Real-world evidence of systemic treatment practices for biliary tract cancer in Japan: Results of a database study.

PURPOSE: To describe the real-world treatment patterns of systemic therapies for biliary tract cancer (BTC) and to examine the frequency and management of biliary infection in Japan. METHODS: Patients diagnosed with BTC and prescribed systemic therapy between January 2011 and September 2020 were retrieved from the Japanese Medical Data Vision database. The look-back period was set to 5 years. Patient characteristics, treatment patterns, and biliary infection-induced treatment interruption were analyzed. RESULTS: The full analysis set comprised 22 742 patients with a mean age of 71.0 years and 61.6% were male. The most common BTC type was extrahepatic cholangiocarcinoma (44.6%). The three most common first-line regimens were S-1 monotherapy (33.0%), gemcitabine+cisplatin (32.5%), and gemcitabine monotherapy (18.7%) over the entire observation period (January 2011-September 2021). Patients who received monotherapies tended to be older. Biliary infection-induced treatment interruption occurred in 29.5% of patients, with a median time to onset of 64.0 (interquartile range 29.0-145.0) days. The median duration of intravenous antibiotics was 12.0 (interquartile range 4.0-92.0) days. CONCLUSIONS: These results demonstrated potential challenges of BTC in Japanese clinical practice particularly use of multiple regimens, commonly monotherapies, which are not recommended as first-line treatment, and the management of biliary infections during systemic therapy.

Changes in disease burden and treatment reality in patients with severe asthma.

BACKGROUND: Biologics are clinically available for patients with severe asthma, but changes in asthma control over time are unknown. We examined changes in disease burden and treatment in severe asthma patients. METHODS: This retrospective study used a Japanese health insurance database (Cross Fact) and included patients aged ≥16 years treated continuously with an inhaled corticosteroid (ICS) for a diagnosis of asthma in each calendar year from 2015 to 2019. Severe asthma was defined as annual use of high-dose ICS plus one or more asthma controller medications four or more times, oral corticosteroids for ≥183 days, or biologics for ≥16 weeks. Changes in asthma exacerbations, prescriptions, and laboratory testing were examined. RESULTS: Demographic characteristics were similar throughout the study. The number and proportion of patients with severe asthma among those with asthma increased (2724; 15.3% in 2015 vs 4485; 19.0% in 2019). The proportion of severe asthma patients with two or more asthma exacerbations decreased from 24.4% to 21.5%. Odds ratios (95% confidence interval) of ≥2 asthma exacerbations in each year compared with 2015 were 0.96 (0.85-1.08) in 2016 and 0.86 (0.76-0.97) in 2017, with significant reductions observed in subsequent years. Short-acting beta agonists and oral corticosteroid prescriptions for asthma exacerbations decreased and long-acting muscarinic antagonist and biologic prescriptions for maintenance treatment increased. CONCLUSIONS: This study showed improvements in disease burden and treatment in severe asthma patients. There remains an unmet medical need for patients with severe asthma, given the proportion who continue to have asthma exacerbations.

Effects of Dietary Brown Rice and Sake Lees on the Growth Performance and Color of Meat in Broiler Chicks.

In this study, we examined whether brown rice and sake lees (domestic feed ingredients) could replace corn and soybean meal (major imported feed ingredients) in broiler chick feed. In Experiment 1, 21-day-old broiler chicks were assigned to two groups and fed a corn-soybean- or a brown rice-soybean-based diet for three weeks (3 birds × 4 replicates/group). Dietary brown rice significantly improved body weight gain and feed conversion ratio. Brown rice feeding also significantly increased L* (lightness) in the thigh and significantly decreased a* (redness) and b* (yellowness) in the thigh and b* in the fat. In Experiment 2, 21-day-old broiler chicks were assigned to three groups and fed either a corn-soybean-based diet for 3 weeks, a corn-soybean-based diet for the first 2 weeks followed by a brown rice sake lees-based diet for the last week, or a brown rice sake lees-based diet for 3 weeks (3 birds × 4 replicates/group). Replacement of the imported feed ingredients significantly improved the feed conversion ratio. The a* values for the breast, thigh, and fat, and the b* values for the thigh and fat were significantly decreased by rice and sake lees feeding for 3 weeks. The a* values for the breasts and fat were significantly decreased by rice and sake lees feeding for 1 week. These results suggest that brown rice and sake lees can be used as replacements for imported feed ingredients such as corn and soybean meal in broiler chicks without detrimental effects on growth performance. These domestic feed ingredients may benefit local production and consumption of poultry in Japan.

A Retrospective Claims Database Study to Clarify Treatment Reality of Asthma Patients Before and After Referral to a Specialist.

Purpose: Japanese guidelines recommend that patients with uncontrolled asthma be referred by non-specialists to specialists (allergists and/or pulmonologists). This study investigated the reality of clinical practice in asthma patients referred to specialists in Japan. Patients and Methods: This was a retrospective, observational cohort study of asthma patients in a health insurance claim database (Cross Fact) referred from facilities with non-specialists to those with specialists from January 2016 to December 2018. The referred asthma patients were defined as patients with ≥4 inhaled corticosteroid (ICS)-containing prescriptions during a 1-year baseline period, with an asthma diagnosis, and who had visited a facility with specialists. Asthma exacerbation, maintenance treatment, laboratory tests, and medical procedures before and after referral were analyzed. Results: Data for 2135 patients were extracted, of which 420 with referral codes were analyzed. The proportion of patients with asthma exacerbations was 50.2% (95% confidence interval [CI]: 45.4-55.1%) before referral and 37.4% (95% CI: 32.7-42.2%) after, a significant decrease (P<0.001; McNemar test). The proportions of patients prescribed ICS alone, long-acting beta-agonists (LABA), and ICS/LABA were lower after referral than before, but the proportions of patients prescribed long-acting muscarinic antagonists (LAMA), ICS/LABA/LAMA, and biologics increased after referral. More asthma-related laboratory tests were performed after referral, and spirometry incidence increased from 16.4% before referral to 51.4% after referral. Conclusion: This study shows a decrease in asthma exacerbations, change in asthma treatments, and increase in laboratory tests after referral to a specialist, suggesting that referrals to specialists lead to better management of asthma.

Reforms of regulatory pathways for approval of new antineoplastic drugs in Japan from 2004 to 2019 and accompanying changes in pivotal clinical trial designs.

Background The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) was established in 2004. Since then, various pieces of legislation, notices, and guidelines have been issued, and the regulatory approval pathways for domestic drugs have been diversified. However, the effects of these measures have not been fully examined. We examined the impact of these measures on the approval of antineoplastic drugs and the design of pivotal clinical trials for efficacy assessment by the PMDA. Methods We collected data on the antineoplastic drugs approved by the PMDA in fiscal years 2004-2019. We extracted the approval review pathways and the pivotal clinical trial designs from the PMDA review reports, and analyzed them to identify patterns. Results In total, 387 indications in oncology were approved by the PMDA in fiscal years 2004-2019, or 365 indications excluding multiple regulatory pathways. The number of approved indications generally increased year on year (p < 0.001). The largest number of approved indications was under the Orphan Drug Designation (31%, 114/365) and this continues to increase (p < 0.001). In the 288 indications for which clinical trial data were submitted for review, the pivotal clinical trial designs changed significantly (p < 0.001) after the guideline on clinical evaluation for antineoplastic drugs was revised in 2006. Conclusion The number of indications in oncology approved by the PMDA has been increasing over the past 16 years, alongside changes in regulatory pathways. The 2006 guideline on clinical evaluation had a particular impact on pivotal clinical trial designs.

Meta-analyses on progression-free survival as a surrogate endpoint for overall survival in triple-negative breast cancer.

PURPOSE: Earlier studies suggest progression-free survival (PFS) may be used as a surrogate endpoint for overall survival (OS) in metastatic breast cancer, which could shorten follow-up duration and speed up assessment of treatment effects. However, to our knowledge, the association between them is still unclear in advanced or metastatic triple-negative breast cancer (TNBC). METHODS: A literature-based meta-analysis followed by correlation analysis was conducted in advanced or metastatic TNBC. Weighted multiple regression analysis was then used to test the strength of the association between medians of PFS and OS, and the association between HRPFS and HROS. RESULTS: Fourteen randomized clinical trials published between January 2007 and August 2019, 31 median pairs for PFS and OS, and 17 pairs for HRPFS and HROS from 3,880 patients were selected. The Pearson correlation coefficient between medians of PFS and OS was 0.84 (95% confidence interval (CI) 0.68-0.92, p < 0.001), and the correlation coefficient between HRPFS and HROS was 0.86 (95% CI 0.63-0.95, p < 0.001). Weighted multiple regression analysis showed HRPFS was the most significant predictor of HROS among covariates analyzed (p < 0.001). Both the medians of PFS and OS correlation, and the HRPFS and HROS correlation were 0.79 (p < 0.001), 0.80 (p = 0.001), respectively, in the 11 trials excluding immunotherapy and bevacizumab-based therapy trials. CONCLUSIONS: Our analysis suggests PFS can be strongly correlated with OS and considered a valid surrogate endpoint for OS in advanced or metastatic TNBC.

Expression of multiple cbb3 cytochrome c oxidase isoforms by combinations of multiple isosubunits in Pseudomonas aeruginosa.

The ubiquitous opportunistic human pathogen Pseudomonas aeruginosa has five terminal oxidases for aerobic respiration and uses them under different growth conditions. Two of them are cbb3-type cytochrome c oxidases encoded by the gene clusters ccoN1O1Q1P1 and ccoN2O2Q2P2, which are the main terminal oxidases under high- and low-oxygen conditions, respectively. P. aeruginosa also has two orphan gene clusters, ccoN3Q3 and ccoN4Q4, encoding the core catalytic CcoN isosubunits, but the roles of these genes have not been clarified. We found that 16 active cbb3 isoforms could be produced by combinations of four CcoN, two CcoO, and two CcoP isosubunits. The CcoN3- or CcoN4-containing isoforms were produced in the WT cell membrane in response to nitrite and cyanide, respectively. The strains carrying these isoforms were more resistant to nitrite or cyanide under low-oxygen conditions. These results indicate that P. aeruginosa gains resistance to respiratory inhibitors using multiple cbb3 isoforms with different features, which are produced through exchanges of multiple core catalytic isosubunits.

DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1.

PURPOSE: An anti-HER2 antibody-drug conjugate with a novel topoisomerase I inhibitor, DS-8201a, was generated as a new antitumor drug candidate, and its preclinical pharmacologic profile was assessed. EXPERIMENTAL DESIGN: In vitro and in vivo pharmacologic activities of DS-8201a were evaluated and compared with T-DM1 in several HER2-positive cell lines and patient-derived xenograft (PDX) models. The mechanism of action for the efficacy was also evaluated. Pharmacokinetics in cynomolgus monkeys and the safety profiles in rats and cynomolgus monkeys were assessed. RESULTS: DS-8201a exhibited a HER2 expression-dependent cell growth-inhibitory activity and induced tumor regression with a single dosing at more than 1 mg/kg in a HER2-positive gastric cancer NCI-N87 model. Binding activity to HER2 and ADCC activity of DS-8201a were comparable with unconjugated anti-HER2 antibody. DS-8201a also showed an inhibitory activity to Akt phosphorylation. DS-8201a induced phosphorylation of Chk1 and Histone H2A.X, the markers of DNA damage. Pharmacokinetics and safety profiles of DS-8201a were favorable and the highest non-severely toxic dose was 30 mg/kg in cynomolgus monkeys, supporting DS-8201a as being well tolerated in humans. DS-8201a was effective in a T-DM1-insensitive PDX model with high HER2 expression. DS-8201a, but not T-DM1, demonstrated antitumor efficacy against several breast cancer PDX models with low HER2 expression. CONCLUSIONS: DS-8201a exhibited a potent antitumor activity in a broad selection of HER2-positive models and favorable pharmacokinetics and safety profiles. The results demonstrate that DS-8201a will be a valuable therapy with a great potential to respond to T-DM1-insensitive HER2-positive cancers and low HER2-expressing cancers. Clin Cancer Res; 22(20); 5097-108. ©2016 AACR.

Enzymatic characterization and in vivo function of five terminal oxidases in Pseudomonas aeruginosa.

The ubiquitous opportunistic pathogen Pseudomonas aeruginosa has five aerobic terminal oxidases: bo(3)-type quinol oxidase (Cyo), cyanide-insensitive oxidase (CIO), aa3-type cytochrome c oxidase (aa3), and two cbb(3)-type cytochrome c oxidases (cbb(3)-1and cbb(3)-2). These terminal oxidases are differentially regulated under various growth conditions and are thought to contribute to the survival of this microorganism in a wide variety of environmental niches. Here, we constructed multiple mutant strains of P. aeruginosa that express only one aerobic terminal oxidase to investigate the enzymatic characteristics and in vivo function of each enzyme. The Km values of Cyo, CIO, and aa3 for oxygen were similar and were 1 order of magnitude higher than those of cbb(3)-1 and cbb(3)-2, indicating that Cyo, CIO, and aa3 are low-affinity enzymes and that cbb(3)-1 and cbb(3)-2 are high-affinity enzymes. Although cbb(3)-1 and cbb(3)-2 exhibited different expression patterns in response to oxygen concentration, they had similar Km values for oxygen. Both cbb(3)-1 and cbb(3)-2 utilized cytochrome c4 as the main electron donor under normal growth conditions. The electron transport chains terminated by cbb(3)-1 and cbb(3)-2 generate a proton gradient across the cell membrane with similar efficiencies. The electron transport chain of aa3 had the highest proton translocation efficiency, whereas that of CIO had the lowest efficiency. The enzymatic properties of the terminal oxidases reported here are partially in agreement with their regulatory patterns and may explain the environmental adaptability and versatility of P. aeruginosa.

Developing a practical toxicogenomics data analysis system utilizing open-source software.

Comprehensive gene expression analysis has been applied to investigate the molecular mechanism of toxicity, which is generally known as toxicogenomics (TGx). When analyzing large-scale gene expression data obtained by microarray analysis, typical multivariate data analysis methods performed with commercial software such as hierarchical clustering or principal component analysis usually do not provide conclusive outputs by themselves. To best utilize the TGx data for toxicity evaluation in the drug development process, fit-for-purpose customization of the analytical algorithm with user-friendly interface and intuitive outputs are required to practically address the toxicologists' demands. However, commercial software is usually not very flexible in the customization of their functions or outputs. Owing to the recent advancement and accumulation of open-source software contributed by bioinformaticians all over the world, it becomes easier for us to develop practical and fit-for-purpose analytical software by ourselves with fairly low cost and efforts. The aim of this article is to present an example of developing an automated TGx data processing system (ATP system), which implements gene set-level analysis toxicogenomic profiling by D-score method and generates straightforward output that makes it easy to interpret the biological and toxicological significance of the TGx data. Our example will provide basic clues for readers to develop and customize their own TGx data analysis system which complements the function of existing commercial software.

Siglec-15, a member of the sialic acid-binding lectin, is a novel regulator for osteoclast differentiation.

Osteoclasts are tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells derived from monocyte/macrophage-lineage precursors and are critically responsible for bone resorption. In giant cell tumor of bone (GCT), numerous TRAP-positive multinucleated giant cells emerge and severe osteolytic bone destruction occurs, implying that the emerged giant cells are biologically similar to osteoclasts. To identify novel genes involved in osteoclastogenesis, we searched genes whose expression pattern was significantly different in GCT from normal and other bone tumor tissues. By screening a human gene expression database, we identified sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) as one of the genes markedly overexpressed in GCT. The mRNA expression level of Siglec-15 increased in association with osteoclast differentiation in cultures of mouse primary unfractionated bone marrow cells (UBMC), RAW264.7 cells of the mouse macrophage cell line and human osteoclast precursors (OCP). Treatment with polyclonal antibody to mouse Siglec-15 markedly inhibited osteoclast differentiation in primary mouse bone marrow monocyte/macrophage (BMM) cells stimulated with receptor activator of nuclear factor κB ligand (RANKL) or tumor necrosis factor (TNF)-α. The antibody also inhibited osteoclast differentiation in cultures of mouse UBMC and RAW264.7 cells stimulated with active vitamin D(3) and RANKL, respectively. Finally, treatment with polyclonal antibody to human Siglec-15 inhibited RANKL-induced TRAP-positive multinuclear cell formation in a human OCP culture. These results suggest that Siglec-15 plays an important role in osteoclast differentiation.