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Dyskeratosis congenita is a disease of impaired tissue maintenance downstream of telomere dysfunction. Characteristically, patients present with the clinical triad of nail dystrophy, oral leukoplakia, and skin pigmentation defects, but the disease involves degenerative changes in multiple organs. Mutations in telomere-binding proteins such as TINF2 (TRF1-interacting nuclear factor 2) or in telomerase, the enzyme that counteracts age related telomere shortening, are causative in dyskeratosis congenita. We present a patient who presented with severe hypoxemia at age 13. The patient had a history of myelodysplastic syndrome treated with bone marrow transplant at the age of 5. At age 18 she was hospitalized for an acute pneumonia progressing to respiratory failure, developed renal failure and ultimately, she and her family opted to withdraw support as she was not a candidate for a lung transplant. Sequencing of the patient's TINF2 locus revealed a heterozygous mutation (c.844C > T, Arg282Cys) which has previously been reported in a subset of dyskeratosis congenita patients. Tissue sections from multiple organs showed degenerative changes including disorganized bone remodeling, diffuse alveolar damage and small vessel proliferation in the lung, and hyperkeratosis with hyperpigmentation of the skin. Autopsy samples revealed a bimodal distribution of telomere length, with telomeres from donor hematopoietic tissues being an age-appropriate length and those from patient tissues showing pathogenic shortening, with the shortest telomeres in lung, liver, and kidney. We report for the first time a survey of degenerative changes and telomere lengths in multiple organs in a patient with dyskeratosis congenita.

OBJECTIVES: Newborn screening for severe combined immunodeficiency (SCID) was instituted in California in 2010. In the ensuing 6.5 years, 3 252 156 infants in the state had DNA from dried blood spots assayed for T-cell receptor excision circles (TRECs). Abnormal TREC results were followed-up with liquid blood testing for T-cell abnormalities. We report the performance of the SCID screening program and the outcomes of infants who were identified. METHODS: Data that were reviewed and analyzed included demographics, nursery summaries, TREC and lymphocyte flow-cytometry values, and available follow-up, including clinical and genetic diagnoses, treatments, and outcomes. RESULTS: Infants with clinically significant T-cell lymphopenia (TCL) were successfully identified at a rate of 1 in 15 300 births. Of these, 50 cases of SCID, or 1 in 65 000 births (95% confidence interval 1 in 51 000–1 in 90 000) were found. Prompt treatment led to 94% survival. Infants with non-SCID TCL were also identified, diagnosed and managed, including 4 with complete DiGeorge syndrome who received thymus transplants. Although no cases of typical SCID are known to have been missed, 2 infants with delayed-onset leaky SCID had normal neonatal TREC screens but came to clinical attention at 7 and 23 months of age. CONCLUSIONS: Population-based TREC testing, although unable to detect immune defects in which T cells are present at birth, is effective for identifying SCID and clinically important TCL with high sensitivity and specificity. The experience in California supports the rapid, widespread adoption of SCID newborn screening.

We mapped the cytokine response to hematopoietic stem cell transplantation (HSCT) by assaying 51 cytokines and chemokines each week for 100 days in 51 children receiving allogeneic (n = 44) or autologous HSCT (n = 7). Assay values were reported as mean fluorescence intensity (MFI). Log transformation converted MFI to clinically relevant measures (ie, pg/mL). We searched for potential markers of transplant complications by using mixed treatment by subject analysis of variance. Global cytokine secretion in HSCT recipients was significantly lower than in concurrent control patients (n = 11). Coincident with the nadir in WBC count, the concentration of many cytokines declined further by the second and third week. All analytes (except monokine induced by gamma interferon [MIG]) subsequently rebounded by week 4 (coincident with engraftment and recovery of WBC count) but often still remained well below control levels. Concurrent with the collective nadir of multiple cytokines, monocyte chemoattractant protein 1 (MCP-1), growth-regulated oncogene alpha (GRO-a), and leptin surged during weeks 2 to 4. High levels of leptin persisted throughout the 100 post-transplant days. Also during weeks 2 to 4, hepatocyte growth factor (HGF) and IL-6 surged in children with complications but not in those without complications. The peak in HGF was more pronounced in veno-occlusive disease (VOD). HGF and IL-6 secretion rose at least 2 weeks before the clinical diagnosis of VOD or graft-versus-host disease (GVHD). From week 4 onward in all groups, the MFI of the cytokine resistin increased to 5 to 15 times above concurrent control. HGF has now emerged in 3 or more biomarker discovery efforts for GVHD (and in our population for VOD as well). HGF (with or without IL-6) should be investigated as a potential predictive biomarker of VOD or GVHD. Alternatively, the hyperinflammatory "signature" provided by a multicytokine assay may be predictive.

The purpose of this study is to evaluate the survival of pediatric patients undergoing autologous bone marrow transplantation (auBMT) for relapsed or refractory Hodgkin lymphoma (rrHL) and to identify factors that might contribute to their outcome. We reviewed the records and clinical course of 89 consecutive rrHL patients ≤ 21 years old who underwent auBMT at Stanford Hospitals and Clinics and the Lucile Packard Children's Hospital, Stanford between 1989 and 2012. We investigated, by multiple analyses, patient, disease, and treatment characteristics associated with outcome. Endpoints were 5-year overall and event-free survival. Our findings include that cyclophosphamide, carmustine, and etoposide (CBV) as a conditioning regimen for auBMT is effective for most patients ≤ 21 years old with rrHL (5-year overall survival, 71%). Transplantation after the year 2001 was associated with significantly improved overall survival compared with our earlier experience (80% compared with 65%). Patients with multiply relapsed disease or with disease not responsive to initial therapy fared less well compared with those with response to initial therapy or after first relapse. Administration of post-auBMT consolidative radiotherapy (cRT) also appears to contribute to improved survival. We are able to conclude that high-dose chemotherapy with CBV followed by auBMT is effective for the treatment of rrHL in children and adolescents. Survival for patients who undergo auBMT for rrHL has improved significantly. This improvement may be because of patient selection and improvements in utilization of radiotherapy rather than improvements in chemotherapy. Further investigation is needed to describe the role of auBMT across the entire spectrum of patients with rrHL and to identify the most appropriate preparative regimen with or without cRT therapy in the treatment of rrHL in young patients.

Objective: The goal of this retrospective study was to analyze the incidence and outcome of invasive fungal disease in a large cohort of pediatric patients after allogeneic stem cell transplant at Stanford University from 2005-2012 treated with modern antifungal prophylaxis. In comparison with prior studies, this study is unique in including prophylaxis with voriconazole and dosing information on antifungal prophylaxis, as well as the prevalence of transaminitis in this population and relation to antifungal prophylaxis. Patients and Methods: Data was analyzed for 152 pediatric patients between the ages of 0-21 years who received allogeneic stem cell transplantation for any diagnosis at Stanford University between 2005 and 2012. Both related and unrelated donors were used, including bone marrow, cord blood, and peripheral blood stem cell sources. All patients received antifungal prophylaxis, although the specific medication used and dosing was at the discretion of the treating physician. Patients were categorized as having proven, probable, or possible fungal disease based on the EORTC/MSG classification. Rates of invasive fungal disease and level of transaminitis were analyzed by type of antifungal prophylaxis as well as dosing in milligrams per kilogram. Results: The overall mortality in this cohort was 29%. Of those, 57% of the deaths were due to relapse, 20% due to infectious complications (3 fungal, 3 sepsis, 2 viral, 1 toxoplasmosis), 16% due to organ failure, and 7% due to GVHD. Twenty five patients were diagnosed with fungal disease prior to transplant and these patients were excluded from this analysis. In the 127 patients with no prior history of fungal disease, 60% were on fluconazole prophylaxis, 32% were on voriconazole, 7% were on micafungin or caspofungin and 2% were on amphotericin. Nine of these patients subsequently developed proven or probable invasive fungal disease. Patients who developed invasive fungal disease had a significantly higher mortality rate (67%) compared with those who did not (25%). However, these two groups did not differ on type of antifungal prophylaxis, underlying diagnosis, donor source, product used or age. There was no difference in level of transaminitis based on type of antifungal prophylaxis (voriconazole vs. fluconazole) or dose used in milligrams per kilogram. Conclusions: In those patients who develop invasive fungal disease after transplant, mortality has decreased over time but remains substantial at 67%. This data did not support the use of one antifungal over another for prophylaxis of invasive fungal disease in pediatric patients. Voriconazole and fluconazole caused similar levels of transaminitis. 237

s / Biol Blood Marrow Transplant 19 (2013) S279eS312 S312 lymphocyte infusion (DLI) was superior to that of patients without prophylactic DLI (38.0% vs 11.8%,P1⁄40.001). Sex, age, conditioning regimen (dosage of ATG), number of HLA mismatched or the number of stem cells infused were not the factors affecting OS, DFS and relapse. Multivariate analysis showed that the significant factors associated with higher OS were the use of prophylactic DLI, the disease type of AML and occurrence of chronic GVHD. Conclusions: Haploidentical allo-HSCT can cure a significant proportion of refractory/relapsed acute leukemia patients. Prophylactic DLI can reduce relapse and increase survival; for patients with refractory/relapsed ALL, other post-transplant therapy should be explored.