Single-nuclei transcriptomes from human adrenal gland reveal distinct cellular identities of low and high-risk neuroblastoma tumors

Childhood neuroblastoma has a remarkable variability in outcome. Age at diagnosis is one of the most important prognostic factors, with children less than 1 year old having favorable outcomes. Here we study single-cell and single-nuclei transcriptomes of neuroblastoma with different clinical risk groups and stages, including healthy adrenal gland. We compare tumor cell populations with embryonic mouse sympatho-adrenal derivatives, and post-natal human adrenal gland. We provide evidence that low and high-risk neuroblastoma have different cell identities, representing two disease entities. Low-risk neuroblastoma presents a transcriptome that resembles sympatho- and chromaffin cells, whereas malignant cells enriched in high-risk neuroblastoma resembles a subtype of TRKB+ cholinergic progenitor population identified in human post-natal gland. Analyses of these populations reveal different gene expression programs for worst and better survival in correlation with age at diagnosis. Our findings reveal two cellular identities and a composition of human neuroblastoma tumors reflecting clinical heterogeneity and outcome.

Single-nuclei transcriptomes from human adrenal gland reveals distinct cellular identities of low and high-risk neuroblastoma tumors.

Childhood neuroblastoma has a remarkable variability in outcome. Age at diagnosis is one of the most important prognostic factors, with children less than 1 year old having favorable outcomes. We studied single-cell and single-nuclei transcriptomes of neuroblastoma with different clinical risk groups and stages, including healthy adrenal gland. We compared tumor cell populations with embryonic mouse sympatho-adrenal derivatives, and post-natal human adrenal gland. We provide evidence that low and high-risk neuroblastoma have different cell identities, representing two disease entities. Low-risk neuroblastoma presents a transcriptome that resembles sympatho- and chromaffin cells, whereas malignant cells enriched in high-risk neuroblastoma resembles an unknown subtype of TRKB+ cholinergic progenitor population identified in human post-natal gland. Analyses of these populations revealed different gene expression programs for worst and better survival in correlation with age at diagnosis. Our findings reveal two cellular identities and a composition of human neuroblastoma tumors reflecting clinical heterogeneity and outcome.

Prevalence of COVID-19-related risk factors and risk of severe influenza outcomes in cancer survivors: a matched cohort study using linked English electronic health records data

BackgroundPeople with active cancer are recognised as at risk of COVID-19 complications, but it is unclear whether the much larger population of cancer survivors is at elevated risk. We aimed to address this by comparing cancer survivors and cancer-free controls for (i) prevalence of comorbidities considered risk factors for COVID-19; and (ii) risk of severe influenza, as a marker of susceptibility to severe outcomes from epidemic respiratory viruses.MethodsWe included survivors (≥1 year) of the 20 most common cancers, and age, sex and general practice-matched cancer-free controls, derived from UK primary care data linked to cancer registrations, hospital admissions and death registrations. Comorbidity prevalences were calculated 1 and 5 years from cancer diagnosis. Risk of hospitalisation or death due to influenza was compared using Cox models adjusted for baseline demographics and comorbidities.Findings108,215 cancer survivors and 523,541 cancer-free controls were included. Cancer survivors had more asthma, other respiratory, cardiac, diabetes, neurological, renal, and liver disease, and less obesity, compared with controls, but there was variation by cancer site. There were 205 influenza hospitalisations/deaths, with cancer survivors at higher risk than controls (adjusted HR 2.78, 95% CI 2.04-3.80). Haematological cancer survivors had large elevated risks persisting for >10 years (HR overall 15.17, 7.84-29.35; HR >10 years from cancer diagnosis 10.06, 2.47-40.93). Survivors of other cancers had evidence of raised risk up to 5 years from cancer diagnosis only (HR 2.22, 1.31-3.74).InterpretationRisks of severe COVID-19 outcomes are likely to be elevated in cancer survivors. This should be taken into account in policies targeted at clinical risk groups, and vaccination for both influenza, and, when available, COVID-19, should be encouraged in cancer survivors.FundingWellcome Trust, Royal Society, NIHR.Research in contextEvidence before this studyFew data are available to date on how COVID-19 affects cancer survivors. We searched PubMed with the keywords “influenza cancer survivors” to identify studies that compared severe influenza outcomes in cancer survivors and in a control group. No study was identified.Added value of this studyIn this matched cohort study of routinely collected electronic health records, we demonstrated raised risks of influenza hospitalisation or mortality in survivors from haematological malignancies for >10 years after diagnosis, and in survivors from solid cancers up to 5 years after diagnosis.Implications of all the available evidenceCancer survivorship appears to be an important risk factor for severe influenza outcomes, suggesting that cancer survivors may also be at raised risk of poor COVID-19 outcomes. This should be taken into account in public health policies targeted at protecting clinical risk groups. Influenza vaccination should be encouraged in this group, and may need to be extended to a wider population of medium- to long-term cancer survivors than currently recommended.

The Optimal Duration of Adjuvant Chemotherapy in Colon Cancer

Adjuvant chemotherapy for colon cancer (UICC stage II and III) has been under investigation over the last 30 years, regarding treatment duration and regimens. In this review, choice of regimen, its duration, possible limitations and future perspectives are discussed. Monotherapy with 5-fluorouracil was followed by addition of oxaliplatin, resulting in improved 3-yr disease free survival (DFS) and overall survival (OS) rates, but also increased peripheral sensory neurotoxicity (PSN). The International Duration Evaluation of Adjuvant therapy (IDEA) collaboration demonstrated less toxicity, especially PSN, when shortening treatment duration to 3 months. However, formally, the anticipated non-inferiority of 3 months with fluoropyrimidine (FP)/oxaliplatin over 6 months (at 3-yr DFS) was not met for all patients groups, although subgroup analyses showed non-inferiority with capecitabine/oxaliplatin (CAPOX) rather than with FOLFOX, and also in relation to the prognostic information (e.g., clinical low-risk group, pT1-3 N0). In addition, first data of newer parameters like Immunoscore® and ctDNA show promising results as stratification parameters. Further investigations to better define clinical risk groups and prognostic factors are mandatory. Besides this, individual decision-making of treatment intensity (FP or FP/oxaliplatin) and duration should always consider patient characteristics and preferences, also given the absolute relatively small differences and their clinical relevance.

Cost-effectiveness of paediatric influenza vaccination in the Netherlands

BackgroundThis study evaluates the cost-effectiveness of extending the Dutch influenza vaccination programme for elderly and clinical risk groups to include paediatric influenza vaccination, taking indirect protection into account.MethodsAn age-structured dynamic transmission model was used that was calibrated to influenza-associated GP visits over four seasons (2010/11 to 2013/14). The clinical and economic impact of different paediatric vaccination strategies were compared over 20 years, varying the targeted age range, the vaccine type for children and the vaccine type for elderly and clinical risk groups. Outcome measures include averted symptomatic infections and deaths, societal costs and quality-adjusted life years (QALYs), incremental cost-effectiveness ratios, and net health benefits (NHBs), using a willingness-to-pay threshold of €20,000 per QALY gained.ResultsAt an assumed coverage of 50%, adding vaccination of 2- to 17-year-olds with quadrivalent-live-attenuated influenza vaccine (Q-LAIV) to the current influenza vaccination programme was estimated to avert on average 406,270 symptomatic cases and 83 deaths per season compared to vaccination of elderly and risk groups with trivalent inactivated vaccine (TIV), and was cost-saving (cumulative 20-year savings of 36,396 QALYs and €1,680 million; NHB: 120,411 QALYs). This strategy dominated paediatric vaccination strategies targeting 2- to 6-year-olds or 2- to 12-year-olds, or paediatric vaccination strategies with TIV. The highest NHB was obtained when 2- to 17-year-olds were vaccinated with Q-LAIV and existing target groups switched from TIV to quadrivalent inactivated vaccine (NHB: 132,907 QALYs).ConclusionModelling indicates that paediatric influenza vaccination reduces the disease burden of influenza substantially and is cost-saving.