Pediatric neurosurgery through the lens of time-driven activity-based costing: a pilot study.

OBJECTIVE: Time-driven activity-based costing (TDABC) is a method used in cost accounting that has gained traction in health economics to identify value optimization initiatives. It measures time, assigns value to time increments spent on a patient, and integrates the cost of material and human resources utilized in each episode of care. In this study, the authors report the first use of TDABC to evaluate costs in a pediatric neurosurgical practice. METHODS: A clinical pathway was developed with a multifunction team. A time survey among each care team member, including surgeons, medical assistants (MAs), and patient service representatives (PSRs), was carried out prospectively over a 10-week period at a pediatric neurosurgery clinic. Consecutive patient encounters for Chiari malformation (CM), hydrocephalus, or tethered cord syndrome (TCS) were included. Encounters were categorized as new or established. Relative annual personnel costs, using the salary of a PSR as a reference (i.e., 1.0-unit cost), were calculated for all members using departmental financial data after adjustments. The relative capacity cost rates (minute-1) for each personnel, a representation of per capita cost per minute, were then derived, and the relative costs per visit were calculated. RESULTS: A total of 110 visits (24 new, 86 established) were captured, including 40% CM, 41% hydrocephalus, and 19% TCS encounters. Surgeons had the highest relative capacity cost rate (118.4 × 10-6), more than 10-fold higher than that of an MA or PSR (10.65 × 10-6 and 9.259 × 10-6, respectively). Surgeons also logged more time with patients compared with the rest of the care team in nearly all visits (p ≤ 0.002); consequently, the total visit costs were primarily driven by the surgeon cost (p < 0.0001). Overall, surgeon cost constituted the vast majority of the total visit cost (92%-93%), regardless of whether the visits were new or established. Visit costs did not differ by diagnosis. On average, new visits took longer than established visits (p < 0.001). This difference was largely driven by new CM visits (44.3 ± 13.7 minutes), which were significantly longer than established CM visits (29.8 ± 9.2 minutes; p = 0.001). CONCLUSIONS: TDABC may reveal opportunities to maximize value by highlighting instances of variability and high cost in each module of care delivery. Physician leaders in pediatric neurosurgery may be able to use this information to allocate costs and streamline value care pathways.

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.