Impaired sleep affects quality of life in children during maintenance treatment for acute lymphoblastic leukemia: an exploratory study

Contains fulltext : 97021.pdf (publisher's version ) (Open Access)BACKGROUND: With the increase of pediatric cancer survival rates, late effects and quality of life (QoL) have received more attention. Disturbed sleep in pediatric cancer is a common clinical observation, but research on this subject is sparse. In general, sleep problems can lead to significant morbidity and are associated with impaired QoL. Information on sleep is essential to develop interventions to improve QoL. METHODS: Children (2-18 years) with acute lymphoblastic leukemia (ALL) were eligible for this multi-center study. The Children's Sleep Habits Questionnaire (CSHQ), Child Health Questionnaire (CHQ) and Pediatric Quality of Life Inventory 3.0 Acute Cancer Version (PedsQL) were used to assess sleep and QoL halfway through maintenance therapy. Sleep and QoL were measured during and after dexamethasone treatment (on-dex and off-dex). RESULTS: Seventeen children participated (age 6.7 +/- 3.3 years, 44% boys). Children with ALL had more sleep problems and a lower QoL compared to the norm. There were no differences on-dex and off-dex. Pain (r = -0.6; p = 0.029) and worry (r = -0.5; p = 0.034) showed a moderate negative association with sleep. Reduced overall QoL was moderately associated with impaired overall sleep (r = -0.6; p = 0.014) and more problems with sleep anxiety (r = -0.8; p = 0.003), sleep onset delay (r = -0.5; p = 0.037), daytime sleepiness (r = -0.5; p = 0.044) and night wakenings (r = -0.6; p = 0.017). CONCLUSION: QoL is impaired in children during cancer treatment. The results of this study suggest that impaired sleep may be a contributing determinant. Consequently, enhanced counseling and treatment of sleep problems might improve QoL. It is important to conduct more extensive studies to confirm these findings and provide more detailed information on the relationship between sleep and QoL, and on factors affecting sleep in pediatric ALL and in children with cancer in general

Presence of osteoclast-like multinucleated giant cells in the bone and nonostotic lesions of Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a disease that can involve one or multiple organ systems characterized by an accumulation of CD1a+ Langerhans-like cells as well as several other myeloid cell types. The precise origin and role of one of these populations, the multinucleated giant cell (MGC), in this disease remains unknown. This work shows that in three different lesional tissues, bone, skin, and lymph node, the MGCs expressed the characteristic osteoclast markers, tartrate-resistant acid phosphatase and vitronectin receptor, as well as the enzymes cathepsin K and matrix metalloproteinase-9. Although, in bone lesions, the osteoclast-like MGCs were only CD68+, in the nonostotic sites, they coexpressed CD1a. The presence of osteoclast-like MGCs may be explained by the production of osteoclast-inducing cytokines such as receptor activator of nuclear factor κB ligand and macrophage colony-stimulating factor by both the CD1a+ LCH cells and T cells in these lesions. As osteoclast-derived enzymes play a major role in tissue destruction, the osteoclast-like nature of MGCs in all LCH lesions makes them a potential target for the treatment of this disease

Histone deacetylase inhibitors enhance expression of NKG2D ligands in Ewing sarcoma and sensitize for natural killer cell-mediated cytolysis

Background: Ewing sarcoma patients have a poor prognosis despite multimodal therapy. Integration of combination immunotherapeutic strategies into first-/second-line regimens represents promising treatment options, particularly for patients with intrinsic or acquired resistance to conventional therapies. We evaluated the susceptibility of Ewing sarcoma to natural killer cell-based combination immunotherapy, by assessing the capacity of histone deacetylase inhibitors to improve immune recognition and sensitize for natural killer cell cytotoxicity. Methods: Using flow cytometry, ELISA and immunohistochemistry, expression of natural killer cell receptor ligands was assessed in chemotherapy-sensitive/-resistant Ewing sarcoma cell lines, plasma and tumours. Natural killer cell cytotoxicity was evaluated in Chromium release assays. Using ATM/ATR inhibitor caffeine, the contribution of the DNA damage response pathway to histone deacetylase inhibitor-induced ligand expression was assessed. Results: Despite comparable expression of natural killer cell receptor ligands, chemotherapy-resistant Ewing sarcoma exhibited reduced susceptibility to resting natural killer cells. Interleukin-15-activation of natural killer cells overcame this reduced sensitivity. Histone deacetylase inhibitor-pretreatment induced NKG2D-ligand expression in an ATM/ATR-dependent manner and sensitized for NKG2D-dependent cytotoxicity (2/4 cell lines). NKG2D-ligands were expressed in vivo, regardless of chemotherapy-response and disease stage. Soluble NKG2D-ligand plasma concentrations did not differ between patients and controls. Conclusion: Our data provide a rationale for combination immunotherapy involving immune effector and target cell manipulation in first-/second-line treatment regimens for Ewing sarcoma

Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma

Background. Neuroblastoma is a childhood tumor derived from cells of the neural crest, with a widely variable outcome. Differences in the behavior and prognosis of the tumor suggest that neuroblastoma can be divided into several biologic subgroups. We evaluated the most frequent genetic abnormalities in neuroblastoma to determine their prognostic value. Methods. We used Southern blot analysis to study the allelic loss of chromosomes 1p, 4p, 11q, and 14q, the duplication of chromosome 17q, and the amplification of the N-myc oncogene in 89 neuroblastomas. We also determined the nuclear DNA content of the tumor cells. Results. Allelic loss of chromosome 1p, N-myc amplification, and extra copies of chromosome 17q were significantly associated with unfavorable outcomes. In a multivariate analysis, loss of chromosome 1p was the most powerful prognostic factor. It provided strong prognostic information when it was included in multivariate models containing the prognostic factors of age and stage or serum ferritin level and stage. Among the patients with stage I, II, or IVS disease, the mean (±SD) three-year event-free survival was 100 percent in those without allelic loss of chromosome 1p and 34±15 percent in those with such loss; the rates of three- year event-free survival among the patients with stage III and stage IV disease were 53±10 percent and 0 percent, respectively. Conclusions. The loss of chromosome 1p is a strong prognostic factor in patients with neuroblastoma, independently of age and stage. It reliably identifies patients at high risk in stages I, II, and IVS, which are otherwise clinically favorable. More intensive therapy may be considered in these patients. Patients in stages III and IV with allelic loss of chromosome 1p have a very poor outlook, whereas those without such loss are at moderate risk

Modifications to the Cauchy–Born rule: Applications in the deformation of single-walled carbon nanotubes

AbstractThis paper presents a study of the Cauchy–Born (CB) rule as applied to the deformation analysis of single-walled carbon nanotubes (SWNTs) that are modeled as 2-dimensional manifolds. The C–C bond vectors in the SWNT are assumed to deform according to the local deformation gradient as per the CB rule or a modified version thereof. Aspects of the CB rule related to spatial inhomogeneity of the deformation gradient at the atomic scale are investigated in the context of a specific class of extension–twist deformation problems. Analytic expressions are derived for the deformed bond lengths using the standard CB rule as well as modified versions of the standard CB rule. Since the deformation map is conveniently prescribed in this work, it is possible to compare the performance of these deformation rules with the exact solution (i.e. the exact analytic expression for the deformed bond vectors) given directly by the deformation map. This approach provides insights into the CB rule and its possible modifications for use in more complicated deformations where an explicit deformation map is not available. Specifically, it is concluded that in the case of inhomogeneous deformations at the atomic scale for which the CB rule is only approximate (as demonstrated in Section 1 of this paper), the mean value theorem in calculus can be used as a guide to modify the CB rule and construct a more rigorous and accurate atomistic–continuum connection. The deformed bond lengths are used to formulate an enriched continuum hyperelastic strain energy density function based on interatomic potentials (the multi-body Tersoff–Brenner [Tersoff, J., 1988. New empirical approach for the structure and energy of covalent systems. Phys. Rev. B 37, 6991–7000; Brenner, D.W., 1990. Empirical potential for hydrocarbons for use in simulating the chemical vapor deposition of diamond films. Phys. Rev. B 42, 9458–9471] empirical interatomic potential for carbon-carbon bonds is used in this work). The deformation map (and hence the deformation gradient, the bond vectors and the continuum strain energy density) contains certain parameters, some of which are imposed and others determined as a result of energy minimization in the standard variational formulation. Numerical results for kinematic coupling and binding energy per atom are presented in the case of imposed extension and twist deformations on representative chiral, zig-zag and armchair nanotubes using the CB rule and its modifications. These results are compared with the exact solution based on the deformation map which serves as a basis for evaluating the efficacy of these deformation rules. The ideas presented in this paper can also be directly extended to other lattices

Macrophages inhibit human osteosarcoma cell growth after activation with the bacterial cell wall derivative liposomal muramyl tripeptide in combination with interferon-γ

Drug Delivery Technolog

In Situ Detection of HY-Specific T Cells in Acute Graft-versus-Host Disease–Affected Male Skin after Sex-Mismatched Stem Cell Transplantation

HY-specific T cells are presumed to play a role in acute graft-versus-host disease (aGVHD) after female-to-male stem cell transplantation (SCT). However, infiltrates of these T cells in aGVHD-affected tissues have not yet been reported. We evaluated the application of HLA-A2/HY dextramers for the in situ detection of HY-specific T cells in cryopreserved skin biopsy specimens. We applied the HLA-A2/HY dextramers on cryopreserved skin biopsy specimens from seven male HLA-A2+ pediatric patients who underwent stem cell transplantation with confirmed aGVHD involving the skin. The dextramers demonstrated the presence of HY-specific T cells. In skin biopsy specimens of three male recipients of female grafts, 68% to 78% of all skin-infiltrating CD8+ T cells were HY-specific, whereas these cells were absent in biopsy specimens collected from sex-matched patient–donor pairs. Although this study involved a small and heterogeneous patient group, our results strongly support the hypothesis that HY-specific T cells are actively involved in the pathophysiology of aGVHD after sex-mismatched stem cell transplantation