Neuroendocrine prostate carcinoma (NEPC) accounts for less than 1% of prostate neoplasms and has extremely poorer prognosis than the typical androgen receptor pathway-positive adenocarcinoma of the prostate (ARPC). However, very few cases in which de novo NEPC and APRC are diagnosed simultaneously in the same tissue have been reported. We report herein a 78-year-old man of de novo metastatic NEPC coexisting with ARPC treated at Ehime University Hospital. Visium CytAssist Spatial Gene Expression analysis (10× genetics) was performed using formalin-fixed, paraffin-embedded (FFPE) samples. The neuroendocrine signatures were upregulated in NEPC sites, and androgen receptor signatures were upregulated in ARPC sites. TP53, RB1, or PTEN and upregulation of the homologous recombination repair genes at NEPC sites were not downregulated. Urothelial carcinoma markers were not elevated. Meanwhile, Rbfox3 and SFRTM2 levels were downregulated while the levels of the fibrosis markers HGF, HMOX1, ELN, and GREM1 were upregulated in the tumor microenvironment of NEPC. In conclusion, the findings of spatial gene expression analysis in a patient with coexisting ARPC and de novo NEPC are reported. The accumulation of cases and basic data will help with the development of novel treatments for NEPC and improve the prognosis of patients with castration-resistant prostate cancer.

Intraductal carcinoma of the prostate (IDCP) has recently attracted increasing interest owing to its unfavorable prognoses. To effectively identify the IDCP-specific gene expression profile, we took a novel approach of characterizing a typical IDCP case using spatial gene expression analysis. A formalin-fixed, paraffin-embedded sample was subjected to Visium CytAssist Spatial Gene Expression analysis. IDCP within invasive prostate cancer sites was recognized as a distinct cluster separate from other invasive cancer clusters. Highly expressed genes defining the IDCP cluster, such as MUC6, MYO16, NPY, and KLK12, reflected the aggressive nature of high-grade prostate cancer. IDCP sites also showed increased hypoxia markers HIF1A, BNIP3L, PDK1, and POGLUT1; decreased fibroblast markers COL1A2, DCN, and LUM; and decreased immune cell markers CCR5 and FCGR3A. Overall, these findings indicate that the hypoxic tumor microenvironment and reduced recruitment of fibroblasts and immune cells, which reflect morphological features of IDCP, may influence the aggressiveness of high-grade prostate cancer.

Background: Prostate‐specific membrane antigen (PSMA) is highly expressed in poorly differentiated, metastatic, and castration‐resistant prostate cancers. Recently, 68Ga‐PSMA positron emission tomography/computed tomography has been successfully developed as an effective diagnostic tool for prostate cancer. However, the pathophysiological functions of PSMA in prostate tumors remain unclear.Methods: We examined the protein expression of PSMA in tumor endothelial cells in human prostate tumors by immunohistochemistry. Prostate cancer tissues were resected by robotic surgery in 2019 at Ehime University from patients with prostate cancer. In vitro, we prepared conditioned medium (CM) derived from a PSMA‐positive human prostate cancer cell line, LNCaP, cultured on collagen I gels. We then examined PSMA expression in human umbilical vascular endothelial cells (HUVECs) cultured with the CM. We assessed angiogenic activities by treatment of HUVECs with LNCaP‐derived CM using a tube formation assay that mimics angiogenesis.Results: Immunohistochemistry of PSMA and CD31, a marker of endothelial cells, and PSMA‐expressing tumor endothelial cells were observed in 4 of 33 prostate cancer patients (12.1%). We also found that the 10,000g pellet fraction of the LNCaP‐derived CM containing PSMA‐positive membranes, such as microvesicles transformed HUVECs “PSMA‐negative” into “PSMA‐positive.” Furthermore, treatment of HUVECs with the 10,000g pellet fraction of the LNCaP‐derived CM significantly promoted tube formation, mimicking angiogenesis in a PSMA‐dependent manner.Conclusions: Our findings revealed the existence of PSMA‐positive tumor endothelial cells in human prostate tumors, which enhances tumor angiogenesis in prostate cancer tissues.

Immune checkpoint inhibitor (ICI) therapy increases the risk of immune-related adverse events (irAEs). In particular, combination checkpoint blockade (CCB) targeting inhibitory CTLA-4 and PD-1 receptors could lead to irAEs at a higher rate than ICI monotherapy. Management of irAEs is important while using ICIs. However, there are no reliable biomarkers for predicting irAEs. The aim of this study was to elucidate early B cell changes after CCB therapy in patients with renal cell carcinoma (RCC) and verify whether B cells can be a predictor of irAEs. This prospective cohort study was conducted with 23 Japanese patients with metastatic RCC. An increase in the proportion of CD21^lo B cells and CD21^lo memory B cells was confirmed following CCB therapy. Although there were no differences in clinical outcomes between irAE and no-irAE groups, the proportion of CD21^lo B cells at baseline was lower in the irAE group, with a significant increase after the first cycle of CCB therapy. Further analysis revealed a moderate correlation between irAEs and CD21^lo B cell levels at baseline (area under the curve: 0.83, cut-off: 3.13%, sensitivity: 92.3, specificity: 70.0). This finding indicates that patients with low baseline CD21^lo B cell levels warrant closer monitoring for irAEs. The clinical registration number by the Certified Review Board of Ehime University is No. 1902011.

Background: The therapeutic efficacy of extended lymph node dissection (ePLND) for intermediate- and high-risk (IR/HR) prostate cancer remains controversial. This study evaluated whether PLND improved biochemical recurrence (BCR) rates in patients with prostate cancer undergoing robotic-assisted radical prostatectomy (RARP) using a propensity matching method with cases from two facilities. Methods: The study included 1002 patients with IR/HR disease who underwent RARP at two facilities with equivalent surgical techniques and hospital size but different ePLND policies for IR/HR between July 2012 and November 2022. We compared perioperative outcomes, complications, and biochemical recurrence-free survival (bRFS) between the centers. Results: After propensity matching, 221 and 124 cases, each at intermediate and high risk, respectively, were compared. Except for age, preoperative clinicopathological variables did not differ significantly between the matched ePLND and non-PLND groups. A median of 18 lymph nodes were assessed in the dissection group. The 3-year bRFS rates did not differ significantly between ePLND and non-PLND among intermediate-risk and high-risk patients. The dissection group had significantly longer operative times and more complications associated with ePLND, including lower extremity edema, pelvic hematoma, and neuropathy. A multivariable Cox regression analysis performed after propensity adjustment identified initial prostate-specific antigens, pathological tumor stage (high-risk only), and positive surgical margins as independent prognostic factors for bRFS while ePLND was not significant. Conclusions: These results suggest that ePLND may not be necessary in intermediate- to high-risk PCa patients undergoing RARP, although further study with a longer follow-up is required.