Prospective feasibility and safety assessment of surgical biopsy for patients with newly diagnosed diffuse intrinsic pontine glioma.

Background: Diagnosis of diffuse intrinsic pontine glioma (DIPG) has relied on imaging studies, since the appearance is pathognomonic, and surgical risk was felt to be high and unlikely to affect therapy. The DIPG Biology and Treatment Study (DIPG-BATS) reported here incorporated a surgical biopsy at presentation and stratified subjects to receive FDA-approved agents chosen on the basis of specific biologic targets. Methods: Subjects were eligible for the trial if the clinical features and imaging appearance of a newly diagnosed tumor were consistent with a DIPG. Surgical biopsies were performed after enrollment and prior to definitive treatment. All subjects were treated with conventional external beam radiotherapy with bevacizumab, and then stratified to receive bevacizumab with erlotinib or temozolomide, both agents, or neither agent, based on O6-methylguanine-DNA methyltransferase status and epidermal growth factor receptor expression. Whole-genome sequencing and RNA sequencing were performed but not used for treatment assignment. Results: Fifty-three patients were enrolled at 23 institutions, and 50 underwent biopsy. The median age was 6.4 years, with 24 male and 29 female subjects. Surgical biopsies were performed with a specified technique and no deaths were attributed to the procedure. Two subjects experienced grade 3 toxicities during the procedure (apnea, n = 1; hypertension, n = 1). One subject experienced a neurologic deficit (left hemiparesis) that did not fully recover. Of the 50 tumors biopsied, 46 provided sufficient tissue to perform the study assays (92%, two-stage exact binomial 90% CI: 83%-97%). Conclusions: Surgical biopsy of DIPGs is technically feasible, associated with acceptable risks, and can provide biologic data that can inform treatment decisions.

Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma.

Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.

The initial use of free-running electromyography to detect early motor tract injury during resection of intramedullary spinal cord lesions.

OBJECTIVE: The resection of intramedullary spinal cord lesions (ISCLs) can be complicated by neurological deficits. Neuromonitoring has been used to reduce intraoperative risk. We have used somatosensory evoked potentials (SEPs) and muscle-derived transcranial electrical motor evoked potentials (myogenic TCE-MEPs) to monitor ISCL removal. We report our retrospective experience with the addition of free-running electromyography (EMG). METHODS: Thirteen patients underwent 14 monitored ISCL excisions. Anesthesia was maintained with minimal inhalant to reduce motoneuron suppression and enhance the myogenic TCE-MEPs. Free-running EMG was examined in the four limbs for evidence of abnormal bursts, prolonged tonic discharge, or sudden electrical silence. Warning of an electromyographic abnormality or myogenic TCE-MEP loss prompted interventions, including blood pressure elevation, a pause in surgery, a wake-up test, or termination of surgery. Pre- and postoperative neurological examinations determined the incidence of new deficits. RESULTS: The combined use of free-running EMG and myogenic TCE-MEPs detected all eight patients with a new motor deficit after surgery; there was one false-positive report. In three of the eight true-positive cases, an electromyographic abnormality immediately anticipated loss of the myogenic TCE-MEPs. Two patients with abnormal EMGs but unchanged myogenic TCE-MEPs experienced mild postoperative worsening of motor deficits; myogenic TCE-MEPs alone would have generated false-negative reports in these cases. CONCLUSION: During resection of ISCLs, free-running EMG can supplement motor tract monitoring by TCE-MEPs. Segmental and suprasegmental elicitation of neurotonic discharges can be observed in four-limb EMG. Abnormal electromyographic bursts, tonic discharge, or abrupt electromyographic silence may anticipate myogenic TCE-MEP loss and predict a postoperative motor deficit.

Nonteratomatous tumors in the pediatric sacral region.

STUDY DESIGN: Two institutional experiences in nonteratomatous sacral tumors of the child were analyzed retrospectively. OBJECTIVES: To examine noncongenital nonteratomatous sacral tumors, which are more common in older infants and, as a group, are rare. SUMMARY OF BACKGROUND DATA: Pediatric sacral tumors usually occur in the newborn period, with most of these tumors being sacrococcygeal teratomas. Other common benign congenital tumors of the sacrum include lipomas, dermoids, and epidermoids. METHODS: Six patients were found in a 6-year period. Four patients underwent posterior resection of their tumors. One underwent a combined anterior and posterior approach. One patient underwent a posterior resection and will undergo a second stage anterior approach later to allow for chemotherapy and radiation to shrink the intrapelvic portion of the tumor. RESULTS: Ages ranged from 8 to 11 years. Three were males, and three were females. Five of six presented with back pain, three had constipation, and two had gait difficulties. Pathologies were diverse. They included ganglioneuroma (n = 1), myxopapillary ependymoma (n = 2), primitive neuroectodermal tumor (n = 1), aneurysmal bone cyst (n = 1), and Ewing's sarcoma (n = 1). No progression of disease has occurred in the follow-up period of 1.5 to 7 years (average, 5 years). Radical resection did not result in instability. CONCLUSIONS: In contradistinction to adults, in whom chordomas and metastases are the most common primary and secondary tumors, the pediatric group does not have a predominant pathology. Tumors may attain extremely large sizes and may be very vascular. Multiple therapeutic methods may be required, including adjuvant chemotherapy and, possibly, embolization. Because of the wide range of pathologies, prognosis is varied.

Intramedullary cavernous angiomas of the spinal cord in the pediatric age group: a pediatric series.

The authors have reviewed available data from 7 pediatric patients with intramedullary spinal cord cavernous angioma (ISCCA) reported in the literature, and added from their own series 2 pediatric patients, for a total of 9 patients. This group of pediatric patients' clinical presentation, course, management and outcome were compared to their adult counterparts as reported in the literature. In contrast to adults, children with symptomatic ISCCA do not show a gender imbalance and the thoracic spinal cord is not predominantly involved. Pediatric patients commonly present with an acute episode and rapid deterioration. A more favorable outcome has been reported in children as compared to adults in the face of relatively similar presenting deficits. As in adults, magnetic resonance imaging (MRI) remains the diagnostic and postoperative test of choice. Complete resection affords the best chance for cure. Symptomatic children with ISCCA characteristically present with an acute deficit and rapid deterioration. MRI of the entire neuraxis is recommended for lesion multiplicity. An attempt at total resection and long-term MRI follow-up are recommended.