Jennifer Moliterno

Integrated genomic characterization of IDH1-mutant glioma malignant progression

Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors. To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA methylation profiling, demonstrated nonlinear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways and upregulation of the FOXM1- and E2F2-mediated cell cycle transitions, as well as epigenetic silencing of developmental transcription factor genes bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extraterminal (BET) family as a potential therapeutic approach.

Gamma Knife surgery for the treatment of melanoma metastases: the effect of intratumoral hemorrhage on survival

OBJECT Gamma Knife surgery (GKS) improves overall survival in patients with malignant melanoma metastatic to the brain. In this study the authors investigated which patient- or treatment-specific factors influence survival of patients with melanoma brain metastases; they pay particular interest to pre- and post-GKS hemorrhage. METHODS Demographic, treatment, and survival data on 59 patients with a total of 208 intracranial metastases who underwent GKS between 1998 and 2007 were abstracted from treatment records and from the Connecticut Tumor Registry. Multivariate analysis was used to identify factors that independently affected survival. RESULTS Survival was significantly better in patients with solitary metastasis (p = 0.04), lesions without evidence of pre-GKS hemorrhage (p = 0.004), and in patients with total tumor volume treated < 4 cm(3) (p = 0.02). Intratumoral bleeding occurred in 23.7% of patients pre-GKS. Intratumoral bleeding occurred at a mean of 1.8 months post-GKS at a rate of 15.2%. Unlike the marked effect of pretreatment bleeding, posttreatment bleeding did not independently affect survival. Sex, systemic control, race, metastases location, whole-brain radiation therapy, chemotherapy, history of antithrombotic medications, and cranial surgery had no independent association with survival. CONCLUSIONS These data corroborate previous findings that tumor burden (either as increased number or total volume of lesions) at the time of GKS is associated with diminished patient survival in those with intracerebral melanoma metastases. Patients who were noted to have hemorrhagic melanoma metastases prior to GKS appear to have a worse prognosis following GKS compared with patients with nonhemorrhagic metastases, despite similar rates of bleeding pre- and post-GKS treatment. Gamma Knife surgery itself does not appear to increase the rate of hemorrhage.

Novel VLDLR microdeletion identified in two Turkish siblings with pachygyria and pontocerebellar atrophy

Congenital ataxia with cerebellar hypoplasia is a heterogeneous group of disorders that presents with motor disability, hypotonia, incoordination, and impaired motor development. Among these, disequilibrium syndrome describes a constellation of findings including non-progressive cerebellar ataxia, mental retardation, and cerebellar hypoplasia following an autosomal recessive pattern of inheritance and can be caused by mutations in the Very Low Density Lipoprotein Receptor (VLDLR). Interestingly, while the majority of patients with VLDL-associated cerebellar hypoplasia in the literature use bipedal gait, the previously reported patients of Turkish decent have demonstrated similar neurological sequelae, but rely on quadrupedal gait. We present a consanguinous Turkish family with two siblings with cerebellar atrophy, predominantly frontal pachygyria and ataxic bipedal gait, who were found to have a novel homozygous deletion in the VLDLR gene identified by using high-density single nucleotide polymorphism microarrays for homozygosity mapping and identification of CNVs within these regions. Discovery of disease causing homozygous deletions in the present Turkish family capable of maintaining bipedal movement exemplifies the phenotypic heterogeneity of VLDLR-associated cerebellar hypoplasia and ataxia.

Gastric bypass: a risk factor for neural tube defects?

Gastric bypass surgery has become a safe and acceptable surgical weight loss treatment for individuals who suffer from morbid obesity. Patients who undergo this procedure are subject to vitamin deficiencies due to an iatrogenic malabsorptive state. Folate, a vitamin known for its role in the prevention of neural tube defects (NTDs), can be part of the deficiency spectrum resulting from this procedure. The authors describe the case of a woman who was nonadherent to multivitamin treatment after undergoing gastric bypass surgery. Her lack of understanding and appreciation of the relationship between gastric bypass surgery, folate deficiency, and NTDs may have contributed to her noncompliance with daily multivitamin consumption. As a result, her potential problems with folate absorption could have contributed to her subsequently giving birth to a child with a myelomeningocele. Thus, patient awareness and counseling along with aggressive vitamin supplementation among this particular population may help prevent the occurrence of NTDs after gastric bypass surgery.

Survival in patients treated for anaplastic meningioma.

OBJECT While most meningiomas are benign, 1%-3% display anaplastic features, with little current understanding regarding the molecular mechanisms underlying their formation. In a large single-center cohort, the authors tested the hypothesis that two distinct subtypes of anaplastic meningiomas, those that arise de novo and those that progress from lower grade tumors, exist and exhibit different clinical behavior. METHODS Pathology reports and clinical data of 37 patients treated between 1999 and 2012 for anaplastic meningioma at Memorial Sloan-Kettering Cancer Center (MSKCC) were retrospectively reviewed. Patients were divided into those whose tumors arose de novo and those whose tumors progressed from previously documented benign or atypical meningiomas. RESULTS Overall, the median age at diagnosis was 59 years and 57% of patients were female. Most patients (38%) underwent 2 craniotomies (range 1-5 surgeries) aimed at gross-total resection (GTR; 59%), which afforded better survival when compared with subtotal resection according to Kaplan-Meier estimates (median overall survival [OS] 3.2 vs 1.3 years, respectively; p = 0.04, log-rank test). Twenty-three patients (62%) presented with apparently de novo anaplastic meningiomas. Compared with patients whose tumors had progressed from a lower grade, those patients with de novo tumors were significantly more likely to be female (70% vs 36%, respectively; p = 0.04), experience better survival (median OS 3.0 vs 2.4 years, respectively; p = 0.03, log-rank test), and harbor cerebral hemispheric as opposed to skull base tumors (91% vs 43%, respectively; p = 0.002). CONCLUSIONS Based on this single-center experience at MSKCC, anaplastic meningiomas, similar to glial tumors, can arise de novo or progress from lower grade tumors. These tumor groups appear to have distinct clinical behavior. De novo tumors may well be molecularly distinct, which is under further investigation. Aggressive GTR appears to confer an OS advantage in patients with anaplastic meningioma, and this is likely independent of tumor progression status. Similarly, those patients with de novo tumors experience a survival advantage likely independent of extent of resection.

Integrated genomic analyses of de novo pathways underlying atypical meningiomas

Meningiomas are mostly benign brain tumours, with a potential for becoming atypical or malignant. On the basis of comprehensive genomic, transcriptomic and epigenomic analyses, we compared benign meningiomas to atypical ones. Here, we show that the majority of primary (de novo) atypical meningiomas display loss of NF2, which co-occurs either with genomic instability or recurrent SMARCB1 mutations. These tumours harbour increased H3K27me3 signal and a hypermethylated phenotype, mainly occupying the polycomb repressive complex 2 (PRC2) binding sites in human embryonic stem cells, thereby phenocopying a more primitive cellular state. Consistent with this observation, atypical meningiomas exhibit upregulation of EZH2, the catalytic subunit of the PRC2 complex, as well as the E2F2 and FOXM1 transcriptional networks. Importantly, these primary atypical meningiomas do not harbour TERT promoter mutations, which have been reported in atypical tumours that progressed from benign ones. Our results establish the genomic landscape of primary atypical meningiomas and potential therapeutic targets.

High-viscosity polymethylmethacrylate cement for endoscopic anterior cranial base reconstruction

Endoscopic endonasal transsphenoidal surgery (ETSS) is an effective, minimally invasive approach for the resection of anterior skull base tumors. Cerebrospinal leakage is a common complication, and repair of the anterior skull base defect with alloplastic materials has been used to minimize the risk of postoperative CSF rhinorrhea and meningitis. Injectable cements, such as low-viscosity polymethylmethacrylate (PMMA), are useful for cranial base reconstruction because they are easy to shape to the contour of the defect. These low-viscosity materials, however, are more susceptible to leakage into the nasal cavity prohibiting their use and are prone to cracking upon hardening. Cement extravasation not only obstructs the operators view during placement, but it is also associated with significant local and systemic complications. High-viscosity (HV) PMMA-based cement and its specialized delivery system have recently been shown to be safe and effective in human applications. Moreover, its constant high viscosity significantly reduces cement leakage and its associated complications. The authors hypothesized that this type of cement would therefore be ideal for ETSS to repair anterior skull base defects. The authors report their experience using HV-PMMA to reconstruct the anterior skull base in 12 patients following ETSS. The unique puttylike consistency of this material is easy to work, malleable, does not leak into the nasal cavity, does not aspirate into suction tubing, and hardens without cracks in less than 10 minutes. None of the 12 patients suffered postoperative CSF leaks or infections more than 8 months, on average, after surgery. Although not necessary in all cases of ETSS, the authors conclude that HV-PMMA, if needed, may be an excellent choice for reconstructing the anterior skull base after ETSS. Further studies are needed to better assess the long-term outcomes of HV-PMMA cement and its use in repairing skull base defects after extended ETSS.

Pineal parenchymal tumor of intermediate differentiation with papillary features: a continuum of primary pineal tumors?

Pineal parenchymal tumors comprise a rare group of primary neoplasms of the pineal gland. We describe a case involving a 29-year-old woman who presented with signs and symptoms of hydrocephalus secondary to a pineal region tumor obstructing the third ventricle. Surgical resection was performed and pathological analysis revealed a novel diagnosis consistent with a pineal parenchymal tumor of intermediate differentiation (PPTID) with transition to a papillary tumor of the pineal region (PTPR). To our knowledge, this particular pineal region tumor pathology has not yet been reported in the literature and highlights the continuum with which primary pineal tumors exist. We provide a review of the existing literature on pineal region tumors, specifically PTPR and PPTID, and offer insight into the management of these rare neoplasms.

Feasibility and safety of GliaSite brachytherapy in treatment of CNS tumors following neurosurgical resection.

PURPOSE To investigate feasibility and safety of GliaSite brachytherapy for treatment of central nervous system (CNS) tumors following neurosurgical resection. We report mature results of long-term follow-up, outcomes and toxicity. MATERIALS AND METHODS In the period from 2004 to 2007, 10 consecutive adult patients with recurrent, newly diagnosed, and metastatic brain malignancies underwent GliaSite brachytherapy following maximally safe neurosurgical resection. While 6/10 (60%) patients were treated for recurrence, having previously been treated with external beam radiotherapy (EBRT), 4/10 (40%) received radiotherapy (RT) for the first time. A median dose of 52.0 Gy (range, 45.0 - 60.0 Gy) was prescribed to 0.5 cm - 1.0 cm from the balloon surface. Radiation Therapy Oncology Group (RTOG) criteria were used to assess toxicities associated with this technique. Follow-up was assessed with MRI scans and was available on all enrolled patients. RESULTS Median follow-up was 38 months (range, 18 - 57 months). Mean size of GliaSite balloon was 3.4 cm (range, 2.0 - 4.0 cm). Median survival was 14.0 months for the entire cohort after the treatment. The 17.6 and 16.0 months average survival for newly diagnosed and recurrent high grade gliomas (HGG), respectively, translated into a three-month improvement in survival in patients with newly diagnosed HGG compared to historical controls (P = 0.033). There were no RTOG grades 3 or 4 acute or late toxicities. Follow-up magnetic resonance imaging (MRI) imaging did not identify radiation necrosis. CONCLUSIONS Our data indicate that treatment with GliaSite brachytherapy is feasible, safe and renders acceptable local control, acute and long-term toxicities. We are embarking on testing larger numbers of patients with this treatment modality.

Molecular and genetic pathways in gliomas: the future of personalized therapeutics

In the last few decades, we have seen significant advances in brain imaging, which have resulted in more detailed anatomic and functional localization of gliomas in relation to the eloquent cortex, as well as improvements in microsurgical techniques and enhanced delivery of adjuvant stereotactic radiation. While these advancements have led to a relatively modest improvement in clinical outcomes for patients with malignant gliomas, much more work remains to be done. As with other types of cancer, we are now rapidly moving past the era of histopathology dictating treatment for brain tumors and into the realm of molecular diagnostics and associated targeted therapies, specifically based on the genomic architecture of individual gliomas. In this review, we discuss the current era of molecular glioma characterization and how these profiles will allow for individualized, patient-specific targeted treatments.