Background
Surgical resection is the only method for curative treatment of biliary tract cancer (BTC). Recently, an improved efficacy has been revealed in patients with initially unresectable locally ...advanced BTC to improve the prognosis by the advent of useful cancer chemotherapy. The aim of this study was to evaluate the effect of downsizing chemotherapy in patients with initially unresectable locally advanced BTC.
Methods
Initially unresectable locally advanced cases were defined as those in which therapeutic resection could not be achieved even by proactive surgical resection. Gemcitabine was administered intravenously once a week for 3 weeks followed by 1 week’s respite. Patients whose disease responded to chemotherapy were reevaluated to determine whether their tumor was resectable.
Results
Chemotherapy with gemcitabine was provided to 22 patients with initially unresectable locally advanced BTC. Tumor was significantly downsized in nine patients, and surgical resection was performed in 8 (36.4%) of 22 patients. Surgical resection resulted in R0 resection in four patients and R1 resection in four patients. Patients who underwent surgical resection had a significantly longer survival compared with those unable to undergo surgery.
Conclusions
Preoperative chemotherapy enables the downsizing of initially unresectable locally advanced BTC, with radical resection made possible in a certain proportion of patients. Downsizing chemotherapy should be proactively carried out as a multidisciplinary treatment strategy for patients with initially unresectable locally advanced BTC with the aim of expanding the surgical indication.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Although fibroblast growth factor 19 (FGF19) can promote liver carcinogenesis in mice, its involvement in human hepatocellular carcinoma (HCC) has not been well investigated. FGF19, a member of the ...FGF family, has unique specificity for its receptor FGFR4. This study aimed to clarify the involvement of FGF19 in the development of HCC.
We investigated human FGF19 and FGFR4 expression in 40 hepatocellular carcinoma specimens using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) analysis and immunohistochemistry. Moreover, we examined the expression and the distribution of FGF19 and FGFR4 in 5 hepatocellular carcinoma cell lines (HepG2, HuH7, HLE, HLF, and JHH7) using RT-PCR and immunohistochemistry. To test the role of the FGF19/FGFR4 system in tumor progression, we used recombinant FGF19 protein and small interfering RNA (siRNA) of FGF19 and FGFR4 to regulate their concentrations.
We found that FGF19 was significantly overexpressed in HCCs as compared with corresponding noncancerous liver tissue (P < 0.05). Univariate and multivariate analyses revealed that the tumor FGF19 mRNA expression was an independent prognostic factor for overall and disease-free survival. Moreover, we found that the FGF19 recombinant protein could increase the proliferation (P < 0.01, n = 12) and invasion (P < 0.01, n = 6) capabilities of human hepatocellular carcinoma cell lines and inhibited their apoptosis (P < 0.01, n = 12). Inversely, decreasing FGF19 and FGFR4 expression by siRNA significantly inhibited proliferation and increased apoptosis in JHH7 cells (P < 0.01, n = 12). The postoperative serum FGF19 levels in HCC patients was significantly lower than the preoperative levels (P < 0.01, n = 29).
FGF19 is critically involved in the development of HCCs. Targeting FGF19 inhibition is an attractive potential therapeutic strategy for HCC.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Background Although gemcitabine has been widely used as a first-line chemo reagent for patients with pancreatic cancer, the response rate remains low. We previously identified Annexin II as ...a factor involved in gemcitabine resistance against pancreatic cancer. The aims of this study were to elucidate the signaling mechanism by which Annexin II induces gemcitabine resistance and to develop a new therapy that overcomes the resistance against gemcitabine. Methods We compared the specific profiles of 12 targeted phosphorylated ( p- ) signaling proteins in gemcitabine-resistant (GEM-) and its wild-type pancreatic cancer cell lines (MIA PaCa-2) using the Bio-Plex assay system. We also evaluated the expression levels of Annexin II and two phosphoproteins, which showed different expressions in these two cell lines, by immunohistochemistry. Results Annexin II overexpression was significantly associated with rapid recurrence after gemcitabine-adjuvant chemotherapy in patients with resected pancreatic cancer ( P < 0.05). Bio-Plex analysis showed up-regulation of p -Akt in GEM-MIA PaCa-2 cells in which Annexin II is highly expressed. The expression level of p -Akt was significantly correlated with that of the downstream protein, p -mTOR, in pancreatic cancer tissues. Inhibition of mTOR phosphorylation canceled gemcitabine resistance in GEM-MIA PaCa-2 cells. Conclusions The Akt/mTOR pathway is involved in mechanisms of gemcitabine resistance induced by Annexin II in pancreatic cancer cells. This indicates that combination therapy with the mTOR inhibitor may overcome gemcitabine resistance. Annexin II as an indicator for selection of gemcitabine resistance could thus be applied to the development of novel tailor-made approaches for pancreatic cancer treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background It is still not clear how combined vascular resection affects the outcome of patients with hilar cholangiocarcinoma. Our aim was to evaluate implications of combined vascular resection in ...patients with hilar cholangiocarcinoma by analyzing the outcomes of all patients who underwent operative resection. Methods A total of 161 of 228 consecutive patients with hilar cholangiocarcinoma underwent bile duct resection with various types of hepatectomy (88%) and pancreaticoduodenectomy (4%). Combined vascular resection was carried out in 43 patients. Thirty-four patients had portal vein resection alone, 7 patients had both portal vein and hepatic artery resection, and 2 patients had right hepatic artery resection only. The outcomes were compared between the 3 groups: the portal vein resection alone (34), hepatic artery resection (9), and non-vascular resection (118). Results Histologically-positive tumor invasion to the portal vein beyond the adventitia was present in 80% of 44 patients undergoing combined portal vein resection. Operative mortality occurred in 11 (7%) patients. The survival rates of the non-vascular resection group were better than that of the portal vein resection alone and the hepatic artery resection groups: 1, 3, and 5 years after curative resection, 72%, 52%, and 41% versus 47%, 31%, and 25% ( P < .05), and 17%, 0%, and 0% ( P < .0001), respectively. Multivariate analysis showed 4 independent prognostic factors of adverse effect on survival after operation; operative curability, lymph node metastases, portal vein resection, and hepatic artery resection. Conclusions Although both portal vein and hepatic artery resection are independent poor prognostic factors after curative operative resection of locally advanced hilar cholangiocarcinoma, portal vein resection is acceptable from an operative risk perspective and might improve the prognosis in the selected patients, however, combined hepatic artery resection can not be justified.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Many authors at high-volume centers all over the world have reported improved outcomes of hilar cholangiocarcinoma by several aggressive surgical approaches such as extended hepatic resection, ...combined vascular resection, and hepatopancreaticoduodenectomy in recent years. There has been great progress in the surgical treatment of hilar cholangiocarcinoma with these previous efforts by aggressive hepatobiliary surgeons. In particular, surgical techniques, diagnostic modalities, and perioperative management have been remarkably improved as compared with before. Herein we report the surgical outcome for both hilar cholangiocarcinoma of Bismuth types II, III, and IV and intrahepatic cholangiocarcinoma involving the hepatic duct confluence during the recent 8-year period between 2001 and 2008 at our institution, the Department of General Surgery at Chiba University. From our recent experienced results, it can be concluded that the surgical strategy for hilar cholangiocarcinoma has been improved remarkably, and major surgical hepatectomy can be done with relative safety, and these aggressive surgical approaches, including combined vascular resection, may be warranted for the surgical treatment of hilar cholangiocarcinoma. However, the adoption of new innovative therapeutic approaches might be required for further improvement of surgical outcome of hilar cholangiocarcinoma.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background The mechanisms of immunonutrition on reducing infectious complications are still poorly understood. This prospective randomized study was designed to determine whether immunonutrition ...influences the following factors: cell-mediated immunity, differentiation of T helper type 1 (Th1) and Th2 cells, interleukin (IL)-17-producing CD4+ helper T (Th17) cell response, and infectious complication rate after pancreaticoduodenectomy. Methods Thirty patients who underwent pancreaticoduodenectomy were divided into 3 groups. Ten patients in the perioperative group received immune-enhancing diets enriched with arginine, omega-3 fatty acids, and RNA for 5 days before operative resection, which was prolonged after operative resection by enteral infusion. Ten patients in the postoperative group received early postoperative enteral infusion of the same enriched formula with no artificial nutrition before operative resection. Ten patients in the control group received total parenteral nutrition postoperatively. The primary endpoint was immune responses; the secondary endpoint was the rate of infectious complications. Results Concanavalin A (Con A)- or phytohemagglutinin (PHA)-stimulated lymphocyte proliferation and natural killer cell activity were significantly higher in the perioperative group than in the other groups. Messenger RNA (mRNA) expression levels of T-bet, interferon-γ (IFN-γ), related orphan receptor γt (RORγt), and interleukin-17F (IL-17F) were significantly higher in the perioperative group than in the other groups. In the perioperative group, the rate of infectious complications was significantly reduced compared with that in the other groups. Conclusion Perioperative immunonutrition reduced stress-induced immunosuppression after a major stressful operative resection. The modulation of Th1/Th2 differentiation and Th17 response may play important roles in this immunologic effect.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Background Postoperative hepatic insufficiency is a critical complication after extended hepatic resection in patients with biliary tract malignancies, the majority of whom suffer from ...obstructive jaundice. The aim of this study was to assess clinical parameters linked to this type of liver dysfunction. Methods A total of 111 patients were retrospectively reviewed. Patient background, pre- and intraoperative parameters, and a ratio of remnant liver volume/entire liver volume (RLV/ELV) as a volumetric parameter were compared between patients with and without postoperative hyperbilirubinemia and subsequent fatal outcome. Results Logistic regression indicated that only RLV/ELV ratio was an independent factor influencing postoperative hyperbilirubinemia, and RLV/ELV ratio and indocyanine green retention rate at 15 minutes (ICG-R15) were factors affecting survival. Patients with RLV/ELV less than 40% had 7.6 times the risk of postoperative hyperbilirubinemia, while no patients with RLV/ELV greater than 40% and ICG-R15 less than 25% died of liver failure. Conclusions The RLV/ELV ratio was the factor with the greatest impact on liver dysfunction after extended hepatectomy in patients with biliary tract malignancies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
To evaluate the influence of confluence pattern of the right posterior sectional bile duct (RPSBD) on clinocopathological outcome in patients with hilar cholangiocarcinoma who underwent left ...hemihepatectomy (LH).
Biliary vascular anatomy may affect the cutting line of proximal bile ducts, especially in case of LH, because of the shorter distance from the sectional ramification to the ductal confluence. However, there were few studies as to the relationship between anatomic variation and clinocopathological outcome.
A total of 209 patients with hilar cholangiocarcinoma underwent surgical resection. We retrospectively investigated confluence patterns of the RPSBD in relation to the right portal vein (RPV) by preoperative imaging studies in 63 patients who underwent LH, and classified them into 3 groups (supraportal type: the RPSBD runs cranially around the RPV; infraportal type: the RPSBD runs caudally to the RPV; combined type: one segmental duct runs infraraportally and the other supraportally to the RPV). Furthermore, the effects of these variations on clinocopathological outcome were evaluated.
The supraportal type was observed in 53 cases (84.1%), the infraportal type in 8 cases (12.7%), and the combined type in 2 cases (3.2%). Although most of the clinocopathological features were similar between the groups, positive margin of proximal bile duct was significantly lower in the infraportal group, as compared with the supraportal group. Furthermore, it was noted that there was no incidence of bilioenteric anastomotic leakage in the infraportal group.
Negative proximal margin and secure reconstruction were more easily achieved in the infraportal group than in the supraportal group. Preoperative evaluation of confluence pattern of RPSBD may be clinically useful for the management of hilar cholangiocarcinoma when applied to left-sided hepatectomy.
Background
Gemcitabine has been shown to exhibit significant clinical activity against pancreatic cancer and has become a first-line chemotherapeutic for this disease in recent years. However, there ...are still many patients who do not respond to this treatment and it is expected to improve the clinical outcome if we can develop a method to predict the efficacy of gemcitabine before treatment. The purpose of this study was to determine novel factors that make pancreatic cancer resistant to gemcitabine.
Materials and methods
Using the high-resolution proteomic approach, agarose two-dimensional gel electrophoresis, we compared protein profiling of a gemcitabine-resistant pancreatic cancer cell line with its wild-type.
Results
We identified Annexin II as an up-regulated protein in the gemcitabine-resistant pancreatic cancer cell line. Immunohistochemistry demonstrated that Annexin II was mainly expressed at the cell surface of pancreatic cancer cells. Interestingly, Annexin II overexpression in cancer cells was significantly associated with rapid recurrence after gemcitabine adjuvant chemotherapy in postoperative patients (
P
= .0078), and its staining was also an independent prognostic indicator of recurrence in pancreatic cancer patients who underwent adjuvant gemcitabine treatment after curative surgery on multivariate analysis (
P
= .0047). In addition, inhibition of Annexin II expression by siRNA in pancreatic cancer cell lines increased the cytotoxic efficacy of gemcitabine. These results indicate that Annexin II overexpression may induce gemcitabine resistance in pancreatic cancer resulting in rapid recurrence.
Conclusions
Analysis of Annexin II expression in cancer tissues may predict the clinical outcome of gemcitabine treatment, leading to the development of a new method for tailor-made treatment for this disease.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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