Citations

Background: As machine learning becomes increasingly utilized in orthopaedic clinical research, the application of machine learning methodology to cohort data from the Multicenter ACL Revision Study (MARS) presents a valuable opportunity to translate data into patient-specific insights. Purpose: To apply novel machine learning methodology to MARS cohort data to determine a predictive model of revision anterior cruciate ligament reconstruction (rACLR) graft failure and features most predictive of failure. Study Design: Cohort study; Level of evidence, 3. Methods: The authors prospectively recruited patients undergoing rACLR from the MARS cohort and obtained preoperative radiographs, surgeon-reported intraoperative findings, and 2- and 6-year follow-up data on patient-reported outcomes, additional surgeries, and graft failure. Machine learning models including logistic regression (LR), XGBoost, gradient boosting (GB), random forest (RF), and a validated ensemble algorithm (AutoPrognosis) were built to predict graft failure by 6 years postoperatively. Validated performance metrics and feature importance measures were used to evaluate model performance. Results: The cohort included 960 patients who completed 6-year follow-up, with 5.7% (n = 55) experiencing graft failure. AutoPrognosis demonstrated the highest discriminative power (model area under the receiver operating characteristic curve: AutoPrognosis, 0.703; RF, 0.618; GB, 0.660; XGBoost, 0.680; LR, 0.592), with well-calibrated scores (model Brier score: AutoPrognosis, 0.053; RF, 0.054; GB, 0.057; XGBoost, 0.058; LR, 0.111). The most important features for AutoPrognosis model performance were prior compromised femoral and tibial tunnels (placement and size) and allograft graft type used in current rACLR. Conclusion: The present study demonstrated the ability of the novel AutoPrognosis machine learning model to best predict the risk of graft failure in patients undergoing rACLR at 6 years postoperatively with moderate predictive ability. Femoral and tibial tunnel size and position in prior ACLR and allograft use in current rACLR were all risk factors for rACLR failure in the context of the AutoPrognosis model. This study describes a unique model that can be externally validated with larger data sets and contribute toward the creation of a robust rACLR bedside risk calculator in future studies. Registration: NCT00625885 (ClinicalTrials.gov identifier).

There is an increased risk of infection in patients with cancer that results in higher morbidity and mortality. Several risk factors can predispose these patients to infectious complications. Some such factors include immunocompromised states like neutropenia, allogeneic hematopoietic cell transplantation, and graft-versus-host disease, while others include immunosuppressive agents like corticosteroids, purine analogs, monoclonal antibodies, and other emerging cancer therapeutics like CAR T-cell therapy. The NCCN Guidelines for the Prevention and Treatment of Cancer-Related Infections address infection concerns that may be observed in these immunocompromised populations and characterize the major pathogens to which patients with cancer are susceptible, with a focus on the prevention, diagnosis, and treatment of major common and opportunistic infections. This paper highlights 2 recently updated sections of the guidelines, namely, infection concerns related to CAR T-cell therapy and antimicrobial prophylaxis recommendations, including vaccination, in patients at high-risk for infections.

Abstract Recurrent glioblastoma (rGBM) is a lethal brain tumor with no effective standard of care option and an extremely poor prognosis (median survival 6 to 8 months after first recurrence). Sonodynamic therapy (SDT) is a non-invasive combination therapy that utilizes a drug, aminolevulinic acid HCL (SONALA-001, ALA), and a device, the Exablate 4000 Type 2.0 to deliver MR-guided focused ultrasound (MRgFUS). Preclinical studies have shown that SDT activates protoporphyrin IX (PpIX) to generate reactive oxygen species that lead to tumor cell death and improved survival in animal glioma models. A first-in-human Phase 0 trial (NCT04559685) indicated that ALA SDT was well-tolerated and not associated with off-target cellular or radiographic effects and provided direct evidence of reactive oxygen species formation and targeted tumor cell death in recurrent high-grade glioma (rHGG). SDT-202 is a Phase 1/2 multicenter, open-label, dose escalation and expansion study (NCT05370508) of iv SONALA-001 (ALA) in combination with MRgFUS for SDT in patients with progressive or recurrent GBM. Dose escalation will include an initial drug and energy dose escalation of ALA SDT utilizing an accelerated titration design with single subject cohorts for dose level cohorts 1 and 2, followed by cohort 3 with 3 + 3 design for additional dose escalation. SONALA-001 is administered 6 to 9 hours prior to MRgFUS treatment. Once the RP2D is determined, Phase 2 dose expansion will enroll approximately 36 additional subjects to assess safety and efficacy of repeated cycles of ALA SDT at the optimized RP2D. Endpoints of this study are safety evaluation, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and determination of pharmacokinetic (PK) parameters. The Phase 2 portion will further characterize safety of RP2D along with evaluation of efficacy with PFS6 (mRANO), ORR, CBR, DOR, DOCR, TTR, and OS. Preliminary PK and safety results will be presented.

Background: Second-generation highly cross-linked polyethylene (HXLPE) has revolutionized total hip arthroplasty. However, the long-term risks and benefits of HXLPE in primary total knee arthroplasty (TKA) remain unknown. This randomized clinical trial evaluated implant survivorship, complications, radiographic results, and clinical outcomes of HXLPE and conventional ultra-high molecular weight polyethylene (UHMWPE) inserts in primary TKAs. Methods: We enrolled 518 patients (518 knees) who underwent primary TKA in 3 centers within 1 tertiary referral network. The mean age was 67 years, the mean body mass index was 32 kg/m 2 , and 58% of the patients were women. All of the patients underwent primary TKA with a cemented posterior-stabilized tibial insert and patellar resurfacing. Randomization proceeded via stratified dynamic allocation. The patients were blinded to their study group allocation: those in the control group (254 knees) underwent TKA with an UHMWPE insert (N2Vac; Stryker); those in the treatment group (264 knees) received an HXLPE insert (X3; Stryker). Kaplan-Meier survivorship, radiographic results, and clinical outcomes were assessed. This trial was registered with ClinicalTrials.gov. The mean follow-up was 11 years. Results: The 10-year overall survivorship free from any revision and from any reoperation was 96% and 94%, respectively. There were no differences in the risk of revision or reoperation between the groups (p > 0.05). There were a total of 19 revisions. Revision indications included periprosthetic joint infection (14 knees), instability (4 knees), and open reduction and internal fixation (ORIF) for a patellar fracture due to osteolysis around a UHMWPE insert (1 knee). There were no revisions due to polyethylene wear, osteolysis, or fracture of the post in the HXLPE group. The radiographic results and clinical outcomes were otherwise similar. Conclusions: Notably, no wear-related failures were identified in the HXLPE group, but there was 1 case of osteolysis in the UHMWPE group. Level of Evidence: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

Background: Revision anterior cruciate ligament (ACL) reconstruction has been documented to have inferior outcomes compared with primary ACL reconstruction. The reasons why remain unknown. Purpose: To determine whether surgical factors performed at the time of revision ACL reconstruction can influence a patient’s outcome at 6-year follow-up. Study Design: Cohort study; Level of evidence, 2. Methods: Patients who underwent revision ACL reconstruction were identified and prospectively enrolled between 2006 and 2011. Data collected included baseline patient characteristics, surgical technique and pathology, and a series of validated patient-reported outcome instruments: Knee injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC) subjective form, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Marx activity rating score. Patients were followed up for 6 years and asked to complete the identical set of outcome instruments. Regression analysis was used to control for baseline patient characteristics and surgical variables to assess the surgical risk factors for clinical outcomes 6 years after surgery. Results: A total of 1234 patients were enrolled (716 men, 58%; median age, 26 years), and 6-year follow-up was obtained on 79% of patients (980/1234). Using an interference screw for femoral fixation compared with a cross-pin resulted in significantly better outcomes in 6-year IKDC scores (odds ratio [OR], 2.2; 95% CI, 1.2-3.9; P = .008) and KOOS sports/recreation and quality of life subscale scores (OR range, 2.2-2.7; 95% CI, 1.2-4.8; P < .01). Use of an interference screw compared with a cross-pin resulted in a 2.6 times less likely chance of having a subsequent surgery within 6 years. Use of an interference screw for tibial fixation compared with any combination of tibial fixation techniques resulted in significantly improved scores for IKDC (OR, 1.96; 95% CI, 1.3-2.9; P = .001); KOOS pain, activities of daily living, and sports/recreation subscales (OR range, 1.5-1.6; 95% CI, 1.0-2.4; P < .05); and WOMAC pain and activities of daily living subscales (OR range, 1.5-1.8; 95% CI, 1.0-2.7; P < .05). Use of a transtibial surgical approach compared with an anteromedial portal approach resulted in significantly improved KOOS pain and quality of life subscale scores at 6 years (OR, 1.5; 95% CI, 1.02-2.2; P≤ .04). Conclusion: There are surgical variables at the time of ACL revision that can modify clinical outcomes at 6 years. Opting for a transtibial surgical approach and choosing an interference screw for femoral and tibial fixation improved patients’ odds of having a significantly better 6-year clinical outcome in this cohort.

Background Advanced neuromuscular training prepares patients with anterior cruciate ligament reconstruction (ACLR) for sport participation. Return-to-sport testing often includes single-leg hop tests, yet combining motor and cognitive tasks (i.e., dual-task) might reveal neurocognitive reliance. Purpose/Hypothesis This study examined changes in performance on visuomotor reactions tests and single-leg hop tests following advanced neuromuscular training in patients with ACLR. The hypothesis was that performance would improve less on reaction tests than on single-leg hop tests. Study Design Quasi experimental, Pretest-Posttest Methods Twenty-five patients with ACLR (11 males) completed 10 sessions of advanced neuromuscular training and pre-and post-training testing. Reaction tests outcomes were from a platform and visual display. The double-leg reaction test involved touching target dots with either leg for 20 seconds; correct touches and errors were recorded. The single-leg reaction test involved hopping on the test leg to 10 target dots; hop time and errors were recorded. Single-leg hop tests included forward, triple, crossover triple, and timed hop; limb symmetry index was recorded. Effect sizes were calculated for corrected touches on the double-leg reaction test, surgical side hop time on the single-leg reaction test, and surgical side hop distance or time on single-leg hop tests. Results Correct touches on the double-leg reaction test significantly increased from pre- to post-training (20.4 +/- 4.3 vs. 23.9 +/- 2.8, p<0.001). Hop time on the single-leg reaction test significantly decreased from pre- to post-training (Surgical leg 13.2 vs. 12.3 seconds, non-surgical leg 13.0 vs. 12.1 seconds, p=0.003). Mean errors did not significantly change on either reaction test (p> 0.05). Cohens d effect sizes in descending order was single-leg hop tests (d=0.9 to 1.3), double-leg reaction test (d=0.9), and single-leg reaction test (d=0.5). Conclusion Motor performance improved after advanced neuromuscular training, but the effect size was less on visuomotor reaction tests than single-leg hop tests. The results suggest persistence of neurocognitive reliance after ACLR and a need for more dual-task challenges in training. Level of Evidence 3

ABSTRACT Background Nab ‐sirolimus (ABI‐009, nab ‐rapamycin; Aadi Bioscience Inc. [Aadi]) is a human albumin‐bound form of sirolimus nanoparticles, a potent mTOR inhibitor. This phase I trial was conducted to define dose‐limiting toxicities (DLT), maximum tolerated or recommended phase II dose (MTD/RP2D), and pharmacokinetics of Nab ‐sirolimus in combination with temozolomide and irinotecan. Methods Using a rolling 6 design, Nab ‐sirolimus was administered intravenously (IV) on days (D) 1 and 8 of cycle (C) 1. In subsequent cycles, Nab ‐sirolimus was administered D1 and D8 in combination with temozolomide (125 mg/m 2 /dose, maximum 250 mg/dose) and irinotecan (90 mg/m 2 /dose) orally, daily on D1–5. Cycle duration was 21 days. Three dose levels (DL) of Nab ‐sirolimus were investigated (DL1: 35 mg/m 2 /dose, DL‐1: 20 mg/m 2 /dose, and DL‐2: 15 mg/m 2 /dose). The observation period for estimating the MTD/RP2D was defined by cycles 1 and 2. Results Thirty‐three patients were enrolled, 32 were eligible. Dose determination included 17 evaluable patients, median (range) age 12 (2–20) years and six additional patients were enrolled (four evaluable for toxicity) on a pharmacokinetic cohort. C1 or C2 DLTs were primarily thrombocytopenia including 2/5 patients at DL1, 2/6 patients at DL‐1, and 1/6 patients at DL‐2. One patient (DL1) with Ewing Sarcoma had a partial response and remained on study for 35 cycles. Rapamycin clearance was dose dependent. Irinotecan clearance and its active metabolite SN‐38 exposure were not affected by coadministration with Nab ‐sirolimus. Conclusion The MTD for Nab ‐sirolimus was 15 mg/m 2 /dose IV on D1 and D8 in combination with temozolomide 125 mg/m 2 /dose and oral irinotecan 90 mg/m 2 /dose daily for 5 days during 21D cycles. Trial Registration ClinicalTrials.gov identifier NCT02975882

Objectives: Ice hockey is a physically demanding sport, with young athletes prone to anterior cruciate ligament (ACL) injuries. Currently, there is a paucity of data examining the results of ACL reconstruction (ACLR) in competitive hockey players. The purpose of this study was to assess return to hockey (RTH) and reoperation rates following ACLR for ACL injuries in a cohort of competitive hockey players. Methods: All competitive ice hockey players (including, youth, high school, juniors, collegiate, or professional) with a history of ACL injury and subsequent ACLR at a single academic institution between 2000 and 2022 were identified. Exclusion criteria included ACL injuries that did not occur during hockey, history of ACLR prior to hockey injury, and recreational hockey players. Graft failure was defined as a retear (as determined via clinical or advanced imaging evaluation) and/or revision ACLR. Results: Ultimately, 50 knees in 44 hockey players were included at a mean (± standard deviation) follow-up time of 7.0 years ± 5.4 years (Table 1). The mean age at the time of index surgery was 18.9 years ± 3.0 years, with 38 males (76%), and the distribution of bone-patellar tendon-bone (BPTB) and hamstring tendon (HT) autografts was 40 (80%) and 10 (20%), respectively. RTH occurred in 66% of hockey players at a mean of 10.2 months ± 6.2 months. Graft failure occurred in 9 knees (18%) at a mean of 5.9 years ± 5.8 years after the index ACLR. All patients who sustained a retear underwent reoperation. Kaplan-Meier survivorship free from surgical failure of the entire cohort was 94% at 1 year, 88% at 5 years, 74% at 10 years, and 67% at 15 years (Figure 1A). BPTB autograft demonstrated a lower failure rate compared with HT autograft (13% vs 40%; P = 0.041) and was associated with better survival compared with HT autograft up to 15 years after the index ACLR (80% vs 39%; P = 0.047; Figure 1B). Conclusions: ACL injury remains a concern for competitive hockey players after ACLR. Return to competitive ice hockey was observed in 66% of athletes after ACLR, with 18% of hockey players experiencing graft failure and undergoing subsequent reoperation. BPTB autograft was associated with better survival than HT autograft.

Abstract Obstructive sleep apnoea (OSA) is associated with an increased risk for cognitive impairment and dementia, which likely involves Alzheimer’s disease pathology. Non-rapid eye movement slow-wave activity (SWA) has been implicated in amyloid clearance, but it has not been studied in the context of longitudinal amyloid accumulation in OSA. This longitudinal retrospective study aims to investigate the relationship between polysomnographic and electrophysiological SWA features and amyloid accumulation. From the Mayo Clinic Study of Aging cohort, we identified 71 participants ≥60 years old with OSA (mean baseline age = 72.9 ± 7.5 years, 60.6% male, 93% cognitively unimpaired) who had at least 2 consecutive Amyloid Pittsburgh Compound B (PiB)-PET scans and a polysomnographic study within 5 years of the baseline scan and before the second scan. Annualized PiB-PET accumulation [global ΔPiB(log)/year] was estimated by the difference between the second and first log-transformed global PiB-PET uptake estimations divided by the interval between scans (years). Sixty-four participants were included in SWA analysis. SWA was characterized by the mean relative spectral power density (%) in slow oscillation (SO: 0.5–0.9 Hz) and delta (1–3.9 Hz) frequency bands and by their downslopes (SO-slope and delta-slope, respectively) during the diagnostic portion of polysomnography. We fit linear regression models to test for associations among global ΔPiB(log)/year, SWA features (mean SO% and delta% or mean SO-slope and delta-slope), and OSA severity markers, after adjusting for age at baseline PiB-PET, APOE ɛ4 and baseline amyloid positivity. For 1 SD increase in SO% and SO-slope, global ΔPiB(log)/year increased by 0.0033 (95% CI: 0.0001; 0.0064, P = 0.042) and 0.0069 (95% CI: 0.0009; 0.0129, P = 0.026), which were comparable to 32% and 59% of the effect size associated with baseline amyloid positivity, respectively. Delta-slope was associated with a reduction in global ΔPiB(log)/year by −0.0082 (95% CI: −0.0143; −0.0021, P = 0.009). Sleep apnoea severity was not associated with amyloid accumulation. Regional associations were stronger in the pre-frontal region. Both slow-wave slopes had more significant and widespread regional associations. Annualized PiB-PET accumulation was positively associated with SO and SO-slope, which may reflect altered sleep homeostasis due to increased homeostatic pressure in the setting of unmet sleep needs, increased synaptic strength, and/or hyper-excitability in OSA. Delta-slope was inversely associated with PiB-PET accumulation, suggesting it may represent residual physiological activity. Further investigation of SWA dynamics in the presence of sleep disorders before and after treatment is necessary for understanding the relationship between amyloid accumulation and SWA physiology.