Safety and efficacy of depatuxizumab mafodotin in Japanese patients with malignant glioma: A nonrandomized, phase 1/2 trial.

INTELLANCE-J was a phase 1/2 study of a potent antibody-drug conjugate targeting epidermal growth factor receptor (EGFR), depatuxizumab mafodotin (Depatux-M), as a second- or first-line therapy, alone or combined with chemotherapy or chemoradiotherapy in 53 Japanese patients with World Health Organization (WHO) grade III/IV glioma. In second-line arms, patients with EGFR-amplified recurrent WHO grade III/IV glioma received Depatux-M plus chemotherapy (temozolomide) or Depatux-M alone regardless of EGFR status. In first-line arms, patients with newly diagnosed WHO grade III/IV glioma received Depatux-M plus chemoradiotherapy. The study was halted following lack of survival benefit with first-line Depatux-M in the global trial INTELLANCE-1. The primary endpoint was 6-month progression-free survival (PFS) in patients with EGFR-amplified tumors receiving second-line Depatux-M plus chemotherapy. Common nonocular treatment-emergent adverse events (TEAEs) with both second-line and first-line Depatux-M included lymphopenia (42%, 33%, respectively), thrombocytopenia (39%, 47%), alanine aminotransferase increase (29%, 47%), and aspartate aminotransferase increase (24%, 60%); incidence of grade ≥3 TEAEs was 66% and 53%, respectively. Ocular side effects (OSEs) occurred in 93% of patients receiving second-line Depatux-M plus chemotherapy and all patients receiving second-line Depatux-M alone or first-line Depatux-M plus chemoradiotherapy. Most OSEs were manageable with dose modifications and concomitant medications. The 6-month PFS estimate was 25.6% (95% confidence interval [CI] 11.4-42.6), and median PFS was 2.1 months (95% CI 1.9-3.9) with second-line Depatux-M plus chemotherapy in the EGFR-amplified subgroup. This study showed acceptable safety profile of Depatux-M alone or plus chemotherapy/chemoradiotherapy in Japanese patients with WHO grade III/IV glioma. The study was registered at ClinicalTrials.gov (NCT02590263).

Gene expression profiling of 19q-loss astrocytomas suggest a specific pattern associated with the better prognosis.

PURPOSE: We previously reported that there was a subgroup of IDH-mutated astrocytomas harboring only 19q-loss showing oligodendroglioma-like morphology and significantly longer overall survival (OS) compared with 19q-intact astrocytomas. The aim of this study was to further explore the biological characteristics of this possible subgroup and obtain insight into the mechanism of their relatively benign clinical behavior. METHODS: We compared gene expression pattern between five 19q-loss and five 19q-intact IDH-mutated astrocytomas by microarray analysis. RESULTS: By comparing expression levels of genes of 19q-loss astrocytomas to those of 19q-intact astrocytomas, 102 up-regulated genes and 162 down-regulated genes were extracted. The down-regulated genes clustered heavily to 19q and 4p while the up-regulated genes clustered to 4q. It was noteworthy that fibroblast growth factor 1 associated with stem cell maintenance and multiple genes associated with glioma progression were down-regulated in 19q-loss astrocytomas, and these results were validated with the independent TCGA data set. On t-SNE analysis of the 19q-loss astrocytomas with other IDH-mutant glioma subgroups from the TCGA datasets, the expression pattern of the 19q-loss astrocytomas showed no shift toward oligodendrogliomas with 1p/19q codeletion but rather constituted a subgroup of astrocytoma. CONCLUSIONS: These findings suggested that 19q-loss in astrocytomas is more likely acquired event rather than an early event in oncogenesis like the 1p/19q-codeletion in oligodendrogliomas, and that the biological features of 19q-loss astrocytomas are possibly related to differentially expressed genes associated with stem cell maintenance and glioma progression.

Intracranial subarachnoid hemorrhage caused by an aneurysm at the thoracic spinal region: case report and literature review.

Background: The most common cause of intracranial subarachnoid hemorrhage (SAH) is an intracranial aneurysm or other vascular lesion; however, spinal lesions have also been implicated. Furthermore, vascular lesions rarely occur in the thoracolumbar region. We herein presented a case of intracranial SAH caused by an isolated aneurysm in the thoracic spinal artery.Case presentation: A 79-year-old woman developed the sudden onset of headaches in the parietal and occipital regions followed by vomiting. Head computed tomography (CT) scans showed SAH in the basal cistern and around the parietal lobe cortex. Cerebral angiography detected no aneurysm or vascular malformation. Spinal CT on day 1 showed extensive SAH at the posterior surface of the spinal cord, which was the most prominent at the level of T9/10, and spinal angiography subsequently revealed an aneurysm fed by the T10 radicular artery. The aneurysm was resected by T8-10 laminectomy, and the patient recovered with no long-term neurological deficit.Conclusions: A literature review revealed 17 cases of intracranial SAH from thoracolumbar vascular lesions. Most cases resulted in poor functional outcomes, which occurred in the later phase of the disease and may have been avoided with earlier diagnoses and interventions. We suggest whole spine CT as a useful tool for rapid screening of this rare lesion, and is recommended when an initial survey for intracranial lesions does not detect any likely lesions. Furthermore, ventricular reflux on head CT may lead to an accurate diagnosis in the absence of spinal symptoms.

Brain invasion by chronic lymphocytic leukemia.

Brain invasion by chronic lymphocytic leukemia (CLL) is very rare, and only a handful of cases have been reported. We here report a case of 61-year-old woman who had been treated for CLL for 14 years presenting with a progressive mental disturbance. Magnetic resonance imaging (MRI) showed discontinuous ring-enhancing lesions compatible with the "open ring" sign, which was considered a demyelinating disorder, in both the frontal lobes. However, on histological examination of the biopsied specimen, infiltration of small lymphocytes positive for CD5, CD20, and CD23, indicating brain invasion by CLL, was seen. The leukemia cells occupied the Virchow-Robin space and infiltrated into the brain parenchyma. The arterioles in the Virchow-Robin space were compressed and occluded with the tumor cells, while CD163-positive cells infiltrated the brain parenchyma. Myelin staining demonstrated myelinoclasis in the infiltrated brain tissue. The MRI findings in the present case probably reflected myelinoclasis, suggesting rare brain invasion by CLL. The possibility of lymphoma should not be eliminated based on the MRI findings.

IDH-mutated astrocytomas with 19q-loss constitute a subgroup that confers better prognosis.

IDH-mutant gliomas are classified into astrocytic or oligodendroglial tumors by 1p/19q status in the WHO 2016 classification, with the latter presenting with characteristic morphology and better prognosis in general. However, the morphological and genetic features within each category are varied, and there might be distinguishable subtypes. We analyzed 170 WHO grade II-IV gliomas resected in our institution. 1p/19q status was analyzed by microsatellite analysis, and genetic mutations were analyzed by next-generation sequencing and Sanger sequencing. For validation, the Brain Lower Grade Glioma dataset of The Cancer Genome Atlas was analyzed. Of the 42 grade III IDH-mutated gliomas, 12 were 1p-intact/19q-intact (anaplastic astrocytomas [AA]), 7 were 1p-intact/19q-loss (AA), and 23 showed 1p/19q-codeletion (anaplastic oligodendrogliomas). Of the 88 IDH-wild type glioblastomas (GBMs), 14 showed 1p-intact/19q-loss status. All of the seven 1p-intact/19q-loss AAs harbored TP53 mutation, but no TERT promotor mutation. All 19q-loss AAs had regions presenting oligodendroglioma-like morphology, and were associated with significantly longer overall survival compared to 19q-intact AAs (P = .001). This tendency was observed in The Cancer Genome Atlas Lower Grade Glioma dataset. In contrast, there was no difference in overall survival between the 19q-loss GBM and 19q-intact GBM (P = .4). In a case of 19q-loss AA, both oligodendroglial morphology and 19q-loss disappeared after recurrence, possibly indicating correlation between 19q-loss and oligodendroglial morphology. We showed that there was a subgroup, although small, of IDH-mutated astrocytomas harboring 19q-loss that present oligodendroglial morphology, and also were associated with significantly better prognosis compared to other 19q-intact astrocytomas.

Distinct molecular profile of diffuse cerebellar gliomas.

Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the importance of analyzing molecular characteristics of gliomas stratified by brain region. Therefore, to elucidate molecular characteristics of diffuse cerebellar gliomas (DCGs), 27 adult, mostly glioblastoma cases were analyzed. Comprehensive analysis using whole-exome sequencing, RNA sequencing, and Infinium methylation array (n = 17) demonstrated their distinct molecular profile compared to gliomas in other brain regions. Frequent mutations in chromatin-modifier genes were identified including, noticeably, a truncating mutation in SETD2 (n = 4), which resulted in loss of H3K36 trimethylation and was mutually exclusive with H3F3A K27M mutation (n = 3), suggesting that epigenetic dysregulation may lead to DCG tumorigenesis. Alterations that cause loss of p53 function including TP53 mutation (n = 9), PPM1D mutation (n = 2), and a novel type of PPM1D fusion (n = 1), were also frequent. On the other hand, mutations and copy number changes commonly observed in cerebral gliomas were infrequent. DNA methylation profile analysis demonstrated that all DCGs except for those with H3F3A mutations were categorized in the "RTK I (PDGFRA)" group, and those DCGs had a gene expression signature that was highly associated with PDGFRA. Furthermore, compared with the data of 315 gliomas derived from different brain regions, promoter methylation of transcription factors genes associated with glial development showed a characteristic pattern presumably reflecting their tumor origin. Notably, SOX10, a key transcription factor associated with oligodendroglial differentiation and PDGFRA regulation, was up-regulated in both DCG and H3 K27M-mutant diffuse midline glioma, suggesting their developmental and biological commonality. In contrast, SOX10 was silenced by promoter methylation in most cerebral gliomas. These findings may suggest potential tailored targeted therapy for gliomas according to their brain region, in addition to providing molecular clues to identify the region-related cellular origin of DCGs.

Genome-wide methylation profiles in primary intracranial germ cell tumors indicate a primordial germ cell origin for germinomas.

Intracranial germ cell tumors (iGCTs) are the second most common brain tumors among children under 14 in Japan. The World Health Organization classification recognizes several subtypes of iGCTs, which are conventionally subclassified into pure germinoma or non-germinomatous GCTs. Recent exhaustive genomic studies showed that mutations of the genes involved in the MAPK and/or PI3K pathways are common in iGCTs; however, the mechanisms of how different subtypes develop, often as a mixed-GCT, are unknown. To elucidate the pathogenesis of iGCTs, we investigated 61 GCTs of various subtypes by genome-wide DNA methylation profiling. We showed that pure germinomas are characterized by global low DNA methylation, a unique epigenetic feature making them distinct from all other iGCTs subtypes. The patterns of methylation strongly resemble that of primordial germ cells (PGC) at the migration phase, possibly indicating the cell of origin for these tumors. Unlike PGC, however, hypomethylation extends to long interspersed nuclear element retrotransposons. Histologically and epigenetically distinct microdissected components of mixed-GCTs shared identical somatic mutations in the MAPK or PI3K pathways, indicating that they developed from a common ancestral cell.

Classification of adult diffuse gliomas by molecular markers-a short review with historical footnote.

Classification of gliomas, first established by Cushing and Bailey in early 20th century, has been based on histological features that were associated with clinical behavior of the tumor fairly well. However, inter-observer variation in the diagnosis and heterogeneous clinical outcome within a single entity have been problematic in some cases. Accumulation of molecular information of gliomas over the past two to three decades gradually elucidated the mechanism of oncogenesis and progression of gliomas at the molecular level, and it now appears to be possible to classify gliomas by the molecular markers, especially in adult diffuse gliomas that constitute ~25-30% of the primary intracranial tumors. Most powerful molecular markers to classify those tumors are those that appear to be involved in the early phases of oncogenesis, including IDH1/2, TP53, TERT, ATRX and 1p/19q co-deletion. Interesting tight negative and positive correlations among those molecular genetic alterations enable clearer definition of entities and better prognosis prediction in adult diffuse gliomas.

Homozygously deleted gene DACH1 regulates tumor-initiating activity of glioma cells.

Loss or reduction in function of tumor suppressor genes contributes to tumorigenesis. Here, by allelic DNA copy number analysis using single-nucleotide polymorphism genotyping array and mass spectrometry, we report homozygous deletion in glioblastoma multiformes at chromosome 13q21, where DACH1 gene is located. We found decreased cell proliferation of a series of glioma cell lines by forced expression of DACH1. We then generated U87TR-Da glioma cells, where DACH1 expression could be activated by exposure of the cells to doxycycline. Both ex vivo cellular proliferation and in vivo growth of s.c. transplanted tumors in mice are reduced in U87TR-Da cells with DACH1 expression (U87-DACH1-high), compared with DACH1-nonexpressing U87TR-Da cells (U87-DACH1-low). U87-DACH1-low cells form spheroids with CD133 and Nestin expression in serum-free medium but U87-DACH1-high cells do not. Compared with spheroid-forming U87-DACH1-low cells, adherent U87-DACH1-high cells display lower tumorigenicity, indicating DACH1 decreases the number of tumor-initiating cells. Gene expression analysis and chromatin immunoprecipitation assay reveal that fibroblast growth factor 2 (FGF2/bFGF) is transcriptionally repressed by DACH1, especially in cells cultured in serum-free medium. Exogenous bFGF rescues spheroid-forming activity and tumorigenicity of the U87-DACH1-high cells, suggesting that loss of DACH1 increases the number of tumor-initiating cells through transcriptional activation of bFGF. These results illustrate that DACH1 is a distinctive tumor suppressor, which does not only suppress growth of tumor cells but also regulates bFGF-mediated tumor-initiating activity of glioma cells.

Rise of oligodendroglioma hypermutator phenotype from a subclone harboring TP53 mutation after TMZ treatment.

Oligodendrogliomas characterized and defined by 1p/19q co-deletion are slowly growing tumors showing better prognosis than astrocytomas. TP53 mutation is rare in oligodendrogliomas while the vast majority of astrocytomas harbor the mutation, making TP53 mutation mutually exclusive with 1p/19q codeletion in lower grade gliomas virtually. We report a case of 51-year-old woman with a left fronto-temporal oligodendroglioma that contained a small portion with a TP53 mutation, R248Q, at the initial surgery. On a first, slow-growing recurrence 29 months after radiation and nitrosourea-based chemotherapy, the patient underwent TMZ chemotherapy. The recurrent tumor responded well to TMZ but developed a rapid progression after 6 cycles as a malignant hypermutator tumor with a MSH6 mutation. Most of the recurrent tumor lacked typical oligodendroglioma morphology that was observed in the primary tumor, while it retained the IDH1 mutation and 1p/19q co-deletion. The identical TP53 mutation observed in the small portion of the primary tumor was universal in the recurrence. This case embodied the theoretically understandable clonal expansion of the TP53 mutation with additional mismatch repair gene dysfunction leading to hypermutator phenotype. It thus indicated that TP53 mutation in oligodendroglioma, although not common, may play a critical role in the development of hypermutator after TMZ treatment.

Symptomatic recurrence of intracranial arterial dissections: follow-up study of 143 consecutive cases and pathological investigation.

BACKGROUND AND PURPOSE: The frequency and pattern of symptomatic recurrence of spontaneous intracranial arterial dissection (IAD) are unknown. METHODS: A follow-up study of 143 patients (85 men, 58 women; mean age, 50.7 [7-83] years) with spontaneous IADs at The University of Tokyo and affiliated hospitals from 1980 to 2000 was conducted. Tissue samples of IAD vessels obtained from 13 patients at various intervals from onset were also examined histologically. RESULTS: With a mean follow-up of 8.2 years, symptomatic recurrence occurred in 47 patients (33%). Of 37 cases initially presenting with hemorrhage, 35 developed hemorrhagic recurrence with a mean interval of 4.8 days, and 2 developed nonhemorrhagic recurrences after 21 and 85 months, respectively. Of 10 patients initially presenting with nonhemorrhagic symptoms, 1 developed hemorrhagic recurrence 4 days later, and 9 developed nonhemorrhagic recurrences with a mean interval of 8.6 months. Histopathologically, the affected vessels in the acute stage of hemorrhage (days 0-6) demonstrated insufficient granulation formation within the pseudolumen, followed by marked intimal thickening around the pseudolumen and recanalizing vessel formation in the late stage (>day 30). In the late stage of brain ischemia, subintimal and subadventitial hemorrhage accompanied with intimal thickening was observed. CONCLUSIONS: These data indicate that IAD is a disease carrying a relatively high risk of symptomatic recurrence, apparently occurring in 3 phases and patterns: early hemorrhagic recurrence, late nonhemorrhagic recurrence, and chronic fusiform aneurysm transformation. Knowledge of this triphasic recurrence and corresponding histopathological characteristics help determine the treatment and follow-up strategy for IAD patients.

Significance of IDH mutations varies with tumor histology, grade, and genetics in Japanese glioma patients.

Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are found frequently in malignant gliomas and are likely involved in early gliomagenesis. To understand the prevalence of these mutations and their relationship to other genetic alterations and impact on prognosis for Japanese glioma patients, we analyzed 250 glioma cases. Mutations of IDH1 and IDH2 were found in 73 (29%) and 2 (1%) cases, respectively. All detected mutations were heterozygous, and most mutations were an Arg132His (G395A) substitution. IDH mutations were frequent in oligodendroglial tumors (37/52, 71%) and diffuse astrocytomas (17/29, 59%), and were less frequent in anaplastic astrocytomas (8/29, 28%) and glioblastomas (13/125, 10%). The pilocytic astrocytomas and gangliogliomas did not have either mutation. Notably, 28 of 30 oligodendroglial tumors harboring the 1p/19q co-deletion also had an IDH mutation, and these alterations were significantly correlated (P < 0.001). The association between TP53 and IDH mutation was significant in diffuse astrocytomas (P = 0.0018). MGMT promoter methylation was significantly associated with IDH mutation in grade 2 (P < 0.001) and grade 3 (P = 0.02) gliomas. IDH mutation and 1p/19q co-deletion were independent favorable prognostic factors for patients with grade 3 gliomas. For patients with grade 3 gliomas and without 1p/19q co-deletion, IDH mutation was strongly associated with increased progression-free survival (P < 0.0001) and overall survival (P < 0.0001), but no such marked correlation was observed with grade 2 gliomas or glioblastomas. Therefore, IDH mutation would be most useful when assessing prognosis of patients with grade 3 glioma with intact 1p/19q; anaplastic astrocytomas account for most of these grade 3 gliomas.

The Japan Neurosurgical Database: Statistics Update 2018 and 2019.

Each year, the Japan Neurosurgical Society (JNS) reports up-to-date statistics from the Japan Neurosurgical Database regarding case volume, patient demographics, and in-hospital outcomes of the overall cohort and neurosurgical subgroup according to the major classifications of main diagnosis. We hereby report patient demographics, in-hospital mortality, length of hospital stay, purpose of admission, number of medical management, direct surgery, endovascular treatment, and radiosurgery of the patients based on the major classifications and/or main diagnosis registered in 2018 and 2019 in the overall cohort (523283 and 571143 patients, respectively) and neurosurgical subgroup (177184 and 191595 patients, respectively). The patient demographics, disease severity, proportion of purpose of admission (e.g., operation, 33.9-33.5%) and emergent admission (68.4-67.8%), and in-hospital mortality (e.g., cerebrovascular diseases, 6.3-6.5%; brain tumor, 3.1-3%; and neurotrauma, 4.3%) in the overall cohort were comparable between 2018 and 2019. In total, 207783 and 225217 neurosurgical procedures were performed in the neurosurgical subgroup in 2018 and 2019, respectively, of which endovascular treatment comprised 19.1% and 20.3%, respectively. Neurosurgical management of chronic subdural hematoma (19.4-18.9%) and cerebral aneurysm (15.4-14.8%) was most common. Notably, the proportion of management of ischemic stroke/transient ischemic attack, including recombinant tissue plasminogen activator infusion and endovascular acute reperfusion therapy, increased from 7.5% in 2018 to 8.8% in 2019. The JNS statistical update represents a critical resource for the lay public, policy makers, media professionals, neurosurgeons, healthcare administrators, researchers, health advocates, and others seeking the best available data on neurosurgical practice.

Polar spongioblastoma: A high-grade glioma that does not contain the IDH1 mutation or 1p/19q LOH.

We report a case of an unusual glioma termed "primitive polar spongioblastoma" that displayed characteristic palisading tumor cells at the light microscopic level. The patient was a 52-year-old woman who underwent subtotal removal for a left frontotemporal tumor. The palisading pattern was present throughout the tumor. Several glial markers were revealed by immunohistochemical examination, but no neuronal markers were observed. Genetic studies showed O-6-methylguanine-DNA methyltransferase (MGMT) methylation, wild type IDH1, and the absence of 1p/19q loss of heterozygosity (LOH) in the tumor genes. Based on histological and genetic features, this tumor might not be suited to any of neuroepithelial tumor in the recent WHO classification. We consider that cases such as this should be temporarily set under a separate heading and be entrusted to future investigation after more cases have been accumulated.

Middle meningeal artery embolization for chronic subdural hematoma with high risk of recurrence: A single institution experience.

BACKGROUND: Middle meningeal artery (MMA) embolization can be a treatment option for selected cases of chronic subdural hematoma (CSDH) patients. However, appropriate timing of this procedure or the conditions to be considered are still not standardized. METHODS: Between 2008 and 2018, 18 symptomatic CSDH patients underwent MMA embolization at our institution. The timing of embolization and the risk factors for recurrence of CSDH, the recurrence rate after an embolization, and the complication were thoroughly reviewed. RESULTS: Of the 18 cases, 16 patients were male. The median age at MMA embolization was 78.5 years (range, 66-98 years). The median follow-up period were eight months (range, 2-53 months). Possible risk factors for CSDH recurrence harbored by those patients were age > 74 yrs (10), brain atrophy (4), separated hematoma (3), coagulopathy (3), anticoagulant administration (3), and thrombocytopenia (1). No recurrence or complication was observed in any of the patients after the embolization. CONCLUSIONS: MMA embolization is effective and safe in preventing recurrence of CSDH with high risk of recurrence, and could be a standard treatment for such cases.

Middle Cerebral Artery Aneurysm Associated with Moyamoya Disease.

BACKGROUND: We report a rare case of unruptured middle cerebral artery aneurysm associated with moyamoya disease. CASE DESCRIPTION: A 48-year-old woman with an 8-year history of moyamoya disease developed a de novo aneurysm at the bifurcation of the right middle cerebral artery. The aneurysm showed rapid enlargement in size in 1 year and surgical treatment was performed. Preoperative images could not clearly define the anatomical relationship between the aneurysm and the surrounding vessels. Intraoperative findings indicated that segmental occlusion of normal arteries that was not visualized made it difficult to define the vascular anatomy. In addition, those occlusions accompanied by improved M1 flow after administration of cilostazol was speculated to have increased hemodynamic stress, leading to the relatively rapid progress of the aneurysm. CONCLUSIONS: Understanding the complexity of such process may be valuable in proper decision-making in the management of moyamoya disease patients.

Peculiar Characteristics of Arteriovenous Malformations Arising in the Galenic Region.

Arteriovenous malformations (AVM) are congenital vascular lesions fed by arterial feeders originating from branches of the internal carotid artery (ICA) or vertebrobasilar artery. We experienced unique AVMs arising in the midline Galenic region, receiving blood supply from the ICA/vertebral artery systems and the external carotid artery system. We retrospectively reviewed data on eight patients who had an AVM arising in the Galenic region and were treated in the University of Tokyo Hospital between 1990 and 2019. The median age at diagnosis was 62 years. Three cases (38%) presented with obstructive hydrocephalus due to aqueduct obstruction caused by an engorged vein of Galen. In all cases, feeders from dural arteries were present and the vein of Galen was the primary drainer. All patients underwent stereotactic radiosurgery. Five patients were followed for > two years; nidus obliteration was confirmed in one, and > 75% shrinkage was confirmed in three, while one patient died due to hemorrhage. Altogether, AVMs arising in the Galenic region are rare and exhibit several peculiar characteristics including the presence of dural feeders, an older age at presentation and presentation with obstructive hydrocephalus.