Shih-Shan Lang

Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas

Astrocytomas are the most common type of brain tumors in children. Activated BRAF protein kinase mutations are characteristic of pediatric astrocytomas with KIAA1549-BRAF fusion genes typifying low-grade astrocytomas and V600EBRAF alterations characterizing distinct or higher-grade tumors. Recently, BRAF-targeted therapies, such as vemurafenib, have shown great promise in treating V600E-dependent melanomas. Like V600EBRAF, BRAF fusion kinases activate MAPK signaling and are sufficient for malignant transformation; however, here we characterized the distinct mechanisms of action of KIAA1549-BRAF and its differential responsiveness to PLX4720, a first-generation BRAF inhibitor and research analog of vemurafenib. We found that in cells expressing KIAA1549-BRAF, the fusion kinase functions as a homodimer that is resistant to PLX4720 and accordingly is associated with CRAF-independent paradoxical activation of MAPK signaling. Mutagenesis studies demonstrated that KIAA1549-BRAF fusion-mediated signaling is diminished with disruption of the BRAF kinase dimer interface. In addition, the KIAA1549-BRAF fusion displays increased binding affinity to kinase suppressor of RAS (KSR), an RAF relative recently demonstrated to facilitate MEK phosphorylation by BRAF. Despite its resistance to PLX4720, the KIAA1549-BRAF fusion is responsive to a second-generation selective BRAF inhibitor that, unlike vemurafenib, does not induce activation of wild-type BRAF. Our data support the development of targeted treatment paradigms for BRAF-altered pediatric astrocytomas and also demonstrate that therapies must be tailored to the specific mutational context and distinct mechanisms of action of the mutant kinase.

Follow-up Imaging to Detect Recurrence of Surgically Treated Pediatric Arteriovenous Malformations

OBJECT The true postoperative incidence of arteriovenous malformation (AVM) recurrence in the pediatric population remains largely unreported. Some literature suggests that delayed imaging studies should be obtained at 6 months to 1 year after negative findings on a postoperative angiogram. The aim of this study was to describe the timing of AVM recurrences after resection and the neuroimaging modalities on which the recurrences were detected. METHODS This study was performed in a retrospective cohort of all pediatric patients treated surgically for AVM resection by a single neurosurgeon between 2005 and 2010. Patients were followed after resection with MR angiography (MRA) or conventional angiography, when possible, at various time points. A visual scale for compactness of the initial AVM nidus was used, and the score was correlated with probability of recurrence after surgery. RESULTS A total of 28 patients (13 female, 15 male) underwent an AVM resection. In 18 patients (64.3%) an intraoperative angiogram was obtained. In 4 cases the intraoperative angiogram revealed residual AVM, and repeat resections were performed immediately. Recurrent AVMs were found in 4 children (14.3%) at 50, 51, 56, and 60 weeks after the initial resection. Recurrence risk was 0.08 per person-year. No patient with normal results on an angiogram obtained at 1 year developed a recurrence on either a 5-year angiogram or one obtained at 18 years of age. All patients with recurrence had a compactness score of 1 (diffuse AVM); a lower compactness score was associated with recurrence (p = 0.0003). CONCLUSIONS All recurrences in this cohort occurred less than 15 months from the initial resection. The authors recommend intraoperative angiography to help ensure complete resection at the time of the surgery. Follow-up vascular imaging is crucial for detecting recurrent AVMs, and conventional angiography is preferred because MRA can miss smaller AVMs. One-year follow-up imaging detected these recurrences, and no one who had negative results on an angiogram obtained at 1 year had a late recurrence. However, not all of the patients have been followed for 5 years or until 18 years of age, so longer follow-up is required for these patients. A lower compactness score predicted recurrent AVM in this cohort.

Surgical Treatment of Brain Tumors in Infants Younger than Six Months of Age and Review of the Literature

OBJECTIVE Brain tumors are rare in infants who are younger than six months of age. These tumors can be challenging to treat surgically. We analyzed a modern series of patients treated by a multidisciplinary team at a tertiary care center and performed a literature review of this unique population. METHODS Retrospective clinical data were collected for patients surgically treated for intracranial mass lesions at The Childrens Hospital of Philadelphia from 1998 to 2007. Dermoid cysts and other skull-based lesions were excluded from the analysis. RESULTS Sixteen patients younger than six months of age underwent surgery for primary intracranial mass lesions. The median age of the patients at surgery was 5.2 months (range, 1.4-6 months of age). Children most often presented with a bulging fontanelle, hydrocephalus, or macrocephaly (seven patients). Vomiting was seen in five patients, cranial nerve palsies in one patient, and seizures in three patients. All patients had tumor resections and postoperatively were monitored in the intensive care unit. The final pathology consisted of atypical teratoid/rhabdoid tumor (three patients), primitive neuroectodermal tumor/medulloblastoma (three patients), choroid plexus papilloma (two patients), astrocytoma (two patients), ganglioglioma (two patients), desmoplastic infantile ganglioglioma (two patients), glioblastoma multiforme (one patient), and choroid plexus carcinoma (one patient). Two intraoperative deaths occurred. Of the surviving 14, a gross total resection was achieved in four. Adjuvant therapy was determined by a multidisciplinary team composed of neuro-oncology, neurosurgery, and radiation oncology. Seven patients were treated with chemotherapy, and one patient had proton beam therapy. Five-year overall survival was 45%. The eight surviving patients had neurological sequelae, and developmental outcome was variable. CONCLUSIONS Brain tumors are uncommon in children younger than six months of age. Patients present with a variety of tumor pathologies. Children who survive have neurological sequelae. More studies are necessary to understand the impact that different treatment options, tumor pathology, and tumor location have on neurological outcome.

An institutional series and literature review of pial arteriovenous fistulas in the pediatric population: clinical article.

OBJECT Pial arteriovenous fistulas (PAVFs) are a rare form of cerebrovascular disease that tend to be overrepresented in the pediatric population. There have been limited studies of the clinical features and outcomes in this group of patients. Here, the authors attempt to better delineate this clinical entity with institutional cases and a review of the literature. METHODS A retrospective review of cases at our institution was performed to identify all pediatric patients treated for a PAVF between 2000 and 2012. RESULTS Five patients treated for a PAVF were identified. Patients had a mean age of 1.9 years at diagnosis, and the most common presenting symptoms were seizure and macrocephaly. Patients were treated primarily with embolization, and 3 patients required both N-butyl cyanoacrylate (NBCA) glue and coiling. Four of the patients had complete obliteration of the PAVF and had a pediatric overall performance category score of either 1 (n = 3) or 2 (n = 1) at follow-up. There was 1 death due to heart failure. Analysis of the literature review suggested that a younger age or presence of intracerebral hemorrhage (ICH) or congestive heart failure (CHF) at presentation likely predicts a worse prognosis. Older patients presented more often with ICH, whereas younger patients presented significantly more often in CHF. The majority of pediatric patients reported on in the literature were treated with endovascular embolization, most commonly with NBCA glue alone. Most patients (65.4%) in the literature had an excellent outcome without neurological deficit. CONCLUSIONS Pial AVFs represent a serious yet rare form of cerebrovascular disease. Pediatric patients with ICH or CHF at presentation or those who are very young are likely to have a worse prognosis. Endovascular management of these patients has greatly changed the natural history of this disease, but the complication and mortality rates suggest the need for continued insights and advances in treatment.

Endoscopic Microvascular Decompression: A Stepwise Operative Technique.

Background/Aims: Microvascular decompression (MVD) of the trigeminal nerve is a widely accepted treatment for patients with trigeminal neuralgia caused by vascular compression. The neuroendoscope is rapidly becoming a complementary tool in minimally invasive neurosurgery of the ventral anterior skull base. Its adoption in the lateral approach to the posterior fossa has been slower and has been used primarily as an adjunct to conventional microscopic surgical techniques, e.g. endoscope-assisted microsurgery. Methods: In this paper, we describe a stepwise, technical commentary on a purely endoscopic MVD of the trigeminal nerve via the retrosigmoid route. Results: From our experience, the endoscope provides excellent visualization of the neurovascular relationship. By allowing full visualization of the trigeminal nerve, endoscopy may likely lead to an increase in the number of successful MVDs and a decrease in the number of complications. Conclusion: We believe endoscopic MVD is a safe and effective method of accessing the trigeminal nerve in the cerebellopontine angle and of performing MVD. This endoscopic technique can be implemented in other neurosurgical and neuro-otological procedures such as resection of cerebellopontine angle masses.

Lower incidence of reoperation with longer shunt survival with adult ventriculoperitoneal shunts placed for hemorrhage-related hydrocephalus.

OBJECTIVE The incidence of reoperation for ventriculoperitoneal shunts (VPS) in adults, although lower than in pediatric patients, is not insignificant. We hypothesize that adult VPS placed for hemorrhage-related hydrocephalus have a lower incidence of reoperation than those placed for other types of hydrocephalus. METHODS We retrospectively reviewed all adult (>/= 20 yr) VPS initially placed from February 2001 to August 2006 at the University of Florida. We determined the incidence and time interval to reoperation. Follow-up was conducted by telephone interview and review of medical records. RESULTS A total of 286 adult VPS were initially placed: 96 (34%) hemorrhage and 190 (66%) nonhemorrhage. A total of 15 (16%) hemorrhage patients underwent 22 shunt reoperations, compared with 50 (27%) nonhemorrhage patients who underwent 82 shunt reoperations (P = 0.0316). A Poisson regression analysis of the number of reoperations, factoring hemorrhage, age, and sex, demonstrated a significantly lower incidence of reoperation in hemorrhage patients (P = 0.0900). A Cox proportional hazards model analysis of time to first reoperation, factoring hemorrhage, age, and sex, demonstrated a significantly longer shunt survival in hemorrhage patients (P = 0.0404). CONCLUSION Adult VPS placed for hemorrhage-related hydrocephalus have a significantly lower incidence of reoperation and significantly longer shunt survival. This result may be related to an incidence of transient shunt dependency in patients with hemorrhage-related hydrocephalus. However, the precise mechanism remains unclear.

Evaluation of Optical Coherence Tomography to Detect Elevated Intracranial Pressure in Children

Importance Detecting elevated intracranial pressure in children with subacute conditions, such as craniosynostosis or tumor, may enable timely intervention and prevent neurocognitive impairment, but conventional techniques are invasive and often equivocal. Elevated intracranial pressure leads to structural changes in the peripapillary retina. Spectral-domain (SD) optical coherence tomography (OCT) can noninvasively quantify retinal layers to a micron-level resolution. Objective To evaluate whether retinal measurements from OCT can serve as an effective surrogate for invasive intracranial pressure measurement. Design, Setting, and Participants This cross-sectional study included patients undergoing procedures at the Children’s Hospital of Philadelphia from September 2014 to June 2015. Three groups of patients (n = 79) were prospectively enrolled from the Craniofacial Surgery clinic including patients with craniosynostosis (n = 40). The positive control cohort consisted of patients with hydrocephalus and suspected intracranial hypertension (n = 5), and the negative control cohort consisted of otherwise healthy patients undergoing a minor procedure (n = 34). Main Outcomes and Measures Spectral-domain OCT was performed preoperatively in all cohorts. Children with cranial pathology, but not negative control patients, underwent direct intraoperative intracranial pressure measurement. The primary outcome was the association between peripapillary retinal OCT parameters and directly measured elevated intracranial pressure. Results The mean (SD) age was 34.6 (45.2) months in the craniosynostosis cohort (33% female), 48.9 (83.8) months in the hydrocephalus and suspected intracranial hypertension cohort (60% female), and 59.7 (64.4) months in the healthy cohort (47% female). Intracranial pressure correlated with maximal retinal nerve fiber layer thickness (r = 0.60, P ⩽ .001), maximal retinal thickness (r = 0.53, P ⩽ .001), and maximal anterior retinal projection (r = 0.53, P = .003). Using cut points derived from the negative control patients, OCT parameters yielded 89% sensitivity (95% CI, 69%-97%) and 62% specificity (95% CI, 41%-79%) for detecting elevated intracranial pressure. The SD-OCT measures had high intereye agreement (intraclass correlation, 0.83-0.93) and high intragrader and intergrader agreement (intraclass correlation ≥0.94). Conventional clinical signs had low sensitivity (11%-42%) for detecting intracranial hypertension. Conclusions and Relevance Noninvasive quantitative measures of the peripapillary retinal structure by SD-OCT were correlated with invasively measured intracranial pressure. Optical coherence tomographic parameters showed promise as surrogate, noninvasive measures of intracranial pressure, outperforming other conventional clinical measures. Spectral-domain OCT of the peripapillary region has the potential to advance current treatment paradigms for elevated intracranial pressure in children.

Development of an outpatient protocol for lumbar discectomy: our institutional experience.

BACKGROUND Traditionally, lumbar discectomy has involved overnight hospital admission. Recent literature supports the shift to same-day lumbar discectomy because of improved outcomes and better patient satisfaction scores. A successful protocol for outpatient lumbar discectomies was proposed and implemented at a single institution. The aim of this study is to perform a quantitative and qualitative analysis of this institutional model. METHODS Retrospective clinical data were collected for patients who underwent a lumbar discectomy during the period 2008-2012. Admission and readmission rates, emergency department (ED) visit rates, surgical complications, and differences between neurosurgeons specializing in spinal procedures and neurosurgeons not specializing in spinal procedures were analyzed before and after implementation of the outpatient surgery protocol. RESULTS Of 1011 cases identified, 643 cases of lumbar discectomy were performed before the implementation of the protocol, and 368 cases were performed after implementation. The admission rate before the start date of the outpatient protocol was 96.4% versus 50.3% after implementation. After protocol implementation, the most common reasons for admission were uncontrolled pain (18.9%), late operative start times (14.1%), comorbidities (13%), and intraoperative operating room complications (11.9%). Intraoperative complications consisted almost exclusively of dural tears. The 30-day readmission rate after protocol initiation was 4.6% (n = 17 of 368) versus 2.3% (n = 15 of 643) before initiation (P = 0.046), and ED visit rate not requiring an admission was 2.2% (n = 8 of 368) versus 1.1% (n = 7 of 643) before initiation (P = 0.170). CONCLUSIONS Our data demonstrate that a collaborative protocol for outpatient discectomy can be implemented in a safe and effective manner despite a statistical increase in hospital readmissions. The percentage rates of readmissions and ED visits accounted for a very small percentage of the overall number of cases after protocol implementation. Improvements in perioperative pain management and ensuring that outpatient lumbar discectomies are scheduled early in the day may further decrease the number of admissions. Future studies should examine the societal and financial impact of same-day discectomy versus overnight hospital stays.

Fully Endoscopic Microvascular Decompression: Our Early Experience

Background. Microvascular decompression (MVD) is a widely accepted treatment for neurovascular disorders associated with facial pain and spasm. The endoscope has rapidly become a standard tool in neurosurgical procedures; however, its adoption in lateral approaches to the posterior fossa has been slower. The endoscope is used primarily to assist conventional microscopic techniques. We are interested in developing fully endoscopic approaches to the cerebellopontine angle, and here, we describe our preliminary experience with this procedure for MVD. Methods. A retrospective review of our two-year experience from 2011 to 2012, transitioning from using conventional microscopic techniques to endoscope-assisted microsurgery to fully endoscopic MVD, is provided. We also reviewed our preliminary outcomes during this transition. Results. There was no difference in the surgical duration of these three procedures. In addition, the majority of procedures performed in 2012 were fully endoscopic, suggesting the ease of incorporating this solo tool into practice. Pain outcomes of fully endoscopic MVD appear to be very similar to those of both conventional and endoscope-assisted MVDs. Complications occurred in all groups at equally low rates. Conclusion. Fully endoscopic MVD is both safe and effective. By enhancing visualization of structures within the cerebellopontine angle, endoscopy may prove to be a valuable adjunct or alternative to conventional microscopic approaches.

Conservative Management of Presumed Low-Grade Gliomas in the Asymptomatic Pediatric Population

OBJECTIVE The optimal management of asymptomatic children with small, nonenhancing intracranial lesions presumed to be low-grade gliomas (LGGs) is not entirely clear in the literature. However, surgical intervention via resection or biopsy is not without risk and is of questionable long-term benefit in children with stable lesions. We present a series of 12 patients with incidentally detected, small, nonenhancing, intracranial lesions that were managed with watchful waiting and serial magnetic resonance imaging (MRI) scans. METHODS We retrospectively reviewed a series of 12 children (eight boys, four girls) with T1 hypointense and T2 hyperintense intracranial lesions <2 cm without enhancement or surrounding edema. RESULTS Most patients (n = 5, 41.7%) received MRI studies after suffering a traumatic injury with evidence of an abnormality seen on computed tomography scan. Others received MRI scan as part of headache work-up (n = 4, 33.3%). The majority of lesions were located infratentorially (n = 8, 66.7%), whereas other locations included the frontal lobe and thalamus. The median age of the patients upon identification of the intracranial abnormality was 10 years (range, 1-19 years of age). Patients were followed for a median of 16.7 months (range, 2.7-59.5 months). The most common diagnosis based on clinical and radiographic features of these lesions consisted of LGG. No patient underwent surgery, radiation therapy, or chemotherapy except one patient, in whom the lesion grew in size. Surgical pathologic diagnosis in this case confirmed World Health Organization grade II astrocytoma. CONCLUSIONS Our case series suggests that conservative management and close follow-up of incidental radiographic lesions consistent with LGGs is a safe and effective initial strategy in the pediatric population. In cases in which lesion size or quality changes, surgical resection may be necessary to confirm diagnosis. Further studies that include a larger number of patients and longer follow-up period are required to compare outcomes between this approach and initial surgical, radiation, or chemotherapy management strategies.