Lack of Association of Vascular Risk Factors with HIV-Associated Neurocognitive Disorders in cART-Treated Adults Aged ≥ 50 Years in Tanzania.

HIV-associated neurocognitive disorders (HAND) are highly prevalent in those ageing with HIV. High-income country data suggest that vascular risk factors (VRFs) may be stronger predictors of HAND than HIV-disease severity, but data from sub-Saharan Africa are lacking. We evaluated relationships of VRFs, vascular end-organ damage and HAND in individuals aged ≥ 50 in Tanzania. c-ART-treated individuals were assessed for HAND using consensus criteria. The prevalence of VRFs and end organ damage markers were measured. The independent associations of VRFs, end organ damage and HAND were examined using multivariable logistic regression. Data were available for 153 individuals (median age 56, 67.3% female). HAND was highly prevalent (66.7%, 25.5% symptomatic) despite well-managed HIV (70.5% virally suppressed). Vascular risk factors included hypertension (34%), obesity (10.5%), hypercholesterolemia (33.3%), diabetes (5.3%) and current smoking (4.6%). End organ damage prevalence ranged from 1.3% (prior myocardial infarction) to 12.5% (left ventricular hypertrophy). Measured VRFs and end organ damage were not independently associated with HAND. The only significant association was lower diastolic BP (p 0.030, OR 0.969 (0.943-0.997). Our results suggest that vascular risk factors are not major drivers of HAND in this setting. Further studies should explore alternative aetiologies such as chronic inflammation.

Evidence of spatial clustering of childhood acute lymphoblastic leukemia cases in Greater Mexico City: report from the Mexican Inter-Institutional Group for the identification of the causes of childhood leukemia.

Background: A heterogeneous geographic distribution of childhood acute lymphoblastic leukemia (ALL) cases has been described, possibly, related to the presence of different environmental factors. The aim of the present study was to explore the geographical distribution of childhood ALL cases in Greater Mexico City (GMC). Methods: A population-based case-control study was conducted. Children <18 years old, newly diagnosed with ALL and residents of GMC were included. Controls were patients without leukemia recruited from second-level public hospitals, frequency-matched by sex, age, and health institution with the cases. The residence address where the patients lived during the last year before diagnosis (cases) or the interview (controls) was used for geolocation. Kulldorff's spatial scan statistic was used to detect spatial clusters (SCs). Relative risks (RR), associated p-value and number of cases included for each cluster were obtained. Results: A total of 1054 cases with ALL were analyzed. Of these, 408 (38.7%) were distributed across eight SCs detected. A relative risk of 1.61 (p<0.0001) was observed for the main cluster. Similar results were noted for the remaining seven ones. Additionally, a proximity between SCs, electrical installations and petrochemical facilities was observed. Conclusions: The identification of SCs in certain regions of GMC suggest the possible role of environmental factors in the etiology of childhood ALL.

Loss of ALK hotspot mutations in relapsed neuroblastoma.

ALK is the most commonly mutated oncogene in neuroblastoma with increased mutation frequency reported at relapse. Here we report the loss of an ALK mutation in two patients at relapse and a paired neuroblastoma cell line at relapse. ALK detection methods including Sanger sequencing, targeted next-generation sequencing and a new ALK Agena MassARRAY technique were used to detect common hotspot ALK variants in tumors at diagnosis and relapse from two high-risk neuroblastoma patients. Copy number analysis including single nucleotide polymorphism array and array comparative genomic hybridization confirmed adequate tumor cell content in DNA used for mutation testing. Case 1 presented with an ALK F1174L mutation at diagnosis with a variant allele frequency (VAF) ranging between 23.5% and 28.5%, but the mutation was undetectable at relapse. Case 2 presented with an ALK R1257Q mutation at diagnosis (VAF = 39%-47.4%) which decreased to <0.01% at relapse. Segmental chromosomal aberrations were maintained between diagnosis and relapse confirming sufficient tumor cell content for mutation detection. The diagnostic SKNBE1n cell line harbors an ALK F1174S mutation, which was lost in the relapsed SKNBE2c cell line. To our knowledge, these are the first reported cases of loss of ALK mutations at relapse in neuroblastoma in the absence of ALK inhibitor therapy, reflecting intra-tumoral spatial and temporal heterogeneity. As ALK inhibitors are increasingly used in the treatment of refractory/relapsed neuroblastoma, our study highlights the importance of confirming whether an ALK mutation detected at diagnosis is still present in clones leading to relapse.

Temporal clustering of neuroblastic tumours in children and young adults from Ontario, Canada.

BACKGROUND: The aetiology of neuroblastic tumours is likely to involve both genetic and environmental factors. A number of possible environmental risk factors have been suggested, including infection. If an irregular temporal pattern in incidence is found, this might suggest that a transient agent, such as an infection, is implicated. Previous work has found evidence for temporal clustering in children and young adults living in northern England. METHODS: We examined data from a second population-based registry from Ontario, Canada to determine whether there was evidence of temporal clustering of neuroblastic tumours. Cases diagnosed in children and young adults aged 0-19 years between 1985 and 2016 were extracted from the population-based Pediatric Oncology Group of Ontario Networked Information System (POGONIS). A modified version of the Potthoff-Whittinghill method was used to test for temporal clustering. Estimates of extra-Poisson variation (EPV) and standard errors (SE) were obtained. RESULTS: Eight hundred seventy-six cases of neuroblastic tumours were diagnosed during the study period. Overall, no evidence of temporal clustering was found between fortnights, between months or between quarters within years. However, significant EPV was found between years within the full study period (EPV = 1.05, SE = 0.25; P = 0.005). CONCLUSIONS: The findings are consistent with the possibility that a transient agent, such as an infection that is characterised by 'peaks and troughs' in its occurrence, might be implicated in the aetiology of neuroblastic tumours. However, this pattern may also reflect a long-term increase in the numbers of cases, rather than peaks and troughs.

Changing epidemiology and age-specific incidence of cutaneous malignant melanoma in England: An analysis of the national cancer registration data by age, gender and anatomical site, 1981-2018.

BACKGROUND: The incidence of cutaneous malignant melanoma, which is mostly attributable (86%) to UV radiation exposure, has been steadily increasing over the past four decades in predominantly fair-skinned populations. Although public health campaigns are increasing sun-protective behaviour in England, their effect on melanoma incidence is largely unknown. We conducted a retrospective population-based cohort study to examine whether there have been changes in the epidemiology of melanoma in England during the past four decades. METHODS: Individual level data for patients diagnosed with melanoma in England during 1981-2018 were obtained from the Office for National Statistics/Public Health England. Average annual incidence rates were calculated by three age categories (0-34, 35-64, 65+ years), gender and anatomical site during the seven five-year time periods (1981-85 to 2011-15) and the recent three-year period (2016-18). The percentage change in incidence was calculated as change in the average incidence rate from the first (1981-85) to the last time period (2016-18). The Average Annual Percentage Change (AAPC) was estimated using the slope of the linear trend line fitted to the incidence rates by year of diagnosis. FINDINGS: During the 38-year period (1981-2018), a total of 265,302 cases of melanoma (45.7% males, 54.3% females) were registered in England. The average annual number of cases increased from 837/year in 1981-85 to 6963/year in 2016-18 in males (+732%), and from 1609/year in 1981-85 to 6952/year in 2016-18 in females (+332%). In the young age-group (0-34 years), the average annual incidence rates initially increased from 1981-85 to 2001-05 and then stabilised during the recent period (2006-18). In the middle age group (35-64 years), the rates increased by +332% (AAPC, 10.4%) in males (from 5.6/100,000 in 1981-85 to 24.2/100,000 in 2016-18) and +185% (AAPC, 5.7%) in females (from 10.2/100,000 in 1981-85 to 29.1/100,000 in 2016-18); and in the old age-group (65+ years) the rates increased by +842% (AAPC, 25.7%) in males (from 9.6/100,000 in 1981-85 to 90.4/100,000 in 2016-18) and +381% (AAPC, 11.2%) in females (from 12.5/100,000 in 1981-85 to 60.1/100,000 in 2016-18). The largest increase in incidence in both males and females was observed for melanoma of the trunk (+817%, AAPC, 24.8% in males and +613%, AAPC, 18.3% in females), followed by melanoma of upper limb (+750%, AAPC, 22.9% in males and 518%, AAPC, 15.5% in females). INTERPRETATION: It appears that the incidence of melanoma among young people in England has stabilised (or levelled off) in recent decades, whereas it continues to increase substantially in older population. These findings suggest that public health campaigns targeted at children/adolescents/parents may be favourably influencing melanoma incidence. The steeper increase in incidence in males is consistent with their relatively greater sun exposure and poor sun-protective behaviour. All the available evidence suggests that the enormous increase in the melanoma of the trunk and upper limb, since the 1980s, is most likely due to increasing trend in intermittent high intensity recreational UV radiation exposure (e.g. sunbathing, holidaying in places with strong sunlight, indoor tanning). FUNDING: This work was supported by Brighton and Sussex Medical School (BSMS).

International trends in the incidence of brain tumours in children and young-adults and their association with indicators of economic development.

INTRODUCTION: Childhood brain tumours (CBTs) are the second most common type of cancer in individuals aged 0-24 years globally and cause significant morbidity and mortality. CBT aetiology remains poorly understood, however previous studies found higher CBT incidence in high-income countries (HIC) compared to low-middle income countries (LMIC), suggesting a positive relationship between incidence and wealth. MATERIALS & METHODS: Aggregated data from Cancer Incidence in Five Continents (CI5) were used to explore CBT epidemiology. Incidence rate ratios (IRR) compared CBT rates between twenty-five geographically and economically diverse countries. The relationship between incidence and economic development was explored using linear regression models and Spearman's rank correlation tests. Trends in CBT incidence between 1978 and 2012 were investigated using average annual percentage changes (AAPC). RESULTS: CBT incidence was highest in North America and lowest in Africa. CBT incidence rates increased significantly with increasing GDP per capita (p = 0.006). Gini index was significantly negatively associated with CBT incidence. Incidence decreased with increasing income inequality within countries, indicated by higher Gini indices (p = 0.040). Increasing and decreasing CBT incidence trends were observed within individual countries, although only Italy (p = 0.02) and New Zealand (p < 0.005) experienced statistically significant changes over time. CONCLUSIONS: The excess disease found in HIC may be explained by environmental risk factor exposure increasing CBT risk in wealthy populations. However, systematic limitations of substandard cancer detection and reporting in LMIC may mean incidence disparities result from misinformation bias rather than genuine differences in risk factor exposure. Further research is required to comprehensively describe CBT epidemiology and explain study findings.

A systematic review of re-induction chemotherapy for children with relapsed high-risk neuroblastoma.

BACKGROUND: Despite aggressive multimodal therapy, >50% of children with high-risk neuroblastoma (HRNB) relapse. Survival after relapse is rare, and no consensus currently exists on the most effective therapy. OBJECTIVE: To conduct a systematic review of the literature on effectiveness of re-induction chemotherapy in children with relapsed HRNB. METHODS: Database searches were performed to identify studies looking at response to 1st line chemotherapy for children >12 months at diagnosis with first relapse of HRNB. Studies not reporting separate outcomes for HRNB patients or of refractory patients only were excluded. Two independent reviewers extracted the data and assessed study quality using a modified Newcastle-Ottawa tool. RESULTS: Nine studies were identified fitting the inclusion criteria. All except one were single arm cohorts, and two were retrospective database reviews from single centres. One was a multicentre randomised controlled trial. All used a version of the validated International Neuroblastoma Response Criteria with 8 recording best ever response and 1 at a specified time, and 5 had central review. The proportion of relapsed patients varied from 24 to 100% with 30-93% receiving upfront myeloablative therapy. The response rate varied from 6 to 64%; however, because of heterogeneity, studies were not directly comparable, and no single treatment emerged as the most effective re-induction therapy. CONCLUSIONS: To date, there is no clear superior re-induction therapy for 1st relapse of HRNB. Randomised controlled trials with separate arms for relapsed versus refractory disease are needed to determine optimal re-induction chemotherapy to act as a backbone for testing newer targeted agents.

Socio-economic patterning in early mortality of patients aged 0-49 years diagnosed with primary bone cancer in Great Britain, 1985-2008.

BACKGROUND: Studies have shown marked improvements in survival between 1981 and 2000 for Ewing sarcoma patients but not for osteosarcoma. This study aimed to explore socio-economic patterning in early mortality rates for both tumours. PROCEDURE: The study analysed all 2432 osteosarcoma and 1619 Ewing sarcoma cases, aged 0-49 years, diagnosed in Great Britain 1985-2008 and followed to 31/12/2009. Logistic regression models were used to calculate risk of dying within three months, six months, one year, three years and five years after diagnosis. Associations with Townsend deprivation score and its components were examined at small-area level. Urban/rural status was studied at larger regional level. RESULTS: For osteosarcoma, after age adjustment, mortality at three months, six months and one year was associated with higher area unemployment, OR = 1.05 (95% CI 1.00, 1.10), OR = 1.04 (95% CI 1.01, 1.08) and OR = 1.04 (95% CI 1.02, 1.06) respectively per 1% increase in unemployment. Mortality at six months was associated with greater household non-car ownership, OR = 1.02 (95% CI 1.00, 1.03). For Ewing sarcoma, there were no significant associations between mortality and overall Townsend score, nor its components for any time period. For both tumours increasing mortality was associated with less urban and more remote rural areas. CONCLUSIONS: This study found that for osteosarcoma, early mortality was associated with residence at diagnosis in areas of higher unemployment, suggesting risk of early death may be socio-economically determined. For both tumours, distance from urban centres may lead to greater risk of early death.

Is there a socioeconomic variation in survival from renal tumours in children and young people resident in northern England (1968-2012)?

BACKGROUND: Despite strong evidence of a social gradient in cancer survival among UK adults, studies in children and young people remain inconclusive and have not included renal tumours. This study investigated the relationship between socioeconomic status and survival from renal tumours among children and young people. PROCEDURE: Kaplan-Meier estimation and Cox regression were used to analyse survival for all 209 renal tumours in children and young people (0-24 years) diagnosed 1968-2012 and registered by a specialist population-based registry. Sociodemographic and clinicopathologic variables, including paternal occupation at birth, were also analysed. RESULTS: No significant disparity in overall renal tumour and Wilms tumour (WT) survival was observed according to paternal social class [p=0.988 and 0.808, respectively]. The strongest predictor of survival was stage, with late stage (III-IV) disease having a 4-fold higher risk of death compared to early stage (I-II) disease [p<0.001]. Similarly, high mortality-risk was seen for late stage WT in children aged 0-14 years (Hazard Ratio=6.37; 95% CI=2.60-15.59). CONCLUSIONS: This study did not detect a significant social gradient in renal tumour survival. The identification of tumour stage as a strong predictor of survival irrespective of age, necessitates the development of appropriate public health interventions that target early diagnosis and treatment.

Can changes in population mixing and socio-economic deprivation in Cumbria, England explain changes in cancer incidence around Sellafield?

Previously excesses in incident cases of leukaemia and non-Hodgkin lymphoma have been observed amongst young people born or resident in Seascale, Cumbria. These excesses have not been seen more recently. It is postulated that the former apparent increased risk was related to 'unusual population mixing', which is not present in recent years. This study investigated changes in measures of population mixing from 1951-2001. Comparisons were made between three specified areas. Area-based measures were calculated (migration, commuting, deprivation, population density). All areas have become more affluent, although Seascale was consistently the most affluent. Seascale has become less densely populated, with less migration into the ward and less diversity with respect to migrants' origin. There have been marked changes in patterns of population mixing throughout Cumbria. Lesser population mixing has been observed in Seascale in recent decades. Changes in pattern and nature of population mixing may explain the lack of recent excesses.

A geographical study of thyroid cancer incidence in north-west England following the Windscale nuclear reactor fire of 1957.

The Windscale nuclear reactor fire at Sellafield, United Kingdom, in October 1957 led to an uncontrolled release of iodine-131 (radioactive half-life, 8 d) into the atmosphere. Contamination from the accident was most pronounced in the counties of Cumbria and Lancashire, north-west England. Radioiodine concentrates in the thyroid gland producing an excess risk of thyroid cancer, notably among those exposed as children, which persists into later life. For an initial investigation of thyroid cancer incidence in north-west England, data were obtained on cases of thyroid cancer among people born during 1929-1973 and diagnosed during 1974-2012 while resident in England, together with corresponding populations. Incidence rate ratios (IRRs), with Poisson 95% confidence intervals (CIs), compared thyroid cancer incidence rates in Cumbria and in Lancashire with those in the rest of England. For those aged <20 years in 1958, a statistically significantly increased IRR was found for those diagnosed during 1974-2012 while living in Cumbria (IRR = 1.29; 95% CI 1.09-1.52), but the equivalent IRR for Lancashire was marginally non-significantly decreased (IRR = 0.91; 95% CI 0.80-1.04). This pattern of IRRs was also apparent for earlier births, and the significantly increased IRR in Cumbria extended to individuals born in 1959-1963, who would not have been exposed to iodine-131 from the Windscale accident. Moreover, significant overdispersion was present in the temporal distributions of the IRRs, so that Poisson CIs substantially underestimate statistical uncertainties. Consequently, although further investigations are required to properly understand the unusual patterns of thyroid cancer IRRs in Cumbria and Lancashire, the results of this preliminary study are not consistent with an effect of exposure to iodine-131 from the Windscale accident.

Trends in mortality rates in female genital organs and breast cancers in Hungary between 1979 and 2013.

OBJECTIVE: This study investigated annual and seasonal trends in deaths for cancers of the female genital organs and breast in Hungary between 1979 and 2013. STUDY DESIGN: Data on the numbers of cancer deaths were obtained from the published nationwide population register. Joinpoint regression was applied to investigate the yearly trends in cancer mortality rates. Cyclic trends were investigated using logistic regression, Edwards' and Walter-Elwood methods. RESULTS: The majority of deaths from cancers of the female genital organs and breast occurred in winter but using the observed numbers of deaths a significant seasonal pattern was only revealed for deaths from breast cancer with a peak in January and a nadir in July. However, seasonality in the proportion of deaths from female genital organs and breast cancers out of deaths from all causes detected a different peak and nadir. The proportion of female genital organs and breast cancer deaths out of deaths from all causes was higher around the end of summer and significant seasonal variation with a peak in August and nadir in February was revealed. CONCLUSION: This Hungarian study suggests that there was a significant seasonal effect on female genital organs and breast cancer mortality. Both seasonal patterns are interesting and informative to potentiate prevention. Our findings suggest that infectious diseases may increase the risk of the mortality among the immune deficient patents.

Temporal clustering of neuroblastic tumours in children and young adults from Northern England.

BACKGROUND: The aetiology of neuroblastic tumours is unclear with both genetic and environmental factors implicated. The possibility that an infectious agent may be involved has been suggested. 'Temporal clustering' occurs if cases display an irregular temporal distribution and may indicate the involvement of an agent that exhibits epidemicity. We tested for the presence and nature of temporal clustering using population-based data from northern England. METHODS: We extracted all cases of neuroblastic tumours diagnosed in children and young adults aged 0-24 years during 1968-2011 from the Northern Region Young Persons' Malignant Disease Registry. This is a population-based registry, covering a population of approximately 900,000 young persons, and includes all cases resident in northern England at the time of diagnosis. Tests for temporal clustering were applied using a modified version of the Potthoff-Whittinghill method. Estimates of extra-Poisson variation (ß) and standard errors (SEs) were obtained. RESULTS: 227 cases of neuroblastic tumours were diagnosed during the study period. All the analyses between fortnights and between months found significant extra-Poisson variation, with ß = 0.846 (SE = 0.310, P = 0.004) for the analysis between fortnights within months. Restricting the analyses to the 76 cases diagnosed at ages less than 18 months showed significant extra-Poisson variation between fortnights within months (ß = 1.532, SE = 0.866, P = 0.038), but not between months. In contrast, analyses of cases aged 18 months to 24 years showed significant extra-Poisson variation between quarters within years, as well as over shorter timescales. CONCLUSIONS: Transient environmental agents may be involved in the aetiology of neuroblastic tumours. The initiating factor might be a geographically-widespread agent that occurs in 'mini-epidemics'.

Socioeconomic patterning in the incidence and survival of teenage and young adult men aged between 15 and 24 years diagnosed with non-seminoma testicular cancer in northern england.

PURPOSE: Previous research from developed countries has shown a marked increase in the incidence of testicular cancer in the past 50 years. This has also been demonstrated in northern England, along with improving 5-year survival. The present study aims to determine if socioeconomic factors may play a role in both etiology and survival from non-seminoma testicular cancer. MATERIALS AND METHODS: We extracted all 214 cases of non-seminoma testicular cancer diagnosed in teenage and young adult men aged between 15 and 24 years during 1968 to 2006 from the Northern Region Young Persons' Malignant Disease Registry, which is a population-based specialist regional registry. Negative binomial regression was used to examine the relationship between incidence and both the Townsend deprivation score (and component variables) and small-area population density. Cox regression was used to analyze the relationship between survival and both deprivation and population density. RESULTS: Decreased incidence was associated with living in areas of higher household overcrowding for young adults aged between 20 and 24 years (relative risk per 1% increase in household overcrowding = 0.79; 95% CI: 0.66-0.94) but no association was detected for young people aged between 15 and 19 years. Community-level household unemployment was associated with worse survival (hazard ratio per 1% increase in household unemployment = 1.04; 95% CI: 1.00-1.08). CONCLUSIONS: This study has shown that increased risk of non-seminoma testicular cancer in teenage and young adult men may be associated with some aspect of more advantaged living. In contrast, greater deprivation is linked with worse survival prospects. The study was ecological by design and so these area-based results may not necessarily apply to individuals.

Investigating the relationship between mortality from respiratory diseases and childhood acute lymphoblastic leukaemia in Hungary.

Our aim was to investigate the ecological association between death from infectious disease of the respiratory system and the risk of acute lymphoid leukaemia (ALL) in children aged less than 7 years. Poisson regression analyses were carried out using overall data and gender-specific models. The study included 176 cases (92(52.3 %) boys and 84 (47.7 %) girls) of ALL in those aged 0-6 years in South Hungary. Eight cases were diagnosed before the age of 1 year. A significant risk of ALL disease was observed with higher levels of mortality from the chronic respiratory diseases (p = 0.035) and pneumonia (p = 0.010) among children aged 2-5 years (Odds Ratio for trend was 1.001 and 95%CI [1.000-1.002] and Odds ratio for trend was 1.013 and 95%CI [1.003-1.023], respectively). Significantly increased risk of childhood ALL was detected among children under 1 year of age residing in areas around birth with higher levels of mortality from influenza (Odds Ratio (OR) for trend was 1.05; 95%CI [1.01-1.09]; p = 0.012). This risk was also detected in girls (p < 0.001), but not in boys (p = 0.43). Our findings provide new evidence that will help to understand the different pattern of female and male childhood ALL occurrence , but further studies are needed using detailed individual medical history to clarify the role of influenza and other infectious diseases in the etiology of childhood ALL and to explain gender-specific effects.