Dual functions of angiopoietin-like protein 2 signaling in tumor progression and anti-tumor immunity.

Angiopoietin-like protein 2 (ANGPTL2) is a secreted glycoprotein homologous to angiopoietins. Previous studies suggest that tumor cell-derived ANGPTL2 has tumor-promoting function. Here, we conducted mechanistic analysis comparing ANGPTL2 function in cancer progression in a murine syngeneic model of melanoma and a mouse model of translocation renal cell carcinoma (tRCC). ANGPTL2 deficiency in tumor cells slowed tRCC progression, supporting a tumor-promoting role. However, systemic ablation of ANGPTL2 accelerated tRCC progression, supporting a tumor-suppressing role. The syngeneic model also demonstrated a tumor-suppressing role of ANGPTL2 in host tumor microenvironmental cells. Furthermore, the syngeneic model showed that PDGFRα+ fibroblasts in the tumor microenvironment express abundant ANGPTL2 and contribute to tumor suppression. Moreover, host ANGPTL2 facilitates CD8+ T-cell cross-priming and enhances anti-tumor immune responses. Importantly, ANGPTL2 activates dendritic cells through PIR-B-NOTCH signaling and enhances tumor vaccine efficacy. Our study provides strong evidence that ANGPTL2 can function in either tumor promotion or suppression, depending on what cell type it is expressed in.

Effect of HLA Genotype on Anti-PD-1 Antibody Treatment for Advanced Renal Cell Carcinoma in the SNiP-RCC Study.

Immune checkpoint blockade therapies are widely used for cancer treatment, including advanced renal cell carcinoma (RCC). This study aimed to investigate the impact of zygosity in HLA genes and individual HLA genotypes on the efficacy of an anti-PD-1 Ab, nivolumab, in treating advanced RCC. Patient enrollment was conducted across 23 institutions in Japan from August 19, 2019, to September 30, 2020, with follow-up concluding on March 31, 2021. HLA genotype imputation of HLA-A, B, and C, DQB1, and DRB1 loci was performed. Among 222 patients, the presence of at least one homozygosity of the HLA-II allele significantly improved the best objective response (hazard ratio, 0.34; 95% confidence interval, 0.21-0.96; p = 0.042). The HLA evolutionary divergence (HED) of the HLA-A and HLA-B loci was higher than the HLA-C (p < 0.0001 and p < 0.0001, respectively), with high HED of the HLA-B locus correlating to clinical benefits in nivolumab treatment (hazard ratio, 0.44; 95% confidence interval, 0.21-0.90; p = 0.024) and improving cancer-specific survival compared with the low group (p = 0.0202). Additionally, high HED of the HLA-B locus was correlated with the number of infiltrated CD8+ cells in the tumor microenvironment (correlation coefficient, 0.4042). These findings indicate that the diversity of the HLA-B locus plays a significant role in the anti-tumor effect of nivolumab treatment in advanced RCC, potentially offering insights for improved risk stratification in nivolumab treatment and leading to better medical management of advanced RCC.

Aging-associated and CD4 T-cell-dependent ectopic CXCL13 activation predisposes to anti-PD-1 therapy-induced adverse events.

Clinical success of immune-checkpoint blockade (ICB) cancer immunotherapy is compromised by increased risk of immune-related adverse events (irAEs). However, mechanistic action(s) of immune responses underlying development of irAE remain not fully explored. Here, we found that in tumor-bearing aged, but not young, mice, antiprogrammed death receptor (PD)-1 therapy elicited irAE-like multiorgan dysfunctions with ectopic accumulation of T and B cells in damaged organs. In this preclinical model, the organ toxicities were mediated by immunoglobulin G (IgG) deposition because administration of IG from ICB-treated aged mice induced the pathogenicity specifically in naïve aged hosts. Mechanistically, CD4 T-cell-derived interleukin (IL)-21 upregulated B-cell-homing chemokine, CXCL13, preferentially in irAE organs from aged mice treated with anti-PD-1 therapy. The ICB-induced pathogenicity was alleviated by B-cell depletion or by blockade of IL-21 or CXCL13 activity. These results suggest that age-associated immune regulatory milieu contributes to the formation of tertiary lymphoid structure-like lymphocytic aggregates in irAE organs and irAE-related toxicity employing IL-21-CXCL13-auto-antibody axis. Supporting this, a systemic increase in CXCL13 and Il21 expression in CD4 T cells correlated with irAE incidence in ICB-treated patients. These findings provide rationale for therapeutic usefulness of CXCL13 in irAE management.

Dysfunction of sinus macrophages in tumor-bearing host induces resistance to immunotherapy.

Sinus macrophages in draining lymph nodes (DLNs) are involved in anti-tumor immune reactions. CD169 (Sialoadhesin, Siglec-1) is expressed on sinus macrophages and is considered a surrogate marker for the immunostimulatory phenotype of macrophages. In this study, the significance of sinus macrophages in immunotherapy was evaluated using mouse models. Treatment with anti-programmed death-ligand 1 (PD-L1) antibody suppressed the subcutaneous tumor growth of MC38 and E0771 cells but was not effective against MB49 and LLC tumors. Decreased cytotoxic T-lymphocyte (CTL) infiltration in tumor tissues and CD169 expression in sinus macrophages were observed in MB49 and LLC cells compared to corresponding parameters in MC38 and E0771 cells. The anti-tumor effects of the anti-PD-L1 antibody on MC38 and E0771 cells were abolished when sinus macrophages in DLNs were depleted, suggesting that sinus macrophages are involved in the therapeutic effect of the anti-PD-L1 antibody. Naringin activated sinus macrophages. Naringin inhibited tumor growth in MB49- and LLC-bearing mice but did not affect that in MC38- and E0771-bearing mice. The infiltration of CTLs in tumor tissues and their activation were increased by naringin, and this effect was impaired when sinus macrophages were depleted. Combination therapy with naringin and anti-PD-L1 antibody suppressed MB49 tumor growth. In conclusion, CD169-positive sinus macrophages in DLNs are critical for anti-tumor immune responses, and naringin suppresses tumor growth by activating CD169-positive sinus macrophages and anti-tumor CTL responses. The activation status of sinus macrophages has been suggested to differ among tumor models, and this should be investigated in future studies.

Regression and growth rates in androgen deprivation therapy for advanced castration-sensitive prostate cancer.

PURPOSE: No study has compared cancer regression (d) and growth (g) rates in patients with advanced castration-sensitive prostate cancer (CSPC) treated with androgen deprivation therapy. The comparison of d and g rates provides insight into the differential impact of ADT regimens on tumor dynamics, potentially guiding more personalized treatment strategies. Therefore, we aimed to estimate these rates and evaluate their impact on survival outcomes. METHODS: Sequential prostate-specific antigen (PSA) data was obtained from the KYUCOG-1401 trial including patients with advanced CSPC randomized to gonadotropin-releasing hormone (GnRH) antagonist (group A) and GnRH agonist plus bicalutamide (group B). d and g rates were estimated by applying mathematical models and were compared in subgroups. PSA-progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival (OS) were compared by lower and higher than the median of these rates. RESULTS: Patients with higher PSA and higher extent of disease score at enrollment presented higher d rates (0.03965 vs. 0.03546, p = 0.0006) and (0.03947 vs. 0.03587, p = 0.0113) for groups A and B, respectively. The median d rate was lower for group A than group B (0.03306 vs. 0.039965, respectively [p = 0.0002]). The median g rate was higher for group A than group B (0.00016 vs. 0.00002, respectively [p = 0.0014]). The g rate, but not the d rate discriminated PSA-PFS, rPFS, and OS. CONCLUSION: Our results suggest that GnRH agonist plus bicalutamide reduced PSA level faster and suppressed PSA rising longer than GnRH antagonist. Moreover, measuring the g rate can predict PSA-PFS, rPFS, and OS in patients with advanced CPSC treated with androgen deprivation therapy. These findings suggest that incorporating g rate measurements into clinical practice could improve prognostic accuracy and guide treatment decisions in advanced CSPC.

A retrospective study of prognostic factors and prostate-specific antigen dynamics in Japanese patients with metastatic hormone-sensitive prostate cancer who received combined androgen blockade therapy with bicalutamide.

BACKGROUND: This retrospective observational study explored the therapeutic potential of combined androgen blockade (CAB) with bicalutamide (Bic-CAB) as an initial treatment for metastatic hormone-sensitive prostate cancer (mHSPC) in Japan. METHODS: The electronic health records of 159 patients with mHSPC from three Japanese institutions who received initial treatment with Bic-CAB between 2007 and 2017 were analyzed. The time to prostate-specific antigen (PSA) progression, duration of Bic-CAB treatment, and overall survival (OS), with various definitions for PSA progression, were assessed. A multivariate Cox proportional hazards model was constructed using clinical parameters to predict time to the end of Bic-CAB treatment and OS. RESULTS: The median observation period was 46.4 months, and the median age of patients at diagnosis was 71 years. A total of 46.5% patients experienced PSA progression with a median survival duration of 29 months (according to Prostate Cancer Clinical Trials Working Group 3 criteria), and 49.1% patients achieved a PSA nadir < 0.2 ng/mL in a median time of 4.7 months. When stratified by PSA nadir and PSA change, patients at low risk for disease progression with a small PSA change due to low initial PSA had a 5-year OS of 100% and a 10-year OS of 75%. The OS during the observation period was 72.9 months. CONCLUSION: These findings highlight the potential effect of Bic-CAB in patients with mHSPC who were at low risk for disease progression. Initial treatment with Bic-CAB and adjusting treatment early based on PSA dynamics may be a reasonable treatment plan for these patients.

GnRH antagonist monotherapy versus a GnRH agonist plus bicalutamide for advanced hormone-sensitive prostate cancer; KYUCOG-1401.

OBJECTIVES: To compare the effectiveness and safety of gonadotropin-releasing hormone (GnRH) antagonist monotherapy to combined androgen blockade (CAB) with a GnRH agonist and bicalutamide in patients with advanced hormone-sensitive prostate cancer (HSPC). METHODS: The study was conducted as KYUCOG-1401 trial (UMIN000014243) and enrolled 200 patients who were randomly assigned to either group A (GnRH antagonist monotherapy followed by the addition of bicalutamide) or group B (CAB by a GnRH agonist and bicalutamide). The primary endpoint was PSA progression-free survival. The secondary endpoints were the time to CAB treatment failure, radiographic progression-free survival, overall survival, changes in serum parameters, including PSA, hormones, and bone and lipid metabolic markers, and adverse events. RESULTS: PSA progression-free survival was significantly longer in group B (hazard ratio [HR], 95% confidence interval [CI]; 1.40, 1.01-1.95, p = 0.041). The time to CAB treatment failure was slightly longer in group A (HR, 95% CI; 0.80, 0.59-1.08, p = 0.146). No significant differences were observed in radiographic progression-free survival or overall survival. The percentage of patients with serum testosterone that did not reach the castration level was higher at 60 weeks (p = 0.046) in group A. No significant differences were noted in the serum levels of bone metabolic or lipid markers between the two groups. An injection site reaction was more frequent in group A. CONCLUSIONS: The present results support the potential of CAB using a GnRH agonist and bicalutamide as a more effective treatment for advanced HSPC than GnRH antagonist monotherapy.

Clinicopathological characteristics of adrenocortical carcinoma in the Kyushu-Okinawa area of Japan.

OBJECTIVE: Adrenocortical carcinoma is a rare condition, with limited comprehensive reports from Japan. This study aimed to review Japan's data on adrenocortical carcinoma by assessing information from 46 patients-with adrenocortical carcinoma across 10 Japanese university hospitals. METHODS: We conducted a retrospective multi-institutional analysis of the clinical characteristics of adrenocortical carcinoma in Japan. We evaluated data from 46 patients across 10 university hospitals over 10 years and analyzed the relationship between clinicopathological characteristics and overall survival. RESULTS: Five- and 10-year overall survival rates were 59% and 53%, respectively. Overall survival was significantly different among the tumor-node-metastasis system for adrenocortical carcinoma of the American Joint Committee on Cancer/International Union Against Cancer, with the worst prognosis in stage IV (p = 0.0044). In our cohort, neither the Weiss score nor the Ki-67 proliferation index correlated with overall survival. Adjuvant treatment did not yield improved overall survival, whereas resection of the primary tumor in stage IV disease was significantly associated with improved overall survival (p = 0.0262). Out of the cases evaluated for plasma hormones, plasma cortisol, aldosterone, testosterone, and DHEA-S levels were measured at 23%, 42%, 29%, and 62%, respectively, demonstrating higher levels than the upper normal limits. CONCLUSION: Patients with stage IV adrenocortical carcinoma had a poor prognosis; however, resection of the primary tumor in stage IV disease was associated with prolonged survival. The results of this study are expected to contribute to future treatment of adrenocortical carcinoma in Japan.

Overexpression of SerpinB9 in non-seminomatous germ cell tumors.

Serpinb9 is an inhibitor of granzyme B and is potentially involved in the immune escape of tumor cells. In the present study, bioinformatics analysis using open databases suggested that SerpinB9 is overexpressed in testicular embryonal carcinoma. Immunohistological analysis was performed on 28 cases of testicular germ cell tumors to investigate the relationship between SerpinB9 expression in testicular germ cell tumors and the tumor immune environment. SerpinB9 was significantly upregulated in the non-seminoma group and inversely correlated with the number of tumor-infiltrating CD8-positive cells. In addition, yolk sac tumors were characterized by the loss of human leukocyte antigen-class I expression. These findings suggest that SerpinB9 contributes to the immune escape of testicular germ cell tumors. Targeting therapy for SerpinB9 might therefore be useful in immunotherapy for testicular germ cell tumors resistant to immune checkpoint inhibitors.

Effect of genetic polymorphisms on outcomes following nivolumab for advanced renal cell carcinoma in the SNiP-RCC trial.

BACKGROUND: Anti-PD-1 antibodies are widely used for cancer treatment including advanced renal cell carcinoma (RCC). However, their therapeutic and adverse effects vary among patients. This study aimed to identify genetic markers that predict outcome after nivolumab anti-PD-1 antibody treatment for advanced RCC. METHODS: This study was registered on the website of the University Hospital Medical Information Network (protocol ID, UMIN000037739). Patient enrollment was conducted at 23 institutions in Japan between August 19, 2019, and September 30, 2020. Patient follow-up ended on March 31, 2021. Patients were treated with nivolumab for advanced clear cell RCC. A genome-wide association study was performed in the development set, while genotyping of target regions in the validation set was undertaken. Single nucleotide polymorphisms (SNPs) in genes of interest CD274, PDCD1LG2 and PDCD1 were genotyped in the combined set. The primary endpoint was the association of SNPs with objective response following nivolumab treatment. As secondary endpoints, the associations of SNPs with radiographic progression-free survival (rPFS) and treatment-related grade ≥ 3 adverse events (AEs) were evaluated. RESULTS: A genome-wide association study followed by a validation study identified that SNPs in FARP1 (rs643896 and rs685736) were associated with objective response and rPFS but not AEs following nivolumab treatment. Furthermore, SNPs in PDCD1LG2 (rs822339 and rs1411262) were associated with objective response, rPFS, and AEs following nivolumab treatment. Genetic risk category determined according to the number of risk alleles in SNPs (rs643896 in FARP1 and rs4527932 in PDCD1LG2) excellently predicted objective response and rPFS in nivolumab treatment. CONCLUSION: This study revealed that SNPs in FARP1 and PDCD1LG2 were correlated with outcome in nivolumab treatment. The use of these SNPs may be beneficial in selecting appropriate treatment for individual patients and may contribute to personalized medicine.

Predictive value of CXCL10 for the occurrence of immune-related adverse events in patient with renal cell carcinoma.

Immune checkpoint inhibitors (ICIs) have recently improved the prognosis of various cancers. By contrast, some immune-related adverse events (irAEs) caused by ICIs are fatal and have become problematic. The pathogenesis of irAEs remains unknown and must be elucidated to establish biomarkers. This study investigated plasma cytokine, chemokine, and anti-CD74 autoantibody levels in patients with renal cell carcinoma (RCC) and analyzed their association with irAEs. In a discovery cohort of 13 patients, plasma levels of chemokine (C-X-C motif) ligand (CXCL) 1, IL-17A, IL-1ß, IL-6, IL-8, CXCL10, MCP-1, and TNFα were measured at baseline and post-dose 1. Only CXCL10, at post-dose 1 but not at baseline, was significantly associated with grade 2 or higher irAEs (P = 0.0413). Plasma CXCL10 levels were then measured at baseline and post-dose 1 in an extended cohort of 43 patients with RCC who received ICI-based treatment. Higher plasma CXCL10 levels both at baseline and post-dose1 were significantly associated with the occurrence of grade 2 or higher irAEs (P = 0.0246 and 0.0137, respectively). Plasma CXCL13 levels, which we measured in a previous study, were significantly higher in patients with grade 2 or higher irAEs at baseline but not at post-dose 1 (P = 0.0037 and 0.052, respectively). No significant association between plasma anti-CD74 autoantibody level and both irAE pneumonitis and any grade 2 or higher irAE was observed. In conclusion, plasma CXCL10 is significantly associated with the occurrence of irAEs in patients with RCC treated with ICIs. CXCL10 is a potential predictive and on-treatment biomarker for irAEs.

Real-world treatment outcomes of patients with penile cancer in the Kyushu-Okinawa area of Japan in the pre-guideline era.

OBJECTIVES: To understand the real-world outcomes for patients with penile cancer in the Kyushu-Okinawa area before the introduction of practice guidelines in Japan. METHODS: We retrospectively collected medical information on patients with penile squamous cell carcinoma and penile intraepithelial neoplasia at 12 university hospitals and their affiliated hospitals in the Kyushu-Okinawa area from January 2009 to December 2020. Patients with unknown clinical stage were excluded. Patient background characteristics and survival, as well as pretreatment factors involved in survival, were investigated. RESULTS: A total of 196 patients were included. Patients with clinical stage 0, I, IIA, IIB, IIIA, IIIB and IV comprised 9.7, 26.0, 22.4, 2.6, 10.7, 14.3 and 14.3%, respectively. The median follow-up was 26 months, and the mean 5-year overall survival and cancer-specific survival rates were 74.3 and 79.8%, respectively. On univariate analysis, tumor diameter ≥ 30 mm, penile shaft tumor, Eastern Cooperative Oncology Group performance status ≥ 1, cT ≥ 3, cN ≥ 2 and cM1 were associated with significantly poorer cancer-specific survival. On multivariate analysis, pretreatment factors of cN ≥ 2 (hazard ratio, 32.5; 95% confidence interval, 5.08-208; P = 0.0002), Eastern Cooperative Oncology Group performance status ≥ 1 (4.42; 1.79-10.9; P = 0.0012) and cT ≥ 3 (3.34; 1.11-10.1; P = 0.0319) were identified as independent prognostic factors. CONCLUSIONS: The study revealed basic data for future penile cancer treatment and research, including survival rates according to clinical stages, and identified cN ≥ 2, Eastern Cooperative Oncology Group performance status ≥ 1 and cT ≥ 3 at initial diagnosis as independent prognostic factors. Evidence for penile cancer in Japan is particularly scarce, and future large-scale prospective studies are warranted.

Clinical factors for tumor response, progression, and survival in nivolumab for advanced renal cell carcinoma in the SNiP-RCC study.

BACKGROUND: This study is part of the SNPs in Nivolumab PD-1 inhibitor for RCC (SNiP-RCC). Here we aimed to reveal clinical factors for tumor response, progression, and survival in nivolumab for advanced clear cell renal cell carcinoma (RCC) in Japanese patients. METHODS: We included patients from 23 institutions in Japan. We evaluated the objective response, radiographic progression-free survival (PFS), overall survival (OS), and treatment-related grade ≥ 3 (serious adverse events [SAEs]). RESULTS: We included 222 patients. The median age was 69 years (interquartile range 62-74 years), and 71% of the patients were male. Pancreas metastasis, lung metastases, prior cytokine therapy, and SAEs, were associated with objective response. The median PFS was 18 months. Liver metastases (hazard ratio [HR], 1.61), age ≥ 75 (HR, 0.48), previous resection of primary sites (HR, 0.47), and SAEs (HR, 0.47) were independent prognostic factors for PFS. Karnofsky Performance Status <70 (HR, 2.90), high platelets (HR, 4.48), previous resection of primary sites (HR, 0.23), and pathological grade (HR, 0.19 for grade 2 and HR, 0.12 for grade 3) were independent prognostic factors for OS. SAEs were reported in 45 (20.3%) cases. In the group of patients with prior nephrectomy, SAEs were associated with objective response, PFS, and OS. CONCLUSION: The SNiP-RCC study identified clinical parameters correlated with treatment outcomes in Japanese patients with priorly treated advanced clear cell RCC undergoing nivolumab monotherapy.

Targeting chemoresistance in Xp11.2 translocation renal cell carcinoma using a novel polyamide-chlorambucil conjugate.

Renal cell carcinoma with Xp11.2 translocation involving the TFE3 gene (TFE3-RCC) is a recently identified subset of RCC with unique morphology and clinical presentation. The chimeric PRCC-TFE3 protein produced by Xp11.2 translocation has been shown to transcriptionally activate its downstream target genes that play important roles in carcinogenesis and tumor development of TFE3-RCC. However, the underlying molecular mechanisms remain poorly understood. Here we show that in TFE3-RCC cells, PRCC-TFE3 controls heme oxygenase 1 (HMOX1) expression to confer chemoresistance. Inhibition of HMOX1 sensitized the PRCC-TFE3 expressing cells to genotoxic reagents. We screened for a novel chlorambucil-polyamide conjugate (Chb) to target PRCC-TFE3-dependent transcription, and identified Chb16 as a PRCC-TFE3-dependent transcriptional inhibitor of HMOX1 expression. Treatment of the patient-derived cancer cells with Chb16 exhibited senescence and growth arrest, and increased sensitivity of the TFE3-RCC cells to the genotoxic reagent etoposide. Thus, our data showed that the TFE3-RCC cells acquired chemoresistance through HMOX1 expression and that inhibition of HMOX1 by Chb16 may be an effective therapeutic strategy for TFE3-RCC.

Summary of the Clinical Practice Guidelines for Penile Cancer 2021 by the Japanese Urological Association.

Penile cancer is a rare cancer for which no medical guidelines have been established before in Japan. These guidelines aim to standardize, as much as possible, the therapeutic modality for penile cancer, for which empirical evidence is limited on a global scale, thereby bolstering therapeutic outcomes for patients with penile cancer. The new guidelines conform to the Minds Guide for Developing Clinical Practice Guidelines (2017) as much as possible. However, virtually no randomized comparative studies and meta-analyses based on such randomized studies have been conducted. Therefore, only the findings available at present were listed after conducting an exhaustive literature review of items with extremely low evidence levels and for which bodies of evidence and grades of recommendation were not evaluated. Clinical questions were set for items with a relatively large number of studies, including retrospective studies. However, since it is virtually impracticable to summarize bodies of evidence by systematic reviews, recommendation grades and evidence levels were discussed and determined by the consensus panel of the Preparatory Committee. The following were outlined: epidemiological, pathological, diagnostic, therapeutic, follow-up, and quality of life-related findings. Additionally, seven clinical questions were established to determine recommendation grades and evidence levels. We hope that these guidelines will prove to be useful to medical professionals engaged in clinical practice related to penile cancer in Japan and anticipate that critical reviews of the guidelines will lead to further refinement of the next edition.

[A Retrospective Study of Lymph Node Dissection for Renal Cell Carcinoma].

We retrospectively analyzed the effect of lymph node dissection (LND) in patients with renal cell carcinoma (RCC). Of 151 patients who underwent nephrectomy for RCC, 86 underwent LND. No distant metastasis (M0) was present in 71 patients, although distant metastasis (M1) was present in 15. Three (4.2%) and eight (53%) patients in the M0 and M1 groups, respectively, were clinical N-stage positive. Two (2.8%) and three (20%) patients in the M0 and M1 groups, respectively, were pathological N-stage positive. Both pathological N stage-positive patients in the M0 group were pathologically diagnosed with microphthalmia transcription family translocation RCC. The clinical and pathological positive node areas exhibited concordance in all three pathological N stage-positive patients in the M1 group. Chylous leakage occurred in 16 (19%) patients in the LND group (p＜0.05). Extended LND was a statistically significant risk factor for chylous leakage in the multivariate analysis. Only limited cases should undergo LND, owing to the low frequency of positive pathological lymph node metastasis, and high complication rate.

Prostate cancer C5a receptor expression and augmentation of cancer cell proliferation, invasion, and PD-L1 expression by C5a.

BACKGROUND: The treatment of castration-resistant prostate cancer (CRPC) is a urological issue. Recent studies have revealed cancer promotion via the C5a-C5a receptor (C5aR) system. To establish a new therapeutic target for CRPC, we investigated an association of the system with CRPC progression and evasion from the antitumor immune responses. METHODS: C5aR and PD-L1 were immunostained in the prostate cancer (PC) tissues. The relationship of PC C5aR expression to clinicopathological parameters was analyzed. CRPC cell lines were examined for C5aR expression by real-time reverse transcription polymerase chain reaction, immunoblotting, and flow cytometry. C5a effects were examined on CRPC cell glutamine consumption, proliferation, invasion, and PD-L1 expression. RESULTS: PC cells expressed C5aR in 83 of the 161 patients (52%) and in three of the six CRPC patients. Basal cells, but not luminal cells, of noncancerous prostate glands expressed C5aR. Three CRPC cell lines expressed C5aR. C5a increased CRPC cell glutamine consumption 2.1-fold, proliferation 1.3-1.6-fold, and invasion 2-3-fold in a C5a-concentration and a C5aR-dependent manner. High expression of C5aR did not relate to the PC patients' clinical parameters but the PD-L1-positive rate was higher in the C5aR high-expression patients (37.5%) compared to low- or no expression patients (17.8%), and double-positive PC cells were present. C5a increased CRPC cell PD-L1 production 1.4-fold and cell-surface expression 2.6-fold. CONCLUSIONS: C5aR expression of PC cells in patients' tissues and C5a augmentation of C5aR-dependent CRPC proliferation, invasion, and PD-L1 expression suggested participation of the C5a-C5aR system in CRPC promotion and evasion from antitumor immune responses. Targeting this signaling pathway may provide a useful therapeutic option for CRPC.

Prognostic value of pre-treatment risk stratification and post-treatment neutrophil/lymphocyte ratio change for pembrolizumab in patients with advanced urothelial carcinoma.

BACKGROUND: Pembrolizumab is effective in a limited number of patients with advanced urothelial carcinoma (UC). Therefore, we evaluated the prognostic value of clinical biomarkers following pembrolizumab treatment in patients with advanced UC. METHODS: We retrospectively reviewed the medical records of 121 patients with platinum-refractory advanced UC who received pembrolizumab. Inflammation-based prognostic scores before and 6 weeks after the treatment were recorded. The categorical variables influencing overall survival (OS) and objective response rate (ORR) were analyzed. RESULTS: Multivariate analyses showed that pretreatment Eastern Cooperative Oncology Group (ECOG) performance score (PS), presence of only lymph node metastasis (only LN mets), C-reactive protein (CRP), and neutrophil/lymphocyte ratio (NLR) were independent prognostic factors for OS (P = 0.0077; RR = 2.42, P = 0.0049; RR = 0.36, P = 0.0047; RR = 2.53, and P = 0.0079; RR = 2.33, respectively). The pretreatment risk stratification using ECOG PS, only LN mets, CRP, and NLR was used for estimating the OS (P < 0.0001) and ORR (P < 0.0001). Furthermore, changes in NLR in response to pembrolizumab were significantly associated with the OS (P = 0.0002) and ORR (P = 0.0023). This change was also significantly correlated with OS even in the high-risk group stratified by this pretreatment risk stratification (P = 0.0069). CONCLUSIONS: This pretreatment risk stratification may be used for estimating the OS and ORR of patients with advanced UC treated with pembrolizumab. If changes in NLR in response to pembrolizumab treatment improve, pembrolizumab should be continued.

Surveillance of urachal abscess in the Kyushu-Okinawa area of Japan.

OBJECTIVE: To report a multicenter experience with the management of urachal abscess treatment in Japan. METHODS: This was a retrospective study of 263 cases of urachal abscess managed at 12 university hospitals in the Kyushu-Okinawa region over a 10-year period. Age, sex, abscess size, clinical symptoms, type of urachal remnants, and treatment were collected and analyzed. RESULTS: The average age was 29.8 ± 18.1 years, with males accounting for approximately two-thirds of the study population. The average abscess size was 1.7 cm (range 0-11 cm). The most common presenting symptom was umbilical secretion (66%), followed by abdominal pain (46%). A total of 127 patients (48.3%) were treated with antibiotics alone, whereas 136 patients (51.7%) received surgical treatment. The surgical approach was laparotomy in 75 patients (61.0%) and laparoscopic surgery in 48 patients (39.0%). Regarding the type of urachal remnant, the urachus sinus (180 patients) accounted for 68.4% of the total. CONCLUSIONS: To our knowledge, this study represents the first report on urachal abscess treatment in Japan. Our data show that the clinical symptoms might vary depending on the type of urachus remnant. It should be noted that gross hematuria, a characteristic symptom of urachal cancer, is rare in patients with urachal abscess.

High T-cell infiltration in tumor tissue and younger age predict the response to pembrolizumab in recurrent urothelial cancer.

Targeting the programmed cell death-1 signaling pathway has been approved for the anti-cancer therapy in several cancers including urothelial cancer. To determine predictive factors of the responsiveness to pembrolizumab in urothelial cancer patients, a retrospective study that used clinical information and paraffin-embedded samples obtained from patients diagnosed with urothelial cancer between 2015 and 2020 were performed. Seventeen patients who underwent total cystectomy or nephroureterectomy of the primary lesion and were treated with pembrolizumab for chemo-resistant disease were enrolled, and immunohistochemical analysis was performed. A key difference in the characteristics between the non-responder group and the responder group was the age of the patients (74 vs. 63 years, p = 0.0194). Although there was no statistically significant difference, the histological subtype with sarcomatoid and micropapillary components was only seen in the non-responder group, and squamous differentiation and lymph node metastasis were only seen in cases with a complete response. In the results of immunohistochemistry, the density of CD8-positive T-cells and Tregs was significantly increased in the responder group than in the non-responder group. In conclusion, younger age and a high number of tumor-infiltrating lymphocytes were predictive factors of a good response to immune checkpoint inhibitors, although further studies with more enrolled patients are necessary.