Search

ObjectiveChronic subdural hematoma (CSDH) is a common disease in neurosurgery, which usually occurs in the elderly. Seizure is one of the postoperative complications in CSDH patients and can affect patient outcomes. There is currently no consensus on whether antiepileptic drugs should be prescribed prophylactically. The aim of this study was to evaluate independent risk factors for postoperative seizures and unfavorable outcomes in CSDH patients.MethodsWe reviewed 1,244 CSDH patients who had undergone burr-hole craniotomy in this study. Patient clinical data, CT scan results, recurrence and outcome data were collected. We divided the patients into two groups based on whether they had a postoperative seizure. Percentages and χ2 tests were applied for categorical variables. Standard deviations and two-sided unpaired t-tests were applied for continuous variables. Stepwise logistic regression analyses were performed to identify the independent factors of postoperative seizures and unfavorable outcomes.ResultsThe incidence of seizures after CSDH surgery was 4.2% in this study. There was no significant difference in recurrence rate between seizure and non-seizure patients (p = 0.948), and the outcome of seizure patients was significantly poor (p p p = 0.031), cardiac disease (p = 0.037), brain infarction (p = 0.001) and trabecular hematoma (p p = 0.028). Hypertension is an independent risk factor for unfavorable outcome in seizure patients (p = 0.038).ConclusionSeizures after CSDH surgery were associated with postoperative complications, higher mortality and poorer clinical outcomes at follow-up. We believe that alcohol consumption, cardiac disease, brain infarction and trabecular hematoma are independent risk factors for seizures. The use of urokinase is a protective factor against seizures. Patients with postoperative seizures need more stringent management of their blood pressure. A prospective randomized study is necessary to determine which subgroups of CSDH patients would benefit from antiepileptic drugs prophylaxis.

BackgroundThe geriatric nutritional risk index (GNRI) is a simple index for evaluating the nutrition status of elderly patients. Many investigations have demonstrated that this index is associated with the prognosis of several diseases. This study aims to identify the relationship between the GNRI and recovery in elderly mild traumatic brain injury (mTBI) patients.MethodsA total of 228 mTBI patients older than 65 years were included in this study. mTBI was defined as an injury to the brain with a loss of consciousness of 30 min or less, a duration of posttraumatic amnesia of ResultsThe receiver operating curve (ROC) analysis demonstrated that the cutoff value of GNRI was 97.85, and the area under the curve (AUC) was 0.860. Compared to the patients with a high GNRI, the patients with a low GNRI were older, had a higher prevalence of anemia, acute subdural hematoma, and subarachnoid hemorrhage, had a higher age-adjusted Charlson Comorbidity Index value, and had lower levels of albumin, lymphocytes, and hemoglobin. Multivariable analysis showed that high GNRI was associated with a lower risk of 6-month incomplete recovery (OR, 0.770, 95% CI: 0.709–0.837, p < 0.001).ConclusionThe GNRI has utility as part of the objective risk assessment of incomplete 6-month functional recovery in elderly patients with mTBI.

Purpose Contralateral hematoma progression (CHP) is a common condition among bilateral chronic subdural hematoma (bCSDH) patients after the unilateral evacuation. Investigations focusing on this topic are limited. The author aims to identify risk factors correlated with the CHP. Methods 82 patients with bCSDH who underwent the unilateral evacuation in Beijing Tiantan Hospital from 2011 to 2021 were included in this retrospective study. Clinical information and radiological features of these patients were collected and analyzed. Chi Square test, Student t test and Mann-Whitney test was performed to find variables which were statistically significant (p p = 0.025). Contralateral hematoma locating on the curved side was more likely to progress (p = 0.007). The other risk factors including pre- and post-operative volume of hematoma in the non-surgical side and the wide type of contralateral hematoma. The multivariate analysis demonstrated that the wide type of contralateral hematoma was one of the independent risk factors for CHP (OR = 8.769, p = 0.020, 95%CI 1.410-54.545). Moreover, the opposite hematoma locating on the curved side was also associated with the contralateral progression independently (OR = 7.103, p = 0.033, 95%CI 1.168–43.213). Conclusion For bCSDH patients, wide contralateral hematoma may increase the risk of CHP. Moreover, non-operative hematoma which locates on the curved side of skull is also an independent risk factor for the enlargement of opposite hematoma. Patients with such radiological characteristic may need additional medical treatment and rigorous follow-up to prevent the progression of contralateral hematoma.

Background Chronic subdural hematomas (CSDHs) are one of the most common neurosurgical conditions. The standard surgical technique includes burr-hole craniostomy, followed by intraoperative irrigation and placement of subdural closed-system drainage. The drainage is generally removed after 48 hours, which can be described as fixed-time drainage strategy. According to literature, the recurrence rate is 5–33% with this strategy. In our retrospective study, postoperative hematoma volume was found to significantly increase the risk of recurrence. Based on these results, an exhaustive drainage strategy is conducted to minimize postoperative hematoma volume and achieve a low recurrence rate and good outcomes. Methods This is a prospective, multicenter, randomized controlled trial designed to include 304 participants over the age of 18–90 years presenting with a symptomatic CSDH verified on cranial computed tomography or magnetic resonance imaging. Participants will be randomly allocated to perform exhaustive drainage (treatment group) or fixed-time drainage (control group) after one-burr hole craniostomy. The primary endpoint will be recurrence indicating a reoperation within 6 months. Discussion This study will validate the effect and safety of exhaustive drainage after one-burr hole craniostomy in reducing recurrence rates and provide critical information to improve CSDH surgical management. Trial registration Clinicaltrials.gov, NCT04573387. Registered on October 5, 2020. (https://www.clinicaltrials.gov/ct2/show/study/NCT04573387.)

We conducted a meta-analysis to analyze the effects of pneumocephalus after chronic subdural hematoma (CSDH) surgery on hematoma recurrence, mortality, and functional outcomes. In this meta-analysis, following PRISMA guidelines, PubMed, Embase, Cochrane Library, and Web of Science online databases were queried using the keywords "pneumocephalus," "pneumoencephalos," "intracranial pneumatocele," "pneumo encephalon," "subdural air," and "chronic subdural hematoma." The results were limited to English-language articles. Through the online database, we identified a total of 276 articles and finally included 14 articles for meta-analysis. The results showed that the recurrence rate in the pneumocephalus group was higher than that in the control group, with a pooled OR of 3.35 (CI: 2.51-4.46, P 0.001). There was no difference in recurrence rate between the no/few and moderate pneumocephalus groups (OR: 1.27, CI: 0.68-2.37, P = 0.46), but the recurrence rate of the large pneumocephalus group was significantly higher than that of the moderate group, with a pooled OR of 3.29 (CI: 1.71-6.32, P 0.001). This study failed to show higher mortality and worse outcomes in the pneumocephalus group than in the control. Pneumocephalus after surgical evacuation of CSDH was associated with the recurrence rate of hematoma. Pneumocephalus affecting recurrence was correlated with gas volume, and moderate pneumocephalus may have less impact, while patients with large pneumocephalus are more likely to recur than those with moderate pneumocephalus. More prospective cohort studies are needed for further investigation and verification. This meta-analysis was registered (PROSPERO CRD42022321800).

ObjectiveA previous study with a limited number of patients has shown that blood type A was a risk factor in the recurrence of CSDH. The primary objective of this study was to investigate the association between the recurrence of CSDH and ABO blood type based on a larger sample size.MethodsThe authors reviewed in-patients with symptomatic CSDH from August 2011 to August 2021. Hospitalization information and data on long-term outcomes and recurrence among these patients were gathered. For all clinical variables, numbers (percentages) and mean ± standard deviations were used for categorical and continuous variables, respectively. For intergroup comparisons, the χ2 test or one-way ANOVA was carried out. Multivariable logistic regression analyses were performed to identify the association between CSDH recurrence and blood types.ResultsWe included 1,556 inpatients in this study. The recurrence rate of CSDH showed no differences among different blood types. In the multivariable logistic regression analyses, ABO blood type (A: OR, 1.064; 95% CI, 0.467–2.851, p = 0.793; B: OR, 0.682, 95% CI, 0.315–1.269, p = 0.164; AB: OR, 0.537, 95% CI, 0.426–1.861, p = 0.357) was not a significantly independent predictor of CSDH recurrence.ConclusionsOur study demonstrated that ABO blood type was not a risk factor in the recurrence of CSDH. Thus, we should not pay too much attention to ABO blood type in terms of CSDH recurrence.

BackgroundGiven the men's predominance in the prevalence of chronic subdural hematoma (CSDH), we investigated the relationship between sex differences and clinical features of CSDH.MethodsWe retrieved a large collection of clinical factors from CSDH patients between August 2011 and May 2019, and analyzed the differences and similarities in the clinical data and outcomes between men and women.ResultsIn total 1,307 CSDH patients were enrolled in this study. When we did not account for age, a greater proportion of women relative to men manifested diabetes (p = 0.001) and cardiac disease (p = 0.035) prior to the onset of CSDH. Regarding recovery outcome and recurrence rate, we observed no significant differences between men and women. The sole difference between women and men after surgery was that women experienced more complications than men (p = 0.044), and both length of hospital stay (p < 0.001, B = 0.159, Exp [B] = 1.172, 95% CI = 1.078–1.274) and the presence of cardiac disease (p = 0.002, B = 2.063, Exp [B] = 7.867, 95% CI = 2.167–28.550) were identified as independent risk factors. After accounting for age, women with CSDH exhibited more frequent disorders of consciousness at admission than men in group of ≤ 40-year-old patients (p = 0.018), while proportion of women with diabetes was higher than that of men in 41–79 year-old group (p < 0.001). However, women after surgery experienced more complications (p = 0.047), longer length of hospital stays (p = 0.005), and higher mortality at discharge (p = 0.035) than men in middle-aged group. Finally, length of hospital stay (p < 0.001, B = 0.186, Exp [B] = 1.205, 95% CI = 1.091–1.331) and cardiac disease (p = 0.017, B = 2.040, Exp [B] = 7.693, 95% CI = 1.430–41.372) impacted occurrence of complications in women 41–79-year-old, while duration of drainage catheter use (p < 0.001, B = 1.132, beta = 0.280) and complications (p < 0.001, B = 5.615, beta = 0.366) were identified as independent risk factors for length of hospital stay in the same group of women.ConclusionsAlthough sex differences did not constitute a crucial factor in all the CSDH patients, we still need to pay closer attention to disparities between men and women with respect to complications, length of hospital stay, and mortality at discharge in the various age groups (particularly with respect to 41–79 year-old women patients), to provide satisfactory management and treatment of CSDH patients.

Background Scalp metastases from anaplastic oligodendroglioma (AO) are extremely rare and mostly involve intracranial recurrence or widely metastatic disease. Here we describe an exceptional case of histopathologically proven scalp metastasis of AO 6 years after surgical resection and postoperative adjuvant radiation. Case Description A 42-year-old woman presented with several months of progressive headache and dizziness. Preoperative magnetic resonance imaging (MRI) showed an irregular enhancing lesion in the left frontal lobe extending to the ependymal surface. Left frontal craniotomy was performed through a coronal approach, and gross total resection was achieved. Pathologic examination confirmed a World Health Organization grade III AO. The patient subsequently received 60 Gy of external beam radiotherapy in 30 fractions over 6 weeks. During 8 years of follow-up, the patient remained symptom free, and no evidence of intracranial recurrence was found. However, 6 years after intracranial tumor resection, the patient noticed a subcutaneous mass in her right frontal scalp, which was the site contralateral to her craniotomy. MRI revealed a homogeneously marked enhancing nodular lesion in the subcutaneous tissue of the right frontal scalp without intracranial recurrence. Gross total resection was performed, and the pathologic findings, which identified the mass as an AO, were consistent with those of the primary left frontal tumor. Conclusions This study presents a rare case of long-term AO scalp metastasis without intracranial recurrence. Intraoperative seeding and longer survival for oligodendroglial tumors may cause this rare entity. Optimal surgical strategies and standard operative procedures can promote the prevention of iatrogenic seeding.

To investigate clinical characteristics and outcomes of chronic subdural hematomas (CSDHs) in different age ranges.A retrospective collection of data from CSDH patients ≤40 years, 41-79 years, and ≥80 years of age between August 2011 and May 2017 was performed. The differences and similarities of clinical data and outcomes among three groups were analyzed.A total of 1118 CSDH patients were included. We found that 64.5% patients had arachnoid cyst/ventriculoperitoneal shunt in patients ≤40 years, 4.3% in the 41-79 years group, and 3.2% in the ≥80 years group (P 0.001). Headache was the most frequent symptom in the ≤40 years group (88.2%) and the 41-79 years group (60.9%), while the most frequent symptom in the ≥ 80 years group was limb weakness (80.4%). The history of head trauma was not significantly different between the three groups. After burr hole drainage craniostomy, the disappearance or alleviation of symptoms, duration of catheter drainage, and length of hospital stay were not significantly different, while the recurrence rate was also not significantly different between the three groups. Post-operation complications are an independent risk factor contributing to the death of patients of 41-79 years (P0.001, B = 3.140, Exp (B) = 23.103, 95% CI = 5.142-103.809) and of ≥ 80 years (P = 0.001, B=2.831, Exp (B) = 16.970, 95% CI = 3.365-85.567). The history of antithrombotic drug was an independent risk factor of complications in patients of 41-79 years (P = 0.042, B =1.341, Exp (B) =3.823, 95% CI = 1.048-13.942) and patients of ≥ 80 years (P = 0.026, B=1.399, Exp (B) = 4.052, 95% CI = 1.178-13.933), while complications were also an independent risk factor contributing to the outcome in patients of 41-79 years (P 0.001, B =2.254, Exp (B) =0.314, 95% CI = 0.089-1.103) and patients of ≥ 80 years (P = 0.006, B=2.074, Exp (B) = 7.953, 95% CI = 1.791-35.313). In the ≤40 years group, all patients had a good outcome (MRS score 0-3), while 98.2% (851/867) of the cases in the 41-79 years group and 94.3% (149/158) of the cases in the ≥ 80 years group saw a good outcome (P = 0.001).Our results clearly display the common and different clinical data of CSDH in all age ranges, which is crucial to improve the management and treatment of patients with CSDH.

Objective Common treatments for obstructive hydrocephalus caused by malignant midline intracranial tumors during the perioperative period include ventriculoperitoneal shunt (VPS) placement/endoscopic third ventriculostomy (ETV) and direct tumor resection, but which of these treatments is superior remains unclear. The purpose of this study is to explore the management of hydrocephalus during the perioperative period and subsequent outcomes. Methods Data from 372 patients with obstructive hydrocephalus due to malignant midline intracranial tumors under the age of 18 years referred to the Department of Pediatric Neurosurgery at Beijing Tiantan Hospital between January 2018 and September 2019 were collected. We also collected their clinical features and outcomes for further statistical analysis. Results A total of 372 pediatric patients were treated for obstructive hydrocephalus. In total, 215 patients underwent preoperative VPS placement; the effectiveness of preoperative VPS placement was 98.1% (211/215), and the mean duration of relapse was 63.5 ± 15.7 days. Forty children underwent ETV before tumor removal; the effectiveness of preoperative ETV was 90.0% (36/40), and the mean duration of relapse was 53.8 ± 44.9 days. A total of 117 patients underwent direct tumor resection after being diagnosed; the recurrence rate of hydrocephalus was 20.5% (24/117), and the mean duration of relapse was 125.0 ± 170.8 days. There was a significant difference between preoperative VPS placement followed by resection and postoperative VPS placement and preoperative ETV followed by resection and postoperative VPS placement (p = 0.013). Conclusion Malignant midline intracranial tumors in pediatric patients usually lead to obstructive hydrocephalus, and preoperative intervention for hydrocephalus (VPS or ETV) will improve patient outcomes. The optimal management strategy for obstructive hydrocephalus due to malignant midline intracranial tumors is preoperative VPS placement or ETV due to their low hydrocephalic recurrence rates and high effectiveness.

Chronic subdural hematoma (CSDH) is a common neurosurgical disease. Many patients with CSDH take antiplatelet (AP) drugs. Several studies have focused merely on the relationship between AP drug use and recurrence without deeply analyzing the specific clinical features of these patients. The primary objective of this study was to investigate the detailed clinical characteristics and outcomes of CSDH patients with a history of AP therapy.A total of 1181 CSDH patients over 40 years of age who received burr-hole craniostomy were enrolled. Clinical information, computed tomographic findings, and data on long-term outcomes and recurrence among these patients were gathered. We divided these patients into two groups according to whether they had a history of AP therapy. Percentages and χ2 tests were applied for categorical variables. Standard deviations and 2-sided unpaired t-tests were applied for continuous variables. Univariate and multivariate logistic regression analyses were performed to identify independent factors of the outcomes (6 months after discharge).AP therapy was not related to the outcomes of patients with CSDH (P = 0.48), and there were no differences in recurrence between the AP and non-AP group. Only Bender grade (P 0.01, B = -3.14, Exp (B) = 0.04, 95% CI 0.01-0.29) was associated with the outcomes of patients in the AP group. The incidence of complications in the AP group was higher than that in the non-AP group (P 0.01). Postoperative thrombotic events may be more likely to occur in the AP group than in the non-AP group (P = 0.02). Patients in the AP group were older (P 0.01) and had more comorbidities (P 0.01).Patients treated with AP therapy had more complications. The outcomes of patients treated with AP therapy were associated with their status of admission. Patients treated with AP therapy were at greater risk for postoperative thrombotic events. The recurrence rate of CSDH did not appear to be affected by AP therapy.

Background: The clinical features of chronic subdural hematomas (CSDHs) in patients with and without a history of head trauma have remained unclear. Here, we investigated differences in clinical characteristics in CSDH patients with and without head trauma.Methods: We retrospectively collected clinical characteristics of CSDH patients who had undergone exhaustive drainage strategies via burr-hole craniostomies from August 2011 to May 2019. We divided patients into a trauma group (i.e., head trauma) and a no-trauma group. Chi-square tests or t-tests were used to analyze differences in clinical characteristics between the two groups. Multiple linear regression analysis was performed to analyze the relationships between the clinical characteristics and either reduction of the hematoma cavity or length of the hospital stay in CSDH patients with trauma.Results: We collected data from 1,307 CSDH patients, among whom 805 patients had a history of head trauma whereas 502 patients did not. The mean age of patients with head trauma was 64.0 ± 16.1 years, while that of patients without head trauma was significantly younger at 61.5 ± 17.9 years (p = 0.010). Furthermore, more patients in the no-trauma group had a history of hypertension compared to those in the trauma group (40.2 vs. 32.9%, p = 0.007). Dizziness occurred in 29.2% of patients with trauma and in 23.1% of patients without trauma (p = 0.016). A greater number of patients with trauma showed a reduction of hematoma cavity after surgery compared to that of patients without trauma (p = 0.002). The length of hospital stay in patients with trauma was 7.9 ± 4.5 days, which was longer than that of patients without trauma (7.3 ± 3.7 days, p = 0.016). In contrast, there were no significant different differences between the two groups in terms of the densities of hematomas on computed-tomography scans, complications, mortality rates, recurrence rates, or outcomes.Conclusion: Our findings indicate that there were some noteworthy differences in the clinical and pathogenic characteristics of CSDH patients with and without head trauma. However, our findings also indicate that if an optimal treatment method is employed, such as our exhaustive drainage strategy, similar treatment outcomes can be achieved between these groups.

Background: Clinical features in chronic subdural hematomas (CSDH) patients with and without history of head trauma are not clear. Here, we seek to investigate difference of clinical characteristics in CSDH patients with and without head trauma.Methods: Retrospectively collected clinical characteristics of CSDH patients, who were performed exhaustive drainage strategy in burr-hole craniostomy from August 2011 to May 2019. Divided patients into trauma and no trauma groups. Chi-square test or t-test was used to analyze differences of clinical characteristics between two groups. Multiple linear regression analysis was performed to analyze relationships between clinical characteristics and reduction of hematoma cavity and length of hospital stay in CSDH patients with trauma.Results: 1,307 CSDH patients were collected. 805 patients occurred history of head trauma, 502 patients without it. Mean age of patients with trauma was 64.0 ± 16.1 years, while 61.5 ± 17.9 years in patients without trauma (p=0.010). More patients occurred hypertension in without trauma group than trauma group (40.2% vs 32.9%, p=0.007). Dizziness occurred in 29.2% patients with trauma, 23.1% in patients without trauma (p=0.016). Reduction of hematoma cavity after surgery in patients without trauma was less than ones with trauma (p=0.002). Length of hospital stay in patients with trauma was 7.9 ± 4.5 days, which was longer than patients without trauma (7.3 ± 3.7 days, p=0.016). No significantly different densities of hematoma on CT, complications, mortality, recurrence rate and outcome were found between two groups.Conclusion: Pathogenesis and some clinical characteristics occur differences in CSDH patients with and without trauma, but if we choose an optimal treatment method, such as our exhaustive drainage, and we can achieve the same effect.

Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of cancer deaths worldwide. Currently, efficient genetic markers for diagnosis and treatment of ESCC are lacking. MicroRNAs (miRNAs) are global genetic regulators that control cancer gene expression by binding to the 3′untranslated regions (3′UTRs) of targeting mRNAs. In addition, miRNAs function as oncogenes or tumor suppressors in the progression of tumors. In the current study, we found that hsa-miR-875-5p (miR-875-5p) exhibited amplification in ESCC according to the TCGA database. Then, xCELLigence Real-Time Cell Analyzer (RTCA)-MP system and colony formation assays were employed to detect cell proliferationand colony formationability. The results showed that miR-875-5p promoted the proliferation ESCC cells. Subsequently, transwell results indicated that miR-875-5p promoted the invasion and migration of ESCC cells. Furthermore, we showed that miR-875-5p was able to bind to CAPZA13’UTR, which contains the single nucleotide polymorphism (SNP), rs373245753, as reported in our previous study involving WGS and WES on ESCC. Subsequently, mRNA affinity pull-down assays verifiedthat the SNP disrupts miR-875-5p binding to CAPZA1. The current study is the first demonstration that miR-875-5p may function as an oncogene via down-regulation of CAPZA1 expression in ESCC.

Background The prognosis for esophageal squamous cell carcinoma (ESCC) patients with lymph node metastasis (LNM) is still dismal. Elucidation of the LNM associated genomic alteration and underlying molecular mechanisms may provide clinical therapeutic strategies for ESCC treatment. Methods Joint analysis of ESCC sequencing data were conducted to comprehensively survey SCNAs and identify driver genes which significantly associated with LNM. The roles of miR-548k in lymphangiogensis and lymphatic metastasis were validated both in vitro and in vivo. ESCC tissue and blood samples were analyzed for association between miR-548k expression and patient clinicopathological features and prognosis and diagnosis. Results In the pooled cohort of 314 ESCC patients, we found 76 significant focused regions including 43 amplifications and 33 deletions. Clinical implication analysis revealed a panel of genes associated with LNM with the most frequently amplified gene being MIR548K harbored in the 11q13.3 amplicon. Overexpression of miR-548k remarkably promotes lymphangiogenesis and lymphatic metastasis in vitro and in vivo. Furthermore, we demonstrated that miR-548k modulating the tumor microenvironment by promoting VEGFC secretion and stimulating lymphangiogenesis through ADAMTS1/VEGFC/VEGFR3 pathways, while promoting metastasis by regulating KLF10/EGFR axis. Importantly, we found that serum miR-548k and VEGFC of early stage ESCC patients were significantly higher than that in healthy donators, suggesting a promising application of miR-548k and VEGFC as biomarkers in early diagnosis of ESCC. Conclusions Our study comprehensively characterized SCNAs in ESCC and highlighted the crucial role of miR-548k in promoting lymphatic metastasis, which might be employed as a new diagnostic and prognostic marker for ESCC. Electronic supplementary material The online version of this article (10.1186/s12943-018-0871-4) contains supplementary material, which is available to authorized users.

Glioma is the most common type of primary brain tumors in the central nervous system (CNS). Migfilin occurs in human glioma and enhances cellular motility via the epidermal growth factor receptor (EGFR) pathway. However, the underlying molecular mechanism is not fully understood. In this study, we found that Migfilin promoted matrix metalloproteinase-2 (MMP-2) activity, and restrained the expression of tissue inhibitor of metalloproteinase 2 (TIMP2), which is an MMP-2 inhibitor. Functional and structural studies showed that the LIM1 domain of Migfilin was required for Migfilin-mediated TIMP2 expression inhibition and MMP-2 activity, and was also necessary in promoting cell motility. Furthermore, Migfilin-induced EGFR phosphorylation was greatly reduced by MMP-2 inhibitor (GM6001) or siRNA, while Migfilin-induced MMP-2 activation was also blocked by the EGFR inhibitor (AG1478) or siRNA. MMP-2 and EGFR inhibitors and their siRNAs can block Migfilin-induced migration and invasion, respectively. These results demonstrated that EGFR and MMP-2 signalings may form a positive feedback loop to enhance Migfilin-induced migration and invasion. Finally, we detected that the expression of Migfilin, EGFR phosphorylation (Tyr1173) and MMP-2 activity had a positive correlation in the clinical glioma sample. Taken together, these results suggest that Migfilin is a critical regulator in cellular motility by driving the EGFR-MMP-2 feedback loop, and may be considered as a potential therapeutic target in glioma.

Oesophageal carcinoma is the fourth leading cause of cancer-related death in China, and more than 90% of these tumours are oesophageal squamous cell carcinoma (ESCC). Although several ESCC genomic sequencing studies have identified mutated somatic genes, the number of samples in each study was relatively small, and the molecular basis of ESCC has not been fully elucidated. Here, we performed an integrated analysis of 490 tumours by combining the genomic data from 7 previous ESCC projects. We identified 18 significantly mutated genes (SMGs). PTEN, DCDC1 and CUL3 were first reported as SMGs in ESCC. Notably, the AJUBA mutations and mutational signature4 were significantly correlated with a poorer survival in patients with ESCC. Hierarchical clustering analysis of the copy number alteration (CNA) of cancer gene census (CGC) genes in ESCC patients revealed three subtypes, and subtype3 exhibited more CNAs and marked for worse prognosis compared with subtype2. Moreover, database annotation suggested that two significantly differential CNA genes (PIK3CA and FBXW7) between subtype3 and subtype2 may serve as therapeutic drug targets. This study has extended our knowledge of the genetic basis of ESCC and shed some light into the clinical relevance, which would help improve the therapy and prognosis of ESCC patients.

// Yunwei Ou 1, 2, 3, 4, 7 , Zitong Zhao 2 , Weimin Zhang 2 , Qingnan Wu 2 , Chuanyue Wu 5, 6 , Xuefeng Liu 2 , Ming Fu 2 , Nan Ji 1 , Dan Wang 1 , Jiaji Qiu 1 , Liwei Zhang 1 , Chunjiang Yu 4 , Yongmei Song 2 , Qimin Zhan 2 1 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China 2 State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China 3 Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China 4 Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing 100093, China 5 Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA 6 Department of Biology and Shenzhen Key Laboratory of Cell Microenvironment, South University of Science and Technology of China, Shenzhen, 518055, China 7 China National Clinical Research Center for Neurological Diseases, Beijing 100050, China Correspondence to: Chunjiang Yu, email: cjyu1955@sina.com Yongmei Song, email: symlh2006@163.com Qimin Zhan, email: zhanqimin@pumc.edu.cn Keywords: EGFR, glioma, Kindlin-2, transcription Received: April 20, 2016 Accepted: August 11, 2016 Published: October 04, 2016 ABSTRACT Kindlin-2 promotes carcinogenesis through regulation of cell-cell and cell-extracellular matrix adhesion. However, the role of Kindlin-2 in glioma has not been elucidated. We investigated Kindlin-2 expression in 188 human glioma tissue samples. High Kindlin-2 expression was correlated with high pathological grade and a worse prognosis. Kindlin-2 promoted glioma cell motility and proliferation both in vitro and in vivo . Importantly, Kindlin-2 activated the EGFR pathway and increased EGFR mRNA levels. In addition to up-regulating Y-box binding protein-1 (YB-1) and β-catenin expression, Kindlin-2 formed a transcriptional complex with YB-1 and β-catenin that bound to the EGFR promoter and enhanced transcription. The β-catenin/YB-1/EGFR pathway was required for Kindlin-2-mediated functions. Our data provide a better understanding of the mechanisms underlying glioma progression, and suggest that Kindlin-2 may be a biomarker and therapeutic target in glioma.

Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of cancer deaths worldwide. Currently, efficient genetic markers for diagnosis and treatment of ESCC are lacking. MicroRNAs (miRNAs) are global genetic regulators that control cancer gene expression by binding to the 3′untranslated regions (3′UTRs) of targeting mRNAs. In addition, miRNAs function as oncogenes or tumor suppressors in the progression of tumors. In the current study, we found that hsa-miR-875-5p (miR-875-5p) exhibited amplification in ESCC according to the TCGA database. Then, xCELLigence Real-Time Cell Analyzer (RTCA)-MP system and colony formation assays were employed to detect cell proliferationand colony formationability. The results showed that miR-875-5p promoted the proliferation ESCC cells. Subsequently, transwell results indicated that miR-875-5p promoted the invasion and migration of ESCC cells. Furthermore, we showed that miR-875-5p was able to bind to CAPZA13’UTR, which contains the single nucleotide polymorphism (SNP), rs373245753, as reported in our previous study involving WGS and WES on ESCC. Subsequently, mRNA affinity pull-down assays verifiedthat the SNP disrupts miR-875-5p binding to CAPZA1. The current study is the first demonstration that miR-875-5p may function as an oncogene via down-regulation of CAPZA1 expression in ESCC.

The aim of the study was to observe the efficacy of nonsurgical treatment with Chinese herbal medicine (CHM) for chronic subdural hematoma (CSDH). This study includes clinical results of a STROBE-compliant retrospective study.Forty patients diagnosed with CSDH were recruited from outpatient. Different CHM prescriptions were dispensed for each patient based on syndrome differentiation until the patient had a stable neurologic condition for 2 weeks and/or CSDH completely resolved according to the computed tomography scan. Markwalder grading scale for neurologic symptoms and head computed tomography scan for hematoma volumes were performed before and after CHM treatment to evaluate efficacy.Patients received uninterrupted CHM treatment for 2.81 ± 1.45 months (0.75-6 months). The hematoma volume significantly reduced from 73.49 ± 35.43 mL to 14.72 ± 15.94 mL (P 50% decrease in the hematoma volume and complete improvement in neurologic symptoms. The linear regression analysis suggested that change in hematoma was significantly related to the duration of CHM treatment (R = 0.334; P < .001; Ŷ = 25.03 + 11.91X). Leonurus heterophyllus Sweet (Yi-Mu-Cao, 90.5%), Semen persicae (Tao-Ren, 88.8%), and Acorus tatarinowii Schott (Shi-Chang-Pu, 86.2%) were the top 3 single Chinese herbs prescribed in CHM treatment.The CHM treatment for CSDH based on syndrome differentiation with appropriate duration relieved neurologic symptoms quickly and promoted hematoma absorption effectively. It could be an effective nonsurgical therapy for CSDH.

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide and the fourth most lethal cancer in China. However, although genomic studies have identified some mutations associated with ESCC, we know little of the mutational processes responsible. To identify genome-wide mutational signatures, we performed either whole-genome sequencing (WGS) or whole-exome sequencing (WES) on 104 ESCC individuals and combined our data with those of 88 previously reported samples. An APOBEC -mediated mutational signature in 47% of 192 tumors suggests that APOBEC-catalyzed deamination provides a source of DNA damage in ESCC. Moreover, PIK3CA hotspot mutations (c.1624G>A [p.Glu542Lys] and c.1633G>A [p.Glu545Lys]) were enriched in APOBEC -signature tumors, and no smoking-associated signature was observed in ESCC. In the samples analyzed by WGS, we identified focal ( CBX4 and CBX8 . In our combined cohort, we identified frequent inactivating mutations in AJUBA , ZNF750 , and PTCH1 and the chromatin-remodeling genes CREBBP and BAP1 , in addition to known mutations. Functional analyses suggest roles for several genes ( CBX4 , CBX8 , AJUBA , and ZNF750 ) in ESCC. Notably, high activity of hedgehog signaling and the PI3K pathway in approximately 60% of 104 ESCC tumors indicates that therapies targeting these pathways might be particularly promising strategies for ESCC. Collectively, our data provide comprehensive insights into the mutational signatures of ESCC and identify markers for early diagnosis and potential therapeutic targets.

To introduce an effective strategy to treat patients with chronic subdural hematoma (CSDH) that can achieve a low recurrence rate and good outcome.Surgical patients with CSDH from August 2011 to May 2017 in our hospital were collected retrospectively. An exhaustive drainage strategy to treat CSDH with burr-hole craniostomy was conducted. All patients were drained, and catheter was removed when natural drainage ceased or when drainage was complete using urokinase. Clinical characteristics were reviewed and analyzed. Following this strategy, predictors of recurrence requiring reoperation and outcome were analyzed.In total, 1126 patients with CSDH who were treated with burr-hole craniostomy were included. Using the exhaustive drainage strategy, recurrence rate was only 1.9% (21/1117) with follow-up rate of 99.2%. 97.0% (1092/1117) of patients gained good outcome (modified Rankin scale scores 0-3) at 6 months after discharge. Postoperative hematoma volume (P = 0.001, B = 0.028, Exp (B) = 1.028, 95% CI 1.011-1.046), diabetes (P = 0.022, B = 1.082, Exp (B) = 2.950, 95% CI 1.169-7.440), bilateral hematoma (P = 0.011, B = 1.213, Exp (B) = 3.363, 95% CI 1.323-8.547), and complications (P = 0.013, B = 1.483, Exp (B) = 4.408, 95% CI 1.365-14.235) significantly increased the probability of recurrence. In contrast, use of urokinase (P = 0.007, B = -1.435, Exp (B) = 0.238, 95% CI 0.085-0.671) reduced recurrence. Finally, age (P = 0.026, B = 0.056, Exp (B) = 1.057, 95% CI 1.007-1.110), complications (P0.001, B = 1.710, Exp (B) = 5.529, 95% CI 2.104-14.531), and Bender grade (P0.001, B = 1.165, Exp (B) = 3.205, 95% CI 1.325-7.750) were significant predictors of outcome.The exhaustive drainage strategy is safe and effective for reducing recurrence rate and achieving good outcome in patients with CSDH. This procedure merits recommendation in clinical practice.

To investigate the clinical characteristics, treatment, and outcomes of chronic subdural hematomas (CSDH) in young patients.We retrospectively reviewed young patients under 40 years of age who received diagnoses of and were surgically treated for CSDH between August 2011 and May 2017. Clinical data, computed tomographic findings, surgical outcomes, and recurrence were collected for further analysis.A total of 101 patients (92 male; 91.1%) were analyzed. Ages ranged from 1 to 40 years (27.3 ± 10.5), and 59 (58.4%) patients had a history of recent head trauma. The most frequent symptoms were headache (86.1%) and dizziness (26.7%). A total of 60 (59.4%) patients had arachnoid cyst (AC), and 8 (7.9%) patients had ventriculoperitoneal (V-P) shunt. After burr hole drainage craniotomy, all patients experienced good outcomes, and 1 patient experienced recurrence requiring reoperation. Sixty-eight patients with AC/V-P shunts had a higher incidence of head trauma (P = 0.014), younger age at onset (P0.001), and lower incidence of dizziness (P = 0.013) than did those without AC/V-P shunts. Surgical recurrence rates and outcomes did not differ significantly between patients with and without AC/V-P shunts.Headache is the most common symptom, and AC/V-P shunts are risk factors of CSDH in young patients. AC/V-P shunt-associated CSDH is associated with younger morbidity. Head trauma is a risk factor for AC/V-P shunt-associated CSDH, but is not significance in patients without AC/V-P shunts. Catheter drainage through a burr hole may be the first-choice surgical procedure in treatment of CSDH in young patients, including AC/V-P shunt-associated CSDH.

Background TP53 gene mutations occur in more than 50% of human cancers and the vast majority of these mutations in human cancers are missense mutations, which broadly occur in DNA binding domain (DBD) (Amino acids 102–292) and mainly reside in six “hotspot” residues. TP53 G245C and R273H point mutations are two of the most frequent mutations in tumors and have been verified in several different cancers. In the previous study of the whole genome sequencing (WGS), we found some mutations of TP53 DBD in esophageal squamous cell carcinoma (ESCC) clinical samples. We focused on two high-frequent mutations TP53 p.G245C and TP53 p.R273H and investigated their oncogenic roles in ESCC cell lines, p53-defective cell lines H1299 and HCT116 p53−/−. Results MTS and colony formation assays showed that mutant TP53 G245C and R273H increased cell vitality and proliferation. Flow cytometry results revealed inhibition of ultraviolet radiation (UV)- and ionizing radiation (IR)- induced apoptosis and disruption of TP53-mediated cell cycle arrest after UV, IR and Nocodazole treatment. Transwell assays indicated that mutant TP53 G245C and R273H enhanced cell migration and invasion abilities. Moreover, western blot revealed that they were able to suppress the expression of TP53 downstream genes in the process of apoptosis and cell cycle arrest induced by UV, which suggests that these two mutations can influence apoptosis and growth arrest might be due, at least in part, to down-regulate the expression of P21, GADD45α and PARP. Conclusions These results indicate that mutant TP53 G245C and R273H can lead to more aggressive phenotypes and enhance cancer cell malignancy, which further uncover TP53 function in carcinogenesis and might be useful in clinical diagnosis and therapy of TP53 mutant cancers. Electronic supplementary material The online version of this article (10.1186/s12860-018-0167-y) contains supplementary material, which is available to authorized users.

Supplementary Methods and Figures. (DOCX 3297 kb)

Tumor necrosis factor receptor-associated protein 1 (TRAP1), an important member of mitochondrial heat shock protein 90 family, is involved in multiple biological processes in several types of tumors. However, its pathological role in esophageal squamous cell cancer (ESCC) remains unknown. Herein, we demonstrated the clinical value of TRAP1, and its role in apoptosis and motility in ESCC. The clinical potential of TRAP1 was investigated through immunohistochemical analysis in 328 ESCC samples, which revealed that strong TRAP1 expression was associated with increased risk of lymph node metastasis, while high TRAP1 expression correlated with poor prognosis. Expression of TRAP1 was found to be an independent prognostic factor for patients with ESCC. Additionally, the upregulation of TRAP1 antagonized cisplatin-induced apoptosis while its downregulation sensitized cells to cisplatin-induced apoptosis. As revealed by the transwell assay, TRAP1 overexpression promoted cellular migration and invasion as compared to the control groups. In contrast, silencing of endogenous TRAP1 expression attenuated the ability of migration and invasion. Finally, the molecular mechanism investigated in the present study demonstrated that TRAP1-mediated migration and invasion occurred through STAT3/MMP2 signaling pathway. In conclusion, TRAP1 may be considered as a molecular predictive marker for prognosis and a novel molecular candidate for therapeutic target in ESCC.

Mig-2 (also known as Kindlin-2 and FERMT2) is an important regulator of integrin activation and cell-extracellular matrix adhesion, and involved in carcinogenesis and tumor progression. The aim of this study was to investigate the role of mig-2 in cisplatin-induced apoptosis of human glioma cells in vitro.The expression of mig-2 was modulated in human glioma H4, HS 683 and U-87 MG cells by transfection with a plasmid carrying mig-2 or mig-2 siRNA. Cisplatin-induced apoptosis was detected using Annexin V/PI staining and flow cytometry, as well as MTS analyses. The expression of apoptosis-related or signaling proteins was examined using Western blotting analysis. H4 cells were transfected with plasmids carrying mig-2 mutants to determine the functional domain of mig-2.In the 3 glioma cell lines tested, overexpression of mig-2 significantly attenuated cisplatin-induced apoptosis, whereas knock-down of mig-2 potentiated the apoptosis. The mechanisms of action of mig-2 were further addressed in H4 cells: overexpression of mig-2 markedly reduced cleaved caspase-9, caspase-8, caspase-3 and PARP, as well as p-JNK and p-p38, and increased p-AKT in cisplatin-treated H4 cells, whereas mig-2 siRNA reversely changed these apoptosis-related and signaling proteins. Furthermore, pretreatment with JNK inhibitor SP600125 and p38 inhibitor SB203580, or with AKT inhibitor LY294002 abolished the effects of mig-2 on cisplaxtin-induced apoptosis. In H4 cells, GFP-mig-2 F3 plasmid that contained only the F3 subdomain showed the same efficiency in attenuating cisplatin-induced apoptosis, as the mig-2 wild-type vector did, whereas GFP-mig-2 (1-541) plasmid that lacked the F3 subdomain was inactive.Mig-2 significantly attenuates the antitumor action of cisplatin against human glioma cells in vitro through AKT/JNK and AKT/p38 signaling pathways. The F3 subdomain of mig-2 is necessary and sufficient for this effect.

The role of cyclin B1 in the clinical therapeutic sensitivity of human esophageal squamous cell carcinoma (ESCC) remains to be defined. In this study, we found that elevated cyclin B1 expression attenuated the apoptosis induced by cisplatin or paclitaxel, while knockdown of cyclin B1 enhanced cisplatin or paclitaxel sensitivity in ESCC cells. Cyclin B1-mediated apoptosis may rely on the Bcl-2-dependent mitochondria-regulated intrinsic death pathway, and the antagonizing effect of cyclin B1 on chemotherapeutic agent-induced apoptosis was through PTEN/Akt pathway. Therefore, cyclin B1 might be a therapeutic target for the development of specific and efficient approaches in the treatment of ESCC.

The presynaptic cytomatrix protein Piccolo, encoded by PCLO, is frequently mutated and amplified in esophageal squamous cell carcinoma (ESCC), but its exact roles in ESCC remain unclear. Here we report that Piccolo expression correlates significantly with clinical stage, patient survival and tumor embolus. Functional studies demonstrate that PCLO knockdown remarkably attenuates ESCC malignancy in vitro and in vivo, and ectopic EGFR expression partially compensates for Piccolo loss. PCLO knockdown promotes ubiquitination and degradation of EGFR, which is associated with the negative regulatory effect of Piccolo on E3 ligase Siah1. An anti-Piccolo monoclonal antibody inhibited tumor proliferation in a mouse model of ESCC. These results demonstrate that Piccolo contributes to tumor aggressiveness in ESCC, likely by stabilizing EGFR and promoting EGFR-dependent signaling. Our results further suggest that Piccolo may represent a novel prognostic biomarker and therapeutic target for patients with ESCC.

Leptomeningeal metastasis (LM) is caused by the spread of malignant tumor cells into the subarachnoid space. However, classification and staging of LM in the spinal canal is rare in the literature. The authors reviewed the records of 58 Chinese patients with LM for clinical features, neuroimaging, and treatments. Gadolinium-enhanced magnetic resonance imaging (MRI) of brain and spinal cord were performed in all patients. Removal of intracranial tumors was performed in all patients and diagnoses were confirmed by histology. The study group consisted of 58 patients, with 29 cases presenting with intraspinal symptoms. Of the 58, 8 patients underwent intraspinal tumor removal, 8 received radiotherapy alone, 9 received chemotherapy alone, and 34 patients received combined radiochemotherapy. We classified LM into 3 types: type L or leptomeninges LM, is subdivided into 2 subtypes (subtype LI and LII (a,b)), type N or nerve root LM is subdivided into 2 subtypes (subtype NI and NII (a,b)), and type M or mixed-type LM. We also divided LM into stages of I-IV according to the symptoms and the volume of the tumor based on spinal axial MRI. Type LI LM often occurs in patients with intracranial and intraspinal tumors found simultaneously. Patients who receive surgery for intracranial tumors may present with type N LM. Surgery is suitable for patients with NI LM and LIIb LM in stages III–IV, presenting with severe spinal symptoms. The prognosis is better for type N LM than type L LM.

Oesophageal cancer is one of the most aggressive cancers and is the sixth leading cause of cancer death worldwide(1). Approximately 70% of global oesophageal cancer cases occur in China, with oesophageal squamous cell carcinoma (ESCC) being the histopathological form in the vast majority of cases (>90%)(2,3). Currently, there are limited clinical approaches for the early diagnosis and treatment of ESCC, resulting in a 10% five-year survival rate for patients. However, the full repertoire of genomic events leading to the pathogenesis of ESCC remains unclear. Here we describe a comprehensive genomic analysis of 158 ESCC cases, as part of the International Cancer Genome Consortium research project. We conducted whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases, of which 53 cases, plus an additional 70 ESCC cases not used in the whole-genome and whole-exome sequencing, were subjected to array comparative genomic hybridization analysis. We identified eight significantly mutated genes, of which six are well known tumour-associated genes (TP53, RB1, CDKN2A, PIK3CA, NOTCH1, NFE2L2), and two have not previously been described in ESCC (ADAM29 and FAM135B). Notably, FAM135B is identified as a novel cancer-implicated gene as assayed for its ability to promote malignancy of ESCC cells. Additionally, MIR548K, a microRNA encoded in the amplified 11q13.3-13.4 region, is characterized as a novel oncogene, and functional assays demonstrate that MIR548K enhances malignant phenotypes of ESCC cells. Moreover, we have found that several important histone regulator genes (MLL2 (also called KMT2D), ASH1L, MLL3 (KMT2C), SETD1B, CREBBP and EP300) are frequently altered in ESCC. Pathway assessment reveals that somatic aberrations are mainly involved in the Wnt, cell cycle and Notch pathways. Genomic analyses suggest that ESCC and head and neck squamous cell carcinoma share some common pathogenic mechanisms, and ESCC development is associated with alcohol drinking. This study has explored novel biological markers and tumorigenic pathways that would greatly improve therapeutic strategies for ESCC.

Filamin binding LIM protein 1, also known as migfilin, is a skeleton organization protein that binds to mitogen-inducible gene 2 at cell-extracellular matrix adhesions. The aim of this study was to investigate the role of migfilin in cisplatin-induced apoptosis in human glioma cells, to determine the functional domains of migfilin, and to elucidate the molecular mechanisms underlying the regulation of cisplatin-related chemosensitivity. The human glioma cell lines Hs683, H4, and U-87 MG were transfected with pEGFP-C2-migfilin to elevate the expression level of migfilin. RNA interference was used to reduce the expression of migfilin. To determine the functional domains of migfilin, U-87 MG cells were transfected with plasmids of migfilin deletion mutants. After treatment with cisplatin (40 μmol/L) for 24 h, the cell viability was assessed using the MTS assay, and the cell apoptotic was examined using the DAPI staining assay and TUNEL analysis. Expression levels of apoptosis-related proteins were detected by Western blot analysis. Overexpression of migfilin significantly enhanced cisplatin-induced apoptosis in Hs683, H4, and U-87 MG cells, whereas downregulation of migfilin expression inhibited the chemosensitivity of these cell lines. The N-terminal region of migfilin alone was able to enhance the cisplatin-induced apoptosis. However, despite the existence of the N-terminal region, mutants of migfilin with any one of three LIM domains deleted led to a function loss. Furthermore, apoptotic proteins (PARP and caspase-3) and the anti-apoptotic protein Bcl-xL were modulated by the expression level of migfilin in combination with cisplatin. The LIM1-3 domains of migfilin play a key role in sensitizing glioma cells to cisplatin-induced apoptosis through regulation of apoptosis-related proteins.

Background: The oncogenesis and developmental mechanisms of glioma must be clarified to control the disease. Results: Migfilin relates to pathological grades, prognosis of glioma, and regulates motility of glioma cells. Conclusion: Migfilin mediates migration and invasion through EGFR-induced PLC-γ and STAT3 pathways. Significance: Migfilin helps us better understand the pathogenesis of glioma, and Migfilin may be a molecular marker in diagnosis and an indicator in prognosis., Migfilin is critical for cell shape and motile regulation. However, its pathological role in glioma is unknown. Using an immunohistochemical staining assay, we demonstrate that there is a significant correlation between expression of Migfilin and pathological tumor grade in 217 clinical glioma samples. High Migfilin expression is associated with poor prognosis for patients with glioma. Investigation of the molecular mechanism shows that Migfilin promotes migration and invasion in glioma cells. Moreover, Migfilin positively modulates the expression and activity of epidermal growth factor receptor, and Migfilin-mediated migration and invasion depend on epidermal growth factor receptor-induced PLC-γ and STAT3-signaling pathways. Our results may provide significant clinical application, including use of Migfilin as a molecular marker in glioma for early diagnosis and as an indicator of prognosis.