Fraser Brims

Serum Mesothelin for Early Detection of Asbestos-Induced Cancer Malignant Mesothelioma

Background: Malignant mesothelioma is an aggressive, almost uniformly fatal tumor, primarily caused by exposure to asbestos. Since the recent discovery that serum mesothelin is a sensitive and highly specific biomarker for mesothelioma, one of the key issues raised is whether mesothelin levels represent a useful screening test for asbestos-exposed at-risk individuals. In this study, soluble mesothelin was determined in sequential serum samples collected from asbestos-exposed individuals before the development of mesothelioma. Methods: Archival serum samples from 106 individuals who developed mesothelioma, 99 asbestos-exposed individuals from the Wittenoom Cancer Surveillance Program, and 109 non–asbestos-exposed individuals from the Busselton Health Survey were identified. Serum mesothelin concentrations were determined using the MESOMARK assay. Results: Longitudinal mesothelin levels determined in healthy asbestos-exposed individuals over a period of 4 years were stable (Pearsons r = 0.96; P < 0.0001). There was no correlation between mesothelin concentration and cumulative asbestos exposure. Mesothelin concentrations were greater than the threshold value of 2.5 nmol/L in the penultimate serum sample before the diagnosis of mesothelioma in 17 of 106 people. Using an increase above the 95% confidence interval of the mean of a given individuals longitudinal mesothelin results, 33 of 82 individuals had increasing mesothelin levels before diagnosis. Conclusion: In a population with a high pretest probability of developing mesothelioma, the serum biomarker mesothelin is elevated in absolute terms in 15% and in relative terms in 40% of the group. Impact: Future studies examining a combination of biomarkers could improve sensitivity of screening. Cancer Epidemiol Biomarkers Prev; 19(9); 2238–46. ©2010 AACR.

Original ResearchDisorders of the PleuraPostmortem Findings of Malignant Pleural Mesothelioma: A Two-Center Study of 318 Patients

BACKGROUND Malignant pleural mesothelioma (MPM) is an incurable cancer with a rising incidence. MPM is often perceived as a locally invasive cancer, and the exact cause of death is poorly understood.This two-center study describes the anatomic features of patients with MPM at postmortem. METHODS The Western Australia Mesothelioma Registry (Australia) and Coroner’s Office reports from the Avon region (England) were interrogated for the postmortem records of confirmed mesothelioma cases. RESULTS Postmortem records of 318 patients with pleural mesothelioma (169 from Western Australia and 149 from Avon) were identified. Most patients (91.5%) were men (mean age, 68.4 ± 11.5 years), and MPM was right-sided in 55.3%. Extrapleural dissemination of tumor was found in 87.7% of cases and lymph node involvement in 53.3%. Tumor dissemination in extra thoracicsites was common (55.4% of patients), and almost all organs were involved, including liver(31.9%), spleen (10.8%), thyroid (6.9%), and the brain (3.0%). Pulmonary emboli were found in 6% of cases and considered as directly contributing to death in 13 patients (4.1%). The precise cause of death could only be determined in 63 (19.8%) cases even after postmortem. The BMI was significantly lower in cases that had no identifiable anatomic cause of death at postmortem(18.8 ± 4.3 vs 21.0 ± 4.7, P = .034). CONCLUSIONS In this largest, to our knowledge, postmortem series on MPM, extrathoracic dissemination of mesothelioma was common and often under recognized. No anatomic cause of death was identified in the majority of patients even at autopsy, raising the possibility of physiologic and metabolic causes of death.

Air quality, tobacco smoke, urban crowding and day care: modern menaces and their effects on health.

Background: The known adverse health effects of outdoor air pollution were reduced in the last century by effective legislation and pollution control. Although combustion of biomass fuels in the indoor environment remains a major hazard in developing countries, there has been a change in the nature of the traffic-generated air pollutants in outdoor air in developed countries. The role of day care and siblings in increasing the risk of infection early in life contrasts with protection from allergic disease later. Methods: The mechanisms of how these pollutants exert their effects are poorly understood, but there is emerging evidence that the toxic effects may be related to infection. This synopsis discusses the epidemiologic relationship of the menaces of modern living, including air pollution, urban crowding and infection, and will explore some of the mechanisms of how they act synergistically to cause exacerbations of illnesses in individuals with preexisting respiratory conditions, such as asthma. It will also discuss the roles of day care and siblings in relation to respiratory disease risk. Results: Current evidence suggests that much of the morbidity and mortality related to sources of both indoor and outdoor pollution occur by causing or interacting with respiratory infection and other acute or chronic health conditions, such as asthma. Conclusion: Improvements in air quality through efforts to tackle environmental problems such as pollution and tobacco smoke will help achieve better health. Day care and siblings increase infectious disease early in life but are associated with protection against development of allergic disease later.

Respiratory Chest Pain: Diagnosis and Treatment

Chest pain from respiratory causes is a common complaint and may indicate the presence of a serious or even life-threatening pathologic condition. Most chest pains are the result of irritation or inflammation of the parietal pleura, as the visceral pleura is insensate, although pain may arise from direct malignant invasion or trauma to the chest wall. Rapid recognition with appropriate understanding of the anatomy and physiology of chest pain from respiratory causes is vital to ensure timely and appropriate therapy.

Up-regulation of the Extrinsic Coagulation Pathway in Acute Asthma—A Case Study

Introduction. In the normal airway, the hemostatic balance is antithrombotic and favors fibrinolysis. Acute asthma is associated with inflammatory cell infiltrate and plasma exudation in the airways. Postmortem specimens following status asthmaticus suggest a role for the activation of the extrinsic coagulation cascade and intraluminal fibrin formation. The authors report a chance observation of fibrin formation in the airways of a patient with moderate asthma 5 days before a severe exacerbation requiring hospital admission. Methods. Alpha-2 macroglobulin, an index of plasma leakage, coagulation factors, and D-dimers were measured by enzyme-linked immunosorbent assay (ELISA) in hypertonic saline-induced sputum, as part of a study into airway repair in stable asthma. All subjects were required to have stable symptoms and measures of asthma prior to sampling. Results. The subjects baseline forced expiratory volume in one second (FEV1) was 94% predicted and fraction of exhaled nitric oxide (FeNO) level was 30 ppb prior to sputum induction. Differential sputum cell count revealed an airways neutrophilia (neutrophils 81.1%, eosinophils 0.19%). D-dimers were 70-fold and 22-fold higher than the median value for patients with stable moderate and severe asthma, respectively. Plasma exudation was 42-fold higher than in stable moderate asthma, but on a par with levels found in severe stable asthma, and locally produced coagulation factors may therefore be involved. Levels of fibrinogen, plasminogen, plasminogen activator inhibitor (PAI)-1 and thrombin-activatable fibrinolysis inhibitor (TAFI) were all at least an order of magnitude higher than those seen in stable moderate or severe asthma. Conclusions. Acute exacerbation of moderate asthma appears to be associated with a shift to a profibrinogenic, possibly antifibrinolytic, environment in the airways.

A Novel Clinical Prediction Model for Prognosis in Malignant Pleural Mesothelioma Using Decision Tree Analysis

Introduction: Malignant pleural mesothelioma (MPM) is a rare cancer with a heterogeneous prognosis. Prognostic models are not widely utilized clinically. Classification and regression tree (CART) analysis examines the interaction of multiple variables with a given outcome. Methods: Between 2005 and 2014, all cases with pathologically confirmed MPM had routinely available histological, clinical, and laboratory characteristics recorded. Classification and regression tree analysis was performed using 29 variables with 18‐month survival as the dependent variable. Risk groups were refined according to survival and clinical characteristics. The model was then tested on an external international cohort. Results: A total of 482 cases were included in the derivation cohort; the median survival was 12.6 months, and the median age was 69 years. The model defined four risk groups with clear survival differences (p < 0.0001). The strongest predictive variable was the presence of weight loss. The group with the best survival at 18 months (86.7% alive, median survival 34.0 months, termed risk group 1) had no weight loss, a hemoglobin level greater than 153 g/L, and a serum albumin level greater than 43 g/L. The group with the worst survival (0% alive, median survival 7.5 months, termed risk group 4d) had weight loss, a performance score of 0 or 1, and sarcomatoid histological characteristics. The C‐statistic for the model was 0.761, and the sensitivity was 94.5%. Validation on 174 external cases confirmed the models ability to discriminate between risk groups in an alternative data set with fair performance (C‐statistic 0.68). Conclusions: We have developed and validated a simple, clinically relevant model to reliably discriminate patients at high and lower risk of death using routinely available variables from the time of diagnosis in unselected populations of patients with MPM.

Outcomes and complications following medical thoracoscopy.

Introduction:  Thoracoscopy is an invasive procedure that may be performed by physicians for the investigation of exudative pleural effusion using local anaesthesia, conscious sedation and a rigid thoracoscope.

Identifying high risk individuals for targeted lung cancer screening: Independent validation of the PLCOm2012 risk prediction tool

Lung cancer screening with computerised tomography holds promise, but optimising the balance of benefits and harms via selection of a high risk population is critical. PLCOm2012 is a logistic regression model based on U.S. data, incorporating sociodemographic and health factors, which predicts 6‐year lung cancer risk among ever‐smokers, and thus may better predict those who might benefit from screening than criteria based solely on age and smoking history. We aimed to validate the performance of PLCOm2012 in predicting lung cancer outcomes in a cohort of Australian smokers. Predicted risk of lung cancer was calculated using PLCOm2012 applied to baseline data from 95,882 ever‐smokers aged ≥45 years in the 45 and Up Study (2006–2009). Predictions were compared to lung cancer outcomes captured to June 2014 via linkage to population‐wide health databases; a total of 1,035 subsequent lung cancer diagnoses were identified. PLCOm2012 had good discrimination (area under the receiver‐operating‐characteristic‐curve; AUC 0.80, 95%CI 0.78–0.81) and excellent calibration (mean and 90th percentiles of absolute risk difference between observed and predicted outcomes: 0.006 and 0.016, respectively). Sensitivity (69.4%, 95%CI, 65.6–73.0%) of the PLCOm2012 criteria in the 55–74 year age group for predicting lung cancers was greater than that using criteria based on ≥30 pack‐years smoking and ≤15 years quit (57.3%, 53.3‐61.3%; p < 0.0001), but specificity was lower (72.0%, 71.7–72.4% versus 75.2%, 74.8–75.6%, respectively; p < 0.0001). Targeting high risk people for lung cancer screening using PLCOm2012 might improve the balance of benefits versus harms, and cost‐effectiveness of lung cancer screening.

Absence of germline mutations in BAP1 in sporadic cases of malignant mesothelioma

Malignant mesothelioma (MM) is a uniformly fatal tumour caused predominantly by exposure to asbestos. It is not known why some exposed individuals get mesothelioma and others do not. There is some epidemiological evidence of host susceptibility. BAP1 gene somatic mutations and allelic loss are common in mesothelioma and recently a BAP1 cancer syndrome was described in which affected individuals and families had an increased risk of cancer of multiple types, including MM. To determine if BAP1 mutations could underlie any of the sporadic mesothelioma cases in our cohort of patients, we performed targeted deep sequencing of the BAP1 exome on the IonTorrent Proton sequencer in 115 unrelated MM cases. No exonic germline BAP1 mutations of known functional significance were observed, further supporting the notion that sporadic germline BAP1 mutations are not relevant to the genetic susceptibility of MM.

Advance care planning uptake among patients with severe lung disease: a randomised patient preference trial of a nurse-led, facilitated advance care planning intervention

Objective Advance care planning (ACP) clarifies goals for future care if a patient becomes unable to communicate their own preferences. However, ACP uptake is low, with discussions often occurring late. This study assessed whether a systematic nurse-led ACP intervention increases ACP in patients with advanced respiratory disease. Design A multicentre open-label randomised controlled trial with preference arm. Setting Metropolitan teaching hospital and a rural healthcare network. Participants 149 participants with respiratory malignancy, chronic obstructive pulmonary disease or interstitial lung disease. Intervention Nurse facilitators offered facilitated ACP discussions, prompted further discussions with doctors and loved ones, and assisted participants to appoint a substitute medical decision-maker (SDM) and complete an advance directive (AD). Outcome measures The primary measure was formal (AD or SDM) or informal (discussion with doctor) ACP uptake assessed by self-report (6 months) and medical notes audit. Secondary measures were the factors predicting baseline readiness to undertake ACP, and factors predicting postintervention ACP uptake in the intervention arm. Results At 6 months, formal ACP uptake was significantly higher (p<0.001) in the intervention arm (54/106, 51%), compared with usual care (6/43, 14%). ACP discussions with doctors were also significantly higher (p<0.005) in the intervention arm (76/106, 72%) compared with usual care (20/43, 47%). Those with a strong preference for the intervention were more likely to complete formal ACP documents than those randomly allocated. Increased symptom burden and preference for the intervention predicted later ACP uptake. Social support was positively associated with ACP discussion with loved ones, but negatively associated with discussion with doctors. Conclusions Nurse-led facilitated ACP is acceptable to patients with advanced respiratory disease and effective in increasing ACP discussions and completion of formal documents. Awareness of symptom burden, readiness to engage in ACP and relevant psychosocial factors may facilitate effective tailoring of ACP interventions and achieve greater uptake. Trial registration number ACTRN12614000255684.