Oxygen supply maps for hypoxic microenvironment visualization in prostate cancer.

BACKGROUND: Intratumoral hypoxia plays an important role with regard to tumor biology and susceptibility to radio- and chemotherapy. For further investigation of hypoxia-related changes, areas of certain hypoxia must be reliably detected within cancer tissues. Pimonidazole, a 2-nitroimindazole, accumulates in hypoxic tissue and can be easily visualized using immunohistochemistry. MATERIALS AND METHODS: To improve detection of highly hypoxic versus normoxic areas in prostate cancer, immunoreactivity of pimonidazole and a combination of known hypoxia-related proteins was used to create computational oxygen supply maps of prostate cancer. Pimonidazole was intravenously administered before radical prostatectomy in n = 15 patients, using the da Vinci robot-assisted surgical system. Prostatectomy specimens were immediately transferred into buffered formaldehyde, fixed overnight, and completely embedded in paraffin. Pimonidazole accumulation and hypoxia-related protein expression were visualized by immunohistochemistry. Oxygen supply maps were created using the normalized information from pimonidazole and hypoxia-related proteins. RESULTS: Based on pimonidazole staining and other hypoxia.related proteins (osteopontin, hypoxia-inducible factor 1-alpha, and glucose transporter member 1) oxygen supply maps in prostate cancer were created. Overall, oxygen supply maps consisting of information from all hypoxia-related proteins showed high correlation and mutual information to the golden standard of pimonidazole. Here, we describe an improved computer-based ex vivo model for an accurate detection of oxygen supply in human prostate cancer tissue. CONCLUSIONS: This platform can be used for precise colocalization of novel candidate hypoxia-related proteins in a representative number of prostate cancer cases, and improve issues of single marker correlations. Furthermore, this study provides a source for further in situ tests and biochemical investigations.

Prostate cancer risk prediction using the novel versions of the European Randomised Study for Screening of Prostate Cancer (ERSPC) and Prostate Cancer Prevention Trial (PCPT) risk calculators: independent validation and comparison in a contemporary European cohort.

OBJECTIVES: To externally validate and compare the two novel versions of the European Randomised Study for Screening of Prostate Cancer (ERSPC)-prostate cancer risk calculator (RC) and Prostate Cancer Prevention Trial (PCPT)-RC. PATIENTS AND METHODS: All men who underwent a transrectal prostate biopsy in a European tertiary care centre between 2004 and 2012 were retrospectively identified. The probability of detecting prostate cancer and significant cancer (Gleason score ≥7) was calculated for each man using the novel versions of the ERSPC-RC (DRE-based version 3/4) and the PCPT-RC (version 2.0) and compared with biopsy results. Calibration and discrimination were assessed using the calibration slope method and the area under the receiver operating characteristic curve (AUC), respectively. Additionally, decision curve analyses were performed. RESULTS: Of 1 996 men, 483 (24%) were diagnosed with prostate cancer and 226 (11%) with significant prostate cancer. Calibration of the two RCs was comparable, although the PCPT-RC was slightly superior in the higher risk prediction range for any and significant prostate cancer. Discrimination of the ERSPC- and PCPT-RC was comparable for any prostate cancer (AUCs 0.65 vs 0.66), while the ERSPC-RC was somewhat better for significant prostate cancer (AUCs 0.73 vs 0.70). Decision curve analyses revealed a comparable net benefit for any prostate cancer and a slightly greater net benefit for significant prostate cancer using the ERSPC-RC. CONCLUSIONS: In our independent external validation, both updated RCs showed less optimistic performance compared with their original reports, particularly for the prediction of any prostate cancer. Risk prediction of significant prostate cancer, which is important to avoid unnecessary biopsies and reduce over-diagnosis and overtreatment, was better for both RCs and slightly superior using the ERSPC-RC.

Long-lasting fibrin matrices ensure stable and functional angiogenesis by highly tunable, sustained delivery of recombinant VEGF164.

Clinical trials of therapeutic angiogenesis by vascular endothelial growth factor (VEGF) gene delivery failed to show efficacy. Major challenges include the need to precisely control in vivo distribution of growth factor dose and duration of expression. Recombinant VEGF protein delivery could overcome these issues, but rapid in vivo clearance prevents the stabilization of induced angiogenesis. Here, we developed an optimized fibrin platform for controlled delivery of recombinant VEGF, to robustly induce normal, stable, and functional angiogenesis. Murine VEGF164 was fused to a sequence derived from α2-plasmin inhibitor (α2-PI1-8) that is a substrate for the coagulation factor fXIIIa, to allow its covalent cross-linking into fibrin hydrogels and release only by enzymatic cleavage. An α2-PI1-8-fused variant of the fibrinolysis inhibitor aprotinin was used to control the hydrogel degradation rate, which determines both the duration and effective dose of factor release. An optimized aprotinin-α2-PI1-8 concentration ensured ideal degradation over 4 wk. Under these conditions, fibrin-α2-PI1-8-VEGF164 allowed exquisitely dose-dependent angiogenesis: concentrations ≥25 µg/mL caused widespread aberrant vascular structures, but a 500-fold concentration range (0.01-5.0 µg/mL) induced exclusively normal, mature, nonleaky, and perfused capillaries, which were stable after 3 mo. Optimized delivery of fibrin-α2-PI1-8-VEGF164 was therapeutically effective both in ischemic hind limb and wound-healing models, significantly improving angiogenesis, tissue perfusion, and healing rate. In conclusion, this optimized platform ensured (i) controlled and highly tunable delivery of VEGF protein in ischemic tissue and (ii) stable and functional angiogenesis without introducing genetic material and with a limited and controllable duration of treatment. These findings suggest a strategy to improve safety and efficacy of therapeutic angiogenesis.

Bilaterally positive biopsy cores are associated with non-organ-confined disease in prostate cancer patients eligible for active surveillance.

PURPOSE: To investigate the association between the laterality of diagnostic prostate cancer-positive biopsy cores and definitive tumor stage on final pathology (organ-confined versus non-organ-confined). PATIENTS AND METHODS: This is a retrospective analysis of 165 men after radical prostatectomy fulfilling our active surveillance criteria at the time of surgery. Nominal variables were compared using Fisher's exact test, continuous variables using Mann-Whitney test. Odds ratios including 95% Wald and probabilities including 95% Wilson confidence intervals are provided. RESULTS: 5 (3%) patients had non-organ-confined disease: 2 out of 144 (1%) patients with unilateral and 3 out of 17 (18%) patients with bilateral cancer-positive biopsy cores (p = 0.009). The estimated odds ratio for non-organ-confined disease was 14.67 (95% confidence interval 1.55-189.23) for patients with bilateral compared to patients with unilateral cancer-positive biopsy cores. The sensitivity, specificity and accuracy of bilaterally positive biopsies as an additional criterion to identify non-organ-confined disease are 60, 91 and 90%, respectively. CONCLUSION: In our cohort, patients with bilaterally positive biopsy cores were significantly more likely to harbor a non-organ-confined tumor than patients with unilaterally positive cores. Due to their high specificity, bilaterally positive biopsies may represent a reasonable exclusion criterion for active surveillance if our results are corroborated in further studies.

Lateral temperature spread of monopolar, bipolar and ultrasonic instruments for robot-assisted laparoscopic surgery.

OBJECTIVE: To assess critical heat spread of cautery instruments used in robot-assisted laparoscopic (RAL) surgery. MATERIALS AND METHODS: Thermal spread along bovine musculofascial tissues was examined by infrared camera, histology and enzyme assay. Currently used monopolar, bipolar and ultrasonic laparoscopic instruments were investigated at various power settings and application times. The efficacy of using an additional Maryland clamp as a heat sink was evaluated. A temperature of 45 °C was considered the threshold temperature for possible nerve damage. RESULTS: Monopolar instruments exhibited a mean (sem) critical thermal spread of 3.5 (2.3) mm when applied at 60 W for 1 s. After 2 s, the spread was >20 mm. For adjustable bipolar instruments the mean (sem) critical thermal spread was 2.2 (0.6) mm at 60 W and 1 s, and 3.6 (1.3) mm at 2 s. The PK and LigaSure forceps had mean (sem) critical thermal spreads of 3.9 (0.8) and 2.8 (0.6) mm respectively, whereas the ultrasonic instrument reached 2.9 (0.8) mm. Application of an additional Maryland clamp as a heat sink, significantly reduced the thermal spread. Histomorphometric analyses and enzyme assay supported these findings. CONCLUSIONS: All coagulation devices used in RAL surgery have distinct thermal spreads depending on power setting and application time. Cautery may be of concern due to lateral temperature spread, causing potential damage to sensitive structures including nerves. Our results provide surgeons with a resource for educated decision-making when using coagulation devices during robotic procedures.

Adipose-derived stem cells (ADSCs) and muscle precursor cells (MPCs) for the treatment of bladder voiding dysfunction.

PURPOSE: Bladder outflow obstruction (BOO) is common in the elderly and can result in bladder voiding dysfunction (BVD) due to severe bladder muscle damage. The goal of this research was to evaluate the use of adult stem cells for the treatment of BVD due to decreased muscle contractility in a rat model. MATERIALS AND METHODS: Adipose-derived stem cells (ADSCs) and muscle precursor cells (MPCs) were harvested from male Lewis rats and expanded in culture. BOO was induced by tying a suture around the urethra. Six weeks after obstruction, the development of BVD was confirmed by cystometric analysis in conscious rats, histology and molecular investigations. Injection of ADSCs or MPCs into the bladder wall and synchronous deligation was performed 6 weeks after the obstruction. After stem-cell treatment, morphological and functional changes were assessed. Age-matched rats and animals without cellular therapy but deligation-only served as controls. RESULTS: Voiding pressures decreased progressively 6 weeks after obstruction with increased bladder capacities. Structural changes of the detrusor muscle occurred during the time of obstruction with an increased connective tissue-to-smooth muscle ratio and decreased SMA/smoothelin expression. After stem-cell injection, improved voiding pressures and voiding volumes were observed together with recovered tissue architecture. RT-PCR and Western blotting showed an up-regulation of important contractile proteins. CONCLUSIONS: We established a reliable model for BVD and demonstrated that ADSCs and MPCs can prevent pathophysiological remodelling and provide regenerated bladder tissue and function.

Pure bipolar plasma vaporization of the prostate: the Zürich experience.

INTRODUCTION AND OBJECTIVES: Bipolar plasma vaporization (BPV) has been introduced as an alternative to transurethral resection of the prostate (TURP). Promising short-term results, but inferior mid-term results compared to TURP have been reported following first-generation bipolar electrovaporization. Outcome data following second-generation BPV are still scarce. The aim of this investigation was to evaluate the intra- and postoperative outcomes of contemporary BPV in a center with long-standing expertise on laser vaporization of the prostate. METHODS: A consecutive series of 83 patients undergoing BPV in a tertiary referral center was prospectively evaluated. The investigated outcome parameters included the maximum flow rate (Qmax), postvoid residual volume, International Prostate Symptom Score (IPSS)/quality of life (Qol), and prostate-specific antigen (PSA) tests. Follow-up investigations took place after 6 weeks, 6 months, and 12 months. The Wilcoxon signed-rank test was used to compare pre- and post-treatment parameters. RESULTS: The median (range) preoperative prostate volume was 41 mL (17-111 mL). The preoperative IPSS, Qol, Qmax, and residual volume were 16 (2-35), 4 (0-6), 10.1 mL/s (3-29.3 mL/s), and 87 mL (0-1000 mL), respectively. One third of the patients were undergoing platelet aggregation inhibition (PAI). No intraoperative complications occurred. Postoperatively, 13 patients (15.7%) had to be recatheterized. Three patients (3.6%) had clot retention and 28 patients (34%) reported any grade of dysuria. After 6 weeks, all outcome parameters improved significantly and remained improved over the 12-month observation period [IPSS: 3 (0-2); Qol: 1 (0-4); Qmax: 17.2 mL/s (3.2-56 mL/s); residual volume 11 mL (0-190 mL)]. The PSA reduction was 60% at study conclusion. Three patients (3.6%) developed a urethral stricture and four patients (4.8%) bladder neck sclerosis. Re-resections were not necessary. CONCLUSIONS: Contemporary BPV is a safe and efficacious treatment option even for patients undergoing PAI. Early urinary retention and temporary dysuria seem to be specific side effects of the treatment. Bleeding complications are rare. Long-term follow-up is needed to confirm these promising short-term results.

Electrosurgery in urology: recent advances.

Inadequate hemostasis is one of the most important causes of morbidity and mortality following urological surgery. Despite the long-term usage of coagulation, there is an ongoing development of new devices, including bipolar transurethral resection of the prostate or new vessel-sealing devices. A thorough understanding of the advantages and disadvantages of these new instruments can improve the operative experience for both the urologist and patient. The optimal coagulation system should be small, efficient, easy to handle and with low heat spread. In this article, we analyze different electrothermal coagulation systems and modern tissue-sealing devices in urological applications with the aim to substantiate the advantages and disadvantages of each technique in terms of efficacy and safety.