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Kenta Hasumi,1,2 Yukihiro Yoshida,1 Masaya Yotsukura,1 Kazuo Nakagawa,1 Koichi Goto,2 Shun-ichi Watanabe1 1Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan; 2Department of Comprehensive Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, JapanCorrespondence: Kenta Hasumi; Yukihiro Yoshida, Department of Thoracic Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan, Tel +81-3-3542-2511, Email khasumi@ncc.go.jp; yukiyosh@ncc.go.jpBackground: This study investigated perioperative clinical information, surgical findings, and postoperative courses of patients who underwent reoperation due to bleeding after the surgery for pulmonary malignancies.Methods: We identified patients who underwent reoperation due to postoperative bleeding from 6989 patients who had had operations for pulmonary malignancies between January 2007 and July 2019. Data were retrospectively collected from medical charts.Results: Twenty-two patients (0.3%) underwent reoperation for hemostasis. The reason for reoperation was a shock state with minimum systolic blood pressure < 90 mm Hg in 12 patients (55%), persistent bloody drainage of 100 mL/h or more in 15 patients (68%), and intrathoracic hematoma on a chest X-ray image in 14 patients (64%). All those three findings were observed in five patients (23%), two in nine patients (41%), and one in eight patients (36%). The source of bleeding could not be identified during reoperation in four patients (18%). In the regression analysis, the coefficient of determination between the amount of drainage from a chest drain and the volume of intrathoracic hematoma found during reoperation was 0.31, indicating poor correlation. Postoperative complications and death occurred in two (9%) and zero patients, respectively.Conclusion: Reoperation due to bleeding is required in certain cases. The amount of drainage from a chest drain does not necessarily reflect the volume of intrathoracic hematoma and it is hard to estimate the total amount of bleeding. The decision to perform reoperation for hemostasis should be comprehensively made on the basis of clinical signs and chest X-ray findings.Keywords: bleeding, hemostasis, lung neoplasms, thoracic surgery, intraoperative complications, reoperation

Kazuharu Nakagawa, Kanako Yoshimi, Akira Yoshizawa, Kota Aritaki, Kohei Yamaguchi, Ayako Nakane, Haruka Tohara Department of Dysphagia Rehabilitation, Division of Gerontology and Gerodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, JapanCorrespondence: Kanako Yoshimi, Department of Dysphagia Rehabilitation, Division of Gerontology and Gerodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan, Tel/Fax +81 3-5803-5560, Email k.yoshimi.gerd@tmd.ac.jpPurpose: Oral rehydration solutions (ORSs) are effective in replacing fluids and electrolytes and are widely used. OS-1 Jelly (Otsuka Pharmaceutical Factory, Tokushima, Japan) is a jelly drink corresponding to code 2-1 of the 2021 Japanese Dysphagia Diet. Although jelly drinks are less likely to be aspirated than liquids, their physical properties vary depending on the product. Therefore, the severity of dysphagia may affect intake status. This study aimed to investigate the association between the intake status of ORS jelly and swallowing function.Patients and Methods: Thirty-six patients with dysphagia who required videoendoscopic swallowing evaluation at our university hospital were enrolled. Videoendoscopic swallowing evaluation was performed, and each participant swallowed 5 mL of OS-1 Jelly or thickened water modified to International Dysphagia Diet Standardization Initiative (IDDSI) level 2 three times. Statistical analysis was performed to determine the difference in the number of swallows, time until the swallowing reflex, position for inducing the swallowing reflex, presence of pharyngeal residue, penetration, or aspiration between ORS jelly and thickened water.Results: The time until the swallowing reflex was induced and the position of the swallowing reflex triggered were significantly earlier for ORS jelly (p=0.012, p=0.001). The incidence of pharyngeal residue was significantly lower with ORS jelly (p=0.002). The Penetration-Aspiration Scale score was similar for both samples (p=0.062), and no aspiration was observed in either sample.Conclusion: Patients with dysphagia who can swallow thickened water modified to IDDSI level 2 can consume ORS jelly. ORS jelly, which requires no thickening and can be easily and safely consumed, is effective for water and electrolyte intake in patients with dysphagia.Keywords: oral rehydration solutions, swallowing function, fluid intake, electrolyte supply

Tsukasa Kuwana, Kosaku Kinoshita, Shingo Ihara, Nami Sawada, Toru Hosokawa, Tomokazu Mutoh, Umefumi Iguchi, Katsuhiro Nakagawa, Junko Yamaguchi Division of Emergency and Critical Care Medicine, Department of Acute Medicine, Nihon University School of Medicine, Tokyo, JapanCorrespondence: Kosaku Kinoshita, Division of Emergency and Critical Care Medicine, Department of Acute Medicine, Nihon University School of Medicine, 30-1 Oyaguchi Kamichou Itabashi-ku, Tokyo, Japan, Tel +81-3-3972-8111, Fax +81-3-5995-1069, Email kinoshita.kosaku@nihon-u.ac.jpPurpose: The characteristics of patients with severe COVID-19 pneumonia who underwent direct hemoperfusion using polymyxin B-immobilized fiber column (PMX-DHP), in addition to steroids and immunomodulators, remain unclear.Patients and Methods: We conducted a retrospective observational study on 31 patients with severe COVID-19 pneumonia treated with PMX-DHP in an intensive care unit (ICU) from December 2020 to September 2021.Results: Outcomes 28 days after admission to the ICU were 20 in the survival group and 11 in the death group. Parameters significantly different between the survival and death group before PMX-DHP were percentage of invasive mechanical ventilation (25% vs 72.7%, P = 0.0209), PaO2/FIO2 (P/F) ratio (104.5 vs 75, P = 0.0317), and sequential organ failure assessment (SOFA) score (2 vs 3, P = 0.0356). Invasive mechanical ventilation avoidance rate was significantly different between the survival (100%) and death group (0%) (P = 0.0012). P/F ratio, respiratory ratio (RR), and lymphocyte counts improved significantly after PMX-DHP for all patients. The lymphocyte counts changed significantly in the survival (P < 0.0001), but not the death group (P = 0.7927).Conclusion: PMX-DHP, in addition to steroids and immunomodulators, may improve oxygenation and alleviate tachypnea by modulating the lymphocyte numbers and levels of various mediator against severe COVID-19 pneumonia. It may be better to perform PMX-DHP before multi organ dysfunction and lung injury has progressed. Furthermore, the early increase in lymphocyte counts after PMX-DHP might be an indicate a positive outcome.Keywords: IL-6, lymphocyte, P/F ratio, respiratory rate, SOFA

Motoko Tachihara,1 Kayoko Tsujino,2 Takeaki Ishihara,3 Hidetoshi Hayashi,4 Yuki Sato,5 Takayasu Kurata,6 Shunichi Sugawara,7 Isamu Okamoto,8 Shunsuke Teraoka,9 Koichi Azuma,10 Haruko Daga,11 Masafumi Yamaguchi,12 Takeshi Kodaira,13 Miyako Satouchi,14 Mototsugu Shimokawa,15 Nobuyuki Yamamoto,9 Kazuhiko Nakagawa4 On behalf of members of the West Japan Oncology Group (WJOG)1Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe City, Japan; 2Department of Radiation Oncology, Hyogo Cancer Center, Akashi City, Japan; 3Division of Radiation Oncology, Kobe University Graduate School of Medicine, Kobe City, Japan; 4Department of Medical Oncology, Kindai University, Osakasayama City, Japan; 5Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe City, Japan; 6Department of Thoracic Oncology, Kansai Medical University Hospital, Hirakata City, Japan; 7Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai City, Japan; 8Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka City, Japan; 9Internal Medicine III, Wakayama Medical University, Wakayama, Japan; 10Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Fukuoka City, Japan; 11Department of Medical Oncology, Osaka City General Hospital, Osaka, Japan; 12Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka City, Japan; 13Departments of Radiation Oncology, Aichi Cancer Center Hospital, Nagoya City, Aichi, Japan; 14Department of Thoracic Oncology, Hyogo Cancer Center, Akashi City, Japan; 15Department of Biostatistics, Yamaguchi University Graduate School of Medicine Yamaguchi, Ube City, JapanCorrespondence: Motoko TachiharaDivision of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe City, 650-0017, JapanTel +81-78-382-5660Fax +81-78-382-5661Email mt0318@med.kobe-u.ac.jpAbstract: Durvalumab (anti-programmed cell death ligand-1) administration after concurrent chemoradiotherapy (cCRT) has improved the survival of patients with unresectable, locally advanced (LA) stage III non-small cell lung cancer (NSCLC). Some patients are unable to complete cCRT and cannot receive immunotherapy due to poor performance status based on adverse events after cCRT. Immunotherapy plays an important role in anti-programmed cell death ligand-1 (PD-L1)-positive advanced NSCLC and is replacing chemotherapy. In addition, radiotherapy and immunotherapy have been reported to have a synergistic effect. This Phase II, multicenter study (DOLPHIN, WJOG11619L, JapicCTI-194840) is designed to assess the efficacy and safety of durvalumab plus concurrent curative radiation therapy for PD-L1-positive unresectable LA-NSCLC without chemotherapy. Unresectable LA stage III NSCLC patients aged 20 years or older with a World Health Organization/Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and PD-L1 positivity are enrolled. The patients will receive curative radiation therapy (60 Gy) plus durvalumab 10 mg/kg every 2 weeks (q2w) for up to 12 months until there is evidence of disease progression (PD) or unacceptable toxicity. The primary endpoint is the 12-month progression-free survival rate as assessed by an independent central review. The secondary endpoints are progression-free survival, overall survival, objective response rate, treatment completion rate, and safety. Recruitment began in September 2019.Keywords: clinical study, locally advanced non-small cell lung cancer, immunotherapy, programmed cell death ligand-1, durvalumab, radiation

Taiki Miyazawa,1 Mayuko Itaya,2 Gregor C Burdeos,3 Kiyotaka Nakagawa,2 Teruo Miyazawa1 1New Industry Creation Hatchery Center (NICHe), Tohoku University, Sendai, Miyagi, Japan; 2Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, Miyagi, Japan; 3Institute for Animal Nutrition and Physiology, Christian Albrechts University Kiel, Kiel, GermanyCorrespondence: Taiki MiyazawaNew Industry Creation Hatchery Center (NICHe), Tohoku University, 6-6-10 Aramaki Aza Aoba, Aoba-Ku, Sendai, Miyagi, 980-8579, JapanTel/Fax +81 22 795 3205Email taiki.miyazawa0110@gmail.comAbstract: Surfactants, whose existence has been recognized as early as 2800 BC, have had a long history with the development of human civilization. With the rapid development of nanotechnology in the latter half of the 20th century, breakthroughs in nanomedicine and food nanotechnology using nanoparticles have been remarkable, and new applications have been developed. The technology of surfactant-coated nanoparticles, which provides new functions to nanoparticles for use in the fields of nanomedicine and food nanotechnology, is attracting a lot of attention in the fields of basic research and industry. This review systematically describes these “surfactant-coated nanoparticles” through various sections in order: 1) surfactants, 2) surfactant-coated nanoparticles, application of surfactant-coated nanoparticles to 3) nanomedicine, and 4) food nanotechnology. Furthermore, current progress and problems of the technology using surfactant-coated nanoparticles through recent research reports have been discussed.Keywords: drug delivery system, drug targeting, food science, food packaging, nonionic surfactants, safety assessment

Yoshiko Hara,1 Ayako Nakane,2 Haruka Tohara,2 Kazumasa Kubota,1 Kazuharu Nakagawa,2 Koji Hara,2 Kohei Yamaguchi,2 Kanako Yoshimi,2 Shunsuke Minakuchi1 1Department of Gerodontology and Oral Rehabilitation, Division of Gerontology and Gerodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; 2Department of Dysphagia Rehabilitation, Division of Gerontology and Gerodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, JapanCorrespondence: Ayako NakaneDepartment of Dysphagia Rehabilitation, Division of Gerontology and Gerodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, JapanTel/Fax +81-3-5803-5562Email fujigerd@tmd.ac.jpPurpose: We aimed to determine the efficacy of interferential current transcutaneous electrical sensory stimulation (IFC-TESS) in patients with dementia who were being treated for dysphagia in nursing homes under normal living conditions.Patients and Methods: This study recruited 54 nursing home residents (13 males, 41 females; mean age, 84.5 ± 10.7 years) with dysphagia and dementia. IFC-TESS was performed with Gentle Stim® (Careido Co. Ltd., Kanagawa, Japan) for 15 minutes. Two sessions per day were administered 5 days per week, for 3 weeks. The outcomes included the improvement of the patients’ cough reflexes and nutritional states across the 3 weeks of intervention; the former was evaluated with the cough test based on the changes in cough latency time and cough frequency, while the latter was assessed based on changes in the functional oral intake scale (FOIS) score and oral calorie intake.Results: The cough latency times before and after the 3-week intervention were 15.8 (7.0– 60.0) and 6.7 (3.6– 30.7) s/min, respectively; the cough frequencies were 5.0 (0.0– 5.0) and 5.0 (5.0– 5.0) t/min, respectively; the FOIS scores were 5.0 (5.0– 6.0) and 5.0 (5.0– 6.0), respectively; and oral calorie intakes were 1300.0 (862.5– 1420.0) and 1300.0 (1005.0– 1462.5) kcal/day, respectively. All parameters significantly improved across the intervention (p < 0.05). When the results were adjusted for age, sex, body mass index, mini nutritional assessment results, Barthel index, and mini-mental state examination scores, IFC-TESS improved the cough reflex and oral calorie intake in older nursing home residents with dementia.Conclusion: Cervical IFC-TESS can improve the cough reflexes and nutritional states of patients with dysphagia and dementia in nursing homes. As it has previously been difficult to perform active rehabilitation with dementia patients, IFC-TESS may be effective and practicable for the rehabilitation of this patient population.Keywords: cough frequency, cough latency time, FOIS, IFC-TESS, oral calorie intake

Dai Sonoda,1,2 Yosuke Matsuura,1 Junji Ichinose,1 Masayuki Nakao,1 Hironori Ninomiya,3 Mingyon Mun,1 Yuichi Ishikawa,3 Ken Nakagawa,1 Yukitoshi Satoh,2 Sakae Okumura11Department of Thoracic Surgical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan; 2Department of Thoracic Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan; 3Department of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, JapanPurpose: Most postoperative recurrences of non-small cell lung cancer (NSCLC) develop within 5 years after curative resection, with ultra-late recurrences developing over 10 years after the resection being rare. This study aimed to analyze the features of ultra-late recurrence in cases with NSCLC who had undergone curative resection.Patients and methods: Among 1458 consecutive cases with NSCLC who underwent curative resection with systematic lymph node dissection during 1990–2006, 12 cases developed recurrence over 10 years after the resection. We defined the recurrence developing over 10 years after the resection as ultra-late recurrence and analyzed the factors related to it.Results: Among the 1458 cases, recurrence developed in 476 (32.6%) cases. Of them, ultra-late recurrence developed in 12 (2.5%) cases. The ultra-late recurrence was histopathologically classified as adenocarcinoma in 11 cases and atypical carcinoid in 1 case. All cases were of invasive carcinoma. We compared ultra-late recurrence cases with non-recurrence cases and showed that none of the examined factors significantly influenced ultra-late recurrence; however, lymphatic invasion was close to significantly influencing it. There were two cases in which recurrence developed over 15 years after the resection; both cases were of adenocarcinoma with anaplastic lymphoma kinase (ALK) rearrangement.Conclusion: There is a possibility of ultra-late recurrence developing over 10 years after the resection of any invasive NSCLC. Lymphatic invasion is close to significantly influencing ultra-late recurrence. Furthermore, a long follow-up period may be required in cases with adenocarcinoma with ALK rearrangement because it has the possibility of recurrence over 15 years after the resection.Keywords: lung cancer, recurrence, resection, ALK rearrangement

Chizuru Namiki,1 Koji Hara,1 Haruka Tohara,1 Kenichiro Kobayashi,2 Ariya Chantaramanee,1 Kazuharu Nakagawa,1 Takayuki Saitou,2 Kohei Yamaguchi,1 Kanako Yoshimi,1 Ayako Nakane,1 Shunsuke Minakuchi1 1Department of Gerodontology, Division of Gerontology and Gerodontology, Tokyo Medical and Dental University, Tokyo, Japan; 2Kobayashi Dental Clinic, Tokyo, Japan Purpose: Producing tongue pressure (TP) by pushing the tongue against the palate consists of lifting the tongue muscles and elevating the floor of the mouth via suprahyoid muscle contraction. Though studies have shown that tongue-pressure resistance training (TPRT) increases tongue function, none have focused on suprahyoid muscle function enhancements. Our study aimed to verify whether TPRT improves both tongue function and hyoid movement during swallowing.Materials and methods: Eighteen patients (mean age: 76.8±6.2 years) with presbyphagia presenting with symptoms such as coughing and choking were enrolled. All patients performed daily living activities independently. None of the participants had diseases causing dysphagia or previous oral or pharyngeal surgery. Participants were instructed to push their tongues against the palate as hard as possible with their mouths closed for 10 seconds, and then resting for 10 seconds. A set consisted of five consecutive exercise and resting periods; two sets per day were performed for a month. TP and the oral diadochokinetic rate (ODKR), measured by repetitions of the syllables /ta/ and /ka/, assessed tongue function. The extent of anterior and superior hyoid movement and parameters related to swallowing, including the penetration aspiration scale (PAS) and the normalized residue ratio scale (NRRS) in the valleculae (NRRSv) and piriform sinus (NRRSp), were evaluated based on videofluoroscopic data.Results: The anterior (P=0.031) and superior hyoid movement (P=0.012), TP (P=0.002), ODKR/ta/ (P=0.034), ODKR/ka/ (P=0.009), and the width of the upper esophageal sphincter (P=0.001) were larger at follow-up than at baseline. NRRSp (P=0.022), PAS (P=0.016), and pharyngeal transit times (P=0.004) were smaller at follow-up than at baseline.Conclusion: TPRT improved tongue strength, dexterity, both anterior and superior hyoid elevation, and swallowing functions. Therefore, TPRT could improve tongue function and suprahyoid muscle function simultaneously and contribute to prevention of sarcopenic dysphagia. Keywords: sarcopenic dysphagia, swallowing muscle, tongue function, suprahyoid muscle

Kazuo Nakagawa,1 Shoji Takahashi,2 Masahiro Endo,3 Yasuhisa Ohde,2 Hiroaki Kurihara,4 Takashi Terauchi5 1Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo, 2Division of Thoracic Surgery, 3Division of Diagnostic Radiology, Shizuoka Cancer Center, Shizuoka, 4Department of Diagnostic Radiology, National Cancer Center Hospital, 5Department of Nuclear Medicine, Cancer Institute Hospital, Tokyo, Japan Objective: Although 18-fluorine fluorodeoxyglucose positron emission tomography (18F-FDG PET) is thought to be useful for predicting the histological grade of thymic epithelial tumors (TETs), it remains controversial. To date, just a few of many previous studies have included only resected cases. Therefore, we investigated 18F-FDG PET findings only in patients with resected TETs. Patients and methods: A total of 112 patients with TETs consisting of 92 thymomas and 20 thymic carcinomas (TCs), resected at two institutes (Shizuoka Cancer Center [Shizuoka] and National Cancer Center Hospital [Tokyo]) between October 2002 and December 2015, were evaluated. Spearman rank correlation coefficient was used to assess the association between the maximum standardized uptake value (SUVmax) in the tumor and both the histological subtype and tumor stage. The cutoff value of SUVmax for differentiating thymoma from TC was calculated. Results: The SUVmax was strongly related to both the World Health Organization (WHO) histological subtype and tumor stage based on the eighth edition of the tumor-node-metastasis (TNM) classification (Spearman rank correlation coefficient =0.485 and 0.432; p = 0.000 and 0.000, respectively). There was a significant difference between thymoma and TC. The optimal SUVmax cutoff value for differentiating thymoma from TC was 4.58 (sensitivity: 80% and specificity: 78.3%). In contrast, there was no significant difference between low-risk (type A, AB, and B1) and high-risk (type B2 and B3) thymoma, or between type B3 thymoma and the other subtypes. Conclusion: Our results suggest that 18F-FDG PET is useful for differentiating thymoma from TC, but not for predicting the histologic grade of thymoma. Keywords: 18F-FDG PET, thymic epithelial tumors, thymoma, thymic carcinoma, WHO histological subtype, TNM classification

Takahiro Harigae,1 Kiyotaka Nakagawa,1 Taiki Miyazawa,2 Nao Inoue,3 Fumiko Kimura,1 Ikuo Ikeda,3 Teruo Miyazawa4,5 1Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan; 2Vascular Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA; 3Laboratory of Food and Biomolecular Science, Graduate School of Agricultural Science, 4Food and Biotechnology Innovation Project, New Industry Creation Hatchery Center, 5Food and Health Science Research Unit, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan Purpose: Curcumin (CUR), the main polyphenol in turmeric, is poorly absorbed and rapidly metabolized following oral administration, which severely curtails its bioavailability. Poly-(lactic-co-glycolic acid)-based CUR nanoparticles (CUR-NP) have recently been suggested to improve CUR bioavailability, but this has not been fully verified. Specifically, no data are available about curcumin glucuronide (CURG), the major metabolite of CUR found in the plasma following oral administration of CUR-NP. Herein, we investigated the absorption and metabolism of CUR-NP and evaluated whether CUR-NP improves CUR bioavailability.Methods: Following oral administration of CUR-NP in rats, we analyzed the plasma and organ distribution of CUR and its metabolites using high-performance liquid chromatography-tandem mass spectrometry. To elucidate the mechanism of increased intestinal absorption of CUR-NP, we prepared mixed micelles comprised of phosphatidylcholine and bile salts and examined the micellar solubility of CUR-NP. Additionally, we investigated the cellular incorporation of the resultant micelles into differentiated Caco-2 human intestinal cells.Results: Following in vivo administration of CUR-NP, CUR was effectively absorbed and present mainly as CURG in the plasma which contained significant amounts of the metabolite compared with other organs. Thus, CUR-NP increased intestinal absorption of CUR rather than decreasing metabolic degradation and conversion to other metabolites. In vitro, CUR encapsulated in CUR-NP was solubilized in mixed micelles; however, whether the micelles contained CUR or CUR-NP had little influence on cellular uptake efficiency. Therefore, we suggest that the high solubilization capacity of CUR-NP in mixed micelles, rather than cellular uptake efficiency, explains the high intestinal absorption of CUR-NP in vivo.Conclusion: These findings provide a better understanding of the bioavailability of CUR and CUR-NP following oral administration. To improve the bioavailability of CUR, future studies should focus on enhancing the resistance to metabolic degradation and conversion of CUR to other metabolites, which may lead to novel discoveries regarding food function and disease prevention. Keywords: absorption, metabolism, bioavailability, mixed micelles, Caco-2, HPLC-MS/MS

Taiki Miyazawa,1,2 Kiyotaka Nakagawa,1,2 Takahiro Harigae,2 Ryo Onuma,2 Fumiko Kimura,2 Tomoyuki Fujii,3 Teruo Miyazawa4,5 1Vascular Biology Laboratory, Jean Mayer USDA (United States Department of Agriculture)-Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA; 2Food and Biodynamic Chemistry Laboratory, 3Terahertz Optical & Food Engineering Laboratory, Graduate School of Agricultural Science, 4Food and Biotechnology Innovation Project, New Industry Creation Hatchery Center (NICHe), 5Food and Health Science Research Unit, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan Purpose: Biodegradable nanoparticles (NPs) composed of poly(D, L-lactide-co-glycolide) (PLGA) have attracted considerable attention as delivery systems of drugs and antioxidative compounds, such as β-carotene (BC). Intravenous (IV) administration of BC-containing PLGA-NPs (BC-PLGA-NPs) coated with polysorbate 80 (PS80) has been shown to effectively deliver BC to the brain. However, the whole-body distribution profile of BC is still not clear. Therefore, we investigated the accumulation of BC in various organs, including the brain, following IV administration of PS80-coated BC-PLGA-NPs in rats.Methods: PS80-coated and uncoated BC-PLGA-NPs were prepared by solvent evaporation, and administered intravenously to Sprague Dawley rats at a BC dose of 8.5 mg/rat. Accumulation of BC in various organs (brain, heart, liver, lungs, and spleen) and blood plasma was evaluated by high performance liquid chromatography with ultraviolet (UV) detection, 1 hour after administration.Results: We prepared PS80-coated BC-PLGA-NPs with an entrapment efficiency of 14%, a particle size of 260 nm, and a zeta potential of -26 mV. Coating with PS80 was found to result in significant accumulation of BC in the lungs, rather than in the brain and other tissues. Further, plasma levels of BC in the PS80-coated BC-PLGA-NP group were much lower than those of the uncoated BC-PLGA-NP group.Conclusion: Following IV administration, PS80-coated BC-PLGA-NPs are quickly transferred from plasma circulation to the lungs, rather than the brain. Significant accumulation of BC in the lungs may be useful for health-related applications. Keywords: β-carotene, intravenous administration, nanoparticles, poly(D, L-lactide-co-glycolide) (PLGA), polysorbate 80 (PS80), tissue distribution

Masayuki Takeda,1 Isamu Okamoto,2 Kazuhiko Nakagawa1 1Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka, 2Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Abstract: Angiogenesis is an essential process in the development, growth, and metastasis of malignant tumors including lung cancer. Several angiogenesis inhibitors have been developed as potential therapies for non-small-cell lung cancer (NSCLC). Nintedanib is a small-molecule tyrosine kinase inhibitor that targets receptors for vascular endothelial growth factor, platelet-derived growth factor, and fibroblast growth factor as well as RET (rearranged during transfection) and Flt3. When administered as monotherapy, nintedanib was well tolerated at doses up to 250 mg or 200 mg twice daily in European and Japanese patients, respectively, with liver toxicity featuring prominently among dose-limiting toxicities in both populations. A recent Phase III trial demonstrated that treatment with the combination of nintedanib and docetaxel resulted in a significant and clinically meaningful improvement in both progression-free survival and overall survival compared with docetaxel alone in predefined NSCLC patients with adenocarcinoma tumor histology. Although the incidence of elevated alanine aminotransferase or aspartate aminotransferase as well as of diarrhea was higher in patients treated with nintedanib plus docetaxel, most of these adverse events were manageable with supportive treatment or dose reduction. The results of completed and ongoing clinical trials of nintedanib monotherapy and combination therapy for the treatment of NSCLC are summarized in this study. Keywords: nintedanib, non-small-cell lung cancer, dose-limiting toxicity, hepatotoxicity

Yukiko Tanamachi,1 Junji Saruwatari,1 Madoka Noai,1 Ryoko Kamihashi,1 Hiromi Soraoka,1 Yuki Yoshimori,1 Naoki Ogusu,1 Kentaro Oniki,1 Norio Yasui-Furukori,2 Takateru Ishitsu,3,4 Kazuko Nakagawa1,5 1Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; 2Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Japan; 3Kumamoto Saishunso National Hospital, Koshi, Japan; 4Kumamoto Ezuko Ryoiku Iryo Center, Kumamoto, Japan; 5Center for Clinical Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan Background: Although patients with moderate intellectual disability (ID) are known to have higher rates of being overweight and obese than those without ID, there are no current data regarding the relationship between ID and weight gain in epilepsy patients treated with valproic acid (VPA). Patients and methods: The possible association between moderate ID and an overweight status at the time of initiation of VPA therapy (baseline) was investigated using a logistic regression analysis in 143 patients with epilepsy. Among the 119 nonoverweight patients at baseline, the longitudinal association between moderate ID and the weight status during VPA therapy was retrospectively examined using a Cox hazards regression analysis and the generalized estimating equations approach, while also paying careful attention to associations with other patient characteristics. Results: The proportion of patients with moderate ID was 52.4% among the 143 study subjects. The presence of moderate ID was not associated with an overweight status at baseline (P=0.762). Among the nonoverweight patients at baseline, 16 subjects were newly diagnosed as being overweight during treatment with VPA (3.6±2.1 years). The presence of moderate ID was significantly associated with the incidence of an overweight status after starting VPA therapy (adjusted hazard ratio =6.72, P=0.007). The patient age at baseline and treatment with co-administered carbamazepine, clobazam, and zonisamide significantly influenced the degree of weight fluctuation during VPA therapy among the patients with moderate ID (P

Kento Nakagawa, Takashi Obu, Kazuyuki KanosueFaculty of Sport Sciences, Waseda University, Tokorozawa, Saitama, Japan Purpose: To investigate the potential benefit of post-race wearing of unstable shoes (Masai Barefoot Technology [MBT]) on recovery from marathon race–induced fatigue.Patients and methods: Forty-five runners who participated in a full marathon race were divided into three groups: 1) MBT shoes, 2) trail running shoes, and 3) control (CON). Participants ran a full marathon with their own running shoes, and then put on the assigned shoes immediately after the race. They continued to wear the assigned shoes for the ensuing 3 days. The CON group wore their usual shoes. Estimates of post-race fatigue were made by the participants on questionnaires that utilized a visual analog scale. Estimates were made just after the race, as well as for the next 3 days.Results: The subjective fatigue of the MBT group was lower than that of the CON (P

Yosuke Togashi,1 Hidetoshi Hayashi,1–3 Kazuhiko Nakagawa,2 Kazuto Nishio1 1Department of Genome Biology, 2Department of Medical Oncology, Kindai University Faculty of Medicine, 3Department of Medical Oncology, Kishiwada Municipal Hospital, Osaka, Japan Abstract: Gefitinib, an epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI), has been approved in Japan for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) based on Phase II clinical trials since 2002. Erlotinib, another EGFR-TKI, was also approved a few years thereafter. In 2004, activating mutations in the EGFR gene were discovered to be a predictive biomarker for EGFR-TKI treatment, and gefitinib, which is not effective for patients with EGFR wild-type NSCLC, has since been used only in patients with EGFR-mutated NSCLC. In contrast, erlotinib is potentially effective for the treatment of EGFR wild-type NSCLC. Similar to gefitinib, erlotinib is also effective for EGFR-mutated NSCLC and has been used as an initial treatment for patients with advanced EGFR-mutated NSCLC. Both gefitinib and erlotinib can be used in a Japanese clinical setting. The approved daily dose of erlotinib (150 mg) is equal to the maximum tolerated dose of erlotinib. In contrast, the daily dose of gefitinib has been set at 250 mg, which is approximately one-third of the maximum tolerated dose of gefitinib. Accordingly, a higher serum concentration can be achieved using erlotinib, compared with gefitinib. This advantage can be applied to the treatment of central nervous system metastases (brain metastasis and carcinomatous meningitis), the treatment of which is complicated by the difficulty drugs have penetrating the blood–brain barrier. Although patients with EGFR-mutated NSCLC respond dramatically to EGFR-TKIs, some patients have a poor response and the majority eventually undergo disease progression. To overcome such resistance, several novel treatment strategies, such as combination therapy and next-generation EGFR-TKIs, have been attempted. Keywords: non-small-cell lung cancer, epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib, EGFR mutation

Junji Saruwatari,1,* Norio Yasui-Furukori,2,* Ryoko Kamihashi,1 Yuki Yoshimori,1 Kentaro Oniki,1 Shoko Tsuchimine,2 Madoka Noai,1 Yasushi Sato,3 Taku Nakagami,4 Norio Sugawara,2 Manabu Saito,2 Akira Fujii,2 Ayami Kajiwara,1 Shuichi Mihara,5 Yasuhiro Ogata,6 Sunao Kaneko,2 Kazuko Nakagawa1,71Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, 2Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, 3Department of Psychiatry, Hirosaki Aiseikai Hospital, Hirosaki, 4Department of Psychiatry, Odate Municipal General Hospital, Odate, 5Mihara Life Care Clinic, Kumamoto, 6Japanese Red Cross Kumamoto Health Care Center, Kumamoto, 7Center for Clinical Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan*These authors contributed equally to this paperBackground: This study investigated the possible association between common and potentially functional polymorphisms of antioxidant enzymes and metabolic abnormalities in patients with schizophrenia.Methods: The possible associations of the glutathione S-transferase (GST) M1 null and GSTT1 null genotypes, and the superoxide dismutase 2 (SOD2) Val16Ala polymorphism with the risks of being overweight and having metabolic syndrome were examined using a logistic regression analysis in 154 schizophrenic Japanese patients and 203 controls.Results: Among smokers with schizophrenia, the risks of being overweight and having decreased high-density lipoprotein cholesterol were significantly higher in those with the GSTM1 null genotype than in those with the present genotype (odds ratio 3.20 and 3.15, P=0.03 and P=0.04, respectively), while among nonsmokers with schizophrenia, the risk of an abnormal waist circumference was lower in those with the GSTM1 null genotype (odds ratio 0.34, P=0.04). The risk of a decreased high-density lipoprotein cholesterol level was significantly higher in patients with the combined GSTM1 null and GSTT1 present genotypes than in those with the present genotypes of both genes (odds ratio 3.60, P

Masahiro Yamada*, Takeshi Ueno*, Naoki Tsukimura, Takayuki Ikeda, Kaori Nakagawa, Norio Hori, Takeo Suzuki, Takahiro OgawaLaboratory of Bone and Implant Sciences, The Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, Biomaterials and Hospital Dentistry, UCLA School of Dentistry, Los Angeles, CA, USA *These authors contributed equally to this workAbstract: The mechanism by which hydroxyapatite (HA)-coated titanium promotes bone–implant integration is largely unknown. Furthermore, refining the fabrication of nanostructured HA to the level applicable to the mass production process for titanium implants is challenging. This study reports successful creation of nanopolymorphic crystalline HA on microroughened titanium surfaces using a combination of flame spray and low-temperature calcination and tests its biological capability to enhance bone–implant integration. Sandblasted microroughened titanium implants and sandblasted + HA-coated titanium implants were subjected to biomechanical and histomorphometric analyses in a rat model. The HA was 55% crystallized and consisted of nanoscale needle-like architectures developed in various diameters, lengths, and orientations, which resulted in a 70% increase in surface area compared to noncoated microroughened surfaces. The HA was free from impurity contaminants, with a calcium/phosphorus ratio of 1.66 being equivalent to that of stoichiometric HA. As compared to microroughened implants, HA-coated implants increased the strength of bone–implant integration consistently at both early and late stages of healing. HA-coated implants showed an increased percentage of bone–implant contact and bone volume within 50 µm proximity of the implant surface, as well as a remarkably reduced percentage of soft tissue intervention between bone and the implant surface. In contrast, bone volume outside the 50 µm border was lower around HA-coated implants. Thus, this study demonstrated that the addition of pure nanopolymorphic crystalline HA to microroughened titanium not only accelerates but also enhances the level of bone–implant integration and identified the specific tissue morphogenesis parameters modulated by HA coating. In particular, the nanocrystalline HA was proven to be drastic in increasing osteoconductivity and inhibiting soft tissue infiltration, but the effect was limited to the immediate microenvironment surrounding the implant.Keywords: osseointegration, dental and orthopedic implant, nanotechnology, bone–implant integration, HA, calcium phosphate

Masayuki Takeda1, Isamu Okamoto1, Yasumasa Nishimura2, Kazuhiko Nakagawa11Department of Medical Oncology, 2Department of Radiation Oncology, Kinki University Faculty of Medicine, Osaka, JapanAbstract: The epidermal growth factor receptor (EGFR) is a promising therapeutic target in non-small cell lung cancer, and several therapeutic agents that target this receptor, including EGFR tyrosine kinase inhibitors and monoclonal antibodies to EGFR, have been developed. Such monoclonal antibodies have shown efficacy in combination with chemotherapy and radiotherapy. Nimotuzumab (h-R3) is a humanized monoclonal antibody to EGFR, and its effects in combination with radiation have been sufficiently promising to warrant further investigation in several types of cancer. Furthermore, the typical severe dermatologic toxicities associated with other monoclonal antibodies to EGFR have not been observed with nimotuzumab. We here summarize the results of preclinical studies as well as of previous and ongoing clinical trials of nimotuzumab for the treatment of non-small cell lung cancer.Keywords: non-small cell lung cancer, epidermal growth factor receptor, antibody