Publications by authors named "Etsuro Hatano"

225 Publications

Treatment algorithm for thrombocytopenia in patients with chronic liver disease undergoing planned invasive procedures.

Hepatol Res 2021 Sep 23. Epub 2021 Sep 23.

Department of Radiology, Hyogo College of Medicine, Hyogo, Japan.

Thrombocytopenia is highly prevalent in patients with chronic liver disease (CLD) and these patients often require invasive procedures that carry a risk of bleeding. To prevent bleeding, guidelines recommend increasing platelet counts in patients with CLD who have thrombocytopenia and are planned to undergo invasive procedures. There are currently two options to increase platelet counts in patients in this setting: platelet transfusion or thrombopoietin receptor agonists (TPORAs). Several treatment algorithms have been developed in the US to help physicians choose the best course of treatment for each patient; however, to date, no such algorithm has been proposed in other countries, where the choice of treatment has been based on each physician's judgement and experience. Here, we discuss the pathogenesis and treatment of thrombocytopenia in patients with CLD, we review and present current evidence of the efficacy of TPORAs for the treatment of thrombocytopenia in patients with CLD, and we present our expert opinion on a Japanese treatment algorithm for thrombocytopenia in patients with CLD who are planned to undergo invasive procedures. This algorithm aims to provide guidance for optimal decision making in the selection of TPORA therapy or platelet transfusion based on the latest evidence and according to actual clinical practice. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/hepr.13715DOI Listing
September 2021

A Novel Real-time Navigation System for Lymphaticovenular Anastomosis Using Projection Mapping with Indocyanine Green Fluorescence.

Plast Reconstr Surg Glob Open 2021 Aug 16;9(8):e3758. Epub 2021 Aug 16.

Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

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http://dx.doi.org/10.1097/GOX.0000000000003758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8367030PMC
August 2021

Anatomy of the Middle Hepatic Vein Tributaries to Promote Safer Hepatic Vein-Guided Liver Resection.

J Gastrointest Surg 2021 Jul 29. Epub 2021 Jul 29.

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Shogo-in Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.

Background: In laparoscopic anatomic liver resection, an increasingly common procedure, the hepatic vein-guided approach is widely used although the hepatic vein tributaries can be a major source of bleeding in the event of inadvertent injury. This report describes the anatomy of the middle hepatic vein (MHV) including its tributaries based on reconstructed three-dimensional computed tomography images and provides anatomic data to enable safe middle hepatic vein-guided liver resection.

Methods: Following simulation modeling of the hepatic vasculatures, reconstructed MHV data was pooled from 35 healthy liver donors. Yields of the MHV tributaries were analyzed to enable MHV-guided liver resection.

Results: A total of 252 tributaries were identified in the 35 donors. The MHV yielded fewer tributaries from its anterior and posterior aspects than from its right-side and left-side aspects (40 [15.9%], 13 [5.2%], 93 [36.9%], and 106 [42.1%], respectively). The MHV tributaries from the anterior and posterior aspects were smaller in diameter than those from the right-side and left-side aspects (median, 3.0, 2.0, 4.8, and 4.0 mm, respectively).

Discussion: Our simulation revealed that MHV dissection from the anterior or posterior aspect poses a lower risk of injury to the MHV tributaries compared to dissection from either lateral aspect. In addition, MHV dissection from the anterior or posterior aspect allows for safer identification and isolation of the thick MHV tributaries originating from the lateral aspects. Ideally, the anterior or posterior aspect of the MHV should be accessed and exposed before the lateral aspects are dissected to minimize the risk of MHV tributary injury.
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http://dx.doi.org/10.1007/s11605-021-05074-2DOI Listing
July 2021

Management of Hepatocellular Carcinoma in Japan: JSH Consensus Statements and Recommendations 2021 Update.

Liver Cancer 2021 Jun 19;10(3):181-223. Epub 2021 May 19.

Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.

The Clinical Practice Manual for Hepatocellular Carcinoma was published based on evidence confirmed by the Evidence-based Clinical Practice Guidelines for Hepatocellular Carcinoma along with consensus opinion among a Japan Society of Hepatology (JSH) expert panel on hepatocellular carcinoma (HCC). Since the JSH Clinical Practice Guidelines are based on original articles with extremely high levels of evidence, expert opinions on HCC management in clinical practice or consensus on newly developed treatments are not included. However, the practice manual incorporates the literature based on clinical data, expert opinion, and real-world clinical practice currently conducted in Japan to facilitate its use by clinicians. Alongside each revision of the JSH Guidelines, we issued an update to the manual, with the first edition of the manual published in 2007, the second edition in 2010, the third edition in 2015, and the fourth edition in 2020, which includes the 2017 edition of the JSH Guideline. This article is an excerpt from the fourth edition of the HCC Clinical Practice Manual focusing on pathology, diagnosis, and treatment of HCC. It is designed as a practical manual different from the latest version of the JSH Clinical Practice Guidelines. This practice manual was written by an expert panel from the JSH, with emphasis on the consensus statements and recommendations for the management of HCC proposed by the JSH expert panel. In this article, we included newly developed clinical practices that are relatively common among Japanese experts in this field, although all of their statements are not associated with a high level of evidence, but these practices are likely to be incorporated into guidelines in the future. To write this article, coauthors from different institutions drafted the content and then critically reviewed each other's work. The revised content was then critically reviewed by the Board of Directors and the Planning and Public Relations Committee of JSH before publication to confirm the consensus statements and recommendations. The consensus statements and recommendations presented in this report represent measures actually being conducted at the highest-level HCC treatment centers in Japan. We hope this article provides insight into the actual situation of HCC practice in Japan, thereby affecting the global practice pattern in the management of HCC.
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http://dx.doi.org/10.1159/000514174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237791PMC
June 2021

Antithrombin Together with NETs Inhibitor Protected Against Postoperative Adhesion Formation in Mice.

Cell Physiol Biochem 2021 Jul;55(4):400-412

Department of Gastroenterological Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan,

Background/aims: Postoperative adhesions may induce adverse outcomes in patients. Adhesion formation is initiated by fibrin accumulation at the surgical site which is followed by local neutrophilia and the establishment of neutrophil extracellular traps (NET). Previous reports have suggested that the preventive efficacy of reagents designed to reduce postoperative adhesion is inversely correlated with neutrophilia and NET production. Antithrombin (AT) is a natural inhibitor of thrombin, a key factor in coagulation. Here, we evaluate whether treatment with AT and/or NET inhibitors prevent or reduce postoperative adhesion formation in mice.

Methods: Mice were treated with AT and/or NET inhibitors before and/or after cecum cauterization and their adhesion scores were evaluated on day 7 post-operation. Immunochemistry/ immunofluorescence analyses were also performed and we used GSK484, an inhibitor of peptidyl arginine deiminase 4 (PAD4), as the NET inhibitor.

Results: AT or GSK484 partially rescued postoperative adhesion formation in mice. AT prevented thrombin-induced plasminogen activator inhibitor 1 and interleukin-6 expression in mesothelial cells in vitro. However, AT could not prevent neutrophilia or NETs formation around the injured serosa. Finally, we investigated a combination of AT and a PAD4 inhibitor and found that this could inhibit almost all adhesion formation in these animals. Since AT-inactivating proteases are liberated following NET release, they might dampen the biological action of the AT treatment. This suggests that NET inhibitors might allow AT to exert its full action in the surgically injured serosa.

Conclusion: Combined treatment with AT and GSK484 may effectively attenuate postoperative adhesion production in mice.
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http://dx.doi.org/10.33594/000000392DOI Listing
July 2021

Fibroblast growth factor receptor 2 (FGFR2) fusions in Japanese patients with intrahepatic cholangiocarcinoma.

Jpn J Clin Oncol 2021 May;51(6):911-917

Department of Surgery, Japanese Red Cross Ishinomaki Hospital, Ishinomaki, Japan.

Objective: Fibroblast growth factor receptor gene alterations have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer that has a poor prognosis. This study evaluated the frequency of fibroblast growth factor receptor 2 fusions in clinical specimens from Japanese patients with iCCA.

Methods: This study enrolled 116 patients who had histologically or cytologically confirmed adenocarcinoma and been diagnosed as relapsing after resection or with unresectable intrahepatic cholangiocarcinoma. We evaluated the frequency of fibroblast growth factor receptor 2 fusions-positive cells in their specimens using break-apart fluorescent in situ hybridization 'for 114 patients who met the study protocol'.

Results: Of a total of 114 cases, six (5.3%) were identified as fibroblast growth factor receptor 2 fusions-positive with a high frequency (87% or more) of fibroblast growth factor receptor 2 fusions-positive tumour cells whereas the remainder, with the exception of three cases with indeterminate results, were identified as fibroblast growth factor receptor 2 fusions-negative. The patients' baseline characteristics as well as their objective response rates, disease control rates, times to progression, and times to treatment failure with previous or ongoing first-line chemotherapy did not have any obvious relationship to the proportion of fibroblast growth factor receptor 2 fusions-positive case.

Conclusions: Further detailed elucidation of fibroblast growth factor receptor 2 fusion status is expected to contribute to the development of promising therapeutic options for patients suffering from recurrent or unresectable intrahepatic cholangiocarcinoma.
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http://dx.doi.org/10.1093/jjco/hyab029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448429PMC
May 2021

Sinusoidal Obstruction Syndrome Promotes Liver Metastatic Seeding of Colorectal Cancer Cells in a Rat Model.

Anticancer Res 2021 Apr;41(4):1803-1810

Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background/aim: Sinusoidal obstruction syndrome (SOS) after neoadjuvant chemotherapy with oxaliplatin for colorectal liver metastases (CRLM) has been reported to lead to early recurrence. This study investigated the effects of SOS on the development of CRLM in a rat model.

Materials And Methods: RCN-H4 cells were injected into the spleen or liver of ten monocrotaline-treated (SOS group) and ten untreated (control group) rats. The number and size of liver tumors were compared between the groups.

Results: The number of liver tumors in the splenic RCN-H4 injection model was significantly higher in the SOS group than in the control group (332±213 vs. 16±5, p=0.029); however, the largest tumor diameter in the hepatic model was similar between groups (6.2±1.8 vs. 6.4±2.4 mm, p=0.87).

Conclusion: SOS promotes CRLM development by splenic RCN-H4 cell injection. This might be due to the higher incidence of cancer cell implantation into the liver.
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http://dx.doi.org/10.21873/anticanres.14946DOI Listing
April 2021

Survey of surgical resections for neuroendocrine liver metastases: A project study of the Japan Neuroendocrine Tumor Society (JNETS).

J Hepatobiliary Pancreat Sci 2021 Jun 20;28(6):489-497. Epub 2021 Apr 20.

Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan.

Background/purpose: Hepatic resection is considered the treatment of choice for neuroendocrine liver metastases (NELM). However, the safety and efficacy of resection have not been fully evaluated using a large cohort. The aim of the present study was to collect real-world data regarding hepatic resections for NELM.

Methods: A retrospective, multicenter survey was conducted. The background characteristics of patients undergoing an initial hepatic resection for NELM, the operative details, pathological findings, and patient outcomes were investigated.

Results: A total of 222 patients were enrolled from 30 institutions. The primary tumor site was the pancreas in 58.6%, and the presentation of NELM was synchronous in 63.1% of the cases. Concomitant resection of the primary tumor and liver metastases was performed for 66.4% of the synchronous metastases, and the 90-day morbidity and mortality rates were 12.6% and 0.9%, respectively. The operations resulted in R2 resections in 26.1% of the cases, and 83.4% of the patients experienced recurrence after R0/1 resections. However, the patients were treated using multiple modalities after R2 resection or recurrence, and the overall survival rate was relatively favorable, with 5-year and 10-year survival rates of 70.2%, and 43.4%, respectively. Univariable and multivariable analyses identified the tumor grading (G3) of the primary tumor as a significant prognostic factor for both the recurrence-free and overall survivals.

Conclusions: The present data confirmed the safety of the surgical resection of NELM. Although recurrences were frequent, the survival outcomes after resection were favorable when a multi-disciplinary treatment approach was used.
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http://dx.doi.org/10.1002/jhbp.956DOI Listing
June 2021

Cathepsin B and D deficiency in the mouse pancreas induces impaired autophagy and chronic pancreatitis.

Sci Rep 2021 03 23;11(1):6596. Epub 2021 Mar 23.

Department of Genetics, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.

The major lysosomal proteases, Cathepsin B (CTSB), Cathepsin D (CTSD) and Cathepsin L (CTSL), are implicated in autophagic activity. To investigate the role of each cathepsin in the exocrine pancreas, we generated mice in which the pancreas was specifically deficient in Ctsb, Ctsd and Ctsl. Each of these gene knockout (KO) and Ctsb;Ctsl and Ctsd;Ctsl double-knockout (DKO) mice were almost normal. However, we found cytoplasmic degeneration in the pancreatic acinar cells of Ctsb;Ctsd DKO mice, similar to autophagy related 5 (Atg5) KO mice. LC3 and p62 (autophagy markers) showed remarkable accumulation and the numbers of autophagosomes and autolysosomes were increased in the pancreatic acinar cells of Ctsb;Ctsd DKO mice. Moreover, these Ctsb;Ctsd DKO mice also developed chronic pancreatitis (CP). Thus, we conclude that both Ctsb and Ctsd deficiency caused impaired autophagy in the pancreatic acinar cells, and induced CP in mice.
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http://dx.doi.org/10.1038/s41598-021-85898-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988038PMC
March 2021

Safety of Combined Division vs Separate Division of the Splenic Vein in Patients Undergoing Distal Pancreatectomy: A Noninferiority Randomized Clinical Trial.

JAMA Surg 2021 May;156(5):418-428

Second Department of Surgery, Wakayama Medical University, Kimiidera, Wakayama, Japan.

Importance: In distal pancreatectomy (DP), the splenic vein is isolated from the pancreatic parenchyma prior to being ligated and divided to prevent intra-abdominal hemorrhage from the splenic vein stump with pancreatic fistula (PF). Conversely, dissecting the splenic vein with the pancreatic parenchyma is easy and time-saving.

Objective: To establish the safety of combined division of the splenic vein compared with separate division of the splenic vein.

Design, Setting, And Participants: This study was designed as a multicenter prospective randomized phase 3 trial. All results were analyzed using the modified intent-to-treat set. Patients undergoing DP for pancreatic body and tail tumors were eligible for inclusion. Patients were randomly assigned between August 10, 2016, and July 30, 2019.

Interventions: Patients were centrally randomized (1:1) to either separate division of the splenic vein or combined division of the splenic vein.

Main Outcomes And Measures: The primary end point was the incidence of grade B/C PF, and the incidence of intra-abdominal hemorrhage was included as one of the secondary end points.

Results: A total of 318 patients were randomly assigned, and 2 patients were excluded as ineligible. Of the 316 remaining patients, 150 (50.3%) were male. The modified intent-to-treat population constituted 159 patients (50.3%) in the separate division group and 157 patients (49.7%) in the combined division group. In the modified intent-to-treat set, the proportion of grade B/C PF in the separate division group was 27.1% (42 of 155) vs 28.6% (44 of 154) in the combined division group (adjusted odds ratio, 1.108; 95% CI, 0.847-1.225; P = .047), demonstrating noninferiority of the combined division of the splenic vein against separate division. The incidence of postoperative intra-abdominal hemorrhage in the 2 groups was identical at 1.3%.

Conclusions And Relevance: This study demonstrated noninferiority of the combined division of the splenic vein compared with separate division of the splenic vein regarding safety. Thus, isolating the splenic vein from the pancreatic parenchyma is deemed unnecessary.

Trial Registration: ClinicalTrials.gov Identifier: NCT02871804.
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http://dx.doi.org/10.1001/jamasurg.2021.0108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931136PMC
May 2021

Oncogenic transcriptomic profile is sustained in the liver after the eradication of the hepatitis C virus.

Carcinogenesis 2021 05;42(5):672-684

Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Hepatocellular carcinoma (HCC) developing after hepatitis C virus (HCV) eradication is a serious clinical concern. However, molecular basis for the hepatocarcinogenesis after sustained virologic response (SVR) remains unclear. In this study, we aimed to unveil the transcriptomic profile of post-SVR liver tissues and explore the molecules associated with post-SVR carcinogenesis. We analysed 90 RNA sequencing datasets, consisting of non-cancerous liver tissues including 20 post-SVR, 40 HCV-positive and 7 normal livers, along with Huh7 cell line specimens before and after HCV infection and eradication. Comparative analysis demonstrated that cell cycle- and mitochondrial function-associated pathways were altered only in HCV-positive non-cancerous liver tissues, whereas some cancer-related pathways were up-regulated in the non-cancerous liver tissues of both post-SVR and HCV-positive cases. The persistent up-regulation of carcinogenesis-associated gene clusters after viral clearance was reconfirmed through in vitro experiments, of which, CYR61, associated with liver fibrosis and carcinogenesis in several cancer types, was the top enriched gene and co-expressed with cell proliferation-associated gene modules. To evaluate whether this molecule could be a predictor of hepatocarcinogenesis after cure of HCV infection, we also examined 127 sera from independent HCV-positive cohorts treated with direct-acting antivirals (DAAs), including 60 post-SVR-HCC patients, and found that the elevated serum Cyr61 was significantly associated with early carcinogenesis after receiving DAA therapy. In conclusion, some oncogenic transcriptomic profiles are sustained in liver tissues after HCV eradication, which might be a molecular basis for the liver cancer development even after viral clearance. Among them, up-regulated CYR61 could be a possible biomarker for post-SVR-HCC.
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http://dx.doi.org/10.1093/carcin/bgab014DOI Listing
May 2021

Landmarks to identify segmental borders of the liver: A review prepared for PAM-HBP expert consensus meeting 2021.

J Hepatobiliary Pancreat Sci 2021 Jan 23. Epub 2021 Jan 23.

Center for Advanced Treatment of Hepatobiliary and Pancreatic Diseases, Ageo Central General Hospital, Saitama, Japan.

Background: In preparation for the upcoming consensus meeting in Tokyo in 2021, this systematic review aimed to analyze the current available evidence regarding surgical anatomy of the liver, focusing on useful landmarks, strategies and technical tools to perform precise anatomic liver resection (ALR).

Methods: A systematic review was conducted on MEDLINE/PubMed for English articles and on Ichushi database for Japanese articles until September 2020. The quality assessment of the articles was performed in accordance with the Scottish Intercollegiate Guidelines Network (SIGN).

Results: A total of 3169 manuscripts were obtained, 1993 in English and 1176 in Japanese literature. Subsequently, 63 English and 20 Japanese articles were selected and reviewed. The quality assessment of comparative series and case series was revealed to be usually low; only six articles were qualified as high quality. Forty-two articles focused on analyzing intersegmental/sectional planes and their relationship with specific hepatic landmark veins. In 12 articles, the authors aimed to investigate liver surface anatomic structures, while 36 articles aimed to study technological tools and contrast agents for surgical segmentation during ALR. Although Couinaud's classification has remained the cornerstone in daily diagnostic/surgical practices, it does not always portray the realistic liver segmentation and there has been no standardization on which a single strategy should be followed to perform precise ALR.

Conclusions: A global consensus should be pursued in order to establish clear guidelines and proper recommendations to perform ALR in the era of minimally invasive surgery.
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http://dx.doi.org/10.1002/jhbp.899DOI Listing
January 2021

Severity of liver fibrosis using shear wave elastography is influenced by hepatic necroinflammation in chronic hepatitis patients, but not in cirrhotic patients.

Hepatol Res 2021 Apr 25;51(4):436-444. Epub 2021 Feb 25.

Ultrasound Imaging Center, Hyogo College of Medicine Hospital, Nishinomiya, Japan.

Aim: Shear wave elastography (SWE) in patients with chronic liver diseases is a noninvasive useful method for the diagnosis of liver fibrosis severity, which can be an alternative to liver biopsy. However, the liver stiffness measurement using SWE can be affected by various factors including hepatic inflammation, extrahepatic cholestasis, heart failure, and underlying liver diseases. The aim of this study is to clarify the correlation between liver stiffness using SWE and hepatic necroinflammation serologically and pathologically.

Methods: A total of 843 patients with chronic liver disease who received liver biopsy were analyzed. Liver stiffness measurement using transient elastography (TE) and virtual touch quantification (VTQ) were carried out on the same day as the liver biopsy. The correlation between SWE and hepatic inflammation was analyzed serologically and pathologically.

Results: The liver stiffness values increased significantly with the progression of liver fibrosis and inflammation (overall p < 0.001). In patients with F0-1, F2, and F3, TE and VTQ values of A2 or A3 were significantly higher than those of A0 or A1 (p value, all <0.05), but not in patients with F4. The median alanine aminotransferase (ALT) values increased significantly with the progression of liver inflammation (p < 0.001). Moreover, TE and VTQ in patients with ALT ≥70 IU/L were significantly higher than those in patients with ALT <70 IU/L (p < 0.01), but not in patients with F4.

Conclusion: Shear wave elastography can be affected by hepatic necroinflammation in F0-F3 fibrosis, but not in F4.
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http://dx.doi.org/10.1111/hepr.13617DOI Listing
April 2021

A New Ultrasonographic "Fluttering Sign" for Hepatic Hemangioma.

Ultrasound Med Biol 2021 04 5;47(4):941-946. Epub 2021 Jan 5.

Division of Hepatobiliary and Pancreatic Disease, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.

The aim of the study described here was to clarify the diagnostic value of the fluttering sign, a new sign that characterizes hepatic hemangiomas in gray-scale ultrasonography (US). It refers to a phenomenon in which the speckled echogenicity inside the hemangioma changes continuously and seems to be moving. A total of 172 hemangiomas diagnosed with contrast-enhanced US were evaluated. The fluttering sign was found in 123 of 172 hemangiomas (71.5%). Its prevalence was significantly higher than that of the marginal strong echo (89/172, 51.7%, p < 0.001), posterior acoustic enhancement (103/172, 59.9%, p = 0.031) and chameleon sign (100/172, 58.1%, p = 0.013). In addition, the fluttering sign was observed significantly more frequently in mixed or hypo-echoic tumors than in hyper-echoic tumors (p < 0.001), relatively large tumors (p < 0.001) and tumors that were less than 5 cm from the body surface (p = 0.015). The fluttering sign in gray-scale US has great potential to be a new complementary sign for the diagnosis of hemangioma.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2020.12.004DOI Listing
April 2021

The impact of peritoneal lavage cytology in biliary tract cancer (KHBO1701): Kansai Hepato-Biliary Oncology Group.

Cancer Rep (Hoboken) 2021 04 6;4(2):e1323. Epub 2020 Dec 6.

Kansai Hepato-Biliary Oncology Group, Osaka, Japan.

Background: Only few studies in literature have analyzed the clinical effects of peritoneal lavage status in biliary tract cancers.

Aim: We aimed to assess the effect of cytology-positive peritoneal lavage on survival for patients with biliary tract cancer who underwent curative resection.

Methods: The KHBO1701 study was a multi-institutional retrospective study that assessed the clinical effects of peritoneal lavage cytology in biliary tract cancers. Using clinicopathological data from 11 Japanese institutions, we compared long-term outcomes between patients with cytology-positive and cytology-negative peritoneal lavage.

Results: Of 169 patients who underwent curative resection, 164 were cytology-negative, and five were cytology-positive. The incidence of portal invasion and preoperative carbohydrate antigen 19-9 levels were higher in the cytology-positive group than in the cytology-negative group. The incidence of peritoneal metastatic recurrence was also higher, and overall survival tended to be worse in the cytology-positive group. In contrast, recurrence-free survival was similar between the cytology-negative and cytology-positive groups.

Conclusions: The positive status of peritoneal lavage cytology could moderately affect the survival of patients with biliary tract cancers. Given that surgical resection is the only curative treatment option, it may be acceptable to resect biliary tract cancers without other non-curative factors, regardless of peritoneal lavage cytology status.
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http://dx.doi.org/10.1002/cnr2.1323DOI Listing
April 2021

Blockade of Tumor Necrosis Factor by Etanercept Prevents Postoperative Adhesion Formation in Mice.

Cell Physiol Biochem 2020 Oct;54(5):1041-1053

Department of Gastroenterological Surgery, Hyogo College of Medicine, Nishinomiya, Japan,

Background/aims: Although adhesion formation is a frequent adverse event following intraperitoneal surgery, efficient prophylactic interventions have not yet been established. We recently reported that blockade of interleukin (IL)-6 prevented postoperative adhesion after cecum cauterization. Intriguingly, this intervention dampened tumor necrosis factor (TNF) induction in the injured serosa. Herein, we addressed whether TNF might be a key target and, if so, how TNF blockade rescued adhesion formation.

Methods: Mice were administered an anti-TNF biologic (etanercept) on days -2 and -1 before and upon cecal cauterization. The adhesion scores were evaluated at day 7 postoperatively. Histological alterations were examined by immunochemistry/immunofluorescence studies. We incubated human neutrophils and mesothelial cell line cells with recombinant TNF in the presence of etanercept and measured transcript levels of cytokines and chemokines by quantitative reverse transcription-polymerase chain reaction (RT-qPCR).

Results: Etanercept rescued mice from adhesion formation, accompanied by a robust reduction of neutrophilia in the injured serosa. Immunofluorescence revealed a substantial formation of neutrophil extracellular traps (NETs) with the potential to induce tissue damage and profibrotic responses. In contrast, the etanercept-treated mice lacked NET formation. In addition, etanercept inhibited TNF-induced IL-6, TNF, and neutrophil-recruiting chemokines in neutrophils and mesothelial cells, a major cellular source of myofibroblasts in the adhesion band.

Conclusion: Prophylactic administration of etanercept might be a potential strategy for preventing postoperative adhesion formation.
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http://dx.doi.org/10.33594/000000286DOI Listing
October 2020

Enhanced patterns on intraoperative contrast-enhanced ultrasonography predict outcomes after curative liver resection in patients with hepatocellular carcinoma.

Surg Today 2021 May 22;51(5):764-776. Epub 2020 Sep 22.

Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan.

Purpose: This study aimed to clarify what hepatocellular carcinoma (HCC) phenotype, as categorized by intraoperative contrast-enhanced ultrasonography (CEUS), showed a high risk of recurrence after hepatic resection.

Methods: Patients who underwent initial curative hepatectomy with intraoperative CEUS for a single HCC nodule were retrospectively assigned to three patterns of fine (FI), vascular (VA), and irregular (IR) according to the maximum intensity projection pattern based on intraoperative CEUS. Staining was performed for Ki-67, pyruvate kinase type M2 (PKM2), and vascular endothelial growth factor (VEGF) to assess the tumor proliferative activity, tumor glucose metabolism, and angiogenesis, respectively.

Results: Of 116 patients, 18, 50, and 48 were assigned to the FI, VA and IR patterns, respectively. IR patients demonstrated a significantly worse prognosis for both the recurrence-free survival (RFS) and overall survival (OS) (P = 0.0002, 0.0262, respectively) than did patients with other patterns. A multivariate analysis revealed an IR pattern in intraoperative CEUS to be an independent predictive factor for a poor RFS, and major hepatectomy and an IR pattern were independent predictive factors for a poor OS. An IR pattern was closely related to the tumor size (≥ 3.3 cm) and poor histological differentiation and showed a high Ki-67 index, low VEGF expression, and high PKM2 expression.

Conclusion: IR-pattern HCCs as classified by intraoperative CEUS may be associated with a higher risk of recurrence and worse outcomes in HCC patients after hepatic resection than other patterns.
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http://dx.doi.org/10.1007/s00595-020-02145-wDOI Listing
May 2021

Cytoglobin-expressing cells in the splenic cords contribute to splenic fibrosis in cirrhotic patients.

Histol Histopathol 2020 Nov 18;35(11):1319-1328. Epub 2020 Sep 18.

Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.

Background And Aim: Among several noninvasive evaluation methods of portal hypertension (PH), the measurement of spleen stiffness is a reliable method for predicting esophageal variceal bleeding; however, the underlying mechanisms for increased stiffness remain unclear. We attempted to elucidate the pathological changes to the spleen and the underlying mechanisms in patients with PH.

Methods: Histological examination was performed using splenic tissues from 42 patients with PH who underwent laparoscopic splenectomy, and the results were compared with those from patients without PH.

Results: In addition to splenic sinus congestion, diffuse fibrosis was detected in the splenic cords in the red pulp of patients with PH. The degree of the fibrosis was well correlated with severity in thrombocytopenia and splenomegaly. Cells expressing α-smooth muscle actin dramatically increased in the splenic cord. Cytoglobin (Cygb) expression was detected in human splenic cords as reported in animal reticular cells, and fluorescent double immunostaining revealed that these cells expressed α-smooth muscle actin in patients with PH, suggesting transformation of Cygb-expressing cells to myofibroblastic cells. Expression levels of nicotinamide adenine dinucleotide phosphate oxidase (NOX) 2, nitrotyrosine, and transforming growth factor-β were markedly upregulated in the red pulp of patients with PH, implying a significant role of oxidative stress in the mechanism for splenic fibrosis.

Conclusion: Splenic fibrosis progresses along with advancement of PH. Cygb-expressing cells in the splenic cord possibly participate in this process through mechanisms including oxidative stress.
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http://dx.doi.org/10.14670/HH-18-257DOI Listing
November 2020

What is a precise anatomic resection of the liver? Proposal of a new evaluation method in the era of fluorescence navigation surgery.

J Hepatobiliary Pancreat Sci 2021 Jun 4;28(6):479-488. Epub 2020 Oct 4.

Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background/purpose: Indocyanine green (ICG) fluorescence navigation has been adapted for anatomic liver resection (AR) but an objective method for evaluation of its validity is required. This pilot study aimed to propose a new method to evaluate the accuracy of parenchymal division along the plane between hepatic segments and estimate the real-time navigation efficacy for AR by the Medical Imaging Projection System (MIPS), which continuously demonstrates the transection plane using projection mapping with ICG fluorescence.

Methods: Ten patients who underwent open AR using liver segmentation with ICG fluorescence technique between August 2016 and July 2019 were included: six patients under MIPS guidance (MIPS group), while four using only conventional ICG fluorescence technique before parenchymal resection (non-MIPS group). Densitometry of the captured fluorescence image was performed to evaluate the fluorescence area ratio of each transection plane. The accurate fluorescence area ratio was calculated by subtracting the fluorescence area rate on the resected side from that on the remnant side.

Results: The accurate fluorescence area ratio of the MIPS group and the non-MIPS group was 23.0 ± 12.6% and 5.6 ± 9.5%, respectively (P = .038).

Conclusions: Based on the results of our new method, real-time navigation using the MIPS may facilitate performing AR along the plane between hepatic segments.
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http://dx.doi.org/10.1002/jhbp.824DOI Listing
June 2021

Intraoperative Ultrasound Elastography Is Useful for Determining the Pancreatic Texture and Predicting Pancreatic Fistula After Pancreaticoduodenectomy.

Pancreas 2020 07;49(6):799-805

From the Department of Surgery.

Objectives: Pancreatic fistula (PF) is one of the most common complications after pancreaticoduodenectomy (PD). The soft pancreatic texture is known to be an important predictive factor for PF after PD. However, its evaluation is dependent on the sense of touch by the operator during operation, thus not objective. The aim of this study was to investigate the relationship between mean elasticity via intraoperative ultrasound elastography and histological pancreatic hardness, as well as predictive factor of PF after PD.

Methods: Forty-eight patients who underwent ultrasound elastography during PD and had pancreatic parenchyma histologically evaluated were included.

Results: Pancreatic fistula was noted in 20 patients. There were significant differences in the histological pancreatic fibrosis rate between soft pancreas group (8.2%) and hard pancreas group (28.4%, P < 0.05) and in the mean elasticity between soft pancreas group (1.94 m/s) and hard pancreas group (3.17 m/s, P < 0.05). The mean elasticity was significantly correlated with pancreatic fibrosis rate (P < 0.05). A multivariate analysis revealed that the mean elasticity of less than 2.2 m/s was a significant predictor of PF after PD (P = 0.003).

Conclusions: Intraoperative ultrasound elastography could predict pancreatic texture objectively. The mean elasticity of less than 2.2 m/s was a significant predictor of PF after PD.
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http://dx.doi.org/10.1097/MPA.0000000000001576DOI Listing
July 2020

Conversion to complete resection with mFOLFOX6 with bevacizumab or cetuximab based on K-RAS status for unresectable colorectal liver metastasis (BECK study): Long-term results of survival.

J Hepatobiliary Pancreat Sci 2020 Aug 9;27(8):496-509. Epub 2020 Jun 9.

Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background/purpose: To investigate the long-term outcome and entire treatment course of patients with technically unresectable CRLM who underwent conversion hepatectomy and to examine factors associated with conversion to hepatectomy.

Methods: Recurrence and survival data with long-term follow-up were analyzed in the cohort of a multi-institutional phase II trial for technically unresectable colorectal liver metastases (the BECK study).

Results: A total of 22/12 patients with K-RAS wild-type/mutant tumors were treated with mFOLFOX6 + cetuximab/bevacizumab. The conversion R0/1 hepatectomy rate was significantly higher in left-sided primary tumors than in right-sided tumors (75.0% vs 30.0%, P = .022). The median follow-up was 72.6 months. The 5-year overall survival (OS) rate in the entire cohort was 48.1%. In patients who underwent R0/1 hepatectomy (n = 21), the 5-year RFS rate and OS rate were 19.1% and 66.3%, respectively. At the final follow-up, seven patients had no evidence of disease, five were alive with disease, and 20 had died from their original cancer. All 16 patients who achieved 5-year survival underwent conversion hepatectomy, and 11 of them underwent further resection for other recurrences (median: 2, range: 1-4).

Conclusions: Conversion hepatectomy achieved a similar long-term survival to the results of previous studies in initially resectable patients, although many of them experienced several post-hepatectomy recurrences. Left-sided primary was found to be the predictor for conversion hepatectomy.
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http://dx.doi.org/10.1002/jhbp.747DOI Listing
August 2020

Hepatectomy using a novel cart-based indocyanine green fluorescence imaging system.

Surg Today 2020 Oct 29;50(10):1308-1313. Epub 2020 Apr 29.

Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.

Indocyanine green (ICG) fluorescence has been used effectively in imaging for locating hepatic tumors and evaluating hepatic segmentation. We report our initial experience of performing hepatic resection using the novel cart-based ICG fluorescence device LIGHTVISION. This device has several promising features, including the fact that there is no need to switch off the room light, it has hands-free operability, and it can be located away from the workspace to facilitate a good field of vision. We used the LIGHTVISION for 15 patients and detected 59 nodules (86.8%) in a total of 68 tumors in the resected specimens during surgery. The LIGHTVISION was used to identify the hepatic segments in ten patients, and the boundaries of the segment were clearly visualized on the liver surface on fluorescent images in all patients. All tumors were resected with surgical margins. Thus, the LIGHTVISION appears to be very useful for navigation in liver surgery.
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http://dx.doi.org/10.1007/s00595-020-02005-7DOI Listing
October 2020

Improvement in Hyperglycemia Prevents Surgical Site Infection Irrespective of Insulin Therapy in Non-diabetic Patients Undergoing Gastrointestinal Surgery.

World J Surg 2020 05;44(5):1450-1458

Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.

Background: Intensive glycemic control is recommended to prevent surgical site infections (SSI). Our aim was to evaluate retrospectively the effect of improvement in hyperglycemia irrespective of insulin use on the incidence of SSI in non-diabetic patients.

Methods: The highest blood glucose (BG) concentration within 12 h (early peak BG) and the final BG from 12 to 24 h after surgery were evaluated in patients who underwent gastrointestinal surgery. Patients with an early peak BG of ≥150 mg/dL were divided into those with persistent (final BG of ≥150 mg/dL) and improved hyperglycemia (final BG of <150 mg/dL). Patients without hyperglycemia and those with late-onset hyperglycemia were also assessed for SSI risk.

Results: Overall, 1612 patients were studied (diabetes, n = 293). Although hyperglycemia increased the SSI rates in non-diabetic patients, no correlation was demonstrated in patients with diabetes at any cutoff final BG defining htperglycemia except for 180 mg/dL. Hyperglycemia improved without insulin therapy in 283 of 512 non-diabetic patients who had early hyperglycemia. The adjusted standardized residual for those with SSI and persistent hyperglycemia was 5.2 (P < 0.05). In contrast, the absence of hyperglycemia was a significant preventive factor for SSI. In the multivariate analyses, persistent hyperglycemia was an independent risk factor for SSI (odds ratio 1.54; 95% confidence interval 1.03-2.31).

Conclusions: Remission of hyperglycemia within 24 h after surgery prevented SSI in non-diabetic patients. Considering that hyperglycemia improved in approximately half of patients without insulin therapy, commencement of insulin dosing after two consecutive BGs of ≥150 mg/dL might be reasonable, especially in general wards.
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http://dx.doi.org/10.1007/s00268-020-05371-yDOI Listing
May 2020

Objective Response by mRECIST Is an Independent Prognostic Factor for Overall Survival in Hepatocellular Carcinoma Treated with Sorafenib in the SILIUS Trial.

Liver Cancer 2019 Nov 8;8(6):505-519. Epub 2019 Oct 8.

National Cancer Center Hospital, Tokyo, Japan.

Objective: In SILIUS (NCT01214343), combination of sorafenib and hepatic arterial infusion chemotherapy did not significantly improve overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC) compared with sorafenib alone. In this study, we explored the relationship between objective response by mRECIST and OS in the sorafenib group, in the combination group, and in all patients in the SILIUS trial.

Methods: Association between objective response and OS in patients treated with sorafenib ( = 103) or combination ( = 102) and all patients ( = 205) were analyzed. The median OS of responders was compared with that of non-responders. Landmark analyses were performed according to objective response at several fixed time points, as sensitivity analyses, and the effect on OS was evaluated by Cox regression analysis with objective response as a time-dependent covariate, with other prognostic factors.

Results: In the sorafenib group, OS of responders ( = 18) was significantly better than that of non-responders ( = 78) ( < 0.0001), where median OS was 27.2 (95% CI, 16.0-not reached) months for responders and 8.9 (95% CI, 6.5-12.6) months for non-responders. HRs from landmark analyses at 4, 6, and 8 months were 0.45 ( = 0.0330), 0.37 ( = 0.0053), and 0.36 ( = 0.0083), respectively. Objective response was an independent predictor of OS based on unstratified Cox regression analyses. In the all patients and the combination group, similar results were obtained.

Conclusions: In the SILIUS trial, objective response by sorafenib assessed by mRECIST is an independent prognostic factor for OS in patients with HCC.
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http://dx.doi.org/10.1159/000503032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883462PMC
November 2019

Anti-interleukin-6 receptor antibody treatment ameliorates postoperative adhesion formation.

Sci Rep 2019 11 26;9(1):17558. Epub 2019 Nov 26.

Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.

Postoperative adhesion formation often ruins the quality of life or is an obstacle to illnesses with curative operation such as cancer. Previously we demonstrated that interferon-γ-promoted fibrin deposition drove postoperative adhesion formation. However, its underlying cellular and molecular mechanisms remain poorly understood. We found that myofibroblasts of the adhesion predominantly expressed signature molecules of mesothelial cells that line the serosa. Microarray analysis revealed IL-6 as a key underlying player, supported by elevated IL-6 levels in the peritoneal fluid of post-laparotomy human subjects. Injured serosa of cecum-cauterized mice also exhibited induction of Il6, which was followed by Tnf, concomitant with rapid accumulation of neutrophils, substantial population of which expressed TGF-β1, a master regulator of fibrosis. Besides, neutrophil-ablated mice showed reduction in induction of the adhesion, suggesting that TGF-β1neutrophils triggered the adhesion. Human neutrophils expressed TGFB1 in response to TNF-α and TNF in response to IL-6. Moreover, anti-IL-6 receptor monoclonal antibody abrogated neutrophil recruitment and adhesion formation. Thus, IL-6 signaling represents a potential target for the prevention of postoperative adhesions.
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http://dx.doi.org/10.1038/s41598-019-54175-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879753PMC
November 2019

ALPlat criterion for the resection of hepatocellular carcinoma based on a predictive model of posthepatectomy liver failure.

Surgery 2020 02 11;167(2):410-416. Epub 2019 Nov 11.

Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: The indocyanine green test is used widely to evaluate the risk of posthepatectomy liver failure for hepatocellular carcinoma. A more convenient and reliable scoring system is desired owing to limited accuracy and availability of the indocyanine green test. This study aimed to establish a new selection criterion for liver resection in HCC.

Methods: We reviewed retrospectively 876 patients undergoing a partial hepatectomy for hepatocellular carcinoma between 2007 and 2015 in 8 affiliated hospitals. Posthepatectomy liver failure grades B and C were regarded as posthepatectomy liver failure. We identified the risk factors for posthepatectomy liver failure and established a predictive model based on a formula for the probability of posthepatectomy liver failure. External validation was performed in an additional cohort of 250 patients.

Results: Posthepatectomy liver failure occurred in 92 patients (11%). The area under the receiver operating characteristic curve for the prediction of posthepatectomy liver failure was 0.646 for the platelet count, 0.641 for albumin, 0.623 for the percentage of liver remnant, and 0.607 for the plasma disappearance rate of indocyanine green. Logistic regression analysis provided a formula for the probability of posthepatectomy liver failure consisting of platelet count, albumin, and liver remnant. We defined platelet count + 90 × albumin as the ALPlat index and established an ALPlat-based criterion for operative resection that secured the same risk assumed by the indocyanine green-based criterion (Makuuchi's criterion). This criterion exhibited a greater sensitivity and specificity than the indocyanine green-based criterion in the validation cohort.

Conclusion: The ALPlat criterion is a simple and useful method to assess liver function and to make therapeutic decisions in patients with hepatocellular carcinoma.
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http://dx.doi.org/10.1016/j.surg.2019.09.021DOI Listing
February 2020

Clinical practice guidelines for hepatocellular carcinoma: The Japan Society of Hepatology 2017 (4th JSH-HCC guidelines) 2019 update.

Hepatol Res 2019 Oct 6;49(10):1109-1113. Epub 2019 Sep 6.

The committee for Revision of the Clinical Practice Guidelines for Hepatocellular Carcinoma, Tokyo, Japan.

The fourth version of Clinical Practice Guidelines for Hepatocellular Carcinoma was revised by the Japan Society of Hepatology, according to the methodology of evidence-based medicine and partly to the Grading of Recommendations Assessment, Development, and Evaluation system, which was published in October 2017 in Japanese. New or revised recommendations were described, herein, with a special reference to the surveillance, diagnostic, and treatment algorithms.
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http://dx.doi.org/10.1111/hepr.13411DOI Listing
October 2019

Randomised phase II trial of mFOLFOX6 plus bevacizumab versus mFOLFOX6 plus cetuximab as first-line treatment for colorectal liver metastasis (ATOM trial).

Br J Cancer 2019 07 9;121(3):222-229. Epub 2019 Jul 9.

Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, Japan.

Background: Chemotherapy with biologics followed by liver surgery improves the resection rate and survival of patients with colorectal liver metastasis (CRLM). However, no prospective study has compared the outcomes of chemotherapy with bevacizumab (BEV) versus cetuximab (CET).

Methods: The ATOM study is the first randomised trial comparing BEV and CET for initially unresectable CRLM. Patients were randomly assigned in a 1:1 ratio to receive mFOLFOX6 plus either BEV or CET. The primary endpoint was progression-free survival (PFS).

Results: Between May 2013 and April 2016, 122 patients were enrolled. Median PFS was 11.5 months (95% CI 9.2-13.3 months) in the BEV group and 14.8 months (95% CI 9.7-17.3 months) in the CET group (hazard ratio 0.803; P = 0.33). Patients with a smaller-number but larger-sized metastases did better in the CET group. In the BEV and CET groups, the response rates were 68.4% and 84.7% and the resection rates were 56.1% and 49.2%, respectively.

Conclusion: Although CET achieved a better response rate than BEV for patients with a small number of large liver metastases, both biologics had similar efficacy regarding liver resection and acceptable safety profiles. To achieve optimal PFS, biologics should be selected in accordance with patient conditions.

Trial Registration: This trial is registered at ClinicalTrials.gov (number NCT01836653), and UMIN Clinical Trials Registry (UMIN-CTR number UMIN000010209).
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http://dx.doi.org/10.1038/s41416-019-0518-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738101PMC
July 2019
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