Language：English   Publisher：Neuro Oncology  

Background. A previous Phase II clinical trial, conducted from 1995 to 2003, evaluated CNS germ cell tumors (GCTs) using a three-group treatment stratification based on histopathology. The primary objective of the study was to assess the long-term efficacy of standardized treatment regimens, while the secondary objective focused on identifying associated long-term complications. Methods. A total of 228 patients were classified into 3 groups for treatment: germinoma (n = 161), intermediate prognosis (n = 38), and poor prognosis (n = 28), excluding one mature teratoma case. Treatment involved stratified chemotherapy regimens and varied radiation doses/coverage. Clinical data was retrospectively analyzed at a median follow-up of 18.5 years. Results. The treatment outcomes for germinoma, with or without syncytiotrophoblastic giant cells, were similar. The 10- and 20-year event-free survival rates for the germinoma, intermediate, and poor prognosis groups were 82/76/49% and 73/66/49%, respectively. Overall survival (OS) rates were 97/87/61% at 10 years and 92/70/53% at 20 years. Germinomas in the basal ganglia, treated without whole-brain radiation therapy (WBRT), frequently relapsed but were effectively managed with subsequent WBRT. Deaths in germinoma cases had varied causes, whereas deaths in the poor prognosis group were predominantly disease-related. Nineteen treatment-related complications were identified in 16 patients, with cumulative event rates of 1.9% at 10 years and 11.3% at 20 years. OS rates at 1 and 2 years post-relapse for tumors initially classified as germinoma, intermediate, and poor prognosis were 94/88/18% and 91/50/9%, respectively. Conclusions. Initial treatment intensity is crucial for managing non-germinomatous GCTs, while long-term follow-up for relapse and complications is imperative in germinomas. Irradiation extending beyond the immediate tumor site is essential for basal ganglia germinomas. Addressing relapse in non-germinomatous GCT remains a significant challenge.

DOI： 10.1093/neuonc/noae229

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Language：English   Publisher：Anticancer Research  

Background/Aim: Pancreatic cancer is a major cause of mortality in the world. It is one of most aggressive diseases, with a 5-year survival rate of <10%. Cancer associated fibroblasts (CAFs) are the predominant non-cancer cells in pancreatic cancer tissues, playing a critical role in modulating the extracellular matrix (ECM). The ECM, maintained by CAFs, significantly impacts the sensitivity of cancer cells to anti-cancer drugs, contributing to tumor progression and resistance to both chemotherapy and immunotherapy. Therefore, targeting CAFs and the ECM may enhance the effectiveness of therapies like FOLFIRINOX. This study aimed to develop a novel oncolytic virotherapy for treatment-resistant pancreatic cancer. Materials and Methods: In the first screening assay, we found that coxsackievirus B3 (CVB3) exhibited potent oncolytic activity. We examined whether CVB3 has oncolytic effects on human pancreatic cancer cells in vitro, and whether it has oncolytic activity against cancer-associated fibroblasts (CAFs) in pancreatic cancer. Results: CVB3 demonstrated potent oncolytic effects in two out of three pancreatic cancer cell lines tested. Additionally, CVB3 demonstrated a cell-killing effect on CAFs, indicating its dual activity against both pancreatic cancer cells and the supportive stromal environment. Conclusion: CVB3 shows promise as an oncolytic virus effective against pancreatic cancer cells and CAFs, suggesting its potential as a novel virotherapy for pancreatic cancer. These findings highlight CVB3 as a candidate for further development as a therapeutic modality aimed at improving drug sensitivity and patient prognosis in pancreatic cancer.

DOI： 10.21873/anticanres.17348

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Language：English  

DOI： 10.1186/s40170-024-00364-0

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PubMed

Language：English   Publisher：Pathology Research and Practice  

Previously, we constructed a DNA-based next-generation sequencing (NGS) panel for an integrated diagnosis of gliomas according to the 2021 World Health Organization classification system. The aim of the current study was to evaluate the feasibility of a modified panel to include fusion gene detection via RNA-based analysis. Using this bimodal DNA/RNA panel, we analyzed 210 cases of gliomas and others to identify fusion genes in addition to gene alterations, including TERT promoter (TERTp) mutation and 1p/19q co-deletion, in formalin-fixed paraffin-embedded tissues. Of the 210 patients, fusion genes were detected in tumors of 35 patients. Eighteen of 112 glioblastomas (GBs) harbored fusion genes, including EGFR and FGFR3 fusions. In IDH-mutant astrocytoma, 6 of 30 cases showed fusion genes such as MET and NTRK2 fusions. Eleven molecular GBs and 20 not-elsewhere-classified cases harbored no gene fusions. Other 11 tumors including ependymoma, pilocytic astrocytoma, diffuse hemispheric glioma, infant-type hemispheric glioma, and solitary fibrous tumors exhibited diagnostic fusion genes. Overall, our results suggest that the all-in-one bimodal DNA/RNA panel is reliable for detecting diagnostic gene alterations in accordance with the latest WHO classification. The integrative pathological and molecular strategy could be valuable in confirmation of diagnosis and selection of treatment options for brain tumors.

DOI： 10.1016/j.prp.2024.155598

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Language：English   Publisher：Neuropathology  

Since the World Health Organization (WHO) 2016 revision, the number of molecular markers required for diffuse gliomas has increased, placing a burden on clinical practice. We have established an in-house, molecular diagnostic platform using Senshin-Iryo, a feature of Japan's unique healthcare system, and partially modified the analysis method in accordance with the WHO 2021 revision. Herein, we review over a total 5 years of achievements using this platform. Analyses of IDH, BRAF, and H3 point mutations, loss of heterozygosity (LOH) on 1p/19q and chromosomes 10 and 17, and MGMT methylation were combined into a set that was submitted to Senshin-Iryo as “Drug resistance gene testing for anticancer chemotherapy” and was approved in August 2018. Subsequently, in October 2021, Sanger sequencing for the TERT promoter mutation was added to the set, and LOH analysis was replaced with multiplex ligation-dependent probe amplification (MLPA) to analyze 1p/19q codeletion and newly required genetic markers, such as EGFR, PTEN, and CDKN2A from WHO 2021. Among the over 200 cases included, 54 were analyzed after the WHO 2021 revision. The laboratory has maintained a diagnostic platform where molecular diagnoses are confirmed within 2 weeks. Initial expenditures exceeded the income from patient copayments; however, it has gradually been reduced to running costs alone and is approaching profitability. After the WHO 2021 revision, diagnoses were confirmed using molecular markers obtained from Senshin-Iryo in 38 of 54 cases (70.1%). Among the remaining 16 patients, only four (7.4%) were diagnosed with diffuse glioma, not elsewhere classified, which was excluded in 12 cases where glioblastoma was confirmed by histopathological diagnosis. Our Senshin-Iryo trial functioned as a salvage system to overcome the transition period between continued revisions of WHO classification that has caused a clinical dilemma in the Japanese healthcare system.

DOI： 10.1111/neup.12970

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

先進医療制度を利用して確立した、びまん性神経膠腫の施設内分子診断プラットフォームを5年間使用して得た成果をまとめた。本プラットフォームでは、IDH・BRAF・H3の各遺伝子の点突然変異、染色体1p/19q・10番染色体・17番染色体のヘテロ接合性喪失(LOH)、およびMGMT遺伝子のメチル化を解析する検査をワンセットにして先進医療の「抗悪性腫瘍剤治療における薬剤耐性遺伝子検査」として申請し、2018年8月に承認された。2021年10月にはTERT遺伝子プロモーター変異を標的とするSanger法塩基配列検査も上記の検査セットに追加した。同時にLOH解析法をMLPA法に置き換える変更も加えた。MLPA法での検査対象は、1p/19q共欠失と、WHO分類2021年版で新たに必要となったEGFR、PTEN、CDKN2Aといった遺伝子マーカーとした。WHO分類2021年改訂後、本先進医療検査での分子マーカー所見によって診断が確定した症例は54名中38名(70.1%)に上った。残り16名のうち4名(7.4%)は「びまん性神経膠腫、NEC」と診断され、12名は膠芽腫と病理組織診断された。これまで日本の医療制度下では、改訂を続けるWHO分類の移行期に臨床現場でジレンマが発生してきた。本研究で行った先進医療の試みは、その移行期を乗り切るための救済システムとして機能したことが示された。

Language：English   Publisher：Neuro Oncology Advances  

Background. Homozygous deletion of the tumor suppression genes cyclin‑dependent kinase inhibitor 2A/B (CDKN2A/B) is a strong adverse prognostic factor in IDH‑mutant gliomas, particularly astrocytoma. However, the impact of hemizygous deletion of CDKN2A/B is unknown. Furthermore, the influence of CDKN2A/B status in IDH‑ mutant and 1p/19q‑codeleted oligodendroglioma remains controversial. We examined the impact of CDKN2A/B status classification, including hemizygous deletions, on the prognosis of IDH‑mutant gliomas. Methods. We enrolled 101 adults with IDH‑mutant glioma between December 2002 and November 2021. CDKN2A/B deletion was evaluated with multiplex ligation‑dependent probe amplification (MLPA). Immunohistochemical anal‑ ysis of p16/MTAP and promoter methylation analysis with methylation‑specific MLPA was performed for cases with CDKN2A/B deletion. Kaplan − Meier plots and Cox proportion hazards model analyses were performed to evaluate the impact on overall (OS) and progression‑free survival. Results. Of 101 cases, 12 and 4 were classified as hemizygous and homozygous deletion, respectively. Immunohistochemistry revealed p16‑negative and MTAP retention in cases with hemizygous deletion, whereas homozygous deletions had p16‑negative and MTAP loss. In astrocytoma, OS was shorter in the order of homozy‑ gous deletion, hemizygous deletion, and copy‑neutral groups (median OS: 38.5, 59.5, and 93.1 months, respec‑ tively). Multivariate analysis revealed hazard ratios of 9.30 (P = .0191) and 2.44 (P = .0943) for homozygous and hemizygous deletions, respectively. Conclusions. CDKN2A/B hemizygous deletions exerted a negative impact on OS in astrocytoma. Immunohistochemistry of p16/MTAP can be utilized to validate hemizygous or homozygous deletions in combina‑ tion with conventional molecular diagnosis.

DOI： 10.1093/noajnl/vdae069

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

症例は75歳の男性で,2020年進行胃癌に対して腹腔鏡下胃全摘術を施行した.病理診断で口側断端にリンパ管侵襲を認め非治癒切除と判断した.免疫染色検査でHER2[3+]であり,術後化学療法としてトラスツズマブ+カペシタビン+シスプラチン療法8コースとカペシタビン単剤療法を16コース施行した.術後約2年で左下肢の脱力感および転倒のため近医搬送となった.CTで転移性脳腫瘍を指摘され当院へ転院となった.その他の転移はなく,脳神経外科で開頭腫瘍摘出術を施行した.術後病理より胃癌の転移性腫瘍と判断した.トラスツズマブ投与後の頭蓋内単独再発例であったため,頭蓋内も含めた全身の治療効果を期待してニボルマブ単独投与を行い,術後6ヵ月現在無再発経過中である.今回,我々はHER2陽性進行胃癌の切除後に抗HER2療法を行い,その後に単独脳転移を呈した1例を経験したため報告する.(著者抄録)

DOI： 10.1093/neuonc/noae064.271

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Language：English   Publisher：Cancers  

Glioma is one of the most common primary central nervous system (CNS) tumors, and its molecular diagnosis is crucial. However, surgical resection or biopsy is risky when the tumor is located deep in the brain or brainstem. In such cases, a minimally invasive approach to liquid biopsy is beneficial. Cell-free DNA (cfDNA), which directly reflects tumor-specific genetic changes, has attracted attention as a target for liquid biopsy, and blood-based cfDNA monitoring has been demonstrated for other extra-cranial cancers. However, it is still challenging to fully detect CNS tumors derived from cfDNA in the blood, including gliomas, because of the unique structure of the blood–brain barrier. Alternatively, cerebrospinal fluid (CSF) is an ideal source of cfDNA and is expected to contribute significantly to the liquid biopsy of gliomas. Several successful studies have been conducted to detect tumor-specific genetic alterations in cfDNA from CSF using digital PCR and/or next-generation sequencing. This review summarizes the current status of CSF-based cfDNA-targeted liquid biopsy for gliomas. It highlights how the approaches differ from liquid biopsies of other extra-cranial cancers and discusses the current issues and prospects.

DOI： 10.3390/cancers16051009

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Language：English   Publisher：Neuroradiology  

Purpose: This study aimed to compare assessments by radiologists, artificial intelligence (AI), and quantitative measurement using synthetic MRI (SyMRI) for differential diagnosis between astrocytoma, IDH-mutant and oligodendroglioma, and IDH-mutant and 1p/19q-codeleted and to identify the superior method. Methods: Thirty-three cases (men, 14; women, 19) comprising 19 astrocytomas and 14 oligodendrogliomas were evaluated. Four radiologists independently evaluated the presence of the T2-FLAIR mismatch sign. A 3D convolutional neural network (CNN) model was trained using 50 patients outside the test group (28 astrocytomas and 22 oligodendrogliomas) and transferred to evaluate the T2-FLAIR mismatch lesions in the test group. If the CNN labeled more than 50% of the T2-prolonged lesion area, the result was considered positive. The T1/T2-relaxation times and proton density (PD) derived from SyMRI were measured in both gliomas. Each quantitative parameter (T1, T2, and PD) was compared between gliomas using the Mann–Whitney U-test. Receiver-operating characteristic analysis was used to evaluate the diagnostic performance. Results: The mean sensitivity, specificity, and area under the curve (AUC) of radiologists vs. AI were 76.3% vs. 94.7%; 100% vs. 92.9%; and 0.880 vs. 0.938, respectively. The two types of diffuse gliomas could be differentiated using a cutoff value of 2290/128 ms for a combined 90^th percentile of T1 and 10^th percentile of T2 relaxation times with 94.4/100% sensitivity/specificity with an AUC of 0.981. Conclusion: Compared to the radiologists’ assessment using the T2-FLAIR mismatch sign, the AI and the SyMRI assessments increased both sensitivity and objectivity, resulting in improved diagnostic performance in differentiating gliomas.

DOI： 10.1007/s00234-024-03288-0

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Language：English  

DOI： 10.25259/SNI_734_2024

PubMed

Language：Japanese   Publisher：日本老年脳神経外科学会  

高齢化が進む我が国では、高齢者の頭部画像検査数も諸外国に比べて多く、高齢者に無症候性の良性脳腫瘍が見つかる頻度も増加してきており、その治療については若年者と違った対応が求められる。今回、当院で2013～2024年に80歳以上の高齢者髄膜腫に対して初回治療を行った12例について後方視的に解析し、高齢者髄膜腫に対する外科治療の適応や問題点について考察した。12例中11例に摘出術を行った。残りの1例は状態が悪く摘出術の適応はないと判断し、塞栓術と放射線治療を行い、緩和治療に移行した。摘出術を行った11例中、8例はSimpson Grade II以上の摘出、3例はGrade IVの摘出であった。術後のKPSは50～100(中央値90)で、術前と比べて明らかに低下したものが1例あった。治療後の転帰は、1年以内に原疾患で死亡したものが2例、他の要因で死亡したものが3例あった。代表例4例を提示した。

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Language：English   Publisher：Neuroradiology  

This study aimed to investigate whether arterial spin labeling (ASL) features allow differentiation of oligodendroglioma, IDH-mutant and 1p/19q-codeleted (IDHm-codel) from diffuse glioma with IDH-wildtype (IDHw) or astrocytoma, IDH-mutant (IDHm-noncodel). Participants comprised 71 adult patients with pathologically confirmed diffuse glioma, classified as IDHw, IDHm-noncodel, or IDHm-codel. Subtraction images were generated from paired-control/label images on ASL and used to assess the presence of a cortical high-flow sign. The cortical high-flow sign was defined as increased ASL signal intensity within the tumor-affecting cerebral cortex compared with normal-appearing cortex. Regions without contrast enhancement on conventional MR imaging were targeted. The frequency of the cortical high-flow sign on ASL was compared among IDHw, IDHm-noncodel, and IDHm-codel. As a result, the frequency of the cortical high-flow sign was significantly higher for IDHm-codel than for IDHw or IDHm-noncodel. In conclusion, the cortical high-flow sign could represent a hallmark of oligodendroglioma, IDH-mutant, and 1p/19q-codeleted without intense contrast enhancement.

DOI： 10.1007/s00234-023-03186-x

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Language：English   Publisher：The Japan Neurosurgical Society  

<p>We aimed to retrospectively determine the resection rate of fluid-attenuated inversion recovery (FLAIR) lesions to evaluate the clinical effects of supramaximal resection (SMR) on the survival of patients with glioblastoma (GBM). Thirty-three adults with newly diagnosed GBM who underwent gross total tumor resection were enrolled. The tumors were classified into cortical and deep-seated groups according to their contact with the cortical gray matter. Pre- and postoperative FLAIR and gadolinium-enhanced T1-weighted imaging tumor volumes were measured using a three-dimensional imaging volume analyzer, and the resection rate was calculated. To evaluate the association between SMR rate and outcome, we subdivided patients whose tumors were totally resected into the SMR and non-SMR groups by moving the threshold value of SMR in 10% increments from 0% and compared their overall survival (OS) change. An improvement in OS was observed when the threshold value of SMR was 30% or more. In the cortical group (n = 23), SMR (n = 8) tended to prolong OS compared with gross total resection (GTR) (n = 15), with the median OS of 69.6 and 22.1 months, respectively (p = 0.0945). Contrastingly, in the deep-seated group (n = 10), SMR (n = 4) significantly shortened OS compared with GTR (n = 6), with median OS of 10.2 and 27.9 months, respectively (p = 0.0221). SMR could help prolong OS in patients with cortical GBM when 30% or more volume reduction is achieved in FLAIR lesions, although the impact of SMR for deep-seated GBM must be validated in larger cohorts.</p>

DOI： 10.2176/jns-nmc.2022-0351

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CiNii Research

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1542203301

CiNii Research

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： https://doi.org/10.1093/noajnl/vdac178

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publisher：Neuropathology  

The mutation p.K27M in H3F3A (H3 K27M mutation) is mainly detected in diffuse midline glioma. However, recent studies have demonstrated that H3 K27M mutation could also be observed in a subset of gangliogliomas. Importantly, most H3 K27-mutated ganglioglioma cases also harbor BRAF V600E mutation. Herein, we report a rare case of H3 K27M-mutated ganglioglioma grade 3 without BRAF mutation arising in the medial temporal lobe in an elderly man. A small biopsy specimen was sampled. The pathological diagnosis was diffuse astrocytoma. The tumor progressed gradually during an 18-month follow-up period. Gadolinium enhancement on magnetic resonance imaging was noted 36 months after the biopsy. The patient was referred to a hospital for tumor resection. Histological analysis of resected specimens led to a diagnosis of ganglioglioma grade 3 with H3 K27M mutation. The patient underwent concurrent temozolomide chemotherapy with radiotherapy. Although the patient's condition deteriorated after chemotherapy due to disease progression, he survived for more than 23 months after tumor resection. We present this rare case and discuss the involvement of H3 K27M mutation in ganglioglioma grade 3.

DOI： 10.1111/neup.12793

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Language：English   Publisher：World Neurosurgery  

Background: Controversies exist regarding the aggressive recurrence of glioblastoma after bevacizumab treatment. We analyzed the clinical impact of bevacizumab approval in Japan by evaluating the clinical course and relapse pattern in patients with glioblastoma. Methods: We included 100 patients with IDH-wild-type glioblastoma from September 2006 to February 2018 in our institution. The patients were classified into the pre-bevacizumab (n = 51) and post-bevacizumab (n = 49) groups. Overall, progression-free, deterioration-free, and postprogression survivals were compared. We analyzed the relapse pattern of 72 patients, whose radiographic progressions were evaluated. Results: Significant improvement in progression-free (pre-bevacizumab, 7.5 months; post-bevacizumab, 9.9 months; P = 0.0153) and deterioration-free (pre-bevacizumab, 8.5 months; post-bevacizumab, 13.8 months; P = 0.0046) survivals was seen. These survival prolongations were strongly correlated (r: 0.91, P < 0.0001). The nonenhancing tumor pattern was novel in the post-bevacizumab era (5 of 33). The presence of a nonenhancing tumor did not indicate poor postprogression survival (hazard ratio: 0.82 [0.26–2.62], P = 0.7377). The rate of early focal recurrence was significantly lower (P = 0.0155) in the post-bevacizumab (4 of 33) than in the pre-bevacizumab (18 of 39) era. There was a significant decrease in early focal recurrence after approval of bevacizumab in patients with unresectable tumors (P = 0.0110). The treatment era was significantly correlated with a decreased rate of early focal recurrence (P = 0.0021, univariate analysis; P = 0.0144, multivariate analysis). Conclusions: Approval of first-line bevacizumab in Japan for unresectable tumors may prevent early progression and clinical deterioration of glioblastoma without worsening the clinical course after relapse.

DOI： 10.1016/j.wneu.2021.12.075

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publisher：(株)メディカ出版