I-Shu Chen

Endoscopic papillary large balloon dilation alone without sphincterotomy for the treatment of large common bile duct stones

BackgroundLethal pancreatitis has been reported after treatment for common bile duct stones using small endoscopic papillary balloon dilation.MethodsWe retrospectively evaluated the safety and efficacy of using large balloon dilation alone without the use of sphincterotomy for the treatment of large common bile duct stones in Kaohsiung Veterans General Hospital. Success rate of stone clearance, procedure-related adverse events and incidents, frequency of mechanical lithotripsy use, and recurrent stones were recorded.ResultsA total of 247 patients were reviewed in the current study. The mean age of the patients was 71.2 years. Most of them had comorbidities. Mean stone size was 16.4 mm. Among the patients, 132 (53.4%) had an intact gallbladder and 121 (49%) had a juxtapapillary diverticulum. The mean size of dilating balloon used was 13.2 mm. The mean duration of the dilating procedure was 4.7 min. There were 39 (15.8%) patients required the help of mechanical lithotripsy while retrieving the stones. The final success rate of complete retrieval of stones was 92.7%. The rate of pancreatic duct enhancement was 26.7% (66/247). There were 3 (1.2%) adverse events and 6 (2.4%) intra-procedure bleeding incidents. All patients recovered completely after conservative and endoscopic treatment respectively, and no procedure-related mortality was noted. 172 patients had a follow-up duration of more than 6 months and among these, 25 patients had recurrent common bile duct stones. It was significantly correlated to the common bile duct size (p = 0.036)ConclusionsEndoscopic papillary large balloon dilation alone is simple, safe, and effective in dealing with large common bile duct stones in relatively aged and debilitated patients.

Risk factors of mortality in perforated peptic ulcer

OBJECTIVE To assess the risk factors that influence mortality from perforated peptic ulcer. DESIGN Retrospective study. SETTING General hospital, Taiwan. SUBJECTS 179 patients who had their perforated peptic ulcers operated on and who had minimum follow-up of one year. MAIN OUTCOME MEASURES Mortality. RESULTS The overall mortality was 15% (26/179). Of the 26 patients who died, the cause of death was uncontrolled systemic infection in 21 (81%), hypovolaemic shock in 2, and fatal arrhythmia and heart failure in 1 each. 15 of the patients who died of sepsis did not have fulminant abdominal sepsis. Most deaths occurred early after operation, (range 1-96 days). Old age, preoperative shock, and type of operation seemed to be related to these deaths on univariate analysis, but multivariate analysis showed that coexisting medical illness, delayed treatment, and low albumin concentration were independent risk factors for mortality. CONCLUSIONS To improve the result of treatment of perforated peptic ulcer, the diagnosis and treatment should not be delayed, the associated medical illnesses should be treated, and nutritional support should be given.

Is Hepatectomy Beneficial in the Treatment of Multinodular Hepatocellular Carcinoma

BACKGROUND/PURPOSE Hepatectomy remains the standard treatment for primary hepatocellular carcinoma (HCC). However, its role in the treatment of multinodular HCC (MNHCC) is unknown. METHODS The study consisted of 599 patients undergoing curative hepatic resection for HCC between October 1990 and June 2006, in which 112 patients had MNHCC (tumor number > or = 2). The type of MNHCC was classified into: A, nodules involving one or two adjoining segments; B, large tumor with satellite nodules involving three or more segments; C, three or fewer nodules that are scattered in remote segments; and D, more than three separate tumors. Univariate and multivariate analyses were used to identify the prognostic factors related to postoperative survival. During the same period of time, and from our database of 178 patients with pathologically proven MNHCC who were undergoing nonsurgical multidisciplinary therapy, 48 patients with serum albumin level > or = 3.5 g/dL, total bilirubin < 2 mg/dL, tumor number < or = 3, and tumor size < or = 5 cm were compared with 38 patients with the same condition treated with hepatectomy, in which 16 received one-block resection and 22 underwent multiple-site resection. RESULTS The overall 1-, 3- and 5-year survival rates for patients with single-tumor HCC and MNHCC were 88.0%, 69.2% and 58.4%, and 86.1%, 55.5% and 29.9%, respectively (p < 0.001). Alpha-fetoprotein > 400 ng/mL, total tumor size > 5 cm, largest tumor size > 5 cm, total tumor number > 3, microvascular invasion, non-A type MNHCC and multiple-site resection were poor prognostic factors for MNHCC in the hepatectomy group. Multivariate analysis revealed that only multiple-site hepatic resection was an independent adverse factor related to postoperative survival. In addition, patients who underwent one-block resection had significantly better survival compared with the nonsurgical group (p = 0.0016), but the multiple-site resection subgroup did not. CONCLUSION The prognosis of MNHCC is poor in comparison with that of single-nodular HCC. Hepatectomy is the treatment of choice if the tumors can be removed by one-block resection and liver function reserve is acceptable.

Melittin-induced [Ca2+]i increases and subsequent death in canine renal tubular cells

The effect of melittin on cytosolic free Ca2+ concentration ([Ca2+]i) and viability is largely unknown. This study examined whether melittin alters Ca2+ levels and causes Ca2+-dependent cell death in Madin-Darby canine kidney (MDCK) cells. [Ca2+]i and cell death were measured using the fluorescent dyes fura-2 and WST-1 respectively. Melittin at concentrations above 0.5 μM increased [Ca2+]i in a concentration-dependent manner. The Ca2+ signal was reduced by 75% by removing extracellular Ca2+. The melittin-induced Ca2+ influx was also implicated by melittin-caused Mn2+ influx. After pretreatment with 1 μM thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor), melittin-induced Ca2+ release was inhibited; and conversely, melittin pretreatment abolished thapsigargin-induced Ca2+ release. At concentrations of 0.5–20 μM, melittin killed cells in a concentration-dependent manner. The cytotoxic effect of 0.5 μM melittin was nearly completely reversed by prechelating cytosolic Ca2+ with BAPTA. Melittin at 0.5–2 μM caused apoptosis as assessed by flow cytometry of propidium iodide staining. Collectively, in MDCK cells, melittin induced a [Ca2+]i rise by causing Ca2+ release from endoplasmic reticulum and Ca2+ influx from extracellular space. Furthermore, melittin can cause Ca2+-dependent cytotoxicity in a concentration-dependent manner.

Safrole-Induced Ca2+ Mobilization and Cytotoxicity in Human Pc3 Prostate Cancer Cells

The effect of the carcinogen safrole on intracellular Ca2+ mobilization and on viability of human PC3 prostate cancer cells was examined. Cytosolic free Ca2+ levels ([Ca2+]i) were measured by using fura-2 as a probe. Safrole at concentrations above 10 μM increased [Ca2+]i in a concentration-dependent manner with an EC50 value of 350 μ M. The Ca2+ signal was reduced by more than half after removing extracellular Ca2+ but was unaffected by nifedipine, nicardipine, nimodipine, diltiazem, or verapamil. In Ca2+-free medium, after treatment with 650 μM safrole, 1 μM thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor) failed to release Ca2+. Neither inhibition of phospholipase C with U73122 nor modulation of protein kinase C activity affected safrole-induced Ca2+ release. Overnight incubation with 0.65–65 μM safrole did not affect cell viability, but incubation with 325–625 μM safrole decreased viability. Collectively, the data suggest that in PC3 cells, safrole induced a [Ca2+]i increase by causing Ca2+ release from the endoplasmic reticulum in a phospholipase C- and protein kinase C-independent fashion, and by inducing Ca2+ influx. Safrole can decrease cell viability in a concentration-dependent manner.

Hepatitis B Genotype C Correlated with Poor Surgical Outcomes for Hepatocellular Carcinoma

BACKGROUND Genotype B and C are the predominant hepatitis B virus (HBV) strains in Taiwan. We aimed to investigate the role of genotype in HBV-related hepatocellular carcinoma (HCC) after resection. STUDY DESIGN From October 2005 to November 2008, 64 patients who underwent liver resection for HBV-related HCC were enrolled. HBV genotypes were determined by molecular method. Patient characteristics, biochemical, tumor, and viral factors were evaluated for their prognostic significance. RESULTS During a mean follow-up of 26.6 ± 13.2 months, patients infected with genotype C had higher HBV viral load (p = 0.007) and worse disease-free survival rate (p = 0.028) than patients with genotype B. By univariate analysis, genotype C, alanine transaminase >50 U/L, tumor size ≥5 cm, and microvascular invasion were associated with tumor recurrence. Further multivariate analysis demonstrated genotype C remained a significant risk factor (p = 0.034). CONCLUSIONS Genotype C is a strong risk factor for HCC recurrence after resection. More intensive monitoring for recurrence should be considered in patients with genotype C.

DESIPRAMINE-INDUCED Ca2+-INDEPENDENT APOPTOSIS IN MG63 HUMAN OSTEOSARCOMA CELLS: DEPENDENCE ON P38 MITOGEN-ACTIVATED PROTEIN KINASE-REGULATED ACTIVATION OF CASPASE 3

1 It has been shown that the antidepressant desipramine is able to induce increases in [Ca2+]i and cell death in MG63 human osteosacroma cells, but whether apoptosis is involved is unclear. In the present study, the effect of desipramine on apoptosis and the underlying mechanisms were explored. It was demonstrated that desipramine induced cell death in a concentration‐ and time‐dependent manner. 2 Cells treated with 100–800 mmol/L desipramine showed typical apoptotic features, including an increase in sub‐diploid nuclei and activation of caspase 3, indicating that these cells underwent apoptosis. Immunoblotting revealed that 100 mmol/L desipramine activated extracellular signal‐regulated kinase (ERK), c‐Jun N‐terminal kinase (JNK) and p38 mitogen‐activated protein kinase (MAPK). Although pretreatment of cells with 20 mmol/L PD98059 (an ERK inhibitor) or 20 mmol/L SP600125 (an inhibitor of JNK) did not inhibit cell death, the addition of 20 mmol/L SB203580 (a p38 MAPK inhibitor) partially rescued cells from apoptosis. Desipramine‐induced caspase 3 activation required p38 MAPK activation. 3 Pretreatment of cells with BAPTA/AM (20 mmol/L) to prevent desipramine‐induced increases in [Ca2+]i did not protect cells from death. 4 The results of the present study suggest that, in MG63 human osteosarcoma cells, desipramine causes Ca2+‐independent apoptosis by inducing p38 MAPK‐associated activation of caspase 3.

Intraoperative hyperthermic intraperitoneal chemotherapy as adjuvant chemotherapy for advanced gastric cancer patients with serosal invasion

Background: To evaluate hyperthermic intraperitoneal chemotherapy (HIPEC) as an adjuvant chemotherapy in advanced gastric cancer (AGC) patients with serosal invasion. Methods: Patients who received radical surgery and palliative surgery between January 2002 and December 2010 were retrospectively examined. Patients were divided into two groups, namely, one group that underwent surgery and another group that underwent surgery with HIPEC. All patients who received HIPEC had suspected serosal invasion on an abdominal computed tomography or by the surgeons assessment during the operation. Results: The prophylactic groups included 83 patients who underwent gastrectomy alone. A total of 29 patients underwent gastrectomy with HIPEC. The 5‐year survival rates were 10.7% and 43.9%, respectively. The 5‐year mean survival times were 22.66 (17.55–25.78) and 34.81 (24.97–44.66) months (p = 0.029), respectively. There were 52 patients who had a recurrence of carcinomatosis among 133 patients who had resections (52/133, 39.1%). The 3‐year disease‐free survival rate for carcinomatosis was 28.87% in the group that received surgery alone, whereas it was 66.03% in the group that received HIPEC. There was no significant difference in the rate of complication between the two groups in the prophylactic group (p = 0.542). Thus, curative surgery with HIPEC had a better prognosis for AGC with serosal invasion. The carcinomatosis recurrence time was longer in patients who underwent gastrectomy with HIPEC and received R0 resection. Conclusion: The survival benefit of HIPEC as an adjuvant therapy for gastric cancer patients with serosal invasion should be validated in a large cohort.

Number of involved lymph nodes is important in the prediction of prognosis for primary duodenal adenocarcinoma

Background: The significance of lymph node involvement regarding the prognosis of primary duodenal adenocarcinoma remains controversial. This study aims to evaluate the prognostic accuracy of nodal metastasis using the seventh edition American Joint Committee on Cancer staging system in patients with primary duodenal adenocarcinoma. Methods: Between 1993 and 2010, 36 patients who had undergone surgical resection for primary duodenal adenocarcinoma at the Kaohsiung Veterans General Hospital were retrospectively reviewed. Results: The median disease‐free survival for all patients was 19 months and the median overall survival was 21 months. Lymph node metastases were found in 26 (72%) of the patients, and 14 patients (39%) patients had in excess of three positive lymph nodes (N2). Patients with N2 disease had significantly reduced overall survival, as compared to patients with three or fewer positive lymph nodes (N1; p = 0.036). In univariate analysis, factors including age >75 years, body weight loss, tumor size ≤4 cm, N2 disease and lymph node ratio >0.4 predicted shorter overall survival. Multivariate analysis demonstrated that N2 and lymph node ratio >0.4 are significant risk factors associated with overall survival (p = 0.026 and p = 0.042 respectively). N2 is also the only independent predictive factor for disease‐free survival (p = 0.023). Conclusion: Subdivision of metastatic lymph nodes into N1 and N2 improves predictive ability. The seventh edition American Joint Committee on Cancer staging system is applicable in the present study with regard to the prediction of the prognosis for primary duodenal adenocarcinoma.

Effect of riluzole on Ca2+ movement and cytotoxicity in Madin-Darby canine kidney cells.

Riluzole is a drug used in the treatment of amyotrophic lateral sclerosis; however, its in vitro action is unclear. In this study, the effect of riluzole on intracellular Ca2 - concentration ([Ca2 -]i) in Madin-Darby canine kidney (MDCK) cells was investigated using the Ca2 --sensitive fluorescent dye, fura-2. Riluzole (100 -500 mM) caused a rapid and sustained increase of [Ca2 -]i in a concentration-dependent manner (EC50 = 150 mM). Some 40 and 50% of this [Ca2 -]i increase was prevented by the removal of extracellular Ca2 - and the addition of La3 -, respectively, but was unchanged by dihydropyridines, verapamil and diltiazem. In Ca2 --free medium, thapsigargin -an inhibitor of the endoplasmic reticulum (ER) Ca2 --ATPase -caused a monophasic [Ca2-]i increase, after which the increasing effect of riluzole on [Ca2 -]iwas attenuated by 70%; in addition, pre-treatment with riluzole abolished thapsigargin-induced [Ca2 -]i increases. U73122, an inhibitor of phospholipase C (PLC), abolished ATP (but not riluzole)-induced [Ca2 -]i increases. At concentrations of 250 and 500 mM, riluzole killed 40 and 95% cells, respectively. The cytotoxic effect of riluzole (250 mM) was unaltered by pre-chelating cytosolic Ca2 - with BAPTA. Collectively, in MDCK cells, riluzole rapidly increased [Ca2 -]i by stimulating extra-cellular Ca2 - influx via an La3 --sensitive pathway and intracellular Ca2 - release from the ER via, as yet, unidentified mechanisms. Furthermore, riluzole caused Ca2 --unrelated cytotoxicity in a concentration-depen-dent manner.