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We measured the magnetoresistance in bilayer quantum Hall (QH) state at fractional filling factor ν=2/3. Surprisingly, for different QH areas and two types of hysteresis were observed by controlling the total electron density and the density difference in two layers. Two QH areas and one type of hysteresis are novel characteristic of bilayer systems. [Copyright &y& Elsevier]

Purpose: This study identified the factors affecting cerebral microbleed (CMBs) development. Moreover, their effects on intelligence and memory and association with stroke in patients with germinoma who had long-term follow-up were evaluated., Methods: This study included 64 patients with germinoma who were histologically and clinically diagnosed with and treated for germinoma. These patients were evaluated cross-sectionally, with a focus on CMBs on susceptibility-weighted magnetic resonance imaging (SWI), brain atrophy assessed through volumetric analysis, and intelligence and memory., Results: The follow-up period was from 32 to 412 (median: 175.5) months. In total, 43 (67%) patients had 509 CMBs and 21 did not have CMBs. Moderate correlations were observed between the number of CMBs and time from initial treatments and recurrence was found to be a risk factor for CMB development. Increased temporal CMBs had a marginal effect on the processing speed and visual memory, whereas brain atrophy had a statistically significant effect on verbal, visual, and general memory and a marginal effect on processing speed. Before SWI acquisition and during the follow-up periods, eight strokes occurred in four patients. All of these patients had ≥ 15 CMBs on SWI before stroke onset. Meanwhile, 33 patients with < 14 CMBs or 21 patients without CMBs did not experience stroke., Conclusion: Patients with a longer time from treatment initiation had a higher number of CMBs, and recurrence was a significant risk factor for CMB development. Furthermore, brain atrophy had a stronger effect on memory than CMBs. Increased CMBs predict the stroke onset., (© 2024. The Author(s).)

Background: This study investigated the factors influencing short-term survivors (STS) after gross total resection (GTR) in patients with IDH1 wild-type primary glioblastoma., Methods: We analyzed five independent cohorts who underwent GTR, including 83 patients from Kitasato University (K-cohort), and four validation cohorts of 148 patients from co-investigators (V-cohort), 66 patients from the Kansai Molecular Diagnosis Network for the Central Nervous System tumors, 109 patients from the Cancer Genome Atlas, and 40 patients from the Glioma Longitudinal AnalySiS. The study defined STS as those who had an overall survival ≤ 12 months after GTR with subsequent radiation therapy, and concurrent and adjuvant temozolomide (TMZ)., Results: The study included 446 patients with glioblastoma. All cohorts experienced unexpected STS after GTR, with a range of 15.0-23.9% of the cases. Molecular profiling revealed no significant difference in major genetic alterations between the STS and non-STS groups, including MGMT, TERT, EGFR, PTEN, and CDKN2A. Clinically, the STS group had a higher incidence of non-local recurrence early in their treatment course, with 60.0% of non-local recurrence in the K-cohort and 43.5% in the V-cohort., Conclusions: The study revealed that unexpected STS after GTR in patients with glioblastoma is not uncommon and such tumors tend to present early non-local recurrence. Interestingly, we did not find any significant genetic alterations in the STS group, indicating that such major alterations are characteristics of GB rather than being reliable predictors for recurrence patterns or development of unexpected STS., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hypertrophic cardiomyopathy (HCM) is an inherited disorder characterized by left ventricular hypertrophy and diastolic dysfunction, and increases the risk of arrhythmias and heart failure. Some patients with HCM develop a dilated phase of hypertrophic cardiomyopathy (D-HCM) and have poor prognosis; however, its pathogenesis is unclear and few pathological models exist. This study established disease-specific human induced pluripotent stem cells (iPSCs) from a patient with D-HCM harboring a mutation in MYBPC3 (c.1377delC), a common causative gene of HCM, and investigated the associated pathophysiological mechanisms using disease-specific iPSC-derived cardiomyocytes (iPSC-CMs). We confirmed the expression of pluripotent markers and the ability to differentiate into three germ layers in D-HCM patient-derived iPSCs (D-HCM iPSCs). D-HCM iPSC-CMs exhibited disrupted myocardial sarcomere structures and an increased number of damaged mitochondria. Ca 2+ imaging showed increased abnormal Ca 2+ signaling and prolonged decay time in D-HCM iPSC-CMs. Cell metabolic analysis revealed increased basal respiration, maximal respiration, and spare-respiratory capacity in D-HCM iPSC-CMs. RNA sequencing also showed an increased expression of mitochondrial electron transport system-related genes. D-HCM iPSC-CMs showed abnormal Ca 2+ handling and hypermetabolic state, similar to that previously reported for HCM patient-derived iPSC-CMs. Although further studies are required, this is expected to be a useful pathological model for D-HCM., (© 2024. The Author(s).)

The present study examined the surgical outcome and prognosis of patients with poorly cohesive carcinoma (PCC), and characterized the molecular pathological factors, epithelial-mesenchymal transition (EMT) and interstitial signals of the disease. A total of 281 patients who underwent gastric cancer (GC) surgery between April 2015 and August 2020 were included. Furthermore, tissue samples from another 197 patients with GC who underwent surgery between 1999 and 2003 were assessed using a tissue microarray. Preoperatively treated cases and endoscopic submucosal dissection cases were excluded, and multiple blocks containing the invasion region were collected for tissue microarray. For tissue microarray analysis, the clinicopathological factors of protein wnt3a (wnt3a), leucine-rich repeat-containing G-protein coupled receptor 5, transforming growth factor-β-induced, phosphorylated serine/threonine-protein kinase mTOR and E-cadherin expression were collected as EMT markers. The results of the surgical case evaluation and tissue microarray indicated that PCC was more common in younger patients and women, as the ratio of women to men was higher in the PCC group compared with that in the non-PCC group. However, none of the results revealed that the prognosis was worse in all patients with PCC compared with the non-PCC group. Furthermore, in the tissue microarray study, PCC samples exhibited significantly decreased expression of the cell adhesion molecule E-cadherin, suggesting enhanced EMT, which activates wnt3a signaling. PCC with increased EMT was significantly associated with a poor prognosis., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Nakazawa et al.)

Introduction: It is hard to realize the extent of the expected postoperative neurological deficit for patients themselves. The provision of appropriate information can contribute not only to examining surgical indications but also to filling the gap between patient and expert expectations. We hypothesized that propofol infusion into the intracranial arteries (ssWada) could induce focal neurological symptoms with preserved wakefulness, enabling the patients to evaluate the postsurgical risk subjectively., Methods: Presurgical evaluation using ssWada was performed in 28 patients with drug-resistant epilepsy. Based on anatomical knowledge, propofol was super-selectively infused into the intracranial arteries including the M1, M2, and M3 segments of the middle cerebral artery (MCA), A2 segment of the anterior cerebral artery, and P2 segment of the posterior cerebral artery to evaluate the neurological and cognitive symptoms. We retrospectively analyzed a total of 107 infusion trials, including their target vessels, and elicited symptoms of motor weakness, sensory disturbance, language, unilateral hemispatial neglect (UHN), and hemianopsia. We evaluated preserved wakefulness which enabled subjective evaluations of the symptoms and comparison of the subjective experience to the objective findings, besides adverse effects during the procedure., Results: Preserved wakefulness was found in 97.2% of all trials. Changes in neurological symptoms were positively evaluated for motor weakness in 51.4%, sensory disturbance in 5.6%, language in 48.6%, UHN in 22.4%, and hemianopsia in 32.7%. Six trials elicited seizures. Multivariate analysis showed significant correlations between symptom and infusion site of language and left side, language and MCA branches, motor weakness and A2 or M2 superior division, and hemianopsia and P2. Transient adverse effect was observed in 8 cases with 12 infusion trials (11.2 %)., Conclusion: The ssWada could elicit focal neurological symptoms with preserved wakefulness. The methodology enables specific evaluation of risk for cortical resection and subjective evaluation of the expected outcome by the patients., Competing Interests: Declaration of competing interest The authors have no competing interest in this study., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Juvenile nephronophthisis is an inherited renal ciliopathy with cystic kidney disease, renal fibrosis, and end-stage renal failure in children and young adults. Mutations in the NPHP1 gene encoding nephrocystin-1 protein have been identified as the most frequently responsible gene and cause the formation of cysts in the renal medulla. The molecular pathogenesis of juvenile nephronophthisis remains elusive, and no effective medicines to prevent end-stage renal failure exist even today. No human cellular models have been available yet. Here, we report a first disease model of juvenile nephronophthisis using patient-derived and gene-edited human induced pluripotent stem cells (hiPSCs) and kidney organoids derived from these hiPSCs. We established NPHP1-overexpressing hiPSCs from patient-derived hiPSCs and NPHP1-deficient hiPSCs from healthy donor hiPSCs. Comparing these series of hiPSCs, we found abnormalities in primary cilia associated with NPHP1 deficiency in hiPSCs. Kidney organoids generated from the hiPSCs lacking NPHP1 formed renal cysts frequently in suspension culture with constant rotation. This cyst formation in patient-derived kidney organoids was rescued by overexpression of NPHP1 . Transcriptome analysis on these kidney organoids revealed that loss of NPHP1 caused lower expression of genes related to primary cilia in epithelial cells and higher expression of genes related to the cell cycle. These findings suggested the relationship between abnormality in primary cilia induced by NPHP1 loss and abnormal proliferative characteristics in the formation of renal cysts. These findings demonstrated that hiPSC-based systematic disease modeling of juvenile nephronophthisis contributed to elucidating the molecular pathogenesis and developing new therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Arai, Ito, Shimizu, Shimoda, Song, Matsuo-Takasaki, Hayata and Hayashi.)

Background: Despite the recent developments in the treatment of advanced or recurrent gastric cancer, the median survival time remains shorter than 15 months. Herein, we report a case of postoperative gastric cancer recurrence in which a complete clinical response was achieved with trastuzumab deruxtecan as 6th-line treatment., Case Presentation: A 70-year-old man underwent abdominal contrast-enhanced computed tomography (CT) during follow-up after rectal cancer surgery. The CT revealed an enlarged perigastric lymph node. After further examination, the patient's condition was diagnosed as gastric cancer cT2N1H0P0M0 cStage IIA. The patient underwent distal gastrectomy and D2 lymph node dissection. The resulting pathological diagnosis was pT1bN3aH0P0 pStageIIB, HER2 score 3+. Abdominal contrast-enhanced CT 19 months postoperatively revealed para-aortic lymph node recurrence, thus systemic chemotherapy courses were planned. The primary treatment was a combination of S-1, cisplatin, and trastuzumab administered in 11 courses. However, there was an enlargement of the para-aortic lymph node which was evaluated as progressive disease. Systematic chemotherapy with various regimens was continued until the 5th-line treatment. However, therapeutic benefits were not achieved and lung metastasis was observed. Trastuzumab deruxtecan (TDXD) was initiated as 6th-line treatment. Abdominal contrast-enhanced CT at 4 months after the start of treatment showed marked shrinkage of the enlarged para-aortic lymph node and disappearance of the lung metastasis in the right upper lung lobe, which was evaluated as partial response (PR). The para-aortic lymph node metastasis was evaluated as PR with only a slight accumulation of SUV-Max 2.66 with a shrinking trend by positron emission tomography-computed tomography (PET-CT) performed after 1 year. Tumor markers CEA, CA19-9, and CA125 also improved significantly. PET-CT after 1 year and 4 months showed no lymph node enlargement or accumulation, indicating a complete response (CR). All tumor markers also normalized. The patient has maintained clinical CR without additional treatment to date., Conclusions: We report the apparent first case of postoperative gastric cancer recurrence successfully treated with TDXD, achieving clinical CR with TDXD as a 6th-line treatment., (© 2024. The Author(s).)

The detection of copy number variations (CNVs) and somatic mutations in cancer is important for the selection of specific drugs for patients with cancer. In cancers with sporadic tumor cells, low tumor content prevents the accurate detection of somatic alterations using targeted sequencing. To efficiently identify CNVs, we performed tumor cell enrichment using tissue suspensions of formalin-fixed paraffin-embedded (FFPE) tissue sections with low tumor cell content. Tumor-enriched and residual fractions were separated from FFPE tissue suspensions of intestinal and diffuse-type gastric cancers containing sporadic tumor cells, and targeted sequencing was performed on 225 cancer-related genes. Sequencing of a targeted panel of cancer-related genes using tumor-enriched fractions increased the number of detectable CNVs and the copy number of amplified genes. Furthermore, CNV analysis using the normal cell-enriched residual fraction as a reference for CNV scoring allowed targeted sequencing to detect CNV characteristics of diffuse-type gastric cancer with low tumor content. Our approach improves the CNV detection rate in targeted sequencing with tumor enrichment and the accuracy of CNV detection in archival samples without paired blood., (© 2024. The Author(s).)

Pathologic α-synuclein (α-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid β precursor-like protein 1 (Aplp1) interacts with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic α-syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by α-syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of α-syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by α-syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for α-syn PFF induced pathology deepens our insight about molecular mechanisms of cell-to-cell transmission of pathologic α-syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinson's disease and related α-synucleinopathies., (© 2024. The Author(s).)

Background: Most colon cancers that develop in the intestinal tract within the inguinal hernia sac are identified by incarceration. However, treatment methods for these cases vary depending on the pathology. Cases showing perforation or abscess formation require emergency surgery for infection control, while cases with no infection generally involve oncological resection, with laparoscopic surgery also being an option. We encountered a case of Incomplete bowel obstruction secondary to sigmoid colon cancer within the hernial sac. We report the process leading to the selection of the treatment method and the surgical technique, along with a review of the literature., Case Presentation: A 79-year-old man presented to our hospital complaining of a left inguinal bulge (hernia) and pain in the same area. The patient had the hernia for more than 20 years. Using computed tomography, we diagnosed an incomplete bowel obstruction caused by a tumor of the intestinal tract within the hernial sac. Since imaging examination showed no signs of strangulation or perforation, we decided to perform elective surgery after a definitive diagnosis. After colonoscopy, we diagnosed sigmoid colon cancer with extra-serosal invasion; however, we could not insert a colorectal tube. Although we proposed sigmoid resection and temporary ileostomy, we chose the open Hartmann procedure because the patient wanted a single surgery. For the hernia, we simultaneously used the Iliopubic Tract Repair method, which does not require a mesh. Eight months after the surgery, no recurrence of cancer or hernia was observed., Conclusions: We report a case of advanced sigmoid colon cancer with a long-standing inguinal hernia that later became incomplete bowel obstruction. Although previous studies have used various approaches among the available surgical methods for cancer within the hernial sac, such as inguinal incision, laparotomy, and laparoscopic surgery, most hernias are repaired during the initial surgery using a non-mesh method. For patients with inguinal hernias that have become difficult to treat, the complications of malignancy should be taken into consideration and the treatment option should be chosen according to the pathophysiology., (© 2024. The Author(s).)

Objective We aimed to reveal detailed on-treatment lipid profiles, lipid-related surrogate markers, and factors predicting failure to achieve the guideline-recommended lipid management goal following guideline-recommended statin treatment in Japanese patients with acute myocardial infarction (AMI). Methods and Results Sixty AMI patients who underwent coronary intervention and had received rosuvastatin 10 mg/day since the start of their hospitalization were assessed for on-treatment lipid-related profiles, including high-sensitivity C-reactive protein, small dense low-density lipoprotein cholesterol (sd LDL-C), and lipoprotein (a), at the 12-week follow-up. Patients who failed to achieve the guideline-recommended lipid management at 12 weeks were defined as the "unachieved group." Univariate and multivariate logistic regression analyses were performed to evaluate the predictors of inclusion in the unachieved group after high-dose statin treatment. Despite the use of high-dose rosuvastatin, 61.7% of the enrolled AMI patients were included in the unachieved group. In addition, the unachieved group had higher sd LDL-C and lipoprotein (a) levels than the achieved group. Logistic regression analyses demonstrated that low baseline high-density lipoprotein cholesterol (HDL-C) levels and the absence of diabetes were predictors of inclusion in the unachieved group. Conclusion More than half of the Japanese AMI patients treated with rosuvastatin 10 mg/day did not achieve the guideline-recommended goal of lipid management and still had lipid-related residual risk at 12 weeks. Particular attention should be paid to patients with low baseline HDL-C levels and those without diabetes with regard to their on-treatment lipid profiles.

Focal epilepsy is associated with intermittent brief population discharges (interictal spikes), which resemble sentinel spikes that often occur at the onset of seizures. Why interictal spikes self-terminate whilst seizures persist and propagate is incompletely understood. We used fluorescent glutamate and GABA sensors in an awake rodent model of neocortical seizures to resolve the spatiotemporal evolution of both neurotransmitters in the extracellular space. Interictal spikes were accompanied by brief glutamate transients which were maximal at the initiation site and rapidly propagated centrifugally. GABA transients lasted longer than glutamate transients and were maximal ∼1.5 mm from the focus where they propagated centripetally. Prior to seizure initiation GABA transients were attenuated, whilst glutamate transients increased, consistent with a progressive failure of local inhibitory restraint. As seizures increased in frequency, there was a gradual increase in the spatial extent of spike-associated glutamate transients associated with interictal spikes. Neurotransmitter imaging thus reveals a progressive collapse of an annulus of feed-forward GABA release, allowing seizures to escape from local inhibitory restraint., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Glioma is a primary brain tumor and the assessment of its molecular profile in a minimally invasive manner is important in determining treatment strategies. Among the molecular abnormalities of gliomas, mutations in the isocitrate dehydrogenase (IDH) gene are strong predictors of treatment sensitivity and prognosis. In this study, we attempted to non-invasively diagnose glioma development and the presence of IDH mutations using multivariate analysis of the plasma mid-infrared absorption spectra for a comprehensive and sensitive view of changes in blood components associated with the disease and genetic mutations. These component changes are discussed in terms of absorption wavenumbers that contribute to differentiation., Methods: Plasma samples were collected at our institutes from 84 patients with glioma (13 oligodendrogliomas, 17 IDH-mutant astrocytoma, 7 IDH wild-type diffuse glioma, and 47 glioblastomas) before treatment initiation and 72 healthy participants. FTIR-ATR spectra were obtained for each plasma sample, and PLS discriminant analysis was performed using the absorbance of each wavenumber in the fingerprint region of biomolecules as the explanatory variable. This data was used to distinguish patients with glioma from healthy participants and diagnose the presence of IDH mutations., Results: The derived classification algorithm distinguished the patients with glioma from healthy participants with 83% accuracy (area under the curve (AUC) in receiver operating characteristic (ROC) = 0.908) and diagnosed the presence of IDH mutation with 75% accuracy (AUC = 0.752 in ROC) in cross-validation using 30% of the total test data. The characteristic changes in the absorption spectra suggest an increase in the ratio of β-sheet structures in the conformational composition of blood proteins of patients with glioma. Furthermore, these changes were more pronounced in patients with IDH-mutant gliomas., Conclusions: The plasma infrared absorption spectra could be used to diagnose gliomas and the presence of IDH mutations in gliomas with a high degree of accuracy. The spectral shape of the protein absorption band showed that the ratio of β-sheet structures in blood proteins was significantly higher in patients with glioma than in healthy participants, and protein aggregation was a distinct feature in patients with glioma with IDH mutations., (© 2024. The Author(s).)

Background: Distant recurrence can occur by infiltration along white matter tracts or dissemination through the cerebrospinal fluid (CSF). This study aimed to clarify the clinical features and mechanisms of recurrence in the dentate nucleus (DN) in patients with supratentorial gliomas. Based on the review of our patients, we verified the hypothesis that distant DN recurrence from a supratentorial lesion occurs through the dentato-rubro-thalamo-cortical (DRTC) pathway., Methods: A total of 380 patients with supratentorial astrocytoma, isocitrate dehydrogenase (IDH)-mutant (astrocytoma), oligodendroglioma, IDH mutant and 1p/19q-codeleted (oligodendroglioma), glioblastoma, IDH-wild type (GB), and thalamic diffuse midline glioma, H3 K27-altered (DMG), who underwent tumor resection at our department from 2009 to 2022 were included in this study. Recurrence patterns were reviewed. Additionally, clinical features and magnetic resonance imaging findings before treatment, at the appearance of an abnormal signal, and at further progression due to delayed diagnosis or after salvage treatment of cases with recurrence in the DN were reviewed., Results: Of the 380 patients, 8 (2.1%) had first recurrence in the DN, 3 were asymptomatic when abnormal signals appeared, and 5 were diagnosed within one month after the onset of symptoms. Recurrence in the DN developed in 8 (7.4%) of 108 cases of astrocytoma, GB, or DMG at the frontal lobe or thalamus, whereas no other histological types or sites showed recurrence in the DN. At the time of the appearance of abnormal signals, a diffuse lesion developed at the hilus of the DN. The patterns of further progression showed that the lesions extended to the superior cerebellar peduncle, tectum, tegmentum, red nucleus, thalamus, and internal capsule along the DRTC pathway., Conclusion: Distant recurrence along the DRTC pathway is not rare in astrocytomas, GB, or DMG at the frontal lobe or thalamus. Recurrence in the DN developed as a result of the infiltration of tumor cells through the DRTC pathway, not dissemination through the CSF., (© 2024. The Author(s).)

Chronic inflammation caused by infiltrating immune cells can promote colitis-associated dysplasia/colitic cancer in ulcerative colitis (UC) by activating inflammatory cytokine signalling through the IL-6/p-STAT3 and TNFα/NF-κB pathways. Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed on high endothelial venules promotes the migration of immune cells from the bloodstream to the gut via interaction with α4β7 integrin expressed on the immune cells. MAdCAM-1, has therefore drawn interest as a novel therapeutic target for treating active UC. However, the role of MAdCAM-1-positive endothelial cells in immune cell infiltration in dysplasia/colitic cancers remains unclear. We evaluated the expression of MAdCAM-1, CD31 and immune cell markers (CD8, CD68, CD163 and FOXP3) in samples surgically resected from 11 UC patients with dysplasia/colitic cancer and 17 patients with sporadic colorectal cancer (SCRC), using immunohistochemical staining. We used an azoxymethane/dextran sodium sulphate mouse model (AOM/DSS mouse) to evaluate whether dysplasia/colitic cancer could be suppressed with an anti-MAdCAM-1 blocking antibody by preventing immune cell infiltration. The number of MAdCAM-1-positive vessels and infiltrating CD8 + , CD68 + and CD163 + immune cells was significantly higher in dysplasia/colitic cancer than in normal, SCRC and UC mucosa. In AOM/DSS mice, the anti-MAdCAM-1 antibody reduced the number, mean diameter, depth of tumours, Ki67 positivity, number of CD8 + , CD68 + and CD163 + immune cells and the IL-6/p-STAT3 and TNF-α/NF-κB signalling. Our results indicate that targeting MAdCAM-1 is a promising strategy for controlling not only UC severity but also carcinogenesis and tumour progression by regulating inflammation/immune cell infiltration in patients with UC., (© 2023 UICC.)

Two-dimensional (2D) materials offer potential as substrates for biosensing devices, as their properties can be engineered to tune interactions between the surface and biomolecules. Yet, not many methods can measure these interactions in a liquid environment without introducing labeling agents such as fluorophores. In this work, we harness interferometric scattering (iSCAT) microscopy, a label-free imaging technique, to investigate the interactions of single molecules of long dsDNA with 2D materials. The millisecond temporal resolution of iSCAT allows us to capture the transient interactions and to observe the dynamics of unlabeled DNA binding to a hexagonal boron nitride (hBN) surface in solution for extended periods (including a fraction of 10%, of trajectories lasting longer than 110 ms). Using a focused ion beam technique to engineer defects, we find that DNA binding affinity is enhanced at defects; when exposed to long lanes, DNA binds preferentially at the lane edges. Overall, we demonstrate that iSCAT imaging is a useful tool to study how biomolecules interact with 2D materials, a key component in engineering future biosensors., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Glioblastoma (GBM) is one of the most aggressive and deadly brain tumors; however, its current therapeutic strategies are limited. Selenoprotein P (SeP; SELENOP, encoded by the SELENOP gene) is a unique selenium-containing protein that exhibits high expression levels in astroglia. SeP is thought to be associated with ferroptosis sensitivity through the induction of glutathione peroxidase 4 (GPX4) via selenium supplementation. In this study, to elucidate the role of SeP in GBM, we analyzed its expression in GBM patients and found that SeP expression levels were significantly higher when compared to healthy subjects. Knock down of SeP in cultured GBM cells resulted in a decrease in GPX1 and GPX4 protein levels. Under the same conditions, cell death caused by RSL3, a ferroptosis inducer, was enhanced, however this enhancement was canceled by supplementation of selenite. These results indicate that SeP expression contributes to preserving GPX and selenium levels in an autocrine/paracrine manner, i.e., SeP regulates a dynamic cycling-selenium storage system in GBM. We also confirmed the role of SeP expression in ferroptosis sensitivity using patient-derived primary GBM cells. These findings indicate that expression of SeP in GBM can be a significant therapeutic target to overcome anticancer drug resistance., (© 2024. The Author(s).)

Background/aim: Recently, inactivating somatic mutations of SWI/SNF chromatin-remodeling genes in cancers have been reported. However, few studies have been performed regarding the immunological analysis of the tumor microenvironment (TME) in chromatin remodeling complex gene-mutated tumors. In the present study, we identified cancer patients harboring various mammalian SWI/SNF complex mutations and investigated the immunological features in those mutated cancers., Patients and Methods: Cancer patients harboring any type of chromatin remodeling complex gene mutation were selected and clinicopathological features were compared between chromatin remodeling complex gene expression-low and expression-high groups. Specifically, expression levels of immune response-associated genes and cancer-associated genes were compared between the SMARCA4 expression-low and expression-high groups using volcano plot analysis., Results: Among cancers harboring PBRM1, SAMRACA4 and ARID2 gene mutations, T-cell marker and mature B-cell marker genes were up-regulated in the tumor. Specifically, T-cell effector genes (CD8B, CD40LG), central memory marker genes (CD27, CCR7) and mature B-cell marker genes (CD20, CD38, CD79 and IRF4) were up-regulated, and cancer-associated genes including MYB, MYC and AURKB genes were down-regulated in the SMARCA4 expression-low group. Remarkably, heatmap of gene expression and immunohistochemistry (IHC) data demonstrated that the tertiary lymphoid structure (TLS) gene signature of mature B cells was up-regulated in SMACA4 gene-mutated stomach cancers., Conclusion: These results suggest that immune tumor microenvironment status, such as mature B cell recruitment featuring the TLS gene signature and immune activation mediated by cancer signal down-regulation, might contribute to the classification of SMARCA4 gene-mutated tumors as immune checkpoint blockade therapy-sensitive target tumors., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Although recent advances in genome editing technology with homology-directed repair have enabled the insertion of various reporter genes into the genome of mammalian cells, the efficiency is still low due to the random insertion of donor vectors into the host genome. To efficiently select knocked-in cells without random insertion, we developed the "double-tk donor vector system," in which the expression units of the thymidine kinase of herpes simplex virus (HSV-tk) are placed on both outer sides of homology arms. This system is superior in enriching knocked-in human induced pluripotent stem cells (hiPSCs) than conventional donor vector systems with a single or no HSV-tk cassette. Using this system, we efficiently generated fluorescent reporter knockin hiPSCs targeting POU5F1 (OCT3/4), EEF1A1, H2BC21 (H2B clustered histone 21), ISL1, and MYH7 genes. These results indicate that the double-tk donor vector system enables efficient selection of knocked-in hiPSCs carrying reporter proteins., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Laparoscopic gastrectomy (LG) indications have been extended to advanced gastric cancer requiring expansive lymph node dissection. Despite the huge benefits of this minimally invasive surgery, major complications such as postoperative pancreatic fistula (POPF) remain a concern. With technical advances in surgical procedures, the treatment outcomes of gastric cancer surgery have improved. However, effective methods for preventing POPF have not yet been established. Herein, we examined the usefulness of polyglycolic acid (PGA) sheets for preventing POPF after LG., Methods: We retrospectively assessed 142 patients who underwent curative LG at our institution between January 2017 and August 2022. The 142 patients were divided into 2 groups; PGA group (n = 61): the site of lymph node dissection at the superior margin of the pancreas and pancreatic head was covered with PGA sheets, and nPGA group (n = 81): the site was not covered. We retrospectively compared the short-term surgical outcomes including POPF incidence., Results: There was no significant difference in the background factors between the 2 groups and in the incidence of Grade II or higher postoperative complications according to the Clavien-Dindo (CD) classification. However, the incidence of CD Grade II or higher POPF was significantly lower in the PGA group than in the nPGA group (.0% vs 2.3%, respectively, P = .007)., Conclusions: There was no POPF in any of the 61 patients in the PGA group. This outcome suggests that POPF incidence may be reduced by covering the lymph node dissection site with PGA sheets after LG., Competing Interests: Declaration of Conflicting InterestsThe authors declare that they have no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The region behind the coronary calcium could not be visualized by intravascular ultrasound (IVUS) because of acoustic shadow. However, some pathological studies have shown that IVUS delineated the vessel border behind thin coronary calcium sheets. This study aimed to reveal whether recent IVUS can visualize the region behind thin coronary calcium sheets. Using 534 cross-sectional optical frequency domain images (OFDI), including severe calcified coronary lesions, calcium sheet thickness was measured by every 1°. Accordingly, the visibility of the vessel border behind the coronary calcium sheet was evaluated using 60-MHz IVUS images, which were longitudinally linked with OFDI ones. After carefully coordinating with the axial position, the association between the IVUS-derived permeability of the coronary calcium sheet and calcium thickness was evaluated. The maximum and mean calcium thickness by OFDI was 0.88 ± 0.39 and 0.62 ± 0.30 mm, respectively. By 60-MHz IVUS, 12.1% of the coronary calcium sheets had permeable segments. Comparing between OFDI and IVUS images, 48.6% of the coronary calcium sheets with maximum thickness ≤ 0.3 mm were sometimes permeable by 60-MHz IVUS, whereas most > 0.5 mm thick calcium sheets were impermeable. In the receiver operating characteristic curve analysis, the best cutoff values for the maximum and mean thickness of permeable calcium were 0.48 and 0.31 mm, respectively. Thus, 60-MHz IVUS can occasionally visualize the region behind a thin coronary calcium sheet. When using 60-MHz IVUS, this finding may be a predictive marker of calcium sheet with a thickness of < 0.5 mm., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

We herein report a case of anti-gamma aminobutyric acid type A receptor antibody-associated encephalitis (anti-GABA A -RE) with progressive aphasia and generalized tonic-clonic seizures. Cerebral magnetic resonance imaging (MRI) showed cortical brain lesions coupled with hypermetabolism on fluorodeoxyglucose-positron emission tomography. After two courses of methylprednisolone pulse therapy, improvements in neurological symptoms without sequelae and the total disappearance of MRI lesions were observed. Upon encountering patients with refractory status epilepticus, multifocal cerebral MRI lesions, and suspected autoimmune encephalitis, especially in cases with thymoma, it would be prudent to suspect anti-GABA A -RE and consider the evaluation of anti-GABA A receptor antibody and methylprednisolone pulse therapy.

Purpose: The anatomical association between the lesion and the perforating arteries supplying the pyramidal tract in insulo-opercular glioma resection should be evaluated. This study reported a novel method combining the intra-arterial administration of contrast medium and ultrahigh-resolution computed tomography angiography (UHR-IA-CTA) for visualizing the lenticulostriate arteries (LSAs), long insular arteries (LIAs), and long medullary arteries (LMAs) that supply the pyramidal tract in two patients with insulo-opercular glioma., Methods: This method was performed by introducing a catheter to the cervical segment of the internal carotid artery. The infusion rate was set at 3 mL/s for 3 s, and the delay time from injection to scanning was determined based on the time-to-peak on angiography. On 2- and 20-mm-thick UHR-IA-CTA slab images and fusion with magnetic resonance images, the anatomical associations between the perforating arteries and the tumor and pyramidal tract were evaluated., Results: This novel method clearly showed the relationship between the perforators that supply the pyramidal tract and tumor. It showed that LIAs and LMAs were far from the lesion but that the proximal LSAs were involved in both cases. Based on these results, subtotal resection was achieved without complications caused by injury of perforators., Conclusion: UHR-IA-CTA can be used to visualize the LSAs, LIAs, and LMAs clearly and provide useful preoperative information for insulo-opercular glioma resection., (© 2023. The Author(s).)

The prevalence of allergic conjunctivitis in itchy eyes has increased constantly worldwide owing to environmental pollution. Currently, anti-allergic and antihistaminic eye drops are used; however, there are many unknown aspects about the neural circuits that transmit itchy eyes. We focused on the gastrin-releasing peptide (GRP) and GRP receptor (GRPR), which are reportedly involved in itch transmission in the spinal somatosensory system, to determine whether the GRP system is involved in itch neurotransmission of the eyes in the trigeminal sensory system. First, the instillation of itch mediators, such as histamine (His) and non-histaminergic itch mediator chloroquine (CQ), exhibited concentration-dependent high levels of eye scratching behavior, with a significant sex differences observed in the case of His. Histological analysis revealed that His and CQ significantly increased the neural activity of GRPR-expressing neurons in the caudal part of the spinal trigeminal nucleus of the medulla oblongata in GRPR transgenic mice. We administered a GRPR antagonist or bombesin-saporin to ablate GRPR-expressing neurons, followed by His or CQ instillation, and observed a decrease in CQ-induced eye-scratching behavior in the toxin experiments. Intracisternal administration of neuromedin C (NMC), a GRPR agonist, resulted in dose-dependent excessive facial scratching behavior, despite the absence of an itch stimulus on the face. To our knowledge, this is the first study to demonstrate that non-histaminergic itchy eyes were transmitted centrally via GRPR-expressing neurons in the trigeminal sensory system, and that NMC in the medulla oblongata evoked facial itching., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Takanami, Kuroiwa, Ishikawa, Imai, Oishi, Hashino, Shimoda, Sakamoto and Koide.)

N 2 O is an important greenhouse gas influencing global warming, and agricultural land is the predominant (anthropogenic) source of N 2 O emissions. Here, we report the high N 2 O-reducing activity of Bradyrhizobium ottawaense, suggesting the potential for efficiently mitigating N 2 O emission from agricultural lands. Among the 15 B. ottawaense isolates examined, the N 2 O-reducing activities of most (13) strains were approximately five-fold higher than that of Bradyrhizobium diazoefficiens USDA110 T under anaerobic conditions. This robust N 2 O-reducing activity of B. ottawaense was confirmed by N 2 O reductase (NosZ) protein levels and by mitigation of N 2 O emitted by nodule decomposition in laboratory system. While the NosZ of B. ottawaense and B. diazoefficiens showed high homology, nosZ gene expression in B. ottawaense was over 150-fold higher than that in B. diazoefficiens USDA110 T , suggesting the high N 2 O-reducing activity of B. ottawaense is achieved by high nos expression. Furthermore, we examined the nos operon transcription start sites and found that, unlike B. diazoefficiens, B. ottawaense has two transcription start sites under N 2 O-respiring conditions, which may contribute to the high nosZ expression. Our study indicates the potential of B. ottawaense for effective N 2 O reduction and unique regulation of nos gene expression towards the high performance of N 2 O mitigation in the soil., (© 2023. The Author(s).)

We investigated the potential dual application of two Bradyrhizobium strains (B. diazoefficiens USDA110 and B. ottawaense SG09) and plant growth-promoting bacteria, PGPB (Pseudomonas spp.: OFT2 and OFT5), to improve nodulation and N 2 -fixation in soybean plants. The growth-promoting effects of dual inoculation were observed on plant growth, physiology, and nodulation of soybean under normal conditions compared with plants individually inoculated with either USDA110 or SG09. Both OFT2 and OFT5 promoted N 2 -fixation by 11% and 56%, respectively, when dual inoculation with USDA110 and by 76% and 81%, respectively, when dual inoculation with SG09. Salinity stress significantly reduces soybean growth, physiology, nutrient uptake, nodulation, and N 2 -fixation. However, these adverse effects were attenuated by the dual inoculation of PGPB and rhizobia depending on the combination of inoculants. In particular, dual inoculation of PGPB with SG09 was more effective in enhancing the salt tolerance of soybean by reducing salt-induced ethylene production and improving nutrient uptake. However, no such effect was observed with the combined inoculation of USDA110 and OFT5. An effective symbiotic association between SG09 and two Pseudomonas bacteria can be considered a beneficial approach to improving the symbiotic efficiency of nodulation and mitigating salinity stress in soybeans., (© 2023. Springer Nature Limited.)

The occipital transtentorial approach (OTA) is one of the useful approaches to the lesions of the pineal region, dorsal brainstem, and supracerebellar region. However, a wide operative field is sometimes difficult to obtain due to the tentorial sinus and bridging veins. This study evaluated the usefulness of preoperative simulation of OTA, specifically including the cerebellar tentorium in 9 patients. All patients underwent computed tomography angiography and venography and gadolinium-enhanced three-dimensional T1-weighted magnetic resonance images (Gd-3D-T1WI). The images were fused, and the cerebellar tentorium, vessels, and tumor were manually extracted from Gd-3D-T1WI to obtain the simulation images. Visualization of the cerebellar tentorium could discriminate between bridging veins from the occipital lobe and cerebellum, and recognize the site of bridging to the tentorial sinus and variants which may interfere with the tentorial incision. Simulation of the tentorial incision was also possible based on the relationships between the tumor, tentorial sinus, bridging vein, and cerebellar tentorium. The simulation suggested that safe tentorial incision was difficult in two sides because of the crossed tentorial sinus draining the left basal vein and draining veins from the glioblastoma. The OTA was performed in eight cases, and no difficulty was experienced in the tentorial incision in all cases. The simulation findings of the bridging vein and tentorial sinus were consistent with the intraoperative findings. Preoperative simulation including the cerebellar tentorium is useful for determining the optimum and safe side and required extent of the tentorial incision necessary for tumor resection with the OTA., (© 2023. The Author(s).)

Most plants interact with various soil microorganisms as they grow through the soil. Root nodule symbiosis by legumes and rhizobia is a well-known phenomenon of plant-microbe interactions in the soil. Although microscopic observations are useful for understanding the infection processes of rhizobia, nondestructive observation methods have not been established for monitoring interactions between rhizobia and soil-grown roots. In this study, we constructed Bradyrhizobium diazoefficiens strains that constitutively express different fluorescent proteins, which allows identification of tagged rhizobia by the type of fluorophores. In addition, we constructed a plant cultivation device, Rhizosphere Frame (RhizoFrame), which is a soil-filled container made of transparent acrylic plates that allows observation of roots growing along the acrylic plates. Combining fluorescent rhizobia with RhizoFrame, we established a live imaging system, RhizoFrame system, that enabled us to track the nodulation processes with fluorescence stereomicroscope while retaining spatial information about roots, rhizobia, and soil. Mixed inoculation with different fluorescent rhizobia using RhizoFrame enabled the visualization of mixed infection of a single nodule with two strains. In addition, observation of transgenic Lotus japonicus expressing auxin-responsive reporter genes indicated that RhizoFrame system could be used for a real-time and nondestructive reporter assay. Thus, the use of RhizoFrame system is expected to enhance the study of the spatiotemporal dynamics of plant-microbe interactions in the soil., (© 2023. The Author(s).)

Background: Sequential tyrosine kinase inhibitors (TKIs) following immune checkpoint inhibitors (ICIs) increases the incidence of serious adverse events (SAEs). However, the factors and the types of TKIs that affect the incidence of SAEs remain unknown., Methods: We retrospectively reviewed advanced non-small cell lung cancer (NSCLC) patients who received sequential TKIs following ICIs between November 2015 and April 2021. All AEs were evaluated using Common Terminology Criteria for Adverse Events (CTCAE) ver 5.0., Results: Among 1,638 NSCLC patients who received ICIs, 63 patients received sequential TKIs following ICIs. The types of TKIs included EGFR-TKIs in 48 patients, ALK-TKIs in 10 patients, and others in 5 patients. The median dosing interval was 57 days (range: 7-698). Eighteen (28.6%) patients developed SAEs (Grade 3/4 or hospitalized). The incidence of SAEs and withdrawal of TKIs due to AEs were significantly higher in patients (n = 40) who initiated TKI treatment within 3 months after ICIs than in patients (n = 23) who initiated TKI treatment 3 months after ICIs (SAEs, 40.0% vs. 4.3%, p < 0.01; withdrawal rate: 57.5% vs. 21.7%, p < 0.01). There was no significant difference in the incidence of SAEs and withdrawal rate due to AEs between EGFR-TKIs and other TKIs (SAE, 22.9% vs. 40.0%, p = 0.20; withdrawal rate: 41.7% vs. 53.3%, p = 0.55)., Conclusion: The dosing interval from last ICI to the initiation of TKI treatment can affects the incidence of SAEs and the withdrawal rate due to AEs regardless of the types of TKIs., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Lipopolysaccharides are a type of polysaccharide mainly present in the bacterial outer membrane of Gram-negative bacteria. Recent studies have revealed that lipopolysaccharides contribute to the immune response of the host by functioning as a cancer antigen. We retrospectively recruited 198 patients with gastric cancer who underwent surgery. The presence of lipopolysaccharides was determined using immunohistochemical staining, with the intensity score indicating positivity. The relationship between lipopolysaccharides and CD8, PD-L1, TGFBI (a representative downstream gene of TGF-β signaling), wnt3a, and E-cadherin (epithelial-mesenchymal transition marker) was also investigated. Thereafter, we identified 20 patients with advanced gastric cancer receiving nivolumab and investigated the relationship between lipopolysaccharides and nivolumab sensitivity. After staining for lipopolysaccharides in the nucleus of cancer cells, 150 negative (75.8%) and 48 positive cases (24.2%) were found. The lipopolysaccharide-positive group showed increased cancer stromal TGFBI expression ( p < 0.0001) and PD-L1 expression in cancer cells ( p = 0.0029). Lipopolysaccharide positivity was significantly correlated with increased wnt3a signaling ( p = 0.0028) and decreased E-cadherin expression ( p = 0.0055); however, no significant correlation was found between lipopolysaccharide expression and overall survival rate ( p = 0.71). In contrast, high TGFBI expression in the presence of LPS was associated with a worse prognosis than that in the absence of LPS ( p = 0.049). Among cases receiving nivolumab, the lipopolysaccharide-negative and -positive groups had disease control rates of 66.7% and 11.8%, respectively ( p = 0.088). Lipopolysaccharide positivity was associated with wnt3a, TGF-β signaling, and epithelial-mesenchymal transition and was considered to tend to promote therapeutic resistance to nivolumab.

Immunogenic neoantigens derived from somatic mutations in cancer have been identified through clinical studies with the cloning of tumor-infiltrating T cells, and cancer driver gene mutation-derived epitopes have been reported; however, these are rare. At present, the validation of epitopes predicted in silico is difficult as human T-cell clonal diversity cannot be reproduced in vitro or in experimental animal models. To confirm the epitope peptides presented by human leukocyte antigen (HLA) class I molecules predicted in silico , biochemical methods such as major histocompatibility complex (MHC) stabilization assays and mass spectrometry-mediated identification have been developed based on HLA-A*02:01 monoallelic T2 cells and HLA-C*01:02 monoallelic LCL721.221 cells. Therefore, in the present study, to prevent confusion due to peptide cross-presentation among HLA molecules, HLA class I monoallelic B-cell clones were generated from the TISI cell line by knocking out HLA-ABC and TAP2 , and knocking in HLA alleles. To explore cancer driver mutations as potential targets for immunotherapy, exome sequencing data from 5,143 patients with cancer enrolled in a comprehensive genome analysis project at the Shizuoka Cancer Center were used to identify somatic amino acid substituted mutations and the 50 most frequent mutations in five genes, TP53, EGFR, PIK3CA, KRAS and BRAF , were identified. Using NetMHC4.1, the present study predicted whether epitopes derived from these mutations are presented on major HLA-ABC alleles in Japanese individuals and synthesized 138 peptides for MHC stabilization assays. The authors also attempted to examine the candidate epitopes at physiological temperatures by using antibody clone G46-2.6, which can detect HLA-ABC, independent of β2-microglobulin association. In the assays, although the peptide-induced HLA expression levels were associated with the predicted affinities, the respective HLA alleles exhibited varying degrees of responsiveness, and unexpectedly, p53-mutant epitopes with predicted weak affinities exhibited strong responses. These results suggested that MHC stabilization assays using completely monoallelic HLA-expressing B-cell lines are useful for evaluating the presentation of neoantigen epitopes., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Iizuka et al.)

Background: It is still unclear whether patients with advanced non-small cell lung cancer (NSCLC), with disease progression after initial immune checkpoint inhibitor (ICI) therapy, would benefit from ICIs readministration., Patients and Methods: We retrospectively collected data from patients with advanced NSCLC who received ICI retreatment. Depending on the disease status at the discontinuation of the initial ICI therapy, the patients were divided into two groups: with disease progression (PD group) and without disease progression (Without PD group). Patients in the Without PD group were required to experience disease progression during the treatment-free period. Efficacy was assessed by measuring the objective response rate (ORR) and progression-free survival in retreatment (PFS-R), while safety was assessed using the incidence of immune-related adverse events (irAEs)., Results: 30 (46.7%) of 64 eligible patients were included in the PD group and 34 (53.1%) in the Without PD group. Patients in the Without PD group had better clinical outcomes than those in the PD group (ORR, 29.4% vs. 6.7%; p = 0.03, median PFS-R, 4.1 months vs. 2.2 months, hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.36-1.04; p = 0.07). Multivariate Cox regression analysis showed that patients in the Without PD group had significantly longer PFS-R than those in the PD group (HR 0.42, 95% CI, 0.21-0.85; p = 0.015). In terms of safety, 28.1% of patients observed irAEs during ICI retreatment, and the incidence rate of grade 3 or higher irAEs was 7.8%. Specifically, of the 28 patients who discontinued their initial ICI treatment because of irAEs, 35.7% developed irAEs, and 28.6% experienced relapsed irAEs during ICI retreatment., Conclusion: Immune checkpoint inhibitor retreatment demonstrated efficacy in patients who discontinued initial ICI therapy for reasons other than disease progression. However, ICI retreatment was ineffective in patients with disease progression during the initial ICI treatment., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Remnant gastric cancer (RGC) encompasses all cancers arising from the remnant stomach. Various studies have reported on RGC and its prognosis, but no consensus on its surgical treatment and postoperative management has been reached. Moreover, the correlation between the clinicopathological characteristics and long-term outcomes of RGC remains unclear. This study investigated the clinicopathological factors associated with the long-term survival of RGC patients., Methods: The medical records (March 1993-September 2020) of 104 RGC patients from Tokyo Medical University Hospital database were analyzed. Of these 104 patients, the medical records of 63 patients who underwent surgical curative resection were analyzed using R. Kaplan-Meier plots of cumulative incidence of RGC were made. Differences in survival rates were compared using the log-rank test. Prognostic factors were analyzed using multivariate Cox regression analysis ( P < .05)., Results: Of the 104 RGC patients, 63 underwent total remnant stomach excision. The median time from the first surgery to the total excision was 10 years. The 5-year survival rate of the 63 RGC patients was .55 ((95% CI); .417-.671). The clinicopathological factors that were significantly associated with the long-term outcome of the RGC patients were tumor diameter (≥3.5 cm), presence or absence of combined resection of multiple organs, tumor invasion (deeper than T2), TNM stage, and postoperative morbidity. The multivariate Cox regression analysis showed that tumor invasion depth was the only independent prognostic factor for RGC patients [HR (95% CI): 5.49 (2.629-11.5), P ≤ .005]., Conclusions: Among prognostic factors, tumor invasion depth was the only independent factor affecting RGC's long-term outcome.

Background and Aim: Linked color imaging (LCI) is useful for screening in the gastrointestinal tract; however, its true clinical benefit has not been determined. The aim of this study was to determine the objective advantage of LCI for detection of upper gastrointestinal neoplasms., Methods: Nine endoscopists, including three novices, three trainees, and three experts, prospectively performed eye tracking. From 30 cases of esophageal or gastric neoplasm and 30 normal cases without neoplasms, a total of 120 images, including 60 pair images of white light imaging (WLI) and LCI taken at the same positions and angles, were randomly shown for 10 s. The sensitivity of tumor detection as a primary endpoint was evaluated and sensitivities by organ, size, and visual gaze pattern were also assessed. Color differences (ΔE using CIE1976 [L*a*b*]) between lesions and surrounding mucosa were measured and compared with detectability., Results: A total of 1080 experiments were completed. The sensitivities of tumor detection in WLI and LCI were 53.7% (50.1-56.8%) and 68.1% (64.8-70.8%), respectively (P = 0.002). LCI provided higher sensitivity than WLI for the novice and trainee groups (novice: 42.2% [WLI] vs 65.6% [LCI], P = 0.003; trainee: 54.4% vs 70.0%, P = 0.045). No significant correlations were found between sensitivity and visual gaze patterns. LCI significantly increased ΔE, and the diagnostic accuracy with WLI depended on ΔE., Conclusions: In conclusion, LCI significantly improved sensitivity in the detection of epithelial neoplasia and enabled epithelial neoplasia detection that is not possible with the small color difference in WLI. (UMIN000047944)., (© 2023 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Gastrointestinal stromal tumors (GIST) with KIT exon 11 deletions involving in codons 557-558 ( KIT Δ557-558) exhibit higher proliferation rates and shorter disease-free survival times compared with GISTs with other KIT exon 11 mutations. We analyzed 30 GIST cases and observed genomic instability and global DNA hypomethylation only in high-risk malignant GISTs with KIT Δ557-558. Whole-genome sequencing revealed that the high-risk malignant GISTs with KIT Δ557-558 (12 cases) had more structural variations (SV), single-nucleotide variants, and insertions and deletions compared with the low-risk, less malignant GISTs with KIT Δ557-558 (six cases) and the high-risk (six cases) or low-risk (6 cases) GISTs with other KIT exon 11 mutations. The malignant GISTs with KIT Δ557-558 showed higher frequency and significance in copy number (CN) reduction on chromosome arms 9p and 22q, and 50% of them had LOH or CN-dependent expression reduction in CDKN2A . In addition, SVs with driver potential were detected in 75% of them, in which AKT3 and MGMT were recurrently identified. Genome-wide DNA methylation and gene expression analyses showed global intergenic DNA hypomethylation, SNAI2 upregulation, and higher expression signatures, including p53 inactivation and chromosomal instability, as characteristics of malignant GISTs with KIT Δ557-558 that distinguished them from other GISTs. These genomic and epigenomic profiling results revealed that KIT Δ557-558 mutations are associated with increased genomic instability in malignant GISTs., Significance: We present genomic and epigenomic insights into the malignant progression of GISTs with KIT exon 11 deletions involving in 557-558, demonstrating their unique chromosomal instability and global intergenic DNA hypomethylation., (© 2023 The Authors; Published by the American Association for Cancer Research.)

This study investigated the effectiveness and safety of low-dose salvage craniospinal irradiation (CSI) for recurrent germinoma. We retrospectively reviewed long-term tumor control and late adverse effects in 15 recurrent germinoma patients treated at our hospital between 1983 and 2019. Following the first recurrence of germinoma, seven were treated with 24-30 Gy of salvage CSI, three underwent non-CSI, and five were treated with only chemotherapy. CSI achieved a significantly better recurrence-free survival rate after the first recurrence compared to other strategies (100% vs 33%, p < 0.001: log-rank test). To evaluate the safety of salvage CSI, we assessed the outcomes at the final follow-up of seven patients who received salvage CSI at first recurrence and three patients who received salvage CSI at second recurrence. The median follow-up period was 220 months after initial treatment. Five patients who received 40-50 Gy of radiation therapy or underwent multiple radiation therapy before salvage CSI were classified into Group A, whereas five patients treated with platinum-based chemotherapy and 24-32 Gy of radiation therapy to the primary site, whole ventricle, or whole brain were classified into Group B. In Group A, one had endocrine dysfunction and the other had visual dysfunction. None were socially independent. Meanwhile, in Group B, no endocrine or visual dysfunction was found, and three patients were socially independent. Salvage CSI achieved excellent tumor control in recurrent germinoma and was safe in patients initially treated with low-dose radiation therapy and chemotherapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)