Outcomes of hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by combined immunodeficiency, eczema, microthrombocytopenia, autoimmunity, and lymphoid malignancies. Gene therapy (GT) to modify autologous CD34+ cells is an emerging alternative treatment with advantages over standard allogeneic hematopoietic stem cell transplantation for patients who lack well-matched donors, avoiding graft-versus-host-disease. We report the outcomes of a phase 1/2 clinical trial in which 5 patients with severe WAS underwent GT using a self-inactivating lentiviral vector expressing the human WAS complementary DNA under the control of a 1.6-kB fragment of the autologous promoter after busulfan and fludarabine conditioning. All patients were alive and well with sustained multilineage vector gene marking (median follow-up: 7.6 years). Clinical improvement of eczema, infections, and bleeding diathesis was universal. Immune function was consistently improved despite subphysiologic levels of transgenic WAS protein expression. Improvements in platelet count and cytoskeletal function in myeloid cells were most prominent in patients with high vector copy number in the transduced product. Two patients with a history of autoimmunity had flares of autoimmunity after GT, despite similar percentages of WAS protein-expressing cells and gene marking to those without autoimmunity. Patients with flares of autoimmunity demonstrated poor numerical recovery of T cells and regulatory T cells (Tregs), interleukin-10-producing regulatory B cells (Bregs), and transitional B cells. Thus, recovery of the Breg compartment, along with Tregs appears to be protective against development of autoimmunity after GT. These results indicate that clinical and laboratory manifestations of WAS are improved with GT with an acceptable safety profile. This trial is registered at clinicaltrials.gov as #NCT01410825.

Literature Review of Spinal Cord Glioblastoma.

OBJECTIVES: This systematic review aims to investigate spinal cord glioblastoma (scGBM) and correlations between patient traits and survival outcome, as well as differences in cohorts administered temozolomide or total resections, through an analysis of published cases reported up to October 2016. METHODS: We obtained patient data by querying PubMed and Google Scholar with predetermined search terms and inclusion criteria that enabled the identification of relevant case reports. Survival was compared using Kaplan-Meier curves and log-rank analyses. RESULTS: Of 153 patients with scGBM identified through a literature search, 135 met the predetermined search and inclusion criteria. Median overall survival (OS) for the resulting cohort was 12 (95% CI, 10-14) months. The female sex was found to significantly predict worse outcomes, and a sizable number of patients with long-term disease were found to have afflictions of the thoracic spinal cord. Neither the pediatric, temozolomide nor total resection subgroups had significantly improved survival characteristics, by log-rank analysis, relative to counterparts. CONCLUSIONS: These data elucidate the characteristics of patients with scGBM. For more sophisticated and in-depth analyses in the future, it is imperative that time-of-treatment information is recorded in future case reports. In addition, all case reports should be made available to prevent publication bias.