Adjuvant 5-fluorouracil and portal vein infusion chemotherapy followed by gemcitabine for pancreatic cancer.

BACKGROUND: Although adjuvant gemcitabine (GEM) monotherapy improves the overall survival (OS) of patients with resected pancreatic cancer, its efficacy requires further improvement. This multicenter, phase II study investigated the efficacy of adjuvant portal vein infusion (PVI) chemotherapy followed by GEM therapy in patients with resected pancreatic cancer. METHODS: 5-fluorouracil (250 mg/day) and heparin (2000 IU/day) PVI chemotherapy were combined with systemic administration of mitomycin C (4 mg; days 6, 13, 20, and 27) and cisplatin (10 mg; days 7, 14, 21, and 28) for 4 weeks (PI4W), followed by GEM (1000 mg/m2; days 1, 8, and 15 every 4 weeks for 6 months). The primary endpoint was relapse-free survival (RFS) and the secondary endpoints were OS and treatment completion. RESULTS: Between November 2010 and August 2013, 53 patients who underwent complete resection were enrolled, including 30, 20, and 3 patients who underwent pancreaticoduodenectomies and distal and total pancreatectomies, respectively. In total, 51 (96.2%) patients underwent R0 resection, of whom 3, 2, 12, 35, 0, and 1 had stages IA, IB, IIA, IIB, III, and IV cancer, respectively, and 47 (88.7%) patients completed PI4W. The median RFS was 22.0 months (1-, 3-, 5, and 10 years RFS: 64.9%, 38.1%, 38.1%, and 38.1%, respectively), whereas the median OS was 32.0 months (1-, 3-, 5, and 10 years OS:86.6%, 47.2%, 44.4%, and 44.4%, respectively). CONCLUSION: Treatment with PI4W followed by GEM for 6 months after surgery may be beneficial in patients undergoing curative resection of pancreatic cancer.

Isolated IgG4-related cholecystitis with localized gallbladder wall thickening mimicking gallbladder cancer: a case report and literature review.

BACKGROUND: IgG4-related cholecystitis, which is a manifestation of IgG4-related disease in the gallbladder, is associated with autoimmune pancreatitis or IgG4-related sclerosing cholangitis in most cases; isolated gallbladder lesions without systemic manifestations are very rare. Gallbladder wall thickening is often diffuse, but sometimes localized, in which case, differentiation from gallbladder cancer becomes difficult. The characteristic features of IgG4-related cholecystitis on imaging that would enable differentiation from gallbladder cancer remain poorly described. CASE PRESENTATION: We present a rare case of isolated IgG4-related cholecystitis with localized gallbladder wall thickening that was clinically difficult to distinguish from malignancy before resection. An 82-year-old man was referred to our hospital because of gallbladder wall thickening on abdominal ultrasonography without any symptoms. Dynamic computed tomography of the abdomen showed localized wall thickening from the body to the fundus of the gallbladder that was enhanced from an early stage with a prolonged contrast effect. There were no other findings, such as pancreatic enlargement and bile duct dilatation. Magnetic resonance cholangiopancreatography revealed neither dilatation nor stenosis of the bile duct and pancreatic duct. Endoscopic ultrasonography (EUS) showed a smooth layered thickening of the gallbladder wall with a maximum thickness of 6 mm and a well-preserved outermost hyperechoic layer in the same area. Laparoscopic cholecystectomy was performed because malignancy could not be completely ruled out. Pathological examination of a resected specimen revealed IgG4-positive plasma cell infiltration, fibrosis, and phlebitis. Although the serum IgG4 level measured after resection was normal, the condition was ultimately diagnosed as probable IgG4-related cholecystitis according to the 2020 revised comprehensive diagnostic criteria for IgG4-related disease. The EUS images reflected the pathological findings, in which lymphocytic infiltration was distributed in a laminar fashion in the gallbladder wall. CONCLUSIONS: Although rare, isolated IgG4-related cholecystitis with localized wall thickening mimicking gallbladder cancer remains a clinical problem. A smooth laminar thickening of the gallbladder wall on EUS imaging could be one of the most informative characteristics for differentiating IgG4-related cholecystitis from gallbladder cancer.

Intraoperative laparoscopic detection of sentinel lymph nodes with indocyanine green and superparamagnetic iron oxide in a swine gallbladder cancer model.

Mapping of sentinel lymph nodes (SLNs) can enable less invasive surgery. However, mapping is challenging for cancers of difficult-to-access visceral organs, such as the gallbladder, because the standard method using radioisotopes (RIs) requires preoperative tracer injection. Indocyanine green (ICG) and superparamagnetic iron oxide (SPIO) have also been used as alternative tracers. In this study, we modified a previously reported magnetic probe for laparoscopic use and evaluated the feasibility of detecting SLNs of the gallbladder using a laparoscopic dual tracer method by injecting ICG and SPIO into five swine and one cancer-bearing swine. The laparoscopic probe identified SPIO nanoparticles in the nodes of 4/5 swine in situ, the magnetic field counts were 2.5-15.9 µT, and fluorescence was detected in SLNs in all five swine. ICG showed a visual lymph flow map, and SPIO more accurately identified each SLN with a measurable magnetic field quite similar to the RI. We then developed an advanced gallbladder cancer model with lymph node metastasis using recombination activating gene 2-knockout swine. We identified an SLN in the laparoscopic investigation, and the magnetic field count was 3.5 µT. The SLN was histologically determined to be one of the two metastatic lymph nodes. In conclusion, detecting the SLNs of gallbladder cancer in situ using a dual tracer laparoscopic technique with ICG and SPIO was feasible in a swine model.

Successful outcomes after laparoscopic spleen-preserving pancreatic resection for a desmoid tumor: A case report.

INTRODUCTION: Desmoid tumors are slowly growing neoplasms that arise from fibroblasts. These tumors are locally aggressive and have a high rate of recurrence after surgery. Pancreatic desmoid tumors are extremely rare. The indications and outcomes of laparoscopic surgery for pancreatic desmoid tumors have not been fully elucidated. This report therefore aimed to describe a rare case of a pancreatic desmoid tumor in a patient who was successfully treated with laparoscopic spleen-preserving pancreatic resection. PRESENTATION OF CASE: We report a case of a 60-year-old man who presented with back pain. Contrast-enhanced computed tomography scan revealed a circumscribed tumor in the pancreatic tail measuring 3 cm. The patient underwent laparoscopic spleen-preserving distal pancreatectomy. Pathological analysis revealed a desmoid tumor infiltrating the pancreatic parenchyma. There was no evidence of recurrence at 36 months of follow-up. DISCUSSION AND CONCLUSION: Isolated sporadic pancreatic desmoid tumors are extremely rare. Laparoscopic radical resection could be a safe and effective treatment for this benign but locally aggressive tumor. To the best of our knowledge, this is the first study to report a patient with a pancreatic desmoid tumor who was successfully treated with laparoscopic surgery.

A prospective feasibility study of one-year administration of adjuvant S-1 therapy for resected biliary tract cancer in a multi-institutional trial (Tokyo Study Group for Biliary Cancer: TOSBIC01).

BACKGROUND: Although surgery is the definitive curative treatment for biliary tract cancer (BTC), outcomes after surgery alone have not been satisfactory. Adjuvant therapy with S-1 may improve survival in patients with BTC. This study examined the safety and efficacy of 1 year adjuvant S-1 therapy for BTC in a multi-institutional trial. METHODS: The inclusion criteria were as follows: histologically proven BTC, Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, R0 or R1 surgery performed, cancer classified as Stage IB to III. Within 10 weeks post-surgery, a 42-day cycle of treatment with S-1 (80 mg/m2/day orally twice daily on days 1-28 of each cycle) was initiated and continued up to 1 year post surgery. The primary endpoint was adjuvant therapy completion rate. The secondary endpoints were toxicities, disease-free survival (DFS), and overall survival (OS). RESULTS: Forty-six patients met the inclusion criteria of whom 19 had extrahepatic cholangiocarcinoma, 10 had gallbladder carcinoma, 9 had ampullary carcinoma, and 8 had intrahepatic cholangiocarcinoma. Overall, 25 patients completed adjuvant chemotherapy, with a 54.3% completion rate while the completion rate without recurrence during the 1 year administration was 62.5%. Seven patients (15%) experienced adverse events (grade 3/4). The median number of courses administered was 7.5. Thirteen patients needed dose reduction or temporary therapy withdrawal. OS and DFS rates at 1/2 years were 91.2/80.0% and 84.3/77.2%, respectively. Among patients who were administered more than 3 courses of S-1, only one patient discontinued because of adverse events. CONCLUSIONS: One-year administration of adjuvant S-1 therapy for resected BTC was feasible and may be a promising treatment for those with resected BTC. Now, a randomized trial to determine the optimal duration of S-1 is ongoing. TRIAL REGISTRATION: UMIN-CTR, UMIN000009029. Registered 5 October 2012-Retrospectively registered, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000009347.

Efficacy and safety of preoperative 5-fluorouracil, cisplatin, and mitomycin C in combination with radiotherapy in patients with resectable and borderline resectable pancreatic cancer: a long-term follow-up study.

BACKGROUND: We aimed to evaluate the efficacy and safety of 5-fluorouracil-based neoadjuvant chemoradiotherapy (NACRT) in patients with resectable/borderline resectable pancreatic ductal adenocarcinoma (PDAC). METHODS: This retrospective study investigated the clinicopathological features and > 5-year survival of patients with T3/T4 PDAC who underwent NACRT at our institute between 2003 and 2012. RESULTS: Seventeen resectable and eight borderline resectable patients were included. The protocol treatment completion and resection rates were 92.0% and 68.0%, respectively. Two patients failed to complete chemotherapy owing to cholangitis or anorexia. Common grade 3 toxicities included anorexia (12%), neutropenia (4%), thrombocytopenia (4%), anemia (4%), and leukopenia (12%). Pathologically negative margins were achieved in 94.1% of patients who underwent pancreatectomy. Pathological response according to Evans' classification was grade IIA in 10 patients (58.8%), IIB in 5 patients (29.4%), and IV in 2 patients (11.8%). Postoperative pancreatic fistulas were observed in four patients (23.5%), delayed gastric emptying in one patient (5.9%), and other operative morbidities in four patients (23.5%). The 1-, 2-, 5-, and 10-year overall survival rates were 73.9%, 60.9%, 60.9%, and 39.1%, respectively (median follow-up period, 80.3 months). CONCLUSIONS: NACRT is tolerable and beneficial for resectable/borderline resectable PDAC, even in the long-term.

Clinical predictive factors of long-term survival after curative resection of pancreatic cancer: a retrospective study.

Pancreatic ductal adenocarcinoma (PDAC) continues to have the poorest prognosis of all gastrointestinal malignancies, even after the tumor has been completely resected. However, only a proportion of patients achieve 5-year survival after resection. The factors predictive of achieving 5-year survival remain unclear. The aim of this study was to investigate the pre- and postoperative clinicopathological characteristics of PDAC patients with a >5-year survival after curative resection. We retrospectively reviewed patients who underwent pancreatectomy for PDAC between January 1995 and December 2011. Logistic regression analysis was performed to determine the predictive factors for 5-year survival. One hundred and fifty-one patients were enrolled, including 38 patients with 5-year survival (actual 5-year survival rate, 25.2%). The independent preoperative factors predictive of achieving 5-year survival included serum albumin levels (odds ratio [OR]: 5.06, 95.0% confidence interval [CI]: 1.49-17.19; P = 0.009) and neoadjuvant chemoradiotherapy (OR: 3.02, 95.0% CI: 1.00-9.08; P = 0.049). Venous infiltration (OR: 2.99, 95.0% CI: 1.09-8.25; P = 0.034), liver recurrence (OR: 0.17, 95.0% CI: 0.04-0.69; P = 0.013), and perioperative portal vein infusion chemotherapy (OR: 3.06, 95.0% CI: 1.09-8.25; P = 0.028) were found to be independent postoperative predictive factors for achieving 5-year survival. Serum albumin levels could be a biomarker for predicting the prognosis of PDAC patients after curative resection. Liver recurrence and perioperative portal vein infusion chemotherapy were independent postoperative factors, suggesting that perioperative portal vein infusion chemotherapy could be promising for improving the survival rate of PDAC patients after curative resection.

Development of a novel mouse model of hepatocellular carcinoma with nonalcoholic steatohepatitis using a high-fat, choline-deficient diet and intraperitoneal injection of diethylnitrosamine.

BACKGROUND: The incidence of hepatocellular carcinoma with nonalcoholic steatohepatitis is increasing, and its clinicopathological features are well established. Several animal models of nonalcoholic steatohepatitis have been developed to facilitate its study; however, few fully recapitulate all its clinical features, which include insulin resistance, inflammation, fibrosis, and carcinogenesis. Moreover, these models require a relatively long time to produce hepatocellular carcinoma reliably. The aim of this study was to develop a mouse model of hepatocellular carcinoma with nonalcoholic steatohepatitis that develops quickly and reflects all clinically relevant features. METHODS: Three-week-old C57BL/6J male mice were fed either a standard diet (MF) or a choline-deficient, high-fat diet (HFCD). The mice in the MF + diethylnitrosamine (DEN) and HFCD + DEN groups received a one-time intraperitoneal injection of DEN at the start of the respective feeding protocols. RESULTS: The mice in the HFCD and HFCD + DEN groups developed obesity early in the experiment and insulin resistance after 12 weeks. Triglyceride levels peaked at 8 weeks for all four groups and decreased thereafter. Alanine aminotransferase levels increased every 4 weeks, with the HFCD and HFCD + DEN groups showing remarkably high levels; the HFCD + DEN group presented the highest incidence of nonalcoholic steatohepatitis. The levels of fibrosis and steatosis varied, but they tended to increase every 4 weeks in the HFCD and HFCD + DEN groups. Computed tomography scans indicated that all the HFCD + DEN mice developed hepatic tumors from 20 weeks, some of which were glutamine synthetase-positive. CONCLUSIONS: The nonalcoholic steatohepatitis-hepatocellular carcinoma model we describe here is simple to establish, results in rapid tumor formation, and recapitulates most of the key features of nonalcoholic steatohepatitis. It could therefore facilitate further studies of the development, oncogenic potential, diagnosis, and treatment of this condition.

Mass-forming type 1 autoimmune pancreatitis mimicking pancreatic cancer.

We reported three cases of mass-forming type 1 autoimmune pancreatitis (AIP) that were preoperatively suspected to be pancreatic cancer, and reviewed their clinicopathological features. Radiological findings in the patients revealed hypoattenuating masses in the early phase or a stricture of the main pancreatic duct with upstream dilatation, which was consistent with the diagnosis of pancreatic cancer. Histopathologically, the lesions were well demarcated and met all diagnostic criteria for immunoglobulin G4 (IgG4)-related AIP, including the presence of periductal lymphoplasmacytic infiltration, obliterative phlebitis, storiform fibrosis and abundant IgG4-positive plasma cells. However, the adjacent uninvolved pancreatic duct and lobular structures were well preserved. And in all patients, none or some of the aforementioned characteristics were observed. We suggest that some cases of focal AIP may progress to more severe grades and exhibit mass formation, although remaining localized. These focal cases of AIP are difficult to distinguish from pancreatic cancer. To our knowledge, this report is the first to present a histopathological comparison of mass-forming AIP with the adjacent uninvolved pancreatic tissues.

Successful resolution of a hemorrhagic pancreatic pseudocyst ruptured into the stomach complicating obstructive pancreatitis due to pancreatic cancer: a case report.

BACKGROUND: Hematemesis is uncommon as an initial presenting symptom in pancreatic cancer. We present herein a case of a pseudoaneurysm that ruptured and fistulized into the stomach. The pseudoaneurysm was secondary to a pancreatic pseudocyst complicating obstructive pancreatitis due to pancreatic cancer. The patient was successfully treated using trans-arterial embolization followed by curative surgery. CASE PRESENTATION: A 61-year-old man presented to the emergency room with hematemesis. Laboratory examinations revealed a low level of hemoglobin (5.0 g/dl). The patient had presented to another hospital due to hematemesis 1 month before presenting to our hospital. A low-density mass in the pancreatic body with dilatation of the distal main pancreatic duct and a pseudocyst in the pancreatic tail had been observed by radiology at the previous hospital. Further investigation had been planned. Abdominal computed tomography on admission to our hospital demonstrated a pseudoaneurysm in close contact with the wall of the pseudocyst of the pancreatic tail, compressing the stomach. The pseudoaneurysm had not been detected by abdominal computed tomography at the previous hospital. Emergency selective angiography revealed that the pseudoaneurysm arose from the left gastroepiploic artery branching from the splenic artery. Trans-arterial embolization of the left gastroepiploic artery through the splenic artery was successfully performed. Elective distal pancreatectomy and splenectomy with regional lymph node dissection combined with partial resection of the stomach was performed 3 weeks after coil embolization. Pathological examination revealed a moderately differentiated tubular adenocarcinoma in the pancreatic body with regional lymph node metastasis and revealed the pseudoaneurysm rupturing into the pancreatic pseudocyst. The patient has experienced no tumor recurrence or metastasis during 1 year of follow-up. CONCLUSIONS: Spontaneous rupture of a pseudoaneurysm is a rare and potentially lethal complication of a pancreatic pseudocyst. Most affected patients have a history of alcoholism and suffer from acute or chronic pancreatitis. To our knowledge, this is the first reported case of a hemorrhagic pancreatic pseudocyst complicating obstructive pancreatitis due to pancreatic cancer.

Adenosquamous carcinoma of the ampulla of Vater: a case report and literature review.

BACKGROUND: Adenosquamous carcinoma of the ampulla of Vater is extremely rare, and its clinicopathological features are limited and described in few previous case reports. Here, we report curative resection of adenosquamous carcinoma of the ampulla of Vater at an early stage. CASE PRESENTATION: An 81-year-old woman was referred to our hospital for investigation of the frequent elevation of hepatic and biliary enzymes and dilatation of the intrahepatic bile ducts. Preoperative examinations revealed an exposed reddish tumor in the ampulla of Vater, which was diagnosed on biopsy to be adenocarcinoma with squamous cell carcinoma component. Pylorus-preserving pancreaticoduodenectomy with regional lymph node dissection was performed. Pathological examinations revealed the presence of two malignant components in the lesion, including poorly differentiated tubular adenocarcinoma and squamous cell carcinoma, without invasion beyond the sphincter of Oddi or into the duodenal submucosa. These squamous cell carcinoma and adenocarcinoma components in the tumor comprised approximately 30 and 70% of the lesion, respectively. No metastasis into regional lymph nodes was observed, and the patient experienced no tumor recurrence or metastasis until 20 months after surgery. CONCLUSION: We identified only six reported cases of adenosquamous carcinoma of the ampulla of Vater in the English literature, and all of these patients died of recurrence within 14 months after surgery. To the best of our knowledge, this is the first report of adenosquamous carcinoma of the ampulla of Vater that was curatively resected at an early stage. Although more number of studies on clinicopathological findings are required to determine the appropriate surgical indication, we suggest that surgery remains the mainstay therapy for adenosquamous carcinoma of the ampulla of Vater detected at an early stage.

Two Cases of Pathological Complete Response to Neoadjuvant Chemoradiation Therapy in Pancreatic Cancer.

Neoadjuvant chemoradiation therapy (NACRT) is increasingly used in patients with a potentially or borderline resectable pancreatic ductal adenocarcinoma (PDA) and it has been shown to improve survival and reduce locoregional metastatic disease. It is rare for patients with PDA to have a pathological complete response (pCR) to NACRT, but such patients reportedly have a good prognosis. We report the clinicopathological findings of two cases of pCR to NACRT in PDA. Both patients underwent pancreatectomy after NACRT (5-fluorouracil, mitomycin C, cisplatin, and radiation). Neither had residual invasive carcinoma and both showed extensive fibrotic regions with several ducts regarded as having pancreatic intraepithelial neoplasia 3/carcinoma in situ in their post-therapy specimens. It is noteworthy that both patients had a history of a second primary cancer. They both had comparatively good outcomes: one lived for 9 years after the initial pancreatectomy and the other is still alive without recurrence after 2 years.

Long-term complete response of advanced hepatocellular carcinoma treated with multidisciplinary therapy including reduced dose of sorafenib: case report and review of the literature.

An 83-year-old man underwent computed tomography during a routine check-up due to a history of surgical treatment for pancreatic cancer. Two tumors were detected in the anterior segment of the liver. A needle biopsy of the larger tumor was performed, and pathological examination showed that the tumor was a poorly differentiated hepatocellular carcinoma. Resection was not performed considering the patient's poor physical condition. Thus, transcatheter arterial chemoembolization and radiofrequency ablation of the tumors were performed. Three months later, residual tumor of the larger lesion and multiple pulmonary metastases were detected. This time, continuous hepatic arterial infusion chemotherapy was performed. Although the pulmonary metastases markedly reduced, tumor thrombi appeared in the right portal vein on computed tomography. Finally, sorafenib was administered, which led to disappearance of the tumor thrombi and no other signs of recurrence 8 months after initiation of sorafenib on computed tomography. Although sorafenib administration has continued at reduced doses of 200 mg per day or less due to hypertension, complete response has persisted for the past 34 months. It is noteworthy that sorafenib has been given at reduced doses, but a long-term complete response is maintained in a patient who had portal tumor thrombi and distant metastasis. Herein, we present this rare case of advanced hepatocellular carcinoma controlled with reduced doses of sorafenib following multidisciplinary therapy, describe our single center experience with sorafenib use in patients with hepatocellular carcinoma, and review previous reports that focused on dose reduction of sorafenib.

Phase I pilot study of Wilms tumor gene 1 peptide-pulsed dendritic cell vaccination combined with gemcitabine in pancreatic cancer.

This study aimed to evaluate the feasibility of and immune response to Wilms tumor gene 1 (WT1) peptide-pulsed dendritic cell vaccination combined with gemcitabine (DCGEM) as a first-line therapy among patients with advanced pancreatic cancer. Ten HLA-A*2402 patients were treated with WT1 peptide-pulsed DC vaccination (1 × 10(7) cells) on days 8 and 22 and gemcitabine (1000 mg/m(2) ) on days 1, 8 and 15. Induction of a WT1-specific immune response was evaluated using the delayed-type hypersensitivity (DTH) skin test, interferon-γ enzyme-linked immunospot and HLA tetramer assays, along with assays for various immunological factors. DCGEM was well-tolerated, and the relative dose intensity of gemcitabine was 87%. Disease control associated with a low neutrophil/lymphocyte ratio was observed in all three patients with DTH positivity; it was also correlated with a low percentage of granulocytic myeloid derived suppressor cells in the pretreatment peripheral blood (P = 0.017). Patients with liver metastases and high levels of inflammatory markers such as C-reactive protein and interleukin-8 (IL-8) showed poor survival even though a WT1-specific immune response was induced in them. WT1 peptide-pulsed DCGEM is feasible and effective for inducing anti-tumor T-cell responses. Our results support future investigations for pancreatic cancer patients with non-liver metastases and favorable immunological conditions. This trial was registered with the University hospital Medical Information Network (UMIN) Clinical Trials Registry (http://www.umin.ac.jp/ctr/ number: UMIN-000004855).

Concomitant pancreatic endocrine neoplasm and intraductal papillary mucinous neoplasm: a case report and literature review.

We report a case of concomitant pancreatic endocrine neoplasm (PEN) and intraductal papillary mucinous neoplasm (IPMN). A 74-year-old man had been followed-up for mixed-type IPMN for 10 years. Recent magnetic resonance images revealed an increase in size of the branch duct IPMN in the pancreas head, while the dilation of the main pancreatic duct showed minimal change. Although contrast-enhanced computed tomography and magnetic resonance imaging did not reveal any nodules in the branch duct IPMN, endoscopic ultrasound indicated a suspected nodule in the IPMN. A malignancy in the branch duct IPMN was suspected and we performed pylorus-preserving pancreatoduodenectomy with lymphadenectomy. The resected specimen contained a cystic lesion, 10 x 10 mm in diameter, in the head of the pancreas. Histological examination revealed that the dilated main pancreatic duct and the branch ducts were composed of intraductal papillary mucinous adenoma with mild atypia. No evidence of carcinoma was detected in the specimen. Incidentally, a 3-mm nodule consisting of small neuroendocrine cells was found in the main pancreatic duct. The cells demonstrated positive staining for chromogranin A, synaptophysin, and glucagon but negative staining for insulin and somatostatin. Therefore, the 3-mm nodule was diagnosed as a PEN. Since the mitotic count per 10 high-power fields was less than 2 and the Ki-67 index was less than 2%, the PEN was pathologically classified as low-grade (G1) according to the 2010 World Health Organization (WHO) criteria. Herein, we review the case and relevant studies in the literature and discuss issues related to the synchronous occurrence of the relatively rare tumors, PEN and IPMN.

Mesenchymal stem cells regulate epithelial-mesenchymal transition and tumor progression of pancreatic cancer cells.

Cancer-associated fibroblasts contribute to cancer progression that is caused by epithelial-mesenchymal transition (EMT). Recently, mesenchymal stem cells (MSCs) were found to be the major candidate involved in the development of tumor-promoting cancer stroma. Here we report that α-smooth muscle actin-positive myofibroblast-like cells originating from MSCs contribute to inducing EMT in side population cells of pancreatic cancer. More importantly, MSC-derived myofibroblasts function to maintain tumor-initiating stem cell-like characteristics, including augmenting expression levels of various stemness-associated genes, enhancing sphere- forming activity, promoting tumor formation in a mouse xenograft model, and showing resistance to anticancer drugs. Furthermore, both γ-secretase inhibitor and siRNA directed against Jagged-1 attenuated MSC-associated E-cadherin suppression and sphere formation in pancreatic cancer side population cells. Thus, our results suggest that MSC-derived myofibroblasts play important roles in regulating EMT and tumor-initiating stem cell-like properties of pancreatic cancer cells through an intermediating Notch signal.

Combined effect of dehydroxymethylepoxyquinomicin and gemcitabine in a mouse model of liver metastasis of pancreatic cancer.

Activation of nuclear factor-κB (NF-κB) has been implicated in metastasis of pancreatic cancer. We investigated the effects of the novel NF-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) on the inhibition of liver metastasis of pancreatic cancer in a mouse model of clinical liver metastasis. Nude mice were xenografted by intra-portal-vein injection with the human pancreatic adenocarcinomas cell line AsPC-1 via small laparotomy. Mice were treated with DHMEQ and gemcitabine (GEM), alone or in combination. The combination of GEM + DHMEQ showed a stronger antitumor effect than either monotherapy. Apoptosis induction in the metastatic foci was greatest in the DHMEQ + GEM group. Significant reductions in the numbers of neovessels were also seen in the DHMEQ and/or GEM groups. Cell growth inhibition assays revealed no synergistic effect of combination therapy, although each monotherapy had an individual cytotoxic effect. Combination therapy produced the greatest inhibition of tumor cell invasiveness in chemoinvasion assay. In addition, combination therapy significantly down-regulated the expression level of matrix metalloproteinase (MMP)-9 mRNA in AsPC-1 cells. DHMEQ also markedly down-regulated interleukin-8 and MMP-9, while GEM caused moderate down-regulation of vascular endothelial growth factor in metastatic foci, demonstrated by quantitative reverse transcription-polymerase chain reaction. These results demonstrate that DHMEQ can exert anti-tumor effects by inhibiting angiogenesis and tumor cell invasion, and by inducing apoptosis. Combination therapy with DHMEQ and GEM also showed potential efficacy. DHMEQ is a promising drug for the treatment of advanced pancreatic cancer.

Proposed indications for limited resection of early ampulla of Vater carcinoma: clinico-histopathological criteria to confirm cure.

BACKGROUND: Limited resection is reserved for patients with high operative risk or benign adenomas. We aimed to define indications for limited resection of early ampulla of Vater carcinoma with curative intent through detailed preoperative examinations and histopathological evaluations. METHODS: We performed a retrospective cohort study of all consecutive Japanese patients who underwent resection for ampulla of Vater neoplasms at our hospital from 1986 to 2010. RESULTS: A total of 75 patients were identified. Moderately/poorly differentiated histology, lympho-vascular/perineural invasion, and duodenal/pancreatic invasion were significant risk factors for lymph node metastases. Macroscopically, non-exposed protruded- or ulcerative-type disease did not correlate directly with lymph node metastases; however, these tumor types were associated with other invasive features. In a subset of early carcinomas fulfilling the conditions of exposed protruded adenoma or papillary/well-differentiated adenocarcinoma determined by endoscopic biopsy, negative duodenal invasion determined by endoscopic ultrasonography, no tumor infiltration into the pancreatic duct determined by intraductal ultrasound, and diameter of the pancreatic duct ≤3 mm determined by endoscopic retrograde cholangiopancreatography (N = 11), the incidence of lymph node metastasis and tumor infiltration into the pancreatic duct was 0%. CONCLUSION: Strictly selected patients with early ampulla of Vater carcinomas may benefit from limited resection if the resected specimen is evaluated to confirm all histopathological criteria.

Current status of endoscopic papillary balloon dilation for the treatment of bile duct stones.

BACKGROUND/PURPOSE: While endoscopic sphincterotomy (EST) is performed worldwide for the removal of common bile duct stones, many biliary endoscopists hesitate to regard endoscopic papillary balloon dilation (EPBD) as a standard procedure for treatment. Therefore, the aim of this review is to re-evaluate the status of EPBD for the treatment of common bile duct stones. RESULTS: A major benefit of EPBD is preservation of papillary function, which is not complete but may be greater than that after EST. The disadvantages of EPBD compared with EST are that EPBD is difficult to use for the removal of larger stones because of the smaller biliary opening, it requires more frequent use of mechanical lithotripsy, and it is associated with a higher incidence of pancreatitis, although the risks of bleeding and perforation are low. Since the biliary sphincter is easily dilated with a balloon catheter, EPBD may be effective for patients with anatomic anomalies, such as after gastric bypass surgery or in the presence of a periampullary diverticulum. No standard procedure exists to reduce the risk of acute pancreatitis with EPBD. CONCLUSION: EPBD is feasible, however, we must pursue less hazardous techniques of papillary balloon dilation. Furthermore, we must understand the benefits and limitations of EPBD and determine whether it could provide clinical benefits for long-term complications.