Anaplastic ganglioglioma: a report of three cases and review of the literature.

Gangliogliomas are rare tumors of the central nervous system that are thought to arise from a glioneuronal precursor and consist of both neuronal and glial elements. Grade III, or anaplastic ganglioglioma (AGG), most commonly affects children and young adults, generally arises in a supratentorial location, is highly epileptogenic, and often results in diffuse local and distant failure within the craniospinal axis. Pathologically, these tumors are graded by the degree of malignancy in their glial portion and radiologic diagnosis is difficult due to the wide variation in its degree of solid and cystic components, contrast uptake, and calcification patterns. This report presents three cases of AGG, with initial treatment including subtotal resection followed by conformal radiotherapy. In the case where the AGG developed in the setting of an existent low-grade astrocytoma, the patient received no chemotherapy. Both of the other de novo cases were managed with adjuvant chemoradiotherapy with temozolomide. Recurrence occurred at 6, 16, and 20 months following therapy. Two of the three patients experienced symptomatic decline at recurrence, but experienced Karnofsky performance status (KPS) improvement after salvage therapy, including the reduction of cranial neuropathy and balance. All patients had a significant reduction in presenting symptoms following salvage therapy. Patients died at 23, 20, and 22 months following initial surgical management, respectively. A review of anaplastic and malignant gangliogliomas is presented in the context of these three cases.

Evaluation of the role of secretory sphingomyelinase and bioactive sphingolipids as biomarkers in hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare systemic inflammatory syndrome that results from unrestrained immune cell activation. Despite significant advances in the understanding of the pathophysiology of HLH, interventions remain limited for this often-fatal condition. Secretory sphingomyelinase (S-SMase) is a pro-inflammatory lipid hydrolase that is upregulated in several inflammatory conditions, including HLH. S-SMase promotes the formation of ceramide, a bioactive lipid implicated in several human disease states. However, the role of the S-SMase/ceramide pathway in HLH remains unexplored. To further evaluate the role of S-SMase upregulation in HLH, we tested the serum of patients with HLH (n = 16; primary = 3, secondary = 13) and healthy control patients (n = 25) for serum S-SMase activity with tandem sphingolipid metabolomic profiling. Patients with HLH exhibited elevated levels of serum S-SMase activity, with concomitant elevations in several ceramide species and sphingosine, while levels of sphingosine-1-phosphate were significantly decreased. Importantly, the ratio of C16 -ceramide:sphingosine was uniquely elevated in HLH patients that died despite appropriate treatment, but remained low in HLH patients that survived, suggesting that this ratio may be of prognostic significance. Together, these results demonstrate upregulation of the S-SMase/ceramide pathway in HLH, and suggest that the balance of ceramide and sphingosine determine clinical outcomes in HLH. .

Risk factors associated with metastatic site failure in patients with high-risk neuroblastoma.

Purpose: This retrospective study sought to identify predictors of metastatic site failure (MSF) at new and/or original (present at diagnosis) sites in high-risk neuroblastoma patients. Methods and materials: Seventy-six high-risk neuroblastoma patients treated on four institutional prospective trials from 1997 to 2014 with induction chemotherapy, surgery, myeloablative chemotherapy, stem-cell rescue, and were eligible for consolidative primary and metastatic site (MS) radiotherapy were eligible for study inclusion. Computed-tomography and I-123 MIBG scans were used to assess disease response and Curie scores at diagnosis, post-induction, post-transplant, and treatment failure. Outcomes were described using the Kaplan-Meier estimator. Cox proportional hazards frailty (cphfR) and CPH regression (CPHr) were used to identify covariates predictive of MSF at a site identified either at diagnosis or later. Results: MSF occurred in 42 patients (55%). Consolidative MS RT was applied to 30 MSs in 10 patients. Original-MSF occurred in 146 of 383 (38%) non-irradiated and 18 of 30 (60%) irradiated MSs (p = 0.018). Original- MSF occurred in post-induction MIBG-avid MSs in 68 of 81 (84%) non-irradiated and 12 of 14 (85%) radiated MSs (p = 0.867). The median overall and progression-free survival rates were 61 months (95% CI 42.6-Not Reached) and 24.1 months (95% CI 16.5-38.7), respectively. Multivariate CPHr identified inability to undergo transplant (HR 32.4 95%CI 9.3-96.8, p < 0.001) and/or maintenance chemotherapy (HR 5.2, 95%CI 1.7-16.2, p = 0.005), and the presence of lung metastases at diagnosis (HR 4.4 95%CI 1.7-11.1, p = 0.002) as predictors of new MSF. The new MSF-free survival rate at 3 years was 25% and 87% in patients with and without high-risk factors. Conclusions: Incremental improvements in systemic therapy influence the patterns and type of metastatic site failure in neuroblastoma. Persistence of MIBG-avidity following induction chemotherapy and transplant at MSs increased the hazard for MSF.