Indications for conversion hepatectomy for initially unresectable colorectal cancer with liver metastasis.

PURPOSE: Selected patients with initially unresectable colorectal cancer (CRC) and liver metastases undergo conversion surgery after appropriate chemotherapy. The prognosis of these patients is good, with some even cured of the disease. This retrospective, single-institution study analyzes the clinical importance of patient characteristics on the outcomes of conversion hepatectomy. METHODS: We evaluated 229 consecutive patients with initially unresectable CRC and liver metastasis, who underwent systemic chemotherapy. The patients were assigned to groups depending on conversion hepatectomy. RESULTS: Conversion hepatectomy was performed in 30 patients (13.1%). The proportion of patients with extrahepatic metastasis was significantly lower in the conversion group than in the unresectable group (30.0 vs. 66.8%; P < 0.01). The rate of left-sided primary colorectal tumors was significantly higher in the conversion group than in the unresectable group (96.7 vs. 65.8%; P < 0.01). Multivariate analyses identified that left-sided tumors, no extrahepatic metastasis, H1 or H2 grade CLM, and treatment with molecular-targeted agents were associated with conversion hepatectomy (odds ratios: 16.314, 4.216, 7.631, and 4.070; P < 0.01). Overall survival was significantly longer in the conversion group than in the unresectable group (MST: 50.0 versus 14.7 months; P < 0.01). CONCLUSION: Left-sided primary tumors, absence of extrahepatic metastases, H1 or H2 grade, and use of molecular-targeted agents were associated with successful conversion hepatectomy; thus, patients with these characteristics may be candidates for conversion therapy.

Health-related quality of life after esophagectomy in patients with esophageal cancer.

Esophageal cancer is one of the malignant tumors with the poorest prognosis. Esophagectomy, which is the mainstay of curative-intent treatments, imposes excessive surgical stress on the patients, and postoperative morbidity and mortality rates after esophagectomy remain high. On the other hand, the number of survivors after esophagectomy for esophageal cancer is increasing due to recent improvements in surgical techniques and multidisciplinary treatments for this cancer. However, esophagectomy still has a great influence on the fundamental aspect of patients' lives, that is, the health-related quality of life (HR-QOL), including their physical, emotional, and social functions in the short- and long-term postoperatively. HR-QOL is a multifactorial concept used to assess the symptoms and functional changes caused by the disease itself and treatments from the patients' perspectives. Therefore, assessing the HR-QOL of patients with esophageal cancer after esophagectomy is becoming increasingly important. However, the status of HR-QOL changes after esophagectomy has not been satisfactorily evaluated, and there is no worldwide consensus as to how the postoperative HR-QOL can be improved. This review aimed to raise awareness of healthcare providers, such as surgeons and nurses, on the importance of HR-QOL in patients with esophageal cancer after curative-intent esophagectomy by providing multifaceted information concerning the short- and long-term HR-QOLs, including the status of changes and the determinants of HR-QOL after esophagectomy, and furthermore, essential points for improvement of HR-QOL after esophagectomy.

Simultaneous splenectomy improves outcomes after adult living donor liver transplantation.

BACKGROUND & AIMS: Small-for-size graft (SFSG) syndrome is a major cause of graft loss after living donor liver transplantation (LDLT). Splenectomy (Spx) is an option to prevent this catastrophic complication, but its effect remains controversial. Herein, we aimed to elucidate the effect of simultaneous Spx on graft function and long-term outcomes after LDLT. METHODS: Three hundred and twenty patients were divided into 2 groups: those undergoing (n = 258) and those not undergoing (n = 62) simultaneous Spx. To overcome selection bias, propensity score matching (PSM) was performed (n = 50 in each group). RESULTS: Before PSM, recipients undergoing simultaneous Spx showed better graft function on post-operative day (POD) 7 and 14, as well as lower sepsis frequency within 6 months after LDLT and better graft survival rates compared to those not undergoing Spx. After PSM, compared to patients not undergoing Spx, those undergoing Spx had a lower frequency of early graft dysfunction on POD 7 (p = 0.04); a lower frequency of SFSG syndrome (p = 0.01), lower serum total bilirubin levels (p = 0.001), and lower international normalized ratio (p = 0.004) on POD 14; lower sepsis frequency within 6 months after LDLT (p = 0.02), and better graft survival rates (p = 0.04). Univariate analysis revealed that not undergoing Spx (hazard ratio 3.06; 95% CI 1.07-11.0; p = 0.037) was the only risk factor for graft loss after LDLT. CONCLUSIONS: Simultaneous Spx may prevent SFSG syndrome and is a predictive factor for graft survival after LDLT. Simultaneous Spx is recommended when a small graft (≤35% of standard liver weight) is predicted preoperatively, or for patients with portal hypertension or high portal pressure (above 20 mmHg) after reperfusion in LDLT. LAY SUMMARY: Living donor liver transplantation (LDLT) for patients with acute or chronic liver failure is an alternative to overcome the deceased donor shortage. The potential mismatch between graft and body size is a problem that needs to be solved for LDLT recipients. Herein, we evaluated the impact of simultaneous splenectomy and showed that it was associated with favorable outcomes in patients undergoing LDLT.

Prognostic Impact of Vessels that Encapsulate Tumor Cluster (VETC) in Patients who Underwent Liver Transplantation for Hepatocellular Carcinoma.

BACKGROUND: There is limited published information about prognostic value of vessels that encapsulate tumor cluster (VETC) based on their involvement with immune cells in hepatocellular carcinoma (HCC). Our goal was to evaluate prognostic impact of VETC in patients who underwent living-donor liver transplantation (LDLT) for HCC, focusing on the involvement of VETC with immune status in tumor microenvironment (TME). METHODS: Using a database of 150 patients who underwent LDLT for HCC, immunohistochemical staining of CD34 for VETC, angiopoietin-2 (Ang-2), CD3, and CD68, was reviewed with patients' clinicopathological factors. RESULTS: A strong correlation between VETC pattern and malignant potential in HCC was observed; larger tumor size (P < 0.001), more numbers of tumors (P = 0.003), higher α-fetoprotein levels (P = 0.001), higher des-γ-carboxy prothrombin levels (P = 0.022), microvascular invasion (P < 0.001), and poor differentiation (P = 0.010). Overall survival (OS) of patients with VETC(+) was significantly lower than those with VETC(-) (P = 0.021; 5-year OS rates, 72.0% vs. 87.1%). Furthermore, the ratio of CD3(+) cells was significantly lower in VETC(+) group (P = 0.001), indicating that VETC activity may be strongly correlated with lymphocyte activity. Moreover, combination status of VETC(+)/CD3low was an independent risk factor for mortality (hazard ratio 2.760, 95% confidence interval 1.183-6.439, P = 0.019). Additionally, the combination of VETC expression with immune status (low CD3 levels) enabled further classification of patients based on their clinical outcome. CONCLUSIONS: Our results show the prognostic impact of VETC expression, tumor-infiltrating lymphocytes (TILs), and their combination in the setting of LDLT for HCC, which can be a novel prognostic biomarker for mortality after LDLT.

Association of inflammatory biomarkers with long-term outcomes after curative surgery for mass-forming intrahepatic cholangiocarcinoma.

PURPOSE: Inflammatory biomarkers such as the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) are reportedly predictive of the long-term outcomes of several cancers. We evaluated their correlations with the post-surgical long-term outcomes of patients with mass-forming (MF) intrahepatic cholangiocarcinoma (ICC). METHODS: The subjects of this study were 52 patients who underwent hepatic resection for MF-ICC at our hospital. We measured the cutoff values of NLR, LMR and PLR, using receiver operating characteristic curves, and compared the survival rates of patients with high vs. those with low values. We also evaluated a prognostic scoring system based on significant inflammatory biomarkers. RESULTS: The cutoff values for NLR, LMR, and PLR were 1.93, 4.78, and 98, respectively. The high-NLR and low-LMR groups had significantly worse prognoses than the low-NLR and high-LMR groups. We designed a scoring system using the inflammation score (IS) based on NLR and LMR values, stratifying patients into three groups with scores of 0, 1, or 2. The IS was significantly correlated with overall survival (OS), with 5-year survival rates by the IS score of 100% for 0, 61% for 1, and 32% for 2 (P = 0.011). The IS was found to be an independent predictor of OS in multivariate analysis. CONCLUSIONS: Our IS scoring system may predict long-term outcomes after surgery for MF-ICC.

Laparoscopic spleen-preserving distal pancreatectomy for a solid-cystic intraabdominal desmoid tumor at a gastro-pancreatic lesion: a case report.

BACKGROUND: We report a case of an intraabdominal desmoid tumor that occurred at a gastro-pancreatic lesion with spontaneous cystic features, and present the successful laparoscopic resection of the tumor. CASE PRESENTATION: A 20-mm retroperitoneal cystic mass with a solid component was found adjacent to the stomach and pancreatic body in a 52-year-old woman with no history of familial adenomatous polyposis. Laparoscopic spleen-preserving distal pancreatectomy with wedge resection of the stomach was performed, and complete resection was achieved without intraoperative and postoperative complications. Histopathological examination by immunohistochemistry enabled diagnosis of a desmoid tumor that had originated from the stomach and invaded the pancreatic parenchyma with a spontaneous cystic change. We herein report an extremely rare case of an intraabdominal desmoid tumor with a spontaneous cystic change. CONCLUSION: Regardless of its rarity, desmoid tumor should be included in the preoperative differential diagnosis of a cystic intraabdominal mass, and laparoscopic function-preserving surgery may be an optimal treatment option.

Risk factors for the metabolic syndrome components of hypertension, diabetes mellitus, and dyslipidemia after living donor liver transplantation.

BACKGROUND: Metabolic syndrome (MS) is the most common long-term complication after liver transplantation, and it has been increasing in incidence. The aim of this study was to clarify the risk factors for each MS component -hypertension, diabetes mellitus, and dyslipidemia-after living-donor liver transplantation (LDLT), including characteristics of living-donors. METHODS: Data related to clinicopathological parameters including MS components in 461 consecutive patients who underwent LDLT were analyzed retrospectively. RESULTS: Prevalence of all MS components (hypertension, diabetes mellitus, and dyslipidemia) increased from 9.3%, 16.5%, and 7.2% before LDLT to 44.9%, 45.3%, and 50.8% after LDLT, respectively. By multivariate logistic regression analysis, the three factors, cyclosporine use (OR 2.086, P = 0.001), recipient age (OR 1.036, P = 0.001), and BMI (OR 1.072, P = 0.026) were independent predictors for post-LDLT hypertension. Next, the three factors, male recipient (OR 2.471, P < 0.001), recipient age (OR 1.039, P = 0.002), and donor BMI (OR 1.124, P = 0.012) were independent for post-LDLT diabetes mellitus. The four factors, cyclosporine use (OR 2.015, P = 0.001), prolonged prednisolone use (OR 1.928, P = 0.002), recipient age (OR 1.019, P = 0.037), and GRWR (OR 0.316, P = 0.037) were independent for post-LDLT dyslipidemia as well. CONCLUSIONS: Not only recipient-related factors but also donor-related factors were independently associated with each targeted post-LDLT MS component.

Significance of bile culture surveillance for postoperative management of pancreatoduodenectomy.

BACKGROUND: The management of infectious complications is important in pancreatoduodenectomy (PD). We sought to determine the significance of preoperative surveillance bile culture in perioperative management of PD. METHODS: This study enrolled 69 patients who underwent PD for malignant tumors at a single institute between 2014 and 2017. Surveillance bile culture was performed before or during surgery. Correlations between the incidence of infectious postoperative complications and clinicopathological parameters, including bile cultures, were evaluated. RESULTS: Preoperative positive bile culture was confirmed in 28 of 51 patients (55%). Bile culture was positive in 27 of 30 cases (90%) with preoperative biliary drainage, and 1 of 21 cases (5%) without drainage (p < 0.01). Preoperative isolated microorganisms in bile were consistent with those detected in surgical sites in 11 of 27 cases (41%). Cases with positive multi-drug-resistant bacteria in preoperative bile culture showed significantly higher incisional SSI after PD (p = 0.01). The risk factors for the incidence of organ/space SSI were soft pancreatic texture (p = 0.01) and smoking history (p = 0.02) by multivariate analysis. Preoperative positive bile culture was neither associated with organ/space SSI nor overall postoperative complications. CONCLUSIONS: Preoperative surveillance bile culture is useful for the management of wound infection, prediction of causative pathogens for infectious complications, and the selection of perioperative antibiotic prophylaxis.

Lymphocyte-to-Monocyte Ratio Is a Predictor of Survival After Liver Transplantation for Hepatocellular Carcinoma.

Recent studies revealed that systemic inflammation was correlated with poorer prognosis in various cancers. We investigated the prognostic value of the lymphocyte-to-monocyte ratio (LMR) in patients who underwent living donor liver transplantation (LDLT) for hepatocellular carcinoma (HCC). We retrospectively analyzed the records of 216 patients who underwent LDLT for HCC. Patients were divided into high (n = 126) and low (n = 90) LMR groups. Their clinicopathological parameters and survival times were compared. To determine the mechanisms of the change in the LMR, we performed immunohistochemical analyses of CD3 and CD68 expression. A low LMR was significantly associated with a high Model for End-Stage Liver Disease score; a high Child-Pugh score; elevation of alpha-fetoprotein, des-gamma-carboxyprothrombin, and neutrophil-to-lymphocyte ratio; larger tumor size; more tumors; and poorer prognosis. A low LMR was associated with poor prognosis and represented an independent prognostic factor, particularly among patients beyond the Milan criteria. The ratio of CD3-positive to CD68-positive cells was significantly lower in the low-LMR group. In conclusion, our results show that the LMR was an independent predictor of survival of patients with HCC beyond the Milan criteria who underwent LDLT. The LMR reflected the immune status of the tumor microenvironment.

Potential effect of recombinant thrombomodulin on ischemia-reperfusion liver injury in rats.

AIM: Liver ischemia-reperfusion (I/R) injury is a severe complication of liver surgery. However, the responsible molecular mechanism remains unclear. High-mobility group box 1 (HMGB1) is released from the nuclei of cells and behaves as a damage-associated molecular pattern. The aim of this study is to reveal the roles of HMGB1 and the effects of recombinant thrombomodulin (rTM) in I/R liver injury. METHODS: Rats underwent partial hepatic ischemia followed by reperfusion, and changes in HMGB1 were assessed. Recombinant thrombomodulin was used as an inhibitor of HMGB1. RESULTS: In rats with I/R injury, the HMGB1 level significantly decreased in the liver tissue and significantly increased in the serum after surgery (P < 0.001 for both). No difference in the HMGB1 level in the hepatocytes was observed between the rTM(-) group and rTM(+) group after surgery. Conversely, the serum HMGB1 level was significantly lower in the rTM(+) group than the rTM(-) group after surgery (P < 0.001). The levels of tumor necrosis factor-α and interleukin-6 in the liver tissue 24 h after surgery were significantly lower in the rTM(+) group than the rTM(-) group (P < 0.001). The plasma alanine aminotransferase level at 24 h after surgery of the rTM(+) group was significantly decreased after surgery compared with that of the rTM(-) group (P < 0.001). The necrotic area of the liver tissue 24 h after surgery was significantly smaller in the rTM(+) group than the rTM(-) group (P < 0.001). CONCLUSIONS: Recombinant thrombomodulin can serve as a treatment for I/R liver injury by inhibiting HMGB1.

Pro-angiogenic TIE-2-expressing monocytes/TEMs as a biomarker of the effect of sorafenib in patients with advanced hepatocellular carcinoma.

Sorafenib, a multi-kinase inhibitor, inhibits tumor angiogenesis and is the first-line systemic therapy for patients with advanced hepatocellular carcinoma (HCC). However, due to its limited effects and frequent occurrence of side effects, biomarkers are needed to predict the effects of sorafenib. We considered the possibility of using TIE-2-expressing monocytes (TEMs) to predict the response in sorafenib-treated patients with advanced HCC. TEMs serve as a diagnostic marker of HCC and are related to angiogenesis. We analyzed 25 advanced HCC patients and prospectively evaluated TEMs before (Pre TEMs) and at 1 month after initial therapy (T1m TEMs). The radiologic response was evaluated by modified Response Evaluation Criteria in Solid Tumors (mRECIST). Median survival time (MST) was significantly longer in the partial response/stable disease (PR/SD) group (21.8 months) than in the PD group (8.7 months). ΔTEMs (changes of T1m TEMs compared to Pre TEMs) were significantly lower in the PR/SD group than in the PD group. MST of the ΔTEMs low group (14.2 months) was significantly longer than that of the high group (8.7 months). Univariate and multivariate Cox regression analyses showed that ΔTEMs [hazard ratio (HR) = 8.53, 95% confidence interval (CI) = 1.51-48.16, p = 0.015] and Child-Pugh class (HR = 5.59, 95% CI = 1.06-29.63, p = 0.043) were independently associated with overall survival. Our results suggest that ΔTEMs could serve as a biomarker for predicting radiologic response and overall survival in sorafenib-treated patients with advanced HCC.

Indoleamine-2,3-dioxygenase as an effector and an indicator of protective immune responses in patients with acute hepatitis B.

UNLABELLED: Indoleamine-2, 3-dioxygenase (IDO), an interferon-γ-inducible enzyme catalyzing tryptophan into kynurenine, exerts dual functions in infectious diseases, acting as a suppressor of intracellular pathogens and as an immune regulator. We explored the roles of IDO in hepatitis B virus (HBV) clearance from infected patients. We examined IDO activity, serum chemokines, and cytokines in 53 HBV-positive patients (25 acute hepatitis, 14 chronic hepatitis, and 14 hepatic flare) and 14 healthy volunteers. In order to clarify the mechanisms of IDO induction and its impact on HBV replication, we used a culture model consisting of human natural killer cells, plasmacytoid dendritic cells, and HBV-transfected Huh7 cells in which IDO expression is controlled. A robust activation of IDO with an inverse correlation of alanine aminotransferase at the peak was observed in patients with acute hepatitis B but not in patients with hepatic flare. In acute hepatitis patients who eventually cleared HBV, IDO activity, chemokine (C-X-C motif) ligand 9 (CXCL9), CXCL10, and CXCL11 increased at the peak of alanine aminotransferase. In contrast, in patients with hepatic flare, IDO activity remained at lower levels during the observation period, regardless of the surge of CXCL9, CXCL10, and CXCL11 at the alanine aminotransferase peak. Natural killer cells and plasmacytoid dendritic cells synergistically produced interferon-γ and interferon-α, thereby enhancing IDO activity and HBV suppression in Huh7 cells. Such suppressor capacity of IDO on HBV was abrogated in IDO-knockout cells and recovered by the reinduction of IDO in the cells. CONCLUSION: IDO is an anti-HBV effector and an indicator of subsequent immune responses operative during the early phase of infection; its activity is boosted by coexisting natural killer cells and plasmacytoid dendritic cells.

Evaluation of graft stiffness using acoustic radiation force impulse imaging after living donor liver transplantation.

Acoustic radiation force impulse (ARFI) imaging is an ultrasound-based modality to evaluate tissue stiffness using short-duration acoustic pulses in the region of interest. Virtual touch tissue quantification (VTTQ), which is an implementation of ARFI, allows quantitative assessment of tissue stiffness. Twenty recipients who underwent living donor liver transplantation (LDLT) for chronic liver diseases were enrolled. Graft types included left lobes with the middle hepatic vein and caudate lobes (n = 11), right lobes (n = 7), and right posterior segments (n = 2). They underwent measurement of graft VTTQ during the early post-LDLT period. The VTTQ value level rose after LDLT, reaching a maximum level on postoperative day 4. There were no significant differences in the VTTQ values between the left and right lobe graft types. Significant correlations were observed between the postoperative maximum value of VTTQ and graft volume-to-recipient standard liver volume ratio, portal venous flow to graft volume ratio, and post-LDLT portal venous pressure. The postoperative maximum serum alanine aminotransferase level and ascites fluid production were also significantly correlated with VTTQ. ARFI may be a useful diagnostic tool for the noninvasive and quantitative evaluation of the severity of graft dysfunction after LDLT.

Chronic expanding hematoma of the liver: a case report and review of the literature.

Chronic expanding hematoma (CEH) is defined as a hematoma that grows slowly over a month or longer. CEH with a primary hepatic origin is extremely rare. An 85-year-old man presented with general malaise and low-grade fever. His medical history included hypertension and postoperative appendicitis, and he was taking oral aspirin. Computed tomography showed a 7-cm mass in liver S7 with calcification at the margin. On contrast-enhanced magnetic resonance imaging, the inside of the mass showed heterogeneous hyperintensity on T1-weighted images, mainly low intensity on T2-weighted images, and mild hyperintensity in some areas. Under the preoperative diagnosis of suspected CEH, hemorrhagic cyst, or hepatocellular carcinoma, S7 partial liver resection and cholecystectomy were performed. Histopathological findings showed that the mass was continuous with the liver and protruded extrahepatically, and was covered with a hard fibrous capsule. The capsule contained hematomas ranging from obsolete to relatively fresh, with no neoplastic lesions. He was diagnosed with CEH in the liver. This subcapsular hepatic hematoma was pathologically shown to be a CEH. Complete surgical resection was effective in treating this CEH in the liver.

Neutrophil-lymphocyte ratio reflects hepatocellular carcinoma recurrence after liver transplantation via inflammatory microenvironment.

BACKGROUND & AIMS: Although the Milan criteria (MC) have been used to select liver transplantation candidates among patients with hepatocellular carcinoma (HCC), many patients exceeding the MC have shown good prognosis. Preoperative neutrophil-lymphocyte ratio (NLR) is a predictor of patient prognosis, but its mechanism has never been clarified. METHODS: We assessed outcomes in 158 patients who had undergone living-donor liver transplantation (LDLT) for HCC. Recurrence-free survival (RFS) was determined in patients with high (≥ 4) and low (<4) NLR. Levels of expression of vascular endothelial growth factor (VEGF), interleukin (IL)-8, IL-17, CD68, and CD163 were measured. RESULTS: The 5-year RFS rate was significantly lower in patients with high (n=26) than with low (n=132) NLR (30.3% vs. 89.0%, p<0.0001), in patients with high (n=15) than with low (n=79) NLR who met the MC (73.6% vs. 100%, p=0.0008) and in patients with high (n=11) than with low (n=53) NLR who exceeded the MC (0% vs. 76.1%, p=0.0002). Tumor expression of VEGF, IL8, IL-17, CD68, and CD163 was similar in the high and low NLR groups, but serum and peritumoral IL-17 levels were significantly higher in the high-NLR group (p=0.01 each). The density of peritumoral CD163 correlated with the density of peritumoral IL-17-producing cells (p=0.04) and was significantly higher in the high-NLR group (p=0.005). CONCLUSIONS: NLR predicts outcomes after LDLT for HCC via the inflammatory tumor microenvironment. Combined with the MC, NLR may be a new criterion for LDLT candidates with HCC.

Preoperative neutrophil-to-lymphocyte ratio is a predictor of survival after hepatectomy for hepatocellular carcinoma: a retrospective analysis.

OBJECTIVE: To clarify the prognostic value of the preoperative blood neutrophil-to-lymphocyte ratio (NLR) in patients undergoing hepatectomy for hepatocellular carcinoma (HCC). BACKGROUND: Although a high NLR has been reported to be a predictor of poor survival in patients with various cancers, it has not been extensively examined in patients with HCC. METHODS: This retrospective study enrolled 958 patients who underwent hepatectomy without preoperative therapy for HCC from 1996 to 2009. Clinicopathological parameters, including NLR, were evaluated to identify predictors of overall and recurrence-free survival after hepatectomy. Univariate and multivariate analyses were performed, using the Cox proportional hazards model. The best cutoff was determined with time-dependent receiver operating characteristic curve. To determine the mechanism of NLR elevation, immunohistological examination using CD163 staining was performed in 150 patients. RESULTS: Univariate and multivariate analyses showed that NLR was an independent prognostic factor in overall and recurrence-free survival. The best cutoff of NLR was 2.81, and 238 of 958 patients (24.8%) had NLR of more than 2.81. The 5-year survival rate after hepatectomy was 72.9% in patients with NLR less than 2.81 and 51.5% in those with NLR 2.81 or more (P < 0.0001). CD163-positive cell counts were significantly higher in tumors in the group with NLR 2.81 or more than in the group with NLR less than 2.81 (P = 0.0004). CONCLUSIONS: Our results show that NLR is an independent predictor of survival after hepatectomy in patients with HCC. Accumulation of tumor-associated macrophages in the tumor is associated with a high NLR.

Tumor-associated macrophage promotes tumor progression via STAT3 signaling in hepatocellular carcinoma.

OBJECTIVE: Signal transducer and activator of transcription 3 (STAT3) is activated in hepatocellular carcinoma (HCC), and tumor-associated macrophage plays an important role in tumor progression. Therefore, we examined STAT3 activation, cytokine expression and infiltration of tumor-associated macrophages in resected HCCs as well as the alteration of cell growth and migration by cytokine stimulation in HCC cell lines. METHODS: Immunohistochemical staining of phosphorylated STAT3 (pSTAT3), CD163, interleukin (IL)-6, Ki-67 and Bcl-XL was performed for 101 cases of resected HCC, and correlations between pSTAT3 staining and clinicopathological findings were analyzed. In HCC cell lines (PLC/PRF/5 and Huh7), cell proliferation and migration by IL-6 stimulation and S3I-201 (STAT3 inhibitor) treatment were analyzed. RESULTS: In HCC specimens, the pSTAT3-positive group showed high levels of α-fetoprotein (p = 0.0276), large tumor size (p = 0.0092), frequent intrahepatic metastasis (p = 0.0214), high Ki-67 (p = 0.0002) and Bcl-XL (p = 0.0001), poor prognosis (p = 0.0234), and high recurrence rate (p = 0.0003). CD163-positive cells were frequently observed in the pSTAT3-positive group (p = 0.0013). In two HCC cell lines, IL-6 stimulation promoted cell proliferation and migration via the STAT3 phosphorylation, and S3I-201 inhibited this activation. CONCLUSIONS: STAT3 activation was correlated with aggressive behavior of HCC and may be mediated via tumor-associated macrophage. We expect that STAT3 signaling and tumor-associated macrophages can be attractive therapeutic targets in HCC patients.

Impact of tumor size, number of tumors and neutrophil-to-lymphocyte ratio in liver transplantation for recurrent hepatocellular carcinoma.

AIM: Hepatocellular carcinoma (HCC) is primarily treated with hepatic resection and/or locoregional therapy. When HCC recurs and further treatment is no longer possible owing to poor liver function, liver transplantation (LT) or living-donor LT (LDLT) is considered. The aim of this study was to clarify risk factors for tumor recurrence after LDLT in patients with recurrent HCC. METHODS: The study comprised 104 patients who had undergone LDLT because of end-stage liver disease with recurrent HCC. The recurrence-free survival rates after the LDLT were calculated. Risk factors for tumor recurrence were identified. RESULTS: The 1-, 3- and 5-year recurrence-free survival rates were 89.6%, 80.3% and 78.4%, respectively. By univariate analysis, the factors affecting recurrence-free survival were the sum of the largest tumor size and number of tumors of 8 or more (P < 0.0001), des-γ-carboxy prothrombin of more than 300 mAU/mL (P = 0.0001), and a neutrophil-to-lymphocyte ratio (NLR) of 4 or more (P = 0.0002), α-fetoprotein of more than 400 ng/mL (P = 0.0001) and bilobar tumor distribution (P = 0.046). A multivariate analysis identified independent risk factors for post-LDLT tumor recurrence including the sum of tumor size and number of tumors of 8 or more (P = 0.0004) and an NLR of 4 or more (P = 0.01). The 1- and 3- year recurrence-free survival rates in the recipients who had both risk factors were 30.0% and 15.0%, respectively. CONCLUSION: LDLT should not be performed for patients who have both independent risk factors after any treatments for HCC.

A rare point mutation in the Ras oncogene in hepatocellular carcinoma.

PURPOSE: The Ras gene is one of the oncogenes most frequently detected in human cancers, and codes for three proteins (K-, N-, and H-Ras). The aim of this study was to examine the mutations in codons 12, 13 and 61 of the three Ras genes in cases of human hepatocellular carcinoma (HCC). METHODS: Paired samples of HCC and corresponding non-malignant liver tissue were collected from 61 patients who underwent hepatectomy. A dot-blot analysis was used to analyze the products of the polymerase chain reaction (PCR) amplification of codons 12, 13, and 61 of K-, N- and H-Ras for mutations. RESULTS: Only one mutation (K-Ras codon 13; Gly to Asp) was detected among the 61 patients. Interestingly, this patient had a medical history of surgery for both gastric cancer and right lung cancer. No mutations were found in codons 12 and 61 of K-Ras or codons 12, 13 and 61 of the N-Ras and H-Ras genes in any of the HCCs or corresponding non-malignant tissues. CONCLUSIONS: These findings indicated that the activation of Ras proto-oncogenes by mutations in codons 12, 13, and 61 does not play a major role in hepatocellular carcinogenesis.