Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 16 de 16
Filtrar
1.
Histopathology ; 84(5): 863-876, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38196202

RESUMO

AIMS: Treatment options for advanced urothelial carcinoma (aUC) rapidly evolved: besides immunomodulative therapeutic options and inhibitors targeting Fibroblast growth factor receptor (FGFR) alterations, two new antibody-drug conjugates (ADC), sacituzumab govitecan (SG) and enfortumab vedotin (EV), have been approved. However, little is known about the associations of specific aUC properties and the surface target expression of TROP2 and NECTIN-4. Our aim was to characterize associations of TACSTD2/TROP2 and NECTIN-4/NECTIN-4 protein and gene expression with morphomolecular and clinicopathological characteristics of aUC in two large independent cohorts. METHODS AND RESULTS: The TCGA BLCA (n = 405) and the CCC-EMN (n = 247) cohorts were retrospectively analysed. TROP2/TACSTD2 and NECTIN-4/NECTIN-4 are highly expressed at the protein and transcript level in aUC, and their expression status did not correlate with patient survival in both cohorts. NECTIN-4/NECTIN-4 expression was higher in luminal tumours and reduced in squamous aUCs. NECTIN-4 was negative in 10.6% of samples, and 18.4% of samples had low expression (H-score <15). The TROP2 negativity rate amounted to 6.5%. TACSTD2 and NECTIN-4 expression was reduced in neuroendocrine-like and/or protein-based double-negative tumours. TROP2- and NECTIN-4-negative tumours included one sarcomatoid and four neuroendocrine aUC. FGFR3 alterations and PD-L1 expression on tumour and immune cells did not associate with TROP2 or NECTIN-4 expression. CONCLUSIONS: TACSTD2/TROP2 and NECTIN-4/NECTIN-4 are widely expressed in aUC, independent of FGFR3 alterations or PD-L1 expression, thus representing a suitable target for ADC treatment in the majority of aUC. The expression loss was associated with aggressive morphomolecular aUC subtypes, i.e. neuroendocrine(-like) and sarcomatoid aUC.


Assuntos
Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/genética , Nectinas/genética , Antígeno B7-H1 , Estudos Retrospectivos , Moléculas de Adesão Celular/metabolismo , Antígenos de Neoplasias/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética
2.
BJU Int ; 134(5): 755-762, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38717014

RESUMO

OBJECTIVE: To investigate and compare the performance of urinary cytology and the Xpert BC Monitor test in the detection of bladder cancer in various clinically significant patient cohorts, including patients with carcinoma in situ (CIS), in a prospective multicentre setting, aiming to identify potential applications in clinical practice. PATIENTS AND METHODS: A total of 756 patients scheduled for transurethral resection of bladder tumour (TURBT) were prospectively screened between July 2018 and December 2020 at six German University Centres. Central urinary cytology and Xpert BC Monitor tests were performed prior to TURBT. The diagnostic performance of urinary cytology and the Xpert BC Monitor was evaluated according to sensitivity (SN), specificity (SC), negative predictive value (NPV) and positive predictive value (PPV). Statistical comparison of urinary cytology and the Xpert BC Monitor was conducted using the McNemar test. RESULTS: Of 756 screened patients, 733 (568 male [78%]; median [interquartile range] age 72 [62-79] years) were included. Bladder cancer was present in 482 patients (65.8%) with 258 (53.5%) high-grade tumours. Overall SN, SC, NPV and PPV were 39%, 93%, 44% and 92% for urinary cytology, and 75%, 69%, 59% and 82% for the Xpert BC Monitor. In patients with CIS (concomitant or solitary), SN, SC, NPV and PPV were 59%, 93%, 87% and 50% for urinary cytology, and 90%, 69%, 95% and 50% for the Xpert BC Monitor. The Xpert BC Monitor missed four tumours (NPV = 98%) in patients with solitary CIS, while potentially avoiding 63.3% of TURBTs in inconclusive or negative cystoscopy and a negative Xpert result. CONCLUSION: Positive urinary cytology may indicate bladder cancer and should be taken seriously. The Xpert BC Monitor may represent a useful diagnostic tool for correctly identifying patients with solitary CIS and unsuspicious or inconclusive cystoscopy.


Assuntos
Carcinoma in Situ , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/urina , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/patologia , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Carcinoma in Situ/urina , Carcinoma in Situ/diagnóstico , Carcinoma in Situ/patologia , Estudos Prospectivos , Sensibilidade e Especificidade , Citodiagnóstico/métodos , Valor Preditivo dos Testes
3.
Int J Mol Sci ; 25(12)2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38928033

RESUMO

Bladder cancer (BC) is the 12th most commonly diagnosed cancer worldwide. Although there are several well-established molecular and immunological classifications, prognostic and predictive markers for tumor cells and immune cells are still needed. Using a tissue microarray, we analyzed the expression of the chemokine CC motif ligand 5 (CCL5) by immunohistochemistry (IHC) in 175 muscle-invasive BC samples. The application of a single cutoff for the staining status of tumor cells (TCs; positive vs. negative) and immune cells (ICs; positive vs. negative) revealed 75 patients (42.9%) and 123 patients (70.3%) with CCL5-positive TCs or ICs, respectively. IHC results were associated with prognostic and predictive data. Multivariate Cox regression analysis revealed that positive CCL5 staining in TCs was associated with significantly shorter disease-specific survival (DSS; RR = 1.51; p = 0.047), but CCL5-negative ICs were associated with significantly shorter overall survival (OS; RR = 1.66; p = 0.005), DSS (RR = 2.02; p = 0.001) and recurrence-free survival (RFS; RR = 1.94; p = 0.002). Adjuvant chemotherapy was favorable for patients with CCL5-negative ICs for OS (RR = 0.30; p = 0.006), DSS (RR = 0.36; p = 0.022) and RFS (RR = 0.41; p = 0.046) but not for patients with CCL5-positive ICs, except in the subgroup of N1 + N2 patients, where it was associated with better OS. We suggest that CCL5 expression can be a prognostic and predictive marker for muscle-invasive bladder cancer patients.


Assuntos
Biomarcadores Tumorais , Quimiocina CCL5 , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/mortalidade , Quimiocina CCL5/metabolismo , Quimiocina CCL5/genética , Masculino , Feminino , Idoso , Prognóstico , Pessoa de Meia-Idade , Biomarcadores Tumorais/metabolismo , Invasividade Neoplásica , Idoso de 80 Anos ou mais , Adulto , Imuno-Histoquímica
4.
Adv Anat Pathol ; 30(3): 203-210, 2023 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-36730368

RESUMO

Genitourinary malignancies include a broad spectrum of distinct tumor entities occurring in the kidney, the urinary tract, the prostate, the adrenal glands, the penis, and testicles. Each tumor entity presents with unique biological characteristics, especially in terms of immunobiology. The immune landscape of genitourinary malignancies differs between immunoreactive tumors like urothelial carcinoma or carcinomas of the kidney, for which several immunotherapeutic treatment options have been approved in the past years. In contrast, prostate cancer presents with low immunogenicity and previous trials exploring immune checkpoint inhibitors and other immunotherapeutic agents did not proof substantial survival benefits. In this review, we are presenting a streamlined overview on the role of surgical pathologists within the contemporary practice of immune oncology. It includes current indications for pathologic programmed death-ligand 1 (PD-L1) assessment and important pathologic considerations on PD-L1 testing harmonization including interassay and algorithm variabilities. In addition, we will discuss emerging biomarkers beyond PD-L1 and their potential to predict immunotherapy responses including tumor mutational burden, microsatellite instability, gene expression signatures, and histologic factors.


Assuntos
Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Masculino , Humanos , Antígeno B7-H1 , Patologistas , Receptor de Morte Celular Programada 1/metabolismo , Biomarcadores Tumorais/metabolismo , Imunoterapia
5.
BMC Pediatr ; 22(1): 192, 2022 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-35410162

RESUMO

BACKGROUND: In neonatal patients with necrotizing enterocolitis (NEC) the inflammatory response is mediated by a plurality of different proteins. The proteins olfactomedin 4 (OLFM4) and lysozyme (LYZ) are part of the intestinal mucosal defense and especially OLFM4 has rarely been evaluated in neonatal gastrointestinal diseases. The aim of this study was to analyze whether expression levels of both proteins of innate immunity, OLFM4 and lysozyme, were increased during NEC in neonates. METHODS: Intestinal tissues of patients with NEC were examined with immunohistochemical staining of formalin-fixed and paraffin-embedded sections of resected tissue using antibodies against OLFM4 and lysozyme. Staining-positive tissues were semi-quantitatively scored from 0 (no staining), 1 (weak staining), 2 (moderate staining) to 3 (highly intense staining) by two individual investigators. Intestinal tissue of infants with volvulus was used as a control as other intestinal tissue without major inflammation was not available. RESULTS: Both applied antibodies against OLFM4 showed different staining patterns with higher staining intensity of the antibody OLFM4 (D1E4M). OLFM4 (median score of the antibody OLFM4 (D1E4M): 3.0) and lysozyme (median score: 3.0) are highly expressed in intestinal and immune cells during NEC. Expression of OLFM4 and lysozyme in the control samples with volvulus was observable but significantly lower (median score of the antibody OLFM4 (D1E4M): 1.25; median score of the antibody against LYZ: 2.0; p = 0.033 and p = 0.037, respectively). CONCLUSIONS: Both proteins, OLFM4 and lysozyme, may play a role in the pathogenesis of NEC in neonatal patients, but the exact mechanisms of OLFM4 and lysozyme function and their role in immunological responses have not yet been resolved in detail. These observations add new insights as basis for further large-scale population research.


Assuntos
Enterocolite Necrosante , Doenças Fetais , Doenças do Recém-Nascido , Volvo Intestinal , Enterocolite Necrosante/etiologia , Fator Estimulador de Colônias de Granulócitos , Humanos , Lactente , Recém-Nascido , Mucosa Intestinal/metabolismo , Volvo Intestinal/complicações , Muramidase , Proteínas
6.
Int J Mol Sci ; 23(18)2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36142180

RESUMO

Methylene blue (MB) is a dye used for histology with clinical importance and intercalates into nucleic acids. After MB staining of formalin fixed paraffin embedded (FFPE) muscle invasive bladder cancer (MIBC) and normal urothelium, specific regions could be microdissected. It is not known if MB influences RNA used for gene expression studies. Therefore, we analyzed MIBC using five different RNA isolation methods comparing patient matched FFPE and fresh frozen (FF) tissues pre-stained with or without MB. We demonstrate a positive impact of MB on RNA integrity with FF tissues using real time PCR with no interference of its chemical properties. FFPE tissues showed no improvement of RNA integrity, which we propose is due to formalin induced nucleotide crosslinks. Using direct multiplex RNA hybridization the best genes for normalization of MIBC and control tissues were identified from 34 reference genes. In addition, 5SrRNA and 5.8SrRNA were distinctive reference genes detecting <200 bp fragments important for mRNA analyses. Using these normalized RNAs from MB stained MIBC and applying multiplex RNA hybridization and mRNA sequencing, a minimal gene expression panel precisely identified luminal and basal MIBC tumor subtypes, important for diagnosis, prognosis and chemotherapy response.


Assuntos
RNA , Neoplasias da Bexiga Urinária , Formaldeído/química , Perfilação da Expressão Gênica/métodos , Humanos , Azul de Metileno/farmacologia , Nucleotídeos , Inclusão em Parafina/métodos , RNA/análise , RNA/genética , RNA Mensageiro/genética , Fixação de Tecidos/métodos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética
7.
Pathologie (Heidelb) ; 45(6): 363-370, 2024 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-39110167

RESUMO

BACKGROUND: Muscle-invasive and metastatic urothelial carcinoma (UC) represents a heterogeneous disease entity with numerous morphological, molecular, and immunological phenotypes. AIMS: This article aims to provide an overview of current histopathological, molecular, and immunological prognostic and predictive factors in muscle-invasive and metastatic UC. RESULTS AND DISCUSSION: Muscle-invasive and metastatic UC exhibits a wide range of divergent differentiations and histological subtypes. The correct diagnosis of these morphological variants is essential, as they may determine the clinical course and may also present specific and potentially therapeutically targetable molecular alterations (e.g., HER2 alterations in micropapillary UC). The morphological subtypes largely correlate with the six molecular consensus subtypes. Furthermore, morphological and molecular subtypes are associated with immunological properties that are relevant for modern immunotherapies, such as the PD-L1 status. Numerous immunotherapy studies in the setting of curatively treatable muscle-invasive UC will be reported in 2024 and 2025, likely leading to an increasing number of PD-L1 testing indications.


Assuntos
Carcinoma de Células de Transição , Invasividade Neoplásica , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/genética , Prognóstico , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/imunologia , Carcinoma de Células de Transição/genética , Imunoterapia/métodos , Metástase Neoplásica , Bexiga Urinária/patologia , Bexiga Urinária/imunologia
8.
Virchows Arch ; 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38833173

RESUMO

Rhabdomyosarcoma (RMS) of the urinary bladder in adults and elderly is an exceptionally rare neoplasm that displays poorly differentiated solid (alveolar-like) small cell pattern, frequently indistinguishable from small cell neuroendocrine carcinoma (SCNEC). However, the histogenesis of RMS and SCNEC and their inter-relationship have not been well studied and remained controversial. We herein analyzed 23 SCNEC and 3 small round cell RMS of the bladder for neuroendocrine (synaptophysin + chromogranin A) and myogenic (desmin + myogenin) marker expression and for TERT promoter mutations. In addition, the RMS cohort and one SCNEC that was revised to RMS were tested for gene fusions using targeted RNA sequencing (TruSight Illumina Panel which includes FOXO1 and most of RMS-related other genes). Overall, significant expression of myogenin and desmin was observed in one of 23 original SCNEC justifying a revised diagnosis to RMS. On the other hand, diffuse expression of synaptophysin was noted in 2 of the 4 RMS, but chromogranin A was not expressed in 3 RMS tested. TERT promoter mutations were detected in 15 of 22 (68%) SCNEC and in two of three (67%) assessable RMS cases, respectively. None of the four RMS cases had gene fusions. Our data highlights phenotypic and genetic overlap between SCNEC and RMS of the urinary bladder. High frequency of TERT promoter mutations in SCNEC is in line with their presumable urothelial origin. In addition, the presence of TERT promoter mutation in 2 of 3 RMS and lack of FOXO1 and other gene fusions in all 4 RMSs suggest a mucosal (urothelial) origin, probably representing extensive monomorphic rhabdomyoblastic transdifferentiation in SCNEC.

9.
Virchows Arch ; 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39028359

RESUMO

Carcinoma in situ (CIS) of the bladder is a known parameter regarding the prognosis and recurrence tendency of urothelial carcinomas. Nevertheless, there is little evidence whether the amount of CIS or other precursor lesions, as well as the quantified tumor mass of muscle-invasive urothelial carcinoma, has an influence on the survival or recurrence rate of affected patients. From 80 patients with muscle invasive urothelial bladder cancer and radical cystectomy, 23 samples each were obtained as part of a whole organ mapping in a single institution study, in which the precursor lesions and tumor area were digitally measured and further correlated to pathological standard parameters, patient survival, molecular luminal and basal subtypes, and immune infiltration. Significant correlations were found between tumor mass and surface lining CIS amount for pT-stage, lymphovascular invasion, and perineural infiltration. Furthermore, an increased tumor mass as well as an increased amount of CIS combined with an increased tumor mass showed a significantly reduced survival rate in multivariable analysis (HR = 2.75; P = 0.019 vs. HR = 3.54; P = 0.002) as well as a significantly increased recurrence. No correlations could be found with molecular subtypes and immune infiltration. The exact measurement of the tumor mass with and without the CIS surface area, whether manually or, more specifically, digitally, could be incorporated into routine diagnostics and implemented as an independent predictor for patient post-surgical outcomes. It can therefore serve as an additional predictor for risk stratification and, if necessary, intensified follow-up care or therapy.

10.
Virchows Arch ; 2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39191994

RESUMO

Recent studies have revealed an association between TP53 mutations and endocrine resistance in hormone receptor-positive, HER2-negative breast cancer (HR + HER2 -BC). Aberrant p53 immunostaining (IHC) patterns may provide a surrogate marker for TP53 mutations. Building upon a ternary algorithm of aberrant staining patterns, this study evaluates the reliability of p53 IHC as screening tool for TP53 mutations in BC (NST). Furthermore, it describes the histopathological and molecular characteristics of TP53-mutated cases, along with the mutational status of PIK3CA. This study comprised 131 early-stage, node-negative BCs with available core biopsies and resection specimens. Cases were categorized as follows: HR + HER2 - (85 cases), HER2 + (21 cases) and triple negative (TN, 25 cases). Aberrant IHC staining patterns for p53 were defined as overexpression (OE), complete absence (CA) and cytoplasmic (CY). In addition, targeted sequencing of TP53 and PIK3CA genes was performed. TP53 mutations were identified in 53 of 126 cases (42.1%). Within HR + HER2 - cases, TP53 mutations were found in 17 of 80 cases (21.3%). IHC accurately predicted TP53 mutation in 96.2% of cases with a specificity of 100%. Additionally, there was a significant agreement between missense mutations and OE, as well as between truncating mutations and CA (κ 73% and 76%). CY was observed in two TN cases with truncating mutations within the nuclear localization signalling domain of p53. TP53-mutated cases exhibited higher grade, greater nuclear pleomorphism and higher Ki-67 proliferation index and were associated with the PIK3CA wild-type status (p < 0.001). p53 IHC may provide a useful screening tool for identifying TP53-mutated BC of NST.

11.
J Pathol Clin Res ; 10(2): e12369, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38504364

RESUMO

Upper tract urothelial carcinoma (UTUC) is a rare and aggressive, yet understudied, urothelial carcinoma (UC). The more frequent UC of the bladder comprises several molecular subtypes, associated with different targeted therapies and overlapping with protein-based subtypes. However, if and how these findings extend to UTUC remains unclear. Artificial intelligence-based approaches could help elucidate UTUC's biology and extend access to targeted treatments to a wider patient audience. Here, UTUC protein-based subtypes were identified, and a deep-learning (DL) workflow was developed to predict them directly from routine histopathological H&E slides. Protein-based subtypes in a retrospective cohort of 163 invasive tumors were assigned by hierarchical clustering of the immunohistochemical expression of three luminal (FOXA1, GATA3, and CK20) and three basal (CD44, CK5, and CK14) markers. Cluster analysis identified distinctive luminal (N = 80) and basal (N = 42) subtypes. The luminal subtype mostly included pushing, papillary tumors, whereas the basal subtype diffusely infiltrating, non-papillary tumors. DL model building relied on a transfer-learning approach by fine-tuning a pre-trained ResNet50. Classification performance was measured via three-fold repeated cross-validation. A mean area under the receiver operating characteristic curve of 0.83 (95% CI: 0.67-0.99), 0.8 (95% CI: 0.62-0.99), and 0.81 (95% CI: 0.65-0.96) was reached in the three repetitions. High-confidence DL-based predicted subtypes showed significant associations (p < 0.001) with morphological features, i.e. tumor type, histological subtypes, and infiltration type. Furthermore, a significant association was found with programmed cell death ligand 1 (PD-L1) combined positive score (p < 0.001) and FGFR3 mutational status (p = 0.002), with high-confidence basal predictions containing a higher proportion of PD-L1 positive samples and high-confidence luminal predictions a higher proportion of FGFR3-mutated samples. Testing of the DL model on an independent cohort highlighted the importance to accommodate histological subtypes. Taken together, our DL workflow can predict protein-based UTUC subtypes, associated with the presence of targetable alterations, directly from H&E slides.


Assuntos
Carcinoma de Células de Transição , Aprendizado Profundo , Neoplasias da Bexiga Urinária , Neoplasias Urológicas , Humanos , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/química , Carcinoma de Células de Transição/diagnóstico , Carcinoma de Células de Transição/genética , Neoplasias Urológicas/diagnóstico , Neoplasias Urológicas/genética , Estudos Retrospectivos , Antígeno B7-H1 , Inteligência Artificial , Fluxo de Trabalho , Biomarcadores Tumorais/análise , Técnicas de Diagnóstico Molecular
12.
Methods Mol Biol ; 2684: 249-255, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37410239

RESUMO

Since 2016, the immunotherapeutic agents targeting PD-1 and PD-L1 are an integral part in first-line and second-line treatment of advanced or metastatic urothelial cancer. By PD-1 and PD-L1 inhibition with these drugs, the immune system is supposed to regain the capacity to actively kill cancer cells. Meanwhile, PD-L1 assessment is prescribed for patients not being eligible for platinum-based chemotherapy in first-line settings in metastatic disease (for monotherapy with atezolizumab or pembrolizumab) and for patients who are intended to receive adjuvant nivolumab treatment following radical cystectomy. Several challenges which are highlighted in this chapter affect PD-L1 testing in daily routine including availability of representative tissue materials, inter-observer variability, and different available PD-L1 immunohistochemistry assays with different analytical properties.


Assuntos
Antígeno B7-H1 , Neoplasias da Bexiga Urinária , Humanos , Receptor de Morte Celular Programada 1 , Anticorpos Monoclonais/uso terapêutico , Neoplasias da Bexiga Urinária/patologia , Nivolumabe/uso terapêutico
13.
Methods Mol Biol ; 2684: 283-291, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37410241

RESUMO

FGFR alterations in urothelial carcinoma are key driver alterations of tumorigenesis and are long recognized. In 2019 the Food and Drug Administration (FDA) approved the first pan-FGFR inhibitor, as the first specific targeted therapy in urothelial carcinoma. To receive the drug, alteration testing is required, and only alteration carriers can profit of this new agent. Due to this clinical need of detection and analysis of FGFR, here we describe two distinct and specific analytical methodologies: the SNaPshot analysis of nine FGFR3 point mutations and the QIAGEN therascreen® FGFR RGQ RT-PCR Kit, the FDA-approved companion diagnostic kit.


Assuntos
Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Neoplasias Urológicas , Humanos , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias Urológicas/genética , Neoplasias Urológicas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Mutação Puntual
14.
Sci Rep ; 13(1): 15437, 2023 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-37723173

RESUMO

To determine whether Xpert bladder cancer monitor, a noninvasive PCR-based biomarker test, can predict the need for 2nd transurethral resection of the bladder (TURB) better than clinical assessment. Patients scheduled for TURB were prospectively screened. After initial TURB, patients were assigned to 2nd TURB or follow-up cystoscopy at 3 months (FU) by clinicians' discretion. Central urine cytology and Xpert monitor tests were performed prior to the 1st TURB and 2nd TURB or FU, respectively. Statistical analysis to compare clinical assessment and Xpert monitor comprised sensitivity (SENS), specificity (SPEC), NPV and PPV. Of 756 screened patients, 171 were included (114 with 2nd TURB, 57 with FU). Residual tumors were detected in 34 patients who underwent 2nd TURB, and recurrent tumors were detected in 2 patients with FU. SENS and SPEC of Xpert monitor were 83.3% and 53.0%, respectively, PPV was 32.6% and NPV was 92.1%. Clinical risk assessment outperformed Xpert monitor. In patients with pTa disease at initial TURB, Xpert monitor revealed a NPV of 96%. Xpert monitor was not superior than clinical assessment in predicting the need for 2nd TURB. It might be an option to omit 2nd TURB for selected patients with pTa disease.


Assuntos
Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/diagnóstico , Bexiga Urinária , Cistoscopia , Neoplasia Residual , Reação em Cadeia da Polimerase
15.
Eur Urol ; 83(2): 133-142, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36372626

RESUMO

BACKGROUND: The value of programmed cell death ligand-1 (PD-L1) to predict durable responses to immune checkpoint inhibitors (ICIs) in metastatic urothelial carcinoma (mUC) is inconsistent. We hypothesize that the use of archived primary tumor material (PRIM) for PD-L1 testing in clinical trials not properly reflecting the metastatic disease status (MET) contributes to this clinical issue. OBJECTIVE: To analyze the predictive and prognostic value of PD-L1, spatial immunephenotypes, and major histocompatibility complex class I (MHC-I) determined in patient-matched PRIM/MET. DESIGN, SETTING, AND PARTICIPANTS: PD-L1, spatial immunephenotypes, and MHC-I were examined in 154 mUC patients with at least one available pretreatment MET (138 patient-matched PRIM/MET pairs). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PD-L1, spatial immunephenotype, and MHC-I status of (patient-matched PRIM and) pretreatment MET were correlated with chemotherapy and ICI response and outcomes. RESULTS AND LIMITATIONS: Discordance rates in patient-matched PRIM/MET were 25/30%, 36%, and 49% for PD-L1 (CPS10/IC5%), immunephenotypes, and MHC-I (loss vs preserved), respectively. Correlations with chemotherapy and ICI responses were observed for immunephenotypes and MHC-I status determined in MET (not for PD-L1 alone), but not in PRIM. In case of ICIs, patients with cytotoxic tumor immune microenvironment (TIME) showed durable responses with disease control rates of 90% and a hazard ratio for disease progression/death of 0.05 (95% confidence interval: 0.01-0.65) versus patients with immunedepleted MET (disease control rate 29%). MET MHC-I status added an incremental value to predict durable ICI responses. Limitations include the partly retrospective design and the lack of MET multisampling on individual patient level. CONCLUSIONS: The TIME is subject to substantial dynamics during metastatic evolution. MET immunephenotypes and MHC-I statuses show promising potential to predict chemotherapy and durable ICI responses, while the PRIM TIME does not. Thus, future clinical trials should rather rely on pretreatment MET biopsies reflecting the current immunological disease state than on PRIM. PATIENT SUMMARY: Prediction of chemotherapy and responses to immune checkpoint inhibitors might be possible using representative pretreatment metastatic biopsies.


Assuntos
Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Carcinoma de Células de Transição/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Antígeno B7-H1 , Estudos Retrospectivos , Microambiente Tumoral
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA