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We recently reported that glycolipid compositions of gadoid fish nerve tissues are unique in the abundance of 1) galactosyl diacylglycerol and its sulfate ester; 2) glucosyl ceramide; and 3) fatty acid ester of cerebroside (J. Lipid Res. 1992. 33: 1351-1359). The present paper reports the characterization of less polar glycolipids isolated from Alaskan pollack brain. Of twelve glycolipids purified by column chromatography, four were of the galactosyl diacylglycerol type. Chemical analysis, infrared spectrometry, and a permethylation study followed by gas chromatography-mass spectrometry revealed that they were 1,2-di-O-acyl-3-beta (6-O-acyl-D-galactopyranosyl)-sn-glycerol and 1,2-di-O-acyl-3-beta(2'-O-acyl-D-galactopyranosyl)-sn-glycerol, and mixtures of these two isomers, with slightly different fatty acid compositions, respectively. The other eight less polar glycolipids were pure forms or mixtures of isomeric forms of cerebroside fatty acid esters in which the substituted position of the acyl group on the hexose moiety varied. The permethylation study revealed that they were 6-O-acyl-beta-D-galactopyranosyl, 6-O-acyl-beta-D-glucopyranosyl, 2-O-acyl-galactosyl, 2-O-acyl-glucosyl, 3- or 4-O-acyl-galactosyl, and 3-O-acyl-glucosyl ceramides, the 6-O- and 2-O-acyl isomers being predominant. This is the first report of the natural occurrence of 1) acyl galactosyl diacylglycerol in animal tissues and 2) acyl glucosyl ceramide in nerve tissues.

Glycolipids were isolated from nerve tissues of gadoid fishes including Alaskan pollack and Pacific cod. Their chemical structures were determined by gas-liquid chromatography and gas chromatography-mass spectrometry, and their constituents were analyzed in detail and compared with those of glycolipids from other fish groups. The results revealed that gadoid fish nerve membranes contain peculiar glycolipid molecular species that are distinctly different from those in other teleostean fishes and higher vertebrates. The mole percentage ratio of the four major glycolipids (cerebroside-sulfatide-galactosylglyceride-sulfogalactosylglyce ride) was 48:12:25:15, indicating profound accumulation of glycoglycerolipids. Galactosylglyceride and sulfogalactosylglyceride were primarily of the diacyl type (greater than 90%), the major fatty acids being 16:0 and 18:1. An abundance of glucocerebroside (25 to 55% of cerebroside) and its fatty acid ester (37 to 47% of ester cerebroside) was noted. Cerebroside and sulfatide were characterized by the absence of hydroxy and odd numbered fatty acids, and 24:1 acid was a predominant component of both glucocerebroside and galactocerebroside. Subcellular fractionation revealed that myelin membranes comprised such unusual glycolipid constituents as those seen in whole nerve tissues. A vertebrate whose nerve membranes consist of such peculiar glycolipid molecules has not previously been reported. The characteristics of the glycolipid composition in gadoid fishes are discussed in relation to myelin functions, physicochemical properties of nerve membranes, and the phylogenic significance of this fish group.

Donryu strain rats through two generations were fed semi-purified diets supplemented with safflower seed oil (rich in linoleic acid) or with perilla seed oil (rich in alpha-linolenic acid), or a conventional laboratory chow (normal control diet). Brightness-discrimination learning ability was determined to be the highest in the perilla oil-fed group, followed by the normal group, and then by the safflower group, extending our earlier observation in a different strain of rat that alpha-linolenic acid is a factor in maintaining high learning ability (Yamamoto, N., M. Saitoh, A. Moriuchi, M. Nomura, and H. Okuyama. 1987. J. Lipid Res. 28: 144-151). After the brightness-discrimination learning test was administered, extinction of learning was measured. The time required for extinction was significantly longer in the safflower group than in either the perilla group or the normal diet group. Thus, the dietary alpha-linolenate/linoleate balance affected both the learning and the extinction of learning. The glycolipids of the cerebrum, cerebellum, and olfactory lobe were analyzed. Although the fatty acid compositions of the sulfatide and gangliosides were significantly different in the three parts of the brain, relatively little difference was observed in the fatty acids of glycolipids between the safflower group and the perilla group, suggesting that gross changes in brain glycolipids are not responsible for the differences in learning abilities between these dietary groups.

Infrared laser stimulation of the cochlea has been proposed as a possible alternative to conventional auditory prostheses. Whereas previous studies have focused primarily on the short-term effects of laser stimulation, the practical application of this technics requires an investigation into whether prolonged laser exposure can induce neural responses and safely. This study assessed the effect of laser-induced damage to the cochlea on auditory perception using Mongolian gerbils (Meriones unguiculatus) trained with a classical conditioning task. The broadband noise was presented as a conditioned stimulus, and reward licking was recorded as a conditioned response. After training, the subject's cochlea was exposed to a continuous pulsed laser for 15 h. Broadband noise of various intensities was presented without pairing it with water before and after laser exposure to assess the decrease in auditory perception due to laser-induced injury. The licking rate did not change after laser exposure of 6.6 W/cm 2 or weaker but drastically decreased after 26.4 W/cm 2 or higher. These findings showed, for the first time, that the safety margin of long-term, at least several hours, cochlear laser stimulation exists and will contribute to the appropriate delimitation of the safe and effective laser stimulation parameters in future research., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

TAFRO syndrome, first reported in 2010, is a systemic inflammatory disease with a rapid onset and potentially fatal course if not treated promptly and appropriately. The name is derived from the initial letters describing the characteristic symptoms of thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly. It is sometimes considered a special subtype of idiopathic multicentric Castleman disease (iMCD) because lymph node biopsies often reveal the pathology findings seen in iMCD. However, its clinical manifestations and prognoses are not well documented. Since the clinical manifestations and prognoses of TAFRO syndrome differ significantly from those of iMCD, it is recognized as an independent disease concept and considered to partially overlap with the pathology of MCD. The pathogenesis of TAFRO syndrome remains largely unknown. Due to the lack of appropriate treatment, it often presents with multiple organ dysfunction and fatality. In this review, we summarized new findings on the pathogenesis of TAFRO syndrome and discussed current effective therapies and future treatment strategies.

Background and Aims: Skeletal muscle loss has been identified as a prognostic factor in patients with unresectable hepatocellular carcinoma (uHCC) undergoing treatment with lenvatinib (LEN). While atezolizumab plus bevacizumab (ATZ-BEV) is recommended as first-line therapy for uHCC, the impact of skeletal muscle loss in these patients remains unclear. Methods: We enrolled 97 patients treated with either LEN or ATZ-BEV as their first-line therapy and divided them into two groups based on the presence or absence of a low psoas muscle index (low PMI) before treatment. We compared patient characteristics and overall survival (OS) between the groups. Additionally, we investigated the transition of the PMI during drug therapy, specifically before treatment, at the initial evaluation, and after the end of treatment. Results: Seventy percent of patients in the LEN group and seventy-one percent in the ATZ-BEV group had a low PMI. Multivariate analysis across all patients revealed a low PMI (hazard ratio [HR] 3.25, p = 0.0004) as a prognostic factor for OS. The PMI decreased more in the LEN group compared to the ATZ-BEV group. In the Barcelona Clinic Liver Cancer-C group, the OS of ATZ-BEV therapy was significantly better than that of LEN therapy when a low PMI was present ( p = 0.046). Conclusions: A low PMI emerges as a significant prognostic factor in uHCC patients undergoing drug therapy, not only in LEN therapy but also in ATZ-BEV therapy. Additionally, ATZ-BEV therapy may be more favorable for sarcopenic patients with advanced HCC stages.

Immune checkpoint inhibitors (ICI) are promising therapeutic agents for relapsed or refractory classical Hodgkin's lymphoma (RRcHL). This retrospective study evaluated patients with RRcHL registered in the clinical research program Tohoku-Hematology-Forum-26, between 2016 and 2020, and treated with ICI in 14 centers in Northeast Japan. We analyzed the usage, efficacy, and safety of ICI therapy (ICIT). Among a total of 27 patients with RRcHL, 21 and nine were treated with nivolumab and/or pembrolizumab, respectively. The best response was complete response (CR), partial response (PR), stable disease (SD), and progressive disease in 11 (40.8%), seven (25.9%), eight (29.6%), and one (3.7%) patient, respectively. In all patients undergoing ICIT, the 2-year progression-free survival and 2-year overall survival (OS) were 48.6% and 87.4%, respectively. The 2-year OS for patients with CR, PR, and SD were 100%, 68.6%, and 87.5%, respectively. A total of 36 events of immune-related adverse events (irAEs) or immune-related like adverse events (irlAEs) were observed in 19 of the 27 patients (70.4%). Two thirds of these irAEs or irlAEs were grade 1-2 and controllable. During the observation period, ICIT was discontinued in 22 of 27 (81.4%) patients due to CR, inadequate response, irAE and patient circumstances in five (22.7%), seven (31.8%), eight (36.4%) and two patients (9.1%), respectively. Therapy-related mortality-associated irAE were observed in only one patient during ICIT. These results suggest that ICIT for RRcHL is effective and safe in real-world settings. The optimal timing of induction and duration of ICIT remains to be established.

Background: Non-invasive diagnosis of disease stage in Fabry cardiomyopathy with multimodality imaging is pivotal when deciding on the appropriate time to initiate enzyme replacement therapy. However, this approach has not been well established., Methods and Results: We enrolled 14 patients with Fabry disease. All patients were evaluated using echocardiography and contrast cardiac magnetic resonance (CMR), and were divided into either an early-stage group without left ventricular hypertrophy (LVH; wall thickness >12 mm) or late gadolinium enhancement (LGE; n=7; median age 37 years; 4 female), or an advanced-stage group with LVH and/or LGE (n=7; median age 66 years; 7 female). Strain data from echocardiography and T1 mapping on CMR were compared between the groups. In the advanced-stage group, all strain data were impaired. In the early-stage group, localized longitudinal strain in the basal posterolateral segment was already reduced but both localized and global circumferential strain remained preserved. On CMR analysis, global and localized native T1 shortening were observed in the early-stage group, but were pseudo-normalized in the advanced-stage group. In logistic regression analysis, localized circumferential strain had significant diagnostic value for differentiating between early- and advanced stage (P=0.037) and significantly improved the predictive power of the model containing localized native T1 in CMR., Conclusions: A combination of localized native T1 in CMR and echocardiographic strain parameters could be useful for staging Fabry cardiomyopathy., Competing Interests: The authors have nothing to disclose in connection with this article., (Copyright © 2024, THE JAPANESE CIRCULATION SOCIETY.)

The outcomes of relapsed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) resistant to new drugs such as tyrosine kinase inhibitors, inotuzumab ozogamicin (InO) and blinatumomab are dismal. We treated two cases of Ph+ALL resistant to these drugs that achieved long-term survival after treatment with chimeric antigen receptor (CAR)-T cell therapy or a second allogeneic hematopoietic stem cell transplantation (HCT) with a sequential conditioning regimen. Case 1: A 15-year-old boy was diagnosed with Ph+ALL. Despite the second HCT after the treatment of ponatinib and blinatumomab, hematological relapse occurred. InO was ineffective and he was transferred to a CAR-T center. After the CAR-T cell therapy, negative measurable residual disease (MRD) was achieved and maintained for 38 months without maintenance therapy. Case 2: A 21-year-old man was diagnosed with Ph+ALL. Hematological relapse occurred after the first HCT. Despite of the treatment with InO, ponatinib, and blinatumomab, hematological remission was not achieved. The second HCT was performed using a sequential conditioning regimen with clofarabine. Negative MRD was subsequently achieved and maintained for 42 months without maintenance therapy. These strategies are suggestive and helpful to treat Ph+ALL resistant to multiple immunotherapies.

Background: The use of serum soluble interleukin 2 receptor (sIL-2R) for the diagnosis of febrile illnesses has not been examined. In this study, febrile patients were classified according to etiology and disease, and serum sIL-2R levels were evaluated. We determined whether serum sIL-2R is a useful marker for differentiating between malignant lymphoma (ML) and non-ML patients and between patients with ML and Kikuchi disease, which present similar clinical manifestations. Methods: This study was a cross-sectional study and included 344 patients with uncomplicated hemophagocytic syndrome, who had a fever of 38 °C or higher within 1 week of admission to our institution. Patient serum sIL-2R was measured, and the serum sIL-2R values are shown as median and IQR. Results: Serum sIL-2R increased above the upper reference limit in all disease groups with fever. The serum sIL-2R level in ML patients (n = 13) was 4760 (2120-6730) U/mL and significantly higher ( p < 0.001) than the level of 998 (640-1625) U/mL in non-ML patients ( n = 331). The serum sIL-2R level in ML patients ( n = 13) was also significantly higher ( p < 0.001) compared with that in patients with Kikuchi disease ( n = 20; 705 (538-1091) U/mL). Conclusions: Serum sIL-2R tends to exceed the upper reference limit in patients with febrile illnesses. We conclude that the measurement of serum sIL-2R is useful for differentiating ML from non-ML and ML from Kikuchi disease.

There are no clear criteria for selecting elderly patients with hematologic malignancies eligible for allogeneic hematopoietic stem cell transplantation (HSCT). This study aimed to evaluate inflammatory and nutritional status biomarkers as prognostic indicators of allogeneic HSCT in elderly patients. We compared the prognostic effects of 4 representative pretransplantation biomarkers: C-reactive protein-to-albumin ratio (CAR), Glasgow Prognostic Score (GPS), prognostic nutritional index (PNI), and albumin-to-globulin ratio (AGR). A total of 143 patients age ≥60 years who underwent their first allogeneic HSCT for a hematologic malignancy were enrolled between 2010 and 2020 in our single-center cohort. The median patient age was 65 years (range, 60 to 72 years). Pretransplantation high CAR, high GPS, and low PNI scores were associated with poor overall survival (OS), but the AGR was not associated with OS. Among the 4 biomarkers, CAR stratified OS most significantly (P < .001). Multivariate analyses identified only high CAR as an independent prognostic factor associated with OS (hazard ratio [HR], 1.98; P = .031) and showed that a Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) score ≥3 also was associated with OS (HR, 2.04; P = .012). High CAR was correlated with poor performance status, male sex, and high Disease Risk Index, but not with high HCT-CI score. When the patients were stratified into 3 groups according to a composite risk assessment using CAR and HCT-CI, the 3-year OS decreased significantly with increasing scores (82.8%, 50.3%, and 27.0%, respectively; P < .0001). In conclusion, CAR is the most useful prognostic indicator among the inflammatory and nutritional status biomarkers for allogeneic HSCT in elderly patients. Inflammatory and nutritional status in the elderly may be important prognostic factors for allogeneic HSCT independent of HCT-CI score., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background/aim: Elotuzumab, an anti-SLAMF7 monoclonal antibody, can enhance immune activity via elevated antibody-dependent cellular cytotoxicity and reduced SLAMF7 + CD8 + CD57 + regulatory T-cells (Tregs). This multicenter observational study investigated the kinetics of lymphocytes in myeloma patients treated with elotuzumab, lenalidomide, and dexamethasone (ERd) by two-color flow cytometry using peripheral blood samples., Patients and Methods: Twenty-one patients were included in this study. The median duration of ERd was 22.6 months, and the cutoff time for long-duration ERd was two years., Results: The CD2 + CD16 + and CD16 + CD57 - NK cells were significantly increased over time in the long-duration ERd group compared to those in the short-duration ERd group (p=0.035 and p<0.001). The CD8 + and CD16 - CD57 + lymphocytes, identified as low-activity NK cells or SLAMF7 + Tregs, were significantly increased in the patients whose ERd outcome was progressive disease (PD) compared to those in the non-PD group (p=0.023 and p<0.001). The mean CD4/CD8 ratio and CD19 + lymphocyte counts in the long-duration ERd group were significantly lower than those in the short-duration ERd group, although the kinetics of them did not change over time (p=0.016 and p=0.011). When the cutoff value of CD4/CD8 ratio was 0.792 according to ROC curves, the two-year time to next treatment (TTNT) in the low CD4/CD8 group was significantly longer than that in the high CD4/CD8 group (80.0% vs. 15.0%, p=0.024)., Conclusion: The change in NK cells and CD8 + Tregs predicted long-duration ERd and PD, and maintaining low CD4/8 ratio predicted long TTNT, suggesting that these lymphocyte fractions might be biomarkers for a durable therapeutic effect of ERd in myeloma patients., Competing Interests: K. Suzuki received personal fees from Takeda Pharmaceutical Company, Janssen Pharmaceutical K.K., Sanofi, Celgene, outside the submitted work; M. Matsumoto received honoraria from Bristol-Myers Squibb K.K., Janssen Pharmaceutical and Takeda Pharmaceutical, Ono Pharmaceutical, Sanofi K.K., outside the submitted work; K. Suzuki received honoraria from Takeda, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, Abbvie and Janssen, consulted for Amgen, Takeda, and Bristol-Myers Squibb, and received research funding from Bristol-Myers Squibb. The other Authors declare that they have no conflicts of interest., (Copyright 2024, International Institute of Anticancer Research.)

Objective Zinc-α2-glycoprotein (ZAG) is secreted by various organs, such as liver, kidney and adipose tissue, is involved in lipolysis, and may contribute to the pathogenesis of chronic liver disease (CLD). We therefore assessed whether or not ZAG is a surrogate marker for the hepatorenal function, body composition and all causes of mortality, as well as complications, including ascites, hepatic encephalopathy (HE) and portosystemic shunts (PSS) in CLD. Methods Serum ZAG levels were measured in 180 CLD patients upon hospital admission. The associations of ZAG levels with the liver functional reserve and clinical parameters were investigated using a multiple regression analysis. Kaplan-Meier analyses were performed to evaluate the associations of the ZAG/creatinine ratio (ZAG/Cr) and prognostic factors with mortality. Results High serum ZAG levels were associated with preserving the liver function and renal insufficiency. A multiple regression analysis showed that the estimated glomerular filtration rate (p<0.0001), albumin-bilirubin (ALBI) score (p=0.0018) and subcutaneous fat area (p=0.0023) had a significant independent correlation with serum ZAG levels. Serum ZAG levels were elevated in the absence of HE (p=0.0023) and PSS (p=0.0003). In all patients and those without hepatocellular carcinoma (HCC), the cumulative mortality rate was significantly decreased in patients with a high ZAG/Cr compared with those with a low ZAG/Cr (p=0.0018 and p=0.0002, respectively). The ZAG/Cr, presence of HCC, ALBI score and psoas muscle index were independent predictors of the prognosis in CLD patients. Conclusion Serum ZAG levels are associated with the hepatorenal function and can be used to predict the survival in CLD patients.

Objectives and Methods: This single-center retrospective study was performed to evaluate the safety and efficacy of FMS-like tyrosine kinase 3 (FLT3) inhibitors before and after allogeneic hematopoietic cell transplantation (HCT) in relapsed/refractory patients with FLT3-mutation positive acute myeloid leukemia (AML)., Results: Ten patients who met the eligibility criteria were included. Eight of them achieved hematological remission at HCT, within a median span of 79 days (range: 43-197). In post-HCT, patients started maintenance therapy (MT; median time-to-start 79 days, range: 43-197), and the median duration of MT was 390 days (range: 67-815). Grade 3 hematological adverse events (AEs) were found in two patients, and non-hematological AEs were found in five patients. Nine patients underwent either dose reduction, discontinuation of therapy, or a switch to another FLT3 inhibitor due to AEs. Disease relapse occurred in one patient during MT. At the time of the last follow-up, seven patients are alive and disease-free, while three have died due to infection or transplant complications., Conclusion: In relapsed/refractory FLT3 mutation-positive AML, the use of FLT3 inhibitors can lead to high response rates and provide a safe bridge from HCT to MT. If sufficient attention is paid to safety, this therapy is expected to prevent disease relapse even with reduced dosages.

Hepatocellular carcinoma (HCC) is estimated to be the fourth leading cause of cancer-related deaths globally, and its overall prognosis is dismal because most cases are diagnosed at a late stage and are unamenable to curative treatment. The emergence of immune checkpoint inhibitors (ICIs) has dramatically improved the therapeutic efficacy for advanced hepatocellular carcinoma; however, their response rates remain unsatisfactory, partly because >50% of HCC exhibit an ICI-nonresponsive tumor microenvironment characterized by a paucity of cytotoxic T cells (immune-cold), as well as difficulty in their infiltration into tumor sites (immune excluded). To overcome this limitation, combination therapies with locoregional therapies, including ablation, transarterial embolization, and radiotherapy, which are usually used for early stage HCCs, have been actively explored to enhance ICI efficacy by promoting the release of tumor-associated antigens and cytokines, and eventually accelerating the so-called cancer-immunity cycle. Various combination therapies have been investigated in early- to late-phase clinical trials, and some have shown promising results. This comprehensive article provides an overview of the immune landscape for HCC to understand ICI efficacy and its limitations and, subsequently, reviews the status of combinatorial therapies of ICIs with locoregional therapy for HCC.

A 70-year-old man was diagnosed with hepatocellular carcinoma (HCC) with portal vein invasion and lung metastases, for which atezolizumab plus bevacizumab (ATZ/BEV) was initiated. After two months, computed tomography revealed tumor growth accompanied by ascites, right ventricular invasion, exacerbation of the lung metastases, and main portal vein invasion. However, continuation of ATZ/BEV caused remarkable size reductions in all lesions, finally resulting in the disappearance of the vascular invasion and lung metastases after nine cycles of treatment. The tumor growth was considered to reflect pseudoprogression, which is difficult to distinguish from hyperprogression. We herein report a remarkable HCC case of pseudoprogression on ATZ/BEV.

Background/aims: Pemafibrate is a selective peroxisome proliferator-activated receptor α modulator that improves serum alanine aminotransferase (ALT) in dyslipidemia patients. Pemafibrate was reported to reduce ALT in non-alcoholic fatty liver disease (NAFLD) patients, but efficacy was not clearly elucidated due to the small size of previous study populations. Therefore, we explored pemafibrate efficacy in NAFLD patients., Methods: We retrospectively evaluated pemafibrate efficacy on liver enzymes ( n = 132) and liver shear wave velocity (SWV, n = 51) in NAFLD patients who had taken pemafibrate for at least 24 weeks., Results: Patient ALT levels were decreased from 81.0 IU/L at baseline to 48.0 IU/L at week 24 ( P < 0.0001). Serum levels of aspartate aminotransferase (AST), γ-glutamyl transpeptidase (γ-GTP) and triglyceride (TG) were significantly decreased, and high-density lipoprotein cholesterol and platelet count were significantly increased, with no change in body weight being observed. Study participant SWV values decreased from 1.45 m/s at baseline to 1.32 m/s at week 48 ( P < 0.001). Older age ( P = 0.035) and serum TG levels ( P = 0.048) were significantly associated with normalized ALT. Changes in AST, ALT, γ-GTP and body weight were significantly correlated with change in SWV., Conclusion: Pemafibrate significantly improves liver function, serum TG and liver stiffness in NAFLD patients. Pemafibrate is a promising therapeutic agent for NAFLD and may be a candidate for NAFLD patients with elevated TG., Competing Interests: HN received Honoraria from Kowa Pharmaceutical Co., Ltd. The remaining 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 Sugimoto, Iwasa, Eguchi, Tamai, Shigefuku, Fujiwara, Tanaka, Kobayashi, Ikoma, Kaito and Nakagawa.)

Background: Invasive pulmonary Aspergillus and invasive bronchial aspergillosis is a life-threatening opportunistic fungal infection that predominantly affects immunocompromised hosts. A case series and review found that the mortality rate of invasive bronchial aspergillosis is high, at about 40%, and 23.7% of invasive bronchial aspergillosis patients require mechanical ventilator management. There are few reports of life-saving cases with venovenous extracorporeal membrane oxygenation as rescue therapy in invasive pulmonary Aspergillus and invasive bronchial aspergillosis. Here, we report a case of invasive bronchial aspergillosis and invasive pulmonary Aspergillus that was successfully treated with venovenous extracorporeal membrane oxygenation, and combined systemic and intratracheal instillation of liposomal amphotericin B., Case Presentation: We present the case of a 61-year-old Japanese man with invasive tracheobronchial-pulmonary aspergillosis while receiving chemotherapy for malignant lymphoma. Bronchoscopy revealed trachea covered with pseudomembranous necrotizing tissue, the culture revealed Aspergillus fumigatus, and the histological findings of pseudomembranous revealed fungal hyphae. The patient required venovenous extracorporeal membrane oxygenation because of respiratory failure for atelectasis and obstructive pneumoniae. While continuing systemic administration of liposomal amphotericin B, intratracheal instillation liposomal amphotericin B was performed by bronchoscopy three times a week. Although the respiratory conditions improved and the patient was discontinued on venovenous extracorporeal membrane oxygenation, he ultimately died of recurrence of malignant lymphoma., Conclusion: Intratracheal instillation of liposomal amphotericin B is safe, and liposomal amphotericin B instillation allowed a targeted high local drug concentration, which led to improvement in the invasive bronchial aspergillosis. In addition, since the patient was supported with venovenous extracorporeal membrane oxygenation, we were able to perform safe bronchoscopic debridement of airway lesions and intratracheal instillation of liposomal amphotericin B., (© 2022. The Author(s).)

Rationale: Thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, and organomegaly (TAFRO) syndrome are nonmalignant but life-threatening systemic inflammatory disorders. However, many patients are refractory to treatment, resulting in significant morbidity and mortality. Additionally, established treatment options are unavailable. Therefore, we present 2 cases of adults with the iMCD-TAFRO syndrome refractory to initial treatment but responded to Janus kinase (JAK) inhibitors with ruxolitinib. The report reveals that these rare adult cases of the refractory and treatment-resistant iMCD-TAFRO syndrome can be treated using JAK inhibitors., Patient Concerns: Case 1 is a 36-year-old previously healthy male patient who presented with fever and general fatigue for 2 weeks. Case 2 is a 42-year-old previously healthy female patient who presented with fever and general fatigue., Diagnosis: The diagnosis met the 2015 criteria for TAFRO syndrome, as determined by All Japan TAFRO Syndrome Research Group in the Research Program for Intractable Disease by the Ministry of Health, Labor and Welfare (MHLW) Japan., Interventions: Treatment with tocilizumab and several immunosuppressants were ineffective. So, we performed ruxolitinib., Outcomes: Each patient received ruxolitinib, the general condition improved, and CRP levels decreased., Lessons: These cases showed that ruxolitinib was effective for treatment-resistant/ refractory TAFRO syndrome. Further prospective studies are needed on using ruxolitinib with a small number of cases., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Studies have reported that COVID-19 is associated not only with pneumonia but also with cerebrovascular disease. Consequently, medical personnel involved in treating stroke in the emergency medicine setting have been placed in a situation that requires them to provide treatment while always remaining mindful of the possibility of COVID-19. Here, we describe the current state of stroke treatment during the COVID-19 pandemic. Four patients with stroke and concomitant COVID-19 were treated at our facility. We treated 3 patients with cerebral infarction and 1 patient with cerebral venous sinus thrombosis. All 3 patients with cerebral infarction had a poor outcome. This was attributed in part to the poor general condition of the patients due to concomitant COVID-19, as well as to the severity of the major artery occlusion and cerebral infarction. One patient with cerebral venous sinus thrombosis had a good outcome. Anticoagulant therapy was administered at our hospital and resulted in a stable clinical course. Our hospital has worked to establish an examination and treatment system that enables mechanical thrombectomy to be performed even during the COVID-19 pandemic. We devised a protocol showing the steps to be taken from initial treatment to admission to the cerebral angiography room. Our hospital was able to continue accepting requests for emergency admission thanks to the examination and treatment system we established. Up-to-date information should continue to be collected to create examination and treatment systems., Competing Interests: The authors have no conflicts of interest to disclose., (2022, National Center for Global Health and Medicine.)

Background: Hepatic sarcopenia is one of many complications associated with chronic liver disease (CLD) and has a high mortality rate; however, the liver-muscle axis is not fully understood. Therefore, few effective treatments exist for hepatic sarcopenia, the best of which being branched-chain amino acid (BCAA) supplementation to help increase muscle mass. Our aim was to investigate the molecular mechanism(s) of hepatic sarcopenia focused on bile acid (BA) composition., Methods: The correlation between serum BA levels and psoas muscle mass index (PMI) was examined in 73 CLD patients. Gastrocnemius muscle phenotype and serum BA levels were assessed in CLD rats treated with BCAA. Mouse skeletal muscle cells (C2C12) were incubated with lithocholic acid (LCA), G-protein-coupled receptor 5 (TGR5) agonist or TGR5 antagonist to assess skeletal muscle hypertrophy., Results: In human CLD, serum LCA levels were the sole factor positively correlated with PMI and were significantly decreased in both the low muscle mass group and the deceased group. Serum LCA levels were also shown to predict patient survival. Gastrocnemius muscle weight significantly increased in CLD rats treated with BCAA via suppression of protein degradation pathways, coupled with a significant increase in serum LCA levels. LCA treated C2C12 hypertrophy occurred in a concentration-dependent manner linked with TGR5-Akt pathways based upon inhibition results via a TGR5 antagonist., Conclusions: Our results indicate LCA-mediated skeletal muscle hypertrophy via activation of TGR5-IGF1-Akt signaling pathways. In addition, serum LCA levels were associated with skeletal muscle mass in cirrhotic rats, as well as CLD patients, and predicted overall patient survival., Funding: This research was supported by JSPS KAKENHI Grant Number 22K08011 and 21H02892, and AMED under Grant Number JP21fk0210090 and JP22fk0210115. Maintaining cirrhotic rats were partially supported by Otsuka Pharmaceutical Company., Competing Interests: YT, AE, RS, HK, MT, RS, YK, MI, YT, HN No competing interests declared, (© 2022, Tamai, Eguchi et al.)

In asymptomatic patients with mitral regurgitation (MR), data of exercise-induced pulmonary hypertension (EIPH) are limited, and feasibility of evaluating EIPH is not high. We aimed to investigate prognostic impact of EIPH and its substitute parameters. Exercise stress echocardiography (ESE) were performed in 123 consecutive patients with moderate to severe degenerative MR. The endpoint was a composite of death, hospitalization for heart failure, and worsening of symptoms. EIPH [tricuspid regurgitation peak gradient (TRPG) at peak workload ≥ 50 mmHg] was shown in 57 patients (46%). TRPG at low workload was independently associated with TRPG at peak workload (β = 0.67, p < 0.001). Early surgical intervention (within 6 months after ESE) was performed in 65 patients. Of the remaining 58 patients with the watchful waiting strategy, the event free survival was lower in patients with EIPH than in patients without EIPH (48.1 vs. 97.0% at 1-year, p < 0.001). TRPG at low workload ≥ 35.0 mmHg as well as EIPH were associated with poor prognosis in patients with the watchful waiting strategy. In conclusion, the importance of ESE and evaluating EIPH in patients with MR was re-acknowledged. TRPG at peak workload can be predicted by TRPG at low workload, and TRPG at low workload may be useful in real-world clinical settings., (© 2022. The Author(s).)

Infrared laser stimulation has been studied as an alternative approach to auditory prostheses. This study evaluated the feasibility of infrared laser stimulation of the cochlea from the outer ear, bypassing the middle ear function. An optic fiber was inserted into the ear canal, and a laser was used to irradiate the cochlea through the tympanic membrane in Mongolian gerbils. A pulsed infrared laser (6.9 mJ/cm 2 ) and clicking sound (70 peak-to-peak equivalent sound pressure level) were presented to the animals. The amplitude of the laser-evoked cochlear response was systematically decreased following insertion of a filter between the tympanic membrane and cochlea; however, the auditory-evoked cochlear response did not decrease. The filter was removed, and the laser-evoked response returned to around the original level. The amplitude ratio and the relative change in response amplitude before and during filter insertion significantly decreased as the absorbance of the infrared filter increased. These results indicate that laser irradiation could bypass the function of the middle ear and directly activate the cochlea. Therefore, laser irradiation from the outer ear is a possible alternative for stimulating the cochlea, circumventing the middle ear.

Background: As the global population ages, the number of older adults working after retirement is increasing. However, knowledge regarding working conditions for health and happiness among this population is insufficient. Therefore, we examined the association between work-related factors (e.g., employment status, daily working time, work-related stress) and happiness among working older adults., Methods: This cross-sectional study recruited Japanese older adults, aged 65 years and older, who were engaged in paid work, during their annual health checkups. Self-administered questionnaires were used to assess happiness, employment status, daily working time, and work-related stress (i.e., job strain, job control, job suitability, and relationships at work)., Results: The data of 520 men and 168 women were analyzed (mean ages, 68.5 years and 68.0 years, respectively). The results of the multivariable ordinal logistic regression analysis indicated that low job suitability was negatively associated with happiness in men (odds ratio [OR]=0.46; 95% confidence interval [CI], 0.28-0.78; p=0.004). In women, long working hours and low job control were negatively associated with happiness-working &gt;8 hours daily (OR=0.29; 95% CI, 0.12-0.71; p=0.008) and low job control (OR=0.29; 95% CI, 0.12-0.72; p=0.009)., Conclusion: The results showed that low job suitability for men and long daily working time and low job control for women were negatively associated with happiness. These findings suggest the need to improve working conditions to enhance the well-being of working older adults.

Background: Fragmented cytokeratin 18 (fCK18) is released from damaged hepatocytes undergoing apoptosis and is recognized as a liver condition biomarker. We have developed a highly sensitive serum fCK18 CLEIA and reported that serum levels of this caspase-derived protein were significantly associated with hepatocyte ballooning, thus assisting in the accurate diagnosis of nonalcoholic steatohepatitis (NASH). We aim to investigate serum fCK18 levels in a variety of chronic liver diseases and to explore its potential as a prognostic marker of survival in hepatocellular carcinoma (HCC) patients., Methods: Serum fCK18 levels were measured using a highly sensitive CLEIA in 497 chronic liver disease patients (297 outpatients and 200 hospitalized with HCC)., Results: In 497 chronic liver disease patients, serum fCK18 levels were significantly correlated with overall liver condition, including ALT, FIB-4 index and albumin-bilirubin (ALBI) score and were significantly increased in patients with HCC. In 200 HCC patients, serum fCK18 levels were significantly correlated with alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP), and were significantly associated with HCC stage, whereas FIB-4 index and ALBI score were not changed based on HCC stage. The Survival group had significantly lower levels of serum fCK18, AFP, DCP, FIB-4 index and ALBI score. A ROC analysis yield area under the curve (AUC) value of 0.728 for serum fCK18 is a significantly high value when compared to AUC measurements for other factors. Notably, AUROC values for serum fCK18 levels were constant in the short- and long-term by time-dependent ROC analysis for the prediction of HCC patient survival. HCC patients with serum fCK18 measured at < 1.15 ng/mL, AFP < 7.7 ng/mL, DCP < 133 mAU/mL, ALBI score < -2.97 or FIB-4 index < 6.4 had significantly longer rates of survival when compared to patients with values exceeding these thresholds. Serum fCK18 (HR, 3.5; P < 0.0001), DCP (HR, 3.2; P < 0.0001) and Barcelona Clinic Liver Cancer (BCLC) (HR, 2.4; P = 0.001) values were independent predictors of patient survival. [Conclusion] Serum fCK18 levels reflect overall liver function, the level of liver fibrosis and the progression of HCC, and are a potential predictor of survival in HCC patients., Competing Interests: Author's MY, KO, KS and TY were employed by Sysmex Corporation. The remaining 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 © 2022 Eguchi, Iwasa, Tamai, Yamada, Okuno, Shigefuku, Yoshikawa, Tempaku, Sakaguchi, Tanaka, Sugimoto, Kobayashi, Yamaguchi and Nakagawa.)