The Negative Prognostic Role of Inflammatory Biomarkers in Patients With Chronic Cerebrospinal Venous Insufficiency.

BACKGROUND: The pathologic consequences of inflammatory responses in chronic cerebrospinal venous insufficiency (CCSVI) remains poorly understood. Hence, this study was aimed to evaluate the peripheral inflammatory biomarkers in patients with intracranial and extracranial CCSVI pathology. In addition, the relationship between inflammatory cytokine profile and CCSVI prognosis was also evaluated. METHODS: Patients diagnosed with CCSVI between July 2017 and July 2019 were included and subsequently divided into 3 groups based on the location of stenosis. The inflammatory biomarker assay included neutrophil-to-lymphocyte ratios (NLRs), platelet-to-lymphocyte ratios (PLRs), red blood cell distribution widths (RDW), C-reactive protein (CRP) levels, interleukin-6 (IL-6) levels, and neuron-specific enolase levels. Clinical outcomes were assessed using the modified Rankin Scale and Patient Global Impression of Change score. Univariate and multivariate regression analyses were performed to identify significant prognostic factors for poorer outcomes. Finally, we established a nomogram based on the multivariate regression analysis. RESULTS: We enrolled 248 patients in total, including 102 males and 146 females, with an average age of 57.85±12.28 years. Compared with patients with internal jugular vein stenosis, cerebral venous sinus stenosis (CVSS) patients were mostly younger and had been suffering from headaches and severe papilledema. Higher levels of NLR, RDW, and CRP were also observed in the CVSS group. Multivariate analysis indicated that NLR, PLR, and IL-6 were the independent prognostic factors for poor CCSVI outcomes. CONCLUSIONS: The clinical presentations and increases in NLR, PLR, IL-6, and CRP levels could be distinctly marked in patients with CVSS-related CCSVI than that in internal jugular vein stenosis-related CCSVI, indicating poor prognostic outcomes in these patients. A proinflammatory state might be associated with CCSVI pathology.

Potential Anti-Inflammatory and Anti-Coagulation Effects of One-Time Application of Remote Ischemic Conditioning in Patients With Subacute/Chronic Cerebral Arteriostenosis and Venostenosis.

BACKGROUND: Remote ischemic conditioning (RIC) is an extremely simple, non-invasive, and cost-effective method with a neuroprotective effect. This study aimed to evaluate the immediate effects of one-time application of RIC on inflammation and coagulation in patients with chronic cerebral vascular stenosis, and compare the different effects of RIC on cerebral arteriostenosis and cerebral venostenosis. METHOD: A total of 47 patients with defined cerebral arteriostenosis (n=21) or venostenosis (n=26) were prospectively enrolled. RIC intervention was given once with 5 cycles of inflating and deflating for 5 minutes alternately. Blood was sampled 5 minutes before and after RIC for inflammatory and thrombophilia biomarkers. Differences in inflammatory and thrombotic variables at differing time points in the group were assessed using paired t tests or Wilcoxon matched-pairs signed-rank test. RESULTS: Patients with cerebral arteriostenosis had a higher level of pre-RIC neutrophil-to-lymphocyte ratio ( P =0.034), high-sensitivity C-reactive protein ( P =0.037), and fibrinogen ( P =0.002) than that with cerebral venostenosis. In the arterial group, levels of fibrinogen ( P =0.023) decreased, and interleukin-6 levels were elevated ( P =0.019) after a single RIC. Age was negatively related to interleukin-6, C-reactive protein, and fibrinogen. CONCLUSION: One-time RIC interventions may show seemingly coexisted proinflammatory and anti-coagulation effects of a single bout on patients with cerebral arteriostenosis. Older age was a negative predictor for multiple biomarkers in the cerebral arteriostensosis group. The protective effect of RIC on cerebral venostenosis patients needs to be further studied in a larger sample size.

Use of Batroxobin in Central and Peripheral Ischemic Vascular Diseases: A Systematic Review.

Background and Purpose: The mechanism of action of Batroxobin included the decomposition of the fibrinogen to fibrin degradation products (FDPs) and D-dimer and mobilization of endothelial cells to release endogenous nt-PA and to promote thrombolysis. This review aims to summarize current study findings about batroxobin on correcting cerebral arterial, venous, and peripheral vascular diseases, to explore the mechanism of batroxobin on anti-thrombosis process. Methods: A thorough literature search was conducted utilizing the PubMed Central (PMC) and EMBASE databases to identify studies up to June 2021. Data from clinical studies and animal experiments about batroxobin were extracted, integrated and analyzed based on Cochrane handbook for systematic reviews of interventions approach and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P), including the condition of subjects, the usage and dosage, research observation index and main findings. Results: A total of 62 studies were enrolled in this systematic review, including 26 clinical studies and 36 animal experiments. The 26 clinical studies involved 873 patients with arterial ischemic events, 92 cases with cerebral venous thrombosis, 13 cases with cerebral cortical vein thrombosis, and 1,049 cases with peripheral vascular diseases. These patients included 452 males and 392 females aged 65.6 ± 5.53 years. The results revealed that batroxobin had broad effects, including improving clinical prognosis (n = 12), preventing thrombosis (n = 7), promoting thrombolysis (n = 6), and improving vascular cognitive dysfunction (n = 1). The effects of batroxobin on reducing neuronal apoptosis (n = 8),relieving cellular edema (n = 4), improving spatial memory (n = 3), and promoting thrombolysis (n = 13) were concluded in animal experiments. The predominant mechanisms explored in animal experiments involved promoting depolymerization of fibrinogen polymers (n = 6), regulating the expression of related molecules (n = 9); such as intercellular adhesion molecule, heat shock proteins, tumor necrosis factor), reducing oxidative stress (n = 5), and reducing inflammation response (n = 4). Conclusion: Batroxobin can correct both arterial and venous ischemic diseases by promoting depolymerization of fibrinogen polymers, regulating the expression of related molecules, reducing oxidative stress, and reducing the inflammation response.

Clinical characteristics, inflammation and coagulation status in patients with immunological disease-related chronic cerebrospinal venous insufficiency.

BACKGROUND: Immunological disease-related chronic cerebrospinal venous insufficiency (CCSVI) is rarely reported. This study aimed to analyze clinical characteristics, inflammation, and coagulation status in patients with immunological disease-related CCSVI. METHODS: Patients with CCSVI were enrolled from 2017 to 2019 and divided into three cohorts based on their immunological disease backgrounds, including groups with confirmed autoimmune disease, with suspected/subclinical autoimmune disease, and with non-immunological etiology. Immunological, inflammatory, and thrombophilia biomarker assay in blood samples were obtained. Mann-Whitney U test or Fisher's exact test was used to compare continuous variables or categorical variables between the CCSVI patients with or without the immunological etiology. Spearman's correlation analysis was conducted among age, baseline neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), interleukin-6 (IL-6), C-reactive protein (CRP), and neuron-specific enolase (NSE) in the three groups. RESULTS: A total of 255 consecutive patients with CCSVI were enrolled, including three subgroups: CCSVI with confirmed autoimmune disease (n=41), CCSVI with suspected/subclinical autoimmune disease (n=116) and CCSVI with non-immunological etiology (n=98). In the first subgroup, a series of 41 cases was confirmed with eight different autoimmune diseases including antiphospholipid syndrome (n=18), Sjögren's syndrome (n=8), immunoglobulin G4-related disease (n=7), Behçet's disease (n=2), autoimmune hepatitis (n=2), Wegener's granulomatosis (n=2), systemic sclerosis (n=1) and AQP4 antibody-positive neuromyelitis optica spectrum disorder (n=1). Groups with immunological etiology did not show a higher incidence of thrombophilia or increased pro-inflammatory biomarkers (e.g., neutrophil, IL-6). However, patients with non-immunological etiology had a higher baseline level of CRP. Additionally, baseline PLR was moderately correlated to NLR and CRP in CCSVI patients with non-immunological etiology and suspected/subclinical autoimmune disease. CONCLUSIONS: The formation of CCSVI may be based on the inflammatory process, facilitated by multiple risk factors, among which medical history of immunological diseases may play a significant role due to the intricate relationship between inflammation and coagulation. Moreover, CCSVI may also cause an independent inflammatory injury in venous walls, leading to focal stenosis or thrombus, without attacks from autoimmune antibodies.

The clinical characteristic, diagnosis, treatment, and prognosis of cerebral cortical vein thrombosis: a systematic review of 325 cases.

Cerebral cortical vein thrombosis (CCVT) is a rare type of cerebral venous thrombosis, which is frequently combined with cerebral venous sinus thrombosis (CVST). We aimed to compare the difference of clinical features between the isolated and the combined subtypes of CCVT. A literature search was conducted utilizing the PubMed Central and EMBASE databases to identify studies up to Dec 2019. Clinical manifestations, presumable risk factors, imaging modalities, radiological findings, treatment, and prognosis in patients with CCVT were recorded. 335 publications were identified (n = 325, 141 males and 184 females, mean age 40.24 ± 16.26 years). Headaches (46.8%), motor/sensory disorders (43.3%), and seizures (42.5%) were commonly seen. Pregnancy/postpartum (n = 29), oral contraception use (n = 15), fertility drug use (n = 4) ranked the top three comorbidities of CCVT in female patients, while for general populations, thrombophilia, invasive interventions in the cerebrospinal system, as well as malignancy, would be the common risk factors. MRV and DSA were more likely to confirm diagnosis. More than 30% of CCVT presented brain lesions, including infarction (6.5%) and hemorrhage (24.0%). Isolated CCVT was prone to develop hemorrhagic infarction while combined CCVT was more likely to have ischemic lesions. More than 90% of the patients acquired good outcomes at discharge or short-term follow-up (within one year). There is a difference between Isolated CCVT and CCVT combined CVST on the sites and types of brain lesions. MRV and DSA may contribute to the final diagnosis. Most patients acquired complete or partial recovery of clinical symptoms or imaging presentations after long-term anticoagulation (3-6 months).

The prognostic role of Ki-67/MIB-1 in meningioma: A systematic review with meta-analysis.

BACKGROUND: Ki-67 is a typical immunohistochemical marker for cell proliferation. Higher expression of Ki-67 is correlated with poor clinical outcomes in several cancers. However, the prognostic value of Ki-67 on the prognosis of meningiomas is still controversial. The purpose of this meta-analysis was to evaluate the prognostic value of Ki-67 in meningiomas. METHODS AND MATERIALS: We searched Medline and EMBASE from inception to December 31, 2018, to identify relevant articles. Using a fixed or random effects model, pooled hazard ratios (HRs) for overall survival (OS) and disease/progression/recurrence-free survival (D/P/RFS) were estimated. RESULTS: A total of 43 studies, comprising 5012 patients, were included in this analysis. Higher Ki-67 expression levels were significantly associated with worse OS (HR = 1.565; 95% CI: 1.217-2.013) and D/P/RFS (HR = 2.644; 95% CI: 2.264-3.087) in meningiomas. Subgroup analysis revealed that all the included factors (ethnicity, tumor grade, HR sources, definition of cutoffs, cutoff values) for heterogeneity investigation can affect the pooled results. Among them, the definitions of cutoffs and cutoff values factor are the two main contributors toward heterogeneity. Multivariable meta-regression analysis also showed that methodologies used for cutoff value definition contributed to the high inner-study heterogeneity. CONCLUSIONS: Higher Ki-67 expression levels negatively influenced survival in meningiomas. A higher cutoff value (>4%) is more appropriate for prognosis prediction. It is highly recommended that Ki-67 expression profile could be assessed in meningiomas treatment for predicting survival. And patients with elevated expression of Ki-67 need to have close follow-ups.

Baseline Red Blood Cell Distribution Width as a Predictor of Stroke Occurrence and Outcome: A Comprehensive Meta-Analysis of 31 Studies.

Background: Red blood cell distribution width (RDW) may be a potential biomarker of inflammation in patients with stroke. Elevated RDW is associated with higher incidence of stroke, unfavorable functional outcome, and increased mortality, although results are inconsistent in the reported literature. This study aims to evaluate the predictive power of RDW regarding stroke occurrence and outcome. Methods: A thorough literature search was conducted utilizing the PubMed Central (PMC) and EMBASE databases to identify studies up to May 2019. Data from these studies were pooled, and combined odds ratios/risk ratios (ORs/RRs) were estimated for the risk of stroke, functional outcome, and mortality. A subgroup analysis was also performed to explore heterogeneity in terms of population status, demographic factors (age, gender distribution, and country), and vascular risk factors (hypertension, diabetes mellitus, and current smoking). Results: A total of 31 studies with 3,487,896 patients were included in the analysis. Elevated RDW was found to be a risk factor in ischemic stroke (OR/RR 1.528; 95% confidence interval [CI] = 1.372-1.703), whereas combined OR in subarachnoid hemorrhage (SAH) was not statistically significant (OR/RR 1.835; 95% CI = 0.888-3.792). Elevated RDW posed increased risk in populations with conventionally higher risk of stroke, such as atrial fibrillation (AF) (OR/RR 1.292; 95% CI = 1.107-1.508) and diabetes mellitus (OR/RR 2.101; 95% CI = 1.488-2.968), and in community cohorts (OR/RR 1.245; 95% CI = 1.216-1.275). In addition, higher RDW was associated with unfavorable functional outcome, either at discharge (OR/RR 1.220; 95% CI = 1.070-1.39) or at 90 days (OR/RR 1.277; 95% CI = 1.155-1.413). Higher mortality was found in patients with increased RDW (OR/RR 1.278; 95% CI = 1.221-1.337), independent of demographic factors (age, gender distribution, and country). Conclusions: Baseline RDW should be integrated into clinical practice as a predictor of ischemic stroke occurrence and outcome. Future studies should also explore the dynamic change of RDW in post-stroke patients to evaluate the clinical significance of RDW and its impact on the inflammatory state of ischemic stroke.

Prognostic role of pretreatment red blood cell distribution width in patients with cancer: A meta-analysis of 49 studies.

Red blood cell distribution width (RDW) has been recently demonstrated to be a predictor of inflammation. High pretreatment RDW level is associated with poor survival outcomes in various malignancies, although the results are controversial. We aimed to investigate the prognostic role of RDW. A systematic literature search was performed in MEDLINE and EMBASE till April 2018. Pooled hazard ratios (HRs) were estimated for overall survival (OS) and combined disease-free survival, progression-free survival, and recurrence-free survival (DFS/PFS/RFS). 49 studies with 19,790 individuals were included in the final analysis. High RDW level adversely affected both OS and DFS/PFS/RFS. For solid cancers, colorectal cancer (CRC) had the strongest relationship with poor OS, followed by hepatic cancer (HCC). Negative OS outcomes were also observed in hematological malignancies. Furthermore, patients at either early or advanced stage had inverse relationship between high pretreatment RDW and poor OS. Studies with cut-off values between 13% and 14% had worse HRs for OS and DFS/PFS/RFS than others. Furthermore, region under the curve (ROC) analysis was used widely to define cut-off values and had relatively closer relationship with poorer HRs. In conclusion, our results suggested that elevated pretreatment RDW level could be a negative predictor for cancer prognosis.

Prognostic role of pretreatment circulating MDSCs in patients with solid malignancies: A meta-analysis of 40 studies.

Myeloid-derived suppressor cells (MDSCs) have been shown to contribute to tumor progression, mainly through immune suppression. Inverse correlations have been observed between MDSC levels and patient survival for various malignancies. The purpose of this meta-analysis was to evaluate the prognostic value of pretreatment circulating MDSCs. We searched MEDLINE and EMBASE from their inceptions to September 2017 to identify relevant articles. Using a fixed or random effects model, pooled hazard ratios (HRs) were estimated for overall survival (OS) and combined disease-free survival, progression-free survival, and recurrence-free survival (DFS/PFS/RFS). A total of 40 studies comprising 2721 were included. For solid tumors, high levels of pretreatment circulating MDSCs were significantly associated with worse OS (HR = 1.796, 95% CI = 1.587-2.032) and DFS/PFS/RFS (HR = 2.459, 95% CI = 2.018-2.997). Breast cancer showed the largest association between high MDSC levels and worse OS (pooled HR = 3.053). Elevated MDSCs were also associated with worse OS for mixed-stage tumors (pooled HR = 1.659) and advanced-stage tumors (pooled HR = 2.337). Furthermore, both monocytic-MDSCs (M-MDSCs) and granulocytic or polymorphonuclear (PMN-MDSCs) showed negative associations with survival outcomes. Overall, high levels of pretreatment circulating MDSCs negatively influenced survival in most cancers. Pretreatment circulating MDSCs should be taken into account to further improve prognostic evaluation and develop novel therapeutic strategies.

Anatomic Study of Craniocervical Junction and Its Surrounding Structures in Endoscopic Transoral-Transpharyngeal Approach.

PURPOSE: This study aims to provide accurate and comprehensive data of craniocervical junction and its peripheral structures in order to provide a profound insight of craniocervical junction as well as to avoid complications during surgical procedures related to it. METHODS: Computed tomographic angiography (CTA) images of 120 individuals were reviewed, the measurements were performed on coronal, sagittal, and axial planes after 3-dimensional volume reconstruction. The authors measured pharyngeal tubercle, foramen magnum, and tuberculum anterius atlantis, which located based on the position of incisor. The anatomic features of other important bony landmarks, internal carotid artery, and vertebral artery were also fully studied so as to avoid being injured during the transoral-transpharyngeal procedure. RESULTS: During the endoscopic surgery to craniocervical junction, the bending angle of neuroendoscopy should be 14.27 ±â€Š4.51° and the entering depth should be about 72.57 ±â€Š8.72 mm. It is safe to work within the angle of 77.73 ±â€Š3.15° in axial plane and the safe penetration width from the axial midline is 20.05 ±â€Š3.11 mm in the level of foramina magnum. The distance from axial middle line to hypoglossal canal, external opening of carotid canal, and inner edge of jugular foramen was 9.78 ±â€Š0.72, 24.50 ±â€Š1.26, and 24.33 ±â€Š1.68 mm, respectively. CONCLUSIONS: These data in this study are valuable for neurosurgeons in clinical practice to reduce the possibility of complications and maximize the safety of surgeries; these data also contribute to the understanding of the anatomy of craniocervical junction and its surrounding structures.

Meta-analysis of the prognostic value of the neutrophil-to-lymphocyte ratio in oral squamous cell carcinoma.

BACKGROUND: A number of studies have assessed the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in oral squamous cell carcinoma (OSCC), but their results regarding the predictive value of NLR in OSCC are inconsistent. We therefore performed a meta-analysis to clarify the association between NLR and clinical outcome in OSCC. METHODS: We searched the MEDLINE and Web of Science to identify potential studies investigating the association between NLR and survival in OSCC. RESULTS: A total of 10 studies, enrolling 2135 patients with OSCC, were included. A higher NLR was a negative predictor for both disease-specific survival (hazard ratio [HR] = 1.93, 95% CI: 1.47-2.54) and overall survival (HR = 1.56, 95% CI: 1.28-1.90). CONCLUSION: This suggests a higher NLR is predictive of a poorer prognosis in OSCC. Because determination of NLR is non-invasive and cost-effective, it could be widely used for predicting prognosis in OSCC.

Immune-Related Adverse Events Associated with Anti-PD-1/PD-L1 Treatment for Malignancies: A Meta-Analysis.

Background: Treatment of cancers with programmed cell death protein 1 (PD-1) pathway inhibitors can lead to immune-related adverse events (irAEs), which could be serious and even fetal. Therefore, clinicians should be aware of the characteristics of irAEs associated with the use of such drugs. Methods: The MEDLINE, EMBASE, and Cochrane databases were searched to find potential studies using the following strategies: anti-PD-1/PD-L1 treatment; irAEs; and cancer. R© package Meta was used to pool incidence. Results: Forty-six studies representing 12,808 oncologic patients treated with anti-PD-1/PD-L1 agents were included in the meta-analysis. The anti-PD-1/PD-L1 agents included nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and BMS-936559. The tumor types were melanomas, Hodgkin lymphomas, urothelial carcinomas, breast cancers, non-small cell lung cancers, renal cell carcinomas (RCC), colorectal cancers, and others. We described irAEs according to organ systems, namely, the skin (pruritus, rash, maculopapular rash, vitiligo, and dermatitis), endocrine system (hypothyroidism, hyperthyroidism, hypophysitis, thyroiditis, and adrenal insufficiency), digestive system (colitis, diarrhea, pancreatitis, and increased AST/ALT/bilirubin), respiratory system (pneumonitis, lung infiltration, and interstitial lung disease), and urinary system (increased creatinine, nephritis, and renal failure). In patients treated with the PD-1 signaling inhibitors, the overall incidence of irAEs was 26.82% (95% CI, 21.73-32.61; I2, 92.80) in any grade and 6.10% (95% CI, 4.85-7.64; I2, 52.00) in severe grade, respectively. The development of irAEs was unrelated to the dose of anti-PD-1/PD-L1 agents. The incidence of particular irAEs varied when different cancers were treated with different drugs. The incidence of death due to irAEs was around 0.17%. Conclusion: The occurrence of irAEs was organ-specific and related to drug and tumor types.