Initial treatment costs of organ-confined prostate cancer: a general perspective.

With the increasing prevalence of prostate cancer and evolving methods for the definitive treatment of OCPCa, health economic analyses will be critically important, albeit difficult to carry out. Preliminary studies point to RPP as the most cost-effective treatment for OCPCa. The quickest postoperative recovery, in experienced hands, occurs in RARP and RPP, with ORPP having a slightly, but statistically in significant, shorter hospital stay. It should be stressed that initial treatment costs are not the only important factor in healthcare costs. Readmission for early and late complications and the loss of productivity resulting from variation in time to return to work, need also to be considered. Loss of productivity may also vary in cost between different institutions and countries depending upon the proportion of patients employed. Further large-scale multicentre studies are necessary to assess this.

Nephron-sparing surgery: a call for greater application of established techniques.

OBJECTIVES: To examine the results of open partial nephrectomy (OPN) over a 15-year period in a large UK teaching hospital and to compare results with other series including minimally invasive techniques, as nephron-sparing techniques are still under-utilized in the surgical treatment of renal carcinoma. A standardized technique is described that we think minimizes the risk of postoperative urinoma. PATIENTS AND METHODS: We retrospectively reviewed a series of 141 patients who underwent OPN performed over a 15-year period in one centre by the senior author (D.M.A.W.). A notable feature of this series compared with others is the high proportion of patients undergoing other major synchronous surgery. RESULTS: In all, 141 patients underwent 147 OPNs, with six undergoing bilateral procedures, of which 82 were for imperative indications (single kidney, bilateral synchronous tumours, or pre-existing renal impairment). There were three perioperative deaths, two in patients undergoing other synchronous major surgery. In all, 38 patients had postoperative complications: 28 patients required blood transfusion (four required intervention for their bleeding), five required acute dialysis and three late dialysis. There was a 90% cancer-specific survival rate at a median follow-up of 2 years. CONCLUSIONS: This series confirms the trend towards improved outcomes and decreased complications in OPN at a time when its place is challenged by minimally invasive techniques.

HumanMethylation450K Array-Identified Biomarkers Predict Tumour Recurrence/Progression at Initial Diagnosis of High-risk Non-muscle Invasive Bladder Cancer.

BACKGROUND: High-risk non-muscle invasive bladder cancer (HR-NMIBC) is a clinically unpredictable disease. Despite clinical risk estimation tools, many patients are undertreated with intra-vesical therapies alone, whereas others may be over-treated with early radical surgery. Molecular biomarkers, particularly DNA methylation, have been reported as predictive of tumour/patient outcomes in numerous solid organ and haematologic malignancies; however, there are few reports in HR-NMIBC and none using genome-wide array assessment. We therefore sought to identify novel DNA methylation markers of HR-NMIBC clinical outcomes that might predict tumour behaviour at initial diagnosis and help guide patient management. PATIENTS AND METHODS: A total of 21 primary initial diagnosis HR-NMIBC tumours were analysed by Illumina HumanMethylation450 BeadChip arrays and subsequently bisulphite Pyrosequencing. In all, 7 had not recurred at 1 year after resection and 14 had recurred and/or progressed despite intra-vesical BCG. A further independent cohort of 32 HR-NMIBC tumours (17 no recurrence and 15 recurrence and/or progression despite BCG) were also assessed by bisulphite Pyrosequencing. RESULTS: Array analyses identified 206 CpG loci that segregated non-recurrent HR-NMIBC tumours from clinically more aggressive recurrence/progression tumours. Hypermethylation of CpG cg11850659 and hypomethylation of CpG cg01149192 in combination predicted HR-NMIBC recurrence and/or progression within 1 year of diagnosis with 83% sensitivity, 79% specificity, and 83% positive and 79% negative predictive values. CONCLUSIONS: This is the first genome-wide DNA methylation analysis of a unique HR-NMIBC tumour cohort encompassing known 1-year clinical outcomes. Our analyses identified potential novel epigenetic markers that could help guide individual patient management in this clinically unpredictable disease.

Prostate cancer risk and exposure to ultraviolet radiation: further support for the protective effect of sunlight.

Recent studies have suggested that exposure to ultraviolet (UV) radiation may be protective to some internal cancers including that in the prostate. We describe a confirmatory study in 212 prostatic adenocarcinoma and 135 benign prostatic hypertrophy patients designed to determine whether previous findings showing a protective effect for UV exposure could be reproduced. We used a validated questionnaire to obtain data on aspects of lifetime exposure to UV. The data confirmed that higher levels of cumulative exposure, adult sunbathing, childhood sunburning and regular holidays in hot climates were each independently and significantly associated with a reduced risk of this cancer.

Associations between prostate cancer susceptibility and parameters of exposure to ultraviolet radiation.

Low sunlight exposure confers increased prostate cancer risk. In a study conducted in northern England, we investigated how combinations of exposure measures affect this risk. Recursive partitioning was used to identify combinations of exposure parameters that distinguished 453 prostate cancers from 312 benign hypertrophy patients. Sunbathing score most significantly defined cancer patients; 78.7% men with low scores (8.0) had cancer. These subgroups were stratified by childhood sunburning, holidays in a hot climate and skin type such that subgroups with a 13.0-fold increased risk of cancer were identified.

Polymorphisms in the vitamin D receptor gene, ultraviolet radiation, and susceptibility to prostate cancer.

Ultraviolet radiation (UVR) exposure may protect against prostate cancer development via a mechanism involving vitamin D. The vitamin D receptor (VDR) gene is therefore a candidate susceptibility factor for prostate cancer. This possibility has been previously investigated with conflicting results. We examined the association of VDR genotypes (variants at the CDX-2, Fok1, and Taq1 sites), haplotypes, and genotype combinations with risk by studying 368 prostate cancer and 243 benign prostatic hypertrophy (BPH) patients. CDX-2, Fok1, and Taq1 genotype and haplotype frequencies were not significantly different in cancer and BPH patients. As the impact of VDR polymorphisms may depend on UVR exposure, we studied associations of variants with risk in men stratified into low (below median) and high (above median) cumulative exposure/year groups. In men with UVR exposure above the median (1,100 hr/year), CDX-2 GA and AA (odds ratios [OR] = 2.11 and 2.02, respectively) and Fok1 ff (OR = 2.91) were associated with increased prostate cancer risk. No associations were observed for Taq1 genotypes. Of the genotype combinations, relative to all other CDX-2 and Taq1 and combinations, GGTT (P = 0.022, OR = 0.30), and relative to all other Fok1 and Taq1 combinations, FFTT (P = 0.026, OR = 0.35) were associated with reduced prostate cancer risk in the presence of the main effects. None of the other two- or three-genotype combinations was associated with risk. These data indicate that VDR variants influence prostate cancer risk and that this association is dependent on the extent of UVR exposure.

Day case laparoscopic nephrectomy.

PURPOSE: To report our initial experience with day case surgery (DS) laparoscopic nephrectomy (LN) and to assess its feasibility and safety. PATIENTS AND METHODS: Twenty-six consecutive patients, planned for DS LN between January 2006 and December 2009 at a single urologic center, were enrolled in this retrospective observational study. Every patient underwent LN after a standard pathway of care for DS. We collected data regarding demographic information, medical comorbidities, preoperative and postoperative symptoms, admission as well as discharge time and date. The success rate of DS and reasons for unplanned overnight admission and readmission were collected and evaluated. RESULTS: There were 12 (46.15%) women and 14 (53.84%) men with a median age of 46 years (range 11-77 y). The LN was on the left side in 15 (57.7%) patients and on the right side in 11 (42.3%) patients. Fifteen (57.7%) patients had benign diseases associated with nonfunctioning kidney and 11 (42.3%) patients had renal masses. The most common symptom was loin pain-53.3% for the patients with nonfunctioning kidneys; the majority of patients with tumors (45.6%) were asymptomatic. Twenty-two (84.61%) patients were successfully discharged the same day. Six (23.07%) patients were readmitted after surgery. CONCLUSIONS: The DS LN is feasible and safe. We believe that the results should be easily reproducible. Increasing experience may help to develop more rigorous preoperative, intraoperative, and discharge criteria to increase the success rate and to decrease the readmission rate for DS LN.

Routine day-case laparoscopic pyeloplasty: a paradigm shift?

PURPOSE: To determine whether day-case surgery (DS) laparoscopic pyeloplasty (LP) is feasible and safe. PATIENTS AND METHODS: Thirty-two consecutive patients, planned for DS LP between March 2006 and January 2010 at a single urologic center, were enrolled in this retrospective observational study. Every patient underwent LP after a standard pathway of care for DS. We collected demographic and medical information, including renographic data. The success rate of DS and reasons for unplanned overnight admission and readmission were collected and evaluated. RESULTS: There were 20 (62.5%) females and 12 (37.5%) males with a median age of 37 years (range 11 to 69 y). The pelviureteral junction obstruction was on the left side in 19 (59.3%) patients and on the right side in 13 (40.6%) patients. The most common symptom was loin pain (68.75%). The majority of patients were classified according to their physical status as American Society of Anesthesiologists (ASA) 1 (59.37%), ASA 2 (37.5%), and only one patient (3.1%) as ASA 3. Surgical time varied from 90 to 210 minutes (mean 148.9 min, standard deviation 34.70). Twenty-five (78.12%) patients were successfully discharged on the same day. Two (6.25%) patients were readmitted after surgery. On follow-up renography, 96.15% had improved drainage. This is a small retrospective study reporting initial experience. CONCLUSIONS: The DS LP is feasible and safe. To improve the success rate and to decrease the readmission rate, objective preoperative, intraoperative, and discharge criteria should be developed for DS and validated in randomized studies.

An objective scoring system for laparoscopic nephrectomy.

BACKGROUND AND PURPOSE: The current first-line recommended modality for nephrectomy is by the laparoscopic approach. This is one of the most frequent laparoscopic interventions conducted in urology. From a skills acquisition and delivery perspective in minimally invasive urologic surgery, there is a paucity of objective scoring systems for advanced laparoscopic urologic procedures. We developed a system of direct observation with structured criteria to evaluate the surgical conduction of laparoscopic nephrectomy (LN). We tested the application and preliminary validity of the scoring system. METHODS: Sixty cases of prerecorded LN performed in four teaching hospitals were each analyzed by four mentors. Each mentor scored each case based on a 100-point scoring systemthat comprised 20 key steps for LN (each step ranging 0 to 5). Steps included port placement and safety checks in addition to the actual case. In addition, a negative marking system based on a 50-point index scoring system was deployed such that technically unsound techniques were penalized. The sum of the two resulted in the final score. The final scores independently submitted for each recorded case were analyzed and compared. The system was then used to predict the experience of a surgeon for 10 pilot cases. The cases included a mix of five fellows and five experienced laparoscopic urologic surgeons. The cases were blinded to the independent assessors. A further 20 cases involving 10 cases performed by a trainee who sufficiently completed training (as deemed by the recent award of a certificate of specialist training in urology) vs one who is not ready were reviewed. RESULTS: There was no significant difference in the scores submitted by each of the four mentors for each of the cases observed. There was a strong correlation between overall score and seniority/experience of the performing surgeon of each case; ie, it was able to predict whether an experienced surgeon or laparoscopic fellow performed the case. It was able to predict accurately between a trainee who sufficiently completed training vs one who is "not ready." CONCLUSION: The scoring system was a reliable tool for assessing the performance of LN and accurately predicts the level of experience of the surgeon. This system could be a useful supplementary tool for assessing the baseline skill and progress of trainees.

Associations between timing of exposure to ultraviolet radiation, T-stage and survival in prostate cancer.

BACKGROUND: Exposure to ultraviolet radiation (UVR) has been inversely associated with prostate cancer risk. We determined if skin type and UVR exposure are linked with parameters of prostate cancer outcome. METHODS: We used a questionnaire to determine UVR exposure parameters and skin type in 553 men with prostate cancer and, using logistic regression and survival analysis, studied their association with T-stage, Gleason score, and survival after starting hormone manipulation therapy. RESULTS: UVR exposures 10, 20, and 30 years before diagnosis were inversely associated with T-stage. The odds ratio (OR) for UVR exposure 10 years before diagnosis was lowest (OR=0.69, 95% CI=0.56-0.86). ORs were lower in men with skin types I/II than III/IV. Skin types I/II were associated with longer survival after commencing hormone therapy (hazard ratio=0.62, 95% CI=0.40-0.95). CONCLUSIONS: Our finding that UVR exposure is beneficial is compatible with accumulating data showing sunlight has a protective effect on disease phenotype.

Associations between G/A1229, A/G3944, T/C30875, C/T48200 and C/T65013 genotypes and haplotypes in the vitamin D receptor gene, ultraviolet radiation and susceptibility to prostate cancer.

Ultraviolet radiation (UVR) may protect against prostate cancer via a mechanism involving vitamin D. Thus, the vitamin D receptor (VDR) gene is a susceptibility candidate, though published data are discrepant. We studied the association of prostate cancer risk with five VDR single nucleotide polymorphisms (SNPs): G/A(1229) (SNP 1), A/G(3944) (SNP 2), T/C(30875) (SNP 3), C/T(48200) (SNP 4) and C/T(65013) (SNP 5), in 430 cancer and 310 benign prostatic hypertrophy (BPH) patients. The SNP 2 GG genotype frequency was lower in cancer than BPH patients (odds ratio = 0.63, 95% CI = 0.41-0.98, p = 0.039). SNPs 1 and 2, and SNPs 4 and 5, were in linkage disequilibrium. Two copies of haplotypes comprising SNPs 1-2, G-G (odds ratio = 0.63, p = 0.039), SNPs 2-3 G-C (odds ratio = 0.45, p = 0.008) and SNPs 1-2-3 G-G-C (odds ratio = 0.44, p = 0.006), but not SNPs 1-3, G-C (odds ratio = 0.81, p = 0.34), were associated with reduced risk (reference, no copies of the haplotypes). These associations were observed after stratification of subjects by extent of UVR exposure. These data show that SNP 2 GG genotype mediates prostate cancer risk, complementing studies reporting this allele is protective in malignant melanoma pathogenesis. They further suggest that published associations of risk with SNP 1 may result from linkage disequilibrium with SNP 2.

Susceptibility to prostate cancer: studies on interactions between UVR exposure and skin type.

Recent studies have proposed that exposure to ultraviolet radiation (UVR) protects against development of some internal cancers including that in prostate. This effect may be mediated by UVR-induced cutaneous synthesis of vitamin D. It is also proposed that ability to pigment in response to UVR will influence susceptibility to prostate cancer through its effects on vitamin D synthesis. We wished to determine first, whether ability to pigment, as assessed by skin type, influences the extent of exposure to UVR, secondly, whether skin type is associated with prostate cancer susceptibility and thirdly, whether such an effect is mediated by the extent of UVR exposure. We studied 453 prostatic adenocarcinoma and 312 benign prostatic hypertrophy (BPH) patients using a validated questionnaire to assess two parameters of exposure; months of cumulative exposure per year and adult sunbathing score. We used analysis of variance to show that cancer cases with sun-sensitive skin (skin type 1) had lower cumulative exposure per year (P = 0.014) and sunbathing scores (P < 0.0001) than those with type 4, possibly because of a tendency to avoid exposure. Further, cumulative exposure per year and sunbathing score were significantly lower in cancer compared with BPH patients (P < 0.001 and P < 0.001, respectively). While the proportion of subjects with skin types 1 and 2 was lower in cancer than BPH patients, these were not significantly different (logistic regression analysis, skin type 1 versus type 4; P = 0.11). We used recursive partitioning to determine if skin type influenced susceptibility to prostate cancer in subgroups stratified by exposure. Analysis of the data showed that in men with low sunbathing scores, skin type 1 conferred protection compared with skin types 2-4 (OR = 4.78, 95% CI 3.01-8.25, P < 0.0009). These findings indicate that susceptibility to prostate cancer is in part determined by extent of exposure to UVR and that ability to pigment mediates this effect.

Glutathione S-transferase GSTP1 genotypes are associated with response to androgen ablation therapy in advanced prostate cancer.

We determined whether the glutathione S-transferase GSTP1 Ile105 --> Val105 substitution is associated with response to androgen ablation therapy in patients with advanced prostate cancer. As response may be associated with tumor grade, Gleason score, clinical T stage and presence of metastases we also determined if GSTP1 genotypes were associated with these prognostic parameters. We speculated that GSTP1 Ile105/Ile105 would be linked with good response to androgen ablation therapy and, low/moderate tumor grade, 1/2 clinical T-stage, Gleason score < 6 and, no metastases. Genotype frequencies in cases and controls were not significantly different (P = 0.70) indicating that allelism in GSTP1 is not associated with susceptibility. There was no association between GSTP1 (Ile105/Ile105 versus Ile105/Val105 and Val105/Val105) and grade (P = 0.28, OR = 0.92), Gleason score (P = 0.84, OR = 0.94) or metastatic state (P = 0.68, OR = 0.88) though the frequency of GSTP1 Ile105/Ile105 was higher in cases with stage 1/2 tumors than those with stage 3/4 tumors (P = 0.03, OR = 1.89). GSTP1 Val105/Val105 was also associated with response to hormone ablation therapy. Thus, the GSTP1 Ile105/Ile105 frequency was significantly higher in 86/118 patients who demonstrated a good response than in those with poor response (P = 0.03, OR = 2.70). We speculate that the association of GSTP1 with response results from an effect of the gene product early in carcinogenesis.