Long-term Recurrence Rates of Low-risk Non-muscle-invasive Bladder Cancer-How Long Is Cystoscopic Surveillance Necessary?

BACKGROUND: While low-risk non-muscle-invasive bladder cancer (LR-NMIBC) has a low propensity to progress, the risk of recurrence remains high (50% within 4 yr). Guidelines recommend cystoscopic surveillance after resection, but the necessary duration of follow-up is debated. OBJECTIVE: To determine the risk of recurrence beyond 5 yr after diagnosis in patients with LR-NMIBC, and to identify risk factors of recurrence. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter retrospective observational study, patients who received their first transurethral bladder tumor resection before 2016 for LR-NMIBC were included. Low risk was defined as a primary, solitary, low grade, Ta bladder tumor measuring <3 cm. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was determination of the recurrence rates at 1, 2, and 5 yr. The secondary endpoints included overall recurrence-free survival (RFS) and high-risk RFS. A univariate analysis and multivariable logistic regression were performed to assess the risk factors for recurrence over the study period. RESULTS AND LIMITATIONS: The median age of the 577 patients was 70.9 yr, and 126 (21.8%) patients were female. The median follow-up was 69.6 (interquartile range: 58.4) mo, and recurrence was observed in 236 (40.9%) patients. The 1-, 2-, and 5-yr RFS rates were 81.6% (95% confidence interval 78.4-84.9), 72.4% (68.7-76.3), and 59.2% (55-63.8), respectively. Recurrence after 5 yr was observed in 13.1% (28/213). High-risk recurrence, defined as the first recurrence of a high-grade and/or ≥T1 tumor, occurred in 6.2% (36/579) overall and 2.8% (6/213) after 5 yr. The lack of a single postoperative dose of chemotherapy and tumor size >2 cm were prognostic factors of recurrence. CONCLUSIONS: The risk of recurrence in patients with LR-NMIBC decreases progressively after the 1st year and remains low beyond 5 yr. Discontinuation of endoscopic surveillance after 5 yr in patients with LR-NMIBC can be discussed. Treatment with postoperative chemotherapy and tumor size <2 cm may be relevant variables to identify patients who will benefit from cystoscopic follow-up as short as 12 mo. PATIENT SUMMARY: In this study, we observed that 13% of patients who did not have a recurrence during the first 5 yr following the diagnosis of low-risk non-muscle-invasive bladder cancer will recur after this time point. Discontinuation of cystoscopic surveillance can be discussed after 5 yr in these patients.

Current Perioperative Therapy for Muscle Invasive Bladder Cancer.

Radical cystectomy is curative in only approximately 50% of patients with muscle-invasive bladder cancer. Although perioperative radiotherapy has been tested with the intent of improving locoregional disease control, there currently is no role for this modality in routine care. Perioperative systemic therapy is used with the intent of reducing the risk of systemic recurrence. Robust trial evidence supports the use of neoadjuvant cisplatin-based chemotherapy, with adjuvant chemotherapy offered as an alternative if neoadjuvant therapy is not administered. Perioperative immunotherapy represents the next frontier in perioperative therapy. Further biomarker development is required to guide treatment in individual patients.

Ceramide mediates inhibition of the renal epithelial sodium channel by tumor necrosis factor-alpha through protein kinase C.

To determine whether ceramide mediates regulation of the renal epithelial sodium channel (ENaC) by tumor necrosis factor-alpha (TNF-alpha), confocal microscopy and patch-clamp experiments were performed in A6 distal nephron cells. We found that TNF-alpha (100 ng/ml) had no effect on ENaC activity and ceramide level when the cells were grown in the presence of aldosterone, but significantly inhibited ENaC and induced ceramide production after the cells were pretreated with LY 294002, an inhibitor of phosphatidylinositol 3-kinase, for 24 h. The inhibition of ENaC induced by TNF-alpha was mimicked by exogenous sphingomyelinase (0.1 U/ml) and C(2)-ceramide (50 microM), but neither C(2)-dihydroceramide, a membrane-impermeable analog of C(2)-ceramide, nor choline, and abolished by pretreatment with GF109203X, a protein kinase C (PKC) inhibitor. C(2)-ceramide failed to affect ENaC in the cells pretreated with GF109203X, but not in the cells pretreated with PD-98059, a mitogen-activated protein kinase kinase inhibitor. C(2)-ceramide induced the externalization of phosphatidylserine (PS) in control A6 cells, but not in the cells pretreated with GF109203X. Together with our previous finding that cytosolic PS maintains ENaC activity in A6 cells, these data suggest that ceramide mediates TNF-alpha inhibition of the renal ENaC via a pathway associated with PKC-dependent externalization of PS.