Abstract Diffuse large B cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma. Currently, approximately 40% of DLBCL patients treated with standard of care therapies, which include a combination of immunotherapy (rituximab; R) and chemotherapy (CHOP), will have disease that is refractory or will relapse. Tumor-associated macrophages can phagocytose opsonised DLBCL tumor cells and are therefore centrally important in determining therapeutic outcomes for patients treated with R-CHOP. Recent data from our lab and from others suggests that the modulation of sphingosine-1-phosphate (S1P) signalling may therapeutically benefit some patients with this tumor. Here, we have investigated the effects of S1P on macrophage functions relevant to DLBCL. We show that S1P signalling through the major receptor, S1P-receptor 1 (S1PR1), suppresses the phagocytosis of rituximab-opsonized DLBCL cells. However, we also show that chemotherapy potently induces monocyte recruitment to DLBCL tumors in vivo and that S1PR1 is a primary mediator of monocyte migration both in vitro and in vivo. According to our data, S1PR1 signalling inhibitors could improve the therapeutic efficacy of rituximab-based therapies for DLBCL patients. However, our data suggests that these drugs should be given only after chemotherapy and before rituximab administration so as to maximize the S1P-mediated recruitment of therapeutic macrophages to the tumor site. Citation Format: Tracey Adams Perry, Lauren Lupino, Katerina Vrzalikova, Navta Masand, Pamela R. Kearns, Paul G. Murray. Sphingosine-1-phosphate receptor 1 signalling modulates macrophage recruitment to diffuse large B cell lymphomas and the phagocytosis of rituximab-opsonized tumor cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2657.
The COVID-19 pandemic poses an unprecedented health crisis in all socio-economic regions across the globe.While the pandemic has had a profound impact on access to and delivery of health care by all services, it has been particularly disruptive for the care of patients with lifethreatening noncommunicable diseases (NCDs) such as the treatment of children and young people with cancer.The reduction in child mortality from preventable causes over the last 50 years has seen childhood cancer emerge as a major unmet health care need.Whilst survival rates of 85% have been achieved in high income countries, this has not yet been translated into similar outcomes for children with cancer in resource-limited settings where survival averages 30%.Launched in 2018, by the World Health Organization (WHO), the Global Initiative for Childhood Cancer (GICC) is a pivotal effort by the international community to achieve at least 60% survival for children with cancer by 2030.The WHO GICC is already making an impact in many countries but the disruption of cancer care during the COVID-19 pandemic threatens to set back this global effort to improve the outcome for children with cancer, wherever they may live.As representatives of the global community committed to fostering the goals of the GICC, we applaud the WHO response to the COVID-19 pandemic, in particular we support the WHO's call to ensure the needs of patients with life threatening NCDs including cancer are not compromised during the pandemic.Here, as collaborative partners in the GICC, we highlight specific areas of focus that need to be addressed to ensure the immediate care of children and adolescents with cancer is not disrupted during the pandemic; and measures to sustain the development of cancer care so the long-term goals of the GICC are not lost during this global health crisis.
To describe postexposure prophylaxis (PEP) against varicella zoster virus (VZV) in children being treated for malignancy in the UK and Ireland: the population at risk, frequency of exposure, clinical practice and attitudes among healthcare providers.
Design
An observational study in three parts: (1) a retrospective survey of serostatus at diagnosis of malignancy, (2) collation of varicella zoster immune globulin (VZIG) dispensing data over a 3-year period and (3) an online survey of paediatric oncologists9 clinical practice and beliefs in relation to VZV disease and its prevention.
Setting
UK and Ireland.
Participants
Children diagnosed with malignancy in 2009 (serostatus survey) or receiving VZIG between April 2006 and March 2009 (VZIG dispensing study). Paediatric oncologists and haematologists working in tertiary paediatric oncology centres and related shared care units in the UK and Ireland (physician survey).
Results
Of 1500 children diagnosed with malignancy each year, at least 24% are VZV seronegative. Few centres make efforts to prevent household exposure by vaccinating VZV-susceptible family members. Exposures to VZV result in the administration of PEP to approximately 250 children with cancer annually: half receive an intramuscular injection of VZIG while the remainder receive a course of oral aciclovir. The choice of PEP is made by doctors. There is no consensus among paediatric oncologists as to which is the better option, reflecting the lack of a secure evidence base.
Conclusions
A randomised controlled trial to compare the effectiveness and acceptability of VZIG and aciclovir as PEP against varicella is both desirable and feasible.
Expression of three major classes of glutathione S‐transferases (GSTs), i.e. α, μ and π class, P‐glycoprotein (P‐gp) and multidrug resistance‐associated protein (MRP) were studied in childhood acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML) and normal peripheral blood lymphocytes by flow cytometry. In vitro cytotoxicity of 4‐hydroxy‐ifosfamide (IFOS), daunorubicin (DNR) and prednisolone (PRED) was assessed by the MTT assay. Expression of α, μ and π class GST did not significantly differ between leukaemic cells from 100 initial and 14 unrelated relapse ALL patients (GSTα P =0.26; GSTμ P = 0.09; GSTπ P = 0.13). The expression of GSTα (1.4‐fold, P = 0.0004), GSTπ (1.3‐fold, P = 0.001) and to a lesser extent also GSTμ (1.1‐fold, P = 0.03) was higher in ALL compared with normal peripheral blood lymphocytes. Expression of GSTμ and GSTπ was significantly higher in 18 AML compared with 100 ALL patients at initial diagnosis (respectively 1.3‐fold, P = 0.0005 and 2‐fold, P < 0.0001). In contrast, GSTα was median 2‐fold lower expressed in the AML samples ( P < 0.0001). Expression levels of α, μ and π class GSTs were not related to the degree of resistance to IFOS, DNR and PRED nor to immunophenotype, white blood cell count or age at presentation of childhood ALL. One exception was a remarkably low expression of GSTα in IFOS‐sensitive samples compared with a heterogenous expression in IFOS‐resistant samples ( P = 0.02). Expression of GSTπ, but not of GSTα or GSTμ, weakly correlated with the expression of MRP (Rs 0.36, P = 0.002, n = 74) but not with P‐gp. However, a high expression of both GSTπ and MRP was not associated with in vitro resistance to IFOS, DNR or PRED. The present data suggest that expression of GSTs is not linked to the degree of resistance to IFOS, DNR and PRED or clinical risk factors in childhood ALL. Whether the high expression of GSTμ and GSTπ in AML cells contributes to the relative resistance to IFOS, DNR and PRED compared with ALL samples ( P 0.0001) warrants further study.
The COVID-19 pandemic is one of the most serious global challenges to delivering affordable and equitable treatment to children with cancer we have witnessed in the last few decades. This Special Report aims to summarise general principles for continuing multi-disciplinary care during the SARS-CoV-2 (COVID-19) pandemic. With contributions from the leadership of the International Society for Paediatric Oncology (SIOP), Children's Oncology Group (COG), St Jude Global programme and Childhood Cancer International, we have sought to provide a framework for healthcare teams caring for children with cancer during the pandemic. We anticipate the burden will fall particularly heavily on children, their families and cancer services in low- and middle- income countries. Therefore, we have brought together the relevant clinical leads from SIOP- Europe, COG and SIOP-PODC (Pediatric Oncology in Developing Countries) to focus on the six most curable cancers that are part of the WHO Global Initiative in Childhood Cancer. We provide some practical advice for adapting diagnostic and treatment protocols for children with cancer during the pandemic, the measures taken to contain it (e.g. extreme social distancing) and how to prepare for the anticipated recovery period.
Summary Clofarabine is a second‐generation purine nucleoside analogue, which has shown promising activity in relapsed and refractory paediatric acute lymphoblastic leukaemia (ALL). This report summarizes the early United Kingdom experience of clofarabine for the treatment of paediatric ALL in 23 patients, outside of the context of a clinical trial. Our results demonstrated that clofarabine‐based chemotherapy regimes were effective and well‐tolerated in this heavily pre‐treated group, with an overall response rate of 67% when used in combination regimes. Responses were seen in both B and T cell disease and in patients with adverse cytogenetics.
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