Cost-Effectiveness of Unselected Multigene Germline and Somatic Genetic Testing for Epithelial Ovarian Cancer.

BACKGROUND: Parallel panel germline and somatic genetic testing of all patients with ovarian cancer (OC) can identify more pathogenic variants (PVs) that would benefit from PARP inhibitor (PARPi) therapy, and allow for precision prevention in unaffected relatives with PVs. In this study, we estimate the cost-effectiveness and population impact of parallel panel germline and somatic BRCA testing of all patients with OC incorporating PARPi therapy in the United Kingdom and the United States compared with clinical criteria/family history (FH)-based germline BRCA testing. We also evaluate the cost-effectiveness of multigene panel germline testing alone. METHODS: Microsimulation cost-effectiveness modeling using data from 2,391 (UK: n=1,483; US: n=908) unselected, population-based patients with OC was used to compare lifetime costs and effects of panel germline and somatic BRCA testing of all OC cases (with PARPi therapy) (strategy A) versus clinical criteria/FH-based germline BRCA testing (strategy B). Unaffected relatives with germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 PVs identified through cascade testing underwent appropriate OC and breast cancer (BC) risk-reduction interventions. We also compared the cost-effectiveness of multigene panel germline testing alone (without PARPi therapy) versus strategy B. Unaffected relatives with PVs could undergo risk-reducing interventions. Lifetime horizon with payer/societal perspectives, along with probabilistic/one-way sensitivity analyses, are presented. Incremental cost-effectiveness ratio (ICER) and incremental cost per quality-adjusted life year (QALY) gained were compared with £30,000/QALY (UK) and $100,000/QALY (US) thresholds. OC incidence, BC incidence, and prevented deaths were estimated. RESULTS: Compared with clinical criteria/FH-based BRCA testing, BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 germline testing and BRCA1/BRCA2 somatic testing of all patients with OC incorporating PARPi therapy had a UK ICER of £51,175/QALY (payer perspective) and £50,202/QALY (societal perspective) and a US ICER of $175,232/QALY (payer perspective) and $174,667/QALY (societal perspective), above UK/NICE and US cost-effectiveness thresholds in the base case. However, strategy A becomes cost-effective if PARPi costs decrease by 45% to 46% or if overall survival with PARPi reaches a hazard ratio of 0.28. Unselected panel germline testing alone (without PARPi therapy) is cost-effective, with payer-perspective ICERs of £11,291/QALY or $68,808/QALY and societal-perspective ICERs of £6,923/QALY or $65,786/QALY. One year's testing could prevent 209 UK BC/OC cases and 192 deaths, and 560 US BC/OC cases and 460 deaths. CONCLUSIONS: Unselected panel germline and somatic BRCA testing can become cost-effective, with a 45% to 46% reduction in PARPi costs. Regarding germline testing, unselected panel germline testing is highly cost-effective and should replace BRCA testing alone.

Assessment of mismatch repair deficiency in ovarian cancer.

BACKGROUND: Hereditary causes of ovarian cancer include Lynch syndrome, which is due to inherited pathogenic variants affecting one of the four mismatch repair genes involved in DNA repair. The aim of this study was to evaluate tumour mismatch repair deficiency and prevalence of Lynch syndrome in high-risk women referred to the Manchester Centre for Genomic Medicine with ovarian cancer over the past 20 years. METHODS: Women with ovarian cancer diagnosed before the age of 35 years and/or with a suggestive personal or family history of Lynch syndrome cancers underwent tumour testing with immunohistochemistry for mismatch repair deficiency and, where indicated, MLH1 promoter methylation testing followed by constitutional testing for Lynch syndrome. RESULTS: In total, 261 ovarian cancers were tested and 27 (10.3%; 95% CI 6.9% to 14.7%) showed mismatch repair deficiency by immunohistochemistry. Three of 7 with MLH1 loss showed MLH1 promoter hypermethylation, and 18 of the remaining 24 underwent constitutional testing for Lynch syndrome. A further 15 women with mismatch repair proficient tumours underwent constitutional testing because of a strong family history of Lynch syndrome cancers. Pathogenic variants were identified in 9/33 (27%) women who underwent constitutional testing, aged 33-59 years (median 48 years), including one whose tumour was mismatch repair proficient. Most Lynch syndrome tumours were of endometrioid histological subtype. CONCLUSIONS: Tumour mismatch repair deficiency identified by immunohistochemistry is a useful prescreen for constitutional testing in women with ovarian cancer with personal or family histories suggestive of Lynch syndrome.

Assessment of the stability of citrate-buffered flucloxacillin for injection when stored in two commercially available ambulatory elastomeric devices: INfusor LV (Baxter) and Accufuser (Woo Young Medical): a study compliant with the NHS Yellow Cover Document (YCD) requirements.

Objectives: To investigate the effect of pH and buffers on the degradation rate of flucloxacillin and to determine if flucloxacillin can be stabilised using a buffered diluent for up to 14 days when stored at 2°C-8°C including a 24-hour infusion period at 32°C in two elastomeric devices (Accufuser and INfusor LV) filled to 240 mL. Testing as per the NHS Pharmaceutical Quality Assurance Committee Yellow Cover Document (YCD) requirements. Methods: A validated stability indicating high-performance liquid chromatography method was used for assessing the stability of flucloxacillin diluted in 0.3% w/v citrate-buffered saline pH 7.0 when stored at 2°C-8°C in two ambulatory devices (Accufuser and INfusor LV). Flucloxacillin at 10 and 50 mg/mL diluted in 0.3% w/v citrate-buffered saline pH 7.0 to a final volume of 240 mL and stored at 2°C-8°C, including 24 hours at 32°C, was tested from two batches in replicate (n=3) at five time points for up to 14 days according to the requirements of the YCD. Results: Greater than 95% of the zero-time concentration of flucloxacillin at 10 and 50 mg/mL remained when stored at 2°C-8°C after 14 days including 24 hours at 32°C in both Accufuser and INfusor LV devices. Conclusions: Flucloxacillin sodium stability was improved, and complied with UK national standards, by using a diluent of 0.3% w/v citrate-buffered saline pH 7 in both Accufuser and INfusor LV ambulatory devices when filled to 240 mL. The data support assigning a shelf-life of up to 14 days (13 days stored at 2°C-8°C and 24 hours at 32°C). Flucloxacillin may now be used appropriately as a continuous 24-hour infusion in outpatient parenteral antimicrobial therapy services, providing further opportunity to avoid or shorten patient hospital stays, as well as support ideal antimicrobial stewardship principles.

New challenges for BRCA testing: a view from the diagnostic laboratory.

Increased demand for BRCA testing is placing pressures on diagnostic laboratories to raise their mutation screening capacity and handle the challenges associated with classifying BRCA sequence variants for clinical significance, for example interpretation of pathogenic mutations or variants of unknown significance, accurate determination of large genomic rearrangements and detection of somatic mutations in DNA extracted from formalin-fixed, paraffin-embedded tumour samples. Many diagnostic laboratories are adopting next-generation sequencing (NGS) technology to increase their screening capacity and reduce processing time and unit costs. However, migration to NGS introduces complexities arising from choice of components of the BRCA testing workflow, such as NGS platform, enrichment method and bioinformatics analysis process. An efficient, cost-effective accurate mutation detection strategy and a standardised, systematic approach to the reporting of BRCA test results is imperative for diagnostic laboratories. This review covers the challenges of BRCA testing from the perspective of a diagnostics laboratory.

External quality assessment of BRAF molecular analysis in melanoma.

The availability of BRAF inhibitors has given metastatic melanoma patients an effective new treatment choice and molecular testing to determine the presence or absence of a BRAF codon 600 mutation is pivotal in the clinical management of these patients. This molecular test must be performed accurately and appropriately to ensure that the patient receives the most suitable treatment in a timely manner. Laboratories have introduced such testing; however, some experience low sample throughput making it critical that an external quality assurance programme is available to help promote a high standard of testing, reporting and provide an educational aspect for BRAF molecular testing. Laboratories took part in three rounds of external quality assessment (EQA) during a 12-month period giving participants a measure of the accuracy of genotyping, clinical interpretation of the result and experience in testing a range of different samples. Formalin fixed paraffin embedded tissue sections from malignant melanoma patients were distributed to participants for BRAF molecular testing. The standard of testing was generally high but distribution of a mutation other than the most common, p.(Val600Glu), highlighted concerns with detection or reporting of the presence of rarer mutations. The main issues raised in the interpretation of the results were the importance of clear unambiguous interpretation of the result tailored to the patient and the understanding that the treatment is different from that given to other stratified medicine programmes. The variability in reporting and wide range of methodologies used indicate a continuing need for EQA in this field.

Human variation and risk assessment: microarray and other studies utilizing human hepatocytes and human liver subcellular preparations.

The new paradigms proposed for human health risk assessment stress the need for the use of human and human-derived cell lines, and this review summarizes the use of primary human hepatocytes and hepatocyte subcellular preparations for the investigation of the metabolism and metabolic interactions of environmental chemicals. This includes interactions based on inhibition, induction, and activation. The role of cytotoxicity is also considered. The use of hepatocytes and hepatocyte preparations provides especially important information for the investigation of human variation and is summarized. This area is, at present, relatively neglected but will in the future be essential for accurate assessment of human health risk. A detailed summary of an initial attempt to utilize microarray technology for the study of genome-wide effects is included.

Primary care-led commissioning: applying lessons from the past to the early development of clinical commissioning groups in England.

BACKGROUND: The current reorganisation of the English NHS is one of the most comprehensive ever seen. This study reports early evidence from the development of clinical commissioning groups (CCGs), a key element in the new structures. AIM: To explore the development of CCGs in the context of what is known from previous studies of GP involvement in commissioning. DESIGN AND SETTING: Case study analysis from sites chosen to provide maximum variety across a number of dimensions, from September 2011 to June 2012. METHOD: A case study analysis was conducted using eight detailed qualitative case studies supplemented by descriptive information from web surveys at two points in time. Data collection involved observation of a variety of meetings, and interviews with key participants. RESULTS: Previous research shows that clinical involvement in commissioning is most effective when GPs feel able to act autonomously. Complicated internal structures, alongside developing external accountability relationships mean that CCGs' freedom to act may be subject to considerable constraint. Effective GP engagement is also important in determining outcomes of clinical commissioning, and there are a number of outstanding issues for CCGs, including: who feels 'ownership' of the CCG; how internal communication is conceptualised and realised; and the role and remit of locality groups. Previous incarnations of GP-led commissioning have tended to focus on local and primary care services. CCGs are keen to act to improve quality in their constituent practices, using approaches that many developed under practice-based commissioning. Constrained managerial support and the need to maintain GP engagement may have an impact. CONCLUSION: CCGs are new organisations, faced with significant new responsibilities. This study provides early evidence of issues that CCGs and those responsible for CCG development may wish to address.

Community nursing in systems reform: the London polyclinic experience.

Internationally, the polyclinic has been a feature of many health systems. The recent UK policy shift towards enhanced coordination of care closer to home resulted in the development of polyclinics, most notably in London. This article explores the background to the development of polyclinics and draws on the early experience of developments in London to explore what their impact has been, and is likely to be, on community nursing. Emerging findings from an evaluation of four pilot polyclinics suggests that rather than one model, polyclinics evolved in distinctively different ways more appropriately labelled as polysystems. Although policy makers clearly identified community nursing as being one of the key components of integrated, community-based care, the evaluation suggests a focus on high-level organizational restructuring and system change can shift attention from what many would consider core activities such as community health services.

Governance for health and wellbeing in the English NHS.

OBJECTIVES: Shifting the focus of health-care systems towards prevention has proved difficult to achieve. Governance structures are complex, incentives may conflict and there are many competing priorities. We explored the influence of governance and incentive arrangements on commissioning for health and well-being in the English National Health Service (NHS) and the governance paradoxes which emerge. METHODS: Qualitative and quantitative methods were employed. We carried out one national and two regional focus groups; a national online survey of primary care trusts (PCTs); and 99 semi-structured interviews in 10 purposively selected case study sites across England. Interviewees included decision-makers in PCTs, practice-based commissioners, Chairs of Local Involvement Networks (LINks) and of Overview and Scrutiny committees (OSCs) and Voluntary and Community Sector (VCS) members of local health and wellbeing partnerships. RESULTS: Case study sites differed in the extent to which they reflected a public health ethos throughout the commissioning cycle, incentivized preventive services through contractual flexibilities or prioritized investment in health and wellbeing. Practice-based commissioners were tangentially involved in the commissioning cycle, public health partnerships or local health needs assessment. While commissioning for health and wellbeing involves working through partnerships, performance management regimes favoured single organizational success. Preventive services were considered at increased risk in times of financial stringency. CONCLUSIONS: As the NHS in England undergoes further reorganization, it is important to ensure that a systematic, strategic and population-based approach to commissioning is not lost. Governance and incentive arrangements should be critically assessed for their impact on population health and wellbeing.

Pay for performance schemes in primary care: what have we learnt?

BACKGROUND: Pay for performance (P4P) schemes have become increasingly popular innovations in primary care and have generated questions about their effect on improving quality of care. AIMS: To provide a brief outline of the international evidence on the relationship between P4P schemes and quality improvement. METHOD: We conducted a literature search using relevant databases and reference lists of retrieved articles which discussed P4P schemes, quality in primary care and the Quality and Outcomes Framework (QOF). These included two recent systematic reviews of P4P schemes. RESULTS: Evidence on the effect of P4P on quality is limited. What we can say is that P4P schemes can have an effect on the behaviour of physicians and can lead to better clinical management of disease, but that there is cause for concern about the impact on the quality of care. CONCLUSION: P4P schemes need to take more account of broader definitions of quality, as whilst they can have a positive impact on incentivised clinical processes, it is not clear that this translates into improving the experience and outcome of care.

Semiquantitative assessment of immunohistochemistry for mismatch repair proteins in Lynch syndrome.

AIMS: To assess semiquantitative immunohistochemistry as used in the diagnosis of Lynch syndrome. METHODS AND RESULTS: Tumour sections from 51 mutation carriers and 17 controls were stained with antibodies against MLH1, MSH2, MSH6 and PMS2. Intensity of immunoreactivity and percentage positivity were recorded on scales of 0-3 and 0-4, respectively. These scores were multiplied for a score of 0-12 per slide. Receiver-operator characteristic (ROC) curves of staining performance for the identification of mutation carriers were evaluated, and optimum cut-offs calculated. The area under the MLH1 ROC curve was 0.981 [95% confidence interval (CI) 0.952, 1.000]. The area under the MSH2 ROC curve was 0.899 (95% CI 0.796, 1.000). For MLH1 staining, a score

New labour and reform of the English NHS: user views and attitudes.

BACKGROUND: The British National Health Service has undergone significant restructuring in recent years. In England this has taken a distinctive direction where the New Labour Government has embraced and intensified the influence of market principles towards its vision of a 'modernized' NHS. This has entailed the introduction of competition and incentives for providers of NHS care and the expansion of choice for patients. OBJECTIVES: To explore how users of the NHS perceive and respond to the market reforms being implemented within the NHS. In addition, to examine the normative values held by NHS users in relation to welfare provision in the UK. DESIGN AND SETTING: Qualitative interviews using a quota sample of 48 recent NHS users in South East England recruited from three local health economies. RESULTS: Some NHS users are exhibiting an ambivalent or anxious response to aspects of market reform such as patient choice, the use of targets and markets and the increasing presence of the private sector within the state healthcare sector. This has resulted in a sense that current reforms, are distracting or preventing NHS staff from delivering quality of care and fail to embody the relationships of care that are felt to sustain the NHS as a progressive public institution. CONCLUSION: The best way of delivering such values for patients is perceived to involve empowering frontline staffs who are deemed to embody the same values as service users, thus problematizing the current assumptions of reform frameworks that market-style incentives will necessarily gain public consent and support.

Benchmark for evaluating the quality of DNA sequencing: proposal from an international external quality assessment scheme.

BACKGROUND: In the past 15 years, clinical laboratory science has been transformed by the use of technologies that cross the traditional boundaries between laboratory disciplines. However, during this period, issues of quality have not always been given adequate attention. The European Molecular Genetics Quality Network (EMQN) has developed a novel external quality assessment scheme for evaluation of DNA sequencing. We report the results of an international survey of the quality of DNA sequencing among 64 laboratories from 21 countries. METHODS: Current practice for DNA sequence analysis was established by use of an online questionnaire. Participating laboratories were provided with 4 DNA samples of validated genotype. Evaluation of the results included assessing the quality of sequence data, variant genotypes, and mutation nomenclature. To accommodate variations in mutation nomenclature, variants indicated by participants were scored for compliance with 3 acceptable marking schemes. RESULTS: A total of 346 genotypes were analyzed. Of these, 19 (5%) genotyping errors were made. Of these, 10 (53%) were false-negative and 9 (47%) were false-positive results. A further 27 (8%) errors were made in naming mutations. Results were analyzed for 3 indicators of data quality: PHRED quality scores, Quality Read Length, and Quality Read Overlap. Most laboratories produced results of acceptable diagnostic quality as judged by these indicators. The results were used to calculate a consensus benchmark for DNA sequencing against which individual laboratories could rank their performance. CONCLUSIONS: We propose that the consensus benchmark can be used as a baseline against which the aggregate and individual laboratory standard of DNA sequencing may be tracked from year to year.