RESUMO
BACKGROUND: Severe chronic hypoxia is associated with tumour necrosis. In patients with muscle invasive bladder cancer (MIBC), necrosis is prognostic for survival following surgery or radiotherapy and predicts benefit from hypoxia modification of radiotherapy. Adding mitomycin C (MMC) and 5-fluorouracil (5-FU) chemotherapy to radiotherapy improved locoregional control (LRC) compared to radiotherapy alone in the BC2001 trial. We hypothesised that tumour necrosis would not predict benefit for the addition of MMC and 5-FU to radiotherapy, but would be prognostic. METHODS: Diagnostic tumour samples were available from 230 BC2001 patients. Tumour necrosis was scored on whole-tissue sections as absent or present, and its predictive and prognostic significance explored using Cox proportional hazards models. Survival estimates were obtained by Kaplan-Meier methods. RESULTS: Tumour necrosis was present in 88/230 (38%) samples. Two-year LRC estimates were 71% (95% CI 61-79%) for the MMC/5-FU chemoradiotherapy group and 49% (95% CI 38-59%) for the radiotherapy alone group. When analysed by tumour necrosis status, the adjusted hazard ratios (HR) for MMC/5-FU vs. no chemotherapy were 0.46 (95% CI: 0.12-0.99; P=0.05, necrosis present) and 0.55 (95% CI: 0.31-0.98; P=0.04, necrosis absent). Multivariable analysis of prognosis for LRC by the presence vs. absence of necrosis yielded a HR=0.89 (95% CI 0.55-1.44, P=0.65). There was no significant association for necrosis as a predictive or prognostic factor with respect to overall survival. CONCLUSIONS: Tumour necrosis was neither predictive nor prognostic, and therefore MMC/5-FU is an appropriate radiotherapy-sensitising treatment in MIBC independent of necrosis status.
Assuntos
Quimiorradioterapia/métodos , Fluoruracila/administração & dosagem , Mitomicina/administração & dosagem , Fator de Necrose Tumoral alfa/metabolismo , Neoplasias da Bexiga Urinária/terapia , Adulto , Idoso , Feminino , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Mitomicina/uso terapêutico , Invasividade Neoplásica , Valor Preditivo dos Testes , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologiaAssuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Anticorpos Anticitoplasma de Neutrófilos/sangue , Glomerulonefrite/tratamento farmacológico , Imunossupressores/administração & dosagem , Falência Renal Crônica/epidemiologia , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/mortalidade , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Progressão da Doença , Monitoramento de Medicamentos/métodos , Feminino , Seguimentos , Glomerulonefrite/sangue , Glomerulonefrite/imunologia , Glomerulonefrite/mortalidade , Humanos , Imunossupressores/efeitos adversos , Rim/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Falência Renal Crônica/imunologia , Falência Renal Crônica/prevenção & controle , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Medição de Risco/métodosRESUMO
BACKGROUND: BC2001 showed combining chemotherapy (5-FU + mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature predicted benefit from hypoxia-modifying radiosensitisation in BCON and hypothesised that only patients with low hypoxia scores (HSs) would benefit from chemotherapy in BC2001. BC2001 allowed conventional (64Gy/32 fractions) or hypofractionated (55Gy/20 fractions) radiotherapy. An exploratory analysis tested an additional hypothesis that hypofractionation reduces reoxygenation and would be detrimental for patients with hypoxic tumours. METHODS: RNA was extracted from pre-treatment biopsies (298 BC2001 patients), transcriptomic data generated (Affymetrix Clariom-S arrays), HSs calculated (median expression of 24-signature genes) and patients stratified as hypoxia-high or -low (cut-off: cohort median). PRIMARY ENDPOINT: invasive loco-regional control (ILRC); secondary overall survival. FINDINGS: Hypoxia affected overall survival (HR = 1.30; 95% CI 0.99-1.70; p = 0.062): more uncertainty for ILRC (HR = 1.29; 95% CI 0.82-2.03; p = 0.264). Benefit from chemotherapy was similar for patients with high or low HSs, with no interaction between HS and treatment arm. High HS associated with poor ILRC following hypofractionated (n = 90, HR 1.69; 95% CI 0.99-2.89 p = 0.057) but not conventional (n = 207, HR 0.70; 95% CI 0.28-1.80, p = 0.461) radiotherapy. The finding was confirmed in an independent cohort (BCON) where hypoxia associated with a poor prognosis for patients receiving hypofractionated (n = 51; HR 14.2; 95% CI 1.7-119; p = 0.015) but not conventional (n = 24, HR 1.04; 95% CI 0.07-15.5, p = 0.978) radiotherapy. INTERPRETATION: Tumour hypoxia status does not affect benefit from BC2001 chemotherapy. Hypoxia appears to affect fractionation sensitivity. Use of HSs to personalise treatment needs testing in a biomarker-stratified trial. FUNDING: Cancer Research UK, NIHR, MRC.
Assuntos
Hipóxia , Mitomicina , Humanos , Intervalo Livre de Doença , Fracionamento da Dose de Radiação , Biomarcadores , Resultado do TratamentoRESUMO
Tumour hypoxia status provides prognostic information and predicts response to hypoxiamodifying treatments. A previous study by our group derived a 24gene signature to assess hypoxia in bladder cancer. The objectives of the present study were to compare platforms for generating signature scores, identify cutoff values for prospective studies, assess intratumour heterogeneity and confirm hypoxia relevance. Briefly, RNA was extracted from prospectively collected diagnostic biopsies of muscle invasive bladder cancer (51 patients), and gene expression was measured using customised Taqman Low Density Array (TLDA) cards, NanoString and Clariom S arrays. Crossplatform transferability of the gene signature was assessed using regression and concordance analysis. The cutoff values were the cohort median expression values. Intra and intertumour variability were determined in a retrospective patient cohort (n=51) with multiple blocks (218) from the same tumour. To demonstrate relevance, bladder cancer cell lines were exposed to hypoxia (0.1% oxygen, 24 h), and extracted RNA was run on custom TLDA cards. Hypoxia scores (HS) values showed good agreement between platforms: Clariom S vs. TLDA (r=0.72, P<0.0001; concordance 73%); Clariom S vs. NanoString (r=0.84, P<0.0001; 78%); TLDA vs. NanoString (r=0.80, P<0.0001; 78%). Cutoff values were 0.047 (TLDA), 7.328 (NanoString) and 6.667 (Clariom S). Intratumour heterogeneity in gene expression and HS (coefficient of variation 3.9%) was less than intertumour (7.9%) variability. HS values were higher in bladder cancer cells exposed to hypoxia compared with normoxia (P<0.02). In conclusion, the present study revealed that application of the 24gene bladder cancer hypoxia signature was platform agnostic, cutoff values determined prospectively can be used in a clinical trial, intratumour heterogeneity was low and the signature was sensitive to changes in oxygen levels in vitro.
Assuntos
Neoplasias da Bexiga Urinária , Biomarcadores Tumorais/genética , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Hipóxia/genética , Oxigênio , Estudos Prospectivos , RNA , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologiaRESUMO
We report for the time a patient with recurrence of tubulointerstitial nephritis and uveitis (TINU) following renal transplantation. Our patient was diagnosed at the age of 8 years and, despite treatment with systemic steroids, developed established renal failure. At the age of 17 years, he underwent a live-related donor renal transplant. Immunosuppression included tacrolimus, mycophenolate mofetil and prednisolone. Having had normal renal function for 3 years after transplantation, he developed uveitis and decline in the graft function. A biopsy of the allograft demonstrated recurrent granulomatous interstitial nephritis. The recurrence of TINU following transplantation suggests a role for circulating autoantibodies in the disease pathology.
Assuntos
Transplante de Rim/efeitos adversos , Nefrite Intersticial/complicações , Nefrite Intersticial/terapia , Uveíte/complicações , Uveíte/terapia , Autoanticorpos/sangue , Criança , Humanos , Imunossupressores , Masculino , Nefrite Intersticial/patologia , Recidiva , Síndrome , Transplante Homólogo , Resultado do Tratamento , Uveíte/patologiaRESUMO
Quantitative real time polymerase chain reaction (qPCR) data are normalised using endogenous control genes. We aimed to: (1) demonstrate a pathway to identify endogenous control genes for qPCR analysis of formalin-fixed paraffin-embedded (FFPE) tissue using bladder cancer as an exemplar; and (2) examine the influence of probe length and sample age on PCR amplification and co-expression of candidate genes on apparent expression stability. RNA was extracted from prospective and retrospective samples and subject to qPCR using TaqMan human endogenous control arrays or single tube assays. Gene stability ranking was assessed using coefficient of variation (CoV), GeNorm and NormFinder. Co-expressed genes were identified from The Cancer Genome Atlas (TCGA) using the on-line gene regression analysis tool GRACE. Cycle threshold (Ct) values were lower for prospective (19.49 ± 2.53) vs retrospective (23.8 ± 3.32) tissues (p < 0.001) and shorter vs longer probes. Co-expressed genes ranked as the most stable genes in the TCGA cohort by GeNorm when analysed together but ranked lower when analysed individually omitting co-expressed genes indicating bias. Stability values were < 1.5 for the 20 candidate genes in the prospective cohort. As they consistently ranked in the top ten by CoV, GeNorm and Normfinder, UBC, RPLP0, HMBS, GUSB, and TBP are the most suitable endogenous control genes for bladder cancer qPCR.
Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias/patologia , Humanos , Neoplasias/metabolismo , Inclusão em Parafina , Estudos Prospectivos , RNA/metabolismo , RNA/normas , Reação em Cadeia da Polimerase em Tempo Real/normas , Padrões de Referência , Análise de Regressão , Estudos Retrospectivos , Proteínas Ribossômicas/genética , Proteína de Ligação a TATA-Box/genéticaRESUMO
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/patologiaRESUMO
Development of malignancy after solid-organ trans?lant is a well-known long-term complication of immunosuppressive therapy. Thus far, there are no specific oncologic recommendations regarding management of de novo tumors in transplanted kidneys. Here, we present the case of a 63-year-old male patient who developed a de novo renal cell carcinoma 6 years after the transplant procedure. The patient underwent nephron-sparing surgery with transperitoneal enucleation of the tumor. We discuss the decision-making process and the operative challenges that we faced. We conclude that this technique should be considered as a therapeutic strategy for selected patients so that transplant nephrectomy can be avoided.
Assuntos
Carcinoma de Células Renais/cirurgia , Falência Renal Crônica/cirurgia , Neoplasias Renais/cirurgia , Transplante de Rim/efeitos adversos , Tratamentos com Preservação do Órgão , Aloenxertos , Carcinoma de Células Renais/induzido quimicamente , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Tomada de Decisão Clínica , Humanos , Imunossupressores/efeitos adversos , Falência Renal Crônica/diagnóstico , Neoplasias Renais/induzido quimicamente , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
BACKGROUND: Fibrillary glomerulonephritis is a rare cause of progressive renal dysfunction, often leading to the need for dialysis within a few years. The role of immunosuppressive treatment is still uncertain although this has been tried with variable success. CASE PRESENTATION: A 56 year old woman with the antiphospholipid antibody syndrome (IgM anticardiolipin antibodies) was seen in the nephrology clinic with haematuria, proteinuria, and worsening renal function. A renal biopsy demonstrated a mesangial proliferative glomerulonephritis on light microscopy and smaller fibrils (10.6-13.8 nm in diameter) than is usual for fibrillary glomerulonephritis (typically 18-22 nm) on electron microscopy. Amyloidosis was excluded following detailed evaluation. On account of rapidly worsening renal failure she was started on cyclophosphamide and prednisolone which led to the partial recovery and stabilization of her renal function. CONCLUSION: This case highlights the need for routine electron microscopy in native renal biopsies, where the differential diagnosis is wide and varied and the light and immunofluorescence microscopic findings may be non specific.
Assuntos
Síndrome Antifosfolipídica/tratamento farmacológico , Ciclofosfamida/administração & dosagem , Glomerulonefrite/tratamento farmacológico , Imunossupressores/administração & dosagem , Prednisolona/administração & dosagem , Síndrome Antifosfolipídica/diagnóstico , Combinação de Medicamentos , Feminino , Glomerulonefrite/diagnóstico , Humanos , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Purpose: Hypoxia modification improves overall survival in muscle-invasive bladder cancer patients who undergo radiotherapy. There is evidence that hypoxic tumors benefit most from hypoxia modification. The study aimed to identify or derive a hypoxia gene signature that predicts benefit from hypoxia-modifying treatment in bladder cancer.Experimental Design: Published hypoxia signatures were tested and a new one derived by analyzing bladder cancer transcriptomic data from public databases. Tumor samples were available from the BCON phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON). Gene expression data were generated for 151 tumors using Affymetrix Human 1.0 Exon ST arrays and used for independent validation.Results: A 24-gene signature was derived, which was prognostic in four of six independent surgical cohorts (n = 679; meta HR, 2.32; 95% CI, 1.73-3.12; P < 0.0001). The signature was also prognostic in BCON patients receiving radiotherapy alone (n = 75; HR for local relapse-free survival, 2.37; 95% CI, 1.26-4.47; P = 0.0076). The signature predicted benefit from CON (n = 76; HR, 0.47; 95% CI, 0.26-0.86; P = 0.015). Prognostic significance (P = 0.017) and predictive significance (P = 0.058) remained after adjusting for clinicopathologic variables. A test for interaction between hypoxia status and treatment arms was significant (P = 0.0094).Conclusions: A 24-gene hypoxia signature has strong and independent prognostic and predictive value for muscle-invasive bladder cancer patients. The signature can aid identification of patients likely to benefit from the addition of carbogen and nicotinamide to radiotherapy. Clin Cancer Res; 23(16); 4761-8. ©2017 AACR.
Assuntos
Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/radioterapia , Idoso , Dióxido de Carbono/administração & dosagem , Ensaios Clínicos Fase III como Assunto , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Hipóxia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Niacinamida/administração & dosagem , Oxigênio/administração & dosagem , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de RiscoAssuntos
Exposição Ambiental/efeitos adversos , Intoxicação por Chumbo/fisiopatologia , Urânio/intoxicação , Guerra , Adulto , Bósnia e Herzegóvina , Terapia por Quelação , Humanos , Intoxicação por Chumbo/diagnóstico , Intoxicação por Chumbo/tratamento farmacológico , Masculino , Pessoa de Meia-IdadeRESUMO
Breast core biopsy is one of the major nonoperative methods of diagnosis. Increasingly, there is also a need to provide prognostic data to facilitate timely patient management. We present the results from 500 patients with invasive breast carcinoma, who underwent core biopsy followed by a therapeutic surgical procedure. Grade and type of the invasive and in situ carcinoma, together with the presence or absence of vascular invasion, were determined in both biopsy and definitive surgical excision and the results compared. There was 67% agreement with overall grade (kappa value 0.48), with scores for tubule formation, pleomorphism, and mitotic scoring achieving values of 82%, 73%, and 58%, respectively. Only 60% of grade 1 and 2 carcinomas showed concordance, but 84% of grade 3 tumors showed agreement between core and excision results. Tumor typing, vascular invasion, and grading of ductal carcinoma in situ had agreement values of 74%, 69%, and 65%, respectively. The major problem with assessing prognostic factors on needle biopsy specimens is undersampling of the most informative areas. However, in those patients in whom preoperative assessment of prognostic factors is most likely to be beneficial, i.e., those with grade 3 carcinomas, a high level of agreement was achieved in this large study.
Assuntos
Biópsia por Agulha/métodos , Neoplasias da Mama/patologia , Carcinoma/patologia , Neoplasias da Mama/classificação , Neoplasias da Mama/cirurgia , Carcinoma/classificação , Carcinoma/cirurgia , Carcinoma in Situ/patologia , Carcinoma in Situ/cirurgia , Feminino , Humanos , Mitose , Invasividade Neoplásica/patologia , Prognóstico , Estudos Prospectivos , Reprodutibilidade dos Testes , Resultado do TratamentoRESUMO
Patients with macromastia often comment on a lack of sensation in their nipple-areola complex. A study was designed to investigate the cause of this decreased sensation. Two hypotheses were proposed. First, the decreased sensation could result from neuropraxia of the sensory nerve fibers secondary to traction caused by the heavy breast parenchyma. The second hypothesis proposed that tissue expansion of the nipple and areola by the voluminous breast parenchyma caused a decrease in nerve fibers per surface area and hence decreased sensory perception. Sixty-one patients were assessed in the study. All patients underwent surgery in which histological biopsy of either the areola alone (31 reduction mammaplasty patients) or the nipple and areola (30 mastectomy patients) was possible. Before surgery, each nipple-areola complex was tested with Weinstein Enhanced Sensory Test monofilaments as a quantitative test of tactile sensation. Breast cup size, ptosis, and weight of tissue excised were recorded to allow general assessment of the breast size. The nipple and areola biopsy specimens were assessed using immunohistochemistry (S-100 polyclonal antibody, Dako Z311) to measure nerve fiber count per unit area. Statistical analysis was undertaken to find any association among sensitivity, breast cup size, ptosis, weight of tissue resected, and nerve fiber density in the nipple and areola biopsy specimens. Sensitivity at the areola decreased with increasing breast cup size (r = 0.47, p < 0.001) and ptosis (r = 0.42, p = 0.002 for increasing distance between inframammary crease and nipple; r = 0.49, p < 0.001 for increasing manubrium to nipple distance). There was a weak correlation between nerve fiber density at the areola and breast cup size (r = -0.22, p = 0.1). Sensitivity at the nipple was higher than at the areola. Nerve fiber density count at the nipple was higher than at the areola, but there was no statistically significant correlation between nipple sensitivity and breast cup size, ptosis, or weight of tissue resected. The results suggest that the areola and nipple are different in their neuroanatomy. The areola is a thin, pliable structure that is predisposed to stretch as the breast enlarges and therefore experience a decrease in nerve fiber density. The nipple is a compact structure that is less likely to stretch with breast enlargement. In the nipple, neither sensory perception nor nerve fiber density varied with size or breast ptosis. The perceived lack of sensation in the nipple-areola complex is multifactorial. This study shows that neither traction injury to the sensory nerves nor decreased nerve density alone can explain the subjective numbness reported by patients with macromastia. Psychological factors, such as dissatisfaction with body form or interpretation of lack of sensation in the areola as also affecting the nipple, may influence the patient's assessment of the nipple-areola sensitivity.
Assuntos
Mama/patologia , Mamilos/inervação , Sensação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Mamoplastia , Mastectomia , Pessoa de Meia-Idade , Fibras Nervosas/patologia , Mamilos/patologia , Estimulação Física , Limiar Sensorial , TatoRESUMO
The mammalian ureter contains a water-tight epithelium surrounded by smooth muscle. Key molecules have been defined which regulate ureteric bud initiation and drive the differentiation of ureteric mesenchyme into peristaltic smooth muscle. Less is known about mechanisms underlying the developmental patterning of the multilayered epithelium characterising the mature ureter. In skin, which also contains a multilayered epithelium, cytokeratin 15 (CK15), an acidic intermediate filament protein, marks cells whose progeny contribute to epidermal regeneration following wounding. Moreover, CK15+ precursor cells in skin can give rise to basal cell carcinomas. In the current study, using transcriptome microarrays of embryonic wild type mouse ureters, Krt15, coding for CK15, was detected. Quantitative polymerase chain reaction analyses confirmed the initial finding and demonstrated that Krt15 levels increased during the fetal period when the ureteric epithelium becomes multilayered. CK15 protein was undetectable in the ureteric bud, the rudiment from which the ureter grows. Nevertheless, later in fetal development, CK15 was immunodetected in a subset of basal urothelial cells in the ureteric stalk. Superficial epithelial cells, including those positive for the differentiation marker uroplakin III, were CK15-. Transformation-related protein 63 (P63) has been implicated in epithelial differentiation in murine fetal urinary bladders. In wild type fetal ureters, CK15+ cells were positive for P63, and p63 homozygous null mutant ureters lacked CK15+ cells. In these mutant ureters, sections of the urothelium were monolayered versus the uniform multilayering found in wild type littermates. Human urothelial cell carcinomas account for considerable morbidity and mortality. CK15 was upregulated in a subset of invasive ureteric and urinary bladder cancers. Thus, in ureter development, the absence of CK15 is associated with a structurally simplified urothelium whereas, postnatally, increased CK15 levels feature in malignant urothelial overgrowth. CK15 may be a novel marker for urinary tract epithelial precursor cells.
Assuntos
Carcinoma Basocelular/genética , Células Epiteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Queratina-15/genética , Ureter/metabolismo , Neoplasias da Bexiga Urinária/genética , Urotélio/metabolismo , Idoso , Animais , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/patologia , Diferenciação Celular , Embrião de Mamíferos , Células Epiteliais/patologia , Feminino , Feto , Regulação da Expressão Gênica no Desenvolvimento , Homozigoto , Humanos , Queratina-15/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Morfogênese/genética , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Análise Serial de Tecidos , Transativadores/genética , Transativadores/metabolismo , Transcriptoma , Ureter/citologia , Ureter/embriologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Uroplaquina III/genética , Uroplaquina III/metabolismo , Urotélio/patologiaRESUMO
BACKGROUND AND PURPOSE: Addition of carbogen and nicotinamide (hypoxia-modifying agents) to radiotherapy improves the survival of patients with high risk bladder cancer. The study investigated whether histopathological tumour features and putative hypoxia markers predicted benefit from hypoxia modification. MATERIALS AND METHODS: Samples were available from 231 patients with high grade and invasive bladder carcinoma from the BCON phase III trial of radiotherapy (RT) alone or with carbogen and nicotinamide (RT+CON). Histopathological tumour features examined were: necrosis, growth pattern, growing margin, and tumour/stroma ratio. Hypoxia markers carbonic anhydrase-IX and glucose transporter-1 were examined using tissue microarrays. RESULTS: Necrosis was the only independent prognostic indicator (P=0.04). Necrosis also predicted benefit from hypoxia modification. Five-year overall survival was 48% (RT) versus 39% (RT+CON) (P=0.32) in patients without necrosis and 34% (RT) versus 56% (RT+CON) (P=0.004) in patients with necrosis. There was a significant treatment by necrosis strata interaction (P=0.001 adjusted). Necrosis was an independent predictor of benefit from RT+CON versus RT (hazard ratio [HR]: 0.43, 95% CI 0.25-0.73, P=0.002). This trend was not observed when there was no necrosis (HR: 1.64, 95% CI 0.95-2.85, P=0.08). CONCLUSIONS: Necrosis predicts benefit from hypoxia modification in patients with high risk bladder cancer and should be used to select patients; it is simple to identify and easy to incorporate into routine histopathological examination.
Assuntos
Dióxido de Carbono/uso terapêutico , Niacinamida/uso terapêutico , Oxigênio/uso terapêutico , Neoplasias da Bexiga Urinária/radioterapia , Idoso , Idoso de 80 Anos ou mais , Anidrase Carbônica IV/análise , Hipóxia Celular , Feminino , Transportador de Glucose Tipo 1/análise , Humanos , Masculino , Pessoa de Meia-Idade , Necrose , Risco , Neoplasias da Bexiga Urinária/química , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologiaRESUMO
Urothelial carcinomas of the bladder are a heterogeneous group of tumours, although some histological sub-variants are rare and sparsely reported in the literature. Diagnosis of sub-variants from conventional urothelial carcinoma can be challenging, as they may mimic the morphology of other malignancies or benign tumours and therefore their distinction is important. For the first time, the spectral pathology of some of these sub-variants has been documented by infrared microspectroscopy and an attempt made to profile their biochemistry. It is important not only to identify and separate the cancer-associated epithelial tissue spectra from common tissue features such as stroma or blood, but also to detect the signatures of tumour sub-variants. As shown, their spectroscopic signals can change dramatically as a consequence of differentiation. Example cases are discussed and compared with histological evaluations.
Assuntos
Carcinoma/diagnóstico , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Neoplasias da Bexiga Urinária/diagnóstico , Algoritmos , Biópsia , Carcinoma/patologia , Diferenciação Celular , Análise por Conglomerados , Diagnóstico por Imagem/métodos , Glicogênio/química , Humanos , Metástase Neoplásica , Fenótipo , Análise de Componente Principal , Espectrofotometria/métodos , Análise Espectral Raman/métodos , Máquina de Vetores de Suporte , Neoplasias da Bexiga Urinária/patologia , Urotélio/patologiaRESUMO
PURPOSE: Tumor hypoxia is associated with a poor prognosis, hypoxia modification improves outcome, and hypoxic status predicts benefit from treatment. Yet, there is no universal measure of clinical hypoxia. The aim of this study was to investigate whether a 26-gene hypoxia signature predicted benefit from hypoxia-modifying treatment in both cancer types. EXPERIMENTAL DESIGN: Samples were available from 157 T2-T4 laryngeal cancer and 185 T1-T4a bladder cancer patients enrolled on the accelerated radiotherapy with carbogen and nicotinamide (ARCON) and bladder carbogen nicotinamide (BCON) phase III randomized trials of radiotherapy alone or with carbogen and nicotinamide (CON) respectively. Customized TaqMan low density arrays (TLDA) were used to assess expression of the 26-gene signature using quantitative real-time PCR. The median expression of the 26 genes was used to derive a hypoxia score (HS). Patients were categorized as TLDA-HS low (≤median) or TLDA-HS high (>median). The primary outcome measures were regional control (RC; ARCON) and overall survival (BCON). RESULTS: Laryngeal tumors categorized as TLDA-HS high showed greater benefit from ARCON than TLDA-HS low tumors. Five-year RC was 81% (radiotherapy alone) versus 100% (CON) for TLDA-HS high (P=0.009). For TLDA-HS low, 5-year RC was 91% (radiotherapy alone) versus 90% (CON; P=0.90). TLDA-HS did not predict benefit from CON in bladder cancer. CONCLUSION: The 26-gene hypoxia signature predicts benefit from hypoxia-modifying treatment in laryngeal cancer. These findings will be evaluated in a prospective clinical trial.
Assuntos
Hipóxia Celular/genética , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Neoplasias Laríngeas/radioterapia , Neoplasias da Bexiga Urinária/radioterapia , Dióxido de Carbono/administração & dosagem , Hipóxia Celular/efeitos da radiação , Feminino , Humanos , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/patologia , Masculino , Niacinamida/administração & dosagem , Oxigênio/administração & dosagem , Radiossensibilizantes/administração & dosagem , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologiaRESUMO
The incidence of acute rheumatic fever has seen a dramatic decline over the last 15 to 20 years in most developed countries and treatment of this disease has changed little since. The ease of travel and immigration and the cosmopolitan nature of many cities mean that occasionally the disease will come to the attention of clinicians not familiar with its presentation, resulting in delayed diagnosis and treatment. We present a case of recurrent acute rheumatic fever in a patient who was initially thought to be suffering from acute bacterial endocarditis on her previously diseased rheumatic aortic valve. This culminated in her undergoing urgent aortic valve replacement during a phase of the illness that should have been treated with high dose anti-inflammatory medication. Therefore, clinicians should be aware of this condition and include it in their differential diagnosis of the febrile patient with a previous history of rheumatic fever. We briefly discuss the diagnostic dilemma of patients suffering from this condition and in differentiating it from acute endocarditis.