Modulation of the tumor microenvironment in non-muscle-invasive bladder cancer by OncoTherad® (MRB-CFI-1) nanoimmunotherapy: effects on tumor-associated macrophages, tumor-infiltrating lymphocytes, and monoamine oxidases.

Non-muscle-invasive bladder cancer (NMIBC) presents management challenges due to its high recurrence rate and a complex tumor microenvironment (TME). This study investigated the effects of OncoTherad® (MRB-CFI1) nanoimmunotherapy on the TME of BCG-unresponsive NMIBC, focusing on alterations in monoamine oxidases (MAO-A and MAO-B) and immune markers: CD163, FOXP3, CD8, and CX3CR1. A comparative analysis of immunoreactivities was made before and after OncoTherad® treatment and an immune score (IS) was established to evaluate the correlation between immunological changes and clinical outcomes. Forty bladder biopsies of twenty patients were divided into 2 groups (n = 20/group): 1 (pre-treatment biopsies); and 2 (post-treatment biopsies). Our results showed stable MAO-A levels but a significant (p < 0.05) decrease in MAO-B immunoreactivity after treatment, suggesting OncoTherad®'s efficacy in targeting the tumor-promoting and immunosuppressive functions of MAO-B. Significant (p < 0.05) reductions in CD163 and FOXP3 immunoreactivities were seen in post-treatment biopsies, indicating a decreased presence of M2 macrophages and Tregs. Corroborating with these results, we observed reductions in tumor histological grading, focality and size, factors that collectively enhanced recurrence-free survival (RFS) and pathological complete response (PCR). Moreover, elevated IFN-γ immunoreactivities in treated biopsies correlated with increased counts of CD8+ T cells and higher CX3CR1 expression, underscoring OncoTherad®'s enhancement of cytotoxic T cell functionality and overall antitumor immunity. The IS revealed improvements in immune responses post-treatment, with higher scores associated with better RFS and PCR outcomes. These findings validate OncoTherad®'s capability to modify the bladder cancer microenvironment favorably, promoting effective immune surveillance and response.

OncoTherad® (MRB-CFI-1) Nanoimmunotherapy: A Promising Strategy to Treat Bacillus Calmette-Guérin-Unresponsive Non-Muscle-Invasive Bladder Cancer: Crosstalk among T-Cell CX3CR1, Immune Checkpoints, and the Toll-Like Receptor 4 Signaling Pathway.

This study assessed the safety and efficacy of OncoTherad® (MRB-CFI-1) nanoimmunotherapy for non-muscle invasive bladder cancer (NMIBC) patients unresponsive to Bacillus Calmette-Guérin (BCG) and explored its mechanisms of action in a bladder cancer microenvironment. A single-arm phase I/II study was conducted with 44 patients with NMIBC who were unresponsive to BCG treatment. Primary outcomes were pathological complete response (pCR) and relapse-free survival (RFS). Secondary outcomes comprised response duration and therapy safety. Patients' mean age was 65 years; 59.1% of them were refractory, 31.8% relapsed, and 9.1% were intolerant to BCG. Moreover, the pCR rate after 24 months reached 72.7% (95% CI), whereas the mean RFS reached 21.4 months. Mean response duration in the pCR group was 14.3 months. No patient developed muscle-invasive or metastatic disease during treatment. Treatment-related adverse events occurred in 77.3% of patients, mostly grade 1-2 events. OncoTherad® activated the innate immune system through toll-like receptor 4, leading to increased interferon signaling. This activation played a crucial role in activating CX3CR1+ CD8 T cells, decreasing immune checkpoint molecules, and reversing immunosuppression in the bladder microenvironment. OncoTherad® has proved to be a safe and effective therapeutic option for patients with BCG-unresponsive NMIBC, besides showing likely advantages in tumor relapse prevention processes.

Is there room for behavioral and modifiable health-related targets in the lower urinary tract symptoms' scenario.

PURPOSE: To better understand potential modifiable risk factors guiding preventive interventions against lower urinary tract symptoms (LUTS). METHODS: A prospective cross-sectional study, including healthy men aged 40-70 years under routine urological evaluation, measured the strength of association between the International Prostate Symptom Score (IPSS) and socio-demographic, lifestyle, and health-related factors using logistic and linear regression adjusted for confounding factors. Men with urethral or prostate surgery were excluded. RESULTS: Among 743 men, mean age 59.64 ± 9.66, 22.6% reported moderate, and 5.0% severe LUTS. The adjusted odds of severe LUTS increased with: increasing age (OR = 1.07, 95% CI = 1.05-1.09, p < .0001), increasing prostate volume (OR = 1.02, 95% CI = 1.01-1.04, p = .004), decreasing education (tertiary qualification, no versus yes, OR = 2.34; 95% CI = 1.16-4.70; p = .0133), delayed ejaculation (yes versus no, OR = 2.63, 95% CI = 1.43-4.83, p < .0001), and increasing blood pressure (systolic ≥130 mmHg, OR = 2.03, 95% CI = 1.44-2.86, p < .0001 or diastolic ≥85 mmHg, OR = 1.47, 95% CI = 1.03-2.10, p = .0345); severe LUTS decreased with: increasing the weekly sexual frequency (OR = 0.80, 95% CI = 0.69-0.91, p = .0012) and increasing HDL cholesterol (OR = 0.98, 95% CI = 0.97-0.99, p = .037). Odds were not significant for age of sexual initiation, precocious ejaculation, masturbatory pattern, physical activity, smoking, alcohol consumption, penile length (objective and subjective), abdominal circumference, obesity, comorbid conditions, metabolic syndrome, serum glycaemia, testosterone, SHBG, PSA, and estradiol. CONCLUSIONS: One in every four men under routine urological evaluation who considered themselves healthy present moderate and severe LUTS. Modifiable behavioral (education, sexual frequency, and ejaculation) and health-related (blood pressure and HDL cholesterol) targets were identified for future interventional studies and potential preventive actions and patient counseling.

Is metabolic syndrome truly a risk factor for male lower urinary tract symptoms or just an epiphenomenon?

To define whether the association of male lower urinary tract symptoms (LUTS) and metabolic syndrome (MS) is real or simply an epiphenomenon, 490 male adults (mean age 58 ± 9 years) underwent International Prostate Symptom Score (IPSS), physical and prostate digital examinations, blood analysis, and urinary tract transabdominal ultrasound with prostate volume measurement. Mild, moderate, and severe LUTS were found in 350 (71.4%), 116 (23.7%), and 24 (4.9%) patients, respectively. MS was present in 198 (40.4%) patients, representing 37.4% (131 of 350) of those with mild LUTS, 46.5% (54 of 116) of those with moderate, and 54.1% (13 of 24) of those with severe. The odds ratio of MS having moderate or severe LUTS was 2.1. MS was more common in older age, higher body mass index, and larger prostate size. Moderate and severe LUTS were more frequent in older age, lower levels of high density cholesterol, and higher blood pressure. Older age and body mass index had significant relative risk for lower urinary tract symptoms and only age remained independent factor for LUTS on multivariate analysis. Our results suggest that the association of male LUTS, prostate volume, and MS might be coincidental and related to older age.