Imbalance in ALR ubiquitination accelerates the progression of nonalcoholic steatohepatitis to hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. Accumulating evidence indicates that non-alcoholic steatohepatitis (NASH) is a key predisposing factor for HCC occurrence. However, the precise mechanisms driving NASH transition to HCC remain largely obscure. Augmenter of liver regeneration (ALR) is a sulfhydryl oxidase and cytochrome c reductase that functions as an important regulator of mitochondrial dynamics. In this study, we focused on ALR ubiquitination-mediated degradation and its potential contribution to NASH-driven HCC progression at the mitochondrial level. Hepatic ALR expression in HCC patients was determined using immunohistochemical analysis. Mice with liver-specific deletion of ALR (ALRCKO) and ALRWT mice were fed a western diet (WD) and high-sugar solution for induction of NASH. HCC in animals was induced via peritoneal administration of CCl4. ALR expression was markedly decreased in liver tissues of patients with NASH and HCC compared with non-NASH and non-tumor tissues. Similarly, in ALRWT mice, the ALR level in tumor tissue was reduced relative to that in para-tumor tissue. In the ALRCKO group, mice fed WD plus CCl4 developed HCC starting at week 12 while ALRWT mice fed WD plus CCl4 developed HCC at week 24. Analysis of protein posttranslational modifications revealed ubiquitylation (Ub) and deubiquitination (DUb) of ALR by murine double minute 2 (MDM2) and ubiquitin-specific protease 36 (USP36), respectively. Imbalance between Ub and DUb of ALR resulted in profound ALR degradation, which appeared to be reversibly associated with Edmondson-Steiner tumor grade. Rescue of ALR levels via gene transfection abolished tumor malignant features to a certain extent in vitro. Notably, ALR deletion substantially enhanced mitochondrial fission by activating Drp1 phosphorylation at Ser616, thus disrupting the balance of mitochondrial dynamics between fission and fusion and severely impairing oxidative phosphorylation (OXPHOS) and ATP synthesis, instead enhancing anaerobic metabolism, which might be attributed to steatotic hepatocyte transition into the malignant HCC phenotype. Hepatic ALR depletion via dysregulation of ubiquitination is a critical aggravator of NASH-HCC progression and represents a promising therapeutic target for related liver diseases.

AID assists DNMT1 to attenuate BCL6 expression through DNA methylation in diffuse large B-cell lymphoma cell lines.

The BCL6 proto-oncogene encodes a transcriptional repressor, which is required for germinal centers (GCs) formation and lymphomagenesis. Previous studies have been reported that the constitutive expression of BCL6 leads to diffuse large B cell lymphoma (DLBCL) through activation-induced cytidine deaminase (AID) mediated chromosomal translocations and mutations. However, other DLBCLs (45%) without structural variants were characterized by abnormally high level of BCL6 expression through an unknown mechanism. Herein, we report that deficiency in AID or methyltransferase 1 (DNMT1) triggers high level of BCL6 expression. AID-DNMT1 complex binds to -0.4 kb -0 kb region of BCL6 promoter and contributes to generate BCL6 methylation which results in inhibition of BCL6 expression. The proteasome pathway inhibitor MG132 induces accumulation of AID and DNMT1, causes decreased BCL6 expression, and leads to cell apoptosis and tumor growth inhibition in DLBCL cell xenograft mice. These findings propose mechanistic insight into an alternative cofactor role of AID in assisting DNMT1 to maintain BCL6 methylation, thus suppress BCL6 transcription in DLBCL. This novel mechanism will provide a new drug selection in the therapeutic approach to DLBCL in the future.

Role of TLR4 Receptor Complex in the Regulation of the Innate Immune Response by Fibronectin.

Chronic inflammation and subsequent tissue fibrosis are associated with a biochemical and mechanical remodeling of the fibronectin matrix. Due to its conformational lability, fibronectin is considerably stretched by the contractile forces of the fibrotic microenvironment, resulting in the unfolding of its Type III domains. In earlier studies, we have shown that a peptide mimetic of a partially unfolded fibronectin Type III domain, FnIII-1c, functions as a Damage Associated Molecular Pattern (DAMP) molecule to induce activation of a toll-like receptor 4 (TLR4)/NF-B pathway and the subsequent release of fibro-inflammatory cytokines from human dermal fibroblasts. In the current study, we evaluated the requirement of the canonical TLR4/MD2/CD14 receptor complex in the regulation of FnIII-1c induced cytokine release. Using dermal fibroblasts and human embryonic kidney (HEK) cells, we found that all the components of the TLR4/MD2/CD14 complex were required for the release of the fibro-inflammatory cytokine, interleukin 8 (IL-8) in response to both FnIII-1c and the canonical TLR4 ligand, lipopolysaccharide (LPS). However, FnIII-1c mediated IL-8 release was strictly dependent on membrane-associated CD14, while LPS could use soluble CD14. These findings demonstrate that LPS and FnIII-1c share a similar but not identical mechanism of TLR4 activation in human dermal fibroblasts.

Neurogenic Niche Conversion Strategy Induces Migration and Functional Neuronal Differentiation of Neural Precursor Cells Following Brain Injury.

Glial scars formed after brain injuries provide permissive cues for endogenous neural precursor/stem cells (eNP/SCs) to undergo astrogenesis rather than neurogenesis. Following brain injury, eNP/SCs from the subventricular zone leave their niche, migrate to the injured cortex, and differentiate into reactive astrocytes that contribute to glial scar formation. In vivo neuronal reprogramming, directly converting non-neuronal cells such as reactive astrocytes or NG2 glia into neurons, has greatly improved brain injury repair strategies. However, reprogramming carries a high risk of future clinical applications such as tumorigenicity, involving virus. In this study, we constructed a neural matrix to alter the adverse niche at the injured cortex, enabling eNP/SCs to differentiate into functional neurons. We found that the neural matrix functioned as a "glial trap" that largely concentrated and limited reactive astrocytes to the core of the lesion area, thus altering the adverse niche. The eNP/SCs migrated toward the injured cortex and differentiated into functional neurons. In addition, regenerated neurites extended across the boundary of the injured cortex. Mice treated with the neural matrix demonstrated significant behavioral recovery. For the first time, we induced eNP/SC-derived functional neurons in the cortex after brain injury without the use of viruses, microRNAs, or small molecules. Our novel strategy of applying this "glial trap" to obtain functional neurons in the injured cortex may provide a safer and more natural therapeutic alternative to reprogramming in future clinical applications.

Identification and characterization of a murine model of BCR­ABL1+ acute B­lymphoblastic leukemia with central nervous system metastasis.

Breakpoint cluster region (BCR)­Abelson murine leukemia (ABL)1+ acute B­lymphoblastic leukemia (B­ALL) is a disease associated with a dismal prognosis and a high incidence of central nervous system (CNS) metastasis. However, BCR­ABL1+ B­ALL with CNS infiltration has not been previously characterized, at least to the best of our knowledge. In the present study, a murine model of BCR­ABL1+ B­ALL with CNS metastasis was established using retroviral transduction. The vast majority of BCR­ABL1+ leukemic cells were found to be immature B cells with a variable proportion of pro­B and pre­B populations. The present results indicated that the BCR­ABL1+ B­leukemic cells expressed high levels integrin subunit alpha 6 (Itga6) and L­selectin adhesion molecules, and have an intrinsic ability to disseminate and accumulate in CNS tissues, predominantly in meninges. On the whole, these results provide an approach for addressing the mechanisms of BCR­ABL1+ B­ALL with CNS metastasis and may guide the development of novel therapeutic strategies.

RAG2 involves the Igκ locus demethylation during B cell development.

The genes encoding the immunoglobulin κ light chain are assembled during B cell development by V(D)J recombination. For efficient rearrangement, the Igκ locus must undergo a series of epigenetic changes. One such epigenetic mark is DNA methylation. The mechanism that the Igκ locus is selectively demethylated at the pre-B cell stage has not previously been characterized. Here, we employed bisulfite DNA-modification assays to analyze the methylation status of the Igκ locus in primary pre-B cells from RAG-deficient mice with pre-rearranged Igh knock-in allele. We observed that the Igκ locus was hypermethylated in RAG2-deficient pre-B cells but hypomethylated in RAG1-deficient pre-B cells, indicating that wild-type (WT) RAG2 involves the Igκ locus demethylation in a RAG1-independent manner prior to rearrangement. We generated a series of RAG2 mutants between residue 350 and 383. We showed that these mutants mediated the Igκ rearrangement but failed to regulate the Igκ gene demethylation. We further analyzed that these mutants could increase RAG recombinase activity in vivo. We conclude that residues 350-383 region are responsible for endogenous Igκ locus demethylation at pre-B cells. We propose that WT RAG2 has an intrinsic function to regulate the Igκ locus demethylation.

Epigenetic modifications of the VH region after DJH recombination in Pro-B cells.

The variable region of murine immunoglobulin heavy chain (Igh) is assembled by sequential DH -JH and VH -DJH recombination. The accessibility of the Igh locus determines the order of rearrangement. Because of the large number of VH genes and the lack of a suitable model, the epigenetic modifications of VH genes after DJH recombination have not previously been characterized. Here, we employed two v-Abl pro-B cell lines, in which the Igh locus is in germline and DJH -recombined configurations, respectively. The DJH junction displays the characteristics of a recombination centre, such as high levels of activation-associated histone modifications and recombination-activating gene protein (RAG) binding in DJH -rearranged pro-B cells, which extend the recombination centre model proposed for the germline Igh locus. The different domains of the VH region have distinct epigenetic characteristics after DJH recombination. Distal VH genes have higher levels of active histone modifications, germline transcription and Pax5 binding, and good quality recombination signal sequences. Proximal VH genes are relatively close to the DJH recombination centre, which partially compensates for the low levels of the above active epigenetic modifications. DJH recombination centre might serve as a cis-acting element to regulate the accessibility of the VH region. Furthermore, we demonstrate that RAG weakly binds to functional VH genes, which is the first detailed assessment of RAG dynamic binding to VH genes. We provide a way for VH -DJH recombination in which the VH gene is brought into close proximity with the DJH recombination centre for RAG binding by a Pax5-dependent chromosomal compaction event, and held in this position for subsequent cleavage and VH -DJH joining.

Hematoma Changes During Clot Resolution After Experimental Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Hematoma clearance occurs in the days after intracerebral hemorrhage (ICH) and has not been well studied. In the current study, we examined changes in the hematoma in a piglet ICH model. The effect of deferoxamine on hematoma was also examined. METHODS: The ICH model was induced by an injection of autologous blood into the right frontal lobe of piglets. First, a natural time course of hematoma changes ≤7 days was determined. Second, the effect of deferoxamine on hematoma changes was examined. Hemoglobin and membrane attack complex levels in the hematoma were examined by enzyme-linked immunosorbent assay. Immunohistochemistry and Western blotting were used to examine CD47 (a regulator of erythrophagocytosis), CD163 (a hemoglobin scavenger receptor), and heme oxygenase-1 (a heme degradation enzyme) in the clot. RESULTS: After ICH, there was a reduction in red blood cell diameter within the clot with time. This was accompanied by membrane attack complex accumulation and decreased hemoglobin levels. Erythrophagocytosis occurred in the hematoma, and this was associated with reduced clot CD47 levels. Activated macrophages/microglia were CD163 and hemeoxygenase-1 positive, and these accumulated in the clot with time. Deferoxamine treatment attenuated the process of hematoma resolution by reducing member attack complex formation and inhibiting CD47 loss in the clot. CONCLUSIONS: These results indicate that membrane attack complex and erythrophagocytosis contribute to hematoma clearance after ICH, which can be altered by deferoxamine treatment.

Effect of Gender on Iron-induced Brain Injury in Low Aerobic Capacity Rats.

Brain iron overload has a key role in brain injury after intracerebral hemorrhage (ICH). Low aerobic capacity is a risk factor for cardiovascular disease and our previous study demonstrated that ICH-induced brain injury is enhanced in rats with low aerobic capacity (low capacity runners; LCRs). We have found that ICH-induced injury is less in female rats compared with that in males. In the present study, we examined the effects of gender on iron-induced brain injury in rats with low aerobic capacity. Adult male and female LCR rats had an intracaudate injection of FeCl2 (50 µl 0.5 mM). T2 Magnetic resonance imaging was carried out at 24 h to determine brain swelling and T2 brain lesion volume. Albumin leakage, an indicator of blood-brain barrier (BBB) disruption, and heme oxygenase-1 (HO-1, a stress marker) levels were determined. Male LCR rats had more severe hemisphere swelling (difference of ipsilateral to contralateral hemisphere volume: 16.6 ± 4.1 vs 11.1 ± 2.6 % in females, p < 0.05) and larger T2 lesion volumes (120 ± 28 vs 87 ± 27 mm(3) in females, p < 0.05) after iron injection. Iron also resulted in more severe BBB disruption in the ipsilateral hemisphere of males (albumin levels: 7,717 ± 1,502 pixels in males vs 5,287 ± 1,342 pixels in females; p < 0.05). The immunoreactivity of HO-1 was also significantly higher in males than females (HO-1/ß-actin: 1.31 ± 0.44 vs 1.03 ± 0.05, p < 0.05). Female LCR rats had less iron-induced brain swelling, smaller lesion volumes, and reduced BBB disruption and HO-1 upregulation compared with male LCR rats. This may contribute to the reduced ICH-induced brain injury found in females.

Acetazolamide Attenuates Thrombin-Induced Hydrocephalus.

Our previous studies demonstrated that thrombin is an important factor in brain injury after intracerebral and intraventricular hemorrhage. This study examined the effect of acetazolamide, a carbonic anhydrase inhibitor, on thrombin-induced hydrocephalus. There were two parts in this study. First, rats had an injection of either 50 µl saline or 3 U thrombin into the right lateral ventricle. Second, rats had an injection of 3 U thrombin into the right lateral ventricle and were treated with either vehicle or acetazolamide (30 mg/kg, intraperitoneally (IP)) at 1 h after thrombin infusion. Lateral ventricle volumes were measured in magnetic resonance imaging T2 images and the brains were used for histology analysis at 24 h later. Intraventricular injection of thrombin induced significantly larger ventricle volume (27.8 ± 3.7 vs 8.5 ± 1.3 mm(3), n = 6, p < 0.01) and more ventricular wall damage (the breakdown of the ependymal layer, 20.2 ± 3.1 vs 2.4 ± 0.8 %, n = 6, p < 0.01) compared with saline injection. Acetazolamide treatment (30 mg/kg, IP) markedly attenuated thrombin-induced hydrocephalus (16.1 ± 4.2 mm(3) vs 29.5 ± 5.3 mm(3), n = 6, p < 0.01). These results suggest decreasing CSF production by acetazolamide attenuated thrombin-induced hydrocephalus in rats.

Effects of Aerobic Capacity on Thrombin-Induced Hydrocephalus and White Matter Injury.

We have previously shown that intracerebral hemorrhage-induced brain injury is less in rats bred for high aerobic capacity (high capacity runners; HCR) compared with those bred for low aerobic capacity (low capacity runners; LCRs). Thrombin, an essential component in the coagulation cascade, is produced after cerebral hemorrhage. Intraventricular injection of thrombin causes significant hydrocephalus and white matter damage. In the present study, we examined the effect of exercise capacity on thrombin-induced hydrocephalus and white matter damage. Mid-aged (13-month-old) female LCRs (n = 13) and HCRs (n = 12) rats were used in this study. Rats received an intraventricular injection of thrombin (3 U, 50 µl). All rats underwent magnetic resonance imaging (MRI) at 24 h and were then euthanized for brain histology and Western blot. The mortalities were 20 % in LCRs and 33 % in HCRs after thrombin injection (p > 0.05). No rats died after saline injection. Intraventricular thrombin injection resulted in hydrocephalus and periventricular white matter damage as determined on MRI. In LCR rats, thrombin induced significant ventricle enlargement (23.0 ± 2.3 vs12.8 ± 1.9 mm(3) in LCR saline group; p < 0.01) and white matter lesion (9.3 ± 7.6 vs 0.6 ± 0.5 mm(3) in LCR saline group, p < 0.05). In comparison, in HCR rats thrombin induced less ventricular enlargement (17.3 ± 3.9 vs 23.0 ± 2.3 mm(3) in LCRs, p < 0.01) and smaller white matter lesions (2.6 ± 1.2 mm(3) vs 9.3 ± 7.6 mm(3) in LCRs, p < 0.05). In LCR rats, there was also upregulation of heat shock protein-32, a stress marker, and microglial activation in the periventricular white matter. These changes were significantly reduced in HCR rats. Intraventricular injection of thrombin caused more white matter damage and hydrocephalus in rats with low aerobic capacity. A differential effect of thrombin may contribute to differences in the effects of cerebral hemorrhage with aerobic capacity.

Role of lipocalin-2 in brain injury after intracerebral hemorrhage.

Lipocalin-2 (LCN2) is a siderophore-binding protein involved in cellular iron transport and neuroinflammation. Both iron and inflammation are involved in brain injury after intracerebral hemorrhage (ICH) and this study examined the role of LCN2 in such injury. Male adult C57BL/6 wild-type (WT) or LCN2-deficient (LCN2(-/-)) mice had an intracerebral injection of autologous blood or FeCl2. Control animals had a sham operation or saline injection. T2-weighted magnetic resonance imaging and behavioral tests were performed at days 1, 3, 7, 14, and 28 after injection. In WT mice, brain LCN2 levels were increased in the ipsilateral basal ganglia after ICH or iron injection. Lipocalin-2-positive cells were astrocytes, microglia, neurons, and endothelial cells. Intracerebral hemorrhage resulted in a significant increase in ferritin expression in the ipsilateral basal ganglia. Compared with WT mice, ICH caused less ferritin upregulation, microglia activation, brain swelling, brain atrophy, and neurologic deficits in LCN2(-/-) mice (P<0.05). The size of the lesion induced by FeCl2 injection as well as the degree of brain swelling and blood-brain barrier disruption were also less in LCN2(-/-) mice (P<0.05). These results suggest a role of LCN2 in enhancing brain injury and iron toxicity after ICH.

Analysis of prognostic factors and treatment of anaplastic meningioma in China.

Meningioma is the most frequently reported primary brain and central nervous system tumor. However, malignant meningioma is rare with the anaplastic subtype the most common. This subtype of meningioma is fatal with a high recurrence rate and poor survival. A retrospective review of anaplastic meningioma patients treated in one of the largest neurosurgical centers in China between 2003 and 2008 was conducted. From 70 identified patients, seven were lost to follow-up, but the remaining 63 patients were studied for prognostic factors. The mean follow-up time was 84.9±standard deviation (SD) of 19.7months. Tumor recurred in 35 out of 63 (55.6%) patients. Thirty-three (52.4%) patients had died by the most recent follow-up, and the median overall survival (OS) was 70.0±9.7months. The 3year and 5year survival rates were 68.3% and 54.7%, respectively. The median progression-free survival (PFS) was 52.0±9.9months, whereas the 3year and 5year PFS rates were 60.2% and 43.9%, respectively. We found that preoperative KPS, extent of tumor resection, radiotherapy, tumor location and previous history of meningioma were factors related to PFS. In the non-recurrent group, the preoperative Karnofsky Performance Scale (KPS), extent of tumor resection and radiotherapy correlated with PFS. However, multivariate analysis identified radiotherapy as the only independent factor affecting PFS (p=0.007). Additionally, MIB-1 proliferation index failed to identify a cut-off point to predict the prognosis for anaplastic meningioma. This study provides an overview of the epidemiology and treatment of anaplastic meningioma in China using a large population.

Iron-induced necrotic brain cell death in rats with different aerobic capacity.

Brain iron overload has a key role in brain injury after intracerebral hemorrhage (ICH). Our recent study demonstrated that ICH-induced brain injury was greater in low capacity runner (LCR) than in high capacity runner (HCR) rats. The present study examines whether iron-induced brain injury differs between LCRs and HCRs. Adult male LCR and HCR rats had an intracaudate injection of iron or saline. Rats were euthanized at 2 and at 24 h after T2 magnetic resonance imaging, and the brains were used for immunostaining and Western blotting. LCRs had more hemispheric swelling, T2 lesion volumes, blood-brain barrier disruption, and neuronal death at 24 h after iron injection (p < 0.05). Many propidium iodide (PI)-positive cells, indicative of necrotic cell death, were observed in the ipsilateral basal ganglia of both HCRs and LCRs at 2 h after iron injection. PI fluorescence intensity was higher in LCRs than in HCRs. In addition, membrane attack complex (MAC) expression was increased at 2 h after iron injection and was higher in LCRs than in HCRs. The PI-positive cells co-localized with MAC-positive cells in the ipsilateral basal ganglia. Iron induces more severe necrotic brain cell death, brain swelling, and blood-brain barrier disruption in LCR rats, which may be related with complement activation and MAC formation.

Regulation of the innate immune response by fibronectin: synergism between the III-1 and EDA domains.

Fibronectin is a critical component of the extracellular matrix and alterations to its structure will influence cellular behavior. Matrix fibronectin is subjected to both mechanical and biochemical regulation. The Type III domains of fibronectin can be unfolded in response to increased cellular contractility, included or excluded from the molecule by alternative splicing mechanisms, or released from the matrix by proteolysis. Using Inflammatory Cytokine microarrays we found that the alternatively spliced fibronectin Type III domain, FnEDA, and the partially unfolded III-1 domain, FnIII-1c, induced the expression of a multitude of pro-inflammatory cytokines in human dermal fibroblasts, most notably CXCL1-3, IL-8 and TNF-α. FnIII-1c, a peptide representing an unfolded intermediate structure of the first Type III domain has been shown to initiate the toll-like receptor-4 (TLR4)-NFκB-dependent release of cytokines from human dermal fibroblasts (You, et al., J. Biol. Chem., 2010). Here we demonstrate that FnIII-1c and the alternatively spliced FnEDA domain induce a TLR4 dependent activation of p38 MAP kinase and its downstream effector, MAPKAP Kinase-2 (MK-2), to regulate cytokine expression in fibroblasts. RT-qPCR analysis indicated that the p38-MK-2 pathway regulates IL-8 mRNA stability. Interestingly, addition of FnIII-1c and FnEDA synergistically enhanced TLR4-dependent IL-8 release. These data indicate that Fn contains two Type III domains which can activate TLR signaling to induce an inflammatory response in fibroblasts. Furthermore, our data identifies the NF-κB and p38/MK2 signaling pathways as transducers of signals initiated in response to structural changes in fibronectin.

Minimal invasive trans-eyelid approach to anterior and middle skull base meningioma: a preliminary study of Shanghai Huashan hospital.

Transpalpebral or trans-eyelid approach is a modified trans-orbital access to lesions of anterior cranial fossa and sellar region. But whether this approach is also suitable for tumors extending laterally to the temporal lobe or middle cranial fossa is not clarified. We would like to share our experiences from the cadaveric anatomy study to clinical operations. We used 5 cadavers to study trans-eyelid approaches in a step-by-step fashion. And then assisted by an experienced ophthalmologist for incisions, we treated 3 female patients via this approach: One with spheno-orbital meningioma, one with sellar tuberculum meningioma, and the other with medial sphenoidal wing meningioma. After studying the cadavers, we made several revisions to the previously reported approach: 1) move the incision close to the edge of the eyelid, which resembled the double-eyelid incision. 2) A vascularized periosteum flap was dissected for repairing the opened frontal sinus and reconstruction of the skull base. 3) The dura was sutured up with a slice of temporalis muscle. Then we treated 3 patients by this approach. All tumors were totally resected as Simpson Grade I. Complications included orbital apex syndrome and transient oculomotor paralysis because of tumor invasion into orbit and cavernous sinus. No cerebrospinal fluid leakage. We find that trans-eyelid approach is suitable for lesions not only at anterior cranial base or sellar region, but also extending to middle cranial base, especially around sphenoidal wings within 2 cm range or spheno-orbital region. Thus, we propose whether it appropriate to nominate this approach as 'trans-eyelid pterional approach', since it may treat some anterior and middle cranial fossa lesions with a mini-craniotomy around pterion.

Application of CUSA Excel ultrasonic aspiration system in resection of skull base meningiomas.

BACKGROUND: Here, we introduced our short experience on the application of a new CUSA Excel ultrasonic aspiration system, which was provided by Integra Lifesciences corporation, in skull base meningiomas resection. METHODS: Ten patients with anterior, middle skull base and sphenoid ridge meningioma were operated using the CUSA Excel ultrasonic aspiration system at the Neurosurgery Department of Shanghai Huashan Hospital from August 2014 to October 2014. There were six male and four female patients, aged from 38 to 61 years old (the mean age was 48.5 years old). Five cases with tumor located at anterior skull base, three cases with tumor on middle skull base, and two cases with tumor on sphenoid ridge. RESULTS: All the patents received total resection of meningiomas with the help of this new tool, and the critical brain vessels and nerves were preserved during operations. All the patients recovered well after operation. CONCLUSIONS: This new CUSA Excel ultrasonic aspiration system has the advantage of preserving vital brain arteries and cranial nerves during skull base meningioma resection, which is very important for skull base tumor operations. This key step would ensure a well prognosis for patients. We hope the neurosurgeons would benefit from this kind of technique.

Lymphoplasmacyte-rich meningioma: our experience with 19 cases and a systematic literature review.

OBJECTIVE: To investigate the clinicopathological characteristics, prognosis, pathology, and differential diagnosis of LPM by analyzing our experience and reviewed relevant literature. We also postulated the necessity of postoperative adjuvant therapy. METHODS: 19 patients with LPM underwent surgical treatment from 2007 through 2010 in our department. The clinical charts of the patients, including surgical, histological, and follow-up records, as well as imaging studies, were analyzed retrospectively. Other 43 cases searched from the literature were also included, so that 62 LPM cases were summarized and reviewed together. RESULTS: The summarized 62 patients comprised 30 males and 31 females aged 9 years to 79 years (40.7±18.3 years). The most common locations were convexity, skull base, para-sagittal and cervical canal. Multiple or diffuse lesions were found in 8 cases. There were 13 patients had peripheral blood abnormalities (21%). One-third of the cases had moderate to severe peritumoral brain edema. Thirty-eight patients had total resection, 12 patients not specified while 12 received subtotal resection or only biopsy. MIB-1 was available in 24 cases and a third of them were higher than 3%. Follow-up more than 3 year was only completed in 19/62 cases. Seven cases suffered recurrence and two of them died after 2 years of operation. CONCLUSION: LPM is a very rare benign variant of intracranial meningioma. Both lesions and hematological abnormalities have a predilection for younger individuals. Preoperative diagnosis of this subtype of meningioma is still difficult. Surgical resection is the primary treatment option, and supportive care for those not totally removed is very important, because the recurrence rate for this subtype is rather low. However, the massive infiltration of lymphocytes and plasma cells in LPMs are still controversial and the long-term follow-ups are needed. Radiotherapy is not recommended, and hormonal or immune-inhibitor therapy might be helpful.

Intraoperative ultrasound assistance in resection of intracranial meningiomas.

OBJECTIVE: Intracranial meningiomas, especially those located at anterior and middle skull base, are difficult to be completely resected due to their complicated anatomy structures and adjacent vessels. It's essential to locate the tumor and its vessels precisely during operation to reduce the risk of neurological deficits. The purpose of this study was to evaluate intraoperative ultrasonography in displaying intracranial meningioma and its surrounding arteries, and evaluate its potential to improve surgical precision and minimize surgical trauma. METHODS: Between December 2011 and January 2013, 20 patients with anterior and middle skull base meningioma underwent surgery with the assistance of intraoperative ultrasonography in the Neurosurgery Department of Shanghai Huashan Hospital. There were 7 male and 13 female patients, aged from 31 to 66 years old. Their sonographic features were analyzed and the advantages of intraoperative ultrasonography were discussed. RESULTS: The border of the meningioma and its adjacent vessels could be exhibited on intraoperative ultrasonography. The sonographic visualization allowed the neurosurgeon to choose an appropriate approach before the operation. In addition, intraoperative ultrasonography could inform neurosurgeons about the location of the tumor, its relation to the surrounding arteries during the operation, thus these essential arteries could be protected carefully. CONCLUSIONS: Intraoperative ultrasonography is a useful intraoperative technique. When appropriately applied to assist surgical procedures for intracranial meningioma, it could offer very important intraoperative information (such as the tumor supplying vessels) that helps to improve surgical resection and therefore might reduce the postoperative morbidity.

Papillary meningioma: clinical and histopathological observations.

Papillary meningioma is a rare subtype of malignant meningiomas, which is classified by the World Health Organization as Grade III. Because of lack of large sample size case studies, many of the specific characteristics of papillary meningioma are unclear. This study investigated by retrospective analysis the clinical, radiological and histopathological findings of 17 papillary meningioma patients who underwent surgical resection or biopsy, to assess the characteristics of papillary meningioma. Eight female and nine male patients were included, with a mean age of 40 (range: 6 to 55) years. Tumors were mostly located in the cerebral convexity and showed irregular margins, absence of a peritumoral rim, heterogeneous enhancement and severe peritumoral brain edema on preoperative images. Brain invasion was often confirmed during the operations, with abundant to exceedingly abundant blood supply. Intratumoral necrosis and mitosis was frequently observed on routinely stained sections. The average MIB-1 labeling index was 6.9%. Seven cases experienced tumor recurrence or progression, while seven patients died 6 to 29 months after operation. Radiation therapy was given in 52.9% of all cases. Univariate analysis showed that only the existence of intratumoral necrosis and incomplete resection correlated with tumor recurrence. The 3-year progression free survival was 66.7% after gross total resection and 63.6% for other cases. The 3-year mortality rate was 50% after gross total resection and 63.6% for other cases. Papillary meningioma has specific clinical and histopathological characteristics. Tumor recurrence (or progression) and mortality are common. Gross total tumor resection resulted in less recurrence and mortality.