The histone–lysine N-methyltransferase (KMT2) family comprises a set of lysine methyltransferases that methylate the lysine 4 residue on histone H3 (H3K4). KMT2 family members demonstrate different substrate specificity in vitro and their methyltransferase activities are dependent, to varying degrees, on association with three core subunits (WD repeat protein 5, retinoblastoma binding protein 5 and ASH2L). KMT2 family members have intrinsically different biochemical properties and are recruited to different genomic regions owing to their distinct domain structures and distinct interacting proteins. KMT2 family members have important roles in transcription regulation. Among them, KMT2C and KMT2D are crucial for monomethylation of H3K4 at distal regulatory enhancers, whereas KMT2F and KMT2G are responsible for the majority of H3K4 trimethylation at transcription start sites. There is extensive interplay between KMT2-dependent H3K4 methylation and DNA methylation, underlying the potential epigenetic stability of this histone methylation. Mutations in the KMT2 family are among the most common genetic aberrations in human cancer — including haematological malignancies as well as solid tumours, such as large intestine, lung, endometrial, breast, bladder and brain cancers. Mutations in the KMT2 family frequently involve the SET domain and the plant homeotic domains. Of somatic mutations in cancers with known zygosity, heterozygous mutations predominate. These features suggest that the wild-type KMT2 allele may be required for tumour survival, similar to KMT2A-rearranged mixed lineage leukaemia. KMT2 family members may have distinct roles in cancer. Although it remains unclear whether cancer-derived KMT2 mutations are 'drivers' or 'passengers', mechanistic studies in animal models suggest that KMT2C may be a tumour suppressor and KMT2A and KMT2D may be proteins derived from proto-oncogenes. The targeting of the fusion protein and wild-type KMT2A, as well as their interacting proteins, has emerged as a promising strategy to treat mixed lineage leukaemia, and may apply more broadly to a variety of cancers.

Over the last decade, human cell transplantation and neural stem cell trials have examined the feasibility and safety of these potential therapies for treatment of a variety of neurological disorders. However, significant safety concerns have surrounded these trials due to the possibility of ectopic, uncontrolled cellular growth and tumor formation. The authors present the case of an 18-year-old woman who sustained a complete spinal cord injury at T10–11. Three years after injury, she remained paraplegic and underwent olfactory mucosal cell implantation at the site of injury. She developed back pain 8 years later, and imaging revealed an intramedullary spinal cord mass at the site of cell implantation, which required resection. Intraoperative findings revealed an expanded spinal cord with a multicystic mass containing large amounts of thick mucus-like material. Histological examination and immunohistochemical staining revealed that the mass was composed mostly of cysts lined by respiratory epithelium, submucosal glands with goblet cells, and intervening nerve twigs. This is the first report of a human spinal cord mass complicating spinal cord cell transplantation and neural stem cell therapy. Given the prolonged time to presentation, safety monitoring of all patients with cell transplantation and neural stem cell implantation should be maintained for many years.

To describe the spectral-domain optical coherence tomography (SD OCT) features of peripheral retinal findings using an ultra-widefield (UWF) steering technique to image the retinal periphery. Observational study. A total of 68 patients (68 eyes) with 19 peripheral retinal features. Spectral-domain OCT-based structural features. Nineteen peripheral retinal features, including vortex vein, congenital hypertrophy of the retinal pigment epithelium, pars plana, ora serrata pearl, typical cystoid degeneration (TCD), cystic retinal tuft, meridional fold, lattice and cobblestone degeneration, retinal hole, retinal tear, rhegmatogenous retinal detachment, typical degenerative senile retinoschisis, peripheral laser coagulation scars, ora tooth, cryopexy scars (retinal tear and treated retinoblastoma scar), bone spicules, white without pressure, and peripheral drusen, were identified by peripheral clinical examination. Near-infrared scanning laser ophthalmoscopy images and SD OCT of these entities were registered to UWF color photographs. Spectral-domain OCT resolved structural features of all peripheral findings. Dilated hyporeflective tubular structures within the choroid were observed in the vortex vein. Loss of retinal lamination, neural retinal attenuation, retinal pigment epithelium loss, or hypertrophy was seen in several entities, including congenital hypertrophy of the retinal pigment epithelium, ora serrata pearl, TCD, cystic retinal tuft, meridional fold, lattice, and cobblestone degenerations. Hyporeflective intraretinal spaces, indicating cystoid or schitic fluid, were seen in ora serrata pearl, ora tooth, TCD, cystic retinal tuft, meridional fold, retinal hole, and typical degenerative senile retinoschisis. The vitreoretinal interface, which often consisted of lamellae-like structures of the condensed cortical vitreous near or adherent to the neural retina, appeared clearly in most peripheral findings, confirming its association with many low-risk and vision-threatening pathologies, such as lattice degeneration, meridional folds, retinal breaks, and rhegmatogenous retinal detachments. Ultra-widefield steering-based SD OCT imaging of the retinal periphery is feasible with current commercially available devices and provides detailed anatomic information of the peripheral retina, including benign and pathologic entities, not previously imaged. This imaging technique may deepen our structural understanding of these entities and their potentially associated macular and systemic pathologies, and may influence decision-making in clinical practice, particularly in areas with teleretinal capabilities but poor access to retinal specialists.

Major advances in the study of inherited retinal diseases (IRDs) have placed efforts to develop treatments for these blinding conditions at the forefront of the emerging field of precision medicine. As a result, the growth of clinical trials for IRDs has increased rapidly over the past decade and is expected to further accelerate as more therapeutic possibilities emerge and qualified participants are identified. Although guided by established principles, these specialized trials, requiring analysis of novel outcome measures and endpoints in small patient populations, present multiple challenges relative to study design and ethical considerations. This position paper reviews recent accomplishments and existing challenges in clinical trials for IRDs and presents a set of recommendations aimed at rapidly advancing future progress. The goal is to stimulate discussions among researchers, funding agencies, industry, and policy makers that will further the design, conduct, and analysis of clinical trials needed to accelerate the approval of effective treatments for IRDs, while promoting advocacy and ensuring patient safety.

Next generation sequencing of vitreoretinal lymphomas from small-volume intraocular liquid biopsies: new routes to targeted therapies