A patient who underwent conversion surgery after atezolizumab plus bevacizumab for hepatocellular carcinoma with portal vein thrombosis and perihepatic lymph node metastases achieved a pathological complete response.

Here, we present a patient with hepatocellular carcinoma complicated by tumor thrombosis into the main portal trunk and perihepatic lymph node metastases who was treated with atezolizumab plus bevacizumab. Shrinkage of the main tumor, portal vein thrombosis, and lymph node metastases were achieved; therefore, hepatectomy with lymphadenectomy could be performed. Final pathology indicated a complete pathological response in the main tumor, portal vein thrombosis, and perihepatic lymph nodes. The patient is currently alive with no evidence of recurrence on radiological assessment at 3 months after surgery.

Neural-net-based cell deconvolution from DNA methylation reveals tumor microenvironment associated with cancer prognosis.

DNA methylation is a pivotal epigenetic modification that defines cellular identity. While cell deconvolution utilizing this information is considered useful for clinical practice, current methods for deconvolution are limited in their accuracy and resolution. In this study, we collected DNA methylation data from 945 human samples derived from various tissues and tumor-infiltrating immune cells and trained a neural network model with them. The model, termed MEnet, predicted abundance of cell population together with the detailed immune cell status from bulk DNA methylation data, and showed consistency to those of flow cytometry and histochemistry. MEnet was superior to the existing methods in the accuracy, speed, and detectable cell diversity, and could be applicable for peripheral blood, tumors, cell-free DNA, and formalin-fixed paraffin-embedded sections. Furthermore, by applying MEnet to 72 intrahepatic cholangiocarcinoma samples, we identified immune cell profiles associated with cancer prognosis. We believe that cell deconvolution by MEnet has the potential for use in clinical settings.

Adverse events induced by durvalumab and tremelimumab combination regimens: a systematic review and meta-analysis.

Background: Immune checkpoint inhibitors (ICIs) have shown remarkable therapeutic outcomes among cancer patients. Durvalumab plus tremelimumab (DT) is under investigation as a new ICI combination therapy, and its efficacy has been reported in various types of cancer. However, the safety profile of DT remains unclear, especially considering rare adverse events (AEs). Objective: We aimed to assess the frequency of AEs associated with DT. Design: This study type is a systematic review and meta-analysis. Data Sources and Methods: Four databases were searched for articles. Randomized trials, single-arm trials, and prospective and retrospective observational studies were included. The type of cancer, previous treatment, and performance status were not questioned. Major AE indicators such as any AE and the pooled frequency of each specific AE were used as outcomes. As a subgroup analysis, we also compared cases in which DT was performed as first-line treatment with those in which it was performed as second-line or later treatment. The protocol for this systematic review was registered on the University Hospital Medical Information Network (UMIN) Center website (ID: UMIN000046751). Results: Forty-one populations including 3099 patients were selected from 30 articles. Pooled frequencies of key AE indicators are shown below: any AEs, 77.8% [95% confidence interval (CI): 67.9-87.6]; grade ⩾ 3 AEs, 29.3% (95% CI: 24.2-34.4); serious AEs, 34.9% (95% CI: 28.1-41.7); AE leading to discontinuation, 13.3% (95% CI: 9.3-17.4); treatment-related deaths, 0.98% (95% CI: 0.5-1.5). AEs with a frequency exceeding 15% are shown below: fatigue, 30.1% (95% CI: 23.8-36.3); diarrhea, 21.7% (95% CI: 17.8-25.6); pruritus 17.9% (95% CI: 14.4-21.3); decreased appetite, 17.7% (95% CI: 13.7-22.0); nausea, 15.6% (95% CI: 12.1-19.6). There were no significant differences in these pooled frequencies between subgroups. Conclusions: The incidence of any AE in DT therapy was approximately 78%, and the incidence of grade 3 or higher AEs was approximately 30%, which was independent of prior therapy.

Interleukin-17 in Liver Disease Pathogenesis.

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 ß1 (TGF-ß1) 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 t (RORγt). 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.

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

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.

Reappraisal of Prognostic Impact of Tumor SUVmax by 18F-FDG-PET/CT in Intrahepatic Cholangiocarcinoma.

BACKGROUND: We previously reported that tumor standardized uptake value (SUVmax) by 18F-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 18F-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.

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

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.

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

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.

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

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.Experimental Design: 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 NRDC 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 (n = 79) and validation (n = 19) cohorts. A correlation was observed between serum protein levels and cancerous tissue mRNA levels of NRDC (Spearman ρ = 0.413; P = 0.006). The gene knockdown of NRDC in ICC cell lines attenuated cell proliferation, migration, and tumor growth in xenografts, and increased sensitivity to gemcitabine. The gene knockdown of NRDC 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 NRDC and EMT-inducing transcription factors, ZEB1 and SNAI1, 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.

The Relationship Between 18F-FDG Uptake on PET/CT and Markers of Systemic Inflammatory Response in Patients Undergoing Surgery for Intrahepatic Cholangiocarcinoma.

BACKGROUND/AIM: This study evaluated the prognostic relationship between tumor 18F-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 18F-FDG-PET scans before surgery were analyzed. 18F-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.

Usefulness of Preoperative 18F-FDG-PET in Detecting Invasive Intraductal Papillary Neoplasm of the Bile Duct.

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 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) to differentiate between non-invasive IPNB, invasive IPNB, and papillary cholangiocarcinoma (CCA). PATIENTS AND METHODS: The maximum standardized uptake values (SUVmax) of 11 patients with IPNB (6 non-invasive and 5 invasive) and 20 with papillary CCA who underwent pre-surgical 18F-FDG-PET were assessed. The SUVmax cut-off that predicts an invasive component was determined using receiver operating characteristic (ROC) curve analysis. RESULTS: The SUVmax 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 SUVmax cut-off of 4.5, which had 94.5% accuracy, 76.0% sensitivity, and 100% specificity. CONCLUSION: Our data suggest that the preoperative 18F-FDG-PET SUVmax can differentiate non-invasive IPNB from invasive IPNB and papillary CCA.

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

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.

Preoperative metabolic tumor volume of intrahepatic cholangiocarcinoma measured by 18F-FDG-PET is associated with the KRAS mutation status and prognosis.

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 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET). METHODS: A retrospective analysis was performed on 50 consecutive patients with ICC who underwent curative hepatectomy after 18F-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 18F-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 18F-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 18F-FDG-PET may provide useful information for tumor molecular profiles and prognosis.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

Phase I clinical trial of olprinone in liver surgery.

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.