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.

Understanding the role of tumor stem cells in glioblastoma multiforme: a review article.

It has been hypothesized that cancer stem cells (CSC) may account for the pathogenesis underlying various tumors, including GBM. Markers of these CSCs can be potentially used as therapeutic targets. In this review, we discuss the most recent information regarding CSCs, their molecular biology and their potential role in GBM.

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.

Activated EGFR signaling increases proliferation, survival, and migration and blocks neuronal differentiation in post-natal neural stem cells.

Recent evidence supports the notion that transformation of undifferentiated neural stem cell (NSC) precursors may contribute to the development of glioblastoma multiforme (GBM). The over-expression and mutation of the epidermal growth factor receptor (EGFR), along with other cellular pathway mutations, plays a significant role in GBM maintenance progression. Though EGFR signaling is important in determining neural cell fate and conferring astrocyte differentiation, there is a limited understanding of its role in NSC and tumor stem cell (TSC) biology. We hypothesized that EGFR expression and mutation in post-natal NSCs may contribute to cellular aggressiveness including enhanced cellular proliferation, survival and migration. Stable subclones of C17.2 murine NSCs were transfected to over-express either the wild-type EGFR (wtEGFR) or its most common mutated variant EGFRvIII. Activated EGFR signaling in these cells induced behaviors characteristic of GBM TSCs, including enhanced proliferation, survival and migration, even in the absence of EGF ligand. wtEGFR activation was also found to block neuronal differentiation and was associated with a dramatic increase in chemotaxis in the presence of EGF. EGFRvIII expression lead to an increase in NSC proliferation and survival, while it simultaneously blocked neuronal differentiation and promoted glial fate. Our findings suggest that activated EGFR signaling enhances the aggressiveness of NSCs. Understanding the regulatory mechanisms of NSCs may lend insight into deregulated mechanisms of GBM TSC invasion, proliferation, survival and resistance to current treatment modalities.

Intracranial benign fibrous histiocytomas: a case report and review.

Fibrous histiocytomas are rare lesions, more commonly encountered in soft tissues and bones. They are uncommon as an intracranial lesion. Although there have been several reports about malignant fibrous histiocytomas, less is known about the benign variant of these intracranial tumors as they are often misclassified as other types of tumors. We describe a child who presented with seizure and was subsequently found to have a large temporal lesion. Pathology revealed benign fibrous histiocytoma. We also review other cases reported in the literature in an effort to provide further insight into the diagnosis and management of this rare tumor.

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.

Quality of life and behavioral follow-up study of pediatric survivors of craniopharyngioma.

OBJECT: The authors set out to evaluate the quality of life (QOL), social-emotional functioning, and behavioral functioning of children treated surgically for craniopharyngiomas. METHODS: Twelve girls and 17 boys with a mean age at diagnosis of 8 +/- 3.8 years were surgically treated between 1985 and 1998 at the New York University Medical Center. After a mean follow-up period of 6.8 +/- 3.5 years, these 29 patients were administered either the 36-item Short Form Health Survey version 2 or the Child Health Questionnaire-Parent Form to assess QOL, as well as the Achenbach Child Behavior Checklist or Young Adult Checklist to measure social-emotional and behavioral functioning. Patients older than 19 years of age and parents of patients younger than 19 years of age reported low average overall physical QOL, with overall psychosocial QOL in the average range. Behavioral difficulties were noted, including internalizing, attention, somatic, and social difficulties. Further analyses indicated that retrochiasmatic tumor location, recurrence, and additional surgery were associated with poorer outcomes. In contrast, hydrocephalus, tumor size, and sex were not prognostic variables, and patients significantly improved as post-operative time increased. CONCLUSIONS: Attention toward late effects arising after the treatment of pediatric craniopharyngioma, including decreased postoperative physical health and behavioral functioning, is warranted. Future approaches to treatment should consider the documented effects of either gross-total resection or limited surgery followed by cranial irradiation on QOL, with specific evaluation for those with retrochiasmatic tumors, a recurrent tumor, or the need for additional surgery. Psychosocial QOL and social-emotional functioning should be maintained through ongoing counseling and education.

Neurosurgical approach.

Glioblastoma multiforme is a highly infiltrative tumor that typically has a central region of necrosis surrounded by contrast-enhancing proliferative tumor cells surrounded by diffuse isolated tumor cells that migrate into the brain. The goal of surgery is often directed toward the central necrotic region and the imaging-defined enhancing margin. To limit morbidity from removing functional brain tissue, the infiltrative tumor cells found in surrounding brain are generally not considered part of the surgical target. This is also the site where tumors recur after treatment. It is well accepted by most surgeons and neuro-oncologists that, when possible, aggressive resection of malignant gliomas is the preferred initial step in management. Although there are limited randomized prospective studies that address extent of resection and survival, the benefit of aggressive surgical resection will not be debated in this report. Tumor resection to the maximum extent that is safely possible can decrease tumor burden and thereby enhance the effects of adjuvant therapies, improve symptoms from mass effect, reduce the frequency of seizures, and provide tissue for pathological and genomic studies to better identify and test novel therapy.Surgery for glioblastoma is highly dependent on imaging. Magnetic resonance imaging can provide an anatomic definition of the lesion and functional capacity of critical cortical regions and allow for precise localization within the brain. The common use of stereotactic guidance, intraoperative imaging, functional magnetic resonance imaging, and physiologic monitoring have enhanced the surgeon's ability to achieve aggressive tumor removal while protecting the patient from neurologic impairment. This review will address the use of these techniques as an important first step in managing patients with glioblastoma.

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 operator's 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.

Four novel SCN1A mutations in Turkish patients with severe myoclonic epilepsy of infancy (SMEI).

Severe myoclonic epilepsy of infancy (SMEI) (OMIM #607208), also known as Dravet syndrome, is a rare genetic disorder characterized by frequent generalized, unilateral clonic or tonic-clonic seizures that begin during the first year of life. Heterozygous de novo mutations in the SCN1A gene, which encodes the neuronal voltage-gated sodium channel α subunit type 1 (Nav1.1), are responsible for Dravet syndrome, with a broad spectrum of mutations and rearrangements having been reported. In this study, the authors present 4 novel mutations and confirm 2 previously identified mutations in the SCN1A gene found in a cohort of Turkish patients with Dravet syndrome. Mutational analysis of other responsible genes, GABRG2 and PCDH19, were unrevealing. The authors' findings add to the known spectrum of mutations responsible for this disease phenotype and once again reinforce our understanding of the allelic heterogeneity of this disease.

The role of dose escalation with intracavitary brachytherapy in the treatment of localized CNS malignancies: outcomes and toxicities of a prospective study.

PURPOSE: This single-institution prospective study was designed to investigate the feasibility and safety of dose escalation with GliaSite (Proxima Therapeutics Inc., Alpharetta, GA) brachytherapy for the treatment of patients with newly diagnosed and recurrent central nervous system (CNS) tumors after neurosurgical resection. We now report mature results of this trial, its outcomes, and a toxicity profile. METHODS AND MATERIALS: Ten adult consecutive patients with recurrent and newly diagnosed CNS malignancies underwent GliaSite brachytherapy after maximally safe neurosurgical resection between 2004 and 2007. GliaSite balloon was placed intraoperatively, and the size was selected so as to conform to the surgical cavity. Low-dose-rate radiation was delivered with an aqueous solution of organically bound (125)I (Iotrex: sodium 3-((125)I)-iodo-4-hydroxybenzenesulfonate; Proxima Therapeutics Inc.), introduced into the balloon portion of the device via a subcutaneous port. Two to 3 weeks later, the device was filled with Iotrex for a median dwell time of 94.3 hours (range, 68.0-120.5 hours), after which the balloon was explanted. A commercial 3-D planning system was used for a detailed analysis of dosimetry. Median dose of 52.0 Gy (range, 45.0-60.0 Gy) was prescribed 0.5-1.0 cm from the balloon surface. Radiation Therapy Oncology Group (RTOG) criteria were used to assess acute and long-term toxicities associated with this technique. Followup was assessed with MRI scans and was available on all enrolled patients. RESULTS: Median followup for surviving patients was 38 months (range, 18-57 months). Mean size of GliaSite balloon was 3.4 cm (range, 2.0-4.0 cm). Mean volume of filling was 19.0 cc (range, 4.0-35.0 cc). Median activity of Iotrex was 301.6 mCi (range, 95.0-515.4 mCi). Median survival was 14.0 months for the entire cohort after the treatment with the GliaSite device. Of our cohort, 6/10 (60%) patients sustained recurrence (20% local and 40% distant). Median time to recurrence after treatment with GliaSite was 8.0 months, and median time to death after recurrence was 7.5 months. There were no RTOG Grade 3 or 4 acute or late toxicities. Followup MRI imaging did not identify any evidence of radiation necrosis. CONCLUSIONS: Our data indicate that treatment with GliaSite balloon brachytherapy is feasible and safe, while rendering acceptable local control and minimal acute and long-term toxicities for newly diagnosed and recurrent CNS malignancies. These encouraging results compel us to embark on testing larger numbers of patients with this treatment modality.

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.

Results and risk factors for recurrence following single-level tubular lumbar microdiscectomy.

OBJECT: The use of minimally invasive surgical techniques, including microscope-assisted tubular lumbar microdiscectomy (tLMD), has gained increasing popularity in treating lumbar disc herniations (LDHs). This particular procedure has been shown to be both cost-efficient and effective, resulting in outcomes comparable to those of open surgical procedures. Lumbar disc herniation recurrence necessitating reoperation, however, remains an issue following spinal surgery, with an overall reported incidence of approximately 3-13%. The authors' aim in the present study was to report their experience using tLMD for single-level LDH, hoping to provide further insight into the rate of surgical recurrence and to identify potential risk factors leading to this complication. METHODS: The authors retrospectively reviewed the cases of 217 patients who underwent tLMD for single-level LDH performed identically by 2 surgeons (J.B., R.H.) between 2004 and 2008. Evaluation for LDH recurrence included detailed medical chart review and telephone interview. Recurrent LDH was defined as the return of preoperative signs and symptoms after an interval of postoperative resolution, in conjunction with radiographic demonstration of ipsilateral disc herniation at the same level and pathological confirmation of disc material. A cohort of patients without recurrence was used for comparison to identify possible risk factors for recurrent LDH. RESULTS: Of the 147 patients for whom the authors were able to definitively assess symptomatic recurrence status, 14 patients (9.5%) experienced LDH recurrence following single-level tLMD. The most common level involved was L5-S1 (42.9%) and the mean length of time to recurrence was 12 weeks (range 1.5-52 weeks). Sixty-four percent of the patients were male. In a comparison with patients without recurrence, the authors found that relatively lower body mass index was significantly associated with recurrence (p = 0.005), such that LDH in nonobese patients was more likely to recur. CONCLUSIONS: Recurrence rates following tLMD for LDH compare favorably with those in patients who have undergone open discectomy, lending further support for its effectiveness in treating single-level LDH. Nonobese patients with a relatively lower body mass index, in particular, appear to be at greater risk for recurrence.

Corticorelin acetate injections for the treatment of peritumoral brain edema.

BACKGROUND: The use of corticosteroids has been shown to be effective in the management of vasogenic edema caused by brain tumors, and is currently the standard of care. The associated systemic side effects, however, can be even more debilitating than the primary disease process, ultimately warranting premature discontinuation of steroids in some patients. In response, corticorelin acetate, a synthetic targeted human corticotropin-releasing factor (hCRF) analogue, has been developed to simulate the benefits of corticosteroids in treating peritumoral brain edema (PBE), while sparing the systemic toxicity. OBJECTIVE: This article reviews the development of corticorelin acetate and its potential role in treating PBE as an alternative to standard corticosteroid therapy. METHODS: Relevant articles and abstracts were obtained from searches of the medical and chemical literature databases, as well as from the references from published articles. RESULTS/CONCLUSION: Animal studies and a Phase I randomized trial have demonstrated that hCRF is well tolerated and effective in reducing PBE and its associated signs and symptoms. In addition, the effectiveness of this drug may be helpful in sparing the use of corticosteroid therapy in patients with brain tumors, with the results from several multicenter, randomized, placebo-controlled, Phase III clinical trials currently pending.

Gastric bypass: a risk factor for neural tube defects? Case report.

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.