The utility of novel technologies in the diagnosis of chronic myeloid malignancies

The approach to diagnosing the myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) is primarily based on a subjective morphological assessment that is neither sensitive nor specific. Objective measures such as a cytogenetic assessment yield results in only a proportion of patients. Over the past 2 decades a range of new technologies have been developed which have the potential to revolutionise the diagnosis of these conditions by providing an objective measure of disease. This research aimed to investigate the utility of novel technologies in the diagnosis of MDS and MDS/MPN overlap syndromes, in particular chronic myelomonocytic leukaemia (CMML). The technologies utilized throughout the research included flow cytometry, single nucleotide polymorphism (SNP) arrays and high throughput sequencing (HTS). With the latter, a novel HTS panel was designed to target genes commonly mutated in myeloid malignancies. This was initially used to investigate a cohort of patients in whom a diagnosis could not be reached on initial analysis but subsequently developed a myeloid malignancy. Somatic mutations were detected at a very high frequency in the pre-diagnostic sample suggesting that targeted sequencing, in particular, could confirm clonality. This technology was further investigated on large cohorts of patients presenting with a monocytosis or cytopenia in whom mutations correlated strongly with survival and blood count trajectories as well as being predictive of a subsequent diagnosis. The detection of somatic mutations in those with persistent monocytosis or cytopenia, particularly with a clone size >20% and co-occuring mutations, is clinically important and patients should be managed as per those with confirmed disease. HTS is therefore essential in the diagnosis of these patients. This does however raise concerns regarding funding and change management and will likely necessitate rationalization of the diagnostic service. Overall, there is significant potential to transform the diagnostic approach to this group of disorders

The use of targeted sequencing and flow cytometry to identify patients with a clinically significant monocytosis

The diagnosis of chronic myelomonocytic leukaemia (CMML) remains centred on morphology, meaning the distinction from a reactive monocytosis is challenging. Mutational analysis and immunophenotyping have been proposed as potential tools for diagnosis however have not been formally assessed in combination. We aimed to investigate the clinical utility of these technologies by performing targeted sequencing, in parallel to current gold standard techniques, on consecutive samples referred for investigation of monocytosis over a 2-year period (n=283). Results were correlated with the morphological diagnosis and objective outcome measures including overall survival (OS) and longitudinal blood counts. Somatic mutations were detected in 79% of patients, being invariably identified in those with a confirmed diagnosis (99%) though also in 57% of patients with non-diagnostic BM features. The OS in non-diagnostic mutated patients was indistinguishable from those with CMML (p=0.118) and significantly worse than unmutated patients (p=0.0002). On multivariate analysis age, ASXL1, CBL, DNMT3A, NRAS & RUNX1 mutations retained significance. Furthermore, the presence of a mutation was associated with a progressive fall in haemoglobin/platelet levels and increasing monocyte counts compared with mutation negative patients. Of note, the immunophenotypic features of non-diagnostic mutated patients were comparable to CMML patients and the presence of aberrant CD56 was highly specific for detecting a mutation. Overall, somatic mutations are detected at high frequency in patients referred with a monocytosis irrespective of diagnosis. In those without a WHO defined diagnosis, the mutation spectrum, immunophenotypic features and OS are indistinguishable from CMML patients and these patients should be managed as such

Factors influencing referral to and uptake and attendance of pulmonary rehabilitation for chronic obstructive pulmonary disease: a qualitative evidence synthesis of the experiences of service users, their families, and healthcare providers (Protocol)

This is a protocol for a Cochrane Review (Qualitative). The object ives are as follows: • To identify factors that influence referral to pulmonary rehab ilitation for COPD from the perspective of service users, thei r family/carers, and healthcare providers. • To identify factors that influence uptake of pulmonary rehabil itation for COPD (i.e. at least one attendance of an assessment or first programme session) from the perspective of service users , their family/carers, and healthcare providers. • To identify factors that influence attendance at pulmonary reha bilitation programmes for COPD from the perspective of servi ce users, their family/carers, and healthcare providers. • To develop an inductive explanatory framework for how these f actors may interact to contribute to better or poorer uptake or completion of pulmonary rehabilitation in order to guide acti ons of healthcare decision-makers to improve opportunities fo r people with COPD to benefit from pulmonary rehabilitation

Improving the quality and content of midwives’ discussions with low-risk women about their options for place of birth: Co-production and evaluation of an intervention package

Objective: Women's planned place of birth is gaining increasing importance in the UK, however evidence suggests that there is variation in the content of community midwives’ discussions with low risk women about their place of birth options. The objective of this study was to develop an intervention to improve the quality and content of place of birth discussions between midwives and low-risk women and to evaluate this intervention in practice. Design: The study design comprised of three stages: (1) The first stage included focus groups with midwives to explore the barriers to carrying out place of birth discussions with women. (2) In the second stage, COM-B theory provided a structure for co-produced intervention development with midwives and women representatives; priority areas for change were agreed and the components of an intervention package to standardise the quality of these discussions were decided. (3) The third stage of the study adopted a mixed methods approach including questionnaires, focus groups and interviews with midwives to evaluate the implementation of the co-produced package in practice. Setting: A maternity NHS Trust in the West Midlands, UK. Participants: A total of 38 midwives took part in the first stage of the study. Intervention design (stage 2) included 58 midwives, and the evaluation (stage 3) involved 66 midwives. Four women were involved in the intervention design stage of the study in a Patient and Public Involvement role (not formally consented as participants). Findings: In the first study stage participants agreed that pragmatic, standardised information on the safety, intervention and transfer rates for each birth setting (obstetric unit, midwifery-led unit, home) was required. In the second stage of the study, co-production between researchers, women and midwives resulted in an intervention package designed to support the implementation of these changes and included an update session for midwives, a script, a leaflet, and ongoing support through a named lead midwife and regular team meetings. Evaluation of this package in practice revealed that midwives’ knowledge and confidence regarding place of birth substantially improved after the initial update session and was sustained three months post-implementation. Midwives viewed the resources as useful in prompting discussions and aiding communication about place of birth options. Key conclusions and implications for practice: Co-production enabled development of a pragmatic intervention to improve the quality of midwives’ place of birth discussions with low-risk women, supported by COM-B theory. These findings highlight the importance of co-production in intervention development and suggest that the place of birth package could be used to improve place of birth discussions to facilitate informed choice at other Trusts across the UK

Somatic Mutations and the Risk of Undifferentiated Autoinflammatory Disease in MDS: An Under-Recognized but Prognostically Important Complication

Objectives: We theorized that myelodysplastic syndrome (MDS) with somatic mutations and karyotype abnormalities are associated with autoinflammation, and that the presence of autoinflammatory disease affected prognosis in MDS.Methods: One hundred thirty-four MDS patients were assessed for the prevalence of autoinflammatory complications and its link with karyotypes and somatic mutation status. Autoinflammatory complications were described either as well-defined autoinflammatory diseases (AD) or undifferentiated “autoinflammatory disease” (UAD) (defined as CRP over 10.0 mg/L on five consecutive occasions, taken at separate times and not explained by infection). Several patient characteristics including demographic, clinical, laboratory, cytogenetics charts, and outcomes, were compared between different groups.Results: Sixty-two (46.3%) patients had an autoinflammatory complication manifesting as arthralgia (43.5% vs. 23.6%, p = 0.0146), arthritis (30.6% vs. 15.3%, p = 0.0340), skin rash (27.4% vs. 12.5%, p = 0.0301), pleuritis (14.5% vs. 4.2%, p = 0.0371) and unexplained fever (27.4% vs. 0%, p <0.0001). AD were found in 7.4% of MDS patients (with polymyalgia rheumatic being the most frequently one). Classical autoimmune diseases were found only in 4 MDS patients (3.0%). Transcription factor pathway mutations (RUNX1, BCOR, WTI, TP53) (OR 2.20 [95%CI 1.02–4.75], p = 0.0451) and abnormal karyotypes (OR 2.76 [95%CI 1.22–6.26], p = 0.0153) were associated with autoinflammatory complications. Acute leukaemic transformation was more frequent in MDS patients with autoinflammatory features than those without (27.4% vs. 9.7%, p = 0.0080).Conclusions: Autoinflammatory complications are common in MDS. Somatic mutations of transcription factor pathways and abnormal karyotypes are associated with greater risk of autoinflammatory complications, which are themselves linked to malignant transformation and a worse prognosis

Divergent clonal evolution of blastic plasmacytoid dendritic cell neoplasm and chronic myelomonocytic leukemia from a shared TET2-mutated origin

From Springer Nature via Jisc Publications RouterHistory: received 2020-11-25, rev-recd 2021-02-15, accepted 2021-03-11, registration 2021-03-12, pub-electronic 2021-04-08, online 2021-04-08, pub-print 2021-11Publication status: PublishedFunder: Oglesby Charitable TrustFunder: Pickering family donationFunder: Blood Cancer UK Clinician Scientist Fellowship (15030) Oglesby Charitable Trus

Myeloid malignancies in the real-world : Occurrence, progression and survival in the UK’s population-based Haematological Malignancy Research Network 2004–15

Background: Population-based information on cancer incidence, prevalence and outcome are required to inform clinical practice and research; but contemporary data are lacking for many myeloid malignancy subtypes. Methods: Set within a socio-demographically representative UK population of ~4 million, myeloid malignancy data (N = 5231 diagnoses) are from an established patient cohort. Information on incidence, survival (relative & overall), transformation/progression, and prevalence is presented for >20 subtypes. Results: The median diagnostic age was 72.4 years (InterQuartile Range 61.6-80.2), but there was considerable subtype heterogeneity, particularly among the acute myeloid leukaemias (AML) where medians ranged from 20.3 (IQR 13.9-43.8) for AML 11q23 through to 73.7 (IQR 57.3-79.1) for AML with no recurrent genetic changes. Five-year Relative Survival (RS) estimates varied hugely; from 85% for indolent/treatable conditions like chronic myeloid leukaemia (89.8%, 95% CI 84.0-93.6). With a couple of notable exceptions, males experienced higher rates and worse survival than females: the age-standardized incidence rates of several conditions was 2-4 higher in males than females, and the 5-year RS for all subtypes combined was 48.8% (95% CI 46.5-51.2) and 60.4% (95% CI 57.7-62.9) for males and females respectively. During follow-up (potential minimum 2 years and maximum 11 years) myelodysplastic syndrome (MDS) progression to AML ranged from 25% for refractory anaemia with excess blasts through to 5% for refractory anaemia with ring sideroblasts: the median interval between MDS and AML diagnosis was 9.0 months (IQR 4.8-17.4 months). Conclusions: The marked incidence and outcome variations seen by subtype, sex and age, confirm the requirement for "real-world" longitudinal data to inform aetiological hypotheses, healthcare planning, and future monitoring of therapeutic change. Several challenges for routine cancer registration were identified, including the need to link more effectively to diagnostic and clinical data sources, and to review policies on the recording of progressions and transformations