ALDH2 polymorphism rs671 is a predictor of PD-1/PD-L1 inhibitor efficacy against thoracic malignancies.

BACKGROUND: Aldehyde dehydrogenase 2 (ALDH2) plays an important role in the endogenous aldehyde detoxification of various types of cells. ALDH2*2, a variant allele of the ALDH2 polymorphism rs671, leads to decreased enzymatic activity. ALDH2*2 may enhance tumor antigen presentation due to aldehyde-induced DNA damage while suppressing peripheral blood T cell counts and T cell activation. METHODS: On the basis of our hypothesis that rs671 affects the sensitivity of immune checkpoint inhibitors (ICIs), we evaluated the effects of rs671 on patients with thoracic malignancies who started ICI therapy in 2016-2019. The cohort consisted of 105 cases, including 64 cases with adenocarcinoma and 30 cases with squamous cell carcinoma, 49 of whom were ALDH2*2 carriers. The first ICI was PD-1/PD-L1 inhibitor (Nivolumab, Pembrolizumab, or Atezolizumab) in all cases. RESULTS: The best response to anti-PD-1/PD-L1 therapy (partial response/stable disease/progressive disease) was 36%/50%/14% in the rs671(-) cases; however, the response was relatively poor in the rs671(+) cases (27%/29%/45%, respectively) (p = 0.002). The hazard ratio (95% confidence interval) of disease progression within the observation period of 6 months for the rs671(+) cases was estimated to be 5.0 (2.5-10) after the adjustment for covariates, including sex, Brinkman index, treatment line, tumor tissue programmed death-ligand 1 positivity rate, tumor tissue EGFR mutation. This association was also maintained in a stratified analysis, suggesting that ALDH2*2 is an independent negative predictive factor for the short-term prognosis of anti-PD-1/PD-L1 therapy. Thus, the progression-free survival (PFS) ratio of the rs671(+) cases decreased rapidly after ICI initiation but was eventually higher than that of the rs671(-) cases (restricted mean survival time in 12 months from 2 to 3 years afterward was 1.3 times that of the rs671(-) cases). Moreover, the highest PFS ratio after 2 years among sub-groups was found in the first-line treatment sub-group of rs671(+) group (40%). CONCLUSIONS: Our study suggests that rs671 may be an accurate and cost-effective predictor of PD-1/PD-L1 inhibitor treatment, in which optimal case selection is an important issue.

[Development and Evaluation of Screening Culture Medium for Detection of Drug-Resistant Gram Negative Rods Containing Stealth Type CPE].

There is a report that an infection by medicine resistant bacteria will be the number one cause of death in 2050 according to the recommendation of WHO, and the CPE (carbapenem-producing Enterobacteriaceae) infection is regarded as a problem in particular. When detecting CPE, it is important how to detect stealth type CPE sensitive to carbapenem series medicines. So we used the 2 types of screening culture medium, "KBM" CRE-JU culture medium (CRE-JU culture medium) and the FRPM culture medium, and tried to detect drug-resistant gram-negative bacilli such as CPE, stealth type CPE, ESBL-producing bacteria, and excess AmpC-producing bacteria (AmpC-producing bacteria), etc. in combination of this culture mediums. As a result, CRE-JU culture medium showed a difference in the growth of CPE depending on the amount of inoculated bacteria while ß-lactamase non-producing strain and other strains except for high concentration ESBL-producing bacteria and AmpC-producing bacteria were un-growing. Most of the CRE, stealth type CPE, ESBL-producing bacteria and AmpC-producing bacteria grew in the FRPM culture medium while most of the ß-lactamase non-producing strains with a MIC value of meropenem (MEPM) of 2 µg/mL or less were un-growing. From these results, it was suggested that when a strain grown on CRE-JU and FRPM culture mediums, it could be distinguished as CPE, and when strains grown on FRPM culture medium which were un-grown on CRE-JU culture medium, it could be distinguished as drug-resistant bacteria such as stealth type CPE, ESBL-producing bacteria, and AmpC-producing bacteria. When strains not grown on CRE-JU and FRPM culture mediums, it could be distinguished as sensitive.

Establishment of the MID-NET® medical information database network as a reliable and valuable database for drug safety assessments in Japan.

PURPOSE: To establish a new medical information database network (designated MID-NET® ) to provide real-world data for drug safety assessments in Japan. METHODS: This network was designed and developed by the Ministry of Health, Labour and Welfare and the Pharmaceuticals and Medical Devices Agency in collaboration with 23 hospitals from 10 healthcare organizations across Japan. MID-NET® is a distributed and closed network system that connects all collaborative organizations through a central data center. A wide variety of data are available for analyses, including clinical and administrative information. Several coding standards are used to standardize the data stored in MID-NET® to allow the integration of information originating from different hospitals. A rigorous and consistent quality management system was implemented to ensure that MID-NET® data are of high quality and meet Japanese regulatory standards (good post-marketing study practice and related guidelines). RESULTS: MID-NET® was successfully established as a reliable and valuable medical information database and was officially launched in April 2018. High data quality with almost 100% consistency was confirmed between original data in hospitals and the data stored in MID-NET® . A major advantage is that approximately 260 clinical laboratory test results are available for analysis. CONCLUSIONS: MID-NET® is expected to be a major data source for drug safety assessments in Japan. Experiences and best practices established in MID-NET® may provide a model for the future development of similar database networks.

The utilization and challenges of Japan's MID-NET® medical information database network in postmarketing drug safety assessments: A summary of pilot pharmacoepidemiological studies.

PURPOSE: To examine the potential role of Medical Information Database Network (MID-NET® ), a newly established Japanese medical information database network, in postmarketing drug safety assessments through the characterization of its advantages and limitations in five pilot studies. METHODS: The pilot studies were designed to address three major objectives in postmarketing drug safety assessments, ie, the examination of actual drug utilization, the impact of safety-related regulatory actions, and drug-associated risks. The five studies were conducted on the following topics: (a) utilization of codeine-containing products and its relationship with respiratory depression, (b) impact of a Dear Healthcare Professional letter on hypocalcemia incidence associated with denosumab (Ranmark® ) use, (c) risk of acute myocardial infarction associated with antidiabetic drug use, (d) risk of glucose metabolism disorders associated with atypical antipsychotic drug use, and (e) prospective monitoring of abnormal laboratory test results during new drug prescriptions. RESULTS: The pilot studies were successfully conducted and demonstrated the value of MID-NET® in postmarketing drug safety assessments. In particular, the ability to utilize laboratory test results as objective clinical indicators is a major advantage of this database. Potential limitations include a relatively small sample size and a lack of patient-level data linkages among hospitals. CONCLUSIONS: MID-NET® was confirmed to be a valuable database for postmarketing drug safety assessments. The use of laboratory test results to define clinical outcomes may allow more objective and accurate analyses to be conducted. These studies furthered our understanding of the characteristics of MID-NET® , including its advantages and limitations.

[Direct identification method for bacteria in positive blood culture bottles using MALDI biotyper].

We investigated the relevance of direct identification method for bacteria from blood culture bottles using MALDI Biotyper(Bruker Co.). One hundred fourteen bacterial strains obtained from blood culture bottles were analyzed using the pretreatment method recommended by Bruker Corporation. The identification rate with recommended pretreatment was 76.3% (87/114). Twenty seven samples that were not identified with the pretreatment method were further analyzed using our modified method. Of these, twelve were identified, improving the identification rate to 86.8% (99/114). These results suggest that our modified pretreatment combined with pretreatment method recommended by Bruker Corporation yields improved identification of bacteria from blood culture bottles using MALDI Biotyper system.

A fully integrated and automated detection system for single nucleotide polymorphisms of UGT1A1 and CYP2C19.

The need for examinations of single nucleotide polymorphisms (SNPs) on drug metabolizing enzymes is accelerating. Especially, SNPs of UTG1A1 and CYP2C19 are important for patients who are treated with irinotecan and proton pump inhibitors, respectively. Thus, a method for the rapid, fully automated, and accurate measurement of these SNPs is desired. We genotyped 109 Japanese volunteers for UGT1A1*6, UGT1A1*28, CYP2C19*2, and CYP2C19*3 with the quenching probe (QP) method. Only 90 min after whole blood was applied, QP method enabled to detect these SNPs automatically. The results obtained by QP method were absolutely identical to those examined by the conventional direct sequencing. These findings indicate that the QP method will enable point-of-care testing in clinical laboratories and patient-oriented therapy with its convenience and speed for patients who are treated with irinotecan or proton pump inhibitors.

[Influences of %T>MIC achievement probability due to the difference of the MIC measurement concentration range-analysis of meropenem for Pseudomonas aeruginosa-].

We attempted to analyze any influences to %T>MIC achievement probability due to the difference of the MIC measurement concentration range of MEPM for 613 strains of Pseudomonas aeruginosa by the Monte Carlo simulation method. As for the analysis, we calculated the achievement probability of 30% and 50% for MEPM %T>MIC by the administration volume of MEPM: 250 mg, 500 mg, and 1,000 mg, the administration time: 0.5 h, and 3 h, the administration frequency: 2 times, and 3 times, and the renal excretion capability: Normal, Slight, Moderate, and High abnormal with the 3 types of MIC concentration measurement level 1) <=0.06~>=256 µg/ml: 13 levels, 2) <=0.5~>=32 µg/ml: 7 levels, and 3) <=1~>=16 µg/ml: 5 levels. As the result, we found the following findings; 1. In terms of the administration of normal renal excretion capability, 250 mg, in comparison with 500 mg and 1,000 mg, indicated the differential due to the difference of MIC measurement concentration range. 2. The administration volume of MEPM 500 mg which has been recommended shown the less differential of the achievement probability due to the difference of MIC measurement concentration range. As the renal excretion was shifted through Normal to Slight to Moderate to High abnormal, the differential of the achievement probability due to the difference of MIC measurement concentration range was gradually decreased. With these results, PK/PD analysis is possible for the 5 levels measurement concentration. It is significant that the facility using the automated microbiology analyzer can provide not only the MIC report, but also the information on the appropriate administration method for antibacterial drug by PK/PD analysis.

Expression of Myc target gene mina53 in subtypes of human lymphoma.

Mina53 (mina) was identified as a gene, which is directly induced by the oncogene c-myc. Elevated expression of Mina53 protein was found in >80% of colon cancer and esophageal squamous cell carcinoma (ESCC). Patients with high expression of Mina53 had shorter survival, suggesting the prognostic usefulness of Mina53. We studied Mina53 expression in lymphoma subtypes to examine its diagnostic significance and its possible role in lymphoma-genesis. Surgical cases of 28 lymphoma and 4 non-neoplastic tissues were stained immunochemically using anti-Mina53 monoclonal antibody. Mina53 expression correlated well with c-Myc expression in lymphoma, suggesting that c-Myc is a controlling factor for mina53 expression also in lymphomas. Although the expression of Mina53 as well as c-Myc was less frequent in lymphoma compared with those of colon and ESCC, increased expression of Mina53 was found in Burkitt-like lymphoma (1/1), Hodgkin's lymphoma (3/5), diffuse large B cell lymphoma (DLBCL) (5/13), lymphomas with a transition from follicular to DLBCL (1/2), with none in follicular (0/4) and T cell lymphoma (0/3). Analyses of the data suggested that Mina53 was frequently expressed in aggressive types of B cell lymphoma. To get more information about the expression of Mina53 in DLBCL, which most frequently occurs among lymphomas, we analyzed the expression of Mina53 in another 21 DLBCL specimens, which were in more advanced stages than those described above. The expression level of Mina53 correlated to the international prognostic index (IPI) values with statistical significance (r=0.477, P=0.0275). Notably, in this group, Mina53 expression did not correlate with c-Myc expression, suggesting that other factor(s) besides c-Myc largely affect the expression of Mina53 in advanced DLBCL. These results suggest that although Mina53 expression is not prominent in lymphoma in general, it may be related to tumor progression of B cell lymphoma.