Outcomes in patients with Gleason score 8-10 prostate cancer: relation to preoperative PSA level

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? High‐grade prostate cancers are associated with poor disease‐specific outcomes. A proportion of these tumours produce little PSA. This study demonstrates that among Gleason 8–10 prostate cancers, some of the worst survival outcomes are associated with the lowest PSA levels.

OBJECTIVE

• ? To assess outcomes of patients with Gleason score 8–10 prostate cancer (CaP) with a low (≤2.5 ng/mL) vs higher preoperative serum PSA levels.

PATIENTS AND METHODS

• ? From 1983 to 2003, 5544 patients underwent open radical prostatectomy, of whom 354 had a Gleason 8–10 tumour in the prostatectomy specimen.
• ? Patients were stratified according to preoperative PSA level into four strata: ≤2.5 ng/mL (n= 31), 2.6–4 ng/mL (n= 31), 4.1–10 ng/mL (n= 174), and >10 ng/mL (n= 118).
• ? We compared biochemical progression‐free survival (PFS), metastasis‐free survival (MFS), and cancer‐specific survival (CSS) as a function of preoperative PSA level.

RESULTS

• ? Patients with PSA level ≤2.5 ng/mL were more likely to have seminal vesicle invasion (P= 0.003).
• ? On Kaplan–Meier survival analysis, patients with a PSA level ≤2.5 ng/mL had proportionately worse outcomes than their counterparts with higher PSA levels.
• ? The 7‐year PFS in the PSA ≤2.5 ng/mL stratum was lower than those of the PSA 2.6–4 ng/mL and 4–10 ng/mL strata (36% vs 50 and 42%, respectively); however, the lowest 7‐year PFS was found in those with a PSA level >10 ng/mL (32%, P= 0.02).
• ? Gleason score 8–10 tumours with a PSA level ≤2.5 ng/mL also tended to have the lowest 7‐year MFS (75, 93, 89 and 92% for PSA level ≤2.5, 2.6–4, 4.1–10 and >10 ng/mL, respectively, P= 0.2) and CSS (81, 100, 94 and 90% for PSA level ≤2.5, 2.6–4, 4.1–10 and >10 ng/mL, respectively, P= 0.3), although these differences were not statistically significant.
• ? In the subset with palpable disease, Gleason grade 8–10 disease with PSA level ≤2.5 ng/mL also was associated with a worse prognosis.

CONCLUSIONS

• ? In patients with Gleason grade 8–10 disease, a proportion of these tumours are so poorly differentiated that they produce relatively little PSA.
• ? Patients with high‐grade, low‐PSA tumours had less favourable outcomes than many of those with higher PSA levels.

     

Upper urinary tract transitional cell carcinoma: location is not correlated with prognosis

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Tumour location has been shown to be of prognostic importance in UUT‐TCC, with tumours of renal pelvis having a better prognosis than ureteral tumours. Patients from Balkan Endemic Nephropathy (BEN) areas had a higher frequency of pelvis tumours. Also, we found that belonging to a BEN area is an independent predictor of disease recurrence.

OBJECTIVE

• ? To identify the impact of tumour location on the disease recurrence and survival of patients who were treated surgically for upper urinary tract transitional cell carcinoma (UUT‐TCC).

PATIENTS AND METHODS

• ? A single‐centre series of 189 consecutive patients who were treated surgically for UUT‐TCC between January 1999 and December 2009 was evaluated.
• ? Patients who had previously undergone radical cystectomy, preoperative chemotherapy or contralateral UUT‐TCC were excluded.
• ? In all, 133 patients were available for evaluation. Tumour location was categorized as renal pelvis or ureter based on the location of the dominant tumour.
• ? Recurrence‐free probabilities and cancer‐specific survival were estimated using the Kaplan–Meier method and Cox regression analyses.

RESULTS

• ? The 5‐year recurrence‐free and cancer‐specific survival estimates for the cohort in the present study were 66% and 62%, respectively.
• ? The 5‐year bladder‐only recurrence‐free probability was 76%. Using multivariate analysis, only pT classification (hazard ratio, HR, 2.46; P= 0.04) and demographic characteristics (HR, 2.86 for areas of Balkan endemic nephropathy, vs non‐Balkan endemic nephropathy areas; 95% confidence interval, 1.37–5.98; P= 0.005) were associated with disease recurrence
• ? Tumour location was not associated with disease recurrence in any of the analyses.
• ? There was no difference in cancer‐specific survival between renal pelvis and ureteral tumours (P= 0.476).
• ? Using multivariate analysis, pT classification (HR, 8.04; P= 0.001) and lymph node status (HR, 4.73; P= 0.01) were the only independent predictors associated with a worse cancer‐specific survival.

CONCLUSION

• ? Tumour location is unable to predict outcomes in a single‐centre series of consecutive patients who were treated with radical nephroureterectomy for UUT‐TCC.

     

Late bacille Calmette-Guérin infection with a large focal urinary bladder ulceration as a complication of bladder cancer treatment

Study Type – Therapy (case series)
Level of Evidence 4 What's known on the subject? and What does the study add? Intravesical BCG treatment has been used worldwide for many decades but there are only a few published reports on persisting BCG infection of the urinary bladder. This is the first report on large tuberculosis‐like ulcers of the urinary bladder after intravesical BCG treatment. The finding results in a recommendation to take urine cultures for mycobacteriae in patients with unclear inflammatory lesions in the bladder after instillation of BCG.

OBJECTIVE

• ? To report a late bacille Calmette–Guérin (BCG) complication previously not described in the literature.

PATIENTS AND METHODS

• ? We reviewed our database with 858 patients treated with BCG from 1986 to 2008 and identified 13 male patients (1.8% of all male patients) who had a large tuberculous‐like bladder ulcer.

RESULTS

• ? All patients had high‐grade tumours and seven had tumours invading lamina propria before BCG treatment. A solitary ulceration or inflammatory lesion, 10–50 mm in diameter, was seen at routine follow‐up cystoscopy 2–34 months (median 8 months) after the first instillation. Significantly more patients had been treated with BCG‐RIVM than with BCG‐Tice (10/320 vs. three of 454, P < 0.01). BCG was cultured from urine 3–34 months (median 14 months) after the last instillation.
• ? So far, eight patients have been successfully treated with rifampicin and isoniazid. Nine patients are still tumour‐free 15–66 months (median 44 months) after the last transurethral resection before BCG treatment.
• ? Another three patients had one to two non‐invasive recurrences. One patient had an invasive recurrence and underwent cystectomy. The present study is limited by biases associated with its retrospective design.

CONCLUSIONS

• ? This is the first report on persisting BCG infections with large inflammatory lesions in the bladder. Treatment is effective and the oncological outcome is good.
• ? Mycobacterial cultures of the urine should be performed in BCG‐patients with unclear inflammatory lesions in the bladder since a delayed diagnosis of a persistent BCG infection could result in a permanently reduced bladder capacity.
• ? Large studies are warranted to study differences in efficacy and side‐effects between different BCG strains.

     

Underestimation of Gleason score at prostate biopsy reflects sampling error in lower volume tumours

Study Type – Diagnostic (case series) Level of Evidence 4 What's known on the subject? and What does the study add? The Gleason score of prostate cancer is frequently underestimated at the time of diagnostic biopsy, although the contribution of sampling error to its incidence is unknown. We show that under‐graded tumours are significantly smaller that tumours concordant for the higher grade, indicating that incomplete tumour sampling plays a significant role in Gleason score assignment error.

OBJECTIVE

• ? To determine the influence of tumour and prostate gland volumes on the underestimation of prostate cancer Gleason score in diagnostic core biopsies.

PATIENTS AND METHODS

• ? Patients undergoing radical prostatectomy with matched diagnostic biopsies were identified from a prospectively recorded database.
• ? Tumour volumes were measured in serial whole‐mount sections with image analysis software as part of routine histological assessment.
• ? Differences in various metrics of tumour and prostate volume between upgraded tumours and tumours concordant for the lower or higher grade were analysed.

RESULTS

• ? In all, 684 consecutive patients with Gleason score 6 or 7 prostate cancer on diagnostic biopsy were identified.
• ? Of 298 patients diagnosed with Gleason 6 tumour on biopsy, 201 (67.4%) were upgraded to Gleason 7 or higher on final pathology. Similarly, of 262 patients diagnosed with Gleason 3 + 4 = 7 prostate cancer on initial biopsy, 60 (22.9%) were upgraded to Gleason score 4 + 3 = 7 or higher.
• ? Tumours upgraded from Gleason 6 to 7 had a significantly lower index tumour volume (1.73 vs 2 mL, P= 0.029), higher calculated prostate volume (41.6 vs 39 mL, P= 0.017) and lower relative percentage of tumour to benign glandular tissue (4.3% vs 5.9%, P= 0.001) than tumours concordant for the higher grade.
• ? Similarly, tumours that were Gleason score 3 + 4 on biopsy and upgraded on final pathology to 4 + 3 were significantly smaller as measured by both total tumour volume (2.3 vs 3.3 mL, P= 0.005) and index tumour volume (2.2 vs 3, P= 0.027) and occupied a smaller percentage of the gland volume (6.3% vs 8.9%, P= 0.017) compared with tumours concordant for the higher grade.
• ? On multivariate analysis, lower prostate weight (hazard ratio 0.97, 95% confidence interval 0.96–0.99, P < 0.001) and larger total tumour volume (hazard ratio 1.87, 95% confidence interval 1.4–2.6, P < 0.001) independently predicted an upgrade in Gleason score from 6 to 7. In tumours upgraded from biopsy Gleason 3 + 4, only higher index tumour volume (hazard ratio 3.1, 95% confidence interval 1.01–9.3, P= 0.048) was a significant predictor of upgrading on multivariate analysis.

CONCLUSIONS

• ? Under‐graded tumours are significantly smaller than tumours concordant for the higher grade, indicating that incomplete tumour sampling plays a significant role in Gleason score assignment error.
• ? Surrogate measures of tumour volume may predict those at greatest risk of Gleason score upgrade.

     

Surveillance guidelines based on recurrence patterns after radical cystectomy for bladder cancer: the Canadian Bladder Cancer Network experience

Study Type – Prognosis (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Radical cystectomy with pelvic lymph node dissection is recognized as the standard of care for carcinoma invading bladder muscle and for refractory non‐muscle‐invasive bladder cancer. Owing to high recurrence and progression rates, a two‐pronged strict surveillance regimen, consisting of both functional and oncological follow‐up, has been advocated. It is also well recognized that more aggressive tumours with extravesical disease and node‐positive disease recur more frequently and have worse outcomes. This study adds to the scant body of literature available regarding surveillance strategies after radical cystectomy for bladder cancer. In the absence of any solid evidence supporting the role of strict surveillance regimens, this extensive examination of recurrence patterns in a large multi‐institutional project lends further support to the continued use of risk‐stratified follow‐up and emphasizes the need for earlier strict surveillance in patients with extravesical and node‐positive disease.

OBJECTIVES

• ? To review our data on recurrence patterns after radical cystectomy (RC) for bladder cancer (BC).
• ? To establish appropriate surveillance protocols.

PATIENTS AND METHODS

• ? We collected and pooled data from a database of 2287 patients who had undergone RC for BC between 1998 and 2008 in eight different Canadian academic centres.
• ? Of the 2287 patients, 1890 had complete recurrence information and form the basis of the present study.

RESULTS

• ? A total of 825 patients (43.6%) developed recurrence.
• ? According to location, 48.6% of recurrent tumours were distant, 25.2% pelvic, 14.5% retroperitoneal and 11.8% to multiple regions such as pelvic and retroperitoneal or pelvic and distant.
• ? The median (range) time to recurrence for the entire population was 10.1 (1–192) months with 90 and 97% of all recurrences within 2 and 5 years of RC, respectively.
• ? According to stage, pTxN+ tumours were more likely to recur than ≥pT3N0 tumours and ≤pT2N0 tumours (5‐yr RFS 25% vs. 44% vs. 66% respectively, P < 0.001). Similarly, pTxN+ tumours had a shorter median time to recurrence (9 months, range 1–72 months) than ≥pT3N0 tumours (10 months, range 1–70 months) or ≤pT2N0 tumours (14 months, range 1–192 months, P < 0.001).

CONCLUSIONS

• ? Differences in recurrence patterns after RC suggest the need for varied follow‐up protocols for each group.
• ? We propose a stage‐based protocol for surveillance of patients with BC treated with RC that captures most recurrences while limiting over‐investigation.

     

Trends in the use of radiotherapy and radical surgery for patients with bladder urothelial cell carcinoma in East Anglia, 1995-2006

Study Type – Prevalence (retrospective cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? In the UK, specialist services for the management of urological cancers have been reconfigured substantially in recent time periods. Socioeconomic inequalities in relative survival from bladder cancer have also been documented. In part of an English region, use of radical surgery to manage the most common type of bladder cancer increased and use of radiotherapy decreased during 1995–2006, most probably reflecting increasing availability of specialist surgical management. There was no evidence for differences in the use of radiotherapy or radical surgery between patients of different socio‐economic groups.

OBJECTIVE

• ? To examine the use of radiotherapy and radical surgery for bladder urothelial cell carcinoma (UCC) before, during and after national initiatives for reorganization of uro‐oncology services.

PATIENTS AND METHODS

• ? Population‐based data (1995–2006) from a cancer registry with stable coding practices were analysed.
• ? Bladder UCC was defined using relevant International Classification of Disease site and morphology codes.
• ? Time trends in the use of radiotherapy and radical surgery, and other predictors of their use were examined.

RESULTS

• ? Of 4639 bladder UCC patients aged ≥40 years (76% men), stage information was available for 4303 (93%).
• ? Morphology and stage case mix remained stable during the study period.
• ? Radiotherapy use decreased significantly (from 31% in 1995–1998 to 22% in 2003–2006, P < 0.001) among patients of any stage, whilst radical surgery use increased significantly (from 8 to 13%, P < 0.001), particularly among stage II–IV patients.
• ? The proportion of patients treated by both radiotherapy and surgery also decreased notably (from 4.0 to 1.1%).
• ? Women were significantly more likely to present in stages II–IV [odds ratio (OR) = 1.22, 95% confidence interval (CI) = 1.06–1.40, P= 0.005], and less likely to be treated with radiotherapy (OR = 0.84, 95% CI: 0.72–0.99, P= 0.036).

CONCLUSIONS

• ? Use of radical surgery in UCC invading bladder muscle increased and use of radiotherapy decreased during the study period, most probably reflecting the increasing availability of specialist surgical management. Sociodemographic variation in treatment was limited to lower use of radiotherapy in women.
• ? Further research should encompass treatment timeliness and other aspects of care quality, as well as exploring potential differences in endoscopic treatments for disease not invading bladder muscle.

     

Automatic evaluation of ultrasonography-estimated bladder weight and bladder wall thickness in community-dwelling men with presumably normal bladder function

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? The diagnostic potential of ultrasound derived measurements of bladder wall thickness and bladder weight in men with LUTS and varying degrees of BOO have been explored. However, there is a paucity of such measurements in the asymptomatic population with which to compare such patients. This study investigates these measurements in community‐dwelling men with presumably normal bladder function.

OBJECTIVE

• ? To identify measurements of ultrasonography (US)‐derived bladder wall thickness (BWT) and bladder weight in community‐dwelling men with presumably normal bladder function.

SUBJECTS AND METHODS

• ? A total of 100 male volunteers underwent transabdominal US measurements of BWT and bladder weight, using the BVM 9500 bladder scanner (Verathon Medical, Bothell, WA, USA), at a variety of bladder filling volumes.
• ? The data were explored for any correlation between measurements of BWT and US‐estimated bladder weight (UEBW) with subject age, height, weight, body mass index (BMI), International Consultation on Incontinence Questionnaire – Male Lower Urinary Tract Symptoms (ICIQ M‐LUTS) score, International Prostate Symptom Score (IPSS) and IPSS Quality of Life index (IPSS QoL).

RESULTS

• ? Several statistically significant but weak correlations were observed: BWT and weight (r= 0.216, P= 0.032); BWT and BMI (r= 0.246, P= 0.014); UEBW and weight (r= 0.304, P= 0.002); and UEBW and BMI (r= 0.260, P= 0.009).
• ? Bladder filling volume appeared to have a greater effect on BWT than on UEBW, although this could not be determined accurately.
• ? There was a substantial difference in measurements of BWT and UEBW in the assessment of inter‐ and intra‐observer reliability testing.

CONCLUSION

• ? Further studies are required to validate automated measurements of BWT and UEBW and to investigate such measurements in the symptomatic and asymptomatic male population.

     

Under-grading of <4 cm renal masses on renal biopsy

Study Type – Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? It is well documented that biopsy of small renal masses is inaccurate and tends to under‐estimate tumour grade compared with surgical specimens. To our knowledge there has not been a study showing grading discrepancy between biopsy and surgical excision in a large population‐based cohort.

OBJECTIVE

• ? To determine whether differences exist in tumour grade between patients who undergo partial nephrectomy (PN) and those who undergo ablation for renal tumours.

PATIENTS AND METHODS

• ? Data was obtained using the Surveillance, Epidemiology and End Results database. Patients with solitary renal tumours of <4 cm treated with ablation or PN and with renal cell carcinoma (RCC) histopathology were identified.
• ? Tissue diagnosis in the ablation specimens was obtained from biopsy reports, whereas tissue from PN specimens was determined from surgical pathology.
• ? Variables analysed included: year of diagnosis, age, sex, race/ethnicity, marital status, population density, education, poverty level, and tumour size.
• ? Stacked bar graphs were created to compare the distributions of grade and histology between the groups. Multinomial logistic regression was used to determine factors independently associated with grade.

RESULTS

• ? In all, 7704 (87.4%) patients underwent PN and 1114 (12.6%) underwent either radiofrequency ablation or cryoablation.
• ? The PN patients were younger at diagnosis (59 vs 68 years, P < 0.001), more likely to be married (70% vs 64%, P < 0.001), and had smaller tumours (2.4 vs 2.6 cm, P < 0.001).
• ? There were no differences in the distribution of histology between the PN and ablation groups.
• ? Tumour grade was significantly lower in tumours treated with ablation.
• ? Compared with grade 1 disease, those undergoing ablation were 30% less likely to have grade 2 (P < 0.001), 30% less likely to have grade 3 (P < 0.001), and 92% less likely to have grade 4 disease (P < 0.01) than those having PN.

CONCLUSIONS

• ? There is a strong association between grade and treatment type in patients with small renal masses after controlling for baseline characteristics.
• ? As grade is determined by different methods, we think that this shows systematic under‐grading in biopsy of small renal masses.

     

A methylation assay for the detection of non-muscle-invasive bladder cancer (NMIBC) recurrences in voided urine

What's known on the subject? and What does the study add? Multiple studies report on the detection of methylation in voided urine samples as a possible approach for the follow‐up of non‐muscle invasive bladder cancer patients. Previous studies analyze methylation gene panels in a mixture of primary and recurrent tumours. As primary tumours are larger than recurrent tumours and thus easier to detect in urine, validation of methylation markers in urine samples from patients with primary tumours will result in a test sensitivity that does not reflect the true sensitivity of the assay. This study is the first to select a subset of genes specifically methylated in non‐muscle invasive bladder cancer recurrences and validates the gene panel in two independent sets of urine samples from recurrent patients, thus simulating the disease course according to the clinical presentation.

OBJECTIVE

• ? To develop a methylation‐specific multiplex ligation‐dependent probe amplification (MS‐MLPA) assay for the detection of non‐muscle invasive bladder cancer (NMIBC) recurrences in voided urine.

PATIENTS AND METHODS

• ? Genes frequently methylated in NMIBC tumours (n= 37) were selected to develop a BC‐specific MS‐MLPA assay.
• ? Genes methylated in blood from patientswith BC (n= 29) and genes methylated in urine from patients with no history of BC (n= 46) were excluded.
• ? A four‐gene panel with the highest predictive value was selected from the initial assay. This four‐gene panel was tested and validated on urine from patients with a histologically confirmed recurrence (n= 68 test set; n= 49 validation set) and urine samples from patients without BC (n= 91, test set) and urine from recurrence‐free BC (rec‐free BC) patients (n= 60, validation set).
• ? A model was developed to predict the probability of having a recurrence based on methylation of the four‐gene panel and a threshold probability with the highest sensitivity and specificity was determined.
• ? The outcome of the model was validated on BC urine samples (n= 65) and on urine samples from rec‐free BC patients (n= 29).

RESULTS

• ? The BC MS‐MLPA assay consisted of 23 methylation probes. The selected four‐gene panel included: APC_a, TERT_a, TERT_b, and EDNRB. This panel reached an area under the receiver operating characteristic curve (AUC) of 0.82 (test set) and AUC 0.69 (validation set). Sensitivity and specificity for the detection of a concomitant tumour were 63.3% and 58.3% respectively (test set) and 72.3% and 55.2%, respectively (validation set).

CONCLUSIONS

• ? We have developed a methylation detection assay specifically for the detection of recurrences in patients with NMIBC in voided urine.
• ? The findings are promising and improvement of this test could eventually contribute to a more individualized patient friendly surveillance.

     

Ureteroscopic and extirpative treatment of upper urinary tract urothelial carcinoma: a 15‐year comprehensive review of 160 consecutive patients

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Upper urinary tract urothelial carcinomas (UTUC) have historically been treated with radical, extirpative surgery, primarily nephroureterectomy with bladder‐cuff excision. In general, there has been growing interest in renal preservation, as evidenced by the broadening application of nephron‐sparing surgery for renal parenchymal tumours. Beyond imperative reasons such as tumour in a solitary kidney, bilateral disease, or comorbidities preventing radical surgery, there is a growing role for endoscopic management of upper tract tumours. The aim has been to obtain similar oncological results to those of extirpative surgery, while preserving long‐term renal function. Properly selecting patients for these therapies, designing specific treatments based on a complex presentation, and general information with regard to outcomes and risks for patient counselling have been based historically on results from relatively small series without long‐term follow‐up. This study reflects all patients with UTUC treated by a single tertiary referral surgeon, accrued prospectively over 15 years using the same surgical techniques and treatment algorithms throughout the entire study period, with 10‐year survival data. The consecutively accrued nature and size of the study groups, uniformity in treatments, statistical review and long‐term follow‐up provide baseline oncological data that could help frame future study.

OBJECTIVE

• ? To present long‐term oncological outcomes of all patients treated surgically for upper urinary tract urothelial carcinoma (UTUC) over a 15‐year period.

PATIENTS AND METHODS

• ? All patients (N= 160) treated from January 1996 to August 2011 were prospectively studied and placed into three distinct groups after initial diagnostic ureteroscopy (URS): Group 1: low grade lesions treated with URS (n= 66); Group 2: high grade lesions palliatively treated with URS (n= 16); and Group 3: extirpative surgery (nephroureterectomy [NU]; n= 80).
• ? Statistical analysis was performed using Kaplan–Meier methodology to calculate overall (OS), cancer‐specific (CSS) and metastasis‐free survival (MFS).

RESULTS

• ? The median patient age at presentation was 73 years, and the mean (range) follow‐up time was 38.2 (1–185) months. At initial diagnostic URS, 71 (44.4%) patients presented with high grade and 89 (55.6%) patients presented with low grade disease.
• ? The 2‐, 5‐ and 10‐year CSS rates were 98, 87 and 81% for patients with low grade disease, and 97, 87 and 78% for patients treated with URS (Group 1), not significantly different from those patients with low grade disease treated with NU (Group 3), (P= 0.54).
• ? Of the patients treated with URS for low grade disease, 10 (15.2%) progressed to high grade disease at a mean time of 38.5 months.
• ? Patients with high grade disease treated with NU had a 2‐, 5‐, and 10‐year CSS of 70, 53 and 38%, with a MFS of 55, 45 and 35%.
• ? Median survival of patients with high grade disease treated with palliative URS was 29.2 months with a 2‐year OS of 54%.
• ? On multivariate analysis only high grade lesion on initial presentation was found to be a significant factor (P < 0.001; hazard ratio = 7.27).

CONCLUSIONS

• ? Grade is the most significant predictor of OS and CSS in those with UTUC, regardless of treatment method.
• ? Ureteroscopic and extirpative therapy are acceptable options for those with low grade disease showing excellent long‐term CSS.
• ? Extirpative therapy was found to result in relatively poor long‐term CSS in patients with high grade disease, underscoring the need for adjuvant or neoadjuvant therapies.

     

Frequency of regulatory T cells in peripheral blood and in tumour‐infiltrating lymphocytes correlates with poor prognosis in renal cell carcinoma

What’s known on the subject? and What does the study add? Treg overexpression has been demonstrated in several neoplasms, including liver, breast, pancreas and melanoma, while it has not been well evaluated in renal cancer. In renal cancer patients versus controls we found an increased expression of these cells, especially in tumour‐infiltrating lymphocytes. Moreover, Treg frequency significantly correlated with pathological stage, nuclear grade and prognostic models.

OBJECTIVE

• ? To compare the frequency of T regulatory cells (Tregs) in peripheral blood of patients (pPB) affected by renal cell carcinoma (RCC) both with the frequency of Tregs found in PB of healthy donors (hPB) and that of Tregs present in tumour infiltrating lymphocytes (TILs). To verify in vitro the inhibitory activity of tumour isolated Tregs on the effector T cells and, finally, to assess the prognostic role of Treg frequency determination.

PATIENTS AND METHODS

• ? Treg frequency in hPB, pPB and TILs was evaluated in 30 patients and 20 healthy controls by measuring both membrane‐CD25 and intracytoplasmic‐Foxp3 expression by flow cytometry.
• ? Treg inhibitory activity was evaluated by an in vitro proliferation assay performed on total, CD25‐depleted mononuclear cells (MNC) and CD25‐depleted MNC cultured in the presence of purified CD25⁺ Tregs.
• ? Finally, Treg frequency in pPB and TIL were correlated with conventional prognostic factors and scores of University of California Los Angeles and Kattan predictive models.

RESULTS

• ? Treg frequency was higher in TILs than in pPB (P= 0.002), whereas there were no important differences between hPB and pPB. CD25⁺ cells isolated either from PB and tumours showed the ability to significantly suppress in vitro both proliferation and interferon‐γ production by CD25‐depleted MNC, thus demonstrating that they are active Tregs.
• ? Treg frequency was found to significantly correlate both with pathological stage (pPB, P= 0.03; TIL, P= 0.04) and nuclear grade (TIL, P= 0.005), both for UCLA and Kattan models (all: P < 0.05 for both pPB and TIL).

CONCLUSION

• ? Treg frequency is significantly higher in TIL than in pPB of patients with RCC. Tregs showed in vitro an inhibitory activity on effector T cells isolated from kidney tumours. The increase in both peripheral and intratumoral Tregs in subjects affected with RCC were associated with worse prognosis.

     

Secondary bladder cancer after upper tract urothelial carcinoma in the US population

Study Type – Prognosis (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? It is known that a certain percentage of patients treated for upper tract urothelial carcinoma (UTUC) will go on to develop a secondary bladder cancer; however, the risk factors for developing a secondary bladder tumour have not been studied in a population‐based setting. Given the large changes in how UTUC has been diagnosed and managed in recent years, this study aimed to evaluate the natural history of UTUC in the US population over a 30‐year period, with a particular emphasis on the development of secondary bladder cancer.

OBJECTIVE

• ? To assess the natural history of upper tract urothelial carcinoma (UTUC) and the development of lower tract secondary cancer.

PATIENTS AND METHODS

• ? Patients diagnosed with UTUC between 1975 and 2005 were identified within nine Surveillance, Epidemiology and End Results registries.
• ? Baseline characteristics of patients with and without secondary bladder cancer were compared.
• ? A multivariate logistic regression model was fitted to test if the year of diagnosis predicted the likelihood of developing a secondary bladder cancer.

RESULTS

• ? Of the 5212 patients with UTUC, 242 (4.6%) had a secondary bladder cancer (range: 1.7–8.2%).
• ? There was a mean interval of 26.5 (95% CI: 22.2–30.8) months between cancer diagnoses.
• ? Compared with those without secondary tumours, patients with secondary bladder malignancy were more likely to present with larger tumours (4.2 vs 3.1 cm, P < 0.001) and with tumours located in the ureter (P < 0.001).
• ? Year of diagnosis was not a predictor of the likelihood of having a secondary bladder malignancy in a multivariate analysis controlling for demographic and tumour characteristics (odds ratio: 0.99; 95% CI: 0.95–1.03)

CONCLUSIONS

• ? Patients with larger urothelial tumours located in the ureter were those most likely to develop a secondary lower tract tumour.
• ? No longitudinal changes in the rate of secondary bladder cancer were noted among patients with UTUC over the 30‐year study period.

     

Comparison of the rate, location and size of positive surgical margins after laparoscopic and robot-assisted laparoscopic radical prostatectomy

Study Type – Therapy (case series) Level of Evidence 4

OBJECTIVE

• ? To review and compare the rate, location and size of positive surgical margins (PSMs) after pure laparoscopic radical prostatectomy (LRP) and robot‐assisted laparoscopic radical prostatectomy (RALP).

PATIENTS AND METHODS

• ? The study comprised 200 patients who underwent RALP and 200 patients who underwent LRP up to January 2008.
• ? We compared patient age, body mass index, preoperative prostate‐specific antigen (PSA), preoperative stage and grade, prostate size, pathological stage and grade and neurovascular bundle preservation, as well as PSM rate, size and location.
• ? Continuous and categorical data were compared using Student’s t‐test and Pearson’s chi‐squared test.
• ? Multivariate regression analyses were used to identify preoperative and intraoperative predictors of PSMs.

RESULTS

• ? Although the PSM rate was similar between the two groups (LRP: 12% vs RALP: 13.5%; P= 0.76), location and size were not. PSMs after LRP were mostly at the apex (58.3%; P= 0.038), while most PSMs after RALP were posterolateral ([PL] 48%; P= 0.046).
• ? In addition, the median margin size after RALP was significantly smaller than after LRP (RALP: 2 mm vs LRP: 3.5 mm; P= 0.041).
• ? In univariate and multivariate analyses, tumour‐node‐metastasis (TNM) stage and preoperative PSA were the only independent preoperative predictors of PSMs (P= 0.044 and P= 0.01, respectively).

CONCLUSION

• ? The PSM risk is dependent on TNM stage and preoperative PSA and not the surgical technique, when comparing LRP with RALP.

     

Comparison of oncological outcomes after segmental ureterectomy or radical nephroureterectomy in urothelial carcinomas of the upper urinary tract: results from a large French multicentre study

Study Type – Therapy (multi‐centre retrospective cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Upper urinary tract urothelial carcinomas (UUT‐UCs) are rare tumours. Because of the aggressive pattern of UC, radical nephroureterectomy (RNU) with bladder cuff removal remains the ‘gold‐standard’ treatment. However, conservative strategies, such as segmental ureterectomy (SU) or endourological management, have also been developed in patients with imperative indications. Some teams are now advocating the use of conservative management more commonly in cases of elective indications of UUT‐UCs. Due to the paucity of cases of UUT‐UC, only limited data are available on the oncological outcomes afforded by conservative management. We retrospectively investigated the oncological outcomes after SU and RNU in a large multi‐institutional database. Overall, 52 patients were treated with SU and 416 with RNU. There was no statistical difference between the RNU and SU groups for the 5‐year probability of cancer‐specific survival, recurrence‐free survival and metastasis‐free survival. The type of surgery was not a significant prognostic factor in univariate analysis. The results were the same in a subgroup analysis of only unifocal tumours of the distal ureter with a diameter of <2 cm and of low stage (≤T2). Our results suggest that oncological outcomes after conservative treatment with SU are comparable to RNU for the management of UUT‐UC in select cases.

OBJECTIVE

• ? To compare recurrence‐free survival (RFS), metastasis‐free survival (MFS) and cancer‐specific survival (CSS) after segmental ureterectomy (SU) vs radical nephroureterectomy (RNU) for urothelial carcinoma (UC) of the upper urinary tract (UUT‐UC) located in the ureter.

PATIENTS AND METHODS

• ? We performed a multi‐institutional retrospective review of patients with UUT‐UC who had undergone RNU or SU between 1995 and 2010.
• ? Type of surgery, Tumour‐Node‐Metastasis status, tumour grade, lymphovascular invasion and positive surgical margin were tested as prognostic factors for survival.

RESULTS

• ? In all, 52 patients were treated with SU and 416 with RNU. The median (range) follow‐up was 26 (10–48) months.
• ? The 5‐year probability of CSS, RFS and MFS for SU and RNU were 87.9% and 86.3%, respectively (P= 0.99); 37% and 47.9%, respectively (P= 0.48); 81.9% and 85.4%, respectively (P= 0.51).
• ? In univariable analysis, type of surgery (SU vs RNU) failed to affect CSS, RFS and MFS (P= 0.94, 0.42 and 0.53, respectively).
• ? In multivariable analyses, pT stage and pN stage achieved independent predictor status for CSS (P= 0.005 and 0.007, respectively); the positive surgical margin and pT stage were independent prognostic factors of RFS and MFS (P= 0.001, 0.04, 0.009 and 0.001, respectively).
• ? The main limitation of the study is its retrospective design, which is due to the rarity of the disease.

CONCLUSIONS

• ? Short‐term oncological outcomes after conservative treatment with SU are comparable to RNU for the management of UUT‐UC in select cases and should be considered an option.
• ? In every other case, RNU still represents the ‘gold standard’ for the treatment of UUT‐UC.

     

Angiotensin II type 1 (AT-1) receptor inhibition partially prevents the urodynamic and detrusor changes associated with bladder outlet obstruction: a mouse model

Study Type – Therapy (case control) Level of Evidence 3b What's known on the subject? and What does the study add? Angiotensin II is the main effector peptide in the bladder local renin‐angiotensin system. This experiment demonstrates the role of this local renin‐angiotensin system with respect to bladder outlet obstruction.

OBJECTIVE

• ? To determine if treatment with an angiotensin II type 1 (AT‐1) receptor antagonist, losartan, can prevent the structural and functional changes that occur in a mouse model of bladder outlet obstruction (BOO).

MATERIALS AND METHODS

• ? Twenty‐four Balb/CAN mice underwent partial urethral obstruction for 6 weeks.
• ? Twelve mice were given oral losartan (10 mg/kg/day), and 12 were not. Six mice served as unobstructed controls, and six unobstructed mice were given oral losartan (10 mg/kg/day) to determine the effect of angiotensin II inhibition on the normal bladder.
• ? Bladder capacity (C), detrusor pressure during voiding (Pdet) and volume at first non‐voiding contraction (NVC1) as a percentage of C were recorded after 6 weeks.
• ? Bladders were stained with haematoxylin and eosin for measurement of detrusor muscular thickness, and graded as 1 = atrophy (<100 µm thick), 2 = normal (100–200 µm thick), 3 = hypertrophy (>200 µm thick) compared with controls.

RESULTS

• ? Compared with controls, BOO mice had greater C (153.5 ± 20.9 vs 57.5 ± 7.4 µl, P < 0.01), higher Pdet (28.8 ± 2.1 vs 12.1 ± 2.1 mm Hg), lower NVC1 (median = 24% vs 54% P= 0.03). BOO mice manifested greater bladder weight (93.2 ± 11.7 mg vs 26.8 ± 2.40 mg, P < 0.01) and greater detrusor muscle thickness (median 3 vs 2, P= 0.02).
• ? Compared with untreated BOO mice, mice treated with losartan had greater mean C (248.8 ± 28.6 vs 153.5 ± 20.9 µL, P= 0.01), no significant change in mean Pdet (24.7 ± 1.6 vs 28.8 ± 2.1 mm Hg, P= 0.2) and a higher mean NVC1 (47% vs 24%, P= 0.02).
• ? Treatment with losartan mediated an insignificant reduction in mean bladder weight (68.1 ± 9.1 mg vs 93.2 ± 11.7 mg, P= 0.10), but a significant reduction in detrusor muscle thickness (median 2 vs 3, P= 0.02). Losartan did not mediate any significant structural or functional changes in the unobstructed mouse bladder.

CONCLUSION

• ? In a mouse model of BOO, treatment with an AT‐1 antagonist partially prevented the urodynamic and structural changes that otherwise occur with BOO.

     

Impact of comorbidity on complications after nephrectomy: use of the Clavien Classification of Surgical Complications

Study Type – Retrospective (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Tumour characteristics, physical status and comorbidities are considered important for surgical outcome and prognosis. The present study objectively evaluates the association between comorbidity and postoperative complications after nephrectomy for RCC, by using the modified Clavien Classification of Surgical Complications to grade complications after nephrectomy.

OBJECTIVE

• ? To present a single‐centre experience of open nephrectomy for lesions suspected for renal cell carcinoma (RCC), evaluating the association between comorbidity and postoperative complications using a standardized classification system for postoperative complications.

PATIENTS AND METHODS

• ? Clinicopathological data of 198 patients undergoing open radical or partial nephrectomy for lesions suspected of RCC were retrospectively analysed.
• ? Comorbidity scored by the Charlson comorbidity index (CCI), body mass index, age, gender, surgical procedure and surgical history were examined as predictive factors for postoperative complications, which were scored using the modified Clavien Classification of Surgical Complications (CCSC).

RESULTS

• ? The overall complication rate was 34%: 7% grade I, 15% grade II, 5% grade III, 3% grade IV and 4% grade V. Preoperative comorbidities were present in 51% of all patients.
• ? There were significantly more major complications (CCSC >2) in patients with major comorbidities (CCI >2), at 16% vs 7% (P= 0.018).
• ? Patients with high‐stage RCC had significantly more severe complications than low‐stage RCC (P= 0.018).
• ? In multivariable analysis, comorbidity (odds ratio [OR] 7.55, P= 0.004) and tumour stage 3–4 (OR 6.23, P= 0.007) were independent predictive factors for major complications.

CONCLUSIONS

• ? Major complications occur significantly more often when major comorbidities are present.
• ? Comorbidity scores can be used in risk stratification for complications and should be considered during decision‐making and counselling of patients before nephrectomy.

     

Secondary cancers after intensity‐modulated radiotherapy,brachytherapy and radical prostatectomy for the treatment of prostate cancer: incidence and cause‐specific survival outcomes according to the initial treatment intervention

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Radiation Therapy for prostate cancer can increase the risk for the development of second cancers after treatment. This study highlights the fact that such second cancers within the pelvis do occur but are not as common as previously reported. In this report we also note that even among patients who develop second cancers, if detected earlier, the majority are alive 5 years after the diagnosis.

OBJECTIVE

• ? To report on the incidence of secondary malignancy (SM) development after external beam radiotherapy (EBRT) and brachytherapy (BT) for prostate cancer and to compare this with a cohort contemporaneously treated with radical prostatectomy (RP).

MATERIALS AND METHODS

• ? Between 1998 and 2001, 2658 patients with localized prostate cancer were treated with RP (n= 1348), EBRT (n= 897) or BT (n= 413).
• ? Using the RP cohort as a control we compared the incidence of SMs, such as rectal or bladder cancers noted within the pelvis, and the incidence of extrapelvic SMs.

RESULTS

• ? The 10‐year SM‐free survival for the RP, BT and EBRT cohorts were 89%, 87%, and 83%, respectively (RP vs EBRT, P= 0.002; RP vs BT, P= 0.37).
• ? The 10‐year likelihoods for bladder or colorectal cancer SM development in the RP, BT and EBRT groups were 3%, 2% and 4%, respectively (P= 0.29).
• ? Multivariate analysis of predictors for development of all SMs showed that older age (P= 0.01) and history of smoking (P < 0.001) were significant predictors for the development of a SM, while treatment intervention was not found to be a significant variable.
• ? Among 243 patients who developed a SM, the 5‐year likelihood of SM‐related mortality among patients with SMs in the EBRT and BT groups was 43.7% and 15.6%, respectively, compared with 26.3% in the RP cohort; P= 0.052).

CONCLUSIONS

• ? The incidence of SM after radiotherapy was not significantly different from that after RP when adjusted for patient age and smoking history.
• ? The incidence of bladder and rectal cancers was low for both EBRT‐ and BT‐treated patients.
• ? Among patients who developed a SM, the likelihood of mortality related to the SM was not significantly different among the treatment cohorts.

     

Prognostic value of apoptotic markers in squamous cell carcinoma of the urinary bladder

Study Type – Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Apoptotic pathways are important in carcinogenesis. Many studies, involving small numbers of patients, have found an association between one or two apoptotic markers and some of the pathological features of squamous cell carcinoma (SCC). This study included a large number of patients who had undergone radical cystectomy (RC) for SCC with long‐term follow‐up, allowing us to study biomarker alterations and their prognostic role. This is the first study on the prognostic role of a panel of apoptotic‐related markers in SCC of the urinary bladder, introducing the novel concept of a prognostic marker score based on the number of altered markers. We found that apoptotic markers can improve prediction of oncological outcomes after RC for SCC and might potentially help in patient selection for adjunct therapies.

OBJECTIVE

• ? To evaluate the association of cleaved caspase‐3 (CC‐3), Bax, COX‐2, and p53 expression with pathological features and clinical outcomes in patients with squamous cell carcinoma (SCC) of the urinary bladder.

METHODS

• ? Immunohistochemistry for CC‐3, Bax, COX‐2, and p53 was performed on tissue microarray sections of radical cystectomy specimens with pure SCC from 1997 to 2003. The relationship between the expression of these markers and pathological features was assessed.
• ? A prognostic marker score (PS) was defined as favourable if ≤2 biomarkers were altered and unfavourable if >2 biomarkers were altered and the association of the PS with oncological outcomes was examined.

RESULTS

• ? The study included 151 patients, of whom 98 were men and 53 were women, with a mean age of 52 years. SCC was associated with schistosomiasis (bilharziasis) in 122 (81%) patients.
• ? Pathological stage was T2 in 50%, T3 in 38%, T1 in 6% and T4 in 6% of patients. Tumours were low grade in 53%, lymph node metastasis was found in 30.5% and lymphovascular invasion was found in 16% of patients.
• ? Median follow‐up was 63.2 months.
• ? Advanced stage was associated with COX‐2, p53 and CC‐3 alterations and high grade was associated with COX‐2 alterations (P < 0.05). The total number of altered markers and unfavourable PS were associated with both disease recurrence and bladder cancer‐specific mortality in Kaplan–Meier analyses (P < 0.05). Unfavourable PS was an independent predictor of disease recurrence (hazard ratio [HR] 2.694, 95% confidence interval [CI] 1.386–5.235, P= 0. 003) and bladder cancer‐specific mortality (HR 2.868, 95% CI 1.209–6.802, P= 0. 017) in multivariable Cox regression analysis.

CONCLUSION

• ? Markers of apoptosis pathways may play an important role in the prognosis of SCC of the bladder. An increased number of altered markers and an unfavourable PS may identify patients who might benefit from multimodal therapies.

     

Prognostic factors and outcome in patients with T1 high‐grade bladder cancer: can we identify patients for early cystectomy?

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Although several papers have attempted to identify individual risk factors for T1 high‐grade (T1HG) urothelial carcinoma of the bladder for disease recurrence or progression, and nomograms have been generated to aid in the prediction of disease progression, there has been a lack of systematic examination of which factors predict clinically important outcomes. Treatment of T1HG remains controversial, particularly with regards to timing of radical cystectomy. Patients with T1HG bladder cancer are at a significant risk of progression and death from disease. Primary tumours, sessile architecture, and trigonal location are factors associated with worse outcome and may be used to counsel patients towards early cystectomy.

OBJECTIVE

• ? To assess outcome in patients with T1 high‐grade (T1HG) bladder cancer treated at a single academic institution and to determine the prognostic factors that can help in counselling patients towards early cystectomy.

PATIENTS AND METHODS

• ? Records of 2570 patients with bladder cancer treated from 1995 to 2005 were reviewed. Only patients diagnosed with T1HG disease were included in the analysis.
• ? Collected variables included various clinicopathological parameters, use of statins, smoking, as well as dates of recurrence, progression, radical cystectomy and death.
• ? Recurrence‐free survival (RFS) and worsening‐free survival (WFS) were analyzed.
• ? Multivariate Cox proportional regression analysis was employed to verify the prognostic significance of various variables.

RESULTS

• ? In total, 278 (10.8%) patients were identified as having T1HG disease on transurethral resection.
• ? 66% of patients who recurred, and 36.3% developed stage progression after a median (range) follow‐up of 3 (0.1–15.4) years.
• ? 30% patients who underwent radical cystectomy, and 9% were dead of disease.
• ? The 5‐year RFS and WFS rates were 26.6% and 49.4%, respectively.
• ? On multivariate analysis, only non‐trigonal tumour location, restaging transurethral resection, history of previous carcinoma not invading bladder muscle and adjuvant bacille Calmette‐Guérin (BCG) therapy were significantly associated with prolonged RFS, whereas papillary tumour architecture, history of previous carcinoma not invading bladder muscle and adjuvant BCG therapy were significantly associated with prolonged WFS.

CONCLUSIONS

• ? Patients with T1HG bladder cancer are at a significant risk of progression and death from disease.
• ? Primary tumours, sessile architecture and trigonal location are factors associated with a worse outcome and may be used to counsel patients towards early cystectomy.