Katsunobu Tawada

Phase II Study of Oral S-1 and Concurrent Radiotherapy in Patients With Unresectable Locally Advanced Pancreatic Cancer

PURPOSE S-1 is an oral fluoropyrimidine derivative that has demonstrated favorable antitumor activity in patients with metastatic pancreatic cancer. The aim of this study was to evaluate safety and efficacy of S-1 and concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer. METHODS AND MATERIALS Patients with histopathologically proven, unresectable, locally advanced pancreatic cancer were eligible. Radiotherapy was delivered in 1.8 Gy daily fractions to a total dose of 50.4 Gy over 5.5 weeks. S-1 was administered orally twice a day at a dose of 80 mg/m(2)/day from day 1 to 14 and 22 to 35. Two weeks after the completion of chemoradiotherapy, maintenance chemotherapy with S-1 was administered for 28 days every 6 weeks until progression. RESULTS Thirty-four patients were enrolled in this study. The most common Grade 3 toxicities during chemoradiotherapy were anorexia (24%) and nausea (12%). The overall response rate was 41% (95% confidence interval, 25%-58%) and overall disease control rate (partial response plus stable disease) was 97%. More than 50% decrease in serum CA 19-9 was seen in 27 of 29 evaluable patients (93%). The median progression-free survival was 8.7 months. The median overall survival and 1-year survival rate were 16.8 months and 70.6%, respectively. CONCLUSIONS Oral S-1 and concurrent radiotherapy exerted a promising antitumor activity with acceptable toxicity in patients with locally advanced pancreatic cancer. This combination therapy seems to be an attractive alternative to conventional chemoradiotherapy using 5-fluorouracil infusion.

A long-term controlled trial of endoscopic pancreatic stenting for treatment of main pancreatic duct stricture in chronic pancreatitis.

BACKGROUND/AIMS Endoscopic pancreatic stenting (EPS) has been used to treat main pancreatic duct (MPD) stricture in chronic pancreatitis (CP), with favourable reported results. However, most studies were retrospective and uncontrolled. We conducted a longterm prospective controlled study of EPS for treatment of MPD stricture in CP. METHODOLOGY Consecutive patients with CP were treated to remove pancreatic stones by extracorporeal shock-wave lithotripsy or endoscopic basket extraction. After treatment, 41 patients were enrolled in the study upon meeting the criteria of complete removal of stones, pain relief after the treatment, and dominant stricture of the MPD. Twenty patients chose EPS, while 22 control patients did not. We compared recurrence of pain and pancreatic function between groups for over 3 years of follow-up. RESULTS The mean follow-up period was 62.5 ± 20.9 months. Pain recurred in 15% of EPS patients (3/20) and in 50.0% of control patients (11/22), a significant difference (p<0.05). Progression of exocrine insufficiency in the EPS group was significantly slower than in the control group (p<0.05), while endocrine function showed no difference between groups. CONCLUSIONS EPS reduced pain recurrence and slowed down the progression of exocrine insufficiency in CP patients with MPD stricture.

Comparison of branch duct and main pancreatic duct mural nodules in intraductal papillary mucinous neoplasm.

1. Van den Bruel A, Maes A, De Potter T, et al. Clinical relevance of thyroid fluorodeoxyglucose-whole body positron emission tomography incidentaloma. J Clin Endocrinol Metab. 2002;87:1517Y1520. 2. Frilling A, Tecklenborg K, Weber F, et al. Importance of adrenal incidentaloma in patients with a history of malignancy. Surgery. 2004;136:1289Y1296. 3. Maeda A, Uesaka K, Matsunaga K, et al. Metastatic tumors of the pancreas. Pancreas. 2008;37:234Y236. 4. Konstantinidis IT, Dursun A, Zheng H, et al. Metastatic tumors in the pancreas in the modern era. J Am Coll Surg. 2010;211:749Y753. 5. Nguyen VX, Nguyen CC, Nguyen BD. F-FDG PET/CT imaging of the pancreas: spectrum of diseases. JOP. 2011;12:557Y566. 6. Bruzoni M, Johnston E, Sasson AR. Pancreatic incidentalomas: clinical and pathologic spectrum. Am J Surg. 2008;195:329Y332. 7. Lahat G, Ben Haim M, Nachmany I, et al. Pancreatic incidentalomas: high rate of potentially malignant tumors. J Am Coll Surg. 2009;209(3):313Y319. 8. Majhail NS, Urbain JL, Albani JM, et al. F-18 fluorodeoxyglucose positron emission tomography in the evaluation of distant metastases from renal cell carcinoma. J Clin Oncol. 2003;21:3995Y4000.

Transpancreatic precut papillotomy in patients with difficulty in selective biliary cannulation.

BACKGROUND/AIMS Transpancreatic precut papillotomy (TPPP) is considered as an effective method in patients with difficulty in selective biliary cannulation. However, the use of placing a pancreatic duct stent as a measure against post-ERCP pancreatitis has not been clarified. Here we examine the methods of implementing TPPP safely. METHODOLOGY TPPP was conducted on patients with difficulty in selective biliary cannulation. The incidence of pancreatitis was compared between group P(+) in which a spontaneous dislodgement type pancreatic duct stent was placed and group P(-) without a duct stent. RESULTS The success rate of biliary cannulation was 83.3% at the first ERCP and finally 93.9%. Post-ERCP pancreatitis was observed in 9.09% of patients. The success rate of placement of pancreatic duct stent in the P(+) group was 100%. The incidence of pancreatitis in the P(+) group was 4.1% and the mean post-ERCP amylase level was 340.071 ±420.035IU/L. The incidence of pancreatitis in the P(-) group was 23.5% and the mean post-ERCP amylase level was 661.250±772.285IU/L. The incidence of pancreatitis and the mean post-ERCP amylase level were significantly lower in the P(+) group (p<0.05). CONCLUSIONS In the patients with difficulty in selective biliary cannulation, TPPP is a useful technique for biliary cannulation. The placement of a spontaneous dislodgement type pancreatic duct stent after TPPP may be useful for prevention of post-ERCP pancreatitis.

Current situation of endoscopic treatment for common bile duct stones.

BACKGROUND/AIMS The progression of endoscopy and devices as well as newly developed treatment methods have enabled endoscopic lithotomy. In this study, we examined to what degree is it possible to endoscopically treat patients who are diagnosed as having common bile duct stones. METHODOLOGY Lithotomy was conducted using a backward side-viewing endoscope for patients without surgical history of upper gastrointestinal tract and patients with stomach reconstructed with Billroth-I method, using an ordinary endoscope for patients with stomach reconstructed with Billroth-II method (Bil-II) and using a double balloon endoscope for patients with difficulty in reaching the papilla or patients of Roux-en-Y anastomosis (R-Y). As for treatment methods, we selected endoscopic sphincterotomy as the first choice for papilla treatment and selected endoscopic papillary balloon dilation for patients with bleeding tendency or patients of Bil-II or R-Y. For patients with multiple stones or giant stones, lithotripsy was selected depending on judgment of the endoscopist. RESULTS Endoscopic complete lithotomy was successful in 97.7% (168/172). An accidental disease was observed in 2.9% (5/172). In one patient with the perforated gastrointestinal tract, a surgery was performed but others were mild. CONCLUSIONS Common bile duct stones can be endoscopically treated safely with high rate.

Quantitative Analysis of Vascular Endothelial Growth Factor in Liver Metastases from Pancreatic Carcinoma as a Predictor of Chemotherapeutic Effect and Prognosis

Purpose: In pancreatic carcinoma, vascular endothelial growth factor (VEGF) expression at the primary site has been suggested to be a prognostic parameter. We quantitatively analyzed VEGF expression in liver metastases from pancreatic carcinoma and examined the correlation among VEGF expression in liver metastases, clinicopathologic factors, and clinical outcome. Experimental Design: The subjects consisted of 23 patients with pancreatic adenocarcinoma who had liver metastases and were treated with S-1 and gemcitabine as the first-line treatment. VEGF expression was quantitated by enzyme immunoassay in biopsy specimens of liver metastases and nontumorous liver tissue, and in plasma. In 10 of the 23 patients, VEGF expression was also quantitated in biopsy specimens of the primary pancreatic tumor. All samples were collected before treatment. Results: The VEGF level in nontumorous liver tissue was 36.6 ± 10.0 pg/mg protein versus 376.8 ± 106.1 pg/mg protein in liver metastases (P = 0.0016). Pretreatment VEGF levels in plasma and in primary pancreatic carcinoma did not correlate with VEGF levels in the corresponding liver metastases. The median VEGF level in liver metastases (138.9 pg/mg protein) was used as the cutoff value between high and low VEGF expression in liver metastases. Patients showing high VEGF expression had a significantly longer progression-free survival and overall survival than patients showing low VEGF expression in liver metastases (P = 0.0219 and P = 0.0074, respectively). Conclusions: Evaluation of VEGF levels in liver metastases might be useful in assessing the prognosis of patients with metastatic pancreatic carcinoma who are under systemic chemotherapy.

Hypertonic saline-epinephrine local injection therapy for post-endoscopic sphincterotomy bleeding: removal of blood clots using pure ethanol local injection.

Purpose: Bleeding following endoscopic sphincterotomy (EST) is a rare but unavoidable complication of the procedure. We routinely perform local injection of hypertonic saline-epinephrine (HSE) for the treatment of post-EST bleeding. Any blood clot is removed only by irrigation with water after local injection of pure ethanol into the blood clot to cause crusting. We evaluated the usefulness of this treatment method. Methods: Subjects were 8 patients (1.2%) with post-EST bleeding requiring hemostatic intervention among 682 patients undergoing EST. After determination of the bleeding point, local injection of HSE was performed. When an adherent blood clot was present, pure ethanol was injected into the blood clot and then irrigation with water was performed to remove the blood clot. Results: Endoscopic hemostasis was successfully achieved in all the 8 patients (100%). In 4 patients (50%), the adherent blood clots were successfully removed only with pure ethanol local injection into the blood clot followed by irrigation with water. No complications of the hemostatic procedure occurred in any patients. Conclusions: This study indicated that hemostasis with HSE local injection can be safe and useful for the treatment of post-EST bleeding, and also that blood clot removal with pure ethanol local injection can be useful.

Abstract A39: The exploration of novel strategy for treatment of pancreactic ductal adenocarcinoma targeting tumor microenvironment with multi-kinase inhibitors

Background and Aim: Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease in humans. Previously, we have reported a genetically engineered mouse PDAC progression model which has pancreatic-specific transforming growth factor-beta receptor type II knockout in the context of Kras activation (Ijichi H, et al 2006). This model shows PDAC with 100% penetrance and recapitulates the signature of human PDAC well. Using this model, we explored novel treatment for PDAC. Materials and Methods: At first, to investigate whether the mice model is suitable for the drug screening, the mice were treated with gemcitabine (12.5 mg/kg) by intraperitoneal (i.p.) injection or S-1 (8.4 mg/kg) per oral, which are the standard drug for human PDAC. To the next, for single agent treatment, mice were treated orally 6 times a week with vehicle (0.5 % carboxymethyl cellulose, CMC), sunitinib (40 mg/kg), and axitinib (30mg/kg), both of which are multikinase inhibitors targeting vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR) from the 3 weeks of age. For combined agent experiment, mice were treated orally with vehicle (0.5 % CMC) or axitinib from the 3 weeks of age and also treated with saline or gemcitabine, i.p. twice a week from the 4 weeks of age. Treatment continued until 8 weeks of age. Moreover, for the survival analysis, the drug treatment was continued until the mice became distressed according to the same schedule stated above. In vivo anti-tumor effect and survival time were assessed. Immunostaining of tumor tissue for caspase 3, Ki67, CD31, F4/80 and VEGF was performed. Azan staining also performed for the assessment of fibrosis in the tumor. Results: Gemcitabine and S-1 showed antiproliferative effect and prolonged overall survival of these mice compared to control, as well as human cases. Median survival time of single use of axtinib and sunitinib group was significantly longer (p <0.01) than that of control group. Axitinib and sunitinib group showed significantly stronger anti-tumor effect in vivo (p <0.01). In the combined treatment experiment, gemcitabine plus axitinib-treated group showed statistically significant longer survival and more anti-tumor effect than that of gemcitabine or axtinib alone-treated group (p <0.01). Axitinib and sunitinib group showed significantly higher caspase 3 stainng and lower Ki67 staining than that of control (p <0.01). Microvessel density (CD 31 staining) of axitinib and sunitinib group was significantly lower than that of control (p <0.01). F4/80 staining was significantly lower in axitinib and sunitinib-treated group than that of control (p <0.05). VEGF expression of axitinib and sunitinib group was significantly lower than that of control a (p <0.001). Azan staining showed significantly lower fibrosis in axitinib and sunitinib-treated group compared to control (p <0.01). Conclusion: Targeting not only cancer cells but also tumor microenvironment, such as angiogenesis, infiltration of immune cells, and fibrosis, with the use of multikinase inhibitors in addition to gemcitabine, may be a promising therapeutics for PDAC.