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Adult diffuse gliomas form a heterogeneous group of tumors of the central nervous system that vary greatly in histology and prognosis. A significant advance during the last decade has been the identification of a set of genetic lesions that correlate well with histology and clinical outcome in diffuse gliomas. Most characteristic driver mutations consist of isocitrate dehydrogenase 1 ( IDH1 ) and IDH2 , and H3 histone family member 3A , which are strongly associated with DNA and histone methylation patterns. A well-characterized DNA methylation aberration is on the O6-methylguanine-DNA methyltransferase promoter. This aberration is associated with an improved response to the DNA alkylating agent, temozolomide. Methylation alterations are used for classification or treatment decisions of diffuse gliomas. This supports the importance of considering epigenomic aberrations in the pathogenesis of gliomas. Recent DNA methylation analyses revealed a small group of IDH mutant diffuse gliomas exhibiting decreased DNA hypermethylation resulting in substantial unfavorable prognosis comparable to glioblastoma. Thus, DNA methylation patterns may become a new standard that replaces the conventional grading system based on histological diagnosis. In this review, we summarize recent developments regarding the contributions of methylation patterns to the pathogenesis of adult diffuse glioma, the interactions between methylation patterns and driver mutations, and potential epigenomic targeted therapies.

Seishi Ogawa, Atsushi Natsume and colleagues report analyses of large sets of sequence data of grade II and III gliomas. They find three distinct subtypes of grade II and III gliomas characterized by discrete mutation profiles and distinct clinical behaviors. Grade II and III gliomas are generally slowly progressing brain cancers, many of which eventually transform into more aggressive tumors. Despite recent findings of frequent mutations in IDH1 and other genes, knowledge about their pathogenesis is still incomplete. Here, combining two large sets of high-throughput sequencing data, we delineate the entire picture of genetic alterations and affected pathways in these glioma types, with sensitive detection of driver genes. Grade II and III gliomas comprise three distinct subtypes characterized by discrete sets of mutations and distinct clinical behaviors. Mutations showed significant positive and negative correlations and a chronological hierarchy, as inferred from different allelic burdens among coexisting mutations, suggesting that there is functional interplay between the mutations that drive clonal selection. Extensive serial and multi-regional sampling analyses further supported this finding and also identified a high degree of temporal and spatial heterogeneity generated during tumor expansion and relapse, which is likely shaped by the complex but ordered processes of multiple clonal selection and evolutionary events.

The myeloid differentiation primary response gene 88 (MYD88) L265P mutation is a disease‐specific mutation of primary central nervous system lymphoma (PCNSL) among the central nervous system tumors. Accordingly, this mutation is considered a reliable diagnostic molecular marker of PCNSL. As the intra‐operative diagnosis of PCNSL is sometimes difficult to achieve using histological examinations alone, intra‐operative detection of the MYD88 L265P mutation could be effective for the accurate diagnosis of PCNSL. Herein, we aimed to develop a novel rapid genotyping system (GeneSoC) using real‐time polymerase chain reaction (PCR) based on microfluidic thermal cycling technology. This real‐time PCR system shortened the analysis time, which enabled the detection of the MYD88 L265P mutation within 15 min. Rapid detection of the MYD88 L265P mutation was performed intra‐operatively using GeneSoC in 24 consecutive cases with suspected malignant brain tumors, including 10 cases with suspected PCNSL before surgery. The MYD88 L265P mutation was detected in eight cases in which tumors were pathologically diagnosed as PCNSL after the operation, while wild‐type MYD88 was detected in 16 cases. Although two of the 16 cases with wild‐type MYD88 were pathologically diagnosed as PCNSL after the operation, MYD88 L265P could be detected in all eight PCNSL cases harboring MYD88 L265P. The MYD88 L265P mutation could also be detected using cell‐free DNA derived from the cerebrospinal fluid of two PCNSL cases. Detection of the MYD88 L265P mutation using GeneSoC might not only improve the accuracy of intra‐operative diagnosis of PCNSL but also help the future pre‐operative diagnosis through liquid biopsy of cerebrospinal fluid. In this manuscript, we developed a rapid genotyping system using a real‐time PCR device (GeneSoC), which could detect MYD88 L265P within 15 min. We could detect MYD88 L265P in 8 PCNSL cases during surgery. The MYD88 L265P mutation could also be detected using cell‐free DNA derived from the cerebrospinal fluid of two PCNSL cases.

Cushing's syndrome is caused by excess cortisol production from the adrenocortical gland. In corticotropin-independent Cushing's syndrome, the excess cortisol production is primarily attributed to an adrenocortical adenoma, in which the underlying molecular pathogenesis has been poorly understood. We report a hotspot mutation (L206R) in PRKACA, which encodes the catalytic subunit of cyclic adenosine monophosphate (cAMP)–dependent protein kinase (PKA), in more than 50% of cases with adrenocortical adenomas associated with corticotropin-independent Cushing's syndrome. The L206R PRKACA mutant abolished its binding to the regulatory subunit of PKA (PRKAR1A) that inhibits catalytic activity of PRKACA, leading to constitutive, cAMP-independent PKA activation. These results highlight the major role of cAMP-independent activation of cAMP/PKA signaling by somatic mutations in corticotropin-independent Cushing's syndrome, providing insights into the diagnosis and therapeutics of this syndrome.

PurposeThe aim of this study was to assess the effect of the extent of resection (EOR) of tumors on survival in a series of patients with grade II and III gliomas (GII/III-gliomas) who underwent awake brain mapping.MethodsWe retrospectively analyzed 126 patients with GII/III-gliomas in the dominant and non-dominant hemisphere who underwent awake brain surgery at the same institution between December 2012 and May 2020.ResultsEOR cut-off values for improved progression-free survival (PFS) were determined by a receiver operator characteristic (ROC) analysis of 5-year PFS. The ROC for EOR showed a cut-off value of ≥ 85.3%. The median PFS rate of patients with GII/III-gliomas in the group with an EOR ≥ 100%, including supratotal resection (n = 47; median survival [MS], not reached), was significantly higher than that in the group with an EOR < 90% (n = 52; MS, 43.1 months; 95% CI 37.7–48.5 months; p = 0.03). In patients with diffuse astrocytomas and anaplastic astrocytomas, the group with EOR ≥ 100%, including supratotal resection (n = 25; MS, not reached), demonstrated a significantly better PFS rate than did the group with an EOR < 100% (n = 45; MS, 35.8 months; 95% CI 19.9–51.6 months; p = 0.03). Supratotal or gross total resection was correlated with better PFS in IDH-mutant type of diffuse astrocytomas and anaplastic astrocytomas (n = 19; MS, not reached vs. n = 35; MS, 40.6 months; 95% CI 22.3–59.0 months; p = 0.02). By contrast, supratotal or gross total resection was not associated with longer PFS rates in patients with IDH-wild type of diffuse astrocytomas and anaplastic astrocytomas.ConclusionsThe present study demonstrates a significant association between tumor EOR and survival in patients with GII/III gliomas. The EOR cut-off value for 5-year PFS was ≥ 85.3%. It is noteworthy that supratotal or gross total resection significantly correlated with better PFS in IDH-mutant type of WHO grade II and III astrocytic tumors. In light of our finding that EOR did not correlate with PFS in patients with aggressive IDH-wild type of diffuse astrocytomas and anaplastic astrocytomas, we suggest treatments that are more intensive will be needed for the control of these tumors.

We aimed to investigate clinical parameters that affected the results of navigated repetitive transcranial magnetic stimulation (nrTMS) language mapping by comparing the results of preoperative nrTMS language mapping with those of direct cortical stimulation (DCS) mapping. In the prospective, non-randomized study, patients had to meet all of the following inclusion criteria: the presence of left- or right-side brain tumors in the vicinity of or inside the areas anatomically associated with language functions; awake brain surgery scheduled; and age >18 years. Sixty one patients were enrolled, and this study included 42 low-grade gliomas and 19 high-grade gliomas (39 men, 22 women; mean age, 41.1 years, range 18–72 years). The tumor was located in the left and right hemisphere in 50 (82.0%) and 11 (18.0%) patients, respectively. In the 50 patients with left-side gliomas, nrTMS language mapping showed 81.6% sensitivity, 59.6% specificity, 78.5% positive predictive value, and 64.1% negative predictive value when compared with the respective DCS values for detecting language sites in all regions. We then investigated how some parameters, including age, tumor type, tumor volume, and the involvement of anatomical language-related regions, affected different subpopulations. Based on the receiver operating curve statistics, subgroup analysis showed that the non-involvement of language-related regions afforded significantly better the area under the curve (AUC) values (AUC = 0.81, 95% confidence interval (CI): 0.74–0.88) than the involvement of language-related regions (AUC = 0.58, 95% CI: 0.50–0.67; p  < 0.0001). Our findings suggest that nrTMS language mapping could be a reliable method, particularly in obtaining responses for cases without tumor-involvement of classical perisylvian language areas.

Adult-type diffuse gliomas are divided into Astrocytoma, IDH-mutant, Oligodendroglioma, IDH-mutant and 1p/19q-codeleted and Glioblastoma, IDH-wildtype based on the IDH mutation, and 1p/19q codeletion status. To determine the treatment strategy for these tumors, pre-operative prediction of IDH mutation and 1p/19q codeletion status might be effective. Computer-aided diagnosis (CADx) systems using machine learning have been noted as innovative diagnostic methods. However, it is difficult to promote the clinical application of machine learning systems at each institute because the support of various specialists is essential. In this study, we established an easy-to-use computer-aided diagnosis system using Microsoft Azure Machine Learning Studio (MAMLS) to predict these statuses. We constructed an analysis model using 258 adult-type diffuse glioma cases from The Cancer Genome Atlas (TCGA) cohort. Using MRI T2-weighted images, the overall accuracy, sensitivity, and specificity for the prediction of IDH mutation and 1p/19q codeletion were 86.9%, 80.9%, and 92.0%, and 94.7%, 94.1%, and 95.1%, respectively. We also constructed an reliable analysis model for the prediction of IDH mutation and 1p/19q codeletion using an independent Nagoya cohort including 202 cases. These analysis models were established within 30 min. This easy-to-use CADx system might be useful for the clinical application of CADx in various institutes.

Isocitrate dehydrogenase wild-type ( IDH wt) diffuse astrocytomas feature highly infiltrative patterns, such as a gliomatosis cerebri growth pattern with widespread involvement. Among these tumors, localized IDH wt histologically diffuse astrocytomas are rarer than the infiltrative type. The aim of this study was to assess and describe the clinical, radiographic, histopathological, and molecular characteristics of this rare type of IDH wt histologically diffuse astrocytomas and thereby provide more information on how its features affect clinical prognoses and outcomes. We retrospectively analyzed the records of five patients with localized IDH wt histologically diffuse astrocytomas between July 2017 and January 2020. All patients were female, and their mean age at the time of the initial treatment was 55.0 years. All patients had focal disease that did not include gliomatosis cerebri or multifocal disease. All patients received a histopathological diagnosis of diffuse astrocytomas at the time of the initial treatment. For recurrent tumors, second surgeries were performed at a mean of 12.4 months after the initial surgery. A histopathological diagnosis of glioblastoma was made in four patients and one of gliosarcoma in one patient. The initial status of IDH1 , IDH2 , H3F3A , HIST1H3B , and BRAF was “wild-type” in all patients. TERT promoter mutations (C250T or C228T) were detected in four patients. No tumors harbored a 1p/19q codeletion, EGFR amplification, or chromosome 7 gain/10 loss (+ 7/ − 10). We assessed clinical cases of localized IDH wt histologically diffuse astrocytomas that resulted in malignant recurrence and a poor clinical prognosis similar to that of glioblastomas. Our case series suggests that even in patients with histologically diffuse astrocytomas and those who present with radiographic imaging findings suggestive of a localized tumor mass, physicians should consider the possibility of IDH wt histologically diffuse astrocytomas.

This case of PJRT shows negative linking on ventriculoatrial intervals after atrial differential pacing. Interpreting the results of atrial differential pacing may be challenging in cases where the pacing site affects retrograde conduction or when retrograde conduction is unstable.