Douglas C. Miller

Induction Chemotherapy and Conformal Radiation Therapy for Very Young Children With Nonmetastatic Medulloblastoma: Children's Oncology Group Study P9934

PURPOSE P9934 was a prospective trial of systemic chemotherapy, second surgery, and conformal radiation therapy (CRT) limited to the posterior fossa and primary site for children between 8 months and 3 years old with nonmetastatic medulloblastoma. The study was open from June 2000 until June 2006. PATIENTS AND METHODS After initial surgery, children received four cycles of induction chemotherapy, followed by age- and response-adjusted CRT to the posterior fossa (18 or 23.4 Gy) and tumor bed (cumulative 50.4 or 54 Gy) and maintenance chemotherapy. Neurodevelopmental outcomes were evaluated and event-free survival (EFS) results were directly compared with a previous study of multiagent chemotherapy without irradiation (Pediatric Oncology Group [POG] trial 9233). RESULTS Seventy-four patients met eligibility requirements. The 4-year EFS and overall survival probabilities were 50% ± 6% and 69% ± 5.5%, respectively, which compared favorably to the results from POG 9233. Analysis showed that the desmoplastic/nodular subtype was a favorable factor in predicting survival. Our 4-year EFS rate was 58% ± 8% for patients with desmoplasia. Whereas seven of 10 patients who had disease progression before CRT had primary-site failure, 15 of 19 patients who progressed after CRT had distant-site failure. Neurodevelopmental assessments did not show a decline in cognitive or motor function after protocol-directed chemotherapy and CRT. CONCLUSION The addition of CRT to postoperative chemotherapy in young children with nonmetastatic medulloblastoma increased event-free survival compared with the use of postoperative chemotherapy alone. Future studies will use histopathologic typing (desmoplastic/nodular versus nondesmoplastic/nodular) to stratify patients for therapy by risk of relapse.

Histology predicts a favorable outcome in young children with desmoplastic medulloblastoma: a report from the children's oncology group.

Contemporary therapy for medulloblastoma results in adverse neurocognitive effects on young children, particularly those under the age of 3. Stratification of patients by risk group may allow toxic treatment to be avoided.

Isolation and characterization of a population of stem-like progenitor cells from an atypical meningioma

The majority of meningiomas are benign tumors associated with favorable outcomes; however, the less common aggressive variants with unfavorable outcomes often recur and may be due to subpopulations of less-differentiated cells residing within the tumor. These subpopulations of tumor cells have tumor-initiating properties and may be isolated from heterogeneous tumors when sorted or cultured in defined medium. We report the isolation and characterization of a population of tumor-initiating cells derived from an atypical meningioma. We identify a tumor-initiating population from an atypical meningioma, termed meningioma-initiating cells (MICs). These MICs self-renew, differentiate, and can recapitulate the histological characteristics of the parental tumor when transplanted at 1000 cells into the flank regions of athymic nude mice. Immunohistochemistry reveals stem-like protein expression patterns similar to neural stem and progenitor cells (NSPCs) while genomic profiling verified the isolation of cancer cells (with defined meningioma chromosomal aberrations) from the bulk tumor. Microarray and pathway analysis identifies biochemical processes and gene networks related to aberrant cell cycle progression, particularly the loss of heterozygosity of tumor suppressor genes CDKN2A (p16(INK4A)), p14(ARF), and CDKN2B (p15(INK4B)). Flow cytometric analysis revealed the expression of CD44 and activated leukocyte adhesion molecule (ALCAM/CD166); these may prove to be markers able to identify this cell type. The isolation and identification of a tumor-initiating cell population capable of forming meningiomas demonstrates a useful model for understanding meningioma development. This meningioma model may be used to study the cell hierarchy of meningioma tumorogenesis and provide increased understanding of malignant progression.

Baló's concentric sclerosis: imaging findings and pathological correlation

Balós concentric sclerosis is a primary inflammatory central nervous system demyelinating disease that is considered a rare, radiographically and pathologically distinct variant of multiple sclerosis. Balós concentric sclerosis is characterized by alternating rings of demyelinated and myelinated axons, and it is most frequently diagnosed postmortem by autopsy or, more recently, by magnetic resonance imaging without pathologic verification. This report is of a case of Balós concentric sclerosis in which the patient presented with left-sided focal sensorimotor deficits. The patients lesion demonstrated characteristics of Balós concentric sclerosis by magnetic resonance imaging, but since a neoplastic process was also suspected initially, the patient underwent a surgical biopsy. This pathology sample now provides the opportunity to correlate the tissue diagnosis of demyelination with characteristic magnetic resonance imaging findings; this comparison is infrequently found in the literature.

Lung adenocarcinomas metastatic to the brain with and without ultrastructural evidence of rootlets: An electron microscopic and immunohistochemical study using cytokeratins 7 and 20 and villin

Adenocarcinomas metastatic to brain from lung or colon may pose differentiation difficulties. Ultrastructurally, both may have brush borders with rootlets. This study examines the ultrastructural morphology and immunohistochemical expression of villin (associated with rootlets), cytokeratin 7 (present in lung adenocarcinomas), and cytokeratin 20 (present in colon adenocarcinomas) in 19 formalin-fixed sequential surgical biopsies of lung adenocarcinomas metastatic to brain as compared to 13 colonic adenocarcinoma metastases. Of lung tumor metastases, mucinous differentiation with rootlets was most common [6/19(32%)]. All colon tumor metastases were cytokeratin 7(-), 20(+), and profusely villin(+). Well-formed rootlets were seen. All lung metastases were cytokeratin 7(+) and 20(-). 5/6(83%) lung metastases with rootlets were focally villin(+). 12/13(95%) without rootlets were villin(-). Rootlets are extremely common in lung adenocarcinoma metastatic to brain. Villin immunoreactivity closely correlates with rootlets. Its distribution is a useful adjunct to cytokeratin 7 and 20 in differentiation of lung versus colon adenocarcinomas metastatic to the brain.

Brainstem disconnection: two additional patients and expansion of the phenotype.

Brainstem disconnection (BD) is a rare posterior fossa abnormality defined by the nearly complete absence of a brainstem segment with the rostral and caudal brainstem portions connected only by a thin cord of tissue. The outcome is poor and the majority of children die within the first 2 months of life without achieving developmental milestones. We report on the cases of two children with BD and a prolonged spontaneous survival. Neither patient required intubation or mechanical ventilation and each survived longer than 2 months (one child died at the age of 8 months, the other is alive at the age of 4.5 years). In addition, patient 1 is the only child with BD reported so far who achieved some developmental milestones. Although the long-term neurodevelopmental outcome of BD remains unfavorable, the expansion of the phenotypic spectrum may be important in terms of counseling.

Leukoencephalopathy, Cerebral Calcifications, and Cysts in Two Sisters

BACKGROUND The triad of leukoencephalopathy with cerebral calcifications and cysts is a rare syndrome consisting of these three radiographic findings first described by Labrune et al. in 1996. The inheritance pattern and genetic mutation responsible for this syndrome (if any) have not been determined. PATIENT DESCRIPTION We report the occurrence of this syndrome in siblings. Two sisters presented with leukoencephalopathy, cerebral calcifications, and cysts approximately 10 years apart, one at 18 years with longstanding epilepsy and the other at 25 years with postpartum stroke-like signs. In both individuals, computed tomography revealed calcifications in the basal ganglia and subcortical white matter as well as supratentorial cysts. Magnetic resonance imaging demonstrated diffuse white matter increased T2 signal and bilateral supratentorial cysts with enhancing walls. Both patients underwent biopsy, one an open biopsy and the other a stereotactic biopsy, with sections of the resected tissue revealing gliosis with Rosenthal fibers, myelin loss, and calcifications, plus in the larger sample cystic spaces and thick-walled abnormal blood vessels with hemosiderin deposition in the adjacent tissues. CONCLUSION In these siblings, the triad of radiological findings, histopathologic findings, and lack of extraneurological findings on physical examination suggest an occurrence of familial leukoencephalopathy, cerebral calcifications, and cysts with probable autosomal recessive inheritance.

The Negative Impact of Anemia in Outcome from Traumatic Brain Injury

BACKGROUND Whether anemia complicating traumatic brain injury (TBI) has an impact on patient outcomes is controversial; therefore, recommendations for blood transfusions for such patients are inconsistent. We hypothesized that patient outcome after TBI would be worse in patients with lower hemoglobin levels. METHODS We retrospectively reviewed records of patients with TBI and head Abbreviated Injury Scale >3 with abnormal head computed tomography findings and neurologic injury. The relationships between initial hemoglobin and lowest hemoglobin during hospitalization at threshold values of ≤7, ≤8, ≤9, and ≤10 g/dL were investigated relative to Glasgow Outcome Score at last follow-up not exceeding 1 year. RESULTS Of 939 patients meeting inclusion criteria, initial and lowest hemoglobin concentrations were significant predictors of poor outcome (P < 0.0001). For each 1 g/dL higher hemoglobin value, the likelihood of a good outcome increased by 33%. More severe levels of initial anemia were associated with lower Glasgow Coma Scale, greater head Abbreviated Injury Scale, and greater Injury Severity Score (P < 0.0001). Female patients had worse outcome than male patients only for initial hemoglobin between 7 and 8 g/dL (P < 0.05). Blood transfusion was associated with poorer outcome at hemoglobin levels ≤9 and ≤10 g/dL (P < 0.05), but not at lower hemoglobin thresholds. CONCLUSIONS Patient outcome after TBI is worse in patients with lower hemoglobin. Initial hemoglobin and lowest hemoglobin after admission are independently associated with poor outcome. Our data support consideration of blood transfusion when hemoglobin is ≤8 g/dl.

Pigmented papillary epithelial neoplasm of the pituitary fossa: a distinct lesion of uncertain histogenesis.

Primary pigmented intracranial neoplasms are strikingly uncommon. The differential diagnosis is limited and includes both epithelial and nonepithelial tumors, most of which arise within or near the ventricular system. The authors describe a 42-year-old man who presented with a pigmented papillary epithelial lesion that arose within the sella and exhibited suprasellar extension and bony erosion. Following external beam radiotherapy and multiple surgical resections, tumor growth became rapid, necessitating additional debulking procedures. Pathologic evaluation of subsequent lesional tissue samples revealed an anaplastic lesion with malignant epithelial and spindle cell components. Occasional epithelial cells showed features reminiscent of the original papillary lesion, whereas others exhibited oncocytic morphologic features. This case represents the only report, to our knowledge, of a pigmented papillary epithelial neoplasm arising within the pituitary fossa. Although the histogenesis of this tumor is enigmatic, this appears to be a distinct lesion characterized by aggressive growth and the capacity for anaplastic progression.

Deregulated expression of EZH2 in congenital brainstem disconnection.

Congenital brainstem disconnection (CBSD) is an enigmatic embryo-fetal defect presenting as (sub)total absence of a segment between mesencephalon and lower brainstem. Rostro-caudal limits of the defect vary while the basal pons is always involved and the cerebellum is globally hypoplastic. A recent update and review[1] lists 14 cases, including 3 brain autopsy studies[1-3]. Necrosis and glial- or inflammatory reactions were absent. Inferior olivary nuclei were small or absent, pontine nuclei depleted, and the cerebellar dentate nuclei dysplastic. Supra-tentorial parts were normal in size, shape and microscopic structure. Frequent associated findings were vertebral segmentation defects(4/14) and hydronephrosis(3/14). No intra-familial recurrence or consanguinity were recorded. We considered interference with the developing rhombencephalon by an epigenetic mechanism as possible cause of CBSD. We probed the role of PRC2 (Polycomb Repressive Complex 2), member of the polycomb group of chromatin modifying proteins (PcG) with a cell-fate conserving function in organ development[4-7]. PRC2 acts by promotor binding as well as by modification of histone H3 through its catalytic subunit EZH2 (Enhancer of Zeste2) that tri-methylates the free ending tail of H3 at lysine 27 to H3K27me3 (with H3K27me2 as intermediate step). H3K27me3 blocks transcription of developmental genes to consolidate the mature stage of cell lineage on completed development[7]. Advantageous use can be made of anti-H3K27me3 antibody staining of nuclear chromatin on routinely prepared autopsy tissue sections to study EZH2 activity, an application more commonly used in neoplastic studies[8], but not routinely applied in human malformations. The absence of immunoreactivity in a developmental setting is due to immaturity, as in embryonic stem cells, or to an abnormal persistence (or even reversal) to that state with loss of control over tissue specific development. A large number of genes are known to undergo maturational silencing by histone modification. For example, EZH2 stabilizes the identity of individual vertebral body segments as well as brainstem development by silencing HOX genes[9,10]. Another role for EZH2, sustaining normal pontine neuron migration from the embryonic rhombic lip to the mature site of function has been identified by rhombomere specific knockout of Ezh2 in mouse embryos[11]. This finding prompted the present study. This article is protected by copyright. All rights reserved.