Toll-like receptor 7 agonist, GS-986, is an immune-stimulant inducing follicular helper T cells and expanding HBs antigen-specific B cells in vitro.

BACKGROUNDS AND AIMS: Toll-like receptor (TLR) agonists have been developed as adjuvants to efficiently induce antiviral immune responses. Specificity and potency of these compounds are essential requirements for clinical trial applications. In patients with hepatitis B virus (HBV) infections, sustained loss of hepatitis B surface antigen (HBsAg) is a therapeutic goal, which may be achievable by the sequential activation of follicular helper T cells (Tfh) and antibody-secreting B cells. We aimed to elucidate whether novel TLR7 agonist, GS-986, could activate immune responses involved in HBV elimination. METHODS: To clarify the impact of GS-986 on pDCs, we quantified the expression levels of surface markers and evaluated for Tfh induction in a culture model consisting of human pDCs with allogeneic naïve CD4+ T cells. In addition, we examined whether GS-986 could enhance HBs antibody production capacity using PBMC from CHB patients. RESULTS: pDCs from CHB patients had lower OX40L expression and as well as impaired capacity for Tfh induction compared with those from healthy donors. However, GS-986-stimulated pDCs from CHB patients expressed OX40L and produced IL-6 and IL-12, resulting in the induction of IL-21-producing Tfh cells (CXCR5+ PD-1+ CD4+ ) from naïve CD4+ T cells. The Tfh-inducing capacity of GS-986 was reduced in the presence of an anti-OX40L blocking antibody. Furthermore, GS-986 promoted HBsAg-specific antibody production in PBMCs from CHB patients. CONCLUSIONS: GS-986 is an adjuvant that stimulates pDCs to induce Tfh differentiation and antigen-specific B-cell production. This immune profile may be beneficial for therapeutic application as an immune modulator in CHB patients.

Conversion surgery after lenvatinib treatment for multiple lung metastases from hepatocellular carcinoma.

Although systemic treatment for hepatocellular carcinoma has advanced after the development of tyrosine kinase inhibitors such as sorafenib and lenvatinib, the effectiveness of a single tyrosine kinase inhibitor in survival extension of unresectable hepatocellular carcinoma is limited to a few months. Therefore, novel treatment options are required for unresectable hepatocellular carcinomas, including those with multiple lung metastases. This case report describes a hepatocellular carcinoma patient with a recurrence of multiple lung metastases, which was successfully treated with conversion pneumonectomy after treatment with tyrosine kinase inhibitors. A 79-year-old man underwent right hepatectomy for hepatocellular carcinoma, along with removal of the tumor thrombus in the inferior vena cava. Multiple lung metastases were detected 4 months after hepatectomy. Treatment with tyrosine kinase inhibitors, mainly lenvatinib, resulted in complete remission of the lung metastases, except for one lesion in segment 3 of the right lung which gradually enlarged. Twenty-three months after hepatectomy, partial resection of the right lung was performed using video-assisted thoracic surgery for this residual lesion in the right lung. The patient remained disease-free for 11 months after conversion pneumonectomy, without any adjuvant therapies. This is the first case report of multiple lung metastases originating from hepatocellular carcinoma which were successfully treated with conversion pneumonectomy after treatment with tyrosine kinase inhibitors. Conversion pneumonectomy after systemic therapy with tyrosine kinase inhibitors should be considered as a treatment strategy for patients with unresectable multiple lung metastases from hepatocellular carcinomas.

Peripheral-dominant liver fibrosis and tumor distribution in a mouse model of congestive hepatopathy.

AIM: Congestive hepatopathy often leads to liver fibrosis and hepatocellular carcinoma. Imaging modalities provided clinical evidence that elevation of liver stiffness and tumor occurrence are mainly induced in the periphery of the liver in patients with congestive hepatopathy. However, clinical relevance of liver stiffness and liver fibrosis is unclear because liver congestion itself increases liver stiffness in congestive hepatopathy. It also unclear which factors configure such regional disparity of tumor development in patients with congestive hepatopathy. To answer these questions, we evaluated the macroscopic spatial distribution of liver fibrosis and tumors in the murine model of congestive hepatopathy. METHODS: Chronic liver congestion was induced by partial ligation of the suprahepatic inferior vena cava. Distribution of liver congestion, fibrosis, and tumors in partial ligation of the suprahepatic inferior vena cava mice were assessed by histological findings, laser microdissection (LMD)-based qPCR and enhanced computed tomography. LMD-based RNA-sequencing was performed to identify causal factors that promote tumor development in congestive hepatopathy. RESULTS: Liver fibrosis was mainly induced in the periphery of the liver and co-localized with distribution of liver congestion. Liver tumors were also induced in the periphery of the liver where liver congestion and fibrosis occurred. LMD-based RNA-sequencing revealed the upregulation of extracellular matrix/collagen fibril-, wound healing-, angiogenesis-, morphogenesis-, and cell motility-related signaling pathways in periphery of liver compared with liver center. CONCLUSIONS: Our findings showed the experimental relevance of liver congestion, fibrosis, and tumor development in congestive hepatopathy, and may provide important locational information. Macroscopic regional disparity observed in this murine model should be considered to manage patients with congestive hepatopathy.

Impact of comorbid renal dysfunction in patients with hepatocellular carcinoma on long-term outcomes after curative resection.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, the number of patients with chronic kidney disease (CKD) is on the rise because of the increase in lifestyle-related diseases. AIM: To establish a tailored management strategy for HCC patients, we evaluated the impact of comorbid renal dysfunction (RD), as stratified by using the estimated glomerular filtration rate (EGFR), and assessed the oncologic validity of hepatectomy for HCC patients with RD. METHODS: We enrolled 800 HCC patients who underwent hepatectomy between 1997 and 2015 at our university hospital. We categorized patients into two (RD, EGFR < 60 mL/min/1.73 m2; non-RD, EGFR ≥ 60 mL/min/1.73 m2) and three groups (severe CKD, EGFR < 30 mL/min/1.73 m2; mild CKD, 30 ≤ EGFR < 60 mL/min/1.73 m2; control, EGFR ≥ 60 mL/min/1.73 m2) according to renal function as defined by the EGFR. Overall survival (OS) and recurrence-free survival (RFS) were compared among these groups with the log-rank test, and we also analyzed survival by using a propensity score matching (PSM) model to exclude the influence of patient characteristics. The mean postoperative observation period was 64.7 ± 53.0 mo. RESULTS: The RD patients were significantly older and had lower serum total bilirubin, aspartate aminotransferase, and aspartate aminotransferase levels than the non-RD patients (P < 0.0001, P < 0.001, P < 0.05, and P < 0.01, respectively). No patient received maintenance hemodialysis after surgery. Although the overall postoperative complication rates were similar between the RD and non-RD patients, the proportions of postoperative bleeding and surgical site infection were significantly higher in the RD patients (5.5% vs 1.8%; P < 0.05, 3.9% vs 1.8%; P < 0.05, respectively), and postoperative bleeding was the highest in the severe CKD group (P < 0.05). Regardless of the degree of comorbid RD, OS and RFS were comparable, even after PSM between the RD and non-RD groups to exclude the influence of patient characteristics, liver function, and other causes of death. CONCLUSION: Comorbid mild RD had a negligible impact on the prognosis of HCC patients who underwent curative hepatectomy with appropriate perioperative management, and close attention to severe CKD is necessary to prevent postoperative bleeding and surgical site infection.

Myeloid immune checkpoint ILT3/LILRB4/gp49B can co-tether fibronectin with integrin on macrophages.

LILRB4 (B4, also known as ILT3/CD85k) is an immune checkpoint of myeloid lineage cells, albeit its mode of function remains obscure. Our recent identification of a common ligand for both human B4 and its murine ortholog gp49B as the fibronectin (FN) N-terminal 30 kDa domain poses the question of how B4/gp49B regulate cellular activity upon recognition of FN in the plasma and/or the extracellular matrix. Since FN in the extracellular matrix is tethered by FN-binding integrins, we hypothesized that B4/gp49B would tether FN in cooperation with integrins on the cell surface, thus they should be in close vicinity to integrins spatially. This scenario suggests a mode of function of B4/gp49B by which the FN-induced signal is regulated. The FN pull-down complex was found to contain gp49B and integrin ß 1 in bone marrow-derived macrophages. The confocal fluorescent signals of the three molecules on the intrinsically FN-tethering macrophages were correlated to each other. When FN-poor macrophages adhered to culture plates, the gp49-integrin ß 1 signal correlation increased at the focal adhesion, supporting the notion that gp49B and integrin ß 1 become spatially closer to each other there. Adherence of RAW264.7 and THP-1 cells to immobilized FN induced phosphorylation of spleen tyrosine kinase, whose level was augmented under B4/gp49B deficiency. Thus, we concluded that B4/gp49B can co-tether FN in cooperation with integrin in the cis configuration on the same cell, forming a B4/gp49B-FN-integrin triplet as a regulatory unit of a focal adhesion-dependent pro-inflammatory signal in macrophages.

Liver metastasis 13 years after the resection of a malignant triton tumor originating in the duodenum.

This is an additional case report of a malignant triton tumor arising in the duodenum that was removed by pancreatoduodenectomy. Liver and gallbladder dysfunctions were detected in a regular blood examination during a follow-up for hypertension in a 62-year-old woman with a previous surgical history for a malignant Triton tumor in the duodenum 13 years ago. Further examinations revealed a metastatic liver tumor originating from the malignant triton tumor in the duodenum. Since the progression of the liver tumor was detected after radiation therapy, complete resection was performed by right hepatectomy. Curative hepatectomy resulted in disease-free survival for 1 year and 5 months in an extremely rare case of liver metastasis derived from a malignant triton tumor in the duodenum.

A case of alveolar echinococcosis in the liver that ruptured into the pericardium treated by a combination of hepatectomy and albendazole.

BACKGROUND: Alveolar echinococcosis (AE) is a rare parasitic disease caused by the larva of Echinococcus multilocularis. It nearly always occurs in the liver, and cardiac involvement is extremely rare. Liver resection is the most effective intervention for AE because the only potentially curative treatment is removal of the lesion. Even when complete resection is not performed, long-term survival can be expected after surgical removal of most of the lesion with lifelong administration of albendazole (ABZ). CASE PRESENTATION: A 64-year-old man who lived in Hokkaido was referred to our hospital due to abnormalities in biliary enzymes. According to the findings from enhanced computed tomography and magnetic resource imaging of the abdomen, transthoracic echocardiography and serologic tests, he was diagnosed with hepatic AE with rupture into the pericardium. He underwent extended left hemi-hepatectomy with reconstruction of the inferior vena cava and opening of the pericardium with drainage as reduction surgery. Pathological examination revealed echinococcal infection in the pericardium as well as the liver. He started chemotherapy with 400 mg ABZ per Day 67 days after surgery. Although the surgical margin was positive in the pathological findings, he was alive 19 months later with no regrowth of the echinococcal lesion. CONCLUSION: AE with cardiac involvement is extremely rare. Even if the complete removal of cardiac-involved AE is not possible, surgical debulking with lifelong ABZ treatment can successfully manage the disease.

Sphingosine-1-phosphate promotes tumor development and liver fibrosis in mouse model of congestive hepatopathy.

BACKGROUND AND AIMS: Chronic liver congestion reflecting right-sided heart failure (RHF), Budd-Chiari syndrome, or Fontan-associated liver disease (FALD) is involved in liver fibrosis and HCC. However, molecular mechanisms of fibrosis and HCC in chronic liver congestion remain poorly understood. APPROACH AND RESULTS: Here, we first demonstrated that chronic liver congestion promoted HCC and metastatic liver tumor growth using murine model of chronic liver congestion by partial inferior vena cava ligation (pIVCL). As the initial step triggering HCC promotion and fibrosis, gut-derived lipopolysaccharide (LPS) appeared to induce LSECs capillarization in mice and in vitro. LSEC capillarization was also confirmed in patients with FALD. Mitogenic factor, sphingosine-1-phosphate (S1P), was increased in congestive liver and expression of sphingosine kinase 1, a major synthetase of S1P, was increased in capillarized LSECs after pIVCL. Inhibition of S1P receptor (S1PR) 1 (Ex26) and S1PR2 (JTE013) mitigated HCC development and liver fibrosis, respectively. Antimicrobial treatment lowered portal blood LPS concentration, LSEC capillarization, and liver S1P concentration accompanied by reduction of HCC development and fibrosis in the congestive liver. CONCLUSIONS: In conclusion, chronic liver congestion promotes HCC development and liver fibrosis by S1P production from LPS-induced capillarized LSECs. Careful treatment of both RHF and liver cancer might be necessary for patients with RHF with primary or metastatic liver cancer.

Outcomes of reduction hepatectomy combined with postoperative multidisciplinary therapy for advanced hepatocellular carcinoma.

BACKGROUND: The prognosis of advanced hepatocellular carcinoma (HCC) that is not indicated for curative hepatectomy remains poor, despite advances in the treatment of HCC, including the development of tyrosine kinase inhibitors (TKIs). The outcomes of reduction hepatectomy and multidisciplinary postoperative treatment for advanced HCC that is not indicated for curative hepatectomy, including those of recently treated cases, should be investigated. AIM: To examine the outcomes of combination treatment with reduction hepatectomy and multidisciplinary postoperative treatment for advanced HCC that is not indicated for curative hepatectomy. METHODS: Thirty cases of advanced HCC that were not indicated for curative hepatectomy, in which reduction hepatectomy was performed between 2000 and 2018 at the Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, were divided into postoperative complete remission (POCR) (+) and POCR (-) groups, depending on whether POCR of all evaluable lesions was achieved through postoperative treatment. The cases in the POCR (-) group were subdivided into POCR (-) TKI (+) and POCR (-) TKI (-) groups, depending on whether TKIs were administered postoperatively. RESULTS: The 5-year overall survival rate and mean survival time (MST) after reduction hepatectomy were 15.7% and 28.40 mo, respectively, for all cases; 37.5% and 56.55 mo, respectively, in the POCR (+) group; and 6.3% and 14.84 mo, respectively, in the POCR (-) group (P = 0.0041). Tumor size, major vascular invasion, and the number of tumors in the remnant liver after the reduction hepatectomy were also found to be related to survival outcomes. The number of tumors in the remnant liver was the only factor that differed significantly between the POCR (+) and POCR (-) groups, and POCR was achieved significantly more frequently when ≤ 3 tumors remained in the remnant liver (P = 0.0025). The MST was 33.52 mo in the POCR (-) TKI (+) group, which was superior to the MST of 10.74 mo seen in the POCR (-) TKI (-) group (P = 0.0473). CONCLUSION: Reduction hepatectomy combined with multidisciplinary postoperative treatment for unresectable advanced HCC that was not indicated for curative hepatectomy was effective when POCR was achieved via multidisciplinary postoperative therapy. To achieve POCR, reduction hepatectomy should aim to ensure that ≤ 3 tumors remain in the remnant liver. Even in cases in which POCR is not achieved, combined treatment with reduction hepatectomy and multidisciplinary therapy can improve survival outcomes when TKIs are administered.

Hepatectomy and immune checkpoint inhibitor treatment for liver metastasis originating from non-cutaneous melanoma: a report of three cases.

The outcomes of hepatectomy alone for liver metastasis derived from non-cutaneous melanoma are insufficient, and the outcomes of systemic therapy alone are also insufficient, even since the development of immune checkpoint inhibitors (ICIs). We report the cases of three patients, in whom liver metastasis derived from non-cutaneous melanoma was treated with hepatectomy combined with ICI therapy, which was administered in various settings. One patient received ICI treatment for recurrent melanoma and survived 107 months after the first hepatectomy, one patient received both preoperative and adjuvant ICI treatment and has been disease-free for 27 months, and another patient received postoperative ICI treatment after reduction hepatectomy and has been alive with disease for 47 months. Since long-term survival is possible, hepatectomy combined with ICI therapy should be considered for the treatment of liver metastasis derived from non-cutaneous melanoma.

The impact of elastography with virtual touch quantification of future remnant liver before major hepatectomy.

BACKGROUND: Liver elastography with virtual touch quantification (VTQ) measures the velocity of the shear wave generated by a short-duration acoustic force impulse, with values expressed in units of velocity (m/s). VTQ can evaluate right or left hepatic lobes separately. VTQ might be appropriate for the evaluation of future remnant liver after hepatectomy. METHODS: We analyzed 95 patients underwent liver elastography with VTQ and both future remnant liver and resected side before hepatectomy of more than two sections, except for central bisectionectomy. We divided the patients into a high VTQ group (≥1.52 m/s, n=37, 39%) and a low VTQ group (<1.52 m/s, n=58, 61%) according to the VTQ of future remnant liver. Transient elastography could not be performed in 22 cases due to tumor size. We defined the group with liver stiffness measurement (LSM) ≥7.9 kPa as the high LSM group (n=29, 40%) and those with LSM <7.9 kPa as the low LSM group (n=44, 60%). We investigated the outcome after hepatectomy and the correlations between the VTQ of future remnant liver and other indicators for hepatic fibrosis. RESULTS: The high VTQ group showed significantly higher postoperative ascites (19% vs. 3%; P=0.01), pathological fibrosis (19% vs. 5%; P=0.03), and rates of patients with postoperative T-bil ≥2.0 mg/dL (70% vs. 40%; P<0.01). The high LSM group showed no significant postoperative outcomes compared to the low LSM group. The high VTQ group showed a higher frequency of male gender (78% vs. 57%; P=0.03), higher indocyanine green retention rate at 15 min (ICGR15) (10.5% vs. 6.3%; P<0.01), hyaluronic acid (100 vs. 67 ng/mL; P=0.02), type IV collagen 7S (7.6 vs. 5.1 ng/mL; P<0.01), Mac-2 binding protein glycan isomer (M2BPGi) (1.19 vs. 1.00; P=0.01), Fibrosis-4 (FIB-4) index (2.25 vs. 1.76; P=0.01), and aspartate aminotransferase to platelet ratio index (APRI) score (0.64 vs. 0.41; P<0.01). We also observed an especially strong positive correlation between the high VTQ and hyaluronic acid or type IV collagen 7S. CONCLUSIONS: Elastography with VTQ for future remnant liver before major hepatectomy is an accurate and useful method as a preoperative evaluation.

A case of laparoscopic hepatectomy for a primary hepatic neuroendocrine tumor.

Neuroendocrine tumors (NETs) account for approximately 1-2% of all gastrointestinal tumors. In particular, primary hepatic NETs (PHNETs) are extremely rare. A 42-year-old female patient was given a diagnosis of liver tumor after a medical check-up with ultrasonography. An enhanced CT scan and MRI were suggestive for a hepatic hemangioma or adenoma, but the possibility of hepatocellular carcinoma could not be denied. Moreover, this tumor grew larger, so we performed a laparoscopic partial hepatectomy for the diagnosis and treatment of the patient. Pathological examination revealed that the tumor cells were spindle-shaped, forming glandular-tubular structures, and had less visible nucleoli and increased mitotic figures on H&E staining. Immunohistochemical findings indicated that CK19, MOC-31, CD56, synaptophysin, and chromogranin A were positive; CK7, AFP, and glypican-3 were negative; and the Ki-67 index was 3.6%, so the final diagnosis was a PHNET G2. PHNETs differ from other NETs, as they do not produce biologically active polypeptides or amines. As a result, there are no manifestations of carcinoid syndrome. In addition, PHNETs grow slowly, and most patients show no symptoms in the early stages. Laparoscopic hepatectomy is a very useful procedure for diagnosis and treatment in such cases and can be performed safely.

Myostatin as a fibroblast-activating factor impacts on postoperative outcome in patients with hepatocellular carcinoma.

AIM: In patients with liver cirrhosis, high levels of serum myostatin are associated with poor prognosis. We aimed to clarify the influence of myostatin on the prognosis of patients with non-alcoholic fatty liver disease-hepatocellular carcinoma (NAFLD-HCC) without cirrhosis and on the progression of liver fibrosis. METHODS: Serum myostatin levels were evaluated in 234 patients who underwent primary surgical resection for single HCC. To clarify the impact of myostatin on liver fibrosis, we established human primary liver fibroblasts from resected livers, and cultured them in the presence of myostatin. RESULTS: The median age was 67.4 years, the median L3 skeletal muscle mass index was 44.4 cm2 /m2 , and the median body mass index was 23.4 kg/m2 . Eighty-two (35.0%) patients had sarcopenia (L3 skeletal muscle mass index: men <42, women <38 cm2 /m2 ). The etiologies of liver disease were hepatitis B virus (n = 61), hepatitis C virus (n = 86), and non-B non-C hepatitis (n = 87) including NAFLD (n = 74). High preoperative serum myostatin and vascular invasion were independent predictors of poor overall survival (OS). High serum myostatin was associated with poor OS in patients with no sarcopenia (n = 152). In patients without advanced liver fibrosis (Fibrosis stage, 0-2; n = 58), high levels of serum myostatin were also associated with poor OS, regardless of sarcopenia. Serum myostatin levels were increased with the progression of liver fibrosis. Liver fibroblasts were activated and produced collagen following stimulation with myostatin. CONCLUSIONS: In patients with NAFLD-HCC without advanced liver fibrosis, high levels of serum myostatin were associated with poor OS. Myostatin activated primary fibroblasts and stimulated collagen production.

Central Hepatectomy Versus Major Hepatectomy for Centrally Located Hepatocellular Carcinoma: A Propensity Score Matching Study.

BACKGROUND: In terms of anatomical liver sectionectomy approaches, both a central hepatectomy (CH) and major hepatectomy (MH) are feasible options for a centrally located hepatocellular carcinoma (HCC). METHODS: We retrospectively reviewed the surgical outcomes of central HCC patients who underwent CH or MH. MH includes hemihepatectomy or trisectionectomy, whereas CH involves a left medial sectionectomy, right anterior sectionectomy, or central bisectionectomy. The surgical outcomes were compared before and after propensity score matching (PSM). RESULTS: A total of 233 patients were enrolled, including 132 in the CH group and 101 in the MH group. The MH group cases were pathologically more advanced and had poorer overall survival rates than the CH group. After PSM, 68 patients were selected into each group, both of which showed similar overall and recurrence-free survival outcomes. The CH group showed a tendency for a longer operation time; however, other perioperative outcomes were similar between the two groups. Multivariate analyses of our matched HCC patients revealed that the type of surgery (CH or MH) was not an independent prognostic factor. More patients in the matched CH group experienced a repeat hepatectomy for recurrence and no patients in this group underwent a preoperative portal vein embolization. CONCLUSIONS: The short- and long-term surgical outcomes of CH and MH for a centrally located HCC are similar under a matched clinicopathological background. CH has the advantage of not requiring a preoperative portal vein embolization and increased chances of conducting a repeat hepatectomy for recurrence.

Functional transition: Inconsistently parallel to the increase in future liver remnant volume after preoperative portal vein embolization.

BACKGROUND: Preoperative portal vein embolization (PVE) is a widely used strategy to enable major hepatectomy in patients with insufficient liver remnant. PVE induces hypertrophy of the future liver remnant (FLR) and a shift of the functional reserve to the FLR. However, whether the increase of the FLR volume (FLRV) corresponds to the functional transition after PVE remains unclear. AIM: To investigate the sequential relationship between the increase in FLRV and functional transition after preoperative PVE using 3-dimensional (3D) computed tomography (CT) and 99mTc-galactosyl-human serum albumin (99mTc-GSA) single-photon emission computed tomography (SPECT) fusion images. METHODS: Thirty-three patients who underwent major hepatectomy following PVE at the Department of Gastroenterological Surgery I, Hokkaido University Hospital between October 2013 and March 2018 were enrolled. Three-phase dynamic multidetector CT and 99mTc-GSA SPECT scintigraphy were performed at pre-PVE, and at 1 and 2 wk after PVE; 3D 99mTc-GSA SPECT CT-fused images were constructed from the Digital Imaging and Communications in Medicine data using 3D image analysis system. Functional FLRV (FFLRV) was defined as the total liver volume × (FLR volume counts/total liver volume counts) on the 3D 99mTc-GSA SPECT CT-fused images. The calculated FFLRV was compared with FLRV. RESULTS: FFLRV increased by a significantly larger extent than FLRV at 1 and 2 wk after PVE (P < 0.01). The increase in FFLRV and FLRV was 55.1% ± 41.6% and 26.7% ± 17.8% (P < 0.001), respectively, at 1 wk after PVE, and 64.2% ± 33.3% and 36.8% ± 18.9% (P < 0.001), respectively, at 2 wk after PVE. In 3 of the 33 patients, FFLRV levels decreased below FLRV at 2 wk. One of the three patients showed rapidly progressive fatty changes in FLR. The biopsy at 4 wk after PVE showed macro- and micro-vesicular steatosis of more than 40%, which improved to 10%. Radical resection was performed at 13 wk after PVE. The patient recovered uneventfully without any symptoms of pos-toperative liver failure. CONCLUSION: The functional transition lagged behind the increase in FLRV after PVE in some cases. Evaluating both volume and function is needed to determine the optimal timing of hepatectomy after PVE.

Increased Frequency of Dysfunctional Siglec-7-CD57+PD-1+ Natural Killer Cells in Patients With Non-alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is a progressive disorder that can develop into liver fibrosis and hepatocellular carcinoma. Natural killer (NK) cells have been shown to protect against liver fibrosis and tumorigenesis, suggesting that they may also play a role in the pathogenesis of NAFLD. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of inhibitory and activating receptors expressed by many cell types, including NK cells. Here, we investigated the phenotypic profiles of peripheral blood and intrahepatic NK cells, including expression of Siglecs and immune checkpoint molecules, and their association with NK cell function in patients with NAFLD. Immune cells in the peripheral blood of 42 patients with biopsy-proven NAFLD and 13 healthy volunteers (HVs) were identified by mass cytometry. The function of various NK cell subpopulations was assessed by flow cytometric detection of intracellular IFN-γ and CD107a/LAMP-1, a degranulation marker, after in vitro stimulation. We found that peripheral blood from NAFLD patients, regardless of fibrosis stage, contained significantly fewer total CD56+ NK cell and CD56dim NK cell populations compared with HVs, and the CD56dim cells from NAFLD patients were functionally impaired. Among the Siglecs examined, NK cells predominantly expressed Siglec-7 and Siglec-9, and both the expression levels of Siglec-7 and Siglec-9 on NK cells and the frequencies of Siglec-7+CD56dim NK cells were reduced in NAFLD patients. Notably, Siglec-7 levels on CD56dim NK cells were inversely correlated with PD-1, CD57, and ILT2 levels and positively correlated with NKp30 and NKp46 levels. Further subtyping of NK cells identified a highly dysfunctional Siglec-7-CD57+PD-1+CD56dim NK cell subset that was increased in patients with NAFLD, even those with mild liver fibrosis. Intrahepatic NK cells from NAFLD patients expressed elevated levels of NKG2D and CD69, suggesting a more activated phenotype than normal liver NK cells. These data identify a close association between NK cell function and expression of Siglec-7, CD57, and PD-1 that could potentially be therapeutically targeted in NAFLD.

Laparoscopic hepatectomy for hepatic angiomyolipoma with preoperative diagnosis of other malignancy: a report of 2 cases.

BACKGROUND: Hepatic angiomyolipoma (HAML) is a rare liver tumor, and hepatectomy is the only effective treatment. Due to the difficulty of correct diagnosis of HAML before surgery by image studies, more than 36.6% of reported HAMLs are misdiagnosed as other malignant liver tumors before surgery. As there are only few reported cases in which HAMLs were removed using laparoscopic hepatectomy, the effectiveness of laparoscopic hepatectomy for such HAMLs in which are diagnosed as other malignant liver tumor before surgery has not been reported. Case presentation Case 1: a 58-year-old female with a history of treatment for autoimmune hepatitis was preoperatively diagnosed with hepatocellular carcinoma (size: 20 mm) in segment 7 (S7) of the liver. The tumor was removed by laparoscopic partial resection and was diagnosed as a HAML through a pathological examination. The patient's postoperative course was good, and she was recurrence-free at 37 months after the hepatectomy. Case 2: a 29-year-old female with a history of surgery for a right mature cystic teratoma was referred to our department to receive treatment for a growing 20-mm liver tumor with some calcification, which arose in S3 of the liver. A metastatic liver tumor derived from the mature cystic teratoma was suspected, and laparoscopic left lateral sectionectomy was performed. The liver tumor was diagnosed as a HAML after a pathological examination. The patient's postoperative course was unremarkable, and more than 54 months have passed since the hepatectomy without any recurrence. CONCLUSIONS: Two cases in which HAMLs were preoperatively diagnosed as other malignant liver tumor were successfully removed by laparoscopic hepatectomy with a correct postoperative diagnosis. Laparoscopic hepatectomy for the present 2 cases of HAML seemed to be effective for providing a correct diagnosis after the curative removement of liver tumor with a smaller invasion compared to open hepatectomy, and for denying risk of dissemination of the malignant tumor by needle biopsy that had to be considered before ruling out malignant tumor.

Impact of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging on the prognosis of hepatocellular carcinoma after surgery.

BACKGROUND AND AIM: Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (EOB-MRI) has been recognized as a useful imaging technique to distinguish the biological behavior of hepatocellular carcinoma (HCC). METHODS: We analyzed 217 hepatectomy recipients with HCCs measuring 10 cm or less. We divided the patients into a decreased intensity (DI) group (n = 189, 87%) and an increased or neutral intensity (INI) group (n = 28, 13%) according to the ratio of tumor intensity to liver intensity during the hepatobiliary phase (HBP). According to the ratio of the maximum tumor diameter (including peritumoral hypointensity) between HBP images and precontrast T1-weighted images (RHBPP), we divided the patients as follows: The group whose RHBPP was ≥1.036 was the high RHBPP group (n = 60, 28%), and the group whose RHBPP was <1.036 was the low RHBPP group (n = 157, 72%). We investigated the prognoses and clinicopathological characteristics of these patients. RESULTS: DI versus INI was not a prognostic factor for either survival or recurrence; however, a high RHBPP was an independent predictor of unfavorable survival and recurrence in patients. In addition, the INI group showed significantly lower α-fetoprotein (AFP) levels and higher rates of well-differentiated HCC and ICGR15 ≥15% than the DI group. The high RHBPP group showed significantly higher rates of vascular invasion and poorly differentiated HCC than the low RHBPP group. CONCLUSIONS: A high RHBPP by EOB-MRI is a preoperative predictor of vascular invasion and an unfavorable prognostic factor for survival and recurrence. These patients might be considered for highly curative operations such as anatomical liver resection.

Predictive value of gadoxetic acid enhanced magnetic resonance imaging for posthepatectomy liver failure after a major hepatectomy.

BACKGROUND: We assessed the usefulness of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid enhanced magnetic resonance imaging for the prediction of posthepatectomy liver failure (PHLF) after a major hepatectomy. METHODS: We reviewed 140 cases involving a hepatectomy of two or more sections between 2010 and 2016 (study cohort). We used the standardized remnant hepatocellular uptake index (SrHUI) which was calculated by: SrHUI = future remnant liver volume × [(signal intensity of remnant liver on hepatobiliary phase images/signal intensity of spleen on hepatobiliary phase images) - 1]/body surface area. Validation of the SrHUI was performed in another cohort of 52 major hepatectomy cases between 2017 and 2018 (validation cohort). RESULTS: The SrHUI of patients with PHLF was significantly lower than that of non-PHLF cases. Receiver operating characteristic analysis and the Youden index revealed that the SrHUI cutoff value for the prediction of PHLF and PHLF grade ≥ B were 0.313 L/m2 and 0.257 L/m2 , respectively. In the validation cohort, the cutoff value of SrHUI for the prediction of PHLF or PHLF grade ≥ B had a sensitivity of 75.0% or 88.8%, and specificity of 78.1% or 91.6%, respectively. CONCLUSIONS: The SrHUI value is a predictor for PHLF after a major hepatectomy.

Prognoses, outcomes, and clinicopathological characteristics of very elderly patients with hepatocellular carcinoma who underwent hepatectomy.

OBJECTIVES: The aim was to evaluate the prognostic factors, clinicopathological characteristics, and surgical outcomes after hepatectomy in very elderly patients with hepatocellular carcinoma (HCC). METHODS: We analyzed 796 patients with HCC from 2000 to 2017. Patients aged 80 years or older were classified into the very elderly group (group VE; n = 49); patients younger than 80 years old and aged 65 years or older were classified into the elderly group (group E; n = 363), and patients younger than 65 years old were classified into the young group (group Y; n = 384). We investigated the prognoses, clinicopathological characteristics, and surgical outcomes after hepatectomy. RESULTS: The number of surgical procedures and outcomes, including morbidities, was not significantly different. Groups VE, E, and Y showed similar prognoses in terms of both survival and recurrence. In group VE, prothrombin activity (PA) < 80% and PIVKA-II ≥ 400 mAU/ml were unfavorable factors for survival, and PIVKA-II ≥ 400 mAU/ml and the presence of portal venous invasion (PVI), hepatic venous invasion, and fibrosis were unfavorable factors for recurrence. In group E, ChE < 180 IU/l, AFP ≥ 20 ng/ml, tumor size ≥ 10 cm, and the presence of multiple tumors, PVI, and hepatic venous invasion (HVI) were unfavorable factors for survival, and ChE < 180 IU/l, tumor size ≥ 10 cm, and the presence of multiple tumors, PVI, and HVI were unfavorable factors for recurrence. In group Y, AFP ≥ 20 ng/ml, the presence of multiple tumors, poor differentiation, PVI, HVI, and blood loss ≥ 400 ml were unfavorable factors for survival, and PA < 80%, albumin < 3.5 g/dl, AFP ≥ 20 ng/ml, tumor size ≥ 10 cm, and the presence of multiple tumors, poor differentiation, and PVI were unfavorable factors for recurrence. CONCLUSIONS: Tumor factors might have limited influence on the prognosis of very elderly patients, and liver function reserve might be important for the long-term survival of very elderly patients. Hepatectomy can be performed safely, even in very elderly patients. Hepatectomy should not be avoided in very elderly patients with HCC if patients have a good general status because these patients have the same prognoses as nonelderly individuals.