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Whether organ-preserving pancreatic surgery has an advantage in postoperative short- and long-term outcomes or not is still unknown because only small case series studies have been available to date. In this multicenter retrospective study, we aimed to elucidate the clinical advantage and disadvantage of organ-preserving pancreatectomy among patients with low-grade malignant pancreatic tumors and benign pancreatic diseases.We included patients diagnosed with benign or low-malignant pancreatic tumor who underwent pancreaticoduodenectomy (PD) in 621 cases, duodenum-preserving pancreatic head resection (DPPHR) in 31 cases, middle pancreatectomy (MP) in 148 cases, distal pancreatectomy (DP) in 814 cases, and spleen-preserving distal pancreatectomy (SPDP) in 259 cases between January 1, 2013, and December 31, 2017. Preoperative backgrounds, surgical outcomes and pre- and postoperative (3, 6, 12, 24, and 36 months) nutritional status were compared between these procedures.In terms of short-term outcomes, the incidence of pancreatic fistula in patients who underwent MP was significantly higher than in patients with standard pancreatectomy. As for the long-term pancreatic functions in the cases of head or body lesion, both exocrine and endocrine functions after MP were significantly favorable compared with the PD group from 3 to 36 months after surgery. In pancreatic body or tail lesion, significant advantage of endocrine function, but not exocrine function, was found in the MP group compared to standard DP at all time points.MP may contribute to the improvement of postoperative quality of life for patients with pancreatic body low-malignant tumors, rather than PD or DP; however, reducing the incidence of short-term complications such as pancreatic fistula is a future challenge.

In 1981, we developed the first antithrombogenic bypass catheter for the portal system. This catheter-bypass procedure relieved the time limitation caused by portal occlusion and facilitated safe and easy resection and reconstruction of the portal vein or hepatic artery. We thereafter explored isolated pancreatoduodenectomy, in which pancreatoduodenectomy is performed under non-touch isolation techniques. It is difficult to perform isolated pancreatoduodenectomy because of the complex arterial anatomy of the peripancreatic head region. In 1992, a mesenteric approach was developed for pancreatoduodenectomy. This approach allows dissection from the non-cancerous side and determination of both cancer-free margins and resectability followed by systematic lymphadenectomy around the superior mesenteric artery. This approach also enables early ligation of the inferior pancreatoduodenal artery and dorsal pancreatic artery branches from the superior mesenteric artery, as well as complete excision of the total mesopancreas (which is thought to be the second portion of the pancreatic head nerve plexus). Through this development of the mesenteric approach and antithrombogenic catheter-bypass procedure, our isolated pancreatoduodenectomy was finally established in 1992. This is the ideal surgery for pancreatic head cancer from both surgical and oncological aspects. We herein introduce the precise surgical techniques.

Background Radical antegrade modular pancreatosplenectomy (RAMPS) is an isolation procedure in pancreatosplenectomy for pancreatic body/tail cancer. Connective tissues around the bifurcation of the celiac axis are dissected, followed by median-to-left retroperitoneal dissection. This procedure has the potential to isolate blood and lymphatic flow to the area of the pancreatic body/tail and the spleen to be excised. This is achieved by division of the inflow artery, transection of the pancreas, and then division of the outflow vein in the early phases of surgery. In cases of pancreatic ductal adenocarcinoma (PDAC), the procedure has been shown to decrease intraoperative blood loss and increase R0 resection rate by complete clearance of the lymph nodes. This trial investigates whether the isolation procedure can prolong the survival of patients with pancreatic ductal adenocarcinoma who undergo distal pancreatosplenectomy (DPS) compared with those that undergo the conventional approach. Methods/design Patients with PDAC scheduled to undergo DPS are randomized before surgery to undergo either a conventional procedure (arm A) or to undergo the isolation procedure (arm B). In arm A, the pancreatic body, tail, and spleen are mobilized, followed by removal of the regional lymph nodes. The splenic vein is transected at the end of the procedure. The timing of division of the splenic artery (SA) is not restricted. In arm B, regional lymph nodes are dissected, then we transect the root of the SA, the pancreas, then the splenic vein. At the end of the procedure, the pancreatic body/tail and spleen are mobilized and removed. In total, 100 patients from multiple Japanese high-volume centers will be randomized. The primary endpoint is 2-year recurrence-free survival by intention-to-treat analysis. Secondary endpoints include intraoperative blood loss, R0 resection rate, and overall survival. Discussion If this trial shows that the isolation procedures can improve survival with a similar R0 rate and with a similar number of lymph node dissections to the conventional procedure, the isolation procedure is expected to become a standard procedure during DPS for PDAC. Conversely, if there were no significant differences in endpoints between the groups, it would demonstrate justification of either procedure from surgical and oncological points of view. Trial registration UMIN Clinical Trials Registry UMIN000041381. Registered on 10 August 2020. ClinicalTrials.gov NCT04600063. Registered on 22 October 2020.

The peripancreatic arterial system forms various arterial arcades and collateral branches; therefore, it stands to reason that the arterial supply into the pancreatic head region should be controlled as a whole peripancreatic arterial arcade rather than as the three major supplying arteries during isolated pancreatoduodenectomy (PD). We investigated the clinical importance of early control of the whole peripancreatic arterial arcade during PD. The subjects of this retrospective study were 63 consecutive patients who underwent PD via a mesenteric approach at our hospital between October, 2014 and February, 2017. The patients were divided into an early control group (n = 27) and a late control group (n = 36) for comparative analysis. The peripancreatic arterial arcades and collateral branches were seen on preoperative multidetector row computed tomography (CT) images and during PD in all 63 patients. The early control group had significantly less intraoperative blood loss than the late control group. Early control of the whole peripancreatic arterial arcade was an independent factor associated with lower intraoperative blood loss in the multivariable analysis (P = 0.012). The arterial supply into the pancreatic head region should be controlled as a whole peripancreatic arterial arcade rather than as the three major supplying arteries during isolated PD.

In this study, the precipitation of minerals onto rock surfaces was investigated to consider whether sealing of pores and cracks in rock can be accelerated. Cylindrical specimens were prepared and then kept in purified water with powders of high-strength and ultra-low-permeability concrete (HSULPC), which will be used to confine transuranic wastes in Japan. Then, the rock specimens were weighed and the surfaces of rock specimens were inspected under a microscope. It was recognized that precipitation occurred on the surface of the rock specimens. It was also shown that precipitation did not occur on rock specimens kept in water without HSULPC. The weight of all specimens stored in HSULPC increased, and the observed weight change was larger for rocks with higher porosities. It is concluded that precipitation of minerals occurs on the rock surface when the rock is kept in water with HSULPC powders. From the results obtained in this study, it is suggested that the sealing of pores and cracks in rock can be accelerated by the precipitation of calcium compounds using HSULPC. It is concluded that HSULPC is useful for underground radioactive waste disposal.

Background Early ligation of the inferior pancreatoduodenal artery has been advocated to reduce blood loss during pancreatoduodenectomy. However, the impact of early ligation of the dorsal pancreatic artery (DPA) remains unclear. This study was performed to investigate the clinical implications of early ligation of the DPA. Methods From October 2014 to April 2017, 34 consecutive patients underwent pancreatoduodenectomy using a mesenteric approach. The patients were divided into the early DPA ligation group (n = 15) and late DPA ligation group (n = 19). The clinical features were retrospectively compared between the two groups (H29-044). Results Preoperative multidetector row computed tomography and intraoperative findings revealed that the right branch of the DPA supplied the pancreatic head region in all cases. Intraoperative blood loss was significantly lower in the early than late ligation group (median 609 ml [range 94-1,013 ml] vs. 764 ml [range 367-1,828 ml], respectively; P = 0.008). Multivariable analysis revealed that early DPA ligation was independently associated with blood loss (P = 0.023). The DPAs arising from the superior mesenteric artery underwent early ligation at a significantly higher rate. Conclusions Early ligation of the DPA during pancreaticoduodenectomy with a mesenteric approach could reduce intraoperative blood loss.

Background This study sought to evaluate the predictors of malignancy in the 2012 international consensus guidelines for intraductal papillary mucinous neoplasms (IPMNs) and validate their diagnostic value relative to the 2006 guidelines. Methods Between 2002 and 2014, 177 consecutive patients who underwent curative resection of IPMN were reviewed. Based on the 2012 guidelines, high-risk stigmata (mural nodule with enhancement, main pancreatic duct [MPD] ≥ 10 mm, and obstructive jaundice) and worrisome features (cyst size ≥ 30 mm, thickened cyst wall, mural nodule without enhancement, MPD 5–9 mm, an abrupt change in MPD diameter, and lymphadenopathy) were assessed, and predictive and diagnostic values were analyzed statistically. Results Multivariate analysis identified obstructive jaundice (odds ratio [OR], 23.9; P P = .017) and lymphadenopathy (OR, 5.84; P = .027) as independent predictive factors, with an accuracy of 69.8, 67.4, and 66.3%, respectively. Operative intervention was indicated in 156 patients (94.0%) using the 2006 guidelines, and in 130 (78.3%) using the 2012 guidelines. The accuracy of the 2006 guidelines was 35.5% compared with 44.8% for the 2012 guidelines. The area under the curve (AUC) for the 2006 and 2012 guidelines was 0.65 and 0.67, respectively; ΔAUC was 0.02, which was not statistically significant. When the worrisome features were combined with high-risk stigmata, the AUC increased to 0.79. Conclusion Obstructive jaundice, abrupt change in MPD diameter, and lymphadenopathy were independent predictive factors in the 2012 guidelines with high accuracy. Using the new guidelines, the number of patients with IPMN managed with observation and the predictive accuracy increased.

Isolated pancreatoduodenectomy (PD) is an ideal surgery for pancreatic head cancer. In cancer surgery, ‘isolated' means en bloc resection using a non-touch isolation technique. I have been developing isolated PD for pancreatic cancer since 1981. In this operation, the most important and first step is to use a mesenteric approach instead of Kocher's maneuver. The precise surgical techniques of the mesenteric approach are introduced in this paper.

Despite recent advances in surgical techniques including staple closure and ultrasonic devices, the reported incidence of postoperative pancreatic fistula (POPF) after distal pancreatectomy (DP) remains high. Therefore, we devised a new strategy in which the pancreatic stump is enveloped with the elevated jejunum (EJ) by a modified Blumgart anastomotic technique. Eighty-one patients who underwent open DP with splenectomy from January 2008 to December 2014 were enrolled. Comparisons were made between 42 patients who underwent placement of an EJ patch using the modified Blumgart method after scalpel transection and 39 patients who underwent scalpel transection alone, using unmatched and propensity score-matched analysis. After 25 patients from each group were selected by propensity score matching, the EJ patch technique was significantly associated with a lower incidence of clinically relevant POPF (P = 0.036). Multivariate analysis showed that the EJ patch was an independent predictor of a lower incidence of POPF (odds ratio, 0.16; 95 % confidence interval, 0.01–0.48; P = 0.017) as was the estimated remnant pancreatic volume. Addition of the EJ patch improves postoperative outcomes in patients who undergo open DP with splenectomy by scalpel transection and hand-sewn closure of the pancreatic remnant.

Background Gastric venous congestion and bleeding in association with total pancreatectomy (TP) were evaluated. Methods Thirty‐eight patients of TP were retrospectively analyzed. TP was classified as TP with distal gastrectomy (TPDG), pylorus‐preserving TP (PPTP), subtotal stomach‐preserving TP (SSPTP), and TP with segmental duodenectomy (TPSD). Results Portal vein or superior mesenteric vein resection and reconstruction was performed in 24 patients (62.2%). Gastric bleeding occurred immediately after tumor resection in one of eight patients who underwent SSPTP, and urgent anastomosis between the right gastroepiploic and left ovarian vein stopped the bleeding. Another case of gastric bleeding was observed a few hours after TP in one of nine patients who underwent PPTP, and hemostasis was achieved after conservative therapy. Gastric bleeding was not observed in 16 patients who underwent TPDG and five who underwent TPSD. Some patients underwent preservation of gastric drainage veins (left gastric vein, right gastric vein, or right gastroepiploic vein). Neither patient with bleeding underwent preservation of a gastric drainage vein. Conclusions To preserve the subtotal or whole stomach when performing TP, one of the gastric drainage veins should undergo preservation or reconstruction, and anastomosis between the right gastroepiploic vein and left ovarian vein may be beneficial.

OBJECTIVES Pancreatectomy is still associated with a high morbidity rate, even in high-volume centers, and a leading cause of morbidity is represented by postoperative pancreatic fistula (POPF). Many previous studies have evaluated the risk factors for the occurrence of POPF, but protracted courses of POPF have not been fully discussed. METHODS This study included 900 patients who underwent pancreatectomy between January 1991 and June 2013 after exclusion of patients who underwent total pancreatectomy. Subgroup analysis of the duration of drain placement was conducted among patients with POPF to identify predictive factors for a protracted course of POPF. RESULTS Overall, 292 patients (32.4%) had clinically relevant POPF (grade B/C). The length of drain placement in patients with a body mass index (BMI) of 25 kg/m(2) or greater was significantly longer than that in patients with a BMI of less than 25 kg/m(2) (44.8 ± 25.2 vs 33.8 ± 21.2 days, respectively; P = 0.001). The operative procedure, duct diameter, and pancreatic texture, which were independent risk factors for clinically relevant POPF, did not delay removal of the drainage tubes. CONCLUSIONS A BMI of 25 kg/m(2) or greater was the only factor associated with delayed POPF healing. Vigilant postoperative management after pancreatectomy should be considered in obese patients.

OBJECTIVE The purpose of this study was to evaluate the prognostic relevance of SMAD4 expression in pancreatic cancer. METHODS We analyzed the correlations between SMAD4 expression and clinicopathological parameters and outcome in 174 patients with pancreatic cancer. Specimens were also classified into subtypes reflecting epithelial-to-mesenchymal transition, based on E-cadherin and vimentin. RESULTS We found that 59.8% (104/174) of patients were SMAD4 and 40.2% (70/174) were SMAD4. Disease-specific survival in patients with SMAD4 was significantly better than that in SMAD4. SMAD4 status was significantly correlated with portal vein invasion, lymph vessel invasion, and perineural invasion and was an independent prognostic factor. SMAD4 was significantly associated with mesenchymal phenotype. The loss of SMAD4 expression was found in 49.4% of patients with no vascular invasion, 61.9% with portal vein invasion, 76.5% with common hepatic artery invasion, and 80.8% with superior mesenteric artery invasion. In addition, the specimens from 59.0% of patients with local recurrence, 66.7% of those with both local and distant recurrence, and 73.7% of those with distant recurrence were SMAD4. CONCLUSIONS The loss of SMAD4 expression is an independent prognostic factor and seems to be associated with tumor progression, pattern of failure, and epithelial-to-mesenchymal transition status. Preoperative stratification based on SMAD4 could lead to appropriate treatment strategy.

Background Potential benefits of local extirpation of benign pancreatic head tumors are tissue conservation of pancreas, stomach, duodenum and common bile duct (CBD) and maintenance of pancreatic functions. Methods Medline/PubMed, Embase and Cochrane Library databases were searched to identify studies applying duodenum-preserving total or partial pancreatic-head resection (DPPHRt/p) and reporting short- and long-term outcomes. Twenty-four studies, including 416 patients who underwent DPPHRt/p, were identified for systematic analysis. The meta-analysis was based on 10 prospective controlled and 4 retrospective controlled cohort studies, comparing 293 DPPHRt/p resections with 372 pancreato-duodenectomies (PD). Results, systematic analysis Of 416 patients, 75.7% underwent total and 24.3% partial head resection, while 47.1% included segmentectomy of duodenum and CBD. The most common pathology was cystic neoplasm (65.8%) and endocrine tumors (13.4%). The frequencies of severe postoperative complications of 8.8%, pancreatic fistula of 19.2%, re-operation of 1.7% and hospital mortality of 0.48%, indicate a low level of early post-operative complications. Meta-analysis DPPHRt/p significantly preserved the level of exocrine (IV = −0.67, 95% CI −0.98 to −0.35, p = 0.0001) and endocrine (IV = 18.20, fixed, 95% CI −0.92 to 25.48, p = 0.0001) pancreatic functions compared to PD when the pre- and postoperative functional status in both groups are analyzed. There were no significant differences between DPPHRt/p and PD in frequency of pancreatic fistula, delayed gastric emptying or hospital mortality. Conclusion DPPHRt/p for benign neoplasms and neuro-endocrine tumors of the pancreatic head is associated with a low level of early-postoperative complications and a better conservation of exocrine and endocrine functions.

Mesenteric approach is an artery‐first approach during pancreaticoduodenectomy (PD). In the present study, we evaluated clinical and oncological benefits of this procedure for pancreatic ductal adenocarcinoma (PDAC) of the pancreas head. Between 2000 and 2015, 237 consecutive PDAC patients underwent PD. Among them, 72 experienced the mesenteric approach (mesenteric group) and 165 the conventional approach (conventional group). A matched‐pairs group consisted of 116 patients (58 patients in each group) matched for age, gender, resectability status, and neoadjuvant therapy. Surgical and oncological outcomes were compared between the two groups in unmatched‐ and matched‐pair analyses. Intraoperative blood loss was lower in the mesenteric group than in the conventional group in both resectable PDAC (R‐PDAC) and borderline resectable PDAC (BR‐PDAC) on unmatched‐ and matched‐pairs analyses (R‐PDAC, unmatched: 312.5 vs 510 mL, P=.008; matched: 312.5 vs 501.5 mL, P=.023; BR‐PDAC, unmatched: 507.5 vs 935 mL, P

The poor prognosis for pancreatic cancer after surgery has been attributed to a strong tendency of the cancer cells to spread along the peripancreatic neural plexuses and to infiltrate into the retropancreatic tissue. The concept of the nerve plexus around the pancreatic head was first reported by Yoshioka in 1958, and the Japan Pancreas Society has incorporated this concept and a corresponding diagram in the General Rules for the Study of Pancreatic Cancer. In this classification, the extrapancreatic nerve plexuses were categorized into seven groups: pancreatic head plexus I (PL ph I), pancreatic head plexus II (PL ph II), superior mesenteric arterial plexus (PL sma), common hepatic artery plexus (PL cha), plexus within the hepatoduodenal ligament (PL hdl), splenic plexus (PL sp), and celiac plexus (PL ce). After extrapancreatic nerve plexus invasion, particularly PL ph I and PL sma invasion, was found to have a correlation with patient prognosis and lymph node involvement along the superior mesenteric artery, it was adopted as a staging factor in the General Rules for the Study of Pancreatic Cancer. In 2007, Gockel et al. introduced the concept of the “mesopancreas.” The mesopancreas is a retropancreatic structure extending from the back of the pancreatic head to the superior mesenteric artery, including the lymphatic system, vessels, and nerves, which corresponds to PL ph I and PL ph II according to the General Rules for the Study of Pancreatic Cancer. The mesopancreas was reported to be the most frequent site of R1 resections; therefore, total excision of the mesopancreas and complete circumferential lymphadenectomy have recently been considered to be key points in curative surgery.

The ideal surgery for pancreatic head cancer is isolated pancreatoduodenectomy (PD). “Isolated” means non-touch isolation techniques. Before manipulating pancreatic head cancer, all arteries supplying the pancreatic head region and all drainage veins for this region are ligated and divided, followed by pancreatectomy. The first step in isolated PD is a mesenteric approach. The inferior pancreaticoduodenal artery from the superior mesenteric artery is ligated and divided using the mesenteric approach. If the time to resect and reconstruct the portal venous system is expected to be prolonged, the congested portal venous blood is bypassed from a branch of the superior mesenteric vein to the femoral vein or umbilical vein using an antithrombogenic catheter. The concepts, intention, and precise surgical techniques of isolated PD are discussed in this paper.

Morphological subtypes of intraductal papillary mucinous neoplasm (IPMN) have been established. Invasive IPMNs include colloid carcinoma and tubular carcinoma. Few studies have explored the association between the morphological and invasive subtypes in a large population. Clinical relevance of the morphological subtypes remains unclear. One hundred sixty-nine consecutive patients who underwent curative resection of IPMN were enrolled. The intraductal components were classified into four distinct epithelial subtypes: gastric, intestinal, pancreatobiliary, and oncocytic. The invasive components were classified as colloid or tubular. The numbers of patients with gastric, intestinal, pancreatobiliary, and oncocytic subtypes were 123, 42, 3, and 1, respectively. Fifty-six patients had invasive cancer (tubular type, 42; colloid type, 14). The proportions of gastric type IPMN within each histological grade were 88 % among adenomas, 43 % among noninvasive carcinomas, 41 % among minimally invasive carcinomas, and 74 % among invasive carcinomas. Gastric subtype was more commonly associated with branch duct type and intestinal subtype with main duct type, and these tendencies were statistically significant (P = 0.0131). Furthermore, there was a strong correlation between gastric and tubular types and between intestinal and colloid types (P

Background Superior mesenteric vein–portal vein confluence resection combined with pancreatoduodenectomy (SMPVrPD) is occasionally required for resection of pancreatic head tumors. It remains unclear whether such situations require splenic vein (SV) reconstruction for decompression of left-sided portal hypertension (LSPH). Methods The data from 93 of 104 patients who underwent pancreatoduodenectomy (PD) for pancreatic head malignancies were reviewed. Surgical outcomes in three groups—standard PD (control group), PD combined with vascular resection and SV preservation (SVp group), and SMPVrPD with SV resection (SVr group)—were compared. The influence of division and preservation of the two natural confluences (left gastric vein–portal vein and/or inferior mesenteric vein–SV confluences) on portal hemodynamics were evaluated using three-dimensional computed tomographic portography. Results No mortality occurred. The morbidity rates were not significantly different among the three groups (18/43, 8/21, and 7/29, respectively; p = 0.306). In the SVr group, three patients had gastric remnant venous congestion, and three had esophageal varices without hemorrhagic potential. No patients had splenomegaly, or severe or prolonged thrombocytopenia. These LSPH-associated findings were less frequently observed when the two confluences were preserved. Conclusions SMPVrPD without SV reconstruction can be safely conducted. Additionally, preservation of these two confluences may reduce the risk of LSPH.

Background Peritoneal lavage cytology (CY) is used in the diagnosis and staging of various cancers. The clinical significance of positive cytology results in patients with pancreatic cancer is yet to be determined. Methods Peritoneal washing samples were collected from consecutive patients with pancreatic cancer between July 1991 and December 2012. The correlations between cytology results, clinicopathological parameters and recurrence patterns were evaluated. The prognostic impact of CY status, regarding resectability and the effectiveness of adjuvant chemotherapy, were analysed. Results Of 523 included patients, 390 underwent resection. Patients with tumours at least 2 cm in diameter were more likely to have CY+ status than patients with tumours smaller than 2 cm (48 of 312 versus 3 of 78 respectively; P = 0·005) and there was a significant correlation between CY+ status and tumour invasion of the anterior pancreatic capsule (43 of 276 versus 8 of 113 with no invasion of the capsule; P = 0·030). Although the overall survival of patients with resected CY+ tumours was worse than that of patients with resected CY− tumours, it was significantly better than the survival of unresected patients regardless of CY status. Multivariable analysis of all patients who had pancreatectomy did not identify CY+ as an independent prognostic factor. Patients with CY+ tumours tended to develop peritoneal metastasis more often than those with CY− tumours, although not significantly so. The median survival time of 34 patients with resected CY+ tumours who received adjuvant chemotherapy was better than that of 17 patients who had surgery alone, although this was not statistically significant (15·3 versus 10·0 months; P = 0·057). Conclusion CY+ status is not clinically equivalent to gross peritoneal metastasis in patients with pancreatic cancer. Curative resection is still recommended regardless of CY status. Presented to the 98th Annual Clinical Congress of the American College of Surgeons, Chicago, Illinois, USA, October 2012

Background Pancreatic cancer has a dismal prognosis that is attributed to common local invasiveness and metastasis. Epithelial-to-mesenchymal transition (EMT) plays an important role in cancer invasion and metastasis and is associated with early dissemination. The aim of this study was to evaluate the association between EMT and the prognoses for patients with pancreatic cancer. Methods Immunohistochemistry of E-cadherin and vimentin was performed on surgical specimens from 174 patients who underwent resection of their pancreatic cancers. Tumoral stainings of E-cadherin and vimentin were graded, and EMT statuses were determined by calculating the ratio of vimentin to E-cadherin, whereby patients were categorized into 3 groups: epithelial, intermediate, and mesenchymal. The correlations between EMT statuses and clinicopathologic factors and prognoses were analyzed. Results There was a significant correlation between EMT status and CA19-9 levels ( P = .020); peritoneal washing cytology ( P = .025); portal vein invasion ( P = .038); and lymph node metastasis ( P = .030). The median survival for patients with epithelial tumors was 40.2 months as compared to 13.7 months for patients with mesenchymal tumors. Multivariate analysis demonstrated that perineural invasion ( P = .024); lymph node metastasis ( P = .033); and EMT status ( P P = .002); however, no significant difference was seen in patients with epithelial tumors. Conclusion EMT status is an important prognostic factor for pancreatic cancer and is associated with portal vein invasion and lymph node metastasis.

The objective of this study was to evaluate the relevance of defining borderline resectable (BR) pancreatic cancer as a distinct entity in the treatment scheme of pancreatic cancer as proposed by the National Comprehensive Cancer Network.Among 375 patients with pancreatic cancer, 137 patients were deemed to have resectable disease (R) by preoperative imaging studies, whereas 96 were found to have an unresectable disease during surgery. The remaining 142 patients fulfilled the definition of BR and were further classified into 3 subgroups based on the National Comprehensive Cancer Network guidelines: portal vein invasion (PV[+]), common hepatic artery invasion (CHA[+]), and superior mesenteric artery invasion (SMA[+]). PV(+) was subdivided into types B, C, and D according to the degree of portal vein invasion.Patients in the R group had significantly better survival than those in the PV(+) group (P = 0.0038), who in turn survived significantly longer than those classified as SMA(+) (P = 0.041). Type B patients survived significantly longer than did types C and D patients (P = 0.013 and P = 0.030, respectively). In PV(+) patients, compliance with postoperative chemotherapy at 3 and 6 months was 56.9% and 44.6%, respectively, substantially inferior to patients with resectable disease (72.6% and 54.7%, respectively).The optimal treatment strategy may differ among various subgroups within the BR category.

A multicenter survey was conducted to explore the role of adjuvant surgery for initially unresectable pancreatic cancer with a long-term favorable response to non-surgical cancer treatments. Clinical data including overall survival were retrospectively compared between 58 initially unresectable pancreatic cancer patients who underwent adjuvant surgery with a favorable response to non-surgical cancer treatments over 6 months after the initial treatment and 101 patients who did not undergo adjuvant surgery because of either unchanged unresectability, a poor performance status, and/or the patients’ or surgeons’ wishes. Overall mortality and morbidity were 1.7 and 47 % in the adjuvant surgery group. The survival curve in the adjuvant surgery group was significantly better than in the control group (p

Since 1981, the Japan Pancreas Society has been hosting a nationwide pancreatic cancer registry. To commemorate its 30th anniversary, we review its history and latest achievement.During 3 decades, more than 350 leading institutions in Japan contributed voluntarily to register and periodic follow-up. The registry was modified to protect privacy by encrypting and hash algorithm.From 1981 to 2007, 32,619 cumulative records were analyzed. The overall survival of invasive cancer was improved significantly. More patients with earlier stage or with intraductal and cystic neoplasms underwent resection. The strongest prognostic factor of Union for International Cancer Control (UICC) stage IIA and IIB tubular adenocarcinoma in the pancreatic head was histological grade, followed by tumor size, extent of lymph node dissection, and postoperative chemotherapy. The 5-year survival rate of Union for International Cancer Control stage 0 reached 85%. The improvement of survival of patients with invasive cancer in Japan can be attributed to the introduction of effective chemotherapies, regionalization, and the earlier diagnosis and treatment. Simple definition of "early pancreatic cancer" is needed.At the 30th year anniversary, the Japan Pancreas Society nationwide pancreatic cancer registry is more shining than ever for current perspectives and for future diagnostic and treatment tactics.

Pancreaticoduodenectomy is performed for pancreatic head cancer that originated from the dorsal or ventral primordium. Although the extent of lymph node (LN) dissection is the same irrespective of the origin, the lymphatic continuities may differ between the 2 primordia.Between March 2003 and September 2010, 152 patients underwent pancreaticoduodenectomy for pancreatic cancer. One hundred six patients were assigned into 2 groups according to tumor location on preoperative computed tomography, and their clinical and pathological features were retrospectively analyzed in view of the embryonic development of the pancreas.Sixty of 106 patients were classified with tumors that were derived from the dorsal pancreas (D group) and 46 from the ventral pancreas (V group). The frequency of LN involvement around the middle colic artery (LN 15) in the D group was higher than in the V group (P = 0.008). The rate of additional resection of the pancreas tended to be higher in the D group (P = 0.067).The present study showed the detailed pattern of spread of pancreatic ductal carcinoma to the LNs and provided important information for determining the optimal surgical strategy.

Background After pancreatoduodenectomy in patients with celiac axis stenosis or obstruction, it becomes problematic to maintain the upper abdominal organ blood flow, especially to the liver. The aim of this study was to investigate the celiac axis stenosis caused by median arcuate ligament (MAL) compression and to classify it according to preoperative image findings. Methods From January 1989 to November 2010, 562 patients underwent operations for diseases of the pancreatic head region in our department. To diagnose celiac artery compression by the MAL, angiography was used in the early period and 3-dimensional image reconstruction of multidetector-row computed tomography was used from 2004. The morphologic characteristics of the celiac axis stenosis were analyzed during intraoperative treatment. Results Twelve (2.1%) patients were diagnosed with MAL compression, and 8 of these patients only underwent MAL division to restore the celiac artery blood flow. One patient required conservation of the collateral circulation, and 2 patients needed arterial reconstruction. In the analysis of the level of origin of the celiac axis, there were no remarkable differences between nonstenotic and stenotic cases, or between mild and severe stenotic cases. Morphologic grades were defined based on the preoperative image findings and consequent intraoperative treatments. Conclusion Preoperative grading of celiac axis stenosis could make pancreatoduodenectomy safer with maintenance of the upper abdominal organ blood flow in patients with MAL compression.

Background Wrapping is thought to prevent pancreatic fistula and postoperative hemorrhage for pancreaticoduodenectomy (PD), and we analyzed whether omentum/falciform ligament wrapping decreases postoperative complications after PD. Methods This is a retrospective study of wrapping using the omentum/falciform ligament in patients that underwent PD between January 2006 and June 2008 in 139 institutions that were members of the Japanese Society of Pancreatic Surgery. Results Ninety-one institutions responded to the questionnaires, and data were accumulated from 3,288 patients. The data from 2,597 patients were acceptable for analysis; 918 (35.3%) patients underwent wrapping and 1,679 patients did not. A pancreatic fistula occurred in 623 patients (37.3%) in the nonwrapping group, in comparison to 393 patients (42.8%) in the wrapping group (P = .006). The incidence of a grade B/C pancreatic fistula was lower in the nonwrapping group than the wrapping group (16.7% vs 21.5%; P = .002). An intra-abdominal hemorrhage occurred in 54 patients (3.2%) in the nonwrapping group, which was similar to the incidence in the wrapping group (32 patients; 3.5%). The mortality was 1.3% and 1.0% in nonwrapping and wrapping groups, respectively. A multivariate analysis revealed 7 independent risk factors for pancreatic fistula; male, hypoalbuminemia, soft pancreas, long operation time, extended resection, pylorus preservation, and omentum wrapping. There were 4 independent risk factors for early intra-abdominal hemorrhage and 2 independent risk factors for late intra-abdominal hemorrhage. Conclusion This retrospective study revealed that omentum wrapping did not decrease the incidence of pancreatic fistula. An additional validation study is necessary to evaluate the efficacy of wrapping for PD.

Although several studies have reported that locally administering oncolytic viruses effectively targets malignancies, the efficacy of systemically administered oncolytic viruses is restricted. Recently, however, it was reported that systemic administration of oncolytic vesicular stomatitis virus adsorbed onto antigen-specific lymphocytes was effective against malignancies. We hypothesized that intravenously administering such virus might have significant potential in treatment of the malignant tumors. We adsorbed oncolytic herpes simplex virus-1 mutant R3616 onto lymphocytes harvested from mice with acquired antitumor immunity. We administered adsorbed R3616 to peritoneally disseminated tumors and analyzed the efficacy of this treatment. Mice administered adsorbed R3616 survived significantly longer than mice administered R3616 adsorbed onto non-specific lymphocytes, or mice administered either virus or tumor antigen-specific lymphocytes alone. In this context, herpes oncolytic virus is a promising treatment not only for primary lesions, but also for multiple metastasizing lesions. This treatment strategy may become one of the most effective methods for systemic virus delivery.

症例は77歳の男性で，特に自覚症状はなかったが，他科疾患フォロー中に，スクリーニングの上部消化管内視鏡検査で十二指腸腫瘍を指摘された．十二指腸下行脚乳頭部側で乳頭部よりわずかに口側に10mm大の隆起性病変を認め，低緊張性十二指腸造影検査では，腫瘍の下縁と乳頭部上縁の距離は約2cmであった．生検で腺癌と診断され，超音波内視鏡検査で深達度MPと診断されたため，高齢で基礎疾患を多く有するが，手術の方針とした．十二指腸下行脚は膵頭部からの剥離がある程度可能であり，低侵襲手術として幽門側胃切除術を施行した．病理組織学的には，Brunner腺発生の腺癌であり，胃癌取扱い規約（第14版）に則ると，pT1pN0 H0 P0 CY0 M0 ly0 v0 pPM（－）pDM（－）pStage IAであった．術後1年経過するが，無再発生存中である．

A retrospective study was performed to clarify the correlation between radiographic type of portal vein (PV) invasion and pathological grade of PV wall invasion, and their correlation with postoperative prognosis.In many patients with pancreatic cancer, PV resection is necessary to increase resectability and obtain cancer-free margins.We analyzed 671 patients who had undergone surgery for invasive adenocarcinoma of the pancreas between July 1981 and June 2010. Radiographic types of PV invasion of pancreatic head cancer were classified into A (normal), B (unilateral narrowing), C (bilateral narrowing), or D (complete obstruction with collateral veins), by portography or computed tomography. Pathological grades of PV wall invasion were classified as 0 (no invasion), 1 (tunica adventitia), 2 (tunica media), or 3 (tunica intima).Four hundred and sixty-three patients underwent resection, and PV resection was performed in 297. Combined arterial vessel resection was performed in 16 cases. No significant difference in operative mortality was observed between PV preservation (0.6%) and PV-only resection (2.1%), and no operative deaths occurred after 1999. Radiographic classification of PV invasion correlated with incidence of pathological PV wall invasion. In pancreatic head carcinoma, no pathological PV wall invasion was observed in type A (n = 111). Pathological PV invasion was observed in 51% of type B (42/82), 74% of type C (72/97), and 93% of type D (63/68). Long-term survival (5 years) was observed in types A and B, and grades 0 and 1 subgroups.Pancreatectomy with PV resection can be performed safely. Even in radiographic classification type B, pathological PV wall invasion was observed in 51% of patients. Long-term survival was observed in types A and B, and grades 0 and 1.

The usefulness of enteral nutrition via a nasointestinal tube for patients who develop postoperative pancreatic fistula (POPF) after miscellaneous pancreatectomy procedures has been reported. However, no clear evidence regarding whether oral intake is beneficial or harmful during management of POPF after distal pancreatectomy (DP) is currently available. To investigate the effects of oral food intake on the healing process of POPF after DP. Multi-institutional randomized controlled trial in Nagoya University Hospital and 4 affiliated hospitals. Patients who developed POPF were randomly assigned to the dietary intake (DI) group (n=15) or the fasted group (no dietary intake [NDI] group) (n=15). The primary endpoint was the length of drain placement. No significant differences were found in the length of drain placement between the DI and NDI groups (12 [6-58] and 12 [7-112] days, respectively; P=0.786). POPF progressed to a clinically relevant status (grade B/C) in 5 patients in the DI group and 4 patients in the NDI group (P=0.690). POPF-related intra-abdominal hemorrhage was found in 1 patient in the NDI group but in no patients in the DI group (P=0.309). There were no significant differences in POPF-related intra-abdominal hemorrhage, the incidence of other complications, or the length of the postoperative hospital stay between the 2 groups. Food intake did not aggravate POPF and did not prolong drain placement or hospital stay after DP. There may be no need to avoid oral DI in patients with POPF.

Oncolytic viruses are a promising method of cancer therapy, even for advanced malignancies. HF10, a spontaneously mutated herpes simplex type 1, is a potent oncolytic agent. The interaction of oncolytic herpes viruses with the tumor microenvironment has not been well characterized. We injected HF10 into tumors of patients with recurrent breast carcinoma, and sought to determine its effects on the tumor microenvironment. Six patients with recurrent breast cancer were recruited to the study. Tumors were divided into two groups: saline-injected (control) and HF10-injected (treatment). We investigated several parameters including neovascularization (CD31) and tumor lymphocyte infiltration (CD8, CD4), determined by immunohistochemistry, and apoptosis, determined by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Median apoptotic cell count was lower in the treatment group (P=0.016). Angiogenesis was significantly higher in treatment group (P=0.032). Count of CD8-positive lymphocytes infiltrating the tumors was higher in the treatment group (P=0.008). We were unable to determine CD4-positive lymphocyte infiltration. An effective oncolytic viral agent must replicate efficiently in tumor cells, leading to higher viral counts, in order to aid viral penetration. HF10 seems to meet this criterion; furthermore, it induces potent antitumor immunity. The increase in angiogenesis may be due to either viral replication or the inflammatory response.

Molecular mechanisms behind the oncogenesis of gastric cancer (GC) have yet to be identified. A novel candidate tumor-suppressor gene, which is also associated with inhibition of epidermal growth factor (EGF), was sought by means of double combination array analysis for use as a prognostic marker of GC. This consisted of expression array and single nucleotide polymorphism array analysis, along with a literature search. Cancerous and noncancerous tissues from an 82-year-old man with GC were analyzed simultaneously. The expression array and literature search identified that the suppressor of cytokine signaling 4 (SOCS4), a negative feedback regulator of EGF signaling, had significantly attenuated expression in tumor tissue. Although chromosomal deletion was not found at 14q22 where SOCS4 is located, numerous CpG sites were observed in the promoter region of the SOCS4 gene. Several GC cell lines showed reactivation of SOCS4 mRNA expression after treatment with 5-aza-2′-deoxycytidine. Using surgically resected specimens, we found that 40 of 50 (80%) tumor tissues exhibited promoter hypermethylation of the SOCS4 gene. Consequently, SOCS4 expression in tumor tissues was significantly weaker than in noncancerous counterparts (P

The current classification of pancreatic cancer is based only on anatomic location of metastatic lymph nodes (LNs). On the other hand, the number of metastatic LNs has been used in staging of colorectal, esophageal, and gastric cancers. The aim of this study was to assess the prognostic impact of the number or ratio of the metastatic LNs in pancreatic body and tail carcinoma.Eighty-five patients with pancreatic body and tail adenocarcinoma who underwent pancreatectomy were included. Location, number, ratio of metastatic LNs, and the survival of patients were analyzed.Forty patients with LN metastasis had poor prognosis (P = 0.007). The prognoses of patients with 5 or more metastatic LNs were poorer than those with less than 5 metastatic LNs (P = 0.046), and patients with a metastatic LN ratio of 0.2 or more had the worst prognosis. Multivariate analysis revealed that 5 or more metastatic LNs and metastatic LN ratio of 0.2 or more were independent prognostic factors for survival (P = 0.0015 and P = 0.014, respectively).These results indicate that the number and the ratio of metastatic LNs can be used to predict poor patient survival and as a staging strategy.

Pylorus-preserving pancreatoduodenectomy (PPPD) has replaced conventional pancreatoduodenectomy with a distal gastrectomy (cPD) as the most commonly performed procedure. However, there has been no evidence from prospective studies to indicate the overwhelming superiority of PPPD over cPD. A recent report revealed that resection of the pyloric ring reduced the incidence of delayed gastric emptying (DGE) in a randomized controlled trial. In 158 patients with pancreatic head cancer, the perioperative outcomes and long-term nutritional consequences were retrospectively compared among three types of pancreatoduodenectomy: cPD; PPPD; and subtotal stomach-preserving pancreatoduodenectomy (SSPPD), in which the pyloric ring and duodenum were removed and more than 90% of the stomach was preserved. The incidence of DGE was significantly higher in the PPPD group than in the cPD and SSPPD groups (27.3 vs. 5.8 and 5.4%, respectively; P = 0.0012). The serum albumin concentration and total lymphocyte count at 1 year postoperatively were significantly higher in the SSPPD group than in the PPPD group (P = 0.0303 and P = 0.0203, respectively). The patients in the SSPPD group showed longer survival times than the patients in the cPD and PPPD groups (median survival times, 21.3, 17.1, and 17.7 months, respectively), although the differences did not reach statistical significance. Our results suggest that preservation of the pyloric ring without vagal innervation has little significance, and that SSPPD with better perioperative and long-term outcomes is more suitable as a standard procedure for patients with pancreatic head cancer.

Background Hepatectomy is one of the best curative therapies for hepatocellular carcinoma (HCC). The negative impact of postoperative complications on long-term survival has been investigated in patients with several kinds of cancers. To clarify the impact of postoperative complications on long-term survival in patients who undergo hepatectomy for HCC, we conducted a comparative analysis of 376 patients using the modified Clavien classification and identified the predictors of postoperative complications. Methods Patients were assigned into two groups: those with (N = 177) and those without complications (N = 199). The clinical data, surgical outcome, and long-term survival of patients were analyzed retrospectively. Results The cumulative overall survival rates of the patients with complications were significantly less than those of the patients without complications (P

To assess the prognostic effect of intraoperative radiotherapy (IORT) in unresectable pancreatic cancer.We reviewed 198 patients with unresectable pancreatic cancer, which was found during experimental laparotomy. Liver metastasis was observed in 70 patients, peritoneal metastasis in 44, liver and peritoneal metastasis in 23 and locally advanced tumor in 61. Treatment consisted of IORT with or without postoperative chemotherapy. Overall survival (OS) and prognostic factors were evaluated for each pattern of disease spread.IORT was performed in 120 patients, and chemotherapy was administered in 80. Sixty patients did not receive either treatment. OS in the untreated group was significantly inferior to that for IORT alone and IORT plus gemcitabine (GEM)-based chemotherapy. IORT and GEM-based chemotherapy were identified as independent prognostic factors [hazard ratio (HR) = 0.51, p0.001; HR = 0.43, p0.001]. IORT was an independent prognostic determinant for patients with peritoneal metastasis (HR = 0.24, p = 0.011) but not for those with liver metastasis (HR = 0.78, p = 0.381).IORT followed by GEM-based chemotherapy is the recommended treatment strategy in unresectable pancreatic cancer. and IAP.

A combination of fluorouracil and leucovorin (5-FU/LV) with oxaliplatin (FOLFOX) is an established first-line therapy for metastatic colorectal cancer (mCRC). However, the cumulative neurotoxicity of oxaliplatin often requires therapy to be discontinued while the patient is still responding. A strategy to stop FOLFOX, deliver 5-FU/LV as a maintenance therapy and reintroduce FOLFOX was found to be equivalent in terms of efficacy while neurotoxicity was substantially reduced. The aim of this study was to evaluate feasibility of a stop-and-go strategy with S-1, an oral fluoropyrimidine derivative, as a maintenance therapy administered between modified FOLFOX6 (mFOLFOX6) as a first-line treatment of mCRC.Thirty patients with untreated mCRC were treated with six cycles of mFOLFOX6 followed by maintenance therapy with oral S-1. Reintroduction of mFOLFOX6 was scheduled after four cycles of S-1 or upon tumor progression. The primary endpoint was duration of disease control (DDC).Twenty-one of the 30 patients who achieved responses or stabilizations received S-1 maintenance therapy. mFOLFOX6 was reintroduced in 15 patients. Median DDC and progression-free survival were 9.3 and 7.9 months, respectively. The response rates and disease control rates were 40.0 and 86.6% for the initial mFOLFOX6, 23.8 and 57.1% for S-1 maintenance therapy and 20.0 and 73.3% for mFOLFOX6 reintroduction, respectively. Twenty-eight patients (93.3%) had peripheral neuropathy, but grade 3 neurotoxicity was observed in only 1 patient (3.3%).The planned oxaliplatin stop-and-go strategy with oral S-1 maintenance therapy was feasible as a first-line treatment for Japanese mCRC patients. Further prospective randomized control study is warranted.

Resection of hepatocellular carcinoma (HCC) located in the right liver often requires hepatic mobilization. However, exposure of the HCC may be restricted when using the conventional abdominal approach (AA). In such cases, a thoracoabdominal approach (TA) can provide a good operating field. Although several studies have reported on the TA for hepatectomy for HCC, none have been published since 2003. Accordingly, this issue seemed to have been resolved, based on the advantages of this approach. However, surgical instruments are constantly improving and hepatectomy may be possible without the TA. Data were retrospectively collected from 284 consecutive patients who underwent primary hepatectomy for HCC located in the right liver between January 1991 and December 2009. We compared the perioperative outcomes between patients who underwent the TA (n = 111) and those who underwent the AA (n = 173). Patient characteristics of both groups were comparable. The morbidity rate (Clavien grade ≥ 1) was significantly greater with the TA than with the AA (64.2 vs. 49.2%, p = 0.01), as was operative time (median = 370 vs. 315 min, p = 0.001) and hospital stay (median = 25 vs. 21 days, p = 0.005). There were no differences in hospital mortality or overall or disease-free survival. The TA provides no additional benefits over the AA in terms of safety and postoperative outcomes. We recommend that the TA should be used in exceptional circumstances because it resulted in a higher morbidity rate and longer operative time and postoperative hospitalization compared with the AA.

Protein production within the secretory pathway is accomplished by complex but organized processes. Here, we demonstrate that the growth factor midkine interacts with LDL receptor-related protein 1 (LRP1) at high affinity (K(d) value, 2.7 nm) not only at the cell surface but also within the secretory pathway during biosynthesis. The latter premature ligand-receptor interaction resulted in aggregate formation and consequently suppressed midkine secretion and LRP1 maturation. We utilized an endoplasmic reticulum (ER) retrieval signal and an LRP1 fragment, which strongly bound to midkine and the LRP1-specialized chaperone receptor-associated protein (RAP), to construct an ER trapper. The ER trapper efficiently trapped midkine and RAP and mimicked the premature ligand-receptor interaction, i.e. suppressed maturation of the ligand and receptor. The ER trapper also diminished the inhibitory function of LRP1 on platelet-derived growth factor-mediated cell migration. Complementary to these results, an increased expression of RAP was closely associated with midkine expression in human colorectal carcinomas (33 of 39 cases examined). Our results suggest that the premature ligand-receptor interaction plays a role in protein production within the secretory pathway.