Publications by authors named "Simon Crouch"

63 Publications

A predictive algorithm using clinical and laboratory parameters may assist in ruling out and in diagnosing MDS.

Blood Adv 2021 08;5(16):3066-3075

Department of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

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.
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http://dx.doi.org/10.1182/bloodadvances.2020004055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405190PMC
August 2021

Reducing mosquito-borne disease transmission to humans: A systematic review of cluster randomised controlled studies that assess interventions other than non-targeted insecticide.

PLoS Negl Trop Dis 2021 07 29;15(7):e0009601. Epub 2021 Jul 29.

The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia.

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.
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http://dx.doi.org/10.1371/journal.pntd.0009601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354450PMC
July 2021

Genomics-informed responses in the elimination of COVID-19 in Victoria, Australia: an observational, genomic epidemiological study.

Lancet Public Health 2021 08 10;6(8):e547-e556. Epub 2021 Jul 10.

Victorian Department of Health, Melbourne, VIC, Australia.

Background: A cornerstone of Australia's ability to control COVID-19 has been effective border control with an extensive supervised quarantine programme. However, a rapid recrudescence of COVID-19 was observed in the state of Victoria in June, 2020. We aim to describe the genomic findings that located the source of this second wave and show the role of genomic epidemiology in the successful elimination of COVID-19 for a second time in Australia.

Methods: In this observational, genomic epidemiological study, we did genomic sequencing of all laboratory-confirmed cases of COVID-19 diagnosed in Victoria, Australia between Jan 25, 2020, and Jan 31, 2021. We did phylogenetic analyses, genomic cluster discovery, and integrated results with epidemiological data (detailed information on demographics, risk factors, and exposure) collected via interview by the Victorian Government Department of Health. Genomic transmission networks were used to group multiple genomic clusters when epidemiological and genomic data suggested they arose from a single importation event and diversified within Victoria. To identify transmission of emergent lineages between Victoria and other states or territories in Australia, all publicly available SARS-CoV-2 sequences uploaded before Feb 11, 2021, were obtained from the national sequence sharing programme AusTrakka, and epidemiological data were obtained from the submitting laboratories. We did phylodynamic analyses to estimate the growth rate, doubling time, and number of days from the first local infection to the collection of the first sequenced genome for the dominant local cluster, and compared our growth estimates to previously published estimates from a similar growth phase of lineage B.1.1.7 (also known as the Alpha variant) in the UK.

Findings: Between Jan 25, 2020, and Jan 31, 2021, there were 20 451 laboratory-confirmed cases of COVID-19 in Victoria, Australia, of which 15 431 were submitted for sequencing, and 11 711 met all quality control metrics and were included in our analysis. We identified 595 genomic clusters, with a median of five cases per cluster (IQR 2-11). Overall, samples from 11 503 (98·2%) of 11 711 cases clustered with another sample in Victoria, either within a genomic cluster or transmission network. Genomic analysis revealed that 10 426 cases, including 10 416 (98·4%) of 10 584 locally acquired cases, diagnosed during the second wave (between June and October, 2020) were derived from a single incursion from hotel quarantine, with the outbreak lineage (transmission network G, lineage D.2) rapidly detected in other Australian states and territories. Phylodynamic analyses indicated that the epidemic growth rate of the outbreak lineage in Victoria during the initial growth phase (samples collected between June 4 and July 9, 2020; 47·4 putative transmission events, per branch, per year [1/years; 95% credible interval 26·0-85·0]), was similar to that of other reported variants, such as B.1.1.7 in the UK (mean approximately 71·5 1/years). Strict interventions were implemented, and the outbreak lineage has not been detected in Australia since Oct 29, 2020. Subsequent cases represented independent international or interstate introductions, with limited local spread.

Interpretation: Our study highlights how rapid escalation of clonal outbreaks can occur from a single incursion. However, strict quarantine measures and decisive public health responses to emergent cases are effective, even with high epidemic growth rates. Real-time genomic surveillance can alter the way in which public health agencies view and respond to COVID-19 outbreaks.

Funding: The Victorian Government, the National Health and Medical Research Council Australia, and the Medical Research Future Fund.
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http://dx.doi.org/10.1016/S2468-2667(21)00133-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270762PMC
August 2021

Suppression of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) After a Second Wave in Victoria, Australia.

Clin Infect Dis 2021 08;73(3):e808-e810

Department of Health and Human Services, Victorian Government , Melbourne, Australia.

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.
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http://dx.doi.org/10.1093/cid/ciaa1882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799206PMC
August 2021

Buruli ulcer: a new case definition for Victoria.

Commun Dis Intell (2018) 2020 Nov 21;44. Epub 2020 Nov 21.

Victorian Government Department of Health and Human Services.

Abstract: Laboratory-confirmed infection with Mycobacterium ulcerans is currently notifiable to health departments in several jurisdictions. Accurate surveillance is imperative to understanding current and emerging areas of endemicity and to facilitate research into a neglected tropical disease with poorly-understood transmission dynamics. The state of Victoria currently reports some of the highest numbers of M. ulcerans cases in the world each year, with 340 cases notified in 2018 (an incidence of 5.5 per 100,000 population). In May 2019, a group of clinical, laboratory and public health experts met to discuss a new case definition for the surveillance of M. ulcerans disease in Victoria, incorporating clinical and epidemiological elements. The new case definition supports important public health messaging and actions for residents and visitors to popular tourist areas in Victoria.
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http://dx.doi.org/10.33321/cdi.2020.44.93DOI Listing
November 2020

Targeted sequencing in DLBCL, molecular subtypes, and outcomes: a Haematological Malignancy Research Network report.

Blood 2020 05;135(20):1759-1771

Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.

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.
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http://dx.doi.org/10.1182/blood.2019003535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259825PMC
May 2020

Distinct genetic changes reveal evolutionary history and heterogeneous molecular grade of DLBCL with MYC/BCL2 double-hit.

Leukemia 2020 05 16;34(5):1329-1341. Epub 2019 Dec 16.

Department of Pathology, University of Cambridge, Cambridge, UK.

Using a Burkitt lymphoma-like gene expression signature, we recently defined a high-risk molecular high-grade (MHG) group mainly within germinal centre B-cell like diffuse large B-cell lymphomas (GCB-DLBCL), which was enriched for MYC/BCL2 double-hit (MYC/BCL2-DH). The genetic basis underlying MHG-DLBCL and their aggressive clinical behaviour remain unknown. We investigated 697 cases of DLBCL, particularly those with MYC/BCL2-DH (n = 62) by targeted sequencing and gene expression profiling. We showed that DLBCL with MYC/BCL2-DH, and those with BCL2 translocation, harbour the characteristic mutation signatures that are associated with follicular lymphoma and its high-grade transformation. We identified frequent MYC hotspot mutations that affect the phosphorylation site (T58) and its adjacent amino acids, which are important for MYC protein degradation. These MYC mutations were seen in a subset of cases with MYC translocation, but predominantly in those of MHG. The mutations were more frequent in double-hit lymphomas with IG as the MYC translocation partner, and were associated with higher MYC protein expression and poor patient survival. DLBCL with MYC/BCL2-DH and those with BCL2 translocation alone are most likely derived from follicular lymphoma or its precursor lesion, and acquisition of MYC pathogenic mutations may augment MYC function, resulting in aggressive clinical behaviour.
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http://dx.doi.org/10.1038/s41375-019-0691-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192846PMC
May 2020

Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways.

Hum Mol Genet 2020 01;29(1):70-79

Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10-13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10-12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.
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http://dx.doi.org/10.1093/hmg/ddz228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001601PMC
January 2020

Impact of treatment with iron chelation therapy in patients with lower-risk myelodysplastic syndromes participating in the European MDS registry.

Haematologica 2020 03 5;105(3):640-651. Epub 2019 Jul 5.

St. James's Institute of Oncology, Leeds Teaching Hospitals, Leeds, UK.

Iron overload due to red blood cell (RBC) transfusions is associated with morbidity and mortality in lower-risk myelodysplastic syndrome (MDS) patients. Many studies have suggested improved survival after iron chelation therapy (ICT), but valid data are limited. The aim of this study was to assess the effect of ICT on overall survival and hematologic improvement in lower-risk MDS 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 (OS), treating receipt of chelation as a time-varying variable. Additionally, chelated and non-chelated patients were compared using a propensity-score matched model. Of 2,200 patients, 224 received iron chelation. The hazard ratio and 95% confidence interval for OS for chelated patients, adjusted for age, sex, comorbidity, performance status, cumulative RBC transfusions, Revised-International Prognostic Scoring System (IPSS-R), and presence of ringed sideroblasts was 0.50 (0.34-0.74). The propensity-score analysis, matched for age, sex, country, RBC transfusion intensity, ferritin level, comorbidity, performance status, and IPSS-R, and, in addition, corrected for cumulative RBC transfusions and presence of ringed sideroblasts, demonstrated a significantly improved OS 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 OS and hematopoiesis in transfused lower-risk MDS patients. This trial was registered at
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http://dx.doi.org/10.3324/haematol.2018.212332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049356PMC
March 2020

Impact of red blood cell transfusion dose density on progression-free survival in patients with lower-risk myelodysplastic syndromes.

Haematologica 2020 03 6;105(3):632-639. Epub 2019 Jun 6.

Department of Tumor Immunology - Nijmegen Center for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands

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 (<1×10): 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
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http://dx.doi.org/10.3324/haematol.2018.212217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049377PMC
March 2020

The impact of rheumatological disorders on lymphomas and myeloma: a report on risk and survival from the UK's population-based Haematological Malignancy Research Network.

Cancer Epidemiol 2019 04 4;59:236-243. Epub 2019 Mar 4.

Department of Health Sciences, University of York, York, UK.

Background: Autoimmune inflammatory disease increases the risk of diffuse large B-cell lymphoma (DLBCL) and marginal zone lymphoma (MZL), but findings for other mature B-cell malignancies are equivocal. Furthermore, it has been suggested that the increase in DLBCL is due to the activated B-cell (ABC) subtype; but data on this, and the impact of inflammatory co-morbidities on survival, are sparse and contradictory.

Methods: Data are from an established UK population-based cohort. Patients (n = 6834) diagnosed between 01/2009 and 08/2015 are included; DLBCL (n = 1771), myeloma (n = 1760), chronic lymphocytic leukaemia (CLL, n = 1580), MZL (n = 936), and follicular lymphoma (FL, n = 787). Information on rheumatological disorders and deaths was obtained by record-linkage to nationally compiled Hospital Episode Statistics, with age-and sex-matched individuals (n = 68,340) from the same catchment population (˜4 million people) providing the comparator.

Results: Significantly increased risks for DLBCL (OR = 2.3, 95% CI 1.8-2.8) and MZL (OR = 2.0, 95% CI 1.5-2.7) were found for those with rheumatological disorders; the site distribution of those with/without rheumatological conditions differing for DLBCL (p = 0.007) and MZL (p = 0.002). No increases in risk were observed for the remaining mature B-cell malignancies, and no associations with survival were detected for DLBCL (age-adjusted HR = 1.2, 95% CI 0.9-1.6) or MZL (age-adjusted HR = 1.0, 95% CI 0.6-1.9). Furthermore, whilst our findings provide evidence for an association with rheumatological disease severity for DLBCL, they offer little support for the notion that the association is driven by an increase in the incidence of the ABC subtype.

Conclusion: Our findings support the hypothesis that the chronic activation and proliferation of specific B-cell populations which characterize autoimmune disease increase the potential for the lymphomagenic events that lead to DLBCL and MZL in both males and females; but have no impact on the development of CLL, FL or MM, or on survival.
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http://dx.doi.org/10.1016/j.canep.2019.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452783PMC
April 2019

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

Blood 2019 03 3;133(12):1325-1334. Epub 2019 Jan 3.

Epidemiology and Cancer Statistics Group, University of York, York, United Kingdom.

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 ( = .118) and significantly worse than in unmutated patients ( = .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.
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http://dx.doi.org/10.1182/blood-2018-08-867333DOI Listing
March 2019

Cell-of-origin in diffuse large B-cell lymphoma: findings from the UK's population-based Haematological Malignancy Research Network.

Br J Haematol 2019 05 8;185(4):781-784. Epub 2018 Nov 8.

Epidemiology & Cancer Statistics Group, Department of Health Sciences, University of York, York, UK.

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http://dx.doi.org/10.1111/bjh.15619DOI Listing
May 2019

Epidemiology of Buruli Ulcer Infections, Victoria, Australia, 2011-2016.

Emerg Infect Dis 2018 11;24(11):1988-1997

Buruli ulcer (BU) is a destructive soft-tissue infection caused by the environmental pathogen Mycobacterium ulcerans. In response to rising BU notifications in the state of Victoria, Australia, we reviewed all cases that occurred during 2011-2016 to precisely map the time and likely place of M. ulcerans acquisition. We found that 600 cases of BU had been notified; just over half were in residents and the remainder in visitors to defined BU-endemic areas. During the study period, notifications increased almost 3-fold, from 66 in 2013 to 182 in 2016. We identified 4 BU-endemic areas: Bellarine Peninsula, Mornington Peninsula, Frankston region, and the southeastern Bayside suburbs of Melbourne. We observed a decline in cases on the Bellarine Peninsula but a progressive increase elsewhere. Acquisitions peaked in late summer. The appearance of new BU-endemic areas and the decline in established areas probably correlate with changes in the level of local environmental contamination with M. ulcerans.
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http://dx.doi.org/10.3201/eid2411.171593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199991PMC
November 2018

A Generic Model for Follicular Lymphoma: Predicting Cost, Life Expectancy, and Quality-Adjusted-Life-Year Using UK Population-Based Observational Data.

Value Health 2018 10 24;21(10):1176-1185. Epub 2018 Apr 24.

Epidemiology & Cancer Statistics Group (ECSG), Department of Health Sciences, University of York, York, UK.

Objectives: To use real-world data to develop a flexible generic decision model to predict cost, life expectancy, and quality-adjusted life-years (QALYs) for follicular lymphoma (FL) in the general patient population.

Methods: All patients newly diagnosed with FL in the UK's population-based Haematological Malignancy Research Network (www.hmrn.org) between 2004 and 2011 were followed until 2015 (N = 740). Treatment pathways, QALYs, and costs were incorporated into a discrete event simulation to reflect patient heterogeneity, including age and disease management. Two scenario analyses, based on the latest National Institute for Health and Clinical Excellence (NICE) guidelines (rituximab induction therapy for newly diagnosed asymptomatic patients and rituximab maintenance therapy for patients between treatments), were conducted and their economic impacts were compared to current practice.

Results: Incidence-based analysis revealed expected average lifetime costs ranging from £6,165 [US$7,709] to £63,864 [US$79,862] per patient, and average life expectancy from 75 days to 17.56 years. Prevalence-based analysis estimated average annual treatment costs of £60-65 million [US$75-80 million], accounting for approximately 10% of the United Kingdom's annual National Health Service budget for hematological cancers as a whole. Assuming that treatment effects reported in trials are applicable to all patient groups, scenario analyses for two recent NICE guidelines demonstrated potential annual cost savings for the United Kingdom that ranged with uptake frequency from £0.6 million to £11 million [US$0.75-2.75 million].

Conclusions: Costs, survival, and QALYs associated with FL vary markedly with patient characteristics and disease management. Allowing the production of more realistic outcomes across the patient population as a whole, our model addresses this heterogeneity and is a useful tool with which to evaluate new technologies/treatments to support healthcare decision makers.
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http://dx.doi.org/10.1016/j.jval.2018.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191529PMC
October 2018

Early platelet count kinetics has prognostic value in lower-risk myelodysplastic syndromes.

Blood Adv 2018 08;2(16):2079-2089

Department of Tumor Immunology-Nijmegen Center for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

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%, < 10), regardless of baseline IPSS-revised or absolute platelet counts. Relative neutrophil 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 ( < 10). 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.
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http://dx.doi.org/10.1182/bloodadvances.2018020495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113605PMC
August 2018

Change in Physiological Variables in the Last Two Weeks of Life: An Observational Study of Hospitalized Adults With Heart Failure.

J Pain Symptom Manage 2018 05 31;55(5):1335-1340. Epub 2018 Jan 31.

Wolfson Palliative Care Research Centre, Hull York Medical School, University of Hull, Hull, UK.

Context: 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.

Objectives: To use routinely collected data to explore evidence for physiological change in the final two weeks of life in end-stage heart failure.

Methods: 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: 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.

Conclusions: 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.
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http://dx.doi.org/10.1016/j.jpainsymman.2018.01.006DOI Listing
May 2018

Lupus-related single nucleotide polymorphisms and risk of diffuse large B-cell lymphoma.

Lupus Sci Med 2017 12;4(1):e000187. Epub 2017 Nov 12.

Department of Health Sciences, University of York, York, UK.

Objective: Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide 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.
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http://dx.doi.org/10.1136/lupus-2016-000187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715504PMC
November 2017

A non-healing ulcer in a healthy young woman.

Aust Fam Physician 2017 Nov;46(11):855-856

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November 2017

Emergency admission and survival from aggressive non-Hodgkin lymphoma: A report from the UK's population-based Haematological Malignancy Research Network.

Eur J Cancer 2017 06 13;78:53-60. Epub 2017 Apr 13.

Queen's Centre for Oncology and Haematology, Castle Hill Hospital, Cottingham, HU16 5JQ, UK.

Background: Non-Hodgkin lymphoma (NHL) is often diagnosed after emergency presentation, a route associated with poor survival and an indicator of diagnostic delay. Accounting for around half of all NHLs, diffuse large B-cell lymphoma (DLBCL) is of particular interest since although it is potentially curable with standardised chemotherapy it can be challenging to identify at an early stage in the primary care setting.

Patients And Methods: Set within a socio-demographically representative United Kingdom population of around 4 million people, data are from an established patient cohort. This report includes all patients (≥18 years) diagnosed with DLBCL 2004-2011 (n = 1660). Emergency admissions were identified via linkage to Hospital Episode Statistics using standard methods, and survival was examined using proportional hazards regression.

Results: Two out of every five patients were diagnosed following an emergency admission, and this was associated with advanced disease and poor survival (p < 0.001). Among the 80% of patients treated with curative chemotherapy, survival discrepancies emerged at the point of diagnosis; the adjusted hazard ratio (emergency versus non-emergency) at one month being 4.0 (95% confidence interval 1.9-8.2). No lasting impact was evident in patients who survived for 12 months or more.

Conclusion: Emergency presentation impacts negatively on DLBCL survival; patients presenting via this route have significantly poorer outcomes than patients with similar clinical characteristics who present via other routes.
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http://dx.doi.org/10.1016/j.ejca.2017.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446261PMC
June 2017

Estimating the prevalence of hematological malignancies and precursor conditions using data from Haematological Malignancy Research Network (HMRN).

Cancer Causes Control 2016 08 28;27(8):1019-26. Epub 2016 Jun 28.

Department of Health Sciences, University of York, Seebohm Rowntree Building, Heslington, York, YO10 5DD, UK.

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.
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http://dx.doi.org/10.1007/s10552-016-0780-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958130PMC
August 2016

The prognosis of translocation positive diffuse large B-cell lymphoma depends on the second hit.

J Pathol Clin Res 2015 Jul 30;1(3):125-133. Epub 2015 Mar 30.

Division of Molecular HistopathologyDepartment of PathologyUniversity of CambridgeUK; Department of HistopathologyAddenbrooke's Hospital, Cambridge University Hospitals NHS Foundation TrustCambridgeUK.

A proportion of translocation positive diffuse large B-cell lymphomas (DLBCL) harbour a and/or translocation, known as double-hit DLBCL, and are clinically aggressive. It is unknown whether there are other genetic abnormalities that cooperate with translocation and form double-hit DLBCL, and whether there is a difference in clinical outcome between the double-hit DLBCL and those with an isolated translocation. We investigated gene mutations along with and translocations in a total of 234 cases of DLBCL, including 81 with translocation. mutations were investigated by PCR and sequencing, while and translocation was studied by interphase fluorescence in situ hybridization. The majority of translocation positive DLBCLs (60/81 = 74%) had at least one additional genetic hit. In translocation positive DLBCL treated by R-CHOP ( = 67), mutation and but not translocation had an adverse effect on patient overall survival. In comparison with DLBCL with an isolated translocation, cases with double-hits had the worst overall survival, followed by those with double-hits. In translocation negative DLBCL treated by R-CHOP ( = 101), mutation, and translocation had no impact on patient survival. The prognosis of translocation positive DLBCL critically depends on the second hit, with mutations and translocation contributing to an adverse prognosis. It is pivotal to investigate both mutations and translocations in translocation positive DLBCL, and to distinguish double-hit DLBCLs from those with an isolated translocation.
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http://dx.doi.org/10.1002/cjp2.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915334PMC
July 2015

Impact of family structure and socio-demographic characteristics on child health and wellbeing in same-sex parent families: A cross-sectional survey.

J Paediatr Child Health 2016 May 3;52(5):499-505. Epub 2016 May 3.

The Jack Brockhoff Child Health and Wellbeing Program, The Melbourne School of Population and Global Health, The University of Melbourne, Carlton, Victoria, Australia.

Unlabelled: Children with same-sex attracted parents develop well in terms of their health and wellbeing. There are many recognised factors that have an impact on child health, in general, including individual, family and wider social mediators. The aim of this study is to determine the impact of family structure and socio-demographic characteristics on child health and wellbeing in Australian same-sex parent families.

Methods: A cross-sectional survey of self-identified same-sex attracted parents from across Australia was used to collect information on child health and wellbeing between May and December 2012. Mixed-effects multiple linear regression models were used to identify associations between family structure/socio-demographic characteristics and child wellbeing. Child health outcomes were measured using the Child Health Questionnaire and the Strengths and Difficulties Questionnaire.

Results: In same-sex parent families, biological relationships, parental gender and parental education were not significantly associated with health and wellbeing. Parental income, rurality and stable parental relationships were associated with health and wellbeing, and living in a single-parent household was associated with poorer wellbeing.

Conclusions: Stable dual parent families offer good outcomes for children with same-sex attracted parents. Family processes are most important. This study does not support the assertion that children require both male and female parents, nor that biological relationships are essential to health and wellbeing. This study provides scientific data from a cross-sectional Australian-based study to describe and understand health determinants for children in family contexts that comprise same-sex parent and all family contexts. It recommends equitable, stigma-free family support.
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http://dx.doi.org/10.1111/jpc.13171DOI Listing
May 2016

Absolute risk of cardiovascular disease events, and blood pressure- and lipid-lowering therapy in Australia.

Med J Aust 2016 May;204(8):320

National Centre for Epidemiology and Population Health, Australian National University, Canberra, ACT.

Objective: To quantify absolute cardiovascular disease (CVD) risk and treatment in Australian adults.

Design, Participants: Cross-sectional representative study of 9564 people aged 18 years or more who had participated in the 2011-12 Australian National Health Measures Survey (response rate for those aged 45-74 years: 46.5%).

Main Outcome Measures: Prior CVD was ascertained and 5-year absolute risk of a primary CVD event calculated (using the Australian National Vascular Disease Prevention Alliance algorithm; categories: low [< 10%], moderate [10-15%], and high [> 15%] risk) on the basis of data on medical history, risk factors and medications, derived from interviews, physical measurements, and blood and urine samples.

Results: Absolute CVD risk increased with age and was higher among men than women. Overall, 19.9% (95% CI, 18.5-21.3%) of Australians aged 45-74 years had a high absolute risk of a future CVD event (an estimated 1 445 000 people): 8.7% (95% CI, 7.8-9.6%) had prior CVD (estimated 634 000 people) and 11.2% (95% CI, 10.2-12.2%) had high primary CVD risk (estimated 811 000 people). A further 8.6% (95% CI, 7.4-9.8%, estimated 625 000) were at moderate primary CVD risk. Among those with prior CVD, 44.2% (95% CI, 36.8-51.6%) were receiving blood pressure- and lipid-lowering medications, 35.4% (95% CI, 27.8-43.0%) were receiving only one of these, and 20.4% (95% CI, 13.9-26.9%) were receiving neither. Corresponding figures for high primary CVD risk were 24.3% (95% CI, 18.3-30.3%); 28.7% (95% CI, 22.7-34.7%); and 47.1% (95% CI, 39.9-54.3%).

Conclusions: About one-fifth of the Australian population aged 45-74 years (about 1.4 million individuals) were estimated to have a high absolute risk of a future CVD event. Most (estimated 970 000) were not receiving currently recommended combination blood pressure- and lipid-lowering therapy, indicating substantial potential for health gains by increasing routine assessment and treatment according to absolute CVD risk.
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http://dx.doi.org/10.5694/mja15.01004DOI Listing
May 2016

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

Cancer Epidemiol 2016 06 16;42:186-98. Epub 2016 Apr 16.

Queens Centre for Oncology, Castle Hill Hospital, HU16 5JQ, UK.

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 72.4years (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 <5% for aggressive entities like therapy-related AML (2.6%, 95% Confidence Interval 0.4-9.0) to >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 11years) 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 4.8-17.4months).

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.
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http://dx.doi.org/10.1016/j.canep.2016.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911595PMC
June 2016

Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes.

Hum Mol Genet 2016 Apr 9;25(8):1663-76. Epub 2016 Feb 9.

Centre for Big Data Research in Health, University of New South Wales, Sydney, NSW, Australia.

Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82,P-value = 8.5 × 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51,P-value = 4.0 × 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk.
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http://dx.doi.org/10.1093/hmg/ddw027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854019PMC
April 2016
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