COVID-19 prevalence and mortality in patients with cancer and the effect of primary tumour subtype and patient demographics: a prospective cohort study

BACKGROUND: Patients with cancer are purported to have poor COVID-19 outcomes. However, cancer is a heterogeneous group of diseases, encompassing a spectrum of tumour subtypes. The aim of this study was to investigate COVID-19 risk according to tumour subtype and patient demographics in patients with cancer in the UK. METHODS: We compared adult patients with cancer enrolled in the UK Coronavirus Cancer Monitoring Project (UKCCMP) cohort between March 18 and May 8, 2020, with a parallel non-COVID-19 UK cancer control population from the UK Office for National Statistics (2017 data). The primary outcome of the study was the effect of primary tumour subtype, age, and sex and on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevalence and the case-fatality rate during hospital admission. We analysed the effect of tumour subtype and patient demographics (age and sex) on prevalence and mortality from COVID-19 using univariable and multivariable models. FINDINGS: 319 (30·6%) of 1044 patients in the UKCCMP cohort died, 295 (92·5%) of whom had a cause of death recorded as due to COVID-19. The all-cause case-fatality rate in patients with cancer after SARS-CoV-2 infection was significantly associated with increasing age, rising from 0·10 in patients aged 40-49 years to 0·48 in those aged 80 years and older. Patients with haematological malignancies (leukaemia, lymphoma, and myeloma) had a more severe COVID-19 trajectory compared with patients with solid organ tumours (odds ratio [OR] 1·57, 95% CI 1·15-2·15; p<0·0043). Compared with the rest of the UKCCMP cohort, patients with leukaemia showed a significantly increased case-fatality rate (2·25, 1·13-4·57; p=0·023). After correction for age and sex, patients with haematological malignancies who had recent chemotherapy had an increased risk of death during COVID-19-associated hospital admission (OR 2·09, 95% CI 1·09-4·08; p=0·028). INTERPRETATION: Patients with cancer with different tumour types have differing susceptibility to SARS-CoV-2 infection and COVID-19 phenotypes. We generated individualised risk tables for patients with cancer, considering age, sex, and tumour subtype. Our results could be useful to assist physicians in informed risk-benefit discussions to explain COVID-19 risk and enable an evidenced-based approach to national social isolation policies. FUNDING: University of Birmingham and University of Oxford

In Search of Chineseness: The Choice of the Ho Sisters

Identifying the family of Sir Robert Ho Tung (1862-1956) as a distinct entrepreneurial family in Hong Kong, this paper explores how the articulations of Chineseness by his two daughters - Irene and Florence -are related both to British colonial ideology and the emergence of different Chinese nationalistic discourses. Separated by an age difference of 11 years, Irene (1904-2007) and Florence (1915- ) received similar educations in their early years, but the two sisters followed very different life paths. Irene became an outstanding career woman and married late. Florence was married at the age of 17 and confined her role to the family setting. The life-stories of Florence Yeo and Irene Cheng question the meaning of Chineseness--both from the perspective of the Eurasians themselves and from the various perspectives found within the Chinese community. The social experience of the Ho daughters explains to what extent Eurasians were accepted by other Chinese as truly Chinese, and to what extent they were considered foreign. Why did the Chinese part of the Ho family traditions appear to be the more dominant influence in shaping their members' personal identities? This paper suggests that the problem of identification reveals a local pattern that is often ideological and political. This paper relates the question of social identity to the notion of modernity and nationalism through a review of liminality in the socio-political and cultural identification in the Hong Kong community. Firstly, it investigates the social drives and the cultural-historical currents which induced Eurasian women to identify themselves as Chinese. Secondly, it examines to what extent the Chineseness revealed in this social identity was characterised by modern ideology and the particular socio-historical landscape

A cascade of irx1a and irx2a controls shh expression during retinogenesis

In animal retina, hedgehog expression drives waves of neurogenesis, but genetic programs that control its expression during retinal neurogenesis are poorly elucidated. We have previously reported that irx1a is required for propagation of the sonic hedgehog (shh) expression waves in developing zebrafish retina. Here, we found that irx2a is expressed in the developing retina and that knockdown of irx2a results in a retinal phenotype strikingly similar to that of irx1a morphants. The expression of irx2a in retina ganglion cells was shown to be irx1a- and ath5-dependent suggesting that irx1a and ath5 are transcriptional regulators of irx2a. Furthermore, irx2a expression could rescue impaired propagation of shh waves in irx1a morphants. Together, these observations suggest that Irx2 functions downstream of irx1a to control shh expression in the retina. We proposed a novel transcriptional cascade of ath5-irx1a-irx2a in the regulation of hedgehog waves during vertebrate retinal development. © 2010 Wiley-Liss, Inc.link_to_OA_fulltex

VCAM-1-targeted MRI Enables Detection of Brain Micrometastases from Different Primary Tumors

Purpose: A major issue for the effective treatment of brain metastasis is the late stage of diagnosis with existing clinical tools. The aim of this study was to evaluate the potential of vascular cell adhesion molecule 1 (VCAM-1)-targeted MRI for early detection of brain micrometastases in mouse models across multiple primary tumor types. Experimental Design: Xenograft models of brain micrometastasis for human breast carcinoma (MDA231Br-GFP), lung adenocarcinoma (SEBTA-001), and melanoma (H1_DL2) were established via intracardiac injection in mice. Animals (n = 5–6/group) were injected intravenously with VCAM-1–targeted microparticles of iron oxide (VCAM-MPIO) and, subsequently, underwent T2*-weighted MRI. Control groups of naïve mice injected with VCAM-MPIO and tumor-bearing mice injected with nontargeting IgG-MPIO were included. Results: All models showed disseminated micrometastases in the brain, together with endothelial VCAM-1 upregulation across the time course. T2*-weighted MRI of all tumor-bearing mice injected with VCAM-MPIO showed significantly more signal hypointensities (P < 0.001; two-sided) than control cohorts, despite a lack of blood–brain barrier (BBB) impairment. Specific MPIO binding to VCAM-1–positive tumor-associated vessels was confirmed histologically. VCAM-1 expression was demonstrated in human brain metastasis samples, across all three primary tumor types. Conclusions: VCAM-1–targeted MRI enables the detection of brain micrometastases from the three primary tumor types known to cause the majority of clinical cases. These findings represent an important step forward in the development of a broadly applicable and clinically relevant imaging technique for early diagnosis of brain metastasis, with significant implications for improved patient survival

VCAM-1 targeted magnetic resonance imaging enables detection of brain micrometastases from different primary tumours

Purpose: A major issue for the effective treatment of brain metastasis is the late stage of diagnosis with existing clinical tools. The aim of this study was to evaluate the potential of vascular cell adhesion molecule-1 (VCAM-1) targeted magnetic resonance imaging (MRI) for early detection of brain micrometastases in mouse models across multiple primary tumour types. Experimental Design: Xenograft models of brain micrometastasis for human breast carcinoma (MDA231Br-GFP), lung adenocarcinoma (SEBTA-001) and melanoma (H1_DL2) were established via intracardiac injection in mice. Animals (n=5-6/group) were injected intravenously with VCAM-1 targeted microparticles of iron oxide (VCAM-MPIO) and, subsequently, underwent T2*-weighted MRI. Control groups of naïve mice injected with VCAM-MPIO and tumour-bearing mice injected with non-targeting IgG-MPIO were included. Results: All models showed disseminated micrometastases in the brain, together with endothelial VCAM-1 upregulation across the time-course. T2*-weighted MRI of all tumour-bearing mice injected with VCAM-MPIO showed significantly more signal hypointensities (p&lt;0.001; two-sided) than control cohorts, despite a lack of blood-brain barrier impairment. Specific MPIO binding to VCAM-1 positive tumour-associated vessels was confirmed histologically. VCAM-1 expression was demonstrated in human brain metastasis samples, across all three primary tumour types. Conclusions: VCAM-1-targeted MRI enables detection of brain micrometastases from the three primary tumour types known to cause the majority of clinical cases. These findings represent an important step forward in the development of a broadly applicable and clinically relevant imaging technique for early diagnosis of brain metastasis, with significant implications for improved patient survival

V6 PRIMROSE: A national trainee collaborative-led, multicentre prospective audit on the care of breast cancer patients with central nervous system disease in the UK

PRIMROSE A national trainee collaborative-led, multicentre prospective audit on the care of breast cancer patients with central nervous system disease in the UK Mark P Lythgoe1, Vinton WT Cheng2, Hayley S McKenzie3, Amy Kwan4, Apostolos Konstantis5, Ruichong Ma6, Pei J Teo7, Amanda Fitzpatrick8, Laura Woodhouse9 & Carlo Palmieri10 on behalf of the BNTRC† and PRIMROSE study group 1Imperial College Healthcare NHS Trust, London, 2Leeds Cancer Centre, Leeds, 3University of Southampton, Southampton, 4University of Sheffield, Sheffield, 5The Princess Alexandra NHS Trust, Harlow 6Oxford University Hospitals NHS Trust, Oxford, 7Worcestershire Acute Hospitals NHS Trust, Worcester, 8Institute of Cancer Research, London, 9The Christie NHS Foundation Trust, Manchester, 10University of Liverpool, Liverpool, †British Neurosurgical Trainee Research Collaborative Introduction Breast cancer is the commonest cancer in the UK and the 4th leading cause of cancer-related death. Breast cancer brain metastases (BCBM) are a poor prognostic indicator and associated with very poor survival and only a minority of patients survive >1 year despite oncological treatment. The rising prevalence of patients with BCBM represent an increasing unmet healthcare need. However, in the UK there is a paucity of data about prevalence, survival and management. Guidance on managing brain metastases is improving, however it is unclear how this has been applied in the context of BCBM and whether recommended standards are uniformly applied across the UK Methods PRIMROSE is a trainee collaborative-led initiative to estimate BCBM prevalence, assess current practice (comparing national/international standards) and determine long term outcomes/sequalae. Anonymised data is being pooled via secure REDCap database collating demographics, clinico-pathological information, prior treatment, BCBM treatment and other key variables. All UK hospitals can register, with recruitment driven by trainees via the UK Breast Cancer Trainees Research Collaborative Group and British Neurosurgical Trainee Research Collaborative. Senior oversight will be provided by a local consultant oncologist or neurosurgeon. Results Opened in Jan 2020, 180 datasets have been entered, despite significant disrupted due to COVID-19 from Feburary to May). Over 25 sites are open/in the process of joining. Trainee networks have been established in all regions of the UK with the exception of Yorkshire and The Humber, East of England and North East England. Promotion of the network has occurred at significant oncology conferences (e.g. San Antonio Breast Meeting, and National Cancer Research Institute). We plan to expand to all major UK neurosurgical and oncology centres by December 2020, with data collection completed by December 2021. Conclusions PRIMROSE demonstrates the utility of trainee collaborative networks in rapidly organising large-scale multicentre data collection to understand care of patients at a national level. Such information will be important for identifying current pactice and act as a benchmark for improving local service delivery for patients with BCBM

Leptin-mediated modulation of steroidogenic gene expression in hypoxic zebrafish embryos: Implications for the disruption of sex steroids

Hypoxia can impair reproduction of fishes through the disruption of sex steroids. Here, using zebrafish (Danio rerio) embryos, we investigated (i) whether hypoxia can directly affect steroidogenesis independent of pituitary regulation via modulation of steroidogenic gene expression, and (ii) the role of leptin in hypoxia-induced disruption of steroidogenesis. Exposure of fertilized zebrafish embryos to hypoxia (1.0 mg O 2 L -1) from 0-72 h postfertilization (hpf), a developmental window when steroidogenesis is unregulated by pituitary influence, resulted in the up-regulation of cyp11a, cyp17, and 3β-hsd and the down-regulation of cyp19a. Similar gene expression patterns were observed for embryos exposed to 10 mM cobalt chloride (CoCl 2, a chemical inducer of hypoxia-inducible factor 1, HIF-1), suggesting a regulatory role of HIF-1 in steroidogenesis. Testosterone (T) and estradiol (E2) concentrations in hypoxic embryos were greater and lesser, respectively, relative to the normoxic control, thus leading to an increased T/E2 ratio. Expression of the leptin-a gene (zlep-a) was up-regulated upon both hypoxia and CoCl 2 treatments. Functional assays suggested that under hypoxia, elevated zlep-a expression might activate cyp11a and 3β-hsd and inhibit cyp19a. Overall, this study indicates that hypoxia, possibly via HIF-1-induced leptin expression, modulates sex steroid synthesis by acting directly on steroidogenic gene expression. © 2012 American Chemical Society.link_to_subscribed_fulltex