Enzalutamide (ENZA), a next-generation non-steroidal androgen receptor (AR) inhibitor, plays a pivotal role in the management of both hormone-sensitive (HSPC) and androgen deprivation-resistant prostate cancer (ARPC). This paper presents real-world clinical outcomes of ENZA in a subgroup of metastatic HSPC (mHSPC) patients included in the ARON-3 study. Clinical information was extracted retrospectively from medical records at 29 cancer centres in 9 countries worldwide. Overall Survival (OS) was calculated from starting ENZA to death from any cause and the time on treatment (ToT) from ENZA initiation to discontinuation for any reason. The Kaplan–Meier method was used to estimate OS and ToT. PSA90 was defined as a ≥90% PSA reduction from baseline, and PSA0.2 as the achievement of an ultra-low PSA level ≤0.2 ng/ml. Adverse events (AEs) were categorised according to Common Terminology Criteria for Adverse Events v5.0. The study population comprised 424 patients treated with ENZA for mHSPC, of whom 80 (19%) had lymph node-only metastases, 265 (63%) bone-only metastases, and 50 (12%) visceral metastases. 273 patients (64%) had synchronous metastases and 151 (36%) had developed metachronous metastases. A total of 228 patients were diagnosed with low-volume disease, and 196 patients (46%) with high-volume disease. The median ToT was 31.8 months, and the median OS was not reached. The median time to PSA90 (achieved in 76% of patients) and PSA0.2 (59% of patients) was 6.0 months and 8.3 months, respectively. Statistically significant associations were identified between lymph node-only patterns, PSA90 and ultra-low PSA responses, and longer treatment duration and better overall survival. Grade 3–4 AEs were observed in 9% of patients <70 years and in 10% ≥70 years. Real-world clinical practice corroborates the findings from clinical trials, confirming the effectiveness and safety of ENZA in mHSPC patients.
Infections remain a key challenge during treatment of multiple myeloma (MM) patients with anti-BCMA and -GPRC5D bispecific antibodies (bsAbs). However, the underlying mechanism behind different rates and severity of infections induced by the two bsAbs remains poorly understood. Single-cell RNA-sequencing performed in bone marrow aspirates of 11 MM patients and 8 healthy donors revealed BCMA expression on mature B cells and, surprisingly, in small pre-B cells within B-cell precursors. By contrast, GPRC5D expression was restricted to normal and malignant plasma cells (PCs). Next-generation flow cytometry immune profiling showed that anti-BCMA bsAbs severely depleted bone marrow (BM) mature B cells (4.9%→0%; p<0.001) and normal PCs (0.17% → <0.0002%; p<0.001) during treatment of 62 relapsed MM patients. This was observed in early and late time points of therapy. Additional flow cytometry (N=31) and single-cell RNA-sequencing studies (N=8) demonstrated that, in contrast to anti-GPRC5D, anti-BCMA bsAbs also depleted immature and small pre-B cells. The MIcγ1 mouse model was used as a negative control of BCMA expression in all stages of the B-cell lineage, which confirmed no depletion of any B-cell subset after anti-BCMA treatment. In conclusion, we show that while GPRC5D bsAbs selectively target PCs, anti-BCMA bsAbs target both PCs and B cells from the small pre-B stage onwards. Our study provides mechanistic insight into the increased infection risk with anti-BCMA therapy and lays a foundation for individualized bsAb strategies in MM. Moreover, dual targeting of B cells and PCs may have therapeutic potential in other B cell malignancies or autoimmune diseases.
BACKGROUND:This pilot study examined whether oxidative-nitrosative stress is associated with clinical status in amyotrophic lateral sclerosis (ALS). We analyzed associations between plasma markers of oxidative-nitrosative imbalance and ALSFRS-R, disease duration, survival, and routine biochemical parameters. METHODS:Twenty-nine ALS patients fulfilling the Gold Coast diagnostic criteria were enrolled. Plasma levels of 3-nitrotyrosine (3-NT), 8-oxo-2'-deoxyguanosine (8-oxodG), malondialdehyde (MDA), glutathione (GSH), non-protein thiols (NP-SH), and non-protein disulfides (NP-SS-NP), as well as creatinine, urea, uric acid and BMI, were measured. Associations with ALSFRS-R and disease duration were evaluated using non-parametric correlation analyses and second-order polynomial regression (adjusted R2), while survival was explored using Kaplan-Meier analysis and multivariable Cox regression. Given the modest sample, we considered statistical power and applied Benjamini-Hochberg false discovery rate (FDR) correction within marker families. RESULTS:At the uncorrected significance level, 3-NT showed a positive correlation with ALSFRS-R and a negative correlation with disease duration, and NP-SH correlated negatively with disease duration; however, these associations did not remain significant after FDR correction (FDR-adjusted p ≥ 0.099). Other oxidative-nitrosative markers and biochemical parameters showed no robust relationships with clinical measures. In Cox models, 3-NT was not significantly associated with survival (HR 3.44 per 1 nM, 95% CI 0.25-47.97, p = 0.358), whereas older age predicted higher mortality (HR 1.05 per year, 95% CI 1.00-1.10, p = 0.036). CONCLUSIONS:3-NT and NP-SH exhibited the strongest trends among the investigated markers, but their clinical associations in this small cross-sectional cohort remain exploratory and require confirmation in larger longitudinal studies.
Objective To compare the diagnostic performance- including adequacy, accuracy, safety, sensitivity, specificity, and predicitve values- of transvaginal tru-cut biopsy and ascitic fluid cytology in women with gynaecologic tumours. Methods A retrospective review was conducted of women with gynaecologic tumours who underwent ultrasound-guided transvaginal tru-cut biopsy and ascitic fluid cytology at the Department of Obstetrics and Gynaecology, University Hospital Hradec Kralove, between January 2018 and December 2021. Results A total of 104 women with gynaecologic tumours underwent transvaginal tru-cut biopsy, of whom 47 also had ascitic fluid cytology. The diagnostic accuracy [93.3% (95% CI: 84.1%-97.4%) vs. 83.9% (95% CI: 67.4%-92.9%)], sensitivity [93.3% (95% CI: 82.1%-97.7%) vs. 79.2% (95% CI: 59.5%-90.8%)], and negative predictive value [82.4% (95% CI: 59.0%-93.8%) vs. 58.3% (95% CI: 32.0%-80.7%)] were higher for transvaginal tru-cut biopsy compared to ascitic fluid cytology. Adequacy [93.3% (95% CI: 86.8%-96.7%) vs. 93.6% (95% CI: 82.8%-97.8%)], specificity [93.3% (95% CI: 70.2%-98.8%) vs. 100.0% (95% CI: 64.6%-100.0%)], and positive predictive value [97.7% (95% CI: 88.2%-99.6%) vs. 100.0% (95% CI: 83.2%-100.0%)] were similar for the two methods. Only one tru-cut biopsy was complicated by bleeding, giving an overall complication rate of 1% (95% CI: 0.2%-5.3%). There was no complication with ascitic fluid cytology. Concordance of tru-cut histopathological diagnoses with ascitic fluid cytological diagnoses was 78% (95% CI: 63.6%-87.5%). Conclusion Ultrasound-guided tru-cut biopsy provides more diagnostic information than ascitic fluid cytology and is the preferred method when feasible. However, ascitic fluid cytology remains a safe and practical option when biopsy is unavailable.
