Expression of Epithelial-Mesenchymal Transition Proteins in Pancreatic Anaplastic (Undifferentiated) Carcinoma.

OBJECTIVES: The aim of this study was to identify an association of pancreatic anaplastic carcinoma (APC) with the epithelial-mesenchymal transition (EMT). METHODS: Resected APCs (n = 24) were examined to assess components of APCs, including carcinomatous, transitional, and sarcomatous regions. Analysis was performed based on the immunoreactivity of E-cadherin and 3 EMT-related proteins: Slug (zinc finger protein SNAI2), Twist (Twist-related protein 1), and Zeb1 (zinc finger E-box-binding homeobox 1). Expression score was determined based on staining intensity and stained area of the target cells. Finally, we performed a hierarchical clustering based on the expression pattern of E-cadherin and EMT-related proteins of the sarcomatous component. RESULTS: The expression score of E-cadherin decreased in the order of sarcomatous > transitional > carcinomatous components (P < 0.01). Although there were significant differences in the immunohistochemical scores of Slug, Twist, and Zeb1 between carcinomatous and transitional components (P < 0.01), the significant difference in immunohistochemical score of Zeb1 between transitional and sarcomatous components was found (P < 0.05). Furthermore, APCs were divided into 2 subgroups based on the expression patterns of E-cadherin and EMT-related proteins (hierarchical clustering analysis). Consequently, these subgroups were distinguished by Twist expression. CONCLUSIONS: Epithelial-mesenchymal transition plays an essential role in the pathogenesis of APC.

[A case of non-invasive IPMC with fibrotic lesion-like "tubular complex"].

A 73-year-old man was incidentally diagnosed with a cystic lesion in the pancreatic body. Ultrasonography, abdominal computed tomography, magnetic resonance imaging, endoscopic retrograde cholangiopancreatography, and endoscopic ultrasound were performed, and a nodule was detected in the cystic lesion along with an irregularity of the main pancreatic duct. An initial diagnosis of a mixed-type intraductal papillary mucinous neoplasm was made, and a central pancreatectomy was performed. However, the final diagnosis was altered to non-invasive intraductal papillary mucinous carcinoma (IPMC). The histopathological examination revealed a fibrotic lesion that was similar to "tubular complex" findings observed in mouse models of pancreatic cancer. The fibrotic lesion was placed between the main pancreatic duct lesion and branch-duct cystic lesion. The changes reflected in branch-level stenosis may be caused by IPMC growth.

Feasibility Assessment of Modified FOLFOX-6 as adjuvant treatment after resection of liver metastases from colorectal cancer: analyses of a multicenter phase II clinical trial (Miyagi-HBPCOG Trial-001).

BACKGROUND/AIMS: This multicenter and single arm phase II clinical trial was performed to examine the safety and efficacy of modified FOLFOX6 (mFOLFOX6) as adjuvant treatment after resection of liver metastases from colorectal cancer. METHODOLOGY: Patients who had undergone R0-1 resection of liver metastases were assigned to 12 cycles of mFOLFOX6. The primary end point was disease-free survival (DFS). RESULTS: We enrolled 49 cases and analyzed adverse events in 48 cases, since in one patient cancer recurred before starting treatment. As to the relative dose intensity, 5-FU was 78.8%, and oxaliplatin was 75.9%. Adverse events of Grade 3 and above includ- ed 18 cases of neutropenia (37.5%), 4 cases of sensory neuropathy (8.3%), 4 cases of thrombocytopenia (8.3%) and 4 cases of allergy (8.3%), and there were no cases of fatality caused by adverse events. The most difference of adverse event compared with MOSAIC trial (Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer) was thrombocytopenia. The 2-year DFS was 59.2% (95% CI: 36.7-78.4) in the 49 enrolled cases. CONCLUSION: mFOLFOX6 after hepatectomy was tolerable. And mFOLFOX6 also seemed to improve DFS. mFOLFOX is one of the options for such patients and appears promising as an adjuvant treatment.

Neoadjuvant chemotherapy with gemcitabine and S-1 for resectable and borderline pancreatic ductal adenocarcinoma: results from a prospective multi-institutional phase 2 trial.

BACKGROUND: Surgical resection is the only curative strategy for pancreatic ductal adenocarcinoma (PDAC), but recurrence rates are high even after purported curative resection. First-line treatment with gemcitabine and S-1 (GS) is associated with promising antitumor activity with a high response rate. The aim of this study was to assess the feasibility and efficacy of GS in the neoadjuvant setting. METHODS: In a multi-institutional single-arm phase 2 study, neoadjuvant chemotherapy (NAC) with gemcitabine and S-1, repeated every 21 days, was administered for two cycles (NAC-GS) to patients with resectable and borderline PDAC. The primary end point was the 2-year survival rate. Secondary end points were feasibility, resection rate, pathological effect, recurrence-free survival, and tumor marker status. RESULTS: Of 36 patients enrolled, 35 were eligible for this clinical trial conducted between 2008 and 2010. The most common toxicity was neutropenia in response to 90% of the relative dose intensity. Responses to NAC included radiological tumor shrinkage (69%) and decreases in CA19-9 levels (89%). R0 resection was performed for 87% in resection, and the morbidity rate (40%) was acceptable. The 2-year survival rate of the total cohort was 45.7%. Patients who underwent resection without metastases after NAC-GS (n = 27) had an increased median overall survival (34.7 months) compared with those who did not undergo resection (P = 0.0017). CONCLUSIONS: NAC-GS was well tolerated and safe when used in a multi-institutional setting. The R0 resection rate and the 2-year survival rate analysis are encouraging for patients with resectable and borderline PDAC.

Ipsilateral percutaneous transhepatic portal vein embolization with gelatin sponge particles and coils in preparation for extended right hepatectomy for hilar cholangiocarcinoma.

PURPOSE: To evaluate the effectiveness and safety of ipsilateral percutaneous transhepatic portal vein embolization (PTPVE) with gelatin sponge particles and coils to induce lobar hypertrophy in patients with hilar cholangiocarcinoma in preparation for extended right hepatectomy. MATERIALS AND METHODS: Between 1999 and 2004, PTPVE was performed in 22 patients with hilar cholangiocarcinoma (mean age, 67 years; range, 57-77 y; 16 men and six women). Percutaneous puncture of the right portal vein was performed under ultrasound guidance. A reverse-curve catheter was used for right portal vein embolization. Coils were used to occlude second-order branches. The future liver remnant volume was assessed by comparing computed tomographic scans before and 14-24 days after PTPVE. RESULTS: PTPVE was technically successful in all cases. The average increase in ratio of future liver remnant volume to total liver volume was 8.6%. Liver function tests after PTPVE but before surgery showed no significant changes. Nineteen patients underwent hepatic resection without liver failure. In three patients, tumors could not be removed because of detection of extrahepatic disease. One patient who underwent successful hepatic resection had an abscess in the removed right lobe. CONCLUSION: Ipsilateral PTPVE with gelatin sponge and coils appears to be effective and safe for extended right hepatectomy for hilar cholangiocarcinoma.

Operated hepatocellular carcinoma in two HIV- and HCV-positive hemophilic patients.

Some hemophilic patients in Japan suffer from infections with both human immunodeficiency virus (HIV) and hepatitis virus because they received contaminated nonheated blood products. Coinfection with HIV appears to accelerate the course of chronic hepatitis. Although powerful antiviral therapy was introduced as HIV treatment and the prognosis of HIV patients was dramatically improved, the risk of rapid progression of hepatitis and carcinogenesis remains for the patients. Recently, we performed surgery for hepatocellular carcinoma (HCC) in two hemophilic patients with HIV and hepatitis C virus (HCV) coinfection. Case 1 was a 52-years-old man who suffered from liver cirrhosis, hypersplenism, and hyperammonemia due to portosystemic shunt. A recent abdominal computed tomography (CT) scan had revealed a low-density area in segment VI of the liver. Splenectomy and partial resection of the liver were performed. Case 2 was a 66-year-old man who had been diagnosed with chronic hepatitis at age 50, and HIV infection at age 52 years. When his serum alpha-fetoprotein level was increased, CT scan of the liver revealed a mass in segment VIII. Subsegmentectmy of the liver was performed. Although the CD4 value in each patient was lower than 200 micro l, the operations were safely carried out and no major complication occurred. Because the chance of encountering HCC patients infected with HIV and HCV is increasing in Japan, we should consider the perioperative care of these patients, as well as the protection of medical workers against HIV infection.

Do peritoneal macrophages play an essential role in the progression of acute pancreatitis in rats?

INTRODUCTION: Macrophages are considered to play an essential role in the events leading to systemic inflammatory response. Some are known to reside in the peritoneal cavity but there are no reports defining the participation of peritoneal macrophages (PMs) in the progression of acute pancreatitis. AIM: To clarify the role of PMs in the progression of acute pancreatitis. METHODOLOGY: Acute pancreatitis was induced in rats from which macrophages other than PMs were greatly depleted, and in rats greatly depleted of macrophages including PMs. Macrophages were depleted by the injection of liposome encapsulated dichloromethylene bisphosphonate. After the induction of acute pancreatitis, local pancreatic inflammation, intraperitoneal inflammation and lung injury were compared between the 2 groups. RESULTS: Local pancreatic inflammation did not differ between the 2 groups. However, intraperitoneal inflammation was clearly improved by the depletion of PMs. Serum cytokine level and lung injury were also improved by the depletion of PMs. CONCLUSION: Peritoneal macrophages extend inflammation from the pancreas to the peritoneal cavity and subsequently induce lung injury in acute pancreatitis. Peritoneal macrophages play an essential role in the systemic inflammatory response and the progression of acute pancreatitis in the rat.

Gene therapy for intraperitoneally disseminated pancreatic cancers by Escherichia coli uracil phosphoribosiltransferase (UPRT) gene mediated by restricted replication-competent adenoviral vectors.

Although patients with unresectable pancreatic tumors have been treated with 5-fluorouracil (5FU)-based combination chemotherapy, the drug resistance of cancer cells presents a crucial therapeutic problem. It was reported that UPRT overcomes 5FU resistance. UPRT catalyzes the synthesis of 5-fluorouridine monophosphate (FUMP) from Uracil and phosphoribosylpyrophosphate (PRPP). The antitumor effect of 5FU is enhanced by augmenting 5-fluorodeoxyuridine monophosphate (FdUMP) converted from FUMP, which inhibits thymidylate synthetase (TS). We first demonstrated that injecting an E1-deficient adenoviral vector (Adv) expressing UPRT (AxCAUPRT) followed by 5-FU treatment resulted in a volume reduction of xenotransplanted human tumors. In examining the therapeutic effect of AxCAUPRT/5-FU against peritoneal dissemination, we found that non-selective gene transduction of AxCAUPRT caused severe adverse effects arising from the increase of F-dUMP in normal intestine. Because the therapeutic gene delivered by a restricted replication-competent Adv lacking 55 kDa E1B protein (AxE1AdB) is speculated to be expressed selectively in tumors, mice with established tumors were injected with AxE1AdB and E1-deleted Adv expressing the lacZ reporter gene (AxCAlacZ). The expression of the reporter gene (lacZ) was selectively enhanced in disseminated tumors. The therapeutic advantage of restricted replication competent Adv that expresses UPRT (AxE1AdB-UPRT) was evaluated in an intraperitoneal disseminated tumor model. To study the anti-tumor effect of AxE1AdB-UPRT/5FU, mice with disseminated AsPC-1 tumors were administered the Adv, followed by the 5FU treatment. It was shown that the treatment with AxE1AdB-UPRT/5FU caused a dramatic reduction of the disseminated tumor burden without toxicity in normal tissues. Our results showed that the AxE1AdB-UPRT/5FU system is a promising tool for intraperitoneal disseminated pancreatic cancer.

Murine dendritic cell-induced tumor apoptosis is partially mediated by nitric oxide.

Dendritic cells (DC) are potent antigen-presenting cells that are important for the priming of antitumor cytotoxic T cells. Recent reports suggest that DC may also have direct cytotoxic effector functions against selected tumor-cell lines by mechanisms that are dependent on dendritic cell-tumor cell contact in vitro. The authors report that ex vivo-generated murine DC induce the apoptosis of a panel of syngeneic and allogeneic murine tumors. Apoptosis of the MCA205 fibrosarcoma tumor-cell line by C57BL/6-derived DC was not mediated by Fas/FasL interactions and, in contrast to other studies, DC-tumor cell contact was not required to effect tumor-cell killing by DC. Therefore, the authors postulated that tumor-cell killing was mediated by an apoptotic factor that was secreted by DC. Even though DC did not secrete such apoptotic cytokines as interferon-alpha or tumor necrosis factor-alpha, they did secrete nitric oxide, and tumor apoptosis was partially abrogated by the nitric oxide synthase antagonist NG-monomethyl-L-arginine. Therefore, the authors' data demonstrate a novel mechanism for DC-induced tumor-cell apoptosis that does not require DC-tumor cell contact and is partially mediated by nitric oxide.