Late toxicity following craniospinal radiation for early-stage medulloblastoma.

BACKGROUND: The purpose of this study is to review late toxicity following craniospinal radiation for early-stage medulloblastoma. MATERIAL AND METHODS: Between 1963 and 2008, 53 children with stage M0 (n = 50) or M1 (n = 3) medulloblastoma were treated at our institution. The median age at diagnosis was 7.1 years (range 1.2-18.5). The median craniospinal irradiation (CSI) dose was 28.8 Gy (range 21.8-38.4). The median total dose, including boost, was 54 Gy (range 42.4-64.8 Gy). Since 1963, the CSI dose has been incrementally lowered and the high-risk boost volume reduced. Twenty-one patients (40%) received chemotherapy in their initial management, including 12 who received concurrent chemotherapy. Late sequelae were evaluated by analyzing medical records and conducting phone interviews with surviving patients and/or care-takers. Complications were graded using the NCI Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: The median follow-up for all patients was 15.4 years (range 0.4-44.4) and for living patients it was 24 years (range 5.6-44.4). The overall survival, cause-specific survival, and progression-free survival rates at 10 years were 67%, 67%, and 71%, respectively. Sixteen patients (41% of patients who survived five years or more) developed grade 3 + toxicity; 15 of these 16 patients received a CSI dose > 23.4 Gy. The most common grade 3 + toxicities for long-term survivors are hearing impairment requiring intervention (20.5%) and cognitive impairment (18%) prohibiting independent living. Four patients developed secondary (non-skin) malignancies, including three meningiomas, one rhabdomyosarcoma, and one glioblastoma multiforme. Three patients (5.6%) died from treatment complications, including radionecrosis, severe cerebral edema, and fatal secondary malignancy. CONCLUSION: Ongoing institutional and cooperative group efforts to minimize radiation exposure are justified given the high rate of serious toxicity observed in our long-term survivors. Follow-up through long-term multidisciplinary clinics is important and warranted for all patients exposed to radiotherapy in childhood.

Local control in non-metastatic medulloblastoma.

BACKGROUND: A single-institution review of long-term outcomes and factors affecting local control (LC) following radiotherapy for non-metastatic medulloblastoma. MATERIAL AND METHODS: From 1963 to 2008, 50 children (median age, 7.3 years; range 1.2-18.5) with stage M0 medulloblastoma were treated with radiotherapy; half underwent a gross total resection (no visible residual tumor) or near-total resection (< 1.5 cm(3) of gross disease remaining after resection). Median craniospinal dose was 28.8 Gy (range 21.8-38.4 Gy). Median total dose to the posterior fossa was 54.3 Gy (range 42.4-64.8 Gy). Eighteen patients (36%) received chemotherapy as part of multimodality management, including 11 who received concurrent chemotherapy. RESULTS: Median follow-up was 15.7 years (range 0.3-44.4 years) for all patients and 26.6 years (range 7.3-44.4 years) for living patients. The 10-year overall survival, cancer-specific survival, and progression-free survival rates were 65%, 65%, and 69%. The 10-year LC rate was 84% and did not significantly change across eras. Four percent of patients experienced local progression five years after treatment. On univariate analysis, chemotherapy and overall duration of radiotherapy ≤ 45 days were associated with improved LC. Patients receiving chemotherapy had a 10-year 100% LC rate versus 76% in patients not receiving chemotherapy (p = 0.0454). When overall radiotherapy treatment lasted ≤ 45 days, patients experienced a superior 95% 10-year LC rate (vs. 73% in patients treated > 45 days; p = 0.0419). Three patients (6%) died from treatment complications, including radionecrosis/cerebellar degeneration, severe cerebral edema leading to herniation, and secondary malignancy. CONCLUSIONS: While we cannot draw definitive conclusions given the retrospective nature of our study, our long-term data suggest that reductions in craniospinal dose and boost target volume to reduce toxicity have not compromised disease control in the modern era. Our data also support analyses that implicate duration of radiotherapy, rather than interval between surgery and radiotherapy, as a factor in LC. Chemotherapy in multimodality management of medulloblastoma may have an underappreciated role in improving LC rates.

Intracranial ependymomas treated with radiotherapy: long-term results from a single institution.

The purpose of the study is to report long-term outcomes following surgery and radiotherapy for intracranial ependymoma. We retrospectively reviewed the medical records of patients treated with radiotherapy for localized intracranial ependymomas from 1964 to 2006. Patients with subependymomas and ependymoblastomas, and those undergoing re-irradiation, were excluded. Our study population is 44 patients: 37 infratentorial lesions, 7 supratentorial. All patients had postoperative radiotherapy; most received sub-total resection and one-third received gross total resection. Most patients received local radiotherapy alone (median tumor dose 55 Gy); one-quarter received craniospinal irradiation (median dose 35 Gy). The 5- and 10-year local-control rates for all patients were 60 and 46%, respectively; 23% of local recurrences occurred after 5 years. Ninety-five percent of the patients recurred at the primary site; 5% had spinal seeding with no evidence of disease at the primary site. No patient who received craniospinal irradiation recurred in the spine. The 5- and 10-year disease-free survival and overall-survival rates for all patients were 60 and 42% and 57 and 43%, respectively. On multivariate analysis, age ≥18 years, gross total resection and infratentorial site were associated with improved local control. No patient with continuous local control had grade 4 or 5 toxicities; 27% of patients had grade 2 or 3 toxicities. One patient developed a radiation-induced meningioma >20 years after radiotherapy. Maximal safe resection followed by adjuvant radiotherapy provided local control in one-half of patients at 10 years. Age, extent of surgery, and location were identified as major independent prognostic factors in patients with intracranial ependymomas.

Recombinant human bone morphogenetic protein-2 as an adjunct for spine fusion in a pediatric population.

BACKGROUND/AIMS: Recombinant human bone morphogenetic protein-2 (rhBMP-2) is responsible for multiple different signaling processes including positive effects on bone formation and fusion. In 2002, rhBMP-2 was approved for use in anterior lumbar spinal fusion by the Food and Drug Administration. Since that time, rhBMP-2 use for spinal fusion has become widespread. The use of rh-BMP2 for pediatric spinal fusion, however, has not been widely reported. We report the experience of the use of rhBMP-2 for pediatric spinal fusion at the University of Florida. METHODS: Data on patients under the age of 18 years who underwent spinal fusion with rhBMP-2 as an adjunct were retrospectively collected. Of these, 17 met the inclusion criteria and were reviewed. Two patients did not have adequate postoperative imaging. Fifteen patients were included in the final review. RESULTS: All 15 patients showed osseous fusion. Complications included one CSF leak and one wound infection, one misplaced screw requiring revision, and one case of adjacent segment kyphosis requiring extension of the original construct. CONCLUSION: rhBMP-2 is a successful adjunct for fusion in pediatric patients. Many of these patients had congenital defects that historically decrease fusion rates. rhBMP-2 appears safe and has an associated high rate of osseous fusion.

Aggressive surgical management of patients with Chiari II malformation and brainstem dysfunction.

BACKGROUND/AIMS: Chiari II malformation represents a group of developmental abnormalities involving the caudal displacement of the cervicomedullary junction, pons, fourth ventricle, and medulla. This constellation of malformations is strongly associated with myelomeningocele (MM) and is a known cause of neurologic deterioration in older MM patients. We describe the evaluation and management of 4 adult MM patients who presented with brainstem compression and a retroflexed odontoid who were subject to aggressive surgical management including occipitocervical (OC) fusion with good clinical results. METHODS: Four MM patients who underwent OC fusion for new-onset brainstem dysfunction and myelopathy were identified in the practice of the principal investigator (D.W.P.) from 2003 to 2008. RESULTS: The initial evaluation of these patients included consideration of other diagnoses, such as hydrocephalus due to shunt malfunction and tethered cord. These patients were treated with aggressive surgical management. In some cases, multiple surgeries were performed. All 4 patients were treated with cervical decompression and OC fixation and initially had good outcomes. No patients required transoral decompression. Three of the 4 had stable improvement at their last follow-up appointment (mean follow-up of 9 months). CONCLUSION: Late deterioration in older MM patients may be secondary to brainstem or cervical spinal cord compression from ventral odontoid compression and Chiari II malformation, hydrocephalus, hydromyelia, or tethered cord. These patients may benefit from more than one surgery. Posterior decompression and OC fusion can avoid a morbid transoral odontoid resection, greatly improve patients' symptoms and prevent further neurologic decline.

Late Effects After Radiotherapy for Childhood Low-grade Glioma.

OBJECTIVES: This single-institution report describes long-term disease control and late effects in pediatric patients with low-grade glioma (LGG) following radiotherapy (RT). MATERIALS AND METHODS: Twenty-nine pediatric patients with LGG were treated with photon-based RT from 1970 to 2004 (mean age at time of RT, 9.8 y; range, 0.6 to 19 y). One patient underwent gross total resection, 25 underwent subtotal resection or biopsy, and 3 were treated based on radiographic characteristics alone. Three patients underwent chemotherapy before RT. The median RT dose was 54 Gy (range, 40 to 55 Gy). RESULTS: The median follow-up was 17.8 years (range, 1.6 to 36.8 y) for all patients and 19.9 years (range, 1.6 to 36.8 y) for all living patients. The 5-, 10-, and 20-year local control and progression-free survival rates were equivalent at 82%, 74%, and 63%, respectively. The 5-, 10-, and 20-year cause-specific survival and overall survival rates were equivalent at 89%, 85%, and 58%, respectively. On univariate analysis, age below 4 years during treatment was associated with significantly inferior local control (P=0.0067), cause-specific survival (P=0.0021), and overall survival (P=0.0021). Of the 23 survivors analyzed for late toxicity, 15 (65%) developed grade 3+ toxicity. The most common Common Terminology Criteria for Adverse Events grade 3 toxicity (30% of survivors) was serious cognitive disability. Four patients (14%) died secondary to treatment complications, all occurring over a decade after completing RT. CONCLUSIONS: Over half of children diagnosed with LGG survive >20 years after RT; this report reveals the chronicity of toxicity beyond the typically reported follow-up. Our findings inform the therapeutic ratio of RT in this disease and may help guide late-effect screening recommendations.

Brainstem angiocentric glioma: report of 2 cases.

Angiocentric glioma is a rare tumor that was recognized by the WHO Classification of Tumours of the Central Nervous System as a distinct clinicopathological entity in 2007. Since this initial description, the vast majority of cases of angiocentric glioma reported in the literature have involved tumors of the cerebral hemispheres. To date, only 1 case of angiocentric glioma arising from the posterior midbrain has been reported. The authors present the cases of 2 pediatric patients who were found to have brainstem angiocentric gliomas. The clinical course, radiological and pathological features, treatment, and follow-up are described. The first case is one of a 5-year-old girl who presented with double vision, headache, and nausea and was found to have a midbrain lesion with pathological features consistent with angiocentric glioma. She was treated with resection and endoscopic third ventriculostomy (ETV), followed by close observation and serial neuroimaging. The second case is one of a 6-year-old boy who presented with progressive mouth drooping and problems with balance. He was found to have a pontine lesion with pathological features consistent with angiocentric glioma. This patient was treated with ETV, followed by close observation and serial neuroimaging. This report includes 6 and 1.5 years of follow-up of the patients, respectively. While there are limited data regarding the prognosis or long-term management of patients with brainstem angiocentric gliomas, the cases described in this report suggest an indolent course for this tumor, similar to the course of angiocentric gliomas located in the cerebral hemispheres.

Functional Subclone Profiling for Prediction of Treatment-Induced Intratumor Population Shifts and Discovery of Rational Drug Combinations in Human Glioblastoma.

PURPOSE: Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors. EXPERIMENTAL DESIGN: Here, we used 33 single cell-derived subclones generated from five clinical glioblastoma specimens for exploring intra- and interindividual spectra of drug resistance profiles in vitro In a personalized setting, we explored whether differences in pharmacologic sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors. RESULTS: Subclones from individual tumors exhibited a remarkable heterogeneity of drug resistance to a library of potential antiglioblastoma compounds. A more comprehensive intratumoral analysis revealed that stable genetic and phenotypic characteristics of coexisting subclones could be correlated with distinct drug sensitivity profiles. The data obtained from differential drug response analysis could be employed to predict clonal population shifts within the naïve parental tumor in vitro and in orthotopic xenografts. Furthermore, the value of pharmacologic profiles could be shown for establishing rational strategies for individualized secondary lines of treatment. CONCLUSIONS: Our data provide a previously unrecognized strategy for revealing functional consequences of intratumor heterogeneity by enabling predictive modeling of treatment-related subclone dynamics in human glioblastoma. Clin Cancer Res; 23(2); 562-74. ©2016 AACR.

A diplopia dilemma.

A 38-year-old man experienced double vision with pupillary abnormalities and convergence retraction nystagmus. A mass, which responded to radiation therapy, was seen as the cause of his dorsal midbrain syndrome. The neural control of vertical eye movements is reviewed and the management of a third ventricular-pineal region mass discussed.

Development of syringohydromyelia associated with Dandy-Walker malformation: treatment with cystoperitoneal shunt placement. Case report.

Dandy-Walker malformation (DWM) is a well-described clinical entity, which includes vermian agenesis, posterior fossa cysts, and frequently, hydrocephalus. The authors report the clinical course and present the radiographic findings pertaining to a 1-month-old girl with DWM who was treated initially with a ventriculoperitoneal shunt and endoscopic fenestration of a posterior fossa cyst. After decompression for hydrocephalus, an increased mass effect at the foramen magnum from her posterior fossa cyst was demonstrated, as well as subsequent development of syringohydromyelia from C-4 to T-7. She was treated with a cystoperitoneal shunt. At the 6-month follow-up examination, the child (15 months of age) had achieved gains in developmental milestones, and complete resolution of the syrinx was established through MR imaging. This is the fourth nonautopsy pediatric case of DWM-associated syringohydromyelia reported in the literature and the third in a child to demonstrate impaction of the posterior fossa cyst at the foramen magnum leading to syrinx formation with subsequent treatment and resolution. Spinal imaging may be useful in the evaluation of patients with DWM who do not experience expected improvement after shunt procedures.

Frameless, pinless stereotactic neurosurgery in children.

OBJECT: Frameless neuronavigation has been established as a useful adjunct to intracranial surgery; however, the procedure is limited in young children by the need for rigid skull fixation with pins. Pin fixation is difficult and hazardous for patients younger than 2 years of age. Minor risks have been associated with pin fixation in older patients also, including scalp laceration, skull fracture, and epidural hematoma. METHODS: The authors adapted a pinless head fixation system, consisting of a beanbag device, for use with frameless neuronavigation. This system was used to perform intracranial neurosurgical procedures in nine patients. CONCLUSIONS: This pinless, frameless method provides a new option for children who are unable to sustain rigid head fixation. It is also an alternative to rigid pin fixation for patients of any age.

Brainstem stereotactic biopsy sampling in children.

OBJECT: Although it is widely accepted that biopsy sampling is not indicated for the diagnosis and empiric treatment of diffuse pontine glioma, it is common to encounter patients with brainstem lesions that cannot be diagnosed on the basis of imaging studies alone. In cases not amenable to resection, a tissue diagnosis may still be necessary to make appropriate treatment recommendations. The authors retrospectively reviewed their institutional experience with stereotactic biopsy procedures in pediatric patients during a 4-year period. METHODS: A three-dimensional graphics workstation was used for trajectory planning to obtain biopsy samples of brainstem lesions in 10 patients. One patient experienced mild diplopia postoperatively. No other morbidity was noted; no patient died as a result of the procedure. The biopsy procedure yielded a pathological diagnosis in all cases. A later resection in one patient resulted in a change in diagnosis. Overall, the pathological findings were varied, and in some cases the tissue diagnosis altered the treatment recommendations. CONCLUSIONS: The findings in this small series suggest that brainstem stereotactic biopsy sampling in children is a safe procedure with a high diagnostic yield. In patients in whom radiographic findings are not consistent with diffuse pontine glioma and resection is not appropriate, stereotactic biopsy sampling should be considered.

Long-term growth and alignment after occipitocervical and atlantoaxial fusion with rigid internal fixation in young children.

OBJECT The long-term consequences of atlantoaxial (AA) and occipitocervical (OC) fusion and instrumentation in young children are unknown. Anecdotal reports have raised concerns regarding altered growth and alignment of the cervical spine after surgical intervention. The purpose of this study was to determine the long-term effects of these surgeries on the growth and alignment of the maturing spine. METHODS A multiinstitutional retrospective chart review was conducted for patients less than or equal to 6 years of age who underwent OC or AA fusion with rigid instrumentation at 9 participating centers. All patients had at least 3 years of clinical and radiographic follow-up data and radiographically confirmed fusion. Preoperative, immediate postoperative, and most recent follow-up radiographs and/or CT scans were evaluated to assess changes in spinal growth and alignment. RESULTS Forty children (9 who underwent AA fusion and 31 who underwent OC fusion) were included in the study (mean follow-up duration 56 months). The mean vertical growth over the fused levels in the AA fusion patients represented 30% of the growth of the cervical spine (range 10%-50%). Three different vertical growth patterns of the fusion construct developed among the 31 OC fusion patients during the follow-up period: 1) 16 patients had substantial growth (13%-46% of the total growth of the cervical spine); 2) 9 patients had no meaningful growth; and 3) 6 patients, most of whom presented with a distracted atlantooccipital dislocation, had a decrease in the height of the fused levels (range 7-23 mm). Regarding spinal alignment, 85% (34/40) of the patients had good alignment at follow-up, with straight or mildly lordotic cervical curvatures. In 1 AA fusion patient (11%) and 5 OC fusion patients (16%), we observed new hyperlordosis (range 43°-62°). There were no cases of new kyphosis or swan-neck deformity, evidence of subaxial instability, or unintended subaxial fusion. No preoperative predictors of these growth patterns or alignment were evident. CONCLUSIONS These results demonstrate that most young children undergoing AA and OC fusion with rigid internal fixation continue to have good cervical alignment and continued growth within the fused levels during a prolonged follow-up period. However, some variability in vertical growth and alignment exists, highlighting the need to continue close long-term follow-up.

Neonatal hypothalamic hamartoma: a differentiating nonlethal hamartoblastoma.

The authors report on a patient with a large hypothalamic hamartoma with a cleft lip and palate and seizures. Neuroimaging revealed a large extraaxial, intradural mass in the prepontine and interpeduncular cisterns with significant distortion of the brainstem. A stereotactic transfontanel needle biopsy revealed a cellular lesion that contained immature-appearing neuroepithelial cells consistent with prior descriptions of hypothalamic hamartoblastoma. While having a low level of proliferation by Ki67 (MIB-1) labeling, the lesion also contained evidence of neuronal maturation, with many cells expressing neuronal nuclear antigen as observed during immunohistochemical analysis. Further clinical evaluation revealed no other significant congenital abnormalities, and the patient was discharged home. Outpatient follow up has continued for 2 years and the patient has been doing well, requiring no further treatment. This case illustrates that, despite its immature and proliferative histological appearance, this rare neonatal mass can be regarded as a "differentiating" hypothalamic hamartoma and can have a favorable prognosis.

Endoscopic-assisted repair of craniosynostosis.

OBJECT: The goal of the craniofacial surgeon has always been the correction of form and function with prevention of associated morbidity and death. Through the pioneering work of Jimenez and Barone, minimally invasive approaches to the surgical correction of craniosynostosis are now gaining wider acceptance. Here the authors review the technique for endoscopic-assisted repair of craniosynostosis from the perspective of a new minimally invasive approach. They also assess the safety, efficacy, and results of the early treatment of infants with craniosynostosis in a small series of children who underwent surgery at this institution. METHODS: Data regarding synostosis type, operative time, patient age, blood loss, transfusion rates, duration of hospitalization, and complications were collected. Nineteen patients (12 girls and seven boys) between the ages of 1.2 and 5 months of age were treated with the endoscope-assisted technique. The mean operative time was 97 minutes. Five (26%) of 19 children received a blood transfusion. Most patients were discharged home the morning after surgery. The clinical courses of two patients who required additional major craniofacial reconstructions are discussed. There were no deaths, dural sinus tears, cerebrospinal fluid leaks, neurological injuries, or infections, and there were no complications related to the use of helmet therapy. Seventeen of the 19 patients achieved excellent cosmetic results with a single surgery. CONCLUSIONS: This small series supports larger experiences and indicates that early treatment of craniosynostosis with minimally invasive, endoscope-assisted techniques is safe; limits blood transfusion, hospital stay, and operative time; and represents a valuable alternative to the traditional calvarial reconstruction methods.

Isolated anisocoria from an endodermal cyst of the third cranial nerve mimicking an Adie's tonic pupil.

We present only the second reported case in the literature of a neuroenteric cyst involving the third cranial nerve. Our case is highlighted by the initial presentation of an isolated anisocoria, initially believed to represent an Adie's tonic pupil as interpreted by pharmacologic testing. False-positive results may occur with the dilute pilocarpine test.

Embryonal tumor with multilayered rosettes of the fourth ventricle: case report.

Embryonal tumor with multilayered rosettes (ETMR) is a recently described pathological entity. These primitive central nervous system tumors harbor amplification of the 19q13.42 locus and resultant overexpression of the LIN28A protein. Although the WHO currently recognizes 3 distinct histopathological entities-embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma-recent studies indicate that these tumors have a common molecular profile and clinical course and that they are now classified as a single entity. Here the authors present a case of ETMR located in the fourth ventricle in a 12-month-old boy. The histopathology featured areas of neuropil-like stroma and highly cellular foci with characteristic multilayered rosettes. The authors discuss the clinical, radiological, and histopathological findings in this case and compare them with data in previously published cases in the literature. A review of studies assessing the molecular mechanisms underlying these tumors is also presented.

Ogilvie's syndrome after pediatric spinal deformity surgery: successful treatment with neostigmine.

Ogilvie's syndrome is a rare and potentially fatal disease that can easily be mistaken for postoperative ileus. Also known as acute colonic pseudo-obstruction, early recognition and diagnosis of the syndrome allows for treatment prior to bowel perforation and requisite abdominal surgery. The authors report a case of Ogilvie's syndrome following spinal deformity correction and tethered cord release in an adolescent who presented with acute abdominal distension, nausea, and vomiting on postoperative Day 0. The patient was initially diagnosed with adynamic ileus and treated conservatively with bowel rest, reduction in narcotic dosage, and a regimen of stool softeners, laxatives, and enemas. Despite this treatment, her clinical course failed to improve, and she demonstrated significant colonic distension radiographically. Intravenous neostigmine was administered as a bolus with a rapid and dramatic response. This case is the first reported instance of neostigmine use for Ogilvie's syndrome treatment following a pediatric neurosurgical operation.

Temporary percutaneous pedicle screw fixation for treatment of thoracolumbar injuries in young adults.

OBJECTIVE: Bone-only injuries of the spine, including Chance fractures, are commonly managed nonoperatively. However, selected patients may benefit from surgical stabilization. In this report, the authors describe a method of temporary internal fixation with percutaneous pedicle screws for patients with intractable pain and thoracolumbar fractures. METHODS: We reviewed the medical records and imaging studies of three patients 17 to 21 years old with thoracolumbar fractures that were treated with temporary internal fixation. The patients had bone-only injuries without a major deformity. Additionally, they had severe pain that was uncontrolled with parenteral pain medications and prevented mobilization with traditional external bracing. For fixation, pedicle screws were placed percutaneously in the level above and below the fracture. No arthrodesis was performed. After 6 months, fracture healing was evaluated radiographically. Once confirmed, the instrumentation was removed. Outcomes examined include length of stay, pain control, time to ambulation, and fracture healing. RESULTS: Three patients were included in the review, ages 17 to 21 (mean 18.7) years. Two patients had classic Chance fractures, and the third had bilateral pars fractures with a compression fracture at the same level. All patients had severe pain despite bracing. Postoperatively, all patients had significant pain reduction that facilitated rapid mobilization. At 6 months after surgery, fracture healing was verified with radiographic imaging and the instrumentation was removed. There were no complications. CONCLUSIONS: Temporary internal bracing of bone-only thoracolumbar fractures in young adults is a safe and effective treatment strategy in selected patients. This procedure provides rapid pain control and early mobilization without sacrificing any spinal motion segments.