Seiko Hirono

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.

Improvement of Delayed Gastric Emptying in Pylorus-Preserving Pancreaticoduodenectomy: Results of a Prospective, Randomized, Controlled Trial

Objective:To determine if an antecolic or a retrocolic duodenojejunostomy during pylorus-preserving pancreaticoduodenectomy (PpPD) was associated with the least incidence of delayed gastric emptying (DGE), in a prospective, randomized, controlled trial. Summary Background Data:The pathogenesis of DGE after PpPD has been speculated to be related to factors such as inflammation, ischemia, gastric atony, motilin levels, and type of surgical procedure. Previous retrospective studies have shown a lower incidence of DGE after antecolic duodenojejunostomy. A prospective trial is needed. Methods:Forty patients were enrolled in this trial between May 2002 and April 2004. Just before duodenojejunostomy during PpPD, the patients were randomly assigned to undergo either an antecolic or a retrocolic duodenojejunostomy. Results:DGE occurred in 5% of patients with the antecolic route for duodenojejunostomy versus 50% with the retrocolic route (P = 0.0014). Those with the antecolic route had a significantly shorter duration of postoperative nasogastric tube drainage than did those with the retrocolic route (4.2 days versus 18.9 days, respectively, P = 0.047). By postoperative day 14, all patients with the antecolic route could take solid foods, while only 55% (11 of 20) of the patients with the retrocolic route could take solid foods (P = 0.0007). The length of stay in the hospital was 28 days for the antecolic group versus 48 days for the retrocolic group (P = 0.018). Conclusions:Antecolic reconstruction for duodenojejunostomy during PpPD decreases postoperative morbidity and length of hospital stay by decreasing DGE. Our data suggest that PpPD with antecolic duodenojejunostomy is a safer operation.

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.

Whole-exome sequencing of human pancreatic cancers and characterization of genomic instability caused by MLH1 haploinsufficiency and complete deficiency

Whole-exome sequencing (Exome-seq) has been successfully applied in several recent studies. We here sequenced the exomes of 15 pancreatic tumor cell lines and their matched normal samples. We captured 162,073 exons of 16,954 genes and sequenced the targeted regions to a mean coverage of 56-fold. This study identified a total of 1517 somatic mutations and validated 934 mutations by transcriptome sequencing. We detected recurrent mutations in 56 genes. Among them, 41 have not been described. The mutation rates varied widely among cell lines. The diversity of the mutation rates was significantly correlated with the distinct MLH1 copy-number status. Exome-seq revealed intensive genomic instability in a cell line with MLH1 homozygous deletion, indicated by a dramatically elevated rate of somatic substitutions, small insertions/deletions (indels), as well as indels in microsatellites. Notably, we found that MLH1 expression was decreased by nearly half in cell lines with an allelic loss of MLH1. While these cell lines were negative in conventional microsatellite instability assay, they showed a 10.5-fold increase in the rate of somatic indels, e.g., truncating indels in TP53 and TGFBR2, indicating MLH1 haploinsufficiency in the correction of DNA indel errors. We further analyzed the exomes of 15 renal cell carcinomas and confirmed MLH1 haploinsufficiency. We observed a much higher rate of indel mutations in the affected cases and identified recurrent truncating indels in several cancer genes such as VHL, PBRM1, and JARID1C. Together, our data suggest that MLH1 hemizygous deletion, through increasing the rate of indel mutations, could drive the development and progression of sporadic cancers.

Predictors of malignancy in intraductal papillary mucinous neoplasm of the pancreas: analysis of 310 pancreatic resection patients at multiple high-volume centers.

Objectives The present study was a retrospective investigation of predictors of malignancy in intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Methods The subjects were 310 patients who underwent pancreatic resection at 3 high-volume centers. Preoperative laboratory and imaging findings were analyzed in logistic regression analyses. Endoscopic ultrasonography measurements were essential for the size of mural nodules, and a central review was conducted for pathological diagnosis. Results Pathological diagnosis was benign IPMN in 150 cases and malignant in 160 (noninvasive carcinoma, n = 100; invasive, n = 60). In multivariate analysis, size of mural nodules, diameter of main pancreatic duct, and cyst size of branch pancreatic duct were independent predictors of malignancy, and areas under the receiver operating characteristic curve for these 3 factors were 0.798, 0.643, and 0.601, respectively. With 7 mm taken as the cutoff value for the size of mural nodules, the diagnosis of malignant IPMN had sensitivity of 74.3% and specificity of 72.7%. Carcinoma without nodules was present in 15 patients (15/160 [9.4%]). Conclusions The size of mural nodules measured with endoscopic ultrasonography showed high predictive ability. However, about 10% of carcinoma patients did not have nodules, and the handling of the diagnosis in such cases is a problem for the future.

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.