Early Developmental Trajectories in Infants With Neurofibromatosis 1.

Objective: To examine the trajectories of cognitive, motor and behavioural development in infants with NF1 compared to infants without a family history of neurodevelopmental difficulties. Study design: Infants with NF1 and low-risk controls were recruited from 5 months of age and followed longitudinally. Data from standardised tests was gathered at 5, 10 and 14 months and developmental trajectories of motor, language, behaviour, sleep, social development and parent-infant interaction were examined. Linear mixed modelling was used to estimate group differences in cognitive and behavioural measures over time. Results: No group differences were observed on Mullen Scale of Early Learning, overall adaptive functioning, temperament or behavioural measures. There were no group differences observed on measures of social communication or parent-infant interaction. Over the course of development, the NF1 group slept less and took more time to settle to sleep as compared to the control group. Maternal education was significantly associated with cognitive and behavioural developmental outcomes in both groups. Conclusion: Cognitive, social and behavioural impairments are a cause of significant functional morbidity in children with NF1. This report is the first study to investigate the trajectories of cognitive, motor and behavioural development in infancy in NF1. Our results demonstrate that overall cognitive and behavioural developmental trajectories of the NF1 group in the infancy period are similar to controls. Given previous reports of delayed development in the NF1 cohort by 40 months, early clinical interventions strategies to promote sleep hygiene may be beneficial to optimise developmental outcomes.

Pilocytic astrocytoma of the optic nerve with intracystic hemorrhage in an adult: illustrative case.

BACKGROUND: Optic pathway gliomas are uncommon, accounting for 3-5% of childhood brain tumors, and are mostly classified as pilocytic astrocytomas (PAs). PAs of the optic nerve are particularly rare in adults. OBSERVATIONS: The authors presented the case of PA of the left optic nerve in a 49-year-old woman along with detailed pathological and molecular analyses and sequential magnetic resonance imaging. The tumor had progressed during 5 years of follow-up along with cyst formation and intracystic hemorrhage; it had a thick capsule and contained xanthochromic fluid. The boundary between tumor and optic nerve was unclear. B-type Raf kinase (BRAF) V600E point mutations or translocations, IDH1-R132H mutations, loss of alpha-thalassemia/mental retardation X-linked, and 1p/19q codeletion were negative. LESSONS: BRAF alterations in pediatric PAs of the optic nerve are less frequent than those observed in PAs in other lesions; the same molecular pattern was observed in the adult case, without changes in BRAF. Surgical management should be indicated only in cases with severely impaired vision or disfigurement because there is no clear border between the tumor and optic nerve. Further discussion is needed to optimize the treatment for adult optic pathway gliomas, including radiotherapy, chemotherapy, and molecular-targeted therapies, in addition to surgical intervention.

Case report: Neurofibromatosis type 1 gastrointestinal stromal tumor and small bowel adenocarcinoma with a novel germline NF1 frameshift mutation.

A synchronous case of small bowel adenocarcinoma(SAB) is reported, accompanied with gastrointestinal stromal tumor(GIST),and gangliocytomain in an elderly woman with neurofibromatosis type 1 (NF-1). A 67-year-old female was hospitalized with the chief complaint of abdominal pain, the computed tomography scan indicated a large bowel mass. Multiple tumors were found in the small intestine, through which two larger tumors (7 cm and 1.5 cm) were resected. A novel germline NF1 mutation and a PMS2 mutation were identified after genetic testing, followed by the exploration of possible relationship between them in promoting tumorigenesis. Our results suggest multiple gastrointestinal tumors emerging in NF1 patients, and genetic testing can better guide postoperative treatment in a more efficient way.

The recurrent plexiform neurofibroma of the scalp in neurofibromatosis type 1: illustrative case.

BACKGROUND: Plexiform neurofibroma is a benign tumor of the peripheral nerves. It is an unusual variant of neurofibroma originating from all parts of the nerve. Plexiform neurofibroma is primarily pathognomonic and exhibits an unusual variant from neurofibromatosis type 1 (NF1). The possibility of malignancy and recurrence are the main reasons for long-term, close follow-up. OBSERVATIONS: The authors report a case of a 14-year-old girl with a recurrent plexiform neurofibroma derived from the peripheral nerves, which also presented with a typical sign of NF1 disease. The aim of the tumor resection is symptomatic relief. LESSONS: Accomplishing a good outcome can be related to good perioperative planning and a precise operative procedure. The result of anatomical pathology determines the prognosis of the patient. Clinical examination and radiological studies are needed to evaluate the recurrence of complications after surgical procedures.

Surgical repair of a large intrathoracic meningocele associated with neurofibromatosis type 1 after failed cystoperitoneal shunts: illustrative case.

BACKGROUND: Surgical treatment of intrathoracic meningoceles, commonly associated with neurofibromatosis type 1 (NF1), aims to reduce sac size for symptomatic relief. The procedures can be divided into cerebrospinal fluid diversion and definitive repair. The authors describe the management of an intrathoracic meningocele in a 56-year-old female with preexisting NF1. OBSERVATIONS: The patient presented with progressive dyspnea. Magnetic resonance imaging revealed a left hemithoracic meningocele arising from the thecal sac at C7-T2. Two attempts at diversion by cystoperitoneal shunts resulted in recurrence. For definitive repair, T2-3 costotransversectomy was performed, and intradural closure of the meningocele opening was performed utilizing spinal dura and autologous fascia lata graft. Trapezius muscle regional flap was turned for reinforcement. Persistent leak warranted reoperation 7 days later. A transthoracic approach was undertaken using video-assisted thoracoscopic resection of the sac at aortic arch level, with reinforcement by latissimus dorsi flap and synthetic materials. Mechanical pleurodesis was performed. Intradural repair of the meningocele opening was revised. LESSONS: Inherent dural abnormality makes repair difficult for meningoceles associated with NF1. A combined intradural and thoracoscopic approach with regional muscle flap and synthetic material reinforcement is a unique method for definitive treatment. Some essential points of perioperative management are highlighted.

Disseminated craniospinal low-grade glioma in a patient with NF-1 without optic pathway pathology: illustrative case.

BACKGROUND: Neurofibromatosis type 1 (NF-1) is a neurocutaneous autosomal dominant disorder that predisposes patients to develop intracranial low-grade gliomas (LGGs). Most LGGs in patients with NF-1 involve the optic pathway but can arise anywhere throughout the central nervous system. NF-1-related disseminated pediatric LGG (dPLGG) in the absence of a dominant optic pathway glioma has not been described. OBSERVATIONS: The authors discussed a case of a 10-year-old boy who presented with consideration for biopsy with nonoptic pathway PLGG with craniospinal dPLGG in the setting of NF-1. The patient's primary lesion, located in the right medulla, was initially treated with surveillance before induction chemotherapy with carboplatin and vincristine was initiated. However, surveillance imaging demonstrated significant increase in size and enhancement, and subsequent craniospinal imaging demonstrated extensive nodular dissemination in the cervicothoracic spine. A biopsy and molecular testing were subsequently performed to further evaluate the tumor, and the patient was diagnosed with dPLGG with CDKN2A deletion. LESSONS: Thorough craniospinal magnetic resonance imaging evaluation and biopsy in nonoptic pathway-dominant brain lesions in NF-1 are warranted in patients with atypical clinical and radiological findings in whom standard chemotherapeutic therapy fails.

Outcomes of growing rods in a series of early-onset scoliosis patients with neurofibromatosis type 1.

OBJECTIVE: Early-onset scoliosis (EOS) is not uncommon in patients with neurofibromatosis type 1 (NF1). Despite conservative treatment, spinal deformities progress and require early surgical intervention. To avoid potential interference with chest and trunk growth, growing rods (GRs) have been used effectively in EOS of various etiologies. In this study the authors sought to analyze the outcomes of GRs in EOS patients with NF1. METHODS: This was a retrospective single-center cohort study that included consecutive EOS patients with NF1 who were treated with GRs and were followed up for a minimum of 2 years. Clinical and radiological analyses were performed preoperatively and until the last follow-up. RESULTS: From to 2008 to 2017, 18 patients (6 male, 12 female) underwent GR surgery (14 single GRs, 4 dual GRs) at a mean age of 8 ± 2.1 years. Mean follow-up was 5 ± 2.4 years. Fifty-five lengthenings were performed at a mean rate of 3 lengthenings per patient (range 0-7). Ten of 14 single GRs (71%) were converted into dual GRs during treatment. No patient underwent definitive posterior spinal fusion (PSF) at GR treatment completion. The mean initial and last follow-up major curves were 57° and 36°, respectively (p < 0.001, 37% correction). The average T1-S1 increase was 13 mm/yr. Six of 9 hyperkyphotic patients had normal kyphosis at last follow-up. There were 26 complications involving 13 patients (72%), with 1 patient who required unplanned revision. The primary complications were instrumentation related, consisting of 17 proximal hook dislodgments, 6 distal pedicle screw pullouts, and 2 rod fractures. Only 1 patient experienced a mechanical complication after dual GR implantation. There were no wound infections. CONCLUSIONS: The GR technique provided satisfactory spinal deformity control in EOS patients with NF1 while allowing substantial spinal growth. Adequately contoured dual GRs with proximal hooks placed in nondystrophic regions should be used to minimize implant-related complications. Surgeons should not attempt to correct kyphosis at GR implantation.

Halo-gravity traction for the treatment of pediatric cervical spine disorders.

OBJECTIVE: Halo-gravity traction (HGT) is an effective and safe method for gradual correction of severe cervical deformities in adults. However, the literature is limited on the use of HGT for cervical spine deformities that develop in children. The objective of the present study was to evaluate the safety and efficacy of HGT for pediatric cervical spine deformities. METHODS: Twenty-eight patients (18 females) whose mean age was 11.3 ± 5.58 years (range 2-24.9 years) underwent HGT. Common indications included kyphosis (n = 12), rotatory subluxation (n = 7), and basilar invagination (n = 6). Three children (11%) received traction to treat severe occipitocervical instability. For these 3 patients, traction combined with a halo vest, with bars attached rigidly to the vest, but with the ability to slide through the connections to the halo crown, was used to guide the corrective forces and moments in a specific and controlled manner. Patients ambulated with a wheelchair or halo walker under constant traction. Imaging was done before and during traction to evaluate traction efficacy. The modified Clavien-Dindo-Sink classification was used to categorize complications. RESULTS: The mean duration of HGT was 25 days (IQR 13-29 days), and the mean traction was 29% ± 13.0% of body weight (IQR 19%-40% of body weight). The mean kyphosis improved from 91° ± 20.7° (range 64°-122°) to 56° ± 17.6° (range 32°-96°) during traction and corresponded to a mean percentage kyphosis correction of 38% ± 13.8% (range 21%-57%). Twenty-five patients (89%) underwent surgical stabilization, and 3 patients (11%) had rotatory subluxation that was adequately reduced by traction and were treated with a halo vest as their definitive treatment. The mean hospital stay was 35 days (IQR 17-43 days).Nine complications (32%) occurred: 8 grade I complications (28%), including 4 cases of superficial pin-site infection (14%) and 4 cases of transient paresthesia (14%). One grade II complication (4%) was seen in a child with Down syndrome and a preexisting neurological deficit; this patient developed flaccid paralysis that rapidly resolved with weight removal. Six cases (21%) of temporary neck discomfort occurred as a sequela of a preexisting condition and resolved without treatment within 24-48 hours. CONCLUSIONS: HGT in children is safe and effective for the gradual correction of cervical kyphosis, atlantoaxial subluxation, basilar invagination, and os odontoideum. Cervical traction is an additional tool for the pediatric spine surgeon if uncertainties exist that the spinal alignment required for internal fixation and deformity correction can be safely achieved surgically. Common complications included grade I complications such as superficial pin-site infections and transient paresthesias. Halo vest gravity traction may be warranted in patients with baseline neurological deficits and severe occipitocervical instability to reduce the chance of catastrophic movement.

Safe marginal resection of atypical neurofibromas in neurofibromatosis type 1.

OBJECTIVE: Patients with neurofibromatosis type 1 (NF1) are predisposed to visceral neurofibromas, some of which can progress to premalignant atypical neurofibromas (ANFs) and malignant peripheral nerve sheath tumors (MPNSTs). Though subtotal resection of ANF may prevent malignant transformation and thus deaths with no neural complications, local recurrences require reoperation. The aim of this study was to assess the surgical morbidity associated with marginal resection of targeted ANF nodules identified via preoperative serial volumetric MRI and 18F-FDG-PET imaging. METHODS: The authors analyzed clinical outcomes of 16 NF resections of 21 tumors in 11 NF1 patients treated at the NIH Clinical Center between 2008 and 2018. Preoperative volumetric growth rates and 18F-FDG-PET SUVMax (maximum standardized uptake value within the tumor) of the target lesions and any electromyographic or nerve conduction velocity abnormalities of the parent nerves were measured and assessed in tandem with postoperative complications, histopathological classification of the resected tumors, and surgical margins through Dunnett's multiple comparisons test and t-test. The surgical approach for safe marginal resection of ANF was also described. RESULTS: Eleven consecutive NF1 patients (4 male, 7 female; median age 18.5 years) underwent 16 surgical procedures for marginal resections of 21 tumors. Preoperatively, 13 of the 14 (93%) sets of serial MRI studies and 10 of the 11 (91%) 18F-FDG-PET scans showed rapid growth (≥ 20% increase in volume per year) and avidity (SUVMax ≥ 3.5) of the identified tumor, respectively (median tumor size 48.7 cm3; median growth rate 92% per year; median SUVMax 6.45). Most surgeries (n = 14, 88%) resulted in no persistent postoperative parent nerve-related complications, and to date, none of the resected tumors have recurred. The median length of postoperative follow-up has been 2.45 years (range 0.00-10.39 years). Histopathological analysis confirmed significantly greater SUVMax among the ANFs (6.51 ± 0.83, p = 0.0042) and low-grade MPNSTs (13.8, p = 0.0001) than in benign neurofibromas (1.9). CONCLUSIONS: This report evaluates the utility of serial imaging (MRI and 18F-FDG-PET SUVMax) to successfully detect ANF and demonstrates that safe, fascicle-sparing gross-total, extracapsular resection of ANF is possible with the use of intraoperative nerve stimulation and microdissection of nerve fascicles.

Perioperative acute neurological deficits in instrumented pediatric cervical spine fusions.

OBJECTIVE: Pediatric cervical deformity is a complex disorder often associated with neurological deterioration requiring cervical spine fusion. However, limited literature exists on new perioperative neurological deficits in children. This study describes new perioperative neurological deficits in pediatric cervical spine instrumentation and fusion. METHODS: A single-center review of pediatric cervical spine instrumentation and fusion during 2002-2018 was performed. Demographics, surgical characteristics, and neurological complications were recorded. Perioperative neurological deficits were defined as the deterioration of preexisting neurological function or the appearance of new neurological symptoms. RESULTS: A total of 184 cases (160 patients, 57% male) with an average age of 12.6 ± 5.30 years (range 0.2-24.9 years) were included. Deformity (n = 39) and instability (n = 36) were the most frequent indications. Syndromes were present in 39% (n = 71), with Down syndrome (n = 20) and neurofibromatosis (n = 12) the most prevalent. Eighty-seven (48%) children presented with preoperative neurological deficits (16 sensory, 16 motor, and 55 combined deficits).A total of 178 (96.7%) cases improved or remained neurologically stable. New neurological deficits occurred in 6 (3.3%) cases: 3 hemiparesis, 1 hemiplegia, 1 quadriplegia, and 1 quadriparesis. Preoperative neurological compromise was seen in 4 (67%) of these new deficits (3 myelopathy, 1 sensory deficit) and 5 had complex syndromes. Three new deficits were anticipated with intraoperative neuromonitoring changes (p = 0.025).Three (50.0%) patients with new neurological deficits recovered within 6 months and the child with quadriparesis was regaining neurological function at the latest follow-up. Hemiplegia persisted in 1 patient, and 1 child died due a complication related to the tracheostomy. No association was found between neurological deficits and indication (p = 0.96), etiology (p = 0.46), preoperative neurological symptoms (p = 0.65), age (p = 0.56), use of halo vest (p = 0.41), estimated blood loss (p = 0.09), levels fused (p = 0.09), approach (p = 0.07), or fusion location (p = 0.07). CONCLUSIONS: An improvement of the preexisting neurological deficit or stabilization of neurological function was seen in 96.7% of children after cervical spine fusion. New or progressive neurological deficits occurred in 3.3% of the patients and occurred more frequently in children with preoperative neurological symptoms. Patients with syndromic diagnoses are at higher risk to develop a deficit, probably due to the severity of deformity and the degree of cervical instability. Long-term outcomes of new neurological deficits are favorable, and 50% of patients experienced complete neurological recovery within 6 months.

Genetic basis of intracranial aneurysm formation and rupture: clinical implications in the postgenomic era.

OBJECTIVE: Despite the prevalence and impact of intracranial aneurysms (IAs), the molecular basis of their pathogenesis remains largely unknown. Moreover, there is a dearth of clinically validated biomarkers to efficiently screen patients with IAs and prognosticate risk for rupture. The aim of this study was to survey the literature to systematically identify the spectrum of genetic aberrations that have been identified in IA formation and risk of rupture. METHODS: A literature search was performed using the Medical Subject Headings (MeSH) system of databases including PubMed, EMBASE, and Google Scholar. Relevant studies that reported on genetic analyses of IAs, rupture risk, and long-term outcomes were included in the qualitative analysis. RESULTS: A total of 114 studies were reviewed and 65 were included in the qualitative synthesis. There are several well-established mendelian syndromes that confer risk to IAs, with variable frequency. Linkage analyses, genome-wide association studies, candidate gene studies, and exome sequencing identify several recurrent polymorphic variants at candidate loci, and genes associated with the risk of aneurysm formation and rupture, including ANRIL (CDKN2B-AS1, 9p21), ARGHEF17 (11q13), ELN (7q11), SERPINA3 (14q32), and SOX17 (8q11). In addition, polymorphisms in eNOS/NOS3 (7q36) may serve as predictive markers for outcomes following intracranial aneurysm rupture. Genetic aberrations identified to date converge on posited molecular mechanisms involved in vascular remodeling, with strong implications for an associated immune-mediated inflammatory response. CONCLUSIONS: Comprehensive studies of IA formation and rupture have identified candidate risk variants and loci; however, further genome-wide analyses are needed to identify high-confidence genetic aberrations. The literature supports a role for several risk loci in aneurysm formation and rupture with putative candidate genes. A thorough understanding of the genetic basis governing risk of IA development and the resultant aneurysmal subarachnoid hemorrhage may aid in screening, clinical management, and risk stratification of these patients, and it may also enable identification of putative mechanisms for future drug development.

Need for arthrodesis following facetectomy for spinal peripheral nerve sheath tumors: an institutional experience and review of the current literature.

OBJECTIVE: Spinal peripheral nerve sheath tumors (PNSTs) are a group of rare tumors originating from the nerve and its supporting structures. Standard surgical management typically entails laminectomy with or without facetectomy to gain adequate tumor exposure. Arthrodesis is occasionally performed to maintain spinal stability and mitigate the risk of postoperative deformity, pain, or neurological deficit. However, the factors associated with the need for instrumentation in addition to PNST resection in the same setting remain unclear. METHODS: An institutional tumor registry at a tertiary care center was queried for patients treated surgically for a primary diagnosis of spinal PNST between 2002 and 2016. An analysis focused on patients in whom a facetectomy was performed during the resection. The addition of arthrodesis at the index procedure comprised the primary outcome. The authors also recorded baseline demographics, tumor characteristics, and surgery-related variables. Logistic regression was used to identify factors associated with increased risk of fusion surgery. RESULTS: A total of 163 patients were identified, of which 56 (32 had facetectomy with fusion, 24 had facetectomy alone) were analyzed. The median age was 48 years, and 50% of the cohort was female. Age, sex, and race, as well as tumor histology and size, were evenly distributed between patients who received facetectomy alone and those who had facetectomy and fusion. On univariate analysis, total versus subtotal facetectomy (OR 9.0, 95% CI 2.01-64.2; p = 0.009) and cervicothoracic versus other spinal region (OR 9.0, 95% CI 1.51-172.9; p = 0.048) were significantly associated with increased odds of performing immediate fusion. On multivariable analysis, only the effect of total facetectomy remained statistically significant (OR 6.75, 95% CI 1.47-48.8; p = 0.025). CONCLUSIONS: The authors found that total facetectomy and cervicothoracic involvement may be highly associated with the need for concomitant arthrodesis at the time of index surgery. These findings may help surgeons to determine the best surgical planning for patients with PNST.

Results of more than 20 years of follow-up in pediatric patients with moyamoya disease undergoing pial synangiosis.

OBJECTIVEThere are limited data on the long-term outcomes for children undergoing surgical revascularization for moyamoya disease (MMD) in North America. The authors present a series of pediatric MMD patients who underwent a standard revascularization procedure, pial synangiosis, more than 20 years previously at a single institution by a single surgical team.METHODSThis study is a retrospective review of all patients aged 21 years or younger treated for MMD at Boston Children's Hospital who were operated on more than 20 years previously by the senior author (R.M.S.). Radiographic and operative reports, outpatient clinical records, and communications with patients and families were reviewed to document current clinical status, ability to perform daily activities, and concurrent or new medical conditions.RESULTSA total of 59 patients (38 female [64.4%], 21 male [35.6%]; median age at surgery 6.2 years [IQR 0.5-21 years]) were identified who were diagnosed with MMD and underwent surgical revascularization procedures more than 20 years previously. Clinically, all but 2 patients (96.6%) presented with the following symptoms alone or in combination: 43 (73%) presented with stroke, 22 (37%) with transient ischemic attack, 12 (20%) with seizures, 7 (12%) with headache, 3 (5%) with choreiform movements, and 2 (3%) with hemorrhage; MMD was incidentally detected in 2 patients (3%). Five patients had unilateral MMD at presentation, but 3 of these ultimately progressed to develop bilateral MMD after an average of 16 months; therefore, pial synangiosis was ultimately performed in a total of 116 hemispheres during the study period. Clinical follow-up was available at a median interval of 20.6 years (IQR 16.1-23.2 years). Modified Rankin Scale scores were stable or improved in 43 of 50 patients with evaluable data; 45 of 55 are currently independent. There were 6 patient deaths (10.2%; 3 due to intracranial hemorrhage, 2 due to tumor-related complications, and 1 due to pulmonary artery stenosis), 4 of whom had a history of previous cranial radiation. One patient (1.7%) experienced a late stroke. Synangiosis vessels remained patent on all available late MRI and MRA studies. Four patients reported uneventful pregnancies and vaginal deliveries years following their revascularization procedures.CONCLUSIONSRevascularization for MMD by pial synangiosis appears to confer protection from stroke for pediatric patients over long-term follow-up. A history of cranial radiation was present in 4 of the 5 patients who died and in the lone patient with late stroke. Most patients can expect productive, independent lives following revascularization surgery in the absence of significant preoperative neurological deficits and comorbidities.

Childhood brain tumors: current management, biological insights, and future directions.

Brain tumors are the most common solid tumors in children, and, unfortunately, many subtypes continue to have a suboptimal long-term outcome. During the last several years, however, remarkable advances in our understanding of the molecular underpinnings of these tumors have occurred as a result of high-resolution genomic, epigenetic, and transcriptomic profiling, which have provided insights for improved tumor categorization and molecularly directed therapies. While tumors such as medulloblastomas have been historically grouped into standard- and high-risk categories, it is now recognized that these tumors encompass four or more molecular subsets with distinct clinical and molecular characteristics. Likewise, high-grade glioma, which for decades was considered a single high-risk entity, is now known to comprise multiple subsets of tumors that differ in terms of patient age, tumor location, and prognosis. The situation is even more complex for ependymoma, for which at least nine subsets of tumors have been described. Conversely, the majority of pilocytic astrocytomas appear to result from genetic changes that alter a single, therapeutically targetable molecular pathway. Accordingly, the present era is one in which treatment is evolving from the historical standard of radiation and conventional chemotherapy to a more nuanced approach in which these modalities are applied in a risk-adapted framework and molecularly targeted therapies are implemented to augment or, in some cases, replace conventional therapy. Herein, the authors review advances in the categorization and treatment of several of the more common pediatric brain tumors and discuss current and future directions in tumor management that hold significant promise for patients with these challenging tumors.

Targeting IL-13Rα2 for effective treatment of malignant peripheral nerve sheath tumors in mouse models.

OBJECTIVEMalignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas that harbor a high potential for metastasis and have a devastating prognosis. Combination chemoradiation aids in tumor control and decreases tumor recurrence but causes deleterious side effects and does not extend long-term survival. An effective treatment with limited toxicity and enhanced efficacy is critical for patients suffering from MPNSTs.METHODSThe authors recently identified that interleukin-13 receptor alpha 2 (IL-13Rα2) is overexpressed on MPNSTs and could serve as a precision-based target for delivery of chemotherapeutic agents. In the work reported here, a recombinant fusion molecule consisting of a mutant human IL-13 targeting moiety and a point mutant variant of Pseudomonas exotoxin A (IL-13.E13 K-PE4E) was utilized to treat MPNST in vitro in cell culture and in an in vivo murine model.RESULTSIL-13.E13 K-PE4E had a potent cytotoxic effect on MPNST cells in vitro. Furthermore, intratumoral administration of IL-13.E13 K-PE4E to orthotopically implanted MPNSTs decreased tumor burden 6-fold and 11-fold in late-stage and early-stage MPNST models, respectively. IL-13.E13 K-PE4E treatment also increased survival by 23 days in the early-stage MPNST model.CONCLUSIONSThe current MPNST treatment paradigm consists of 3 prongs: surgery, chemotherapy, and radiation, none of which, either singly or in combination, are curative or extend survival to a clinically meaningful degree. The results presented here provide the possibility of intratumoral therapy with a potent and highly tumor-specific cytotoxin as a fourth treatment prong with the potential to yield improved outcomes in patients with MPNSTs.

C2 neurofibromas in neurofibromatosis type 1: genetic and imaging characteristics.

OBJECTIVEC2 nerve root neurofibromas have been reported frequently in patients with neurofibromatosis type 1 (NF1), although their genetic and imaging characteristics are unexplored. The aim of this study was to characterize genetic and spinal imaging findings in a large cohort of NF1 patients with C2 neurofibromas.METHODSThe authors performed a review of national NF1 referrals between 2009 and 2016. Inclusion criteria were at least 1 C2 root neurofibroma and cervical-spine or whole-spine MRI scans available for analysis. Blinded imaging review was performed by a neuroradiologist with an interest in NF1.RESULTSFifty-four patients with 106 C2 neurofibromas were included. The median age was 32.5 years (range 15-61 years), and there were slightly more male patients (33 vs 21 female patients). Splice-site (30%) and missense (20%) variants were frequent. Spinal neurofibromas were distributed in all spine regions (65%) or in the cervical spine alone (22%). Most (93%) C2 neurofibromas were visible on MRI scans of the head. Intradural invasion and cord compression in the cervical spine included the C2 level in 95% and 80% of patients, respectively. Compared with all other cervical spine neurofibromas in these patients, C2 neurofibromas had higher rates of intraspinal extension (75% vs 32%; OR 6.20, 95% CI 3.85-9.97; p < 0.001), intradural invasion (53% vs 26%; OR 3.20, 95% CI 2.08-4.92; p < 0.001), and cord compression (25% vs 13%; OR 2.26, 95% CI 1.35-3.79; p = 0.002). However, C2 neurofibromas had lower rates of extraforaminal growth beyond the transverse process (12% vs 62%; OR 0.09, 95% CI 0.05-0.16; p < 0.001).CONCLUSIONSC2 neurofibromas are associated with an aggressive intraspinal phenotype, limited growth outside the spinal canal, and an uncommon genetic profile. These observations require future study.

Optic pathway-hypothalamic glioma hemorrhage: a series of 9 patients and review of the literature.

OBJECTIVEHemorrhage (also known as apoplexy) in optic pathway gliomas (OPGs) is rare. Because of the variable presentations and low incidence of OPG hemorrhages, little is known about their clinical course and the best treatment options. The aim of this work was to review risk factors, clinical course, and treatment strategies of optic glioma hemorrhages in the largest possible number of cases.METHODSA total of 34 patients were analyzed. Nine new cases were collected, and 25 were identified in the literature. Data regarding demographics, radiological and histological features, treatment, and outcome were retrospectively reviewed.RESULTSThe majority of patients were younger than 20 years. Only 3 patients were known to have neurofibromatosis. The histopathological diagnosis was pilocytic astrocytoma in the majority of cases. Five patients had intraorbital hemorrhages, whereas 29 patients had intracranial hemorrhage; the majority of intracranial bleeds were treated surgically. Six patients, all with intracranial hemorrhage, died due to recurrent bleeding, hydrocephalus, or surgical complications. No clear risk factors could be identified.CONCLUSIONSIntracerebral OPG hemorrhages have a fatal outcome in 20% of cases. Age, hormonal status, neurofibromatosis involvement, and histopathological diagnosis have been suggested as risk factors for hemorrhage, but this cannot be reliably established from the present series. The goals of surgery should be patient survival and prevention of further neurological and ophthalmological deterioration.

MLN8237 treatment in an orthoxenograft murine model for malignant peripheral nerve sheath tumors.

OBJECTIVEMalignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas arising from peripheral nerves. MPNSTs have increased expression of the oncogene aurora kinase A, leading to enhanced cellular proliferation. This makes them extremely aggressive with high potential for metastasis and a devastating prognosis; 5-year survival estimates range from a dismal 15% to 60%. MPNSTs are currently treated with resection (sometimes requiring limb amputation) in combination with chemoradiation, both of which demonstrate limited effectiveness. The authors present the results of immunohistochemical, in vitro, and in vivo analyses of MLN8237 for the treatment of MPNSTs in an orthoxenograft murine model.METHODSImmunohistochemistry was performed on tumor sections to confirm the increased expression of aurora kinase A. Cytotoxicity analysis was then performed on an MPNST cell line (STS26T) to assess the efficacy of MLN8237 in vitro. A murine orthoxenograft MPNST model transfected to express luciferase was then developed to assess the efficacy of aurora kinase A inhibition in the treatment of MPNSTs in vivo. Mice with confirmed tumor on in vivo imaging were divided into 3 groups: 1) controls, 2) mice treated with MLN8237, and 3) mice treated with doxorubicin/ifosfamide. Treatment was carried out for 32 days, with imaging performed at weekly intervals until postinjection day 42. Average bioluminescence among groups was compared at weekly intervals using 1-way ANOVA. A survival analysis was performed using Kaplan-Meier curves.RESULTSImmunohistochemical analysis showed robust expression of aurora kinase A in tumor cells. Cytotoxicity analysis revealed STS26T susceptibility to MLN8237 in vitro. The group receiving treatment with MLN8237 showed a statistically significant difference in tumor size compared with the control group starting at postinjection day 21 and persisting until the end of the study. The MLN8237 group also showed decreased tumor size compared with the doxorubicin/ifosfamide group at the conclusion of the study (p = 0.036). Survival analysis revealed a significantly increased median survival in the MLN8237 group (83 days) compared with both the control (64 days) and doxorubicin/ifosfamide (67 days) groups. A hazard ratio comparing the 2 treatment groups showed a decreased hazard rate in the MLN8237 group compared with the doxorubicin/ifosfamide group (HR 2.945; p = 0.0134).CONCLUSIONSThe results of this study demonstrate that MLN8237 is superior to combination treatment with doxorubicin/ifosfamide in a preclinical orthoxenograft murine model. These data have major implications for the future of MPNST research by providing a robust murine model as well as providing evidence that MLN8237 may be an effective treatment for MPNSTs.

Isolated optic nerve gliomas: a multicenter historical cohort study.

OBJECTIVE Isolated optic nerve gliomas (IONGs) constitute a rare subgroup of optic pathway gliomas (OPGs). Due to the rarity of this condition and the difficulty in differentiating IONGs from other types of OPGs in most clinical series, little is known about these tumors. Currently, due to lack of evidence, they are managed the same as any other OPG. METHODS The authors conducted a multicenter retrospective cohort study aimed at determining the natural history of IONGs. Included were patients with clear-cut glioma of the optic nerve without posterior (chiasmatic/hypothalamic) involvement. At least 1 year of follow-up, 2 MRI studies, and 2 neuro-ophthalmological examinations were required for inclusion. RESULTS Thirty-six patients with 39 tumors were included in this study. Age at diagnosis ranged between 6 months and 16 years (average 6 years). The mean follow-up time was 5.6 years. Twenty-five patients had neurofibromatosis Type 1. During the follow-up period, 59% of the tumors progressed, 23% remained stable, and 18% (all with neurofibromatosis Type 1) displayed some degree of spontaneous regression. Fifty-one percent of the patients presented with visual decline, of whom 90% experienced further deterioration. Nine patients were treated with chemotherapy, 5 of whom improved visually. Ten patients underwent operation, and no local or distal recurrence was noted. CONCLUSIONS Isolated optic nerve gliomas are highly dynamic tumors. Radiological progression and visual deterioration occur in greater percentages than in the general population of patients with OPGs. Response to chemotherapy may be better in this group, and its use should be considered early in the course of the disease.

Effect of higher implant density on curve correction in dystrophic thoracic scoliosis secondary to neurofibromatosis Type 1.

OBJECTIVE The aim of this study was to investigate how implant density affects radiographic results and clinical outcomes in patients with dystrophic scoliosis secondary to neurofibromatosis Type 1 (NF1). METHODS A total of 41 patients with dystrophic scoliosis secondary to NF1 who underwent 1-stage posterior correction between June 2011 and December 2013 were included. General information about patients was recorded, as were preoperative and postoperative scores from Scoliosis Research Society (SRS)-22 questionnaires. Pearson correlation analysis was used to analyze the associations among implant density, coronal Cobb angle correction rate and correction loss at last follow-up, change of sagittal curve, and apical vertebral translation. Patients were then divided into 2 groups: those with low-density and those with high-density implants. Independent-sample t-tests were used to compare demographic data, radiographic findings, and clinical outcomes before surgery and at last follow-up between the groups. RESULTS Significant correlations were found between the implant density and the coronal correction rate of the main curve (r = 0.505, p < 0.01) and the coronal correction loss at final follow-up (r = -0.379, p = 0.015). There was no significant correlation between implant density and change of sagittal profile (p = 0.662) or apical vertebral translation (p = 0.062). The SRS-22 scores improved in the appearance, activity, and mental health domains within both groups, but there was no difference between the groups in any of the SRS-22 domains at final follow-up (p > 0.05 for all). CONCLUSIONS Although no significant differences between the high- and low-density groups were found in any of the SRS-22 domains at final follow-up, higher implant density was correlated with superior coronal correction and less postoperative correction loss in patients with dystrophic NF1-associated scoliosis.