Qi Songtao

IDH mutations predict longer survival and response to temozolomide in secondary glioblastoma

Recent studies have shown that isocitrate dehydrogenase1/2 (IDH1/2) mutations occur frequently in secondary glioblastoma. This study aimed to investigate their impact on temozolomide chemosensitivity and relationship with O(6)‐methylguanine DNA methyltransferase (MGMT) promoter methylation in secondary glioblastoma. Searches for IDH1 and IDH2 mutations, 1p19q codeletion, MGMT promoter methylation, and p53 expression were carried out in a series of 86 secondary glioblastomas and correlated with progression‐free survival and overall survival. Response to temozolomide was evaluated by progression‐free survival, as well as by tumor size on successive MRI scans, then correlated with molecular alterations. IDH (IDH1 or IDH2) mutations were found in 58/79 patients (73.4%). IDH mutation, MGMT promoter methylation, and 1p19q codeletion were associated with prolonged progression‐free survival in univariate (P < 0.001, P < 0.001, P = 0.003, respectively) and multivariate analysis (P < 0.001, P < 0.001, P = 0.035, respectively). IDH mutation (P = 0.001) and MGMT promoter methylation (P = 0.011) were correlated with a higher rate of objective response to temozolomide. Further analysis of response to temozolomide showed that patients with both IDH mutation and MGMT promoter methylation had the best response rate to temozolomide. IDH mutation appears to be a significant marker of positive chemosensitivity in secondary glioblastoma. Use of IDH status combined with MGMT promoter status as a stratification factor seems appropriate in future clinical trials involving temozolomide for the treatment of patients with secondary glioblastoma. (Cancer Sci 2012; 103: 269–273)

The arachnoid sleeve enveloping the pituitary stalk: anatomical and histologic study.

BACKGROUNDThe arachnoid membrane in the suprasellar region may affect the growth pattern of sellar and suprasellar tumors however, the topographic relationships between the pituitary stalk and the surrounding arachnoid membranes remained unclear. OBJECTIVEThe aim of this study was to evaluate the anatomical and histological characteristics of the arachnoid membranes. METHODSMicrosurgical dissection and anatomical observation were performed in 16 formalin-fixed adult cadaver heads. In the other 5 adult cadaver heads, histologic sections of sellar-suprasellar specimens were studied under light microscopy. RESULTSAn arachnoid sleeve enveloping the pituitary stalk of variable length presented in all specimens, which was formed by direct upward extension of the basal arachnoid membrane covering the diaphragma sellae. In the majority of specimens, the arachnoid sleeve was reinforced by the arachnoid trabeculae originating from the basal arachnoid membrane, the Liliequist membrane, and the medial carotid membrane. CONCLUSIONThe relationship between the pituitary stalk and the surrounding arachnoid membrane is important in evaluating the growth patterns of the sellar and suprasellar tumors, and their topographical relationships.

Association between the XRCC1 Arg399Gln polymorphism and risk of cancer: evidence from 297 case-control studies.

Background The Arg399Gln polymorphism in the X-ray cross-complementing group 1 (XRCC1) had been implicated in cancer susceptibility. The previous published data on the association between XRCC1 Arg399Gln polymorphism and cancer risk remained controversial. Methodology/Principal Findings To derive a more precise estimation of the association between the XRCC1 Arg399Gln polymorphism and overall cancer risk, we performed a meta-analysis of 297 case-control studies, in which a total of 93,941 cases and 121,480 controls were included. Overall, significantly increased cancer risk was observed in any genetic model (dominant model: odds ration [OR] = 1.04, 95% confidence interval [CI] = 1.01–1.07; recessive model: OR = 1.08, 95% CI = 1.03–1.13; additive model: OR = 1.09, 95% CI = 1.04–1.14) when all eligible studies were pooled into the meta-analysis. In further stratified and sensitivity analyses, significantly elevated hepatocellular and breast cancers risk were observed in Asians (dominant model: OR = 1.39, 95% CI = 1.06–1.84) and in Indians (dominant model: OR = 1.64, 95% CI = 1.31–2.04; recessive model: OR = 1.94, 95% CI = 1.09–3.47; additive model: OR = 2.06, 95% CI = 1.50–2.84), respectively. Conclusions/Significance This meta-analysis suggests the participation of XRCC1 Arg399Gln is a genetic susceptibility for hepatocellular cancer in Asians and breast cancer in Indians. Moreover, our work also points out the importance of new studies for Arg399Gln association in some cancer types, such as glioma, gastric cancer, and oral cancer, where at least some of the covariates responsible for heterogeneity could be controlled, to obtain a more conclusive understanding about the function of the XRCC1 Arg399Gln polymorphism in cancer development.

Membranous layers of the pituitary gland: histological anatomic study and related clinical issues.

OBJECTIVE The purpose of this study was to examine the membranous layers of the human pituitary gland and their relationships with invasive adenomas. METHODS Histological and microdissection techniques were used to study 8 fetal and 10 adult human cadavers, respectively. The distribution of the membranous layers was observed, and their thickness was measured. The results were analyzed histologically and anatomically. RESULTS In all specimens, the pituitary glands were found to be coated by 2 membranous layers, the inner layer being referred to here as the lamina propria and the outer as the pituitary capsule. In all specimens, the 2 membranes were intact with no histological defects. An interstice or cavity between the 2 layers was found on the surface of the adenohypophysis. However, as these 2 layers got closer and closer to each other, they began to adhere on the surface of the neurohypophysis. The thickness of the pituitary capsule was not constant like that of the lamina propria: the inferolateral part of the capsule was thicker than the other parts. The medial wall of the cavernous sinus (CS) was also a bilayered membrane just like the other CS walls: the 2 layers of the medial CS wall were composed of the lateral part of the pituitary capsule and the fibrous layer. Many fibrous trabeculae arising from this fibrous layer divided the CS into several small venous spaces and connected the internal carotid arteries with the medial wall. CONCLUSION The terminology for the 2 membranous layers, the lamina propria and the pituitary capsule, seemed to be more appropriate and representative of the histological features of the pituitary layers. The lateral part of the capsule and the fibrous layer constituted the medial wall of the CS, which has a superior part that is weaker than the thicker inferior part. It is still difficult to postulate the criteria needed to predict CS invasion. However, the distance between the 2 sides of the internal carotid artery might be another predictive criterion to preoperatively diagnose CS invasion by adenomas. Enhanced knowledge of these membranes may be of assistance in finding a useful criterion.

Does the calcification of adamantinomatous craniopharyngioma resemble the calcium deposition of osteogenesis/odontogenesis?

Calcification in adamantinomatous craniopharyngioma (ACP) is troublesome for surgical intervention. The aim of this study was to examine the osteogenic proteins that play important roles in the calcium deposition of the odontogenic/osteogenic tissues in craniopharyngioma.

Preoperative radiologic characters to predict hemangiopericytoma from angiomatous meningioma

BACKGROUND Hemangiopericytoma is clinically difficult to be differentiated from angiomatous meningioma. We set out to determine if the preoperative MRI parameters can predict HPC from angiomatous meningioma. METHODS A retrospective review of medical records was conducted for12 HPC patients and 17 angiomatous meningiomas. WHO-2007 grading was used for histopathological diagnosis. Preoperative radiologic parameters included tumor location, tumor size, tumor shape, T1-weighted signal, T2-weighted signal, T1-weighted Gd-enhanced image, ADC value, Flair signal, peritumoral edema (PTE), dural tail sign (DTS), vessel voids sign, arachnoid layer on T2-weighted MRI, tumor hemorrhage and necrosis were analyzed. Univariate analyses were conducted to examine the association between radiological or clinical and histopathological features. Binary logistic regression model was used to evaluate if the parameters predict the occurrence of HPC. RESULTS Five parameters, included age, gender, ADC value, necrosis and T1 enhancement was found significantly different between two types after univariate analyses. Binary logistic regression model demonstrated ADC value was the sole independent predictor of HPC (p=0.039, OR: 14.5, CI-3.7-38.6). CONCLUSIONS ADC value may be used as a simple and useful optional tool in differentiating primary intracranial HPC from angiomatous meningioma. The combination of ADC value with the data acquired from pre and post-contrast MR scans may further help improve the reliability in the differential diagnosis.

Calretinin is expressed in the stroma of adamantinomatous craniopharyngioma and may induce calcification.

OBJECTIVES Calretinin is expressed in many tumors. However, the role of calretinin in craniopharyngiomas (CPs) remains unknown. PATIENTS AND METHODS The study included 77 adamantinomatous CP (ACP). ACP calcification was divided into several categories on the basis of the incidence and extent of the calcium deposits evident on computed tomography (CT) images. The presence and expression pattern of calretinin were investigated using immunohistochemistry and western blotting. CP cell culture and small interfering (si)RNA of calretinin transfection was also carried out to clarify the role of calretinin in ACP calcification. RESULTS 61 cases exhibited calcification on CT, and 63 samples were immunopositive to calretinin. The western blotting results were consistent with the immunohistochemical findings. Calretinin expressions differed significantly among ACP groups basing on calcification degree, and a positive correlation was observed between calretinin expression and calcification degree (r=0.853, P<0.001). Calretinin siRNA transfection further demonstrated the role calretinin played in ACP calcification. CONCLUSIONS Calretinin is expressed in the tumor stoma of calcified ACP, and its expression correlated with calcification degree. Drugs that target calretinin to reduce calcification and improve the postoperative function of ACP patients should be further researched.

TPD52L2 impacts proliferation, invasiveness and apoptosis of glioblastoma cells via modulation of wnt/β-catenin/snail signaling

Intratumoral heterogeneity greatly hinders efficiency of target therapy in glioblastoma (GBM). To decipher the underlying mechanisms of heterogeneity, patient-derived adult GBM cells were separately isolated from margins of T1 gadolinium enhancing tumor lesions (PNCs) and T1 gadolinium enhancing core lesions (ECs). Single clone culture was conducted in ECs and U87MG cell line to screen clones with distinct biological phenotypes. Single cell clones with diverse phenotypes were simultaneously separated from ECs and U87 cell line. PNCs, GCs(H) and U87(H) exhibited longer cellular protrusion than ECs, GCs(L) and U87(L), respectively. Cell strains with longer protrusion exhibited higher invasive ability and lower sensitivity to temozolomide (TMZ) and radiation. Subsequently, TPD52L2 was verified as the functional protein to regulate the cellular heterogeneity by the proteomics analysis. Downregulation of TPD52L2 enhanced cell invasion whereas inhibited cell proliferation rate and sensitivity to chemotherapy in vivo and in vitro, this condition was reversed when TPD52L2 was overexpressed. The invasiveness was facilitated by up-regulating CTNNB1/β-catenin and SNAI1/Snail mediated EMT process. In addition, the clinical data of 88 GBM cases in our neurosurgery center was analyzed to reveal the influence of TPD52L2 in the prognosis of GBM. Low expression of TPD52L2 exacerbated prognosis of GBM patients received standard radiotherapy plus concomitant and adjuvant TMZ (Stupp strategy). Taken together, TPD52L2 is an important biomarker influencing GBM prognosis.