The NHS England 100,000 Genomes Project: feasibility and utility of centralised genome sequencing for children with cancer

Background Whole-genome sequencing (WGS) of cancers is becoming an accepted component of oncological care, and NHS England is currently rolling out WGS for all children with cancer. This approach was piloted during the 100,000 genomes (100 K) project. Here we share the experience of the East of England Genomic Medicine Centre (East-GMC), reporting the feasibility and clinical utility of centralised WGS for individual children locally.Methods Non-consecutive children with solid tumours were recruited into the pilot 100 K project at our Genomic Medicine Centre. Variant catalogues were returned for local scrutiny and appraisal at dedicated genomic tumour advisory boards with an emphasis on a detailed exploration of potential clinical value.Results Thirty-six children, representing one-sixth of the national 100 K cohort, were recruited through our Genomic Medicine Centre. The diagnoses encompassed 23 different solid tumour types and WGS provided clinical utility, beyond standard-of-care assays, by refining (2/36) or changing (4/36) diagnoses, providing prognostic information (8/36), defining pathogenic germline mutations (1/36) or revealing novel therapeutic opportunities (8/36).Conclusion Our findings demonstrate the feasibility and clinical value of centralised WGS for children with cancer. WGS offered additional clinical value, especially in diagnostic terms. However, our experience highlights the need for local expertise in scrutinising and clinically interpreting centrally derived variant calls for individual children.Subject terms: Cancer genomics, Cancer genomics     

Reflex responses to baroreceptor, chemoreceptor and nociceptor inputs in single renal sympathetic neurones in the rabbit and the effects of anaesthesia on them

Reflex responses of renal postganglionic neurones to stimulation of arterial baroreceptors, arterial and central chemoreceptors and cutaneous nociceptors, and the rhythmicity of their resting activity were studied in paralyzed, artificially ventilated rabbits, anaesthetized with either alfathesin or chloralose-urethane. A 'vasoconstrictor' response pattern was seen in all units. Perivascular balloon-induced falls in blood pressure increased firing while pressure rises silenced 90% of units and reduced firing in the rest. Resting activity was linked to pressure changes within the cardiac cycle and to the artificial respiratory cycle. The largest excitation occurred during hypoxia and injections of CO2 saturated solutions into the carotid artery while hypercapnia and stimulation of cutaneous nociceptors only slightly increased firing. Parameters characterizing rhythmicities and reflex responses were unimodally distributed with no apparent subgrouping of units on quantitative grounds. Unit response patterns were similar to those recorded in the whole renal nerve. With one exception, no silent units were found which responded to the afferent inputs studied. Nor was there a small-spike fibre group which was excited by angiotensin. However, reflex responses were significantly influenced by the anaesthetic regime selected for use. Under alfathesin, baroreceptor and chemoreceptor reflexes were double those found with chloralose-urethane. Under chloralose-urethane, hypoxia increased both rhythmicities, while under alfathesin, cardiac rhythmicity was decreased and respiratory rhythmicity was variably affected. We concluded that renal sympathetic neurones are a functionally uniform population which behave like vasoconstrictors.     

Perisilicone proliferation after vitrectomy for proliferative vitreoretinopathy

From 1983 to 1986, silicone oil injections were used to treat 31 patients with retinal detachment (RD) and advanced proliferative vitreoretinopathy (PVR). In 19 eyes (61%), perisilicone proliferation (PSP) developed causing recurrent RDs in 15 eyes (49%). At an average of 5 weeks after surgery, PSP occurred and was characterized by extensive transparent preretinal membranes with denser focal areas. Microscopic examination of five preretinal membranes showed droplets of silicone oil and necrotic cells on the silicone side and glial or retinal pigment epithelial cells, or both, on the retinal side, often in layers separated by extracellular matrix. Silicone oil was present in periretinal membranes removed several months after the intraocular silicone had been evacuated indicating that silicone within cells may persist despite the removal of silicone. The use of silicone oil to provide tamponade in eyes with recurrent PVR is associated with a high incidence of periretinal proliferation that frequently leads to recurrent RD and visual failure.     

Embolization of intracranial aneurysms with Guglielmi detachable coils augmented by microballoons.

We describe two cases in which balloons were used to aid in the occlusion of intracranial aneurysms with Guglielmi detachable coils. In both patients, initial attempts to place coils within the aneurysmal sac failed, as the loops of the coil repeatedly protruded through a wide aneurysmal neck into the parent vessel. Temporary balloons placed across the neck of these small, wide-necked aneurysms, the bridging balloon technique, effectively narrowed the necks, providing support for the formation of a proper coil basket, which was not possible without the balloon. Follow-up studies at 1 year showed good results in both patients.