Publications by authors named "Hideki Kobara"

298 Publications

Effect of Aspirin on G/G Cell Cycle Arrest and microRNA Signatures in Pancreatic Adenocarcinoma Cells.

Anticancer Res 2022 Aug;42(8):4037-4048

Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.

Background/aim: Anti-inflammatory drugs, such as aspirin, have attracted attention as anticancer agents that can be applied to standard chemotherapy for pancreatic cancer. This study aimed to examine the antitumour effects and possible fundamental mechanisms of aspirin in pancreatic cancer cells.

Materials And Methods: We appraised the antitumour effects of aspirin on cell proliferation and tumour growth, cell cycle distribution, apoptosis, signalling pathways, angiogenesis-related proteins, and phosphorylated receptor tyrosine kinases (p-RTKs) and identify miRNAs associated with its antitumour effects.

Results: Aspirin inhibited cell proliferation in pancreatic cancer cell lines and induced G/G cell cycle arrest by decreasing the expression of cyclin D1. Aspirin inactivated glycogen synthase kinase (GSK)-3β but had no effect on the p38 mitogen-activated protein kinase (MAPK) pathway, p-RTKs, or angiogenesis-related molecules. Aspirin treatment statistically increased the expression of 274 miRNAs in PANC-1 cells and 30 miRNAs in PK-8 cells and suppressed the expression of 294 miRNAs in PANC-1 cells and 13 miRNAs in PK-8 cells.

Conclusion: Aspirin inhibited the proliferation of pancreatic cancer cells and induced cell cycle arrest. Aspirin also inactivated GSK-3β but not the p38 MAPK pathway. Thus, aspirin may be used in combination with chemotherapeutic agents for pancreatic cancer.
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http://dx.doi.org/10.21873/anticanres.15900DOI Listing
August 2022

Cholecystocolic fistula closed using endoscopic therapy alone: A case report.

Medicine (Baltimore) 2022 Jul 22;101(29):e29680. Epub 2022 Jul 22.

Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan.

Background: Cholecystocolic fistula (CCF) is a known but rare complication of cholelithiasis. Treatment for CCF is generally surgical. As the number of elderly patients has increased in recent years, many cases require non-surgical treatment; therefore, endoscopic treatment has gained importance.

Patient Concerns And Diagnosis: An 87-year-old woman presented with impaired consciousness and symptoms of anorexia. Computed tomography showed cholecystitis and a fistula between the gallbladder and transverse colon. Colonoscopy revealed a CCF. The condition was diagnosed as CCF caused by acute cholecystitis.

Interventions And Outcomes: The patient declined surgery due to her age. Endoscopic fistula closure was performed using a through-the-scope clip after endoscopic naso-gallbladder drainage. Successful closure of the fistula resulted in improvement of cholecystitis and anorexia. The patient was discharged after one month. It has been more than 18 months since the procedure, there has been no recurrence.

Conclusion: This report on successful endoscopic closure of a CCF indicates that it may be useful for patients who decline surgery.
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http://dx.doi.org/10.1097/MD.0000000000029680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9302365PMC
July 2022

Clinical and technical outcomes of endoscopic closure of post-endoscopic submucosal dissection defects: a literature review over one decade.

Dig Endosc 2022 Jul 2. Epub 2022 Jul 2.

Departments of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Japan.

Endoscopic submucosal dissection (ESD), which enables curative en bloc resection of early gastrointestinal neoplasms, has been an attractive minimally invasive surgery during the past two decades. Large post-ESD defects must be carefully managed to prevent adverse events (AEs). The major AEs comprise delayed bleeding (DB) and delayed perforation (DP), and overall AEs comprise DB plus DP. This review aimed to clarify the clinical efficacy and technical outcomes of endoscopic prophylactic closure for post-ESD defects. We identified studies involving ≥10 patients up to March 2022 in which endoscopic closure was applied for gastric, duodenal, and colorectal post-ESD defects. In the stomach, total rates of overall AEs and DB were significantly lower in the closure than non-closure group. In the duodenum, total rates of overall AEs, DB, and DP were significantly lower in the closure group. In the colorectum, total rates of overall AEs and DB were significantly lower in the closure group. Closure techniques, categorized into three groups (clip-based techniques, mechanical clipping, and surgical stitch-based techniques), were illustrated. Endoscopic closure demonstrated a certain ability to reduce DB after gastric, duodenal, and colorectal ESD as well as DP after duodenal ESD. Considering closure-associated costs, the indications and limitations of closure techniques should be further investigated.
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http://dx.doi.org/10.1111/den.14397DOI Listing
July 2022

Effectiveness of second-look endoscopy after gastric endoscopic submucosal dissection in patients taking antithrombotic agents: a multicenter propensity score matching analysis.

Gastric Cancer 2022 Sep 27;25(5):916-926. Epub 2022 May 27.

Department of Gastroenterology, Aichi Medical University Hospital, Aichi, Japan.

Background: The risk of bleeding after gastric endoscopic submucosal dissection (ESD) in antithrombotic agent users has increased, and its management remains a problem. Second-look endoscopy (SLE) following gastric ESD in antithrombotic agent users may be effective in preventing delayed bleeding, but this requires elucidation. Therefore, this study aimed to investigate the efficacy of SLE in reducing bleeding after gastric ESD in patients receiving antithrombotic agents.

Methods: This retrospective cohort study was conducted at 19 referral hospitals in Japan. A total of 1,245 patients who were receiving antithrombotic agents underwent gastric ESD between January 2013 and July 2018. The incidence of delayed bleeding was compared between SLE and non-SLE groups using propensity score matching analysis.

Results: Overall, 858 patients (SLE group, 657 patients; non-SLE group, 201 patients) were analyzed. After matching, 198 pairs were created. Delayed bleeding occurred in 10 patients (5.1%) in the SLE group and 16 patients (8.1%) in the non-SLE group [odds ratio (OR) 0.605, 95% confidence interval (CI) 0.23-1.46, p = 0.310]. In the subgroup analysis, SLE reduced the incidence of delayed bleeding in patients receiving heparin bridging therapy (6.3% and 40.0%, respectively; p = 0.004). In the SLE group, prophylactic coagulation did not significantly reduce delayed bleeding compared to the no treatment group (14.6% and 8.6%, respectively; p = 0.140).

Conclusions: SLE was ineffective in reducing bleeding after gastric ESD in antithrombotic agent users, overall. A prospective comparative study is warranted to definitively evaluate the effectiveness of SLE in reducing bleeding in high-risk patients.
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http://dx.doi.org/10.1007/s10120-022-01303-yDOI Listing
September 2022

Efficacy and Safety of Neoadjuvant Chemoradiation Therapy Administered for 5 Versus 2 Weeks for Resectable and Borderline Resectable Pancreatic Cancer.

Pancreas 2022 03;51(3):269-277

From the Departments of Gastroenterological Surgery.

Objectives: Indications of preoperative treatment for resectable (R-) or borderline resectable (BR-) pancreatic ductal adenocarcinoma (PDAC) are unclear, and the protocol remains to be standardized.

Methods: Included 65 patients with R- and BR-PDAC with venous involvement (V-) received neoadjuvant chemoradiotherapy with S-1 and 50 Gy of radiation as the 5-week regimen. The outcomes of this group were compared with those of 52 patients who underwent S-1 and 30 Gy of radiation as the 2-week regimen, previously collected as our prospective phase II study.

Results: Compared with the 2-week regimen, there were no significant differences in the rate of protocol completion, adverse events, mortality and morbidity, or R0 resection in the 5-week regimen. In subgroup analyses of R-PDAC, there were no significant differences in overall survival and recurrence-free survival between the groups. In contrast, the 5-week regimen had significantly better overall survival and recurrence-free survival than the 2-week regimen for BRV-PDAC. Similar results were observed after propensity score matching analysis.

Conclusions: The 5-week regimen of neoadjuvant chemoradiotherapy has good clinical efficacy and safety for R- and BRV-PDAC. The 5-week regimen could achieve better outcomes than the 2-week regimen for BRV-PDAC. In contrast, both regimens achieved similar outcomes for R-PDAC.
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http://dx.doi.org/10.1097/MPA.0000000000002011DOI Listing
March 2022

Characteristics of colorectal neuroendocrine tumors in patients prospectively enrolled in a Japanese multicenter study: a first report from the C-NET STUDY.

J Gastroenterol 2022 Aug 13;57(8):547-558. Epub 2022 May 13.

Department of Gastroenterology, Kitasato University Hospital, Kanagawa, Japan.

Background: This is the first report from a multicenter prospective cohort study of colorectal neuroendocrine tumor (NET), the C-NET STUDY, conducted to assess the long-term outcomes of the enrolled patients. This report aimed to elucidate the clinicopathological features of the enrolled patients and lesions.

Methods: Colorectal NET patients aged 20-74 years were consecutively enrolled and followed up at 50 institutions. The baseline characteristics and clinicopathological findings at enrollment and treatment were assessed.

Results: A total of 495 patients with 500 colorectal NETs were included. The median patient age was 54 years, and 85.3% were asymptomatic. The most frequent lesion location was the lower rectum (88.0%); 99.4% of the lesions were clinically diagnosed to be devoid of metastatic findings, and 95.4% were treated with endoscopic resection. Lesions < 10 mm comprised 87.0% of the total, 96.6% had not invaded the muscularis propria, and 92.6% were classified as WHO NET grade 1. Positive lymphovascular involvement was found in 29.2% of the lesions. Its prevalence was high even in small NETs with immunohistochemical/special staining for pathological assessment (26.4% and 40.9% in lesions sized < 5 mm and 5-9 mm, respectively). Among 70 patients who underwent radical surgery primarily or secondarily, 18 showed positive lymph node metastasis.

Conclusions: The characteristics of real-world colorectal NET patients and lesions are elucidated. The high positivity of lymphovascular involvement in small NETs highlights the necessity of assessing the clinical significance of positive lymphovascular involvement based on long-term outcomes, which will be examined in later stages of the C-NET STUDY.

Trial Registration Number: UMIN000025215.
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http://dx.doi.org/10.1007/s00535-022-01877-5DOI Listing
August 2022

Tumor metabolic alterations after neoadjuvant chemoradiotherapy predict postoperative recurrence in patients with pancreatic cancer.

Jpn J Clin Oncol 2022 Aug;52(8):879-887

Department of Gastroenterological Surgery, Kagawa University, Kita-gun, Kagawa, Japan.

Objective: We investigated the metabolic changes in pancreatic ductal adenocarcinoma to identify the mechanisms of treatment response of neoadjuvant chemoradiation therapy.

Methods: Frozen tumor and non-neoplastic pancreas tissues were prospectively obtained from 88 patients with pancreatic ductal adenocarcinoma who underwent curative-intent surgery. Sixty-two patients received neoadjuvant chemoradiation therapy and 26 patients did not receive neoadjuvant therapy (control group). Comprehensive analysis of metabolites in tumor and non-neoplastic pancreatic tissue was performed by capillary electrophoresis-mass spectrometry.

Results: Capillary electrophoresis-mass spectrometry detected 90 metabolites for analysis among more than 500 ionic metabolites quantified. There were significant differences in 27 tumor metabolites between the neoadjuvant chemoradiation therapy and control groups. There were significant differences in eight metabolites [1-MethylnNicotinamide, Carnitine, Glucose, Glutathione (red), N-acetylglucosamine 6-phosphate, N-acetylglucosamine 1-phosphate, UMP, Phosphocholine] between good responder and poor responder for neoadjuvant chemoradiation therapy. Among these metabolites, phosphocholine, Carnitine and Glutathione were associated with recurrence-free survival only in the neoadjuvant chemoradiation therapy group. Microarray confirmed marked gene suppression of choline transporters [CTL1-4 (SLC44A1-44A4)] in pancreatic ductal adenocarcinoma tissue of neoadjuvant chemoradiation therapy group.

Conclusion: The present study identifies several important metabolic consequences and potential neoadjuvant chemoradiation therapy targets in pancreatic ductal adenocarcinoma. Choline metabolism is one of the key pathways involved in recurrence of the patients with pancreatic ductal adenocarcinoma who received neoadjuvant chemoradiation therapy.
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http://dx.doi.org/10.1093/jjco/hyac074DOI Listing
August 2022

Endoscopic features of colorectal lymphoma according to histological type.

JGH Open 2022 Apr 6;6(4):257-262. Epub 2022 Apr 6.

Endoscopy Division National Cancer Center Hospital Chuo City Tokyo Japan.

Background And Aim: This study aimed to investigate the relationship between the histological type of colorectal lymphoma and its endoscopic features.

Methods: We retrospectively analyzed patients with primary colorectal lymphoma who were diagnosed using colonoscopy and biopsy specimens at the National Cancer Center Hospital, Tokyo, Japan. The lesions were macroscopically classified into the following types via colonoscopy: polypoid, ulcerative, multiple lymphomatous polyposis, diffuse, and mixed.

Results: A total of 117 lesions were identified in 90 patients enrolled in this study. Of these, 59 (50%) were located in the ileocecal region, 23 (20%) in the rectum, 9 (8%) in the transverse colon, 8 (7%) in the sigmoid colon, 7 (6%) in the descending colon, and 4 (3%) in the ascending colon. Moreover, the most common histological subtypes were diffuse large B-cell lymphoma (DLBCL) in 39 patients (43%) and mantle cell lymphoma (MCL) in 23 patients (26%), followed by follicular lymphoma (FL; 17%), mucosa-associated lymphoid tissue (MALT) lymphoma (9%), peripheral T-cell lymphoma-NOS (2%), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL; 2%), and Burkitt lymphoma (1%). More than half of the DLBCL (52%), MCL (52%), and MALT (56%) lymphomas were macroscopically classified as polypoid types. In contrast, FL lesions showed various macroscopic types. The majority of DLBCL (62%) and FL (78%) lesions were distributed in the ileocecal region. MCL lesions tended to be widely spread in various sites of the large intestine.

Conclusions: Colorectal lymphomas showed macroscopically distinctive features depending on the histological type. Understanding the macroscopic classification of the lesions by colonoscopy and its distribution may be helpful in diagnosing the type of lymphoma and determining the malignant grade based on the histological types.
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http://dx.doi.org/10.1002/jgh3.12738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9021707PMC
April 2022

Outcomes of Patients with Left-Sided Obstructive Colorectal Cancer: Comparison between Self-Expandable Metallic Stent and Other Treatment Methods.

Dig Surg 2022 22;39(2-3):117-124. Epub 2022 Apr 22.

Department of Gastroenterological Surgery, Kagawa University, Takamatsu, Japan.

Introduction: This multi-institutional retrospective study aimed to evaluate the efficacy of preoperative self-expandable metallic stent (SEMS) placement for patients with left-sided obstructive colorectal cancer (OCRC).

Methods: Overall, 520 consecutive patients who received treatment for OCRC were enrolled. Of these, the data of 253 patients who underwent primary tumour resection for left-sided OCRC were reviewed. The short- and long-term outcomes were compared between the SEMS group and other three groups: transanal decompression tube (TaDT), decompressing stoma (DS), and emergency resection (ER).

Results: The SEMS group had a higher frequency of laparoscopic surgery (p < 0.001), lesser frequency of postoperative stoma (p < 0.001), and more dissected lymph nodes (p < 0.001) than the other groups. Moreover, the SEMS group had shorter postoperative hospital stays than the TaDT, DS, and ER groups (p = 0.005, p = 0.037, and p < 0.001, respectively). The Kaplan-Meier survival curves of recurrence-free survival and overall survival did not differ significantly between the SEMS group and the other three groups in patients with stage II and III diseases.

Discussion/conclusion: Elective surgery after SEMS placement may improve short-term outcomes compared to other treatment strategies, with similar long-term outcomes.
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http://dx.doi.org/10.1159/000524645DOI Listing
June 2022

Risk factors and prediction of bleeding after gastric endoscopic submucosal dissection in patients on antithrombotic therapy: newly developed bleeding prediction application software, SAMURAI model.

J Clin Biochem Nutr 2022 Mar 3;70(2):189-196. Epub 2021 Dec 3.

2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University Hospital, 2-7 Daigakumachi Takatsuki, Osaka 569-8686, Japan.

Bleeding after gastric endoscopic submucosal dissection (ESD) remains problematic, especially in patients receiving antithrombotic therapy. Therefore, this study aimed to identify the risk factors. In this retrospective study, patients ( = 1,207) who underwent gastric ESD while receiving antithrombotic therapy were enrolled at Osaka Medical and Pharmaceutical University Hospital and 18 other referral hospitals in Japan. Risks of post-ESD bleeding were calculated using multivariable logistic regression. The dataset was divided into a derivation cohort and a validation cohort. We created a prediction model using the derivation cohort. The accuracy of the model was evaluated using the validation cohort. Post-ESD bleeding occurred in 142 (11.8%) participants. Multivariable analysis yielded an odds ratio of 2.33 for aspirin, 4.90 for P2Y12 receptor antagonist, 1.79 for cilostazol, 0.95 for other antithrombotic agents, 6.53 for warfarin, 5.65 for dabigatran, 7.84 for apixaban, 10.45 for edoxaban, 6.02 for rivaroxaban, and 1.46 for heparin bridging. The created prediction model was called safe ESD management using the risk analysis of post-bleeding in patients with antithrombotic therapy (SAMURAI). This model had good predictability, with a C-statistic of 0.77. In conclusion, use of the SAMURAI model will allow proactive management of post-ESD bleeding risk in patients receiving antithrombotic therapy.
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http://dx.doi.org/10.3164/jcbn.21-136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8921730PMC
March 2022

Beige mucosa observable under narrow-band imaging indicates the active sites of eosinophilic esophagitis.

J Gastroenterol Hepatol 2022 May 9;37(5):891-897. Epub 2022 Mar 9.

Division of Gastroenterology, Department of Internal Medicine 2, Kawasaki Medical School, Okayama, Japan.

Background And Aim: The majority of patients with eosinophilic esophagitis (EoE) are likely to have observable features under narrow-band imaging, namely beige mucosa. However, the histological features and clinical implications of beige mucosa have not been investigated. The aim of this study was to determine whether beige mucosa could serve as an endoscopic marker for predicting active inflammatory sites of EoE.

Methods: We retrospectively analyzed both the narrow-band images and biopsied specimens of 77 esophageal lesions from 35 consecutive patients with EoE. We divided these specimens into two groups: target biopsied specimens from beige mucosa (beige group) and specimens biopsied from non-beige mucosa (non-beige group). The number of eosinophils per high-powered field, thickness of the superficial differentiated cell layer, and depth of the hemoglobin component from the surface layer were compared between the two groups.

Results: Forty-four out of the 45 specimens were diagnosed as histological active lesions in the beige group. The sensitivity, specificity, and overall accuracy of beige mucosa in predicting EoE activity were 97.8%, 96.9%, and 97.8%, respectively. Compared with the non-beige group, specimens in the beige group had a significantly thinner superficial differentiated cell layer.

Conclusions: Beige mucosa is associated with thinning of the normal superficial differentiated cell layer, and these histological changes in the active inflammatory sites of EoE could be recognized endoscopically as color differences. Beige mucosa may serve as an endoscopic indicator for predicting the histological activity of EoE.
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http://dx.doi.org/10.1111/jgh.15808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9311190PMC
May 2022

Characterization of Cisplatin Effects in Lenvatinib-resistant Hepatocellular Carcinoma Cells.

Anticancer Res 2022 Mar;42(3):1263-1275

Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan;

Background/aim: Drug resistance to molecular targeted agents, such as lenvatinib, is an important issue. The aim of this study was to explore the mechanism of lenvatinib resistance and to investigate potential drugs that may improve the treatment of lenvatinib-resistant (LR) hepatocellular carcinoma (HCC).

Materials And Methods: LR cells were developed by long-term culture under lenvatinib exposure. We analyzed the biological characteristics of LR cells in vitro, and investigated the antitumor effects and endogenous mechanisms of cisplatin in LR cells.

Results: The proliferative potential of LR cells was enhanced by activation of ERK signaling and changes in several miRNAs. Cisplatin inhibited cell proliferation of LR cells and induced G2/M cell cycle arrest. Furthermore, cisplatin triggered the DNA damage response, via the ATM/ATR-Chk1/Chk2 signaling pathway.

Conclusion: Proliferation of LR cells was induced upon ERK signaling activation. Cisplatin exerted antitumor effects in LR cells and was involved in the regulation of miRNAs associated with drug resistance.
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http://dx.doi.org/10.21873/anticanres.15593DOI Listing
March 2022

Efficacy of endoscopic ligation with O-ring closure for prevention of bleeding after gastric endoscopic submucosal dissection under antithrombotic therapy: a prospective observational study.

Endoscopy 2022 02 25. Epub 2022 Feb 25.

Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.

Background: We examined the efficacy of a novel endoscopic ligation technique with O-ring closure (E-LOC) to prevent bleeding after gastric endoscopic submucosal dissection (ESD) under antithrombotic therapy.

Methods: This single-center prospective study involved consecutive patients who were taking antithrombotic agents and underwent gastric ESD. E-LOC was performed by anchoring the nylon loop with hemoclips on both defect edges and/or the exposed muscle layer, and using O-ring band ligation around these deployed clips. The primary outcome was post-ESD bleeding rate. Secondary outcomes were complete closure rate, procedure time, sustained closure rate, and complications.

Results: 48 patients were finally analyzed. The post-ESD bleeding rate was 0 %, the complete closure rate was 97.9 %, and the mean closure time was 29.9 minutes. The sustained closure rate was 95.8 % at postoperative day 2-3 and 33.3 % at postoperative day 10-11. No complications occurred.

Conclusion: E-LOC may be an effective option for closing mucosal defects after gastric ESD under antithrombotic therapy. However, the preventive effect on post-ESD bleeding should be further investigated in high risk groups.
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http://dx.doi.org/10.1055/a-1782-3448DOI Listing
February 2022

Significance of Cortical Ribboning as a Biomarker in the Prodromal Phase of Sporadic Creutzfeldt-Jakob Disease.

Intern Med 2022 Feb 19. Epub 2022 Feb 19.

Department of Gastroenterology and Neurology, Graduate School of Medicine and Faculty of Medicine, Kagawa University, Japan.

A 63-year-old woman who presented for orofacial dystonia showed cortical ribboning, a typical MRI finding in sporadic Creutzfeldt-Jakob disease (sCJD). However, real-time quaking-induced conversion (RT-QuIC), the most sensitive method for an early diagnosis of sCJD, was negative. She developed sCJD six months later, at which time RT-QuIC became positive. The cerebral blood flow showed a decrease in the cerebral cortex (especially in the supramarginal gyrus) consistent with cortical ribboning, but an increase in the basal ganglia, probably involved in orofacial dystonia. Cortical ribboning on MRI might be a better biomarker than RT-QuIC in the prodromal phase of sCJD.
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http://dx.doi.org/10.2169/internalmedicine.8354-21DOI Listing
February 2022

Advanced endoscopic gastric defect closure: Preventive effects on post-endoscopic submucosal dissection bleeding.

Dig Endosc 2022 03 17;34(3):483-484. Epub 2022 Feb 17.

Departments of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.

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http://dx.doi.org/10.1111/den.14248DOI Listing
March 2022

Antitumor Effect of Regorafenib on MicroRNA Expression in Hepatocellular Carcinoma Cell Lines.

Int J Mol Sci 2022 Jan 31;23(3). Epub 2022 Jan 31.

Department of Gastroenterology and Neurology, Faculty of Medicine, Graduate School of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho 761-0793, Kita-gun, Kagawa, Japan.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and is one of the leading causes of cancer-related deaths worldwide. Regorafenib, a multi-kinase inhibitor, is used as a second-line treatment for advanced HCC. Here, we aimed to investigate the mechanism of the antitumor effect of regorafenib on HCC and evaluate altered microRNA (miRNA) expression. Cell proliferation was examined in six HCC cell lines (HuH-7, HepG2, HLF, PLC/PRF/5, Hep3B, and Li-7) using the Cell Counting Kit-8 assay. Xenografted mouse models were used to assess the effects of regorafenib in vivo. Cell cycle analysis, western blotting analysis, and miRNA expression analysis were performed to identify the antitumor inhibitory potential of regorafenib on HCC cells. Regorafenib suppressed proliferation in HuH-7 cell and induced G0/G1 cell cycle arrest and cyclin D1 downregulation in regorafenib-sensitive cells. During miRNA analysis, miRNA molecules associated with the antitumor effect of regorafenib were found. Regorafenib suppresses cell proliferation and tumor growth in HCC by decreasing cyclin D1 via alterations in intracellular and exosomal miRNAs in HCC.
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http://dx.doi.org/10.3390/ijms23031667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8835935PMC
January 2022

A cerebrospinal fluid microRNA analysis: Progressive supranuclear palsy.

Mol Med Rep 2022 Mar 18;25(3). Epub 2022 Jan 18.

Department of Gastroenterology, Faculty of Medicine, Kagawa University, Miki‑Cho, Kagawa 761‑0793, Japan.

Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy described as a syndrome of postural instability, supranuclear vertical gaze palsy, dysarthria, dystonic rigidity of the neck and trunk, dementia, and pseudobulbar palsy. The clinical diagnosis of PSP is often difficult because there are no established biomarkers, and diagnosis is currently based on clinical and imaging findings. Furthermore, the etiology and pathogenesis of PSP remain unknown. Dysregulation of microRNAs (miRNAs/miRs) has been reported to serve an important role in neurodegenerative diseases. However, the miRNA profiles of patients with PSP are rarely reported. The present study aimed to examine cerebrospinal fluid miRNAs, which are considered to be more sensitive indicators of changes in the brain, to elucidate the pathophysiology of PSP and to establish specific biomarkers for diagnosis. The present study used a microarray chip containing 2,632 miRNAs to examine cerebrospinal fluid miRNA expression levels in 11 patients with PSP aged 68‑82 years. A total of 8 age‑ and sex‑matched controls were also included. A total of 38 miRNAs were significantly upregulated and one miRNA was significantly downregulated in the cerebrospinal fluid of patients with PSP. The patients were divided into two groups based on disease stage (early onset and advanced), and changes in miRNA expression were examined. The miRNAs that were most significantly upregulated or downregulated in the early onset group were miR‑204‑3p, miR‑873‑3p and miR‑6840‑5p. The target genes of these miRNAs were associated with molecules related to the ubiquitin‑proteasome system and autophagy pathway. Furthermore, these miRNAs were found to target genes that have been reported to have epigenetic changes following an epigenome‑wide association study of brain tissues of patients with PSP. This suggested that these miRNAs and genes may have some involvement in the pathogenesis of PSP. However, the sample size of the present study was small; therefore, a greater number of patients with PSP should be examined in future studies.
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http://dx.doi.org/10.3892/mmr.2022.12604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8809115PMC
March 2022

Surgical management and outcomes of obstructive colorectal cancer in elderly patients: A multi-institutional retrospective study.

Surgery 2022 07 5;172(1):60-68. Epub 2022 Jan 5.

Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan.

Background: The outcomes and prognostic factors of elderly patients with obstructive colorectal cancer are unknown. This was the focus of our multi-institutional retrospective study.

Methods: Medical records of 520 patients (elderly [group E, aged ≥75 years, n = 271]; and nonelderly [group NE, aged <75 years, n = 249]) who received treatment for obstructive colorectal cancer in 2008 to 2018 at 14 leading hospitals in Kagawa prefecture (Japan) were reviewed. Short- and long-term outcomes of patients who underwent tumor resection (n = 438) were compared between the groups. Their prognostic factors were identified.

Results: The tumor resection rate was 79% (n = 213) and 90% (n = 225) in groups E and NE, respectively. Group E had more emergency resections (27 [12.7%] vs 15 [6.6%], P = .037), shorter operating times (194 vs 221 min, P < .001), fewer dissected lymph nodes (14 vs 17, P = .004), and less adjuvant chemotherapy (47 [26.8%] vs 122 [76.7%], p < .001) than group NE. Postoperative complication rates and recurrence-free survival were not significantly different between the groups. Overall survival was significantly lower in group E than in group NE. Distant metastases and no postoperative chemotherapy were independent poor prognostic factors for overall survival in groups E and NE. Emergency resection (hazard ratio:1.83; 95% confidence interval: 1.02-3.26) was a significant poor prognostic indicator in group E only.

Conclusions: The short-term outcomes and recurrence-free survival of elderly and nonelderly patients with obstructive colorectal cancer were similar, although the 90-day mortality rate of the elderly patients was higher. Furthermore, elective surgery after bowel decompression is associated with a better outcome in the elderly.
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http://dx.doi.org/10.1016/j.surg.2021.12.007DOI Listing
July 2022

Telomerase Reverse Transcriptase Promoter Mutations in Human Hepatobiliary, Pancreatic and Gastrointestinal Cancer Cell Lines.

In Vivo 2022 Jan-Feb;36(1):94-102

Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan;

Background/aim: The promoter region of the telomerase reverse transcriptase (TERT) gene is a regulatory element capable of affecting TERT expression, telomerase activity, and telomerase length. Mutations within the TERT promoter region are the most common mutations in many cancers. In this study, we characterized the TERT promoter mutation status in hepatobiliary, pancreatic, and gastrointestinal cancer cell lines.

Materials And Methods: TERT promoter mutation status was assessed by digital PCR in 12 liver cancer, 5 cholangiocarcinoma (CCA), 12 pancreatic cancer, 17 gastrointestinal cancer, and 3 healthy control cell lines.

Results: The C228T promoter mutation was detected in 9 liver cancer lines, and the C250T TERT mutation was detected in 1 oesophageal squamous cell carcinoma line.

Conclusion: The C228T promoter mutation is specific to liver cancer cell lines among various gastrointestinal cancer cell lines. These data will contribute to future research on the tumorigenic mechanisms and clinical use of digital PCR to detect mutations.
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http://dx.doi.org/10.21873/invivo.12680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8765179PMC
January 2022

Evaluating the Effect of Lenvatinib on Sorafenib-Resistant Hepatocellular Carcinoma Cells.

Int J Mol Sci 2021 Dec 2;22(23). Epub 2021 Dec 2.

Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki 761-0793, Japan.

Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related deaths worldwide. Sorafenib has been used as a first-line systemic treatment for over a decade. However, resistance to sorafenib limits patient response and presents a major hurdle during HCC treatment. Lenvatinib has been approved as a first-line systemic treatment for advanced HCC and is the first agent to achieve non-inferiority against sorafenib. Therefore, in the present study, we evaluated the inhibition efficacy of lenvatinib in sorafenib-resistant HCC cells. Only a few studies have been conducted on this topic. Two human HCC cell lines, Huh-7 and Hep-3B, were used to establish sorafenib resistance, and in vitro and in vivo studies were employed. Lenvatinib suppressed sorafenib-resistant HCC cell proliferation mainly by inducing G1 cell cycle arrest through ERK signaling. Hep-3B sorafenib-resistant cells showed partial cross-resistance to lenvatinib, possibly due to the contribution of poor autophagic responsiveness. Overall, the findings suggest that the underlying mechanism of lenvatinib in overcoming sorafenib resistance in HCC involves FGFR4-ERK signaling. Lenvatinib may be a suitable second-line therapy for unresectable HCC patients who have developed sorafenib resistance and express FGFR4.
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http://dx.doi.org/10.3390/ijms222313071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657692PMC
December 2021

Hepatocellular carcinoma induces body mass loss in parallel with osmolyte and water retention in rats.

Life Sci 2022 Jan 4;289:120192. Epub 2021 Dec 4.

Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan.

Aims: The number of cancer survivors with cardiovascular disease is increasing. However, the effect of cancer on body fluid regulation remains to be clarified. In this study, we evaluated body osmolyte and water imbalance in rats with hepatocellular carcinoma.

Main Methods: Wistar rats were administered diethylnitrosamine, a carcinogenic drug, to establish liver cancer. We analyzed tissue osmolyte and water content, and their associations with aldosterone secretion.

Key Findings: Hepatocellular carcinoma rats had significantly reduced body mass and the amount of total body sodium, potassium, and water. However, these rats had significantly increased relative tissue sodium, potassium, and water content per tissue dry weight. Furthermore, these changes in sodium and water balance in hepatocellular carcinoma rats were significantly associated with increased 24-h urinary aldosterone excretion. Supplementation with 0.25% salt in drinking water improved body weight reduction associated with sodium and water retention in hepatocellular carcinoma rats, which was suppressed by treatment with spironolactone, a mineralocorticoid receptor antagonist. Additionally, the urea-driven water conservation system was activated in hepatocellular carcinoma rats.

Significance: These findings suggest that hepatocellular carcinoma induces body mass loss in parallel with activation of the water conservation system including aldosterone secretion and urea accumulation to retain osmolyte and water. The osmolyte and water retention at the tissue level may be a causative factor for ascites and edema formation in liver failure rats.
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http://dx.doi.org/10.1016/j.lfs.2021.120192DOI Listing
January 2022

Low prevalence of biliary tract cancer with defective mismatch repair genes in a Japanese hospital-based population.

Oncol Lett 2022 Jan 4;23(1). Epub 2021 Nov 4.

Department of Gastroenterological Surgery, Kagawa University, Miki, Kagawa 761-0793, Japan.

Recent studies have reported that immune checkpoint inhibitors are effective against various defective mismatch repair (dMMR)/microsatellite instability-high (MSI-H) cancers. A limited number of reports are available on the frequency of dMMR/MSI-H carcinoma in biliary tract cancer (BTC), describing its clinicopathological characteristics and prognosis. The latter carcinoma is also associated with Lynch syndrome (LS). The present study was performed to investigate the frequency of patients with dMMR/MSI-H in BTC and the clinical characteristics of BTC with dMMR/MSI-H in a single institution in Japan. A total of 116 patients with BTC who underwent curative surgical resection at Kagawa University Hospital between January 2008 and December 2017 were included. The protein expression levels of the mismatch repair (MMR) genes [mutL homolog 1 (MLH1), mismatch repair endonuclease PMS2 (PMS2), MutS homolog (MSH)2 and MSH6] were assessed by immunohistochemistry (IHC) using formalin-fixed paraffin-embedded tissue specimens. Subsequently, MSI testing was performed on patients who exhibited loss of MMR protein expression. Loss of expression of one or more proteins was detected in five cases (4.3%). Loss of MLH1/PMS2 expression was observed in one case of intrahepatic cholangiocarcinoma, whereas loss of PMS2 expression was noted in one case of perihilar cholangiocarcinoma. Loss of MSH2/MSH6 and MSH6 expression was noted in two cases of distal cholangiocarcinoma and loss of PMS2 expression in one case of ampullary carcinoma. Out of the five patients, two demonstrated MSI-H. Microsatellite stability was observed in two cases and for one case, no data were available. Two MSI-H cases were patients with loss of expression of MLH1/PMS2 and MSH2/MSH6. None of the five patients exhibited a past medical history or family history of suspected LS. The frequency of dMMR in BTC was ~5%, which was similar to that reported by similar studies performed in other countries. In the present study, IHC appeared to be more useful than MSI testing for detecting MMR abnormalities with regards to the detection rate. Furthermore, there may only be a limited number of patients with BTCs who are likely to benefit from the therapeutic effects of treatment with immune checkpoint inhibitors.
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http://dx.doi.org/10.3892/ol.2021.13122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8607234PMC
January 2022

Efficacy of polyglycolic acid sheeting with fibrin glue for perforations related to gastrointestinal endoscopic procedures: a multicenter retrospective cohort study.

Surg Endosc 2022 07 23;36(7):5084-5093. Epub 2021 Nov 23.

Division of Endoscopy, Shizuoka Cancer Center, Shizuoka, Japan.

Objectives: Gastrointestinal (GI) perforations are one of the major adverse events of endoscopic procedures. Polyglycolic acid (PGA) sheets with fibrin glue have been reported to close GI perforations. However, its clinical outcome has not yet been fully investigated; thus, we conducted a multicenter retrospective observational study to assess the efficacy of PGA sheeting for GI perforation.

Methods: The medical records of patients who underwent PGA sheeting for endoscopic GI perforations between April 2013 and March 2018 in 18 Japanese institutions were retrospectively analyzed. PGA sheeting was applied when the clip closure was challenging or failed to use. Perforations were filled with one or several pieces of PGA sheets followed by fibrin glue application through an endoscopic catheter. Nasal or percutaneous drainage and endoscopic clipping were applied as appropriate. Clinical outcomes after PGA sheeting for intraoperative or delayed perforations were separately evaluated.

Results: There were 66 intraoperative and 24 delayed perforation cases. In intraoperative cases, successful closure was attained in 60 cases (91%). The median period from the first sheeting to diet resumption was 6 days (interquartile range [IQR], 4-8.8 days). Large perforation size (≥ 10 mm) and duodenal location showed marginal significant relationship to higher closure failure of intraoperative perforations. In delayed perforation cases, all cases had successful closure. The median period from the first sheeting to diet resumption was 10 days (IQR, 6-37.8 days). No adverse events related to PGA sheeting occurred.

Conclusion: Endoscopic PGA sheeting could be a therapeutic option for GI perforations related to GI endoscopic procedures.
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http://dx.doi.org/10.1007/s00464-021-08873-5DOI Listing
July 2022

Flexible Magnifying Endoscopy with Narrow Band Imaging for Diagnosing Uterine Cervical Neoplasms: A Multicenter Prospective Study.

J Clin Med 2021 Oct 16;10(20). Epub 2021 Oct 16.

Department of Gynecology, Kochi Red Cross Hospital, Kochi, 2-13-51 Shinhonmachi, Kochi 780-8562, Japan.

We aimed to investigate the diagnostic ability of magnifying endoscopy with narrow band imaging (ME-NBI) for cervical intraepithelial neoplasia grade 2 or worse (CIN2+). This was a multicenter prospective study. Eligible patients had positive Pap smear results or follow-up high-grade cytology or CIN3 diagnosed in referring hospitals. Patients underwent ME-NBI by a gastrointestinal endoscopist, followed by colposcopy by a gynecologist. One lesion with the worst finding was considered the main lesion. Punch biopsies were collected from all indicated areas and one normal area. The reference standard was the highest histological grade among all biopsy specimens. The primary endpoint was the detection rate of patients with CIN2+ in the main lesion. The secondary endpoints were diagnostic ability for CIN2+ lesions and patients' acceptability. We enrolled 88 patients. The detection rate of ME-NBI for patients with CIN2+ was 79% (95% CI: 66-88%; = 1.000), which was comparable to that of colposcopy (79%; = 1.000). For diagnosing CIN2+ lesions, ME-NBI showed a better sensitivity than colposcopy (87% vs. 74%, respectively; = 0.302) but a lower specificity (50% vs. 68%, respectively; = 0.210). Patients graded ME-NBI as having significantly less discomfort and involving less embarrassment than colposcopy. ME-NBI did not show a higher detection ability than colposcopy for patients with CIN2+, whereas it did show a better patient acceptability.
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http://dx.doi.org/10.3390/jcm10204753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8536977PMC
October 2021

The Role of Long Non-Coding RNA and microRNA Networks in Hepatocellular Carcinoma and Its Tumor Microenvironment.

Int J Mol Sci 2021 Sep 30;22(19). Epub 2021 Sep 30.

Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki 761-0793, Japan.

Hepatocellular carcinoma (HCC) is a common liver malignancy with high morbidity and poor prognosis. Long non-coding RNAs (lncRNAs) are involved in crucial biological processes of tumorigenesis and progression, and play four major regulatory roles, namely signal, decoy, guide, and scaffold, to regulate gene expression. Through these processes, lncRNAs can target microRNAs (miRNAs) to form lncRNA and miRNA networks, which regulate cancer cell proliferation, metastasis, drug resistance, and the tumor microenvironment. Here, we summarize the multifaceted functions of lncRNA and miRNA networks in the pathogenesis of HCC, the potential use of diagnostic or prognostic biomarkers, and novel therapeutic targets in HCC. This review also highlights the regulatory effects of lncRNA and miRNA networks in the tumor microenvironment of HCC.
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http://dx.doi.org/10.3390/ijms221910630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508708PMC
September 2021

[A case of adult intussusception in the transverse colon with an advanced ileal Peutz-Jeghers type polyp associated with cancer].

Nihon Shokakibyo Gakkai Zasshi 2021 ;118(10):959-966

Department of Gastroenterology and Neurology, Kagawa University.

A man in his thirties was admitted to the hospital because of upper abdominal pain. Computed tomography showed intussusception in the ascending and transverse colon. After spontaneous discontinuation, endoscopy revealed a 25-mm 0-I tumor in the ileum. An emergency operation was performed the next day due to intussusception recurrence. The tumor was hyperplastic intestinal epithelium with dendritic smooth muscle fascicles and partly cancerous. The patient had no clinical features of Peutz-Jeghers syndrome. Therefore, the patient was diagnosed with Peutz-Jeghers type polyps based on pathological findings. This case is considered to be a rare case of intussusception in the transverse colon due to Peutz-Jeghers type polyp with canceration.
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http://dx.doi.org/10.11405/nisshoshi.118.959DOI Listing
October 2021

Clinical Efficacy of Novel Patient-Covering Negative-Pressure Box for Shielding Virus Transmission during Esophagogastroduodenoscopy: A Prospective Observational Study.

Diagnostics (Basel) 2021 Sep 14;11(9). Epub 2021 Sep 14.

Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.

Esophagogastroduodenoscopy (EGD) has a high risk of virus transmission during the current coronavirus disease 2019 era, and preventive measures are under investigation. We investigated the effectiveness of a newly developed patient-covering negative-pressure box system (Endo barrier) (EB) for EGD. Eighty consecutive unsedated patients who underwent screening EGD with EB use were prospectively enrolled. To examine the aerosol ratio before, during, and after EGD, 0.3- and 0.5-μm aerosols were measured every 60 s using an optical counter. Moreover, the degree of contamination of the examiners' goggles and vinyl gowns was assessed before and after EGD using a rapid adenosine triphosphate (ATP) test for simulated droplets. Data were available in 73 patients and showed that 0.3- and 0.5-μm particles did not increase in 95.8% (70/73) and 94.5% (69/73) of patients during EGD under EB. There were no significant differences in the total 0.3- or 0.5-μm particle counts before versus after EGD. The difference in the ATP levels before and after EGD was -0.6 ± 16.6 relative light units (RLU) on goggles and 1.59 ± 19.9 RLU on gowns (both within the cutoff value). EB use during EGD may provide a certain preventive effect against aerosols and droplets, decreasing examiners' exposure to viruses.
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http://dx.doi.org/10.3390/diagnostics11091679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8470820PMC
September 2021

Miniature-probe endoscopic ultrasonography using a rubber balloon to evaluate gastrointestinal carcinomas in poor underwater conditions.

Endoscopy 2022 Aug 27;54(8):E466-E467. Epub 2021 Sep 27.

Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita, Kagawa, Japan.

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http://dx.doi.org/10.1055/a-1625-3639DOI Listing
August 2022

Gastrointestinal Residue Removal Using a Balloon Overtube under Ultrathin Endoscopic Navigation: Ex Vivo and In Vivo Experimental Studies.

J Clin Med 2021 Aug 25;10(17). Epub 2021 Aug 25.

Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.

Pooled gastric residues involving blood clots and food interrupt appropriate endoscopic intervention, leading to poor outcomes in endoscopic hemostasis and lifesaving. However, procedures and devices that enable the effective removal of gastrointestinal residues remain unsatisfactory. This study aimed to evaluate the efficacy and safety of our developed suction method in ex vivo and in vivo studies. We created a hand-made device with a large suction diameter, consisting of a balloon overtube and an ultrathin endoscope for navigation. In the ex vivo study, we compared the success rate and the suctioning time for four types of simulated residue between a standard endoscope and our device. Our device had s significantly higher suction ability and a shorter procedure time than the standard endoscope. The subsequent in vivo animal study involved five beagle dogs that were administered with food jelly to mimic gastric residue. Suction was performed twice for five dogs (ten attempts). The outcome measure was the successful procedure rate; secondary outcomes were procedure-associated complications and procedure time. The procedure was successful in all attempts, without any complications. The mean procedure time was 5 min. This novel method enabled the efficient and safe removal of gastric residue, and our findings will likely lead to the development of the instrument.
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http://dx.doi.org/10.3390/jcm10173796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432193PMC
August 2021
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