Clinical and molecular features of patients with IDH1 wild-type primary glioblastoma presenting unexpected short-term survival after gross total resection.

BACKGROUND: This study investigated the factors influencing short-term survivors (STS) after gross total resection (GTR) in patients with IDH1 wild-type primary glioblastoma. METHODS: We analyzed five independent cohorts who underwent GTR, including 83 patients from Kitasato University (K-cohort), and four validation cohorts of 148 patients from co-investigators (V-cohort), 66 patients from the Kansai Molecular Diagnosis Network for the Central Nervous System tumors, 109 patients from the Cancer Genome Atlas, and 40 patients from the Glioma Longitudinal AnalySiS. The study defined STS as those who had an overall survival ≤ 12 months after GTR with subsequent radiation therapy, and concurrent and adjuvant temozolomide (TMZ). RESULTS: The study included 446 patients with glioblastoma. All cohorts experienced unexpected STS after GTR, with a range of 15.0-23.9% of the cases. Molecular profiling revealed no significant difference in major genetic alterations between the STS and non-STS groups, including MGMT, TERT, EGFR, PTEN, and CDKN2A. Clinically, the STS group had a higher incidence of non-local recurrence early in their treatment course, with 60.0% of non-local recurrence in the K-cohort and 43.5% in the V-cohort. CONCLUSIONS: The study revealed that unexpected STS after GTR in patients with glioblastoma is not uncommon and such tumors tend to present early non-local recurrence. Interestingly, we did not find any significant genetic alterations in the STS group, indicating that such major alterations are characteristics of GB rather than being reliable predictors for recurrence patterns or development of unexpected STS.

Frontotemporal craniotomy with skin incision along the superior temporal line outside the hairline in bald male patients with temporal gliomas.

A head skin incision is inevitable in neurosurgical procedures and is usually concealed within the hairline. Androgenetic alopecia (AGA) is a progressive hair loss disorder or baldness highly prevalent in men. Therefore, if bald male patients require neurosurgical procedures, skin incisions cannot be concealed, but this subject is yet to be discussed in the literature. This study presents a frontotemporal craniotomy using a skin incision along the superior temporal line, ignoring the hairline in bald male patients. Thirty-three patients with temporal gliomas underwent surgical removal between 2015 and 2022. They were divided into three groups: bald male patients with skin incisions not concealed in the hairline (minimum group, n = 13), bald and non-bald male patients with skin incisions concealed in the hairline (male group, n = 11), and female patients with skin incisions concealed in the hairline (female group, n = 9). In the minimum group, patients had no complaints regarding the incision scar. Cosmetic outcome was excellent, and no cases showed surgical site infection or peripheral facial nerve palsy. Compared with the male and female groups, the minimum group had the shortest skin incision length; however, the craniotomy size and extent of resection were similar. Skin incision for frontotemporal craniotomy cannot be hidden in bald male patients, and the preferred location for the incision is unknown. The skin incision along the superior temporal line is a cosmetically favorable, feasible, and safe procedure.

Angiographic evaluation of the distance from the top of the jugular bulb to the inferior petrosal sinus-internal jugular vein junction: simple classification and identification method for the orifice of the non-visualized inferior petrosal sinus during neuroendovascular surgery.

BACKGROUND: The inferior petrosal sinus (IPS) is the transvenous access route for neurointerventional surgery that is occasionally undetectable on digital subtraction angiography (DSA) because of blockage by a clot or collapse. This study was aimed at analyzing the distance from the jugular bulb (JB) to the IPS-internal jugular vein (IJV) junction and proposing a new anatomical classification system for the IPS-IJV junction to identify the non-visualized IPS orifice. METHODS: DSA of 708 IPSs of 375 consecutive patients were retrospectively investigated to calculate the distance from the top of the JB to the IPS-IJV junction, and a simple classification system based on this distance was proposed. RESULTS: The median distance from the top of the JB to the IPS-IJV junction was 20.8 ± 14.7 mm. Based on the lower (10.9 mm) and upper (31.1 mm) quartiles, IPS-IJV junction variants were: type I, 0-10 mm (22.3%); type II, 11-30 mm (45.8%); type III, > 31 mm (23.9%); and type IV, no connection to the IJV (8.0%). Bilateral distances showed a positive interrelationship, with a correlation coefficient of 0.86. The bilateral symmetry type (visualized IPSs bilaterally) according to our classification occurred in 267 of 300 (89.0%) patients. CONCLUSIONS: In this study, the IPS-IJV junction was located far from the JB (types II and III), with a higher probability (69.6%). This distance and the four-type classification demonstrated high degrees of homology with the contralateral side. These results would be useful for identifying the non-visualized IPS orifice.

Ventricular opening and cerebrospinal fluid circulation accelerate the biodegradation process of carmustine wafers suggesting their immunomodulation potential in the human brain.

PURPOSE: Opening the ventricular system during glioblastoma surgery is often necessary, but the consequent effect on the tumor microenvironment of glioblastoma remains unknown. Implantation of carmustine wafer enables direct drug delivery to the tumor site; however, the exact mechanism of the wafer's biodegradation process is unclear, and the available data is limited to in vivo non-human mammalian studies. We hypothesized that the ventricular opening affects the degradation process of the wafer and the glioblastoma tumor microenvironment. METHODS: This study included 30 glioblastoma patients. 21 patients underwent carmustine wafer implantation during initial surgery. All patients underwent repeated surgical resection upon recurrence, allowing for pathological comparison of changes associated with wafer implantation. Immunohistochemical analyses were performed using CD68, TMEM119, CD163, IBA1, BIN1, and CD31 antibodies to highlight microglia, macrophages, and tumor vascularity, and the quantitative scoring results were correlated with clinical, molecular, and surgical variables, including the effect of the ventricular opening. RESULTS: The carmustine wafer implanted group presented significantly less TMEM119-positive microglia within the tumor (P = 0.0002). Simple and multiple regression analyses revealed that the decrease in TMEM119-positive microglia was correlated with longer intervals between surgeries and opened ventricular systems. No correlation was observed between age, methylated O6-methylguanine DNA methyltransferase promoter expression, and the extent of surgical resection. CONCLUSIONS: Our study findings strongly suggest that biomaterials may possess immunomodulation capacity, which is significantly impacted by the ventricular opening procedure. Furthermore, our data highlights the pathophysiological effects of the ventricular opening within the surrounding human brain, especially after the wafer implantation.

Glioma stem cell (GSC)-derived autoschizis-like products confer GSC niche properties involving M1-like tumor-associated macrophages.

Spontaneous necrosis is a defining feature of glioblastomas (GBMs), the most malignant glioma. Despite its strong correlations with poor prognosis, it remains unclear whether necrosis could be a possible cause or mere consequence of glioma progression. Here we isolated a particular fraction of necrotic products spontaneously arising from glioma cells, morphologically and biochemically defined as autoschizis-like products (ALPs). When administered to granulocyte macrophage colony-stimulating factor (GM-CSF)-primed bone marrow-derived macrophage/dendritic cells (Mφ/DCs), ALPs were found to be specifically engulfed by Mφs expressing a tumor-associated macrophage (TAM) marker CD204. ALPs from glioma stem cells (GSCs) had higher activity for the TAM development than those from non-GSCs. Of note, expression of the Il12b gene encoding a common subunit of IL-12/23 was upregulated in ALPs-educated Mφs. Furthermore, IL-12 protein evidently enhanced the sphere-forming activity of GBM patient-derived cells, although interestingly IL-12 is generally recognized as an antitumoral M1-Mφ marker. Finally, in silico analysis of The Cancer Genome Atlas (TCGA) transcriptome data of primary and recurrent GBMs revealed that higher expression of these IL-12 family genes was well correlated with more infiltration of M1-type TAMs and closely associated with poorer prognosis in recurrent GBMs. Our results highlight a role of necrosis in GSC-driven self-beneficial niche construction and glioma progression, providing important clues for developing new therapeutic strategies against gliomas.

Postcentral gyrus resection of opercular gliomas is a risk factor for motor deficits caused by damaging the radiologically invisible arteries supplying the descending motor pathway.

BACKGROUND: Postoperative motor deficits are among the worst morbidities of glioma surgery. We aim to investigate factors associated with postoperative motor deficits in patients with frontoparietal opercular gliomas. METHODS: Thirty-four patients with frontoparietal opercular gliomas were retrospectively investigated. We examined the postoperative ischemic changes and locations obtained from MRI. RESULTS: Twenty-one patients (62%) presented postoperative ischemic changes. Postoperative MRI was featured with ischemic changes, all located at the subcortical area of the resection cavity. Six patients had postoperative motor deficits, whereas 28 patients did not. Compared to those without motor deficits, those with motor deficits were associated with old age, pre- and postcentral gyri resection, and postcentral gyrus resection (P = 0.023, 0,024, and 0.0060, respectively). A merged image of the resected cavity and T1-weighted brain atlas of the Montreal Neurological Institute showed that a critical area for postoperative motor deficits is the origin of the long insular arteries (LIAs) and the postcentral gyrus. Detail anatomical architecture created by the Human Connectome Project database and T2-weighted images showed that the subcortical area of the operculum of the postcentral gyrus is where the medullary arteries supply, and the motor pathways originated from the precentral gyrus run. CONCLUSIONS: We verified that the origin of the LIAs could damage the descending motor pathways during the resection of frontoparietal opercular gliomas. Also, we identified that motor pathways run the subcortical area of the operculum of the postcentral gyrus, indicating that the postcentral gyrus is an unrecognized area of damaging the descending motor pathways.

Ribosomal protein S6 promotes stem-like characters in glioma cells.

Glioblastoma multiforme (GBM), a lethal brain tumor developing in the white matter of the adult brain, contains a small population of GBM stem cells (GSCs), which potentially cause chemotherapeutic resistance and tumor recurrence. However, the mechanisms underlying the pathogenesis and maintenance of GSCs remain largely unknown. A recent study reported that incorporation of ribosomes and ribosomal proteins into somatic cells promoted lineage trans-differentiation toward multipotency. This study aimed to investigate the mechanism underlying stemness acquisition in GBM cells by focusing on 40S ribosomal protein S6 (RPS6). RPS6 was significantly upregulated in high-grade glioma and localized at perivascular, perinecrotic, and border niches in GBM tissues. siRNA-mediated RPS6 knock-down significantly suppressed the characteristics of GSCs, including their tumorsphere potential and GSC marker expression; STAT3 was downregulated in GBM cells. RPS6 overexpression enhanced the tumorsphere potential of GSCs and these effects were attenuated by STAT3 inhibitor (AG490). Moreover, RPS6 expression was significantly correlated with SOX2 expression in different glioma grades. Immunohistochemistry data herein indicated that RPS6 was predominant in GSC niches, concurrent with the data from IVY GAP databases. Furthermore, RPS6 and other ribosomal proteins were upregulated in GSC-predominant areas in this database. The present results indicate that, in GSC niches, ribosomal proteins play crucial roles in the development and maintenance of GSCs and are clinically associated with chemoradioresistance and GBM recurrence.

Oligodendrocyte Progenitor Cells in the Tumor Microenvironment.

Glioblastoma (GBM) develops from adult brain white matter and is the most common and lethal primary brain tumor, characterized by rapid growth and invasion. GBM tumors frequently spread into the contralateral hemisphere, including in the beginning of tumor development. However, after complete resection of the tumor mass and chemo-radiotherapy, GBM commonly recurs around the tumor removal site, suggesting that the microenvironment at the tumor border provides therapeutic resistance to GBM cells. To improve patient prognosis, understanding the microenvironment at the tumor border is critical. Several microRNAs (miRNAs) show higher expression at the tumor border, with the top three involved in oligodendrocyte differentiation. Oligodendrocyte progenitor cells (OPCs) may induce stemness and chemo-radioresistance in GBM cells, providing a supportive function to promote GBM. This review describes important features of OPCs and insights into the "border niche," a unique microenvironment that allows GBM cells to survive and recur at the tumor border.

[A Case of Familial Schwannomatosis Occurring as Intraorbital Schwannoma].

A 67-year-old male presenting with left exophthalmos and progressive visual disturbance was referred to our department. Tumors at the supraclavicular fossa and dorsal femoral region were resected at ages 27 and 45 years. His father and son had both been diagnosed with spinal tumors, and his son's tumor was pathologically diagnosed as a schwannoma. Brain MRI of his son demonstrated no intracranial tumor. Brain MRI of the patient revealed a multilobular tumor of 2 cm diameter compressing the optic nerve medially within the left muscle cone, and no other intracranial tumors. However, large masses lateral to the pharynx and intercostal nerve, as well as multiple spinal tumors were detected. Transcranial total resection of the intraorbital tumor was performed. The pathological diagnosis was consistent with a schwannoma. These clinical characteristics fulfilled the diagnostic criteria of familial schwannomatosis. The postoperative course was uneventful. His visual dysfunction and eye movement disorder resolved completely. The intraorbital tumor was believed to originate from the lacrimal nerve. Sequencing of all exons for SMARCB1 and LZTR1 using DNA extracted from the tumor did not reveal any mutations. This case is the third report on familial schwannomatosis in Japan.

Novel metal chelating molecules with anticancer activity. Striking effect of the imidazole substitution of the histidine-pyridine-histidine system.

Previously we have reported a metal chelating histidine-pyridine-histidine system possessing a trityl group on the histidine imidazole, namely HPH-2Trt, which induces apoptosis in human pancreatic adenocarcinoma AsPC-1 cells. Herein the influence of the imidazole substitution of HPH-2Trt was examined. Five related compounds, HPH-1Trt, HPH-2Bzl, HPH-1Bzl, HPH-2Me, and HPH-1Me were newly synthesized and screened for their activity against AsPC-1 and brain tumor cells U87 and U251. HPH-1Trt and HPH-2Trt were highly active among the tested HPH compounds. In vitro DNA cleavage assay showed both HPH-1Trt and HPH-2Trt completely disintegrate pUC19 DNA. The introduction of trityl group decisively potentiated the activity.

Prognostic impact of completion of initial high-dose methotrexate therapy on primary central nervous system lymphoma: a single institution experience.

BACKGROUND: This retrospective single-center study assessed the feasibility, outcomes, and side-effects of high-dose methotrexate (HD-MTX) plus procarbazine in the treatment of immunocompetent patients with primary central nervous system lymphoma (PCNSL). METHODS: Ninety-one patients diagnosed with PCNSL between January 2001 and December 2011 were treated with HD-MTX plus procarbazine. To reduce neurotoxicity in patients aged ≥60 years, only those not responding to chemotherapy and patients with relapse underwent whole-brain irradiation. RESULTS: All 91 consecutive patients were scheduled to receive HD-MTX. Their median age was 66 years (range 32-88 years) and their median Karnofsky performance score was 40 (range 20-100). While 56 patients (61.5 %) completed 3 cycles of HD-MTX chemotherapy and 48 (52.7 %) showed a complete response, treatment was stopped in 11 patients (12.1 %) due to toxicity. The median overall survival and progression-free survival were 40.6 and 11.7 months, respectively. Overall survival was significantly improved in patients who completed 3 cycles of chemotherapy compared with those did not (56.4 vs 24.0 months; p = 0.013 by univariate and p = 0.022 by multivariate analysis). CONCLUSIONS: Initial treatment with HD-MTX plus procarbazine was effective in patients with PCNSL. Completion of 3 cycles of HD-MTX chemotherapy was a significant independent prognostic factor for patient survival.

[Brain tumor stem cells].

Glioblastoma multiforme (GBM) is the most frequent and aggressive brain tumor, and which harbors not only rapidly dividing cells but also small populations of slowly dividing and dormant cells with tumorigenesity-, self-renewal-, and multi-lineage differentiation capabilities. GBM stem cells (GSCs), which are resistant to conventional chemo -radiotherapy and may be a cause of local recurrence and dissemination. Additionally, heterogeneity of GSCs in the same tumor had been shown by the innovation of microarray and sequencing technology. However, outcome in patients with GBM remains unsatisfactory. Accumulation of the clinical evidence and basic research findings targeting for GSCs and their specific microenvironments (GSC niches) raise the possibility of new treatments to overcome GBM.

Antitumor effect of fibrin glue containing temozolomide against malignant glioma.

Temozolomide (TMZ), used to treat glioblastoma and malignant glioma, induces autophagy, apoptosis and senescence in cancer cells. We investigated fibrin glue (FG) as a drug delivery system for the local administration of high-concentration TMZ aimed at preventing glioma recurrence. Our high-power liquid chromatography studies indicated that FG containing TMZ (TMZ-FG) manifested a sustained drug release potential. We prepared a subcutaneous tumor model by injecting groups of mice with three malignant glioma cell lines and examined the antitumor effect of TMZ-FG. We estimated the tumor volume and performed immunostaining and immunoblotting using antibodies to Ki-67, cleaved caspase 3, LC3 and p16. When FG sheets containing TMZ (TMZ-FGS) were inserted beneath the tumors, their growth was significantly suppressed. In mice treated with peroral TMZ plus TMZ-FGS the tumors tended to be smaller than in mice whose tumors were treated with TMZ-FGS or peroral TMZ alone. The TMZ-FGS induced autophagy, apoptosis and senescence in subcutaneous glioma tumor cells. To assess the safety of TMZ-FG for normal brain, we placed it directly on the brain of living mice and stained tissue sections obtained in the acute and chronic phase immunohistochemically. In both phases, TMZ-FG failed to severely damage normal brain tissue. TMZ-FG may represent a safe new drug delivery system with sustained drug release potential to treat malignant glioma.

Combination of neuroendoscopic hematoma evacuation and endovascular coil embolization for a ruptured anterior choroidal artery aneurysm in patients with moyamoya disease: illustrative cases.

BACKGROUND: The treatment strategy for hemorrhagic moyamoya disease (MMD) due to a ruptured aneurysm at the distal portion of the anterior choroidal artery remains controversial. The authors successfully treated the ruptured aneurysm with neuroendoscopic hematoma evacuation, followed by endovascular coil embolization. OBSERVATIONS: The authors encountered two patients with massive hemorrhagic MMD whose MMD had already been diagnosed and who had a periventricular anastomosis due to a ruptured aneurysm of the distal portion of the anterior choroidal artery involving the periventricular anastomosis. In both cases, neuroendoscopic hematoma evacuation was performed for hemorrhagic MMD in the acute phase, followed by endovascular coil embolization of the ruptured aneurysm in the chronic phase. In both endovascular treatments, the patient's condition was stabilized by hematoma evacuation, allowing a detailed preoperative evaluation of the anatomical findings of the vessel and functional findings of intraoperative neurophysiological monitoring using continuous monitoring of motor evoked potentials to preserve motor function. LESSONS: Combination therapy can be useful for hemorrhagic MMD in patients with diagnosed MMD with a periventricular anastomosis. Additionally, a preoperative understanding of the vascular construction and intraoperative neurophysiological monitoring will aid in the successful coil embolization of aneurysms at the distal portion of the anterior choroidal artery with hemorrhagic MMD.

Long-term outcomes of multidisciplinary treatment combining surgery and stereotactic radiotherapy with Novalis for craniopharyngioma.

Craniopharyngiomas are difficult to resect completely, recurrence is frequent, and hypothalamic/pituitary function may be affected after surgery. Therefore, the ideal treatment for craniopharyngiomas is local control with preservation of hypothalamic and pituitary functions. The purpose of this study is to retrospectively evaluate the long-term efficacy and adverse events of stereotactic radiotherapy (SRT) with Novalis for craniopharyngioma. This study included 23 patients with craniopharyngiomas who underwent surgery between 2006 and 2021 and underwent SRT as their first irradiation after surgery. The median post-irradiation observation period was 88 months, with the overall survival rates of 100 % at 10 years and 85.7 % at 20 years. One patient died of adrenal insufficiency 12 years after irradiation. The local control rate of the cystic component was 91.3 % at 5 years, 83.0 % at 15 years, with no increase in the solid component. No delayed impairment of visual or pituitary function due to irradiation was observed. No new hypothalamic dysfunction was observed after radiation therapy. No delayed adverse events such as brain necrosis, cerebral artery stenosis, cerebral infarction, or secondary brain tumors were also observed. SRT was safe and effective over the long term in patients irradiated in childhood as well as adults, with no local recurrence or adverse events. We believe that surgical planning for craniopharyngioma with stereotactic radiotherapy in mind is effective in maintaining a good prognosis and quality of life.

Prognostic value of isocitrate dehydrogenase 1, O6-methylguanine-DNA methyltransferase promoter methylation, and 1p19q co-deletion in Japanese malignant glioma patients.

BACKGROUND: To determine the prognostic value of isocitrate dehydrogenase 1 (IDH1) mutation, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and 1p/19q co-deletion in Japanese patients with malignant gliomas. METHODS: We studied 267 malignant gliomas, which included 171 glioblastomas (GBMs), 40 anaplastic astrocytomas (AAs), 30 anaplastic oligodendrogliomas (AOs), and 26 anaplastic oligoastrocytomas (AOAs). These malignant gliomas were divided into 2 groups (Group 1: GBM + AA, Group 2: AO + AOA) according to the presence of the oligodendroglioma component. We examined IDH1 mutation and MGMT promoter methylation in each group by direct sequencing and methylation-specific PCR, respectively. We further examined 1p/19q co-deletion in Group 2 by fluorescence in situ hybridization. Survival between groups was compared by Kaplan-Meier analysis. RESULTS: In Group 1, patients with IDH1 mutations exhibited a significantly longer survival time than patients with wild-type IDH1. However, no significant difference was observed in Group 2, although patients with IDH1 mutations tended to show prolonged survival. For both Group 1 and Group 2, patients with MGMT methylation survived longer than those without this methylation. Further, patients with 1p/19q co-deletion showed significantly better outcome in Group 2. CONCLUSIONS: Our study confirms the utility of IDH1 mutations and MGMT methylation in predicting the prognosis of Group 1 patients (GBM + AA) and demonstrated that IDH1 mutations may serve as a more reliable prognostic factor for such patients. We also showed that MGMT methylation and 1p/19q co-deletion rather than IDH1 mutations were prognostic factors for Group 2 patients (AOA + AO). Our study suggests that patients survive longer if they have IDH1 mutations and undergo total resection. Further, irrespective of MGMT promoter methylation status, the prognosis of glioma patients can be improved if total resection is performed. Moreover, our study includes the largest number of Japanese patients with malignant gliomas that has been analyzed for these three markers. We believe that our findings will increase the awareness of oncologists in Japan of the value of these markers for predicting prognosis and designing appropriate therapeutic strategies for treating this highly fatal disease.

Frontotemporal Craniotomy for Clipping of Unruptured Aneurysm Using a Diamond-Coated Thread Wire Saw and Reconstruction Using Calcium Phosphate Cement without Metal Fixation.

Metal fixation systems for cranial bone flaps cut by a drill are convenient devices for cranioplasty, but cause several complications. We use modified craniotomy using a fine diamond-coated threadwire saw (diamond T-saw) to reduce the bone defect, and osteoplasty calcium phosphate cement without metal fixation. We report our outcomes and tips of this method. A total of 78 consecutive patients underwent elective frontotemporal craniotomy for clipping of unruptured intracranial aneurysms between 2015 and 2019. The follow-up periods ranged from 13 to 66 months. The bone fixation state was evaluated by bone computed tomography (CT) and three-dimensional CT (3D-CT). The diamond T-saw could minimize the bone defect. Only one wound infection occurred within 1 week postoperatively, and no late infection. No pain, palpable/cosmetically noticeable displacement of the bone flap, fluid accumulations, or other complications were observed. The condition of bone fixation and the cosmetic efficacy were thoroughly satisfactory for all patients, and bone CT and 3D-CT demonstrated that good bone fusion. No complication typical of metal fixation occurred. Our method is technically easy and safety, and achieved good mid-term bone flap fixation in the mid-term course, so has potential for bone fixation without the use of metal plates.

Wnt/ß­catenin signaling is a novel therapeutic target for tumor suppressor CYLD­silenced glioblastoma cells.

Tumor suppressor cylindromatosis (CYLD) dysfunction by its downregulation is significantly associated with poor prognosis in patients with glioblastoma (GBM), the most aggressive and malignant type of glioma. However, no effective treatment is currently available for patients with CYLD­downregulated GBM. The aim of the present study was to identify the crucial cell signaling pathways and novel therapeutic targets for CYLD downregulation in GBM cells. CYLD knockdown in GBM cells induced GBM malignant characteristics, such as proliferation, metastasis, and GBM stem­like cell (GSC) formation. Comprehensive proteomic analysis and RNA sequencing data from the tissues of patients with GBM revealed that Wnt/ß­catenin signaling was significantly activated by CYLD knockdown in patients with GBM. Furthermore, a Wnt/ß­catenin signaling inhibitor suppressed all CYLD knockdown­induced malignant characteristics of GBM. Taken together, the results of the present study revealed that Wnt/ß­catenin signaling is responsible for CYLD silencing­induced GBM malignancy; therefore, targeting Wnt/ß­catenin may be effective for the treatment of CYLD­negative patients with GBM with poor prognosis.

Combination of a ptgs2 inhibitor and an epidermal growth factor receptor-signaling inhibitor prevents tumorigenesis of oligodendrocyte lineage-derived glioma-initiating cells.

Recent findings have demonstrated that malignant tumors, including glioblastoma multiforme (GBM), contain cancer-initiating cells (CICs; also known as cancer stem cells), which self-renew and are malignant. However, it remains controversial whether such CICs arise from tissue-specific stem cells, committed precursor cells, or differentiated cells. Here, we sought to examine the origin of the CICs in GBM. We first showed that the overexpression of oncogenic HRas(L61) transformed p53-deficient oligodendrocyte precursor cells (OPCs) and neural stem cells (NSCs) into glioma-initiating cell (GIC)-like cells in mice. When as few as 10 of these GIC-like cells were transplanted in vivo, they formed a transplantable GBM with features of human GBM, suggesting that these GIC-like cells were enriched in CICs. DNA microarray analysis showed that widespread genetic reprogramming occurred during the OPCs' transformation: they largely lost their OPC characteristics and acquired NSC ones, including the expression of prominin1, hmga2, ptgs2, and epiregulin. In addition, the combination of a Ptgs2 inhibitor and an epidermal growth factor receptor (EGFR)-signaling inhibitor prevented the tumorigenesis of transformed OPCs and human GICs (hGICs) obtained from anaplastic oligodendroglioma, but not of transformed NSCs or hGICs obtained from GBM. Together, these findings suggest that GBM can arise from either OPCs or NSCs and that the therapeutic targets for GBM might be different, depending on each GIC's cell-of-origin.

Salvage treatment with temozolomide in refractory or relapsed primary central nervous system lymphoma and assessment of the MGMT status.

High-dose methotrexate (HD-MTX) is effective in the initial treatment of primary central nervous system lymphoma (PCNSL). Because treatment options in patients with progressive or recurrent PCNSL are limited, prognosis is poor. Temozolomide, a well-tolerated oral alkylating agent that permeates the blood brain barrier (BBB), is effective against malignant glioma and recurrent PCNSL. The gene for the deoxyribonucleic acid (DNA) repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT), which is closely related to cellular sensitivity to alkylating agents, is inactivated by promoter hypermethylation. We evaluated the results of temozolomide treatment and the methylation status of the promoter region of the MGMT gene in 17 patients (median age 68 years) with refractory or relapsed PCNSL. They were immunocompetent and had received initial treatment with HD-MTX (3.5 g/m(2)) with or without irradiation. All were treated with temozolomide 150-200 mg/m(2), for 5 days in the course of 28 days; treatment was continued until disease progression. We observed five complete remissions, five partial responses (PRs) with stable disease (SD), and seven with disease progression. Median overall survival after the temozolomide treatment was 6.7 months. One patient manifested grade 3 neutropenia and thrombocytopenia. Eleven tumor specimens were available for MGMT analysis. MGMT promoter methylation (mMGMT) in the tumor tissue was found in 4 (36.4%), the other seven harbored a non-methylated MGMT promoter (nmMGMT). There was no statistically significant difference in median overall survival between patients with mMGMT (11.1 months) and nmMGMT (6.7 months) (P = 0.63). Although some patients were elderly and had been heavily pre-treated, temozolomide resulted in a complete response (CR) in 29% and was well tolerated without any major toxicity.