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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.

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

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.

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.

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 angiographic appearance of acute necrotizing pancreatitis (ANP) demonstrates ischemic change with vasospasm in and around the pancreas. We investigated the role of vasospasm in pancreatic ischemia and necrosis in the early phase of human ANP.The relationship between the angiographic abnormalities and the perfusion status of the pancreas documented by contrast-enhanced computed tomography (CE-CT) was examined in 102 patients with ANP who were admitted during the early phase of the disease.Ischemic change with vasospasm on angiography of the intrapancreatic and extrapancreatic arteries was observed and corresponded with the poorly perfused area of the pancreas detected by CE-CT done at admission. Resultant pancreatic necrosis was confirmed on follow-up CE-CT examination consistent with the location where angiography demonstrated ischemic change with vasospasm. Severe ischemic change on angiography was primarily observed in patients in whom more than 50% of the pancreas was poorly perfused. The extent of the ischemic change was correlated with the extent of the poorly perfused area of the pancreas and the mortality rate.These results suggest that vasospasm is involved in the development of pancreatic ischemia and necrosis in the early phase of ANP.

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).

Macrophages are considered to play an essential role in the events leading to systemic inflammatory response. Some are known to reside in the peritoneal cavity but there are no reports defining the participation of peritoneal macrophages (PMs) in the progression of acute pancreatitis.To clarify the role of PMs in the progression of acute pancreatitis.Acute pancreatitis was induced in rats from which macrophages other than PMs were greatly depleted, and in rats greatly depleted of macrophages including PMs. Macrophages were depleted by the injection of liposome encapsulated dichloromethylene bisphosphonate. After the induction of acute pancreatitis, local pancreatic inflammation, intraperitoneal inflammation and lung injury were compared between the 2 groups.Local pancreatic inflammation did not differ between the 2 groups. However, intraperitoneal inflammation was clearly improved by the depletion of PMs. Serum cytokine level and lung injury were also improved by the depletion of PMs.Peritoneal macrophages extend inflammation from the pancreas to the peritoneal cavity and subsequently induce lung injury in acute pancreatitis. Peritoneal macrophages play an essential role in the systemic inflammatory response and the progression of acute pancreatitis in the rat.

A cooperative national survey between 1991 and 1994 recently clarified the status of acute necrotizing pancreatitis in Japan. The overall mortality rate was 20.8%; however, the mortality rate in patients with infection was 33.3%, and the mortality rate in patients who underwent surgery was 27.4%. With regard to surgical procedures, drainage procedures (mobilization of the pancreatic bed and retroperitoneal drainage) were performed most frequently, and one third of the patients who underwent drainage procedures needed reoperation. Although debridement of the necrotic tissue (necrosectomy or resection of the pancreas) was performed in 33.3%, the mortality rate was 35.3%. There was no difference in the mortality rate between early and delayed operation. Recently two new modalities have been advocated for the management of severe acute pancreatitis in Japan. One is continuous regional arterial infusion of protease inhibitor and antibiotics, and the other is continuous hemodiafiltration. Further work is needed to establish the most effective procedures for the management of acute necrotizing pancreatitis and debridement of pancreatic infection.

急性膵炎において膵が壊死に進展する機序には，膵の虚血や微小血栓形成による血管の途絶など血流障害が関与しているが，最近，vasospasmが急性膵炎の重症化因子として注目されている．急性壊死性膵炎における発症早期の血管造影所見はvasospasmによる虚血性変化が特徴的で，vasospasmは造影CTにおける膵の造影不良域と一致している．また，vasospasmによる虚血性変化の程度は膵の造影不良域の大きさ，死亡率と相関している．重症急性膵炎ではnon-occlusive mesenteric ischemia（NOMI）を合併することがあり，血管造影所見では膵の動脈と上腸間膜動脈およびその分枝のvasospasmが同時に認められている．急性膵炎によって惹起されるvasospasmは急性壊死性膵炎における膵の血流障害すなわち膵虚血に関与しているものと考えられる．

急性膵炎の診断・治療の進歩により，重症急性膵炎の死亡率は著しく低下している．重症度をできるだけ早期に判定し，重症急性膵炎と判定された場合には高次医療施設で適切な治療を受けることが救命率の改善に繋がるため，急性膵炎診療において重症度判定基準は不可欠である．しかし，我が国の急性膵炎重症度判定基準は18項目の予後因子からなる煩雑なもので，臨床現場ではきわめて使いにくい．また，類似の病態を示す予後因子の重複もみられ，発症早期に出現しにくい臨床徴候が含まれている．初期輸液が測定値に直接的に影響を及ぼす予後判定因子もみられる．単純CTは膵病変の評価が難しく，CT Gradeも死亡率と相関していない．また，判定基準では，軽症・中等症・重症に分類されているが，軽症・中等症は死亡率にも差がなく，治療方針が同じであり，これを分ける臨床的意義は少ない．こうした問題点をふまえて現在，改定案が作成されている．