Comparison of endoscopic third ventriculostomy versus cerebrospinal fluid shunt procedures for the treatment of pediatric hydrocephalus in Taiwan.

PURPOSE: Pediatric hydrocephalus is the most common cause of surgically treatable neurological disease in children. Controversies exist whether endoscopic third ventriculostomy (ETV) or cerebrospinal fluid (CSF) shunt placement is the most appropriate treatment for pediatric hydrocephalus. This study aimed to compare the risk of re-operation and death between the two procedures. METHODS: We performed a retrospective population-based cohort study and included patients younger than 20-years-old who underwent CSF shunt or ETV for hydrocephalus from the Taiwan National Health Insurance Research Database. RESULTS: A total of 3,555 pediatric patients from 2004 to 2017 were selected, including 2,340 (65.8%) patients that received CSF shunt placement and 1215 (34.2%) patients that underwent ETV. The incidence of all-cause death was 3.31 per 100 person-year for CSF shunt group and 2.52 per 100 person-year for ETV group, with an adjusted hazard ratio (HR) of 0.79 (95% confidence interval [CI] = 0.66-0.94, p = 0.009). The cumulative incidence competing risk for reoperation was 31.2% for the CSF shunt group and 26.4% for the ETV group, with an adjusted subdistribution HR of 0.82 (95% CI = 0.70-0.96, p = 0.015). Subgroup analysis showed that ETV was beneficial for hydrocephalus coexisting with brain or spinal tumor, central nervous system infection, and intracranial hemorrhage. CONCLUSION: Our data indicates ETV is a better operative procedure for pediatric hydrocephalus when advanced surgical techniques and instruments are available.

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21.

Medulloblastoma (MB) is the most common type of malignant childhood brain tumor. We previously showed that inhibitors of apoptosis proteins (IAP) small-molecule inhibitors (LCL161 or LBW242) combined with chemotherapy have synergistic antiproliferative effects on MB cells. The synergistic antitumor effects of combination treatments happen through induction of autophagy and caspase-3/7-activated apoptosis. Here, we investigated the effects of IAP inhibitors or silencing IAP on cell cycle regulation. We discovered that treatment with IAP inhibitors or their combination with conventional chemotherapy (vincristine or cisplatin), as well as RNAi knockdown of cIAP1/2 or XIAP arrested MB cells in the G2/M phase through downregulation of cyclin B1-CDK1 and cyclin A-CDK1/2. Among these three IAPs, only silencing cIAP1 expression enhanced p21 dependent-G2/M phase accumulation. IAP inhibitors reduced cIAP1 expression and increased p21 expression in time course experiments. Furthermore, cIAP1 can govern p21 proteasomal degradation via neddylation in lieu of ubiquitination. Inhibition of IAPs significantly abrogated cIAP1-mediated p21 degradation. We also observed an inverse correlation between nuclear cIAP1 and nuclear p21 expressions in MB tumor tissues. These findings provide new mechanistic evidence of the influence of IAP inhibitors on MB cell proliferation through disruption of the cell cycle.

Blockade of Inhibitors of Apoptosis Proteins in Combination with Conventional Chemotherapy Leads to Synergistic Antitumor Activity in Medulloblastoma and Cancer Stem-Like Cells.

BACKGROUND: Medulloblastoma (MB) is the most common pediatric primary malignant brain tumor. Approximately one-third of MB patients succumb to treatment failure and some survivors suffer detrimental side effects. Hence, the purpose of this study is to explore new therapeutic regimens to overcome chemotherapeutic agent resistance or reduce chemotherapy-induced toxicity. METHODS: We detected the expression of inhibitors of apoptosis proteins (IAPs) in MB and CD133+ MB cell lines and MB tissues using immunoblotting and immunohistochemical staining. The antitumor effects of inhibitors against IAPs on MB or CD133+ MB cells were evaluated by MTT assay, Annexin V/PI analysis, and caspase-3/7 activity. Autophagy was assessed by the conversion of light chain (LC) 3-I to LC3-II and Cyto-ID autophagy detection kit. RESULTS: MB cells showed higher expression of IAPs compared to normal astrocytes and normal brain tissues. Conventional chemotherapeutic agents combined with small-molecule IAP inhibitors (LCL161 or LBW242) showed a synergistic effect in MB cells. Combined treatments triggered apoptosis in MB cells through activation of caspase-3/7 and autophagic flux simultaneously. In addition, we found that CD133+ MB cells with features of cancer stem cells displayed higher levels of X-linked inhibitor of apoptosis (XIAP) and cellular inhibitor of apoptosis 1/2 (cIAP1/2), and were hypersensitive to treatment with IAP inhibitors. CONCLUSIONS: These results shed light on the biological effects of combination therapy on MB cells and illustrate that IAP inhibitors are more effective for CD133+ stem-like MB cells.

Risk of death in patients with post-traumatic cerebrospinal fluid leakage--analysis of 1773 cases.

BACKGROUND: Post-traumatic cerebrospinal fluid (CSF) leakage is one of the most troublesome conditions associated with head trauma. CSF fistulae, meningitis/central nervous infection, or even death may accompany it. Few studies have discussed post-traumatic CSF leakage as a risk factor in mortality following head trauma. We conducted this cohort study to examine the issue. METHODS: We reviewed the records in the Taiwan Traumatic Brain Injury (TBI) Registry System between 1993 and 2008. The study group included patients with acute TBI and post-traumatic CSF leakage, and the control group included cases with TBI but without CSF leakage, selected randomly at a 5:1 ratio with respect to the study group. The demographic data, Glasgow Coma Scale, brain computerized tomography, association of skull fractures and intracranial lesions, and 1-year mortality rates between these two cohorts were reviewed meticulously and analyzed statistically. RESULTS: Of 174,236 cases, 1773 with post-traumatic CSF leakage were included in the study group, and 8865 cases in the control group. Of the total 10,638 sampled cases, 406 (3.8%) died during the 1-year follow-up period, 159 (9.0%) cases in the CSF leakages group, and 247 (2.8%) in the control group. The patients with CSF leakage had a significantly higher mortality rate within 1 year (adjusted hazard ratio = 1.44, p < 0.001) than those without. We divided the CSF leakage group into three subgroups: otorrhea (n = 568), rhinorrhea (n = 302), and tension pneumocephalus (n = 903). The mortality rates were 8.5% (48/568) in the otorrhea subgroup, 10.9% (33/302) in the rhinorrhea subgroup, and 8.6% (78/903) in the tension pneumocephalus subgroup. The cases with CSF rhinorrhea had a significantly higher mortality rate than the other two subgroups (p < 0.05). All three subgroups had significantly higher mortality rates than the control group during the 1-year follow-up period (adjusted hazard ratios = 2.29, 1.35, and 1.32 in the rhinorrhea, tension pneumocephalus, and otorrhea subgroups, respectively). CONCLUSION: Post-traumatic CSF leakages had higher mortality rates than those without CSF leakages in TBI cases, and the cases with CSF rhinorrhea had worse outcomes compared with CSF leakages with pneumocephalus or otorrhea.

Roles of microRNA-1 in hypoxia-induced apoptotic insults to neuronal cells.

Hypoxia is a common occurrence in brain tumors and traumatic brain injury. microRNA (miR)-1 participates in the regulation of brain development and neuronal function. Interestingly, miR-1 can mediate ischemia-induced injury to cardiomyocytes. This study was designed to evaluate the roles of miR-1 in hypoxia-induced insults to neurons and the possible mechanisms. Exposure of neuro-2a cells to oxygen/glucose deprivation (OGD) or cobalt chloride decreased cell viability and induced cell apoptosis in time-dependent manners. In parallel, OGD caused augmentation of cellular Bax and cytochrome c levels, a reduction in the mitochondrial membrane potential (MMP), activation of caspase-3, and fragmentation of DNA. miR-1 was induced in neuro-2a cells by OGD. Knocking down miR-1 expression using specific antisense inhibitors significantly alleviated OGD-induced neuronal death. Administration of OGD to neuro-2a cells induced heat-shock protein (HSP)-70 messenger (m)RNA and protein expressions. A bioinformatic search revealed that miR-1-specific binding elements exist in the 3'-untranslated region of HSP-70 mRNA. Overexpression of miR-1 simultaneously attenuated OGD-induced HSP-70 mRNA and protein expressions. In comparison, knocking down miR-1 expression synergistically enhanced OGD-induced HSP-70 mRNA. As to the mechanism, reducing miR-1 expression lowered OGD-induced alterations in the MMP, caspase-3 activation, DNA fragmentation, and cell apoptosis. Taken together, this study shows that miR-1 can target HSP-70 expression and consequently mediate hypoxia-induced apoptotic insults to neuro-2a cells via an intrinsic Bax-mitochondrion-caspase protease pathway.

A Prospective Randomized Study of Brain Tissue Oxygen Pressure-Guided Management in Moderate and Severe Traumatic Brain Injury Patients.

The purpose of this study was to compare the effect of PbtO2-guided therapy with traditional intracranial pressure- (ICP-) guided treatment on the management of cerebral variables, therapeutic interventions, survival rates, and neurological outcomes of moderate and severe traumatic brain injury (TBI) patients. From 2009 to 2010, TBI patients with a Glasgow coma scale <12 were recruited from 6 collaborative hospitals in northern Taiwan, excluding patients with severe systemic injuries, fixed and dilated pupils, and other major diseases. In total, 23 patients were treated with PbtO2-guided management (PbtO2 > 20 mmHg), and 27 patients were treated with ICP-guided therapy (ICP < 20 mmHg and CPP > 60 mmHg) in the neurosurgical intensive care unit (NICU); demographic characteristics were similar across groups. The survival rate in the PbtO2-guided group was also significantly increased at 3 and 6 months after injury. Moreover, there was a significant correlation between the PbtO2 signal and Glasgow outcome scale-extended in patients from 1 to 6 months after injury. This finding demonstrates that therapy directed by PbtO2 monitoring is valuable for the treatment of patients with moderate and severe TBI and that increasing PaO2 to 150 mmHg may be efficacious for preventing cerebral hypoxic events after brain trauma.

Posterior Cerebral Artery Pseudoaneurysm, a Rare Complication of Pituitary Tumor Transsphenoidal Surgery: Case Report and Literature Review.

Endoscopic endonasal transsphenoidal surgery for pituitary tumors has been the standard therapy for decades. This approach offers surgeons an effective, safe, and wide exposure to the pituitary gland, with a relatively low mortality rate and acceptable complication rates. However, severe complications, including cerebrospinal fistula, meningitis, neural component injury, and vascular injury, may occur. One of the most common and severe complications is carotid artery injury; however, only 2 posterior cerebral artery injuries with pseudoaneurysm formation have been reported previously. One of them received bypass surgery and recovered well, but the other received endovascular treatment and died of intracranial hypertension. Herein, we report a rare case of iatrogenic pseudoaneurysm formation with hemorrhage after transsphenoidal surgery, in which tumor traction-related adjacent vessel injury was most likely. Aneurysm clipping, vascular bypass, and embolization are considered reasonable choices depending on the patient's condition for iatrogenic aneurysm formation. In our case, no surgical or endovascular intervention was performed, and the aneurysm healed spontaneously 3 weeks later.

Comparison of percutaneous endoscopic lumbar discectomy and open lumbar surgery for adjacent segment degeneration and recurrent disc herniation.

Objective. The goal of the present study was to examine the clinical results of percutaneous endoscopic lumbar discectomy (PELD) and open lumbar surgery for patients with adjacent segment degeneration (ASD) and recurrence of disc herniation. Methods. From December 2011 to November 2013, we collected forty-three patients who underwent repeated lumbar surgery. These patients, either received PELD (18 patients) or repeated open lumbar surgery (25 patients), due to ASD or recurrence of disc herniation at L3-4, L4-5, or L5-S1 level, were assigned to different groups according to the surgical approaches. Clinical data were assessed and compared. Results. Mean blood loss was significantly less in the PELD group as compared to the open lumbar surgery group (P < 0.0001). Hospital stay and mean operating time were shorter significantly in the PELD group as compared to the open lumbar surgery group (P < 0.0001). Immediate postoperative pain improvement in VAS was 3.5 in the PELD group and -0.56 in the open lumbar surgery group (P < 0.0001). Conclusion. For ASD and recurrent lumbar disc herniation, PELD had more advantages over open lumbar surgery in terms of reduced blood loss, shorter hospital stay, operating time, fewer complications, and less postoperative discomfort.

Elimination of cancer stem-like cells and potentiation of temozolomide sensitivity by Honokiol in glioblastoma multiforme cells.

Glioblastoma multiforme (GBM) is the most common adult malignant glioma with poor prognosis due to the resistance to radiotherapy and chemotherapy, which might be critically involved in the repopulation of cancer stem cells (CSCs) after treatment. We had investigated the characteristics of cancer stem-like side population (SP) cells sorted from GBM cells, and studied the effect of Honokiol targeting on CSCs. GBM8401 SP cells possessed the stem cell markers, such as nestin, CD133 and Oct4, and the expressions of self-renewal related stemness genes, such as SMO, Notch3 and IHH (Indian Hedgehog). Honokiol inhibited the proliferation of both GBM8401 parental cells and SP cells in a dose-dependent manner, the IC50 were 5.3±0.72 and 11±1.1 µM, respectively. The proportions of SP in GBM8401 cells were diminished by Honokiol from 1.5±0.22% down to 0.3±0.02% and 0.2±0.01% at doses of 2.5 µM and 5 µM, respectively. The SP cells appeared to have higher expression of O6-methylguanine-DNA methyltransferase (MGMT) and be more resistant to Temozolomide (TMZ). The resistance to TMZ could be only slightly reversed by MGMT inhibitor O6-benzylguanine (O6-BG), but markedly further enhanced by Honokiol addition. Such significant enhancement was accompanied with the higher induction of apoptosis, greater down-regulation of Notch3 as well as its downstream Hes1 expressions in SP cells. Our data indicate that Honokiol might have clinical benefits for the GBM patients who are refractory to TMZ treatment.

Sensory axonal dysfunction in cervical radiculopathy.

OBJECTIVE: The aim of this study was to evaluate changes in sensory axonal excitability in the distal nerve in patients with cervical radiculopathy. METHODS: The patients were classified by the findings of cervical MRI into two subgroups: 22 patients with C6/7 root compression and 25 patients with cervical cord and root compression above/at C6/7. Patients were investigated using conventional nerve conduction studies (NCS) and nerve excitability testing. Sensory nerve excitability testing was undertaken with stimulation at the wrist and recording from digit II (dermatome C6/7). The results were compared with healthy controls. Both preoperative and postoperative tests were performed if the patient underwent surgery. RESULTS: Sensory axonal excitability was significantly different in both cohorts compared with healthy controls, including prolonged strength-duration time constant, reduced S2 accommodation, increased threshold electrotonus hyperpolarisation (TEh (90-100 ms)), and increased superexcitability. The changes in these excitability indices are compatible with axonal membrane hyperpolarisation. In five patients who underwent surgery, the postoperative sensory excitability was tested after 1 week, and showed significant changes in TE (TEh (90-100 ms) and TEh slope, p<0.05) between presurgery and postsurgery. CONCLUSIONS: The present study demonstrated distal nerve axonal hyperpolarisation in patients with cervical radiculopathy. These findings suggest that the hyperpolarised pattern might be due to Na(+)-K(+) ATPase overactivation induced by proximal ischaemia, or could reflect the remyelinating process. Distal sensory axons were hyperpolarised even though there were no changes in NCS, suggesting that nerve excitability testing may be more sensitive to clinical symptoms than NCS in patients with cervical radiculopathy.

Solitary intracranial osteoma with attachment to the falx: a case report.

BACKGROUND: Intracranial osteomas are uncommon lesions that usually arise from the inner table of the cranium. There are few reports in the literature of intracranial osteomas with meninges attachment and without direct relation with the skull bone; these osteomas were mostly attached with dura. We report a rare osteoma with falx attachment. CASE: A 64-year-old woman presented with a 3-month history of intermittent tinnitus and dizziness. The scout film of petrous bone computed tomography scan revealed a high-density lesion in the frontal area. Magnetic resonance imaging showed a 2.5-cm mass attached to the surface of the falx in the right frontal parasagittal area. The patient underwent right frontal craniotomy, and a bony hard mass was found located in the right frontal parasagittal region extra-axially, with its medial surface attached to the falx. It could not be broken down by the cavitron ultrasonic surgical aspirator or even the cutting loop and was detached from the falx and removed in one piece. Histopathological examination showed a nodule with bony trabeculae and bone marrow tissue, compatible with osteoma. The postoperative course was uneventful, and the patient was discharged from the hospital with no neurological deficits one week after operation. CONCLUSIONS: This is the first case report in the English literature of an intracranial osteoma arising from the falx. Because of their slow growth and their locations in silent brain areas, intracranial osteomas are usually diagnosed incidentally. Surgical resection is the primary treatment choice.

MicroRNA-495 inhibits proliferation of glioblastoma multiforme cells by downregulating cyclin-dependent kinase 6.

BACKGROUND: Glioblastoma multiforme (GBM) is the most aggressive type of glioma and carries the poorest chances of survival. There is therefore an urgent need to understand the mechanisms of glioma tumorigenesis and develop or improve therapeutics. The aim of this study was to assess the possible prognostic value of cyclin-dependent kinase 6 (CDK6) and the effects of microRNA-495 (miR-495) manipulation on CDK6 expression and cell survival in glioma cells. METHODS: Analyses of clinical specimens from GBM patients were used. Expression of CDK6 was analyzed by real-time polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemistry. Expression of CDK6 was also analyzed after over-expression of miR-495 in T98 cells; both cell proliferation and RB phosphorylation were examined. Cell proliferation, cell cycle distribution, and RB phosphorylation were also examined after knockdown of CDK6 in U87-MG and T98 cells. RESULTS: Analyses of clinical specimens from GBM patients identified that CDK6 is significantly expressed in gliomas. CDK6 antigen expression was higher in tumor cores and margins than in adjacent normal brain tissues, and higher levels of CDK6 expression in the tumor margin correlated with decreased survival. Over-expression of miR-495 in T98 cells downregulated the expression of CDK6 and inhibited retinoblastoma phosphorylation, and knockdown of CDK6 in U87-MG and T98 cells by siRNAs resulted in cell cycle arrest at the G1/S transition and inhibition of cell proliferation. CONCLUSIONS: This study revealed miR-495 is down-regulated in glioma tissues. Furthermore, miR-495 regulated CDK6 expression and involved in glioma cell growth inhibition, which indicated the possible role of miR-495 in tumor progression.

Early enteral nutrition and clinical outcomes of severe traumatic brain injury patients in acute stage: a multi-center cohort study.

Guidelines for patients with severe traumatic brain injury (sTBI) published in 2007 recommend providing early nutrition after trauma. Early enteral nutrition (EN) started within 48 h post-injury reduces clinical malnutrition, prevents bacterial translocation from the gastrointestinal tract, and improves outcome in sTBI patients sustaining hypermetabolism and hypercatabolism. The aim of this study was to examine the effect of early EN support on survival rate, Glasgow Coma Scale (GCS) score, and clinical outcome of sTBI patients. Medical records of sTBI patients with GCS scores 4-8 were recruited from 18 hospitals in Taiwan, excluding patients with GCS scores ≤3. During 2002-2010, data from 145 EN patients receiving appropriate calories and nutrients within 48 h post-trauma were collected and compared with 152 non-EN controls matched for gender, age, body weight, initial GCS score, and operative status. The EN patients had a greater survival rate and GCS score on the 7th day in the intensive care unit (ICU), and a better outcome at 1 month post-injury. After adjusting for age, gender, initial GCS score, and recruitment period, the non-EN patients had a hazard ratio of 14.63 (95% CI 8.58-24.91) compared with EN patients. The GCS score during the first 7 ICU days was significantly improved among EN patients with GCS scores of 6-8 compared with EN patients with GCS scores of 4-5 and non-EN patients with GCS scores of 6-8. This finding demonstrates that EN within 48 h post-injury is associated with better survival, GCS recovery, and outcome among sTBI patients, particularly in those with a GCS score of 6-8.

Minimally invasive decompression with posterior column reinforcement for the treatment of symptomatic osteoporotic fracture with spinal stenosis in lumbar vertebrae.

An osteoporotic fracture (OF) in the second to fifth lumbar vertebrae with spinal stenosis may be an indication for surgical treatment, but carries the risks of instability or instrumentation failure. Modified surgical procedures have been developed to manage patients with challenging OF. We retrospectively studied 12 patients (three male, nine female; mean age±standard deviation=73.5±7.2 years) who underwent minimally invasive decompression and posterior column reinforcement with polymethylmethacrylate. During a mean follow-up period of 24.8±3.1 months, pain severity and functional impairment were both significantly reduced, as measured by the visual analog scale and the Oswestry disability index. Nine patients (75%) experienced a satisfactory outcome while the other three (25%) were unchanged. Plain radiographs showed stable spinal alignment and immobilization of flexion-extension within the PMMA construct. Five complications were managed successfully, including one by revision surgery. These procedures are a feasible surgical option in the elderly population studied.

Comparison of the kinematic features between the in vivo active and passive flexion-extension of the subaxial cervical spine and their biomechanical implications.

STUDY DESIGN: An in vivo motion analysis of active and passive kinematic cervical flexion-extension. OBJECTIVE: The study was aimed at investigating the differences between the active and passive kinematic sagittal motions of the subaxial cervical spine. SUMMARY OF BACKGROUND DATA: The biomechanical behavior of the cadaver spinal column is different from that of the in vivo spine. Two major issues were concerned: the complex neuromuscular control of the in vivo cervical spinal motion and the unknown true nature of the passive cervical spinal motion. The kinematic characteristics of active and passive spinal motions need to be clarified. METHODS: The active and passive motion patterns of the subaxial spine in the sagittal plane were recorded by digital video fluoroscopy. The motion of functional units from C3-C4 to C6-C7 of the cervical spine were processed using Image J, an image processing software, in both active and passive cervical motions. The Cobb's angle was measured in serial flexion and extension motions, and a comparison of this angle in both active and passive motions was made in 12 patients with degenerative disc herniation. RESULTS: The difference between active and passive gentle flexion was minimal, and the degree of their correlation was high. The differences in the degree of gentle extension between active and passive motion were variable, and their correlation was low. During early passive flexion, the degree of flexion at the upper level was less and that at the lower level was more as compared to that observed at the respective levels in early active flexion. CONCLUSION: In gentle flexion, the active and passive cervical spinal motions are closely approximated, which implies that the active neuromuscular control mainly plays the buffer-and-brake mechanism without placing additional load on the spine. In contrast, the degree of passive extension is limited, and active neuromuscular control may place additional load on the spine.

Activation of imidazoline I2B receptors is linked with AMP kinase pathway to increase glucose uptake in cultured C2C12 cells.

Guanidine, the active ingredient extracted from Galega officinalis, is introduced as a ligand for imidazoline I2 receptor (I2R) because guanidine decreased plasma glucose via an activation of I2BR to increase glucose uptake into skeletal muscle isolated from Wistar rats. However, the signals for this action of guanidine remained obscure. In the present study, we used the cultured skeletal muscle fibroblast named C2C12 cell line to investigate this point. We found that guanidine increased the phosphorylation of AMP-activated protein kinase (AMPK) in addition to the higher of glucose transporter GLUT4 expression and glucose uptake. These effects of guanidine were blocked by the pretreatment with I2R antagonist BU224 but not by the blockade of I2AR amiloride. Moreover, compound C at concentrations sufficient to inhibit AMPK blocked the guanidine-induced glucose uptake and GLUT4 protein level. These results suggested that guanidine increases glucose uptake via an activation of I2BR through AMPK activation in skeletal muscle cell; this view has not been mentioned before.

Stereotactic brain biopsy: Single center retrospective analysis of complications.

OBJECTIVE: Stereotactic biopsy is a widely used surgical technique for the histological diagnosis of intracranial lesions. Potential risks of this procedure, such as hemorrhage, seizure, and infection have been established, and different risk factors have been characterized. However, these risks have been addressed by only few studies conducted in Asian countries. MATERIALS AND METHODS: The study group is comprised of 299 consecutive stereotactic biopsy procedures by 11 neurosurgeons between 2004 and 2007. The pre-operative medical conditions, methods of biopsy and postoperative complications were analyzed. RESULT: The overall diagnostic yield was 90.64%. Complications were observed in 7.36% of the cases, with symptomatic hemorrhages occurring in 4.35% of the cases, and the overall mortality rate in this study population was 1.34%. Patients with liver cirrhosis were at a higher risk of hemorrhage. Other clinical, radiological, or histological variables were not associated with an increased risk of complications. CONCLUSION: Stereotactic brain biopsy is a safe and reliable way to obtain a histological diagnosis. Based on our recent clinical experiences, the data suggests that more attention should be paid to liver cirrhotic patients, since the chance on hemorrhage is significantly larger.