Contemporary management of mesothelioma.

Pleural mesothelioma (PM) is an aggressive asbestos-associated thoracic malignancy with a median survival of 12-18 months. Due to continued asbestos use in many nations, global incidence is rising. Causes due to non-occupational, environmental exposure are also rising in many countries despite utilisation bans. For many years, platinum--pemetrexed chemotherapy was the solitary licensed therapy, but first-line combination immune checkpoint blockade has recently demonstrated improved outcomes, with both regimes tested in predominantly late-stage cohorts. In the second-line setting, single-agent nivolumab has been shown to extend survival and is now available for routine use in some regions, while second-line chemotherapy has no proven role and opportunities for clinical trials should be maximised in relapsed disease. Surgery for "technically resectable" disease has been offered for decades in many expert centres, but the recent results from the phase III MARS2 trial have challenged this approach. There remains no robustly proven standard of care for early-stage PM. The clinical trial landscape for PM is complex and increasingly diverse, making further development of specialist PM multidisciplinary teams an important priority in all countries. The observation of improving outcomes in centres that have adopted this service model emphasises the importance of high-quality diagnostics and equitable access to therapies and trials. Novel therapies targeting a range of aberrations are being evaluated; however, a better understanding of the molecular drivers and their associated vulnerabilities is required to identify and prioritise treatment targets.

Staging by Thoracoscopy in potentially radically treatable Lung Cancer associated with Minimal Pleural Effusion (STRATIFY): protocol of a prospective, multicentre, observational study.

INTRODUCTION: Recurrence rate following radical therapy for lung cancer remains high, potentially reflecting occult metastatic disease, and better staging tools are required. Minimal pleural effusion (mini-PE) is associated with particularly high recurrence risk and is defined as an ipsilateral pleural collection (<1/3 hemithorax on chest radiograph), which is either too small to safely aspirate fluid for cytology using a needle, or from which fluid cytology is negative. Thoracoscopy (local anaesthetic thoracoscopy (LAT) or video-assisted thoracoscopic surgery (VATS)) is the gold-standard diagnostic test for pleural malignancy in patients with larger symptomatic effusions. Staging by Thoracoscopy in potentially radically treatable Lung Cancer associated with Minimal Pleural Effusion (STRATIFY) will prospectively evaluate thoracoscopic staging in lung cancer associated-mini-PE for the first time. METHODS AND ANALYSIS: STRATIFY is a prospective multicentre observational study. Recruitment opened in January 2020. The primary objective is to determine the prevalence of detectable occult pleural metastases (OPM). Secondary objectives include assessment of technical feasibility and safety, and the impact of thoracoscopy results on treatment plans, overall survival and recurrence free survival. Inclusion criteria are (1) suspected/confirmed stages I-III lung cancer, (2) mini-PE, (3) Performance Status 0-2 (4), radical treatment feasible if OPM excluded, (5) ≥16 years old and (6) informed consent. Exclusion criteria are any metastatic disease or contraindication to the chosen thoracoscopy method (LAT/VATS). All patients have LAT or VATS within 7 (±5) days of registration, with results returned to lung cancer teams for treatment planning. Following an interim analysis, the sample size was reduced from 96 to 50, based on a lower-than-expected OPM rate. An MRI substudy was removed in November 2022 due to pandemic-related site setup/recruitment delays. These also necessitated a no-cost recruitment extension until October 2023. ETHICS AND DISSEMINATION: Protocol approved by the West of Scotland Research Ethics Committee (Ref: 19/WS/0093). Results will be published in peer-reviewed journals and presented at international meetings. TRIAL REGISTRATION NUMBER: ISRCTN13584097.

Shock Index Predicts Outcome in Patients with Suspected Sepsis or Community-Acquired Pneumonia: A Systematic Review.

BACKGROUND: To improve outcomes for patients who present to hospital with suspected sepsis, it is necessary to accurately identify those at high risk of adverse outcomes as early and swiftly as possible. To assess the prognostic accuracy of shock index (heart rate divided by systolic blood pressure) and its modifications in patients with sepsis or community-acquired pneumonia. METHODS: An electronic search of MEDLINE, EMBASE, Allie and Complementary Medicine Database (AMED), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Open Grey, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (WHO ITRP) was conducted from conception to 26th March 2019. Eligible studies were required to assess the prognostic accuracy of shock index or its modifications for outcomes of death or requirement for organ support either in sepsis or pneumonia. The methodological appraisal was carried out using the Downs and Black checklist. Evidence was synthesised using a narrative approach due to heterogeneity. RESULTS: Of 759 records screened, 15 studies (8697 patients) were included in this review. Shock index ≥ 1 at time of hospital presentation was a moderately accurate predictor of mortality in patients with sepsis or community-acquired pneumonia, with high specificity and low sensitivity. Only one study reported outcomes related to organ support. CONCLUSIONS: Elevated shock index at time of hospital presentation predicts mortality in sepsis with high specificity. Shock index may offer benefits over existing sepsis scoring systems due to its simplicity.

Are Early Warning Scores Useful Predictors for Mortality and Morbidity in Hospitalised Acutely Unwell Older Patients? A Systematic Review.

BACKGROUND: Early warning scores (EWSs) are used to identify deteriorating patients for appropriate interventions. We performed a systematic review to examine the usefulness of EWSs in predicting inpatient mortality and morbidity (transfer to higher-level care and length of hospital stay) in older people admitted to acute medical units with sepsis, acute cardiovascular events, or pneumonia. METHODS: A systematic review of published and unpublished databases was conducted. Cochrane's tool for assessing Risk of Bias in Non-Randomised Studies-of Interventions (ROBINS-I) was used to appraise the evidence. A narrative synthesis was performed due to substantial heterogeneity. RESULTS: Five studies (n = 12,057) were eligible from 1033 citations. There was an overall "moderate" risk of bias for all studies. The predictive ability of EWSs regarding mortality was reported in one study (n = 274), suggesting EWSs were better at predicting survival, (negative predictive value >90% for all scores). Three studies (n = 1819) demonstrated a significant association between increasing modified EWSs (MEWSs) and increased risk of mortality. Hazards ratios for a composite death/intensive care (ICU) admission with MEWSs ≥5 were significant in one study (p = 0.003). Two studies (n = 1421) demonstrated that a MEWS ≥6 was associated with 21 times higher probability of mortality (95% Confidence Interval (CI): 2.71⁻170.57) compared with a MEWS ≤1. A MEWS of ≥5 was associated with 22 times higher probability of mortality (95% CI: 10.45⁻49.16). CONCLUSION: Increasing EWSs are strongly associated with mortality and ICU admission in older acutely unwell patients. Future research should be targeted at better understanding the usefulness of high and increasing EWSs for specific acute illnesses in older adults.

Has primary care antimicrobial use really been increasing? Comparison of changes in different prescribing measures for a complete geographic population 1995-2014.

Objectives: To elucidate how population trends in total antimicrobials dispensed in the community translate into individual exposure. Methods: Retrospective, population-based observational study of all antimicrobial prescribing in a Scottish region in financial years 1995, 2000 and 2005-14. Analysis of temporal changes in all antimicrobials and specific antimicrobials measured in: WHO DDD per 1000 population; prescriptions per 1000 population; proportion of population with ≥1 prescription; mean number of prescriptions per person receiving any; mean DDD per prescription. Results: Antimicrobial DDD increased between 1995 and 2014, from 5651 to 6987 per 1000 population [difference 1336 (95% CI 1309-1363)]. Prescriptions per 1000 fell (from 821 to 667, difference -154, -151 to -157), as did the proportion prescribed any antimicrobial [from 39.3% to 30.8% (-8.5, -8.4 to -8.6)]. Rising mean DDD per prescription, from 6.88 in 1995 to 10.47 in 2014 (3.59, 3.55-3.63), drove rising total DDD. In the under-5s, every measure fell over time (68.2% fall in DDD per 1000; 60.7% fall in prescriptions per 1000). Among 5-64 year olds, prescriptions per 1000 were lowest in 2014 but among older people, despite a reduction since 2010, the 2014 rate was still higher than in 2000. Trends in individual antimicrobials provide some explanation for overall trends. Conclusions: Rising antimicrobial volumes up to 2011 were mainly due to rising DDD per prescription. Trends in dispensed drug volumes do not readily translate into information on individual exposure, which is more relevant for adverse consequences including emergence of resistance.

Higher extracellular fluid volume in women is concealed by scaling to body surface area.

OBJECTIVE: The objective was to assess body surface area (BSA) for scaling extracellular fluid volume (ECV) in comparison with estimated lean body mass (LBM) and total body water (TBW) across a range of body mass indices (BMI). METHODS: This was a multi-centre study from 15 centres that submitted raw data from routine measurement of GFR in potential kidney transplant donors. There were 819 men and 1059 women in total. ECV was calculated from slope-intercept and slope-only measurements of GFR. ECV was scaled using two methods: Firstly, division of ECV by the scaling variable (ratio method), and secondly the regression method of Turner and Reilly. Subjects were placed into five BMI groups: < 20, 20-24.9, 25-29.9, 30-34.9, and 35 + kg/m(2). LBM and TBW were estimated from previously published, gender-specific prediction equations. RESULTS: Ratio and regression scaling gave almost identical results. ECV scaled to BSA by either method was higher in men in all BMI groups but ECV scaled to LBM and TBW was higher in women. There was, however, little difference between men and women in respect to ECV per unit weight in any BMI group, even though women have 10% more adipose tissue. The relations between TBW and BSA and between LBM and BSA, but not between LBM and TBW, were different between men and women. CONCLUSION: Lean tissue in women contains more extracellular water than in men, a difference that is obscured by scaling to BSA. The likely problem with BSA is its insensitivity to body composition.

The reliability of glomerular filtration rate measured from plasma clearance: a multi-centre study of 1,878 healthy potential renal transplant donors.

PURPOSE: The objective of the study was to undertake a clinical audit of departmental performance in the measurement of glomerular filtration rate (GFR) using the coefficient of variation (CV) of extracellular fluid volume (ECFV) as the benchmark. ECFV is held within narrow limits in healthy subjects, narrower than GFR, and should therefore have a low CV. METHODS: Fifteen departments participated in this retrospective study of healthy renal transplant donors. Data were analysed separately for men (n ranged from 28 to 115 per centre; total = 819) and women (n = 28-146; 1,059). All centres used the slope-intercept method with blood sample numbers ranging from two to five. Subjects did not fast prior to GFR measurement. GFR was scaled to body surface area (BSA) and corrected for the single compartment assumption. GFR scaled to ECFV was calculated as the terminal slope rate constant and corrected for the single compartment assumption. ECFV/BSA was calculated as the ratio of GFR/BSA to GFR/ECFV. RESULTS: The departmental CVs of ECFV/BSA and GFR/BSA ranged from 8.3 to 25.8% and 12.8 to 21.9%, respectively, in men, and from 9.6 to 21.1% and 14.8 to 23.7%, respectively, in women. Both CVs correlated strongly between men and women from the same centre, suggesting department-specific systematic errors. GFR/BSA was higher in men in 14 of 15 centres, whereas GFR/ECFV was higher in women in 14 of 15 centres. Both correlated strongly between men and women, suggesting regional variation in GFR. CONCLUSION: The CV of ECFV/BSA in normal subjects is a useful indicator of the technical robustness with which GFR is measured and, in this study, indicated a wide variation in departmental performance.

Extracellular fluid volume and glomerular filtration rate in 1878 healthy potential renal transplant donors: effects of age, gender, obesity and scaling.

UNLABELLED: Aim. The aim of this study was to investigate the influence of age, gender, obesity and scaling on glomerular filtration rate (GFR) and extracellular fluid volume (ECV) in healthy subjects. METHODS: This is a retrospective multi-centre study of 1878 healthy prospective kidney transplant donors (819 men) from 15 centres. Age and body mass index (BMI) were not significantly different between men and women. Slope-intercept GFR was measured (using Cr-51-EDTA in 14 centres; Tc-99m-DTPA in one) and scaled to body surface area (BSA) and lean body mass (LBM), both estimated from height and weight. GFR was also expressed as the slope rate constant, with one-compartment correction (GFR/ECV). ECV was measured as the ratio, GFR to GFR/ECV. RESULTS: ECV was age independent but GFR declined with age, at a significantly faster rate in women than men. GFR/BSA was higher in men but GFR/ECV and GFR/LBM were higher in women. Young women (<30 years) had higher GFR than young men but the reverse was recorded in the elderly (>65 years). There was no difference in GFR between obese (BMI>30 kg/m2) and non-obese men. Obese women, however, had lower GFR than non-obese women and negative correlations were observed between GFR and both BMI and %fat. The decline in GFR with age was no faster in obese versus non-obese subjects. ECV/BSA was higher in men but ECV/LBM was higher in women. ECV/weight was almost gender independent, suggesting that fat-free mass in women contains more extracellular water. BSA is therefore a misleading scaling variable. CONCLUSION: There are several significant differences in GFR and ECV between healthy men and women.