Publications by authors named "Shintaro Yagi"

213 Publications

Correction to: Dynamic switch of immunity and antitumor effects of metformin in rat spontaneous esophageal carcinogenesis.

Cancer Immunol Immunother 2021 Sep 7. Epub 2021 Sep 7.

Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan.

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http://dx.doi.org/10.1007/s00262-021-03039-7DOI Listing
September 2021

Dynamic switch of immunity and antitumor effects of metformin in rat spontaneous esophageal carcinogenesis.

Cancer Immunol Immunother 2021 Aug 16. Epub 2021 Aug 16.

Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan.

Chronic inflammation contributes to tumor development by creating a local microenvironment that facilitates neoplastic transformation and potentiates the progression of cancer. Esophageal cancer (EC) is an inflammation-associated malignancy with a poor prognosis. The nature of the switch between chronic inflammation of the esophagus and EC-related immunological changes remains unclear. Here, we examined the dynamic alterations of immune cells at different stages of chronic esophagitis, Barrett's esophagus (BE) and EC using an esophageal spontaneous carcinogenesis rat model. We also investigated the anticancer effects of metformin. To stimulate EC carcinogenesis, chronic gastroduodenal reflux esophagitis via esophagojejunostomy was induced in 120 rats in metformin-treated and non-treated (control) groups. After 40 weeks, BE and EC developed in 96.7% and 63.3% of the control group, and in 66.7% and 23.3% of the metformin-treated group, respectively. Flow cytometric analysis demonstrated that the balance of M1/M2-polarized or phospho-Stat3-positive macrophages, regulatory T, cytotoxic T, natural killer (NK), NK T cells, and Th17 T cells was dynamically changed at each stage of the disease and were resolved by metformin treatment. These findings clarify the immunity in esophageal carcinogenesis and suggest that metformin could suppress this disease by improving the immunosuppressive tumor microenvironment and immune evasion.
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http://dx.doi.org/10.1007/s00262-021-03027-xDOI Listing
August 2021

Reply to: "Understanding HBcrAg components improves the interpretation of clinical HBcrAg assay results".

J Hepatol 2021 Oct 8;75(4):998-999. Epub 2021 Jul 8.

Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya, Japan; Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2021.06.047DOI Listing
October 2021

[Complete Remission of Metastatic Renal Cell Carcinoma with Invasion of the Duodenum and Pancreas after Treatment with Nivolumab Plus Ipilimumab Followed by Axitinib and Surgery : A Case Report].

Hinyokika Kiyo 2021 May;67(5):197-203

The Department of Urology, Kyoto University Hospital.

A man in his 60s was diagnosed with clear cell carcinoma of the right kidney with multiple lung metastases, tumor thrombus of the inferior vena cava (IVC), and invasion of the duodenum and pancreas. Ipilimumab plus nivolumab was administered as first-line therapy. After 3 treatment courses, computed tomography (CT) demonstrated a slight decrease in the size of the primary tumor and lung metastases. However, the patient became hemodynamically unstable due to persistent duodenal bleeding during treatment despite frequent blood transfusions. Axitinib was then initiated as second-line therapy. The duodenal bleeding ceased 10 days after starting axitinib and his anemia remissed. Subsequent CT showed further decrease in the size of the primary tumor and lung metastases. The patient underwent right nephrectomy after improvement of nutrition. IVC thrombectomy, and pancreaticoduodenectomy. The lung metastases disappeared on postoperative imaging and no additional treatment was provided. Twelve months after surgery, he was in good health and showed no signs of recurrence.
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http://dx.doi.org/10.14989/ActaUrolJap_67_5_197DOI Listing
May 2021

Micro- and macro-borderless surgery using a newly developed high-resolution (4K) three-dimensional video system.

PLoS One 2021 12;16(5):e0250559. Epub 2021 May 12.

Department of Organ Fabrication, Keio University School of Medicine, Tokyo, Japan.

Objective: Microsurgery using conventional optical microscopes or surgical loupes features a limited field of view and imposes a serious strain on surgeons especially during long surgeries. Here we advocate the micro- and macro-borderless surgery (MMBS) using a novel high-resolution (4K) three-dimensional (3D) video system. This study aimed to confirm the applicability of this concept in several surgical procedures.

Methods: We evaluated the possible use and efficacy of MMBS in the following experiments in porcine subjects. Experiment 1 (non-inferiority test) consisted of dissection and anastomosis of carotid artery, portal vein, proper hepatic artery, and pancreatoduodenectomy with surgical loupe versus MMBS. Experiment 2 (feasibility test) consisted of intra-abdominal and intra-thoracic smaller arteries anastomosed by MMBS as a pre-clinical setting. Experiment 3 (challenge on new surgery) consisted of orthotopic liver transplantation of the graft from a donor after circulatory death maintained by machine perfusion. Circulation of the cardiac sheet with a vascular bed in experiment 2 and liver graft during preservation in experiment 3 was evaluated with indocyanine green fluorescence imaging equipped with this system.

Results: Every procedure was completed by MMBS. The operator and assistants could share the same field of view in heads-up status. The focal depth was deep enough not to be disturbed by pulsing blood vessels or respiratory movement. The tissue circulation could be evaluated using fluorescence imaging of this system.

Conclusions: MMBS using the novel system is applicable to various surgeries and valuable for both fine surgical procedures and high-level surgical education.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250559PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115828PMC
May 2021

Analyses Focused on Organisms Would Enhance the Value of Detecting Occult Bacteremia.

J Am Coll Surg 2021 Jul 16;233(1):161-162. Epub 2021 Apr 16.

Kanazawa, Japan.

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http://dx.doi.org/10.1016/j.jamcollsurg.2021.03.031DOI Listing
July 2021

Clinical efficacy of a novel, high-sensitivity HBcrAg assay in the management of chronic hepatitis B and HBV reactivation.

J Hepatol 2021 Aug 21;75(2):302-310. Epub 2021 Mar 21.

Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya, Japan; Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan. Electronic address:

Background & Aims: A fully automated, novel high-sensitivity hepatitis B core-related antigen assay (iTACT-HBcrAg) has been developed. We demonstrate the clinical utility of iTACT-HBcrAg for monitoring chronic hepatitis B (CHB) and for the early detection of HBV reactivation.

Methods: After fundamental assessments, the clinical performance of iTACT-HBcrAg was compared with other HBV markers. i) Serial sera, available from 161 HBeAg-negative patients with CHB and persistently undetectable HBV DNA, were measured by iTACT-HBcrAg and a conventional HBcrAg assay (G-HBcrAg). ii) Serial sera from 13 HBV-reactivated patients were measured by iTACT-HBcrAg and an ultra-high-sensitivity HBsAg immune complex transfer-chemiluminescent enzyme immunoassay (lower limit of detection; 0.0005 IU/ml, ICT-CLEIA) to compare HBV DNA detection. iii) To elucidate the various HBcrAg components detected by iTACT-HBcrAg, OptiPrep density gradient centrifugation analysis was performed on sera obtained before and after HBV reactivation.

Results: The analytical performance of iTACT-HBcrAg was satisfactory. The sensitivity of iTACT-HBcrAg (2.1 Log U/ml) was approximately 10-fold greater than that of G-HBcrAg (2.8 Log U/ml). i) HBcrAg was detectable in the sera of 97.5% (157/161) of patients with CHB by iTACT-HBcrAg, of whom 75.2% (121/161) had ≥2.8 Log U/ml HBcrAg and 22.4% (36/161) had 2.1-2.8 Log U/ml HBcrAg, which was undetectable by G-HBcrAg. ii) 9 and 2 of 13 HBV-reactivated patients were HBcrAg-positive by iTACT-HBcrAg before and at HBV DNA positivity, respectively; 7 and 4 were HBcrAg-positive by iTACT-HBcrAg before and at HBsAg-positivity by ICT-CLEIA, respectively. iii) The HBcrAg detected by iTACT-HBcrAg before HBV reactivation was contained in empty particles (22 KDa precore protein).

Conclusions: iTACT-HBcrAg could be used to better monitor responses to anti-HBV treatments in HBeAg-negative patients and for the early detection of HBV reactivation.

Lay Summary: A fully automated, novel high-sensitivity hepatitis B core-related antigen assay (iTACT-HBcrAg) has been developed. iTACT-HBcrAg can be used to monitor HBeAg-negative patients with chronic hepatitis B, as well as for the early detection of HBV reactivation. iTACT-HBcrAg could be used as a general marker of disease progression and treatment response.
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http://dx.doi.org/10.1016/j.jhep.2021.02.017DOI Listing
August 2021

Reply to: "Predicted Volume or Actual Weight for Graft Selection Policy in Living-donor Liver Transplantation".

Transplantation 2021 04;105(4):e44-e45

Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kyoto University Graduate School of Medicine, Kyoto, Japan.

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http://dx.doi.org/10.1097/TP.0000000000003584DOI Listing
April 2021

Pretransplant Body Composition Abnormality Has a Negative Impact Especially on Living Donor Liver Transplantation.

Transplantation 2021 03;105(3):e37-e38

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

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http://dx.doi.org/10.1097/TP.0000000000003562DOI Listing
March 2021

Clinical validation of quantitative SARS-CoV-2 antigen assays to estimate SARS-CoV-2 viral loads in nasopharyngeal swabs.

J Infect Chemother 2021 Apr 3;27(4):613-616. Epub 2020 Dec 3.

Department of Microbiology and Infectious Diseases, Toho University School of Medicine, 5-21-16 Omori-nishi, Ota-ku, 143-8540, Tokyo, Japan.

Background: Expansion of the testing capacity for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important issue to mitigate the pandemic of coronavirus disease-2019 (COVID-19) caused by this virus. Recently, a sensitive quantitative antigen test (SQT), Lumipulse® SARS-CoV-2 Ag, was developed. It is a fully automated chemiluminescent enzyme immunoassay system for SARS-CoV-2.

Methods: In this study, the analytical performance of SQT was examined using clinical specimens from nasopharyngeal swabs using reverse transcription polymerase chain reaction (RT-PCR) as a control.

Results: Receiver operating characteristic analysis of 24 SARS-CoV-2-positive and 524 -negative patients showed an area under the curve of 0.957 ± 0.063. Using a cut-off value of 1.34 pg/ml, the sensitivity was 91.7%, the specificity was 98.5%, and the overall rate of agreement was 98.2%. In the distribution of negative cases, the 99.5 percentile value was 1.03 pg/ml. There was a high correlation between the viral load calculated using the cycle threshold value of RT-PCR and the concentration of antigen. The tendency for the antigen concentration to decrease with time after disease onset correlated with that of the viral load.

Conclusions: Presented results indicate that SQT is highly concordant with RT-PCR and should be useful for the diagnosis of COVID-19 in any clinical setting. Therefore, this fully automated kit will contribute to the expansion of the testing capability for SARS-CoV-2.
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http://dx.doi.org/10.1016/j.jiac.2020.11.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713570PMC
April 2021

Utility of the antigen test for coronavirus disease 2019: Factors influencing the prediction of the possibility of disease transmission.

Int J Infect Dis 2021 Mar 2;104:65-72. Epub 2021 Jan 2.

Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan. Electronic address:

Objectives: Rapid antigen testing (RAT) for coronavirus disease 2019 (COVID-19) has lower sensitivity but high accuracy during the early stage when compared to reverse transcription quantitative polymerase chain reaction (RT-qPCR). The aim of this study was to investigate the concordance between RAT and RT-qPCR results, and their prediction of disease transmission.

Methods: This single-center retrospective observational study of inpatients with COVID-19 was conducted from March 6 to June 14, 2020. Nasopharyngeal swabs were used to perform RAT and RT-qPCR. The primary endpoint was concordance between RAT and RT-qPCR results. The secondary endpoints were the factors causing disagreement in the results and the estimated transmissibility in RT-qPCR-positive patients with mild symptoms.

Results: Overall, 229 samples in viral transport medium (VTM) were obtained from 105 patients. The positive and negative concordance rates for VTM were 41% vs 99% (κ = 0.37) and 72% vs 100% (κ = 0.50) for samples collected on disease days 2-9. An increased body temperature (odds ratio 0.54) and absence of drugs with potential antiviral effect (odds ratio 0.48) yielded conflicting results. RAT was associated with the ability to end isolation (OR 0.11, 95% confidence interval 0.20-0.61).

Conclusions: RAT and RT-qPCR results were highly consistent for samples collected at the appropriate time and could be useful for inferring the possibility of transmissibility.
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http://dx.doi.org/10.1016/j.ijid.2020.12.079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778366PMC
March 2021

Immunochromatographic test for the detection of SARS-CoV-2 in saliva.

J Infect Chemother 2021 Feb 23;27(2):384-386. Epub 2020 Dec 23.

Department of Microbiology and Infectious Diseases, Toho University School of Medicine, 5-21-16 Omori-nishi, Ota-ku, 1438540, Tokyo, Japan.

We evaluated the rapid immunochromatographic test for severe acute respiratory coronavirus 2 (SARS-CoV-2) antigen detection using 16 saliva specimens collected from 6 COVID-19 hospitalized patients, and detected N-antigen in 4 of 7 RT-PCR positive specimens. This POCT detected SARS-CoV-2 antigen in saliva and would be useful for COVID-19 diagnosis.
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http://dx.doi.org/10.1016/j.jiac.2020.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755575PMC
February 2021

Evaluation of clinical utility of novel coronavirus antigen detection reagent, Espline® SARS-CoV-2.

J Infect Chemother 2021 Feb 23;27(2):319-322. Epub 2020 Dec 23.

Department of Microbiology and Infectious Diseases, Toho University School of Medicine, 5-21-16 Omori-nishi, Ota-ku, 143-8540, Tokyo, Japan.

Background: To prevent the novel coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is necessary to perform early identification and isolation of people shedding the infectious virus in biological materials with high viral loads several days prior to symptom onset. Rapid antigen tests for infectious diseases are useful to prevent the pandemic spread in clinical settings.

Methods: We evaluated a SARS-CoV-2 antigen test, Espline® SARS-CoV-2 reagent, with reverse transcription polymerase chain reaction (RT-PCR) as reference test, using 129 nasopharyngeal swab specimens collected from COVID-19 hospitalized patients or from patients suspected having COVID-19-like symptoms. Out of these, 63 RT-PCR positive and 66 RT-PCR negative specimens were identified.

Results: Among 63 RT-PCR positive specimens, 25 were positive in the Espline test. Test sensitivity was estimated based on the 532.4 copies/reaction of SARS-CoV-2 RNA obtained through receiver operating characteristic analysis. When the specimens were classified based on time since symptom onset, Espline test sensitivity were 73.3% and 29.2% in specimens collected before day 9 and after day 10, respectively.

Conclusion: Although the overall sensitivity of the Espline® SARS-CoV-2 reagent compared with RT-PCR is less, this antigen test can be useful in identifying people with high risk of virus transmission with high viral loads in order to prevent the pandemic and is useful for diagnosing COVID-19 within 30 min.
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http://dx.doi.org/10.1016/j.jiac.2020.11.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757343PMC
February 2021

Liver Regeneration after Hepatectomy and Partial Liver Transplantation.

Int J Mol Sci 2020 Nov 9;21(21). Epub 2020 Nov 9.

Department of Hepatobiliary, Pancreas and Transplant Surgery, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.

The liver is a unique organ with an abundant regenerative capacity. Therefore, partial hepatectomy (PHx) or partial liver transplantation (PLTx) can be safely performed. Liver regeneration involves a complex network of numerous hepatotropic factors, cytokines, pathways, and transcriptional factors. Compared with liver regeneration after a viral- or drug-induced liver injury, that of post-PHx or -PLTx has several distinct features, such as hemodynamic changes in portal venous flow or pressure, tissue ischemia/hypoxia, and hemostasis/platelet activation. Although some of these changes also occur during liver regeneration after a viral- or drug-induced liver injury, they are more abrupt and drastic following PHx or PLTx, and can thus be the main trigger and driving force of liver regeneration. In this review, we first provide an overview of the molecular biology of liver regeneration post-PHx and -PLTx. Subsequently, we summarize some clinical conditions that negatively, or sometimes positively, interfere with liver regeneration after PHx or PLTx, such as marginal livers including aged or fatty liver and the influence of immunosuppression.
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http://dx.doi.org/10.3390/ijms21218414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665117PMC
November 2020

Pretransplantation splenomegaly frequently persists after liver transplantation and can manifest as hypersplenism and graft fibrosis - a retrospective study.

Transpl Int 2020 12 9;33(12):1807-1820. Epub 2020 Nov 9.

Division of Hepato Biliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

The risk factors and clinical impact of post-transplantation splenomegaly (SM) are poorly understood. We investigated the predictors and impacts of post-transplantation SM in 415 LT patients at Kyoto University Hospital from April 2006 to December 2015. First, the predictors and clinical consequences of SM three years post-transplantation were analyzed among spleen-preserved recipients. Second, the clinical data of surviving recipients three years post-transplantation were compared between splenectomized and spleen-preserved recipients. There was no difference in indication for liver transplantation between these two groups. Third, survival outcomes were compared between splenectomized and spleen-preserved recipients. SM was determined as a SV/body surface area (BSA) higher than 152 ml/m . In the first analysis, preoperative SM occurred in 79.9% recipients and SM persisted three years post-transplantation in 72.6% recipients among them. Preoperative SV/BSA was the only independent predictor of three year post-transplantation SM, which was associated with lower platelet (PLT), white blood cell (WBC) counts and significant graft fibrosis (21.4% vs. 2.8%). In the second analysis, spleen-preservation was related to lower PLT, WBC counts and a higher proportion of significant graft fibrosis (26.7% vs. 7.1%) three years post-transplantation. In the third analysis, spleen-preserved recipients showed worse survival than splenectomized recipients. In conclusion, preoperative SM frequently persists more than three years post-transplantation and is associated with subclinical hypersplenism, graft fibrosis, graft loss, and even death.
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http://dx.doi.org/10.1111/tri.13761DOI Listing
December 2020

Left-posterior approach for artery-first en bloc resection in laparoscopic distal pancreatectomy for left-sided pancreatic cancer.

Langenbecks Arch Surg 2020 Dec 6;405(8):1251-1258. Epub 2020 Nov 6.

Division of Hepatobiliary Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine Kyoto University, 54 Shogoin Kawarahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.

Purpose: We describe a "left-posterior approach" in which the important steps in laparoscopic distal pancreatectomy (LDP) for left-sided pancreatic cancer are accomplished in the direction caudal and dorsal to the pancreas.

Methods: The patients who underwent LDP with a left-posterior approach at our hospital from January 2016 to April 2020 were reviewed to evaluate the short-term postoperative outcomes. In LDP, we first dissected retroperitoneal tissues above the left renal vein and superior mesenteric artery, yielding the mobilization of the pancreatic body widely. Then, the splenic artery was divided behind the ventrally lifted pancreas as an artery-first approach. The regional lymphadenectomy was performed in an en bloc manner consecutively in the same operative field. The neck of the pancreas was transected with a linear stapler after mobilization of the spleen.

Results: In nine patients (five men and four women) aged 76 years (range: 64-82 years), the operative time was 398 min (276-482 min) with the estimated blood loss of 40 ml (0-80 ml). No patients developed grade B/C pancreatic fistula or delayed gastric emptying. Postoperative complications classified as grade III in the Clavien-Dindo classification occurred in one patient (abdominal abscess). The pathology confirmed R0 resection in all patients who had pancreatic cancer (n = 5), IPMNs (n = 3), and high-grade pancreatic intraepithelial neoplasia (PanIN) (n = 1). The number of retrieved lymph nodes was 35 (11-49).

Conclusion: The procedure with a left-posterior approach is a rational surgical technique in LDP for left-sided pancreatic cancer.
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http://dx.doi.org/10.1007/s00423-020-02021-8DOI Listing
December 2020

Eosinophilic peritonitis with colon cancer: a case report.

BMC Gastroenterol 2020 Oct 27;20(1):353. Epub 2020 Oct 27.

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

Background: Eosinophilic gastrointestinal disorders (EGIDs) are a rare group of inflammatory disorders that can occur anywhere along the gastrointestinal tract, from the esophagus to the rectum. In particular, those with malignant or benign tumors are extremely rare.

Case Presentation: A 62-year-old man was referred to our hospital with a chief complaint of abdominal fullness. The peripheral white blood cell count was 19,400/µL, and the eosinophil count was 13,300/µL. Abdominal computed tomography showed massive ascites. Cytology of the ascitic fluid showed a large amount of eosinophils and no malignancy. Upper and lower gastrointestinal endoscopies were performed on the suspicion of EGIDs, and colon cancer with no other abnormalities was found. The biopsies of the cancer lesions and non-cancer lesions also showed significant differences in eosinophil counts per high-power field (HPF) between the cancer and non-cancer lesions (median 77.5 [IQR 52-115] vs. 40.5 [35-56]/HPF, P < 0.05). Exploratory laparoscopy showed cloudy massive ascites and thickening of the mesentery. Pathological examination of the mesentery showed a large amount of eosinophils (median 177.5 [IQR 91-227]/HPF) and no malignancy. Based on these findings, it was suspected that the massive ascites due to eosinophilic peritonitis could be associated with colon cancer. Steroid administration resulted in immediate disappearance of the ascites, and laparoscopic left hemicolectomy was safely performed 6 weeks after steroid administration.

Conclusion: This report presented a case of eosinophilic peritonitis that could be related to colon cancer. Exploratory laparoscopy was useful to detect the cause of ascites. The possibility that eosinophilic peritonitis was associated with colon cancer is discussed based on the histopathological findings.
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http://dx.doi.org/10.1186/s12876-020-01500-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590699PMC
October 2020

Donor-dominant one-way matching of human leukocyte antigen-A/B/DR alleles predicts graft-versus-host disease following living donor liver transplantation.

Hepatol Res 2021 Jan 20;51(1):135-148. Epub 2020 Oct 20.

Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Aim: Graft-versus-host disease (GVHD) following liver transplantation is rare but fatal. Therefore, it is important to identify possible risk factors before transplantation. Although it has been suggested that donor-dominant one-way human leukocyte antigen (HLA) matching of three loci (HLA-A/B/DR) is associated with the occurrence of GVHD, the precise significance of HLA matching including HLA-C/DQ/DP remains unclear.

Methods: We retrospectively analyzed the impact of donor-dominant one-way HLA matching at six HLA loci at the allele level on GVHD using clinical registry data from 1759 cases who underwent living donor liver transplantation between June 1990 and June 2019. We extracted cases with donor-dominant one-way HLA matching at the antigen level and reconfirmed them at the allele level using preserved DNA samples.

Results: Three of four cases (75%) who developed GVHD showed donor-dominant one-way HLA matching at three HLA-A/B/DR loci. These cases also showed donor-dominant one-way HLA matching at HLA-C/DQ/DP. Three of six cases (50%) with donor-dominant one-way HLA matching at three loci of HLA-A/B/DR developed GVHD. Notably, none of the cases with donor-dominant one-way HLA matching at one or two HLA-A/B/DR loci developed GVHD, irrespective of matching status at HLA-C/DQ/DP. The HLA matching status at the antigen level was revised in 22 of 56 cases, following reconfirmation at the allele level.

Conclusions: Pairing of donors and recipients with donor-dominant one-way HLA matching at three HLA-A/B/DR loci should be avoided to prevent GVHD. No impact of HLA-C/DQ/DP on GVHD was identified. For liver transplantation, HLA genotypes should be determined at the allele level.
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http://dx.doi.org/10.1111/hepr.13579DOI Listing
January 2021

Is 0.6% Reasonable as the Minimum Requirement of the Graft-to-recipient Weight Ratio Regardless of Lobe Selection in Adult Living-donor Liver Transplantation?

Transplantation 2021 Sep;105(9):2007-2017

Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: Several studies reported favorable outcomes of small-for-size grafts with graft-to-recipient weight ratio (GRWR) <0.8% in living-donor liver transplantation (LDLT). However, their indications should be carefully determined because they must have been indicated for low-risk cases over larger grafts with 0.8% ≤ GRWR. Furthermore, evidence for minimum requirements of GRWR remains inconclusive. We investigated the safety of small-for-size grafts against larger grafts by adjusting for confounding risk factors, and minimum requirement of graft volume in adult LDLT.

Methods: We enrolled 417 cases of primary adult-to-adult LDLT in our center between 2006 and 2019. The outcomes of small grafts (0.6% ≤ GRWR < 0.8%, n = 113) and large grafts (0.8% ≤ GRWR, n = 289) were mainly compared using a multivariate analysis and Kaplan-Meier estimates.

Results: The multivariate analysis showed that small grafts were not a significant risk factor for overall graft survival (GS). In the Kaplan-Meier analysis, small grafts did not significantly affect overall GS regardless of lobe selection (versus large grafts). However, GRWR < 0.6% was associated with poor overall GS. Although there were no significant differences between the 2 groups, unadjusted Kaplan-Meier curves of small grafts were inferior to those of large grafts in subcohorts with ABO incompatibility, and donor age ≥50 years.

Conclusions: Similar outcomes were observed for small and large graft use regardless of lobe selection. 0.6% in GRWR was reasonable as the minimum requirement of graft volume in LDLT. However, small grafts should be indicated carefully for high-risk cases.
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http://dx.doi.org/10.1097/TP.0000000000003472DOI Listing
September 2021

Reply.

Liver Transpl 2021 02 5;27(2):307-308. Epub 2020 Nov 5.

Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kyoto University Graduate School of Medicine, Kyoto, Japan.

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http://dx.doi.org/10.1002/lt.25900DOI Listing
February 2021

Liver transplantation in patients with portal vein thrombosis: A strategic road map throughout management.

Surgery 2020 12 26;168(6):1160-1168. Epub 2020 Aug 26.

Department of Surgery, Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background: Liver transplantation in the setting of portal vein thrombosis is an intricate issue that occasionally necessitates extraordinary procedures for portal flow restoration. However, to date, there is no consensus on a persistent management strategy, particularly with extensive forms. This work aims to introduce our experience-based surgical management algorithm for portal vein thrombosis during liver transplantation and to clarify some of the debatable circumstances associated with this problematic issue.

Methods: Between 2006 and 2019, 494 adults underwent liver transplantation at our institute. Ninety patients had preoperative portal vein thrombosis, and 79 patients underwent living donor liver transplantation. Our algorithm trichotomized the management plan into 3 pathways based on portal vein thrombosis grade. The surgical procedures implemented included thrombectomy, interposition vein grafts, jump grafts from the superior mesenteric vein, jump grafts from a collateral and renoportal anastomosis in 56, 13, 11, 4, and 2 patients, respectively. Four patients with mural thrombi did not require any special intervention.

Results: Thirteen patients experienced posttransplant portal vein complications. They all proved to have a patent portal vein by the end of follow-up regardless of the management modality. No significant survival difference was observed between cohorts with versus without portal vein thrombosis. The early graft loss rate was significantly higher with advanced grades (P = .048) as well as technically demanding procedures (P = .032).

Conclusion: A stepwise broad-minded strategy should always be adopted when approaching advanced portal vein thrombosis during liver transplantation. An industrious preoperative evaluation should always be carried out to locate the ideal reliable source for portal flow restoration.
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http://dx.doi.org/10.1016/j.surg.2020.07.023DOI Listing
December 2020

De novo hepatocellular carcinoma in living donor liver grafts: A Japanese multicenter experience.

Hepatol Res 2020 Dec 27;50(12):1365-1374. Epub 2020 Sep 27.

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Aim: Direct-acting antivirals for hepatitis C virus have reduced the decompensation risk. Immunosuppressants for transplantation raise the risk of occurrence of de novo malignancies. We assessed the probabilities of and risk factors for de novo hepatocellular carcinoma (HCC) development post-living donor liver transplantation (LDLT).

Methods: We retrospectively evaluated the data of developed HCC in a graft including metastatic HCC post-LDLT from 2779 adult cases collected from nine major liver transplantation centers in Japan.

Results: Of 2779 LDLT adult recipients, 34 (1.2%) developed HCCs in their grafts. Of 34, five HCCs appeared to be de novo because of a longer period to tumor detection (9.7 [6.4-15.4] years) and no HCC within the native liver of the two recipients. The donor origin of three of five de novo HCCs was confirmed using microsatellite analysis in resected tissue. Primary disease of all five was hepatitis C virus-related cirrhosis, of which two were treated with direct-acting antivirals. Four of five developed HCC de novo in the hepatitis B core antibody-positive grafts. De novo HCCs had favorable prognosis; four of five were cured with complete remission. However, recurrent HCC (n = 29) in the graft had a poorer outcome, especially in patients with neutrophil to lymphocyte ratio scores above 4 (median survival time, 262 [19-463] days).

Conclusion: Analysis of the database from major liver transplantation institutes in Japan revealed that de novo HCCs determined by microsatellite analysis were rarely detected, but the majority were successfully treated. LDLT recipients with higher risks of de novo HCC, including those with hepatitis B core antibody-positive grafts, should be carefully followed by surveillance of the liver graft.
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http://dx.doi.org/10.1111/hepr.13565DOI Listing
December 2020

Comparison of automated SARS-CoV-2 antigen test for COVID-19 infection with quantitative RT-PCR using 313 nasopharyngeal swabs, including from seven serially followed patients.

Int J Infect Dis 2020 Oct 12;99:397-402. Epub 2020 Aug 12.

Central Clinical Laboratory, Yamanashi Central Hospital, Kofu, Yamanashi, Japan; The University of Tokyo, Bunkyo-ku, Tokyo, Japan.

In routine clinical practice, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is determined by reverse-transcription PCR (RT-PCR). In the current pandemic, a more rapid and high-throughput method is in growing demand. Here, we validated the performance of a new antigen test (LUMIPULSE) based on chemiluminescence enzyme immunoassay. A total of 313 nasopharyngeal swabs (82 serial samples from 7 infected patients and 231 individual samples from 4 infected patients and 215 uninfected individuals) were analyzed for SARS-CoV-2 with quantitative RT-PCR (RT-qPCR) and then subjected to LUMIPULSE. We determined the cutoff value for antigen detection using receiver operating characteristic curve analysis and compared the performance of the antigen test with that of RT-qPCR. We also compared the viral loads and antigen levels in serial samples from seven infected patients. Using RT-qPCR as the reference, the antigen test exhibited 55.2% sensitivity and 99.6% specificity, with a 91.4% overall agreement rate (286/313). In specimens with > 100 viral copies and between 10 and 100 copies, the antigen test showed 100% and 85% concordance with RT-qPCR, respectively. This concordance declined with lower viral loads. In the serially followed patients, the antigen levels showed a steady decline, along with viral clearance. This gradual decline was in contrast with the abrupt positive-to-negative and negative-to-positive status changes observed with RT-qPCR, particularly in the late phase of infection. In summary, the LUMIPULSE antigen test can rapidly identify SARS-CoV-2-infected individuals with moderate to high viral loads and may be helpful for monitoring viral clearance in hospitalized patients.
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http://dx.doi.org/10.1016/j.ijid.2020.08.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422837PMC
October 2020

Living donor liver transplantation for combined hepatocellular-cholangiocarcinoma: A case series of four patients.

Int J Surg Case Rep 2020 28;74:46-52. Epub 2020 Jul 28.

Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Introduction: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver carcinoma whose components include both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Indications for liver transplantation for cHCC-CCA remain controversial.

Case Presentations: Four patients underwent living donor liver transplantation (LDLT) for cHCC-CCA. All patients had multiple tumor nodules preoperatively diagnosed as HCC. Postoperative pathological examinations revealed that one of the tumors was cHCC-CCA. Cases 1 and 2 underwent LDLT for cirrhosis with HCC tumors that met Milan criteria. Case 3 underwent LDLT for recurrent HCC tumors with nonalcoholic steatohepatitis. Although the preoperative examinations showed that the patient met the Kyoto, but not Milan criteria, postoperative pathological examinations revealed that the patient did meet Milan criteria. The three patients who met Milan criteria on postoperative pathological examination had no recurrences after LDLT. Case 4 had multiple tumors with alcoholic liver cirrhosis. Although the preoperative examinations showed that the patient did not meet Milan criteria-but did meet Kyoto criteria-, on postoperative pathological examinations, the patient met neither Millan nor Kyoto criteria. He died of tumor recurrence 15 months after LDLT.

Discussion And Conclusions: Our experiences suggested that patients who meet Millan or Kyoto criteria experienced acceptable outcomes of LDLT for cHCC-CCA. By itself, cHCC-CCA is not contraindication for liver transplantation.
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http://dx.doi.org/10.1016/j.ijscr.2020.07.069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424173PMC
July 2020

Utility of Mac-2 Binding Protein Glycosylation Isomer to Evaluate Graft Status After Liver Transplantation.

Liver Transpl 2021 02 1;27(3):403-415. Epub 2020 Oct 1.

Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University, Kyoto, Japan.

Mac-2 binding protein glycosylation isomer (M2BPGi) is a novel liver fibrosis biomarker, but there are few studies on M2BPGi in liver transplantation (LT) recipients. This study aimed to evaluate the utility of M2BPGi measurement in LT recipients. We collected the clinicopathological data of 233 patients who underwent a liver biopsy at Kyoto University Hospital after LT between August 2015 and June 2019. The median values of M2BPGi in patients with METAVIR fibrosis stages F0, F1, F2, and ≥F3 were 0.61, 0.76, 1.16, and 1.47, respectively, whereas those in patients with METAVIR necroinflammatory indexes A0, A1, and ≥A2 were 0.53, 1.145, and 2.24, respectively. Spearman rank correlation test suggested that the necroinflammatory index had a stronger correlation to the M2BPGi value than the fibrosis stage. The area under the receiver operating characteristic curve of M2BPGi to predict ≥A1 was 0.75, which was significantly higher than that of any other liver fibrosis and inflammation marker. Patients with a rejection activity index (RAI) of ≥3 had a higher M2BPGi value than those with RAI ≤ 2 (P = 0.001). Patients with hepatitis C virus viremia had a higher M2BPGi value than sustained virological responders or those with other etiologies. In conclusion, the present study demonstrated that M2BPGi values are more strongly influenced by necroinflammatory activity and revealed M2BPGi, which has been thought to be a so-called fibrosis marker, as a disease activity marker in transplant recipients. M2BPGi measurement may be useful to detect early stage liver inflammation that cannot be detected by routine blood examination of LT recipients.
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http://dx.doi.org/10.1002/lt.25870DOI Listing
February 2021

Visceral adiposity is an independent risk factor for high intra-operative blood loss during living-donor liver transplantation; could preoperative rehabilitation and nutritional therapy mitigate that risk?

Clin Nutr 2021 03 1;40(3):956-965. Epub 2020 Jul 1.

Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background & Aims: Blood loss during liver transplantation (LT) is one of the major concerns of the transplant team, given the potential negative post-transplant outcomes related to it. Blood loss was reported to be higher in certain body compositions, such as obese patients, undergoing LT. Therefore, we aimed to study the risk factors for high blood loss (HBL) during adult living donor liver transplant (ALDLT) including the body composition markers; visceral-to-subcutaneous adipose tissue area ratio (VSR), skeletal muscle index and intramuscular adipose tissue content. In June 2015, an aggressive perioperative rehabilitation and nutritional therapy (APRNT) program was prescribed in our institute for the patients with abnormal body composition.

Methods: We retrospectively analyzed 394 patients who had undergone their first ALDLT between 2006 and 2019. Risk factors for HBL were analyzed in the total cohort. Differences in blood loss and risk factors were analyzed in relation to the APRNT.

Results: Multivariate risk factor analysis in the total cohort showed that a high VSR (odds ratio (OR): 1.98, 95% confidence interval (CI): 1.19-3.29, P = 0.009), was an independent risk factor for HBL during ALDLT, as well as a history of upper abdominal surgery, simultaneous splenectomy and the presence of a large amount of ascites. After the introduction of the APRNT, a significantly lower blood loss was observed during the ALDLT recipient operation (P = 0.003). Moreover, the significant difference in blood loss observed between normal and high VSR groups before the application of the APRNT (P < 0.001), was not observed with the APRNT (P = 0.85). Likewise, before the APRNT, only high VSR was a risk factor for HBL by multivariate analysis (OR: 2.34, CI: 1.33-4.09, P = 0.003). Whereas with the APRNT, high VSR was no longer a significant risk factor for HBL even by univariate analysis (OR: 0.89, CI: 0.26-3.12, P = 0.86).

Conclusion: Increased visceral adiposity was an independent risk factor for high intraoperative blood loss during ALDLT recipient operation. With APRNT, high VSR was not associated with high blood loss. Therefore, APRNT might have mitigated the risk of high blood loss related to high visceral adiposity.
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http://dx.doi.org/10.1016/j.clnu.2020.06.023DOI Listing
March 2021

Diagnostic potential of presepsin in bacterial infection following hepato-biliary-pancreatic surgery: A prospective observational study.

J Hepatobiliary Pancreat Sci 2020 Oct 21;27(10):756-766. Epub 2020 Aug 21.

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

Background/purpose: The aim in the present study was to elucidate the diagnostic ability of presepsin for postoperative infectious complications following major hepato-biliary-pancreatic (HBP) surgery.

Methods: Between 2017 and 2019, 50 patients with major hepatectomy and 55 patients with pancreatoduodenectomy were enrolled. Presepsin, the neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP), and procalcitonin (PCT) were prospectively measured for the first 2 weeks after surgery. The diagnostic abilities of these biomarkers were compared multidirectionally.

Results: All biomarkers returned to normal ranges within 2 weeks after surgery. However, presepsin, unlike the other biomarkers, showed less nonspecific elevation in response to the invasiveness of the surgical procedure immediately after surgery. Receiver operating characteristic curve analysis revealed that presepsin (area under the curve (AUC), 0.959) had a greater ability to discriminate bacterial infection than PCT (AUC, 0.723), CRP (AUC, 0.800), and the NLR (AUC, 0.804). A very high sensitivity of 93.3% and a specificity of 89.2% were achieved at the cutoff value of 620 pg/mL. Multivariable analysis revealed that presepsin on day 3 (P = .013) independently predicted bacterial infection after HBP surgery.

Conclusions: Presepsin may have a better predictive ability than existing biomarkers for infection following major HBP surgery, which may help us achieve faster and more accurate detection of bacterial infections.
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http://dx.doi.org/10.1002/jhbp.802DOI Listing
October 2020

Living-donor liver transplantation: Right versus left.

Int J Surg 2020 Oct 30;82S:128-133. Epub 2020 Jun 30.

Department of General Surgery, Digestive Disease & Surgery Institute, Cleveland Clinic, Cleveland, OH, USA.

A dilemma of graft selection between right or left livers occurs during the planning of living-donor liver transplantation (LDLT) as well as splitting a whole liver graft into full right/full left grafts in deceased-donor liver transplantation. The right liver's relation to the whole liver could be considered as the trunk of a tree; it has a larger volume, the main axis of bile ducts, and the inferior vena cava mainly belongs to the right liver. Therefore, it was considered as the standard graft in LDLTs. Whether to procure the middle hepatic vein (MHV) with a right liver graft or to leave it attached to the left-liver remnant largely depends on the transplant institute. Recently, most transplant institutes tend to leave the MHV with the left liver for the sake of donor safety. Unlike hepatectomy for liver tumors, it is vital to preserve inflow and outflow for both the resected as well as the remaining livers. While procuring any graft type, the most important is to procure a liver graft with reconstructable portal veins, hepatic arteries, hepatic veins, and bile ducts, which should be well preoperatively planned using 3D-computed tomography with considerations given to graft volume and potential congestion areas.
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http://dx.doi.org/10.1016/j.ijsu.2020.06.022DOI Listing
October 2020
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