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Hidenori Maruyama,1 Fumiya Sano,2 Reiko Sakaguchi,3 Keisuke Okamoto,4 Itaru Miura5 1Medical Science, Sumitomo Pharma Co., Ltd, Osaka, Japan; 2Department of Data Science, Drug Development Division, Sumitomo Pharma Co., Ltd, Tokyo, Japan; 3Department of Clinical Research, Drug Development Division, Sumitomo Pharma Co., Ltd, Tokyo, Japan; 4Department of Clinical Operation, Drug Development Division, Sumitomo Pharma Co., Ltd, Tokyo, Japan; 5Department of Neuropsychiatry, Fukushima Medical University, Fukushima, JapanCorrespondence: Hidenori Maruyama, Tel +81-80-4368-2576, Fax +81-6-6203-5733, Email hidenori.maruyama@sumitomo-pharma.co.jpPurpose: To evaluate the effect of lurasidone on a new, patient Life Engagement scale in schizophrenia.Patients and Methods: This post-hoc analysis included participants (ages 18 to 74) diagnosed with schizophrenia who were randomized to lurasidone (40 mg/day) or placebo in a 6-week double-blind efficacy study and those who continued in a subsequent 12-week open-label extension study during which patients received either 40 or 80/mg day lurasidone (flexibly dosed). Change in life engagement was measured using the Positive and Negative Syndrome Scale (PANSS) 11-item Life Engagement subscale score, and individual subscale items, at week 6 during the double-blind phase and extension phase week 12 during the open-label extension phase.Results: Analysis focused on 478 subjects randomized to lurasidone or placebo during the 6-week trial, and 146 who received lurasidone during the extension phase. During the 6-week trial, there was a significantly greater change on the PANSS11 Life Engagement subscale score from baseline to week 6 in the lurasidone group compared to the placebo group (mean changes of − 6.4 and − 4.8, respectively, p = 0.006; effect size = 0.27). Further improvement was evident during the extension phase for patients who received lurasidone in both phases, with a mean change from double-blind baseline to week 12 of the open-label treatment phase of − 10.1 on in PANSS11 Life Engagement subscale.Conclusion: This post-hoc analysis suggests that lurasidone may improve life engagement in patients with schizophrenia, a meaningful outcome from patients’ perspective. Further studies are needed to confirm this effect.Eudract Number: Trial registration: EudraCT Numbers: 2016-000060-42; 2016-000061-23.Keywords: lurasidone, schizophrenia, antipsychotic agents, life engagement, efficacy

Shunsuke Sakakura,1,* Fumihiro Yamaguchi,1,* Takashi Abe,1 Hidekazu Cho,1 Shohei Shimizu,1 Ayaka Mase,1 Yusuke Shikama,1 Haruhiko Maruyama2 1Department of Respiratory Medicine, Showa University Fujigaoka Hospital, Yokohama, Japan; 2Division of Parasitology, Department of Infectious Diseases, Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki, Japan*These authors contributed equally to this workCorrespondence: Fumihiro Yamaguchi, Department of Respiratory Medicine, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-ku, Yokohama, 227-8501, Japan, Tel +81-45-971-1151, Email f_y@med.showa-u.ac.jpAbstract: The Paragonimus westermani infection is a parasitic foodborne infection that induces systemic symptoms with eosinophilia in humans. Here, we described pneumothorax in addition to pulmonary opacities with eosinophilia in a man with a positive P. westermani serology. He was misdiagnosed with chronic eosinophilic pneumonia (CEP) during the initial phase. Paragonimiasis can share similar clinical findings with CEP in cases where the worm is confined to the lungs. The findings of the current study suggest that paragonimiasis and CEP can be distinguished from each other by the presence of various symptoms. Notably, eosinophilia with pneumothorax should be an important diagnostic factor for paragonimiasis.Keywords: Paragonimus westermani, chronic eosinophilic pneumonia, paragonimiasis, pneumothorax

Itaru Miura,1 Kei Watabe,2 Reiko Sakaguchi,3 Keisuke Okamoto,4 Hidenori Maruyama5 1Department of Neuropsychiatry, Fukushima Medical University, Fukushima, Japan; 2Department of Data Science, Drug Development Division, Sumitomo Pharma Co., Ltd, Tokyo, Japan; 3Department of Clinical Research, Drug Development Division, Sumitomo Pharma Co., Ltd, Tokyo, Japan; 4Department of Clinical Operation, Drug Development Division, Sumitomo Pharma Co., Ltd, Tokyo, Japan; 5Medical Affairs, Sumitomo Pharma Co., Ltd, Tokyo, JapanCorrespondence: Itaru Miura, Department of Neuropsychiatry, Fukushima Medical University 1 Hikarigaoka, Fukushima, 960-1295, Japan, Tel +81-24-547-1331, Fax +81-24-548-6735, Email itaru@fmu.ac.jpPurpose: To evaluate the effectiveness and safety of lurasidone 80 mg/day (versus the 40 mg/day dose) during a 12-week, open-label extension study in patients with an acute exacerbation of schizophrenia who had completed a 6-week double-blind study of lurasidone.Patients and Methods: A total of 289 adult patients with schizophrenia completed the double-blind study and enrolled in the 12-week extension study. Lurasidone was flexibly dosed at 40 or 80 mg/day. Effectiveness measures included the Positive and Negative Syndrome Scale (PANSS) subscale scores, Clinical Global Impression-Severity Scale (CGI-S), and Calgary Depression Scale for Schizophrenia (CDSS), analyzed based on last observation carried forward (LOCF-endpoint). Safety/tolerability assessments included adverse events, body weight, laboratory tests, and discontinuation due to adverse events.Results: Mean endpoint change was greater for lurasidone in modal doses of 80 mg/d (N=136) vs 40 mg/d (N=153) on the PANSS positive subscale (− 3.0 vs − 2.3), PANSS negative subscale (− 1.9 vs − 1.7), PANSS General Psychopathology subscale (− 5.1 vs − 3.8), the CGI-S score (− 0.5 vs − 0.4), and the CDSS score (− 0.7 vs − 0.1). Discontinuation rates due to adverse events on lurasidone modal 80 mg/d vs 40 mg/d were 4.4% vs 7.2%; and the most common adverse events in the modal 80 mg/d group were nasopharyngitis, 7.4% (vs 4.6% on modal 40 mg/d), constipation, 5.9% (vs 2.0%), and headache, 5.9% (vs 2.0%).Conclusion: In patients with acute schizophrenia treated with lurasidone 40 mg/d, increasing the dose to 80 mg/d was well tolerated, and was associated with greater improvement in PANSS subscale scores compared to continued treatment with a dose of 40 mg/d.Keywords: lurasidone, schizophrenia, extension treatment, dose escalation, effectiveness, safety

Koki Tsuchiya,1 Koji Ishikawa,1 Soji Tani,1 Yusuke Oshita,2 Takuma Kuroda,1 Ryo Yamamura,1 Haruka Emori,1 Hiroshi Maruyama,1 Akira Matsuoka,1 Yoshifumi Kudo,1 Toshiyuki Shirahata,1 Tomoaki Toyone,1 Takashi Nagai,1 Katsunori Inagaki11Department of Orthopaedic Surgery, Showa University School of Medicine, Tokyo 142-8666, Japan; 2Department of Orthopaedic Surgery, Yamanashi Red Cross Hospital, Yamanashi, JapanAbstract: Discontinuation of denosumab during osteoporosis treatment leads to rapid loss of bone mineral density and induces a bone turnover rebound effect. Previous studies have reported analysis based on dual-energy X-ray absorptiometry scanning (DXA). Here, we report the first case involving analysis of three-dimensional bone mineral density and bone strength, measured by quantitative computed tomography (QCT) after discontinuation of denosumab. An 82-year-old woman who discontinued denosumab because of patient’s wish was administered the fifth dose after a gap of 14 months. Her bone mineral density evaluated by DXA and QCT, bone strength, and bone turnover marker levels showed significant rebound phenomenon. The levels of the cortical parameters of the hip were also decreased indicating an increased risk of femoral fractures after denosumab interruption. Our case highlights the increased risk of fractures after discontinuation of denosumab. Therefore, denosumab must be used judiciously without interruption in the dosage schedule.Keywords: lumbar spine, femoral neck, bone turnover markers, cortical bone, biomechanical analysis

Glypicans are a family of glycosylphosphatidylinositol-anchored cell surface heparan sulfate proteoglycans implicated in the control of cellular growth and differentiation. Here we show that glypican-1 is strongly expressed in human breast cancers, whereas expression of glypican-1 is low in normal breast tissues. In contrast, the expression of glypican-3 and -4 is only slightly increased in breast cancers by comparison with normal breast tissues, and glypican-2 and -5 are below the level of detection by Northern blotting in both normal and cancer samples. Treatment of MDA-MB-231 and MDA-MB-468 breast cancer cells with phosphoinositide-specific phospholipase-C abrogated the mitogenic response to two heparin-binding growth factors, heparin-binding epidermal growth factor-like growth factor and fibroblast growth factor 2. Stable transfection of these cells with a glypican-1 antisense construct markedly decreased glypican-1 protein levels and the mitogenic response to the same heparin-binding growth factors, as well as that to heregulin alpha, heregulin beta, and hepatocyte growth factor. Syndecan-1 was also expressed at high levels in both breast cancer tissues and breast cancer cells when compared with normal breast tissues. There was a good correlation between glypican-1 and syndecan-1 expression in the tumors. However, clones expressing the glypican-1 antisense construct did not exhibit decreased syndecan-1 levels, indicating that loss of responsiveness to heparin-binding growth factors in these clones was not due to altered syndecan-1 expression. Furthermore, 8 of 10 tumors with stage 2 or 3 disease exhibited high levels of glypican-1 by Northern blot analysis. In contrast, low levels of glypican-1 mRNA were evident in 1 of 10 tumors with stage 2 or 3 disease and in 9 of 10 tumors with stage 1 disease. Taken together, these data suggest that glypican-1 may play a pivotal role in the ability of breast cancer cells to exhibit a mitogenic response to multiple heparin-binding growth factors and may contribute to disease progression in this malignancy.

Cytokeratin 20 belongs to the epithelial subgroup of the intermediate filament family. Because of its restricted range of expression in humans, it has become an important tool for detecting and identifying metastatic cancer cells by immunohistochemistry and by PCR analysis. Despite its widespread diagnostic use in colorectal cancer and occasional use in pancreatic cancer, little is known about the expression of CK 20 in these tumors in vivo. Therefore, in the present study we characterized CK 20 expression in pancreatic and colorectal cancer by comparison with its expression in the normal pancreas and colon. Tissue samples from 24 patients with pancreatic cancer and from 41 patients with colorectal cancer were examined for CK 20 expression by Northern blot analysis, immunohistochemistry, and in situ hybridization. CK 20 expression was observed in the cancer cells of both cancer types. A subgroup of the pancreatic cancers exhibited a 3.2-fold increase in CK 20 mRNA by comparison with respective normal controls. In contrast, colon cancers underexpressed CK 20 mRNA by comparison with the respective controls. In the normal tissues, CK 20 immunoreactivity was relatively faint and sparse in the pancreatic ductal cells but intense and abundant in the apical portions of the colonic mucosa. CK 20 immunoreactivity was also evident in the ductal cells from the chronic pancreatitis-like lesions adjacent to the cancer cells. Furthermore, distant metastases from pancreas carcinomas exhibited strong CK 20 immunoreactivity. It is concluded that CK 20 is overexpressed in pancreatic cancer and that it can serve as an excellent marker for metastatic pancreatic cancer.