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We present a case of late symptom onset of COVID-19 infection 72 days after initial diagnosis in an immunocompromised 53-year-old man. SARS-CoV-2 was cultured from his sputum sample at this time, and genomic sequencing suggested reinfection was unlikely. After receipt of convalescent plasma, SARS-CoV-2 became undetectable by PCR 111 days after diagnosis, although SARS-CoV-2 antibodies remained not detectable. This case posed difficult public health management issues in a low prevalence COVID-19 setting as the person required extended home isolation given his prolonged SARS-CoV-2 PCR detection.

Contains fulltext : 237720.pdf (Publisher’s version ) (Open Access) We present a noninvasive Web-based app to help exclude or diagnose myelodysplastic syndrome (MDS), a bone marrow (BM) disorder with cytopenias and leukemic risk, diagnosed by BM examination. A sample of 502 MDS patients from the European MDS (EUMDS) registry (n > 2600) was combined with 502 controls (all BM proven). Gradient-boosted models (GBMs) were used to predict/exclude MDS using demographic, clinical, and laboratory variables. Area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were used to evaluate the models, and performance was validated using 100 times fivefold cross-validation. Model stability was assessed by repeating its fit using different randomly chosen groups of 502 EUMDS cases. AUC was 0.96 (95% confidence interval, 0.95-0.97). MDS is predicted/excluded accurately in 86% of patients with unexplained anemia. A GBM score (range, 0-1) of less than 0.68 (GBM < 0.68) resulted in a negative predictive value of 0.94, that is, MDS was excluded. GBM ≥ 0.82 provided a positive predictive value of 0.88, that is, MDS. The diagnosis of the remaining patients (0.68 ≤ GBM < 0.82) is indeterminate. The discriminating variables: age, sex, hemoglobin, white blood cells, platelets, mean corpuscular volume, neutrophils, monocytes, glucose, and creatinine. A Web-based app was developed; physicians could use it to exclude or predict MDS noninvasively in most patients without a BM examination. Future work will add peripheral blood cytogenetics/genetics, EUMDS-based prospective validation, and prognostication.

Countries worldwide are experiencing a second wave of coronavirus disease 2019 (COVID-19), which is proving to be difficult to control. We describe the combination of physical distancing, mandatory mask wearing, movement restrictions, and enhanced test, trace, and isolation efforts that can be used to successfully suppress community transmission to zero.

Available evidence suggests that in most patients with LR-MDS the risk of death is not related to disease progression but is mainly attributable to non-leukemic death. 2,17 In addition, a proportion of these patients have prolonged survival that precludes the design of clinical trials adopting OS as a primary endpoint. These challenges have resulted in potentially biased assessment of the effectiveness and appropriate use of the available interventions in this patient population. The EUMDS Registry has identified novel meaningful outcome indicators and clinical endpoints, and reliable measures of response to HCI (Figure 4). The results of our analysis indicate that RBCT density is strongly associated with a decreased OS, even at relatively low dose densities. In addition, we observed that an early decrease in platelet count is an independent adverse prognostic indicator in LR-MDS, and combining relative platelet drop and transfusion dependency allows early identification of patients at risk of rapid progression, and may guide early therapeutic interventions, including allogeneic hematopoietic stem cell transplantation or experimental interventions. Taken together, these results indicate that regular RBCT requirement, early platelet count kinetics, and restriction in HRQoL are early independent and meaningful outcome indicators, and reliable measures of effectiveness of therapeutic interventions, evaluated in this set of studies. These findings support the integration of RBCT requirement and HRQoL in the general core outcome sets and in response criteria in patients with LR-MDS, and have important implications for clinical practice and the design of clinical endpoints. Our results strongly support the adoption of freedom from transfusion as a meaningful clinical endpoint in patients with LR-MDS. Anemia is the main determinant of therapeutic intervention in patients with LR-MDS, and ESA are recommended as first-line treatment for patients with symptomatic anemia. 10 The observational studies within the EUMDS Registry showed that the response rate, as well as the capacity of these agents to delay the onset of a regular RBCT need, is most pronounced in RBCT-naïve patients. These results identified early initiation of treatment with ESA as a major treatment response indicator, and indicate that ESA should be recommended in LR-MDS patients with symptomatic anemia before starting regular RBCT. After the onset of RBCT dependency, patients with LR-MDS are prone to long-term accumulation of iron. 1,43 The EUMDS Registry studies provided evidence that elevated LPI levels are associated with reduced survival in RBCT dependent patients, whereas iron chelation therapy normalizes LPI levels. These findings suggest that NTBI and LPI may serve as early indicators of iron toxicity and a means to measure the effectiveness of iron chelation therapy in patients with LR-MDS. However, qualified NTBI and LPI are only currently available in specialized laboratories. 44 Large observational cohorts with detailed clinical and laboratory data, like the EUMDS cohort, are the ideal framework in which to identify well defined MDS subtypes that may benefit from novel targeted treatments. An example of such a subtype is MDS with loss of parts of chromosome 5, namely del5q; these patients have a relatively favorable outcome on lenalidomide treatment. In order to identify homogeneous subsets of patients within MDS, preliminary evidence has suggested that recently identified mutations in splicing factors may recognize distinct disease entities within myeloid neoplasms. 45 Splicing modulators are now in pre-clinical testing, and are very likely to lead to the introduction of effective drugs for specific groups of MDS patients. Luspatercept, a specific inhibitor of growth and differentiation factor-11, a member of the transforming growth factor β superfamily, induced substantial improvement of anemia, especially in patients with ring sideroblasts. 46 Characterization of individual cases by new genetic markers (one of the main objectives of the MDS-RIGHT project) will allow refined classification of patients into biological subgroups that are expected to respond differently to therapeutic interventions to guide discontinuation of those interventions that are less effective or less cost-effective. The main question is whether RCT data and retrospective cohort data in selected tertiary care centers are representative of the 'real world' data of the older patients with LR-MDS in the general population. A careful comparison of the 'real world' data and the RCT data will be needed in order to provide a clear answer to these questions. Meanwhile, the current analyses of data collected over 10 years in the EUMDS Registry provides relevant and important information which could help assess prognosis and response to standard interventions in this older patient group.

We recently published results of targeted sequencing applied to 928 unselected cases of DLBCL registered in the Haematological Malignancy Research Network (HMRN) registry (1). Clustering allowed us to resolve five genomic subtypes. These subtypes shared considerable overlap with those proposed in two independent genomic studies(2, 3), suggesting the potential to use genetics to stratify patients by both risk and biology. In the original studies, clustering techniques were applied to sample cohorts to reveal molecular substructure, but left open the challenge of how to classify an individual patient. This was addressed by the LymphGen classification tool (4). LymphGen assigns an individual case to one of six molecular subtypes. The tool accommodates data from exome or targeted sequencing, either with or without copy number variant (CNV) data. Separate gene expression data allows classification of a seventh, MYC-driven subtype defined by a double hit (DHL) or molecular high-grade (MHG) gene expression signature(5-7).

Recognition of dying is a difficult task in end-stage heart failure, yet it remains an important clinical skill in providing good palliative care to these patients.To use routinely collected data to explore evidence for physiological change in the final two weeks of life in end-stage heart failure.This was a retrospective cohort study of routinely collected data from hospital inpatients dying as a result of heart failure during a one-year period in a U.K. hospital. Data were analyzed using descriptive techniques and multilevel modeling.Results were obtained on 81 patients. Respiratory function (evidenced by falling oxygen saturation and rising respiratory rate) deteriorated by a clinically significant amount in the final two weeks of life (P 0.001). Renal function (evidenced by rising serum urea and creatinine) also demonstrated a clinically significant deterioration over the same period (P 0.001 and P = 0.005, respectively). Serum albumin fell over a period of months (P 0.001). Heart rate and blood pressure did not demonstrate clinically significant change over the same period.Deteriorating respiratory and renal function may indicate imminent dying in heart failure. A fall in serum albumin may signify poor prognosis over a timescale of weeks to months. Conversely, hemodynamic parameters may remain relatively stable in the final days of life and should not be reassuring in end-stage heart failure patients.

Iron overload due to red blood cell transfusions is associated with morbidity and mortality in lower-risk myelodysplastic syndrome patients. Many studies suggested improved survival after iron chelation therapy, but valid data are limited. The aim of this study was to assess the effect of iron chelation on overall survival and hematological improvement in lower-risk myelodysplastic syndrome patients in the European MDS registry. We compared chelated patients with a contemporary, non-chelated control group within the European MDS registry, that met the eligibility criteria for starting iron chelation. A Cox proportional hazards model was used to assess overall survival, treating receipt of chelation as a time-varying variable. Additionally, chelated and non-chelated patients were compared using a propensity-score matched model. Of 2200 patients, 224 received iron chelation. The hazard ratio and 95% confidence interval for overall survival for chelated patients, adjusted for age, sex, comorbidity, performance status, cumulative red blood cell transfusions, IPSS-R, and presence of ringed sideroblasts was 0.50 (0.34-0.74). The propensity-score analysis, matched for age, sex, country, red blood cell transfusion intensity, ferritin level, comorbidity, performance status, and IPSS-R and additionally corrected for cumulative red blood cell transfusions and presence of ringed sideroblasts, demonstrated a significantly improved overall survival for chelated patients with a hazard ratio of 0.42 (0.27-0.63) compared to non-chelated patients. Up to 39% of chelated patients reached an erythroid response. In conclusion, our results suggest that iron chelation may improve overall survival and hematopoiesis in transfused lower-risk myelodysplastic syndrome patients. This trial was registered at www.clinicaltrials.gov as #NCT00600860.

Based on the profile of genetic alterations occurring in tumor samples from selected diffuse large B-cell lymphoma (DLBCL) patients, 2 recent whole-exome sequencing studies proposed partially overlapping classification systems. Using clustering techniques applied to targeted sequencing data derived from a large unselected population-based patient cohort with full clinical follow-up (n = 928), we investigated whether molecular subtypes can be robustly identified using methods potentially applicable in routine clinical practice. DNA extracted from DLBCL tumors diagnosed in patients residing in a catchment population of ∼4 million (14 centers) were sequenced with a targeted 293-gene hematological-malignancy panel. Bernoulli mixture-model clustering was applied and the resulting subtypes analyzed in relation to their clinical characteristics and outcomes. Five molecular subtypes were resolved, termed MYD88, BCL2, SOCS1/SGK1, TET2/SGK1, and NOTCH2, along with an unclassified group. The subtypes characterized by genetic alterations of BCL2, NOTCH2, and MYD88 recapitulated recent studies showing good, intermediate, and poor prognosis, respectively. The SOCS1/SGK1 subtype showed biological overlap with primary mediastinal B-cell lymphoma and conferred excellent prognosis. Although not identified as a distinct cluster, NOTCH1 mutation was associated with poor prognosis. The impact of TP53 mutation varied with genomic subtypes, conferring no effect in the NOTCH2 subtype and poor prognosis in the MYD88 subtype. Our findings confirm the existence of molecular subtypes of DLBCL, providing evidence that genomic tests have prognostic significance in non-selected DLBCL patients. The identification of both good and poor risk subtypes in patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) clearly show the clinical value of the approach, confirming the need for a consensus classification.

Progression-free survival (PFS) of patients with lower-risk myelodysplastic syndromes (MDS) treated with red blood cell transfusions is usually reduced, but it is unclear whether transfusion dose density is an independent prognostic factor. The European MDS Registry collects prospective data at 6-monthly intervals from newly diagnosed lower-risk myelodysplastic syndromes patients in 16 European countries and Israel. Data on the transfusion dose density - the cumulative dose received at the end of each interval divided by the time since the beginning of the interval in which the first transfusion was received - were analyzed using proportional hazards regression with time-varying co-variates, with death and progression to higher-risk MDS/acute myeloid leukemia as events. Of the 1,267 patients included in the analyses, 317 died without progression; in 162 patients the disease had progressed. PFS was significantly associated with age, EQ-5D index, baseline World Health Organization classification, bone marrow blast count, cytogenetic risk category, number of cytopenias, and country. Transfusion dose density was inversely associated with PFS (P-4): dose density had an increasing effect on hazard until a dose density of 3 units/16 weeks. The transfusion dose density effect continued to increase beyond 8 units/16 weeks after correction for the impact of treatment with erythropoiesis-stimulating agents, lenalidomide and/or iron chelators. In conclusion, the negative effect of transfusion treatment on PFS already occurs at transfusion densities below 3 units/16 weeks. This indicates that transfusion dependency, even at relatively low dose densities, may be considered as an indicator of inferior PFS. This trial was registered at www.clinicaltrials.gov as #NCT00600860.

Background Mosquito control interventions are widely used to reduce mosquito-borne diseases. It is unclear what combination of interventions are most effective in reducing human disease. A novel intervention study for Buruli ulcer targeting mosquito vectors was proposed for a Buruli ulcer-endemic area of Victoria, Australia. The local community expressed a preference for avoiding widespread residual spraying of pyrethroids. To inform the design of a future cluster randomised control study (cRCT) for Buruli ulcer prevention in Victoria, we conducted a systematic literature review. Aims The aim was to describe cRCT designs which investigated interventions other than non-targeted insecticide for reducing mosquito-borne disease transmission, and comment on the strengths and weaknesses of these study designs. Methods Five medical research databases were searched for eligible literature from the earliest available sources up to 5 July 2019 (Medline, Embase, Web of Science, EBM Reviews, CAB Direct). Reference lists of identified studies were hand searched. Eligible studies were cRCTs using targeted chemical or biological mosquito control interventions, or mosquito breeding source reduction, with the occurrence of mosquito-borne disease as an outcome. Results Eight eligible cRCTs, conducted between 1994–2013 were identified in a variety of settings in the Americas and Asia. Interventions to reduce dengue transmission were mass adult trapping and source reduction. Interventions to reduce malaria transmission were largescale larvicide administration and (topical and spatial) repellent use. Three studies showed the intervention was associated with statistically significant reductions in the disease of interest and entomological indicators. High community engagement with the intervention were common to all three. In two studies, large buffer zones reduced contamination between study arms. Heterogeneity was reduced through increasing study cluster numbers, cluster matching and randomisation. Conclusion High community engagement is vital for a cRCT reducing mosquito-borne disease with a mosquito control intervention. These findings support a mosquito breeding source reduction intervention for Aedes control in a future study of Buruli ulcer prevention if local communities are supportive and very engaged. Regular administration of larvicide to sites unsuited to source reduction may supplement the intervention., Author summary Mosquito control interventions are widely used to reduce mosquito-borne diseases, but it is unclear what combination of interventions are most effective in reducing human disease. Given the wide range of mosquito species and the diseases they transmit, different interventions strategies have been implemented across many regions globally, with varying degrees of success. This literature review identified three intervention studies which did not include non-targeted use of insecticide and were associated with statistically significant reductions in the disease of interest and in entomological indicators following the intervention. High community engagement is vital for the success of a cluster randomised control study aiming to reduce mosquito-borne disease with a mosquito control intervention, such as breeding source reduction for Aedes control. In two studies, large buffer zones reduced contamination between study intervention and control arms. Differences between the study arms were reduced through increasing study cluster numbers, cluster matching and randomisation. Regular administration of larvicide to potential breeding sites that are unsuitable for source reduction may supplement this intervention strategy.

Background. The severity of hematopoietic impairment and the kinetics of disease progression in lower risk myelodysplastic syndromes (LR-MDS) are extremely variable. Genomic profiling has the potential to inform the clinical management of these disorders, including improved classification, risk assessment and therapeutic choice. In the present study, based on a comprehensive mutation analysis in a large and clinically well-characterized cohort of LR-MDS patients, either recruited into the European MDS Registry or referred to European excellence centers involved in the MDS-RIGHT project, we adopted unsupervised hierarchical clustering analyses to identify relevant genetically defined disease subtypes within early stage MDS. Methods. The dataset comprised 856 cases identified as LR-MDS based on IPSS risk low or intermediate-1. Median age was 73 years (range 36-98); IPSS-R risk was very low in 30.1% of patients, low in 50.4%, intermediate in 19.5%. We investigated possible sub-structure amongst patients according to their mutational profiles, and correlated this sub-structure with relevant endpoints. For this analysis, unsupervised clustering was used, based on a mixture model of multivariate Bernoulli distributions. The optimal number of clusters was chosen using the Bayes Information Criterion (BIC), with secondary structure identified with the Akaike Information Criterion (AIC). Results. This analysis identified three distinct clusters within LR-MDS. Cluster 1 comprised exclusively patients with SF3B1 mutation, either isolated or associated with other mutations (SF3B1-mutant cluster) (37% of patients). Cluster 2 was characterized by excess mutations associated with higher risk disease (high-risk (HR) cluster) (27% of patients), including a significantly higher prevalence of ASXL1, IDH1/IDH2, SRSF2, RUNX1, CBL and EZH2 mutations (P The three recognized clusters showed distinct clinical features and outcome measures. Patients within HR cluster were significantly older (P=.008) and showed significant enrichment in WHO categories with multi-lineage dysplasia and excess blasts (P HR-cluster showed significantly lower overall survival (OS) compared to CHIP-like and SF3B1-mutant clusters (median 2.6 vs 6.8 or 6.4 years; P Conclusion. Mutation profiling identifies meaningful clusters of lower risk MDS with distinct molecular pathways, clinical features and endpoints. These results represent a robust basis to inform genetic ontogeny-based classification and individual risk assessment, as well as to inspire biology-driven clinical trials in lower risk MDS. Disclosures Symeonidis: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi/Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; WinMedica: Research Funding; Celgene: Honoraria, Research Funding; Astellas: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stauder:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva: Research Funding. Fenaux:Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Van Marrewijk:EUMDS and MDS-RIGHT (Providing the right care to the right patient with MyeloDysplastic Syndrome at the right time) project: Other: Project manager of the EUMDS Registry.

The diagnosis of chronic myelomonocytic leukemia (CMML) remains centered on morphology, meaning that the distinction from a reactive monocytosis is challenging. Mutational analysis and immunophenotyping have been proposed as potential tools for diagnosis; however, they have not been formally assessed in combination. We aimed to investigate the clinical utility of these technologies by performing targeted sequencing, in parallel with 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%) but also in 57% of patients with nondiagnostic bone marrow features. The OS in nondiagnostic mutated patients was indistinguishable from those with CMML (P = .118) and significantly worse than in unmutated patients (P = .0002). On multivariate analysis, age, ASXL1, CBL, DNMT3A, NRAS, and RUNX1 mutations retained significance. Furthermore, the presence of a mutation was associated with a progressive decrease in hemoglobin/platelet levels and increasing monocyte counts compared with mutation-negative patients. Of note, the immunophenotypic features of nondiagnostic 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 World Health Organization–defined diagnosis, the mutation spectrum, immunophenotypic features, and OS are indistinguishable from CMML patients, and these patients should be managed as such.

Background Diffuse large B-cell lymphoma (DLBCL) is the commonest non-Hodgkin lymphoma. Previous studies examining the cost of treating DLBCL have generally focused on a specific first-line therapy alone; meaning that their findings can neither be extrapolated to the general patient population nor to other points along the treatment pathway. Based on empirical data from a representative population-based patient cohort, the objective of this study was to develop a simulation model that could predict costs and life expectancy of treating DLBCL. Methods All patients newly diagnosed with DLBCL in the UK’s population-based Haematological Malignancy Research Network (www.hmrn.org) in 2007 were followed until 2013 (n = 271). Mapped treatment pathways, alongside cost information derived from the National Tariff 2013/14, were incorporated into a patient-level simulation model in order to reflect the heterogeneities of patient characteristics and treatment options. The NHS and social services perspective was adopted, and all outcomes were discounted at 3.5 % per annum. Results Overall, the expected total medical costs were £22,122 for those treated with curative intent, and £2930 for those managed palliatively. For curative chemotherapy, the predicted medical costs were £14,966, £23,449 and £7376 for first-, second- and third-line treatments, respectively. The estimated annual cost for treating DLBCL across the UK was around £88–92 million. Conclusions This is the first cost modelling study using empirical data to provide ‘real world’ evidence throughout the DLBCL treatment pathway. Future application of the model could include evaluation of new technologies/treatments to support healthcare decision makers, especially in the era of personalised medicine. Electronic supplementary material The online version of this article (doi:10.1007/s10198-016-0775-4) contains supplementary material, which is available to authorized users.

In this study we aimed to test the associations between area-level ethnic density and health for Pakistani and White British residents of Bradford, England.The sample consisted of 8610 mothers and infant taking part in the Born in Bradford cohort. Ethnic density was measured as the percentage of Pakistani, White British or South Asian residents living in a Lower Super Output Area. Health outcomes included birth weight, preterm birth and smoking during pregnancy. Associations between ethnic density and health were tested in multilevel regression models, adjusted for individual covariates and area deprivation.In the Pakistani sample, higher own ethnic density was associated with lower birth weight (β = -0.82, 95% CI: -1.63, -0.02), and higher South Asian density was associated with a lower probability of smoking during pregnancy (OR = 0.99, 95% CI: 0.98, 1.00). Pakistani women in areas with 50-70% South Asian residents were less likely to smoke than those living in areas with less than 10% South Asian residents (OR = 0.39, 95% CI: 0.16, 0.97). In the White British sample, neither birth weight nor preterm birth was associated with own ethnic density. The probability of smoking during pregnancy was lower in areas with 10-29.99% compared to10% South Asian density (OR = 0.79, 95% CI: 0.64, 0.98).In this sample, ethnic density was associated with lower odds of smoking during pregnancy but not with higher birth weight or lower odds of preterm birth. Possibly, high levels of social disadvantage inhibit positive effects of ethnic density on health.

This study investigates the value of performing a staging bone marrow in patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and classical hodgkin lymphoma (CHL). The results of 3112 staging bone marrow examinations were assessed for impact on prognostic assessment and critical treatment decisions. The detection of marrow involvement altered the disease-specific prognostic index for 4·3% of DLBCL, 6·2% of FL and 0·6% of CHL but marrow involvement in DLBCL was an independent prognostic factor. Knowing the marrow status potentially changed treatment in 92 patients, detection of these patients would have required 854 examinations to be performed.

Summary Objectives We conducted a systematic review that aimed to document and describe how (1) expectation of benefit from treatment (response expectancies) were measured and reported in acupuncture trials, and (2) examine any effect on outcomes. Design We searched MEDLINE, EMBASE, AMED, CIHAHL, CENTRAL and Science and Technology Proceedings up to November 2007 for randomised (RCT) and quasi-randomised (CCT) controlled trials and prospective controlled cohorts of acupuncture as treatment for a medical or psychological condition in adults. An update citation search was conducted in April 2010. We included studies that mentioned soliciting response expectancies. Results We found 58 RCTs that fulfilled our inclusion criteria. Around half referenced one of five published instruments, most of which were designed to measure sham credibility and included one question on response expectancy. A wide range of question phrasing and response scales was used. There was some evidence that response scales may influence the measurement of expectations. Eight trials analysed the association between pre-randomisation expectations for assigned treatment and outcomes, and six the effect of pre-randomisation expectations across all patients independent of treatment allocation. Some showed associations but others did not. Conclusions There is some evidence that response expectancies interact with outcomes in acupuncture trials however the variety of question phrasing and analysis methods precludes drawing a firm conclusion about for whom and under which circumstance. To further our understanding of expectations, more methodological work is needed to standardise the questions and response scales that are used.

Prognosis of lower-risk (International Prognostic Scoring System [IPSS] low/intermediate-1) myelodysplastic syndrome (MDS) is heterogeneous and relies on steady-state assessment of cytopenias. We analyzed relative drops in neutrophil and platelet counts during the first 6 months of follow-up of lower-risk MDS patients. We performed a landmark analysis of overall survival (OS) of lower-risk MDS patients prospectively included in the European LeukaemiaNet MDS registry having a visit at 6 +/- 1 month from inclusion to assess the prognostic relevance of relative drops in neutrophils and platelets, defined as (count at landmark - count at inclusion)/count at inclusion. Of 2102 patients, 807 were eligible for the stringent 6-month landmark analysis. Median age was 73 years. Revised IPSS was very low, low, and intermediate/higher in 26%, 43%, and 31% of patients, respectively. A relative drop in platelets >25% at landmark predicted shorter OS (5-year OS, 21.9% vs 48.6% with platelet drop 25% had no significant impact on OS. We built a classifier based on red blood cell transfusion dependence (RBC-TD) and relative platelet drop >25% at landmark. Patients with none (62%), either (27%), or both criteria (11%) had 5-year OS of 53.3%, 32.7%, and 9.0%, respectively (P < 10(-4)). This classifier was validated in an independent cohort of 335 patients. Combining relative platelet drop >25% and RBC-TD at 6 months from diagnosis provides an inexpensive and noninvasive way to predict outcome in lower-risk MDS. This study was registered at www.clinicaltrials.gov as #NCT00600860.

Background: Population-based information about cancer occurrence and survival are required to inform clinical practice and research; but for most lymphomas data are lacking. Methods: Set within a socio-demographically representative UK population of nearly 4 million, lymphoma data (N ¼ 5796) are from an established patient cohort. Results: Incidence, survival (overall and relative) and prevalence estimates for 420 subtypes are presented. With few exceptions, males tended to be diagnosed at younger ages and have significantly (Po0.05) higher incidence rates. Differences were greatest at younger ages: the o15 year male/female rate ratio for all subtypes combined being 2.2 (95% CI 1.3–3.4). These gender differences impacted on prevalence; most subtype estimates being significantly (Po0.05) higher in males than females. Outcome varied widely by subtype; survival of patients with nodular lymphocyte predominant Hodgkin lymphoma approached that of the general population, whereas less than a third of those with other B-cell (e.g., mantle cell) or T-cell (e.g., peripheral-T) lymphomas survived for Z5 years. No males/female survival differences were detected. Conclusions: Major strengths of our study include completeness of ascertainment, world-class diagnostics and generalisability. The marked variations demonstrated confirm the requirement for ‘real-world’ data to inform aetiological hypotheses, health-care planning and the future monitoring of therapeutic changes.

Objective: Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genomewide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods: GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis. Results: Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765. Conclusions: These data suggest several plausible genetic links between DLBCL and SLE. © 2017 BMJ Publishing Group. All rights reserved.

Background: Recognising dying remains a difficult clinical skill which has gained increasing importance in the United Kingdom since the Neuberger review. Clinical and research methods exist to aid recognition of dying but do not exhibit the level of accuracy required for such an important decision. Aim: To explore change in key clinical parameters as cancer patients near the end of life. Design: This is a retrospective cohort study of terminally ill patients. Data were collected from hospital case-notes. Case-note data were analysed using multilevel modelling to explore absolute values and rates of change of given variables. Setting/participants: Hospital in-patients who died from solid-tumour malignancies within a 3-month period in 2009 formed the cohort. The setting was an acute hospital trust in the North of England. Results: A total of 15,337 data points from the case-notes of 102 patients were analysed. There was a clinically and statistically significant deterioration in respiratory function and renal function over the last 2 weeks of life. Heart rate and serum sodium also changed but did not vary greatly from normal limits. White cell parameters, haemoglobin and albumin showed evidence for change over longer periods. Conclusion: Results demonstrate statistically and clinically significant change in routinely measured respiratory and renal function variables during the final 2 weeks of life in people dying with cancer. Although useful in acute early warning scores, in a terminally ill patient, relative haemodynamic stability should not be interpreted as reassuring. Further work is needed to understand how these findings apply to the individual or inform other prognostic work.

Guidelines recommend exercise-based cardiac rehabilitation (EBCR) for patients with heart failure (HF). However, established research has not investigated the longer-term outcomes including mortality and hospitalisation in light of the contemporary management of HF.This was a systematic review including a meta-analysis of EBCR on all-cause mortality, hospital admission, and standardised exercise capacity using four separate exercise tests in patients with heart failure over a minimum follow-up of six months from January 1999-January 2013. Electronic searches were performed in the databases: Medline, CENTRAL, EMBASE, CINAHL, and PsycINFO constrained to randomised controlled trials (RCTs).A total of 46 separate RCTs qualified for the meta-analysis, which employed conventional methods for binary and continuous data. The relative risk (RR) ratio for hospital admission (12 studies) was significantly reduced (RR ratio 0.65; 95% confidence interval (CI) 0.50-0.84; p = 0.001), but mortality (21 studies) was not (RR ratio 0.88; 95% CI 0.77-1.02; p = 0.08). The standardised exercise capacity (26 studies) showed a standardised mean difference (SMD) in favour of the exercise group as compared with the controls (SMD 0.98, 95% CI 0.59-1.37; p 0.001). Women and elderly people were less frequently enrolled in the RCTs independent of the outcomes. Heterogeneity was moderate to high in the analysis of hospital admission and the standardised exercise capacity demonstrated through skewedness in their funnel plots.EBCR in patients with HF is associated with significant improvements in exercise capacity and hospital admission over a minimum of six months follow-up, but not in all-cause mortality.

Objectives We present a new method for determining prevalence estimates together with estimates of their precision, from incidence and survival data using Monte-Carlo simulation techniques. The algorithm also provides for the incidence process to be marked with the values of subject level covariates, facilitating calculation of the distribution of these variables in prevalent cases. Methods Disease incidence is modelled as a marked stochastic process and simulations are made from this process. For each simulated incident case, the probability of remaining in the prevalent sub-population is calculated from bootstrapped survival curves. This algorithm is used to determine the distribution of prevalence estimates and of the ancillary data associated with the marks of the incidence process. This is then used to determine prevalence estimates and estimates of the precision of these estimates, together with estimates of the distribution of ancillary variables in the prevalent sub-population. This technique is illustrated by determining the prevalence of acute myeloid leukaemia from data held in the Haematological Malignancy Research Network (HMRN). In addition, the precision of these estimates is determined and the age distribution of prevalent cases diagnosed within twenty years of the prevalence index date is calculated. Conclusion Determining prevalence estimates by using Monte-Carlo simulation techniques provides a means of calculation more flexible that traditional techniques. In addition to automatically providing precision estimates for the prevalence estimates, the distribution of any measured subject level variables can be calculated for the prevalent sub-population. Temporal changes in incidence and in survival offer no difficulties for the method.

The high frequency of somatic mutations in myelodysplastic syndromes (MDS) provides an additional biomarker modality for MDS diagnosis. This has significant potential in the investigation of cytopenias particularly in cases with All patient samples referred for unexplained cytopenia or suspected MDS to the Haematological Malignancy Diagnostic Service in the UK over a 2-year period (July 2014-2016) were included. Samples were analysed using established diagnostic assays (morphology, flow cytometry, cytogenetics) and in parallel subjected to targeted sequencing of 27 genes commonly mutated in myeloid malignancies. Outcome data was captured including serial blood count data, subsequent diagnoses and overall survival. A subgroup of 37 mutation negative samples underwent extended genotyping of 126 genes. A total of 2089 samples passed QC for targeted sequencing. Of these, 538 had a confirmed diagnosis (26%), the majority of which were diagnosed with a myeloid malignancy (449/538; 83%). Mutations were commonly identified in the latter with ≥1 somatic mutation +/or karyotypic abnormality detected in 91% of patients. Importantly, mutations were also detected in 28% of non-diagnostic (ND) samples (412/1496). The spectrum of mutations was similar between ND and MDS samples, though varied in frequency. In ND samples TET2, SRSF2 and DNMT3A mutations predominated (47%, 22%, 19% respectively) while SF3B1, TET2 and ASXL1 were most frequently mutated in MDS (25%, 24%, 24% respectively). The number of mutations detected per sample and the variant allele fraction (VAF) was also significantly lower in ND samples (median no. of mutations 1 vs 2; median VAF 17.7% vs 35.1%; p To determine the clinical significance of mutations, correlation was made with subsequent diagnoses and clinical outcome. Follow-up bone marrow samples were received in 205 ND samples and 82 of these had a confirmed diagnosis of which 61 had a myeloid malignancy. The presence of a mutation at baseline was strongly associated with a subsequent myeloid diagnosis (NDmut vs NDunmut ;13% vs 0.5%; p1 mutation; p Importantly the presence of a mutation impacted significantly on survival in the ND group (odds ratio=1.59; p By analysing a large unselected cohort of cytopenic patients, this study has demonstrated the power of mutation analysis to predict both a subsequent myeloid diagnosis and clinical outcome in those without a confirmed diagnosis. While standard techniques will identify some of these patients over time, crucially, those at highest risk can remain undetected. Identifying these patients would ensure close clinical follow-up and provide an opportunity for early intervention. Ultimately this will facilitate the development of predictive models and refine diagnostic algorithms and this work is ongoing. Disclosures Cargo: Celgene: Research Funding. Evans:Diaceutics: Honoraria; Novartis: Honoraria. Papaemmanuil:Celgene: Research Funding.

Aims Aspirin and statins are established therapies for acute myocardial infarction (MI), but their benefits in patients with chronic heart failure (HF) remain elusive. We investigated the impact of aspirin and statins on long-term survival in patients hospitalized with acute MI complicated by HF. Methods and results Of 4251 patients in the Evaluation of Methods and Management of Acute Coronary Events (EMMACE)-1 and -2 observational studies, 1706 patients had HF. A propensity score-matching method estimated the average treatment effects (ATEs) of aspirin and statins on survival over 90 months. ATEs were calculated as relative risk differences in all-cause mortality comparing patients receiving aspirin and statins with controls, respectively. Moreover, combined aspirin and statins vs. none (ATE I), aspirin or statins vs. none (ATE II), and aspirin and statins vs. aspirin or statins (ATE III) were assessed. The median survival times of the ATE I, ATE II and ATE III were 25, 50, and 85 months, respectively. Regarding aspirin, the ATE was significantly improved at 6, 12, and 90 months [ATE 6 months: 10%, 95% confidence interval (CI) 3–18%], where the ATE of statins favoured survival at 1–24 months (ATE 1 month: 5%, 95% CI 0.3–10%). Mortality was lower at 1, 6, and 24 months in those who received aspirin and statins (ATE I). When the combination was compared with either treatment alone, an effect persisted between 6 and 90 months (ATE III). Conclusion In patients with acute MI complicated by HF, prescription of aspirin and statins either alone or together was associated with better long-term survival.

Objective To review reporting of preferences in acupuncture studies and their effect on clinical outcomes. Study Design and Setting Systematic review of published randomized and quasi-randomized controlled trials of acupuncture reporting participant preferences for randomization or treatment or using a preference design. Results Of the 31 included trials, 5 reported on randomization preference, 18 on treatment preference, and 1 reported on both. Seven used a preference design. Four out of seven trials noted that the group with preferences had different baseline characteristics (less education, worse baseline measure score, and greater or fewer years with pain). There was a tendency for greater attrition in nonpreference arms at 6 months but not earlier. Around three-quarters of participants turned down randomization in favor of nontrial treatment, and preference for acupuncture was around 20% when offered multiple treatments. Questions used to elicit preferences varied across trials and were poorly reported. Ten trials reported the effects of preferences on outcomes; only one detected a statistically (but not clinically) significant difference. Conclusion There is little evidence that preferences cause detectable effects on outcomes in acupuncture trials; however, trials use inconsistent methods and poorly report these data. Monitoring the level and effect of preferences in trials is recommended.

Objective: Well-established cancer registries that routinely link to death registrations can estimate prevalence directly by counting patients alive at a particular point in time (observed prevalence). Such direct methods can only provide prevalence for the years over which the registry has been operational. Time-defined estimates, including 5- and 10-year prevalence, may however underestimate the total cancer burden, and compared with other cancers, there is a lack of accurate information on the total prevalence of hematological malignancy subtypes. Accordingly, we aimed to estimate prevalence (observed and total prevalence) of hematological malignancies and precursor conditions by clinically meaningful subtypes using data from the UK’s specialist population-based register, the Haematological Malignancy Research Network (www.hmrn.org). Methods: Observed and total prevalences were estimated from 15,810 new diagnoses of hematological malignancies from 2004 to 2011 and followed up to the 31 August 2011 (index data). Observed prevalence was calculated by the counting method, and a method based on modelling incidence and survival was used to estimate total prevalence. Estimates were made according to current disease classification for the HMRN region and for the UK. Results: The overall observed and total prevalence rates were 281.9 and 548.8 per 100,000, respectively; the total number of observed and total prevalent cases in the UK was estimated as 165,841 and 327,818 cases, as expected variation existed by disease subtype reflecting the heterogeneity in underlying disease incidence, survival and age distribution of hematological cancers. Conclusions: This study demonstrates the importance of estimating ‘total’ prevalence rather than ‘observed’ prevalence by current disease classification (ICD-O-3), particularly for subtypes that have a more indolent nature and for those that are curable. Importantly, these analyses demonstrate that relying on observed prevalence alone would result in a significant underestimation of the relative burden of some subtypes. While many of these cases may be considered cured and no longer being actively treated, people in this survivorship phase may have long-term medical needs and accordingly, it is important to provide accurate counts to allow for healthcare planning.

International guidelines recommend referral for cardiac rehabilitation (CR) after acute myocardial infarction (AMI). However, the impact on long-term survival after CR referral has not been adjusted by time-variance. We compared the effects of CR referral after hospitalization for AMI in two consecutive decades.A total of 2196 and 2055 patients were recruited in the prospective observational studies of the Evaluation of the Methods and Management of Acute Coronary Events (EMMACE) -1 and 2 in 1995 and 2003, (1995: median age 72 years, 39% women, 74% referred vs 2003: median age 71 years, 36% women, 64% referred) and followed up through September 2010. Survival functions showed CR referral to be an independent predictor for survival in 2003, but not in 1995 (hazard ratio (HR), 0.90; 95% confidence interval [CI]; 0.70 to 1.17, p = 0.44 in 1995 vs HR, 0.80; 95% CI, 0.66 to 0.96, p = 0.02 in 2003) when patients entered the model at three months after discharge and had a common exit at 90 months. Significant positive and negative predictors for CR referral were beta-blocker prescription (+), reperfusion (+) and age (-) in 1995, and reperfusion (+), revascularization (+), heart failure (HF) (+), antiplatelets (+), angiotensin-converting-enzyme inhibitor (ACE-I) (+), statins (+), diabetes (-), and the modified Global Registry of Acute Cardiac Events (GRACE) risk score (-) in 2003.CR referral was associated with improved survival in 2003, but not in 1995 in patients admitted with acute MI.

thompson c., yang h. & crouch s. (2012) Clinical simulation fidelity and nurses’ identification of critical event risk: a signal detection analysis. Journal of Advanced Nursing68(11), 2477–2485. Abstract Aims. This article is a report of a study exploring the effect of increasing fidelity on nurses’ risk detection in clinical simulation and the effect of clinical experience on nurses’ risk detection ability. Background. Clinical environments can be recreated successfully using simulation. However, how judgement changes as simulation fidelity increases is unknown. Knowledge of the effects of increased fidelity on judgement may help in the design of educational interventions seeking to improve clinical judgement in nurses. Design. Quasi experimental signal detection study. Method. During 2008–2009, using a quasi experimental signal detection design, 63 nursing students and 34 experienced nurses were presented with 25 paper and 25 human simulator ‘cases’ based on real patient records from a single UK National Health Service hospital. Nurses judged whether a simulated case was ‘at risk’ or ‘not at risk’ of a critical event. Clinical judgement performance was measured using standard signal detection measures. Findings. Judgement performance, as measured by hit rates and signal detection ability were significantly lower in higher fidelity clinical simulations. False alarm rates and bias (β) did not differ according to the fidelity of simulation. Clinical experience did not predict the ability to detect risk. Conclusion. As fidelity of simulation increased, both novice and experienced nurses’ were less likely to be able to separate important clinical risk from clinical noise in a simulated clinical environment.

Survival from childhood acute lymphoblastic leukaemia (ALL) has continued to improve in economically-developed regions of the world, but 20% of patients still die within 5-years of diagnosis. Treatment is prolonged and complex; and as survival rates plateau, factors relating to socio-economic status and/or treatment adherence are increasingly scrutinised as potentially important determinants of outcome.Predicated on the frame-work of the United Kingdom (UK) NHS, the relationship between socio-demographic factors and ALL survival is examined here using data from a large follow-up study conducted in the 1990s. One thousand five hundred and fifty nine children (0-14 years) diagnosed in England, ScotlandWales during the era of the national UKALL XI randomized-controlled trial (RCT) were followed-up for an average of 15.9 years (20,826.3 person-years). Area-based deprivation scores and father's occupational social class at the time of the child's birth were used as markers of socio-economic status. Information on deaths was obtained from the NHS Information Centre for Health and Social Care. All children were included in the analyses, irrespective of RCT enrolment or participation in the founding epidemiological study (www.UKCCS.org).Survival effects were assessed using proportional hazards regressions models.Survival varied with both area-based deprivation at diagnosis (hazard ratio (HR) 1.29; 95% confidence interval (CI) 1.05-1.57) and fathers occupational social class at birth (HR 1.12; 95% CI 0.97-1.29); the divergence beginning 6-9 months after diagnosis, and widening thereafter during home-administered therapy. The findings became more marked when analyses were restricted to those enrolled in UKALL XI (n = 1341). As expected, survival differences were also observed with sex, and age at diagnosis.The existence of significant social disparities in ALL survival, which are not due to treatment accessibility, is of major clinical importance. Trends should be monitored and further research into potentially modifiable risk factors conducted.

Background Data on causes of death (COD) in patients with lower-risk (LR-MDS) is limited and sometimes conflicting. In contrast to higher-risk MDS, many LR-MDS patients die from conditions associated with advanced age, not directly associated with the underlying disease. Infections and cardiovascular disorders (CVD) have been reported as frequent COD in LR-MDS, but whether the incidence is higher than in age-matched population, is not known. The EUMDS Registry has been collecting prospective observational data on LR-MDS since 2008. The comprehensive clinical and laboratory data provides a unique chance to assess the impact of LR-MDS on survival either by causes related to MDS or indirectly related to MDS by aggravation of co-morbidities. Objectives To assess the impact of MDS and associated co-morbidities on COD in patients with LR-MDS and to evaluate the COD in the whole group and across participating countries. Methods: We evaluated clinical and laboratory data of LR-MDS patients registered in EUMDS registry from 2008 to 2018. Data were obtained by 145 centers from 16 European countries and Israel. MDS related causes of death were defined as infection, bleeding, MDS progression and AML transformation. Overall survival(OS) and relative survival(RS) were estimated using the Stata program 'strel' with age, sex and country specific background obtained from national life tables for the CONCORD program. RS is a standard approach used to take into account competing causes of death by adjusting for the age and sex specific mortality in the general population, estimating the excess mortality in these patients compared to that seen in the general population of each country. Results Overall data on 2235 LR-MDS patients was available in the EUMDS registry. Of these, 822 (36,7%) patients had died at the time of analysis. Median age was 77 years and 65% of the patients were male. Nearly half of them (46.9%) were diagnosed as IPPS low risk. The MDS-Comorbidity Index was low, intermediate and high in 55.7%, 37.5% and 6.8% of patients respectively. The most common COD were those considered as related to MDS 41.7% (Table 1). Deaths due to cardiovascular and pulmonary diseases were reported in 10.1% and 4.9% respectively. Other reasons (e.g. liver, renal failure, second malignancy) were found in 18.2%. In 25% of patients, the precise reason of death remained unknown. The proportion of MDS related COD were different between participating countries with lower rates in Germany (30%), France (31.3%) and higher in Portugal (55%), Greece (55.2%) and Romania (63.1%). Median follow-up was 2.1 years (0.1-10 years). Five-year overall survival in the whole cohort was 47.1% (95% CI: 44.1%-49.9%) and 5-year relative survival (attributed to MDS/AML only) was 59.1% (95% CI:55.4%-62.5%)(Figure 1). One year overall and relative survival was 90.4% (95% CI:89.1%-91.6%) and 94.4% (95% CI:93%-95.5%) respectively. Conclusions: MDS- related complications are the most common causes of death in LR-MDS patients. Comparison of overall and relative survival supports that observation and indicates that excess mortality in LR-MDS patients can be mainly explained by MDS/AML related causes. Interestingly, the strongest influence of MDS/AML attributable deaths was observed during the first year from diagnosis. Disclosures Fenaux: Janssen: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria; Otsuka: Honoraria, Research Funding. Stauder:Teva: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Germing:Novartis: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria, Research Funding. de Witte:Novartis: Research Funding; Celgene: Honoraria, Research Funding; Amgen: Consultancy, Research Funding. Smith:Jazz Pharmaceuticals: Research Funding; Johnson & Johnson: Research Funding; Gilead Sciences: Consultancy; Novartis: Research Funding.

Background: Myelodysplastic syndromes (MDS) are diagnosed with a bone marrow examination (BME), an invasive procedure that patients (pts) would rather avoid. Earlier (Oster et al, Leuk Lymph 2018) we developed a logistic regression (LoR) model to diagnose MDS by incorporating 6 variables (age, gender, Hb, WBC, PLT, MCV) into a formula (Figure 1A). We improved the model using data from 178 MDS pts (47 from Tel Aviv, 131 from the EUMDS registry), and 178 controls (ASH 2017). Here we significantly improve the model using a much larger dataset (501 pts; 501 controls) and additional variables. Methods: The EUMDS registry contains data on 2600 BME-proven MDS pts. A random sample of 501 MDS pts from the registry was combined with 501 controls with no MDS (ruled out with BME). Gradient-boosted models (GBM) were used to predict having or not having MDS, using the variables age, gender, Hb, WBC, PLT, MCV, neutrophils, monocytes, glucose, and creatinine (Figure 1B). Area under the ROC curve (AUC), sensitivity and specificity were used to evaluate the models, and model performance was validated by using 100 times 5-fold cross-validation. Model stability was also assessed by repeating the fit of the models using different randomly chosen groups of 501 EUMDS pts as cases. Results: The AUC was 0.97 (95% CI 0.96-0.98, Figure 2), compared with an AUC of 0.87 (0.84-0.91) achieved previously. Under cross-validation, AUC was 89%. Maximizing the sum of sensitivity and specificity led to sensitivity of 88% and specificity of 95%. This means we can calculate a threshold "GBM score," assigning a subject to "MDS" or "no MDS" status with a specificity of 95% and a sensitivity of 88%. Alternatively, we can set two GBM score thresholds G1 & G2, where a GBM score > G2 provides 95% specificity and a score < G1 provides 95% sensitivity. A score between these two cutoffs gives an indeterminate probability of disease. Only 24% of our MDS patients and 15% of our control patients fall into this indeterminate region, compared with about 50% in our earlier model. The most influential variables were MCV, creatinine and neutrophils. Repeated random choice of cases from the EUMDS registry led to stable results. Conclusions: Using easily accessible parameters, MDS can be diagnosed or excluded non-invasively with high accuracy in a substantially large portion of patients. While the Logistic Regression model (Figure 1A) can be used with a relatively simple formula, the Gradient Boosted Model (Figure 1B) is more complex. The GBM combines the variables and the interactions among them, achieving an AUC that represents an excellent predictive ability and a considerable improvement over the previous model. Adding peripheral blood cytogenetic/genetic information could further improve non-invasive MDS diagnosis, and obviate the need for bone marrow examination in many patients. We continue to improve and validate the model. An on-line calculator/app for use in a clinical setting is being developed and will be presented. Disclosures Smith: Jazz Pharmaceuticals: Research Funding; Johnson & Johnson: Research Funding; Novartis: Research Funding; Gilead Sciences: Consultancy. Fenaux:Celgene: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Stauder:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Germing:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria.

PurposeRearrangement of MYC occurs in a proportion of diffuse large B-cell lymphomas (DLBCL), where they may be associated with an adverse clinical outcome. The aim of this study was to determine the frequency of MYC translocations in DLBCL and their prognostic impact in the era of cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (CHOP-R) therapy.Patients and MethodsThree hundred three patients with previously untreated DLBCL, with no evidence of underlying follicular lymphoma, were investigated using immunohistochemistry and interphase fluorescent in situ hybridization for MYC, BCL6, and t(14;18)/BCL2 rearrangements. All patients (median age, 71.1 years; range, 23 to 96 years) were treated when CHOP-R was standard therapy for DLBCL and observed for a maximum of 4 years. Overall survival (OS) at 3 years was 49% (95% CI, 42% to 56%).ResultsMYC rearrangements were demonstrated in 35 (14%) of 245 biopsies with data available. Of these, 26 (74%) also had a t(14;18), 10 (26%) were BCL6 and MYC rearranged, and seven had all three abnormalities. Only age, International Prognostic Index, and MYC rearrangement retained prognostic significance in the final model. OS was significantly worse for patients with rearrangement of MYC (survival probability at 2 years = 0.35 in v 0.61 in the nonrearranged group).ConclusionThe presence of a MYC rearrangement is a strongly adverse prognostic factor in CHOP-R–treated patients and can be used in combination with patients' age and IPI to accurately predict clinical outcome. In DLBCL, rearrangement of MYC is rarely found as the sole genetic abnormality and the poor prognosis of these patients is likely to reflect a synergistic effect alongside deregulation of BCL6 or BCL2.

OBJECTIVE: To compare the frequency of brain tumor signs and symptoms in children with and without brain tumors. METHODS: This was a UK population-based retrospective analysis of primary care records. Participants were 195 children (1–14 years) newly diagnosed with brain tumors and 285 controls matched by age, gender, and region. Comparisons included total number of prediagnosis consultations, number with ≥1 symptom suggestive of a brain tumor, total number of symptoms, number of different symptoms, and number of visits with specific combinations of symptoms. RESULTS: On average, cases consulted more often than controls between birth and diagnosis/pseudodiagnosis with brain tumor signs and symptoms. Their consultation rate with ≥1 suggestive symptom escalated in the 2 years before diagnosis. Symptom prevalence was higher among cases than controls, a relative difference of 3.29 times as many consultations with ≥1 suggestive symptom (95% confidence interval [CI]: 2.82–3.83) and 7.01 as many with more than 1 (95% CI: 5.38–9.13). In each 6-month period in the 4 years before diagnosis, cases had at least twice as many consultations with ≥1 suggestive symptom (20.81 times as many in the 6 months before diagnosis [95% CI: 14.29–30.30]) and 2–3 times more records of suggestive symptoms (28.35 times more in the 6 months before diagnosis [95% CI: 19.05–42.19]). Symptoms rarely or not observed among control children included head tilt, odd head movements, odd posture, back or neck stiffness, and unsteadiness without obvious cause. CONCLUSION Key to identifying the 1 child among many who merits prompt investigation is recognition of unusual symptoms, or specific symptom patterns.

Between 1998 and 2003, 214 people with Hodgkin's lymphoma and 214 controls randomly selected from population registers in the north of England (after matching for age and sex) were recruited and their primary care medical records examined for details of clinical diagnoses due to infectious and non-infectious conditions in the preceding 15 years. In the year before diagnosis of Hodgkin's lymphoma, almost all cases (99%) visited their general practitioner (GP) at least once. In comparison with controls, the excess was evident both for visits with an infection (odd's ratio (OR)=2.1; 95% confidence interval (CI) 1.4–3.2) and for visits with non-infectious problems (OR=17.2; 95% CI 6.7–43.9). During the rest of the 15-year period prior to diagnosis, the proportion of people visiting their GP with a non-infectious condition did not differ between cases and controls. In contrast, compared to controls, there was an excess of cases visiting the GP with an infection, a finding that was evident for at least a decade prior to diagnosis and increased linearly with time (P=0.02). This excess was not due to a specific infection(s) and may reflect underlying immune abnormality. Alternatively, infection may cause B-cell proliferation from which a malignant clone may evolve.

Highlights • Age and performance status were predicative of treatment and survival. • Sixty percent of patients ≥75 yrs were treated with curative intent. • Performance status was more discriminatory of treatment and survival than age. • Socio-economic factors were not predictive of survival. • Clinical characteristics aide interpretation of socio-demographic treatment/outcome trends., Aim To examine the influence of patient’s age and socio-economic status on treatment and outcome in diffuse large B-cell lymphoma (DLBCL); an aggressive curable cancer, with an incidence rate that increases markedly with age but varies little with socio-economic status. Methods Set within a representative UK population of around 4 million, data are from an established patient cohort. This report includes all patients (≥18years) newly diagnosed with DLBCL 2004–2012, with follow-up to February 2015. Results Of the 2137 patients (median age 70.2 years) diagnosed with denovo DLBCL, 1709 (80%) were treated curatively/intensively and 1161(54.3%) died during follow-up. Five-year overall and relative survival (RS) estimates were 46.2% (95% CI 44.0–48.4%) and 54.6% (52.1%-57.0%) respectively for all patients, and 58.5% (56.1–60.9%) and 67.0% (64.3–69.6%) for intensively treated patients. 96.3% of patients

Background In trials, ‘therapist intensive’ complex interventions are typically delivered over time, during which a relationship between the practitioner and participant may develop. Such relationships are sometimes criticised as obscuring any ‘true’ treatment effect. Limiting interactions is one strategy that might be used to try to control for the effect of a therapeutic relationship. Objectives We conducted systematic review into the rationale, methods and effects of constraining relationships in controlled trials and cohort studies of acupuncture, including studies published before 2008 with an update citation search in 2010. Methods We searched six databases without keyword restrictions. Meta-analysis and meta-regression were used to explore the effect of relationship constraint on pain outcomes. Results Eighty-one of 785 (10.3%) trials reported constraining relationships. Most did not state the reason for constraint, describe the nature of the limitation, provide information on how the constrained relationship was monitored or note protocol adherence. Where a reason was reported, this was primarily to maintain participant blinding, rarely was it stated that the constraint was to control the therapeutic relationship. We found no evidence of an effect of constraint on pain outcomes (percentage heterogeneity explained, p=0.89). These results were robust to variation in trial quality and design. Conclusions Acupuncture trials appear to be constrained mostly to try to prevent participant unblinding to their allocated treatment, not to control the therapeutic relationship. The apparent lack of monitoring and negligible effects on pain outcomes of the included trials indicate the need for more high-quality randomised controlled trials investigating the effect of constraint.

BackgroundIron overload/toxicity due to red blood cell transfusions (RBCT) is associated with morbidity and mortality in various patient groups, including patients with lower-risk myelodysplastic syndrome (LR-MDS). Many studies suggested improved overall survival (OS) after iron chelation therapy (ICT), but most studies suffer from methodological problems. In daily practice, many transfused LR-MDS patients receive ICT according to (inter)national guidelines to counteract the effects of RBCT. The value of ICT in LR-MDS remains unproven. The aim of this study is to assess the effect of ICT on OS in LR-MDS patients. MethodsThe EUMDS registry, prospectively collects observational data on LR-MDS patients from 142 centers in 16 countries in Europe and Israel. Three iron chelators are available in Europe for treatment of secondary iron overload, but availability varies between countries. We first assessed the impact of treatment of the three iron chelators on OS. Secondly, we compared the chelated patients with a contemporary control group within the EUMDS registry. The control group consisted of patients who met the eligibility criteria for using ICT (≥15 RBC units, RBCT intensity of ≥1 RBC unit/month during a six-month period between visits, or serum ferritin ≥1000 µg/L), but who did not receive ICT. A Cox proportional hazards model was used, treating receipt of ICT as an time-varying variable. Finally, all transfused chelated and non-chelated patients were compared with a propensity-score matched model (3:1 nearest matching with replacement) in which more confounding factors could be added to Cox model in order to deal with confounding as adequately as possible. ResultsThe EUMDS registry included 2205 patients as of July 2017. At this point, 205 patients received ICT. Table 1 shows the follow-up duration for all patients. Of the chelated patients, 154 received deferasirox as initial chelator, 39 deferoxamine, and 12 deferiprone. Nineteen patients switched from one chelator to another, but usually the treatment period of the 2nd chelator was short compared to the 1st chelator (data not shown). The median time on chelation for all 205 patients was 13 months (range 3-42). Patients receiving ICT were on average younger, had better performance scores and less comorbidities compared to the control group (table 2). Comparison of three iron chelators The OS from the start of ICT for 154 patients treated with deferasirox is not significantly different compared to deferoxamine (n=39; p=0.058). The Hazard Ratio (HR) and 95% confidence intervals (CI) for OS (deferasirox as reference group) adjusted for age, sex, comorbidity, performance status, and cumulative number of RBCT for deferoxamine was 1.95 (0.85-4.50) and for deferiprone 0.38 (0.04-4.06) (Table 2). Comparison with non-chelated control group The control group consisted of 657 non-chelated patients (table 2). The crude HR and 95% CI for OS for all chelated patients was 0.66 (0.52-0.85) (non-chelated group as reference). After adjusting for age, sex, comorbidity, performance status, RBCT intensity, cumulative number of RBCT, and IPSS-R, the HR was 0.75 (0.50-1.15). When the analysis was restricted to the patients treated with deferasirox, the crude HR was 0.61 (0.46-0.81) and the adjusted HR was 0.79 (0.51-1.22). Propensity-matched model The chelated and non-chelated patients were matched for age, RBCT intensity, ferritin level, comorbidity, and performance status. 128 chelated patients and 223 controls could be matched, the overlap of propensity scores in both groups was good (data not shown). The crude HR and 95% CI for OS for the chelated group (non-chelated group as reference) was 0.77 (0.55-1.07). When correcting for age, sex, comorbidity, performance status, RBCT intensity, cumulative RBCT number, and IPSS-R, the HR was 0.62 (0.39-0.98). When we again restricted the analysis to deferasirox, the crude HR was 0.71 (0.48-1.06) and the adjusted HR was 0.58 (0.33-1.01). Conclusion OS of LR-MDS patients treated with ICT, was better compared to a large, control group and significantly better in a propensity-score matched model. In the absence of randomized, controlled trials proving the survival advantage of ICT, our large, prospective, observational study of clinical practice in Europe and Israel provides sound evidence of a beneficial effect of ICT on OS. Disclosures Fenaux: Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Sanz: Gamida Cell: Research Funding. skov-Holm: Celgene: Research Funding. Almeida: Alexion: Honoraria; Bristol Meyer Squibb: Honoraria; Servier: Consultancy; Celgene: Consultancy; Novartis: Consultancy. Germing: Novartis: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria, Research Funding. Itzykson: Janssen: Research Funding; Novartis: Research Funding. Guerci-Bresler: BMS: Speakers Bureau; Incyte: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Speakers Bureau.

Background Chronic myelomonocytic leukaemia (CMML) presents a diagnostic challenge to the haematologist. Distinguishing between a reactive monocytosis and clonal expansion is difficult, and current diagnostic criteria allow for a diagnosis of CMML even in the absence of a clonal marker of disease as long as the monocytosis is persistent. This fails to correctly identify patients with prolonged reactive changes, increasing mis-diagnoses. More recently, large sequencing studies have identified somatic mutations in >90% of patients with CMML, providing potential objective evidence to support a diagnosis. To investigate the utility of high throughput sequencing to discriminate clonal disease and therefore improve diagnosis of CMML, we performed mutational analysis on all samples referred for investigation of a monocytosis to the Haematological Malignancy Diagnostic Service (HMDS) over a 2 year period. The aim of this study was to determine the frequency of mutations in this patient group and whether the presence of mutations can predict disease and outcome. Methods Samples from all patients (initial and follow-up) referred to HMDS with a monocytosis or suspected CMML between July 2014-July 2016 were included in the study. Those with a previous history of a myeloid malignancy diagnosed before July 2014 were excluded. 377 samples from 297 patients were processed and reported according to using current gold standard techniques, with targeted sequencing of 27 recurrently mutated genes in myeloid malignancies performed in parallel. Extracted DNA was sequenced using an Illumina MiSeq and analysed using an in-house pipeline. Detected variants were reported down to a minimum variant allele fraction of 5% and coverage of 100X. Low level variants were confirmed by repeat sequencing and SRSF2 regions were infilled using Sanger sequencing. Data from the literature as well as public online databases (dbSNP, COSMIC, ClinVar) and Alamut Visual were evaluated to annotate likely pathogenic variants. Results Of the164 patients who presented with an initial bone marrow sample, 95 had a confirmed diagnosis of CMML, of which 93 had a demonstrable mutation (98%). The spectrum of mutations in this group reflects that reported in the literature with TET2, SRSF2 and ASXL1 being most frequently mutated. A further 15 patients, all with mutations, were diagnosed with an alternative myeloid malignancy. In those without a confirmed diagnosis by conventional means, a somatic mutation was detected in 62% (39/54) of cases. Importantly, those with a mutation had both phenotypic and genotypic features indistinguishable from the CMML group. In particular CD56 overexpression by immunophenotyping was found almost exclusively in patients with a mutation whether a diagnosis was confirmed or not. To date, a follow-up sample has been received from 7 mutation-positive patients, of which 5 were diagnostic. All 5 cases had identical mutational profiles in the paired samples. In 133 patients, a peripheral blood sample was received as the initial specimen and 71% (94/133) of these harboured a mutation. As yet, 94 patients have not had a subsequent bone marrow biopsy so a conventional diagnosis has not been made. In those with a follow-up bone marrow sample (n=39), the mutational profile between paired samples was found to be highly concordant (98%). In addition, the detection of a mutation in the peripheral blood was strongly predictive of a myeloid malignancy in the bone marrow. Of the 30 patients with a detectable mutation, 29 had a confirmed diagnosis, including 20 patients with CMML, 5 with AML and 4 with other chronic myeloid malignancies. The remaining 9 patients without a mutation showed no morphological evidence of disease in the bone marrow (sensitivity 96.7%; CI 82.8%-99.9%, specificity 100%; CI 66.4%-100%). Conclusion This study has shown that patients investigated for a monocytosis commonly harbour somatic mutations which can be detected in the peripheral blood at a high frequency and with high confidence. The presence of a mutation correlates strongly with a CMML phenotype and detection in the peripheral blood is strongly predictive of a bone marrow diagnosis. Screening of peripheral blood samples using a targeted gene panel provides a highly effective tool to diagnose CMML. Follow-up of this patient group is ongoing and updated results will be available for presentation at the meeting. Disclosures Cargo: Celgene: Honoraria, Research Funding; Novartis: Honoraria.

Although there is increasing evidence that immune dysregulation in children who develop acute lymphoblastic leukemia (ALL) is detectable from birth, debate about the role of infectious exposures in infancy continues. With the aim of quantifying children's infectious exposures, investigators have used a number of infection exposure proxies, but there is a lack of consistency in findings, with some markers indicating increased ALL risks and others decreased risks, the disparity being evident both within and between studies. Accordingly, the authors conducted an in-depth analysis of key infection exposure proxies used in the United Kingdom Childhood Cancer Study, a national population-based case-control study conducted over the period 1991-1996, which combined data from medical records, parental interview, and population census. This longitudinal approach revealed the marked deterioration in immune response that emerged around 5 months prior to ALL diagnosis and confirmed that infectious diagnoses in the first year of life were significantly increased (P0.05) in children who developed leukemia between 2 and 14 years of age, as well as in those who had birth orders1, were not breastfed, lived in deprived areas, or were diagnosed with eczema. By contrast, no association between infectious illness and preschool activity was detected, the lower infection levels among controls whose mothers reported attendance contributing to a significantly reduced ALL odds ratio.

Background: Increased understanding of the relationship between lymphomas and co-morbidities is likely to provide valuable insights into the natural history of these disorders. Methods: 761 cases with lymphoma (310 diffuse large B-cell [DLBCL]; 226 follicular [FL]; and 225 Hodgkin [HL]) and 761 unaffected age and sex matched controls were recruited and their histories of infection and non-infection diagnoses in primary care records were compared using negative binomial regression. Results: No differences were observed between the infectious illness patterns of DLBCL and FL cases and their matched controls over the 15 years preceding lymphoma diagnosis. A marked excess of infectious illness episodes was recorded for HL cases compared to their controls; evident at least a decade prior to HL diagnosis. For non-infectious consultations an excess of case over control visits emerged 4-6 years before DLBCL and FL diagnosis; no specific co-morbidity associations were found. No case-control differences for non-infectious conditions were apparent for HL. Conclusion: There are substantial variations in patterns of illness prior to diagnosis of the three lymphoma subtypes examined. The excess of infectious diagnoses prior to HL may point to underlying immune abnormality, but there was no suggestion of this for DLBCL and FL where a generalized excess of non-infectious conditions was evident. (C) 2010 Elsevier Ltd. All rights reserved.

BACKGROUND: Data on the burden of genital warts in terms of treatment costs and detriment to quality of life (QoL) are required to assess cost-effectiveness of quadrivalent human papillomavirus vaccination. We investigated the cost of treatment and period of time for which QoL is affected to obtain estimates of quality-adjusted life year (QALY) loss associated with an episode of genital warts. METHODS: Adults diagnosed with genital warts attending the York sexually transmitted disease clinic during two 3-month periods in 2006 and 2007 were enrolled (n = 189). Data on cost of treatment and duration of episode of care were collected from a retrospective case note review. QALY loss was calculated by applying estimates of the duration of time for which QoL was affected to the previously reported detriment to QoL associated with genital warts. RESULTS: The average cost per episode of care was 286 US dollars (139 pound, 95% CI: 246-327 US dollars). Estimated loss of QALYs ranged from 0.0045 (95% CI: 0.0014-0.0078) to 0.023 (95% CI: 0.0072-0.039). CONCLUSIONS: Genital warts present a significant burden both to individuals and to the health service. Data on the burden of genital warts should be incorporated into economic evaluations of human papillomavirus vaccination strategies.

The association between infections occurring in the first 2 years of life and development of eczema was investigated in 1,782 control children from a national population-based case-control study in the United Kingdom conducted over the period 1991-1996. Dates of eczema and infectious diagnoses were ascertained from contemporaneously collected primary care records. Children diagnosed with eczema before the age of 2 years had more prior clinically diagnosed infections recorded than did children without eczema (rate ratio = 1.26, 95% confidence interval (CI): 1.18, 1.36). The difference in infection rates between children with and without eczema was apparent from birth and throughout the first 2 years of life. As expected, compared with children of second or higher birth order, those firstborn were at increased risk of eczema (p = 0.020); however, the relation between eczema and prior infection was evident only among children of second or higher birth order and not among firstborn children (rate ratio = 1.45, 95% CI: 1.32, 1.59, and rate ratio = 1.08, 95% CI: 0.98, 1.20, respectively). The authors' results are consistent with the notion that the association between birth order and eczema is unlikely to be attributable to variations in early infectious exposure.