Lonicera japonica Thunb. Ethanol Extract Exerts a Protective Effect on Normal Human Gastric Epithelial Cells by Modulating the Activity of Tumor-Necrosis-Factor-α-Induced Inflammatory Cyclooxygenase 2/Prostaglandin E2 and Matrix Metalloproteinase 9.

Gastric inflammation-related disorders are commonly observed digestive system illnesses characterized by the activation of proinflammatory cytokines, particularly tumor necrosis factor-α (TNF-α). This results in the induction of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PEG2) and matrix metallopeptidase-9 (MMP-9). These factors contribute to the pathogenesis of gastric inflammation disorders. We examined the preventive effects of Lonicera japonica Thunb. ethanol extract (Lj-EtOH) on gastric inflammation induced by TNF-α in normal human gastric mucosa epithelial cells (GES-1). The GES-1 cell line was used to establish a model that simulated the overexpression of COX-2/PGE2 and MMP-9 proteins induced by TNF-α to examine the anti-inflammatory properties of Lj extracts. The results indicated that Lj-EtOH exhibits significant inhibitory effects on COX-2/PEG2 and MMP-9 activity, attenuates cell migration, and provides protection against TNF-α-induced gastric inflammation. The protective effects of Lj-EtOH are associated with the modulation of COX-2/PEG2 and MMP-9 through the activation of TNFR-ERK 1/2 signaling pathways as well as the involvement of c-Fos and nuclear factor kappa B (NF-κB) signaling pathways. Based on our findings, Lj-EtOH exhibits a preventive effect on human gastric epithelial cells. Consequently, it may represent a novel treatment for the management of gastric inflammation.

Altered microbiome of serum exosomes in patients with acute and chronic cholecystitis.

BACKGROUND: This study aimed to investigate the differences in the microbiota composition of serum exosomes from patients with acute and chronic cholecystitis. METHOD: Exosomes were isolated from the serum of cholecystitis patients through centrifugation and identified and characterized using transmission electron microscopy and nano-flow cytometry. Microbiota analysis was performed using 16S rRNA sequencing. RESULTS: Compared to patients with chronic cholecystitis, those with acute cholecystitis exhibited lower richness and diversity. Beta diversity analysis revealed significant differences in the microbiota composition between patients with acute and chronic cholecystitis. The relative abundance of Proteobacteria was significantly higher in exosomes from patients with acute cholecystitis, whereas Actinobacteria, Bacteroidetes, and Firmicutes were significantly more abundant in exosomes from patients with chronic cholecystitis. Furthermore, functional predictions of microbial communities using Tax4Fun analysis revealed significant differences in metabolic pathways such as amino acid metabolism, carbohydrate metabolism, and membrane transport between the two patient groups. CONCLUSIONS: This study confirmed the differences in the microbiota composition within serum exosomes of patients with acute and chronic cholecystitis. Serum exosomes could serve as diagnostic indicators for distinguishing acute and chronic cholecystitis.

Integrative multiomics enhancer activity profiling identifies therapeutic vulnerabilities in cholangiocarcinoma of different etiologies.

OBJECTIVES: Cholangiocarcinoma (CCA) is a heterogeneous malignancy with high mortality and dismal prognosis, and an urgent clinical need for new therapies. Knowledge of the CCA epigenome is largely limited to aberrant DNA methylation. Dysregulation of enhancer activities has been identified to affect carcinogenesis and leveraged for new therapies but is uninvestigated in CCA. Our aim is to identify potential therapeutic targets in different subtypes of CCA through enhancer profiling. DESIGN: Integrative multiomics enhancer activity profiling of diverse CCA was performed. A panel of diverse CCA cell lines, patient-derived and cell line-derived xenografts were used to study identified enriched pathways and vulnerabilities. NanoString, multiplex immunohistochemistry staining and single-cell spatial transcriptomics were used to explore the immunogenicity of diverse CCA. RESULTS: We identified three distinct groups, associated with different etiologies and unique pathways. Drug inhibitors of identified pathways reduced tumour growth in in vitro and in vivo models. The first group (ESTRO), with mostly fluke-positive CCAs, displayed activation in estrogen signalling and were sensitive to MTOR inhibitors. Another group (OXPHO), with mostly BAP1 and IDH-mutant CCAs, displayed activated oxidative phosphorylation pathways, and were sensitive to oxidative phosphorylation inhibitors. Immune-related pathways were activated in the final group (IMMUN), made up of an immunogenic CCA subtype and CCA with aristolochic acid (AA) mutational signatures. Intratumour differences in AA mutation load were correlated to intratumour variation of different immune cell populations. CONCLUSION: Our study elucidates the mechanisms underlying enhancer dysregulation and deepens understanding of different tumourigenesis processes in distinct CCA subtypes, with potential significant therapeutics and clinical benefits.

A novel technique of sutureless omentopexy during dual-incision laparoscopic peritoneal dialysis catheter insertion to prevent catheter dysfunction due to omental wrapping.

BACKGROUND: Omental wrapping (OW) is the leading cause of obstruction of the peritoneal dialysis (PD) catheter, which interferes with dialysis treatment. Routinely or selectively performing omentopexy during laparoscopic PD catheter placement has been suggested to prevent OW. However, most of the published techniques for performing this adjunctive procedure require additional incisions and suturing. Herein, we aimed to report our experience in performing omentopexy with a sutureless technique during dual-incision PD catheter insertion. We also performed a comparative analysis to assess the benefit/risk profile of routine omentopexy in these patients. METHODS: This retrospective study enrolled 469 patients who underwent laparoscopic PD catheter insertion. Their demographic characteristics and operative details were collected from the database of our institution. Omentopexy was performed by fixing the inferior edge of the omentum to the round ligament of the liver using titanium clips. For analysis, the patients were divided into the omentopexy group and the non-omentopexy group. We also reviewed the salvage management and outcomes of patients who experienced OW. RESULTS: The patients were categorized into the omentopexy (n = 81) and non-omentopexy (n = 388) groups. The patients in the non-omentopexy group had a higher incidence of OW, whereas no patient in the omentopexy group experienced this complication (5.2% vs. 0.0%, p = 0.033). The median operative time was 27 min longer in patients who underwent omentopexy than in those who did not [100 (82-118) min vs. 73 (63-84) min, p < 0.001]. One patient had an intra-abdominal hematoma after omentopexy and required salvage surgery to restore catheter function. The complication rate of omentopexy was 1.2% (1/81). CONCLUSION: Sutureless omentopexy during laparoscopic PD catheter insertion is a safe and reliable technique that does not require additional incisions and suturing. Routinely performing omentopexy provides clinical benefits by reducing the risk of catheter dysfunction due to OW.

Laparoscopic liver resection is associated with less significant muscle loss than the conventional open approach.

BACKGROUND: Laparoscopic liver resections (LLR) have been shown a treatment approach comparable to open liver resections (OLR) in hepatocellular carcinoma (HCC). However, the influence of procedural type on body composition has not been investigated. The aim of the current study was to compare the degree of skeletal muscle loss between LLR and OLR for HCC. METHODS: By using propensity score matching (PSM) analysis, 64 pairs of patients were enrolled. The change of psoas muscle index (PMI) after the operation was compared between the matched patients in the LLR and OLR. Risk factors for significant muscle loss (defined as change in PMI > mean change minus one standard deviation) were further investigated by multivariate analysis. RESULTS: Among patients enrolled, there was no significant difference in baseline characteristics between the two groups. The PMI was significantly decreased in the OLR group (P = 0.003). There were also more patients in the OLR group who developed significant muscle loss after the operations (P = 0.008). Multivariate analysis revealed OLR (P = 0.023), type 2 diabetes mellitus, indocyanine green retention rate at 15 min (ICG-15) > 10%, and cancer stage ≧ 3 were independent risk factors for significant muscle loss. In addition, significant muscle loss was associated with early HCC recurrence (P = 0.006). Metabolomic analysis demonstrated that the urea cycle may be decreased in patients with significant muscle loss. CONCLUSION: LLR for HCC was associated with less significant muscle loss than OLR. Since significant muscle loss was a predictive factor for early tumor recurrence and associated with impaired liver metabolism, LLR may subsequently result in a more favorable outcome.

Purely laparoscopic feeding jejunostomy: a procedure which deserves more attention.

BACKGROUND: Laparoscopic procedure has inherent merits of smaller incisions, better cosmesis, less postoperative pain, and earlier recovery. In the current study, we presented our method of purely laparoscopic feeding jejunostomy and compared its results with that of conventional open approach. METHODS: We retrospectively reviewed our patients from 2012 to 2019 who had received either laparoscopic jejunostomy (LJ, n = 29) or open ones (OJ, n = 94) in Chang Gung Memorial Hospital, Linkou. Peri-operative data and postoperative outcomes were analyzed. RESULTS: In the current study, we employed 3-0 Vicryl, instead of V-loc barbed sutures, for laparoscopic jejunostomy. The mean operative duration of LJ group was about 30 min longer than the OJ group (159 ± 57.2 mins vs 128 ± 34.6 mins; P = 0.001). There were no intraoperative complications reported in both groups. The patients in the LJ group suffered significantly less postoperative pain than in the OJ group (mean NRS 2.03 ± 0.9 vs. 2.79 ± 1.2; P = 0.002). The majority of patients in both groups received early enteral nutrition (< 48 h) after the operation (86.2% vs. 74.5%; P = 0.143). CONCLUSIONS: Our study demonstrated that purely laparoscopic feeding jejunostomy is a safe and feasible procedure with less postoperative pain and excellent postoperative outcome. It also provides surgeons opportunities to enhance intracorporeal suture techniques.

Serum metabolites may be useful markers to assess vascular invasion and identify normal alpha-fetoprotein in hepatocellular carcinoma undergoing liver resection: a pilot study.

PURPOSE: Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver with a dismal prognosis. Vascular invasion, among others, is the most robust indicator of postoperative recurrence and overall survival after liver resection for HCC. Few studies to date have attempted to search for effective markers to predict vascular invasion before the operation. The current study would examine the plasma metabolic profiling via 1H-NMR of HCC patients undergoing liver resection and aim to search for potential biomarkers in the early detection of HCC with normal alpha-fetoprotein (AFP) and the diagnosis of vascular invasion preoperatively. MATERIALS AND METHODS: HCC patients scheduled to receive liver resections for their HCC were recruited and divided into two separate groups, investigation cohort and validation cohort. Their preoperative blood samples were collected and subjected to a comprehensive metabolomic profiling using 1H-nuclear magnetic resonance spectroscopy (NMR). RESULTS: There were 35 HCC patients in the investigation group and 22 patients in the validation group. Chronic hepatitis B remained the most common etiology of HCC, followed by chronic HCV infection. The two study cohorts were essentially comparable in terms of major clinicopathological variables. After 1H-nuclear NMR analysis, we found in the investigation cohort that HCC with normal alpha-fetoprotein (AFP < 15 ng/mL) had significantly higher serum level of O-acetylcarnitine than those with higher AFP (AFP ≥ 15 ng/mL, P = 0.025). In addition, HCC with microscopic vascular invasion (VI) had significantly higher preoperative serum level of formate than HCC without microscopic VI (P = 0.023). These findings were similar in the validation cohort. CONCLUSION: A comprehensive metabolomic profiling of HCC demonstrated that serum metabolites may be utilized to assist the early diagnosis of AFP-negative HCC patients and recognition of microvascular invasion in order to facilitate preoperative surgical planning and postoperative follow-up. Further, larger scale prospective studies are warranted to consolidate our findings.

Actin cytoskeleton remodeling drives epithelial-mesenchymal transition for hepatoma invasion and metastasis in mice.

High invasiveness is a hallmark of human hepatocellular carcinoma (HCC). Large tumors predict invasion and metastasis. Epithelial-mesenchymal transition (EMT) is crucial for cancer invasion and metastasis. However, the mechanisms whereby large tumors tend to undergo EMT remain unclear. We conducted a subgenome-wide screen and identified KLHL23 as an HCC invasion suppressor by inhibiting EMT. KLHL23 binds to actin and suppresses actin polymerization. KLHL23 silencing induced filopodium and lamellipodium formation. Moreover, EMT was suppressed by KLHL23 through its action on actin dynamics. Traditionally, actin cytoskeleton remodeling is downstream of EMT reprogramming. It is therefore intriguing to ask why and how KLHL23 inversely regulates EMT. Activation of actin cytoskeleton remodeling by either KLHL23 silencing or treatment with actin cytoskeleton modulators augmented cellular hypoxic responses in a cell-density-dependent manner, resulting in hypoxia-inducible factor (HIF) and Notch signals and subsequent EMT. Environmental hypoxia did not induce EMT unless actin cytoskeleton remodeling was simultaneously activated and only when cells were at high density. The resulting EMT was reversed by either adenosine 5'-triphosphate supplementation or actin polymerization inhibitors. Down-regulation of KLHL23 was associated with invasion, metastasis, and poor prognosis of HCC and pancreatic cancer. Correlations of tumor size with EMT and inverse association of expression of KLHL23 with HIF/Notch signals were further validated in patient-derived xenograft HCCs in mice. CONCLUSION: Simultaneously activation of actin cytoskeleton remodeling by intrinsic (such as KLHL23 down-regulation) or microenvironment cues is crucial for cell-density-dependent and hypoxia-mediated EMT, providing a mechanistic link between large tumor size and invasion/metastasis. Our findings provide a means of developing the prevention and treatment strategies for tumor invasion and metastasis. (Hepatology 2018;67:2226-2243).

Stapleless laparoscopic left lateral sectionectomy for hepatocellular carcinoma: reappraisal of the Louisville statement by a young liver surgeon.

BACKGROUND: Laparoscopic liver resection has been regarded as the standard treatment for liver tumors located at the left lateral liver sector. However, few studies have reported the results of laparoscopic left lateral sectionectomy (LLS) for HCC, not to mention the feasibility of this emerging technique for the less experienced liver surgeons. The current study would reappraise the Louisville statement by examining the outcome of LLS performed by a young liver surgeon. METHODS: We retrospectively reviewed two separate groups of patients who underwent open or laparoscopic left lateral sectionectomies at Chung Gung Memorial Hospital, Linkou. All laparoscopic hepatectomies were performed by the index young surgeon following a stepwise stapleless LLS. The surgical results and oncological outcomes of laparoscopic vs. open hepatectomies (LH and OH, respectively) with the surgical indication of HCC at left lateral liver sector were further compared and analyzed. RESULTS: 18 of 29 patients in the laparoscopic group and 75 patients in the conventional open group had primary HCC. The demographic data was essentially the same for the two groups. Statistical analysis revealed that the LH group had smaller tumor size, higher blood transfusion requirement, longer duration of inflow control and parenchymal transection, and longer operation time. However, no significant difference was observed in terms of complication rate, mortality rate, and hospital stay between the two groups. After adjusting for tumor size, LH and OH showed no statistical difference in the amount of blood transfusion, operation time and patient survival. CONCLUSIONS: This study demonstrated that stapleless LLS is a safe and feasible procedure for less experienced liver surgeons to resect HCC located at the left lateral liver sector. This stepwise stapleless LSS can not only achieve surgical results comparable to OH but also can provide a platform for liver surgeons to apply laparoscopic technique before conducting more complicated liver resections.

The miR-200b-ZEB1 circuit regulates diverse stemness of human hepatocellular carcinoma.

Accumulating evidence suggests that human hepatocellular carcinoma (HCC) can be derived from cancer stem cells (CSCs), which contribute to tumor initiation, metastasis, chemoresistance, and recurrence. A great variety of HCC CSCs resulting in diverse clinical manifestations have been reported. However, how CSC diversity is regulated and generated remains unclear. Here we report that the miR-200b-ZEB1 circuit is closely involved with the induction and maintenance of a diverse group of CSCs. We found that miR-200b downregulation occurred in early HCC and associated with poor prognosis. The downregulation was attributable to genome deletion and promoter methylation of the miR-200a/b/429 gene. Ectopic expression of miR-200b or silencing of ZEB1 led to a decrease in CD13+ and CD24+ HCC CSCs and an increase in EpCAM+ HCC CSCs. Mechanistically, miR-200b directly suppressed BMI1 and ZEB1 expressions. ZEB1 recognized promoters of CD13, CD24, and EpCAM genes resulting in CD13 and CD24 upregulation and EpCAM downregulation. Neither miR-200b nor ZEB1 had obvious effects on CD133 or CD90 expression. Silencing CD13 or CD24 expression suppressed tumorigenicity of HCC cells. Ectopic expression of CD24 reversed the suppression of tumorigenicity by ectopic expression of miR-200b. Clinically, miR-200b downregulation was coupled with ZEB1 upregulation in approximately two-thirds of HCC patients. ZEB1 expression was positively correlated with CD13 and CD24 expressions in HCCs, while miR-200b expression was positively correlated with EpCAM. Our findings suggest that the miR-200b-ZEB1 circuit is a master regulator of diverse stemness of HCC, which differentiates HCCs into those containing CD13+ /CD24+ CSCs from those containing EpCAM+ CSCs.

RAM score is an effective predictor for early mortality and recurrence after hepatectomy for hepatocellular carcinoma.

BACKGROUND: Liver resection had been regarded as a standard treatment for primary hepatocellular carcinoma (HCC). However, early mortality and recurrence after surgery were still of major concern. RAM (Risk Assessment for early Mortality) scoring system is a newly developed tool for assessing early mortality after hepatectomy for HCC. In this study, we compared RAM scoring system with ALBI and MELD scores for their capability of predicting short-term outcome. METHODS: We retrospectively reviewed patients with hepatocellular carcinoma who were treated with hepatectomy at Chang Gung Memorial Hospital between 1986 and 2015. Their clinical characteristics and perioperative variables were collected. We applied RAM, albumin-bilirubin (ALBI), and model for end-stage liver disease (MELD) scoring systems to predict early mortality and early recurrence in HCC patients after surgery. We investigated the discriminative power of each scoring system by receiver operating characteristic (ROC) curve and area under the ROC curve (AUC). RESULTS: A total of 1935 patients (78% male) who underwent liver resection for HCC were included in this study. The median follow-up period was 41.9 months. One hundred and forty-nine patients (7.7%) died within 6 months after hepatectomy (early mortality). All the three scoring systems were effective predictor for early mortality, with higher score indicating higher risk of early mortality (AUC of RAM = 0.723, p < 0.001; AUC of ALBI = 0.682, p < 0.001; AUC of MELD = 0.590, p = 0.002). Cox regression multivariate analysis demonstrated that the RAM class was the most significant independent predictor of early mortality after surgery, while MELD grade failed to discriminatively predict early mortality. In addition to early mortality, the RAM score was also predictive of early recurrence in HCC after surgery. CONCLUSIONS: This study demonstrated that RAM score is an effective and user-friendly bedside scoring system to predict early mortality and early recurrence after hepatectomy for HCC. In addition, the predictive capability of RAM score is superior to ALBI and MELD scores. Further study is warranted to validate our findings.

The long-term outcomes of thyroid function after subtotal thyroidectomy for Graves' hyperthyroidism.

BACKGROUND: Surgical management of Graves' disease (GD) is changing from subtotal to total thyroidectomy because the latter eliminates the risk of recurrence. However, to preserve thyroid function in a euthyroid state, subtotal thyroidectomy is still performed for GD in non-Western countries. Therefore, we designed a study to investigate the long-term outcomes in GD patients after subtotal thyroidectomy and the correlation between remnant weight and postoperative thyroid function. MATERIALS AND METHODS: This was a retrospective cohort observation study. Between January 2005 and December 2011, 415 consecutive GD patients treated by subtotal thyroidectomy were enrolled. All data were collected from 385 patients who underwent bilateral subtotal thyroidectomy and 57 patients who underwent the Hartley-Dunhill operation. The median postoperative follow-up time was 72 months (range 12-144 months). RESULTS: The mean weight of the preserved thyroid remnant was 5.1 g. Persistent or recurrent hyperthyroidism was observed in 119 (28.7%) patients. The median time of recurrence was 36 months (range 12-120 months). Hypothyroidism developed in over 50% of patients. A euthyroid state was achieved in only 19.3% of patients, and the rate did not increase significantly as remnant weight increased. Based on a Cox regression analysis, the remnant weight is an independent risk factor for persistent or recurrent hyperthyroidism (hazard ratio: 1.323, 95% confidence interval: 1.198-1.461, P < 0.001). CONCLUSIONS: Subtotal thyroidectomy with the intent to maintain a euthyroid state is not an optimal surgical strategy for the definitive treatment of GD because the persistence or recurrence rate is high and the euthyroid rate is lower than expected.

Impact of spontaneous tumor rupture on prognosis of patients with T4 hepatocellular carcinoma.

BACKGROUND AND OBJECTIVES: Compare the outcomes of three groups of patients with T4 hepatocellular carcinoma (HCC): tumor rupture with shock (RS group), tumor rupture without shock (R group), and no tumor rupture (NR group). MATERIALS AND METHODS: We retrospectively reviewed 221 patients with T4 HCC from 2010 to 2012. The clinical background and prognosis were analyzed. RESULTS: Overall in-hospital mortality rate was 18.1%; overall median survival time was 4 months. The NR group were more likely to have multiple and infiltrative tumors (P < 0.001). Relative to the NR group, the R + RS group had better survival rates at 6 months (49.2% vs. 32.2%), 1 year (35.3% vs. 21.0%), 3 years (22.5% vs. 11.0%), and 5 years (17.7% vs. 5.5%) (P = 0.010). Patients in the RS group had a higher in-hospital mortality rate, but significantly better long-term survival than the NR and R group (P < 0.001). Multivariate analysis indicated that Child-Pugh class B or C, presence of portal venous thrombosis, and absence of shock were significantly associated with poor survival. CONCLUSION: Patients with tumor rupture and shock had worse in-hospital survival. However, patients without decompensated liver cirrhosis and portal venous thrombosis, and eligible for curative treatment had favorable long-term outcome. J. Surg. Oncol. 2016;113:789-795. © 2016 The Authors. Journal of Surgical Oncology Published by Wiley Periodicals, Inc.

Functional genomics identified a novel protein tyrosine phosphatase receptor type F-mediated growth inhibition in hepatocarcinogenesis.

UNLABELLED: It is unclear how proliferating cells elicit suppression on cell proliferation and how cancer cells evade this growth suppression. Using a loss-of-function screening of the human kinome and phosphatome to identify genes suppressing tumor initiation in human hepatocellular carcinoma (HCC), we identified 19 genes and characterized one of the top-scoring tumor suppressor candidates, protein tyrosine phosphatase receptor type F (PTPRF). We found that PTPRF was induced during cell proliferation by cell-cell contact. Ectopic expression of wild-type PTPRF, but not the phosphatase-inactive mutant, suppressed cell proliferation and colony formation in soft-agar assays. In contrast, PTPRF silencing led to cell hyperproliferation, enhanced tumor colony formation in soft agar, and increased xenograft tumor growth in nude mice. Mechanistically, PTPRF silencing showed aberrant ERK-dependent signaling including the phosphorylation/stabilization of v-myc avian myelocytomatosis viral oncogene homolog (MYC) through the direct activation of v-src avian sarcoma viral oncogene homolog (SRC) and suppression of PP2A. This PTPRF-mediated growth suppression during cell proliferation functioned independently of the Hippo-Yap pathway. Clinically, PTPRF was down-regulated in 42% HCC (37/89), 67% gastric cancer (27/40), and 100% colorectal cancer (40/40). PTPRF up-regulation was found in 24% HCC (21/89) and associated with better clinical outcomes. CONCLUSION: A novel PTPRF-mediated growth suppression pathway was identified by way of a functional genomics screening in human hepatoma cells. Induction of PTPRF by cell-cell contact during cell proliferation quenched the activated ERK-dependent proliferation signaling to prevent cell hyperproliferation and tumor initiation. PTPRF down-regulation in HCC facilitated tumor development. Our findings shed light on how cancer cells can evade growth suppression and open a new avenue for future development of anticancer therapies.

Intrahepatic biliary mucinous cystic neoplasms: clinicoradiological characteristics and surgical results.

BACKGROUND: Intrahepatic biliary mucinous cystic neoplasms are rare hepatic tumors and account for less than 5% of intrahepatic cystic lesions. Accurate preoperative diagnosis is difficult and the outcome differs among various treatment modalities.The aim of this study is to investigate the clinico-radiological characteristics of intrahepatic biliary mucinous cystic neoplasms and to establish eligible diagnostic and treatment suggestions. METHODS: Nineteen patients with intrahepatic biliary cystadenomas and two patients with biliary cystadenocarcinomas were retrospectively reviewed. Their clinico-radiological variables and survival outcome were analyzed. RESULTS: Of the 19 patients with biliary cystadenoma, 16 (84.2 %) were female. 11 (57.9 %) patients had symptoms before operation with the most common presenting symptom being abdominal pain. Among the patients with available data, serum and cystic fluid CA 19-9 levels were invariably elevated and the CA 19-9 level in the cystic fluid was significantly higher than that in the serum. Loculations (84.2 %) and septations (63.2 %) were the most common radiologic findings. For treatment, 11 (57.9 %) patients received radical resection by either enucleation or hepatic resection, while the remaining 8 (42.1 %) patients underwent only fenestration of liver cysts. Radical resection provided a significantly better clinical outcome than fenestration in terms of tumor recurrence (p = 0.018). The only two male patients with biliary cystadenocarcinoma received radical hepatic resection and achieved a disease-free survival of 16.5 months and 33 months, respectively. CONCLUSION: Intrahepatic biliary mucinous cystic neoplasms are rare and preoperative diagnosis is difficult. Internal septations and loculations on radiologic examinations should raise some suspicion of this diagnosis. Complete tumor excision is the standard treatment that may provide patients with better long term results after the operation.

Impact of epidermal growth factor receptor protein and gene alteration on Taiwanese hepatocellular carcinomas.

BACKGROUND AND AIM: Epidermal growth factor receptor (EGFR) overexpression is associated with disease progression and poor survival in a variety of solid tumors. The role of EGFR in hepatocellular carcinoma (HCC) remains controversial. METHODS: One hundred thirty-eight HCCs were analyzed for total EGFR (t-EGFR) and phospho-EGFR (p-EGFR) expression and gene amplification using immunohistochemistry and fluorescence in situ hybridization. The role of EGFR was analyzed in relation to the clinicopathological features. RESULTS: Weak to strong p-EGFR immunostaining was noted in 42 of the 138 HCCs. p-EGFR expression correlated with alcoholism (P = 0.03) and chronic hepatitis B infection (P = 0.041). There was no correlation between t-EGFR expression and any of the clinicopathological features. Amplification of the EGFR gene was not identified in the 138 HCCs, but 39.1% of the HCCs showed balanced polysomy of both the EGFR gene and centromere 7. Moreover, 65 tumors showed > 2.2 copies per tumor cell. EGFR copy number gain (CNG) was significantly correlated with gender (P = 0.0491), tumor grade (P = 0.006), and vascular invasion (P = 0.005). HCCs with EGFR CNG also had a poor recurrence-free survival (RFS), as compared with HCCs without EGFR CNG (P = 0.031). When exploring the impact of gender, a significant association of EGFR CNG was found with tumor grade (P = 0.044) and cirrhosis (P = 0.015) exclusively in the male group only; however, the OS and RFS analysis show no significant difference between male and female groups. CONCLUSIONS: EGFR CNG was related to crucial clinicopathological features and early recurrence, indicating that EGFR CNG might be a poor prognosis factor for Taiwanese HCC.

Comparison study of gastrinomas between gastric and non-gastric origins.

BACKGROUND: Gastrinomas are one of the neuroendocrine tumors with potential distant metastasis. Most gastrinomas are originated from pancreas and duodenum, but those of gastric origin have been much less reported. The aim of the study is to compare gastrinomas of gastric and non-gastric origins. METHODS: Four hundred twenty-four patients with neuroendocrine tumor by histological proof in Chang Gung Memorial Hospital, Linkou branch in the past 10 years were included. A total of 109 (25.7 %) cases were identified of upper gastrointestinal origins, of which 20 (18.3 %) were proven gastrinomas. The clinical characteristics were collected and analyzed retrospectively. RESULTS: In our study, 21 tumors of the 20 cases were identified by pathologic proof, 11 (55 %) had resection or endoscopic mucosa resection, 9 of gastric origins, 9 of duodenal origins, 2 of pancreatic origins, and 1 of hepatic origins. One case had multiple lesions. Patients with gastric gastrinomas had older age, higher levels of gastrin, seemingly smaller tumor size (p = 0.024, 0.030, and 0.065, respectively), and usually lower grade in differentiation (p = 0.035). Though gastric gastrinomas had a high recurrent rate (80 %), the lymph node and liver involvement was less common. Gastrinomas with liver involvement/metastasis had a high mortality rate where 80 % died of liver dysfunction. CONCLUSIONS: Gastrinomas originating from stomach had higher gastrin level and lower tumor grading and presented at older age. The long-term outcome was probably better than non-gastric origin because of lower grading and less lymph node and liver involvement.

Clinical features and prognosis in hepatectomy for colorectal cancer with centrally located liver metastasis.

BACKGROUND: Hepatic metastasectomy for patients with primary colorectal cancer offers better long-term outcome, and chemotherapy can increase the rate of hepatic resectability for patients with initially inoperable disease. The pattern of liver metastasis and status of the primary tumor are rarely discussed in the analysis of long-term outcome. In this report, we evaluate the influence of the pattern of metastasis on clinical features and prognosis. METHODS: One hundred and fifty-nine patients who underwent hepatic metastasectomy with curative intent for liver metastasis of colorectal cancer between October 1991 and December 2006 were enrolled. Patients were grouped according to whether liver metastasis was centrally or peripherally located, based on imaging and operative findings. Patient demographics, characteristics of the primary and metastatic tumors, and surgical outcomes were analyzed for long-term survival. RESULTS: A greater proportion of patients with centrally located metastases were male, as compared with those with peripherally located metastases. Compared with patients with peripherally located metastases, patients with centrally located metastases were more likely to have multiple lesions (P = 0.016), involvement of multiple segments (P = 0.006), large metastases (P < 0.001), and bilobar distribution of metastases (P < 0.001). The estimated 5-year recurrence-free and overall survival rates were 22.4% and 34.2%, respectively. Univariate analysis revealed that centrally located metastasis, primary tumor in the transverse colon, metastasis in regional lymph nodes, initial extrahepatic metastasis, synchronous liver metastasis, multiple lesions, poorly differentiated tumor, and resection margin <10 mm were significant poor prognostic factors for recurrence-free survival and overall survival. Cox regression analysis showed that inadequate resection margin and centrally located liver metastasis were significant predictors of shorter overall survival. CONCLUSIONS: In colorectal cancer, centrally located liver metastasis represents a poor prognostic factor after hepatectomy, and is associated with early recurrence. Neoadjuvant chemotherapy may be used to downstage centrally located liver metastases to improve outcome.

Expression profile of microRNA-200 family in hepatocellular carcinoma with bile duct tumor thrombus.

OBJECTIVE: The aim of this study was to assess the role of the miR-200 family in the pathogenesis of hepatocellular carcinoma with bile duct tumor thrombus (HCC-BDTT). BACKGROUND: Hepatocellular carcinoma with bile duct tumor thrombus is a challenging condition because of its rarity and dismal prognosis. Epithelial-to-mesenchymal transition (EMT) is considered a critical step in the progression and metastasis of HCC and is regulated by the microRNA-200 (miR-200) family. METHODS: Thirty patients with HCC-BDTT were enrolled and 1240 patients with conventional HCC (cHCC) served as clinicopathologic controls. Sixty age- and sex-matched cHCC patients were selected to compare the miR-200 family expression profile and immunohistochemical characteristics. Gain- and loss-of-function studies of the miR-200 family were conducted using the hepatoma cell lines. RESULTS: Although the mean size of HCC-BDTT was smaller than that of cHCC, the former had a higher incidence of vascular invasion and a poorer long-term survival. The expressions of miR-200c and miR-141 were downregulated in HCC-BDTT (4.5- and 4.8-fold decrease, respectively). Downregulation of both miR-200c and miR-141 independently predicted disease-free survival. The HCC-BDTT, but not cHCC, exhibited overexpression of ZEB1, Twist, transforming growth factor-ß receptor type II, and vimentin, and aberrant E-cadherin expression, indicating EMT. The HCC-BDTT demonstrated increased expression in IL-6 and stemness factor Bmi1, but reduced level of metastasis-suppressive protein, insulin-like growth factor-binding protein 4. The invasive ability of the highly aggressive Mahlavu cell was attenuated by pre-miR-200c+141, whereas the invasive ability of the less aggressive Huh7 cell was enhanced by anti-miR-200c+141. CONCLUSIONS: Simultaneous silencing of miR-200c and miR-141 was likely to be responsible for the development of HCC-BDTT via ZEB1-directed EMT activation and Sec23a-mediated secretome.

Absence of Survival Impact from Hepatitis During Immunotherapy in 193 Patients with Advanced Hepatocellular Carcinoma - An Observational Study from Taiwan.

Background: Hepatitis often occurs after initiating immune checkpoint inhibitor (ICI) treatment. The time and grade of hepatitis after ICI starts and the prognostic role of immune-related hepatitis in patients with advanced hepatocellular carcinoma (aHCC) remain unclear. Methods: In this real-world analysis, we enrolled aHCC patients receiving ICIs, documented the highest level of liver enzymes during/after ICIs, and analyzed the survival impact of different hepatitis patterns. Results: One hundred and ninety-three aHCC patients receiving ICIs were recruited. During ICIs, 88.6% of patients experienced aspartate transaminase (AST) elevations (Grade III/IV: 7.8%). For alanine transaminase (ALT), 81.3% had elevated levels (Grade III/IV: 3.6%), and 41.5% of patients had elevated bilirubin levels (Grade 3/4: 6.7%). The median AST, ALT, and total bilirubin values significantly increased after ICI treatment initiated (all p < 0.001) and, similarly, after excluding progressive disease (p = 0.014, p = 0.002, p < 0.001). The median time of hepatitis occurrence is from the 4.0th to 15.9th weeks. Multivariable analysis showed that patterns of liver enzyme change of AST and total bilirubin in patients receiving ICIs significantly correlate to overall survival (OS, p = 0.009 and 0.001, respectively). After ICI termination, patients with elevated bilirubin (p = 0.003) and AST (p = 0.005) would indicate poor survival, with adjustment of viral hepatitis and ICI responses. Conclusion: Hepatitis emerges between the 4th and 20th weeks post-ICI initiation. Changes in liver enzymes during ICI therapy do not directly affect OS, implying the safety of ICI use when corticosteroids are promptly administered if clinically indicated.