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.

Died of wounds: a mortality review.

OBJECTIVES: Combat casualty care is a complex system involving multiple clinicians, medical interventions and casualty transfers. Improving the performance of this system requires examination of potential weaknesses. This study reviewed the cause and timing of death of casualties deemed to have died from their injuries after arriving at a medical treatment facility during the recent conflicts in Iraq and Afghanistan, in order to identify potential areas for improving outcomes. METHODS: This was a retrospective review of all casualties who reached medical treatment facilities alive, but subsequently died from injuries sustained during combat operations in Afghanistan and Iraq. It included all deaths from start to completion of combat operations. The UK military joint theatre trauma registry was used to identify cases, and further data were collected from clinical notes, postmortem records and coroner's reports. RESULTS: There were 71 combat-related fatalities who survived to a medical treatment facility; 17 (24%) in Iraq and 54 (76%) in Afghanistan. Thirty eight (54%) died within the first 24 h. Thirty-three (47%) casualties died from isolated head injuries, a further 13 (18%) had unsurvivable head injuries but not in isolation. Haemorrhage following severe lower limb trauma, often in conjunction with abdominal and pelvic injuries, was the cause of a further 15 (21%) deaths. CONCLUSIONS: Severe head injury was the most common cause of death. Irrespective of available medical treatment, none of this group had salvageable injuries. Future emphasis should be placed in preventative strategies to protect the head against battlefield trauma.

Acute shoulder injuries: A clinical review of diagnosis and management in the deployed Naval environment.

Musculoskeletal injuries of the shoulder are a common presentation in primary care. Injuries to this highly mobile region can have a profound impact on the range of movement, resulting in severe functional limitation. The shoulder can also be one of the more complicated regions to examine due to its high mobility, poor localisation of pain and numerous supporting structures. This article aims to review the anatomy of the shoulder, examination technique and the pathology underlying common acute injuries in order to provide guidance to medical personnel deployed with the Royal Navy and Royal Marines.

Translational research to improve the treatment of severe extremity injuries.

OBJECTIVES: Severe extremity injuries are the most significant injury sustained in combat wounds. Despite optimal clinical management, non-union and infection remain common complications. In a concerted effort to dovetail research efforts, there has been a collaboration between the UK and USA, with British military surgeons conducting translational studies under the auspices of the US Institute of Surgical Research. This paper describes 3 years of work. METHODS: A variety of studies were conducted using, and developing, a previously validated rat femur critical-sized defect model. Timing of surgical debridement and irrigation, different types of irrigants and different means of delivery of antibiotic and growth factors for infection control and to promote bone healing were investigated. RESULTS: Early debridement and irrigation were independently shown to reduce infection. Normal saline was the most optimal irrigant, superior to disinfectant solutions. A biodegradable gel demonstrated superior antibiotic delivery capabilities than standard polymethylmethacrylate beads. A polyurethane scaffold was shown to have the ability to deliver both antibiotics and growth factors. DISCUSSION: The importance of early transit times to Role 3 capabilities for definitive surgical care has been underlined. Novel and superior methods of antibiotic and growth factor delivery, compared with current clinical standards of care, have been shown. There is the potential for translation to clinical studies to promote infection control and bone healing in these devastating injuries.

Mortality, survival and residual injury burden of Royal Navy and Royal Marine combat casualties sustained in 11-years of operations in Iraq and Afghanistan.

We present eleven years of prospectively-gathered data defining the full spectrum of the United Kingdom's (UK) Naval Service (Royal Navy and Royal Marines) casualties, and characterise the injury patterns, recovery and residual functional burden from the conflicts of the last decade. The UK Military Trauma Registry was searched for all Naval Service personnel injured between March 2003 and April 2013. These records were then cross-referenced with the records of the Naval Service Medical Board of Survey (NSMBOS), which evaluates injured Naval Service personnel for medical discharge, continued service in a reduced capacity or Return to Full Duty (RTD). Population at risk data was calculated from service records. There were 277 casualties in the study period: 63 (23%) of these were fatalities. Of the 214 survivors, 63 or 29% (23% of total) were medically discharged; 24 or 11% (9% of total) were placed in a reduced fitness category with medical restrictions placed on their continued military service. A total of 127 individuals (46% of the total and 59% of survivors) RTD without any restriction. The greatest number of casualties was sustained in 2007. There was a 3% casualty risk per year of operational service for Naval Service personnel. The most common reason cited by Naval Service Medical Board of Survey (NSMBOS) for medical downgrading or discharge was injury to the lower limb, with upper limb trauma the next most frequent. This study characterises the spectrum of injuries sustained by the Naval Service during recent conflicts with a very high rate of follow-up. Extremity injuries pose the biggest challenge to reconstructive and rehabilitative services striving to maximise the functional outcomes of injured service personnel.

The incidence of pelvic fractures with traumatic lower limb amputation in modern warfare due to improvised explosive devices.

AIMS: A frequently-seen injury pattern in current military experience is traumatic lower limb amputation as a result of improvised explosive devices (IEDs). This injury can coexist with fractures involving the pelvic ring. This study aims to assess the frequency of concomitant pelvic fracture in IED-related lower limb amputation. METHODS: A retrospective analysis of the trauma charts, medical notes, and digital imaging was undertaken for all patients arriving at the Emergency Department at the UK military field hospital in Camp Bastion, Afghanistan, with a traumatic lower limb amputation in the six months between September 2009 and April 2010, in order to determine the incidence of associated pelvic ring fractures. RESULTS: Of 77 consecutive patients with traumatic lower limb amputations, 17 (22%) had an associated pelvic fracture (eleven with displaced pelvic ring fractures, five undisplaced fractures and one acetabular fracture). Unilateral amputees (n = 31) had a 10% incidence of associated pelvic fracture, whilst 30 % of bilateral amputees (n = 46) had a concurrent pelvic fracture. However, in bilateral, trans-femoral amputations (n = 28) the incidence of pelvic fracture was 39%. CONCLUSIONS: The study demonstrates a high incidence of pelvic fractures in patients with traumatic lower limb amputations, supporting the routine pre-hospital application of pelvic binders in this patient group.

Femoral acetabular impingement: the sex- and age-linked distribution of alpha angles in 146 patients of service age without pre-existing osteoarthritic or other hip pathology.

The use of the alpha angle to help the diagnosis of Femoral Acetabular Impingement (FAI) is common. However, there is currently no standard value available across an asymptomatic pre-arthritic population. We present the first large cohort of Computerised Tomography (CT) based alpha angles in patients with no history of hip pathology, including intra- and interobserver validation. We carried out a retrospective analysis of 73 consecutive individuals (146 hip joints) with ages ranging from 18 to 39 years. The age range 18-39 represents 82.4% of those currently serving in the UK Armed Forces. The cohort was drawn from those patients who had received a CT scan in the Lothian Region between 1 Jan 2011 and 31 Dec 2011 due to abdominal pathology. These patients had their electronic patient record checked to rule out any hip-related problems. The alpha angle of Nötzli was measured on the axial view bilaterally. The mean value for the 18-39 age range was found to be 51.89 degree for the left hip and 52.53 degree for the right. Femoral alpha angle is a reproducible measurement for assessing the femoral neck. However, there is wide variability in the alpha angle for patients, irrespective of the presence of symptoms. Our results would suggest that the alpha angle alone should not be used to diagnose FAI in service personnel, as even large angles may be normal.

Genetic testing and screening of individuals at risk of NF2.

Genetic testing and management of the at-risk individual for neurofibromatosis type 2 (NF2) is complicated by the well-documented risk of mosaicism that causes a milder later onset more asymmetrical disease course. Risks of NF2 were derived from genetic testing of over 1000 individuals through the Manchester NF2-testing service. Individuals are at risk of NF2 or have 'potential' NF2 if they have features of the disease that fall short of diagnostic criteria or are the first-degree relative of someone with NF2 or suspected NF2. The present protocol devised for the Nationally Commissioned Group (NCG) NF2 service in England addresses the risks, genetic testing and screening protocol for individuals at risk of NF2. Screening with cranial magnetic resonance imaging is advised until the risk of NF2 falls below a pragmatic threshold of 1%. Multiple case scenarios are shown to illustrate how to use the protocol.

Aggressive soft tissue infections and amputation in military trauma patients.

Due to the nature of IED injuries, during the conflicts in Iraq and Afghanistan The traditional, two-stage amputation for unsalvageable combat lower limb injuries has evolved into a strategy of serial debridement and greater use of plastic surgical techniques in order to preserve residual limb length. This study aimed to characterise the current treatment of lower limb loss with particular focus on the impact of specific wound infections. The UK military trauma registry and clinical notes were reviewed for details of all lower limb amputation identifying: 51 patients with 70 lower limb amputations. The mean number of debridements per stump prior to closure was 4.1 (95% CI 3.5-4.7). A final more proximal amputation level was required in 21 stumps (30%). Recovery of A. hydrophillia from wounds was significantly associated with a requirement for a more proximal amputation level (p=0.0038) and greater number of debridements (p=0.0474) when compared to residual limb wounds withoutA. hydrophillia.

The carrier clinic: an evaluation of a novel clinic dedicated to the follow-up of BRCA1 and BRCA2 carriers--implications for oncogenetics practice.

BACKGROUND: A novel oncogenetic clinic was established in 2002 at the Royal Marsden NHS Foundation Trust offering advice and specialist follow-up for families with a germline mutation in BRCA1 or BRCA2. The remit of this multidisciplinary clinic, staffed by individuals in both oncology and genetics, is to provide individualised screening recommendations, support in decision making, risk reducing strategies, cascade testing, and an extensive research portfolio. METHODS: A retrospective analysis was performed to evaluate uptake of genetic testing, risk reducing surgery and cancer prevalence in 346 BRCA1/BRCA2 families seen between January 1996 and December 2006. RESULTS: 661 individuals attended the clinic and 406 mutation carriers were identified; 85.8% mutation carriers have chosen to attend for annual follow-up. 70% of mutation carriers elected for risk reducing bilateral salpingo-oophorectomy (RRBSO). 32% of unaffected women chose risk reducing bilateral mastectomy. 32% of women with breast cancer chose contralateral risk reducing mastectomy at time of diagnosis. Some women took over 8 years to decide to have surgery. 91% of individuals approached agreed to participate in research programmes. INTERPRETATION: A novel specialist clinic for BRCA1/2 mutation carriers has been successfully established. The number of mutation positive families is increasing. This, and the high demand for RRBSO in women over 40, is inevitably going to place an increasing demand on existing health resources. Our clinic model has subsequently been adopted in other centres and this will greatly facilitate translational studies and provide a healthcare structure for management and follow-up of such people who are at a high cancer risk.

Management of intestinal injury in deployed UK hospitals.

INTRODUCTION: Definitive laparotomy (DL), with completion of all surgical tasks at first laparotomy has traditionally been the basis of surgical care of severe abdominal trauma. Damage control surgery (DCS) with a goal of physiological normalisation achieved with termination of operation before completion of anatomical reconstruction, has recently found favour in management of civilian trauma. This study aims to characterise the contemporary UK military surgeon's approach to abdominal injury. PATIENTS AND METHODS: A retrospective analysis was performed on British service personnel who underwent a laparotomy for intestinal injury at UK forward hospitals from November 2003 to March 2008 as identified from the Joint Theatre Trauma Registry. Patient demographics, mechanism and pattern of injury and clinical outcomes were recorded. Surgical procedures at first and subsequent laparotomy were evaluated by an expert panel. RESULTS: 22 patients with intestinal injury underwent laparotomy and survived to be repatriated; all patients subsequently survived to hospital discharge. Mechanism of injury was GSW in seven and blast in 13. At primary laparotomy, as defined by the operating surgeon, 15/22 underwent DL and 7/22 underwent DCS. Mean Injury Severity Score (ISS) was 19 for DL patients compared to 29 for DCS patients (p = 0.021). Of the 15 patients undergoing DL nine had primary repair (suture or resection/ anastomosis), one of which subsequently leaked. Unplanned re-look was required in 4/15 of the DL cases. CONCLUSION: This review examines the activity of British military surgeons over a time period where damage control laparotomy has been introduced into regular practice. It is performed at a ratio of approximately 1:2 to DL and appears to be reserved, in accordance with military surgical doctrine, for the more severely injured patients. There is a high rate of unplanned relook procedures for DL suggesting DCS may still be underused by military surgeons. Optimal methods of selection and implementation of DCS after battle injury to the abdomen remain unclear.

Report of a Delphi exercise to inform the design of a research programme on screening for thoracic aortic disease.

OBJECTIVES: To inform the design of a clinical trial of a targeted screening programme for relatives of individuals affected by thoracic aortic disease, we performed a consensus exercise as to the acceptability of screening, the optimal sequence and choice of tests, long-term patient management, and choice of trial design. METHODS: Working with the Aortic Dissection Awareness UK & Ireland patient association, we performed a Delphi exercise with clinical experts, patients, and carers, consisting of three rounds of consultation followed by a final multi-stakeholder face-to-face workshop. RESULTS: Thirty-five experts and 84 members of the public took part in the surveys, with 164 patients and clinicians attending the final workshop. There was substantial agreement on the need for a targeted screening pathway that would employ a combined approach (imaging + genetic testing). The target population would include the first- and second-degree adult (> 15 years) relatives, with no upper age limit of affected patients. Disagreement persisted about the screening process, sequence, personnel, the imaging method to adopt, computed tomography (CT) scan vs magnetic resonance imaging (MRI), and the specifics of a potential trial, including willingness to undergo randomisation, and measures of effectiveness and acceptability. CONCLUSION: A Delphi process, initiated by patients, identified areas of uncertainty with respect to behaviour, process, and the design of a targeted screening programme for thoracic aortic disease that requires further research prior to any future trial.

Can cutaneous telangiectasiae as late normal-tissue injury predict cardiovascular disease in women receiving radiotherapy for breast cancer?

BACKGROUND: Overall, approximately 5% of patients show late normal-tissue damage after radiotherapy with a smaller number having a risk of radiation-induced heart disease. Although the data are conflicting, large studies have shown increased risks of cardiovascular disease (CVD) for irradiated patients compared with non-irradiated ones, or for those treated to the left breast or chest wall compared with those treated to the right. Cutaneous telangiectasiae as late normal-tissue injury have so far only been regarded as a cosmetic burden. METHODS: The relationship between late normal-tissue radiation injury phenotypes in 149 irradiated breast cancer patients and the presence of cardiovascular disease were examined. RESULTS: A statistically significant association between the presence of skin telangiectasiae and the long-term risk of CVD was shown in these patients (P=0.017; Fisher's exact test). INTERPRETATION: This association may represent initial evidence that telangiectasiae can be used as a marker of future radiation-induced cardiac complications. It could also suggest a common biological pathway for the development of both telangiectasiae and CVD on the basis of a genetically predisposed endothelium. To our knowledge this is the first reported study looking at this association.

PVL Staphylococcus aureus osteomyelitis complicating septic arthritis in a UK soldier serving in Iraq.

Musculoskeletal infections caused by Panton-Valentine Leukocidin (PVL) secreting Stapylococcus aureus in children and adolescents have previously been reported. We report the first adult case in a 26 year-old British Army soldier who presented with a S. aureus septic arthritis. He was treated by surgical washout and antibiotics and discharged but was readmitted five months later with an ipsilateral femoral osteomyelitis requiring debridement. The causative S. aureus grown from tissue biopsy taken at time of surgery was found to encode the PVL gene. Whilst there is evidence that soldiers in Iraq have a greater rate of S. aureus colonisation on their skin, the proportion that encode the PVL gene is similar to that observed in the UK. Soldiers are however, subject to the known risk factors that increase vulnerability to PVL secreting S. aureus infection. Military clinicians need to be aware of PVL secreting S. aureus and have a low threshold for requesting specific testing in aggressive musculoskeletal S. aureus infections.

Biallelic mutation of MSH2 in primary human cells is associated with sensitivity to irradiation and altered RAD51 foci kinetics.

BACKGROUND: Reports of differential mutagen sensitivity conferred by a defect in the mismatch repair (MMR) pathway are inconsistent in their conclusions. Previous studies have investigated cells established from immortalised human colorectal tumour lines or cells from animal models. METHODS: We examined primary human MSH2-deficient neonatal cells, bearing a biallelic truncating mutation in MSH2, for viability and chromosomal damage after exposure to DNA-damaging agents. RESULTS: MSH2-deficient cells exhibit no response to interstrand DNA cross-linking agents but do show reduced viability in response to irradiation. They also show increased chromosome damage and exhibit altered RAD51 foci kinetics after irradiation exposure, indicating defective homologous recombinational repair. DISCUSSION: The cellular features and sensitivity of MSH2-deficient primary human cells are broadly in agreement with observations of primary murine cells lacking the same gene. The data therefore support the view that the murine model recapitulates early features of MMR deficiency in humans, and implies that the variable data reported for MMR-deficient immortalised human cells may be due to further genetic or epigenetic lesions. We suggest caution in the use of radiotherapy for treatment of malignancies in individuals with functional loss of MSH2.

Audit of prescription of anti-malarial prophylaxis to patients admitted to Royal Centre for Defence Medicine (RCDM) following evacuation from Afghanistan.

INTRODUCTION: For most of the year Military personnel deployed to Afghanistan are required to take anti-malarial chemoprophylaxis (AMC). This audit aims to quantify how many personnel taking AMC in theatre have it continued at RCDM. METHOD: A database kept at RCDM was searched for details of all evacuated patients. Records of these patients were then searched to find out which had been admitted, how many had been taking AMC prior to admission and how many were prescribed it in hospital. RESULTS: During the study period 40 patients were evacuated to RCDM. 26 of these were admitted and had notes available and were therefore included in the study. 9 of these had been taking AMC prior to admission; of them, only 4 had been continued on AMC by the time they were admitted to RCDM. CONCLUSION: Insufficient numbers of patients taking AMC prior to admission have it continued as an inpatient. Awareness of this issue needs to be raised at all points of the medical evacuation chain.