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1.
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
2.
Nucleic Acids Res ; 48(5): 2220-2231, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-32020194

RESUMO

Hybridization chain reaction (HCR) was a significant discovery for the development of nanoscale materials and devices. One key challenge for HCR is the vulnerability to background leakage in the absence of the initiator. Here, we systematically analyze the sources of leakage and refine leak-resistant rule by using molecular thermodynamics and dynamics, biochemical and biophysical methods. Transient melting of DNA hairpin is revealed to be the underlying cause of leakage and that this can be mitigated through careful consideration of the sequence thermodynamics. The transition threshold of the energy barrier is proposed as a testing benchmark of leak-resistance DNA hairpins. The universal design of DNA hairpins is illustrated by the analysis of hsa-miR-21-5p as biomarker when used in conjunction with surface-enhanced Raman spectroscopy. We further extend the strategy for specific signal amplification of miRNA homologs. Significantly, it possibly provides a practical route to improve the accuracy of DNA self-assembly for signal amplification, and that could facilitate the development of sensors for the sensitive detection of interest molecules in biotechnology and clinical medicine.


Assuntos
DNA/química , Sequências Repetidas Invertidas , MicroRNAs/química , Hibridização de Ácido Nucleico/métodos , Pareamento de Bases , Benchmarking , DNA/genética , DNA/metabolismo , Exossomos/química , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Simulação de Dinâmica Molecular , Conformação de Ácido Nucleico , Desnaturação de Ácido Nucleico , Análise Espectral Raman , Termodinâmica , Neoplasias da Bexiga Urinária/química , Neoplasias da Bexiga Urinária/urina
3.
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
4.
BMC Cancer ; 19(1): 1195, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31805976

RESUMO

BACKGROUND: To discover biomarker panels that could distinguish cancers (BC and RCC) from healthy controls (HCs) and bladder cancers (BC) from renal cell carcinoma (RCC), regardless of whether the patients have haematuria. In addition, we also explored the altered metabolomic pathways of BC and RCC. METHODS: In total, 403 participants were enrolled in our study, which included 146 BC patients (77 without haematuria and 69 with haematuria), 115 RCC patients (94 without haematuria and 21 with haematuria) and 142 sex- and age-matched HCs. Their midstream urine samples were collected and analysed by performing UPLC-MS. The statistical methods and pathway analyses were applied to discover potential biomarker panels and altered metabolic pathways. RESULTS: The panel of α-CEHC, ß-cortolone, deoxyinosine, flunisolide, 11b,17a,21-trihydroxypreg-nenolone and glycerol tripropanoate could distinguish the patients with cancer from the HCs (the AUC was 0.950) and the external validation also displayed a good predictive ability (the AUC was 0.867). The panel of 4-ethoxymethylphenol, prostaglandin F2b, thromboxane B3, hydroxybutyrylcarnitine, 3-hydroxyphloretin and N'-formylkynurenine could differentiate BC from RCC without haematuria. The AUC was 0.829 in the discovering group and 0.76 in the external validation. The metabolite panel comprising 1-hydroxy-2-oxopropyl tetrahydropterin, 1-acetoxy-2-hydroxy-16-heptadecyn-4-one, 1,2-dehydrosalsolinol and L-tyrosine could significantly discriminate BC from RCC with haematuria (AUC was 0.913). Pathway analyses revealed altered lipid and purine metabolisms between cancer patients and HCs, together with disordered amino acid and purine metabolisms between BC and RCC with haematuria. CONCLUSIONS: UPLC-MS urine metabolomic analyses could not only differentiate cancers from HCs but also discriminate BC from RCC. In addition, pathway analyses demonstrated a deeper metabolic mechanism of BC and RCC.


Assuntos
Carcinoma de Células Renais/diagnóstico , Neoplasias Renais/diagnóstico , Metabolômica/métodos , Urinálise/métodos , Neoplasias da Bexiga Urinária/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Carcinoma de Células Renais/química , Carcinoma de Células Renais/urina , Diagnóstico Diferencial , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Neoplasias Renais/química , Neoplasias Renais/urina , Metabolismo dos Lipídeos , Masculino , Redes e Vias Metabólicas , Pessoa de Meia-Idade , Purinas/metabolismo , Sensibilidade e Especificidade , Neoplasias da Bexiga Urinária/química , Neoplasias da Bexiga Urinária/urina , Adulto Jovem
5.
Hum Pathol ; 94: 11-15, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31669177

RESUMO

Nested variant of urothelial carcinoma is a rare variant of urothelial carcinoma morphologically characterized by infiltrative nests of cytologically bland urothelial cells. It is widely recognized that nested variant of urothelial carcinoma can closely mimic von Brunn nests. However, nested variant of urothelial carcinoma with tubule formation can also resemble nephrogenic adenoma, where immunohistochemical positivity for PAX8 has been used to establish the diagnosis of nephrogenic adenoma. Following anecdotal examples of PAX8 positive nested variant of urothelial carcinoma, we formally evaluated 23 cases of nested variant of urothelial carcinoma from 2011 to 2018. Cases were collected from our institution and evaluated for their architectural pattern and PAX8 expression. Except for 1 case from the renal pelvis, cases were located in the bladder. The majority (14/23 [61%]) showed solid nests with at least focal tubular differentiation. PAX8 immunoreactivity was strong (3+) in 7 (30%), moderate (2+) in 6 (26%), and negative in 10 (44%) cases. Four (57%) of the cases with strong expression and 3 (50%) of those with moderate staining showed diffuse immunoreactivity. Moderate-strong immunoreactivity was seen in 4/6 (66.7%) cases with solid nests, 8/14 (57.1%) with solid nests and tubules, and 1/3 (33.3%) with large nests. In conclusion, PAX8 can be positive in a significant proportion of nested variant of urothelial carcinoma cases, and recognition of this finding is important to avoid misdiagnosis of nested variant of urothelial carcinoma as nephrogenic adenoma based on PAX8 expression, particularly in cases with tubular differentiation and limited sampling.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma/química , Imuno-Histoquímica , Neoplasias Renais/química , Fator de Transcrição PAX8/análise , Neoplasias da Bexiga Urinária/química , Urotélio/química , Adulto , Idoso , Carcinoma/patologia , Diferenciação Celular , Diagnóstico Diferencial , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/patologia , Urotélio/patologia
6.
Investig Clin Urol ; 60(5): 343-350, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501796

RESUMO

Purpose: To investigate whether measurement of urinary calprotectin can serve as a biomarker in the diagnosis of primary bladder cancer and to confirm its diagnostic role in determining high grade and stage disease. Materials and Methods: Urinary calprotectin was measured in spot urine samples from patients with primary bladder cancer and control subjects. To confirm levels in urine, tissue samples were also obtained from bladder tumor and healthy trigone of bladder by transurethral resection in both groups. Finally, calprotectin levels in tissue and urine of the patients and control subjects were compared and their diagnostic potential was investigated in high grade and stage bladder cancers. Results: Of 82 participants, 52 were patients with bladder cancer and 30 were control subjects. The two groups were comparable in terms of age, smoking status, and comorbidities. Tissue and urinary calprotectin levels were significantly higher in the bladder cancer group. In subgroup analyses, urinary calprotectin levels were significantly higher in patients with high-grade, muscle-invasive tumors. After receiver operating characteristic analyses, the sensitivity and specificity of urinary calprotectin was 100% and 96.7%, respectively, in the diagnosis of primary bladder cancer. High grade and stage bladder cancers were detected with sensitivity and specificity of 70% and 74.2%, and 80% and 84.8%, respectively. Conclusions: Urinary calprotectin may be a valuable parameter in the diagnosis of primary bladder cancer with high sensitivity and specificity. Furthermore, it may be useful in the prediction of high grade and stage disease. However, more investigations are needed.


Assuntos
Complexo Antígeno L1 Leucocitário/análise , Neoplasias da Bexiga Urinária/química , Neoplasias da Bexiga Urinária/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/urina , Complexo Antígeno L1 Leucocitário/biossíntese , Complexo Antígeno L1 Leucocitário/urina , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/complicações , Neoplasias da Bexiga Urinária/metabolismo
7.
Am J Surg Pathol ; 43(12): 1638-1643, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31368912

RESUMO

Although there are 5 well-described morphologic patterns of (nonglandular) urothelial carcinoma in situ (CIS), we have encountered a novel pattern of flat urothelial carcinoma with plasmacytoid features characterized by a triad of morphologic findings including abnormal architecture with cellular rounding, enlarged nuclei with eccentric nuclear localization, and dense globular eosinophilic cytoplasm. A total of 23 cases of plasmacytoid CIS (mean age: 74.1 y, range: 58 to 91 y) were collected and reviewed. We excluded cases in which the diagnostic biopsy had any of the following findings admixed in the same tissue biopsy sample as the plasmacytoid CIS: traditional patterns of CIS, noninvasive glandular CIS, papillary urothelial carcinoma, or invasive carcinoma. Immunostains for CK20, CD44, p53, and e-cadherin were performed on available blocks. History of prior urothelial neoplasia, prior treatment, and clinical follow-up were obtained from medical records and pathology re-review. Immunohistochemical analysis of plasmacytoid CIS showed diffuse/strong CK20 reactivity in 96% of cases (23/24), an abnormal p53 reactivity pattern (either overexpression or "null phenotype") in 37% of cases (7/19), absence of CD44 reactivity in the neoplastic cells in 63% of cases (15/24), and retained membranous e-cadherin expression in 100% of cases (18/18). Clinical follow-up (average follow-up time: 37.7 mo, range: 7 to 115 mo) showed recurrence/new occurrence in 52% of cases (12/23), including all 4 of the 23 patients who initially presented with de novo plasmacytoid CIS (ie, no prior or concomitant urothelial neoplasia). The histologic features, the immunophenotype, the association with other forms of urothelial neoplasia, and the risk of recurrence and progression in de novo lesions support that plasmacytoid CIS represents a novel pattern of flat urothelial carcinoma. These histologic features may be more subtle than in other more typical patterns of CIS and should be carefully distinguished from therapy-related/reactive changes.


Assuntos
Carcinoma in Situ/patologia , Plasmócitos/patologia , Neoplasias da Bexiga Urinária/patologia , Urotélio/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Carcinoma in Situ/química , Carcinoma in Situ/terapia , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Fenótipo , Plasmócitos/química , Fatores de Risco , Resultado do Tratamento , Neoplasias da Bexiga Urinária/química , Neoplasias da Bexiga Urinária/terapia , Urotélio/química
9.
ACS Sens ; 4(8): 2124-2130, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31313911

RESUMO

Detection of biomarkers in complex samples is a significant health plan strategy for medical diagnosis, therapy monitoring, and health management. However, high background noise resulting from impurities and other analytes in complex samples has hampered the improvement of detection sensitivity and accuracy. Herein, an ultralow background biochip based on time-gated luminescent probes supported by photonic crystals (PCs) was successfully developed for detection of bladder cancer (BC)-related miRNA biomarkers with high sensitivity and specificity in urine samples. Coupled with the time-gated luminescence of long-lifetime luminescence probes and the luminescence-enhanced capability of PCs, the short-lived autofluorescence can be efficiently removed; thus, the detection sensitivity will be significantly improved. Benefiting from these merits, a detection limit of 26.3 fM is achieved. Furthermore, the biochip exhibits excellent performance in urinary miRNA detection, and good recoveries are also obtained. The developed biochip possesses unique properties of ultralow background and luminescence enhancement, thus offering a suitable tool for the detection of BC-related miRNA in urine. With rational design of probe sequences, the biochip holds great potential for many other biomarkers in real patient samples, making it valuable in areas such as medical diagnosis and disease evaluation.


Assuntos
Biomarcadores Tumorais/urina , Técnicas Biossensoriais , Substâncias Luminescentes/química , Medições Luminescentes , MicroRNAs/urina , Neoplasias da Bexiga Urinária/química , Humanos , Microscopia Eletrônica de Transmissão , Tamanho da Partícula , Propriedades de Superfície , Fatores de Tempo , Neoplasias da Bexiga Urinária/urina
10.
J Pathol ; 249(3): 308-318, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31232464

RESUMO

Molecular subtypes of urothelial carcinoma may be divided into luminal and nonluminal tumors. Nonluminal tumors are composed of cases with basal/squamous-like or small cell/neuroendocrine features, with a consensus on the molecular characteristics of the respective subtype. In contrast, luminal tumors are more disparate with three to five suggested subtypes and with definitions that do not always cohere. To resolve some of these disparities we assembled a cohort of 344 luminal tumors classified as urothelial-like (Uro), with the subtypes UroA, UroAp, UroB, and UroC, or genomically unstable (GU) according to the LundTax system. Cases were systematically analyzed by immunohistochemistry using antibodies for proteins representing important biological processes or cellular states: KRT5, EGFR, and CDH3 for the integrity of a basal cell layer; CCNB1, Ki67, and FOXM1 for proliferation; FGFR3 and ERBB2 for receptor tyrosine kinase status; CCND1, CDKN2A(p16), RB1, and E2F3 for cell cycle regulation; PPARG, GATA3, and TP63 for the differentiation regulatory system; and KRT20 and UPK3 for the differentiation readout. We show that Uro tumors form one, albeit heterogenous, group characterized by FGFR3, CCND1, and RB1 expression, but low or absence of CDKN2A(p16) and ERBB2 expression. The opposite expression pattern is observed in GU cases. Furthermore, Uro tumors are distinguished from GU tumors by showing a high RB1/p16 expression ratio. Class defining characteristics were independent of pathological stage and growth pattern, and thus intrinsic. In Uro tumors, proliferation was limited to a well-defined single layer of basal-like cells in UroA tumors but occurred throughout the tumor parenchyma, independent of the basal layer, in the more progressed UroAp and UroC tumors. A similar change in proliferation topology was not observed in GU. We conclude that luminal urothelial carcinomas consist, at the molecular pathology level, of two major subtypes, the larger heterogenous Uro and the biologically distinct GU subtype. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma/química , Neoplasias da Bexiga Urinária/química , Urotélio/química , Biomarcadores Tumorais/genética , Carcinoma/classificação , Carcinoma/genética , Carcinoma/patologia , Diferenciação Celular , Proliferação de Células , Humanos , Imuno-Histoquímica , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias da Bexiga Urinária/classificação , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Urotélio/patologia
11.
Urology ; 131: 150-156, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31201825

RESUMO

OBJECTIVE: To evaluate programmed death ligand 1 (PD-L1) staining fidelity between the primary tumor and associated lymph node metastases in bladder cancer. To secondarily evaluate whether neoadjuvant chemotherapy (NAC) affects this relationship. METHODS: Sixty-seven subjects with residual bladder cancer on cystectomy and associated positive lymph nodes were identified between 2008 and 2015. PD-L1 staining of tumor cells was evaluated using H score and 49 specimens were also evaluated using combined positive score (CPS). Univariable and multivariable logistic regression analysis were used to assess how various clinical variables affected odds of PD-L1 fidelity between primary and metastatic tumors. RESULTS: Tumor PD-L1 staining was concordant in 79.1% of cases and CPS was concordant in 79.6% of cases. NAC did not significantly impact odds of PD-L1 or CPS fidelity (OR 1.974, 95% CI 0.673-5.784, OR 0.500, 95% CI 0.093-2.700). Among clinical variables analyzed on univariable analysis of tumor PD-L1 fidelity, H-score, and PD-L1 staining intensity were associated with significantly increased odds of PD-L1 fidelity and the association with staining intensity was confirmed on multivariable analysis. CONCLUSION: PD-L1 fidelity between primary bladder tumors and nodal metastases was observed in >75% of cases in this study. Additionally, NAC was not shown to diminish this propensity to maintain PD-L1 staining status. Further standardization of immunohistochemistry of tumor and infiltrating imsmune cells in metastatic bladder cancer is needed to improve application of therapeutics.


Assuntos
Antígeno B7-H1/análise , Metástase Linfática/patologia , Neoplasias da Bexiga Urinária/química , Neoplasias da Bexiga Urinária/patologia , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estudos Retrospectivos , Coloração e Rotulagem , Neoplasias da Bexiga Urinária/tratamento farmacológico
12.
Int J Radiat Oncol Biol Phys ; 104(4): 809-818, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30885775

RESUMO

PURPOSE: Organ-confined muscle-invasive bladder cancer is treated with cystectomy or bladder preservation techniques, including radiation therapy. There are currently no biomarkers to inform management decisions and aid patient choice. Previously we showed high levels of MRE11 protein, assessed by immunohistochemistry (IHC), predicted outcome after radiation therapy, but not cystectomy. Therefore, we sought to develop the MRE11 IHC assay for clinical use and define its relationship to clinical outcome in samples from 2 major clinical trials. METHODS AND MATERIALS: Samples from the BCON and BC2001 randomized controlled trials and a cystectomy cohort were stained using automated IHC methods and scored for MRE11 in 3 centers in the United Kingdom. RESULTS: Despite step-wise creation of scoring cards and standard operating procedures for staining and interpretation, there was poor intercenter scoring agreement (kappa, 0.32; 95% confidence interval, 0.17-0.47). No significant associations between MRE11 scores and cause-specific survival were identified in BCON (n = 132) and BC2001 (n = 221) samples. Reoptimized staining improved agreement between scores from BCON tissue microarrays (n = 116), but MRE11 expression was not prognostic for cause-specific survival. CONCLUSIONS: Manual IHC scoring of MRE11 was not validated as a reproducible biomarker of radiation-based bladder preservation success. There is a need for automated quantitative methods or a reassessment of how DNA-damage response relates to clinical outcomes.


Assuntos
Biomarcadores Tumorais/análise , Proteína Homóloga a MRE11/análise , Neoplasias da Bexiga Urinária/química , Neoplasias da Bexiga Urinária/radioterapia , Idoso , Idoso de 80 Anos ou mais , Cistectomia , Feminino , Humanos , Imuno-Histoquímica/métodos , Imuno-Histoquímica/normas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes , Análise de Sobrevida , Resultado do Tratamento , Reino Unido , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia
13.
Scand J Urol ; 53(1): 45-50, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30806186

RESUMO

Background: Response to neoadjuvant cisplatin treatment in bladder cancer has been linked to expression of Bcl-2 protein by cancer cells. The objective of this study was to test Bcl-2 as a predictive marker of neoadjuvant cisplatin chemotherapy response in a patient cohort from randomized cystectomy trials. Methods: Tumor samples were taken from 247 patients with T2-T4 bladder cancer enrolled in two randomized trials comparing cystectomy with or without neoadjuvant chemotherapy. Tissue microarrays from pre-intervention transurethral resection specimens were assessed for Bcl-2 protein status by immunohistochemistry. Extension of staining above 10% was regarded as positive. Downstaging and survival ratios in relation to Bcl-2 immunoreactivity and neoadjuvant chemotherapy utilization were calculated using the log rank test and multivariate Cox proportional hazards regression analyses. Results: Bcl-2 expression was positive in 38% and negative in 62% of the 236 evaluable patients. Bcl-2 negative patients receiving neoadjuvant chemotherapy had a significant increase in survival (p = 0.009), while Bcl-2 positive patients showed no difference (p = 0.4). However, the interaction variable between neoadjuvant chemotherapy and biomarker status was not significant (p = 0.38). When the prognostic value was assessed in the no-chemotherapy group, 5-year overall survival times were significantly better among Bcl-2 positive patients than among Bcl-2 negative patients (42 months vs 33 months, p = 0.04), but again Bcl-2 status did not remain independent when other factors were adjusted. Also, in a multivariate analysis with all patients, Bcl-2 was not significant. Conclusions: Bcl-2 status is not an independent predictor of neoadjuvant cisplatin chemotherapy response and is not prognostic in muscle-invasive bladder cancer.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células de Transição/química , Carcinoma de Células de Transição/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/análise , Neoplasias da Bexiga Urinária/química , Neoplasias da Bexiga Urinária/tratamento farmacológico , Carcinoma de Células de Transição/cirurgia , Quimioterapia Adjuvante , Cistectomia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Valor Preditivo dos Testes , Estudos Prospectivos , Resultado do Tratamento , Neoplasias da Bexiga Urinária/cirurgia
14.
Urol Oncol ; 37(6): 353.e9-353.e15, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30737158

RESUMO

OBJECTIVE: In rare cases, differential diagnosis between bladder cancer (BC) and gynecological tract cancer (GTC) is difficult because of anatomical proximity and morphological similarity. We analyzed expression status of sex steroid hormone receptors in BC in this study. First, we investigated their usefulness as a histological marker for differential diagnosis. Second, we considered their roles in BC histogenesis. METHODS: Estrogen receptor α (ERα) and progesterone receptor (PgR) expression was investigated by immunohistochemistry in 125 BCs obtained by transurethral resection or biopsy, then in nonneoplastic background mucosa (trigone, fundus, and dome) of 33 total cystectomy samples. They were evaluated as positive when ≥ 1% of 500 subject cells were immunoreactive with moderate or strong intensities. RESULTS: ERα and PgR were positive in 38.4% and 3.2% of BCs, respectively, suggesting that ERα status alone could not definitely differentiate between BC and GTC. ERα expression was not significantly associated with age and sex of BC patients and histopathology of BCs. Although not significant, ERα expression was more frequent in higher grade (G1/G2 vs. G3/G4; P = 0.143) and marginally associated with advanced stage of BCs (pTis/pTa/pT1 vs. pT2/pT3, P = 0.056). ERα expression was significantly more frequent in background mucosa with ERα-positive BC (In the epithelium and stroma; both P < 0.001). ERα expression was continuously observed from normal to malignant epithelium in some cases. Although not significant, Brunn's nest or cystitis glandularis was more frequent in background mucosa with ERα-positive BC (P = 0.218). Analyses of nonneoplastic mucosa in cystectomy revealed that ERα was more frequently positive in urothelium of trigone, a predilection site for cystitis glandularis, than those of fundus and dome, with a significant difference between trigone and dome (P = 0.034). These data suggest that chronic inflammation may up-regulate ERα in the background epithelium, especially in trigone, and ERα expression in BC might be the reflection of bladder epithelium from which BC arose. CONCLUSIONS: Usefulness of ERα was limited in differential diagnosis between BC and GTC. ERα up-regulation might not play a critical role in the development of BC because it was already noted in the background bladder mucosa.


Assuntos
Receptor alfa de Estrogênio/análise , Receptores de Progesterona/análise , Neoplasias da Bexiga Urinária/química , Neoplasias da Bexiga Urinária/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Receptor alfa de Estrogênio/biossíntese , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Progesterona/biossíntese , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
15.
Virchows Arch ; 474(3): 333-339, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30607556

RESUMO

Metastatic breast carcinoma to the urinary bladder is rare. Eleven cases of metastatic breast carcinoma to the bladder are described in this report, including one case with a tumor to tumor metastasis. The patients ranged from 51 to 83 years of age. The time intervals between the diagnosis of primary breast cancer and the occurrence of bladder metastases ranged from 41 to 336 months. There were seven cases of invasive ductal carcinoma and four cases of invasive lobular carcinoma. In one case, a lobular carcinoma of the breast metastasized to a concurrent squamous cell carcinoma of the bladder. The immunophenotypic status of estrogen receptor and Her2 expression of the metastatic carcinomas were all concordant with the primary tumors. In nine patients with follow-up available, seven patients died of the disease ranging from 1 to 23 months after the diagnosis of the bladder metastasis and two patients were alive at 5 months of follow-up. To date, this report is the largest single series of patients with breast carcinoma metastatic to the bladder. It is the first reported instance of lobular carcinoma of the breast metastasizing to a squamous cell carcinoma of the bladder.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/secundário , Carcinoma Lobular/secundário , Carcinoma de Células Escamosas/patologia , Neoplasias da Bexiga Urinária/secundário , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biópsia , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Carcinoma Ductal de Mama/química , Carcinoma Ductal de Mama/mortalidade , Carcinoma Ductal de Mama/terapia , Carcinoma Lobular/química , Carcinoma Lobular/mortalidade , Carcinoma Lobular/terapia , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/terapia , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/análise , Receptores Estrogênicos/análise , Fatores de Tempo , Neoplasias da Bexiga Urinária/química , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/terapia
17.
Carcinogenesis ; 40(1): 84-92, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30395172

RESUMO

CD73 is an adenosine-producing cell surface enzyme, which exerts strong anti-inflammatory and migration modulating effects in many cell types. We evaluated the potential of CD73 as a biomarker in predicting the outcome of bladder carcinoma. CD73 expression in tumor and stromal cells was analyzed using immunohistochemistry in 270 bladder cancer (BC) patients [166 non-muscle-invasive BC (NMIBC) and 104 muscle-invasive BC (MIBC) tumors]. The correlations of CD73 with clinical and pathological characteristics were evaluated with Pearson's and Fischer's tests. The Kaplan-Meier method and Cox proportional hazards regression models were used to analyze the association between CD73 expression and outcome. CD73 expression showed substantial variation in basal and suprabasal layers of the cancerous epithelium, stromal fibroblasts, endothelial cells and lymphocytes in different tumor specimens. In log-rank analyses, CD73 expression in cancer cells associated with better survival both in NMIBC and MIBC, whereas CD73 positivity in stromal fibroblasts associated with impaired survival in NMIBC. In multivariable models, CD73 negative epithelial cells in both BC types and CD73 negative endothelial cells in MIBC were independent factors predicting poor outcome. We conclude that in contrast to many other cancer types, high CD73 expression in BC predicts favorable prognosis.


Assuntos
5'-Nucleotidase/análise , Neoplasias da Bexiga Urinária/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Proteínas Ligadas por GPI/análise , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias da Bexiga Urinária/química
18.
Virchows Arch ; 474(1): 13-20, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30302546

RESUMO

Urachal carcinoma (UrC) is an exceedingly rare neoplasm that develops from the urachus, an embryologic remnant of the urogenital sinus and allantois. The most commonly encountered histologic subtype is adenocarcinoma. The aim of this study is to characterize a series of UrC by morphology, immunohistochemistry, and molecular analysis. We retrospectively investigated seven cases of UrCs and assessed patient symptoms, imaging, histologic features, immunohistochemical profile, molecular characteristics, pathologic stages, and type of treatment. Immunostaining for CK7, CK20, Muc-2, CDX2, GATA3, ß-catenin, and CK34ßE12 was carried out on each neoplasm and on seven non-neoplastic urachal remnants as the control group. Additionally, a mutational analysis was performed using the QIAact Actionable Insights Tumor Panel Kit, which analyzes KRAS, NRAS, KIT, BRAF, PDGFRA, ALK, EGFR, ERBB2, PIK3CA, ERBB3, ESR1, and RAF1. Our cohort comprised five females and two males with a mean age of 64 years. UrCs consisted of two mucinous cystadenocarcinomas and five invasive, non-cystic adenocarcinomas. Carcinoma antigen expression profile was positive for CK20 and negative for CK34ßE12 and GATA3 in all cases. Five of seven cases stained positively for Muc-2 and CDX2. On the contrary, non-neoplastic urachal remnants were immunoreactive for CK34ßE12, CK7, and GATA3. Mutational analysis gave a positive result in four out of seven (57.1%) cases. All four positive tumors showed RAS mutation and one an additional mutation in PIK3CA. Urachal tumors exhibit peculiar morphologic, immunohistochemical, and molecular features. Due to the advanced stage at presentation, individualized treatment should be undertaken.


Assuntos
Biomarcadores Tumorais , Cistadenocarcinoma Mucinoso/diagnóstico , Análise Mutacional de DNA , Imuno-Histoquímica , Mutação , Neoplasias da Bexiga Urinária/diagnóstico , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Biópsia , Cistadenocarcinoma Mucinoso/química , Cistadenocarcinoma Mucinoso/genética , Cistadenocarcinoma Mucinoso/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/química , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
19.
Mod Pathol ; 32(5): 717-724, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30443013

RESUMO

There is a clinical need to identify novel biomarkers to improve diagnostic accuracy for the detection of urothelial tumors. The current study aimed to evaluate keratin 17 (K17), an oncoprotein that drives cell cycle progression in cancers of multiple anatomic sites, as a diagnostic biomarker of urothelial neoplasia in bladder biopsies and in urine cytology specimens. We evaluated K17 expression by immunohistochemistry in formalin-fixed, paraffin embedded tissue specimens of non-papillary invasive urothelial carcinoma (UC) (classical histological cases), high grade papillary UC (PUC-LG), low grade papillary UC (PUC-HG), papillary urothelial neoplasia of low malignant potential (PUNLMP), and normal bladder mucosa. A threshold was established to dichotomize K17 status in tissue specimens as positive vs. negative, based on the proportion of cells that showed strong staining. In addition, K17 immunocytochemistry was performed on urine cytology slides, scoring positive test results based on the detection of K17 in any urothelial cells. Mann-Whitney and receiver operating characteristic analyses were used to compare K17 expression between histologic diagnostic categories. The median proportion of K17 positive tumor cells was 70% (range 20-90%) in PUNLMP, 30% (range 5-100%) in PUC-LG, 20% (range 1-100%), in PUC-HG, 35% (range 5-100%) in UC but staining was rarely detected (range 0-10%) in normal urothelial mucosa. Defining cases in which K17 was detected in ≥10% of cells were considered positive, the sensitivity of K17 in biopsies was 89% (95% CI: 80-96%) and the specificity was 88% (95% CI: 70-95%) to distinguish malignant lesions (PUC-LG, PUC-HG, and UC) from normal urothelial mucosa. Furthermore, K17 immunocytochemistry had a sensitivity of 100% and a specificity of 96% for urothelial carcinoma in 112 selected urine specimens. Thus, K17 is a sensitive and specific biomarker of urothelial neoplasia in tissue specimens and should be further explored as a novel biomarker for the cytologic diagnosis of urine specimens.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma/química , Imuno-Histoquímica , Queratina-17/análise , Neoplasias da Bexiga Urinária/química , Urotélio/química , Carcinoma/patologia , Humanos , Gradação de Tumores , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Neoplasias da Bexiga Urinária/patologia , Urotélio/patologia
20.
J Biophotonics ; 12(10): e201800165, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30168296

RESUMO

Non-invasive detection of urinary bladder cancer remains a significant challenge. Urinary volatile organic compounds (VOCs) are a promising alternative to cell-based biomarkers. Herein, we demonstrate a novel diagnosis system based on an optic fluorescence sensor array for detecting urinary bladder cancer VOCs biomarkers. This study describes a fluorescence-based VOCs sensor array detecting system in detail. The choice of VOCs for the initial part was based on an extensive systematic search of the literature and then followed up using urinary samples from patients with urinary bladder transitional cell carcinoma. Canonical discriminant analysis and partial least squares discriminant analysis (PLS-DA) were employed and correctly detected 31/48 urinary bladder cancer VOC biomarkers and achieved an overall 77.75% sensitivity and 93.25% specificity by PLS-DA modelling. All five urine samples from bladder cancer patients, and five healthy controls were successfully identified with the same sensor arrays. Overall, the experiments in this study describe a real-time platform for non-invasive bladder cancer diagnosis using fluorescence-based gas-sensor arrays. Pure VOCs and urine samples from the patients proved such a system to be promising; however, further research is required using a larger population sample.


Assuntos
Dispositivos Ópticos , Espectrometria de Fluorescência/instrumentação , Neoplasias da Bexiga Urinária/química , Compostos Orgânicos Voláteis/análise , Biomarcadores/análise , Humanos , Sistemas Automatizados de Assistência Junto ao Leito
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