Novel patient-derived xenograft and cell line models for therapeutic screening in NF2-associated schwannoma.

Treatment of schwannomas in patients with neurofibromatosis type 2 (NF2) is extremely unsatisfactory, and innovative therapeutic approaches are urgently needed. However, the lack of clinically relevant NF2-associated schwannoma models has severely hampered drug discovery in this rare disease. Here we report the first establishment and characterization of patient-derived xenograft (PDX) and cell line models of NF2-associated schwannoma, which recapitulates the morphological and histopathological features of patient tumors, retain patient NF2 mutations, and maintain gene expression profiles resembling patient tumor profiles with the preservation of multiple key signaling pathways commonly dysregulated in human schwannomas. Using gene expression profiling, we identified elevated PI3K/AKT/mTOR networks in human NF2-associated vestibular schwannomas. Using high-throughput screening of 157 inhibitors targeting the PI3K/AKT/mTOR pathways in vitro, we identified a dozen inhibitors (such as BEZ235, LY2090314, and AZD8055) with significant growth-suppressive effects. Interestingly, we observed that three cell lines displayed differential therapeutic responses to PI3K/AKT/mTOR inhibitors. Furthermore, we demonstrated that two orally bioavailable inhibitors, AZD8055 and PQR309, suppressed NF2-associated schwannoma growth both in vitro and in vivo. In conclusion, our novel patient-derived models of NF2-associated schwannoma closely mimic the phenotypes and genotypes of patient tumors, making them reliable preclinical tools for testing novel personalized therapies. © 2022 The Pathological Society of Great Britain and Ireland.

Partial response to Chinese patent medicine Kangliu pill for adult glioblastoma: A case report and review of the literature.

BACKGROUND: Glioblastoma is the most common type of brain tumor and is invariably fatal, with a mean survival time of 8-15 mo for recently diagnosed tumors, and a 5-year survival rate of only 7.2%. The standard treatment for newly diagnosed glioblastoma includes surgery followed by concurrent chemoradiotherapy and further adjuvant temozolomide. However, the prognosis remains poor and long-term survival is rare. This report aimed to demonstrate a new therapeutic strategy for the treatment of glioblastoma. CASE SUMMARY: A patient was referred to the Department of Neurosurgery with an intracranial space-occupying lesion with a maximum diameter of approximately 5 cm. The tumor was compressing functional areas, and the patient accordingly underwent partial resection and concurrent chemoradiotherapy. The imaging and pathological findings were consistent with a diagnosis of glioblastoma with oligodendroglioma differentiation (World Health Organization IV). The patient was finally diagnosed with glioblastoma. However, the patient discontinued treatment due to intolerable side effects, and was prescribed Kangliu pill (KLP) 7.5 g three times/d, which he has continued to date. Significant shrinkage of the tumor (maximum diameter reduced from about 3.5 to about 2 cm) was found after 3 mo of KLP therapy, and the tumor was further reduced to about 1 cm after 3 years. The patient's symptoms of headache, limb weakness, and left hemiplegia were relieved, with no side effects. CONCLUSION: KLP has been a successful intervention for glioblastoma, and the current case indicates that traditional Chinese medicine may offer effective alternative therapies for glioblastoma.

Survival and Prognostic Factors of Adult Intracranial Ependymoma: A Single-institutional Analysis of 236 Patients.

Adult intracranial ependymomas (EPNs) are extremely rare brain tumors. Currently, clinical and molecular factors that could inform individualized treatment strategies are still lacking for EPNs in this age group. The aim of this study was to investigate potential prognostic indicators and rational therapeutic management in a large cohort of adult intracranial EPNs. Adult patients who underwent resection of World Health Organization (WHO) grade II or III intracranial EPNs were included. The demographic features, clinicopathologic manifestations, molecular subgroups, and outcomes were retrospectively analyzed. Overall survival and progression-free survival were calculated using the Kaplan-Meier analysis. Potential prognostic indicators were identified using multivariable Cox proportional hazards model. This cohort included 236 adult patients with a mean age of 36.2 years (range: 18 to 72 y) at diagnosis. The tumor location was supratentorial (ST) in 102 (43.2%) and infratentorial in 134 (56.8%). Pathologic analysis revealed 43.1% of ST-EPNs with RELA fusion and 88.1% of posterior fossa ependymomas (PF-EPNs) with positive H3K27me3 staining. Gross total removal was achieved in 169 cases (71.6%). During follow-up, 97 (41.1%) patients had disease progression and 39 (16.5%) died. Kaplan-Meier analysis showed that patients with H3K27me3-positive PF-EPN had excellent survival, whereas patients with RELA fusion-positive ST-EPN or H3K27me3-negative PF-EPN had poor prognosis (progression-free survival: P=1.3E-16, overall survival: P=2.5E-12). Multivariate analysis showed that molecular subgroup, extent of resection, and Ki-67 index were strong independent prognostic indicators. In conclusion, our study provides essential information on the prognostic prediction of adult intracranial EPNs that will assist in establishing appropriate risk stratification and individualized treatment strategies in future clinical trials.

An adult case of diffuse midline glioma with H3 K27M mutation.

Cartilaginous metaplasia is rare in primary central nervous system (CNS) neoplasms and has not been described in the histone 3 (H3) gene (H3) with a substitution of lysine to methionine (H3 K27M mutant) diffuse midline glioma before. Here, we report a case of H3 K27M mutant diffuse midline glioma with cartilaginous metaplasia in a 56-year-old woman. Magnetic resonance imaging (MRI) revealed a ring-enhanced lesion located in the medulla oblongata and extended superiorly into the fourth ventricle. The tumor was macroscopically completely resected. Histologically, the tumor was composed of a gliomatous component and a well-differentiated cartilaginous component. Microvascular proliferation and necrosis were noted. According to immunohistochemical staining, glial cells were diffusely and strongly positive for glial fibrillary acidic protein (GFAP), oligodendrocyte lineage transcription factor 2 (Olig2), H3 K27M, and S-100 protein but negative for H3K27me3. The chondrocytes also were positive for GFAP and S-100 protein. The H3 K27M mutation was confirmed by sequencing in both the gliomatous and cartilaginous components, suggesting a common origin from the same progenitor cells. Based on these findings, the tumor was diagnosed as a diffuse midline glioma with H3 K27M mutation with widespread cartilaginous metaplasia, corresponding to WHO grade IV. This is an extremely rare H3 K27M mutant diffuse midline glioma with cartilaginous metaplasia, and reporting this unusual case adds to the understanding of this tumor type.

MYB-QKI rearrangement in angiocentric glioma.

AIMS: To evaluate the occurrence and diagnostic value of MYB-QKI rearrangement status in angiocentric glioma (AG) in Chinese patients. MATERIALS AND METHODS: 27 cases were collected from six hospitals, followed by a retrospective analysis of clinical, radiological, and morphological data. MYB protein expression was assessed by immunohistochemical staining (IHC), and the MYB-QKI rearrangement was detected by fluorescence in situ hybridization (FISH). RESULTS: Among the 27 cases (16 males), the median age at surgery was 17 years (range 3 - 43 years); 24 (88.9%) cases had a history of refractory epilepsy, and the mean history of pre-surgical epilepsy was 13 years (range 1.5 - 27 years); 26 (96.3%) cases had lesions located in the superficial cerebrocortical regions, and 1 (3.7%) case had a lesion in the brainstem. Except for the classic histological features, the involvement of superficial cortex extending to the leptomeninges, microcalcification, and cystic pattern with microcystic formations was observed in 11 (40.7%), 3 (11.1%), and 4 (14.8%) cases, respectively. IHC showed that all 27 cases were positive for glial fibrillary acidic protein (GFAP) and vimentin, and negative for neuronal nuclear antigen (NeuN). The positive rates of epithelial membrane antigen (EMA) and D2-40 were 81.5% (22/27) and 74.1% (20/27), respectively. A total of 14 (51.9%) cases were positive for MYB. The rate of Ki-67 proliferation was 1 - 5% in 25 cases, and in 2 cases with anaplastic features it was 10 and 20%. MYB-QKI rearrangement was revealed by FISH examination in 95.8% (23/24) of the AGs, including 3 cases with atypical histological appearance. CONCLUSION: Compared to IHC, FISH was more appropriate for detecting MYB-QKI rearrangement. MYB-QKI rearrangement was detected in the majority of Chinese AG cases, and therefore represents a potential diagnostic biomarker for AG.

Clinico-neuropathological features of isocitrate dehydrogenase 2 gene mutations in lower-grade gliomas.

BACKGROUND: Mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes are important for both the integrated diagnosis and the prognosis of diffuse gliomas. The p.R132H mutation of IDH1 is the most frequently observed IDH mutation, while IDH2 mutations were relatively rarely studied. The aim of the study was to determine the pathological and genetic characteristics of lower-grade gliomas that carry IDH2 mutations. METHODS: Data from 238 adult patients with lower-grade gliomas were retrospectively analyzed. The status of IDH1/2 gene mutations, telomerase reverse transcriptase (TERT) promoter mutations, O-methylguanine-DNA-methyltransferase (MGMT) promoter methylation, 1p/19q co-deletion and the expressions of IDH1 R132H, alpha-thalassemia X-linked mental retardation, and p53 were evaluated. Progression-free survival (PFS) and overall survival (OS) were calculated via Kaplan-Meier estimation using the log-rank test. RESULTS: Totally, 71% (169/238) of patients were positive for IDH mutations, including 12 patients harboring mutations in IDH2. Among the 12 patients with IDH2 mutations, ten patients harbored the R172K mutation, one patient harbored the R172S mutation and one harbored the R172W mutation. Of these, 11 tumors occurred in the frontal lobe and showed morphology typical of oligodendroglioma. The proportion of grade II tumors was higher than that of grade III tumors in IDH2 mutant-gliomas. IDH2 mutations were frequently associated with TERT promoter mutations, 1p/19q co-deletion and MGMT promoter methylation. IDH2 mutations were associated with better outcomes compared with IDH wild-type gliomas (P < 0.05). However, the PFS and OS did not differ from that of IDH1 mutant patients (P = 0.95 and P = 0.60, respectively). CONCLUSIONS: IDH2 mutations are more frequent in oligodendrogliomas and associated with a better prognosis. IDH2 mutations may segregate in distinct clinico-pathological and genetic subtypes of gliomas, and therefore may merit routine investigation.

Structural Evolution of Core-Shell Gold Nanoclusters: Aun- (n = 42-50).

Gold nanoclusters have attracted great attention in the past decade due to their remarkable size-dependent electronic, optical, and catalytic properties. However, the structures of large gold clusters are still not well-known because of the challenges in global structural searches. Here we report a joint photoelectron spectroscopy (PES) and theoretical study of the structural evolution of negatively charged core-shell gold nanoclusters (Aun-) for n = 42-50. Photoelectron spectra of size-selected Aun- clusters are well resolved with distinct spectral features, suggesting a dominating structural type. The combined PES data and density functional calculations allow us to systematically identify the global minimum or candidates of the global minima of these relatively large gold nanoclusters, which are found to possess low-symmetry structures with gradually increasing core sizes. Remarkably, the four-atom tetrahedral core, observed first in Au33-, continues to be highly robust and is even present in clusters as large as Au42-. Starting from Au43-, a five-atom trigonal bipyramidal core appears and persists until Au47-. Au48- possesses a six-atom core, while Au49- and Au50- feature seven- and eight-atom cores, respectively. Notably, both Au46- and Au47- contain a pyramidal Au20 motif, which is stacked with another truncated pyramid by sharing a common 10-atom triangular face. The present study sheds light on our understanding of the structural evolution of the medium-sized gold nanoclusters, the shells and core as well as how the core-shell structures may start to embrace the golden pyramid (bulk-like) fragment.

Glioneuronal tumours with features of rosette-forming glioneuronal tumours of the fourth ventricle and dysembryoplastic neuroepithelial tumours: a report of three cases.

AIMS: To study three atypical glioneuronal tumours (GNTs), in order to shed light on the clinical and pathological features of this diverse tumour group. METHODS AND RESULTS: Clinical and neuropathological data for each case were retrospectively reviewed. Case 1 involved a 17-year-old boy with left leg movement difficulty. A mass lesion in the basal ganglia was detected radiologically; histopathological features included neurocytic/perivascular rosettes and a pilocytic astrocytoma component. Case 2 involved a 33-year-old man with intractable epilepsy. His left parietal lobe contained a cyst-like mass, resembling dysembryoplastic neuroepithelial tumour and rosette-forming glioneuronal tumour of the fourth ventricle microscopically. Case 3 involved a 21-year-old woman with a mass lesion in the mesencephalic tegmentum extending to the third and fourth ventricles and the suprasellar region. The lesion contained perivascular/neurocytic rosettes and an oligodendroglioma-like component. None of the tumours expressed an isocitrate dehydrogenase I mutation of the R132H type or contained a 1p/19q deletion, a BRAF(V600E) mutation, or KIAA1549-BRAF fusion. CONCLUSIONS: We describe three GNTs with atypical histopathology and locations. Additional cases and molecular studies are needed to better understand the biological nature of GNTs and to refine their classification system.

Benign giant-cell tumor of the common bile duct: a case report.

Primary giant-cell tumors rarely arise in the common bile duct. We herein report a case of primary giant-cell tumor of the common bile duct. The patient was an 81-year-old male who was diagnosed with a well-defined 1.2-cm mass projecting into the lumen of the middle common bile duct. Excision of the gallbladder and extrahepatic bile duct and a Roux-en-Y cholangiojejunostomy were performed. Histologically, the tumor had no association with carcinomas of epithelial origin and was similar to giant-cell tumors of the bone. The tumor consisted of a mixture of mononuclear and multinucleated osteoclast-like giant cells. The mononuclear cells showed no atypical features, and their nuclei were similar to those of the multinucleated giant cells. CD68 was expressed on the mononuclear and multinucleated osteoclast-like giant cells, whereas CD163 immunoreactivity was restricted to the mononuclear cells. Six months after the operation, the patient was still alive and had no recurrence. The interest of this case lies in the rarity of this entity, the difficulty of preoperative diagnosis, and this tumor's possible confusion with other malignant tumors.

Intraneural perineurioma affecting multiple nerves: a case report and literature review.

Intraneural perineurioma is a neoplasm of perineurial cells, corresponding to WHO grade I. We present a case of intraneural perineurioma affecting multiple nerves, which usually involved one or two of major nerve trunks in one patient. We describe the clinical presentation, magnetic resonance (MR) neurography characteristics, and pathological characteristics. The differential diagnosis with other diseases, such as neurofibroma, Schwannomatosis and HNPP, will also be discussed. We also review the literature in efforts to highlight recent studies on intraneural perineurioma and heighten and awareness for the possible presentations of this disorder.

[Mutation of isocitrate dehydrogenase gene in Chinese patients with glioma].

OBJECTIVE: To investigate mutation status of isocitrate dehydrogenase (IDH) 1 and IDH2 genes in Chinese patients with gliomas in correlation with clinicopathological characteristics. METHODS: Formalin-fixed and paraffin-embedded (FFPE) tissue samples of 234 gliomas were collected including the matched blood samples in 30 patients. DNA was extracted, followed by PCR-Sanger sequencing to detect IDH1 and IDH2 gene mutations. Immunohistochemistry was performed using mutation-specific antibody recognizing IDH1R132H mutation. Immunostains for p53 and epidermal growth factor receptor (EGFR) were also performed. Oligodendroglial tumors with IDH mutation were double stained with IDH1R132H and GFAP by immunofluorescence to investigate the location of IDH1R132H expression. RESULTS: (1) By IDH1 heterozygous somatic mutation analysis, Arg132His (c: G395A) was found in 31.6% (74 of 234) of the cases. IDH mutations were more frequent in oligoastrocytomas (9/13), anaplastic oligoastrocytomas (7/11), oligodendrogliomas(18/26, 69.2%), anaplastic oligodendrogliomas (8/10), and less frequent in diffuse astrocytomas (17/47, 36.2%), anaplastic astrocytomas (5/18), and glioblastomas (10/69, 14.5%). The mutation rate inversely correlated with the tumor grade in a linear fashion in astrocytic tumors (P = 0.007). Primary glioblastomas were characterized by a lower frequency of mutations than secondary glioblastomas (5/55 vs. 5/14, P = 0.036); IDH mutation was not detected in pilocytic astrocytoma and ependymoma. No IDH2 mutation was identified in this study cohort. (2) Immunohistochemistry of IDH1R132H demonstrated a strong cytoplasmic staining in 80 cases, which was highly correlated with IDH mutation status (P = 0.001). IDH1R132H was highly specific to tumor cells. (3) p53 immunostain was significantly correlated the IDH mutation in diffuse astrocytoma, anaplastic astrocytoma and secondary glioblastomas (P = 0.007, 0.026, 0.038 respectively). (4) No correlation between EGFR and IDH mutation was found. CONCLUSIONS: High prevalence of IDH heterozygous somatic mutation occurs in the earlier stage of gliomas, which can be detected by mutation-specific antibody IDH1R132H. Furthermore, evaluation of p53 and EGFR expression combined with IDH mutation analysis may significantly aid in the diagnosis and differential diagnoses of gliomas in Chinese patients.

Unraveling the mechanisms of O2 activation by size-selected gold clusters: transition from superoxo to peroxo chemisorption.

The activation of dioxygen is a key step in CO oxidation catalyzed by gold nanoparticles. It is known that small gold cluster anions with even-numbered atoms can molecularly chemisorb O(2) via one-electron transfer from Au(n)(-) to O(2), whereas clusters with odd-numbered atoms are inert toward O(2). Here we report spectroscopic evidence of two modes of O(2) activation by the small even-sized Au(n)(-) clusters: superoxo and peroxo chemisorption. Photoelectron spectroscopy of O(2)Au(8)(-) revealed two distinct isomers, which can be converted from one to the other depending on the reaction time. Ab initio calculations show that there are two close-lying molecular O(2)-chemisorbed isomers for O(2)Au(8)(-): the lower energy isomer involves a peroxo-type binding of O(2) onto Au(8)(-), while the superoxo chemisorption is a slightly higher energy isomer. The computed detachment transitions of the superoxo and peroxo species are in good agreement with the experimental observation. The current work shows that there is a superoxo to peroxo chemisorption transition of O(2) on gold clusters at Au(8)(-): O(2)Au(n)(-) (n = 2, 4, 6) involves superoxo binding and n = 10, 12, 14, 18 involves peroxo binding, whereas the superoxo binding re-emerges at n = 20 due to the high symmetry tetrahedral structure of Au(20), which has a very low electron affinity. Hence, the two-dimensional (2D) Au(8)(-) is the smallest anionic gold nanoparticle that prefers peroxo binding with O(2). At Au(12)(-), although both 2D and 3D isomers coexist in the cluster beam, the 3D isomer prefers the peroxo binding with O(2).

Probing the electronic properties and structural evolution of anionic gold clusters in the gas phase.

Gold nanoparticles have been discovered to exhibit remarkable catalytic properties in contrast to the chemical inertness of bulk gold. A prerequisite to elucidate the molecular mechanisms of the catalytic effect of nanogold is a detailed understanding of the structural and electronic properties of gold clusters as a function of size. In this review, we describe joint experimental studies (mainly photoelectron spectroscopy) and theoretical calculations to probe the structural properties of anionic gold clusters. Electronic properties and structural evolutions of all known Au(n)(-) clusters as experimentally confirmed to date are summarized, covering the size ranges of n = 3-35 and 55-64. Recent experimental efforts in resolving the isomeric issues of small gold clusters using Ar-tagging, O(2)-titration and isoelectronic substitution are also discussed.

Two-photon photoemission study of the coverage-dependent electronic structure of chemisorbed alkali atoms on a Ag(111) surface.

We report a systematic investigation of the electronic structure of chemisorbed alkali atoms (Li-Cs) on a Ag(111) surface by two-photon photoemission spectroscopy. Angle-resolved two-photon photoemission spectra are obtained for 0-0.1 monolayer coverage of alkali atoms. The interfacial electronic structure as a function of periodic properties and the coverage of alkali atoms is observed and interpreted assuming ionic adsorbate/substrate interaction. The energy of the alkali atom σ-resonance at the limit of zero coverage is primarily determined by the image charge interaction, whereas at finite alkali atom coverages, it follows the formation of a dipolar surface field. The coverage- and angle-dependent two-photon photoemission spectra provide information on the photoinduced charge-transfer excitation of adsorbates on metal surfaces. This work complements the previous work on alkali/Cu(111) chemisorption [Phys. Rev. B 2008, 78, 085419].

Structure evolution of gold cluster anions between the planar and cage structures by isoelectronic substitution: Au(n)- (n = 13-15) and MAu(n)- (n = 12-14; M = Ag, Cu).

The structural and electronic effects of isoelectronic substitution by Ag and Cu atoms on gold cluster anions in the size range between 13 and 15 atoms are studied using a combination of photoelectron spectroscopy and first-principles density functional calculations. The most stable structures of the doped clusters are compared with those of the undoped Au clusters in the same size range. The joint experimental and theoretical study reveals a new C(3v) symmetric isomer for Au(13)(-), which is present in the experiment, but has hitherto not been recognized. The global minima of Au(14)(-) and Au(15)(-) are resolved on the basis of comparison between experiment and newly computed photoelectron spectra that include spin-orbit effects. The coexistence of two isomers for Au(15)(-) is firmly established with convincing experimental evidence and theoretical calculations. The overall effect of the isoelectronic substitution is minor on the structures relative to those of the undoped clusters, except that the dopant atoms tend to lower the symmetries of the doped clusters.