Citations

Background Endovascular thrombectomy (EVT) has transformed acute ischemic stroke (AIS) care, with onset-to-puncture (OTP) time widely recognized as a critical determinant of outcome. However, emerging evidence suggests that in-hospital procedure time (PT)—from arterial puncture to final recanalization—may have an equally or more significant impact. This study examines the relative contribution of PT versus OTP to functional outcomes in patients with AIS undergoing EVT. Methods A retrospective analysis was conducted of 6644 patients with AIS treated at 44 international stroke centers from the Stroke Thrombectomy and Aneurysm Registry (STAR; 2016–2023). Multivariable regression, time-equivalence analysis, and marginal effects modeling were used to assess associations between PT, OTP, and 90-day modified Rankin Scale (mRS) outcomes. Centers were stratified by procedural efficiency and compared using propensity score matching (PSM). Mediation analysis evaluated whether PT accounted for inter-center differences. Results PT and OTP were independently associated with functional outcomes; however, PT had a significantly stronger effect (adjusted OR for mRS 0–2: PT=0.56 vs OTP=0.96 per hour). Each 5 min increase in PT was equivalent to 78–100 min of additional OTP in outcome impact. Centers with faster average PT had higher rates of functional independence (number needed to treat (NNT)=10), fewer complications, and lower symptomatic intracranial hemorrhage rates. PT significantly mediated the relationship between center tier and outcomes (Sobel’s P<0.001). Conclusion While minimizing OTP remains important, PT exerts a greater influence on outcomes after EVT. Procedural efficiency should be emphasized in stroke systems of care and included in center performance metrics to improve patient outcomes.

Abstract PARP inhibitors (PARPis) are now a standard of care for high-grade serous ovarian cancer (HGSOC), but resistance to these drugs poses a significant concern, necessitating the exploration of novel treatment strategies. Here we investigated the mechanism underlying enhanced PARPi activity in HGSOC cells following treatment with brigatinib—a second-generation anaplastic lymphoma kinase (ALK) inhibitor approved for treating lung cancer. Our previous work has shown that brigatinib is a dual inhibitor of tyrosine kinases FAK and EPHA2 with subsequent additive reduction in downstream PI3K/AKT and MAPK/ERK cell survival signaling. Suppression of these pathways conferred PARPi sensitivity to HGSOC cell lines and patient-derived xenograft (PDX) models, particularly in those with high FAK and EPHA2. To dissect the mechanism linking the FAK/EPHA2 – AKT/ERK pathway to PARPi synergy, we focused on proteomics approaches which revealed that FRA1—an Activator Protein 1 (AP-1) transcription factor known to be downstream of AKT/ERK—and its targets were decreased by brigatinib treatment. In subsequent phosphoproteomics approaches and cell-based confirmatory studies, a phosphorylation crucial for FRA1 stability was found to be disrupted, leading to reduction in total FRA1 protein levels and synergy with PARPis. To explore how FRA1 mediates response to PARPis, immunoblotting analysis revealed that PARPis increased the abundance of FRA1 in HGSOC cells at early timepoints, indicating potential involvement in an adaptive survival response. Follow-up pharmacologic and gene silencing techniques demonstrated that brigatinib still reduces FRA1 in PARPi-treated cells, and FRA1 depletion induces apoptosis when combined with PARPi to levels comparable to brigatinib treatment. Overall, our studies unveil a beneficial ALK-independent effect of brigatinib that may offer new avenues for considering its repurposing as a HGSOC therapy through disruption of a PARPi-induced adaptive survival mechanism. Citation Format: Julie R. Duffield, Xiaonan Hou, Benjamin W. Wilson, Anjali Prasad, Iman K. McKeon-Makki, Amelia M. Huehls, Xinyan Wu, Cristina Correia, Melissa C. Larson, Fergus J. Couch, Ann L. Oberg, Scott H. Kaufmann, Larry M. Karnitz, Arun Kanakkanthara. A PARP-inhibitor-induced early adaptive survival response is tackled through depletion of FRA1 by brigatinib in high-grade serous ovarian carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A024.

Objectives To develop an internationally validated, structured robot‐assisted radical nephroureterectomy (RARNU) training programme through expert consensus. Materials and Methods A RARNU‐specific questionnaire was developed/adapted from previously published, validated questionnaires for robot‐assisted urological procedures. This included five key domains and 11 surgical steps. In all, 30 upper tract urothelial carcinoma experts were invited to participate. A two‐stage modified Delphi approach was employed. Consensus was defined as ≥80% agreement. Modifications and additional statements were proposed during the second round following qualitative/quantitative feedback from the initial round. Results Response rates for the first and second Delphi rounds were 80% (24/30) and 92% (22/24), respectively. All agreed that adoption of a standardised training curriculum can improve clinical outcomes during the RARNU learning curve. There was ≥92% agreement on all proposed RARNU steps. Five RARNU clinical modules of increasing complexity were defined using individual step difficulty and number of prior RARNU cases required, with ≥96% agreement among respondents. Respondents unanimously agreed that the final assessment should be based on a procedure‐specific scale focusing on the hilar dissection, ureteric dissection, and bladder cuff excision steps. No consensus was reached for the annual minimum RARNU volume required for eligibility as a RARNU curriculum host centre. Conclusion This is the first structured training curriculum for RARNU using international expert consensus. This will help guide surgical educators and trainees toward independent completion of a full RARNU.

Background: Patients with acute ischemic stroke secondary to distal and medium vessel occlusion (AIS-DMVO) and minor strokes present a challenge in determining the most appropriate emergent treatment. Factors leading to early neurological deterioration (END) in this patient population are understudied, but END is known to result in poor functional outcomes. Therefore, we aimed to investigate the factors contributing to END in minor AIS-DMVO cases. Methods: We included patients with AIS-DMVO and minor strokes from 37 sites across North America, Asia, and Europe. Minor stroke was defined as a baseline National Institutes of Health Stroke Scale (NIHSS) score of ⩽5. The primary outcome measure, END, was defined as a shift of ⩾4 points in the NIHSS score at day one after treatment compared to baseline. Univariable and multivariable logistic regression analyses were performed to identify factors associated with END. Results: Among 559 consecutive patients with DMVO and minor strokes, END was reported in 68 patients. In multivariable analysis, mechanical thrombectomy (MT) was independently associated with higher odds of END (adjusted odds ratio [aOR] 2.37, 95% CI 1.12–5.02, p = 0.02), while intravenous thrombolysis (IVT) was associated with lower odds of END (aOR 0.46, 95% CI 0.26–0.81, p = 0.008). However, the association between MT and END was no longer statistically significant in the IPTW-adjusted analysis (OR 1.65, 95% CI 0.69–3.98, p = 0.26). Hypertension and antiplatelet use at baseline were also independently associated with END. Among MT-treated patients, successful and excellent recanalization and first-pass effect were protective against END. Conclusion: MT was associated with END in patients with minor AIS-DMVO, although this association was not significant after IPTW adjustment. IVT was independently associated with reduced risk of END. These findings support careful patient selection and further study in randomized trials.

Bone health is a key determinant of success in spine surgery, making preoperative assessment of bone quality essential to optimal surgical risk stratification. Magnetic resonance imaging (MRI)-based vertebral bone quality (VBQ) score offers a novel approach to assess bone health in spine surgery candidates. The ability of MRI to assess bone quality without exposure to ionizing radiation makes it a potentially advantageous alternative to other traditional measures of bone density. VBQ has additionally shown potential to predict adverse outcomes, such as fragility fractures, instrumentation failure, subsidence and proximal junctional kyphosis. Variations of VBQ, such as endplate bone quality, S1 VBQ, and cervical VBQ, provide targeted insights at specific anatomical regions and potentially enhance the predictive accuracy of VBQ. However, clinical application of VBQ is limited by variability in MRI systems, patient-specific factors, and lack of standardized threshold values. This review aims to critically evaluate VBQ scores as an opportunistic, MRI-based assessment of bone health and its potential role in predicting surgical outcomes. While VBQ may provide some valuable insights into bone health, its role in preoperative risk assessment likely remains supplementary and requires further research to establish clinical validity and optimal cutoffs.

Background: Gluteus medius tears and atrophy cause lateral hip pain, limp, and functional impairment. We developed the “broken wing sign,” a novel physical examination test for detecting gluteus medius tendon tears and muscle degeneration. This study evaluated its diagnostic accuracy and clinical utility against magnetic resonance imaging (MRI) and intraoperative findings. Methods: We prospectively examined 59 patients (75 hips; mean age, 69.5 ± 10.8 years; 48 women) with suspected hip abductor insufficiency. The broken wing sign was tested with patients prone, the knee flexed at 90°, and the hip actively extended. A positive sign involved ≥10° of compensatory external hip rotation, visible as an inward drift of the foot, indicating gluteus medius (and resulting internal rotation) weakness. MRI served as the reference standard for classifying gluteus medius integrity as no tear, partial, full-thickness, or massive. Fatty infiltration was graded (Goutallier grades 0 to 4), quantified, and analyzed for a correlation with the examination findings. Diagnostic accuracy metrics were calculated. Results: The broken wing sign demonstrated high accuracy (sensitivity, 81.8%; specificity, 80.0%; positive predictive value [PPV], 91.8%; negative predictive value, 61.5%; diagnostic odds ratio, 17.8). An external rotation threshold of ≥30° yielded 100% specificity and 100% PPV for a tear. The sign detected acute tears with no or minimal fatty infiltration (100% sensitivity for massive tears). The degree of the external rotation angle was strongly correlated with muscle atrophy with fatty infiltration, showing 88.0% sensitivity for Goutallier grade ≥3 and 100% sensitivity for grade 4. Conclusions: The broken wing sign is clinically useful for diagnosing gluteus medius tendon tears and muscle atrophy, particularly massive tears and advanced fatty degeneration. It effectively guides MRI utilization and surgical planning, serving as a valuable initial diagnostic tool in the clinical setting. Level of Evidence: Diagnostic Level II . See Instructions for Authors for a complete description of levels of evidence.

OBJECTIVE Proximal junctional kyphosis (PJK) affects 5%–61% of patients following thoracolumbar fusion. Many patients are asymptomatic, but a plurality require surgical revision at a cost of $75,000 per case. This analysis sought to analyze the degree to which bone quality and paraspinal muscle sarcopenia influence PJK failure mode. METHODS Patients undergoing thoracolumbar instrumented fusion with an upper instrumented vertebra (UIV) at the thoracolumbar junction (T10–L2) were identified and data were gathered on surgery, bone quality, pre- and postoperative sagittal alignment, and paraspinal muscle cross-sectional area (CSA). PJK was defined as a ≥ 10° increase in proximal junctional angle from the first postoperative radiograph. PJK was classified as discoligamentous failure (type 1), bone failure (type 2), or screw-bone interface failure (type 3) according to the Yagi-Boachie system. Bone quality was assessed by Hounsfield units (HUs) and the vertebral bone quality (VBQ) score at the UIV. RESULTS One hundred fifty patients were identified (median age 67 years, 53.3% female), 46 of whom experienced PJK (22 type 1, 13 type 2, 11 type 3). The median time to onset was most rapid for type 2 events (2.6 months). There were no differences between patients experiencing PJK versus controls regarding bone quality (HUs or VBQ score) or paraspinal muscle CSA on univariate comparison. However, subdivision by PJK type showed patients experiencing bone failure (type 2) PJK had significantly lower HUs at the UIV and UIV+1 relative to those experiencing type 1 PJK or no PJK (all p < 0.05). The VBQ score trended toward being significant, with a higher VBQ score (worse bone quality) in those suffering type 2 PJK, but did not reach statistical significance (p = 0.07). Patients experiencing discoligamentous failure PJK (type 1) had small multifidus CSA (390 mm 2 ) relative to patients experiencing type 2 (516 mm 2 ) or type 3 (440 mm 2 ) PJK and patients who did not experience PJK (481 mm 2 ), although the difference did not reach statistical significance. On time-to-event analysis, low HUs of the UIV/UIV+1 predicted type 2 (hazard ratio [HR] 0.81, 95% CI 0.70–0.93; p = 0.002) and type 2/3 PJK (HR 0.87, 95% CI 0.78–0.96; p = 0.006) but not type 1 PJK. Low UIV multifidus CSA trended toward being a significant predictor of type 1 PJK (HR 0.85, 95% CI 0.69–1.05; p < 0.10). CONCLUSIONS The combination of underlying bone quality and paraspinal musculature CSA at the UIV appeared to influence failure mode among patients who underwent lumbosacral instrumented fusion terminating at the thoracolumbar junction.

OBJECTIVE The present investigation aimed to 1) develop a new CT-based assessment of endplate bone density (endplate Hounsfield unit [EP-HU]) and 2) analyze if EP-HU was a better predictor than vertebral Hounsfield unit (HU) for subsidence after anterior cervical discectomy and fusion (ACDF). METHODS All adult patients who underwent one- to three-level ACDF with a titanium interbody for radiculopathy and/or myelopathy at an academic center between 2018 and 2020 were retrospectively identified. Based on preoperative sagittal CT scans (left, right, and middle cuts), 2-mm superior and inferior endplate regions were circumscribed with the free draw tool to account for endplate surface undulations. The average of the superior and inferior EP-HUs on all CT cuts was used to calculate EP-HU. Cervical vertebral HUs were determined from the average of axial CT cranial, middle, and caudal cuts circumscribing only trabecular bone. The interbody subsidence of the cranial and caudal endplates of each ACDF level was directly measured on the endplate-facing surface of both coronal and sagittal cuts of postoperative CT scans (at 1 year) to determine the maximum subsidence (subsidence defined as ≥ 2 mm). Univariate and stepwise logistic regression analyses were used to compare subsidence based on CT bone metrics. Receiver operating characteristic (ROC) curve analyses were used to determine the probability of subsidence based on EP-HUs and vertebral HUs. RESULTS A total of 35 patients were included. Subsidence occurred at 32 of 67 unique fusion levels. Subsidence was associated with older age (p = 0.008), diabetes diagnosis (p = 0.015), and decreased interbody length (p = 0.019). EP-HUs exhibited moderate correlation with cervical vertebral HUs (Pearson’s ρ = 0.63). Subsidence was significantly associated with decreased total EP-HUs (subsidence: 475 HU, no subsidence: 543 HU; p = 0.019) and decreased lumbar vertebral HUs (subsidence: 296 HU, no subsidence: 341 HU; p = 0.011). ROC curve analysis identified an optimal EP-HU cutoff of 512.30 (area under the curve [AUC] = 0.701) to predict subsidence. The AUC of the vertebral HUs with respect to subsidence was 0.662. EP-HUs < 512.30 predicted subsidence (OR 6.67, p = 0.001) independent of significant demographic and surgical factors. CONCLUSIONS CT cervical EP-HUs rather than vertebral cervical trabecular HUs may be more efficacious in predicting subsidence after ACDF.

Abstract Introduction There is convincing evidence that overall adiposity increases the risks of several cancers. Whether the distribution of adiposity plays a similar role is unclear. Methods We used 2-sample Mendelian randomization (MR) to examine causal relationships of 5 adiposity distribution traits (abdominal subcutaneous adipose tissue (ASAT); visceral adipose tissue (VAT); gluteofemoral adipose tissue (GFAT); liver fat; and pancreas fat) with the risks of 12 obesity-related cancers (endometrial, ovarian, breast, colorectal, pancreas, multiple myeloma, liver, kidney (renal cell), thyroid, gallbladder, esophageal adenocarcinoma, and meningioma). Results Sample size across all genome-wide association studies (GWAS) ranged from 8407 to 728 896 (median: 57 249). We found evidence that higher genetically predicted ASAT increased the risks of endometrial cancer, liver cancer, and esophageal adenocarcinoma (odds ratios (OR) and 95% confidence intervals (CI) per standard deviation (SD) higher ASAT = 1.79 (1.18 to 2.71), 3.83 (1.39 to 10.53), and 2.34 (1.15 to 4.78), respectively). Conversely, we found evidence that higher genetically predicted GFAT decreased the risks of breast cancer and meningioma (ORs and 95% CIs per SD higher genetically predicted GFAT = 0.77 (0.62 to 0.97) and 0.53 (0.32 to 0.90), respectively). We also found evidence for an effect of higher genetically predicted VAT and liver fat on increased liver cancer risk (ORs and 95% CIs per SD higher genetically predicted adiposity trait = 4.29 (1.41 to 13.07) and 4.09 (2.29 to 7.28), respectively). Discussion Our analyses provide novel insights into the relationship between adiposity distribution and cancer risk. These insights highlight the potential importance of adipose tissue distribution alongside maintaining a healthy weight for cancer prevention.