Postoperative disappearance of leptomeningeal enhancement around the brainstem in glioblastoma.

PURPOSE: Leptomeningeal enhancement (LME) suggests leptomeningeal dissemination (LMD) of tumor cells, which is a complication of end-stage glioblastoma, and is associated with a poor prognosis. However, magnetic resonance imaging (MRI) occasionally indicates the disappearance of peri-brainstem LME after surgical resection of glioblastoma. Since preoperative LMD may affect treatment indications, we aimed to analyze the clinical significance of preoperative LME of the brainstem in glioblastoma. METHODS: We retrospectively collected clinical and radiological data from consecutive patients with glioblastoma and preoperative LME of the brainstem, who were treated at our hospital between 2017 and 2020. RESULTS: Among 112 patients with glioblastoma, nine (8%) showed preoperative LME of the brainstem. In comparison with tumors without LME, tumor size was significantly associated with the preoperative LME of the brainstem (p = 0.016). In addition, there was a trend toward significance for a relationship between deep tumor location and preoperative LME of the brainstem (p = 0.058). Notably, among six patients who underwent surgical resection for glioblastoma with LME of the brainstem, four showed significant radiological disappearance of the LME on postoperative MRI. This suggests that the LME did not result from LMD in these cases. Moreover, these four patients lived longer than would be expected from the presence of LMD. However, this LME disappearance was not observed after biopsy or chemoradiotherapy. CONCLUSIONS: These findings suggest that preoperative LME does not necessarily indicate the presence of untreatable LMD; moreover, LME may disappear after surgical tumor resection. Thus, transient preoperative LME could be attributed to other mechanisms, including impaired venous flow due to intratumoral arteriovenous shunts, which can be resolved by reducing the tumor burden.

Importance of Age and Noncontrast-Enhancing Tumor as Biomarkers for Isocitrate Dehydrogenase-Mutant Glioblastoma: A Multicenter Study.

PURPOSE: This study aimed to investigate the most useful clinical and magnetic resonance imaging (MRI) parameters for differentiating isocitrate dehydrogenase (IDH)-mutant and -wildtype glioblastomas in the 2016 World Health Organization Classification of Tumors of the Central Nervous System. METHODS: This multicenter study included 327 patients with IDH-mutant or IDH-wildtype glioblastoma in the 2016 World Health Organization classification who preoperatively underwent MRI. Isocitrate dehydrogenase mutation status was determined by immunohistochemistry, high-resolution melting analysis, and/or IDH1/2 sequencing. Three radiologists independently reviewed the tumor location, tumor contrast enhancement, noncontrast-enhancing tumor (nCET), and peritumoral edema. Two radiologists independently measured the maximum tumor size and mean and minimum apparent diffusion coefficients of the tumor. Univariate and multivariate logistic regression analyses with an odds ratio (OR) were performed. RESULTS: The tumors were IDH-wildtype glioblastoma in 306 cases and IDH-mutant glioblastoma in 21. Interobserver agreement for both qualitative and quantitative evaluations was moderate to excellent. The univariate analyses revealed a significant difference in age, seizure, tumor contrast enhancement, and nCET ( P < 0.05). The multivariate analysis revealed significant difference in age for all 3 readers (reader 1, odds ratio [OR] = 0.960, P = 0.012; reader 2, OR = 0.966, P = 0.048; reader 3, OR = 0.964, P = 0.026) and nCET for 2 readers (reader 1, OR = 3.082, P = 0.080; reader 2, OR = 4.500, P = 0.003; reader 3, OR = 3.078, P = 0.022). CONCLUSIONS: Age and nCET are the most useful parameters among the clinical and MRI parameters for differentiating IDH-mutant and IDH-wildtype glioblastomas.

An epileptogenic intracranial cystic lesion lined with fallopian tube-type epithelium: illustrative case.

BACKGROUND: Intracranial cystic lesions are often a trigger for epileptic seizures. However, there has never been a report of a cystic lesion lined with fallopian tube-type epithelium. OBSERVATIONS: A 48-year-old female presented with a cystic lesion in the right occipital lobe, which gradually grew over 8 years. Right occipital lobe epilepsy was diagnosed based on visual aura, convulsive seizures, and electroencephalogram findings and the cyst was surgically removed. Further examination revealed the cyst was lined with ciliated cells, which had morphological and immunohistochemical features similar to those of fallopian tube epithelium. LESSONS: The characteristics of the cyst did not conform to any known types of benign cystic lesion. To the authors' knowledge, no such cyst has been reported before. The authors discuss the origins and pathogenesis of this unfamiliar cystic lesion.

[Dystrophia myotonica Type 1 associated with glioblastoma: a case report].

This case involved a 65-year-old woman, who had been suffered from weakness in both legs for 10 years. She had not been diagnosed of dystrophia myotonica type 1 (DM1) despite her son's diagnosis of DM and her distinct facial features and gait anomaly. During her son's recent clinical visit, she was finally suspected of having DM. She was sent to our institution, where a distinct muscle atrophy and grip myotonia were observed and a genetical examination was performed. The sequencing data confirmed her diagnosis of DM1 due to the distinct 230-900 CTG repeats found in the dystrophia myotonica protein kinase gene 3' untranslated region. A brain MRI revealed an abnormal lesion with irregular ring-enhancement at the right temporal lobe. Because of the steady growth of the lesion during one month observation, a surgical intervention was performed in our institution. The histopathological examination gave a diagnosis of glioblastoma multiforme (GBM). The clinical management of the patient required special cares during the perioperative periods due to the distinct pathological manifestation of DM. The risk of developing cancer in DM patients has been estimated about twice as much as general population. Since GBM developed in the DM patient is rarely reported, we present this rare case with a few insights: the difficulties of the clinical management of DM patients under the perioperative stress; the pathological contribution of DM to the malignant transformation of the glial cells.

Diffusely infiltrating glioma with CREBBP-BCORL1 fusion showing overexpression of not only BCORL1 but BCOR: A case report.

BCORL1 encodes a transcriptional corepressor homolog to BCOR. BCORL1 rearrangements have been previously described as rare events, and among them, CREBBP-BCORL1 has been reported only in 2 cases of ossifying fibromyxoid tumors. Herein, we present the first case of diffusely infiltrating glioma with CREBBP-BCORL1 involving a 17-year-old female patient. Histologically, the tumor was composed of a diffusely infiltrative proliferation of small tumor cells with moderate cellularity showing prominent microcystic formation. DNA methylation analysis revealed that the current case and a previously reported anaplastic ependymoma with EP300-BCORL1 were clustered together in close proximity to but distinct from methylation class high-grade neuroepithelial tumor with BCOR alteration. RNA sequencing demonstrated high mRNA expression of not only BCORL1 but BCOR, and the latter was compatible with diffuse nuclear expression of BCOR detected by immunohistochemistry. Our findings suggest that central nervous system tumors with CREBBP/EP300-BCORL1 may exhibit diverse morphologies but form a distinct DNA methylation group and that BCORL1 fusion genes may lead to upregulation of both BCOR and BCORL1.

An initial experience of machine learning based on multi-sequence texture parameters in magnetic resonance imaging to differentiate glioblastoma from brain metastases.

PURPOSE: To evaluate the performance of a machine learning method based on texture parameters in conventional magnetic resonance imaging (MRI) in differentiating glioblastoma (GB) from brain metastases (METs). MATERIALS AND METHODS: In this retrospective study conducted between November 2008 and July 2017, we included 73 patients diagnosed with GB (n = 73) and METs (n = 53) who underwent contrast-enhanced 3 T brain MRI. Twelve histogram and texture parameters were assessed on T2-weighted images (T2WIs), apparent diffusion coefficient maps (ADCs), and contrast-enhanced T1-weighted images (CE-T1WIs). A prediction model was developed for a machine learning method, and the area under the receiver operating characteristic curve of this model was calculated through 5-fold cross-validation. Furthermore, machine learning method's performance was compared with three board-certified radiologists' judgments. RESULTS: Univariate logistic regression model showed that the area under the curve (AUC) was highest with the standard value of T2WIs (0.78), followed by the maximum value of T2WIs (0.764), minimum value of T2WIs (0.738), minimum values of CE-T1WIs and contrast of T2WIs (0.733), and mean value of T2WIs (0.724). AUC calculated using the support vector machine was comparable to that calculated by the three radiologists (0.92 vs. 0.72, p < .01; 0.92 vs. 0.73, p < .01; and 0.92 vs. 0.86, p = .096). CONCLUSION: In differentiating GB from METs on the basis of texture parameters in MRI, the performance of the machine learning method based on convention MRI was superior to that of the univariate method, and comparable to that of the radiologists.

2-Methylthio Conversion of N6-Isopentenyladenosine in Mitochondrial tRNAs by CDK5RAP1 Promotes the Maintenance of Glioma-Initiating Cells.

2-Methylthio-N6-isopentenyl modification of adenosine (ms2i6A) is an evolutionally conserved modification found in mitochondrial (mt)-tRNAs. Cdk5 regulatory subunit-associated protein 1 (CDK5RAP1) specifically converts N6-isopentenyladenosine (i6A) to ms2i6A at position A37 of four mt-DNA-encoded tRNAs, and the modification regulates efficient mitochondrial translation and energy metabolism in mammals. Here, we report that the ms2 conversion mediated by CDK5RAP1 in mt-tRNAs is required to sustain glioma-initiating cell (GIC)-related traits. CDK5RAP1 maintained the self-renewal capacity, undifferentiated state, and tumorigenic potential of GICs. This regulation was not related to the translational control of mt-proteins. CDK5RAP1 abrogated the antitumor effect of i6A by converting i6A to ms2i6A and protected GICs from excessive autophagy triggered by i6A. The elevated activity of CDK5RAP1 contributed to the amelioration of the tumor-suppressive effect of i6A and promoted GIC maintenance. This work demonstrates that CDK5RAP1 is crucial for the detoxification of endogenous i6A and that GICs readily utilize this mechanism for survival.

Dural arteriovenous fistula associated with intratumor hemorrhage.

Dural arteriovenous fistula (dAVF) associated with an intracranial tumor is a relatively rare condition. Furthermore, to our knowledge, this is the first case report of dAVF associated with intratumor hemorrhage. We experienced this very rare case and report it here, along with a literature review. A 59-year-old woman presented with transient aphasia and dysgraphia. Computed tomography, magnetic resonance imaging, and angiography showed left anterior cranial fossa dAVF and a tumor with an intratumor hemorrhage. Cerebral angiography demonstrated AV shunts from the left ethmoidal artery via cortical vein flow into the superior sagittal sinus. She underwent shunt-point extirpation for the dAVF and removal of the tumor. The histological finding indicated transitional meningioma. The patient was discharged without any neurological deficit. A dAVF with intratumor hemorrhage is very rare and may be due to the venous congestion of the tumor draining vein by venous hypertension caused by the dAVF.

BCL2 expression is associated with a poor prognosis independent of cellular origin in primary central nervous system diffuse large B-cell lymphoma.

PURPOSE: Primary central nervous system diffuse large B-cell lymphoma (CNS-DLBCL) is a distinct clinicopathological entity with a poor prognosis. Concurrent MYC and BCL2 overexpression predicts inferior prognosis in systemic DLBCL, although their prognostic significance remains unclear in primary CNS-DLBCL. METHODS: Pretreatment diagnostic biopsy samples were retrospectively evaluated for 79 patients with primary CNS-DLBCL who were treated between January 2001 and December 2017. Histological and immunohistochemical testing were performed to evaluate the patients' statuses for various markers, which were also evaluated for associations with survival outcomes. RESULTS: According to the Hans criteria, 26 patients (32.9%) had the germinal center B-cell subtype and 53 patients (67.1%) had the activated B-cell subtype. Forty-one cases (51.9%) were positive for MYC (expression of ≥ 40%), 33 cases (41.8%) were positive for BCL2 (expression of ≥ 70%), 22 patients (27.8%) were positive for both MYC and BCL2, and 27 patients (34.2%) were negative for both MYC and BCL2. There were no significant differences in survival between the germinal center and activated B-cell subtypes. Furthermore, MYC positivity was not associated with overall survival (p = 0.369) or progression-free survival (PFS) (p = 0.253). However, BCL2 positivity was significantly associated with poor overall survival (p = 0.039) and PFS (p = 0.036). Co-expression of MYC and BCL2 was not associated with survival. CONCLUSION: Our data suggest that evaluating BCL2 expression may help predict the prognosis in cases of primary CNS-DLBCL.

Differentiating Between Primary Central Nervous System Lymphomas and Glioblastomas: Combined Use of Perfusion-Weighted and Diffusion-Weighted Magnetic Resonance Imaging.

OBJECTIVE: The purpose of this study was to determine whether combined diffusion-weighted imaging and dynamic susceptibility contrast-enhanced perfusion-weighted imaging magnetic resonance imaging can be used to differentiate between common malignant brain tumors, including lymphomas and high-grade gliomas. METHODS: We evaluated 87 patients with histologically confirmed brain tumors, including 33 primary central nervous system lymphomas (PCNSLs) and 54 glioblastomas (GBMs). All patients underwent conventional magnetic resonance imaging, diffusion-weighted imaging, and perfusion-weighted imaging before surgical removal of the lesion or stereotactic biopsy. RESULTS: The maximum relative cerebral blood volume (rCBV) ratios of GBMs were significantly higher than those of PCNSLs (P < 0.0001). The maximum rCBVs helped to distinguish PCNSLs from GBMs with 97.0% sensitivity, 90.7% specificity, and 0.98 area under the curve. The minimum apparent diffusion coefficients (ADCs) of PCNSLs were significantly lower than those of GBMs (P < 0.0001). At an rCBV cutoff value of 4.0 and a minimum ADC of 1.0 × 10-3 mm2/second, it was possible to differentiate between PCNSLs and GBMs. CONCLUSIONS: The combination of rCBV and ADC can facilitate the differentiation between PCNSLs and GBMs.

Molecular imaging using an anti-human tissue factor monoclonal antibody in an orthotopic glioma xenograft model.

Nuclear medicine examinations for imaging gliomas have been introduced into clinical practice to evaluate the grade of malignancy and determine sampling locations for biopsies. However, these modalities have some limitations. Tissue factor (TF) is overexpressed in various types of cancers, including gliomas. We thus generated an anti-human TF monoclonal antibody (mAb) clone 1849. In the present study, immunohistochemistry performed on glioma specimens using anti-TF 1849 mAb showed that TF expression in gliomas increased in proportion to the grade of malignancy based on the World Health Organization (WHO) classification, and TF was remarkably expressed in necrosis and pseudopalisading cells, the histopathological hallmarks of glioblastoma multiforme (GBM). Furthermore, in both fluorescence and single-photon emission computed tomography/computed tomography (SPECT/CT) imaging studies, anti-TF 1849 IgG efficiently accumulated in TF-overexpressing intracranial tumours in mice. Although further investigation is required for a future clinical use of immuno-SPECT with 111In-labelled anti-TF 1849 IgG, the immuno-SPECT may represent a unique imaging modality that can visualize the biological characteristics of gliomas differently from those obtained using the existing imaging modalities and may be useful to evaluate the grade of malignancy and determine sampling locations for biopsies in patients with glioma, particularly GBM.

A case of an epithelioid glioblastoma with the BRAF V600E mutation colocalized with BRAF intact low-grade diffuse astrocytoma.

Epithelioid glioblastomas are one of the rarest histological variants of glioblastomas, which are not formally recognized by the World Health Organization (WHO) classification. Epithelioid glioblastomas usually occur as primary lesions, but there have been several reports of secondary epithelioid glioblastomas or epithelioid glioblastomas with pre- or co-existing lesions to date. The serine/threonine-protein kinase B-Raf (BRAF) V600E mutation has been found at a high frequency of 54% in epithelioid glioblastomas. We present a case of a 26-year-old female patient with an epithelioid glioblastoma with the BRAF V600E mutation in her right frontal lobe. In the present case, a low-grade diffuse astrocytoma component had colocalized with the epithelioid glioblastoma. The component presented prominent calcification on neuroimages as well as by histology, and low-grade diffuse astrocytoma was considered to be a precursor lesion of an epithelioid glioblastoma. However, the BRAF V600E mutation was detected only in epithelioid glioblastoma but not in low-grade diffuse astrocytoma. To the best of our knowledge, this is the first report demonstrating a discrepancy in the BRAF V600E mutation states between epithelioid glioblastoma and colocalized low-grade astrocytoma.

Prognostic impact of completion of initial high-dose methotrexate therapy on primary central nervous system lymphoma: a single institution experience.

BACKGROUND: This retrospective single-center study assessed the feasibility, outcomes, and side-effects of high-dose methotrexate (HD-MTX) plus procarbazine in the treatment of immunocompetent patients with primary central nervous system lymphoma (PCNSL). METHODS: Ninety-one patients diagnosed with PCNSL between January 2001 and December 2011 were treated with HD-MTX plus procarbazine. To reduce neurotoxicity in patients aged ≥60 years, only those not responding to chemotherapy and patients with relapse underwent whole-brain irradiation. RESULTS: All 91 consecutive patients were scheduled to receive HD-MTX. Their median age was 66 years (range 32-88 years) and their median Karnofsky performance score was 40 (range 20-100). While 56 patients (61.5 %) completed 3 cycles of HD-MTX chemotherapy and 48 (52.7 %) showed a complete response, treatment was stopped in 11 patients (12.1 %) due to toxicity. The median overall survival and progression-free survival were 40.6 and 11.7 months, respectively. Overall survival was significantly improved in patients who completed 3 cycles of chemotherapy compared with those did not (56.4 vs 24.0 months; p = 0.013 by univariate and p = 0.022 by multivariate analysis). CONCLUSIONS: Initial treatment with HD-MTX plus procarbazine was effective in patients with PCNSL. Completion of 3 cycles of HD-MTX chemotherapy was a significant independent prognostic factor for patient survival.

Characteristics of brain metastases from esophageal carcinoma.

BACKGROUND: Esophageal carcinoma (EC) is a major malignancy with a poor prognosis. Although esophageal cancers rarely metastasize to the brain, the number of patients diagnosed with brain metastases (BM) from EC is steadily increasing. Therefore, the risk factors for BM from EC should be known. Here we reviewed our experiences and the previous literature regarding BM from EC. METHODS: Between 2000 and 2013, we retrospectively reviewed the clinical features and neurological findings of 19 patients diagnosed with and treated for BM from EC to determine the clinical risk factors and features. RESULTS: In all patients, the lesions were partially or completed located in the thoracic esophagus, and the average size of the EC lesion at diagnosis was 5.8 ± 2.9 cm, which was smaller than the previously reported size of EC lesions accompanied by BM. Patients without lung metastases were more common than those with lung metastases. The lesions in the 13 patients included squamous cell carcinoma (SqCC) in 9 (69.2%) and small cell carcinoma (SmCC) in 3 (23.0%). Six patients were not examined. Although there was no trend toward a higher incidence of BM in patients with adenocarcinoma and SqCC, this trend was observed in patients with SmCC. Excluding a single patient with SmCC, all patients had beyond stage III disease at EC diagnosis. CONCLUSIONS: Our study suggests that BM can occur in patients with EC lesions smaller than those previously reported; moreover, SmCC may be a risk factor for BM from EC.

Antitumor effect of fibrin glue containing temozolomide against malignant glioma.

Temozolomide (TMZ), used to treat glioblastoma and malignant glioma, induces autophagy, apoptosis and senescence in cancer cells. We investigated fibrin glue (FG) as a drug delivery system for the local administration of high-concentration TMZ aimed at preventing glioma recurrence. Our high-power liquid chromatography studies indicated that FG containing TMZ (TMZ-FG) manifested a sustained drug release potential. We prepared a subcutaneous tumor model by injecting groups of mice with three malignant glioma cell lines and examined the antitumor effect of TMZ-FG. We estimated the tumor volume and performed immunostaining and immunoblotting using antibodies to Ki-67, cleaved caspase 3, LC3 and p16. When FG sheets containing TMZ (TMZ-FGS) were inserted beneath the tumors, their growth was significantly suppressed. In mice treated with peroral TMZ plus TMZ-FGS the tumors tended to be smaller than in mice whose tumors were treated with TMZ-FGS or peroral TMZ alone. The TMZ-FGS induced autophagy, apoptosis and senescence in subcutaneous glioma tumor cells. To assess the safety of TMZ-FG for normal brain, we placed it directly on the brain of living mice and stained tissue sections obtained in the acute and chronic phase immunohistochemically. In both phases, TMZ-FG failed to severely damage normal brain tissue. TMZ-FG may represent a safe new drug delivery system with sustained drug release potential to treat malignant glioma.

New treatment strategies to eradicate cancer stem cells and niches in glioblastoma.

Glioblastoma multiforme (GBM) harbors are not only rapidly dividing cells but also small populations of slowly dividing and dormant cells with tumorigenesity, self-renewal, and multi-lineage differentiation capabilities. Known as glioblastoma stem cells (GSCs), they are resistant to conventional chemo- and radiotherapy and may be a causative factor in recurrence. The treatment outcome in patients with GBM remains unsatisfactory and their mean survival time has not improved sufficiently. We studied clinical evidence and basic research findings to assess the possibility of new treatment strategies that target GSCs and their specific microenvironments (GBM niches) and raise the possibility of adding new treatments to eradicate GSCs and GBM niches.

Skull metastasis from intrahepatic cholangiocarcinoma: report of 3 cases and review of the literature.

Skull metastases occur in patients with various malignancies; however, those resulting from intrahepatic cholangiocarcinoma (ICC) have been rarely reported. In our hospital, 324 patients were diagnosed with metastatic brain or skull tumors from June 1969 to June 2011, but only 3 of them (0.9%) developed skull metastases from ICC. We report the case of 3 patients with skull metastases from ICC. A combination of computed tomography (CT), contrast-enhanced magnetic resonance imaging (MRI), 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), and methionine-PET were used for imaging. Sites of tumors were the lateral left orbit and right parietal bone in case 1, the left parietal bone, left temporal bone, and lateral left orbit in case 2, the right petrous bone, right occipital bone, and upper cervical vertebra in case 3. The metastases were confirmed to have originated from ICC by biopsy in two of the cases and diagnosed by MRI and FDG-PET in case 2. Radiosurgery and radiotherapy had positive effects on symptom improvement and cosmetic problems.

Discovery of an uncovered region in fibrin clots and its clinical significance.

Despite the pathological importance of fibrin clot formation, little is known about the structure of these clots because X-ray and nuclear magnetic resonance (NMR) analyses are not applicable to insoluble proteins. In contrast to previously reported anti-fibrin monoclonal antibodies (mAbs), our anti-fibrin clot mAb (clone 102-10) recognises an uncovered region that is exposed only when a fibrin clot forms. The epitope of the 102-10 mAb was mapped to a hydrophobic region on the Bß chain that interacted closely with a counterpart region on the γ chain in a soluble state. New anti-Bß and anti-γ mAbs specific to peptides lining the discovered region appeared to bind exclusively to fibrin clots. Furthermore, the radiolabelled 102-10 mAb selectively accumulated in mouse spontaneous tumours, and immunohistochemistry using this mAb revealed greater fibrin deposition in World Health Organization (WHO) grade 4 glioma than in lower-grade gliomas. Because erosive tumours are apt to cause micro-haemorrhages, even early asymptomatic tumours detected with a radiolabelled 102-10 mAb may be aggressively malignant.

NC-6300, an epirubicin-incorporating micelle, extends the antitumor effect and reduces the cardiotoxicity of epirubicin.

Epirubicin is widely used to treat various human tumors. However, it is difficult to achieve a sufficient antitumor effect because of dosage limitation to prevent cardiotoxicity. We hypothesized that epirubicin-incorporating micelle would reduce cardiotoxicity and improve the antitumor effect. NC-6300 comprises epirubicin covalently bound to PEG polyaspartate block copolymer through an acid-labile hydrazone bond. The conjugate forms a micellar structure of 40-80 nm in diameter in an aqueous milieu. NC-6300 (10, 15 mg/kg) and epirubicin (10 mg/kg) were given i.v. three times to mice bearing s.c. or liver xenograft of human hepatocellular carcinoma Hep3B cells. Cardiotoxicity was evaluated by echocardiography in C57BL/6 mice that were given NC-6300 (10 mg/kg) or epirubicin (10 mg/kg) in nine doses over 12 weeks. NC-6300 showed a significantly potent antitumor effect against Hep3B s.c. tumors compared with epirubicin. Moreover, NC-6300 also produced a significantly longer survival rate than epirubicin against the liver orthotopic tumor of Hep3B. With respect to cardiotoxicity, epirubicin-treated mice showed significant deteriorations in fractional shortening and ejection fraction. In contrast, cardiac functions of NC-6300 treated mice were no less well maintained than in control mice. This study warrants a clinical evaluation of NC-6300 in patients with hepatocellular carcinoma or other cancers.