Carrie R. Muh

PI-3 Kinase-PTEN Signaling Node: An Intercept Point for the Control of Angiogenesis

Angiogenesis is tightly regulated by opposing mechanisms in mammalian cells and is controlled by the angiogenic switch. Other review articles have described a central role for the PTEN/PI-3 kinase/AKT signaling node in the coordinate control of cell division, tumor growth, apoptosis, invasion and cellular metabolism [1, 2]. In this review, we focus on literature that supports the PTEN/PI-3 kinase/AKT signaling node as a major control point for the angiogenic switch in both the on and off positions. We also discuss the rationale for designing small molecule drugs that target the PTEN/PI-3 kinase/AKT signaling node for therapeutic intervention. Our hypothesis is that, instead of inhibiting one cell surface receptor, such as VEGFR2 with bevacizumab (Avastin), thereby leaving a significant number of receptors free to pulse angiogenic signals, a more effective strategy may be to regulate signaling through an intercept node where redundant cell surface receptor signals converge to transmit important signaling events within the cell. This therapeutic configuration brings coordinate control over multiple cell surface receptors in concert with a physiologic response which may combine arrest of cell cycle progression with growth inhibition and the induction of genes involved in specialized functions such as movement, which are all required for the complex process of angiogenesis to occur in a temporal-spatial paradigm.

PTEN status mediates 2ME2 anti-tumor efficacy in preclinical glioblastoma models: role of HIF1α suppression

AbstractGlioblastoma (GBM) is the most common brain cancer and is highly lethal in both adults and children. 2-methoxyestradiol (2ME2) is a microtubule inhibitor that potently inhibits HIF1α, GBM angiogenesis and tumor growth in preclinical models. In patients, 2ME2 exhibits low toxicity and promising but inconsistent efficacy. Given its preclinical potency and its tolerability in patients, we sought to determine whether 2ME2 therapy could be enhanced by addressing resistance via combination therapy, and with biomarkers to identify responsive glioma subgroups. We demonstrate that the PTEN–PI3K axis regulates HIF1α in glioma models. We utilized isogenic-pairs of glioma cell lines, deficient in PTEN or stably reconstituted with PTEN, to determine the role of PTEN in 2ME2 sensitivity in vitro and in vivo. Chou–Talalay synergy studies reveal significant synergy when a pan-PI3K inhibitor is combined with 2ME2. This synergistic activity was correlated with a synergistic suppression of HIF1α accumulation under hypoxic conditions in glioma models. In vivo, 2ME2 markedly inhibited tumor-induced angiogenesis and significantly reduced tumor growth only in a PTEN reconstituted GBM models in both subcutaneous and orthotopic intracranial mouse models. Collectively, these results: (1) suggest that PTEN status predicts sensitivity to 2ME2 and (2) justify exploration of 2ME2 combined with pan-PI3K inhibitors for the treatment of this intractable brain cancer.

Morphometric Analysis of Predictors of Cervical Syrinx Formation in the Setting of Chiari I Malformation.

Background/Aims: We performed a morphometric analysis of Chiari I malformations to look for predictors of cervical syrinx formation. Methods: Eighteen patients with Chiari I malformation and associated cervical syrinx and 16 patients with Chiari I malformation without associated cervical syrinx were included in the study. Chiari I size was obtained from the radiology report; foramen magnum diameter, cerebellar volume, posterior fossa volume and intracranial volume were calculated using OsiriX software, and average measurements were compared between the two groups. Results and Conclusion: Patients with Chiari I with syrinx had an average tonsillar descent of 13.03 ± 5.31 mm compared to 9.25 ± 3.31 mm in the Chiari I without syrinx group (p < 0.05). Patients with Chiari I and syrinx also showed increased cerebellar crowding with a higher cerebellar volume to posterior fossa volume ratio; however, this difference was not significant (0.83 vs. 0.81; p = 0.1872). No difference between groups was found in posterior fossa volume, intracranial volume and foramen magnum diameter. Therefore, only Chiari I size based on the extent of tonsillar herniation was found to be a determinant of cervical syrinx formation.

Rates and predictors of success and failure in repeat epilepsy surgery: A meta‐analysis and systematic review

Medically refractory epilepsy is a debilitating disorder that is particularly challenging to treat in patients who have already failed a surgical resection. Evidence regarding outcomes of further epilepsy surgery is limited to small case series and reviews. Therefore, our group performed the first quantitative meta‐analysis of the literature from the past 30 years to assess for rates and predictors of successful reoperations.

Current and Emerging Surgical Therapies for Severe Pediatric Epilepsies

The use of epilepsy surgery in various medically resistant epilepsies is well established. For patients with intractable pediatric epilepsy, the role of intracranial electrodes, resective surgery, hemispherectomy, corpus callosotomy, neurostimulation, and multiple subpial transections continues to be very effective in select cases. Newer treatment and diagnostic methods include laser thermal ablation, minimally invasive surgeries, stereo electroencephalography, electrocorticography, and other emerging techniques. This article will review the established and emerging surgical therapies for severe pediatric epilepsies, their respective indications and overall efficacy.

Clinical problem solving: monster on the hook--case problems in neurosurgery.

BACKGROUND AND OBJECTIVE:Nonfunctioning and functioning pituitary tumors can present in numerous ways. They may be difficult to diagnose correctly and, even with proper treatment, may lead to complications. METHODS:We present the case of a patient who presented with a large, invasive sellar mass and underwent both medical and surgical treatment for this lesion. The patients course did not progress as was expected from his initial workup. RESULTS:The patients history, physical examination, laboratory values, pathologic specimens, and radiologic findings are discussed. His management before, during, and after medical therapy and surgery is reviewed by pituitary experts from 2 different institutions. Aspects of diagnosis and management of sellar lesions are presented and reviewed in the literature. CONCLUSION:Neurosurgeons frequently treat patients with sellar lesions and should remember that despite modern laboratory, pathologic, and radiologic techniques, the diagnosis and treatment of these lesions is not always clear.

Non-functioning Adenomas: Diagnosis and Treatment

Nonfunctioning pituitary adenomas are benign lesions that generally present secondary to mass effect on the pituitary gland or optic nerves, leading to hypopituitarism and visual field defects. Surgical removal via a transsphenoidal approach is a safe and effective treatment for the vast majority of patients with these lesions. Here we will discuss the diagnosis and treatment of nonfunctioning pituitary adenomas.

Cortical Language Areas and Plasticity in Pediatric Patients with Epilepsy: a Review

Chronic injury to the brain from seizure activity is associated with decreased language skills in pediatric patients, as measured on neuropsychological tests for language function and academic achievement. This makes the study of language in patients with epilepsy clinically necessary. Functional magnetic resonance imaging and direct electrical cortical stimulation have been used to evaluate aspects of cortical language processing in healthy adults and in adults with epilepsy or other neurological insults. Results of these studies help to locate cortical language areas that are involved with modality-specific language processing (visual naming, auditory naming, sentence-completion, and repetition) and the neuroplasticity of language areas in the setting of neurological injury and reorganization. A better understanding of language processing contributes to a more efficient and efficacious electrical cortical stimulation mapping of language areas for patients with intractable epilepsy who are undergoing preresection evaluation. Most of the current literature on localization and reorganization of cortical language areas in the setting of epilepsy concerns the adult patient population, whereas the literature on pediatric patients is substantially lacking in comparison. This article reviews the conclusions drawn thus far from Wada, magnetoencephalography, functional magnetic resonance imaging, and electrical cortical stimulation language studies on types of language reorganization seen in pediatric patients with intractable temporal lobe epilepsy and the clinical factors associated with reorganization, and proposes future directions of research to further the academic and clinical understanding of language processing in pediatric patients.

Risk Factors for Delayed Referral to a Craniofacial Specialist for Treatment of Craniosynostosis

Objective To assess the impact of age at referral on treatment options in craniosynostosis and to identify risk factors for referral delays in this population. Study design A retrospective cohort study was performed on patients with an abnormal head shape diagnosis treated at a single academic medical center between January 1, 2004 and January 1, 2014. Newly diagnosed patients with craniosynostosis were identified and referral patterns were examined. A multivariate logistic regression model was used to identify risk factors associated with the range of ages at initial referral. Results A total of 477 patients were evaluated at our institution, 197 of whom were subsequently diagnosed with craniosynostosis. The median age at initial appointment was 5.6 months (mean 8.2 months). Only 28% of children were referred within 3 months of birth. Patients referred within 3 months of birth were less likely to have had preappointment imaging than those patients referred slightly later (OR 2.53, CI 1.07‐5.98, P = .035). Several variables were associated with referral after 12 months of age including multiple suture involvement (OR 4.21, CI 1.06‐16.68, P = .041), minority race (OR 4.96, CI 1.91‐12.9, P ≤ .0001), and referral by a nonpediatrician (OR 6.9, CI 1.73‐27.49, P = .006). Conclusions Obtaining imaging before referral to a specialist for abnormal head shape was associated with a delay in evaluation and potentially increases radiation exposure and limits treatment options in patients with craniosynostosis. In addition, children from minority groups, children referred from someone other than a pediatricians office, and those with multiple suture craniosynostosis are at increased risk of delayed referral. Further studies into the cause of these delays are warranted.

Temporary Lumbar Drain as Treatment for Pediatric Fulminant Idiopathic Intracranial Hypertension.

Fulminant idiopathic intracranial hypertension (FIIH) is a subtype of idiopathic intracranial hypertension (IIH) characterized by rapid, severe, progressive vision loss. Surgical intervention is often performed either as a cerebrospinal fluid (CSF) shunt procedure or an optic nerve sheath fenestration or, at times, both. These surgical procedures carry a significant risk of morbidity and failure. We present 2 patients in whom a temporary lumbar drain was successfully used in the management of medically undertreated pediatric FIIH, and circumvented the need for surgical intervention.