Background: Pediatric posterior fossa ependymoma contributes to morbidity and mortality in children. Following gross total resection and adjuvant radiotherapy, there is a known risk of local recurrence that portends a dismal prognosis. We sought to characterize survival in a molecularly defined cohort with an emphasis on recurrence patterns that influence outcome. Methods: This study was approved by the Ethics Board of the Hospital for Sick Children. We performed a twenty-year single-center retrospective study to identify clinical, demographic and treatment characteristics of patients with pathologically diagnosed posterior fossa ependymoma. Results: There were 60 patients identified that underwent primary resection. Recurrence rate in the cohort was 48% with 29 cases of recurrent ependymoma occurring at a mean time of 24 months after index surgery. No mortalities were observed among patients undergoing primary resection without recurrent disease. Median cohort survival was 12.3 years in the primary cohort and and 6.32 years among patients recurrent ependymoma. Recurrent disease was significantly associated with worse overall survival after multivariate analysis (HR = 0.024). Conclusions: We highlight overall survival and factors influencing mortality in pediatric posterior fossa ependymoma. Recurrent disease confers a worse prognosis. We describe for the first time survival trends following local and distant recurrences managed through multiple resections.

Group-3 medulloblastoma (MBL) is highly resistant to radiation (IR) and chemotherapy and has the worst prognosis. Hence, there is an urgent need to elucidate targets that sensitize these tumors to chemotherapy and IR. Employing standard assays for viability and sensitization to IR, we identified PRDX1 as a therapeutic target in Group-3 MBL. Specifically, targeting PRDX1 by RNAi or inhibition by Adenanthin led to specific killing and sensitization to IR of Group-3 MBL cells. We rescued sensitization of Daoy and UW228 cells by hypermorphic expression of PRDX1. PRDX1 knockdown caused oxidative DNA damage and induced apoptosis. We correlated PRDX1 expression to patient outcomes in a validated MBL tumor-microarray. Whole genome sequencing identified pathways/genes that were dysregulated with PRDX1 inhibition or silencing. Our in vivo studies in mice employing flank/orthotopic tumors from patient derived xenografts/Group-3 MBL cells confirmed in vitro observations. Animals with tumors in which PRDX1 was targeted by RNAi or Adenanthin (using mini osmotic pumps) showed decreased tumor burden and increased survival when compared to controls. Since, Adenanthin does not cross the blood brain barrier (BBB) we used HAV6 peptide to transiently disrupt the BBB and deliver Adenanthin to the tumor. Immunohistochemistry confirmed that targeting PRDX1 resulted in increased oxidative DNA damage, apoptosis and decreased proliferation. In summary, we have validated PRDX1 as a therapeutic target in group-3 MBL, identified Adenanthin as a potent chemical inhibitor of PRDX1 and confirmed the role of HAV peptide (in the transient modulation of BBB permeability) in an orthotopic model of group-3 MBL.

Coinfection with human immunodeficiency virus (HIV) and viral hepatitis is associated with high morbidity and mortality in the absence of clinical management, making identification of these cases crucial. We examined characteristics of HIV and viral hepatitis coinfections by using surveillance data from 15 US states and two cities. Each jurisdiction used an automated deterministic matching method to link surveillance data for persons with reported acute and chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections, to persons reported with HIV infection. Of the 504 398 persons living with diagnosed HIV infection at the end of 2014, 2.0% were coinfected with HBV and 6.7% were coinfected with HCV. Of the 269 884 persons ever reported with HBV, 5.2% were reported with HIV. Of the 1 093 050 persons ever reported with HCV, 4.3% were reported with HIV. A greater proportion of persons coinfected with HIV and HBV were males and blacks/African Americans, compared with those with HIV monoinfection. Persons who inject drugs represented a greater proportion of those coinfected with HIV and HCV, compared with those with HIV monoinfection. Matching HIV and viral hepatitis surveillance data highlights epidemiological characteristics of persons coinfected and can be used to routinely monitor health status and guide state and national public health interventions.

Background: Aggressive surgical resections of posterior fossa tumours result in tremendous neurological sequelae as a result of damage to the brainstem. As such we sought to re-evaluate the role of aggressive surgical resections in the molecular era. Methods: 820 posterior fossa ependymoma and 787 medulloblastoma were genomically profiled and correlated with pertinent clinical variables. Results: Across 787 medulloblastoma cases, the value of extent of resection was greatly dampened when accounting for molecular subgroup. Near-total resections are equivalent to gross total resections across all four subgroups even when correcting for treatment. The prognostic value of a gross total resection as compared to a subtotal resection (>1.5cm2 residual) was restricted to Group 4 tumours (HR 1.26). Across 820 posterior fossa ependymoma PFA ependymoma was a very high risk group compared to PFB ependymoma, and a subtotal PFA ependymoma conferred an extremely poor prognosis. Gross totally resected PFB ependymoma could be cured with surgery alone. Prognostic nomograms in both medulloblastoma and ependymoma revealed molecular subgroup to be the most important predictor of outcome. Conclusions: The prognostic benefit of EOR for patients with medulloblastoma is marginal after accounting for molecular subgroup affiliation. In both molecular subgroups of posterior fossa ependymoma, gross total resection remains an important predictor of outcome.

Background: Inflicted head injury is a major cause of infant morbidity and mortality. The extent of traumatic brain injury in infants is often best characterized by diffusion weighted magnetic resonance imaging. In this cases series we describe four infants aged 6-19 months, with small unilateral subdural hematomas secondary to abusive head trauma accompanied by extensive areas of restricted diffusion weighted imaging isolated to the cerebral white matter. Methods: Retrospective, single-centre case series of four children with small unilateral subdural hematomas with early and delayed MR imaging with diffusion weighted imaging. Results: In three cases there was acute diffusion restriction ispilateral to the subdural, while in one case diffusion restriction was present bilaterally. All patients had multiple seizures and bilateral multilayered retinal hemorrhages. After non-surgical treatment, all patients survived albeit with significant motor and cognitive deficits and significant cortical atrophy on long-term followup imaging. Conclusions: These four cases highlight that relatively small subdural hematomas following child abuse can manifest with extensive white matter injury only evident at early stages with diffusion weighted imaging. We propose that selective white matter injury as a result of either reperfusion or axonal degeneration in response to the initial insult accounts for this novel pattern of infantile traumatic brain injury.

Theorem: If any conic be inscribed in a given triangle and a confocal to it pass through the circumcentre, then the circle through the intersection of these two confocals touches the nine-points circle of the triangle.

The substance of this paper is contained in Chrystal, chap, xxv., §§13, and 15 to 20, with some applications thereof occurring in chap. xxvi. But it is treated here in a fresh manner which would seem simpler on several points. This mode of presentation was, in the start, suggested by Peano's method given by Prof. Gibson in his “Note on the Fundamental Inequality Theorems Connected with ex and xm,” in Vol. XVIII. of the Proceedings.