Establishment and characterization of patient-derived xenograft of a rare pediatric anaplastic pleomorphic xanthoastrocytoma (PXA) bearing a CDC42SE2-BRAF fusion.

Pleomorphic xanthoastrocytoma (PXA) is a rare subset of primary pediatric glioma with 70% 5-year disease free survival. However, up to 20% of cases present with local recurrence and malignant transformation into more aggressive type anaplastic PXA (AXPA) or glioblastoma. The understanding of disease etiology and mechanisms driving PXA and APXA are limited, and there is no standard of care. Therefore, development of relevant preclinical models to investigate molecular underpinnings of disease and to guide novel therapeutic approaches are of interest. Here, for the first time we established, and characterized a patient-derived xenograft (PDX) from a leptomeningeal spread of a patient with recurrent APXA bearing a novel CDC42SE2-BRAF fusion. An integrated -omics analysis was conducted to assess model fidelity of the genomic, transcriptomic, and proteomic/phosphoproteomic landscapes. A stable xenoline was derived directly from the patient recurrent tumor and maintained in 2D and 3D culture systems. Conserved histology features between the PDX and matched APXA specimen were maintained through serial passages. Whole exome sequencing (WES) demonstrated a high degree of conservation in the genomic landscape between PDX and matched human tumor, including small variants (Pearson's r = 0.794-0.839) and tumor mutational burden (~ 3 mutations/MB). Large chromosomal variations including chromosomal gains and losses were preserved in PDX. Notably, chromosomal gain in chromosomes 4-9, 17 and 18 and loss in the short arm of chromosome 9 associated with homozygous 9p21.3 deletion involving CDKN2A/B locus were identified in both patient tumor and PDX sample. Moreover, chromosomal rearrangement involving 7q34 fusion; CDC42SE-BRAF t (5;7) (q31.1, q34) (5:130,721,239, 7:140,482,820) was identified in the PDX tumor, xenoline and matched human tumor. Transcriptomic profile of the patient's tumor was retained in PDX (Pearson r = 0.88) and in xenoline (Pearson r = 0.63) as well as preservation of enriched signaling pathways (FDR Adjusted P < 0.05) including MAPK, EGFR and PI3K/AKT pathways. The multi-omics data of (WES, transcriptome, and reverse phase protein array (RPPA) was integrated to deduce potential actionable pathways for treatment (FDR < 0.05) including KEGG01521, KEGG05202, and KEGG05200. Both xenoline and PDX were resistant to the MEK inhibitors trametinib or mirdametinib at clinically relevant doses, recapitulating the patient's resistance to such treatment in the clinic. This set of APXA models will serve as a preclinical resource for developing novel therapeutic regimens for rare anaplastic PXAs and pediatric high-grade gliomas bearing BRAF fusions.

Single-Institution Comparative Study of Magnetic Resonance-Guided Laser Interstitial Thermal Therapy and Open Corpus Callosotomy.

OBJECTIVE: Open corpus callosotomy (CC) poses a higher risk of perioperative morbidity than does magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) for treatment of drop and generalized seizures without documented superiority. We present a single-institution comparison between open and MRgLITT CC. METHODS: A 2-year retrospective review was performed of patients who underwent open and MRgLITT CC (January 2019-January 2021). Demographics, surgical outcome data, hospital costs, and interhemispheric connectivity with diffusion tensor imaging were compared. RESULTS: The average age in years was 9.3 and 11.4 for CC (n = 4) and MRgLITT (n = 9), respectively. Preoperative drop seizure frequency was higher in CC (25 vs. 14.5 seizures/day; P = 0.59). At 10 months follow-up, the reduction in drop seizure frequency was better in open CC, but not statistically significant (93.8% vs. 64.3%; P = 0.21). The extent of CC ablation did not correlate with seizure reduction (Pearson coefficient = 0.09). An inverse correlation between interhemispheric connectivity change (diffusion tensor imaging analysis) and drop seizure frequency reduction was noted (Pearson coefficient = -0.97). Total hospital cost was significantly lower in MRgLITT ($67,754 vs. $107,111; P = 0.004), attributed to lower intensive care unit (1.1 vs. 4 days; P= 0.004) and total hospital stay (1.8 vs. 10.5 days; P = 0.0001). Postoperative hydrocephalus was present in 75% of patients in the CC group compared with zero in the MRgLITT group. CONCLUSIONS: Our middle-volume single-institution experience shows the safety, efficacy, and cost-effective benefit of MRgLITT compared with the traditional CC with therapeutic equipoise. This study is limited by the number of patients and, hence, further patient enrollment or multicenter study is warranted.

Iatrogenic Spinal Deformity Following Spinal Intradural Arachnoid Cyst Fenestration Despite Minimal Access With Laminoplasty and Endoscopy in a Pediatric Patient.

Spinal intradural arachnoid cysts (SAC) are non-neoplastic lesions that can cause spinal cord compression and present with myelopathy, radiculopathy, and/or back pain. Because these cysts typically span multiple levels, endoscopy could be a useful tool to avoid wide exposure. We present an 8-year-old patient with a history of gait imbalance and urinary incontinence who was found to have a SAC spanning C7 to T6 causing spinal cord compression. An osteoplastic laminoplasty was performed from T4 to T7 followed by ultrasonic verification of intracystic septations, dural opening, and cyst fenestration. A flexible endoscope was then introduced into the cystic cavity to guide complete rostral and caudal decompression of the arachnoid cyst. At six months follow-up, the patient was able to ambulate independently, but his urinary incontinence remained unchanged. Despite the combination of ultrasound and neuroendoscopy to minimize exposure, our patient suffered from worsening kyphosis from 36 degrees preoperative to 55 degrees postoperative and worsening scoliosis from 17 to 39 degrees which required treatment with a thoracolumbar sacral orthosis. Preoperative imaging demonstrated a reverse S-shaped scoliosis with the apex at T6 and T7 which were the levels included in the laminoplasty. This illustrates the need for careful preoperative risk stratification to avoid this postoperative complication.

Preoperative and Postoperative Gait Analysis and Video for Selective Dorsal Rhizotomy in Focal Hemiplegic Spasticity: 2-Dimensional Operative Video.

Selective dorsal rhizotomy (SDR) has been a well-established neurosurgical treatment option for ambulatory children with spastic diplegic cerebral palsy to reduce spasticity. Outcomes for SDR for spastic lower extremity hemiparesis has been less well described. In our experience, hemi-SDR has been an excellent intervention for children with suboptimal spasticity control despite maximizing pharmacologic and chemodenervation treatments. In Video 1, we demonstrate a focal segmental hemi-SDR at the L5-S1 level in a 7-year-old male patient with spastic hemiparesis secondary to a dysembryoplastic neuroepithelial tumor in the right inferior frontoparietal area. Rhizotomy was performed with identification and selective sectioning of dorsal nerve roots with abnormal stimulation patterns as determined by electrophysiology and clinical correlation. Dorsal nerve root fibers with unsustained discharges were spared. Postoperatively, the patient participated well in inpatient and outpatient therapies with significant progress in his mobility and activities of daily living. The patient showed improvement in gait velocity (51%), internal pressure ratio (+0.05), and step length (41% on the left and 27% on the right) 20 months after hemi-SDR. He also demonstrated a step length ratio closer to 1 (0.89) showing a more equal step length bilaterally and improved weight acceptance on the affected side. There were no changes observed on the left upper extremity. This positive outcome on spasticity control and function supports the need for further prospective studies for hemi-SDR as a treatment option for children with spastic hemiparesis.

Characterization of standard work tools for intrathecal baclofen therapy.

PURPOSE: Intrathecal baclofen (ITB) has been an effective therapy since the 1980s, with widely reported revision, infection, and complication rates. Publications targeting surgical workflow have resulted in decreased infection and revision rates, but a standard workflow for the entire pathway has not been described. To present, define, and test standard work tools for patients receiving ITB to promote uniformity and standard of care in the field. METHODS: A multidisciplinary approach from the movement disorder program of a tertiary care center defined all steps comprising the ITB pathway, and then developed standard work tools to decrease variability with respect to preoperative workup, day of surgery protocol, post-operative care, and also evaluation and treatment with respect to pump infection or malfunction. RESULTS: Defined steps used at specific points of ITB pathway are presented with a single institution's outcome using the protocol from July 2017 to November 2020. A total of 60 procedures were performed. The overall complication rate was 14.5% at 6 months. Complications included an infection rate of 3.6% at 6 months, wound revision rate of 1.8% at 6 months, CSF leak rate of 1.7% at 6 months, and a 30-day readmission rate related to initial surgery of 6.7%. CONCLUSIONS: Workflow efficiency and optimization for ITB patients can be used to obtain lower complication rates compared to historical cohorts in literature. A single-center, retrospective review highlights this.

Toxicological effects of trichloroethylene exposure on immune disorders.

Trichloroethylene (TCE) is one of the most common ground water contaminants in USA. Even though recent regulation mandates restricted utilization of TCE, its use is not completely prohibited, especially in industrial and manufacturing processes. The risk of TCE on human health is an ongoing field of study and its implications on certain diseases such as cancer has been recognized and well-documented. However, the link between TCE and immune disorders is still an under-studied area. Studies on the risk of TCE on the immune system is usually focused on certain immune class disorders, but consensus on the impact of TCE on the immune system has not been established. This review presents representative work that investigates the effect of TCE on immune disorders and highlights future opportunities. We attempt to provide a broader perspective of the risks of TCE on the immune system and human health.