Asbestos-related lung cancer: Clinical characteristics and survival outcomes in an Australian cohort seeking workers compensation.

BACKGROUND AND OBJECTIVES: Due to difficulties in identifying sufficient-sized cohorts there remains uncertainty about prognostic and clinical differences that may be unique to asbestos-related lung cancer (ARLC). In this study, we use the Helsinki Criteria to define a group of ex-workers with lung cancer attributable to asbestos exposure and investigate differences that may exist. METHODS: A total of 529 patients seeking workers' compensation for their lung cancer were assigned to either ARLC or the non-ARLC based on parameters defined in the Helsinki Criteria. Clinical and survival details were collected and analyzed. RESULTS: In our study population, ARLC patients were on average older (72.1 ± 7.8) than non-ARLC patients (66.5 ± 10.2, P < 0.001) and were more likely to be diagnosed as a result of incidental findings or screening program (P < 0.001). The groups were similar in terms of clinical characteristics with the only difference being that plaques were more prevalent among ARLC patients (P < 0.001). Differences were observed for median overall survival (OS), ARLC (9 months) and non-ARLC (13 months, P = 0.005), as well for treatment (P = 0.01). After adjusting for age, however, these differences disappeared. CONCLUSIONS: Age at diagnosis, pleural plaques, and asymptomatic presentation were the attributes that we identified as significantly different between asbestos-related cancer and other lung cancers. In this cohort, ARLC patients were older diagnosis and with worse overall survival.

Trends in treatment episodes for methamphetamine smoking and injecting in Australia, 2003-2019.

INTRODUCTION: We examined trends in Australian treatment episodes for smoking and injecting methamphetamine from 2003 to 2019. METHODS: Data from the Alcohol and Other Drug Treatment National Minimum Data Set, where amphetamines were the principal drug of concern, were analysed from 2003 to 2019. Rates were calculated per 100 000 population aged 10-100 years. Joinpoint software was used to identify changepoints and estimate the annual percentage change (APC) in the rate of treatment episodes. Treatment episode characteristics were compared for smoking versus injecting in 2019. RESULTS: The rate of treatment episodes for methamphetamine increased from 77 to 262 per 100 000 population between 2003 and 2019 (average APC 8%, P < 0.001), this being due to treatment episodes for smoking methamphetamine (average APC 32%, P < 0.001) with no significant increase in treatment episodes for injecting methamphetamine (average APC 3%). Treatment episodes for smoking increased sharply from 2003 to 2008 (APC 72%, P < 0.001) and again from 2010 to 2016 (APC 46%, P < 0.001), this upward trend being attenuated between 2016 and 2019 (APC 7%, P = 0.012). Treatment episodes for methamphetamine smoking (cf. injecting) involved younger clients (median age 30 vs. 35 years, P < 0.001) who were more likely to receive assessment or case management only (37% vs. 29%, P < 0.001). DISCUSSION AND CONCLUSIONS: Increased methamphetamine treatment episodes in Australia since 2003 are due mostly to smoking the drug, this occurring among younger cohort who receive less substantive treatment than clients who inject methamphetamine.

Associations between sun sensitive pigmentary genes and serum prostate specific antigen levels.

BACKGROUND: Melanoma and prostate cancer may share risk factors. This study examined the association between serum PSA levels, which is a risk factor for prostate cancer, and variants in some melanoma-associated pigmentary genes. METHODS: We studied participants, all aged 70+ years, in the Concord Health and Ageing in Men Project who had no history of prostatitis or received treatment for prostate disease (n = 1033). We genotyped variants in MC1R (rs1805007, rs1805008), ASIP (rs4911414, rs1015362), SLC45A2 (rs28777, rs16891982), IRF4 (rs12203592), TYRP1 (rs1408799), TYR (rs1126809, rs1042602), SLC24A2 (rs12896399), and OCA2 (rs7495174). Generalised linear dominant models with Poisson distribution, log link functions and robust variance estimators estimated adjusted percentage differences (%PSA) in mean serum PSA levels (ng/mL) between variant and wildtype (0%PSA = reference) genotypes, adjusting for age, body mass index, serum 25OHD levels and birth regions (Australia or New Zealand (ANZ), Europe or elsewhere). RESULTS: Serum PSA levels were strongly associated with advancing age and birth regions: mean PSA levels were lower in Europe-born (-29.7%) and elsewhere-born (-11.7%) men than ANZ-born men (reference). Lower %PSA was observed in men with variants in SLC45A2: rs28777 (-19.6;95%CI: -33.5, -2.7), rs16891982 (-17.3;95%CI:-30.4,-1.7) than in wildtype men (reference). There were significant interactions between birth regions and PSA levels in men with variants in MC1R (rs1805007; p-interaction = 0.0001) and ASIP (rs4911414; p-interaction = 0.007). For these genes %PSA was greater in ANZ-born men and lower in Europe- and elsewhere-born men with the variant than it was in wildtype men. In a post hoc analysis, serum testosterone levels were increased in men with MC1R rs1805007 and serum dihydrotestosterone in men with ASIP rs1015362. CONCLUSION: Men with SNPs in SLC45A2, who have less sun sensitive skin, have lower PSA levels. Men with SNPs in MC1R and ASIP, who have more sun sensitive skin, and were born in ANZ, have higher PSA levels. Androgens may modify these apparent associations of pigmentary genes and sun exposure with PSA levels. IMPACT: PSA levels and possibly prostate cancer risk may vary with sun sensitivity and sun exposure, the effects of which might be modified by androgen levels.

Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: a first-in-man, phase 1, open-label, dose-escalation study.

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 × 109, 7 × 109, and 9 × 109 TargomiRs either once or twice weekly, but after analysis of data from the first eight patients, all subsequent patients started protocol treatment at 1 × 109 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 × 109 TargomiRs twice weekly; anaphylaxis and cardiomyopathy, respectively, in two patients given 5 × 109 TargomiRs once weekly but who received reduced dexamethasone prophylaxis; and non-cardiac pain in one patient who received 5 × 109 TargomiRs once weekly. We established that 5 × 109 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.