Publications by authors named "Hiroaki Fuji"

23 Publications

  • Page 1 of 1

Immunotherapy-based targeting of MSLN activated portal fibroblasts is a strategy for treatment of cholestatic liver fibrosis.

Proc Natl Acad Sci U S A 2021 Jul;118(29)

Department of Surgery, University of California San Diego Medical Center, La Jolla, CA 92161;

We investigated the role of mesothelin (Msln) and thymocyte differentiation antigen 1 (Thy1) in the activation of fibroblasts across multiple organs and demonstrated that Msln mice are protected from cholestatic fibrosis caused by Mdr2 (multidrug resistance gene 2) deficiency, bleomycin-induced lung fibrosis, and UUO (unilateral urinary obstruction)-induced kidney fibrosis. On the contrary, Thy1 mice are more susceptible to fibrosis, suggesting that a Msln-Thy1 signaling complex is critical for tissue fibroblast activation. A similar mechanism was observed in human activated portal fibroblasts (aPFs). Targeting of human MSLN aPFs with two anti-MSLN immunotoxins killed fibroblasts engineered to express human mesothelin and reduced collagen deposition in livers of bile duct ligation (BDL)-injured mice. We provide evidence that antimesothelin-based therapy may be a strategy for treatment of parenchymal organ fibrosis.
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http://dx.doi.org/10.1073/pnas.2101270118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307749PMC
July 2021

Interleukin-17 in Liver Disease Pathogenesis.

Semin Liver Dis 2021 Jun 15. Epub 2021 Jun 15.

Department of Surgery, University of California, San Diego, La Jolla, CA.

Interleukin 17A (IL-17A)-producing T helper 17 (Th17) cells were identified as a subset of T helper cells that play a critical role in host defense against bacterial and fungal pathogens. Th17 cells differentiate from Th0 naïve T-cells in response to transforming growth factor β1 (TGF-β1) and IL-6, the cytokines which also drive development of liver fibrosis, require activation of transcription factor retinoic acid receptor-related orphan nuclear receptor gamma (RORγ). IL-17A signals through the ubiquitously expressed receptor IL-17RA. Expression of IL-17RA is upregulated in patients with hepatitis B virus/hepatitis C virus (HBV/HCV) infections, nonalcoholic steatohepatitis (NASH), alcohol-associated liver disease (AALD), hepatocellular carcinoma (HCC), and experimental models of chronic toxic liver injury. The role of IL-17 signaling in the pathogenesis of NASH- and AALD-induced metabolic liver injury and HCC will be the focus of this review. The role of IL-17A-IL-17RA axis in mediation of the cross-talk between metabolically injured hepatic macrophages, hepatocytes, and fibrogenic myofibroblasts will be discussed.
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http://dx.doi.org/10.1055/s-0041-1730926DOI Listing
June 2021

Different clinical risk scores for prediction of early mortality after liver resection for hepatocellular carcinoma: which is the best?

ANZ J Surg 2019 10 6;89(10):1275-1280. Epub 2019 Aug 6.

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

Background: Prediction of early mortality after hepatectomies for hepatocellular carcinoma is essential to identify high-risk patients and to decrease the operative mortality rate. Several post-operative clinical risk scores were developed recently to predict mortality post-hepatectomy; however, which one is the best remains undefined. Therefore, the aim of this study was to evaluate the performance of the different post-operative clinical risk scores in predicting early mortality after hepatectomies.

Methods: A total of 240 patients who underwent liver resection for hepatocellular carcinoma at our hospital between June 2011 and July 2016 were retrospectively reviewed. Post-operative clinical risk scores including 50-50 criteria, peak bilirubin >7 mg/dL, model for end-stage liver disease (MELD), risk assessment for early mortality and Hyder scores were evaluated for their performance in predicting early mortality after hepatic resection using the receiver operating characteristic (ROC) curve.

Results: The 90-day mortality rate after hepatic resection was around 2.5%. The 50-50 criteria and peak bilirubin >7 mg/dL were weak predictors of early mortality with low sensitivity (area under the ROC curve: 0.65, 0.66, respectively), whereas, Hyder, risk assessment for early mortality, and post-operative MELD were good predictors of early mortality (area under the ROC curve: 0.89, 0.91 and 0.88, respectively). Moreover, MELD score on post-operative day 3 was an independent risk factor for 90-day mortality with an odds ratio of 1.4 (95% confidence interval 1.06-1.81, P = 0.02).

Conclusions: Post-operative clinical risk scores, especially MELD, were capable of predicting early mortality after liver resection and should be used to identify high-risk patients and provide them with more intensive medical care.
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http://dx.doi.org/10.1111/ans.15368DOI Listing
October 2019

Reappraisal of Prognostic Impact of Tumor SUVmax by F-FDG-PET/CT in Intrahepatic Cholangiocarcinoma.

World J Surg 2019 May;43(5):1323-1331

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

Background: We previously reported that tumor standardized uptake value (SUVmax) by F-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) was a potential predictor in patients undergoing surgery for intrahepatic cholangiocarcinoma (ICC). However, the prognostic value of SUVmax in the era of multidisciplinary strategy has remained unclear. The aim of this study was to reappraise the prognostic value of tumor SUVmax in patients undergoing surgery for ICC.

Methods: Data from 82 consecutive ICC patients, who underwent F-FDG-PET/CT and subsequent surgery between 2006 and 2017, were retrieved from a prospectively maintained institutional database. Adjuvant strategy was administrated during this study period in our center.

Results: Tumor SUVmax was associated with tumor size (p = 0.002) and tumor number (p = 0.005), but not associated with T and N stage classified by American Joint Committee on Cancer-classification system, and other tumor factors. According to the tumor SUVmax cut-off values of 8.0 based on the minimum p value approach, actuarial 5-year overall survival (OS) rates in patients undergoing upfront surgery for ICC were significantly stratified at 54.7% versus 26.0% (low vs. high tumor SUVmax group, p = 0.008). The actuarial 3-year disease-free survival (DFS) rates were also significantly stratified at 41.0% versus 18.3% (p < 0.001). Multivariate Cox regression analyses revealed that tumor SUVmax retained its significance on OS (p = 0.039) as well as DFS (p < 0.001).

Conclusion: Even in the era of multidisciplinary strategy, high tumor SUVmax still represents poor prognosis in patients undergoing surgery for ICC. These patients, therefore, would probably be required more effective strategies.
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http://dx.doi.org/10.1007/s00268-019-04917-zDOI Listing
May 2019

The Relationship Between F-FDG Uptake on PET/CT and Markers of Systemic Inflammatory Response in Patients Undergoing Surgery for Intrahepatic Cholangiocarcinoma.

Anticancer Res 2019 01;39(1):341-346

Department of Surgery, Kyoto University, Kyoto, Japan.

Background/aim: This study evaluated the prognostic relationship between tumor F-fluorodeoxyglucose (FDG) uptake on positron-emission tomography (PET)/computed tomography (CT) imaging and markers of systemic inflammatory response (SIR) in patients undergoing surgery for intrahepatic cholangiocarcinoma (ICC).

Patients And Methods: Between 2002 and 2016, 94 patients with ICC who underwent F-FDG-PET scans before surgery were analyzed. F-FDG uptake was quantified as a maximum standardized uptake value (SUVmax). The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and C-reactive protein (CRP) were selected as SIR markers.

Results: There was no strong correlation between SUVmax and, NLR, PLR and CRP (all Pearson's |r| <0.40). Multivariate Cox regression analyses identified high tumor SUVmax (≥8) and high NLR (≥5) as independent predictors of poor overall survival (p=0.013 and p=0.002) and disease-free survival (p<0.001 and p=0.004).

Conclusion: Prognostic information provided by tumor SUVmax and SIR markers may be independent prognostic factors in patients undergoing surgery for ICC.
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http://dx.doi.org/10.21873/anticanres.13117DOI Listing
January 2019

Serum Nardilysin, a Surrogate Marker for Epithelial-Mesenchymal Transition, Predicts Prognosis of Intrahepatic Cholangiocarcinoma after Surgical Resection.

Clin Cancer Res 2019 01 23;25(2):619-628. Epub 2018 Oct 23.

Department of Pharmacology, Shiga University of Medical Science, Otsu, Japan.

Purpose: Few studies have investigated prognostic biomarkers in patients with intrahepatic cholangiocarcinoma (ICC). Nardilysin (NRDC), a metalloendopeptidase of the M16 family, has been suggested to play important roles in inflammation and several cancer types. We herein examined the clinical significance and biological function of NRDC in ICC. We measured serum NRDC levels in 98 patients with ICC who underwent surgical resection in two independent cohorts to assess its prognostic impact. We also analyzed mRNA levels in cancerous tissue specimens from 43 patients with ICC. We investigated the roles of NRDC in cell proliferation, migration, gemcitabine sensitivity, and gene expression in ICC cell lines using gene silencing.

Results: High serum NRDC levels were associated with shorter overall survival and disease-free survival in the primary ( = 79) and validation ( = 19) cohorts. A correlation was observed between serum protein levels and cancerous tissue mRNA levels of (Spearman = 0.413; = 0.006). The gene knockdown of in ICC cell lines attenuated cell proliferation, migration, and tumor growth in xenografts, and increased sensitivity to gemcitabine. The gene knockdown of was also accompanied by significant changes in the expression of several epithelial-mesenchymal transition (EMT)-related genes. Strong correlations were observed between the mRNA levels of and EMT-inducing transcription factors, and , in surgical specimens from patients with ICC.

Conclusions: Serum NRDC, a possible surrogate marker reflecting the EMT state in primary tumors, predicts the outcome of ICC after surgical resection.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0124DOI Listing
January 2019

Optimal introduction of laparoscopic liver resection for Child-Pugh B.

Asian J Endosc Surg 2019 Jul 21;12(3):287-293. Epub 2018 Aug 21.

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

Introduction: Surgery for Child-Pugh B liver function is considered risky because of its high morbidity rate and the acceptable indication criteria for laparoscopic liver resection (LLR) for Child-Pugh B patients have not been identified. We conducted a retrospective cohort study to determine the optimal introduction of LLR for Child-Pugh B patients based on our single-institute experience.

Methods: A total of 17 Child-Pugh B patients underwent LLR between 2005 and 2017. Their clinical outcomes were compared to those of LLR for Child-Pugh A patients (103 cases), conventional open liver resection for Child-Pugh B patients (19 cases), and radiofrequency ablation (RFA) for Child-Pugh B patients (20 cases) during the same period.

Results: LLR for Child-Pugh B patients had a significantly higher conversion rate than LLR for Child-Pugh A patients (Child-Pugh A vs B: 3.9% vs 35.3%, P < 0.01). However, patients who successfully underwent laparoscopic resection (11 cases) had fewer postoperative ascites and shorter postoperative hospital stays compared to patients who underwent conventional open liver resection. In comparison to the RFA group, the LLR group more frequently had lesions in the left lateral segment (LLR vs RFA: 50.0% vs 10.0%, P = 0.02) and exophytic tumor (21.4% vs 0%, P = 0.02) than did the RFA group. Also, compared to the RFA group, the LLR group had a lower local recurrence rate (0% vs 15%, P = 0.25) and a longer recurrence-free survival (P = 0.049), but the overall survival was similar between the two groups.

Conclusions: In the treatment of Child-Pugh B liver malignancy, the minimal invasiveness of LLR was revealed. Our results suggest that lesions in the left lateral segment and exophytic tumors are good indications for LLR for Child-Pugh B.
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http://dx.doi.org/10.1111/ases.12634DOI Listing
July 2019

Usefulness of Preoperative F-FDG-PET in Detecting Invasive Intraductal Papillary Neoplasm of the Bile Duct.

Anticancer Res 2018 Jun;38(6):3677-3682

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

Background/aim: Preoperative identification of the invasive component remains challenging in intraductal papillary neoplasm of the bile duct (IPNB). We evaluated the ability of preoperative F-fluorodeoxyglucose positron emission tomography (F-FDG-PET) to differentiate between non-invasive IPNB, invasive IPNB, and papillary cholangiocarcinoma (CCA).

Patients And Methods: The maximum standardized uptake values (SUV) of 11 patients with IPNB (6 non-invasive and 5 invasive) and 20 with papillary CCA who underwent pre-surgical F-FDG-PET were assessed. The SUV cut-off that predicts an invasive component was determined using receiver operating characteristic (ROC) curve analysis.

Results: The SUV in patients with invasive IPNB and papillary CCA were significantly higher than in patients with non-invasive IPNB (p=0.035 and 0.0025, respectively). ROC curve analysis revealed an optimal SUV cut-off of 4.5, which had 94.5% accuracy, 76.0% sensitivity, and 100% specificity.

Conclusion: Our data suggest that the preoperative F-FDG-PET SUV can differentiate non-invasive IPNB from invasive IPNB and papillary CCA.
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http://dx.doi.org/10.21873/anticanres.12645DOI Listing
June 2018

Necrostatin-7 suppresses RANK-NFATc1 signaling and attenuates macrophage to osteoclast differentiation.

Biochem Biophys Res Commun 2018 09 7;503(2):544-549. Epub 2018 Jul 7.

Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Pathobiology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan. Electronic address:

Osteoclasts play a crucial role in osteolytic bone diseases, such as osteoporosis, rheumatoid arthritis, periodontitis, Paget's disease of bone and bone metastatic tumors. Therefore, controlling osteoclast differentiation and function has been considered a promising therapeutic strategy. Here, we show that necrostatin (Nec)-7, an inhibitor of programmed necrosis, strongly suppressed receptor activator of nuclear factor (NF)-κB ligand (RANKL)-induced osteoclastogenesis and bone resorption, without compromising macrophage colony-stimulating factor (M-CSF)-supported survival and growth of osteoclast precursor cells. Accordingly, Nec-7 significantly decreased the levels of RANKL-induced osteoclastogenic marker genes, such as cathepsin K. Mechanistically, Nec-7 neither affected MAPK nor NF-κB activation; however, it strongly inhibited the RANKL receptor (RANK) to nuclear factor of activated T cells c1 (NFATc1) signaling. Lentiviral expression of RANK in bone marrow-derived macrophages significantly restored osteoclastogenesis and NFATc1 amplification in Nec-7-treated cells. In this study, we revealed that Nec-7-sensitive pathways are crucially involved in osteoclast formation and function. Investigation of the molecular mechanism(s) through which Nec-7 inhibits RANK-NFATc1 signaling axis may lead to the development of new therapeutic strategies for bone disease.
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http://dx.doi.org/10.1016/j.bbrc.2018.05.153DOI Listing
September 2018

Preoperative metabolic tumor volume of intrahepatic cholangiocarcinoma measured by F-FDG-PET is associated with the KRAS mutation status and prognosis.

J Transl Med 2018 04 11;16(1):95. Epub 2018 Apr 11.

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

Background: Surgical resection remains the mainstay of curative treatment for intrahepatic cholangiocarcinoma (ICC). Prognosis after surgery is unsatisfactory despite improvements in treatment and post-operative clinical management. Despite developments in the molecular profiling of ICC, the preoperative prediction of prognosis remains a challenge. This study aimed to identify clinical prognostic indicators by investigating the molecular profiles of ICC and evaluating the preoperative imaging data of F-fluorodeoxyglucose positron emission tomography (F-FDG-PET).

Methods: A retrospective analysis was performed on 50 consecutive patients with ICC who underwent curative hepatectomy after F-FDG-PET examination. To evaluate the molecular profiles of ICC, KRAS mutation status was assessed in resected specimens. For the assessment of glucose uptake, we observed the expression of glucose transporter-1 (GLUT-1) by immunohistochemistry. The data of F-FDG-PET were re-evaluated as follows: maximum standardized uptake value, metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Cut-off values were determined using receiver operating characteristic (ROC) curve analysis. Cumulative overall survival (OS) was analyzed using the Kaplan-Meier analysis.

Results: Overall, 16 (32.0%) patients had mutations in KRAS. Patients with mutated KRAS exhibited shorter OS than those with wild-type KRAS (5-year OS, 0% vs. 35.1%, P < 0.001). GLUT-1 expression was significantly higher in tumors with mutated KRAS than in tumors with wild-type KRAS (median, 4.0 vs. 1.0, P < 0.001). Survival was significantly different when stratified by expression of GLUT-1 (5-year OS, 0% vs. 46.5%, P <0.001). Among the F-FDG-PET parameters, the MTV and TLG were significantly higher in the mutated KRAS group than in the wild-type KRAS group (P = 0.013 and P = 0.026, respectively). ROC curve analysis revealed a cut-off value of 38 for the MTV, with the highest accuracy (area under the curve = 0.789; 95% confidence interval, 0.581-0.902) for predicting KRAS mutation. This cut-off value permitted stratification of OS (high vs. low: 5-year OS, 13.1% vs. 36.7%, P = 0.008).

Conclusions: High MTV is associated with KRAS mutation and poor postoperative outcomes in patients with ICC, suggesting that the MTV of ICC measured by F-FDG-PET may provide useful information for tumor molecular profiles and prognosis.
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http://dx.doi.org/10.1186/s12967-018-1475-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896043PMC
April 2018

Long-Term Survival of Recurrent Intrahepatic Cholangiocarcinoma: The Impact and Selection of Repeat Surgery.

World J Surg 2018 06;42(6):1848-1856

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

Background: Definitive guidelines for recurrent intrahepatic cholangiocarcinoma (ICC) do not exist. This study has focused on the repeat surgery when analyzing the survival outcomes of recurrent ICC. We evaluated the relationship between clinicopathological features of the primary tumor and implementation of the repeat surgery to identify its potential selection criteria.

Methods: A total of 108 patients with recurrent ICC between 1993 and 2015 were analyzed. Of these, 15 patients underwent repeat surgery and 93 did not.

Results: Seven out of 29 patients with intrahepatic recurrence and eight out of 44 patients with extrahepatic recurrence were amenable to the repeat surgery. Thirty-five patients with simultaneous or consequent intrahepatic recurrence and extrahepatic recurrence were not amenable to the repeat surgery. Patients who underwent repeat surgery had a lower proportion of lymph node metastases (n = 0 [0%] vs. n = 47 [50.5%], p < 0.001), multiple tumors in the primary tumor (n = 1 [6.7%] vs. n = 31 [33.3%], p = 0.037), or early recurrence (≤ 1 year; n = 4 [26.7%] vs. n = 62 [66.7%], p = 0.003). Survival after recurrence (SAR) was better in patients who underwent repeat surgery than in those who did not (median SAR time: 91.6 vs. 10.4 months, and 3-year survival: 86.7 vs. 8.7%, respectively, p < 0.001).

Conclusions: Repeat surgery for recurrent ICC with an appropriate selection can be associated with prolonged survival. Regarding the feasibility, nodal status, number of tumors on the primary tumor, and time to recurrence may be considered as selection criteria.
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http://dx.doi.org/10.1007/s00268-017-4387-7DOI Listing
June 2018

A Propensity Score-Based Analysis of Laparoscopic Liver Resection for Liver Malignancies in Elderly Patients.

J Invest Surg 2019 Jan 17;32(1):75-82. Epub 2017 Oct 17.

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

Purpose: Laparoscopic liver resection is safe, feasible and associated with less blood loss, shorter hospital stays and fewer postoperative complications in the working age patients with malignant liver tumors. However, it is still unclear if the elderly patients with malignant liver tumors would also benefit from that approach as the younger patients. So, the aim of the study was to compare the clinical outcomes of laparoscopic versus open liver resection for malignant liver tumors in elderly patients.

Materials And Methods: Between March 2009 and July 2016, all elderly patients (≥70 years old) who underwent laparoscopic (n = 40) and open (n = 202) liver resection for malignant liver tumors were included. A one to one propensity score matching analysis was performed, based on 6 covariates, to decrease the selection bias.

Results: There was no significant difference between the laparoscopic and open liver resection groups regarding the patient characteristics and tumor features. The operative time was comparable between both groups (Laparoscopic group 259 min vs Open group 308 min, p = .86), while patients who underwent laparoscopic liver resection had lower intraoperative blood loss (30 ml vs 517 ml, p < .0001), shorter hospital stays (10 days vs 23 days, p < .0001), and less overall morbidity (15% vs 38%, p = .04). The one-, three-, and five-year survival for patients with hepatocellular carcinoma was comparable between both groups (Laparoscopic group 96%, 74%, 47%, vs Open group 94%, 71%, 48%, p = .82), whereas The one-, three-, and five-year recurrence-free survival for patients with hepatocellular carcinoma was significantly higher in the laparoscopic group (88%, 60%, 60% vs 54%, 25%, 19%, p = .019).

Conclusions: Laparoscopic approach for minor liver resection in elderly patients is safe and feasible with less blood loss, a shorter hospital stay, less postoperative complications and a better oncological outcome.
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http://dx.doi.org/10.1080/08941939.2017.1373170DOI Listing
January 2019

Evaluation of a new energy device for parenchymal transection in laparoscopic liver resection.

Asian J Endosc Surg 2018 May 12;11(2):123-128. Epub 2017 Oct 12.

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

Introduction: THUNDERBEAT (TB) is a novel device that uses both ultrasonic and advanced bipolar energies for hemostasis. Several recent human studies have proved the safety and efficacy of TB in different surgical procedures, but there have been no similar studies about its efficacy in hepatic parenchymal transection. Therefore, the aim of the study was to assess the safety and efficacy of the TB device in laparoscopic liver resection.

Methods: This retrospective study compared TB and ultrasonic Harmonic devices in 80 patients who underwent laparoscopic liver resection from 2010 to 2016 in our institution. To reduce the selection bias, the two groups were matched in a 1-to-2 ratio on the basis of propensity scores.

Results: There were no differences in the preoperative patient characteristics between the two groups. The extent of liver resection was comparable between the groups. Although the Harmonic group's intraoperative blood loss and operative time were less than that of the TB group, the differences were not statistically significant (P = 0.08, P = 0.32, respectively). Postoperative complications, mortality within 90 days, and hospital stay were comparable between the two groups.

Conclusion: TB is as safe and effective for parenchymal transection in laparoscopic hepatectomy as ultrasonic devices, but it is not a superior alternative.
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http://dx.doi.org/10.1111/ases.12432DOI Listing
May 2018

Actin-binding protein coronin 1A controls osteoclastic bone resorption by regulating lysosomal secretion of cathepsin K.

Sci Rep 2017 03 16;7:41710. Epub 2017 Mar 16.

Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.

Osteoclasts degrade bone matrix proteins via the secretion of lysosomal enzymes. However, the precise mechanisms by which lysosomal components are transported and fused to the bone-apposed plasma membrane, termed ruffled border membrane, remain elusive. Here, we identified coronin 1A as a negative regulator of exocytotic release of cathepsin K, one of the most important bone-degrading enzymes in osteoclasts. The modulation of coronin 1A expression did not alter osteoclast differentiation and extracellular acidification, but strongly affected the secretion of cathepsin K and osteoclast bone-resorption activity, suggesting the coronin 1A-mediated regulation of lysosomal trafficking and protease exocytosis. Further analyses suggested that coronin 1A prevented the lipidation-mediated sorting of the autophagy-related protein LC3 to the ruffled border and attenuated lysosome-plasma membrane fusion. In this process, the interactions between coronin 1A and actin were crucial. Collectively, our findings indicate that coronin 1A is a pivotal component that regulates lysosomal fusion and the secretion pathway in osteoclast-lineage cells and may provide a novel therapeutic target for bone diseases.
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http://dx.doi.org/10.1038/srep41710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5353622PMC
March 2017

Real-time Navigation for Liver Surgery Using Projection Mapping With Indocyanine Green Fluorescence: Development of the Novel Medical Imaging Projection System.

Ann Surg 2018 06;267(6):1134-1140

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

Objective: The aim of the present study was to evaluate the usefulness of a new imaging device, the Medical Imaging Projection System (MIPS), which uses the indocyanine green emission signal and active projection mapping, for liver resection.

Background: During anatomic liver resection, surgeons cannot completely view the intraparenchymal structure. Although a fluorescent imaging technique using indocyanine green has recently been developed for hepatobiliary surgery, limitations in its application for real-time navigation persist.

Methods: We conducted a retrospective review of surgical and clinical outcomes for 23 patients who underwent anatomic hepatectomy using the MIPS and 29 patients who underwent the procedure without MIPS guidance, between September 2014 and September 2015.

Results: Preoperative characteristics were comparable between the 2 groups. No significant between-group differences were identified with regard to surgical and clinical outcomes. The demarcation lines were clearly projected by the MIPS in 21 patients; however, the boundary line was undetectable in 2 patients.

Conclusions: We developed the MIPS to address limitations in current intraoperative imaging methods. Our retrospective analysis provides evidence of the feasibility and clinical utility of the MIPS to identify anatomical landmarks for parenchymal dissection. The MIPS holds promise as a novel real-time navigation system for liver resection.
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http://dx.doi.org/10.1097/SLA.0000000000002172DOI Listing
June 2018

A Novel Biomarker-Based Preoperative Prognostic Grading System for Predicting Survival After Surgery for Intrahepatic Cholangiocarcinoma.

Ann Surg Oncol 2017 May 20;24(5):1351-1357. Epub 2017 Jan 20.

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

Background: Although treatment strategies for intrahepatic cholangiocarcinoma (ICC) are shifting towards multidisciplinary approaches, preoperative radiographic methods for identifying patients requiring further therapy are unclear. This study was designed to establish a prognostic grading system using preoperatively available objective biomarkers.

Methods: A novel preoperative prognostic grading system for predicting survival after surgery for ICC was developed from multivariate analysis of 134 ICC patients who underwent surgery between 1996 and 2015 using preoperatively available biomarkers.

Results: The median overall survival time and 3- and 5 year survival rates were 33.3 months, 48, and 38%, respectively. Of the preoperative biomarkers, the neutrophil-to-lymphocyte ratio (≥5), and C-reactive protein (≥5 mg/L) and carbohydrate antigen 19-9 (≥500 IU/mL) levels were independently associated with poor overall survival. Based on the presence of these factors, the preoperative prognostic grades were defined as follows: grade 1, no factor; grade 2, one factor; and grade 3, two or three factors. The median overall survival time and 3- and 5 year survival rates of patients with grade 1 (70.3 months, 66, and 53%, respectively) were higher than those of patients with grade 2 (23.4 months, 37, and 30%, respectively; P = 0.004) and grade 3 (8.8 months, 5% both; 2 vs. 3, P < 0.001). Multivariable analysis revealed that the preoperative prognostic grading system independently predicted survival after adjusting for known prognostic factors.

Conclusions: A novel biomarker-based preoperative prognostic grading system for ICC significantly stratifies survival after surgery and may identify patients requiring further treatment.
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http://dx.doi.org/10.1245/s10434-016-5708-zDOI Listing
May 2017

Chronological Profiling of Plasma Native Peptides after Hepatectomy in Pigs: Toward the Discovery of Human Biomarkers for Liver Regeneration.

PLoS One 2017 6;12(1):e0167647. Epub 2017 Jan 6.

Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.

Liver regeneration after partial hepatectomy (PHx) is a time-dependent process, which is tightly regulated by multiple signaling cascades. Failure of this complex process leads to posthepatectomy liver failure (PHLF), which is associated with a high rate of mortality. Thus, it is extremely important to establish a useful biomarker of liver regeneration to help prevent PHLF. Here, we hypothesized that alterations in the plasma peptide profile may predict liver regeneration following PHx and hence we set up a diagnostic platform for monitoring posthepatectomy outcome. We chronologically analyzed plasma peptidomic profiles of 5 partially hepatectomized microminipigs using the ClinProtTM system, which consists of magnetic beads and MALDI-TOF/TOF MS. We identified endogenous circulating peptides specific to each phase of the postoperative course after PHx in pigs. Notably, peptide fragments of histones were detected immediately after PHx; the presence of these fragments may trigger liver regeneration in the very acute phase after PHx. An N-terminal fragment of hemoglobin subunit α (3627 m/z) was detected as an acute-phase-specific peptide. In the recovery phase, the short N-terminal fragments of albumin (3028, 3042 m/z) were decreased, whereas the long N-terminal fragment of the protein (8926 m/z) was increased. To further validate and extract phase-specific biomarkers using plasma peptidome after PHx, plasma specimens of 4 patients who underwent PHx were analyzed using the same method as we applied to pigs. It revealed that there was also phase-specificity in peptide profiles, one of which was represented by a fragment of complement C4b (2378 m/z). The strategy described herein is highly efficient for the identification and characterization of peptide biomarkers of liver regeneration in a swine PHx model. This strategy is feasible for application to human biomarker studies and will yield clues for understanding liver regeneration in human clinical trials.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167647PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5218562PMC
August 2017

Phase I clinical trial of olprinone in liver surgery.

Surg Today 2017 Aug 27;47(8):918-927. Epub 2016 Dec 27.

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

Purpose: Post-hepatectomy liver failure is one of the most serious complications liver surgeons must overcome. We previously examined olprinone, a selective phosphodiesterase III inhibitor, and demonstrated its hepatoprotective effects in rats and pigs. We herein report the results of a phase I clinical trial of olprinone in liver surgery (UMIN000004975).

Methods: Twenty-three patients who underwent hepatectomy between 2011 and 2015 were prospectively registered. In the first 6 cases, olprinone (0.1 μg/kg/min) was administered for 24 h from the start of surgery. In the remaining 17 cases, olprinone (0.05 μg/kg/min) was administered from the start of surgery until just before the transection of the liver parenchyma. The primary endpoint was safety, and the secondary endpoint was efficacy. For the evaluation of efficacy, the incidence of post-hepatectomy liver failure in 20 hepatocellular carcinoma patients was externally compared with 20 propensity score-matched patients.

Results: No intraoperative side effects were observed, and the morbidity rates in the analyzed cohorts were acceptable. The rate of post-hepatectomy liver failure frequency tended to be lower in the olprinone group.

Conclusions: The safety of olprinone in liver surgery was confirmed. The efficacy of olprinone will be re-evaluated in clinical trials.
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http://dx.doi.org/10.1007/s00595-016-1461-yDOI Listing
August 2017

Prospective registry for laparoscopic liver resection.

Asian J Endosc Surg 2017 May 14;10(2):173-178. Epub 2016 Dec 14.

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

Introduction: Laparoscopic liver resection (LLR) has been widely performed throughout the world. Although prospective registry studies to clarify the safety of LLR have been feasible, no prior multicenter prospective study has addressed this issue. We have conducted a multicenter prospective cohort study to reveal the current status of LLR in Japan.

Methods: From April 2015 to March 2016, candidates for LLR were preoperatively enrolled at 12 institutions. The primary end-point was surgical safety, which was evaluated based on surgical factors and on short-term and midterm outcomes.

Results: A total of 102 patients were enrolled. Planned laparoscopic procedures included 96 pure laparoscopies, 1 hand-assisted laparoscopy, and 5 hybrid techniques. Non-anatomical partial resection or left lateral sectionectomy were performed in almost all cases. The median duration of surgery was 221 min. The median blood loss was 80.5 mL. Conversion was required for four patients (3.9%). The 90-day postoperative morbidities with grades more severe than II in the Clavien-Dindo classification were observed in six patients (5.9%). The median postoperative hospital stay was 9.5 days. No cases involved reoperation or mortality.

Conclusion: Minor resection of LLR has been performed safely. To ensure the safe dissemination of LLR, including for major resection, a larger multicenter prospective study is required.
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http://dx.doi.org/10.1111/ases.12351DOI Listing
May 2017

[A case of recurrent colon cancer developed thrombosis in superior mesenteric vein after chemotherapy].

Gan To Kagaku Ryoho 2013 May;40(5):659-61

Dept. of Surgery, Tenri Hospital, Japan.

A 48-year-old man was administered bevacizumab+FOLFOX for lymph node recurrence of colon cancer in the abdominal cavity, and developed serious thrombosis of the portal system after 6 courses of the chemotherapy. We discontinued it promptly and anticoagulant therapy with urokinase was started immediately, but a complete dissolution was not achieved. Preservation therapy using anticoagulants for a long duration was effective for controling the of clinical symptom of thrombosis. The result of 6 courses of chemotherapy was CR, and the effect continues today, without further treatment 2 years later.
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May 2013

[Improved QOL in a case of remnant gastric cancer with common bile duct obstruction treated with weekly paclitaxel therapy and cholecystojejunostomy].

Gan To Kagaku Ryoho 2012 Jan;39(1):123-6

Dept. of Surgery, Kishiwada City Hospital.

We report a patient with unresectable remnant gastric cancer with common bile duct stricture, whose quality of life(QOL) was improved by switching to cholecystojejunostomy from percutaneous transhepatic gallbladder drainage(PTGBD). He was a 69-year-old man who underwent distal gastrectomy(Billroth I reconstruction)3 years previously, and he vomited many times due to cancer at the anastomosis. It could not be resected because of its involvement with the hepatoduodenal ligament, and therefore, gastrojejunostomy was performed. Four days later, abdominal pain occurred and gallbladder swelling was observed, resulting from common bile duct obstruction. PTGBD relieved the pain, and four courses of S-1/cisplatin (CDDP)treatment were performed. The bile duct stenosis was still so severe that the chemotherapy regimen was changed to weekly paclitaxel(PTX). The bile amount of PTGBD decreased after its four courses and the tube, which was a great burden for the patient, was removed. Because abdominal pain recurred in 2 weeks, the tube needed to be reinserted. An endoscopic stent was not inserted successfully. We performed cholecystojejunostomy and he was finally free from the PTGBD tube. The spread of cancer to the cystic duct was controlled by continuing the PTX for more than 20 courses. Thus, this case highlights PTX's contribution toward improving the patient's QOL.
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January 2012

Gastric carcinoid with hypergastrinemia: report of three cases.

Case Rep Med 2010 22;2010. Epub 2010 Sep 22.

Department of Surgery, Kishiwada City Hospital, 1001 Gakuhara-cho, Kishiwada-shi, Osaka 596-8501, Japan.

We report 3 cases of gastric carcinoids with hypergastrinemia. Case 1: A 60-year-old man had a 2 cm carcinoid of the stomach and underwent partial resection. Involvement of the muscularis propria and lymph nodes metastasis were observed microscopically. Follow-up gastroscopy revealed another carcinoid lesion and total gastrectomy was performed. Case 2: A 67-year-old woman with multiple carcinoids of the entire stomach underwent antrectomy. No growth of residual tumors has been detected so far. Case 3: A 61-year-old man had a tumor near the esophagogastric junction and underwent total gastrectomy. Carcinoid component was diffusely intermingled with adenocarcinoma in the tumor and invaded into the subserosa. In all 3 cases, the serum gastrin level was high and atrophic gastritis was microscopically observed. Carcinoid tumor in Case 3 was different from those in Cases 1 and 2 and interestingly, gastric carcinoid with hypergastrinemia showed various types of appearance.
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http://dx.doi.org/10.1155/2010/348761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946604PMC
July 2011

[A case of advanced ascending colon cancer, curatively resected after complete response in left supraclavicular and paraaortic lymph nodes and liver metastases to FOLFOX4 therapy].

Gan To Kagaku Ryoho 2010 Feb;37(2):323-6

Dept. of Surgery, Kishiwada City Hospital.

We report a resected case of ascending colon cancer with left supraclavicular and paraaortic lymph nodes and liver metastases which completely responded in terms of metastases but not the primary tumor to FOLFOX4 therapy. A 62-year-old woman with epigastric discomfort was initially diagnosed as malignant lymphoma by FDG-PET with abnormal accumulation at left supraclavicular and paraaortic lesions. Pathological examination of the supraclavicular lymph nodes showed undifferentiated adenocarcinoma, and ascending colon cancer was detected by colonoscopy which was a mixture of various types of differentiation. FOLFOX4 therapy was effective for metastatic lesions but colon tumor did not regress and was accompanied by abdominal pain. Macroscopically, a curative right hemicolectomy was performed, and microscopic examination revealed that the tumor had become a mass of undifferentiated cancer cells. Thus, the present case demonstrates the dedifferentiation of colon cancer during chemotherapy.
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February 2010
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