記述言語：英語   出版者・発行元：Neuro Oncology  

Background. The 5th edition of the World Health Organization Classification of Tumors of the CNS introduced a subclassification of tumors based on key molecular markers. In adult-type diffuse gliomas, isocitrate dehydrogenase (IDH) and telomerase reverse transcriptase (TERT) promoter mutations play pivotal roles in the molecular classification. This study developed a rapid genotyping system using GeneSoC, a real-time PCR platform with microfluidic thermal cycling capable of completing 50 cycles of PCR within 20 min. Methods. To establish optimal analytical conditions, frozen tumor tissues from 67 patients and artificial DNA vectors were analyzed using this system. This system demonstrated a detection limit of at least 5% variant allele frequency for the IDH1 R132H and TERT promoter C228T/C250T mutations. Subsequently, intraoperative testing was performed in 120 cases using this system. Results. The sensitivity and specificity of IDH1 R132H mutation were 0.985 and 0.982, respectively, whereas those of TERT promoter C228T/C250T mutation were 1.000 and 1.000, respectively. These mutations were detected intraoperatively within approximately 25 min after tumor tissue collection. Furthermore, this assay identified tumor boundaries in an IDH-mutated glioma case, where IDH1 R132H mutations could not be detected. Conclusions. The GeneSoC^®︎-based rapid genotyping system may be effective not only for intraoperative diagnosis of diffuse glioma but also for detecting tumor boundaries.

DOI： 10.1093/neuonc/noaf188

Open Access

Web of Science

Scopus

PubMed

DOI： 10.1093/neuonc/noaf201.1566

Web of Science

DOI： 10.1093/neuonc/noaf201.0981

Web of Science

DOI： 10.1093/neuonc/noaf193.346

Web of Science

DOI： 10.1093/neuonc/noaf193.395

Web of Science

記述言語：英語   出版者・発行元：Seizure  

Purpose: This study aimed to evaluate the efficacy and safety of intravenous perampanel (IV-PER) in routine clinical practice. Methods: Patients who received IV-PER at Nagoya University Hospital or one of the 21 affiliated institutions between June 2024 and March 2025 were included. Indications for IV-PER included treatment for epileptic seizures, particularly acute symptomatic seizures, and prophylactic use before or after surgery. The primary endpoint was the seizure suppression rate within 7 days of treatment initiation, and the secondary endpoint was the incidence of adverse events (AEs). Clinical data were recorded daily, and blood tests were conducted within 2 weeks of administration. Enrolled patients were categorized into three groups based on the underlying etiology: cerebrovascular disease (CD), brain tumor (BT), and traumatic brain injury (TBI). Treatment efficacy and safety were assessed across these groups. Results: Of the 237 patients, 74, 116, and 47 were classified into the CD, BT, and TBI groups, respectively. The overall seizure suppression rate within 7 days was 89.0 %. Rates by group were 87.8 % (CD), 96.6 % (BT), and 72.3 % (TBI). When stratified by indication, the rates were 99.3 % for prophylactic use, 69.4 % for focal seizures, and 74.4 % for generalized seizures. Regarding AEs, somnolence was reported in 3 patients and irritability in one. Laboratory abnormalities included anemia, elevated liver enzymes, elevated creatine kinase, and hyponatremia. A total of 71 patients experienced one of these. Conclusions: This large multicenter prospective registry demonstrates that IV-PER can be safely used for seizure management during the 7-day acute phase in real-world clinical settings.

DOI： 10.1016/j.seizure.2025.07.023

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：International Journal of Clinical Oncology  

Background: Tumor treating fields (TTFields) treatment has been an important option for the treatment of glioblastoma. The introduction of novel treatment options may lead to distinct recurrence patterns compared to those observed with conventional therapies; however, the specific recurrence pattern during TTFields treatment has not been elucidated. Methods and results: Here, we analyzed 39 cases of glioblastoma treated with TTFields. Although a usage rate of more than 75% is recommended, among 39 cases, 18 discontinued TTFields treatment owing to requests by patients with lower usage rates. In these discontinued cases, patients exhibiting sensory aphasia were more frequently included compared to those who continued TTFields (44.4%, p < 0.001). Among 21 cases involving patients who continued TTFields, tumor recurrence was observed in 15 of those cases. Five out of 15 cases (33.3%) exhibited recurrence in distant parenchyma from the primary lesion. A higher usage rate and relatively longer use of TTFields were observed in these five cases, along with more favorable progression-free survival than those in the other 10 cases (p = 0.019, p = 0.040, and p = 0.024, respectively). In one case, recurrent tumors with lower grade glioma histology but molecular markers characteristic for glioblastoma, IDH-wildtype were indentified. This tumor arose in an area that received a lower local minimum power density of TTFields compared to the primary lesion, following long-term TTFields therapy. Conclusions: Long-term use of TTFields might be correlated with a high frequency of distant parenchymal recurrence in cases with favorable response.

DOI： 10.1007/s10147-025-02775-5

Open Access

Web of Science

Scopus

PubMed

記述言語：英語  

DOI： 10.7759/cureus.80941

PubMed

記述言語：英語   出版者・発行元：Acta Neuropathologica Communications  

Diffuse hemispheric glioma H3 G34-mutant (DHG) has been identified as a distinct pediatric-type high-grade glioma, according to the World Health Organization (WHO) classification of central nervous system tumors. Widely accepted treatment options include surgery, radiation, and conventional chemotherapy. However, the efficacy of the surgical resection remains unclear. Although there are some reports, a comprehensive understanding of the clinical characteristics, pathogenesis, and outcomes of DHG is insufficient to evaluate the efficacy of maximal tumor resection. We retrospectively analyzed nine cases of DHG, focusing on imaging features and progression patterns. Initial Magnetic Resonance Imaging (MRI) revealed T2/FLAIR high lesions with minimal or no contrast enhancement in all cases. The lesions exhibited T2/FLAIR hyperintensities and focal diffusion restriction in the deep white matter, with most showing high methionine accumulation, suggesting deep white matter infiltration at the time of diagnosis. The extent of white matter infiltration in tumor resection cases was significantly negatively correlated with the extent of resection (EOR). In addition, cases with EOR of 90% or more had significantly longer progression-free survival (PFS) and overall survival (OS). However, achieving an EOR of 90% or more was possible in fewer than half of the cases, primarily in those with relatively limited white matter involvement. Histopathological findings of the tumor obtained by initial resection and autopsy revealed extensive deep white matter infiltration, with one patient demonstrating tumor invasion into the brainstem at death. Our study highlights early deep white matter infiltration of DHGs, complicating surgical resection, and potentially contributing to a poor prognosis. While EOR may influence survival to some extent, residual lesions extensively infiltrate the white matter and eventually invade the brainstem and contralateral brain, thereby contributing to mortality. These findings underscore the challenges of managing DHGs and emphasize the need for further research on effective therapeutic strategies, particularly to understand and target their unique progression patterns.

DOI： 10.1186/s40478-025-01945-w

Open Access

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：BMC Cancer  

Background: Glioblastoma (GB) is the most common and aggressive primary malignant brain tumor in adults. To date, no effective treatment has been reported for recurrent GB (rGB). Long noncoding RNA taurine upregulated gene 1 (TUG1), which is highly expressed in GB, resolves the formation of R-loops, thereby maintaining tumor growth. TUG1-targeting antisense oligonucleotide (ASO) (TUG1ASO) is a nucleotide therapeutic with drug delivery system that targets TUG1, demonstrating efficacy against GB in mouse models. This multicenter, first-in-human, phase I trial aims to investigate the safety and maximum tolerated dose (MTD) of TUG1ASO. Methods: This study will enroll patients aged 18–75 years with rGB following postoperative temozolomide plus radiation therapy. The primary endpoints will be the safety and tolerability of TUG1ASO and the MTD. The secondary endpoints will be the response rate, duration of response, progression-free survival, overall survival, and pharmacokinetics of TUG1ASO. Dose escalation will be performed utilizing a 3 + 3 design with four dose levels. Unless the discontinuation criteria are met, four cycles will be administered, with each cycle lasting 7 days. Administration of TUG1ASO will be possible until the discontinuation criteria are met. Discussion: TUG1ASO is the first oligonucleotide therapeutic with drug delivery system targeting TUG1, expected to show an efficacy in rGB patients. In this first-in-human study, safety, tolerability and MTD of this new targeted therapy will be confirmed to find the recommended dose for the further clinical trial. This study may contribute to develop a new treatment option for rGB patients. Trial registration: Japan Registry of Clinical Trials (jRCT) 2041230136, registration date May 17, 2024. Registry: jRCT2041230136. Registration date: May 17, 2024. Study dates: January 1, 2024, to present.

DOI： 10.1186/s12885-025-13623-0

Open Access

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Neuro Oncology Advances  

Background Isocitrate dehydrogenase-mutant astrocytomas (A-IDHm) with the homozygous deletion of cyclin-dependent kinase 2A/B (CDKN2A/B-HD) have been classified as grade 4 in the WHO 2021 classification (WHO2021). This study aimed to find survival differences in subgroups stratified by CDKN2A/B status and traditional histological grades (hGs). Methods The frequency and prognostication of CDKN2A/B-HD in primary A-IDHm were analyzed based on hGs. A systematic review and meta-analysis were performed following the PRISMA guidelines using three databases (registration CRD42024570409). Effect sizes were evaluated using the hazard ratio (HR) and restricted mean survival time (RMST) for overall survival (OS). Results Thirty-three articles with 3739 A-IDHm patients were included. The pooled frequencies of CDKN2A/B-HD were 3.3% [95% confidence interval (CI): 1.9-5.8], 11.0% [CI: 8.6-14.0], and 39.1% [CI: 34.0-44.5] in hG-II, hG-III, and hG-IV, respectively, after excluding the outliers. CDKN2A/B-HD significantly impaired OS in patients with hG-III (pooled HR (pHR), 3.61; CI, 2.72-4.78) and hG-IV (pHR, 1.93; CI, 1.43-2.61), and it was not evident in hG-II due to the paucity of the data. pHR showed better survival in patients with grade-2 tumors over grade-3 (WHO2021) (pHR 1.44, CI 1.09-1.90, P = .01, 1184 patients), although the RMST difference was only 7.1 months at 100 months (N = 1162). Among the grade-4 tumors, CDKN2A/B-HD hG-IV had the worst survival (RMST at 60 months, 32 months). Conclusion The prognosis of A-IDHm can be stratified by hG and CDKN2A/B-HD. However, evidence is insufficient for the classification of hG-II with CDKN2A/B-HD.

DOI： 10.1093/noajnl/vdaf171

Open Access

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Neuro Oncology Advances  

Background Tumor treating fields (TTFields) therapy is an important treatment for glioblastoma. However, there have been few reports showing the effectiveness thereof in clinical settings worldwide. The aim of this study was to examine the efficacy of TTFields therapy by comparing patients with compliance rates above 75% with those below 75% during the first 3 months of treatment. Methods Data were retrospectively collected from electronic medical records for consecutive patients with newly diagnosed World Health Organization grade 4 gliomas who received TTFields therapy at 12 institutes in Japan from January 2018 to December 2023. Results In total, 157 patients received TTFields therapy. We analyzed 116 patients who used TTFields for at least the first 3 months. The median age was 57 years; 67 patients were male; and the median KPS before the start of adjuvant temozolomide was 90. The average compliance rate was 78.3%. The median progression-free survival (PFS) and overall survival (OS) were 11.9 months and 23.7 months, respectively. A high compliance rate of TTFields ≥75% for the first 3 months was achieved in 67 patients and was a significant prognostic factor on PFS (P=.04). The median PFS for patients with high and low compliance rates was 12.6 and 9.0 months, respectively; the median OS was 25.3 and 21.3 months, respectively (P=.15). Conclusions TTFields use rate ≥75% in the first 3 months was significantly associated with improved PFS. There was a tendency for OS to be extended. Further analysis with a larger number of cases is required.

DOI： 10.1093/noajnl/vdaf203

Open Access

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：一般社団法人 日本脳神経外科学会  

Isocitrate dehydrogenase (IDH)-mutant astrocytomas with homozygous deletion of cyclin-dependent kinase 2A/B (CDKN2A/B-HomoD) are categorized to grade 4 in the new World Health Organization (WHO) classification. However, the clinical implications of CDKN2A/B-HomoD in oligodendrogliomas remain unclear. This study systematically reviewed and meta-analyzed the literature on molecularly defined oligodendrogliomas (mOlig) to find the frequency and prognostic significance of CDKN2A/B gene alterations. Overall survival was worse in patients with CDKN2A/B-HomoD [pooled hazard ratio (pHR) 2.44; 95% confidential interval (CI), 1.59-3.76; P < 0.0001; 7 studies, 1,012 patients] than in those without CDKN2A/B-HomoD. Although the frequency (95% CI) was very low in grade 2 tumors (0.31%; 0.02-0.4) than in grade 3 tumors (9.4%; 6.2-14.0; I² = 52.0%), pHR of multivariate analyses with covari-ates of WHO grade and age was still significant (P = 0.017). In contrast, the method in CDKN2A/B evaluation was a significant factor for the heterogeneity in frequency. The pooled frequency of CDKN2A/B-HomoD in grade 3 mOlig by fluorescence in situ hybridization (FISH) (20.3%) was higher than that by other methods (7.3%; P < 0.0006), probably due to the lower threshold for CDKN2A/B-HomoD in FISH studies that was used in this analysis. The frequency (95% CI) of other alterations of the CDKN2A/B gene, i.e., mutation, hemizygous deletion, and promoter methylation, was estimated as 1.48% (0.6-3.5), 15.9% (9.8-24.7), and 20.6% (13.7-29.8), respectively. The clinical significance of these alterations remains unclear due to the immaturity of the investigations.

DOI： 10.2176/jns-nmc.2024-0105

Open Access

Web of Science

Scopus

PubMed

CiNii Research

記述言語：英語   出版者・発行元：Neuro Oncology Advances  

Background. The EF-14 clinical trial demonstrated the safety and efficacy of tumor-treating fields (TTFields) for newly diagnosed glioblastoma. This study aimed to clarify the current status, safety, and efficacy of TTFields in Japanese patients who meet the EF-14 inclusion criteria. Methods. This was a multicenter retrospective cohort study. Background, treatment, and outcome data of patients who satisfied the inclusion criteria of the EF-14 trial were collected from 45 institutions across Japan. The rate, determinants, and current status of TTField use, including its safety and efficacy in terms of progression and survival, were retrospectively investigated. This study was conducted in accordance with the STROBE checklist. Results. Among the 607 patients enrolled, 70 were excluded due to progressive disease during radiation and temozolomide therapy, age > 80 years old, and Karnofsky Performance Status score of <70. Among the remaining 537 patients, 210 (39%) underwent TTField treatment. Multivariate analysis revealed younger age and spouse as a caregiver as significant factors for TTField use. The compliance rate of TTField use exceeded 75% in 60% of patients, with a median TTField usage duration of 11 months. Skin disorders requiring medical treatment occurred in 56% of patients. Multivariate Cox proportional hazards analysis in the whole series and propensity score-matched analysis revealed that TTField use was not a prognostic factor for progression-free survival (PFS) or overall survival (OS). Conclusions. TTField use did not have a substantial effect on either PFS or OS in Japanese patients with glioblastoma, despite compliance rates comparable to those observed in the EF-14.

DOI： 10.1093/noajnl/vdae176

Open Access

Web of Science

Scopus

PubMed

DOI： 10.1093/neuonc/noae165.0803

Web of Science

DOI： 10.1093/neuonc/noae165.0672

Web of Science

DOI： 10.1093/neuonc/noae165.0748

Web of Science

DOI： 10.1093/neuonc/noae165.1103

Web of Science

記述言語：英語   出版者・発行元：Acta Neuropathologica Communications  

Mutations in the isocitrate dehydrogenase (IDH) gene are recognized as the key drivers in the oncogenesis of astrocytoma and oligodendroglioma. However, the significance of IDH mutation in tumor maintenance and malignant transformation has not been elucidated. We encountered a unique case of IDH-mutant astrocytoma that, upon malignant transformation, presented two distinct intratumoral components: one IDH-wildtype and one IDH-mutant. The IDH-wild-type component exhibited histological findings similar to those of small cell-type glioblastoma with a higher Ki-67 index than the IDH-mutant component. Despite their genetic divergence, both components exhibited similar comprehensive methylation profiles within the CpG island and were classified into methylation class of “Astrocytoma, IDH-mutant; High Grade” by the German Cancer Center (DKFZ) classifier v11.4. Phylogenetic analysis demonstrated that the IDH-wildtype component emerged as a subclonal component of the primary tumor. Detailed molecular analyses revealed that the loss of the IDH mutation was induced by the hemizygous loss of the entire arm of chromosome 2, on which IDH1 gene is located. Notably, the IDH-wild-type subclones uniquely acquired CDKN2A/B homozygous deletion and PDGFRA amplification, which is a marker of the aggressive phenotype of astrocytoma, IDH-mutant. Because these genetic abnormalities can drive oncogenic pathways, such as the PI3K/AKT/mTOR and RB signaling pathway, IDH-mutant gliomas that acquired these mutations were no longer dependent on the initial driver mutation, the IDH mutation. Molecular analysis of this unique case provides insight that in a subset of astrocytoma, IDH-mutant that acquired these genetic abnormalities, IDH mutation may not play a pivotal role in tumor growth and acquisition of these genetic abnormalities may contribute to the acquisition of resistance to IDH inhibitors.

DOI： 10.1186/s40478-024-01879-9

Open Access

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Head and Neck  

Background: This study aimed to examine treatment outcomes and postoperative complications associated with salvage skull base surgery following radical proton beam therapy (PBT). Methods: Nine patients who underwent salvage skull base surgery following curative PBT as the initial treatment at our institution between September 2002 and May 2023 were retrospectively reviewed. Results: The cohort comprised four males and five females with a mean age of 48.1 years. The average proton dose administered during initial therapy was 68.5 Gy (relative biological effectiveness). Among the salvage surgeries, eight were anterior skull base surgeries, and one was an anterior middle skull base surgery. No local recurrences or perioperative deaths were observed. Postoperative complications occurred in three patients (33.3%), all experiencing surgical site infections, with one also having cerebrospinal fluid leakage. Conclusion: The study demonstrates that salvage skull base surgery after PBT effectively achieves local control and safety in patients with recurrent sinonasal malignancies.

DOI： 10.1002/hed.27709

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Japanese Journal of Clinical Oncology  

Background: This study aimed to investigate what treatment are selected for malignant brain tumors, particularly glioblastoma (GBM) and primary central nervous system lymphoma (PCNSL), in real-world Japan and the costs involved. Methods: We conducted a questionnaire survey regarding treatment selections for newly diagnosed GBM and PCNSL treated between July 2021 and June 2022 among 47 institutions in the Japan Clinical Oncology Group-Brain Tumor Study Group. We calculated the total cost and cost per month of the initial therapy for newly diagnosed GBM or PCNSL. Results: The most used regimen (46.8%) for GBM in patients aged ≤74 years was 'Surgery + radiotherapy concomitant with temozolomide'. This regimen's total cost was 7.50 million JPY (Japanese yen). Adding carmustine wafer implantation (used in 15.0%), TTFields (used in 14.1%), and bevacizumab (BEV) (used in 14.5%) to the standard treatment of GBM increased the cost by 1.24 million JPY for initial treatment, and 1.44 and 0.22 million JPY per month, respectively. Regarding PCNSL, 'Surgery (biopsy) + rituximab, methotrexate, procarbazine, and vincristine (R-MPV) therapy' was the most used regimen (42.5%) for patients of all ages. This regimen incurred 1.07 million JPY per month. The three PCNSL regimens based on R-MPV therapy were in ultra-high-cost medical care (exceeding 1 million JPY per month). Conclusions: Treatment of malignant brain tumors is generally expensive, and cost-ineffective treatments such as BEV are frequently used. We believe that the results of this study can be used to design future economic health studies examining the cost-effectiveness of malignant brain tumors.

DOI： 10.1093/jjco/hyae116

Open Access

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：BMC Cancer  

Background: Stereotactic irradiation has become the mainstay treatment for brain metastases (BM), and whole-brain radiotherapy (WBRT) is often used for symptom palliation. However, the survival time of patients with BM undergoing palliative WBRT (pWBRT) is limited, making it difficult to select patients who should receive treatment. Methods: We collected patient data from 2016 to 2022 at the Shizuoka Cancer Center and retrospectively analyzed the factors related to survival time. Overall survival (OS) was defined as the survival time after WBRT. Results: A total of 301 patients (median age, 66 years) who underwent pWBRT were included. The primary cancers were lung, breast, gastrointestinal tract, and other cancers in 203 (67%), 38 (13%), 33 (11%), and 27 (9%) patients, respectively. Median OS of all patients was 4.1 months. In the multivariate analysis, male sex (hazard ratio [HR]:1.4), Karnofsky Performance Status (KPS) ≤ 60 (HR:1.7), presence of extracranial metastasis (ECM) (HR:1.6), neutrophil-lymphocyte ratio (NLR) ≥ 5 (HR:1.6), and lactate dehydrogenase (LDH) ≥ upper limit of normal (ULN) (HR:1.3) were significantly associated with shorter OS (all P < 0.05). To predict the OS, we created a prognostic scoring system (PSS). We gave one point to each independent prognostic factor. Median OS for patients with scores of 0–2, 3, and 4–5 were 9.0, 3.5 and 1.7 months, respectively (P < 0.001). Conclusions: Male sex, KPS ≤ 60, presence of ECM, NLR ≥ 5, and LDH ≥ ULN were poor prognostic factors for patients with BM undergoing pWBRT. By PSS combining these factors, it may be possible to select patients who should undergo pWBRT.

DOI： 10.1186/s12885-024-12729-1

Open Access

Web of Science

Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：World Neurosurgery  

Background: In the treatment of nonsmall cell lung cancer (NSCLC), a disease-free survival of 5 years is a criterion for cure. This study aimed to evaluate the characteristics and outcomes of patients with brain metastases of NSCLC after a disease-free survival of 5 years (late recurrent brain metastasis [LRBM]). Methods: We reviewed 1281 consecutive patients with brain metastasis of lung cancer at a single institute between November 2014 and December 2022. Relevant articles were retrieved from PubMed. Only peer-reviewed journals published in English were included. Results: Six patients (0.47%) showed LRBM. Three were male. The median age at lung cancer diagnosis was 45 years. The histological diagnosis of all patients was adenocarcinoma. Driver gene mutations were observed in five patients. The median latency period from lung cancer treatment to the development of brain metastasis was 13 years. All patients had no metastasis to any other organs and underwent craniotomies. The median follow-up duration after craniotomy was 3.5 years. No local intracranial recurrences were observed. Three patients had distant intracranial recurrences at 7, 2, and 0.6 years after craniotomy. Five patients survived for 8, 4, 3, 2, and 0.3 years after craniotomy. One patient experienced re-recurrence in the lung 4 years after craniotomy and died 3.7 years later. In our systematic review, only six studies described LRBM of NSCLC. Conclusions: LRBM is rare in patients with NSCLC. In our institution, many of these patients harbored driver gene mutations, and achieved long-term survival with aggressive local therapy. Multicenter analysis is mandatory.

DOI： 10.1016/j.wneu.2024.03.139

Open Access

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Anticancer Research  

Background/Aim: Brain metastasis, a leading cause of cancer death, is a clinical challenge. Recently, genetic characterization of brain metastatic lesions based on next generation sequencing-based advanced technologies, such as single-cell RNA sequencing, has been performed to develop novel efficient therapies. The present study aimed to investigate brain-metastasis-specific biomarkers as well as relevant prognostic factors. Patients and Methods: The genetic profiles and expression levels of immune response-associated genes and 820 cancer-associated genes were compared between primary cancer lesions and metastatic cancer lesions obtained from nine cancer patients at the Shizuoka Cancer Center. Cytokine and chemokine marker genes were analyzed via quantitative PCR. T-cell receptor (TCR) repertoire profiling was performed for the same patients. For survival analysis, survival data of 52 cancer patients with brain metastases were utilized. Results: Comparison of driver mutation profiling between primary and metastatic lesions revealed shared core mutations in both lesions and a few new mutations in metastatic lesions. A high tumor mutation burden (TMB) was detected in metastatic lesions. Volcano plot analysis revealed specific features of the metastatic tumor microenvironment, such as cancer signaling promotion and immune suppression due to decreased immune cell infiltration. Survival analysis revealed that three genes, the TREML2 gene, the BTLA gene on activated microglia and the CERS2 gene on metastatic tumor, were potent prognostic factors. Conclusion: High TMB in metastatic lesions indicates potential benefit from immune checkpoint inhibitor usage for brain metastasis and TREML2 and BTLA are factors associated with poor prognosis. Activated microglia may be novel targets for the treatment of brain metastasis.

DOI： 10.21873/anticanres.17001

Open Access

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Nagoya Journal of Medical Science  

Gliosarcoma (GS), a morphological variant of glioblastoma, pathologically shows a biphasic pattern with gliomatous and sarcomatous components. It has been reported that GS has much higher metastatic capacity than glioblastoma. A few reports on the pathology of the extracranial metastasis of GS have shown that metastatic lesions had a sarcomatous component alone or a mixture of gliomatous and sarcomatous ones. Therefore, it is considered that GS tends to disseminate hematogenously due to its mesenchymal sarcomatous component. Herein, we report an autopsy case of GS with multiple extracranial metastases treated by craniotomy, radiotherapy, and bevacizumab. In this case, metastatic lesions at autopsy contained a gliomatous component alone, but no sarcomatous component. In addition, the sarcomatous component disappeared from the intracranial lesion at autopsy after the administration of bevacizumab. In this report, we discuss the clinical course and pathological findings at the initial state, recurrence, and autopsy, including the results of whole-genome analysis.

DOI： 10.18999/nagjms.85.4.828

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Cell Stem Cell  

COVID-19 is linked to endotheliopathy and coagulopathy, which can result in multi-organ failure. The mechanisms causing endothelial damage due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain elusive. Here, we developed an infection-competent human vascular organoid from pluripotent stem cells for modeling endotheliopathy. Longitudinal serum proteome analysis identified aberrant complement signature in critically ill patients driven by the amplification cycle regulated by complement factor B and D (CFD). This deviant complement pattern initiates endothelial damage, neutrophil activation, and thrombosis specific to organoid-derived human blood vessels, as verified through intravital imaging. We examined a new long-acting, pH-sensitive (acid-switched) antibody targeting CFD. In both human and macaque COVID-19 models, this long-acting anti-CFD monoclonal antibody mitigated abnormal complement activation, protected endothelial cells, and curtailed the innate immune response post-viral exposure. Collectively, our findings suggest that the complement alternative pathway exacerbates endothelial injury and inflammation. This underscores the potential of CFD-targeted therapeutics against severe viral-induced inflammathrombotic outcomes.

DOI： 10.1016/j.stem.2023.09.001

Web of Science

Scopus

PubMed

DOI： 10.1093/neuonc/noad137.383

Web of Science

記述言語：英語  

DOI： 10.1055/a-2161-7710

Web of Science

PubMed

記述言語：英語   出版者・発行元：Brain Tumor Pathology  

The WHO 2021 classification defines IDH wild type (IDHw) histologically lower-grade glioma (hLGG) as molecular glioblastoma (mGBM) if TERT promoter mutation (pTERTm), EGFR amplification or chromosome seven gain and ten loss aberrations are indicated. We systematically reviewed articles of IDHw hLGGs studies (49 studies, N = 3748) and meta-analyzed mGBM prevalence and overall survival (OS) according to the PRISMA statement. mGBM rates in IDHw hLGG were significantly lower in Asian regions (43.7%, 95% confidence interval [CI: 35.8–52.0]) when compared to non-Asian regions (65.0%, [CI: 52.9–75.4]) (P = 0.005) and were significantly lower in fresh-frozen specimen when compared to formalin-fixed paraffin-embedded samples (P = 0.015). IDHw hLGGs without pTERTm rarely expressed other molecular markers in Asian studies when compared to non-Asian studies. Patients with mGBM had significantly longer OS times when compared to histological GBM (hGBM) (pooled hazard ratio (pHR) 0.824, [CI: 0.694–0.98], P = 0.03)). In patients with mGBM, histological grade was a significant prognostic factor (pHR 1.633, [CI: 1.09–2.447], P = 0.018), as was age (P = 0.001) and surgical extent (P = 0.018). Although bias risk across studies was moderate, mGBM with grade II histology showed better OS rates when compared to hGBM.

DOI： 10.1007/s10014-023-00463-8

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Neuropathology  

DOI： 10.1111/neup.12873

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Journal of Neuro Oncology  

Purpose: The initial brain metastasis velocity (iBMV) was recently reported as a survival predictor after brain metastases (BM) in patients treated by stereotactic radiosurgery. In this study, we validated whether iBMV is a prognostic tool, regardless of treatment modality, in patients with non-small cell lung cancer (NSCLC) with metachronous BM. Methods: We retrospectively reviewed consecutive 3,792 new lung cancer cases in which no BM was found on magnetic resonance (MR) screening between February 2014 and December 2019, and enrolled 176 NSCLC patients with subsequent BM. Overall survival (OS) was calculated from the date of MR to identify the time from BM to death. Results: The median iBMV score was 1.9. We used an iBMV score of 2.0 as the cutoff level, as previously reported. An iBMV score ≥ 2.0 was significantly associated with older age, high neutrophil-to-lymphocyte ratio, and Stage IV (P = 0.04, 0.02, and 0.02, respectively). The median OS was 0.92 years. The median OS for patients with iBMV score ≥ 2.0 and < 2.0 were 0.59 years and 1.33 years, respectively (P < 0.001). Multivariate analysis showed that an iBMV score ≥ 2.0, ECOG performance status score of 1–3, Stage IV, and non-adenocarcinoma histology were independent poor prognostic factors (hazard ratio (HR), 1.94; P = 0.0001; HR, 1.53; P = 0.04; HR, 1.45; P = 0.04; and HR, 1.14; P = 0.03, respectively). Patients with iBMV scores of < 2.0 were more likely to undergo craniotomy or stereotactic irradiation. Conclusions: An iBMV score ≥ 2.0 is an independent predictor of survival in NSCLC patients with metachronous BM, regardless of the treatment modality.

DOI： 10.1007/s11060-023-04300-y

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Radiation Oncology  

After publication of this article [1], the authors reported that (1) In Table 1, first column, under ‘RPA’, 3 lines should start with ‘1, 2, 3’, respectively (instead of ‘12, 3, blank’); (2) In 5 spots the value ‘x cm [3]’ should have read ‘x cm3’. The original article [1] has been corrected.

DOI： 10.1186/s13014-023-02206-7

Open Access

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Neuro Oncology Advances  

Background: Cerebrospinal fluid (CSF) cytology remains the gold standard approach for diagnosing of leptomeningeal metastases (LM), but has clinical problems due to its low sensitivity. This systemic review and meta-analysis evaluated the diagnostic accuracy of the novel CSF biomarkers of liquid biopsy and magnetic resonance imaging (MRI) for detecting LM in patients with solid cancers. Methods: A systematic search of electronic databases was conducted to identify all published diagnostic accuracy studies on CSF liquid biopsies and MRI since January 2000 with registration for PROSPERO (#CRD42022301988). Articles were selected based on pre-defined inclusion and exclusion criteria following the PRISMA 2020 statement. Results: The search yielded 3790 citations, and 10 studies with 668 patients were included in the final analysis. The pooled prevalence of LM was 50.9% (340/668). The respective sensitivity and specificity for index tests were as follows: circulating tumor cells (CTC), 87.0% (95% confidence interval [CI] 77.9-92.6%) and 93.8% (86.9-97.2%); cell-free tumor DNA, 97.9% (19.3-100%) and 89.0% (25.3-99.5%); MRI 59.4% (60.7-76.9%) and 97.6% (77.3-99.8%); cytology, 71.9% (54.7-82.9%) and 100%. The diagnostic odds ratio was 100.6 (29.38-344.09) for CTC and 93.3 (88.42-1034.05) for MRI. Conclusion: Novel CSF liquid biopsies and MRI may offer improved diagnostic accuracy for LM from solid cancers; however, further research is required to specify the threshold values and to construct standards for individual primary cancers.

DOI： 10.1093/noajnl/vdad002

Open Access

Web of Science

Scopus

PubMed