Drug review process advancement and required manufacturer and contract research oraganization responses.

The United States Senate passed the "FDA Modernization Act 2.0." on September 29, 2022. Although the effectiveness of this Bill, which aims to eliminate the mandatory use of laboratory animals in new drug development, is limited, it represents a significant trend that will change the shape of drug applications in the United States and other countries. However, pharmaceutical companies have not taken major steps towards the complete elimination of animal testing from the standpoint of product safety, where they prioritize patient safety. Nonetheless, society is becoming increasingly opposed to animal testing, and efforts will be made to use fewer animals and conduct fewer animal tests as a natural and reasonable response. These changes eventually alter the shape of new drug applications. Based on the assumption that fewer animal tests will be conducted or fewer animals will be used in testing, this study explored bioinformatics and new technologies as alternatives to compensate for reduced information and provide a picture of how future new drug applications may look. The authors also discuss the directions that pharmaceutical companies and nonclinical contract research organizations should adopt to promote the replacement, reduction, and refinement of animals used in research, teaching, testing, and exhibitions.

Lethal hemopericardium caused by infection of mitral annular calcification: An autopsy case report.

Mitral annular calcification (MAC) is a chronic and degenerative condition involving calcification of the mitral annulus. MAC is a risk factor for coronary artery disease, cardiovascular events, stroke, and cardiovascular death. However, patients with MAC are often asymptomatic. Herein, we present the first case of cardiac tamponade due to infection of MAC in forensic pathology. An 80-year-old woman was found in cardiopulmonary arrest shortly after experiencing fatigue. She was transferred to a hospital, and despite chest compression and ventilation, she was pronounced dead due to no response. Postmortem computed tomography, autopsy, and histological examination showed MAC, abscess formation involving Gram-positive cocci on the MAC, and fistulation of the abscess into the intracardial pericardial cavities, resulting in a massive lethal hemopericardium.

Can right ventricular endomyocardial biopsy predict left ventricular fibrosis beforehand in dilated cardiomyopathy?

AIMS: Myocardial fibrosis of the left ventricle (LV) is a prognostic factor in dilated cardiomyopathy (DCM). This study aims to evaluate whether fibrosis of right ventricular (RV) endomyocardial biopsy (EMB) can predict the degree of LV fibrosis beforehand in DCM. METHODS AND RESULTS: Fibrosis extent in 70 RV-EMB specimens of DCM diagnosis was compared with that in the whole cross-sectional LV of excised hearts in the same patients (52 explanted hearts for transplant and 18 autopsied hearts). The median interval between biopsy and excision was 4.1 (0.13-19.3) years. The fibrosis area ratio of the EMBs and excised hearts were evaluated via image analysis. The distribution of cardiovascular magnetic resonance-late gadolinium enhancement (LGE) in the intraventricular septum was classified into four quartile categories. The fibrosis area ratio in RV-EMB correlated significantly with that in the short-axis cut of the LV of excised hearts (r = 0.82, P < 0.0001) and with a diffuse pattern of LGE (r = 0.71, P = 0.003). In a multivariate model, after adjusting for the interval between biopsy performance and heart excision, the fibrosis area ratio in RV-EMB was associated with that in LV-excised heart (regression coefficient, 0.82; 95% confidence interval, 0.68-0.95; P < 0.0001). CONCLUSIONS: The fibrosis observed in RV-EMB positively correlated with the extent of fibrosis in the LV of excised hearts in patients with DCM. The study findings may help predict LV fibrosis, considered a prognostic factor of DCM through relatively accessible biopsy techniques.

Relationship Between Results of Pathological Evaluation of Endomyocardial Biopsy and Echocardiographic Indices in Patients With Non-Ischemic Cardiomyopathy.

Background: Endomyocardial biopsy (EMB) is a useful modality in diagnosing the origin of cardiomyopathy and the condition of the impaired myocardium. However, the usefulness of obtaining an EMB from the right and left ventricles (RV and LV, respectively), and its associations with echocardiographic parameters, have not been explored. Methods and Results: Ninety-five consecutive patients with non-ischemic cardiomyopathy excluding myocarditis who underwent EMB between July 2017 and May 2019 were studied. Seventy-nine RV and 93 LV biopsy specimens were pathologically analyzed. The relationships among echocardiographic data before EMB and pathologically measured cardiomyocyte diameter (CMD) and interstitial fibrosis (IF) were evaluated. CMD in both LV and RV specimens correlated with echocardiographic LV morphology, but only CMD in the LV was significantly correlated with cardiac function evaluation, including LV ejection fraction, E' and E/E'. In contrast, there were no significant correlations between IF in either the LV or RV and any echocardiographic parameters measured. Furthermore, CMD of both ventricles was significantly correlated with B-type natriuretic peptide (BNP) concentration at EMB, whereas IF of the LV was barely related and IF of the RV was not significantly correlated with BNP concentrations. Conclusions: Pathologically evaluated CMD of EMB specimens of the LV may be more related to functional parameters for heart failure status and LV geometry on echocardiographic examination, than IF.

Case Report: Molecular autopsy underlie COVID-19-associated sudden, unexplained child mortality.

Herein, we report a child with COVID-19 and seemingly no underlying disease, who died suddenly. The autopsy revealed severe anemia and thrombocytopenia, splenomegaly, hypercytokinemia, and a rare ectopic congenital coronary origin. Immunohistochemical analysis demonstrated that the patient had acute lymphoblastic leukemia of the B-cell precursor phenotype (BCP-ALL). The complex cardiac and hematological abnormalities suggested the presence of an underlying disease; therefore, we performed whole-exome sequencing (WES). WES revealed a leucine-zipper-like transcription regulator 1 (LZTR1) variant, indicating Noonan syndrome (NS). Therefore, we concluded that the patient had underlying NS along with coronary artery malformation and that COVID-19 infection may have triggered the sudden cardiac death due to increased cardiac load caused by high fever and dehydration. In addition, multiple organ failure due to hypercytokinemia probably contributed to the patient's death. This case would be of interest to pathologists and pediatricians because of the limited number of NS patients with LZTR1 variants; the complex combination of an LZTR1 variant, BCP-ALL, and COVID-19; and a rare pattern of the anomalous origin of the coronary artery. Thus, we highlight the significance of molecular autopsy and the application of WES with conventional diagnostic methods.

An unusual case of fatal hypothermia involving topical diphenhydramine.

PURPOSE: Diphenhydramine is an antihistamine drug widely used to alleviate symptoms caused by allergies and the common cold. Diphenhydramine-involved fatalities have been reported in the past but usually involving overdose by ingestion. We report a peculiar case of fatal hypothermia during non-winter season involving topical diphenhydramine. METHODS: A 23-year-old male with no known preexisting medical conditions was found dead in the bathroom of his apartment with a small amount of running water on his back. Postmortem examinations and toxicological analysis on blood and urine were performed. RESULTS: Color difference was apparent between the right and left cardiac blood. Wischnewski spots were observed in the gastric mucosa. Histological examination revealed no obvious findings that could attribute to serious cardiovascular events. Drug screening by gas chromatograph-tandem mass spectrometry (GC/MS/MS) detected diphenhydramine in blood and urine. Further quantification revealed the postmortem concentrations to be 0.44 µg/mL in blood and 2500 µg/mL in urine. CONCLUSIONS: The cause of death was determined to be hypothermia. Diphenhydramine-induced drowsiness and possible intrinsic cardiac factor may have led to prolonged impaired consciousness, preventing his ability to escape from the running cold water leading to hypothermia and death.

Short-term administration of Polypodium leucotomos extract does not inhibit CYP3A4-mediated metabolism of midazolam in healthy subjects: an open-label, two-period, fixed-sequence study.

The extract of Polypodium leucotomos is used as a dietary supplement for its ultraviolet radiation-protective properties. Polypodium leucotomos extract reportedly inhibits CYP3A, which is important for drug metabolism in vitro in human microsomes and in vivo in rats. In this study, we explored the inhibitory effect of the P. leucotomos extract on CYP3A4-mediated midazolam metabolism in humans. This open-label, two-period, fixed-sequence study was performed on six healthy, Japanese, male volunteers. During period 1 (control), midazolam (1 mg) was orally administered. After a wash-out period of at least 5 days, period 2 was initiated. Subjects ingested P. leucotomos extract (240 mg) once in the morning and once at noon on the day before midazolam administration, and once the next morning (thrice overall). Midazolam was administered as in period 1. Blood samples were regularly collected for 8 hours after drug administration, and serum midazolam concentration was determined by ultra-fast liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters of midazolam were calculated and compared between the two periods. The area under the concentration-time curve was 19.18 ± 3.65 ng h/ml, maximum serum concentration was 7.81 ± 1.25 ng/ml, and half-life was 2.32 ± 0.35 hours during period 2. These parameters did not differ from those recorded in period 1 (area under the concentration-time curve: 18.74 ± 2.97 ng h/ml, maximum serum concentration: 8.78 ± 1.67 ng/ml, half-life: 2.52 ± 0.52 h). Therefore, short-term oral administration of P. leucotomos extract did not cause food-drug interactions mediated by CYP3A4 inhibition in humans.

Abnormal Microscopic Findings in the Placenta Correlate With the Severity of Fetal Heart Failure.

BACKGROUND: This study investigated the association between placental pathology and fetal heart failure.Methods and Results: Singletons with a congenital heart defect (CHD) and/or arrhythmia (n=168) and gestational age-matched controls (n=52) were included in the study. The associations between macro- and microscopic abnormal findings of the placenta and the severity of fetal heart failure were evaluated using the cardiovascular profile (CVP) score. Nine features were microscopically identified and assessed in sections of the placenta: premature villi, edematous villi, fibrotic villi, chorioamnionitis, chorangiosis, fibrin deposition, subchorionic hematoma, infarcted villi, and nucleated red blood cells in villous vessels. Among singletons with CHD and/or arrhythmia, the final CVP score was ≥8 in 140 cases, 6 or 7 in 15 cases, and ≤5 in 13 cases. Microscopic analysis showed that the frequency and severity of premature and edematous villi and increased nucleated red blood cells in villous vessels were greater in cases of fetal heart failure. These microscopic findings were more common and severe in cases with a final CVP score ≤5 than in gestational age-matched controls. The prevalence of abnormal macroscopic findings of the placenta and umbilical cord was similar regardless of the severity of fetal heart failure. CONCLUSIONS: Premature and edematous villi and increased nucleated red blood cells in villous vessels were correlated with the severity of fetal heart failure in cases of CHD and/or arrhythmia.

Local Variation and Age-Related Change in Atrial and Ventricular Myocardial Contiguity at the Atrioventricular Junction in Human Hearts.

Background: We explored the histologic patterns of and age-related changes in atrial and ventricular myocardial contiguity at the left and right atrioventricular (AV) junction that could be a target site for catheter ablation. Methods and Results: Twenty-three structurally normal adult hearts obtained at autopsy were studied. The 2 AV annuli were divided into 13 clinically recognized portions in which we measured distance between the atrial and ventricular myocardium at the AV junction. Overall, measured distance was less on the right than left side (mean [±SD] 0.74±0.59 vs. 1.15±0.78 mm, respectively), and distance increased gradually with age. The gap was smallest at the anterolateral portion on the right side and posterolateral portion on the left side. Three specific features were noted, namely extension of the ventricular myocardium (coarse trabeculae) towards the atrium on the right side of the AV junction, extension of the atrial myocardium onto the AV valve leaflets, and a collection of small myocardial cells, perhaps including specialized cells, in the right anterolateral portion. No concealed AV muscular connections were found. Conclusions: Contiguity and separation of the myocardium at the AV junction have specific patterns, and myocardial proximity is influenced by age. These histologic features of the AV junction may prove to be informative for catheter ablation of tachyarrhythmias related to the AV junction.

High accessory pathway conductivity blocks antegrade conduction in Wolff-Parkinson-White syndrome: A simulation study.

BACKGROUND: Wolff-Parkinson-White (WPW) syndrome is characterized by an anomalous accessory pathway (AP) that connects the atrium and ventricles, which can cause abnormal myocardial excitation and cardiac arrhythmias. The morphological and electrophysiological details of the AP remain unclear. The size and conductivity of the AP may affect conduction and WPW syndrome symptoms. METHODS: To clarify this issue, we performed computer simulations of antegrade AP conduction using a simplified wall model. We focused on the bundle size of the AP and myocardial electrical conductivity during antegrade conduction (from the atrium to the ventricle). RESULTS: We found that a thick AP and high ventricular conductivity promoted antegrade conduction, whereas a thin AP is unable to deliver the transmembrane current required for electric conduction. High ventricular conductivity amplifies transmembrane current. These findings suggest the involvement of a source-sink mechanism. Furthermore, we found that high AP conductivity blocked antegrade conduction. As AP conductivity increased, sustained outward transmembrane currents were observed. This finding suggests the involvement of an electrotonic effect. CONCLUSIONS: The findings of our theoretical simulation suggest that AP size, ventricular conductivity, and AP conductivity affect antegrade conduction through different mechanisms. Our findings provide new insights into the morphological and electrophysiological details of the AP.

Kamikihito, a traditional Japanese Kampo medicine, increases the secretion of oxytocin in rats with acute stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Kamikihito (KKT) is a Kampo medicine that is prescribed in Japan for the treatment of anemia, insomnia and mental anxiety in Japan. However, its precise mechanism of action remains unclear. AIM OF THE STUDY: This study aimed to evaluate the possible antistress effect of KKT in rats with acute stress and the contribution of oxytocin to the process. MATERIALS AND METHODS: Acute immobilization stress (AIS; for 90 min) was used to assess the effect of KKT on acute stress. Male Wistar rats were orally treated with KKT. Parameters of stress were evaluated, and concentrations of oxytocin in plasma and cerebrospinal fluid (CSF) were measured. RESULTS: AIS-induced defecation and fecal weight were significantly decreased because of treatment with KKT. The plasma levels of stress-related hormones following AIS were investigated. The pre-administration of KKT significantly increased adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) levels following AIS. Conversely, there was no significant change in the plasma oxytocin level. Microdialysis and hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) were used to monitor the oxytocin secretion in CSF. Oxytocin level increased during AIS following the treatment of KKT. At 30 min after AIS, the level remained higher than before AIS. Furthermore, using an open field test, the locomotion (exploratory behavior) immediately after AIS was examined. The total traveled distance decreased after AIS; however, the decrease was significantly inhibited by the treatment of KKT. However, the effect of KKT was obstructed by the pre-administration of the oxytocin receptor antagonist. CONCLUSIONS: These results suggest that KKT has antistress activity and increased oxytocin secretion may be a mechanism underlying this phenomenon.

High-throughput identification and determination of aminoglycoside antibiotics in human plasma using UPLC-Q-ToF-MS.

Aminoglycosides are a class of broad-spectrum antibiotics with several clinical uses. Owing to the ototoxicity and nephrotoxicity of aminoglycosides, therapeutic drug monitoring is required. This study aimed to devise a high-throughput method for identification and quantitative determination of aminoglycoside antibiotics in human plasma samples using ultra-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-Q-ToF-MS). Plasma samples (100 µL) spiked with five aminoglycosides (streptomycin, spectinomycin, amikacin, kanamycin, and gentamycin) and an internal standard (ribostamycin) were diluted and centrifuged in aqueous formic acid and acetonitrile. The clear supernatant extract was evaporated and reconstituted in the mobile phase, of which 4 µL was subjected to UPLC-Q-ToF-MS. Prominent peaks were observed for the drugs within 3 min. The recoveries of five aminoglycosides from plasma samples were 92.6-120%. The regression equations showed excellent linearity (0.9999 ≥ r2 ≥ 0.9987) within the range of 1.0-100 µg/mL, and detection limits of 0.5-2.0 µg/mL. The coefficients of the intra- and inter-day variations for five drugs were less than 11.8%, while the accuracy of quantitation was in the range of 89-111%. In this study, a novel method was presented for identification and determination of aminoglycosides in human plasma samples using UPLC-Q-ToF-MS analysis. This method can be applied to high-throughput analysis used for clinical and environmental purposes.

Pathological findings after third- and second-generation everolimus-eluting stent implantations in coronary arteries from autopsy cases and an atherosclerotic porcine model.

Pathological changes after third-generation drug-eluting stent implantation remain unclear. We compared the tissue responses of coronary arteries after the implantation of third-generation abluminal biodegradable-polymer everolimus-eluting stent (3rd EES) and second-generation durable-polymer EES (2nd EES) using autopsy specimens and an atherosclerotic porcine model. We compared the histology of stented coronary arteries obtained by autopsy performed 1-10 months after 3rd EES (n (number of cases) = 4, stent-implanted period of 3-7 months) and 2nd EES (n (number of cases) = 9, stent-implanted period of 1-10 months) implantations. The ratio of covered stent struts was higher with 3rd EESs than with 2nd EESs (3rd; 0.824 ± 0.032 vs. 2nd; 0.736 ± 0.022, p = 0.035). Low-density lipoprotein receptor knockout minipigs were stented with 3rd or 2nd EES in the coronary arteries and the stented regions were investigated. The fibrin deposition around the 2nd EES was more prominent. Additionally, higher density of smooth muscle cells was confirmed after the 3rd EES implantation. Pathological examination after the 3rd EES demonstrated a combination of less fibrin deposition and more rapid acquisition of well-developed neointima as compared to the 2nd EES at autopsy and the atherosclerotic porcine model.

Advantages and challenges for noninvasive atrial fibrillation ablation.

PURPOSE: Although catheter ablation is an effective therapy for atrial fibrillation (AF), risks remain and improved efficacy is desired. Stereotactic radiotherapy is a well-established therapy used to noninvasively treat malignancies with precision. We sought to evaluate stereotactic arrhythmia radioablation (STAR) as a therapeutic option for treating AF. METHODS AND RESULTS: Three cancer patients with drug refractory AF were enrolled. Planning software using 3-D CT of the left atrium was used to design a desired ablation volume encompassing antral circumferential pulmonary vein isolation, roof and floor lines to create a "box" lesion set. After planning, patients were treated in the radioablation suite. STAR was able to deliver the intended radiation dose to the target in all 3 patients. No complications were observed over a follow-up period of 24 months. One patient with paroxysmal AF died from deterioration of cancer. The autopsy revealed evidence of fibroblasts and fibrogenesis in the region of atrial tissues targeted with radioablation. In one of these patients, left atrial posterior wall electrograms recorded from the esophagus before and 3 months after STAR indicated successful electrical isolation. CONCLUSIONS: This is the first report of non-invasive radioablation of the left atrium with demonstration of successful electrical isolation. Although STAR may be safe and effective in delivering ablative energy to the left atrium, further evaluation is warranted regarding effectiveness.

Fragmented QRS complex in patients with systemic lupus erythematosus at the time of diagnosis and its relationship with disease activity.

OBJECTIVE: Cardiovascular disease is an important contributor to the mortality rate of patients with systemic lupus erythematosus (SLE), which is related to SLE disease activity. Fragmented QRS (fQRS) complexes, defined by additional spikes in the QRS complex, are useful for identifying myocardial scars on electrocardiography and can be an independent predictor of cardiac events. We aimed to assess the relationship between disease activity in patients with SLE and fQRS at the time of diagnosis. METHODS: Forty-four patients with SLE were included. Patients with cardiac diseases, other rheumatic diseases, and prior treatment at the time of electrocardiography measurement were excluded. The appearance of fQRS represented exposure. The primary outcome was SLE Disease Activity Index 2000 (SLEDAI-2K). Multiple regression analysis was conducted to assess the association between fQRS and SLEDAI-2K adjusted for age, sex, and time from the estimated onset date to the date of diagnosis. RESULTS: Among patients with SLE at diagnosis, 26 (59.1%) had fQRS. The median SLEDAI-2K was 18 (interquartile range [IQR], 12-22) and 9 (IQR, 8-15) in the fQRS(+) and fQRS(-) groups, respectively. SLEDAI-2K was significantly higher in the fQRS(+) group than in the fQRS(-) group (regression coefficient, 2.69; 95% confidence interval, 0.76-4.61; p = 0.008). CONCLUSION: Our results suggested that fQRS(+) patients with SLE had high disease activity. fQRS could likely detect subclinical myocardial involvement in patients with SLE and predict long-term occurrence of cardiac events.

Chemerin-9, a potent agonist of chemerin receptor (ChemR23), prevents atherogenesis.

Plasma levels of chemerin, an adipocytokine produced from the adipose tissues and liver, are associated with metabolic syndrome and coronary artery disease (CAD). Chemerin and its analog, chemerin-9, are known to bind to their receptor, ChemR23. However, whether chemerin and chemerin-9 affect atherogenesis remains to be elucidated. We investigated the expression of chemerin and ChemR23 in human coronary arteries and cultured human vascular cells. The effects of chemerin and chemerin-9 on atheroprone phenomena were assessed in human THP1 monocytes, human umbilical vein endothelial cells (HUVECs), and human aortic smooth muscle cells (HASMCs) and aortic lesions in Apoe-/- mice. In patients with CAD, a small amount of ChemR23, but not chemerin, was expressed within atheromatous plaques in coronary arteries. Chemerin and ChemR23 were expressed at high levels in THP1 monocytes, THP1-derived macrophages, and HUVECs; however, their expression in HASMCs was weak. Chemerin and chemerin-9 significantly suppressed the tumor necrosis factor-α (TNF-α)-induced mRNA expression of adhesion and pro-inflammatory molecules in HUVECs. Chemerin and chemerin-9 significantly attenuated the TNF-α-induced adhesion of THP1 monocytes to HUVECs and macrophage inflammatory phenotype. Chemerin and chemerin-9 suppressed oxidized low-density lipoprotein (oxLDL)-induced macrophage foam cell formation associated with down-regulation of CD36 and up-regulation of ATP-binding cassette transporter A1 (ABCA1). In HASMCs, chemerin and chemerin-9 significantly suppressed migration and proliferation without inducing apoptosis. In the Apoe-/- mice, a 4-week infusion of chemerin-9 significantly decreased the areas of aortic atherosclerotic lesions by reducing intraplaque macrophage and SMC contents. Our results indicate that chemerin-9 prevents atherosclerosis. Therefore, the development of chemerin analogs/ChemR23 agonists may serve as a novel therapeutic target for atherosclerotic diseases.

High-throughput method to analyze tegafur and 5-fluorouracil in human tears and plasma using hydrophilic interaction liquid chromatography/tandem mass spectrometry.

RATIONALE: We developed a new high-throughput method to analyze tegafur (FT) and 5-fluorouracil (5-FU) in tear and plasma samples using hydrophilic interaction liquid chromatography (HILIC)/tandem mass spectrometry (MS/MS). METHODS: The tear samples (10 µL) spiked with FT, 5-FU, and 5-chlorouracil (internal standard) were diluted using 40 µL of 2 M ammonium acetate and 250 µL of acetonitrile with 2% formic acid; 20 µL of plasma spiked with the two drugs and internal standard was diluted with 80 µL of 2 M ammonium acetate and 500 µL of acetonitrile with 2% formic acid. After centrifugation, the clear supernatant extract (15 µL) was directly injected into the HILIC/MS/MS instrument, and each drug was separated on a Unison UK-Amino column (50 mm × 3 mm i.d., 3 µm particle size) with a linear gradient elution system composed of 10 mM ammonium acetate (pH 6.8) and acetonitrile at a flow rate of 0.7 mL/min. We performed quantification by multiple reaction monitoring (MRM) with negative-ion atmospheric-pressure chemical ionization. RESULTS: Distinct peaks were observed for the drugs on each MRM channel within 2 min. The regression equations showed good linearity within the range 0.04-4.0 µg/mL for the tear and plasma samples with detection limits at 0.02-0.04 µg/mL. Recoveries for target analytes (FT and 5-FU) for the tear and plasma samples were in the 94-128% and 94-104% ranges, respectively. The intra- and inter-day coefficients of variation for the two drugs were lower than 10.8%. The accuracies of quantitation were 97-115% for both samples. CONCLUSIONS: We established a high-throughput, reproducible, and practical procedure for analyzing FT and 5-FU in human tear and plasma samples using HILIC/MS/MS analysis with an aminopropyl-bonded mixed-mode separation column. This method can be applied to the high-throughput routines used in clinical analyses.

Intracardiac Thrombosis and Heart Failure in a Patient with Hepatocellular Carcinoma and Cardiac Amyloidosis and an Implanted Cardiac Resynchronization Therapy Device.

BACKGROUND Intracardiac thrombosis has been known to be associated with not only hepatocellular carcinoma but also with amyloidosis and use of a cardiac implantable electronic device. We report a case of a continuous tumor thrombus with hepatocellular carcinoma from the portal vein and hepatic vein to the right atrium via the inferior vena cava in a patient with a cardiac amyloidosis and an implanted cardiac resynchronization therapy (CRT) device. CASE REPORT A 68-year-old female first admitted to our hospital because of heart failure with an AL type primary cardiac amyloidosis. After 3 years, she underwent an implantation of a CRT device for biventricular pacing following repeated episodes of heart failure and low left ventricular ejection fraction of 34% with NYHA class III. Again, she presented with symptoms of heart failure and cardiomegaly on chest x-ray at 7 years after the CRT device implantation. The echocardiography showed a huge echogenic mass occupying the right atrium, and 64 multi-detector computed tomography showed a lobulated heterogeneously enhancing mass of hepatocellular carcinoma in the right upper lobe of her liver and a continuous tumor thrombus from the portal vein and hepatic vein to the right atrium via the inferior vena cava. CONCLUSIONS Intracardiac thrombosis and heart failure occurred in a patient with hepatocellular carcinoma and cardiac amyloidosis, who had an implanted CRT device, which resulted not only in hypercoagulability by the hepatocellular carcinoma itself and the accumulation of various risk factors, but also the progression of myocardial damage with the development of amyloidosis.

Establishment of the Global SEND Alliance (G-SEND) in Japan and efficient creation of electronic SEND datasets between CROs.

The Standard for Exchange of Nonclinical Data (SEND), adopted by the US Food and Drug Administration (FDA), is a set of regulations for digitalization and standardization of nonclinical study data; thus, related organizations have begun implementing processes in support of SEND. The Global Editorial and Steering Committee (GESC), which provides oversight of the International Harmonization of Nomenclature and Diagnostic Criteria (INHAND), has prepared the SEND Controlled Terminology (CT) for toxicologic pathology. SEND provides electronic data standards created by the Clinical Data Interchange Standards Consortium (CDISC), and CDISC also collaborates in the implementation of SEND. Furthermore, the Pharmaceutical Users Software Exchange (PhUSE), which includes members of the US FDA, has conducted various activities to promote realistic and effective methods to implement SEND. As we reported in 2015, there is a significant variation in the efficiency and quality of SEND data implementation across pharmaceutical companies and contractors (CROs) globally. To address this problem, the Global SEND Alliance (G-SEND) was established in August 2018 to facilitate the coordination and standardization of SEND datasets across CROs in Asia. This paper reports the first method for organizationally and jointly creating consistent SEND datasets between CROs using G-SEND.