Publications by authors named "Atsushi Nakayama"

74 Publications

Efficient construction of the hexacyclic ring core of palau'amine: the p concept for proceeding with unfavorable equilibrium reactions.

Chem Sci 2021 Sep 11;12(36):12201-12210. Epub 2021 Aug 11.

Graduate School of Pharmaceutical Sciences, Tokushima University 1-78 Shomachi Tokushima 770-8505 Japan

Palau'amine has received a great deal of attention as an attractive synthetic target due to its intriguing molecular architecture and significant immunosuppressive activity, and we achieved its total synthesis in 2015. However, the synthesized palau'amine has not been readily applicable to the mechanistic study of immunosuppressive activity, because it requires 45 longest linear steps from a commercially available compound. Here, we report the short-step construction of the ABCDEF hexacyclic ring core of palau'amine. The construction of the CDE tricyclic ring core in a single step is achieved by our p concept for proceeding with unfavorable equilibrium reactions, and a palau'amine analog without the aminomethyl and chloride groups is synthesized in 20 longest linear steps from the same starting material. The palau'amine analog is confirmed to retain the immunosuppressive activity. The present synthetic approach for a palau'amine analog has the potential for use in the development of palau'amine probes for mechanistic elucidation.
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http://dx.doi.org/10.1039/d1sc03260gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457368PMC
September 2021

Total Synthesis and Structure Confirmation of -Anhydromevalonate-5-phosphate, a Key Biosynthetic Intermediate of the Archaeal Mevalonate Pathway.

J Nat Prod 2021 Oct 1;84(10):2749-2754. Epub 2021 Oct 1.

Graduate School of Science, Osaka City University, 3-3-138, Sugimoto, Sumiyoshi, Osaka, 558-8585, Japan.

The mevalonate pathway is an upstream terpenoid biosynthetic route of terpenoids for providing the two five-carbon units, dimethylallyl diphosphate, and isopentenyl diphosphate. Recently, -anhydromevalonate-5-phosphate (tAHMP) was isolated as a new biosynthetic intermediate of the archaeal mevalonate pathway. In this study, we would like to report the first synthesis of tAHMP and its enzymatic transformation using one of the key enzymes, mevalonate-5-phosphate dehydratase from a hyperthermophilic archaeon, . Starting from methyl tetrolate, a Cu-catalyzed allylation provided an -trisubstituted olefin in a stereoselective manner. The resulting -olefin was transformed to tAHMP by cleavage of the olefin and phosphorylation. The structure of the synthetic tAHMP was unambiguously determined by NOESY analysis.
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http://dx.doi.org/10.1021/acs.jnatprod.1c00615DOI Listing
October 2021

Outcomes of endoscopic resection for superficial duodenal tumors: 10 years' experience in 18 Japanese high-volume centers.

Endoscopy 2021 Sep 8. Epub 2021 Sep 8.

Cancer Center, School of Medicine, Keio University, Tokyo, Japan.

Background And Study Aim: There is no enough data for endoscopic resection (ER) of superficial duodenal epithelial tumors (SDETs) due to its rarity. There are two main kinds of ER techniques for SDETs: EMR and ESD. In addition, modified EMR techniques, underwater EMR (UEMR) and cold polypectomy (CP), are getting popular. We conducted a large-scale retrospective multicenter study to clarify detailed outcomes of duodenal ER.

Patients And Methods: Patients with SDETs who underwent ER at 18 institutions from January 2008 to December 2018 were included. The rates of en bloc resection and delayed adverse events (AEs) (defined as delayed bleeding or perforation) were analyzed. Local recurrence was analyzed using Kaplan-Meier method.

Results: In total, 3107 patients (including 1017 receiving ESD) were included. En bloc resection rates were 79.1%, 78.6%, 86.8%, and 94.8%, and delayed AE rates were 0.5%, 2.2%, 2.8%, and 7.3% for CP, UEMR, EMR and ESD, respectively. The delayed AE rate was significantly higher for ESD group than non-ESD group among lesions less than 19 mm (7.4% vs 1.9%, p<0.0001), but not among lesions larger than 20 mm (6.1% vs 7.1%, p=0.6432). The local recurrence rate was significantly lower in ESD group than non-ESD group (p<0.001). Furthermore, for lesions larger than 30 mm, the cumulative local recurrence rate at 2 years was 22.6% in non-ESD group compared to only 1.6% in ESD group (p<0.0001).

Conclusions: ER outcomes for SDETs were generally acceptable. ESD by highly experienced endoscopists might be an option for very large SDETs.
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http://dx.doi.org/10.1055/a-1640-3236DOI Listing
September 2021

A Case of Large Duodenal Lymphangioma as Struggled to Diagnose Because of Well Localized Morphology.

Am J Gastroenterol 2021 09;116(9):1824

Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.14309/ajg.0000000000001178DOI Listing
September 2021

Efficacy of partial injection underwater endoscopic mucosal resection for superficial duodenal epithelial tumor: Propensity score-matched study (with video).

Dig Endosc 2021 Aug 9. Epub 2021 Aug 9.

Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Tokyo, Japan.

Background And Aim: Underwater endoscopic mucosal resection (UEMR) has been reported as effective endoscopic treatment for superficial duodenal epithelial tumors (SDETs). However, it has been reported that a notable problem of UEMR for SDETs is that en bloc resection rate is relatively low. Therefore, we proposed a novel technique to improve en bloc resection rate: UEMR combining partial submucosal injection (PI-UEMR). The aim of this study is to evaluate efficacy and safety of PI-UEMR for SDETs by comparing to UEMR.

Methods: This is a retrospective observational study in a single center. The patients who underwent UEMR or PI-UEMR from June 2010 to August 2020 were included in this study. Eligible patients were selected from included patients in a 1:1 ratio using propensity score matching. The clinical outcomes of endoscopic resection (procedure time, en bloc resection rate, complication rate [immediate perforation, delayed bleeding, delayed perforation]), and histopathological diagnosis (adenoma/cancer) were compared between each group.

Results: Two hundred and twenty-eight patients were included in this study. Of included patients, 47 patients were selected in each group by propensity score matching. There were no statistical differences in procedure time (11 ± 1.2 min vs. 9 ± 1.2 min, P = 0.30), complication rate (immediate perforation [0% vs. 2%, P = 0.12], delayed bleeding [0% vs. 2%, P = 0.12], and no delayed perforation) and histopathological diagnosis (adenoma; 100% vs. 96%, P = 0.14) in each group. However, en bloc resection rate of PI-UEMR was significantly higher than UEMR (96% vs. 83%, P < 0.05).

Conclusion: Partial submucosal injection UEMR might be superior procedure for en bloc resection in SDETs compare to UEMR.
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http://dx.doi.org/10.1111/den.14103DOI Listing
August 2021

Endoscopic hand suturing for mucosal defect closure after gastric endoscopic submucosal dissection may reduce the risk of postoperative bleeding in patients receiving antithrombotic therapy.

Dig Endosc 2021 May 21. Epub 2021 May 21.

Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Tokyo, Japan.

Objectives: Endoscopic hand suturing (EHS) is expected to decrease the risk of post-endoscopic submucosal dissection (ESD) bleeding by closing mucosal defects. We investigated the efficacy of EHS after gastric ESD in patients with antithrombotic agents.

Methods: In this prospective single-arm trial, patients taking antithrombotic agents for cardiovascular disease, arrhythmia, cerebrovascular disease and/or peripheral arterial disease and having <3-cm gastric neoplasms were recruited. The mucosal defects after ESD were closed by EHS in which the needle was delivered through an overtube, and the mucosal rim of the defect was continuously sutured in a linear fashion by manipulating the needle grasped with the needle holder, followed by cutting the remnant suture and retrieval of the needle. The primary endpoint was the incidence of postoperative bleeding within 4 weeks after ESD.

Results: Twenty-two lesions in 20 patients (continuing antiplatelet agents in 11, anticoagulant agents in eight, both in one) underwent ESD followed by EHS. All defects (median size, 30 mm; range, 12-51 mm) were completely closed by EHS and remained closed on postoperative day 3. The median number of stitches was six (range, 4-8) and median suturing time was 36 (range, 24-60) min. There were no adverse events during/after EHS or postoperative bleeding.

Conclusions: Postoperative bleeding was not observed in patients taking antithrombotic agents without perioperative cessation. EHS appears to be useful for prevention of post-gastric ESD bleeding in high-risk patients. (Clinical registration number: UMIN000024184).
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http://dx.doi.org/10.1111/den.14045DOI Listing
May 2021

Predictors of technical difficulty for complete closure of mucosal defects after duodenal endoscopic resection.

Gastrointest Endosc 2021 Oct 27;94(4):786-794. Epub 2021 Apr 27.

Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Tokyo, Japan.

Background And Aims: It has been reported that the prophylactic closure of mucosal defects after duodenal endoscopic resection (ER) can reduce delayed adverse events; however, under certain circumstances, this can be technically challenging. Therefore, the aim of this study was to determine the predictors of difficulty during the complete closure of mucosal defects after duodenal ER.

Methods: This was a retrospective study of duodenal lesions that underwent ER between July 2010 and May 2020. We reviewed the endoscopic images and analyzed the relationships between the degree of closure or closure time and clinical features of the lesions using univariate and multivariate analyses.

Results: We analyzed 698 lesions. The multivariate analysis revealed that lesion location in the medial or anterior wall (odds ratio, 2.8; 95% confidence interval, 1.36-5.85; P < .01) and a large lesion size (odds ratio, 1.4; 95% confidence interval, 1.07-1.89; P = .03) were independent predictors of an increased risk of incomplete closure. Moreover, a large lesion size (β coefficient, .304; P < .01), an occupied circumference over 50% (β coefficient, .178; P < .01), intraoperative perforation (β coefficient, .175; P < .01), treatment period (β coefficient, .143; P < .01), and treatment with endoscopic submucosal dissection (β coefficient, .125; P < .01) were independently and positively correlated with a prolonged closure time in the multiple regression analysis.

Conclusions: This study revealed that lesion location in the medial or anterior wall and lesion size affected the incomplete closure of mucosal defects after duodenal ER, and lesion size, occupied circumference, intraoperative perforation, treatment period, and treatment method affected closure time.
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http://dx.doi.org/10.1016/j.gie.2021.04.017DOI Listing
October 2021

Superficial nonampullary duodenal epithelial tumor: a rare case accompanied by cancer component as subepithelial lesion.

Gastrointest Endosc 2021 08 12;94(2):427-428. Epub 2021 Jun 12.

Department of Research and Development for Minimal Invasive Treatment, Cancer Center, Keio University, Tokyo, Japan.

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http://dx.doi.org/10.1016/j.gie.2021.04.001DOI Listing
August 2021

Feasibility Study of Partial Submucosal Injection Technique Combining Underwater EMR for Superficial Duodenal Epithelial Tumors.

Dig Dis Sci 2021 Mar 15. Epub 2021 Mar 15.

Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University, School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Background And Aims: Endoscopic mucosal resection (EMR) and Underwater EMR have been reported as effective endoscopic treatment for superficial duodenal tumor (SDET). However, a notable problem of EMR for SDET is technical difficulty for the lesion with non-lifting sign, and it of UEMR is that en bloc resection rate is relatively low. Therefore, we performed partial submucosal injection combining UEMR (PI-UEMR). The aim of this study is to evaluate feasibility and safety of this technique for duodenal tumor.

Methods: This is a prospective observational study from tertiary care hospital. We performed PI-UEMR in patients with SDET that is 13-20 mm in diameter, or less than 13 mm with technical difficulty for EMR and UEMR from January 2019 to March 2020. Primary outcome was en bloc resection rate. Secondary outcomes were R0 resection rate, mean total procedure time, intra- and post-procedure complication.

Results: Thirty patients were included in this study. Mean age was 62 ± 12 years old. Three fourths lesions were located at anal side from major papilla. Median lesion size was 12 mm [IQR 10-16 mm]. Twenty-four cases were taken endoscopic biopsy in prior hospital and observed biopsy scar. En bloc resection rate was 97%. Ro resection rate was 83%. Mean total procedure time was 17 ± 12 min. And there was an only one case of complication, intra-procedure bleeding that was controllable endoscopically.

Conclusions: PI-UEMR might be very useful and safe technique of endoscopic resection for SDET including relatively large lesions.
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http://dx.doi.org/10.1007/s10620-021-06925-3DOI Listing
March 2021

Development of a mugineic acid family phytosiderophore analog as an iron fertilizer.

Nat Commun 2021 03 10;12(1):1558. Epub 2021 Mar 10.

Department of Pharmaceutical Sciences, Tokushima University, Tokushima, Japan.

Iron (Fe) is an essential nutrient, but is poorly bioavailable because of its low solubility in alkaline soils; this leads to reduced agricultural productivity. To overcome this problem, we first showed that the soil application of synthetic 2'-deoxymugineic acid, a natural phytosiderophore from the Poaceae, can recover Fe deficiency in rice grown in calcareous soil. However, the high cost and poor stability of synthetic 2'-deoxymugineic acid preclude its agricultural use. In this work, we develop a more stable and less expensive analog, proline-2'-deoxymugineic acid, and demonstrate its practical synthesis and transport of its Fe-chelated form across the plasma membrane by Fe(III)•2'-deoxymugineic acid transporters. Possibility of its use as an iron fertilizer on alkaline soils is supported by promotion of rice growth in a calcareous soil by soil application of metal free proline-2'-deoxymugineic acid.
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http://dx.doi.org/10.1038/s41467-021-21837-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946895PMC
March 2021

External drainage of bile and pancreatic juice after endoscopic submucosal dissection for duodenal neoplasm: Feasibility study (with video).

Dig Endosc 2021 Sep 4;33(6):977-984. Epub 2021 Jan 4.

Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Tokyo, Japan.

Background And Aims: Endoscopic submucosal dissection (ESD) for superficial duodenal epithelial tumors (SDETs) is technically difficult and has a high risk of adverse events. Endoscopic nasobiliary and nasopancreatic duct drainage (ENBPD) may reduce the risk of delayed adverse events by preventing exposure of the post-ESD mucosal defect to bile and pancreatic juice. This study was performed to evaluate the safety and feasibility of ENBPD after duodenal ESD.

Methods: Patients who underwent ESD for SDETs from July 2010 to March 2020 were included. We collected data on the success rate of ENBPD, adverse events due to insertion of a side-viewing endoscope, and pancreatitis after ENBPD. We also collected the clinical outcomes of duodenal ESD, including the incidence rate of delayed adverse events (defined as bleeding or perforation found after the endoscopic procedure).

Results: Among 70 patients without complete closure of the post-ESD mucosal defect, ENBPD was successfully performed in all 25 patients including 21 cases inserted immediately after ESD and four cases inserted later. There were no adverse events associated with ENBPD procedure intraoperatively, while pancreatitis after ENBPD occurred in four patients (16.0%). No patients who underwent immediate ENBPD required intervention for an intra-abdominal abscess or delayed perforation, whereas 3 of 49 patients (6.1%) who did not undergo immediate ENBPD required surgery or drainage of an abscess.

Conclusions: Endoscopic nasobiliary and nasopancreatic duct drainage is technically feasible and might provide effective prophylaxis for delayed adverse events, even if a large mucosal defect is present after ESD.
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http://dx.doi.org/10.1111/den.13907DOI Listing
September 2021

Concise Total Synthesis of Tronocarpine.

Angew Chem Int Ed Engl 2021 01 9;60(2):635-639. Epub 2020 Nov 9.

Graduate School of Pharmaceutical Sciences, Tokushima University, 1-78 Shomachi, Tokushima, Tokushima, 770-8505, Japan.

A concise total synthesis of tronocarpine, a chippiine-type indole alkaloid, was accomplished. The key feature of this total synthesis is a one-pot construction of the pentacyclic skeleton containing an azabicyclo[3.3.1]nonane core by tandem cyclization from an indole derivative with all carbon side chains and functional groups. This tandem cyclization consists of α,β-unsaturated aldehyde formation, intramolecular aldol reaction, six-membered lactamization, azide reduction, and seven-membered lactamization. The stereochemical outcome in this tandem cyclization is controlled by the stereocenter at the C14 position. This strategy can be utilized to synthesize other chippiine-type alkaloids with azabicyclo[3.3.1]nonane skeletons.
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http://dx.doi.org/10.1002/anie.202009966DOI Listing
January 2021

Water pressure method for duodenal endoscopic submucosal dissection (with video).

Gastrointest Endosc 2021 04 25;93(4):942-949. Epub 2020 Aug 25.

Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.

Background And Aims: Duodenal endoscopic submucosal dissection (ESD) is considered technically challenging and has a high risk of adverse events. However, we recently made some progress with the ESD technique and device by introducing 2 features: a water pressure (WP) method and a second-generation ESD knife (DualKnife) with a water jet function (DualKnife J). The present study aimed to assess whether these changes improved the clinical outcomes of duodenal ESD.

Methods: This was a retrospective observational study. Among all patients who underwent ESD for superficial duodenal epithelial tumors from June 2010 to December 2018, patients in whom a single expert performed the procedure were included in this study. Various factors, including the use of the WP method and ESD devices (DualKnife or DualKnife J) and the treatment phase (early, mid, and late), were analyzed to determine whether they were associated with intraprocedural perforation and procedure time. Treatment phase was assigned by dividing the study population equally into 3 subgroups according to the treatment phase.

Results: The procedure time was significantly shorter, and the proportion of patients with intraprocedural perforations was the lowest in the late phase. Multivariate analysis of the use of the WP method revealed that it significantly decreased the intraprocedural perforation rate (odds ratio, 0.39; 95% confidence interval, 0.16-0.96), and analysis of the use of both the WP method (β coefficient, -0.40; P < .01) and the DualKnife J (β coefficient, -0.10; P = .032) revealed they were independently and negatively correlated with procedure time.

Conclusion: The present study reveals that the WP method significantly reduced the intraprocedural perforation rate and that both the WP method and the DualKnife J significantly shortened procedure times for duodenal ESD.
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http://dx.doi.org/10.1016/j.gie.2020.08.018DOI Listing
April 2021

A Case of Duodenal Tumor Adjacent to the Diverticulum That Was Resected by the Technique of Partial Submucosal Injection Combined with Underwater Endoscopic Mucosal Resection.

Dig Dis 2021 11;39(1):70-74. Epub 2020 Jun 11.

Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Tokyo, Japan.

A 66-year-old male was referred to our hospital for treatment of duodenal tumor. The most difficult part was that the lesion was adjacent to duodenal diverticulum. Endoscopic mucosal resection (EMR) was difficult because submucosal injection spread broadly and quickly and makes it difficult to visualize the diverticulum edge of the lesion. Simple underwater EMR (UEMR) had risk for perforation at the diverticulum part because duodenal diverticulum is spurious diverticulum that defects the proper muscle layer. Therefore, to make sufficient distance between diverticulum and the lesion, we performed partial submucosal injection into only the diverticulum side of the lesion combined with simple UEMR. The lesion was resected en bloc without any adverse events. Histopathological diagnosis was tubular adenoma with moderate atypia and surgical margin negative. Partial submucosal injection combined with simple UEMR might be useful for duodenal tumor that has any technical difficulties as in this case.
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http://dx.doi.org/10.1159/000509323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949217PMC
February 2021

Automatic detection of cervical lymph nodes in patients with oral squamous cell carcinoma using a deep learning technique: a preliminary study.

Oral Radiol 2021 Apr 6;37(2):290-296. Epub 2020 Jun 6.

Department of Oral and Maxillofacial Radiology, Aichi-Gakuin University School of Dentistry, 2-11 Suemori-dori, Chikusa-ku, Nagoya, 464-8651, Japan.

Objective: To apply a deep learning object detection technique to CT images for detecting cervical lymph nodes metastasis in patients with oral cancers, and to clarify the detection performance.

Methods: One hundred and fifty-nine metastatic and 517 non-metastatic lymph nodes on 365 CT images in 56 patients with oral squamous cell carcinoma were examined. The images were arbitrarily assigned to training, validation, and testing datasets. Using the neural network, 'DetectNet' for object detection, the training procedure was conducted for 1000 epochs. Testing image datasets were applied to the learning model, and the detection performance was calculated.

Results: The learning curve indicated that the recall (sensitivity) for detecting metastatic and non-metastatic lymph nodes reached 90% and 80%, respectively, while the model performance recall by applying the test dataset was 73.0% and 52.5%, respectively. The recall for detecting level IB and Level II metastatic lymph nodes was relatively high.

Conclusions: A system that has the potential to automatically detect cervical lymph nodes was constructed.
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http://dx.doi.org/10.1007/s11282-020-00449-8DOI Listing
April 2021

Efficacy of a new image-enhancement technique for achieving hemostasis in endoscopic submucosal dissection.

Gastrointest Endosc 2020 Sep 1;92(3):667-674. Epub 2020 Jun 1.

Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University, School of Medicine, Tokyo, Japan.

Background And Aims: Hemostasis during endoscopic submucosal dissection (ESD) can sometimes be challenging and stressful for the endoscopist. Therefore, we aimed to assess the usefulness of dual red imaging (DRI), a new image enhancement technique that uses 3 wavelengths (540, 600, and 630 nm) to visualize bleeding points and to examine the efficacy of DRI in shortening the time required to achieve hemostasis (hemostasis time) during ESD.

Methods: DRI and white-light imaging (WLI) were used alternately for managing 378 bleeding events in 97 patients undergoing ESD. Hemostasis time for each hemostasis event was measured. Using portable eye-tracking glasses, 4 experienced endoscopists were shown random videos of intraoperative bleeding during ESD (20 cases each on WLI and DRI) and identified the bleeding point in each video. The mean distances of eye movement per unit of time until the bleeding point were identified in each video and compared between the WLI and DRI groups.

Results: Average hemostasis time was significantly shorter in the DRI group. The mean distance of eye movement was significantly shorter in the DRI group than in the WLI group for all endoscopists.

Conclusions: DRI can offer useful images to help in clearly detecting bleeding points and in facilitating hemostasis during ESD. It is feasible and may help in successfully performing ESD that is safer and faster than WLI. (Clinical trial registration number: UMIN000018309.).
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http://dx.doi.org/10.1016/j.gie.2020.05.033DOI Listing
September 2020

Biodiscovery of antibacterial constituents from the endolichenic fungi isolated from .

3 Biotech 2020 May 24;10(5):212. Epub 2020 Apr 24.

1The Graduate School, University of Santo Tomas, Manila, Philippines.

A total of nine endolichenic fungi were isolated from the foliose lichen (Nyl.) Hale. Of the nine endolichenic fungi, three taxa (, , ) showed antibacterial activities as determined by the disk diffusion assay against ESKAPE bacterial pathogens. gave the most active fungal extract with zone of inhibition values of 15 mm and 19 mm against and respectively. Further chromatographic purification of the ethyl acetate extract led to the isolation and identification of bis(2-ethylhexyl)terephthalate (), acetyl tributyl citrate (), and fusarubin (). Acetyl tributyl citrate () exhibited moderate antibacterial activity against and
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http://dx.doi.org/10.1007/s13205-020-02213-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182646PMC
May 2020

Synthesis and Antimicrobial Evaluation of Side-Chain Derivatives based on Eurotiumide A.

Mar Drugs 2020 Jan 30;18(2). Epub 2020 Jan 30.

Graduate School of Pharmaceutical Sciences and Research Cluster on "Innovative Chemical Sensing", Tokushima University, 1-78-1 Shomachi, Tokushima 770-8505, Japan.

Side-chain derivatives of eurotiumide A, a dihydroisochroman-type natural product, have been synthesized and their antimicrobial activities described. Sixteen derivatives were synthesized from a key intermediate of the total synthesis of eurotiumide A, and their antimicrobial activities against two Gram-positive bacteria, methicillin-susceptible and methicillin-resistant (MSSA and MRSA), and a Gram-negative bacterium, , were evaluated. The results showed that derivatives having an iodine atom on their aromatic ring instead of the prenyl moiety displayed better antimicrobial activity than eurotiumide A against MSSA and . Moreover, we discovered that a derivative with an isopentyl side chain, which is a hydrogenated product of eurotiumide A, is the strongest antimicrobial agent against all three strains, including MRSA.
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http://dx.doi.org/10.3390/md18020092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074549PMC
January 2020

Endoscopic removal of foreign bodies: A retrospective study in Japan.

World J Gastrointest Endosc 2020 Jan;12(1):33-41

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.

Background: The ingestion of foreign bodies (FBs) and food bolus impaction (FBI) in the digestive tract are commonly encountered clinical problems. Methods to handle such problems continue to evolve offering advantages, such as the avoidance of surgery, reduced cost, improved visualization, reduced morbidity, and high removal success rate. However, to date, no studies have evaluated the endoscopic management of FBs in Japan.

Aim: To elucidate level of safety and efficacy in the endoscopic management of FBs and FBI.

Methods: A total of 215 procedures were performed at Keio University Hospital between November 2007 and August 2018. Data were collected from medical charts, and endoscopic details were collected from an endoscopic reporting system. Procedures performed with a flexible gastrointestinal endoscope were only taken into account. Patients who underwent a technique involving FB or FBI from the digestive tract were only included. Data on patient sex, patient age, outpatient, inpatient, FB type, FB location, procedure time, procedure type, removal device type, success, and technical complications were reviewed and analyzed retrospectively.

Results: Among the 215 procedures, 136 (63.3%) were performed in old adults (≥ 60 years), 180 (83.7%) procedures were performed in outpatients. The most common type of FBs were press-through-pack (PTP) medications [72 (33.5%) cases], FBI [47 (21.9%)], Anisakis parasite (AP) [41 (19.1%) cases]. Most FBs were located in the esophagus [130 (60.5%) cases] followed by the stomach [68 (31.6%) cases]. AP was commonly found in the stomach [39 (57.4%) cases], and it was removed using biopsy forceps in 97.5% of the cases. The most common FBs according to anatomical location were PTP medications (40%) and dental prostheses (DP) (40%) in the laryngopharynx, PTP (48.5%) in the esophagus, AP (57.4%) in the stomach, DP (37.5%) in the small intestine and video capsule endoscopy device (75%) in the colon. A transparent cap with grasping forceps was the most commonly used device [82 (38.1%) cases]. The success rate of the procedure was 100%, and complication were observed in only one case (0.5%).

Conclusion: Endoscopic management of FBs and FBI in our Hospital is extremely safe and effective.
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http://dx.doi.org/10.4253/wjge.v12.i1.33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939123PMC
January 2020

Feasibility of endoscopic submucosal dissection for colorectal neoplasia at anastomotic sites: a retrospective study.

Surg Endosc 2020 12 13;34(12):5495-5500. Epub 2020 Jan 13.

Division of Research and Development for Minimally Invasive Treatment, Cancer Center, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Background: Metachronous colorectal lesions sometimes occur at anastomotic sites following colorectal surgery, which increases the risk of developing colorectal cancer. However, these lesions are difficult to treat even with minimally invasive methods such as endoscopic submucosal dissection (ESD). Thus, we aimed to evaluate the outcomes of ESD for colorectal lesions at anastomotic sites following colorectal surgery.

Methods: We retrospectively investigated 11 patients with post-surgical colorectal lesions at anastomotic sites who later underwent ESD from May 2010 to April 2019 at Keio University Hospital, Tokyo, Japan. We examined the patients' background (tumor location, macroscopic type, tumor size, histological type, and depth of invasion) and treatment outcomes (procedure duration, en bloc resection rate, R0 resection rate, and adverse events).

Results: The patients' mean age was 66 years. There were two lesions in the transverse colon, six in the rectum, one in the anal canal, and two in the ileal pouch. The median tumor size was 25 mm. The macroscopic types were the protruded type (1 lesion) and the flat or depressed type (10 lesions). The pathological diagnoses were adenoma (4 lesions), intramucosal cancer (corresponding to high-grade dysplasia) (6 lesions), and muscularis propria cancer (1 lesion). The median procedure duration was 50 min; en bloc resection rate was 88.9% and R0 resection rate was 66.7%. The only adverse event was delayed post-ESD bleeding.

Conclusions: A high en bloc resection rate without perforation was achieved with ESD for lesions at anastomotic sites. Although ESD for lesions at anastomotic sites is a technically challenging procedure because of severe submucosal fibrosis, this approach could prevent the need for repeated surgical resection.
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http://dx.doi.org/10.1007/s00464-019-07346-0DOI Listing
December 2020

Endoscopic suturing promotes healing of mucosal defects after gastric endoscopic submucosal dissection: endoscopic and histologic analyses in in vivo porcine models (with video).

Gastrointest Endosc 2020 05 3;91(5):1172-1182. Epub 2020 Jan 3.

Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University, School of Medicine, Tokyo.

Background And Aims: Endoscopic suturing of mucosal defects after endoscopic submucosal dissection (ESD) is expected to prevent postoperative adverse events. We aimed to endoscopically and histologically evaluate the healing process of post-ESD mucosal defects closed with endoscopic hand suturing (EHS) in in vivo porcine models.

Methods: Twelve mucosal defects (2 cm in size) were created in 2 pigs (6 defects per pig). Initially, 2 defects were created: one was closed with EHS (sutured group) and the other was kept open (control group). On postoperative days (PODs) 7 and 14, 2 additional defects were created in each session, and they were treated in the same manner as in the initial procedure. On POD 21, the entire stomach, with the 6 lesion sites, was extracted for histologic evaluation after endoscopic observation.

Results: Endoscopically, all sutured sites remained closed in all sessions (PODs 7, 14, and 21). Histologically, on POD 14, the epithelium and muscularis mucosae were appropriately connected. The mucosae were covered with the epithelium without inversion of the mucosal edge in the sutured group, whereas the ulcer bed was exposed in the control group. Furthermore, the degree of neovascularity and fibroblasts in the submucosa was smaller in the sutured group than that in the control group.

Conclusions: Our findings suggest that endoscopic suturing promotes healing of post-ESD mucosal defects histologically in in vivo porcine models. Thus, endoscopic mucosal closure after ESD might be clinically useful for the prevention of delayed perforation/bleeding if secure suturing is performed endoscopically.
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http://dx.doi.org/10.1016/j.gie.2019.12.032DOI Listing
May 2020

[Diversity-oriented Symposium: Diversity Experiences through Study Abroad].

Yakugaku Zasshi 2020 ;140(1):23-24

Graduate School of Pharmaceutical Sciences, Tokushima University.

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http://dx.doi.org/10.1248/yakushi.19-00186-FDOI Listing
August 2020

Predictors of technical difficulty with duodenal ESD.

Endosc Int Open 2019 Dec 10;7(12):E1755-E1760. Epub 2019 Dec 10.

Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Tokyo, Japan.

 Duodenal endoscopic submucosal dissection (ESD) is still considered technically challenging; however, few studies have objectively analyzed predictors of the technical difficulty. Therefore, the aim of the current study was to elucidate predictors of the technical difficulty of duodenal ESD.  This was a retrospective observational study. From June 2010 to June 2017, a total of 174 consecutive patients with superficial duodenal epithelial neoplasia who underwent ESD were included in this study. We tried to identify predictors for technical difficulty of ESD by defining technical difficulty as either procedure time > 100 minutes or intraprocedural perforation. Moreover, we constructed a scoring system consisting of factors that were significant in the multivariate analysis.  The proportion of patients with technical difficulty was 34.5 %. In the multivariate analysis, lesion location in flexural part [odds ratio (OR), 2.61; 95 % confidence interval (CI), 1.02 - 6.68], larger lesion size (> 40 mm) (OR, 5.26; 95% CI, 2.15 - 12.9), and occupied circumference > 50 % of the duodenum (OR, 5.80; 95 % CI, 1.83 - 18.4) were associated with technical difficulty.  A lesion location in flexural part, lesion size >40 mm and occupied circumference > 50 % were risk factors for technical difficulty of duodenal ESD.
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http://dx.doi.org/10.1055/a-0967-4744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904240PMC
December 2019

Nasometric Scores in spinal and bulbar muscular atrophy - Effects of palatal lift prosthesis on dysarthria and dysphagia.

J Neurol Sci 2019 Dec 15;407:116503. Epub 2019 Oct 15.

Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Electronic address:

Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disease affecting only males characterized by progressive muscular atrophy and weakness in bulbar and limb muscles. The present study aimed to evaluate the features of velopharyngeal dysfunction (VPD) in SBMA subjects by an acoustic analysis of speech. Twenty-three genetically confirmed patients with SBMA were enrolled and assessed their speech by measuring the nasalance score with a Nasometer II. The nasalance scores of the SBMA group was higher than that of healthy controls (p = .035) and significantly correlated with the total score of the revised amyotrophic lateral sclerosis functional rating scale (rs = -0.520, p = .011). On the basis of the results of the VPD study, the efficacy of a palatal lift prosthesis (PLP) was assessed in two patients with SBMA to treat their VPD. The PLP improved dysarthria in both cases, although the impact of the prosthesis on dysphagia was not consistent. The present study suggested that the nasalance score is a useful quantitative measurement to evaluate VPD in patients with SBMA. A PLP may improve dysarthria in SBMA patients by reducing VPD, but the clinical application of this procedure should be considered carefully in view of its possible negative effect on dysphagia.
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http://dx.doi.org/10.1016/j.jns.2019.116503DOI Listing
December 2019

Management of perforation related to endoscopic submucosal dissection for superficial duodenal epithelial tumors.

Gastrointest Endosc 2020 05 26;91(5):1129-1137. Epub 2019 Sep 26.

Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Tokyo, Japan.

Background And Aims: Endoscopic submucosal dissection (ESD) is being performed more frequently as a local treatment for superficial duodenal epithelial tumors (SDETs). However, ESD for SDETs is technically difficult because of specific anatomic features that increase the risk of perforation and often require surgery. This study was performed to evaluate the management of ESD-related perforation in patients with SDETs.

Methods: Patients who underwent ESD for SDETs from July 2010 to December 2018 were studied. We collected data on complete closure, insertion of endoscopic nasobiliary and pancreatic duct drainage (ENBPD) tubes, and additional interventions. We also evaluated clinical outcomes, including the fasting period, hospital stay, and maximum serum C-reactive protein level.

Results: ESD was completed in 264 patients with SDETs. Perforation was observed in 36 patients, including 4 patients with delayed perforation. Among 32 patients with intraoperative perforation, complete closure was achieved in 13 patients. Compared with patients without complete closure, the fasting period and hospital stay were significantly shorter and the maximum serum C-reactive protein level was significantly lower in patients with complete closure, which were equivalent to those in patients without perforation. In patients without complete closure for mucosal defect, no additional interventions were required when an ENBPD tube was inserted, whereas 2 patients without ENBPD tube insertion underwent additional interventions such as percutaneous drainage and a surgical operation.

Conclusions: Perforation associated with ESD for SDETs required complex conservative management with complete closure or insertion of an ENBPD tube.
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http://dx.doi.org/10.1016/j.gie.2019.09.024DOI Listing
May 2020

How I do it: Endoscopic diagnosis for superficial non-ampullary duodenal epithelial tumors.

Dig Endosc 2020 Mar 31;32(3):417-424. Epub 2019 Oct 31.

Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Tokyo, Japan.

There are no reports on detailed endoscopic diagnosis of superficial non-ampullary duodenal epithelial tumors (SNADET) except for relatively small case series. Herein, we conducted a prospective observational study to investigate the relationship between endoscopic findings and histopathological diagnosis of SNADET. A total of 163 SNADET diagnosed using magnified endoscopic examination with image-enhanced endoscopy (IEE-ME) were prospectively registered in this study. We investigated location, size, macroscopic type, color, and IEE-ME findings including surface structure (closed- or open-loop) and presence of white opaque substance (WOS) in SNADET. We analyzed association between these findings and histopathological diagnosis of SNADET based on the Vienna classification (VCL) using logistic regression analysis. In univariate analysis, lesion size, superficial structure, and WOS deposition showed statistical significance, and the oral side of the lesion location showed statistical tendency for association with VCL C4/5. In multivariate analysis, lesion size (odds ratio [OR], 2.92; 95% CI, 1.94-4.39; P < 0.05) and negative WOS (OR, 5.59; 95% CI, 1.72-18.1; P < 0.05) were significantly associated with VCL C4/5 lesions. Superficial structures with a closed-loop pattern on the surface showed statistical tendency for predicting VCL C4/5 lesions (OR, 2.15; 95% CI, 0.86-5.37; P = 0.10). Based on these findings, we concluded that negative WOS by IEE-ME and lesion size were independent predictors of VCL C4/5 SNADET. These factors may help us to understand of pathophysiology of SNADET and to select appropriate therapeutic strategies.
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http://dx.doi.org/10.1111/den.13538DOI Listing
March 2020

Feasibility study comparing underwater endoscopic mucosal resection and conventional endoscopic mucosal resection for superficial non-ampullary duodenal epithelial tumor < 20 mm.

Dig Endosc 2020 Jul 31;32(5):753-760. Epub 2019 Oct 31.

Division of Research and Development for Minimally Invasive Treatment, Cancer Center, Keio University School of Medicine, Tokyo, Japan.

Background And Aim: Underwater endoscopic mucosal resection (UEMR) has been reported as an alternative to conventional EMR for superficial non-ampullary duodenal epithelial tumors (SNADET). However, the detailed outcomes are unclear. This study aimed to compare the clinical outcomes between UEMR and EMR for SNADET <20 mm.

Patients And Methods: This is a retrospective observational study using a prospective maintained database. From November 2017 to December 2018, 104 consecutive cases of attempted UEMR for SNADET <20 mm were prospectively allocated. A total of 240 cases of attempted EMR were chosen as historical controls. We compared technical success rate, defined as the resection rate without conversion to ESD; en bloc resection rate; R0 resection rate; and adverse event rate. Next, multivariate analyses were constructed to identify predictors of conversion to ESD, piecemeal resection, and RX or R1 (RX/R1) resection.

Results: Technical success rate of UEMR was significantly higher than that of EMR (87% and 70%, P < 0.01). En bloc resection and R0 resection rates of UEMR were significantly lower than those of EMR (en bloc resection: 87% vs 96%, P < 0.01; R0 resection: 67% vs 80%, P = 0.05). Concerning adverse events, there were no significant differences. In multivariate analyses, attempted EMR, lesion size and depressed type were independent predictors of conversion to ESD. Attempted UEMR was an independent predictor of piecemeal resection and RX/R1 resection.

Conclusion: The present study indicated that UEMR could be a feasible endoscopic resection method for SNADET (UMIN000025442).
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http://dx.doi.org/10.1111/den.13524DOI Listing
July 2020

Asymmetric Total Syntheses and Structure Elucidations of (+)-Eurotiumide F and (+)-Eurotiumide G.

Chem Pharm Bull (Tokyo) 2019 ;67(9):953-958

Graduate School of Pharmaceutical Sciences, Tokushima University.

Asymmetric total syntheses of dihydropyran containing natural products, (+)-eurotiumide F and (+)-eurotiumide G have been described. These total syntheses revealed the absolute configuration of eurotiumide F and G, and confirmed the reported structure of eurotiumide F and revised the reported structure of eurotiumide G. Highlight of these syntheses is thermal rearrangement with 4-methoxyisochroman-1-one derivative having propargyl ether on phenolic ether under thermal condition to construct dihydropyran ring. X-Ray crystallographic analysis of (+)-eurotiumide G clarified the stereochemistry at the C1-position.
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http://dx.doi.org/10.1248/cpb.c18-00948DOI Listing
October 2019

What echocardiographic indices are predictive of patent ductus arteriosus surgical closure in early preterm infants? A prospective multicenter cohort study.

J Cardiol 2019 Dec 27;74(6):512-518. Epub 2019 Jun 27.

Saitama Medical Center, Saitama Medical University, Kawagoe, Japan. Electronic address:

Background: No echocardiographic indices for predicting the need for preterm patent ductus arteriosus (PDA) surgery have been tested with an adequate sample size. We tested the hypothesis that some echocardiographic indices have better predictive ability for the need for PDA surgery.

Methods: We prospectively collected data from infants with gestational ages between 23 and 29 weeks at 34 Japanese neonatal intensive care units over 14 months. Data points were 1, 3, 7, and 14 days of age and, if applicable, before PDA surgery. We assessed five echocardiographic indices. Volume and dimension indices were adjusted for birth body weight (BBW). For each echocardiographic index, the worst value among all data points in nonsurgical patients or the value just before surgery in surgical patients was used. Multivariate logistic regression was applied with adjustment for clinical status.

Results: In total, 691 patients were analyzed, of whom 61 (8.8%) underwent surgery, as guided using the criteria in the protocol. The areas under the receiver-operating characteristic curve for PDA diameter (0.86) and PDA diameter/BBW (0.86) were the largest, followed by those of left pulmonary artery end-diastolic velocity (LPAedv) (0.80), and left atrial volume/BBW (0.80).

Conclusions: Considering the measurement's easiness and independence of body size, PDA diameter and LPAedv may serve as useful indices for assessing the need for PDA surgery in early preterm infants.
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http://dx.doi.org/10.1016/j.jjcc.2019.05.004DOI Listing
December 2019

CT evaluation of extranodal extension of cervical lymph node metastases in patients with oral squamous cell carcinoma using deep learning classification.

Oral Radiol 2020 04 13;36(2):148-155. Epub 2019 Jun 13.

Department of Oral and Maxillofacial Radiology, Aichi-Gakuin University School of Dentistry, 2-11 Suemori-dori, Chikusa-ku, Nagoya, 464-8651, Japan.

Objective: To clarify CT diagnostic performance in extranodal extension of cervical lymph node metastases using deep learning classification.

Methods: Seven-hundred and three CT images (178 with and 525 without extranodal extension) in 51 patients with cervical lymph node metastases from oral squamous cell carcinoma were enrolled in this study. CT images were cropped to an arbitrary size to include lymph nodes and surrounding tissues. All images were automatically divided into two datasets, assigning 80% as the training dataset and 20% as the testing dataset. The automated selection was repeated five times. Each training dataset was imported to a deep learning training system "DIGITS". Five learning models were created after 300 epochs of the learning process using a neural network "AlexNet". Each testing dataset was applied to each created learning model and resulting five performances were averaged as estimated diagnostic performances. A radiologist measured the minor axis and three radiologists evaluated central necrosis and irregular borders of each lymph node, and the diagnostic performances were obtained.

Results: The deep learning accuracy of extranodal extension was 84.0%. The radiologists' accuracies based on minor axis ≥ 11 mm, central necrosis, and irregular borders were 55.7%, 51.1% and 62.6%, respectively.

Conclusions: The deep learning diagnostic performance in extranodal extension was significantly higher than that of radiologists. This method is expected to improve diagnostic accuracy by further study with increasing the number of patients.
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http://dx.doi.org/10.1007/s11282-019-00391-4DOI Listing
April 2020
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