Tumor suppressor functions of DAXX through histone H3.3/H3K9me3 pathway in pancreatic NETs.

Pancreatic neuroendocrine tumors (PanNETs) have considerable malignant potential. Frequent somatic mutations and loss of DAXX protein expression have been found in PanNETs. DAXX is known as a transcriptional repressor; however, molecular functions underlying DAXX loss remain unclear in PanNETs. We evaluated DAXX expression by immunohistochemistry in 44 PanNETs. DAXX-knockdown (KD) and -knockout (KO) PanNET cells were analyzed for in vitro and vivo The target genes were screened by microarray and chromatin immunoprecipitation (ChIP) assays for DAXX, histone H3.3 and H3K9me3 complex. In clinicopathological features, low DAXX expression was significantly correlated with nonfunctional tumors, higher Ki-67 index and WHO grade. Microarray and ChIP assays of DAXX-KD/KO identified 12 genes as the direct targets of DAXX transcriptional repressor. Among them, expression of five genes including STC2 was suppressed by DAXX/H3.3/H3K9me3 pathway. DAXX-KD/KO cells enhanced sphere forming activity, but its effect was suppressed by knockdown of STC2 In xenograft models, tumorigenicity and tumor vessel density were significantly increased in DAXX-KO cells with high expression of STC2. Clinically, higher recurrence rate was recognized in PanNETs with low expression of DAXX and high expression of STC2 than others (P = 0.018). Our data suggest that DAXX plays as a tumor suppressor and DAXX/H3.3 complex suppresses target genes by promoting H3K9me3 in PanNETs. Combination of DAXX loss and its target gene STC2 overexpression might be effective biomarkers and therapeutic candidates.

Emergency Cholecystectomy for Patients on Antiplatelet Therapy.

The use of antiplatelet therapy (APT) and/or anticoagulant therapy (ACT) continues to increase due to the aging population. Because the management of patients with acute cholecystitis receiving APT/ACT is still unclear, surgeons are sometimes faced with the difficult decision to delay surgery. We aimed to analyze characteristics and surgical risks of patients who underwent emergency cholecystectomy for acute cholecystitis without discontinuing APT. We conducted a retrospective review of 113 patients between 2006 and 2014. Treatment outcomes among 13 patients who underwent cholecystectomy without discontinuing APT (the cAPT group), 11 patients who discontinued APT and ACT (the D group), and 89 patients who did not receive preoperative APT and/or ACT (the No APT group) were compared. There were no significant differences in intraoperative blood loss, conversion to open surgery, and bleeding-related complications. However, the incidence of intraoperative blood transfusion was higher in the cAPT group (P = 0.04). They presented with severe local inflammation; thus, it was difficult to stop bleeding from the gallbladder bed. Hemostatic tools for liver surgery were used to control bleeding. Emergency cholecystectomy was tolerable for patients with acute cholecystitis while continuing APT. However, in case of severe local inflammation, there is a greater risk for massive hemorrhage.

Acquired Resistance with Epigenetic Alterations Under Long-Term Antiangiogenic Therapy for Hepatocellular Carcinoma.

Antiangiogenic therapy is initially effective for several solid tumors including hepatocellular carcinoma; however, they finally relapse and progress, resulting in poor prognosis. We here established in vivo drug-tolerant subclones of human hepatocellular carcinoma cells by long-term treatment with VEGF receptor (VEGFR) inhibitor and serial transplantation in immunocompromised mice (total 12 months), and then compared them with the parental cells in molecular and biological features. Gene expression profiles elucidated a G-actin monomer binding protein thymosin ß 4 (Tß4) as one of the genes enriched in the resistant cancer cells relative to the initially sensitive ones. Highlighting epigenetic alterations involved in drug resistance, we revealed that Tß4 could be aberrantly expressed following demethylation of DNA and active modification of histone H3 at the promoter region. Ectopic overexpression of Tß4 in hepatocellular carcinoma cells could significantly enhance sphere-forming capacities and infiltrating phenotypes in vitro, and promote growth of tumors refractory to the VEGFR multikinase inhibitor sorafenib in vivo Clinically, sorafenib failed to improve the progression-free survival in patients with Tß4-high hepatocellular carcinoma, indicating that Tß4 expression could be available as a surrogate marker of susceptibility to this drug. This study suggests that Tß4 expression triggered by epigenetic alterations could contribute to the development of resistance to antiangiogenic therapy by the acquisition of stemness, and that epigenetic control might be one of the key targets to regulate the resistance in hepatocellular carcinoma. Mol Cancer Ther; 16(6); 1155-65. ©2017 AACR.

Surgical pitfalls of jejunal vein anatomy in pancreaticoduodenectomy.

BACKGROUND: Pancreaticoduodenectomy (PD) is the standard surgical procedure for treating pancreatic head cancers. Considerable knowledge of proximal jejunal and pancreatic vein anatomy is a prerequisite for performing PD surgery safely, yet there appear to be no detailed descriptions of first and second jejunal vein (J1V, J2V) anatomy available in the literature. STUDY DESIGN: Adults with hepatobiliary-pancreatic disease underwent multidetector-row computed tomography with intravenous contrast (n = 155), and SYNAPSE 3D (Fujifilm Medical, Tokyo, Japan) was used to generate 3D-CT images. RESULTS: In 84% of patients, J1V and J2V formed a common trunk (FJT). There were three patterns of branches, related to the presence or absence of FJT formation and the anatomical relationships between the superior mesenteric artery (SMA) and the jejunal veins, as follows: Type 1 (n = 98, 63%) characterized by an FJT located dorsal to SMA; Type 2 (n = 32, 21%), where the FJT was located ventral to the SMA; and Type 3 (n = 25, 16%), where J1V and J2V each drained separately into the SMV. CONCLUSIONS: J1V and J2V usually formed an FJT, and separate J1V and J2V drainage into the SMV was uncommon. Preoperative information on individual patient venous anatomy would increase the safety of the PD procedure.

ARID2 modulates DNA damage response in human hepatocellular carcinoma cells.

BACKGROUND & AIMS: Recent genomic studies have identified frequent mutations of AT-rich interactive domain 2 (ARID2) in hepatocellular carcinoma (HCC), but it is not still understood how ARID2 exhibits tumor suppressor activities. METHODS: We established the ARID2 knockout human HCC cell lines by using CRISPR/Cas9 system, and investigated the gene expression profiles and biological functions. RESULTS: Bioinformatic analysis indicated that UV-response genes were negatively regulated in the ARID2 knockout cells, and they were sensitized to UV irradiation. ARID2 depletion attenuated nucleotide excision repair (NER) of DNA damage sites introduced by exposure to UV as well as chemical compounds known as carcinogens for HCC, benzo[a]pyrene and FeCl3, since xeroderma pigmentosum complementation group G (XPG) could not accumulate without ARID2. By using large-scale public data sets, we validated that ARID2 knockout could lead to similar molecular changes between in vitro and in vivo settings. A higher number of somatic mutations in the ARID2-mutated subtypes than that in the ARID2 wild-type across various types of cancers including HCC was observed. CONCLUSIONS: We provide evidence that ARID2 knockout could contribute to disruption of NER process through inhibiting the recruitment of XPG, resulting in susceptibility to carcinogens and potential hypermutation. These findings have implications for therapeutic targets in cancers harboring ARID2 mutations. LAY SUMMARY: Recent genomic studies have identified frequent mutations of ARID2, a component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, in hepatocellular carcinoma, but it is not still understood how ARID2 exhibits tumor suppressor activities. In current study, we provided evidence that ARID2 knockout could contribute to disruption of DNA repair process, resulting in susceptibility to carcinogens and potential hypermutation. These findings have far-reaching implications for therapeutic targets in cancers harboring ARID2 mutations.

Refractory Long-Term Cholangitis After Pancreaticoduodenectomy: A Retrospective Study.

BACKGROUND: Postoperative cholangitis is one of the major late complications after pancreaticoduodenectomy (PD), and recurrent cholangitis has a negative impact on patients' quality of life. However, detailed reports are scarce. The aim of this study was to investigate the clinical features of postoperative cholangitis after PD. METHODS: Between January 2007 and December 2013, 155 consecutive patients underwent PD. Of these, 113 patients were included in this study. Cholangitis was diagnosed according to the criteria in the revised Tokyo Guidelines 2013, and repeated cholangitis with three or more episodes was defined as 'refractory cholangitis'. Data from patients with refractory cholangitis were retrospectively analyzed. RESULTS: Refractory cholangitis was observed in 21 patients (18.6%). Of these, 17 patients experienced cholangitis within 1 year after PD, and 10 patients had biliary strictures. These patients required an average of two interventional or endoscopic treatments for stricture dilatation, which led to remission. The 2-year cumulative incidence rate for refractory cholangitis was 18.9% (95% CI 11.65-26.15). Multivariate analysis revealed five risk factors for developing refractory cholangitis: benign disease (odds ratio [OR] 18.52; P = 0.001), long operation time (OR 18.73; P = 0.002), elevated C-reactive protein (OR 6.55; P = 0.014), elevated alkaline phosphatase (OR 6.03; P = 0.018), and the presence of pneumobilia (OR 28.81; P = 0.009). CONCLUSIONS: Postoperative refractory cholangitis after PD usually developed within a year. Almost half of the patients had biliary strictures, and aggressive dilatation might be effective to achieve remission in these patients.

Preoperative direct bilirubin to prothrombin time ratio index to prevent liver failure after minor hepatectomy.

BACKGROUND: The most reliable index to predict the safety of hepatectomy for patients with poor liver function remains unknown. We aimed to construct a novel preoperative index to predict early liver failure (ELF) and mortality due to recurrence-free liver failure (MLF) after hepatectomy. METHODS: Between 2000 and 2012, 385 consecutive patients with hepatocellular carcinoma undergoing curative minor hepatectomy were divided into two sequential cohorts: training set (n = 143) and validation set (n = 242), and observed until 2015. RESULTS: Prothrombin time and direct bilirubin were independent predictors of both ELF and MLF in the training set. Thus we devised a novel index, the direct bilirubin to prothrombin time ratio index (DBPTRI). The areas under ROC curves of DBPTRI for predicting ELF and MLF were 0.78 and 0.93, respectively, in the validation set. Using a preoperative DBPTRI cut off of 4.2, we accurately predicted ELF and MLF in 86.8% and 88.4% of patients, respectively. DBPTRI was the best predictor of ELF and MLF when compared with conventional indices such as ICG-R15 and Child-Pugh score. Moreover, the 5-year overall survival rates of the patients with low and high DBPTRI were 59% and 36%, respectively (P < 0.0001). CONCLUSIONS: DBPTRI may serve as a simple, non-invasive index for estimating liver failure after hepatectomy.

Clinical application of the biomarkers for the selection of adjuvant chemotherapy in pancreatic ductal adenocarcinoma.

BACKGROUND: For the establishment of personalized therapy, we investigated biomarkers that can contribute to the selection of adjuvant therapy for pancreatic ductal adenocarcinoma (PDAC). METHODS: Between 2005 and 2014, of 141 consecutive patients with PDAC who underwent R0 or R1 resection, 61 patients given gemcitabine and 31 patients given S-1 as adjuvant therapy were enrolled. We evaluated the correlation between treatment outcomes and the expressions of intratumoral human antigen R (HuR), human equilibrative nucleoside transporter 1 (hENT1), thymidylate synthetase (TS) and dihydropyrimidine dehydrogenase (DPD). RESULTS: There were no significant differences in clinicopathological features between the gemcitabine and S-1 groups. Among those with high HuR expression and high hENT1 expression, the disease-free survival (DFS) was significantly higher with gemcitabine than with S-1 (MST: 26.2 vs. 11.8 months, P = 0.024; 20.2 vs. 10.2 months, P = 0.029, respectively). Moreover, high HuR/hENT1 (high HuR or high hENT1) was significantly associated with better outcome for gemcitabine (HR for DFS: 0.43, P = 0.027) and low HuR/hENT1 was significantly associated with worse outcome for gemcitabine (HR for DFS: 2.24, P = 0.021). TS and DPD expression levels were not informative in this examination. CONCLUSIONS: HuR and hENT1 were good candidates as selective biomarkers and this study's concept could contribute to personalized therapy for PDAC patients.

Proteasome activity is required for the initiation of precancerous pancreatic lesions.

Proteasome activity is significantly increased in advanced cancers, but its role in cancer initiation is not clear, due to difficulties in monitoring this process in vivo. We established a line of transgenic mice that carried the ZsGreen-degron(ODC) (Gdeg) proteasome reporter to monitor the proteasome activity. In combination with Pdx-1-Cre;LSL-Kras(G12D) model, proteasome activity was investigated in the initiation of precancerous pancreatic lesions (PanINs). Normal pancreatic acini in Gdeg mice had low proteasome activity. By contrast, proteasome activity was increased in the PanIN lesions that developed in Gdeg;Pdx-1-Cre;LSL-Kras(G12D) mice. Caerulein administration to Gdeg;Pdx-1-Cre;LSL-Kras(G12D) mice induced constitutive elevation of proteasome activity in pancreatic tissues and accelerated PanIN formation. The proteasome inhibitor markedly reduced PanIN formation in Gdeg;Pdx-1-Cre;LSL-Kras(G12D) mice (P = 0.001), whereas it had no effect on PanIN lesions that had already formed. These observations indicated the significance of proteasome activity in the initiation of PanIN but not the maintenance per se. In addition, the expressions of pERK and its downstream factors including cyclin D1, NF-κB, and Cox2 were decreased after proteasome inhibition in PanINs. Our studies showed activation of proteasome is required specifically for the initiation of PanIN. The roles of proteasome in the early stages of pancreatic carcinogenesis warrant further investigation.

Macroscopic morphology for estimation of malignant potential in pancreatic neuroendocrine neoplasm.

PURPOSE: Pancreatic neuroendocrine neoplasm (Pan-NEN) representing approximately 1.3 % of pancreatic malignancy cases in incidence has been a so rare disease that it remains major problem to analyze the malignant potential. The aim of this study was to verify whether the macroscopic morphology of Pan-NEN, a novel pathological classification, contributes to malignant potential. METHODS: From a total of 86 patients with Pan-NEN, 41 surgical sections obtained from the primary site were classified by their morphology into a simple nodular (SN) group and a non-SN group. The non-SN group was further divided into three subtypes: simple nodular with extranodular growth (SNEG), confluent multinodular (CM), and infiltrative (IF). The clinicopathological features of the SN and the non-SN groups were retrospectively compared. RESULTS: Overall 5-year survival rates with and without surgical resection were 94 and 48 %, respectively. SN and non-SN types were identified in 21 and 20 patients, respectively. The non-SN group comprised 14 SNEG type, 2 CM type, and 4 IF type. Synchronous lymph node metastases (p = 0.009), synchronous liver metastases (p = 0.048), microinvasion to an adjacent organ (p < 0.001), vascular invasion (p = 0.023), and neural invasion (p = 0.019) were more significant in the non-SN group than in the SN group. As judged by WHO 2004 classification and TNM stages (AJCC and ENETS), non-SN type showed malignant trend (p < 0.05). Moreover, overall 5-year survival rates of SN and non-SN groups were 100 and 84.4 %, respectively (p = 0.048). CONCLUSIONS: Non-SN tumors may have higher malignant potential than SN tumors.

Expression of connective tissue growth factor in the livers of non-viral hepatocellular carcinoma patients with metabolic risk factors.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) associated with metabolic risk factors, such as diabetes and obesity, has been increasing. However, the underlying mechanism that links these diseases remains unclear. METHODS: We performed genome-wide expression analysis of human liver tissues of non-viral HCC patients with or without metabolic risk factors. The upregulated genes that associated with diabetes and obesity were investigated by in vitro and in vivo experiments, and immunohistochemistry of human liver tissues was performed. RESULTS: Among the upregulated genes, connective tissue growth factor (CTGF) expression was induced to a greater extent by combined glucose and insulin administration to human hepatoma cells. Genome-wide expression analysis revealed upregulation of a chemokine network in CTGF-overexpressing hepatoma cells, which displayed an increased ability to induce in vitro activation of macrophages, and in vivo infiltration of liver macrophages. Immunohistochemistry of human liver tissues validated the correlations between CTGF expression and diabetes or obesity as well as activation of liver macrophages in patients with non-viral HCC. Recurrence-free survival was significantly poorer in the CTGF-positive patients compared with the CTGF-negative patients (p = 0.002). Multivariate analysis determined that CTGF expression (HR 2.361; 95 % CI 1.195-4.665; p = 0.013) and vascular invasion (HR 2.367; 95 % CI 1.270-4.410; p = 0.007) were independent prognostic factors for recurrence of non-viral HCC. CONCLUSIONS: Our data suggest that CTGF could be involved in oncogenic pathways promoting non-viral HCC associated with metabolic risk factors via induction of liver inflammation and is expected to be a novel HCC risk biomarker and potential therapeutic target.

Dominant Expression of DCLK1 in Human Pancreatic Cancer Stem Cells Accelerates Tumor Invasion and Metastasis.

Patients with pancreatic cancer typically develop tumor invasion and metastasis in the early stage. These malignant behaviors might be originated from cancer stem cells (CSCs), but the responsible target is less known about invisible CSCs especially for invasion and metastasis. We previously examined the proteasome activity of CSCs and constructed a real-time visualization system for human pancreatic CSCs. In the present study, we found that CSCs were highly metastatic and dominantly localized at the invading tumor margins in a liver metastasis model. Microarray and siRNA screening assays showed that doublecortin-like kinase 1 (DCLK1) was predominantly expressed with histone modification in pancreatic CSCs with invasive and metastatic potential. Overexpression of DCLK1 led to amoeboid morphology, which promotes the migration of pancreatic cancer cells. Knockdown of DCLK1 profoundly suppressed in vivo liver metastasis of pancreatic CSCs. Clinically, DCLK1 was overexpressed in the metastatic tumors in patients with pancreatic cancer. Our studies revealed that DCLK1 is essential for the invasive and metastatic properties of CSCs and may be a promising epigenetic and therapeutic target in human pancreatic cancer.

CD73 as a therapeutic target for pancreatic neuroendocrine tumor stem cells.

Identification and purification of cancer stem cells (CSCs) lead to the discovery of novel therapeutic targets; however, there has been no study on isolation of the CSC population among pancreatic neuroendocrine tumors (pNETs). This study aimed to identify pNET CSCs and to characterize a therapeutic candidate for pNET CSCs. We identified CSCs by aldehyde dehydrogenase (ALDH) activity in pNET clinical specimens and cell lines. We verified whether or not these cells have the stemness property in vivo and in vitro. ALDHhigh cells, but not control bulk cells, formed spheres, proliferated under hypoxic condition as well as normoxic condition and promoted cell motility, which are features of CSCs. Injection of as few as 10 ALDHhigh cells led to subcutaneous tumor formation, and 105 ALDHhigh cells, but not control bulk cells, established metastases in mice. Comprehensive gene expression analysis revealed that genes associated with mesenchymal stem cells, including CD73, were overexpressed in ALDHhigh cells. Additionally, the in vitro and in vivo effects of an inhibitor of CD73 were investigated. The CD73 inhibitor APCP significantly attenuated in vitro sphere formation and cell motility, as well as in vivo tumor growth observed for ALDHhigh cells. Finally, its expression was evaluated using clinical pNET tissue samples. Immunohistochemical analysis of clinical tissue samples demonstrated CD73 expression was significantly correlated with the invasion into adjacent organs. Since recent studies revealed CD73 as a potential biomarker of anti-PD-1 immune checkpoint therapy, CD73 might be a promising therapeutic target for pNET CSCs.

The difficulty of laparoscopic liver resection.

Grading of difficulty is needed for laparoscopic liver resection (LLR). Indications for LLR are expanding worldwide from minor to major resections, particularly in institutions having surgeons with advanced skills. If the degrees of surgical difficulty were defined, it would serve as a useful guide when introducing LLR and stepping up to the more advanced LLR. As no previous study has addressed the degrees of difficulty of various LLR procedures, we devised a practical scoring system for this purpose. We extracted the following five factors from preoperative information to score difficulty levels: (1) tumor location, (2) extent of liver resection, (3) tumor size, (4) proximity to major vessels, and (5) liver function. This difficulty index is comprised of the cumulative score for the five individual factors. There has not yet been a standard definition of difficulty. Our proposed scoring system might be a practical means of assessing the difficulty of LLR procedures. However, this system must be prospectively validated.

Distinct clinicopathological phenotype of hepatocellular carcinoma with ethoxybenzyl-magnetic resonance imaging hyperintensity: association with gene expression signature.

BACKGROUND: Although hepatocellular carcinoma (HCC) is mostly a lower intensity lesion in the hepatobiliary phase on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging, some HCCs were shown as a higher intensity lesion (high HCC). This study aimed to reveal the clinicopathological and biological properties of high HCC. METHODS: Patients who underwent curative hepatectomy as the first treatment for HCC were included. HCC was defined as high HCC if the ratio between the signal intensity of the HCC and the background liver was greater than or equal to 1.0. We retrospectively performed clinicopathological and global gene expression analyses. RESULTS: Of the 77 patients, 14 had high HCC. Serum protein induced by vitamin K absence or antagonist II levels in high HCC were lower, and the high HCCs were well differentiated. The 3-year disease-free survival rates in high HCC and low HCC patients were 90% and 54%, respectively (P = .035). Overall survival did not differ significantly. Global gene expression analysis revealed that SLCO1B3 was upregulated in high HCC. CONCLUSIONS: Clinicopathological analysis revealed low-grade malignancy in high HCCs compared with low HCCs. The expression of SLCO1B3 was key to the hyperintensity in the hepatobiliary phase of ethoxybenzyl-diethylenetriamine pentaacetic acid magnetic resonance imaging.

Novel Aurora/vascular endothelial growth factor receptor dual kinase inhibitor as treatment for hepatocellular carcinoma.

We previously identified Aurora B kinase as the only independent factor predictive of the aggressive recurrence of hepatocellular carcinoma (HCC). In this preclinical study, JNJ-28841072, a novel Aurora/vascular endothelial growth factor receptor dual kinase inhibitor, was evaluated for treatment of HCC. In vitro and in vivo effects of JNJ-28841072 were analyzed using human HCC cell cultures and xenograft models. An orthotopic liver xenograft model was used for the pharmacobiological effects on Aurora kinase and vascularization in hepatic tumors. JNJ-28841072 suppressed in vitro phosphorylation of histone H3 with induction of cell polyploidy and death in a dose-dependent manner (IC50  = 0.8-1.2 µM). In s.c. human HCC xenografts, remarkable inhibition of tumor growth was observed after JNJ-28841072 treatment (P = 0.0005). In orthotopic liver xenografts, the treatment with JNJ-28841072 significantly suppressed in vivo phosphorylation of histone H3 (P = 0.0008), vessel formation (P = 0.018), normoxic area (P = 0.0001), and hepatoma growth (P = 0.038). Our preclinical studies indicate that JNJ-28841072 is a promising novel therapeutic approach for the treatment of HCC. It might be worthy of evaluation in further studies.

Advances in reduced port laparoscopic liver resection.

Reduced port surgery has been attracting attention in the field of minimally invasive surgery. Although the use of SILS is becoming widespread, technical difficulty has delayed its adoption for laparoscopic liver resection. Recently, advances in laparoscopic liver resection have been made in tandem with advances in surgical skill and devices. The main driver in conventional laparoscopic liver resection's evolution to become less surgically invasive seems to be single-incision laparoscopic liver resection (SILLR). To date, most reports on SILLR have been single case reports or case series. Only a few cohort studies on conventional laparoscopic surgery and SILLR have been conducted. Recent reports have described the use of SILLR for well-localized lesions and solitary tumors located in the anterolateral segments of the liver or left liver lobe, but its application remains limited to partial resection and left lateral sectionectomy. The feasibility and safety of SILLR have been demonstrated, but additional work is needed for standardization of the procedure.

A novel therapeutic combination sequentially targeting aurora B and Bcl-xL in hepatocellular carcinoma.

BACKGROUND: Effective therapeutic combinations targeting the oncogenic pathway still are unknown in human hepatocellular carcinoma (HCC). The authors previously identified aberrant expression of aurora B kinase as the independent predictor for the lethal recurrence of HCC, showing that AZD1152 induced in vitro and in vivo apoptosis with polyploidy in human HCC cells. In this preclinical study, the combined effects of molecular-targeted therapies were evaluated based on the cellular response of aurora B inhibition. METHODS: This study analyzed the expression of Bcl-2 family proteins in polyploidization induced by AZD1152 and the in vitro synergistic effects of AZD1152 with control of the Bcl-2 family pathway in human HCC cells. The in vivo effects of the combination therapy targeting the specific molecules were evaluated using subcutaneous tumor xenograft models. RESULTS: The findings showed that Bcl-xL was specifically overexpressed in AZD1152-induced polyploid HCC cells. The combination of AZD1152 followed by Bcl-xL/2 inhibitor ABT263 induced synergistically cellular apoptosis (p < 0.001) and growth inhibition (p < 0.0001). Interestingly, the reverse sequential administration of AZD1152 combined with pretreatment of ABT263 was less effective than the original one. In vivo studies using tumor xenografts of human HCC cells showed that combination therapy of ABT263 after AZD1152 pretreatment induced significant intratumoral apoptosis (p < 0.05) and remarkable anti-tumor effects (p < 0.05) without a severe adverse effect compared with the monotherapy. CONCLUSION: Based on Bcl-xL overexpression in polyploidy induced by aurora B inhibition, the rationale for therapeutic combinations targeting aurora B and Bcl-xL was demonstrated in the authors' preclinical studies, leading to a promising novel approach for the mechanism-based treatment of human HCC.

Prognostic role of Child-Pugh score 5 and 6 in hepatocellular carcinoma patients who underwent curative hepatic resection.

BACKGROUND: It is unclear whether Child-Pugh score discriminates a prognosis of the Child-Pugh A patients who underwent hepatic resection for hepatocellular carcinoma. METHODS: Between April 2000 and March 2011, 361 patients with Child-Pugh A who underwent curative hepatectomy were divided into 2 groups: Child-Pugh score 5 points group (CPS5) and Child-Pugh score 6 points group (CPS6); both CPS5 (n = 274) and CPS6 (n = 87) groups were compared. RESULTS: Overall survival rates (1/2/5 years of the CPS5 and CPS6 groups were 90.9%/82.5%/62.4% and 80.6%/68.0%/47.6%, respectively) and disease-free survival rates (67.6%/51.8%/30.1% and 36.9%/16.0%/5.9%, respectively) showed that the CPS5 group was significantly better than the CPS6 group. Multivariate analysis revealed that Child-Pugh score at overall survival (P = .0125) and disease-free survival (P = .0103) was a significant prognostic factor. CONCLUSIONS: The overall survival and disease-free survival in Child-Pugh A showed quite a difference between the CPS5 and CPS6 groups. However, CPS5 and CPS6 may be a useful prognostic marker of hepatocellular carcinoma patients with hepatic resection.

Age-related clinicopathologic and molecular features of patients receiving curative hepatectomy for hepatocellular carcinoma.

BACKGROUND: Age-related differences of clinicopathologic features, outcomes, and molecular properties of hepatocellular carcinoma remain unclarified. METHODS: We classified patients who underwent hepatectomy for hepatocellular carcinoma into 3 groups by age bracket; younger group (<50 years), middle-aged group (50 to 79 years), and elderly group (≥80 years) and compared age-related features. RESULTS: Hepatitis viral infection was dominant in the younger group (hepatitis B virus [HBV]; 67%) and middle-aged group (hepatitis C virus [HCV]; 56%), whereas the elderly group showed a significantly higher rate without hepatitis virus infection (absence of HBV and HCV infection, 66%; P = .0001). There was a significantly greater proportion of age-associated pre-existing comorbidity in the elderly group (89%; P = .0004). Liver cirrhosis in the elderly group (24%) was significantly lower than other groups (younger, 67%; middle-aged, 50%; P = .0058). There was no significant difference in perioperative and postoperative outcomes among these groups. Microarray analysis revealed age-related upregulation of androgen and phosphatidylinositol 3-kinase pathways in the tumor tissue and downregulation of the fibrosis-related pathways in the noncancerous liver tissue. CONCLUSIONS: Based on increased correlation with the absence of HBV and HCV infection and pre-existing comorbidity, the age-related carcinogenic pathways might play a critical role in elderly hepatocarcinogenesis.