Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: To evaluate the safety and pathological complete response (pCR) rate of radiotherapy with atezolizumab as bladder-preserving therapy for invasive bladder cancer. PATIENTS AND METHODS: A multicenter, phase II study was conducted with clinically T2-3 or very high-risk T1 bladder cancer patients who were poor candidates for or refused radical cystectomy. Here, we report our interim analysis of pCR as a key secondary endpoint ahead of the progression-free survival rate primary endpoint. Radiotherapy (41.4 Gy to the small pelvic field and 16.2 Gy to the whole bladder) was given plus 1200 mg intravenous atezolizumab every 3 weeks. After 24 treatment weeks, response was assessed after transurethral resection and tumor programmed cell death ligand-1(PD-L1) expression was assessed using tumor-infiltrating immune cell scores. RESULTS: Forty-five patients enrolled from January 2019 to May 2021 were analyzed. The most common clinical T stage was T2 (73.3%), followed by T1 (15.6%) and T3 (11.1%). Most tumors were solitary (77.8%), small (<3 cm) (57.8%), and without concurrent carcinoma in situ (88.9%). Thirty-eight patients (84.4%) achieved pCR. High pCR rates were achieved in older patients (90.9%) and in patients with high PD-L1-expressing tumors (95.8% vs. 71.4%). Adverse events (AEs) occurred in 93.3% of patients, with diarrhea being the most common (55.6%), followed by frequent urination (42.2%) and dysuria (20.0%). The frequency of grade 3 AEs was 13.3% while no grade 4 AEs were observed. CONCLUSION: Combination therapy with radiotherapy and atezolizumab provides high pCR rates and acceptable toxicity, indicating it could be a promising option for bladder preservation therapy.

DOI： 10.1016/j.ijrobp.2023.05.013

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CiNii Books

Language：English   Publisher：International Journal of Radiation Oncology Biology Physics  

Purpose: Bladder preservation therapy in combination with atezolizumab and radiation therapy trial, which was a multicenter, open-label, single-arm phase 2 study, showed a promisingly high interim clinical complete response (cCR) rate of 84.4% (38/45). In the present study, we aimed to identify potential tissue biomarkers for achieving cCR using bladder preservation therapy in combination with atezolizumab and radiation therapy. Methods and Materials: We used tumor tissue samples of the bladder and blood samples collected from patients at baseline to analyze the tumor immune microenvironment at baseline using an integrated approach of immunophenotyping, genomic, and tumor-infiltrating lymphocyte (TIL) profiling. Results: Immune phenotype analysis revealed that cCR rates of patients with the desert phenotype were as similarly high as patients with excluded/inflamed phenotypes (73.3% [11/15] vs 93.3% [14/15], P = .33) despite lower programmed death-ligand 1 expression levels in the desert phenotype. Genomic and TIL profiling then revealed that increased CD8+ and CD204+ TIL infiltration, high CD8:forkhead box protein P3 ratios in the stroma of the excluded/inflamed phenotypes, and gene alterations, such as CDK12, GNAS, NOTCH2, and AR1D1A, were associated with a high cCR rate (93.3%). Furthermore, the characteristics of these dual TILs, CD8-forkhead box protein P3 ratios, and gene alterations (especially FGFR3) bifurcated the desert phenotype into 2 subgroups with different cCR rates (100% [11/11] and 0% [0/4]). Conclusions: These potential subgroups, defined by combined molecular subclass and immune phenotype, could lead to the identification of good responders to atezolizumab plus radiation therapy for invasive bladder cancer. However, given the small cohort size and limited number of tumor samples, these findings should be viewed as hypothesis-generating and require further validation in larger studies.

DOI： 10.1016/j.ijrobp.2024.12.019

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PubMed

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Bladder cancer is one of the most common cancers among men worldwide. Although multiple genomic mutations and epigenetic alterations have been identified, an efficacious molecularly targeted therapy has yet to be established. Therefore, a novel approach is anticipated. Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane glycoprotein that is highly expressed in various cancers. In this study, we evaluated bladder cancer patient samples and found that GPNMB protein abundance is associated with high-grade tumors, and both univariate and multivariate analyses showed that GPNMB is a prognostic factor. Furthermore, the prognosis of patients with high GPNMB levels was significantly poorer in those with nonmuscle invasive bladder cancer (NMIBC) than in those with muscle invasive bladder cancer (MIBC). We then demonstrated that knockdown of GPNMB in MIBC cell lines with high GPNMB inhibits cellular migration and invasion, whereas overexpression of GPNMB further enhances cellular migration and invasion in MIBC cell lines with originally low GPNMB. Therefore, we propose that GPNMB is one of multiple driver molecules in the acquisition of cellular migratory and invasive potential in bladder cancers. Moreover, we revealed that the tyrosine residue in the hemi-immunoreceptor tyrosine-based activation motif (hemITAM) is required for GPNMB-induced cellular motility.

DOI： 10.1111/pin.13419

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Genitourinary sarcomas are rare in adults and few large-scale studies on adult genitourinary sarcoma are reported. We aimed to elucidate the clinical characteristics, survival outcomes, and prognostic factors for overall survival of adult genitourinary sarcoma in Japan. METHODS: A hospital-based cancer registry data in Japan was used to identify and enroll patients diagnosed with genitourinary sarcoma in 2013. The datasets were registered from 121 institutions. RESULTS: A total of 116 men and 39 women were included, with a median age of 66 years. The most common primary site was the kidney in 47 patients, followed by the paratestis in 36 patients. The most common histological type was liposarcoma in 54 patients, followed by leiomyosarcoma in 25 patients. The 5-year overall survival rates were 57.6%. On univariate analysis, male gender, paratestis as primary organ, and histological subtype of liposarcoma were predictive of favorable survival while primary kidney, bladder, or prostate gland location were predictive of unfavorable survival. On multivariate analysis, primary paratestis was an independent predictor of favorable survival while primary kidney, bladder, or prostate gland were independent predictors of unfavorable survival. CONCLUSIONS: This is the first report showing the clinical characteristics and survival outcomes of adult genitourinary sarcoma in Japan using a real-world large cohort database.

DOI： 10.1186/s12885-024-11952-0

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Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: To investigate whether seminal plasma (SP)/serum ratios of multiple trace elements (TEs) can classify patients with male subfertility. METHODS: SP/serum ratios of 20 TEs (lithium, sodium, magnesium, phosphorus, sulfur, potassium, calcium, manganese, iron, cobalt, copper, zinc, arsenic, selenium, rubidium, strontium, molybdenum, cesium, barium, and thallium) were calculated for healthy volunteers (n = 4) and those consulting for male subfertility (n = 245). Volunteer semen samples were collected by split ejaculation into early and subsequent fractions, and SP/serum ratio data were compared between fractions. The patients' SP/serum ratio data were used in an unsupervised clustering analysis and qualitatively compared with the data from the fractions of ejaculation from the volunteers. Semen quality parameters and pregnancy outcomes were compared between patient clusters. RESULTS: The early fraction of volunteers was characterized by lower phosphorus and arsenic and 18 other higher TEs than the subsequent fraction. Cluster analysis classified patients into four distinct clusters, one sharing characteristics with the early fraction and another with the subsequent fraction. One cluster with the early fraction characteristics had significantly lower semen volume and higher pregnancy rates from spontaneous pregnancies or intrauterine insemination. CONCLUSIONS: Classification of patients based on SP/serum ratios of multiple TEs represents the dominance of fractions of ejaculation samples.

DOI： 10.1002/rmb2.12584

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PubMed

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