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Kaori Hisanaga,1 Hiroshi Uchino,1 Naoko Kakisu,1 Masahiko Miyagi,1 Fukumi Yoshikawa,1 Genki Sato,1 Kazutoshi Isobe,2 Kazuma Kishi,2 Sakae Homma,3 Takahisa Hirose1 1Division of Diabetes, Metabolism and Endocrinology, Department of Medicine, Toho University Graduate School of Medicine, Tokyo, Japan; 2Department of Respiratory Medicine, Toho University Graduate School of Medicine, Tokyo, Japan; 3Department of Advanced and Integrated Interstitial Lung Disease Research, School of Medicine, Toho University, Tokyo, JapanCorrespondence: Hiroshi UchinoDivision of Diabetes, Metabolism and Endocrinology, Department of Medicine, Toho University Graduate School of Medicine, 6-11-1 Omori-Nishi, Ota-Ku, Tokyo, 143-8541, JapanTel +81-3-3762-4151Fax +81-3-3765-6488Email h.uchino@med.toho-u.ac.jpBackground: Although immune checkpoint inhibitors (ICIs) are promising in the treatment of advanced cancer, their use is associated with immune-related adverse events (irAEs) that affect endocrine organ systems. Although development of irAEs was associated with improved cancer-specific survival, the risk of irAEs is unclear. We investigated the association of pre-ICI comorbidities—including diabetes—with irAEs, overall survival (OS), and progression-free survival (PFS) in advanced lung cancer.Methods: Patients with lung cancer who were treated with ICIs during the period from September 1, 2015 through July 31, 2018 were retrospectively enrolled. All data were collected from the NEPTUNE database of university patients. Hazard ratios were estimated by using Cox regression weighted for propensity scores. Odds ratios were calculated by logistic regression and adjusted for unbalanced variables. The Kaplan–Meier method was used to compare OS, and the generalized Wilcoxon test was used to compare median survival.Results: Among the 88 patients identified, 22 (25.0%) had diabetes (DM) before ICI treatment and 57 (75.0%) did not (non-DM); irAEs developed in 12.2% of patients with DM and in 9.1% of patients in non-DM (p=0.87). Diabetes status was not associated with irAE risk in relation to baseline characteristics (age, sex, TNM staging, thyroid and renal function) or in propensity score–matched analysis (age, TNM staging). During a mean follow-up of 30 months, OS and cancer-specific PFS were significantly higher in patients who developed irAEs (Kaplan–Meier estimates, p=0· 04 and 0· 03, respectively). In propensity score–matched analysis, diabetes was significantly associated with lower OS (multivariate hazard ratio, 0· 36; 95% CI, 0· 13– 0· 98) unrelated to irAEs. Irrespective of irAEs, PFS was also lower among patients with DM than among non-DM patients (Kaplan–Meier estimate, p=0· 04).Conclusion: Pre-existing diabetes was associated with higher mortality in advanced lung cancer, regardless of irAE development during treatment with ICI.Keywords: immune checkpoint inhibitor, diabetes, overall survival, progression-free survival

OBJECTIVE: Wound repair dysfunction is becoming a major public health issue worldwide. Yes-associated protein (YAP) has previously been reported to be closely related to wound healing, while how YAP accelerates wound healing via regulating autophagy needs to be further probed. MATERIALS AND METHODS: ICR male mice were involved in two independent animal experiments; the mice were randomly allocated into control, autophagy inhibitor (3-MA) (injection), and 3-MA (drip) group or control, si-NC, si-YAP group (8 mice for each). Full-thickness excisional wounds (8 mm) in mice were created by punch to construct an in vivo wound model to observe the effects of autophagy inhibitor (3-MA) (by injection and drip) and si-YAP by electrotransfection. RESULTS: Firstly, we found that the autophagy inhibitor (3-MA) accelerated wound closure in vivo. Loss-of-function experiments subsequently revealed that YAP knockdown led to increased proliferation and migration of fibroblasts as well as reduced autophagy, resulting in accelerated wound healing. In addition, our results revealed that YAP could positively regulate Engrailed-1 (En1) expression in fibroblasts. En1 knockdown also promoted the proliferation and migration of fibroblasts, meanwhile resulting in increased mammalian target of rapamycin (mTOR) levels and reduced autophagy in fibroblasts. CONCLUSIONS: YAP knockdown repressed autophagy in fibroblasts to accelerate wound closure by regulating the En1/mTOR axis. [ABSTRACT FROM AUTHOR]

Kenji Kishi, Kazutoshi Kubo, Tetsu Tomita, Kazuhiko Nakamura, Norio Yasui-Furukori Department of Neuropsychiatry, Hirosaki University Graduate School of Medicine, Hirosaki, Japan Abstract: Some patients with insulinoma present with neuropsychiatric symptoms and are often misdiagnosed with psychiatric disease. We present the case of a 72-year-old Japanese female who exhibited violent behavior while asleep and received a diagnosis of suspected rapid eye movement sleep behavior disorder (RBD). She was admitted to the psychiatry ward after receiving levomepromazine 25 mg intramuscularly. The patient’s blood glucose level was 27 mg/dL at the time of hospitalization, and a biochemical examination revealed that her insulin level was 9.1 µU/mL and C-peptide level was 2.16 ng/mL. A contrast-enhanced computed tomography revealed a mass 8 mm in diameter in the pancreatic head. The diagnosis was changed from RBD to insulinoma. The sleep behavior disorder disappeared after continuous glucose administration. After enucleation of the insulinoma, the administration of glucose was discontinued, and her blood glucose levels recovered. This case suggests that insulinoma should be considered by physicians and psychiatrists in the differential diagnosis of patients with symptoms presenting as RBD. Keywords: insulinoma, differential diagnosis, hypoglycemia, rapid eye movement sleep behavior disorder

Kenichiro Shimizu,1 Yutaka Yoshii,1 Miyuki Morozumi,2 Naoko Chiba,2 Kimiko Ubukata,2 Hironori Uruga,3 Shigeo Hanada,3 Nayuta Saito,1 Tsukasa Kadota,1 Saburo Ito,1 Hiroshi Wakui,1 Naoki Takasaka,1 Shunsuke Minagawa,1 Jun Kojima,1 Hiromichi Hara,1 Takanori Numata,1 Makoto Kawaishi,1 Keisuke Saito,4 Jun Araya,1 Yumi Kaneko,1 Katsutoshi Nakayama,1 Kazuma Kishi,3 Kazuyoshi Kuwano1 1Division of Respiratory Diseases, Department of Internal Medicine, The Jikei University School of Medicine, 2Department of Infectious Diseases, Keio University School of Medicine, 3Department of Respiratory Medicine, Respiratory Center, Toranomon Hospital, 4Department of Respiratory Medicine, The Jikei University Daisan Hospital, Tokyo, Japan Abstract: Respiratory infection is a major cause of exacerbation in chronic obstructive pulmonary disease (COPD). Infectious contributions to exacerbations remain incompletely described. We therefore analyzed respiratory tract samples by comprehensive real-time polymerase chain reaction (PCR) in combination with conventional methods. We evaluated multiple risk factors for prolonged hospitalization to manage COPD exacerbations, including infectious agents. Over 19 months, we prospectively studied 46 patients with 50 COPD exacerbations, collecting nasopharyngeal swab and sputum samples from each. We carried out real-time PCR designed to detect six bacterial species and eleven viruses, together with conventional procedures, including sputum culture. Infectious etiologies of COPD exacerbations were identified in 44 of 50 exacerbations (88%). Infections were viral in 17 of 50 exacerbations (34%). COPD exacerbations caused by Gram-negative bacilli, including enteric and nonfermenting organisms, were significantly associated with prolonged hospitalization for COPD exacerbations. Our results support the use of a combination of real-time PCR and conventional methods for determining both infectious etiologies and risk of extended hospitalization. Keywords: COPD, exacerbation, etiology, real-time PCR, prolonged hospitalization, risk factor

Yusuke Shimizu,1 Shigeaki Suzuki,2 Tomohisa Nagasao,1 Hisao Ogata,1 Masaki Yazawa,1 Norihiro Suzuki,2 Kazuo Kishi1 1Department of Plastic and Reconstructive Surgery, 2Department of Neurology, Keio University School of Medicine, Tokyo, JapanPurpose: Currently, only a few reports have recommended surgery as a suitable treatment for blepharoptosis associated with myasthenia gravis. The present study aims to introduce our surgical criteria, surgical options, outcomes, and precautions for medically refractory myasthenic blepharoptosis. Patients and methods: Eight patients who failed to respond to at least 2 years of medical treatment and who underwent blepharoptosis surgery, from January 2008 to December 2011, were enrolled in this study. Medical records, photographs, and questionnaire results regarding postoperative status were evaluated. Of the eleven procedures performed, four involved frontal suspension, four involved external levator advancement, one involved nonincisional transconjunctival levator advancement, and two involved subbrow blepharoplasty with orbicularis oculi muscle tucking. The margin reflex distance improved postoperatively in seven patients. Results: Seven patients had very minimal scarring, and one had minimal scarring. Five patients showed no eyelid asymmetry, one had subtle asymmetry, and two had obvious asymmetry. Seven patients were very satisfied, and one patient was satisfied with the overall result. Postoperative complications included mild lid lag with incomplete eyelid closure, prolonged scar redness, and worsened heterophoria. No patient experienced postoperative exposure keratitis or recurrent blepharoptosis during the study period. Conclusion: Our results indicate that blepharoptosis surgery is effective for patients with myasthenia gravis, especially those with residual blepharoptosis despite multiple sessions of medical treatments. We recommend that neurologists and surgeons collaborate more systematically and discuss comprehensive treatment plans to increase the quality of life for patients with myasthenia gravis.Keywords: ptosis, myasthenia gravis, ocular myasthenia, blepharoplasty

This article discusses a case of a 64-year-old man who was found to have a pancreatic head mass during a follow-up for colon cancer. The mass was confirmed to be a solid pseudopapillary neoplasm (SPN) through a biopsy. The tumor had invaded the main pancreatic duct and showed high-grade malignant transformation. Metastases developed in the para-aortic lymph nodes and liver one year after surgery. The article highlights the importance of careful treatment for patients with SPN suspected of having high-grade malignant transformation. [Extracted from the article]