Royal Devon and Exeter Hospital

About: Royal Devon and Exeter Hospital is a healthcare organization based out in Exeter, United Kingdom. It is known for research contribution in the topics: Population & Randomized controlled trial. The organization has 2282 authors who have published 2526 publications receiving 78866 citations. The organization is also known as: RD&E.

Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Abstract: Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed p-values of association ranged between 0.005-1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.

Ultrasonographic study of sucking and swallowing by newborn infants.

Abstract: SIRWeber and colleagues (DMCN, 28, 19-24) included in their results on bottle-fed babies a trace (their Fig. 2) drawn from a video screen showing suck-swallow cycles and a respiratory trace recorded from a Graseby Dynamics Apnoea Alarm. Commenting on the co-ordination of swallowing and breathing, the authors state: ‘In some of the babies the swallows occurred consistently in the end-expiratory pause (between expiration and inspiration). This was noted particularly in fourand five-day-old babies. In others, notably babies at two days of age, the breath was held during either inspiration or expiration, in association with a swallowing motion’. In our series of observations on bottle-fed babies, made on a much larger sample than that reported by Weber et al. and using different techniques to record sucking, swallowing and respiration, we have found that the pattern for two-day-old babies is commonly a form which we have called ‘immature’. It later develops, over about five to eight days, into a more ‘mature’ pattern. We were disturbed to find that the patterns we had observed over many measurements did not agree with those of Weber et al. In particular, our recordings show that the swallow of a mature infant is almost always preceded by an inspiration and followed by an expiration. In those cases when swallowing occurs on expiration, the expiratory flow is arrested as a swallow takes place and then ccntinues before an inspiration. We have no record, from over 100 recordings, of an infant swallowing at end-expiration. To confirm our findings we have Fig. 1. Signals from three transducers recorded simultaneously from eight-day-old baby during resting respiration. Upper trace: thermistor anemometer held at naris. Centre trace: pressure drop across naris, indicating direction of nasal airflow. Bottom trace: Graseby Apnoea Monitor output (E = expiration, I = inspiration). Difference in height of anemometer trace is partly due to inhaled air more easily avoiding the transducer.

Intramedullary spinal metastasis from carcinoma of the cervix.

Abstract: Intramedullary spinal metastases are rare and prior to the availability of MRI were seldom diagnosed antemortem. Lung and breast carcinoma are the most common primary sources. Cervical carcinoma is the least likely source of intramedullary spinal metastases. A case of intramedullary spinal metastases is described in a 29-year-old woman with squamous cell carcinoma of the cervix.

The role of molecular genetics in the clinical management of sporadic medullary thyroid carcinoma: A systematic review

Abstract: Background The significant variation in the clinical behaviour of sporadic medullary thyroid carcinoma (sMTC) causes uncertainty when planning the management of these patients. Several tumour genetic and epigenetic markers have been described, but their clinical usefulness remains unclear. The aim of this review was to evaluate the evidence for the use of molecular genetic and epigenetic profiles in the risk stratification and management of sMTC. Methods MEDLINE and Embase databases were searched using the MeSH terms "medullary carcinoma", "epigenetics", "molecular genetics", "microRNAs"; and free text terms "medullary carcinoma", "sporadic medullary thyroid cancer", "sMTC", "RET", "RAS" and "miR". Articles containing less than ten subjects, not focussing on sMTC, or not reporting clinical outcomes were excluded. Risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale. Results Twenty-three studies met the inclusion criteria, and key findings were summarized in themes according to the genetic and epigenetic markers studied. There is good evidence that somatic RET mutations predict higher rates of lymph node metastasis and persistent disease, and worse survival. There are also several good quality studies demonstrating associations between certain epigenetic markers such as tumour miR-183 and miR-375 expression and higher rates of lymph node and distant metastasis, and worse survival. Conclusions There is a growing body of evidence that tumour genetic and epigenetic profiles can be used to risk stratify patients with sMTC. Further research should focus on the clinical applicability of these findings by investigating the possibility of tailoring management to an individual's tumour mutation profile.

Association of Hemochromatosis HFE p.C282Y Homozygosity With Hepatic Malignancy

Abstract: Importance Hereditary hemochromatosis is predominantly caused by theHFEp.C282Y homozygous pathogenic variant. Liver carcinoma and mortality risks are increased in individuals with clinically diagnosed hereditary hemochromatosis, but risks are unclear in mostly undiagnosed p.C282Y homozygotes identified in community genotyping. Objective To estimate the incidence of primary hepatic carcinoma and death byHFEvariant status. Design, Setting, and Participants Cohort study of 451 186 UK Biobank participants of European ancestry (aged 40-70 years), followed up from baseline assessment (2006-2010) until January 2018. Exposures Men and women withHFEp.C282Y and p.H63D genotypes compared with those with neitherHFEvariants. Main Outcomes and Measures Two linked co–primary outcomes (incident primary liver carcinoma and death from any cause) were ascertained from follow-up via hospital inpatient records, national cancer registry, and death certificate records, and from primary care data among a subset of participants for whom data were available. Associations between genotype and outcomes were tested using Cox regression adjusted for age, assessment center, genotyping array, and population genetics substructure. Kaplan-Meier lifetable probabilities of incident diagnoses were estimated from age 40 to 75 years byHFEgenotype and sex. Results A total of 451 186 participants (mean [SD] age, 56.8 [8.0] years; 54.3% women) were followed up for a median (interquartile range) of 8.9 (8.3-9.5) years. Among the 1294 male p.C282Y homozygotes, there were 21 incident hepatic malignancies, 10 of which were in participants without a diagnosis of hemochromatosis at baseline. p.C282Y homozygous men had a higher risk of hepatic malignancies (hazard ratio [HR], 10.5 [95% CI, 6.6-16.7];P Conclusions and Relevance Among men withHFEp.C282Y homozygosity, there was a significantly increased risk of incident primary hepatic malignancy and death compared with men without p.C282Y or p.H63D variants; there was not a significant association for women. Further research is needed to understand the effects of early diagnosis and treatment.