Pediatric multicellular tumor spheroid models illustrate a therapeutic potential by combining BH3 mimetics with Natural Killer (NK) cell-based immunotherapy

The induction of apoptosis is a direct way to eliminate tumor cells and improve cancer therapy. Apoptosis is tightly controlled by the balance of pro- and antiapoptotic Bcl-2 proteins. BH3 mimetics neutralize the antiapoptotic function of Bcl-2 proteins and are highly promising compounds inducing apoptosis in several cancer entities including pediatric malignancies. However, the clinical application of BH3 mimetics in solid tumors is impeded by the frequent resistance to single BH3 mimetics and the anticipated toxicity of high concentrations or combination treatments. One potential avenue to increase the potency of BH3 mimetics is the development of immune cell-based therapies to counteract the intrinsic apoptosis resistance of tumor cells and sensitize them to immune attack. Here, we describe spheroid cultures of pediatric cancer cells that can serve as models for drug testing. In these 3D models, we were able to demonstrate that activated allogeneic Natural Killer (NK) cells migrated into tumor spheroids and displayed cytotoxicity against a wide range of pediatric cancer spheroids, highlighting their potential as anti-tumor effector cells. Next, we investigated whether treatment of tumor spheroids with subtoxic concentrations of BH3 mimetics can increase the cytotoxicity of NK cells. Notably, the cytotoxic effects of NK cells were enhanced by the addition of BH3 mimetics. Treatment with either the Bcl-XL inhibitor A1331852 or the Mcl-1 inhibitor S63845 increased the cytotoxicity of NK cells and reduced spheroid size, while the Bcl-2 inhibitor ABT-199 had no effect on NK cell-mediated killing. Taken together, this is the first study to describe the combination of BH3 mimetics targeting Bcl-XL or Mcl-1 with NK cell-based immunotherapy, highlighting the potential of BH3 mimetics in immunotherapy.

SARS-CoV-2 in pediatric cancer: a systematic review

The outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019 in Wuhan challenges pediatric oncologists in an unexpected way. We provide a comprehensive overview, which systematically summarizes and grades evidence (QoE) on SARS-CoV-2 infections in pediatric cancer patients at 1.5 years of pandemic. A systematic literature search in PubMed combined with an additional exploratory literature review in other international databases was conducted to identify studies on children (aged < 18 years) with a malignant disease and COVID-19 infections. In total, 45 reports on 1003 pediatric cancer patients with SARS-CoV-2 infections were identified out of 1397 reports analyzed. The clinical course of COVID-19 was reported mild or moderate in 358 patients (41.7%), whereas 11.1% of patients showed severe COVID-19. In 12.7% of patients, chemotherapy was postponed, whereas 19% of patients with different underlying malignancies received chemotherapy during SARS-CoV-2 infection. Twenty-five patients with SARS-CoV-2 infections died, potentially related to COVID-19.Conclusion: Despite a favorable COVID-19 outcome in most pediatric cancer patients, the morbidity is reported higher than in children without comorbidities. However, no severe COVID-19 complications were associated to the continuation of chemotherapy in some cohort studies and reports on two patients. Therefore, the risk of cancer progress or relapse due to interruption of chemotherapy has carefully to be weighed against the risk of severe COVID-19 disease with potentially fatal outcome. What is Known:• Most of pediatric patients with malignant diseases show an asymptomatic, mild or moderate clinical course of SARS-CoV-2 infection. • Current need for a basis for decision-making, whether to stop or interrupt cancer treatment in a patient infected with SARS-CoV-2, and when to continue chemotherapy. What is New:• Review results comprising over 1000 pediatric COVID-19 cancer patients confirm mild courses of SARS-CoV-2 infection in most patients but also show the attributable mortality is at least 10 times higher compared to reports on hospitalized children without comorbidities.• Review identifies that chemotherapy was continued despite SARS-CoV-2 positivity in 18% of patients with individual chemotherapy modification according to the clinical course of SARS-CoV-2 infection and existing comorbidities. On this basis, no severe COVID-19 complications were associated to the continuation of chemotherapy in several cohort studies and two case reports.

Collaborative Legacy Building to Alleviate Emotional Pain and Suffering in Pediatric Cancer Patients: A Case Review

Childhood cancer patients experience emotional hardship associated with their life-threatening diagnoses. Interdisciplinary team members working in pediatric cancer care can help alleviate physical pain and psychological suffering of children by facilitating collaborative legacy-building activities with patients and families. The contents of this article aim to support legacy building as a medium for emotional healing prior to the end of life. The authors use a case review to contextualize legacy-building projects and provide a comprehensive overview of methods and considerations for these initiatives.

A Dynamic Approach for Early Risk Prediction of Gram-Negative Bloodstream Infection and Systemic Inflammatory Response Syndrome in Febrile Pediatric Hemato-Oncology Patients

The aim of this paper was to evaluate the usefulness of C-Reactive Protein (CRP), Procalcitonin (PCT) and Interleukine 6 (IL6) biomarkers in predicting the existence of Gram negative bloodstream infections (Gr-BSI) or the development of Systemic Inflammatory Response Syndrome (SIRS) during the first 24 hours of fever in pediatric cancer patients. The present study included a total of 103 consecutive fever episodes in 44 hemato-oncological pediatric patients, from whom samples for biomarkers CRP, PCT and IL6 were taken upon initial evaluation and then between 12 and 24 hours after.An IL6 value at the first evaluation (IL6-1) higher than 164 pg/ml and an increase in CRP higher than 291% between the first and subsequent samples (CRP-2vs1) showed a statistically significant OR of 26.03 and 19.62, respectively, in multivariate analysis.Conclusion: IL6-1 and CRP-2vs1 showed a strong, independent correlation with Gr-BSI and SIRS episodes and, therefore, could be used as reliable predictors of these kinds of severe episodes. The approach taken in our study, using biomarker variations over time as a variable, has shown itself to be an improvement in the predictive model.