Sham-operation-controlled animal study to assess alterations in blood flow in the spinal cord in a chronic compression model. Laboratory investigation.
Cervical myelopathy is a common cause of ...disability in elderly patients. Hypothesis was made that ischemia subsequent to the spinal cord compression plays an important role in the pathogenesis of the spinal cord dysfunction. This study was undertaken to assess alterations in the blood flow of the spinal cord under chronic compression in a rat model.
Histologic study of spinal cord from patients with spondylotic myelopathy showed ischemic tissue changes. Experimentally, spinal cord hypoperfusion in combination with chronic spinal cord compression induced myelopathy in dogs. We previously showed that chronic compression of the spinal cord in rats produces gradual deterioration of mobility of the animals accompanied by cord tissue degeneration compatible with ischemic changes.
Chronic compression of the cervical spinal cord was implemented by implantation of a thin urethane polymer sheet under the C5-C6 laminae, which expands by absorbing tissue water over 48-72 hours. The control group underwent sham operation. Twelve weeks later, blood flow to the C3-C4 and C5-C6 spinal cord segments were measured by fluorescent microsphere methods.
In the control group, the blood flow in the C5-C6 segment was larger than C3-C4 segment. In the compression group, the blood flow in the C5-C6 was significantly reduced compared to the C3-C4 segment.
Under chronic focal spinal cord compression, there was a decrease of the blood flow in the compressed segment in comparison to the rostral segment. Our data are compatible with the hypothesis that alteration in the spinal cord blood flow contributes to pathogenesis of myelopathy.
Atypical teratoid/rhabdoid tumors (AT/RT) are rare, highly malignant neoplasms of the central nervous system that predominantly occur in infants, and are characterized by the presence of rhabdoid ...cells and inactivation of
INI1
or (extremely rarely)
BRG1
. The vast majority of AT/RT are recognized as primary tumors; however, rare AT/RT or INI1-deficient RT arising from other primary tumors have been reported. To better characterize secondary RT, we performed a histological and molecular analysis of four RT arising from pleomorphic xanthoastrocytoma (PXA), anaplastic PXA, low-grade astrocytoma, or ependymoma. Histologically, although conventional AT/RT are usually not largely composed of rhabdoid cells, three secondary RT were composed mainly of rhabdoid cells, two of which arising from (anaplastic) PXA exhibited marked nuclear pleomorphism reminiscent of that in the precursor lesions. Regarding
INI1
alterations, although mutations including small indels are frequent in conventional AT/RT, only in one secondary RT had a mutation. Moreover, together with previously reported cases, biallelic
INI1
inactivation in secondary RT was mostly due to biallelic focal and/or broad deletions. Although conventional AT/RT have stable chromosomal profiles, i.e., the frequency of copy number changes involving chromosomes other than chromosome 22 is remarkably low, our array comparative genomic hybridization analysis revealed numerous copy number changes in the secondary RT. In conclusion, secondary RT of the central nervous system are clinicopathologically and molecularly different from conventional pediatric AT/RT, and a nosological issue is whether these secondary RT should be called secondary “AT/RT” as most of the reported cases were.
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.
Even after the introduction of the WHO 2016 classification, heterogeneity within each category still exists, and the next challenges would include whether we can further refine subtyping of gliomas. Our analysis of 170 diffuse gliomas suggested that there appeared to be a subgroup of IDH‐mutated astrocytomas characterized by isolated 19q‐loss, oligodendroglial morphology and significantly better prognosis compared to other 19q‐intact astrocytomas, providing with a new genetic‐morphological‐clinical association that may characterize a small but distinct subtype within anaplastic astrocytoma.
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.
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.
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.
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.
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.
To elucidate the mechanisms of malignant progression of lower-grade glioma, molecular profiling using methylation array, whole-exome sequencing, and RNA sequencing was performed for 122, 36 and 31 ...gliomas, respectively. This cohort included 24 matched pairs of initial lower-grade gliomas and recurrent tumors, most of which showed malignant progression. Nearly half of IDH-mutant glioblastomas that had progressed from lower-grade gliomas exhibited characteristic partial DNA demethylation in previously methylated genomic regions of their corresponding initial tumors, which had the glioma CpG island methylator phenotype (G-CIMP). In these glioblastomas, cell cycle-related genes, RB and PI3K-AKT pathway genes were frequently altered. Notably, late-replicating domain was significantly enriched in the demethylated regions that were mostly located in non-regulatory regions, suggesting that the loss of DNA methylation during malignant transformation may involve mainly passive demethylation due to a delay in maintenance of methylation during accelerated cell division. Nonetheless, a limited number of genes including IGF2BP3, which potentially drives cell proliferation, were presumed to be upregulated due to demethylation of their promoter. Our data indicated that demethylation of the G-CIMP profile found in a subset of recurrent gliomas reflects accelerated cell divisions accompanied by malignant transformation. Oncogenic genes activated by such epigenetic change represent potential therapeutic targets.
Immune-based therapies have shown limited efficacy in glioma thus far. This might be at least in part due to insufficient numbers of neoantigens, thought to be targets of immune attack. In addition, ...we hypothesized that dynamic genetic and epigenetic tumor evolution in gliomas might also affect the mutation/neoantigen landscape and contribute to treatment resistance through immune evasion. Here, we investigated changes in the neoantigen landscape and immunologic features during glioma progression using exome and RNA-seq of paired primary and recurrent tumor samples obtained from 25 WHO grade II-IV glioma patients (glioblastoma, IDH-wild-type,
= 8; grade II-III astrocytoma, IDH-mutant,
= 9; and grade II-III oligodendroglioma, IDH-mutant, 1p/19q-codeleted,
= 8). The number of missense mutations, predicted neoantigens, or expressed neoantigens was not significantly different between primary and recurrent tumors. However, we found that in individual patients the ratio of expressed neoantigens to predicted neoantigens, designated the "neoantigen expression ratio," decreased significantly at recurrence (
= 0.003). This phenomenon was particularly pronounced for "high-affinity," "clonal," and "passenger gene-derived" neoantigens. Gene expression and IHC analyses suggested that the decreased neoantigen expression ratio was associated with intact antigen presentation machinery, increased tumor-infiltrating immune cells, and ongoing immune responses. Our findings imply that decreased expression of highly immunogenic neoantigens, possibly due to persistent immune selection pressure, might be one of the immune evasion mechanisms along with tumor clonal evolution in some gliomas.
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