Comparison of actionable events detected in cancer genomes by whole-genome sequencing, in silico whole-exome and mutation panels.

BACKGROUND: Next-generation sequencing is used in cancer research to identify somatic and germline mutations, which can predict sensitivity or resistance to therapies, and may be a useful tool to reveal drug repurposing opportunities between tumour types. Multigene panels are used in clinical practice for detecting targetable mutations. However, the value of clinical whole-exome sequencing (WES) and whole-genome sequencing (WGS) for cancer care is less defined, specifically as the majority of variants found using these technologies are of uncertain significance. PATIENTS AND METHODS: We used the Cancer Genome Interpreter and WGS in 726 tumours spanning 10 cancer types to identify drug repurposing opportunities. We compare the ability of WGS to detect actionable variants, tumour mutation burden (TMB) and microsatellite instability (MSI) by using in silico down-sampled data to mimic WES, a comprehensive sequencing panel and a hotspot mutation panel. RESULTS: We reveal drug repurposing opportunities as numerous biomarkers are shared across many solid tumour types. Comprehensive panels identify the majority of approved actionable mutations, with WGS detecting more candidate actionable mutations for biomarkers currently in clinical trials. Moreover, estimated values for TMB and MSI vary when calculated from WGS, WES and panel data, and are dependent on whether all mutations or only non-synonymous mutations were used. Our results suggest that TMB and MSI thresholds should not only be tumour-dependent, but also be sequencing platform-dependent. CONCLUSIONS: There is a large opportunity to repurpose cancer drugs, and these data suggest that comprehensive sequencing is an invaluable source of information to guide clinical decisions by facilitating precision medicine and may provide a wealth of information for future studies. Furthermore, the sequencing and analysis approach used to estimate TMB may have clinical implications if a hard threshold is used to indicate which patients may respond to immunotherapy.

Real-life effectiveness of omalizumab in severe allergic asthma above the recommended dosing range criteria.

BACKGROUND: Omalizumab (Xolair) dosing in severe allergic asthma is based on serum IgE and bodyweight. In Australia, patients eligible for omalizumab but exceeding recommended ranges for IgE (30-1500 IU/mL) and bodyweight (30-150 kg) may still receive a ceiling dose of 750 mg/4 weeks. About 62% of patients receiving government-subsidized omalizumab are enrolled in the Australian Xolair Registry (AXR). OBJECTIVES: To determine whether AXR participants above the recommended dosing ranges benefit from omalizumab and to compare their response to within-range participants. METHODS: Data were stratified according to dose range status (above-range or within-range). Further sub-analyses were conducted according to the reason for being above the dosing range (IgE only vs. IgE and weight). RESULTS: Data for 179 participants were analysed. About 55 (31%) were above recommended dosing criteria; other characteristics were similar to within-range participants. Above-range participants had higher baseline IgE [812 (IQR 632, 1747) IU/mL vs. 209 (IQR 134, 306) IU/mL] and received higher doses of omalizumab [750 (IQR 650, 750) mg] compared to within-range participants [450 (IQR, 300, 600) mg]. At 6 months, improvements in Juniper 5-item Asthma Control Questionnaire (ACQ-5, 3.61 down to 2.01 for above-range, 3.47 down to 1.93 for within-range, P < 0.0001 for both) and Asthma Quality of Life Questionnaire (AQLQ mean score (3.22 up to 4.41 for above-range, 3.71 up to 4.88 for within-range, P < 0.0001) were observed in both groups. Forced expiratory volume in one second (FEV1 ) improved among above-range participants. There was no difference in response between above-range and within-range participants. Above-range participants due to either IgE alone or IgE and weight had similar improvements in ACQ-5, AQLQ and FEV1 . CONCLUSIONS AND CLINICAL RELEVANCE: Patients with severe allergic asthma above recommended dosing criteria for omalizumab have significantly improved symptom control, quality of life and lung function to a similar degree to within-range participants, achieved without dose escalation above 750 mg.

Effectiveness and response predictors of omalizumab in a severe allergic asthma population with a high prevalence of comorbidities: the Australian Xolair Registry.

BACKGROUND: Severe asthma is a high impact disease. Omalizumab targets the allergic inflammatory pathway; however, effectiveness data in a population with significant comorbidities are limited. AIMS: To describe severe allergic asthma, omalizumab treatment outcomes and predictors of response among the Australian Xolair Registry participants. METHODS: A web-based post-marketing surveillance registry was established to characterise the use, effectiveness and adverse effects of omalizumab (Xolair) for severe allergic asthma. RESULTS: Participants (n = 192) (mean age 51 years, 118 female) with severe allergic asthma from 21 clinics in Australia were assessed, and 180 received omalizumab therapy. They had poor asthma control (Asthma Control Questionnaire, ACQ-5, mean score 3.56) and significant quality of life impairment (Asthma-related Quality of Life Questionnaire score 3.57), and 52% were using daily oral corticosteroid (OCS). Overall, 95% had one or more comorbidities (rhinitis 48%, obesity 45%, cardiovascular disease 23%). The omalizumab responder rate, assessed by an improvement of at least 0.5 in ACQ-5, was high at 83%. OCS use was significantly reduced. The response in participants with comorbid obesity and cardiovascular disease was similar to those without these conditions. Baseline ACQ-5 ≥ 2.0 (P = 0.002) and older age (P = 0.05) predicted the magnitude of change in ACQ-5 in response to omalizumab. Drug-related adverse events included anaphylactoid reactions (n = 4), headache (n = 2) and chest pains (n = 1). CONCLUSION: Australian patients with severe allergic asthma report a high disease burden and have extensive comorbidity. Symptomatic response to omalizumab was high despite significant comorbid disease. Omalizumab is an effective targeted therapy for severe allergic asthma with comorbidity in a real-life setting.

Coccidioidomycosis in returned Australian travellers.

Coccidioidomycosis is a fungal infection caused by Coccidioides species. The disease has wide clinical presentation and a distinct geographical distribution. We describe two cases of coccidioidomycosis in returned Australian travellers who presented to Nambour Hospital. Knowledge of the international geographical distribution of endemic fungal infections and their clinical manifestations can assist in earlier diagnosis and appropriate management.

Ploidy as a prognostic determinant in surgically treated lung cancer.

The usefulness of tumour ploidy as a prognostic determinant in lung cancer was evaluated in a group of 100 surgically treated patients. Archival paraffin sections of the tumours were analysed by flow cytometry. 45% of tumours were aneuploid and 55% were diploid. Overall, patients with aneuploid tumours had significantly shorter survival (p less than 0.0005) than those with diploid tumours. The subset of patients without nodal involvement at operation and with diploid tumours had a particularly long survival rate. Of these 45 patients 41 (91%) were alive at 2 years compared with only 16 (55%) of the 29 with aneuploid tumours (p less than 0.05). A group with such a favourable prognosis has not previously been recognised except when staging is based on total mediastinal nodal clearance. Ploidy was found to be independent of age, sex, type of operation, site of primary tumour, histology, or TNM category. On Cox multivariate analysis ploidy was the most important and independent prognostic determinant. Therefore, in patients with operable lung cancer, ploidy should be taken into account in planning of management, in estimation of prognosis, and in stratification for treatment trials.

Saltwater drowning and near-drowning accidents involving children. A five-year total population study in south-east Queensland.

A large total population study of childhood saltwater immersion accidents is reported. A total of 49 cases (16 fatalities, 33 survivors) occurred in the five year period from 1971 to 1975 in southeastern Queensland. As a group, more children survive a potentially fatal saltwater immersion (67%) than do those who lose consciousness in freshwater (50%). The serious saltwater accident rate (loss of consciousness or death) in childhood (from 0 to 15 years inclusive, is 3.37/100,000 children per year at risk (fatality rate 1.12). This is low; comparison with freshwater data shows that although the surf presents special hazards to children, it is very much safer than other types of water. Age-specific and site-specific accident and survival rates for saltwater immersions are presented for the first time. Toddlers are disproportionately represented (33% of all children) and their survival rates are lowest. Boating and the use of surfboards, in current practice, are negligible threats to children. The saltwater immersion rate is increasing (although the absolute risk is small) and reasons for this are discussed. Childhood saltwater immersions were unaffected by tidal state. All but one case of immersion occurred during daylight hours, and in younger children immersion occurred often on weekends.