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.

Leiomyosarcoma of the transverse colon with lymph node metastasis and malignant transformation: a case report.

BACKGROUND: The concept of GIST was established in 1998, clearly differentiating between gastrointestinal leiomyosarcoma and GISTs among gastrointestinal mesenchymal tumors. Lymph node metastasis is extremely rare in true gastrointestinal leiomyosarcoma, and there are no reports of malignant transformation from leiomyoma. CASE PRESENTATION: The patient was an old woman who had undergone endoscopic mucosal resection for an Is polyp on the left side of the transverse colon at the age of 73. She was diagnosed with leiomyoma with positive surgical margins. Subsequently, she presented to our institution with a sensation of pressure in the upper abdominal region as a chief complaint at the age of 76 years. Abdominal computed tomography and colorectal endoscopy showed a tumor lesion with invagination of the intestines in the transverse colon, the same site as that of the previously resected leiomyoma. A biopsy suggested a smooth muscle tumor, and we performed partial left transverse colectomy and lymph node dissection under a diagnosis of recurrence and enlargement of the previously incompletely resected leiomyoma. Histopathological examination revealed spindle-shaped tumor cells, and the mitotic activity was 30-40/10 high-power field. Tumor cells were immunohistologically positive for α-smooth muscle actin and h-caldesmon; partially positive for desmin; negative for c-kit, CD34, DOG-1, and the S-100 protein; and showed a Ki-67 labeling index of 70-80%. She was diagnosed with leiomyosarcoma malignantly transformed from leiomyoma. Metastasis was found in 1 of the 14 resected lymph nodes. The patient did not undergo adjuvant chemotherapy, but has survived with no recurrence at 2 years after the surgery. CONCLUSIONS: We have reported a case of leiomyosarcoma of the transverse colon with lymph node metastasis that was malignantly transformed from a leiomyoma.

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.

Artificial intelligence predicts the progression of diabetic kidney disease using big data machine learning.

Artificial intelligence (AI) is expected to support clinical judgement in medicine. We constructed a new predictive model for diabetic kidney diseases (DKD) using AI, processing natural language and longitudinal data with big data machine learning, based on the electronic medical records (EMR) of 64,059 diabetes patients. AI extracted raw features from the previous 6 months as the reference period and selected 24 factors to find time series patterns relating to 6-month DKD aggravation, using a convolutional autoencoder. AI constructed the predictive model with 3,073 features, including time series data using logistic regression analysis. AI could predict DKD aggravation with 71% accuracy. Furthermore, the group with DKD aggravation had a significantly higher incidence of hemodialysis than the non-aggravation group, over 10 years (N = 2,900). The new predictive model by AI could detect progression of DKD and may contribute to more effective and accurate intervention to reduce hemodialysis.

Number of positive lymph nodes and lymphatic invasion are significant prognostic factors after pancreaticoduodenectomy for distal cholangiocarcinoma.

Background: Early recurrence of distal cholangiocarcinoma (DCC) may result in a poorer prognosis. This study aimed to evaluate the clinicopathological factors that predict survival and recurrence in patients with DCC. Methods: Fifty-five patients with DCC who underwent pancreaticoduodenectomy between 2005 and 2015 were studied retrospectively. The following clinicopathological parameters were analyzed as predictors of disease-free survival (DFS) and overall survival (OS): sex, age, body mass index, presence of biliary tract decompression, macroscopic type, histological type, tumor size, TNM classification, lymph node metastasis ratio, number of positive lymph nodes (PLNs), lymphatic invasion, venous invasion, perineural invasion, proximal bile duct margin, dissected margin, portal system invasion, arterial system invasion, stage, and residual tumor. Results: Univariate analysis showed that contiguous extension of the primary tumor, PLN, lymphatic invasion, venous invasion, perineural invasion, and stage were significant prognostic factors for DFS and OS. Multivariate analysis revealed that PLN and lymphatic invasion were prognostic for DFS and OS (P<0.001). Significant differences in OS and DFS were found in analyses stratified by PLN (0, 1, 2 vs ≥3) and lymphatic invasion (0 vs 1, 2, 3). Conclusion: Among the clinicopathological parameters analyzed, PLN and lymphatic invasion were confirmed as prognostic factors for DCC.

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.

Risk Prediction of Diabetic Nephropathy via Interpretable Feature Extraction from EHR Using Convolutional Autoencoder.

This paper describes a technology for predicting the aggravation of diabetic nephropathy from electronic health record (EHR). For the prediction, we used features extracted from event sequence of lab tests in EHR with a stacked convolutional autoencoder which can extract both local and global temporal information. The extracted features can be interpreted as similarities to a small number of typical sequences of lab tests, that may help us to understand the disease courses and to provide detailed health guidance. In our experiments on real-world EHRs, we confirmed that our approach performed better than baseline methods and that the extracted features were promising for understanding the disease.

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.

Quantification of the steric influence of alkylphosphine-sulfonate ligands on polymerization, leading to high-molecular-weight copolymers of ethylene and polar monomers.

A series of palladium/alkylphosphine-sulfonate catalysts were synthesized and examined in the homopolymerization of ethylene and the copolymerization of ethylene and polar monomers. Catalysts with alkylphosphine-sulfonate ligands containing sterically demanding alkyl substituents afforded (co)polymers whose molecular weight was increased by up to 2 orders of magnitude relative to polymers obtained from previously reported catalyst systems. The polymer molecular weight was found to be closely correlated to the Sterimol B5 parameter of the alkyl substituents in the alkylphosphine-sulfonate ligands. Thus, the use of bulky alkylphosphine-sulfonate ligands represents an effective and versatile method to prepare high-molecular-weight copolymers of ethylene and various polar monomers, which are difficult to obtain by previously reported methods.