Benjamin Mercier

PURPOSE: Clinical trials for cancer tend to be less available in regions of the United States corresponding to high socioeconomic vulnerability; however, specific patterns for renal cell carcinoma (RCC) have yet to be reported. The aim of this study was to evaluate the current county-level distribution of RCC trials in the United States and identify factors contributing to disparities of access. METHODS: We performed a cross-sectional analysis of all interventional trials on ClinicalTrials.gov enrolling adult patients with RCC between June 1, 2019, and June 1, 2025. After mapping each US study site to its corresponding county, we used a zero-inflated negative binomial (ZINB) model to evaluate the relationship between county-level trial availability and corresponding Social Vulnerability Index (SVI) designations, renal cancer incidence rates, and renal cancer mortality rates. Trial characteristics were extracted and summarized descriptively. Incidence rate ratios were estimated to quantify the relationship between trial availability and county-level characteristics. RESULTS: In total, 289 trials met the inclusion criteria, corresponding to a total of 5,028 unique trial sites. Only 672 (21.4%) of all US counties had at least 1 trial site; no state had a trial in every county. Compared with high-SVI counties, counties with low, low-medium, and medium-high SVIs had 3.1-fold, 2.0-fold, and 1.8-fold higher trial incidence rates (all P < .001). Higher renal cancer incidence and mortality rates were not significantly associated with county-level trial prevalence ( P = .55 and P = .40, respectively). CONCLUSION: Most US counties lacked RCC clinical trial representation. Counties with higher social vulnerability had fewer trials, highlighting key structural disparities in access to new RCC interventions within the United States and emphasizing the importance of accounting for regional social vulnerability in the trial design and site selection process.

Demographic and clinical characteristics of the study cohort (N = 30).

Immunohistochemical expression for 21 cell surface markers across testicular germ cell tumor subtypes and histologic components.

Immunohistochemical staining of selected cell surface markers across testicular GCT subtypes. A, CLDN6 (membranous staining) in seminoma, (B) CLDN6 (membranous staining) in yolk sac tumor, (C) EGFR (membranous staining) in seminoma, (D) EGFR (membranous staining) in teratoma, (E) TAG72 (membranous and cytoplasmic staining) in seminoma, (F) TAG72 (membranous and cytoplasmic staining) in choriocarcinoma, (G) TROP2 (membranous staining) in seminoma, (H) TROP2 (membranous staining) in teratoma, (I) Nectin-4 (membranous and cytoplasmic staining) in seminoma, (J) Nectin-4 (membranous and cytoplasmic staining) in teratoma, (K) GPNMB (membranous and cytoplasmic staining) in seminoma, (L) GPNMB (membranous and cytoplasmic staining) in embryonal carcinoma, (M) c-MET (nuclear staining) in seminoma, (N) c-MET (nuclear staining) in embryonal carcinoma, (O) HER2 (membranous staining) in teratoma, and (P) c-MET (membranous and cytoplasmic staining) in choriocarcinoma.

Antibodies used for immunohistochemistry, including clone, catalog number, and vendor.

To characterize clinically actionable cell surface proteins in testicular germ cell tumors (GCT), we retrospectively analyzed archival formalin-fixed, paraffin-embedded orchiectomy specimens from 30 patients, including 11 with pure seminoma and 19 with mixed GCTs. Immunohistochemistry was performed for 21 surface antigens using an automated platform. Staining intensity (0 to 3+) and the percentage of positive tumor cells were used to derive H-scores (0–300). Expression was summarized by patient classification and histologic component; high expression was defined as H-score ≥100. Claudin-6 (CLDN6) was diffusely and strongly expressed, with H-score ≥100 in 100% of pure seminomas and 89.5% of mixed GCTs. At the component level, 100% of seminoma and 92.9% of embryonal carcinoma samples reached this threshold. Epidermal growth factor receptor (EGFR) showed high expression in 68.4% of mixed GCTs and 45.5% of pure seminomas, with most enrichment in teratoma components (73.3%, ≥100; mean H-score, 212). TROP2 was markedly upregulated in mixed GCTs (78.9%, ≥100; mean, 194.7), particularly in teratoma components (86.7%, ≥100). Nectin-4 and glycoprotein nonmetastatic melanoma B (GPNMB) were expressed in smaller but notable subsets, including teratoma and seminoma, whereas most remaining antigens, including CD19, DLL3, FOLR1, and BCMA, showed minimal or no expression. These findings demonstrate a distinct surface antigen landscape in testicular GCTs, with CLDN6, EGFR, and TROP2 emerging as leading candidates for further translational evaluation. The enrichment of these targets highlights antigenic heterogeneity within GCTs and supports further validation in appropriate disease settings, including metastatic, posttreatment, and relapsed or refractory disease.Significance:Relapsed or refractory testicular GCT remains a clinical challenge with limited treatment options. We evaluated cell surface antigens of primary GCTs and identified CLDN6, EGFR, and TROP2 as candidate targets for antigen-directed approaches. These findings provide a rationale for future validation in metastatic and posttreatment disease settings.

Background: Sarcomatoid carcinoma of the upper urinary tract (SCUT) is a rare and aggressive malignancy. Due to its rarity, the molecular landscape and the prevalence of potentially targetable alterations are poorly characterized. We aimed to compare the clinical, pathological, and genomic profiles of SCUT and upper tract urothelial carcinoma (UTUC). Methods: We leveraged the Tempus Lens clinically annotated genomic dataset to extract clinicopathologic and somatic genomic alteration data from patients with UTUC and SCUT. Patients with any-stage disease who underwent either blood- or tissue-based next-generation sequencing were included. Baseline clinical and demographic characteristics were summarized using descriptive statistics. Comparisons between groups were performed using Wilcoxon rank-sum test for continuous variables and the Chi-square test/Fisher’s exact test for categorical variables. Mutational frequencies and pairwise comparisons were performed to assess significant differences between groups. Results: In total, 1721 patients were included, of which 1600 (93%) had UTUC and 121 (7%) had SCUT. Patients with SCUT were younger at diagnosis, 61 years (interquartile range (IQR) 54, 70), compared to UTUC, 71 years (IQR 64, 77) (p < 0.001), and were more likely to have node-positive disease at presentation (all p < 0.001). SCUT patients were more likely to show visceral metastases to the lung (44% vs. 21%), bone (31% vs. 17%), and brain (7% vs. 1%), compared to UTUC (all p < 0.05). Among SCUT patients, the most common genomic alterations were TERT (30%), TP53 (29%), NF2 (19%), PTEN (13%), SETD2 (12%), PBRM1 (12%), and BAP1 (8%). Among UTUC patients, the most common were TERT (52%), TP53 (52%), KMT2D (30%), FGFR3 (25%), ARID1A (20%), and KDM6A (18%). Compared to UTUC, SCUT was significantly enriched with NF2, SETD2, PBRM1, PTEN, and BAP1 (all p < 0.05). SCUT was depleted in FGFR3 (0% vs. 25%) and FGF4 (0% vs. 8%) mutations compared to UTUC (both p < 0.05). Targetable alterations were observed in SCUT, including NF2, SETD2, and PTEN. Conclusion: Compared with UTUC, SCUT exhibits a more aggressive clinical and genomic phenotype, characterized by enrichment in NF2, SETD2, PBRM1, and PTEN. These findings underscore the divergent molecular landscape of SCUT and highlight potentially targetable genomic alterations.

To characterize clinically actionable cell surface proteins in testicular germ cell tumors (GCTs), we retrospectively analyzed archival formalin-fixed paraffin-embedded orchiectomy specimens from 30 patients, including 11 with pure seminoma and 19 with mixed GCTs. Immunohistochemistry was performed for 21 surface antigens using an automated platform. Staining intensity (0-3+) and percentage of positive tumor cells were used to derive H-scores (0-300). Expression was summarized by patient classification and histologic component; high expression was defined as H-score ≥100. CLDN6 was diffusely and strongly expressed, with H-score ≥100 in 100% of pure seminomas and 89.5% of mixed GCTs. At the component level, 100% of seminoma and 92.9% of embryonal carcinoma samples reached this threshold. EGFR showed high expression in 68.4% of mixed GCTs and 45.5% of pure seminomas, with most enrichment in teratoma components (73.3% ≥100; mean H-score 212.0). TROP2 was markedly upregulated in mixed GCTs (78.9% ≥100; mean 194.7), particularly in teratoma components (86.7% ≥100). Nectin-4 and GPNMB were expressed in smaller but notable subsets, including teratoma and seminoma, whereas most remaining antigens, including CD19, DLL3, FOLR1, and BCMA, showed minimal or no expression. These findings demonstrate a distinct surface antigen landscape in testicular GCTs, with CLDN6, EGFR, and TROP2 emerging as leading candidates for further translational evaluation. Enrichment of these targets highlights antigenic heterogeneity within GCTs and supports further validation in appropriate disease settings including metastatic, post-treatment, and relapsed or refractory disease.

Background: Bladder cancer disproportionately affects non-high-income countries, yet clinical trials underrepresent global diversity. We assessed global availability of bladder cancer trials, their alignment with disease burden, and barriers to equitable care. Methods: We queried ClinicalTrials.gov for adult bladder cancer trials from June 2019 to June 2024, excluding observational and non-oncologic trials. Trial characteristics were summarized descriptively, and country data came from the Global Cancer Observatory. Countries were classified per World Bank Ranking (WBR) into high-income (HICs), upper middle-income (UMICs), lower middle-income (LMICs), and low-income countries (LICs). Trials were categorized as HIC-only, non-HIC, or mixed-income trials. Fisher’s exact and Kruskal–Wallis tests compared groups. Multivariable logistic regression assessed associations between trial availability and WBR, national health expenditure, and gross national income (GNI). Univariable linear regression and ANOVA assessed the association between the mortality-to-incident ratio and WBR. Results: Of 611 trials, 75.1% were HIC-only, 16.9% non-HIC, and 8.0% mixed-income trials. Non-HIC trials were mainly academic-sponsored (80.6%), while all mixed-income trials had pharmaceutical sponsorship (p < 0.001). Non-HIC trials had lower enrollment, less pharmaceutical funding, fewer multinational collaborations, and fewer basket, multi-arm, early-phase designs (all p < 0.001). Mixed-income trials were larger, led by HICs, had broader eligibility criteria, more novel therapies, and more frequent use of overall survival endpoints. Trial availability was lower in UMICs (p = 0.011), LMICs (p = 0.024), and absent in LICs, and positively associated with higher national health expenditure (p = 0.007) and GNI (p = 0.001). Conclusions: Bladder cancer trials remain concentrated in HICs. Mixed-income trials expand access in non-high-income countries, but are exclusively led by HICs and require balanced sponsorship, early-phase research, and lasting local benefits.

Purpose: Aberrant alternative splicing (AS) events have been implicated in cancer progression; however, their role in metastatic renal cell carcinoma (mRCC) remains underexplored. This study aims to identify AS events associated with clinical benefits from immune checkpoint inhibitors and targeted therapies in mRCC. Materials and methods: We conducted a retrospective analysis on 101 patients with mRCC who received systemic therapy and underwent RNA sequencing. Patients were divided into subgroups based on ICIs (alone or in combination) and targeted therapies. Responders and non-responders were classified according to Response Evaluation Criteria in Solid Tumors V.1.1 criteria. Differential gene expression and splicing analyses were performed between responders and non-responders in each cohort. Novel AS events were analyzed for their potential to generate peptide neoantigens through major histocompatibility complex (MHC) class I binding predictions. Results: Outlier splicing analysis identified 10 aberrant splice events specific to mRCC. AS analysis revealed 461 differentially spliced events between responders and non-responders in the ICI cohort and 253 in the targeted therapy cohort, with intron retention as the predominant motif. Thirteen unique AS events were enriched in responders, including PTPN6 and ACTN1 . Predictive neoantigen analysis identified high MHC class I binding potential in peptides from AS events in IFFO1 and ZNF692 . High splice burden was linked to an immunogenic tumor microenvironment, characterized by enriched antigen processing and adaptive immune responses. Conclusions: This study provides a comprehensive analysis of AS events in mRCC, highlighting intron retention as potential biomarkers for treatment response. Identified AS-derived neoantigens may serve as potential targets for adoptive cell therapy strategies.