Fulminant hepatitis in a hepatitis B surface antigen-positive patient with adult T-cell leukemia-lymphoma after mogamulizumab monotherapy.

We report a case of fulminant hepatitis in a hepatitis B surface antigen (HBsAg)-positive patient with aggressive adult T-cell leukemia-lymphoma who received monotherapy with an anti-CCR4 monoclonal antibody, mogamulizumab, with decreased hepatitis B virus (HBV)- DNA levels by entecavir prophylaxis. Although HBV reactivation-related hepatitis was considered in the differential diagnosis, the patient did not meet the conventional criteria for HBV reactivation and was finally diagnosed with drug-induced hepatitis. Considering that the immunoenhancing effects of mogamulizumab can lead to HBV reactivation-related hepatitis in HBsAg-positive patients, we should differentiate drug-induced hepatitis from HBV reactivation, especially in patients receiving immunomodulatory drugs, if HBV-DNA levels are reduced by antiviral prophylaxis.

Clinical Significance of Cytomegalovirus Reactivation in Patients With Plasma Cell Dyscrasia Who Were Treated With Anti-CD38 Monoclonal Antibody: A Retrospective Analysis in a Single Institution.

INTRODUCTION: Anti-CD38 monoclonal antibodies (mAbs) have improved the prognosis of patients with plasma cell dyscrasia (PCD), but are also associated with increased infectious adverse events. Cytomegalovirus (CMV) is a common latent pathogen that is reactivated in immunocompromised individuals. Although CMV reactivation has mostly been reported after high-dose chemotherapy followed by stem cell transplantation in patients with PCD, cases of reactivation during anti-CD38 mAb therapy have been reported recently. Due to limited studies, we aimed to determine the frequency and impact of CMV reactivation during anti-CD38 mAb therapy. PATIENTS AND METHODS: This retrospective analysis included 154 consecutive patients with PCD who were treated with anti-CD38 mAbs at a single institution. RESULTS: Seventy-six patients were evaluated for CMV reactivation by CMV pp65 antigen testing, and 29 (38%) patients, including nine with newly diagnosed PCD, showed positive results. Patients who tested positive for the CMV pp65 antigen had substantially lower serum albumin levels than those who tested negative. However, the two groups showed no marked difference in the concurrent anti-PCD medications or baseline absolute lymphocyte count. Although most patients showing positive results in the CMV pp65 antigen test had mild or no symptoms, with fever being the most common symptom, some patients developed CMV end-organ disease. In addition, CMV reactivation interfered with the course of anti-PCD treatment in most patients, necessitating dose reductions, delays, and discontinuation of chemotherapy. CONCLUSION: This study provides an overview of the clinical impact of CMV reactivation in patients with PCD treated with anti-CD38 mAb-containing regimens.

Development of a chimeric cytokine receptor that captures IL-6 and enhances the antitumor response of CAR-T cells.

The efficacy of chimeric antigen receptor (CAR)-engineered T cell therapy is suboptimal in most cancers, necessitating further improvement in their therapeutic actions. However, enhancing antitumor T cell response inevitably confers an increased risk of cytokine release syndrome associated with monocyte-derived interleukin-6 (IL-6). Thus, an approach to simultaneously enhance therapeutic efficacy and safety is warranted. Here, we develop a chimeric cytokine receptor composed of the extracellular domains of GP130 and IL6RA linked to the transmembrane and cytoplasmic domain of IL-7R mutant that constitutively activates the JAK-STAT pathway (G6/7R or G6/7R-M452L). CAR-T cells with G6/7R efficiently absorb and degrade monocyte-derived IL-6 in vitro. The G6/7R-expressing CAR-T cells show superior expansion and persistence in vivo, resulting in durable antitumor response in both liquid and solid tumor mouse models. Our strategy can be widely applicable to CAR-T cell therapy to enhance its efficacy and safety, irrespective of the target antigen.

High CD62L expression predicts the generation of chimeric antigen receptor T cells with potent effector functions.

Efficient generation of chimeric antigen receptor (CAR) T cells is highly influenced by the quality of apheresed T cells. Healthy donor-derived T cells usually proliferate better than patients-derived T cells and are precious resources to generate off-the-shelf CAR-T cells. However, relatively little is known about the determinants that affect the efficient generation of CAR-T cells from healthy donor-derived peripheral blood mononuclear cells (PBMC) compared with those from the patients' own PBMC. We here examined the efficiency of CAR-T cell generation from multiple healthy donor samples and analyzed its association with the phenotypic features of the starting peripheral blood T cells. We found that CD62L expression levels within CD8+ T cells were significantly correlated with CAR-T cell expansion. Moreover, high CD62L expression within naïve T cells was associated with the efficient expansion of T cells with a stem cell-like memory phenotype, an indicator of high-quality infusion products. Intriguingly, genetic disruption of CD62L significantly impaired CAR-T cell proliferation and cytokine production upon antigen stimulation. Conversely, ectopic expression of a shedding-resistant CD62L mutant augmented CAR-T cell effector functions compared to unmodified CAR-T cells, resulting in improved antitumor activity in vivo. Collectively, we identified surface expression of CD62L as a concise indicator of potent T cell proliferation. CD62L expression is also associated with functional properties of CAR-T cells. These findings are potentially applicable to selecting optimal donors to massively generate CAR-T cell products.

Electrical promontory stimulation test using a portable peripheral nerve stimulator with an ear canal electrode.

OBJECTIVE: An intact cochlear nerve is necessary for successful cochlear implantation (CI). Although the promontory stimulation test (PST) using a promontory stimulator (PS) and a transtympanic needle electrode is invasive, it is still commonly used to verify cochlear nerve function. PSs are currently unavailable because they are no longer manufactured; however, considering that PST continues to be beneficial in certain situations, alternative equipment is needed. The PNS-7000® (PNS) was developed as a neurologic instrument for stimulating the peripheral nerves. This study investigated the usefulness of the ear canal stimulation test (ECST) using PNS with a silver ball ear canal electrode, which is a new noninvasive alternative technique to the PST. METHODS: ECST was performed from November 2013 to December 2018 using PS and PNS for patients with severe to profound sensorineural hearing loss. The electrical threshold, most comfortable loudness level, uncomfortable loudness level, dynamic range, and gap detection were measured in the ECST. The results of these measured PNS items were compared with PS. RESULTS: ECST was performed in 61 ears of 35 patients (age, 59.9 ± 20.1 years) using PS and PNS. The sound sensation was elicited in 51 (83.6%) and 52 (85.2%) ears with PS and PNS, respectively. All items excluding GAP were measured in 46 (75%) and 43 (70%) ears at 50 and 100 Hz, respectively. GAP was measured in 33 ears by the ascending and descending methods using PS and PNS. Spearman's rank-order correlation coefficient revealed a significant positive linear correlation between the PS and PNS results in all measurements. No significant difference was found between the PS and PNS thresholds in all measured items. CONCLUSIONS: PNS is a useful instrument for performing ECST as a new alternative to PS. ECST using a silver ball electrode is a less invasive and easier test than PST.

Effect of Eicosapentaenoic Acid/Docosahexaenoic Acid on Coronary High-Intensity Plaques Detected Using Noncontrast T1-weighted Imaging: The AQUAMARINE EPA/DHA Randomized Study.

AIM: Omega-3 fatty acids have emerged as a new option for controlling the residual risk for coronary artery disease (CAD) in the statin era. Eicosapentaenoic acid (EPA) is associated with reduced CAD risk in the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention trial, whereas the Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia trial that used the combination EPA/docosahexaenoic acid (DHA) has failed to derive any clinical benefit. These contradictory results raise important questions about whether investigating the antiatherosclerotic effect of omega-3 fatty acids could help to understand their significance for CAD-risk reduction. METHODS: The Attempts at Plaque Vulnerability Quantification with Magnetic Resonance Imaging Using Noncontrast T1-weighted Technic EPA/DHA study is a single-center, triple-arm, randomized, controlled, open-label trial used to investigate the effect of EPA/DHA on high-risk coronary plaques after 12 months of treatment, detected using cardiac magnetic resonance (CMR) in patients with CAD receiving statin therapy. Eligible patients were randomly assigned to no-treatment, 2-g/day, and 4-g/day EPA/DHA groups. The primary endpoint was the change in the plaque-to-myocardium signal intensity ratio (PMR) of coronary high-intensity plaques detected by CMR. Coronary plaque assessment using computed tomography angiography (CTA) was also investigated. RESULTS: Overall, 84 patients (mean age: 68.2 years, male: 85%) who achieved low-density lipoprotein cholesterol levels of ＜100 mg/dL were enrolled. The PMR was reduced in each group over 12 months. There were no significant differences in PMR changes among the three groups in the primary analysis or analysis including total lesions. The changes in CTA parameters, including indexes for detecting high-risk features, also did not differ. CONCLUSION: The EPA/DHA therapy of 2 or 4 g/day did not significantly improve the high-risk features of coronary atherosclerotic plaques evaluated using CMR under statin therapy.

Epigenetic profiles guide improved CRISPR/Cas9-mediated gene knockout in human T cells.

Genetic modification of specific genes is emerging as a useful tool to enhance the functions of antitumor T cells in adoptive immunotherapy. Current advances in CRISPR/Cas9 technology enable gene knockout during in vitro preparation of infused T-cell products through transient transfection of a Cas9-guide RNA (gRNA) ribonucleoprotein complex. However, selecting optimal gRNAs remains a major challenge for efficient gene ablation. Although multiple in silico tools to predict the targeting efficiency have been developed, their performance has not been validated in cultured human T cells. Here, we explored a strategy to select optimal gRNAs using our pooled data on CRISPR/Cas9-mediated gene knockout in human T cells. The currently available prediction tools alone were insufficient to accurately predict the indel percentage in T cells. We used data on the epigenetic profiles of cultured T cells obtained from transposase-accessible chromatin with high-throughput sequencing (ATAC-seq). Combining the epigenetic information with sequence-based prediction tools significantly improved the gene-editing efficiency. We further demonstrate that epigenetically closed regions can be targeted by designing two gRNAs in adjacent regions. Finally, we demonstrate that the gene-editing efficiency of unstimulated T cells can be enhanced through pretreatment with IL-7. These findings enable more efficient gene editing in human T cells.

Percutaneous left ventricular assist devices in refractory cardiac arrest: The role of chest compressions.

Background: Recent studies describe an emerging role for percutaneous left ventricular assist devices such as Impella CP® as rescue therapy for refractory cardiac arrest. We hypothesized that the addition of mechanical chest compressions to percutaneous left ventricular assist device assisted CPR would improve hemodynamics by compressing the right ventricle and augmenting pulmonary blood flow and left ventricular filling. We performed a pilot study to test this hypothesis using a swine model of prolonged cardiac arrest. Methods: Eight Yorkshire swine were anesthetized, intubated, and instrumented for hemodynamic monitoring. They were subjected to untreated ventricular fibrillation for 5.75 (SD 2.90) minutes followed by mechanical chest compressions for a mean of 20.0 (SD 5.0) minutes before initiation of percutaneous left ventricular assist device. After percutaneous left ventricular assist device initiation, mechanical chest compressions was stopped (n = 4) or continued (n = 4). Defibrillation was attempted 4, 8 and 12 minutes after initiating percutaneous left ventricular assist device circulatory support. Results: The percutaneous left ventricular assist device + mechanical chest compressions group had significantly higher percutaneous left ventricular assist device flow prior to return of spontaneous heartbeat at four- and twelve-minutes after percutaneous left ventricular assist device initiation, and significantly higher end tidal CO2 at 4-minutes after percutaneous left ventricular assist device initiation, when compared with the percutaneous left ventricular assist device alone group. Carotid artery flow was not significantly different between the two groups. Conclusion: The addition of mechanical chest compressions to percutaneous left ventricular assist device support during cardiac arrest may generate higher percutaneous left ventricular assist device and carotid artery flow prior to return of spontaneous heartbeat compared to percutaneous left ventricular assist device alone. Further studies are needed to determine if this approach improves other hemodynamic parameters or outcomes after prolonged cardiac arrest.

Effect of percutaneous ventricular assisted device on post-cardiac arrest myocardial dysfunction in swine model with prolonged cardiac arrest.

BACKGROUND: It remains unclear if percutaneous left ventricular assist device (pLVAD) reduces post-cardiac arrest myocardial dysfunction. METHODS: This is a prespecified analysis of a subset of swine that achieved return of spontaneous circulation (ROSC) in a study comparing pLVAD, transient aortic occlusion (AO), or both during cardiopulmonary resuscitation (CPR). Devices were initiated after 24 minutes of ventricular fibrillation cardiac arrest (8 min no-flow and 16 min mechanical CPR). AO was discontinued post-ROSC, and pLVAD support or standard care were continued. Beginning 60 minutes post-ROSC, pLVAD support was weaned to < 1.0 L/min and subsequently removed at 240 minutes. The primary outcome was cardiac index (CI), stroke volume index (SVI), and left ventricular ejection fraction (LVEF) at 240 minutes post-ROSC. Data are shown as mean (standard error). RESULTS: Seventeen swine achieved ROSC without complication and were included in this analysis (pLVAD group, n = 11 and standard care group, n = 6). For the primary outcomes, the pLVAD group had significantly higher CI of 4.2(0.3) vs. 3.1(0.4) L/min/m2 (p = 0.043) and LVEF 60(3) vs. 49(4) % (p = 0.029) at 240 minutes after ROSC when compared with the standard care group, while SVI was not statistically significantly different (32[3] vs. 23[4] mL/min/m2, p = 0.054). During the first 60 minutes post-ROSC, the pLVAD group had significantly higher coronary perfusion pressure, lower LV stroke work index, and total pulmonary resistance index. CONCLUSION: These results suggest that early pLVAD support after ROSC is associated with better recovery myocardial function compared to standard care after prolonged cardiac arrest.

Changes in neurological outcomes of out-of-hospital cardiac arrest during the COVID-19 pandemic in Japan: a population-based nationwide observational study.

Background: There is growing interest in the indirect negative effects of coronavirus disease 2019 (COVID-19) on mortality. We aimed to assess its indirect effect on out-of-hospital cardiac arrest (OHCA) outcomes. Methods: We analysed a prospective nationwide registry of 506,935 patients with OHCA between 2017 and 2020. The primary outcome was favourable neurological outcome (Cerebral Performance Category 1 or 2) at 30 days. The secondary outcomes were public access defibrillation (PAD) and bystander-initiated chest compression. We performed an interrupted time series (ITS) analysis to assess changes in the trends of these outcomes around the declaration of a state of emergency (April 7 - May 25, 2020). We also performed a subgroup analysis stratified by infection spread status. Findings: We identified 21,868 patients with OHCA witnessed by a bystander who had an initial shockable heart rhythm. ITS analysis showed a drastic decline in PAD use (relative risk [RR], 0.60; 95% confidence interval [CI], 0.49-0.72; p < 0.0001) and a reduction in favourable neurological outcomes (RR, 0.79; 95% CI, 0.68-0.91; p = 0.0032) all over Japan after the state of emergency was declared when compared with the equivalent time period in previous years. The decline in favourable neurological outcomes was more pronounced in areas with COVID-19 spread than in areas without spread (RR, 0.70; 95% CI, 0.58-0.86 vs. RR, 0.87; 95% CI, 0.72-1.03; p for effect modification = 0.019). Interpretation: COVID-19 is associated with worse neurological outcomes and less PAD use in patients with OHCA. Funding: None.

Haemodynamic impact of aortic balloon occlusion combined with percutaneous left ventricular assist device during cardiopulmonary resuscitation in a swine model of cardiac arrest.

AIM: To investigate the effect of tandem use of transient balloon occlusion of the descending aorta (AO) and percutaneous left ventricular assist device (pl-VAD) during cardiopulmonary resuscitation in a large animal model of prolonged cardiac arrest. METHODS: Ventricular fibrillation was induced and left untreated for 8 minutes followed by 16 minutes of mechanical CPR (mCPR) in 24 swine, under general anesthesia. Animals were randomized to 3 treatment groups (n = 8 per group): A) pL-VAD (Impella CP®) B) pL-VAD+AO, and C) AO. Impella CP® and the aortic balloon catheter were inserted via the femoral arteries. mCPR was continued during treatment. Defibrillation was attempted 3 times starting at minute 28 and then every 4 minutes. Haemodynamic, cardiac function and blood gas measurements were recorded for up to 4 hours. RESULTS: Coronary perfusion pressure (CoPP) in the pL-VAD+AO Group increased by a mean (SD) of 29.2(13.94) mmHg compared to an increase of 7.1(12.08) and 7.1(5.95) mmHg for groups pL-VAD and AO respectively (p = 0.02). Similarly, cerebral perfusion pressure (CePP) in pL-VAD+AO increased by a mean (SD) of 23.6 (6.11), mmHg compared with 0.97 (9.07) and 6.9 (7.98) mmHg for the other two groups (p < 0.001). The rate of return of spontaneous heartbeat (ROSHB) was 87.5%, 75%, and 100% for pL-VAD+AO, pL-VAD, and AO. CONCLUSION: Combined AO and pL-VAD improved CPR hemodynamics compared to either intervention alone in this swine model of prolonged cardiac arrest.

Therapeutic Effect of Argatroban During Cardiopulmonary Resuscitation and Streptokinase During Extracorporeal Cardiopulmonary Resuscitation in a Porcine Model of Prolonged Cardiac Arrest.

Prolonged cardiac arrest (CA) causes microvascular thrombosis which is a potential barrier to organ reperfusion during extracorporeal cardiopulmonary resuscitation (ECPR). The aim of this study was to test the hypothesis that early intra-arrest anticoagulation during cardiopulmonary resuscitation (CPR) and thrombolytic therapy during ECPR improve recovery of brain and heart function in a porcine model of prolonged out-of-hospital CA. DESIGN: Randomized interventional trial. SETTING: University laboratory. SUBJECTS: Swine. INTERVENTIONS: In a blinded study, 48 swine were subjected to 8 minutes of ventricular fibrillation CA followed by 30 minutes of goal-directed CPR and 8 hours of ECPR. Animals were randomized into four groups (n = 12) and given either placebo (P) or argatroban (ARG; 350 mg/kg) at minute 12 of CA and either placebo (P) or streptokinase (STK, 1.5 MU) at the onset of ECPR. MEASUREMENTS AND MAIN RESULTS: Primary outcomes included recovery of cardiac function measured by cardiac resuscitability score (CRS: range 0-6) and recovery of brain function measured by the recovery of somatosensory-evoked potential (SSEP) cortical response amplitude. There were no significant differences in recovery of cardiac function as measured by CRS between groups (p = 0.16): P + P 2.3 (1.0); ARG + P = 3.4 (2.1); P + STK = 1.6 (2.0); ARG + STK = 2.9 (2.1). There were no significant differences in the maximum recovery of SSEP cortical response relative to baseline between groups (p = 0.73): P + P = 23% (13%); ARG + P = 20% (13%); P + STK = 25% (14%); ARG + STK = 26% (13%). Histologic analysis demonstrated reduced myocardial necrosis and neurodegeneration in the ARG + STK group relative to the P + P group. CONCLUSIONS: In this swine model of prolonged CA treated with ECPR, early intra-arrest anticoagulation during goal-directed CPR and thrombolytic therapy during ECPR did not improve initial recovery of heart and brain function but did reduce histologic evidence of ischemic injury. The impact of this therapeutic strategy on the long-term recovery of cardiovascular and neurological function requires further investigation.

Developing an artificial intelligence-based headache diagnostic model and its utility for non-specialists' diagnostic accuracy.

BACKGROUND: Misdiagnoses of headache disorders are a serious issue. Therefore, we developed an artificial intelligence-based headache diagnosis model using a large questionnaire database in a specialized headache hospital. METHODS: Phase 1: We developed an artificial intelligence model based on a retrospective investigation of 4000 patients (2800 training and 1200 test dataset) diagnosed by headache specialists. Phase 2: The model's efficacy and accuracy were validated. Five non-headache specialists first diagnosed headaches in 50 patients, who were then re-diagnosed using AI. The ground truth was the diagnosis by headache specialists. The diagnostic performance and concordance rates between headache specialists and non-specialists with or without artificial intelligence were evaluated. RESULTS: Phase 1: The model's macro-average accuracy, sensitivity (recall), specificity, precision, and F values were 76.25%, 56.26%, 92.16%, 61.24%, and 56.88%, respectively, for the test dataset. Phase 2: Five non-specialists diagnosed headaches without artificial intelligence with 46% overall accuracy and 0.212 kappa for the ground truth. The statistically improved values with artificial intelligence were 83.20% and 0.678, respectively. Other diagnostic indexes were also improved. CONCLUSIONS: Artificial intelligence improved the non-specialist diagnostic performance. Given the model's limitations based on the data from a single center and the low diagnostic accuracy for secondary headaches, further data collection and validation are needed.

CD83 expression characterizes precursor exhausted T cell population.

T cell exhaustion is a main obstacle against effective cancer immunotherapy. Exhausted T cells include a subpopulation that maintains proliferative capacity, referred to as precursor exhausted T cells (TPEX). While functionally distinct and important for antitumor immunity, TPEX possess some overlapping phenotypic features with the other T-cell subsets within the heterogeneous tumor-infiltrating T-lymphocytes (TIL). Here we explore surface marker profiles unique to TPEX using the tumor models treated by chimeric antigen receptor (CAR)-engineered T cells. We find that CD83 is predominantly expressed in the CCR7+PD1+ intratumoral CAR-T cells compared with the CCR7-PD1+ (terminally differentiated) and CAR-negative (bystander) T cells. The CD83+CCR7+ CAR-T cells exhibit superior antigen-induced proliferation and IL-2 production compared with the CD83- T cells. Moreover, we confirm selective expression of CD83 in the CCR7+PD1+ T-cell population in primary TIL samples. Our findings identify CD83 as a marker to discriminate TPEX from terminally exhausted and bystander TIL.

Aberrant tryptophan metabolism leads to unfavorable outcomes in lenalidomide-treated myeloma patients.

Indoleamine 2,3-dioxygenase 1 (IDO), an enzyme that metabolizes tryptophan (Trp) to kynurenine (Kyn), is an important microenvironmental factor suppressing antitumor immunity. Here, we investigated the clinical impact of aberrant Trp metabolism in patients with multiple myeloma (MM) treated with lenalidomide (Len) and evaluated its effects on T cell immunity ex vivo. Kyn and Trp concentrations were quantified in sera from 72 patients with relapsed or refractory MM prior to the initiation of therapy with Len plus dexamethasone (Ld). Associations of the Kyn/Trp ratio with progression-free survival (PFS) and overall survival (OS) were analyzed. The expressions of IDO in tumor and stromal cells were evaluated during co-culture, and the effects of culture medium containing low Trp and high Kyn concentrations on T cells in the presence of Len were investigated. Patients with high serum Kyn/Trp ratios (≥46.0, n = 22) had significantly shorter PFS and OS than those with low ratios (4.9 vs. 12.6 months, and 15.5 vs. 45.7 months, respectively). MM cells promoted IDO expression in stromal cells during co-culture in both a direct contact and an indirect manner. Incubation in medium with a high Kyn/Trp ratio significantly inhibited T cell cytokine production and upregulated the expression of inhibitory immune receptors. These effects were sustained even in the presence of Len. In conclusion, a high serum Kyn/Trp ratio is associated with poor prognosis in patients with MM. We propose that aberrant Trp metabolism reduces anti-tumor immunity and the efficacy of Len therapy.