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Summary: Prostate cancer remains one of the leading causes of cancer‐related death in the world. There have been significant advances in chemotherapy, hormonal therapy and targeted therapy options for patients with castrate‐resistant disease. However, these systemic treatments are often associated with unwanted toxicities. Targeted therapy with radiopharmaceuticals has become of key interest to limit systemic toxicity and provides a more precision oncology approach to treatment. Strontium‐89, Samarium‐153 EDTMP and Radium‐223 have been trialled with mixed results. Strontium‐89 and Samarium‐153 EDTMP have shown benefits in palliating metastatic bone pain but with no impact on survival outcomes. Early therapeutic radiopharmaceuticals targeting PSMA that were developed were beta‐emitting agents, but recently alpha‐emitting agents are being investigated as potentially superior options. Radium‐223 is the first alpha‐particle emitter therapeutic agent approved by the FDA, with phase III trial evidence showing benefits in overall survival and delay in symptomatic skeletal events for patients. Recently, 177‐Lutetium‐PSMA‐617 has demonstrated significant survival advantages in pre‐treated metastatic castrate‐resistant cancer patients in a number of phase II and III studies. Furthermore, 225‐Actinium‐PSMA‐617 also showed promise even in patients pre‐treated with 177‐Lutetium‐PSMA‐617. Hence, there has been an explosion of radiopharmaceutical treatment options for patients with prostate cancer. This review explores past and current theranostic capacities in the radiopharmaceutical treatment of metastatic castrate‐resistant prostate cancer. [ABSTRACT FROM AUTHOR]

Background: The standard of care in newly diagnosed metastatic non‐small cell lung cancer (NSCLC) is to test for aberrations in three genes for driver mutations – ALK, ROS1 and epidermal growth factor receptor (EGFR) – and also for immunohistochemistry to be performed for programmed death‐ligand 1 expression level. Next‐generation sequencing (NGS), with or without RNA fusion testing, is increasingly used in standard clinical practice to identify patients with potentially actionable mutations. Stratification of NGS mutation tiers is currently based on the European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT) Tiers I–V and X. Aim: Our aim was to analyse NSCLC tumour samples for the prevalence of Tiers I–V mutations to establish guidance for current and novel treatments in patients with metastatic disease. Methods: NGS was performed employing the Oncomine Precision Assay (without RNA fusion testing) that interrogates DNA hotspot variants across 45 genes to screen 210 NSCLC tissue samples obtained across six Sydney hospitals between June 2021 and March 2022. Results: In our cohort, 161 of 210 (77%) had at least one gene mutation identified, with 41 of 210 (20%) having two or more concurrent mutations. Tier I mutations included 42 of 210 (20%) EGFR mutations (EIA) and five of 210 (3%) MET exon 14 skipping mutations (EIB). Non‐Tier I variants included 22 of 210 (11%) KRAS G12C hotspot mutations (EIIB), with a further 47 of 210 (22%) having non‐G12C KRAS (EX) mutations. NGS testing revealed an additional 15% of cases with Tier II ESCAT mutations in NSCLC. Forty‐six percent of patients also demonstrated potential Tier III and IV mutations that are currently under investigation in early‐phase clinical trials. Conclusions: In addition to identifying patients with genomic alterations suitable for clinically proven standard‐of‐care therapeutic options, the 45‐gene NGS panel has significant potential in identifying potentially actionable non‐Tier 1 mutations that may become future standard clinical practice in NSCLC. [ABSTRACT FROM AUTHOR]

Abstract Background Proteins of the mammalian PYHIN (IFI200/HIN-200) family are involved in defence against infection through recognition of foreign DNA. The family member absent in melanoma 2 (AIM2) binds cytosolic DNA via its HIN domain and initiates inflammasome formation via its pyrin domain. AIM2 lies within a cluster of related genes, many of which are uncharacterised in mouse. To better understand the evolution, orthology and function of these genes, we have documented the range of PYHIN genes present in representative mammalian species, and undertaken phylogenetic and expression analyses. Results No PYHIN genes are evident in non-mammals or monotremes, with a single member found in each of three marsupial genomes. Placental mammals show variable family expansions, from one gene in cow to four in human and 14 in mouse. A single HIN domain appears to have evolved in the common ancestor of marsupials and placental mammals, and duplicated to give rise to three distinct forms (HIN-A, -B and -C) in the placental mammal ancestor. Phylogenetic analyses showed that AIM2 HIN-C and pyrin domains clearly diverge from the rest of the family, and it is the only PYHIN protein with orthology across many species. Interestingly, although AIM2 is important in defence against some bacteria and viruses in mice, AIM2 is a pseudogene in cow, sheep, llama, dolphin, dog and elephant. The other 13 mouse genes have arisen by duplication and rearrangement within the lineage, which has allowed some diversification in expression patterns. Conclusions The role of AIM2 in forming the inflammasome is relatively well understood, but molecular interactions of other PYHIN proteins involved in defence against foreign DNA remain to be defined. The non-AIM2 PYHIN protein sequences are very distinct from AIM2, suggesting they vary in effector mechanism in response to foreign DNA, and may bind different DNA structures. The PYHIN family has highly varied gene composition between mammalian species due to lineage-specific duplication and loss, which probably indicates different adaptations for fighting infectious disease. Non-genomic DNA can indicate infection, or a mutagenic threat. We hypothesise that defence of the genome against endogenous retroelements has been an additional evolutionary driver for PYHIN proteins.