Shuichi Hiraki

Impact of Postoperative Infection on Long-Term Survival After Potentially Curative Resection for Gastric Cancer

We focused on the impact of postoperative infection on long-term survival after potentially curative resection for gastric cancer. Postoperative surgical and medical complications have been implicated as a negative predictor of long-term outcome in various malignancies. However, there have been no published reports assessing the impact of complications arising from postoperative infection on survival in gastric cancer. We studied a population of 1,332 patients who underwent curative resection for gastric cancer. These patients were divided into two groups based on the occurrence (141 patients, 10.6%) or absence (1,191 patients, 89.4%) of postoperative complications due to infection. We investigated the demographic and clinicopathological features of each patient with and without postoperative complications from infection, and thereby the impact of postoperative infection on long-term survival. Patients with postoperative infection had significantly higher frequency of males, upper side tumor location, and total gastrectomy as a surgical procedure, more advanced stage of gastric cancer, and greater age compared with those without postoperative infection. Patients with complications due to postoperative infection had significantly more unfavorable outcome compared with those patients without postoperative infection. Multivariate analysis demonstrated that age, preoperative comorbidity, blood transfusion, tumor depth, nodal involvement, and postoperative infection correlated with overall survival. We conclude that postoperative complications from infection are a predictor of adverse clinical outcome in patients with gastric cancer. However, further immunological study and prospective trials are necessary to confirm the biological significance of these findings.

CD47 is an adverse prognostic factor and a therapeutic target in gastric cancer.

CD47 is an antiphagocytic molecule that acts via ligation to signal regulatory protein alpha on phagocytes; its enhanced expression and therapeutic targeting have recently been reported for several malignancies. However, CD47 expression in gastric cancer is not well documented. Immunohistochemical expression of CD47 in surgical specimens was investigated. Expression of CD47 and CD44, a known gastric cancer stem cell marker, were investigated in gastric cancer cell lines by flow cytometry. MKN45 and MKN74 gastric cancer cells were sorted by fluorescence‐activated cell sorting according to CD44 and CD47 expression levels, and their in vitro proliferation, spheroid‐forming capacity, and in vivo tumorigenicity were studied. In vitro phagocytosis of cancer cells by human macrophages in the presence of a CD47 blocking monoclonal antibody (B6H12) and the survival of immunodeficient mice intraperitoneally engrafted with MKN45 cells and B6H12 were compared to experiments using control antibodies. Immunohistochemistry of the clinical specimens indicated that CD47 was positive in 57 out of 115 cases, and its positivity was an independent adverse prognostic factor. Approximately 90% of the MKN45 and MKN74 cells expressed CD47 and CD44. CD47hi gastric cancer cells showed significantly higher proliferation and spheroid colony formation than CD47lo, and CD44hiCD47hi cells showed the highest proliferation in vitro and tumorigenicity in vivo. B6H12 significantly enhanced in vitro phagocytosis of cancer cells by human macrophages and prolonged the survival of intraperitoneal cancer dissemination in mice compared to control antibodies. In conclusion, CD47 is an adverse prognostic factor and promising therapeutic target in gastric cancer.

Detection of microbial DNA in the blood of surgical patients for diagnosing bacterial translocation.

Bacterial translocation sometimes occurs in patients during surgical stress and is associated with an increased incidence of septic morbidity. However, no reliable method has been established for diagnosing bacterial translocation in humans. Identification of minute quantities of microbial-specific DNA has been made possible using polymerase chain reaction (PCR) techniques. The aims of this study were to determine the prevalence of bacterial translocation in patients with surgical stress using PCR techniques and to evaluate the usefulness of blood PCR techniques for diagnosing bacterial translocation. DNA was extracted from the blood of 52 surgical patients (24 elective major surgery patients and 28 septic patients) and 10 healthy controls. PCR techniques were used to amplify genes from Escherichia coli, Bacteroides fragilis, a region of 16S ribosomal RNA found in many gram-positive and gram-negative bacteria, and Candida albicans. Bacterial and Candida albicans DNA were not detected in healthy volunteers. Enteric bacterial DNA was detected in patients with hepatic lobectomy, and Candida albicans DNA was detected in patients with esophagectomy on the first postoperative day. Enteric bacterial and Candida albicans DNA were detected in septic patients with findings diagnostic of bacterial translocation, such as small bowel obstruction, ulcerative colitis, or supramesenteric arterial occlusion or in those who had undergone chemotherapy for advanced colon cancer. However, none of the patients were positive by the blood culture technique. The PCR method is more sensitive than blood cultures for detecting bacterial components in the blood of septic patients and is a valuable tool for verifying bacterial translocation in patients who have undergone hepatic lobectomy or esophagectomy. It is also valuable in septic patients who do not have a defined focus of infection.

Photodynamic therapy using nanoparticle loaded with indocyanine green for experimental peritoneal dissemination of gastric cancer

Although there have been multiple advances in the development of novel anticancer agents and operative procedures, prognosis of patients with advanced gastric cancer remains poor, especially in patients with peritoneal metastasis. In this study, we established nanoparticles loaded with indocyanine green (ICG) derivatives: ICG loaded lactosomes (ICGm) and investigated the diagnostic and therapeutic value of photodynamic therapy (PDT) using ICGm for experimental peritoneal dissemination of gastric cancer. Experimental peritoneal disseminated xenografts of human gastric cancer were established in nude mice. Three weeks after intraperitoneal injection of the cancer cells, either ICGm (ICGm‐treated mice) or ICG solution (ICG‐treated mice) was injected through the tail vein. Forty‐eight hours after injection of the photosensitizer, in vivo and ex vivo imaging was carried out. For PDT, 48 h after injection of the photosensitizer, other mice were irradiated through the abdominal wall, and the body weight and survival rate were monitored. In vivo imaging revealed that peritoneal tumors were visualized through the abdominal wall in ICGm‐treated mice, whereas only non‐specific fluorescence was observed in ICG‐treated mice. The PDT reduced the total weight of the disseminated nodules and significantly improved weight loss and survival rate in ICGm‐treated mice. In conclusion, ICGm can be used as a novel diagnostic and therapeutic nanodevice in peritoneal dissemination of gastric cancer.

Postoperative serum concentrations of high mobility group box chromosomal protein-1 correlates to the duration of SIRS and pulmonary dysfunction following gastrointestinal surgery.

OBJECTIVE To clarify the time course of changes in the serum HMGB-1 concentrations in patients undergoing major gastrointestinal surgery, and to investigate whether the serum HMGB-1 levels correlate with the postoperative clinical course of the patients. METHODS Twenty-eight patients with alimentary tract carcinoma who underwent elective gastrointestinal surgery were enrolled in this study. The correlation between the serum HMGB-1 levels and the postoperative clinical course were evaluated. RESULTS Serum HMGB-1 concentrations in patients who underwent surgery for gastrointestinal cancer increased gradually during postoperative days, and reached peak concentrations on postoperative day 3 (POD3). There was a statistically significant positive correlation between the serum HMGB-1 levels on POD3 or POD5 and the duration of SIRS (r = 0.68, P < 0.001, r = 0.45, P < 0.05, respectively). A significantly positive correlation was found between the serum HMGB-1 levels on POD3 or POD5 and the heart rates on POD3 or POD5. Furthermore, there was a negative correlation between the serum HMGB-1 levels and PaO2/FiO2 ratio on POD3. CONCLUSIONS Serum HMGB-1 levels increase after major gastrointestinal surgery, and the serum peak HMGB-1 levels correlate with the duration of SIRS and postoperative pulmonary dysfunction.

Neutralization of IL-10 restores the downregulation of IL-18 receptor on natural killer cells and interferon-γ production in septic mice, thus leading to an improved survival.

ABSTRACT The objective of the study was to investigate the mechanisms of insufficient interferon-&ggr; (IFN-&ggr;) response to interleukin 18 (IL-18) and the treatment for the insufficient response in septic mice. Interleukin 18 stimulation does not restore IFN-&ggr; production by blood mononuclear cells in septic patients but does restore its production in postoperative patients. Although sepsis impairs the IFN-&ggr; response to IL-18, little is known about why the IL-18/IFN-&ggr;–mediated immune response is ineffective in patients with sepsis. A cecal ligation and puncture was made in C57BL/6 mice following a sublethal lipopolysaccharide challenge to examine their IFN-&ggr; response to IL-18, focusing on natural killer (NK) cells and cytokines. We next examined the effect of neutralization of IL-10 on the NK cell and survival in septic mice. Interleukin 18 injection did not restore IFN-&ggr; production in septic (cecal ligation and puncture) mice. Despite an increase in the numbers of liver NK cells, the IL-18 receptor (IL-18R) expression was decreased in the septic mice compared with sham mice. Serum IL-10 levels were positively correlated with the percentage of liver NK cells, but negatively with their IL-18R expression. Neutralization of IL-10 restored the IL-18R expression on liver NK cells and restored the IFN-&ggr; response in the septic mice, improving their survival. Sepsis might impair IL-18R expression on liver and spleen NK cells and impair the IL-18–mediated IFN-&ggr; response. Neutralization of IL-10 may restore this response in septic hosts, thereby improving survival.

Systemic inflammatory response syndrome as a predictor of anastomotic leakage after esophagectomy

PurposeEsophageal anastomotic leakage is still a major cause of morbidity and mortality after esophagectomy. We conducted this study to elucidate how anastomotic leakage affects the systemic inflammatory response syndrome (SIRS) criteria.MethodsThe subjects of this retrospective study were 61 patients who underwent esophagectomy. We evaluated their preoperative status, the surgical procedures, and postoperative systemic response, including white blood cell count, heart rate, respiratory rate, body temperature, and laboratory data up to postoperative day (POD) 4.ResultsAnastomotic leakage developed in nine patients (14.8%) and was found on POD 7 on average. These patients had a significantly longer hospital stay than those without leakage. Although no difference was observed in postoperative changes of any of the SIRS criteria, the postoperative incidence of SIRS was significantly higher in the patients with anastomotic leakage on POD 4. The number of positive criteria for SIRS was also significantly higher in patients with anastomotic leakage than in those without leakage on PODs 3 and 4.ConclusionsThe SIRS scoring system is valuable for evaluating the severity of systemic inflammatory response caused by anastomosis leakage, and may serve as an indicator for prompt management.

Theranostic Photosensitive Nanoparticles for Lymph Node Metastasis of Gastric Cancer

BackgroundPreoperative and intraoperative diagnoses of lymph node (LN) metastasis in patients with gastric cancer is essential to determine the extent of LN dissection in order to establish individualized treatment strategies. We investigated the theranostic value of a newly developed drug delivery system employing nanoparticles loaded with the indocyanine green (ICG) derivative ICG-loaded lactosome (ICGm) using a murine draining LN metastasis model of gastric cancer.MethodsIn the experimental draining LN metastasis model of human gastric cancer, the right hind footpads of nude mice were injected with cancer cells. Three weeks later, either ICGm or ICG solution was injected through the tail vein. Forty-eight hours after the administration of a photosensitizer, in vivo and ex vivo imaging and photodynamic therapy (PDT) were performed, and size of the LNs was measured.ResultsIn vivo imaging revealed metastatic LNs in the ICGm-treated mice but not in the ICG-treated mice. PDT using ICGm induced apoptosis and significantly inhibited the growth of metastatic LNs.ConclusionsICGm presents a novel theranostic nanodevice for LN metastasis of gastric cancer.

Laparoscopic treatment for median arcuate ligament syndrome: the usefulness of intraoperative Doppler ultrasound to confirm the decompression of the celiac artery.

The median arcuate ligament syndrome is an unusual disease associated with postprandial epigastric pain, and the optimal treatment of this syndrome remains to be established. A 52-year-old woman manifested in our hospital postprandial epigastric pain, and extrinsic compression of the celiac trunk revealed by an abdominal computed tomography. After the induction of general anesthesia, the celiac artery origin was completely skeletonized using a laparoscopic dissector and vessel sealing system. Intraoperative Doppler ultrasound demonstrated that, after surgery, the stenosis of the celiac artery, and poststenotic dilatation observed before the release of the median arcuate ligament, had completely disappeared. In conclusion, the laparoscopic release of the median arcuate ligament is a minimally invasive treatment for median arcuate ligament syndrome. The intraoperative Doppler ultrasound is useful for confirming the decompression of the celiac artery, although long-term follow-up is mandatory.

Peritoneal computed tomography attenuation values reflect the severity of peritonitis caused by gastrointestinal perforations

BACKGROUND The aim of this study was to evaluate the peritoneal computed tomography (CT) attenuation values and relate them to the severity of peritonitis in patients with gastrointestinal tract (GI) perforations. METHODS A total of 56 consecutive patients with GI perforations who underwent CT scan and emergency laparotomy in our hospital were enrolled in this study. The CT attenuation values of the peritoneum were measured on a workstation by 2 independent investigators, and were investigated in relation to the severity of illness and hospital mortality. RESULTS Peritoneal CT attenuation values in hospital nonsurvivors were significantly lower than those in survivors. There was significant negative correlation between peritoneal CT attenuation values and sequential organ failure assessment score, acute physiology and chronic health evaluation II score, and the Mannheim peritonitis index. CONCLUSIONS The evaluation of peritoneal CT attenuation values in patients with peritonitis is simple and can be used for objective assessment of the severity of peritonitis.