Urinary NGAL may be a potential noninvasive diagnostic biomarker of renal scarring.

Estimation of urinary neutrophil-gelatinase associated lipocalin may be useful as a noninvasive diagnostic or prognostic biomarker for renal scarring.

Indoleamine 2,3‐dioxygenase 1 (IDO1) is a key enzyme associated with immunomodulation through its regulation of the tryptophan‐kynurenine (Kyn) pathway in advanced cancers, including metastatic renal cell carcinoma (mRCC). However, the failure of IDO1 inhibitors when used in combination with immune checkpoint inhibitors (ICIs), as observed in clinical trials, raises a number of questions. This study aimed to investigate the association of tryptophan 2,3‐dioxygenase (TDO) and IDO1 with cancer development and resistance to immunotherapy in patients with RCC. In our analysis of RCC tissue samples, tissue Kyn levels were elevated in advanced‐stage RCC and correlated well with TDO expression levels in RCC tumor cells. In patients with mRCC, TDO rather than IDO1 was expressed in RCC tumor cells, showing a strong association with Kyn expression. Furthermore, immunohistochemical staining of TDO was strongly associated with the staining intensity of forkhead box P3, as well as ICI therapy response and survival in patients with mRCC. Our study is the first to show that TDO expression in tumor tissues is associated with progression and survival, confirming its potential as a predictive biomarker of primary resistance to immunotherapy in patients with mRCC. Our findings suggest that strategies aimed at inhibiting TDO, rather than IDO1, in combination with ICI therapy may aid in the control of mRCC progression.

Abbreviations & Acronyms AUC = area under the receiver operating characteristic curve BMI = body mass index CNN = convolutional neural network DL = deep learning Grad-CAM = gradientweighted class activation mapping IQR = interquartile range ML = machine learning MRI = magnetic resonance imaging MUL = membranous urethral length NADT = neoadjuvant antiandrogen deprivation therapy NS = nerve sparing PC = prostate cancer PPUI = post-prostatectomy urinary incontinence PSA = prostate-specific antigen PV = prostate volume QOL = quality of life RARP = robot-assisted radical prostatectomy UI = urinary incontinence VGG-16 = Visual Geometry Group-16

Objectives To assess the impact of two cycles of neoadjuvant chemotherapy (NAC) in patients who underwent nephroureterectomy for high‐risk cN0M0 upper tract urothelial carcinoma (UTUC), and to evaluate the efficacy of NAC in patients with localised disease (≤cT2). Patients and Methods We retrospectively analysed patients with high‐risk cN0M0 UTUC who received NAC followed by surgery, compared with a matched cohort who underwent initial surgery at Fujita Health University during 2005–2019. Baseline and tumour characteristics, overall survival (OS), cancer‐specific survival (CSS), and recurrence‐free survival (RFS) were compared between the cohorts. Cox proportional hazards models were used to identify predictors of survival. Results There were 117 and 67 patients in the study group and the control group, respectively. Significantly higher pathological downstaging (pDS) and lower lymphovascular invasion (LVI) were observed in the study group than in the control group (48% vs 22%, P = 0.008 and 29% vs 46%, P = 0.045, respectively). The NAC group had significantly better 5‐year OS (79% vs 53%, P = 0.003), 5‐year CSS (84% vs 66%, P = 0.008), and 5‐year RFS (80% vs 61%, P = 0.001) than the control group. The OS benefit of NAC was observed even in patients with localised (≤cT2) disease (P = 0.019). Patients with LVI showed significantly worse CSS both in pathologically locally advanced (≥pT3) and in localised (≤pT2) tumours (P = 0.048 and P = 0.018, respectively). Multivariate analysis identified LVI, NAC, and pDS as independent predictors of OS. Male sex and post‐NAC LVI were identified as predictors of worse survival in patients who underwent NAC. Conclusions Two cycles of NAC improved the survival of patients with high‐risk UTUC, even in patients with localised disease. Although two cycles of NAC appear to be effective in cN0M0 high‐risk UTUC including localised disease, additional larger sample size multicentre prospective studies comparing short‐course NAC regimens followed by surgery and surgery alone are required.