Junichi Nishijima

Circulating interleukin 6 as a useful marker for predicting postoperative complications

We examined postoperative serial changes in the levels of serum interleukin 6 (IL-6), serum acute phase reactants (APRs) and plasma neutrophil elastase (NE) in patients with various cancers and reviewed these changes in patients who did, and did not, show postoperative complications. Serum IL-6 level was elevated after surgery, peaking on the first postoperative day. Elevation of serum APRs and plasma NE levels also followed. There was a significant correlation between the serum peak level of IL-6 and those of APRs and NE (P less than 0.01). Moreover, there was a significant difference in the serum IL-6 level in patients with and without complications. The relationship between the serum IL-6 greater than 400 pg/ml and the incidence of postoperative complications was also marked. These results suggest that circulating IL-6 is a clinically useful marker for the earliest detection and prediction of postoperative complications.

Serum Interleukin 6, C-Reactive Protein and Pancreatic Secretory Trypsin Inhibitor (Psti) as Acute Phase Reactants After Major Thoraco-Abdominal Surgery

We measured serum immunoreactive interleukin 6 (IL-6) levels in patients after major thoraco-abdominal surgery and compared them with changes in serum C-reactive protein (CRP) and pancreatic secretory trypsin inhibitor (PSTI) levels. Serum IL-6 levels were elevated earlier than serum CRP or PSTI. There were significant relationships between the peak levels of serum IL-6 and the operation time (p less than 0.05) or the volume of blood loss during surgery (p less than 0.05), showing that serum IL-6 can be a useful laboratory test for the evaluation of tissue injuries due to surgical intervention. Though there was a significant relationship between the peak levels of IL-6 and CRP (p less than 0.01), there was no relationship between the peak levels of IL-6 and PSTI.

Development of a radioimmunoassay for human group-II phospholipase A2 and demonstration of postoperative elevation.

A radioimmunoassay (RIA) for the determination of human group-II phospholipase A2 (M-PLA2) has been developed. M-PLA2 was purified from human spleen. Monoclonal antibody (IgG) was prepared by fusion of splenic cells from immunized mice with M-PLA2 and the mouse myeloma cell line NS-1. The RIA was carried out by a single antibody method. The assay is sensitive (0.78 micrograms/l), reproducible and specific. In healthy individuals, the serum M-PLA2 concentration ranges from 1.4 to 4.2 micrograms/l, the average being 2.2 +/- 0.1 micrograms/l (mean +/- SE). Using the RIA, we found increased serum M-PLA2 in patients with various infections and malignant tumors. We also showed the postoperative transient elevation of serum M-PLA2 in cases without any infectious complications. The elevation was independent of the surgical procedure or site. The maximum serum M-PLA2 level was seen on the 2nd to 4th postoperative day. In these patients, the serum M-PLA2 and C-reactive protein levels were significantly correlated. The present study indicated that serum M-PLA2 is an acute phase reactant.

Protease inhibitors (gabexate mesylate and ulinastatin) stimulate intracellular chemiluminescence in human neutrophils

The effect of protease inhibitors on the intracellular production of free radicals was investigated by measuring chemiluminescence (CL) elicited from phagocytosed luminol‐bound microspheres (Lumispheres) in human neutrophils stimulated with formylmethionyl‐leucyl‐phenylalanine (fMLP), interleukin‐8 (IL‐8), phorbol 12‐myristate 13‐acetate, or diacylglycerol. Both gabexate mesylate (Foy) and ulinastatin (Miraclid), urinary trypsin inhibitor, increased intracellular CL in a dose dependent manner. Compared to control buffer without protease inhibitor, gabexate mesylate (322 μg/ml) caused about a 10‐fold increase in intracellular CL in stimulated neutrophils, and ulinastatin (3100 U/ml) a twofold increase in neutrophils stimulated with fMLP or IL‐8. When the protease inhibitors were added to the cell suspension after the phagocytosis of lumispheres, CL responses rapidly increased again to the level which was observed when both protease inhibitors and neutrophil stimulants were incubated simultaneously. In contrast, extracellular release of oxygen metabolites from stimulated neutrophils, assayed by a conventional measurement of luminol‐dependent CL, was reduced by the protease inhibitors in a dose dependent fashion. When luminol‐unbound microspheres were incubated with neutrophils stimulated by fMLP in luminol solution, extracellular CL was almost completely inhibited by gabexate mesylate. These results indicate that the protease inhibitors enhance the generation of intracellular CL and suppress the extracellular release of free radicals.

Usefulness of an estimation of physiologic ability and surgical stress (E-PASS) scoring system to predict the incidence of postoperative complications in gastrointestinal surgery

Surgical intervention induces various host responses to maintain homeostasis. When postoperative inflammation is intense and persists for a long time, postoperative complications may occur, sometimes developing into multiple organ failure. Therefore, it is very important to assess surgical stress and predict the risk of morbidity and mortality. Using a new scoring system, an estimation of physiologic ability and surgical stress (E-PASS) scoring system, surgical stress following gastrointestinal surgery was evaluated to assess the feasibility of this scoring system. This system comprises a preoperative risk score (PRS), a surgical stress score (SSS), and a comprehensive risk score (CRS) that is calculated from both the PRS and the SSS. The relationship of the E-PASS score to the incidence of morbidity and mortality was examined. The relationship between the E-PASS score and a sequential organ failure (SOFA) score was also evaluated. The CRS had a significant positive correlation between not only the incidence but also the grade of postoperative complications. Total maximum SOFA score in patients with a CRS of more than 1 was significantly higher than that in patients with a CRS of less than 1. In conclusion, the E-PASS scoring system will be useful for predicting and recognizing the risk of postoperative complications. This scoring system is brief, simple, and reproducible and can be useful in all types of hospitals.

Enhanced attachment and elastase-releasing capacity of neutrophils after surgery

Perioperative changes in neutrophil attachment level and neutrophil elastase-releasing capacity were examined in patients who underwent surgery for either esophageal or gastric cancer. The neutrophil attachment level was significantly increased in both groups to approximately three times that of the preoperative value. The elastase-releasing capacity of nonstimulated neutrophils was not significantly changed, but it was significantly increased in neutrophils stimulated by N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP). Moreover, both neutrophil attachment and elastase-releasing capacity of FMLP-stimulated neutrophils were more enhanced in patients with postoperative complications than in patients without complications. Peak levels of serum interleukin 6, serum alpha 1 proteinase inhibitor, and plasma neutrophil elastase were also significantly higher in patients with postoperative complications than in patients without. These results suggest that during the postoperative period, neutrophils may be primed and activated in response to inflammatory mediators such as cytokines, and that such an alteration of neutrophil functions may reflect the extent of inflammation and may, at times, be implicated in postoperative complications.

Purification and some properties of membrane-associated phospholipase A2 of human spleen.

Membrane-associated phospholipase A2 was purified to homogeneity from human spleen. The enzyme was solubilized from the particulate fraction by the addition of KBr, and purified by reverse-phase high-performance liquid chromatography. The estimated molecular weight of the enzyme was 14,000. The enzyme had a pH optimum around 9.5, required the presence of Ca2+ for its activity, and hydrolyzed phosphatidylethanolamine more efficiently than phosphatidylcholine.

Serum immunoreactive pancreatic phospholipase A2 in patients with various malignant tumors.

The high incidence (40.6%) of elevated serum pancreatic phospholipase A2 (PLA2) was demonstrated in patients with various malignancies. Serum PLA2 was significantly increased in cancer patients compared with healthy sex- and age-matched blood donors (358.4 +/- 168.0 vs. 241.7 +/- 69.0 ng/dl; p less than 0.01). No correlation was observed between serum PLA2 and carcinoembryonic antigen (CEA) in these patients. Although patients with advanced and distantly metastatic cancer of the liver, gallbladder and pancreas showed higher PLA2 levels in serum than those with early cancer, patients with other cancers showed no correlation between serum PLA2 and clinical stage. A combined assay of PLA2 and CEA increased the sensitivity of detection of cancers to 60.8%.

Gastric neuroendocrine tumors in our institutions according to the WHO 2010 classification.

In 2010, World Health Organization classified gastric neuroendocrine tumor (NET) as follows: NET grade (G) 1, NET G2, neuroendocrine carcinoma (NEC). We reviewed 22 gastric NETs that were encountered in our institutions. Nine, 6, and 4 were NET G1, G2, and NEC, respectively. We also encountered 3 NET G3. NET G1 was treated with observation in 2 patients, endoscopic mucosal resection (EMR) in 3, and gastrectomy in 4 patients. No recurrence was experienced during a median of 53 months of follow-up. All NET G2 was treated with gastrectomy. No patient experienced recurrence during a median of 25 months of follow-up. NET G3 was treated with gastrectomy. One patient died of liver metastasis 52 months after gastrectomy. For NEC, gastrectomy was performed in 3 cases and no patients died of tumor-related death. We conclude that the prognoses of NET G1 and G2 were good. We also experienced long-term survivors of NEC. An accumulation of more patients is needed for further investigation.

Prognostic Factors for Gastrectomy in Elderly Patients

The decision to undergo surgery for gastric cancer patients aged ≥85 years should be made carefully. We retrospectively reviewed the prognostic factors of gastrectomy for 64 patients aged ≥85 years who had undergone curative gastrectomy for gastric cancer. The effects of various clinical characteristics and surgical interventions on survival were retrospectively analyzed. Univariate analysis revealed that sex (male/female; P = 0.001), the extent of gastric resection (total/distal; P = 0.028), the extent of lymph node dissection (D2/<D2; P = 0.019), and blood loss (P = 0.005) were significant prognostic factors for overall survival. Multivariate analysis demonstrated that sex was the only independent prognostic factor. For pneumonia-specific survival, sex was also the only prognostic factor by multivariate analysis.Prognoses of males aged ≥85 years after gastrectomy were significantly worse than those of females, as they were more likely to die of pneumonia.