Che-Chuan Loong

Evidence for the early involvement of interleukin 17 in human and experimental renal allograft rejection.

Inflammatory processes can stimulate renal epithelial cells to release cytokines, chemoattractants and matrix proteins into the interstitium, thus contributing to interstitial injury during acute allograft rejection. To test the role of interleukin 17 (IL‐17) in this process, cultured human renal epithelial cells (hRECs) were first established and treated with or without human IL‐17 (hIL‐17) for 2, 4, 8 and 10 h in vitro. Significant elevations of IL‐6 and IL‐8 levels were noted in the supernatants in a dose‐dependent and time‐dependent manner, as also for IL‐6 mRNA expression. Secondly, using a rat acute allograft rejection model, the correlation between IL‐17 expression and histopathological changes was serially studied. The results demonstrated that increased expression of IL‐17 protein on infiltrating mononuclear cells (MNCs) was detectable on day 2. This corresponds to the borderline change of acute rejection according to the Banff classification, and it increased progressively to day 5. Serial study of IL‐6, IL‐8 and IL‐17 mRNA expression of the renal allograft confirmed IL‐17 mRNA expression in the allograft early on post‐transplant day 2, whereas IL‐6 and IL‐8 expression started on day 3. Thirdly, IL‐17 expression was observed in human renal allograft and urinary sediment. IL‐17 protein expression was found in human subclinical (borderline) rejection renal allograft biopsy tissue and none in biopsy tissue not showing any evidence of rejection. There was also a 100% detectable rate of IL‐17 mRNA expression in the MNCs of urinary sediment of patients with subclinical borderline rejection. These results demonstrate that hRECs exposed to IL‐17 can produce inflammatory mediators with the potential to stimulate early alloimmune responses, which may also serve to give warning of acute renal allograft rejection. Copyright

Thromboelastography-guided transfusion decreases intraoperative blood transfusion during orthotopic liver transplantation: randomized clinical trial.

OBJECTIVE To test in a prospective randomized study the hypothesis that use of thromboelastography (TEG) decreases blood transfusion during major surgery. MATERIAL AND METHODS Twenty-eight patients undergoing orthotopic liver transplantation were recruited over 2 years. Patients were randomized into 2 groups: those monitored during surgery using point-of-care TEG analysis, and those monitored using standard laboratory measures of blood coagulation. Specific trigger points for transfusion were established in each group. RESULTS In patients monitored via TEG, significantly less fresh-frozen plasma was used (mean [SD], 12.8 [7.0] units vs 21.5 [12.7] units). There was a trend toward less blood loss in the TEG-monitored patients; however, the difference was not significant. There were no differences in total fluid administration and 3-year survival. CONCLUSION Thromboelastography-guided transfusion decreases transfusion of fresh- frozen plasma in patients undergoing orthotopic liver transplantation, but does not affect 3-year survival.

Serum Interleukin-10 But Not Interleukin-6 Is Related to Clinical Outcome in Patients With Resectable Hepatocellular Carcinoma

OBJECTIVE To evaluate the clinical significance of preoperative serum levels of interleukin-10 (IL-10) and interleukin-6 (IL-6) in patients with resectable hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA IL-10 is an immunosuppressive factor and IL-6 is a multifunctional cytokine that plays a role in host defense mechanisms. Both have been reported to be related to the disease prognosis in some human solid tumors. Their role in human HCC has not been investigated. METHODS Preoperative serum samples of 67 patients with HCC who underwent potentially curative resection and 27 normal healthy donors were assayed. Levels of IL-10 and IL-6 were determined by enzyme-linked immunosorbent assay. The clinical significance of serum IL-10 and IL-6 was evaluated and compared with conventional clinicopathologic factors. RESULTS Levels of IL-10 and IL-6 were significantly higher in patients with HCC than in healthy subjects. There was no correlation between IL-10 and IL-6 levels. Tumor resection resulted in a decrease in IL-10 and IL-6 levels. On univariate analysis, patients with high IL-10 levels had a worse disease-free survival, but IL-6 levels had no correlation with the disease-free survival. Multivariate analysis identified IL-10 levels as a predictor of postresectional outcome, in addition to the well-established clinical risk factors. CONCLUSIONS In patients with HCC, the preoperative serum IL-10 level is related to the clinical outcome. IL-10 may play an important role in the progression of HCC.

A new prognostic model for hepatocellular carcinoma based on total tumor volume: The Taipei Integrated Scoring system

BACKGROUND & AIMS The currently used staging systems for hepatocellular carcinoma (HCC) are not satisfactory. The optimal prognostic model for HCC is still under intense debate. This study aimed to propose a new staging system for HCC based on total tumor volume (TTV) and to compare it with the currently used systems. METHODS A total of 2030 HCC patients undergoing different treatment strategies were retrospectively analyzed. TTV was defined as the sum of the volume of each tumor [(4/3)x3.14x(radius of tumor in cm)(3)]. The discriminatory ability of the TTV-based staging system and the four current systems, including the Barcelona Clinic Liver Cancer, Cancer of the Liver Italian Program (CLIP), Japan Integrated Staging system, and Tokyo system, was examined by comparing the Akaike information criterion (AIC) using the Cox proportional hazards model. RESULTS A higher TTV correlated well with the decreased survival in HCC patients (p<0.001). Among the 12 TTV-based staging systems, the TTV-Child-Turcotte-Pugh (CTP)-alpha-fetoprotein (AFP) combination provided the lowest AIC value. The TTV-CTP-AFP model consistently showed a better prognostic ability in comparison to the current four staging systems. In 936 HCC patients receiving curative treatment, the TTV-CTP-AFP model provided the second best predictive accuracy following the CLIP score. Alternatively, in 1094 patients undergoing non-curative treatment, the TTV-CTP-AFP model exhibited the smallest AIC value. CONCLUSIONS TTV may be a feasible tumoral prognostic predictor for HCC. In this single-hospital study that included patients with early to advanced cancer stages, the TTV-CTP-AFP model provides the best prognostic ability among 12 TTV-based and currently used staging systems.

Selecting an optimal staging system for hepatocellular carcinoma: comparison of 5 currently used prognostic models.

Selecting an appropriate staging system is crucial to predict the outcome of patients with hepatocellular carcinoma (HCC). The optimal prognostic model for HCC is under intense debate. This study investigated the prognostic ability of the 5 currently used staging systems, Barcelona Clinic Liver Cancer (BCLC), Cancer of the Liver Italian Program (CLIP), Japan Integrated Scoring (JIS) system, tumor‐node‐metastasis (TNM), and Tokyo score, for HCC.

Interval Appendectomy after Conservative Treatment of an Appendiceal Mass

IntroductionThe purpose of this study was to clarify the role of interval appendectomy after conservative treatment of an appendiceal mass.MethodsFrom January 1998 to December 2003, patients with an appendiceal mass who received conservative treatment at the Taipei Veterans General Hospital were studied retrospectively. Data on demographics, rate of appendicitis recurrence, duration of hospital stay, and complication rate were collected and analyzed.ResultsA total of 165 patients were included (89 males, 76 females). The mean age was 53.6 years (range 7–89 years). The rate of appendicitis recurrence after conservative treatment was 25.5%; most recurred within 6 months after discharge (83.3%). The benefit of preventing recurrence is less than 16% if interval appendectomy is performed 6 weeks after discharge and less than 10% if it is done 12 weeks later. The complication rate of appendectomy performed before or after recurrence was 10% in both groups. The duration of the second hospital stay for patients who underwent interval appendectomy before or after recurrence was 4.43 ± 3.32 vs. 6.75 ± 5.73 days (P = 0.023). Of the 165 patients, 17 (10.3%) had their diagnosis changed after survey or surgery, and 5 (3.03%) were found to have colon cancer upon follow-up.ConclusionsPatients who recovered from conservative treatment of an appendiceal mass should undergo colonoscopy or barium enema to detect any underlying diseases and to rule out coexistent colorectal cancer. Routine interval appendectomy benefits less than 20% of patients.

Autophagy inhibition enhances apoptosis triggered by BO-1051, an N-mustard derivative, and involves the ATM signaling pathway.

In a previous study, BO-1051, an N-mustard linked with a DNA-affinic molecule, was shown to target various types of cancer cell lines. In the present study, we aimed to investigate the cytotoxicity, as well as the underlying mechanism, of BO-1051. We found that BO-1051 simultaneously induced apoptosis and autophagy in hepatocellular carcinoma cell lines. DNA double strand breaks induced by BO-1051 activated the ATM signaling pathway and subsequently resulted in caspase-dependent apoptosis. When autophagy was inhibited in its early or late stages, apoptosis was significantly enhanced. This result indicated autophagy as a cytoprotective effect against BO-1051-induced cell death. We further inhibited ATM activation using an ATM kinase inhibitor or ATM-specific siRNA and found that while apoptosis was blocked, autophagy also diminished in response to BO-1051. We not only determined a signaling pathway induced by BO-1051 but also clarified the linkage between DNA damage-induced apoptosis and autophagy. We also showed that BO-1051-induced autophagy acts as a cytoprotective reaction and downstream target of the ATM-signaling pathway. This research revealed autophagy as a universal cytoprotective response against DNA damage-inducing chemotherapeutic agents, including BO-1051, cisplatin, and doxorubicin, in hepatocellular carcinoma cell lines. Autophagy contributes to the remarkable drug resistance ability of liver cancer.

Incidence and odds ratio of appendicitis as first manifestation of colon cancer: A retrospective analysis of 1873 patients

Background and Aim:  Obstruction of the lumen of the appendix is the major cause of appendicitis. Tumors could obstruct this lumen and cause appendicitis in the elderly. The association between appendicitis and colon cancer has not been sufficiently investigated, and this study was designed to clarify this association.

Deterioration of hepatic functional reserve in patients with hepatocellular carcinoma after resection: incidence, risk factors, and association with intrahepatic tumor recurrence.

Hepatocellular carcinoma (HCC) is frequently associated with liver cirrhosis. Patients with HCCs undergoing surgical resection may have declining hepatic functional reserve over time. However, the incidence and risk factors of hepatic decompensation, and its relation to postoperative tumor recurrence are unknown. This study investigated 241 HCC patients (208 male; age 61 ± 13 years) undergoing resection with a long-term follow-up. The Child-Pugh scoring system was used to evaluate the postoperative deterioration of liver reserve, defined as a sustained increment in the Child-Pugh score by 2 or more. The 1-, 3-, and 5-year cumulative probabilities of postoperative decompensation were 14%, 32%, and 56%, respectively, during a follow-up period of 27 ± 18 months (range 3-75 months). The average increment in Child-Pugh score was 1.4 ± 1.1 in 2.3 ± 1.5 years, or 0.6 point per year. Altogether, 74 (31%) patients developed postoperative hepatic decompensation during the follow-up period, 43 (58%) of whom had decompensation within 2 years of resection. Large (> 3 cm) tumor size was the only independent predictor associated with hepatic decompensation (relative risk 1.7, 95% confidence interval 1.1–2.8, p = 0.041) and was a significant risk factor for intrahepatic tumor recurrence (p = 0.018). Patients with tumor recurrence more frequently (40% of 109 patients vs. 23% of 132 patients, p = 0.005) and more rapidly (0.8 vs. 0.4 point per year) developed hepatic decompensation than those without recurrence. In conclusion, large HCCs are closely associated with hepatic decompensation in patients after resection. Tumor recurrence may predispose to the development of hepatic decompensation in these patients.

Diabetes mellitus as an independent prognostic predictor and its association with renal dysfunction in patients with hepatocellular carcinoma.

Background: Patients with hepatocellular carcinoma (HCC) often have coexisting cirrhosis, which may predispose to the development of diabetes mellitus (DM). Diabetic HCC patients may have renal insufficiency and a subsequent worse outcome. This study investigated the interaction between DM, cirrhosis and renal dysfunction and the impact of these factors on HCC.