A case of immunoglobulin G4-related sclerosing mesenteritis without other organ involvement.

A 64-year-old man presented to our hospital with abdominal pain and 4-5 episodes of watery diarrhea per day for 2 months. Abdominal ultrasound examination revealed a mass in the peritoneal cavity, and computed tomography showed a 13.4 cm mass in the mesentery and a 3 cm mass in the mesocolon. The patient underwent laparoscopic partial resection for diagnosis. Microscopically, abundant fibrosis and numerous immunoglobulin (Ig) G4-positive plasma cells were observed. The serum level of IgG4 was 665 mg/dl postoperatively. These findings suggested that the lesion was consistent with IgG4-related sclerosing mesenteritis. Oral steroids resulted in rapid disappearance of symptoms and a decrease in masses. Recently, sclerosing mesenteritis are reported as IgG4-related disease or mimicking IgG4-related disease but multiple lesions rarely occur in the same organ. We report a case of IgG4-related sclerosing mesenteritis with multiple lesions without involvement of other organs, such as the pancreas and salivary glands.

Laparoscopic cholecystectomy with aberrant bile duct detected by intraoperative fluorescent cholangiography concomitant with angiography: A case report.

INTRODUCTION: Laparoscopic cholecystectomy is the standard surgical treatment for patients with benign gallbladder disease. However, bile duct injury continues to be reported as a surgical complication. Intraoperative cholangiography is recommended to reduce the risk of bile duct injury during laparoscopic cholecystectomy. Intraoperative cholangiography using indocyanine green, which is excreted into bile and shows fluorescence under infrared light, has recently been reported as useful in preventing bile duct injury during laparoscopic cholecystectomy. We report here a case of laparoscopic cholecystectomy with an aberrant bile duct detected by intraoperative fluorescent cholangiography concomitant with angiography. PRESENTATION OF CASE: An 82-year-old woman was diagnosed with cholecystolithiasis and underwent laparoscopic cholecystectomy. An aberrant bile duct branching from the right side of the common hepatic duct was detected by intraoperative indocyanine green fluorescent cholangiography. Furthermore, we were able to confirm the cystic artery by reinjecting indocyanine green during the procedure. Laparoscopic cholecystectomy was performed safely without injuring the aberrant bile duct, despite no recognition of the abnormality on preoperative computed tomography or magnetic resonance imaging. DISCUSSION AND CONCLUSIONS: Aberrant bile ducts are rare anatomical variation and clinically important because of the susceptibility to injury during cholecystectomy. Our case reported for the first time that fluorescence cholangiography concomitant with angiography was useful for identifying an aberrant bile duct and the cystic artery during laparoscopic cholecystectomy.

Evaluation of laparoscopic cholecystectomy using indocyanine green cholangiography including cholecystitis: A retrospective study.

Intraoperative cholangiography involving the excretion of fluorescent indocyanine green (ICG) into the bile is used to determine biliary anatomy in laparoscopic cholecystectomy (LC). This study aimed to evaluate the features of intraoperative ICG cholangiography, in LC with cholecystitis, and compared the delineation of the cystic duct (CD) between ICG cholangiography and magnetic resonance cholangiopancreatography (MRCP).Participants comprised 65 patients undergoing LC using ICG cholangiography.Fifty-eight patients (89.2%) were diagnosed with gallbladder stones and 32 (49.2%) with acute cholecystitis. ICG cholangiography identified CD in 54 patients (83.1%) and did not identify CD in 11 patients (16.9%). The mean value of the fluorescence intensity in the identified CD group by ICG cholangiography was 87.6 ±â€Š31.5 arbitrary unit and that in the not identified CD group by ICG cholangiography was 24.4 ±â€Š10.1 arbitrary unit (P < .001). Compared with the patients in the identified CD group, those in the not identified CD group had higher incidence of acute cholecystitis (P < .001), and higher conversion rates (P = .003). A correlation between the delineation of CD by ICG cholangiography and MRCP was analyzed, and it revealed a correlation between each other (P = .002)Inflammation had harmful effects with regard to the passing of CD. If we can identify CD or common bile duct with ICG cholangiography, we may be able to perform LC with confidence, even in the presence of severe inflammation.

Clinical Implication of the Relationship Between High Mobility Group Box-1 and Tumor Differentiation in Hepatocellular Carcinoma.

BACKGROUND/AIM: High mobility group box-1 (HMGB1) induces the release of proinflammatory cytokines and chemokines as a late-acting mediator of inflammation. Hepatocellular carcinoma (HCC) is a typical inflammation-related cancer. However, little is known about the relationship between HCC and HMGB1 and its receptor RAGE (receptor for advanced glycation end products). This study analyzes the clinicopathological relevance of HMGB1 expression level and the effect of HMGB1 expression on the characteristics of HCC. MATERIALS AND METHODS: Samples from 75 HCC patients including 13 with positive hepatitis B surface antigen and 36 with hepatitis C antibody were studied. The expression of HMGB1 in paired cancer and non-cancerous tissues from patients with HCC was assessed using reverse-transcription polymerase chain reaction (RT-PCR) and western blotting. Quantitative RT-PCR data were analyzed in association with the clinicopathological factors of patients with HCC. RESULTS: The expression of HMGB1 mRNA in HCC was high in well-differentiated tumors, but declined as tumors dedifferentiated to moderately and poorly differentiated HCC. The levels of HMGB1 mRNA showed a negative correlation with the presence of portal invasion (p=0.005) and the rise of serum PIVKA-II (p=0.034). There was no clear correlation between HMGB1 expression and proliferation activity of HCC using Ki-67 staining. CONCLUSION: In HCC, HMGB1 expression level correlated inversely with tumor differentiation. The RAGE-HMGB1 interaction may play a greater role in the early stages of HCC tumorigenesis than during cancer development.

Prognostic significance of CD68, CD163 and Folate receptor-ß positive macrophages in hepatocellular carcinoma.

Cluster of differentiation (CD)68 may be used as a pan-macrophage or M1 marker, whereas CD163 may be used as an M2 marker. Furthermore, folate receptor (FR)ß exhibits an M2-like functional profile. In the present study, CD68 and CD163 were used to evaluate and classify tumor-associated macrophages (TAMs). The expression of CD68, CD163 and FRß by TAMs in hepatocellular carcinoma (HCC) Tissues was investigated. Samples from 105 patients with HCC were evaluated using immunohistochemistry. The results revealed that CD68 and CD163 overexpression was associated with a worse prognosis. The number of CD68 positive cells observed was significantly higher in patients with stage IV cancer. Furthermore, an increase in CD68 positive cells was observed in patients with median tumor size ≥3.5 cm and in patients with poorly differentiated HCC. The number of CD163 positive cells was also significantly increased in patients with median tumor size ≥3.5 cm and in those with poorly differentiated HCC. A low CD163/68 ratio was correlated with a worse outcome. The ratio was significantly lower in patients with stage IV cancer, patients with des-gamma-carboxy prothrombin abnormalities, patients with blood vessel infiltration and patients with intrahepatic metastasis. The number of FRß positive cells was not correlated with clinicopathological features. The results of the present study indicate that overexpression of CD68 and CD163 may be associated with a worse patient outcome. The evaluation of CD68 and CD163 positive cells in a cancer microenvironment is controversial. TAMs are not simply cells with single markers or restricted M1 or M2 phenotypes; they are more diverse and heterogeneous. Further studies are required to determine the cross-interaction between diverse TAMs and the tumor microenvironment.

[A Case of Adult Undifferentiated Sarcoma of the Liver with Intraatrial Metastasis].

A 24-year-old woman was admitted to the hospital for abdominal pain. Abdominal contrast-enhanced computed tomography( CT)revealed a cystic mass measuring 11×8 cm in the left lobe of the liver with extravasation. Vascular embolization was performed, but extravasation remained on CT images. She was then transferred to our hospital. We performed an emergency extended left hepatectomy. Histopathological examination revealed solid proliferation of spindle-shaped cells. Immunohistochemical staining showed that the tumor cells were positive for vimentin and negative for AE1/AE3. Thus, a diagnosis of undifferentiated sarcoma was confirmed. Multiple recurrent tumors were recognized on CT images of the lung and right atrium taken 1 year and 10 months post-surgery. Partial resection of the tumor was performed for the right atrial mass, the left lingular segment, the left inferior lobe, and the right middle lobe. Pathological diagnosis confirmed metastasis of undifferentiated sarcoma from the liver. Chemotherapy consisting of vincristine, actinomycin D, and cyclophosphamide(VAC) was not effective, and the patient died 31 months after the primary surgery. Undifferentiated sarcoma of the liver is a rare malignant mesenchymal tumor, whose occurrence is extremely rare in adults. Although surgical treatment is the first choice, outcomes remain poor. Multimodality treatment should be used to improve the outcome.

Management of horizontal duodenal perforation: a report of three cases and review of literature.

BACKGROUND: Perforation of the horizontal duodenum is very rare due to the presence in retroperitoneal space. It depicts an unusual clinical picture and is difficult to diagnose, leading to increased morbidity and mortality. The treatment strategies are usually varied and based on small series of cases, literature reviews, and expert opinions. CASE PRESENTATION: Here, we presented three cases of horizontal duodenal perforation in three different clinical processes. The first case, a 30-year-old male patient, presented with abdominal pain and hematemesis after experiencing a physical assault on the previous day. Computed tomography (CT) scan showed rupture of the horizontal duodenum. It was repaired by side-to-side duodenojejunostomy. Postoperatively, he had anastomotic leakage, disseminated intravascular coagulation, and pulmonary failure and recovered after a long hospital stay. The second case, an 81-year-old female, had duodenal perforation with endoscopic coagulation of the bleeding diverticulum. Segmental resection of the duodenum and side-to-side duodenojejunostomy were performed. Postoperatively, there was slight anastomotic leakage, but surgical intervention was not needed. The third case, an 89-year-old female, was a patient with obstructive jaundice due to pancreas head carcinoma, who developed perforation of the horizontal duodenum during endoscopic retrograde cholangiopancreatography (ERCP). After unsuccessful conservative management, duodenojejunostomy at the perforated site and gastric bypass were performed. The postoperative course was uneventful. CONCLUSION: Early suspicion and investigation is necessary for cases of abdominal injuries. CT scan is the investigation of choice. The management options should be based on the clinical condition of the patient, comorbidities, surgical expertise, existing guidelines, and available resources.

Surgical treatment for the excluded bile leakage from Spiegel lobe after right hemihepatectomy: A case report.

INRODUCTION: The treatments of excluded bile duct leakage after hepatectomy are not easy and various strategies have been reported, such as surgery, ethanol or fibrin glue injection, and portal vein embolization. PRESENTATION OF CASE: A 72-year-old man with a surgical history of laparoscopic ileocecal resection for diverticular bleeding was diagnosed as having hepatocellular carcinoma. Right hemihepatectomy was performed, and computed tomography examination on postoperative day 9 showed abdominal fluid collection in the right subphrenic space. Percutaneous intra-abdominal fluid drainage was performed and it was diagnosed as bile leakage. After that it was diagnosed as excluded bile leakage from the Spiegel lobe by drip infusion cholangiographic-computed tomography and endoscopic retrograde cholangiography. To improve this clinical condition, we performed the Spiegel lobe excision on postoperative day 48. The postoperative course was uneventful and the patient was discharged. DISCUSSION: According to the postoperative examination, it appeared that the bile duct from the Spiegel lobe joined to the right main bile duct or the bile duct of the right posterior section. This bile duct anomaly was not detected preoperatively on imaging examination. It is most likely that the bile duct from the Spiegel lobe was cut when the hepatoduodenal ligament in the hepatic hilum was peeled. To prevent excluded bile leakage, the hepatoduodenal ligament should be carefully peeled and ligated instead of using energy devices. CONCLUSION: We consider that surgical treatment for postoperative excluded bile leakage is both a quick and reliable procedure in patients with acceptable liver function and anatomical subject.

Multiple malignant epithelioid mesotheliomas of the liver and greater omentum: a case report and review of the literature.

BACKGROUND: Malignant mesothelioma commonly arises from the pleura, but can also arise from the peritoneum, pericardium, and tunica vaginalis testis. However, malignant mesothelioma of the liver is extremely rare and coexistence with malignant mesothelioma of the greater omentum has not been described in the literature. In this case report, we present a case of multiple malignant mesothelioma of the liver and greater omentum. CASE PRESENTATION: A 36-year-old woman was admitted to our hospital for the evaluation of an elastic hard mass in the right upper abdomen. Abdominal contrast computed tomography showed a cystic mass measuring 13 × 14 × 11 cm in the right liver lobe with enhanced mural nodule. Abnormal accumulation was identified in the liver and lower abdominal area on 18F-fluorodeoxyglucose positron emission tomography. The patient underwent hepatectomy of the posterior segment and partial resection of the omentum. The final pathological diagnosis was low-grade multiple malignant epithelioid mesothelioma based on characteristic immunohistochemical findings. As of 6 months postoperatively, the patient has shown no disease recurrence. CONCLUSIONS: We present the first case of a 36-year-old woman with multiple malignant mesothelioma of the liver and greater omentum.

[Case Report of an Acute Focal Bacterial Nephritis Associated with Adjuvant Chemotherapy in Esophageal Cancer Patient].

We report a case of acute focal bacterial nephritis(AFBN)as a complication of chemotherapy in esophageal cancer patient. A 54-year-old woman underwent thoracoscopic esophagectomy for thoracic esophageal cancer. The final pathological diagnosis was a squamous cell carcinoma, pT1b, N2(No. 110), M0, pStage II . She received adjuvant chemotherapy with docetaxel, CDDP and 5-FU(mDCF)in our hospital from February, 2016. There was no complication in first course. She visited our hospital with complaints of a fever and right flank pain on the 22 nd day after second course of chemotherapy. There was a severe inflammation reaction in the laboratory test. An enhanced CT revealed swelling and partial low density area in the right kidney. Therefore, we diagnosed AFBN, and administrated antibiotic levofloxacin for 16 days. Her symptom improved immediately, and renal function was normal when followed up 10 months later.

Expression of Maternal Embryonic Leucine Zipper Kinase (MELK) Correlates to Malignant Potentials in Hepatocellular Carcinoma.

BACKGROUND/AIM: Maternal embryonic leucine zipper kinase (MELK) is categorized as a member of AMP-activated protein kinase families. Various MELK-associated cellular and biological processes affect multiple stages of tumorigenesis. The aim of the present study was to clarify the relationship between MELK expression and hepatocellular carcinoma (HCC) clinicopathological features. MATERIALS AND METHODS: In thirty conserved frozen primary HCC and non-HCC samples MELK mRNA expression was examined by quantitative real-time polymerase chain reaction (PCR). RESULTS: HCC tissues exhibited significantly higher expression levels compared to non-cancerous tissues. MELK expression had a statistically parallel correlation between tumor diameter and protein induced by vitamin K absence or antagonist II (PIVKA-II). The overall survival (OS) and recurrence-free survival (RFS) of the low MELK mRNA expression group was significantly longer than that of the high MELK mRNA expression group. CONCLUSION: MELK expression in HCC is extremely intense compared to its expression reported in other types of cancer. MELK could be a promising effective tumor marker of HCC and further consideration is needed.

Survival Benefits of Small Anatomical Resection of the Liver for Patients with Hepatocellular Carcinoma and Impaired Liver Function, Based on New-Era Imaging Studies.

BACKGROUND: It has been reported that anatomical resection of the liver may be preferred for primary hepatocellular carcinoma (HCC), and is at least recommended for systematic removal of a segment confined by tumor-bearing portal tributaries. However, nonanatomical resection (NAR) is often selected because of the patient's background, impairment of liver function, and tumor factors. The aims of the present study were to retrospectively compare the recurrence-free survival (RFS) rates for cases of partial resection (PR) and for small anatomical resection (SAR), which is regarded as NAR for primary HCC with impaired liver function. PATIENTS AND METHODS: So-called NAR was performed for a primary and solitary (≤ 5cm) HCC in 47 patients; the patients were classified into PR (n=25) and SAR (n=22) groups. Clinicopathological factors, survival data, and recurrence patterns were compared between groups. RESULTS: There were no significant differences in the preoperative characteristics between the two groups. Operative time was significantly longer in the SAR group than in the PR group. There was no significant difference in the postoperative morbidity and tumor pathological characteristics between the two groups. The RFS of the SAR group was significantly better than those of the PR group. Although there was no significant difference in the pattern of recurrence between the two groups, the rate of intrahepatic recurrence in the same segment as the initial tumor tended to be higher in the PR group than in the SAR group. Multivariate analysis revealed that only the PR operative procedure was significant independent risk factor for poorer RFS. CONCLUSION: Compared with PR, SAR effectively improves the rate of RFS after surgery for a primary and solitary HCC with impaired liver function.

The Evaluation of Liver Function and Surgical Influence by ICGR15 after Chemotherapy for Colorectal Liver Metastases.

Background; Approximately 60% of patients with colorectal cancer develop liver metastasis at some point after diagnosis. The aim of this study is to investigate whether the evaluation of ICGR15 preoperatively is a useful clinical indicator of hepatic injury following chemotherapy and to investigate the influence of multiple chemotherapies on liver function. Results; Mean ICGR15 values were higher in patients ≥65 years (P = 0.047) and in patients with ≥3 cycles (P = 0.022) and ≥6 cycles (P = 0.001) of systemic chemotherapy. ICGR15 values tended to be higher in patients with postoperative complications (P = 0.085). Patients receiving systemic chemotherapy for ≥6 cycles had higher levels of AST (P = 0.003), ALT (P = 0.015), and alkaline phosphatase (ALP) (P = 0.041). Patients receiving systemic chemotherapy for ≥3 cycles had higher levels of AST (P = 0.015) and ALP (P = 0.015). Conclusions; Because the pathological diagnosis is usually established only after operation, preoperative evaluation such as the identification of sinusoidal injury is difficult. Based on this study, higher ICGR15 values may provide an indication of surgical complications and be a predictor of liver dysfunction following frequent cycles of chemotherapy. Hepatectomy should be performed with the utmost care in such patients, and the number of cycles of preoperative chemotherapy should probably be as low as possible.

Prognostication by inflammation-based score in patients with locally advanced pancreatic cancer treated with chemoradiotherapy.

BACKGROUND: An association between inflammatory/immunonutritional status and patient prognosis has been reported in various types of cancer. The aim of this study was to evaluate the utility of inflammatory/immunonutritional factors as therapeutic predictors for patients with locally advanced pancreatic cancer treated with chemoradiotherapy (CRT). METHODS: Ninety-six patients with histologically proven locally advanced pancreatic adenocarcinoma who underwent CRT were enrolled in this study. We evaluated significance of inflammation-based factors as predictors of therapeutic effect and prognosis. RESULTS: The median progression free survival (PFS) and overall survival (OS) of all patients was 10 and 18 months, respectively. A Glasgow prognostic score (GPS) of 2 and plasma fibrinogen levels ≥ 400 mg/dL were independent predictors of poor PFS and OS. A prognostic nutritional index (PNI) ≥ 45 was a predictor of a significantly better reduction rate of the primary tumor. The prognosis between patients with GPS 0/1 and fibrinogen <400 mg/dL, GPS 2 or fibrinogen ≥400 mg/dL, and GPS 2 and fibrinogen ≥400 mg/dL were significantly different. Patients with GPS 2 and/or plasma fibrinogen ≥ 400 mg/dL had significantly higher incidence of metastasis within 6 months after CRT. CONCLUSIONS: GPS, fibrinogen, PNI are useful therapeutic and prognostic predictors in patients with locally advanced pancreatic cancer treated with CRT.

Problems of Long Survival Following Surgery in Patients with NonBNonC-HCC: Comparison with HBV and HCV Related-HCC.

BACKGROUND: The number of patients with hepatocellular carcinoma (HCC) in the absence of both hepatitis B virus surface antigen (HBsAg) and hepatitis C virus antibody (HCVAb) (NBNC-HCC) has been rapidly increasing in Japan. The objective of this study was to compare the clinical and pathological characteristics between patients with the NBNC-HCC, those with HBsAg positive HCC (B-related HCC) and HCVAb positive HCC (C-related HCC). A better understanding will facilitate the development of postoperative strategies to better manage patients with NBNC-HCC. METHODS: Consecutive 219 patients with primary HCC: (B-related, n=35; C-related, n = 104; NBNC, n = 80) were treated by hepatic resection or ablation. Clinicopathological characteristics including postoperative course were retrospectively compared between the three groups. RESULTS: When comparing within stage I and II, the NBNC-HCC group had improved recurrence free survival (RFS) compared to the C-related HCC (p = 0.013) but had not been good overall survival (OS). Moreover, the NBNC-HCC group showed higher rate of death due to other cancers and cardiovascular disease (p = 0.011) compared to the C-related HCC. Multivariate analysis revealed that the only prognostic factor for RFS in the NBNC-HCC group was high serum total bilirubin. CONCLUSIONS: In the patients with the NBNC-HCC, elevated serum bilirubin could predict poor RFS after surgery. Furthermore, patients must be carefully followed-up not only for HCC but also for the occurrence of other critical diseases including multiple other cancers.

Anatomical laparoscopic hepatectomy for hepatocellular carcinoma using indocyanine green fluorescence imaging.

PURPOSE: It is important to minimize surgical invasiveness in the therapy of patients with hepatocellular carcinoma (HCC), and consequently laparoscopic hepatic resection is widely performed. However, most anatomical resections, except left lateral sectionectomy, remain difficult technically, and laparoscopy-assisted procedures have been introduced as an alternative approach because of the safety and curative success of the operation. We reported previously pure laparoscopic subsegmentectomy of the liver using puncture of the portal branch under percutaneous ultrasound (US) with artificial ascites. Herein, we describe pure anatomical laparoscopic segmentectomy using the puncture method with indocyanine green (ICG) injection under laparoscopic US. PATIENTS AND METHODS: Pure laparoscopic segmentectomy was planned for 2 patients with HCC of the liver. Identification of the segment was performed by ICG injection for optical imaging using near-infrared fluorescence under laparoscopic US guidance. RESULTS: The procedures were completed successfully, and the postoperative courses were uneventful. CONCLUSIONS: Pure laparoscopic segmentectomy for HCC with a conventional puncture technique by ICG injection under laparoscopic US is considered to be a useful procedure featuring both low invasiveness and curative success.

Closure of the pancreas in distal pancreatectomy: comparison between bare stapler and reinforced stapler.

BACKGROUND/AIMS: Pancreatic fistula (PF) is a major complication after distal pancreatectomy (DP). Popularization of laparoscopic surgery for DP has promoted the use of stapler for transection and closing of the pancreas. METHODOLOGY: We reviewed the medical records of 50 consecutive patients who underwent DP with stapler. Patients were divided into 2 groups: bare stapler (n=36) and reinforced stapler (n=14). We assessed the incidence of postoperative PF, systemic inflammatory response syndrome (SIRS), and intra-abdominal fluid collection on postoperative day 7. RESULTS: The numbers of patients who developed grade A, grade B, and grade C PF were 17 (34%), 6 (12%), and 0, respectively. The incidence of postoperative PF was significantly lower in the reinforced stapler group (p=0.017). None of the patients in the reinforced stapler group developed grade B PF. Patients in the bare stapler group showed significantly higher incidence of postoperative SIRS (p=0.046), more extensive fluid collection (p=0.020), and longer postoperative hospital stay (p=0.023). CONCLUSIONS: Decreased leakage of postoperative pancreatic juice into the abdominal cavity associated with the usage of the reinforced stapler may lead to reduced inflammatory reaction, low incidence of PF, and early hospital discharge.

Clinical implication of ZEB-1 and E-cadherin expression in hepatocellular carcinoma (HCC).

BACKGROUND: While recent research has shown that expression of ZEB-1 in a variety of tumors has a crucial impact on patient survival, there is little information regarding ZEB-1 expression in hepatocellular carcinoma (HCC). This study investigated the co-expression of ZEB-1 and E-cadherin in HCC by immunohistochemistry and evaluated its association with clinical factors, including patient prognosis. METHODS: A total of 108 patients with primary HCC treated by curative hepatectomy were enrolled. ZEB-1 expression was immunohistochemically categorized as positive if at least 1% cancer cells exhibited nuclear staining. E-cadherin expression was divided into preserved and reduced expression groups and correlations between ZEB-1 and E-cadherin expression and clinical factors were then evaluated. RESULTS: With respect to ZEB-1 expression, 23 patients were classified into the positive group and 85 into the negative group. Reduced E-cadherin expression was seen in 44 patients and preserved expression in the remaining 64 patients. ZEB-1 positivity was significantly associated with reduced expression of E-cadherin (p = 0.027). Moreover, significant associations were found between ZEB-1 expression and venous invasion and TNM stage. ZEB-1 positivity was associated with poorer prognosis (p = 0.025). Reduced E-cadherin expression was significantly associated with intrahepatic metastasis and poorer prognosis (p = 0.047). In particular, patients with both ZEB-1 positivity and reduced E-cadherin expression had a poorer prognosis (p = 0.005). Regardless of E-cadherin status, ZEB-1 was not a significant prognostic factor by multivariate analysis. There was no statistical difference in overall survival when E-cadherin expression was reduced in the ZEB-1 positive group (p = 0.24). CONCLUSIONS: Positive ZEB-1 expression and loss of E-cadherin expression are correlated with poor prognosis in HCC patients and malignancy of ZEB-1 positive tumors involves EMT.

Suppression of SOCS3 in macrophages prevents cancer metastasis by modifying macrophage phase and MCP2/CCL8 induction.

Inflammation has been demonstrated to play important roles in tumorigenesis, tumor progression, and metastasis. STAT3 has been shown to be frequently activated in a variety of human cancer cells and STAT3 signaling promotes the growth and survival of tumor cells. However, the role of STAT3 of myeloid cells associated with tumors is currently unknown. Suppressor of cytokine signaling-3 (SOCS3) has been shown to be a negative regulator of STAT3. In this study, we used macrophage specific SOCS3 conditional knockout (cKO) mice to investigate the effect of the hyperactivation of STAT3 in macrophages on tumor development and metastasis. In a subcutaneous transplantation model of B16F10 melanoma cells, although tumor sizes were not significantly different, SOCS3-cKO mice survived longer than wild-type (WT) mice did. SOCS3-cKO mice exhibited fewer lung and liver metastatic tumor nodules than WT mice when B16F10 was challenged intravenously. SOCS3(-/-) macrophages stimulated with tumor lysates in vitro exhibited prolonged STAT3 phosphorylation and produced less amount of TNFα and IL-6, and higher amount of MCP2/CCL8 than WT macrophages. MCP/CCL8 was induced via STAT3 and exhibited anti-tumor metastatic effect in WT mice. These data suggest that hyperactivation of STAT3 in myeloid cells simultaneously exerted an anti-inflammatory as well as anti-tumor effects. Thus, the targeted inhibition of SOCS3 activity in macrophages may be therapeutic for the suppression of tumor metastasis.

SOCS1 regulates type I/type II NKT cell balance by regulating IFNgamma signaling.

Suppressor of cytokine signaling-1 (SOCS1) has been shown to be an essential negative regulator of cytokine responses, including those of IFNγ, IL-2, IL-4 and IL-7. SOCS1 deficiency resulted in hyperactivation not only of T cells in general but also of NKT cells specifically. Consistent with previous reports, T- and NKT-cell-specific deletion of Socs1 in mice resulted in enhanced sensitivity to ConA-induced hepatitis. Compared with wild-type (WT) NKT cells, SOCS1-deficient NKT cells produced larger quantities of IFNγ in response to ConA and proliferated faster in response to IL-2 and IL-15. To our surprise, however, SOCS1-deficient NKT cells did not respond to the synthetic glycolipid ligand alpha-galactosylceramide (α-GalCer), though they did respond to sulfatide. α-GalCer-CD1d-tetramer-positive type I NKT [invariant NKT (iNKT)] cells were marginally detected in the periphery of SOCS1-conditional knockout (cKO) mice, suggesting that most of the SOCS1-deficient NKT cells at the periphery were type II NKT cells. Consistently, invariant Vα14 expression was much lower in SOCS1-deficient NKT cells than in WT NKT cells, indicating that iNKT cell homeostasis was abnormal in SOCS1-cKO mice. This reduction in iNKT cells was not observed in mice of an IFNγ-deficient background. These results suggest that SOCS1 is an important regulator of the balance between type I and type II NKT cells at the periphery.