Oxidative stress, caused by the imbalance between reactive species generation and the dysfunctional capacity of antioxidant defenses, is one of the characteristic features of cancer. Here, we quantified hydrogen peroxide in the tumor microenvironment (TME) and demonstrated that hydrogen peroxide concentrations are elevated in tumor interstitial fluid isolated from murine breast cancers in vivo, when compared with blood or normal subcutaneous fluid. Therefore, we investigated the effects of increased hydrogen peroxide concentration on immune cell functions. NK cells were more susceptible to hydrogen peroxide than T cells or B cells, and by comparing T, B, and NK cells' sensitivities to redox stress and their antioxidant capacities, we identified peroxiredoxin-1 (PRDX1) as a lacking element of NK cells' antioxidative defense. We observed that priming with IL15 protected NK cells' functions in the presence of high hydrogen peroxide and simultaneously upregulated PRDX1 expression. However, the effect of IL15 on PRDX1 expression was transient and strictly dependent on the presence of the cytokine. Therefore, we genetically modified NK cells to stably overexpress PRDX1, which led to increased survival and NK cell activity in redox stress conditions. Finally, we generated PD-L1–CAR NK cells overexpressing PRDX1 that displayed potent antitumor activity against breast cancer cells under oxidative stress. These results demonstrate that hydrogen peroxide, at concentrations detected in the TME, suppresses NK cell function and that genetic modification strategies can improve CAR NK cells' resistance and potency against solid tumors.

Background and Purpose: Non-muscle-invasive bladder cancer (NMIBC) constitutes a heterogeneous group of tumors with different prognoses. This population-based study aimed to report real-world cancer-specific survival (CSS) of NMIBC and create a prognostic nomogram based on the identified risk factors. Methods: The Surveillance, Epidemiology, and End Results database was searched for patients diagnosed with NMIBC from 2004 to 2015, who underwent transurethral resection of the bladder tumor. The dataset was divided into development and validation cohorts. Factors associated with CSS were identified using Cox proportional hazards and used to develop a prognostic nomogram. Results: In total, 98,238 patients with NMIBC were included. At the median follow-up of 124 months (IQR 81–157 months), cancer-specific mortality (CSM) was highest for T1HG (19.52%), followed by Tis (15.56%), similar for T1LG and TaHG (10.88% and 9.23%, respectively), and lowest for TaLG (3.76%). Multivariable Cox regression for CSS prediction was utilized to develop a nomogram including the following risk factors: tumor T category and grade, age, tumor size and location, histology type, primary character, race, income, and marital status. In the validation cohort, the model was characterized by an AUC of 0.824 and C-index that reached 0.795. Conclusions: To conclude, NMIBC is associated with a significant risk of long-term CSM especially, but not only, in patients with T1HG. Rarely diagnosed TaHG and T1LG tumors should be regarded as high-risk due to approximately 10% CSM. T category, grading, and age remain the most powerful determinants of CSS in NMIBC, but sociodemographic factors might also influence its prognosis.

Objectives: Although smoking is a well-recognized causative factor of urothelial bladder cancer and accounts for 50% of cases, less is known about the prognostic significance of smoking on non-muscle invasive bladder cancer (NMIBC) prognosis. This systematic review and meta-analysis aimed to evaluate the effect of smoking on the risk of NMIBC recurrence and progression. Materials and methods: We systematically searched Medline, Web of Science and Scopus databases for original articles published before October 2021 regarding the effect of smoking on NMIBC recurrence and progression. Information about smoking status and the number of events or odds ratio or hazard ratio for event-free survival must have been reported to include the study in the analysis. Quality In Prognosis Studies tool was utilized for the risk of bias assessment. Results: We selected 64 eligible studies, including 28 617 patients with NMIBC with available data on smoking status. In a meta-analysis of 28 studies with 7885 patients, we found that smokers (current/former) were at higher risk for recurrence (OR = 1.68; 95% CI 1.34–2.09; P < 0.0001) compared to never smokers. Subgroup analysis of 2967 patients revealed that current smokers were at a 1.24 higher risk of recurrence (OR = 1.24; 95% CI 1.02–1.50; P = 0.03) compared to former smokers. A meta-analysis of the hazard ratio revealed that smokers are at higher risk of recurrence (HR = 1.31; 95%CI 1.15–1.48; P < 0.0001) and progression (HR = 1.18; 95%CI 1.08–1.29; P < 0.001) compared to never smokers. Detrimental prognostic effect of smoking on progression, but not for recurrence risk was also noted in the subgroup analysis of high-risk patients (HR = 1.30; 95%CI 1.09–1.55; P = 0.004) and BCG-treated ones (HR = 1.15; 95%CI 1.06–1.25; P < 0.001). Conclusion: In conclusion, patients with non-muscle invasive bladder cancer and a history of smoking have a worse prognosis regarding recurrence-free and progression-free survival compared to non-smokers.

CD37 is a tetraspanin expressed prominently on the surface of B cells. It is an attractive molecular target exploited in the immunotherapy of B cell-derived lymphomas and leukemia. Currently, several monoclonal antibodies targeting CD37 as well as chimeric antigen receptor-based immunotherapies are being developed and investigated in clinical trials. Given the unique role of CD37 in the biology of B cells, it seems that CD37 constitutes more than a docking point for monoclonal antibodies, and targeting this molecule may provide additional benefit to relapsed or refractory patients. In this review, we aimed to provide an extensive overview of the function of CD37 in B cell malignancies, providing a comprehensive view of recent therapeutic advances targeting CD37 and delineating future perspectives.

Objective: To report real‐world rates of non‐muscle‐invasive bladder cancer (NMIBC) recurrence and progression within a European multicentre cohort with detailed information on intravesical instillation courses, as contemporary data on oncological outcomes in NMIBC are limited.Patients and methods: A total of 1918 patients with NMIBC treated with transurethral resection of bladder tumour (TURBT) were retrospectively identified from six tertiary‐referral European centres (2015–2022). Patients were stratified according to European Association of Urology 2021 criteria into low‐ (LR), intermediate‐ (IR), high‐ (HR) and very high‐risk (VHR) categories. Cumulative incidence plots and multivariable competing risks regression models addressing 5‐year rates of high‐grade (HG) recurrence and progression were fitted. Sensitivity analyses focused on patients receiving intravesical instillations and tested for the effect of adequate course (Bacillus Calmette‐Guérin: five or more induction + two or more maintenance instillations; mitomycin C: complete induction + ≥11 maintenance instillations).Results: Of all NMIBC patients identified, 467 (24.3%) were LR vs 582 (30.3%) IR vs 739 (38.5%) HR vs 130 (6.8%) VHR. The median (interquartile range) follow‐up after TURBT was 26 (12–46) months. The 5‐year HG recurrence rates were 7.2% in LR vs 17.3% in IR vs 26.7% in HR vs 30.9% in VHR patients, resulting in a three‐, five‐ and seven‐fold higher risk of IR, HR and VHR, respectively, relative to LR (all P < 0.001). The 5‐year progression rates were 3.9% in LR vs 5.2% in IR vs 13.6% in HR vs 31.6% in VHR patients, resulting in a six‐ and nine‐fold higher risk for HR and VHR, respectively, relative to LR (all P < 0.001). In all, 1001 (52.2%) patients underwent intravesical instillations. Those receiving adequate instillation course (244/1001 [24.3%]) had lower HG‐recurrence (hazard ratio 0.3, P < 0.001) and progression (hazard ratio 0.2, P = 0.001) risk.Conclusions: Patients with HR/VHR NMIBC face significantly higher HG recurrence and progression risks. While tailored treatment strategies are needed, adherence to adequate instillation course remains crucial for optimising oncological outcomes.

The currently available EORTC, CUETO and EAU2021 risk stratifications were originally developed to predict recurrence and progression in non-muscle-invasive bladder cancer (NMIBC). However, they have not been validated to differentiate between high-grade (HG) and low-grade (LG) recurrence-free survival (RFS), which are distinct events with specific implications. We aimed to evaluate the accuracy of available risk models and identify additional risk factors for HG RFS and PFS among NMIBC patients treated with Bacillus Calmette–Guérin (BCG). We retrospectively included 171 patients who underwent transurethral resection of the bladder tumor (TURBT), of whom 73 patients (42.7%) experienced recurrence and 29 (17%) developed progression. Initially, there were 21 low-grade and 52 high-grade recurrences. EORTC2006, EORTC2016 and CUETO recurrence scoring systems lacked accuracy in the prediction of HG RFS (C-index 0.63/0.55/0.59, respectively). EAU2021 risk stratification, EORTC2006, EORTC2016, and CUETO progression scoring systems demonstrated low to moderate accuracy (C-index 0.59/0.68/0.65/0.65) in the prediction of PFS. In the multivariable analysis, T1HG at repeat TURBT (HR = 3.17 p < 0.01), tumor multiplicity (HR = 2.07 p < 0.05), previous history of HG NMIBC (HR = 2.37 p = 0.06) and EORTC2006 progression risk score (HR = 1.1 p < 0.01) were independent predictors for HG RFS. To conclude, available risk models lack accuracy in predicting HG RFS and PFS in -NMIBC patients treated with BCG.