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1.  Transplantation Outcomes for Severe Combined Immunodeficiency, 2000–2009 
The New England journal of medicine  2014;371(5):434-446.
The Primary Immune Deficiency Treatment Consortium was formed to analyze the results of hematopoietic-cell transplantation in children with severe combined immunodeficiency (SCID) and other primary immunodeficiencies. Factors associated with a good transplantation outcome need to be identified in order to design safer and more effective curative therapy, particularly for children with SCID diagnosed at birth.
We collected data retrospectively from 240 infants with SCID who had received transplants at 25 centers during a 10-year period (2000 through 2009).
Survival at 5 years, freedom from immunoglobulin substitution, and CD3+ T-cell and IgA recovery were more likely among recipients of grafts from matched sibling donors than among recipients of grafts from alternative donors. However, the survival rate was high regardless of donor type among infants who received transplants at 3.5 months of age or younger (94%) and among older infants without prior infection (90%) or with infection that had resolved (82%). Among actively infected infants without a matched sibling donor, survival was best among recipients of haploidentical T-cell–depleted transplants in the absence of any pretransplantation conditioning. Among survivors, reduced-intensity or myeloablative pre-transplantation conditioning was associated with an increased likelihood of a CD3+ T-cell count of more than 1000 per cubic millimeter, freedom from immunoglobulin substitution, and IgA recovery but did not significantly affect CD4+ T-cell recovery or recovery of phytohemagglutinin-induced T-cell proliferation. The genetic subtype of SCID affected the quality of CD3+ T-cell recovery but not survival.
Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection. All available graft sources are expected to lead to excellent survival among asymptomatic infants. (Funded by the National Institute of Allergy and Infectious Diseases and others.)
PMCID: PMC4183064  PMID: 25075835
2.  Newborn Screening for SCID and T Cell Lymphopenia in California: Results of the First Two Years 
Assay of T cell receptor excision circles (TRECs) in dried blood spots (DBS) obtained at birth permits population-based newborn screening (NBS) for severe combined immunodeficiency (SCID).
To report the first 2 years of TREC NBS in California.
Since August 2010, California has conducted SCID newborn screening. A high-throughput TREC qPCR assay using DNA isolated from routine DBS was developed. Samples with initial low TREC values had repeat DNA isolation with qPCR for TRECs and a genomic control, and immunophenotyping was performed within the screening program for infants with incomplete or abnormal results. Outcomes were tracked.
Of 993,724 infants screened, 50 (1/19,900; 0.005%) had significant T cell lymphopenia. Fifteen (1/66,250) required hematopoietic cell or thymus transplantation or gene therapy; these infants had typical SCID (11), leaky SCID or Omenn syndrome (3), or complete DiGeorge syndrome (1). Survival to date in this group is 93%. Other T lymphopenic infants had variant SCID or combined immunodeficiency (6), genetic syndromes associated with T cell impairment (12), secondary T lymphopenia (9) or preterm birth (8). All T lymphopenic infants avoided live vaccines and received appropriate interventions to prevent infections. TREC test specificity was excellent: only 0.08% of infants required a second test and 0.016% required lymphocyte phenotyping by flow cytometry.
TREC NBS in California has achieved early diagnosis of SCID and other conditions with T lymphopenia, facilitating management and optimizing outcomes. Furthermore, NBS has revealed the incidence, causes and follow-up of T lymphopenia in a large, diverse population.
PMCID: PMC3759317  PMID: 23810098
Severe combined immunodeficiency (SCID); newborn screening (NBS); T cell receptor excision circle (TREC); T cell lymphopenia (TCL); DiGeorge syndrome
3.  Autologous Tumor Lysate-pulsed Dendritic Cell Immunotherapy for Pediatric Patients with Newly Diagnosed or Recurrent High-grade Gliomas 
Anticancer research  2013;33(5):2047-2056.
Immunotherapy has the potential to improve clinical outcomes with little toxicity for pediatric patients with brain tumors. We conducted a pilot feasibility study of tumor lysate-pulsed dendritic cell (DC) vaccination in pediatric patients (1 to 18 years old) with newly diagnosed or recurrent high-grade glioma (HGG). A total of nine DC vaccine doses, each containing 1×106 cells per dose were administered to three out of the seven originally enrolled patients. Toxicities were limited to mild side-effects, except in one case of elevated alkaline phosphatase, which resolved without clinical consequences. Two patients with primary lesions amongst the three vaccinated were alive at the time of writing, both without evidence of disease. Pre- and post-vaccination tumor samples from a patient with an anaplastic oligoastrocytoma that recurred failed to demonstrate immune cell infiltration by immunohistochemistry. Peripheral cytokine levels were evaluated in one patient following DC vaccination and demonstrated some changes in relation to vaccination. DC vaccine is tolerable and feasible with some limitations for pediatric patients with HGG. Dendritic cell based immunotherapy may provide some clinical benefit in pediatric patients with glioma, especially for patients with minimal residual disease, but further investigation of this modality is required.
PMCID: PMC4018463  PMID: 23645755
Pediatric neuro-oncology; high grade glioma; dendritic cell vaccine; immunotherapy
4.  Clinical Outcome in Pediatric Glial and Embryonal Brain Tumors Correlates With In Vitro Multi-Passageable Neurosphere Formation 
Pediatric blood & cancer  2010;55(4):644-651.
Cultured brain tumors can form neurospheres harboring tumorigenic cells with self renewal and differentiation capacities. Renewable neurosphere formation has clinical predictive value in adult malignant gliomas, yet its prognostic role for pediatric brain tumors is unknown.
Established neurosphere conditions were used for culturing samples from glial, embryonal and mixed glioneuronal tumors from 56 pediatric patients. Potential associations between neurosphere formation and clinical outcome were analyzed retrospectively.
Thirty-seven percent of all samples formed renewable neurospheres. Analysis of available clinical outcome data from 51 patients demonstrated significantly increased hazard ratios (HR) for both disease progression (HR=9.9, P < 0.001) and death (HR=16.6, P < 0.01) in the neurosphere forming group. Furthermore, neurosphere formation correlated with adverse progression free survival (PFS) in glial and embryonal tumors, but not in mixed glioneuronal tumors. Overall survival (OS) was significantly worse for neurosphere-forming patients with embryonal tumors, as a group and amongst the subgroup with medulloblastoma, but not in the glial group. Multivariate analysis showed that neurosphere formation was associated with diminished PFS and OS independent of age, gender, or treatment. Neurosphere formation was an independent predictor of diminished PFS of glial tumors after adjusting for grade. Multivariate analysis, adjusting for both Ki67 staining and neurosphere formation, demonstrated that neurosphere formation remained predictive of progression whereas Ki67 did not.
Neurosphere formation is more predictive of pediatric brain tumor progression than semi-quantitative Ki67 staining. Pediatric brain tumor derived neurospheres may provide a predictive model for preclinical explorations.
PMCID: PMC4017922  PMID: 20589659
brain; brain tumors; cancer biology; CNS tumors; neuro-oncology; outcomes research; tumors
5.  Quantitative detection of PfHRP2 in saliva of malaria patients in the Philippines 
Malaria Journal  2012;11:175.
Malaria is a global health priority with a heavy burden of fatality and morbidity. Improvements in field diagnostics are needed to support the agenda for malaria elimination. Saliva has shown significant potential for use in non-invasive diagnostics, but the development of off-the-shelf saliva diagnostic kits requires best practices for sample preparation and quantitative insight on the availability of biomarkers and the dynamics of immunoassay in saliva. This pilot study measured the levels of the PfHRP2 in patient saliva to inform the development of salivary diagnostic tests for malaria.
Matched samples of blood and saliva were collected between January and May, 2011 from eight patients at Palawan Baptist Hospital in Roxas, Palawan, Philippines. Parasite density was determined from thick-film blood smears. Concentrations of PfHRP2 in saliva of malaria-positive patients were measured using a custom chemiluminescent ELISA in microtitre plates. Sixteen negative-control patients were enrolled at UCLA. A substantive difference between this protocol and previous related studies was that saliva samples were stabilized with protease inhibitors.
Of the eight patients with microscopically confirmed P. falciparum malaria, seven tested positive for PfHRP2 in the blood using rapid diagnostic test kits, and all tested positive for PfHRP2 in saliva. All negative-control samples tested negative for salivary PfHRP2. On a binary-decision basis, the ELISA agreed with microscopy with 100 % sensitivity and 100 % specificity. Salivary levels of PfHRP2 ranged from 17 to 1,167 pg/mL in the malaria-positive group.
Saliva is a promising diagnostic fluid for malaria when protein degradation and matrix effects are mitigated. Systematic quantitation of other malaria biomarkers in saliva would identify those with the best clinical relevance and suitability for off-the-shelf diagnostic kits.
PMCID: PMC3422183  PMID: 22631858
6.  High-Dose Chemotherapy with Autologous Hematopoietic Stem-Cell Rescue for Pediatric Brain Tumor Patients: A Single Institution Experience from UCLA 
Journal of Transplantation  2011;2011:740673.
Background. Dose-dependent response makes certain pediatric brain tumors appropriate targets for high-dose chemotherapy with autologous hematopoietic stem-cell rescue (HDCT-AHSCR). Methods. The clinical outcomes and toxicities were analyzed retrospectively for 18 consecutive patients ≤19 y/o treated with HDCT-AHSCR at UCLA (1999–2009). Results. Patients' median age was 2.3 years. Fourteen had primary and 4 recurrent tumors: 12 neural/embryonal (7 medulloblastomas, 4 primitive neuroectodermal tumors, and a pineoblastoma), 3 glial/mixed, and 3 germ cell tumors. Eight patients had initial gross-total and seven subtotal resections. HDCT mostly consisted of carboplatin and/or thiotepa ± etoposide (n = 16). Nine patients underwent a single AHSCR and nine ≥3 tandems. Three-year progression-free and overall survival probabilities were 60.5% ± 16 and 69.3% ± 11.5. Ten patients with pre-AHSCR complete remissions were alive/disease-free, whereas 5 of 8 with measurable disease were deceased (median followup: 2.3 yrs). Nine of 13 survivors avoided radiation. Single AHSCR regimens had greater toxicity than ≥3 AHSCR (P < .01). Conclusion. HDCT-AHSCR has a definitive, though limited role for selected pediatric brain tumors with poor prognosis and pretransplant complete/partial remissions.
PMCID: PMC3087896  PMID: 21559259
7.  Transplantation for Congenital Bone Marrow Failure Syndromes 
Bone Marrow Research  2010;2011:849387.
Congenital bone marrow failure syndromes (BMFSs) are relatively rare disorders characterized by aberrant development in one or more hematopoietic lineages. Genetic alterations have now been identified in most of these disorders although the exact role of the molecular defects has yet to be elucidated. Most of these diseases are successfully managed with supportive care, however, treatment refractoriness and disease progression—often involving malignant transformation—may necessitate curative treatment with hematopoietic stem cell transplantation. Due to the underlying molecular defects, the outcome of transplantation for BMFS may be dramatically different than those associated with transplantation for more common diseases, including leukemia. Given recent improvements in survival and molecular diagnosis of bone marrow failure syndrome patients presenting at adult ages without physical stigmata, it is important for both pediatric and adult hematologists to be aware of the possible diagnosis of BMF syndromes and the unique approaches required in treating such patients.
PMCID: PMC3199936  PMID: 22046571

Results 1-7 (7)