Psychological quality of life (QOL), health-related QOL (HRQOL), and life satisfaction outcomes and their associated risk factors are reviewed for the large cohort of survivors and siblings in the Childhood Cancer Survivor Study (CCSS). This review includes previously published manuscripts that used CCSS data focused on psychological outcome measures, including the Brief Symptom Inventory (BSI-18), the Medical Outcomes Survey Short Form-36 (SF-36), the Cantril Ladder of Life, and other self-report questionnaires. Comparisons and contrasts are made between siblings and survivors, and to normative data when available, in light of demographic/health information and abstracted data from the medical record. These studies demonstrate that a significant proportion of survivors report more symptoms of global distress and poorer physical, but not emotional, domains of HRQOL. Other than brain tumor survivors, most survivors report both good present and expected future life satisfaction. Risk factors for psychological distress and poor HRQOL are female sex, lower educational attainment, unmarried status, annual household income less than $20,000, unemployment, lack of health insurance, presence of a major medical condition, and treatment with cranial radiation and/or surgery. Cranial irradiation impacted neurocognitive outcomes, especially in brain tumor survivors. Psychological distress also predicted poor health behaviors, including smoking, alcohol use, fatigue, and altered sleep. Psychological distress and pain predicted use of complementary and alternative medicine. Overall, most survivors are psychologically healthy and report satisfaction with their lives. However, certain groups of childhood cancer survivors are at high risk for psychological distress, neurocognitive dysfunction, and poor HRQOL, especially in physical domains. These findings suggest targeting interventions for groups at highest risk for adverse outcomes and examining the positive growth that remains despite the trauma of childhood cancer.

In the original version of Figure 2B, two of the patient identifiers were incorrectly noted. OS-11 and OS-12 were listed twice. The second instances should have been labeled as CID-11 and CID-12, respectively. The correct figure panel is below.The authors regret the error.

Wiskott Aldrich syndrome (WAS) is caused by mutations in the WAS IntroductionWiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency caused by mutations of the WAS gene that is widely expressed within hematopoietic cells. 1 The clinical phenotype of WAS is characterized by congenital thrombocytopenia, combined immunodeficiency, and eczema. 1 The WAS protein (WASp) includes several functional domains that couple signal transduction to reorganization of the actin cytoskeleton. As a result, WASp has significant influence on processes such as cell adhesion, migration, assembly/turnover of cell surface receptors, and immunologic synapse formation. 1,2 Several studies in patients with WAS and in Was knock-out (WKO) mice have shown that WASp plays a critical role in the function of T and natural killer lymphocytes and dendritic cells. 1,3 However, the importance of WASp in B-cell development and function is less clearly defined. In vitro studies have shown that WASp-deficient B cells display defective actin polymerization on activation, 4 and impaired migration in response to CXCL13 5 ; however, calcium mobilization and proliferation after B-cell receptor ligation were found to be normal or only slightly reduced. 3 Studies in heterozygous Was ϩ/Ϫ mice have found progressive in vivo selection for WASp-expressing cells in T, B, and natural killer lineages. 6 Within the B-cell lineage, such selective advantage was especially prominent in marginal zone (MZ) B cells. 2,6 However, the in vivo effect of selective deficiency of WASp expression within a single lineage has not been analyzed so far and is of critical importance to understand WAS pathophysiology. Recently, with the use of a chimeric BM transplantation reconstitution model, Becker-Herman et al have provided evidence that lack of WASp expression in B lymphocytes causes immune dysregulation and may lead to fatal autoimmunity. 7 However, mixed chimerism in non-B lineages, irradiation-induced load of The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. 2819BLOOD, 22 MARCH 2012 ⅐ VOLUME 119, NUMBER 12For personal use only. on May 9, 2018. by guest www.bloodjournal.org From apoptotic bodies, and homeostatic B-cell proliferation may also have contributed to autoimmunity in that model.We describe here the generation of mice in which the Was locus has been floxed by homologous recombination. By crossing these mice to mb1-Cre knock-in mice, 8 which express the Cre recombinase under control of the CD79a promoter, the Was locus is selectively and efficiently deleted in B cells only, allowing analysis of the effect of B cell-restricted deficiency of WASp in vivo. Methods MiceAll mice were bred on a C57BL/6 background. WKO mice have been described. 3 Mb1-Cre mice 8 were a generous gift from Dr Michael Reth (Max Planck Institute of Immunobiology, ...

• Hematopoietic cell transplantation results in long-term survival.• Primary graft failure is very high and the predominant cause of death.We report the international experience in outcomes after related and unrelated hematopoietic transplantation for infantile osteopetrosis in 193 patients. Thirty-four percent of transplants used grafts from HLA-matched siblings, 13% from HLA-mismatched relatives, 12% from HLA-matched, and 41% from HLA-mismatched unrelated donors. The median age at transplantation was 12 months. Busulfan and cyclophosphamide was the most common conditioning regimen. Long-term survival was higher after HLA-matched sibling compared to alternative donor transplantation. There were no differences in survival after HLAmismatched related, HLA-matched unrelated, or mismatched unrelated donor transplantation. The 5-and 10-year probabilities of survival were 62% and 62% after HLA-matched sibling and 42% and 39% after alternative donor transplantation (P 5 .01 and P 5 .002, respectively). Graft failure was the most common cause of death, accounting for 50% of deaths after HLA-matched sibling and 43% of deaths after alternative donor transplantation. The day-28 incidence of neutrophil recovery was 66% after HLA-matched sibling and 61% after alternative donor transplantation (P 5 .49). The median age of surviving patients is 7 years. Of evaluable surviving patients, 70% are visually impaired; 10% have impaired hearing and gross motor delay. Nevertheless, 65% reported performance scores of 90 or 100, and in 17%, a score of 80 at last contact. Most survivors >5 years are attending mainstream or specialized schools. Rates of veno-occlusive disease and interstitial pneumonitis were high at 20%. Though allogeneic transplantation results in long-term survival with acceptable social function, strategies to lower graft failure and hepatic and pulmonary toxicity are urgently needed. (Blood. 2015;126(2):270-276)

Wiskott–Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency disorder characterized by the triad of eczema, thrombocytopenia, and severe and often recurrent infections. Despite the rarity of this disorder, our understanding of the molecular and cellular pathogenesis of WAS has continued to increase. Advances in the use of diagnostic tools, the provision of supportive care, and improvements in allogeneic hematopoietic stem cell transplantation have significantly reduced the morbidity and mortality associated with this disorder. Exciting advancements in the care of patients with WAS have also occurred, including the successful application of autologous gene-modified hematopoietic stem cell transplantation.

Recombination Activating Genes 1 and 2 (RAG1 and RAG2) play a critical role in T and B cell development by initiating the recombination process that controls expression of T cell receptor (TCR) and immunoglobulin genes. Mutations in the RAG1 and RAG2 genes in humans cause a broad spectrum of phenotypes, including severe combined immune deficiency (SCID) with lack of T and B cells, Omenn syndrome, leaky SCID, and combined immune deficiency with granulomas or autoimmunity (CID-G/AI). Using next generation sequencing, we analyzed the T and B cell receptor (TCR, BCR) repertoire in 12 patients with RAG mutations presenting with Omenn syndrome (n=5), leaky SCID (n=3), or CID-G/AI (n=4). Restriction of repertoire diversity skewed usage of Variable (V), Diversity (D), and Joining (J) segment genes, and abnormalities of CDR3 length distribution were progressively more prominent in patients with a more severe phenotype. Skewed usage of V,D and J segment genes was present also within unique sequences, indicating a primary restriction of repertoire. Patients with Omenn syndrome had a high proportion of class-switched immunoglobulin heavy chain transcripts and increased somatic hypermutation rate, suggesting in vivo activation of these B cells. These data provide a framework for better understanding the phenotypic heterogeneity of RAG deficiency.

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Objective To identify risk factors for adverse psychological outcomes among adult siblings of long-term survivors of childhood cancer. Methods Cross-sectional, self-report data from 3,083 adult siblings (mean age 29 years, range 18-56 years) of 5+ year survivors of childhood cancer were analyzed to assess psychological outcomes as measured by the Brief Symptom Inventory-18 (BSI-18). Sociodemographic and health data, reported by both the siblings and their matched cancer survivors were explored as risk factors for adverse sibling psychological outcomes through multivariable logistic regression. Results Self-reported symptoms of psychological distress, as measured by the global severity index of the BSI-18, were reported by 3.8% of the sibling sample. Less than 1.5% of siblings reported elevated scores on two or more of the subscales of the BSI-18. Risk factors for sibling depression included having a survivor brother (OR 2.22, 95% CI 1.42-3.55), and having a survivor with impaired general health (OR 2.15, 95% CI 1.18-3.78). Siblings who were younger than the survivor reported increased global psychological distress (OR 1.81, 95% CI 1.05-3.12), as did siblings of survivors reporting global psychological distress (OR 2.32, 95% CI 1.08-4.59). Siblings of sarcoma survivors reported more somatization than did siblings of leukemia survivors (OR 2.07, 95% CI 1.05-3.98). Conclusions These findings suggest that siblings of long-term childhood cancer survivors are psychologically healthy in general. There are, however, small subgroups of siblings at risk for long-term psychological impairment who may benefit from preventive risk-reduction strategies during childhood while their sibling with cancer is undergoing treatment.