Reduction in asthma exacerbation rate after mepolizumab treatment initiation in patients with severe asthma: A real-world database study in Japan.

OBJECTIVE: To investigate the changes in asthma exacerbation, as well as in oral corticosteroid (OCS) use, exacerbation-related healthcare resource utilization (HRU), and healthcare costs before and after mepolizumab treatment initiation in patients with severe asthma who started treatment with mepolizumab in a real-world clinical setting in Japan. METHODS: A retrospective, observational, self-controlled study was conducted in Japan using a hospital-based administrative claims database. Patients who were diagnosed with asthma and who were new users of mepolizumab were included in the study. The primary outcome was the incidence rate of any asthma exacerbation/patient-year during the 12-month period before (baseline period) and after (follow-up period) the first mepolizumab prescription. Secondary outcome measures included the proportion of patients with ≥1 any asthma exacerbation, patients with exacerbation requiring hospitalization, the incidence rate of exacerbations requiring hospitalization/patient-year, the median daily OCS dose (OCS sparing effect), exacerbation-related HRU (hospitalization length, the proportion of patients with emergency visits, and the number of emergency/outpatient visits), and associated costs. RESULTS: Of the 377 patients included, 56.2% were ≥65 years of age. Following the first mepolizumab prescription, incidence rates for any asthma exacerbation were reduced by 40.6% (4.00/patient-year to 2.38/patient-year; the incidence rate ratio [95% confidence interval]: 0.60 [0.53-0.67]; p < 0.0001) from the baseline to follow-up periods. The incidence rate of exacerbations requiring hospitalization was reduced by 55.8% (0.37/patient-year to 0.16/patient-year) from the baseline to follow-up periods. The proportion of patients experiencing any exacerbation decreased from 84.4% to 57.8% and those requiring hospitalization decreased from 23.9% to 10.3% both from the baseline to follow-up periods. The median daily OCS dose decreased by 44.6% (median [interquartile range]: 6.7 [4.7-9.9] mg/day to 3.3 [0.9-5.6] mg/day) from the last baseline quarter to the 4th quarter of the follow-up period. All exacerbation-related HRUs decreased from the baseline to follow-up periods. Inpatient cost reduced by >50% (123,279 Japanese Yen [JPY]/patient-year vs. 57,283 JPY/patient-year), reducing the total cost by 80,716 JPY from the baseline to follow-up periods. CONCLUSION: Mepolizumab was effective in treating patients with severe asthma by reducing the incidence rates of exacerbations and exacerbation requiring hospitalization, OCS dose, exacerbation-related HRU, and cost in routine clinical practice in Japan.

The prevalence, burden of disease, and healthcare utilization of patients with eosinophilic granulomatosis with polyangiitis in Japan: a retrospective, descriptive cohort claims database study.

OBJECTIVES: To estimate eosinophilic granulomatosis with polyangiitis (EGPA) prevalence and disease burden in patients with newly diagnosed EGPA in Japan. METHODS: This retrospective descriptive cohort study (GSK ID: 209751, HO-18-19652) used administrative claim data from patients (aged ≤74 years) with EGPA (study period: January 1, 2005-December 31, 2017), identified from their first ICD-10 code for EGPA (index). Data were examined during the 12 months before (baseline) and 12 months following the index date (follow-up). EGPA prevalence, respiratory comorbidities, all-cause healthcare utilization, and oral corticosteroid (OCS) use were assessed. RESULTS: EGPA prevalence (95%CI) increased from 4.2 (0,23.7)/million people (2005) to 38.0 (31.8,45.1)/million people (2017), was generally more common in females versus males, and increased with age. Of the 45 patients with newly diagnosed EGPA, 57.8% had acute bronchitis and 42.2% had upper respiratory tract infections during baseline. During follow-up, 60.0% of patients were hospitalized at least once and 77.8% used OCS (OCS dependent [≥80% of days]: 73.1%). CONCLUSIONS: In Japan, EGPA prevalence increased over time, was generally more common in females, and increased with patient age. EGPA burden was high; respiratory comorbidities were common, and most patients required hospitalization and OCS use. Our data suggest additional EGPA treatment options are needed.

Esterification of Tertiary Amides: Remarkable Additive Effects of Potassium Alkoxides for Generating Hetero Manganese-Potassium Dinuclear Active Species.

Invited for the cover of this issue are the groups of Fahmi Himo and Kazushi Mashima at Stockholm University and Osaka University. The image depicts a Mn-K scissor, which is able to break a C-N bond, represented by a tree branch. Read the full text of the article at 10.1002/chem.202001447.

Esterification of Tertiary Amides: Remarkable Additive Effects of Potassium Alkoxides for Generating Hetero Manganese-Potassium Dinuclear Active Species.

A catalyst system of mononuclear manganese precursor 3 combined with potassium alkoxide served as a superior catalyst compared with our previously reported manganese homodinuclear catalyst 2 a for esterification of not only tertiary aryl amides, but also tertiary aliphatic amides. On the basis of stoichiometric reactions of 3 and potassium alkoxide salt, kinetic studies, and density functional theory (DFT) calculations, we clarified a plausible reaction mechanism in which in situ generated manganese-potassium heterodinuclear species cooperatively activates the carbonyl moiety of the amide and the OH moiety of the alcohols. We also revealed details of the reaction mechanism of our previous manganese homodinuclear system 2 a, and we found that the activation free energy (ΔG≠ ) for the manganese-potassium heterodinuclear complex catalyzed esterification of amides is lower than that for the manganese homodinuclear system, which was consistent with the experimental results. We further applied our catalyst system to deprotect the acetyl moiety of primary and secondary amines.

Tunable Ligand Effects on Ruthenium Catalyst Activity for Selectively Preparing Imines or Amides by Dehydrogenative Coupling Reactions of Alcohols and Amines.

Selective dehydrogenative synthesis of imines from a variety of alcohols and amines was developed by using the ruthenium complex [RuCl2 (dppea)2 ] (6 a: dppea=2-diphenylphosphino-ethylamine) in the presence of catalytic amounts of Zn(OCOCF3 )2 and KOtBu, whereas the selective dehydrogenative formation of amides from the same sources was achieved by using another ruthenium complex, [RuCl2 {(S)-dppmp}2 ] [6 d: (S)-dppmp=(S)-2-((diphenylphosphenyl)methyl)pyrrolidine], in the presence of catalytic amounts of Zn(OCOCF3 )2 and potassium bis(trimethylsilyl)amide (KHMDS). Our previously reported ruthenium complex, [Ru(OCOCF3 )2 (dppea)2 ] (8 a), was the catalyst precursor for the imine synthesis, whereas [Ru(OCOCF3 )2 {(S)-dppmp}2 ] (8 d), which was derived from the treatment of 6 d with Zn(OCOCF3 )2 and characterized by single-crystal X-ray analysis, was the pre-catalyst for the amide formation. Control experiments revealed that the zinc salt functioned as a reagent for replacing chloride anions with trifluoroacetate anions. Plausible mechanisms for both selective dehydrogenative coupling reactions are proposed based on a time-course study, Hammett plot, and deuterium-labeling experiments.

[A multicenter trial of regional medical cooperation for cancer chemotherapy after the great East Japan earthquake].

The Great East Japan Earthquake was the first disaster we experienced after the administration of oncology care had mostly shifted from hospitals to outpatient departments in Japan. Disaster medical assistance teams(DMATs)were deployed immediately after the disaster, and actively assisted during the acute phase of the catastrophe. After experiencing the earthquake, we realized the necessity of medical support teams, even for chronic disease. Here we report a multicenter trial of regional medical cooperation for cancer chemotherapy. First, soon after the earthquake, representatives from the regional hospitals discussed the proper roles for each institution. As agreed to in the discussion, cancer patients were redistributed from a disaster base hospital to a local general hospital, and oncologists supported the other regional hospitals on a regular basis. This broad regional network functioned well and patients resumed their treatment as soon as the situation allowed. Second, we performed a survey of the patients and found that the most important problem was patients' lack of understanding of their own illnesses. Third, we conducted an opinion survey of medical professionals on regional medical cooperation. Based on the trial, we found it important in disasters to establish regional cooperation and solid communication systems, and to promote patient education.

Benefit of Prompt Vs Delayed Initiation of Triple Therapy Following an Exacerbation in Patients with COPD in Japan: A Retrospective Cohort Study.

Purpose: There is currently limited evidence for the optimal timing of triple therapy initiation in Japan, which is crucial for optimizing strategies for the effective treatment of chronic obstructive pulmonary disease (COPD). This study assessed the impact of prompt vs delayed initiation of triple therapy following a COPD exacerbation on clinical and economic outcomes in patients in Japan. Patients and Methods: Retrospective cohort study of patients in the Medical Data Vision Co., Ltd. database initiating triple therapy as single-inhaler triple therapy (fluticasone furoate/umeclidinium/vilanterol or budesonide/glycopyrronium/formoterol) or multiple-inhaler triple therapy within 180 days of a moderate-to-severe exacerbation (index). For the main analysis, patients were categorized as prompt or delayed initiators, initiating triple therapy within 0-30 days or 31-180 days of index, respectively. Inverse probability of treatment weighting based on propensity scores was used to adjust for measured confounders between prompt and delayed cohorts. Results: For the main analysis, 610 (60.3%) and 402 (39.7%) patients were prompt and delayed initiators, respectively. The rate of subsequent moderate-to-severe exacerbations following index exacerbation was numerically lower in prompt vs delayed initiators (weighted rate ratio 0.95, 95% confidence interval [CI]: 0.74-1.21; P = 0.6603). Time-to-first subsequent moderate-to-severe exacerbation increased significantly in prompt vs delayed initiators (weighted hazard ratio 0.77, 95% CI: 0.64-0.93; P = 0.0053). In patients indexed on a severe exacerbation, delayed initiation resulted in significantly higher 90-day all-cause readmissions vs prompt initiation (42.1% vs 30.6%; P = 0.0329 [weighted estimates]). Weighted healthcare resource utilization rates were numerically lower in prompt vs delayed initiators, and weighted direct costs (all cause and COPD-related) were significantly lower in prompt initiators. Conclusion: This real-world study demonstrated that earlier initiation of triple therapy resulted in several benefits in clinical outcomes for COPD and may also reduce the economic burden of COPD management in Japan.

Phase II study of biweekly cetuximab plus mFOLFOX6 or mFOLFIRI as second-line treatment for metastatic colorectal cancer and exploratory analysis of associations between DNA methylation status and the efficacy of the anti-EGFR antibody: T-CORE1201.

Background: Little is known about the biweekly combined use of cetuximab and chemotherapy as second-line treatment of metastatic colorectal cancer (mCRC). Recently, DNA methylation status has been reported to be a new possible predictor of the efficacy from the anti-epidermal growth factor receptor (EGFR) antibody treatment. The purpose of this study was to examine the efficacy and safety of biweekly cetuximab plus mFOLFOX6 or mFOLFIRI as a second-line treatment for KRAS exon 2 wild-type mCRC. We also investigated the predictability of DNA methylation status on the efficacy of the EGFR antibody-containing treatment. Methods: Patients who were refractory or intolerant to the first-line chemotherapy were enrolled and received biweekly cetuximab plus mFOLFOX6 or mFOLFIRI. The primary endpoint was progression-free survival (PFS). Tumor evaluations were performed every 2 months using Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events version 4.0. DNA methylation status of colorectal cancer cells was defined by a modified MethyLight assay. Results: Sixty-six cases were enrolled. The median PFS (mPFS) was 5.1 [95% confidence interval (CI), 3.8-7.6] months. The median overall survival (mOS) was 12.7 (95% CI, 7.5-15.3) months. Grade 3 or higher neutropenia occurred in 53.0% of patients, whereas skin disorders with a grade 3 or higher occurred in <15% of patients. In multivariate analysis, DNA methylation status could not be an independent predictor of PFS [hazard ratio (HR), 1.43; P=0.39] and OS (HR, 2.13; P=0.086). However, in RAS/BRAF wild-type patients, the mPFS and mOS in the low-methylated colorectal cancer (LMCC) group was numerically better than those in the highly-methylated colorectal cancer (HMCC) group, although the difference was not statistically significant [mPFS: 8.5 (95% CI, 6.1-10.9) vs. 3.3 (95% CI, 1.2-not reached) months, P=0.79; ΔmPFS, 5.2 months; mOS: 15.3 (95% CI, 11.9-23.5) vs. 6.5 (95% CI, 3.1-not reached) months, P=0.53; ΔmOS, 8.8 months]. Conclusions: Biweekly cetuximab plus mFOLFOX6 or mFOLFIRI is a useful second-line therapy for mCRC. DNA methylation status warrants further exploration as a predictive biomarker for anti-EGFR efficacy in mCRC.

Safety verification trials of mFOLFIRI and sequential IRIS + bevacizumab as first- or second-line therapies for metastatic colorectal cancer in Japanese patients.

OBJECTIVE: S-1 is effective in sequential combination with irinotecan (IRIS) in treating metastatic colorectal cancer. We conducted a randomized phase II trial of modified leucovorin, fluorouracil and irinotecan (mFOLFIRI) + bevacizumab and sequential IRIS + bevacizumab as first- or second-line therapies. METHODS: Sixty metastatic colorectal cancer patients were randomly assigned to receive mFOLFIRI + bevacizumab or sequential IRIS + bevacizumab (7.5 mg/kg of bevacizumab and 150 mg/m(2) of irinitecan, and 80 mg/m(2)/day of S-1 orally from day 3 until day 16 as a 3-week course). The primary endpoint was the safety of each method until week 12, with the secondary endpoint being the comparison of the safety and efficacy of the two methods. RESULTS: The safety of the two treatments was comparable, except that G3 anorexia and diarrhoea were less frequent with sequential IRIS + bevacizumab. The overall response rate was 62% [95% confidence interval (CI) 40.1-79.8] versus 72% (95% CI 50.6-86.2), and progression-free survival was 324 days (95% CI 247-475) versus 345 days (95% CI 312-594) with mFOLFIRI + bevacizumab versus IRIS + bevacizumab, respectively. CONCLUSION: Sequential IRIS + bevacizumab is a safe and effective method of systemic chemotherapy against metastatic colorectal cancer and is compatible with mFOLFIRI + bevacizumab.

[Specific adverse events caused by monoclonal antibodies, focusing on the prophylaxis and management].

Monoclonal antibodies play important roles in medical oncology. The antibodies were designed as specific molecular targeting drugs and supposed to have less toxicity to normal cells compared to classical cytotoxic agents. Indeed, they do not have severe bone marrow suppression, nausea, or vomiting unlike cytotoxic drugs. On the other hand, clinicians often undergo characteristic adverse events we have never experienced before the appearance of the molecular targeting drugs. To fully utilize these powerful yet particular medicines, we have to be well aware of their severe or fatal adverse events and comprehend how to manage those toxic events. In this manuscript, important adverse events including infusion reaction, gastrointestinal perforation, cardiotoxicity, venous thromboembolism, and interstitial lung disease are subjects for discussion.

[Poorly-differentiated neuroendocrine carcinoma of ascending colon with liver metastases successfully treated with carboplatin and etoposide].

We present the case of a 76-year-old woman with a poorly-differentiated neuroendocrine carcinoma (PDNEC) of the ascending colon with liver metastases responding to calboplatin (CBDCA)/etoposide (ETP). She was admitted to our hospital with bloody stools, and was diagnosed with ascending colon cancer and multiple liver tumors. Total colonoscopy showed a Type 2 tumor in the ascending colon, and histological findings revealed adenocarcinoma from biopsy specimens. Right hemicolectomy with lymph nodes dissection was performed. Histologically, the tumor displayed PDNEC, the last feature identified by immunohistochemical markers for chromogranin and synaptophysin. After surgery, a combination of CBDCA and ETP was administered based on the chemotherapy for small-cell lung carcinoma in elderly, and there was a partial response and good control without emerging new lesions for more than two years.

Prevalence and Characteristics of Individuals with Preserved Ratio Impaired Spirometry (PRISm) and/or Impaired Lung Function in Japan: The OCEAN Study.

PURPOSE: Many individuals with obstructive airway disease (OAD), including chronic obstructive pulmonary disease (COPD) and asthma, remain undiagnosed, despite the potential for reducing disease burden through early detection and treatment. OCEAN aimed to determine the prevalence of, and characteristics associated with, impaired lung function in a Japanese population, with the goal of improving strategies for early OAD detection. METHODS: OCEAN was an observational, cross-sectional study in sequentially recruited Japanese individuals ≥40 years of age undergoing routine health examinations. Participants completed screening questionnaires and spirometry testing. Airflow limitation was defined as forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) <0.7 by pre-bronchodilator spirometry. Preserved ratio impaired spirometry (PRISm) was defined as FEV1/FVC ≥0.7 and FEV1 <80% predicted. The primary endpoint was prevalence of spirometry-based airflow limitation and PRISm. The characteristics of study participants were reported as secondary endpoints. RESULTS: Overall, 2518 individuals were included; 79% were <60 years of age (mean 52.0 years). Airflow limitation and PRISm were observed in 52 (2.1%) and 420 (16.7%) participants, respectively. FEV1 in the PRISm group was between that in the no airflow limitation/PRISm and airflow limitation groups, FVC was similar in the PRISm and airflow limitation groups. The PRISm group had higher mean body mass index and a higher proportion of comorbid metabolic disease compared with the airflow limitation group. The prevalence of airflow limitation and PRISm was highest among current smokers (3.9% and 21.3%, respectively) versus former or never smokers. CONCLUSION: A significant proportion of Japanese individuals <60 years of age attending their annual health examination had impaired lung function (airflow limitation and PRISm); prevalence was highest among current smokers. These findings support screening of current or former smokers ≥40 years of age using patient-reported questionnaires to inform the need for spirometry to confirm an OAD diagnosis.

Utility of Self-Administered Questionnaires for Identifying Individuals at Risk of COPD in Japan: The OCEAN (Okinawa COPD casE finding AssessmeNt) Study.

Purpose: A considerable proportion of patients with chronic obstructive pulmonary disease (COPD) remain undiagnosed and untreated even though they may have a burden of respiratory symptoms that impact quality of life. The OCEAN study assessed the ability of screening questionnaires to identify individuals with, or at risk of, COPD by comparing questionnaire outcomes with spirometric measures of lung function. Methods: This observational study included participants ≥40 years of age presenting for their annual health examination at a single medical center in Okinawa, Japan. Participants completed COPD screening questionnaires (CAPTURE and COPD-Q), the Chronic Airways Assessment Test (CAAT), and general demographic and health-related questionnaires. The performance characteristics of CAPTURE and COPD-Q were compared with spirometry-based airflow limitation by calculating the area under the receiver operating characteristic (ROC-AUC) curve. Results: A total of 2518 participants were included in the study; 79% of whom were <60 years of age (mean 52.0 years). A total of 52 (2.1%) participants had airflow limitation defined as forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) <0.7, and 420 (16.7%) participants were classified as Preserved Ratio Impaired Spirometry (PRISm). Among participants with PRISm, 75 (17.9%) had a CAAT total score ≥10. Airflow limitation and PRISm were more prevalent in current smokers versus past smokers. For the CAPTURE questionnaire, ROC-AUC for screening airflow limitation, PRISm, and PRISm with a CAAT total score ≥10 were 0.59, 0.55, and 0.69, respectively; for COPD-Q, these three clinical features were 0.67, 0.58 and 0.68, respectively. Conclusion: This study demonstrated that CAPTURE and COPD-Q appear to be effective screening tools for identifying symptomatic individuals with undiagnosed, or at risk of developing COPD in adults ≥40 years of age in Okinawa. Furthermore, early diagnosis and management of PRISm is important to improve future outcomes and the societal burden of disease.

PRL-2 increases Epo and IL-3 responses in hematopoietic cells.

Dual specificity protein tyrosine phosphatase PRL-2 is overexpressed in pediatric acute myeloid leukemia (AML) and is located at human chromosome 1p35, a region often rearranged or amplified in malignant lymphoma and B-cell chronic lymphocytic leukemia (B-CLL). Little is known of the significance of PRL-2 expression in hematopoietic malignancies. Herein we demonstrated that ectopic expression of PRL-2 in murine pre-B-cell line Baf3ER and mouse bone marrow cells induced key features associated with malignant progression and metastasis. PRL-2-transfected Baf3ER cells had augmented growth responses to hematopoietic growth factors Epo or IL-3 with shortened cell cycle, reduced requirement (5x) for Epo in cell survival, increased cell migration (3x), reduced cell adhesion (5x), and conversion to an immature cell morphology in association with increased expression (3x) of stem cell marker Bmi-1. When transduced into mouse bone marrow cells, PRL-2 increased Epo-induced colony formation (4x) and gave rise to larger colonies. These observations provide evidences implicating PRL-2 as a pathogenic molecule in hematopoietic malignancies and suggest its potential as a novel therapeutic target.

Attainment of a Long-term Favorable Outcome by Sunitinib Treatment for Pancreatic Neuroendocrine Tumor and Renal Cell Carcinoma Associated with von Hippel-Lindau Disease.

von Hippel-Lindau (VHL) disease, caused by germline mutations in the VHL gene, is a hereditary autosomal-dominant disorder which predisposes the individual to various malignant and benign tumors. VHL acts as a tumor suppressor, mainly through the negative regulation of hypoxia-inducible factors. Molecular-targeted drugs against vascular endothelial growth factor-signaling pathways, a target of hypoxia-inducible factors, have recently been introduced into clinical practice for the treatment of patients with sporadic renal cell carcinoma and pancreatic neuroendocrine tumors. However, whether such treatments are effective in patients with VHL disease remains to be elucidated. We herein report a Japanese patient with VHL disease who was successfully treated with sunitinib for approximately 5 years.

AFP-producing hepatoid adenocarcinoma in association with Barrett's esophagus with multiple liver metastasis responding to paclitaxel/CDDP: a case report.

A case of alpha-fetoprotein (AFP)-producing hepatoid adenocarcinoma in association with Barrett's esophagus with multiple liver metastases, responding to chemotherapy, is reported. A 47-year-old man was admitted to our hospital with abdominal pain after subtotal esophagectomy for an esophageal adenocarcinoma in association with Barrett's esophagus, and was diagnosed as having multiple liver tumors. Most tumor markers were normal, but the serum AFP level was markedly elevated. Dynamic computed tomography and ferumoxide enhanced magnetic resonance imaging did not provide evidence of any primary hepatocellular carcinoma. Since microscopic examination of the resected tumor showed a poorly-differentiated adenocarcinoma with hepatoid features displaying AFP-immunoreactivity, the liver tumors were thus considered to be metastatic deposits. Surgery was not feasible so chemotherapeutic agents were tried, and the combination of paclitaxel (TXL) and cisplatin (CDDP) gave a partial response and good control for a period. This is the first report, to our knowledge, of effective chemotherapy for liver metastases from an AFP-producing hepatoid adenocarcinoma of the esophagus.