Arkadius Kocot

Analysis of sex differences in cancer-specific survival and perioperative mortality following radical cystectomy: results of a large German multicenter study of nearly 2500 patients with urothelial carcinoma of the bladder.

BACKGROUND Outcome of patients with urothelial carcinoma of the bladder (UCB) varies between sexes. Although overall incidence is higher in men, cancer-specific survival (CSS) has been suggested to be lower in women. Although the former effect is attributed to greater exposure to carcinogens in men, the latter has not been elucidated. OBJECTIVES The aim of the study was to identify sex-specific outcomes based on one of the largest databases of patients with UCB who underwent radical cystectomy (RC). METHODS This retrospective multicenter series comprised 2483 patients in Stage M0 who underwent RC for UCB from 1989 to 2008; 20.4% of patients were women. The impact of sex on CSS in the entire study group and in specific subgroups was analyzed. The median follow-up time was 42 months (interquartile range, 21-79). RESULTS Histopathologic criteria of pathologic tumor (pT), pathologic nodal (pN), grade, lymphovascular invasion (LVI), and associated carcinoma in situ (CIS) of the study did not differ between sexes. The percentage of female patients increased over time. Five-year CSS in female patients was significantly lower than in male patients (60% vs 66%; P = 0.005). In multivariate analysis adjusted to other covariates, tumor stage ≥pT3 (hazard ratio [HR] = 2.44; P < 0.001), positive pN status (HR = 1.91; P < 0.001), LVI (HR = 1.48; P < 0.001), lower count of lymph nodes removed (HR = 0.98; P = 0.002), older age (HR = 1.01; P < 0.001), and female gender (HR = 1.26; P = 0.011) had an independent impact on CSS. Deterioration of CSS in female patients was pronounced when LVI was present (HR = 1.57; P < 0.001) and when RC was performed in the earlier time period (HR = 2.44; P < 0.001). However, women showed significantly lower perioperative mortality (within 90 days after RC) compared with men. CONCLUSIONS After RC for UCB, cancer-specific mortality was higher in female patients; this disadvantage was more pronounced in earlier time periods. In addition, worse outcome of women with verified LVI was shown to be comparable with men. These findings were suggestive of different tumor biology and potentially unequal access to timely RC in earlier time periods because of reduced awareness of UCB in women. Further studies are required to improve UCB outcome in both sexes, notably in female patients.

Testis-sparing Surgery Versus Radical Orchiectomy in Patients With Leydig Cell Tumors

OBJECTIVES To compare retrospectively the outcome of testis-sparing surgery (TSS) to radical orchiectomy (RO) in patients with Leydig cell tumor (LCT). METHODS Between 1992 and 2008, 16 patients with LCT of the testis were identified. All but 1 tumor could be detected by ultrasonography. Alpha-fetoprotein and beta-human chorionic gonadotropin levels were normal in all patients. Eight patients underwent RO (mean age at surgery 42 years [27-61]; median tumor size 12.9 mm [10-25]) and the remaining 8 underwent TSS (mean age at surgery 34 years [18-49]; median tumor size 8.6 mm [4-23]). Staging (abdominal computed tomography and chest x-ray or thoracic computed tomography) was negative in all patients. RESULTS Median follow-up was 77 months (17-186) after RO and 42 months (1-86 months) after TSS. There was no local recurrence or metastasis in patients after RO. A metachronous LCT was removed from the spermatic cord 29 months after TSS of the ipsilateral testis in 1 patient. Another patient underwent surgical exploration of the testis 31 months after ipsilateral TSS because of a suspicious lesion identified in ultrasonography; a tumor was ruled out by histopathology. CONCLUSIONS In the medium term, TSS is a safe procedure in patients with LCT <25 mm.

Prognostic Value of Perinodal Lymphovascular Invasion Following Radical Cystectomy for Lymph Node-positive Urothelial Carcinoma

BACKGROUND Metastasis of urothelial carcinoma of the bladder (UCB) into regional lymph nodes (LNs) is a key prognosticator for cancer-specific survival (CSS) after radical cystectomy (RC). Perinodal lymphovascular invasion (pnLVI) has not yet been defined. OBJECTIVE To assess the prognostic value of histopathologic prognostic factors, especially pnLVI, on survival. DESIGN, SETTING, AND PARTICIPANTS A total of 598 patients were included in a prospective multicentre study after RC for UCB without distant metastasis and neoadjuvant and/or adjuvant chemotherapy. En bloc resection and histopathologic evaluation of regional LNs were performed based on a prospective protocol. The final study group comprised 158 patients with positive LNs (26.4%). INTERVENTION Histopathologic analysis was performed based on prospectively defined morphologic criteria of LN metastases. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Multivariable Cox proportional hazard regression models determined prognostic impact of clinical and histopathologic variables (age, gender, tumour stage, surgical margin status, pN, diameter of LN metastasis, LN density [LND], extranodal extension [ENE], pnLVI) on CSS. The median follow-up was 20 mo (interquartile range: 11-38). RESULTS AND LIMITATIONS Thirty-one percent of patients were staged pN1, and 69% were staged pN2/3. ENE and pnLVI was present in 52% and 39%, respectively. CSS rates after 1 yr, 3 yr, and 5 yr were 77%, 44%, and 27%, respectively. Five-year CSS rates in patients with and without pnLVI were 16% and 34% (p<0.001), respectively. PN stage, maximum diameter of LN metastasis, LND, and ENE had no independent influence on CSS. In the multivariable Cox model, the only parameters that were significant for CSS were pnLVI (hazard ratio: 2.47; p=0.003) and pT stage. However, pnLVI demonstrated only a minimal gain in predictive accuracy (0.1%; p=0.856), and the incremental accuracy of prediction is of uncertain clinical value. CONCLUSIONS We present the first explorative study on the prognostic impact of pnLVI. In contrast to other parameters that show the extent of LN metastasis, pnLVI is an independent prognosticator for CSS.

Tumor thrombus of inferior vena cava in patients with renal cell carcinoma - clinical and oncological outcome of 50 patients after surgery

BackgroundTo evaluate oncological and clinical outcome in patients with renal cell carcinoma (RCC) and tumor thrombus involving inferior vena cava (IVC) treated with nephrectomy and thrombectomy.MethodsWe identified 50 patients with a median age of 65 years, who underwent radical surgical treatment for RCC and tumor thrombus of the IVC between 1997 and 2010. The charts were reviewed for pathological and surgical parameters, as well as complications and oncological outcome.ResultsThe median follow-up was 26 months. In 21 patients (42%) distant metastases were already present at the time of surgery. All patients underwent radical nephrectomy, thrombectomy and lymph node dissection through a flank (15 patients/30%), thoracoabdominal (14 patients/28%) or midline abdominal approach (21 patients/42%), depending upon surgeon preference and upon the characteristics of tumor and associated thrombus. Extracorporal circulation with cardiopulmonary bypass (CPB) was performed in 10 patients (20%) with supradiaphragmal thrombus of IVC. Cancer-specific survival for the whole cohort at 5 years was 33.1%. Survival for the patients without distant metastasis at 5 years was 50.7%, whereas survival rate in the metastatic group at 5 years was 7.4%. Median survival of patients with metastatic disease was 16.4 months.On multivariate analysis lymph node invasion, distant metastasis and grading were independent prognostic factors. There was no statistically significant influence of level of the tumor thrombus on survival rate. Indeed, patients with supradiaphragmal tumor thrombus (n = 10) even had a better outcome (overall survival at 5 years of 58.33%) than the entire cohort.ConclusionsAn aggressive surgical approach is the most effective therapeutic option in patients with RCC and any level of tumor thrombus and offers a reasonable longterm survival. Due to good clinical and oncological outcome we prefer the use of CPB with extracorporal circulation in patients with supradiaphragmal tumor thrombus. Cytoreductive surgery appears to be beneficial for patients with metastatic disease, especially when consecutive therapy is performed. Although sample size of our study cohort is limited consistent with some other studies lymph node invasion, distant metastasis and grading seem to have prognostic value.

Reactive antibodies against bacillus Calmette-Guerin heat-shock protein-65 potentially predict the outcome of immunotherapy for high-grade transitional cell carcinoma of the bladder.

Intravesical immunotherapy with Mycobacterium bovis (M. bovis) bacillus Calmette‐Guerin (BCG) is the current standard of care against superficial, high‐grade transitional cell carcinoma (TCC) of the urinary bladder (carcinoma in situ and pathologic T1, grade 3 disease). However, individual patient outcome is barely predictable because of the lack of serum markers. Consequently, progression to muscle‐invasive bladder cancer and critical delay of treatments (such as neoadjuvant combination chemotherapy and/or radical cystectomy) often occur. The objectives of this study were to identify a marker for measuring the BCG‐induced immune response and to predict the outcomes and potential improvements of BCG immunotherapy.

Impact of miR-21, miR-126 and miR-221 as Prognostic Factors of Clear Cell Renal Cell Carcinoma with Tumor Thrombus of the Inferior Vena Cava

Clear cell renal cell carcinoma (ccRCC) characterized by a tumor thrombus (TT) extending into the inferior vena cava (IVC) generally indicates poor prognosis. Nevertheless, the risk for tumor recurrence after nephrectomy and thrombectomy varies. An applicable and accurate prediction system to select ccRCC patients with TT of the IVC (ccRCC/TT) at high risk after nephrectomy is urgently needed, but has not been established up to now. To our knowledge, a possible role of microRNAs (miRs) for the development of ccRCC/TT or their impact as prognostic markers in ccRCC/TT has not been explored yet. Therefore, we analyzed the expression of the previously described onco-miRs miR-200c, miR-210, miR-126, miR-221, let-7b, miR-21, miR-143 and miR-141 in a study collective of 74 ccRCC patients. Using the expression profiles of these eight miRs we developed classification systems that accurately differentiate ccRCC from non-cancerous renal tissue and ccRCC/TT from tumors without TT. In the subgroup of 37 ccRCC/TT cases we found that miR-21, miR-126, and miR-221 predicted cancer related death (CRD) accurately and independently from other clinico-pathological features. Furthermore, a combined risk score based on the expression of miR-21, miR-126 and miR-221 was developed and showed high sensitivity and specificity to predict cancer specific survival (CSS) in ccRCC/TT. Using the combined risk score we were able to classify ccRCC/TT patients correctly into high and low risk cases. The risk stratification by the combined risk score (CRS) will benefit from further cohort validation and might have potential for clinical application as a molecular prediction system to identify high- risk ccRCC/TT patients.

Frozen Section Analysis of Ureteral Margins in Patients Undergoing Radical Cystectomy for Bladder Cancer: Differential Impact of Carcinoma in situ in the Bladder on Reliability and Impact on Tumour Recurrence in the Upper Urinary Tract

Background: Patients undergoing radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) are at risk for upper urinary tract recurrence (UUTR), especially in case of carcinoma in situ (CIS). Data on the impact of CIS in the urinary bladder on ureteral tumour involvement or UUTR are conflicting. We presently evaluate the accuracy of intraoperative frozen section analysis (FSA) of the ureteral margin, the incidence of ureteral tumour involvement and their impact on UUTR in patients undergoing RC for UCB with versus without CIS of the bladder. Material and Methods: Between 2003 and 2007, 243 patients underwent RC in our department. 176 of these for UCB, either without CIS (n = 117, group I) or solitary/concomitant CIS (n = 59, group II). FSA was performed. Patients were followed up for UUTR. Results: Overall, 403 ureteral margins - including re-resections - were analysed (group I, n = 232; group II, n = 171). One patient (0.85%) in group I and 21 patients (35.6%) in group II had tumour involvement of the ureter (p < 0.0001) at the time of RC. The false-negative rate of FSA compared to final histopathology was 0.4% (1/232) for group I and 2.9% (5/171) for group II, respectively. Mean duration of follow-up was 26 months (1-72). In group II, 2 patients (1.1%) had UUTR in the follow-up; both had initially positive and subsequently false-negative FSA. Conclusions: Tumour involvement of the ureter is found significantly more often in solitary or concomitant CIS of the bladder. Intraoperative ureteral FSA is accurate and should be recommended in these patients. Ureteral tumour involvement predisposes to UUTR especially with initial positive margins mandating careful follow-up.

Long-Term Results of a Staged Approach: Continent Urinary Diversion in Preparation for Renal Transplantation

PURPOSE We provide the long-term results of renal transplantation into continent urinary intestinal reservoirs as a planned 2-stage procedure. MATERIALS AND METHODS Between November 1990 and January 2009, 18 patients underwent cadaveric or living related renal transplantation into continent urinary reservoirs (continent cutaneous diversion 16, orthotopic substitution 2). All patients were prospectively followed. RESULTS Of these patients 15 are currently free of dialysis. At a mean followup of 89.2 months (range 2 to 188) 13 patients had a serum creatinine ranging from 0.6 to 3.1 mg/dl (mean 1.49) after the first transplantation. Two patients underwent a second transplantation 12 and 122 months after loss of the transplant for renal vein thrombosis and chronic allograft dysfunction, respectively. Two additional patients had to resume hemodialysis 62 and 109 months after renal transplantation. The second transplantation was delayed mainly due to compliance problems. One patient died of fulminant septicemia after laparotomy elsewhere for bowel obstruction with normal renal function before that episode. The continence mechanism needed correction in 3 patients, and 2 further revisions were required for ureteral kinking and lymphocele. The patients with orthotopic substitution (2) voided to completion and showed complete continence. All patients with cutaneous diversion were continent day and night with easy catheterization. CONCLUSIONS This study is among the largest single series to date of renal transplantation into continent urinary diversions. Long-term followup confirms that this approach is a safe and socially well accepted treatment option in carefully selected patients.

Oncological Outcome of Primary versus Secondary Muscle-Invasive Bladder Cancer Is Comparable after Radical Cystectomy

Background: High-risk non-muscle-invasive bladder cancer (NMIBC) progressing to muscle-invasive bladder cancer (MIBC) is associated with adverse tumour biology. It is unclear, however, whether outcome of NMIBC progressing to MIBC is adverse compared to primary MIBC and whether NMIBC of higher risk of progression to MIBC is adverse compared to NMIBC of lower risk. Objective: Our objective was to assess cancer-specific survival (CSS) following radical cystectomy (RC) for primary MIBC and for NMIBC progressing to MIBC in dependence of EORTC risk score. Materials and Methods: Clinical and histopathological characteristics and CSS of 150 patients were assessed. Secondary MIBCs were stratified by EORTC risk score at the last transurethral resection of bladder tumour for NMIBC. Results: CSS did not differ significantly between primary and secondary MIBC (p = 0.521). Secondary MIBC with high EORTC score had significantly shorter CSS compared to secondary MIBC with intermediate EORTC score (p = 0.029). In multivariable analysis, pathological tumour stage (HR = 3.77; p = 0.020) and lymph node stage (HR = 2.34; p = 0.022) were significantly correlated with CSS. Conclusion: While the outcome of secondary MIBC is not generally adverse compared to primary MIBC, the EORTC risk score not only reflects high risk of progression of NMIBC to MIBC, but also worse outcome following RC for secondary MIBC. Timely RC should thus be debated in high-risk NMIBC.

The devastated bladder outlet: treatment options.

Purpose of review The purpose of this study is to review and discuss recently published studies of therapeutic options in cases with the combination of severe sphincteric damage and recurrent stricture of the bladder neck or anastomosis in patients with postradical prostatectomy. Recent findings Recent focus has been on successful management of recurrent bladder neck contracture with urethral dilatation or endoscopic techniques even in patients with prior history of additional radiation therapy. In addition, some authors include injectable agents in their armamentarium for the treatment of recurrent bladder neck stricture. Failure of all attempts to restore the bladder outlet and urethral patency results in a devastated bladder outlet with persistence of urinary incontinence, sometimes worsened when combined with recurrent obstruction. For this small subgroup of patients with severe damage of the lower urinary tract, treatment options are rare. In the current literature, several case series can be found, but no clinical trials exist to provide an evidence-based approach to this severe disorder. Open reconstructive techniques or urinary diversion with reservoirs made from bowel are necessary in these patients. In recent studies, laparoscopic and robot-assisted approaches have also been described. Summary In case of a ‘nonreconstructible’ devastated bladder outlet treatment, options are limited. These devastating conditions require a definitive surgical solution. Bladder neck closure, continent vesicostomy in most cases combined with augmentation or urinary diversion with or without cystectomy are last resort techniques for this problem.