CD1d expression in glioblastoma is a promising target for NKT cell-based cancer immunotherapy.

Glioblastoma is the most common and aggressive type of brain tumor with high recurrence and fatality rates. Although various therapeutic strategies have been explored, there is currently no effective treatment for glioblastoma. Recently, the number of immunotherapeutic strategies has been tested for malignant brain tumors. Invariant natural killer T (iNKT) cells play an important role in anti-tumor immunity. To address if iNKT cells can target glioblastoma to exert anti-tumor activity, we assessed the expression of CD1d, an antigen-presenting molecule for iNKT cells, on glioblastoma cells. Glioblastoma cells from 10 of 15 patients expressed CD1d, and CD1d-positive glioblastoma cells pulsed with glycolipid ligand induced iNKT cell-mediated cytotoxicity in vitro. Although CD1d expression was low on glioblastoma stem-like cells, retinoic acid, which is the most common differentiating agent, upregulated CD1d expression in these cells and induced iNKT cell-mediated cytotoxicity. Moreover, intracranial administration of human iNKT cells induced tumor regression of CD1d-positive glioblastoma in orthotopic xenografts in NOD/Shi-scid IL-2RγKO (NOG) mice. Thus, CD1d expression represents a novel target for NKT cell-based immunotherapy for glioblastoma patients.

Eighty percent survival rate at 15 years for 1p/19q co-deleted oligodendroglioma treated with upfront chemotherapy irrespective of tumor grade.

INTRODUCTION: Chromosomes 1p/19q co-deletion is a robust molecular marker for the diagnosis of oligodendroglial tumors, and has been included in the 2016 WHO modified classification. Although treatment for oligodendroglioma is controversial, upfront chemotherapy is regarded as one of the treatment option for low-grade tumor. We have treated all the 1p/19q co-deleted oligodendrogliomas, both grades II and III, with upfront chemotherapy without conventional radiotherapy for 20 years. The clinical experience from this trial may be suggestive for understanding of the biological features of oligodendroglioma with 1p/19q co-deletion toward precision medicine. METHODS: This is a long-term retrospective data of the non-selected patients with 1p/19q co-deleted oligodendrogliomas uniformly treated with up-front chemotherapy. Seventy consecutive patients (48 with grade II and 22 with grade III tumors) were included. RESULTS: The median follow-up period was 13 years. The 5-, 10-, and 15-year progression-free survival (PFS) rates were 85.7%, 54.8%, and 31.5%, respectively, and the median PFS was 146 months. In most cases, tumor recurrence was remained local and could be controlled by salvage surgery and/or chemotherapy. The 5-, 10-, and 15-year overall survival (OS) rates were 96.8%, 88.7%, and 80.0%, respectively, and the median OS was not reached. These survival data compared favorably with previous large clinical studies employing radiotherapy. Tumor grades based on World Health Organization classification, extent of surgery, and age affected neither PFS nor OS. Most patients were able to return to their premorbid social life. CONCLUSIONS: The long-term results drawn from 20-years of single institution experience show that the patients with 1p/19q co-deleted oligodendrogliomas can be successfully treated with up-front chemotherapy alone without compromising OS.

Transforming growth factor-ß and stem cell markers are highly expressed around necrotic areas in glioblastoma.

Invasion into surrounding normal brain and resistance to genotoxic therapies are the main devastating aspects of glioblastoma (GBM). These biological features may be associated with the stem cell phenotype, which can be induced through a dedifferentiation process known as epithelial-mesenchymal transition (EMT). We show here that tumor cells around pseudopalisading necrotic areas in human GBM tissues highly express the most important EMT inducer, transforming growth factor (TGF-ß), concurrently with the EMT-related transcriptional factor, TWIST. In addition, the stem cell markers CD133 and alkaline phosphatase (ALPL) were also highly expressed around necrotic foci in GBM tissues. The high expression of TGF-ß around necrotic regions was significantly correlated with shorter progression-free survival and overall survival in patients with GBM. High expression of stem cell markers, ALPL, CD133, and CD44 was also correlated with poor outcomes. These results collectively support the hypothesis that tissue hypoxia induces the stem cell phenotype through TGF-ß-related EMT and contributes to the poor outcome of GBM patients.

IDH1 mutation is prognostic for diffuse astrocytoma but not low-grade oligodendrogliomas in patients not treated with early radiotherapy.

Despite accumulating knowledge regarding molecular backgrounds, the optimal management strategy for low-grade gliomas remains controversial. One reason is the marked heterogeneity in the clinical course. To establish an accurate subclassification of low-grade gliomas, we retrospectively evaluated isocitrate dehydrogenase-1 (IDH1) mutation in clinical specimens of diffuse astrocytomas (DA) and oligodendroglial tumors separately. No patients were treated with early radiotherapy, and modified PCV chemotherapy was used for postoperative residual tumors or recurrence in oligodendroglial tumors. Immunohistochemical evaluation of IDH status, p53 status, O(6)-methylguanine methyltransferase expression, and the MIB-1 index were performed. The 1p and 19q status was analyzed with fluorescence in situ hybridization. Ninety-four patients were followed for a median period of 8.5 years. For DAs, p53 was prognostic for progression- free survival (PFS) and IDH1 was significant for overall survival (OS) with multivariate analysis. In contrast, for oligodendroglial tumors, none of the parameters was significant for PFS or OS. Thus, the significance of IDH1 mutation is not clear in oligodendroglial tumors that are homogeneously indolent and chemosensitive. In contrast, DAs are heterogeneous tumors including some potentially malignant tumors that can be predicted by examining the IDH1 mutation status.

Stereotactic radiosurgery in combination with up-front high-dose methotrexate as a first-line treatment for newly diagnosed primary central nervous system lymphoma.

The efficacy of stereotactic radiosurgery (SRS) instead of whole brain radiotherapy (WBRT) following high-dose methotrexate (HD-MTX) for primary central nervous system lymphoma (PCNSL) is unclear. To clarify whether SRS in combination with up-front HD-MTX supplements the effect of HD-MTX in remaining or refractory lesions after initial HD-MTX treatment. The authors conducted a retrospective review for newly diagnosed PCNSL patients who underwent SRS after HD-MTX as a first-line treatment. The local control (LC), the progression-free survival (PFS), the recurrence patterns, the salvage treatments, the overall survival (OS), the Karnofsky Performance Status (KPS), the activities of daily living (ADL) were analyzed as well as radiosurgical parameters. Twenty patients underwent SRS for 51 lesions with the median volume of 0.45 cm(3). The median age at SRS was 67 (range 37-82). The median KPS at SRS was 90. The LC rate at 2 years was 86.0 %, the median PFS after SRS was 17 months, necessitating additional SRS and chemotherapy. The median OS was 52 months. No significant side effects related to SRS were observed. During follow-up period, the good ADL preservation was achieved for 13 months from SRS. Patients with KPS ≥ 90 at SRS demonstrated longer ADL preservation (32 months from SRS). SRS following up-front HD-MTX without WBRT provided excellent LC, acceptable OS and the long ADL preservation period. These benefits may be more emphasized especially in patients with good KPS, but should be validated in a large patient population.

Postnatal development of Blake's pouch cyst: a case report and new insight for its pathogenesis.

Blake's pouch cyst (BPC), a rare cystic malformation in the posterior fossa, is believed to be caused by the congenital expansion of the posterior membranous area that normally regresses during embryogenesis. However, due to the wide spectrum of the onset pattern and age of patients, the natural history and the pathogenesis are poorly understood. The authors describe the case of a girl who admitted with headache and right abducens nerve paresis at the age of 3 years and 10 months. Magnetic resonance (MR) imaging demonstrated a tetraventricular hydrocephalus, an open aqueduct, and a posterior fossa cyst compatible with BPC. Multiple tumors were also noticed in the ventricular wall. Tumor biopsy and an endoscopic third ventriculostomy were performed. Intraoperative observation confirmed the BPC, and pathological diagnosis was pilomyxoid astrocytoma. In retrospect, MR imaging was performed twice in the past, at the age of 8 months and again at 22 months, and no anomaly was detected, suggesting that Blake's pouch was once regressed. Therefore, a BPC in this patient was certainly developed after her second or third year of life. The ventricular tumors may influence the cerebrospinal fluid (CSF) absorption, which triggered the re-expansion of BPC from the possible remnant of Blake's pouch. This is a rare but important report providing evidence that in addition to the classic congenital BPC in which the remnant of Blake's pouch remains persistent, there could be postnatal or secondary BPC, which develops after birth. Possible mechanisms include that the remnant of Blake's pouch, which originally disappears, may re-expand postnatally in association with unknown trigger or a change in CSF dynamics or absorption.

Continuous intraoperative monitoring of abnormal muscle response in microvascular decompression for hemifacial spasm; a real-time navigator for complete relief.

Intermittent monitoring of abnormal muscle response (iAMR) has been reported to be useful for improving the surgical outcome of microvascular decompression (MVD) for hemifacial spasm (HFS). However, iAMR has not elucidated the relationship between AMR change and the corresponding surgical procedure, or the pathogenesis of AMR and HFS. The purpose of this study is to clarify the usefulness of continuous AMR monitoring (cAMR) for improving the surgical results of MVD and for understanding the relationship between AMR change and corresponding surgical procedure, and the pathogenesis of AMR and HFS. Fifty consecutive patients with HFS treated by MVD under cAMR monitoring, which continuously records AMR every minute throughout the surgical period, were retrospectively analyzed. The patients were assessed for the presence of HFS 1 week after the surgery and at final follow-up. Forty-six patients showed the complete disappearance of HFS. In 32, AMR disappeared abruptly and simultaneously with decompression of an offending vessel. AMR showed dynamic and various changes including temporary disappearance, or sudden, gradual, or componential disappearance before and during the decompression procedure, and even during the dural and skin closure after the initial decompression procedure. Facial spasm remained in four patients despite permanent AMR disappearance. cAMR monitoring improves the outcome of MVD. Although the main cause of HFS and AMR is vascular compression at the facial nerve, hyperexcitability of the facial nucleus is also involved in the pathogenesis of HFS and AMR. The proportional involvement of these causes differs between patients.

Successful resection of bilateral parafalcine meningioma with unilateral interhemispheric and contralateral transfalcine approach under nonintubated spontaneous breathing conditions: illustrative case.

BACKGROUND: The best surgical approach for resecting bilateral parafalcine meningioma, as well as the optimal anesthesia and airway management for craniotomy in patients with interstitial pneumonia (IP) for preventing postsurgical exacerbation, remains unclear. OBSERVATIONS: A 66-year-old female with a history of multiple relapses of IP underwent craniotomy for resection of a 4.5-cm bilateral parafalcine meningioma located just beneath the inferior sagittal sinus. To avoid mechanical ventilation or high-concentration oxygenation, the entire procedure was performed under nonintubated spontaneous breathing conditions with a supraglottic airway/laryngeal mask airway (SGA/LMA) device. Half of the tumor was resected using the ipsilateral interhemispheric approach, while the remaining half was resected using the contralateral transfalcine approach (CTA). No brain retractors were required. Preoperative embolization contributed toward reducing blood loss and surgery duration. During most of the operation, additional oxygen administration was not required. The postoperative course was uneventful, without exacerbation of the IP. LESSONS: This case demonstrated the utility and feasibility of a unilateral interhemispheric approach combined with CTA for resection of a bilateral parafalcine meningioma. Additionally, this case provides an alternative method of airway and anesthesia management with an SGA/LMA device and nonintubated spontaneous breathing for the prevention of postoperative acute exacerbation of IP.

[Leptomeningeal carcinomatosis following 27 years remission from breast cancer with epidermoid: a case report].

We herein report a patient with leptomeningeal carcinomatosis (LC) in long-term remission from breast cancer, co-existing with a posterior fossa epidermoid and an increase in the serum CA19-9 level which complicated the diagnosis. A 59-year-old woman underwent a left mastectomy due to breast cancer 27 years ago. She was admitted to our hospital suffering from a headache and diplopia. Her serum CA19-9 level on admission was elevated, and diffusion weighted images showed a high-intensity tumor in the prepontine and left cerebello-pontine cistern. A left lateral suboccipital craniotomy with endoscopic assistance was performed for tissue sampling. The pathological diagnosis was an epidermoid and LC from breast cancer. She died of progression of leptomeningeal carcinomatosis 31 days after surgery. LC alone following long-term remission from breast cancer is extremely rare. Meningeal irritation co-existing with an epidermoid mimicking chemical meningitis is even rarer. Pathological confirmation is required for such rare cases.

Clinicopathological and Genomic Features of Pediatric Intracranial Myxoid Mesenchymal Tumor with both of EWSR1-CREM Gene Fusion and MAP3K13 Mutation: A Case Report and Comparison with Adult Cases in the Literature.

Intracranial myxoid mesenchymal tumors (IMMTs) with EWSR1-CREB1 family gene fusion are rare brain neoplasms characterized by gene fusion between the EWSR1 gene and one of the cyclic AMP response element-binding (CREB) family transcription factor (CREB1, ATF1, or CREM) genes. Although half of reported cases are pediatric, the clinical, histologic, and genomic features of IMMTs with EWSR1 rearrangement in pediatric populations are not yet well clarified. Here we describe the case of a 7-year-old girl who presented with seizures due to an extra-axial tumor in the left parietal convexity. Gross total resection was achieved, and the tumor displayed a multilobular structure with solid hypercellular and myxoid hypocellular areas, separated by a variable amount of stroma. The hypercellular areas consisted of round to polygonal cells, whereas the myxoid areas were ovoid to spindled cells. Immunophenotypically, the tumor cells were positive for vimentin, desmin, and EMA. Next-generation sequencing of tumoral DNA revealed EWSR1-CREM gene fusion and a pathogenic mutation of MAP3K13. No recurrence was detected 9 months after resection, without chemotherapy or radiotherapy. In comparison to other pediatric and adult patients with EWSR1 rearrangement, many clinical, radiological, and immunohistochemical features were shared. However, signs of elevated intracranial pressure were more frequently observed, and postoperative radiation was less frequently administered for pediatric patients. Gross total resection (GTR) was the key prognostic factor for better disease control especially among pediatric patients. Further reports of cases with EWSR1 rearrangement with detailed genetic profiles are essential for clarifying the oncogenic pathway and establishing a standard treatment strategy.

The role of optimal cut-off diagnosis in 11C-methionine PET for differentiation of intracranial brain tumor from non-neoplastic lesions before treatment.

PURPOSE: Amino acid positron emission tomography (PET) may provide additional information to computed tomography and magnetic resonance imaging for detecting the pretreatment diagnosis of intracranial lesions. The purpose of this study was to investigate the role of cutoff values of 11C-METPET, an amino acid PET tracer, in the differentiation of pretreatment brain tumors from non-neoplastic lesions. METHODS: This retrospective cohort study analyzed 101 pretreatment patients with a definitive diagnosis out of a total of 425 consecutive 11C-METPET imaging studies. The standardized uptake values (SUV) and the ratios of lesion to contralateral normal frontal-lobe gray matter uptake (L/N ratios) were measured. Cutoff values for the differential diagnosis of brain tumors from non-neoplastic lesions were determined using receiver operating characteristics curve (ROC) analysis. RESULTS: Based on the ROC analyses, the cutoffs were 3.33 for maximum SUV, 2.54 for mean SUV, 2.33 for peak SUV, 2.04 for Lmax/Nmean, and 2.23 for Lmax/Nmax. The sensitivity and specificity of these cutoffs were 69.2% and 82.6%, respectively, for maximum SUV, 64.1% and 91.3% for mean SUV, 69.2% and 91.3% for peak SUV, 70.5% and 91.3% for Lmax/Nmax and 75.6% and 82.6% for Lmax/Nmean. CONCLUSION: In differentiating intracranial brain tumor from non-neoplastic lesion with 11C-METPET, the use of optimal cutoff values indicates the high specificity, which means that positive result indicates the high likelihood of brain tumor. Considering the high specificity of 11C-METPET, more invasive examinations such as biopsy may be considered in positive cases.

Metabolic, immunohistochemical, and genetic profiling of a cerebellar liponeurocytoma with spinal dissemination: a case report and review of the literature.

Cerebellar liponeurocytoma (cLNC), categorized as a World Health Organization grade II tumor, is a rare neoplasm characterized by advanced neuronal/neurocytic differentiation and focal lipid accumulation in neuroepithelial tumor cells. However, the expression and genetic profiling of cLNC have been poorly studied. A 44-year-old woman with a three-year history of cerebellar ataxia and numbness in lower extremities underwent radiological examination revealing multiple contrast-enhancing tumors at the floor of the fourth ventricle and in the lower vermis, and spinal dissemination. The high uptake of 11 C-methionine in positron emission tomography (Met-PET) supported the preoperative cLNC diagnosis. Subtotal removal of the tumor around the obex and inferior vermis was performed. Histologically, the tumor was composed of small, uniform cells with round nuclei in a sheet-like fashion. Tumor cells were diffusely reactive for the neuronal markers synaptophysin and neurofilament. Vacuolate cells with a displacement of nuclei suggested the accumulation of lipid, which was further supported by immunohistochemical staining of S-100. These findings confirmed the diagnosis of cLNC. Next-generation sequencing of tumoral DNA detected a splice site mutation in the ATRX gene. Further reports of cLNC cases with detailed expression and genetic profiles are essential for precise diagnosis and clarifying the oncogenic pathway in cLNC.

Oncological and functional outcomes of supratotal resection of IDH1 wild-type glioblastoma based on 11C-methionine PET: a retrospective, single-center study.

The oncological and functional outcomes in glioblastoma (GBM) patients following supratotal resection (SupTR), involving complete resection of contrast-enhancing enhanced (CE) tumors and areas of methionine (Met) uptake on 11C-met positron emission tomography (Met-PET), are unknown. We conducted a retrospective review in newly diagnosed, IDH1 wild-type GBM patients, comparing SupTR with gross total resection (GTR), in which only CE tumor tissue was resected. All patients underwent standard radiotherapy and temozolomide treatment, and were followed for tumor recurrence and overall survival (OS). Among the 30 patients included in this study, 7 underwent SupTR and 23 underwent GTR. Awake craniotomy with cortical and subcortical mapping was more frequently performed in the SupTR group than in the GTR group. During the follow-up period, significantly different patterns of disease progression were observed between groups. Although more than 80% of recurrences were local in the GTR group, all recurrences in the SupTR group were distant. Median OS in the GTR and SupTR groups was 18.5 months (95% confidence interval [CI] 14.2-35.1) and not reached (95% CI 30.5-not estimable), respectively; this difference was statistically significant (p = 0.03 by log-rank test). No postoperative neurocognitive decline was evident in patients who underwent SupTR. Compared to GTR alone, aggressive resection of both CE tumors and areas with Met uptake (SupTR) under awake craniotomy with functional mapping results in a survival benefit associated with better local control and neurocognitive preservation.

White matter dissection and structural connectivity of the human vertical occipital fasciculus to link vision-associated brain cortex.

The vertical occipital fasciculus (VOF) is an association fiber tract coursing vertically at the posterolateral corner of the brain. It is re-evaluated as a major fiber tract to link the dorsal and ventral visual stream. Although previous tractography studies showed the VOF's cortical projections fall in the dorsal and ventral visual areas, the post-mortem dissection study for the validation remains limited. First, to validate the previous tractography data, we here performed the white matter dissection in post-mortem brains and demonstrated the VOF's fiber bundles coursing between the V3A/B areas and the posterior fusiform gyrus. Secondly, we analyzed the VOF's structural connectivity with diffusion tractography to link vision-associated cortical areas of the HCP MMP1.0 atlas, an updated map of the human cerebral cortex. Based on the criteria the VOF courses laterally to the inferior longitudinal fasciculus (ILF) and craniocaudally at the posterolateral corner of the brain, we reconstructed the VOF's fiber tracts and found the widespread projections to the visual cortex. These findings could suggest a crucial role of VOF in integrating visual information to link the broad visual cortex as well as in connecting the dual visual stream.

Natural history of de novo high grade glioma: first description of growth parabola.

Etiopathogenesis and physiopathology of gliomas are largely unknown. Recently, many authors have proved a strict correlation between the velocity of diametric expansion (VDE) on the magnetic resonance imaging (MRI) and the biological behavior of these tumors, especially in low grade gliomas (LGGs). Unfortunately, natural history of High Grade Gliomas (HGGs) has not been well clarified because of its fast progression, late diagnoses and early surgical intervention. We describe, for the first time to our knowledge, the case of asymptomatic patient with an incidentally discovered de novo HGG with a total of 17 months of follow-up. A male patient was referred to our consultation for routinely follow-up after meningioma resection 5 years before. He underwent MRI every year without any neuroradiological alterations. A new MRI image presented a non-enhancing lesion in the right temporal lobe with 3.55 cm of mean tumor diameter (MTD) and 35.6 mm/year of VDE. After two months interval, the lesion had 3.97 cm of MTD and 27.8 mm/year of VDE. Although we have strongly suggested surgical resection, patient have delayed the operation for personal issues. After other 3 months, the tumor showed enhancement with 4.5 of MTD and 17.4 mm/year of VDE. We speculate that the descending parabola is due to initial mass effect and hypoxia of the tumor core. We also underline the crucial role of the VDE determining, in order to predict the nature of the lesion and address the most effective treatment for each patient.

Association between serum anti­ASXL2 antibody levels and acute ischemic stroke, acute myocardial infarction, diabetes mellitus, chronic kidney disease and digestive organ cancer, and their possible association with atherosclerosis and hypertension.

The aim of the present study was to identify novel antibody markers for the early diagnosis of atherosclerosis in order to improve the prognosis of patients at risk for acute ischemic stroke (AIS) and acute myocardial infarction (AMI). A first screening involved the serological identification of antigens by recombinant cDNA expression cloning and identified additional sex combs­like 2 (ASXL2) as a target antigen recognized by serum IgG antibodies in the sera of patients with atherosclerosis. Antigens, including the recombinant glutathione S­transferase­fused ASXL2 protein and its synthetic peptide were then prepared to examine serum antibody levels. Amplified luminescence proximity homogeneous assay­linked immunosorbent assay, which incorporates glutathione­donor beads and anti­human­IgG­acceptor beads, revealed significantly higher serum antibody levels against the ASXL2 protein and its peptide in the patients with AIS, diabetes mellitus, AMI, chronic kidney disease, esophageal squamous cell carcinoma, or colorectal carcinoma compared with those in healthy donors. The ASXL2 antibody levels were well associated with hypertension complication, but not with sex, body mass index, habitual smoking, or alcohol intake. These results suggest that the serum ASXL2 antibody marker can discriminate between hypertension­induced atherosclerotic AIS and AMI, as well as a number of digestive organ cancers.

Mechanism of Corpus Callosum Infarction Associated with Acute Hydrocephalus: Clinical, Surgical, and Radiological Evaluations for Pathophysiology.

BACKGROUND: Corpus callosum (CC) infarction has been reported to be rare because of the rich blood supply in the CC. The pathophysiology of CC infarction associated with acute hydrocephalus is unknown. The aim of the present study was to clarify the characteristics and mechanism of CC infarction associated with acute noncommunicating hydrocephalus (ANCH). METHODS: We reviewed clinical the data from all patients who had undergone surgical intervention for ANCH at Chiba University Hospital from January 2008 to March 2018. Patients with vascular lesions, a history of hydrocephalus, and lacking magnetic resonance imaging studies were excluded. The clinical, surgical, and radiological parameters were obtained retrospectively for pathophysiological analysis. RESULTS: A total of 23 patients with ANCH who had undergone surgical intervention and had met the inclusion criteria were included in the present study. Of the 23 patients, 6 (23%) had developed CC infarction. All CC infarctions were located in the splenium. Although no clinical or surgical features were associated with splenial infarction, the radiological parameters of lateral ventricle enlargement and a narrower callosal angle at the posterior commissure and the foramen of Monro were significantly associated with splenial infarction. CONCLUSION: The present study has presented evidence that increased intraventricular pressure by ANCH applied transversely in the splenium will directly induce compression of the superior branch of the posterior callosal artery and pericallosal pial plexus, resulting in splenium-specific infarction in patients with ANCH.

Feasibility study of finalizing the extended adjuvant temozolomide based on methionine positron emission tomography (Met-PET) findings in patients with glioblastoma.

In the management of patients with newly diagnosed glioblastoma, there is no standard duration for adjuvant temozolomide treatment. This study aimed to assess the feasibility of finalizing adjuvant temozolomide treatment on the basis of methionine uptake in methionine positron emission tomography (Met-PET). We conducted a retrospective review of glioblastoma patients who underwent more than twelve cycles of temozolomide (extended temozolomide) treatment after resection and concomitant chemoradiotherapy with no evidence of recurrence on MRI. In addition to the methionine uptake value at the completion of extended temozolomide, local and distant recurrence and progression-free survival were also analyzed. Forty-four patients completed the extended temozolomide treatment. Among these, 18 experienced some type of tumor recurrence within one year. A Tmax/Nave value of 2.0 was the optimal cut-off value indicating progression. More than 80% of the patients with low methionine uptake completed the temozolomide treatment, and subsequent basic MRI observations showed no recurrence within one year after Met-PET. Subgroups with high uptake (≥2.0), even with continuation of temozolomide treatment, showed more frequent tumor progression than patients with low uptake (<2.0) who completed the extended temozolomide treatment (p < 0.001, odds ratio 14.7, 95% CI 3.46-62.3). The tumor recurrence rate increased in stepwise manner according to methionine uptake. Finalization of the extended temozolomide treatment on the basis of low uptake value was feasible with a low recurrence rate. Compared to MRI, Met-PET shows better ability to predict tumor progression in long-term glioblastoma survivors with extended temozolomide use.

Hammock Middle Cerebral Artery and Delayed Infarction in Lenticulostriate Artery After Staged Resection of Giant Insular Glioma.

BACKGROUND: Delayed infarction in the lenticulostriate artery (LSA) area after insular glioma resection is not common, and its pathophysiology remains unknown. CASE DESCRIPTION: A 32-year-old right-handed man with a giant insular low-grade glioma with frontal and temporal extension underwent awake craniotomy with an intentional staged surgery strategy. Preoperative radiologic images demonstrated a diagonally elevated middle cerebral artery (MCA) by the temporal tumor and a significantly compressed striatum. With intraoperative subcortical direct electrical stimulation, the resection was finalized in the temporal part of the tumor due to the semantic paraphasia induced in the temporal stem, fatigue, and loss of concentration. The immediate postoperative clinical course was uneventful. However, on postoperative day 20, he suddenly experienced right hemiparesis. Repeated images revealed infarction in the LSA area. The previously compressed striatum was then relieved and relocated to its original position in just 20 days, and the M1 segment of the MCA was remarkably downward, in which the MCA resembled a hammock. Angiography confirmed the hammock-shaped MCA and significantly stretched LSA, suggesting the combination of freed striatum from the compression and loss of temporal structure by the tumor resection as the key mechanism of severe dislocation of the MCA and delayed ischemia. CONCLUSIONS: In a staged resection of giant insular glioma, attention should be paid to a possible severe dislocation of the MCA in a delayed postoperative period, which may lead to LSA stretching and delayed infarction.

Real-time methylation-specific PCR for the evaluation of methylation status of MGMT gene in glioblastoma.

The methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) gene is a strong predictor for the efficacy of temozolomide chemotherapy and survival periods. However, the correlation between the extent of methylation and the difference in survival times has not been fully clarified. Simple and quantitative evaluations of the methylation status in the promotor region of the MGMT gene are expected to be worldwide standardized diagnostics. We applied real-time semi-quantitative methylation-specific polymerase chain reaction (SQ-MSP) of the MGMT gene promoter region to 84 glioblastoma patients. The SQ-MSP result showed that the ΔCt value, which represents the difference between uCt and mCt (uCt value - mCt value), is inversely correlated with overall survival. With adequate cutoff setting, this assay showed that those patients suffering from a tumor with low ΔCt (methylated) survived significantly longer than those having tumors with high ΔCt (un-methylated). The most significant difference was observed when the cutoff was set at a ΔCt of 2. Using this cutoff point, the result of MGMT immunohistochemical analysis was also significantly correlated with the methylation status examined with real-time SQ-MSP. These results collectively show that MGMT promoter methylation status actually affects patients' survival and protein expression depending on its methylation level, and the extent of methylated CpGs would be better assessed with real-time SQ-MSP than with the standard gel-based MSP. This method is cost- and labor-saving compared with pyrosequencing, and significantly contributes to the accurate and objective prediction of patient survival.