Combined cytotoxic and immune-stimulatory gene therapy for primary adult high-grade glioma: a phase 1, first-in-human trial.

BACKGROUND: High-grade gliomas have a poor prognosis and do not respond well to treatment. Effective cancer immune responses depend on functional immune cells, which are typically absent from the brain. This study aimed to evaluate the safety and activity of two adenoviral vectors expressing HSV1-TK (Ad-hCMV-TK) and Flt3L (Ad-hCMV-Flt3L) in patients with high-grade glioma. METHODS: In this dose-finding, first-in-human trial, treatment-naive adults aged 18-75 years with newly identified high-grade glioma that was evaluated per immunotherapy response assessment in neuro-oncology criteria, and a Karnofsky Performance Status score of 70 or more, underwent maximal safe resection followed by injections of adenoviral vectors expressing HSV1-TK and Flt3L into the tumour bed. The study was conducted at the University of Michigan Medical School, Michigan Medicine (Ann Arbor, MI, USA). The study included six escalating doses of viral particles with starting doses of 1×1010 Ad-hCMV-TK viral particles and 1×109 Ad-hCMV-Flt3L viral particles (cohort A), and then 1×1011 Ad-hCMV-TK viral particles and 1×109 Ad-hCMV-Flt3L viral particles (cohort B), 1×1010 Ad-hCMV-TK viral particles and 1×1010 Ad-hCMV-Flt3L viral particles (cohort C), 1×1011 Ad-hCMV-TK viral particles and 1×1010 Ad-hCMV-Flt3L viral particles (cohort D), 1×1010 Ad-hCMV-TK viral particles and 1×1011 Ad-hCMV-Flt3L viral particles (cohort E), and 1×1011 Ad-hCMV-TK viral particles and 1×1011 Ad-hCMV-Flt3L viral particles (cohort F) following a 3+3 design. Two 1 mL tuberculin syringes were used to deliver freehand a mix of Ad-hCMV-TK and Ad-hCMV-Flt3L vectors into the walls of the resection cavity with a total injection of 2 mL distributed as 0·1 mL per site across 20 locations. Subsequently, patients received two 14-day courses of valacyclovir (2 g orally, three times per day) at 1-3 days and 10-12 weeks after vector administration and standad upfront chemoradiotherapy. The primary endpoint was the maximum tolerated dose of Ad-hCMV-Flt3L and Ad-hCMV-TK. Overall survival was a secondary endpoint. Recruitment is complete and the trial is finished. The trial is registered with ClinicalTrials.gov, NCT01811992. FINDINGS: Between April 8, 2014, and March 13, 2019, 21 patients were assessed for eligibility and 18 patients with high-grade glioma were enrolled and included in the analysis (three patients in each of the six dose cohorts); eight patients were female and ten were male. Neuropathological examination identified 14 (78%) patients with glioblastoma, three (17%) with gliosarcoma, and one (6%) with anaplastic ependymoma. The treatment was well-tolerated, and no dose-limiting toxicity was observed. The maximum tolerated dose was not reached. The most common serious grade 3-4 adverse events across all treatment groups were wound infection (four events in two patients) and thromboembolic events (five events in four patients). One death due to an adverse event (respiratory failure) occurred but was not related to study treatment. No treatment-related deaths occurred during the study. Median overall survival was 21·3 months (95% CI 11·1-26·1). INTERPRETATION: The combination of two adenoviral vectors demonstrated safety and feasibility in patients with high-grade glioma and warrants further investigation in a phase 1b/2 clinical trial. FUNDING: Funded in part by Phase One Foundation, Los Angeles, CA, The Board of Governors at Cedars-Sinai Medical Center, Los Angeles, CA, and The Rogel Cancer Center at The University of Michigan.

Psychological morbidity among adults with cerebral palsy and spina bifida.

BACKGROUND: Very little is known about the risk of developing psychological morbidities among adults living with cerebral palsy (CP) or spina bifida (SB). The objective of this study was to compare the incidence of and adjusted hazards for psychological morbidities among adults with and without CP or SB. METHODS: Privately insured beneficiaries were included if they had an International Classification of Diseases, Ninth revision, Clinical Modification diagnostic code for CP or SB (n = 15 302). Adults without CP or SB were also included (n = 1 935 480). Incidence estimates of common psychological morbidities were compared at 4-years of enrollment. Survival models were used to quantify unadjusted and adjusted hazard ratios for incident psychological morbidities. RESULTS: Adults living with CP or SB had a higher 4-year incidence of any psychological morbidity (38.8% v. 24.2%) as compared to adults without CP or SB, and differences were to a clinically meaningful extent. Fully adjusted survival models demonstrated that adults with CP or SB had a greater hazard for any psychological morbidity [hazard ratio (HR): 1.60; 95% CI 1.55-1.65], and all but one psychological disorder (alcohol-related disorders), and ranged from HR: 1.32 (1.23, 1.42) for substance disorders, to HR: 4.12 (3.24, 5.25) for impulse control disorders. CONCLUSIONS: Adults with CP or SB have a significantly higher incidence of and risk for common psychological morbidities, as compared to adults without CP or SB. Efforts are needed to facilitate the development of improved clinical screening algorithms and early interventions to reduce the risk of disease onset/progression in these higher-risk populations.

A Simplified Approach to Myelomeningocele Defect Repair.

BACKGROUND: Repair of the soft tissue defect in myelomeningoceles remains challenging. The literature currently lacks a systematic approach, reporting high rates of complications. We present outcomes from the largest series to date and describe a simplified approach that minimizes morbidity and streamlines decision making. METHODS: Patients 1 year or younger who underwent myelomeningocele repair between 2008 and 2018 were reviewed. Flap types were categorized by tissue composition. Complications were dichotomized into early and late (<30 days and >30 days postoperative, respectively). Logistic regression was used to measure the impact of flap tissue composition and skin closure technique on odds of postoperative complications. RESULTS: Ninety-seven patients met inclusion criteria. Reoperation was required in only 3 (3.0%) patients-1 for wound dehiscence and 2 for surgical site infections. Zero cases of tethered cord or cerebrospinal fluid leak occurred. The most common minor complications were early wound complications (n = 18, 18.6%) and early infection (n = 5, 5.2%). Fascia-only flaps and muscle + other tissue flaps were not associated with higher odds of complications compared with muscle-only flaps (odds ratio [OR], 2.13; 95% confidence interval [CI], 0.53-8.50, P = 0.29; OR = 2.87, 95% CI 0.66-12.51, P = 0.16, respectively). Rhomboid flaps for skin closure were associated with higher odds of complications (OR, 4.47; 95% CI, 1.00-19.97; P = 0.05). CONCLUSIONS: Our approach to myelomeningocele repair demonstrated no cases of secondary tethered cord or cerebrospinal fluid leak, and reoperative rates were extremely low. Because complications were unrelated to flap type, we recommend a simplified approach using any tissue type for dural coverage and 2-layer primary closure of the skin.

Computed Tomography in Patients With Craniosynostosis: A Survey to Ascertain Practice Patterns Among Craniofacial Surgeons.

BACKGROUND: In patients with craniosynostosis, imaging remains up to the discretion of the plastic surgeon or neurosurgeon. To inform best practice guidelines, we sought to obtain data surrounding the frequency at which craniofacial surgeons order computed tomography (CT), as well as indications. We hypothesized that we would identify considerable variation in both imaging and associated indications. METHODS: We surveyed members of the American Society of Maxillofacial Surgeons and the American Society of Craniofacial Surgeons to measure the frequency of preoperative and postoperative head CTs, as well as indications. Initial items were piloted with 2 craniofacial surgeons and 1 neurosurgeon, using interviews to ensure content validity. χ2 Tests were used to measure associations between operative volume, years in practice, and imaging. RESULTS: Eighty-five craniofacial surgeons responded (13.8% response rate), with the majority (63.5%) having performed a craniosynostosis operation in the last month. Only 9.4% of surgeons never order preoperative CTs. Of those who do, the most common indications included diagnosis confirmation (31.2%) and preoperative planning (27.3%). About 25% of surgeons always obtain postoperative head CTs, usually to evaluate surgical outcomes (46.7%). Only 13.3% of respondents order 2 or more postoperative scans. Higher operative volume was associated with a lower likelihood of ordering preoperative head CTs (P = 0.008). CONCLUSIONS: The majority of surgeons obtain preoperative head CTs, whereas only 25% obtain CTs postoperatively, often to evaluate outcomes. Because outcomes may be evaluated clinically, this is a poor use of resources and exposes children to radiation. Consensus guidelines are needed to create best practices and limit unnecessary studies.

Intraoperative Phase Contrast MRI Analysis of Cerebrospinal Fluid Velocities During Posterior Fossa Decompression for Chiari I Malformation.

BACKGROUND: Cerebrospinal fluid (CSF) velocity at the craniovertebral junction (CVJ) is known to be altered in patients with Chiari I malformation (CMI), and normalization of CSF velocities is associated with symptom resolution. However, preoperative and intraoperative prediction methods have thus far failed to identify patients in whom CSF velocities can be normalized with posterior fossa decompression (PFD) without duraplasty. Phase contrast MRI (PC-MRI) may assist not only in diagnosis of CMI but also in guiding the intraoperative decision to perform duraplasty during PFD. PURPOSE: To use intraoperative MRI data to quantify changes in CSF hydrodynamics at the CVJ during each step of PFD with duraplasty (PFDD) in 12 consecutive patients. STUDY TYPE: Retrospective case series with all patients imaged before, during and after decompression, and all data analyzed postprocedure. POPULATION/SUBJECTS: Pediatric patients, mean age 14 years (range 4-18), undergoing PFD for CMI. FIELD STRENGTH/SEQUENCE: Intraoperative studies involved a dedicated 1.5T Siemens MRI imager. PC-MRI scans were in the axial plane at the CVJ. ASSESSMENT: Two observers assessed measurements. STATISTICAL TEST: The equality of matched pairs of observations was tested using the Wilcoxon matched-pairs signed-ranks test. RESULTS: Data analyses of the PC-MRI demonstrated a marked and immediate increase in CSF velocity at the posterior CVJ during PFDD. Mean cranially-directed velocities increased by a mean of 1.049cm/s (P = 0.028) from preincision to postoperative measurement. There was a mean 0.45 cm/s (P = 0.022) increase in mean cranial velocity from preincision to bone decompression scans, and a mean 0.48 cm/s (P = 0.018) increase in mean velocity from preincision to duraplasty. DATA CONCLUSION: In all subjects, significant increases in the mean and peak velocities of cranially- and caudally-directed velocities were observed from preincision to post-PFDD scans at the posterior CVJ. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2020;51:1463-1470.

Surgical Hypercorrection of Trigonocephaly: Evaluation of Surgical Outcomes.

BACKGROUND: A lasting correction of trigonocephaly is difficult to achieve, as a durable correction requires significant expansion to overcome galeal restriction and soft tissue recoil of the scalp. High rates of relapse have been reported throughout the literature. The specific aim of this study was to determine if the senior author's method of "hypercorrection" decreases relapse and the need for subsequent revisional surgery. METHODS: Patients who underwent operative correction of metopic craniosynostosis between 1988 and 2011 were reviewed. All patients underwent the "hypercorrection" technique performed by the senior author. Hypercorrection consisted of a fronto-orbital advancement of 2.5 to 3.5 cm and a concomitant hyperexpansion of bitemporal projection. Split cranial bone grafting ensured adequate coverage of the significantly expanded cranial vault. Only patients who had at least 5 years of follow-up were included for review of outcomes. Relapse was defined as recurrence of bitemporal constriction or lateral orbital retrusion, requiring surgical correction. RESULTS: Fifty-eight patients met criteria. Mean age at the time of surgery was 11 months. Mean follow-up was 9.0 years. During this time, 2 patients exhibited relapse requiring camouflage procedures. Cranial bone defects were found in 4 patients (7%), 3 of whom underwent cranial bone grafting, while 1 underwent methylmethacrylate placement at an outside institution. One patient underwent fat grafting for areas of soft tissue irregularity. No patients exhibited persistent sequelae of hypercorrection significant enough to require repeat fronto-orbital advancement. CONCLUSION: Surgical hypercorrection of trigonocephaly seems to minimize relapse and the need for revision in long-term follow-up and is therefore an important technique to consider.

The Role of Preoperative Imaging in the Management of Nonsyndromic Lambdoid Craniosynostosis.

BACKGROUND: The necessity of imaging for patients with craniosynostosis is controversial. Lambdoid synostosis is known to be associated with additional anomalies, but the role of imaging in this setting has not been established. The purpose of this study was to evaluate the impact of preoperative imaging on intraoperative and postoperative management among patients undergoing operative intervention for lambdoid craniosynostosis. METHODS: A retrospective review of patients undergoing cranial vault remodeling for lambdoid craniosynostosis between January 2006 and 2014 was conducted. Patient demographics, age at computed tomography scan, age at surgery, results of the radiologic evaluation, operative technique, and modification of the diagnosis following the radiologic studies were analyzed. A pediatric neuroradiology and the surgical team interpreted the radiographs. The primary outcome was change in intraoperative or postoperative management based on imaging results. RESULTS: A total of 11 patients were diagnosed with lambdoid synostosis. Of these patients, 81.8% had abnormalities on imaging relevant to operative planning. The most common anomalies were Chiari I malformation (45%) and venous anomalies of the posterior fossa (36%). Preoperative imaging altered the management of 9 (81.8%) patients. Closer follow-up was required for 6 patients (54%). Suboccipital decompression was performed in 4 patients (36%). Venous anomalies were found in 4 patients (36%). The diagnosis was changed from positional plagiocephaly to lambdoid synostosis in 2 patients (18%). CONCLUSIONS: Given the frequency and significance of radiographic abnormalities in the setting of lamboid synostosis, preoperative imaging should be considered during the operative planning phase as it can affect postoperative and intraoperative management.

Cerebrospinal fluid velocity amplitudes within the cerebral aqueduct in healthy children and patients with Chiari I malformation.

PURPOSE: To assess the effects of cerebrospinal fluid (CSF) bidirectional motion in Chiari malformation type I (CMI), we monitored CSF velocity amplitudes on phase contrast MRI (PC-MRI) in patients before and after surgery; and in healthy volunteers. MATERIALS AND METHODS: 10 pediatric volunteers and 10 CMI patients participated in this study. CMI patients underwent PC-MRI scans before and approximately 14 months following surgery. Two parameters-amplitude of mean velocity (AMV) and amplitude of peak velocity (APV) of CSF-were derived from the data. Measurements were made at the mid-portion of the cerebral aqueduct, and anterior and posterior compartments of the spinal canal at the craniovertebral junction (CVJ). RESULTS: AMV and APV within the cerebral aqueduct were greater in preoperative assessments of the CMI patients compared to normal volunteers. Statistical significance was noted when comparing aqueductal AMV between the preoperative values and normal controls (P = 0.03), and before and after surgery in the CMI patients (P = 0.02). Lower values of AMV (P = 0.02) were noted in the anterior CVJ compartment in the patients before and after surgery when compared to the normal volunteers. There were no significant correlations (P = 0.06) noted for the APV at the CVJ between the normal control and patients, before or after surgery. CONCLUSION: In pediatric CMI patients, AMV for CSF within the cerebral aqueduct and anterior CVJ subarachnoid space are significantly elevated preoperatively and normalize following surgery. Given the biphasic CSF motion, measuring amplitude accounts for cranial and caudal flow. It may offer an alternative parameter to assess postsurgical outcome. J. Magn. Reson. Imaging 2016;44:463-470.

Role of Protease-Activated Receptor-1 in Glioma Growth.

Activation of a thrombin receptor, protease-activated receptor-1 (PAR-1), induces angiogenesis, cell proliferation, and invasion in tumors. The present study examined the effect of host PAR-1 gene deletion on glioma growth in a mouse model. F98 glioma cells were implanted into the right caudate of either wild type (WT) or PAR-1 knockout (KO) mice. Mice underwent magnetic resonance imaging (MRI) and the brains were used for measurements of brain water content and tumor mass. Levels of hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) were also measured by ELISA (enzyme-linked immunosorbent assay). We found brain water content in the ipsilateral hemisphere and the tumor mass were significantly lower in PAR-1 KO than WT mice at day 12 after implantation of F98 cells (p < 0.05). HIF-1α protein levels in the ipsilateral hemisphere were higher in the WT mice (373 ± 25 pg/g brain tissue vs 333 ± 35 pg/g brain tissue in PAR-1 KO mice, p < 0.05) 7 days after F98 cell implantation. VEGF protein levels were also higher in the ipsilateral hemisphere of WT mice (219 ± 21 vs 166 ± 22 pg/g brain tissue in PAR-1 KO mice, p < 0.01). In conclusion, PAR-1 has a role in glioma growth and could be a new therapeutic target for gliomas.

Endoscopic Strip Craniectomy for Craniosynostosis: Do We Really Understand the Indications, Outcomes, and Risks?

Endoscopic strip craniectomy with postoperative helmet therapy has been introduced as a means to correct various forms of craniosynostosis. Although some authors have deemed the procedure safe and effective, many questions remain regarding this promising yet developing approach. The authors discuss 4 cases where patients were inadequately treated with endoscopic strip craniectomy resulting in a recommendation of complete secondary open cranial vault reconstruction. In addition, the authors present the findings from an informal survey of craniofacial colleagues to highlight an important discrepancy between published and anecdotal reports of complications. Finally, the authors highlight the need for further investigation into the proper indications and clinical outcomes of endoscopic strip craniectomy to better understand the role of this technique in the treatment of craniosynostosis.

Bone Mineral Content in Infants With Myelomeningocele, With and Without Treadmill Stepping Practice.

PURPOSE: To study development of bone mineral content (BMC) in infants with myelomeningocele (MMC) who did or did not receive upright supported stepping practice (USSP) and in infants with typical development (TD). METHODS: We tested 36 infants across the ages of 1 to 18 months. Dual-energy x-ray absorptiometry was used to collect raw BMC data for the whole body, legs, and arms, which were normalized using anthropometrics. RESULTS: Whole-body BMC generally increased with age; values for infants with MMC were slightly lower than those for infants with TD. Bone mineral content for legs and arms was lower for infants with MMC than for infants with TD. Between MMC groups, the group receiving USSP showed increases in BMC with age. CONCLUSION: Bone mineralization in infants with MMC begins to lag compared with infants with TD across infancy, and daily USSP can improve BMC as early as the first year of life.

Tenascin-C: a novel candidate marker for cancer stem cells in glioblastoma identified by tissue microarrays.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor, with dismal survival outcomes. Recently, cancer stem cells (CSCs) have been demonstrated to play a role in therapeutic resistance and are considered to be the most likely cause of cancer relapse. The identification of CSCs is an important step toward finding new and effective ways to treat GBM. Tenascin-C (TNC) protein has been identified as a potential marker for CSCs in gliomas based on previous work. Here, we have investigated the expression of TNC in tissue microarrays including 17 GBMs, 18 WHO grade III astrocytomas, 15 WHO grade II astrocytomas, 4 WHO grade I astrocytomas, and 7 normal brain tissue samples by immunohistochemical staining. TNC expression was found to be highly associated with the grade of astrocytoma. It has a high expression level in most of the grade III astrocytomas and GBMs analyzed and a very low expression in most grade II astrocytomas, whereas it is undetectable in grade I astrocytomas and normal brain tissues. Double-immunofluorescence staining for TNC and CD133 in GBM tissues revealed that there was a high overlap between theses two positive populations. The results were further confirmed by flow cytometry analysis of TNC and CD133 in GBM-derived stem-like neurospheres in vitro. A limiting dilution assay demonstrated that the sphere formation ability of CD133(+)/TNC(+) and CD133(-)/TNC(+) cell populations is much higher than that of the CD133(+)/TNC(-) and CD133(-)/TNC(-) populations. These results suggest that TNC is not only a potential prognostic marker for GBM but also a potential marker for glioma CSCs, where the TNC(+) population is identified as a CSC population overlapping with part of the CD133(-) cell population.

CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity.

Amplification of the C19MC oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In this study, we sought to evaluate the diagnostic specificity of C19MC and LIN28, and the clinical and biological spectra of C19MC amplified and/or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that C19MC alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas. C19MC amplified/LIN28+ group 1 CNS-PNETs arose predominantly in children <4 years old; a majority arose in the cerebrum but 24 % (13/54) of tumors had extra-cerebral origins. Notably, group 1 CNS-PNETs encompassed several histologic classes including embryonal tumor with abundant neuropil and true rosettes (ETANTR), medulloepithelioma, ependymoblastoma and CNS-PNETs with variable differentiation. Strikingly, gene expression and methylation profiling analyses revealed a common molecular signature enriched for primitive neural features, high LIN28/LIN28B and DNMT3B expression for all group 1 CNS-PNETs regardless of location or tumor histology. Our collective findings suggest that current known histologic categories of CNS-PNETs which include ETANTRs, medulloepitheliomas, ependymoblastomas in various CNS locations, comprise a common molecular and diagnostic entity and identify inhibitors of the LIN28/let7/PI3K/mTOR axis and DNMT3B as promising therapeutics for this distinct histogenetic entity.

CD90 is identified as a candidate marker for cancer stem cells in primary high-grade gliomas using tissue microarrays.

Although CD90 has been identified as a marker for various kinds of stem cells including liver cancer stem cells (CSCs) that are responsible for tumorigenesis, the potential role of CD90 as a marker for CSCs in gliomas has not been characterized. To address the issue, we investigated the expression of CD90 in tissue microarrays containing 15 glioblastoma multiformes (GBMs), 19 WHO grade III astrocytomas, 13 WHO grade II astrocytomas, 3 WHO grade I astrocytomas and 8 normal brain tissues. Immunohistochemical analysis showed that CD90 was expressed at a medium to high level in all tested high-grade gliomas (grade III and GBM) whereas it was barely detectable in low-grade gliomas (grade I and grade II) and normal brains. Double immunofluorescence staining for CD90 and CD133 in GBM tissues revealed that CD133(+) CSCs are a subpopulation of CD90(+) cells in GBMs in vivo. Flow cytometry analysis of the expression of CD90 and CD133 in GBM-derived stem-like neurospheres further confirmed the conclusion in vitro. The expression levels of both CD90 and CD133 were reduced along with the loss of stem cells after differentiation. Furthermore, the limiting dilution assay demonstrated that the sphere formation ability was comparable between the CD90(+)/CD133(+) and the CD90(+)/CD133(-) populations of GBM neurospheres, which is much higher than that of the CD90(-)/CD133(-) population. We also performed double staining for CD90 and a vascular endothelial cell marker CD31 in tissue microarrays which revealed that the CD90(+) cells were clustered around the tumor vasculatures in high-grade glioma tissues. These findings suggest that CD90 is not only a potential prognostic marker for high-grade gliomas but also a marker for CSCs within gliomas, and it resides within endothelial niche and may also play a critical role in the generation of tumor vasculatures via differentiation into endothelial cells.

Minimizing transfusions in primary cranial vault remodeling: the role of aminocaproic acid.

BACKGROUND: Cranial vault remodeling (CVR) for craniosynostosis is a procedure with the potential for significant blood loss. Aminocaproic acid (ACA) has been used at our institution during CVR for its antifibrinolytic effects. The purpose of this study was to investigate the effect of ACA on blood loss and transfusion rates during primary CVR. METHODS: Three hundred eighty-three patients with craniosynostosis underwent primary CVR at a single institution by a single surgeon over 15 years. Patients were included if they received either ACA or no antifibrinolytic. The estimated blood loss (EBL) and volume of blood transfused was recorded. Thrombotic-related complications were identified. Comparisons were made between subgroups using independent Student t test and Fisher exact test. RESULTS: Among the study population, 148 patients met inclusion criteria. ACA was given to 30 patients, while 118 patients received no antifibrinolytic. There was no difference in the average intraoperative EBL between the ACA (322 mL) and control groups (327 mL, P > 0.05). Additionally, the incidence of transfusion was not significantly different between subgroups (97% vs. 86%, respectively, P > 0.05). Patients treated with ACA, however, received lower average perioperative transfusion volumes (25.5 mL/kg) compared to control patients (53.3 mL/kg, P < 0.0001). Furthermore, patients in the ACA subgroup were less likely to require a second unit of blood (21% vs. 43%, P < 0.0001) and therefore had fewer exposures to donor blood antigens (ARR = 22%, NNT = 4.6). CONCLUSIONS: The use of intraoperative ACA minimizes blood transfusion volumes and donor exposures in children who undergo primary CVR for craniosynostosis. Antifibrinolytics should be considered for routine use in pediatric craniofacial surgery.

Low Prevalence of Clinically Significant Hyponatremia following Cranial Vault Reconstruction for Single-Suture Craniosynostosis.

BACKGROUND: Patients are commonly monitored for hyponatremia after intracranial procedures, yet the prevalence of hyponatremia after cranial vault reconstruction (CVR) remains unclear. The purpose of this study is to define the prevalence, risk factors, and complications of hyponatremia after CVR to optimize postoperative sodium surveillance protocols. METHODS: Patients with nonsyndromic, single-suture craniosynostosis who underwent primary CVR between 2009 and 2020 at Michigan Medicine were included (n = 231). Demographic, intraoperative, and postoperative characteristics were compared by postoperative hyponatremia status at P < 0.05 significance. Hyponatremia was defined as mild (<135 mEq/L), moderate (<130 mEq/L), or severe (<125 mEq/L) based on the lowest postoperative laboratory draw. RESULTS: Twenty-three patients (10.0%) developed mild postoperative hyponatremia. No patient developed moderate or severe postoperative hyponatremia. On multivariable regression, decreased preoperative sodium level (P = 0.03) and decreased preoperative weight (P = 0.02) were significantly associated with mild postoperative hyponatremia. No patient developed complications or required hospital readmission because of hyponatremia. CONCLUSIONS: This large retrospective cohort study of patients with nonsyndromic single-suture craniosynostosis demonstrated a 10% prevalence of mild, clinically inconsequential hyponatremia and 0% prevalence of moderate or severe, clinically significant hyponatremia after primary CVR. Patients with low preoperative sodium level or weight were at increased risk for developing mild postoperative hyponatremia. The results suggest that patients with preoperative sodium greater than 140 mEq/L or preoperative weight greater than 10 kg may be candidates for limited postoperative sodium surveillance; however, future prospective studies are warranted before implementation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Influence of socioeconomic status on clinical outcomes of diffuse midline glioma and diffuse intrinsic pontine glioma.

OBJECTIVE: Given the lack of a definitive treatment and the poor prognosis of patients with diffuse midline glioma (DMG) and diffuse intrinsic pontine glioma (DIPG), socioeconomic status (SES) may affect treatment access and therefore survival. Therefore, this study aimed to examine the relationship between SES and treatment modalities, progression-free survival (PFS), and overall survival (OS) in children with DMG/DIPG. METHODS: A retrospective, single-institution review was conducted of medical records of patients ≤ 18 years of age who had DMG or DIPG that was diagnosed between 2000 and 2022. Patient demographics, surgical interventions, chemotherapy, radiation therapy, clinical trial enrollment, and medical care-related travel were extracted. SES variables (education and mean income) for associated patient census tracts were collected and stratified. Statistical analysis using unpaired t-tests, chi-square analysis, and log-rank tests was conducted. RESULTS: Of the 96 patients who met the inclusion criteria, the majority were female (59%) and non-Hispanic White (57%). The median PFS, median OS, and time from diagnosis to treatment did not differ between races/ethnicities or sex. Ninety-one of 96 patients had census tract data available. Patients from higher-income census tracts (> 50% of families with annual household income greater than $50,000) had a longer median OS (480 vs 235 days, p < 0.001) and traveled significantly longer distances for medical care (1550 vs 1114 miles, p = 0.048) than families from lower-income census tracts. Patients from the highest education quartile traveled significantly farther for treatment than the lowest education quartile (mean 2964 vs 478 miles, p = 0.047). Patients who received both oral and intravenous chemotherapy were more likely to be from higher-income census tracts than those who received intravenous or no chemotherapy. Duration of PFS, rates of clinical trial enrollment, biopsy rates, H3K27 mutation status, ventriculoperitoneal shunt placement rates, and radiotherapy rates were not associated with SES variables. CONCLUSIONS: Patients from families from higher-income census tracts experienced longer OS and traveled farther for treatment. Patients from families from higher-education-level census tracts traveled more often for treatment. The authors' findings suggest that SES influences DMG and DIPG OS. More studies should be done to understand the role of SES in the outcomes of children with DMG/DIPG.

A road map for the treatment of pediatric diffuse midline glioma.

Recent clinical trials for H3K27-altered diffuse midline gliomas (DMGs) have shown much promise. We present a consensus roadmap and identify three major barriers: (1) refinement of experimental models to include immune and brain-specific components; (2) collaboration among researchers, clinicians, and industry to integrate patient-derived data through sharing, transparency, and regulatory considerations; and (3) streamlining clinical efforts including biopsy, CNS-drug delivery, endpoint determination, and response monitoring. We highlight the importance of comprehensive collaboration to advance the understanding, diagnostics, and therapeutics for DMGs.

Immunohistochemical staining, laser capture microdissection, and filter-aided sample preparation-assisted proteomic analysis of target cell populations within tissue samples.

An important problem involves isolating subpopulations of cells defined by protein markers in clinical tissue samples for proteomic studies. We describe a method termed Immunohistochemical staining, laser capture microdissection (LCM) and filter-aided sample preparation (FASP)-Assisted Proteomic analysis of Target cell populations within tissue samples (ILFAPT). The principle of ILFAPT is that a target cell population expressing a protein of interest can be lit up by immunohistochemical staining and isolated from tissue sections using LCM for FASP and proteomic analysis. Using this method, we isolated a small population of CD90(+) stem-like cells from glioblastoma multiforme tissue sections and identified 674 high-confidence (false discovery rate < 0.01) proteins from 32 nL of CD90(+) cells by LC-MS/MS using an Orbitrap Elite mass spectrometer. We further quantified the relative abundance of proteins identified from equal volumes of LCM-captured CD90(+) and CD90(-) cells, where 109 differentially expressed proteins were identified. The major group of these differentially expressed proteins was relevant to cell adhesion and cellular movement. This ILFAPT method has demonstrated the ability to provide in-depth proteome analysis of a very small specific cell population within tissues. It can be broadly applied to the study of target cell populations within clinical specimens.