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Open Forum Infectious Diseases ; 8(SUPPL 1):S337, 2021.
Article in English | EMBASE | ID: covidwho-1746525


Background. COVID-19 infection is usually mild in children. Progression to severe disease with multiple organ systems compromise described as Multi Inflammatory Syndrome in Children (MIS-C) is a rare occurrence believed to be immunologically mediated. Previous reports describe a possible link between children of Latino origin and high incidence of MIS-C in the US. 40% of the total population in Western Massachusetts is of Latino origin. Methods. Retrospective chart review of 30 children admitted to Baystate Medical Center in Springfield, Massachusetts from April 2020-June 2021 meeting Centers for Disease Control and Prevention (CDC) criteria for MIS-C. Demographics, laboratory data, and clinical outcomes including progression to Macrophage Activation Syndrome (MAS) were analyzed. Results. 60% of children were Hispanic. Mean age (9.1 yrs). Range (3m-20 yrs). COVID PCR positive (78%) and COVID Antibody positive (68%). The most common symptom was fever (96.8%) followed by gastrointestinal symptoms (84%). Respiratory symptoms (29%), dermatological manifestations (39%). Most common comorbidity, asthma (19%) followed by obesity (17%). Leukocytosis (47%), lymphopenia (45%), Anemia (55%), thrombocytopenia (20%), high CRP (90%), ferritinemia (57%), acute kidney injury (20%), elevated liver enzymes (53%), 52% children had electrocardiogram (EKG) abnormalities, 34% had abnormal echocardiograms, none displayed coronary artery dilation. Progression to MAS (20%). All patients were treated with intravenous immunoglobulin G, steroids, aspirin, and anakinra (IL1 receptor antagonist) if progression to MAS. All patients survived. Conclusion. In our population, gastrointestinal symptoms were predominant despite a high prevalence of asthma and obesity, previous reports of children with MIS-C describe predominance of respiratory manifestations. We did not encounter any coronary aneurysms during admission. Most children had positive PCR or Antibodies for COVID 19 and showed important abnormalities in multiple cell lines and inflammatory markers. More research is needed to fully understand ethnical risk factors associated with disease severity especially the risk of progression to MAS from MIS-C in children of Latino origin diagnosed with COVID 19 infection.

Annals of Oncology ; 32:S530, 2021.
Article in English | EMBASE | ID: covidwho-1432841


Background: Outcomes in RAS-mutant metastatic colorectal cancer (mCRC) remain poor and patients have limited therapeutic options. Adavosertib is the first small molecule inhibitor of WEE1 kinase. We hypothesised that aberrations in DNA replication seen in mCRC with both RAS and TP53 mutations would sensitise tumours to WEE1 inhibition. Methods: Patients with newly diagnosed mCRC were registered into FOCUS4 and tested for TP53 and RAS mutations. Those with both mutations who were stable or responding after 16 weeks of chemotherapy were randomised 2:1 between Adavosertib or active monitoring (AM). The primary outcome was progression-free-survival (PFS). Results: Between Jul 2017 and Mar 2020 718 patients were registered into FOCUS4;247 (34%) were RAS/TP53-mutant. 69 patients were randomised from 25 UK hospitals (44 to Adavosertib;25 to AM) and recruitment terminated early due to COVID-19 and following DMEC review of efficacy data. Adavosertib was associated with a PFS improvement over AM (median 3.61 vs 1.87 months;HR=0.35[95% CI 0.18-0.68], p=0.0022). In pre-specified subgroup analysis, Adavosertib activity was greater in left-sided tumours HR=0.24 [95% CI 0.11–0.51], versus right-sided HR=1.02 [95% CI 0.41–2.56] (interaction p=0.043). Adavosertib activity was limited to tumours with KRAS12/13 mutations, rather than mutations in extended KRAS or NRAS (interaction p=0.01). Overall survival (OS) was not improved with Adavosertib vs AM (median 14.0 vs 12.8 months;HR=0.92[95%CI 0.44-1.94], p=0.93);however in left-sided tumours, median OS was 14.1 vs 11.3 months (HR=0.37 [95%CI 0.15-0.87]) and 6.5 vs 15.5 months in right-sided (HR=2.15 [95%CI 0.72-6.43], interaction p=0.0047). Adavosertib was well tolerated;grade 3 toxicities were diarrhoea (9%), nausea (5%) and neutropenia (7%). Conclusions: In this phase II randomised trial, Adavosertib improved PFS compared with AM and demonstrates potential as a well-tolerated therapy for RAS/TP53-mutant mCRC. Activity was greater in patients with left-sided tumours, with potential impact on OS. Further testing is required in this sizable population of unmet need. Clinical trial identification: ISRCTN90061546. Legal entity responsible for the study: The authors. Funding: MRC/NIHR, CRUK, AstraZeneca. Disclosure: J. Seligmann: Financial Interests, Personal, Invited Speaker: Pierre Fabre;Financial Interests, Personal, Invited Speaker: Merck Serono;Financial Interests, Personal, Advisory Board: Pierre Fabre;Financial Interests, Personal, Expert Testimony: Roche Diagnostics;Financial Interests, Personal, Invited Speaker: Servier. T. Maughan: Financial Interests, Personal, Advisory Board: AstraZeneca;Financial Interests, Personal, Advisory Board: Pierre Fabre;Financial Interests, Personal, Advisory Board: Pfizer;Financial Interests, Institutional, Funding: AstraZeneca;Financial Interests, Institutional, Funding: Psioxus;Financial Interests, Institutional, Funding: Merck KGAA. All other authors have declared no conflicts of interest.