Citations

Abstract The standard of care for hip labral tears is arthroscopic repair, with labral reconstruction performed more commonly for irreparable tears in order to avoid isolated labral debridement. However, labral reconstruction can be technically demanding. We provide a concise step‐by‐step guide for performing labral reconstruction or augmentation using a modified retrograde pull‐through technique, including tips, tricks, and surgeon pearls, and pitfalls. Despite the procedure's technically challenging nature, we believe our technique highlights several important steps to improve the practicality and efficiency of the case and produce satisfactory patient outcomes. Technique Video video See video under supplementary data.

AbstractHeightened muscle sympathetic nerve activity (MSNA) contributes to impaired vasodilatory capacity and vascular dysfunction associated with aging and cardiovascular disease. The contribution of elevated MSNA to the vasodilatory response during passive leg movement (PLM) is not fully understood. This study tested the hypothesis that elevated MSNA diminishes the vasodilatory response to PLM in healthy young males (n = 11, 25 ± 2 yr). Post exercise circulatory occlusion (PECO) following 2 min of isometric handgrip (HG) exercise performed at 25% (ExPECO 25%) and 40% (ExPECO 40%) maximum voluntary contraction was used to incrementally engage the metaboreceptors and augment MSNA. Control trials were performed without PECO (ExCON 25% and ExCON 40%) to account for changes due to HG exercise. PLM was performed 2 min after exercise and hemodynamics were assessed. MSNA was recorded by microneurography in the peroneal nerve (n = 8). Measures of MSNA (i.e., burst incidences) increased during ExPECO 25% (+15 ± 5 burst/100 bpm) and ExPECO 40% (+22 ± 4 burst/100 bpm) and returned to pre‐HG levels during ExCON trials. Leg vascular conductance (vasodilation) during PLM was reduced by 16% and 44% during ExPECO 25% and ExPECO 40%, respectively. These findings indicate elevated MSNA attenuates the vasodilatory response to PLM and the magnitude of reduction in vasodilation during PLM is graded with the degree of sympathoexcitation.

Background: Medial patellofemoral ligament reconstruction is frequently indicated for recurrent lateral patellar instability. The preoperative presence and severity of a J-sign have been associated with poorer postoperative outcomes. Purpose: To determine the underlying anatomic factors that contribute to the presence, severity, and jumping quality of the J-sign. Study Design: Cross-sectional study; Level of evidence, 3. Methods: All patients undergoing evaluation for patellar instability at a single institution between 2013 and 2023 and healthy controls without patellar instability were included. Patients with a history of knee osteotomies were excluded. The presence of a jumping J-sign and its relationship to patellofemoral measures including the Caton-Deschamps Index (CDI), trochlear dysplasia (Dejour grade), tibial tubercle–trochlear groove (TT-TG) distance, tibial tubercle lateralization, trochlear bump height, mechanical alignment, femoral anteversion, tibial torsion, trochlear medialization, patellar width, axial patellar/trochlear overlap, patellar height, trochlear height, and knee rotation angle (KRA) were measured using standardized 1.5-T magnetic resonance imaging (MRI). Univariate pairwise and multivariable analyses were performed to determine the factors associated with J-sign presence, severity, and quality. Results: Of the 130 knees with patellar instability, 89 (68.5%) demonstrated a J-sign on physical examination. In total, 44 (33.8%) patients demonstrated a 1-quadrant J-sign, 32 (24.6%) demonstrated a 2-quadrant smooth J-sign, and 13 (10.0%) demonstrated a jumping J-sign. A total of 22 control, noninstability cases were included. On multivariable analysis, increasing TT-TG distance (OR, 1.1 increase per millimeter; P = .04), external KRA (OR, 1.1 increase per degree; P = .02), and increasing CDI (OR, 1.3 increase per 0.1 increase in CDI; P = .02) were associated with J-sign presence. Increasing bump height (OR, 1.72 increase per millimeter; P = .007) and decreasing patellar width (OR, 0.89 decrease per millimeter; P = .076) were associated with a larger J-sign, when present. Increasing bump height (OR, 1.80 increase per millimeter; P = .018), increasing patellar width (OR, 1.33 increase per millimeter; P = .047), and decreasing CDI (OR, 0.009 decrease per 0.01 increase in ratio; P = .008) were associated with a jumping J-sign in comparison with a smooth 2-quadrant J-sign. A KRA of 10° (AUC, 0.70) and a cartilaginous bump height of 6.6 mm (AUC, 0.73) were thresholds associated with jumping J-sign presence. Conclusion: The presence of a J-sign is associated with MRI findings of relatively greater external tibiofemoral rotation, increased TT-TG distance, and increased patellar height, while J-sign severity and jumping quality are associated with the presence of additional underlying trochlear factors such as increased bump height. The anatomic drivers identified in this study should be further evaluated as possible factors associated with suboptimal outcomes after surgical management.

Abstract Determining the balance between DNA double strand break repair (DSBR) pathways is essential for understanding treatment response in cancer. We report a method for simultaneously measuring non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ) and show that HR and MMEJ are therapeutically-targetable treatment resistance mechanisms in glioblastoma. Using a targeted screen of clinically relevant small molecules, we identify the ATM kinase inhibitor, AZD1390, as a potent dual HR/MMEJ inhibitor. Mechanistic studies in GBM cell lines show that AZD1390 suppresses DSB end resection and blocks radiation-induced phosphorylation of DSBR proteins including nibrin, Rad50, and Mettl16. Interestingly, AZD1390 enhances the cytotoxic effects of TMZ and radiation in both treatment-naïve and treatment-resistant GBM samples harboring mutations in the TP53 gene. We show that TP53 mutation is associated with upregulation of ATM pathway genes in GBM patient samples along with heightened ATM-dependent HR and MMEJ in GBM cell lines. Finally, we show that TP53-mutant GBMs fail to arrest in G2 phase after radiation/AZD1390 or TMZ/AZD1390 combinations and instead attempt mitosis, leading to mitotic cell death. Expression of the mitotic DSBR factor, RHINO1, is associated with poor prognosis in patients with TP53-mutant GBMs, suggesting that factors that promote efficient mitotic DSBR protect TP53-mutant GBMs from treatment-induced cell death. This report identifies ATM-dependent HR and MMEJ as targetable resistance mechanisms in TP53-mutant GBM and establishes ATM inhibition as a potential strategy for overcoming intrinsic and acquired treatment resistance in TP53-mutant GBMs. Citation Format: Daniel J Laverty, Shiv Gupta, Gary Bradshaw, Jiajia Chen, Brett L Carlson, Nery Matias Calmo, Shulan Tian, Jann N Sarkaria, Zachary D Nagel. ATM inhibitors exploit checkpoint defects and ATM-dependent double strand break repair to induce mitotic cell death in TP53-mutant glioblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A011.

We describe the design and results from the BraTS 2023 Intracranial Meningioma Segmentation Challenge. The BraTS Meningioma Challenge differed from prior BraTS Glioma challenges in that it focused on meningiomas, which are typically benign extra-axial tumors with diverse radiologic and anatomical presentation and a propensity for multiplicity. Nine participating teams each developed deep-learning automated segmentation models using image data from the largest multi-institutional systematically expert annotated multilabel multi-sequence meningioma MRI dataset to date, which included 1000 training set cases, 141 validation set cases, and 283 hidden test set cases. Each case included T2, FLAIR, T1, and T1Gd brain MRI sequences with associated tumor compartment labels delineating enhancing tumor, non-enhancing tumor, and surrounding non-enhancing FLAIR hyperintensity. Participant automated segmentation models were evaluated and ranked based on a scoring system evaluating lesion-wise metrics including dice similarity coefficient (DSC) and 95% Hausdorff Distance. The top ranked team had a lesion-wise median dice similarity coefficient (DSC) of 0.976, 0.976, and 0.964 for enhancing tumor, tumor core, and whole tumor, respectively and a corresponding average DSC of 0.899, 0.904, and 0.871, respectively. These results serve as state-of-the-art benchmarks for future pre-operative meningioma automated segmentation algorithms. Additionally, we found that 1286 of 1424 cases (90.3%) had at least 1 compartment voxel abutting the edge of the skull-stripped image edge, which requires further investigation into optimal pre-processing face anonymization steps.

Repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis and familial frontotemporal dementia (ALS/FTD). To identify molecular defects that take place in the dorsolateral frontal cortex of patients with C9orf72 ALS/FTD, we compared healthy controls with C9orf72 ALS/FTD donor samples staged based on the levels of cortical phosphorylated TAR DNA binding protein (pTDP-43), a neuropathological hallmark of disease progression. We identified distinct molecular changes in different cell types that take place during FTD development. Loss of neurosurveillance microglia and activation of the complement cascade take place early, when pTDP-43 aggregates are absent or very low, and become more pronounced in late stages, suggesting an initial involvement of microglia in disease progression. Reduction of layer 2-3 cortical projection neurons with high expression of CUX2/LAMP5 also occurs early, and the reduction becomes more pronounced as pTDP-43 accumulates. Several unique features were observed only in samples with high levels of pTDP-43, including global alteration of chromatin accessibility in oligodendrocytes, microglia, and astrocytes; higher ratios of premature oligodendrocytes; increased levels of the noncoding RNA NEAT1 in astrocytes and neurons, and higher amount of phosphorylated ribosomal protein S6. Our findings reveal progressive functional changes in major cell types found in the prefrontal cortex of C9orf72 ALS/FTD patients that shed light on the mechanisms underlying the pathology of this disease.

Abstract Background Inter‐fractional and intra‐fractional positioning and motion monitoring based on implanted fiducials through kilovoltage (kV) imaging is a cost‐effective approach to enhance intact prostate radiotherapy treatment accuracy. However, comprehensive studies for three‐dimensional (3D) position extraction and the corrective action threshold are lacking. Purpose To develop and verify a fiducial motion monitoring system with 3D position information based on triggered kV images taken during treatment delivery, and to comprehensively evaluate the recommended thresholds for corrective action during treatment. Methods An in‐house fiducial triangulation algorithm was developed to monitor fiducial positions using subsequent kV triggered images. The precision of fiducial triangulation and motion detection was validated on a pelvis phantom with four fiducial inserts. A retrospective study was conducted on prostate cancer patients who received either moderately hypofractionated radiotherapy (MHRT, n = 16) or stereotactic body radiotherapy (SBRT, n = 12), categorized by endo‐rectal balloon (ERB) use. Intra‐fractional positions relative to isocenter were computed, and these positions were analyzed in comparison to the original marker locations of the patient's treatment plan. A linear regression fit was used per fraction to determine correlation coefficients between motions in the left–right (LR), superior–inferior (SI), and anterior–posterior (AP) directions. Average fraction time (AFT) of treatment was reported based on the observed average time spent on steps in the workflow and the percentage of fiducials caught outside of the current two‐dimensional (2D) tolerance threshold of 5 mm. The observed 3D offsets were used to estimate AFT for various 3D tolerance thresholds. Results Overall, our triangulation method proved to be very precise for static cases, where phantom measurements revealed a fiducial position triangulation precision of mm for stationary targets, but had a spread of mm for targets with 1 mm of motion. Employing triangulation, true motion exceeding 5 mm was detected above 4.0 mm in magnitude 90.9% of the time, a noticeable improvement in comparison to the 28%–65% successful detection rate reported by 2D projection methods. Most detection errors were attributed to depth disparity. Similar to other reports, correlation coefficients for intra‐fractional motion generally indicated no LR/SI, no LR/AP, and weak positive SI/AP correlations for MHRT and SBRT patients. Offsets beyond a 3D tolerance threshold of 5 mm were observed at a rate of 4.25%–5.25%, while the 5 mm 2D out‐of‐tolerance catch‐rate was 1.6%. The AFT was 8.1–8.2 min using the 2D tolerance threshold of 5 mm. In comparison, the estimated AFT for the proposed 3D tolerance monitoring of offsets beyond 2–5 mm was slightly higher at 8.2–10.9 min due to the higher amount of out‐of‐tolerance instances for the higher precision intra‐fractional motion management. Conclusions Our study showcases a promising subsequent kV‐based triangulation method for intra‐fractional prostate motion monitoring. Acquiring 3D motion information results in higher out‐of‐tolerance catch‐rates particularly in the depth dimension of the kV images, which is perpendicular to the treatment beam. Failure to properly observe and catch these offsets would result in sub‐optimal conformality and accuracy of the dose delivery.

ImportanceMyeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.ObjectiveTo determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.Design, Settings, and ParticipantsVerdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.InterventionsEligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale–Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.ResultsA total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR <1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, −23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.Conclusions and RelevanceResults demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.Trial RegistrationClinical Trial Identifiers: NCT04297683 and NCT04436510

ImportanceAmyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.ObjectiveTo determine the effects of pridopidine, a σ1-receptor agonist, in ALS.Design, Settings, and ParticipantsPridopidine was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind, platform trial. The study was conducted at 54 sites in the US from January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses.InterventionsEligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n = 121) or matching oral placebo (n = 42) for a planned duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation.ResultsAmong 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR <1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n = 121; placebo, n = 163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively).Conclusions and RelevanceIn this 24-week study, pridopidine did not impact the progression of ALS.Trial RegistrationClinicalTrials.gov Identifiers: NCT04297683, NCT04615923

Importance The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression. Objective To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS. Design, Setting, and Participants Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens. Interventions Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing. Main Outcomes and Measures The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; <1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164). Results Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified. Conclusions and Relevance In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources. Trial Registration ClinicalTrials.gov Identifier: NCT04297683