Neuroprotective effects respond to cerebral ischemia without susceptibility to HB-tumorigenesis in VHL heterozygous knockout mice.

The von Hippel-Lindau (VHL) tumor suppressor gene plays a prominent role in the development of hemangioblastomas (HBs) within specific regions of the human' central nervous system (CNS). Alterations in VHL gene are rarely observed in the more common features of human VHL-related tumors in animal models, and VHL heterozygous knockout (VHL+/-) mice do not develop HBs. We tested whether VHL heterozygous knockout mice exhibited genetic predisposition to the development of HBs and conferred a selective advantage involving growth of blood vessels to its carrier. No differences were observed between wild-type and VHL+/- mice in development ad reproduction. The heterozygous VHL+/- mice did not develop higher genetic susceptibility to CNS-HBs over their lifetime. Furthermore, this recessive VHL gene heterozygosity is relatively stable. Interestingly, we found these heterozygous VHL+/- mice gained an advantage conferring to angiogenic ability in a particular environment, compared with wild-type mice. The heterozygous VHL+/- mice obviously enhanced hypoxia inducible factor-1 (HIF)-dependent and Twist1 angiogenic mechanism in response to acute cerebral ischemia, resulting in decreased cerebral tissue damage and neuroprotective response through neovascularization. Our findings provide evidence of partial loss function of VHL as a novel precise therapeutic target in acute cerebral ischemia.

Whole exome sequencing identified genetic variations in Chinese hemangioblastoma patients.

Hemangioblastomas (HBs) are uncommon tumors characterized by the presence of inactivating alterations in the von Hippel-Lindau (VHL) gene in inherited cases and by infrequent somatic mutation in sporadic entities. We performed whole exome sequencing on 11 HB patients to further elucidate the genetics of HBs. A total of 270 somatic variations in 219 genes, of which there were 86 mutations in 67 genes, were found in sporadic HBs, and 184 mutations were found in 154 genes in familial HBs. C: G>T: A and T: A>C: G mutations are relatively common in most HB patients. Genes harboring the most significant mutations include PCDH9, KLHL12, DCAF4L1, and VHL in sporadic HBs, and ZNF814, DLG2, RIMS1, PNN, and MUC7 in familial HBs. The frequency of CNV varied considerably within sporadic HBs but was relatively similar within familial HBs. Five genes, including OTOGL, PLCB4, SCEL, THSD4, and WWOX, have CNVs in the six patients with sporadic HBs, and three genes, including ABCA6, CWC27, and LAMA2, have CNVs in the five patients with familial HBs. We found new genetic mutations and CNVs that might be involved in HBs; these findings highlight the complexity of the tumorigenesis of HBs and pinpoint potential therapeutic targets for the treatment of HBs.

CD41 and CD45 expression marks the angioformative initiation of neovascularisation in human haemangioblastoma.

The initiation and formation of haemangioblastoma (HB) neovascularisation remain unknown, with concomitant controversy on its cytological origin. We detected HB-derived specific haematopoietic progenitors identified by surface expression of CD41 and CD45, which are similar to human embryonic vasculogenesis. CD41/CD45 cells expressed mesodermal markers, including SCL, Flk1 and c-kit. CD41 also seemed to appear before CD45 on haematopoietic progenitors. In vitro analysis showed that the CD41(+)/CD45 subpopulation gave rise to occasional primitive erythroid activity and endothelial marker expression. Meanwhile, kinetic investigation of the CD41(+)/CD45(+) subpopulation showed that some molecules, including SCL, Flk1 and c-kit, were involved in vascular formation. The CD45(+)/c-kit(+) population that lacked primitive haematopoiesis came from CD41(+) cells. Acquisition of CD45 expression by the haematopoietic progenitors was associated with advanced differentiation towards the vascular cell lineage. Taken together, the present data suggested that CD41 and CD45 expression marked the onset of HB neovascularisation and the stepwise development of the angioformative period. Our findings provide new insights into the mechanisms of HB neovascularisation and the underlying therapeutic targets of anti-vascular treatment.

Single nucleotide polymorphisms of matrix metallopeptidase 3 and risk of gliomas in a Chinese Han population.

Matrix metallopeptidases (MMPs) play an important role in central nervous system tumor growth, invasion and spreading. The currently available data provide clear evidence for the involvement of MMP3 in the pathophysiology of glioma. The study aims to explore the association of single nucleotide polymorphisms (SNPs) across the MMP3 gene with glioma risk. Three haplotype tagging and additional two promoter SNPs were genotyped among 766 glioma patients and 824 cancer-free controls from East China. None of these polymorphisms alone had a significant effect on risk of gliomas. However, when three promoter polymorphisms were evaluated together by the number of putative risk of genotypes (i.e., rs645419AA, 632478CA+AA, rs522616AA), a statistically significantly increased risk of gliomas was associated with the combined genotypes with two to three risk genotypes, compared with those with zero to one risk genotypes (adjusted odds ratio (OR) = 1.32; 95% confidence interval (CI) = 1.03-1.68). This increased risk was also more pronounced among adults (adjusted OR = 1.14, 95%CI = 1.02-1.27), males (adjusted OR = 1.19, 95%CI = 1.05-1.36), smokers (adjusted OR = 1.28, 95%CI = 1.07-1.52), subjects with no family history of cancer (adjusted OR = 1.21, 95%CI = 1.07-1.37), and patients with nonastrocytic gliomas (adjusted OR = 1.23, 95%CI = 1.06-1.43). In summary, our results suggest that any one of MMP3 variants may not have a substantial effect on glioma risk, but a joint effect of MMP3 promoter polymorphisms may contribute to risk of gliomas, particularly for adult gliomas.

A genetic variant in the APE1/Ref-1 gene promoter -141T/G may modulate risk of glioblastoma in a Chinese Han population.

BACKGROUND: The human apurinic/apyrimidinic endonuclease 1/Redox effector factor-1 (APE1/Ref-1) is implicated in tumor development and progression. Recently, the APE1/Ref-1 promoter -141T/G variant (rs1760944) has been reported to be associated with lung cancer risk. Given the importance of APE1/Ref-1 in both DNA repair and redox activity, we speculate that the -141T/G polymorphism may confer individual susceptibility to gliomas or its subtypes. METHODS: The APE1/Ref-1 -141T/G polymorphism was analyzed in a case-control study including 766 glioma patients (among them 241 glioblastoma, 284 astrocytomas except for glioblastoma and 241 other gliomas) and 824 cancer-free controls from eastern China. Genotyping was performed with Sequenom MassARRAY iPLEX platform by use of allele-specific MALDI-TOF mass spectrometry assay. We estimated odds ratios (ORs) and 95% confidence intervals (95% CIs) using unconditional logistic regression. A test of trend was calculated using the genotype as an ordinal variable in the regression model. For each statistically significant association identified, we estimated the false positive reporting probability (FPRP). FPRP values less than 0.2 were consider to indicate robust associations. RESULTS: The significant association between the APE1/Ref-1 promoter -141T/G polymorphism and glioma risk was not observed. However, the stratified analysis by histology revealed the variant allele G significantly decreased glioblastoma risk (OR = 0.80, 95% CI = 0.65-0.98, P = 0.032). Individuals with the homozygous -141GG genotype exhibited 46% reduced risk of glioblastoma (adjusted OR = 0.54, 95% CI 0.34-0.87, P = 0.012), compared with the TT homozygote. This result remained robust given the prior probabilities of 25% (FPRP = 0.052) and 10% (FPRP = 0.140), but not with a prior probability of 1% (FPRP = 0.643). The P-associated with the trend test was 0.014. CONCLUSIONS: Our results suggest that a specific genetic variant located in the APE1/Ref-1 promoter may modulate risk of glioblastoma, but not for other histological gliomas. Larger studies with more APE1 polymorphisms are required to validate these preliminary findings.

Possible association between genetic variants in the H2AFX promoter region and risk of adult glioma in a Chinese Han population.

H2AFX, a histone H2A gene family member X, is a key component in the detection of and response to DNA double-strand breaks (DSBs) caused by ionizing radiation (IR), a known risk factor for glioma. Thus, genetic variants in the H2AFX promoter region that may result in abnormal protein expression could confer susceptibility to glioma. In this case-control study, we genotyped three common single-nucleotide polymorphisms (SNPs) (rs643788, rs8551, and rs2509851) in the H2AFX promoter region in 669 adult glioma patients and 638 cancer-free controls. The associations between each SNP or haplotype and glioma risk were estimated by calculating odds ratios (ORs) and the corresponding 95% confidence interval (CI) using unconditional logistic regression models, with adjustment for age and sex. The H2AFX rs643788 A variant genotypes were significantly associated with reduced risk of glioma (GA versus GG: adjusted OR = 0.72, 95% CI = 0.56-0.94; GA/AA versus GG: adjusted OR = 0.75, 95% CI = 0.59-0.94), compared with the common GG genotype. Furthermore, this decreased risk was more evident among those aged ≥ 45 years (adjusted OR = 0.64, 95% CI = 0.45-0.90), male subjects (adjusted OR = 0.70, 95% CI = 0.50-0.96), and patients with glioblastoma (adjusted OR = 0.66, 95% CI = 0.46-0.94). These results suggest that a common variant in the H2AFX promoter region may modulate risk of glioma, particularly for adult glioma. However, our findings need to be replicated in other independent populations.

Multiple intracranial cavernous malformations: clinical features and treatment.

BACKGROUND: Although patients with MCMs have increasingly been found in clinics, little has been focused on them. Thus, we intended to investigate these patients' clinical presentations, family history, radiological characters, and treatment strategy. METHODS: A retrospective review of the files and family investigations were conducted for 30 patients with MCMs. All patients underwent MRI examination. Symptomatic patients underwent the surgical treatment with image-guided technique. RESULTS: There were 19 male and 11 female patients with a total 79 lesions. The common presentations were seizures, hemorrhages, or focal neurological deficits. Nine patients had positive or doubtful family history. The FLAIR sequence of MRI showed the highest sensitivity in the detection of CM lesions. In 27 symptomatic patients with 69 lesions, total removal was achieved in 19 patients with 48 lesions. In the other 8 patients with 21 lesions, 13 lesions were removed. Preoperative symptoms were improved in 21 patients and unchanged in 5. Preoperative neurological deficits temporarily worsened in one, and a new onset of seizure occurred in other one; but both gradually improved during the follow-up period. Among 3 patients with asymptomatic MCMs, one patient had hemorrhage during the follow-up period and underwent surgical operation. CONCLUSIONS: Because a high frequency of family CM occurs in MCMs, a detailed family investigation is mandatory for each patient with MCM. Selection of higher sensitive MRI sequence would contribute to detection of more CM lesions. Microsurgery assisted with the neuroimaging techniques is the treatment of choice for symptomatic MCMs.

Diagnosis and surgical treatment of brainstem hemangioblastomas.

OBJECTIVE: The study aims to elucidate the advance of diagnosis and surgical treatment of brainstem hemangioblastomas (BSHs). METHODS: The data of the following patients treated in one institute were retrospectively analyzed: (1) patients with a single tumor on the brainstem which was verified by surgery and pathology; (2) patients without von Hippel-Lindau disease or multiple hemangioblastomas. RESULTS: Thirty-three patients with BSHs were identified, accounting for 15.5% of all intracranial hemangioblastomas surgically treated from August 1989 to May 2002 in Huashan Hospital. There were 17 males and 16 females. The patients were aged from 16 to 65 years with an average age of 45 years. The clinical manifestations were nonspecific. Magnetic resonance imaging and digital subtraction angiography were the major diagnostic modalities. Tumors were located on oblongata (14), ponto-oblongata (9), pons (6), and cervicomedulla (4). Tumors were solid in 29 cases, cyst in 4 cases, and had a small size in 5 (< or =3 cm), large in 19 (3.1-4 cm), and giant in 9 (>4 cm). Extra-brainstem (EBS) type (including the fourth-ventricle hemangioblastomas) was seen in 25 cases, and intrabrainstem (IBS) type in 8 cases. Preoperative embolization was performed in 12 cases since 1996. Mild hypothermia with or without hypotension was done during the operation in 10 cases. Total tumor removal was achieved in 31 patients (94%), and incomplete removal in 2 cases. Two patients with EBS type and giant solid tumors died after operation. Follow-up study (range, 1-12 years; mean, 5 years) was available in 31 patients. Karnofsky performance scale scores were > or =80 in 25 patients (80.6%), 60 to 70 in 4 patients (12.9%), and 40 to 50 in 2 patients (6.5%). CONCLUSION: Two types of BSHs can be identified. Patients with cystic IBS type could obtain excellent outcome after operations. Patients with giant or large solid BSHs remain a challenge to neurosurgeons. A combined strategy of preoperative embolization, mild hypothermia with or without hypotension, microsurgical technique, and intensive perioperative management are mandatory for removal of these kinds of tumors with acceptable morbidity and mortality.

Neurosurgical Management of Brainstem Hemangioblastomas: A Single-Institution Experience with 116 Patients.

OBJECTIVE: Brainstem hemangioblastomas (HBs) are considered one of the most challenging lesions in surgical procedures. We present our institutional experience with 116 patients over a period of 20 years in the treatment of HBs. METHODS: We evaluated the results of microsurgical treatment and highlighted the management strategies. There were 60 male and 56 female patients including 13 cases with clinical evidence of von Hippel-Lindau disease. Tumors were solid in 99 cases and cystic in 17 cases. Tumors were small (≤2 cm) in 43 cases, large (2-4 cm) in 45 cases, and giant (≥4 cm) in 28 cases. RESULTS: Radical removal was achieved in 111 patients (95.7%), and incomplete removal was achieved in 5 cases (4.3%). The immediate postoperative mortality and morbidity were 7.8% and 17.2%, respectively. Detailed analyses of outcomes showed that surgical complications were related to some tumor characteristics. Follow-up study was available in 83 patients by Karnofsky performance scale scores. Most patients maintained their preoperative neurologic status. There were 17 patients with surgical disability who demonstrated a clear improvement with rehabilitation treatment. Worsening of neurologic deficits occurred in 2 patients. Ectopic recurrent lesions developed in 2 patients. CONCLUSIONS: Based on our experience, microsurgery is safe and effective, and excellent outcomes can be obtained for cystic or small tumors. We advocate early surgical intervention for sporadic HBs; giant solid HBs remain a challenge, and meticulous microsurgical technique and perioperative management are vital. Long-term monitoring also is recommended.

Neuronavigator-guided glioma surgery.

OBJECTIVE: To evaluate the effectiveness of neuronavigator-guided surgery for the resection of gliomas. METHODS: A total of 80 patients with gliomas underwent surgical treatment under the StealthStation neuronavigator to estimate the extent of the tumors. In 27 cases, the measurements of brain shifts at the dura, cortical surface and lesion margin were recorded during the operations. A technique termed "micro-catheter fence post" was used in superficial gliomas to compensate for brain shift. RESULTS: Mean fiducial error and predicted accuracy in the 80 cases were 2.03 mm +/- 0.89 mm and 2.43 mm +/- 0.99 mm, respectively. The shifts at the dura, cortical surface and lesion margin were 3.44 mm +/- 2.39 mm, 7.58 mm +/- 3.75 mm, and 6.55 mm +/- 3.19 mm, respectively. Although neuronavigation revealed residual tumors, operations were discontinued in 5 cases of deep-seated gliomas. In the other 75 cases, total tumor removals were achieved in 62 (82.7%), and subtotal removals were achieved in 13 (17.3%). Post-operation, neurological symptoms were improved or unchanged in 68 cases (85.0%), and worsened in 12 (15.0%). No deaths occurred during the operations and post-operations. CONCLUSIONS: Intraoperative brain shifts mainly contribute to the fail of spatial accuracy during neuronavigator-guided glioma surgery. The "micro-catheter fence post" technique used for glioma surgery is shown to be useful for compensating for intraoperative brain shifts. This technique, thus, contributes to an increase in total tumor removal and a decrease in surgical complications.

Image-guided resection of cerebral cavernous malformations.

OBJECTIVE: To evaluate retrospectively the effectiveness of image-guided navigation techniques in the management of cerebral CMs. METHODS: Between July 1997 and January 2001, 44 patients underwent image-guided resection of cerebral CMs. To counteract brain shift, a small silicon catheter was implanted as a guide in the case of deep-seated lesions (except in the case of brain stem CMs) and before excision of multiple lesions. RESULTS: A total of 27 men and 17 women with a mean age of 35 years underwent surgical procedures (5 patients had multiple lesions). The lesions were located in the frontal (n = 14), lobe temporal lobe (n = 12), parietal lobe (n = 6), cerebellum (n = 6), thalamus (n = 5), pons (n = 5), and orbital region (n = 1). Under the guidance of a StealthStation navigator, total removal of the lesions was achieved in all patients. Follow-up revealed marked improvement of preoperative symptoms in 26 patients and no additional deficits in 13 patients. Five patients suffered from additional neurological deficits, but two of them gradually improved during the follow-up period. CONCLUSIONS: With the assistance of an image-guided surgical system, functional areas can be effectively avoided and surgical injury can be decreased. This system is well suited for accurate localization and safe resection of small, deep-seated CMs.

[Image-guided microsurgery in resection of intracranial cavernous hemangioma].

OBJECTIVE: To study the methods and effectiveness of image-guided microsurgery in resection of intracranial cavernous hemangioma. METHODS: Between July 1997 and January 2001, 44 patients with intracranial cavernous hemangioma, 27 males and 17 females with a mean age of 35 years, among which 5 cases had multiple lesions, underwent image-guided microsurgery. The locations of lesions included frontal lobe (n = 14), temporal lobe (n = 12), parietal lobe (n = 6), cerebellum (n = 6), thalamus (n = 5), pons (n = 5), and orbital lobe (n = 1). A small silicon catheter, used as a guider, was implanted to the deep-seated lesion (except the brain stem lesions) before excision of the lesion in order to prevent brain shift. RESULTS: Total removal of the lesions was achieved in all patients without operational death. Follow-up revealed marked improvement of symptoms in 26 case and no change of symptom(s) in 13 cases. 5 cases suffered from additional neurological deficits, mainly exacerbation of hemiparalysis and aphasia, the condition of two of which, however, gradually improved within the period of follow-up. No residue of lesion and relapse were found during follow up. CONCLUSION: With the assistance of the image-guided surgical system, functional area can be effectively avoided, and surgical injury can be decreased. It is well suited for accurate localization and safe resection of small, deep-seated cavernous malformations.

[Integrating functional magnetic resonance imaging in neuronavigation surgery of brain tumors involving motor cortex].

OBJECTIVE: To assess the value of integrating blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) in neuronavigation surgery of brain tumors involving motor cortex. METHODS: A total of 58 patients with brain tumors in or directly adjacent to the motor cortex, with 18 lesions located in primary motor area, 18 lesions located in premotor area, 11 lesions located in primary motor sensory area, 9 lesions located in primary sensory area, and 2 lesions located in supplementary motor area respectively, were randomly divided into 2 groups: trial group including 30 cases undergoing BOLD navigation and control group with 28 cases undergoing routine navigation. A prospective random and matched controlled study was carried out to compare the clinical outcome between the two groups. For the patients in the trial group, the motor tasks consisted of simple flexion-extension finger movements and finger-to-thumb touching in a repeating, pre-planned sequence of either hand. A standard 1.5 T MR system had been utilized to localize the cortical motor hand area, using the BOLD contrast technique. The BOLD images were integrated with the routine navigational MR images (T1-weighted three-dimensional fast spoiled gradient recalled sequence), and then co-registered to the neuronavigation system. For the patients in the control group, the navigational MR imaging examinations were carried out only. RESULTS: The statistics analysis confirmed a good balance of main variations between the trial and control groups. The percentage of completely resection of tumors was 86.7% in trial group and 60.7% in control group (P < 0.05). The postoperative contralateral extremities muscle strength were 4.3 +/- 1.1 degree for trial group and 2.5 +/- 1.9 degree for the control group (P < 0.01). The motor functional deficit was observed in 23.3% of the cases of trial group and 71.4% of the cases in trial group (P < 0.05). The mean Karnofsky prognosis scale of the trial group was 88 +/- 27, significantly higher than that of the control group (65 +/- 32, P < 0.01). CONCLUSION: BOLD functional MR imaging is of great value in surgical planning and intraoperative functional brain mapping of motor cortex individually. To integrate BOLD data with the routine navigational MR images can supply more precise and real-time information about the relationship between lesions and neighboring cortical motor area. It should be used in neuronavigation surgery to increase the ratio of total resection of brain tumors and decrease the risk of postoperative hemiplegia.

[Role of diffusion tensor imaging in neuronavigation surgery of brain tumors involving pyramidal tracts].

OBJECTIVE: To explore the role of diffusion tensor imaging (DTI) in neuronavigation surgery of brain tumors involving pyramidal tracts. METHODS: Forty-nine patients with brain tumors involving pyramidal tracts were randomly divided into trial group (DTI navigation) and control group (traditional navigation). The patients in trial group underwent DTI and T1 weighted 3D navigational magnetic resonance imaging (MRI) studies. The main white matter tracts were constructed by the DTI datasets, and merged to the anatomical structure, which was delineated by the T1-weighted three-dimensional fast spoiled gradient recalled sequence (3D/FSPGR). The relationship between the tumors and adjacent pyramidal tracts were segmented and reconstructed for three-dimensional visualization. RESULTS: In 25 patients of trial group and 24 patients of control group, the statistic analysis confirmed well balance of main variations. The tumors were completely resected in 12 patients (50.0%) of control group and in 20 patients (80.0%) of trial group (P < 0.05). Postoperative aggravated contralateral extremities weakness or hemiplegia due to pyramidal tract injury occurring in 75.0% cases of control group whereas only 20.0% patients in trial group (P < 0.01). The mean Karnofsky scale were 69.58 +/- 23.49 and 84.80 +/- 23.49 respectively in control and trial groups (P < 0.05). The excellent outcome ratio (Karnofsky scale = 90 - 100) was 37.5% in control group and 72.0% in trial group respectively (P < 0.05). CONCLUSIONS: DTI allows individual estimation of large fiber tracts of brain. Furthermore, to integrate spatial three-dimensional information concerning the white matter tracts into traditional neuronavigation images during surgery, was valuable in presenting topographical character of involving (shift or erosive) pyramidal tracts and relationship with the margins of neighboring tumors. The mapping of large fiber tracts was a safe, efficient, reliable technique. DTI should be routinely used in neuronavigation surgery of brain tumor involving pyramidal tracts to plan the optimal trajectory and ensure total resection of the lesions during operation, as well as to decrease potential disability after operation and to shorten the length of hospitalization.

Clinical evaluation and follow-up outcome of diffusion tensor imaging-based functional neuronavigation: a prospective, controlled study in patients with gliomas involving pyramidal tracts.

OBJECTIVE: To evaluate diffusion tensor imaging (DTI)-based functional neuronavigation in surgery of cerebral gliomas with pyramidal tract (PT) involvement with respect to both perioperative assessment and follow-up outcome. METHODS: A prospective, randomized controlled study was conducted between 2001 and 2005. A consecutive series of 238 eligible patients with initial imaging diagnosis of cerebral gliomas involving PTs were randomized into study (n = 118) and control (n = 120) groups. The study cases underwent DTI and three-dimensional magnetic resonance imaging scans. The maps of fractional anisotropy were calculated for PT mapping. Both three-dimensional magnetic resonance imaging data sets and fractional anisotropy maps were integrated by rigid registration, after which the tumor and adjacent PT were segmented and reconstructed for presurgical planning and intraoperative guidance. The control cases were operated on using routine neuronavigation. RESULTS: There was a trend for high-grade gliomas (HGGs) in the study group to be more likely to achieve gross total resection (74.4 versus 33.3%, P < 0.001). There was no significant difference of low-grade gliomas resection between the two groups. Postoperative motor deterioration occurred in 32.8% of control cases, whereas it occurred in only 15.3% of the study cases (P < 0.001). The 6-month Karnofsky Performance Scale score of study cases was significantly higher than that of control cases (86 +/- 20 versus 74 +/- 28 overall, P < 0.001; 93 +/- 10 versus 86 +/- 17 for low-grade gliomas, P = 0.013; and 77 +/- 27 versus 53 +/- 32 for HGGs, P = 0.001). For 81 HGGs, the median survival of study cases was 21.2 months (95% confidence interval, 14.1-28.3 mo) compared with 14.0 months (95% confidence interval, 10.2-17.8 mo) of control cases (P = 0.048). The estimated hazard ratio for the effect of DTI-based functional neuronavigation was 0.570, representing a 43.0% reduction in the risk of death. CONCLUSION: DTI-based functional neuronavigation contributes to maximal safe resection of cerebral gliomas with PT involvement, thereby decreasing postoperative motor deficits for both HGGs and low-grade gliomas while increasing high-quality survival for HGGs.