Long-Term Oncologic Outcome of an Initial Series of Laparoscopic Radical Prostatectomy for Clinically Localized Prostate Cancer After a Median Follow-up of 10 Years.

INTRODUCTION: When laparoscopic radical prostatectomy (LRP) was introduced as a novel treatment option for prostate cancer, it had to compete with the established open techniques. The short- and intermediate-term oncologic and functional outcomes were encouraging and comparable to those with retropubic radical prostatectomy. However, the long-term oncologic safety for LRP has yet to be fully elucidated. We evaluated the long-term oncologic outcomes of an initial series of patients who had undergone LRP. PATIENTS AND METHODS: An initial unselected and consecutive series of 100 patients who had undergone LRP for clinically localized prostate cancer from 1999 to 2001 was identified. The pre-, intra-, and postoperative data were collected. Biochemical recurrence (BCR) was defined as a prostate-specific antigen (PSA) value of ≥ 0.2 ng/mL. The outcome measures were cancer control (CC), BCR-free survival (BCRFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: The mean patient age was 64 ± 7 years, and the mean preoperative PSA level was 9.6 ± 8.3 ng/mL. Of the 100 patients, 79 (79%) had stage pT2 and 15 (15%) had stage pT3 disease. Positive surgical margins were found in 25 patients (25%; 16.4% for pT2 and 40% for pT3). The median follow-up time was 126 months (range, 60-176 months). The 5-year CC rate was 82%. The estimated 10-year BCRFS was 83% and 80% for patients with stage pT2 and pT3 tumors, respectively. The median time to BCR was 52 months (range, 6-144 months). The estimated 10-year CSS and OS was 98% and 93%, respectively. CONCLUSION: Our long-term follow-up data from an initial unselected patient cohort have indicated that LRP offers excellent long-term oncologic control for patients with localized prostate cancer.

Positive fibroblast growth factor receptor 3 immunoreactivity is associated with low-grade non-invasive urothelial bladder cancer.

In addition to conventional clinicopathological parameters, molecular markers are also required in order to predict the course of disease in patients with urothelial bladder cancer (BC). Little is known about fibroblast growth factor receptor 3 (FGFR3) immunoreactivity and the clinical significance it may possess with regard to BC. The present study aimed to investigate the immunoreactivity of FGFR3 in primary urothelial bladder tumours, with regard to clinicopathological features and FGFR3 mutation status. Tissue microarrays were used to immunohistochemically analyse FGFR3 expression in 255 primary, unselected patients with BC. FGFR3 mutations were detected using SNaPshot analysis. Positive FGFR3 immunoreactivity was identified in 113/207 analysable cases (54.6%), and was significantly associated with FGFR3 mutation (P<0.001), low tumour stage (P<0.001), low histological grade (P<0.001) and a papillary growth pattern (P<0.001). Positive FGFR3 immunostaining (P=0.002) and FGFR3 mutation (P=0.002) were found to be significantly associated with increased disease-specific survival following univariate analysis, demonstrating a median follow-up period of 75 months. Using multivariate analyses, FGFR3 immunoreactivity was found not to be independent of classical pathological parameters. Immunohistochemical expression of FGFR3 is an early occurrence during the carcinogenesis of papillary non-invasive BC. The presence of FGFR3 immunoreactivity in non-invasive papillary urothelial carcinomas may be utilised as an indicator of tumours possessing low-grade features and good prognosis.

Interaction of antidepressant and antipsychotic drugs with the human organic cation transporters hOCT1, hOCT2 and hOCT3.

Besides the three antidepressant-sensitive, Na(+)- and Cl(-)-dependent monoamine transporters, Na(+)-independent organic cation transporters (OCTs) are known to transport monoamines. However, little is known about the interactions of psychotropic drugs with human (h) OCTs. In the present study, a series of diverse antidepressant and antipsychotic drugs were examined for their inhibitory potency at hOCT1, hOCT2 and hOCT3 by measuring inhibition of [(3)H]-MPP(+) uptake into HEK293 cells stably expressing one of the three hOCTs. The inhibitory potencies (IC(50)s) ranged from 1 to 900 µM. Most of the examined drugs showed highest inhibitory potency at hOCT1 which is very sparsely expressed in the brain and mainly involved in renal and hepatic clearance of cationic drugs. At their upper therapeutic plasma concentrations, several drugs are expected to inhibit by more than 20 % hOCT1 and could thus interfere with the pharmacokinetics of hOCT1-transported drugs in the kidney and liver, namely trimipramine, desipramine and fluoxetine (by about 37 %), levomepromazine and nefazodone (by about 32 %), and clozapine and amitriptyline (by about 22 %). At hOCT2 and hOCT3, which are involved in monoamine homeostasis in the brain, IC(50)s of most psychoactive drugs were in the high micromolar range. At their upper plasma concentrations, only three compounds, bupropion, nefazodone and clozapine, showed potential for inhibition, of about 18 % at hOCT2 (bupropion), about 22 % at hOCT3 (nefazodone) and of approximately 10 % at hOCT2 and hOCT3 (clozapine). Thus, under the assumption of a tenfold accumulation in the brain, bupropion, nefazodone and clozapine may notably inhibit the corresponding hOCTs. It remains to be shown whether such a direct inhibition plays a role in the clinical effects of these three drugs.

Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain.

Organic cation transporters (OCTs) are polyspecific carriers implicated in low-affinity, corticosteroid-sensitive extraneuronal catecholamine uptake in peripheral tissues. The three main OCT subtypes, OCT1, OCT2 and OCT3, are also present in the brain, but their central role remains unclear. In the present study, we investigated by comparative in situ hybridization analysis the regional distribution of these transporters in rat brain and compared their functional properties in stably transfected HEK293 cells expressing human or rat OCTs. In rat brain, OCT2 and OCT3 mRNAs are expressed predominantly in regions located at the brain-cerebrospinal fluid border, with OCT3 mRNA expression extending to regions that belong to monoaminergic pathways such as raphe nuclei, striatum and thalamus. After normalization with MPP+ uptake, OCT2 and OCT3 subtypes share a similar monoamine preference profile, with higher transport efficacies for epinephrine and histamine than for the other monoamines. Interestingly, a significant level of epinephrine transport, previously only shown for rOCT2, is achieved by most OCTs subtypes. Finally, another novel finding was that OCTs are sensitive to 3,4-methylenedioxymetamphetamine (MDMA), phencyclidine (PCP), MK-801 and ketamine. Altogether, all our results suggest a functional specialization of OCT subtypes, based both on their intrinsic properties and their differential regional expression pattern in the brain.

Discrepancy between morphologic and functional criteria of optimal stent deployment using intravascular ultrasound and pressure derived myocardial fractional flow reserve.

BACKGROUND: Pressure derived myocardial FFR, a functional index of epicardial stenosis has been proposed for the assessment of optimal stent deployment. The following study evaluated the potential of serial fractional flow reserve (FFR) measurements in comparison to the 'gold standard' intravascular ultrasound (IVUS) for optimal stent deployment and its long-term outcome. METHODS: 35 patients with a single de novo lesion underwent PTCA followed by stent implantation with an initial inflation pressure of 12 atm. If optimal stent expansion using IVUS-criteria were not fulfilled, re-dilatation at 16 atm as well as additional inflations with larger balloon sizes were performed to reach the procedural end-point. IVUS and FFR were performed after each dilatation (n = 136). Angiography was repeated after 6 months. RESULTS: In 30 pts who fulfilled IVUS criteria, mean lumen area (2.9+/-1.3 mm2) increased after PTCA and stent implantation to 10.0+/-3.0 mm2. In six pts, optimum stent deployment according to a value of FFR0.94 was not reached. Four of six pts reached the IVUS criteria at 12 atm and two pts at 16 atm, respectively. Positive and negative predictive values of FFR were 26 and 64%. Three of the 30 pts (10%) revealed a restenosis at three months follow-up. One of these restenosis was seen in a patient with a post-procedural FFR<0.94. CONCLUSIONS: FFR was not valid to predict optimal stent expansion according to IVUS criteria but could delineate under-expanded stents despite a reasonable angiographic appearance. Morphologic (IVUS) and functional criteria (FFR) for optimal stent deployment revealed a comparably low restenosis rate.