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Introduction: Hayabusa2 spacecraft returned samples from near-Earth C-type asteroid 162173 Ryugu to the Earth on 6 Dec. 2020 [1]. Since the samples had been returned, we continue describing individual Ryugu particles for their images, weights, visible and infrared spectra with the optical microscope Nikon SMZ1270i, the balance Mettler-Toledo XP404s, the monochronic digital microscope Kiralux CS895MU with six-bands filters for incident light, the FT-IR Jasco VIR-300 and the infrared microscope MicrOmega, respectively [1, 2]. So far, 404 individual Ryugu particles have been handpicked and described for all or some of the methods [3-11]. Surface morphologies and bulk densities of individual Ryugu particles: As mentioned in [3, 4], individual Ryugu particles have been grouped into angular or rounded in their shapes and smooth and rough in their morprologues. In total, those having rounded-shape (59%) and rough-surface (80%) are dominant in them. The relationship with their optical morphologies and surface mineralogizes were confirmed for the four individual Ryugu particles with an electron microscope [12], indicating those showing smooth surfaces showing space-weathering features on their surfaces. Although it is still poor in statistics, surface morphologies might reflect their mineralogical feature such as space weathering. Bulk densities of individual Ryugu particles were calculated based on the volume estimated from their three-dimensional size and to be 1283 ± 231 kg m-3 in an average of 156 individual Ryugu particles [1]. All the bulk densities of 404 individual Ryugu particles were plotted in the viewgraph of [4], showing the same tendency as reported in [1]. As pointed before, individual Ryugu particles vary from 500 to 2500 kg m-3 in bulk densities, indicating their porosities should vary largely from particles to particles, or errors in volume estimation are large [8]. More accurate volume evaluation such as three-dimensional imaging [8] or X-ray computed tomography [13] should be applied more for individual Ryugu particles to reveal their "real" bulk and grain densities. Infrared and visible reflectance spectra of individual Ryugu particles: So far, 244 of individual Ryugu particles have been analyzed for their infrared reflectance spectra with the FT-IR. 2.7µm absorption, corresponding to presence of -OH, have been detected from all of them, indicating ubiquitous presence of hydrous minerals in Ryugu samples. 3.4 µm absorption features, corresponding to presence of carbonate or -CH, have been detected from 48% of them. As pointed before [3], this should be partially due to their heterogeneous distribution of carbonate and/or organic components in them, and that the spectral feature in 3.4 µm is much weaker than 2.7 µm. It is difficult to detect spectral feature other than 2.7 µm for the particle comparable to or smaller than effective beam size of FT-IR, ~2 mm. The MicrOmega will help to detect minor spectral features from such small particles, even though there is limitation of number of analyses per day (2 individual particles per day). Visible spectra of individual Ryugu samples have been also analyzed with the digital microscope of muti-band filters [7]. The average spectrum of 69 individual Ryugu particles are comparable to that of bulk Ryugu samples, indicating there is no spectrally different particle among them. Due to the schedule of analyses, not all of the individual Ryugu particles have been analyzed for the visible spectra, but we should proceed the analysis to understand overall spectral features of Ryugu samples. Ryugu sample database and international announcement of opportunity (AO) for Ryugu samples: All the obtained initial description data shown above is open in public by the Ryugu Sample Database System (https://darts.isas.jaxa.jp/curation/hayabusa2/) [14]. The first international AO is ongoing based on this database, and the samples will be distributed to principal investigators of selected research proposals from this June (see detail in https://jaxa-ryugu-sample-ao.net/). Additionally, the second AO will be released in this summer. [ABSTRACT FROM AUTHOR]

In-situ analysis of major elements using laser-induced breakdown spectroscopy (LIBS) is essential for future lunar landing missions, yet its performance under lunar conditions remains not fully understood. This uncertainty arises from the absence of an atmosphere and the diverse range of surface materials, which vary in chemical composition from anorthosites to basalts, and in physical properties from fine regolith to boulders. To address these challenges, we developed and cross-validated a multivariate LIBS calibration model by measuring 169 compressed fine powders of geologic samples under vacuum. These samples fully encompass the bulk composition range of lunar meteorites. We investigated the applicability of the model to a wider range of samples by measuring lunar meteorites, terrestrial anorthites, and lunar simulants in various physical forms, including rock chips and soils with different grain sizes and bulk densities. For powder samples, the quantification accuracy, assessed using root mean squared error (RMSE), resulted in 2.5 wt% SiO 2 , 0.25 wt% TiO 2 , 1.2 wt% Al 2 O 3 , 1.3 wt% MgO, 1.2 wt% CaO, 0.33 wt% Na 2 O, 0.47 wt% K 2 O (0.060 wt% K 2 O in the <1 wt% range), and 1.5 wt% T-Fe 2 O 3. For rock chip samples, the RMSEs were 3.1 wt% SiO 2 , 0.32 wt% TiO 2 , 2.2 wt% Al 2 O 3 , 2.5 wt% MgO, 2.0 wt% CaO, 0.33 wt% Na 2 O, 0.089 wt% K 2 O, and 2.1 wt% T-Fe 2 O 3. Despite significant differences in physical conditions between powders and rocks, their RMSEs remained consistent within a factor of two. Changes in grain size or bulk density of soils had relatively minor effects on the RMSE. These RMSEs confirm that the quantification accuracy of LIBS is sufficient to distinguish the subgroups within the lunar anorthosite suite (e.g., anorthosites vs. norites) and basalts (e.g., high-Ti vs. low-Ti) across a range of soil types, from coarse to fine and from loose to compact, as well as rocks. Furthermore, our analysis shows that LIBS can differentiate between "purest" and "pure" anorthosites (98 and 95 vol% plagioclase, respectively) based on the 3σ detection limits of Mg and Fe lines. These capabilities of LIBS align well with the goals of future lunar exploration, such as locating ilmenite-rich soils for resource extraction, detecting purest anorthosites to understand early lunar evolution, and identifying noritic impact melts to refine lunar chronology. Overall, our results demonstrate that LIBS serves as a versatile tool for rapid geochemical characterization on the Moon. [Display omitted] • We evaluated the performance of LIBS for in-situ compositional analysis in future lunar missions. • Our samples cover the full compositional range of lunar materials, with variations in physical properties. • LIBS can accurately classify anorthosites and basalts into their respective subgroups. • This accuracy is maintained for both rock and soil samples, with minimal influence from grain size and compaction. • LIBS can identify the purest anorthosites based on the detectabilities of Mg and Fe lines. [ABSTRACT FROM AUTHOR]

The opioid system plays crucial roles in modulating social behaviors in both humans and animals. However, the pharmacological profiles of opioids regarding social behavior and their therapeutic potential remain unclear. Multiple pharmacological, behavioral, and immunohistological c-Fos mapping approaches were used to characterize the effects of μ-opioid receptor agonists on social behavior and investigate the mechanisms in naive mice and autism spectrum disorder-like (ASD-like) mouse models, such as prenatally valproic acid-treated mice and Fmr1-KO mice. Here, we report that low-dose morphine, a μ-opioid receptor agonist, promoted social behavior by selectively activating neurons in prosocial brain regions, including the nucleus accumbens, but not those in the dorsomedial periaqueductal gray (dmPAG), which are only activated by analgesic high-dose morphine. Critically, intra-dmPAG morphine injection counteracted the prosocial effect of low-dose morphine, suggesting that dmPAG neural activation suppresses social behavior. Moreover, buprenorphine, a μ-opioid receptor partial agonist with less abuse liability and a well-established safety profile, ameliorated social behavior deficits in two mouse models recapitulating ASD symptoms by selectively activating prosocial brain regions without dmPAG neural activation. Our findings highlight the therapeutic potential of brain region-specific neural activation induced by low-dose opioids for social behavior deficits in ASD.

Silica polymorphs occur under various pressures and temperature conditions, and their characteristics can be used to better understand the complex metamorphic history of planetary materials. Here, we conducted isothermal heating experiments of silica polymorphs in basaltic eucrites to assess their formation and stability. We revealed that each silica polymorph exhibits different metamorphic responses: (1) Quartz recrystallizes into cristobalite when heated at ≥ 1040 °C. (2) Monoclinic (MC) tridymite recrystallizes into no other polymorphs when heated at ≤ 1070 °C. (3) Silica glass recrystallizes into quartz when heated at 900-1010 °C, and recrystallize into cristobalite when heated at ≥ 1040 °C. These results suggest that MC tridymite in eucrites does not recrystallize into other polymorphs during the reheating events, nor does it recrystallize from other silica phases below the solidus temperature of eucrite (~ 1060 °C). Additionally, we found that pseudo-orthorhombic (PO) tridymite crystallizes from quenched melts in the samples heated at ≥ 1070 °C. Previously, cristobalite has been considered as the initial silica phase, which crystallizes from eucritic magma. Our findings suggest that the first crystallizing silica minerals may not always be cristobalite. These require a reconsideration of the formation process of silica minerals in eucrites., (© 2024. The Author(s).)

Objectives: This study aimed to investigate the characteristics of patients with recurrent or advanced non-small cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors (TKIs) or immune-checkpoint inhibitors (ICIs) who developed secondary malignancies, as well as evaluate the impact of these secondary malignancies on the course of lung cancer., Materials and Methods: This study included 112 patients with postoperative recurrent or advanced NSCLC, who received TKIs, ICIs, or immune combination therapy as the primary treatment modality between April 1, 2013, and March 31, 2020, and achieved long-term survival (≥2 years). Secondary malignancies were defined as newly diagnosed cancers in other organs occurring after NSCLC treatment initiation., Results: Among the 112 patients, 10 (8.9%) developed 12 carcinomas, including third primary malignancies. Univariate analysis, considering secondary malignancies as the outcome, revealed a non-significant trend towards a higher incidence of secondary malignancies in smokers compared to non-smokers., Conclusion: This study found that 8.9% of patients with advanced NSCLC who received TKIs, ICIs, or immune combination therapy and survived ≥2 years developed secondary malignancies. This underscores the importance of early diagnosis and treatment, even during lung cancer treatment, to identify suspicious lesions in other organs either via imaging or physical examinations., (© 2024 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Introduction: Trophoblast cell surface antigen 2 (TROP2) is a transmembrane glycoprotein overexpressed in various cancer types. Although TROP2-targeting therapy is currently attracting attention, little is known about TROP2 expression in thymic carcinoma., Methods: TROP2 gene expression in thymic epithelial tumors was analyzed using RNA-sequencing (RNA-seq) data for 122 cases obtained from The Cancer Genome Atlas. Immunohistochemistry (IHC) staining with anti-TROP2 antibody (SP295) was performed in 26 cases of thymic carcinoma tissues surgically resected at Juntendo University., Results: RNA-seq data analysis from The Cancer Genome Atlas revealed that TACSTD2 (gene encoding TROP2) expression was significantly higher in thymic carcinoma than in thymoma (adjusted p  = 6.64e-05). There was also a trend of increasing expression in the order of thymoma type B1, B2, B3, and thymic carcinoma. As for IHC in thymic carcinoma, TROP2 expression was localized to the membrane of cancer cells. Intensity 0, 1, and 2 was observed in six (23.1%), 11 (42.3%), and nine (34.6%) cases, respectively, leading to TROP2 positivity in 20 cases (76.9%). The median proportion of TROP2-positive tumor cells and the median H-score were 25.0% (range: 0%-100%) and 25.0 (range: 0-200), respectively. No relevant factors were identified in the analysis of TROP2 expression and patient background. Although not significant, high TROP2 expression (H-score ≥ 50) tended to be associated with shorter survival., Conclusions: TROP2 expression in thymic carcinoma was confirmed by both RNA-seq and IHC, with high expression observed in IHC for intensity (76.9%) and proportion. TROP2 could be a potential target in thymic carcinoma., Competing Interests: Dr. Asao reports honoraria from AstraZeneca K.K., Bristol-Myers K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eli Lilly Japan K.K, Merck Biopharma Co., Ltd., Merck Sharp & Dohme K.K, Nippon Boehringer Ingelheim Co., Ltd., Nippon Kayaku Co., Ltd., Ono Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Company Limited outside of the submitted work. Dr. Shukuya reports grants and honoraria from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., and Merck Sharp & Dohme K.K. and honoraria from Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb Company, Nippon Kayaku Co., Ltd., Takeda Pharmaceutical Company, Pfizer Inc., and Eisai Co., Ltd. outside of the submitted work. Dr. Fumiyuki Takahashi reports grants from 10.13039/100004325AstraZeneca, 10.13039/100017346Nippon Boehringer Ingelheim, 10.13039/100009947Merck Sharp & Dohme, 10.13039/100004336Novartis, and Lilly Japan outside of the submitted work. Dr. Kazuhisa Takahashi reports grants and honoraria from Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Novartis Pharma K.K., Eli Lilly Japan K.K., Nippon Kayaku Co., Ltd., Takeda Pharmaceutical Company Limited, and grants from 10.13039/100018036Nippon Shinyaku Co., Ltd., Tsumura & Co., Teijin Pharma Limited, 10.13039/100015990Sanofi K.K., Shionogi & Co., Ltd., Bayer Yakuhin, Ltd., 10.13039/501100002973Daiichi Sankyo Co., Ltd., Nipro Pharma Corporation, 10.13039/100010740Asahi Kasei Pharma Corporation, Kyowa Kirin Co., Ltd., and honoraria from Merck Sharp & Dohme K.K., AstraZeneca K.K., Merck Biopharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Bristol-Myers K.K., Meiji Seika Pharma Co., Ltd., Viatris Inc., Janssen Pharmaceutical K.K., Abbott Japan LLC, and Thermo Fisher Scientific Inc. outside the submitted work. The remaining authors declare no conflict of interest., (© 2024 The Authors.)

Objectives: In this study, we explored the clinical outcomes of non-small cell lung cancer (NSCLC) patients with EGFR Exon20 in-frame insertions (Exon20ins), and the impact of the location of Exon20ins on these clinical outcomes., Materials and Methods: The efficacies of current systemic therapies in NSCLC patients harboring Exon20ins were investigated using a large-scale clinico-genomic database of LC-SCRUM-Asia, and compared with that of amivantamab in the CHRYSALIS trial., Results: Of the 11,397 patients enrolled in LC-SCRUM-Asia, Exon20ins were detected in 189 patients (1.7 %). Treatment with classical EGFR tyrosine-kinase inhibitors (classical TKIs) was associated with a significantly shorter progression-free survival (PFS) in NSCLC patients with Exon20ins as compared with Exon19 deletions and L858R. Post platinum-based chemotherapy, classical TKIs and immune checkpoint inhibitors (ICIs) were associated with a shorter PFS than with docetaxel in patients with Exon20ins (HR [95 % CI]; TKIs vs docetaxel, 2.16 [1.35-3.46]; ICIs vs docetaxel, 1.49 [1.21-1.84]). Patients treated with amivantamab in the CHRYSALIS trial showed a risk reduction in PFS and overall survival as compared with LC-SCRUM-Asia patients treated with docetaxel, classical TKIs, or ICIs. Among the 189 patients, Exon20ins were classified as near-loop or far-loop insertions in 115 (61 %) and 56 (30 %) patients, respectively. Treatment with osimertinib was associated with a longer PFS in patients with Exon20ins in near-loop as compared with far-loop (median, 5.6 vs. 2.0 months; HR [95 % CI], 0.22 [0.07-0.64])., Conclusions: After platinum-based chemotherapy, classical TKIs and ICIs are less effective in NSCLC patients with Exon20ins, and amivantamab may be a promising targeted therapy. There is a possibility that the location of Exon20ins has an impact on the efficacy of TKIs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hibiki Udagawa reports grants from Takeda and Boehringer Ingelheim outside the current study. Shingo Matsumoto reports grants from Chugai Pharmaceutical, MSD and Janssen Pharmaceutical and honoraria for lectures from Merck and Eli Lilly outside the current study. Terufumi Kato reports grants from Abbvie, Amgen, AstraZeneca, BeiGene, BluePrint, Chugai, Daiichi-Sankyo, Eli Lilly, Haihe, Merck, MSD, Novartis, Pfizer, Regeneron, Takeda and Turning Point and honoraria for lectures from Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceutical, Merck, MSD, Novartis, Ono, Pfizer, Taiho, and Takeda and other from AstraZeneca, BeiGene, Daiichi-Sankyo, Janssen Pharmaceutical, Merck, MSD, Novartis, Pfizer and Eli Lilly outside the current study. Hiroshi Yokouchi reports grants from AstraZeneca, Sanofi, Bristol-Myers Squibb, MSD, Takeda, Daiichi-Sankyo, Chugai Pharmaceutical, Abbvie, Amgen and Taiho and honoraria for lectures from AstraZeneca outside the current study. Naoki Furuya reports honoraria for lectures from Eli Lilly, AstraZeneca, Boehringer Ingelheim, Chugai, Bristol Myers Squibb, Taiho, Pfizer and Novartis. Ryo Toyozawa reports grants from Abbvie, Amgen, AnHeart Therapeutics, Daiichi-Sankyo, Eli Lilly, Novartis, Pfizer, and Takeda and honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Chugai, Eli Lilly, MSD, Novartis, Ono, Pfizer, Taiho, and Takeda outside the current study. Kadoaki Ohashi reports grants from Amgen, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eli Lilly and Novartis and honoraria for lectures from AstraZeneca, Chugai, Eli Lilly, Kyowa Kirin and Novartis and other from Momotaro-gene, Genentech and Novartis outside the current study. Kazumi Nishino reports grants from Abbvie, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Daiichi-Sankyo, Janssen Pharmaceutical, Merck, Merus, MSD, Novartis, Ono, Pfizer, Sanofi, Taiho, and Takeda and honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Eli Lilly, Janssen Pharmaceutical, Merk, Nippon Kayaku, Pfizer and Roche Diagnostics and other from AstraZeneca, Eli Lilly and Pfizer outside the current study. Atsushi Nakamura reports honoraria for lectures from AstraZeneca, Chugai, Eli Lilly, Taiho, Merck, Nippon Kayaku, Novartis, Pfizer and Thermo Fisher Scientific outside the current study. Eiji Iwama reports honoraria for lectures from AstraZeneca, Bayer, Chugai, Life Technologies, Novartis, Pfizer and Takeda outside the current study. Seiji Niho reports grants from Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Kyowa Kirin, Nippon Kayaku, Ono, Shionogi, Taiho and Teijin Pharma and honoraria for lectures from Amgen, AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Janssen Pharmaceutical, Kyorin, MSD, Nippon Kayaku, Novartis, Ono, Pfizer, Taiho and Takeda outside the current study. Tetsuya Sakai reports honoraria for lectures from AstraZeneca, Chugai, Merck, MSD, Novartis and Thermo Fisher Scientific outside the current study. Yuji Shibata reports grants from Blueprint, MSD and Novartis and honoraria for lectures from AstraZeneca, Bristol-Myers Squibb, Chugai, Eli Lilly, Merck, Ono, Pfizer and Takeda outside the current study. Hiroki Izumi reports grants from Amgen, AstraZeneca, Bristol-Myers Squibb, Chugai, Eisai, MSD, Merck, Ono and Takeda outside the current study. Kaname Nosaki reports grants from Abbvie, AnHeart Therapeutics, AstraZeneca, Chugai, Daiichi Sankyo, MSD and Takeda and honoraria for lectures from AstraZeneca, Chugai, Eli Lilly, Janssen Pharmaceutical, Merck, MSD, Novartis, Ono, Pfizer, Taiho and Takeda and other from Abbvie and Daiichi Sankyo outside the current study. Shigeki Umemura reports honoraria for lectures from Chugai outside the current study. Yoshitaka Zenke reports grants from Amgen, AstraZeneca, Daiichi-Sankyo, GSK, Merck, MSD and Roche and honoraria for lectures from Amge, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Kyowa kirin, MSD, Nihon Kayaku, Novartis, Ono, Taiho and Takeda outside the current study. Kiyotaka Yoh reports grants from Abbvie, AstraZeneca, Chugai, Daiichi-Sankyo, Eli Lilly, MSD, Pfizer, Taiho and Takeda and honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, Janssen Pharmaceutical, Kyowa kirin, Novartis and Taiho and other from Boehringer Ingelheim outside the current study. Grace K. M. Low was a full-time employee of Janssen when this study was performed and received long-term incentives from Janssen. She is currently not an employee of Janssen. Jianmin Zhuo is employed by Janssen China. Koichi Goto reports grants from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Blueprint, Craif, Daiichi-Sankyo, Eisai, Eli Lilly, Haihe Biopharma, Ignyta, Janssen Pharmaceutical, KISSEI PHARMACEUTICAL, Kyowa Kirin, Life Technologies Japan, Loxo Oncology, LSI Medience Corporation, MEDICAL&BIOLOGICAL LABORATORIES, Merck, Merus, MSD, Novartis, Ono, Pfizer, Precision Medicine Asia, RIKEN GENESIS, Sumitomo Pharma, Spectrum Pharmaceuticals, Sysmex Corporation, Taiho, Takeda, Turning Point Therapeutics and Xcoo and honoraria for lectures from Amgen, Amoy Diagnosties Co, AstraZeneca, Bayer, Boehringer Ingelheim, Blueprint, Daiichi-Sankyo, Eisai, Eli Lilly, Guardant Health Inc, Haihe Biopharma, Janssen Pharmaceutical, Medpace Japan, Merck, Nippon Kayaku, Novartis, Ono, Otsuka, RIKEN GENESIS CO, Taiho and Takeda and other from Amgen, Daiichi-Sankyo, Eli Lilly outside the current study., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Pembrolizumab is a programmed death-ligand 1 inhibitor that was initially indicated for monotherapy in patients with advanced lung cancer. The Japanese Lung Cancer Society conducted an observational study on pembrolizumab using confirmative data obtained through postmarketing all-case surveillance (PMACS), which was performed by a pharmaceutical company under the Japanese law in 2017., Methods: This multicenter observational study was conducted by the Japanese Lung Cancer Society using PMACS data with the newly created central registration system regarding patients with NSCLC who received pembrolizumab monotherapy between February 1, 2017 and June 30, 2017; a new database was created by adding the clinical information regarding prognosis for 3 years after therapy to the existing data collected by PMACS., Results: A total of 300 patients from 43 facilities were enrolled in this study. The median overall survival and progression-free survival after pembrolizumab initiation were 558 and 188 days, respectively. Moreover, the 1- and 3-year survival rates were 58.9% and 33.7%, respectively. Results of multivariate analysis revealed performance status ( p < 0.0001), histology ( p = 0.0118), previous chemotherapy ( p = 0.0007), programmed death-ligand 1 expression status ( p = 0.0195), and previous steroid use ( p = 0.0460) as significant factors that affected overall survival. The toxicity profile was similar to that previously reported., Conclusions: In this first attempt to use PMACS data, we successfully collected clinical information and found the real-world efficacy and safety of pembrolizumab., (© 2022 The Authors.)

Purpose: Transforming growth factor β (TGFβ)-mediated epithelial-mesenchymal transition (EMT) of alveolar epithelial cells contributes to pulmonary fibrosis. Dasatinib (DAS), a potent and broad-spectrum tyrosine kinase inhibitor, has been widely studied as an anti-cancer agent. However, the therapeutic application of DAS for pulmonary fibrosis has not been clarified. Our purpose here is to investigate the effect of DAS on TGFβ1-induced EMT in human alveolar and bronchial epithelial cells in vitro and to evaluate the efficacy of DAS on lung fibrosis in vivo., Methods: TGFβ1-stimulated human alveolar epithelial (A549) and bronchial epithelial (BEAS-2B) cells were treated with or without DAS in vitro. Murine pulmonary fibrosis model was generated by injection of bleomycin (BLM)., Results: A549 and BEAS-2B cells exposed to TGFβ1 underwent EMT, as indicated by downregulation of epithelial protein E-cadherin and induction of the mesenchymal proteins, fibronectin and type I and type IV collagen. These effects were dramatically suppressed by DAS treatment, which also prevented Smad2 and Smad3 phosphorylation. DAS inhibited TGFβ1-induced cell motility and migration. Furthermore, DAS administration significantly attenuated lung fibrosis in mice by histological analysis. Treatment with DAS also significantly reduced the levels of collagen and fibronectin and phosphorylation of Smad2 in the lung tissues of the murine model., Conclusions: These findings suggest that DAS inhibited TGFβ-mediated EMT of alveolar and bronchial epithelial cells and attenuated BLM-induced lung fibrosis in mice by suppressing the TGFβ/Smad pathway. DAS may be a promising and novel anti-fibrotic agent for preventing lung fibrosis.

Background: Interstitial lung diseases induced by anticancer agents (ILD-AA) are rare adverse effects of anticancer therapy. However, prognostic biomarkers for ILD-AA have not been identified in patients with advanced lung cancer. Our aim was to analyze the association between serum biomarkers sialylated carbohydrate antigen Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D), and clinical characteristics in patients diagnosed with ILD-AA., Methods: Between April 2011 and March 2016, 1224 advanced lung cancer patients received cytotoxic agents and epidermal growth factor receptor tyrosine kinase inhibitors at Juntendo University Hospital and Juntendo University Urayasu Hospital. Of these patients, those diagnosed with ILD-AA were enrolled in this case control study. ΔKL-6 and ΔSP-D were defined as the difference between the levels at the onset of ILD-AA and their respective levels prior to development of ILD-AA. We evaluated KL-6 and SP-D at the onset of ILD-AA, ΔKL-6 and ΔSP-D, the risk factors for death related to ILD-AA, the chest high resolution computed tomography (HRCT) findings, and survival time in patients diagnosed with ILD-AA., Results: Thirty-six patients diagnosed with ILD-AA were enrolled in this study. Among them, 14 patients died of ILD-AA. ΔSP-D in the patients who died was significantly higher than that in the patients who survived. However, ΔKL-6 did not differ significantly between the two groups. Moreover, ΔSP-D in patients who exhibited diffuse alveolar damage was significantly higher than that in the other patterns on HRCT. Receiver operating characteristic curve analysis was used to set the optimal cut off value for ΔSP-D at 398 ng/mL. Survival time for patients with high ΔSP-D (≥ 398 ng/mL) was significantly shorter than that for patients with low ΔSP-D. Multivariate analysis revealed that ΔSP-D was a significant prognostic factor of ILD-AA., Conclusions: This is the first research to evaluate high ΔSP-D (≥ 398 ng/mL) in patients with ILD-AA and to determine the risk factors for ILD-AA in advanced lung cancer patients. ΔSP-D might be a serum prognostic biomarker of ILD-AA. Clinicians should evaluate serum SP-D during chemotherapy and should carefully monitor the clinical course in patients with high ΔSP-D.

A 62-year-old man with asthma presented with a 1-month history of wheezing and exertional dyspnea. Although the wheezing symptoms disappeared after systemic corticosteroid therapy, the exertional dyspnea and hypoxemia did not improve. A diagnosis of intravascular large B-cell lymphoma (IVLBCL) with pulmonary involvement was suspected because of the increased serum lactic dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL-2R) level, increased alveolar-arterial oxygen difference (AaDO 2 ), decreased pulmonary diffusing capacity for carbon monoxide (D LCO ) and scintigraphic, computed tomography (CT) and 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT findings. The patient was diagnosed as having IVLBCL with pulmonary involvement based on a pathological analysis of a random skin biopsy and a transbronchial lung biopsy. IVLBCL should be considered in patients with symptoms of asthma that are refractory to corticosteroid treatment.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by rapid progression. The mechanisms that lead to a shift from initial therapeutic sensitivity to ultimate therapeutic resistance are poorly understood. Although the SCLC genomic landscape led to the discovery of promising agents targeting genetic alterations that were already under investigation, results have been disappointing. Achievements in targeted therapeutics have not been observed for over 30 years. Therefore, the underlying disease biology and novel targets urgently require a better understanding. Epigenetic regulation is deeply involved in the cellular plasticity that could shift tumor cells to the malignant phenotype. We have focused on a histone modifier, LSD1, that is overexpressed in SCLC and is a potent therapeutic target. Interestingly, the LSD1 splice variant LSD1+8a, the expression of which has been reported to be restricted to neural tissue, was detected and was involved in the expression of neuroendocrine marker genes in SCLC cell lines. Cells with high expression of LSD1+8a were resistant to CDDP and LSD1 inhibitor. Moreover, suppression of LSD1+8a inhibited cell proliferation, indicating that LSD1+8a could play a critical role in SCLC. These findings suggest that LSD1+8a should be considered a novel therapeutic target in SCLC.

Background: Advanced non-small cell lung cancer (NSCLC) patients often develop thromboembolic events, including cerebral infarction (CI). However, the relationship between advanced NSCLC and CI has not been thoroughly investigated. We examined the association between advanced NSCLC and CI and risk factors for CI in advanced or post-operative recurrent NSCLC patients., Methods: We retrospectively investigated 515 patients diagnosed with advanced or post-operative recurrent NSCLC at Juntendo University Hospital between April 2009 and March 2014., Results: Among the 515 patients evaluated, 15 patients (2.9%) developed CI after diagnosis of advanced or post-operative recurrent NSCLC. Univariate and multivariate analyses were conducted, and brain metastasis was the only significant independent risk factor for CI (odds ratio 5.24, 95% confidence interval 1.72-16.10, p = 0.004). The incidence was 6.3% in these patients. The median survival time was 36 days, and 1-year survival rate was 6.7% after development of CI. Overall survival from diagnosis of advanced NSCLC or post-operative recurrence was significantly shorter in patients with CI than in patients without CI (223 days versus 895 days; HR, 3.46; 95% confidence interval, 2.04-6.02; p = 0.001)., Conclusions: The incidence of CI is high in advanced or post-operative recurrent NSCLC, and is especially higher in patients with brain metastasis than in those without brain metastasis. Moreover, CI may affect patient's prognosis. Careful monitoring for the development of CI in patients with advanced or post-operative recurrent NSCLC is needed, especially for patients with brain metastasis.

Purpose: Docetaxel or pemetrexed monotherapy is recommended either as a second-line treatment for non-small cell lung cancer (NSCLC) patients without EGFR mutation or ALK fusion genes or as a third-line treatment for patients with EGFR mutation or ALK fusion. However, efficacy and survival for these two settings have not been compared, leaving it unclear whether these two populations can be included in the same clinical trials. Moreover, prognostic factors for patients who are recommended to receive docetaxel/pemetrexed monotherapy are largely unknown., Methods: Docetaxel or pemetrexed was administered to 67 EGFR wild-type patients as a second-line treatment following one platinum-based combination chemotherapy and to 17 EGFR mutant patients as a third-line treatment following EGFR tyrosine kinase inhibitors and one platinum-based combination chemotherapy. Docetaxel and pemetrexed were administered at 60 and 500 mg/m(2), respectively, every 3 weeks until disease progression, intolerable toxicity, or patient refusal. Overall survivals (OSs) between the two groups were compared using the log-rank test, and prognostic factors were evaluated via Cox's proportional hazards models., Results: The median OS was 345.5 days in the EGFR wild-type second-line group and 616 days in the EGFR mutant third-line group. Multivariate analyses revealed that the stage before first-line treatment, performance status, and EGFR status were significant prognostic factors., Conclusions: When planning clinical studies of NSCLC patients recommended to receive docetaxel or pemetrexed as single-agent chemotherapy, the EGFR status and stage before first-line treatment should be considered as stratification factors of randomized clinical studies.

Background: Non-small cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) need to be approached carefully given the high incidence of pulmonary toxicity. Pemetrexed (PEM) is the key drug for the treatment of NSCLC. However, its safety, especially with respect to the exacerbation of ILD, and efficacy in NSCLC patients with ILD have yet to be established., Method: We investigated the safety and efficacy of PEM monotherapy in NSCLC patients with or without idiopathic interstitial pneumonia (IIPs). The medical charts of these patients were retrospectively reviewed., Results: Twenty-five patients diagnosed as having IIPs (IIPs group) and 88 patients without ILD (non-ILD group) were treated with PEM monotherapy at Juntendo University Hospital between 2009 and 2013. In the IIPs group, 12 patients were found to have usual interstitial pneumonitis (UIP) on chest computed tomography (CT) (UIP group) and the other 13 patients showed a non-UIP pattern on chest CT (non-UIP IIPs group). Three patients in the IIPs group (2 in the UIP group and 1 in the non-UIP IIPs group) and 1 in the non-ILD group developed pulmonary toxicity during treatment (3.5% overall, 12.0% in the IIPs group versus 1.1% in the non-ILD group). Moreover, all 3 patients in the IIPs group died of pulmonary toxicity. Overall survival tended to be longer in the non-ILD group than in the IIPs group (p = 0.08). Multivariate analyses demonstrated that IIPs was the only significant independent risk factor for PEM-related pulmonary toxicity., Conclusion: We found that the incidence of PEM-related pulmonary toxicity was significantly higher amongst NSCLC patients with IIPs than among those without IIPs. Particular care must be taken when administering PEM to treat NSCLC patients with IIPs.

Two patients with atherosclerotic ischemic cerebrovascular disease presented with transdural anastomoses. A 74-year-old woman had a cerebral infarct, and a 76-year-old man had dementia. Patients with atherosclerotic ischemic cerebrovascular disease may have developed transdural anastomoses, so care must be taken not to damage these functions during revascularization surgery.

The aim of the present study was to determine the binding characteristics of phenytoin (PHT) to serum proteins in the adults. Binding parameters of PHT to serum proteins in our study were compared with in vivo or in vitro binding parameters of PHT to serum proteins reported by other investigators. Serum samples in the study were obtained from 36 adult patients (17 men, 19 women) receiving PHT monotherapy. A total of 43 steady-state concentrations were analyzed in the study. Patients' age ranged from 16 to 73 years (mean [SD], 42.9 [14.7] years). The in vivo population binding parameters of PHT to serum proteins and theoretical minimal unbound serum PHT fraction (fu) were determined using an equation derived from the Scatchard equation. The association constant (K) was 0.014 L x micromol(-1), whereas the total concentration of binding sites (n(Pt)) was 754 micromol x L(-1). The number of binding sites per albumin molecule (n) was 1.16, whereas binding ability (n.K) was 0.016 L x micromol(-1). The fu was 0.087. The n.K is approximately 1.2 times higher in PHT monotherapy patients of Pospísil and Perlík (ie, 0.0191 L x micromol(-1)) than in all our patients. The association constant is approximately 1.3 times higher in the in vitro study of Monks et al (ie, 0.0186 L x micromol(-1)) than in our study, whereas n is similar between the two studies. The fu in our patients is similar to the unbound serum PHT fraction in patients receiving PHT therapy reported by Richens (ie, 0.1). Our results suggest that there may be small differences in the binding affinity of PHT to serum proteins between in vivo and in vitro studies. The unbound serum fraction of PHT in epileptic patients can be assumed to be relatively constant in the therapeutic concentration range of PHT.

The aim of the present study was to determine the gender-related binding characteristics of phenytoin (PHT) to serum proteins in adult patients with epilepsy. Serum samples examined in the study were obtained from 80 adult patients (40 men and 40 women) with epilepsy on PHT monotherapy. Their age ranged from 16 to 64 years (mean [SD], 36.0 [11.7] years). Protein binding of PHT was evaluated by ultrafiltration under current laboratory routine conditions (25 +/- 3 degrees C). The in vivo binding parameters of PHT to serum proteins were determined using a binding equation derived from the Scatchard equation for a one-site binding model. No significant differences were observed in age and serum concentrations of albumin between male and female patients (p > 0.05), but significant differences were observed in serum concentrations of total and unbound PHT between the two groups (p < 0.05). The mean association constant of PHT to serum proteins is the same value of 0.008 L micromol(-1) between male and female patients, whereas total concentration of binding sites seems to be similar between the two groups (1389 micromol L(-1) for men and 1345 micromol L(-1) for women). No significant differences were observed in binding characteristics of PHT to serum proteins between male and female patients (p > 0.05). Our results show that gender does not have a significant effect on the binding characteristics of PHT to serum proteins in adult patients receiving monotherapy under normal pathophysiologic conditions.

The effects of temperature on binding characteristics of phenytoin (PHT) to serum proteins were determined in adult patients with epilepsy. Serum samples examined in the study were obtained from 47 adult patients (29 men, 18 women) with epilepsy on PHT monotherapy. Ages ranged from 18 to 64 years (mean [SD], 36.8 [12.1] years). Protein binding of PHT was evaluated by ultrafiltration under current laboratory routine conditions (25 +/- 3 degrees C) or at a temperature of 37 degrees C. The in vivo binding parameters of PHT to serum proteins were determined using a binding equation derived from the Scatchard equation for a one-site binding model. Significant differences were observed in serum concentrations of unbound PHT between paired data (P <.05). The mean association constants (K) of PHT to serum proteins are 0.009 L micromol(-1) at 25 +/- 3 degrees C and 0.003 L micromol(-1) at 37 degrees C, whereas mean total concentrations of binding sites [n(Pt)] are 1215 micromol L(-1) for 25 +/- 3 degrees C and 2263 micromol L(-1) for 37 degrees C. Significant differences were observed in binding characteristics of PHT to serum proteins between the data determined in different conditions of ultrafiltration (P <.05). Our study confirms that binding affinity for PHT-serum protein interaction is approximately 67% lower at 37 degrees C than at 25 +/- 3 degrees C, and, consequently, binding potential [K.n(Pt)] is approximately 38% lower at 37 degrees C than at 25 +/- 3 degrees C.

Objectives: To determine the binding characteristics of phenytoin to serum proteins in the Japanese population and to compare these with those reported by other investigators., Method: Serum samples examined in the study were obtained from 72 patients (35 males, 37 females) receiving phenytoin monotherapy. The patients' ages ranged from 1 to 73 years (1-15 years, 36 subjects; 16-44 years, 20 subjects; 45-64 years, 13 subjects; > or = 65 years, 3 subjects)., Results: The in vivo population binding parameters of phenytoin to serum proteins and theoretical minimal unbound serum phenytoin fraction (fu) were determined using the Scatchard equation. The association constant (K) was 0.020 1/micromol, while the total concentration of binding sites (n(Pt) was 556 micromol/l. The number of binding sites per albumin molecule (n) was 0.85, while binding ability (n.K) was 0.017 l/micromol. The fu was 0.083. The n.K is approximately 1.1 times higher in patients of Pospísil et al. (26) (i.e. 0.0191 l/micromol) than in all our patients. The association constant is approximately 1.1 times higher in our study than in the in vitro study of Monks et al. (23) (i.e. 0-0186 l/micromol), while n is similar between the two studies. The fu in our patients is similar to the unbound serum phenytoin fraction in adult patients receiving phenytoin therapy reported by Richens (2) (i.e. 0.1)., Conclusion: Our results suggest that there may be small differences in the binding characteristics of phenytoin to serum proteins between Japanese and non-Japanese subjects. The unbound serum fraction of phenytoin in our patients with epilepsy can be assumed to be relatively constant in the therapeutic concentration range of phenytoin.

A 20-year-old male was admitted comatose immediately after a motorcycle accident. Initial computed tomography demonstrated traumatic subarachnoid hemorrhage, and the diagnosis of traumatic internal carotid artery occlusion was established by angiography. Conservative management improved his symptoms, but eventually he died from delayed traumatic apoplexy. Traumatic internal carotid artery occlusion is relatively rare, but is serious and requires early diagnosis and treatment. For patients with severe head trauma and vascular occlusion, anticoagulants are contraindicated, and frequent follow-up angiography is recommended.

A case of teratoma in the pineal region which recurred 4 years after the first tumor removal was reported in this paper. When the patient was 5 years old, she, complained of headache and vomiting, and visited our hospital. As a heterogeneous mass with no enhancement effect was found in the pineal region by CT scan, she was admitted on November 9, 1976. There was no abnormalities on physical examination but neurological examination revealed slight disturbance of conjugate upward gaze (Parinaud's sign). Left vertebral angiogram demonstrated posterior superior displacement of posterior choroidal artery and downward displacement of Rosenthal vein, but early venous filling and tumor stain were not seen. Under preoperative diagnosis of a teratoma in the pineal region, the first operation (left occipital craniotomy and total removal of the tumor) was performed on November 24, 1975. Microscopic examinations revealed that the removed tumor was a mature teratoma in the pineal region. Postoperative course was uneventful and discharged on December 20, 1975. The follow-up study was continued at outside clinic after discharge. There was no signs of recurrence until 3 years after the first operation, but on January, 1981 (4 years after the first operation), she suffered from severe headache and vomiting again and re-admitted to our hospital on February 3, 1981. There was no remarkable neurological deficits except for the mild intracranial hypertensive sign and no changes of findings on angiogram. But CT findings were markedly characteristic. It revealed a heterogenous mass with remarkable enhancement effect in the pineal region and ventricular enlargement. Because a mixed type (teratomatous and germinomatous) of pineal tumors was suspected from the CT findings, irradiation was done after V-P shunt. The tumor was reduced to half size after the first course of 2000 rads irradiation, but there is no more reduction of the size of the tumor following the second course of 2000 rads (total 4000 rads) irradiation. Against the residual tumor, tumor removal was performed on June 2, 1981. Microscopically, the most part of the resected tumor showed fibrous changes caused by irradiation and partially teratomatous compartment. From this result (radiosensitivity and histology) the authors assumed that the recurred tumor could be a mixed type (germinoma and teratoma) of pineal tumor. Postoperative course was uneventful except for a transient disturbance of conjugate upward gaze and she was discharged on June 25, 1981. And now, there is no signs of recurrence 12 months after the second operation. Conclusively, it will be stressed that we should continue follow-up study the case even after total removal of teratoma, especially in the pineal region. Moreover, it was considered that there is a possibility of the changes of the histological features on recurrence of the pineal teratoma. When germinomatous compartment is suspected, irradiation is the first choice and then microsurgical operation should be done against residual tumor.