Real-world data of HER2-negative early breast cancer patients treated with anthracycline and/or taxane regimens in Japan.

BACKGROUND: Anthracycline- and taxane-based chemotherapy regimens are established treatments for human epidermal growth factor receptor (HER)2-negative early-stage breast cancer with high risk of recurrence. This study examined the prevalence of these chemotherapy regimens as perioperative therapy, the patterns of retreatment, and factors influencing prescription choices in Japan. METHODS: This observational cohort study focused on high-risk early-stage breast cancer patients not undergoing anti-HER2 therapy, utilizing data from a hospital-based claims database in Japan spanning from April 2008 to September 2021. RESULTS: Of 42,636 high-risk patients who underwent breast cancer surgery, 32,133 (75.4%) were categorized as having luminal-type (received endocrine therapy) and 10,503 (24.6%) as having triple-negative cancer (not receiving any endocrine therapies). Most patients (98.7%) with luminal-type breast cancer received perioperative therapy, and 40.3% of those received anthracycline/taxane. In the triple-negative group, 57.0% of all patients received perioperative therapy and of those, 93.4% received anthracycline/taxane. Being over 40 years old, having an early stage (clinical stage ≤ II), and receiving treatment in non-specialized facilities were associated with less use of anthracycline/taxane in the luminal-type group. For the triple-negative group, associated factors with less use of anthracycline/taxane included being over 60 years old, treatment in small hospital (capacity < 200 beds), and treatment in non-specialized facilities. CONCLUSIONS: Approximately half the patients in both the luminal-type and triple-negative groups were prescribed anthracycline and/or taxane for perioperative chemotherapy. The choice was associated with patient age, cancer stage, and the scale and specialization of the treatment facilities. This study sheds light on the current state of breast cancer treatment practices in Japan.

Oral Corticosteroid Reduction Between Biologics Initiated and Non-Initiated Patients with Severe Asthma.

Purpose: The oral corticosteroid (OCS)-sparing effect of several biologics (BIOs) has been shown in clinical trials. To date, no study has evaluated differences in OCS dose reduction between BIO-initiated and BIO-non-initiated patients in real-world clinical practice. We compared dose reductions in maintenance OCS between BIO-initiated and BIO-non-initiated severe asthma patients in a real-world setting. Patients and Methods: This retrospective cohort study used the data from the Diagnosis Procedure Combination database of Medical Data Vision in Japan. Severe asthma patients with continuous use of OCS were selected from December 2015 to February 2020. The primary endpoint was the proportion reduction in daily maintenance OCS dose from Week 0 to Week 24. Analyses were performed using inverse probability treatment weighting. Results: In total, 2927 patients were included (BIO-initiated: 239 patients, BIO-non-initiated: 2688 patients). Adjusted median (quartile [Q] 1-Q3) proportion reduction in daily maintenance OCS dose at Week 24 from the index date was 25.0% (0.0-100.0%) and 0.0% (0.0-83.3%) in the BIO-initiated and BIO-non-initiated groups, respectively (Hodges-Lehmann estimate [95% confidence interval], 0.0000% [0.0000-0.3365%]). Respective proportions of patients in the BIO-initiated and BIO-non-initiated groups achieving dose reductions from the index date in the daily maintenance OCS dose at Week 24 were >0% reduction, 56.6% and 44.1% (odds ratio [OR] 1.6554); ≥25% reduction, 50.5% and 40.6% (OR 1.4888); ≥50% reduction, 42.8% and 33.7% (OR 1.4714); and 100% reduction, 26.2% and 24.4% (OR 1.1005). Conclusion: Among severe asthma patients, the daily dose of maintenance OCS was reduced with BIO treatment. Although a higher percentage of patients in the BIO-initiated group had an OCS reduction of ≤75% than the BIO-non-initiated group, we found no clear difference in OCS reduction. Our findings will be justified by further research that incorporates a longer observation period and variables excluded from this study. Trial Registration: ClinicalTrials.gov (NCT05136547).

Targeting apolipoprotein E and N-terminal amyloid ß-protein precursor interaction improves cognition and reduces amyloid pathology in Alzheimer's mice.

Apolipoprotein E (apoE) interaction with amyloid ß-protein precursor (APP) has garnered attention as the therapeutic target for Alzheimer's disease (AD). Having discovered the apoE antagonist (6KApoEp) that blocks apoE binding to N-terminal APP, we tested the therapeutic potential of 6KApoEp on AD-relevant phenotypes in amyloid ß-protein precursor/presenilin 1 (APP/PS1) mice that express each human apoE isoform of apoE2, apoE3, or apoE4 (designated APP/PS1/E2, APP/PS1/E3, or APP/PS1/E4 mice). At 12 months of age, we intraperitoneally administered 6KApoEp (250 µg/kg) or vehicle once daily for 3 months. At 15 months of age, blockage of apoE and N-terminal APP interaction by 6KApoEp treatment improved cognitive impairment in most tests of learning and memory, including novel object recognition and maze tasks in APP/PS1/E2, APP/PS1/E3, and APP/PS1/E4 mice versus each vehicle-treated mouse line and did not alter behavior in nontransgenic littermates. Moreover, 6KApoEp therapy ameliorated brain parenchymal and cerebral vascular ß-amyloid deposits and decreased abundance of amyloid ß-protein (Aß) in APP/PS1/E2, APP/PS1/E3, and APP/PS1/E4 mice versus each vehicle-treated mouse group. Notably, the highest effect in Aß-lowering by 6KApoEp treatment was observed in APP/PS1/E4 mice versus APP/PS1/E2 or APP/PS1/E3 mice. These effects occured through shifting toward lessened amyloidogenic APP processing due to decreasing APP abundance at the plasma membrane, reducing APP transcription, and inhibiting p44/42 mitogen-activated protein kinase phosphorylation. Our findings provide the preclinical evidence that 6KApoEp therapy aimed at targeting apoE and N-terminal APP interaction is a promising strategy and may be suitable for patients with AD carrying the apoE4 isoform.

Comparison of Intra-Familial Transmission of Influenza Virus From Index Patients Treated With Baloxavir Marboxil or Oseltamivir Using an Influenza Transmission Model and a Health Insurance Claims Database.

BACKGROUND: Influenza affects approximately a billion people globally, including > 10 million Japanese individuals every year. Baloxavir marboxil (baloxavir [BXM]; a selective cap-dependent endonuclease inhibitor) is approved for influenza treatment in Japan. We compared the incidence of intra-familial transmission of influenza between BXM and oseltamivir (OTV) treatments using a simulation model. METHODS: Using the JMDC Claims Database, we identified index case (IC) as the first family member diagnosed with influenza during the 2018-19 influenza season, and classified the families into BXM or OTV group per the drug dispensed to ICs. Using a novel influenza intra-familial infection model, we simulated the duration of influenza infection in ICs based on agent-specific virus shedding periods. Intra-familial infections were defined as non-IC family members infected during the agent-specific viral shedding period in ICs. The virus incubation periods in the non-IC family members were considered to exclude secondary infections from potentially external exposure. The primary endpoint was proportion of families with intra-familial infections. For between-group comparisons, we used a multivariate logistic regression model. RESULTS: The median proportion of families with intra-familial transmission was 9.57% and 19.35% in the BXM (N = 84 672) and OTV (N = 62 004) groups, respectively. The multivariate odds ratio of 1.73 (2.5th-97.5th percentiles, 1.68-1.77) indicated a substantially higher incidence of intra-familial infections in the OTV group versus the BXM group. Subgroup analyses by ICs' age category, virus type, and month of onset revealed similar trends favoring BXM. CONCLUSIONS: BXM treatment of ICs may contribute to a greater reduction in intra-familial influenza transmission than OTV treatment.

Effects of Lusutrombopag on Post-invasive Procedural Bleeding in Thrombocytopenic Patients with Chronic Liver Disease.

INTRODUCTION: Thrombocytopenia can increase the bleeding risk in patients with chronic liver disease (CLD) undergoing invasive procedures. Prophylactic platelet transfusion (PT) is often performed to increase platelet counts in patients with CLD undergoing invasive procedures to prevent bleeding. Lusutrombopag, a small-molecule thrombopoietin receptor agonist, is expected to be an alternative therapy to prophylactic PT. This study aimed to compare the effects between lusutrombopag and PT. METHODS: Data were obtained from a Japanese administrative database (April 2008-May 2019). Patients aged ≥ 18 years who underwent planned invasive procedures after the first CLD diagnosis and were observed for ≥ 30 days prior to invasive procedures were considered eligible. Patients who underwent planned invasive procedures with lusutrombopag prescription at 5-30 days before the procedure were categorized as the lusutrombopag group, whereas those who received PT at 1 day before and/or on the same day as the procedure, without lusutrombopag prescription, were classified as the PT group. Outcomes, including bleeding frequency during hospitalization and average medical costs (costs for prophylactic treatment and total costs between the day of the invasive procedure and 30 days after the invasive procedure), were compared between the groups after matching. RESULTS: Among 738,878 patients with CLD, 379 cases for each group were identified after matching. The incidence of bleeding events was lower in the lusutrombopag group than in the PT group (3.7% vs. 8.2%, p < 0.001). Average medical costs were lower in the lusutrombopag group than in the PT group ($6667 as of August 2021 vs. $7170, p = 0.011). CONCLUSION: Lusutrombopag is suggested to be effective as a prophylactic treatment for bleeding prevention in patients with CLD undergoing planned invasive procedures.

Comparison of the incidence of bleeding between baloxavir marboxil and other anti-influenza drugs among outpatients with influenza virus infection: A retrospective cohort study using an employment-based health insurance claims database in Japan.

PURPOSE: Alerts for bleeding events are included in the Japanese package inserts of some anti-influenza drugs, including baloxavir marboxil and oseltamivir. However, there are few reports on the incidence of bleeding events during treatment with anti-influenza drugs. This large-scale quantitative assessment compared the incidence of bleeding events in influenza patients treated with baloxavir and other anti-influenza drugs and in untreated patients. METHODS: This retrospective cohort study used a large-scale Japanese employment-based health insurance claims database provided by JMDC Inc. and included outpatients diagnosed with influenza between October 1, 2018 and April 11, 2019. Bleeding events were identified by International Classification of Diseases 10th revision codes. Incidences were compared between patients treated with baloxavir or neuraminidase inhibitors and untreated patients. Odds ratios were calculated after exact matching to adjust for potential confounders. RESULTS: Among 529 201 influenza episodes, 30 964 were untreated and 498 237 were treated with anti-influenza drugs: baloxavir, 207 630; oseltamivir, 143 722; zanamivir, 28 208; peramivir, 5304; laninamivir, 113 373. Crude incidence proportions for total bleeding up to 20 days after influenza diagnosis were similar among treated groups, with a slightly higher value for peramivir (0.21% vs. 0.19% for baloxavir, oseltamivir, zanamivir, and laninamivir), and 0.30% in untreated patients. After exact matching, the incidence of bleeding for baloxavir was similar to that for other anti-influenza treatments (odds ratios for baloxavir were 0.90-0.99 compared to other therapies). CONCLUSIONS: Based on real-world observation using a large-scale claims database, a similar incidence of bleeding events was observed in recipients of the different anti-influenza drugs.

Changes in Platelet Counts and Thrombocytopenia Risk in Patients with Chronic Liver Disease with Different Etiologies Using Real-World Japanese Data.

INTRODUCTION: Thrombocytopenia, a common complication of chronic liver disease (CLD), adversely affects the treatment in patients requiring invasive procedures. Multiple pathophysiological mechanisms contribute to the development of thrombocytopenia; thus, its incidence could differ among CLD etiologies. We investigated the risk of decline in platelet counts and developing thrombocytopenia across different CLDs in a real-world Japanese setting. METHODS: A Japanese claims database including 25 million patients (April 2008-August 2018) was used. Patients with at least one CLD diagnosis were classified into nine mutually exclusive categories: hepatitis B, hepatitis C, hepatitis B and C, unspecified viral hepatitis, autoimmune hepatitis, toxin/drug-induced hepatitis, alcoholic hepatitis, nonalcoholic steatohepatitis, and others. A random effects model was used to estimate the changes in platelet counts; proportional hazard analyses were used to examine factors associated with the incidence of thrombocytopenia based on the diagnosis. Patients with laboratory test data as variables were included in each analysis. RESULTS: The simulation included 68,536 patients. The mean values representing changes in the platelet count were significantly negative in the hepatitis C patients and negative, though non-significant, in the hepatitis B, toxin/drug-induced hepatitis, alcoholic hepatitis, and nonalcoholic steatohepatitis patients. In the proportional hazard analysis, 708 of 22,728 patients had thrombocytopenia. The hazard ratio (HR) was significantly high for patients with hepatitis B (HR, 2.879; p < 0.001), hepatitis C (HR, 1.876; p < 0.001), and hepatitis B and C (HR, 2.992; p < 0.001). CONCLUSION: A decreasing tendency in platelet counts was observed in most CLD etiologies, with hepatitis C showing a significant decrease. The incidence of thrombocytopenia was mostly associated with hepatitis B and/or C. Further research is warranted to elucidate the discrepancy between the decline in platelet counts and thrombocytopenia diagnosis, considering the factors relevant to the diagnosis, such as the frequency of outpatient visits and CLD treatment.

Change in Antidepressant Use After Initiation of ADHD Medication in Japanese Adults with Comorbid Depression: A Real-World Database Analysis.

PURPOSE: To better understand the treatment of comorbid depression in adults with attention-deficit/hyperactivity disorder (ADHD) by investigating the prescription patterns of antidepressants, anxiolytics, and hypnotics after commencing ADHD medication. PATIENTS AND METHODS: In this retrospective observational study in Japan, the data of patients initiating ADHD medication while already receiving antidepressants (ADHD group) and of patients prescribed antidepressants but not diagnosed with ADHD (control group) were extracted from an electronic medical record database. Additionally, one-to-one matching for patients in both groups was performed using sex, age, baseline dosage of antidepressants, and any comorbid psychiatric disorders as covariates. The observation period included a 1-month baseline period and a 6-month follow-up period. The percentage of patients prescribed antidepressants and the mean prescribed dosages were compared between matched-cohort groups. Prescriptions for anxiolytics and hypnotics were also assessed. RESULTS: In the matched cohorts, consisting of 239 patients in the ADHD group and 239 patients from the unmatched control cohort of 10,485, the percentage of patients prescribed antidepressants decreased from baseline in both groups to 94.1% in the ADHD group and 89.5% in the control group during the first month of follow-up, and 77.0% and 78.7%, respectively, during the last month. There were no significant differences between groups in the percentages of patients prescribed antidepressants or in the mean prescribed dosages of antidepressants at any time point over the follow-up period. Prescribed dosages of anxiolytics and hypnotics tended to be lower in the ADHD group. CONCLUSION: The two groups were medicated similarly with respect to their depressive symptoms over 6 months. Our results suggest that in patients with ADHD and comorbid depression, which is more likely to be more severe than in depression without ADHD, depressive symptoms are managed following initiation of add-on ADHD medication, without requiring higher antidepressant dosages than in patients with depression only.

Efficacy and Safety of Medication for Attention-Deficit Hyperactivity Disorder in Children and Adolescents with Common Comorbidities: A Systematic Review.

INTRODUCTION: Comorbid psychiatric conditions in children and adolescents with attention-deficit hyperactivity disorder (ADHD) occur frequently, complicate management, and are associated with substantial burden on patients and caregivers. Very few systematic reviews have assessed the efficacy and safety of medications for ADHD in children and adolescents with comorbidities. Of those that were conducted, most focused on a particular comorbidity or medication. In this systematic literature review, we summarize the efficacy and safety of treatments for children and adolescents with ADHD and comorbid autism spectrum disorders, oppositional defiant disorder, Tourette's disorder and other tic disorders, generalized anxiety disorder, and major depressive disorder. METHODS: We searched MEDLINE, Embase, and ClinicalTrials.gov (to October 2019) for studies of patients (aged < 18 years) with an ADHD diagnosis and the specified comorbidities treated with amphetamines, methylphenidate and derivatives, atomoxetine (ATX), and guanfacine extended-release (GXR). For efficacy, placebo-controlled randomized controlled trials (RCTs) or meta-analyses of RCTs were eligible for inclusion; for safety, all study types were eligible. The primary efficacy outcome measure was ADHD Rating Scale IV (ADHD-RS-IV) total score. RESULTS: Of 2177 publications/trials retrieved, 69 were included in this systematic literature review (5 meta-analyses, 37 placebo-controlled RCTs, 16 cohort studies, 11 case reports). A systematic narrative synthesis is provided because insufficient data were retrieved to combine ADHD-RS-IV total scores or effect sizes. Effect sizes for ADHD-RS-IV total scores were available for ten RCTs and ranged from 0.46 to 1.0 for ATX and from 0.92 to 2.0 for GXR across comorbidities. The numbers and types of adverse events in children with comorbidities were consistent with those in children without comorbidities, but treatment should be individualized to ensure children can tolerate the lowest effective dose. CONCLUSION: Limited information is available from placebo-controlled RCTs on the efficacy (by ADHD-RS-IV) or safety of medication in children with ADHD and psychiatric comorbidities. Further studies are required to support evidence-based drug selection for these populations.

Patient journey through cases of depression from claims database using machine learning algorithms.

Health insurance and acute hospital-based claims have recently become available as real-world data after marketing in Japan and, thus, classification and prediction using the machine learning approach can be applied to them. However, the methodology used for the analysis of real-world data has been hitherto under debate and research on visualizing the patient journey is still inconclusive. So far, to classify diseases based on medical histories and patient demographic background and to predict the patient prognosis for each disease, the correlation structure of real-world data has been estimated by machine learning. Therefore, we applied association analysis to real-world data to consider a combination of disease events as the patient journey for depression diagnoses. However, association analysis makes it difficult to interpret multiple outcome measures simultaneously and comprehensively. To address this issue, we applied the Topological Data Analysis (TDA) Mapper to sequentially interpret multiple indices, thus obtaining a visual classification of the diseases commonly associated with depression. Under this approach, the visual and continuous classification of related diseases may contribute to precision medicine research and can help pharmaceutical companies provide appropriate personalized medical care.

Comparison of Household Transmission of Influenza Virus From Index Patients Treated With Baloxavir Marboxil or Neuraminidase Inhibitors: A Health Insurance Claims Database Study.

BACKGROUND: Baloxavir marboxil (baloxavir) is expected to reduce influenza transmission by rapid reduction of viral load. The incidence of household transmission was compared between index patients (IPs) treated with baloxavir and those treated with neuraminidase inhibitors. METHODS: Using a Japanese claims database, the first family members with influenza diagnosis during the 2018-2019 influenza season were identified as IPs, and the diagnosis date was designated day 1. According to the anti-influenza drug dispensed to the IP, their families were classified into the oral baloxavir group and 3 controls: oral oseltamivir group (a primary control), inhaled zanamivir group, and inhaled laninamivir group. A household transmission was defined as influenza diagnosed for any non-IP family members during days 3-8. The incidence of household transmission was compared between groups using a logistic regression model adjusting backgrounds of IPs. RESULTS: The proportion of families with household transmission was 17.98% (15 226 of 84 672) in the baloxavir group and 24.16% (14 983 of 62 004) in the oseltamivir group. The covariate-adjusted odds ratio (oseltamivir/baloxavir) was 1.09 (95% confidence interval [95% CI], 1.05-1.12), which indicated significantly lower incidence in the baloxavir group. The adjusted odds ratios (controls/baloxavir) against zanamivir and laninamivir were 0.93 (95% CI, .89-.97) and 0.99 (95% CI, .96-1.02), respectively. CONCLUSIONS: Baloxavir may contribute to reduction in household transmission compared with oseltamivir. In comparison between baloxavir and inhalants, a similar reduction was not shown and it might be due to unmeasured confounding by administration route differences.

Comparison of Hospitalization Incidence in Influenza Outpatients Treated With Baloxavir Marboxil or Neuraminidase Inhibitors: A Health Insurance Claims Database Study.

BACKGROUND: Baloxavir marboxil (baloxavir) is a single-dose, oral antiinfluenza drug with a novel mechanism of action. We compared the incidence of hospitalization in patients treated with baloxavir vs neuraminidase inhibitors. METHODS: In this retrospective, observational, cohort study, we used real-world patient data extracted from a Japanese health insurance claims database. The enrollment period was 1 October 2018 to 17 April 2019. On day 1, eligible patients (N = 339 007) received baloxavir, oseltamivir, zanamivir, or laninamivir. Baseline characteristics were standardized using the inverse probability of treatment weighting method. The primary end point was the incidence of hospitalization (days 2-14). Secondary end points included antibacterial use, secondary pneumonia, and additional antiinfluenza drug use. RESULTS: Compared with the baloxavir group, the incidence of hospitalization was greater in the oseltamivir group (risk ratio [RR] and 95% confidence interval [CI], 1.41 [1.00-2.00]; risk difference [RD] and 95% CI, 0.06 [.01-.12]) and zanamivir group (RR, 1.85 [1.23-2.78]; RD, 0.11 [.02-.20]). Oseltamivir-treated patients were less likely to require antibacterials than baloxavir-treated patients (RR, 0.87 [.82-.91]). However, oseltamivir-treated patients were more likely to be hospitalized with antibacterials (RR, 1.70 [1.21-2.38]) or antibacterial injection (RR, 1.67 [1.17-2.38]) than baloxavir-treated patients (post hoc analysis). Compared with baloxavir-treated patients, additional antiinfluenza drug use was greater in oseltamivir-, zanamivir-, and laninamivir-treated patients (RR, 1.51 [1.05-2.18], 2.84 [2.04-3.96], and 1.68 [1.35-2.10], respectively). CONCLUSIONS: Baloxavir is an efficacious antiinfluenza treatment that may reduce hospitalization compared with oseltamivir and zanamivir. CLINICAL TRIALS REGISTRATION: University hospital Medical Information Network Clinical Trials Registry (UMIN000038159).

Efficacy and safety of guanfacine extended-release in Japanese adults with attention-deficit/hyperactivity disorder: Exploratory post hoc subgroup analyses of a randomized, double-blind, placebo-controlled study.

AIM: Previously, we reported on the efficacy and safety of guanfacine extended-release (GXR) in Japanese adults with attention-deficit/hyperactivity disorder (ADHD) from a phase 3, double-blind, placebo-controlled, randomized trial. In this exploratory post hoc analysis, we assessed the efficacy and/or safety of GXR in the following subgroups: ADHD-combined (ADHD-C) and ADHD-predominantly inattentive (ADHD-I) subtypes, age (≥31, <31 years), sex (male, female), and body weight (≥50, <50 kg). METHODS: The primary efficacy endpoint was change from baseline in the Japanese version of the investigator-rated ADHD-Rating Scale-IV (ADHD-RS-IV) with adult prompts (total scores) at week 10. RESULTS: The efficacy analysis population included 200 patients (GXR, 100; placebo, 100). ADHD-RS-IV total score effect sizes (GXR vs placebo) were similar across all subgroups (total population: 0.52, ADHD-C: 0.51, ADHD-I: 0.52, ≥31 years: 0.61, <31 years: 0.47, male: 0.50, female: 0.57). There were no major differences in the incidence/types of treatment-emergent adverse events (TEAEs) across the subgroups. The incidence of significant TEAEs (34.3%, 10.6%) and TEAEs leading to discontinuation (34.3%, 12.1%) were approximately three times higher in females than males, respectively. The incidence of TEAEs in patients weighing <50 kg and ≥50 kg was 100% and 73.6% during dose optimization and 40% and 24.4% during the maintenance period, respectively. CONCLUSION: Findings from this post hoc analysis in adults with ADHD support the efficacy and safety of GXR regardless of ADHD subtype, age, or sex and suggest that careful monitoring for TEAEs and GXR dose optimization is considered for all patients, as needed.

Safety and efficacy of guanfacine extended-release in adults with attention-deficit/hyperactivity disorder: an open-label, long-term, phase 3 extension study.

BACKGROUND: To assess the safety and efficacy of long-term administration of guanfacine extended-release (GXR) in adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: In this open-label, long-term, phase 3 extension study in Japan, 150 patients transitioned from a double-blind trial, and 41 newly enrolled patients received once daily GXR (starting dose 2 mg/day, maintenance dose 4-6 mg/day) for 50 weeks. Primary outcome measures were the frequency and nature of treatment-emergent adverse events (TEAEs); secondary outcome measures included the change from week 0 in ADHD Rating Scale IV with Adult Prompts (ADHD-RS-IV; Japanese version) total and subscale scores, Conners' Adult ADHD Rating Scales (CAARS), Clinical Global Impression-Improvement (CGI-I) and Patient Global Impression-Improvement (PGI-I) scales, and quality of life (QoL) and executive functioning measures. RESULTS: Of all patients, 94.2% (180/191) reported ≥1 TEAE and 19.9% (38/191) discontinued because of a TEAE. Most TEAEs were mild to moderate in severity; there were two serious TEAEs and no deaths. Commonly reported TEAEs (≥10% of patients) were somnolence, thirst, nasopharyngitis, decreased blood pressure, postural dizziness, bradycardia, malaise, constipation, and dizziness. Mean changes from week 0 in ADHD-RS-IV total and subscale scores and CAARS subscale scores were significantly improved in former placebo or GXR patients and new patients at last observation (p < .0001), and the percentage of patients with very much or much improved CGI-I and PGI-I scores increased. CONCLUSIONS: There were no major safety concerns during long-term GXR administration in adults with ADHD. After long-term treatment, patients had significant improvements from baseline in ADHD symptoms, QoL, and executive functioning. TRIAL REGISTRATION: Japan Primary Registries Network ( https://rctportal.niph.go.jp/en/ ): JapicCTI-163232, registered 04/21/2016.

Efficacy and Safety of Guanfacine Extended-Release in the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults: Results of a Randomized, Double-Blind, Placebo-Controlled Study.

OBJECTIVE: To assess guanfacine extended-release (GXR) efficacy and safety in adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: This phase 3, double-blind, placebo-controlled study (conducted between October 2016 and July 2017) included Japanese patients aged ≥ 18 years with ADHD (DSM-5). Patients received GXR (n = 101) or placebo (n = 100) titrated from 2 mg/d to 4-6 mg/d (dose-optimization; 5 weeks), followed by 4-6 mg/d (dose-maintenance; 5 weeks), then tapered doses to 2 mg/d (2 weeks). Primary endpoint was change from baseline in total score on the Japanese version of the ADHD-Rating Scale IV with adult prompts (ADHD-RS-IV) at week 10. Other measures were ADHD-RS-IV subscales, Clinical Global Impression-Improvement scale (CGI-I) and Patient Global Impression-Improvement scale (PGI-I) (percentage of patients very much improved/much improved), treatment-emergent adverse event (TEAE) incidences, and TEAEs leading to discontinuation. RESULTS: Compared with placebo, there was statistically significantly greater improvement in ADHD-RS-IV total score reduction with GXR (least squares mean ± SE: GXR vs placebo, -11.55 ± 1.10 vs -7.27 ± 1.07; P = .0005; effect size 0.52). There were significantly greater improvements in GXR for ADHD-RS-IV inattention (-7.39 ± 0.79 vs -4.89 ± 0.76; P = .0032) and hyperactivity-impulsivity (-3.84 ± 0.54 vs -2.10 ± 0.52; P = .0021) subscale scores, CGI-I scores (48.1% vs 22.6%; P = .0007), and PGI-I scores (25.3% vs 11.8%; P = .0283). More patients in the GXR versus the placebo group reported TEAEs (81.2% vs 62.0%) and discontinued due to TEAEs (19.8% vs 3.0%). The main TEAEs in the GXR group were somnolence, thirst, blood pressure decrease, nasopharyngitis, postural dizziness, and constipation; most TEAEs were mild to moderate in severity. CONCLUSIONS: In Japanese adults with ADHD, GXR improved ADHD symptoms without any major safety concerns. Trial Registration: Japan Primary Registries Network (https://rctportal.niph.go.jp/en): JapicCTI-163231

Phase II/III Study of Lisdexamfetamine Dimesylate in Japanese Pediatric Patients with Attention-Deficit/Hyperactivity Disorder.

Objective: To further define the efficacy and safety profiles of lisdexamfetamine dimesylate (LDX) in Japanese pediatric patients with attention-deficit/hyperactivity disorder (ADHD). Methods: This was a multicenter, randomized, double-blind, placebo-controlled study of LDX 30, 50, or 70 mg/day for 4 weeks in 76 patients 6-17 years of age with ADHD in Japan. The primary efficacy endpoint was the change in the ADHD Rating Scale-IV (ADHD-RS-IV) total score from baseline to 4 weeks. Secondary efficacy endpoints were: Conners' Third Edition (Japanese version) Parent Rating Scale (Conners 3), Clinical Global Impression-Improvement (CGI-I) scale, and Parent Global Assessment (PGA) scale. Results: Change in the ADHD-RS-IV total score from baseline to 4 weeks was significantly greater (p < 0.0001) in all LDX dosage groups versus placebo (30 mg, -16.38; 50 mg, -18.10; 70 mg, -16.47; placebo, -2.78). At all time points, improvements (decreases) in the ADHD-RS-IV total score were significantly greater in all LDX groups versus placebo. At weeks 3 and 4, improvements from baseline in Conners 3 inattention plus hyperactivity/impulsivity subscale scores were significantly greater (p ≤ 0.0082) for all LDX dosages versus placebo. At week 4, the proportion of LDX-treated patients "much improved" or "very much improved" was 61%-71% on the CGI-I scale (p ≤ 0.0019) and 56%-65% on the PGA scale (p ≤ 0.0170). LDX was generally well tolerated. The most frequent treatment-emergent adverse events (AEs) were decreased appetite, headache, and initial insomnia. No severe/serious AEs occurred, and no AEs specific to Japanese patients were evident. Conclusions: The superiority of LDX 30, 50, and 70 mg/day over placebo was confirmed in Japanese pediatric patients with ADHD, and no major safety or tolerability concerns were identified.

Long-term study of lisdexamfetamine dimesylate in Japanese children and adolescents with attention-deficit/hyperactivity disorder.

AIMS: As an extension of a phase 2/3 study evaluating the efficacy and safety of lisdexamfetamine dimesylate (LDX) 30, 50, or 70 mg/d for 4 weeks in Japanese patients aged 6-17 years with attention-deficit/hyperactivity disorder (ADHD), this study evaluated its long-term safety and efficacy. METHODS: This was a multicenter, open-label study of LDX for 53 weeks. Safety was assessed by regular medical examination for treatment-emergent adverse events (TEAEs); regular recording of body weight, vital signs, and laboratory test values; and completion of dependence questionnaires. Efficacy was assessed using Japanese versions of the ADHD-Rating Scale-IV (ADHD-RS-IV) and Conners' 3rd edition Parent Rating Scale (Conners 3); plus Clinical Global Impression-Improvement (CGI-I), Clinical Global Impression-Severity, and Parent Global Assessment (PGA) scales. RESULTS: Of 132 enrolled patients, 104 completed the trial. Most frequent treatment-related TEAEs were decreased appetite (73.5%), initial insomnia (39.4%), and weight decrease (22.0%). Most TEAEs were mild (82.6% of patients). There were no serious or severe TEAEs or deaths. No treatment-related TEAEs were associated with blood pressure or pulse rate, and no patient had a QTcF interval >500 ms. Statistically significant improvement from baseline to week 53 was observed in the mean ADHD-Rating Scale-IV total score and mean Conners 3 subscale scores. Most patients showed improvement on the CGI-I (78%) and PGA (76.5%) scales. CONCLUSIONS: No significant safety issues were observed with LDX 30, 50, or 70 mg/d administered for 1 year in Japanese children and adolescents with ADHD. LDX was associated with long-term reductions in ADHD symptoms and severity.

Characterization of the metastatic potential of the floating cell component of MIA PaCa-2, a human pancreatic cancer cell line.

In pancreatic cancer, morphologically and functionally heterogeneous cancer cells reside within the same patient. The heterogeneity is believed to promote metastasis and resistance to chemoradiotherapy. MIA PaCa-2, an established human pancreatic ductal adenocarcinoma (PDAC) cell line, contains round and spindle-shaped adherent cells, as well as, round floating cells. In this study, we aimed to assess if the floating cells might have greater metastatic potential and/or be more resistant to drug-induced apoptosis compared to adherent cells. Time-lapse analysis revealed that the two types of adherent cells transformed bilaterally, and some of the adherent, round cells converted to floating cells. Flow cytometry and electron microscopy showed that approximately 90% of the floating cells were viable. qRT-PCR analysis revealed that floating cells expressed lower levels of integrins and ATP-binding cassette (ABC) transporters than adherent cells. In contrast, except for vimentin, floating cells expressed more epithelial to mesenchymal transition markers than adherent cells. Floating cells included a larger population of G2/M-phase cells, and migration assays revealed a decreased migration ability by floating cells relative to adherent cells. A cell aggregation assay showed that the aggregative properties of the floating cells were lower than those of the adherent cells. In 3D culture, spheres derived from floating cells were more sensitive to anti-cancer drugs, including gemcitabine, 5-FU, and abraxane, than those derived from adherent cells. Expression levels of stemness markers in the spheres derived from floating cells were lower than those derived from adherent cells. Morphological characterization of human PDAC cell lines may help to clarify the series of alterations cancer cells undergo during the metastatic process and may contribute to the development of new PDAC diagnostics and more patient-specific treatments for those with PDAC.

Rap1b Promotes Notch-Signal-Mediated Hematopoietic Stem Cell Development by Enhancing Integrin-Mediated Cell Adhesion.

Hematopoietic stem cells (HSCs) emerge from hemogenic endothelium (HE) within the ventral portion of the dorsal aorta during vertebrate development. In zebrafish, Notch signaling induces HE specification from posterior lateral plate mesoderm (PLPM) cells as they migrate over the ventral surface of the somite. During migration, PLPM cells make close contact with Notch-ligand-expressing somitic cells to acquire HE identity. Herein, we show in zebrafish that the small GTPase Rap1b regulates HSC development by potentiating Notch-mediated HE specification. PLPM cells migrate toward the midline along the somite boundary where fibronectin accumulates. Rap1b stimulates integrin ß1 to enhance PLPM cell adhesion to fibronectin localized at the somite boundary. Rap1b-induced integrin-ß1-mediated adhesion to fibronectin leads to the spreading of PLPM cells to facilitate their physical contact with the Notch-ligand-expressing somitic cells, thereby promoting Notch-mediated HE specification. Thus, we have revealed an unexpected role of Rap1-induced integrin-mediated cell adhesion in HSC development.