Chemical and in vitro toxicological comparison of emissions from a heated tobacco product and the 1R6F reference cigarette.

It has previously been found that, compared with cigarette smoke, the aerosols generated by heated tobacco products contain fewer and lower harmful and potentially harmful constituents (HPHCs) and elicit lower biological activity in in vitro models and lower smoking-related exposure biomarker levels in clinical studies. It is important to accumulate such scientific evidences for heated tobacco products with a novel heating system, because different heating system may affect the quantitative aspect of the amount of HPHCs and the qualitative aspect of the biological activity of the aerosol generated. Here, the chemical properties of, and toxicological responses to aerosols emitted by DT3.0a, a new heated tobacco product with a novel heating system, and cigarette smoke (CS) were compared, using chemical analyses, in vitro battery (standardized genotoxicity and cytotoxicity) assays, and mechanistic (ToxTracker and two-dimensional cell culture) assays. Regular- and menthol-flavored DT3.0a and standard 1R6F reference cigarettes were tested. Selected HPHC yields were lower in DT3.0a aerosol than 1R6F CS. The genotoxicity-related assays indicated that DT3.0a aerosol was not genotoxic, regardless of metabolic activation. The other biological assays indicated that less cytotoxicity induction and oxidative stress response were elicited by DT3.0a aerosol compared with 1R6F CS. Similar results were found for both regular and menthol DT3.0a. Like previous reports for heated tobacco products with other heating systems, the results of this study indicated that DT3.0a aerosols have chemical and biological properties less likely to be harmful than 1R6F CS.

In vitro evaluation of mutagenic, cytotoxic, genotoxic and oral irritation potential of nicotine pouch products.

Non-clinical in vitro studies were conducted to investigate the characteristics of extracts from tobacco free nicotine pouches alongside a reference snus product and/or 1R6F reference cigarette. In vitro investigations were conducted in the Neutral Red Uptake (NRU) cytotoxicity assay, Bacterial Reverse Mutation (Ames) assay, and in vitro Mammalian Cell Micronucleus (ivMN) assay. These products were also investigated for their oral irritation potential in the EpiGingival™ 3D tissue model. Results from the Ames, in vitro Micronucleus and NRU assays indicated that the tested products were non-mutagenic, non-genotoxic and non-cytotoxic in contrast to results obtained for the 1R6F reference cigarette. Results from Complete Artificial Saliva (CAS) extracts from these products also failed to be classified as irritants (as measured using the MTT assay), in the EpiGingival™ 3D tissue model.

Effects of antioxidant capacity on micronucleus induction by cigarette smoke in mammalian cells.

We have compared micronucleus (MN) induction by cigarette smoke in the L5178Y, TK6, and CHL/IU cell lines. The test sample was total particulate matter of 3R4F reference cigarette smoke, suspended in DMSO. After 3-h treatment, with or without a rat liver S9 metabolic activation system, followed by 24-h recovery, dose-dependent MN increases were seen in all cell lines. However, CHL/IU and TK6 cells were more resistant than L5178Y cells (comparison by Benchmark Doses with PROAST software). 3R4F smoke generates reactive oxygen species (ROS). Therefore, we explored the relationship between the sensitivities to 3R4F smoke and the antioxidant capacities of the cell lines. While the total antioxidant capacities were not significantly different among the cell lines, cellular glutathione (GSH) was higher in CHL/IU cells than in L5178Y cells. Pretreatment of CHL/IU cells with a GSH precursor, N-acetylcysteine (NAC), reduced the genotoxicity/cytotoxicity of 3R4F, whereas an inhibitor of GSH biosynthesis, buthionine sulfoximine (BSO), enhanced it. The effects of NAC and BSO were also seen after treatment with allyl isothiocyanate, a ROS-generating chemical, but not with mitomycin C, a ROS-independent genotoxicant. Pretreatment with NAC increased cellular thiol levels. From the present results, the genotoxicity and cytotoxicity of cigarette smoke differs among these cell lines in a manner that may be related to their antioxidant thiol levels.

[Mediastinal Growing Teratoma Syndrome during Chemotherapy, Presenting as a Huge and Inoperable Tumor].

A 22-year-old male was diagnosed with a metastatic nonseminomatous germ cell tumor in the mediastinum with an elevated serum alpha-fetoprotein(AFP)concentration. Histopathological findings following percutaneous biopsy revealed the presence of a mature teratoma. Bleomycin, etoposide, and cisplatin(BEP)chemotherapy resulted decreased his serum AFP. However, the tumor became enlarged and was deemed inoperable due to size. Radiographic examination indicated diffuse calcification of the tumor mass. Growing teratoma syndrome in a patient with a primary mediastinal nonseminomatous germ cell tumor is extremely rare.

[Desensitization Therapy for Osimertinib in Patients Who Developed Toxic Erythema - Two Case Reports].

We encountered 2 cases of T790M-positive non-small cell lung cancer in patients who developed toxic erythema within a week after initiation of osimertinib(80mg/day)therapy. Since osimertinib was regarded as the suspected drug, we adminis- tered desensitization therapy for osimertinib at an initial dose of 10mg/day. During the process of dose escalation, slight eruption and flare were observed, but we were able to provide appropriate treatment. Osimertinib therapy was continued and conferred tumor reduction in both cases. We report the clinical course and suggest that desensitization therapy is an alternative therapy for patients who present with drug-induced allergic reaction.

Negative and positive control ranges in the bacterial reverse mutation test: JEMS/BMS collaborative study.

A large-scale study was conducted by multiple laboratories affiliated with the Japanese Environmental Mutagen Society and the Bacterial Mutagenicity Study Group to investigate possible proficiency indicators for the bacterial reverse mutation test with a preincubation procedure. Approximately 30 laboratories generated negative and positive control count data and dose-response curves of the positive control articles for the bacterial reverse mutation test, with assays conducted annually from 2013 to 2016. Overall, the majority of the negative and positive control counts for Salmonella Typhimurium strains TA100, TA1535, TA98, and TA1537, and Escherichia coli strain WP2uvrA, with and without S9 mix, were within the range of the means ±2× standard deviation. The negative counts were normally distributed (strains TA100, TA98, and WP2uvrA) or followed Poisson distribution (strains TA1535 and TA1537), and the positive control counts for all strains were approximately normally distributed. In addition, the distribution of the negative and positive control counts was relatively constant over the 4 years. The number of revertant colonies increased in a dose-dependent linear or exponential fashion up to the recommended doses for the respective positive control articles in Japan. These data are valuable for determining the acceptance criteria and an estimation of the laboratory proficiency for the bacterial reverse mutation test.

Chemical analysis and in vitro toxicological evaluation of aerosol from a novel tobacco vapor product: A comparison with cigarette smoke.

The recent rapid increase in the prevalence of emerging tobacco- and nicotine-containing products, such as e-cigarettes, is being driven in part by their reduced-risk potential compared to tobacco smoking. In this study, we examined emission levels for selected cigarette smoke constituents, so-called "Hoffmann analytes", and in vitro toxicity of aerosol from a novel tobacco vapor product (NTV). The NTV thermally vaporizes a nicotine-free carrier liquid to form an aerosol which then passes through tobacco, where it absorbs tobacco-derived flavors and nicotine. The NTV results were compared with those for 3R4F cigarette smoke. Chemical analysis of the NTV aerosol demonstrated that Hoffmann analyte levels were substantially lower than in 3R4F smoke and that the most were below quantifiable levels. Results from in vitro bacterial reverse mutation, micronucleus and neutral red uptake assays showed that, in contrast with 3R4F smoke, the NTV aerosol failed to demonstrate any measurable genotoxicity or cytotoxicity. The temperature of tobacco during NTV use was measured at approximately 30 °C, which may explain the lower Hoffmann analyte emission and in vitro toxicity levels. These results suggest that the aerosol from the NTV has a very different toxicological profile when compared with combustible cigarette smoke.

Late-onset rejection of a unilateral donor lung with vascular C4d deposition in bilateral living-donor lobar lung transplantation: an autopsy case report.

A 37-year-old woman had undergone bilateral living-donor lobar lung transplantation 11 years previously for idiopathic pulmonary arterial hypertension. Her father donated the right lobe and her brother donated the left lobe. She subsequently developed progressively worsening respiratory dysfunction due to pneumonia. CT showed left dominant pulmonary artery dilatation, bronchial wall thickening and airway stenosis, followed by sudden death. An autopsy showed marked pathologic left dominant rejection of the pulmonary artery, small airway and large airway. Notably, only the left lung showed C4d vascular deposition, thus suggesting that antibody-mediated lung rejection may have occurred.

[A case of etanercept-induced pneumonitis].

A 64-year-old man was admitted to our hospital because of fever and dyspnea with marked hypoxemia and diffuse ground-glass opacities in bilateral lung fields revealed by a chest CT scan. He had used etanercept therapy for his rheumatoid arthritis. His PaO2/FiO2 had decreased to 130.4 Torr. On bronchoalveolar lavage, lymphocytes were elevated to 54.4% and bacteria culture was negative. We diagnosed drug-induced pneumonitis caused by etanercept, clinically and started high dose corticosteroid therapy. Despite his severe hypoxemia, the corticosteroid therapy and use of non-invasive positive pressure ventilation improved his condition. Interstitial lung disease induced by etanercept is rare, and a severe case requiring mechanical ventilation has never been reported. Because of the critical condition it can cause, it is suggested that evaluation of interstitial pneumonia is crucial.