The effect of off-label use of reduced-dose direct oral anticoagulants therapy in the treatment of pulmonary embolism comparable to standard-dose therapy.

Direct oral anticoagulants (DOACs) have been shown to be effective and safe in preventing pulmonary embolism recurrence. In this single-center retrospective observational study, we aimed to evaluate the efficacy and safety of reduced-dose DOACs in 86 consecutive patients with acute pulmonary embolism. Patients were divided into standard-dose and reduced-dose DOACs groups. Initial clot volume did not significantly differ between the two groups (standard-dose DOACs vs. reduced-dose DOACs, 18.8 [Q1-Q3 7.3-30.8] mL vs. 10.0 [Q1-Q3 3.2-27.9] mL, p = 0.1). Follow-up computed tomography (CT) within 30 days showed a higher rate of clot volume reduction or disappearance in the standard-dose group compared to the reduced-dose group (standard-dose DOACs vs. reduced-dose DOACs, 81.6% vs. 53.9%, p = 0.02). However, at the final follow-up CT, there was no significant difference in clot volume change between the two groups (standard-dose DOACs vs. reduced-dose DOACs, 91.5% vs. 82.0%, p = 0.19). Major bleeding occurred in two patients in the standard-dose group (4.3%) and three patients in the reduced-dose DOACs group (7.7%) (p = 0.5). In conclusion, while standard-dose DOACs demonstrated superior efficacy in early clot reduction, reduced doses of apixaban and edoxaban showed comparable efficacy and safety profiles in long-term treatment of acute pulmonary embolism in certain patients.

Effect of valproic acid on the formation and migration of cranial neural crest cells at the early developmental stages in rat embryos.

Cranial neural crest cells (NCCs) are critical for craniofacial development. The administration of valproic acid (VPA) to pregnant females causes craniofacial malformations in offspring. However, the in vivo influence of VPA on mammalian cranial NCCs remains unclear. In this study, we aimed to elucidate the developmental stage-specific effect of VPA on cranial NCCs through the administration of a single dose of VPA to pregnant rat females immediately prior to the formation of the cranial neural crest (NC). We performed whole-mount immunohistochemistry or in situ hybridization to examine localization changes of gene transcripts associated with the epithelial-mesenchymal transition of the cranial NC (i.e., cranial NCC formation) and cranial NCC migration. The results showed that Hoxa2 mRNA was abnormally detected and Sox9 mRNA expression was decreased in the midbrain-rhombomere (R) 1/2 NC, which forms cranial NCCs that migrate to the frontonasal mass (FNM) and branchial arch (BA) 1, through VPA administration, thus reducing the formation of SNAI2-positive NCCs. Hoxa2-positive NCCs were detected normally in BA2 and abnormally in FNM and BA1, which are normally Hox-free, implying VPA-induced abnormal cranial NCC migration. In vitro verification experiments using the whole embryo culture system revealed that midbrain-R4 NCC migration was abnormal. These results indicate that VPA reduces the formation/delamination of the midbrain-R1/2 NCCs in a developmental stage-specific manner and subsequently causes the abnormal migration of R4 NCCs, which suggests that the abnormal formation and migration of cranial NCCs contribute to the inhibition of axonal elongation in the trigeminal nerve and a reduction in head size.

Radiofrequency Ablation of Re-entrant Atrial Tachycardia Originating from the Superior Vena Cava with a High-resolution, 3-dimensional Mapping System.

An 80-year-old man with no previous history of catheter ablation or cardiac surgery underwent catheter ablation for atrial tachycardia (AT). We suspected that the mechanism causing AT was re-entry indicated by the entrainment phenomenon during AT and through activation mapping with a 3-dimensional mapping system (EnSite™ X EP system; Abbott, Chicago, IL, USA). We used a multipolar catheter (Advisor™ HD Grid Mapping Catheter; Abbott) inserted into the superior vena cava (SVC) to accomplish activation mapping. The AT circuit was localized inside the SVC with a fractionated potential recorded on its right lateral wall. A similar fractionated potential was observed in the surrounding area. These areas functioned as the critical isthmus of the AT. Radiofrequency (RF) catheter ablation at these sites eliminated the tachycardia. After RF delivery, no tachycardia was induced by programmed stimulation, even during isoproterenol infusion. Consequently, there was no recurrence of tachycardia even after catheter ablation.

Low-dose gemcitabine plus nab-paclitaxel versus standard-dose gemcitabine plus nab-paclitaxel in elderly patients with metastatic pancreatic cancer: A randomized Phase II trial.

Background and Aim: A multicenter, open-label randomized Phase II trial was conducted to determine whether low-dose gemcitabine plus nab-paclitaxel (GnP) could improve tolerability and show equivalent efficacy to the standard-dose GnP for elderly patients with metastatic pancreatic cancer. Methods: Consecutive patients aged ≥65 years with metastatic pancreatic cancer who presented at one of four Japanese referral centers between November 2016 and January 2021 were enrolled. The 60 patients were randomly assigned to low- or standard-dose groups with a 1:1 ratio. Patients in the low-dose GnP group received gemcitabine at a dose of 250 mg/m2 and nab-paclitaxel at 125 mg/m2. Results: Low-dose GnP significantly decreased the rate of cases requiring dose reduction (16.7% vs 63.3%). The response rate (36.7% vs 33.3%) and progression-free survival (7.3 vs 8 months) were comparable between the low- and standard-dose groups as determined by independent review. The difference in the median overall survival between the two groups was not significant (7.9 vs 12 months). The proportion of patients with hematologic and non-hematologic treatment-related adverse events was comparable between the two groups. Conclusion: Low-dose GnP had an equivalent efficacy to conventional therapy; however, it did not reduce adverse events.

Histopathological characteristics of the arrhythmogenic right ventricular cardiomyopathy presenting the electrocardiographic characteristics with Brugada syndrome.

INTRODUCTION: The histopathological characteristics of the overlapping disease states of Brugada syndrome (BrS) and arrhythmogenic right ventricular cardiomyopathy (ARVC) have not been fully elucidated. METHODS: A 71-year-old man showed coved-type ST-segment elevation with the right precordial leads, and the echocardiography demonstrated right ventricular (RV) dilatation. After 11 months, he died of a polymorphic VT storm. RESULTS: The pathological tissue demonstrated fibrofatty degeneration in the free wall of the RV outflow tract based on the heart autopsy. CONCLUSION: The overlapping disease states of BrS and ARVC showed histopathological characteristics consistent with ARVC.

The safety and efficacy of Ringer's solution loading with rectal diclofenac for prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: The RESOLUTION-PEP study.

Objectives: We evaluated the safety and efficacy of aggressive hydration with rectal non-steroidal anti-inflammatory drugs for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). Methods: This prospective, single-arm, multicenter trial was conducted at 12 institutions between October 2020 and August 2021. We enrolled 231 patients who had intact papillae and were scheduled to undergo ERCP. All patients were administered rectal diclofenac before ERCP. They received aggressive hydration with intravenous lactated Ringer's solution in an initial bolus of 5 ml/kg at the start of ERCP, followed by 3 ml/kg/h for 8 h after the procedure. The primary outcome was the occurrence of PEP. Secondary outcomes included PEP severity, hyperamylasemia, and adverse events. Results: The mean age of the patients was 68.8 ± 13.7 years, and 81 patients (35.1%) were 75 years or older. Thirteen patients developed PEP (5.6%, 95% confidence interval 3.0%-9.4%). There were 11 cases (4.8%) of mild pancreatitis and two cases (0.9%) of severe pancreatitis. Forty-five patients (19.5%) developed hyperamylasemia and one patient developed non-severe peripheral edema. Conclusions: Aggressive hydration combined with rectal diclofenac may be a promising strategy for the prevention of PEP. Furthermore, it is safe even for older individuals.

Feasibility and efficacy of endoscopic reintervention after covered metal stent placement for EUS-guided hepaticogastrostomy: A multicenter experience.

Background and Objectives: Although the use of a long metal stent is favored for EUS-guided hepaticogastrostomy (EUS-HGS) for the relief of malignant biliary obstruction (MBO), endoscopic reintervention (E-RI) at the time of recurrent biliary obstruction (RBO) is challenging due to a long intragastric portion. This study evaluated the feasibility and safety of E-RI after a long partially covered metal stent (L-PCMS) placement during EUS-HGS. Materials and Methods: We performed a multicenter retrospective study between January 2015 and December 2019 examining patients with MBO who underwent E-RI for RBO through the EUS-HGS route after the L-PCMS placement. Technical and clinical success rates, details of E-RI, adverse events (AEs), stent patency, and survival time were evaluated. Results: Thirty-three patients at eight referral centers in Japan who underwent E-RI through the EUS-HGS route were enrolled. The location of MBO was distal in 54.5%. The median intragastric length of the L-PCMS was 5 cm. As the first E-RI attempt, E-RI via the distal end of the existing L-PCMS was successful in 60.6%. The overall technical and clinical success rates of E-RI were 100% and 81.8%, respectively. Liver abscess was noted in one patient. A proximal biliary stricture was associated with the clinical ineffectiveness of E-RI in multivariable analysis (odds ratio, 12.5, P = 0.04). The median survival and stent patency duration after E-RI were 140 and 394 days, respectively. Conclusions: Our study findings suggest that E-RI for RBO after EUS-HGS with a L-PCMS is technically feasible and clinically effective, without any severe AEs, especially for patients with distal MBO.

Efficacy of EUS-guided celiac plexus neurolysis in combination with EUS-guided celiac ganglia neurolysis for pancreatic cancer-associated pain: a multicenter prospective trial.

OBJECTIVES: This study evaluated the efficacy of endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) in combination with EUS-guided celiac ganglia neurolysis (EUS-CGN) for pancreatic cancer-associated pain. METHODS: This multicenter prospective trial was registered in the University Hospital Medical Information Network (UMIN000031228). Fifty-one consecutive patients with pancreatic cancer-associated pain who presented at one of five Japanese referral centers between February 2018 and March 2021 were enrolled. EUS-CGN was added in cases of visible celiac ganglia. The primary endpoint was effectiveness, defined as a decrease in the numerical rating scale (NRS) by ≥ 3 points. NRS data were prospectively acquired at 1 week after the procedure to evaluate its effectiveness and the extent of pain relief. RESULTS: The technical success rates of EUS-CPN and EUS-CGN were 100% and 80.4%, respectively. The overall efficacy rate was 82.4% [90% confidence interval (CI) 71.2-90.5, P < 0.0001]. The complete pain relief rate was 27.4%. The adverse events rate was 15.7%. The average pain relief period was 72 days. The efficacy rate was higher in the EUS-CPN plus EUS-CGN group than in the EUS-CPN alone group. EUS-CPN plus EUS-CGN was superior to EUS-CPN alone for achieving complete pain relief (P = 0.045). EUS-CGN did not improve the average length of the pain relief period. CONCLUSIONS: EUS-CPN combined with EUS-CGN is safe, feasible, and effective for pain relief in patients with pancreatic cancer. The patients who received additional EUS-CGN had a better short-term response. CLINICAL TRIAL NUMBER: UMIN000031228.

Short coupling interval with high burden of atrial ectopy predicts recurrence after atrial fibrillation ablation.

Atrial ectopy (AE) with a short coupling interval (S-AE) causes atrial fibrillation (AF). A higher burden of AE is associated with recurrence after AF ablation. However, a few reports have evaluated the prognostic impact of both AE burden and S-AE after the acute phase of ablation. This study aimed to assess the characteristics of AE beyond the blanking period in predicting the recurrence. We retrospectively analyzed 173 patients who underwent first catheter ablation for AF and 24-h Holter recording following a 3-month blanking period. AE was defined as a narrow QRS complex occurring < 75% earlier than the prior reference R-R interval. We investigated the relationship between the AE's characteristics in Holter recordings and atrial arrhythmia recurrence. Forty-two patients (24%) had a recurrence during a median 488-day follow-up. Patients with S-AE (minimum coupling interval ratio of AE ≤ 45%) had a higher recurrence rate than those without S-AE (44.9% vs. 16.1%, p < 0.001). Moreover, patients with AE ≥ 241/day exhibited a significantly higher recurrence rate than those with AE < 241/day (44.3% vs. 10.7%, p < 0.001). In multivariate analysis, S-AE with a higher AE burden was an independent predictor of recurrence (hazard ratio 5.82, 95% confidence interval: 2.64-12.82, p < 0.001). Kaplan-Meier analysis showed that patients with S-AE and a higher AE burden had the worst prognosis for recurrence (p < 0.001). The combination of a higher AE burden with S-AE could be an efficient predictor of recurrence. These results can help to develop follow-up strategies after AF ablation.

Usefulness of P-wave duration in patients with sick sinus syndrome as a predictor of atrial fibrillation.

BACKGROUND: This study aimed to clarify P-wave duration (PWD) ability before pacemaker implantation to predict worsening atrial fibrillation (AF) burden after the procedure. METHODS: We retrospectively investigated 75 patients who underwent permanent pacemaker implantation due to sick sinus syndrome (SSS) at Komaki City Hospital between January 2006 and May 2019. Worsening AF burden was defined as an increase in the number of AF episodes, each lasting ≥5.5 hours a day. RESULTS: In the study population, 17 patients (23%) had worsening AF burden during the follow-up period. These patients had significantly longer PWD in lead Ⅱ (117.9 ± 19.9 ms vs 101.3 ± 20.0 ms, P = .002) than the patients without worsening AF burden. The best discriminative cutoff value for PWD in lead Ⅱ was 108 ms (sensitivity, 77%; specificity, 67%). In multivariate analysis, PWD in lead II ≥108 ms (hazard ratio, 5.395; 95% confidence interval, 1.352-21.523; P = .017) was an independent predictor of worsening AF burden. Patients with PWD in lead II <108 ms showed a significantly higher event-free rate against worsening AF burden than those with PWD in lead II ≥108 ms (81% vs 9%, P = .005). CONCLUSIONS: Prolonged PWD before pacemaker implantation was the most important independent predictor of worsening AF burden after the procedure. In patients with SSS, prolonged PWD can be a useful marker for predicting worsening of AF burden after pacemaker implantation.

Endoscopic ultrasound-guided biliary drainage for malignant biliary obstruction with surgically altered anatomy: a multicenter prospective registration study.

BACKGROUND: Endoscopic treatment for malignant biliary obstruction (MBO) in patients bearing surgically altered anatomy (SAA) is not well-established. Although endoscopic ultrasound-guided biliary drainage (EUS-BD) has emerged as a new treatment option for MBO, limited data are available regarding the efficacy and safety of EUS-BD in patients with SAA. We conducted a multicenter prospective registration study to evaluate the efficacy and safety of EUS-BD in this population. METHODS: This study involved 10 referral centers in Japan. Patients with SAA who were scheduled to receive EUS-BD for unresectable MBO between May 2016 and September 2018 were prospectively registered. The primary endpoint was technical success and the secondary outcomes were clinical success, procedure time, procedure-related adverse events (AEs), stent patency, and overall survival. RESULTS: In total, 40 patients were prospectively enrolled. The surgical reconstruction methods were gastrectomy with Roux-en-Y reconstruction (47.5%), gastrectomy with Billroth-II reconstruction (15%), pancreaticoduodenectomy (27.5%), and hepaticojejunostomy with Roux-en-Y reconstruction (10%). EUS-BD was performed for primary biliary drainage in 31 patients and for rescue biliary drainage in nine patients. Transmural stenting alone (60%), antegrade stenting alone (5%), and a combination of the two techniques (35%) were selected for patients treated with EUS-BD. Technical and clinical success rates were 100% (95% confidence interval, 91.2-100.0%) and 95% (95% confidence interval, 83.1-99.4%), respectively. Mean procedure time was 36.5 min. Early AEs were noted in six patients (15%): three self-limited bile leak, one bile peritonitis, and two pneumoperitonea. Late AEs occurred in six patients (15%): one jejunal ulcer and five stent occlusions. Stent patency rate after 3 months of survival was 95.7% (22/23). Median overall survival was 96 days. CONCLUSION: EUS-BD for MBO in patients with SAA appears to be effective and safe not only as a rescue drainage technique after failed endoscopic retrograde cholangiography but also as a primary drainage technique. CLINICAL TRIAL REGISTRATION: UMIN000022101.

Reduced exercise capacity and clinical outcomes following acute myocardial infarction.

Reduced exercise capacity is known to be an important predictor of poor prognosis and disability in patients with cardiovascular diseases and chronic heart failure, and even members of the general population. However, data about exercise capacity assessed by cardiopulmonary exercise testing (CPX) in acute myocardial infarction (AMI) patients who underwent primary percutaneous coronary intervention (PCI) is scarce. Among 594 consecutive AMI patients who underwent primary PCI, we examined 136 patients (85.3% men, 64.9 ± 11.9 years) who underwent CPX during hospitalization for AMI. CPX was usually performed 5 days after the onset of AMI. Reduced exercise capacity was defined as peak VO2 ≤ 12. Clinical outcomes including all-cause death, myocardial infarction, and hospitalization due to heart failure were followed. Among 136 patients, reduced exercise capacity (peak VO2 ≤ 12) was seen in 38 patients (28%). Patients with reduced exercise capacity were older, more likely to have hypertension, and had lower renal function. In echocardiography, patients with reduced exercise capacity had higher E/e' and larger left atrial dimension. Multivariate logistic analysis showed that E/e' (OR 1.19, 95% CI 1.09-1.31, p < 0.001) was an independent predictor of reduced exercise capacity (peak VO2 ≤ 12). Median follow-up term was 12 months (IQR 9-22). The occurrence of composite endpoints of all-cause death, myocardial infarction, and hospitalization due to heart failure was significantly higher in patients with peak VO2 ≤ 12 than those with peak VO2 > 12 (p < 0.001). Reduced exercise capacity following primary PCI in AMI patients is associated with diastolic dysfunction and may lead to poorer clinical outcomes.

Comparison of the efficacy and safety of endoscopic ultrasound-guided choledochoduodenostomy and hepaticogastrostomy for malignant distal biliary obstruction: Multicenter, randomized, clinical trial.

BACKGROUND AND AIM: Endoscopic ultrasound-guided biliary drainage (EUS-BD) can be carried out by two different approaches: choledochoduodenostomy (CDS) and hepaticogastrostomy (HGS). We compared the efficacy and safety of these approaches in malignant distal biliary obstruction (MDBO) patients using a prospective, randomized clinical trial. METHODS: Patients with malignant distal biliary obstruction after failed endoscopic retrograde cholangiopancreatography were randomly selected for either CDS or HGS. The procedures were carried out at nine tertiary centers from September 2013 to March 2016. Primary endpoint was technical success rate, and the noninferiority of HGS to CDS was examined with a one-sided significance level of 5%, where the noninferiority margin was set at 15%. Secondary endpoints were clinical success, adverse events (AE), stent patency, survival time, and overall technical success including alternative EUS-BD procedures. RESULTS: Forty-seven patients (HGS, 24; CDS, 23) were enrolled. Technical success rates were 87.5% and 82.6% in the HGS and CDS groups, respectively, where the lower limit of the 90% confidence interval of the risk difference was -12.2% (P = 0.0278). Clinical success rates were 100% and 94.7% in the HGS and CDS groups, respectively (P = 0.475). Overall AE rate, stent patency, and survival time did not differ between the groups. Overall technical success rates were 100% and 95.7% in the HGS and CDS groups, respectively (P = 0.983). CONCLUSIONS: This study suggests that HGS is not inferior to CDS in terms of technical success. When one procedure is particularly challenging, readily switching to the other could increase technical success.

Acute Bilateral Oculomotor Nerve Palsy in an Adult Patient with Neisseria meningitidis.

A 69-year-old woman was admitted to our hospital with a fever, dizziness, and headache caused by Neisseria meningitidis. After ceftriaxone was administered, she suddenly developed bilateral oculomotor nerve palsy. Intra-orbital magnetic resonance imaging using appropriate sequences revealed that her bilateral third intracranial nerves were enlarged and enhanced. She achieved complete recovery by two months after additional short-term treatment with intravenous immunoglobulin and methylprednisolone. Although intracranial nerve disorders that result from bacterial meningitis are most frequently reported in children, it is noteworthy that it can also cause focal intracranial nerve inflammation with ophthalmoparesis in N. meningitidis infection in adults.

Clinical significance of the timing of early recurrence of atrial arrhythmia after pulmonary vein isolation: a two-institution clinical study.

Early recurrence of atrial arrhythmia (ERAA) after ablation frequently occurs, but there is limited evidence about ERAA-timing. This study aimed to investigate the association between ERAA-timing and late recurrence. We retrospectively investigated 332 patients who underwent PVI for paroxysmal atrial fibrillation at Nagoya University Hospital and Komaki City Hospital. Seventy-six patients (23%) had ERAA. The cutoff value of the first ERAA for late recurrence was set as 3 days, with a specificity of 77% and sensitivity of 43%. On multivariate analysis, first ERAA beyond 3 days (hazard ratio, 2.477; 95% confidence interval, 1.168-5.25; p = 0.018) and large left atrial diameter (LAD) (hazard ratio, 1.101; 95% confidence interval, 1.024-1.184; p = 0.009) were independent predictors for late recurrence. Patients who had first ERAA within 3 days and no ERAA beyond 3 days showed a significantly higher recurrence-free rate than those who had first ERAA beyond 3 days and those who had ERAA both within 3 days and beyond 3 days (89% versus 39%, 44%; p < 0.001). Moreover, the patients with ERAA within 3 days and LAD ≤ 37.7 mm showed a significantly higher recurrence-free rate than those with ERAA beyond 3 days and LAD > 37.7 mm, and as compared with the other patients (100% versus 26% and 60%, respectively; p < 0.001). ERAA beyond 3 days after ablation was a predictor for late recurrence. Among patients with ERAA, those with ERAA within 3 days and smaller LAD showed favorable prognosis after ablation.

Neurilemmoma Mimicking a Multilocular Cystic Lesion of the Liver.

Neurilemmomas are benign tumors arising from the sheaths of peripheral nerves. They appear rarely in the abdominal cavity. We herein report an 80-year-old man with a multilocular cystic neurilemmoma mimicking a liver lesion. Preoperative images showed a lesion in the porta hepatis. Although a preoperative diagnosis was difficult, surgery was undertaken because of the possibility of malignancy. Histologically, the tumor consisted of spindle-shaped cells with positivity for S-100 protein. The final diagnosis was a neurilemmoma. Porta hepatic neurilemmomas are rare. When we encounter a multilocular cystic lesion of the liver, neurilemmoma should be considered in the differential diagnosis.