Breast cancer (BC) risk prediction allows systematic identification of individuals at highest and lowest risk. We extend the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation ...Algorithm (BOADICEA) risk model to incorporate the effects of polygenic risk scores (PRS) and other risk factors (RFs).
BOADICEA incorporates the effects of truncating variants in BRCA1, BRCA2, PALB2, CHEK2, and ATM; a PRS based on 313 single-nucleotide polymorphisms (SNPs) explaining 20% of BC polygenic variance; a residual polygenic component accounting for other genetic/familial effects; known lifestyle/hormonal/reproductive RFs; and mammographic density, while allowing for missing information.
Among all factors considered, the predicted UK BC risk distribution is widest for the PRS, followed by mammographic density. The highest BC risk stratification is achieved when all genetic and lifestyle/hormonal/reproductive/anthropomorphic factors are considered jointly. With all factors, the predicted lifetime risks for women in the UK population vary from 2.8% for the 1st percentile to 30.6% for the 99th percentile, with 14.7% of women predicted to have a lifetime risk of ≥17-<30% (moderate risk according to National Institute for Health and Care Excellence NICE guidelines) and 1.1% a lifetime risk of ≥30% (high risk).
This comprehensive model should enable high levels of BC risk stratification in the general population and women with family history, and facilitate individualized, informed decision-making on prevention therapies and screening.
The CanRisk Tool (https://canrisk.org) is the next-generation web interface for the latest version of the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) ...state-of-the-art risk model and a forthcoming ovarian cancer risk model.
The tool captures information on family history, rare pathogenic variants in cancer susceptibility genes, polygenic risk scores, lifestyle/hormonal/clinical features, and imaging risk factors to predict breast and ovarian cancer risks and estimate the probabilities of carrying pathogenic variants in certain genes. It was implemented using modern web frameworks, technologies, and web services to make it extensible and increase accessibility to researchers and third-party applications. The design of the graphical user interface was informed by feedback from health care professionals and a formal evaluation.
This freely accessible tool was designed to be user friendly for clinicians and to boost acceptability in clinical settings. The tool incorporates a novel graphical pedigree builder to facilitate collection of the family history data required by risk calculations.
The CanRisk Tool provides health care professionals and researchers with a user-friendly interface to carry out multifactorial breast and ovarian cancer risk predictions. It is the first freely accessible cancer risk prediction program to carry the CE marking.
There have been over 3,100 account registrations, and 98,000 breast and ovarian cancer risk calculations have been run within the first 9 months of the CanRisk Tool launch.
There is a growing focus on the development of multi-factorial cancer risk prediction algorithms alongside tools that operationalise them for clinical use. BOADICEA is a breast and ovarian cancer ...risk prediction model incorporating genetic and other risk factors. A new user-friendly Web-based tool (CanRisk.org) has been developed to apply BOADICEA. This study aimed to explore the acceptability of the prototype CanRisk tool among two healthcare professional groups to inform further development, evaluation and implementation.
A multi-methods approach was used. Clinicians from primary care and specialist genetics clinics in England, France and Germany were invited to use the CanRisk prototype with two test cases (either face-to-face with a simulated patient or via a written vignette). Their views about the tool were examined via a semi-structured interview or equivalent open-ended questionnaire. Qualitative data were subjected to thematic analysis and organised around Sekhon's Theoretical Framework of Acceptability.
Seventy-five clinicians participated, 21 from primary care and 54 from specialist genetics clinics. Participants were from England (n = 37), France (n = 23) and Germany (n = 15). The prototype CanRisk tool was generally acceptable to most participants due to its intuitive design. Primary care clinicians were concerned about the amount of time needed to complete, interpret and communicate risk information. Clinicians from both settings were apprehensive about the impact of the CanRisk tool on their consultations and lack of opportunities to interpret risk scores before sharing them with their patients.
The findings highlight the challenges associated with developing a complex tool for use in different clinical settings; they also helped refine the tool. This prototype may not have been versatile enough for clinical use in both primary care and specialist genetics clinics where the needs of clinicians are different, emphasising the importance of understanding the clinical context when developing cancer risk assessment tools.
Frequent upwelling of cold deep water rich in dissolved inorganic nutrients but low in oxygen concentrations and pH is well documented in so-called Eastern-boundary systems. As a consequence vast ...areas of the continental shelf can turn corrosive to the mineral aragonite, vital to a number of marine organisms. This phenomenon is projected to become more severe with ongoing ocean acidification. Although upwelling is also known to occur in Western-boundary systems, the impact on present day aragonite saturation state (Ω arag ) is virtually unknown, let alone for the decades to come. Here we identified 37 events during 18 weeks of continuous measurements in Cape Byron Marine Park, Australia, by prolonged drops in ocean temperature of up to 5 ◦ C, oxygen concentrations by 34%, pH by 0.12 and Ω_arag by 0.9 units in a matter of hours. Extrapolating present day upwelling to a Pre-Industrial setting shows that ongoing ocean acidification has already lead to the crossing of a number of biological and geochemcial Ω_arag thresholds. If representative for the East Australian shelf, modelling further suggests that coral reefs with low coral cover could become net dissolving within the next 30 years. With the Great Barrier Reef estimated to currently contribute more than A$6 billion annually to the Australian economy, this would come at a considerable financial cost.
Patients with cancer are purported to have poor COVID-19 outcomes. However, cancer is a heterogeneous group of diseases, encompassing a spectrum of tumour subtypes. The aim of this study was to ...investigate COVID-19 risk according to tumour subtype and patient demographics in patients with cancer in the UK.
We compared adult patients with cancer enrolled in the UK Coronavirus Cancer Monitoring Project (UKCCMP) cohort between March 18 and May 8, 2020, with a parallel non-COVID-19 UK cancer control population from the UK Office for National Statistics (2017 data). The primary outcome of the study was the effect of primary tumour subtype, age, and sex and on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevalence and the case–fatality rate during hospital admission. We analysed the effect of tumour subtype and patient demographics (age and sex) on prevalence and mortality from COVID-19 using univariable and multivariable models.
319 (30·6%) of 1044 patients in the UKCCMP cohort died, 295 (92·5%) of whom had a cause of death recorded as due to COVID-19. The all-cause case–fatality rate in patients with cancer after SARS-CoV-2 infection was significantly associated with increasing age, rising from 0·10 in patients aged 40–49 years to 0·48 in those aged 80 years and older. Patients with haematological malignancies (leukaemia, lymphoma, and myeloma) had a more severe COVID-19 trajectory compared with patients with solid organ tumours (odds ratio OR 1·57, 95% CI 1·15–2·15; p<0·0043). Compared with the rest of the UKCCMP cohort, patients with leukaemia showed a significantly increased case–fatality rate (2·25, 1·13–4·57; p=0·023). After correction for age and sex, patients with haematological malignancies who had recent chemotherapy had an increased risk of death during COVID-19-associated hospital admission (OR 2·09, 95% CI 1·09–4·08; p=0·028).
Patients with cancer with different tumour types have differing susceptibility to SARS-CoV-2 infection and COVID-19 phenotypes. We generated individualised risk tables for patients with cancer, considering age, sex, and tumour subtype. Our results could be useful to assist physicians in informed risk–benefit discussions to explain COVID-19 risk and enable an evidenced-based approach to national social isolation policies.
University of Birmingham and University of Oxford.
Individuals with cancer, particularly those who are receiving systemic anticancer treatments, have been postulated to be at increased risk of mortality from COVID-19. This conjecture has considerable ...effect on the treatment of patients with cancer and data from large, multicentre studies to support this assumption are scarce because of the contingencies of the pandemic. We aimed to describe the clinical and demographic characteristics and COVID-19 outcomes in patients with cancer.
In this prospective observational study, all patients with active cancer and presenting to our network of cancer centres were eligible for enrolment into the UK Coronavirus Cancer Monitoring Project (UKCCMP). The UKCCMP is the first COVID-19 clinical registry that enables near real-time reports to frontline doctors about the effects of COVID-19 on patients with cancer. Eligible patients tested positive for severe acute respiratory syndrome coronavirus 2 on RT-PCR assay from a nose or throat swab. We excluded patients with a radiological or clinical diagnosis of COVID-19, without a positive RT-PCR test. The primary endpoint was all-cause mortality, or discharge from hospital, as assessed by the reporting sites during the patient hospital admission.
From March 18, to April 26, 2020, we analysed 800 patients with a diagnosis of cancer and symptomatic COVID-19. 412 (52%) patients had a mild COVID-19 disease course. 226 (28%) patients died and risk of death was significantly associated with advancing patient age (odds ratio 9·42 95% CI 6·56–10·02; p<0·0001), being male (1·67 1·19–2·34; p=0·003), and the presence of other comorbidities such as hypertension (1·95 1·36–2·80; p<0·001) and cardiovascular disease (2·32 1·47–3·64). 281 (35%) patients had received cytotoxic chemotherapy within 4 weeks before testing positive for COVID-19. After adjusting for age, gender, and comorbidities, chemotherapy in the past 4 weeks had no significant effect on mortality from COVID-19 disease, when compared with patients with cancer who had not received recent chemotherapy (1·18 0·81–1·72; p=0·380). We found no significant effect on mortality for patients with immunotherapy, hormonal therapy, targeted therapy, radiotherapy use within the past 4 weeks.
Mortality from COVID-19 in cancer patients appears to be principally driven by age, gender, and comorbidities. We are not able to identify evidence that cancer patients on cytotoxic chemotherapy or other anticancer treatment are at an increased risk of mortality from COVID-19 disease compared with those not on active treatment.
University of Birmingham, University of Oxford.
The causative virus, SARS-CoV-2, is a new strain of betacoronavirus previously not identified in humans and thought to be of zoonotic origin.1 The presentation of COVID-19 varies from no or minor ...symptoms akin to the common cold, to severe acute respiratory distress syndrome, resulting in severely impaired respiratory function.1 SARS-CoV-2 is highly contagious through direct transfer of respiratory droplets during coughing and sneezing or indirect fomite spread via contaminated surfaces.2 This simple transmission, coupled with international travel, has enabled rapid spread of the virus with more than 870 000 cases and 43 000 deaths reported worldwide as of April 1, 2020.3 Approximately 2·5 million individuals live with, or have a history of, cancer in the UK, with 1000 new diagnoses each day.4 Of these patients, a substantial proportion require, are undergoing, or are recovering from surgery and complex treatments. Conversely, many cancer treatments for solid tumours have little effect on lymphocyte populations or inflammatory responses. ...SARS-CoV-2 infection is highly unlikely to affect all patients with cancer equally. ...substantial reallocation of resources away from cancer care services could potentially have unintended cancer-related implications, including increased morbidity and mortality. ...real-time collection, analysis, and dissemination of data from our cancer centres about SARS-CoV-2 infection rates in patients with cancer, and their disease outcomes, is needed.
Dilapidations insurance should significantly reduce uncertainty about costs for occupiers at lease-end, report Nick Mace and Simon Hartley Uncertainty is the bane of most businesses: it deters ...investment, obstructs forward planning and plays havoc with the balance sheet. ...a number of insurance products in recent years have been designed to make matters more certain. The day before the trial, the landlord accepted the tenant's formal settlement offer of £700,000, but the trial judge decided that the tenant should face a costs sanction for unreasonable failure to mediate, depriving it of its costs for the relevant period.
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