Adrian Joyce

Genetic and epigenetic analysis of von Hippel-Lindau (VHL) gene alterations and relationship with clinical variables in sporadic renal cancer.

Genetic and epigenetic changes in the von Hippel-Lindau (VHL) tumor suppressor gene are common in sporadic conventional renal cell carcinoma (cRCC). Further insight into the clinical significance of these changes may lead to increased biological understanding and identification of subgroups of patients differing prognostically or who may benefit from specific targeted treatments. We have comprehensively examined the VHL status in tissue samples from 115 patients undergoing nephrectomy, including 96 with sporadic cRCC. In patients with cRCC, loss of heterozygosity was found in 78.4%, mutation in 71%, and promoter methylation in 20.4% of samples. Multiplex ligation-dependent probe amplification identified intragenic copy number changes in several samples including two which were otherwise thought to be VHL-noninvolved. Overall, evidence of biallelic inactivation was found in 74.2% of patients with cRCC. Many of the mutations were novel and approximately two-thirds were potentially truncating. Examination of these and other published findings confirmed mutation hotspots affecting codons 117 and 164, and revealed a common region of mutation in codons 60 to 78. Gender-specific differences in methylation and mutation were seen, although not quite achieving statistical significance (P = 0.068 and 0.11), and a possible association between methylation and polymorphism was identified. No significant differences were seen between VHL subgroups with regard to clinicopathologic features including stage, grade, tumor size, cancer-free and overall survival, with the exception of a significant association between loss of heterozygosity and grade, although a possible trend for survival differences based on mutation location was apparent.

Uroplakin gene expression in normal human tissues and locally advanced bladder cancer

The uroplakins are widely regarded as urothelium‐specific markers of terminal urothelial cytodifferentiation. This study investigated the expression of the four uroplakin genes, UPIa, UPIb, UPII and UPIII, in a wide range of normal human tissues to determine tissue specificity and in advanced transitional cell carcinoma (TCC) to examine gene expression in primary and metastatic disease. In the urinary tract, all four uroplakins were expressed by urothelium and UPIII was also expressed by prostatic glandular epithelium. UPIa and UPII appeared to be urothelium‐specific, but UPIb was detected in several non‐urothelial tissues, including the respiratory tract, where it was associated with squamous metaplasia of tracheal and bronchial epithelia. The ten cases of primary TCC and corresponding lymph node metastases demonstrated that each uroplakin gene could be expressed at the mRNA level. No single uroplakin gene was expressed in all primary tumours or metastases, but 80% of the primary tumours and 70% of the lymph node metastases expressed at least one uroplakin gene. UPIII mRNA was often expressed in the absence of UPIII protein. These results confirm that in human tissues the expression of UPIa and UPII genes is highly specific to urothelium and suggest that the tight differentiation‐restricted expression of uroplakin genes in normal urothelium is lost following malignant transformation. Copyright

Analysis of VHL gene alterations and their relationship to clinical parameters in sporadic conventional renal cell carcinoma

Purpose: This study aimed to carry out a comprehensive analysis of genetic and epigenetic changes of the von Hippel Lindau (VHL) gene in patients with conventional (clear cell) renal cell carcinoma and to determine their significance relative to clinicopathologic characteristics and outcome. Experimental Design: The VHL status in 86 conventional renal cell carcinomas was determined by mutation detection, loss of heterozygosity (LOH), and promoter methylation analysis, extending our original cohort to a total of 177 patients. Data were analyzed to investigate potential relationships between VHL changes, clinical parameters, and outcome. Results: LOH was found in 89.2%, mutation in 74.6%, and methylation in 31.3% of evaluable tumors; evidence of biallelic inactivation (LOH and mutation or methylation alone) was found in 86.0% whereas no involvement of VHL was found in only 3.4% of samples. Several associations were suggested, including those between LOH and grade, nodal status and necrosis, mutation and sex, and methylation and grade. Biallelic inactivation may be associated with better overall survival compared with patients with no VHL involvement, although small sample numbers in the latter group severely limit this analysis, which requires independent confirmation. Conclusions: This study reports one of the highest proportions of conventional renal cell carcinoma with VHL changes, and suggests possible relationships between VHL status and clinical variables. The data suggest that VHL defects may define conventional renal cell carcinomas but the clinical significance of specific VHL alterations will only be clarified by the determination of their biological effect at the protein level rather than through genetic or epigenetic analysis alone. (Clin Cancer Res 2009;15(24):7582–92)

Radiofrequency ablation (RFA) of renal cell carcinoma (RCC): experience in 200 tumours

To evaluate our clinical experience with percutaneous image‐guided radiofrequency ablation (RFA) of 200 renal tumours in a large tertiary referral university institution.

Cytokeratin 20 expression by non-invasive transitional cell carcinomas: potential for distinguishing recurrent from non-recurrent disease.

Although approximately 50% of patients with non‐invasive (Ta) papillary transitional cell carcinoma show no recurrence of their disease, current histopathological approaches cannot distinguish this sub‐group from those patients in whom the disease will recur. In this 5 year retrospective study, we have shown that cytokeratin 20 (CK20) was expressed in 19 of 29 (65.5%) of non‐invasive papillary tumours of grades 1 or 2. CK20 expression patterns were predictive of disease non‐recurrence in a sub‐group of eight patients, representing 51.7% of patients with non‐recurrent disease. In normal bladder mucosa, CK20 expression was restricted to the terminally‐differentiated superficial cell. In eight CK20‐positive tumours which showed no recurrence at 5 years, CK20 expression was either restricted to, or most intense in, the luminal cells of the papillae. This pattern of expression was not seen in any of the 15 tumours from the recurrent group. Disruption of normal CK20 expression was highly significantly correlated with recurrent tumours. These results suggest that changes in the expression of differentiation‐associated antigens, such as CK20, may be useful in predicting benign versus malignant behaviour and may, therefore, be useful in defining treatment strategies.

Urolithiasis in pregnancy. I: pathophysiology, fetal considerations and diagnosis

Urolithiasis in pregnancy represents a major diagnostic and therapeutic challenge to the GP, obstetrician, urologist, radiologist and anaesthetist. Urolithiasis presenting during pregnancy is a cause of major concern, considering the potential adverse effects of radiation exposure, any invasive surgical procedures and anaesthesia on the mother and fetus. The incidence of urolithiasis during pregnancy is 0.026–0.531% [2,3], complicates 1 : 200 to 1 : 2000 pregnancies [4] and may be a contributing factor in up to 40% of premature births [3]. The incidence of symptomatic stones has been calculated to be the same during pregnancy as in nonpregnant women of childbearing age [5]. Multiparous women seem to be affected more often than primiparae by a ratio of <3 : 1 [3,6,7]. However, the incidence in multiparous women is no greater when adjusted for age [8]. Folger [9] reported that pain resulting from urinary stones is the most common cause of abdominal pain requiring hospitalization during pregnancy. Leftand right-side calculi occur with equal frequency and ureteric stones seem to occur about twice as often as renal calculi. Interestingly, 80–90% of patients present in the second or third trimester of pregnancy, but rarely in the first trimester [10]. The management of urolithiasis during pregnancy is often challenging, requiring close co-operation between urologist, radiologist and obstetrician. Fortunately, with conservative management, 70–80% of symptomatic calculi pass spontaneously with no sequelae [10].

Urolithiasis in pregnancy. II: management

Urolithiasis complicates 0.026–0.531% of pregnancies [1,2] and presents an interesting challenge to the obstetrician, radiologist and urologist. The management of stone disease in pregnancy is initially conservative. Surgical measures are reserved for patients with sepsis, intractable pain, acute renal failure or for patients who fail to respond to conservative management. Herein we provide a comprehensive review of the management of stone disease in pregnancy and outline a treatment algorithm.

Limitations of extracorporeal shock wave lithotripsy

Purpose of review Extracorporeal shock wave lithotripsy (ESWL) is the preferred modality for the treatment of renal and upper ureteric calculi. The present review focuses on the limitations of ESWL, where recent developments have tried to identify patients who are unlikely to succeed with ESWL and where improvements in shock wave delivery may increase successful stone fragmentation. Recent findings Evaluation of patients prior to ESWL is especially important, and the use of imaging in the decision process, with the use of computed tomography attenuation values and skin-to-stone distance, can help improve our ability to identify suitable patients for shock wave treatment. Continued research into the methods of shock wave delivery techniques and lithotripter designs will help achieve better stone fragmentation rates with reduced side effects. Summary The importance of traditional factors in predicting ESWL success, such as stone size, location, composition and renal anatomy, are well known. More recently, authors have created nomograms to predict stone-free outcome after ESWL. Others have used the information obtained from computed tomography to predict stone comminution. In addition, modifications in shock wave delivery by altering shock rate and voltage have been researched in an effort to improve shock wave efficacy.

The British Association of Urological Surgeons: guidelines for training in laparoscopy

To report the guidelines of the British Association of Urological Surgeons (BAUS), commissioned by the National Institute for Health and Clinical Excellence (NICE) in response to safety concerns about the rapid uptake of new, complex laparoscopic procedures.

Challenge of percutaneous nephrolithotomy in patients with spinal neuropathy

Objective:  To assess the technical difficulties, associated complications and stone clearance rates in patients with spinal neuropathy undergoing percutaneous nephrolithotomy.