Search

BackgroundContinuous regional arterial infusion (CRAI) of protease inhibitor nafamostat mesilate (NM) is used in the context of predicted severe acute pancreatitis (SAP) to prevent the development of pancreatic necrosis. Although this therapy is well known in Japan, its efficacy and safety remain unclear.MethodsThis investigator-initiated and -driven, multicenter, open-label, randomized, controlled trial (UMIN000020868) enrolled 39 patients with predicted SAP and low enhancement of the pancreatic parenchyma on computed tomography (CT). Twenty patients were assigned to the CRAI group, while 19 served as controls and were administered NM at the same dose intravenously (IV group). The primary endpoint was the development of pancreatic necrosis as determined by CT on Day 14, judged by blinded central review.ResultsThere was no difference between the CRAI and IV groups regarding the percentages of participants who developed pancreatic necrosis (more than 1/3 of the pancreas: 25.0%, range 8.7–49.1% vs. 15.8%, range 3.4–39.6%, respectively,P = 0.694; more than 2/3 of the pancreas: 20%, range 5.7–43.7% vs. 5.3%, range 0.1–26.0%, respectively,P = 0.341). The early analgesic effect was evaluated based on 24-h cumulative fentanyl consumption and additional administration by intravenous patient-controlled analgesia. The results showed that the CRAI group used significantly less analgesic. There were two adverse events related to CRAI, namely bleeding and splenic infarction.ConclusionsCRAI with NM did not inhibit the development of pancreatic necrosis although early analgesic effect of CRAI was superior to that of IV. Less-invasive IV therapy can be considered a viable alternative to CRAI therapy.

Infected acute necrotic collections (ANC) and walled-off necrosis (WON) of the pancreas are associated with high mortality. The difference in mortality between open necrosectomy and minimally invasive therapies in these patients remains unclear. This retrospective multicenter cohort study was conducted among 44 institutions in Japan from 2009 to 2013. Patients who had undergone invasive treatment for suspected infected ANC/WON were enrolled and classified into open necrosectomy and minimally invasive treatment (laparoscopic, percutaneous, and endoscopic) groups. The association of each treatment with mortality was evaluated and compared. Of 1159 patients with severe acute pancreatitis, 122 with suspected infected ANC or WON underwent the following treatments: open necrosectomy (33) and minimally invasive treatment (89), (laparoscopic three, percutaneous 49, endoscopic 37). Although the open necrosectomy group had a significantly higher mortality on univariate analysis (p = 0.047), multivariate analysis showed no significant associations between open necrosectomy or Charlson index and mortality (p = 0.29, p = 0.19, respectively). However, age (for each additional 10 years, p = 0.012, odds ratio [OR] 1.50, 95% confidence interval [CI] 1.09–2.06) and revised Atlanta criteria-severe (p = 0.001, OR 7.84, 95% CI 2.40–25.6) were significantly associated with mortality. In patients with acute pancreatitis and infected ANC/WON, age and revised Atlanta criteria-severe classification are significantly associated with mortality whereas open necrosectomy is not. The mortality risk for patients undergoing open necrosectomy and minimally invasive treatment does not differ significantly. Although minimally invasive surgery is generally preferred for patients with infected ANC/WON, open necrosectomy may be considered if clinically indicated.

BACKGROUND Rapid urinary trypsinogen-2 dipstick test and levels of urinary trypsinogen-2 and trypsinogen activation peptide (TAP) concentration have been reported as prognostic markers for the diagnosis of acute pancreatitis. AIM To reconfirm the validity of all these markers in the diagnosis of acute pancreatitis by undertaking a multi-center study in Japan. METHODS Patients with acute abdominal pain were recruited from 17 medical institutions in Japan from April 2009 to December 2012. Urinary and serum samples were collected twice, at enrollment and on the following day for measuring target markers. The diagnosis and severity assessment of acute pancreatitis were assessed based on prognostic factors and computed tomography (CT) Grade of the Japanese Ministry of Health, Labour, and Welfare criteria. RESULTS A total of 94 patients were enrolled during the study period. The trypsinogen-2 dipstick test was positive in 57 of 78 patients with acute pancreatitis (sensitivity, 73.1%) and in 6 of 16 patients with abdominal pain but without any evidence of acute pancreatitis (specificity, 62.5%). The area under the curve (AUC) score of urinary trypsinogen-2 according to prognostic factors was 0.704, which was highest in all parameter. The AUC scores of urinary trypsinogen-2 and TAP according to CT Grade were 0.701 and 0.692, respectively, which shows higher than other pancreatic enzymes. The levels of urinary trypsinogen-2 and TAP were significantly higher in patients with extended extra-pancreatic inflammation as evaluated by CT Grade. CONCLUSION We reconfirmed urinary trypsinogen-2 dipstick test is useful as a marker for the diagnosis of acute pancreatitis. Urinary trypsinogen-2 and TAP may be considered as useful markers to determine extra-pancreatic inflammation in acute pancreatitis.

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.

This study investigated corneal endothelial cell density (ECD) in pseudoexfoliation (PEX) syndrome patients and evaluated the clinical factors associated with ECD for 51 eyes of 41 phakic patients with pseudoexfoliation (PEX group) and 201 eyes of 117 patients with age-related cataracts (control group) as an age-matched control to the PEX group. Variable clinical factors, including ECD, central corneal thickness (CCT), anterior chamber depth (ACD), number of anti-glaucoma eye drops and severity of PEX, were examined using multivariate analyses. Severity of PEX was as follows: Mild in 28 eyes, Moderate in 16 eyes, and Severe in 7 eyes. The mean ECD was 2,548 ± 409 cells/mm

This study investigated corneal endothelial cell density (ECD) in pseudoexfoliation (PEX) syndrome patients and evaluated the clinical factors associated with ECD for 51 eyes of 41 phakic patients with pseudoexfoliation (PEX group) and 201 eyes of 117 patients with age-related cataracts (control group) as an age-matched control to the PEX group. Variable clinical factors, including ECD, central corneal thickness (CCT), anterior chamber depth (ACD), number of anti-glaucoma eye drops and severity of PEX, were examined using multivariate analyses. Severity of PEX was as follows: Mild in 28 eyes, Moderate in 16 eyes, and Severe in 7 eyes. The mean ECD was 2,548 ± 409 cells/mm2 in the PEX group and 2,757 ± 282 cells/mm2 in the control group, respectively, and ECD in the PEX group was significantly lower than that in the control group (P = 0.02). Multivariate analyses revealed that the severity of PEX [−176.8, 95% confidence interval (CI) (−244.5, −109.2), P

Background: We aimed to compare the efficacy and safety of irinotecan/S-1 (IRIS) therapy with S-1 monotherapy in patients with gemcitabine-refractory pancreatic cancer. Methods: Patients were treated with oral S-1 (80–120 mg for 14 days every 4 weeks) plus intravenous irinotecan (100 mg m−2 on days 1 and 15 every 4 weeks; IRIS group) or oral S-1 group (80–120 mg daily for 28 days every 6 weeks). The primary endpoint was progression-free survival (PFS). Results: Of 137 patients enrolled, 127 were eligible for efficacy. The median PFS in the IRIS group and S-1 monotherapy group were 3.5 and 1.9 months, respectively (hazard ratio (HR)=0.77; 95% confidence interval (CI), 0.53–1.11; P=0.18), while the median overall survival (OS) were 6.8 and 5.8 months, respectively (HR=0.75; 95% CI, 0.51–1.09; P=0.13). Response rate was significantly higher in the IRIS group than in the S-1 monotherapy group (18.3% vs 6.0%, P=0.03). Grade 3 or higher neutropenia and anorexia occurred more frequently in the IRIS group. Conclusions: There was a trend for better PFS and OS in the IRIS group that could be a treatment arm in the clinical trials for gemcitabine-refractory pancreatic cancer.

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

Purpose To assess retrospectively the cause of hepatic failure related to hepatic arterial embolization (HAE) for hemostasis after pancreaticoduodenectomy or hepatic lobectomy. Materials and Methods Between June 1993 and March 2006, Twenty HAEs in 17 patients (15 men, two women; mean age, 64 years) were performed. Angiographic findings, including portal vein stenosis, collateral arterial pathways after HAE, and the difference of embolic materials, were recorded. The morbidity (hepatic failure and abscess) and mortality were detailed according to collateral arterial pathways, portal vein stenosis, and embolic material used. Results Bleeding was controlled in all patients, although two patients required repeat embolization. Hepatic failure ( n = 8) and abscess ( n = 2) arose in nine of 20 HAEs. Death occurred after six of eight HAEs complicated by hepatic failure. The morbidity and mortality rates of HAE were 45% and 30%, respectively. Hepatic complication was eight times more likely to occur ( P = .005) in cases with no hepatic collaterals involving hepatic, replaced, or accessory hepatic arteries. Death was observed only in the cases without hepatic collaterals ( P = .011). The correlation between the embolization outcome and the presence of portal vein stenosis or the difference of embolic materials was not significant ( P > .61). Conclusions HAE can be used to successfully control bleeding secondary to hepatic arterial rupture. In the absence of hepatic collaterals, collateral circulation distal to the occlusion from nonhepatic sources may be inadequate and lead to hepatic failure after HAE.

Purpose To investigate the long-term outcome of autologous cultivated oral mucosal epithelial transplantation (COMET) for the treatment of the scar phase of severe ocular surface disorders. Participants This study involved 19 eyes of 17 patients who received autologous COMET for total limbal stem-cell deficiency. Methods Autologous cultivated oral mucosal epithelial sheets were created using amniotic membrane as a substrate. Clinical efficacy was evaluated by best-corrected visual acuity and visual acuity at the postoperative 36th month. The clinical results (clinical conjunctivalisation, corneal opacification, corneal neovascularisation and symblepharon formation) were evaluated and graded on a scale from 0 to 3 according to their severity. Clinical safety was evaluated by the presence of persistent epithelial defects, ocular hypertension and infections. Results Autologous cultivated oral mucosal epithelial sheets were successfully generated for all 17 patients. All patients were followed up for more than 36 months; the mean follow-up period was 55 months and the longest follow-up period was 90 months. During the long-term follow-up period, postoperative conjunctivalisation and symblepharon were significantly inhibited. All eyes manifested various degrees of postoperative corneal neovascularisation, but it gradually abated and its activity was stable at 6 months after surgery. Best-corrected visual acuity was improved in 18 eyes (95%) during the follow-up periods, and visual acuity at the postoperative 36th month was improved in 10 eyes (53%). Conclusions These long-term clinical results strongly support the conclusion that tissue-engineered cultivated oral mucosal epithelial sheets are useful in reconstructing the ocular surface of the scar phase of severe ocular surface disorders.

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.

Objective: Acute mesenteric ischemia is potentially fatal, but prognostic factors have not yet been established. This study was undertaken to elucidate them. Methods: This is a retrospective cohort study, consisting of 110 patients who had been treated in the past 5 years, from 26 national hospitals in Japan. Results: The overall in-hospital mortality rate was 51%. Logistic regression analysis demonstrated two independent prognostic factors, electrocardiogram scale with an odds ratio of 1.7 (95% CI 1.2–2.4) and shock index of 11 (95% CI 1.5–80). A stepwise analysis gave a prediction equation for in-hospital mortality (R) using these variables and age score. We further modified this equation to a simpler scoring system (S) using the same variables. Both R and S showed a good discriminatory ability as determined by areas under the receiver-operating characteristic curve (0.83, 95% CI: 0.74–0.91 for R; 0.82, 95% CI 0.74–0.91 for S). The observed mortality rates increased as the R or S increased (19% at R Conclusion: The new prediction rules can be used at any hospital and may be promising tools for medical decision-making, informed consent and reviewing quality of care.

Tumor necrosis factor (TNF) is a potent inflammatory cytokine that contributes to airway inflammation in asthma. Previous studies have reported that a G-to-A transition at position -308 (-308G/A, also referred to as TNF-alpha-308*1 and 308*2 respectively), is associated with asthma, but other studies have shown conflicting results. To investigate a possible association between the TNF-308G/A polymorphism and asthma, we performed transmission disequilibrium tests and a case-control study (family samples: 495 members in 165 Japanese trio families with one asthmatic child and both parents; case-control samples: 461 Japanese asthmatic children and 465 healthy controls). To increase the sample size and power, we performed a meta-analysis of all available relevant studies, including 2,477 asthmatics and 3,217 controls. We did not find a significant association between the TNF-308G/A polymorphism and childhood atopic asthma in two independent Japanese populations (P0.05); however, meta-analysis revealed that the TNF-308G/A polymorphism was statistically significantly associated with asthma. The combined odds ratio with a fixed effects model and with a random effects for TNF-308A was 1.46 (95% confidence interval [CI], 1.27-1.68, P=0.0000001) and 1.46 (95% CI, 1.20-1.77, P=0.00014) respectively. Our data further support the importance of the TNF region in the development of asthma.

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.

This study evaluated a novel non-verbal communication method for people with severe motor and intellectual disabilities (SMID) based on a biochemical marker, salivary amylase. The physical and psychological status of 10 people with SMID was quantitatively evaluated using a hand-held salivary amylase activity monitor. Each patient needed daily gastric and/or bronchial tube exchanges and these medical procedures were thought to cause severe distress and pain. Salivary amylase activity and heart rate were simultaneously measured during 32 medical procedures. The medical procedures resulted in a significant mean increase for individuals of 70% in salivary amylase activity. The increase in salivary amylase activity was more than four-fold that observed for heart rate. The structural equation modelling analysis also demonstrated a significant correlation between pain and salivary amylase activity. Our data indicate that salivary amylase activity might be used as a non-verbal method of assessing pain in people with SMID.

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.

It has recently been recognized that anandamide (arachidonylethanolamide), which is an endogeneous-cannabinoid (endocannabinoid), mediates septic shock. Cannabinoid means a mind-active material in cannabis (marijuana). Anandamide is mainly produced by macrophages. Cannabinoid 1 (CB1) receptor, which is one of the cannabiniod receptors, is also known to mediate hypotensive shock. The role of endocannabinoids in the progression of acute pancreatitis is unclear. The aims of this study are to clarify their relationship and to find a new therapeutic strategy by regulating the endocannabinoid signaling in acute pancreatitis. Male Wistar rats were injected with caerulein intravenously to induce mild edematous pancreatitis or injected with 5% sodium taurocholate to the bilio-pancreatic duct to induce severe necrotizing pancreatitis. The animals in the latter group were also injected with a CB1 receptor antagonist, AM251, or vehicle solution to see if the inhibition of endocannabinoids improves their survival. Plasma anandamide level was measured by the liquid chromatography/tandem mass spectrometry method. In both models of acute pancreatitis, the plasma anandamide levels were increased, and the levels were significantly higher in rats with severe necrotizing pancreatitis than those in rats with mild edematous pancreatitis. The mean arterial pressure and survival rate were significantly improved by the treatment with AM251, despite that the local inflammatory changes in the pancreas and various parameters (white blood cells, hematocrit, serum amylase, and serum interleukin-6) were similar. This is the first report to show that endocannabinoids are involved in the deterioration of acute pancreatitis and that the down-regulation of endocannabinoid signaling may be a new therapeutic strategy for severe acute pancreatitis.

The interaction of immature dendritic cells (DC) with irradiated pancreatic cancer cells was examined. Flow cytometric analysis using annexin V and propidium iodide revealed that ionizing radiation (25–35 Gy X-ray) induced both apoptosis and necrosis in pancreatic cancer cell lines. After irradiation, PK-1 and Panc-1 cells were likely to undergo necrosis, whereas MIAPaCa-2 cells underwent apoptosis. When DiO-stained immature DCs were co-incubated with DiI-stained irradiated MIAPaCa-2, it was observed under fluorescent microscopy that DCs phagocytized dead tumor cells as early as 4 h after co-incubation. The DCs’ phagocytosis of irradiated tumor cells was also confirmed by flow cytometry. These results suggest that irradiated pancreatic cancer cells, which undergo both apoptosis and necrosis, could be a good source of tumor-associated antigens for cross-presentation by DCs.

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

症例は64歳の女性で, 糖尿病の悪化と体重減少が出現し, 精査にて膵頭部癌として当科紹介となった. 術前画像評価にて血管浸潤などから根治切除術は困難と判断された. 術中所見においても総肝動脈・固有肝動脈への腫瘍浸潤を認め, 手術診断はStage IVa, 胆道・消化管バイパス術を施行した. 術後5-FU併用放射線療法 (Chemoradiation; 以下, CRTと略記) を施行し, その後外来にてGemcitabine (以下, GEMと略記) 投与を行った. その結果, 原発腫瘍の縮小とCA19-9の著明な減少を認め, 初回手術から9か月後に膵頭十二指腸切除術を施行した. さらに外来でのGEM 投与を継続し, 初回手術から1年7か月経過した2003年4月現在, 画像上再発は認めていない. 根治切除術が施行できない局所進行膵癌に対し, down stagingを視野に入れてCRT とGEM の併用を行うことも選択肢の一つと考えられた.

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 mechanism of metastasis formation remains still largely unknown. Many studies underline the importance and complexity of the initial arrest of the circulating tumour cells in the target organ, a key stage in metastasis occurrence. In our study, we evaluated by visual means the metastasis formation using an in vivo microscopy system in a murine model. Moreover, we investigated the involvement of P-selectin in these processes using immunohistochemistry and P-selectin knockout mice. The present study offers direct evidence of distinct pathways for tumour metastasis formation by a lymphoma cell – EL-4 and a solid tumour cell – C26. Off-line analysis of the images and histological data confirmed that mechanical entrapment of the solid tumour cell, which had a bigger diameter than that of the liver sinusoids, promoted metastasis without any detectable involvement of adhesion molecules. On the other hand, we observed that lymphoma cells, in spite of their smaller diameter as compared to the sinusoids, promoted liver metastasis as well, but with the essential participation in their arrest of P-selectin, indicating an adhesion molecule-mediated pathway. © 2001 Cancer Research Campaign http://www.bjcancer.com

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.