VPS45-associated severe congenital neutropenia (SCN) is a rare disorder characterized by life-threating infections, neutropenia, neutrophil and platelet dysfunction, poor response to filgrastim, and myelofibrosis with extramedullary hematopoiesis. We present a patient with SCN due to a homozygous c.1403C>T (p.P468L) mutation in VPS45, critical regulator of SNARE-dependent membrane fusion. Structural modeling indicates that P468, like the T224 and E238 residues affected by previously reported mutations, cluster in a VPS45 "hinge" region, indicating its critical role in membrane fusion and VPS45-associated SCN. Bone marrow transplantation, complicated by early graft failure rescued with stem cell boost, led to resolution of the hematopoietic phenotype.

A screening protocol including direct nasal endoscopy, noncontrast chest CT, and abdominal ultrasound was effective in detecting invasive mold infections in at-risk patients. Nasosinal involvement often occurs before specific symptoms develop, and sinus CTs are insensitive and nonspecific. Bedside nasal endoscopy precludes radiation exposure associated with sinus CT and was associated with decrease in mold-related mortality, likely due to earlier diagnosis and initiation of appropriate antifungal therapy.

PTLD of the CNS is a rare complication of solid organ transplantation, and there are only case reports/series available in the literature. Current literature suggests that CNS PTLD carries a worse prognosis than PTLD outside the CNS, and most are of B-cell lineage, predominantly monomorphic, and are associated with EBV infection. Because this disorder is so rare, there is no standard chemotherapy for pediatric patients with CNS PTLD and reported therapies for EBV-associated CNS PTLD are heterogeneous with mixed results. Since outcomes of CNS PTLD are historically poor, we attempted to develop a novel therapeutic treatment regimen. Based on a review of the literature and with the help of a multidisciplinary team, we created a regimen of chemotherapy that included dexamethasone and high-dose methotrexate in addition to intravenous and intraventricular Rituximab in two pediatric patients. The intraventricular chemotherapy succeeded in shrinking the tumor in both of our patients; however, as shown in the second case, the clinical outcome depends on the location of the tumor. Systemic and intraventricular therapies hold promise in the management of EBV-associated CNS PTLD; however the rarity of this entity prevents the development of well-designed studies necessary for the establishment of an evidence-based treatment standard.

Background Healthcare associated mold infections (HAEMI) increase morbidity and mortality in children with leukemia. Excavation adjacent to Children’s Medical Center Dallas (CMCD) April 2006–February 2007 provided an opportunity to determine if excavation adjacent to a hospital building is associated with increased risk of developing HAEMI in children receiving intensive chemotherapy for acute leukemia. Methods Children who began receiving intensive chemotherapy for acute leukemia at CMCD from 2004–2008 were identified (N=275). Exposures to the CMCD campus during intensive chemotherapy and duration of neutropenia per exposure were recorded. Proven, probable or possible invasive fungal disease (IFD) was classified using EORTC/MSG guidelines. Institutional guidelines categorized mold infections as definite or possible HAEMI. A bivariate time-to-event model compared the association of excavation with HAEMI and yeast infections, controlling for neutropenia. Results There were 7454 CMCD exposures, 1007(13.5%) during excavation. Of 50 cases of IFD, 31 were HAEMI. By time-to-event analysis exposure to the CMCD campus during the excavation period was significantly associated with HAEMI (HR=2.8, P=0.01) but not yeast infections (HR=0.75, P=0.75). Neutropenia was significantly associated with both HAEMI and yeast infections (P<0.001). Voriconazole prophylaxis did not prevent HAEMI in 42% of the 14 patients with AML who had been receiving this agent. Conclusion This study is the first to demonstrate an association between exposure to hospital construction that includes excavation and HAEMI in pediatric oncology patients. Since neutropenic patients need protection from aerosolized fungal spores during visits to expanding medical centers, preventive strategies with adherence monitoring need additional study.

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