European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2023 Update

European Urology, Journal Year: 2023, Volume and Issue: 84(1), P. 49 - 64

Published: March 24, 2023

Language: Английский

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Circulating and urinary tumour DNA in urothelial carcinoma — upper tract, lower tract and metastatic disease

Nature Reviews Urology, Journal Year: 2023, Volume and Issue: 20(7), P. 406 - 419

Published: March 28, 2023

Language: Английский

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Lethal clinical outcome and chemotherapy and immunotherapy resistance in patients with urothelial carcinoma with MDM2 amplification or overexpression

Journal for ImmunoTherapy of Cancer, Journal Year: 2025, Volume and Issue: 13(1), P. e010964 - e010964

Published: Jan. 1, 2025

The E3 ubiquitin ligase murine double minute 2 (MDM2) binds the p53 transcriptional activation domain and acts as a potent inhibitor of TP53 pathway, one three most crucial oncogenic pathways in urothelial carcinoma (UC). However, clinical significance impact on tumor immune contexture MDM2 amplification UC remain unclear. This study analyzed 240 patients with matched annotations from two local cohorts (ZSHS cohort FUSCC cohort). We assessed correlation between status outcomes, therapeutic efficacy, immunological characteristics by immunohistochemical analysis targeted sequencing. Additionally, 2264 samples five independent external cohorts, genomic, transcriptomic, data, were used for validation. (MDM2 Amp) or protein overexpression (MDM2OE) was associated inferior overall survival cohort, Log-rank p<0.001; p=0.030) reduced response to platinum-based chemotherapy p<0.001) well anti-PD-1/PD-L1 immunotherapy (FUSCC p=0.016) UC, irrespective TP53/p53 status. further linked high-grade tumors dedifferentiated morphology. In addition, an immuno-evasive characterized lower proportion tertiary lymphoid structure infiltration, abundance CD8+ T cells, IFN-γ+ GZMB+ decreased expression checkpoint molecules including programmed death-ligand 1 (PD-L1), death-1 (PD-1) cytotoxic T-lymphocyte-associated 4 (CTLA-4). defines lethal subset prognosis resistance both These are morphology immunosuppressive microenvironment. Accurate assessment can improve risk stratification enable personalized genomics-guided treatment UC.

Language: Английский

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Improving Urothelial Carcinoma Outcomes: The Powerful Combination of Neoadjuvant and Adjuvant Chemotherapy in the Perioperative Period

Annals of Surgical Oncology, Journal Year: 2025, Volume and Issue: unknown

Published: March 27, 2025

Language: Английский

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Fibroblast growth factor receptor 3 mutation attenuates response to immune checkpoint blockade in metastatic urothelial carcinoma by driving immunosuppressive microenvironment

Journal for ImmunoTherapy of Cancer, Journal Year: 2023, Volume and Issue: 11(9), P. e006643 - e006643

Published: Sept. 1, 2023

Background Immune checkpoint blockade (ICB) therapy holds promise in metastatic urothelial carcinoma (UC). Fibroblast growth factor receptor 3 (FGFR3) mutation drives T-cell-depleted microenvironment UC, which led to the hypothesis that FGFR3 might attenuate response ICB patients with UC. The study aims compare prognosis and between FGFR3-mutated FGFR3-wildtype UC after therapy, decode potential molecular mechanisms. Methods Based on single-arm, multicenter, phase 2 trial, IMvigor210, we conducted a propensity score matched (PSM) analysis. After 1:1 ratio PSM method, 39 treated atezolizumab were enrolled. A meta-analysis through systematical database retrieval was for validation. In addition, performed single-cell RNA sequencing three tumors analyzed 58,069 single cells. Results analysis indicated had worse overall survival (OS) comparison (HR=2.11, 95% CI=(1.16 3.85), p=0.015) receiving atezolizumab. median OS 9.2 months (FGFR3-mutated) versus 21.0 (FGFR3-wildtype). lower disease control rate than (41.0% vs 66.7%, p=0.023). involving 938 confirmed associated (HR=1.28, CI=(1.04 1.59), p=0.02). Single-cell transcriptome identified carried stronger immunosuppressive compared exhibited less immune infiltration, T-cell cytotoxicity. Higher TREM2+ macrophage abundance can undermine suppress T cells, potentially contributing formation of an microenvironment. Lower inflammatory-cancer-associated fibroblasts recruited chemokines antitumor immunity but expressed factors promote malignant cell development. cells characterized by high hypoxia/metabolism low interferon phenotype. Conclusions carries Inhibition activate microenvironment, combination FGFR inhibitor targeted be promising therapeutic regimen providing important implications clinical management.

Language: Английский

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Driver mutations of intrahepatic cholangiocarcinoma shape clinically relevant genomic clusters with distinct molecular features and therapeutic vulnerabilities

Theranostics, Journal Year: 2021, Volume and Issue: 12(1), P. 260 - 276

Published: Nov. 10, 2021

Purpose: To establish a clinically applicable genomic clustering system, we investigated the interactive landscape of driver mutations in intrahepatic cholangiocarcinoma (ICC). Methods: The data 1481 ICCs from diverse populations was analyzed to investigate pair-wise co-occurrences or mutual exclusivities among recurrent mutations. Clinicopathological features and outcomes were compared different clusters. Gene expression DNA methylation profiling datasets molecular distinctions mutational ICC cell lines with gene mutation backgrounds used evaluate cluster specific biological behaviors drug sensitivities. Results: Statistically significant mutation-pairs identified across 21 combinations genes. Seven most (TP53, KRAS, SMAD4, IDH1/2, FGFR2-fus BAP1) showed could aggregate into three genetic clusters: Cluster1: represented by tripartite interaction TP53 SMAD4 mutations, exhibited large bile duct histological phenotype high CA19-9 level dismal prognosis; Cluster2: co-association IDH/BAP1 FGFR2-fus/BAP1 mutation, characterized small phenotype, low optimal Cluster3: mutation-free cases intermediate clinicopathological features. These clusters distinct traits, responses therapeutic drugs. Finally, S100P KRT17 as "cluster-specific", "lineage-dictating" "prognosis-related" biomarkers, which combination well stratify Cluster3 two biologically subtypes. Conclusions: This system can be instructive prognostic stratification, classification, optimization.

Language: Английский

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Single-cell atlases link macrophages and CD8⁺ T-cell subpopulations to disease progression and immunotherapy response in urothelial carcinoma

Theranostics, Journal Year: 2022, Volume and Issue: 12(18), P. 7745 - 7759

Published: Jan. 1, 2022

Immune checkpoint inhibitors (ICIs) have revolutionized the management of locally advanced or metastatic urothelial carcinoma. Strikingly, compared to carcinoma bladder (UCB), upper tract (UTUC) has a higher response rate ICIs. The stratification patients most likely benefit from ICI therapy remains major clinical challenge.

Language: Английский

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Highly Sensitive and Specific Detection of Bladder Cancer via Targeted Ultra-deep Sequencing of Urinary DNA

European Urology Oncology, Journal Year: 2022, Volume and Issue: 6(1), P. 67 - 75

Published: April 8, 2022

There is an unmet need for accurate, validated, noninvasive test diagnosing and monitoring bladder cancer (BC). Detection of BC-associated mutations in urinary DNA via targeted deep sequencing could meet this need. To the ability mutational analysis to noninvasively detect BC within context haematuria investigations non–muscle-invasive (NMIBC) surveillance. Capture-based ultra-deep was performed 443 somatic 23 genes 591 urine cell-pellet DNAs from clinic patients 293 NMIBC surveillance patients. Variant calling optimised minimise false positives using samples 162 without BC. The sensitivity specificity diagnosis were determined. Mutational detected 144 165 diagnosed with incident two independent cohorts, yielding overall 87.3% (95% confidence interval [CI] 81.2–92.0%) at 84.8% CI 79.9–89.0%). 97.4% grade 3, 86.5% 2, 70.8% 1 Among patients, 25 out 29 recurrent BCs detected, 86.2% 70.8–97.7%) 62.5% 56.1–68.0%); a positive mutation absence clinically detectable disease associated 2.6-fold increase risk future recurrence. low number recurrences cohort lower detecting pTa are limitations. small panel facilitate testing expedite investigations. Following further validation, also play role Identification alterations that frequently mutated appears be promising strategy reducing reliance on examination telescopic camera inserted through urethra.

Language: Английский

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Novel Use of Circulating Tumor DNA to Identify Muscle-invasive and Non–organ-confined Upper Tract Urothelial Carcinoma

European Urology, Journal Year: 2023, Volume and Issue: 85(3), P. 283 - 292

Published: Oct. 4, 2023

Language: Английский

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Upper Tract Urothelial Carcinoma (UTUC) Diagnosis and Risk Stratification: A Comprehensive Review

Cancers, Journal Year: 2023, Volume and Issue: 15(20), P. 4987 - 4987

Published: Oct. 14, 2023

Diagnosis and risk stratification are cornerstones of therapeutic decisions in the management patients with upper tract urothelial carcinoma (UTUC). Diagnostic modalities provide data that can be integrated, to nomograms tools predict survival adverse outcomes. This study reviews cytology, ureterorenoscopy novel techniques used it (including photodynamic diagnosis, narrow-band imaging, optical coherence tomography, confocal laser endomicroscopy), biopsy. Imaging biomarkers discussed another article. Patient- tumor-related prognostic factors, their association indices, roles different scores predictive discussed. Patient-related factors include age, sex, ethnicity, tobacco consumption, surgical delay, sarcopenia, nutritional status, several blood-based markers. Tumor-related prognosticators comprise stage, grade, presentation, location, multifocality, size, lymphovascular invasion, margins, lymph node mutational landscape, architecture, histologic variants, tumor-stroma ratio. The accuracy validation pre-operative tools, which incorporate various muscle-invasive or non-organ confined disease, help decide on surgery type (radical nephroureterectomy, kidney-sparing procedures) also investigated. Post-operative nomograms, adjuvant chemotherapy plan follow-up explored. Finally, a revision current UTUC is endorsed.

Language: Английский

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