Extended Versus Limited Lymph Node Dissection in Bladder Cancer Patients Undergoing Radical Cystectomy: Survival Results from a Prospective, Randomized Trial.

BACKGROUND: The extent of lymph node dissection (LND) in bladder cancer (BCa) patients at the time of radical cystectomy may affect oncologic outcome. OBJECTIVE: To evaluate whether extended versus limited LND prolongs recurrence-free survival (RFS). DESIGN, SETTING, AND PARTICIPANTS: Prospective, multicenter, phase-III trial patients with locally resectable T1G3 or muscle-invasive urothelial BCa (T2-T4aM0). INTERVENTION: Randomization to limited (obturator, and internal and external iliac nodes) versus extended LND (in addition, deep obturator, common iliac, presacral, paracaval, interaortocaval, and para-aortal nodes up to the inferior mesenteric artery). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was RFS. Secondary endpoints included cancer-specific survival (CSS), overall survival (OS), and complications. The trial was designed to show 15% advantage of 5-yr RFS by extended LND. RESULTS AND LIMITATIONS: In total, 401 patients were randomized from February 2006 to August 2010 (203 limited, 198 extended). The median number of dissected nodes was 19 in the limited and 31 in the extended arm. Extended LND failed to show superiority over limited LND with regard to RFS (5-yr RFS 65% vs 59%; hazard ratio [HR]=0.84 [95% confidence interval 0.58-1.22]; p=0.36), CSS (5-yr CSS 76% vs 65%; HR=0.70; p=0.10), and OS (5-yr OS 59% vs 50%; HR=0.78; p=0.12). Clavien grade ≥3 lymphoceles were more frequently reported in the extended LND group within 90d after surgery. Inclusion of T1G3 tumors may have contributed to the negative study result. CONCLUSIONS: Extended LND failed to show a significant advantage over limited LND in RFS, CSS, and OS. A larger trial is required to determine whether extended compared with limited LND leads to a small, but clinically relevant, survival difference (ClinicalTrials.gov NCT01215071). PATIENT SUMMARY: In this study, we investigated the outcome in bladder cancer patients undergoing cystectomy based on the anatomic extent of lymph node resection. We found that extended removal of lymph nodes did not reduce the rate of tumor recurrence in the expected range.

Update of the ICUD-SIU International Consultation on Bladder Cancer 2018: urinary diversion.

PURPOSE: To provide a comprehensive overview and update of the joint consultation of the International Consultation on Urological Diseases (ICUD) and Société Internationale d'Urologie on Bladder Cancer Urinary Diversion (UD). METHODS: A detailed analysis of the literature was conducted reporting on the different modalities of UD. For this updated publication, an exhaustive search was conducted in PubMed for recent relevant papers published between October 2013 and August 2018. Via this search, a total of 438 references were identified and 52 of them were finally eligible for analysis. An international, multidisciplinary expert committee evaluated and graded the data according to the Oxford System of Evidence-based Medicine. RESULTS: The incidence of early complications has been reported retrospectively in the range of 20-57%. Unfortunately, only a few randomized controlled studies exist within the field of UD. Consequently, almost all studies used in this report are of level 3-4 evidence including expert opinion based on "first principles" research. CONCLUSIONS: Complications rates overall following RC and UD are significant, and when strict reporting criteria are incorporated, they are much higher than previously published. Complications can occur up to 20 years after surgery, emphasizing the need for lifelong follow-up. Progress has been made to prevent complications implementing robotic surgery and fast track protocols. Preoperative patient information, patient selection, surgical techniques, and careful postoperative follow-up are the cornerstones to achieve good results.

Prostate-specific antigen density as a parameter for the prediction of positive lymph nodes at radical prostatectomy.

OBJECTIVE: The aim was to determine the prognostic ability of Partin's tables for a patient collective undergoing radical prostatectomy (RP) and to evaluate the association of prostate-specific antigen (PSA) density (PSAD) and postoperative lymph node status. METHODS: From 1999 to 2006, 393 consecutive patients underwent RP at our Urology department. Patients with Gleason scores < 6, clinical stages >T2c or neoadjuvant hormonal therapy were excluded. Preoperative PSA, biopsy results, digital rectal examination, and prostate size at transrectal ultrasound were recorded. Risk stratification according to the Partin scoring system was performed. Postoperative results were compared with preoperative risk estimation. Univariate and multivariate statistical analysis about prediction of postoperative lymph node status was performed. RESULTS: Lymph node invasion (LNI) was found in 36 patients (9.16%). Kendall's rank correlation analysis revealed a significant association between the number of removed LN and LNI (P = 0.016). Patients with LNI had a significantly higher preoperative PSA and PSAD. Preoperative Gleason score was a significant predictor of LNI. The Partin tables' prediction of organ confined stages, extraprostatic extension, and seminal vesicle invasion was in line with the pathological findings in our collective. PSAD was a significant predictor of LNI in univariate and multivariate analysis. CONCLUSION: The most widely used nomogram is of high value in therapy decision-making, although it remains an auxiliary means. Considering the performance of lymph node dissection, surgeons should be aware of the specifics of the applied nomogram. PSAD appears as a useful adjunctive parameter for preoperative prostate risk estimation and warrants further evaluation.

Prostate-specific antigen persistence after radical prostatectomy as a predictive factor of clinical relapse-free survival and overall survival: 10-year data of the ARO 96-02 trial.

OBJECTIVE: The ARO 96-02 trial primarily compared wait-and-see (WS, arm A) with adjuvant radiation therapy (ART, arm B) in prostate cancer patients who achieved an undetectable prostate-specific antigen (PSA) after radical prostatectomy (RP). Here, we report the outcome with up to 12 years of follow-up of patients who retained a post-RP detectable PSA and received salvage radiation therapy (SRT, arm C). METHODS AND MATERIALS: For the study, 388 patients with pT3-4pN0 prostate cancer with positive or negative surgical margins were recruited. After RP, 307 men achieved an undetectable PSA (arms A + B). In 78 patients the PSA remained above thresholds (median 0.6, range 0.05-5.6 ng/mL). Of the latter, 74 consented to receive 66 Gy to the prostate bed, and SRT was applied at a median of 86 days after RP. Clinical relapse-free survival, metastasis-free survival, and overall survival were determined by the Kaplan-Meier method. RESULTS: Patients with persisting PSA after RP had higher preoperative PSA values, higher tumor stages, higher Gleason scores, and more positive surgical margins than did patients in arms A + B. For the 74 patients, the 10-year clinical relapse-free survival rate was 63%. Forty-three men had hormone therapy; 12 experienced distant metastases; 23 patients died. Compared with men who did achieve an undetectable PSA, the arm-C patients fared significantly worse, with a 10-year metastasis-free survival of 67% versus 83% and overall survival of 68% versus 84%, respectively. In Cox regression analysis, Gleason score ≥8 (hazard ratio [HR] 2.8), pT ≥ 3c (HR 2.4), and extraprostatic extension ≥2 mm (HR 3.6) were unfavorable risk factors of progression. CONCLUSIONS: A persisting PSA after prostatectomy seems to be an important prognosticator of clinical progression for pT3 tumors. It correlates with a higher rate of distant metastases and with worse overall survival. A larger prospective study is required to determine which patient subgroups will benefit most from which treatment option.

Analysis of early morbidity and functional outcome of thulium: yttrium-aluminum-garnet laser enucleation for benign prostate enlargement: patient age and prostate size determine adverse surgical outcome.

OBJECTIVE: To evaluate complications and functional outcome and to identify patient-associated risk factors, we analyzed consecutive patients undergoing thulium:yttrium-aluminum-garnet laser enucleation of the prostate (ThuLEP) in our department. METHODS: A total of 234 patients were prospectively analyzed. Preoperative data, postoperative complications, and outcome at 6, 12, and 24 months were recorded. Individual risk factors for complications and treatment failure were assessed by univariate and multivariate analyses. RESULTS: Mean age at surgery was 72.88 ± 7.83 years. Mean preoperative prostate size was 84.8 ± 34.9 mL. Thirty-day complication rate was 19.7%. Functional treatment failure occurred in 9.0% of all patients. Decline of mean International Prostate Symptom Score was -75%, quality of life index -76%, and postvoid residual -86% at 24 months. Maximum urine flow at 24 months was improved at +231%. In univariate analysis, age >80 years and prostate size <50 mL were significant predictors of complications, which was confirmed by multivariate analysis (P = .0277 and .0409, respectively). Age >80 years, prostate size <80 mL or <50 mL, and American Society of Anesthesiologists classification were significant predictors of functional treatment failure in univariate analysis. Prostate size <80 mL or <50 mL was significantly associated with treatment failure (P < .001) in multivariate analysis. CONCLUSION: ThuLEP is a safe and efficient surgical procedure, even in a patient cohort with high prostate volumes, age, and comorbidities. However, high patient age and small prostate size were significant determinants of adverse outcomes after surgery. To address the question of optimal therapy selection for patients with prostates smaller than 80 mL, further prospective randomized evaluation of ThuLEP and alternative surgical interventions is needed.

Continent ileovesicostomy after bladder neck closure as salvage procedure for intractable incontinence.

INTRODUCTION: We evaluated the success rate of continent vesicostomy using an ileal segment with seroserosally embedded, tapered ileum for bladder augmentation with continent stoma following bladder neck closure (BNC) for severely damaged bladders or persistent urinary incontinence. MATERIAL AND METHODS: A total of 15 patients were treated for persistent urinary incontinence or non-reconstructible bladder outlet between 2003 and 2012. Underlying diagnosis included post-prostatectomy incontinence (n = 5), recurrent bladder neck stenosis (n = 5), neurogenic bladder (n = 3), urethral tumor recurrence following orthotopic neobladder (n = 1) and post-TVT and colposuspension incontinence (n = 1). All patients underwent open BNC, omental interposition and continent vesicoileostomy. The continent outlet was placed in the lower abdomen using a circumferential subcutaneous and skin plasty to avoid retraction. Data collected included age, underlying diagnosis, stoma site, time to complications and need for subsequent surgical revisions. All patients received a standardized questionnaire at the time of data acquisition and were personally interviewed. RESULTS: Median follow-up was 24 months (range: 2-111). Primary BNC was successful in all patients and primary continence rate was 86.7%. Two patients (13.3%) suffered from failure of the continence mechanism, caused by stoma stenosis at skin level and insufficiency of the bladder augmentation and stoma due to local infection. One additional patient developed a mild stomal incontinence without need for further reconstruction. Regardless of the number of revisions, at the last follow-up 93.3% of patients had a functional channel. All complications occurred within the first postoperative year. CONCLUSIONS: This technique is an effective last resort treatment for patients with non-reconstructible bladder outlet.

Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial.

BACKGROUND: Local failure after radical prostatectomy (RP) is common in patients with cancer extending beyond the capsule. Three prospectively randomized trials demonstrated an advantage for adjuvant radiotherapy (ART) compared with a wait-and-see (WS) policy. OBJECTIVE: To determine the efficiency of ART after a 10-yr follow-up in the ARO 96-02 study. DESIGN, SETTING, AND PARTICIPANTS: After RP, 388 patients with pT3 pN0 prostate cancer (PCa) were randomized to WS or three-dimensional conformal ART with 60 Gy. The present analysis focuses on intent-to-treat patients who achieved an undetectable prostate-specific antigen after RP (ITT2 population)--that is, 159 WS plus 148 ART men. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point of the study was progression-free survival (PFS) (events: biochemical recurrence, clinical recurrence, or death). Outcomes were compared by log-rank test. Cox regression analysis served to identify variables influencing the course of disease. RESULTS AND LIMITATIONS: The median follow-up was 111 mo for ART and 113 mo for WS. At 10 yr, PFS was 56% for ART and 35% for WS (p<0.0001). In pT3b and R1 patients, the rates for WS even dropped to 28% and 27%, respectively. Of all 307 ITT2 patients, 15 died from PCa, and 28 died for other or unknown reasons. Neither metastasis-free survival nor overall survival was significantly improved by ART. However, the study was underpowered for these end points. The worst late sequelae in the ART cohort were one grade 3 and three grade 2 cases of bladder toxicity and two grade 2 cases of rectum toxicity. No grade 4 events occurred. CONCLUSIONS: Compared with WS, ART reduced the risk of (biochemical) progression with a hazard ratio of 0.51 in pT3 PCa. With only one grade 3 case of late toxicity, ART was safe. PATIENT SUMMARY: Precautionary radiotherapy counteracts relapse after surgery for prostate cancer with specific risk factors.

The utility of transrectal sonoelastography in preoperative prostate cancer assessment.

AIM: To determine the diagnostic quality of transrectal sonoelastography (SE) in the prediction and localisation of prostate cancer, we prospectively examined patients who had undergone radical prostatectomy in our urology department. METHODS: From April 2010 to January 2011, 61 patients with biopsy-proven prostate cancer underwent preoperative transrectal gray-scale (b-mode) ultrasound and SE of the prostate. Cancer-suspicious areas were documented for b-mode and SE, dividing the prostate into six topographic sectors. Suspicious areas in both modalities were compared to tumour localisation in the prostatectomy specimen. Sensitivity, specificity, positive- and negative predictive values were calculated for both investigation techniques. RESULTS: Prostate cancer was present in 232 of 366 pathological sectors (62 %). B-mode ultrasound showed 113 suspicious sectors, while SE indicated prostate cancer in 157 areas. The precise localisation of at least one pathologically confirmed cancerous lesion was possible in 42/61 (69 %) patients by b-mode ultrasound and 56/61 (92 %) patients by SE (P<0.005). The sensitivity for b-mode ultrasound was 33 % and specificity 74 %. For SE sensitivity was 53 %, while specificity was 74 %. CONCLUSIONS: SE offers a more precise localisation of prostate carcinoma than conventional ultrasound. To investigate the possible advantages of SE in during prostate biopsy and its value in the prediction of extracapsular cancer further studies are required.

Cataract surgery in patients taking alpha-1 antagonists: know the risks, avoid the complications.

BACKGROUND: The growing use of alpha-1 receptor antagonists in the treatment of benign prostatic hyperplasia (BPH) has created a new problem in ophthalmic surgery, the so-called intraoperative floppy iris syndrome (IFIS). This consists of a billowing iris, insufficient pupillary dilation with progressive intraoperative miosis, and protrusion of iris tissue through the tunnel and side port incision that are made for access to the anterior chamber during surgery. IFIS presents particular difficulties in cataract surgery which is carried out through the pupil with manipulations in the immediate vicinity of the iris. The complications range from poor visibility of the operative field to iris damage with the surgical instruments and to rupture of the posterior capsule, with loss of lens material into the vitreous body. METHODS: Selective literature review. RESULTS: Alpha-blockers have a direct effect on the alpha-receptors of the iris but also induce ultrastructural changes in the iridial stroma, leading to IFIS. The most important factor in avoiding complications of IFIS seems to be the ophthalmic surgeon's knowledge that the patient is taking an alpha-1 receptor antagonist. CONCLUSION: A thorough medical history and an optimized information flow among all physicians treating the patient-the urologist, the family physician, and the ophthalmic surgeon-are essential for safe cataract surgery.

Tumor growth in urinary diversion: a multicenter analysis.

BACKGROUND: The risk estimation of secondary tumors after different types of urinary diversion with intestinal segments is possible only for ureterosigmoidostomy owing to the lack of follow-up studies of other forms of urinary diversions. OBJECTIVE: We calculated the prevalence of secondary tumors associated with different forms of urinary diversion, relating the number of reported tumors to the number of performed diversions in German clinics. DESIGN, SETTING, AND PARTICIPANTS: We analyzed the operative records of 44 German clinics for urinary diversions performed from 1970 to 2007 and registered all reported secondary tumors up to 2009. MEASUREMENTS: For statistical comparison of the different tumor prevalences, Fisher exact test was used. Additionally, we compared tumor locations and latency periods in different forms of urinary diversions. RESULTS AND LIMITATIONS: In 17,758 urinary diversions, 32 secondary tumors occurred. The tumor risk in ureterosigmoidostomy (2.58%) and cystoplasty (1.58%) was significantly higher than in other continent forms of urinary diversion (p<0.0001). The risk in orthotopic (ileo-)colonic neobladders (1.29%) was significantly higher (p=0.0001) than in ileal neobladders (0.05%). The difference between ileocecal pouches (0.14%) and ileal neobladders was not significant (p=0.46), and the tumor risk with ileal conduits was minimal (0.02%). CONCLUSIONS: Ureterosigmoidostomies, cystoplasties, and probably orthotopic (ileo-)colonic neobladders bear a significantly increased tumor risk compared with the general population and necessitate regular endoscopic evaluation from at least the fifth postoperative year. Regular endoscopy is not imperative after ileal neobladders and conduits, but with catheterizable ileocecal pouches, it is recommended in the presence of symptoms such as hydronephrosis, chronic urinary infection, and hematuria.

Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen: ARO 96-02/AUO AP 09/95.

PURPOSE: Local failure after radical prostatectomy (RP) is common in patients with cancer extending beyond the capsule. Two randomized trials demonstrated an advantage for adjuvant radiotherapy (RT) compared with a wait-and-see policy. We conducted a randomized, controlled clinical trial to compare RP followed by immediate RT with RP alone for patients with pT3 prostate cancer and an undetectable prostate-specific antigen (PSA) level after RP. METHODS: After RP, 192 men were randomly assigned to a wait-and-see policy, and 193 men were assigned to immediate postoperative RT. Eligible patients had pT3 pN0 tumors. Patients who did not achieve an undetectable PSA after RP were excluded from treatment according to random assignment (n = 78; 20%). Of the remaining 307 patients, 34 patients on the RT arm did not receive RT and five patients on the wait-and-see arm received RT. Therefore, 114 patients underwent RT and 154 patients were treated with a wait-and-see policy. The primary end point was biochemical progression-free survival. RESULTS: Biochemical progression-free survival after 5 years in patients with undetectable PSA after RP was significantly improved in the RT group (72%; 95% CI, 65% to 81%; v 54%, 95% CI, 45% to 63%; hazard ratio = 0.53; 95% CI, 0.37 to 0.79; P = .0015). On univariate analysis, Gleason score more than 6 and less than 7, PSA before RP, tumor stage, and positive surgical margins were predictors of outcome. The rate of grade 3 to 4 late adverse effects was 0.3%. CONCLUSION: Adjuvant RT for pT3 prostate cancer with postoperatively undetectable PSA significantly reduces the risk of biochemical progression. Further follow-up is needed to assess the effect on metastases-free and overall survival.

Serosa lined and tapered ileum as primary and secondary continence mechanism for various catheterizable pouches.

PURPOSE: Incontinence of catheterizable ileocecal pouches with an umbilical stoma using the original Mainz pouch technique can be repaired by a secondary ileal intussusception nipple fixed in the ileocecal valve. In cases of a modified Mainz pouch with ureteral anastomosis to the prevalvular ileal segment another form of troubleshooting is necessary. MATERIALS AND METHODS: In 4 of 112 patients (3.6%) with the modified Mainz pouch described by Roth incontinence or stenosis of the catheterizable stoma occurred. A 24 to 30 cm segment of ileum was isolated. The proximal 8 to 10 cm were tapered and seroserosally embedded in the U-shaped 2 x 8 to 10 cm long remainder of the segment. After excising the insufficient efferent limb this ileal segment was anastomosed to the pouch and the umbilicus with tapered ileum acting as the continence mechanism. In a fifth patient such a segment was used for ileocystoplasty with an umbilical stoma after bladder neck closure. RESULTS: At a median followup of 6 months (range 5 to 64) all 5 patients were fully continent with regular, easy self-catheterization via the umbilicus. CONCLUSIONS: The introduced method seems to be a promising continence mechanism for various forms of catheterizable pouches, not only for troubleshooting.

Adjuvant cisplatin plus methotrexate versus methotrexate, vinblastine, epirubicin, and cisplatin in locally advanced bladder cancer: results of a randomized, multicenter, phase III trial (AUO-AB 05/95).

PURPOSE: Radical cystectomy as standard treatment of muscle-invasive urothelial carcinoma of the urinary bladder cures less than 50% of patients with locally advanced bladder cancer. We compared two adjuvant combination chemotherapies in patients with stage pT3a-4a and/or pathologic node-positive transitional-cell carcinoma of the bladder after radical cystectomy. PATIENTS AND METHODS: A total of 327 patients were randomly assigned to either adjuvant systemic chemotherapy with three cycles of cisplatin 70 mg/qm(2) on day 1 and methotrexate 40 mg/qm(2) on days 8 and 15 of a 21-day cycle (CM) or three cycles of methotrexate 30 mg/qm(2) on days 1, 15, and 22, vinblastine 3 mg/qm(2) on days 2, 15, and 22, epirubicin 45 mg/qm(2) on day 2, and cisplatin 70 mg/qm(2) on day 2 of a 28-day cycle (M-VEC). RESULTS: The hazard ratio for progression-free survival as the primary end point was 1.13 (90% CI, 0.86 to 1.48) for 163 CM patients compared with 164 M-VEC patients whose right-hand limit remained below the upper bound compatible with the noninferiority hypothesis (alpha = .0403). The 5-year progression-free, tumor-specific, and overall survival rates (point estimates +/- SE) for CM versus M-VEC were 46.3% +/- 4.6% v 48.8% +/- 4.5%, 52.0% +/- 4.6% v 52.3% +/- 4.8%, and 46.1% +/- 4.3% v 45.1% +/- 4.6%, respectively. WHO grade 3 and 4 leukopenia occurred in 7.0% of patients treated with CM and 22.2% of patients treated with M-VEC (P < .0001). CONCLUSION: CM cannot be considered inferior to M-VEC with regard to progression-free survival of patients with locally advanced bladder cancer after radical cystectomy. Moreover, patients receiving adjuvant CM combination therapy experienced significantly less grade 3 and 4 leukopenia than patients treated with M-VEC.

Alteration of the LRP1B gene region is associated with high grade of urothelial cancer.

We have delineated regions of interest at chromosome 2q21.2, 2q36.3, and 2q37.1 by deletion mapping of 114 urothelial cancers (UC). Altogether, 17%, 18%, and 63% of the G1, G2, and G3 tumors displayed loss of heterozygosity at chromosome 2q, respectively, The region at 2q21.2 was narrowed down to the LRP1B gene (NT_005129.6). Hemi- and homozygous deletion at the LRP1B gene region was seen in 31 of 114 UCs. Only 8% of the UCs with G1 and none with G2 tumors showed loss of heterozygosity at the LRP1B gene, whereas 49% of the G3 UCs had allelic loss at this region. RT-PCR analysis of the LRP1B gene showed the lack of expression of several exons in 2 of 9 cases analyzed. Our analysis suggests that the LRP1B gene is a candidate tumor suppressor gene in UCs.

High frequency of serum DNA alterations in renal cell carcinoma detected by fluorescent microsatellite analysis.

To date there are no reliable serological markers for renal cell carcinoma (RCC). We applied fluorescent microsatellite analysis (MSA) to detect serum DNA alterations in patients with RCC. Fresh tumour, peripheral blood and serum specimens from 60 consecutive patients treated for malignant renal tumours (n= 53 RCC and n= 7 non-RCC) were prospectively collected. After DNA extraction, we performed MSA with a total of 9 markers from the chromosomal regions 3p, 5q, 7p, 7q, 9p, 13q, 17p and 17q to identify tumour specific serum DNA alterations in Group I (n= 53 RCC); 11 additional markers were used in the first 23 RCCs (Group II) in order to increase sensitivity; and 20 healthy controls were investigated with 10 markers. Besides the histomorphological diagnosis the RCCs were genetically stratified according to the "Heidelberg Classification" of renal tumours. Detection of allelic imbalance and loss of heterozygosity (LOH) was carried out on an automated laser sequencer. In Group I we identified serum DNA alterations in 74% (39/53) of cases. When applying 20 markers, the sensitivity was elevated to 87% (20/23) in Group II. Investigating 20 healthy controls with 10 markers, the method rendered 85% specificity. The highest incidence of alterations was detected for chromosomal regions 3p and 5q. The presence of serum DNA alteration was not associated with tumour nuclear grade but exhibited a trend towards advanced stages (p = 0,044). In RCC, the microsatellite analysis has a high sensitivity in the detection of serum DNA alterations when a sufficient number of markers from various chromosomal regions are used. Advanced tumours tend to express serum DNA alterations more frequently.