Diacylglycerol kinase alpha is a proliferation marker of intrahepatic cholangiocarcinoma associated with the prognosis.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) has a high recurrence rate and a poor prognosis. Thus, the development of effective treatment and prognostic biomarkers is required. High expression of diacylglycerol kinase alpha (DGKα) is a prognostic factor for the recurrence of hepatocellular carcinoma. However, the relationship between DGKα expression and prognosis in ICC has not been reported. METHODS: Immunohistochemistry (IHC) with anti-DGKα antibody was performed on surgical specimens of ICC (n = 69). First, DGKα expression in cancer cells was qualitatively classified into four groups (-, 1+, 2+, 3+) and divided into two groups (DGKα- and DGKα+1 + to 3+). The relationship between clinical features and DGKα expression was analyzed. Second, Ki-67 expression was evaluated as a cell proliferation marker. The number of Ki-67-positive cells was counted, and the relationship with DGKα expression was examined. RESULTS: DGKα IHC divided the patients into a DGKα+ group (1+: n = 15; 2+: n = 5; 3+: n = 5) and a DGKα- group (-: n = 44). In the DGKα+ group, patients were older and had advanced disease. Both overall survival and recurrence-free survival (RFS) were significantly worse in the DGKα+ patients. DGKα+ was identified as an independent prognostic factor for RFS by multivariate analysis. Furthermore, the number of Ki-67-positive cells increased in association with the staining levels of DGKα. CONCLUSION: Pathological DGKα expression in ICC was a cancer proliferation marker associated with recurrence. This suggests that DGKα may be a potential therapeutic target for ICC.

Expression of Wnt5a and ROR2, Components of the Noncanonical Wnt-Signaling Pathway, is Associated with Tumor Differentiation in Hepatocellular Carcinoma.

BACKGROUND: Wnt5a is the key ligand of the noncanonical Wnt pathway, and receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a receptor associated with Wnt5a. The association between the noncanonical Wnt-signaling pathway and carcinogenesis in hepatocellular carcinoma (HCC) is unclear. This study investigated the significance of ROR2 expression in HCC. METHODS: The study examined ROR2 expression in liver cancer cell lines. Immunohistochemical staining of ROR2 was performed on 243 resected HCC specimens. The study investigated ROR2 expression and its association with clinicopathologic factors and prognosis. RESULTS: Findings showed that ROR2 was expressed in well-differentiated Huh7 and HepG2 cells, but not in poorly differentiated HLE and HLF cells. Expression of ROR2 was positive in 147 (60.5%) and negative in 96 (39.5%) HCC specimens. A significant association was shown between ROR2 negativity and high alpha-fetoprotein (AFP) level (P = 0.006), poor differentiation (P = 0.015), and Wnt5a negativity (P = 0.024). The 5-year overall survival (OS) rate for the ROR2-negative group (64.2 %) tended to be worse than for the ROR2-positive group (73.8%), but the difference was not significant (P = 0.312). The 5-year OS rate was 78.7% for the ROR2+Wnt5a+ group, 71.3 % for the ROR2+Wnt5a- group, 80.8% for the ROR2-Wnt5a+ group, and 60.5 % for the ROR2-Wnt5a- group. The OS in the ROR2-Wnt5a- group was significantly poorer than in the ROR2+Wnt5a+ group (P = 0.030). The multivariate analysis showed that Wnt5a-ROR2- was an independent prognostic factor (hazard ratio, 2.058; 95% confidence interval, 1.013-4.180; P = 0.045). CONCLUSIONS: The combination of ROR2 and Wnt5a may be a prognostic indicator for HCC. The Wnt5a/ROR2 signal pathway may be involved in the differentiation of HCC. This pathway may be a new therapeutic target for HCC.

Arginase-1 inhibition reduces migration ability and metastatic colonization of colon cancer cells.

BACKGROUND: Arginase-1 (ARG1), a urea cycle-related enzyme, catalyzes the hydrolysis of arginine to urea and ornithine, which regulates the proliferation, differentiation, and function of various cells. However, it is unclear whether ARG1 controls the progression and malignant alterations of colon cancer. METHODS: We established metastatic colonization mouse model and ARG1 overexpressing murine colon cancer CT26 cells to investigate whether activation of ARG1 was related to malignancy of colon cancer cells in vivo. Living cell numbers and migration ability of CT26 cells were evaluated in the presence of ARG inhibitor in vitro. RESULTS: Inhibition of arginase activity significantly suppressed the proliferation and migration ability of CT26 murine colon cancer cells in vitro. Overexpression of ARG1 in CT26 cells reduced intracellular L-arginine levels, enhanced cell migration, and promoted epithelial-mesenchymal transition. Metastatic colonization of CT26 cells in lung and liver tissues was significantly augmented by ARG1 overexpression in vivo. ARG1 gene expression was higher in the tumor tissues of liver metastasis than those of primary tumor, and arginase inhibition suppressed the migration ability of HCT116 human colon cancer cells. CONCLUSION: Activation of ARG1 is related to the migration ability and metastatic colonization of colon cancer cells, and blockade of this process may be a novel strategy for controlling cancer malignancy.

IFN-γ-STAT1-mediated NK2R expression is involved in the induction of antitumor effector CD8+ T cells in vivo.

The induction of antitumor effector T cells in the tumor microenvironment is a crucial event for cancer immunotherapy. Neurokinin receptor 2 (NK2R), a G protein-coupled receptor for neurokinin A (NKA), regulates diverse physiological functions. However, the precise role of NKA-NK2R signaling in antitumor immunity is unclear. Here, we found that an IFN-γ-STAT1 cascade augmented NK2R expression in CD8+ T cells, and NK2R-mediated NKA signaling was involved in inducing antitumor effector T cells in vivo. The administration of a synthetic analog of double-stranded RNA, polyinosinic-polycytidylic acid (poly I:C), into a liver cancer mouse model induced type I and type II IFNs and significantly suppressed the tumorigenesis of Hepa1-6 liver cancer cells in a STAT1-dependent manner. The reduction in tumor growth was diminished by the depletion of CD8+ T cells. IFN-γ stimulation significantly induced NK2R and tachykinin precursor 1 (encodes NKA) gene expression in CD8+ T cells. NKA stimulation combined with anti-CD3 monoclonal antibody (mAb) treatment significantly augmented IFN-γ and granzyme B production by CD8+ T cells compared with the anti-CD3 mAb alone in vitro. ERK1/2 phosphorylation and IκBα degradation in activated CD8+ T cells were suppressed under NK2R deficiency. Finally, we confirmed that tumor growth was significantly increased in NK2R-deficient mice compared with that in wild-type mice, and the antitumor effects of poly I:C were abolished by NK2R absence. These findings suggest that IFN-γ-STAT1-mediated NK2R expression is involved in the induction of antitumor effector T cells in the tumor microenvironment, which contributes to the suppression of cancer cell tumorigenesis in vivo. In this study, we revealed that IFN-γ-STAT1-mediated NK2R expression is involved in the induction of antitumor effector CD8+ T cells in the tumor microenvironment, which contributes to suppressing the tumorigenesis of liver cancer cells in vivo.

Combination therapy for hepatocellular carcinoma with diacylglycerol kinase alpha inhibition and anti-programmed cell death-1 ligand blockade.

Activation of diacylglycerol kinase alpha (DGKα) augments proliferation and suppresses apoptosis of cancer cells and induces T lymphocyte anergy. We investigated the dual effects of DGKα inhibition on tumorigenesis and anti-tumor immunity with the aim of establishing a novel therapeutic strategy for cancer. We examined the effects of a DGKα inhibitor (DGKAI) on liver cancer cell proliferation and cytokine production by immune cells in vitro and on tumorigenesis and host immunity in a hepatocellular carcinoma (HCC) mouse model. Oral DGKAI significantly suppressed tumor growth and prolonged survival in model mice. Tumor infiltration of T cells and dendritic cells was also enhanced in mice treated with DGKAI, and the production of cytokines and cytotoxic molecules by CD4+ and CD8+ T cells was increased. Depletion of CD8+ T cells reduced the effect of DGKAI. Furthermore, interferon-γ stimulation augmented the expression of programmed cell death-1 ligand (PD-L1) on cancer cells, and DGKAI plus an anti-PD-L1 antibody strongly suppressed the tumor growth. These results suggest that DGKα inhibition may be a promising new treatment strategy for HCC.

Rare case of idiopathic sclerosing cholangitis, which was difficult to distinguish from cholangiocarcinoma: A case report.

It is often difficult to correctly diagnose patients who present with dilation of the bile duct. Cholangiocarcinoma, primary sclerosing cholangitis (PSC) and immunoglobulin (Ig)G4-related sclerosing cholangitis must be considered as potential diagnoses for these cases. The current study presents a 73-year-old female patient who presented with a high fever and abdominal pain. Contrast-enhanced computed tomography and magnetic resonance cholangiopancreatography revealed stenosis and dilation of the intrahepatic bile duct without solid components. It was suspected that the patient had intrahepatic cholangiocarcinoma. A left liver lobectomy, cholecystectomy and distal gastrectomy combined with a D2 lymph node dissection were performed. A pathological examination of the liver revealed increased fibrosis in the stroma, irregular bile duct dilation and clusters of inflamed lymph cells. No carcinoma or IgG4-positive plasma cells were observed and the typical findings of PSC were not detected. Based on these clinical and pathological results, the diagnosis was idiopathic sclerosing cholangitis, which is particularly rare. It is often difficult to preoperatively differentiate between cholangiocarcinoma and benign bile duct stenosis.

L-Carnitine supplementation reduces the general fatigue of cancer patients during chemotherapy.

L-Carnitine (LC) plays an important role in the metabolism of fatty acids, and LC deficiency is associated with a feeling of weakness or general fatigue. Cancer patients receiving chemotherapy often develop LC deficiency, which is considered to be a factor contributing to general fatigue. The aim of the present study was to evaluate the efficacy of LC supplementation as a treatment for general fatigue in cancer patients during chemotherapy. A total of 11 cancer patients who were suffering from general fatigue during chemotherapy in our hospital between September 2014 and December 2015 were examined (6 cases involved adjuvant chemotherapy and 5 cases involved chemotherapy for unresectable or recurrent disease). The patients were administered 1,500 mg/day of levocarnitine per os, and the change in mean daily fatigue from the baseline to 8 weeks was assessed using the Brief Fatigue Inventory. The change in the plasma levels of albumin and the lymphocyte counts from the baseline to 8 weeks were also assessed. LC supplementation reduced general fatigue in all cases. Moreover, LC supplementation maintained the plasma levels of albumin and lymphocyte counts during chemotherapy, and enabled patients to continue chemotherapy sequentially without dose reduction. Therefore, LC supplementation improved general fatigue in all the examined cancer patients during chemotherapy. This treatment may make improve the tolerability of chemotherapy in cancer patients by reducing general fatigue and improving the nutritional status.

Long-term survival and prognosis associated with conversion surgery in patients with metastatic gastric cancer.

In gastric cancer, primary systemic chemotherapy is the standard approach for the management of patients with initially unresectable metastasis, and it occasionally leads to a reduction in the size of the lesion, which facilitates surgical resection. The aim of this study was to examine the prognosis of patients who were able to undergo complete resection following chemotherapy. A total of 10 patients who underwent radical surgery for stage IV primary gastric cancer after chemotherapy between 2009 and 2015 at the Department of Surgery of Hokkaido Social Work Association Obihiro Hospital (Obihiro, Japan) were retrospectively investigated. Three regimens were used (S-1, n=1; S-1 + cisplatin, n=8; and S-1 + docetaxel, n=1). The mean time from chemotherapy to surgery was 210 days. One total gastrectomy + splenectomy + colectomy, one total gastrectomy + splenectomy, four total gastrectomies and three distal gastrectomies were performed. There were two cases of pancreatic fistula formation postoperatively. All the patients survived for >1 year. Of the 10 patients, 5 survived without recurrence. The median survival time was 871.1 days after diagnosis. Therefore, curative resection after chemotherapy is associated with a better prognosis in stage IV gastric cancer patients.

[A Case of Surgical Resection of a Combined Hepatocellular and Cholangiocarcinoma with Hemobilia from Intraductal Tumor Thrombus].

We report a case of combined hepatocellular and cholangiocarcinoma with hemobilia. A 65-year-old man was admitted to our hospital because of pain in the right hypochondralrigion. Abdominal ultrasonography revealed bile duct dilatation in the lateral segment of liver and blood test findings showed elevation of the hepatobiliary enzyme, so ERC was performed and hemorrhage from the duodenal papilla was observed. In cholangiography, dilation of the left hepatic bile duct and filling defect were observed, and in the peroral cholangioscopy, a hemorrhagic papillary elevated lesion was identified in the left hepatic bile duct and diagnosed as adenocarcinoma as a result of biopsy. Left hepatectomy with caudate lobe, extrahepatic bile duct resection, lymph node dissection was performed by diagnosis of intrahepatic cholangiocarcinoma. In the resected specimen, tumor size was 16 mm, which was found in the left hepatic duct and invasived into the liver parenchyma. Histopathological examination revealed a combined hepatocellular and cholangiocarcinoma. Gemcitabin was administered as adjuvant chemotherapy for 8 months, but 1 year and 8 months after the operation, it recurred in the liver. Gemcitabin was administered, but it became PD, now it has changed to S-1 and it is SD for 2 years.

[Four Cases of Gastrointestinal Perforation Associated with Bevacizumab].

Four cases of gastrointestinal perforation associated with bevacizumab(BEV)were examined. Case 1: A 82-year-old male received FOLFIRI plus BEV for recurrent liver metastasis after rectal cancer resection. A lower esophageal perforation occurred 22 days after BEV administration and drainage was performed. Case 2: A 69-year-old female received FOLFOX4 plus BEV for unresectable rectal cancer and liver and lung metastasis. A rectal perforation occurred 6 days after BEV administration and suturing closure of the hole and colostomy was performed. Case 3: A 69-year-old female, received carboplatin(CBDCA) plus pemetrexed(PEM)plus BEV for unresectable left lung cancer and adrenal gland and lymph node metastasis. A small intestinal perforation occurred 15 days after BEV administration and ileocecal resection and primary anastomosis was performed. Case 4: A 73-year-old female received CBDCA plus PEM plus BEV for unresectable left lung carcinoma and pleural metastasis. A diverticulum of sigmoid colon perforation occurred 30 days after BEV administration and suturing closure of the hole and colostomy was performed. When we observe fever, abdominal pain, elevation of the inflammatory reaction after BEV administration, we should immediately examine gastrointestinal perforation.