In vivo efficacy of decitabine as a natural killer cell-mediated immunotherapy against isocitrate dehydrogenase mutant gliomas.

OBJECTIVE: Isocitrate dehydrogenase (IDH) mutations are found in more than 80% of low-grade gliomas and in the majority of secondary glioblastomas. IDH mutation (IDHmut) leads to aberrant production of an oncogenic metabolite that promotes epigenetic dysregulation by inducing hypermethylation to suppress transcription of various tumor suppressor genes. Hypermethylation in IDHmut gliomas leads to transcriptional repression of NKG2D ligands, especially UL16-binding protein (ULBP)-1 and ULBP-3, and subsequent evasion of natural killer (NK) cell-mediated lysis. The demethylating agent 5-aza-2'deoxycytodine (decitabine [DAC]) is a DNA methyltransferase 1 inhibitor that prevents hypermethylation and is capable of restoring NKG2D ligand expression in IDHmut gliomas to resensitize them to NK cells. Given its capacity for sustained epigenetic reprogramming, the authors hypothesized that DCA would be an effective immunotherapeutic agent in treating IDHmut gliomas in an NK cell-dependent manner by upregulating epigenetically repressed activating NKG2D ligands in IDHmut tumors. In this study, the authors sought to use a glioma stem cell, preclinical animal model to determine the efficacy of DAC in IDHmut and IDH wild-type (IDHwt) tumors, and to characterize whether the activity of DAC in gliomas is dependent on NK cell function. METHODS: Xenograft models of IDHwt and IDHmut gliomas were established in athymic-nude mice. When tumors were grossly visible and palpable, mice were treated with either DCA or dimethylsulfoxide intraperitoneally every 7 days. Tumor sizes were measured every 2 to 3 days. After the animals were euthanized, xenografts were harvested and analyzed for the following: tumor expression of NKG2D ligands, tumor susceptibility to human and murine NK cells, immunohistochemistry for NK infiltration, and tumor-infiltrating lymphocyte characterization. RESULTS: DAC significantly inhibited the growth of IDHmut xenografts in the athymic nude mice. This effect was abrogated with NK cell depletion. Ex vivo analysis of tumor cells from harvested xenografts confirmed that DAC increased NKG2D ligand ULBP-1 and ULBP-3 expressions, and enhanced susceptibility to lysis of both human and murine IDHmut glial cells with corresponding NK cells. Immunohistochemical analysis of the xenografts indicated that DCA-treated IDHmut gliomas had a greater level of NK infiltration into the tumor compared with the negative control. Finally, DCA radically altered the tumor-infiltrating lymphocyte landscape of IDHmut glioma xenografts by increasing NK cells, dendritic cells, and M1 macrophages, while decreasing suppressive monocyte infiltration. CONCLUSIONS: DCA displayed novel immunotherapeutic functions in IDHmut gliomas. This effect was critically dependent on NK cells. Additionally, DCA significantly altered the tumor immune landscape in IDHmut gliomas from suppressive to proinflammatory.

Cerebral Infarction Observed on Brain MRI in Unconscious Out-of-Hospital Cardiac Arrest Survivors: A Pilot Study.

BACKGROUND: Cumulative evidence regarding the use of brain magnetic resonance imaging (MRI) for predicting prognosis of unconscious out-of-hospital cardiac arrest (OHCA) survivors treated with targeted temperature management (TTM) is available. Theoretically, these patients are at a high risk of developing cerebral infarction. However, there is a paucity of reports regarding the characteristics of cerebral infarction in this population. Thus, we performed a pilot study to identify the characteristics and risk factors of cerebral infarction and to evaluate whether this infarction is associated with clinical outcomes. METHODS: A single-center, retrospective, registry-based cohort study was conducted at Severance Hospital, a tertiary center. Unconscious OHCA survivors were registered and treated with TTM between September 2011 and December 2015. We included patients who underwent brain MRI in the first week after the return of spontaneous circulation. We excluded patients who underwent any endovascular interventions to focus on "procedure-unrelated" cerebral infarctions. We assessed hypoxic-ischemic encephalopathy (HIE) and procedure-unrelated cerebral infarction separately on MRI. Patients were categorized into the following groups based on MRI findings: HIE (-)/infarction (-), infarction-only, and HIE (+) groups. Conventional vascular risk factors showing p < 0.05 in univariate analyses were entered into multivariate logistic regression. We also evaluated if the presence of this procedure-unrelated cerebral infarction lesion or HIE was associated with a poor clinical outcome at discharge, defined as a cerebral performance category of 3-5. RESULTS: Among 71 unconscious OHCA survivors who completed TTM, underwent MRI, and who did not undergo endovascular interventions, 14 (19.7%) patients had procedure-unrelated cerebral infarction based on MRI. Advancing age [odds ratio (OR) 1.11] and atrial fibrillation (OR 5.78) were independently associated with the occurrence of procedure-unrelated cerebral infarction (both p < 0.05). There were more patients with poor clinical outcomes at discharge in the HIE (+) group (88.1%) than in the infarction-only (30.0%) or HIE (-)/infarction (-) group (15.8%) (p < 0.001). HIE (+) (OR 38.69, p < 0.001) was independently associated with poor clinical outcomes at discharge, whereas infarction-only was not (p > 0.05), compared to HIE (-)/infarction (-). CONCLUSIONS: In this pilot study, procedure-unrelated cerebral infarction was noted in approximately one-fifth of unconscious OHCA survivors who were treated with TTM and underwent MRI. Older age and atrial fibrillation might be associated with the occurrence of procedure-unrelated cerebral infarction, and cerebral infarction was not considered to be associated with clinical outcomes at discharge. Considering that the strict exclusion criteria in this pilot study resulted in a highly selected sample with a relatively small size, further work is needed to verify our findings.

Dose Optimization of Cefpirome Based on Population Pharmacokinetics and Target Attainment during Extracorporeal Membrane Oxygenation.

To obtain the optimal dosage regimen in patients receiving extracorporeal membrane oxygenation (ECMO), we developed a population pharmacokinetics model for cefpirome and performed pharmacodynamic analyses. This prospective study included 15 patients treated with cefpirome during ECMO. Blood samples were collected during ECMO (ECMO-ON) and after ECMO (ECMO-OFF) at predose and 0.5 to 1, 2 to 3, 4 to 6, 8 to 10, and 12 h after cefpirome administration. The population pharmacokinetic model was developed using nonlinear mixed effects modeling and stepwise covariate modeling. Monte Carlo simulation was used to assess the probability of target attainment (PTA) and cumulative fraction of response (CFR) according to the MIC distribution. Cefpirome pharmacokinetics were best described by a two-compartment model. Covariate analysis indicated that serum creatinine concentration (SCr) was negatively correlated with clearance, and the presence of ECMO increased clearance and the central volume of distribution. The simulations showed that patients with low SCr during ECMO-ON had lower PTA than patients with high SCr during ECMO-OFF; so, a higher dosage of cefpirome was required. Cefpirome of 2 g every 8 h for intravenous bolus injection or 2 g every 12 h for extended infusion over 4 h was recommended with normal kidney function receiving ECMO. We established a population pharmacokinetic model for cefpirome in patients with ECMO, and appropriate cefpirome dosage regimens were recommended. The impact of ECMO could be due to the change in patient status on consideration of the small population and uncertainty in covariate relationships. Dose optimization of cefpirome may improve treatment success and survival in patients receiving ECMO. (This study has been registered at ClinicalTrials.gov under identifier NCT02581280.).

Population pharmacokinetics of intravenous sufentanil in critically ill patients supported with extracorporeal membrane oxygenation therapy.

BACKGROUND: Sufentanil is commonly used for analgesia and sedation during extracorporeal membrane oxygenation (ECMO). Both ECMO and the pathophysiological changes derived from critical illness have significant effects on the pharmacokinetics (PK) of drugs, yet reports of ECMO and sufentanil PK are scarce. Here, we aimed to develop a population PK model of sufentanil in ECMO patients and to suggest dosing recommendations. METHODS: This prospective cohort PK study included 20 patients who received sufentanil during venoarterial ECMO (VA-ECMO). Blood samples were collected for 96 h during infusion and 72 h after cessation of sufentanil. A population PK model was developed using nonlinear mixed effects modelling. Monte Carlo simulations were performed using the final PK parameters with two typical doses. RESULTS: A two-compartment model best described the PK of sufentanil. In our final model, increased volume of distribution and decreased values for clearance were reported compared with previous PK data from non-ECMO patients. Covariate analysis showed that body temperature and total plasma protein level correlated positively with systemic clearance (CL) and peripheral volume of distribution (V2), respectively, and improved the model. The parameter estimates of the final model were as follows: CL = 37.8 × EXP (0.207 × (temperature - 36.9)) L h-1, central volume of distribution (V1) = 229 L, V2 = 1640 × (total plasma protein/4.5)2.46 L, and intercompartmental clearance (Q) = 41 L h-1. Based on Monte Carlo simulation results, an infusion of 17.5 µg h-1 seems to reach target sufentanil concentration (0.3-0.6 µg L-1) in most ECMO patients except hypothermic patients (33 °C). In hypothermic patients, over-sedation, which could induce respiratory depression, needs to be monitored especially when their total plasma protein level is low. CONCLUSIONS: This is the first report on a population PK model of sufentanil in ECMO patients. Our results suggest that close monitoring of the body temperature and total plasma protein level is crucial in ECMO patients who receive sufentanil to provide effective analgesia and sedation and promote recovery. TRIAL REGISTRATION: Clinicaltrials.gov NCT02581280 , December 1st, 2014.

Long-term outcome and recurrence factors after percutaneous cholecystostomy as a definitive treatment for acute cholecystitis.

BACKGROUND AND AIM: Percutaneous cholecystostomy (PC) has been frequently used as an alternative treatment for acute cholecystitis in seriously ill patients unfit for surgery. The aim of this study was to investigate the recurrence rate and risk factors of recurrence. METHODS: Medical records of 102 patients who were followed up for more than 1 year after PC tube removal among 716 patients who underwent PC for acute cholecystitis treatment were retrospectively analyzed. RESULTS: The recurrence rate of acute cholecystitis after PC tube removal was 20.6% (21/102), and the mean time to recur was 660 days. Underlying cancer (odds ratio [OR]: 3.369; 95% confidence interval [CI]: 1.006-11.282; P = 0.0489), PC duration shorter than 44 days (OR: 5.596; 95% CI: 1.35-23.201; P = 0.0176), and the presence of common bile duct stone in initial imaging studies (OR: 24.393; 95% CI: 2.696-220.746; P = 0.0045) were positively correlated with recurrence. Tubogram before PC tube removal did not significantly lower the recurrence. However, PC tube clamping for several days significantly lowered the recurrence (OR: 0.108; 95% CI: 0.015-0.794; P = 0.0288). Fifty-nine (57.8%) had acalculous cholecystitis. Calculous cholecystitis was negatively correlated with recurrence (OR: 0.267; 95% CI: 0.074-0.967; P = 0.0444). Receiver operating characteristic curve of the prediction model for recurrence verified its accuracy (area under the curve: 0.8475). CONCLUSION: We should try to keep PC more than 6 weeks and clamp for 1-2 weeks before removal. For those with the presence of common bile duct stones, calculous cholecystitis, and underlying malignancy, we should keep PC for longer duration and carefully observe symptoms and signs of recurrence.

Brachiocephalic Vein Aneurysm Treated with Surgery: A Case Report.

Brachiocephalic vein aneurysm is an extremely rare condition of unknown origin. It may be asymptomatic, presenting as an incidental finding or as a result of complications it causes. We report a case of a 54-year-old man who was asymptomatic and diagnosed with an isolated saccular aneurysm of the left brachiocephalic vein using contrast-enhanced computed tomography. The patient underwent aneurysmectomy through a median sternotomy with no requirement for a vascular graft or cardiopulmonary bypass. The patient had an uneventful postoperative course and remained well two months after the surgery.

Surgery following Extracorporeal Cardiopulmonary Resuscitation in a Patient with an Extracardiac Rupture of Valsalva Sinus Aneurysm.

The rupture of sinus of Valsalva aneurysm (SVA) into the pericardial cavity is extremely rare and fatal. A 52-year-old man presented with an abrupt onset of chest pain and dizziness. An echocardiography and a computed tomographic angiography revealed a giant aneurysm of the noncoronary sinus (NCS) (maximum, 70 mm) and pericardial effusion in favor of tamponade with a moderate degree of aortic insufficiency. On the way to the operating room, he suffered cardiac arrest, and extracorporeal cardiopulmonary resuscitation (ECPR) was initiated immediately. While he was prepared for surgery, the patient was supported by extracorporeal life support (ECLS) until cardiopulmonary bypass (CPB) was initiated. The sinus defect was reconstructed using a Dacron patch, followed by resection of the aneurysm. ECLS and CPB were discontinued successfully in the operating room. This study reports a case of an extracardiac rupture of SVA and the successful completion of surgery following ECPR.

Population Pharmacokinetics and Dose Optimization of Teicoplanin during Venoarterial Extracorporeal Membrane Oxygenation.

The pharmacokinetics (PK) of drugs are known to be significantly altered in patients receiving extracorporeal membrane oxygenation (ECMO). However, clinical studies of the PK of drugs administered during ECMO are scarce, and the proper dosing adjustment has yet to be established. We developed a population PK model for teicoplanin, investigated covariates influencing teicoplanin exposure, and suggested an optimal dosing regimen for ECMO patients. Samples for PK analysis were collected from 10 adult patients, and a population PK analysis and simulations were performed to identify an optimal teicoplanin dose needed to provide a >50% probability of target attainment at 72 h using a trough concentration target of >10 µg/ml for mild to moderate infections and a trough concentration target of >15 µg/ml for severe infections. Teicoplanin was well described by a two-compartment PK model with first-order elimination. The presence of ECMO was associated with a lower central volume of distribution, and continuous renal replacement therapy (CRRT) was associated with a higher peripheral volume of distribution. For mild to moderate infections, an optimal dose was a loading dose (LD) of 600 mg and a maintenance dose (MD) of 400 mg for ECMO patients not receiving CRRT and an LD of 800 mg and an MD of 600 mg for those receiving CRRT. For severe infections, an optimal dose was an LD of 1,000 mg and an MD of 800 mg for ECMO patients not receiving CRRT and an LD of 1,200 mg and an MD of 1,000 mg for those receiving CRRT. In conclusion, doses higher than the standard doses are needed to achieve fast and appropriate teicoplanin exposure during ECMO. (This study has been registered at ClinicalTrials.gov under identifier NCT02581280.).

Transient New-Onset Atrial Fibrillation Is Associated With Poor Clinical Outcomes in Patients With Acute Myocardial Infarction.

BACKGROUND: Atrial fibrillation (AF) is considered to be associated with poor clinical outcomes in patients with acute myocardial infarction (AMI). However, it remains uncertain whether transient new-onset AF (NOAF) during AMI has a subsequent increased risk of poor clinical outcomes. METHODS AND RESULTS: Transient NOAF was defined as AF that developed during AMI without a prior history and not documented for 1 month after discharge. The primary endpoints were major adverse cardiac events (MACE) and all-cause death. We enrolled 2,105 consecutive AMI patients. Overall, AF was observed in 209 (9.9%) and transient NOAF occurred in 102 (4.8%) among 150 patients (7.1%) with NOAF. The transient NOAF group showed higher 1-month (21.8 vs. 7.0%, P<0.001), 2-year (37.8 vs. 20.7%, P<0.001), and 5-year MACE rates (51.8 vs. 28.0%, P<0.001) than the group without AF. In-hospital (16.7 vs. 5.2%, P<0.001), 1-month (17.9 vs. 5.7%, P<0.001), 2-year (30.0 vs. 11.6%, P<0.001), and 5-year mortality rates (36.9 vs. 14.0%, P<0.001) were also higher in patients with transient NOAF. Transient NOAF was a significant independent predictor of both MACE (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.10-2.18, P=0.013) and death (HR 1.87, 95% CI 1.22-2.85, P=0.004). CONCLUSIONS: Transient NOAF was associated with the poorer clinical outcomes and was an important independent predictor of MACE and death in AMI patients. (Circ J 2016; 80: 1615-1623).

Complex fractionated atrial electrograms related to left atrial wall thickness.

INTRODUCTION: The mechanism of complex fractionated atrial electrogram (CFAE) in patients with atrial fibrillation (AF) remains controversial. This study investigated the relationship between CFAE and left atrial (LA) wall thickness. METHODS AND RESULTS: LA muscular wall thickness (excluding fat) was measured by cardiac computed tomography in 31 patients with AF (12 paroxysmal, 19 persistent) prior to catheter ablation procedures. Measurements were performed at 31 distinct LA locations: 3 at roof, 3 at floor, 9 at anterior wall, 9 at posterior wall, 3 at lateral wall, 3 at septum, and 1 at base of the anterior appendage. The range of LA wall thickness (LAWT) varied widely (average 2.4 ± 0.4 mm, range 1.5-3.1 mm) between patients. In addition, there were significant regional differences in LAWT. Each patient had an average of 7.3 ± 3.5 CFAE sites. The LA wall was thicker at CFAE sites (227 sites, 3.0 ± 1.0 mm) than at non-CFAE sites (734 sites, 2.2 ± 0.9 mm, P < 0.001). In 23 of 31 (74%) patients, the LA wall was thicker at CFAE area than at non-CFAE area. There was no difference in LAWT between sites where CFAE vanished and those where CFAE persisted after pulmonary vein isolation (PVI) among sites with CFAE before PVI. The LAWT > 2.5 mm predicted CFAE with a sensitivity of 70% and a specificity of 70%. CONCLUSION: The LAWT correlates well with CFAE areas, suggesting that one of the mechanisms of CFAE might be related to LAWT.

An electrocardiography algorithm combined with clinical features could localize the origins of focal atrial tachycardias in adjacent structures.

AIMS: It is difficult to differentiate the origins of focal atrial tachycardias (ATs) in adjacent structures by electrocardiography (ECG) alone. The aim of this study was to evaluate whether the clinical features of these ATs may help differentiate their origins. METHODS AND RESULTS: One hundred and ninety-four patients (mean age, 43.5 ± 17.9 years; male, 53.6%) who underwent electrophysiological study for focal AT were included. We evaluated accuracy in differentiating the origin of AT by using ECG alone as well as with the addition of the clinical features. Electrocardiographs of ATs originating from the left superior pulmonary vein (LSPV, n = 24) vs. the left atrial appendage (LAA, n = 6), and from the right superior pulmonary vein (RSPV, n = 14) vs. the superior vena cava (SVC, n = 8) showed similar patterns. However, while no ATs from the LAA were found to be related to paroxysmal atrial fibrillation, 22 out of 24 ATs from the LSPV were associated with this condition. After localizing AT by using ECG, this clinical feature helped differentiate the ATs from the LSPV vs. the LAA with 93% accuracy. Moreover, while an on-and-off tachycardia (initiated and terminated more than 10 times per day) was observed in 4 of 8 ATs from the SVC, this pattern was observed in 13 of 14 ATs from the RSPV. After localizing the ATs by using ECG, on-and-off tachycardia helped differentiate the ATs from the RSPV vs. the SVC with 82% accuracy. CONCLUSION: The clinical features and Holter monitoring can give additional information for differentiating the focal ATs originating from the adjacent structures.

Temporal Muscle Thickness and Sarcopenia Components in Healthy Adults, Validated through Allgeun Diagnostic Tool.

Sarcopenia, characterized by progressive muscle loss and functional decline, poses significant risks, including falls, impaired daily activities, and increased mortality. We developed Allgeun, a novel device that measures handgrip strength, muscle mass, and physical performance. This study aimed to investigate whether temporal muscle thickness (TMT) could be used as a sarcopenia marker and to evaluate the usability of Allgeun. This prospective study enrolled 28 participants without medical or neurological disorders. They underwent three-dimensional T1-weighted imaging using a 3 Tesla magnetic resonance imaging scanner. TMT was measured based on T1-weighted images by a board-certified neuroradiologist. Allgeun was used to measure the following three key components of sarcopenia: muscle strength (handgrip strength), muscle mass (calf and thigh circumference), and physical performance (five times the chair stand test). Correlation analysis was conducted between TMT and the results of the handgrip strength, calf and thigh circumferences, and chair stand tests. There were moderate positive correlations between TMT and calf circumference (r = 0.413, p = 0.029), thigh circumference (r = 0.486, p = 0.008), and handgrip strength (r = 0.444, p = 0.018). However, no significant correlation was observed between TMT and physical performance (r = -0.000, p = 0.998). Our findings underscore TMT's potential as an indicator of sarcopenia, particularly regarding muscle mass and strength. Additionally, we demonstrated that the new device, Allgeun, is useful for screening and diagnosing the severity of sarcopenia.

Chiari Type I Revision Decompressive Surgery Indications and Operative Technique: Experience in a Large Adult Cohort.

BACKGROUND: Chiari malformation is characterized by inferior displacement of the cerebellar tonsils through the foramen magnum, frequently resulting in strain related headaches, and motor/sensory dysfunction. Chiari decompression technique varies significantly, possibly contributing to frequent revisions. We reviewed revision Chiari decompressions at our institution to determine the primary indications for revision and outcomes after revision. METHODS: We retrospectively reviewed patients who underwent revision of Chiari decompression at our institution from 2005 to 2020. Demographics, indications for revision surgery, operative techniques, imaging findings, and preoperative/postoperative symptoms were collected. χ2 test was performed to determine statistical significance using a P < 0.05. Independent predictors of operative outcomes were identified. RESULTS: A total of 46 patients (91% females, mean age 38.8 years) were included for analysis. The median time to revision surgery was 69.1 months (range 0-364 months) with headache (n = 37, 80%) being the most commonly recurring symptom. Large craniectomy (n = 28, 61%) was the most frequent indication for revision surgery. Thirty-two (70%) patients underwent cranioplasty, 20 (43%) required duraplasty, 15 (33%) required arachnoid dissection, and 15 (33%) required tonsillar reduction during revision surgery. Postrevision follow-up (at 8.9 ± 5.2 months average, range 1-18 months), revealed an average reduction in all Chiari-related symptoms relative to symptoms before the revision. CONCLUSIONS: The most common indication for revision Chiari decompression was a large craniectomy resulting in cerebellar ptosis. We found that tonsillar reduction paired with modest craniectomy achieved near-complete resolution of symptoms with minimal complications. For patients with recurrent or persistent sequelae of Chiari malformation after decompression, revision may reduce symptom severity.

Arterial Bypass in the Treatment of Complex Middle Cerebral Artery Aneurysms: Lessons Learned from Forty Patients.

OBJECTIVE: Complex middle cerebral artery (MCA) aneurysms incorporating parent or branching vessels are often not amenable to standard microsurgical clipping or endovascular embolization treatments. We aim to discuss the treatment of such aneurysms via a combination of surgical revascularization and aneurysm exclusion based on our institutional experience. METHODS: Thirty-four patients with complex MCA aneurysms were treated with bypass and aneurysm occlusion, 5 with surgical clipping or wrapping only, and 1 with aneurysm excision and primary reanastomosis. Bypasses included superficial temporal artery (STA)-MCA, double-barrel STA-MCA, occipital artery-MCA, and external carotid artery-MCA. After bypass, aneurysms were treated by surgical clipping, Hunterian ligation, trapping, or coil embolization. RESULTS: The average age at diagnosis was 46 years. Of the aneurysms, 67% were large and most involved the MCA bifurcation. Most bypasses performed were STA-MCA bypasses, 12 of which were double-barrel. There were 2 wound-healing complications. All but 2 of the aneurysms treated showed complete occlusion at the last follow-up. There were 3 hemorrhagic complications, 3 graft thromboses, and 4 ischemic insults. The mean follow-up was 73 months. Of patients, 83% reported stable or improved symptoms from presentation and 73% reported a functional status (Glasgow Outcome Scale score 4 or 5) at the latest available follow-up. CONCLUSIONS: Cerebral revascularization by bypass followed by aneurysm or parent artery occlusion is an effective treatment option for complex MCA aneurysms that cannot be safely treated by standard microsurgical or endovascular techniques. Double-barrel bypass consisting of 2 STA branches to 2 MCA branches yields adequate flow replacement in most cases.

All-trans retinoic acid induces durable tumor immunity in IDH-mutant gliomas by rescuing transcriptional repression of the CRBP1-retinoic acid axis.

Diffuse gliomas are epigenetically dysregulated, immunologically cold, and fatal tumors characterized by mutations in isocitrate dehydrogenase (IDH). Although IDH mutations yield a uniquely immunosuppressive tumor microenvironment, the regulatory mechanisms that drive the immune landscape of IDH mutant (IDHm) gliomas remain unknown. Here, we reveal that transcriptional repression of retinoic acid (RA) pathway signaling impairs both innate and adaptive immune surveillance in IDHm glioma through epigenetic silencing of retinol binding protein 1 (RBP1) and induces a profound anti-inflammatory landscape marked by loss of inflammatory cell states and infiltration of suppressive myeloid phenotypes. Restorative retinoic acid therapy in murine glioma models promotes clonal CD4 + T cell expansion and induces tumor regression in IDHm, but not IDH wildtype (IDHwt), gliomas. Our findings provide a mechanistic rationale for RA immunotherapy in IDHm glioma and is the basis for an ongoing investigator-initiated, single-center clinical trial investigating all-trans retinoic acid (ATRA) in recurrent IDHm human subjects.

Left ventricular diastolic function is closely associated with mechanical function of the left atrium in patients with paroxysmal atrial fibrillation.

BACKGROUND: Left ventricular (LV) diastolic dysfunction may be a mechanism of left atrial (LA) electroanatomical remodeling in atrial fibrillation (AF). We evaluated the association between LV diastolic function and LA mechanical function in non-valvular paroxysmal AF (PAF). METHODS AND RESULTS: In 286 patients with PAF (males 73%, 57 ± 11 years), LA size, indexed LA volume, LV diastolic function, and LA appendage flow velocity (LAA-FV) in sinus rhythm were measured using transthoracic echocardiography, transesophageal echocardiography and cardiac computed tomography. The LA voltage map was obtained using NavX contact mapping. Patients with impaired LA mechanical function (LAA-FV <58 cm/s, n=142) showed a higher E/Em ratio (10.3 vs. 9.2, P=0.034) and lower Em velocity (6.8 vs. 7.7 cm/s, P=0.004) than those with preserved function (LAA-FV ≥ 58 cm/s, n=144). The patient population displayed weak correlations of E/Em with LAA-FV (r=-0.19, P=0.003) and LA voltage (r=-0.23, P=0.004), but more significant association of E/Em and LAA-FV (r=-0.39, P<0.001) for age ≥ 55 years and LA diameter ≥ 40 mm. E/Em was an independent predictor of LAA mechanical function (ß=-0.20, P=0.013) even after age, sex, LA size and comorbidities were controlled for. CONCLUSIONS: In patients with non-valvular PAF, LA mechanical function is closely related to the degree of LA remodeling and LV diastolic function. Impaired LV diastolic function significantly contributes to LA electoanatomical remodeling in older patients with a larger LA.

Fate of preoperative atrial fibrillation after correction of atrial septal defect.

BACKGROUND: Atrial fibrillation (AF) is common among adult patients with an atrial septal defect (ASD). Catheter ablation or the Maze procedure can be considered for AF before or concurrently with ASD closure. However, the fate of preoperative AF is not well established. This study examined the postoperative course of patients with AF before undergoing ASD correction. METHODS AND RESULTS: The 471 patients (131 men, 42 ± 14 years) underwent transcatheter closure (n=237, 50%) or surgical repair (n=234, 50%) of an ASD. ECG and Holter monitoring were used to document preoperative and postoperative AF. Forty patients had AF before transcatheter closure (n=10) or surgical repair (n=30) of the ASD. During the follow-up period of 44 ± 28 months, excluding 15 patients who had undergone surgical repair with the Maze procedure, sinus rhythm (SR) was maintained in 7 (88%) of 8 patients with paroxysmal AF. However, only 3 (18%) of 17 patients with persistent AF maintained SR. Among the 15 patients treated with the Maze procedure, 12 (80%) maintained SR. CONCLUSIONS: Hemodynamic correction of ASD was effective in conversion to SR in most patients with preoperative paroxysmal AF. However, the Maze procedure or transcatheter ablation before ASD correction needs to be considered for the treatment of AF in patients with persistent AF.

Prolonged atrial effective refractory periods in atrial fibrillation patients associated with structural heart disease or sinus node dysfunction compared with lone atrial fibrillation.

BACKGROUNDS: Atrial fibrillation (AF) is commonly associated with structural heart disease (SHD) or sinus node dysfunction (SND). We hypothesized that regional atrial effective refractory period (ERP) is different in patients with SHD/SND from lone AF. METHODS: We included 648 patients with AF (age, 56.0 ± 11.0 years; male, 77.3%; paroxysmal AF [PAF], 67.9%; persistent AF [PeAF], 32.1%) who underwent radiofrequency catheter ablation (RFCA), and compared the clinical characteristics in patients with SHD (n = 132) versus without SHD (n = 516) and those with SND (n = 74) versus without SND (n = 574). ERPs were measured at the high and low right atrium, proximal, and distal coronary sinus. RESULTS: (1) Patients with SHD had older age (P < 0.001), greater left atrial (LA) volume (P < 0.001), LA pressure (P = 0.002), and plasma proatrial natriuretic peptide (P = 0.005) than patients without SHD. (2) Patients with SND were older (P = 0.004), more likely female (P = 0.004), and had lower body weight (P < 0.001) and higher E/E' (P < 0.001) than those without SND. (3) The mean atrial ERP was significantly shorter in patients with PeAF than those with PAF (P < 0.001). The mean ERP was significantly longer in patients with AF with SHD/SND than those with lone AF (P = 0.006). (4) The clinical outcomes of RFCA were not significantly different between SHD/SND and lone AF for 14.8 ± 8.5 months of follow-up period. CONCLUSION: The mean atrial ERP was shorter in patients with PeAF than those with PAF due to electrical remodeling. In contrast, AF patients with SHD/SND showed a more prolonged mean atrial ERP than those with lone AF, associated with LA enlargement or left ventricular diastolic dysfunction.

Perirenal Fat and Kidney Function Deterioration in Patients With Acute Decompensated Heart Failure.

Background and Objectives: The thick perirenal fat pad can induce high intracapsular pressure and cause compression of the renal vasculature and resultant congestive nephropathy. The current study investigated the association of perirenal fat thickness with kidney dysfunction in patients with acute decompensated heart failure (ADHF). Methods: Data from 266 patients hospitalized with ADHF were analyzed. Patients were divided into two groups according to the glomerular filtration rate (GFR) at admission (preserved kidney function [GFR ≥60 mL/min/1.73 m2] and reduced kidney function [GFR <60 mL/min/1.73 m2] groups). Right and left posterior perirenal fat thicknesses were measured using computed tomography, and their average values were calculated. Associated factors with reduced kidney function was assessed by logistic regression model, presenting with odds ratio (OR) and confidence interval (CI). Results: Increasing age (OR, 1.08; 95% CI, 1.04-1.12; p<0.001), diabetes mellitus (OR, 2.46; 95% CI, 1.18-5.12; p<0.017), increased log N-terminal pro-B-type natriuretic peptide (NT-proBNP) (OR, 1.82; 95% CI, 1.32-2.52; p<0.001), and increased average perirenal fat thickness (OR, 1.11; 95% CI, 1.06-1.16; p<0.001) were independently associated with reduced kidney function. In the subgroup analyses, patients over 70 years old, the ratio of mitral-to-mitral annular velocity >15, elevated log NT-proBNP had a significantly higher association with increased perirenal fat thickness with reduced kidney function. Conclusions: Thick perirenal fat pads were independently associated with kidney function deterioration in patients hospitalized with ADHF.

Retraction: Serological Predictors for the Recurrence of Atrial Fibrillation After Electrical Cardioversion.

This corrects the article on p.185 in vol.40, PMID: 20421959.