Midterm Survivorship of Robotic-Assisted Lateral Unicompartmental Knee Arthroplasty.

BACKGROUND: Lateral unicompartmental knee arthroplasty (UKA) is a popular alternative to total knee arthroplasty (TKA) for patients with isolated lateral compartment osteoarthritis. Few studies have investigated outcomes following robotic-assisted lateral UKA. The purpose of this study is to evaluate mid-term survivorship and patient-reported outcomes of robotic-assisted lateral UKA. METHODS: A retrospective case series was conducted on all robotic-assisted lateral UKAs performed by a single surgeon between 2013 and 2019. Patient demographics, surgical variables, and Kozinn and Scott criteria were collected. Implant survivorship was estimated using the Kaplan-Meier method with all-cause reoperation and conversion to TKA as endpoints. Participating patients were assessed for patient satisfaction and the Forgotten Joint Score-12. Correlations between patient demographics and patient outcome scores were investigated. RESULTS: In total, 120 lateral UKAs were identified, 84 of which met inclusion criteria, with a mean follow-up of 4.0 years (range 2.0-7.0). Five-year survivorship was 92.9% (95% confidence interval [CI] 84.5-96.7) with all-cause reoperation as the endpoint, and 100% (95% CI 95.0-100) with conversion to TKA as the endpoint. One patient was converted to TKA after the 5-year mark, resulting in a 6-year survival for conversion to TKA of 88.9% (95% CI 44.9-98.5). Average Forgotten Joint Score-12 score was 82.7/100, and patient satisfaction 4.7/5. Mean coronal plane correction was 2.5° ± 1.9° toward the mechanical axis. Neither final postoperative alignment nor failure to meet classic Kozinn and Scott criteria for UKA resulted in differences in patient-reported outcomes. CONCLUSION: The current study demonstrates high mid-term survivorship and excellent patient-reported outcomes with robotic-assisted lateral UKA. Robotic-assisted lateral UKA is a viable treatment option for isolated lateral compartment arthritis even in patients who do not meet classic indications.

Surgical strategies for older patients with glioblastoma.

OBJECTIVE: While adjuvant treatment regimens have been modified for older patients with glioblastoma (GBM), surgical strategies have not been tailored. METHODS: Clinical data of 48 consecutive patients aged 70 years or older, who underwent surgical resection for GBM with intraoperative ultrasonography (IoUS) alone or combination with intraoperative MRI (IoMRI) at Yale New Haven Hospital were retrospectively reviewed. Variables were analyzed, and comparative analyses were performed. RESULTS: The addition of IoMRI was not superior to IoUS alone in terms of overall survival (OS) (P = 0.306), Karnofsky Performance Score (KPS) at postoperative 6 weeks (P = 0.704) or extent of resection (P = 0.263). Length of surgery (LOSx), however, was significantly longer (P = 0.0002) in the IoMRI group. LOSx (P = 0.015) and hospital stay (P = 0.025) were predictors of postoperative complications. Increased EOR (GTR or NTR) (P = 0.030), postoperative adjuvant treatment (P < 0.0001) and postoperative complications (P = 0.006) were predictive for OS. Patients with relatively lower preoperative KPS scores (<70) showed significant improvement at postoperative 6 weeks (P<0.0001). Patients with complications (P = 0.038) were more likely to have lower KPS at postoperative 6 weeks. CONCLUSIONS: Aggressive management with surgical resection should be considered in older patients with GBM, even those with relatively poor KPS. The use of ioMRI in this population does not appear to confer any measurable benefit over ioUS in experienced hands, but prolongs the length of surgery significantly, which is a preventable prognostic factor for impeding care.

Laser interstitial thermal therapy (LITT) vs. bevacizumab for radiation necrosis in previously irradiated brain metastases.

PURPOSE: Both laser interstitial thermal therapy (LITT) and bevacizumab have been used successfully to treat radiation necrosis (RN) after radiation for brain metastases. Our purpose is to compare pre-treatment patient characteristics and outcomes between the two treatment options. METHODS: Single-institution retrospective chart review identified brain metastasis patients who developed RN between 2011 and 2018. Pre-treatment factors and treatment responses were compared between those treated with LITT versus bevacizumab. RESULTS: Twenty-five patients underwent LITT and 13 patients were treated with bevacizumab. The LITT cohort had a longer overall survival (median 24.8 vs. 15.2 months for bevacizumab, p = 0.003) and trended to have a longer time to local recurrence (median 12.1 months vs. 2.0 for bevacizumab), although the latter failed to achieve statistical significance (p = 0.091). LITT resulted in an initial increase in lesional volume compared to bevacizumab (p < 0.001). However, this trend reversed in the long term follow-up, with LITT resulting in a median volume decrease at 1 year post-treatment of - 64.7% (range - 96.0% to + > 100%), while bevacizumab patients saw a median volume increase of + > 100% (range - 63.0% to + > 100%), p = 0.010. CONCLUSIONS: Our study suggests that patients undergoing LITT for RN have longer overall survival and better long-term lesional volume reduction than those treated with bevacizumab. However, it remains unclear whether our findings are due only to a difference in efficacy of the treatments or the implications of selection bias.

Detection of immune responses after immunotherapy in glioblastoma using PET and MRI.

Contrast-enhanced MRI is typically used to follow treatment response and progression in patients with glioblastoma (GBM). However, differentiating tumor progression from pseudoprogression remains a clinical dilemma largely unmitigated by current advances in imaging techniques. Noninvasive imaging techniques capable of distinguishing these two conditions could play an important role in the clinical management of patients with GBM and other brain malignancies. We hypothesized that PET probes for deoxycytidine kinase (dCK) could be used to differentiate immune inflammatory responses from other sources of contrast-enhancement on MRI. Orthotopic malignant gliomas were established in syngeneic immunocompetent mice and then treated with dendritic cell (DC) vaccination and/or PD-1 mAb blockade. Mice were then imaged with [18F]-FAC PET/CT and MRI with i.v. contrast. The ratio of contrast enhancement on MRI to normalized PET probe uptake, which we term the immunotherapeutic response index, delineated specific regions of immune inflammatory activity. On postmortem examination, FACS-based enumeration of intracranial tumor-infiltrating lymphocytes directly correlated with quantitative [18F]-FAC PET probe uptake. Three patients with GBM undergoing treatment with tumor lysate-pulsed DC vaccination and PD-1 mAb blockade were also imaged before and after therapy using MRI and a clinical PET probe for dCK. Unlike in mice, [18F]-FAC is rapidly catabolized in humans; thus, we used another dCK PET probe, [18F]-clofarabine ([18F]-CFA), that may be more clinically relevant. Enhanced [18F]-CFA PET probe accumulation was identified in tumor and secondary lymphoid organs after immunotherapy. Our findings identify a noninvasive modality capable of imaging the host antitumor immune response against intracranial tumors.

SPINT2 is hypermethylated in both IDH1 mutated and wild-type glioblastomas, and exerts tumor suppression via reduction of c-Met activation.

PURPOSE: Both IDH1-mutated and wild-type gliomas abundantly display aberrant CpG island hypermethylation. However, the potential role of hypermethylation in promoting gliomas, especially the most aggressive form, glioblastoma (GBM), remains poorly understood. METHODS: We analyzed RRBS-generated methylation profiles for 11 IDH1WT gliomas (including 7 GBMs), 24 IDH1MUT gliomas (including 6 GBMs), and 5 normal brain samples and employed TCGA GBM methylation profiles as a validation set. Upon classification of differentially methylated CpG islands by IDH1 status, we used integrated analysis of methylation and gene expression to identify SPINT2 as a top cancer related gene. To explore functional consequences of SPINT2 methylation in GBM, we validated SPINT2 methylation status using targeted bisulfite sequencing in a large cohort of GBM samples. We assessed DNA methylation-mediated SPINT2 gene regulation using 5-aza-2'-deoxycytidine treatment, DNMT1 knockdown and luciferase reporter assays. We conducted functional analyses of SPINT2 in GBM cell lines in vitro and in vivo. RESULTS: We identified SPINT2 as a candidate tumor-suppressor gene within a group of CpG islands (designated GT-CMG) that are hypermethylated in both IDH1MUT and IDH1WT gliomas but not in normal brain. We established that SPINT2 downregulation results from promoter hypermethylation, and that restoration of SPINT2 expression reduces c-Met activation and tumorigenic properties of GBM cells. CONCLUSIONS: We defined a previously under-recognized group of coordinately methylated CpG islands common to both IDH1WT and IDH1MUT gliomas (GT-CMG). Within GT-CMG, we identified SPINT2 as a top cancer-related candidate and demonstrated that SPINT2 suppressed GBM via down-regulation of c-Met activation.

Immunosuppressive mechanisms for stem cell transplant survival in spinal cord injury.

Spinal cord injury (SCI) has been associated with a dismal prognosis-recovery is not expected, and the most standard interventions have been temporizing measures that do little to mitigate the extent of damage. While advances in surgical and medical techniques have certainly improved this outlook, limitations in functional recovery continue to impede clinically significant improvements. These limitations are dependent on evolving immunological mechanisms that shape the cellular environment at the site of SCI. In this review, we examine these mechanisms, identify relevant cellular components, and discuss emerging treatments in stem cell grafts and adjuvant immunosuppressants that target these pathways. As the field advances, we expect that stem cell grafts and these adjuvant treatments will significantly shift therapeutic approaches to acute SCI with the potential for more promising outcomes.

Epithelial membrane protein-2 (EMP2) promotes angiogenesis in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor and is associated with an extremely poor clinical prognosis. One pathologic hallmark of GBM is excessive vascularization with abnormal blood vessels. Extensive investigation of anti-angiogenic therapy as a treatment for recurrent GBM has been performed. Bevacizumab, a monoclonal anti-vascular endothelial growth factor A (VEGF-A), suggests a progression-free survival benefit but no overall survival benefit. Developing novel anti-angiogenic therapies are urgently needed in controlling GBM growth. In this study, we demonstrate tumor expression of epithelial membrane protein-2 (EMP2) promotes angiogenesis both in vitro and in vivo using cell lines from human GBM. Mechanistically, this pro-angiogenic effect of EMP2 was partially through upregulating tumor VEGF-A levels. A potential therapeutic effect of a systemic administration of anti-EMP2 IgG1 on intracranial xenografts was observed resulting in both significant reduction of tumor load and decreased tumor vasculature. These results suggest the potential for anti-EMP2 IgG1 as a promising novel anti-angiogenic therapy for GBM. Further investigation is needed to fully understand the molecular mechanisms how EMP2 modulates GBM pathogenesis and progression and to further characterize anti-EMP2 therapy in GBM.

Dendritic cell immunotherapy for brain tumors.

Glioblastomas are characterized by immunosuppression, rapid proliferation, angiogenesis, and invasion into the surrounding brain parenchyma. Limitations in current therapeutic approaches have spurred the development of personalized, patient-specific treatments. Among these, active immunotherapy has emerged as a viable option for glioma treatment. The ability to generate an immune response utilizing patient-derived dendritic cells (DCs) (professional antigen-presenting cells) is especially attractive. This approach to glioma treatment allows for the immunologic targeting and destruction of malignant cells. Data acquired in multiple pre-clinical models and clinical trials have shown significant responses and prolonged survival. Here we provide an overview of the current status of DC vaccination for the treatment of gliomas.

Deconstructing complexity: serial block-face electron microscopic analysis of the hippocampal mossy fiber synapse.

The hippocampal mossy fiber (MF) terminal is among the largest and most complex synaptic structures in the brain. Our understanding of the development of this morphologically elaborate structure has been limited because of the inability of standard electron microscopy techniques to quickly and accurately reconstruct large volumes of neuropil. Here we use serial block-face electron microscopy (SBEM) to surmount these limitations and investigate the establishment of MF connectivity during mouse postnatal development. Based on volume reconstructions, we find that MF axons initially form bouton-like specializations directly onto dendritic shafts, that dendritic protrusions primarily arise independently of bouton contact sites, and that a dramatic increase in presynaptic and postsynaptic complexity follows the association of MF boutons with CA3 dendritic protrusions. We also identify a transient period of MF bouton filopodial exploration, followed by refinement of sites of synaptic connectivity. These observations enhance our understanding of the development of this highly specialized synapse and illustrate the power of SBEM to resolve details of developing microcircuits at a level not easily attainable with conventional approaches.

Angiographic evidence of an inadvertent cannulation of the marginal sinus following central line migration: illustrative case.

BACKGROUND: Central venous catheters (CVCs) play an indispensable role in clinical practice. Catheter malposition and tip migration can lead to severe complications. The authors present a case illustrating the endovascular management of inadvertent marginal sinus cannulation after an internal jugular vein (IJV) catheter tip migration. OBSERVATIONS: A triple-lumen CVC was inserted without complications into the right IJV of a patient undergoing a repeat sternotomy for aortic valve replacement. Two weeks postinsertion, it was discovered that the tip had migrated superiorly, terminating below the torcula in the posterior fossa. In the interventional suite, a three-dimensional venogram confirmed the inadvertent marginal sinus cannulation. The catheter was carefully retracted to the sigmoid sinus to preserve the option of catheter exchange if embolization became necessary. After a subsequent venogram, which displayed an absence of contrast extravasation, the entire catheter was safely removed. The patient tolerated the procedure well. LESSONS: Clinicians must be vigilant of catheter tip migration and malposition risks. Relying solely on postinsertion radiographs is insufficient. Once identified, prompt management of the malpositioned catheter is paramount in reducing morbidity and mortality and improving patient outcomes. Removing a malpositioned catheter constitutes a critical step, best performed by a specialized team under angiographic visualization.

TLR agonists polarize interferon responses in conjunction with dendritic cell vaccination in malignant glioma: a randomized phase II Trial.

In this randomized phase II clinical trial, we evaluated the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas. The primary endpoints were to assess the most effective combination of vaccine and adjuvant in order to enhance the immune potency, along with safety. The combination of ATL-DC vaccination and TLR agonist was safe and found to enhance systemic immune responses, as indicated by increased interferon gene expression and changes in immune cell activation. Specifically, PD-1 expression increases on CD4+ T-cells, while CD38 and CD39 expression are reduced on CD8+ T cells, alongside an increase in monocytes. Poly-ICLC treatment amplifies the induction of interferon-induced genes in monocytes and T lymphocytes. Patients that exhibit higher interferon response gene expression demonstrate prolonged survival and delayed disease progression. These findings suggest that combining ATL-DC with poly-ICLC can induce a polarized interferon response in circulating monocytes and CD8+ T cells, which may represent an important blood biomarker for immunotherapy in this patient population.Trial Registration: ClinicalTrials.gov Identifier: NCT01204684.

Use of a dedicated open transcarotid access system for neurovascular disease.

BACKGROUND: Transcarotid artery revascularization (TCAR) is an increasingly popular technique for the management of extracranial carotid stenosis. Its off-label use in the treatment of intracranial neurovascular disease is poorly described. Our objective is to describe the use of a dedicated open transcarotid access system for the treatment of neurovascular pathologies other than extracranial carotid stenosis. METHODS: We conducted a retrospective review of a prospectively maintained database of consecutive patients who underwent treatment of neurovascular disease at a single academic center using the ENROUTE Transcarotid Arterial Sheath. Demographics, procedural characteristics, and patient outcomes were reported. RESULTS: Twenty patients were included in the study between September 2017 and March 2023. The following pathologies were treated: intracranial atherosclerotic disease (ICAD, nine patients), complex cervico-petrous carotid disease (five patients), intracranial aneurysms (three patients), and large vessel occlusion-acute ischemic stroke (three patients). Eighteen of the 20 cases were performed with active carotid flow reversal. All cases were successfully completed. There were no access-related complications. One periprocedural complication was incurred: a microguidewire perforation during an exchange maneuver for the treatment of ICAD. CONCLUSION: An open transcarotid approach using a dedicated transcarotid system may offer a safe alternative access strategy for the endovascular treatment of complex neurovascular pathologies when a traditional transfemoral or transradial approach is contraindicated or failed.

The Fate of the Inconclusive Periprosthetic Joint Infection Workup and Reliability of Data Points.

In 2018, periprosthetic joint infection (PJI) criteria were revised to include a new category labeled "inconclusive." The purpose of this study was to characterize and describe the fate of the inconclusive PJI workup and to analyze preoperative factors associated with outcomes. We reviewed all PJI workups at our institution during a 3-year period (426 patients). Patients were labeled "infected," "not infected," or "inconclusive" according to 2018 PJI preoperative criteria. In addition to standard diagnostic variables, the presence or absence of clinical elements that increase the pretest probability of infection were collected. Patients with any missing preoperative diagnostic test results and those with clinical follow-up less than 30 days were excluded. Logistic regression was used to identify the factors associated with infection. Two hundred ninety-six workups remained after exclusion criteria were applied, consisting of 66 (22.2%) with a preoperative score of 6 or greater defined as infected, 52 (17.6%) inconclusive (score 2-5), and 178 (60.1%) not infected (score 0-1). Postoperative re-scoring of the inconclusive group based on intraoperative findings as per the 2018 criteria identified 6 of 52 (11.5%) as infected, 12 (23.1%) inconclusive, and 34 (65.4%) not infected. Among those preoperatively scored as inconclusive, variables statistically correlated with the presence of infection included history of PJI, factors that increase skin barrier penetration (eg, psoriasis and venous stasis), and presence of comorbidities predisposing to infection. For patients labeled inconclusive, clinical elements of the pretest probability for infection (eg, history of prior PJI) were as reliable as any diagnostic test, including alpha-defensin, in the diagnosis of PJI. [Orthopedics. 2023;46(5):e291-e297.].

Higher Hospital Frailty Risk Score is associated with increased complications and healthcare resource utilization after endovascular treatment of ruptured intracranial aneurysms.

AIM: To use the Hospital Frailty Risk Score (HFRS) to investigate the impact of frailty on complication rates and healthcare resource utilization in patients who underwent endovascular treatment of ruptured intracranial aneurysms (IAs). METHODS: A retrospective cohort study was performed using the 2016-2019 National Inpatient Sample database. All adult patients (≥18 years) undergoing endovascular treatment for IAs after subarachnoid hemorrhage were identified using ICD-10-CM codes. Patients were categorized into frailty cohorts: low (HFRS <5), intermediate (HFRS 5-15) and high (HFRS >15). Patient demographics, adverse events, length of stay (LOS), discharge disposition, and total cost of admission were assessed. Multivariate logistic regression analysis was used to identify independent predictors of prolonged LOS, increased cost, and non-routine discharge. RESULTS: Of the 33 840 patients identified, 7940 (23.5%) were found to be low, 20 075 (59.3%) intermediate and 5825 (17.2%) high frailty by HFRS criteria. The rate of encountering any adverse event was significantly greater in the higher frailty cohorts (low: 59.9%; intermediate: 92.4%; high: 99.2%, p<0.001). There was a stepwise increase in mean LOS (low: 11.7±8.2 days; intermediate: 18.7±14.1 days; high: 26.6±20.1 days, p<0.001), mean total hospital cost (low: $62 888±37 757; intermediate: $99 670±63 446; high: $134 937±80 331, p<0.001), and non-routine discharge (low: 17.3%; intermediate: 44.4%; high: 69.4%, p<0.001) with increasing frailty. On multivariate regression analysis, a similar stepwise impact was found in prolonged LOS (intermediate: OR 2.38, p<0.001; high: OR 4.49, p<0.001)], total hospital cost (intermediate: OR 2.15, p<0.001; high: OR 3.62, p<0.001), and non-routine discharge (intermediate: OR 2.13, p<0.001; high: OR 4.17, p<0.001). CONCLUSIONS: Our study found that greater frailty as defined by the HFRS was associated with increased complications, LOS, total costs, and non-routine discharge.

Hospital Frailty Risk Score Predicts Adverse Events and Readmission Following a Ventriculoperitoneal Shunt Surgery for Normal Pressure Hydrocephalus.

OBJECTIVE: The aim of this study was to evaluate the impact of a Hospital Frailty Risk Score (HFRS) on unplanned readmission and health care resource utilization in normal pressure hydrocephalus (NPH) patients undergoing a ventriculoperitoneal (VP) shunt surgery. METHODS: A retrospective cohort study was performed using the 2016-2019 Nationwide Readmission Database. All NPH patients (≥60 years) undergoing a VP shunt surgery were identified using ICD-10-CM diagnostic and procedural codes. Patients were dichotomized into 2 cohorts as follows: Low HFRS (<5) and Intermediate-High HFRS (≥5). A multivariate logistic regression analysis was then used to identify independent predictors of adverse event (AE) and 30- and 90-day readmission. RESULTS: Of 13,262 patients, 4386 (33.1%) had an Intermediate-High HFRS score. A greater proportion of the Intermediate-High HFRS cohort experienced at least one AE (1.9 vs. 22.1, P < 0.001). The Intermediate-High HFRS cohort also had a longer length of stay (2.3 ± 2.4 days vs. 7.0 ± 7.7 days, P < 0.001), higher non-routine discharge rate (19.9% vs. 39.9%, P < 0.001), and greater admission cost ($14,634 ± 5703 vs. $21,749 ± 15,234, P < 0.001). The Intermediate-High HFRS cohort had higher rates of 30- (7.6% vs. 11.0%, P < 0.001) and 90-day (6.8% vs. 8.3%, P < 0.001) readmissions. On a multivariate regression analysis, Intermediate-High HFRS compared to Low HFRS was an independent predictor of any AE (odds ratio, 16.6; 95% confidence interval, [12.9-21.5]; P < 0.001) and 30-day readmission (odds ratio, 1.4; 95% confidence interval, [1.2-1.7]; P < 0.001). CONCLUSIONS: Our study suggests that frailty, as defined by HFRS, is associated with increased resource utilization in NPH patients undergoing VP shunt surgery. Furthermore, HFRS was an independent predictor of adverse events and 30-day hospital readmission.

Dendritic Cell Vaccination in Conjunction with a TLR Agonist Polarizes Interferon Immune Responses in Malignant Glioma Patients.

Autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination is a promising immunotherapy for patients with high grade gliomas, but responses have not been demonstrated in all patients. To determine the most effective combination of autologous tumor lysate-pulsed DC vaccination, with or without the adjuvant toll-like receptor (TLR) agonists poly-ICLC or resiquimod, we conducted a Phase 2 clinical trial in 23 patients with newly diagnosed or recurrent WHO Grade III-IV malignant gliomas. We then performed deep, high-dimensional immune profiling of these patients to better understand how TLR agonists may influence the systemic immune responses induced by ATL-DC vaccination. Bulk RNAseq data demonstrated highly significant upregulation of type 1 and type 2 interferon gene expression selectively in patients who received adjuvant a TLR agonist together with ATL-DC. CyTOF analysis of patient peripheral blood mononuclear cells (PBMCs) showed increased expression of PD-1 on CD4+ T-cells, decreases in CD38 and CD39 on CD8+ T cells and elevated proportion of monocytes after ATL-DC + TLR agonist administration. In addition, scRNA-seq demonstrated a higher expression fold change of IFN-induced genes with poly-ICLC treatment in both peripheral blood monocytes and T lymphocytes. Patients who had higher expression of interferon response genes lived significantly longer and had longer time to progression compared to those with lower expression. The results suggest that ATL-DC in conjunction with adjuvant poly-ICLC induces a polarized interferon response in circulating monocytes and specific activation of a CD8+ T cell population, which may represent an important blood biomarker for immunotherapy in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01204684.

Transcarotid artery revascularization (TCAR): a technical video.

Carotid revascularization is an important method of stroke prevention and includes carotid endarterectomy and transfemoral carotid angioplasty and stenting. More recently, a hybrid open-endovascular approach, termed transcarotid artery revascularization (TCAR), is garnering increased attention. Although fundamentally a 'stenting procedure', unlike transfemoral carotid angioplasty and stenting, TCAR allows for a proximal neuroprotection strategy based on flow reversal. In this technical video, we will review operative techniques and nuances of the TCAR procedure, with a particular focus on the neurovascular proceduralist looking to adopt this technique into routine clinical practice(video 1). neurintsurg;14/8/842/V1F1V1Video 1TCAR Technical Video.