Keith Parsons

Protein Kinase C Isoenzyme Patterns Characteristically Modulated in Early Prostate Cancer

Expression of protein kinase C (PKC) isoenzymes -alpha, -beta, -delta, -epsilon, -gamma, -iota, -lambda, -mu, -theta, and -zeta, and of their common receptor for activated C-kinase (RACK)-1, was determined immunohistochemically using specific antibodies in formalin-fixed and paraffin-embedded specimens of early prostatic adenocarcinomas (n = 23) obtained at radical prostatectomy. Expression of each isoenzyme by malignant tissues was compared with nonneoplastic prostate tissues removed at radical cystectomy (n = 10). The most significant findings were decreased PKC-beta expression in early neoplasia when compared to benign epithelium (P < 0.0001), together with a reciprocal increase in expression of PKC-epsilon (P < 0.0001). Detectable levels of PKC-alpha and PKC-zeta were also significantly increased in the cancers (P = 0.045 and P = 0.015 respectively) but did not correlate with either PKC-beta or PKC-epsilon for individual cases. Alterations in the levels of the four PKC isoenzymes occurred specifically and consistently during the genesis and progression of human prostate cancer. PKC-delta, -gamma, and -theta were not expressed in the epithelium of either the benign prostates or the cancers. Levels of expression for PKC-A, -iota, -mu, and RACK-1 were not significantly different between the benign and malignant groups. Although changes in PKC isoenzyme expression may assist in explaining an altered balance between proliferation and apoptosis, it is likely that changes in activity or concentrations of these isoenzymes exert important modulating influences on particular pathways regulating cellular homeostasis. The findings of this study raise an exciting possibility of novel therapeutic intervention to regulate homeostatic mechanisms controlling proliferation and/or apoptosis, including expression of the p170 drug-resistance glycoprotein, intracellular Ca2+ concentrations, and enhanced cellular mobility resulting in the metastatic dissemination of human prostate cancer cells. Attenuation of PKC-beta expression is currently being assessed as a reliable objective adjunct to morphological appearance for the diagnosis of early progressive neoplasia in human prostatic tissues.

GRADING OF BENIGN PROSTATIC OBSTRUCTION CAN PREDICT THE OUTCOME OF TRANSURETHRAL PROSTATECTOMY

PURPOSE We investigate whether urodynamic grading of benign prostatic obstruction and detrusor contractility predicts the outcome of transurethral prostatectomy. MATERIALS AND METHODS A total of 53 patients who were suitable candidates for transurethral prostatectomy completed an assessment protocol before and 3 months after surgery, which included International Prostate Symptom Score, uroflowmetry, ultrasonography (prostatic size and residual urine volume) and standard pressure flow study. The results of the pressure flow study were analyzed to grade obstruction (unequivocal, equivocal or no obstruction) and detrusor contractility (weak or normal) using our simplified pressure flow nomogram. RESULTS Analysis of the pressure flow study data demonstrated that the efficiency of detrusor contraction was weak in 6 of 27 men with unequivocal, 11 of 23 with equivocal and 2 of 3 with no obstruction. Treatment outcome was significantly better in patients with unequivocal obstruction and normal detrusor contractility. Treatment failure occurred in 80% of patients with equivocal obstruction and impaired detrusor contractility, and 100% of the unobstructed group. Urodynamic grading of obstruction and detrusor contractility predicted treatment outcome with a sensitivity of 87%, specificity 93% and positive predictive value 95%. CONCLUSIONS Urodynamic grading of benign prostatic obstruction and detrusor contractility can reliably predict treatment outcome and, therefore, enable the urologist to identify a subgroup of patients who would not benefit from surgery.

p53 and MDM2 in Renal Cell Carcinoma: Biomarkers for Disease Progression and Future Therapeutic Targets?

Renal cell carcinoma (RCC) is the most common type of kidney cancer and follows an unpredictable disease course. To improve prognostication, a better understanding of critical genes associated with disease progression is required. The objective of this review was to focus attention on 2 such genes, p53 and murine double minute 2 (MDM2), and to provide a comprehensive summary and critical analysis of the literature regarding these genes in RCC. Information was compiled by searching the PubMed database for articles that were published or e‐published up to April 1, 2009. Search terms included renal cancer, renal cell carcinoma, p53, and MDM2. Full articles and any supplementary data were examined; and, when appropriate, references were checked for additional material. All studies that described assessment of p53 and/or MDM2 in renal cancer were included. The authors concluded that increased p53 expression, but not p53 mutation, is associated with reduced overall survival/more rapid disease progression in RCC. There also was evidence that MDM2 up‐regulation is associated with decreased disease‐specific survival. Two features of RCC stood out as unusual and will require further investigation. First, increased p53 expression is tightly linked with increased MDM2 expression; and, second, patients who have tumors that display increased p53 and MDM2 expression may have the poorest overall survival. Because there was no evidence to support the conclusion that p53 mutation is associated with poorer survival, it seemed clear that increased p53 expression in RCC occurs independent of mutation. Further investigation of the mechanisms leading to increased p53/MDM2 expression in RCC may lead to improved prognostication and to the identification of novel therapeutic interventions. Cancer 2010.

A Novel Transurethral Microwave Thermal Ablation System to Treat Benign Prostatic Hyperplasia: Results of a Prospective Multicenter Clinical Trial

PURPOSE We evaluated the efficacy, safety and impact on quality of life of a newly designed microwave thermal ablation system in patients with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS Microwave thermal ablation was administered to 154 BPH patients at 3 centers in Canada and the United Kingdom during a single 1 to 2-hour office or clinic procedure without general or regional anesthesia and without need for potent medications necessitating intensive patient monitoring. Various measures of symptoms, voiding function and patient quality of life were assessed at baseline, 6 weeks, and-3, 6, 9 and 12 months after treatment. RESULTS Mean American Urological Association symptom score 12 months after treatment (8.8, 95% confidence interval 7.7 to 10.0) was significantly lower (p < 0.05) by 56% than that at baseline (20.1, 95% confidence interval 19.1 to 21.0). The incidence of mild symptoms increased from 0 to 57%, while that of severe symptoms decreased from 49 to 8%. There was a significant increase (p < 0.05) in peak flow rate of 45% from 9.3 ml. per second (95% confidence interval 8.8 to 9.7) at baseline to 13.4 ml. per second (95% confidence interval 12.5 to 14.4) at 12 months. Similar symptomatic and urodynamic improvements occurred in all prostate volume categories. Convalescence was rapid after treatment with little or no need for home bed rest or restriction of usual activities. Patients expressed a high level of satisfaction with treatment and found the prostate symptoms to be significantly more tolerable. Adverse events were infrequent, transient and readily managed. CONCLUSIONS Microwave thermal ablation proved to be safe and effective for treatment of BPH with a significant positive impact on patient quality of life.

p53 regulation and function in renal cell carcinoma.

Loss of p53 function is a critical event in tumor evolution. This occurs through a range of molecular events, typically a missense p53 mutation followed by loss of heterozygosity. In many cancers, there is compelling evidence that cells that can compromise p53 function have a selective advantage. The situation in renal cell carcinoma is unclear. It has recently been suggested that p53 function is unusually compromised in renal carcinoma cells by a novel dominant, MDM2/p14ARF-independent mechanism. This is hard to reconcile with other recent studies that have identified p53 as an important prognostic indicator. Indeed, one of these latter studies found that the best predictor of poor outcome was the presence of high levels of both p53 (usually indicative of p53 mutation) and MDM2. Thus, it is important that we gain a clearer understanding of the regulation of p53 and the role of MDM2 in renal cell cancer. To address this, we have investigated the transcriptional activity of p53 in a panel of renal cell carcinoma cell lines and the contribution of MDM2 and p14ARF to p53 regulation. We have found that p53 is functional in p53 wild-type renal cell carcinoma cells and that this activity is significantly regulated by MDM2 and to a much lesser extent by p14ARF. Moreover, following induction of DNA damage with UV, the p53 response in these cells is intact. Thus, future studies of renal cell carcinoma that focus on p53 and MDM2 and their role in determining disease outcome will be required to create a better understanding of this notoriously difficult to manage disease.

Combined p53 and MDM2 biomarker analysis shows a unique pattern of expression associated with poor prognosis in patients with renal cell carcinoma undergoing radical nephrectomy.

Whats known on the subject? and What does the study add?

Quantification of Voiding Dysfunction in Patients Awaiting Transurethral Prostatectomy

PURPOSE We investigated the role of advanced urodynamic analysis in the diagnostic evaluation for transurethral resection of the prostate. MATERIALS AND METHODS A total of 62 consecutive patients awaiting transurethral resection of the prostate with the American Urological Association symptom score of more than 12, peak flow rate less than 13 ml. per second and significant residual urine underwent routine video pressureflow studies with advanced urodynamic analysis to quantify outflow function. Postoperative outcome was assessed at 3 months by symptom scores, uroflowmetry and ultrasonography (residual urine). RESULTS The parameters used in the diagnostic evaluation for transurethral resection of the prostate did not correlate with urodynamic diagnosis of unequivocal obstruction. Weak detrusor contractility (without significant obstruction) accounted for voiding dysfunction in 50% of the patients. The results of transurethral resection of the prostate were significantly better in patients with unequivocal compared to equivocal obstruction. Furthermore, patients with unequivocal obstruction but weak detrusor contractility had a significantly poorer treatment outcome. CONCLUSIONS Advanced urodynamic analysis in the diagnostic evaluation of patients with symptomatic benign prostatic hyperplasia can predict treatment outcome and, therefore, allows the urologist to choose the most appropriate therapeutic option for individuals.

Cooled thermotherapy for the treatment of benign prostatic hyperplasia: durability of results obtained with the Targis System

OBJECTIVES To evaluate the durability of benefit associated with cooled high-energy thermotherapy (cooled thermotherapy) using the Targis System with data extending to 5 years after treatment. METHODS At three centers in Canada and the United Kingdom, 150 patients with benign prostatic hyperplasia underwent cooled thermotherapy with the Targis System. This was an outpatient procedure performed without general or regional anesthesia. Patients were followed up at 1 and 6 weeks, 3, 6, and 12 months, and yearly to 5 years. RESULTS Patients were evaluated at 1, 2, 3, 4, and 5 years after treatment (n = 132, 111, 90, 77, and 59, respectively). At these intervals, the American Urological Association symptom scores improved by 11.7 (57%), 12.1 (58%), 11.5 (53%), 10.1 (47%), and 10.6 (47%) points (P <0.0001 for each), the peak flow rates improved by a mean of 4.0 (57%), 4.0 (56%), 3.4 (48%), 3.3 (47%) and 2.4 (37%) mL/s (P <0.0001 for each), and quality-of-life scores improved by 2.6, 2.6, 2.5, 2.3, and 2.3 points (P <0.0001 for each). At least a 50% improvement in the American Urological Association symptom score was observed in 63% to 68% of patients available for follow-up at years 1, 2, and 3 and 50% and 51% of patients available for follow-up at years 4 and 5, respectively. Four patients required repeated microwave thermotherapy, 27 required subsequent invasive treatments, 1 permanent catheterization, 11 required alpha-blockers, and 1 antiandrogen therapy. CONCLUSIONS Cooled thermotherapy with the Targis System produces durable improvements in symptoms, quality of life, and flow rates to at least 5 years after treatment.

Silent hydronephrosis/pyonephrosis due to upper urinary tract calculi in spinal cord injury patients.

Study design: A study of four patients with spinal cord injury (SCI) in whom a diagnosis of hydronephrosis or pyonephrosis was delayed since these patients did not manifest the traditional signs and symptoms.Objectives: To learn from these cases as to what steps should be taken to prevent any delay in the diagnosis and treatment of hydronephrosis/pyonephrosis in SCI patients.Setting: Regional Spinal Injuries Centre, Southport, UK.Methods: A retrospective review of cases of hydronephrosis or pyonephrosis due to renal/ureteric calculus in SCI patients between 1994 and 1999, in whom there was a delay in diagnosis.Results: A T-5 paraplegic patient had two episodes of urinary tract infection (UTI) which were successfully treated with antibiotics. When he developed UTI again, an intravenous urography (IVU) was performed. The IVU revealed a non-visualised kidney and a renal pelvic calculus. In a T-6 paraplegic patient, the classical symptom of flank pain was absent, and the symptoms of sweating and increased spasms were attributed to a syrinx. A routine IVU showed non-visualisation of the left kidney with a stone impacted in the pelviureteric junction. In two tetraplegic patients, an obstructed kidney became infected, and there was a delay in the diagnosis of pyonephrosis. The clinicians attention was focused on a co-existent, serious, infective pathology elsewhere. The primary focus of sepsis was chest infection in one patient and a deep pressure sore in the other. The former patient succumbed to chest infection and autopsy revealed pyonephrosis with an abscess between the left kidney and left hemi-diaphragm and xanthogranulomatous inflammation of perinephric fatty tissue. In the latter patient, an abdominal X-ray did not reveal any calculus but computerised axial tomography showed the presence of renal and ureteric calculi.Conclusions: The symptoms of hydronephrosis may be bizarre and non-specific in SCI patients. The symptoms include feeling unwell, abdominal discomfort, increased spasms, and autonomic dysreflexia. Physicians should be aware of the serious import of these symptoms in SCI patients.

Xanthogranulomatous funiculitis and epididymo-orchitis in a tetraplegic patient

Study design: A case report of xanthogranulomatous funiculitis and epididymo-orchitis. Xanthogranulomatous inflammation is an uncommon, non-neoplastic process characterised by destruction of tissue, which is replaced by a striking cellular infiltrate of lipid-laden macrophages.Case Report: A 21-year male sustained complete tetraplegia at C-6 level, after a fall in 1998. The neuropathic bladder was managed with an indwelling urethral catheter. He had many unsuccessful trials of micturition. Sixteen months after the cervical injury, he noticed swelling of the left side of the scrotum following removal of a blocked catheter. He was prescribed antibacterial therapy. Four weeks later, physical examination revealed a hard and irregular swelling encompassing the testis, epididymis and spermatic cord. The clinical diagnosis was epididymo-orchitis progressing to pyocele. Through a scrotal incision, the swollen testis, epididymis and diseased segment of the spermatic cord were removed en masse. Histopathology showed extensive areas of necrosis, with xanthogranulomatous inflammation in the spermatic cord and to a lesser extent in the testis/epididymis.Conclusion: Repeated episodes of high-pressure urinary reflux along the vas deferens during dyssynergic voiding, and subsequent interstitial extravasation of urine together with chronic, low-grade, suppurative infection possibly led to development of xanthogranulomatous inflammation in the testis and the epididymis. Since tissue destruction is a feature of xanthogranulomatous inflammation, the definite and curative treatment is either complete (or, where applicable, partial) excision of the affected organ in most of the cases.