Motoki Miyazawa

Early Removal of Prophylactic Drains Reduces the Risk of Intra-abdominal Infections in Patients With Pancreatic Head Resection: Prospective Study for 104 Consecutive Patients

Objective:The aim of this study was designed to determine whether the period of drain insertion influences the incidence of postoperative complications. Background Data:The significance of prophylactic drains after pancreatic head resection is still controversial. No report discusses the association of the period of drain insertion and postoperative complications. Methods:A total of 104 consecutive patients who underwent pancreatic head resection were enrolled in this study. To assess the value of prophylactic drains, we prospectively assigned the patients into 2 groups: group I underwent resection from January 2000 to January 2002 (n = 52, drain to be removed on postoperative day 8); group II underwent resection from February 2002 to December 2004 (n = 52, drain to be removed on postoperative day 4). Postoperative complications in the 2 groups were compared. Results:The rate of pancreatic fistula was significantly lower in group II (3.6%) than in group I (23%) (P = 0.0038). The rate of intra-abdominal infections, including intra-abdominal abscess and infected intra-abdominal collections, was significantly reduced in group II (7.7%) compared with group I (38%) (P = 0.0003). Eighteen of 52 (34.6%) patients in group I had an inserted drain beyond 8 days, whereas only 2 of 52 (3.7%) patients in group II had an inserted drain beyond 4 days (P = 0.0002). Cultures of drainage fluid were positive in 16 of 52 (30.8%) patients in group I, and in 2 of 52 (3.7%) patients in group II (P = 0.0002). Intraoperative bleeding (>1500 mL), operative time (>420 minutes, and the period of drain insertion were significant risk factors for intra-abdominal infections (P = 0.043, 0.025, 0.0003, respectively). The period of drain insertion was the only independent risk factor for intra-abdominal infections by multivariate analysis (odds ratio, 6.7). Conclusion:Drain removal on postoperative day 4 was shown to be an independent factor in reducing the incidence of complications with pancreatic head resection, including intra-abdominal infections.

Pylorus Ring Resection Reduces Delayed Gastric Emptying in Patients Undergoing Pancreatoduodenectomy: A Prospective, Randomized, Controlled Trial of Pylorus-Resecting Versus Pylorus-Preserving Pancreatoduodenectomy

Objective:To determine in a prospective randomized controlled trial (RCT) whether pylorus-resecting pancreatoduodenectomy (PrPD) with preservation of nearly the entire stomach reduces the incidence of delayed gastric emptying (DGE) compared with pylorus-preserving pancreatoduodenectomy (PpPD). Background:Several RCTs have compared PpPD and conventional pancreatoduodenectomy with antrectomy. However, no study has reported the difference between PrPD with preservation of nearly the entire stomach and PpPD. Methods:One hundred thirty patients were randomized to preservation of the pylorus ring (PpPD) or to resection of the pylorus ring with preservation of nearly the entire stomach (PrPD). This RCT was registered at clinicaltrials.gov NCT00639314. Results:The incidence of DGE was 4.5% in PrPD and 17.2% in PpPD, a significant difference. Delayed gastric emptying was classified into 3 categories proposed by the International Study Group of Pancreatic Surgery. The proposed clinical grading classified 11 cases of DGE in PpPD into grades A (n = 6), B (n = 5), and C (n = 0) and one case in PrPD into each of the 3 grades. The time to peak 13CO2 content in the 13C-acetate breath test at 1, 3, and 6 months postoperatively was significantly delayed in PpPD compared with PrPD (34.3 ± 24.6 minutes versus 18.7 ± 11.8 minutes, 26.5 ± 21.1 minutes versus 17.3 ± 11.7 minutes, 26.7 ± 18.8 minutes versus 17.4 ± 13.2 minutes, respectively). Pylorus-resecting pancreatoduodenectomy and PpPD had comparable outcomes for quality of life, weight loss, and nutritional status during a 6-month follow-up period. Conclusion:Pylorus-resecting pancreatoduodenectomy significantly reduces of the incidence of DGE compared with PpPD.

Phase I clinical trial using peptide vaccine for human vascular endothelial growth factor receptor 2 in combination with gemcitabine for patients with advanced pancreatic cancer

Vascular endothelial growth factor receptor 2 (VEGFR2) is an essential factor in tumor angiogenesis and in the growth of pancreatic cancer. Immunotherapy using epitope peptide for VEGFR2 (VEGFR2‐169) that we identified previously is expected to improve the clinical outcome. Therefore, a phase I clinical trial combining of VEGFR2‐169 with gemcitabine was conducted for patients with advanced pancreatic cancer. Patients with metastatic and unresectable pancreatic cancer were eligible for the trial. Gemcitabine was administered at a dose of 1000 mg/m2 on days 1, 8, and 15 in a 28‐day cycle. The VEGFR2‐169 peptide was subcutaneously injected weekly in a dose‐escalation manner (doses of 0.5, 1, and 2 mg/body, six patients/one cohort). Safety and immunological parameters were assessed. No severe adverse effect of grade 4 or higher was observed. Of the 18 patients who completed at least one course of the treatment, 15 (83%) developed immunological reactions at the injection sites. Specific cytotoxic T lymphocytes (CTL) reacting to the VEGFR2‐169 peptide were induced in 11 (61%) of the 18 patients. The disease control rate was 67%, and the median overall survival time was 8.7 months. This combination therapy for pancreatic cancer patients was tolerable at all doses. Peptide‐specific CTL could be induced by the VEGFR2‐169 peptide vaccine at a high rate, even in combination with gemcitabine. From an immunological point of view, the optimal dose for further clinical trials might be 2 mg/body or higher. This trial was registered with ClinicalTrial.gov (no. NCT 00622622). (Cancer Sci 2009)

The carcinoembryonic antigen level in pancreatic juice and mural nodule size are predictors of malignancy for branch duct type intraductal papillary mucinous neoplasms of the pancreas.

Objective:Identification of predictors of malignancy for branch duct type intraductal papillary mucinous neoplasms (IPMN). Background:Main duct type IPMN has been recommended for resection. However, the indications for resection of the branch duct type IPMN have been controversial. Methods:We retrospectively analyzed the clinicopathological factors of 134 patients undergoing resection for branch duct type IPMN, excluding main duct type IPMN, to identify predictors of the malignant behavior of this neoplasm. The cutoff values of tumor size, main pancreatic duct (MPD) size, mural nodule size, and carcinoembryonic antigen (CEA) level in the pancreatic juice obtained during preoperative endoscopic retrograde pancreatography (ERP) were analyzed using receiver–operator characteristic curves. Results:We found 7 significant predictors for malignancy in the branch duct type IPMN in a univariate analysis; jaundice, tumor occupying the pancreatic head, MPD size >5 mm, mural nodule size >5 mm, serum carbohydrate antigen (CA)19–9 level, positive cytology in the pancreatic juice, and CEA level in the pancreatic juice >30 ng/mL. In a multivariate analysis, a mural nodule size >5 mm and a CEA level in the pancreatic juice >30 ng/mL were independent factors associated with malignancy. The positive predictive value of a mural nodule size >5 mm and a CEA level in the pancreatic juice >30 ng/mL was 100%, and the negative predictive value was 96.3%. Conclusions:We identified 2 useful predictive factors for malignancy in branch duct type IPMN; a mural nodule size >5 mm and a CEA level in the pancreatic juice obtained by preoperative ERP >30 ng/mL.

A prospective randomized controlled trial of internal versus external drainage with pancreaticojejunostomy for pancreaticoduodenectomy

BACKGROUND A stent often is placed across the pancreaticojejunostomy. However, there is no report compared between internal drainage and external drainage. METHODS We conducted a prospective randomized trial (NCT00628186 registered at http://ClinicalTrials.gov) with 100 patients who underwent pancreaticoduodenectomy and we compared the effects on postoperative course. RESULTS The incidence of pancreatic fistula according to the International Study Group on Pancreatic Fistula criteria was not different (external, 20%; vs internal, 26%), and the incidence of the other complications was similar between stent types. The median postoperative hospital stay was 21 days (range, 8-163 d) in the internal drainage group, which was shorter than the median stay of 24 days (range, 21-88 d) in the external drainage group (P = .016). CONCLUSIONS Both internal drainage and external drainage were safety devices for pancreaticojejunostomy. Internal drainage simplifies postoperative managements and it might shorten postoperative stay for pancreaticoduodenectomy.

A pancreaticoduodenectomy is acceptable for periampullary tumors in the elderly, even in patients over 80 years of age

BACKGROUND Although the mortality rates for pancreaticoduodenectomy have been reported to be low for periampullary tumors at high-volume centers, postoperative results still remain unclear for elderly patients over 80 years of age. METHODS This was a retrospective study of patients who underwent a pancreaticoduodenectomy and consisted of 335 patients who were treated for periampullary tumors between January 1994 and August 2008. The main outcomes were postoperative complications, mortality, and the length of hospital stay among the elderly patients, and they were analyzed in three groups: elderly patients over 80 years old, septuagenarians, and those under 70 years of age. RESULTS The performance status of elderly patients was lower than that of the patients under 70 (P < 0.05), and the elderly had a higher American Society of Anesthesiologists physical status classification score (P < 0.001) as well as low hemoglobin and serum albumin levels (P < 0.01 and P < 0.001, respectively). The incidence of delayed gastric emptying in the elderly was higher; however, there was no significant difference. The other outcomes in the elderly group were similar to those of the other groups. CONCLUSIONS Pancreaticoduodenectomy was considered to be a feasible surgical procedure for elderly patients who had a good performance status.

Surgical strategy for patients with pancreatic body/tail carcinoma: Who should undergo distal pancreatectomy with en-bloc celiac axis resection?

BACKGROUND Indications for distal pancreatectomy with en-bloc celiac axis resection (DP-CAR) in pancreatic carcinoma remain controversial. METHODS Fifty-two consecutive patients with pancreatic cancer who underwent distal pancreatectomy, including 36 standard distal pancreatectomies (standard DP) and 16 DP-CAR were reviewed retrospectively. RESULTS After standard DP, microscopically positive margins were identified at the dissection sites around the transection margins of the splenic arteries and were detected more frequently in the patients with tumors within 10 mm from the root of the splenic artery (14%). After DP-CAR, the estimated overall survival rate in patients who were pathologically negative for portal venous and artery invasion (n = 7) was greater than that of the other patients (n = 9; P = .023, log-rank test). The estimated overall 1- and 2-year survival rates after standard DP/DP-CAR were 81/81% and 52/53%, and the median survival times were 32/25 months, respectively, with no differences noted between the groups. There were no differences in the mortality rates and the incidence of each complication between the 2 groups except for delayed gastric emptying. CONCLUSION DP-CAR was a feasible and safe procedure, similar to standard DP. DP-CAR should be reserved for patients without tumor infiltrating either the portal venous or arterial systems.

Coexpression of MUC16 and mesothelin is related to the invasion process in pancreatic ductal adenocarcinoma.

The invasion process is a crucial step for pancreatic ductal adenocarcinoma (PDAC); however, the genes related to invasion remain unclear. To identify specific genes for the invasion process, we compared microarray data for infiltrating cancer and PanIN‐3, which were harvested from an individual PDAC patient by microdissection. Furthermore, immunohistochemical, coimmunoprecipitation and invasion analyses were performed to confirm the biologic significance of molecules identified by expression profile. In the present study, we focused on MUC16 and mesothelin among 87 genes that were significantly upregulated in infiltrating components compared to PanIN‐3 in all PDAC patients, because MUC16 was the most differently expressed between two regions, and mesothelin was reported as the receptor for MUC16. Immunohistochemical analysis revealed that MUC16 and mesothelin were expressed simultaneously only in infiltrating components and increased at the invasion front, and binding of MUC16 and mesothelin was found in PDAC by immunoprecipitation assay. The downregulation of MUC16 by shRNA and the blockage of MUC16 binding to mesothelin by antibody inhibited both invasion and migration of pancreatic cancer cell line. MUC16 high/mesothelin high expression was an independent prognostic factor for poor survival in PDAC patients. In conclusion, we identified two specific genes, MUC16 and mesothelin, associated with the invasion process in patients with PDAC. (Cancer Sci 2012; 103: 739–746)

Treatment Strategy for Intraductal Papillary Mucinous Neoplasm of the Pancreas Based on Malignant Predictive Factors

BACKGROUND Noninvasive intraductal papillary mucinous neoplasms (IPMNs) have a favorable prognosis; however, the prognosis of invasive intraductal papillary mucinous carcinoma (invasive IPMC) is poor. Identification of predictive factors for differentiating IPMC from benign IPMNs would assist in providing appropriate treatment. DESIGN Retrospective study (1999-2006). SETTING Wakayama Medical University Hospital, Wakayama, Japan. PATIENTS Fifty-four patients with IPMN who underwent surgery; histologic examination showed benign adenomas in 29, carcinoma in situ in 14, and invasive carcinoma in 11 patients. MAIN OUTCOME MEASURES Clinical data, preoperative imaging findings, cytologic findings, tumor markers in serum and pancreatic juice, and overall survival. RESULTS Age of 70 years or older, presence of mural nodules, mural nodule size of 5 mm or larger, and carcinoembryonic antigen (CEA) level in pancreatic juice of 110 ng/mL or higher (as obtained by preoperative endoscopic retrograde pancreatography) were predictive of a malignant IPMN by univariate analysis, and a CEA level of 110 ng/mL or higher in pancreatic juice was identified as the only independent predictive factor for the malignant entity. The presence of jaundice or body weight loss, main pancreatic duct type, presence of mural nodules, mural nodule size of 5 mm or larger, and CEA level in the pancreatic juice of 110 ng/mL or higher were all predictive of invasive IPMCs by univariate analysis. CONCLUSION Measurement of the CEA level in pancreatic juice should be considered in the diagnosis of IPMC.

Stump closure of a thick pancreas using stapler closure increases pancreatic fistula after distal pancreatectomy.

BACKGROUND The appropriate surgical stump closure after distal pancreatectomy (DP) is still controversial. This study investigated the benefits and risks of stapler closure during DP. METHODS The risk factors of pancreatic fistulas were investigated in 122 DPs among 3 types of stump closure: hand-sewn suture (n = 32), bipolar scissors (n = 45), and stapler closure (n = 45). RESULTS There was no significant difference in the incidence of pancreatic fistula between the 3 types of stump closure (hand-sewn suture [44%] vs bipolar scissors [37.7%] vs stapler closure [35.5%]). By using receiver operating characteristics curves, 12 mm was the best cutoff value of the thickness of the pancreas for pancreatic fistulas after DP using stapler closure. Three factors (ie, male sex, body mass index >25 kg/m(2), and stapler closure) were independent risk factors of pancreatic fistulas after DP with a pancreas thicker than 12 mm. CONCLUSIONS A pancreas thicker than 12 mm significantly increased the incidence of pancreatic fistulas after DP using stapler closure.