Kiichi Aoki

Influence of a human protease inhibitor on surgical stress induced immunosuppression.

Background/Aim: Postoperative tissue injury and immunosuppression can occur after major surgery. In this study, we explore the potential benefits of administering a protease inhibitor to treat immunosuppression caused by surgical stress. Methods: Sixteen patients with esophageal cancer were preoperatively allocated at random into two equal groups. A urinary trypsin inhibitor, ulinastatin (UTI), was intravenously administered to the treatment (UTI) group at a dose of 150,000 U every 12 h from the start of surgery until postoperative day 5, whereas the control group received a placebo. One unit of UTI was defined as the amount of UTI necessary to inhibit the activity of 2 µg of bovine pancreatic trypsin by 50%. We measured the plasma levels of polymorphonuclear neutrophil elastase, interleukin 8, circulating T lymphocyte subsets, and mitogenic activity and in vitro production of tumor necrosis factor alpha in lipopolysaccharide-stimulated whole blood. Results: The postoperative serum value of polymorphonuclear neutrophil elastase was significantly lower in the UTI group, but the interleukin 8 concentrations did not significantly vary between the two groups. On the other hand, the severity of the postoperative immunosuppression was reduced in the UTI group, and immune functions, such as the numbers of T lymphocytes, the mitogenic activity of lymphocytes, and the level of tumor necrosis factor alpha production in whole blood, recovered significantly earlier in the UTI group. Conclusion: These data suggest that a protease-modulating therapy may be a new strategy for the treatment of surgical stress induced immune dysfunction.

Significance of Measuring S100A12 and sRAGE in the Serum of Sepsis Patients with Postoperative Acute Lung Injury

Background: There is a report that S100A12 is useful as an early marker of acute lung injury (ALI). The purpose of this study was to determine whether S100A12 or sRAGE is useful as a marker during the development of ALI in postoperative sepsis patients. Methods: The subjects were patients who underwent emergency surgery because of sepsis secondary to perforation of the lower gastrointestinal tract. We conducted a retrospective study comparing 2 groups of patients: a group of 9 patients who developed postoperative ALI, the ALI(+) group, and a group of 8 patients who did not develop postoperative ALI, the ALI(–) group. Their blood S100A12, sRAGE, IFN-γ, WBC count, and CRP values were measured immediately after surgery and on postoperative day 1 (D1). Results: The changes in S100A12 showed significantly higher values immediately postoperatively in the ALI(+) group (p < 0.05). The sRAGE values immediately postoperatively were similar, but on D1, they were significantly higher in the ALI(–) group (p < 0.05). Conclusions: S100A12 increases in the early stage of development of ALI. sRAGE production increases in patients who do not develop ALI.

Infrequent frameshift mutations of polynucleotide repeats in multiple primary cancers affecting the esophagus and other organs.

Frequent frameshift mutations of simple nucleotide repeats in the protein‐encoding regions, as well as replication errors (RERs) at microsatellite loci, have recently been demonstrated in gastrointestinal tumors. These genetic instabilities have been considered indicative of an increased risk of accumulating mutations in cancer‐associated genes and of developing multiple cancers. We studied frameshift (or insertion/ deletion) mutations of simple nucleotide repeats in five genes (TGFβ type II receptor [TGFβRII], E2F4, MSH2, MSH3, and MSH6) in 23 tumors from 12 patients who had synchronous cancers of the esophagus and other organs. Genetic instability at four microsatellite loci, as well as mutations in the TP53, APC, and KRAS2 genes, were also studied. No frameshift mutations were observed in the TGFβRII, MSH3, and MSH6 genes. RER and a deletion mutation of BAT26 in MSH2 were present in one (1/ 23; 4%) gastric cancer. This tumor also carried a deletion mutation in the serine (AGC) repeat of the E2F4 gene. Mutation screening of the TP53, APC, and KRAS2 genes revealed that the synchronous cancers did not carry the same mutations. Our results suggested that genetic instability, such as insertion/ deletion mutations in simple nucleotide repeats, is not significantly associated with the development of multiple primary cancers of the esophagus and other organs, and that these synchronous cancers developed independently according to their different environmental factors. Genes Chromosomes Cancer 23:317–322, 1998.

Problems in neoadjuvant chemoradiotherapy preceding surgery for advanced squamous cell carcinoma of the thoracic esophagus

The adverse effect of neoadjuvant chemoradiotherapy on the postoperative course in esophageal cancer was studied in 9 patients undergoing neoadjuvant chemoradiotherapy preceding surgery for thoracic esophageal carcinoma possibly involving adjacent organs (neoadjuvant group), and 13 patients undergoing surgery without neoadjuvant therapy for same disease (control group). The two groups were compared for volume of intraoperative hemorrhage, surgical duration, frequency of postoperative morbidity, and for postoperative changes in blood platelet counts, and serum thrombopoietin and interleukin-6 levels. Mean intraoperative blood loss was 1121 g (580-1,662 g) in the neoadjuvant group and 546.5 g (274.7-778.3 g) in controls group (Students T test: p < 0.01). No significant difference was seen found between the two groups in the degree of postoperative deterioration in cardiopulmonary function or in interleukin-6 levels. Blood platelet counts decreased in both groups until postoperative day 7, but recovery on postoperative day 14 was significantly depressed in the neoadjuvant group compared to controls. Serum thrombopoietin levels were higher in the neoadjuvant group than in controls (Mann-Whitney U-test: p < 0.05). We found that neoadjuvant chemoradiotherapy induces latent postoperative myelosuppression and may lead to intractable infection.

Effect of Preoperative Methylprednisolone Administration on Coagulation and Fibrinolytic Status in Patients Undergoing Esophageal Cancer Surgery.

食道癌術後には過大侵襲により凝固亢進状態が生じ術後合併症, 臓器障害の発生に関与することが知られている. 食道癌術後凝固線溶系に対するメチルプレドニゾロン (MP) 術前投与の効果を検討する目的で胸部食道癌20例を対象として, MP10mg/kg投与群10例 (MP群), 対照群10例 (C群) を無作為に割り付け検討を行った. 術後C群では血小板数の低下, APTTの延長, AT-III, Plgの低下と凝固亢進, 線溶抑制状態を認めたが, MP群ではAPTTの延長とAT-IIIおよびPlgの低下が有意に抑制されていた. IL-6, CRP, 尿中NAGはMP群で有意に低値で推移し, 人工呼吸期間, SIRS期間も短縮していた. 食道癌手術侵襲に対する術後凝固亢進状態はMP術前投与により制御可能であり, 凝固線溶系上からも術後臓器障害および手術侵襲の軽減に関与するものと考えられた.