United States

### Background
Total Knee Arthroplasty (TKA) is a beneficial procedure in orthopedics, but malpositioning of the femoral TKA component can cause dissatisfaction or failure. Most existing research focuses on coronal and rotational positioning, making positioning in the sagittal plane relatively unexplored. The objective of this systematic review is to determine whether variations in femoral component sagittal alignment (flexion or extension positioning) influence patient-reported outcomes, range of motion, anterior knee pain, component loosening, and prosthesis survival.

### Methods
This systematic review was performed according to the guidelines of the Preferred
Reporting Items for Systematic Review and Meta-Analyses (PRISMA) protocols (PROSPERO ID number: CRD420251044455). A comprehensive search of PubMed, Cochrane Library databases, and SPORTDiscus was performed between January 2015 and April 2025. Keywords included Total Knee Arthroplasty, Revision Total Knee Arthroplasty, Femoral Component, Sagittal Alignment, Femoral Flexion Angle, Extension Alignment, Posterior Condylar Offset, and Patient-Reported Outcome Measures. After screening 2137 initial results, 10 studies were deemed to meet inclusion and exclusion criteria, with 9 being prospective/retrospective cohort studies and 1 Randomized Control Trial (RCT). Study characteristics and outcomes were extracted, and quality assessment performed for using Cochrane Risk of Bias tool (RCTs) and Newcastle-Ottawa Scale (cohort studies).

### Results
A total of 5,205 TKAs were performed among the 10 studies, each with different sagittal alignment grouping thresholds and functional outcome scales. 5/10 studies identified the optimal sagittal alignment to be approximately 1-4° flexion for OKS, WOMAC, KSFS, or KSS functional scores, while 1 study found slightly improved AKSS with 1–5° extension. 2 studies did not identify optimum femoral angles for functional score outcomes. For ROM, 5/10 studies identified the optimum sagittal angle for ROM to be 1-7° flexion. Only 2 studies explored failure rate, with 1 study reporting the best failure rate (0%) in neutral alignment 0-3° and the other stating no cases of loosening at 1 year for any group. Anterior knee pain was only reported by 1 study with best outcomes at 1.4° flexion.

### Conclusion
Of the 10 studies, mild sagittal flexion (1-4°) appears to appropriately balance functional outcomes, ROM, survival, and pain. However, the heterogeneity of the included studies in terms of grouping measurement as well as functional outcomes precluded our ability to conduct a meta-analysis and generate exact quantitative outcomes as to the optimal sagittal alignment of the femoral component. More RCTs are needed to explore sagittal component positioning with consistent femoral flexion angle grouping criteria and clinical outcome measurements.

AMA Research Challenge 2025 

Mild flexion of the femoral component sagittal alignment in TKA may improve long-term clinical outcomes and component survival: A systematic review

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### Background
Acute appendicitis is the most common cause of emergency general surgery in the United States and affects 250,000 adults every year. Readmission after appendectomy is common and represents an opportunity to improve care. We aimed to identify factors associated with 90-day readmission in patients with acute appendicitis to inform patient risk stratification. 

### Methods
We conducted a retrospective chart review of the emergency general surgery registry for patients with acute appendicitis between March 1, 2023, and August 31, 2024, at three hospitals within our healthcare system: one academic (H1) and two community (H2 and H3). Our primary outcome was 90-day hospital readmission. We used descriptive statistics and multivariable logistic regression to assess factors related to readmission, performed a sensitivity analysis excluding early readmissions (<7 days), and stratified models by hospital to evaluate site-level variation. 

### Results
522 patients with acute appendicitis were included; the overall 90-day readmission rate was 13.0%. Readmitted patients were on average older (56 vs 45 years, p<0.001), had higher Charlson Comorbidity Index scores (CCI) (2.1 vs. 1.2, p<0.001), and more often presented with perforated appendicitis (51% vs. 24%, p<0.001). In multivariable regression, operative management was independently associated with reduced odds of readmission (aOR 0.26, 95% CI 0.12–0.53). CCI (aOR 1.25, 95% CI 0.97–1.59) and diabetes (aOR 1.89, 95% CI 0.91–3.93) increased risk but were not statistically significant. Age, perforation status, and discharge disposition were not significant predictors of 90-day readmission. In sensitivity analysis (n=461), CCI (aOR 1.32, 95% CI 1.01–1.72) and ASA score (aOR 2.23, 95% CI 1.03–4.87) were significant predictors, while operative management remained protective (aOR 0.12, 95% CI 0.06–0.25). Older age was associated reduced readmission (aOR 0.95, 95% CI 0.91–0.99), and diabetes was not significant. Hospital-stratified analysis showed operative management was consistently protective across sites (H1 aOR 0.23, 95% CI 0.09–0.64; H2 aOR 0.04, 95% CI 0.009–0.21; H3 aOR 0.05, 95% CI 0.002–1.21). 

### Conclusion
Operative management of acute appendicitis was independently protective against 90-day readmission. Higher CCI and ASA scores increased readmission risk, particularly in patients readmitted beyond 7 days post discharge. These findings highlight the importance of individualized risk stratification, particularly in older comorbid adults, and may inform discharge planning and follow-up strategies.

Factors Affecting 90-Day Readmission After Acute Appendicitis Within a Large Healthcare System

### Background
Hypertensive diseases of pregnancy (HDP) like preeclampsia lead to fetal growth restriction (FGR), where elevated thromboxane A2 (TXA2) levels trigger maternal hypertension, recurrent placental ischemia/reperfusion injury, and fibrosis leading to placental insufficiency and FGR. We recently demonstrated a mechanistic link between procoagulant platelets and neutrophils in the innate immune response to ischemia/reperfusion injury following ischemic stroke - neutrophil extracellular trap (NET) formation. To respond to infection or tissue damage, a subset of neutrophils form NETs. These NETs release lattices of decondensed chromatin decorated with antimicrobial factors into the extracellular space. In ischemic stroke, procoagulant platelets induce NET formation leading to pathogenic inflammation which extends infarct size and compromises neurologic recovery after stroke. In the preclinical stroke model, we showed that Cyclophilin-D (CypD) induces procoagulant platelet formation which induced NETs leading to pathogenic inflammation. However, whether procoagulant platelets and NETs mediate FGR in HDP-related placental insufficiency remains unknown. We hypothesized that platelet-specific Cyclophilin D knockout (CypDplt-/-) mice exhibit decreased FGR and placental NET formation compared to wild-type (WT) mice in a preclinical model of HDP.

### Methods
Pregnant CypDplt-/- and WT mice received a TXA2 analog (U46619; 4 μg/μL at 0.5 μL/hr continuous infusion) or vehicle control (0.5 μL/hr) via micro-osmotic pumps implanted on embryonic day (E) 12.5. At E19, we measured fetal/placental weights and collected pup plasma. We assessed placental NETs and neutrophil levels via Western blotting of placental homogenates for citrullinated histone H3 (citH3) and myeloperoxidase (MPO), respectively. We assessed pup plasma MPO-DNA complex levels as a surrogate for plasma NET levels using an in-house MPO-DNA ELISA.

### Results
Compared to TXA2-treated WT pups, TXA2-treated CypDplt-/- pups showed decreased body weight at E19 (p<0.05), decreased percentage FGR (18% versus 71%), reduced placental MPO (p<0.05), with a trend towards decreased placental citH3 (p=0.051) via western blotting, suggesting decreased placental neutrophils and NETs, respectively, and decreased plasma MPO-DNA complex levels, a surrogate for NET formation (p<0.05). Finally, using a novel NET-inhibitory peptide which we discovered, we demonstrated that NET inhibition in this pre-clinical model decreased FGR in response to TXA2 treatment, a finding correlated with decreased placental (p<0.05) and plasma NET levels (p<0.05), respectively.

### Conclusion
CypDplt-/- TXA2-treated pups show decreased FGR and decreased placental NETs in a preclinical HDP model suggesting that procoagulant platelets trigger platelet activation and NET formation in HDP. Further, NET inhibition may represent a novel therapeutic target to decrease fetal growth restriction in human HDP.





Procoagulant platelets and neutrophil extracellular traps restrict fetal growth in a murine model of hypertensive diseases of pregnancy

### Background
There is limited data on sleep-related breathing disorders (SRBDs) in pediatric patients with single ventricle congenital heart disease (SVCHD) who have undergone surgical correction, but available studies indicate it is
commonly present. The impact of SRBDs in these patients remains poorly understood. This study investigates the prevalence of SRBDs in patients who have undergone the Fontan procedure.

### Methods
We conducted a retrospective chart review of 62 pediatric patients with SVCHD who had undergone the Fontan procedure and had a polysomnographic study (PSG) before or after the Fontan procedure between 2000 and 2024. Data was abstracted from patients’ most recent PSGs and included demographic characteristics,
apnea-hypopnea indices (oAHI and CAI), end-tidal CO2 (ETCO2) and oxygen saturation metrics.

### Results
The cohort’s mean age at the time of their first PSG was 9.1 ± 5.1 years. The cohort’s mean age at the time of the Fontan procedure was 3.6 ± 0.8 years. 66% of the cohort were male (41/62). 37/62 patients (60%) had OSA. 14 subjects exclusively had PSGs performed only before Fontan; 42 subjects exclusively had PSGs only
after Fontan. 10% of patients (6/62) had PSGs both before and after Fontan. The pre-Fontan cohort had 4 mild OSA, 2 moderate OSA and 1 severe OSA. The post-Fontan cohort had 19 mild OSA, 6 moderate OSA and 4 severe OSA. There was improvement in AHI in 2/6 patients who had pre and post Fontan PSG. 6/62 patients
had CSA (CAI ≥ 5/hr.) and none met criteria for hypoventilation (ETCO2 >50 mmHg for >25% of total sleep time). 

The average oAHI pre-Fontan was 3.27 ± 5.1 and the average oAHI post-Fontan was 4.7 ± 8.4. The average oxygen saturation (SpO2) pre-Fontan was 83% and the average SpO2 post-Fontan was 92%. The average SpO2 nadir pre-Fontan was 73% and the average SpO2 nadir post-Fontan was 84%. SpO2 nadir of < 90% was seen in 19 patients prior to the Fontan procedure and in 38 patients after the Fontan procedure.

### Conclusion
There was a high prevalence of SRBDs in pediatric patients with SVCHD patients’ post-surgical correction. Most patients demonstrated mild OSA. Our data suggest that early screening for SRBDs in this population is essential.

Sleep-Related Breathing Disorders in Surgically Corrected Single Ventricle Congenital Heart Disease Patients

### Background
Prostate-specific membrane antigen positron emission tomography/computerized tomography (PSMA PET/CT) has demonstrated high sensitivity for prostate cancer (PCa) metastases, changing the manner in which PCa is managed. This study aims to report PSMA PET/CT data alongside multiparametric mRI workup and pathological reports from ultrasound/MRI biopsy (fBx) as a gold standard in patients cared for in the VCU Health System. 

### Methods
A retrospective analysis of 765 records of patients who received fBx from January 2022 through December 2024 was conducted. Inclusion criteria involved patients who underwent PSMA PET/CT in initial planning (newly diagnosed cases). Exclusion criteria involved patients who received prior prostate treatment, including surgery or radiation. Data recorded from chart review included age, PSA, Prostate Imaging Reporting & Data System (PI-RADS) scores, fBx Gleason Score (GS), and prostate volume. Additionally, the presence of metastasis and how this altered their treatment plan as evidenced by PSMA PET/CT was also distinguished. There were 177 patients with complete data available for analysis. Statistical analysis was performed with GraphPad.

### Results
PSMA PET/CT found 36 patients to be positive for metastatic disease, while 141 were negative. Of those that presented with evidence of metastasis, 27 patients changed their initial treatment plan based on their PSMA PET/CT (75%), compared to 69 patients that presented without metastatic lesions (48.9%). Meanwhile, 9 patients with metastatic involvement as evidenced by PSMA PET/CT did not change their initial treatment regimen (25%), while 72 patients without evidence of metastasis did not (51.1%) The average age of patients included in this study was 68.9 (± 8.61) years. Other descriptive statistics showed an average fBx GS of 7.84 (± 0.97), average PI-RADS of 4.75 (± 0.56), and average prostate volume of 44.65 mL (± 23.49). Lastly, average PSA at time of diagnosis for those with metastasis was 97.13 ng/mL (± 224.53) compared to 23.002 ng/mL (± 52.67) for those without metastasis (p < 0.0406).

### Conclusion
PSMA PET/CT is a valuable imaging modality that not only helps to visualize possible metastatic lesions within patients with prostate cancer, but also alters clinical management in a large proportion of patients in our hospital. Further studies and investigation into the broader utilization of PSMA PET/CT nationwide would prove beneficial.

Characterizing the impact of PSMA PET/CT in the detection and treatment of prostate cancer in the VCU Health System

### Background
Lyme arthritis (LA) is a late-stage manifestation of Lyme disease characterized by joint swelling and pain. LA’s clinical presentation mimics other pathologies such as septic arthritis (SA) and toxic synovitis (TS). Despite their similar presentations, the necessary treatments vary. LA is treated medically, septic arthritis surgically, and TS resolves with conservative therapy. The similar clinical presentations of these pathologies can lead to misdiagnosis, subjecting patients to unnecessary interventions, and prolonged hospitalizations. 
The state of West Virginia has suffered an exponential increase in Lyme disease (LD) over the last decade. The CDC defines high-incidence states as those having an annual incidence of ≥10 confirmed LD cases per 100,000 for three reporting years. Over the span of this study, West Virginia averaged 40.3 cases per 100,000. 
The purpose of this study was to conduct a retrospective review of pediatric patients that presented to our health system with concern for joint infection/inflammation to identify physical examination and laboratory findings that may differentiate between LA, SA, and TS.

### Methods
Pediatric patients were selected for the study based on ICD-9/10 codes suggestive of an infectious/inflammatory/Lyme-related process. The initial group was filtered down to patients who had undergone testing for an infectious process. This group was then manually reviewed, and each patient was assigned to a diagnostic category. Relevant patient information was extracted from their charts. Continuous data were summarized with simple numerical summaries and categorical data as counts and proportions.

### Results
506 patients were analyzed in this study. Subgroup analysis focused on LA, SA, and TS. Patients with LA had the highest proportion of joint swelling, followed by SA. Pain with short arc motion was most prevalent in the SA group and they were least likely to bear weight. LA favored the knee, TS the hip and SA the knee and hip however other joints were also involved. SA presented with the highest CRP, ESR, WBC, %neutrophils, and cell count values. TS had the lowest elevation in CRP, ESR, %neutrophils, and cell count. TS had the highest %lymphocyte and LA the highest platelet count.

### Conclusion
As Lyme disease continues to spread, clinicians will increasingly encounter patients with LA. Clinicians must differentiate between LA and similar pathologies to ensure appropriate treatment and avoid unnecessary interventions. Key differentiating variables, such as anatomic location, CRP, and ESR, can aid in diagnosis, though there are limitations. Clinicians can use this
information to guide treatment decisions for these patients.


Differentiating the Clinical & Laboratory Presentations of Lyme Arthritis, Septic Arthritis, & Toxic Synovitis

South Korea’s healthcare system is internationally recognized for its accessibility and efficiency; however, beneath this success lies an emergency care crisis marked by widespread hospital refusals of critical patients—a phenomenon known as “ER ping-pong.” Patients, particularly in rural regions, are often transferred between multiple facilities before receiving care, with fatal consequences. Recognizing the absence of national data and clear policy guidance, this study sought to quantify provincial emergency admission refusal rates and evaluate structural reforms to improve equitable access to emergency care.

A PRISMA-guided systematic review was conducted using Covidence to assess 46 peer-reviewed studies on emergency access policies across OECD nations. This was combined with quantitative analysis of South Korea’s 2023–2024 national emergency transfer data, made available through the Ministry of Health and Welfare (MOHW) and the Korean Society of Emergency Medicine (KSEM). Provincial refusal rates were estimated and compared with policy frameworks from the United States (Emergency Medical Treatment and Labor Act, EMTALA) and Germany (Sozialgesetzbuch V and Leitstelle dispatch systems).

Findings reveal that refusal rates range from 30% in Seoul to nearly 98% in North Gyeongsang, with rural provinces experiencing rates more than double those of urban centers. Most refusals cited limited ICU capacity or specialist coverage as primary causes. Comparative analysis demonstrated that regions with integrated referral databases, legal stabilization mandates, and regionalized workforce incentives experience significantly lower refusal rates.

This research proposes a multi-tiered reform model for South Korea, including a Standardized Emergency Referral and Triage Protocol (SERTP), expansion of tele-emergency consultation hubs, and a national integrated emergency operations platform, to reduce refusals by an estimated 60% within a decade. These policy addendums provide an actionable blueprint for improving emergency equity and sustainability within South Korea’s universal health system.

Policy Addendums to Resolve South Korea’s Emergency Room Admission Crisis

### Background
As the first applied motor task to develop, assessment of head and trunk control in infants may provide valuable insight into potential developmental delays. While electromyography (EMG) is the gold standard for assessing neuromuscular function, its use in infants is limited due to their size, difficulty establishing normative values, and lack of standard protocols. Existing research in infants largely focuses on discrete tasks in advanced postures, with few studying spontaneous movements or proximal muscle activity. This study aimed to assess the feasibility of using surface EMG during prone play and to identify potential movement biomarkers associated with delayed postural control in young infants. 

### Methods
This pilot study involved five infants aged 3-6 months (mean age = 4.61 months). Subjects played in the prone position while wearing wireless surface EMG sensors (Delsys) based on SENIAM guidelines. Bilateral recordings were taken from muscles involved in proximal control: upper trapezius, lower trapezius, and triceps. Functional motor performance was assessed using the Alberta Infant Motor Scale (AIMS) percentiles. Raw EMG signals were processed in MATLAB®. The metrics analyzed were mean RMS amplitudes (mV), bilateral symmetry index ratios (> or < 1 indicating asymmetry), and onset of activation (s). Association between EMG metrics and AIMS percentile was analyzed using Spearman correlations.

### Results
EMG data was successfully collected for all five infants. There was no significant correlation between AIMS percentile and EMG metrics collected, but interesting trends were observed. Infants in lower percentiles showed greater upper (r= -0.7) and lower trapezius (r= -0.7) activation and overall unbalanced recruitment between muscle groups compared to infants in higher percentiles. Average muscle onset times across all subjects were: lower trapezius (1.3s), upper trapezius (1.6s), and triceps (3.9s). Symmetry indices varied across participants, with the lower trapezius showing the most consistent symmetry (0.88), compared to upper trapezius (1.22) and triceps (1.56). Lower AIMS percentiles were generally associated with greater asymmetry.

### Conclusion
Surface EMG is feasible during prone play. We identified movement biomarkers that may offer early insight into atypical postural control strategies in at-risk infants. Infants with lower motor performance demonstrated more proximal motor unit recruitment, indicating less stability. These infants may be more likely to have asymmetrical recruitment than higher performing infants. Larger sampled studies are needed to further develop the baseline of expected muscle activation patterns. Increased knowledge in this understudied area could aid in identifying potential developmental delays at an earlier age.

Assessment of Proximal Postural Control Biomarkers During Spontaneous Play in Infants Using Surface EMG

### Background
Neurologic illnesses often involve high symptom burden, complex prognostication, and emotionally charged decision-making, making palliative care (PC) skills essential for neurologists. Despite national recommendations, formal training in neuropalliative care remains limited in neurology residencies and fellowships. A prior needs assessment revealed that only 4.5% of U.S. neurocritical care (NCC) fellowship programs had faculty with formal PC training, and many fellows felt underprepared in communication, prognostication, and discussions surrounding life-sustaining treatments. The objective of this study was to develop a novel, scalable palliative care curriculum for neurocritical care fellows that is being expanded across neurology residency and subspecialty fellowship training programs. We aimed to assess feasibility, learner engagement, and changes in self-reported preparedness in serious illness communication using pre/post surveys, performance-based simulation assessments, and qualitative interviews.

### Methods
We piloted a novel, interdisciplinary neuropalliative care curriculum for NCC fellows over three academic years (2022–2025), combining asynchronous didactics from the Education in Palliative and End-of-Life Care for Neurology (EPEC-N) curriculum with in-person, simulation-based training using VitalTalk techniques. Simulation scenarios were collaboratively developed and vetted by neurocritical care and palliative care faculty to reflect realistic, frequently encountered clinical experiences. Building on the success of this pilot, we are expanding the curriculum to neurology residency and fellowship training across subspecialties. Using Kern’s Six-Step Curriculum Development framework and situated learning theory, we created subspecialty-specific simulation scenarios (e.g., stroke, epilepsy, movement disorders), integrated into an academic neurology curriculum. A prospective, mixed-methods study was used to evaluate the program’s feasibility, effectiveness, and impact.

### Results
Preliminary results from the pilot program demonstrate high learner engagement and improved self-reported preparedness in serious illness communication. Fellows reported increased confidence in delivering bad news, discussing prognosis and code status, and managing emotional conversations with families. Program directors identified key competencies, including prognostication (95%), delivering bad news (85%), and discussions on withdrawal of care (80%), as educational priorities. Evaluation tools included pre/post surveys, simulation performance assessments, and qualitative interviews. Data collection and analysis are ongoing.

### Conclusion
This curriculum represents a novel approach to neuropalliative care education by integrating simulation-based training into neurology and subspecialty education for interdisciplinary teams. Grounded in evidence-based communication frameworks and tailored to subspecialty practice, the program addresses a critical training gap in neurology education. Preliminary outcomes support its feasibility and impact on learner confidence and skill development. Future directions include national expansion and integration across neurology subspecialties to establish a sustainable, standardized model for neuropalliative care education.


Development, Implementation and Evaluation of a Novel Neuropalliative Care Education Curriculum

### Background
The majority of people living with HIV globally are women and girls. Although combined antiretroviral therapy (cART) can drastically improve prognosis and prevent vertical transmission, its off-target metabolic and systemic effects in pregnant women and women of childbearing age remain understudied. Concurrent exposure to ubiquitous environmental pollutants, such as per and polyfluoroalkyl substances (PFAS), may interact with cART to impact maternal health, given their shared potential for mitochondrial and cardiotoxicity. Our broader project investigates the combined structural, functional, and molecular impact of cART and a legacy PFAS compound, perfluorooctanesulfonic acid (PFOS), on cardiometabolic outcomes in a rat model. Here, we present findings from non-pregnant animals, which will later be compared to pregnant counterparts.

### Methods
Female Sprague-Dawley rats were treated with cART (abacavir/dolutegravir/lamivudine; Triumeq at 300/25/150 mg/kg/day) or vehicle (aqueous methylcellulose/Tween 80). Animals also received either PFOS-contaminated water, directly mimicking concentrations measured in a North Carolina community, or vehicle (reverse osmosis-filtered water). They received echocardiography and electrocardiography immediately prior to tissue harvest at study day (SD) 27 or SD 49. Tissue and plasma samples underwent PFAS quantification, pathological evaluation, qPCR, and mitochondrial function analysis.

### Results
The non-pregnant cohort demonstrated perturbations in several structural and functional parameters by exposure group. Echocardiography revealed shortened ejection times at SD 26 in the cART group compared to controls, indicating early systolic dysfunction. Rats in the PFOS + cART group showed slower isovolumetric relaxation times and increased ejection fractions at SD 26. Structural changes included increased interventricular septal thickness, posterior wall thickness, and left ventricular (LV) mass in the cART group. At SD 48, persistent hypertrophy was demonstrated by increased LV mass and heart weight:tibia length ratios for the cART-exposed rats. Surprisingly, cART alone did not impact mitochondrial copy number. However, both the PFOS and PFOS + cART groups showed reduced mitochondrial copy numbers and increased deletions, indicating alterations to the mitochondrial genome.

### Conclusion
These findings suggest that cART exposure, particularly in combination with PFOS, alters cardiac structure and function, with early systolic impairment followed by compensatory adaptations. Despite partial recovery over time, persistent hypertrophy suggests cardiac remodeling. Ongoing analysis of pregnant animals will determine whether the added physiologic strain of pregnancy sensitizes the cardiovascular system of the animals. This work highlights a need to evaluate the cardiovascular safety of cART in the context of common environmental exposures, particularly in women of reproductive age.

Cardiac Phenotype and Mitochondrial Effects of Antiretroviral Therapy and PFAS Exposures

### Background
Glioblastoma (GBM) is a highly aggressive malignancy with limited therapeutic advancements despite extensive research. Receptor tyrosine kinase (RTK) amplification, a common feature in glioblastoma (GBM), drives tumor growth/recurrence, therapeutic resistance, and invasion, making RTKs attractive therapeutic targets. Currently, Bevacizumab, the only FDA-approved RTK inhibitor in GBM, improves progression-free survival in patients through vascular normalization. This study evaluates the efficacy of cabozantinib (XL184), a multi-kinase inhibitor targeting various RTKs such as VEGFR2, MET, and AXL, in GBM cancer stem cells (CSCs) and patient-derived xenograft (PDX) models, with a focus on uncovering resistance mechanisms and identifying opportunities for combination therapies. 

### Methods
Nine genomically diverse GBM CSCs were treated with XL184 to assess drug sensitivity. Reverse Phase Protein Array (RPPA) Proteomics at 24h and 72h was used to evaluate changes in key signaling pathways along with a focused analysis of RTK signaling changes. CSC-derived PDX from two proneural (HF2587, HF3016) and one classical (HF2927) GBM were treated with XL184 monotherapy and in combination with TMZ. Tumor growth and survival were monitored. Immunohistochemical (IHC) analysis of CD31 expression to assess angiogenesis was performed with high-resolution microscopy. 

### Results
GBM CSCs exhibited a wide range of sensitivity to XL184 (IC50: 2μM - 34μM). Proteomics showed XL184-mediated inhibition of phospho-VEGFR2, AKT, and ERK, while sub-lethal XL184 doses upregulated phospho-MET and STAT3, suggesting adaptive resistance mechanisms. In vivo, HF2587 (p=0.00022, n>18) and HF2927 (p=0.1847, n>12) xenografts responded to XL184 monotherapy, and in combination with TMZ, with reduced tumor growth and improved survival while HF3016 (p=0.061, n>16) was resistant to monotherapy. HF2587 and HF2927 demonstrated a reduction in vessel density, measured by CD31 expression, compared to normal brain. The non-responsive HF3016 exhibited increased angiogenesis following therapy, a potential indicator of treatment resistance. 

### Conclusion
Insights into CSC signaling and tumor-specific dependencies provide a foundation for biomarker-driven, personalized therapeutic approaches in GBM. The vasculature results, assessed through CD31 immunohistochemistry, demonstrate the modulation of angiogenesis and tumor blood supply by XL184, which is crucial for understanding its therapeutic effects on GBM and the tumor microenvironment. These findings highlight the heterogeneity of XL184 response in GBM and the potential for combination strategies to overcome resistance. Moreover, this work builds on limitations of existing RTK therapies (bevacizumab), offering multi-targeted inhibition with microenvironmental modulation. Additionally, it contributes valuable preclinical evidence supporting a rational framework for designing more targeted, effective interventions in a highly treatment-refractory cancer.

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