Effective treatments for familial hypercholesterolaemia (FH) offer patients the opportunity of normal life expectancy, but lifelong adherence to both lipid-lowering therapies and lifestyle measures ...is challenging, and thus, this is rarely achieved. The aim of this systematic review is to identify attributes of educational interventions that promote adherence to treatment in FH. A systematic literature search was undertaken using Medline, CINAHL, HMIC and Embase. Papers were included based upon pre-defined inclusion and exclusion criteria; the quality of each included paper was assessed using the MERSQI scoring system. Relevant data were extracted, and a narrative synthesis was created. Six relevant studies of varying methodological quality were found amongst 2963 papers identified during the search. In total, there were 619 patients with FH in the intervention arm of the relevant studies. All six studies showed a positive effect of education on adherence to FH treatment; however, only two papers observed a statistically significant effect. Assessment was limited to the short-term. Four themes were identified as important when using education to improve treatment adherence: involving family, patient empowerment, practical problem solving and use of information leaflets. Educational interventions improve short term treatment adherence in patients with FH. Successful interventions are those that involve the whole family, set practical problem solving tasks, and that use techniques to increase the patients self-efficacy. This should all be supported by contemporaneous provision of written, age-appropriate information. There were no studies looking at education and long-term adherence in FH patients, and more research is needed in this area.
Background
Huntington disease prevalence was first estimated in Grampian, northern Scotland in 1984. Molecular testing has since increased ascertainment.
Objective
To estimate the prevalence of ...manifest Huntington disease and identified pre-symptomatic gene expansion carriers (IPGEC) in northern Scotland, and estimate the magnitude of biases in prevalence studies that rely upon routine coding in primary care records.
Methods
Cases were ascertained using North of Scotland genetic laboratory, clinic, and hospital records. Prevalence was calculated for manifest and IPGEC on 01/07/2016 and 01/01/2020 and compared with local published data.
Results
The prevalence of manifest Huntington disease in northern Scotland in 2020 was 14.6 (95% CI 14.3–15.3) per 100,000, and of IPGEC was 8.3 (95% CI 7.8–9.2) per 100,000. Whilst the population of northern Scotland decreased by 0.05% between 2016 and 2020, the number of manifest and identified pre-symptomatic gene expansion carriers increased by 7.4% and 23.3%, respectively. Manifest disease in Grampian increased by 45.9% between 1984 and 2020. More women than men had a diagnosis. General Practice coding underestimated symptomatic molecularly confirmed prevalence by 2.2 per 100,000 people.
Conclusion
Even in an area with previously high ascertainment, there has been a 45.9% increase in manifest Huntington disease over the last 30 years. Within our catchment area, prevalence varies between health board regions with similar community-based services. Such variation in prevalence could have major drug cost and service delivery implications, especially if expensive, complexly administered therapies prove successful. Health services should gather accurate population-based data on a regional basis to inform service planning.
It is frequent for news items to lead to a short lived temporary increase in interest in a particular health related service, however it is rare for this to have a long lasting effect. In 2013, in ...the UK in particular, there has been unprecedented publicity in hereditary breast cancer, with Angelina Jolie's decision to have genetic testing for the BRCA1 gene and subsequently undergo risk reducing mastectomy (RRM), and a pre-release of the NICE guidelines on familial breast cancer in January and their final release on 26th June. The release of NICE guidelines created a lot of publicity over the potential for use of chemoprevention using tamoxifen or raloxifene. However, the longest lasting news story was the release of details of film actress Angelina Jolie's genetic test and surgery.
To assess the potential effects of the 'Angelina Jolie' effect, referral data specific to breast cancer family history was obtained from around the UK for the years 2012 and 2013. A consortium of over 30 breast cancer family history clinics that have contributed to two research studies on early breast surveillance were asked to participate as well as 10 genetics centres. Monthly referrals to each service were collated and increases from 2012 to 2013 assessed.
Data from 12 family history clinics and 9 regional genetics services showed a rise in referrals from May 2013 onwards. Referrals were nearly 2.5 fold in June and July 2013 from 1,981 (2012) to 4,847 (2013) and remained at around two-fold to October 2013. Demand for BRCA1/2 testing almost doubled and there were also many more enquiries for risk reducing mastectomy. Internal review shows that there was no increase in inappropriate referrals.
The Angelina Jolie effect has been long lasting and global, and appears to have increased referrals to centres appropriately.
Purpose The Cancer Esophagus Gefitinib trial demonstrated improved progression-free survival with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib relative to placebo ...in patients with advanced esophageal cancer who had disease progression after chemotherapy. Rapid and durable responses were observed in a minority of patients. We hypothesized that genetic aberration of the EGFR pathway would identify patients benefitting from gefitinib. Methods A prespecified, blinded molecular analysis of Cancer Esophagus Gefitinib trial tumors was conducted to compare efficacy of gefitinib with that of placebo according to EGFR copy number gain (CNG) and EGFR, KRAS, BRAF, and PIK3CA mutation status. EGFR CNG was determined by fluorescent in situ hybridization (FISH) using prespecified criteria and EGFR FISH-positive status was defined as high polysomy or amplification. Results Biomarker data were available for 340 patients. In EGFR FISH-positive tumors (20.2%), overall survival was improved with gefitinib compared with placebo (hazard ratio HR for death, 0.59; 95% CI, 0.35 to 1.00; P = .05). In EGFR FISH-negative tumors, there was no difference in overall survival with gefitinib compared with placebo (HR for death, 0.90; 95% CI, 0.69 to 1.18; P = .46). Patients with EGFR amplification (7.2%) gained greatest benefit from gefitinib (HR for death, 0.21; 95% CI, 0.07 to 0.64; P = .006). There was no difference in overall survival for gefitinib versus placebo for patients with EGFR, KRAS, BRAF, and PIK3CA mutations, or for any mutation versus none. Conclusion EGFR CNG assessed by FISH appears to identify a subgroup of patients with esophageal cancer who may benefit from gefitinib as a second-line treatment. Results of this study suggest that anti-EGFR therapies should be investigated in prospective clinical trials in different settings in EGFR FISH-positive and, in particular, EGFR-amplified esophageal cancer.
Colorectal cancer (CRC) in patients aged under 55 years is on the rise, constituting approximately 10% of cases. Our aim was to determine the survival and clinico-pathological details of young-onset ...CRC (yCRC), as well as audit the referral rate to genetic services and thus establish the incidence of inherited cancer syndromes.
A retrospective case note review was conducted for patients aged under 55 years who were diagnosed with CRC between 2005 and 2015 in the North East of Scotland. Cases were identified by pathology records and data was obtained from patient notes. Analysis was performed using SPSS version 25 (IBM, New York, USA) to produce Kaplan-Meier survival estimates, descriptive statistics and markers predictive for genetic referral.
Data from 345 patients (age range 22-54 years) were identified. The one year, five year and overall survival rates were found to be 89, 63 and 55%, respectively. Most patients (61%) presented with advanced disease. Of 201 patients that met criteria for genetic referral, only 93 (46%) were referred to genetic services. Microsatellite instability (MSI) was identified in 14% of those referred.
Survival in yCRC was found to be better than that in later onset disease, despite higher rates of advanced disease. Patients were under-referred to genetic services, where a significant proportion were found to be MSI positive and investigated for Lynch syndrome.
The GATA family zinc finger transcription factors GATA4 and GATA6 are known to play important roles in the development of the pancreas. In mice, both Gata4 and Gata6 are required for pancreatic ...development. In humans, GATA6 haploinsufficiency can cause pancreatic agenesis and heart defects. Congenital heart defects also are common in patients with GATA4 mutations and deletions, but the role of GATA4 in the developing human pancreas is unproven. We report five patients with deletions (n = 4) or mutations of the GATA4 gene who have diabetes and a variable exocrine phenotype. In four cases, diabetes presented in the neonatal period (age at diagnosis 1-7 days). A de novo GATA4 missense mutation (p.N273K) was identified in a patient with complete absence of the pancreas confirmed at postmortem. This mutation affects a highly conserved residue located in the second zinc finger domain of the GATA4 protein. In vitro studies showed reduced DNA binding and transactivational activity of the mutant protein. We show that GATA4 mutations/deletions are a cause of neonatal or childhood-onset diabetes with or without exocrine insufficiency. These results confirm a role for GATA4 in normal development of the human pancreas.
Von Hippel-Lindau (VHL) disease is an inherited tumour predisposition syndrome and a paradigm for the importance of early diagnosis and surveillance. However, there is limited information on the ..."real world" management of VHL disease.
A national audit of VHL disease in the United Kingdom.
VHL disease was managed mostly via specialist clinics coordinated through regional clinical genetics services (but frequently involving additional specialties). Over the study period, 19 genetic centres saw 842 individuals (393 males, 449 females) with a clinical and/or molecular diagnosis of VHL disease and 74 individuals (35 male, 39 female) with a prior risk of 50% (affected parent). All centres offered retinal, central nervous system and abdominal surveillance to affected individuals and at-risk relatives though surveillance details differed between centres (but complied with international recommendations). Renal lesions detected on the first surveillance scan were, on average, larger than those detected during subsequent scans and the larger the diameter at detection the greater the likelihood of early intervention.
In a state-funded health care system individuals with a rare inherited cancer predisposition syndrome are generally able to access appropriate surveillance and patient management is improved compared to historical data. The "real world" data from this study will inform the future development of VHL management protocols.
Cascade testing the relatives of people with familial hypercholesterolaemia is an efficient approach to identifying familial hypercholesterolaemia. The cascade-testing protocol starts with ...identifying an index patient with familial hypercholesterolaemia, followed by one of three approaches to contact other relatives: indirect approach, whereby index patients contact their relatives; direct approach, whereby the specialist contacts the relatives; or a combination of both direct and indirect approaches. However, it is unclear which protocol may be most effective.
The objectives were to determine the yield of cases from different cascade-testing protocols, treatment patterns, and short- and long-term outcomes for people with familial hypercholesterolaemia; to evaluate the cost-effectiveness of alternative protocols for familial hypercholesterolaemia cascade testing; and to qualitatively assess the acceptability of different cascade-testing protocols to individuals and families with familial hypercholesterolaemia, and to health-care providers.
This study comprised systematic reviews and analysis of three data sets: PASS (PASS Software, Rijswijk, the Netherlands) hospital familial hypercholesterolaemia databases, the Clinical Practice Research Datalink (CPRD)-Hospital Episode Statistics (HES) linked primary-secondary care data set, and a specialist familial hypercholesterolaemia register. Cost-effectiveness modelling, incorporating preceding analyses, was undertaken. Acceptability was examined in interviews with patients, relatives and health-care professionals.
Systematic review of protocols: based on data from 4 of the 24 studies, the combined approach led to a slightly higher yield of relatives tested 40%, 95% confidence interval (CI) 37% to 42% than the direct (33%, 95% CI 28% to 39%) or indirect approaches alone (34%, 95% CI 30% to 37%). The PASS databases identified that those contacted directly were more likely to complete cascade testing (
< 0.01); the CPRD-HES data set indicated that 70% did not achieve target treatment levels, and demonstrated increased cardiovascular disease risk among these individuals, compared with controls (hazard ratio 9.14, 95% CI 8.55 to 9.76). The specialist familial hypercholesterolaemia register confirmed excessive cardiovascular morbidity (standardised morbidity ratio 7.17, 95% CI 6.79 to 7.56). Cost-effectiveness modelling found a net health gain from diagnosis of -0.27 to 2.51 quality-adjusted life-years at the willingness-to-pay threshold of £15,000 per quality-adjusted life-year gained. The cost-effective protocols cascaded from genetically confirmed index cases by contacting first- and second-degree relatives simultaneously and directly. Interviews found a service-led direct-contact approach was more reliable, but combining direct and indirect approaches, guided by index patients and family relationships, may be more acceptable.
Systematic reviews were not used in the economic analysis, as relevant studies were lacking or of poor quality. As only a proportion of those with primary care-coded familial hypercholesterolaemia are likely to actually have familial hypercholesterolaemia, CPRD analyses are likely to underestimate the true effect. The cost-effectiveness analysis required assumptions related to the long-term cardiovascular disease risk, the effect of treatment on cholesterol and the generalisability of estimates from the data sets. Interview recruitment was limited to white English-speaking participants.
Based on limited evidence, most cost-effective cascade-testing protocols, diagnosing most relatives, select index cases by genetic testing, with services directly contacting relatives, and contacting second-degree relatives even if first-degree relatives have not been tested. Combined approaches to contact relatives may be more suitable for some families.
Establish a long-term familial hypercholesterolaemia cohort, measuring cholesterol levels, treatment and cardiovascular outcomes. Conduct a randomised study comparing different approaches to contact relatives.
This study is registered as PROSPERO CRD42018117445 and CRD42019125775.
This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 27, No. 16. See the NIHR Journals Library website for further project information.
Male breast cancer (MBC) is a rare disease that accounts for less than 1% of all breast cancers and male malignancies. Despite recognised clinico-pathological and molecular differences to female ...breast cancer (FBC), the clinical management of MBC follows established FBC treatment strategies. Loss of function mutations in the DNA damage response genes BRCA1 and BRCA2, have been strongly implicated in the pathogenesis of MBC. While there have been extensive clinical advancements in other BRCA-related malignancies, including FBC, improvements in MBC remain stagnant. Here we present a review that highlights the lack of treatment evidence for BRCA-related MBC and the required national and global collaborative effort to address this unmet need. In doing so, we summarise the transformative clinical advancements with poly(ADP-ribose) polymerase (PARP) inhibitors in other BRCA-related cancers namely, FBC and prostate cancer.
Huntington's disease (HD) is a severe neurodegenerative condition that impacts the whole family. Prenatal diagnosis by direct or exclusion testing is available for couples at risk of transmitting HD ...to their children. An ethical problem can arise after prenatal diagnosis for HD if a known 'high risk' pregnancy is continued to term: international guidelines emphasise that this situation should be avoided where possible, as it removes the resulting child's future right to make an informed, autonomous decision about predictive testing. The UK Huntington's Disease Predictive Testing Consortium recorded 21 pregnancies that were tested, identified as high-risk and then continued. In this qualitative study, health professionals reviewed the case notes of 15 of these pregnancies. This analysis generated guidelines for clinical practice. It is recommended that practitioners: (i) remind couples of the long-term consequences of continuing a high risk pregnancy, (ii) ensure couples understand the information provided, (iii) collaborate closely with other professionals involved in the couple's prenatal care, (iv) prepare couples for the procedural aspects of prenatal diagnosis and a possible termination of pregnancy, (v) allow time for in-depth pre-test counselling, (vi) explain the rationale for only making prenatal diagnosis available subject to conditions, whilst allowing for human ambivalence and acknowledging that these 'conditions' cannot be enforced, (vii) monitor the whole clinical process to ensure that it works 'smoothly', (viii) recommend couples do not disclose the result of the prenatal test to protect the confidentiality and autonomy of the future 'high-risk' child, and (ix) offer on-going contact and support.
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