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1.
PLoS One ; 16(8): e0254698, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34383776

RESUMO

BACKGROUND: Pneumonia is a common and severe complication of abdominal surgery, it is associated with increased length of hospital stay, healthcare costs, and mortality. Further, pulmonary complication rates have risen during the SARS-CoV-2 pandemic. This study explored the potential cost-effectiveness of administering preoperative chlorhexidine mouthwash versus no-mouthwash at reducing postoperative pneumonia among abdominal surgery patients. METHODS: A decision analytic model taking the South African healthcare provider perspective was constructed to compare costs and benefits of mouthwash versus no-mouthwash-surgery at 30 days after abdominal surgery. We assumed two scenarios: (i) the absence of COVID-19; (ii) the presence of COVID-19. Input parameters were collected from published literature including prospective cohort studies and expert opinion. Effectiveness was measured as proportion of pneumonia patients. Deterministic and probabilistic sensitivity analyses were performed to assess the impact of parameter uncertainties. The results of the probabilistic sensitivity analysis were presented using cost-effectiveness planes and cost-effectiveness acceptability curves. RESULTS: In the absence of COVID-19, mouthwash had lower average costs compared to no-mouthwash-surgery, $3,675 (R 63,770) versus $3,958 (R 68,683), and lower proportion of pneumonia patients, 0.029 versus 0.042 (dominance of mouthwash intervention). In the presence of COVID-19, the increase in pneumonia rate due to COVID-19, made mouthwash more dominant as it was more beneficial to reduce pneumonia patients through administering mouthwash. The cost-effectiveness acceptability curves shown that mouthwash surgery is likely to be cost-effective between $0 (R0) and $15,000 (R 260,220) willingness to pay thresholds. CONCLUSIONS: Both the absence and presence of SARS-CoV-2, mouthwash is likely to be cost saving intervention for reducing pneumonia after abdominal surgery. However, the available evidence for the effectiveness of mouthwash was extrapolated from cardiac surgery; there is now an urgent need for a robust clinical trial on the intervention on non-cardiac surgery.


Assuntos
Abdome/cirurgia , Clorexidina/uso terapêutico , Modelos Teóricos , Pneumonia/prevenção & controle , COVID-19 , Análise Custo-Benefício , Humanos , Antissépticos Bucais , Pandemias , Complicações Pós-Operatórias/prevenção & controle , Cuidados Pré-Operatórios , Estudos Prospectivos , África do Sul
2.
J Pathol ; 255(2): 132-140, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34156092

RESUMO

Well differentiated liposarcoma (WD-LPS) is a relatively rare tumour, with fewer than 50 cases occurring per year in the UK. These tumours are both chemotherapy- and radiotherapy-resistant and present a significant treatment challenge requiring radical surgery. Little is known of the molecular landscape of these tumours and no current targets for molecular therapy exist. We aimed to carry out a comprehensive molecular characterisation of WD-LPS via whole genome sequencing, RNA sequencing, and methylation array analysis. A recurrent mutation within exon 1 of FOXD4L3 was observed (chr9:70,918,189A>T; c.322A>T; p.Lys108Ter). Recurrent mutations were also observed in Wnt signalling, immunity, DNA repair, and hypoxia-associated genes. Recurrent amplification of HGMA2 was observed, although this was in fact part of a general amplification of the region around this gene. Recurrent gene fusions in HGMA2, SDHA, TSPAN31, and MDM2 were also observed as well as consistent rearrangements between chromosome 6 and chromosome 12. Our study has demonstrated a recurrent mutation within FOXD4L3, which shows evidence of interaction with the PAX pathway to promote tumourigenesis. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

3.
Clin Cancer Res ; 27(1): 288-300, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33028592

RESUMO

PURPOSE: The DNA damage immune response (DDIR) assay was developed in breast cancer based on biology associated with deficiencies in homologous recombination and Fanconi anemia pathways. A positive DDIR call identifies patients likely to respond to platinum-based chemotherapies in breast and esophageal cancers. In colorectal cancer, there is currently no biomarker to predict response to oxaliplatin. We tested the ability of the DDIR assay to predict response to oxaliplatin-based chemotherapy in colorectal cancer and characterized the biology in DDIR-positive colorectal cancer. EXPERIMENTAL DESIGN: Samples and clinical data were assessed according to DDIR status from patients who received either 5-fluorouracil (5-FU) or 5FUFA (bolus and infusion 5-FU with folinic acid) plus oxaliplatin (FOLFOX) within the FOCUS trial (n = 361, stage IV), or neoadjuvant FOLFOX in the FOxTROT trial (n = 97, stage II/III). Whole transcriptome, mutation, and IHC data of these samples were used to interrogate the biology of DDIR in colorectal cancer. RESULTS: Contrary to our hypothesis, DDIR-negative patients displayed a trend toward improved outcome for oxaliplatin-based chemotherapy compared with DDIR-positive patients. DDIR positivity was associated with microsatellite instability (MSI) and colorectal molecular subtype 1. Refinement of the DDIR signature, based on overlapping IFN-related chemokine signaling associated with DDIR positivity across colorectal cancer and breast cancer cohorts, further confirmed that the DDIR assay did not have predictive value for oxaliplatin-based chemotherapy in colorectal cancer. CONCLUSIONS: DDIR positivity does not predict improved response following oxaliplatin treatment in colorectal cancer. However, data presented here suggest the potential of the DDIR assay in identifying immune-rich tumors that may benefit from immune checkpoint blockade, beyond current use of MSI status.

4.
PLoS One ; 15(6): e0232960, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497086

RESUMO

BACKGROUND: Surgical site infection (SSI) is a worldwide problem which has morbidity, mortality and financial consequences. The incidence rate of SSI is high in Low- and Middle-Income countries (LMICs) compared to high income countries, and the costly surgical complication can raise the potential risk of financial catastrophe. OBJECTIVE: The aim of the study is to critically appraise studies on the cost of SSI in a range of LMIC studies and compare these estimates with a reference standard of high income European studies who have explored similar SSI costs. METHODS: A systematic review was undertaken using searches of two electronic databases, EMBASE and MEDLINE In-Process & Other Non-Indexed Citations, up to February 2019. Study characteristics, comparator group, methods and results were extracted by using a standard template. RESULTS: Studies from 15 LMIC and 16 European countries were identified and reviewed in full. The additional cost of SSI range (presented in 2017 international dollars) was similar in the LMIC ($174-$29,610) and European countries ($21-$34,000). Huge study design heterogeneity was encountered across the two settings. DISCUSSION: SSIs were revealed to have a significant cost burden in both LMICs and High Income Countries in Europe. The magnitude of the costs depends on the SSI definition used, severity of SSI, patient population, choice of comparator, hospital setting, and cost items included. Differences in study design affected the comparability across studies. There is need for multicentre studies with standardized data collection methods to capture relevant costs and consequences of the infection across income settings.


Assuntos
Efeitos Psicossociais da Doença , Países em Desenvolvimento/economia , Infecção da Ferida Cirúrgica/epidemiologia , Países Desenvolvidos/economia , Saúde Global , Gastos em Saúde , Recursos em Saúde/economia , Humanos , Incidência , Renda , Tempo de Internação/estatística & dados numéricos , Infecção da Ferida Cirúrgica/economia
5.
EBioMedicine ; 39: 265-271, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30473377

RESUMO

BACKGROUND: Chronic inflammation caused by ulcerative colitis (UC) causes a pro-neoplastic drive in the inflamed colon, leading to a markedly greater risk of invasive malignancy compared to the general population. Despite surveillance protocols, 50% of cases proceed to cancer before neoplasia is detected. The Enhanced Neoplasia Detection and Cancer Prevention in Chronic Colitis (ENDCaP-C) trial is an observational multi-centre test accuracy study to ascertain the role of molecular markers in improving the detection of dysplasia. We aimed to validate previously identified biomarkers of neoplasia in a retrospective cohort and create predictive models for later validation in a prospective cohort. METHODS: A retrospective analysis using bisulphite pyrosequencing of an 11 marker panel (SFRP1, SFRP2, SRP4, SRP5, WIF1, TUBB6, SOX7, APC1A, APC2, MINT1, RUNX3) in samples from 35 patients with cancer, 78 with dysplasia and 343 without neoplasia undergoing surveillance for UC associated neoplasia across 6 medical centres. Predictive models for UC associated cancer/dysplasia were created in the setting of neoplastic and non-neoplastic mucosa. FINDINGS: For neoplastic mucosa a five marker panel (SFRP2, SFRP4, WIF1, APC1A, APC2) was accurate in detecting pre-cancerous and invasive neoplasia (AUC = 0.83; 95% CI: 0.79, 0.88), and dysplasia (AUC = 0.88; (0.84, 0.91). For non-neoplastic mucosa a four marker panel (APC1A, SFRP4, SFRP5, SOX7) had modest accuracy (AUC = 0.68; 95% CI: 0.62,0.73) in predicting associated bowel neoplasia through the methylation signature of distant non-neoplastic colonic mucosa. INTERPRETATION: This multiplex methylation marker panel is accurate in the detection of ulcerative colitis associated dysplasia and neoplasia and is currently being validated in a prospective clinical trial. FUNDING: The ENDCAP-C study was funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) Programme (11/100/29).


Assuntos
Biomarcadores Tumorais/genética , Colite Ulcerativa/complicações , Neoplasias do Colo/diagnóstico , Metilação de DNA , Neoplasias do Colo/genética , Epigênese Genética , Feminino , Humanos , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Análise de Sequência de DNA/métodos
6.
Inflamm Bowel Dis ; 24(7): 1503-1509, 2018 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-29762666

RESUMO

Background and aims: Ulcerative colitis (UC) is associated with a higher background risk of dysplasia and/or neoplasia due to chronic inflammation. There exist few biomarkers for identification of patients with dysplasia, and targeted biopsies in this group of patients are inaccurate in reliably identifying dysplasia. We aimed to examine the epigenome of UC dysplasia and to identify and validate potential biomarkers. Methods: Colonic samples from patients with UC-associated dysplasia or neoplasia underwent epigenome-wide analysis on the Illumina 450K methylation array. Markers were validated by bisulphite pyrosequencing on a secondary validation cohort and accuracy calculated using logistic regression and receiver-operator curves. Results: Twelve samples from 4 patients underwent methylation array analysis and 6 markers (GNG7, VAV3, KIF5C, PIK3R5, TUBB6, and ZNF583) were taken forward for secondary validation on a cohort of 71 colonic biopsy samples consisting of normal uninflamed mucosa from control patients, acute and chronic colitis, "field" mucosa in patients with dysplasia/neoplasia, dysplasia, and neoplasia. Methylation in the beta-tubulin TUBB6 correlated with the presence of dysplasia (P < 0.0001) and accurately discriminated between dysplasia and nondysplastic tissue, even in the apparently normal field mucosa downstream from dysplastic lesions (AUC 0.84, 95% CI 0.81-0.87). Conclusions: Methylation in TUBB6 is a potential biomarker for UC- associated dysplasia. Further validation is needed and is ongoing as part of the ENDCAP-C study.


Assuntos
Colite Ulcerativa/patologia , Neoplasias do Colo/diagnóstico , Metilação de DNA , Mucosa Intestinal/patologia , Tubulina (Proteína)/genética , Adulto , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Colite Ulcerativa/complicações , Neoplasias do Colo/genética , Colonoscopia , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/diagnóstico , Lesões Pré-Cancerosas/genética , Curva ROC
7.
J Clin Endocrinol Metab ; 102(12): 4435-4447, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28945888

RESUMO

Context: Estrogens affect the incidence and progression of colorectal cancer (CRC), although the precise molecular mechanisms remain ill-defined. Objective: The present study investigated prereceptor estrogen metabolism through steroid sulphatase (STS) and 17ß-hydroxysteroid dehydrogenase activity and subsequent nongenomic estrogen signaling in human CRC tissue, in The Cancer Genome Atlas colon adenocarcinoma data set, and in in vitro and in vivo CRC models. We aimed to define and therapeutically target pathways through which estrogens alter CRC proliferation and progression. Design, Setting, Patients, and Interventions: Human CRC samples with normal tissue-matched controls were collected from postmenopausal female and age-matched male patients. Estrogen metabolism enzymes and nongenomic downstream signaling pathways were determined. CRC cell lines were transfected with STS and cultured for in vitro and in vivo analysis. Estrogen metabolism was determined using an ultra-performance liquid chromatography-tandem mass spectrometry method. Primary Outcome Measure: The proliferative effects of estrogen metabolism were evaluated using 5-bromo-2'-deoxyuridine assays and CRC mouse xenograft studies. Results: Human CRC exhibits dysregulated estrogen metabolism, favoring estradiol synthesis. The activity of STS, the fundamental enzyme that activates conjugated estrogens, is significantly (P < 0.001) elevated in human CRC compared with matched controls. STS overexpression accelerates CRC proliferation in in vitro and in vivo models, with STS inhibition an effective treatment. We defined a G-protein-coupled estrogen receptor (GPER) proproliferative pathway potentially through increased expression of connective tissue growth factor in CRC. Conclusion: Human CRC favors estradiol synthesis to augment proliferation via GPER stimulation. Further research is required regarding whether estrogen replacement therapy should be used with caution in patients at high risk of developing CRC.


Assuntos
Neoplasias Colorretais/patologia , Estrogênios/metabolismo , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Esteril-Sulfatase/farmacologia , Ativação Metabólica/efeitos dos fármacos , Animais , Antimetabólitos/farmacologia , Bromodesoxiuridina/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , RNA Interferente Pequeno/genética , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Trials ; 16: 392, 2015 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-26337522

RESUMO

Until recently, insufficient attention has been paid to the fact that surgical interventions are complex. This complexity has several implications, including the way in which surgical interventions are described and delivered in trials. In order for surgeons to adopt trial findings, interventions need to be described in sufficient detail to enable accurate replication; however, it may be permissible to allow some aspects to be delivered according to local practice. Accumulating work in this area has identified the need for general guidance on the design of surgical interventions in trial protocols and reports. Key issues to consider when designing surgical interventions include the identification of each surgical intervention and their components, who will deliver the interventions, and where and how the interventions will be standardised and monitored during the trial. The trial design (pragmatic and explanatory), comparator and stage of innovation may also influence the extent of detail required. Thoughtful consideration of surgical interventions in this way may help with the interpretation of trial results and the adoption of successful interventions into clinical practice.


Assuntos
Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Projetos de Pesquisa , Procedimentos Cirúrgicos Operatórios , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Projetos de Pesquisa/normas , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Procedimentos Cirúrgicos Operatórios/normas , Resultado do Tratamento
11.
BMC Surg ; 15: 30, 2015 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-25887789

RESUMO

BACKGROUND: Over the past 20 years evidence has accumulated confirming the immunomodulatory role of the appendix in ulcerative colitis (UC). This led to the idea that appendectomy might alter the clinical course of established UC. The objective of this body of research is to evaluate the short-term and medium-term efficacy of appendectomy to maintain remission in patients with UC, and to establish the acceptability and cost-effectiveness of the intervention compared to standard treatment. METHODS/DESIGN: These paired phase III multicenter prospective randomised studies will include patients over 18 years of age with an established diagnosis of ulcerative colitis and a disease relapse within 12 months prior to randomisation. Patients need to have been medically treated until complete clinical (Mayo score <3) and endoscopic (Mayo score 0 or 1) remission. Patients will then be randomised 1:1 to a control group (maintenance 5-ASA treatment, no appendectomy) or elective laparoscopic appendectomy plus maintenance treatment. The primary outcome measure is the one year cumulative UC relapse rate - defined both clinically and endoscopically as a total Mayo-score ≥5 with endoscopic subscore of 2 or 3. Secondary outcomes that will be assessed include the number of relapses per patient at 12 months, the time to first relapse, health related quality of life and treatment costs, and number of colectomies in each arm. DISCUSSION: The ACCURE and ACCURE-UK trials will provide evidence on the role and acceptability of appendectomy in the treatment of ulcerative colitis and the effects of appendectomy on the disease course. TRIAL REGISTRATION: NTR2883 ; ISRCTN56523019.


Assuntos
Apendicectomia , Colite Ulcerativa/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Apendicectomia/métodos , Protocolos Clínicos , Feminino , Humanos , Laparoscopia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Qualidade de Vida , Recidiva , Resultado do Tratamento
12.
BMJ Open ; 5(1): e006399, 2015 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-25582453

RESUMO

INTRODUCTION: Cholecystectomy is one of the most common general surgical operations performed. Despite level one evidence supporting the role of cholecystectomy in the management of specific gallbladder diseases, practice varies between surgeons and hospitals. It is unknown whether these variations account for the differences in surgical outcomes seen in population-level retrospective data sets. This study aims to investigate surgical outcomes following acute, elective and delayed cholecystectomies in a multicentre, contemporary, prospective, population-based cohort. METHODS AND ANALYSIS: UK and Irish hospitals performing cholecystectomies will be recruited utilising trainee-led research collaboratives. Two months of consecutive, adult patient data will be included. The primary outcome measure of all-cause 30-day readmission rate will be used in this study. Thirty-day complication rates, bile leak rate, common bile duct injury, conversion to open surgery, duration of surgery and length of stay will be measured as secondary outcomes. Prospective data on over 8000 procedures is anticipated. Individual hospitals will be surveyed to determine local policies and service provision. Variations in outcomes will be investigated using regression modelling to adjust for confounders. ETHICS AND DISSEMINATION: Research ethics approval is not required for this study and has been confirmed by the online National Research Ethics Service (NRES) decision tool. This novel study will investigate how hospital-level surgical provision can affect patient outcomes, using a cross-sectional methodology. The results are essential to inform commissioning groups and implement changes within the National Health Service (NHS). Dissemination of the study protocol is primarily through the trainee-led research collaboratives and the Association of Upper Gastrointestinal Surgeons (AUGIS). Individual centres will have access to their own results and the collective results of the study will be published in peer-reviewed journals and presented at relevant surgical conferences.


Assuntos
Colecistectomia/normas , Doenças da Vesícula Biliar/cirurgia , Adulto , Colecistectomia/métodos , Auditoria Clínica , Estudos Transversais , Procedimentos Cirúrgicos Eletivos , Feminino , Humanos , Irlanda , Tempo de Internação/estatística & dados numéricos , Modelos Logísticos , Masculino , Duração da Cirurgia , Readmissão do Paciente/estatística & dados numéricos , Complicações Pós-Operatórias , Estudos Prospectivos , Reino Unido
13.
Health Econ ; 24(4): 498-504, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24523070

RESUMO

The paper discusses the impact of centre selection on the generalisability of randomised controlled trial (RCT)-based economic evaluations and suggests a future research agenda. The first section briefly reviews the current methods for addressing generalisability. We argue that these methods make no verifiable assumptions about how representative the recruiting centres are to the population of centres in the jurisdiction. The second section uses data from a multicentre RCT to illustrate that cost-effectiveness estimates can be influenced by the sample of recruiting centres. Finally, we propose two concepts that may advance generalisability research. First, we distinguish between the 'research space' and the 'policy space' and argue that policy makers are interested in the latter, while current methods describe the former. Second, we propose a centre-specific generalisability index used at RCT design stage to address generalisability. We conclude that future research should focus on generalisability at RCT design stage rather than on post hoc analyses.


Assuntos
Análise Custo-Benefício/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Análise Custo-Benefício/normas , Humanos , Estudos Multicêntricos como Assunto/métodos , Seleção de Pacientes , Ensaios Clínicos Controlados Aleatórios como Assunto/normas
14.
PLoS One ; 8(10): e75132, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24116028

RESUMO

OBJECTIVE: To systematically evaluate the evidence across surgical specialties as to whether staples or sutures better improve patient and provider level outcomes. DESIGN: A systematic review of systematic reviews and panoramic meta-analysis of pooled estimates. RESULTS: Eleven systematic reviews, including 13,661 observations, met the inclusion criteria. In orthopaedic surgery sutures were found to be preferable, and for appendicial stump sutures were protective against both surgical site infection and post surgical complications. However, staples were protective against leak in ilecolic anastomosis. For all other surgery types the evidence was inconclusive with wider confidence intervals including the possibly of preferential outcomes for surgical site infection or post surgical complication for either staples or sutures. Whilst reviews showed substantial variation in mean differences in operating time (I(2) 94%) there was clear evidence of a reduction in average operating time across all surgery types. Few reviews reported on length of stay, but the three reviews that did (I(2) 0%, including 950 observations) showed a non significant reduction in length of stay, but showed evidence of publication bias (P-value for Egger test 0.05). CONCLUSIONS: Evidence across surgical specialties indicates that wound closure with staples reduces the mean operating time. Despite including several thousand observations, no clear evidence of superiority emerged for either staples or sutures with respect to surgical site infection, post surgical complications, or length of stay.


Assuntos
Procedimentos Ortopédicos/efeitos adversos , Grampeamento Cirúrgico/efeitos adversos , Infecção da Ferida Cirúrgica/etiologia , Técnicas de Sutura/efeitos adversos , Suturas/efeitos adversos , Humanos , Metanálise como Assunto , Resultado do Tratamento , Cicatrização
15.
Exp Mol Pathol ; 95(3): 343-9, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24161956

RESUMO

BACKGROUND: Formalin fixation, duration of tissue storage and tissue enrichment techniques can affect DNA methylation yield but these effects have not been quantitatively measured. The aim is to investigate the relative impact of these conditions on DNA methylation in rectal cancer. METHODS: 10 rectal cancers with matched undissected fresh frozen tissues, laser capture microdissected (LCM) formalin-fixed paraffin-embedded (FFPE) tissues, manual macrodissected FFPE tissues, adjacent normal mucosa and stromal tissues were analysed for APC and LINE-1 methylation using bisulphite pyrosequencing. RESULTS: FFPE cancer tissues, which had been stored for at least 4 years showed similar APC and LINE-1 methylation changes to matched fresh frozen cancer tissues. Laser capture microdissection did not increase the degree of methylation detected compared to manual macrodissection. Analysis of stromal tissues showed that they had undergone significant methylation changes compared to adjacent macroscopically normal mucosa, but not to the same extent as cancer tissues. CONCLUSION: Reliable DNA methylation results can be obtained from FFPE rectal cancer tissues, which have been in long-term storage. Because only minor differences in methylation between macrodissected and LCM cancer tissues were found, our results do not support the routine use of LCM to enrich for cancer cells for DNA methylation studies.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Metilação de DNA , Rim/patologia , Microdissecção e Captura a Laser , Elementos Nucleotídeos Longos e Dispersos/genética , Inclusão em Parafina , Neoplasias Retais/patologia , Células Estromais/patologia , Formaldeído/química , Humanos , Rim/metabolismo , Reação em Cadeia da Polimerase , Neoplasias Retais/genética , Células Estromais/metabolismo
16.
PLoS Genet ; 9(5): e1003488, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23671423

RESUMO

Serrated adenomas form a distinct subtype of colorectal pre-malignant lesions that may progress to malignancy along a different molecular pathway than the conventional adenoma-carcinoma pathway. Previous studies have hypothesised that BRAF mutation and promoter hypermethylation plays a role, but the evidence for this is not robust. We aimed to carry out a whole-genome loss of heterozygosity analysis, followed by targeted promoter methylation and expression analysis to identify potential pathways in serrated adenomas. An initial panel of 9 sessile serrated adenomas (SSA) and one TSA were analysed using Illumina Goldengate HumanLinkage panel arrays to ascertain regions of loss of heterozygosity. This was verified via molecular inversion probe analysis and microsatellite analysis of a further 32 samples. Methylation analysis of genes of interest was carried out using methylation specific PCR (verified by pyrosequencing) and immunohistochemistry used to correlate loss of expression of genes of interest. All experiments used adenoma samples and normal tissue samples as control. SSA samples were found on whole-genome analysis to have consistent loss of heterozygosity at 4p15.1-4p15.31, which was not found in the sole TSA, adenomas, or normal tissues. Genes of interest in this region were PDCH7 and SLIT2, and combined MSP/IHC analysis of these genes revealed significant loss of SLIT2 expression associated with promoter methylation of SLIT2. Loss of expression of SLIT2 by promoter hypermethylation and loss of heterozygosity events is significantly associated with serrated adenoma development, and SLIT2 may represent a epimutated tumour suppressor gene according to the Knudson "two hit" hypothesis.


Assuntos
Adenoma/genética , Neoplasias Colorretais/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas do Tecido Nervoso/genética , Adenoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/patologia , Metilação de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Ligação Genética , Humanos , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade
17.
Trials ; 12: 217, 2011 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-21970469

RESUMO

BACKGROUND: Surgical site infection (SSI) is a common complication following abdominal surgery. It is associated with considerable morbidity and mortality, and its management results in significant cost to health services within both primary and secondary care. Some surgeons believe that the use of a wound-edge protection device may reduce the incidence of SSI. Whilst there is some encouraging evidence showing that such devices may lead to a reduction in SSI, there are no controlled trials of sufficient size or quality to support their routine use. METHODS/DESIGN: 750 patients will be recruited from around 20 surgical units within the United Kingdom. Patients undergoing laparotomy through any major abdominal incision for any indication, elective or emergency, are eligible. Patients under the age of 18, those undergoing a laparoscopic assisted procedure or who have undergone laparotomy within the previous 3 months, and those who are unable to give informed consent will be excluded. Patients will be randomised (1:1 ratio) to the use of a wound-edge protection device or no wound-edge protection device during surgery. Follow up will consist of blinded clinical wound reviews at 5-7 days and 30-33 days postoperatively with a self-completed questionnaire covering the intervening period. Quality of life questionnaires will be completed prior to surgery and at the subsequent wound review points and information on resource usage will also be captured.The primary outcome measure is SSI within 30 days of surgery. Secondary outcomes include the impact of the degree of wound contamination, patient comorbidity, and operative characteristics on the efficacy of a wound-edge protection device in reducing SSI and whether the use of a wound-edge protection device has an effect on health-related quality of life or length of hospital stay and is cost-effective. DISCUSSION: Rossini is the first multicentre observer-blinded randomised controlled trial of sufficient size and quality to establish whether the use of a wound-edge protection device in adult patients undergoing abdominal surgery leads to a lower rate of SSI. The results of this study will be used to inform current surgical practice and may potentially benefit patients undergoing surgery in the future. TRIAL REGISTRATION NUMBER: Current Controlled Trials ISRCTN: ISRCTN40402832.


Assuntos
Protocolos Clínicos , Laparotomia , Infecção da Ferida Cirúrgica/prevenção & controle , Análise Custo-Benefício , Equipamentos e Provisões , Humanos , Avaliação de Resultados em Cuidados de Saúde
18.
Lancet ; 372(9651): 1756-64, 2008 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-18922570

RESUMO

BACKGROUND: Selective inhibition of cyclo-oxygenase-2 has been associated with an increased risk of cardiovascular events in several clinical trials. The Adenomatous Polyp Prevention on Vioxx (APPROVe) study assessed the effect of 3-year treatment with a cyclo-oxygenase-2 inhibitor, rofecoxib (25 mg), on recurrence of neoplastic polyps of the large bowel. We report the cardiovascular outcomes of a long-term follow-up of participants in the trial. METHODS: The APPROVe study is a multicentre, randomised, placebo-controlled, double-blind trial. 2587 patients with a history of colorectal adenomas were recruited at 108 centres worldwide during 2000 and 2001. Participants were followed for adverse events while on treatment and during the following 14 days. However, after early termination of treatment because of cardiovascular toxicity, we attempted to follow up all randomised patients for at least 1 year after stopping study treatment. External committees blindly assessed potential serious cardiovascular events. The focus of the analysis was the combined incidence of non-fatal myocardial infarction, non-fatal stroke, and death from cardiovascular, haemorrhagic, and unknown causes (Antiplatelet Trialists' Collaboration [APTC] combined endpoint). We used Cox proportional hazards regression to calculate endpoint hazard ratios. The study is registered with ClinicalTrials.gov, number NCT0282386. FINDINGS: We obtained extended post-treatment cardiovascular follow-up data from 84% of participants, and extended mortality follow-up from 95%. In total, 59 individuals had an APTC endpoint in the rofecoxib group and 34 in the placebo group (hazard ratio 1.79, 95% CI 1.17-2.73; p=0.006). In the first year after cessation of treatment, there was a non-significant increase in the risks of APTC endpoints. The APTC hazard ratio did not substantially change over time. INTERPRETATION: Use of rofecoxib is associated with increased rates of APTC events. Study data are compatible with an early increase in risk that persists for one year after stopping treatment.


Assuntos
Doenças Cardiovasculares/induzido quimicamente , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Lactonas/efeitos adversos , Sulfonas/efeitos adversos , Doenças Cardiovasculares/mortalidade , Neoplasias Colorretais/prevenção & controle , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Interpretação Estatística de Dados , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Lactonas/uso terapêutico , Masculino , Pessoa de Meia-Idade
19.
Dis Colon Rectum ; 50(2): 257-9, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17180254

RESUMO

Small-bowel adenocarcinoma is an uncommon tumor, comprising<2 percent of all gastrointestinal tract malignancies. These tumors are known to occur in association with Crohn's disease. To date, there have been only two documented cases of adenocarcinoma arising at the site of previous strictureplasty reported in the literature. We report the third such case in a patient with no other premalignant conditions affecting the small bowel and question whether we may see an increasing trend in this type of presentation.


Assuntos
Adenocarcinoma/patologia , Doença de Crohn/patologia , Doença de Crohn/cirurgia , Neoplasias Intestinais/patologia , Intestino Delgado/patologia , Humanos , Masculino , Pessoa de Meia-Idade
20.
Gastroenterology ; 131(6): 1674-82, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17087947

RESUMO

BACKGROUND & AIMS: In human and animal studies, nonsteroidal anti-inflammatory drugs have been associated with a reduced risk of colorectal neoplasia. Although the underlying mechanisms are unknown, inhibition of cyclooxygenase (COX), particularly COX-2, is thought to play a role. We conducted a randomized, placebo-controlled, double-blind trial to assess whether use of the selective COX-2 inhibitor rofecoxib would reduce the risk of colorectal adenomas. METHODS: We randomized 2587 subjects with a recent history of histologically confirmed adenomas to receive daily placebo or 25 mg rofecoxib. Randomization was stratified by baseline use of cardioprotective aspirin. Colonoscopic follow-up evaluation was planned for 1 and 3 years after randomization. The primary end point was all adenomas diagnosed during 3 years' treatment. In a modified intent-to-treat analysis, we computed the relative risk of any adenoma after randomization, using Mantel-Haenszel statistics stratified by low-dose aspirin use at baseline. RESULTS: Adenoma recurrence was less frequent for rofecoxib subjects than for those randomized to placebo (41% vs 55%; P < .0001; relative risk [RR], 0.76; 95% confidence interval [CI], 0.69-0.83). Rofecoxib also conferred a reduction in risk of advanced adenomas (P < .01). The chemopreventive effect was more pronounced in the first year (RR, 0.65; 95% CI, 0.57-0.73) than in the subsequent 2 years (RR, 0.81; 95% CI, 0.71-0.93). As reported previously, rofecoxib was associated with increased risks of significant upper gastrointestinal events and serious thrombotic cardiovascular events. CONCLUSIONS: In this randomized trial, rofecoxib significantly reduced the risk of colorectal adenomas, but also had serious toxicity.


Assuntos
Adenoma/prevenção & controle , Neoplasias Colorretais/prevenção & controle , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Lactonas/uso terapêutico , Sulfonas/uso terapêutico , Adenoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioprevenção/métodos , Colonoscopia , Neoplasias Colorretais/patologia , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Lactonas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sulfonas/efeitos adversos , Fatores de Tempo
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