Zhiyong Qin

Clinical application of motor pathway mapping using diffusion tensor imaging tractography and intraoperative direct subcortical stimulation in cerebral glioma surgery: a prospective cohort study.

BACKGROUNDnGlioma surgery in eloquent areas remains a challenge because of the risk of postoperative motor deficits.nnnOBJECTIVEnTo prospectively evaluate the efficiency of using a combination of diffusion tensor imaging (DTI) tractography functional neuronavigation and direct subcortical stimulation (DsCS) to yield a maximally safe resection of cerebral glioma in eloquent areas.nnnMETHODSnA prospective cohort study was conducted in 58 subjects with an initial diagnosis of primary cerebral glioma within or adjacent to the pyramidal tract (PT). The white matter beneath the resection cavity was stimulated along the PT, which was visualized with DTI tractography. The intercept between the PT border and DsCS site was measured. The sensitivity and specificity of DTI tractography for PT mapping were evaluated. The efficiency of the combined use of both techniques on motor function preservation was assessed.nnnRESULTSnPostoperative analysis showed gross total resection in 40 patients (69.0%). Seventeen patients (29.3%) experienced postoperative worsening; 1-month motor deficit was observed in 6 subjects (10.3%). DsCS verified a high concordance rate with DTI tractography for PT mapping. The sensitivity and specificity of DTI were 92.6% and 93.2%, respectively. The intercepts between positive DsCS sites and imaged PTs were 2.0 to 14.7 mm (5.2u2009±u20092.2 mm). The 6-month Karnofsky performance scale scores in 50 postoperative subjects were significantly increased compared with their preoperative scores.nnnCONCLUSIONnDTI tractography is effective but not completely reliable in delineating the descending motor pathways. Integration of DTI and DsCS favors patient-specific surgery for cerebral glioma in eloquent areas.

TERT promoter mutations contribute to IDH mutations in predicting differential responses to adjuvant therapies in WHO grade II and III diffuse gliomas.

IDH mutations frequently occur in WHO grade II and III diffuse gliomas and have favorable prognosis compared to wild-type tumors. However, whether IDH mutations in WHO grade II and II diffuse gliomas predict enhanced sensitivity to adjuvant radiation (RT) or chemotherapy (CHT) is still being debated. Recent studies have identified recurrent mutations in the promoter region of telomerase reverse transcriptase (TERT) in gliomas. We previously demonstrated that TERT promoter mutations may be promising biomarkers in glioma survival prognostication when combined with IDH mutations. This study analyzed IDH and TERT promoter mutations in 295 WHO grade II and III diffuse gliomas treated with or without adjuvant therapies to explore their impact on the sensitivity of tumors to genotoxic therapies. IDH mutations were found in 216 (73.2%) patients and TERT promoter mutations were found in 112 (38%) patients. In multivariate analysis, IDH mutations (p < 0.001) were independent prognostic factors for PFS and OS in patients receiving genotoxic therapies while TERT promoter mutations were not. In univariate analysis, IDH and TERT promoter mutations were not significant prognostic factors in patients who did not receive genotoxic therapies. Adjuvant RT and CHT were factors independently impacting PFS (RT p = 0.001, CHT p = 0.026) in IDH mutated WHO grade II and III diffuse gliomas but not in IDH wild-type group. Univariate and multivariate analyses demonstrated TERT promoter mutations further stratified IDH wild-type WHO grade II and III diffuse gliomas into two subgroups with different responses to genotoxic therapies. Adjuvant RT and CHT were significant parameters influencing PFS in the IDH wt/TERT mut subgroup (RT p = 0.015, CHT p = 0.015) but not in the IDH wt/TERT wt subgroup. Our data demonstrated that IDH mutated WHO grade II and III diffuse gliomas had better PFS and OS than their IDH wild-type counterparts when genotoxic therapies were administered after surgery. Importantly, we also found that TERT promoter mutations further stratify IDH wild-type WHO grade II and III diffuse gliomas into two subgroups with different responses to adjuvant therapies. Taken together, TERT promoter mutations may predict enhanced sensitivity to genotoxic therapies in IDH wild-type WHO grade II and III diffuse gliomas and may justify intensified treatment in this subgroup.

Metabolic approach for tumor delineation in glioma surgery: 3D MR spectroscopy image–guided resection

OBJECT The extent of resection is one of the most essential factors that influence the outcomes of glioma resection. However, conventional structural imaging has failed to accurately delineate glioma margins because of tumor cell infiltration. Three-dimensional proton MR spectroscopy ((1)H-MRS) can provide metabolic information and has been used in preoperative tumor differentiation, grading, and radiotherapy planning. Resection based on glioma metabolism information may provide for a more extensive resection and yield better outcomes for glioma patients. In this study, the authors attempt to integrate 3D (1)H-MRS into neuronavigation and assess the feasibility and validity of metabolically based glioma resection. METHODS Choline (Cho)-N-acetylaspartate (NAA) index (CNI) maps were calculated and integrated into neuronavigation. The CNI thresholds were quantitatively analyzed and compared with structural MRI studies. Glioma resections were performed under 3D (1)H-MRS guidance. Volumetric analyses were performed for metabolic and structural images from a low-grade glioma (LGG) group and high-grade glioma (HGG) group. Magnetic resonance imaging and neurological assessments were performed immediately after surgery and 1 year after tumor resection. RESULTS Fifteen eligible patients with primary cerebral gliomas were included in this study. Three-dimensional (1)H-MRS maps were successfully coregistered with structural images and integrated into navigational system. Volumetric analyses showed that the differences between the metabolic volumes with different CNI thresholds were statistically significant (p < 0.05). For the LGG group, the differences between the structural and the metabolic volumes with CNI thresholds of 0.5 and 1.5 were statistically significant (p = 0.0005 and 0.0129, respectively). For the HGG group, the differences between the structural and metabolic volumes with CNI thresholds of 0.5 and 1.0 were statistically significant (p = 0.0027 and 0.0497, respectively). All patients showed no tumor progression at the 1-year follow-up. CONCLUSIONS This study integrated 3D MRS maps and intraoperative navigation for glioma margin delineation. Optimum CNI thresholds were applied for both LGGs and HGGs to achieve resection. The results indicated that 3D (1)H-MRS can be integrated with structural imaging to provide better outcomes for glioma resection.

Subgroup characteristics of insular low-grade glioma based on clinical and molecular analysis of 42 cases.

Although the classification of insular glioma has been established based on the anatomical location in order to facilitate personalized surgical resection, the diagnosis based on anatomical and functional characteristics becomes more complex when insular tumors extend into either the frontobasal brain region and/or the temporal lobe, as part of the limbic system. Moreover, prognosis of insular tumor resection is still controversial. Further analysis of subgroup characteristics of insular grade II gliomas based on clinical and molecular analysis is required to reliably determine patients’ survival rates. In this retrospective study 20 purely insular grade II gliomas patients and 22 paralimbic grade II gliomas that involved frontal and/or temporal lobes were compared with regard to epidemiological and clinical characteristics. The molecular profiles including Isocitrate dehydrogenase 1 (IDH1), telomerase reverse transcriptase (TERT) promoter, and P53 mutations, 1p19q co-deletion were analyzed, and microRNA profiles were assessed by microarray and bioinformatics analysis. Purely insular grade II gliomas displayed a high frequency of IDH1 mutations with favorable outcome. IDH1 mutated paralimbic glioma shared many parameters with the purely insular glioma in respect to growth patterns, survival, and microRNA profile, but differed significantly from the IDH1 wild type paralimbic gliomas. Our findings suggest that IDH1 mutations can define subpopulations of insular gliomas with distinct disease entities regardless of tumor extension patterns. These findings could be useful to develop a customized treatmentxa0strategy for insular glioma patients.

Establishment and maintenance of a standardized glioma tissue bank: Huashan experience

Cerebral glioma is the most common brain tumor as well as one of the top ten malignant tumors in human beings. In spite of the great progress on chemotherapy and radiotherapy as well as the surgery strategies during the past decades, the mortality and morbidity are still high. One of the major challenges is to explore the pathogenesis and invasion of glioma at various “omics” levels (such as proteomics or genomics) and the clinical implications of biomarkers for diagnosis, prognosis or treatment of glioma patients. Establishment of a standardized tissue bank with high quality biospecimens annotated with clinical information is pivotal to the solution of these questions as well as the drug development process and translational research on glioma. Therefore, based on previous experience of tissue banks, standardized protocols for sample collection and storage were developed. We also developed two systems for glioma patient and sample management, a local database for medical records and a local image database for medical images. For future set-up of a regional biobank network in Shanghai, we also founded a centralized database for medical records. Hence we established a standardized glioma tissue bank with sufficient clinical data and medical images in Huashan Hospital. By September, 2013, tissues samples from 1,326 cases were collected. Histological diagnosis revealed that 73xa0% were astrocytic tumors, 17xa0% were oligodendroglial tumors, 2xa0% were oligoastrocytic tumors, 4xa0% were ependymal tumors and 4xa0% were other central nervous system neoplasms.

Serological Identification of URGCP as a Potential Biomarker for Glioma

Glioblastoma multiforme (GBM) is one of the most frequent human brain tumor and causes dismal outcome. To identify tumor‐associated antigens in GBM patients may find potential diagnostic markers and immunotherapeutic targets. In this study, we identified a gene termed URGCP using the serological identification of antigens by recombinant A2B5 positive glioma cDNA library. The gene product of URGCP is immunogenic in GBM after tested in allogenic patients serum screening.

Transition over 35 Years in the Incidence Rates of Primary Central Nervous System Tumors in Shanghai, China and Histological Subtyping Based on a Single Center Experience Spanning 60 Years

BACKGROUNDnOnly few epidemiological data on primary central nervous system (CNS) tumors in Shanghai have been reported.nnnMETHODSnAll cases of primary CNS tumors that were registered at Center for Disease Control and Prevention (CDC) were collected (1973-2007: urban Shanghai; 2003-2007: whole Shanghai city). Trends were analyzed using joinpoint analysis and rates were stratified by age, gender and region. Histological data were collected from both CDC and Huashan Hospital.nnnRESULTSnFrom 1973 to 2007, the five-year average incidence rate in urban Shanghai increased in both genders, especially in the elderly population. Joinpoint analysis showed the age-adjusted incidence rate for males increased first but then plateaued, whilst rates for females continued increasing over the 35 years. For the five-year status quo (2003-2007), rural had a higher age- adjusted incidence rate than urban populations, and females higher than males, especially those with advanced age. According to CDC (2003-2007) and Huashan Hospital (1951-2011), the two most common histological subtypes were neuroepithelial tumors (with male predominance) and meningiomas (with female predominance).nnnCONCLUSIONSnIn Shanghai, a steadily increased incidence rate of primary CNS tumors was observed in general, and in the elderly and female population in particular.

Nucleolin overexpression is associated with an unfavorable outcome for ependymoma: a multifactorial analysis of 176 patients

AbstractnEpendymoma typically has a better overall survival rate than most gliomas. Only a few comprehensive clinical studies have been published, but these are mostly from Western countries and use small sample sizes. Histopathological classification is not sufficient to show variable outcomes, and fails to show prognostic markers of the diverse outcomes; hence, it is essential to understand biological mechanisms. In this study, 176 ependymoma samples (World Health Organization grade II and III) were reviewed at Huashan Hospital. Both children and adults were included. We performed multifactorial analyses of clinical prognostic factors and the biomolecular marker expressions of nucleolin, epidermal growth factor receptor (EGFR) and caveolae-associated protein caveolin-1 by immunohistochemistry. We identified the probabilities of progression-free survival and overall survival using univariate and multivariate statistical methods. The participants were diagnosed with ependymomas between 2002 and 2010, including distributions of tumor locations in intracranial and extracranial regions. Nucleolin was overexpressed in 67xa0% of our samples, demonstrating a subgroup with poor outcome; particularly infratentorial and anaplastic ependymomas. There was no significant correlation between the expression of EGFR and caveolin-1 and clinical outcomes. Clinically, inferior prognosis was observed with regard to age (<18xa0years), intracranial location, high grade ependymomas, and incomplete resection. We found that nucleolin was an unfavorable prognostic predictor for ependymomas. Moreover, our findings show a subset of aggravating outcomes in high-grade and posterior fossa tumors.

Augment low-field intra-operative MRI with preoperative MRI using a hybrid non-rigid registration method

BACKGROUNDnPreoperatively acquired diffusion tensor image (DTI) and blood oxygen level dependent (BOLD) have been proved to be effective in providing more anatomical and functional information; however, the brain deformation induced by brain shift and tumor resection severely impairs the correspondence between the image space and the patient space in image-guided neurosurgery.nnnMETHODnTo address the brain deformation, we developed a hybrid non-rigid registration method to register high-field preoperative MRI with low-field intra-operative MRI in order to recover the deformation induced by brain shift and tumor resection. The registered DTI and BOLD are fused with low-field intra-operative MRI for image-guided neurosurgery.nnnRESULTSnThe proposed hybrid registration method was evaluated by comparing the landmarks predicted by the hybrid registration method with the landmarks identified in the low-field intra-operative MRI for 10 patients. The prediction error of the hybrid method is 1.92±0.54 mm, and the compensation accuracy is 74.3±5.0%. Compared to the landmarks far from the resection region, those near the resection region demonstrated a higher compensation accuracy (P-value=.003) although these landmarks had larger initial displacements.nnnCONCLUSIONSnThe proposed hybrid registration method is able to bring preoperatively acquired BOLD and DTI into the operating room and compensate for the deformation to augment low-field intra-operative MRI with rich anatomical and functional information.

Molecular subgroups and B7-H4 expression levels predict responses to dendritic cell vaccines in glioblastoma: an exploratory randomized phase II clinical trial

Dendritic cell (DC)-based vaccination is a promising approach for active-specific immunotherapy, but is currently of limited efficacy. The safety and effectiveness of a DC vaccine (DCV) loaded with glioblastoma stem cell-like (GSC) antigens was assessed in glioblastoma multiforme (GBM) patients. In this double-blind, placebo-controlled phase II clinical trial, 43 GBM patients were randomized after surgery at a 1:1 ratio to receive either DCV (nu2009=u200922) or normal saline placebo (nu2009=u200921). Overall survival (OS) and progression-free survival (PFS) were analysed. Participants were stratified into different molecular subgroups based on the mutation (MT) status of isocitrate dehydrogenase (IDH1/2) and telomerase reverse transcriptase (TERT). Plasma cytokine levels, tumor-infiltrating lymphocyte numbers and immune co-inhibitory molecules PD-L1 and B7-H4 were also assessed. Multivariate Cox regression analysis revealed that DCV treatment significantly prolonged OS (pu2009=u20090.02) after adjusting for IDH1 and TERT promoter MT and B7-H4 expression, primary vs recurrent GBM. Among IDH1wild type (WT) TERTMT patients, DCV treatment significantly prolonged OS (pu2009<u20090.01) and PFS (pu2009=u20090.03) and increased plasma levels of cytokines CCL22 and IFN-γ compared with placebo. Patients with low B7-H4 expression showed significantly prolonged OS (pu2009=u20090.02) after DCV treatment. Therefore, IDH1WTTERTMT and low B7-H4 expression identified subgroups of GBM patients more responsive to GSC DCV-based specific active-immunotherapy.