Inflammatory profile of lower risk myelodysplastic syndromes.

The precise link between inflammation and pathogenesis of myelodysplastic syndrome (MDS) is yet to be fully established. We developed a novel method to measure ASC/NLRP3 protein specks which are specific for the NLRP3 inflammasome only. We combined this with cytokine profiling to characterise various inflammatory markers in a large cohort of patients with lower risk MDS in comparison to healthy controls and patients with defined autoinflammatory disorders (AIDs). The ASC/NLRP3 specks were significantly elevated in MDS patients compared to healthy controls (p < 0.001) and these levels were comparable to those found in patients with AIDs. The distribution of protein specks positive only for ASC was different to ASC/NLRP3 ones suggesting that other ASC-containing inflammasome complexes might be important in the pathogenesis of MDS. Patients with MDS-SLD had the lowest levels of interleukin (IL)-1ß, tumour necrosis factor (TNF), IL-23, IL-33, interferon (IFN) γ and IFN-α2, compared to other diagnostic categories. We also found that inflammatory cytokine TNF was positively associated with MDS progression to a more aggressive form of disease and IL-6 and IL-1ß with time to first red blood cell transfusion. Our study shows that there is value in analysing inflammatory biomarkers in MDS, but their diagnostic and prognostic utility is yet to be fully validated.

Mpox Management: A Holistic Local Response to a Global Threat.

Newly formed local public health units in Victoria have been established to support a place-based approach that tailors and delivers public health initiatives and responds to public health incidents and issues. Initially, post-establishment of these units, public health activities focused on the prevention and control of communicable diseases. In 2022, mpox emerged as a global public health threat. As case numbers rose across Australia, local public health units in Victoria were engaged by the Department of Health to support a localized response to this new threat. The South East Public Health Unit, Monash Health, developed a number of targeted initiatives to control the local spread of mpox, ranging from capacity building of health professionals to increase early diagnosis, contact tracing, facilitating vaccine delivery, and community engagement. This contributed to effective local elimination within 6 months, demonstrating how LPHUs are well placed to engage with local communities and health care providers to respond rapidly to newly emerging public health threats.

Cause of death and excess mortality in patients with lower-risk myelodysplastic syndromes (MDS): A report from the European MDS registry.

Information on causes of death (CoDs) and the impact of myelodysplastic syndromes (MDS) on survival in patients with lower-risk MDS (LR-MDS) is limited. A better understanding of the relationship between disease characteristics, clinical interventions and CoDs may improve outcomes of patients with LR-MDS. We prospectively collected data on patients with LR-MDS in the European MDS registry from 2008 to 2019. Clinical, laboratory and CoDs data were obtained. To examine MDS-specific survival, relative survival (RS) was estimated using national life tables. Of 2396 evaluated subjects, 900 died (median overall survival [OS]: 4.7 years; median follow-up: 3.5 years). The most common CoDs were acute myeloid leukaemia/MDS (20.1%), infection (17.8%) and cardiovascular disease (CVD; 9.8%). Patients with isolated del(5q) and with red cell transfusion needed during the disease course, had a higher risk of fatal CVD. The 5-year OS was 47.3% and the 5-year RS was 59.6%, indicating that most patients died due to their underlying MDS. Older patients (aged >80 years) and the lowest-risk patients were more likely to die from competing causes. This study shows that MDS and its related complications play crucial role in the outcome of patients with LR-MDS.

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

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.

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

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.

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

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

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.

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

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 clinicaltrials.gov identifier: 00600860.

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

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<1×10-4): 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.

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

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.

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

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.

Targeted sequencing identifies patients with preclinical MDS at high risk of disease progression.

The diagnosis of myelodysplastic syndromes (MDS) remains problematic due to the subjective nature of morphologic assessment. The reported high frequency of somatic mutations and increased structural variants by array-based cytogenetics have provided potential objective markers of disease; however, this has been complicated by reports of similar abnormalities in the healthy population. We aimed to identify distinguishing features between those with early MDS and reported healthy individuals by characterizing 69 patients who, following a nondiagnostic marrow, developed progressive dysplasia or acute myeloid leukemia. Targeted sequencing and array-based cytogenetics identified a driver mutation and/or structural variant in 91% (63/69) of prediagnostic samples with the mutational spectrum mirroring that in the MDS population. When compared with the reported healthy population, the mutations detected had significantly greater median variant allele fraction (40% vs 9% to 10%), and occurred more commonly with additional mutations (≥2 mutations, 64% vs 8%). Furthermore, mutational analysis identified a high-risk group of patients with a shorter time to disease progression and poorer overall survival. The mutational features in our cohort are distinct from those seen in the healthy population and, even in the absence of definitive disease, can predict outcome. Early detection may allow consideration of intervention in poor-risk patients.

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

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.

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

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.

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

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.

Is ethnic density associated with health in a context of social disadvantage? Findings from the Born in Bradford cohort.

OBJECTIVES: 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. DESIGN: 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. RESULTS: In the Pakistani sample, higher own ethnic density was associated with lower birth weight (ß = -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 to <10% South Asian density (OR = 0.79, 95% CI: 0.64, 0.98). CONCLUSION: 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.

The clinical impact of staging bone marrow examination on treatment decisions and prognostic assessment of lymphoma patients.

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.

Change in physiological variables in the last 2 weeks of life: an observational study of hospital in-patients with cancer.

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.