David Cranston

The safety and feasibility of extracorporeal high-intensity focused ultrasound (HIFU) for the treatment of liver and kidney tumours in a Western population

High-intensity focused ultrasound (HIFU) provides a potential noninvasive alternative to conventional therapies. We report our preliminary experience from clinical trials designed to evaluate the safety and feasibility of a novel, extracorporeal HIFU device for the treatment of liver and kidney tumours in a Western population. The extracorporeal, ultrasound-guided Model-JC Tumor Therapy System (HAIFU™ Technology Company, China) has been used to treat 30 patients according to four trial protocols. Patients with hepatic or renal tumours underwent a single therapeutic HIFU session under general anaesthesia. Magnetic resonance imaging 12 days after treatment provided assessment of response. The patients were subdivided into those followed up with further imaging alone or those undergoing surgical resection of their tumours, which enabled both radiological and histological assessment. HIFU exposure resulted in discrete zones of ablation in 25 of 27 evaluable patients (93%). Ablation of liver tumours was achieved more consistently than for kidney tumours (100 vs 67%, assessed radiologically). The adverse event profile was favourable when compared to more invasive techniques. HIFU treatment of liver and kidney tumours in a Western population is both safe and feasible. These findings have significant implications for future noninvasive image-guided tumour ablation.

Up-regulation of Delta-like 4 Ligand in Human Tumor Vasculature and the Role of Basal Expression in Endothelial Cell Function

The Notch signaling pathway and the delta-like 4 ligand (DLL4) play key roles in embryonic vascular development. Many of the pathways involved in embryonic vascular development also play important roles in tumor angiogenesis. In this study, we assessed the expression of DLL4 in primary renal cancer and investigated the biological function of DLL4 in primary endothelial cells. Using real-time quantitative PCR and in situ hybridization, we showed that the expression of DLL4 was up-regulated within the vasculature of clear cell-renal cell carcinoma almost 9-fold more than normal kidney and was correlated with the expression of vascular endothelial growth factor (VEGF). The expression of DLL4 in endothelial cells was up-regulated by VEGF and basic fibroblast growth factor synergistically, and by hypoxia through hypoxia-inducible factor 1alpha. Down-regulation of DLL4 expression with RNA interference led to decreased expression of HEY1 and EphrinB2, and the inhibition of endothelial cell proliferation, migration, and network formation, all of which are important processes in tumor angiogenesis. The inhibition of proliferation occurred via the induction of cell cycle arrest in G0-G1 by increased expression of p21 and decreased phosphorylation of retinoblastoma. We conclude that an optimal window of the DLL4 expression is essential for tumor angiogenesis and that selective modulation of the DLL4 expression within human tumors may represent a potential novel antiangiogenic therapy.

Urological Complications in 1,000 Consecutive Renal Transplant Recipients

The urological complications in the first consecutive 1,000 renal transplants at our transplant center are reported with a minimum followup of 12 months. The kidney was implanted in the iliac fossa in all cases and in all but 3 the ureter was inserted into the bladder with a Politano-Leadbetter technique. Overall, there were 71 primary complications in 68 patients (7.1%), which included 36 ureteral obstructions, 25 ureteral or bladder leaks (including ureteral necrosis), 7 bladder outflow obstructions, 2 ureteral stones and 1 case of symptomatic vesicoureteral reflux. The use of high dose steroids in the early years was associated with a 10% urological complication rate, which decreased to 4% in patients receiving low dose steroids thereafter combined with azathioprine or cyclosporine. The urological complication was corrected after 1 procedure in 65 cases and after 2 procedures in 4. No grafts were lost due to urological complications. Two patients died, 1 of sepsis following transurethral resection of the prostate and subsequent ureteral necrosis, and 1 of hemorrhage following nephrostomy tube insertion. Most ureteral complications were treated by an open operation, although in recent years endoscopic techniques have become more common. Meticulous retrieval technique, low dose steroid protocols and rapid diagnosis are the crucial factors associated with a minimal incidence of urological complications after renal transplantation.

The urological complications of renal transplantation: a series of 1535 patients.

Objective  To determine the incidence of urological complications of renal transplantation at one institution, and relate this to donor and recipient factors.

Up-Regulation of Endothelial Delta-like 4 Expression Correlates with Vessel Maturation in Bladder Cancer

Purpose: Angiogenesis and vascular endothelial growth factor (VEGF) expression are associated with a poor outcome in bladder cancer. To understand more about the mechanisms, we studied the role of delta-like 4 (DLL4), an endothelial-specific ligand of the Notch signaling pathway, in bladder cancer angiogenesis. Experimental Design: The expression of DLL4, CD34, and VEGF were studied in a cohort of 60 bladder tumors and 10 normal samples using quantitative PCR. In situ hybridization was used to study the pattern of DLL4 expression in 22 tumor and 9 normal samples. Serial sections were also stained for CD34 and α-smooth muscle actin (α-SMA) using conventional immunohistochemistry. Results: The expression of DLL4 was significantly up-regulated in superficial (P < 0.01) and invasive (P < 0.05) bladder cancers. DLL4 expression significantly correlated with CD34 (P < 0.001) and VEGF (P < 0.001) expression. The in situ hybridization studies showed that DLL4 was highly expressed within bladder tumor vasculature. Additionally, DLL4 expression significantly correlated with vessel maturation as judged by periendothelial cell expression of α-SMA, 98.7% of DLL4-positive tumor vessels coexpressed α-SMA, compared with 64.5% of DLL4-negative tumor vessels (P < 0.001). High DLL4 expression may have prognostic value in superficial and invasive bladder. Conclusion: DLL4 expression is associated with vascular differentiation in bladder cancer; thus, targeting DLL4 may be a novel antiangiogenic therapy.

URINARY VASCULAR ENDOTHELIAL GROWTH FACTOR AND ITS CORRELATION WITH BLADDER CANCER RECURRENCE RATES

PURPOSE Vascular endothelial growth factor (VEGF) is a principal growth factor mediating tumor angiogenesis. The high expression of VEGF within bladder tumors is associated with a poor prognosis. We quantified urinary VEGF and determined its potential as a prognostic marker in bladder cancer. MATERIALS AND METHODS VEGF was measured by enzyme-linked immunosorbent assay in the urine of 261 patients, including 153 undergoing cystoscopic surveillance for bladder cancer and 108 with another advanced malignancy or a benign urological condition. The source of urinary VEGF was studied through its quantification in bladder tumors and normal bladders. RESULTS Urinary VEGF was higher in patients undergoing cystoscopic surveillance for bladder cancer than in those with an advanced nonbladder malignancy (p <0.0001) or a benign urological condition (p = 0.004). The highest levels were noted in patients with bladder cancer compared to those with clear cystoscopy (p <0.0001). In 26 cases the correlation between VEGF protein levels in bladder cancer and urine (r = 0.67, p = 0.003) suggested that the tumor is a source of urinary VEGF. Increased VEGF protein in normal urothelium in 22 patients with bladder cancer compared to that in 7 cadaveric organ donors (p = 0.002) indicates that urinary VEGF may also be derived from nonmalignant urothelium. In 61 cases we established a correlation between urinary VEGF and stage T1 or less superficial bladder tumor recurrence rates (r = 0.45, p <0.0001). CONCLUSIONS Our study demonstrates that VEGF is high in the urine of patients with bladder cancer and it correlates with tumor recurrence rates. VEGF is implicated in the pathogenesis of bladder cancer recurrence. Its quantification may provide a valuable noninvasive marker for the early detection of bladder tumor recurrence as well as a therapy target.

Extracorporeal ablation of renal tumours with high-intensity focused ultrasound

coefficient of the incident tissues and the site intensity achieved [2,3]. In a defined biological environment, the size of the thermal lesion can be controlled by the power and duration of the ultrasound pulses [4]. With higher site intensities ( > 3.5 kW/cm 3 ) cavitation phenomena with bubble implosion and mechanical tissue disruption are added, which are more difficult to control [5,6]. HIFU has been used for targeted tissue ablation in several organs, including the brain, liver, eye, bladder, prostate, testis and kidney [3]. In many experimental studies HIFU ablation of malignant tumours has not been shown to result in tumour cell dissemination or an increased rate of metastases [5].

Extracorporeal high intensity focused ultrasound for renal tumours: a 3-year follow-up.

Study Type – Therapy (case series)
Level of Evidence 4

A double-blind randomized controlled trial and economic evaluation of transurethral resection vs contact laser vaporization for benign prostatic enlargement: a 3-year follow-up.

ObjectiveTo evaluate the effect of contact laser prostate surgery in the treatment of benign prostatic hyperplasia.

Elevated serum vascular endothelial growth factor in patients with hormone‐escaped prostate cancer

Objective To investigate the role of serum vascular endothelial growth factor (VEGF) in the assessment of patients with prostate cancer.