[A Case of Early-Stage Cecal Cancer with Mesenteric Phlebosclerosis Requiring Laparoscopic Right Hemicolectomy of the Colon].

The patient was a 71-year-old woman diagnosed with mesenteric phlebosclerosis(MP)2 years earlier. CT performed to investigate her abdominal pain revealed an ascending colon obstruction. Colonoscopy(CS)revealed MP extending to the ascending colon hepatic flexure with stenosis and a cecal tumor(biopsy tub1). Although the cancerous lesion itself was potentially curable by endoscopic treatment, it was surgically resected because of the ascending colon stenosis caused by the MP that had also caused intestinal obstruction. Intraoperative findings revealed wall thickening and stiffening from the cecum to the ascending colon hepatic flexure. Postoperative pathological examination revealed cecal carcinoma pTis, N0, M0, pStage 0. The background mucosal tissue was consistent with MP, but no findings suggested a relationship between the MP and tumor. Although the relationship between MP and carcinogenesis is unknown, and no such relationship was identified in this case, we report this case because a further accumulation of cases of MP and carcinoma is necessary, considering the rarity of MP itself and the non-negligible number of cases with carcinoma.

Targeting Aspartate Beta-Hydroxylase with the Small Molecule Inhibitor MO-I-1182 Suppresses Cholangiocarcinoma Metastasis.

BACKGROUND: Cholangiocarcinoma is a devastating disease with a 2% 5-year survival if the disease has spread outside the liver. The enzyme aspartate beta-hydroxylase (ASPH) has been demonstrated to be highly expressed in cholangiocarcinoma but not in normal bile ducts and found to stimulate tumor cell migration. In addition, it was found that targeting ASPH inhibits cholangiocarcinoma malignant progression. However, it is not clear whether targeting ASPH with the small molecule inhibitor MO-I-1182 suppresses cholangiocarcinoma metastasis. The current study aims to study the efficacy of MO-I-1182 in suppressing cholangiocarcinoma metastasis. METHODS: The analysis was performed in vitro and in vivo with a preclinical animal model by using molecular and biochemical strategies to regulate ASPH expression and function. RESULTS: Knockdown of ASPH substantially inhibited cell migration and invasion in two human cholangiocarcinoma cell lines. Targeting ASPH with a small molecule inhibitor suppressed cholangiocarcinoma progression. Molecular mechanism studies demonstrated that knockdown of ASPH subsequently suppressed protein levels of the matrix metalloproteinases. The ASPH knockdown experiments suggest that this enzyme may modulate cholangiocarcinoma metastasis by regulating matrix metalloproteinases expression. Furthermore, using an ASPH inhibitor in a rat cholangiocarcinoma intrahepatic model established with BED-Neu-CL#24 cholangiocarcinoma cells, it was found that targeting ASPH inhibited intrahepatic cholangiocarcinoma metastasis and downstream expression of the matrix metalloproteinases. CONCLUSION: ASPH may modulate cholangiocarcinoma metastasis via matrix metalloproteinases expression. Taken together, targeting ASPH function may inhibit intrahepatic cholangiocarcinoma metastasis and improve survival.

Aspartate beta-hydroxylase promotes cholangiocarcinoma progression by modulating RB1 phosphorylation.

Cholangiocarcinoma (CCA) is a highly lethal and aggressive disease. Recently, IDH1/2 mutations have been identified in approximately 20% of CCAs which suggests an involvement of 2-oxoglutarate (2-OG) -dependent dioxygenases in oncogenesis. We investigated if the 2-OG dependent dioxygenase, aspartate beta-hydroxylase (ASPH) was important in tumor development and growth. Immunoassays were used to clarify how ASPH modulates CCA progression by promoting phosphorylation of the retinoblastoma protein (RB1). A xenograft model was employed to determine the role of ASPH on CCA growth. Knockdown of ASPH expression inhibited CCA development and growth by reducing RB1 phosphorylation. Expression of ASPH promoted direct protein interaction between RB1, cyclin-dependent kinases, and cyclins. Treatment with 2-OG-dependent dioxygenase and ASPH inhibitors suppressed the interaction between RB1 and CDK4 as well as RB1 phosphorylation. Knockdown of ASPH expression inhibited CCA progression and RB1 phosphorylation in vivo and they were found to be highly expressed in human CCAs. Knockdown of ASPH expression altered CCA development by modulating RB1 phosphorylation, as one of the major factors regulating the growth of these tumors.

[Resection of Pancreatic Metastasis from Renal Cell Carcinoma 21 Years after Nephrectomy].

We report a case where resection was performed for pancreatic metastasis from renal cell carcinoma 21 years after nephrectomy. A 72-year-old man had undergone total gastrectomy with distal pancreatomy and splenectomy for gastric cancer, and right nephrectomy for primary renal cell carcinoma in 1993. Incidentally, a CT scan performed in 2014 revealed a tumor in the head of the pancreas. Enhanced MRI suggested that the tumor contained some fat tissue. The tumor in the pancreatic body had sharp margins; therefore, we performed subtotal pancreatectomy. The tumor was considered pancreatic metastasis from renal cell carcinoma. Pathological findings indicated clear-cell type carcinoma(G1-G2), which is very similar to renal cell carcinoma. We diagnosed pancreatic metastasis from renal cell carcinoma. The patient has remained well, with no recurrence 20 months after the pancreatectomy.

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.

EpCAM-targeted therapy for human hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most lethal malignancies and the identification of new effective therapies for HCC is urgently needed. We have previously identified EpCAM, one of the hepatic stem/progenitor markers, as a prognostic predictor of patients who received curative hepatectomy for HCC. In this preclinical study, the effects of VB4-845, an immunotoxin targeting EpCAM, were evaluated in HCC. METHODS: In vitro effects of VB4-845 on human HCC cells, the cytotoxic activity, sphere-forming ability, and expression of hepatic stem/progenitor markers were analyzed. In vivo effects of VB4-845 were evaluated using subcutaneous and orthotopic liver xenograft models. RESULTS: In all HCC cell lines expressing EpCAM, VB4-845 showed potent cytotoxicity and was significantly effective in combination with 5-FU (p < 0.05). Although 5-FU did not affect the sphere-forming ability and increased the populations expressing other stem/progenitor markers CD133 and CD13 (p < 0.05), VB4-845 strongly suppressed the sphere-formation and decreased the population expressing CD133 and CD13 (p < 0.0005, <0.01, respectively). In subcutaneous xenograft models, the combination of VB4-845 plus 5-FU showed significant regression of tumors compared with the control (p = 0.016). Moreover, in orthotopic liver xenograft models, the combination therapy dramatically decreased the tumor volume compared with the control (p = 0.0011). CONCLUSIONS: Our preclinical investigation suggests that EpCAM-targeted therapy may offer a promising and novel approach for the treatment of HCC with a poorer prognosis.