Does the surgical technique for management of the distal ureter influence the outcome after nephroureterectomy?

Study Type – Therapy (case series)
Level of Evidence 4 What’s known on the subject? and What does the study add? The resection of the distal ureter and its orifice is an oncological principle during radical nephroureterectomy which is based on the fact that it represents a part of the urinary tract exposed to a considerable risk of recurrence. After removal of the proximal part it is hardly possible to image or approach it by endoscopy during follow‐up. Recent publications on survival after nephroureterectomy do not allow the conclusion that removal of distal ureter and bladder cuff are useless. Several techniques of distal ureter removal have been described but they are not equivalent in term of oncological safety. ? The standard treatment of upper urinary tract urothelial carcinomas (UUT‐UCs) must obey oncological principles, which consist of a complete en bloc resection of the kidney and the ureter, as well as excision of a bladder cuff to avoid tumour seeding. ? The open technique is the ‘gold standard’ of treatment to which all other techniques developed are necessarily compared, and various surgical procedures have been described. ? The laparoscopic stapling technique maintains a closed system but risks leaving behind the ureteric and bladder cuff segments. ? Transvesical laparoscopic detachment and ligation is a valid approach from an oncological stance but is technically difficult. The major inconvenience of the transurethral resection of the ureteric orifice and intussusception techniques is the potential for tumour seeding. ? Management of the distal ureter via the robot‐assisted laparoscopic method is technically feasible, but outcomes from these procedures are still preliminary. ? Therefore, prospective comparative studies with more thorough explorations of these techniques are needed to solve the dilemma of the management of the distal ureter during nephroureterectomy. However, bladder cuff excision should remain the standard of care irrespective of the stage of the disease.     

Deregulation of the protein phosphatase 2A,PP2A in cancer: complexity and therapeutic options

The complexity of the phosphatase, PP2A, is being unravelled and current research is increasingly providing information on the association of deregulated PP2A function with cancer initiation and progression. It has been reported that decreased activity of PP2A is a recurrent observation in many types of cancer, including colorectal and breast cancer (Baldacchino et al. EPMA J. 5:3, 2014; Cristobal et al. Mol Cancer Ther. 13:938–947, 2014). Since deregulation of PP2A and its regulatory subunits is a common event in cancer, PP2A is a potential target for therapy (Baldacchino et al. EPMA J. 5:3, 2014). In this review, the structural components of the PP2A complex are described, giving an in depth overview of the diversity of regulatory subunits. Regulation of the active PP2A trimeric complex, through phosphorylation and methylation, can be targeted using known compounds, to reactivate the complex. The endogenous inhibitors of the PP2A complex are highly deregulated in cancer, representing cases that are eligible to PP2A-activating drugs. Pharmacological opportunities to target low PP2A activity are available and preclinical data support the efficacy of these drugs, but clinical trials are lacking. We highlight the importance of PP2A deregulation in cancer and the current trends in targeting the phosphatase.     

Rat primary hepatocytes show enhanced performance and sensitivity to acetaminophen during three-dimensional culture on a polystyrene scaffold designed for routine use

The in vitro evaluation of hepatotoxicity is an essential stage in the research and development of new pharmaceuticals as the liver is one of the most commonly impacted organs during preclinical toxicity studies. Fresh primary hepatocytes in monolayer culture are the most commonly used in vitro model of the liver but often exhibit limited viability and/or reduction or loss of important liver-specific functions. These limitations could potentially be overcome using three-dimensional (3D) culture systems, but their experimental nature and limited use in liver toxicity screening and drug metabolism has impaired their uptake into commercial screening programs. In this study we use a commercially available polystyrene scaffold developed for routine 3D cell culture to maintain primary rat hepatocytes for use in metabolism and toxicity studies over 72?h. We show that primary hepatocytes retain their natural cuboidal morphology with significantly higher viability (>74%) than cells grown in monolayer culture (maximum of 57%). Hepatocytes in the 3D scaffolds exhibit differential expression of genes associated with phase I, II, and III drug metabolism under basal conditions compared with monolayer culture and can be induced to stably express significantly higher levels of the cytochrome-P450 enzymes 1A2, 2B1, and 3A2 over 48?h. In toxicity studies the hepatocytes in the 3D scaffolds also show increased sensitivity to the model toxicant acetaminophen. These improvements over monolayer culture and the availability of this new easy to use 3D scaffold system could facilitate the uptake of 3D technologies into routine drug screening programs.     

Identification of polyphenolic compounds and black tea extract as potent inhibitors of lipid membrane destabilization by Aβ₄₂ aggregates

Amyloid-β (Aβ) aggregation is a recognized key process in the pathogenesis of Alzheimer's disease (AD). Misfolded Aβ peptides self-assemble into higher-order oligomers that compromise membrane integrity, leading to synaptic degeneration and neuronal cell death. The main aim of this study was to explore whether small-molecule compounds and black tea extract can protect phospholipid membranes from disruption by Aβ aggregates. We first established a robust protocol for aggregating Aβ?? peptides into a range of oligomers that efficiently permeabilized small unilamellar liposomes. Next, 15 natural plant polyphenolic compounds, 8 N'-benzylidene-benzohydrazide (NBB) compounds and black tea extract were assessed for their ability to antagonize liposome permeabilization by the Aβ?? oligomers. Our data indicates that black tea extract, the flavones apigenin and baicalein, and the stilbene nordihydroguaiaretic acid (NDGA) are indeed potent inhibitors. Taking into consideration the results of all the small-molecule polyphenols and NBB compounds, it can be proposed that a dihydroxyphenyl ring structure, alone or as part of a flavone scaffold, is particularly effective for protection against membrane damage by the Aβ?? oligomers. Given the critical role of membrane perforation in the neurodegenerative cascade, these conclusions may guide the design and development of novel therapeutic drugs in AD.     

Mapping of Transrectal Ultrasonographic Prostate Biopsies

Objective. Mapping of transrectal ultrasonographic (TRUS) prostate biopsies is of fundamental importance for either diagnostic purposes or the management and treatment of prostate cancer, but the localization of the cores seems inaccurate. Our objective was to evaluate the capacities of an operator to plan transrectal prostate biopsies under 2‐dimensional TRUS guidance using a registration algorithm to represent the localization of biopsies in a reference 3‐dimensional ultrasonographic volume. Methods. Thirty‐two patients underwent a series of 12 prostate biopsies under local anesthesia performed by 1 operator using a TRUS probe combined with specific third‐party software to verify that the biopsies were indeed conducted within the planned targets. Results. The operator reached 71% of the planned targets with substantial variability that depended on their localization (100% success rate for targets in the middle and right parasagittal parts versus 53% for targets in the left lateral base). Feedback from this system after each series of biopsies enabled the operator to significantly improve his dexterity over the course of time (first 16 patients: median score, 7 of 10 and cumulated median biopsy length in targets of 90 mm; last 16 patients, median score, 9 of 10 and a cumulated median length of 121 mm; P = .046). Conclusions. In addition to being a useful tool to improve the distribution of prostate biopsies, the potential of this system is above all the preparation of a detailed “map” of each patient showing biopsy zones without substantial changes in routine clinical practices.