Riikka Järvinen

Long-term Efficacy of Maintenance Bacillus Calmette-Guérin versus Maintenance Mitomycin C Instillation Therapy in Frequently Recurrent TaT1 Tumours without Carcinoma In Situ: A Subgroup Analysis of the Prospective, Randomised FinnBladder I Study with a 20-Year Follow-up

BACKGROUND The long-term prospective data on bacillus Calmette-Guérin (BCG) and mitomycin C (MMC) instillation therapy are limited. OBJECTIVE To compare the long-term benefit of BCG and MMC maintenance therapy in patients with recurrent bladder carcinoma. DESIGN, SETTING, AND PARTICIPANTS Eighty-nine patients with frequently recurrent TaT1 disease without carcinoma in situ (CIS) were eligible. Originally, the patients were enrolled in the prospective FinnBladder I study between 1984 and 1987 and randomised to receive BCG or MMC. Both regimens involved five weekly instillations, followed by monthly instillations for 2 yr. Because of alkalinising the urine and adjusting the dose to bladder capacity, the average concentration of MMC was low: 30-40 mg in 150-200 ml of phosphate buffer. Overall median follow-up time was 8.5 yr, whereas the median follow-up time of the patients who were still alive was 19.4 yr. MEASUREMENTS Primary end points were time to first recurrence and overall mortality. Secondary end points were progression and disease-specific mortality. RESULTS AND LIMITATIONS Thirty-six of 45 patients (80.0%) in the MMC group experienced recurrence in contrast to 26 of 44 patients (59.1%) in the BCG group. This finding was reflected in significantly lower cumulative incidence estimates in the BCG group (p=0.005). There was a weak trend for fewer progressions (p=0.1) and cancer-specific deaths (p=0.2) in the cumulative incidence analysis, as 4 patients versus 10 patients progressed and 4 patients versus 9 patients died from the disease in the BCG group versus the MMC group, respectively. No difference existed in the overall mortality. The study population, however, was too small for conclusive evidence about progression or survival. CONCLUSIONS An intensive intravesical BCG immunotherapy results in a sustained and significant long-term reduction in recurrence in frequently recurrent bladder carcinoma. The relatively low progression rate during the long follow-up suggests that it may be difficult to show significant differences in overall mortality with a substantially larger but otherwise similar study population. TRIAL REGISTRATION Registration was not considered to be necessary at this stage of the follow-up because the study was initiated as early as 1984 and the last randomisation took place in July 1987, that is, long before the current requirements concerning study registrations were implemented.

Long-term Outcome of Patients with Frequently Recurrent Non–muscle-invasive Bladder Carcinoma Treated with One Perioperative Plus Four Weekly Instillations of Mitomycin C Followed by Monthly Bacillus Calmette-Guérin (BCG) or Alternating BCG and Interferon-α2b Instillations: Prospective Randomised FinnBladder-4 Study

BACKGROUND Recurrent TaT1 non-muscle-invasive bladder cancer (NMIBC) patients should be treated with immediate instillation of chemotherapy after transurethral resection of bladder tumour followed by instillation therapy. OBJECTIVE To present long-term results of a study exploring the effect of initial mitomycin C (MMC) instillations followed by two types of immunotherapy for patients with frequently recurring NMIBC. DESIGN, SETTING, AND PARTICIPANTS Between 1992 and 1996, 236 patients with frequently recurring TaT1 grade 1-2 NMIBC were enrolled in the prospective randomised multicentre FinnBladder-4 study. INTERVENTION One perioperative plus four weekly instillations of MMC followed by monthly bacillus Calmette-Guérin (BCG) or alternating BCG and interferon (IFN)-α2b instillations for up to 1 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Primary end points were time to first recurrence and time to progression. Secondary end points were disease-specific mortality and overall survival. The principal statistical methods were the proportional subdistribution hazards model and Cox proportional hazards model plus cumulative incidence and Kaplan-Meier analyses. RESULTS AND LIMITATIONS The median follow-up was 10.3 yr (maximum: 19.8 yr) in the MMC-BCG group and 8.6 yr (maximum: 19.8 yr) in the MMC-BCG/IFN group. The probability of recurrence was significantly lower in the MMC-BCG group than in the MMC-BCG/IFN group (43% vs 78% at 10 yr and 45% vs 80% at 15 yr, respectively; hazard ratio: 2.86; 95% confidence interval, 1.98-4.13; p<0.001). There were no significant differences in the probability of progression, disease-free mortality, or overall survival. CONCLUSIONS Perioperative plus four weekly MMC instillations followed by monthly BCG, instead of alternating BCG and IFN-α2b instillations, significantly reduce long-term recurrence. PATIENT SUMMARY We demonstrated in non-muscle-invasive bladder cancer patients with exceptionally frequent recurrences that the risk of long-term recurrence was reduced from 78-80% to 43-45% if one perioperative plus four weekly mitomycin C instillations were followed by monthly bacillus Calmette-Guérin (BCG) instillations for 1 yr instead of alternating instillations of BCG and interferon-α2b. TRIAL REGISTRATION The registration was not considered necessary at this stage of the follow-up because the study was initiated as early as in 1992 and the last randomisation took place in 1996, before the current requirements concerning study registrations were implemented.

Long-term results of maintenance treatment of mitomycin C or alternating mitomycin C and bacillus Calmette–Guérin instillation therapy of patients with carcinoma in situ of the bladder: A subgroup analysis of the prospective FinnBladder 2 study with a 17-year follow-up

Abstract Objective. Only a few studies with a long-term follow-up exist on patients with carcinoma in situ (CIS) treated with instillation therapy. The objective was to study the long-term outcome of patients with CIS after mitomycin C (MMC) monotherapy or alternating therapy with MMC and bacillus Calmette–Guérin (BCG). Material and methods. The study population comprised 68 patients with CIS belonging to a larger material of 256 patients with non-muscle-invasive bladder carcinoma who were randomized between 1987 and 1992 in a prospective multicentre study. Patients received the same induction period with MMC and continued with maintenance treatment comprising either monthly instillations of MMC alone or alternating MMC and BCG instillations for up to 2 years. Primary endpoints were cancer-specific and overall mortality. Secondary endpoints were time to first recurrence and time to progression. The principal statistical methods were the Kaplan–Meier method and cumulative incidence analysis. Results. The overall median follow-up time of the patients with CIS was 7.2 years and the median follow-up time of the patients still alive was 17.1 years. The non-stratified probability of dying from bladder carcinoma at 5, 10 and 15 years was 13%, 25% and 28%, respectively. No significant difference was found between the study groups with respect to time to first recurrence, progression, or disease-specific or overall mortality. Conclusions. The long-term bladder cancer-specific mortality was unexpectedly low despite the relatively ineffective instillation therapy and the poor outcome of the patients after progression.

Hand-assisted laparoscopic versus open partial nephrectomy in patients with T1 renal tumor: Comparative perioperative, functional and oncological outcome

Abstract Objective: Studies comparing hand-assisted laparoscopic partial nephrectomy (HALPN) and open partial nephrectomy (OPN) for T1 kidney tumors are scarce. This study investigated the perioperative, functional and oncological outcomes of these methods. Materials and methods: A prospective institutional kidney tumor register was used to identify patients between January 2006 and May 2014 undergoing HALPN (n = 139) or OPN (n = 165) for tumors 7 cm or smaller with non-absolute indication for nephron-sparing surgery. The outcomes were compared using univariate and multivariate statistical methods. Results: HALPN and OPN groups were similar with regard to tumor characteristics but HALPN patients were 2 years younger (p = 0.001) and had less comorbidity. Fewer intraoperative complications were encountered in HALPN than in OPN patients (7.2% vs 12.7%, p = 0.043). HALPN patients had less all-grade postoperative 30 day complications than OPN patients (27% vs 41%, p = 0.037), but there was no significant difference in Clavien 3–5 complications. Glomerular filtration rate 3 months after operation was lower in the HALPN than in the OPN group (7.1 ± 12.7% vs 10.0 ± 12.4%, p = 0.054). There was no difference in overall survival or recurrence-free survival during the median follow-up of 35 months. Conclusions: HALPN is a feasible method to achieve equal perioperative, functional and oncological outcomes compared to OPN in patients with tumors 7 cm or smaller in diameter.

Intravesical Bacillus Calmette-Guérin Versus Combination of Epirubicin and Interferon-α2a in Reducing Recurrence of Non–Muscle-invasive Bladder Carcinoma: FinnBladder-6 Study

BACKGROUND Patients with non-muscle-invasive bladder cancer (NMIBC) belonging to the intermediate-risk group should be treated with intravesical instillations to prevent recurrence and progression. OBJECTIVE We compared the outcome of a monthly maintenance bacillus Calmette-Guérin (BCG) regimen with that of epirubicin (EPI) and interferon-α2a (IFN) in patients with NMIBC. DESIGN, SETTING, AND PARTICIPANTS Our prospective randomized multicenter study comprised 229 eligible patients with frequently recurrent TaT1 grade 1-2 or low-grade NMIBC enrolled between 1997 and 2008. INTERVENTIONS The four-arm study involved a single perioperative instillation of EPI plus five weekly instillations of BCG or EPI/IFN, followed by 11 monthly instillations in the 1-yr BCG or EPI/IFN maintenance arms, further followed by four additional quarterly instillations in the two 2-yr maintenance arms. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Time to recurrence, progression, disease-specific survival, and overall mortality were analyzed using the Kaplan-Meier and cumulative incidence analyses plus the Cox and proportional subdistribution hazards models. RESULTS AND LIMITATIONS The median follow-up time was 7.5 and 7.4 yr in the BCG and EPI/IFN groups, respectively. The probability of recurrence was significantly lower in the BCG group than in the EPI/IFN group. The probability was 39% versus 72% at 7.4 yr, respectively (hazard ratio [HR]: 0.41; 95% confidence interval [CI], 0.28-0.60; p<0.001). There was no significant difference in the probability of progression or in overall survival. However, there was a significant difference in disease-specific mortality in favor of the BCG group (HR: 0.20; 95% CI, 0.04-0.91; p=0.04). CONCLUSIONS The monthly maintenance BCG regimen showed excellent efficacy and was significantly better in preventing recurrence than a similar regimen of EPI/IFN-α2a. PATIENT SUMMARY A monthly bacillus Calmette-Guérin (BCG) regimen showed excellent efficacy and was significantly better in preventing recurrence than a similar regimen of epirubicin and interferon-α2a. TRIAL REGISTRATION Registration was not considered necessary at this stage of the follow-up because the study was initiated as early as in 1997, before the current requirements concerning study registrations were implemented.

Renal Tumor Invasion Depth and Diameter are the Two Most Accurate Anatomical Features Regarding the Choice of Radical Versus Partial Nephrectomy

Background and Aims: To evaluate simple tumor characteristics (renal tumor diameter and parenchymal invasion depth) compared with more complex classifications, that is, Renal Tumor Invasion Index (RTII) and Preoperative Aspects and Dimensions Used for an Anatomical classification, in predicting the type of nephrectomy (radical vs partial) performed. Material and Methods: A total of 915 patients who had undergone either partial nephrectomy (n = 388, 42%) or radical nephrectomy (n = 527, 58%) were identified from the Helsinki University Hospital kidney tumor database between 1 January 2006 and 31 December 2014. Tumor maximum diameter and depth of invasion into the parenchyma were estimated from computed tomography or magnetic resonance imaging images and compared with Preoperative Aspects and Dimensions Used for an Anatomical and Renal Tumor Invasion Index. Logistic regression and receiver operating curves were used to compare the parameters at predicting the type of nephrectomy. Results and conclusion: All the anatomical variables of receiver operating curve/area under the curve analyses were significant predictors for the type of nephrectomy. Parenchymal invasion (area under the curve 0.91; 95% confidence interval, 0.89–0.93), RTII (area under the curve 0.91; 95% confidence interval, 0.89–0.93), and diameter (area under the curve 0.91; 95% confidence interval, 0.89–0.93) performed significantly better than Preoperative Aspects and Dimensions Used for an Anatomical classification (area under the curve 0.88; 95% confidence interval, 0.85–0.89). In multivariable analysis, invasion depth was the best predictor of nephrectomy type (percentage correct, 85.6%). Addition of one anatomic parameter into the model of non-anatomical cofactors improved the accuracy of the model significantly, but the addition of more parameters did not. Parenchymal invasion depth and tumor diameter are the most accurate anatomical features for predicting the nephrectomy type. All potential anatomical classification systems should be tested against these two simple characteristics.

Male urethral reconstruction using vagina as a substitute in a 45X/46XY case.

Repair of failed hypospadias surgery is a challenging operation, which aims to restore normal voiding function without compromising erectile function or penile appearance. A twostage operation is required if a urethra is markedly scarred or penile skin is insufficient to form a pedicled flap. A free graft, often from buccal mucosa, is preferred for urethral reconstruction. However, if the urethral defect is long, other graft donor sites may be required. In some male patients, especially with proximal hypospadias or disorders of sex development (DSDs), a remnant of vagina may be available. In males, it is a diverticulum-like extension from the prostatic urethra, varying in length from 10mm to 8 cm [1]. Its use as a pedicled flap in urethroplasty has been described previously [2]. However, as far as we know, there are no previous reports on the use of vagina as a free graft donor site.

Reply from Authors re: Robert S. Svatek. Long-term Outcomes of the FinnBladder-4 Study. Eur Urol 2015;68:618–9: Which Type of Maintenance Matters?

with the SWOG-8507 regimen [7] [4_TD

Surgery for metastases of renal cell carcinoma: Outcome of treatments and external assessment of Leuven-Udine prognostic groups

DIFF]when preceded by BCG induction. The importance of early tumor control in determining long-term disease-free rates for patients with NMIBC is stressed in this trial with extensive follow-up [1]. Figure 1 in [2_TD

Renal tumour invasion depth and diameter are the two most accurate anatomical features regarding the choice of radical vs partial nephrectomy

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