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Decomposition subsystems have an essential role in forest dynamics but few studies demonstrate the effect of microbial decay traits on seedling regeneration. In the present study, we focused on seedling regeneration on coarse woody material (CWM), which is an important regeneration site for forest tree species, and the effects of wood decay type according to fungal decay preference for wood structural components on seedling colonization. Effects of log properties including wood decay type and other environmental variables on seedling density were evaluated by ordination methods and generalized linear models. In total, 22 woody species were recorded as seedlings on Pinus densiflora logs. By ordination analysis, white rot in heartwood and brown rot in sapwood, as well as canopy openness and log diameter, showed significant association with seedling communities. The factors selected for a generalized linear model for explaining seedling densities of the two dominant seedling species Cryptomeria japonica and P. densiflora included brown rot in sapwood and white rot in heartwood, but the effects were different: a positive effect of brown rot on C. japonica and a negative effect of white rot on P. densiflora. These results suggested that wood decay type could induce niche separation between dominant tree species regenerating on CWM. Key words: forest regeneration, log, rot type, seedling colonization, wood decay fungi. Les sous-systemes de decomposition jouent un role essentiel dans la dynamique forestiere mais peu d'etudes demontrent l'effet des caracteristiques de la decomposition microbienne sur la regeneration des semis. Dans cette etude, nous mettons l'accent sur la regeneration des semis sur le materiel ligneux grossier (MLG), qui constitue un important site de regeneration pour les especes forestieres arbustives, et sur les effets du type de carie dubois, d'apres les preferences des champignons de carie pour les composantes structurales du bois, sur la colonisation des semis. Les effets des proprietes des billes, incluant le type de carie, et des autres variables environnementales sur la densite des semis ont ete evalues avec des methodes d'ordination et des modeles lineaires generalises. Au total, les semis de 22 especes ligneuses ont ete trouves sur les billes du Pinus densiflora. Selon l'analyse par ordination, la carie blanche dans le bois de creur et la carie brune dans le bois d'aubier ainsi que l'ouverture du couvert forestier et le diametre des billes etaient significativement associes a des communautes de semis. Les facteurs retenus pour construire un modele lineaire generalise en vue d'expliquer la densite des semis des deux especes dominantes de semis, soit Cryptomeria japonica et P. densiflora, incluaient la carie brune dans lebois d'aubier et la carie blanche dans lebois de creur mais leur effet etait different: la carie brune avait un effet positif sur C. japonica et la carie blanche avait un effet negatif sur P. densiflora. Ces resultats indiquent que le type de carie du bois pourrait provoquer une differenciation des niches parmi les especes d'arbres dominantes qui se regenerent sur les MLG. [Traduit par la Redaction] Mots-cles: regeneration de la foret, bille, type de carie, colonisation des semis, champignons responsables de la carie du bois., 1. Introduction Environmental heterogeneity created by ecosystem engineers has large impacts on biotic communities and the ecosystem processes (Odling-Smee et al. 2003). Microbes of the decomposition subsystems such as fungi [...]

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis. Mac2-binding protein glycosylated isomer (M2BPGi), a known biomarker for liver fibrosis, is also elevated in other fibrotic tissues. However, its role in PDAC remains unexplored. This study investigates the potential of M2BPGi as a prognostic biomarker for PDAC and elucidates its role in cancer progression., Methods: We analyzed serum M2BPGi levels in 83 PDAC patients and 60 healthy controls, examining the relationship with clinical outcomes. Tissue immunostaining and in vitro experiments were conducted to investigate M2BPGi-secreting cells and its role., Results: Serum M2BPGi levels were significantly higher in PDAC patients than in controls (0.98 vs. 0.59, p < 0.0001). Notably, elevated serum M2BPGi was associated with worse progression-free survival (144 days vs. 260 days, p = 0.017) and overall survival (OS) (245 days vs. 541 days, p < 0.001) following chemotherapy. Multivariable Cox regression analysis further confirmed that a high serum M2BPGi level is an independent risk factor for OS (HR: 2.44, 95% CI 1.26-4.74, p = 0.008). Immunostaining revealed that M2BPGi is secreted by both cancer cells and cancer-associated fibroblasts (CAFs), with high M2BP expression in CAFs correlating with poor prognosis. Furthermore, M2BPGi-secreting CAFs exhibited characteristics of inflammatory CAFs. M2BPGi directly activated mTOR signaling and epithelial-mesenchymal transition in PDAC cells, enhancing their invasive and migratory capabilities., Conclusions: Our findings identify M2BPGi as a promising prognostic biomarker for PDAC. Moreover, we demonstrate that inflammatory CAFs promote tumor invasion and contribute to poor outcomes by secreting M2BPGi, revealing a novel mechanism of PDAC progression., Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interest in this article. Ethics approval: The study was approved by the Institutional Review Board of Kumamoto University (acceptance number 2458), and all patients provided informed consent., (© 2024. Japanese Society of Gastroenterology.)

Biliary amputation neuroma is a rare benign tumor that develops due to the peribiliary dissection of nerve fibers during cholecystectomy, a common bile duct surgery, or lymph node dissection performed in gastric cancer surgery. We report a case of amputation neuroma that presented a challenging differential diagnosis from perihilar cholangiocarcinoma. A 64-year-old man, who had undergone open cholecystectomy 30 years ago, was incidentally found to have a bile duct tumor during computed tomography (CT) following surgery for renal cell carcinoma. He had no specific symptoms, and blood test results showed only a slight elevation in alkaline phosphatase levels. Contrast-enhanced CT revealed a 10-mm solid tumor with contrast effect in the common bile duct. On cholangiography, the tumor appeared as a protruding lesion with a smooth surface unilaterally. Given the atypical findings suggestive of cholangiocarcinoma, three bile duct biopsies were performed. Pathological examination did not rule out adenocarcinoma. The patient opted for surgery;however, an intraoperative rapid histological examination confirmed a benign disease, thereby avoiding extensive surgery. Consequently, a minimally invasive bile duct resection was performed. Postoperative histopathological examination revealed the tumor to be an amputation neuroma. Biliary amputation neuromas are characterized as unilateral protruding lesions with contrast effect or benign strictures. If such findings are observed in a patient with a history of surgery around the bile duct, the possibility of an amputation neuroma should be considered. However, completely ruling out malignancy preoperatively, even when suspecting amputation neuroma, can be challenging;therefore, considering surgery to achieve a definitive diagnosis is reasonable. During surgery, a rapid intraoperative histological examination is useful to avoid extensive procedures. In conclusion, diagnosing an amputation neuroma before surgery can be difficult, as it can mimic malignant tumors such as bile duct cancers. In this case, although a preoperative diagnosis of amputation neuroma was not feasible, performing a rapid intraoperative pathological examination helped avoid extensive surgery.

Background: Endoscopic biliary stenting is a standard treatment for biliary strictures after liver transplantation. Plastic stents are often replaced before stent dysfunction to prevent the development of cholangitis and jaundice. Therefore, the precise duration of stent patency is unclear., Methods: We compared retrospectively the stent patency period and stent dysfunction rate between inside stents (IS) and conventional plastic stents (PS) in 48 patients with post-transplant strictures, distinguishing endoscopic biliary stenting with and without stent dysfunction at stent replacement., Results: In observations focused on the first treatment, the median patency periods were 369 days for IS ( n = 18) and 154 days for PS ( n = 30; p = 0.01), significantly longer for IS. The 1-year cholangitis incidence rate was lower for IS (20% vs. 43%, p = 0.04). Additionally, no stent dislocation was observed for IS, but this occurred for 33.3% of PS ( p = 0.004). Comparing all endoscopic biliary stenting, including second and subsequent procedures, IS again had a longer patency period than PS (356 days, n = 89, vs. 196 days, n = 127, p = 0.009)., Conclusions: IS had a significantly longer patency period than PS, suggesting that IS replacement could be reduced to once per year for patients who prefer less frequent stent replacement., Competing Interests: None., (© 2023 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Lentinula is a broadly distributed group of fungi that contains the cultivated shiitake mushroom, L. edodes . We sequenced 24 genomes representing eight described species and several unnamed lineages of Lentinula from 15 countries on four continents. Lentinula comprises four major clades that arose in the Oligocene, three in the Americas and one in Asia-Australasia. To expand sampling of shiitake mushrooms, we assembled 60 genomes of L. edodes from China that were previously published as raw Illumina reads and added them to our dataset. Lentinula edodes sensu lato (s. lat.) contains three lineages that may warrant recognition as species, one including a single isolate from Nepal that is the sister group to the rest of L. edodes s. lat., a second with 20 cultivars and 12 wild isolates from China, Japan, Korea, and the Russian Far East, and a third with 28 wild isolates from China, Thailand, and Vietnam. Two additional lineages in China have arisen by hybridization among the second and third groups. Genes encoding cysteine sulfoxide lyase ( lecsl ) and γ-glutamyl transpeptidase ( leggt ), which are implicated in biosynthesis of the organosulfur flavor compound lenthionine, have diversified in Lentinula . Paralogs of both genes that are unique to Lentinula ( lecsl 3 and leggt 5b) are coordinately up-regulated in fruiting bodies of L. edodes . The pangenome of L. edodes s. lat. contains 20,308 groups of orthologous genes, but only 6,438 orthogroups (32%) are shared among all strains, whereas 3,444 orthogroups (17%) are found only in wild populations, which should be targeted for conservation.

Species of Hypochnicium ( Polyporales , Basidiomycota ) collected from Japan were studied on their taxonomy by morphological and phylogenetic approaches. Phylogenetic analyses based on a nrDNA LSU and ITS dataset including the Japanese specimens and other publicly available ones show that Hypochnicium is polyphyletic. Since the clade containing the type species H. bombycinum was well-supported, we defined this clade as Hypochnicium s. str., and emended Hypochnicium to include restricted taxa with only smooth basidiospores. The new genus Neohypochnicium is proposed to accommodate the remaining taxa excluded from the genus Hypochnicium s. str., which includes both species with smooth basidiospores and ornamented ones. Three new species, Gyrophanopsis japonica , N. asiaticum and N. perlongicystidiosum are described and illustrated based on morphological and phylogenetic analyses using an ITS region dataset. In addition, the following 15 new combinations are proposed: N. albostramineum , N. aotearoae , N. capitulateum , N. cremicolor , N. cystidiatum , N. geogenium , N. guineense , N. huinayense , N. michelii , N. microsporum , N. patagonicum , N. pini , N. punctulatum , N. subrigescens and N. wakefieldiae . An identification key to Japanese species of Bulbillomyces , Gyrophanopsis , Hypochnicium and Neohypochnicium is provided., (2023, by The Mycological Society of Japan.)

Conventional exercise therapy including aerobic and resistance training is desirable for cardiovascular disease, whereas it is generally considered contraindicated for symptomatic severe aortic valve stenosis (AS). This study aimed to evaluate the safety and efficacy of bodyweight resistance exercise training (BRET), which is low-intensity exercise training in symptomatic patients with severe AS. A BRET program consisting of 8 exercises was performed 3 times a week by patients with AS with physical therapists. For the 78 symptomatic patients with severe AS, the median aortic valve area and mean transaortic valve pressure gradient were 0.56 cm 2 and 48.9 mm Hg, respectively; none showed any harmful changes in blood pressure or heart rate in 11 sessions of the BRET program. There were no adverse events during hospitalization. Meanwhile, Barthel's Index score significantly improved at the time of hospital discharge. In conclusion, the BRET program in this study did not appear to cause harmful changes in hemodynamics during the program or adverse events during hospitalization, and it improved activities of daily living in symptomatic patients with severe AS, allowing doctors and physical therapists to conduct it safely, with less emotional stress, for cardiac rehabilitation for such patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

An accepted murine analogue for the environmental behavior of human SARS coronaviruses was aerosolized in microdroplets of its culture media and saliva to observe the decay of its airborne infectious potential under relative humidity (RH) conditions relevant to conditioned indoor air. Contained in a dark, 10 m 3 chamber maintained at 22°C, murine hepatitis virus (MHV) was entrained in artificial saliva particles that were aerosolized in size distributions that mimic SARS-CoV-2 virus expelled from infected humans' respiration. As judged by quantitative PCR, more than 95% of the airborne MHV aerosolized was recovered from microdroplets with mean aerodynamic diameters between 0.56 and 5.6 μm. As judged by its half-life, calculated from the median tissue culture infectious dose (TCID 50 ), saliva was protective of airborne murine coronavirus through a RH range recommended for conditioned indoor air (60% < RH < 40%; average half-life = 60 minutes). However, its average half-life doubled to 120 minutes when RH was maintained at 25%. Saliva microaerosol was dominated by carbohydrates, which presented hallmarks of vitrification without efflorescence at low RH. These results suggest that dehydrating carbohydrates can affect the infectious potential coronaviruses exhibit while airborne, significantly extending their persistence under the drier humidity conditions encountered indoors., (© The Author(s) 2022. Published by Oxford University Press on behalf of the National Academy of Sciences.)

Background: The standard of care for unresectable, locally advanced non-small-cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT) followed by durvalumab, based on the PACIFIC study. Although multiple Japanese phase II studies have shown high efficacy and tolerability of CRT with cisplatin plus S-1 (SP), no prospective study using durvalumab after SP-based CRT has been reported., Objectives: We conducted a multicenter phase II study of this approach, the interim analysis of which showed a high transition rate to durvalumab consolidation therapy. Here, we report the primary analysis results., Design: In treatment-naïve LA-NSCLC, cisplatin (60 mg/m 2 , day 1) and S-1 (80-120 mg/body, days 1-14) were administered with two 4-week cycles with concurrent thoracic radiotherapy (60 Gy) followed by durvalumab (10 mg/kg) every 2 weeks for up to 1 year., Methods: The primary endpoint was 1-year progression-free survival (PFS). The expected 1-year PFS and its lower limit of the 80% confidence interval (CI) were set as 63% and 47%, respectively, based on the results of TORG1018 study., Results: In all, 59 patients were enrolled, with 51 (86.4%) proceeding to durvalumab. The objective response rate throughout the study was 72.9% (95% CI: 59.7-83.6%). After median follow-up of 21.9 months, neither median PFS nor OS was reached. The 1-year PFS was 72.5% (80% CI: 64.2-79.2%, 95% CI: 59.1-82.2%), while the 1-year overall survival was 91.5% (95% CI: 80.8-96.4%). No grade 5 adverse events were observed throughout the study. The most common adverse event during the consolidation phase was pneumonitis (any grade, 78.4%; grade ⩾3, 2.0%). Eventually, 52.5% of patients completed 1-year durvalumab consolidation therapy from CRT initiation., Conclusion: This study of durvalumab after SP-based CRT met its primary endpoint and found a 1-year PFS of 73% from CRT initiation. This study provides the first prospective data on the prognosis and tolerability of durvalumab consolidation from the initiation of CRT., Trial Registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127., Competing Interests: H.T. received personal fees as honoraria from Boehringer Ingelheim, AstraZeneca, Pfizer, Chugai Pharmaceutical, Bristol-Myers Squibb, and Ono Pharmaceutical. S.T. received research funding from AstraZeneca, and personal fees as honoraria from AstraZeneca, Chugai Pharmaceutical, Taiho Pharmaceutical, and Eli Lilly. T.Misu. received personal fees as honoraria from Chugai Pharmaceutical and AstraZeneca. S.K. received personal fees as honoraria from Chugai Pharmaceutical, Bristol-Myers Squibb, Boehringer Ingelheim, AstraZeneca, Pfizer, Eli Lilly, MSD, Taiho Pharmaceutical, Sanofi, Kyowa Kirin, Hisamitsu Pharmaceutical, Daiichi Sankyo, Nippon Kayaku, and Novartis. N.I. received personal fees as honoraria from AstraZeneca. K.Kusa. received personal fees as honoraria from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, and Nippon Kayaku. N.F. received personal fees as honoraria from Bristol-Myers Squibb, Ono Pharmaceutical, Boehringer Ingelheim, and AstraZeneca. Y.F. received personal fees as honoraria from Bristol-Myers Squibb, Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Novartis, Merck Biopharma, MSD, Boehringer Ingelheim, Taiho Pharmaceutical, and Daiichi Sankyo. T.T. received personal fees as honoraria from Chugai Pharmaceutical. K.Shib. received personal fees as honoraria from AstraZeneca, Taiho Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, and Ono Pharmaceutical. A.B. received research funding from AstraZeneca and personal fees as honoraria from AstraZeneca and Taiho Pharmaceutical. K.Kair. received research funding from AstraZeneca and Nihon Medi-Physics and personal fees as honoraria from Ono Pharmaceutical, Boehringer Ingelheim, Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, AstraZeneca, and Pfizer. N.S. received research funding from Ono Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Chugai Pharmaceutical, Eisai, Daiichi Sankyo, Takeda Pharmaceutical, Shionogi, Nippon Kayaku, and Pfizer, and personal fees as honoraria from Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, AstraZeneca, Boehringer Ingelheim, MSD, Daiichi Sankyo, Novartis, Bristol-Myers Squibb, Pfizer, Takeda Pharmaceutical, and Nippon Kayaku. No potential conflicts of interest were disclosed by the other authors., (© The Author(s), 2022.)

Introduction: This multicenter and prospective study was performed to evaluate the efficacy of tadalafil on patient-reported bother for each symptom in men with lower urinary tract symptoms (LUTS)., Methods: Men with LUTS received 5 mg of tadalafil daily for 4 weeks. We assessed change in symptom severity using both international prostate symptom score (IPSS), and overactive bladder symptom score (OABSS), as well as patient-reported quality of life (QOL: bother or satisfaction) for each symptoms using IPSS-visual analog scale (IPSS-VAS) and OABSS-VAS., Results: We found significant improvements in total IPSS (P < 0.001), including voiding symptoms (P < 0.001), storage symptoms (P < 0.001), and QOL (P < 0.001). All VAS measures corresponding to symptoms in IPSS and OABSS also significantly improved (P < 0.001). The most bothersome symptoms for each patient at baseline evaluated by VAS measures significantly improved (P < 0.001). Patients whose most bothersome symptoms at baseline included IPSS-Q7 (nocturia) showed significantly smaller improvement of VAS measure after treatment than those without it (P = 0.024)., Conclusions: Daily tadalafil significantly improved not only symptom severity of LUTS but also patient-reported QOL on each symptom., (© 2022 John Wiley & Sons Australia, Ltd.)

Background: The standard of care for unresectable, locally advanced non-small cell lung cancer (LA-NSCLC) is chemoradiotherapy (CRT) followed by durvalumab, based on the PACIFIC trial. Disease progression and pneumonitis were reported as the main reasons to preclude the initiation of durvalumab in multiple retrospective studies. However, the transition rate and the reasons for failure to proceed to consolidation therapy with durvalumab after CRT were not evaluated prospectively. Although phase II studies in Japan have shown high efficacy and tolerability of CRT with cisplatin + S-1 (SP), no prospective study using durvalumab after SP-based CRT has yet been reported. We therefore conducted a phase II study to verify the efficacy and safety of durvalumab following SP-based CRT. In this interim analysis, we report the transition rate and the reasons for its failure., Methods: In treatment-naïve LA-NSCLC, cisplatin (60 mg/m 2 , day 1) and S-1 (80-120 mg/body, days 1-14) were administered with two 4-week cycles with concurrent thoracic radiotherapy (60 Gy) followed by durvalumab every 2 weeks for up to 12 months. The primary endpoint was 12 month progression-free survival rate., Results: Fifty-nine patients were enrolled, of whom 86.4% (51/59) proceeded to durvalumab. All of them initiated durvalumab within 42 days after CRT [median 18 days (range: 3-38)], including 27.5% (14/51) in <14 days. Common reasons for failure to proceed to durvalumab were disease progression (2/59, 3.4%) and adverse events (6/59, 10.2%). Among the latter cases, four resumed treatment and proceeded to durvalumab within 42 days on off-protocol. The objective response rate and the disease control rate were 62.7% and 93.2%, respectively. The incidences of ⩾grade 3 pneumonitis, febrile neutropenia, and esophagitis were 0%, 8.5%, and 3.4%, respectively., Conclusion: Regarding durvalumab after CRT, this interim analysis of the SAMURAI study clarified the high transition rate, early introduction, and reasons for failure to proceed to consolidation therapy, which were not determined in the PACIFIC trial., Trial Registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127., Competing Interests: Competing Interests: ST received research funding from AstraZeneca and personal fees as honoraria from AstraZeneca, Chugai Pharmaceutical, Taiho Pharmaceutical, and Eli Lilly. SK received personal fees as honoraria from Chugai Pharmaceutical, Bristol-Myers Squibb, Boehringer Ingelheim, AstraZeneca, Pfizer, Eli Lilly, MSD, Taiho Pharmaceutical, Sanofi, Kyowa Kirin, Hisamitsu Pharmaceutical, DAIICHI SANKYO, Nippon Kayaku, and Novartis. NI received personal fees as honoraria from AstraZeneca. KK received personal fees as honoraria from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, and Nippon Kayaku. TY received research funding from Bristol-Myers Squibb, MSD, Chugai Pharmaceutical, Takeda Pharmaceutical, and Delta-Fly Pharma and personal fees as honoraria from Bristol-Myers Squibb, Ono Pharmaceutical, Nippon Kayaku, Chugai Pharmaceutical, Eli Lilly, AstraZeneca, Novartis, and Takeda Pharmaceutical. TT received personal fees as honoraria from Chugai Pharmaceutical. KS received personal fees as honoraria from AstraZeneca, Taiho Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, and Ono Pharmaceutical. AB received research funding from AstraZeneca and personal fees as honoraria from AstraZeneca and Taiho Pharmaceutical. KK received research funding from AstraZeneca, and Nihon Medi-Physics and personal fees as honoraria from Ono Pharmaceutical, Boehringer Ingelheim, Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, AstraZeneca, and Pfizer. TM received personal fees as honoraria from Chugai Pharmaceutical and AstraZeneca. NS received research funding from Ono Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Chugai Pharmaceutical, Eisai, DAIICHI SANKYO, Takeda Pharmaceutical, SHIONOGI, Nippon Kayaku, and Pfizer and personal fees as honoraria from Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, AstraZeneca, Boehringer Ingelheim, MSD, DAIICHI SANKYO, Novartis, Bristol-Myers Squibb, Pfizer, Takeda Pharmaceutical, and Nippon Kayaku. No potential conflicts of interest were disclosed by other authors., (© The Author(s), 2022.)

We describe two new species of resupinate Sistotrema sensu lato ( Cantharellales ) collected in Japan: S. flavorhizomorphae and S. chloroporum . Both species have urniform basidia with more than four sterigmata and monomitic hyphal system, oil-rich hyphae in subiculum, which is typical for this genus. Sistotrema chloroporum is characterized by poroid hymenophore partly yellowish-green, basidia 4-6-spored, medium-sized basidiospores (4.5-6.5 × 3.5-6 µm), and broadleaf forest habitat. Sistotrema flavorhizomorphae is characterized by hydnoid-irpicoid hymenophore, bright yellowish rhizomorphs, basidia 6-8-spored, small basidiospores (3-3.5 × 2.5-3 µm), and pine forest habitat. Phylogenetic trees inferred from the fungal nrDNA ITS and LSU and the rpb2 sequences supported that both species were distinct and grouped with other ectomycorrhizal Sistotrema and Hydnum species, but their generic boundary was unclear. Mycorrhizae underneath basidiomes of both species were identified and described via molecular techniques. Mycorrhizae of S. chloroporum have similar characteristics to those of other Sistotrema s.l. and Hydnum species, i.e., S. confluens and H. repandum , whereas S. flavorhizomorphae has a distinct morpho-anatomy, for example, a distinct pseudoparenchymatous mantle. Comprehensive characterizations of basidiomes and mycorrhizae improve the taxonomic analysis of mycorrhizal species of Sistotrema s.l., (2022, by The Mycological Society of Japan.)

Introduction: It is not uncommon for patients hospitalized with pneumonia to experience an early relapse. Here, we investigated the factors related to pneumonia recurrence in Japan., Purpose: We aimed to elucidate the factors related to early recurrence after completion of pneumonia treatment., Methods: We examined 696 patients with community-acquired pneumonia (CAP) and nursing and healthcare-associated pneumonia (NHCAP) who were admitted to our hospital between October 2010 and February 2018, excluding those who died during hospitalization. Logistic regression analysis was used to assess the endpoint of recurrence within 30 days after the end of antibiotic treatment., Results: NHCAP, chronic lung disease and duration of antibiotic treatment were significant risk factors for recurrence of pneumonia within 30 days after antibiotic discontinuation. Aspiration pneumonia was not be a significant factor in the early recurrence of pneumonia., Conclusions: Long-term use of antimicrobials may be a risk factor in early recurrence of pneumonia., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

" Kakishimeji " identified as Tricholoma ustale and belonging to Tricholoma sect. Genuina is a common poisonous mushroom in Japan. Kakishimeji contains the toxic compound ustalic acid and causes digestive trouble. However, this fungus is consumed in some regions of Japan without any digestive issues. We clarified the probable species complex of Kakishimeji based on a phylogenetic analysis. We collected 89 basidioma specimens of Kakishimeji and related species from various forest sites in Japan and conducted phylogenetic analyses using 7 nuclear and mitochondrial gene sequences. Kakishimeji was found to consist of four distinct phylogenetic clades based on all DNA regions tested. Of these, two clades included European T. stans and T. albobrunneum type specimens. Another two clades consisted of sister clades to T. pessundatum and T. ustaloides . In addition, all four phylogenetic clades of Kakishimeji had different spore and basidium sizes. Therefore, we regarded the latter two clades as two new Tricholoma species: T. kakishimeji and T. kakishimejioides ., (2021, by The Mycological Society of Japan.)

A novel species of Tricholoma section Tricholoma , namely, T. olivaceonigrum , is described and illustrated based on samples found in an oak woods dominated by Quercus myrsinifolia , an evergreen oak, in Tottori Prefecture, western Japan. It is characterized by a conic-umbonate, dark-greenish olivaceous pileus with blackish innate fibrils; a whitish silky-fibrillose stipe, often faintly tinted pale yellow and with a narrowed subpointed base; subglobose to broadly elliptic spores; and fruiting in early winter. Phylogenetic analysis targeting the internal transcribed spacer region of the ribosomal RNA gene revealed that T. olivaceonigrum forms a well-supported clade sister to T. portentosum . Other morphologically and phylogenetically closely related species of the section Tricholoma are discussed., (2021, by The Mycological Society of Japan.)

Background: Drug time lags occur between the date that new drugs are first approved, often in the USA, and approval is granted in other countries. Multi-regional clinical trials (MRCTs) are a key strategy for simultaneous global development and regulatory submission of new drugs. However, no studies have evaluated the impact of MRCT versus local development on key time points in the drug development lifecycle between the USA and Japan. It is important for pharmaceutical companies planning drug development in Japan to understand when they can start development, when they can catch up in case of development initiation delay, length of time the development period might take, and amount of time that market exclusivity is lost, if Japan does not participate in the MRCT., Objective: The aim of this study was to investigate differences in drug lag in development initiation, New Drug Application (NDA) submission and drug approval, as well as differences in the development and review periods, by local trials and MRCTs between Japan and the USA. We also assessed the advantages and disadvantages of MRCTs for these lags in Japan., Methods: We analyzed drug approvals in Japan between 2016 and 2020 and divided them into local and MRCT groups. Lags in development initiation, NDA submission, and approval of new drugs were calculated by subtracting each date in Japan from the corresponding date in the USA. Our study period was divided into three periods based on the International Conference on Harmonization (ICH) E17 guideline, published in 2017, and the guideline for the Phase I trials in the Japanese population prior to MRCTs, published in 2014. In addition, subgroup analyses by therapeutic area, regulatory background, modality, capital style, and sales ranking (2020) were conducted., Results: We analyzed 174 approvals in Japan and the USA. The differences in the drug lags for development initiation, NDA submission, and approval between the local and MRCT groups were 4.9, 3.5, and 3.2 years, respectively. All three lag times were shorter for the MRCT group than the local group. A development initiation lag in the local group has expanded since publication of the guidelines., Conclusions: For the people of Japan, important drug lags were identified in development initiation, NDA submission, and drug approval dates between local trials and MRCTs that include Japan. It is difficult to recover fully from the delay caused by local development, and it is important to understand the further expansion of drug lags, in cases where Japan is not involved in the MRCT., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Most commercially circulating mushrooms are produced via cultivation using artificially produced mushroom substrates. However, after mushroom harvesting, the disposal of spent mushroom substrates (SMSs) is a serious problem for the mushroom industry owing to the need for a disposal site and the cost involved. Thus, in view of the possibility of recycling SMSs as a soil modifier, we examined the effect of soil mixed with SMSs on the infection of Arabidopsis leaves by Alternaria brassicicola, the causal agent of cabbage leaf spot. The mixing of SMSs used for Hypsizygus marmoreus, Pholiota microspora, Lyophyllum decastes, and Auricularia polytricha into culture soil suppressed the lesion formation caused by A. brassicicola. The defense responses of Arabidopsis were not induced by the culturing of these seedlings in soils containing SMSs. Suppressed lesion formation was observed after the seedlings were treated with volatiles emitted from SMSs that were incubated with soil for 7 days and used for H. marmoreus, P. microspora, L. decastes, A. polytricha, Lentinula edodes, and Cyclocybe cylindracea. The volatiles from the SMSs reduced the elongation of A. brassicicola hyphae. GC-MS analyses of extracts from the SMS containing soils led to the detection of various volatile compounds; among these, skatole, 2,4-di-tert-butylphenol, γ-dodecalactone, butyric acid, guaiacol, 6-amyl-2-pyrone, and 1-octen-3-ol were examined for inhibitory activity on A. brassicicola and found to suppress hyphae elongation. These findings indicate that the antifungal volatile compounds emitted by the SMSs suppress A. brassicicola infection., (Copyright © 2021 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Background: EGFR mutations are good predictive markers of efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKI), but whether comprehensive genomic analysis beyond EGFR itself with circulating tumor DNA (ctDNA) adds further predictive or prognostic value has not been clarified., Methods: Patients with NSCLC who progressed after treatment with EGFR-TKI, and with EGFR T790 M detected by an approved companion diagnostic test (cobas ® ), were treated with osimertinib. Plasma samples were collected before and after treatment. Retrospective comprehensive next-generation sequencing (NGS) of ctDNA was performed with Guardant360 ® . Correlation between relevant mutations in ctDNA prior to treatment and clinical outcomes, as well as mechanisms of acquired resistance, were analyzed., Results: Among 147 patients tested, 57 patients received osimertinib, with an overall response rate (ORR) of 58%. NGS was successful in 54 of 55 available banked plasma samples; EGFR driver mutations were detected in 43 (80%) and T790 M in 32 (59%). The ORR differed significantly depending on the ratio (T790 M allele fraction [AF])/(sum of variant AF) in ctDNA (p = 0.044). The total number of alterations detected in plasma by NGS was higher in early resistance patients (p = 0.025). T790 M was lost in 32% of patients (6 out of 19) after acquired resistance to osimertinib. One patient with RB1 deletion and copy number gains of EGFR, PIK3CA, and MYC in addition to T790 M, showed rapid progression due to suspected small cell transformation., Conclusions: NGS of ctDNA could be a promising method for predicting osimertinib efficacy in patients with advanced NSCLC harboring EGFR T790 M., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: This final analysis of a long-term extension (LTE) study assessed the safety, tolerability, and effectiveness of peficitinib (ASP015K), a pan-Janus kinase inhibitor, in Asian patients with rheumatoid arthritis (RA)., Methods: Patients had previously completed the 12-week phase 2b (RAJ1), or 52-week phase 3 (RAJ3 and RAJ4) peficitinib studies in Japan, Korea, and Taiwan, and received oral peficitinib 50 or 100 mg/day. Dose increase to 150 mg/day or reduction to 50 mg/day was permitted. Efficacy endpoints included American College of Rheumatology (ACR)20/50/70 response rates, 28-joint Disease Activity Score with C-reactive protein (DAS28-CRP), and ACR components. Safety endpoints included treatment-emergent adverse events (TEAEs), and incidence rates (IRs) of adverse events of special interest per 100 patient-years (PY)., Results: Overall, 843 patients received peficitinib for a mean 32.0 months (maximum 85.2 months), and most (64.4%) received peficitinib 100 mg/day as a maximum dose. Respective ACR20/50/70 response rates were maintained from baseline (week 0 of LTE; 71.6, 52.1, and 34.7%) to end of treatment (78.7, 63.3, and 44.1%); continuous improvements in ACR components and DAS28-CRP were observed from the baselines of preceding studies and throughout the LTE. Overall, 796/843 (94.4%) patients experienced TEAEs; most were severity grade 1/2. Most common TEAEs were nasopharyngitis (47.0%) and herpes zoster (17.3%). Drug-related TEAEs leading to permanent discontinuation occurred in 140 (16.6%) patients, and IRs (95% confidence interval) per 100 PY of serious infections, herpes zoster-related disease, and malignancies were 2.7 (2.1, 3.4), 7.3 (6.2, 8.6), and 1.2 (0.9, 1.8), respectively. Two deaths occurred during the study; one each from diffuse large B cell lymphoma and pneumonia, which were, respectively considered probably and possibly related to study drug., Conclusions: Improvements in effectiveness variables were maintained during this long-term study of peficitinib in Asian patients with RA; peficitinib was generally well tolerated over a mean 32 months' duration., Trial Registration: ClinicalTrials.gov. NCT01638013, retrospectively registered on 11 July 2012 https://clinicaltrials.gov/ct2/show/NCT01638013 .

Background: Based on the results of the PACIFIC study, chemoradiotherapy followed by 1-year consolidation therapy with durvalumab was established as the standard of care for unresectable, locally advanced non-small-cell lung cancer (LA-NSCLC). However, some topics not foreseen in that design can be explored, including progression-free survival (PFS) and overall survival (OS) after the start of chemoradiotherapy, the proportion of patients who proceeded to consolidation therapy with durvalumab, and the optimal chemotherapeutic regimens. In Japan, the combination regimen of S-1 + cisplatin (SP), for which the results of multiple clinical studies have suggested a good balance of efficacy and tolerability, is frequently selected in clinical settings. However, the efficacy and safety of consolidation therapy with durvalumab following this SP regimen have not been evaluated. We therefore planned a multicenter, prospective, single-arm, phase II study., Methods: In treatment-naïve LA-NSCLC, two cycles of combination chemotherapy with S-1 (80-120 mg/body, Days 1-14) + cisplatin (60 mg/m 2 , Day 1) will be administered at an interval of 4 weeks, with concurrent thoracic radiotherapy (60 Gy). Responders will then receive durvalumab every 2 weeks for up to 1 year. The primary endpoint is 1-year PFS rate., Discussion: Compared with the conventional standard regimen in Japan, the SP regimen is expected to be associated with lower incidences of pneumonitis, esophagitis, and febrile neutropenia, which complicate the initiation of consolidation therapy with durvalumab, and have higher antitumor efficacy during chemoradiotherapy. Therefore, SP-based chemoradiotherapy is expected to be successfully followed by consolidation therapy with durvalumab in more patients, resulting in prolonged PFS and OS. Toxicity and efficacy results of the SP regimen in this study will also provide information important to the future establishment of the concurrent combination of chemoradiotherapy and durvalumab., Trial Registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127., Competing Interests: Conflict of interest statement: S.T. received research funding from AstraZeneca K.K. N.S. received personal fees as honoraria from Lily Japan, AstraZeneca K.K., MSD Oncology, Chugai Pharmaceutical, Taiho Pharmaceutical, Pfizer Japan Inc., Ono Pharmaceutical, Nippon Boehringer Ingelheim Co., Ltd., and Bristol-Myers Squibb Japan, and research funding from Nippon Boehringer Ingelheim Co., Ltd., (© The Author(s), 2021.)

Evolution of tumor-immune microenviroments (TIMEs) occurs during tumor growth and dissemination. Understanding inter-site tumor-immune heterogeneity is essential to harness the immune system for cancer therapy. While the development of immunotherapy against lung cancer with driver mutations and neuroendocrine tumors is ongoing, little is known about the TIME of large cell neuroendocrine carcinoma (LCNEC) or anaplastic lymphoma kinase ( ALK ) rearrangement-positive lung cancer. We present a case study of a 32-year-old female patient with ALK -rearrangement-positive LCNEC, who had multiple distant metastases including mediastinal lymph-node, bilateral breasts, multiple bones, liver and brain. Multiple biopsy samples obtained from primary lung and three metastatic tumors were analyzed by fluorescent multiplex immunohistochemistry. Tissue localizations of tumor-infiltrating lymphocytes in the tumor nest and surrounding stroma were evaluated. T cell and B cell infiltrations were decreased with distance from primary lung lesion. Although each tumor displayed a unique TIME, all tumors exhibited concomitant regression after treatment with an ALK-inhibitor. This study provides the first evidence of the coexistence of distinct TIME within a single individual with ALK -rearrangement-positive LCNEC. The present study contributes to our understanding of heterogeneous TIMEs between primary and metastatic lesions and provides new insights into the complex interplay between host-immunity and cancer cells in primary and metastatic lesions.

An amendment to this paper has been published and can be accessed via the original article.

Background: Peficitinib (ASP015K), a novel oral Janus kinase inhibitor, has demonstrated efficacy and safety for the treatment of rheumatoid arthritis (RA) in randomized, controlled trials of up to 52 weeks' duration. However, safety and effectiveness after long-term treatment have not been assessed., Methods: This was an interim analysis of an ongoing open-label, multicenter extension study in RA patients who completed phase 2b (RAJ1; 12 weeks) and phase 3 (RAJ3 and RAJ4; 52 weeks) peficitinib studies in Asia (mainly Japan). Eligible patients (n = 843) received oral peficitinib once daily (100 mg, or 50 mg for patients transferring from RAJ1). The peficitinib dose could be increased (up to 150 mg) or reduced (to 50 mg) at the discretion of the investigator. Efficacy variables assessed included American College of Rheumatology (ACR) response rates, ACR components, and disease activity score in 28 joints based on C-reactive protein (DAS28-CRP)., Results: Results up to May 2018 are summarized. Mean peficitinib duration of exposure was 22.7 months and the maximum dose was 100 mg in most (66.5%) patients. ACR responses were maintained during the extension study, with ACR20/50/70 response rates of 71.6%, 52.1%, and 34.7% at week 0 and 78.9%, 61.4%, and 42.7% at end of treatment, respectively. ACR components and DAS28-CRP showed improvements from baselines of the preceding studies and continued to show improvements during the extension study. Treatment-emergent adverse events (TEAEs) were reported in 757/843 (89.8%) patients, the most common being nasopharyngitis (39.7%) and herpes zoster (11.7%). The majority of TEAEs were severity grade 1/2. Drug-related TEAEs leading to permanent study drug discontinuation occurred in 55/843 (6.5%) patients. Regarding AEs of special interest, the incidence per 100 patient-years of serious infections was 2.3 (95% CI 1.6 - 3.1), herpes zoster-related disease 6.8 (95% CI, 5.6 - 8.3), and malignancies 1.1 (95% CI, 0.7 - 1.8). One death from diffuse large B cell lymphoma during the study and one death from uterine sarcoma after the study were considered probably and possibly related to study drug, respectively., Conclusions: The effectiveness of peficitinib was maintained or improved during long-term administration and treatment up to 6 years was well tolerated in Asian patients with RA., Trial Registration: ClinicalTrials.gov, NCT01638013, registered retrospectively 11 July 2012.

Objective: To evaluate the efficacy and safety of the oral Janus kinase (JAK) inhibitor peficitinib versus placebo in Japanese patients with rheumatoid arthritis (RA)., Methods: In this multicentre, double-blind, parallel-group, placebo-controlled phase III study, patients with RA and inadequate response to methotrexate (MTX) were randomised 1:1:1 to placebo, peficitinib 100 mg once daily or peficitinib 150 mg once daily with MTX for 52 weeks. Based on baseline randomisation, at week 12, non-responders receiving placebo were switched to peficitinib until the end of treatment; the remaining patients were switched to peficitinib at week 28. Primary efficacy variables were American College of Rheumatology (ACR)20 response rate at week 12/early termination (ET) and change from baseline in van der Heijde-modified total Sharp score (mTSS) at week 28/ET., Results: 519 patients were randomised and treated. Significantly more (p<0.001) peficitinib (58.6%, 100 mg; 64.4%, 150 mg) than placebo (21.8%) recipients achieved ACR20 response at week 12/ET. Significantly lower (p<0.001) mean changes from baseline in mTSS at week 28/ET occurred in peficitinib (1.62, 100 mg; 1.03, 150 mg) than placebo (3.37) recipients. Peficitinib was associated with haematological and biochemical parameter changes, and increased incidence of serious infections and herpes zoster-related disease. One death from suicide occurred in a patient in the placebo group after switching to peficitinib 100 mg., Conclusions: In Japanese patients with RA and inadequate response to MTX, peficitinib demonstrated significant superiority versus placebo in reducing RA symptoms and suppressing joint destruction. Peficitinib had an acceptable safety and tolerability profile, with no new safety signals compared with other JAK inhibitors., Trial Registration Number: NCT02305849., Competing Interests: Competing interests: TT has received grants from Astellas Pharma, Inc, Chugai Pharmaceutical Co, Ltd, Daiichi Sankyo Co, Ltd, Takeda Pharmaceutical Co, Ltd, AbbVie GK, Asahi Kasei Pharma Corp, Mitsubishi Tanabe Pharma Co, Pfizer Japan, Inc, Eisai Co, Ltd, AYUMI Pharmaceutical Corp, Nippon Kayaku Co, Ltd, and Novartis Pharma KK; speaking fees from AbbVie GK, Bristol-Myers KK, Chugai Pharmaceutical Co, Ltd, Mitsubishi Tanabe Pharma Co, Pfizer Japan, Inc, Astellas Pharma, Inc, Daiichi Sankyo Co, Ltd, Eisai Co, Ltd, Sanofi KK, Teijin Pharma Ltd, Takeda Pharmaceutical Co, Ltd, and Novartis Pharma KK; consultancy fees from AstraZeneca KK, Eli Lilly Japan KK, Novartis Pharma KK, Mitsubishi Tanabe Pharma Co, AbbVie GK, Nippon Kayaku Co, Ltd, Janssen Pharmaceutical KK, Astellas Pharma, Inc, Taiho Pharmaceutical Co, Ltd, Chugai Pharmaceutical Co, Ltd, Taisho Toyama Pharmaceutical Co, Ltd, GlaxoSmithKline KK, and UCB Japan Co, Ltd. YT reports speaking fees and/or honoraria from Daiichi Sankyo, Astellas, Eli Lilly, Chugai, Sanofi, AbbVie, Pfizer, YL Biologics, Bristol-Myers, GlaxoSmithKline, UCB, Mitsubishi-Tanabe, Novartis, Eisai, Takeda, Janssen and Asahi Kasei, and research grants from Mitsubishi-Tanabe, Bristol-Myers, Eisai, Chugai, Takeda, AbbVie, Astellas, Daiichi Sankyo, Ono, MSD and Taisho Toyama. ST reports personal fees from Amgen, Inc, Asahi Kasei Pharma Corporation, Amgen Astellas BioPharma KK, Ono Pharmaceutical Co, Ltd, KYOCERA Medical Corporation, Daiichi Sankyo Co, Ltd, Teijin Pharma Ltd, Eli Lilly Japan KK and Pfizer Japan, Inc; endowments from Astellas Pharma, Inc, AYUMI Pharmaceutical Corporation, Pfizer Japan, Inc, Bristol-Myers Squibb, Daiichi Sankyo Co, Ltd, and Chugai Pharmaceutical Co, Ltd; and grants from Japan Agency for Medical Research and Development, Japan Society for the Promotion of Science (JSPS)/Grant-in-Aid for Scientific Research (A), and JSPS/Grant-in-Aid for Exploratory Research outside the submitted work. AK has received grants from AbbVie, Eisai, Mitsubishi-Tanabe, Pfizer Japan, Takeda Pharmaceutical, Astellas Pharma, MSD, Ono Pharmaceutical, Teijin Pharma, Kyowa Hakko-Kirin, Sumitomo-Dainippon Pharma, Kissei Pharmaceutical, Boehringer Ingelheim, AstraZeneca, Otsuka Pharmaceutical, Chugai Pharmaceutical, Santen Pharmaceutical and Daiichi Sankyo; participated in speaker’s bureaux for AbbVie, Eisai, Takeda Pharmaceutical, Ono Pharmaceutical, Astellas Pharma, Mitsubishi Tanabe, Pfizer Japan, Chugai Pharmaceutical, MSD, and Bristol-Myers KK; and received consultancy fees from Astellas Pharma and Janssen Pharmaceutical KK. KK reports consultancy fees from Eisai Co, Ltd, and Toyama Chemical Co, Ltd and speaker fees from Daiichi Sankyo Co, Ltd, Astellas Pharma, Eli Lilly, Chugai, AbbVie, Pfizer, Bristol-Myers Squibb, UCB, Mitsubishi Tanabe, Takeda, Janssen, Asahi Kasei and AYUMI Pharmaceutical Corporation. MR, HI, SU, YK, TS and EY are employees of Astellas Pharma, Inc. MI has nothing to declare. DvdH has received consultancy honoraria from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda and UCB, and is the owner of Imaging Rheumatology., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To investigate the efficacy and safety of peficitinib, an oral Janus kinase inhibitor, in patients with rheumatoid arthritis (RA)., Methods: In this double-blind phase III study, patients with RA and an inadequate response to prior disease-modifying anti-rheumatic drugs (DMARDs) were randomised to peficitinib 100 mg once daily, peficitinib 150 mg once daily, placebo or open-label etanercept for 52 weeks' treatment; placebo-treated patients were switched at week 12 to peficitinib 100 or 150 mg once daily. The primary endpoint was American College of Rheumatology (ACR)20 response at week 12/early termination (ET). Secondary endpoints (assessed throughout) included ACR20, ACR50 and ACR70 response, changes from baseline in disease activity scores (DAS)28 and ACR core parameters, adverse events (AEs) and changes in clinical or laboratory measurements., Results: In total, 507 patients received treatment. ACR20 response rates at week 12/ET were significantly higher in the peficitinib 100 mg (57.7%) and 150 mg (74.5%) groups versus placebo (30.7%) (p<0.001). ACR50/70 response rates were also higher for both peficitinib doses versus placebo. Improvements in ACR response were maintained until week 52. Changes from baseline in DAS28-C-reactive protein/erythrocyte sedimentation rate and the ACR core set were significantly greater for both peficitinib doses versus placebo at week 12/ET (p<0.001). AE incidence was similar across treatment arms. Incidence of serious infection and herpes zoster-related disease was higher with peficitinib versus placebo, but with no clear dose-dependent increase., Conclusions: In patients with RA and inadequate response to DMARDs, peficitinib 100 mg once daily or 150 mg once daily was efficacious in reducing RA symptoms and was well tolerated compared with placebo., Trial Registration Number: NCT02308163., Competing Interests: Competing interests: YT reports speaking fees and/or honoraria from Daiichi Sankyo, Astellas, Eli Lilly, Chugai, Sanofi, AbbVie, Pfizer, YL Biologics, Bristol-Myers Squibb, GlaxoSmithKline, UCB, Mitsubishi-Tanabe, Novartis, Eisai, Takeda, Janssen and Asahi Kasei, and research grants from Mitsubishi Tanabe, Bristol-Myers Squibb, Eisai, Chugai, Takeda, AbbVie, Astellas, Daiichi Sankyo, Ono, MSD and Taisho Toyama. TT has received grants from Astellas Pharma, Inc., Chugai Pharmaceutical Co. Ltd, Daiichi Sankyo Co. Ltd, Takeda Pharmaceutical Co. Ltd, AbbVie GK, Asahi Kasei Pharma Corp., Mitsubishi Tanabe Pharma Co., Pfizer Japan, Inc., Eisai Co. Ltd, AYUMI Pharmaceutical Corp., Nippon Kayaku Co. Ltd, and Novartis Pharma K.K.; speaking fees from AbbVie GK, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co. Ltd, Mitsubishi Tanabe Pharma Co., Pfizer Japan, Inc., Astellas Pharma, Inc., Daiichi Sankyo Co. Ltd, Eisai Co. Ltd, Sanofi K.K., Teijin Pharma Ltd, Takeda Pharmaceutical Co. Ltd, and Novartis Pharma K.K.; consultancy fees from Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., AbbVie GK, Nippon Kayaku Co. Ltd, Janssen Pharmaceutical K.K., Astellas Pharma, Inc., Taiho Pharmaceutical Co. Ltd, Chugai Pharmaceutical Co. Ltd, Taisho Toyama Pharmaceutical Co. Ltd, GlaxoSmithKline K.K., and UCB Japan Co. Ltd. ST reports personal fees from Amgen, Inc., Asahi Kasei Pharma Corporation, Amgen Astellas BioPharma K.K., Ono Pharmaceutical Co. Ltd, KYOCERA Medical Corporation, Daiichi Sankyo Co. Ltd, Teijin Pharma Ltd, Eli Lilly Japan K.K., and Pfizer Japan, Inc.; endowments from Astellas Pharma, Inc., AYUMI Pharmaceutical Corporation, Pfizer Japan, Inc., Bristol-Myers Squibb, Daiichi Sankyo Co. Ltd, and Chugai Pharmaceutical Co. Ltd; and grants from Japan Agency for Medical Research and Development (AMED), Japan Society for the Promotion of Science (JSPS)/Grant-in-Aid for Scientific Research (A), and Japan Society for the Promotion of Science (JSPS)/Grant-in-Aid for Exploratory Research outside the submitted work. AK reports grants from AbbVie, Eisai, Mitsubishi-Tanabe, Pfizer Japan, Takeda Pharmaceutical, Astellas Pharma, MSD, Ono Pharmaceutical, Teijin Pharma, Kyowa Hakko-Kirin, Sumitomo-Dainippon Pharma, Kissei Pharmaceutical, Boehringer Ingelheim, AstraZeneca, Otsuka Pharmaceutical, Chugai Pharmaceutical, Santen Pharmaceutical and Daiichi Sankyo; participation in speakers’ bureaux for AbbVie, Eisai, Takeda Pharmaceutical, Ono Pharmaceutical, Astellas Pharma, Mitsubishi-Tanabe, Pfizer Japan, Chugai Pharmaceutical, MSD, and Bristol-Myers Squibb K.K.; and consultant fees from Astellas Pharma and Janssen Pharmaceutical K.K. YWS reports a grant from Astellas Pharma, Inc.YHC reports grants for research and clinical trials from Taiwan Ministry of Science and Technology, Taiwan Department of Health, Taichung Veterans General Hospital, National Yang-Ming University, GlaxoSmithKline, Pfizer, Bristol-Myers Squibb, Novartis, AbbVie, Johnson & Johnson, Roche, Sanofi, Chugai Pharma Taiwan Ltd, Boehringer Ingelheim, UCB, MSD, AstraZeneca and Astellas; and honoraria and consultant fees from Pfizer, Novartis, AbbVie, Johnson & Johnson, Bristol-Myers Squibb, Roche, Lilly, GlaxoSmithKline, AstraZeneca, Sanofi, MSD, Chugai Pharma Taiwan Ltd, Astellas, Inova Diagnostics, UCB, Agnitio Science Technology, United Biopharma and Thermo Fisher. MR, HI, SU, YK, RA, TS and EY are employees of Astellas Pharma, Inc., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The optimal duration of antibiotic treatment has not been established for pneumonia patients. Some investigators reported procalcitonin (PCT)-guided antimicrobial stewardship reduces the duration of antibiotic use without increasing mortality in pneumonia patients., Material and Methods: We prospectively enrolled hospitalized community-acquired pneumonia or healthcare-associated pneumonia patients with PCT levels >0.20 ng/mL on admission, who were admitted between 2014 and 2017. PCT levels were measured on days 5, 8 and 11 and every 3 days thereafter if needed. Physicians were encouraged and strongly encouraged to discontinue antibiotics when PCT levels decreased below 0.20 ng/mL and 0.10 ng/mL, respectively. Those admitted between 2010 and 2014 were included in the study as historical controls. Primary endpoints were duration of antibiotic treatment and recurrence of pneumonia within 30 days after antibiotic discontinuation., Results: The PCT-guided and control groups consisted of 116 patients each. Background factors including pneumonia severity and PCT levels did not differ between the 2 groups. Median duration of antibiotic treatment was 8.0 and 11 days in the PCT-guided and control groups, respectively (P < 0.001). Multivariable regression analysis revealed that PCT-guided antibiotic discontinuation (partial regression coefficient [PRC] -1.9319, P < 0.001), PCT (PRC 0.1501, P = 0.0059) and albumin (PRC -1.4398, P = 0.0096) were significantly related to duration of antibiotic treatment. Pneumonia recurrence within 30 days after antibiotic discontinuation was not statistically different between the 2 groups (4.3% vs. 6.0%, P = 0.5541)., Conclusions: PCT-guided antibiotic discontinuation might be useful for shortening the duration of antibiotic treatment without increasing pneumonia recurrence., (Copyright © 2019 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Background/aim: The optimal treatment strategy for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) has not yet been fully determined. The aim of this study was to investigate the optimal management of EGFR-mutant NSCLC patients with BM., Patients and Methods: A multicenter retrospective study was performed on the clinical outcomes of 81 advanced/recurrent EGFR-mutant NSCLC patients with BM treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) (gefitinib n=52 or erlotinib n=29)., Results: Among the 81 patients, 30 patients received upfront cranial radiotherapy (CRT) and 51 did not. The multivariate cox analyses revealed that the use of erlotinib and upfront CRT were independent predictive factors for overall survival (OS) (erlotinib: HR 0.21; 95% CI, 0.10-0.48; p<0.001; upfront CRT: HR 0.42; 95% CI, 0.20-0.88; p=0.022)., Conclusion: Erlotinib and upfront CRT were associated with a favorable prognosis among EGFR-mutant NSCLC patients with BM. Upfront CRT followed by erlotinib may be an appropriate initial management approach for EGFR-mutant NSCLC patients with BM., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Small-bore aspiration catheters (Aspiration Kit ® ) cause less pain than conventional trocar catheters in patients. The objective of this study was to examine the usefulness of these less invasive small-bore aspiration catheters for drainage of pneumothorax., Methods: Baseline characteristics and laboratory test data at admission of 70 patients who were admitted to and underwent drainage treatment for pneumothorax at our hospital between April 2011 and February 2017 were retrospectively reviewed based on their medical records. The primary endpoints were factors associated with drainage treatment failure, and baseline characteristics and laboratory test data were compared between those treated with a small-bore aspiration catheter and those treated with a trocar catheter., Results: The numbers of patients with anticoagulant use (P < 0.0001), ischemic stroke (P = 0.0063), and atrial fibrillation (P = 0.0410) were significantly different between the two groups. No significant intergroup differences were noted with respect to the length of hospitalization, drainage duration, subcutaneous emphysema, and treatment failure. Logistic regression analyses of baseline characteristics showed that the severity of pneumothorax, localization of pneumothorax, and recurrent pneumothorax were significantly associated with drainage treatment failure, but the type of drainage catheter was not significantly associated with treatment failure. [Conclusions] The results suggest that small-bore aspiration catheters, which cause less pain in patients, are potentially useful for pneumothorax drainage., (Copyright © 2018. Published by Elsevier B.V.)

Purpose: This study aimed to elucidate factors related to 30-day mortality of pneumonia occurring outside hospital by comprehensively analyzing data considered relevant to prognosis., Methods: Data considered relevant to prognosis were retrospectively examined from clinical charts and chest X-ray images of all patients with pneumonia occurring outside hospital admitted to our hospital from 2010 to 2016. The primary outcome was 30-day mortality., Results: Data were collected from 534 patients (317 community-acquired pneumonia and 217 nursing- and healthcare associated pneumonia patients; 338 men (63.3%); mean age, 76.2 years-old). Eighty-three patients (9.9%) died from pneumonia within 30 days from the date of admission. The numbers of patients with pneumonia severity index (PSI) classes of I/II/III/IV/V and age, dehydration, respiratory failure, orientation disturbance, pressure (A-DROP) scores of 0/1/2/3/4/5 were 29/66/127/229/83, and 71/107/187/132/30/7, respectively. Mean (standard deviation) body mass index (BMI), serum albumin, blood procalcitonin, white blood cell and C-reactive protein were 20.00 (4.12) kg/m 2 , 3.16 (0.60) g/dL, 3.69 (13.15) ng/mL, 11559.4 (5656.9)/mm 3 , and 10.92 (8.75) mg/dL, respectively. Chest X-ray images from 152 patients exhibited a pneumonia shadow over a quarter of total lung field. Logistic regression analysis revealed that PSI class or A-DROP score, BMI, serum albumin, and extent of pneumonia shadow were related to 30-day mortality. Receiver operating characteristics curve analysis revealed that serum albumin was superior to PSI class or A-DROP score for predicting 30-day mortality., Conclusion: Serum albumin is not less important than PSI class or A-DROP score for predicting 30-day mortality in hospitalized patients with pneumonia occurring outside hospital., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

In view of the possibility that spent mushroom substrates (SMSs) may be used as agricultural materials to prevent crop diseases, we examined the effect of treatment with a hot water extract from the SMS of Lentinula edodes on plant resistance to pathogenic infection. The extract of Le. edodes SMS was sprayed onto the leaves of rice plants, followed by inoculation of the leaves with the conidia of rice blast fungus. The development of lesions was suppressed by treatment with the SMS extract. The extract markedly inhibited the germination of Pyricularia oryzae conidia. We purified compounds 1 , 2 , and 3 , which showed inhibitory effects on conidial germination, from the Le. edodes SMS extract of by successive solvent extraction, column chromatography, and preparative HPLC. Spectroscopic analyses revealed that 1 , 2 , and 3 were phenolic acids with two carboxyl groups in common.

Determinants of interindividual variability in erlotinib pharmacokinetics (PK) and adverse events remain to be elucidated. This study with 50 Japanese non-small-cell lung cancer patients treated with oral erlotinib at a standard dose of 150 mg aimed to investigate whether genetic polymorphisms affect erlotinib PK and adverse events. Single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP1A1, CYP1A2, CYP2D6, CYP3A4, CYP3A5, UGT1A1, UGT2B7, GSTM1, and GSTT1) or efflux transporters (ABCB1, and ABCG2) were analyzed as covariates in a population PK model. The ABCB1 1236C>T (rs1128503) polymorphism, not ABCB1*2 haplotype (1236TT-2677TT-3455TT, rs1128503 TT-rs2032582 TT-rs1045642 TT), was a significant covariate for the apparent clearance (CL/F), with the TT genotype showing a 29.4% decrease in CL/F as compared with the CC and the CT genotypes. A marginally higher incidence of adverse events (mainly skin rash) was observed in the TT genotype group; however, patients with high plasma erlotinib exposure did not always experience skin rash. None of the other SNPs affected PK or adverse events. The ABCB1 genotype is a potential predictor for erlotinib adverse events. Erlotinib might be used with careful monitoring of adverse events in patients with ABCB1 polymorphic variants.

Objectives: To evaluate the impact of morphometric magnetic resonance imaging (MRI) analysis of the prostate zonal anatomy on aging, prostatic hypertrophy and lower urinary tract symptoms in patients from Japan and the USA., Subjects and Methods: A retrospective analysis of 307 men, including 156 men from Japan and 151 from the USA, who consecutively underwent 3-Tesla MRI and International Prostate Symptom Score (IPSS) assessment because of elevated PSA levels. Using Synapse-Vincent (Fujifilm), the prostatic zones were segmented in each axial step-section of the T2-weighted MRI to reconstruct a three-dimensional model of the prostate, which was used to calculate: zonal volumes (whole-gland prostate, transition zone and peripheral zone volumes); the presumed circle area ratio (PCAR); and PZ thickness. Bivariate associations were quantified using Spearman's rank correlation coefficients., Results: The USA subgroup had a greater prostate volume (49 vs 42 mL; P = 0.003) and TZ volume (26 vs 20 mL; P < 0.001) than the Japan subgroup, with no difference in PZ volume (19 vs 20 mL; P = 0.2). There was no age-related increase in PZ volume in either of the subgroups or in the entire cohort (P = 0.9, P = 0.2, P = 0.3, respectively). PZ thickness had a significant negative correlation with PCAR (P < 0.001) and TZ volume (P < 0.001). The greater the increase in the TZ volume with the increase in PCAR, which probably correlates with obstructive pressure, the thinner the PZ became. PCAR had a significant positive correlation with IPSS (P = 0.003) and obstructive symptoms (P = 0.007), while PZ thickness had a significant negative correlation (P = 0.018)., Conclusions: No age-related increases and no differences between the Japanese and the US subgroups were found with regard to PZ volume. The more TZ volume increased, the higher the obstructive pressure and the thinner the PZ became; these changes were associated with increased obstructive symptoms. MRI analysis of prostate zonal anatomy enhanced our understanding of age-related changes in morphology and urinary symptoms., (© 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.)

Introduction: Alectinib has shown marked efficacy and safety in patients with anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangement-positive NSCLC and a good performance status (PS). It has remained unclear whether alectinib might also be beneficial for such patients with a poor PS., Methods: Eligible patients with advanced ALK rearrangement-positive NSCLC and a PS of 2 to 4 received alectinib orally at 300 mg twice daily. The primary end point of the study was objective response rate (ORR), and the most informative secondary end point was rate of PS improvement., Results: Between September 2014 and December 2015, 18 patients were enrolled in this phase II study. Of those patients, 12, five, and one had a PS of 2, 3, or 4, respectively, whereas four patients had received prior crizotinib treatment. The ORR was 72.2% (90% confidence interval: 52.9-85.8%). The ORR did not differ significantly between patients with a PS of 2 and those with a PS of 3 or higher (58.3% and 100%, respectively [p = 0.114]). The PS improvement rate was 83.3% (90% confidence interval: 64.8-93.1%, p < 0.0001), with the frequency of improvement to a PS of 0 or 1 being 72.2%. The median progression-free survival was 10.1 months. Toxicity was mild, with the frequency of adverse events of grade 3 or higher being low. Neither dose reduction nor withdrawal of alectinib because of toxicity was necessary., Conclusions: Alectinib is a treatment option for patients with ALK rearrangement-positive NSCLC and a poor PS., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Renal cell carcinoma (RCC) is the most common type of kidney cancer. However, the mechanisms underlying the progression of the disease are not well understood. The data in this report suggest that canopy FGF signaling regulator 2 (CNPY2) is a promoter of RCC progression. We found that CNPY2 significantly promoted growth of RCC cells and upregulated TP53 gene expression. Although TP53 is widely known as a tumor suppressor, in RCC TP53 promoted tumor cell growth. A typical p53 target gene, CDKN1A, was upregulated by both p53 and CNPY2 in RCC cells, suggesting that CNPY2 increased the expression level of TP53. Consistent with these results, CNPY2 and TP53 expression levels were positively correlated in RCC patients. These findings suggested that CNPY2 promoted cancer cell growth in RCC through regulating TP53 gene expression., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Recent findings have indicated a close relationship between myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-positive hypertrophic pachymeningitis and the limited form of granulomatosis with polyangiitis (GPA). In Japan, MPO-ANCA-positive hypertrophic pachymeningitis predominantly occurs in elderly individuals. We herein describe the cases of two patients with MPO-ANCA-positive hypertrophic pachymeningitis associated with the limited form of GPA who were successfully treated with a combination of corticosteroids and methotrexate. Although methotrexate has been shown to be less effective than cyclophosphamide for inducing the remission of GPA in patients with organ-threatening diseases, its safety and efficacy may make it a useful alternative treatment modality for patients with the limited form of GPA who show meningeal involvement.

The Amazon Forest is a hotspot of biodiversity harboring an unknown number of undescribed taxa. Inventory studies are urgent, mainly in the areas most endangered by human activities such as extensive dam construction, where species could be in risk of extinction before being described and named. In 2015, intensive studies performed in a few locations in the Brazilian Amazon rainforest revealed three new species of the genus Scleroderma: S. anomalosporum, S. camassuense and S. duckei. The two first species were located in one of the many areas flooded by construction of hydroelectric dams throughout the Amazon; and the third in the Reserva Florestal Adolpho Ducke, a protected reverse by the INPA. The species were identified through morphology and molecular analyses of barcoding sequences (Internal Transcribed Spacer nrDNA). Scleroderma anomalosporum is characterized mainly by the smooth spores under LM in mature basidiomata (under SEM with small, unevenly distributed granules, a characteristic not observed in other species of the genus), the large size of the basidiomata, up to 120 mm diameter, and the stelliform dehiscence; S. camassuense mainly by the irregular to stellate dehiscence, the subreticulated spores and the bright sulfur-yellow colour, and Scleroderma duckei mainly by the verrucose exoperidium, stelliform dehiscence, and verrucose spores. Description, illustration and affinities with other species of the genus are provided., Competing Interests: The authors have declared that no competing interests exist.

Silencing of androgen receptor (AR)-meditated androgen signaling is thought to be associated with the development of testicular germ cell tumors (TGCTs). However, the role of the androgen/AR signal in TGCT development has not been investigated. In this study, we show that the androgen/AR signal suppressed the cell growth of seminomas (SEs), a type of TGCT, in vitro and in vivo. Growth of SE cells was suppressed by DHT treatment and reduction of androgen levels by surgical castration promoted cancer cell growth in an in vivo xenograft model. Tryptophan hydroxylase 1 (TPH1), the rate limit enzyme in serotonin synthesis, was one of the genes which expression was reduced in DHT-treated SE cells. TPH1 was highly expressed in SE cancer tissues compared with adjacent normal tissues. Activation of androgen/AR signaling in SE cells reduced the expression of TPH1 in SE cells, followed by the reduction of serotonin secretion in cell culture supernatant. These results suggested that silencing of androgen/AR signaling may cause initiation and progression of SE through increase in TPH1 gene expression level., Competing Interests: The authors declare no conflicts of interest.