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Glioblastoma multiforme (GBM) acquires resistance to bevacizumab (Bev) treatment. Bev affects angiogenic factors other than vascular endothelial growth factor (VEGF), which are poorly understood. We investigated changes in angiogenic factors under and after Bev therapy, including angiopoietin-1 (ANGPT1), angiopoietin-2 (ANGPT2), placental growth factor (PLGF), fibroblast growth factor 2, and ephrin A2 (EphA2). Fifty-four GBM tissues, including 28 specimens from 14 cases as paired specimens from the same patient obtained in three settings: initial tumor resection (naïve Bev), tumors resected following Bev therapy (effective Bev), and recurrent tumors after Bev therapy (refractory Bev). Immunohistochemistry assessed their expressions in tumor vessels and its correlation with recurrent MRI patterns. PLGF expression was higher in the effective Bev group than in the naïve Bev group ( p  = 0.024) and remained high in the refractory Bev group. ANGPT2 and EphA2 expressions were higher in the refractory Bev group than in the naïve Bev group ( p  = 0.047 and 0.028, respectively). PLGF expression was higher in the refractory Bev group compared with the naïve Bev group for paired specimens ( p  = 0.036). PLGF was more abundant in T2 diffuse/circumscribe patterns ( p  = 0.046). This is the first study to evaluate angiogenic factors other than VEGF during effective and refractory Bev therapy in patient-derived specimens.

Purpose The venous plexus of Rektorzik (VPR), first described by Rektorzik in 1858, is a venous plexus around the internal carotid artery in the carotid canal. However, the VPR has never been investigated using the recently developed imaging modalities. In this study, we analyzed the VPR using computed tomography-digital subtraction venography (CT-DSV). Methods This study included 253 patients who had undergone head CT-DSV. The presence or absence of the right and left VPRs and their connecting veins were visually examined by two researchers. Results The VPR was observed in 60 patients (24%), 39 of which showed VPR only on the right side, 10 only on the left side, and 11 on both sides. VPR was significantly more common on the right side ( p  = 0.0002) and was observed more frequently around the horizontal segment of the internal carotid artery than around the vertical segment. The most common veins identified as distal and proximal VPR connections were the cavernous sinus (63/71, 89%) and the anterior condylar confluence (27/71, 38%), respectively. The mean age was significantly lower in patients with the VPR than in those without (53 vs. 57 years, p  = 0.02). Conclusion The VPR was significantly more frequent on the right side and in younger patients but was not a radiographically constant structure. In most cases, the VPR connected the cavernous sinus and anterior condylar confluence. Preoperative evaluation of VPR may lead to refined surgical procedures.

Background and objective In Moyamoya disease, occlusion occurs at the terminus of the bilateral internal carotid artery, resulting in poor visualization of the distal middle cerebral artery (MCA) on imaging. This study aimed to investigate whether the absence of the MCA on non-contrast CT images constitutes a characteristic feature of Moyamoya disease. Methods Patients who were documented as having \"Moyamoya disease\" or \"suspected Moyamoya disease\" for insurance purposes in medical records were selected. Retrospective analysis of their datasets was conducted. Non-contrast head CT images were reviewed to ascertain the presence or absence of the MCA at four specified locations (right proximal, left proximal, right distal, and left distal) within the Sylvian fissure. Results Of the 151 patients identified, 23 cases of Moyamoya disease and 35 cases without Moyamoya disease were investigated. The Moyamoya disease cohort exhibited a significantly higher number of absent MCA observations within the four locations (2.65 vs. 0.83, p<0.001). With a threshold of ≥3 locations devoid of the MCA, the sensitivity and specificity of this finding for Moyamoya disease detection were 61% and 94%, respectively. Conclusions This study represents the first exploration of non-contrast head CT findings indicative of Moyamoya disease. Although cerebral angiography or MRI is indispensable for definitive diagnosis, a subset of patients may not undergo these detailed examinations. Focusing on the \"empty Sylvian fissure sign\" on non-contrast head CT images, frequently encountered in acute medical settings, may help detect patients with Moyamoya disease and support further evaluation.

Lymphomatoid granulomatosis (LYG) is a rare lymphoproliferative disease with angiocentric and angiodestructive infiltrates, and by definition, Epstein-Barr virus (EBV)-associated B-cell malignancy. It most frequently involves the lung, and in some cases, the lesions are confined to the central nervous system (isolated CNS-LYG). However, it remains a controversial disease in terms of pathophysiology, especially in those confined to the CNS. We report the case of a 37-year-old man with CNS lesion pathologically characterized by angiocentric, T-cell-rich lymphoid cell infiltrates that resembled CNS-LYG. The lesion was clinically aggressive with subacute onset and irregular ring-like enhancement on MRI. The resected specimen showed no cytological atypia, EBV-infected cells, or monoclonality for IgH and TCR gene rearrangements. Considering the possibility of latent malignancy, the patient was successfully treated with corticosteroid and chemoradiotherapy with high-dose methotrexate. The present case and the literature suggest that EBV-negative CNS lesions with angiocentric lymphoid infiltrates are probably heterogeneous in their pathogenesis, including those that could fit into the so-called CNS-LYG and those with T-cell predominance. The accumulation of similar cases is warranted for the classification and appropriate treatment of these lesions.

Purpose This multi-institutional phase I/II study was conducted to confirm the safety and explore the clinical utility of preoperative Bevacizumab (Bev) for newly diagnosed glioblastoma (GB). Methods Patients were enrolled based on magnetic resonance imaging (MRI) findings typically suggestive of GB. Preoperative Bev and temozolomide (TMZ) were administered at doses of 10 mg/kg on day 0 and 150 mg/m 2 on days 1–5, respectively. Surgical resection was performed between days 21 and 30, inclusive. The safety and efficacy were evaluated in a total of 15 cases by progression-free survival (PFS), changes in tumor volume, Karnofsky Performance Scale (KPS) and Mini-Mental State Examination (MMSE) scores after preoperative therapy. Results Tumor resection was performed on a mean of day 23.7. Pathological diagnosis was GB, isocitrate dehydrogenase (IDH)-wildtype in 14 cases and GB, IDH-mutant in 1 case. Severe adverse events possibly related to preoperative Bev and TMZ were observed in 2 of the 15 patients, as wound infection and postoperative hematoma and thrombocytopenia. KPS and MMSE scores were significantly improved with preoperative therapy. Tumor volume was decreased in all but one case on T1-weighted imaging with contrast-enhancement (T1CE) and in all cases on fluid-attenuated inversion recovery, with mean volume decrease rates of 36.2% and 54.0%, respectively. Median PFS and overall survival were 9.5 months and 16.5 months, respectively. Conclusion Preoperative Bev and TMZ is safe as long as the instructions are followed. The strategy might be useful for GB in some patients, not only reducing tumor burden, but also improving patient KPS preoperatively. Trial Registration Number: UMIN000025579, jRCT1031180233 https://jrct.niph.go.jp/latest-detail/jRCT1031180233 . Registration Date: Jan. 16, 2017

Aims/Introduction To investigate the national trend in the prescription of first‐line non‐insulin antidiabetic agents and total medical costs (TMCs) after prescribing the drug in Japanese patients with type 2 diabetes. Materials and Methods Using the National Database of Health Insurance Claims and Specific Health Check‐ups of Japan covering almost the entire Japanese population, we calculated the proportion of each antidiabetic drug from 2014 to 2017, and determined the factors associated with drug selection. The TMCs in the first year after starting the drugs were calculated, and factors associated with the costs were also determined. Results Among 1,136,723 new users of antidiabetic agents, dipeptidyl peptidase‐4 inhibitors were the most prescribed (65.1%), followed by biguanides (15.9%) and sodium–glucose cotransporter 2 inhibitors (7.6%). Sodium–glucose cotransporter 2 inhibitor and biguanide use increased during 2014–2017 (2.2%–11.4% and 13.7%–17.2%, respectively), whereas the others decreased. Biguanides were not prescribed at all in 38.2% of non‐Japan Diabetes Society‐certified facilities. The TMCs were the lowest among those who started with biguanides. Fiscal year, age, sex, facility, number of beds and comorbidities were associated with drug choice and TMCs. There were wide regional variations in the drug choice, but not in the TMCs. Conclusions Unlike in the USA and Europe, dipeptidyl peptidase‐4 inhibitor is the most prescribed first‐line medication for type 2 diabetes patients in Japan, while there is a wide variation in the drug choice by facility‐type and prefecture. In this large‐scale, nationwide study of Japanese patients with type 2 diabetes, dipeptidyl peptidase‐4 inhibitors were the most prescribed followed by biguanides, with a wide variation in the drug choice by facility and prefecture. The total medical costs were the lowest among patients who started with biguanides.

Self-compatibility is a highly desirable trait for pear breeding programs. Our breeding program previously developed a novel self-compatible pollen-part Japanese pear mutant ( Pyrus pyrifolia Nakai), ‘415-1’, by using γ-irradiated pollen. ‘415-1’ carries the S -genotype S 4 dS 5 S 5 , with “ d ” indicating a duplication of S 5 responsible for breakdown of self-incompatibility. Until now, the size and inheritance of the duplicated segment was undetermined, and a reliable detection method was lacking. Here, we examined genome duplications and their inheritance in 140 F 1 seedlings resulting from a cross between ‘515-20’ ( S 1 S 3 ) and ‘415-1’. Amplicon sequencing of S-RNase and SFBB18 clearly detected S -haplotype duplications in the seedlings. Intriguingly, 30 partially triploid seedlings including genotypes S 1 S 4 dS 5 , S 3 S 4 dS 5 , S 1 S 5 dS 5 , S 3 S 5 dS 5 , and S 3 S 4 dS 4 were detected among the 140 seedlings. Depth-of-coverage analysis using ddRAD-seq showed that the duplications in those individuals were limited to chromosome 17. Further analysis through resequencing confirmed an 11-Mb chromosome duplication spanning the middle to the end of chromosome 17. The duplicated segment remained consistent in size across generations. The presence of an S 3 S 4 dS 4 seedling provided evidence for recombination between the duplicated S 5 segment and the original S 4 haplotype, suggesting that the duplicated segment can pair with other parts of chromosome 17. This research provides valuable insights for improving pear breeding programs using partially triploid individuals.

BackgroundIntrahepatic hepatocellular carcinoma (HCC) has a high recurrence rate after radiofrequency ablation (RFA). However, to date, no standalone predictive factors for intrahepatic distant recurrence after curative ablation have been reported.AimsThe aim of this study was to investigate predictive factors for intrahepatic distant recurrence after curative treatment with RFA for HCCs.MethodsThis multicenter study consisted of 17 institutions that registered 821 patients. The risk factors for intrahepatic distant recurrence after complete ablation by RFA for primary HCC ≤ 2 cm in diameter were identified in a retrospectively collected training set (n = 636) and then validated in a prospectively collected validation set (n = 185).ResultsThe cumulative intrahepatic distant and local recurrence rates (i.e., entire recurrence rate) in the training set were 23.6% and 53.7% at 1 and 3 years, respectively. The cumulative intrahepatic distant recurrence rates in the training set were 17.0% and 43.8% at 1 and 3 years, respectively. Multivariate analysis of the training set showed that tumor number and serum levels of α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) were independent risk factors for both entire recurrence and intrahepatic distant recurrence. Intrahepatic distant recurrence risk in both the training and validation cohorts was stratified using a scoring system with three factors: tumor number (single or multiple), AFP (< 10 ng/ml or ≥ 10 ng/ml), and DCP (< 50 mAU/ml or ≥ 50 mAU/ml).ConclusionThe scoring system composed of tumor number, AFP, and DCP is useful for classifying the risk of intrahepatic distant recurrence after curative ablation for HCC.