Barthel Index and Age as Predictors of Discharge Destination in Patients with Glioblastoma.

This study aimed to investigate the predictive factors of transfer of glioblastoma multiforme (GBM) patients who underwent rehabilitation in acute care hospitals. We retrospectively identified 85 patients with GBM who underwent rehabilitation at our hospital. Multivariable logistic regression analysis showed that age and Barthel index (BI) at rehabilitation initiation significantly influenced the discharge destination. Cut-off values for these factors were 76 years of age and 30 BI points. These findings could help predict the discharge destination and the choice of rehabilitation strategies of newly diagnosed patients with GBM admitted to an acute care hospital.

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.

The Real-World status and risk factors for a poor prognosis in elderly patients with primary central nervous system malignant lymphomas: a multicenter, retrospective cohort study of the Tohoku Brain Tumor Study Group.

BACKGROUND: Elderly patients with primary central nervous system malignant lymphoma (EL-PCNSL) may not be given sufficient treatment due to their poor pre-treatment Karnofsky Performance Status (KPS) and comorbidities. Therefore, a retrospective, cohort study was performed to evaluate risk factors associated with a poor prognosis of EL-PCNSL in the Tohoku Brain Tumor Study Group. METHODS: Patients aged ≥ 71 years with PCNSL were enrolled from eight centers. Univariate analysis was performed with the log-rank test. A Cox proportional hazards model was used for multivariate analysis. RESULTS: Three of the total 142 cases received best supportive care (BSC). Treatment was given to 30 cases without a pathological diagnosis, 3 cases with cerebrospinal fluid (CSF) cytology, and 100 cases with a pathological diagnosis. After confirmation of no differences in progression-free survival (PFS) and overall survival (OS) between the group treated without pathology and the groups diagnosed by pathology or CSF cytology and between median age ≥ 76 years and < 76 years, a total of 133 patients were studied. The median pre-treatment KPS was 50%. Median PFS and median OS were 16 and 24 months, respectively. Risk factors associated with poor prognosis on Cox proportional hazards model analysis were pre-treatment cardiovascular disease and central nervous system disease comorbidities, post-treatment pneumonia and other infections, and the absence of radiotherapy or chemotherapy. CONCLUSIONS: Pre-treatment comorbidities and post-treatment complications would affect the prognosis. Radiation and chemotherapy were found to be effective, but no conclusions could be drawn regarding the appropriate content of chemotherapy and whether additional radiotherapy should be used.

A surgical case of pediatric spinal medulloepithelioma.

Embryonal tumor with multilayered rosettes (ETMR), C19MC-altered was introduced to the World Health Organization classification of central nervous system tumors in 2016. It is characterized by amplification or fusion of the chromosome 19 microRNA cluster (C19MC) locus at 19q13.42. Medulloepithelioma also an ETMR but lacks C19MC alteration. We report a rare case of spinal medulloepithelioma in a 2-year-old boy and review the literature.

Relationships between recurrence patterns and subventricular zone involvement or CD133 expression in glioblastoma.

INTRODUCTION: We previously reported that CD133 expression correlated with the recurrence pattern of glioblastoma (GBM). Subventricular zone (SVZ) involvement may also be associated with distant recurrence in GBM. Therefore, we herein investigated whether the combined analysis of SVZ involvement and CD133 expression is useful for predicting the pattern of GBM recurrence. MATERIALS AND METHODS: We retrospectively analyzed 167 cases of GBM. Tumors were divided into four groups based on spatial relationships between contrast-enhanced lesions (CEL) and the SVZ or cortex (Ctx) on MRI. The initial recurrence pattern (local/distant) was obtained from medical records. To identify factors predictive of recurrence, we examined CD133 expression by immunohistochemical, clinical (age, sex, KPS, Ki-67 labeling index, surgery, and MRI characteristics), and genetic (IDH1, MGMT, and BRAF) factors. RESULTS: The CD133 expression rate was higher in SVZ-positive tumors than in SVZ-negative tumors (P = 0.046). Distant recurrence was observed in 21% of patients, and no significant difference was noted in recurrence patterns among the four groups. However, strong CD133 expression was associated with a shorter time to distant recurrence in univariate, multivariate, and propensity-matched scoring analyses (P < 0.0001, P = 0.001, and P = 0.0084, respectively). In the combined analysis, distant recurrence was the most frequent (70%) in group III (SVZ-negative, Ctx-positive) GBM and those with high CD133 expression rates (≥ 15%). CONCLUSION: An integrated analysis of CD133 expression and MRI-based tumor classification may be useful for predicting the recurrence pattern of GBM.

[Seven Patients with Pituitary Metastases Treated at Our Department:Case Reports].

Pituitary metastases(PM)are rare and show a poor prognosis. However, recent advances in diagnostic imaging could increase the chances of PM being diagnosed without a history of cancer. Furthermore, it was unclear whether adjuvant therapy could increase the survival of patients with PM or not. To clarify the clinical course of patients with PM, we report seven cases of PM with a literature review. Most patients showed symptomatic adenohypophyseal dysfunction(AD)and diabetes insipidus(DI)as initial symptoms. All patients underwent radiotherapy for PM and showed good local tumor control. However, except for one patient with improved DI, neither AD nor DI improved with radiotherapy. As for the prognosis, three patients with PM without a history of cancer survived longer than those with a history of cancer(20.3 vs. 11.7 months, respectively). In summary, early diagnosis and appropriate hormone replacement therapies are important in PM. Improvement of the general condition enables adjuvant therapy to prolong patient survival.

[Multiloculated Hydrocephalus Complicated by Meningitis and Ventriculitis Treated with Staged Fenestration:A Case Report].

Multiloculated hydrocephalus following severe meningitis with ventriculitis is often therapeutically challenging. Neonatal meningitis is commonly associated with ventricular inflammation, and approximately 30% of patients show septum formation. Although placement of a single ventriculoperitoneal shunt system could serve as optimal treatment for a multiloculated cerebrospinal cavity that is converted into a single chamber, multiple devices are often required for disease stability. We report a case of multiloculated hydrocephalus that occurred after meningitis in a patient who was successfully treated with a single shunt system using staged multimodality treatments.

[Intracranial Pseudoaneurysm Arising after Radiotherapy for Oligodendroglioma:A Case Report].

Intracranial pseudoaneurysms arising after radiotherapy for brain tumors are a relatively rare occurrence and associated with high-volume radiotherapy such as stereotactic radiosurgery. Herein, the authors report a rare case of intracranial pseudoaneurysm after conventional radiotherapy for oligodendroglioma. Case:A 46-year-old female incidentally presented with an intracranial hemorrhage from a middle temporal artery aneurysm. Four years earlier, she underwent surgical resection and conventional radiation therapy for oligodendroglioma. The aneurysm was successfully treated with middle cerebral artery(MCA)aneurysm trapping, in conjunction with a parietal branch superficial temporal artery-MCA bypass, to prevent re-rupture. Formation of intracranial pseudoaneurysm after conventional radiotherapy is extremely rare. However, the occurrence of cerebral aneurysm(s), as well as vascular stenosis during follow-up for brain tumors treated with radiotherapy, should be considered.

[Diffuse Leptomeningeal Glioneuronal Tumor with Subarachnoid Hemorrhage:A Case Report].

Diffuse leptomeningeal glioneuronal tumor(DLGNT)is a rare primary neoplasm of the central nervous system, and is a condition that is newly listed in the 2016 World Health Organization(WHO)classification of tumors of the central nervous system. We report an adult case of DLGNT that was characteristically merged with subarachnoid hemorrhage. A 46-year-old woman reported persistent dizziness upon walking. MRI of the brain revealed a diffuse, infiltrating lesion with high intensity on FLAIR around the cerebellopontine angle to the lateral ventricle and in the leptomeninges of the spinal cord. The lesion on the cerebellopontine angle showed high intensity on T1 weighted images with contrast enhancement. Since diffuse glioma and meningeal carcinomatosis were suspected, we performed an endoscopic biopsy for the lesion in the right lateral ventricle. Although the tumor was tentatively diagnosed as WHO grade II diffuse astrocytoma, a definitive diagnosis could not be obtained. One month after surgery, the patient presented with acute headache and dizziness. CT showed subarachnoid hemorrhage in the cerebellopontine angle. To decompress the intracranial pressure and prevent re-bleeding, and to obtain enough tissue samples for definitive diagnosis, we removed the enhanced lesion and hematoma at the cerebellopontine angle. Tumor tissue was composed of oligodendroglial-like cells and was positive for GFAP, Olig2, synaptophysin, and S100 protein, although it was negative for IDH1R132H. Fluorescent in situ hybridization showed KIAA1566-BRAF fusion; however, neither 1p loss nor 1p19q co-deletion was observed. Together with histological and radiological findings, the tumor was ultimately diagnosed as DLGNT. The patient received maintenance chemotherapy with temozolomide, and the tumor was stable at 18 months after surgery.

[Natural History of Patients with Asymptomatic FLAIR High-signal Lesions Suspected of Lower-grade Gliomas].

The distribution of MRI scans has increased the chance of diagnosing asymptomatic FLAIR high-signal lesions. Herein, we retrospectively analyzed 14 asymptomatic FLAIR high-signal lesions to evaluate their natural course. Fifteen symptomatic(epilepsy)patients with FLAIR high-signal lesions were also analyzed as controls. As a result, all symptomatic patients underwent surgery and were diagnosed with lower-grade gliomas(n=14)and a dysembryoplastic neuroepithelial tumor(n=1). Among the 14 lower-grade gliomas, 11 gliomas were isocitrate dehydrogenase(IDH)-mutant. As previously reported, these results showed that FLAIR high-signal lesions with epilepsy are closely associated with IDH-mutant gliomas. On the other hand, 12 of the 14 asymptomatic patients showed no changes in the size of the lesion and symptoms during the follow-up period. Only 2 patients(14.3%)revealed increased lesions within 38 and 25 months, who were diagnosed with high-grade gliomas. Although there was no difference in the apparent diffusion coefficient value between asymptomatic and symptomatic lesions, low-intensity T1WI on MRI might be useful to discriminate lower-grade gliomas from non-tumor lesions. In conclusion, there is no need for immediate surgery for true asymptomatic lesions; however, we must undergo routine follow-up MRI scans.

Treatment outcomes of hypofractionated radiotherapy combined with temozolomide followed by bevacizumab salvage therapy in glioblastoma patients aged > 75 years.

BACKGROUND: The optimal treatment for elderly patients with glioblastoma has not been established. METHODS: We retrospectively analyzed the safety and efficacy of hypofractionated radiotherapy (45 Gy/15 fr) combined with temozolomide (TMZ) followed by bevacizumab (BEV) salvage treatment in 18 glioblastoma patients aged > 75 years. RESULTS: All of the patients received safe hypofractionated radiotherapy and concomitant TMZ (75 mg/m2), and 14 of 18 patients received maintenance TMZ. We administered BEV to 17 of 18 patients because their Karnofsky Performance Status scores declined and/or recurrence was detected. During the follow-up period (median duration: 17.5 months, range 3-33 months), 12 patients died of their disease. While the median progression-free survival period was 2.5 months, the median overall survival period was 20 months. Adverse events (National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 or 4) occurred in 5 patients. CONCLUSION: Hypofractionated radiotherapy combined with TMZ and BEV salvage treatment was found to be safe and effective in glioblastoma patients aged > 75 years.

Correlation between hypoxic area in primary brain tumors and WHO grade: differentiation from malignancy using 18F-fluoromisonidazole positron emission tomography.

Background 18F-fluoromisonidazole positron emission tomography (FMISO-PET) has been used for identification of hypoxic areas in tumors, and since hypoxia causes hypoxia-inducible factor-1 and enhancement of tumor growth, identifying the hypoxic area in the tumor tissue is important. Purpose To evaluate the usefulness of FMISO-PET in the grading of primary brain tumors. Material and Methods FMISO-PET was performed preoperatively on 41 consecutive patients with pathologically confirmed brain tumor. A neuroradiologist retrospectively measured both maximum standardized uptake value (SUVmax) and mean SUV (SUVmean) in the tumor and normal cerebellar parenchyma. Maximum tumor/normal control ratio (T/Nmax) and mean tumor/normal control ratio (T/Nmean) were calculated and analyzed. Results There was a positive correlation between World Health Organization (WHO) grade and both T/Nmax and T/Nmean (r = 0.731 and 0.713, respectively). When all cases were divided into benign (WHO grade II) and malignant groups (III and IV), there were significant differences between the two groups in both T/Nmax and T/Nmean ( P < 0.001). If the cutoff value was defined as T/Nmax = 1.25 and T/Nmean = 1.23, T/Nmax had a sensitivity of 90.0% and a specificity of 90.9% while T/Nmean had a sensitivity of 93.3% and a specificity of 90.9% in differentiating the benign group from the malignant group. Conclusion Both T/Nmax and T/Nmean in FMISO-PET have a positive correlation with primary brain tumor grading, making FMISO-PET useful in diagnosing the malignancy of primary brain tumors.

[A Surgical Case of Anaplastic Ependymoma Involving a Bridging Vein that Drained Directly into the Occipital Sinus].

INTRODUCTION: The draining veins of the brain stem and cerebellum commonly drain into the petrosal vein and sigmoid sinus, and often drain into the marginal sinus in the caudal part of the posterior fossa. Here, we report a rare case of anaplastic ependymoma involving a bridging vein that drained directly into the occipital sinus. CASE DESCRIPTION: A 6-year-old boy was admitted to our hospital with a 1-month history of nausea, headache, and dizziness. Magnetic resonance imaging(MRI)revealed a markedly enhanced fourth ventricular tumor and obstructive hydrocephalus. Surgical removal was performed via a midline suboccipital approach. When opening the dura, we observed a bridging vein that directly connected the brain stem and the tumor with the occipital sinus. Therefore, the Y-shaped dura mater incision was not inverted, and the tumor was totally removed while preserving the draining vein. After the operation, the patient's clinical course was uneventful. The pathological diagnosis was anaplastic ependymoma(WHO grade III). Subsequently, the patient received radiotherapy and was discharged without any neurological deficits 9 weeks after the operation. At 10 months after the initial surgery, the tumor recurred on the fourth ventricle floor. Thus, we performed a second surgical procedure and noted that the bridging vein had regressed. CONCLUSION: We report a rare draining vein that directly connected the brain stem to the occipital sinus. The tumor was removed without sacrificing this vein. Since the draining system of the posterior fossa is sometimes very complicated, we need to pay attention to it during the pre- and intra-operative periods.

[Treatment of Rathke's Cleft Cyst:Technical Note for Preservation of Pituitary Function].

Pituitary dysfunction, such as panhypopituitarism or diabetes insipidus(DI), is often found in patients with Rathke's cleft cyst. Patients were treated with transsphenoidal microscopic surgery; however, pituitary dysfunction did not usually recover. Recently, endoscopic transsphenoidal surgery(eTSS)has enabled minimally invasive surgery for patients with Rathke's cleft cyst. In this study, we analyzed 22 consecutive patients with Rathke's cleft cyst who underwent eTSS to determine if pituitary dysfunction recovered. The follow-up period ranged from 3 months to 19.25 years(mean, 4.75 years). Preoperative endocrinological evaluation showed impaired secretion of adrenocorticotropic hormone(ACTH)in 4 cases(18.2%), thyroid-stimulating hormone(TSH)in 2 cases(9.1%), hyperprolactinemia in 5 cases(22.7%), growth hormone(GH)in 9 cases(40.9%), and luteinizing hormone(LH)/follicle-stimulating hormone(FSH)in 11 cases(50%). In addition, preoperative DI was found in 2 cases(9.1%). We planned the site of fenestration for the cyst wall using preoperative sagittal magnetic resonance imaging. As a result, the recovery rate for ACTH, GH, and TSH secretion was 25%, 33.3%, and 50%, respectively. On the other hand, two patients with DI and other hormonal deficiencies did not recover pituitary function because of severe inflammation. Pituitary function might be preserved with minimally invasive surgery for Rathke's cleft cyst with mild inflammation.

Opening the ventricle during surgery diminishes survival among patients with newly diagnosed glioblastoma treated with carmustine wafers: a multi-center retrospective study.

Carmustine wafers (CW) were approved in Japan for newly diagnosed and recurrent malignant gliomas during 2013. The ventricle is often opened during surgery to achieve maximum resection. While not generally recommended in such situations, CW might be safely achieved by occluding an opened ventricle using gelform or collagen sheets. However, whether CW implantation actually confers a survival benefit for patients who undergo surgery with an open ventricle to treat glioblastoma remains unclear. Clinical, imaging, and survival data were collected in this multicenter retrospective study of 122 consecutive patients with newly diagnosed glioblastoma to determine adverse events and efficacy. Overall, 54 adverse events of all grades developed in 35 (28.6%) patients, with the most common being new seizures (16%). Adverse events did not significantly differ between patients with opened and closed ventricles during surgery. The 10- and 21.7-month, median, progression-free (PFS) and overall survival (OS), respectively did not significantly differ according to resection rates. However, median PFS and OS were significantly longer among patients with closed, than open ventricles (12.8 vs. 7.4 months; p = 0.0039 and 26.9 vs. 18.6 months; p = 0.011, respectively). Implanting CW into the resection cavity during concomitant radiochemotherapy with temozolomide seems to yield better survival rates without increased adverse events. Occlusion of the ventricular opening during surgery might be safe for CW implantation, but less so for treating patients with newly diagnosed glioblastoma.

[A Case of Lymphocytic Adenohypophysitis Presenting Visual Disturbance in the Third Trimester of Pregnancy].

Lymphocytic hypophysitis(LH)has first been described as an autoimmune endocrinopathy by Goudie in 1962. In particular, lymphocytic adenohypophysitis(LAH)is usually associated with pregnancy and hypopituitarism due to insufficient endocrine of ACTH. However, several cases of LAH in pregnant patients showing only visual disturbances have recently been documented. We treated a patient with LAH presenting only the chiasma syndrome in the third trimester without hypopituitarism. A 27-year-old woman unexpectedly experienced visual disturbance starting in the 28th week of pregnancy. Her symptoms progressed rapidly. MRI revealed a pituitary mass lesion compressing the optic chiasma. In addition, ophthalmological examination revealed bitemporal hemianopsia. The patient underwent endoscopic transsphenoidal surgery(eTSS)during the 30th week of pregnancy. LH was diagnosed histologically during surgery. We performed decompression of optic chiasma. After surgery, the patient's visual field markedly widened and the pituitary mass regressed along with replacement of corticosteroids. In the 37th week of pregnancy, she delivered a healthy baby. We speculate that the reason for the absence of hypopituitarism during pregnancy in patients with LH, especially in the third trimester, might be that the placental endocrine system masks pituitary endocrinopathy. In summary, we report a case of LAH that did not present with hypopituitarism, and eTSS could be performed safely during pregnancy.

Association of ADC of hyperintense lesions on FLAIR images with TERT promoter mutation status in glioblastoma IDH wild type.

Background: Although mutations in telomerase reverse transcriptase (TERT) promoter (TERTp) are the most common alterations in glioblastoma (GBM), predicting TERTp mutation status by preoperative imaging is difficult. We determined whether tumour-surrounding hyperintense lesions on fluid-attenuated inversion recovery (FLAIR) were superior to those of contrast-enhanced lesions (CELs) in assessing TERTp mutation status using magnetic resonance imaging (MRI). Methods: This retrospective study included 114 consecutive patients with primary isocitrate dehydrogenase (IDH)-wild-type GBM. The apparent diffusion coefficient (ADC) and volume of CELs and FLAIR hyperintense lesions (FHLs) were determined, and the correlation between MRI features and TERTp mutation status was analyzed. In a subset of cases, FHLs were histopathologically analyzed to determine the correlation between tumor cell density and ADC. Results: TERTp mutations were present in 77 (67.5%) patients. The minimum ADC of FHLs was significantly lower in the TERTp-mutant group than in the TERTp-wild-type group (mean, 958.9 × 10-3 and 1092.1 × 10-3 mm2/s, respectively, P < 0.01). However, other MRI features, such as CEL and FHL volumes, minimum ADC of CELs, and FHL/CEL ratio, were not significantly different between the two groups. Histopathologic analysis indicated high tumor cell density in FHLs with low ADC. Conclusion: The ADC of FHLs was significantly lower in IDH-wild-type GBM with TERTp mutations, suggesting that determining the ADC of FHLs on preoperative MRI might be helpful in predicting TERTp mutation status and surgical planning.

Usefulness of Serum Soluble Interleukin-2 Receptor Levels for Differentiating between PCNSL and SCNSL.

Serum soluble interleukin-2 receptor (sIL-2R) is a practical tumor marker that is elevated in hematogenous tumors. The purpose of this study was to determine the usefulness of serum sIL-2R for differentiating among malignant brain tumors, including primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL). This study retrospectively investigated the sIL-2R levels in 130 patients with various types of malignant brain tumors, including PCNSL patients (n = 48) and SCNSL (n = 8); metastatic brain tumors (MTs, n = 16); and glioblastoma (GBM, n = 58). The median sIL-2R level (U/mL) of the PCNSL, SCNSL, MTs, and GBM groups were 489.7, 1024.8, 413.3, and 332.7 respectively. The sIL-2R level was significantly higher in the SCNSL group than in the PCNSL or other groups. The area under the ROC curve generated from the sIL-2R level was 0.826 (sensitivity: 0.875, specificity: 0.667, cutoff value: 521 U/mL) for differentiating SCNSL from PCNSL and 0.685 (sensitivity: 0.667, specificity: 0.707, cutoff value: 342 U/mL) for differentiating PCNSL from GBM. Measurement of sIL-2R level was convenient and useful to differentiate between SCNSL and PCSNL, both of which demand different treatment strategies.

MEK-ERK signaling dictates DNA-repair gene MGMT expression and temozolomide resistance of stem-like glioblastoma cells via the MDM2-p53 axis.

Overcoming the resistance of glioblastoma cells against temozolomide, the first-line chemotherapeutic agent of choice for newly diagnosed glioblastoma, is a major therapeutic challenge in the management of this deadly brain tumor. The gene encoding O(6) -methylguanine DNA methyltransferase (MGMT), which removes the methyl group attached by temozolomide, is often silenced by promoter methylation in glioblastoma but is nevertheless expressed in a significant fraction of cases and is therefore regarded as one of the most clinically relevant mechanisms of resistance against temozolomide. However, to date, signaling pathways regulating MGMT in MGMT-expressing glioblastoma cells have been poorly delineated. Here in this study, we provide lines of evidence that the mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-extracellular signal-regulated kinase (ERK)-murine double minute 2 (MDM2)-p53 pathway plays a critical role in the regulation of MGMT expression, using stem-like glioblastoma cells directly derived from patient tumor samples and maintained in the absence of serum, which not only possess stem-like properties but are also known to phenocopy the characteristics of the original tumors from which they are derived. We show that, in stem-like glioblastoma cells, MEK inhibition reduced MDM2 expression and that inhibition of either MEK or MDM2 resulted in p53 activation accompanied by p53-dependent downregulation of MGMT expression. MEK inhibition rendered otherwise resistant stem-like glioblastoma cells sensitive to temozolomide, and combination of MEK inhibitor and temozolomide treatments effectively deprived stem-like glioblastoma cells of their tumorigenic potential. Our findings suggest that targeting of the MEK-ERK-MDM2-p53 pathway in combination with temozolomide could be a novel and promising therapeutic strategy in the treatment of glioblastoma.

FoxO3a functions as a key integrator of cellular signals that control glioblastoma stem-like cell differentiation and tumorigenicity.

Glioblastoma is one of the most aggressive types of human cancer, with invariable and fatal recurrence even after multimodal intervention, for which cancer stem-like cells (CSLCs) are now being held responsible. Our recent findings indicated that combinational inhibition of phosphoinositide-3-kinase/Akt/mammalian target of rapamycin (mTOR) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways effectively promotes the commitment of glioblastoma CSLCs to differentiation and thereby suppresses their tumorigenicity. However, the mechanism by which these two signaling pathways are coordinated to regulate differentiation and tumorigenicity remains unknown. Here, we identified FoxO3a, a common phosphorylation target for Akt and ERK, as a key transcription factor that integrates the signals from these pathways. Combinational blockade of both the pathways caused nuclear accumulation and activation of FoxO3a more efficiently than blockade of either alone, and promoted differentiation of glioblastoma CSLCs in a FoxO3a expression-dependent manner. Furthermore, the expression of a constitutively active FoxO3a mutant lacking phosphorylation sites for both Akt and ERK was sufficient to induce differentiation and reduce tumorigenicity of glioblastoma CSLCs. These findings suggest that FoxO3a may play a pivotal role in the control of differentiation and tumorigenicity of glioblastoma CSLCs by the PI3K/Akt/mTOR and MEK/ERK signaling pathways, and also imply that developing methods targeting effective FoxO3a activation could be a potential approach to the treatment of glioblastoma.