Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1.

Caloric restriction (CR) is known to retard aging and delay functional decline as well as the onset of diseases in most organisms. Ghrelin is secreted from the stomach in response to CR and regulates energy metabolism. We hypothesized that in CR ghrelin has a role in protecting aging-related diseases. We examined the physiological mechanisms underlying the ghrelin system during the aging process in three mouse strains with different genetic and biochemical backgrounds as animal models of accelerated or normal human aging. The elevated plasma ghrelin concentration was observed in both klotho-deficient and senescence-accelerated mouse prone/8 (SAMP8) mice. Ghrelin treatment failed to stimulate appetite and prolong survival in klotho-deficient mice, suggesting the existence of ghrelin resistance in the process of aging. However, ghrelin antagonist hastened death and ghrelin signaling potentiators rikkunshito and atractylodin ameliorated several age-related diseases with decreased microglial activation in the brain and prolonged survival in klotho-deficient, SAMP8 and aged ICR mice. In vitro experiments, the elevated sirtuin1 (SIRT1) activity and protein expression through the cAMP-CREB pathway was observed after ghrelin and ghrelin potentiator treatment in ghrelin receptor 1a-expressing cells and human umbilical vein endothelial cells. Furthermore, rikkunshito increased hypothalamic SIRT1 activity and SIRT1 protein expression of the heart in the all three mouse models of aging. Pericarditis, myocardial calcification and atrophy of myocardial and muscle fiber were improved by treatment with rikkunshito. Ghrelin signaling may represent one of the mechanisms activated by CR, and potentiating ghrelin signaling may be useful to extend health and lifespan.

Clinical efficacy of protein-bound polysaccharide K in patients with gastric cancer undergoing chemotherapy with an oral fluoropyrimidine (S-1).

BACKGROUND: The aim of the present study was to evaluate the clinical significance of protein-bound polysaccharide K (PSK) in patients with primary gastric cancer who were being treated with an oral fluoropyrimidine (S-1). METHODS: Clinical reports of 190 gastric cancer patients treated with S-1 chemotherapy, with or without PSK, at Kochi Medical School between 2007 and 2012 were investigated retrospectively to analyze survival. The neutrophil:lymphocyte ratio (NLR) was also evaluated as indicator of the immunoenhancing effect of PSK. RESULTS: Overall survival was significantly longer in patients treated with S-1 + PSK than in those given S-1 alone (hazard ratio for death, 0.608; 95% confidence interval 0.375-0.985; P = 0.041). Furthermore, there was a tendency for changes in the NLR during chemotherapy to be lower in the S-1 + PSK group than in the S-1 group, but the difference did not reach statistical significance (P = 0.054). When patients were divided into groups based on preoperative NLR (i.e. <2.5 and ≥2.5), the mean (±SEM) NLR 1 month after the beginning of chemotherapy in the NLR ≥2.5 subgroup was significantly lower in patients treated with S-1 + PSK rather than S-1 alone (1.7 ± 0.7 vs. 3.3 ± 4.1, respectively; P = 0.043). CONCLUSIONS: Immunochemotherapy using PSK improves the survival of patients with advanced gastric cancer. The NLR may be a useful biomarker for evaluating prognosis in these patients.

Validation study of the Japanese version of the Faecal Incontinence Quality of Life Scale.

AIM: The aim of the present study was to conduct a psychometric validation of the Japanese version of the FIQL (JFIQL). METHOD: A retrospective analysis of data from the JFIQL was conducted. Wexner scores and Faecal Incontinence Severity Index (FISI) scores were collected prospectively in patients with faecal incontinence who visited our centre between 2008 and 2009. For convergent validity, the JFIQL scores were compared with stages on the Wexner scale for lifestyle alteration. To evaluate reliability, Cronbach's alpha was calculated for internal consistency, whereas a test-retest study was performed to evaluate reproducibility. In assessing responsiveness, JFIQL scores before and after treatments were compared in patients whose FISI scores decreased by ≥ 50%. RESULTS: Convergent validity and internal consistency were determined in 70 patients (49 women; median age 68.5 years). The JFIQL scores were significantly associated with lifestyle alteration stages on the Wexner scale, demonstrating convergent validity in all four domains and the generic score. Cronbach's alpha was > 0.7 for generic scores and all domains except Embarrassment. The intraclass correlations for the 27 patients available for the test-retest study were > 0.7 for generic scores and all domains except Embarrassment. The median JFIQL score improved significantly after treatment in the 23 patients whose FISI scores decreased ≥ 50%, indicating good responsiveness in all four domains and the generic score. CONCLUSION: The JFIQL has been validated and is now ready for use in evaluating the symptom-specific quality of life in Japanese patients with faecal incontinence.

Risk factors and predictors for surgical site infection after hepatic resection.

Strict control of blood glucose levels with insulin in a surgical intensive care unit reduces postoperative morbidity and mortality. The aim of this study was to identify risk factors and the predictors for the prevention of surgical site infection (SSI) in a consecutive series of hepatectomised cases in a single institution. The association between SSI and various clinical parameters was investigated in 152 patients who underwent hepatic resection at Kochi Medical School from January 2000 through March 2007. The incidence of SSI in these patients was 14.5%. Multivariate analysis identified four independent parameters correlating with the occurrence of SSI: (i) body mass index >23.6 kg/m(2); (ii) estimated blood volume loss >810 mL; (iii) presence of postoperative bile leakage of organ/space SSI; and (iv) use of the sliding scale method for postoperative glucose control. There was no observed SSI after liver resection in the group whose postoperative blood glucose levels were controlled by an artificial pancreas. This study reveals that lack of postoperative glycaemic control is associated with a significantly higher incidence of postoperative infectious complications and longer hospitalisation. Obesity and the level of intraoperative estimated blood loss and bile leakage after hepatic resection are also risk factors with predictive value for SSI. Artificial pancreas is a safe and beneficial device to perform postoperative strict glycaemic control without hypoglycaemia for patients who undergo hepatic resection for liver diseases.

Accuracy and reliability of continuous blood glucose monitor in post-surgical patients.

BACKGROUND: The STG-22 is the only continuous blood glucose monitoring system currently available. The aim of this study is to determine the accuracy and reliability of the STG-22 for continuously monitoring blood glucose level in post-surgical patients. METHODS: Fifty patients scheduled for routine surgery were studied in surgical intensive care unit (ICU) of a university hospital. After admission to the ICU, the STG-22 was connected to the patients. An attending physician obtained blood samples from a radial arterial catheter. Blood glucose level was measured using the ABL800FLEX immediately after blood collection at 0, 4, 8, and 16 h post-admission to the ICU (total of 200 blood glucose values). RESULTS: The correlation coefficient (R2) was 0.96. In the Clarke error grid, 100% of the paired measurements were in the clinically acceptable zone A and B. The Bland and Altman analysis showed that bias+/-limits of agreement (percent error) were 0.04(0.7)+/-0.35(6.3) mmol (mg/dl) (7%), -0.11(-2)+/-1.22(22) (15%) and -0.33(-6)+/-1.28(23) (10%) in hypoglycemia (<70(3.89) mmol (mg/dl), normoglycemia (3.89(70)-10(180) mmol (mg/dl), and hyperglycemia (>10(180) mmol (mg/dl), respectively. CONCLUSIONS: The STG-22 can be used for measuring blood glucose level continuously and measurement results are consistent with intermittent measurement (percentage error within 15%). Therefore, the STG-22 is a useful device for monitoring in blood glucose level in the ICU for 16 h.

Can sedation reduce the cardiac stress during gastrointestinal endoscopy? A study with non-invasive automated cardiac flow measurement by color Doppler echocardiography.

BACKGROUND: Upper gastrointestinal endoscopy (UGIE) may cause some cardiac stress. The effect of sedation on hemodynamics during UGIE has not been fully studied, and therefore the aim of this study was to clarify whether or not sedation can reduce cardiac stress dufing UGIE. METHODS: Eight normal male volunteers undergoing UGIE with sedation (0.1 mg/kg of midazolam) and without it (two endoscopies per volunteer in random order) were monitored throughout the procedure by means of electrocardiogram, blood pressure and peripheral oxygen saturation (SpO2). Cardiac output was measured at six points before, during and after endoscopy from automated cardiac flow measurement by color Doppler echocardiography. Serum norepinephrine, epinephrine, dopamine and ACTH concentrations were measured before and after the examination. RESULTS: No significant differences in heart rate, systolic blood pressure, rate-pressure product, cardiac output and left ventricular work index were observed between the sedated and non-sedated groups. SpO2 hardly changed during endoscopy in the non-sedated group, but decreased slightly in the sedated group (P = 0.075). Although all serum catecholamine concentration changes were within normal limits in both groups, after endoscopy only epinephrine concentration was significantly lower in the sedated group than in the non-sedated group (P = 0.0027). CONCLUSIONS: Conscious sedation with midazolam does not reduce the cardiac stress during UGIE.

Hepatic resection for large hepatocellular carcinoma.

BACKGROUND: Long-term survival and prognostic factors after hepatic resection for large hepatocellular carcinoma (HCC) remain to be proved. METHODS: The surgical outcome in 133 consecutive patients with HCC in diameter of > or = 5 cm (large HCC; L group) undergoing hepatic resection was retrospectively clarified and compared with that of 253 patients with HCC in diameter of < 5 cm (small HCC; S group). Postresection prognostic factors were evaluated by univariate and multivariate analysis using Cox's proportional hazards model. RESULTS: The disease-free 3- and 5-year survival rates between L group and S group were 26% versus 42% and 20% versus 25%, respectively (P = 0.0032). The overall 3- and 5-year survival rates between L group and S group were 38% versus 67% and 28% versus 47%, respectively (P < 0.0001). Multivariate analysis revealed that large amount of intraoperative blood transfusion was an independently significant factor of poor disease-free and overall survivals. CONCLUSIONS: Long-term survival in patients with large HCC remains unsatisfactory compared with that in patients with non-large HCC. Restriction of intraoperative blood transfusion may play an important role in the improvement of survival and recurrence in such patients.

Coexpression of vascular endothelial growth factor and p53 protein in squamous cell carcinoma of the esophagus.

OBJECTIVE: p53 plays a role in tumor angiogenesis, and vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis. The aim of the present study was to clarify how expression of p53 protein participates in angiogenesis, and whether the coexpression of VEGF and p53 protein has a significance for angiogenesis and the clinicopathological features in esophageal squamous cell carcinoma (SCC). METHODS: Tissues samples were taken from 60 patients with esophageal SCC after surgery. The expression of VEGF and p53 protein in these SCC was examined immunohistochemically. Microvessel density (MVD) was determined by counting microvessels in tumor sections stained for Factor VIII-related antigen. Ki-67 labeling index (LI) was calculated, based on Ki-67 antigen immunostaining, as a proliferative marker. Apoptotic index (AI) was calculated, based on the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end labeling, to evaluate apoptosis. RESULTS: VEGF expression was observed in 58.3%, and p53 protein expression was observed in 61.7% of the 60 patients. VEGF and p53 protein were significantly coexpressed in 26 (43.4%). Histological venous invasion (p < 0.01) and distant metastasis (p < 0.05) were significantly correlated with p53 protein expression. The two parameters were more frequently observed in the SCC with VEGF/p53 coexpression than in those without the coexpression. The MVD and Ki-67 LI were significantly higher (p < 0.01 and p < 0.001), and the AI was significantly lower (p < 0.001) in the SCC with p53 protein expression than in the SCC without it. The MVD and Ki-67 LI were higher, and the AI was lower in the SCC with VEGF/p53 coexpression than in those without the coexpression. The 5-yr survival rate in patients with the coexpression was poorer than in the other patients. CONCLUSION: These results suggest that mutant p53 expression is associated with angiogenesis and distant metastasis in esophageal SCC, and that the coexpression of p53 and VEGF may play an important role in angiogenesis, and have important clinical significance.

Cavernous hemangioma of the liver with giant cyst formation: degeneration by apoptosis?

Cavernous hemangioma of the liver with cyst formation is a very rare condition. A case of cavernous hemangioma of the liver with unilocular giant cyst formation undergoing surgical removal is reported. Notably, the patient also had Budd-Chiari syndrome with an obstructing lesion in the inferior vena cava. The cystic degeneration of the hemangioma implied a relationship with apoptosis. This is the first reported case of Budd-Chiari syndrome caused by advanced cystic degeneration of hepatic cavernous hemangioma.

Prognostic factors after hepatic resection for hepatocellular carcinoma with hepatitis C viral infection: univariate and multivariate analysis.

OBJECTIVES: Although the incidence of hepatocellular carcinoma (HCC) with hepatitis C virus (HCV) infection is higher than in patients with hepatitis B virus (HBV)-related HCC in Japan, the long-term prognosis and prognostic factors of HCV-related HCC after hepatic resection are poorly understood. METHODS: The surgical outcome of HCV-related HCC in 172 consecutive patients who underwent hepatic resection between 1989 and 1997 was retrospectively clarified. Postresection prognostic factors were evaluated by univariate and multivariate analysis using Cox's proportional hazards model. RESULTS: The overall incidence of postoperative complications was 23.2%, and 11 patients among that group had hospital deaths (6.4%) including 9 (5.2%) operative deaths. The mean and median overall survivals including hospital death after surgery were 41 months and 33 months, respectively. The 3-, 5-, and 7-yr overall survival rates after hepatic resection were 63%, 52%, and 47%, respectively. The 3-, 5-, and 7-yr disease-free survival rates after hepatic resection were 33%, 20%, and 15%, respectively. Multivariate analysis revealed that serum alpha-fetoprotein (AFP) of > or = 1000 ng/ml and the presence of vascular invasion were independent unfavorable prognostic factors affecting overall survival and that AFP of > or = 1000 ng/ml was an independently significant factor of poor disease-free survival. CONCLUSIONS: We found the postresection survival of patients with HCV-related HCC should be stratified by the high value of AFP and the presence of vascular invasion. AFP may be the most powerful predictor of the long-term prognosis and recurrence in such patients.

A squamous cell carcinoma of the gastric cardia showing submucosal progression.

We report a case of squamous cell carcinoma (SCC) of the gastric cardia showing submucosal progression with direct invasion of the liver. A 71-year-old man was admitted with dysphagia. Esophagogastroscopy showed a protruding tumor covered with normal gastric mucosa in the anterior wall of the gastric cardia, although no abnormal findings were detected in the esophagus, including the esophagogastric junction. Serum SCC-related antigen level was elevated (6.6 ng/ml; normal level, less than 2.5 ng/ml). Endoscopic biopsy specimens taken from this tumor did not show malignant cells. Based on these findings, the preoperative diagnosis was a submucosal tumor of the stomach. Laparotomy was done; however, the tumor was not resected because it had direct invasion to the left lateral segment of the liver and adjacent tissues. As the tumor showed continuous bleeding from the stomach after surgery, total gastrectomy, combined with transhiatal lower esophagectomy, left lateral segmentectomy of the liver, splenectomy, and distal pancreatectomy was performed. Because histologic findings showed poorly or moderately differentiated SCC with direct invasion of the liver, the final diagnosis was SCC of the gastric cardia showing submucosal progression with hepatic invasion. Such a case of SCC of the gastric cardia showing submucosal progression is rare, and accurate preoperative diagnosis was very difficult. However, it may be important to consider SCC of the gastric cardia in such a situation.

Cytokine response to human liver ischemia-reperfusion injury during hepatectomy: marker of injury or surgical stress?

BACKGROUND/AIMS: The aim of this study was to evaluate the inflammatory or antiinflammatory cytokine response to ischemia-reperfusion during hepatectomy and to find a useful marker of injury or surgical stress during hepatic ischemia-reperfusion. METHODOLOGY: In 9 patients with liver disease who underwent hepatectomy using the Pringle maneuver, serum cytokines, including alanine transaminase, aspartate transaminase, and hyaluronic acid, were measured just prior to vascular occlusion; 5, 10 and 15 min after initial clamping; and 3 min after initial declamping. RESULTS: The mean concentrations of aspartate transaminase and alanine transaminase did not significantly differ before and after ischemia-reperfusion during hepatectomy. However, mean concentrations of hyaluronic acid after ischemia-reperfusion were significantly (P < 0.03) higher than before clamping. Although there were no significant differences in the mean concentrations of IL-1 beta, IL-6, IL-8, IL-10 and TNF-alpha among, before and after ischemia-reperfusion, the mean concentrations of granulocyte colony-stimulating factor after ischemia-reperfusion and macrophage colony-stimulating factor after reperfusion were significantly (P < 0.05) higher than before clamping. CONCLUSIONS: Although hepatic parenchymal cell function was maintained after ischemia-reperfusion during hepatectomy, sinusoidal endothelial cell dysfunction was found. Release of granulocyte colony-stimulating factor and macrophage colony-stimulating factor after ischemia-reperfusion were also found. These cytokines and hyaluronic acid may be useful indicators in the early phase of human ischemia-reperfusion injury during hepatectomy.

Palliative gastrectomy for advanced gastric cancer.

BACKGROUND/AIMS: Although palliative gastrectomy for advanced gastric cancer may be favorable in selected patients presenting with bleeding and obstruction, little has been reported about the clinical significance of palliative gastrectomy, including prognosis. METHODOLOGY: A retrospective comparison between 84 patients with palliative gastrectomy (PG group) and 100 patients with unresectable operation (UO group) for advanced gastric cancer was carried out. RESULTS: The incidence of serosal invasion, peritoneal dissemination, hepatic and lymph node metastases, and undifferentiated tissue type in the UO group were significantly higher than in the PG group. Median survival after operation in the PG group (20.6 months) was significantly longer than in the UO group (5.7 months). Also, in stage IVb patients, median survival time in the PG group (10.2 months) was significantly longer than in the UO group (5.0 months). However, median survival in the patients with synchronous liver metastasis between PG (8.4 months) and UO (4.6 months) groups was not significantly different. Survival rates after operation of 6 months, 1 year and 2 years in all patients between the palliative gastrectomy group versus UO group were 83.6% versus 38.3% (P < 0.01), 63.0% versus 9.3% (P < 0.01) and 35.2% versus 0% (P < 0.01), respectively. CONCLUSIONS: Palliative gastrectomy compared to unresectable operation may be effective for improvement of prognosis even if stage IVb patients with peritoneal dissemination and/or distant lymph node metastasis. However, it may be unfavorable on survival of patients with synchronous liver metastasis.