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Malignant pleural mesothelioma (MPM) is an incurable malignancy associated with high symptom burden and poor prognosis. The relationship between asbestos exposure and MPM incidence is well-established. The incidence rate of MPM in Australia and New Zealand is among the highest globally. Matching the experience of other nations with legal restrictions on asbestos, incidence is expected to fall. In contrast, the incidence of MPM is rising in the developing nations of the Asia-Pacific as consumption and mining (albeit to a lesser extent) of asbestos continues. The incidence of MPM in these nations is currently low or unknown, reflecting insufficient latency periods since industrial use of asbestos, deficient resources for accurate diagnosis, and lack of occupational disease or cancer registries. The landscape of treatment for MPM is rapidly changing with combination immunotherapy now demonstrating improved survival in the first-line setting. Considering vast global inequity in access to anticancer treatments, establishing minimum standard of care for MPM in developing nations is of greater significance. Here, we review the evidence that form the basis of our minimum-standard recommendations for diagnosis, systemic treatment, management of recurrent pleural effusions, and symptom management. We also briefly review evidence-based treatment that may be considered for those with access.

Asbestos is a naturally occurring mineral consisting of extremely fine fibres that can become trapped in the lungs after inhalation. Occupational and environmental exposures to asbestos are linked to development of lung cancer and malignant mesothelioma, a cancer of the lining surrounding the lung. This review discusses the factors that are making asbestos-induced lung cancer a continuing problem, including the extensive historic use of asbestos and decades long latency between exposure and disease development. Genomic mutations of DNA nucleotides and gene rearrangements driving lung cancer are well-studied, with biomarkers and targeted therapies already in clinical use for some of these mutations. The genes involved in these mutation biomarkers and targeted therapies are also involved in epigenetic mechanisms and are discussed in this review as it is hoped that identification of epigenetic aberrations in these genes will enable the same gene biomarkers and targeted therapies to be used. Currently, understanding of how asbestos fibres trapped in the lungs leads to epigenetic changes and lung cancer is incomplete. It has been shown that oxidoreduction reactions on fibre surfaces generate reactive oxygen species (ROS) which in turn damage DNA, leading to genetic and epigenetic alterations that reduce the activity of tumour suppressor genes. Epigenetic DNA methylation changes associated with lung cancer are summarised in this review, and some of these changes will be due to asbestos exposure. So far, little research has been carried out to separate the asbestos driven epigenetic changes from those due to non-asbestos causes of lung cancer. Asbestos-associated lung cancers exhibit less methylation variability than lung cancers in general, and in a large proportion of samples variability has been found to be restricted to promoter regions. Epigenetic aberrations in cancer are proving to be promising biomarkers for diagnosing cancers. It is hoped that further understanding of epigenetic changes in lung cancer can result in useful asbestos-associated lung cancer biomarkers to guide treatment. Research is ongoing into the detection of lung cancer epigenetic alterations using non-invasive samples of blood and sputum. These efforts hold the promise of non-invasive cancer diagnosis in the future. Efforts to reverse epigenetic aberrations in lung cancer by epigenetic therapies are ongoing but have not yet yielded success.

A number of key immune regulators show prognostic value in malignant pleural mesothelioma (MPM), but the association between Bridging integrator 1 (BIN1), indoleamine 2,3 dioxygenase 1 (IDO1) and patient outcome has not been investigated. We aimed to determine the expression of BIN1 and IDO1, their association with other markers and impact on overall survival (OS) in MPM.The expression of BIN1, IDO1, CD3, CD20 and CD68 were evaluated by immunohistochemistry in 67 patients who underwent pleurectomy/decortication. Survival analyses were performed using the Kaplan Meier method and significant biomarkers were entered into a Cox Regression multivariate model, accounting for known prognostic factors such as age, gender, histological subtype, PD-L1 expression and neutrophil-to-lymphocyte ratio.Immune markers were variably expressed in tumor cells, ranging from 0% to 100% for BIN1 (median: 89%), and 0% to 77.5% for IDO1 (median: 0%). Expression of markers of tumor-infiltrating lymphocytes (TILs) and macrophages ranged from 0% to more than 50%. BIN1 expression was high in 35 patients (51%) and was associated with increased OS (median: 12 vs 6 months for high and low BIN1 respectively,p = 0.03). Multivariate analysis showed BIN1 remained an independent prognostic indicator (HR 0.39; 95% CI: 0.18-0.82, p = 0.01). The majority of patients had immune inflamed tumors (77%) and there was a significant association between TILs and BIN1 (p = 0 0.01), PD-L1 (p=0.04) and CD68+ macrophages in the tumor (p 0.01). There were no significant associations between PD-L1 and BIN1 or IDO1.High BIN1 expression is a favorable prognostic biomarker and is associated with TILs in MPM.

BACKGROUND Survival outcomes for patients with newly diagnosed glioblastoma have not changed significantly since the introduction of concurrent temozolomide with post-surgical radiation followed by adjuvant temozolomide. METHODS Multi-Arm Glioblastoma Australasia (MAGMA) is a recently initiated phase III multi-arm, multi-centre randomized trial for patients with newly diagnosed glioblastoma, led by the Australian Cooperative Trials Group for Neuro-Oncology (COGNO), that will concurrently test multiple treatment questions. Initially, a partial factorial design will be implemented to compare the current standard of care with either or both of (1) neoadjuvant temozolomide and (2) aduvant temozolomide continued beyond six months until progression. MAGMA will transition to a multi-arm multi-stage (MAMS) design as additional tratment question are introduced. Treatment allocation to each question will be balanced (1:1) using minimisation over several stratification factors, including study site, age, IDH-mutation status, surgical extent and randomization to the prior treatment question(s). The primary outcome is overall survival. Secondary outcomes include progression-free survival (measured by mRANO), time to first non-temozolomide systemic treatment, clinically significant toxicity as measured by Grade 2/4 adverse events, and health-related quality of life measures. Parsimonious data collection and a streamlined assessment schedule have been incorporated to mitigate the burden of data collection (such as low grade toxicity from temozolomide), and to encourage participation in regional and rural settings. A consortium model has been adopted to foster neuro-oncology expertise and infrastructure and share academic credit and future design opportunities. PROGRESS Recruitment commenced in September 2020. To date, 60 patients have been recruited from an initial sample size target of 250 patients for each of these initial two treatment questions. Of these 60 patients, 45 have been randomized in Question 1 (neoadjuvant chemotherapy) whilst 50 randomized in Question 2 (prolonged adjuvant chemotherapy). To date, 14 of the 27 intended sites are open to recruitment.

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BACKGROUND Psychoeducation has the potential to support students experiencing distress and help meet the demand for support; however, there is a need to understand how these programs are experienced. Web-based diaries are a useful activity for psychoeducation because of their therapeutic benefits, ability to capture naturalistic data relevant to well-being, and appropriateness for text analysis methods. OBJECTIVE This study aims to examine how university students use electronic diaries within a psychoeducation program designed to enhance mental well-being. METHODS The Science of Happiness course was administered to 154 undergraduate students in a university setting (the United Kingdom). Diaries were collected from the students for 9 weeks. Baseline well-being data were collected using the Short Warwick-Edinburgh Mental Wellbeing Scale (SWEMWBS). The percentage of negative and positive emotion words used in diaries (emotional tone) and use of words from five life domains (social, work, money, health, and leisure) were calculated using the Linguistic Inquiry and Word Count 2015 software. Random effects (generalized least squares) regression models were estimated to examine whether time, diary characteristics, demographics, and baseline well-being predict the emotional tone of diaries. RESULTS A total of 149 students participated in the diary study, producing 1124 individual diary entries. Compliance with the diary task peaked in week 1 (n=1041, 92.62%) and was at its lowest in week 3 (n=807, 71.81%). Compared with week 1, diaries were significantly more positive in their emotional tone during week 5 (mean difference 23.90, 95% CI 16.89-30.90) and week 6 (mean difference 26.62, 95% CI 19.35-33.88) when students were tasked with writing about gratitude and their strengths. Across weeks, moderate and high baseline SWEMWBS scores were associated with a higher percentage of positive emotion words used in diaries (increases compared with students scoring low in SWEMWBS were 5.03, 95% CI 0.08-9.98 and 7.48, 95% CI 1.84-13.12, respectively). At week 1, the diaries of students with the highest levels of baseline well-being (82.92, 95% CI 73.08-92.76) were more emotionally positive on average than the diaries of students with the lowest levels of baseline well-being (59.38, 95% CI 51.02-67.73). Diaries largely focused on the use of social words. The emotional tone of diary entries was positively related to the use of leisure (3.56, 95% CI 2.28-4.85) and social words (0.74, 95% CI 0.21-1.27), and inversely related to the use of health words (−1.96, 95% CI −3.70 to −0.22). CONCLUSIONS We found evidence for short-term task-specific spikes in the emotional positivity of web-based diary entries and recommend future studies examine the possibility of long-term impacts on the writing and well-being of students. With student well-being strategies in mind, universities should value and encourage leisure and social activities.

PURPOSE: To identify the approximately 12% with inherited cancer predisposition, all men with metastatic prostate cancer (mPC) should be offered germline genetic testing. This guides treatment choices and impacts cancer prevention in the family. Limited genetic services globally present a barrier to testing. This study tested a potential solution, “mainstreaming,” where counseling and testing are performed by the patient’s oncologist. PATIENTS AND METHODS: Men with mPC at three Australian sites were offered germline genetic testing at their medical oncology appointment. Panel testing ( ATM, BRCA1, BRCA2, BRIP1, CHEK2, EPCAM, FANCA, HOXB13, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, RAD51D, and TP53) was performed on saliva/blood (Invitae, San Francisco, CA). Primary outcomes were clinician and patient satisfaction. Secondary outcomes included mutation rates and resource allocation. RESULTS: Of 66 men offered testing, 63 (95%) accepted. Four pathogenic variants were identified (two BRCA2, one NBN, and one MSH6). Fifty patients and nine clinicians completed questionnaires. Satisfaction was high. All patients were pleased to have had testing overall, 98% (46 of 47) to have had testing at their usual oncology appointment, and all to receive results from their usual specialist, rather than a separate genetics appointment. A total of 88% (7 of 8) of clinicians felt confident, and all were satisfied with mainstreaming. Mainstreaming was resource efficient, requiring 87% fewer genetic consultations than traditional genetic counseling. CONCLUSION: This study demonstrates that mainstreaming of men with mPC is feasible, resource efficient, and satisfactory for clinicians and patients. Widespread implementation as standard of care would facilitate timely access to genetic testing for men with mPC.

Malignant pleural mesothelioma (MPM) is an aggressive malignancy with limited effective treatment options. Focal adhesion kinase (FAK) inhibitors have been shown to efficiently suppress MPM cell growth initially, with limited utility in the current clinical setting. In this study, we utilised a large collection of MPM cell lines and MPM tissue samples to study the role of E-cadherin (CDH1) and microRNA on the efficacy of FAK inhibitors in MPM. The immunohistochemistry (IHC) results showed that the majority of MPM FFPE samples exhibited either the absence of, or very low, E-cadherin protein expression in MPM tissue. We showed that MPM cells with high CDH1 mRNA levels exhibited resistance to the FAK inhibitor PND-1186. In summary, MPM cells that did not express CDH1 mRNA were sensitive to PND-1186, and MPM cells that retained CDH1 mRNA were resistant. A cell cycle analysis showed that PND-1186 induced cell cycle disruption by inducing the G2/M arrest of MPM cells. A protein−protein interaction study showed that EGFR is linked to the FAK pathway, and a target scan of the microRNAs revealed that microRNAs (miR-17, miR221, miR-222, miR137, and miR148) interact with EGFR 3′UTR. Transfection of MPM cells with these microRNAs sensitised the CHD1-expressing FAK-inhibitor-resistant MPM cells to the FAK inhibitor.

Background and objective Whilst the impact of clinicopathological factors on the prognosis of malignant pleural mesothelioma (MPM) is well understood, socioeconomic and geographic factors have received less attention. We analysed the relationship between geographic and socioeconomic factors upon survival and treatment provision in a large series of patients with MPM. Methods We assessed MPM patients awarded compensation between 2002 and 2009 with additional MPM incidence data from the New South Wales (NSW) Cancer Registry. The impact of geographic remoteness, distance from oncological multidisciplinary team (MDT) and Index of Relative Socioeconomic Advantage and Disadvantage (IRSAD) upon survival, clinical features and treatment received was analysed. Results We identified 910 patients (67% residing in major cities; 92% 70 (hazard ratio (HR) = 1.39), male gender (HR =1.36), non-epithelioid histological subtype (HR = 2.18) and IRSAD status by decreasing quintile (HR = 1.06) were independent prognostic factors. There was no significant advantage for patients residing in major cities (10.6 months vs 8.8 months; P = 0.162) or within 50 km of MDT (10.3 months vs 7.8 months; P = 0.539). Patient's geographic location and distance to MDT did not impact chemotherapy, adjuvant radiotherapy or extrapleural pneumonectomy provision. Socioeconomically disadvantaged patients were significantly less likely to receive chemotherapy (37.4% vs 54.8%; P = 0.001). Conclusion This study provides evidence for differences in the treatment and survival according to socioeconomic status for compensated MPM patients in NSW. Further research is warranted to seek additional explanations for the differences noted by comparing the treatments and outcomes of compensated and non-compensated MPM patients in NSW.

1521 Background: In order to identify the ∼12% with inherited cancer predisposition, it is recommended that all men with metastatic prostate cancer (mPC) be offered testing. This has implications for treatment choices and cancer prevention in family. Limited geneticists/genetic counsellors globally present a major barrier to testing. We tested a potential solution, mainstreaming, where testing is performed by the patient’s oncologist. Methods: Men with mPC at three Australian sites were offered germline genetic testing at their medical oncology appointment. Panel testing ( ATM, BRCA1, BRCA2, BRIP1, CHEK2, EPCAM, FANCA, HOXB13, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, RAD51D and TP53) was performed on saliva/blood (Invitae). Primary outcomes were clinician and patient acceptability (modified Royal Marsden Satisfaction Questionnaires). Secondary outcomes included mutation rates and cost-effectiveness. A sample size of 44 provided 90% power, with a one-sided alpha of 5%, to distinguish a proportion of men happy with mainstreaming of 80% vs. 60% or less. Allowing for 25% drop-out, we aimed to recruit 60 men. Results: Of 66 men offered testing from April to November 2019, 63 (95%) accepted. Four pathogenic variants were identified (2 BRCA2, 1 NBN, 1 MSH6). 48 patients and eight clinicians completed questionnaires. Acceptability was high. All (48/48) patients were happy to have been tested, and 45/48 (94%) were happy to have been tested at their oncology appointment. All were happy to receive their results from their oncologist. All clinicians were satisfied mainstreaming and 88% (7/8) felt confident doing so. Mainstreaming was cost-effective, requiring 87% fewer genetic consultations than traditional genetic counselling. Conclusions: This study shows that mainstreaming of men with mPC is feasible, resource efficient and acceptable to both clinicians and patients. Widespread implementation as a new standard of care would facilitate timely access to genetic testing for men with mPC.

Malignant pleural mesothelioma (MPM) is a cancer that primarily affects older adults. However this patient population is frequently under-represented in clinical studies. Therefore, we studied the impact of advancing age on treatment utilisation and clinical outcomes in an extensive series of minimally selected MPM patients.Patients with MPM receiving compensation from the New South Wales (NSW) Dust Diseases Authority (2002-2009) were assessed. They were categorised by age (70 years, 70-80 years or 80 years) and chi-square testing was used to assess the relationship between clinical and demographic variables, age, treatment and overall survival (OS).We identified 910 patients; 41% were aged70 years, 40% were aged 70-80 years, and 19% were aged80 years old. Median OS decreased with increasing age: 13.5 months in70 years, 9.5 months in 70-80 years and 7.1 months in80 years as did chemotherapy use (66%, 35% and 8% respectively). Radical surgical intervention, adjuvant, and palliative radiotherapy were less frequently used with advanced age. A Kaplan Meier analysis revealed that there was a significant survival advantage (p .001) for patients70 and 70-80 years receiving chemotherapy (16.8 vs 7.0 months; 13.9 vs 5.8 months respectively), but not for patients80 years.Advancing age group of NSW patients with MPM was associated with reduced treatment utilisation and a decline in OS. Prospective studies are warranted to verify if current treatment guidelines are relevant for the older adults with MPM.

Therapeutic dendritic cell vaccination for GBM using primary blood dendritic cells (BDC) has the potential to improve response rates compared with more commonly used monocyte-derived dendritic cells due to their superior antigen-presentation and migration. Combination of vaccination with immune checkpoint inhibitors such as anti-PD-1 antibodies may remove tumour-associated immune suppression and directly enhance DC function. GBM is associated with systemic as well as local immune suppression. Therefore it is critical to understand the immune landscape and effect of current treatments on DC function and modulate this to successfully translate vaccination into patients. To that end, we firstly compared the expression of immune checkpoint molecules (PD-1, CTLA-4, TIM-3, LAG-3, ICOS, CD27 axes) on BDC (DC1, DC 2/3, DC6) and lymphocyte subsets (CD3+, CD4+, CD8+, CD56+, Treg) from newly diagnosed or currently treated GBM patients (GBM) with age-matched healthy donors (HD) using flow cytometry. This analysis revealed that the major BDC subsets were identifiable in HD and GBM but were affected by both corticosteroids and concurrent chemoradiation. Furthermore, phenotypic differences exist between HD and GBM, most notably in expression of PD-L2 by BDC. We tested the functional capacity of CD1c+ BDC from HD and GBM patients. After optimizing the maturation process of CD1c+ BDC, their ability to initiate polyclonal immune responses was determined using one-way mixed leucocyte reactions. To further augment vaccine efficacy and overcome tumour-associated immune suppression, we combined this with immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 antibodies. BDC were loaded with the glioma antigen, CMV-pp65 protein to demonstrate the combined effect of immune checkpoint blockade on cytokine production by intracellular staining, antigen-specific T cell expansion and cytotoxicity. DC vaccination in GBM with BDC is a feasible, rational combination with immune checkpoint inhibitors which enhances cytotoxicity in an antigen-specific fashion.

Malignant pleural mesothelioma (MPM) is an asbestos-induced cancer with poor prognosis that displays characteristic alterations in microRNA expression. Recently it was reported that the expression of a subset of microRNAs can distinguish between MPM and adenocarcinoma of the lung. However, the functional importance of these changes has yet to be investigated. We compared expression of miR-192, miR-193a-3p and the miR-200 family in normal pleura and MPM tumor specimens and found a statistically significant reduction in the levels of miR-193a-3p (3.1-fold) and miR-192 (2.8-fold) in MPM. Transfection of MPM cells with a miR-193a-3p mimic resulted in inhibition of growth and an induction of apoptosis and necrosis in vitro. The growth inhibitory effects of miR-193a-3p were associated with a decrease in MCL1 expression and were recapitulated by RNAi-mediated MCL1 silencing. Targeted delivery of miR-193a-3p mimic using EDV minicells inhibited MPM xenograft tumour growth, and was associated with increased apoptosis. In conclusion, miR-193a-3p appears to have importance in the biology of MPM and may represent a target for therapeutic intervention.

Introduction Malignant pleural mesothelioma (MPM) is an aggressive malignancy linked to asbestos exposure. On a genomic level, MPM is characterized by frequent chromosomal deletions of tumor suppressors, including microRNAs. MiR-137 plays a tumor suppressor role in other cancers, so the aim of this study was to characterize it and its target Y-box binding protein 1 (YBX1) in MPM. Methods Expression, methylation, and copy number status of miR-137 and its host gene MIR137HG were assessed by polymerase chain reaction. Luciferase reporter assays confirmed a direct interaction between miR-137 and Y-box binding protein 1 gene (YBX1). Cells were transfected with a miR-137 inhibitor, miR-137 mimic, and/or YBX1 small interfering RNA, and growth, colony formation, migration and invasion assays were conducted. Results MiR-137 expression varied among MPM cell lines and tissue specimens, which was associated with copy number variation and promoter hypermethylation. High miR-137 expression was linked to poor patient survival. The miR-137 inhibitor did not affect target levels or growth, but interestingly, it increased miR-137 levels by means of mimic transfection suppressed growth, migration, and invasion, which was linked to direct YBX1 downregulation. YBX1 was overexpressed in MPM cell lines and inversely correlated with miR-137. RNA interference–mediated YBX1 knockdown significantly reduced cell growth, migration, and invasion. Conclusions MiR-137 can exhibit a tumor-suppressive function in MPM by targeting YBX1. YBX1 knockdown significantly reduces tumor growth, migration, and invasion of MPM cells. Therefore, YBX1 represents a potential target for novel MPM treatment strategies.

Summary Background TargomiRs are minicells (EnGeneIC Dream Vectors) loaded with miR-16-based mimic microRNA (miRNA) and targeted to EGFR that are designed to counteract the loss of the miR-15 and miR-16 family miRNAs, which is associated with unsuppressed tumour growth in preclinical models of malignant pleural mesothelioma. We aimed to assess the safety, optimal dosing, and activity of TargomiRs in patients with malignant pleural mesothelioma. Methods In this first-in-man, open-label, dose-escalation phase 1 trial at three major cancer centres in Sydney (NSW, Australia), we recruited adults (aged ≥18 years) with a confirmed diagnosis of malignant pleural mesothelioma, measurable disease, radiological signs of progression after previous chemotherapy, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of 3 months or more, immunohistochemical evidence of tumour EGFR expression, and adequate bone marrow, liver, and renal function. Patients were given TargomiRs via 20 min intravenous infusion either once or twice a week (3 days apart) in a traditional 3 + 3 dose-escalation design in five dose cohorts. The dose-escalation steps planned were 5 × 10 9 , 7 × 10 9 , and 9 × 10 9 TargomiRs either once or twice weekly, but after analysis of data from the first eight patients, all subsequent patients started protocol treatment at 1 × 10 9 TargomiRs. The primary endpoints were to establish the maximum tolerated dose of TargomiRs as measured by dose-limiting toxicity, define the optimal frequency of administration, and objective response (defined as the percentage of assessable patients with a complete or partial response), duration of response (defined as time from the first evidence of response to disease progression in patients who achieved a response), time to response (ie, time from start of treatment to the first evidence of response) and overall survival (defined as time from treatment allocation to death from any cause). Analyses were based on the full analysis set principle, including every patient who received at least one dose of TargomiRs. The study was closed for patient entry on Jan 3, 2017, and registered with ClinicalTrials.gov, number NCT02369198, and the Australian Registry of Clinical Trials, number ACTRN12614001248651. Findings Between Sept 29, 2014, and Nov 24, 2016, we enrolled 27 patients, 26 of whom received at least one TargomiR dose (one patient died before beginning treatment). Overall, five dose-limiting toxicities were noted: infusion-related inflammatory symptoms and coronary ischaemia, respectively, in two patients given 5 × 10 9 TargomiRs twice weekly; anaphylaxis and cardiomyopathy, respectively, in two patients given 5 × 10 9 TargomiRs once weekly but who received reduced dexamethasone prophylaxis; and non-cardiac pain in one patient who received 5 × 10 9 TargomiRs once weekly. We established that 5 × 10 9 TargomiRs once weekly was the maximum tolerated dose. TargomiR infusions were accompanied by transient lymphopenia (25 [96%] of 26 patients), temporal hypophosphataemia (17 [65%] of 26 patients), increased aspartate aminotransferase or alanine aminotranferase (six [23%] of 26 patients), and increased alkaline phosphatase blood concentrations (two [8%]). Cardiac events occurred in five patients: three patients had electrocardiographic changes, one patient had ischaemia, and one patient had Takotsubo cardiomyopathy. Of the 22 patients who were assessed for response by CT, one (5%) had a partial response, 15 (68%) had stable disease, and six (27%) had progressive disease. The proportion of patients who achieved an objective response was therefore one (5%) of 22, and the duration of the objective response in that patient was 32 weeks. Median overall survival was 200 days (95% CI 94–358). During the trial, 21 deaths occurred, of which 20 were related to tumour progression and one was due to bowel perforation. Interpretation The acceptable safety profile and early signs of activity of TargomiRs in patients with malignant pleural mesothelioma support additional studies of TargomiRs in combination with chemotherapy or immune checkpoint inhibitors. Funding Asbestos Diseases Research Foundation.

Background: Although the prognosis of most patients presenting with malignant pleural mesothelioma (MPM) is poor, a small proportion survives long term. We investigated factors associated with survival in a large patient series. Methods: All patients registered with the NSW Dust Diseases Board (2002–2009) were included in an analysis of prognostic factors using Kaplan–Meier and Cox regression analysis. On the basis of these analyses, we developed a risk score (Prognostic Index (PI)). Results: We identified 910 patients: 90% male; histology (epithelioid 60% biphasic 13% sarcomatoid 17%); stage (Tx-I-II 48% III-IV 52%); and calretinin expression (91%). Treatment: chemotherapy(CT) 44%, and extrapleural-pneumonectomy (EPP) 6%. Median overall survival (OS) was 10.0 months. Longer OS was associated with: age 20 months: 16% of these receiving EPP, and 66% CT. The PI offered improved prognostic discrimination over one of the existing prognostic models (EORTC). Conclusions: We identified calretinin expression, age, gender, histological subtype, platelet count and haemoglobin level as independent prognostic factors. Patients undergoing EPP or pemetrexed-based chemotherapy demonstrated better survival, but 84% and 34% of long survivors, respectively, did not receive radical surgery or chemotherapy.

Whilst the impact of clinicopathological factors on the prognosis of malignant pleural mesothelioma (MPM) is well understood, socioeconomic and geographic factors have received less attention. We analysed the relationship between geographic and socioeconomic factors upon survival and treatment provision in a large series of patients with MPM.We assessed MPM patients awarded compensation between 2002 and 2009 with additional MPM incidence data from the New South Wales (NSW) Cancer Registry. The impact of geographic remoteness, distance from oncological multidisciplinary team (MDT) and Index of Relative Socioeconomic Advantage and Disadvantage (IRSAD) upon survival, clinical features and treatment received was analysed.We identified 910 patients (67% residing in major cities; 92%50 km from MDT). Median overall survival was 10.0 months. On multivariate analysis, age70 (hazard ratio (HR) = 1.39), male gender (HR =1.36), non-epithelioid histological subtype (HR = 2.18) and IRSAD status by decreasing quintile (HR = 1.06) were independent prognostic factors. There was no significant advantage for patients residing in major cities (10.6 months vs 8.8 months; P = 0.162) or within 50 km of MDT (10.3 months vs 7.8 months; P = 0.539). Patient's geographic location and distance to MDT did not impact chemotherapy, adjuvant radiotherapy or extrapleural pneumonectomy provision. Socioeconomically disadvantaged patients were significantly less likely to receive chemotherapy (37.4% vs 54.8%; P = 0.001).This study provides evidence for differences in the treatment and survival according to socioeconomic status for compensated MPM patients in NSW. Further research is warranted to seek additional explanations for the differences noted by comparing the treatments and outcomes of compensated and non-compensated MPM patients in NSW.

The upregulation of programmed death ligand 1 (PD-L1) is found in many cancers and contributes to evasion of the host's immune defense. In malignant pleural mesothelioma (MPM), PD-L1 expression is associated with the nonepithelioid histological subtype and poor prognosis, but the pathways involved in control of PD-L1 expression in MPM are poorly understood. To address one possible means of PD-L1 regulation we investigated the relationship between dysregulated microRNA levels and PD-L1 expression.PD-L1 expression was analyzed by immunohistochemistry in tissue microarrays prepared from samples from patients undergoing an operation (pleurectomy with or without decortication). MicroRNA expression was analyzed by reverse-transcriptase quantitative polymerase chain reaction. Regulation of PD-L1 expression in cell lines was assessed after transfection with microRNA mimics and small interfering RNAs. Interaction between microRNAs and PD-L1 was analyzed by using argonaute-2 immunoprecipitation and a luciferase reporter assay.In a series of 72 patients with MPM, 18 (25%) had positive PD-L1 staining, and this was more common in patients with the nonepithelioid subtype (p = 0.01). PD-L1 expression was associated with poor survival (median overall survival 4.0 versus 9.2 months with positive versus negative PD-L1 expression [p0.001]), and in multivariate analyses, PD-L1 expression remained a significant adverse prognostic indicator (hazard ratio = 2.2, 95% confidence interval: 1.2-4.1, p0.01). In the same patient series, PD-L1 expression was also associated with downregulation of microRNAs previously shown to have tumor suppressor activity in MPM. The median microRNA expression levels of miR-15b, miR-16, miR-193a-3p, miR-195, and miR-200c were significantly lower in the PD-L1-positive samples. Transfecting MPM cell lines with mimics corresponding to miR-15a and miR-16, both of which are predicted to target PD-L1, led to downregulation of PD-L1 mRNA and protein. In addition, miR-193a-3p, with an alternative G-U-containing target site, also caused PD-L1 downregulation.Together, these data suggest that tumor suppressor microRNAs contribute to the regulation of PD-L1 expression in MPM.

Aims The accurate diagnosis of malignant pleural mesothelioma (MPM) is essential for therapeutic and legal reasons. In 2006 the International Mesothelioma Panel advocated the use of a panel, including two mesothelial and two non-mesothelial immunohistochemical (IHC) markers. We assessed the changing use of IHC for the diagnosis of MPM in Australia over two decades in the context of current best practice. Methods Patients with a confirmed clinico-pathological diagnosis of MPM who underwent extrapleural pneumonectomy or pleurectomy and/or decortication between 1988 and 2006 were identified from the cardiothoracic database at Royal Prince Alfred Hospital and combined with consecutive patients reviewed by the Dust Diseases Board between March 2007 and March 2009. Initial diagnostic pathology reports were reviewed. Results A total of 289 patients were identified. A median of six IHC stains per sample was performed (range 0–18): two (range 0–5) mesothelial markers, two (0–6) carcinoma markers and two epithelial markers. A trend to the higher usage of antibodies in epithelioid tumors versus biphasic and sarcomatoid tumors was noted (P = 0.148 and 0.389, respectively). Testing increased from a median of three stains per sample (1988–1997) to seven (2006–2009). Labeling specimens with > 2 mesothelial markers and > 2 carcinoma markers increased to 72 and 67 percent, respectively, after 2006. Conclusion Reflecting the acceptance of diagnostic panels and increased availability of antibodies, an increase in the use of IHC stains for MPM diagnosis has occurred over the past two decades although uncertainty persists as to the optimal panel composition.

Responses to immune checkpoint inhibitors (CPI) may vary between individuals because of differences in somatic mutations in the tumour and/or germ-line differences in immunological tolerance. To explore the latter, this ongoing study evaluates patients with metastatic non-small cell lung cancer treated with single agent PD-1 or PD-L1 inhibitors from an active treatment pool of over 200 patients. Rare and common germ-line DNA variants are analysed in exceptional responders and non-responders by whole genome sequencing (Illumina HiSeq X Ten). Exceptional responders are defined as individuals with sustained partial (>6 months) or complete response per RECIST criteria with concurrent autoimmune toxicity, implying systemic immune activation. In these individuals, the cumulative burden of rare and common variants in a curated list of immune tolerance genes is analysed and compared to the Medical Genome Reference Bank, comprising whole genome sequences of 1146 well-elderly individuals. Comparisons are made with Fisher Exact test. Recurrent rare variants (Exome Aggregation Consortium (ExAC) frequency 2%) are more frequent within this cohort compared with population standard, for example variant B, a missense mutation within a DNA-repair protein that has ExAC allelic frequency of 2.5% and is present in 30% of our cohort (P = .013). Polygenic risk scores for diseases of impaired immune tolerance within exceptional responders are distinct from control groups. Further analyses of immune-related variants within anti-PD-1/PD-L1 responders and control groups will be presented. Preliminary findings suggest individuals harbouring damaging variants in genes promoting immune tolerance are more responsive to PD-1/PD-L1 inhibitors because basal immune activation is higher, requiring greater reliance on inhibitory checkpoints to maintain homeostasis. Ordinarily, this would be clinically undetectable, however the addition of a pharmacological CPI may more effectively break immune tolerance in this primed environment. Citation Format: Megan B. Barnet, Katherine J. Jackson, Bo Gao, Adnan M. Nagrial, Michael J. Boyer, Wendy A. Cooper, Rina Hui, Anthony Linton, Martin H. Tattersall, Greg Gibson, Jonathan Cebon, Georgina V. Long, Alexander M. Menzies, Richard A. Scolyer, Paul Lacaze, Robert Brink, Timothy Peters, Mark Cowley, Velimir Gayevskiy, David M. Thomas, Mark Pinese, Prunella Blinman, Steven Kao, Christopher C. Goodnow. Exploring the germ-line contribution to exceptional response to PD-1/PD-L1 inhibition in patients with metastatic non-small-cell lung cancer by whole genome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-121.

Background Prognosis of malignant pleural mesothelioma (MPM) is poor, and predicting the outcomes of treatment is difficult. Here we investigate the potential of microRNA expression to estimate prognosis of MPM patients. Methods Candidate microRNAs from microarray profiling of tumor samples from 8 long (median: 53.7 months) and 8 short (median: 6.4 months) survivors following extrapleural pneumonectomy (EPP) were validated by RT-qPCR in 48 additional EPP samples. Kaplan–Meier log ranking was used to further explore the association between microRNA expression and overall survival (OS). Binary logistic regression was used to construct a microRNA signature (miR-Score) that was able to predict an OS of ≥20 months. Performance of the miR-Score was evaluated by receiver operating characteristic (ROC) curve analysis and validated in a series of 43 tumor samples from patients who underwent palliative surgery [pleurectomy/decortication (P/D)]. Results The miR-Score, using expression data of six microRNAs (miR-21-5p, -23a-3p, -30e-5p, -221-3p, -222-3p, and -31-5p), enabled prediction of long survival with an accuracy of 92.3% for EPP and 71.9% for palliative P/D. Hazard ratios for score-negative patients were 4.12 (95% CI: 2.03–8.37) for EPP and 1.93 (95% CI: 1.01–3.69) for P/D. Importantly, adding the miR-Score to a set of clinical selection criteria (histology, age, gender) increased predictive accuracy in the independent validation set from 76.3% for clinical factors only to 87.3%. Conclusions This study has identified a novel 6-microRNA signature (miR-Score) that can accurately predict prognosis of MPM patients.

Background: Malignant pleural mesothelioma (MPM) is an aggressive tumour originating in the thoracic mesothelium. Prognosis remains poor with 9- to 12-month median survival, and new targets for treatments are desperately needed. Methods: Utilising an RNA interference (RNAi)-based screen of 40 genes overexpressed in tumours, including genes involved in the control of cell cycle, DNA replication and repair, we investigated potential therapeutic targets for MPM. Following in vitro characterisation of the effects of target silencing on MPM cells, candidates were assessed in tumour samples from 154 patients. Results: Gene knockdown in MPM cell lines identified growth inhibition following knockdown of NDC80, CDK1 and PLK1. Target knockdown induced cell-cycle arrest and increased apoptosis. Using small-molecule inhibitors specific for these three proteins also led to growth inhibition of MPM cell lines, and Roscovitine (inhibitor of CDK1) sensitised cells to cisplatin. Protein expression was also measured in tumour samples, with markedly variable levels of CDK1 and PLK1 noted. PLK1 expression in over 10% of cells correlated significantly with a poor prognosis. Conclusion: These results suggest that RNAi-based screening has utility in identifying new targets for MPM, and that inhibition of NDC80, CDK1 and PLK1 may hold promise for treatment of this disease.

The modified Glasgow Prognostic Score (mGPS), derived from C-reactive protein (CRP) and albumin levels, and the neutrophil-lymphocyte ratio (NLR) have demonstrated prognostic significance in a number of malignancies.Baseline mGPS and NLR were calculated in a prospective cohort of chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC) (AT-101-CS-205 trial) who received docetaxel and prednisone ± AT101. Cox proportional hazards regression models estimated their effects on overall survival (OS).Of 220 eligible patients, mGPS and neutrophil and lymphocyte counts were available for 184, 193, and 112 patients, respectively. Albumin (hazard ratio [HR], 0.28; 95% confidence interval [CI]: 0.14-0.56; P.001) and CRP (HR, 1.22; 95% CI, 1.00-1.48; P = .048) were independently prognostic for OS. An association between mGPS and OS was found (HR, 1.87; 95% CI, 1.35-2.59; P.001; median survival, 23.5 months at mGPS 0 vs. 9.8 months at mGPS 2). mGPS was significant after controlling for 3 previously published nomograms or NLR (P ≤ .001). NLR was not prognostic for OS (HR, 0.98; P = .91), and no association between mGPS and toxicity was noted.Our results demonstrate the prognostic role of the mGPS in mCRPC over variables previously identified. mGPS is inexpensive, easily measured, and could be incorporated into routine clinical testing if our results are confirmed in a subsequent validation study. The utility of the NLR in mCRPC remains uncertain despite evidence in other malignancies.

The accurate diagnosis of malignant pleural mesothelioma (MPM) is essential for therapeutic and legal reasons. In 2006 the International Mesothelioma Panel advocated the use of a panel, including two mesothelial and two non-mesothelial immunohistochemical (IHC) markers. We assessed the changing use of IHC for the diagnosis of MPM in Australia over two decades in the context of current best practice.Patients with a confirmed clinico-pathological diagnosis of MPM who underwent extrapleural pneumonectomy or pleurectomy and/or decortication between 1988 and 2006 were identified from the cardiothoracic database at Royal Prince Alfred Hospital and combined with consecutive patients reviewed by the Dust Diseases Board between March 2007 and March 2009. Initial diagnostic pathology reports were reviewed.A total of 289 patients were identified. A median of six IHC stains per sample was performed (range 0-18): two (range 0-5) mesothelial markers, two (0-6) carcinoma markers and two epithelial markers. A trend to the higher usage of antibodies in epithelioid tumors versus biphasic and sarcomatoid tumors was noted (P = 0.148 and 0.389, respectively). Testing increased from a median of three stains per sample (1988-1997) to seven (2006-2009). Labeling specimens with 2 mesothelial markers and 2 carcinoma markers increased to 72 and 67 percent, respectively, after 2006.Reflecting the acceptance of diagnostic panels and increased availability of antibodies, an increase in the use of IHC stains for MPM diagnosis has occurred over the past two decades although uncertainty persists as to the optimal panel composition.

The relationship between asbestos exposure and malignant mesothelioma (MM) has been well established. Despite bans on asbestos use in an increasing number of nations, the prolonged latency from exposure to diagnosis, and the ongoing presence and use of these dangerous fibres, have led to the increasing prevalence of this deadly disease worldwide. Whilst occupational contact has been implicated in the bulk of diagnosed cases over the past 50 years, a significant proportion of disease has been linked to para-occupational, domestic and environmental exposure. In this review, we will provide an update on the impact of historical and ongoing asbestos contact in both occupational and non-occupational settings. Furthermore, we will address the unresolved controversies surrounding the use of chrysotile asbestos, the effect of gender and genetics on development of this disease, childhood mesothelioma and co-aetiological factors including SV40 exposure.

Background: Recently we demonstrated that members of the miR-15/16 family of microRNAs are implicated as tumor suppressors in MPM. The MesomiR 1 study is a first in man ongoing phase I study testing treatment with miR-15 /16 mimics packaged in EDV TM nanocells targeted with EGFR antibodies (TargomiRs). Methods: Dose escalation phase I study where patients are allowed to continue experimental therapy beyond the phase I period, if TargomiRs are well tolerated. Fifty per cent of the MTD established for EDV TM nanocells = 5 billion nanocells loaded with 1.5 µg miR 15/16 mimics (TargomiRs), was chosen as the first dose level. The study uses a standard 3-6 patient dose escalation cohort design examining weekly/twice weekly schedules with 3 planned dose levels in 6 cohorts. Based on prior experience with EDV TM nanocells, starting dose is modified for individual patients with elevated (> 5pg/mL) baseline IL-6 levels. All patients receive premedication with dexamethasone, promethazine and paracetamol and are monitored for a minimum period 3 hours after the TargomiR infusion. If treatment is well tolerated it can be repeated on 8 weeks cycles followed by repeat imaging. Quality of Life questionnaires are completed on a weekly basis. Results: The study commenced in Sep 2014 and is open in 3 centres. Five MPM patients enrolled to date received 5 billion TargomiRs and experienced a short ( Conclusions: The MesomiR 1 study is ongoing. TargomiR infusions in the first 5 patients were well tolerated and associated with transient cytokine-mediated reactions.

7586 Background: Whilst the prognosis of most MPM patients is poor, a small proportion demonstrate long term survival. We investigate patient and treatment factors associated with survival and the impact of chemotherapy (CT) and surgery in a large patient series. Methods: Data sets of patients registered with the NSW Dust Diseases Board (2002-2009) were reviewed and prognostic factors such as age, gender, histological subtype and stage evaluated using Kaplan-Meier and Cox regression analysis. The impact of treatment, smoking and asbestos exposure were evaluated and subgroup analyses explored long(er) (>20 months) vs. short(er) (< 20 months) survivors. Results: We identified 910 patients: 90% male; median age 72 yrs; histological subtype (epithelioid 60%; biphasic 13%; sarcomatoid 17%; unknown 10%); stage (Tx-I-II 48%; III-IV 52%); calretinin expression (74.8%). Treatment: CT 41%, extrapleural pneumonectomy (EPP) 6%. Median age of first occupational asbestos exposure was 18 yrs; cumulative exposure 24 yrs....