Opportunities and challenges of circulating biomarkers in neuroblastoma.

Molecular analysis of nucleic acid and protein biomarkers is becoming increasingly common in paediatric oncology for diagnosis, risk stratification and molecularly targeted therapeutics. However, many current and emerging biomarkers are based on analysis of tumour tissue, which is obtained through invasive surgical procedures and in some cases may not be accessible. Over the past decade, there has been growing interest in the utility of circulating biomarkers such as cell-free nucleic acids, circulating tumour cells and extracellular vesicles as a so-called liquid biopsy of cancer. Here, we review the potential of emerging circulating biomarkers in the management of neuroblastoma and highlight challenges to their implementation in the clinic

Dietary salt intake and discretionary salt use in two general population samples in Australia: 2011 and 2014

The limited Australian measures to reduce population sodium intake through national initiatives targeting sodium in the food supply have not been evaluated. The aim was, thus, to assess if there has been a change in salt intake and discretionary salt use between 2011 and 2014 in the state of Victoria, Australia. Adults drawn from a population sample provided 24 h urine collections and reported discretionary salt use in 2011 and 2014. The final sample included 307 subjects who participated in both surveys, 291 who participated in 2011 only, and 135 subjects who participated in 2014 only. Analysis included adjustment for age, gender, metropolitan area, weekend collection and participation in both surveys, where appropriate. In 2011, 598 participants: 53% female, age 57.1(12.0)(SD) years and in 2014, 442 participants: 53% female, age 61.2(10.7) years provided valid urine collections, with no difference in the mean urinary salt excretion between 2011: 7.9 (7.6, 8.2) (95% CI) g/salt/day and 2014: 7.8 (7.5, 8.1) g/salt/day (p = 0.589), and no difference in discretionary salt use: 35% (2011) and 36% (2014) reported adding salt sometimes or often/always at the table (p = 0.76). Those that sometimes or often/always added salt at the table and when cooking had 0.7 (0.7, 0.8) g/salt/day (p = 0.0016) higher salt excretion. There is no indication over this 3-year period that national salt reduction initiatives targeting the food supply have resulted in a population reduction in salt intake. More concerted efforts are required to reduce the salt content of manufactured foods, together with a consumer education campaign targeting the use of discretionary salt

Measurement Properties of the Suicidal Behaviour Questionnaire-Revised in Autistic Adults

Abstract: We explored the appropriateness and measurement properties of a suicidality assessment tool (SBQ-R) developed for the general population, in autistic adults—a high risk group for suicide. 188 autistic adults and 183 general population adults completed the tool online, and a sub-sample (n = 15) were interviewed while completing the tool. Multi-group factorial invariance analysis of the online survey data found evidence for metric non-invariance of the SBQ-R, particularly for items three (communication of suicidal intent) and four (likelihood of suicide attempt in the future). Cognitive interviews revealed that autistic adults did not interpret these items as intended by the tool designers. Results suggest autistic adults interpret key questions regarding suicide risk differently to the general population. Future research must adapt tools to better capture suicidality in autistic adults

Salt intake and dietary sources of salt on weekdays and weekend days in Australian adults

ObjectiveTo assess if there is a difference in salt intake (24 h urine collection and dietary recall) and dietary sources of salt (Na) on weekdays and weekend days.DesignA cross-sectional study of adults who provided one 24 h urine collection and one telephone-administered 24 h dietary recall.SettingCommunity-dwelling adults living in the State of Victoria, Australia.SubjectsAdults (n 598) who participated in a health survey (53&middot;5 % women; mean age 57&middot;1 (95 % CI 56&middot;2, 58&middot;1) years).ResultsMean (95 % CI) salt intake (dietary recall) was 6&middot;8 (6&middot;6, 7&middot;1) g/d and 24 h urinary salt excretion was 8&middot;1 (7&middot;8, 8&middot;3) g/d. Mean dietary and 24 h urinary salt (age-adjusted) were 0&middot;9 (0&middot;1, 1&middot;6) g/d (P=0&middot;024) and 0&middot;8 (0&middot;3, 1&middot;6) g/d (P=0&middot;0017), respectively, higher at weekends compared with weekdays. There was an indication of a greater energy intake at weekends (+0&middot;6 (0&middot;02, 1&middot;2) MJ/d, P=0&middot;06), but no difference in Na density (weekday: 291 (279, 304) mg/MJ; weekend: 304 (281, 327) mg/MJ; P=0&middot;360). Cereals/cereal products and dishes, meat, poultry, milk products and gravy/sauces accounted for 71 % of dietary Na.ConclusionsMean salt intake (24 h urine collection) was more than 60 % above the recommended level of 5 g salt/d and 8&ndash;14 % more salt was consumed at weekends than on weekdays. Substantial reductions in the Na content of staple foods, processed meat, sauces, mixed dishes (e.g. pasta), convenience and takeaway foods are required to achieve a significant consistent reduction in population salt intake throughout the week.<br /

Circulating tumor DNA in patients with colorectal adenomas: assessment of detectability and genetic heterogeneity.

Improving early detection of colorectal cancer (CRC) is a key public health priority as adenomas and stage I cancer can be treated with minimally invasive procedures. Population screening strategies based on detection of occult blood in the feces have contributed to enhance detection rates of localized disease, but new approaches based on genetic analyses able to increase specificity and sensitivity could provide additional advantages compared to current screening methodologies. Recently, circulating cell-free DNA (cfDNA) has received much attention as a cancer biomarker for its ability to monitor the progression of advanced disease, predict tumor recurrence and reflect the complex genetic heterogeneity of cancers. Here, we tested whether analysis of cfDNA is a viable tool to enhance detection of colon adenomas. To address this, we assessed a cohort of patients with adenomas and healthy controls using droplet digital PCR (ddPCR) and mutation-specific assays targeted to trunk mutations. Additionally, we performed multiregional, targeted next-generation sequencing (NGS) of adenomas and unmasked extensive heterogeneity, affecting known drivers such as APC, KRAS and mismatch repair (MMR) genes. However, tumor-related mutations were undetectable in patients' plasma. Finally, we employed a preclinical mouse model of Apc-driven intestinal adenomas and confirmed the inability to identify tumor-related alterations via cfDNA, despite the enhanced disease burden displayed by this experimental cancer model. Therefore, we conclude that benign colon lesions display extensive genetic heterogeneity, that they are not prone to release DNA into the circulation and are unlikely to be reliably detected with liquid biopsies, at least with the current technologies

Can a lifestyle intervention be offered through NHS breast cancer screening?:Challenges and opportunities identified in a qualitative study of women attending screening

Background: Around one third of breast cancers in post-menopausal women could be prevented by decreasing body fatness and alcohol intake and increasing physical activity. This study aimed to explore views and attitudes on lifestyle intervention approaches in order to inform the proposed content of a lifestyle intervention programme amongst women attending breast cancer screening. Methods: Women attending breast cancer screening clinics in Dundee and Glasgow, were invited to participate in focus group discussions (FGD) by clinic staff. The groups were convened out with the clinic setting and moderated by an experienced researcher who attained brief details on socio-demographic background and audio-recorded the discussions. Data analysis was guided by the framework approach. The main topics of enquiry were: Understanding of risk of breast cancer and its prevention, views on engaging with a lifestyle intervention programme offered through breast cancer screening and programme design and content. Results: Thirty one women attended 5 focus groups. Participant ages ranged from 51 to 78 years and 38 % lived in the two most deprived quintiles of residential areas. Women were generally positive about being offered a programme at breast cancer screening but sceptical about lifestyle associated risk, citing genetics, bad luck and knowing women with breast cancer who led healthy lifestyles as reasons to query the importance of lifestyle. Engagement via clinic staff and delivery of the programme by lifestyle coaches out with the screening setting was viewed favourably. The importance of body weight, physical activity and alcohol consumption with disease was widely known although most were surprised at the association with breast cancer. They were particularly surprised about the role of alcohol and resistant to thinking about themselves having a problem. They expressed frustration that lifestyle guidance was often conflicting and divergent over time. The concept of focussing on small lifestyle changes, which were personalised, supported socially and appropriate to age and ability were welcomed. Conclusions: Offering access to a lifestyle programme through breast screening appears acceptable. Explaining the relevance of the target behaviours for breast cancer health, endorsing and utilising consistent messages and identifying personalised, mutually agreed, behaviour change goals provides a framework for programme development

Comparison of microfluidic digital PCR and conventional quantitative PCR for measuring copy number variation

One of the benefits of Digital PCR (dPCR) is the potential for unparalleled precision enabling smaller fold change measurements. An example of an assessment that could benefit from such improved precision is the measurement of tumour-associated copy number variation (CNV) in the cell free DNA (cfDNA) fraction of patient blood plasma. To investigate the potential precision of dPCR and compare it with the established technique of quantitative PCR (qPCR), we used breast cancer cell lines to investigate HER2 gene amplification and modelled a range of different CNVs. We showed that, with equal experimental replication, dPCR could measure a smaller CNV than qPCR. As dPCR precision is directly dependent upon both the number of replicate measurements and the template concentration, we also developed a method to assist the design of dPCR experiments for measuring CNV. Using an existing model (based on Poisson and binomial distributions) to derive an expression for the variance inherent in dPCR, we produced a power calculation to define the experimental size required to reliably detect a given fold change at a given template concentration. This work will facilitate any future translation of dPCR to key diagnostic applications, such as cancer diagnostics and analysis of cfDNA

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

A local human Vδ1 T cell population is associated with survival in nonsmall-cell lung cancer

Funding Information: D.B. has consulted for NanoString, reports honoraria from AstraZeneca and has a patent (PCT/GB2020/050221) issued on methods for cancer prognostication. J.R. and M.A.B. have consulted for Achilles Therapeutics. N.M. has stock options in and has consulted for Achilles Therapeutics. N.M. holds European patents relating to targeting neoantigens (PCT/EP2016/059401), identifying patient response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA loss of heterozygosity (PCT/GB2018/052004) and predicting survival rates of patients with cancer (PCT/GB2020/050221). A.H. attended one advisory board for Abbvie, Roche and GRAIL, and reports personal fees from Abbvie, Boehringer Ingelheim, Takeda, AstraZeneca, Daiichi Sankyo, Merck Serono, Merck/MSD, UCB and Roche for delivering general education/training in clinical trials. A.H. owned shares in Illumina and Thermo Fisher Scientific (sold in 2020) and receives fees for membership of Independent Data Monitoring Committees for Roche-sponsored clinical trials. S.A.Q. is co-founder and Chief Scientific Officer of Achilles Therapeutics. A.C.H. is a board member and equity holder in ImmunoQure, AG and Gamma Delta Therapeutics, and is an equity holder in Adaptate Biotherapeutics and chair of the scientific advisory board. C.S. acknowledges grant support from Pfizer, AstraZeneca, Bristol Myers Squibb, Roche-Ventana, Boehringer Ingelheim, Archer Dx Inc (collaboration in minimal residual disease-sequencing technologies) and Ono Pharmaceuticals, is an AstraZeneca Advisory Board member and Chief Investigator for the MeRmaiD1 clinical trial. C.S has consulted for Amgen, AstraZeneca, Bicycle Therapeutics, Bristol Myers Squibb, Celgene, Genentech, GlaxoSmithKline, GRAIL, Illumina, Medixci, Metabomed, MSD, Novartis, Pfizer, Roche-Ventana and Sarah Cannon Research Institute. C.S. has stock options in Apogen Biotechnologies, Epic Biosciences and GRAIL, and has stock options and is co-founder of Achilles Therapeutics. C.S. holds patents relating: to assay technology to detect tumor recurrence (PCT/GB2017/053289); to targeting neoantigens (PCT/EP2016/059401), identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA loss of heterozygosity (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221); to treating cancer by targeting Insertion/deletion (indel) mutations (PCT/GB2018/051893); to identifying indel mutation targets (PCT/GB2018/051892); to methods for lung cancer detection (PCT/US2017/028013); and to identifying responders to cancer treatment (PCT/GB2018/051912). The remaining authors declare no competing interests. Funding Information: We thank the Oxford Genomics Centre at the Wellcome Centre for Human Genetics (funded by Wellcome Trust grant no. 203141/Z/16/Z) for the generation and initial processing of the RNA-seq data from sorted TILs. We thank S. Bola for technical support and S. Vanloo for administrative support. The GTEx project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by the NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. Y.W. was supported by a Wellcome Trust Clinical Research Career Development Fellowship (no. 220589/Z/20/Z), an Academy of Medical Sciences Starter Grant for Clinical Lecturers, a National Institute for Health Research (NIHR) Academic Clinical Lectureship and the NIHR University College London Hospitals Biomedical Research Centre. D.B. was supported by funding from the NIHR University College London Hospitals Biomedical Research Centre, the ideas 2 innovation translation scheme at the Francis Crick Institute, the Breast Cancer Research Foundation (BCRF) and a Cancer Research UK (CRUK) Early Detection and Diagnosis Project award. M.J.H. is a CRUK Fellow and has received funding from CRUK, NIHR, Rosetrees Trust, UKI NETs and the NIHR University College London Hospitals Biomedical Research Centre. C.S. is Royal Society Napier Research Professor. This work was supported by the Francis Crick Institute which receives its core funding from CRUK (no. FC001169), the UK Medical Research Council (no. FC001169) and the Wellcome Trust (no. FC001169). This research was funded in whole, or in part, by the Wellcome Trust (no. FC001169). For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. C.S. is funded by CRUK (TRACERx, PEACE and CRUK Cancer Immunotherapy Catalyst Network), CRUK Lung Cancer Centre of Excellence (no. C11496/A30025), the Rosetrees Trust, Butterfield and Stoneygate Trusts, NovoNordisk Foundation (ID16584), Royal Society Professorship Enhancement Award (no. RP/EA/180007), the NIHR Biomedical Research Centre at University College London Hospitals, the CRUK–University College London Centre, Experimental Cancer Medicine Centre and the BCRF. This work was supported by a Stand Up To Cancer‐LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (grant no. SU2C-AACR-DT23-17 to S. M. Dubinett and A. E. Spira). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. C.S. receives funding from the European Research Council (ERC) under the European Union’s Seventh Framework Programme (no. FP7/2007-2013) Consolidator Grant (no. FP7-THESEUS-617844), European Commission ITN (no. FP7-PloidyNet 607722), an ERC Advanced Grant (PROTEUS) from the ERC under the European Union’s Horizon 2020 research and innovation program (grant no. 835297), and Chromavision from the European Union’s Horizon 2020 research and innovation program (grant no. 665233). Publisher Copyright: © 2022, The Author(s).Peer reviewedPublisher PD