A multi-centre prospective development study evaluating focal therapy using high intensity focused ultrasound for localised prostate cancer: The INDEX study.

INTRODUCTION: Focal therapy offers the possibility of cancer control, without the side effect profile of radical therapies. Early single centre prospective development studies using high intensity focused ultrasound (HIFU) have demonstrated encouraging genitourinary functional preservation and short-term cancer control. Large multi-centre trials are required to evaluate medium-term cancer control and reproduce functional recovery. We describe the study design of an investigator-led UK multi-centre, single arm trial using HIFU to deliver focal therapy for men with localised prostate cancer. METHODS: One-hundred and forty men with histologically proven localised low or intermediate risk prostate cancer (PSA < 15, Gleason ≤ 7, ≤ T2cN0M0) will undergo precise characterisation of the prostate using a combination of multi-parametric (mp)MRI and transperineal template prostate mapping (TPM) biopsies. Unilateral dominant tumours, the so-called index lesion, will be eligible for treatment provided the contra-lateral side is free of 'clinically significant' disease (as defined by Gleason ≥ 7 or maximum cancer core length ≥4 mm). Patients will receive focal therapy using HIFU (Sonablate 500®). Treatment effect will be assessed by targeted biopsies of the treated area and TPM biopsies at 36-months. RESULTS: Primary outcome is the absence of clinically significant disease based on 36-month post-treatment TPM biopsies. Secondary outcomes address a) genitourinary function using validated patient questionnaires (IPSS, IPSS-QoL, IIEF-15, EPIC-Urinary, EPIC-Bowel, FACT-P, EQ-5D), b) the predictive validity of imaging, and c) risk factors for treatment failure. CONCLUSIONS: INDEX will be the first multi-centre, medium term follow-up trial to evaluate the outcomes of a tissue preserving strategy for men with localised prostate cancer using the TPM-ablate-TPM strategy.

Robotic prostatectomy: the first UK experience.

BACKGROUND: We describe a teamwork approach to setting up the UK's first clinical programme for robotically assisted laparoscopic radical prostatectomy. METHODS: On 22 November 2004 the Imperial Robotic Urological Surgery Group performed their first robotically assisted prostatectomy. Robotically assisted prostatectomy lends itself to division into eight definable stages. A team of four consultant urological surgeons utilized a structured rotating system, using these stages, for time at the console and tableside assisting. Fluidity of surgery was maintained by a surgeon acting as the tableside assistant for the stage prior to moving to the console. Data was collected prospectively for the first 50 cases and parameters associated with the learning curve compared to other reported series. RESULTS: Median operative time of 369.5 mins, median blood loss of 700 ml, with 12% of patients requiring a blood transfusion. Four patients required conversion to an open procedure; one resulting from equipment failure and three due to failure of progression. Four patients had an anastomotic leak with resulting ileus and two patients sustained rectal injuries, which were repaired intraoperatively using the robot. Median hospital stay was 4 days with a 22% positive surgical margin rate. CONCLUSION: Parameters indicative of the learning curve are comparable to existing published initial series of other robotic centres. The use of teamwork has enabled us to provide safe and time-efficient training for four surgeons simultaneously. The structured approach used in this setting demonstrates that urological surgeons of varying laparoscopic experience can acquire the skills necessary to competently perform laparoscopic radical prostatectomy.

PSA recurrence following radical prostatectomy is comparable for all age groups in the UK.

UNLABELLED: Increasing numbers of men are being diagnosed with prostate cancer and undergo operative curative treatment. It has been suggested that outcome after radical prostatectomy (RP) may vary for different age groups. OBJECTIVE: To investigate whether PSA recurrence-free survival after RP is related to age at operation for a cohort of English men. METHODS: A total of 854 patients notes from four Urology units were audited for preoperative staging parameters and follow-up data obtained. The relationship of PSA, age, biopsy Gleason grade, clinical stage, era and institution on PSA recurrence-free survival was competitively assessed with a multivariate model. RESULTS: Only preoperative PSA (P<0.0001) and biopsy Gleason grade (P < 0.0001) were found to be strongly associated with PSA recurrence-free survival on multivariate analysis. PSA recurrence-free survival probabilities at 5 y for patients aged 45-55 y, 55.1-60 y, 60.1-65 y, 65.1-70 y and 70.1-75 y were 0.59 (CI 0.47-0.71), 0.74 (CI 0.64-0.784), 0.56 (CI 0.44-0.68), 0.61 (CI 0.53-0.69) and 0.60 (CI 0.46-0.74), respectively. No significant difference of PSA recurrence-free survival between any of the age groups was found (Log-rank, P = 0.8567). CONCLUSION: No significant difference of pathological variables or biochemical recurrence across the age groups was found. The widely held belief of poorer outcome in younger men selected for RP does not seem to be borne out by this study.

Bicalutamide vs cyproterone acetate in preventing flare with LHRH analogue therapy for prostate cancer--a pilot study.

OBJECTIVE: To evaluate the efficacy of bicalutamide vs cyproterone acetate in preventing PSA flare (as a surrogate for tumour flare) for patients requiring luteinizing hormone-releasing hormone (LHRH) analogue therapy for prostate cancer. PATIENTS AND METHODS: In this pilot study, 40 men were randomized 1 : 1 to bicalutamide 50 mg o.d. or cyproterone acetate 100 mg t.i.d. 5 days prior to goserelin acetate and continued for 21 days thereafter. PSA, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone were obtained before treatment and on days 6, 8, 10, 16, 21 and 28. Primary end point was PSA. Hormone profile and clinical features including urinary symptoms and bone pain were secondary end points. RESULTS: Both groups were equally matched apart from serum creatinine and ALP. The speed and magnitude of the percentage change in median PSA from baseline was increased for the CPA group but there was no statistically significant difference in the two groups. Although those receiving bicalutamide all showed a testosterone peak, this remained within the normal range. No difference in the frequency of drug-specific adverse events was found. None of the patients died or developed cord compression during the study period. CONCLUSION: Bicalutamide is able to suppress the initial PSA surge as effectively as cyproterone acetate albeit slightly delayed. A statement whether bicalutamide is equally good at preventing clinical flare cannot be made and should be assessed in an appropriately powered study.

Contemporary update of cancer control after radical prostatectomy in the UK.

Despite a significant increase of the number of radical prostatectomies (RPs) to treat organ-confined prostate cancer, there is very limited documentation of its oncological outcome in the UK. Pathological stage distribution and changes of outcome have not been audited on a consistent basis. We present the results of a multicentre review of postoperative predictive variables and prostatic-specific antigen (PSA) recurrence after RP for clinically organ-confined disease. In all, 854 patient's notes were audited for staging parameters and follow-up data obtained. Patients with neoadjuvant and adjuvant treatment as well as patients with incomplete data and follow-up were excluded. Median follow-up was 52 months for the remaining 705 patients. The median PSA was 10 ng ml(-1). A large migration towards lower PSA and stage was seen. This translated into improved PSA survival rates. Overall Kaplan-Meier PSA recurrence-free survival probability at 1, 3, 5 and 8 years was 0.83, 0.69, 0.60 and 0.48, respectively. The 5-year PSA recurrence-free survival probability for PSA ranges <4, 4.1-10, 10.1-20 and >20 ng ml(-1) was 0.82, 0.73, 0.59 and 0.20, respectively (log rank, P<0.0001). PSA recurrence-free survival probabilities for pathological Gleason grade 2-4, 5 and 6, 7 and 8-10 at 5 years were 0.84, 0.66, 0.55 and 0.21, respectively (log rank, P<0.0001). Similarly, 5-year PSA recurrence-free survival probabilities for pathological stages T2a, T2b, T3a, T3b and T4 were 0.82, 0.78, 0.48, 0.23 and 0.12, respectively (log rank, P=0.0012). Oncological outcome after RP has improved over time in the UK. PSA recurrence-free survival estimates are less optimistic compared to quoted survival figures in the literature. Survival figures based on pathological stage and Gleason grade may serve to counsel patients postoperatively and to stratify patients better for adjuvant treatment.

Case selection for radical prostatectomy in the UK.

INTRODUCTION: Radical prostatectomy is an increasingly popular treatment option for clinically localised prostate cancer, yet PSA outcome figures are rare in the UK. This makes it difficult to establish appropriate criteria for case selection. We conducted an audit of PSA recurrence of 5 large centres in the south of England and investigated the use of pre-operative PSA to improve case selection and outcome. METHOD: 854 patients notes were audited for pre-operative staging parameters and follow-up data obtained. Patients with neoadjuvant and adjuvant treatment as well as patients with incomplete data and follow-up were excluded. RESULT: Median follow-up was 52 months for the remaining 663 patients. Median PSA was 10 ng/ml. A large improvement of PSA recurrence free survival rates was observed from 1988 to 1998 as a result of change in case selection and stage migration. Overall Kaplan-Meier PSA recurrence free survival probability at 1, 3, 5 and 8 years was 0.83, 0.69, 0.60 and 0.48, respectively. Five-year PSA recurrence free survival probability for PSA ranges <4 ng/ml, 4.1-10 ng/ml, 10.1-20 ng/ml and >20 ng/ml was 0.82, 0.73, 0.59 and 0.20, respectively (Wilcoxon, p < 0.0001). A simulation of biochemical recurrence free survival for patient cohorts with stepwise reduced inclusion PSAs suggests an improved outcome for patients with a pre-operative inclusion PSA of <12 ng/ml. Further reduction of the inclusion PSA does not improve outcome. CONCLUSION: Intermediate PSA recurrence free survival has improved over time in England. PSA recurrence free survival estimates are less optimistic compared to frequently quoted American figures. A reduced pre-operative PSA cut-off for case selection may be used to improve outcome.

Learning curve and stage migration of a radical retropubic prostatectomy series over a 10-y period.

OBJECTIVE: To show the impact of learning curve and patient selection on complication rate and biochemical recurrence-free survival of a UK radical prostatectomy series for localised prostate cancer and to model the influence of common preoperative variables on biochemical recurrence after controlling for learning curve. PATIENTS AND METHODS: From 1989 to 1999, 280 of 350 patients who underwent anatomical radical retropubic prostatectomy (RRP) at our institution had complete records and follow-up of at least 1 y. After exclusions of preoperative staging, factors reflecting the learning curve, early complications and prostate-specific antigen (PSA) outcome were recorded on 217 patients. Procedures before 1995 were compared with procedures after 1995. RESULTS: Comparison of the two groups showed a significant decrease in operating time (mean 152 vs 130 min), blood loss (mean 1500 vs 1000 ml), transfusion rate (83 vs 42%) and hospital stay (mean 7 vs 6 days). Median preoperative PSA changed significantly from 13.2 to 11.5 ng/ml. Only 17% were diagnosed by rectal examination compared to 27% in the early years. The number of clinical T1 tumours increased from 33 to 47%. This did lead to an increase of organ-confined tumours on pathological staging by 25%. Biochemical recurrence-free survival improved significantly after 1995. After controlling for the learning curve PSA and clinical stage were significant predictors of PSA recurrence. CONCLUSION: Time trends of case selection, stage migration and a steep learning curve are shown over a 10-y period. Factors associated with the learning curve as well as case selection have a significant impact on outcome. There may be other as yet not specified factors over time, which have a significant impact on PSA recurrence-free survival. Patients with a PSA of 20 ng/ml and above have a poor outcome and do not appear to be suitable candidates for RRP.

Time trends in case selection, stage and prostate-specific antigen recurrence after radical prostatectomy: a multicentre audit.

OBJECTIVES: To report an audit of preoperative staging variables, case selection, stage migration and prostate-specific antigen (PSA) recurrence at five large centres in the south of England. To establish PSA outcome values after radical prostatectomy for clinically localized prostate cancer in the UK, and enable appropriate patient counselling. PATIENTS AND METHODS: The notes of 854 patients were audited for preoperative staging variables and follow-up data obtained. Patients with neoadjuvant and adjuvant treatment, and with incomplete data and follow-up, were excluded. RESULTS: The median follow-up was 52 months for the remaining 663 patients; the median PSA level was 10 ng/mL. There was a large migration towards lower PSA and stage; this translated into improved PSA survival rates. The overall Kaplan-Meier PSA recurrence-free survival probability at 1, 3, 5 and 8 years was 0.83, 0.69, 0.60 and 0.48, respectively. The 5-year PSA recurrence-free survival probabilities for PSA levels of < 4, 4.1-10, 10.1-20 and > 20 ng/mL were 0.82, 0.73, 0.59 and 0.20, respectively (Wilcoxon, P < 0.001). The PSA recurrence-free survival probabilities for biopsy Gleason grade 2-4, 5 and 6, 7 and 8-10 at 5 years were 0.70, 0.61, 0.55 and 0.21, respectively (Wilcoxon, P < 0.001). Similarly, the 5-year PSA recurrence-free survival probabilities for clinical stages T1a and 1b, T1c, T2a and T2b were 0.79, 0.62, 0.57 and 0.44, respectively (Wilcoxon, P = 0.0012). CONCLUSION: With better case selection the intermediate oncological outcome has improved over time in the UK. PSA recurrence-free survival estimates are less optimistic than the frequently quoted American values. The present values may be used to help in counselling British patients before radical prostatectomy.

Prediction of prostate cancer in extended-field biopsies of the prostate.

OBJECTIVES: To assess the prediction of prostate cancer using extended-field prostatic biopsies (8-11 cores), as such biopsy protocols are recommended to increase the detection of prostate cancer, and as fewer cancers are missed this should improve the prediction of biopsy outcome from the patients' history, transrectal ultrasonography (TRUS) and serum markers. PATIENTS AND METHODS: In all, 260 patients were prospectively evaluated and 206 with a total prostate-specific antigen (PSA) level of < 20 ng/mL were included. All patients were evaluated for age, family history, lower urinary tract symptoms (LUTS), medication for LUTS, previous prostate biopsy, the presence of cysts, a digital rectal examination, calcifications or hypoechoic lesions on TRUS, total and transitional zone volume, total PSA (tPSA), PSA density (tPSAD), total PSA transition zone density (tPSATZD), complexed PSA (cPSA), cPSA density (cPSAD), cPSA transitional zone density (cPSATZD), free/total (f/t)PSA ratio and free/complexed PSA ratio (f/cPSA). Logistic regression was used to predict the outcome; 80% of the patients were used to generate the models and 20% to test the prediction. RESULTS: Two models were constructed; the most accurate contained family history, cPSA, cPSAD, cPSATZD, f/cPSA, PSAD and tPSATZD (sensitivity 91%, specificity 70%). A workable and concise model contained tPSATZD, cPSATZD and f/cPSA, and had a sensitivity of 93% and a specificity of 60%. The best single predictor was tPSATZD with a sensitivity of 92% and a specificity of 55%. Using regression models can produce considerable gains in specificity. This would allow unnecessary prostate biopsies to be avoided for a third of patients compared with tPSA alone. CONCLUSIONS: The present analysis for PSA indices appeared to be slightly more accurate than those in previously published studies. Most of this improvement in diagnostic accuracy was ascribed to the use of an extended-field biopsy protocol. Prostate cancer in a first-degree relative was the only variable that contributed significantly to the regression model. tPSATZD was the best volume-adjusted PSA index. The f/tPSA appeared to be the best test with no volume adjustment, followed by f/cPSA and cPSA. Although the models are cumbersome and expensive for use in general urological practice they could be used to optimize biopsy strategies on the basis of predicted cancer probabilities in screening studies. The cost of the models may compare favourably with tPSA because of the high specificity that can be achieved.

p53 and bcl-2 immunohistochemistry in preoperative biopsies as predictors of biochemical recurrence after radical prostatectomy.

OBJECTIVE: To evaluate p53 and bcl-2 immunohistochemistry in preoperative biopsies and radical prostatectomy specimens, as predictors of biochemical recurrence. PATIENTS AND METHODS: Preoperative biopsies from 73 men, and the radical prostatectomies from these men and from a further 47 men, were evaluated. The serum prostate specific antigen (PSA) level, Gleason score, pathological stage and margin involvement were recorded. The immunohistochemical expression of p53 and bcl-2 was studied on a representative area of tumour with the highest Gleason grade. The median follow-up was 53 months. RESULTS: During the follow-up 47 of the 120 patients had a biochemical recurrence. Capsular penetration was present in 63 (53%) and the surgical margins were positive in 47 (39%). The Gleason score was < 7 in 81 (68%) patients; p53 was positive in 40 (66%) of 61 biopsies and 84 (71%) of 118 prostatectomy specimens. Bcl-2 was positive in eight (13%) of 63 biopsies and 20 (17%) of 118 prostatectomies. On multivariate analysis the biopsy p53, Gleason score and serum PSA were significant predictors of recurrence. On multivariate analysis, capsular penetration, PSA and margin status at prostatectomy were significant predictors of recurrence. There was also a significant interaction between PSA and margin status. Although univariately significant, neither p53 nor bcl-2 featured in the final multivariate model. CONCLUSION: Biopsy p53 status significantly predicts recurrence after radical prostatectomy, but its low specificity and technical issues suggest that it will not be useful in the clinical setting. However, a patient with negative p53 on biopsy is likely to have a good prognosis on prolonged follow-up.

Her-2/neu oncogene amplification in clinically localised prostate cancer.

AIM: To examine the incidence of Her-2/neu oncogene amplification in clinically localised prostate cancer using in situ hybridisation. METHODS: One hundred and seventeen patients, who had undergone radical prostatectomy, were identified and in situ hybridisation was performed on formalin fixed, paraffin wax embedded tissue using the Quantum Appligene probe for Her-2/neu. The enzyme peroxidase was used to detect the probe because this enabled a permanent record to be kept. Tumours in which there were five or more signals in each nucleus in > 20% of the tumour cells were considered to have a significantly increased copy number. A serial section from these tumours was then hybridised with the chromosome 17 alpha satellite probe. The ratio of the percentage of cells showing an increase in Her-2/neu copy number to the number showing polysomy for chromosome 17 was calculated. A ratio above 2 was considered amplified. RESULTS: Biochemical recurrence occurred in 50 (43%) patients and 24 (21%) had clinical recurrence. In situ hybridisation for Her-2/neu was accessible in 114 (97%) patients. A significant increase in copy number was present in two patients (1.75 %), but chromosome 17 hybridisation showed that the increase was the result of polysomy rather than true amplification. Both these patients had a Gleason score of 7 and stage T3; they also had recurrent clinical disease with distal metastasis within two and 19 months. CONCLUSIONS: Increased Her-2/neu oncogene copy number appears to be rare in clinically localised prostatic adenocarcinoma and is related to chromosome 17 polysomy rather than true amplification. As a result, it would not be a useful biomarker for identifying those patients who will have recurrences after radical prostatectomy.

Washin and washout of isoflurane during cardiopulmonary bypass.

To help decide when an inhalational agent should be discontinued during cardiopulmonary bypass (CPB), its rate of washin and washout must be known. Isoflurane one per cent was administered to 14 patients undergoing CPB and isoflurane blood concentrations were measured to determine the time course of washin and washout of this agent. Bubble oxygenators were used for seven patients and membrane oxygenators for the remaining seven. During the administration of isoflurane, isoflurane blood concentrations rose slowly and did not reach a steady state during the time available for washin. Isoflurane blood concentrations decreased by at least 50 per cent within two minutes of turning off the vaporizer, and by 15 minutes the concentration had dropped by 75 per cent. There was a tendency for more rapid elimination of isoflurane in patients undergoing rewarming during this period. There did not appear to be an important difference between bubble and membrane oxygenators in the rate of washin and washout of isoflurane. Within 15 minutes of turning off the vaporizer only 25 per cent of the original blood concentration of isoflurane will remain. The anaesthetist must decide what concentration of isoflurane is acceptable during separation from CPB. Knowledge of the time course of isoflurane washout will allow more accurate determination of when to discontinue its administration in order to reach an acceptable concentration by the time separation from CPB occurs.

Soluble spiroperidol binding factors from bovine caudate nucleus.

Several properties of soluble spiroperidol binding factors separated from bovine caudate nucleus have been investigated by a previously unreported procedure. Data consistent with high particle weight and rapid binding equilibration are reported for high-affinity (+)butaclamol-sensitive components of a digitonin extract. A slower sedimenting component is found that also exhibits high affinity for spiroperidol but is not sensitive to (+)butaclamol. Centrifugation of a caudate nucleus homogenate yields a supernatant that appears to contain a component that exhibits spiroperidol binding that is more sensitive to displacement by (-) than by (+)butaclamol. The procedure used effects rapid separation of bound from unbound tritiated ligand on short columns of Sephadex G-15 followed by extrusion and sectioning of the Sephadex. The radioactivity remaining with each section is determined. The procedure is very rapid; the addition of active phases or the changing of the ionic environment, which may disturb the equilibrium, is avoided; and recovery of the protein free of bound ligand is easily affected.

Spiroperidol binding in the human caudate nucleus.

The displacement of spiroperidol binding by the optical isomers of butaclamol in synaptosomal preparations of the caudate nucleus obtained from parkinsonians and non-parkinsonians at post mortem were investigated. A group of spiroperidol binding sites found in the non-parkinsonians was less strongly expressed or absent in analogous tissue of the parkinsonian. The significance of these findings in relation to Parkinson's disease and its treatment are discussed.

Some notes on fluorescence intensity.

The fluorescent emission spectra for 5 x 10(-6) M p-aminohippuric and p-aminobenzoic acids in mixtures of methyl alcohol and 1,2-propanediol have been determined. The results indicate that at almost invariant dielectric constant the quantum yield of fluorescence is a function of the viscosity of the solvent. The suggestion is made that a collisional quenching mechanism, which involves the rotational diffusion of solvent molecules, is significant in solutions of low viscosity and less so at high viscosities. A prediction, on the basis of the proposed mechanism, of augmentation of the emission spectra of p-aminohippuric acid, after binding to homologous antihapten antibody, is confirmed. A small red shift is also noted at higher viscosities in protein-free solutions or after binding to homologous antibody. It is suggested that, contrary to some interpretations in the literature, a red shift and/or an augmentation of quantum yield of fluorescence may, in specific instances, not be significant of a transfer of the fluorochrome to an environment of lower dielectric constant.