Yoga, Meditation and Mindfulness in pediatric oncology − A review of literature

Purpose: Children and adolescents undergoing treatment for cancer are exposed to a wide variety of stressors both physical and mental. Not only adults but also children and adolescents increasingly practice yoga in a health-promoting manner and to cope with stressful situations. Methods: A review of literature was conducted to present the current outcomes on yoga, meditation and mindfulness for children and adolescents who are affected by an oncological disease. Results: Eight studies were identified that examined yoga treatment for children and adolescents with oncological diseases. Three studies were found on mindfulness in pediatric oncology. The studies summarized here suggest that yoga and mindfulness could help to improve quality of life, reduce fatigue, improve activity and fitness levels, improve sleep quality, increase appetite and decrease anxiety in various stages of the disease and its treatment. The reviewed studies showed that yoga and mindfulness-based interventions for children and adolescents with oncological illnesses are feasible in different settings and are well received. Conclusions: The results of the studies suggest that yoga and mindfulness may help to support children and adolescents during and after oncological treatment. Based on the current body of evidence it is not possible to draw conclusions about the efficacy of yoga and mindfulness-based interventions in pediatric oncology patients. Research must meet this challenge to develop suitable designs to further and better investigate the effects of yoga and mindfulness in children and adolescents with oncological diseases

Model simulation of seasonal growth of Fucus vesiculosus in its benthic community

Numerical models are a suitable tool to quantify impacts of predicted climate change on complex ecosystems but are rarely used to study effects on benthic macroalgal communities. Fucus vesiculosus L. is a habitat-forming macroalga in the Baltic Sea and alarming shifts from the perennial Fucus community to annual filamentous algae are reported. We developed a box model able to simulate the seasonal growth of the Baltic Fucus-grazer-epiphyte system. This required the implementation of two state variables for Fucus biomass in units of carbon (C) and nitrogen (N). Model equations describe relevant physiological and ecological processes, such as storage of C and N assimilates by Fucus, shading effects of epiphytes or grazing by herbivores on both Fucus and epiphytes, but with species-specific rates and preferences. Parametrizations of the model equations and required initial conditions were based on measured parameters and process rates in the near-natural Kiel Outdoor Benthocosm (KOB) experiments during the Biological Impacts of Ocean Acidification project. To validate the model, we compared simulation results with observations in the KOB experiment that lasted from April 2013 until March 2014 under ambient and climate-change scenarios, that is, increased atmospheric temperature and partial pressure of carbon dioxide. The model reproduced the magnitude and seasonal cycles of Fucus growth and other processes in the KOBs over 1 yr under different scenarios. Now having established the Fucus model, it will be possible to better highlight the actual threat of climate change to the Fucus community in the shallow nearshore waters of the Baltic Sea

Sensitivity to cdk1-inhibition is modulated by p53 status in preclinical models of embryonal tumors

Dysregulation of the cell cycle and cyclin-dependent kinases (cdks) is a hallmark of cancer cells. Intervention with cdk function is currently evaluated as a therapeutic option in many cancer types including neuroblastoma (NB), a common solid tumor of childhood. Re-analyses of mRNA profiling data from primary NB revealed that high level mRNA expression of both cdk1 and its corresponding cyclin, CCNB1, were significantly associated with worse patient outcome independent of MYCN amplification, a strong indicator of adverse NB prognosis. Cdk1 as well as CCNB1 expression were readily detectable in all embryonal tumor cell lines investigated. Pharmacological inhibition or siRNA-mediated knockdown of cdk1/CCNB1 induced proliferation arrest independent of MYCN status in NB cells. Sensitivity to cdk1 inhibition was modulated by TP53, which was demonstrated using isogenic cells with wild-type TP53 expressing either dominant-negative p53 or a short hairpin RNA directed against TP53. Apoptosis induced by cdk1 inhibition was dependent on caspase activation and was concomitant with upregulation of transcriptional targets of TP53. Our results confirm an essential role for the cdk1/CCNB1 complex in tumor cell survival. As relapsing embryonal tumors often present with p53 pathway alterations, these findings have potential implications for therapy approaches targeting cdks

Evaluation of an Integrative Care Program in Pediatric Oncology

Purpose: This article discusses the results of an evaluation of the one-year implementation period of an integrative care program at a pediatric oncology ward, which consists of integrative care treatments offered three times a week to the patients. The guiding questions are how the model was implemented, which factors have to be considered for successful implementation, and which factors showed to be obstacles during implementation. Methods: A mixed-methods approach was applied for data saturation. Qualitative data consist of participant observations and informal conversations during the implementation phase. All observational records were filed in the data program MAXQDA. For the quantitative data, all integrative care treatments applied on the intensive care unit were documented and subsequently filed in an Excel sheet. Both sets of data were analyzed for the evaluation. Results: Four main thematic clusters influenced the implementation: (1) the organization and structure of the intensive care unit; (2) mood and atmosphere; (3) feedback on treatment; and (4) time and experience. All factors are interlinked and cannot be looked at independently. Results of the quantitative data show that the most frequent used treatments were those with calming and relaxing effects, followed by treatments for stomachache, nausea, and obstipation. Conclusions: The implementation of an integrative model of care is a process that demands thorough understanding of the complex setting of the ward, ongoing adaptation to the structures and organization of the ward, and the integration of factors like feedback, time, atmosphere, and the mood of parents, patients, and nurses

Synergistic Antitumour Properties of viscumTT in Alveolar Rhabdomyosarcoma

Aqueous mistletoe extracts from the European mistletoe (Viscum album) contain mainly mistletoe lectins and viscotoxins as cytotoxic compounds. Lipophilic triterpene acids, which do not occur in conventional mistletoe preparations, were solubilised with β-cyclodextrins. The combination of an aqueous extract (viscum) and a triterpene-containing extract (TT) recreated a whole mistletoe extract (viscumTT). These extracts were tested on rhabdomyosarcoma in vitro, ex vivo, and in vivo with regard to anticancer effects. Viscum and viscumTT inhibited cell proliferation and induced apoptosis effectively in a dose- dependent manner in vitro and ex vivo, whereas TT showed only moderate inhibitory effects. viscumTT proved to be more effective than the single extracts and displayed a synergistic effect in vitro and a stronger effect in vivo. viscumTT induced apoptosis via the extrinsic and intrinsic pathways, evidenced by the loss of mitochondrial membrane potential and activation of CASP8 and CASP9. CASP10 inhibitor inhibited apoptosis effectively, emphasising the importance of CASP10 in viscumTT-induced apoptosis. Additionally, viscumTT changed the ratio of apoptosis-associated proteins by downregulation of antiapoptotic proteins such as XIAP and BIRC5, thus shifting the balance towards apoptosis. viscumTT effectively reduced tumour volume in patient- derived xenografts in vivo and may be considered a promising substance for rhabdomyosarcoma therapy

Sinusoidal Obstruction Syndrome Following Myeloablative Therapy and Tranexamic Acid Treatment for Hemorrhage in Two Patients with Neuroblastoma

Adverse thromboembolic events following administration of the anti-fibrinolytic agent tranexamic acid (TA), used to prevent/treat excessive blood loss, are rare. We present the clinical course of two young patients (22 and 56 months) receiving busulfan/melphalan (Bu/Mel) high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HSCT) to treat high-risk neuroblastoma, who developed hepatic sinusoidal obstruction syndrome (SOS) within 48 h after systemic TA treatment for a hemodynamically relevant hemorrhage. Defibrotide treatment resolved hepatic SOS, but the short time between TA administration and SOS onset suggests a causal association

BET bromodomain protein inhibition is a therapeutic option for medulloblastoma

Medulloblastoma is the most common malignant brain tumor of childhood, and represents a significant clinical challenge in pediatric oncology, since overall survival currently remains under 70%. Patients with tumors overexpressing MYC or harboring a MYC oncogene amplification have an extremely poor prognosis. Pharmacologically inhibiting MYC expression may, thus, have clinical utility given its pathogenetic role in medulloblastoma. Recent studies using the selective small molecule BET inhibitor, JQ1, have identified BET bromodomain proteins, especially BRD4, as epigenetic regulatory factors for MYC and its targets. Targeting MYC expression by BET inhibition resulted in antitumoral effects in various cancers. Our aim here was to evaluate the efficacy of JQ1 against preclinical models for high-risk MYC-driven medulloblastoma. Treatment of medulloblastoma cell lines with JQ1 significantly reduced cell proliferation and preferentially induced apoptosis in cells expressing high levels of MYC. JQ1 treatment of medulloblastoma cell lines downregulated MYC expression and resulted in a transcriptional deregulation of MYC targets, and also significantly altered expression of genes involved in cell cycle progression and p53 signalling. JQ1 treatment prolonged the survival of mice harboring medulloblastoma xenografts and reduced the tumor burden in these mice. Our preclinical data provide evidence to pursue testing BET inhibitors, such as JQ1, as molecular targeted therapeutic options for patients with high-risk medulloblastomas overexpressing MYC or harboring MYC amplifications

Donor selection in a pediatric stem cell transplantation cohort using PIRCHE and HLA‐DPB1 typing

Background: New strategies to optimize donor selection for hematopoietic stem cell transplantation (HSCT) have mainly been evaluated in adults, but the disease spectrum requiring HSCT differs significantly in children and has consequences for the risk of complications, such as graft-versus-host disease (GvHD). Procedures: Here we evaluated whether HLA-DPB1 and Predicted Indirectly ReCognizable HLA-Epitope (PIRCHE) matching can improve donor selection and minimize risks specific for a pediatric cohort undergoing HSCT in Berlin between 2014 and 2016. Results: The percentage of HLA-DPB1–mismatched HSCT in the pediatric cohort was in line with the general distribution among matched unrelated donor HSCT. Nonpermissive HLA-DPB1 mismatches were not associated with a higher incidence of GvHD, but the incidence of relapse was higher in patients undergoing HSCT from HLA-DPB1–matched transplantations. High PIRCHE-I scores were associated with a significantly higher risk for developing GvHD in patients undergoing HSCT from nine of ten matched unrelated donors. This finding persisted after including HLA-DPB1 into the PIRCHE analysis. Conclusions: Implementing PIRCHE typing in the donor selection process for HSCT in children could particularly benefit children with nonmalignant diseases and support further validation of PIRCHE-based donor selection in a larger number of children treated at different sites

Targeting tachykinin receptors in neuroblastoma

Neuroblastoma is the most common extracranial tumor in children. Despite aggressive multimodal treatment, high-risk neuroblastoma remains a clinical challenge with survival rates below 50%. Adding targeted drugs to first-line therapy regimens is a promising approach to improve survival in these patients. TACR1 activation by substance P has been reported to be mitogenic in cancer cell lines. Tachykinin receptor (TACR1) antagonists are approved for clinical use as an antiemetic remedy since 2003. Tachykinin receptor inhibition has recently been shown to effectively reduce growth of several tumor types. Here, we report that neuroblastoma cell lines express TACR1, and that targeting TACR1 activity significantly reduced cell viability and induced apoptosis in neuroblastoma cell lines. Gene expression profiling revealed that TACR1 inhibition repressed E2F2 and induced TP53 signaling. Treating mice harboring established neuroblastoma xenograft tumors with Aprepitant also significantly reduced tumor burden. Thus, we provide evidence that the targeted inhibition of tachykinin receptor signaling shows therapeutic efficacy in preclinical models for high-risk neuroblastoma

CD171- and GD2-specific CAR-T cells potently target retinoblastoma cells in preclinical in vitro testing

BACKGROUND: Chimeric antigen receptor (CAR)-based T cell therapy is in early clinical trials to target the neuroectodermal tumor, neuroblastoma. No preclinical or clinical efficacy data are available for retinoblastoma to date. Whereas unilateral intraocular retinoblastoma is cured by enucleation of the eye, infiltration of the optic nerve indicates potential diffuse scattering and tumor spread leading to a major therapeutic challenge. CAR-T cell therapy could improve the currently limited therapeutic strategies for metastasized retinoblastoma by simultaneously killing both primary tumor and metastasizing malignant cells and by reducing chemotherapy-related late effects. METHODS: CD171 and GD2 expression was flow cytometrically analyzed in 11 retinoblastoma cell lines. CD171 expression and T cell infiltration (CD3+) was immunohistochemically assessed in retrospectively collected primary retinoblastomas. The efficacy of CAR-T cells targeting the CD171 and GD2 tumor-associated antigens was preclinically tested against three antigen-expressing retinoblastoma cell lines. CAR-T cell activation and exhaustion were assessed by cytokine release assays and flow cytometric detection of cell surface markers, and killing ability was assessed in cytotoxic assays. CAR constructs harboring different extracellular spacer lengths (short/long) and intracellular co-stimulatory domains (CD28/4-1BB) were compared to select the most potent constructs. RESULTS: All retinoblastoma cell lines investigated expressed CD171 and GD2. CD171 was expressed in 15/30 primary retinoblastomas. Retinoblastoma cell encounter strongly activated both CD171-specific and GD2-specific CAR-T cells. Targeting either CD171 or GD2 effectively killed all retinoblastoma cell lines examined. Similar activation and killing ability for either target was achieved by all CAR constructs irrespective of the length of the extracellular spacers and the co-stimulatory domain. Cell lines differentially lost tumor antigen expression upon CAR-T cell encounter, with CD171 being completely lost by all tested cell lines and GD2 further down-regulated in cell lines expressing low GD2 levels before CAR-T cell challenge. Alternating the CAR-T cell target in sequential challenges enhanced retinoblastoma cell killing. CONCLUSION: Both CD171 and GD2 are effective targets on human retinoblastoma cell lines, and CAR-T cell therapy is highly effective against retinoblastoma in vitro. Targeting of two different antigens by sequential CAR-T cell applications enhanced tumor cell killing and preempted tumor antigen loss in preclinical testing