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1.
Science ; 370(6512): 75-82, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33004514

RESUMO

The extent of somatic mutation and clonal selection in the human bladder remains unknown. We sequenced 2097 bladder microbiopsies from 20 individuals using targeted (n = 1914 microbiopsies), whole-exome (n = 655), and whole-genome (n = 88) sequencing. We found widespread positive selection in 17 genes. Chromatin remodeling genes were frequently mutated, whereas mutations were absent in several major bladder cancer genes. There was extensive interindividual variation in selection, with different driver genes dominating the clonal landscape across individuals. Mutational signatures were heterogeneous across clones and individuals, which suggests differential exposure to mutagens in the urine. Evidence of APOBEC mutagenesis was found in 22% of the microbiopsies. Sequencing multiple microbiopsies from five patients with bladder cancer enabled comparisons with cancer-free individuals and across histological features. This study reveals a rich landscape of mutational processes and selection in normal urothelium with large heterogeneity across clones and individuals.


Assuntos
Genes Neoplásicos , Mutagênese , Seleção Genética , Neoplasias da Bexiga Urinária/genética , Bexiga Urinária/patologia , Urotélio/patologia , Desaminases APOBEC/genética , Adulto , Idoso , Biópsia , Montagem e Desmontagem da Cromatina/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutagênicos/análise , Mutação
2.
Science ; 370(6512): 82-89, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33004515

RESUMO

Knowledge of somatic mutation accumulation in normal cells, which is essential for understanding cancer development and evolution, remains largely lacking. In this study, we investigated somatic clonal events in morphologically normal human urothelium (MNU; epithelium lining the bladder and ureter) and identified macroscopic clonal expansions. Aristolochic acid (AA), a natural herb-derived compound, was a major mutagenic driving factor in MNU. AA drastically accelerates mutation accumulation and enhances clonal expansion. Mutations in MNU were widely observed in chromatin remodeling genes such as KMT2D and KDM6A but rarely in TP53, PIK3CA, and FGFR3 KMT2D mutations were found to be common in urothelial cells, regardless of whether the cells experience exogenous mutagen exposure. Copy number alterations were rare and largely confined to small-scale regions, along with copy-neutral loss of heterozygosity. Single AA-associated clones in MNU expanded to a scale of several square centimeters in size.


Assuntos
Ácidos Aristolóquicos/toxicidade , Montagem e Desmontagem da Cromatina/genética , Mutagênicos/toxicidade , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/genética , Urotélio/efeitos dos fármacos , Urotélio/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Proteínas de Ligação a DNA/genética , Histona Desmetilases/genética , Humanos , Mutagênese , Mutação , Proteínas de Neoplasias/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Proteína Supressora de Tumor p53/genética
3.
Ann Biol Clin (Paris) ; 78(5): 527-536, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33026348

RESUMO

We report the case of a man with a primary diagnosis of Waldenström macroglobulinemia. He secondarily presented a diffuse large B cell lymphoma (DLBCL) located in the nasal fossae, which relapsed later in the eye. The diagnosis of these two malignancies is based on a multidisciplinary biological approach using new sensitive and specific techniques. These techniques revealed that the two diseases harbor different B cell clones, indicating a distinct origin. This observation highlights the importance of targeted biological techniques for the diagnosis of these two rare hemopathies. It also shows that it is possible to prove the independent nature of the two tumor clones, thus allowing optimized therapeutic management.


Assuntos
Carcinoma de Células de Transição/diagnóstico , Neoplasias Oculares/secundário , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/patologia , Gamopatia Monoclonal de Significância Indeterminada/diagnóstico , Neoplasias da Bexiga Urinária/diagnóstico , Macroglobulinemia de Waldenstrom/diagnóstico , Idoso , Carcinoma de Células de Transição/sangue , Carcinoma de Células de Transição/complicações , Diagnóstico Diferencial , Neoplasias Oculares/sangue , Neoplasias Oculares/diagnóstico , Testes Hematológicos , Humanos , Imunoglobulina M/análise , Imunoglobulina M/sangue , Imunofenotipagem , Achados Incidentais , Linfoma Difuso de Grandes Células B/sangue , Linfoma Difuso de Grandes Células B/complicações , Masculino , Gamopatia Monoclonal de Significância Indeterminada/sangue , Gamopatia Monoclonal de Significância Indeterminada/complicações , Gamopatia Monoclonal de Significância Indeterminada/patologia , Neoplasias da Bexiga Urinária/sangue , Neoplasias da Bexiga Urinária/complicações , Urotélio/patologia , Baixa Visão/diagnóstico , Baixa Visão/etiologia , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/complicações , Macroglobulinemia de Waldenstrom/patologia
4.
Am J Surg Pathol ; 44(10): 1322-1330, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32931680

RESUMO

Trophoblastic differentiation (including choriocarcinoma) arising in urothelial carcinoma has been described in numerous case reports, but never in a single series. We present a series of these tumors, describing the morphologic spectrum, applying traditional and novel immunohistochemical stains, and characterizing clinical follow-up. We identified 16 cases, arising predominantly in the bladder (N=14), but also the ureter (N=1) and prostatic urethra (N=1). Six of our cases (38%) contained invasive urothelial carcinoma with admixed syncytiotrophoblasts, 8 cases (50%) consisted of invasive urothelial carcinoma with choriocarcinoma, 1 case (6%) showed urothelial carcinoma in situ with associated choriocarcinoma, and 1 case (6%) consisted of pure choriocarcinoma. Other subtypes of variant morphology were seen in 5 of our cases (31%) and included squamous, glandular, lipoid, chordoid/myxoid, and sarcomatoid features. Given the limited specificity of human chorionic gonadotropin immunohistochemistry, we also studied the expression of a novel specific trophoblastic marker, hydroxyl-δ-5-steroid dehydrogenase, as well as Sal-like protein 4. Human chorionic gonadotropin expression was seen in nearly all cases (93%) but was often not limited to the trophoblastic component, staining the urothelial component also in 85% of the cases. Expression of hydroxyl-δ-5-steroid dehydrogenase was more sensitive and more specific, staining 100% of the cases and limited to trophoblasts in all but 1 case. Sal-like protein 4 expression was variable, staining trophoblast in only 50% of cases and staining the urothelial carcinoma component in 43% of those positive cases. Most of our tumors presented at a high stage and were associated with poor clinical outcomes, with at least muscle-invasive disease (pT2) in 10 of the 14 bladder tumors (71%), periureteric fat invasion in the ureter tumor (pT3), distant metastases in 7 of 16 cases (44%) and death of disease in 3 of the 15 patients with follow-up (20%). Our study describes a series of urothelial carcinomas with trophoblastic differentiation, demonstrating the morphologic spectrum of this entity, its frequent association with other subtypes of variant morphology, its characteristic immunoprofile, and its aggressive clinical behavior.


Assuntos
Carcinoma de Células de Transição/patologia , Coriocarcinoma não Gestacional/patologia , Trofoblastos/patologia , Neoplasias Urológicas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Diferenciação Celular , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Urotélio/patologia
5.
J Urol ; 204(6): 1129-1140, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32716694

RESUMO

PURPOSE: The currently available evidence regarding the prognostic and clinical significance of each variant histology subtype of urothelial bladder cancer remains scarce. We assessed the prognostic value of variant histology in patients with urothelial carcinoma of the bladder treated with radical cystectomy. MATERIALS AND METHODS: PubMed®, Web of Science™, Cochrane Library and Scopus® databases were searched for articles published before October 2019 according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. We identified 39 studies comprising 20,544 patients matching our eligibility criteria. RESULTS: Studies were deemed eligible if they compared overall, cancer specific and recurrence-free survival in patients with urothelial carcinoma of the bladder with and without variant histology. Formal meta-analyses were performed for these outcomes. Variant histology was associated with worse cancer specific (pooled HR 1.37, 95% CI 1.24-1.50), overall (pooled HR 1.44, 95% CI 1.26-1.65) and recurrence-free survival (pooled HR 1.32, 95% CI 1.20-1.45). Subgroup analyses demonstrated that "micropapillary" (pooled HR 1.20, 95% CI 1.02-1.41), "plasmacytoid" (pooled HR 2.03, 95% CI 1.17-3.52) and "small cell" variant histology (HR 3.32, 95% CI 1.98-5.59) were also associated with worse overall survival. CONCLUSIONS: Variant histology in patients with urothelial carcinoma of the bladder is associated with increased risks of disease recurrence as well as cancer specific and overall mortality. Variant histology was independently associated with overall survival in the "micropapillary," "plasmacytoid" and "small cell" subgroups. Variant histology should be integrated into prognostic tools to guide risk stratification, treatment planning and patient counseling. However, caution should be exercised in interpreting the conclusions drawn from this study given the limitations, which include the heterogeneity of the population of interest and the retrospective nature of the primary data evaluated.


Assuntos
Carcinoma de Células de Transição/mortalidade , Recidiva Local de Neoplasia/diagnóstico , Neoplasias da Bexiga Urinária/mortalidade , Bexiga Urinária/patologia , Urotélio/patologia , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/cirurgia , Cistectomia , Intervalo Livre de Doença , Humanos , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Prognóstico , Medição de Risco/métodos , Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgia , Urotélio/cirurgia
6.
Medicine (Baltimore) ; 99(28): e21204, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664169

RESUMO

INTRODUCTION: Abundant myxoid stroma rarely occurs in urothelial carcinomas (UCs). We report an 83-year-old woman with UC of the urinary bladder with abundant myxoid stroma. We summarized the clinicopathological features, immunophenotype, diagnosis, and differential diagnosis of this type of bladder cancer, in order to improve the understanding of surgeons and pathologists. PATIENT CONCERNS: An 83-year-old female presented with hematuria and frequent micturition, without odynuria, hypogastralgia, or fever. DIAGNOSIS: The computed tomography scan demonstrated extensive tumors in the anterior wall of the bladder and a soft tissue shadow anterior to the sacrum. Cystoscopy showed massive wide-based tumors located on the anterior and lateral walls of the bladder, with no tumor involving the bladder neck. Multiple punch biopsies were performed, the histologic evaluation of which revealed a poorly differentiated invasive UCs with myxoid stroma. INTERVENTIONS: The patient underwent a laparoscopic radical cystectomy and cutaneous ureterostomy. OUTCOMES: The patient discharged without any complications. Histologic evaluation revealed an invasive UC; the most prominent feature was an abundant myxoid stroma that covered approximately 80% of the lesion and the tumor cells were arranged in cords, small nests, or a sheet-like structure. Immunohistochemically, the tumor cells were positive for CK19, CK20, VEGF, EGFR, p63, 34ßE12, MUC1, GATA3, uroplakin3, and TopII (rate = 15%), while the Ki-67 proliferation index was 10%. The myxoid stroma in the mesenchyme stained positively with AB-PAS and colloidal iron, and some tumor cells stained positive for colloidal iron. Considering the histologic, histochemical, and immunohistochemical findings, a diagnosis of UC with abundant myxoid stroma was made. After surgery, the regular follow-up was continued in clinic, and there was no recurrence for 2 years. CONCLUSION: Morbidity associated with UC with abundant myxoid stroma is very low. The diagnosis mainly depends on histopathological and immunohistochemical findings.


Assuntos
Carcinoma de Células de Transição/diagnóstico , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias Urológicas/diagnóstico , Idoso de 80 Anos ou mais , Biópsia , Cistectomia , Cistoscopia , Diagnóstico Diferencial , Feminino , Humanos , Imunofenotipagem , Bexiga Urinária/patologia , Urotélio/patologia
7.
Lancet Oncol ; 21(6): 776-785, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32631491

RESUMO

BACKGROUND: Most patients with low-grade upper tract urothelial cancer are treated by radical nephroureterectomy. We aimed to assess the safety and activity of a non-surgical treatment using instillation of UGN-101, a mitomycin-containing reverse thermal gel. METHODS: In this open-label, single-arm, phase 3 trial, participants were recruited from 24 academic sites in the USA and Israel. Patients (aged ≥18 years) with primary or recurrent biopsy-proven, low-grade upper tract urothelial cancer (measuring 5-15 mm in maximum diameter) and an Eastern Cooperative Oncology Group performance status score of less than 3 (Karnofsky Performance Status score >40) were registered to receive six instillations of once-weekly UGN-101 (mitomycin 4 mg per mL; dosed according to volume of patient's renal pelvis and calyces, maximum 60 mg per instillation) via retrograde catheter to the renal pelvis and calyces. All patients had a planned primary disease evaluation 4-6 weeks after the completion of initial therapy, in which the primary outcome of complete response was assessed, defined as negative 3-month ureteroscopic evaluation, negative cytology, and negative for-cause biopsy. Activity (complete response, expected to occur in >15% of patients) and safety were assessed by the investigator in all patients who received at least one dose of UGN-101. Data presented are from the data cutoff on May 22, 2019. This study is registered with ClinicalTrials.gov, NCT02793128. FINDINGS: Between April 6, 2017, and Nov 26, 2018, 71 (96%) of 74 enrolled patients received at least one dose of UGN-101. 42 (59%, 95% CI 47-71; p<0·0001) patients had a complete response at the primary disease evaluation visit. The median follow-up for patients with a complete response was 11·0 months (IQR 5·1-12·4). The most frequently reported all-cause adverse events were ureteric stenosis in 31 (44%) of 71 patients, urinary tract infection in 23 (32%), haematuria in 22 (31%), flank pain in 21 (30%), and nausea in 17 (24%). 19 (27%) of 71 patients had study drug-related or procedure-related serious adverse events. No deaths were regarded as related to treatment. INTERPRETATION: Primary chemoablation of low-grade upper tract urothelial cancer with intracavitary UGN-101 results in clinically significant disease eradication and might offer a kidney-sparing treatment alternative for these patients. FUNDING: UroGen Pharma.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Carcinoma/tratamento farmacológico , Portadores de Fármacos , Neoplasias Renais/tratamento farmacológico , Mitomicina/administração & dosagem , Urotélio/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/efeitos adversos , Carcinoma/patologia , Composição de Medicamentos , Feminino , Humanos , Hidrogéis , Israel , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Mitomicina/efeitos adversos , Gradação de Tumores , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Urotélio/patologia
8.
Virchows Arch ; 477(5): 637-649, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32388719

RESUMO

Muscular infiltrating bladder urothelial carcinoma (MIBC) is a highly malignant disease with a poor prognosis. Radical cystectomy is the standard treatment. However, due to surgery and postoperative complications, the quality of life of patients is seriously affected. Therefore, it is increasingly important to find prognostic markers and new therapeutic targets for MIBC. Here, we investigated the expression of PDK1, a key regulator of glucose metabolism, in bladder urothelial carcinoma (BLCA) and its effect on prognosis. The expression pattern of PDK1 was examined by bioinformatics analysis and immunohistochemistry. A total of 101 cases of BLCA were selected for tissue microarrays (TMAs) that contained both tumour and paired normal tissues. We demonstrated that PDK1 expression was correlated with tumour grade and Ki67expression in our TMA cohort (all p values < 0.05). Kaplan-Meier survival analysis showed that patients with MIBC with high PDK1 expression had a worse prognosis than patients with low PDK1 expression (p = 0.016). Multifactor risk analysis showed that increased PDK1 expression was an independent prognostic factor affecting the overall survival of MIBC patients. GSEA showed that the mTOR pathway, HIF pathway, glycolysis, PI3K/AKT/mTOR signalling, etc. were differentially enriched in the PDK1 high expression phenotype. Hence, PDK1 may be a prognostic and therapeutic target for MIBC.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma/enzimologia , Quinase Piruvato Desidrogenase (Transferência de Acetil)/análise , Neoplasias da Bexiga Urinária/enzimologia , Urotélio/enzimologia , Idoso , Biomarcadores Tumorais/genética , Carcinoma/mortalidade , Carcinoma/patologia , Carcinoma/cirurgia , Cistectomia , Bases de Dados Genéticas , Feminino , Humanos , Imuno-Histoquímica , Antígeno Ki-67/análise , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Valor Preditivo dos Testes , Quinase Piruvato Desidrogenase (Transferência de Acetil)/genética , Análise Serial de Tecidos , Resultado do Tratamento , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgia , Urotélio/patologia
9.
Drugs Today (Barc) ; 56(5): 329-335, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32406880

RESUMO

The antibody-drug conjugate enfortumab vedotin is a fully humanized monoclonal antibody targeting Nectin-4 linked to a microtubule-disrupting agent, monomethyl auristatin E, via a protease-cleavable maleimidocaproyl valine-citrulline linker. In this article, we provide a comprehensive review of the preclinical and clinical activity of enfortumab vedotin, which has been recently approved in the U.S. for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who have previously received a programmed cell death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) inhibitor as well as platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. Enfortumab vedotin is the first antibody-drug conjugate approved for patients with urothelial carcinoma.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Imunoconjugados/uso terapêutico , Neoplasias Urológicas/tratamento farmacológico , Humanos , Urotélio/patologia
10.
Am J Clin Pathol ; 154(2): 208-214, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32253420

RESUMO

OBJECTIVES: Bladder cancers invading the muscularis mucosae (MM) are treated differently from those invading the muscularis propria (MP). However, it may be difficult to determine the type of smooth muscle in transurethral resection (TUR) or biopsy specimens. We aimed to investigate the clinicopathologic features of bladder cancers involving smooth muscle of indeterminate type (SMIT) in TUR specimens in comparison with those invading the MM. METHODS: We identified 103 patients with bladder cancer involving SMIT (n = 27) or the MM (n = 76) in TUR specimens. All patients underwent subsequent restaging TUR or cystectomy. RESULTS: Bladder cancer with SMIT invasion showed a significantly higher rate of MP invasion in the subsequent specimens than those invading the MM (52% vs 29%). Lack of MP in the TUR specimens had a significantly higher risk of MP invasion in the subsequent specimens than those with the MP (61% vs 40%). The overall survival time for patients with SMIT invasion was significantly shorter than those with MM invasion. CONCLUSIONS: Bladder cancers with SMIT invasion in TUR specimens show more frequent cancer upstaging in the subsequent specimens and a poorer clinical outcome than those invading the MM, which highlights the importance of a cancer restaging procedure for these patients.


Assuntos
Carcinoma de Células de Transição/patologia , Membrana Mucosa/patologia , Músculo Liso/patologia , Invasividade Neoplásica/patologia , Neoplasias da Bexiga Urinária/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Carcinoma de Células de Transição/cirurgia , Cistectomia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/cirurgia , Músculo Liso/cirurgia , Resultado do Tratamento , Bexiga Urinária/patologia , Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/cirurgia , Urotélio/patologia , Urotélio/cirurgia
11.
AJR Am J Roentgenol ; 214(6): 1220-1228, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32286867

RESUMO

OBJECTIVE. This article provides a brief overview of the clinicopathologic and radiologic correlation of 12 renal neoplasms, encompassing the conventional subtypes of renal cell carcinoma and a few of the newly recognized subtypes from the 2016 World Health Organization classification of renal tumors. In addition, we touch upon infrequent neoplasms that may enter the differential diagnosis of a renal mass, with corresponding radiologic and gross images and histologic findings of case-based examples. CONCLUSION. Familiarity with the radiologic and pathologic characteristics of renal cell carcinoma and other renal neoplasms is important to correctly identify and treat these masses.


Assuntos
Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/patologia , Adenoma/diagnóstico por imagem , Adenoma/patologia , Adenoma Oxífilo/diagnóstico por imagem , Adenoma Oxífilo/patologia , Angiomiolipoma/diagnóstico por imagem , Angiomiolipoma/patologia , Carcinoma Papilar/diagnóstico por imagem , Carcinoma Papilar/patologia , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/patologia , Meios de Contraste , Diagnóstico Diferencial , Humanos , Urotélio/diagnóstico por imagem , Urotélio/patologia
12.
Nat Commun ; 11(1): 1975, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332851

RESUMO

Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical and molecular characteristics. The advancement of UTUC research is hampered by the lack of disease-specific models. Here, we report the establishment of patient derived xenograft (PDX) and cell line models that reflect the genomic and biological heterogeneity of the human disease. Models demonstrate high genomic concordance with the corresponding patient tumors, with invasive tumors more likely to successfully engraft. Treatment of PDX models with chemotherapy recapitulates responses observed in patients. Analysis of a HER2 S310F-mutant PDX suggests that an antibody drug conjugate targeting HER2 would have superior efficacy versus selective HER2 kinase inhibitors. In sum, the biological and phenotypic concordance between patient and PDXs suggest that these models could facilitate studies of intrinsic and acquired resistance and the development of personalized medicine strategies for UTUC patients.


Assuntos
Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Urotélio/patologia , Idoso , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Biópsia , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Feminino , Perfilação da Expressão Gênica , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunoconjugados/farmacologia , Subunidade gama Comum de Receptores de Interleucina/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Transplante de Neoplasias , Fenótipo , Medicina de Precisão , Estudos Prospectivos , Quinolinas/farmacologia , Estudos Retrospectivos , Análise de Sequência de RNA
13.
Comp Immunol Microbiol Infect Dis ; 70: 101463, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32146261

RESUMO

This study aimed to provide mechanistic insights into mitophagy pathway associated with papillomavirus infection in urothelial cells of cattle. The elimination of mitochondria via autophagy, termed mitophagy, is an evolutionarily conserved mechanism for mitochondrial quality control and homeostasis. PINK1/parkin-mediated mitophagy, a ubiquitin-dependent selective autophagy of dysfunctional mitochondria, has been described here, for the first time, in urothelial cells from 25 bladder cancers in cattle infected by bovine papillomavirus (BPV). The expression of BPV-2 and BPV-13 E5 oncoprotein was detected by RT-PCR. Abnormal mitochondria delimited by expanding phagophores, were peculiar ultrastructural features of neoplastic urothelial cells. High levels of mitochondrial phosphorylated PINK1/parkin were observed in neoplastic urothelial cells infected by BPVs. Phosphoparkin interacted with mitofusin 2 (Mfn2) and ubiquitin (Ub), which confirmed that Mfn2 is a parkin receptor at the mitochondrial level, where parkin interacted also with Ub. Furthermore, parkin established a complex that was comprised of optineurin, p62, LC3, laforin, and embryonic stem cell-expressed Ras (ERAS), that interacted with BPV E5 oncoprotein, and Bag3, which, in turn, regulated the formation of a complex composed of Hpc70/Hsp70, CHIP, an HSC70-interacting E3 ubiquitin ligase. It is conceivable that ERAS is involved in mitophagosome maturation via phosphatidylinositol 3-kinase (PI3K) pathway. Bag3, in association with Hsc70/Hsp70, may contribute to the transport and degradation of CHIP-ubiquitinated cargo as this complex recognises ubiquitinated cargos and transports them to aggresomes to be degraded. Furthermore, Bag3 may be involved in mitophagosome formation as it interacted with synaptopodin 2, which is known to play a role in mitophagosome biogenesis.


Assuntos
Carcinoma Papilar/veterinária , Mitofagia , Proteínas Oncogênicas Virais/genética , Infecções por Papillomavirus/veterinária , Ubiquitina-Proteína Ligases/genética , Neoplasias da Bexiga Urinária/veterinária , Animais , Carcinoma Papilar/virologia , Bovinos , Doenças dos Bovinos/virologia , Feminino , Mitocôndrias/patologia , Infecções por Papillomavirus/virologia , Regulação para Cima , Neoplasias da Bexiga Urinária/virologia , Urotélio/patologia , Urotélio/virologia
14.
Sci Rep ; 10(1): 3808, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32123240

RESUMO

Urothelial carcinoma (UC) is a common disease causing significant morbidity and mortality as well as considerable costs for health systems. Extensive aberrant methylation of DNA is broadly documented in early UC, contributing to genetic instability, altered gene expression and tumor progression. However the triggers initiating aberrant methylation are unknown. Recently we discovered that several genes encoding key enzymes of methyl group and polyamine metabolism, including Ornithine Decarboxylase 1 (ODC1), are affected by DNA methylation in early stage UC. In this study, we investigated the hypothesis that these epigenetic alterations act in a feed-forward fashion to promote aberrant DNA methylation in UC. We demonstrate that siRNA-mediated knockdown of ODC1 expression elicits genome-wide LINE-1 demethylation, induction of LINE-1 transcripts and double-strand DNA breaks and decreases viability in primary cultured uroepithelial cells. Similarly, following siRNA-mediated knockdown of ODC1, UC cells undergo double-strand DNA breaks and apoptosis. Collectively, our findings provide evidence that ODC1 gene hypermethylation could be a starting point for the onset of genome-wide epigenetic aberrations in urothelial carcinogenesis. Furthermore, LINE-1 induction enabled by ODC1 interference provides a new experimental model to study mechanisms and consequences of LINE-1 activation in the etiology and progression of UC as well as presumably other cancers.


Assuntos
Epigênese Genética , Ornitina Descarboxilase/deficiência , Ornitina Descarboxilase/genética , Interferência de RNA , Neoplasias Urológicas/patologia , Urotélio/patologia , Apoptose/genética , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/genética , Humanos , RNA Mensageiro/genética , RNA Interferente Pequeno/genética
15.
Hum Pathol ; 98: 81-88, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32142835

RESUMO

Flat urothelial lesions with atypia may pose significant diagnostic challenges. Given frequent increased proliferation rates in florid reactive urothelial atypia and limited studies on the interpretation of p53 stains in the urothelium (following current standard guidelines for correlation with P53 mutation status), we sought to further study the discriminatory value of Ki-67 and p53 for florid reactive urothelial atypia versus urothelial carcinoma in situ (CIS). Bladder specimens diagnosed as reactive urothelial atypia (n = 40) and CIS (n = 40) were assessed by immunohistochemical staining with antibodies for Ki-67, p53, CD44, and CK20. Immunoreactivity was scored based on percent cells positive for Ki-67 and pattern of reactivity with p53 (aberrant: diffuse strong positive or negative; normal: patchy/wild type). CD44 and CK20 reactivity patterns served as adjunctive internal validation controls for reactive urothelial atypia and CIS, as previously described. In reactive urothelial atypia, Ki-67 ranged from 0% to 90% (mean, 34% ± 26) with 30 cases (75%) having >10%. In CIS, Ki-67 ranged from 5% to 95% (mean, 50% ± 25) with 17 cases (43%) having >50%. In all 40 cases (100%) of reactive urothelial atypia, p53 expression had a wild-type pattern. In CIS, aberrant p53 expression was identified in 15 cases (37%): 3 cases (7%) were p53 negative (i.e. null phenotype) and 12 cases (30%) showed strong and diffuse nuclear reactivity (in >85% of cells). The remaining 25 cases (63%) of CIS had a p53 wild-type pattern of expression. Cytoplasmic CK20 immunoreactivity in umbrella cells was seen in 34 cases (85%) of reactive urothelial atypia, and 6 cases (15%) were negative. In addition, 35 cases (88%) of reactive urothelial atypia demonstrated full-thickness CD44 expression, while 5 cases (12%) had expression confined to the basal/parabasal layers of the urothelium. Strong and diffuse CK20 positivity was present in 39 cases (98%) of CIS, and patchy positivity was detected in 1 case (2%). None of the CIS cases overexpressed CD44: 16 cases (40%) showed focal expression in the nonneoplastic basal cell layer; 24 cases (60%) demonstrated no staining. In summary, Ki-67 has poor discriminatory value for reactive urothelial atypia versus CIS and adds little to the classic CK20/CD44 immunophenotype. While p53 sensitivity for CIS is relatively low (30%) and interpretation as either wild type or negative may be challenging in a small subset of cases, strong and diffuse nuclear reactivity was 100% specific in the distinction from florid reactive urothelial atypia in this cohort.


Assuntos
Carcinoma in Situ/química , Proliferação de Células , Imuno-Histoquímica , Antígeno Ki-67/análise , Proteína Supressora de Tumor p53/análise , Neoplasias da Bexiga Urinária/química , Urotélio/química , Carcinoma in Situ/patologia , Diagnóstico Diferencial , Humanos , Receptores de Hialuronatos/análise , Queratina-20/análise , Valor Preditivo dos Testes , Neoplasias da Bexiga Urinária/patologia , Urotélio/patologia
16.
Virchows Arch ; 477(3): 445-454, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32198650

RESUMO

Primary glandular bladder tumours (bladder adenocarcinoma [BAC], urachal adenocarcinoma [UAC], urothelial carcinoma with glandular differentiation [UCg]) are rare malignancies with histological resemblance to colorectal adenocarcinoma (CORAD) in the majority of this subgroup. Definite case numbers are very low, molecular data are limited and the pathogenesis remains poorly understood. Therefore, this study was designed to complement current knowledge by in depth analysis of BAC (n = 12), UAC (n = 13), UCg (n = 11) and non-invasive glandular lesions (n = 19). In BAC, in addition to known alterations in TP53, Wnt, MAP kinase and MTOR pathway, mutations in SMAD4, ARID1A and BRAF were identified. Compared to published data on muscle invasive bladder cancer (BLCA) and CORAD, UCg exhibited frequent "urothelial" like alterations while BAC and UAC were characterised by a more "colorectal" like mutational pattern. Immunohistochemically, there was no evidence of DNA mismatch repair deficiency or PD-L1 tumour cell positivity in any sample. Depending on the used antibody 0-45% of BAC, 0-30% of UCg and 0% UAC cases exhibited PD-L1 expressing tumour associated immune cells. A single BAC (9%, 1/11) showed evidence of ARID1A protein loss, and two cases of UCg (20%, 2/10) showed loss of SMARCA1 and PBRM1, respectively. Taken together, our data suggest at least in part involvement of similar pathways driving tumourigenesis of adenocarcinomas like BAC, UAC and CORAD independent of their tissue origin. Alterations of TERT and FBXW7 in single cases of intestinal metaplasia further point towards a possible precancerous character in line with previous reports.


Assuntos
Neoplasias Epiteliais e Glandulares/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/análise , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/análise , Feminino , Genômica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias Epiteliais e Glandulares/patologia , Bexiga Urinária/patologia , Urotélio/patologia
17.
Hum Pathol ; 98: 32-55, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32035992

RESUMO

Urinary bladder specimens are frequently encountered in the daily practice of surgical pathologists. The spectrum of pathologic entities encountered in bladder specimens is extraordinarily broad, and in some instances, immunohistochemical stains are used to help characterize challenging bladder lesions. Cost-effective biomarker selection tailored to the differential diagnosis facilitates an accurate diagnosis. This comprehensive review is prepared as a reference guide for the use of immunohistochemistry to categorize primary and secondary bladder neoplasms and to evaluate metastatic cancers for possible bladder origin.


Assuntos
Biomarcadores Tumorais/análise , Imuno-Histoquímica , Neoplasias da Bexiga Urinária/química , Neoplasias da Bexiga Urinária/patologia , Urotélio/química , Urotélio/patologia , Diagnóstico Diferencial , Humanos , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Neoplasias da Bexiga Urinária/secundário
18.
BMC Cancer ; 20(1): 140, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32085750

RESUMO

BACKGROUND: Whether or not double J (DJ) stenting during transurethral resection of a bladder tumour (TURBT) harms patients with regard to possible metachronous upper urinary tract urothelial cancer (UUTUC) development remains controversial. This study evaluated the impact of DJ compared to nephrostomy placement during TURBT for bladder cancer (BCa) on the incidence of metachronous UUTUCs. METHODS: We retrospectively analysed 637 patients who underwent TURBT in our department between 2008 and 2016. BCa, UUTUC and urinary drainage data (retrograde/anterograde DJ and percutaneous nephrostomy) were assessed, along with the prevalence of hydronephrosis, and mortality. Chi-square and Fisher's exact test was performed for univariate analyses. Survival analysis was performed by the Kaplan-Meier method and log-rank tests. RESULTS: UUTUC was noted in 28 out of 637 patients (4.4%), whereas only eight (1.3%) developed it metachronously to BCa. Out of these, four patients received DJ stents, while four patients received no urinary drainage of the upper urinary tract. Placement of urinary drainage significantly correlated with UUTUC (50.0% vs. 17.9%; p = 0.041). DJ stenting significantly correlated with UUTUC (50.0% vs. 11%; p <  0.01), while no patient with a nephrostomy tube developed UUTUC. UUTUC-free survival rates were significantly lower for patients with DJ stents than for all other patients (p = 0.001). Patients with or without DJ stents had similar overall survival (OS) rates (p = 0.73), whereas patients with nephrostomy tubes had significantly lower OS rates than all other patients (p <  0.001). CONCLUSIONS: Patients with DJ stenting during TURBT for BCa might have an increased risk of developing metachronous UUTUC. This study indicated advantages in placing nephrostomy tubes rather than DJ stents; however, confirmation requires investigation of a larger cohort. Even so, the increased mortality rate in the nephrostomy group reflected hydronephrosis as an unfavourable prognostic factor.


Assuntos
Segunda Neoplasia Primária/epidemiologia , Nefrotomia/efeitos adversos , Stents/efeitos adversos , Neoplasias da Bexiga Urinária/cirurgia , Neoplasias Urológicas/epidemiologia , Urotélio/patologia , Idoso , Drenagem , Feminino , Alemanha/epidemiologia , Humanos , Incidência , Masculino , Estadiamento de Neoplasias , Segunda Neoplasia Primária/patologia , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias da Bexiga Urinária/patologia , Neoplasias Urológicas/patologia
19.
Indian J Pathol Microbiol ; 63(1): 96-97, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32031131

RESUMO

Inverted papilloma of urothelium is a rare benign tumour accounting for 1-2% of all the urothelial lesions. Morphologically, these are of two main subtypes - trabecular and glandular, of which the former subtype is most frequently encountered compared to the latter. The glandular subtype closely mimics cystitis glandularis and urothelial carcinoma with inverted growth pattern. We discuss a case of a 27-year-old male presenting with hematuria. On cystoscopy, he was found to have a bladder mass which was diagnosed as glandular-type of inverted papilloma on histopathology. The image illustrates the histopathology for easy identification and early diagnosis of this rare entity.


Assuntos
Papiloma Invertido/diagnóstico por imagem , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Adulto , Cistite/patologia , Cistoscopia , Diagnóstico Diferencial , Hematúria/etiologia , Humanos , Imuno-Histoquímica , Masculino , Neoplasias/diagnóstico por imagem , Papiloma Invertido/patologia , Tomografia Computadorizada por Raios X , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/patologia , Urotélio/patologia
20.
Oncol Rep ; 43(4): 1331-1337, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32020226

RESUMO

Patients with urothelial carcinoma frequently fail to respond to first­line chemotherapy using cisplatin and gemcitabine due to development of resistant tumor cells. The aim of the present study was to investigate whether an alternative treatment with tumor necrosis factor­related apoptosis­inducing ligand (TRAIL) that induces tumor cell death via the extrinsic apoptotic pathway may be effective against chemotherapy­resistant urothelial cancer cell lines. The viability of the urothelial cancer cell line RT112 and its chemotherapy­adapted sublines was investigated by MTT assay. The expression of anti­apoptotic proteins was determined by western blotting and the individual roles of cellular inhibitor of apoptosis protein (cIAP)1, cIAP2, x­linked inhibitor of apoptosis protein (XIAP) and induced myeloid leukemia cell differentiation protein (Mcl­1) were investigated by siRNA­mediated depletion. In particular, the bladder cancer sublines that were resistant to gemcitabine and cisplatin were cross­resistant to TRAIL. Resistant cells displayed upregulation of anti­apoptotic molecules compared with the parental cell line. Treatment with the second mitochondrial activator of caspases (SMAC) mimetic LCL­161 that antagonizes cIAP1, cIAP2 and XIAP resensitized chemoresistant cells to TRAIL. The resensitization of tumor cells to TRAIL was confirmed by depletion of antiapoptotic proteins with siRNA. Collectively, the findings of the present study demonstrated that SMAC mimetic LCL­161 increased the sensitivity of the parental cell line RT112 and chemotherapy­resistant sublines to TRAIL, suggesting that inhibiting anti­apoptotic molecules renders TRAIL therapy highly effective for chemotherapy­sensitive and ­resistant urothelial cancer cells.


Assuntos
Proteína 3 com Repetições IAP de Baculovírus/genética , Proteínas Inibidoras de Apoptose/genética , Ligante Indutor de Apoptose Relacionado a TNF/genética , Neoplasias da Bexiga Urinária/tratamento farmacológico , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Apoptose/efeitos dos fármacos , Proteína 3 com Repetições IAP de Baculovírus/antagonistas & inibidores , Caspase 3/efeitos dos fármacos , Inibidores de Caspase/farmacologia , Linhagem Celular Tumoral , Cisplatino/efeitos adversos , Cisplatino/farmacologia , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Ligante Indutor de Apoptose Relacionado a TNF/antagonistas & inibidores , Tiazóis/farmacologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Urotélio/efeitos dos fármacos , Urotélio/metabolismo , Urotélio/patologia , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/antagonistas & inibidores
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