Mamoru Morimoto

Enhancement of the CXCL12/CXCR4 axis due to acquisition of gemcitabine resistance in pancreatic cancer: effect of CXCR4 antagonists

BackgroundThe CXCL12-CXCR4 signaling axis in malignant tumor biology has increased in importance, and these peptides are implicated in tumor growth, invasion and metastasis. The aim of our study was to examine the important role of the axis in pancreatic cancer (PaCa) cells’ relationship with stromal cells in gemcitabine-resistant (GEM-R) tumors and to confirm the effectiveness of CXCR4 antagonists for the treatment of GEM-R PaCa cells.MethodsWe established two GEM-R PaCa cell lines using MIA PaCa-2 and AsPC-1 cells. The expression of CXCR4 mRNA in PaCa cells and the expression of CXCL12 mRNA in fibroblasts were examined by reverse transcription polymerase chain reaction (RT-PCR). The expression of CXCR4 protein in PaCa cells was examined by immunosorbent assay (ELISA) and immunocytochemistry. Using Matrigel invasion assays and animal studies, we then examined the effects of two CXCR4 antagonists, AMD11070 and KRH3955, on the invasiveness and tumorigenicity of GEM-R PaCa cells stimulated by CXCL12.ResultsWe found that the expression of CXCR4 in GEM-R PaCa cells was significantly enhanced by GEM but not in normal GEM-sensitive (GEM-S) PaCa cells. In RT-PCR and ELISA assays, the production and secretion of CXCL12 from fibroblasts was significantly enhanced by co-culturing with GEM-R PaCa cells treated with GEM. In Matrigel invasion assays, the invasiveness of GEM-R PaCa cells treated with GEM was significantly activated by fibroblast-derived CXCL12 and was significantly inhibited by CXCR4 antagonists, AMD11070 and KRH3955. In vivo, the tumorigenicity of GEM-R PaCa cells was activated by GEM, and it was significantly inhibited by the addition with CXCR4 antagonists.ConclusionsOur findings demonstrate that the CXCL12-CXCR4 signaling axis plays an important role in PaCa cells’ resistance to GEM. CXCR4 expression was significantly enhanced by the exposure to GEM in GEM-R PaCa cells but not in GEM-S PaCa cells. Furthermore, CXCR4 antagonists can inhibit the growth and invasion of GEM-R PaCa cells. These agents may be useful as second-line chemotherapy for GEM-R PaCa in the future.

Xanthohumol inhibits angiogenesis by suppressing nuclear factor-κB activation in pancreatic cancer

Xantohumol, a prenylated chalcone from hops (Humulus lupulus L.), has been shown to inhibit proliferation in some cancers. However, little is known regarding the effects of xanthohumol in pancreatic cancer. We have previously reported that activation of the transcription factor nuclear factor‐κB (NF‐κB) plays a key role in angiogenesis in pancreatic cancer. In this study, we investigated whether xanthohumol inhibited angiogenesis by blocking NF‐κB activation in pancreatic cancer in vitro and in vivo. We initially confirmed that xanthohumol significantly inhibited proliferation and NF‐κB activation in pancreatic cancer cell lines. Next, we demonstrated that xanthohumol significantly suppressed the expression of vascular endothelial growth factor (VEGF) and interleukin‐8 (IL‐8) at both the mRNA and protein levels in pancreatic cancer cell lines. We also found that coculture with BxPC‐3 cells significantly enhanced tube formation in human umbilical vein endothelial cells, and treatment with xanthohumol significantly blocked this effect. In vivo, the volume of BxPC‐3 subcutaneous xenograft tumors was significantly reduced in mice treated with weekly intraperitoneal injections of xanthohumol. Immunohistochemistry revealed that xanthohumol inhibited Ki‐67 expression, CD31‐positive microvessel density, NF‐κB p65 expression, and VEGF and IL‐8 levels. Taken together, these results showed, for the first time, that xanthohumol inhibited angiogenesis by suppressing NF‐κB activity in pancreatic cancer. Accordingly, xanthohumol may represent a novel therapeutic agent for the management of pancreatic cancer.

Inflammatory pseudotumor of the liver diagnosed as metastatic liver tumor in a patient with a gastrointestinal stromal tumor of the rectum: report of a case

BackgroundInflammatory pseudotumor (IPT) of the liver is a rare benign lesion. A case of IPT of the liver found in association with a malignant gastrointestinal stromal tumor (GIST) is reported.Case reportA 74-year-old man was admitted to our hospital for a liver tumor. He previously underwent rectal amputation for a malignant GIST. Computed tomography (CT) revealed a low-density area in the liver and dynamic contrast-enhanced MRI (EOB-MRI) showed that the tumor was completely washed out in the delayed phase. 18Fluorine-fluorodeoxyglucose positron emission tomography (FDG-PET) showed strong uptake in the liver. A diagnosis of liver metastasis was made and partial hepatectomy was performed. Microscopic examination showed that the tumor was an IPT.ConclusionDifferential diagnosis between IPT and malignant neoplasms is difficult. Moreover, FDG-PET revealed strong uptake in the tumor. To our knowledge, this is the first patient reported to have an IPT in association with a rectal GIST. This patient is discussed along with a review of the literature.

Laparoscopic-assisted total gastrectomy for early gastric cancer with situs inversus totalis: report of a first case

BackgroundSitus inversus totalis is a relatively rare condition and is an autosomal recessive congenital defect in which an abdominal and/or thoracic organ is positioned as a “mirror image” of the normal position in the sagittal plane. We report our experience of laparoscopic-assisted total gastrectomy with lymph node dissection performed for gastric cancer in a patient with situs inversus totalis.Case presentationA 58-year-old male was diagnosed with cT1bN0N0 gastric cancer. There were no vascular anomalies on abdominal angiographic computed tomography with three-dimensional reconstruction. laparoscopic-assisted total gastrectomy was performed with D1+ lymph node dissection, in accordance with the Japanese Gastric Cancer Treatment Guidelines. There were no intraoperative issues, and no postoperative complications.ConclusionsThis was the first report describing laparoscopic-assisted total gastrectomy with the standard typical lymph node dissection in the English literature. We emphasize that the position of trocars and the standing side of the primary surgeon during the lymph node dissection are critical.

Recanalization of postoperative biliary disconnection with intraductal cholangioscopy-assisted forceps retrieval of rendezvous guidewire

Biliary recanalization is a vital procedure to restore postoperative bile duct obstruction. However, selective guidewire negotiation across the disconnected sites under fluorescence imaging is challenging. We present a case of formidable biliary disconnection after hepatectomy that was recanalized by rendezvous technique using digital cholangioscopy. An 86-year-old man with hepatocellular carcinoma in the right anterior segment showed bile leakage at the resection site after laparoscopic right anterior hepatectomy. Complete obstruction at the right hepatic duct (RHD) and bile spillage at the edge of the right posterior branch (RPB) indicated complete disconnection between the RHD and RPB (▶Fig. 1, ▶Fig. 2), and guidewire negotiation across the lesion failed both endoscopically and percutaneously. Selective negotiation with an intraductal cholangioscope (SpyGlass DS; Boston Scientific, Natick, Massachusetts, USA) allowed the guidewire to reach the obstructed site of the RHD (▶Fig. 3). After balloon dilation of the duct, the cholangioscope was advanced to the intraperitoneal cavity through the obstructed site. Nevertheless, the guidewire passed through the cholangioscope was unable to reach the disconnected RPB because of deep angular misalignment between the RHD and RPB. To create a fistula, a straight-type guidewire was inserted percutaneously through the disconnected RPB. The guidewire was grasped using biopsy forceps (SpyBite; Boston Scientific) under direct visualization (▶Fig. 4) and pulled out into the duodenum, so that the percutaneous catheter could then be advanced into the duodenum (▶Video1). Finally, a plastic stent was inserted endoscopically, followed by removal of the percutaneous catheter (▶Fig. 5). Complete biliary disconnection is an intractable adverse effect of hepatectomy. Moreover, angular misalignment between the disconnected ducts is a serious obstacle for recanalization, which can mean surgical re-operation is required. Several studies have reported the utility of cholangioscopy-assisted guidewire placement in biliary obstruc▶ Fig. 1 Endoscopic retrograde cholangiography showing complete bile duct obstruction after laparoscopic right anterior hepatectomy with no flow of contrast into the right posterior branch. ▶ Fig. 2 Percutaneous transhepatic cholangiography showing bile leakage into the peritoneal cavity with no flow of contrast into the common bile duct. ▶ Fig. 3 Direct cholangioscopy showing the narrow orifice of the biliary obstruction.

Rectal arteriovenous fistula resected laparoscopically after laparoscopic sigmoidectomy: A case report

We report a very rare case of rectal arteriovenous fistula following sigmoidectomy and discuss this case in the context of the existing literature. In April 2011, the patient, a man in his 60s, underwent laparoscopic sigmoidectomy with lymph node dissection for sigmoid colon cancer. Beginning in February 2012, he experienced frequent diarrhea. Abdominal contrast‐enhanced CT revealed local thickening of the rectal wall and rectal arteriovenous fistula near the anastomosis site. Rectitis from the rectal arteriovenous fistula was diagnosed. No improvement was seen with conservative treatment. Therefore, surgical resection was performed laparoscopically and the site of the lesion was confirmed by intraoperative angiography. The arteriovenous fistula was identified and resected. Postoperatively, diarrhea symptoms resolved, and improvement in rectal wall thickening was seen on abdominal CT. No recurrence has been seen as of 1 year postoperatively.