Objective: The package inserts are official clinical decision-making documents that provide pharmacological treatment information. However, it has been noted that package inserts on perinatal drug usage differ greatly from expert opinions. This study identified Japanese package insert drugs that are contraindicated for pregnant women and compared them to foreign risk categories.Methods: The survey included 19,022 drugs on the drug pricing list as of April 2022, with package inserts available on the Pharmaceuticals and Medical Devices Agency website. We retrieved the package inserts with the word “pregnant” in the “Contraindications” section and reviewed the descriptions to exclude those that satisfied the exclusion criteria. We also checked the foreign risk categories of contraindicated ingredients for pregnant women. This study used the Australian Therapeutic Goods Administration’s categorization for prescribing medicines in pregnancy (the TGA classification).Results: Of the 19,022 medicines studied, 4,111 (21.6%) were contraindicated for pregnant women. Conversely, 19 (5.1%) ingredients categorized under the relatively safe TGA classifications A, B1, and B2 were also contraindicated for pregnant Japanese women.Conclusion: This study revealed that Japanese package inserts contraindicate over 20% of drugs for pregnant women. On the other hand, some forbidden ingredients did not match the foreign risk categories. Therefore, healthcare professionals should be aware of the limitations of Japanese package inserts concerning pregnant women and make careful decisions based on both package inserts and additional drug information.

OBJECTIVE: Programmed cell death-ligand 1 (PD-L1) is expressed in tumor cells and has been shown to predict clinical outcomes of several types of malignancies. The aim of this study was to investigate the effects of carbon-ion (C-ion) beam irradiation on PD-L1 expression in human uterine cervical adeno/adenosquamous carcinoma (UCAA) cells and clinical samples and to identify the prognostic factors for outcomes after C-ion radiotherapy (CIRT).METHODS: The effects of C-ion irradiation on PD-L1 expression in human UCAA and cervical squamous cell carcinoma cells were examined by flow cytometry. We examined PD-L1 expression in UCAA biopsy specimens from 33 patients before CIRT started (pre-CIRT) and after 12 Gy (relative biological effectiveness [RBE]) irradiation (post-12Gy-C) in 4 fractions of CIRT to investigate the correlation between PD-L1 status and clinical outcomes.RESULTS: The PD-L1 expression was upregulated by C-ion beam in a dose-dependent manner in HeLa and SiHa cells through phosphorylated Chk1. The overall frequencies of pre-CIRT and post-12Gy-C PD-L1 positivity were 45% (15/33) and 67% (22/33), respectively. The post-12Gy-C PD-L1 expression was significantly elevated compared to the pre-CIRT PD-L1 expression. There was no significant relationship between the pre-CIRT PD-L1 status and clinical outcomes, such as local control (LC), progression-free survival (PFS), and overall survival (OS). However, the post-12Gy-C PD-L1 expression had better correlation with PFS, but not with LC and OS.CONCLUSION: CIRT can induce PD-L1 expression in UCAA and we propose that PD-L1 expression after starting CIRT may become as a predictive prognostic marker in CIRT for UCAA.
Antigens, CD274 ; Biopsy ; Carcinoma, Squamous Cell ; Disease-Free Survival ; Flow Cytometry ; Heavy Ion Radiotherapy ; Humans ; Radiotherapy ; Treatment Outcome ; Uterine Cervical Neoplasms

OBJECTIVE: Programmed cell death-ligand 1 (PD-L1) is expressed in tumor cells and has been shown to predict clinical outcomes of several types of malignancies. The aim of this study was to investigate the effects of carbon-ion (C-ion) beam irradiation on PD-L1 expression in human uterine cervical adeno/adenosquamous carcinoma (UCAA) cells and clinical samples and to identify the prognostic factors for outcomes after C-ion radiotherapy (CIRT). METHODS: The effects of C-ion irradiation on PD-L1 expression in human UCAA and cervical squamous cell carcinoma cells were examined by flow cytometry. We examined PD-L1 expression in UCAA biopsy specimens from 33 patients before CIRT started (pre-CIRT) and after 12 Gy (relative biological effectiveness [RBE]) irradiation (post-12Gy-C) in 4 fractions of CIRT to investigate the correlation between PD-L1 status and clinical outcomes. RESULTS: The PD-L1 expression was upregulated by C-ion beam in a dose-dependent manner in HeLa and SiHa cells through phosphorylated Chk1. The overall frequencies of pre-CIRT and post-12Gy-C PD-L1 positivity were 45% (15/33) and 67% (22/33), respectively. The post-12Gy-C PD-L1 expression was significantly elevated compared to the pre-CIRT PD-L1 expression. There was no significant relationship between the pre-CIRT PD-L1 status and clinical outcomes, such as local control (LC), progression-free survival (PFS), and overall survival (OS). However, the post-12Gy-C PD-L1 expression had better correlation with PFS, but not with LC and OS. CONCLUSION CIRT can induce PD-L1 expression in UCAA and we propose that PD-L1 expression after starting CIRT may become as a predictive prognostic marker in CIRT for UCAA.

Although the recent revision of the ministerial ordinance on Good Post-marketing Study Practice (GPSP) included the utilization of medical information databases for post-marketing surveillance, there has been limited research on the validity of diagnosis codes and other outcome definitions in Japanese databases such as administrative claims (“receipt”) database. This task force proposed how to conduct good validations studies, based on the narrative review on around 100 published papers around the world. The established check list consists of ： (ⅰ) understanding the type of the database (e.g. administrative claims data, electronic health records, disease registry) ； (ii) understanding the setting of the validation study (e.g. “population-based” or not) ； (iii) defining the study outcome ； (iv) determining the way of linkage between databases ； (v) defining the gold standard ； (vi) selecting the sampling method (e.g. using the information of all patients in the database or a hospital, random sampling from all patients, random sampling from patients satisfying the outcome definition, random sampling from patients satisfying and not satisfying the outcome definition, “all possible cases” method) and sample size ； (vii) calculating the measures of validity (e.g. sensitivity, specificity, positive predictive value, negative predictive value) ； and (viii) discussing how to use the result for future studies. In current Japan, where the linkage between databases is logistically and legally difficult, most validation studies would to be conducted on a hospital basis. In such a situation, detailed description of hospital and patient characteristics is important to discuss the generalizability of the validation study result to the entire database. This report is expected to encourage and help to conduct appropriate validation studies.

BACKGROUND/AIMS: Prokinetic drugs such as metoclopramide are frequently used as second-line therapy for patients with gastroesophageal reflux disease. However, their beneficial effects remain unclear. Esophageal motor activities and compliance of the esophagogastric junction (EGJ) are important for prevention of gastroesophageal reflux. Although metoclopramide has been reported to increase lower esophageal sphincter (LES) pressure, its effects on EGJ compliance have not been evaluated. In the present study, we investigated the effects of metoclopramide on esophageal motor activities and EGJ compliance. METHODS: Nine healthy male volunteers without abdominal symptoms were enrolled. Peristaltic esophageal contractions and LES pressure were examined using high-resolution esophageal manometry, while EGJ compliance was evaluated with an endoluminal functional lumen-imaging probe. After obtaining baseline values for esophageal motor activities and EGJ compliance, metoclopramide (10 mg) was intravenously administered, then all measurements were repeated at 15 minutes after administration in each subject. RESULTS: Following administration of metoclopramide, mean resting LES pressure was significantly increased as compared with the baseline (13.7 +/- 9.2 vs 26.7 +/- 8.8 mmHg, P < 0.05). In addition, metoclopramide significantly augmented peristaltic contractions, especially in the distal esophageal segment (P < 0.05). On the other hand, distensibility index did not change after administration (4.5 +/- 0.5 vs 4.1 +/- 0.5 mm2/mmHg), suggesting no significant effect of metoclopramide on EGJ compliance. CONCLUSIONS: Metoclopramide augmented esophageal contractions without changing EGJ compliance in healthy adults.
Adult ; Compliance* ; Esophageal Sphincter, Lower ; Esophagogastric Junction* ; Gastroesophageal Reflux ; Hand ; Healthy Volunteers* ; Humans ; Male ; Manometry ; Metoclopramide* ; Motor Activity* ; Volunteers