospital. Sixty-seven of 87 CRPC patients underwent AAW. We analyzed clinicopathologic parameters to identify predictors of survival in CRPC patients and investigated predictors of good response to AAW. RESULTS Younger age, longer duration of androgen deprivation therapy before CRPC development, and better response to AAW were independent favorable prognostic factors for overall survival. Although better response to AAW was a favorable prognostic factor in this study, trying AAW was not significantly related to overall survival. Duration of hormone therapy was significantly longer in those whose disease responded to AAW (69.9 ± 11.0 months) than those with no response (45.3 ± 5.2 months). CONCLUSION The prognostic benefit of AAW was not clearly determined in this study. However, AAW might be beneficial in patients who have favorable prognostic factors for a response to AAW-that is, those who have received hormone therapy for a long period. However, AAW should not be done in patients who do not have favorable factors and who had a high prostate-specific antigen level at the time of their prostate cancer diagnosis.

Dexamethasone and interleukin-2 combination therapy for advanced renal cell carcinoma in a patient with paraneoplastic inflammatory syndrome.

Abstract  Interleukin‐2 (IL‐2) in combination with dexamethasone was administered to a 48‐year‐old man with renal cell carcinoma accompanied by paraneoplastic inflammatory syndrome, including progressive multiple lung metastases and inferior vena caval tumor thrombus. Although non‐steroidal anti‐inflammatory drugs had no apparent antipyretic effect on the systemic inflammatory syndrome, oral administration of dexamethasone achieved complete antipyresis and improved his quality of life. After a 4‐week period of IL‐2 treatment, regression of metastasized lesions was demonstrated despite concurrent oral administration of dexamethasone. Steroids might reduce the action of immunotherapeutic drugs, but in some cases, combination therapy can achieve both alleviation of the paraneoplastic syndrome and tumor shrinkage.

Establishment of the optimal follow-up schedule after radical prostatectomy

PURPOSE Monitoring the serum level of prostate specific antigen (PSA) is indispensable for surveillance after radical therapy, and the aim of this study was to establish the optimal follow-up schedule. MATERIALS AND METHODS We retrospectively reviewed the clinicopathological data of 1,010 consecutive patients who underwent radical prostatectomy. After excluding patients who received neoadjuvant or adjuvant therapy and those without a nadir PSA level<0.2ng/ml, the remaining 779 patients were enrolled. Biochemical recurrence (BCR) was defined as elevation of PSA to >0.2ng/ml. We investigated the PSA doubling time (PSA-DT) following BCR at various times after surgery. RESULTS During a mean follow-up of 8.8 years, BCR occurred in 180/779 patients. The annual BCR rate was 6% in the first year after surgery, 6% between 1 and 2 years, 3% between 2 and 3 years, 3% between 3 and 5 years, and 2% at >5 years postoperatively. During these periods, the minimum PSA-DT after BCR was 1.6, 2.4, 3.1, 6.1, and 6.4 months, respectively. These minimum PSA-DTs were used to determine the optimal follow-up interval during each period after surgery. If the baseline level is 0.1ng/ml, PSA should be measured at approximately 3-month intervals for the first year, at 4-month intervals between 1 and 2 years, at 6-month intervals between 2 and 3 years, and annually thereafter to definitely detect BCR before the serum PSA level exceeds 0.4ng/ml. CONCLUSION The PSA-DT following BCR varies according to the time after surgery. Our data on minimum PSA-DT values after BCR are useful for setting the optimal follow-up schedule.

Evaluation of prostate‑specific antigen density in the diagnosis of prostate cancer combined with magnetic resonance imaging before biopsy in men aged 70 years and older with elevated PSA

There is an increasing proportion of individuals aged 70 years and older, as well as an increasing life expectancy worldwide. The present study may guide the management of older patients with elevated prostate specific antigen (PSA). The medical records of 241 older men aged >70 years who underwent multiparametric magnetic resonance imaging (mpMRI) before prostate biopsy (PBx) at our institution were reviewed retrospectively. Multiple variables were evaluated as predictors for the diagnosis of prostate cancer (PCa). The variables included serum PSA level, digital rectal examination, size of region of interest on mpMRI, prostate volume and PSA density. PCa was positive in 162 (67.2%). Prostate volume and PSA density were significant PCa predictors (P<0.001). In patients aged 70-75 and >75 years, PSA density was significantly higher in patients with PCa (0.21 ng/ml/cc, P=0.014 and 0.24 ng/ml/cc, P<0.001, respectively). Similarly, PSA density was significant higher in patients with significant PCa (0.24 ng/ml/cc, P=0.004 and 0.29 ng/ml/cc, P<0.001, respectively). The cut-off value of PSA density was calculated using receiver operating characteristic curves. Area under curve of PSA density was 0.698, and the best cut-off value was 0.20 ng/ml/cc. These results indicate that the combination of PSA density with mpMRI before PBx is a helpful method and can be a decision-making model for a selection of PBx.

Prognostic Value of Baseline Serum C-Reactive Protein Level in Intermediate-Risk Group Patients With Metastatic Renal-Cell Carcinoma Treated by First-Line Vascular Endothelial Growth Factor–Targeted Therapy

Micro‐Abstract Because accumulating evidence underlines the association of systemic inflammation with metastatic renal‐cell carcinoma (mRCC) progression, we evaluated baseline C‐reactive protein (CRP) levels as a prognostic marker in 107 intermediate‐risk mRCC patients treated with first‐line targeted therapy. Baseline CRP could be a biomarker correlated with overall survival in the intermediate‐risk group. Its cost efficacy and availability make CRP a helpful tool for reclassifying the intermediate‐risk group. Background: Almost half of patients with metastatic renal‐cell carcinoma (mRCC) are classified as intermediate risk by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model. The aim of this study was to evaluate whether baseline C‐reactive protein (CRP) levels predict overall survival (OS) in intermediate‐risk group mRCC patients. Patients and Methods: Data from 107 intermediate‐risk group mRCC patients receiving first‐line targeted therapy were retrospectively reviewed. We evaluated the correlation between baseline CRP levels as well as other indices and OS. Results: Of the 107 patients with intermediate‐risk disease, 46 patients (43%) were classified as having elevated CRP levels. The elevation of pretreatment serum CRP levels was the independent prognostic factor of OS in patients with intermediate risk (hazard ratio, 4.609; P = .001). The 1‐ and 3‐year survival rates of patients with intermediate–nonelevated CRP were 90.0% and 64.7% compared to the favorable‐risk group, at 92.1% and 68.5%, respectively. In contrast, the 1‐ and 3‐year survival rates of patients with intermediate–elevated CRP were 80.5% and 37.4% compared to the poor‐risk group, at 65.2% and 24.2%, respectively. Conclusion: Baseline CRP levels could divide mRCC patients in the intermediate‐risk group into 2 prognostic subgroups.

Individualized Dosing of Axitinib Based on First-Dose Area Under the Concentration–Time Curve for Metastatic Renal-Cell Carcinoma

Background Previous studies have revealed that higher exposure of axitinib leads to better prognosis in metastatic renal‐cell carcinoma. We thus assessed individualized dosing of axitinib on the basis of the first‐dose area under the concentration–time curve from 0 to 12 hours (AUC0‐12) for sunitinib‐pretreated metastatic renal‐cell carcinoma patients. Patients and Methods In this prospective single‐arm trial, the starting dose of axitinib was 5 mg twice daily. A series of blood samples were taken at predetermined times after the first dose to calculate AUC0‐12. On day 15 of axitinib administration, the dose was adjusted to ensure ≥ 150 ng·h/mL AUC0‐12 at steady state according to first‐dose AUC0‐12. The primary end point was the 6‐month progression‐free survival rate. Results Twenty‐six Japanese patients were enrolled. The median recommended dose based on the first‐dose AUC0‐12 was 2.5 mg (range, 1‐16 mg) twice daily. The 6‐month progression‐free survival rate for all enrolled patients and per‐protocol set, from which 3 patients were excluded for not adjusting to the recommended dose on day 15, was 84.6% (95% confidence interval, 65.5‐94.1) and 82.6% (95% confidence interval, 61.8‐93.3), respectively. The most common nonhematologic adverse events were hypertension, hand–foot syndrome, fatigue, and decreased appetite. Eighteen patients (75%) developed grade 3 hypertension; however, actual blood pressure could be controlled using antihypertensive agents. Other adverse events were manageable during the protocol treatment. Conclusion Individualized dosing of axitinib based on the first‐dose AUC0‐12 might have promising efficacy and manageable toxicity. Micro‐Abstract Individualized dosing of axitinib based on drug exposure remains unknown. In this study we evaluated the efficacy and safety of the recommended axitinib dose on the basis of the first‐dose area under the concentration–time curve from 0 to 12 hours in metastatic renal‐cell carcinoma. Adjusting to the recommended dose lead to promising efficacy and manageable toxicity. The current study provides novel information to develop individualized axitinib treatment.