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OBJECTIVES In patients with severe acute pancreatitis (SAP), early enteral nutrition (EN) is recommended by major clinical practice guidelines, but the exact timing for the initiation of EN is unknown. METHODS We conducted a post hoc analysis of the database for a multicenter (44 institutions) retrospective study of patients with SAP in Japan. The patients were classified into 3 groups according to the timing of EN initiation after the diagnosis of SAP: within 24 hours, between 24 and 48 hours, and more than 48 hours. The primary outcome was in-hospital mortality. RESULTS Of the 1094 study patients, 176, 120, and 798 patients started EN within 24 hours, between 24 and 48 hours, and more than 48 hours after SAP diagnosis, respectively. On multivariable analysis, hospital mortality was significantly better with EN within 48 hours than with more than 48 hours (adjusted odds ratio, 0.49; 95% confidence interval, 0.29-0.83; P < 0.001) but did not significantly differ between the groups with EN starting within 24 hours and between 24 and 48 hours (P = 0.29). CONCLUSIONS Enteral nutrition within 24 hours may not confer any additional benefit on clinical outcomes compared with EN between 24 and 48 hours.

Background Japanese (JPN) guidelines for the management of acute pancreatitis were published in 2006. The severity assessment criteria for acute pancreatitis were later revised by the Japanese Ministry of Health, Labour and Welfare (MHLW) in 2008, leading to their publication as the JPN Guidelines 2010. Following the 2012 revision of the Atlanta Classifications of Acute Pancreatitis, in which the classifications of regional complications of pancreatitis were revised, the development of a minimally invasive method for local complications of pancreatitis spread, and emerging evidence was gathered and revised into the JPN Guidelines. Methods A comprehensive evaluation was carried out on the evidence for epidemiology, diagnosis, severity, treatment, post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis and clinical indicators, based on the concepts of the GRADE system (Grading of Recommendations Assessment, Development and Evaluation). With the graded recommendations, where the evidence was unclear, Meta-Analysis team for JPN Guidelines 2015 conducted an additional new meta-analysis, the results of which were included in the guidelines. Results Thirty-nine questions were prepared in 17 subject areas, for which 43 recommendations were made. The 17 subject areas were: Diagnosis, Diagnostic imaging, Etiology, Severity assessment, Transfer indication, Fluid therapy, Nasogastric tube, Pain control, Antibiotics prophylaxis, Protease inhibitor, Nutritional support, Intensive care, management of Biliary Pancreatitis, management of Abdominal Compartment Syndrome, Interventions for the local complications, Post-ERCP pancreatitis and Clinical Indicator (Pancreatitis Bundles 2015). Meta-analysis was conducted in the following four subject areas based on randomized controlled trials: (1) prophylactic antibiotics use; (2) prophylactic pancreatic stent placement for the prevention of post-ERCP pancreatitis; (3) prophylactic non-steroidal anti-inflammatory drugs (NSAIDs) for the prevention of post-ERCP pancreatitis; and (4) peritoneal lavage. Using the results of the meta-analysis, recommendations were graded to create useful information. In addition, a mobile application was developed, which made it possible to diagnose, assess severity and check pancreatitis bundles. Conclusions The JPN Guidelines 2015 were prepared using the most up-to-date methods, and including the latest recommended medical treatments, and we are confident that this will make them easy for many clinicians to use, and will provide a useful tool in the decision-making process for the treatment of patients, and optimal medical support. The free mobile application and calculator for the JPN Guidelines 2015 is available via http://www.jshbps.jp/en/guideline/jpn-guideline2015.html

Considering that the Japanese (JPN) guidelines for the management of acute pancreatitis were published in Takada et al. (J HepatoBiliary Pancreat Surg 13:2-6, 2006), doubts will be cast as to the reason for publishing a revised edition of the Guidelines for the management of acute pancreatitis: the JPN guidelines 2010, at this time. The rationale for this is that new criteria for the severity assessment of acute pancreatitis were made public on the basis of a summary of activities and reports of shared studies that were conducted in 2008. The new severity classification is entirely different from that adopted in the 2006 guidelines. A drastic revision was made in the new criteria. For example, about half of the cases that have been assessed previously as being 'severe' are assessed as being 'mild' in the new criteria. The JPN guidelines 2010 are published so that consistency between the criteria for severity assessment in the first edition and the new criteria will be maintained. In the new criteria, severity assessment can be made only by calculating the 9 scored prognostic factors. Severity assessment according to the contrast-enhanced computed tomography (CT) grade was made by scoring the poorly visualized pancreatic area in addition to determining the degree of extrapancreatic progress of inflammation and its extent. Changes made in accordance with the new criteria are seen in various parts of the guidelines. In the present revised edition, post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis is treated as an independent item. Furthermore, clinical indicators (pancreatitis bundles) are presented to improve the quality of the management of acute pancreatitis and to increase adherence to new guidelines.

The Japanese Guidelines for the Management of Acute Pancreatitis was published in 2003. However, the impact of the guidelines on physicians’ practice patterns has not been well known. To examine the current clinical practices in the management of acute pancreatitis, we conducted a questionnaire survey with members of three societies involved in the treatment of pancreatic diseases and abdominal emergency medical care. Questions included diagnostic and treatment processes considered important in the management of acute pancreatitis in addition to demographic data, experience in medical care, and areas of specialty of respondents. We also examined changes in the treatment of acute pancreatitis before and after publication of the Guidelines. Of 1,000 society members to whom questionnaires were mailed, 590 responded. Respondents who had read the Guidelines also handled significantly more cases in the most recent 3 years. A variety of changes were observed in the performance of clinical practices before and after publication of the Guidelines. The use of amylase in the assessment of severity decreased significantly, while its use for determination of severity scores increased significantly after publication of the Guidelines. In treatment, use of a nasogastric tube in mild and moderate cases deceased after the Guidelines. The frequency of prophylactic use of antibiotics decreased with mild pancreatitis after publication of the Guidelines. Although it is difficult to attribute these changes to the direct influence of the Guidelines, several changes were observed in performance of clinical practices in accordance with recommendations of the Guidelines.

The clinical course of acute pancreatitis varies from mild to severe. Assessment of severity and etiology of acute pancreatitis is important to determine the strategy of management for acute pancreatitis. Acute pancreatitis is classified according to its morphology into edematous pancreatitis and necrotizing pancreatitis. Edematous pancreatitis accounts for 80-90% of acute pancreatitis and remission can be achieved in most of the patients without receiving any special treatment. Necrotizing pancreatitis occupies 10-20% of acute pancreatitis and the mortality rate is reported to be 14-25%. The mortality rate is particularly high (34-40%) for infected pancreatic necrosis that is accompanied by bacterial infection in the necrotic tissue of the pancreas (Widdison and Karanjia in Br J Surg 80:148-154, 1993; Ogawa et al. in Research of the actual situations of acute pancreatitis. Research Group for Specific Retractable Diseases, Specific Disease Measure Research Work Sponsored by Ministry of Health, Labour, and Welfare. Heisei 12 Research Report, pp 17-33, 2001). On the other hand, the mortality rate is reported to be 0-11% for sterile pancreatic necrosis which is not accompanied by bacterial infection (Ogawa et al. 2001; Bradely and Allen in Am J Surg 161:19-24, 1991; Rattner et al. in Am J Surg 163:105-109, 1992). The Japanese (JPN) Guidelines were designed to provide recommendations regarding the management of acute pancreatitis in patients having a variety of clinical characteristics. This article describes the guidelines for the surgical management and interventional therapy of acute pancreatitis by incorporating the latest evidence for the management of acute pancreatitis in the Japanese-language version of JPN guidelines 2010. Eleven clinical questions (CQ) are proposed: (1) worsening clinical manifestations and hematological data, positive blood bacteria culture test, positive blood endotoxin test, and the presence of gas bubbles in and around the pancreas on CT scan are indirect findings of infected pancreatic necrosis; (2) bacteriological examination by fine needle aspiration is useful for making a definitive diagnosis of infected pancreatic necrosis; (3) conservative treatment should be performed in sterile pancreatic necrosis; (4) infected pancreatic necrosis is an indication for interventional therapy. However, conservative treatment by antibiotic administration is also available in patients who are in stable general condition; (5) early surgery for necrotizing pancreatitis is not recommended, and it should be delayed as long as possible; (6) necrosectomy is recommended as a surgical procedure for infected necrosis; (7) after necrosectomy, a long-term follow-up paying attention to pancreatic function and complications including the stricture of the bile duct and the pancreatic duct is necessary; (8) drainage including percutaneous, endoscopic and surgical procedure should be performed for pancreatic abscess; (9) if the clinical findings of pancreatic abscess are not improved by percutaneous or endoscopic drainage, surgical drainage should be performed; (10) interventional treatment should be performed for pancreatic pseudocysts that give rise to symptoms, accompany complications or increase the diameter of cysts and (11) percutaneous drainage, endoscopic drainage or surgical procedures are selected in accordance with the conditions of individual cases.

The assessment of severity at the initial medical examination plays an important role in introducing adequate early treatment and the transfer of patients to a medical facility that can cope with severe acute pancreatitis. Under these circumstances, "criteria for severity assessment" have been prepared in various countries, including Japan, and these criteria are now being evaluated. The criteria for severity assessment of acute pancreatitis in Japan were determined in 1990 (of which a partial revision was made in 1999). In 2008, an overall revision was made and the new Japanese criteria for severity assessment of acute pancreatitis were prepared. In the new criteria for severity assessment, the diagnosis of severe acute pancreatitis can be made according to 9 prognostic factors and/or the computed tomography (CT) grades based on contrast-enhanced CT. Patients with severe acute pancreatitis are expected to be transferred to a specialist medical center or to an intensive care unit to receive adequate treatment there. In Japan, severe acute pancreatitis is recognized as being a specified intractable disease on the basis of these criteria, so medical expenses associated with severe acute pancreatitis are covered by Government payment.

Practical guidelines for the diagnosis of acute pancreatitis are presented so that a rapid and adequate diagnosis can be made. When acute pancreatitis is suspected in patients with acute onset of abdominal pain and tenderness mainly in the upper abdomen, the diagnosis of acute pancreatitis is made on the basis of elevated levels of pancreatic enzymes in the blood and/or urine. Furthermore, other acute abdominal diseases are ruled out if local findings associated with pancreatitis are confirmed by diagnostic imaging. According to the diagnostic criteria established in Japan, patients who present with two of the following three manifestations are diagnosed as having acute pancreatitis: characteristic upper abdominal pain, elevated levels of pancreatic enzymes, and findings of ultrasonography (US), CT or MRI suggesting acute pancreatitis. Detection of elevated levels of blood pancreatic enzymes is crucial in the diagnosis of acute pancreatitis. Measurement of blood lipase is recommended, because it is reported to be superior to all other pancreatic enzymes in terms of sensitivity and specificity. For measurements of the blood amylase level widely used in Japan, it should be cautioned that, because of its low specificity, abnormal high values are also often obtained in diseases other than pancreatitis. The cut-off level of blood pancreatic enzymes for the diagnosis of acute pancreatitis is not able to be set because of lack of sufficient evidence and consensus to date. CT study is the most appropriate procedure to confirm image findings of acute pancreatitis. Elucidation of the etiology of acute pancreatitis should be continued after a diagnosis of acute pancreatitis. In the process of the etiologic elucidation of acute pancreatitis, judgment whether it is gallstone-induced or not is most urgent and crucial for deciding treatment policy including the assessment of whether endoscopic papillary treatment should be conducted or not. The diagnosis of gallstone-induced acute pancreatitis can be made by combining detection of elevated levels of bilirubin, transamylase (ALT, AST) and ALP detected by hematological examination and the visualization of gallstones by US.

In the care of acute pancreatitis, a prompt search for the etiologic condition of the disease should be conducted. A differentiation of gallstone-induced acute pancreatitis should be given top priority in its etiologic diagnosis because it is related to the decision of treatment policy. Examinations necessary for diagnosing gallstone-induced acute pancreatitis include blood tests and ultrasonography. Early ERCP/ES should be performed in patients with gallstone-induced acute pancreatitis if a complication of cholangitis and a prolonged passage disorder of the biliary tract are suspected. The treatment for bile duct stones with the use of ERCP/ES alone is not recommended in cases of gallstone-induced pancreatitis with gallbladder stones. Cholecystectomy for gallstone-induced acute pancreatitis should be performed using a laparoscopic procedure as the first option as soon as the disease has subsided.

When a diagnosis of acute pancreatitis (AP) is made, fundamental medical treatment consisting of fasting, intravenous (IV) fluid replacement, and analgesics with a close monitoring of vital signs should be immediately started. In parallel with fundamental medical treatment, assessment of severity based on clinical signs, blood test, urinalysis and imaging tests should be performed to determine the way of treatment for each patient. A repeat evaluation of severity is important since the condition is unstable especially in the early stage of AP. At the time of initial diagnosis, the etiology should be investigated by means of blood test, urinalysis and diagnostic imaging. If a biliary pancreatitis accompanied with acute cholangitis or biliary stasis is diagnosed or suspected, an early endoscopic retrograde cholangiopancreatography with or without endoscopic sphincterotomy (ERCP/ES) is recommended in addition to the fundamental medical treatment. In mild cases, the fundamental medical treatment should be continued until clinical symptom is subsided with normal laboratory data. In cases with severe acute pancreatitis (SAP) referral should be considered to medical centers experienced in the treatment of SAP, and intensive care is recommended for preventing both organ failures and infectious complications. Hemodynamic stabilization with vigorous fluid resuscitation, respiratory support and antibiotics are the major parts of intensive care in the early period of SAP. Continuous hemodiafiltration (CHDF) and continuous regional arterial infusion (CRAI) of protease inhibitor and/or antibiotics may be effective to improve pathophysiology of AP especially in the early stage of the disease. In the late stage of AP, infectious complications are critical. If an infectious complication is suspected based on clinical signs, blood test and imaging, a fine needle aspiration (FNA) is recommended to establish a diagnosis. The accuracy of FNA is reported to be 89 ~ 100%. For patients with sterile pancreatitis, non-surgical treatment should be indicated. For patients with infected pancreatic necrosis, therapeutic intervention either by percutaneous, endoscopic, laparoscopic or surgical approach are indicated. The most preferred surgical intervention is necrosectomy, however, non-surgical treatment with antibiotics is still the treatment of choice if the general condition is stable. Necrosectomy should be performed as late as possible. For patients with pancreatic abscess, drainage is recommended.

Gallstones, along with alcohol, are one of the primary etiological factors of acute pancreatitis, and knowledge of the etiology as well as the diagnosis and management of gallstones, is crucial for managing acute pancreatitis. Because of this, evidence regarding the management of gallstone-induced pancreatitis in Japan was collected, and recommendation levels were established by comparing current clinical practices with optimal clinical practices. The JPN Guidelines for managing gallstone-induced acute pancreatitis recommend two procedures: (1) an urgent endoscopic procedure should be performed in patients in whom biliary duct obstruction is suspected and in patients complicated by cholangitis (Recommendation A); and (2) after the attack of gallstone pancreatitis has subsided, a laparoscopic cholecystectomy should be performed during the same hospital stay (Recommendation B).

The basic principles of the initial management of acute pancreatitis are adequate monitoring of vital signs, fluid replacement, correction of any electrolyte imbalance, nutritional support, and the prevention of local and systemic complications. Patients with severe acute pancreatitis should be transferred to a medical facility where adequate monitoring and intensive medical care are available. Strict cardiovascular and respiratory monitoring is mandatory for maintaining the cardiopulmonary system in patients with severe acute pancreatitis. Maximum fluid replacement is needed to stabilize the cardiovascular system. Prophylactic antibiotic administration is recommended to prevent infectious complications in patients with necrotizing pancreatitis. Although the efficacy of the intravenous administration of protease inhibitors is still a matter of controversy, there is a consensus in Japan that a large dose of a synthetic protease inhibitor should be given to patients with severe acute pancreatitis in order to prevent organ failure and other complications. Enteral feeding is superior to parenteral nutrition when it comes to the nutritional support of patients with severe acute pancreatitis. The JPN Guidelines recommend, as optional measures, blood purification therapy and continuous regional arterial infusion of a protease inhibitor and antibiotics, depending on the patient’s condition.

Acute pancreatitis represents a spectrum of disease ranging from a mild, self-limited course to a rapidly progressive, severe illness. The mortality rate of severe acute pancreatitis exceeds 20%, and some patients diagnosed as mild to moderate acute pancreatitis at the onset of the disease may progress to a severe, life-threatening illness within 2–3 days. The Japanese (JPN) guidelines were designed to provide recommendations regarding the management of acute pancreatitis in patients having a diversity of clinical characteristics. This article sets forth the JPN guidelines for the surgical management of acute pancreatitis, excluding gallstone pancreatitis, by incorporating the latest evidence for the surgical management of severe pancreatitis in the Japanese-language version of the evidence-based Guidelines for the Management of Acute Pancreatitis published in 2003. Ten guidelines are proposed: (1) computed tomography-guided or ultrasound-guided fine-needle aspiration for bacteriology should be performed in patients suspected of having infected pancreatic necrosis; (2) infected pancreatic necrosis accompanied by signs of sepsis is an indication for surgical intervention; (3) patients with sterile pancreatic necrosis should be managed conservatively, and surgical intervention should be performed only in selected cases, such as those with persistent organ complications or severe clinical deterioration despite maximum intensive care; (4) early surgical intervention is not recommended for necrotizing pancreatitis; (5) necrosectomy is recommended as the surgical procedure for infected pancreatic necrosis; (6) simple drainage should be avoided after necrosectomy, and either continuous closed lavage or open drainage should be performed; (7) surgical or percutaneous drainage should be performed for pancreatic abscess; (8) pancreatic abscesses for which clinical findings are not improved by percutaneous drainage should be subjected to surgical drainage immediately; (9) pancreatic pseudocysts that produce symptoms and complications or the diameter of which increases should be drained percutaneously or endoscopically; and (10) pancreatic pseudocysts that do not tend to improve in response to percutaneous drainage or endoscopic drainage should be managed surgically.

The diagnosis of acute pancreatitis is based on the following findings: (1) acute attacks of abdominal pain and tenderness in the epigastric region, (2) elevated blood levels of pancreatic enzymes, and (3) abnormal diagnostic imaging findings in the pancreas associated with acute pancreatitis. In Japan, in accordance with criteria established by the Japanese Ministry of Health, Labour, and Welfare, the severity of acute pancreatitis is assessed based on the clinical signs, hematological findings, and imaging findings, including abdominal contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI). Severity must be re-evaluated, especially in the period 24 to 48 h after the onset of acute pancreatitis, because even cases diagnosed as mild or moderate in the early stage may rapidly progress to severe. Management is selected according to the severity of acute pancreatitis, but it is imperative that an adequate infusion volume, vital-sign monitoring, and pain relief be instituted immediately after diagnosis in every patient. Patients with severe cases are treated with broad-spectrum antimicrobial agents, a continuous high-dose protease inhibitor, and continuous intraarterial infusion of protease inhibitors and antimicrobial agents; continuous hemodiafiltration may also be used to manage patients with severe cases. Whenever possible, transjejunal enteral nutrition should be administered, even in patients with severe cases, because it seems to decrease morbidity. Necrosectomy is performed when necrotizing pancreatitis is complicated by infection. In this case, continuous closed lavage or open drainage (planned necrosectomy) should be the selected procedure. Pancreatic abscesses are treated by surgical or percutaneous drainage. Emergency endoscopic procedures are given priority over other methods of management in patients with acute gallstone-associated pancreatitis, patients suspected of having bile duct obstruction, and patients with acute gallstone pancreatitis complicated by cholangitis. These strategies for the management of acute pancreatitis are shown in the algorithm in this article.

Acute pancreatitis is a common disease with an annual incidence of between 5 and 80 people per 100 000 of the population. The two major etiological factors responsible for acute pancreatitis are alcohol and cholelithiasis (gallstones). The proportion of patients with pancreatitis caused by alcohol or gallstones varies markedly in different countries and regions. The incidence of acute alcoholic pancreatitis is considered to be associated with high alcohol consumption. Although the incidence of alcoholic pancreatitis is much higher in men than in women, there is no difference in sexes in the risk involved after adjusting for alcohol intake. Other risk factors include endoscopic retrograde cholangiopancreatography, surgery, therapeutic drugs, HIV infection, hyperlipidemia, and biliary tract anomalies. Idiopathic acute pancreatitis is defined as acute pancreatitis in which the etiological factor cannot be specified. However, several studies have suggested that this entity includes cases caused by other specific disorders such as microlithiasis. Acute pancreatitis is a potentially fatal disease with an overall mortality of 2.1%–7.8%. The outcome of acute pancreatitis is determined by two factors that reflect the severity of the illness: organ failure and pancreatic necrosis. About half of the deaths in patients with acute pancreatitis occur within the first 1–2 weeks and are mainly attributable to multiple organ dysfunction syndrome (MODS). Depending on patient selection, necrotizing pancreatitis develops in approximately 10%–20% of patients and the mortality is high, ranging from 14% to 25% of these patients. Infected pancreatic necrosis develops in 30%–40% of patients with necrotizing pancreatitis and the incidence of MODS in such patients is high. The recurrence rate of acute pancreatitis is relatively high: almost half the patients with acute alcoholic pancreatitis experience a recurrence. When the gallstones are not treated, the risk of recurrence in gallstone pancreatitis ranges from 32% to 61%. After recovering from acute pancreatitis, about one-third to one-half of acute pancreatitis patients develop functional disorders, such as diabetes mellitus and fatty stool; the incidence of chronic pancreatitis after acute pancreatitis ranges from 3% to 13%. Nevertheless, many reports have shown that most patients who recover from acute pancreatitis regain good general health and return to their usual daily routine. Some authors have emphasized that endocrine function disorders are a common complication after severe acute pancreatitis has been treated by pancreatic resection.

Objectives The rat experimental model of continuous regional arterial infusion of protease inhibitor (CRAI) on acute pancreatitis has yet to be established. Therefore, the aims of this study were (1) to establish the rat experimental model of CRAI and (2) to evaluate the effects of nafamostat on rat severe acute pancreatitis via different routes of administration. Methods The rat internal jugular vein or the celiac artery was infused with nafamostat, and the concentration of nafamostat in the lung and pancreas was measured. After the induction of severe acute pancreatitis, rats received intravenous or regional intraarterial infusion of nafamostat and then concentrations of trypsinogen activated peptide (TAP) and serum interleukin (IL-6), and histologic sections of the pancreas were examined and the 96-hour survival rate was evaluated. Results CRAI rats had higher concentrations of nafamostat in the pancreas than those infused intravenously. However, CRAI rats had lower concentrations of nafamostat in the lung that those infused intravenously. CRAI significantly reduced the levels of TAP and pancreatic necrosis. Moreover, the levels of serum IL-6 and the mortality rate were significantly reduced after CRAI compared with the intravenous infusion of nafamostat. Conclusion The effectiveness of the rat experimental model of CRAI on acute pancreatitis was clearly demonstrated. The concentration of nafamostat in the lung and pancreas and the effects of nafamostat differ according to the route of administration.

Small pancreatic cancers, intractable diseases, offer the possibility of cure. Can this be true? Through the National Pancreatic Cancer Registry, the Japan Pancreas Society (JPS) has collected 822 cases of invasive cancer with tumors

On March 1, 1999, a 71-year-old woman was diagnosed as having cholecystolithiasis, for which she underwent laparoscopic cholecystectomy at a local hospital. Intraoperative cholangiography was not performed. No malignant lesion was detected in the gallbladder. In March 2000, a subcutaneous tumor was pointed out at the port site in her abdomen, and resected. Histological examination revealed metastatic adenocarcinoma. On detailed examination, endoscopic retrograde cholangiopancreatography (ERCP) revealed a tumor, about 2 cm in diameter, in the lower bile duct. On June 1, she underwent pylorus-preserving pancreatoduodenectomy at our institute, and several disseminated lesions were detected at the port site and in the abdominal cavity. There have been few reports of bile duct carcinoma that developed peritoneal dissemination caused by leakage of bile during cholecystectomy. Leakage of bile should be prevented during laparoscopic cholecystectomy, even in patients not diagnosed as having cancer preoperatively.

The mortality associated with severe acute pancreatitis is still high, and death in the later stage of the disease is chiefly due to bacterial infection and sepsis. However, objective parameters for the risk of sepsis in acute pancreatitis have not been established.To investigate the value of human leukocyte antigen-DR (HLA-DR) on peripheral monocytes for predicting the development of sepsis during acute pancreatitis.The expression of HLA-DR on peripheral monocytes was measured in 64 patients by flow cytometry at admission and 7 and 14 days after the onset of acute pancreatitis. Twenty-eight patients with severe acute pancreatitis and 36 with mild acute pancreatitis, as determined by the Atlanta classification, were enrolled.Six patients had sepsis, and two of them died during the hospital stay. At admission, the percentage of HLA-DR-expressing cells in the monocyte population was significantly lower in the patients who had sepsis in the later course than in the patients who did not have sepsis. A percentage lower than 80% at admission was observed in 17 patients, and the patients who had persistently low percentages of HLA-DR-expressing monocytes throughout the observation period had sepsis in the later clinical course, whereas the patients in whom expression recovered to the normal range were spared the development of sepsis.In acute pancreatitis, the low percentage of HLA-DR-expressing cells in the monocyte population is a reliable predictor of the development of sepsis. Monitoring of monocyte HLA-DR expression may be a useful marker for identifying the patients who are at high risk of sepsis in acute pancreatitis.

The clinical manifestations of acute pancreatitis (AP) vary significantly from mild to lethal in form, the severity of the disease being largely determined by the actions of various kinds of inflammatory mediators, including cytokines, reactive oxygen species, proteolytic enzymes, and lipids, as well as gaseous mediators. Despite increasing knowledge implicating the involvement of cytokines in the progression of AP, no clinical trials pertaining to cytokine modulation have been performed so far. Progress in intensive care technologies has contributed to the improvement of mortality and morbidity rates in severe AP in the past decade; however, it appears to be reasonable for clinicians to "line up their sights" on the modulation of cytokines as a direct treatment. In contrast to the large body of experimental studies demonstrating the beneficial effects of cytokine modulation on the amelioration of the disease, direct extrapolation from these successful experiments to the clinical situation seems to be extremely difficult.

In clinical settings, the effectiveness of protease inhibitors in the treatment of acute pancreatitis has been still controversial. With the concept that sufficient tissue concentration of protease inhibitor in the pancreas has to be included to achieve its potent inhibitory effect, we applied a continuous regional intra-arterial (CRI) application of low-molecular-weight protease inhibitor, nafamostat mesilate (FUT-175), for closed duodenal loop obstruction model in mongrel dogs. The use of CRI application led to a higher concentration of FUT-175 in the pancreatic tissue (4,453 ± 758 ng/g) when compared with that applied intravenously (905 ± 48 ng/g). Consequently, pancreatic parenchyma in CRI application animals was remarkably preserved, as assessed by the lower extent of pancreatic necrosis (12.4 ± 2.6% in CRI vs. 25.6 ± 1.9% in intravenous). Additionally, the elevation of trypsin-like activity in the pancreas was significantly inhibited in CRI animals. Based on these findings, the dose as well as the route of protease inhibitors should be carefully considered to achieve its beneficial effect.

Interleukin 12 (IL-12) is a heterodimeric cytokine that exerts a potent antitumor effect through its pleiotropic actions. It was recently reported that IL-12 has also a potent antiangiogenic effect through the induction of IFN-gamma, which triggers the production of chemokines such as IP-10 that has been shown to have antiangiogenesis properties. In this study we transfected the IL-12 gene into a human pancreatic adenocarcinoma cell line (PK-1). PK-1 cells transfected with the green fluorescence protein (gfp) gene were used as positive controls. The in vitro growth curve and in vivo tumor growth of transfectants (IL-12/PK-1 and gfp/PK-1) were compared with those of parental cells. The SCID mice used in this study were administered antiasialo GM-1 Ab (100 microg, i.p., twice weekly) to deplete the remaining immunoeffector cells, NK cells. Using a skinfold chamber model, we observed and recorded tumor angiogenesis by intravital microscopy. In vitro growth of IL-12/PK-1 and gfp/PK-1 cells was not different from that of wild-type PK-1 cells (wt/PK-1). However, IL-12 transfected PK-1 cells did not develop into tumors as did the wt/PK-1 cells after subcutaneous inoculation in antiasialo GM-1 Ab administered SCID mice. The growth of IL-12/PK-1 tumors was restored in mice treated with anti-IL-12 antibody. We found that IL-12/PK-1, in contrast to gfp/PK-1 and wt/PK-1, failed to initiate an angiogenic response, as observed in the skinfold chamber model. These results indicate that the antiangiogenesis effect of IL-12 alone, without immune system involvement, is sufficient to block the growth of human pancreatic cancer.

Clinical indicators set forth in the guidelines have been found to contribute to the improvement in compliance with the guidelines. On the other hand, it has been shown that clinical indicators are more effective when individual indicators are presented in the form of a bundle than when they are given separately. Accordingly, in the JPN Guidelines 2010 for management of acute pancreatitis, those indicators that are judged to be important on the basis of a recommendation classification of "A or B" are presented as a pancreatitis bundle. Each item includes assessment of severity after a diagnosis of pancreatitis has been made, differentiation of pathogenesis, management of gallstone-induced pancreatitis, a sufficient dose of fluid replacement and monitoring, pain control, prophylactic administration of wide-spectrum antibiotics and cholecystectomy following resolution of pancreatic symptoms caused by cholecystolithiasis. Hereafter, the efficacy of these indicators and the significance of their achievement should be examined carefully. Then, the assessment of the compliance rate with the guidelines as well as the assessment of the guidelines and pancreatitis itself should become possible.

Objectives It is known that prophylaxis with imipenem reduces the risk of infection accompanying severe acute pancreatitis. In this study,we modified a rat experimental model of severe acute pancreatitis for antibiotic evaluation, and the effect of biapenem was compared with that of imipenem to determine the usefulness of biapenem. Methods Severe acute pancreatitis was induced by 5% sodium taurocholate. Antibiotics were subcutaneously administered at 3 and 6 hours and evaluated at 12 hours after the pancreatitis induction. For pharmacokinetic evaluation, antibiotics were subcutaneously administered at 3 hours after the pancreatitis induction. Results From 3 hours after the induction, bacteria were detected from the pancreas. The total bacterial count increased in a time-dependent manner for 12 hours. Biapenem administration reduced the total bacterial count in the pancreas, as observed in imipenem administration. The plasma concentration of biapenem was almost equivalent to that of imipenem; however, the pancreatic penetration of biapenem was approximately twice that of imipenem in this model. Conclusions Biapenem was suggested to be effective in prophylactic treatment of infectious complications as much as imipenem because of its superior penetration to the pancreas in severe acute pancreatitis.

We present a review of the microvascular morphology of the pancreas and microstructure of the pancreatic lobule, and report our experimental results of the investigation of pancreatic microcirculation following acute pancreatitis. Impairment of pancreatic microcirculation in the early phase of acute pancreatitis may play a key role in the progression of this disease. Possible contributory mechanisms include increased vascular permeability, reduced blood flow, leukocyte-endothelial cell interaction and intravascular thrombus formation. Using an in-vivo microscope system and off-line computer analysis, we achieved direct visualization and quantification of changes in microvascular permeability and leukocyte behavior in pancreas with acute pancreatitis. Bradykinin and oxygen radicals have been demonstrated to be involved in the increase of vascular permeability in the early stage of caerulein pancreatitis. Leukocyte adherence to the vessels in the pancreatic microcirculation is a secondary event following permeability changes in acute pancreatitis. Leukocyte infiltration during exacerbation of acute pancreatitis is mediated by leukocyte-endothelial cell interaction via leukocyte integrin CD11b/18.

The Japanese grading system for severity of acute pancreatitis has evolved from results of a national survey on 2,553 patients managed in 523 major medical centers in Japan between 1982 and 1986. It was devised to embrace the predictive factors that would offer high sensitivity and specificity in rendering an accurate diagnosis. In this system, computed tomographic (CT) examination is used for estimating the severity of acute pancreatitis. Combining criteria from laboratory data, clinical signs, and CT findings, the system appears cumbersome. However, it is actually more flexible in that only few criteria, from the wide range of findings actually covered, are needed to predict severity. Its rationale stems from a national effort to improve the outcome of this life-threatening disease. Further prospective studies are needed to determine its accuracy and superiority.

The health insurance system in Japan is based upon the Universal Medical Care Insurance System, which gives all citizens the right to join an insurance scheme of their own choice, as guaranteed by the provisions of Article 25 of the Constitution of Japan, which states: “All people shall have the right to maintain the minimum standards of wholesome and cultured living.” The health care system in Japan includes national medical insurance, nursing care for the elderly, and government payments for the treatment of intractable diseases. Medical insurance provisions are handled by Employee’s Health Insurance (Social Insurance), which mainly covers employees of private companies and their families, and by National Health Insurance, which provides for the needs of self-employed people. Both schemes have their own medical care service programs for retired persons and their families. The health care system for the elderly covers people 75 years of age and over and bedridden people 65 years of age and over. There is also a system under which the government pays all or part of medical expenses, and/or pays medical expenses not covered by insurance. This is referred to collectively as the “medical expenses payment system” and includes the provision of medical assistance for specified intractable diseases. Because severe acute pancreatitis has a high mortality rate, it is specified as an intractable disease. In order to lower the mortality rate of various diseases, including severe acute pancreatitis, the specification system has been adopted by the government. The cost of treatment for severe acute pancreatitis is paid in full by the government from the date the application is made for a certificate verifying that the patient has an intractable disease.

To evaluate appropriate surgical treatment and to predict prognosis for mucin-producing tumors (MPTs) of the pancreas, we conducted a retrospective clinicopathological study in 25 patients with MPT. Eight patients who had mild dysplasia of the pancreas were diagnosed with benign disease and 17 patients with ductal lesions of the pancreas with severe dysplasia/carcinoma in situ or with invasive foci were diagnosed as malignant. Clinical symptoms and histories, tumor markers, cytological examination, and radiological and gross pathological features were compared in the benign and malignant groups. Clinical symptoms, history, and tumor markers were of no value for predicting prognosis. Cytological examination results were ambiguous because of too many falsenegatives. Radiological features, including the diameters of the cystic space and of the main pancreatic duct (MPD) were shown to be valuable. The significant maximal diameters, above which malignancy was seen, were 30mm for the diameter of the cystic space and 10mm for the MPD. In regard to gross features, the uniformly dilated main duct-type and focally dilated main duct-type were significant indicators of malignancy. Long term follow-up was available in 22 patients. Seven patients died of recurrence of the tumor or other malignancies. We could have predicted prognosis by the radiological features and gross appearance. Surgical treatment should be considered the primary choice for MPT. Total pancreatectomy would be ideal for patients with the uniformly dilated main duct-type. Because of the probability of multicentricity and the transforming potential of mild dysplasia, very careful follow-up is necessary for patients with MPT.

A new strategy for the treatment of acute necrotizing pancreatitis (ANP) is reported. In this prospective study, all patients received intensive medical support. Surgery was performed in patients with infected pancreatic necrosis and/or sepsis. Continuous regional arterial infusion (CRAI) of the protease inhibitor, nafamostat mesilate, and the antibiotic imipenem was initiated in patients with ANP referred to our hospital within 7 days of the onset of the disease. Sixty patients with ANP were allocated to three groups: group I, no CRAI (n =16); group II, CRAI of nafamostat only (n=22); and group III, CRAI of nafamostat mesilate and imipenem (n=22). The mortality rate was 43.3% in group I, 13.6% in group II (P

s / Pancreatology 16 (2016) S1eS130 S109 than 70 years showed pancreas volume over 80 ml, but in those over that age a reduction was observed below 70 ml. Conclusion:We have not found differences related to sex. People older than 70 years showed a decrease in pancreas volume.

The findings in 35 surgically treated patients with insulinoma and 43 tumors of these patients were analyzed to confirm the efficacy of diagnostic modalities and surgical interventions. The rate of accurate preoperative tumor localization was 72% by angiography, 53% by computed tomographic scan, 55% by ultrasonography, and 83% by percutaneous transhepatic portal vein sampling. Extensive operative exposure and palpation detected 81% of the tumors and intraoperative ultrasonography demonstrated 96% of the tumors. Intraoperative ultrasonography was significantly better than any other diagnostic procedure and was able to demonstrate the anatomical relationship of the insulinoma to the essential structures of the pancreas. Intraoperative ultrasonography also helped determine the safest route for enucleating the insulinomas. Five patients (14%) in our series had metastatic diseases; 2 of these patients with metastases beyond the lymph nodes died due to the growth of tumors. The other 33 patients were free of insulinoma syndrome after the removal of the insulinomas. Streptozotocin was used in 1 patient with recurrent malignant insulinoma, with encouraging results.

Infected pancreatic necrosis which spreads extensively in the retroperitoneal space requires open drainage to prevent the formation of residual abscess. With open drainage and repeated debridement, we often encountered patients who suffered from abdominal complications such as prolapse of the small intestine through the wound and injury to the intestine. In order to improve the open drainage method, we combined diverting ileostomy with open drainage. Diverting ileostomy was effective in decompressing the small intestine; this prevented prolapse and reduced the incidence of paralytic ileus. Prophylactic diverting ileostomy appears to result in the reduction of complications during open drainage and has advantages in the subsequent management of critically ill patients with infected pancreatic necrosis.

Pancreatitis remains the most common severe complication of endoscopic retrograde cholangiopancreatography (ERCP). Detailed information about the findings of previous studies concerning post-ERCP pancreatitis has not been utilized sufficiently. The purpose of the present article was to present guidelines for the diagnostic criteria of post-ERCP pancreatitis, and its incidence, risk factors, and prophylactic procedures that are supported by evidence. To achieve this purpose, a critical examination was made of the articles on post-ERCP pancreatitis, based on the data obtained by research studies published up to 2009. At present, there are no standardized diagnostic criteria for post-ERCP pancreatitis. It is appropriate that post-ERCP pancreatitis is defined as acute pancreatitis that has developed following ERCP, and its diagnosis and severity assessment should be made according to the diagnostic criteria and severity assessment of the Japanese Ministry of Health, Labour and Welfare. The incidence of acute pancreatitis associated with diagnostic and therapeutic ERCP is 0.4–1.5 and 1.6–5.4%, respectively. Endoscopic papillary balloon dilation is associated with a high risk of acute pancreatitis compared with endoscopic sphincterotomy. It was made clear that important risk factors include dysfunction of the Oddi sphincter, being of the female sex, past history of post-ERCP pancreatitis, and performance of pancreaticography. Temporary prophylactic placement of pancreatic stents in the high-risk group is useful for the prevention of post-ERCP pancreatitis [odds ratio (OR) 3.2, 95% confidence interval (CI) 1.6–6.4, number needed to treat (NNT) 10]. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduction in the development of post-ERCP pancreatitis (OR 0.46, 95% CI 0.32–0.65). Single rectal administration of NSAIDs is useful for the prevention of post-ERCP pancreatitis [relative risk (RR) 0.36, 95% CI 0.22–0.60, NNT 15] and decreases the development of pancreatitis in both the low-risk group (RR 0.29, 95% CI 0.12–0.71) and the high-risk group (RR 0.40, 95% CI 0.23–0.72) of post-ERCP pancreatitis. As for somatostatin, a bolus injection may be most useful compared with short- or long-term infusion (OR 0.271, 95% CI 0.138–0.536, risk difference 8.2%, 95% CI 4.4–12.0%). The usefulness of gabexate mesilate was not apparent in any of the following conditions: acute pancreatitis (control 5.7 vs. 4.8% for gabexate mesilate), hyperamylasemia (40.6 vs. 36.9%), and abdominal pain (1.7 vs. 8.9%). Formulation of diagnostic criteria for post-ERCP pancreatitis is needed. Temporary prophylactic placement of pancreatic stents in the high-risk group offers the most promise as a means of preventing post-ERCP pancreatitis. As for pharmacological attempts, there are high expectations concerning NSAIDs because they are excellent in terms of cost-effectiveness, ease of use, and safety. There was no evidence of effective prophylaxis with the use of protease inhibitors, especially gabexate mesilate.

Patients who have been diagnosed as having acute pancreatitis should be, on principle, hospitalized. Crucial fundamental management is required soon after a diagnosis of acute pancreatitis has been made and includes monitoring of the conscious state, the respiratory and cardiovascular system, the urinary output, adequate fluid replacement and pain control. Along with such management, etiologic diagnosis and severity assessment should be conducted. Patients with a diagnosis of severe acute pancreatitis should be transferred to a medical facility where intensive respiratory and cardiovascular management as well as interventional treatment, blood purification therapy and nutritional support are available. The disease condition in acute pancreatitis changes every moment and even symptoms that are mild at the time of diagnosis may become severe later. Therefore, severity assessment should be conducted repeatedly at least within 48 h following diagnosis. An adequate dose of fluid replacement is essential to stabilize cardiovascular dynamics and the dose should be adjusted while assessing circulatory dynamics constantly. A large dose of fluid replacement is usually required in patients with severe acute pancreatitis. Prophylactic antibiotic administration is recommended to prevent infectious complications in patients with severe acute pancreatitis. Although the efficacy of intravenous administration of protease inhibitors is still a matter of controversy, there is a consensus in Japan that a large dose of a synthetic protease inhibitor should be given to patients with severe acute pancreatitis in order to prevent organ failure and other complications. Enteral feeding is superior to parenteral nutrition when it comes to the nutritional support of patients with severe acute pancreatitis. The JPN Guidelines recommend, as optional continuous regional arterial infusion and blood purification therapy.

This article addresses the criteria for severity assessment and the severity scoring system of the Ministry of Health and Welfare of Japan; now the Japanese Ministry of Health, Labour, and Welfare (the JPN score). It also presents data comparing the JPN score with the Acute Physiology and Chronic Health Evaluation (APACHE) II score and the Ranson score, which are the major measuring scales used in the United States and Europe. The goal of investigating these scoring systems is the achievement of earlier diagnosis and more appropriate and successful treatment of severe or moderate acute pancreatitis, which has a high mortality rate. This article makes the following recommendations in terms of assessing the severity of acute pancreatitis: (1) Severity assessment is indispensable to the selection of proper initial treatment in the management of acute pancreatitis (Recommendation A). (2) Assessment by a severity scoring system (JPN score, APACHE II score) is important for determining treatment policy and identifying the need for transfer to a specialist unit (Recommendation A). (3) C-reactive protein (CRP) is a useful indicator for assessing severity (Recommendation A). (4) Contrast-enhanced computed tomography (CT) scanning and contrast-enhanced magnetic resonance imaging (MRI) play an important role in severity assessment (Recommendation A). (5) A JPN score of 2 or more (severe acute pancreatitis) has been established as the criterion for hospital transfer (Recommendation A). (6) It is preferable to transfer patients with severe acute pancreatitis to a specialist medical institution where they can receive continuous monitoring and systemic management.

The JPN Guidelines for the Management of Acute Pancreatitis are organized under the subject headings: epidemiology, diagnosis, management strategy, severity assessment and transfer criteria, management of gallstone pancreatitis, nonsurgical management, and surgical management. The Guidelines contain cutting-edge information on each of these subjects, as well as a section on the Japanese medical insurance system which provides information that should prove useful to physicians in other countries. The quality of the evidence was evaluated by the evidence-based classification method used at the Cochrane Library. The levels of recommendation of the individual management methods contained in the Guidelines were determined on the basis of the evaluation of evidence by the consensus of the members of the Working Group (see below). The Japanese Society for Abdominal Emergency Medicine, the Japan Pancreas Society, and the Research Group for Intractable Diseases and Refractory Pancreatic Diseases (which is sponsored by the Japanese Ministry of Health, Labour, and Welfare) were commissioned to produce the JPN Guidelines for the Management of Acute Pancreatitis. A Working Group of 20 physicians specializing in pancreatic diseases and emergency medicine investigated and analyzed 14821 cases retrieved by means of a Medline (1960–2004) search and discussed the available literature on acute pancreatitis (limited to human pancreatitis). The Working Group held many general discussions in order to reach a consensus on the content of the Guidelines. After producing a draft, the Publishing Committee of the JPN Guidelines for the Management of Acute Pancreatitis posted it on a website and asked for comments and criticisms. Subsequently, a final version of the Guidelines was published in Japanese in 2003. The Publishing Committee is now making the Guidelines available to a much wider readership by bringing out an English version.

The currently used diagnostic criteria for acute pancreatitis in Japan are presentation with at least two of the following three manifestations: (1) acute abdominal pain and tenderness in the upper abdomen; (2) elevated levels of pancreatic enzyme in the blood, urine, or ascitic fluid; and (3) abnormal imaging findings in the pancreas associated with acute pancreatitis. When a diagnosis is made on this basis, other pancreatic diseases and acute abdomen can be ruled out. The purpose of this article is to review the conventional criteria and, in particular, the various methods of diagnosis based on pancreatic enzyme values, with the aim of improving the quality of diagnosis of acute pancreatitis and formulating common internationally agreed criteria. The review considers the following recommendations: — Better even than the total blood amylase level, the blood lipase level is the best pancreatic enzyme for the diagnosis of acute pancreatitis and its differentiation from other diseases. — A pivotal factor in the diagnosis of acute pancreatitis is identifying an increase in pancreatic enzymes in the blood. — Ultrasonography (US) is also one of the procedures that should be performed in all patients with suspected acute pancreatitis. — Magnetic resonance imaging (MRI) is one of the most important imaging procedures for diagnosing acute pancreatitis and its intraperitoneal complications. — Computed tomography (CT) is also one of the most important imaging procedures for diagnosing acute pancreatitis and its intraabdominal complications. CT should be performed when a diagnosis of acute pancreatitis cannot be established on the basis of the clinical findings, results of blood and urine tests, or US, or when the etiology of the pancreatitis is unknown. — When acute pancreatitis is suspected, chest and abdominal X-ray examinations should be performed to determine whether any abnormal findings caused by acute pancreatitis are present. — Because the etiology of acute pancreatitis can have a crucial influence on both the treatment policy and severity assessment, it should be evaluated promptly and accurately. It is particularly important to differentiate between gallstone-induced acute pancreatitis, which requires treatment of the biliary system, and alcohol-induced acute pancreatitis, which requires a different form of treatment.

The prognosis of pancreatic cancer is defined by the histology and extent of disease. Preoperative histologic diagnosis and diagnostic imaging are fundamentals in managing the disease, but it is not rare to find unexpected peritoneal dissemination or liver metastasis at the time of operation. The overall resectability rate of pancreatic cancer is 40% in Japan. Resecting the portal vein and peripancreatic plexus were performed on 40% of the patients who underwent pancreatectomy for invasive cancer in the head of the pancreas. Long-term survival was only found in patients who underwent pancreatectomy. Radical lymph node dissection, or combined resection of the large vessels, did not seem to improve survival further than the standard resection. Multidisciplinary treatments combined with surgery were performed, and various effects of postoperative chemotherapy after pancreatectomy, intraoperative- and postoperative-radiation therapy, or postoperative chemotherapy for unresectable tumor, were shown. Development of unconventional therapies and refinement of the conventional therapy should be promoted on a randomized prospective trial basis. To promote this effort, which requires the international comparisons and cooperation, JPS developed a computerized JPS registration system downloadable from the JPS website (http://www.kojin.or.jp/suizou/index.html).