ABSTRACT
A PENTEC analysis of published investigations of central nervous system (CNS) subsequent neoplasms (CNS-SN) in childhood cancer survivors who received radiation therapy (RT) to the brain was performed to estimate the effect of RT dose and gender on the risk of CNS-SN following RT. Through the PENTEC initiative, a systematic literature review was performed to identify published data on CNS-SN after prior cranial RT in childhood cancer survivors. Using the Covidence platform 2,156 studies were screened for potential inclusion. The incidences of CNS-SNs, RT dose, age, gender, primary cancer diagnosis, and latent time from primary diagnosis to CNS-SN were extracted, to assess the factors influencing risk for subsequent meningiomas or subsequent malignant CNS tumors (e.g., gliomas). The odds ratio for CNS-SNs in different dose intervals were calculated and excess odds ratio (EOR) per Gy of developing subsequent meningiomas or malignant tumors was estimated using inverse-variance weighted linear regression to model the risk for CNS-SN versus dose. Forty studies of independent patient cohorts provided information on 736 subsequent malignant tumors with average median latency 10.3 years, and 32 studies provided information on 1,035 subsequent meningiomas with average median latency 20.5 years. Dose-response was derived from 6 studies of 248 subsequent malignant tumors and 7 studies of 557 subsequent meningiomas. The pooled EOR/Gy was 0.45 (95% CI: 0.25, 0.66) for meningiomas and 0.16 (95% CI: 0.11, 0.20) for malignant CNS tumors. The average cumulative incidence of developing a meningioma or malignant CNS tumor at 15 years of follow-up was 2.4% (range, 1.2-6.3%) or 0.9% (range, 0.4-1.8%), respectively. Females had a higher risk of meningioma than males (OR=1.5, 95% CI: 1.2, 1.8;6 studies;50,346 patients) whereas no gender difference was seen in risk of malignant tumors (OR=0.9, 95% CI: 0.7, 1.2;4 studies;32,446 patients). This PENTEC systematic review shows a significant radiation dose-response relationship and higher risk among females for meningioma, akin to the general population, and a highly significant but somewhat less steep relationship for subsequent malignant tumors with no effect of gender. Further evaluation of the effect of age and chemotherapy in relation to dose and gender is necessary to elucidate the risk of CNS-SN after RT. [ FROM AUTHOR] Copyright of International Journal of Radiation Oncology, Biology, Physics is the property of Pergamon Press - An Imprint of Elsevier Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)
ABSTRACT
Background: Further knowledge on adaptive immunity to SARS-CoV-2 (CoV-2) in children is needed in order to define possible immunization strategies and reconsider pandemic control measures. We analyzed anti-CoV-2 antibodies (Ab) and their neutralizing activity (PRNT), alongside antigen (Ag) specific cellular response, in relation to virus load in nasopharyngeal swabs. Methods: We analysed 42 CoV-2 patients at 7 days after symptoms onset. CoV-2 viral load (VL) was measured by RT-PCR and digital droplet PCR on longitudinal samples of nasopharyngeal swabs (NP). Virus infectivity (FFU) was tested by virus focus forming assay. CoV-2 antibodies were investigated by Diasorin (CoV-2 Ab) and neutralization assay (PRNT). CoV-2-specific CD4-CD40L+ T-cells and Spike specific B-cells were analysed by flow cytometry. Plasma proteomic profiling was measured by 2 Olink panels. We calculated the area under the curve (AUC) of the viral load from NP collected every 48 hours up to undetectable VL. Mann-Whitney was used to compare means in individuals with neutralizing activity (PRNT+) or not (PRNT-);linear regression was used to evaluate the associations between virus load and infectivity over time. Principal component analysis (PCA) was used to analyse proteomic data. Results: Higher VL was found in seronegative patients expressed in terms of both CoV-2 Ab (p=0.003) and PRNT (p=0.0007). Similarly, lower FFU was associated with higher CoV-2 Ab (p=0.003;rho=-0.67) and PRNT (p=0.023;rho=-0.46). Further, the AUC of the viral load in NP showed an inverse correlation with CoV-2 Ab (p=0.031;rho=-0.54). Development of humoral response was associated with the presence of CoV-2 specific IgD-CD27+ B cells, with a higher frequency of CoV-2 specific B cells found in seropositive compared to seronegative (p=0.001). Besides, individuals developing neutralizing Ab had higher frequency CD4-CD40L+ T-cells compared to PRNT- (p=0.03). The plasma proteome confirmed the association between cellular and humoral CoV-2 immunity, with PRNT+ showing higher viral signal transduction molecules (SLAMF1, CD244, CLEC4G). Conclusion: This work provides a virological and immunological characterization of SARS-CoV-2 infected children presenting a differential Abmediated neutralizing activity. It demonstrates that children with neutralizing antibodies present reduced viral load, faster virus clearance and lower in vitro infectivity. These data provide information that can drive vaccination endpoints and quarantine measures policies.
ABSTRACT
Background: SARS-CoV-2 (CoV-2) infected children often range from being paucysymptomatic to fully asymptomatic. The impact of this population on the epidemics due to their ability to transmit the virus and achieve protective immunity has been poorly defined. We explored CoV-2 infectivity potential and anti-CoV-2 cellular (CD8, NK and B) and humoral response in symptomatic (SY) and asymptomatic (AS) CoV-2 infected children, screened for a family member resulted infected. Methods: CoV-2 viral load was measured by RT-PCR and digital droplet PCR (ddPCR) on longitudinal samples of nasopharyngeal swabs in 9 AS and 33 SY (samples were paired according to symptoms'onset for SY and first family contact for AS). Virus infectivity was tested by Virus focus forming assay (FFA). CoV-2 antibodies were investigated by Diasorin (CoV-2 Ab) and Ab-mediated neutralization activity (PRNT) at diagnosis, (samples collected >5 days from symptoms onset in SY, or from first family contact in AS were excluded from this timepoint), and in the convalescent phase (CP) (10-14 days after infection). Cellular response was analyzed by flow cytometry: 1) Ag-specific B cells, by a S1+S2 CoV2-R-PE probe;2) Ag-specific CD8+T cells by ICAM+;3) natural-killer (NK) phenotype. Mann-Whitney was used for comparison;linear regression was used to evaluate the associations between virus load and infectivity. Results: AS showed lower viral load (p=0.004) and faster virus clearance (p=0.0002) compared to SY. Virus infectivity was associated with ddPCR (rho=0.66;p=0.002). ASY and SY showed similar levels of CoV-2 Ab and PRNT, at both diagnosis and at follow up. During the CP, the proportion of CoV-2 Ab negative was 33,3% for both groups and PRNT was negative in 16,6% and 15,7% of AS and SY respectively. Anti-CoV-2 cellular immunity was comparable between ASY and SY. Indeed Ag-specific B cells and CD8 T cells were detectable despite symptomatology and no major differences were found between the groups. Total NK frequency was similar between the groups, while a regulatory NK subset (CD56bright NK cells) was higher in AS compared to SY (p=0.01). Conclusion: These data show that AS have a lower infectivity potential compared to SY suggesting that mitigated restrictive measures or alternative screening may be considered for this population. In addition, these patients showed an intact ability to produce humoral and cellular CoV-2 specific responses hence contributing to achieve herd immunity as much as SY.