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.

SPOP is a substrate recognition receptor of the CUL3 ubiquitin E3 complex and is point mutated in 10–15% of prostate cancer patients. Here, it is shown that, in prostate cancer cells, SPOP is involved in the DNA-protein cross-link repair process through the elimination of TOP2A from the TOP2A-DNA complex, which may prevent the genome instability.

Purpose: To develop and validate a new clinical prediction model that accurately predicts the failure of shockwave lithotripsy (SWL) using information obtained from non-contrast-enhanced computed tomography (NCCT). Methods: This multicentre retrospective cohort study consecutively enrolled patients diagnosed with upper urinary tract calculi by NCCT at five hospitals in Japan from January 1, 2006 to December 31, 2016. Among the candidate predictors, we selected the six most significant predictors a priori. The main outcome was SWL failure after three sessions. Model calibration was evaluated by the calibration slope and the Hosmer–Lemeshow test. Discrimination was evaluated by the receiver-operating characteristic curves and the area under the curve (AUC). A multivariable logistic regression analysis was performed; based on the estimated β coefficients, predictive scores were generated. Results: Of 2695 patients, 2271 were included. Patients were divided into the development cohort (1666 patients) and validation cohort (605 patients) according to geographical factors. We developed a clinical prediction model with scores ranging from 0 to 49 points. We named the prediction model the S₃HoCKwave score based on the initials of the predictors (sex, skin-to-stone distance, size, Hounsfield units, colic, and kidney or ureter). As a result of internal validation, the optimism-corrected AUC was 0.72. In the validation cohort, the Hosmer–Lemeshow test did not show statistical significance (P = 0.33), and the AUC was 0.71 (95% confidence interval 0.65–0.76). Conclusions: The S₃HoCKwave score is easy to understand, has a relatively high predictive value, and allows clinicians to make appropriate treatment selections.