A Case of Cotyledonoid-Dissecting Leiomyoma - The Utility of Laparoscopic Biopsy and Gonadotropin-Releasing Hormone Analogs.

Cotyledonoid-dissecting leiomyoma, a very unusual form of uterine leiomyoma, often leads to misdiagnosis as a malignant tumor. Here, we describe a case of a 45-year-old nulliparous woman who underwent a laparoscopic biopsy of a large pelvic mass consisting of multiple flaps. Histologically, the mass was composed of smooth muscle fascicle nodules separated by hydropic connective tissue, and exhibited extensive stromal hyalinization. The tumor was diagnosed as a cotyledonoid-dissecting leiomyoma based on the laparoscopic, pathological, and image findings. Prior to performing radical laparotomy, two courses of leuprorelin were administered in anticipation of tumor reduction and hypoperfusion, and the tumor size reduced remarkably. We demonstrated the utility of laparoscopic biopsy, considering its minimal invasiveness and diagnostic accuracy. Furthermore, the preoperative use of Gonadotropin-releasing hormone (GnRH) analogs to reduce surgical stress may be useful for treating cotyledonoid-dissecting leiomyomas.

Idarucizumab for Emergency Reversal of the Anticoagulant Effects of Dabigatran: Final Results of a Japanese Postmarketing Surveillance Study.

INTRODUCTION: Idarucizumab, a monoclonal antibody fragment that rapidly reverses the anticoagulant effects of dabigatran, was approved in Japan in September 2016, at which time an all-case, postmarketing surveillance (PMS) study was initiated to collect data on idarucizumab in Japanese patients. Interim results were published previously, and the final results are reported herein. METHODS: This multicenter, open-label, uncontrolled, non-interventional PMS study was conducted in Japanese patients who received idarucizumab at the approved dose (2 × 2.5 g/50 ml) and had uncontrolled bleeding (group A) or required an emergency procedure (group B). The primary endpoint was the frequency of adverse drug reactions (ADRs). The secondary endpoint was the maximum extent of reversal of the anticoagulant effects of dabigatran, within 4 h of idarucizumab administration, based on activated partial thromboplastin time (aPTT). RESULTS: The final analysis included 804 patients. ADRs during the idarucizumab treatment and post-treatment periods were reported in 17 of 542 patients (3.1%) in group A and 12 of 240 patients (5.0%) in group B. Thrombotic events were reported in 22 patients (4.1%) in group A and 15 patients (6.3%) in group B, and hypersensitivity occurred in four (0.7%) and five patients (2.1%), respectively. Among 793 patients evaluated for effectiveness, 78 in group A and 26 in group B had aPTT data at baseline (immediately before idarucizumab administration) and within 4 h of idarucizumab administration; in these patients, median maximum percentage reversal within 4 h of idarucizumab administration was 100%. CONCLUSIONS: The final analysis from the PMS study confirms previous findings suggesting that idarucizumab can safely and effectively reverse the anticoagulant effects of dabigatran in Japanese patients in clinical practice. The results support the continued use of idarucizumab in Japan. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov (NCT02946931).

Atrial fibrillation is an irregular heart rhythm (arrhythmia), and the type of atrial fibrillation not caused by a heart valve problem is known as "non-valvular atrial fibrillation" or NVAF. People with NVAF have an increased risk of ischemic stroke, in which a blood clot (thrombus) blocks an artery in the brain. Drugs that inhibit blood clots, known as anticoagulants, are prescribed to people with NVAF to prevent ischemic stroke. Historically, warfarin has been one of the most prescribed anticoagulant drugs. However, a novel anticoagulant drug, known as dabigatran, has clinical advantages over warfarin and is approved in many countries for people with NVAF. People who take anticoagulants may experience life-threatening bleeding or need urgent surgery, and thus rapid and effective reversal of the anticoagulant effects is critical. The drug idarucizumab specifically binds to dabigatran to reverse its anticoagulant effects in people with uncontrolled bleeding or who require an urgent procedure. Idarucizumab was approved for use in Japan in September 2016. In Japan, drug companies are obligated to collect data after a new drug is launched as an approval condition, which is done through a postmarketing surveillance study. Here, we report the final results of a postmarketing surveillance study conducted between September 2016 and November 2020 to evaluate the safety and effectiveness of idarucizumab in Japanese patients receiving dabigatran. The results of our study show that idarucizumab can safely and effectively reverse the anticoagulant effects of dabigatran in Japanese patients, and support the continued use of idarucizumab in Japan in clinical practice.

Novel Opioid Analgesics for the Development of Transdermal Opioid Patches That Possess Morphine-Like Pharmacological Profiles Rather Than Fentanyl: Possible Opioid Switching Alternatives Among Patch Formula.

BACKGROUND: Transdermal fentanyl is widely used in the treatment of severe pain because of convenience, safety, and stable blood concentrations. Nevertheless, patients often develop tolerance to fentanyl, necessitating the use of other opioids; transdermal buprenorphine patch is widely used as an analgesic agent, though available formulation does not provide comparable analgesic effect as transdermal fentanyl patch. Opioids bind to the opioid receptor (OR) to activate both G protein-mediated and ß-arrestin-mediated pathways. We synthesized morphine-related compounds with high transdermal absorbability (N1 and N2) and evaluated their OR activities pharmacologically in comparison with fentanyl and morphine. METHODS: In cells stably expressing µ-opioid receptor (MOR), δ-opioid receptor (DOR), and κ-opioid receptor (KOR), G protein-mediated pathways were assessed using the CellKey and an intracellular cyclic adenosine monophosphate (cAMP) assay, while ß-arrestin-mediated pathways were analyzed with ß-arrestin recruitment and receptor internalization assays. Furthermore, analgesic effects were evaluated using a tail-flick test in mice, and the analgesic effect on fentanyl-tolerant mice was evaluated. RESULTS: In the CellKey and cAMP assays, both N1 and N2 showed the highest affinity for MOR and acted as full agonists as well as partial agonists for DOR and KOR. In the ß-arrestin and internalization assays, only fentanyl acted as a full agonist; N1 and N2 acted as partial agonists of MOR. In the mouse tail-flick test, N1 and N2 showed analgesic effects equivalent to those of fentanyl and morphine. In fentanyl-tolerant mice, fentanyl showed a diminished analgesic effect, whereas N1 and N2 as well as morphine retained their analgesic effects. CONCLUSIONS: While N1 and N2 have higher transdermal absorbability than fentanyl, they also have analgesic effects comparable to those of morphine, suggesting that they may be attractive compounds for the development of novel opioid patches for transitioning from fentanyl patches.

Combination Therapy of Pembrolizumab plus Axitinib for a Patient on Hemodialysis with Metastatic Renal Cell Carcinoma: A Case Report.

Here, we discuss the safety and management of adverse events associated with pembrolizumab plus axitinib combination therapy for metastatic renal cell carcinoma in patients on hemodialysis. A 76-year-old man was diagnosed with cT3aN0M0 renal cell carcinoma due to gross hematuria. Stereoscopic radiotherapy for metastatic lesions of the ipsilateral kidney was performed 9 years after right laparoscopic radical nephrectomy. Soon after, the patient started to receive hemodialysis due to end-stage renal disease. Further stereoscopic radiotherapy was needed for metastasis of the ipsilateral kidney and lung. Fifteen years after diagnosis, systemic therapy was necessary to control new metastases, such as in the right scapular bone. We selected pembrolizumab plus axitinib combination therapy as the first-line systemic therapy for any risk as defined by the International Metastatic RCC Database Consortium. Although we needed to pay attention to the adverse events unique to hemodialysis, he underwent this combination therapy without any difficulty for 6 months. Here, we report the practice of combination therapy in patients on hemodialysis in light of the literature.

Comparing the usefulness of a fluoroscopic navigation system in femoral trochanteric fracture for orthopaedic residents with the conventional method.

INTRODUCTION: Lag screw insertion into the ideal position is essential to obtain good results in open reduction and internal fixation for femoral trochanteric fracture. Tip-apex distance (TAD) is a widely adopted method for evaluating the risk of lag screw cut-out. Adaptive positioning technology (ADAPT) is a fluoroscopic computer-assisted surgery system that enables orthopaedic surgeons to guide the screw into a proper position intraoperatively. A randomized control study concluded that ADAPT resulted in excellent TAD. However, it was not significantly better than conventional methods when performed by fellowship-trained traumatologists. Therefore, we hypothesised that ADAPT would be useful to orthopaedic residents and evaluated this usefulness. METHODS: We reviewed 102 patients who underwent open reduction and internal fixation for femoral trochanteric fracture from May 2017 to March 2019 using Gamma-3 intertrochanteric nails. Two residents performed all procedures; 51 patients underwent surgery using ADAPT and the others underwent surgery without navigation. The number of attempts to drill guide-wire, operation time, lag screw insertion time, radiation exposure time, TAD, and lag screw position were evaluated for each surgeon. RESULTS: In one resident, when using the ADAPT system, the number of attempts to drill guide-wire (p=0.001), lag screw insertion time (p=0.000), radiational exposure time (p=0.009) and TAD (p=0.007) were lower, and the percentage of ideal lag screw position (p=0.035) were better than that in the conventional method. However, there was no significant difference in the performance of another resident with respect to the aforementioned factors, whether using ADAPT or not. CONCLUSION: One resident showed better results with the ADAPT system than with conventional osteosynthesis. However, another resident received no benefit from ADAPT. The efficiency may not apply to everyone as individual competence can influence efficiency when using ADAPT system. Therefore, as a new device, it must be used cautiously because skill or experience may influence its use, especially by orthopaedic residents.

Idarucizumab for Emergency Reversal of Anticoagulant Effects of Dabigatran: Interim Results of a Japanese Post-Marketing Surveillance Study.

INTRODUCTION: Idarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran, and it was approved in Japan in September 2016. An all-case post-marketing surveillance is ongoing to collect data in Japanese patients treated with idarucizumab who had serious bleeding (Group A) or required an urgent procedure (Group B). METHODS: The primary endpoint was the incidence of adverse drug reactions (ADRs). The secondary endpoint was the maximum extent of reversal of the anticoagulant effect of dabigatran based on activated partial thromboplastin time (aPTT) within 4 h after idarucizumab administration. RESULTS: This interim analysis included 262 patients who received idarucizumab. Eighteen patients (6.9%) experienced ADRs within 4 weeks. The reversal effect of idarucizumab based on aPTT within 4 h after idarucizumab administration was assessed in 30 patients and the median maximum percentage reversal was 100%. In Group A, the median time to bleeding cessation in patients without intracranial bleeding was 3.3 h. In Group B, normal intraoperative hemostasis was reported in 63 patients (72.4%). CONCLUSIONS: The results of this interim analysis suggest that idarucizumab is safe and effective for the reversal of dabigatran in Japanese patients in a real-world setting, and support the continued use of idarucizumab. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02946931.

Bioequivalence of a Newly Developed Dabigatran Etexilate Tablet Versus the Commercial Capsule and Impact of Rabeprazole-Induced Elevated Gastric pH on Exposure in Healthy Subjects.

BACKGROUND AND OBJECTIVE: Dabigatran etexilate (DE) is an anticoagulant with proven efficacy and tolerability for stroke prevention in patients with non-valvular atrial fibrillation. For the commercial capsule, a complex formulation is used to maintain the acidic microenvironment required for maximal absorption. Consequently, its efficacy and safety are similar with or without concomitant intake of proton-pump inhibitors (PPIs). A simplified DE tablet formulation was developed and tested in two studies. One investigated bioequivalence (BE) of the novel DE tablet versus the commercial DE capsule. The other investigated DE bioavailability (BA) under pretreatment with the PPI rabeprazole and assessed the effect of elevated pH on exposure to dabigatran. METHODS: BE of the novel DE tablet versus the DE capsule was assessed in a randomized two-treatment, four-period, two-sequence crossover study (NCT03070171). The effect of rabeprazole on the BA of the DE tablet was assessed in an open-label, single-arm study (NCT03143166). Both studies were conducted at sites in Japan. Participants were healthy male volunteers, aged ≥ 20-40 years. In the BE study, participants received the DE tablet or capsule (single oral dose, 110 mg); primary endpoints were area under the concentration-time curve from baseline to the last quantifiable data point (AUC0-tz) and maximum plasma concentration (Cmax) of unconjugated dabigatran. In the relative BA study, participants received the DE tablet (single oral dose, 110 mg) with or without rabeprazole pretreatment (once daily for 5 days, 20 mg); primary endpoints were AUC0-tz and Cmax of total dabigatran. RESULTS: In total, 160 participants were randomized in the BE study; 36 participants were enrolled in the BA study. The 90% confidence intervals of geometric mean (gMean) ratios for AUC0-tz (101.4-116.0%) and Cmax (101.8-116.6%) of unconjugated dabigatran were within pre-defined acceptance criteria for BE. In the relative BA study, the gMeans of AUC0-tz (667 to 192 ng h/mL) and Cmax (83.1 to 21.8 ng/mL) were decreased by approximately 70% when the tablet was administered under rabeprazole pretreatment. The reduction in BA was observed at a mean gastric pH of 5.3. Treatment was well tolerated; no deaths, serious adverse events (AEs) or significant AEs were reported in either study. CONCLUSION: The DE tablet demonstrated BE to the capsule; however, at high gastric pH, BA of the tablet was reduced by approximately 70%, which may lead to reduced efficacy. Data indicate the importance of examining not only BE under standard conditions, but relative BA at elevated gastric pH. Such investigations may avoid the reduced BA at elevated pH that is quite common in the target population (the elderly and/or patients treated with gastric-acid modifying co-medications), and therefore reduce treatment failure with DE. Registration: ClinicalTrials.gov identifier numbers: NCT03070171, and NCT03143166.

Analysis of a Cementless Femoral Stem Neck Fracture Using Scanning Electron Microscopy and the Finite Element Method.

Implant fracture is one of the rarest complications of total hip arthroplasty (THA). A 57-year-old woman experienced a fracture of the femoral stem (AHFIX Q, KYOCERA, Japan) about five years after THA. We examined the broken stem by digital microscopy, scanning electron microscopy, and finite element method. The anterolateral corner of the stem's neck was found to be the origin point of the fracture. Finite element method analysis revealed that the stress concentration was highest in the corner of the hollow for apparatus attachment. The stem's design has been considered one of the risk factors for stem fracture. In this patient, multiple risk factors, including thin stem (the smallest size, NAR #1), use of the long neck (+3 mm), obesity (body mass index: 27.3), and adjacent osteoarthritis (contralateral THA loosening and knee osteoarthritis), were present. To our knowledge, this is the first reported case of an AHFIX Q stem fracture. Surgeons must keep in mind that fracture of the femoral stem in patients with several risk factors is possible even several years after THA.

Prior observation of fear learning enhances subsequent self-experienced fear learning with an overlapping neuronal ensemble in the dorsal hippocampus.

Information from direct experience and observation of others is integrated in the brain to enable appropriate responses to environmental stimuli. Fear memory can be acquired by observing a conspecific's distress. However, it remains unclear how prior fear observation affects self-experienced fear learning. In this study, we tested whether prior observation of a conspecific receiving contextual fear conditioning affects subsequent self-experienced fear conditioning and how neuronal ensembles represent the integration of the observation and self-experience. Test mice observed demonstrator mice experiencing fear conditioning on day 1 and directly experienced fear conditioning on day 2. Contextual fear memory was tested on day 3. The prior observation of fear conditioning promoted subsequent self-experienced fear conditioning in a hippocampus-dependent manner. We visualized hippocampal neurons that were activated during the observation and self-experience of fear conditioning and found that self-experienced fear conditioning preferentially activated dorsal CA1 neurons that were activated during the observation. When mice observed and directly experienced fear conditioning in different contexts, preferential reactivation was not observed in the CA1, and fear memory was not enhanced. These findings indicate that dorsal CA1 neuronal ensembles that were activated during both the observation and self-experience of fear learning are implicated in the integration of observation and self-experience for strengthening fear memory.