Intraoperative Closed Reduction of Traumatic Lateraloptosis: Operative Nuances.

BACKGROUND AND IMPORTANCE: Traumatic lateral spondyloptosis, or lateraloptosis, is the complete lateral dislocation of the spine. Reduction in these dislocations presents unique challenges, especially in cases of preserved neurological function. Open techniques carry significant risks of cerebrospinal fluid leak and neurological injury. For traditional spondyloptosis, off-table closed techniques have been described but may result in loss of the reduction when the patient is transferred to the operative table. An on-table closed reduction technique has potential advantages over previously described open reduction or off-table techniques for the treatment of lateraloptosis. CLINICAL PRESENTATION: The authors describe an on-table closed reduction technique for lateraloptosis, presenting an illustrative case in which the technique was applied. This technique is compared with alternative open and off-table reduction techniques described in the literature. The patient had good mechanical and neurological outcomes. At 14 months postoperatively, she is neurologically intact, back to work involving heavy lifting, and has only moderate back pain. CONCLUSION: On-table closed reduction before open fixation should be considered in cases of lateraloptosis, particularly when there is preserved neurological function.

Percutaneous transluminal angioplasty or stenting of petrous and cavernous internal carotid artery stenosis - a systematic review.

Percutaneous transluminal angioplasty (PTA) and stenting have been used for the treatment of internal carotid artery (ICA) stenosis over the past two decades. A systematic review was performed to understand the efficacy of PTA and/or stenting for petrous and cavernous ICA stenosis. In total, 151 patients (mean age 64.9) met criteria for analysis, 117 (77.5%%) were male and 34 (22.5%) were female. Of the 151 patients, 35 of them (23.2%) had PTA, and 116 (76.8%) had endovascular stenting. Twenty-two patients had periprocedural complications. There was no significant difference in the complication rates between the PTA (14.3%) and stent (14.7%) groups. Distal embolism was the most common periprocedural complication. Average clinical follow up for 146 patients was 27.3 months. Eleven patients (7.5%) out of 146 had retreatment. The treatment of petrous and cavernous ICA with PTA and stenting has relatively significant procedure related complication rates and adequate long-term patency.

Predictors of aneurysmal occlusion following intracranial aneurysms treatment with pipeline embolization device.

PURPOSE: Pipeline embolization device (PED) is thought to induce aneurysmal occlusion through diversion of flow away from the aneurysmal sac with subsequent thrombosis and endothelialization. The impact of different factors especially hypertension (HTN)-a known predisposing factor to hypercoagulability and altered endothelial function-on aneurysmal occlusion after flow diversion has not been studied. We sought to determine predictors of aneurysmal occlusion following PED treatment focusing on impact of blood pressure. METHODS: Database of patients with cerebral aneurysms treated with PED from 2013 to 2019 at our institution was retrospectively reviewed. Patients were defined as hypertensive if (1) they had a documented history of HTN requiring anti-HTN medications or (2) average systolic blood pressure on three measurements was > 130 mmHg. The primary outcome was aneurysm occlusion status at the last imaging follow-up. Multivariable logistic regression model was constructed to assess the effect of HTN on occlusion, controlling for age, smoking, aneurysmal size, fusiform morphology, posterior circulation location, and incorporated branches. RESULTS: A total of 331 aneurysms in 294 patients were identified for this analysis. The mean age was 59 years (79.9% female). Fifty-five percent of the cohort were classified as hypertensive. When controlling for other potential confounders, hypertensive patients trended toward higher odds of achieving complete occlusion compared to non-hypertensive patients (OR = 2.05; 95% CI = 0.99-4.25; p = 0.052). Meanwhile, age (OR = 0.91; 95% CI = 0.88-0.95; p < 0.001) and an incorporated branch into an aneurysm (OR = 0.22; 95% CI = 0.08-0.58; p < 0.002) were associated with decreased odds for complete aneurysmal occlusion. CONCLUSION: Hypertensive patients show a trend toward higher odds of achieving complete occlusion when controlling for potential confounders. The HTN-induced hypercoagulable state, enhanced endothelial activation, and altered extracellular matrix regulation might be the contributing factors. Further research is warranted to explore clinical implications of these findings.

Cost-Effectiveness Analytic Comparison of Neuroimaging Follow-Up Strategies After Pipeline Embolization Device Treatment of Unruptured Intracranial Aneurysms.

BACKGROUND: Flow diversion via a Pipeline embolization device (PED [Medtronic, Dublin, Ireland]) is one of the established modalities for the treatment of unruptured intracranial aneurysms that require a robust follow-up regimen. However, to date, no consensus has been reached regarding the optimal imaging modality and timing intervals for such a strategy. We studied the cost-effectiveness of different neuroimaging follow-up strategies after flow diversion with the PED. METHODS: A decision-analytical study using Markov modeling was performed to compare 5 commonly used multistep follow-up strategies with different combinations of digital subtraction angiography (DSA) and magnetic resonance angiography (MRA): 1) DSA at 6 months and MRA at 12 and 24 months; 2) DSA at 6, 12, and 24 months; 3) MRA at 6, 12, and 24 months; 4) DSA at 6 and 12 months and MRA at 24 months; and 5) DSA at 12 months and MRA at 24 months. The input parameters were mainly collected from the latest meta-analysis, and 1-way, 2-way, and probabilistic sensitivity analyses were conducted to assess the robustness of our model. RESULTS: Strategy 5, incorporating DSA at 12 months and MRA at 24 months, was the most cost-effective strategy for >99% of the 10,000 iterations in the probabilistic sensitivity analysis at a willingness-to-pay threshold of $100,000/quality-adjusted life-year. The result remained robust in the 1- and 2-way sensitivity analyses. CONCLUSIONS: Given the current data, delayed imaging follow-up at 1 year with DSA and 2 years with MRA after PED treatment of unruptured intracranial aneurysms is more cost-effective than early follow-up at 6 months.

Longitudinal Cost Profiles of Pipeline Embolization Device Versus Stent-Assisted Coiling in Propensity-Matched Unruptured Small Anterior Circulation Aneurysms.

BACKGROUND: The cost profiles of stent-assisted coiling (SAC) vs Pipeline embolization device (PED) in small unruptured anterior circulation aneurysms have not been studied. OBJECTIVE: To compare the 2 modalities cost profiles in a propensity-matched cohort controlling for potential technical complexity confounders including size and location. METHODS: Patients treated with either SAC or PED at our institution were identified. Following propensity-score algorithm, 46 patients, 23 in each group were matched. The procedural and follow-up costs in each group were analyzed and compared. RESULTS: Median maximal aneurysm size in the SAC and PED cohort were 5.3 vs 5.1 mm, respectively. Costs of access guide materials were significantly higher in the SAC group (P < .01). The average implant cost was not significantly different between the SAC and PED cohorts (${\$}$13973.2 ± ${\$}$2886.2 vs ${\$}$14,760.7 ± ${\$}$3782.1, respectively; P = .43). Similarly, total procedural costs were not different (${\$}$18341.5 ± 4104 vs ${\$}$17484.3 ± 2914.1, respectively, P = .42). Although there were significantly more total follow-ups (P = .02) and longer follow-up duration (P = .01) in SAC cohort, no significant difference in follow-up costs between the 2 groups was identified (${\$}$20557 ± ${\$}$9247 vs ${\$}$18958 ± ${\$}$9171.9, P = .56). Overall cost was similar between the SAC (${\$}$38898.9 ± ${\$}$9645.5) and PED groups (${\$}$36442.4 ± ${\$}$9076) (P = .38). CONCLUSION: In small unruptured anterior circulation aneurysms (excluding anterior communicating artery aneurysms) matched for technical complexity confounders, SAC and PED offer an overall equivalent economic cost profile. Postprocedural noninvasive imaging was more frequent in the SAC group. However, follow-up costs and total costs were not significantly different.

Cerebral Venous Sinus Thromboses in Patients with SARS-CoV-2 Infection: Three Cases and a Review of the Literature.

INTRODUCTION: Early studies suggest that acute cerebrovascular events may be common in patients with coronavirus disease 2019 (COVID-19) and may be associated with a high mortality rate. Most cerebrovascular events described have been ischemic strokes, but both intracerebral hemorrhage and rarely cerebral venous sinus thrombosis (CVST) have also been reported. The diagnosis of CVST can be elusive, with wide-ranging and nonspecific presenting symptoms that can include headache or altered sensorium alone. OBJECTIVE: To describe the presentation, barriers to diagnosis, treatment, and outcome of CVST in patients with COVID-19. METHODS: We abstracted data on all patients diagnosed with CVST and COVID-19 from March 1 to August 9, 2020 at Boston Medical Center. Subsequently, we reviewed the literature and extracted all published cases of CVST in patients with COVID-19 from January 1, 2020 through August 9, 2020 and included all studies with case descriptions. RESULTS: We describe the clinical features and management of CVST in 3 women with COVID-19 who developed CVST days to months after initial COVID-19 symptoms. Two patients presented with encephalopathy and without focal neurologic deficits, while one presented with visual symptoms. All patients were treated with intravenous hydration and anticoagulation. None suffered hemorrhagic complications, and all were discharged home. We identified 12 other patients with CVST in the setting of COVID-19 via literature search. There was a female predominance (54.5%), most patients presented with altered sensorium (54.5%), and there was a high mortality rate (36.4%). CONCLUSIONS: During this pandemic, clinicians should maintain a high index of suspicion for CVST in patients with a recent history of COVID-19 presenting with non-specific neurological symptoms such as headache to provide expedient management and prevent complications. The limited data suggests that CVST in COVID-19 is more prevalent in females and may be associated with high mortality.

Melanoma Evolves Complete Immunotherapy Resistance through the Acquisition of a Hypermetabolic Phenotype.

Despite the clinical success of T-cell checkpoint blockade, most patients with cancer still fail to have durable responses to immunotherapy. The molecular mechanisms driving checkpoint blockade resistance, whether preexisting or evolved, remain unclear. To address this critical knowledge gap, we treated B16 melanoma with the combination of CTLA-4, PD-1, and PD-L1 blockade and a Flt3 ligand vaccine (≥75% curative), isolated tumors resistant to therapy, and serially passaged them in vivo with the same treatment regimen until they developed complete resistance. Using gene expression analysis and immunogenomics, we determined the adaptations associated with this resistance phenotype. Checkpoint resistance coincided with acquisition of a "hypermetabolic" phenotype characterized by coordinated upregulation of the glycolytic, oxidoreductase, and mitochondrial oxidative phosphorylation pathways. These resistant tumors flourished under hypoxic conditions, whereas metabolically starved T cells lost glycolytic potential, effector function, and the ability to expand in response to immunotherapy. Furthermore, we found that checkpoint-resistant versus -sensitive tumors could be separated by noninvasive MRI imaging based solely on their metabolic state. In a cohort of patients with melanoma resistant to both CTLA-4 and PD-1 blockade, we observed upregulation of pathways indicative of a similar hypermetabolic state. Together, these data indicated that melanoma can evade T-cell checkpoint blockade immunotherapy by adapting a hypermetabolic phenotype.

Merger of dynamic two-photon and phosphorescence lifetime microscopy reveals dependence of lymphocyte motility on oxygen in solid and hematological tumors.

BACKGROUND: Low availability of oxygen in tumors contributes to the hostility of the tumor microenvironment toward the immune system. However, the dynamic relationship between local oxygen levels and the immune surveillance of tumors by tumor infiltrating T-lymphocytes (TIL) remains unclear. This situation reflects a methodological difficulty in visualizing oxygen gradients in living tissue in a manner that is suitable for spatiotemporal quantification and contextual correlation with individual cell dynamics tracked by typical fluorescence reporter systems. METHODS: Here, we devise a regimen for intravital oxygen and cell dynamics co-imaging, termed 'Fast' Scanning Two-photon Phosphorescence Lifetime Imaging Microscopy (FaST-PLIM). Using FaST-PLIM, we image the cellular motility of T-lymphocytes in relation to the microscopic distribution of oxygen in mouse models of hematological and solid tumors, namely in bone marrow with or without B-cell acute lymphocytic leukemia (ALL), and in lungs with sarcoma tumors. RESULTS: Both in bone marrow leukemia and solid tumor models, TILs encountered regions of varying oxygen concentrations, including regions of hypoxia (defined as pO2 below 5 mmHg), especially in advanced-stage ALL and within solid tumor cores. T cell motility was sustained and weakly correlated with local pO2 above 5 mmHg but it was very slow in pO2 below this level. In solid tumors, this relationship was reflected in slow migration of TIL in tumor cores compared to that in tumor margins. Remarkably, breathing 100% oxygen alleviated tumor core hypoxia and rapidly invigorated the motility of otherwise stalled tumor core TILs. CONCLUSIONS: This study demonstrates a versatile and highly contextual FaST-PLIM method for phosphorescence lifetime-based oxygen imaging in living animal tumor immunology models. The initial results of this method application to ALL and solid lung tumor models highlight the importance of oxygen supply for the maintenance of intratumoral T cell migration, define a 5 mmHg local oxygen concentration threshold for TIL motility, and demonstrate efficacy of supplementary oxygen breathing in TIL motility enhancement coincident with reduction of tumor hypoxia.

Glioblastoma stem cell-derived exosomes induce M2 macrophages and PD-L1 expression on human monocytes.

Exosomes can mediate a dynamic method of communication between malignancies, including those sequestered in the central nervous system and the immune system. We sought to determine whether exosomes from glioblastoma (GBM)-derived stem cells (GSCs) can induce immunosuppression. We report that GSC-derived exosomes (GDEs) have a predilection for monocytes, the precursor to macrophages. The GDEs traverse the monocyte cytoplasm, cause a reorganization of the actin cytoskeleton, and skew monocytes toward the immune suppresive M2 phenotype, including programmed death-ligand 1 (PD-L1) expression. Mass spectrometry analysis demonstrated that the GDEs contain a variety of components, including members of the signal transducer and activator of transcription 3 (STAT3) pathway that functionally mediate this immune suppressive switch. Western blot analysis revealed that upregulation of PD-L1 in GSC exosome-treated monocytes and GBM-patient-infiltrating CD14+ cells predominantly correlates with increased phosphorylation of STAT3, and in some cases, with phosphorylated p70S6 kinase and Erk1/2. Cumulatively, these data indicate that GDEs are secreted GBM-released factors that are potent modulators of the GBM-associated immunosuppressive microenvironment.

Ionizing radiation augments glioma tropism of mesenchymal stem cells.

OBJECTIVE Mesenchymal stem cells (MSCs) have been shown to localize to gliomas after intravascular delivery. Because these cells home to areas of tissue injury, the authors hypothesized that the administration of ionizing radiation (IR) to tumor would enhance the tropism of MSCs to gliomas. Additionally, they sought to identify which radiation-induced factors might attract MSCs. METHODS To assess the effect of IR on MSC migration in vitro, transwell assays using conditioned medium (CM) from an irradiated commercially available glioma cell line (U87) and from irradiated patient-derived glioma stem-like cells (GSCs; GSC7-2 and GSC11) were employed. For in vivo testing, green fluorescent protein (GFP)-labeled MSCs were injected into the carotid artery of nude mice harboring orthotopic U87, GSC7-2, or GSC17 xenografts that were treated with either 0 or 10 Gy of IR, and brain sections were quantitatively analyzed by immunofluorescence for GFP-positive cells. These GSCs were used because GSC7-2 is a weak attractor of MSCs at baseline, whereas GSC17 is a strong attractor. To determine the factors implicated in IR-induced tropism, CM from irradiated GSC7-2 and from GSC11 was assayed with a cytokine array and quantitative ELISA. RESULTS Transwell migration assays revealed statistically significant enhanced MSC migration to CM from irradiated U87, GSC7-2, and GSC11 compared with nonirradiated controls and in a dose-dependent manner. After their intravascular delivery into nude mice harboring orthotopic gliomas, MSCs engrafted more successfully in irradiated U87 (p = 0.036), compared with nonirradiated controls. IR also significantly increased the tropism of MSCs to GSC7-2 xenografts (p = 0.043), which are known to attract MSCs only poorly at baseline (weak-attractor GSCs). Ionizing radiation also increased the engraftment of MSCs in strong-attractor GSC17 xenografts, but these increases did not reach statistical significance. The chemokine CCL2 was released by GSC7-2 and GSC11 after irradiation in a dose-dependent manner and mediated in vitro transwell migration of MSCs. Immunohistochemistry revealed increased CCL2 in irradiated GSC7-2 gliomas near the site of MSC engraftment. CONCLUSIONS Administering IR to gliomas enhances MSC localization, particularly in GSCs that attract MSCs poorly at baseline. The chemokine CCL2 appears to play a crucial role in the IR-induced tropism of MSCs to gliomas.

TGF-ß mediates homing of bone marrow-derived human mesenchymal stem cells to glioma stem cells.

Although studies have suggested that bone marrow human mesenchymal stem cells (BM-hMSC) may be used as delivery vehicles for cancer therapy, it remains unclear whether BM-hMSCs are capable of targeting cancer stem cells, including glioma stem cells (GSC), which are the tumor-initiating cells responsible for treatment failures. Using standard glioma models, we identify TGF-ß as a tumor factor that attracts BM-hMSCs via TGF-ß receptors (TGFßR) on BM-hMSCs. Using human and rat GSCs, we then show for the first time that intravascularly administered BM-hMSCs home to GSC-xenografts that express TGF-ß. In therapeutic studies, we show that BM-hMSCs carrying the oncolytic adenovirus Delta-24-RGD prolonged the survival of TGF-ß-secreting GSC xenografts and that the efficacy of this strategy can be abrogated by inhibition of TGFßR on BM-hMSCs. These findings reveal the TGF-ß/TGFßR axis as a mediator of the tropism of BM-hMSCs for GSCs and suggest that TGF-ß predicts patients in whom BM-hMSC delivery will be effective.

The bone marrow microenvironment as niche retreats for hematopoietic and leukemic stem cells.

Leukemia poses a serious challenge to current therapeutic strategies. This has been attributed to leukemia stem cells (LSCs), which occupy endosteal and sinusoidal niches in the bone marrow similar to those of hematopoietic stem cells (HSCs). The signals from these niches provide a viable setting for the maintenance, survival, and fate specifications of these stem cells. Advancements in genetic engineering and microscopy have enabled us to critically deconstruct and analyze the anatomic and functional characteristics of these niches to reveal a wealth of new knowledge in HSC biology, which is quite ahead of LSC biology. In this paper, we examine the present understanding of the regulatory mechanisms governing HSC niches, with the goals of providing a framework for understanding the mechanisms of LSC regulation and suggesting future strategies for their elimination.