Hidaka Kono

Docetaxel in Combination with Prednisolone for Hormone Refractory Prostate Cancer

OBJECTIVE The objective of this study was to evaluate the efficacy and toxicity of docetaxel in combination with prednisolone in Japanese patients with hormone refractory prostate cancer. METHODS Twenty patients with hormone refractory prostate cancer (HRPC) were administered a treatment regimen consisting of docetaxel 75 mg/m(2) once every 3 or 4 weeks and prednisolone 5 mg twice daily at our institution between 2006 and 2008. RESULTS The patients received a median of 5.5 cycles of treatment (range, 2-12 cycles). Nine of the 20 patients (45%) had a >or=50% decrease in serum prostate-specific antigen (PSA). The median duration of response was 4 months (range, 1-11 months). The number of cycles performed, the presence of bone metastasis and the extent of disease had statistically significant associations with the response. Three patients had a transient PSA rise among the patients who ultimately had a response. Grade 3/4 leukopenia and neutropenia occurred in 80.0% and 85.0% of the patients, respectively. Interstitial pneumonia occurred in only one patient; however, the patient recovered. Finally, no treatment-related deaths were seen during the observation period. CONCLUSIONS The combination of docetaxel 75 mg/m(2) every 3 weeks and prednisolone 10 mg daily was effective and well tolerated in Japanese patients with HRPC. The results of this study suggest that a decision concerning discontinuation of this treatment should be carefully considered because a transient PSA rise was observed. Although interstitial pneumonia was rare, the potential risk of its development should be taken into consideration.

Contrast-enhanced Ultrasonography of the Prostate with Sonazoid

OBJECTIVE The diagnosis of prostate cancer is based on the results of ultrasonography-guided needle biopsy of the prostate, but cancer foci are often not visible in conventional transrectal ultrasonography. Sonazoid is a new microbubble contrast agent. The purpose of our study was to compare areas of contrast material enhancement in the prostate at ultrasonography with whole-mount radical prostatectomy specimens to determine if the use of Sonazoid improves the detection rate of prostate cancer. METHODS Fifty patients with biopsy-proven cancer of the prostate who were scheduled to undergo radical prostatectomy were recruited for this study. The day before the operation, each patient was evaluated with ultrasonography at baseline and again during intravenous infusion of Sonazoid. A map of ultrasonography findings was created prospectively at the time of imaging. Following radical prostatectomy, independent mapping of the pathologic results was performed and the maps were compared. RESULTS Ultrasonography evaluation at baseline demonstrated that at least one focus of cancer was identified in 20 of the 50 subjects (40.0%). Meanwhile at least one cancer focus was enhanced in 31 of the 50 patients (62.0%) when Sonazoid was used. The combination of baseline grayscale imaging and contrast-enhanced imaging allowed identification of at least one focus of cancer in 40 patients (80.0%). Contrast-enhanced ultrasonography can improve sensitivity, especially for the detection of large cancer, peripheral zone cancer and highly malignant cancer. CONCLUSIONS Our study has demonstrated significantly improved detection of prostate cancer with the combination of baseline grayscale imaging and contrast-enhanced imaging compared with conventional ultrasonography techniques only, and this technique may be applicable to targeted biopsy.

Regulation of human dendritic cells by a novel specific nuclear factor-κB inhibitor, dehydroxymethylepoxyquinomicin

Regulation of antigen-presenting cells (APC) is crucial in controlling allograft rejection. Dendritic cells (DC) are the most potent APC and must mature to present antigens to T-cell receptors. During DC maturation, nuclear factor-kappaB (NF-kappaB) is a key transcriptional factor. We synthesized dehydroxymethylepoxyquinomicin (DHMEQ), which specifically inhibits the final step of nuclear translocation of activated NF-kappaB proteins and examined its immunoregulatory effects on human monocyte-derived DC (Mo-DC). Regulatory Mo-DC were generated by pretreatment with DHMEQ before LPS stimulation, which were termed dl-DC. DHMEQ pretreatment (5 microg/ml) completely inhibited nuclear translocation of activated NF-kappaB. DHMEQ significantly inhibited DC production of proinflammatory cytokines (IL-6, TNF-alpha, and IL-12 p70) in a dose-dependent manner. IL-12 was most potently inhibited. However, IL-10 production by dl-DC was only moderately affected by DHMEQ. Although CD40 and the expression of HLA-DR (HLA-DR) expression on dl-DC was downregulated, CD80 and CD86 expression was moderately upregulated. Induction of T helper 1 cell responses was efficiently impaired by dl-DC. This confirmed that DHMEQ-treated Mo-DC exhibited immunoregulatory effects. These findings suggest that DHMEQ has potential as an immunosuppressive drug for human immune cells.

Effect of a novel nuclear factor-κB activation inhibitor on renal ischemia-reperfusion injury.

Background In kidney transplantation, the relationship between prolonged warm or cold ischemic storage of kidneys and a higher incidence of delayed graft function is previously known, and delayed graft function has been known to aggravate poor long-term graft survival. We investigated the effect of a novel nuclear factor-&kgr;B activation inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on renal ischemia-reperfusion (I/R) injury. Methods DHMEQ was administered to Lewis rats once just before renal artery clamping (DHMEQ pretreatment group), and the effect on I/R injury was investigated. Results In the DHMEQ pretreatment group, the 24-hr urine volume on days 1 to 3 after I/R was significantly larger, and the protein concentration of the urine on days 2 to 7 was significantly smaller than in the untreated group. The serum creatinine level was significantly improved, and significantly lower levels of the inflammatory cells and inflammatory cytokines were present in the kidneys on day 1. The relative ratio of nuclear to cytoplasmic nuclear factor-&kgr;B and oxidative stress of kidney tissue on day 1 were significantly decreased. Conclusions Treatment with DHMEQ before renal artery clamping may therefore be useful for renal I/R injury and application to renal transplantation is expected.

Renal Arteriolar Injury by Salt Intake Contributes to Salt Memory for the Development of Hypertension

The role of salt intake in the development of hypertension is prominent, but its mechanism has not been fully elucidated. Our aim was to examine the effect of transient salt intake during the prehypertensive period in hypertensive model animals. Dahl salt-sensitive rats and spontaneously hypertensive rats were fed from 6 to 14 weeks with low-salt (0.12% NaCl), normal-salt (0.8% NaCl), high-salt (7% NaCl), or high-sodium/normal-chloride diet and returned to normal-salt diet for 3 months. Rats in the high-salt group saw elevations in blood pressure (BP) not only during the treatment period but also for the 3 months after returning to normal-salt diet. We named this phenomenon salt memory. Renal arteriolar injury was found in the high-salt group at the end of experiment. Dahl salt-sensitive rats were fed from 6 to 14 weeks with high-salt diet with angiotensin receptor blocker, vasodilator, calcium channel blocker, and calcium channel blocker+angiotensin receptor blocker and returned to normal-salt diet. Although BP was suppressed to control levels by vasodilator or calcium channel blocker, elevated renal angiotensin II and renal arteriolar injury were observed, and salt memory did not disappear because of sustained renal arteriolar injury. Calcium channel blocker+angiotensin receptor blocker suppressed renal arteriolar injury, resulting in the disappearance of salt memory. Cross-transplantation of kidneys from Dahl salt-sensitive rats on high salt to control rats caused increase of BP, whereas control kidneys caused reduction in BP of hypertensive rats, inducing the central role of the kidney. These results suggest that renal arteriolar injury through BP and renal angiotensin II elevation plays important roles in the development of salt memory for hypertension.

Prognostic Stratification in Patients Who Received Hormonal Therapy for Prostate-specific Antigen Recurrence after Radical Prostatectomy

The present study was undertaken to investigate the predictors in patients who received hormonal therapy (HT) for prostate-specific antigen recurrence (PSAR) after surgery. Predictors for the progression-free survival were assessed in 55 patients who received HT for PSAR after surgery. In multivariate analysis, primary Gleason grade > or =4 and PSA doubling time (PSA-DT) <6 months were independent predictors. The patients were stratified into low-risk group (Gleason grade <4 and PSA-DT > or =6), high-risk group (Gleason grade > or =4 and PSA-DT <6) and intermediate-risk group (all others). In the intermediate- and high-risk groups, progression-free survival rate was significantly higher in patients with PSA level <2 than in those with PSA level > or =2 at the initiation of HT. Primary Gleason grade > or =4 and PSA-DT <6 months are independent predictors. Patients in the intermediate- and high-risk groups may benefit from early HT for PSAR after surgery.

A case of paraneoplastic liver dysfunction with elevated serum interleukin-6 in clinically localized renal cell carcinoma

Abstract We report a case of paraneoplastic liver dysfunction associated with a renal cell carcinoma, which disappeared after surgery. A 62-year-old male presented with fatigue and weight loss. The most prominent laboratory abnormality was elevated alkaline phosphatase, C-reactive protein, and interleukin-6 while normal aminotransferases. Computed tomography scan revealed a solid mass in the left kidney. A left radical nephrectomy was performed. After the surgery, biochemical abnormalities returned to normal.

672 UNDETECTABLE TUMOR THROUGH PREOPERATIVE MRI PREDICTS ORGAN CONFINED DISEASE AND LOWER TUMOR VOLUME IN PATIENTS WITH CLINICALLY LOCALIZED PROSTATE CANCER

val, DRE estimation of prostate size. TRUS-guided biopsy was performed in all patients with the following variables collected: TRUSestimated prostate size, est. tumor volume, maximum core involvement, no. of positive cores, total no. of cores, and laterality. Multivariate logistic regression generated two versions of the nomogram, one utilizing PSA density based on pathological prostate weight (PSAD-P) and the other employing TRUS-estimated prostate size (PSAD-U). External validation was performed in two separate cohorts consisting of 1151 patients and 392 patients. RESULTS: On multivariate analysis, significant variables predicting GSU were PSAD-U (OR 229, p 0.003), obesity (OR 1.90, p 0.047), no. of positive cores (OR 1.23, p 0.013), and maximum core involvement (OR 1.02, p 0.009). On internal validation, the bootstrap-corrected predictive accuracy was 0.754. External validation revealed a predictive accuracy of 0.653 and 0.664 at outside institutions, respectively. Both versions of the nomogram demonstrated excellent calibration in all three cohorts and decision curves demonstrated high net benefit across a wide range of threshold probabilities. Overall, use of PSAD-U generated a slightly more accurate nomogram than with PSAD-P. CONCLUSIONS: This is an accurate and externally validated clinical nomogram based on clinical and pathological features available at the time of diagnosis that predict the risk of upgrading in patients with Gleason 6 cancer on biopsy. This information can help in counseling patients with their treatment decisions.

2197 BONE SCAN IN PATIENTS WITH NEWLY DIAGNOSED PROSTATE CANCER; TO PERFORM OR NOT?: EXTERNAL VALIDATION OF THE CURRENTLY AVAILABLE GUIDELINES FOR JAPANESE PATIENTS

INTRODUCTION AND OBJECTIVES: The indication for a bone scan to evaluate bone metastases in patients with newly diagnosed prostate cancer (PCa) differs among current guidelines. Furthermore, these guideline recommendations have not yet been fully validated. The aim of the study was to externally validate these current guideline recommendations regarding the need for a staging bone scan in patients with newly diagnosed PCa, and to extract which patients in Japan should undergo such a bone scan. METHODS: The study included 508 consecutive patients with newly diagnosed PCa from January, 2005 to December, 2008 at Keio University Hospital. All patients prospectively underwent a bone scan using technetium Tc 99m methylene diphosphonate at diagnosis. We assessed the association between the results of the bone scan and clinicopathological factors, such as PSA, clinical stage, and biopsy Gleason score. The accuracy of the most updated EAU, AUA, NCCN, American Joint Committee on Cancer (AJCC), American College of Radiology (ACR), and Japanese Urological Association (JUA) guidelines indicating the need for a baseline staging bone scan was evaluated with area under the curve (AUC) estimates. RESULTS: A positive bone scan was detected in 18 patients (3.5%). PSA level (p 0.002), clinical stage (p 0.001), Gleason score (p 0.001), and positive biopsy scores (p 0.002) were higher in patients with a positive bone scan than in patients with a negative bone scan. Serum TP (p 0.006) level was far lower and the CRP (p 0.011), ALP (p 0.001), and FNG (p 0.007) levels were much higher in the bone scan positive group. In multivariate analysis, PSA 20 (p 0.001, HR 12.58) and Gleason sum 8 (p 0.025, HR 3.91) were independent predictors for a positive bone scan. The sensitivity was determined to evaluate the validity of each guideline and the values were as follows: EAU 72.2%, AUA/AJCC 77.8%, NCCN 88.9%, JUA 88.9%, and ACR 94.4%. The overall accuracy values were EAU 79.6%, AUA/AJCC 75.6%, NCCN 77.9%, JUA 74.9%, and ACR 65.6%. CONCLUSIONS: This is the first study aimed at externally validating the current guideline recommendations addressing the need for staging bone scans in Japanese patients with newly diagnosed PCa. The frequency of a positive bone scan was 3.5%, and PSA 20 and Gleason sum 8 independently predicted a positive bone scan. We believe the indication for a bone scan should be modified and updated, taking into consideration racial differences.

ROLE OF ESTROGENS IN PATIENTS WITH HORMONE REFRACTORY PROSTATE CANCER

INTRODUCTION AND OBJECTIVE: The 25,000 American men who die of prostate cancer each year often suffer from fatigue, bone pain, and weight loss. Enrollment in hospice programs improves both the quality of life and the quality of death for this cohort. However, previous data suggest that hospice is often used inappropriately, either through underuse or through improperly-timed referral. We sought to characterize sociodemographic and clinical factors that affect appropriate and inappropriate utilization of hospice services by men with metastatic prostate cancer in a population-based dataset. METHODS: We used linked data from Surveillance, Epidemiology, and End Results and Medicare data to identify a cohort of beneficiaries who died of prostate cancer between 1992 and 2005. We then evaluated the bivariate association between sociodemographic and clinical data and any hospice enrollment. Hospice referrals within 7 days of death or more than 180 days before dying were considered inappropriate. RESULTS: Of the 14,521 men dying of prostate cancer, 7646 (53%) utilized hospice resources. Enrollment within 7 days of death was noted in 1699 subjects (22% of hospice users), and enrollment more than 180 days prior to death was seen in 717 participants (9% of hospice users). Subjects who utilized hospice within the appropriate time frame were enrolled for a mean of 47 days (S.D. 41, range 7-180 days) prior to death, with a median of 31 days. In our bivariate analysis, white ethnicity, partnered status, and achieving at least a high school diploma were significantly associated with hospice use (Table). CONCLUSIONS: Hospice utilization rates in our cohort compared favorably with previous analyses, but the frequency of improperly-timed hospice referrals was similar to prior reports and provides an opportunity for improvement. Bivariate Analysis of Characteristics, by Hospice Utilization, n (%) Characteristic Total No Hospice Any Hospice P Value Ethnicity White Black Other 12,116(83) 1787(12) 618(4) 5535(46) 958(54) 382(62) 6581(54) 829(46) 236(38) <0.01