Makoto Shinzeki

Significant increase of serum high-mobility group box chromosomal protein 1 levels in patients with severe acute pancreatitis.

Objective: Multiple organ failure because of systemic inflammatory response in the early phase and sepsis in the late phase is the main contributor to high mortality in severe acute pancreatitis (SAP). High-mobility group box chromosomal protein 1 (HMGB1) was recently identified as a potent proinflammatory mediator and increases in various pathological conditions such as sepsis. The aim of this study was to investigate contributions of HMGB1 in SAP. Methods: We measured serum HMGB1 concentrations by an enzyme-linked immunosorbent assay in 45 patients with SAP at the time of admission. Furthermore, relationship between their serum HMGB1 levels and clinical factors was analyzed. Results: The mean value of serum HMGB1 levels was significantly higher in patients with SAP (5.4 ± 1.3 ng/mL) than that in healthy volunteers (1.7 ± 0.3 ng/mL). Serum HMGB1 levels were significantly positively correlated with the Japanese severity score and Glasgow score. Serum HMGB1 levels were significantly positively correlated with lactate dehydrogenase, C-reactive protein, and total bilirubin. The HMGB1 levels were higher in patients with organ dysfunction and infection during the clinical course. The HMGB1 levels in nonsurvivors were higher than those in survivors. Serum HMGB1 levels gradually declined after the admission. Conclusions: Serum HMGB1 levels were significantly increased in patients with SAP and were correlated with disease severity. These results suggest that HMGB1 may act as a key mediator for inflammation and organ failure in SAP.

Increased levels of soluble triggering receptor expressed on myeloid cells-1 in patients with acute pancreatitis.

Objective:To determine the contribution of triggering receptor expressed on myeloid cells (TREM)-1 in acute pancreatitis (AP). Design:Prospective study. Setting:General intensive care unit at Kobe University Hospital. Patients:Forty-eight patients with AP and seven patients as control. Interventions:None. Measurements and Main Results:We measured serum concentrations of soluble TREM-1 (sTREM-1) at the time of admission by enzyme-linked immunoadsorbent assay. Serum sTREM-1 levels increased significantly in AP (63 ± 11 pg/mL) and correlated with Ranson score (R = .628, p < .001) and Acute Physiology and Chronic Health Evaluation II score (R = .504, p < .001). Serum TREM-1 levels were higher in patients with early organ dysfunction (which occurred within 7 days after onset) than those without early organ dysfunction (101 ± 19 vs. 25 ± 4 pg/mL, p < .001). Incidences of early organ dysfunction in patients whose serum sTREM-1 levels were ≤40 and >40 pg/mL were 17% and 83%, respectively (p < .001). The usefulness of serum sTREM-1 in detecting early organ dysfunction was superior to that of C-reactive protein, interleukin-6, interleukin-8, Ranson score, and Acute Physiology and Chronic Health Evaluation II score. Serum sTREM-1 levels decreased with resolution of early organ dysfunction. Conclusions:Serum sTREM-1 levels were significantly increased and correlated with disease severity and early organ dysfunction in patients with AP. Serum sTREM-1 level may be a useful marker for early organ dysfunction in AP.

Immunosuppression in patients with severe acute pancreatitis.

BackgroundIn severe acute pancreatitis (SAP), immunologic impairment in the early phase may be linked to subsequent infectious complications. In this study, immunologic alterations in patients with SAP were analyzed, and immunologic parameters related to infectious complications were clarified.MethodsA total of 101 patients with SAP were analyzed retrospectively. Various immunologic parameters on admission were analyzed and compared between the infection group and noninfection group during SAP. Furthermore, chronologic change in the lymphocyte count was investigated, and its utility for predicting infection was compared with conventional scoring systems.ResultsSerum immunoglobulin G (IgG), serum IgM, lymphokine-activated killer cell activity, and natural killer cell activity were low, and the incidence of abnormally low values was 50.0%, 65.0%, 45.5%, and 42.4%, respectively. Serum complement factor 3 was significantly negatively correlated with the APACHE II score. The lymphocyte count was decreased below the normal range, and was significantly negatively correlated with the APACHE II score. CD4-, CD8-, and CD20-positive lymphocyte counts were below the normal range, and CD4- and CD8-positive lymphocyte counts were significantly lower in the infection group. The lymphocyte count on day 14 after admission was significantly lower in the infection group and was more useful for predicting infection than conventional scoring systems.ConclusionsImmunosuppression occurs from the early phase in SAP, and quantitative impairment of lymphocytes, mainly T lymphocytes, may be closely related to infectious complications during SAP. CD4- and CD8-positive lymphocyte counts on admission and the lymphocyte count on day 14 after admission may be useful for predicting infection.

Usefulness of performing a pancreaticojejunostomy with an internal stent after a pancreatoduodenectomy

PurposeIn pancreaticojejunostomy (PJ), the occurrence of an injury during the removal of a stented tube is sometimes related to pancreatitis or late-onset stenosis of the pancreatic duct. In this study, we compare the outcomes of a PJ with an external stent versus an internal stent in a randomized study.MethodsWe compared the complications including pancreatic fistula, mortality, and postoperative hospital stay of 43 patients who had PJ with an external stent (group E) or PJ with an internal stent (group I) after a pancreaticoduodenectomy (PD).ResultsPancreatic fistula occurred in 8 patients (36.4%) in group E, while it only was seen in 7 patients (33.3%) in group I. Pancreatitis was recognized in 3 patients in group E, while there was no patient in whom an obstruction due to an internal stent was suspected.ConclusionPancreaticojejunostomy with an internal stent is therefore considered to be an effective treatment alternative after PD, with an acceptable morbidity and no mortality.

A prospective randomized comparison between pylorus‐ and subtotal stomach‐preserving pancreatoduodenectomy on postoperative delayed gastric emptying occurrence and long‐term nutritional status

Pylorus‐preserving pancreatoduodenectomy (PPPD) has been associated with a high incidence of delayed gastric emptying (DGE). There are few studies comparing DGE associated with PPPD and subtotal stomach‐preserving pancreatoduodenectomy (SSPPD). Moreover, differences between the procedures with respect to long‐term results have not been reported. A prospective randomized study was conducted to compare perioperative complications and long‐term nutritional status with PPPD and SSPPD.

18-Fluorodeoxyglucose Positron Emission Tomography Does Not Aid in Diagnosis of Pancreatic Ductal Adenocarcinoma

BACKGROUND & AIMS There are no accurate and reliable tools for diagnosis of early stage pancreatic ductal adenocarcinoma (PDA) or small metastatic lesions. It is also a challenge to differentiate PDA from focal mass-forming pancreatitis (FMP). There is controversy regarding the efficacy of 18-fluorodeoxyglucose positron-emission tomography (FDG-PET) in the diagnosis of PDA. We investigated whether FDG-PET provides information that, combined with data from other imaging techniques, can aid in decision making for patients with suspected PDA. METHODS We performed a retrospective analysis of data collected from 232 consecutive patients with suspected PDA at Kobe University Hospital from January 2006 through June 2012. All patients underwent a diagnostic imaging protocol that included multidetector row computed tomography, superparamagnetic iron oxide-enhanced magnetic resonance imaging, and FDG-PET. Based on endoscopic ultrasonography, fine-needle aspiration biopsy, or endoscopic retrograde cholangiopancreatography analyses, 218 patients had PDA (89 underwent resection and 129 did not) and 14 patients had FMP (8 had focal mass-forming chronic pancreatitis and 6 had focal mass-forming autoimmune pancreatitis). RESULTS FDG-PET detected 50% of stages 0 and I, 91.9% of stage II, 100% of stage III, and 96.8% of stage IV tumors. Detection was affected significantly by tumor size (P = .024) and T stage (P = .023) in resected tumors. Multidetector row computed tomography detected significantly more liver metastases than FDG-PET. Few para-aortic lymph node or peritoneal metastases were detected by FDG-PET. FDG-PET correctly identified 11 of the 14 patients with FMP (5 of 8 with focal mass-forming chronic pancreatitis and 6 of 6 with focal mass-forming autoimmune pancreatitis). CONCLUSIONS FDG-PET is not effective in detecting early stage PDA and small metastases, or in differentiating PDA from FMP. Combining FDG-PET with current diagnostic techniques for PDA did not provide any decisive information, therefore it should not be included in this analysis.

Role of Toll-Like Receptor 4 in the Pathophysiology of Severe Acute Pancreatitis in Mice

PurposeMultiple organ dysfunction and infection are major contributors to the high mortality associated with severe acute pancreatitis (SAP). Toll-like receptor 4 (TLR4) recognizes the lipopolysaccharide of gram-negative bacilli and is involved in inflammatory response and host defense. We examined the effects of TLR4-deficiency in SAP in mice.MethodsClosed duodenal loop-induced pancreatitis was induced in C3H/HeN (wild-type) and C3H/HeJ (TLR4-deficient) mice. We compared the severity of pancreatitis, liver and kidney dysfunction, and bacterial translocation to the pancreas between the two types of mice 12 h after the induction of SAP.ResultsThe severity of pancreatitis was similar in the two types of mice. The TLR4-deficient mice had significantly lower serum levels of aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine; significantly lower serum levels of interleukin-1 and tumor necrosis factor; reduced apoptosis of the liver and kidney; and a significantly higher rate of positive gram-negative bacterial cultures of the pancreas. TLR4 protein expression in the liver, kidney, and small intestine was increased 4 h after the induction of SAP, and decreased 12 h after the induction of SAP.ConclusionsTLR4 is implicated in the mechanism of organ dysfunction and bacterial translocation in SAP, and TLR4 may trigger the inflammatory response and function defensively against infection.

Treatment strategy against infection : clinical outcome of continuous regional arterial infusion, enteral nutrition, and surgery in severe acute pancreatitis

BackgroundIn severe acute pancreatitis (SAP), infectious complications are the main contributors to high mortality. Since 1995, we have performed continuous regional arterial infusion of protease inhibitor and antibiotics (CRAI) and enteral nutrition (EN) as prevention therapies against infection. When infected pancreatic necrosis was proven, surgical intervention was adapted. The aim of this study was to investigate the clinical outcome of these treatments.MethodsWe examined the relationship between the historical change of treatment strategy and clinical outcome. We divided 84 patients with acute necrotizing pancreatitis into two groups, CRAI (−) and CRAI (+), and compared the outcome. We divided 145 patients with SAP into two groups, EN (−) and EN (+), and compared the outcome. We also analyzed the outcome of surgical treatment.ResultsIn the CRAI (+) group, the incidence of infection, the frequency of surgery, and the mortality rate were lower than those in CRAI (−) group: 34% versus 51%, 27% versus 63% (P < 0.05), and 37% versus 54%, respectively. In the EN (+) group, the frequency of surgery and the mortality rate were lower than those in the EN (−) group: 23% versus 32% and 19% versus 35% (P < 0.05), respectively. These improvement effects were manifest in stage 3 (9 ≤ Japanese Severity Score ≤ 14). Treatment outcome of necrosectomy for infected pancreatic necrosis was still poor. Bleeding and abscess–gut fistula were postoperative life-threatening complications.ConclusionsCRAI and EN may improve the clinical outcome of SAP, reducing infection and averting pancreatic surgery.

Long-term outcome of severe acute pancreatitis

BACKGROUND/PURPOSE This study was undertaken to evaluate the post-discharge outcome of severe acute pancreatitis (SAP) and to clarify the prognostic factors for poor outcome. METHODS In 45 patients, recurrence of acute pancreatitis (AP), transition to chronic pancreatitis (CP), and development of diabetes mellitus (DM) were evaluated. Relationships of the outcome with the findings on admission and the presence/absence of alcohol intake were analyzed. RESULTS The mean follow-up period was 56+/-6 months. Recurrence of AP was noted in 19% of the patients. The recurrence rate was higher in patients with necrotizing pancreatitis than in those without this feature. C-reactive protein and white blood cell (WBC) count were higher in patients with recurrence of AP. Transition to CP was noted in 22% of patients. The transition rate was higher in those with alcoholic SAP than in those with biliary SAP. In patients with transition to CP, the WBC count, hematocrit, Ranson score, and Japanese severity score were higher, and base excess (BE) was lower, compared with these features in patients without this transition. Development of DM was noted in 39% of patients. Blood glucose and BE were higher in patients who developed DM than in those who did not. CONCLUSIONS The degree of inflammation and pancreatic necrosis found on admission for SAP may be related to the recurrence of AP. Alcoholic SAP in which the disease is very severe may contribute to the transition to CP. Patients with impaired glucose tolerance readily develop DM after SAP.

An extremely rare portal annular pancreas for pancreaticoduodenectomy with a special note on the pancreatic duct management in the dorsal pancreas

Fig 1. Dynamic CT imaging showing pancreatic tissue completely encircling the superior mesenteric vein (SMV; arrow) and a dilated main pancreatic duct in the tissue behind the SMV (arrow head). A PREVIOUSLY HEALTHY 81-YEAR-OLD WOMAN with general fatigue was admitted to our hospital in June 2009. Her blood chemistry data were within normal limits except for slightly elevated liver function values. Serum levels of carbohydrate antigen 19-9 and carcinoembryonic antigen were both normal. Gastroduodenoscopy showed an erosive tumor in the ampulla of Vater. Dynamic computed tomography (CT) revealed bilateral intrahepatic biliary dilatation, and the superior mesenteric vein (SMV) circumferentially embedded in the body of the pancreas, as well as a slightly dilated main pancreatic duct (MPD) in the tissue behind the SMV (Fig 1). The MPD was found posteriorly to the SMV and the accessory pancreatic duct (APD) was seen anteriorly to the SMV. The 2 ducts joined in the body of the pancreas to the left side of the