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Homozygous deletion (HD) of CDKN2A is one of the most promising biomarkers for predicting poor prognosis of IDH-mutant diffuse gliomas. The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) recommendations propose that IDH-mutant lower-grade astrocytomas with CDKN2A/B HD be classified as grade IV tumors. Loss of methylthioadenosine phosphorylase (MTAP) immunohistochemistry staining has been proposed as a surrogate of CDKN2A HD in various tumors but its performance has not been fully investigated in diffuse glioma. This study determined whether MTAP immunoreactivity could serve as a proxy for CDKN2A HD in adult-type diffuse glioma, thereby contributing to stratifying patient outcome. MTAP immunohistochemistry staining using clone EPR6893 was scored in 178 diffuse glioma specimens consisting of 77 IDH-mutant astrocytomas, 13 IDH-mutant oligodendrogliomas, and 88 IDH-wildtype glioblastomas. The use of MTAP immunohistochemical deficiency to predict CDKN2A HD was good for IDH-mutant astrocytomas (sensitivity, 88%; specificity, 98%) and IDH-wildtype glioblastomas (sensitivity, 89%; specificity, 100%), but poor for IDH-mutant oligodendrogliomas (sensitivity, 67%; specificity, 57%). Both CDKN2A HD and MTAP immunohistochemical deficiency were significant adverse prognostic factors of overall survival for IDH-mutant astrocytoma (P < 0.001 each), but neither were prognostically significant for oligodendroglioma or IDH-wildtype glioblastoma. IDH-mutant lower-grade astrocytoma with CDKN2A HD and deficient MTAP immunoreactivity exhibited overlapping unfavorable outcome with IDH-mutant glioblastoma. MTAP immunostaining was easily interpreted in 61% of the cases tested, but scoring required greater care in the remaining cases. An alternative MTAP antibody clone (2G4) produced identical scoring results in all but 1 case, and a slightly larger proportion (66%) of cases were considered easy to interpret compared to using EPR6893. In summary, loss of MTAP immunoreactivity could serve as a reasonable predictive surrogate for CDKN2A HD in IDH-mutant astrocytomas and IDH-wildtype glioblastomas and could provide significant prognostic value for IDH-mutant astrocytoma, comparable to CDKN2A HD.

Glioblastomas (GBM) often acquire resistance against temozolomide (TMZ) after continuous treatment and recur as TMZ‐resistant GBM (TMZ‐R‐GBM). Lomustine (CCNU) and nimustine (ACNU), which were previously used as standard therapeutic agents against GBM before TMZ, have occasionally been used for the salvage therapy of TMZ‐R‐GBM; however, their efficacy has not yet been thoroughly examined. Therefore, we investigated the antitumor effects of CCNU and ACNU against TMZ‐R‐GBM. As a model of TMZ‐R‐GBM, TMZ resistant clones of human GBM cell lines (U87, U251MG, and U343MG) were established (TMZ‐R‐cells) by the culture of each GBM cells under continuous TMZ treatment, and the antitumor effects of TMZ, CCNU, or ACNU against these cells were analyzed in vitro and in vivo. As a result, although growth arrest and apoptosis were triggered in all TMZ‐R‐cells after the administration of each drug, the antitumor effects of TMZ against TMZ‐R‐cells were significantly reduced compared to those of parental cells, whereas CCNU and ACNU demonstrated efficient antitumor effects on TMZ‐R‐cells as well as parental cells. It was also demonstrated that TMZ resistance of TMZ‐R‐cells was regulated at the initiation of DNA damage response. Furthermore, survival in mice was significantly prolonged by systemic treatment with CCNU or ACNU but not TMZ after implantation of TMZ‐R‐cells. These findings suggest that CCNU or ACNU may serve as a therapeutic agent in salvage treatment against TMZ‐R‐GBM. We investigated the antitumor effects of lomustine (CCNU) and nimustine (ACNU), which were previously used as standard therapeutic agents for glioblastomas (GBM), against the model cells of human GBM cases, which gained acquired temozolomide (TMZ) resistance after continuous treatment by TMZ (TMZ‐R‐cells). We discovered that the antitumor effects of TMZ against TMZ‐R‐cells were significantly reduced compared to those of parental cells, whereas CCNU and ACNU demonstrated efficient antitumor effects on TMZ‐R‐cells as well as parental cells both in vitro and in vivo. In addition, it was also demonstrated that TMZ resistance of TMZ‐R‐cells was regulated at the level of DNA damage response initiation. These findings suggest that CCNU or ACNU may serve as a therapeutic agent in salvage treatment against GBM cases with acquired TMZ resistance.

Next‐generation sequencing (NGS) of tumor tissue (ie, clinical sequencing) can guide clinical management by providing information about actionable gene aberrations that have diagnostic and therapeutic significance. Here, we undertook a hospital‐based prospective study (TOP‐GEAR project, 2nd stage) to investigate the feasibility and utility of NGS‐based analysis of 114 cancer‐associated genes (the NCC Oncopanel test). We examined 230 cases (comprising more than 30 tumor types) of advanced solid tumors, all of which were matched with nontumor samples. Gene profiling data were obtained for 187 cases (81.3%), 111 (59.4%) of which harbored actionable gene aberrations according to the Clinical Practice Guidelines for Next Generation Sequencing in Cancer Diagnosis and Treatment (Edition 1.0) issued by 3 major Japanese cancer‐related societies. Twenty‐five (13.3%) cases have since received molecular‐targeted therapy according to their gene aberrations. These results indicate the utility of tumor‐profiling multiplex gene panel testing in a clinical setting in Japan. This study is registered with UMIN Clinical Trials Registry (UMIN 000011141). The results of the TOP‐GEAR project (UMIN 000011141) indicate the utility of tumor‐profiling multiplex gene panel testing in a clinical setting in Japan.

Synovial sarcoma is characterized by variable epithelial differentiation and specific SS18 - SSX gene fusions. The diagnosis is primarily based on phenotype, but fusion gene detection is increasingly being considered indispensable, with SS18 break-apart fluorescence in situ hybridization (FISH) being favored in many laboratories. However, SS18 FISH assay produces negative or atypical results in a minority of cases, leaving uncertainties in diagnosis and management. Here, we analyzed this challenging subset of SS18 FISH-negative/atypical synovial sarcoma using RNA sequencing and monoclonal antibodies that recognize SS18-SSX and the SSX C-terminus. Among 99 synovial sarcoma cases that were previously subjected to SS18 break-apart FISH, eight cases were reported as negative and three cases were indeterminate, owing to atypical signal patterns. Three of these 11 tumors (two monophasic and one biphasic) harbored novel EWSR1 - SSX1 fusions, were negative for SS18-SSX staining, and were positive for SSX C-terminus staining. One monophasic tumor harbored a novel MN1 - SSX1 fusion, and showed negative SS18-SSX expression and positive SSX C-terminus staining. Another monophasic tumor carried an SS18L1 - SSX1 fusion, and was weakly positive for SS18-SSX, while SMARCB1 expression was reduced. The presence of these novel and/or rare fusions was confirmed using RT-PCR and Sanger sequencing. EWSR1-SSX1 was further validated by EWSR1 FISH assay. The remaining six tumors (five monophasic and one biphasic) showed strong SS18-SSX expression, and RNA sequencing successfully performed in three cases identified canonical SS18 - SSX2 fusions. Based on a DNA methylation-based unsupervised clustering, the tumors with EWSR1-SSX1 and SS18L1-SSX1 clustered with synovial sarcoma, while the MN1-SSX1 -positive tumor was not co-clustered despite classic histology and immunoprofile. In summary, we discovered novel and rare SSX1 fusions to non- SS18 genes in synovial sarcoma. The expanded genetic landscape carries significant diagnostic implications and advances our understanding of the oncogenic mechanism.

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.

CIC-rearranged sarcoma is characterized by round cell undifferentiated histology, frequent expression of ETV4 and WT1, and aggressive behavior. A clinical encounter of a case with CIC-DUX4 fusion and ERG/CD31 co-expression prompted us to systematically investigate ERG and CD31 expression status in 30 archival cases of CIC-rearranged sarcoma. Half (15) of them showed moderate or strong ERG expression in <5–100% of tumor cells, among which nine showed heterogeneous membranous CD31 reactivity, including four cases each showing diffuse or strong expression. None of them showed uniformly strong and diffuse ERG/CD31 co-expression; however, three cases were initially interpreted and treated as angiosarcoma without response. Except for smaller superficial tumor enrichment, the clinicopathological characteristics of these nine cases of ERG+/CD31+ CIC-rearranged sarcoma did not differ from those of remaining 21 cases. Five showed focal hemorrhagic clefts/cysts, mimicking vascular spaces. All tumors expressed ETV4 and/or nuclear WT1, and fusion to DUX4 was confirmed in seven cases. Four tumors examined by next-generation sequencing harbored no CIC missense mutations. Using DNA methylation profiling, one CD31+ CIC-rearranged sarcoma was clustered with CD31− CIC-rearranged sarcomas, but distant from angiosarcomas. When compared with epithelioid angiosarcomas lacking CIC rearrangements, ERG+/CD31+ CIC-rearranged sarcomas were distinguished by focal myxoid change and the entire lack of vasoformative architecture. The angiosarcomas were characterized by uniform strong expression of ERG and CD31, but none of them were found positive for ETV4 or nuclear WT1. Heterogeneous ERG/CD31 co-expression in a subset of CIC-rearranged sarcoma is a clinically relevant pitfall for angiosarcoma, as these two diseases are treated differently.

Glioblastoma is the most common and devastating type of malignant brain tumor. We recently found that eribulin suppresses glioma growth in vitro and in vivo and that eribulin is efficiently transferred into mouse brain tumors at a high concentration. Eribulin is a non‐taxane microtubule inhibitor approved for breast cancer and liposarcoma. Cells arrested in M‐phase by chemotherapeutic agents such as microtubule inhibitors are highly sensitive to radiation‐induced DNA damage. Several recent case reports have demonstrated the clinical benefits of eribulin combined with radiation therapy for metastatic brain tumors. In this study, we investigated the efficacy of a combined eribulin and radiation treatment on human glioblastoma cells. The glioblastoma cell lines U87MG, U251MG and U118MG, and SJ28 cells, a patient‐derived sphere culture cell line, were used to determine the radiosensitizing effect of eribulin using western blotting, flow cytometry and clonogenic assay. Subcutaneous and intracerebral glioma xenografts were generated in mice to assess the efficacy of the combined treatment. The combination of eribulin and radiation enhanced DNA damage in vitro. The clonogenic assay of U87MG demonstrated the radiosensitizing effect of eribulin. The concomitant eribulin and radiation treatment significantly prolonged the survival of mice harboring intracerebral glioma xenografts compared with eribulin or radiation alone (P < .0001). In addition, maintenance administration of eribulin after the concomitant treatment further controlled brain tumor growth. Aberrant microvasculature was decreased in these tumors. Concomitant treatment with eribulin and radiation followed by maintenance administration of eribulin may serve as a novel therapeutic strategy for glioblastomas. Glioblastoma is the most malignant brain tumor for which no effective treatment is currently available. We showed that eribulin is a radiosensitizer and a concomitant eribulin and radiation treatment followed by maintenance eribulin administration significantly prolonged survival of brain tumor‐bearing mice compared with the eribulin or radiation monotherapy. We propose that a combined eribulin and radiation treatment as a new therapeutic strategy for glioblastoma.

Glioblastoma (GBM) is the most common, but extremely malignant, brain tumor; thus, the development of novel therapeutic strategies for GBMs is imperative. Many tyrosine kinase inhibitors (TKIs) have been approved for various cancers, yet none has demonstrated clinical benefit against GBM. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that is confirmed only during the embryonic development period in humans. In addition, various ALK gene alterations are known to act as powerful oncogenes and therapeutic targets in various tumors. The antitumor activity of various TKIs was tested against three human GBM cell lines (U87MG, LN229, and GSC23), which expressed substantially low ALK levels; second‐generation ALK inhibitors, alectinib and ceritinib, effectively induced GBM cell death. In addition, treatment with either alectinib or ceritinib modulated the activation of various molecules downstream of RTK signaling and induced caspase‐dependent/‐independent cell death mainly by inhibiting signal transducer and activator of transcription 3 activation in human GBM cells. In addition, alectinib and ceritinib also showed antitumor activity against a U87MG cell line with acquired temozolomide resistance. Finally, oral administration of alectinib and ceritinib prolonged the survival of mice harboring intracerebral GBM xenografts compared with controls. These results suggested that treatment with the second‐generation ALK inhibitors, alectinib and ceritinib, might serve as a potent therapeutic strategy against GBM. Anaplastic lymphoma kinase (ALK) inhibitors, alectinib and ceritinib, demonstrated antitumor activity for glioblastoma (GBM) cells which expressed substantially low ALK levels in vitro and in vivo. Treatment with either alectinib or ceritinib induced cell death mainly by inhibiting signal transducer and activator of transcription 3 activation in GBM cells. Alectinib and ceritinib might serve as potent therapeutic agents against GBM.

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with poor prognosis. We investigated intratumoral deoxyribonucleic acid methylation heterogeneity by analyzing 44 tumor samples and 5 normal samples from 6 cases of PDAC by using high-resolution methylation arrays. Two distinct methylation profiles were identified: T1, which is similar to normal pancreatic tissue and is associated with well-differentiated histology, and T2, which is significantly different from normal tissue and is linked to poorly differentiated morphology and squamous features. Validation using The Cancer Genome Atlas (TCGA) confirmed these profiles and revealed the association of T2 with shorter disease-free survival ( p  = 0.04). Differentially methylated region analysis identified the substantial hypomethylation of transcription regulation genes in T2 profiles (false discovery rate [FDR] q < 0.001). Gene set enrichment analysis with TCGA gene expression data demonstrated the upregulation of DNA repair and MYC target genes in T2 samples (FDR q < 0.001). Phylogenetic analysis with our multi-sampling dataset suggested an evolutionary trajectory from T1 to T2 profiles coinciding with aggressive phenotypes and increased genomic instability. Cases exhibited varying degrees of intratumoral heterogeneity from distinctly separated clusters to minimal differences. This comprehensive characterization of the epigenetic landscape of PDAC provides insights into tumor evolution and heterogeneity with potential implications for patient stratification and the development of epigenetic-based diagnostic and therapeutic strategies.

Nelarabine is an effective treatment for T-cell acute lymphoblastic leukemia/lymphoma. Myelopathy is a rare but serious adverse event associated with this drug. Three patients who received nelarabine at the National Cancer Center Hospital from December 2014 to March 2021 developed myelopathy 20 days before, 12 days after, and 29 days after allogeneic hematopoietic cell transplantation (allo-HCT), respectively. Magnetic resonance imaging showed that two of the patients had lesions in the dorsal column or medulla oblongata, and one had no abnormalities in the head or spine. Despite treatment with intravenous immunoglobulin and methylprednisolone, all patients became unable to walk. One patient died on day 101 after allo-HCT due to progressive neurotoxicity. The other two patients showed spontaneous improvement in neurological symptoms, but one died of mucormycosis on day 476. Autopsy revealed spongiosis in the posterior funiculus in both patients who died, and also in the medulla oblongata in one patient. In the surviving patient, positron emission tomography on day 84 showed abnormal accumulation, suggesting continued inflammation. These cases demonstrated pathophysiological features of nelarabine-induced myelopathy and indicate that allo-HCT may worsen the condition. It is necessary to elucidate the underlying mechanism and establish diagnostic methods and therapies.