Fixed- Versus Variable-Dose Prothrombin Complex Concentrate for the Emergent Reversal of Vitamin K Antagonists: A Systematic Review and Meta-Analysis.

OBJECTIVES: Four-factor prothrombin complex concentrate (4-PCC) is recommended for rapid reversal of vitamin K antagonists (VKAs) such as warfarin, yet optimal dosing remains uncertain. DATA SOURCES: A systematic review was conducted of PubMed, Embase, and Ovid MEDLINE (Wolters Kluwer) databases from January 2000 to August 2023 for clinical studies comparing fixed- vs. variable-dose 4-PCC for emergent VKA reversal with at least one reported clinical outcome. STUDY SELECTION: Abstracts and full texts were assessed independently and in duplicate by two reviewers. DATA EXTRACTION: Data were extracted independently and in duplicate by two reviewers using predefined extraction forms. DATA SYNTHESIS: The analysis comprised three randomized trials and 16 cohort studies comprising a total of 323 participants in randomized trials (161 in fixed dosage and 162 in variable dosage) and 1912 patients in cohort studies (858 in fixed-dose and 1054 in variable dose). Extracranial bleeding was the predominant indication, while intracranial hemorrhage varied. Overall, a fixed-dose regimen may be associated with a lower dose of 4-PCC and results in a reduction in 4-PCC administration time compared with a variable-dose regimen. A fixed-dose regimen also likely results in increased clinical hemostasis. While there is no clear difference between the two regimens in terms of achieving a goal international normalized ratio (INR) less than 2, a fixed-dose regimen is less likely to achieve a goal INR less than 1.5. High certainty evidence indicates that the fixed-dose regimen reduces both mortality and the occurrence of thromboembolic events. Additional subgroup analyses provides exploratory data to guide future studies. CONCLUSIONS: A fixed-dose regimen for 4-PCC administration provides benefits over a variable-dose regimen in terms of dose reduction, faster administration time, improved clinical hemostasis, and reduced mortality and thromboembolic events. Further studies are warranted to better refine the optimal fixed-dose regimen.

Obesity and meningioma: a US population-based study paired with analysis of a multi-institutional cohort.

OBJECTIVE: Whether obesity is associated with meningioma and the impact of obesity by gender has been debated. The primary objective of this study was to investigate differences in BMI between male and female patients undergoing craniotomy for meningioma and compare those with patients undergoing craniotomy for other intracranial tumors. The secondary objective was to compare meningioma location and progression-free survival (PFS) between obese and nonobese patients in a multi-institutional cohort. METHODS: National data were obtained from the National Surgical Quality Improvement Program (NSQIP) database. Male and female patients were analyzed separately. Patients undergoing craniotomies for meningioma were compared with patients of the same sex undergoing craniotomies for other intracranial tumors. Institutional data from two academic centers were collected for all male and an equivalent number of female meningioma patients undergoing meningioma resection. Multivariate regression controlling for age was used to determine differences in meningioma location. Kaplan-Meier curves and log-rank tests were computed to investigate differences in PFS. RESULTS: From NSQIP, 4163 male meningioma patients were compared with 24,266 controls, and 9372 female meningioma patients were compared with 21,538 controls. Male and female patients undergoing meningioma resection were more likely to be overweight or obese compared with patients undergoing craniotomy for other tumors, with the odds ratio increasing with increasing weight class (all p < 0.0001). In the multi-institutional cohort, meningiomas were more common along the skull base in male patients (p = 0.0123), but not in female patients (p = 0.1246). There was no difference in PFS between obese and nonobese male (p = 0.4104) or female (p = 0.5504) patients. Obesity was associated with increased risk of pulmonary embolism in both male and female patients undergoing meningioma resection (p = 0.0043). CONCLUSIONS: Male and female patients undergoing meningioma resection are more likely to be obese than patients undergoing craniotomy for other intracranial tumors. Obese males are more likely to have meningiomas in the skull base compared with other locations, but this association was not found in females. There was no significant difference in PFS among obese patients. The mechanism by which obesity increases meningioma incidence remains to be determined.

Radionuclide shuntography for cerebrospinal fluid shunt flow evaluation in adults.

OBJECTIVE: Radionuclide shuntography (RS) performed using 99mTc-DTPA injected into the reservoir of CSF shunts enables evaluation of CSF flow for suspected shunt malfunctions. The goal of this study was to report the authors' institutional experience with RS and evaluate its utility and associated complications. METHODS: The authors retrospectively reviewed all RS studies performed between November 2003 and June 2022. Patients with shunted hydrocephalus who were ≥ 18 years of age were included. Patients undergoing RS for evaluation of Ommaya reservoirs were excluded. Demographics, hydrocephalus etiology, presenting symptoms, study results, subsequent management, complications, and intraoperative diagnoses were recorded. Chi-square tests were reported for categorical variables and standard 2 × 2 contingency methods were used for sensitivity/specificity analysis. RESULTS: The authors identified 211 RS procedures performed in 142 patients. The mean age at procedure was 55.6 ± 20.9 years (mean ± SD). Normal pressure hydrocephalus was the most common hydrocephalus etiology (37.0%), followed by congenital malformations (26.1%) and idiopathic intracranial hypertension (15.6%). Successful radionuclide injection was achieved in 207 studies (98.1%). Shunt patency was confirmed in 63.8% of successful injections, whereas malfunction was demonstrated in 27.1% and abnormally slow flow was seen in 9.2%. RS studies demonstrating shunt malfunction were more likely to result in subsequent revisions than were studies showing patency (86.6% vs 2.9%; p < 0.0001). The overall sensitivity and specificity of RS for detecting shunt malfunction was 92.3% and 96.2%, respectively. The median follow-up time was 29 months, with 151 cases having ≥ 6 months of follow-up. There were no complications or infections attributable to RS in this cohort. CONCLUSIONS: RS is a useful and safe tool in the workup of shunt malfunction.

Adolescent Idiopathic Scoliosis and Pregnancy.

Objective This study examined the interaction between adolescent idiopathic scoliosis (AIS) and pregnancy, focusing on pregnancy outcomes, changes in back pain, and anesthesia use. Methods A retrospective analysis was conducted on adult patients with AIS who gave birth at our institution between 2006 and 2022. Results A total of 163 AIS patients with 263 pregnancies were included. The median age at delivery was 33 (range 18 to 50) years. Among 157 patients with information on prior scoliosis treatment, 66.9% had not received treatment, 20.4% had undergone spinal fusion, and 12.7% had received bracing. Of the 260 pregnancies with available data, 90.4% were delivered at term and 8.5% were preterm. Of the 257 pregnancies with information on anesthesia type, 35.0% received epidural anesthesia, 17.9% received spinal anesthesia, 37.7% received combined spinal and epidural anesthesia, 8.2% received no anesthesia, and 1.2% received intravenous or general anesthesia. Difficulty administering neuraxial anesthesia was reported in 6.1% of cases, and these patients were less likely to receive combined spinal and epidural anesthesia (6.3% versus 39.8%, p = 0.0123). Among 116 cases with recorded back pain during pregnancy, 67.2% reported increased pain, 31.9% reported similar pain, and one patient reported decreased pain. Of the 16 patients with pre and postpartum radiographs, eight showed a Cobb angle increase ≥ 3°, with five patients having an increase ≥ 5°. Conclusions Pregnancy can exacerbate back pain and pose challenges for neuraxial anesthesia in some AIS patients. Further large-scale, multi-institutional studies with standardized data collection are needed to fully understand the impact of pregnancy on AIS.

Intratumoral spatial heterogeneity of BTK kinomic activity dictates distinct therapeutic response within a single glioblastoma tumor.

OBJECTIVE: Despite significant recent efforts applied toward the development of efficacious therapies for glioblastoma (GBM) through exploration of GBM's genome and transcriptome, curative therapeutic strategies remain highly elusive. As such, novel and effective therapeutics are urgently required. In this study, the authors sought to explore the kinomic landscape of GBM from a previously underutilized approach (i.e., spatial heterogeneity), followed by validation of Bruton's tyrosine kinase (BTK) targeting according to this stepwise kinomic-based novel approach. METHODS: Twelve GBM tumor samples were obtained and characterized histopathologically from 2 patients with GBM. PamStation peptide-array analysis of these tissues was performed to measure the kinomic activity of each sample. The Ivy GBM database was then utilized to determine the intratumoral spatial localization of BTK activity by investigating the expression of BTK-related transcription factors (TFs) within tumors. Genetic inhibition of BTK family members through lentiviral short hairpin RNA (shRNA) knockdown was performed to determine their function in the core-like and edge-like GBM neurosphere models. Finally, the small-molecule inhibitor of BTK, ONO/GS-4059, which is currently under clinical investigation in nonbrain cancers, was applied for pharmacological inhibition of regionally specified newly established GBM edge and core neurosphere models. RESULTS: Kinomic investigation identified two major subclusters of GBM tissues from both patients exhibiting distinct profiles of kinase activity. Comparatively, in these spatially defined subgroups, BTK was the centric kinase differentially expressed. According to the Ivy GBM database, BTK-related TFs were highly expressed in the tumor core, but not in edge counterparts. Short hairpin RNA-mediated gene silencing of BTK in previously established edge- and core-like GBM neurospheres demonstrated increased apoptotic activity with predominance of the sub-G1 phase of core-like neurospheres compared to edge-like neurospheres. Lastly, pharmacological inhibition of BTK by ONO/GS-4059 resulted in growth inhibition of regionally derived GBM core cells and, to a lesser extent, their edge counterparts. CONCLUSIONS: This study identifies significant heterogeneity in kinase activity both within and across distinct GBM tumors. The study findings indicate that BTK activity is elevated in the classically therapy-resistant GBM tumor core. Given these findings, targeting GBM's resistant core through BTK may potentially provide therapeutic benefit for patients with GBM.