Tumor budding has been defined as an isolated single cancer cell or a cluster composed of fewer than five cancer cells scattered in the stroma. It is a strong predictor for lymph node metastasis in T1 colorectal cancer. We introduced this concept to T1 non‐muscle invasive bladder cancer and evaluated whether tumor budding could have a prognostic impact on the clinical outcome. We identified 121 consecutive patients with newly diagnosed T1 bladder cancer between 1994 and 2014 at Keio University Hospital. All slides were re‐reviewed by a dedicated uropathologist. Budding foci were counted under ×200 magnification. When the number of budding foci was 10 or more, tumor budding was defined as positive. The relationship between tumor budding and clinical outcomes was assessed using a multivariate analysis. The median follow‐up was 52 months. Tumor budding was positive in 21 patients (17.4%). Tumor budding was significantly associated with T1 substaging, tumor architecture and lymphovascular invasion. The 5‐year progression‐free survival rate in T1 bladder cancer patients with tumor budding was 53.8%, which was significantly lower than that in patients without tumor budding (88.4%, P = 0.001). A multivariate Cox regression analysis revealed that tumor budding was independently associated with stage progression (P = 0.002, hazard ratio = 4.90). In a subgroup of patients treated with bacillus Calmette‐Guérin instillation (n = 88), tumor budding was also independently associated with stage progression (P = 0.003, hazard ratio = 5.65). Tumor budding may be a novel indicator for predicting stage progression in T1 bladder cancer, and would likely be easily introduced in clinical practice.

Cover image: The image represents a 3D heterogeneous tissue. The left blurry part represents a tissue without tissue-clearing methods and the right part shows a tissue after clearing. 3D IMAGING AND QUANTITATIVE ANALYSIS OF INTACT TISSUES AND ORGANS THESIS FOR DOCTORAL DEGREE (Ph.D.

Bacillus Calmette–Guérin induction with or without maintenance is the gold standard therapy for intermediate‐/high‐risk non‐muscle‐invasive bladder cancer; however, one‐third of patients treated with adequate bacillus Calmette–Guérin therapy do not achieve sufficient responses, and this is referred to as “bacillus Calmette–Guérin failure.” The term, bacillus Calmette–Guérin failure, is ambiguous and includes a very heterogeneous population of patients. By strictly focusing on patients who are unlikely to benefit from additional bacillus Calmette–Guérin therapy and who need to be treated with radical cystectomy, the new concept of “bacillus Calmette–Guérin unresponsive” was recently proposed, and might accelerate the development of novel therapeutic options for bacillus Calmette–Guérin‐unresponsive disease. A promising therapeutic strategy for bacillus Calmette–Guérin‐unresponsive disease is the blockade of the programmed cell death‐1/programmed cell death‐ligand 1 pathway, which is considered to be activated by bacillus Calmette–Guérin therapy. Several large clinical trials have been carried out to assess the potential of programmed cell death‐1/programmed cell death‐ligand 1 blockade in bacillus Calmette–Guérin‐naïve high‐risk non‐muscle‐invasive bladder cancer and bacillus Calmette–Guérin‐unresponsive disease. Furthermore, clinical trials that are targeting bacillus Calmette–Guérin‐unresponsive disease with other strategies, such as vaccines, gene therapy, and targeted and cytotoxic therapies, are ongoing. The findings of these trials are awaited in order to establish appropriate bladder‐sparing approaches for patients with bacillus Calmette–Guérin‐unresponsive disease.

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