Analysis of rare disruptive germline mutations in 2135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes.

BACKGROUND: Breast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility. PATIENTS AND METHODS: We included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. ELIGIBILITY CRITERIA: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (<30 years), and (iv) concomitant ovarian cancer. We undertook exome sequencing of cases and carried out gene-level burden testing of rare damaging variants against those from 51 377 ethnicity-matched population controls from gnomAD. RESULTS: 159/2135 (7.4%) cases had a qualifying variant in an established breast cancer susceptibility gene, with minimal evidence of signal in other cancer susceptibility genes. Known breast cancer susceptibility genes PALB2, CHEK2, and ATM were the only genes to retain statistical significance after correcting for multiple testing. Due to the enrichment of hereditary cases in the series, we had good power (>80%) to detect a gene of BRCA1-like risk [odds ratio (OR) = 10.6] down to a population minor allele frequency of 4.6 × 10-5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR = 5.0) down to a population minor allele frequency of 2.8 × 10-4 (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR = 2-3) like CHEK2 and ATM. CONCLUSIONS: This is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of such genes.

The Scottish Brain Health Service Model: Rationale and Scientific Basis for a National Care Pathway of Brain Health Services in Scotland.

In order to address the oft-cited societal, economic, and health and social care impacts of neurodegenerative diseases, such as Alzheimer's disease, we must move decisively from reactive to proactive clinical practice and to embed evidence-based brain health education throughout society. Most disease processes can be at least partially prevented, slowed, or reversed. We have long neglected to intervene in neurodegenerative disease processes, largely due to a misconception that their predominant symptom - cognitive decline - is a normal, age-related process, but also due to a lack of multi-disciplinary collaboration. We now understand that there are modifiable risk factors for neurodegenerative diseases, that successful management of common comorbidities (such as diabetes and hypertension) can reduce the incidence of neurodegenerative disease, and that disease processes begin (and, crucially, can be detected, reduced, and delayed, prevented, or treated) decades earlier in life than had previously been appreciated. Brain Health Scotland, established by Scottish Government and working in partnership with Alzheimer Scotland, propose far-reaching public health and clinical practice approaches to reduce neurodegenerative disease incidence. Focusing here on Brain Health Scotland's clinical offerings, we present the Scottish Model for Brain Health Services. To our knowledge, the Scottish Model for Brain Health, built on foundations of personalised risk profiling, targeted risk reduction and prevention, early disease detection, equity of access, and harnessing comprehensive data to assist in clinical decision-making, marks the first example of a nationwide approach to overhauling clinical, societal, and political approaches to the prevention, assessment, and treatment of neurodegenerative disease.

Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease with an estimated prevalence of 1 in 5000 that is characterized by the presence of vascular malformations (VMs). These result in chronic bleeding, acute hemorrhage, and complications from shunting through VMs. The goal of the Second International HHT Guidelines process was to develop evidence-based consensus guidelines for the management and prevention of HHT-related symptoms and complications. The guidelines were developed using the AGREE II (Appraisal of Guidelines for Research and Evaluation II) framework and GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. The guidelines expert panel included expert physicians (clinical and genetic) in HHT from 15 countries, guidelines methodologists, health care workers, health care administrators, patient advocacy representatives, and persons with HHT. During the preconference process, the expert panel generated clinically relevant questions in 6 priority topic areas. A systematic literature search was done in June 2019, and articles meeting a priori criteria were included to generate evidence tables, which were used as the basis for recommendation development. The expert panel subsequently convened during a guidelines conference to conduct a structured consensus process, during which recommendations reaching at least 80% consensus were discussed and approved. The expert panel generated and approved 6 new recommendations for each of the following 6 priority topic areas: epistaxis, gastrointestinal bleeding, anemia and iron deficiency, liver VMs, pediatric care, and pregnancy and delivery (36 total). The recommendations highlight new evidence in existing topics from the first International HHT Guidelines and provide guidance in 3 new areas: anemia, pediatrics, and pregnancy and delivery. These recommendations should facilitate implementation of key components of HHT care into clinical practice.

Virtual arthroplasty follow-up: five-year data from a district general hospital.

INTRODUCTION: Follow-up after hip and knee arthroplasty is advocated to identify asymptomatic loosening and improve patient satisfaction. There are, however, financial and time implications associated with regular clinic appointments. Assessment through virtual means has been suggested as an alternative. MATERIALS AND METHODS: At the West Suffolk Hospital, following arthroplasty surgery of the lower limb, patients are followed-up via a questionnaire at one and five years postoperatively, then subsequently at five-yearly intervals. Patients are recalled based on the outcome of these assessments. Using a locally compiled data base we identified all patients reviewed between 2011 and 2015 using this virtual assessment process and examined their outcomes. RESULTS: During the five years of follow-up, 5,380 patients were eligible for assessment. Compliance varied from 77% follow up for hips and 83% for knees. Ten patients were recalled following total hip replacement, eight for x-ray changes and one for a poor satisfaction score. Five went on to undergo revision surgery. Some 56 recalls to clinic following knee arthroplasty were seen; 42 due to a poor Oxford Knee Score, 6 with associated x-ray abnormalities and 6 isolated abnormal x-rays. Five subsequently underwent revision surgery; 30 (54%) were discharged after initial review and 18 (32%) were referred to different subspecialties.As a result of the virtual review process, 4,219 clinic appointments were avoided, with no documented admissions as a result of a missed complication from virtual review. DISCUSSION: A virtual arthroplasty clinic significantly reduces the number of patients attending regular follow-up clinics, without compromising safe practice.

Moving into the mainstream: healthcare professionals' views of implementing treatment focussed genetic testing in breast cancer care.

A proportion of breast cancers are attributable to BRCA1 or BRCA2 mutations. Technological advances has meant that mutation testing in newly diagnosed cancer patients can be used to inform treatment plans. Although oncologists increasingly deliver treatment-focused genetic testing (TFGT) as part of mainstream ovarian cancer care, we know little about non-genetics specialists' views about offering genetic testing to newly diagnosed breast cancer patients. This study sought to determine genetics and non-genetics specialists' views of a proposal to mainstream BRCA1 and 2 testing in newly diagnosed breast cancer patients. Qualitative interview study. Nineteen healthcare professionals currently responsible for offering TFGT in a standard (triage + referral) pathway (breast surgeons + clinical genetics team) and oncologists preparing to offer TFGT to breast cancer patients in a mainstreamed pathway participated in in-depth interviews. Genetics and non-genetics professionals' perceptions of mainstreaming are influenced by their views of: their clinical roles and responsibilities, the impact of TFGT on their workload and the patient pathway and the perceived relevance of genetic testing for patient care in the short-term. Perceived barriers to mainstreaming may be overcome by: more effective communication between specialities, clearer guidelines/patient pathways and the recruitment of mainstreaming champions.

Routine germline BRCA1 and BRCA2 testing in patients with ovarian carcinoma: analysis of the Scottish real-life experience.

OBJECTIVE: To determine the rates of germline BRCA1 and BRCA2 mutations in Scottish patients with ovarian cancer, before and after a change in testing policy. DESIGN: Retrospective cohort study. SETTING: Four cancer/genetics centres in Scotland. POPULATION: Patients with ovarian cancer undergoing germline BRCA1 and BRCA2 (gBRCA1/2) sequencing before 2013 (under the 'old criteria', with selection based solely on family history), after 2013 (under the 'new criteria', with sequencing offered to newly presenting patients with non-mucinous ovarian cancer), and in the 'prevalent population' (who presented before 2013, but were not eligible for sequencing under the old criteria but were sequenced under the new criteria). METHODS: Clinicopathological and sequence data were collected before and for 18 months after this change in selection criteria. MAIN OUTCOME MEASURES: Frequency of germline BRCA1, BRCA2, RAD51C, and RAD51D mutations. RESULTS: Of 599 patients sequenced, 205, 236, and 158 were in the 'old criteria', 'new criteria', and 'prevalent' populations, respectively. The frequency of gBRCA1/2 mutations was 30.7, 13.1, and 12.7%, respectively. The annual rate of gBRCA1/2 mutation detection was 4.2 before and 20.7 after the policy change. A total of 48% (15/31) 'new criteria' patients with gBRCA1/2 mutations had a Manchester score of <15 and would not have been offered sequencing based on family history criteria. In addition, 20 patients with gBRCA1/2 were identified in the prevalent population. The prevalence of gBRCA1/2 mutations in patients aged >70 years was 8.2%. CONCLUSIONS: Sequencing all patients with non-mucinous ovarian cancer gives a much higher annual gBRCA1/2 mutation detection rate, with the frequency of positive tests still exceeding the 10% threshold upon which many family history-based models operate. TWEETABLE ABSTRACT: BRCA sequencing all non-mucinous cancer patients increases mutation detection five fold.

Fetal Dysmorphology-Still an Essential Art. Analysis of the Limitations of Microarray in a Fetal Population and a Look Toward the Genome Sequencing Era.

Cytogenomic microarray allows assessment of the genome at higher resolutions than traditional karyotyping. The objective of this study is to evaluate the utility of microarray in a routine fetal autopsy setting before the advent of routine fetal exome/genome sequencing and the issues these technologies may generate. A systematic review of fetal postmortems at 12-24 weeks gestation between January 2011 and December 2014 was undertaken. Cases where there was no consent for audit, research, or genetic testing were excluded as were cases referred to the Procurator Fiscal, stillbirths, and neonatal deaths. Copy number variations were detected in 16 cases. In addition, there was 1 case of uniparental disomy; not all of these were related to the phenotype. There were a number of cases with phenotypic abnormalities and normal array results. Five of these underwent directed mutation analysis-3 were positive. Genetic laboratory investigations such as microarray and Quantitative Fluorescent-Polymerase Chain Reaction may increase the diagnostic yield in the assessment of fetal dysmorphology. However, this study shows that genetic results not only require careful review given the potential uncertain significance but also require phenotypic assessment of the fetus by a competent fetal dysmorphologist to determine the likely causative effect of any detected anomaly. This best practice will also extend to next generation sequencing and interpretation of variants of unknown significance. Fetal medicine teams should ideally include specialists well versed in assessment of fetal anomaly to provide families with the best possible information about the cause of their pregnancy loss and their options for future pregnancies.

Peripheral Blood Gene Expression Changes Associated With Primary Graft Dysfunction After Lung Transplantation.

Recipient responses to primary graft dysfunction (PGD) after lung transplantation may have important implications to the fate of the allograft. We therefore evaluated longitudinal differences in peripheral blood gene expression in subjects with PGD. RNA expression was measured throughout the first transplant year in 106 subjects enrolled in the Clinical Trials in Organ Transplantation-03 study using a panel of 100 hypothesis-driven genes. PGD was defined as grade 3 in the first 72 posttransplant hours. Eighteen genes were differentially expressed over the first year based on PGD development, with significant representation from innate and adaptive immunity genes, with most differences identified very early after transplant. Sixteen genes were overexpressed in the blood of patients with PGD compared to those without PGD within 7 days of allograft reperfusion, with most transcripts encoding innate immune/inflammasome-related proteins, including genes previously associated with PGD. Thirteen genes were underexpressed in patients with PGD compared to those without PGD within 7 days of transplant, highlighted by T cell and adaptive immune regulation genes. Differences in gene expression present within 2 h of reperfusion and persist for days after transplant. Future investigation will focus on the long-term implications of these gene expression differences on the outcome of the allograft.

The manufacture of generic replicas of implants for arthroplasty of the hip and knee: is it regulated and will it save money?

Joint replacement of the hip and knee remain very satisfactory operations. They are, however, expensive. The actual manufacturing of the implant represents only 30% of the final cost, while sales and marketing represent 40%. Recently, the patents on many well established and successful implants have expired. Companies have started producing and distributing implants that purport to replicate existing implants with good long-term results. The aims of this paper are to assess the legality, the monitoring and cost saving implications of such generic implants. We also assess how this might affect the traditional orthopaedic implant companies. Cite this article: Bone Joint J 2016;98-B:892-900.

Assessing clarity and erasability of commercially available pens for surgical site marking: a comparative study in human volunteers.

BACKGROUND: Marking the surgical site is a well-established part of pre-operative protocol and errors in marking have been implicated in wrong site surgery incidents and are a significant patient safety issue. There are many commercially available marker pens and anecdotally very little consistency in which pen is used or the clarity of marking. Previous studies have shown subjective differences between different pens and the current paper sought to support this evidence with objective data and widen the investigation of commercially available pens. METHODS: Eight marker pens were used to mark two separate sites on three caucasian volunteers. These marks were photographed and assessed by six observers before and after the application of chlorhexidine skin preparation. The observers were blinded to which pen was used for each mark, and rated the clarity of the marks subjectively. The photographs were assessed using image analysis software to give an objective measure of clarity against the skin. RESULTS: There was a wide variation between the clarity of marks made by the different pens, and also a wide variation in the resistance to skin preparation. The Pentel N50 pen was the outstanding best performing pen across all categories. CONCLUSIONS: It is recommended that the Pentel N50 black marker pen be used for surgical site marking to improve patient safety and avoid adverse events.

Cost of infection after surgery for intracapsular fracture of the femoral neck.

INTRODUCTION: We investigated the financial and human costs of postoperative infection for intracapsular fracture of the femoral neck at a district general hospital in the UK. METHODS: Data on postoperative infections after surgical treatment for intracapsular fracture of the femoral neck were collected prospectively from June 2005 to April 2009. Infected patients were pairwise-matched (1:2 ratio) with a non-infected group of patients from a database on hip fractures. Costs of additional surgery, duration of hospital stay, and opportunity costs were calculated using Primary Care Trust (PCT) tariffs and PCT-specific data. RESULTS: A total of 525 patients were treated with total hip replacement (n=110) or hip hemiarthroplasty (n=415). Seventeen patients (3.2%) were identified as having a surgical-site infection. Eight (1.5%) deep infections and nine (1.7%) superficial infections were documented. Compared with the non-infected group, duration of hospital stay and the prevalence of mortality doubled. Repeat surgery and the costs associated with hospital admission were increased significantly in the infected group. Mean financial loss associated with an infected patient was £7,726, whereas an uninfected patient brought £153 of profit to the hospital. When opportunity costs were considered, an infected patient represented £24,397 of lost income. CONCLUSIONS: Postoperative infection after surgical treatment for intracapsular fracture of the femoral neck has a significant negative impact on duration of hospital stay and financial costs, and demonstrates a trend towards an increase in the prevalence of mortality.

Cost savings of using a cemented total hip replacement: an analysis of the National Joint Registry data.

The debate whether to use cemented or uncemented components in primary total hip replacement (THR) has not yet been considered with reference to the cost implications to the National Health Service. We obtained the number of cemented and uncemented components implanted in 2009 from the National Joint Registry for England and Wales. The cost of each component was established. The initial financial saving if all were cemented was then calculated. Subsequently the five-year rates of revision for each type of component were reviewed and the predicted number of revisions at five years for the actual components used was compared with the predicted number of revisions for a cemented THR. This was then multiplied by the mean cost of revision surgery to provide an indication of the savings over the first five years if all primary THRs were cemented. The saving at primary THR was calculated to be £10 million with an additional saving during the first five years of between £5 million and £8.5 million. The use of cemented components in routine primary THR in the NHS as a whole can be justified on a financial level but we recognise individual patient factors must be considered when deciding which components to use.

The use of in utero MRI to supplement ultrasound in the foetus at high risk of developmental brain or spine abnormality.

OBJECTIVES: It is widely accepted that the diagnosis of foetal central nervous system (CNS) abnormalities can be improved by performing MRI examinations in utero. Most of the published literature has concentrated on pregnancies in which a developmental abnormality has been detected (or suspected) on ultrasound in an otherwise low-risk pregnancy. In this paper, we test the hypothesis that in utero MRI of the foetal brain in high-risk pregnancies will detect abnormalities not shown by ultrasound at a rate that justifies its use in clinical practice. METHODS: 100 females were recruited into the study from foeto-maternal or clinical genetic departments. They all had a foetus/child with a CNS malformation from an earlier pregnancy, which led to an increased risk of recurrence being quoted for the present pregnancy. All in utero MRI examinations were performed on 1.5 T clinical MRI systems at 18 weeks gestational age or later. RESULTS: In 78% of cases, the ultrasound and MRI results agreed and showed no abnormality. In 13%, ultrasound and MRI described identical abnormal findings. In 9%, the ultrasound and MRI examinations had discrepant findings; in all these cases the MRI findings described more serious CNS pathology. The effects on management were judged to be major, by at least one assessor, in 7/9 of those cases. CONCLUSION: As in many other situations involving antenatal detection of CNS abnormalities, in utero MRI should be considered in females with increased risk of foetal CNS malformation based on the results of an earlier pregnancy. Advances in knowledge In utero MRI of the foetus has an important role in antenatal diagnosis of females carrying a foetus with an increased risk of a brain abnormality.

Insights from next generation sequencing of the cancer genome.

This detailed review provides a history and update of the complex field of cancer genetics. Using examples of progress such as the development of imatinib for chronic myeloid leukemia (which stemmed from the recognition of the Philadelphia chromosome in the 1960s), Michael Stratton, Director of the Sanger Institute in Cambridge is confident that we are now entering the end game of cancer genome sequencing. This has led to other drug therapies, based on knowledge of the molecular changes in some cancers, lung and breast cancers for example.

International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia.

BACKGROUND: HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults. OBJECTIVE: The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease. METHODS: The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches. RESULTS: The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.

A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants.

BACKGROUND: defective DNA repair has a causal role in hereditary colorectal cancer (CRC). Defects in the base excision repair gene MUTYH are responsible for MUTYH-associated polyposis and CRC predisposition as an autosomal recessive trait. Numerous reports have suggested MUTYH mono-allelic variants to be low penetrance risk alleles. We report a large collaborative meta-analysis to assess and refine CRC risk estimates associated with bi-allelic and mono-allelic MUTYH variants and investigate age and sex influence on risk. METHODS: MUTYH genotype data were included from 20 565 cases and 15 524 controls. Three logistic regression models were tested: a crude model; adjusted for age and sex; adjusted for age, sex and study. RESULTS: all three models produced very similar results. MUTYH bi-allelic carriers demonstrated a 28-fold increase in risk (95% confidence interval (CI): 6.95-115). Significant bi-allelic effects were also observed for G396D and Y179C/G396D compound heterozygotes and a marginal mono-allelic effect for variant Y179C (odds ratio (OR)=1.34; 95% CI: 1.00-1.80). A pooled meta-analysis of all published and unpublished datasets submitted showed bi-allelic effects for MUTYH, G396D and Y179C (OR=10.8, 95% CI: 5.02-23.2; OR=6.47, 95% CI: 2.33-18.0; OR=3.35, 95% CI: 1.14-9.89) and marginal mono-allelic effect for variants MUTYH (OR=1.16, 95% CI: 1.00-1.34) and Y179C alone (OR=1.34, 95% CI: 1.01-1.77). CONCLUSIONS: overall, this large study refines estimates of disease risk associated with mono-allelic and bi-allelic MUTYH carriers.

Impaction grafting of the acetabulum with a mixture of frozen, ground irradiated bone graft and porous synthetic bone substitute (Apapore 60).

The clinical and radiological results of 50 consecutive acetabular reconstructions in 48 patients using impaction grafting have been retrospectively reviewed. A 1:1 mixture of frozen, ground irradiated bone graft and Apapore 60, a synthetic bone graft substitute, was used in all cases. There were 13 complex primary and 37 revision procedures with a mean follow-up of five years (3.4 to 7.6). The clinical survival rate was 100%, with improvements in the mean Harris Hip Scores for pain and function. Radiologically, 30 acetabular grafts showed evidence of incorporation, ten had radiolucent lines and two acetabular components migrated initially before stabilising. Acetabular reconstruction in both primary and revision surgery using a 1:1 mixture of frozen, ground, irriadiated bone and Apapore 60 appears to be a reliable method of managing acetabular defects. Longer follow-up will be required to establish whether this technique is as effective as using fresh-frozen allograft.

The Birmingham Hip Resurfacing: 5-year clinical and radiographic results from a District General Hospital.

We prospectively examined the functional and radiographic outcomes of a serial cohort of 104 Birmingham Hip Resurfacings in an independent centre. Final follow-up was to a mean of 61 months, and six cases were lost to follow-up. Excellent results were obtained in 91%, but obese patients had significantly (p < 0.03) poorer post-operative outcomes. Whilst there were no cases of neck fracture neck narrowing of up to 20 mm was noted. Radiolucent lines were present in a single zone in 9.4% (9/96) acetabular and 3.1% (3/96) femoral components. However, no components were definitely loose and there were no revisions for any reason during the period of the study. This independent series confirms that the Birmingham Hip Resurfacing gives excellent early clinical results and little early evidence of radiographic failure. The high rate of neck narrowing gives us cause for concern and we would recommend regular radiographic follow-up.

Early clinical failure of the Birmingham metal-on-metal hip resurfacing is associated with metallosis and soft-tissue necrosis.

The rate and mode of early failure in 463 Birmingham hip resurfacings in a two-centre, multisurgeon series were examined. Of the 463 patients two have died and three were lost to follow-up. The mean radiological and clinical follow-up was for 43 months (6 to 90). We have revised 13 resurfacings (2.8%) including seven for pain, three for fracture, two for dislocation and another for sepsis. Of these, nine had macroscopic and histological evidence of metallosis. The survival at five years was 95.8% (95% confidence interval (CI) 94.1 to 96.8) for revision for all causes and 96.9% (95% CI 95.5 to 98.3) for metallosis. The rate of metallosis related revision was 3.1% at five years. Risk factors for metallosis were female gender, a small femoral component, a high abduction angle and obesity. We do not advocate the use of the Birmingham Hip resurfacing procedure in patients with these risk factors.