CSPG4-targeting CAR-macrophages inhibit melanoma growth.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematological malignancies but has been clinically less effective in solid tumors. Engineering macrophages with CARs has emerged as a promising approach to overcome some of the challenges faced by CAR-T cells due to the macrophage's ability to easily infiltrate tumors, phagocytose their targets, and reprogram the immune response. We engineered CAR-macrophages (CAR-Ms) to target chondroitin sulfate proteoglycan 4 (CSPG4), an antigen expressed in melanoma, and several other solid tumors. CSPG4-targeting CAR-Ms exhibited specific phagocytosis of CSPG4-expressing melanoma cells. Combining CSPG4-targeting CAR-Ms with CD47 blocking antibodies synergistically enhanced CAR-M-mediated phagocytosis and effectively inhibited melanoma spheroid growth in 3D. Furthermore, CSPG4-targeting CAR-Ms inhibited melanoma tumor growth in mouse models. These results suggest that CSPG4-targeting CAR-M immunotherapy is a promising solid tumor immunotherapy approach for treating melanoma. STATEMENT OF SIGNIFICANCE: We engineered macrophages with CARs as an alternative approach for solid tumor treatment. CAR-macrophages (CAR-Ms) targeting CSPG4, an antigen expressed in melanoma and other solid tumors, phagocytosed melanoma cells and inhibited melanoma growth in vivo . Thus, CSPG4-targeting CAR-Ms may be a promising strategy to treat patients with CSPG4-expressing tumors.

Morphological and ultrastructural investigation of the posterior atlanto-occipital membrane: Comparing children with Chiari malformation type I and controls.

INTRODUCTION: The fibrous posterior atlanto-occipital membrane (PAOM) at the craniocervical junction is typically removed during decompression surgery for Chiari malformation type I (CM-I); however, its importance and ultrastructural architecture have not been investigated in children. We hypothesized that there are structural differences in the PAOM of patients with CM-I and those without. METHODS: In this prospective study, blinded pathological analysis was performed on PAOM specimens from children who had surgery for CM-I and children who had surgery for posterior fossa tumors (controls). Clinical and radiographic data were collected. Statistical analysis included comparisons between the CM-I and control cohorts and correlations with imaging measures. RESULTS: A total of 35 children (mean age at surgery 10.7 years; 94.3% white) with viable specimens for evaluation were enrolled: 24 with CM-I and 11 controls. There were no statistical demographic differences between the two cohorts. Four children had a family history of CM-I and five had a syndromic condition. The cohorts had similar measurements of tonsillar descent, syringomyelia, basion to C2, and condylar-to-C2 vertical axis (all p>0.05). The clival-axial angle was lower in patients with CM-I (138.1 vs. 149.3 degrees, p = 0.016). Morphologically, the PAOM demonstrated statistically higher proportions of disorganized architecture in patients with CM-I (75.0% vs. 36.4%, p = 0.012). There were no differences in PAOM fat, elastin, or collagen percentages overall and no differences in imaging or ultrastructural findings between male and female patients. Posterior fossa volume was lower in children with CM-I (163,234 mm3 vs. 218,305 mm3, p<0.001), a difference that persisted after normalizing for patient height (129.9 vs. 160.9, p = 0.028). CONCLUSIONS: In patients with CM-I, the PAOM demonstrates disorganized architecture compared with that of control patients. This likely represents an anatomic adaptation in the presence of CM-I rather than a pathologic contribution.

Combined endovascular and skull base surgical management of pediatric craniocervical pathology: a case series.

OBJECTIVE: Pathological bony abnormalities of the craniocervical region in children sometimes require surgical intervention as part of their management. Rarely, abnormal skeletal or vascular anatomy can render traditional surgical techniques ineffective because of the risk of injury to the vertebral artery. To mitigate these risks, a combined endovascular and skull base approach was devised. The authors describe their experience using vertebral artery sacrifice as an adjunctive surgical method to reduce the risk of inadvertent vertebral artery injury during surgical correction of pediatric craniocervical deformity. METHODS: Three patients underwent vertebral artery sacrifice for structural craniocervical pathologies (1 male, 2 females; ages 12, 14, and 3 years). One patient presented with basilar invagination odontogenic brainstem compression, and the other 2 patients presented with congenital cervical fusion. All patients underwent endovascular left vertebral artery sacrifice after passing balloon test occlusion. RESULTS: No adverse effects from the vertebral artery sacrifice were observed. At the last follow-ups (35, 30, and 32 months), all 3 patients had a satisfactory outcome with no adverse effects as a result of their sacrificed artery. CONCLUSIONS: Endovascular vertebral artery sacrifice followed by skull base approaches can be used to effectively and safely treat craniocervical pathology from a variety of pediatric skeletal abnormalities.

Treatment of hydrocephalus following posterior fossa tumor resection: a multicenter collaboration from the Hydrocephalus Clinical Research Network.

OBJECTIVE: Persistent hydrocephalus following posterior fossa brain tumor (PFBT) resection is a common cause of morbidity in pediatric brain tumor patients, for which the optimal treatment is debated. The purpose of this study was to compare treatment outcomes between VPS and ETV in patients with persistent hydrocephalus following surgical resection of a PFBT. METHODS: A post-hoc analysis was performed of the Hydrocephalus Clinical Research Network (HCRN) prospective observational study evaluating VPS and ETV for pediatric patients. Children who experienced hydrocephalus secondary to PFBT from 2008 to 2021 were included. Primary outcomes were VPS/ETV treatment failure and time-to-failure (TTF). RESULTS: Among 241 patients, the VPS (183) and ETV (58) groups were similar in age, extent of tumor resection, and preoperative ETV Success Score. There was no difference in overall treatment failure between VPS and ETV (33.9% vs 31.0%, p = 0.751). However, mean TTF was shorter for ETV than VPS (0.45 years vs 1.30 years, p = 0.001). While major complication profiles were similar, compared to VPS, ETV patients had relatively higher incidence of minor CSF leak (10.3% vs. 1.1%, p = 0.003) and pseudomeningocele (12.1% vs 3.3%, p = 0.02). No ETV failures were identified beyond 3 years, while shunt failures occurred beyond 5 years. Shunt infections occurred in 5.5% of the VPS cohort. CONCLUSIONS: ETV and VPS offer similar overall success rates for PFBT-related postoperative hydrocephalus. ETV failure occurs earlier, while susceptibility to VPS failure persists beyond 5 years. Tumor histology and grade may be considered when selecting the optimal means of CSF diversion.

Use of the 5-Factor Modified Frailty Index to Predict Hospital-Acquired Infections and Length of Stay Among Neurotrauma Patients Undergoing Emergent Craniotomy/Craniectomy.

OBJECTIVE: Traumatic brain injury is a significant public health concern often complicated by hospital-acquired infections (HAIs); however, previous evaluations of factors predictive of risk for HAI have generally been single-center analyses or limited to surgical site infections. Frailty assessment has been shown to provide effective risk stratification in neurosurgery. We evaluated whether frailty status or age is more predictive of HAIs and length of stay among neurotrauma patients requiring craniectomy/craniotomy. METHODS: In this cross-sectional analysis, the American College of Surgeons National Surgical Quality Improvement Program 2015-2019 dataset was queried to identify neurotrauma patients who underwent craniectomies/craniotomies. The effects of frailty status (using the 5-factor modified frailty index [mFI-5]) and age on occurrence of HAIs and other 30-day adverse events were compared using univariate analysis. The discriminative ability of each measure was defined by multivariate modeling. RESULTS: Of 3284 patients identified, 1172 (35.7%) contracted an HAI postoperatively. Increasing frailty score predicted increased HAI risk (odds ratio [OR] = 1.36, 95% confidence interval [CI] = 1.05-1.77, P = 0.022 for mFI-5 = 1 and OR = 2.01, 95% CI = 1.30-3.11, P = 0.002 for mFI-5≥3), whereas increasing age did not (OR = 0.996, 95% CI = 0.989-1.002, P = 0.009). Median length of stay was significantly longer in patients with HAI (16 days [IQR = 9-23]) versus no HAI (7 days [IQR = 4-13]) (P < 0.001). Median daily costs on the ward and neuro-intensive care unit were higher with HAI than with no HAI (neuro-ICU: $111,818.08 [IQR = 46,418.05-189,947.34] vs. $48,920.41 [IQR = 20,185.20-107,712.54], P < 0.001). CONCLUSIONS: Increasing mFI-5 correlated with increased HAI risk. Neurotrauma patients who developed an HAI after craniectomy/craniotomy had longer hospitalizations and higher care costs. Frailty scoring improves risk stratification among these patients and may assist in reducing total hospital length of stay and total accrued costs to patients.

Stereotactic electroencephalography is associated with reduced opioid and nonsteroidal anti-inflammatory drug use when compared with subdural grids: a pediatric case series.

Patients undergoing surgical intervention for epilepsy mapping are typically administered opioids for pain control. The use of opioids is demonstrably lower after other procedures when a minimally invasive surgery (MIS) technique is used. Our objective was to determine whether using MIS for stereoelectroencephalography (SEEG) resulted in lower opioid requirement by pediatric patients when compared with subdural grid placement after craniotomy (ECoG). A retrospective chart review was conducted to identify patients < 18 years who underwent epilepsy mapping surgery using SEEG or ECoG in 2015-2019. The hospital stay was divided into four time periods, and the total amounts of opioids (converted into morphine milligram equivalents (MMEs)) and nonsteroidal anti-inflammatory drugs (NSAIDs) and pain scores (on numerical rating scale (NRS)) were calculated for each time interval. The two groups were then compared statistically. The study included 31 patients in the SEEG group and 9 in the ECoG group. The SEEG group consumed significantly fewer opioids during the hospital stay than the ECoG group (23.6 vs. 61.7 MMEs; p = 0.041). There were also significant differences in the length of stay (6.9 vs. 12.2 days; p = 0.002), rate of complications (0% vs. 20%; p = 0.006), and total NSAIDs consumed (3,264.8 vs. 12,730.2 mg; p = 0.002). Opioid and NSAID consumption were significantly lower and hospital stays were shorter in pediatric patients who underwent epilepsy mapping via SEEG compared with ECoG. These results suggest that MIS for epilepsy mapping may decrease the overall pain medication use and expedite patient discharge.

Pediatric Holocord Epidural Abscess Treated with Apical Laminotomies with Catheter-directed Irrigation and Drainage.

Spinal epidural abscesses (SEA), while fortunately rare, carry significant risk to affected patients. Optimal treatment of these infections is poorly defined due to the heterogeneity of clinical and radiographic presentations. Urgent surgical evacuation of the infection is critical in cases with spinal cord compression or neurological compromise, though challenges may arise from competing surgical objectives, including the need for successful debridement of the infection, desire to minimize operative intervention, and risk of delayed iatrogenic instability. This is particularly concerning in young children with large multiregional collections. We present the first report case of pediatric holocord abscess treated with apical laminotomies and epidural catheterization for irrigation and drainage. This technique allowed successful treatment while avoiding extensive laminectomies and associated morbidities.