Concomitant Hepatectomy and Atrial Thrombectomy under Cardiopulmonary Bypass versus Staged Hepatectomy in the Treatment for Hepatocellular Carcinoma with Large Right Atrial Tumor Thrombi.

(1) Background: Hepatocellular carcinoma (HCC) with a large right atrium tumor thrombus (RATT) is a rare and critical presentation. Emergency hepatectomy and thrombectomy under cardiopulmonary bypass (CPB) is life-saving and potentially curative. The aim of this study is to propose an appropriate approach for this condition. (2) Methods: In period A (1998 to 2010, n = 7), hepatectomy and thrombectomy were concomitantly performed, and staged hepatectomy was performed in period B (2011 to 2018, n = 17). (3) Results: The median overall survival time (MOST) in the published studies was 14 months. Moreover, the blood loss, blood transfusion rate, length of ICU stays, and hospital costs were significantly reduced in period B. The MOSTs of patients in period A (n = 6) and period B (n = 17) were 14 vs. 18 months (p = 0.099). The median disease-free survival times (MDFTs) in period A (n = 6) and period B (n = 15) were 8 vs. 14 months (p = 0.073), while the MOSTs in period A and period B were 14 vs. 24 months (p = 0.040). (4) Conclusions: Emergency thrombectomy under CPB and staged hepatectomy 4-6 weeks later may be an appropriate approach for HCC with large RATT. However, the optimal waiting interval requires further investigation.

Colo-pancreaticoduodenectomy for locally advanced colon carcinoma-feasibility in patients presenting with acute abdomen.

BACKGROUND: En bloc right hemicolectomy plus pancreaticoduodenectomy (PD) is administered for locally advanced colon carcinoma that invades the duodenum and/or pancreatic head. This procedure may also be called colo-pancreaticoduodenectomy (cPD). Patients with such carcinomas may present with acute abdomen. Emergency PD often leads to high postoperative morbidity and mortality. Here, we aimed to evaluate the feasibility and outcomes of emergency cPD for patients with advanced colon carcinoma manifesting as acute abdomen. METHODS: We retrospectively reviewed 4898 patients with colorectal cancer who underwent curative colectomy during the period from 1994 to 2018. Among them, 30 had locally advanced right colon cancer and had received cPD. Among them, surgery was performed in 11 patients in emergency conditions (bowel obstruction: 6, perforation: 3, tumor bleeding: 2). Selection criteria for emergency cPD were the following: (1) age ≤ 60 years, (2) body mass index < 35 kg/m2, (3) no poorly controlled comorbidities, and (4) perforation time ≤ 6 h. Three patients did not meet the above criteria and received non-emergency cPD after a life-saving diverting ileostomy, followed by cPD performed 3 months later. We analyzed these patients in terms of their clinicopathological characteristics, the early and long-term postoperative outcomes, and compared findings between emergency cPD group (e-group, n = 11) and non-emergency cPD group (non-e-group, n = 19). After cPD, staged pancreaticojejunostomy was performed in all e-group patients, and on 15 of 19 patients in the non-e-group. RESULTS: The non-e-group was older and had a higher incidence of associated comorbidities, while other clinicopathological characteristics were similar between the two groups. None of the patients in the two groups succumbed from cPD. The postoperative complication rate was 63.6% in the e-group and 42.1% in the non-e-group (p = 0.449). The 5-year overall survival rate were 15.9% in the e-group and 52.6% in the non-e-group (p = 0.192). CONCLUSIONS: Emergency cPD is feasible in highly selected patients if performed by experienced surgeons. The early and long-term positive outcomes of emergency cPD are similar to those after non-emergency cPD in patients with acute abdominal conditions.

Locoregional therapies in patients with recurrent intrahepatic cholangiocarcinoma after curative resection.

BACKGROUND: Hepatectomy is one potential treatment for intrahepatic cholangiocarcinoma (IHCC). Recurrent rate is high after curative resection and most recurrences occur within residual liver parenchyma. The aim of this study was to elucidate the impact of different treatment modalities on recurrent diseases in patients with IHCC after primary liver resection. METHODS: Between February 1999 and December 2015, we retrospectively identified patients who received curative resection for IHCC. Patients who experienced recurrences were included. Locoregional therapies included re-hepatectomy, radiofrequent ablation, and transhepatic arterial chemoembolization. These patients were categorized into three groups: intrahepatic recurrence without locoregional therapies (group A), intrahepatic recurrence with locoregional therapies (group B) and extrahepatic metastases (group C). RESULTS: Forty-three patients were included and there were 12, 15, and 16 patients in groups A, B, and C, respectively. The median disease-free survival times were 8.3, 9.1, and 8.7 months in groups A, B, and C (p = 0.099). The median after-recurrence overall survival times (period between recurrence and death/censor) were 6.4, 34.0, and 8.3 months in groups A, B, and C (p = 0.001). Locoregional therapies showed favorable benefit in multivariant analysis (hazard ratio: 0.274, confidence interval: 0.083-0.908, p = 0.010). CONCLUSION: Locoregional therapies offered favorable benefits for patients with recurrent intrahepatic cholangiocarcinoma.

Hepatitis B virus X protein promotes tumor invasion and poor prognosis in hepatocellular carcinoma via phosphorylation of paxillin at Serine 178 by activation of the c-Jun NH2-terminal kinase.

Hepatitis B virus X protein (HBx) plays critical roles in hepatocellular tumorigenesis by activating different signaling pathways, including the c-Jun NH2-terminal kinase (JNK) pathway. Phosphorylation of paxillin (PXN) promotes cell migration via activation of the JNK signaling pathway, but PXN overexpression is not associated with poor outcome in patients with hepatocellular carcinoma (HCC). HBx gene manipulation and Western blotting indicated that phosphorylation of PXN at Serine 178 (pS178-PXN) by HBx may promote invasiveness in HCC cells via HBx-mediated JNK activation. Immunohistochemical analysis indicated a positive correlation between pS178-PXN and HBx expression levels in tumor specimens. The overall survival (OS) and relapse-free survival (RFS) were poorer in patients with high-pS178-PXN expressing or high-HBx expressing tumors than in patients with low-pS178-PXN expressing or low-HBx expressing tumors. In conclusion, phosphorylation of PXN at Serine 178 by HBx-mediated JNK activation may therefore play a critical role in tumor invasiveness and poor prognosis in patients with HBV-infected hepatocellular tumors. The expression levels of pS178-PXN may be a reliable prognostic biomarker to predict the clinical outcomes in patients with HBV-associated HCC.

Liver resection for hepatocellular carcinoma in oldest old patients.

BACKGROUND: For hepatocellular carcinoma (HCC), liver resection is a classical curative modality, despite its technical complexity. The incidence of HCC in the oldest old people (aged ≥ 85 years) is rising along with the global increase in life expectancy. Currently, no report has addressed liver resection for HCC in this aged population. PATIENTS AND METHODS: We conducted a retrospective review of 1889 patients receiving curative liver resection for newly diagnosed HCC from 1992 to 2016. At the time of operation, 1858 of them were aged < 85 years (group A), and 31 were aged ≥ 85 years (group B). Another 18 oldest old patients, whose HCC was considered resectable but were not operated on due to the patient's refusal, served as the control group (group C). The clinicopathological characteristics and early and long-term outcomes were compared between groups A and B. All associated co-morbidities of the patients were well-treated before liver resection. The overall survival (OS) rates were also compared between groups B and C. RESULT: Group B had a significantly higher incidence of associated co-morbidities and hepatitis C infection. Postoperative complication rates and 90-day mortality rates after liver resection did not differ between groups A and B (p = 0.834 and p = 1.000, respectively), though group B had a longer postoperative stay (p = 0.001). In groups A and B, the 5-year disease-free survival rates were 29.7% and 22.6% (p = 0.163), respectively, and their overall survival rates were 43.5% and 35.5% (p = 0.086). The overall survival rate of group B was significantly different from group C (35.5% vs. 0%, p = 0.001). CONCLUSION: Despite a longer postoperative recovery period, liver resection for HCC in the oldest old patients may be justified if co-morbidities are well controlled.

Metabolic risk factors are associated with non-hepatitis B non-hepatitis C hepatocellular carcinoma in Taiwan, an endemic area of chronic hepatitis B.

Metabolic risk factors, such as obesity, fatty liver, high lipidemia, and diabetes mellitus are associated with increased risk for nonviral hepatocellular carcinoma (HCC); however, few nonviral HCC studies have stratified patients according to underlying etiologies. From 2005 to 2011, 3,843 patients with HCC were recruited into the Taiwan Liver Cancer Network. Of these patients, 411 (10.69%) who were negative for hepatitis B virus (HBV), surface antigen, HBV DNA, and anti-hepatitis C virus (HCV) antibody were classified as non-HBV non-HCV (NBNC)-HCC. Detailed clinical analyses of these patients were compared with age- and sex-matched patients with HBV-HCC or HCV-HCC for the associated metabolic risk factors. For this comparison, 420 patients with HBV-HCC and 420 patients with HCV-HCC were selected from the 3,843 patients with HCC. Multivariate analyses showed fatty liver (by echography), high triglyceride levels (>160 mg/dL), and diabetes mellitus history to be significantly associated only with NBNC-HCC and not with the matched patients with HBV- or HCV-HCC. When the patients with HCC were further divided into four groups based on history of alcoholism and cirrhotic status, the group without alcoholism and without cirrhosis exhibited the strongest association with the metabolic risk factors. Based on trend analyses, patients with NBNC-HCC with or without alcoholism were significantly different from the matched patients with HBV- or HCV-HCC, except for patients with alcoholism and cirrhosis, in having more than two of the above three risk factors. Conclusion: Metabolic risk factors are significantly associated with nonviral HCC, especially for patients without alcoholism in Taiwan. Because the prevalence of viral HCC is decreasing due to the success of universal vaccination and antiviral therapy, strategies for cancer prevention, prediction, and surveillance for HCC will require modification. (Hepatology Communications 2018;2:747-759).

Hepatitis B virus X protein represses LKB1 expression to promote tumor progression and poor postoperative outcome in hepatocellular carcinoma.

BACKGROUND: Hepatitis B virus X (HBx) protein plays critical roles in hepatitis B virus (HBV)-associated hepatocellular tumorigenesis through different molecular mechanisms, including inactivation of p53, a key transcription factor of liver kinase B1 (LKB1). We hypothesized that p53 inactivation by HBx protein could decrease LKB1 expression, thereby promoting tumor progression and poor outcomes in patients with HBV-associated hepatocellular carcinoma. METHODS: Manipulation strategies for HBx protein and/or p53 were used to verify that loss of LKB1 could promote colony formation and invasiveness in HepG2 and Hep3B cells. The expressions of HBx protein and LKB1 in 93 hepatocellular carcinomas (HCC) were also evaluated by immunohistochemistry. Kaplan-Meier and Cox regression models were used to assess the prognostic value of both HBx protein and LKB1 proteins in patients with hepatocellular carcinoma. RESULTS: Mechanistically, LKB1 expression was decreased at the transcriptional level after inactivation of p53 by HBx protein. Decreases in LKB1 expression were also associated with HBx protein-mediated colony formation and invasive capabilities. HBx protein, LKB1, and a combination of both proteins had prognostic significance for overall survival and relapse-free survival in our study population. CONCLUSION: The results from cell line experiments and evaluation of patient prognosis according to expression of HBx protein and LKB1 in their HCC strongly support the hypothesis that decreases in LKB1 expression by HBx protein-mediated p53 inactivation may play an important role in HBV-associated hepatocellular tumorigenesis.

Embedding fistulojejunostomy: An easy and secure technique for refractory external pancreatic fistula.

BACKGROUND: Refractory external pancreatic fistula (REPF) is a rare but troublesome event. Fistulojejunostomy with direct suture of the fistula wall to jejunal wall has been demonstrated as a solution. However, it is sometimes technically difficult and some cases of failure were reported. METHODS: An embedding fistulojejunostomy (EFJ) was designed. The fistula tract was detached from the abdominal wall and impactedly inserted into a Roux-en-Y jejunal lumen without direct suture of the fistula wall to the jejunal wall. Five patients with REPF for > 3 months underwent this procedure in the past 10 years. The preoperatively-placed drainage tubes temporarily exteriorized the pancreatic fluid for 30 days. RESULTS: All fistulojejunostomy procedures were accomplished within 15 minutes. Four patients had uneventful recovery with a postoperative hospital stay ≤ 10 days. One patient had wound infection and needed hospitalization for 23 days. Except for one patient who required pancreatic enzyme supplements for 8 months, no other patient had pancreatic exocrine insufficiency. After follow up for 12-124 months, no patient required pancreatic enzyme supplements, and no patient had recurrent fistula or diabetes mellitus. CONCLUSION: EFJ makes fistulojejunostomy easier and more secure with a satisfactory early and long-term outcome. It may be a desirable technique for REPF.

The free inverted omega-shaped flap for circumferential hypopharyngeal reconstruction with simultaneous neck skin defect.

BACKGROUND: Circumferential hypopharyngeal defect with simultaneous skin defect can pose complicated reconstructive challenge for reconstructive microsurgeons. Our experience with the versatile inverted-omega flap tubing design is proposed to accommodate such problem. METHODS: From 2012 to 2015, 13 anterolateral thigh (ALT) flaps and one anteromedial thigh (AMT) flap were harvested for reconstruction of circumferential hypopharyngeal defects with skin defects in 14 patients. All patients were males except one. Patient age ranged from 42 to 67 years (average, 53.1 years). Fifty-seven percent were recurrent cases. All but one patient received preoperative chemoradiotherapy. RESULTS: The average flap size was 29 × 8 cm (range: 25-31 × 6-10 cm2 ). An average of 2.6 perforators was included in each flap (2-4 perforators/flap). All flaps survived. One venous thrombosis was noted and salvaged after thrombolectomy and vein graft. The mean follow-up period was 25 months. The fistula rate was 21.4% (three patients). One fistula never healed because of early recurrence; one fistula healed after surgical intervention; and one fistula need a loco-regional flap for secondary reconstruction. Three postoperative strictures were noted (21.4%). CONCLUSION: For the circumferential hypopharyngeal defect with simultaneous neck skin defect, this inverted-omega ALT tubing design offers an alternative choice for such complicated reconstruction. © 2016 Wiley Periodicals, Inc. Microsurgery, 38:51-59, 2018.

Liver resection for hepatocellular carcinoma in patients with hematological malignancies.

BACKGROUND: Improvements in antimetabolite drugs have prolonged the survival of patient with hematological malignancies. However, these drugs may have hepatotoxic side effects and may induce acute liver failure, chronic liver fibrosis, cirrhosis, or even hepatocellular carcinoma (HCC). Although liver resection remains a curative option for HCC, its role in HCC with hematological malignancies has never been fully explored. METHODS: A retrospective review of 1725 patients who underwent curative liver resection for newly diagnosed HCC between 1994 and 2016 was conducted. Among these patients, 16 had a history of hematological malignancies (HM group). Their hematological malignancies were well-controlled at the time of liver resection. The clinicopathological characteristics of the HM group, along with their short- and long-term outcomes after liver resection, were compared with those of the other 1709 patients without hematological malignancy (non-HM group). RESULTS: All HM group patients were seropositive for hepatitis marker surface for hepatitis B and C. No significant differences were observed in any background characteristics between the two groups. The postoperative complication rate and 90-day mortality in the HM and non-HM groups were 25 and 20.4%, P = 0.754, and 0 and 0.6%, P = 1.000, respectively. The 5-year disease-free and overall survival rates for the HM and non-HM groups were 42.3 and 35.1%, P = 0.552, and 69.5 and 56.9%, P = 0.192, respectively. CONCLUSIONS: Hepatitis markers should be examined during chemotherapy for hematological malignancies. Regular liver imaging studies are recommended for seropositive cases. When HCC occurs secondary to a well-controlled hematological malignancy, liver resection is suggested in selected patients.

Progress of liver resection for hepatocellular carcinoma in Taiwan.

Taiwan is a well-known endemic area of hepatitis B. Hepatocellular carcinoma (HCC) has consistently been the first or second highest cause of cancer death over the past 20 years. This review article describes the progress of liver resection for HCC in Taiwan in the past half century. The mortality rate for HCC resection was 15-30% in Taiwan in the 1970s. The rate decreased to 8-12% in the early 1990s, and it declined to <1-3% recently. The development of new operative instruments, and surgical techniques, increased knowledge of liver anatomy and pathophysiology after hepatectomy, and more precise patient selection have contributed to this improvement. The use of intermittent hepatic inflow blood occlusion, a restrictive blood transfusion policy and intraoperative ultrasonography, have also led to substantial improvements in resectability and safety for HCC resection in Taiwan. Advances in non-operative modalities for HCC treatment have also helped to improve long-term outcomes of HCC resection. Technical innovations have allowed the application of complex procedures such as mesohepatectomy, unroofing hepatectomy, major portal vein thrombectomy, hepatic vein reconstruction in resection of the cranial part with preservation of the caudal part of the liver, and inferior vena cava and right atrium tumor thrombectomy under cardiopulmonary bypass. In selected patients, including patients with end-stage renal failure, renal graft recipients, patients with portal hypertension, hypersplenic thrombocytopenia and/or associated gastroesophageal varices, octogenarian, ruptured HCC, recurrent HCC and metastatic HCC can also be resected with satisfactory survival benefits. We conclude that the results of liver resection for HCC in Taiwan are improving. The indications for HCC resection continue extending with lower the surgical risks and increasing the long-term survival rate.

The "right" way is not always popular: comparison of surgeons' perceptions during laparoscopic cholecystectomy for acute cholecystitis among experts from Japan, Korea and Taiwan.

BACKGROUND: Generally, surgeons' perceptions of surgical safety are based on experience and institutional policy. Our recent pilot survey demonstrated that the acceptable duration of surgery and criteria for open conversion during laparoscopic cholecystectomy (LC) vary among workplaces. METHODS: A web-based survey was distributed to 554 expert LC surgeons in Japan, Korea, and Taiwan. The questionnaire covered LC experience, safety measures and recognition of landmarks, decision-making regarding conversion to open/partial cholecystectomy and the implications of this decision. Overall responses were compared among nations, and then stratified by LC experience level (lifetime cases 200-499, 500-999, and ≥1,000). RESULTS: The response rate was 92.6% (513/554); 67 surgeons with ≤199 LCs were excluded, and responses from 446 surgeons were analyzed. We observed significant differences among nations on almost all questions. Differences that remained after stratification by LC experience were on questions related to acceptable duration of surgery, adoption rates of intraoperative cholangiography, the "critical view of safety" technique, identification of Rouvière's sulcus, recognition of the SS-Inner layer theory, and intraoperative judgment to abandon conventional LC. CONCLUSIONS: Even among experts, surgeons' perceptions during LC are workplace-dependent. A novel grading system of surgical difficulty and standardized LC procedures are paramount to generate high-level evidence.

Randomized, open-label phase 2 study comparing frontline dovitinib versus sorafenib in patients with advanced hepatocellular carcinoma.

UNLABELLED: Angiogenesis inhibition by the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) inhibitor sorafenib provides survival benefit in hepatocellular carcinoma (HCC); however, angiogenic escape from sorafenib may occur due to angiogenesis-associated fibroblast growth factor receptor (FGFR) pathway activation. In addition to VEGFR and PDGFR, dovitinib inhibits FGFR. Frontline oral dovitinib (500 mg/day, 5 days on, 2 days off; n = 82) versus sorafenib (400 mg twice daily; n = 83) was evaluated in an open-label, randomized phase 2 study of Asian-Pacific patients with advanced HCC. The primary and key secondary endpoints were overall survival (OS) and time to tumor progression (TTP) as determined by a local investigator, respectively. Patients included in the study were ineligible for surgical and/or locoregional therapies or had disease progression after receiving these therapies. The median OS (95% confidence interval [CI]) was 8.0 (6.6-9.1) months for dovitinib and 8.4 (5.4-11.3) months for sorafenib. The median TTP (95% CI) per investigator assessment was 4.1 (2.8-4.2) months and 4.1 (2.8-4.3) months for dovitinib and sorafenib, respectively. Common any-cause adverse events included diarrhea (62%), decreased appetite (43%), nausea (41%), vomiting (41%), fatigue (35%), rash (34%), and pyrexia (30%) for dovitinib and palmar-plantar erythrodysesthesia syndrome (66%) and decreased appetite (31%) for sorafenib. Subgroup analysis revealed a significantly higher median OS for patients in the dovitinib arm who had baseline plasma soluble VEGFR1 (sVEGFR1) and hepatocyte growth factor (HGF) below median levels versus at or above the median levels (median OS [95% CI]: sVEGFR1, 11.2 [9.0-13.8] and 5.7 [4.3-7.0] months, respectively [P = .0002]; HGF, 11.2 [8.9-13.8] and 5.9 [5.0-7.6] months, respectively [P = 0.0002]). CONCLUSION: Dovitinib was well tolerated, but activity was not greater than sorafenib as a frontline systemic therapy for HCC. Based on these data, no subsequent phase 3 study has been planned. (Hepatology 2016;64:774-784).

The Hepatitis Viral Status in Patients With Hepatocellular Carcinoma: a Study of 3843 Patients From Taiwan Liver Cancer Network.

Hepatocellular carcinoma (HCC) is the leading cancer death in Taiwan. Chronic viral hepatitis infections have long been considered as the most important risk factors for HCC in Taiwan. The previously published reports were either carried out by individual investigators with small patient numbers or by large endemic studies with limited viral marker data. Through collaboration with 5 medical centers across Taiwan, Taiwan liver cancer network (TLCN) was established in 2005. All participating centers followed a standard protocol to recruit liver cancer patients along with their biosamples and clinical data. In addition, detailed viral marker analysis for hepatitis B virus (HBV) and hepatitis C virus (HCV) were also performed. This study included 3843 HCC patients with available blood samples in TLCN (recruited from November 2005 to April 2011). There were 2153 (56.02%) patients associated with HBV (HBV group); 969 (25.21%) with HCV (HCV group); 310 (8.07%) with both HBV and HCV (HBV+HCV group); and 411 (10.69%) were negative for both HBV and HCV (non-B non-C group). Two hundred two of the 2463 HBV patients (8.20%) were HBsAg(-), but HBV DNA (+). The age, gender, cirrhosis, viral titers, and viral genotypes were all significantly different between the above 4 groups of patients. The median age of the HBV group was the youngest, and the cirrhotic rate was lowest in the non-B non-C group (only 25%). This is the largest detailed viral hepatitis marker study for HCC patients in the English literatures. Our study provided novel data on the interaction of HBV and HCV in the HCC patients and also confirmed that the HCC database of TLCN is highly representative for Taiwan and an important resource for HCC research.

Treatment of synchronous adenocarcinoma and lymphoma of the stomach: A case report.

Gastric cancer is one of the leading causes of cancer-related mortality worldwide. The majority of gastric cancers are diagnosed at an advanced or metastatic stage, with a 5-year survival rate of ~5-20% and a median overall survival of <1 year. Synchronous occurrence of gastric adenocarcinoma and lymphoma is rare, and thus far there is no consensus regarding their management. We herein describe a case of synchronous gastric adenocarcinoma and diffuse large B-cell lymphoma in a patient with chronic hepatitis B and the treatment strategy. A literature review with the most up-to-date treatment options and their application in similar situations was also performed.

DNA methylation markers and serum α-fetoprotein level are prognostic factors in hepatocellular carcinoma.

INTRODUCTION: Hypermethylation of relevant genes may affect the prognosis of patients with cancer. The purpose of this study was to analyze whether methylation of the promoter regions of cell cycle regulators as well as elevated α-Fetoprotein (AFP) levels are useful prognostic factors for patients with hepatocellular carcinoma (HCC). MATERIAL AND METHODS: Nested methylation-specific PCR (nested-MSP) was used to analyze methylation status of the promoter regions of p15, p16, p21, p27, and ras-association domain family 1 (RASSF1A) genes in tumor specimens from 50 patients with HCC. RESULTS: Promoter methylation was most common in the RASSF1A gene (96%), followed by the p16 gene (56%), the p21 gene (44%), the p15 gene (28%), and the p27 gene (2%). Patients with a serum AFP level < 400 ng/mL and an unmethylated p21 promoter had a better prognosis than patients with a serum AFP level ≥ 400 ng/mL and a methylated p21 promoter (overall survival, p = 0.076; disease-free survival, p = 0.016). In addition, patients with full methylation of the promoter region of RASSF1A had a better prognosis than patients with a partially methylated or unmethylated RASSF1A promoter region if their serum AFP level was ≥ 400 ng/mL (overall survival, p = 0.028; disease-free survival, p = 0.078). CONCLUSION: A partially methylated or unmethylated RASSF1A promoter as well as elevated serum AFP level or methylation of p21 in addition to elevated serum AFP level might be associated with poor prognosis in patients with hepatocellular carcinoma.

Akt suppresses DLK for maintaining self-renewal of mouse embryonic stem cells.

Mouse embryonic stem cells (ES cells) can proliferate indefinitely. To identify potential signals involved in suppression of self-renewal, we previously screened a kinase/phosphatase expression library in ES cells, and observed that inhibition of Dual Leucine zipper-bearing Kinase (DLK) increased relative cell numbers. DLK protein was detected in both the pluripotent and differentiated states of mouse ES cells while DLK kinase activity increased upon differentiation. Overexpression of DLK in mouse ES cells displayed reductions in relative cell/colony numbers and Nanog expression, suggesting a suppressive role of DLK in self-renewal. By examining protein sequences of DLK, we identified 2 putative Akt phosphorylation sites at S584 and T659. Blocking PI3K/Akt signaling with LY-294002 enhanced DLK kinase activity dramatically. We found that Akt interacts with and phosphorylates DLK. Mutations of DLK amino acid residues at putative Akt phosphorylation sites (S584A, T659A, or S584A and T659A) diminished the level of DLK phosphorylation. While the mutated DLKs (S584A, T659A, or S584A and T659A) were expressed, a further reduction in cell/colony numbers and Nanog expression appeared in mouse ES cells. In addition, these mutant DLKs (S584A, T659A, or S584A and T659A) exhibited more robust kinase activity and cell death compared to wild type DLK or green fluorescence (GFP) controls. In summary, our results show that DLK functions to suppress self-renewal of mouse ES cells and is restrained by Akt phosphorylation.

Unroofing hepatectomy: a facilitating approach for resection of deep-seated hepatocellular carcinoma adjacent to major intrahepatic vessels in cirrhotic patients.

BACKGROUND AND OBJECTIVES: Unroofing hepatectomy, an alternative approach to remove a deep-seated hepatocellular carcinoma (HCC) adjacent to major intrahepatic vessels by peel-off technique after sacrificing the overlying noncancerous liver, may result in tumor exposure without resection margin. The aim of the study was to examine the value of this approach in cirrhotic patients. METHODS: Between 1998 and 2012, 51 cirrhotic patients underwent unroofing hepatectomy for deep-seated newly-diagnosed HCC adjacent to major intrahepatic vessels (group A). Another 274 cirrhotic patients with similar tumor size and without gross major vessel involvement in the same period were selected as the control cohort (group B). The patients' clinicopathological characteristics, the early and long-term outcomes of the two groups were compared. RESULTS: The HCCs in group A had a significantly higher rate of tumor encapsulation, smaller number of associated satellite nodules, and smaller amount of resected liver weight. Postoperative complication and 90-day mortality rates were similar, but group A patients had a significant better 5-year disease-free (56% vs. 32%, P = 0.011) and overall survival rates (82% vs. 53%, P = 0.008). CONCLUSIONS: In selected cirrhotic patients, unroofing hepatectomy facilitates resection of deep-seated HCC adjacent to major intrahepatic vessels with acceptable early and long-term results.

Methylation-silencing RCC1 expression is associated with tumorigenesis and depth of invasion in gastric cancer.

INTRODUCTION: Regulator of chromosome condensation 1 (RCC1) is a critical cell cycle regulator. We firstly identified RCC1 gene hypermethylation in gastric tumor tissues using the differential methylation hybridization (DMH) microarray, but the role of RCC1 in the pathogenesis of gastric carcinoma is largely unknown. METHODS: Three gastric cancer cell lines (AGS, MKN45, and TSGH9201) were used to analyze RCC1 gene methylation, mRNA and protein expressions. Furthermore, 85 pairs of matched human gastric carcinoma samples in a tissue microarray were used to analyze RCC1 expression by immunohistochemistry staining. RESULTS: A differential methylation pattern was found in TSGH9201 (100%), MKN45 (87%), and AGS (62%) cell lines at the 9th CpG site of RCC1 exon 1. RCC1 mRNA and protein expressions in AGS cells were significantly higher than in TSGH9201 and MKN45 cell lines (P < 0.05). Tissue array data showed that RCC1 expression was detected in 21% (18/85) of gastric carcinoma tissues and in 80% (76/95) of adjacent non-tumor tissues. The expression of RCC1 in gastric carcinoma tissues was significantly lower than in adjacent non-tumor tissues (P < 0.001). Furthermore, an association between RCC1 expression and clinicopathological features showed that RCC1 expression was closely correlated with tumor differentiation and depth of invasion (P < 0.05). CONCLUSIONS: Our data indicate that RCC1 expression is frequently lost in poorly differentiated gastric cell lines and gastric carcinoma tissues. Loss of RCC1 expression is correlated with tumor differentiation and depth of invasion. These findings suggest that RCC1 may play a tumor suppressor role in gastric carcinoma.