Real-world treatment sequencing and survival in previously treated advanced renal cell carcinoma patients receiving nivolumab monotherapy: a UK retrospective cohort study.

BACKGROUND: The CheckMate 025 trial established nivolumab monotherapy as one of the standards of care in previously treated advanced or metastatic renal cell carcinoma (aRCC). However, supporting real-world data is lacking. This study investigated characteristics, treatment sequences and clinical outcomes of patients who received nivolumab monotherapy for previously treated aRCC in the UK. METHODS: This was a retrospective cohort study of aRCC patients treated with nivolumab at second line or later (2L +) at 4 UK oncology centres. Eligible patients commenced nivolumab (index date) between 01 March 2016 and 30 June 2018 (index period). Study data were extracted from medical records using an electronic case report form. Data cut-off (end of follow-up) was 31 May 2019. RESULTS: In total, 151 patients were included with median follow-up of 15.2 months. Mean age was 66.9 years, male preponderance (72.2%), and mostly Eastern Cooperative Oncology Group performance status grade 0-1 (71.5%). Amongst 112 patients with a known International Metastatic RCC Database Consortium score, distribution between favourable, intermediate, and poor risk categories was 20.5%, 53.6%, and 25.9% respectively. The majority of patients (n = 109; 72.2%) received nivolumab at 2L, and these patients had a median overall survival (OS) of 23.0 months [95% confidence interval: 17.2, not reached]. All patients who received nivolumab at 2L had received TKIs at 1L. Amongst the 42 patients (27.8%) who received nivolumab in third line or later (3L +) the median OS was 12.4 months [95% CI: 8.8, 23.2]. The most common reasons for nivolumab discontinuation were disease progression (2L: 61.2%; 3L: 68.8%) and adverse events (2L: 34.7%; 3L: 28.1%). CONCLUSION: This study provides real-world evidence on the characteristics, treatment sequences, and outcomes of aRCC patients who received 2L + nivolumab monotherapy in the UK. Nivolumab-specific survival outcomes were similar to those achieved in the CheckMate 025 trial.

Tackling the burden of the hepatitis C virus in the UK: characterizing and assessing the clinical and economic consequences.

OBJECTIVES: The hepatitis C virus (HCV) remains a significant public health issue. This study aimed to quantify the clinical and economic burden of chronic hepatitis C in the UK, stratified by disease severity, age and awareness of infection, with concurrent assessment of the impact of implementing a treatment prioritization approach. STUDY DESIGN AND METHODS: A previously published back projection, natural history and cost-effectiveness HCV model was adapted to a UK setting to estimate the disease burden of chronic hepatitis C and end-stage liver disease (ESLD) between 1980 and 2035. A published meta-regression analysis informed disease progression, and UK-specific data informed other model inputs. RESULTS: At 2015, prevalence of chronic hepatitis C is estimated to be 241,487 with 22.20%, 33.72%, 17.22%, 16.67% and 10.19% of patients in METAVIR stages F0, F1, F2, F3 and F4, respectively, but is estimated to fall to 193,999 by 2035. ESLD incidence is predicted to peak in 2031. Assuming all patients are diagnosed and treatment is prioritized in F3 and F4 using highly efficacious direct-acting antiviral (DAA) regimens, a 69.85% reduction in ESLD incidence is predicted between 2015 and 2035, and the cumulative discounted medical expenditure associated with the lifetime management of incident ESLD events is estimated to be £1,202,827,444. CONCLUSIONS: The prevalence of chronic hepatitis C is expected to fall in coming decades; however, the ongoing financial burden is expected to be high due to an increase in ESLD incidence. This study highlights the significant costs of managing ESLD that are likely to be incurred without the employment of effective treatment approaches.

Advances in the management of severe aortic stenosis.

BACKGROUND: Recent developments in the management of severe aortic stenosis have resulted in a paradigm shift in the way we view the condition. Patients previously denied intervention in the form of surgical aortic valve replacement (SAVR) are now candidates for transcatheter aortic valve implantation and the risk and age profiles of those undergoing SAVR are rising with the ageing population. This review article is designed to provide an overview of developments in the surgical management of severe aortic stenosis. We also discuss the expanding role of minimally invasive surgical approaches to outline the current techniques available to treat patients with severe aortic stenosis. METHODS: PubMed was searched using the terms 'severe aortic stenosis', 'surgical aortic valve replacement', 'transcatheter aortic valve replacement', 'mechanical aortic valve replacement' and 'sutureless aortic valve replacement'. Selection of articles was based on peer review, journal and relevance. Where possible articles from high-impact factor peer review journals were included. RESULTS: Minimally invasive operative approaches include mini-sternotomy and mini-thoracotomy. Sutureless aortic prostheses reduce aortic cross-clamp time and cardiopulmonary bypass time; however, long-term follow-up data are unavailable at this time. Mechanical prostheses are advised for those under 60. CONCLUSION: Multiple advances in the surgical management of aortic stenosis have occured in the past decade. An evolving spectrum of surgical and transcatheter interventions is now available depending on patient age and operative risk.

Experience of a high-risk aortic valve clinic in Ireland.

BACKGROUND: The advent of transcatheter aortic valve implantation (TAVI) has broadened the management options for severe aortic stenosis. The indications for TAVI are narrow. Selecting those that will benefit most from this intervention warrants careful consideration and input from cardiologists, anaesthetists and cardiac surgeons familiar with TAVI and surgical aortic valve replacement (SAVR). AIMS: The aims of this paper were to assess the feasibility of establishing a high-risk aortic clinic in Ireland, and report stratification of the referred group into those suitable for SAVR, TAVI and conservative management. METHODS: Patient data was prospectively collected by a dedicated clinical nurse specialist. ANOVA was used to assess variance in means between groups. Analyses were performed using IBM SPSS v20 (Armonk, NY: IBM Corp.). RESULTS: A total of 105 patients were assessed. Eighty-five patients were deemed suitable for TAVI, 9 (10.5 %) died awaiting the procedure and a further 6 (7 %) declined intervention. Eleven (10.5 %) underwent conventional SAVR, 1 (0.9 %) a balloon valvuloplasty, 4 (3.8 %) entered surveillance and 4 (3.8 %) were declined treatment. CONCLUSIONS: Establishment of a high-risk aortic clinic is feasible in the Irish context. The advent of TAVI has reduced the proportion of patients denied intervention to a minority. Despite being considered high risk, a number of patients were suitable candidates for SAVR. Measuring frailty continues to provide a challenge; a TAVI-specific frailty assessment tool would be advantageous to patient stratification.

A multicentre analysis of troponin use in clinical practice.

BACKGROUND: The role of troponin quantification in evaluation of patients with suspected acute coronary syndrome is established, but with cost implications. Emerging high-sensitivity troponin and novel multi-marker assays herald further resource implications. AIMS: The objective of this study was to quantify recent trends in troponin usage and costs in a cross-section of hospitals. METHODS: A cross-sectional survey seeking data on troponin usage and costs from six tertiary referral, public access teaching hospitals for consecutive years between 2003 and 2009 was carried out. RESULTS: A median annual increase in the volume of troponin assays requested was identified in all six hospitals, with an average median annual increase of 6.9 % across hospitals (interquartile range 3.4, 10.1 %). This annual increase was not accompanied by a corresponding increase in volume of patients presenting to the Emergency Department (ED) with chest pain. The majority (44-67 %) of troponin requests originated in the ED of hospitals. The median annual spend on troponins per hospital was 115,612 (interquartile range 80,452, 140,918). An analysis of results of assays performed in one centre found that the majority (91 %) of troponin assays performed were in the normal range. CONCLUSIONS: An annual increase in troponin requests without a corresponding increase in patient activity raises the possibility of increasingly indiscriminate troponin testing. The cumulative direct and indirect costs of inappropriate testing are significant. Corrective strategies are necessary to improve patient selection and testing protocols, particularly in the advent of the high-sensitivity troponin assays and novel multi-marker strategies.

Cardiovascular disease burden in acute public hospitals in Ireland: estimates for 2021 and 2031.

BACKGROUND: Ireland is undergoing a demographic shift to a higher proportion of older people in the population. It is expected that this demographic shift will significantly increase the burden of care on an already overstretched acute hospitals system. AIM: This study was conducted to estimate the future burden of care on acute public hospitals pertaining to 'diseases of the circulatory system' and 'procedures on cardiovascular system' in Ireland using Hospital In-Patient Enquiry (HIPE) data for 2006 and population projections for 2021 and 2031. METHODS: Age-specific rates derived from HIPE data for 2006 and census figures for the same year were applied to population projections for 2021 and 2031 to get case number estimates in those years. RESULTS: The number of discharges with a primary diagnosis of diseases of the circulatory system is estimated to increase by 51 % by 2021 and 97 % by 2031 relative to 2006 figures. For people aged 65+ years, case numbers are estimated to increase by 65 % by 2021 and 133 % by 2031 relative to 2006 case numbers. The number of procedures performed is estimated to increase by 47 % by 2021 and 82 % by 2031 relative to 2006 figures. For people aged 65+ years, case numbers are estimated to increase by 63 % by 2021 and 120 % by 2031 relative to 2006 case numbers. CONCLUSION: The results reflect the aging of the Irish population. The expected increases in case numbers will pose significant burden on acute public hospitals and the cost of providing care.

Structural neural phenotype of autism: preliminary evidence from a diffusion tensor imaging study using tract-based spatial statistics.

BACKGROUND AND PURPOSE: There is mounting evidence suggesting widespread aberrations in neural connectivity as the underlying neurobiology of autism. Using DTI to assess white matter abnormalities, this study implemented a voxelwise analysis and tract-labeling strategy to test for a structural neural phenotype in autism. MATERIALS AND METHODS: Subjects included 15 boys with autism and 8 controls, group-matched on age, cognitive functioning, sex, and handedness. DTI data were obtained by using a 3T scanner. FSL, including TBSS, was used to process and analyze DTI data where FA was chosen as the primary measure of fiber tract integrity. Affected voxels were labeled by using an integrated white matter tractography atlas. Post hoc correlation analyses were performed between FA of each affected fiber tract and scores on the Social Responsiveness Scale. RESULTS: The autism group exhibited bilateral reductions in FA involving numerous association, commissural, and projection tracts, with the most severely affected being the forceps minor. The most affected association tracts were the inferior fronto-occipital fasciculus and superior longitudinal fasciculus. There were no areas of increased FA in the autism group. All post hoc correlation analyses became nonsignificant after controlling for multiple comparisons. CONCLUSIONS: This study provides preliminary evidence of reduced FA along many long-range fiber tracts in autism, suggesting aberrant long-range corticocortical connectivity. Although the spatial distribution of these findings suggests widespread abnormalities, there are major differences in the degree to which different tracts are affected, suggesting a more specific neural phenotype in autism.

Increasing cardiac interventions among the aged.

Ireland's over 65 year population is growing. As incidence of coronary events rises with age, there is a growing population of elderly patients with cardiac disease. The changing age profile of patients treated by a tertiary hospital's Cardiology service was quantified using Hospital Inpatient Enquiry data. 53% of CCU admissions were aged > or = 65 years, with admissions aged > or = 85 years in 2008 four times greater than in 2002. Percentages of patients undergoing diagnostic coronary angiography and percutaneous coronary interventions in 1997 aged > or = 70 years were 19% and 18% respectively. By 2007, these percentages had risen to 31% and 34% respectively--greatest increases were in the very elderly age categories. The proportion of ICD recipients aged > 70 years increased from 8% in 2003 to 25% by 2008. The proportion of elderly patients receiving advanced cardiac care is increasing. This trend will continue and has clear resource implications. Outcomes of interventions in the very old need further investigation, since the 'old old' are under-represented in clinical trials.

Isolated chylopericardium.

A 25-year-old male was discovered to have an asymptomatic pericardial effusion during routine pre-employment medical evaluation. During pericardiocentesis 1200 ml of milky-white fluid was obtained; subsequent biochemical evaluation confirmed the chylous nature of this fluid. Following thorough evaluation a diagnosis of isolated chylopericardium was made. Following several recurrences he underwent thoracotomy with ligation of the thoracic duct and creation of a pericardial window. There are relatively few published reports of true isolated chylopericardium and the aetiology and pathogenesis remain unknown. A primary abnormality of the thoracic lymphatic valve system is postulated. The most effective treatment is surgical with ligation of the thoracic duct above the diaphragm and creation of a pericardial window

The consensus-based classification of female sexual dysfunction: barriers to universal acceptance.

Although the CCFSD attempts to clarify and modify the existing definitions of female sexual dysfunctions, the current authors (a sex therapist and a sex researcher) believe that the classification system has significant flaws that will prevent its widespread acceptance and application. The major concern is that the CCFSD is based on the triphasic model of sexual response. The triphasic model is based on male sexual response and does not take into account the documented variety of ways that women respond sexually. Instead, the parameters of male sexual response are extrapolated to women. The current authors suggest an alternative approach that considers a woman's subjective as well as physiological responses, and includes pleasure and satisfaction as characteristics of normal sexual function. A reconsideration of the CCFSD model is suggested and an alternative approach is offered.

Gender differences in the management and outcome of acute myocardial infarction in unselected patients in the thrombolytic era.

This study compares the clinical features, management, and outcome in men and women from a consecutive, unselected series of patients with acute myocardial infarction (AMI) who were admitted to a university cardiac center over a 3-year period. It is a retrospective observational study of 1,059 admissions with AMI identified through the Hospital In-Patient Enquiry (HIPE) registry, validated according to Minnesota Manual criteria, and followed for a period of up to 5 years (median 36 months). Women comprised 40% of all admissions, had a higher hospital mortality (24% vs. 16%, p<0.001), and were less likely to receive thrombolysis (23% vs. 33%, p<0.01), admission to coronary care (65% vs. 77%, p<0.001), or subsequent invasive or noninvasive investigations (55% vs. 63%, p<0.01). However, women with AMI were older than men with AMI (71 vs. 65 years, p<0.001). After adjusting for age, differences that remained significant were prevalence of hypertension (odds ratio [OR] 2.12, 95% confidence intervals [CI] 1.56 to 2.88) and cigarette smoking (OR 0.47, 95% CI 0.35 to 0.65), management in coronary care (OR 0.66, 95% CI 0.49 to 0.88), and hospital mortality (OR 1.48, 95% CI 1.07 to 2.04). Excess mortality occurred predominantly in women <65 years old (18% vs. 8%, OR [multivariate] 2.35, 95% CI 1.19 to 4.56), among whom multivariate analysis demonstrated a significantly lower thrombolysis rate (OR 0.48, 95% CI 0.27 to 0.86). In this group, lack of thrombolysis independently predicted hospital mortality (OR 5.37, 95% CI 1.45 to 19.82). Female gender was not an independent predictor of mortality following AMI (OR 1.42, 95% CI 0.90 to 2.26). Thus, among unselected patients, female gender is associated with, but not an independent predictor of, reduced survival after AMI. Gender differences in mortality are greatest in younger patients, who are less likely to receive thrombolysis and in whom lack of thrombolysis is independently associated with mortality after AMI.

Characteristics and outcomes in patients with acute myocardial infarction with ST-segment depression on initial electrocardiogram.

BACKGROUND: Acute myocardial infarction (AMI) with nonreciprocal ST-segment depression is said to have a poor prognosis, and early diagnosis and treatment are problematic. The aim of this study was to determine the proportion of unselected consecutive patients admitted to a university center with AMI with nonreciprocal ST-segment depression and to characterize these patients in terms of clinical features, treatment, and short- and long-term prognoses. METHODS AND RESULTS: Admission electrocardiographic data on 852 consecutive admissions with AMI were analyzed. Nonreciprocal ST-depression was an admitting feature in 95 (11%) patients, the majority of whom had ST depression >3 mm. These were older (70.3 vs 66.8 years, P <.05), more likely to have had myocardial infarction (40% vs 25%, P <.01), and to have left ventricular failure (56% vs 42%, P <.5), cardiogenic shock (15% vs 9% P =.06), and atrial fibrillation (34% vs 19%, P <.01). Hospital mortality rate was significantly higher (31% vs 17%, P <.01). Patients were less likely to undergo thrombolysis (17% vs 31%, P <.01), angiography (22% vs 35%, P <.05), or percutaneous revascularization (5% vs 9%, P <.01). Patients with ST depression undergoing coronary angiography were more likely to have 3-vessel disease (71% vs 47%, P <.05). Mortality rate at follow-up (median 36 months) was significantly higher in patients with ST depression (56% vs 32%, P <.001). Analysis by individual electrocardiography demonstrated ST-segment depression to be the third most frequent presentation after ST elevation (n = 327) and T-wave changes (n = 258), in whom hospital mortality rates were 24% and 9%, respectively. In multivariate analysis, previous myocardial infarction was an independent predictor of nonreciprocal ST depression at initial examination (odds ratio 2.04 [1.25 to 3.34], P <.005). No electrocardiographic presentation was an independent predictor of death in the hospital after AMI. CONCLUSIONS: In unselected cases of AMI, patients with ST-segment depression make up a significant minority (11%), who are likely to be older with a high prevalence of previous myocardial infarction and multivessel disease, and who have a poor prognosis.

Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial.

BACKGROUND: Bolus fibrinolytic therapy facilitates early efficient institution of reperfusion therapy. Tenecteplase is a genetically engineered variant of alteplase with slower plasma clearance, better fibrin specificity, and high resistance to plasminogen-activator inhibitor-1. We did a double-blind, randomised, controlled trial to assess the efficacy and safety of tenecteplase compared with alteplase. METHODS: In 1021 hospitals, we randomly assigned 16,949 patients with acute myocardial infarction of less than 6 h duration rapid infusion of alteplase (< or = 100 mg) or single-bolus injection of tenecteplase (30-50 mg according to bodyweight). All patients received aspirin and heparin (target activated partial thromboplastin time 50-75 s). The primary outcome was equivalence in all-cause mortality at 30 days. FINDINGS: Covariate-adjusted 30-day mortality rates were almost identical for the two groups--6.18% for tenecteplase and 6.15% for alteplase. The 95% one-sided upper boundaries of the absolute and relative differences in 30-day mortality were 0.61% and 10.00%, respectively, which met the prespecified criteria of equivalence (1% absolute or 14% relative difference in 30-day mortality, whichever difference proved smaller). Rates of intracranial haemorrhage were similar (0.93% for tenecteplase and 0.94% for alteplase), but fewer non-cerebral bleeding complications (26.43 vs 28.95%, p=0.0003) and less need for blood transfusion (4.25 vs 5.49%, p=0.0002) were seen with tenecteplase. The rate of death or non-fatal stroke at 30 days was 7.11% with tenecteplase and 7.04% with alteplase (relative risk 1.01 [95% CI 0.91-1.13]). INTERPRETATION: Tenecteplase and alteplase were equivalent for 30-day mortality. The ease of administration of tenecteplase may facilitate more rapid treatment in and out of hospital.

Regulation of leukocyte trafficking by lipoxins.

Lipoxins are lipoxygenase interaction products formed by transcellular metabolism during host defence and inflammation. In model systems, lipoxins modulate polymorphonuclear leukocytes (PMN) chemotaxis, adhesion molecule expression, inhibit PMN-endothelial cell adhesion, and attenuate cytokine release from epithelial cells. These observations raise the possibility that lipoxins are 'stop signals' for PMN-mediated tissue injury and promote the resolution of acute inflammation.