Yasutoshi Kimura

JPN Guidelines for the management of acute pancreatitis: epidemiology, etiology, natural history, and outcome predictors in acute pancreatitis

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.

TG13: Updated Tokyo Guidelines for the management of acute cholangitis and cholecystitis

In 2007, the Tokyo Guidelines for the management of acute cholangitis and cholecystitis (TG07) were first published in the Journal of Hepato-Biliary-Pancreatic Surgery. The fundamental policy of TG07 was to achieve the objectives of TG07 through the development of consensus among specialists in this field throughout the world. Considering such a situation, validation and feedback from the clinicians’ viewpoints were indispensable. What had been pointed out from clinical practice was the low diagnostic sensitivity of TG07 for acute cholangitis and the presence of divergence between severity assessment and clinical judgment for acute cholangitis. In June 2010, we set up the Tokyo Guidelines Revision Committee for the revision of TG07 (TGRC) and started the validation of TG07. We also set up new diagnostic criteria and severity assessment criteria by retrospectively analyzing cases of acute cholangitis and cholecystitis, including cases of non-inflammatory biliary disease, collected from multiple institutions. TGRC held meetings a total of 35 times as well as international email exchanges with co-authors abroad. On June 9 and September 6, 2011, and on April 11, 2012, we held three International Meetings for the Clinical Assessment and Revision of Tokyo Guidelines. Through these meetings, the final draft of the updated Tokyo Guidelines (TG13) was prepared on the basis of the evidence from retrospective multi-center analyses. To be specific, discussion took place involving the revised new diagnostic criteria, and the new severity assessment criteria, new flowcharts of the management of acute cholangitis and cholecystitis, recommended medical care for which new evidence had been added, new recommendations for gallbladder drainage and antimicrobial therapy, and the role of surgical intervention. Management bundles for acute cholangitis and cholecystitis were introduced for effective dissemination with the level of evidence and the grade of recommendations. GRADE systems were utilized to provide the level of evidence and the grade of recommendations. TG13 improved the diagnostic sensitivity for acute cholangitis and cholecystitis, and presented criteria with extremely low false positive rates adapted for clinical practice. Furthermore, severity assessment criteria adapted for clinical use, flowcharts, and many new diagnostic and therapeutic modalities were presented. The bundles for the management of acute cholangitis and cholecystitis are presented in a separate section in TG13.Free full-text articles and a mobile application of TG13 are available via http://www.jshbps.jp/en/guideline/tg13.html.

Definitions, pathophysiology, and epidemiology of acute cholangitis and cholecystitis: Tokyo Guidelines

This article discusses the definitions, pathophysiology, and epidemiology of acute cholangitis and cholecystitis. Acute cholangitis and cholecystitis mostly originate from stones in the bile ducts and gallbladder. Acute cholecystitis also has other causes, such as ischemia; chemicals that enter biliary secretions; motility disorders associated with drugs; infections with microorganisms, protozoa, and parasites; collagen disease; and allergic reactions. Acute acalculous cholecystitis is associated with a recent operation, trauma, burns, multisystem organ failure, and parenteral nutrition. Factors associated with the onset of cholelithiasis include obesity, age, and drugs such as oral contraceptives. The reported mortality of less than 10% for acute cholecystitis gives an impression that it is not a fatal disease, except for the elderly and/or patients with acalculous disease. However, there are reports of high mortality for cholangitis, although the mortality differs greatly depending on the year of the report and the severity of the disease. Even reports published in and after the 1980s indicate high mortality, ranging from 10% to 30% in the patients, with multiorgan failure as a major cause of death. Because many of the reports on acute cholecystitis and cholangitis use different standards, comparisons are difficult. Variations in treatment and risk factors influencing the mortality rates indicate the necessity for standardized diagnostic, treatment, and severity assessment criteria.

TG13 flowchart for the management of acute cholangitis and cholecystitis

We propose a management strategy for acute cholangitis and cholecystitis according to the severity assessment. For Grade I (mild) acute cholangitis, initial medical treatment including the use of antimicrobial agents may be sufficient for most cases. For non-responders to initial medical treatment, biliary drainage should be considered. For Grade II (moderate) acute cholangitis, early biliary drainage should be performed along with the administration of antibiotics. For Grade III (severe) acute cholangitis, appropriate organ support is required. After hemodynamic stabilization has been achieved, urgent endoscopic or percutaneous transhepatic biliary drainage should be performed. In patients with Grade II (moderate) and Grade III (severe) acute cholangitis, treatment for the underlying etiology including endoscopic, percutaneous, or surgical treatment should be performed after the patient’s general condition has been improved. In patients with Grade I (mild) acute cholangitis, treatment for etiology such as endoscopic sphincterotomy for choledocholithiasis might be performed simultaneously, if possible, with biliary drainage. Early laparoscopic cholecystectomy is the first-line treatment in patients with Grade I (mild) acute cholecystitis while in patients with Grade II (moderate) acute cholecystitis, delayed/elective laparoscopic cholecystectomy after initial medical treatment with antimicrobial agent is the first-line treatment. In non-responders to initial medical treatment, gallbladder drainage should be considered. In patients with Grade III (severe) acute cholecystitis, appropriate organ support in addition to initial medical treatment is necessary. Urgent or early gallbladder drainage is recommended. Elective cholecystectomy can be performed after the improvement of the acute inflammatory process.Free full-text articles and a mobile application of TG13 are available via http://www.jshbps.jp/en/guideline/tg13.html.

JPN Guidelines for the management of acute pancreatitis: medical management of acute pancreatitis

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.

Background: Tokyo Guidelines for the management of acute cholangitis and cholecystitis

There are no evidence-based-criteria for the diagnosis, severity assessment, of treatment of acute cholecysitis or acute cholangitis. For example, the full complement of symptoms and signs described as Charcot’s triad and as Reynolds’ pentad are infrequent and as such do not really assist the clinician with planning management strategies. In view of these factors, we launched a project to prepare evidence-based guidelines for the management of acute cholangitis and cholecystitis that will be useful in the clinical setting. This research has been funded by the Japanese Ministry of Health, Labour, and Welfare, in cooperation with the Japanese Society for Abdominal Emergency Medicine, the Japan Biliary Association, and the Japanese Society of Hepato-Biliary-Pancreatic Surgery. A working group, consisting of 46 experts in gastroenterology, surgery, internal medicine, emergency medicine, intensive care, and clinical epidemiology, analyzed and examined the literature on patients with cholangitis and cholecystitis in order to produce evidence-based guidelines. During the investigations we found that there was a lack of high-level evidence, for treatments, and the working group formulated the guidelines by obtaining consensus, based on evidence categorized by level, according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence of May 2001 (version 1). This work required more than 20 meetings to obtain a consensus on each item from the working group. Then four forums were held to permit examination of the Guideline details in Japan, both by an external assessment committee and by the working group participants (version 2). As we knew that the diagnosis and management of acute biliary infection may differ from country to country, we appointed a publication committee and held 12 meetings to prepare draft Guidelines in English (version 3). We then had several discussions on these draft guidelines with leading experts in the field throughout the world, via e-mail, leading to version 4. Finally, an International Consensus Meeting took place in Tokyo, on 1–2 April, 2006, to obtain international agreement on diagnostic criteria, severity assessment, and management.

Japanese guidelines for the management of acute pancreatitis: Japanese Guidelines 2015.

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.

Clinical and immunological evaluation of anti-apoptosis protein, survivin-derived peptide vaccine in phase I clinical study for patients with advanced or recurrent breast cancer

BackgroundWe previously reported that survivin-2B, a splicing variant of survivin, was expressed in various types of tumors and that survivin-2B peptide might serve as a potent immunogenic cancer vaccine. The objective of this study was to examine the toxicity of and to c linically and immunologically evaluate survivin-2B peptide in a phase I clinical study for patients with advanced or recurrent breast cancer.MethodsWe set up two protocols. In the first protocol, 10 patients were vaccinated with escalating doses (0.1–1.0 mg) of survivin-2B peptide alone 4 times every 2 weeks. In the second protocol, 4 patients were vaccinated with the peptide at a dose of 1.0 mg mixed with IFA 4 times every 2 weeks.ResultsIn the first protocol, no adverse events were observed during or after vaccination. In the second protocol, two patients had induration at the injection site. One patient had general malaise (grade 1), and another had general malaise (grade 1) and fever (grade 1). Peptide vaccination was well tolerated in all patients. In the first protocol, tumor marker levels increased in 8 patients, slightly decreased in 1 patient and were within the normal range during this clinical trial in 1 patient. With regard to tumor size, two patients were considered to have stable disease (SD). Immunologically, in 3 of the 10 patients (30%), an increase of the peptide-specific CTL frequency was detected. In the second protocol, an increase of the peptide-specific CTL frequency was detected in all 4 patients (100%), although there were no significant beneficial clinical responses. ELISPOT assay showed peptide-specific IFN-γ responses in 2 patients in whom the peptide-specific CTL frequency in tetramer staining also was increased in both protocols.ConclusionThis phase I clinical study revealed that survivin-2B peptide vaccination was well tolerated. The vaccination with survivin-2B peptide mixed with IFA increased the frequency of peptide-specific CTL more effectively than vaccination with the peptide alone, although neither vaccination could induce efficient clinical responses. Considering the above, the addition of another effectual adjuvant such as a cytokine, heat shock protein, etc. to the vaccination with survivin-2B peptide mixed with IFA might induce improved immunological and clinical responses.

Reconsideration of Postoperative Oral Intake Tolerance After Pancreaticoduodenectomy: Prospective Consecutive Analysis of Delayed Gastric Emptying According to the ISGPS Definition and the Amount of Dietary Intake

Objective:A prospective consecutive study was planned to evaluate the postpancreaticoduodenectomy (PD) oral intake tolerance. The occurrence of delayed gastric emptying (DGE), as defined by the International Study Group of Pancreatic Surgery (ISGPS), and the amount of dietary intake were analyzed. The risk factors for low oral intake tolerance were additionally determined. Summary Background Data:The causation of DGE after PD is still unclear. Several possible factors have been discussed, such as reconstruction methods and other complications. However, none of them has followed the definition of ISGPS. Methods:Between 2003 and 2007, 101 consecutive patients underwent PD-related surgery, and standard operative procedure was performed on 85 patients. Perioperative data were prospectively collected in all patients, and the patients postoperative dietary intake was recorded for all meals until discharge. As an indicator of early postoperative oral intake tolerance, we added up the dietary intake from postoperative day 1 to 21 and called this value the total amount of dietary intake (TDI). The postoperative outcomes were compared between non-DGE and DGE. The high-low of TDI values was also analyzed. Multivariate analysis for factors associated with the occurrence of DGE and TDI was performed. Results:The occurrence of DGE as defined by ISGPS was 42%. The postoperative outcomes of DGE patients were significantly poor compared with those of non-DGE patients. TDI values were significantly low in DGE patients, and non-DGE patients with low TDI values showed a significantly extended duration of parenteral nutrition and postoperative hospitalization. Operative bleeding (>1,000 mL) and pancreatic fistulas were likely to be associated with DGE occurrence. Gender (women), BMI (>25 kg/m2), postoperative intraabdominal infection, and DGE were significantly associated with low TDI values. Conclusions:The ISGPS definition of DGE seemed feasible for patient management. TDI values provided additional information for analyzing postoperative oral intake tolerance, especially when describing the differences among non-DGE patients. Substantial risk factors for low oral intake tolerance were high BMI, postoperative intraabdominal infection, and DGE.

TG13 antimicrobial therapy for acute cholangitis and cholecystitis.

Therapy with appropriate antimicrobial agents is an important component in the management of patients with acute cholangitis and/or acute cholecystitis. In the updated Tokyo Guidelines (TG13), we recommend antimicrobial agents that are suitable from a global perspective for management of these infections. These recommendations focus primarily on empirical therapy (presumptive therapy), provided before the infecting isolates are identified. Such therapy depends upon knowledge of both local microbial epidemiology and patient-specific factors that affect selection of appropriate agents. These patient-specific factors include prior contact with the health care system, and we separate community-acquired versus healthcare-associated infections because of the higher risk of resistance in the latter. Selection of agents for community-acquired infections is also recommended on the basis of severity (grades I–III). Free full-text articles and a mobile application of TG13 are available via http://www.jshbps.jp/en/guideline/tg13.html.