The Role of Robot-assisted Radical Prostatectomy and Pelvic Lymph Node Dissection in the Management of High-risk Prostate Cancer: A Systematic Review

Context

The role of robot-assisted radical prostatectomy (RARP) for men with high-risk (HR) prostate cancer (PCa) has not been well studied.

Objective

To evaluate the indications for surgical treatment, technical aspects such as nerve sparing (NS) and lymph node dissection (LND), and perioperative outcomes of men with HR PCa treated with RARP.

Evidence acquisition

A systematic expert review of the literature was performed in October 2012, searching the Medline, Web of Science, and Scopus databases. Studies with a precise HR definition, robotic focus, and reporting of perioperative and pathologic outcomes were included.

Evidence synthesis

A total of 12 papers (1360 patients) evaluating RARP in HR PCa were retrieved. Most studies (67%) used the D’Amico classification for defining HR. Biopsy Gleason grade 8–10 was the most frequent HR identifier (61%). Length of follow-up ranged from 9.7 to 37.7 mo. Incidence of NS varied, although when performed did not appear to compromise oncologic outcomes. Extended LND (ELND) revealed positive nodes in up to a third of patients. The rate of symptomatic lymphocele after ELND was 3%. Overall mean operative time was 168 min, estimated blood loss was 189 ml, length of hospital stay was 3.2 d, and catheterization time was 7.8 d. The 12-mo continence rates using a no-pad definition ranged from 51% to 95% with potency recovery ranging from 52% to 60%. The rate of organ-confined disease was 35%, and the positive margin rate was 35%. Three-year biochemical recurrence–free survival ranged from 45% to 86%.

Conclusions

Although the use of RARP for HR PCa has been relatively limited, it appears safe and effective for select patients. Short-term results are similar to the literature on open radical prostatectomy. Variability exists for NS and the template of LND, although ELND improves staging and removes a higher number of metastatic nodes. Further study is required to assess long-term outcomes.     

Blickdiagnose bei der transurethralen Resektion von Harnblasentumoren

Introduction

The gold standard for diagnosis and immediate therapy of bladder cancer is a transurethral resection (TURB) followed by histopathologic evaluation. The aim of this study was to assess the reliability of visual diagnosis by the operating urologist concerning dignity (malignant/benign) and staging compared to histopathologic evaluation. This is especially crucial since early mitomycin C instillation is based on the urologist’s first impression.

Study design and methods

This prospective study included 311 cases of TURB from five German institutions. Surgeons were asked to estimate dignity of the neoplasm, tumor stage, and grade according to a standardized questionnaire.

Results

The subjective estimation/visual diagnosis of the operating urologist achieved a sensitivity with respect to identifying malignant tumors as such of 97%, while specificity was only 41%. Accordingly, the positive (PPV) and negative predictive values (NPV) were 76% and 88%, respectively. In general, muscle invasive cancer was predicted more often than confirmed by pathology (PPV 52%). However, whenever muscle invasive cancer was excluded by the urologist, this was confirmed by the pathologist in most the cases (NPV 95%). The educational degree did not influence the reliability and predictive value of visual diagnosis.

Conclusion

This study shows that urologists cannot reliably distinguish benign from malignant lesions of bladder mucosa—regardless of their educational degree. A reliable diagnosis of a pathologist is definitely needed to plan final therapeutic steps.     

Is there an anti-androgen withdrawal syndrome for enzalutamide?

Background

The anti-androgen withdrawal syndrome (AAWS) can be seen in one-third of patients after discontinuation of first-generation non-steroidal anti-androgen therapy. With the introduction of new agents for anti-androgen therapy as well as alternate mechanisms of action, new therapeutic options before and after docetaxel chemotherapy have arisen (Ohlmann et al. in World J Urol 30(4):495–503, 2012). The question regarding the occurrence of an enzalutamide withdrawal syndrome (EWS) has not been evaluated yet. In this study, we assess prostate-specific antigen (PSA) response after discontinuation of enzalutamide.

Methods

In total 31 patients with metastatic castration-resistant prostate cancer (mCRPC) underwent an enzalutamide withdrawal and were evaluated. Data were gathered from 6 centres in Germany. Patients with continuous oral administration of enzalutamide with rising serum PSA levels were evaluated, starting from enzalutamide withdrawal until subsequent therapy was initiated, follow-up ended or death of the patient occurred. Statistical evaluation was performed applying one-sided binomial testing using R-statistical software, version 3.0.1.

Results

Mean withdrawal follow-up was 6.5 weeks (range 1–26.1 weeks). None of the 31 patients showed a PSA decline. Mean relative PSA rise over all patients was 73.9 % (range 0.5–440.7 %) with a median of 44.9 %.

Conclusions

If existent, an AAWS is at least very rare for enzalutamide in patients with mCRPC after taxane-based chemotherapy and does not play a clinical role in this setting. This may be attributed to the different pharmacodynamics of enzalutamide. Longer duration of therapy or a longer withdrawal interval may reveal a rare EWS in the future.     

Insulin receptors mediate growth effects in cultured fetal neurons. II. Activation of a protein kinase that phosphorylates ribosomal protein S6

As an initial attempt to identify early steps in insulin action that may be involved in the growth responses of neurons to insulin, we investigated whether insulin receptor activation increases the phosphorylation of ribosomal protein S6 in cultured fetal neurons and whether activation of a protein kinase is involved in this process. When neurons were incubated for 2 h with 32Pi, the addition of insulin (100 ng/ml) for the final 30 min increased the incorporation of 32Pi into a 32K microsomal protein. The incorporation of 32Pi into the majority of other neuronal proteins was unaltered by the 30-min exposure to insulin. Cytosolic extracts from insulin-treated neurons incubated in the presence of exogenous rat liver 40S ribosomes and [gamma-32P]ATP displayed a 3- to 8-fold increase in the phosphorylation of ribosomal protein S6 compared to extracts from untreated cells. Inclusion of cycloheximide during exposure of the neurons to insulin did not inhibit the increased cytosolic kinase activity. Activation of S6 kinase activity by insulin was dose dependent (seen at insulin concentration as low as 0.1 ng/ml) and reached a maximum after 20 min of incubation. Addition of phosphatidylserine, diolein, and Ca2+ to the in vitro kinase reaction had no effect on the phosphorylation of ribosomal protein S6. Likewise, treatment of neurons with (Bu)2cAMP did not alter the phosphorylation of ribosomal protein S6 by neuronal cytosolic extracts. We conclude that insulin activates a cytosolic protein kinase that phosphorylates ribosomal S6 in neurons and is distinct from protein kinase-C and cAMP-dependent protein kinase. Stimulation of this kinase may play a role in insulin signal transduction in neurons.     

Modelling and Performance Analysis of MgB2 and Hybrid Magnetic Shields

Superconductors are strategic materials for the fabrication of magnetic shields, and within this class, MgB2 has been proven to be a very promising option. However, a successful approach to produce devices with high shielding ability also requires the availability of suitable simulation tools guiding the optimization process. In this paper, we report on a 3D numerical model based on a vector potential (A)-formulation, exploited to investigate the properties of superconducting (SC) shielding structures with cylindrical symmetry and an aspect ratio of height to diameter approaching one. To this aim, we first explored the viability of this model by solving a benchmark problem and comparing the computation outputs with those obtained with the most used approach based on the H-formulation. This comparison evidenced the full agreement of the computation outcomes as well as the much better performance of the model based on the A-formulation in terms of computation time. Relying on this result, the latter model was exploited to predict the shielding properties of open and single capped MgB2 tubes with and without the superimposition of a ferromagnetic (FM) shield. This investigation highlighted that the addition of the FM shell is very efficient in increasing the shielding factors of the SC screen when the applied magnetic field is tilted with respect to the shield axis. This effect is already significant at low tilt angles and allows compensating the strong decrease in the shielding ability that affects the short tubular SC screens when the external field is applied out of their axis.     

Comparison of immune reconstitution between anti-T-lymphocyte globulin and posttransplant cyclophosphamide as acute graft-versus-host disease prophylaxis in allogeneic myeloablative peripheral blood stem cell transplantation

Anti-T-cell lymphocyte globulin (ATLG) and posttransplant cyclophosphamide (PTCy) are now widely used strategies to prevent graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. Data comparing immune reconstitution (IR) between ATLG and PTCy is scarce. This retrospective study conducted at the University Medical Center Hamburg-Eppendorf (UKE) compares PTCy (n=123) and ATLG (n=476) after myeloablative allogeneic peripheral blood stem cell transplant. Detailed phenotypes of T, B natural killer (NK), natural killer T (NKT) cells were analyzed by multicolor flow at day 30, 100 and 180 posttransplant. Incidence of infections, viral reactivations, GVHD and relapse were collected. Neutrophil engraftment was significantly delayed in the PTCy group (median day 12 vs. day 10, P<0.001) with a high incidence of infection before day+100 in the PTCy arm but a higher Epstein-Barr virus reactivation in the ATLG arm and comparable cytomegalovirus reactivation. Overall incidence of acute GVHD was similar but moderate/severe chronic GVHD was seen more often after PTCy (44% vs. 38%, P=0.005). ATLG resulted in a faster reconstitution of CD8+ T, NK, NKT and gdT cells while CD4 T cells and B cells reconstituted faster after PTCy. Similar reconstitution was observed for T-regulatory cells and B cells. Non-relapse mortality relapse incidence, disease-free survival, and overall survival did not differ significantly between both arms. Even though differences in IR were related to a decreased incidence of infection and moderate/severe cGVHD in the ATLG group they had no impact on any of the other long-term outcomes. However, it remains undetermined which regimen is better as GVHD prophylaxis.     

In vitro quality control of red blood cell concentrates outdated in clinical practice.

The properties of red blood cell (RBC) concentrates stored in different additive solutions have been previously examined under laboratory conditions at the end of shelf-life. However, whether these data are representative for RBC units used in clinical practice has not been shown. Therefore, we examined 164 RBC units from six manufacturers outdated after clinical usage in a hospital-based transfusion service for cellular content, hemolysis, adenosin triphosphate, 2,3-DPG, pH, oxygen saturation and levels of beta-thromboglobulin and proinflammatory cytokines interleukin (IL) 1beta (IL-1), IL-6, IL-8 and tumor necrosis factor alpha (TNFalpha). Results were correlated with the number of interruptions of recommended storage conditions and with different manufacturers. TNFalpha and IL-8 levels in the supernatant of RBC concentrates showed a weak correlation with the number of interruptions of recommended storage conditions (TNFalpha: r = 0.25, P < 0.01; IL-8: r = 0.20, P < 0.01) for the whole series. We detected no significant correlation between hemolysis and interruptions of recommended storage conditions or any of the remaining studied parameters. However, we found significant differences between RBC concentrates supplied by different manufacturers with respect to cellular content and most of the studied parameters. RBC concentrates containing SAG-M from one single manufacturer had higher in vitro hemolysis at the end of shelf-life compared to all other manufacturers (P < 0.05). We conclude from our data that interruptions of optimal conditions for storage of red cell components during cross-match testing and transport in our setting play a minor role for in vitro properties of RBC units at the end of shelf-life. The influence of processes of production, storage and/or transport until entry of RBC units into our blood component depot seems to be much more important for final product quality at the end of shelf-life than subsequent events.