Caitlin Hoffman

Medulloblastoma subgroups remain stable across primary and metastatic compartments

Medulloblastoma comprises four distinct molecular variants with distinct genetics, transcriptomes, and outcomes. Subgroup affiliation has been previously shown to remain stable at the time of recurrence, which likely reflects their distinct cells of origin. However, a therapeutically relevant question that remains unanswered is subgroup stability in the metastatic compartment. We assembled a cohort of 12-paired primary-metastatic tumors collected in the MAGIC consortium, and established their molecular subgroup affiliation by performing integrative gene expression and DNA methylation analysis. Frozen tissues were collected and profiled using Affymetrix gene expression arrays and Illumina methylation arrays. Class prediction and hierarchical clustering were performed using existing published datasets. Our molecular analysis, using consensus integrative genomic data, establishes the unequivocal maintenance of molecular subgroup affiliation in metastatic medulloblastoma. We further validated these findings by interrogating a non-overlapping cohort of 19 pairs of primary-metastatic tumors from the Burdenko Neurosurgical Institute using an orthogonal technique of immunohistochemical staining. This investigation represents the largest reported primary-metastatic paired cohort profiled to date and provides a unique opportunity to evaluate subgroup-specific molecular aberrations within the metastatic compartment. Our findings further support the hypothesis that medulloblastoma subgroups arise from distinct cells of origin, which are carried forward from ontogeny to oncology.

Cerebrospinal Fluid-Related Complications With Autologous Duraplasty and Arachnoid Sparing in Type I Chiari Malformation

OBJECTIVE Although there is a current consensus that Type I Chiari malformations (CM-I) should be treated only in the setting of symptomatic disease, significant controversy surrounds the most appropriate surgical procedure. Recent enthusiasm for osseous decompression without duraplasty is supported by the purportedly lower morbidity of this approach. Precise rates of morbidity with duraplasty, however, have not been reported. This study is intended to assess the cerebrospinal fluid-related morbidity associated with a patient population treated uniformly with autologous duraplasty for symptomatic CM-I. METHODS A review of one surgeons practice (MMS) from 1997 to 2007 identified patients treated for symptomatic CM-I with osseous decompression and autologous duraplasty. A retrospective chart review was then performed for these patients with an emphasis on cerebrospinal fluid-related complications. RESULTS Forty patients were treated for CM-I with decompression and autologous duraplasty. Twenty-four patients presented with a preoperative syrinx. The mean age was 13.3 years, and the median age was 12.9 years (range, 3.3–45.8 yr). The mean follow-up period was 11.4 months (range, 1–101 mo). There was no mortality associated with the procedure. Clinical response was observed in 91.8% of patients, with 70.2% experiencing complete symptomatic resolution and 21.6% experiencing partial improvement. Two patients (5.4%) had persistent symptomatic syringomyelia requiring syringosubarachnoid shunting. There was an overall morbidity rate of 2.5% due to one pseudomeningocele treated with a single percutaneous tap. There were no incidences of cerebrospinal fluid leak, meningitis, or postoperative hydrocephalus. CONCLUSION The cerebrospinal fluid-related morbidity associated with autologous duraplasty for CM-I in a uniformly treated population is negligible. These results challenge the current rationale for a less aggressive surgical approach to CM-I.

Oligodendrocyte Progenitor Cells Promote Neovascularization in Glioma by Disrupting the Blood-Brain Barrier

Enhanced platelet-derived growth factor (PDGF) signaling in glioma drives its development and progression. In this study, we define a unique role for stroma-derived PDGF signaling in maintaining tumor homeostasis within the glioma microenvironment. Large numbers of PDGF receptor-α (PDGFRα)-expressing stromal cells derived from oligodendrocytes progenitor cells (OPC) were discovered at the invasive front of high-grade gliomas, in which they exhibited a unique perivascular distribution. In PDGFRα-deficient host mice, in which orthotopic Gl261 tumors displayed reduced outgrowth, we found that tumor-associated blood vessels displayed smaller lumens and normalized vascular morphology, with tumors in host animals injected with the vascular imaging agent gadolinium also being enhanced less avidly by MRI. Notably, glioma-associated OPC promoted endothelial sprouting and tubule formation, in part by abrogating the inhibitory effect that perivascular astrocytes exert on vascular endothelial conjunctions. Stromal-derived PDGF-CC was crucial for the recruitment and activation of OPC, insofar as mice genetically deficient in PDGF-CC phenocopied the glioma/vascular defects observed in PDGFRα-deficient mice. Clinically, we showed that higher levels of PDGF-CC in glioma specimens were associated with more rapid disease recurrence and poorer overall survival. Our findings define a PDGFRα/PDGF-CC signaling axis within the glioma stromal microenvironment that contributes to vascular remodeling and aberrant tumor angiogenesis in the brain.

The significance of cyst remnants after endoscopic colloid cyst resection: a retrospective clinical case series.

BACKGROUND Controversy surrounds the fate of cyst remnants after endoscopic colloid cyst resection. OBJECTIVE Our study evaluated recurrence rates in patients with total endoscopic resection of colloid cysts vs those with coagulated cyst remnants. METHODS Sixty-five consecutive patients and 67 procedures for endoscopic resection of colloid cysts from 1995 to 2011 were reviewed. Degree of resection was based on intraoperative assessment and postoperative magnetic resonance imaging (MRI). Recurrence rates were compared between patients with complete resection those with coagulated cyst remnants. RESULTS Data analysis was performed of 56 patients and 58 procedures, with no follow-up in 9 patients. All patients had MRI-defined complete resection. On intraoperative assessment, 9 procedures had coagulated remnants and 45 procedures had complete resection (4 data unknown). The overall recurrence rate was 6.89% (4/58), 33.3% (3/9) with cyst remnants, and 2.2% (1/45) with total resection (P = .0124). Maximum follow-up was 144 months (mean, 40.4 months). Mean follow-up was 66.0 months for cyst remnant cases, and 33.5 months for totally resected cases. There was no mortality or permanent morbidity. Transient morbidity included memory deficit (n = 2), aseptic meningitis (n = 1), and local wound infection (n = 1). CONCLUSION Endoscopic colloid cyst resection results in a low overall recurrence rate. Immediate postoperative MRI was insufficient for assessing degree of resection and was a poor predictor of recurrence. Ablation of cyst remnants rather than total removal is associated with a significantly higher rate of recurrence. The primary goal of endoscopic surgery should, therefore, be removal of all cyst contents and wall remnants.

Corrigendum: Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET

Corrigendum: Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET

Associated aneurysms in pediatric arteriovenous malformations and the implications for treatment.

BACKGROUND:Arteriovenous malformations (AVM) with associated aneurysms (AA) increase the risk of hemorrhage in adults. Associated aneurysms are thought to develop over time, and the incidence in children, therefore, has been thought to be minimal, although this has not yet been studied. OBJECTIVE:To define the incidence and morbidity of AA in children and to assess the results of our treatment strategy. METHODS:Patients younger than 18 years of age with pial AVM seen from 2000 to 2009 were reviewed. Demographics, presentation, hemorrhage, AAs, treatment method, and outcome were analyzed. RESULTS:Of 144 patients with AVM, 30 were younger than 18 years of age. AA was identified in 5 of 30 children (16.7%) and 33 of 114 adults (28.9%; P = .25). Mean age at presentation in children was 11.67 years (range, 6 months to 17 years), and mean follow-up was 28.8 months (range, 1-75 months). Hemorrhage at presentation was seen in 80% of patients with AA and 72% with AVM alone. Emergent therapy was required in 60% of patients with AA and 40% with AVM alone (P = .63). Time to treatment was 4.3 days with AA and 27.3 days without (P = .42). There was no difference in outcome between patients with AA and those with AVM alone. CONCLUSION:The incidence of pediatric AA was higher in our series than projected in the current literature. Time to treatment was shorter in children with AA compared with those with AVM alone, although there was no difference in clinical outcome. Although hemorrhage rates were similar, emergent therapy was required more often in patients with AA. Our findings support the need for early diagnosis and treatment of associated aneurysms in children.

A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma

Tumors are capable of coopting hematopoietic cells to create a suitable microenvironment to support malignant growth. Here, we have demonstrated that upregulation of kinase insert domain receptor (KDR), also known as VEGFR2, in a myeloid cell sublineage is necessary for malignant progression of gliomas in transgenic murine models and is associated with high-grade tumors in patients. KDR expression increased in myeloid cells as myeloid-derived suppressor cells (MDSCs) accumulated, which was associated with the transformation and progression of low-grade fibrillary astrocytoma to high-grade anaplastic gliomas. KDR deficiency in murine BM-derived cells (BMDCs) suppressed the differentiation of myeloid lineages and reduced granulocytic/monocytic populations. The depletion of myeloid-derived KDR compromised its proangiogenic function, which inhibited the angiogenic switch necessary for malignant progression of low-grade to high-grade tumors. We also identified inhibitor of DNA binding protein 2 (ID2) as a key upstream regulator of KDR activation during myeloid differentiation. Deficiency of ID2 in BMDCs led to downregulation of KDR, suppression of proangiogenic myeloid cells, and prevention of low-grade to high-grade transition. Tumor-secreted TGF-&bgr; and granulocyte-macrophage CSF (GM-CSF) enhanced the KDR/ID2 signaling axis in BMDCs. Our results suggest that modulation of KDR/ID2 signaling may restrict tumor-associated myeloid cells and could potentially be a therapeutic strategy for preventing transformation of premalignant gliomas.

Malignant astrocytic tumor progression potentiated by JAK-mediated recruitment of myeloid cells

Purpose: While the tumor microenvironment has been known to play an integral role in tumor progression, the function of nonresident bone marrow–derived cells (BMDC) remains to be determined in neurologic tumors. Here we identified the contribution of BMDC recruitment in mediating malignant transformation from low- to high-grade gliomas. Experimental Design: We analyzed human blood and tumor samples from patients with low- and high-grade gliomas. A spontaneous platelet-derived growth factor (PDGF) murine glioma model (RCAS) was utilized to recapitulate human disease progression. Levels of CD11b+/GR1+ BMDCs were analyzed at discrete stages of tumor progression. Using bone marrow transplantation, we determined the unique influence of BMDCs in the transition from low- to high-grade glioma. The functional role of these BMDCs was then examined using a JAK 1/2 inhibitor (AZD1480). Results: CD11b+ myeloid cells were significantly increased during tumor progression in peripheral blood and tumors of glioma patients. Increases in CD11b+/GR1+ cells were observed in murine peripheral blood, bone marrow, and tumors during low-grade to high-grade transformation. Transient blockade of CD11b+ cell expansion using a JAK 1/2 Inhibitor (AZD1480) impaired mobilization of these cells and was associated with a reduction in tumor volume, maintenance of a low-grade tumor phenotype, and prolongation in survival. Conclusions: We demonstrate that impaired recruitment of CD11b+ myeloid cells with a JAK1/2 inhibitor inhibits glioma progression in vivo and prolongs survival in a murine glioma model. Clin Cancer Res; 23(12); 3109–19. ©2016 AACR.

Symptomatic Chiari type I malformation after radiation therapy in an infant: case report.

OBJECTIVEOne previous case report has described the development of a Chiari I malformation in a child after fractionated radiation therapy to the anterior cranial base. The authors present an additional case of a 17-month-old girl treated for an isolated, malignant, rhabdoid tumor of the right neck with neoadjuvant chemotherapy, surgical exploration, and radiation therapy. CLINICAL PRESENTATIONThe patient developed a Chiari I malformation and cervical syringomyelia 1.5 years after the treatment. The patient experienced two episodes of unresponsiveness before diagnosis, and the malformation was then identified on magnetic resonance imaging scans. INTERVENTIONSuboccipital decompressive craniectomy, and C1 laminectomy with autologous duraplasty were performed. RESULTSPostoperative magnetic resonance imaging scans revealed reconstitution of cerebrospinal fluid at the foramen magnum and ascent of the cerebellar tonsils. The patient remains asymptomatic 5.5 years after treatment. CONCLUSIONThe importance of this association is discussed in the context of the increasing use of radiation therapy in young children and infants.

Basic Neurosurgical Procedures

Basic neurosurgical procedures used to treat neurological conditions and emergencies include creating a burr hole, doing a craniotomy for access to the brain, laminectomy for access to the spinal cord, and placing a cerebral shunt. A burr hole is a small opening in the skull that is drilled to reach the dura mater. A craniotomy is a surgical procedure that requires removal of a piece of the skull to access the brain. Removal of the lamina of the spine (laminectomy) is done to gain access to the spinal cord. And finally, a cerebral shunt is used to transport fluids, most commonly cerebrospinal fluid (CSF), from the brain to another body cavity in order to decrease intracranial pressure (ICP). Steps involved in performing these basic neurosurgical procedures are described in this chapter.