Explore the vast range of titles available.

The current standard of diagnosing central nervous system (CNS) lymphoma is stereotactic biopsy, however the procedure has a risk of surgical complication. Liquid biopsy of the CSF is a less invasive, non‐surgical method that can be used for diagnosing CNS lymphoma. In this study, we established a clinically applicable protocol for determining mutations in MYD88 in the CSF of patients with CNS lymphoma. CSF was collected prior to the start of chemotherapy from 42 patients with CNS lymphoma and matched tumor specimens. Mutations in MYD88 in 33 tumor samples were identified using pyrosequencing. Using 10 ng each of cellular DNA and cell‐free DNA (cfDNA) extracted from the CSF, the MYD88 L265P mutation was detected using digital PCR. The conditions to judge mutation were rigorously determined. The median Target/Total value of cases with MYD88 mutations in the tumors was 5.1% in cellular DNA and 22.0% in cfDNA. The criteria to judge mutation were then determined, with a Target/Total value of 0.25% as the cutoff. When MYD88 mutations were determined based on these criteria, the sensitivity and specificity were 92.2% and 100%, respectively, with cellular DNA; and the sensitivity and specificity were 100% with cfDNA. Therefore, the DNA yield, mutated allele fraction, and accuracy were significantly higher in cfDNA compared with that in cellular DNA. Taken together, this study highlights the importance of detecting the MYD88 L265P mutation in cfDNA of the CSF for diagnosing CNS lymphoma using digital PCR, a highly accurate and clinically applicable method. Development of a liquid biopsy for less invasive diagnosis of CNS lymphoma is in progress. In this study, the conditions for detecting the MYD88 L265P mutation by digital PCR were set, and extremely high accuracy was confirmed. This method is fully clinically feasible.

The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) update 3 recommends that histologic grade II and III IDH-wildtype diffuse astrocytic gliomas that harbor EGFR amplification, the combination of whole chromosome 7 gain and whole chromosome 10 loss (7 + /10 −), or TERT promoter (pTERT) mutations should be considered as glioblastomas (GBM), World Health Organization grade IV. In this retrospective study, we examined the utility of molecular classification based on pTERT status and copy-number alterations (CNAs) in IDH-wildtype lower grade gliomas (LGGs, grade II, and III). The impact on survival was evaluated for the pTERT mutation and CNAs, including EGFR gain/amplification, PTEN loss, CDKN2A homozygous deletion, and PDGFRA gain/amplification. We analyzed 46 patients with IDH-wildtype/pTERT-mutant (mut) LGGs and 85 with IDH-wildtype/pTERT-wildtype LGGs. EGFR amplification and a combination of EGFR gain and PTEN loss (EGFR + /PTEN −) were significantly more frequent in pTERT-mut patients (p < 0.0001). Cox regression analysis showed that the pTERT mutation was a significant predictor of poor prognosis (hazard ratio [HR] 2.79, 95% confidence interval [CI] 1.55–4.89, p = 0.0008), but neither EGFR amplification nor EGFR + /PTEN − was an independent prognostic factor in IDH-wildtype LGGs. PDGFRA gain/amplification was a significant poor prognostic factor in IDH-wildtype/pTERT-wildtype LGGs (HR 2.44, 95% CI 1.09–5.27, p = 0.03, Cox regression analysis). The IDH-wildtype LGGs with either pTERT-mut or PDGFRA amplification were mostly clustered with GBM by DNA methylation analysis. Thus, our study suggests that analysis of pTERT mutation status is necessary and sufficient to diagnose IDH-wildtype diffuse astrocytic gliomas with molecular features of glioblastoma. The PDGFRA status may help further delineate IDH-wildtype/pTERT-wildtype LGGs. Methylation profiling showed that IDH-wildtype LGGs without molecular features of GBM were a heterogeneous group of tumors. Some of them did not fall into existing categories and had significantly better prognoses than those clustered with GBM.

Primary central nervous system lymphoma (PCNSL) is a rare malignancy confined to the central nervous system (CNS), and majority of PCNSL is pathologically classified as diffuse large B-cell lymphoma (DLBCL). We have now performed whole-exome sequencing for 41 tumor tissues of DLBCL-type PCNSL and paired normal specimens and also RNA-sequencing for 30 tumors, revealing a very high frequency of nonsynonymous somatic mutations in PIM1 (100 %), BTG2 (92.7 %), and MYD88 (85.4 %). Many genes in the NF-κB pathway are concurrently mutated within the same tumors. Further, focal deletion or somatic mutations in the HLA genes are associated with poor prognosis. Copy number amplification and overexpression of genes at chromosome 7q35 were both found to predict short progression-free survival as well. Oncogenic mutations in GRB2 were also detected, the effects of which in cultured cells were attenuated by inhibitors of the downstream kinases MAP2K1 and MAP2K2. Individuals with tumors positive for MYD88 mutations also harbored the same mutations at a low frequency in peripheral blood mononuclear cells, suggesting that MYD88 mutation-positive precancerous cells originate outside of the CNS and develop into lymphoma after additional genetic hits that confer adaptation to the CNS environment.

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). INTELLANCE‐J was a phase 1/2 study of a potent antibody‐drug conjugate targeting epidermal growth factor receptor (EGFR), depatuxizumab mafodotin, as a second‐ or first‐line therapy, alone or combined with chemotherapy or chemoradiotherapy in Japanese patients with World Health Organization grade III/IV glioma. The results of this trial demonstrate an acceptable safety profile of depatuxizumab mafodotin, with ocular side effects being the most common adverse events that were mostly reversible. Second‐line depatuxizumab mafodotin in combination with temozolomide resulted in a 6‐month progression‐free survival estimate of 25.6% (95% confidence interval 11.4‒42.6) in patients with EGFR‐amplified tumors and showed encouraging antitumor activity in this subgroup of patients (NCT02590263).

CD44 has been postulated as a cell surface coreceptor for augmenting receptor tyrosine kinase (RTK) signaling. However, how exactly CD44 triggers RTK-dependent signaling remained largely unclear. Here we report an unexpected mechanism by which the CD44s splice isoform is internalized into endosomes to attenuate EGFR degradation. We identify a CD44s-interacting small GTPase, Rab7A, and show that CD44s inhibits Rab7A-mediated EGFR trafficking to lysosomes and subsequent degradation. Importantly, CD44s levels correlate with EGFR signature and predict poor prognosis in glioblastomas. Because Rab7A facilitates trafficking of many RTKs to lysosomes, our findings identify CD44s as a Rab7A regulator to attenuate RTK degradation.

The prognostic impact of TERT mutations has been controversial in IDH -wild tumors, particularly in glioblastomas (GBM). The controversy may be attributable to presence of potential confounding factors such as MGM T methylation status or patients’ treatment. This study aimed to evaluate the impact of TERT status on patient outcome in association with various factors in a large series of adult diffuse gliomas. We analyzed a total of 951 adult diffuse gliomas from two cohorts (Cohort 1, n  = 758; Cohort 2, n  = 193) for IDH1/2 , 1p/19q, and TERT promoter status. The combined IDH/TERT classification divided Cohort 1 into four molecular groups with distinct outcomes. The overall survival (OS) was the shortest in IDH wild-type/ TERT mutated groups, which mostly consisted of GBMs ( P  < 0.0001). To investigate the association between TERT mutations and MGMT methylation on survival of patients with GBM, samples from a combined cohort of 453 IDH -wild-type GBM cases treated with radiation and temozolomide were analyzed. A multivariate Cox regression model revealed that the interaction between TERT and MGMT was significant for OS ( P  = 0.0064). Compared with TERT mutant- MGMT unmethylated GBMs, the hazard ratio (HR) for OS incorporating the interaction was the lowest in the TERT mutant- MGMT methylated GBM (HR, 0.266), followed by the TERT wild-type- MGMT methylated (HR, 0.317) and the TERT wild-type- MGMT unmethylated GBMs (HR, 0.542). Thus, patients with TERT mutant- MGMT unmethylated GBM have the poorest prognosis. Our findings suggest that a combination of IDH , TERT , and MGMT refines the classification of grade II-IV diffuse gliomas.

Abstract BACKGROUND Wearable devices with heads-up displays or smart glasses can overlay images onto the sight of the wearer. This technology has never been applied to surgical navigation. OBJECTIVE To assess the applicability and accuracy of smart glasses for augmented reality (AR)-based neurosurgical navigation. METHODS Smart glasses were applied to AR-based neurosurgical navigation. Three-dimensional computer graphics were created based on preoperative magnetic resonance images and visualized in see-through smart glasses. Optical markers were attached to the smart glasses and the patient's head for accurate navigation. Two motion capture cameras were used for registration and continuous monitoring of the location of the smart glasses in relation to the patient's head. After the accuracy was assessed with a phantom, this technique was applied in 2 patients with brain tumors located in the brain surface. RESULTS A stereoscopic view by image overlay through the smart glasses was successful in the phantom and in both patients. Hands-free neuronavigation inside the operative field was available from any angles and distances. The targeting error in the phantom measured in 75 points ranged from 0.2 to 8.1 mm (mean 3.1 ± 1.9 mm, median 2.7 mm). The intraoperative targeting error between the visualized and real locations in the 2 patients (measured in 40 points) ranged from 0.6 to 4.9 mm (mean 2.1 ± 1.1 mm, median 1.8 mm). CONCLUSION Smart glasses enabled AR-based neurosurgical navigation in a hands-free fashion. Stereoscopic computer graphics of targeted brain tumors corresponding to the surgical field were clearly visualized during surgery.

We have previously reported that 12p gain may predict the presence of malignant components and poor prognosis for CNS germ cell tumor (GCT). Recently, 3p25.3 gain was identified as an independent predictor of poor prognosis for testicular GCT. Eighty-one CNS GCTs were analyzed. Copy number was calculated using methylation arrays. Five cases (6.2%) showed 3p25.3 gain, but only among the 40 non-germinomatous GCTs (NGGCTs) (5/40, 12.5%; p  = 0.03). Among NGGCTs, those with a yolk sac tumor component showed a significantly higher frequency of 3p25.3 gain (18.2%) than those without (1.5%; p  = 0.048). NGGCTs with gain showed significantly shorter progression-free survival (PFS) than those without ( p  = 0.047). The 3p25.3 gain and 12p gain were independent from each other. The combination of 3p25.3 gain and/or 12p gain was more frequent among NGGCTs with malignant components (69%) than among those without (29%; p  = 0.02). Germinomas containing a higher number of copy number alterations showed shorter PFS than those with fewer ( p  = 0.03). Taken together, a finding of 3p25.3 gain may be a copy number alteration specific to NGGCTs and in combination with 12p gain could serve as a marker of negative prognosis or treatment resistance. Germinoma with frequent chromosomal instability may constitute an unfavorable subgroup.

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.