Real-world experience of immune checkpoint inhibitors in patients with solid tumours in the Top End of the Northern Territory, Australia from 2016 to 2021: a retrospective observational cohort study.

BACKGROUND: Use of immune checkpoint inhibitors is growing, but clinical trial data may not apply to Indigenous patients or patients living in remote areas. AIMS: To provide real-world incidence of immune-related adverse events (irAE) in the Top End of the Northern Territory and compare incidence between demographic subgroups. METHODS: This retrospective, observational, cohort study collected data from electronic records of patients living in the Top End with solid organ cancer treated with immunotherapy between January 2016 and December 2021. The primary outcome was cumulative incidence of any-grade and severe irAE. Secondary outcomes were overall survival, treatment duration and reason for treatment discontinuation. RESULTS: Two hundred and twenty-six patients received immunotherapy. Forty-eight (21%) lived in a remote or very remote area, and 36 (16%) were Indigenous. Cumulative incidence of any-grade irAE was 54% (122/226 patients); incidence of severe irAE was 26% (59/226 patients). Rates were similar between Indigenous and non-Indigenous patients of any-grade (42% vs 56%, P = 0.11) and severe (11% vs 18%, P = 0.29) irAE. However, Indigenous patients had shorter treatment duration, more frequently discontinued treatment due to patient preference and appeared to have shorter median overall survival than non-Indigenous patients (17.1 vs 30.4 months; hazard ratio (HR) = 1.5, 95% confidence interval (CI) = 0.92-2.66). There was no difference in mortality between remote and urban patients (median overall survival 27.5 vs 30.2 months; HR = 1.1, 95% CI = 0.7-1.7). CONCLUSIONS: Rates of irAE in our cohort are comparable to those in the published literature. There was no significant difference in any-grade or severe irAE incidence observed between Indigenous and non-Indigenous patients.

The quaternary question: Determining allostery in spastin through dynamics classification learning and bioinformatics.

The nanomachine from the ATPases associated with various cellular activities superfamily, called spastin, severs microtubules during cellular processes. To characterize the functionally important allostery in spastin, we employed methods from evolutionary information, to graph-based networks, to machine learning applied to atomistic molecular dynamics simulations of spastin in its monomeric and the functional hexameric forms, in the presence or absence of ligands. Feature selection, using machine learning approaches, for transitions between spastin states recognizes all the regions that have been proposed as allosteric or functional in the literature. The analysis of the composition of the Markov State Model macrostates in the spastin monomer, and the analysis of the direction of change in the top machine learning features for the transitions, indicate that the monomer favors the binding of ATP, which primes the regions involved in the formation of the inter-protomer interfaces for binding to other protomer(s). Allosteric path analysis of graph networks, built based on the cross-correlations between residues in simulations, shows that perturbations to a hub specific for the pre-hydrolysis hexamer propagate throughout the structure by passing through two obligatory regions: the ATP binding pocket, and pore loop 3, which connects the substrate binding site to the ATP binding site. Our findings support a model where the changes in the terminal protomers due to the binding of ligands play an active role in the force generation in spastin. The secondary structures in spastin, which are found to be highly degenerative within the network paths, are also critical for feature transitions of the classification models, which can guide the design of allosteric effectors to enhance or block allosteric signaling.

A healthy patient with bilateral frozen hips preceding bilateral frozen shoulders: a cautionary tale.

Adhesive capsulitis of the shoulder (frozen shoulder) is a common disease characterised by spontaneous onset of pain and restriction of movement, followed by 'thawing', with complete or near-complete resolution. Adhesive capsulitis of the hip has been reported in around a dozen patients. This report describes an otherwise-healthy middle-aged woman with apparent sequential resolving adhesive capsulitis of all four ball-and-socket joints over a 9-year period, initially affecting each hip and then each shoulder sequentially. The likely hip diagnosis became clear only retrospectively with development of the second frozen shoulder, 5 years after the first pain. All joints subsequently resolved within the expected timeframe and the patient remains healthy, other than having mild hypertension. This case illustrates that, when hip precedes shoulder involvement, there is the potential for the frozen hip to receive alternate diagnoses for which invasive open hip surgery could unnecessarily be recommended.