Comparative Effectiveness Analyses of Salvage Prostatectomy and Salvage Radiotherapy Outcomes Following Focal or Whole-Gland Ablative Therapy (High-Intensity Focused Ultrasound, Cryotherapy or Electroporation) for Localised Prostate Cancer.

AIMS: Ablative therapy, such as focal therapy, cryotherapy or electroporation, aims to treat clinically significant prostate cancer with reduced treatment-related toxicity. Up to a third of patients may require further local salvage treatment after ablative therapy failure. Limited descriptive, but no comparative, evidence exists between different salvage treatment outcomes. The aim of this study was to compare oncological and functional outcomes after salvage robot-assisted radical prostatectomy (SRARP) and salvage radiotherapy (SRT). MATERIALS AND METHODS: Data were collected prospectively and retrospectively on 100 consecutive SRARP cases and 100 consecutive SRT cases after ablative therapy failure in a high-volume tertiary centre. RESULTS: High-risk patients were over-represented in the SRARP group (66.0%) compared with the SRT group (48.0%) (P = 0.013). The median (interquartile range) follow-up after SRARP was 16.5 (10.0-30.0) months and 37.0 (18.5-64.0) months after SRT. SRT appeared to confer greater biochemical recurrence-free survival at 1, 2 and 3 years compared with SRARP in high-risk patients (year 3: 86.3% versus 66.0%), but biochemical recurrence-free survival was similar for intermediate-risk patients (year 3: 90.0% versus 75.6%). There was no statistical difference in pad-free continence at 12 and 24 months between SRARP (77.2 and 84.7%) and SRT (75.0 and 74.0%) (P = 0.724, 0.114). Erectile function was more likely to be preserved in men who underwent SRT. After SRT, cumulative bowel and urinary Radiation Therapy Oncology Group toxicity grade I were 25.0 and 45.0%, grade II were 11.0 and 11.0% and grade III or IV complications were 4.0 and 5.0%, respectively. CONCLUSION: We report the first comparative analyses of salvage prostatectomy and radiotherapy following ablative therapy. Men with high-risk disease appear to have superior oncological outcomes after SRT; however, treatment allocation does not appear to influence oncological outcomes for men with intermediate-risk disease. Treatment allocation was associated with a different spectrum of toxicity profile. Our data may inform shared decision-making when considering salvage treatment following focal or whole-gland ablative therapy.

Techniques and Outcomes of Salvage Robot-Assisted Radical Prostatectomy (sRARP).

BACKGROUND: Salvage Robot-Assisted Radical Prostatectomy (sRARP) has been described as feasible treatment for the management of localised prostate cancer (PCa) recurrence after primary treatment. However, no large reports have published cancer and quality outcomes. OBJECTIVE: To report perioperative, functional and oncologic outcomes of sRARP in patients with localised PCa recurrence. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively evaluated 106 patients with local recurrence eligible for sRARP. SURGICAL PROCEDURE: Surgery was performed using the DaVinci Si system similar to the standard approach but with adaptation to the primary treatment. MEASUREMENTS: Peri-operative outcomes included 90-day complication rate. Functional outcomes included rates of incontinence and erectile dysfunction. Oncological outcomes included tumour staging, margin rate and recurrence. RESULTS AND LIMITATIONS: Primary treatment was High Intensity Focused Ultrasound (HIFU) in 59 (56%) patients, 27 (25%) radiotherapy, 10 (9%) seed brachytherapy, 8 (8%) solitary androgen deprivation therapy (ADT), one (1%) cryotherapy and one (1%) electroporation / Nanoknife. Median follow-up was 2.1 years. 90-day complication rate was 8%. At two years or more, 50% were fully continent and 33% were socially continent. Continence rates tended to be better after focal compared to whole-gland treatments. Erectile dysfunction was present in 95%. Positive surgical margin rate was 39%. Biochemical recurrence occurred in 13% and local or metastatic recurrence in 11%. CONCLUSIONS: sRARP is technically more challenging but is a feasible option in high-volume centres for treatment of recurrent PCa. Patients should be counselled that functional outcomes are inferior to primary RARP. Adjustment of surgical technique according to the primary treatment is key for good surgical outcomes. PATIENT SUMMARY: We report our experience with sRARP for the management of localised PCa recurrence after primary treatment. This represents a feasible approach with acceptable peri-operative complications and cancer outcomes. Functional outcomes are inferior to RARP in the primary setting.

Tips and tricks for intracorporeal robot-assisted urinary diversion.

Since 2003, Karolinska University Hospitals have performed totally intracorporeal robotic-assisted radical cystectomy (RARC) in carefully selected patients. As our technique has evolved, the proportion of patients undergoing RARC has progressively increased. Whilst open radical cystectomy remains the gold standard, several high-volume centres have now demonstrated that RARC is both feasible and safe. RARC comprises three stages: radical cystectomy, extended lymph node dissection and urinary diversion. The majority of centres in the United States currently perform RARC utilizing an extracorporeal approach for the urinary diversion stage, perceiving this to be a more accessible option with a reduced risk of complications. We assess the evidence for this perception, reviewing the literature and reporting the functional outcomes and complication rates for a totally intracorporeal RARC approach. We also describe our technique for both intracorporeal orthotopic neobladder and intracorporeal ileal conduit, identifying the potential hazard steps and the 'tips and tricks' to optimize outcomes.

Robot-assisted radical cystectomy with intracorporeal neobladder diversion: The Karolinska experience.

INTRODUCTION: The aim of this report is to describe our surgical technique of totally intracorporeal robotic assisted radical cystectomy (RARC) with neobladder formation. MATERIALS AND METHODS: Between December 2003 and March 2013, a total of 147 patients (118 male, 29 female) underwent totally intracorporeal RARC for urinary bladder cancer. We also performed a systematic search of Medline, Embase and PubMed databases using the terms RARC, robotic cystectomy, robot-assisted, totally intracorporeal RARC, intracorporeal neobladder, intracorporeal urinary diversion, oncological outcomes, functional outcomes, and complication rates. RESULTS: The mean age of our patients was 64 years (range 37-87). On surgical pathology 47% had pT1 or less disease, 27% had pT2, 16% had pT3 and 10% had pT4. The mean number of lymph nodes removed was 21 (range 0-60). 24% of patients had lymph node positive dAQ1isease. Positive surgical margins occurred in 6 cases (4%). Mean follow-up was 31 months (range 4-115 months). Two patients (1.4%) died within 90 days of their operation. Using Kaplan-Meier analysis, overall survival and cancer specific survival at 60 months was 68% and 69.6%, respectively. 80 patients (54%) received a continent diversion with totally intracorporeal neobladder formation. In the neobladder subgroup median total operating time was 420 minutes (range 265-760). Daytime continence and satisfactory sexual function or potency at 12 months ranged between 70-90% in both men and women. CONCLUSIONS: Our experience with totally intracorporeal RARC demonstrates acceptable oncological and functional outcomes that suggest this is a viable alternative to open radical cystectomy.

The impact of multiple biopsies on outcomes of nerve-sparing robotic-assisted radical prostatectomy.

Active surveillance of prostate cancer patients involves subjecting them to multiple prostate biopsies, and we sought to investigate the effects of this on functional outcomes after robotic-assisted radical prostatectomy (RARP). Between May 2009 and December 2009, 367 patients who consecutively underwent RARP by a single surgeon were divided into two groups, one that had single prostate biopsy and another multiple biopsies before RARP. The groups were matched for significant clinicopathologic preoperative variables, and only premorbidly potent low-risk cases that underwent nerve sparing were included. This left 50 and 23 patients for analysis in the single and multiple biopsy groups, respectively. The primary endpoint was potency and continence at 3 and 6 months after surgery. We found continence rates of 84% (83%) and 94% (96%) for single (multiple) biopsy groups at 3 and 6 months, respectively (P=0.88, P=0.77). Multiple biopsy patients had worse postoperative erectile function at 6 months (57% versus 80%, P=0.03). Men subject to multiple preoperative biopsies are more likely to become impotent postoperatively than those who undergo surgery after a single biopsy. This should be borne in mind when counseling men regarding repeat biopsy as part of an active surveillance strategy.

Technique of traction-free nerve-sparing robotic prostatectomy: delicate tissue handling by real-time penile oxygen monitoring.

It is postulated that intraoperative injury to the cavernosal nerves results in hemodynamic and histologic changes within the penis, which manifest clinically as ED. We hypothesize that non-neuronal cause, such as vascular insults due to intraoperative tissue handling, may also have a minor but definite role in penile ischemia and consequent postoperative sexual dysfunction. Between May 2008 and July 2008, 64 patients were enrolled in the study (group 1). Following sterilization, the Odissey Tissue Oximeter probe was placed on the shaft of the penis, 2 cm from its base. The patient underwent continuous penile tissue saturation monitoring. Surgical dissection was altered whenever the oxygen saturation alarm went off until it was restored to 85%. In addition, 192 patients, matched for age, preoperative prostate-specific antigen, clinical stage, baseline sexual function, Charlson comorbidity index and nerve-sparing status operated between October 2007 and July 2008, formed the control group (group 2). These patients did not have any intraoperative tissue oxygenation monitoring. Opening of the endopelvic fascia and steps of nerve sparing were associated with significant drops in oxygen levels, especially if done using torque. Drop in oxygen levels were also noted whenever excessive traction was applied on the Foley catheter, seminal vesicles or prostate during apical dissection. We deliberately modified our surgical steps to make surgery more traction free. A significantly higher percentage of group 1 patients with bilateral nerve sparing had no ED compared with group 2 patients at 6 weeks (24.5% vs 10.4%; P=0.014) and 52 weeks (83.7% vs 68%; P=0.029). Overall, 93.9% of patients in study group had Sexual Health Inventory for Men (SHIM) score of 17 (mild to no ED) at 1 year compared with 78.4% of patients in the control group. We demonstrated that avoidance of ischemic stress, aided by intraoperative penile oxygenation monitoring, may help surgeons improve their technique and thus functional outcomes in patients.

Learning curve for robotic assisted laparoscopic prostatectomy: a multi-institutional study of 3794 patients.

AIM: The aim of this study was to define the learning curve for positive surgical margin (PSM) rate and operative time (OT) for robotic assisted laparoscopic radical prostatectomy (RALP); while the learning curve appears shorter for surgical safety for RALP compared to other surgical modalities, this has not been well established for the above parameters. METHODS: We performed a retrospective cohort study of 3794 patients who underwent RALP between Jan 2003 and Sep 2009 by three surgeons (DL, PW, AKT) from three centers (UPenn, Karolinska, Cornell). Mean overall PSM rates and mean overall OT were calculated for all three surgeons at intervals of 50 RALPs per surgeon, and learning curves for these means were fit using a loess method. R version 2.71 was used for all statistical analysis. RESULTS: The learning curve for PSM rates for all patients demonstrated improvements continued with increasing surgeon experience, with over 1600 cases required to get a PSM rate <10%. When pT3 patients were evaluated, the learning curve started to plateau after 1000-1500 cases. Mean OT plateaued after 750 cases though with further surgical experience the OTs started to climb again. CONCLUSION: The learning curve for RALP is not as short as previously thought, and a large number of cases are needed to get PSM rates and OTs to a minimum. This suggests that RALP should be performed by high volume surgeons in order to optimize patient outcomes.

A gene expression profiling approach assessing celecoxib in a randomized controlled trial in prostate cancer.

BACKGROUND: We performed a pilot study, looking at the COX-2 inhibitor celecoxib, on newly diagnosed prostate cancer patients in the neo-adjuvant setting using DNA microarray analysis. PATIENTS AND METHODS: This was a single-blinded, randomized controlled phase II presurgical (radical prostatectomy) 28-day trial of celecoxib versus no drug in patients with localized T1-2 N0 M0 prostate cancer. cDNA microarray analysis was carried out on prostate cancer biopsies taken from freshly obtained radical prostatectomy samples. Results were confirmed by qPCR analysis of a selection of genes. RESULTS: Multiple genes were differentially expressed in response to celecoxib treatment. Statistical analysis of microarray data indicated 24 genes were up-regulated and 4 genes down-regulated as a consequence of celecoxib treatment. Gene changes e.g. survivin, SRP72kDa, were associated with promoting apoptotic cell death, enhancement of antioxidant processes and tumour suppressor function (p73 and cyclin B1 up-regulation). CONCLUSION: Celecoxib at 400 mg b.i.d. for 4 weeks perioperatively gave rise to changes in gene expression in prostate cancer tissue consistent with enhancement of apoptosis and tumour suppressor function. Given the short time interval for the duration of this study, the data are encouraging and provide a good rationale for conducting further trials of celecoxib in prostate cancer.

Evaluation of the upper urinary tract using transureteric ultrasound--a review of the technique and typical imaging appearances.

Ureteric strictures and pelviureteric junction obstruction often present a diagnostic conundrum to radiologists, particularly after the first-line investigations have failed to provide a definitive answer. Transureteric ultrasonography (TUU) is a relatively novel technique performed by the radiologist, which uses a miniature endoluminal ultrasound probe to interrogate the ureteric anatomy and peri-ureteric soft tissues. In this review, we discuss how TUU is performed, and the normal imaging appearances of the ureter and surrounding anatomical structures. We also focus on the various pathological processes that can be accurately evaluated or diagnosed using TUU including lymphadenopathy, calculi, ureteric neoplasms, ureteritis, crossing vessels and aneurysms. As TUU is not well established in UK practice as yet, we suggest possible indications for its use in the diagnostic work-up of urological patients and future applications.

The evolution of the doctor-patient relationship.

The doctor-patient relationship has undergone a transition throughout the ages. Prior to the last two decades, the relationship was predominantly between a patient seeking help and a doctor whose decisions were silently complied with by the patient. In this paternalistic model of the doctor-patient relationship, the doctor utilises his skills to choose the necessary interventions and treatments most likely to restore the patient's health or ameliorate his pain. Any information given to the patient is selected to encourage them to consent to the doctor's decisions. This description of the asymmetrical or imbalanced interaction between doctor and patient [Parsons T. The social system. Free Press, New York, 1951.](1) has been challenged during the last 20 years. Critics have proposed a more active, autonomous and thus patient-centred role for the patient who advocates greater patient control, reduced physician dominance, and more mutual participation. This patient-centred approach has been described as one where "the physician tries to enter the patient's world, to see the illness through the patient's eyes" [McWhinney I. The need for a transformed clinical method. In: Stewart M, Roter D, Communicating with medical patients. London: Sage, 1989.](2), and has become the predominant model in clinical practice today.

COX-2 inhibition: a possible role in the management of prostate cancer?

There is mounting evidence to support a role for cyclooxygenase-2 (COX-2) inhibitors (coxibs) in the management of prostate cancer. This review considers the current evidence base for the use of coxibs in prostate cancer as well as their adverse event profile. A systematic literature review using the search terms 'cyclooxygenase', 'COX-2', 'coxibs', 'cardiovascular risk', and 'prostate cancer' was performed using Medline. Celecoxib appears safer in terms of cardiovascular toxicity than other coxibs, and this may relate to its lower selectivity for the COX-2 enzyme. This lower selectivity also provides rationale for its putative broader anti-cancer effects, via non-COX-2-dependent pathways that affect cell cycle regulation, angiogenesis, and hypoxic modulation. There are also interacting relationships between COX-2, chronic inflammation, and prostate cancer. There is much promise for the coxibs as anti-cancer agents. The future might be to pharmacologically adapt these agents to exert their COX-2 independent mechanisms of action while minimizing their COX-2-dependent adverse cardiovascular effects.

COX-2 inhibitors and the heart: are all coxibs the same?

The selective COX-2 inhibitors (coxibs) were originally developed to minimise the adverse effects of conventional non-steroidal anti-inflammatory drugs (NSAIDs) while maintaining the same analgesic and anti-inflammatory properties. Many large studies confirmed the improved gastric side effect profile of coxibs compared with non-selective NSAIDs; however, reports of increased cardiovascular morbidity and mortality followed, and the manufacturer Merck was forced to withdraw rofecoxib (Vioxx) from the market. Other coxibs have also either perished or had restrictions placed on their use. However, there seem to be significant differences between coxibs regarding their cardiovascular profiles, and the evidence for a class effect is dubious. In this paper, the current body of knowledge regarding the cardiovascular toxicities of coxibs is reviewed. The take home message for prescribing NSAIDs and those coxibs still on the market seems to be one of caution rather than contraindication, except in patients with significant cardiovascular risk factors.

Gleason scoring varies among pathologists and this affects clinical risk in patients with prostate cancer.

AIMS: To investigate whether our practice of specialist review of all diagnostic biopsies was necessary to prevent misgrading of referred prostate cancer patients, and whether this misclassification, if any, would have resulted in misclassification of clinical risk grouping (Seattle Risk Grouping [SRG]) and subsequent treatment strategy and prognosis. MATERIALS AND METHODS: Important prognostic indicators for prostate cancer include the presenting prostate-specific antigen (PSA), clinical stage and Gleason sum of the tumour. These three variables are incorporated into the SRG cohorts to establish treatment strategy. Patients with prostate cancer referred for brachytherapy had their prostate biopsies reviewed by a reference pathologist (PD) with a special interest in prostate cancer. We compared the agreement between the scoring of the referring pathologists with that of PD, and evaluated if any differences changed the SRG and therefore the clinical risk and treatment strategy for the patients. RESULTS: In only 52% (43/83) of cases, was there total agreement between the two sets of pathologists. The inter-rater agreement was statistically 'fair' (unweighted kappa statistic 0.27). In 90% (36/40) of cases with disagreement, PD assigned higher Gleason sums. In 40% (16/40) of cases with disagreement, the change in Gleason sum altered the SRG; in one out of 16 cases, the SRG was downgraded from 'intermediate' to 'low' risk disease; in six out of 16 cases, it was upgraded from 'low' to 'intermediate' risk, and, in nine out of 16, from 'intermediate' to 'high' risk. CONCLUSION: Our findings confirm previous reports of only limited correlation between pathologists in reporting Gleason sums. In this study, 19% (16/83) of cases had their grading changed to a level that altered clinical risk, almost always (94%; 15/16) to one that worsened prognosis. This would have significantly affected treatment strategy for these patients, and thus we recommend that all centres ensure accurate Gleason grading by the use of pathologists with special interests in prostate cancer.

Evaluation of the mechanisms of damage to flexible ureteroscopes and suggestions for ureteroscope preservation.

AIM: To investigate the causes and costs of flexible ureteroscope damage, and to develop recommendations to limit damage. METHODS: The authors analysed repair figures and possible causes of damage to 35 instruments sent for repair to a leading UK supplier over a 1-year period, and calculated cost figures for maintenance of the instruments as opposed to repair and replacement costs. RESULTS: All damages were handling-induced and therefore did not fall under the manufacturer's warranty: 28 % were damaged by misfiring of the laser inside the instrument; 72 %, mainly crushing and stripping of the ureteroscope shaft tube, were likely to have occurred during out-of-surgery handling, washing and disinfection. Seventeen (4 %) instruments were not repaired and consequently taken out of service due to the extensive costs involved. Eighteen (51 %) ureteroscopes were repaired at an average cost of 10 833 USD. CONCLUSION: Damages to flexible ureteroscopes bear considerable costs. Most damages occur during handling between surgical procedures. Thorough adherence to handling procedures, and courses for theater staff and surgeons on handling flexible instruments may help to reduce these damages and prove a cost-saving investment. The authors provide a list of recommended procedural measures that may help to prevent such damages.

Peritoneovenous shunting is an effective treatment for intractable ascites.

AIM AND METHODS: A retrospective review was carried out of children undergoing peritoneovenous shunting for intractable ascites. RESULTS: 11 children, aged 3 months to 12 years (median 31 months) underwent peritoneovenous shunting over the past 17 years. The duration of ascites ranged from one month to 2.5 years (median two months). The primary pathology consisted of previous surgery in eight (three neuroblastoma, one renal carcinoma, one hepatoblastoma, one adrenal teratoma, one renal artery stenosis, and one diaphragmatic hernia), and cytomegalovirus hepatitis, lymphatic hypoplasia, and lymphohistiocytosis in one patient each. All patients had failed to respond to previous treatment including peritoneal drainage in six patients, diuretics in five, and parenteral nutrition in five. There were no intraoperative problems. Postoperative complications included pulmonary oedema in three patients, shunt occlusion in three, infection in two, and wound leakage in one. Ascites resolved after shunting in 10 patients. Five shunts were removed one to three years after insertion without recurrence of ascites. Three others are free of ascites with shunts in place for less than one year postoperatively. Three children died from their underlying disease: two after resolution of ascites (neuroblastoma) and one in whom the ascites failed to resolve (lymphohisticytosis). CONCLUSIONS: Peritoneovenous shunting is an effective treatment for symptomatic intractable ascites in children (10 of 11 successful cases in this series). Elective removal of the shunt after one year is recommended.

Are we good at thromboembolic disease prophylaxis - an audit of the use of risk assessment forms in emergency medical admissions.

Venous thromboembolism (VTE) is a major cause of morbidity and mortality in hospitalised patients. Thromboprophylaxis is an effective strategy for VTE prevention in high-risk patients. An initial audit in our district general hospital trust showed poor adherence to the thromboembolic risk factors consensus group recommendations and so a risk assessment form (RAF) was devised. We present repeated audits to assess the RAF uptake and its effects on VTE thromboprophylaxis. We also present data analysing perceptions among doctors of the RAF and reasons for its poor completion. We provide compelling evidence that the RAF is an invaluable tool in the assessment of VTE thromboprophylaxis.

Angiogenesis and the tumour hypoxia response in prostate cancer: a review.

The formation of new blood vessels, angiogenesis, is a highly-regulated active process that is critical for the development of the normal and malignant prostate. The vascular endothelial growth factor (VEGF) system assumes a critical role in the angiogenic process. Angiogenesis is a prerequisite for the expansion of solid tumours beyond 1-3 mm3 and is stimulated in response to a hypoxic environment. This review discusses the process of angiogenesis and the key angiogenic mediator, VEGF, and their role in tumour progression and metastasis. A better understanding of the mechanisms behind angiogenesis will ultimately lead to the development of new anti-angiogenic agents in the management of prostate cancer.