Publications by authors named "Hidekazu Suzuki"

523 Publications

A Questionnaire-Based Survey on the Impact of the COVID-19 Pandemic on Gastrointestinal Endoscopy in Asia.

Digestion 2021 Nov 10:1-15. Epub 2021 Nov 10.

Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Japan.

Introduction: The COVID-19 outbreak abruptly restricted gastrointestinal (GI) endoscopy services during the first wave of the pandemic. We aimed to assess the impact of COVID-19 on the practice of GI endoscopy in Asian countries.

Methods: This was an International Questionnaire-based Internet Survey conducted at multiple facilities by the International Gastrointestinal Consensus Symposium. A total of 166 respondents in Japan, China, Hong Kong, South Korea, Philippines, Thailand, Indonesia, and Singapore participated in this study.

Results: The volume of endoscopic screening or follow-up endoscopies and therapeutic endoscopies were markedly reduced during the first wave of the pandemic, which was mainly attributed to the decreased number of outpatients, cancellations by patients, and adherence to the guidelines of academic societies. The most common indications for GI endoscopy during the first wave were GI bleeding, cholangitis or obstructive jaundice, and a highly suspicious case of neoplasia. The most common GI symptoms of COVID-19 patients during the infected period included diarrhea, nausea, and vomiting. The pandemic exacerbated some GI diseases, such as functional dyspepsia and irritable bowel syndrome. There were cases with delayed diagnosis of cancers due to postponed endoscopic procedures, and the prescription of proton pump inhibitors/potassium-competitive acid blockers, steroids, immunosuppressive agents, and biologics was delayed or canceled. The personal protective equipment used during endoscopic procedures for high-risk patients were disposable gloves, disposable gowns, N95 or equivalent masks, and face shields. However, the devices on the patient side during endoscopic procedures included modified surgical masks, mouthpieces with filters, and disposable vinyl boxes or aerosol boxes covering the head. Furthermore, the time for education, basic research, clinical research, and daily clinical practice decreased during the first wave.

Conclusion: This study demonstrated that the COVID-19 pandemic profoundly affected the method of performing GI endoscopy and medical treatment for patients with GI diseases in Asian countries.
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http://dx.doi.org/10.1159/000520287DOI Listing
November 2021

Osimertinib as first-line treatment for advanced epidermal growth factor receptor mutation-positive non-small-cell lung cancer in a real-world setting (OSI-FACT).

Eur J Cancer 2021 Nov 5;159:144-153. Epub 2021 Nov 5.

Department of Respiratory Medicine, Kumamoto University Hospital, 1-1-1 Honjo, Chuo-ku, Kumamoto, Kumamoto 860-8556, Japan.

Background: Osimertinib is the standard of care in the initial treatment for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer. However, clinical data and reliable prognostic biomarkers are insufficient.

Methods: We performed a retrospective multicentre cohort study for 538 EGFR mutation-positive patients, who received osimertinib as the initial treatment between August 2018 and December 2019. The main outcome was progression-free survival (PFS).

Results: The median observation period was 14.7 months (interquartile range 11.4-20.0). The median PFS was 20.5 months (95% confidence interval [CI] 18.6-not reached). Multivariate analysis showed that sex (male) (hazard ratio [HR] 1.99, 95% CI 1.35-2.93, P = 0.001), malignant effusions (HR 1.51, 95% CI 1.11-2.04, P = 0.008), liver metastasis (HR 1.55, 95% CI 1.03-2.33, P = 0.037), advanced unresectable cases (HR 1.71, 95% CI, 1.04-2.82, P = 0.036), mutation type and programmed cell death-ligand 1 (PD-L1) expression were associated with PFS. The L858R (HR 1.55, 95% CI 1.01-2.38, P = 0.043) and uncommon mutations (HR 3.15, 95% CI 1.70-5.83, P < 0.001) were associated with PFS. PD-L1 expression of 1-49% (HR 1.66, 95% CI 1.05-2.63, P = 0.029), ≥50% (HR 2.24, 95% CI 1.17-4.30, P = 0.015) and unknown (HR 1.53, 95% CI 1.05-2.22, P = 0.026) was associated with PFS. The main reasons for treatment discontinuation among 219 patients were disease progression (44.3%), pneumonitis (25.5%) and other adverse events (16.0%).

Conclusion: During initial treatment with osimertinib, PD-L1 expression is significantly related to PFS. Adverse events are a noteworthy reason for discontinuation.
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http://dx.doi.org/10.1016/j.ejca.2021.09.041DOI Listing
November 2021

A potential pathogenic association between periodontal disease and Crohn's disease.

JCI Insight 2021 Oct 28. Epub 2021 Oct 28.

Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America.

Oral conditions are relatively common in patients with inflammatory bowel disease (IBD). However, the contribution of oral maladies to gut inflammation remains unexplored. Here, we investigated the impact of periodontitis on disease phenotypes of IBD patients. In all, 60 IBD patients (42 with ulcerative colitis [UC] and 18 with Crohn's disease [CD]) and 45 non-IBD healthy controls (HCs) were recruited for this clinical investigation. The effects of incipient periodontitis on the oral and gut microbiome, IBD characteristics were examined. In addition, patients were prospectively monitored up to 12 months after enrollment. We found that in both UC and CD patients, the gut microbiome was significantly more similar to the oral microbiome than in HCs, suggesting that ectopic gut colonization by oral bacteria is increased in IBD patients. Incipient periodontitis did not further enhance gut colonization by oral bacteria. The presence of incipient periodontitis did not significantly affect the clinical outcomes of UC and CD patients. However, the short Crohn's disease activity index increased in CD patients with incipient periodontitis but declined or unchanged during the study period in patients without periodontitis. Thus, early periodontitis may associate with worse clinically symptoms in some patients with CD.
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http://dx.doi.org/10.1172/jci.insight.148543DOI Listing
October 2021

Decreased anti-parietal cell antibody titer in the advanced phase of autoimmune gastritis.

Scand J Gastroenterol 2021 Oct 25:1-6. Epub 2021 Oct 25.

Gastroenterology, Toyoshima Endoscopy Clinic, Tokyo, Japan.

Background: Autoimmune gastritis (AIG) is histologically classified into three phases according to the severity of oxyntic mucosal atrophy: early, florid, and end phases. This study aimed to clarify the relationship between the AIG phase and the anti-parietal cell antibody titer.

Methods: Patients who underwent upper gastrointestinal endoscopy were retrospectively reviewed in this study. We enrolled patients who were histologically diagnosed with AIG and serologically tested for anti-parietal cell antibody (APCA). AIG patients were classified into three groups: early, florid, and end phase groups. Clinical characteristics, including APCA titers, were compared among these three groups.

Results: A total of 44 AIG patients were enrolled. There were two patients in the early phase, 11 in the florid phase, and 31 in the end phase. APCA-positive rates were 100% in the early phase, 90.9% in the florid phase, and 90.3% in the end phase. The mean APCA titer was 480 U in the early phase, 220 U in the florid phase, and 150 U in the end phase. There was a stepwise decrease in the APCA titer from the early phase to the end phase. The mean APCA titer for the end phase was significantly lower than that of the early phase or florid phase. Additionally, there was a stepwise decrease in serum gastrin levels from the early phase to the end phase.

Conclusion: AIG progresses from the early phase to the end phase, and the APCA titer shows a decrease. The negativity of APCA could occur, especially in the end phase.
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http://dx.doi.org/10.1080/00365521.2021.1994642DOI Listing
October 2021

Is active exercise effective in preventing metachronous advanced colorectal neoplasm after polypectomy?

Authors:
Hidekazu Suzuki

Dig Endosc 2021 Oct 15. Epub 2021 Oct 15.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan.

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http://dx.doi.org/10.1111/den.14161DOI Listing
October 2021

Whole-genome copy number and immunohistochemical analyses on surgically resected intracholecystic papillary neoplasms.

Pathol Int 2021 Oct 13. Epub 2021 Oct 13.

Department of Pathology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.

Intracholecystic papillary neoplasms are newly defined precancerous lesions. According to Classification of the World Health Organization, they have four histological morphologies, which are biliary, gastric, intestinal, and oncocytic. This study evaluated 17 patients with resected intracholecystic papillary neoplasms in terms of histological, immunohistochemical, and copy number variation (CNV). The histological subtypes included 5 cases of low-grade (5 gastric) and 12 cases of high-grade (6 gastric and 6 biliary) neoplasms. Most cases showed high expression of MUC1, MUC5AC, and CK7, moderate expression of MUC6 and Ki-67, and low expression of CK20, MUC2, and CDX2. The CNV profile identified gain of 7q in 12%, and loss of 1p (18%), 5q (29%), 9p (35%), 12p (17%), 17p (24%), and 19p (18%). No CNVs were observed in low-grade neoplasms, whereas high-grade ones had increasing abnormalities. β-catenin was often expressed in the nucleus of neoplasms with gastric morphology, suggesting the involvement of the Wnt/β-catenin pathway. However, it was not expressed among those with biliary morphology, which instead exhibited high p53 expression. Neoplasms with biliary morphology showed more CNV changes (9p, 17p, 19p losses). Distinct immunological and CNV patterns were seen in both morphologies, suggesting differences in their pathogenesis. More CNVs accumulated with tumor progression.
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http://dx.doi.org/10.1111/pin.13177DOI Listing
October 2021

Efficacy and safety of ramucirumab plus docetaxel in older patients with advanced non-small cell lung cancer: A multicenter retrospective cohort study.

J Geriatr Oncol 2021 Sep 30. Epub 2021 Sep 30.

Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, 1180 Nagasone-cho, Kita-Ku, Sakai City, Osaka 591-8555, Japan.

Objective: Ramucirumab (RAM) plus Docetaxel (DOC) is one of the standard treatments after first-line treatment failure in patients with advanced non-small cell lung cancer (NSCLC). However, little is known about the efficacy and safety of RAM plus DOC in older patients. We aimed to clarify these and elucidate the prognostic factors.

Materials And Methods: In this multicenter retrospective study, conducted at four medical facilities in Japan, we evaluated the efficacy and safety data for two groups (<65 and ≥ 65 years). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and log-rank test. Multivariate analysis was performed to reveal the prognostic factors for better PFS and OS. Patient characteristics and adverse events (AEs) in both groups were compared using the Mann-Whitney's U and Fisher's exact tests for categorical variables.

Results: A total of 237 patients were included, of whom 43% (n = 103), and 57% (n = 134) were aged <65, and ≥ 65 years. Median OS was 12.2 (95% CI: 9.4-15.0), and 14.8 months (95% CI: 10.8-18.8), respectively, and there were no significant differences between the groups (p = 0.534). Multivariate analysis identified DOC dose reduction (none vs performed, HR: 2.66, 95% CI: 1.62-4.35, p < 0.001) as an independent prognostic factor for OS in older patients, and a similar result was shown for the PFS. Grade ≥ 3 all AEs were identified in 42.7% and 56.7% of younger and older patients, respectively, and there was a significant difference between the groups (p = 0.033); however, the difference between the groups disappeared with primary DOC dose reduction (p = 0.526).

Conclusion: The efficacy of RAM plus DOC administration in older, pretreated patients with advanced NSCLC was comparable to those of younger patients, whereas RAM plus DOC should be cautiously administered to older patients because of severe toxicity. Moreover, appropriate DOC dose reduction may be recommended for increased survival benefit and safety in such patients.
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http://dx.doi.org/10.1016/j.jgo.2021.09.004DOI Listing
September 2021

Consistency between the endoscopic Kyoto classification and pathological updated Sydney system for gastritis: A cross-sectional study.

J Gastroenterol Hepatol 2021 Sep 27. Epub 2021 Sep 27.

Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Japan.

Background: Two methods are used to evaluate gastritis: the updated Sydney system (USS) with pathology and Kyoto classification, a new endoscopy-based diagnostic criterion for which evidence is accumulating. However, the consistency of their results is unclear. This study investigated the consistency of their results.

Methods: Patients who underwent esophagogastroduodenoscopy and were evaluated for Helicobacter pylori infection for the first time were eligible. The association between corpus and antral USS scores (neutrophil activity, chronic inflammation, atrophy, and intestinal metaplasia) and Kyoto classification scores (atrophy, intestinal metaplasia, enlarged folds, nodularity, and diffuse redness) was assessed.

Results: Seven-hundred-seventeen patients (mean age, 49.2 years; female sex, 57.9%; 450 H. pylori-positive and 267 H. pylori-negative patients) were enrolled. All endoscopic gastritis cases in the Kyoto classification were associated with high corpus and antral USS scores for neutrophil activity and chronic inflammation. A subanalysis was performed for H. pylori-positive patients. Regarding atrophy and intestinal metaplasia, endoscopic findings were associated with USS scores. Enlarged folds, nodularity, and diffuse redness were associated with high corpus USS scores for neutrophil activity and chronic inflammation, but with low antral USS scores for atrophy and intestinal metaplasia. The Kyoto classification scores were also associated with the pathological topographic distribution of neutrophil activity and intestinal metaplasia.

Conclusions: Among H. pylori-positive individuals, endoscopic and pathological diagnoses were consistent with atrophy and intestinal metaplasia. Enlarged folds, nodularity, and diffuse redness were associated with pathological inflammation (neutrophil activity and chronic inflammation) of the corpus; however, they were inversely associated with pathological atrophy and intestinal metaplasia. The endoscopy-based Kyoto classification of gastritis partially reflects pathology.
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http://dx.doi.org/10.1111/jgh.15693DOI Listing
September 2021

Experimental and translational research in gastrointestinal endoscopy, the Japan Gastroenterological Endoscopy Society and perspective.

Dig Endosc 2021 Sep 24. Epub 2021 Sep 24.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan.

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http://dx.doi.org/10.1111/den.14129DOI Listing
September 2021

Real-world survey of pneumonitis and its impact on durvalumab consolidation therapy in patients with non-small cell lung cancer who received chemoradiotherapy after durvalumab approval (HOPE-005/CRIMSON).

Lung Cancer 2021 11 5;161:86-93. Epub 2021 Sep 5.

Department of Radiation Oncology, Kobe City Medical Center General Hospital, Hyogo, Japan.

Objectives: The incidence of real-world pneumonitis and durvalumab rechallenge during chemoradiotherapy and durvalumab consolidation for non-small cell lung cancer is unknown.

Materials And Methods: We retrospectively evaluated the medical records of 302 consecutive patients diagnosed with non-small cell lung cancer who started chemoradiotherapy between May 2018 and May 2019.

Results: Median age was 70 (range: 40-87) years. Volume of lung parenchyma that received 20 Gy (V20) exceeded 35% in 2% and mean lung dose exceeded 20 Gy in 1% of patients. Durvalumab consolidation was delivered to 225 patients (75%). Overall, 83% (n = 251), 34% (n = 103), 7% (n = 21), and 1% (n = 4) of the patients developed any grade of pneumonitis, symptomatic pneumonitis, ≥grade 3 pneumonitis, and fatal (grade 5) pneumonitis, respectively. Corticosteroids were administered to 25% of the patients to treat pneumonitis. Multivariate analysis identified the predictive factors for the development of symptomatic pneumonitis: V20 Gy or more ≥ 25% (odds ratio [OR]: 2.37, P = 0.008) and mean lung dose (MLD) ≥ 10 Gy (OR: 1.93, P < 0.0047). Of the 52 patients who received corticosteroids for pneumonitis after durvalumab initiation, 21 were rechallenged with durvalumab. Overall, 81% of patients met the PACIFIC study's rechallenge criteria and did not experience a severe pneumonitis relapse.

Conclusion: High V20 and MLD were independent risk factors of symptomatic pneumonitis. More than 80% of the patients who were rechallenged with durvalumab after pneumonitis met the PACIFIC study's rechallenge criteria. Consequently, severe relapse did not occur. Cooperation between radiation and medical oncologists is important for safe chemoradiotherapy and the safe completion of durvalumab consolidation therapy.
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http://dx.doi.org/10.1016/j.lungcan.2021.08.019DOI Listing
November 2021

Long-term cumulative incidence of metachronous advanced colorectal neoplasia after colonoscopy and a novel risk factor: a cohort study.

Eur J Gastroenterol Hepatol 2021 11;33(11):1341-1347

Gastroenterology Division, St. Luke's International University.

Background And Aim: Long-term cumulative incidence of and risk factors for metachronous advanced colorectal neoplasia, including both advanced colorectal adenoma (≥10 mm, or with villous or high-grade dysplasia) and colorectal cancer, are critical for surveillance strategies. The aim of this study was to determine the cumulative incidence of metachronous advanced colorectal neoplasia and its risk factors.

Methods: A retrospective cohort study was conducted on 6720 consecutive individuals who underwent general health check-ups and colonoscopy. Colorectal adenomas at initial colonoscopy were categorized as low-risk (1-2 small [<10 mm] tubular adenomas) or high-risk adenoma (≥3 tubular adenomas of any size; at least one adenoma ≥10 mm; or villous adenoma or adenoma with high-grade dysplasia). Kaplan-Meier estimates and hazard ratio by Cox-proportional hazard regression were calculated.

Results: The cumulative incidence (95% confidence interval [CI]) of metachronous advanced colorectal neoplasia at 5 and 10 years was 5.7% [4.6-7.1], and 11% [8.9-14] in the low-risk adenoma group, and 10% [8.6-13], and 17% [14-21] in high-risk adenoma group, respectively. Adjusted hazard ratio [95% CI] of low-risk adenoma (vs. no colorectal adenoma), high-risk adenoma (vs. no colorectal adenoma), current smoking and positive fecal immunochemical test were 1.34 [1.04-1.74], 1.94 [1.48-2.55], 1.55 [1.2-2.02] and 1.69 [1.35-2.1], respectively. Adjusted hazard ratio [95% CI] of positive fecal immunochemical test was 1.88 [1.29-2.74] in those with normal colonoscopy.

Conclusions: Both low-risk and high-risk adenomas confer substantial risk for metachronous advanced colorectal neoplasia at 10 years. Positive fecal immunochemical test was a significant risk factor for metachronous advanced colorectal neoplasia despite normal colonoscopy.
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http://dx.doi.org/10.1097/MEG.0000000000002259DOI Listing
November 2021

Intraoperative Endoscopy in Transient Adult Jejunojejunal Intussusception.

Case Rep Gastrointest Med 2021 12;2021:3718089. Epub 2021 Jul 12.

Department of Gastroenterology, St. Luke's International Hospital, 9-1 Akashicho, Chuo-ku, Tokyo 104-8560, Japan.

Despite improvements in imaging modalities, causative lead points in adult intussusception may be difficult to diagnose. Such lead points can be malignant, causing recurrence or metastases if left unresected. We describe a case of transient adult jejunojejunal intussusception, in which intraoperative endoscopy was used to confirm the absence of a lead point. A 39-year-old woman with a history of laparoscopic oophorectomy presented with epigastric pain, nausea, and vomiting. Contrast computed tomography revealed jejunojejunal intussusception, with no visible lead point. Spontaneous reduction was confirmed during exploratory laparoscopy. After lysis of adhesions, intraoperative peroral jejunoscopy was performed with the surgeons' assistance. Endoscopy confirmed the absence of tumor, and bowel resection was avoided. No recurrence has been observed during 24 months of follow-up. Intraoperative endoscopy may provide additional reassurance for the absence of a lead point in cases where preoperative enteroscopy cannot be performed and no lead points can be identified on imaging.
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http://dx.doi.org/10.1155/2021/3718089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289613PMC
July 2021

Quantification of image quality of intra-fractional cone-beam computed tomography for arc irradiation with various imaging condition.

Rep Pract Oncol Radiother 2021 9;26(3):495-501. Epub 2021 Jun 9.

Department of Radiology, University of Yamanashi, Yamanashi, Japan.

Background: 3-dimensional intra-cone beam computed tomography (intra-CBCT ) could be a potentially powerful tool for use with arc irradiation such as volumetric modulated arc therapy. The aim of the study was to evaluate the image quality of intra-cone beam computed tomography (intra-CBCT ) for arc irradiation with various imaging condition.

Materials And Methods: Two types of intra-CBCT imaging techniques were evaluated - intra-fractional CBCT with flattening filtered (FF) beam (intra-FF CBCT ) and that with flattening filter free (FFF) beam (intra-FFF CBCT ). For the intra-MV beams, four different field sizes (2 cm × 2 cm, 5 cm × 5 cm, 10 cm × 10 cm, and 20 cm × 20 cm) were used with dose rates of 500 MU/min and 1600 MU/min, for 6 MV FF and 6 MV FFF, respectively. For all image acquisitions, two rotation angles (full-arc and half-arc) were investigated. Thereafter, the linearity, contrast-to-noise ratio (CNR), and uniformity index (UI) of intra-CBCT image were compared with those of conventional CBCT image.

Results: All acquisition conditions had good linearity of the CT value (R > 0.99). For CNR, the change rates from conventional CBCT ranged from 0.6-33.7% for a 2 cm × 2 cm beam, whereas that for a 20 cm × 20 cm beam ranged from 62.7-82.3%. Similarly, the UI increased from 1.5% to 7.0% as the field size increased.

Conclusion: Quality of intra-CBCT image was affected by the field size and acquisition angle. Image quality of intra-CBCT was worse than that of conventional CBCT, but it was better under a smaller field and wider correction angle and would be acceptable for clinical use.
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http://dx.doi.org/10.5603/RPOR.a2021.0066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281903PMC
June 2021

Sitafloxacin for Third-Line Eradication: A Systematic Review.

J Clin Med 2021 Jun 20;10(12). Epub 2021 Jun 20.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Isehara 259-1193, Japan.

Background And Aim: Sitafloxacin-based therapy is a potent candidate for third-line eradication treatment. In this systematic review, we summarise current reports with sitafloxacin-based therapy as a third-line treatment.

Methods: Clinical studies were systematically searched using PubMed, Cochrane library, Web of Science, and the Igaku-Chuo-Zasshi database. We combined data from clinical studies using a random-effects model and calculated pooled event rates, 95% confidence intervals (CIs), and the pooled odds ratio (OR).

Results: We included twelve clinical studies in the present systematic review. The mean eradication rate for 7-day regimens of either PPI (proton pump inhibitor) or vonoprazan-sitafloxacin-amoxicillin was 80.6% (95% CI, 75.2-85.0). The vonoprazan-sitafloxacin-amoxicillin regimen was significantly superior to the PPI-sitafloxacin-amoxicillin regimen (pooled OR of successful eradication: 6.00; 95% CI: 2.25-15.98, < 0.001). The PPI-sitafloxacin-amoxicillin regimen was comparable with PPI-sitafloxacin-metronidazole regimens (pooled OR: 1.06; 95% CI: 0.55-2.07, = 0.86).

Conclusions: Although the 7-day regimen composed of vonoprazan, sitafloxacin, and amoxicillin is a good option as the third-line eradication treatment in Japan, the extension of treatment duration should be considered to further improve the eradication rate. Considering the safety concern of fluoroquinolones, sitafloxcin should be used after confirming drug susceptibility.
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http://dx.doi.org/10.3390/jcm10122722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234224PMC
June 2021

Clue of Diagnosis for Autoimmune Gastritis.

Digestion 2021 1;102(6):903-910. Epub 2021 Jul 1.

Gastroenterology, Toyoshima Endoscopy Clinic, Tokyo, Japan.

Background: The diagnostic clues for autoimmune gastritis (AIG) can be classified into 2 categories: endoscopic findings and pathological diagnosis. We believe that research on the AIG detection rate by endoscopists could provide a better understanding of the diagnosis of AIG. This study aimed to clarify the ratio of the endoscopic and the pathological diagnoses of AIG.

Methods: We retrospectively reviewed consecutive patients who underwent esophagogastroduodenoscopy (EGD). During their first EGD, the gastric mucosa with C2 atrophy or more was biopsied for pathological evaluation based on the updated Sydney system. A gastric biopsy was also performed after Helicobacter pylori eradication, obtaining specimens from at least 2 sites, the greater curvature of the corpus and the antrum. We enrolled patients who were positive for the anti-parietal cell antibody and were diagnosed with AIG, histologically and/or endoscopically. The detection rates of AIG were compared between endoscopic diagnosis and pathological diagnosis.

Results: A total of 10,822 patients underwent EGD during the study period. Finally, 41 patients with AIG were enrolled, leading to an AIG prevalence of 0.38% in this study. As for the clue leading to AIG detection, 31.7% (13/41) were diagnosed through endoscopy (proximal-predominant atrophy), and 68.3% (28/41) were diagnosed pathologically. The AIG detection rate by endoscopists in the posteradication group was significantly lower than in the H. pylori-negative group (p < 0.05).

Conclusion: Endoscopists frequently overlooked AIG, especially in posteradication cases. Pathological assessment using the updated Sydney system after H. pylori eradication might be a promising strategy to detect AIG better.
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http://dx.doi.org/10.1159/000516624DOI Listing
November 2021

Use of residual neural network for the detection of ossification of the posterior longitudinal ligament on plain cervical radiography.

Eur Spine J 2021 08 1;30(8):2185-2190. Epub 2021 Jul 1.

Tokyo Medical University, Tokyo, Japan.

Ossification of the posterior longitudinal ligament (OPLL) causes serious problems, such as myelopathy and acute spinal cord injury. The early and accurate diagnosis of OPLL would hence prevent the miserable prognoses. Plain lateral radiography is an essential method for the evaluation of OPLL. Therefore, minimizing the diagnostic errors of OPLL on radiography is crucial. Image identification based on a residual neural network (RNN) has been recognized to be potentially effective as a diagnostic strategy for orthopedic diseases; however, the accuracy of detecting OPLL using RNN has remained unclear. An RNN was trained with plain lateral cervical radiography images of 2,318 images from 672 patients (535 images from 304 patients with OPLL and 1,773 images from 368 patients of Negative). The accuracy, sensitivity, specificity, false positive rate, and false negative rate of diagnosis of the RNN were calculated. The mean accuracy, sensitivity, specificity, false positive rate, and false negative rate of the model were 98.9%, 97.0%, 99.4%, 2.2%, and 1.0%, respectively. The model achieved an overall area under the curve of 0.99 (95% confidence interval, 0.97-1.00) in which AUC in each fold estimated was 0.99, 0.99, 0.98, 0.98, and 0.99, respectively. An algorithm trained by an RNN could make binary classification of OPLL on cervical lateral X-ray images. RNN may hence be useful as a screening tool to assist physicians in identifying patients with OPLL in future setting. To achieve accurate identification of OPLL patients clinically, RNN has to be trained with other cause of myelopathy.
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http://dx.doi.org/10.1007/s00586-021-06914-0DOI Listing
August 2021

Comparison of endoscopic gastritis based on Kyoto classification between diffuse and intestinal gastric cancer.

World J Gastrointest Endosc 2021 May;13(5):125-136

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Background: Gastric cancers can be categorized into diffuse- and intestinal-type cancers based on the Lauren histopathological classification. These two subtypes show distinct differences in metastasis frequency, treatment application, and prognosis. Therefore, accurately assessing the Lauren classification before treatment is crucial. However, studies on the gastritis endoscopy-based Kyoto classification have recently shown that endoscopic diagnosis has improved.

Aim: To investigate patient characteristics including endoscopic gastritis associated with diffuse- and intestinal-type gastric cancers in ()-infected patients.

Methods: Patients who underwent esophagogastroduodenoscopy at the Toyoshima Endoscopy Clinic were enrolled. The Kyoto classification included atrophy, intestinal metaplasia, enlarged folds, nodularity, and diffuse redness. The effects of age, sex, and Kyoto classification score on gastric cancer according to the Lauren classification were analyzed. We developed the Lauren predictive background score based on the coefficients of a logistic regression model using variables independently associated with the Lauren classification. Area under the receiver operative characteristic curve and diagnostic accuracy of this score were examined.

Results: A total of 499 -infected patients (49.6% males; average age: 54.9 years) were enrolled; 132 patients with gastric cancer (39 diffuse- and 93 intestinal-type cancers) and 367 cancer-free controls were eligible. Gastric cancer was independently associated with age ≥ 65 years, high atrophy score, high intestinal metaplasia score, and low nodularity score when compared to the control. Factors independently associated with intestinal-type cancer were age ≥ 65 years (coefficient: 1.98), male sex (coefficient: 1.02), high intestinal metaplasia score (coefficient: 0.68), and low enlarged folds score (coefficient: -1.31) when compared to diffuse-type cancer. The Lauren predictive background score was defined as the sum of +2 (age ≥ 65 years), +1 (male sex), +1 (endoscopic intestinal metaplasia), and -1 (endoscopic enlarged folds) points. Area under the receiver operative characteristic curve of the Lauren predictive background score was 0.828 for predicting intestinal-type cancer. With a cut-off value of +2, the sensitivity, specificity, and accuracy of the Lauren predictive background score were 81.7%, 71.8%, and 78.8%, respectively.

Conclusion: Patient backgrounds, such as age, sex, endoscopic intestinal metaplasia, and endoscopic enlarged folds are useful for predicting the Lauren type of gastric cancer.
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http://dx.doi.org/10.4253/wjge.v13.i5.125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134854PMC
May 2021

Simultaneous gastric cancer and breast cancer metastases to the stomach with lymph node collision tumor: a case report.

BMC Gastroenterol 2021 May 25;21(1):240. Epub 2021 May 25.

Department of Gastroenterology, St. Luke's International Hospital, 9-1 Akashicho, Chuo-ku, Tokyo, 104-8560, Japan.

Background: While double primary cancers are common in breast cancer patients, co-existence of primary gastric cancer and gastric metastases of breast cancer is exceedingly rare.

Case Presentation: A 51-year-old woman receiving chemotherapy for breast cancer presented with melena and presyncope. A circumferential thickening of the pylorus and small submucosal tumor-like lesions in the gastric fundus and corpus were confirmed on endoscopy. Immunohistochemistry of biopsies revealed that the former was composed of poorly differentiated gastric cancer cells, while the latter were breast cancer metastases. Distal gastrectomy was performed. Pathological evaluation of the resected specimen revealed gastric adenocarcinoma in the pyloric lesion and breast countless cancer metastases throughout the remainder of the stomach, with positive margins. One lymph node had evidence of both stomach cancer and breast cancer metastases, forming a collision tumor. Despite a successful surgery, the patient died 6 months later due to progression of breast cancer.

Conclusion: We report a case of synchronous primary gastric adenocarcinoma and gastric metastases of breast cancer. Inter-disciplinary collaboration is crucial in determining the optimal treatment in double cancers.
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http://dx.doi.org/10.1186/s12876-021-01823-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146653PMC
May 2021

Scoring system for identifying Japanese patients with COVID-19 at risk of requiring oxygen supply: A retrospective single-center study.

J Infect Chemother 2021 Aug 11;27(8):1217-1222. Epub 2021 May 11.

Department of Infectious Diseases, Osaka Habikino Medical Center, Habikino, Osaka, 583-8588, Japan.

Introduction: Japan is facing the threat of medical system collapse due to the rapid spread of coronavirus disease 2019 (COVID-19). The present scoring system may help assess disease severity and oxygen supply requirements in COVID-19 patients.

Methods: Data on patient characteristics at baseline and throughout hospitalization for COVID-19 were extracted from medical records. Disease severity was dichotomized into two categories without or with oxygen supply as asymptomatic, mild, and moderate illness (AMMI), and severe and critical illness (CSI). The AMMI and CSI groups were compared. Predictors of disease severity, previously identified in the outpatient setting, were included in multivariable logistic regression analysis; the obtained coefficients were converted to integers and assigned a score.

Results: A total of 206 patients diagnosed with COVID-19 were included in this study. Correlation between COVID-19 severity and medical information was examined by comparing AMMI and CSI. Age, hemodialysis, and C-reactive protein (CRP) levels were candidate predictors of the need for oxygen supply in patients with COVID-19. Coefficients associated with age, hemodialysis, and CRP were as follows: 1 × age (in years, coded as 0 for values of <50, and as 1 for values of ≥50) + 1 × hemodialysis (coded as 0 for "no", and as 1 for "yes") + 1 × CRP (in mg/dL, coded as 0 for values of <1.0, and as 1 for values of ≥1.0). Patients with scores of ≥2 points required oxygen supply (sensitivity, 68.4%; specificity, 79.0%) CONCLUSION: The present model can help predict disease severity and oxygen requirements in COVID-19 patients in Japan.
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http://dx.doi.org/10.1016/j.jiac.2021.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112289PMC
August 2021

Impact of docetaxel plus ramucirumab on metastatic site in previously treated patients with non-small cell lung cancer: a multicenter retrospective study.

Transl Lung Cancer Res 2021 Apr;10(4):1642-1652

Department of Respiratory Medicine, Osaka Prefectural Medical Center for Respiratory and Allergic Disease, Osaka, Japan.

Background: Docetaxel (DOC) plus ramucirumab (RAM) has been recommended as an optimal therapy for previously treated patients with non-small cell lung cancer (NSCLC). In a clinical setting, there are few reports about DOC plus RAM, therefore its effect on factors such as Eastern Cooperative Oncology Group (ECOG) performance status (PS) and metastatic sites is still unknown.

Methods: We recruited NSCLC patients who received DOC plus RAM in four medical facilities in Japan from June 2016 to March 2020. We retrospectively investigated the overall response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) of DOC plus RAM and conducted univariate and multivariate analyses using PFS as a dependent factor. Patients were followed up until June 30, 2020.

Results: A total of 237 patients were consecutively enrolled. For all patients, the ORR, DCR, and median PFS were 25.2%, 63.9%, and 4.5 months, respectively. The ORR and DCR for malignant pleural effusion (MPE), lung metastasis, and liver metastasis were 7.7% and 53.8%, 30.3% and 77.5%, and 48.6% and 71.4%, respectively. In the multivariate analysis, MPE, lung metastasis, and liver metastasis were not prognostic factors for poor PFS. However, ECOG-PS 2 or more [hazard ratio (HR): 1.66, 95% confidence interval (CI): 1.14-2.40, P=0.008] and brain metastasis (HR: 1.71, 95% CI: 1.23-2.37, P=0.001) were significant and independent factors associated with shorter PFS.

Conclusions: DOC plus RAM could be an optimal therapy for previous treated NSCLC patients with lung and liver metastasis, and furthermore, should be used carefully for patients with poor ECOG-PS or brain metastasis.

Keywords: Docetaxel and ramucirumab; non-small cell lung cancer (NSCLC); metastatic site; poor performance status.
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http://dx.doi.org/10.21037/tlcr-20-1263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107751PMC
April 2021

The ratio of T790M to EGFR-activating mutation predicts response of osimertinib in 1st or 2nd generation EGFR-TKI-refractory NSCLC.

Sci Rep 2021 05 5;11(1):9629. Epub 2021 May 5.

Department of Thoracic Malignancy, Osaka Habikino Medical Center, Habikino 3-7-1, Habikino City, Osaka, 583-8588, Japan.

The most frequent mechanism of resistance after 1st/2nd-generation (G) epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is secondary point mutation Thr790Met (T790M) in EGFR. Afatinib followed by osimertinib (Afa group) may provide better outcomes for T790M-positive non-small cell lung cancer (NSCLC) than 1st-G EGFR-TKI followed by osimertinib (1st-G group). We studied 111 consecutive NSCLC patients with T790M mutation treated with osimertinib after progression following 1st/2nd-G EGFR-TKI between March 28, 2016 and March 31, 2018. We analyzed the ratio of T790M to EGFR-activating mutation (T790M ratio) in post EGFR-TKI resistance re-biopsy tissue using droplet digital polymerase chain reaction. And investigated whether afatinib purified the T790M mutation more than 1st-G EGFR-TKI. Among 60 patients with preserved re-biopsy tissue, we analyzed 38 having adequate DNA content. The response rate in Afa group was 81.8% (n = 11) and 1st-G group was 85.2% (n = 27). The mean T790M ratio in total population was 0.3643. The ratio in those with response to osimertinib was significantly higher than in the non-responders (0.395, 0.202; p = 0.0231) and was similar in Afa and 1st-G group (0.371, 0.362; p = 0.9693). T790M ratio significantly correlated with osimertinib response and was similar between the 1st/2nd-G EGFR-TKIs in 1st/2nd-G EGFR-TKI-refractory tumors.
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http://dx.doi.org/10.1038/s41598-021-89006-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099906PMC
May 2021

The impact of sagittal imbalance on walking in patients with lumbar spinal canal stenosis.

J Orthop Surg (Hong Kong) 2021 May-Aug;29(2):23094990211010522

Department of Orthopedic Surgery, 13112Tokyo Medical University, Tokyo, Japan.

Purpose: Gait and posture disorder severely impedes the quality of life of affected patients with lumbar spinal canal stenosis (LSCS). Despite the major health concern, there is a paucity of literature about the relationships among spatiotemporal gait parameters and spinal sagittal parameters. This is a cross sectional study performed in a single tertiary referral center to determine the relationships among spatiotemporal gait parameters and spinal sagittal parameters in patients with LSCS.

Methods: A total of 164 consecutive patients with LSCS, 87 men and 77 women with mean age of 70.7 years, were enrolled. Spatiotemporal gait parameters were studied using a gait analysis system. Spinal sagittal parameters were studied including sagittal vertical axis (SVA), thoracic kyphosis (TK), lumbar lordosis (LL), sacral slope (SS), pelvic inclination (PI), and pelvic tilt (PT) both in the neutral and stepped positions.

Results: SVA was significantly larger in the stepped position than in the neutral position (neutral position, 72.5 mm; stepped position, 96.8 mm; = 0.003). Parameters regarding the pelvis exhibited significant differences, which could represent pelvic anteversion in the stepped position. By stepwise multiple regression analysis, the prediction models, containing SVA (neutral) and PT (stepped) for double supporting phase, exhibited statistical significance, and accounted for approximately 50% of the variance.

Conclusions: The present study provides statistically established evidence of correlation among spatiotemporal gait parameters and spinal sagittal parameters. Differences between sagittal parameters in neutral and stepped position may stand for the postural control during gait cycle, and increased SVA in neutral position and increased PT in stepped position may correlate with prolonged double supporting phase.
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http://dx.doi.org/10.1177/23094990211010522DOI Listing
August 2021

Editorial: An important milestone for systematizing gastroparesis practice.

Authors:
Hidekazu Suzuki

United European Gastroenterol J 2021 04 22;9(3):285-286. Epub 2021 Apr 22.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.

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http://dx.doi.org/10.1002/ueg2.12064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259234PMC
April 2021

Three Cases of Esophageal Cancer Related to Fanconi Anemia.

Intern Med 2021 Sep 5;60(18):2953-2959. Epub 2021 Apr 5.

Department of Cell Transplantation and Regenerative Medicine, Tokai University, School of Medicine, Japan.

The risk of carcinogenesis increases after 20 years old in patients with Fanconi anemia (FA). We herein report three rare cases of FA combined with esophageal cancer in women; all patients were diagnosed with FA in early childhood. Patients 1 and 2 were diagnosed with advanced and superficial esophageal cancer, respectively, at 21 and 30 years old, respectively. Patient 3 was diagnosed with superficial esophageal cancer, underwent curative surgery at 26 years old, and survived for over 5 years without recurrence. Therefore, establishing a protocol for the early detection of esophageal cancer in FA patients over 20 years old is important.
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http://dx.doi.org/10.2169/internalmedicine.6926-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502673PMC
September 2021

Clinical factors associated with shorter durable response, and patterns of acquired resistance to first-line pembrolizumab monotherapy in PD-L1-positive non-small-cell lung cancer patients: a retrospective multicenter study.

BMC Cancer 2021 Apr 1;21(1):346. Epub 2021 Apr 1.

Department of Thoracic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan.

Background: Despite the wide-spread use of immune checkpoint inhibitors (ICIs) in cancer chemotherapy, reports on patients developing acquired resistance (AR) to ICI therapy are scarce. Therefore, we first investigated the characteristics associated with shorter durable responses of ICI treatment and revealed the clinical patterns of AR and prognosis of the patients involved.

Methods: We conducted a retrospective multi-center cohort study that included NSCLC patients with PD-L1 tumor proportion scores of ≥50% who received first-line pembrolizumab and showed response to the therapy. Among patients showing response, progression-free survival (PFS) was investigated based on different clinically relevant factors. AR was defined as disease progression after partial or complete response based on Response Evaluation Criteria in Solid Tumors. Among patients with AR, patterns of AR and post-progression survival (PPS) were investigated. Oligoprogression was defined as disease progression in up to 5 individual progressive lesions.

Results: Among 174 patients who received first-line pembrolizumab, 88 showed response and were included in the study. Among these patients, 46 (52%) developed AR. Patients with old age, poor performance status (PS), at least 3 metastatic organs, or bone metastasis showed significantly shorter PFS. Among 46 patients with AR, 32 (70%) developed AR as oligoprogression and showed significantly longer PPS than those with non-oligoprogressive AR.

Conclusions: Patients with old age, poor PS, at least 3 metastatic organs, or bone metastasis showed shorter durable responses to pembrolizumab monotherapy. Oligoprogressive AR was relatively common and associated with better prognosis. Further research is required to develop optimal approaches for the treatment of these patients.
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http://dx.doi.org/10.1186/s12885-021-08048-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017679PMC
April 2021

Extracellular Water-to-total Body Water Ratio as an Objective Biomarker for Frailty in Lung Cancer Patients.

Anticancer Res 2021 Mar;41(3):1655-1662

Department of Thoracic Oncology, Osaka Habikino Medical Center, Osaka, Japan.

Background/aim: Our previous study revealed the association between extracellular water-to-total body water ratio (ECW/TBW) and the therapeutic durability of chemotherapy and/or immune checkpoint inhibitors in advanced lung cancer. We retrospectively examined the usefulness of ECW/TBW in detecting frailty compared to other bioelectrical impedance (BIA) parameters in a larger number of patients.

Patients And Methods: Lung cancer patients underwent BIA before anti-cancer therapy at our hospital between June 1, 2018 and July 31, 2020.

Results: Of 99 patients, 26 were assigned to ECW/TBW≥0.4 (higher group: HG) and 57 to ECW/TBW<0.4 (lower group: LG). ECW/TBW increased significantly with performance deterioration and ageing. HG patients had significantly shorter time-to-treatment failure (TTF) than LG patients. In patients with performance status 0-1, those in the HG had shorter TTF than those in the LG. ECW/TBW was the only independent predictor of TTF according to multivariate analysis.

Conclusion: ECW/TBW is an objective biomarker for detecting frailty among lung cancer patients.
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http://dx.doi.org/10.21873/anticanres.14928DOI Listing
March 2021

Gastric linitis plastica due to signet-ring cell carcinoma with Krukenberg tumors diagnosed by endoscopic ultrasound-guided fine-needle aspiration.

Clin J Gastroenterol 2021 Aug 19;14(4):994-1003. Epub 2021 Mar 19.

Department of Gastroenterology, St. Luke's International Hospital, 9-1 Akashicho, Chuo-ku, Tokyo, 104-8560, Japan.

Gastric linitis plastica is a rare condition characterized by the stiffening and thickening of the gastric wall, presenting a "leather bottle" appearance. It is generally associated with infiltration of poorly differentiated gastric cancer cells, but similar findings can arise due to metastases from other cancers and benign inflammatory processes. Despite advances in imaging modalities, pathological evaluation is required for diagnosis. As endoscopic mucosal biopsies may not be diagnostic, endoscopic ultrasound-guided fine-needle aspiration of the thickened stomach wall presents a potential diagnostic option. We report a case which presented with bilateral ovarian tumors and was ultimately diagnosed as gastric signet-ring cell carcinoma with Krukenberg tumors by endoscopic ultrasound-guided fine-needle aspiration of the stomach wall. The preoperative diagnosis allowed the patient to avoid surgery and to start chemotherapy for gastric cancer. We also review the existing literature on endoscopic ultrasound-guided fine-needle aspiration in the context of gastric linitis plastica.
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http://dx.doi.org/10.1007/s12328-021-01387-6DOI Listing
August 2021

Risk Factors for Prolonged Hospital Stay after Endoscopy.

Clin Endosc 2021 Mar 16. Epub 2021 Mar 16.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background/aims: The recovery room used after endoscopy has limited capacity, and an efficient flow of the endoscopy unit is desired. We investigated the duration of hospital stay after endoscopy and the risk factors for prolonged hospital stay among outpatients.

Methods: We retrospectively studied consecutive patients who underwent esophagogastroduodenoscopy or colonoscopy at the Toyoshima Endoscopy Clinic. We collected data on age, sex, body weight, midazolam and pethidine dosage, respiratory depression during endoscopy, and duration of hospital stay after endoscopy (scope out to check out). Risk factors for prolonged hospital stay (>100 minutes) were identified using multiple logistic regression analysis.

Results: We enrolled 3,898 patients, including 3,517 (90.2%) patients tested under sedation and 381 (9.8%) patients tested without sedation. Overall, 442 (11.3%) patients had prolonged stay (>100 min). The mean time difference between sedation group and non-sedation group was 44.2 minutes for esophagogastroduodenoscopy and 39.1 minutes for colonoscopy. Age (odds ratio [OR], 1.025; 95% confidence interval [CI], 1.014-1.036), female sex (OR, 1.657; 95% CI, 1.220-2.249), and midazolam dose (OR, 1.019; 95% CI, 1.013-1.026) were independently associated with prolonged hospital stay after esophagogastroduodenoscopy, with similar results for colonoscopy.

Conclusions: Old age, female sex, and midazolam dose were independent risk factors for prolonged hospital stay after endoscopy.
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http://dx.doi.org/10.5946/ce.2020.292DOI Listing
March 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021
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