Early response of C-reactive protein as a predictor of survival in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors.

BACKGROUND: Pretreatment C-reactive protein (CRP) has been shown to be an independent prognostic factor for metastatic renal cell carcinoma (mRCC) treated with tyrosine kinase inhibitors (TKIs). We further evaluated the early response of CRP after the initiation of TKIs. METHODS: A total of 103 patients (80 men and 23 women) were treated with TKIs for mRCC from 2008-2013. Patients were divided into three groups according to their early CRP kinetics-patients whose baseline CRP levels were <10 mg/L (non-elevated), patients whose baseline CRP levels were ≥10 mg/L and had decreased by >20% at 4 weeks after the initiation of TKIs (early CRP responder), and the remaining patients (non-early CRP responder). The endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: The median follow-up period was 21 (interquartile range 10-34) months. The numbers of patients classified as non-elevated, early CRP responder, and non-early CRP responder were 62, 19, and 22, respectively. The 1-year PFS rates of patients in the non-elevated, early CRP responder, and non-early CRP responder groups were 50, 23, and 9.7%, respectively (p < 0.001). The 1-year OS rates of patients in these three groups were 79, 62, and 36%, respectively (p < 0.001). In multivariate analysis, the early CRP kinetics assessment was a significant independent factor for PFS and OS. CONCLUSIONS: Early CRP response at 4 weeks is predictive of survival for patients with mRCC treated with TKI.

Simple and effective local anesthesia for transperineal extended prostate biopsy: application to three-dimensional 26-core biopsy.

We developed a local anesthetic procedure for three-dimensional 26-core prostate biopsy (3D26PBx), a combination of transperineal 14-core biopsy (TP14PBx) and transrectal 12-core biopsy (TR12PBx). At first, a periapical triangle, confined by the levator ani, the rhabdosphincter and the external anal sphincter muscle, was made visible by transrectal ultrasound. After administration of 1 mL of 1%-lidocaine into the midline perineal skin 1.5 cm above the anus, we inserted a spinal needle toward the periapical triangle for injection of 1.5-2.0 mL of 1%-lidocaine and performed the TP14PBx. After administration of the periprostatic nerve block with 10 mL of 1%-lidocaine, we performed the TR12PBx. The efficacy of the procedure was evaluated prospectively in 45 consecutive men undergoing the 3D26PBx. The 3D26PBx was completed with just local anesthesia in all patients. The pain levels, assessed by an 11-point visual analog scale, were not different between the TP14PBx and the TR12PBx.

Roles of attenuated neuronal nitric-oxide synthase protein expression and accelerated arginase activity in impairing neurogenic relaxation of corpus cavernosum in aged rabbits.

OBJECTIVE: To investigate whether changes in neuronal nitric oxide synthase (nNOS) protein expression and arginase activity are implicated in impairing the neurogenic cavernosal relaxation in aged rabbits, as NO is important in the neurogenic relaxation of corpus cavernosum during the erectile state. MATERIALS AND METHODS: Cavernosal specimens of young adult (3-6 months old) and aged (36-48 months old) rabbits were used for isometric tension experiments, Western blot analysis, cGMP determination and measurements of NOS and arginase activities. RESULTS: The neurogenic relaxation and cGMP production in response to electrical-field stimulation were significantly impaired in aged cavernosal specimens. Western blot analysis showed that nNOS protein was highly expressed in cavernosal specimens from young rabbits, but was undetectable or greatly decreased in old rabbits, with no change in overall NOS activity. Arginase activity in aged cavernosal specimens was significantly higher than in young rabbits. Supplementing with excess l-arginine, or giving S-(2-boronoethyl)-l-cysteine as an arginase inhibitor, significantly increased the neurogenic relaxation at lower frequencies only in the younger rabbits. CONCLUSION: These results suggest that impairment of neurogenic and NO-mediated relaxation in the aged corpus cavernosum possibly results from the down-regulation of nNOS protein. The reduced l-arginine bioavailability to nNOS due to accelerated arginase activity would lead to further impairment of neurogenic NO production, in concert with decreased nNOS protein expression.

The efficiency of Sairei-to for retroperitoneal fibrosis: two case reports.

The conventional approach for management of retroperitoneal fibrosis (RF), an inflammatory process of retroperitoneal fibro-adipose tissue, leading to the compression and obstruction of the ureters and other adjacent organs is ureterolysis with omental wrapping, and an effective alternative to surgery is immunosupressive medication such as oral corticosteroids. Sairei-to (TJ-114) is a traditional herbal medicine used for the treatment of RF in Japan. It has both anti-inflammatory and anti-allergic effects. Here we report two cases of RF successfully treated with Sairei-to. One case was idiopathic and the other was caused by artificial graft-induced vasculitis. Both cases were treated with Sairei-to following the decompression of uremia by precutaneous nephrostomy or indwelling ureteral stents. There was hardly any ureteral obstruction three months after the administration of Sairei-to. They have been doing well for 12 and 26 months. Sairei-to rarely causes side effects such as immunodeficiency, gastro-duodenal ulcer and osteoporosis that often accompany long-term administration of corticosteroids. Sairei-to is a safe and effective medicine for the treatment of RF. We therefore recommend Sairei-to as an alternative for corticosteroid therapy.

Accumulated endogenous nitric oxide synthase inhibitors in inhibiting urethral relaxation following estrogen supplementation in ovariectomized rabbits.

PURPOSE: We investigated the possible role of the endogenous nitric oxide (NO) synthase (NOS) inhibitors N-monomethyl-L-arginine (L-NMMA) and asymmetrical N, N-dimethyl-L-arginine (ADMA) in inhibiting urethral relaxation following estrogen supplementation in ovariectomized rabbits. MATERIALS AND METHODS: A total of 16 mature Japanese White female rabbits were divided into 2 groups. In the control group rabbits were sacrificed 2 weeks after bilateral ovariectomy. In the estrogen group estradiol was administered subcutaneously for 2 weeks with the aid of sustained release pellet from 2 weeks after ovariectomy until sacrifice. Isolated urethra was cut into transverse strips for functional study and processed to determine endogenous NOS inhibitors, NOS activity, dimethylarginine dimethylaminohydrolase (DDAH) activity as a metabolizing enzyme of endogenous NOS inhibitors and cyclic guanosine monophosphate production. RESULTS: Electrical field stimulation produced NO mediated and neurogenic relaxation of the urethral strip in the presence of guanethidine and atropine under contraction with phenylephrine. Relaxation was significantly decreased in the estrogen group and accompanied by decreased cyclic guanosine monophosphate production. Sodium nitroprusside induced relaxation was not different between the 2 groups. The content of L-NMMA plus ADMA in the urethra was significantly increased in the estrogen group. Ca dependent NOS activity in the urethra remained unaffected. DDAH activity was significantly lower in the estrogen group. CONCLUSIONS: Estrogen supplementation leads to decreased NO mediated and neurogenic urethral relaxation through the accumulation of L-NMMA and ADMA in the urethra. The accumulation of NOS inhibitors is possibly brought about by impaired DDAH activity.

Involvement of increased arginase activity in impaired cavernous relaxation with aging in the rabbit.

PURPOSE: Arginase shares L-arginine as a common substrate with nitric oxide (NO) synthase (NOS). We examined whether increased arginase activity is involved in impaired cavernous relaxation with aging in the rabbit. MATERIALS AND METHODS: Young adult (3 to 5 months old) and aged (36 to 48 months old) rabbits were used for the current experiments. Cavernous tissues obtained from the 2 groups were processed for isometric tension experiments, cyclic guanosine monophosphate determination, measurements of NOS and arginase activities, endogenous methylarginines and L-arginine. RESULTS: Carbachol (CCh) produced an endothelium dependent and NO mediated relaxation that was significantly impaired in aged cavernous specimens without change in sodium nitroprusside induced relaxation. Stimulated cyclic guanosine monophosphate production with CCh was significantly decreased in aged cavernous specimens. Ca dependent NOS was predominant in rabbit cavernous specimens. Ca dependent and independent NOS activities remained unchanged in the 2 groups. The tissue contents of N-monomethyl-L-arginine and asymmetric N,N-dimethyl-L-arginine as endogenous NOS inhibitors, symmetrical N,N'-dimethyl-L-arginine and L-arginine as a substrate of NOS were decreased in aged cavernous specimens. Arginase activity was significantly higher in aged cavernous specimens. Impaired CCh induced relaxation in aged cavernous specimens was normalized in the presence of N-hydroxy-L-arginine as an arginase inhibitor or by the supplementation of excess L-arginine. CONCLUSIONS: These results strongly suggest that impaired endothelium dependent and NO mediated cavernous relaxation with aging is due to decreased NO production, which would result from increased arginase activity and probably from decreased L-arginine content.

TNP-470 combined with nicardipine suppresses in vivo growth of PC-3, a human prostate cancer cell line.

We examined effects of TNP-470 with or without nicardipine on in vivo or in vitro growth of a hormone-independent human prostate carcinoma cell line, PC-3. TNP-470 (30 mg/kg, daily) or nicardipine (25 microg/kg, daily) alone had little effects on in vivo growth of PC-3 cells in nude mice, whereas simultaneous administration of both agents significantly inhibited the growth of the xenografts. In vitro proliferation of PC-3 was not affected by TNP-470 and/or nicardipine. Combination of TNP-470 and nicardipine seems beneficial in the treatment of hormone-refractory prostate cancer.

Accumulated endogenous NOS inhibitors, decreased NOS activity, and impaired cavernosal relaxation with ischemia.

We examined whether endogenous inhibitors of nitric oxide (NO) synthesis are involved in the impaired cavernosal relaxation with ischemia in rabbits. Two weeks after cavernosal ischemia caused by partial vessel occlusion, endothelium-dependent and electrical field stimulation (EFS)-induced neurogenic NO-mediated relaxations, but not sodium nitroprusside (SNP)-induced relaxation, were significantly impaired in the isolated corpus cavernosum. The Ca(2+)-dependent NO synthase (NOS) activity and the basal and stimulated cGMP productions with carbachol or EFS were significantly decreased after ischemia. Supplementation of excess L-arginine partially recovered both of the impaired relaxations. The contents of N(G)-monomethyl-L-arginine (L-NMMA) and asymmetric N(G), N(G)-dimethyl-L-arginine (ADMA) but not L-arginine and symmetric N(G),N'(G)-dimethyl-L-arginine (SDMA) were increased in the cavernosal tissues after ischemia. Authentic L-NMMA and ADMA but not SDMA concentration dependently inhibited both relaxations without affecting the relaxation produced by SNP in the control. Excess L-arginine abolished the inhibition with L-NMMA and ADMA. These results suggest that the impaired NO-mediated cavernosal relaxations after ischemia are closely related to the decreased NOS activity and the increased accumulation of L-NMMA and ADMA.