Diffuse gliomas with H3F3A gene mutation such as H3.3 K27M and G34R/V are infrequently found in the cerebral hemisphere. These tumors may be called histone H3 K27M-mutant diffuse non-midline gliomas (NDMG) or H3 G34-mutant diffuse hemispheric gliomas (DHG), respectively. We investigated the clinical, radiological and molecular characteristics and treatment outcomes of patients with H3 K27-mutant NDMG compared with those with H3 G34-mutant DHG. We collected cases of histone H3-mutant diffuse glioma at non-midline location that were enrolled in the Kansai Molecular Diagnosis Network for CNS Tumors. The clinical, radiological and pathological characteristics and DNA methylation were retrospectively analyzed and then compared between cases of NDMG and DHG. We evaluated various factors to examine their effects on overall survival. Included in this study were 16 patients with H3 K27M-mutant NDMG and nine patients with H3 G34R/V-mutant DHG. Patients with NDMG were older than those with DHG (median age: 45 vs. 25 years old). Overall survival times of patients with NDMG were comparable to those of DHG (median overall survival: 20.0 vs. 22.5 months). Female sex, preoperative Karnofsky performance status score ≥ 80 and extensive surgical resection tended be related to better prognoses in the patients with these tumors. H3 K27M-mutant NDMGs were shown to possess similar DNA methylation properties to H3 K27M-mutant DMGs. Diffuse gliomas harboring histone H3 K27M mutation can arise in the cerebral hemisphere in older adults. These findings suggest that H3 K27M-mutant NDMGs show different clinical manifestations to H3 K27M-mutant DMGs and H3 G34R/V-mutant DHGs, despite having similar molecular properties to H3 K27M-mutant DMGs.

Endoscopic surgery, including endoscopic endonasal transsphenoidal surgery (ETSS), requires special psychomotor skills from surgeons. The learning curve in the acquisition of psychomotor skills varies among individuals, and studies about laparoscopy indicate that the difference can be predicted using spatial ability tests. We examined the association between the results of such tests and the learning curve in ETSS to determine the need for a personalized curriculum for ETSS skill training. A total of 30 fifth-year medical students from Kindai University School of Medicine (17 men, 13 women; mean age, 26 years) without ETSS experience completed the spatial orientation test (SOT) for the measurement of spatial visualization ability. They performed the dural incision task (DIT) twice on an ETSS training model for surgical psychomotor skill evaluation. The SOT scores (angle errors) exhibited substantial individual differences in spatial visualization ability, whereas the DIT scores significantly improved in the second trial (Wilcoxon signed-rank test, P = 0.0035). However, no significant difference was observed in the DIT scores between the smaller error and larger error groups of the SOT. The results indicated that two DIT trials were sufficient to acquire psychomotor skills for the DIT as the endoscope was almost fixed and learning only one viewpoint and line of sight combination was adequate. In conclusion, a personalized ETSS training program based on the trainee's spatial ability is not necessary for the DIT. Further research is warranted to determine the effect of spatial ability on more complex tasks, such as suturing in cranial base repair.

BACKGROUND/AIM: Standard treatment options for primary central nervous system lymphoma (PCNSL) include high-dose methotrexate (HD-MTX)-based drug therapy and whole-brain radiation therapy. However, there are many cases in which these standard treatment options are not tolerated for various reasons. In the present study, five cases of refractory/relapsed PCNSL that are difficult to treat with standard treatment were successfully treated by tirabrutinib. PATIENTS AND METHODS: A total of 5 patients (4 women, 1 man) with refractory (n=3) and relapsed (n=2) PCNSL were included. The patients had a median age of 76 years and a median Karnofsky performance status (KPS) of 40. The reasons why standard treatment cannot be given to these patients are the low KPS, renal dysfunction, and resistance to HD-MTX. Administration of a drug via the oral route was challenging in three patients; thus, these patients were administered tirabrutinib in suspension through a nasogastric tube. RESULTS: Imaging findings showed that the patients achieved a 100% response rate to tirabrutinib, with a median survival of 8 months. As symptoms improved, 2 of the 3 patients who were initially administered tirabrutinib via a nasogastric tube were able to receive the drug via the oral route. Three patients developed adverse reactions; however, treatment was not interrupted because they were manageable. CONCLUSION: Tirabrutinib was effective in the treatment of patients who were unable to receive standard treatment options. Tirabrutinib may be considered one of the novel treatment strategies that could improve the prognosis of PCNSL patients in the future.

ABSTRACT: A 20-year-old man had left visual impairment and homonymous hemianopsia. MRI findings suggested enlargement of an optic glioma, because optic glioma was indicated by MRI 14 years earlier without a definite pathological diagnosis. 11C-methionine (MET) PET showed high uptake in the tumor in the parasellar region. Transnasal endoscopic biopsy was performed, and an inflammatory pseudotumor (IPT) was diagnosed based on histopathological findings. High MET uptake in a parasellar IPT has apparently not been previously reported. Clinicians should be aware of the possibility of high MET uptake in IPT, because this image could provide an interpretation pitfall.

30代男性。咳嗽・胸痛・血痰を主訴に近医を受診し、胸部X線で両側肺野に瀰漫性スリガラス状陰影を認められ、当院に紹介された。胸部CTでスリガラス状陰影に加えて多発する結節影を認め、悪性疾患の鑑別のため気管支鏡検査目的に入院となった。気管支鏡で瀰漫性の出血所見を認め、左上葉の結節から生検を行ったが確定診断は得られなかった。悪性疾患等の鑑別が必要であるため胸腔鏡下肺部分切除術を施行し、術中・術後に合併症は認めなかったが、術後3日目に突然の頭痛・嘔吐が出現し、頭部CTで小脳出血を認めた。脳血管病変の精査のためCT angiographyを施行し、明らかな血管異常は認めなかったが、血腫が拡大したため緊急で開頭血腫除去術を施行した。血腫を吸引で除去したところ腫瘍性病変を認めたため、この病巣を摘出して病理組織学的検査を行い、血管肉腫と診断した。肺病変の病理組織学的診断も同様であり、肺血管肉腫原発の転移性脳腫瘍と診断した。

高齢発症てんかん(A)は初回発作後の再発が高率であると報告されているが、発作自体は少量の抗てんかん薬で比較的コントロール可能である。そのため、Aによる機能的予後の悪化を防ぐには可及的早期の治療介入を目指すべきであるが、非専門医によるAの診断は困難であり、多数の症例が潜在化している可能性がある。そこで、潜在するAを顕在化させるために簡便な調査票を用いたスクリーニングを行い、有効性が認められたので報告した。調査票の内容は以下の8項目とした。1)突然の動作停止と反応性の低下を認める。2)無自覚な口部自動症、体幹・四肢の揺れがある。3)意識を失っても倒れない。4)動作停止後、数十秒～数分で何事もなかったように動作再開する。5)意識消失時のことを何も覚えていない。6)意識改善後も数分～数時間は虚ろである。7)易怒性が高い。8)目の焦点が合わないことがある。

BACKGROUND/AIM: Leptomeningeal carcinomatosis (LMC) with hydrocephalus is particularly difficult to treat, and its prognosis is extremely poor. The therapeutic outcomes of 14 patients with LMC-associated hydrocephalus who were treated with cerebrospinal fluid shunting are reported. PATIENTS AND METHODS: The study subjects were 14 LMC patients with solid primary cancer who had developed hydrocephalus. RESULTS: Postoperatively, both symptoms and Karnofsky performance status improved in 100% of patients. Postoperative therapy consisted of whole-brain radiotherapy in 4 cases and molecular targeted therapy in 4, with 6 patients not receiving any postoperative treatment. Median overall survival was 3.7 months, with no significant difference between those who underwent postoperative therapy and those who did not. However, two of those who received molecular targeted therapy survived for more than one year. CONCLUSION: Cerebrospinal fluid shunting for LMC-associated hydrocephalus is an effective therapeutic procedure from the palliative viewpoint. Patients for whom molecular targeted therapy is indicated may have better long-term survival.

We report that tirabrutinib was administered via nasogastric tubes to treat an elderly patient with primary central nervous system lymphoma (PCNSL). The patient was a 76-year-old woman who underwent endoscopic biopsy of multiple intracerebral masses, which resulted in the diagnosis of diffuse large B-cell lymphoma. The patient was diagnosed with PCNSL and was started on an induction regimen of systemic chemotherapy with rituximab in combination with high-dose methotrexate. However, after the second cycle of chemotherapy, the tumor grew rapidly, and the patient went into a coma. As a result, the treatment was changed to nasogastric tube administration of tirabrutinib suspension. After 1 week of tirabrutinib administration, the patient's level of consciousness improved, and furthermore, after 2 weeks of tirabrutinib administration, the patient was able to take tirabrutinib orally. Although oral administration is the standard route of administration for tirabrutinib, this case study showed that the nasogastric tube administration of tirabrutinib suspension is a therapeutic option for patients with impaired consciousness or dysphagia.

BACKGROUND/AIM: Recent advances in systemic chemotherapy, including molecularly targeted therapy, have dramatically improved survival for patients with advanced non-small cell lung cancer. We retrospectively analyzed the clinical outcomes of surgical resection for brain metastases of non-small cell lung cancer cases performed at the Department of Neurosurgery of Kindai University Hospital, Osaka, Japan. PATIENTS AND METHODS: Craniotomy and tumor resection were performed for 56 patients with brain metastases of non-small cell lung cancer. Adenocarcinoma was the most common histological type, appearing in 40 cases, of which 18 were positive for driver gene mutations. RESULTS: Median survival for all 56 patients was 14.5 months, and single brain metastasis and adenocarcinoma were identified as favorable prognostic factors. Analysis limited to the 40 cases of adenocarcinoma identified single brain metastasis as a favorable prognostic factor. Although no significant difference was found for systemic chemotherapy, patients who received molecularly targeted therapy showed a better prognosis than those who received cytotoxic chemotherapy. Analyses of both the entire group and of adenocarcinoma patients alone found that whole-brain radiotherapy showed no significant association with survival. CONCLUSION: Single brain metastasis and adenocarcinoma were identified as favorable prognostic factors, but did not confirm any benefit from whole-brain radiotherapy. These results suggest that multimodal treatment strategies utilizing various methods of treatment, including systemic chemotherapy, may help prolong patient survival in the future.

BACKGROUND: Brain metastasis (BM) is an uncommon complication of sarcomas with a poor prognosis. Little information is available about the feasibility and prognostic factors of surgical resection of BM from sarcomas. METHODS: This study involved a retrospective analysis of 22 patients with BM from sarcomas who underwent resection at six institutes in Japan. Prognostic factors were analyzed to develop a graded prognostic assessment (GPA) using the log-rank test and Cox regression analysis. For validation of this GPA, we collected data on 100 surgical cases from 48 published reports. RESULTS: Postoperative Karnofsky Performance Status (KPS) improved in 50% of our patients. Median overall survival (OS) was 21 months. Multivariate analysis showed age and alveolar soft part sarcoma (ASPS) were significant preoperative prognostic factors (P < 0.05). RTOG-RPA classification had no significant prognostic value. We developed a GPA system for OS after resection of BM. A score of 0 was assigned to patients aged 18-29 years with non-ASPS, 2 to patients aged 18-29 years with ASPS or 30-76 years with non-ASPS, and 4 to patients aged 30-76 years with ASPS. Median OS for patients with GPA scores of 0, 2, and 4 were 6.5, 16.0, and 44.0 months, respectively (P = 0.002). The results were validated by the data of 100 cases compiled (P < 0.001). CONCLUSION: Median OS of patients with BM from sarcomas was comparable to that from carcinomas after resection. A new sarcoma-specific GPA may help patients and clinicians to select resection as an option for treatment of BM from sarcomas.

Aplastic anemia is a rare blood disease characterized by the destruction of the hematopoietic stem cells (HSC) in the bone marrow that, in the majority of cases, is caused by an autoimmune reaction. Patients with aplastic anemia are treated with immunosuppressive drugs and some of them, especially younger individuals with a donor available, can be successfully treated with hematopoietic stem cell transplantation (HSCT). We report here a rare case of post-transplant lymphoproliferative disorder (PTLD) associated with Epstein-Barr virus (EBV) reactivation in a 30-year-old female patient who underwent allogeneic HSCT for severe aplastic anemia. The PTLD, which was diagnosed 230 days after transplantation, was localized exclusively in the central nervous system (specifically in the choroid plexus) and manifested with obvious signs of intracranial hypertension. After receiving three cycles of high dose methotrexate (HD-MTX) combined with rituximab, the patient achieved a complete clinical recovery with normalization of blood cell counts, no evidence of EBV reactivation, and no associated neurotoxicity.

BACKGROUND/AIM: High-mobility group box 1 (HMGB1) is a nuclear DNA-binding protein that exerts a range of proinflammatory actions when it is secreted extracellularly. We hypothesized that HMGB1 released from damaged cells in pituitary apoplexy would exacerbate the neurological symptoms due to acute inflammation. PATIENTS AND METHODS: All the patients included in this study suffered from non-functioning pituitary adenoma. Four patients with apoplexy and three patients without apoplexy were included in this study. They underwent endonasal transsphenoidal endoscopic surgery to resect the tumors. We conducted enzyme-linked immunosorbent assay (ELISA) to measure HMGB1 in the surgical specimens. RESULTS: Patients with apoplexy expressed HMGB1 at significantly higher levels than those in the non-apoplexy group (p=0.0478). CONCLUSION: HMGB1 may be involved in subacute inflammation of pituitary apoplexy. Further work is needed to elucidate the detailed biological significance of HMGB1 in this disease.

Intravascular lymphoma (IVL) is a malignant lymphoma that lacks the expression of cell surface adhesion molecules so that cells fluidly migrate within the blood vessels. The patient in the present study had restricted eye movement caused by IVL, mimicking a cavernous sinus tumor. Because the cavernous sinus lumen is divided into multiple compartments by trabeculae and venous channels, IVL tumor cells were trapped in these compartments, thus forming a mass, which subsequently extended into the contralateral cavernous sinus via the anterior and posterior intercavernous sinuses. This is a rare case of IVL forming a mass inside the cavernous sinus.

Background: Leptomeningeal metastases (LM) pose the most difficult form of cancer metastasis to treat and portend a poor prognosis. Standard treatment has yet to be established, and intrathecal chemotherapy and whole- brain radiotherapy are administered on an empirical basis. Case Description: We report on a 46-year-old woman with LM from human epidermal growth factor receptor 2 (HER2)-positive breast cancer. She was suffering from intractable headaches, severe nausea and vomiting, and cerebellar ataxia. Contrast-enhanced magnetic resonance imaging (MRI) revealed diffuse enhancement of the meninges, mainly in the posterior cranial fossa, and compression of the cerebellum by the profoundly thickened meninges. The first step in the treatment was decompression of the posterior cranial fossa to relieve intracranial hypertension. After surgery, her symptoms immediately improved. The second step was treatment with lapatinib at 1250 mg and capecitabine 1200 mg, which dramatically improved her symptoms and disappeared diffuse abnormal signal enhancement on MRI. Conclusion: We treated a patient with LM from primary HER2-positive breast cancer who responded well to lapatinib plus capecitabine.

INTRODUCTION: The introduction of systemic chemotherapy for advanced hepatocellular carcinoma in recent years has led to the prediction that cases of brain metastases from hepatocellular carcinoma will increase. However, because brain metastases from hepatocellular carcinoma are relatively rare, the characteristics of this pathology are poorly understood. METHODS: We carried out a multicenter retrospective study to verify the characteristics of brain metastases from hepatocellular carcinoma in Japan. RESULTS: A total of 38 patients were enrolled and patient characteristics were poor general condition in many patients due to the progression of primary cancers. Stereotactic radiosurgery/stereotactic radiotherapy alone was the most common treatment (39.5%), with best supportive care provided for 10.5%. Median survival was 6 months, the neurological death rate was 28%, and the rate of brain hemorrhage was high (39.5%). Overall survival was analyzed for correlations with age, etiology of chronic liver disease, albumin-bilirubin (ALBI) grade, RPA classification, control of the primary tumor, number of brain metastases, brain hemorrhage, surgical resection, and radiotherapy. In multivariate analysis, ALBI grade, number of brain metastases and brain hemorrhage showed statistically significant correlation. CONCLUSIONS: A multivariate analysis extracted three items-ALBI grade, number of brain metastases, and brain hemorrhage-as prognostic factors for survival of brain metastases from hepatocellular carcinoma.

BACKGROUND/AIM: Excessive extracellular glutamate activates AMPA-type glutamate receptors (AMPA receptors) and induces seizures. Antagonistic activation of AMPA receptors inhibits epilepsy and glioma growth in in vitro and in vivo studies. This study was conducted to evaluate the clinical impacts of perampanel (PER), a novel AMPA receptor antagonist, on seizures and tumor progression in glioma patients with uncontrollable epilepsy. PATIENTS AND METHODS: Twelve glioma patients with uncontrollable epilepsy were treated with PER. Seizure response, PER concentration, and tumor volume were assessed. RESULTS: Obvious seizure control was observed in 10 analyzed patients (100%) and 6 patients (60%) became seizure-free. Median plasma concentrations of PER were 296 ng/ml in those with 4 mg/day PER treatment and 518 ng/ml in those with 8 mg/day PER treatment. High-intensity lesions in fluid-attenuated inversion recovery of magnetic resonance imaging (MRI) were volumetrically assessed to analyze tumor size. Volume reduction was detected within 6 months in correlation with increased plasma levels of PER. CONCLUSION: PER treatment was effective in uncontrollable epilepsy with gliomas. MRI images showed the inhibition of tumor growth.

[Abstract] Current evidence indicates that glioma stem cell-like cells (GSC_S) in humans play critical roles in the pathogenesis of carcinogenesis ofglioblastoma (GBM ). The GSC_S are known to overexpress members of the adenosine triphosphate-binding cassette (ABC) family transporters to exhibit multidrug resistance. Eradication of the GSC compartment is therefore essential to achieve a stable and long-lasting remission of GBM. To elucidate the characteristics of GSC_S in detail, we generated murine GSC lines from Sleeping Beauty transposon-mediated spontaneous GBM . Using these several cell lines, we evaluated the significance of ABC transporters in the GSC kinetics by cell morphology assays, flow cytometry, and quantitativeRT-PCR for mRNA expressions. As a consequence, we show that siRNA-mediated ABCG2 inhibition enhances the sensitivity of GSC_S to temozolomide (TMZ) and in turn reduces their spheroid-forming capability. Furthermore, we show that GSC_S treated with Abcg2-specific siRNA become sensitive to TMZ and reduce their spheroid-forming capability. In conclusion, our data suggest that targeting of drug transporters in GSC_S is a promising strategy to enhance their chemo-sensitivity for achieving a longlasting remission of GBM .

BACKGROUND: An outstanding issue regarding the surgical treatment of cyst-type metastatic brain tumors is the incomplete resection of cyst walls. Herein we propose a novel surgical technique that can overcome this issue. During a surgical procedure for cystic tumors, autologous fibrin glue is to be injected into the tumor cysts, which solidifies the cyst lumens and cyst walls en bloc with reducing the tumor size. As a result, tumor masses and cyst walls can be removed completely in an en bloc fashion in all cases. METHODS: The illustrative case presented in this report is a patient with metastatic brain tumors in the frontal lobe. When we reached the tumor wall surgically, we first suctioned out the cyst content and subsequently injected autologous fibrin glue into the cyst lumen. The autologous fibrin glue solidified the tumor en bloc, and we resected the tumor mass and the cyst walls in an en bloc fashion. RESULTS: We have applied this technique to four cases with cyst-type metastatic brain tumors. This approach made it possible to perform ideal en bloc resection in all cases. There were no adverse events due to the autologous fibrin glue. CONCLUSION: We developed a novel surgical technique to solidify cyst-type metastatic brain tumors using autologous fibrin glue, which allows en bloc resection of tumor masses and cyst walls quite safely using inexpensive materials. Given these advantages, it appears a promising surgical strategy for cyst-type metastatic brain tumors.

2021 年度は肺癌血行性脳転移マウスモデルの脳組織を採取し、フローサイトメトリー法を用いてマクロファージ分画上の B7-H3 および B7-H5 発現レベルを確認した。同時に脳腫瘍組織より M2 マクロファージを単離して mRNA を抽出し、DNA マイクロアレイを用いたトランスクリプトーム解析を行った。さらにマルチプレックスサイトカイン測定も導入し、限定された臨床検体サンプルから相当量のサイトカイン/ケモカインデータの取得を行なっている。 他者の先行研究では肺癌細胞上に B7-H3 が発現することが示され、B7-H3 を標的とした治療薬が治験レベルで用いられるようになった。そこで我々真相学習アルゴリズムを用いた病理組織解析システム Cu-Cyto を用いて、腫瘍組織中の B7-H3 発現を解析した。上記知見と同様、一部の転移性肺癌細胞は B7-H3 を発現しており、かつ腫瘍組織に浸潤するマクロファージ上にも B7-H3 発現がみられた。 近年腫瘍組織近傍に三次リンパ節様構造物 (Tertiary Lymphoid Structures: TLS または Tertiary Lymphoid Organs: TLO) が形成され、腫瘍増殖あるいは腫瘍制御に関わることが示されている。そこで我々は Cu-Cyto システムを用いて上記腫瘍組織中での TLS/TLO を検索し、これらの発現頻度等を調べた。

マウス担脳腫瘍(神経膠腫)モデルおよびヒト神経膠腫においてWT1ワクチン治療前後の局所での獲得性免疫動態を明らかにし、グレード2/3神経膠腫に対するWT1ワクチン治療の開発を行うことを本研究の目標としている。 Ⅰ：初年度から継続してC57BL/6マウスをモデルとして用い、( I ) 正常マウスおよび( ii ) 担脳腫瘍（203G由来）マウスを作成した。それらに対して脳組織でCD4陽性細胞、CD8陽性細胞を免疫組織学的に同定し、その集族や時間的動態を明らかにした。コントロールとして行った正常マウスに対して、担脳腫瘍マウスの脳では、限局性であったが免疫担当細胞の集族が認められ、局所獲得免疫細胞として評価した。 Ⅱ：ヒトにおいて、グレード2/3神経膠腫初回摘出時および再手術時の腫瘍組織および辺縁組織を用いて検討した。それぞれの腫瘍組織においてWT1の発現およびCD4、CD8陽性細胞を免疫組織学的に同定し、その免疫担当細胞の集族を明らかにした。全ての腫瘍細胞でWT1は発現されていたがグレード３やグレード４神経膠腫に比べ、グレード２神経膠腫に弱い傾向があった。そのなかで治療中ステロイド投与時あるいは抗けいれん剤投与時の上記免疫担当細胞の移動を検討した。 初年度から研究体制の変更を要し、実験を再構築したため満足のいくものではなかった。しかしながら免疫治療の継続実績があり初年度から治療関連で学会発表や論文投稿ができた。

肺がんにおける脳転移発症のメカニズムにM2マクロファージを中心とした免疫機構が関与していることが判明した。さらにマイクロアレイ解析にて、このM2マクロファージの治療標的となり得る遺伝子群も同定することができた。また、この免疫応答は腸内細菌が産生する代謝産物も関与していることを証明した。これらより、今後、脳転移を予防する新たな治療戦略が得られる可能性が示唆された。

転移性脳腫瘍に対してWT1免疫療法を行う妥当性を、動物モデル研究、ヒト免疫反応の研究を通して、治療前後の細胞性免疫反応を中心に解析した。担脳腫瘍マウスモデルでは、脳腫瘍細胞のWT1発現を確認し、限局性であったが免疫担当細胞の集族を明らかにした。しかしながらWT1ペプチドに治療よる効果発現は軽度であった。ヒトにおいて、乳癌の転移性脳腫瘍に対し分子標的治療時の免疫担当細胞の動態解析を行った。腫瘍細胞表面抗原WT1の発現は軽度でありWT1特異的キラーT細胞の変化も軽度であった。しかしながらWT1ペプチドの投与局所皮下組織においてCD4およびCD8免疫担当細胞が集族していることを確認した。

肺がんに対する治療成績向上に伴い転移性脳腫瘍の罹患率が増加している。近年がん増殖・浸潤・転移における免疫系の関わりが明らかとなりつつあり、NSAID の長期投与によるがん死亡率低下が報告された。近年我々は、脳腫瘍発生初期において骨髄由来抑制細胞 (MDSC) が CCL2/CXCL12 ケモカイン依存性に病変部に集積し、発症のトリガーとなり、かつ NSAID により COX-2 阻害により MDSC 抑制および脳腫瘍発生抑制しうることを示してきた。それらの知見を元に、本研究では、特に肺がん転移性脳腫瘍発症における MDSC の影響を、マウスによる非臨床研究およびヒト臨床研究の両面から評価した。

神経膠芽腫の摘出標本を用いた免疫染色を行った。術前にインターフェロンを静脈内投与、局所投与したものと投与なしで比較すると、局所投与した群にのみ誘導型一酸化窒素合成酵素(iNOS)の発現が認められた。このiNOSの発現細胞は二重染色の結果、脳内マクロファージであるミクログリアと判明、インターフェロンでの直接刺激によるものと考えられた。また高濃度のiNOSは大量の一酸化窒素(NO)を誘導することが判明している。次に神経膠芽腫の培養細胞を用いてNO負荷による抗腫瘍効果をDNAマイクロアレイを用いて解析した。NO負荷を与えた群と負荷なしの群で比較したところ、NO負荷では明らかな腫瘍増殖抑制関連の遺伝子が発現増加しており、また腫瘍増殖効果をもつ関連遺伝しの発現低下がみられた。これらの結果より、従来の報告ではインターフェロンの抗腫瘍効果はp53を介したものとされていたが、神経膠芽腫の場合、大量のNO誘導による新たな経路が生じている可能性がある。特に大量のNOによりEGFR-JAK/STAT経路を介している可能性が判明した。さらに培養細胞を用いてインターフェロンによる大量NO誘導療法を増強させるため、リポポリサッカライドを追加し、検討している。またEGFRの分子標的薬剤も追加し、抗腫瘍効果の増強を検討している。神経膠芽腫の新規化学療法としてアルキル化剤のTemozolomideが使用されているが、本薬剤はインターフェロンの併用によりMGMTの不活化が促進された結果、抗腫瘍効果の増強が予想される。このため、現在、全国規模で治験が行われている。これより、本研究結果も合わせてインターフェロンの静脈内投与+局所投与により、抗腫瘍効果が増強され、神経膠芽腫治療が進歩する可能性がある。