Granulocyte transfusions in critically ill children with prolonged neutropenia: side effects and survival rates from a single-center analysis.

UNLABELLED: Granulocyte transfusions for neutropenic patients have been used for over 40 years, although effectiveness, indications, and both patient and donor safety remain debated. This single-center study assessed the side effects, clinical course, and survival of granulocyte transfusions in critically ill pediatric patients, with underlying hemato-oncological disorders, prolonged neutropenia, and proven or suspected severe infection. Donor-specific side effects and influence of donor-specific characteristics on patient outcome were also investigated. A median of 4.02 × 10(10) cells was collected from 39 healthy donors for 118 granulocyte concentrates. Donors reported no significant side effects. Complications for patients were frequent but mostly minor and included vomiting, hypotension, and dyspnea. In one episode of life-threatening dyspnea, association with the granulocyte transfusion could not be ruled out. Overall survival on day 100 was 61.9 %. Patients received a median of 0.13 × 10(10) cells per kg body weight. Doses above this median were associated with a significantly better survival. Lower patient weight and age-/sex-adjusted weight were also associated with better survival. CONCLUSION: Granulocyte mobilization and collection is a safe practice. Transfusions are well tolerated in critically ill patients. Patient weight and transfused cells per kg bodyweight are major determinants of survival in pediatric patients. WHAT IS KNOWN: • Granulocyte transfusions for neutropenic patients have been used for over 40 years • The effectiveness of the technique remains controversial • Patient and donor safety remain debated • New mobilization protocols generate higher yields of granulocytes What is new: • Granulocyte collection can safely be performed • Granulocytes can safely be administered to patients • Lower patient weight and age-/sex-adjusted weight are associated with better survival rates • Patients receiving above 0.13 × 10 (10) cells per kg body weight had an excellent outcome • Further standardized, prospective studies are warranted.

The KDM1A histone demethylase is a promising new target for the epigenetic therapy of medulloblastoma.

BACKGROUND: Medulloblastoma is a leading cause of childhood cancer-related deaths. Current aggressive treatments frequently lead to cognitive and neurological disabilities in survivors. Novel targeted therapies are required to improve outcome in high-risk medulloblastoma patients and quality of life of survivors. Targeting enzymes controlling epigenetic alterations is a promising approach recently bolstered by the identification of mutations in histone demethylating enzymes in medulloblastoma sequencing efforts. Hypomethylation of lysine 4 in histone 3 (H3K4) is also associated with a dismal prognosis for medulloblastoma patients. Functional characterization of important epigenetic key regulators is urgently needed. RESULTS: We examined the role of the H3K4 modifying enzyme, KDM1A, in medulloblastoma, an enzyme also associated with malignant progression in the closely related tumor, neuroblastoma. Re-analysis of gene expression data and immunohistochemistry of tissue microarrays of human medulloblastomas showed strong KDM1A overexpression in the majority of tumors throughout all molecular subgroups. Interestingly, KDM1A knockdown in medulloblastoma cell lines not only induced apoptosis and suppressed proliferation, but also impaired migratory capacity. Further analyses revealed bone morphogenetic protein 2 (BMP2) as a major KDM1A target gene. BMP2 is known to be involved in development and differentiation of granule neuron precursor cells (GNCPs), one potential cell of origin for medulloblastoma. Treating medulloblastoma cells with the specific KDM1A inhibitor, NCL-1, significantly inhibited growth in vitro. CONCLUSION: We provide the first evidence that a histone demethylase is functionally involved in the regulation of the malignant phenotype of medulloblastoma cells, and lay a foundation for future evaluation of KDM1A-inihibiting therapies in combating medulloblastoma.