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.

Factors associated with recurrence and survival length following relapse in patients with neuroblastoma.

BACKGROUND: Despite therapeutic advances, survival following relapse for neuroblastoma patients remains poor. We investigated clinical and biological factors associated with length of progression-free and overall survival following relapse in UK neuroblastoma patients. METHODS: All cases of relapsed neuroblastoma, diagnosed during 1990-2010, were identified from four Paediatric Oncology principal treatment centres. Kaplan-Meier and Cox regression analyses were used to calculate post-relapse overall survival (PROS), post-relapse progression-free survival (PRPFS) between relapse and further progression, and to investigate influencing factors. RESULTS: One hundred eighty-nine cases were identified from case notes, 159 (84.0%) high risk and 17 (9.0%), unresectable, MYCN non-amplified (non-MNA) intermediate risk (IR). For high-risk patients diagnosed >2000, median PROS was 8.4 months (interquartile range (IQR)=3.0-17.4) and median PRPFS was 4.7 months (IQR=2.1-7.1). For IR, unresectable non-MNA patients, median PROS was 11.8 months (IQR 9.0-51.6) and 5-year PROS was 24% (95% CI 7-45%). MYCN amplified (MNA) disease and bone marrow metastases at diagnosis were independently associated with worse PROS for high-risk cases. Eighty percent of high-risk relapses occurred within 2 years of diagnosis compared with 50% of unresectable non-MNA IR disease. CONCLUSIONS: Patients with relapsed HR neuroblastomas should be treatment stratified according to MYCN status and PRPFS should be the primary endpoint in early phase clinical trials. The failure to salvage the majority of IR neuroblastoma is concerning, supporting investigation of intensification of upfront treatment regimens in this group to determine whether their use would diminish likelihood of relapse.

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.

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'.

Increasing incidence of thyroid cancer in Great Britain, 1976-2005: age-period-cohort analysis.

Increases in the incidence of thyroid cancer have been previously reported. The purpose of the present study was to examine temporal trends in the incidence of primary thyroid cancer diagnosed in 0-49 year olds in parts of Great Britain during 1976-2005. Data on 4,337 cases of thyroid cancer were obtained from regional cancer registries. Age-standardized incidence rates (ASRs) were calculated. Negative binomial regression was used to examine effects of age, sex, drift (linear trend), non-linear period and non-linear cohort. The best fitting negative binomial regression model included age (P < 0.001), sex (P < 0.001) and drift (P < 0.001). Non-linear period (P = 0.648) and non-linear cohort (P = 0.788) were not statistically significant. For males aged 0-14, the ASR increased from 0.2 per million persons per year in 1976-1986 to 0.6 in 1997-2005. For males aged 15-29 and 30-49 the ASRs increased from 1.9 to 3.3 and from 7.4 to 12.7, respectively. For females aged 0-14, the corresponding ASR increased from 0.3 to 0.5. For females aged 15-29 and 30-49 the ASRs increased from 6.9 to 12.4 and from 21.2 to 42.3, respectively. For all age groups, there has been a linear increase in incidence of thyroid cancer, which has led to a doubling of the number of cases diagnosed over a twenty year span. The reasons for this increase are not well understood, but it is consistent with findings from other countries.

Season of birth and diagnosis for childhood cancer in Northern England, 1968-2005.

The aim of this study was to investigate seasonal variation in the incidence of cancer in children aged 0-14 years. Details of 2959 primary malignant cases (1659 males, 1300 females), diagnosed during the period 1968-2005, were extracted from a specialist registry (the Northern Region Young Persons' Malignant Disease Registry). Seasonal variation was analysed with respect to month of birth and diagnosis. The chi-squared heterogeneity test was used to test for non-uniform variation. Poisson regression analysis was used to fit sinusoidal (harmonic) models to the data, using month of birth and month of diagnosis, respectively, as covariates in separate models. There was significant sinusoidal variation based on month of birth for acute lymphoblastic leukaemia (ALL) aged 1-6 years (P = 0.04; peak in March). For 0- to 14-year-old boys, there was statistically significant sinusoidal variation in month of birth for acute non-lymphocytic leukaemia (P = 0.04; peak in September) and astrocytoma (P = 0.03; peak in October). Based on month of diagnosis, there was statistically significant sinusoidal variation in girls for all lymphomas (P = 0.048; peak in March) and Hodgkin lymphoma (HL) (P = 0.005; peak in January), and in boys for osteosarcoma (P = 0.049; peak in October). This study confirms previous findings of seasonal variation around the month of birth for childhood ALL (at the peak ages) and provides further evidence of seasonal variation around month of birth for astrocytoma and around month of diagnosis for HL. The results are consistent with a role for environmental factors in the aetiology of these diagnostic groups. Further studies are needed to examine putative candidate agents.

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.

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.

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.

Socioeconomic patterning in the incidence and survival of children and young people diagnosed with malignant melanoma in northern England.

Previous studies have found marked increases in melanoma incidence. The increase among young people in northern England was especially apparent among females. However, overall 5-year survival has greatly improved. The present study aimed to determine whether socioeconomic factors may be involved in both etiology and survival. All 224 cases of malignant melanoma diagnosed in patients aged 10-24 years during 1968-2003 were extracted from a specialist population-based regional registry. Negative binomial regression was used to examine the relationship between incidence and area-based measures of socioeconomic deprivation and small-area population density. Cox regression was used to analyze the relationship between survival and deprivation and population density. There was significantly decreased risk associated with living in areas of higher unemployment (relative risk per 1% increase in unemployment=0.93; 95% confidence interval (CI) 0.90-0.96, P<0.001). Survival was better in less deprived areas (hazard ratio (HR) per tertile of household overcrowding=1.52; 95% CI 1.05-2.20; P=0.026), but this effect was reduced in the period 1986-2003 (HR=0.61; 95% CI 0.40-0.92; P=0.018). This study found that increased risk of melanoma was linked with some aspects of greater affluence. In contrast, worse survival was associated with living in a more deprived area.

Seasonality in the incidence of cervical carcinoma in teenagers and young adults in Northern England, 1968-2005.

Infection with human papillomavirus is an established risk factor for cervical carcinoma. However, the role of other environmental factors is less well established. To further investigate whether other agents may be involved, the authors have analyzed seasonal variation in cervical cancer with respect to month of birth and separately month of diagnosis. All 85 cases diagnosed in 15-24-yr-olds during the period 1968-2005 were extracted from the specialist population-based Northern Region Young Persons' Malignant Disease Registry. The chi-square heterogeneity test was used to assess overall nonuniform variation in month of birth and separately month of diagnosis. Poisson regression analysis was used to fit sinusoidal (harmonic) models to the data using month of birth and month of diagnosis in separate models. Based on month of birth, there was statistically significant heterogeneity (p=.03) and a significant sinusoidal pattern, with an incidence peak involving births in the autumn months (p=.03). Based on month of diagnosis, there was marginally significant heterogeneity (p=.06). The evidence of seasonal variation around time of birth for cervical carcinoma is highly novel and suggests possible early etiological involvement of environmental factors.