Lectin mediated biorecognition as a novel strategy for targeted delivery to bladder cancer.

PURPOSE: Inadequate urothelial delivery of drugs is considered a primary cause of current shortcomings in adjuvant intravesical chemotherapy for bladder cancer. We report what is to our knowledge a novel biorecognitive approach to achieve more regionally selective targeting of malignant tissue and improve urothelial uptake based on specific interaction between lectins and bladder cell glycocalyces. MATERIALS AND METHODS: We assessed the cytoadhesive and cytoinvasive potential of selected plant lectins in 3 human urothelial cell lines, corresponding to healthy tissue, and low and high grade carcinoma, respectively. Flow cytometry and fluorimetry were used to determine binding capacity and specificity in single cells and confluent monolayers. Monensin quenching experiments, microscopic analysis and enzyme treatment allowed further characterization of internalization, the uptake pathway and the potential cause of tumor selectivity. RESULTS: Wheat germ agglutinin had the highest bioadhesive potential while peanut agglutinin was the most potent discriminator between healthy and cancerous tissue (p <0.01). In each case cell interaction was highly specific (greater than 80%) and proved decisive for efficient uptake. Within 60 minutes after exposure greater than 50% of membrane bound lectins were internalized in acidic compartments. Cancer associated aberrant glycosylation likely represents the determining cause of peanut agglutinin selectivity. CONCLUSIONS: Given careful choice of the targeting ligand, the development of carbohydrate based delivery strategies for bladder cancer therapy seems feasible. Lectin bioadhesion may not only mediate preferential accumulation in malignant tissue but also promote cellular internalization via increased recruitment of membrane bound material to physiological uptake routes.

Emergency nephrectomy due to severe urosepsis: a retrospective, multicentre analysis of 65 cases.

OBJECTIVE: To assess the outcome of emergency nephrectomy in a retrospective, multicentre analysis, as emergency nephrectomy due to life-threatening urosepsis is a rare clinical scenario with a high mortality, and there are few reports of clinical data on this issue. PATIENTS AND METHODS: We assessed retrospectively all patients who had a nephrectomy due to life-threatening urosepsis in three referral centres in Vienna between 1994 and 2007. Patient characteristics, survival and risk factors for a fatal outcome were evaluated. RESULTS: In all 65 patients (44 women and 21 men; mean age 65 years) were analysed. The mean interval from the first medical consultation to hospital admission was 4.3 days. Two-thirds of patients were admitted directly from their homes (63%), the remainder being transferred from other departments or hospitals. The most common pathological mechanism leading to urosepsis was acute pyelonephritis, often combined with nephrolithiasis. In all, 36 patients had a urological intervention before nephrectomy, i.e. percutaneous nephrostomy in 17, ureteric stent in 16 and percutaneous abscess drainage in three. Nephrectomy was performed a mean (range) of 5.7 (0-31) days after hospital admission. Thirteen patients (20%) died from septic multi-organ failure after surgery. This group was almost 20 years older than those who survived (78.6 vs 61.8 years), had a higher comorbidity rate, had undergone endourological interventions more frequently (69% vs 52%), had a longer interval to nephrectomy (6.9 vs 5.4 days), higher C-reactive protein level (294.9 vs 136.0 mg/L) and lower platelet counts (229.5 vs 307.7 million/L) at diagnosis. CONCLUSION: Several factors were identified that influence the outcome after emergency nephrectomy for life-threatening urosepsis. Applied to the decision-making process, these risk factors could have a positive impact on establishing a timely indication for nephrectomy that might ultimately reduce the high mortality rate.

Derivation of nephrogenic adenomas from renal tubular cells in kidney-transplant recipients.

BACKGROUND: Nephrogenic adenomas are benign, tumor-like lesions within the urothelial mucosa of the urinary tract that are not uncommon in renal-transplant recipients. We investigated the origin of nephrogenic adenomas in renal-transplant recipients. METHODS: Tissue sections were analyzed by fluorescence in situ hybridization with the use of probes for the X and Y chromosomes, by immunohistochemical methods with the use of antibodies to renal tubular antigens, and by lectin histochemical methods. Forty-six nephrogenic adenomas from 29 patients were analyzed. RESULTS: All nephrogenic adenomas in 14 female recipients of transplants from male donors and 10 male recipients of transplants from female donors showed the same sex-chromosome status as the donor kidney, but not the same sex-chromosome status as the recipient's surrounding bladder tissue. The nephrogenic adenomas from all 6 female recipients of transplants from female donors showed female chromosomes, and those from the 16 male recipients of transplants from male donors showed male chromosomes. The presence of aquaporin 1, PAX2, and lectin-binding capacity for peanut agglutinin, Lotus tetragonolobus agglutinin, and Sophora japonica agglutinin in nephrogenic adenomas indicated an origin from renal tubular cells. CONCLUSIONS: Nephrogenic adenomas in renal-transplant recipients are derived from tubular cells of the renal transplants and are not metaplastic proliferations of the recipient's bladder urothelium.