Kikuo Nutahara

Laparoscopic adrenalectomy : the initial 3 cases

Laparoscopic adrenalectomy was performed on 3 patients with primary aldosteronism. Traction with 2 steel skewers placed subcutaneously over the costal arch was combined with conventional intraperitoneal carbon dioxide gas insufflation. This combination provided a good operative field at 8 mm. Hg insufflation pressure. The laparoscopic approach to the adrenal gland requires neither a large skin and muscle incision nor resection of rib(s), and offers lower morbidity and rapid convalescence. Laparoscopic adrenalectomy is a new minimally invasive operation for the treatment of adrenal adenoma.

Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: Three Years' Experience

BACKGROUND AND OBJECTIVES Autosomal dominant polycystic kidney disease (ADPKD), a frequent cause of end-stage renal disease, has no cure. V2-specific vasopressin receptor antagonists delay disease progression in animal models. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS This is a prospectively designed analysis of annual total kidney volume (TKV) and thrice annual estimated GFR (eGFR) measurements, from two 3-year studies of tolvaptan in 63 ADPKD subjects randomly matched 1:2 to historical controls by gender, hypertension, age, and baseline TKV or eGFR. Prespecified end points were group differences in log-TKV (primary) and eGFR (secondary) slopes for month 36 completers, using linear mixed model (LMM) analysis. Sensitivity analyses of primary and secondary end points included LMM using all subject data and mixed model repeated measures (MMRM) of change from baseline at each year. Pearson correlation tested the association between log-TKV and eGFR changes. RESULTS Fifty-one subjects (81%) completed 3 years of tolvaptan therapy; all experienced adverse events (AEs), with AEs accounting for six of 12 withdrawals. Baseline TKV (controls 1422, tolvaptan 1635 ml) and eGFR (both 62 ml/min per 1.73 m(2)) were similar. Control TKV increased 5.8% versus 1.7%/yr for tolvaptan (P < 0.001, estimated ratio of geometric mean 0.96 [95% confidence interval 0.95 to 0.97]). Corresponding annualized eGFR declined: -2.1 versus -0.71 ml/min per 1.73 m(2)/yr (P = 0.01, LMM group difference 1.1 ml/min per 1.73 m(2)/yr [95% confidence interval 0.24 to 1.9]). Sensitivity analyses including withdrawn subjects were similar, whereas MMRM analyses were significant at each year for TKV and nonsignificant for eGFR. Increasing TKV correlated with decreasing eGFR (r = -0.21, P < 0.01). CONCLUSION ADPKD cyst growth progresses more slowly with tolvaptan than in historical controls, but AEs are common.

Prevalence and Renal Prognosis of Diagnosed Autosomal Dominant Polycystic Kidney Disease in Japan

The prevalence and renal prognosis of diagnosed autosomal dominant polycystic kidney disease (ADPKD) in Japan were estimated. Hospital-based nationwide surveys were conducted in 1995. The number of ADPKD patients who visited hospitals but were not on chronic dialysis was estimated to be 10,000 (95% confidence interval: 8,200–11,900) and that of ADPKD patients on dialysis was 4,590, yielding a prevalence of ADPKD of 117 per million population at the end of 1994 (95% confidence interval: 102–132). The prevalence increased with age and reached a peak value of 261 per million population at the age group of 55–59 years. The rate of end-stage renal disease among living patients was calculated based on the assumption that the prevalence of ADPKD in the population under the age of 55 years was 261 per million population. The rate of end-stage renal disease increased with the progression of the patients’ age, reaching 49% at the age of 65–69 years and declining thereafter. Conclusion: The hospital-based prevalence of ADPKD is lower than the autopsy-based prevalence, suggesting that a fairly large number of these patients do not receive medical care in their lifetime. The probability of end-stage renal disease is at most 50% among ADPKD patients who visit a hospital.

Prognostic Significance of Circulating Tumor Cells in Patients With Hormone Refractory Prostate Cancer

PURPOSE Using the CellSearch System we evaluated whether circulating tumor cells predict survival in patients with hormone refractory prostate cancer. MATERIALS AND METHODS Circulating tumor cells were counted with the CellSearch System in whole blood. This system was developed using epithelial cell adhesion prostate cancer antibody based, immunomagnetic capture and automated staining methodology. Blood samples from 64 patients with hormone refractory prostate cancer were analyzed. RESULTS A threshold of 5 or more circulating tumor cells per 7.5 ml blood was used to evaluate the ability of circulating tumor cells to predict survival. Patient charts were retrospectively examined to determine median overall survival, which was 4 to 27 months (mean +/- SD 14.3 +/- 4.2, median 12.1). Of the 64 patients 32 (50%) had 5 or more circulating tumor cells with a median overall survival of 13.0 months compared with 20.0 months in patients with fewer than 5 (p <0.001). Circulating tumor cells and prostate specific antigen doubling time were significant parameters predicting overall survival on univariate and multivariate analyses. Overall survival in cases that converted from increased to nonincreased circulating tumor cell levels was longer than in cases that converted from nonincreased to increased levels after initiating the circulating tumor cell assay (p = 0.026). CONCLUSIONS In this study 5 or more circulating tumor cells in 7.5 ml blood was associated with survival in patients with hormone refractory prostate cancer. Circulating tumor cells may be an independent predictor of overall survival in patients with hormone refractory prostate cancer but they may also complement prostate specific antigen.

Calcium Channel Blocker versus Angiotensin II Receptor Blocker in Autosomal Dominant Polycystic Kidney Disease

Background: Although hypertension is commonly found in patients with autosomal dominant polycystic kidney disease (ADPKD), there is no consensus about which antihypertensive agents are most appropriate. The effects of calcium channel blockers (CCB) and angiotensin II receptor blockers (ARB) on blood pressure and renoprotection were compared in hypertensive patients with ADPKD. Methods: We randomly assigned 49 participants to CCB amlodipine-based (2.5–10 mg/day) or ARB candesartan-based (2–8 mg/day) regimens. Twenty-five patients (13 males and 12 females) received amlodipine, and 24 patients (13 males and 11 females) received candesartan. This was followed up for 36 months. Results: Baseline characteristics were similar, and blood pressure was well controlled in both groups throughout the study period. Six out of 25 (24.0%) amlodipine and 1 out of 24 (4.2%) candesartan patients were terminated from the protocol due to a twofold increase in serum creatinine and/or decrease in creatinine clearance (Ccr) to half of the baseline. The renal event-free survival rate was significant (p < 0.05, Breslow-Gehan-Wilcoxon test). Serum creatinine was higher in the amlodipine group than in the candesartan group at 24 and 36 months (p < 0.05). The decrease in Ccr at 36 months was larger in the amlodipine group than in the candesartan group (ΔCcr: –20.9 ± 13.1 vs. –4.8 ± 13.8 ml/min, p < 0.01). Urinary protein excretion was significantly lower in the candesartan group than in the amlodipine group at 36 months. Urinary albumin excretion was significantly lower in the candesartan group than in the amlodipine group at 12, 24 and 36 months. Conclusions: The renoprotective effect of candesartan is considered more favorable than amlodipine in the treatment of ADPKD. This is independent of the antihypertensive effect per se.

Mediation of renal cyst formation by hepatocyte growth factor

Hepatocyte growth factor (HGF) is a potent mitogen for renal tubular cells, and HGF and its receptor (c-met proto-oncogene product, Met) can induce lumen formation in epithelial cells. We measured the concentration of HGF in cyst fluids from patients with renal cystic diseases. The concentration of HGF was high in proximal cyst fluid (mean 2.45 vs 0.42 ng/mL in distal cysts). Cyclic AMP concentration was higher in distal than in proximal cysts (663 vs 6.0 pmol/L). mRNA of HGF and Met were co-expressed in cyst walls from cases with polycystic kidney disease. These findings suggest that HGF is a growth factor that may mediate human renal cyst genesis.

DETECTION OF MICROMETASTATIC PROSTATE CANCER CELLS IN THE LYMPH NODES BY REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION IS PREDICTIVE OF BIOCHEMICAL RECURRENCE IN PATHOLOGICAL STAGE T2 PROSTATE CANCER.

PURPOSE We evaluated whether detecting prostate cancer cells by the nested reverse transcriptase-polymerase chain reaction (RT-PCR) in lymph nodes has predictive value for serum prostate specific antigen (PSA) recurrence in patients undergoing radical prostatectomy. MATERIALS AND METHODS We assessed the presence of prostate cancer cells by RT-PCR for prostate specific membrane antigen and PSA assay in lymph nodes dissected from 38 patients with localized prostate cancer treated with radical prostatectomy. The results of nested RT-PCR assay were compared with biochemical recurrence. RESULTS Nested RT-PCR was positive in the lymph nodes of 2 of 18 patients (11%) with stage pT2a and 5 of 20 (25%) with stage pT2b disease. All 7 patients had biochemical recurrence. We noted a significant difference in the Kaplan-Meier recurrence-free actuarial probability curve in those with positive and negative nested RT-PCR results for prostate specific membrane antigen, PSA and prostate specific membrane antigen-PSA in the lymph nodes (p = 3.02x10(-7), 2.23x10(-7) and 3.02x10(-7), respectively). Multivariate analysis of serum PSA, Gleason score and preoperative RT-PCR assay in peripheral blood showed that nested RT-PCR for prostate specific membrane antigen, PSA and prostate specific membrane antigen-PSA in the lymph nodes were independent predictors of recurrence (p = 0.0089, 0.0075 and 0.0089, respectively). CONCLUSIONS Nested RT-PCR of the lymph nodes may be a useful pretreatment prognostic test for patients undergoing radical prostatectomy. Further research is necessary using a much larger number of patients with a longer followup.

Long-term consequence of nephrectomy.

Renal function and blood pressure were assessed in 139 patients after unilateral nephrectomy. Followup ranged from 1 to 57 years, with a mean of 13.0 +/- 1.1 (standard error). Serum creatinine, creatinine clearance, beta 2-microglobulin clearance and blood pressure remained stable during followup. No significant effect of years after unilateral nephrectomy, blood pressure or cause of nephrectomy was observed on creatinine clearance. However, urine excretion of protein (correlation coefficient 0.475, p less than 0.01) and N-acetyl-beta-D-glucosaminidase (correlation coefficient 0.464, p less than 0.01) increased as a function of years after unilateral nephrectomy. Creatinine clearance tended to be low in elderly patients or patients who underwent nephrectomy at an advanced age. Our studies show that despite the late development of proteinuria and tubular injury, unilateral nephrectomy is not associated with deterioration in kidney function or elevation of blood pressure during long-term followup.

Immunomagnetic Quantification of Circulating Tumor Cells as a Prognostic Factor of Androgen Deprivation Responsiveness in Patients With Hormone Naive Metastatic Prostate Cancer

PURPOSE We determined whether circulating tumor cells predict prostate specific antigen failure in patients with metastatic prostate cancer before endocrine therapy and compared their prognostic ability with other clinical factors. MATERIALS AND METHODS Circulating tumor cells were enumerated with the CellSearchtrade mark system in whole blood. This system was developed using epithelial cell adhesion molecule antibody based immunomagnetic capture and automated staining methodology. Prostate cancer cell lines (PC3, LNCaP, DU145) and mixed blood from healthy men were analyzed using this system. Blood samples from 80 patients with metastatic prostate cancer before endocrine therapy were analyzed. Circulating tumor cells were then assessed every 3 months after endocrine therapy in these patients. RESULTS Circulating tumor cell assay accuracy and reliability were determined using prostate cancer cell line (PC3, LNCaP, DU145) spiking experiments, which demonstrated a strong linear correlation (r = 0.99) and a constant recovery rate of 69% +/- 3%, 95% +/- 3% and 89% +/- 2%, respectively. The number of circulating tumor cells found ranged from 0 to 222 per 7.5 ml blood (mean 17 +/- 31, median 14). A threshold of 5 or more circulating tumor cells per 7.5 ml blood was used to evaluate the ability of circulating tumor cells to predict androgen deprivation responsiveness. Of the 80 patients 44 (55%) had 5 or more circulating tumor cells with a median androgen deprivation responsiveness of 17 months compared to more than 32 months for those with fewer than 5 circulating tumor cells (p = 0.007). The presence of circulating tumor cells, nadir prostate specific antigen values and Gleason score were significant parameters predictive of androgen deprivation responsiveness on univariate and multivariate analyses. CONCLUSIONS In this study the presence of 5 or more circulating tumor cells in 7.5 ml blood was associated with androgen deprivation responsiveness in patients with metastatic prostate cancer before endocrine therapy.

Significance of serum free prostate specific antigen in the screening of prostate cancer.

PURPOSE The significance of serum free prostate specific antigen (PSA) in the screening of prostate cancer was examined. MATERIALS AND METHODS A prospective clinical trial was conducted on 701 male volunteers 50 years old or older. Serum free PSA was determined and biopsies were performed if PSA was greater than 4 ng./ml. or if digital rectal examination was suspicious for cancer. RESULTS Of the men 187 (27%) had a PSA of greater than 4 ng./ml. (11%) and/or a suspicious digital rectal examination (19%). Of 116 biopsies performed in the 701 men cancer was detected in 13 (1.9%). PSA detected more tumors (12 of 13, 92%) than digital rectal examination (9, 69%). Receiver operating characteristic analysis showed that the optimal free PSA-to-PSA ratio (free PSA ratio) was 12%. The positive predictive value for cancer according to PSA with free PSA ratio (50%, 10 cancers in 20 biopsies) was significantly greater (p = 0.0473) than that according to PSA alone (24%, 12 cancers in 50 biopsies), which indicated that 30 of 50 biopsies were avoided with only 2 cancers missed when PSA and free PSA were used for biopsy indication. CONCLUSIONS Free PSA determination might eliminate unnecessary biopsies in men with a PSA of more than 4 ng./ml. with minimal missed cancers.