ACAT-1-Regulated Cholesteryl Ester Accumulation Modulates Gemcitabine Resistance in Biliary Tract Cancer.

BACKGROUND: Biliary tract cancer (BTC) has few choices of chemotherapy, including gemcitabine, therefore exploring the mechanisms of gemcitabine resistance is important. We focused on lipid metabolism because biliary tract epithelial cells are essential in cholesterol and bile acid metabolism and the messenger RNA (mRNA) microarray analysis showed high acyl coenzyme A: cholesterol acyltransferase 1 (ACAT-1) expression in BTC gemcitabine-resistant (GR) cell lines. We hypothesized that aberrant accumulation of cholesteryl ester (CE) regulated by ACAT-1 could modulate GR in BTC. METHODS: CE accumulations were measured in human BTC cell lines, and the relationships between CE levels, ACAT-1 expressions, and gemcitabine sensitivity were analyzed. We performed a small-interfering RNA (siRNA)-mediated knockdown and biochemical inhibition of ACAT-1 in BTC cell lines and alterations of gemcitabine sensitivity were evaluated. To evaluate the clinical significance of ACAT-1 in regard to GR, immunohistochemistry was performed and ACAT-1 expressions were analyzed in resected BTC specimens. RESULTS: CE levels were correlated with ACAT-1 expressions and GR in four human BTC cell lines. siRNA-mediated knockdown of ACAT-1 in two independent GR cell clones as well as ACAT-1 inhibitor treatment significantly increased gemcitabine sensitivity; knockdown of ACAT-1: 5.63- and 8.02-fold; ACAT-1 inhibitor: 8.75- and 9.13-fold, respectively. ACAT-1 expression in resected BTC specimens revealed that the disease-free survival of the ACAT-1 low-intensity group (median 2.3 years) had a significantly better outcome than that of the ACAT-1 high-intensity group (median 1.1 years) under gemcitabine treatment after surgery (*p < 0.05). CONCLUSIONS: Our findings suggest that CE and ACAT-1 might be a novel therapeutic target for GR in BTC.

Giant cell arteritis without cranial manifestations caused mesenteric involvement: a case report.

BACKGROUND: Giant cell arteritis (GCA) is a granulomatous vasculitis and targets large vessels with predominance for the aortic arch and the cranial branches. GCA with cranial symptoms shows headache, jaw claudication, and ophthalmologic symptoms and thus was previously called temporal arteritis. Recently, cases of GCA without cranial manifestations and extracranial GCA have been reported. CASE PRESENTATION: A 76-year-old woman was referred to our hospital complaining of sudden abdominal pain and high fever. Her present history of illness did not show any cranial symptoms such as headache, visual disturbance, or stroke. CT images showed severe thickening of the small intestinal mesentery and massive ascites. She was diagnosed to have acute abdomen probably with gastrointestinal perforation and underwent the emergent laparotomy. Excisions of a 60-cm length of the jejunum including the thickening mesenteric lesion were carried out. Marked hypertrophy of the vascular intima and mild stenosis of the arterial lumen were displayed with infiltration of lymphocytes, neutrophils, and eosinophils. Scattered multinucleated giant cells on the endothelium, in the intima, media, and adventitia were demonstrated. Elastica van Gieson stain showed focal loss and fragmentation of the internal elastic lamina. Histopathological examinations showed typical GCA. Her postoperative process was uneventful without any symptoms, and she was followed as an out-patient prescribed with daily doses of 40 mg of prednisolone. CONCLUSIONS: We hereby report a rare case of mesenteric involvement in GCA without cranial manifestations and elucidate the histopathological features of extracranial GCA in arteries as well as veins and jejunum.

A case of adenocarcinoma developed in the small intestine with chronic strongyloidiasis.

We experienced a case of intestinal strongyloidiasis complicated by jejunal carcinoma. A Japanese male in his 50s, who has a 7-year medical history of duodenal ulcers, complained of loss of appetite, nausea, vomiting and diarrhea. Computed tomography and gastroduodenal endoscopic examination revealed a stenosis of the duodenum. To remove the stenosis, gastric bypass surgery was performed. The pathological diagnosis of the resected jejunum was strongyloidiasis and well-differentiated adenocarcinoma with subserosal invasion and vascular infiltration. After administration of Ivermectin, Strongyloides stercoralis was not found in any biopsies or in the specimens of the intestine, which were resected due to cancer recurrence 2 years later. There are three possibilities for the reason of coexistence of S. stercoralis and adenocarcinoma: S. stercoralis caused the adenocarcinoma, S. stercoralis moved to the carcinoma, or just coincidence. Although it is difficult to prove a causal relationship between S. stercoralis and adenocarcinoma, this is the first report of adenocarcinoma developed in the jejunum with chronic strongyloidiasis. The number of nematode infections, including strongyloidiasis, is decreasing in Japan, although not worldwide. Therefore, it should be considered in patients with prolonged intestinal ulcers.

[Long-Term Survival after Locally Advanced Pancreatic Ductal Adenocarcinoma Treated with Multidisciplinary Therapy - A Case Report].

A 60-year-old man visited a hospital with concerns about his physical health, including weight loss, thirst, and polyuria. He was diagnosed with acute onset of diabetes, and a pancreatic head tumor was observed on imaging studies. Computed tomography(CT)indicated that the tumor infiltrated the surrounding major vessels, portal vein(PV, 360 degrees), and superior mesenteric artery(SMA, <180 degrees). Endoscopic ultrasound-guided fine needle aspiration(EUS-FNA)was performed, and he was diagnosed with a borderline resectable(BR)clinical Stage IV a pancreatic ductal adenocarcinoma (PDAC). Chemoradiation therapy(CRT, S-1 plus gemcitabine [GEM] concurrent with 50.4 Gy radiation)followed by chemotherapy( GEM)was performed until a tumor response indicating sufficient reduction of SMA infiltration was observed on imaging studies. Twelve months after initiation of treatment, a pancreaticoduodenectomy and PV resection/reconstruction were performed. The pathological stage was ypT3N0M0(ypStage III ), and SMA infiltration was not detected in the resected specimen. He was discharged after an uneventful course following surgery, and adjuvant S-1 chemotherapy was continued from post-operative day 67 for 4 months. Now at post-operative 57 month, he has survived without recurrence. There have been some reports detailing long-term survival of patients with BR tumors who underwent multidisciplinary therapy as curative resection following preoperative CRT and postoperative adjuvant chemotherapy. During preoperative treatment, it is important to monitor the effects and determine the suitable timing to perform surgery to achieve long-term survival.

[A case of synchronous cancer of the gall bladder, common bile duct, and the papilla of vater].

A 58-year-old man was diagnosed with liver dysfunction during a health exam and subsequently visited a doctor. Abdominal ultrasonography revealed space-occupying lesions in the gall bladder and bile duct, and he was hospitalized for further examination and treatment. Computed tomography (CT), endoscopic retrograde cholangiopancreatography (ERCP), and magnetic resonance cholangiopancreatography (MRCP) revealed double cancer of the gall bladder and bile duct with pancreaticobiliary maljunction (PBM), and we performed a pancreatoduodenectomy. Pathological examination revealed gall bladder and bile duct cancer, and severe dysplasia of the papilla of Vater. We diagnosed synchronous triple cancer because none of the cancers had continuity or vascular invasion. Each cancer was at Stage I, and the patient has survived for 2 years and 6 months without recurrence and no additional treatment. PBM is a mutation of the junction of the pancreatic and bile ducts outside of the duodenal wall, and is a known complication of biliary tract cancer due to the reflux of pancreatic juice and bile. Because K-ras and p53 gene mutations occur in the biliary tract mucosal epithelium, PBM increases the risk of developing multicentric cancer. It is important to consider the existence of double cancer when biliary tract cancer is detected in a PBM patient.

[A case of postpancreaticoduodenectomy local recurrence successfully treated with extended resection].

A 68 -year-old man underwent a pancreaticoduodenectomy after being diagnosed with primary duodenal cancer. The postoperative pathological diagnosis was tub2, SE, ly1, v1, panc3, pn+, N0. Although adjuvant chemotherapy was administered, local recurrence in the portal region was detected 18 months later. The recurrent tumor pressed against the region of the bile duct anastomosis, which caused obstructive jaundice. After serum bilirubin levels were reduced, resection of the recurrent tumors was performed. This required resection of the transverse colon, parts of the portal vein, and the inferior vena cava. The bile duct anastomotic region, which had been infiltrated by the tumor, was excised and rebuilt. The postoperative pathological diagnosis was tub2. The patient continued to receive adjuvant chemotherapy and showed no signs of recurrence 9 months after surgery. Extended resection for local recurrences of primary duodenal cancer may be an effective means of disease control.

[A case of extragastrointestinal stromal tumor with peritoneal dissemination].

Here, we present the case of a 60-year-old man in whom abdominal computed tomography showed a solid abdominal tumor (11 cm in diameter) in the pelvic space, with widely disseminated nodular lesions. Emergency surgery was performed following the rapid onset of intense abdominal pain. Peritoneal disseminations were widespread and the tumor was confirmed to be in the pelvic space. The tumor was not connected to any segment of the intestinal tract but rather to the retroperitoneum. Immunohistochemical staining was positive for c-kit (exon 11 mutation) and CD34 but negative for S-100 protein. Careful postoperative examination did not reveal any lesions in the upper or lower alimentary tract. On the basis of these findings we diagnosed the tumor as an extragastrointestinal stromal tumor (EGIST) originating from the retroperitoneum. After surgery, intravenous infusion of imatinib was started at a full dose of 400mg/day; however, owing to strong adverse effects, the dose was reduced to 200mg/day. Despite halving the dose, the patient has remained lesion-free according to computed tomography for 36 months after the operation. Low-dose imatinib chemotherapy remained efficacious in controlling progression in this case.

A planar gastrointestinal stromal tumor replacing the proper muscle layer causing fecaloma and perforation in the sigmoid colon: a case report and literature review.

A 72-year-old Japanese male with acute abdomen underwent emergency surgery for a preoperative diagnosis of stercoral colonic perforation of the sigmoid colon. A pathological examination revealed a proliferating spindle cell lesion that surrounded the perforation and replaced the muscularis propria without any mass formation. The spindle cells were positive for KIT and CD34 by immunohistochemistry, and somatic mutation of the c-kit gene was found using genomic DNA extracted from the lesion. We diagnosed the spindle cell lesion as a planar gastrointestinal stromal tumor (GIST). We speculate that perforation of the sigmoid colon in this case may be caused by the stasis of stool resulting from abnormal peristalsis of the lesional site. Two other similar cases have been reported in the literature, and showed good prognoses. Although their pathogenesis is unclear, planar GISTs should be considered as a possible cause of idiopathic or stercoral colonic perforation.