Barunashish Brahma

Guiding intracortical brain tumour cells to an extracortical cytotoxic hydrogel using aligned polymeric nanofibres.

Glioblastoma multiforme is an aggressive, invasive brain tumour with a poor survival rate. Available treatments are ineffective and some tumours remain inoperable because of their size or location. The tumours are known to invade and migrate along white matter tracts and blood vessels. Here, we exploit this characteristic of glioblastoma multiforme by engineering aligned polycaprolactone (PCL)-based nanofibres for tumour cells to invade and, hence, guide cells away from the primary tumour site to an extracortical location. This extracortial sink is a cyclopamine drug-conjugated, collagen-based hydrogel. When aligned PCL-nanofibre films in a PCL/polyurethane carrier conduit were inserted in the vicinity of an intracortical human U87MG glioblastoma xenograft, a significant number of human glioblastoma cells migrated along the aligned nanofibre films and underwent apoptosis in the extracortical hydrogel. Tumour volume in the brain was significantly lower following insertion of aligned nanofibre implants compared with the application of smooth fibres or no implants.

Diffuse leptomeningeal neuroepithelial tumor: 9 pediatric cases with chromosome 1p/19q deletion status and IDH1 (R132H) immunohistochemistry.

Leptomeningeal dissemination in children is typical of high-grade, and occasionally low-grade, neoplasms. Rare cases of widely disseminated oligodendroglia-like leptomeningeal tumors, sometimes with associated spinal cord lesions, have been described that respond to treatment and follow an indolent course. Whether these lesions represent an established tumor category or are a unique entity remains to be established. We present 9 pediatric cases of such diffuse leptomeningeal neuroepithelial tumors (DLNT), 8 with assessment of 2 common genetic alterations seen in oligodendrogliomas, 1p and 19q chromosomal deletions and isocitrate dehydrogenase-1 (IDH1) R132H mutations. Four patients were male and 5 female, with a mean age at presentation of 4 years (range, 2 to 7 y). All presented with signs of increased intracranial pressure and diffuse contrast enhancement of the leptomeninges by magnetic resonance imaging. Three had a cervical or upper thoracic spinal cord tumor, and another had a small cerebellar lesion. Leptomeningeal biopsies showed a thickened and fibrotic arachnoid infiltrated by monotonous cells with round nuclei and prominent perinuclear clearing. All cases were strongly immunoreactive for S100 protein, and most showed faint granular synaptophysin reactivity. Six of 8 cases showed deletions of chromosome arm 1p by fluorescence in situ hybridization, 2 of which also had loss of 19q. None of the lesions reacted with IDH1-R132H antibodies. Although the clinicopathologic features show overlap of these DLNT lesions with oligodendroglioma and extraventricular neurocytoma, they do not exactly match either one, suggesting that DLNTs are a distinct tumor entity.

Successful Retreatment of a Child with a Refractory Brainstem Ganglioglioma with Vemurafenib.

A child with brainstem ganglioglioma underwent subtotal resection and focal radiation. Magnetic resonance imaging confirmed tumor progression 6 months later. Another partial resection revealed viable BRAF V600E‐positive residual tumor. Vemurafenib (660 mg/m2/dose) was administered twice daily, resulting in >70% tumor reduction with sustained clinical improvement for 1 year. Vemurafenib was then terminated, but significant tumor progression occurred 3 months later. Vemurafenib was restarted, resulting in partial response. Toxicities included Grade I pruritus and Grade II rash. Vemurafenib was effectively crushed and administered in solution via nasogastric tube. We demonstrate benefit from restarting vemurafenib therapy.

Utility of surveillance imaging after minor blunt head trauma.

OBJECT Nonoperative blunt head trauma is a common reason for admission in a pediatric hospital. Adverse events, such as growing skull fracture, are rare, and the incidence of such morbidity is not known. As a result, optimal follow-up care is not clear. METHODS Patients admitted after minor blunt head trauma between May 1, 2009, and April 30, 2013, were identified at a single institution. Demographic, socioeconomic, and clinical characteristics were retrieved from administrative and outpatient databases. Clinical events within the 180-day period following discharge were reviewed and analyzed. These events included emergency department (ED) visits, need for surgical procedures, clinic visits, and surveillance imaging utilization. Associations among these clinical events and potential contributing factors were analyzed using appropriate statistical methods. RESULTS There were 937 admissions for minor blunt head trauma in the 4-year period. Patients who required surgical interventions during the index admission were excluded. The average age of the admitted patients was 5.53 years, and the average length of stay was 1.7 days; 15.7% of patients were admitted for concussion symptoms with negative imaging findings, and 26.4% of patients suffered a skull fracture without intracranial injury. Patients presented with subdural, subarachnoid, or intraventricular hemorrhage in 11.6%, 9.19%, and 0.53% of cases, respectively. After discharge, 672 patients returned for at least 1 follow-up clinic visit (71.7%), and surveillance imaging was obtained at the time of the visit in 343 instances. The number of adverse events was small and consisted of 34 ED visits and 3 surgeries. Some of the ED visits could have been prevented with better discharge instructions, but none of the surgery was preventable. Furthermore, the pattern of postinjury surveillance imaging utilization correlated with physician identity but not with injury severity. Because the number of adverse events was small, surveillance imaging could not be shown to positively influence outcomes. CONCLUSIONS Adverse events after nonoperative mild traumatic injury are rare. The routine use of postinjury surveillance imaging remains controversial, but these data suggest that such imaging does not effectively identify those who require operative intervention.

Evans blue nanocarriers visually demarcate margins of invasive gliomas

Aggressive surgical resection is the primary therapy for glioma. However, aggressive resection may compromise functional healthy brain tissue. Currently, there are no objective cues for surgeons to distinguish healthy tissue from tumor and determine tumor borders; surgeons skillfully rely on subjective means such as tactile feedback. This often results in incomplete resection and recurrence. The objective of the present study was to design, develop, and evaluate, in vitro and in vivo, a nanoencapsulated visible dye for intraoperative, visual delineation of tumor margins in an invasive tumor model. Liposomal nanocarriers containing Evans blue dye (nano-EB) were developed, characterized, and tested for safety in vitro and in vivo. 3RT1RT2A glioma cells were implanted into brains of Fischer 344 rats. Nano-EB or EB solution was injected via tail vein into tumor-bearing animals. To assess tumor staining, tissue samples were analyzed visibly and using fluorescence microscopy. Area, perimeter ratios, and Manders overlap coefficients were calculated to quantify extent of staining. Nano-EB clearly marked tumor margins in the invasive tumor model. Area ratio of nano-EB staining to tumor was 0.89 ± 0.05, perimeter ratio was 0.94 ± 0.04, Manders R was 0.51 ± 0.08, and M1 was 0.97 ± 0.06. Microscopic tumor border inspection under high magnification verified that nano-EB did not stain healthy tissue. Nano-EB clearly aids in distinguishing tumor tissue from healthy tissue in an invasive tumor model, while injection of unencapsulated EB results in false identification of healthy tissue as tumor due to diffusion of dye from the tumor into healthy tissue.

The use of inside-outside screws for occipitocervical fusion in pediatric patients.

OBJECT The authors describe the use of inside-outside occipital screws in 21 children with occipitocervical instability requiring occipitocervical fusion. METHODS The ages of the patients were from 2 to 15 years, and patients presented with a variety of causes of occipitocervical instability, including congenital disorders, posttraumatic instability, idiopathic degeneration, and postoperative instability. Surgeries frequently included foramen magnum decompression, duraplasty, and laminectomy, but all patients required occipitocervical instrumentation and arthrodesis. Postoperative orthosis included the use of either a cervical collar or halo device. In all but one case, patients were followed postoperatively for at least 12 months. RESULTS The mean age of patients was 9.93 years. Inside-outside screws were used in all reported cases. Rib autograft was used in all patients. In addition, demineralized bone matrix was used in 2 cases, and bone morphogenetic protein was used in 2 patients. Two patients required halo placement, and the other 19 were placed in cervical collars. The average time postoperative orthotics were used was 2.82 months. Arthrodesis was determined radiographically and was noted in all patients. No operative complications were noted; however, postoperative complications included 1 wound infection, 2 cases of hardware loosening, and the need for tracheostomy in 2 patients. CONCLUSIONS Inside-outside screws were found to be a useful component of occipitocervical instrumentation in pediatric patients ranging from 2 to 15 years of age. Arthrodesis was demonstrated in all cases.

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.