Search

Abstract Purpose To assess the diagnostic performance of prostate MRI by estimating the proportion of clinically significant prostate cancer (csPCa) in patients without prostate pathology. Materials and methods This three-center retrospective study included prostate MRI examinations performed for clinical suspicion of csPCa (Grade group ≥ 2) between 2018 and 2022. Examinations were divided into two groups: pathological diagnosis within 1 year after the MRI (post-MRI pathology) is present and absent. Risk prediction models were developed using the extracted eleven common predictive variables from the patients with post-MRI pathology. Then, the csPCa proportion in the patients without post-MRI pathology was estimated by applying the model. The area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and positive and negative predictive values (PPV/NPV) of prostate MRI in diagnosing csPCa were subsequently calculated for patients with and without post-MRI prostate pathology (estimated statistics) with a positive threshold of PI-RADS ≥ 3. Results Of 12,191 examinations enrolled (mean age, 65.7 years ± 8.4 [standard deviation]), PI-RADS 1–2 was most frequently assigned (55.4%) with the lowest pathological confirmation rate of 14.0–18.2%. Post-MRI prostate pathology was found in 5670 (46.5%) examinations. The estimated csPCa proportions across facilities were 12.6–15.3%, 18.4–31.4%, 45.7–69.9%, and 75.4–88.3% in PI-RADS scores of 1–2, 3, 4, and 5, respectively. The estimated (observed) performance statistics were as follows: AUC, 0.78–0.81 (0.76–0.79); sensitivity, 76.6–77.3%; specificity, 67.5–78.6%; PPV, 49.8–66.6% (52.0–67.7%); and NPV, 84.4–87.2% (82.4–86.6%). Conclusion We proposed a method to estimate the probabilities harboring csPCa for patients who underwent prostate MRI examinations, which allows us to understand the PI-RADS diagnostic performance with several metrics. Clinical relevance statement The reported estimated performance metrics are expected to aid in understanding the true diagnostic value of PI-RADS in the entire prostate MRI population performed with clinical suspicion of prostate cancer. Key Points Calculating performance metrics only from patients who underwent prostate biopsy may be biased due to biopsy selection criteria, especially in PI-RADS 1–2. The estimated area under the receiver operating characteristic curve of PI-RADS in the entire prostate MRI population ranged from 0.78 to 0.81 at three facilities. The estimated statistics are expected to help us understand the true PI-RADS performance and serve as a reference for future studies. Graphical Abstract

Abstract Corneal hysteresis (CH) is associated with glaucomatous structural changes. We retrospectively investigated the association between CH and the regional circumpapillary retinal nerve fibre layer thickness (cpRNFLT) in 419 eyes of 419 patients with normal-tension glaucoma (NTG) and primary open-angle glaucoma (POAG). CH was used as the explanatory variable, and cpRNFLT (total and quadrant) was used as the dependent variable. Standardized β coefficients were compared both overall and between the NTG and POAG groups. Multiple regression analysis with CH as the explanatory variable and cpRNFLT parameters as the dependent variables suggested that even after adjusting for age, sex, intraocular pressure (IOP), axial length, and central corneal thickness, all areas of the cpRNFLT were significantly associated with CH, except for the nasal quadrant. In the stratified analysis by glaucoma type, a positive relationship between CH and regional cpRNFLT tended to be maintained in the NTG group but not in the POAG group (P = 0.060 for interaction). Additionally, in the NTG group, the CH-inferior cpRNFLT relationship was particularly strong in the less-IOP fluctuation group. These results suggest that CH may be a potential predictor of anatomical vulnerability around the optic nerve, particularly enhancing the inferior regions of NTG.

Abstract Cisplatin-induced injury to renal proximal tubular cells stems from mitochondrial damage-induced apoptosis and inflammation. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, a potential generator of ROS and ATP, protects against cisplatin-induced nephrotoxicity by promoting the TCA cycle. However, its effects on apoptotic pathways and ROS production in renal tubular cells remain unclear. Here, we investigated the detailed molecular mechanisms of the DCA’s effects by immunoblot, RT-PCR, RNA-sequencing, and RNA-silencing in a murine renal proximal tubular (mProx) cell line and mouse kidneys. In mProx cells, DCA suppressed cisplatin-induced apoptosis by attenuating the JNK/14-3-3/Bax/caspase-9 and death receptor/ligand/caspase-8 pathways without impeding inflammatory signaling. RNA-sequencing demonstrated that DCA increased the cisplatin-reduced expression of cFLIP, a caspase-8 inactivator, and decreased the expression of almost all oxidative phosphorylation (OXPHOS) genes. DCA also increased NF-kB activation and ROS production, probably enhancing the cFLIP induction and OXPHOS gene reduction, respectively. Furthermore, cFLIP silencing weakened the DCA’s anti-apoptotic effects. Finally, in mouse kidneys, DCA attenuated cisplatin-caused injuries such as functional and histological damages, caspase activation, JNK/14-3-3 activation, and cFLIP reduction. Conclusively, DCA mitigates cisplatin-induced nephrotoxicity by attenuating the JNK/14-3-3/Bax/caspase-9 pathway and inhibiting the caspase-8 pathways via cFLIP induction, probably outweighing the cisplatin plus DCA-derived cytotoxic effects including ROS.

Abstract A 26‐year‐old man was diagnosed with B/T‐type mixed‐phenotype acute leukemia (MPAL‐B/T) based on blasts being positive for CD19, cytoplasmic CD3, and cyCD79a, but negative for myeloperoxidase. Acute lymphoblastic leukemia‐based chemotherapy was started, but the leukemia was refractory. He underwent cord blood transplantation with the conditioning regimen of total body irradiation plus cyclophosphamide and cytarabine with granulocyte‐colony stimulating factor priming. Prophylaxis for graft versus host disease was performed with short‐term methotrexate and cyclosporin. The leukemia relapsed in bone marrow 20 months later. At that time, he was treated with inotuzumab ozogamicin because the blasts expressed CD22 (75.4%), but this was ineffective. He was next administered blinatumomab with dexamethasone pretreatment, resulting in a complete remission (CR). He subsequently underwent human leukocyte antigen‐haploidentical peripheral blood stem cell transplantation. He has still maintained a CR for 12 months. Blinatumomab might be a promising treatment and a bridge to stem cell transplantation even in relapsed/refractory CD19‐expressing MPAL‐B/T.

Abstract Background While advanced gastrointestinal stromal tumors (GISTs) are primarily treated with tyrosine kinase inhibitors (TKIs), acquired resistance from specific mutations in KIT or PDGFRA frequently occurs. We aimed to assess the utility of circulating tumor DNA (ctDNA) as a modality of therapeutic decision-making in advanced GIST. Methods We conducted a pooled analysis of SCRUM-Japan studies for advanced GIST patients. We compared patient characteristics analyzed with tissue and blood samples, assessed gene alteration profiles, and evaluated prognostic implications from ctDNA status. Results In 133 patients, tissue and blood samples were analyzed for 89 and 44 patients, respectively. ctDNA was detected in 72.7% of cases; no prior treatment or progressive disease was significantly associated with ctDNA-positivity. ctDNA-positive patients had significantly shorter progression-free survival compared with ctDNA-negative patients (hazard ratio = 3.92; P = 0.007). ctDNA genotyping revealed a complex landscape of gene alterations, characterized by multi-exonic mutations in KIT, compared with tissue-based analysis. Patients who received TKIs matched to the identified KIT mutation in ctDNA demonstrated significantly longer PFS than those with unmatched treatment (median, 8.23 vs. 2.43 months; P

Abstract “NeoRAS WT” refers to the loss of RAS mutations (MTs) following first-line treatment in metastatic colorectal cancer (mCRC). We evaluate the incidence and clinicopathological characteristics of NeoRAS WT mCRC using next-generation sequencing of plasma circulating tumor DNA. Patients with mCRC enrolled in the GOZILA study initially diagnosed with tissue RAS MT mCRC and received subsequent systemic therapy are eligible. NeoRAS WT is defined as the absence of detectable RAS MT in plasma and assessed in all eligible patients (Group A) and in a subgroup with at least one somatic alteration detected in plasma (Group B). Overall, 478 patients are included. NeoRAS WT prevalence is 19.0% (91/478) in Group A and 9.8% (42/429) in Group B. Absence of liver or lymph node metastasis and tissue RAS MTs other than KRAS exon 2 MTs are significantly associated with NeoRAS WT emergence. Overall, 1/6 and 2/6 patients with NeoRAS WT treated with anti-EGFR monoclonal antibodies (mAbs) show partial response and stable disease for ≥6 months, respectively. NeoRAS WT mCRC is observed at a meaningful prevalence, and anti-EGFR mAb-based therapy may be effective.

Objectives: Patients with myeloproliferative neoplasms (MPNs) are at higher risk of developing secondary malignancies. In this study, we focused on patients with MPNs that complicated lymphoid neoplasms. To analyze the real-world status of lymphoid neoplasm treatment in patients with pre-existing MPNs in Japan, we conducted a multicenter retrospective study.Methods: Questionnaires were sent to collect the data on patients who were first diagnosed with either polycythemia vera, essential thrombocythemia or myelofibrosis and who later were complicated with lymphoid neoplasms defined as malignant lymphoma, multiple myeloma, or chronic lymphocytic leukemia/small cell lymphoma.Results: Twenty-four patients with MPNs complicated by lymphoid neoplasms were enrolled (polycythemia vera, n = 8; essential thrombocythemia, n = 14; and primary myelofibrosis, n = 2). Among these, diffuse large B-cell lymphoma (DLBCL) was the most frequently observed (n = 13, 54.1%). Twelve (92.3%) of the patients with DLBCL received conventional chemotherapy. Among these 12 patients, regarding cytoreductive therapy for MPNs, 8 patients stopped treatment, one continued treatment, and two received a reduced dose. Consequently, most patients were able to receive conventional chemotherapy for DLBCL with a slightly higher dose of granulocyte colony-stimulating factor support than usual without worse outcomes. All 3 patients with multiple myeloma received a standard dose of chemotherapy.Conclusion: Our data indicate that if aggressive lymphoid neoplasms develop during the course of treatment in patients with MPNs, it is acceptable to prioritize chemotherapy for lymphoma.

Background Gastric cancer (GC) is one of the most common and deadly malignant diseases worldwide. Despite revolutionary advances, the therapeutic efficacy of anti-PD1/PDL1 monoclonal antibodies in advanced GC is still low due to the emergence of innate and acquired resistance to treatment. Myeloid cells represent the majority of human immune cells. Therefore, their increase, decrease, and abnormality could have a significant impact on the patient’s immune system and the progression of cancer, and reprogramming, inhibiting, and eliminating the tumor-supportive types may improve the immunological situation and efficacy of immunotherapy. However, the significance of myeloid cells in anti-PD1/PDL1 therapy remains unclear in GC. In the WJOG10417GTR study on GC, we sought to identify myeloid determinants that could predict anti-PD1 therapeutic efficacy and also serve as potential therapeutic targets.Methods We collected tumor tissues and peripheral blood from 96 patients with advanced GC before and 1 month after anti-PD1 nivolumab monotherapy, and the isolated whole leucocytes were analyzed by flow cytometry for various immune cell populations, including many myeloid subsets. Then, the relationship between the cellular levels and progression-free survival (PFS) or overall survival (OS) was statistically analyzed.Results We found that high levels of several myeloid subsets expressing molecules that have been targeted in drug discovery but not yet approved for clinical use were significantly associated with shorter PFS/OS as compared with low levels: PDL1+ and CTLA4+ myeloid subsets within tumors at baseline, PDL1+, B7H3+ and CD115+ myeloid subsets in peripheral blood at baseline, and LAG3+, CD155+ and CD115+ myeloid subsets in peripheral blood at post-treatment.Conclusions This study revealed that these myeloid subsets are significant risk factors in nivolumab therapy for advanced GC. Targeting them may be useful as diagnostic biomarkers to predict potential anti-PD1 therapeutic efficacy, and also as therapeutic targets for accelerating the development of new drugs to improve clinical outcomes in immunotherapy for GC.

Abstract Podocyte expression of fibroblast specific protein 1 (FSP1) is observed in various types of human glomerulonephritis. Considering that FSP1 is secreted extracellularly and has been shown to have multiple biological effects on distant cells, we postulated that secreted FSP1 from podocytes might impact renal tubules. Our RNA microarray analysis in a tubular epithelial cell line (mProx) revealed that FSP1 induced the expression of heme oxygenase 1, sequestosome 1, solute carrier family 7, member 11, and cystathionine gamma-lyase, all of which are associated with nuclear factor erythroid 2-related factor (Nrf2) activation. Therefore, FSP1 is likely to exert cytoprotective effects through Nrf2-induced antioxidant activity. Moreover, in mProx, FSP1 facilitated Nrf2 translocation to the nucleus, increased levels of reduced glutathione, inhibited the production of reactive oxygen species (ROS), and reduced cisplatin-induced cell death. FSP1 also ameliorated acute tubular injury in mice with cisplatin nephrotoxicity, which is a representative model of ROS-mediated tissue injury. Similarly, in transgenic mice that express FSP1 specifically in podocytes, tubular injury associated with cisplatin nephrotoxicity was also mitigated. Extracellular FSP1 secreted from podocytes acts on downstream tubular cells, exerting renoprotective effects through Nrf2-mediated antioxidant activity. Consequently, podocytes and tubular epithelial cells have a remote communication network to limit injury.

Abstract Measures of muscle and adipose tissue mass have been associated with outcomes in several malignancies, but studies in multiple myeloma (MM) are inconsistent. The aim of this study was to evaluate the association between muscle and fat areas and radiodensity, and overall survival (OS) in patients with newly diagnosed MM. We included 341 patients diagnosed with MM from 2010–2019 who had an 18F-fluorodeoxyglucose positron emission tomography/computed tomography at diagnosis. A cross-sectional image at the third lumbar vertebrae was segmented into muscle and fat components. Median follow up was 5.7 years. There was no association between sarcopenia and baseline disease characteristics or OS. Low muscle radiodensity was associated with higher disease stage, anemia, and renal failure. OS was 5.6 vs. 9.0 years in patients with muscle radiodensity in the lower vs. middle/upper tertiles, respectively (P = 0.02). High subcutaneous adipose tissue (SAT) radiodensity was associated with higher stage, anemia, thrombocytopenia, hypercalcemia, renal failure, and high LDH. OS was 5.4 years vs. not reached in patients with SAT radiodensity in the upper vs. middle/lower tertiles, respectively (P = 0.001). In conclusion, sarcopenia was not associated with OS in MM patients. High SAT radiodensity and low muscle radiodensity were associated with advanced disease stage and adverse laboratory characteristics.

Introduction: Cell-based bone regenerative therapy exhibits considerable potential in the treatment of bone defects caused by trauma, disease, and congenital anomalies. The periosteum, a fibrous membrane covering the outer surface of bone, plays a crucial role in bone formation and regeneration by sourcing osteoprogenitor cells. The remarkable osteogenic potential of periosteal cells (PCs) has led to the effective clinical implementation of PC-based regenerative therapies and tissue engineering. The abundance of progenitor cells in cultured PCs is well established; however, the heterogeneity of the cell population and its impact on bone regeneration remain uncertain. In this study, we aimed to characterize the heterogeneity of cultured PCs via single-cell RNA-sequencing (scRNA-seq) and to examine their osteogenic potential in vivo. Methods: Human PCs cultivated using the tissue explant method were utilized in this study. scRNA-seq and real-time PCR were performed to examine the cellular heterogeneity and osteogenic capacity of the cultured PCs. Experimental bone formation by the cultured PCs was examined using the rat model of subcutaneous implantation. Results: ScRNA-seq analysis showed that the cultured PCs were categorized into three cell types (osteoprogenitor cells, mesenchymal stem cells, and fibroblasts) with specific gene expression patterns. In addition, the cellular population and osteogenic capacity differed between the central and peripheral regions in the culture dish. The PCs in the central region showed higher osteogenic potential than those in the peripheral region. Conclusions: This study revealed the diversity of the composition of the PCs and their distinct osteogenic capabilities in different regions in the culture dish. The findings may provide promising prospects for the development of more efficacious regenerative therapeutic applications using cultured PCs in the future.

Abstract Background The aims of this study were to evaluate the efficacy, safety, and pharmacokinetics (PK) of continuous intravenous administration of remifentanil in mechanically ventilated patients in the intensive care unit (ICU). Methods This was a multicenter, randomized, double-blinded, fentanyl-controlled, non-inferiority phase 3 study. Patients aged ≥ 20 years requiring 6 h to 10 days mechanical ventilation in an ICU and requiring pain relief were randomly assigned in a 1:1 ratio to receive either remifentanil (n = 98) or fentanyl (n = 98). Dose was titrated from an infusion rate of 1 mL/h (remifentanil: 0.025 µg/kg/min, fentanyl: 0.1 µg/kg/h) until the target level of analgesia (behavioral pain scale [BPS] ≤ 5 or numerical rating score [NRS] ≤ 3) was achieved by escalating the dose in 1 mL/h increasing. Administration was then adjusted to maintain the target level of analgesia until weaning from the ventilator. The primary endpoint was the proportion of patients who did not require rescue fentanyl. Safety was assessed according to standard procedures. PK of remifentanil in the arterial blood was assessed in 24 patients. Results The proportion of patients achieving the primary endpoint in the remifentanil and fentanyl groups was 100% (92/92) and 97.8% (88/90), respectively. The difference between the groups was 2.2% (95% confidence interval, − 0.8–5.3) and non-inferiority of remifentanil to fentanyl was verified (p

Abstract Background Trabeculectomy (trab) is the most effective surgical procedure for lowering IOP and preventing glaucoma progression. However, decline in best-corrected visual acuity (BCVA) is one of the most serious postoperative complications of trab. Here, we investigated methods to predict decreased BCVA after trab in glaucoma patients with good preoperative BCVA. Methods This study included 35 eyes of 35 open-angle glaucoma (OAG) patients (male / female: 21 / 14, age: 64.0 ± 9.7 years old, preoperative intraocular pressure: 15.9 ± 5.4 mmHg, mean deviation: -18.1 ± 5.6 dB) with preoperative BCVA of 0.7 or better who underwent trab and were observed for more than 12 months. As a preoperative analysis, we measured temporal quadrant circumpapillary retinal nerve fiber layer thickness (cpRNFLT) and ganglion cell complex thickness in a central strip between the disc and fovea (csGCCT), an area that corresponds to the location of the papillomacular bundle (PMB) in swept-source optical coherence tomography (OCT). We defined BCVA decline as a loss of more than 3 lines of BCVA after 12 months. Measurement parameters were compared between the BCVA-decline group and the non-BCVA-decline group. Results BCVA decline was detected in 11 cases (31.4%) 12 months after trab. There was a statistically significant difference in axial length (P = 0.049). A single logistic analysis showed that the BCVA-decline group had significantly lower cpRNFLT than the non-BCVA-decline group (27.7 ± 8.0 μm vs. 45.1 ± 5.3 μm, P

Peroxisome proliferator-activated receptor-alpha (PPAR-α) and its exogenous activators (fibrates) promote autophagy. However, whether the deleterious effects of PPAR-α deficiency on doxorubicin (DOX)-induced podocytopathy are associated with reduced autophagy remains to be clarified. We investigated the mechanisms of PPAR-α in DOX-induced podocytopathy and tubular injury in PPAR-α knockout (PAKO) mice and in a murine podocyte cell line. DOX-treated PAKO mice showed higher serum levels of triglycerides and non-esterified fatty acids and more severe podocytopathy than DOX-treated wild-type mice, as evidenced by higher urinary levels of proteins and podocalyxin at 3 days to 2 weeks and higher blood urea nitrogen and serum creatinine levels at 4 weeks. Additionally, there was an increased accumulation of p62, a negative autophagy marker, in the glomerular and tubular regions in DOX-treated PAKO mice at Day 9. Moreover, DOX-treated PAKO mice showed more severe glomerulosclerosis and tubular damage and lower podocalyxin expression in the kidneys than DOX-treated control mice at 4 weeks. Furthermore, DOX treatment increased p-p53, an apoptosis marker, and cleaved the caspase-3 levels and induced apoptosis, which was ameliorated by fenofibrate, a PPAR-α activator. Fenofibrate further enhanced AMPK activation and autophagy under fed and fasting conditions. Conclusively, PPAR-α deficiency enhances DOX-induced podocytopathy, glomerulosclerosis, and tubular injury, possibly by reducing autophagic activity in mouse kidneys.

Abstract Background Several biomarkers have been established for metastatic colorectal cancer (mCRC). We investigated whether plasma angiogenesis factors could predict the efficacy of biologics combined with chemotherapy in first‐line (1L) treatment in patients with RAS wild‐type mCRC and the dynamics of plasma angiogenesis factors at progression during 1L treatment. Methods In this multicenter prospective observational study, serial plasma samples were prospectively collected at pretreatment and progression stages; 17 plasma angiogenesis factors were analyzed using the multiplex assay with Luminex® technology. Interactions between the pretreatment measurements and treatment groups on progression‐free survival (PFS) and overall survival (OS) in patients with RAS wild‐type were assessed using the propensity‐score weighted Cox proportional hazards model. Results From February 2018 to September 2020, 202 patients were enrolled in the 1L cohort; 133 patients had RAS wild‐type (chemotherapy plus bevacizumab [BEV group, n = 33] and plus anti‐epidermal growth factor receptor monoclonal antibodies [aEGFR group, n = 100]). A trend of strong interaction on PFS was observed for interleukin‐8 (IL‐8) (p = 0.0752) and soluble vascular cell adhesion molecule‐1 (sVCAM‐1) (p = 0.0156). Regarding OS, IL‐8 (p = 0.0283), soluble vascular endothelial growth factor‐receptor‐1 (sVEGFR‐1) (p = 0.0777) and sVCAM‐1 (p = 0.0011) tended to differentiate the treatment effect. In 112 patients, plasma samples were evaluable for dynamic analysis (57 and 55 from the BEV and aEGFR groups, respectively). In the BEV group, six factors significantly increased during progression, whereas two decreased. In the aEGFR group, three factors significantly increased, and six decreased. Conclusion Pretreatment plasma IL‐8 and sVCAM‐1 levels could be predictive biomarkers to distinguish BEV and anti‐EGFR mAbs when combined with chemotherapy in the 1L treatment of RAS wild‐type mCRC. Several plasma angiogenesis factors showed significant change at progression in 1L chemotherapy plus biologics for RAS wild‐type mCRC, which are potential biomarkers for selecting an optimal angiogenesis inhibitor in second‐line treatment.

Abstract Background Endothelial dysfunction is common in patients undergoing chronic haemodialysis, and is a major cause of posterior reversible encephalopathy syndrome (PRES). Recently, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been shown to cause endothelial dysfunction by infecting vascular endothelial cells. Several cases of neurological complications in patients without kidney dysfunction, and only a few cases in patients with chronic kidney disease, have been reported in the literature. However, no previous report has yet described PRES associated with SARS-CoV-2 infection among patients undergoing maintenance dialysis. Case presentation A 54-year-old woman undergoing maintenance haemodialysis was admitted to our hospital for status epilepticus. She had developed end-stage kidney disease (ESKD) secondary to diabetic nephropathy. Seven days prior to admission, she had developed fever and was diagnosed with COVID-19. Subsequently her blood pressure increased from 160/90 mmHg to 190/100 mmHg. On admission, she presented with severe hypertension (> 220/150 mmHg), unconsciousness, and epilepticus. CT tomography revealed no signs of brain haemorrhage. Cranio-spinal fluid (CSF) examination revealed no signs of encephalitis, and CSF polymerase chain reaction (PCR) for SARS-CoV-2 was negative. MRI findings revealed focal T2/FLAIR hyperintensity in the bilateral parietooccipital regions, leading to the diagnosis of PRES. Deep sedation and strict blood pressure control resulted in a rapid improvement of her symptoms, and she was discharged without sequelae. Conclusions We report the first case of PRES associated with SARS-CoV-2 infection in a patient undergoing maintenance haemodialysis. Patients undergoing maintenance haemodialysis are at high risk of PRES because of several risk factors. SARS-CoV-2 infection causes direct invasion of endothelial cells by binding to angiotensin-converting enzyme 2 (ACE2), initiating cytokine release, and hypercoagulation, leading to vascular endothelial cell injury and increased vascular leakage. In the present case, SARS-CoV-2 infection possibly be associated with the development of PRES.

Abstract Background Trifluridine/tipiracil (FTD/TPI) prolongs survival in the third- or later-line treatment for advanced gastric cancer (GC), esophagogastric junction (EGJ) adenocarcinoma, and colorectal cancer. While single-arm phase II trials showed promising outcomes of FTD/TPI plus ramucirumab (RAM) as third- or later-line treatments for advanced GC or EGJ cancer, there have been no clinical trials to directly compare FTD/TPI plus RAM with FTD/TPI monotherapy. Therefore, we have started a randomised phase II trial to evaluate the efficacy and safety of FTD/TPI plus RAM compared with FTD/TPI monotherapy as third- or later-line treatments in patients with advanced GC and EGJ adenocarcinoma. Methods This RETREVE trial (WJOG15822G) is a prospective, open-label, randomised, multicentre phase II trial comparing FTD/TPI plus RAM versus FTD/TPI monotherapy in a third- or later-line setting. Eligibility criteria include age of > 20 years; performance status of 0 or 1; unresectable or recurrent gastric or EGJ adenocarcinoma; confirmed HER2 status; refractory or intolerant to fluoropyrimidine, taxane or irinotecan; refractory to RAM (not intolerant); and at least a measurable lesion per RECIST 1.1. FTD/TPI (35 mg/m2 twice daily, evening of day 1 to morning of day 6 and evening of day 8 to morning of day 13) was administered orally every 4 weeks, and RAM (8 mg/kg) was administered intravenously every 2 weeks. The primary endpoint is progression-free survival (PFS), and the secondary endpoints are overall survival, objective response rate, disease control rate, and safety. The expected hazard ratio of PFS is set as 0.7, assuming 4-month PFS rate of 27% in FTD/TPI monotherapy and 40% in FTD/TPI plus RAM. The number of subjects was 110, with a one-sided alpha error of 0.10 and power of 0.70. Discussion This study will clarify the additional effect of RAM continuation beyond disease progression on FTD/TPI in the third- or later-line setting for patients with advanced GC or EGJ cancer. Trial registration jRCTs041220120.

Corynebacterium ulcerans is a closely related bacterium to the diphtheria bacterium C. diphtheriae, and some C. ulcerans strains produce toxins that are similar to diphtheria toxin. C. ulcerans is widely distributed in the environment and is considered one of the most harmful pathogens to livestock and wildlife. Infection with C. ulcerans can cause respiratory or nonrespiratory symptoms in patients. Recently, the microorganism has been increasingly recognized as an emerging zoonotic agent of diphtheria-like illness in Japan. To clarify the overall clinical characteristics, treatment-related factors, and outcomes of C. ulcerans infection, we analyzed 34 cases of C. ulcerans that occurred in Japan during 2001–2020. During 2010–2020, the incidence rate of C. ulcerans infection increased markedly, and the overall mortality rate was 5.9%. It is recommended that adults be vaccinated with diphtheria toxoid vaccine to prevent the spread of this infection.

Abstract We aimed to investigate the impact of glutathione trisulfide (GSSSG) on lipopolysaccharide (LPS)-induced inflammation in retinal glia. Inflammatory responses in mouse-derived glial cells and Wistar rat retinas were stimulated with administration of LPS. Cell survival and proinflammatory cytokine production were examined using the Calcein-AM assay, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Retinal microglia were visualized with immunohistochemistry for Iba1. Administration of LPS (10 µg/mL) or GSSSG (less than 100 µM) did not affect survival of cultured primary Müller cells and established microglial cells (BV-2). RT-qPCR and ELISA indicated that GSSSG inhibited LPS-induced gene upregulation and protein secretion of proinflammatory cytokines in these glial cells and rat retinas. GSSSG inhibited LPS-induced activation of TGF-β-activated kinase 1 (TAK1), which is an upstream kinase of NF-κB, in BV-2 cells. Finally, in vivo experiments indicated that intravitreal administration of GSSSG but not its relative glutathione disulfide (GSSG) inhibited LPS (500 ng)-induced accumulation of Iba1-immunopositive microglia in rat retinas. Taken together, GSSSG has the potential to prevent pathogenesis of inflammation-associated ocular diseases by inhibiting proinflammatory cytokine expression in retinal glial cells.

Abstract Background Light and heavy chain deposition disease (LHCDD) is a rare condition characterised by the deposition of immunoglobulin components in the kidneys. Similarly, Amyloidosis is also caused by the deposition of light chain and/or heavy chain components of immunoglobulins which are folded into amyloid fibrils characterised by Congophilic deposits that exhibit apple-green birefringence under polarised light. Only a handful of reports describing LHCDD with amyloid fibril deposition have been previously published, however, none have characterized the composition of the deposited immunoglobulin components via mass spectrometry. Case presentation We report a case of a 79-year-old Japanese woman with nephrotic syndrome. Bone marrow aspiration revealed a slight proliferation of plasma cells (under 10%). Immunofluorescence assessment of renal biopsy showed amyloid-like deposits in the glomerulus that were positive for IgA and kappa. Further, the Congo red staining of the deposits was faintly positive, and only a slight birefringence was detected. Electron microscopy confirmed fine fibrillar structures and non-amyloid deposits. Finally, mass spectrometry revealed that the deposits were composed of abundant amounts of light chain with small amounts of heavy chain. Therefore, the patient was diagnosed with LHCDD and focal amyloid deposition. Chemotherapy was subsequently initiated, which resulted in haematological and renal response. Under polarised light, faint birefringence with Congo red staining and periodic acid-methenamine silver positivity indicated that the deposits were mostly non-amyloid fibrils with a small component of amyloid fibrils. Generally, the diagnosis of heavy- and light-chain amyloidosis is defined by greater heavy chain deposition compared to the light chain. However, in our case, contrary to the definition, the light-chain deposition was far greater than that of the heavy-chain. Conclusions This is the first case of LHCDD with focal amyloid deposition diagnosed by analysing the glomerular deposits by mass spectrometry.

Background Peripheral venous pressure (PVP) has been shown to be a reliable surrogate for right atrial pressure in assessing congestion in patients with heart failure (HF). Liver fibrosis markers and scores can be useful in assessing organ injury in patients with acute HF. This study aimed to investigate the association of liver fibrosis markers and scores with PVP in patients with acute HF. Methods and Results The 7S domain of the collagen type IV N‐terminal propeptide (P4NP 7S), aspartate aminotransferase‐to‐platelet ratio index, fibrosis‐4, and nonalcoholic fatty liver disease fibrosis score were determined along with PVP measurements before discharge in 229 patients with acute HF. The strongest correlation with PVP was found for P4NP 7S (Pearson r=0.40). Patients with high P4NP 7S levels (≥median [6.2 ng/mL]) had an increased risk of cardiovascular death or HF hospitalization (adjusted hazard ratio [HR], 1.80 [95% CI, 1.09–3.04], P=0.02). The concomitant high PVP (≥mean [8 mm Hg])/high P4NP 7S group, in contrast to the high PVP/low P4NP 7S or low PVP/high P4NP 7S group, had a significant risk relative to the low PVP/low P4NP 7S group for cardiovascular death or HF hospitalization (adjusted HR, 2.63 [95% CI, 1.43–5.05], P=0.002). A sustained elevation in PVP for 1 month postdischarge was associated with a persistent increase in P4NP 7S. Conclusions The study demonstrated the relationship between the liver fibrosis marker P4NP 7S and congestion. PVP and P4NP 7S could be useful for assessing congestion‐related organ injury and predicting prognosis in patients with acute HF.

Abstract Background Glaucoma is multifactorial, but the interrelationship between risk factors and structural changes remains unclear. Here, we adjusted for confounding factors in glaucoma patients with differing risk factors, and compared differences in structure and susceptible areas in the optic disc and macula. Methods In 458 eyes with glaucoma, we determined confounding factors for intraocular pressure (IOP), central corneal thickness (CCT), axial length (AL), LSFG-measured ocular blood flow (OBF), which was assessed with laser speckle flowgraphy-measured mean blur rate in the tissue area (MT) of the optic nerve head, biological antioxidant potential (BAP), and systemic abnormalities in diastolic blood pressure (dBP). To compensate for measurement bias, we also analyzed corrected IOP (cIOP; corrected for CCT) and corrected MT (cMT; corrected for age, weighted retinal ganglion cell count, and AL). Then, we determined the distribution of these parameters in low-, middle-, and high-value subgroups and compared them with the Kruskal–Wallis test. Pairwise comparisons used the Steel–Dwass test. Results The high-cIOP subgroup had significantly worse mean deviation (MD), temporal, superior, and inferior loss of circumpapillary retinal nerve fiber layer thickness (cpRNFLT), and large cupping. The low-CCT subgroup had temporal cpRNFLT loss; the high-CCT subgroup had low cup volume. The high-AL subgroup had macular ganglion cell complex thickness (GCCT) loss; the low-AL subgroup had temporal cpRNFLT loss. The high-systemic-dBP subgroup had worse MD, total, superior, and inferior cpRNFLT loss and macular GCCT loss. The low-BAP subgroup had more male patients, higher dBP, and cpRNFLT loss in the 10 o’clock area. The high-OBF subgroup had higher total, superior and temporal cpRNFLT and macular GCCT. Conclusions Structural changes and local susceptibility to glaucomatous damage show unique variations in patients with different risk factors, which might suggest that specific risk factors induce specific types of pathogenesis and corresponding glaucoma phenotypes. Our study may open new avenues for the development of precision medicine for glaucoma.

Abstract Detection, diagnosis, and treatment of ophthalmic diseases depend on extraction of information (features and/or their dimensions) from the images. Deep learning (DL) model are crucial for the automation of it. Here, we report on the development of a lightweight DL model, which can precisely segment/detect the required features automatically. The model utilizes dimensionality reduction of image to extract important features, and channel contraction to allow only the required high-level features necessary for reconstruction of segmented feature image. Performance of present model in detection of glaucoma from optical coherence tomography angiography (OCTA) images of retina is high (area under the receiver-operator characteristic curve AUC ~ 0.81). Bland–Altman analysis gave exceptionally low bias (~ 0.00185), and high Pearson’s correlation coefficient (p = 0.9969) between the parameters determined from manual and DL based segmentation. On the same dataset, bias is an order of magnitude higher (~ 0.0694, p = 0.8534) for commercial software. Present model is 10 times lighter than Unet (popular for biomedical image segmentation) and have a better segmentation accuracy and model training reproducibility (based on the analysis of 3670 OCTA images). High dice similarity coefficient (D) for variety of ophthalmic images suggested it’s wider scope in precise segmentation of images even from other fields. Our concept of channel narrowing is not only important for the segmentation problems, but it can also reduce number of parameters significantly in object classification models. Enhanced disease diagnostic accuracy can be achieved for the resource limited devices (such as mobile phone, Nvidia’s Jetson, Raspberry pi) used in self-monitoring, and tele-screening (memory size of trained model ~ 35 MB).

Abstract Background This study aimed to compare the clinical features and prognoses of patients with and without diabetes mellitus (DM) who underwent endovascular repair for aortic aneurysm (AA). Methods We analyzed the clinical database of a prospective multicenter study, registering 929 patients who underwent their first endovascular AA repair in Japan between January 2016 and June 2018. The baseline characteristics and prognoses (including all-cause mortality and cardiovascular events) after repair were compared between the DM and non-DM groups. Prognoses were also compared between the groups after propensity score matching. Results In total, 226 patients (24.3%) had DM. Compared with non-DM patients, DM patients had higher pack-years of smoking (P = 0.011), higher body mass index (P = 0.009), lower high-density lipoprotein cholesterol levels (P = 0.038), higher triglyceride levels (P = 0.025), and lower left ventricular ejection fraction (P = 0.005). Meanwhile, the low-density lipoprotein cholesterol and blood pressure levels showed no significant intergroup difference (all P > 0.05). DM patients had a higher prevalence of myocardial infarction (P = 0.016), history of coronary revascularization (P = 0.015), and lower extremity artery disease (P = 0.019). Lesion characteristics and procedures were similar between the groups (all P > 0.05). DM patients had a higher risk of all-cause mortality and cardiovascular events than non-DM patients (both P

Leak testing is one of the important nondestructive testing methods to get the conformance of the product quality. Helium leak testing is the most sensitive nondestructive testing method in the industrial field, and it is usually done by helium leak detector. On the contrast, from basic to more complex leak testing can be done by the partial pressure gauge which is categorized as a quadrupole mass spectrometer. This article explains the basic method of leak testing by the quadrupole mass spectrometer, and also mentions the ultrafine leak testing technique for the vacuum sealed MEMS sensors. [ABSTRACT FROM AUTHOR]

Background and Objectives: Periodontitis is an inflammatory disease in the supporting tissues of the teeth caused by specific microorganisms or groups of microorganisms. P. gingivalis bacterium is the keystone pathogen in periodontitis, so even at low concentrations, it has a considerable influence on the oral community. Antimicrobials and antiplaque agents can be used as adjunctive therapy for periodontitis treatment. Konjac glucomannan (KGM), as a natural polysaccharide, has flavonoid (3,5-diacetyltambulin) and triterpenoids (ambylon) compounds that show antibacterial activity. This research aims to analyze the antibacterial activity of KGM on animal and in vitro periodontitis models. Materials and Methods: The animal study divided 48 mice into four groups (control, KGM, periodontitis, KGM + periodontitis). Mice were given an intervention substance by oral gavage from day 1 to day 14, periodontitis was induced on day 7, and decapitation was performed on day 14. Samples from the right maxillary jaw of mice were used for histological preparations and morphometrics analysis. In vitro studies were carried out by adding several concentrations of KGM (25, 50, and 100 μg/mL) into a planktonic P. gingivalis and P. gingivalis biofilm. Results: In the animal model, KGM could prevent alveolar bone loss in the periodontitis mice model, both in histologic and morphometrics assessments. In vitro, KGM had antibacterial activity against P. gingivalis with better bacteriostatic (15–23%) than bactericidal (11–20%) ability, proven by its ability to inhibit P. gingivalis proliferation. Conclusions: KGM can be considered to have the potential as an antibacterial agent to prevent periodontitis. The prevention of periodontitis may improve patient well-being and human quality of life.

This study examined the temperature-related piezoresistance issues of p-type doped 3C-silicon carbide (3C-SiC) materials. Previously, we proposed piezoresistance temperature models that describe phenomena based on the ionization energies of materials oriented for high-temperature operations. This study aimed to determine the ionization energy as a function of the aluminum doping concentration of 3C-SiC. However, at the low-temperature region a drastic decrease in the piezoresistive coefficient was observed, and it was predicted to occur when materials possessing large impurity ionization energy are used under negative thermal strained conditions. This phenomenon is in contrast to the conventional piezoresistance factor $P(N,T)$ that is based on narrow band-gap materials such as silicon or germanium; thus, it provides new insights into low-temperature piezoresistance phenomena.

We examine the temperature dependence of the piezoresistive coefficients of silicon carbide (SiC) and gallium nitride (GaN) crystals, which are prospective materials for high-temperature applications owing to their wide-bandgap properties. The temperature-dependent piezoresistive coefficients of these materials were obtained by modeling experimental resistance changes using thermomechanical numerical simulations. This work reports the piezoresistive coefficients of 4H-SiC and GaN at the high-temperature environments, which are still not well researched. The results revealed that the temperature dependences of piezoresistive coefficients were strongly related to the ionization energy, and a high ionization energy stabilized the values of the piezoresistive coefficients at high temperatures. Our proposed temperature modeling method helps in predicting the temperature dependence of the piezoresistive coefficient using the value at the room temperature and the ionization energy of the material, which is useful for evaluating the piezoresistive effect at different temperatures during device simulations.

Periodontitis is defined as an oral bacterial dysbiosis-induced persistent inflammation on dental supporting tissue resulting in periodontal tissue breakdown and alveolar bone destruction. The disease is initiated by the interaction between periodontopathogens and the host immune system. Its development and severity can be associated with several systemic diseases, such as cardiovascular disease (CVD), diabetes mellitus, and rheumatoid arthritis (RA). Moreover, the latest research has suggested that the oral and gut microbiome hypothesis lays the oral and systemic connection mechanism. Bacterial homeostasis and restoration in the oral cavity and intestine become therapeutics concepts. Concerning the treatment of periodontitis, a local inflammatory condition, prolonged systemic administration of antibiotics is no longer recommended due to bacterial resistance issues. Probiotics and several bioactive metabolites have been widely investigated to address the needs of host modulation therapy in periodontitis. Evidence suggests that the use of probiotics helps downregulate the inflammation process through the regulation of toll-like receptor 4 (TLR4) and the production of fatty acid, targeting reactive oxygen species (ROS). In brief, several herbals have anti-inflammatory properties by inhibiting pro-inflammatory cytokines and mediators, including mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB). Consistently, improvement of periodontal pocket depth (PPD) and gingival index (GI) was seen in a group given melatonin as an adjunct treatment. In all, this review will highlight host modulation agents regarding periodontitis therapy, plausible mechanisms on how probiotics and metabolites work on periodontal restoration, and their reported studies. Limitations given by published studies will be elaborated, while future directions will be proposed.

Background. Periodontitis is an inflammatory disease caused by specific microorganisms that gradually damage the periodontal and tooth-supporting tissues, thereby reducing a person’s quality of life. Periodontal disease is closely associated with high reactive oxygen species (ROS) levels, with a high receptor activator of nuclear factor kβ ligand (RANKL)/osteoprotegerin (OPG) ratio. Konjac glucomannan (KGM) is produced from the porang root, which has several properties. For example, it can reduce oxidative stress. The current study analyzed the osteoclastogenesis inhibitory and antioxidant properties of KGM based on histomorphometric findings, RANKL/OPG ratio, and ROS levels in the Swiss Webster mouse periodontitis model. Methods. Eight-week-old male Swiss Webster mice were divided into the nonligation, nonligation + KGM, ligation + Porphyromonas gingivalis, and ligation + P. gingivalis + KGM groups. KGM suspension was administered for 14 days. Periodontitis induction was performed from 7th to 14th day. On the 14th day, maxillae, gingival, and gingival crevicular fluid samples were collected to assess the histomorphometry of bone damage, gene expression ratio of RANKL/OPG, and ROS protein levels. Results. The periodontitis group pretreated with KGM presented with significantly reduced alveolar bone damage, RANKL/OPG ratio, and ROS level than without KGM group. KGM treatment had no harmful/toxic effects in mice. Conclusion. Administration of KGM could act as an adjunctive in periodontal therapy by suppressing periodontal disease via osteoclastogenesis inhibitory and antioxidant properties.

Abstract Background Mucosa associated lymphoid tissue (MALT) lymphoma of the orbit is rare, often indolent, but can recur, and spread to extra‐nodal sites. Pleural and retroperitoneum recurrences of MALT lymphoma are rare. Case A 65‐year‐old man was referred to our hospital due to right pleural effusion and difficulty in breathing. He had a medical history of having undergone surgery for MALT lymphoma of the left orbit. A chest computed tomography (CT) scan showed right pleural thickness, pleural effusion, and a retroperitoneal mass, spreading from the muscular layer to the subcutaneous layer. The thickened pleural lesion was surgically biopsied and diagnosed as a recurrence of MALT lymphoma. Conclusion Pleural effusion should be carefully examined and monitored for the possibility of recurrence in MALT lymphoma patients.

‘Globemaster’ is an ornamental hybrid cultivar whose parent plants are Allium cristophii and A. macleanii. The chemical constituents of ‘Globemaster’ bulbs have not yet been examined; thus, a systematic phytochemical investigation was undertaken herein. A series of chromatographic separations of the MeOH extract of ‘Globemaster’ bulbs afforded 27 steroidal glycosides (1–27), which are classified into 23 spirostanol glycosides (1–8 and 11–25), two furostanol glycosides (9 and 26), a pregnane glycoside (10), and a cholestane glycoside (27). The structures of the hitherto undescribed compounds (1–10) were determined from the two-dimensional NMR spectroscopic data and hydrolysis. The cytotoxicity of the isolated compounds (1–27) toward HL-60 human promyelocytic leukemia cells, A549 human adenocarcinoma lung cancer cells, and SBC-3 human small-cell lung cancer cells was evaluated. Compounds 8, 22, 23, 24, and 26 exhibited cytotoxicity toward all cell lines in a dose-dependent manner, with IC50 values in the 1.3–49 µM range.

Abstract Heartwood colour is often an important factor in determining timber prices. However, the determinants of intraspecific variation in heartwood colour, which is useful information for sustainable wood marketing, are little understood, especially at the local scale in cool temperate forests. Because heartwood is produced as a secondary compound and photosynthesis is regulated by nitrogen (N) in cool temperate forests, we hypothesized that (1) soil conditions determine heartwood colour even at a local scale within a tree species and (2) N, specifically, can be an important driver of the intraspecific variation in heartwood colour in the trees of cool temperate forests. To test these hypotheses, we investigated the relationship between the colour values (luminescence, redness, and yellowness) of heartwood from Juglans mandshurica var. sachalinensis and the soil parameters in a cool temperate forest. Among the soil properties, not soil N but soil magnesium (Mg) contents alone had a significant influence on the redness and yellowness of the heartwood. Higher soil Mg contents resulted in increased redness and yellowness of the heartwood in our study, probably due to the increase in phenolics and the colouring of the tannins in the heartwood with Mg. Our results indicate that even at a local scale, soil condition can determine the intraspecific variation in heartwood colour and that forest managers can utilize edaphic information to predict heartwood colour for timber marketing.