Nozomu Furuta

Diagnosis of pheochromocytoma using [123I]- compared with [131I]-metaiodobenzylguanidine scintigraphy

Background: Patient with pheochromocytoma (PCT) cannot be cured without operation, therefore, preoperative determination of the localization of PCT should be performed accurately. [131I]‐Metaiodobenzylguanidine (MIBG) scintigraphy is a gold standard for the diagnosis of PCT. However, [123I]‐MIBG is also found to accumulate in PCT. In order to clarify the usefulness of [123I]‐MIBG scintigraphy for the local detection of PCT, we compared the distribution of [123I]‐ and [131I]‐MIBG in patients with or without PCT.

Flutamide-induced hepatic dysfunction in relation to steady-state plasma concentrations of flutamide and its metabolites

The frequency, severity, and outcome of flutamide-induced hepatic injury were prospectively evaluated in 55 patients with prostate cancer who received 125 mg of flutamide 3 times a day (daily dose: 375 mg) combined with an agonistic analogue of luteinizing hormone-releasing hormone. In addition, we examined plasma and urine concentrations of flutamide and its major metabolites 4 weeks after the beginning of flutamide therapy, and evaluated their significance in predicting flutamide-induced hepatic dysfunction. Hepatic function could be assessed in 50 patients and hepatic dysfunction during therapy was observed in 9 patients (18%); 3 patients (6%) were classified as having moderate liver dysfunction and 6 (12%) were classified as having mild liver dysfunction. The steady-state plasma levels of flutamide and its biologic active metabolite, hydroxyflutamide (OH-Flu), were not related to hepatic dysfunction. However, the concentration of another major metabolite, 4-nitro-3-(trifluoromethyl)phenylamine (FLU-1) was considerably higher in 2 patients who developed clinically significant hepatic dysfunction. These findings suggest that clinically significant hepatic dysfunction could be induced in patients with compromised flutamide metabolism, which leads to a high concentration of FLU-1. Based on results of this study, we propose that plasma FLU-1 levels are one of the predictive factors for flutamide-induced hepatic dysfunction. This hypothesis will be confirmed in a large-scale study.

Adjuvant chemotherapy with vinblastine, adriamycin, and UFT for renal-cell carcinoma

SummaryVAU therapy (vinblastine, Adriamycin, and UFT) was given postoperatively to 31 patients with stage I, II, or III renal-cell carcinoma, and the incidence of relapse as well as the survival of patients were studied. Administration was started at 7–14 days post-surgery; 5 mg/m2 vinblastine and 30 mg/m2 Adriamycin were given i.v. once every 4 weeks for a total of five courses, and three capsules of UFT (containing 300 mg tegafur) were given p.o. every day for 2–3 years. The postoperative observation period ranged from 2 years and 6 months to 7 years and 1 month (mean, 4 years and 2 months). The 1-year survival of patients was 100%, and the 3- and 5-year survival values were 96%. These results were significantly better (P<0.01) than the respective values (81%, 72%, and 60%) obtained for the historical controls, i.e., the 60 patients with stage I, II, or III renal-cell carcinoma who received no chemotherapy. Side effects such as alopecia, gastrointestinal symptoms, and myelosuppression were encountered, but all symptoms were so mild and transient that discontinuation of the treatment was not necessary. As VAU therapy might be useful as adjuvant chemotherapy for renal-cell carcinoma, it seems to merit further study.

Successful treatment of nephrotic syndrome caused by recurrent IgA nephropathy with chronic active antibody-mediated rejection three years after kidney transplantation.

Yaginuma T, Yamamoto H, Mitome J, Kobayashi A, Yamamoto I, Tanno Y, Hayakawa H, Miyazaki Y, Yokoyama K, Utsunomiya Y, Miki J, Yamada H, Furuta N, Yamaguchi Y, Hosoya T. Successful treatment of nephrotic syndrome caused by recurrent IgA nephropathy with chronic active antibody‐mediated rejection three years after kidney transplantation.
Clin Transplant 2011: 25 (Suppl. 23): 28–33.
© 2011 John Wiley & Sons A/S.

Successful treatment of monomorphic primary central nervous system post‐transplantation lymphoproliferative disorder 5 years after kidney transplantation

A 31‐year‐old man underwent living‐related kidney transplantation in 2004 as a consequence of primary focal segmental glomerulosclerosis (FSGS). Four years after the transplantation, we confirmed nephrotic syndrome caused by recurrent FSGS. We performed plasmapheresis and low‐density lipoprotein adsorption. We also combined steroid therapy with a reduction in the dose of tacrolimus and an increased dose of mycophenolate mofetil. The nephrotic syndrome improved dramatically with this combined therapeutic approach.

Analysis of features of recurrence after radical nephrectomy in patients with N0M0 renal cell carcinoma

AbstractBackground. To reduce unnecessary tests for patients with renal cell carcinoma (RCC) at low risk of metastasis, we designed a postoperative surveillance protocol for N0M0 RCC, based on the features of recurrence. Methods. Of 462 N0M0 RCC patients who underwent radical nephrectomy, 180 patients (39%) showed recurrence. We stratified these patients according to pathologi-cal T-stage (pT-stage) with consideration given to the pathological grade of malignancy (grade). A surveillance protocol was designed based on calculated disease-free survival rates. Results. The median time until recurrence was 36 months (range, 1 to 228 months), and 78.3% of all patients, recurrence was diagnosed within 5 years. The rate of recurrence increased in accordance with increased pT-stage: pT1a, 9.9% (10/101); pT1b, 29.8% (39/131); pT2, 41.7% (20/48); pT3a, 58.8% (60/102); pT3b, 60.9% (42/69); pT3c, 71.4% (5/7); pT4, 100% (4/4). Significant differences in disease-free survival rates were observed among the patients at all pT-stages, except for pT1b vs pT2, pT2 vs pT3a, pT3a vs pT3b, and pT3c vs pT4. Basically, a 5-year follow-up was conducted, except for the patients with pT1b (grade 1 + 2), pT2 (grade 1 + 2), pT3a (grade 1, 3), and pT3b (grade 1 + 2), who showed recurrence more than 5 years postoperatively. Conclusion. We conclude that our surveillance protocol for N0M0 RCC after nephrectomy, based on pT-stage and grade, is to some extent a reasonable guideline. However, a further survey of prognostic factors for RCC is necessary, because of the difficulty in predicting recurrence in patients with a low pT-stage and because of the presence of patients with late recurrence.

Effects of nerve growth factor and glucocorticoid on cultured human pheochromocytoma cells

Primary cell cultures of two human pheochromocytomas (PC) that were associated with high serum levels of adrenaline and noradrenaline were developed to study the effects of nerve growth factor (NGF) and dexamethasone on the morphology and function of PC cells in vitro. By phase-contrast microscopy, cultured cells were small and hyperchromatic on the first day of culture; neurite-like processes that extended to other cells developed several days later and were maintained for more than 3 months. NGF (100ng/ml), dexamethasone (10−5M), or NGF + dexamethasone were added to the culture media 2 weeks after the cultured cells had stabilized. Catecholamine concentrations in the medium were maintained at higher levels after addition of NGF, dexamethasone, or NGF + dexamethasone as compared to control cells. In the presence of NGF, extension of neurite-like processes was clearly accelerated, while high levels of dexamethasone inhibited growth of processes. These in vitro studies showed that the addition of NGF or the removal of dexamethasone induces differentiation of adrenal neurons present in pheochromocytomas, suggesting that adrenocortical steroid hormones influence the morphological control of adrenal medullary cells.

OUTCOMES AFTER SURGICAL TREATMENT OF UPPER TRACT UROTHELIAL CARCINOMA

(Objectives) We retrospectively investigated the prognostic factors and the role of adjuvant chemotherapy against upper tract urothelial carcinoma (UTUC) after surgery. (Materials and methods) 343 patients of UTUC who underwent radical nephroureterectomy at Jikei University Hospital and affiliated institutions between January 2004 and February 2012 were retrospectively analyzed. A chi-squared test was used for categorical variables. Survival probabilities after surgery were estimated using the Kaplan-Meier method. Multivariate Cox regression models addressed overall survival and cancer-specific survival after surgery. (Results) The 5-year overall and cancer-specific survival rates were 64.6% and 74.6%, respectively. On multivariate analysis, higher age, male, higher pT-stage and lymphovascular invasion (LVI) were associated with worse overall survival and higher pT-stage and LVI were associated with worse cancer-specific survival. 44 patients (G3 and ≥pT3) who received cisplatin-based adjuvant chemotherapy had improved overall survival (P=0.044). (Conclusions) Higher pT-stage, LVI were important prognostic variables associated with oncologic outcomes. Cisplatin-based adjuvant chemotherapy offered a significant benefit to overall survival in high risk UTUC (G3 and ≥pT3), but more investigations are needed to confirm its utility.

MP17-06 ROLE OF SPINAL α2-ADRENOCEPTORS AND IMIDAZOLINE RECEPTORS IN THE CONTROL OF VOIDING AND CONTINENCE REFLEXES IN CONSCIOUS RATS

and immunocytochemistry, amphotericin-perforated patch-clamp electrophysiology on native freshly-isolated human DSM cells, as well as functional studies on DSM contractility of DSM isolated strips from donor patients, and the novel TRPM4 channel inhibitor 9phenathrol. RESULTS: RT-PCR experiments detected mRNA message for TRPM4 channels in whole DSM tissue and single DSM cells. Western blot analysis and immunohistochemical staining revealed TRPM4 protein expression in whole DSM tissue. Immunocytochemical experiments further detected TRPM4 protein expression in isolated single DSM cells. Voltage-clamp experiments on freshlyisolated native human DSM cells showed that inhibition of TRPM4 channels with 9-phenathrol significantly decreased the transient inward cation currents (TICCs) activity, when recorded at -70 mV. Pretreatment of DSM cells with xestospongin C, an inositol-3phosphate receptor inhibitor, abolished the TICCs. Current-clamp experiments demonstrated that inhibition of TRPM4 channels with 9-phenathrol hyperpolarized DSM cell resting membrane potential by w11 mV. In vitro functional studies on DSM contractility revealed that TRPM4 channel inhibitor 9-phenantrol significantly attenuated the spontaneous phasic, carbachol-induced, and nerve-evoked contractions in human DSM isolated strips in a concentration-dependent manner. CONCLUSIONS: Our results demonstrate the novel finding that TRPM4 channels are expressed in human DSM and support the concept that they regulate human DSM excitability and contractility. Therefore, TRPM4 channels may be considered as novel targets for treatment of overactive bladder.

951 ANALYSIS OF TRANSIENT RECEPTOR POTENTIAL CHANNELS RELATED TO BLADDER OVERACTIVITY INDUECED BY PELVIC ORGAN CROSS-SENSITIZATION IN RATS

INTRODUCTION AND OBJECTIVES: Pelvic organ cross-sensitization has been proposed as one of the pathogenesis of bladder pain syndrome/interstitial cystitis. Thus, we examined changes in bladder function after the stimulation of transient receptor potential (TRP) channels in the colon, uterus or stomach because TRP channels are one of the main nociceptive receptors. METHODS: Under isoflurane anesthesia, a polyethylene catheter was implanted into the colon, uterus or stomach as well as the bladder in female Sprague-Dawley rats, and cystometry was then performed in an awake condition. 1) Capsaicin (TRPV1 activator; 1, 3, 10 & 30mM), R1747 (TRPV4 activator; 1, 3, 10 & 30mM), allyl isothiocyanate (AITC: TRPA1 activator; 1, 3, 10 & 30%) or menthol (TRPM8 activator; 3, 10, 30 & 100%) was cumulatively applied in a 50ul solution of each dose with 30min intervals into the colon, uterus or stomach. 2) Time-dependent changes in bladder function were examined after 30% AITC injection into the colon or uterus. We also examined changes in bladder function when ruthenium red (RR: TRPA1 inhibitor) was intrathecally (i.t.; 0.03ug, 5ul) or intravenously (i.v.; 3mg/kg, 0.5ml/ kg) applied 30min before or 120min after colon AITC injection. RESULTS: 1) There were no significant changes in bladder function after the TRPV1, V4 or M8 stimulation in the colon or uterus, whereas threshold pressure (TP) and intercontraction interval (ICI) were significantly decreased by 10% or greater AITC injection into the colon or 30% AITC injection into the uterus. None of TRP channel stimulations in the stomach influenced bladder function. 2) TP and ICI were significantly decreased from 30 min and 60 min after 30% AITC injection, respectively, in the colon. TP and ICI were significantly decreased 60 min after AITC injection in the uterus, and became stable after 120min. Bladder overactivity induced by colon AITC application was prevented by the pretreatment of RR (i.v. and i.t.). On the other hand, only the i.t., but not i.v., application of RR increased TP and ICI significantly when RR was applied after the induction of colon-toblabber cross-sensitization. CONCLUSIONS: Bladder overacitvity occurs from 30–60 min after the stimulation of TRPA1 channels, but not TRPV1, V4 or M8, in the colon or uterus, indicating the importance of TRPA1 for the pelvic organ cross-sensitization. In addition, central sensitization seems to be involved in the pelvic organ cross-sensitization because i.t. application of a TRPA1 inhibitor can attenuate the colon-to-bladder cross-sensitization.