Increased circulating polymorphonuclear myeloid-derived suppressor cells are associated with prognosis of metastatic castration-resistant prostate cancer.

Introduction: Myeloid-derived suppressor cell (MDSC) exhibits immunosuppressive functions and affects cancer progression, but its relationship with prostate cancer remains unclear. We elucidated the association of polymorphonuclear MDSC (PMN-MDSC) and monocytic MDSC (M-MDSC) levels of the total peripheral blood mononuclear cells (PBMCs) with prostate cancer progression and evaluated their roles as prognostic indicators. Methods: We enrolled 115 patients with non-metastatic hormone-sensitive prostate cancer (nmHSPC, n = 62), metastatic hormone-sensitive prostate cancer (mHSPC, n = 23), and metastatic castration-resistant prostate cancer (mCRPC, n = 30). Subsequently, the proportions of MDSCs in each disease progression were compared. Log-rank tests and multivariate Cox regression analyses were performed to ascertain the associations of overall survival. Results: The patients with mCRPC had significantly higher PMN-MDSC percentage than those with nmHSPC and mHSPC (P = 7.73 × 10-5 and 0.0014). Significantly elevated M-MDSC levels were observed in mCRPC patients aged <70 years (P = 0.016) and with a body mass index (BMI) <25 kg/m2 (P = 0.043). The high PMN-MDSC group had notably shorter median survival duration (159 days) than the low PMN-MDSC group (768 days, log-rank P = 0.018). In the multivariate analysis including age, BMI, and MDSC subset, PMN-MDSC was significantly associated with prognosis (hazard ratios, 3.48; 95% confidence interval: 1.05-11.56, P = 0.042). Discussion: PMN-MDSC levels are significantly associated with mCRPC prognosis. Additionally, we highlight the remarkable associations of age and BMI with M-MDSC levels in mCRPC, offering novel insights into MDSC dynamics in prostate cancer progression.

T-Cell Receptor Repertoire as a Predictor of Immune-Related Adverse Events in Renal Cell Carcinoma.

Immune checkpoint inhibitors (ICIs) are effective in treating renal cell carcinoma (RCC) but can also cause immune-related adverse events (irAEs). The relationship between irAEs and the T-cell receptor (TCR) repertoire in RCC patients treated with ICIs remains unclear. We analyzed the relationship between the severity and diversity of irAEs and the TCR repertoire in RCC patients who received dual checkpoint inhibitors (ipilimumab + nivolumab). The TCRß (TRB) repertoires were characterized in peripheral blood samples from six patients with RCC before the initiation of ICI therapy. The diversity and clonality of the TCR repertoire were compared between patients with grade 2 and grade 3 irAEs. The median proportion of top 10 unique reads in the TCR repertoire was significantly higher in grade 3 compared with grade 2 irAEs in RCC patients receiving immune checkpoint inhibitors (grade 2: 0.196%; grade 3: 0.346%; p = 0.0038). We provide insight into the relationship between TCR repertoire and irAEs in RCC patients treated with ICIs. TCR repertoire clonality may be associated with the development of irAEs in RCC patients.

Genetic association of mosaic loss of chromosome Y with prostate cancer in men of European and East Asian ancestries: a Mendelian randomization study.

Background: Genomic instability is a significant hallmark of aging and has a major impact on aging biology. Mosaic loss of chromosome Y (mLOY) in blood cells is a common chromosomal abnormality in aging men and is considered an indicator of genomic instability. Previous studies have indicated a connection between mLOY and prostate cancer risk, but the causal relationship has not been fully established. Methods: To determine the causal effect of mLOY on prostate cancer, we conducted a Mendelian Randomization (MR) study in two ancestral groups. We utilized 125 and 42 mLOY-associated variants as instrumental variables (IVs) in European and East Asian GWAS of prostate cancer, respectively. Summary-level data on prostate cancer was obtained from the PRACTICAL consortium (79,148 cases and 61,106 controls of European ancestry) and the Biobank Japan consortium (5,408 cases and 103,939 controls of East Asian ancestry). A single population was used to assess the causal relationship in East Asian ancestry. Our main method for obtaining MR results was inverse-variance weighted (IVW), and we conducted sensitivity analyses to confirm the robustness of our results. Finally, we combined the estimates from both sources using a fixed-effects meta-analysis. Results: Our MR analysis using the IVW method showed that a one-unit increase in genetically predicted mLOY was associated with an increased risk of prostate cancer in the PRACTICAL consortium (OR = 1.09%, 95% CI: 1.05-1.13, p = 1.2 × 10-5), but not in the Biobank Japan consortium (OR = 1.13%, 95% CI: 0.88-1.45, p = 0.34). Sensitivity analyses robustly indicated increased odds ratios for prostate cancer with every one-unit increase in genetically predicted mLOY for the PRACTICAL consortium. Furthermore, mLOY was found to be associated with prostate cancer risk in a meta-analysis of both sources (OR = 1.09%, 95% CI: 1.05-1.13, p = 8.0 × 10-6). Conclusion: Our MR study provides strong evidence that higher mLOY increases the risk of prostate cancer. Preventing mLOY may be a means of reducing the risk of developing prostate cancer.

Kidney Transplantation for a Patient With Protein C Deficiency Using Activated Protein C Concentrate: A Case Report.

BACKGROUND: Thrombophilia causes thrombosis after kidney transplantation (KT). Protein C deficiency is a rare form of hereditary thrombophilia. To our knowledge, there are few reports on KT for patients with protein C deficiency, and there are no reports of KT in patients with protein C deficiency administered with activated protein C concentrate. METHOD: Here we reported the case of a patient with protein C deficiency who underwent KT without the occurrence of any fresh thrombosis after administration of an activated protein C concentrate. The patients was a 49-year-old woman diagnosed with immunoglobulin A nephropathy at 20 years of age. During pregnancy, she experienced deep vein thrombosis of the lower extremities and pulmonary embolism for which she was started on warfarin. After a thorough examination, the patient was diagnosed with protein C deficiency. The patient had end-stage kidney disease and received a preemptive living donor kidney transplant from her mother. RESULTS: To prevent thrombosis, we switched from oral warfarin to continuous heparin 7 days before surgery. Heparin was discontinued 6 hours before surgery, and continuous activated protein C concentrate was administered 12 hours before surgery. Heparin administration was resumed 6 hours after the surgery. Warfarin administration was restarted 3 days after the surgery, and heparin was discontinued 11 days post-surgery. The surgery was performed without complications. After the KT, the patient's renal function steadily improved, and no fresh thrombosis were observed. CONCLUSIONS: Thrombosis can cause graft loss and pulmonary embolism, thus appropriate administration of activated protein C concentrate may help prevent thrombosis.