Shuyu Hao

Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas

Gliomas arising in the brainstem and thalamus are devastating tumors that are difficult to surgically resect. To determine the genetic and epigenetic landscape of these tumors, we performed exomic sequencing of 14 brainstem gliomas (BSGs) and 12 thalamic gliomas. We also performed targeted mutational analysis of an additional 24 such tumors and genome-wide methylation profiling of 45 gliomas. This study led to the discovery of tumor-specific mutations in PPM1D, encoding wild-type p53–induced protein phosphatase 1D (WIP1), in 37.5% of the BSGs that harbored hallmark H3F3A mutations encoding p.Lys27Met substitutions. PPM1D mutations were mutually exclusive with TP53 mutations in BSG and attenuated p53 activation in vitro. PPM1D mutations were truncating alterations in exon 6 that enhanced the ability of PPM1D to suppress the activation of the DNA damage response checkpoint protein CHK2. These results define PPM1D as a frequent target of somatic mutation and as a potential therapeutic target in brainstem gliomas.

The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults

Brainstem and thalamic gliomas are rare, and they are poorly understood in adults. Genetic aberrations that occur in these tumors are still unknown. In this study, we investigated whether thalamic gliomas have different genetic aberrations and clinical outcomes compared with brainstem gliomas in adults. Forty-three glioma samples were selected, including 28 brainstem and 15 thalamic gliomas. The frequency of the K27M mutation in adult midline gliomas was 58.1%. High-grade gliomas in the thalamus were statistically significantly more numerous than brainstem gliomas. Patients with K27M mutant brainstem gliomas had a significantly shorter overall survival than patients with wild-type tumors (P = .020) by Cox regression after adjustment for other independent risk factors. However, there was no statistical tendency toward a poorer overall survival in thalamic gliomas containing the K27M mutation compared with wild-type tumors. The presence of the K27M mutation significantly corresponded with mutations in TP53 in thalamic gliomas. Interestingly, the K27M mutation was mutually exclusive with mutations in IDH1, which was detected only in brainstem gliomas. The microarray data identified 86 differentially expressed genes between brainstem and thalamic gliomas with the K27M mutation. The cyclin-dependent kinase 6 (CDK6) gene, which plays an important role in cancer pathways, was found to be differentially expressed between brainstem and thalamic gliomas with K27M mutations. Although the K27M mutation was frequently observed in adult brainstem and thalamic gliomas, this mutation tended to be associated with a poorer prognosis in brainstem gliomas but not in thalamic gliomas. Brainstem gliomas may present different genetic aberrations from thalamic gliomas. These differences may provide guidance for therapeutic decisions for the treatment of adult brainstem and thalamic gliomas, which may have different molecular targets.

Diagnosis and Management of Adult Intracranial Neurenteric Cysts

BACKGROUND:Intracranial neurenteric cysts are rare, benign lesions of the central nervous system. OBJECTIVE:To analyze our experience with these lesions and conduct a review of the literature with the aim of identifying a rational approach to diagnosis and management. METHODS:Seven patients underwent surgical treatment for intracranial neurenteric cysts from July 2000 to December 2008. The general strategy was to perform complete resection whenever possible. The clinical, radiological, operative, and pathological findings of the patients were reviewed retrospectively. RESULTS:This series included 3 women and 4 men. The age of hospitalized patients ranged from 19 to 55 years, with an average age of 34 years. Headache and dizziness were the most common chief symptoms. The imaging spectrum for these lesions is broad, leading to several preoperative misdiagnoses. All 7 lesions were resected by a far lateral transcondylar or retrosigmoid approach. Total tumor resection was achieved in 3 patients. Four patients presented transient fever postoperatively. All patients were healthy and showed no signs of tumor recurrence at their latest follow-up. CONCLUSION:Intracranial neurenteric cysts ventral to the brainstem are rare lesions occurring in young adults. These lesions should be considered in the differential diagnosis for intracranial extra-axial cystic lesions anterior to the brainstem. Total surgical resection seems to be the most effective therapeutic method, although radical resection at the risk of impairing the brainstem is not recommended. This benign lesion has a favorable overall prognosis.

Foramen magnum meningiomas: experiences in 114 patients at a single institute over 15 years.

BACKGROUNDnAlthough there has been great development in the anatomical understanding and operative techniques for skull base tumors, controversy still exists regarding the optimal surgical strategies for the FMMs. We report clinical and radiologic features as well as the surgical findings and outcome for patients with FMM treated at our institution over the last 15 years.nnnMETHODSnWe reviewed 114 consecutive cases of FMM operated between May 1993 and June 2008 in the neurosurgery department at Beijing Tiantan Hospital.nnnRESULTSnThere were 68 female and 46 male patients (mean age, 52.3 years; range, 28-76 years). Foramen magnum meningiomas were classified as anterior (80 cases), anterolateral (24 cases), and posterolateral (10 cases). Mean duration of symptoms was 11.7 months (ranging from 1.5 to 240 months). Cervico-occipital pain (80.7%) and headache and dizziness (42.1%) were the most common presenting symptoms. The preoperative KPS was 72.5 +/- 8.3. Mean maximum diameter of the tumors on MRI was 3.35 cm (range, 1.5-4.7 cm). Posterior midline approach was performed in 10 cases, far-lateral retrocondylar approach in 97 cases, and extended far-lateral approach in 7 cases. Gross total resection was achieved in 86.0% of patients and subtotal resection in 14.0%. Surgical mortality was 1.8%. Follow-up data were available for 93 patients, with a mean follow-up of 90.3 months (range, 1-180 months), of which 59 (63.4%) lived a normal life (KPS, 80-100).nnnCONCLUSIONnOur experience suggests that most anterior and anterolateral FMMs can be completely resected by a far-lateral retrocondylar approach without resection of the occipital condyle. Complete resection of the tumor should be attempted at the first operation. Postoperative management of FMM is important for the prognosis.

Natural Malignant Transformation of an Intracranial Epidermoid Cyst

Malignant transformation of intracranial epidermoid cyst (EC) is very rare, and when it does occur, the clinical course is aggressive. We present an unusual case of natural malignant transformation of an intracranial EC, without a history of surgery. A 61-year-old woman was diagnosed with an EC in the right cerebellopontine angle and prepontine cistern 6 years before the operation described in this report. Her neurological symptoms deteriorated in the 2 months prior to the present admission. Magnetic resonance imaging revealed an irregular, nodular enhanced lesion in the cerebellopontine angle, prepontine cistern, and temporoparietal lobe. Subtotal resection of the lesion was performed. Pathological examination revealed malignant transformation of the EC. The patient died on postoperative day 36 from brainstem infarction, chemical meningitis, and hydrocephalus. Spontaneous rupture of the EC could have contributed to the malignant transformation. This could have been avoided by early removal of the EC.

Application of intraoperative indocyanine green videoangiography for resection of spinal cord hemangioblastoma: Advantages and limitations

Hemangioblastomas constitute 2-15% of intramedullary spinal cord tumors. Identification of the feeding arteries and draining veins is crucial for an en bloc tumor resection and cure. We report our experience using intraoperative indocyanine green (ICG) videoangiography during the surgical resection of spinal cord hemangioblastomas (SH) and evaluate the advantages and limitations of this technique. Seven patients with an SH underwent resection with the assistance of intraoperative ICG videoangiography. The ICG videoangiography images were analyzed, and the preoperative, intraoperative, and postoperative images were compared. ICG videoangiography clearly revealed the feeding arteries and enlarged draining veins and assisted in defining the tumor borders in five of the seven patients (patients one, two, four, five, and seven). By contrast, patient three had a devascularized residual tumor located deep in the spinal cord parenchyma, which did not take up the fluorescent dye and therefore was not visualized by ICG videoangiography. In addition, in patient six, only the draining veins could be visualized in the ventrolateral tumor, because it was covered by the spinal cord parenchyma. Six tumors were completely removed, and one was partially removed. None of our patients had significant neurological deterioration after surgery. ICG videoangiography provided real-time information about the tumor vasculature during surgery for SH and aided in intraoperative decision-making. However, for deep tumors and ventral tumors, the benefits of this technique might be limited.

Surgical Treatment and Long-Term Outcomes of Thalamic Cavernous Malformations

OBJECTIVEnResection of thalamic cavernous malformations (CMs) is controversial. The goals of this study were to evaluate the outcome of thalamic CMs after surgical resection, assess predictors of prognosis, and review the literature.nnnMETHODSnThe authors used the modified Rankin scale (mRS) to retrospectively evaluate the presentation, surgery, and outcomes of 27 consecutive patients who underwent thalamic CMs microresection using six different approaches between 1998 and 2010.nnnRESULTSnForty-eight hemorrhages occurred in 27 patients (13 men, 14 women; mean age 33.9 years) with a preoperative mRS score of 2.6 ± 1.0 and a preoperative bleeding rate per patient year of 5.2%. Complete resection was achieved in 26 patients (96.3%) without surgical mortality. The postoperative mRS score at discharge was 1.9 ± 1.0. One lesion rebled 1 month after complete surgical resection. After a mean follow-up duration of 48.7 ± 43.2 months, the mean mRS score was 1.2 ± 1.2 and the postoperative rebleeding rate was 0.91% per patient-year. With regard to neurological function, 81.5% of patients improved, 11.1% stabilized, and 7.4% worsened. Good outcomes (mRS score ≤2, living independently) were achieved in 21 patients (77.8%). Long-term surgical morbidity was observed in five patients (18.2%). A multivariate logistic regression analysis identified age (<40 years) as the only predictor of the postoperative mRS score (≤ 2) (odds ratio, 1.24, 95% confidence interval, 1.02-1.52; P = 0.035).nnnCONCLUSIONSnTo our knowledge, this is the largest case series reported in the literature to date. Patients with thalamic CMs can obtain a favorable prognosis using microsurgery; an appropriate microsurgical approach contributes to an excellent outcome.

Association of ERCC1 C8092A and ERCC2 Lys751Gln polymorphisms with the risk of glioma: a meta-analysis.

Objectives To comprehensively evaluate the association of ERCC1 C8092A and ERCC2 Lys751Gln polymorphisms with the risk of glioma. Methods Potential studies were searched and selected through the Pubmed/MEDLINE, EMBASE, the China National Knowledge Infrastructure (CNKI) platforms, WanFang and VIP database up to June 2013. Two investigators independently reviewed full text and included studies met inclusion criteria. Combined odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated in a fixed-effects model or a random-effects model according to results of heterogeneity test. All analyses were performed by Revman 5.2 and Stata 10.0 software. Results A total of 10 studies were included in our meta-analysis, including 3,580 glioma patients and 4,728 controls. Overall, ERCC1 C8092A polymorphism was associated with the risk of glioma (AA vs. CC: ORu200a=u200a1.29, 95%CI: 1.07–1.55, Pu200a=u200a0.01; recessive model: ORu200a=u200a1.29; 95% CI: 1.07–1.55, Pu200a=u200a0.01). When stratified by ethnicity, significant association was only observed in the Chinese population (AA vs. CC: ORu200a=u200a1.37, 95%CI: 1.03–1.81, Pu200a=u200a0.03; recessive model: ORu200a=u200a1.34; 95% CI: 1.02–1.75, Pu200a=u200a0.04). For ERCC2 Lys751Gln polymorphism, no significant association was found between ERCC2 Lys751Gln polymorphism and the risk of glioma in different genetic models. A significant association of ERCC2 Lys751Gln polymorphism with the risk of glioma was identified in the Caucasian population under recessive model (ORu200a=u200a0.87; 95% CI: 0.78–0.98, Pu200a=u200a0.02), but not in the Chinese population. Conclusion This meta-analysis suggested that the AA genotype of ERCC1 C8092A polymorphism might increase the susceptibility of glioma in the Chinese population. And the TT genotype of ERCC2 Lys751Gln polymorphism may decrease the risk of glioma in the Caucasian population. But the small number of studies and moderate methodological quality require cautious interpretation of the study results.

Surgical treatment of spinal vascular malformations performed using intraoperative indocyanine green videoangiography

This study aims to evaluate the benefits of intraoperative indocyanine green (ICG) videoangiography and associated surgical outcomes of patients with spinal vascular malformations. ICG videoangiography was used during 24 surgical interventions to treat spinal vascular malformations at the Beijing Tiantan Hospital from August 2009 to May 2011. The vascular malformations were removed or the fistulae were occluded with the assistance of ICG videoangiography. The completeness of fistula clipping or nidus extirpation and each patients neurological status were evaluated. Among these 24 patients, there were seven with spinal dural arteriovenous fistulae, five glomus arteriovenous malformations, one juvenile arteriovenous malformation, nine perimedullary arteriovenous fistulae, and two perimedullary arteriovenous fistulae in combination with perimedullary arteriovenous malformations. Intraoperative ICG videoangiography confirmed the definite clipping of the fistulous points and complete removal of intramedullary arteriovenous malformations in all but one patient. All patients had satisfactory preservation of spinal cord blood supply and venous return. No adverse effects or complications related to ICG videoangiography occurred. Three patients were lost to follow up; 21 patients were followed clinically with a mean follow up of 7.5 months. The neurological deficits completely resolved in six patients, improved significantly in 10, remained stable in two, and were aggravated in three patients. Our experience shows that intraoperative ICG videoangiography offers useful information on the pathological and physiological vascular anatomy encountered during surgery for spinal vascular malformations.

Microsurgical treatment of intracranial chondroma

Intracranial chondromas are rare benign tumors. Little data are available on the diagnosis and treatment of these tumors. Thus, we aimed to describe a large series of patients with intracranial chondroma and to analyze and discuss the clinical features and microsurgical treatment of these patients. We retrospectively analyzed the clinical data of 30 patients (12 males and 18 females; mean age 35.4 years; age range 16-60 years) who had pathologically confirmed intracranial chondroma treated at our hospital from September 1996 to June 2008. Surgery was performed on all 30 patients: five patients underwent postoperative radiotherapy; 26 patients were followed up postoperatively for a mean duration of 45.8 months. The surgical approach was selected according to tumor location. Total resection was achieved in 11 patients, subtotal resection in 13, and partial resection in nine (three patients had recurrent chondroma). Follow-up showed that 21 patients recovered without recurrences, three had recurrence, and two patients died. The clinical manifestations included headache and multiple cranial nerve lesions. Imaging usually showed a well-demarcated extramedullary tumor, centrally located, without surrounding brain edema, partially calcified (73.3%) and with minimal vascularity, often accompanied by erosion and destruction of surrounding bone (56.7%). It is difficult to totally remove an intracranial chondroma, and it is not possible to differentiate a chondroma from a myxoma or chordoma at the cranial base on the basis of clinical manifestations and neuroradiological findings. Selection of the appropriate surgical approach is important for resection of the tumor.