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Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies are currently lacking. Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 (KRASG12) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRASG12 mutations were significantly associated with poor survival, also in analyses restricted to the RAS/RAF mutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800 patients) and found that KRASG12 mutations (n = 279) were predictive biomarkers for reduced overall survival (OS) benefit of FTD/TPI versus placebo (unadjusted interaction P = 0.0031, adjusted interaction P = 0.015). For patients with KRASG12 mutations in the RECOURSE trial, OS was not prolonged with FTD/TPI versus placebo (n = 279; hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.73-1.20; P = 0.85). In contrast, patients with KRASG13 mutant tumors showed significantly improved OS with FTD/TPI versus placebo (n = 60; HR = 0.29; 95% CI = 0.15-0.55; P < 0.001). In isogenic cell lines and patient-derived organoids, KRASG12 mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRASG12 mutations are biomarkers for reduced OS benefit of FTD/TPI treatment, with potential implications for approximately 28% of patients with mCRC under consideration for treatment with FTD/TPI. Furthermore, our data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Demência Frontotemporal , Neoplasias Retais , Humanos , Proteínas Proto-Oncogênicas p21(ras)/genética , Uracila/uso terapêutico , Trifluridina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Pirrolidinas/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias Retais/tratamento farmacológico , Combinação de Medicamentos , Mutação/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
OBJECTIVE: Oesophageal cancer patients have complex care needs. Cancer clinical nurse specialists play a key role in coordinating their care but often have heavy workloads. Digital health interventions can improve patient care but there are few examples for oesophageal cancer. This paper aims to describe the multidisciplinary co-design process of a digital health intervention to improve the experience of care and reduce unmet needs among patients with oesophageal cancer. METHODS: A theory-based, multi-disciplinary, co-design approach was used to inform the developmental process of the digital health intervention. Key user needs were elicited using mixed methodology from systematic reviews, focus groups and interviews and holistic need assessments. Overarching decisions were discussed among a core team of patients, carers, health care professionals including oncologists and cancer clinical nurse specialists, researchers and digital health providers. A series of workshops incorporating a summary of findings of key user needs resulted in the development of a minimum viable product. This was further refined after a pilot study based on feedback from end users. RESULTS: The final digital health intervention consists of a mobile app feature for patients and carers connected to a dashboard with supporting additional features for clinical nurse specialist. It contains a one-way messaging function for clinical nurse specialists to communicate with patients, functions for patients to record weight and holistic need assessment results which could be viewed by their clinical nurse specialists as well as a library of informative articles. CONCLUSIONS: The multidisciplinary co-design of a digital health intervention providing support for oesophageal cancer patients and health care professionals has been described. Future studies to establish its impact on patient outcomes are planned.
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INTRODUCTION: Heart failure (HF) in hypertrophic cardiomyopathy (HCM) is associated with high morbidity and mortality. Predictors of HF, in particular the role of myocardial fibrosis and microvascular ischemia remain unclear. We assessed the predictive value of cardiovascular magnetic resonance (CMR) for development of HF in HCM in an observational cohort study. METHODS: Serial patients with HCM underwent CMR, including adenosine first-pass perfusion, left atrial (LA) and left ventricular (LV) volumes indexed to body surface area (i) and late gadolinium enhancement (%LGE- as a % of total myocardial mass). We used a composite endpoint of HF death, cardiac transplantation, and progression to NYHA class III/IV. RESULTS: A total of 543 patients with HCM underwent CMR, of whom 94 met the composite endpoint at baseline. The remaining 449 patients were followed for a median of 5.6 years. Thirty nine patients (8.7%) reached the composite endpoint of HF death (n = 7), cardiac transplantation (n = 2) and progression to NYHA class III/IV (n = 20). The annual incidence of HF was 2.0 per 100 person-years, 95% CI (1.6-2.6). Age, previous non-sustained ventricular tachycardia, LV end-systolic volume indexed to body surface area (LVESVI), LA volume index ; LV ejection fraction, %LGE and presence of mitral regurgitation were significant univariable predictors of HF, with LVESVI (Hazard ratio (HR) 1.44, 95% confidence interval (95% CI) 1.16-1.78, p = 0.001), %LGE per 10% (HR 1.44, 95%CI 1.14-1.82, p = 0.002) age (HR 1.37, 95% CI 1.06-1.77, p = 0.02) and mitral regurgitation (HR 2.6, p = 0.02) remaining independently predictive on multivariable analysis. The presence or extent of inducible perfusion defect assessed using a visual score did not predict outcome (p = 0.16, p = 0.27 respectively). DISCUSSION: The annual incidence of HF in a contemporary ambulatory HCM population undergoing CMR is low. Myocardial fibrosis and LVESVI are strongly predictive of future HF, however CMR visual assessment of myocardial perfusion was not.
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Cardiomiopatia Hipertrófica/diagnóstico por imagem , Circulação Coronária , Insuficiência Cardíaca/etiologia , Imageamento por Ressonância Magnética , Microcirculação , Imagem de Perfusão do Miocárdio , Miocárdio/patologia , Adulto , Idoso , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/patologia , Cardiomiopatia Hipertrófica/fisiopatologia , Progressão da Doença , Feminino , Fibrose , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Volume Sistólico , Fatores de Tempo , Função Ventricular EsquerdaRESUMO
BACKGROUND: Post-thrombotic syndrome is a common complication of iliofemoral deep venous thrombosis (IFDVT). Existing evidence and National Institute for Health and Care Excellence guidelines suggest that this can be reduced by prompt thrombolytic therapy or thrombectomy. We aimed to evaluate the characteristics of IFDVT patients and to identify whether patients are being offered the recommended treatment pathway. METHODS: A multicenter cross-sectional study was conducted across eight hospital sites in the North West London region, of which two were hub hospitals in their local vascular service networks. Patients with proximal DVT were identified using International Classification of Diseases, Tenth Revision coding during a 1-year period. Data on demographics, diagnostic methods used, interventions, and referrals were extracted from electronic and paper medical records. RESULTS: During the study period, 132 patients with IFDVT were identified (mean age, 59.4 years; 55% female); 75% of these patients had an IFDVT. In this cohort, the biggest predisposing factors were previous DVT (n = 35), malignant disease (n = 35), and immobility (n = 20). In total, 104 patients were administered anticoagulation, and 88 of these patients received anticoagulation within 24 hours. The cases of 45 patients were either discussed with or promptly referred to a vascular service, after which 20 patients were treated solely with anticoagulation, whereas 20 patients received thrombolysis of varying methods. CONCLUSIONS: A significant proportion (56%) of symptomatic IFDVT patients are not being appropriately referred to or discussed with vascular services. Of these, 43% would have been eligible for consideration of early thrombus removal. Adherence to the National Institute for Health and Care Excellence guidelines could be improved by increasing awareness among emergency department colleagues.
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Anticoagulantes/uso terapêutico , Veia Femoral , Veia Ilíaca , Padrões de Prática Médica , Encaminhamento e Consulta , Terapia Trombolítica , Trombose Venosa/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Estudos Transversais , Feminino , Veia Femoral/diagnóstico por imagem , Fidelidade a Diretrizes , Humanos , Veia Ilíaca/diagnóstico por imagem , Londres , Masculino , Pessoa de Meia-Idade , Síndrome Pós-Trombótica/etiologia , Síndrome Pós-Trombótica/prevenção & controle , Guias de Prática Clínica como Assunto , Terapia Trombolítica/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Trombose Venosa/complicações , Trombose Venosa/diagnóstico por imagemRESUMO
PURPOSE: Serum sodium derangement is the most common electrolyte disturbance among patients admitted to intensive care. This study aims to validate the association between dysnatremia and serum sodium fluctuation with mortality in surgical intensive care patients. METHOD: We performed a retrospective analysis of the Medical Information Mart for Intensive Care II database. Dysnatremia was defined as a sodium concentration outside physiologic range (135-145mmol/L) and subjects were categorized by severity of dysnatremia and sodium fluctuation. Univariate and multivariable logistic regressions were used to test for associations between sodium fluctuations and mortality. RESULTS: We identified 8600 subjects, 39% of whom were female, with a median age of 66years for analysis. Subjects with dysnatremia were more likely to be dead at 28 days (17% vs 7%; P<.001). There was a significant association between sodium fluctuation and mortality at 28 days (adjusted odds ratio per 1mmol/L change, 1.10 [95% confidence interval, 1.08-1.12; P<.001]), even in patients who remained normotremic during their intensive care unit stay (1.12 [95% confidence interval, 1.09-1.16; P<.001]) CONCLUSIONS: This observational study validates previous findings of an association between serum sodium fluctuations and mortality in surgical intensive care patients. This association was also present in subjects who remained normonatremic throughout their intensive care unit admission.
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Sódio/sangue , Procedimentos Cirúrgicos Operatórios/mortalidade , Desequilíbrio Hidroeletrolítico/mortalidade , Idoso , Idoso de 80 Anos ou mais , Cuidados Críticos , Bases de Dados Factuais , Inglaterra , Feminino , Mortalidade Hospitalar , Humanos , Unidades de Terapia Intensiva , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Período Pós-Operatório , Estudos Retrospectivos , Medicina Estatal , Desequilíbrio Hidroeletrolítico/sangueRESUMO
BACKGROUND: Social media use is growing inexorably, and there is public appetite for evidence-based information. Little is known about engagement by plastic surgeons with social media. The aim of this study was to examine posting about plastic surgery on Twitter, to best inform how board-certified plastic surgeons could use the hashtag #PlasticSurgery as a tool to educate patients and the public. METHODS: A prospective analysis of 2880 "tweets" containing the words "plastic surgery" was performed. The following were assessed: identity of author, use of the hashtag #PlasticSurgery, subject matter, whether link to study was provided, and whether posts by surgeons were self-promotional or educational. RESULTS: Social media posting about plastic surgery is dominated by the public, accounting for 70.6 percent of posts versus only 6.0 percent by plastic surgeons. Only 5.4 percent of all tweets contained the hashtag #PlasticSurgery, although almost half of those that did were by plastic surgeons. Of these, 61.3 percent of posts by plastic surgeons were about aesthetic surgery; additional posts were about basic science, patient safety, and reconstruction (13.9, 4.0, and 2.3 percent, respectively). Eighteen scientific articles were referenced, with a link to the Journal site posted in two tweets. Of posts by plastic surgeons, 37.0 percent were self-promotional. CONCLUSIONS: The American Society of Plastic Surgeons and its Journal have recognized that social media may be used to educate and engage. Board-certified plastic surgeons have a great opportunity to promote evidence-based plastic practice by means of #PlasticSurgery in the interests of supporting patients and the profession.