Continuous interscalene versus phrenic nerve-sparing high-thoracic erector spinae plane block for total shoulder arthroplasty: a randomized controlled trial.

PURPOSE: The high-thoracic erector spinae plane block (HT-ESPB) has been reported as an effective analgesic modality for the shoulder region without phrenic nerve palsy. The goal of this study was to compare the HT-ESPB as a phrenic nerve-sparing alternative to an interscalene block for total shoulder arthroplasty. METHODS: Thirty patients undergoing total shoulder arthroplasty at Stanford Health Care (Palo Alto, CA, USA) were enrolled in a double-blind randomized controlled trial. We randomized 28 patients to receive either an interscalene or HT-ESPB perineural catheter preoperatively; 26 patients were included in the final analysis. The study was powered for the primary outcome of incidence of hemidiaphragmatic paralysis in the postanesthesia care unit (PACU). Other outcome measures included incentive spirometry volume, brachial plexus motor and sensory exams, adverse events, pain scores, and opioid consumption. RESULTS: The incidence of hemidiaphragmatic paralysis in the HT-ESPB catheter group was significantly lower than in the interscalene catheter group (0/12, 0% vs 14/14, 100%; P < 0.001). No statistically significant differences were found in pain scores and opioid consumption (in oral morphine equivalents) between the interscalene and HT-ESPB groups through postoperative day (POD) 2. Nevertheless, the mean (standard deviation) point estimates for opioid consumption for the HT-ESPB group were higher than for the interscalene group in the PACU (HT-ESPB: 24.8 [26.7] mg; interscalene: 10.7 [21.7] mg) and for POD 0 (HT-ESPB: 20.5 [25.0] mg; interscalene: 6.7 [12.0] mg). In addition, cumulative postoperative opioid consumption was significantly higher at POD 0 (PACU through POD 0) in the HT-ESPB group (45.3 [39.9] mg) than in the interscalene group (16.6 [21.9] mg; P = 0.04). CONCLUSIONS: This study suggests that continuous HT-ESPB can be a phrenic nerve-sparing alternative to continuous interscalene brachial plexus blockade, although the latter provided superior opioid-sparing in the immediate postoperative period. This was a small sample size study, and further investigations powered to detect differences in analgesic and quality of recovery score endpoints are needed. STUDY REGISTRATION: www. CLINICALTRIALS: gov (NCT03807505); registered 17 January 2019.

RéSUMé: OBJECTIF: Le bloc des muscles érecteurs du rachis du haut thorax (BMER-HT) a été rapporté comme une modalité analgésique efficace pour la région de l'épaule et ce, sans paralysie du nerf phrénique. L'objectif de cette étude était de comparer ce bloc en tant qu'alternative épargnant le nerf phrénique à un bloc interscalénique pour l'arthroplastie totale de l'épaule. MéTHODE: Trente patients bénéficiant d'une arthroplastie totale de l'épaule au centre de soins Stanford Health Care (Palo Alto, CA, États-Unis) ont été recrutés dans une étude randomisée contrôlée à double insu. Nous avons randomisé 28 patients à recevoir un cathéter périneural interscalénique ou un BMER-HT en préopératoire; 26 patients ont été inclus dans l'analyse finale. Le calcul de puissance de l'étude a été effectué pour répondre au critère d'évaluation principal, qui était l'incidence de paralysie hémidiaphragmatique en salle de réveil. Les autres issues mesurées comprenaient les volumes de spirométrie, les examens moteurs et sensoriels du plexus brachial, les événements indésirables, les scores de douleur et la consommation d'opioïdes. RéSULTATS: L'incidence de paralysie hémidiaphragmatique dans le groupe cathéter BMER-HT était significativement plus faible que dans le groupe cathéter interscalénique (0/12, 0 % vs 14/14, 100 %; P < 0,001). Aucune différence statistiquement significative n'a été observée dans les scores de douleur et la consommation d'opioïdes (en équivalents morphine par voie orale) entre les groupes interscalénique et BMER-HT jusqu'au jour postopératoire (JPO) 2. Néanmoins, en salle de réveil, les estimations ponctuelles moyennes (écart type) de la consommation d'opioïdes pour le groupe BMER-HT étaient plus élevées que pour le groupe interscalénique (BMER-HT : 24,8 [26,7] mg; interscalénique : 10,7 [21,7] mg), ainsi qu'au JPO 0 (BMER-HT : 20,5 [25,0] mg; interscalénique: 6,7 [12,0] mg). De plus, la consommation cumulative d'opioïdes postopératoires était significativement plus élevée au JPO 0 (salle de réveil jusqu'au JPO 0) dans le groupe BMER-HT (45,3 [39,9] mg) que dans le groupe interscalénique (16,6 [21,9] mg; P = 0,04). CONCLUSION: Cette étude suggère que le BMER-HT continu peut être une alternative au bloc interscalénique continu du plexus brachial pour épargner le nerf phrénique, bien que le bloc interscalénique ait fourni une épargne d'opioïdes supérieure en période postopératoire immédiate. Il s'agissait d'une étude de petite taille d'échantillon, et d'autres études visant à détecter les différences dans les scores des critères d'évaluation en matière d'analgésie et de qualité de la récupération sont nécessaires. ENREGISTREMENT DE L'éTUDE: www.clinicaltrials.gov (NCT03807505); enregistrée le 17 janvier 2019.

Radiographic assessment of surgical treatment of post-traumatic syringomyelia.

Context: Symptomatic post-traumatic syringomyelia can affect the quality of life in patients whose neurologic function has already been impacted by a spinal cord injury.Objective: To investigate the radiographic and clinical outcomes following surgery for syringomyelia, we present a literature review along with a case series from a single surgeon's experience.Methods: A retrospective review was conducted on patients with post-traumatic syringomyelia who were treated by a single surgeon. Thirty-four patients who underwent surgical treatment consisting of syrinx fenestration, lysis of adhesions, and duraplasty were identified. In addition, a narrative literature review was conducted with a primary focus on diagnosis and management of post-traumatic syringomyelia.Results: Literature review suggests that regardless of age, sex, vertebral location, or severity of trauma, patients who experience a spinal cord injury should be closely monitored for post-traumatic syringomyelia. Retrospective review of our 34 patients revealed 24 patients for whom pre- and post- operative MRI was available. The predominant location of the injury was cervical (15). The average syrinx length, measured in spinal segments, was similar when comparing pre- and post-operative MRIs; average syrinx length was 5.5 and 5.4 spinal segments, respectively. In contrast, syrinx axial dimension was decreased in 16 of the patients post-operatively and stable or increased in the other eight. The change in syrinx size did not correlate with clinical outcomes.Conclusion: Current surgical treatment of post-traumatic syringomyelia involves restoration of normal CSF flow dynamics; further prospective work is needed to correlate the clinical state, radiographic measures, and efficacy of surgical intervention.

Tumor-induced peripheral immunosuppression promotes brain metastasis in patients with non-small cell lung cancer.

INTRODUCTION: Brain metastases are a significant source of morbidity and mortality for patients with lung cancer. Lung cancer can induce local and systemic immunosuppression, promoting tumor growth and dissemination. One mechanism of immunosuppression is tumor-induced expansion of programmed death-ligand 1 (PD-L1) expressing myeloid cells. Here, we investigate peripheral blood immune phenotype in NSCLC patients with or without brain metastasis. METHODS: Peripheral blood was collected from patients with lung metastatic brain tumors and pre-metastatic lung cancer. Immunosuppressive monocytes, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) were quantified through flow cytometry. T cell reactivity was analyzed via ELISpot. Brain metastasis conditioned media was collected from tumor-derived cell cultures and analyzed for cytokines by ELISA. Naïve monocytes were stimulated with brain metastasis conditioned media to evaluate PD-L1 stimulation. RESULTS: Patients with brain metastatic lung carcinoma demonstrated increased peripheral monocyte PD-L1, MDSC abundance, and Treg percentage compared to early stage pre-metastatic patients and healthy controls. Patients with elevated peripheral monocyte PD-L1 had less reactive T cells and worse survival. Brain metastasis conditioned media stimulation increased monocyte PD-L1, and conditioned media IL-6 levels correlated with PD-L1 induction. Treatment with anti-IL-6 or anti-IL-6 receptor antibodies reduced PD-L1 expression. In summary, patients with lung cancer and brain metastases exhibit multiple markers of peripheral immunosuppression. CONCLUSIONS: The frequency of PD-L1+ myeloid cells correlated with the presence of brain metastases. Tumor-derived IL-6 was capable of inducing PD-L1+ myeloid cells in vitro, suggesting that monitoring of immunosuppressive factors in peripheral blood may identify new targets for therapeutic intervention in selected patients.

Systemic and local immunosuppression in patients with high-grade meningiomas.

AIM: Despite current treatments, high-grade meningiomas continue to have a poor prognosis. Immunotherapy targeting immune checkpoints, such as PD-L1, has demonstrated significant success in controlling numerous malignancies. In this study, we investigate the extent of systemic and local immunosuppression in meningiomas to assess the potential benefit of immune checkpoint inhibitors for the treatment of high-grade meningiomas. METHODS: Peripheral blood was collected from patients undergoing resection of meningiomas (WHO grade I, n = 18; grade II, n = 25; grade III, n = 10). Immunosuppressive myeloid cells (CD45+CD11b+PD-L1+), myeloid-derived suppressor cells (MDSCs) (CD11b+CD33+HLA-DRlow), and regulatory T cells (Tregs) (CD3+CD4+CD25+FoxP3+) were quantified through flow cytometry. Tissue sections from the same patients were assessed for PD-L1 expression and T cell infiltration via immunohistochemistry. RESULTS: Patients with grade III meningiomas demonstrated increased peripheral monocyte PD-L1 compared to patients with grade I/II meningiomas and healthy controls. Peripheral MDSC abundance was increased in grades II and III meningioma patients. PD-L1 staining of meningioma tissue demonstrated increased positivity in grade III meningiomas. Intratumoral PD-L1 was not associated with progression-free survival. High-grade meningiomas had increased T-cell infiltration. However, a significant proportion of these T cells were exhausted PD1+ T cells and immunosuppressive Tregs. CONCLUSIONS: Patients with meningiomas exhibit signs of peripheral immunosuppression, including increased PD-L1 on myeloid cells and elevated MDSC abundance proportional to tumor grade. Additionally, the tumors express substantial PD-L1 proportional to tumor grade. These results suggest a role for immune checkpoint inhibitors targeting the PD-L1/PD-1 pathway in combination with standard therapies for the treatment of high-grade meningiomas.

Lymphopenia predicts response to stereotactic radiosurgery in lung cancer patients with brain metastases.

BACKGROUND: Stereotactic radiosurgery (SRS) can enhance immune activation and improve disease control through stimulation of anti-tumor immunity. However, patients with cancer receiving chemotherapy are often immunosuppressed, which may impact the efficacy of SRS. Here we investigate the relationship between systemic lymphopenia and response to SRS in patients with brain-metastatic lung cancer. METHODS: We reviewed 125 patients with lung cancer brain metastases treated with SRS between January 2014 and May 2017. Complete blood counts from the time of SRS were reviewed, and lymphopenia was defined as absolute lymphocyte count < 1×109 cells/L. Kaplan-Meier survival analysis and cox proportional-hazards models were used to evaluate risks of progression and death. RESULTS: The median age was 65 years (range 43-86), with 54% female patients. Lymphopenia was present in 60 patients. In univariate analysis, lymphopenic patients had significantly shorter PFS (HR = 2.995, p < 0.0001) and OS (HR = 3.928, p < 0.0001). When accounting for age, gender, smoking history, ECOG score, surgery, and tumor histology in a multivariate model, lymphopenia remained significantly predictive of worse PFS (HR = 1.912, p = 0.002) and OS (HR = 2.257, p < 0.001). Patients who received immunotherapy within 3 months of SRS demonstrated significantly shorter PFS (HR = 3.578, p = 0.006) and OS (HR = 6.409, p = 0.001) if lymphopenic. CONCLUSIONS: Brain-metastatic lung cancer patients with lymphopenia treated with SRS had significantly worse PFS and OS. The effect of lymphopenia was even more pronounced in patients receiving immunotherapy. These data demonstrate the significant impact of deficient immunity on disease control and survival. Lymphopenic patients may benefit from interventions to improve immune function prior to SRS for brain metastases.

Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth.

PURPOSE: Upregulation of programmed death-ligand 1 (PD-L1) on circulating and tumor-infiltrating myeloid cells is a critical component of GBM-mediated immunosuppression that has been associated with diminished response to vaccine immunotherapy and poor survival. Although GBM-derived soluble factors have been implicated in myeloid PD-L1 expression, the identity of such factors has remained unknown. This study aimed to identify factors responsible for myeloid PD-L1 upregulation as potential targets for immune modulation. EXPERIMENTAL DESIGN: Conditioned media from patient-derived GBM explant cell cultures was assessed for cytokine expression and utilized to stimulate naïve myeloid cells. Myeloid PD-L1 induction was quantified by flow cytometry. Candidate cytokines correlated with PD-L1 induction were evaluated in tumor sections and plasma for relationships with survival and myeloid PD-L1 expression. The role of identified cytokines on immunosuppression and survival was investigated in vivo utilizing immunocompetent C57BL/6 mice bearing syngeneic GL261 and CT-2A tumors. RESULTS: GBM-derived IL6 was identified as a cytokine that is necessary and sufficient for myeloid PD-L1 induction in GBM through a STAT3-dependent mechanism. Inhibition of IL6 signaling in orthotopic murine glioma models was associated with reduced myeloid PD-L1 expression, diminished tumor growth, and increased survival. The therapeutic benefit of anti-IL6 therapy proved to be CD8+ T-cell dependent, and the antitumor activity was additive with that provided by programmed death-1 (PD-1)-targeted immunotherapy. CONCLUSIONS: Our findings suggest that disruption of IL6 signaling in GBM reduces local and systemic myeloid-driven immunosuppression and enhances immune-mediated antitumor responses against GBM.

The immune checkpoint protein PD-L1 induces and maintains regulatory T cells in glioblastoma.

Glioblastoma (GBM) promotes immunosuppression through upregulation of PD-L1 and regulatory T cell (Treg) expansion, but the association of these suppressive factors has not been well elucidated. Here, we investigate a role of PD-L1 in expanding Tregs and the value of targeting the PD-1 receptor to inhibit Treg expansion. Quantitative RNA sequencing data from The Cancer Genome Atlas were evaluated for an association between CD274 and FOXP3 transcript expressions and impact of FOXP3 on clinical outcomes. Peripheral leukocytes from patients with newly diagnosed GBM were profiled for PD-L1+ myeloid expressions and Treg abundance. Healthy lymphocytes were assessed for impact of recombinant PD-L1 on expansion of the inducible Treg (iTreg) population. iTreg function was evaluated by the capacity to suppress effector T cell proliferation. Specificity of responses were confirmed by pharmacologic inhibition of the PD-1 receptor. Increased PD-L1 mRNA expression in GBM corresponded to increased FOXP3 mRNA (p = 0.028). FOXP3 elevation had a negative impact on overall survival (HR = 2.0; p < 0.001). Peripheral PD-L1 positivity was associated with an increased Treg fraction (p = 0.008). Lymphocyte activation with PD-L1 co-stimulation resulted in greater iTreg expansion compared to activation alone (18.3% vs. 6.5%; p < 0.001) and improved preservation of the Treg phenotype. Suppressive capacity on naïve T cell proliferation was sustained. Nivolumab inhibited PD-L1-induced Treg expansion (p < 0.001). These results suggest that PD-L1 may expand and maintain immunosuppressive Tregs, which are associated with decreased survival in glioma patients. Blockade of the PD-L1/PD-1 axis may reduce Treg expansion and further improve T cell function beyond the direct impact on effector cells.

Disrupted female estrous cyclicity in the intrahippocampal kainic acid mouse model of temporal lobe epilepsy.

OBJECTIVE: Reproductive dysfunction is a comorbidity that commonly occurs with temporal lobe epilepsy (TLE). Characterization of this comorbidity in various models of TLE in mice will greatly facilitate mechanistic investigations of the relationship between reproductive disorders and seizures initiated in the hippocampus. Here we investigate the impact on female reproductive estrous cyclicity in the intrahippocampal kainic acid mouse model of TLE and demonstrate the utility of using this model for future mechanistic studies. METHODS: Kainic acid (KA) or saline vehicle was stereotaxically injected in the right dorsal hippocampus of adult female C57BL/6J mice. Development of epilepsy was assessed by video monitoring for behavioral seizures. Reproductive function was assessed by daily estrous cycle monitoring and ovarian morphology. Estrous cycles were monitored for up to 2 months after injection. Ovarian morphology was examined by histological staining and assessment of follicular and luteal development. RESULTS: We observed spontaneous behavioral seizures in 82% of kainic-acid-treated mice. Irregular estrous cycles developed within 2 months after kainic acid injection. Sixty-seven percent of KA-treated mice showed disrupted estrous cycles, typically characterized by increased estrous cycle length, increased time spent in diestrus (nonfertile stage), and decreased time spent in estrus by 42 days post-KA injection. The estrous cycle disruption, however, was not accompanied by major changes in ovarian morphology or follicular development. KA-treated mice also displayed increased weight gain compared to control mice. SIGNIFICANCE: These data indicate that comorbid female irregular estrous cyclicity arises in the intrahippocampal kainic acid mouse model of TLE. This is the first demonstration of disrupted reproductive endocrine function in a mouse model of TLE initially produced by an insult specifically targeted to the hippocampus. This model should thus be useful for basic studies investigating the neural mechanisms driving comorbid reproductive dysfunction in epilepsy in women.