Citations

Background: The Latarjet and other bony augmentation procedures are commonly used to treat anterior shoulder instability in the setting of significant glenoid bone loss. Although several fixation strategies have been reported, the biomechanical strength of these techniques remains poorly understood. Purpose: To perform a systematic review of the biomechanical strength of glenoid bony augmentation procedures for anterior shoulder instability. Study Design: Systematic review; Level of evidence, 4. Methods: A systematic search of the Medline, Embase, Web of Science, and Cochrane Library databases was performed to identify biomechanical studies evaluating various fixation strategies for coracoid and other bone transfer procedures for anterior shoulder instability. Biomechanical results included load to failure with both compression and traction forces, stiffness, and cyclic displacement. The quality of included articles was assessed based on the Quality Appraisal for Cadaveric Studies (QUACS) scale. Results: A total of 21 biomechanical studies comprising 486 specimens were included. The number of screws used and the addition of washers were found to significantly increase rigidity and load to failure. The comparison of fixation techniques demonstrated mixed results in load to failure between screw and alternative constructs including suture buttons and suture anchors. However, studies that tested graft displacement consistently found more graft displacement in buttons compared with screws. The median and mean of the QUACS scale were both 12, with a range of 10-13. Conclusion: Biomechanical studies consistently demonstrated that when glenoid bone grafts were fixed with screws, the number of screws and use of washers significantly increased construct rigidity and load to failure. Different metal screw materials and sizes did not consistently demonstrate a significant difference in biomechanical strength. There are mixed results when comparing suture buttons to screw fixation. The evaluated studies revealed that all double metal screw constructs and the majority of suture button and anchor constructs were able to withstand the glenohumeral load reflective of activities of daily living using a 150-N threshold.

Objective To evaluate cochlear implant speech perception among patients with sporadic inner ear schwannoma who underwent ipsilateral implantation. Study Design Retrospective multi-institutional cohort study. Setting Eleven tertiary academic medical centers across Germany, Denmark, and the United States. Patients One hundred six patients with sporadic inner ear schwannoma who received an ipsilateral cochlear implant from 2011 to 2022. Interventions Ipsilateral cochlear implantation with observation, stereotactic radiosurgery, or microsurgery for tumor management. Main Outcome Measures Monosyllabic speech perception testing scores and rates of open-set speech perception. Results Among 106 patients studied, 101 (95%) achieved open-set speech perception with a median of 24 months (interquartile range [IQR] 12–42 mo) of audiometric follow-up. Median ipsilateral monosyllabic speech perception testing achieved was 72% (IQR 54–85%), and median ipsilateral AzBio in quiet was 75% (IQR 46–90%). Most (91 of 106 [86%]) underwent microsurgery for tumor control, with cochlear implantation performed simultaneously in 98% (89 of 91) of these patients. The ability to achieve gross total resection significantly differed by tumor complexity, with 97% of low-complexity tumors, 100% of intermediate complexity, and 0% of high-complexity tumors undergoing gross total resection (p < 0.001). However, among patients managed with microsurgery, there was not a statistically significant difference in post-cochlear implantation monosyllabic speech perception scores across complexity groupings, with median scores of 75 and 70% for patients with tumors of low or intermediate complexity and those with tumors of high complexity, respectively (p = 0.5). Eight of 102 patients (8%) assessed experienced deterioration in cochlear implant performance over time. Among the subset of 39 patients with available MRI to review, the region of surveillance interest could be visualized postoperatively on MRI in all cases. Conclusions Open-set speech perception is achieved in most patients with inner ear schwannoma undergoing ipsilateral cochlear implantation. Although cochlear implantation in high-complexity inner ear schwannomas is only possible with incomplete tumor resection, long-term open-set speech perception outcomes are similar to lower-complexity tumors.

Introduction: ELA026 is a first-in-class human monoclonal antibody directed against signal regulatory protein (SIRP)α/β1/γ and is under clinical investigation in secondary hemophagocytic lymphohistiocytosis (sHLH). sHLH is a life-threatening hyperinflammatory condition caused by failure to terminate the activation and proliferation of natural killer (NK), T cells and macrophages after an initial immune response. There are no approved therapies for sHLH. With a mortality rate of approximately 50% at 2 months (Lionel et al. 2023), malignancy-associated HLH (mHLH) is the deadliest subtype of sHLH. Cytotoxic, multi-agent chemotherapy (including etoposide) does not address the poor prognosis associated with mHLH (Xie et al. 2013). Directly targeting the pathogenic SIRP(+) myeloid cells and T lymphocytes represents a novel approach to resolving this severe hyperinflammatory condition. Methods: This is an open-label, single-arm, Phase 1b global multicenter study (NCT05416307) evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of ELA026 in adult and pediatric patients with newly diagnosed and previously treated sHLH. The study is expanding enrollment to evaluate a fixed-dose regimen consisting of a priming phase of 0.1 mg/kg Day 1 and 0.3 mg/kg Days 2-4, followed by a maintenance phase of 0.5 mg/kg twice weekly beginning on Day 8. ELA026 is administered intravenously, with the option to transition to subcutaneous administration upon hospital discharge. The treatment period is 12 weeks with the option to extend in patients deriving ongoing clinical benefits. Enrollment in this cohort is restricted to frontline settings based on the experience that relapsed/refractory sHLH patients exhibited poor survival even with HLH disease control and died from complications related to severe baseline comorbidities. Response is evaluated using a modified HLH-2004 criteria (Locatelli et al. 2020) and survival is calculated from the time of HLH diagnosis. All patients receive dexamethasone as background therapy and premedication initially. Patients with mHLH may also receive cancer-directed therapies concurrently. Primary pharmacodynamic (PD) effects (monocyte and lymphocyte reduction) and secondary PD effects (C-reactive protein [CRP], ferritin, and sCD25 reduction) were best evaluated and attributed to ELA026 during windows of treatment without concurrent chemotherapy effects. Results: As of July 15, 2024, 12 treatment-naïve mHLH patients have enrolled in all cohorts of the study, with a median age of 47 years (range 21-78). The following malignancies were represented: 7 T-cell lymphoma, 2 DLBCL, 1 AML, 1 Hodgkin lymphoma, and 1 T-cell ALL. In this group, response rate was 100% with 2 mCR and 9 PR by Week 4 and survival was 88% at 2 months (7/8; 4 patients are alive and have not reached 2 months on study). Median survival has not been reached; median follow-up is 2.3 months (range 0.1-15.9 months). In terms of PD effects, monocyte and lymphocyte reduction generally occurred following the first priming dose and ferritin and CRP were reduced by an average of 40% and 50% by Day 6, respectively, for patients with windows of ELA026 treatment without concurrent chemotherapy effects. Study-wide (all patients dosed), treatment-related infusion reactions (~20%) and cytopenias (~30%) were generally manageable with supportive care and dosing modifications. One serious adverse event, a grade 4 infusion reaction, was assessed as related in a relapsed/refractory mHLH patient with acute liver failure and poor hemodynamic reserve. Infection risks are expected for this patient population, which were mitigated with growth factor support and antimicrobial prophylaxis. No deaths were related to study drug. Updated study results will be provided at the 2024 ASH meeting in San Diego. Conclusion: Data suggest ELA026 is well-tolerated to date in sHLH patients and results in a 100% response rate and improved 2-month survival in treatment-naïve mHLH patients. The study is enrolling in an expanded cohort to further assess efficacy in this patient population.

Background Primary Central Nervous System Lymphoma Patients (PCNSL) is a rare and aggressive form of NHL in the central nervous system or vitreoretinal space. Despite high initial response rates of high dose methotrexate-based regimens, most patients will relapse in less than two years with poor prognosis. There are no approved treatments for Relapsed/Refractory (R/R) PCNSL, representing a clear unmet medical need. IRAK4 kinase activity is required for TLR and IL-1R signaling in a variety of myeloid and lymphoid cell types, including PCNSL. Recruitment of IRAK4 to these receptors and subsequent activation is facilitated by the MyD88 adaptor protein, which is mutated in ~70% of PCNSL. This leads to constitutive activation of the NF-κB signaling pathway, increased inflammation, and tumor growth. Emavusertib is a novel and potent oral inhibitor of IRAK4, which has demonstrated the ability to cross the blood-brain barrier in PCNSL xenografts. In preclinical studies, the combination of emavusertib with Bruton tyrosine kinase inhibitors (BTKi) showed in vitro synergy of inhibition and re-sensitization of BTKi-resistant cell lines. Emavusertib + ibrutinib has demonstrated an acceptable safety profile across a broad population of R/R NHL patients, including PCNSL. Aim We present updated safety and efficacy of emavusertib in combination with ibrutinib in patients with R/R PCNSL most recently treated with BTKi regimen. Methods The safety, clinical activity, and potential biomarkers of emavusertib in R/R PCNSL are being investigated in the ongoing open-label, Phase 1/2 TakeAim Lymphoma trial (NCT03328078). The eligible patients with R/R PCNSL received emavusertib (100-300 mg BID) in combination with ibrutinib (560 mg QD) continuously until tumor progression or unacceptable toxicity. Disease staging at screening and anti-cancer therapeutic responses were evaluated according to the IPCG Response Criteria Guideline for PCNSL. Results As of 10 July 2024, 13 R/R PCNSL patients, with prior BTK exposure, received emavusertib at 100 - 300 mg BID in combination with ibrutinib at 560mg QD. The median age was 60 years (range 44 - 79). The median number of prior lines of anti-cancer therapies was 2 (range 2 - 5). Median emavusertib/ibrutinib treatment duration was 51 days (range 17 - 503). The preliminary efficacy data in 12 evaluable patients whose most recent treatment regimen included a BTKi and were treated with the combination of emavusertib and ibrutinib showed 3 complete remission (CR), 1 unconfirmed complete Response (CRu) and 2 partial responses (PR) and an overall response rate of 50%. Treatment is on-going for 5 patients with one patient pending the first assessment. All responders demonstrated more than 80% reduction in target lesion size compared to baseline. Two of the responders with a CR demonstrated durable response, with 1 patient having a duration of response (DOR) of approximately 9 months, and the second patient having a DOR of 12 months with response ongoing. Grade ≥3 Treatment-emergent adverse events (TEAEs) were reported in 7 (53.8%) patients, while Grade ≥3 treatment-related adverse events (TRAEs) were reported in 4 (30.8%) patients. No fatal TRAE were reported and the majority of Grade ≥ 3 TEAEs and all Grade ≥ 3 TRAEs were reversible and manageable. Conclusion Emavusertib in combination with ibrutinib shows promising efficacy and was well tolerated with an acceptable safety profile in R/R PCNSL patients with prior BTKi exposure. The combination of emavusertib + ibrutinib may overcome BTKi resistance and has the potential to show improved anti-cancer activity. Enrollment in this trial is ongoing (NCT03328078).

Objective To analyze cases of medial migration of vestibular schwannomas to propose an underlying mechanism. Study Design Retrospective chart review. Patients Ten patients from one institution with sporadic vestibular schwannomas that demonstrated medial migration toward the cerebellopontine angle on serial imaging were reviewed. Interventions Among the 10 patients studied, 8 patients underwent stereotactic radiosurgery and 2 were managed with wait-and-scan. All serial imaging was analyzed throughout follow-up. Main Outcome Measures Volumetric and linear measurements were used to assess vestibular schwannoma growth. The fundal fluid cap length was measured from the most lateral end of the neoplasm within the internal auditory canal to the medial end of the cochlea. Pure tone averages of 0.5, 1, 2, and 3 kHz, word recognition scores, and AAO-HNS hearing class were used to assess levels of hearing loss per patient. Results Tumor growth exhibited a positive correlation with medial migration. Of the 10 patients studied, 9 exhibited tumor volume growth from initial to most recent imaging. Median changes in tumor volumes and fundal fluid cap lengths from initial diagnosis to the most recent imaging regardless of intervention were 130 mm3 (range 1,400–2,970) and 2.8 mm (range 1.8–6.0), respectively. Migration was noted in 4 patients prior to any intervention, in 4 patients postradiosurgery, and in 2 patients before and after radiosurgery. Therefore, half of the tumors studied migrated before an intervention and half migrated postradiosurgery. No correlation of migration and hearing decline was observed. Conclusion Medial migration of vestibular schwannoma is associated with an increase in tumor volume, supporting a “tumor squeeze” mechanism within a conical internal auditory canal toward the wider porus acusticus and cerebellopontine angle.

Purpose To compare Medicaid and Medicare rates for the 20 most commonly billed orthopaedic sports medicine procedures. Methods Medicaid reimbursement rates were obtained from state‐specific fee schedules. Medicare rates were collected from the Centers for Medicare & Medicaid Services Physician Fee Schedule, along with relative value units for each procedure. State rates were compared using averages and dollar differences. Reimbursement rates were adjusted for cost of living using the Medicare Wage Index. Variability between states and between procedures was assessed using coefficients of variation. Results Mean Medicaid reimbursement was lower than that of Medicare for 19 of the 20 procedures. In total, Medicaid reimbursed surgeons 14.9% less when data were unadjusted and 26.0% less when data were adjusted for cost of living. Variation in Medicare rates between states was constant, with a coefficient of variation of 0.06. For Medicaid, the coefficients of variation ranged from 0.27 to 0.70 for unadjusted data and from 0.35 to 0.69 for adjusted data. Conclusions On average, Medicaid reimburses orthopaedic sports medicine specialists less than does Medicare, with substantial variability between states. Adjustment for cost of living increases the percentage difference and the variability between states’ Medicaid reimbursement rates. Level of Evidence Level IV, economic analysis.

Congenital cytomegalovirus (cCMV) is the most common infectious cause of disability in children, including sensorineural hearing loss. There is interest in developing a pre-conception vaccine that could confer protective immunity on a woman of child-bearing age, hence resulting in a reduced cCMV disease burden. Other populations, including solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) patients, could also benefit from CMV vaccination. To review and discuss vaccines that are in clinical development, a workshop, sponsored by the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID), was empaneled. At this workshop, correlates of protective immunity against CMV, epidemiologic features of CMV transmission, and vaccine platforms in development were reviewed. Representatives from academia, pharma, and the NIH engaged in discussion on the current state-of-the-art in CMV vaccinology. A summary of the presentations from this is provided in this report.

AbstractBackgroundCochlear implants (CIs) are used to rehabilitate moderate to profound sensorineural hearing loss and stimulate the auditory system via a multichannel electrode array positioned in the scala tympani. Imaging evaluation of CIs is substantially degraded by metallic artifacts. Photon‐counting detector (PCD)‐CT has the potential to minimize such artifacts, though this has not been convincingly established in prior studies. This study compared the visualization of CI electrodes on PCD‐CT to conventional energy integrating detector (EID)‐CT.Materials and MethodsFive patients with CIs were prospectively recruited to undergo temporal bone imaging on both EID‐CT and PCD‐CT scanners yielding 2D and 3D Volume Rendering Technique (VRT) images. Three nonblinded neuroradiologists reviewed 2D and 3D VRT images for the ability to resolve CI electrode leads using a Likert scale. The average Likert scores of PCD‐CT versus EID‐CT were calculated for each reader for both 2D and 3D VRT images. (Likert scores 1–5 based on inferior to superior rating of PCD‐CT compared to EID‐CT). Inter‐rater agreement was assessed using Krippendorff's alpha with ordinal weights. ResultsFive patients underwent temporal bone CT for CI array evaluation. As evidenced by 5‐point Likert scales that were independently used by the three reviewers, this study demonstrated superior resolution of CI electrode array using PCD‐CT as compared to EID‐CT with an average score of 4.2 ± 0.8 for 2D images and 4.9 ± 0.4 for 3D VRT images.ConclusionsPCD‐CT is superior to EID‐CT in the visualization of CI electrodes, particularly in 3D VRT imaging.

Abstract Historically, treatment options for blastic plasmacytoid dendritic cell neoplasm (BPDCN) were limited to conventional chemotherapy, adopted from regimens used to treat acute myeloid or acute lymphoblastic leukemias, or lymphomas. Nowadays, a novel therapy targeting CD123 is available to treat BPDCN. Yet, regardless of treatment choice, achieving a first complete remission represents the main goal of therapy, because it represents the best opportunity to prolong survival in BPDCN, if offered an allogeneic hematopoietic cell transplant (allo-HCT) as consolidative therapy. Although no specific conditioning regimen is considered standard of care in allo-HCT–eligible patients, recent data from 2 large registries reported a survival advantage when offering total body irradiation–based myeloablative conditioning (MAC) regimens. Unfortunately, applicability of MAC regimens is not feasible in patients who are older/unfit, which represents a considerable proportion of patients presenting worldwide. In such cases, reduced intensity conditioning regimens represent the next best option. Autologous HCT could be considered in patients who are older/unfit who did not have bone marrow involvement at initial presentation and at time of the procedure, albeit data supporting this option are less abundant. Future research is needed to decipher the interplay between clinical, genetic, and molecular features of the disease to personalize treatment accordingly, by enhancing efficacy and avoiding unnecessary toxicities.

Germline variants in the NSD1 gene are responsible for Sotos syndrome, while somatic variants promote neoplastic cell transformation. Our previous studies revealed three alternative RNA isoforms of NSD1 present in fibroblast cell lines (FBs): the canonical full transcript and 2 alternative transcripts, termed AT2 (NSD1 Δ5Δ7) and AT3 (NSD1 Δ19–23 at the 5′ end). The precise molecular pathways affected by each specific isoform of NSD1 are uncharacterized to date. To elucidate the role of these isoforms, their expression was suppressed by siRNA knockdown in FBs and protein expression and transcriptome data was explored. We demonstrate that one gene target of NSD1 isoform AT2 is ARP3 actin-related protein 3 homolog B (ACTR3B). We show that loss of both canonical NSD1 and AT2 isoforms impaired the ability of fibroblasts to regulate the actin cytoskeleton, and we observed that this caused selective loss of stress fibers. Our findings provide novel insights into NSD1 function by distinguishing isoform function and demonstrating an essential role of NSD1 in regulating the actin cytoskeleton and stress fiber formation in fibroblasts.