Jun-Te Hsu

Management and outcome of bleeding pseudoaneurysm associated with chronic pancreatitis.

BackgroundA bleeding pseudoaneurysm in patients with chronic pancreatitis is a rare and potentially lethal complication. Optimal treatment of bleeding peripancreatic pseudoaneurysm remains controversial. This study reports on experience at Chang Gung Memorial Hospital (CGMH) in managing of bleeding pseudoaneurysms associated with chronic pancreatitis.MethodsThe medical records of 9 patients (8 males and 1 female; age range, 28 – 71 years; median, 36 years) with bleeding pseudoaneurysms associated with chronic pancreatitis treated at CGMH between Aug. 1992 and Sep. 2004 were retrospectively reviewed. Alcohol abuse (n = 7;78%) was the predominant predisposing factor. Diagnoses of bleeding pseudoaneurysms were based on angiographic (7/7), computed tomographic (4/7), ultrasound (2/5), and surgical (2/2) findings. Whether surgery or angiographic embolization was performed was primarily based on patient clinical condition. Median follow-up was 38 months (range, 4 – 87 months).ResultsAbdominal computed tomography revealed bleeding pseudoaneurysms in 4 of 7 patients (57%). Angiography determined correct diagnosis in 7 patients (7/7, 100%). The splenic artery was involved in 5 cases, the pancreaticoduodenal artery in 2, the gastroduodenal artery in 1, and the middle colic artery in 1. Initial treatment was emergency (n = 4) or elective (n = 3) surgery in 7 patients and arterial embolization in 2. Rebleeding was detected after initial treatment in 3 patients. Overall, 5 arterial embolizations and 9 surgical interventions were performed; the respective rates of success of these treatments were 20% (1/5) and 89% (8/9). Five patients developed pseudocysts before treatment (n = 3) or following intervention (n = 2). Pseudocyst formation was identified in 2 of the 3 rebleeding patients. Five patients underwent surgical treatment for associated pseudocysts and bleeding did not recur. One patient died from angiography-related complications. Overall mortality rate was 11% (1/9). Surgery-related mortality was 0%.ConclusionAngiography is valuable in localizing bleeding pseudoaneurysms. In this limited series, patients with bleeding pseudoaneurysms associated with chronic pancreatitis treated surgically seemingly obtained good outcomes.

The Role of MIP-1α in the Development of Systemic Inflammatory Response and Organ Injury following Trauma Hemorrhage

Although MIP-1α is an important chemokine in the recruitment of inflammatory cells, it remains unknown whether MIP-1α plays any role in the development of systemic inflammatory response following trauma-hemorrhage (T-H). C57BL/6J wild type (WT) and MIP-1α-deficient (KO) mice were used either as control, subjected to sham operation (cannulation or laparotomy only or cannulation plus laparotomy) or T-H (midline laparotomy, mean blood pressure 35 ± 5 mmHg for 90 min, followed by resuscitation) and sacrificed 2 h thereafter. A marked increase in serum α-glutathione transferase, TNF-α, IL-6, IL-10, MCP-1, and MIP-1α and Kupffer cell cytokine production was observed in WT T-H mice compared with shams or control. In addition lung and liver tissue edema and neutrophil infiltration (myeloperoxidase (MPO) content) was also increased following T-H in WT animals. These inflammatory markers were markedly attenuated in the MIP-1α KO mice following T-H. Furthermore, compared with 2 h, MPO activities at 24 and 48 h after T-H declined steadily in both WT and KO mice. However, normalization of MPO activities to sham levels within 24 h was seen in KO mice but not in WT mice. Thus, MIP-1α plays an important role in mediating the acute inflammatory response following T-H. In the absence of MIP-1α, acute inflammatory responses were attenuated; rapidly recovered and less remote organ injury was noted following T-H. Thus, interventions that reduce MIP-1α levels following T-H should be useful in decreasing the deleterious inflammatory consequence of trauma.

Mechanism of estrogen-mediated attenuation of hepatic injury following trauma-hemorrhage: Akt-dependent HO-1 up-regulation

Protein kinase B (Akt) is known to be involved in proinflammatory and chemotactic events in response to injury. Akt activation also leads to the induction of heme oxygenase (HO)‐1. Up‐regulation of HO‐1 mediates potent, anti‐inflammatory effects and attenuates organ injury. Although studies have shown that 17β‐estradiol (E2) prevents organ damage following trauma‐hemorrhage, it remains unknown whether Akt/HO‐1 plays any role in E2‐mediated attenuation of hepatic injury following trauma‐hemorrhage. To study this, male rats underwent trauma‐hemorrhage (mean blood pressure, ∼40 mmHg for 90 min), followed by fluid resuscitation. At the onset of resuscitation, rats were treated with vehicle, E2 (1 mg/kg body weight), E2 plus the PI‐3K inhibitor (Wortmannin), or the estrogen receptor (ER) antagonist (ICI 182,780). At 2 h after sham operation or trauma‐hemorrhage, plasma α‐GST and hepatic tissue myeloperoxidase (MPO) activity, IL‐6, TNF‐α, ICAM‐1, cytokine‐induced neutrophil chemoattractant‐1, and MIP‐2 levels were measured. Hepatic Akt and HO‐1 protein levels were also determined. Trauma‐hemorrhage increased hepatic injury markers (α‐GST and MPO activity), cytokines, ICAM‐1, and chemokine levels. These parameters were markedly improved in the E2‐treated rats following trauma‐hemorrhage. E2 treatment also increased hepatic Akt activation and HO‐1 expression compared with vehicle‐treated, trauma‐hemorrhage rats, which were abolished by coadministration of Wortmannin or ICI 182,780. These results suggest that the salutary effects of E2 on hepatic injury following trauma‐hemorrhage are in part mediated via an ER‐related, Akt‐dependent up‐regulation of HO‐1.

p38 MAPK-dependent eNOS upregulation is critical for 17β-estradiol- mediated cardioprotection following trauma-hemorrhage

Studies have shown that p38 MAPK and nitric oxide (NO), generated by endothelial NO synthase (eNOS), play key roles under physiological and pathophysiological conditions. Although administration of 17beta-estradiol (E2) protects cardiovascular injury from trauma-hemorrhage, the mechanism by which E2 produces those effects remains unknown. Our objective was to determine whether the E2-mediated activation of myocardial p38 MAPK and subsequent eNOS expression/phosphorylation would protect the heart following trauma-hemorrhage. To study this, male Sprague-Dawley rats underwent soft-tissue trauma (midline laparatomy) and hemorrhagic shock (mean blood pressure 35-40 mmHg for 90 min), followed by fluid resuscitation. Animals were pretreated with specific p38 MAPK inhibitor SB-203580 (SB; 2 mg/kg), and nonselective NO synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 30 mg/kg) 30 min before vehicle (cyclodextrin) or E2 (100 microg/kg) treatment, followed by resuscitation, and were killed 2 h thereafter. Cardiovascular performance and other parameters were measured. E2 administration following trauma-hemorrhage increased cardiac p38 MAPK activity, eNOS expression and phosphorylation at Ser(1177), and nitrate/nitrite levels in plasma and heart tissues; these were associated with normalized cardiac performance, which was reversed by SB administration. In addition, E2 also prevented trauma-hemorrhage-induced increase in cytokines (IL-6 and TNF-alpha), chemokines (macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant-1), and ICAM-1, which was reversed by l-NAME administration. Administration of E2 following trauma-hemorrhage attenuated cardiac tissue injury markers, myeloperoxidase activity, and nitrotyrosine level, which were reversed by treatment with SB and l-NAME. The salutary effects of E2 on cardiac functions and tissue protection following trauma-hemorrhage are mediated, in part, through activation of p38 MAPK and subsequent eNOS expression and phosphorylation.

Mechanism of estrogen-mediated intestinal protection following trauma-hemorrhage: p38 MAPK-dependent upregulation of HO-1

p38 MAPK has been reported to regulate the inflammatory response in various cell types via extracellular stimuli. p38 MAPK activation also results in the induction of heme oxygenase (HO)-1, which exerts potent anti-inflammatory effects. Although studies have shown that 17beta-estradiol (E(2)) prevented organ dysfunction following trauma-hemorrhage, it remains unknown whether p38 MAPK/HO-1 plays any role in E(2)-mediated attenuation of intestinal injury under those conditions. To study this, male rats underwent trauma-hemorrhage (mean blood pressure approximately 40 mmHg for 90 min) followed by fluid resuscitation. At the onset of resuscitation, rats were treated with vehicle, E(2) (1 mg/kg body wt), the p38 MAPK inhibitor SB-203580 (2 mg/kg body wt) or E(2) plus SB-203580. Two hours thereafter, intestinal myeloperoxidase (MPO) activity and lactate, TNF-alpha, IL-6, ICAM-1, cytokine-induced neutrophil chemoattractant (CINC)-1, and macrophage inflammatory protein (MIP)-2 levels were measured. Intestinal p38 MAPK and HO-1 protein levels were also determined. Trauma-hemorrhage led to an increase in intestinal MPO activity and lactate, TNF-alpha, IL-6, ICAM-1, CINC-1, and MIP-2 levels. This was accompanied with a decrease in intestinal p38 MAPK activity and increase in HO-1 expression. Administration of E(2) normalized all the above parameters except HO-1, which was further increased following trauma-hemorrhage. Administration of SB-203580 with E(2) abolished the E(2)-mediated restoration of the above parameters as well as the increase in intestinal HO-1 expression following trauma-hemorrhage. These results suggest that the p38 MAPK/HO-1 pathway plays a critical role in mediating the salutary effects of E(2) on shock-induced intestinal injury.

Selective inhibition of iNOS attenuates trauma-hemorrhage/resuscitation-induced hepatic injury

Although trauma-hemorrhage produces tissue hypoxia, systemic inflammatory response and organ dysfunction, the mechanisms responsible for these alterations are not clear. Using a potent selective inducible nitric oxide (NO) synthase inhibitor, N-[3-(aminomethyl) benzyl]acetamidine (1400W), and a nonselective NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), we investigated whether inducible NO synthase plays any role in producing hepatic injury, inflammation, and changes of protein expression following trauma-hemorrhage. To investigate this, male Sprague-Dawley rats were subjected to midline laparotomy and hemorrhagic shock (mean blood pressure 35-40 mmHg for approximately 90 min) followed by fluid resuscitation. Animals were treated with either vehicle (DMSO) or 1400W (10 mg/kg body wt ip), or L-NAME (30 mg/kg iv), 30 min before resuscitation and killed 2 h after resuscitation. Trauma-hemorrhage/resuscitation induced a marked hypotension and increase in markers of hepatic injury (i.e., plasma alpha-glutathione S-transferase, tissue myeloperoxidase activity, and nitrotyrosine formation). Hepatic expression of iNOS, hypoxia-inducible factor-1alpha, ICAM-1, IL-6, TNF-alpha, and neutrophil chemoattractant (cytokine-induced neutrophil chemoattractant-1 and macrophage inflammatory protein-2) protein levels were also markedly increased following trauma-hemorrhage/resuscitation. Administration of the iNOS inhibitor 1400W significantly attenuated hypotension and expression of these mediators of hepatic injury induced by trauma-hemorrhage/resuscitation. However, administration of L-NAME could not attenuate hepatic dysfunction and tissue injury mediated by trauma-hemorrhage, although it improved mean blood pressure as did 1400W. These results indicate that increased expression of iNOS following trauma-hemorrhage plays an important role in the induction of hepatic damage under such conditions.

Impact of HER-2 Overexpression/Amplification on the Prognosis of Gastric Cancer Patients Undergoing Resection: A Single-Center Study of 1,036 Patients

BACKGROUND Opinions regarding the impact of human epidermal growth factor receptor (HER)-2 overexpression or HER-2 amplification on the prognosis of gastric cancer patients are mixed. The present study attempted to clarify this issue by investigating a large cohort of surgical patients. METHODS We investigated 1,036 gastric cancer patients undergoing curative-intent resection. Their surgical specimens were evaluated for HER-2 expression by immunohistochemistry (IHC), and those with HER-2 expression levels of 2+ were additionally subjected to fluorescence in situ hybridization (FISH). Data on demographic and clinicopathological features and relevant prognostic factors in these patients were analyzed. RESULTS HER-2 positivity was noted in 64 (6.1%) of 1,036 gastric cancer patients, including 46 patients whose HER-2 expression level was 3+ on IHC and 18 patients whose FISH results were positive. On univariate analysis, HER-2 positivity was more often associated with differentiated histology, intestinal type, and negative resection margins, whereas only differentiated histology was independently associated with HER-2 positivity in a logistic regression model. For stage I-IV gastric cancer, HER-2 was not a prognostic factor. In a subpopulation study, although HER-2 positivity emerged as a favorable prognostic factor for stage III-IV gastric cancer on univariate analysis, it failed to be an independent prognostic factor after multivariate adjustment. CONCLUSIONS The prevalence of HER-2 positivity, determined using standardized assays and scoring criteria in a large cohort of gastric cancer patients after resection, was 6.1%. HER-2 positivity was phenotypically associated with differentiated histology. HER-2 is not an independent prognostic factor for gastric cancer.

Role of extracellular signal-regulated protein kinase (ERK) in 17β-estradiol-mediated attenuation of lung injury after trauma-hemorrhage

BACKGROUND Extracellular signal-regulated protein kinase (ERK) is known to be involved in pro-inflammatory and chemotactic events in response to injury. The aim of this study is to elucidate whether ERK plays any role in 17beta-estradiol (E2)-mediated attenuation of lung injury and pro-inflammatory mediators after trauma-hemorrhage. METHODS Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure approximately 40 mm Hg for 90 min) followed by fluid resuscitation. At the onset of resuscitation, rats were treated with vehicle (cyclodextrin), E2 (1 mg/kg body weight [BW]), or the ERK inhibitor PD98059 (2 mg/kg BW). At 2 h after sham operation or trauma-hemorrhage, various parameters were measured. RESULTS Trauma-hemorrhage led to a significant increase in lung ERK phosphorylation, which was associated with increased lung myeloperoxidase activity, wet-to-dry weight ratio, interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, intercellular adhesion molecule (ICAM)-1, cytokine-induced neutrophil chemoattractant (CINC)-1, and macrophage inflammatory protein-2 levels. Circulatory IL-6, TNF-alpha, and lactate levels were also increased after trauma-hemorrhage compared with shams. Administration of E2 or ERK inhibitor PD98059 after trauma-hemorrhage attenuated the trauma-hemorrhage-induced increase in lung injury markers, ERK phosphorylation and cytokines/chemokines, ICAM-1 production, as well as circulatory cytokines and lactate levels. CONCLUSION These results collectively suggest that the salutary effects of E2 on the lung after trauma-hemorrhage are mediated via an ERK pathway and subsequent downregulation of pro-inflammatory mediator production.

Evaluation of the potential therapeutic role of a new generation of vitamin D analog, MART-10, in human pancreatic cancer cells in vitro and in vivo.

Pancreatic cancer is a lethal disease with no known effective chemotherapy and radiotherapy, and most patients are diagnosed in the late stage, making them unsuitable for surgery. Therefore, new therapeutic strategies are urgently needed. 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] is known to possess antitumor actions in many cancer cells in vitro and in vivo models. However, its clinical use is hampered by hypercalcemia. In this study, we investigated the effectiveness and safety of a new generation, less calcemic analog of 1α,25(OH)2D3, 19-nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3 (MART-10), in BxPC-3 human pancreatic carcinoma cells in vitro and in vivo. We demonstrate that MART-10 is at least 100-fold more potent than 1α,25(OH)2D3 in inhibiting BxPC-3 cell proliferation in a time- and dose-dependent manner, accompanied by a greater upregulation of cyclin-dependent kinase inhibitors p21 and p27 and a greater downregulation of cyclin D3 and cyclin-dependent kinases 4 and 5, leading to a greater increase in the fraction of cells in G0/G1 phase. No induction of apoptosis and no effect on Cdc25 phosphatases A and C were observed in the presence of either MART-10 or 1α,25(OH)2D3. In a xenograft mouse model, treatment with 0.3 µg/kg body weight of MART-10 twice/week for 3 weeks caused a greater suppression of BxPC-3 tumor growth than the same dose of 1α,25(OH)2D3 without inducing hypercalcemia and weight loss. In conclusion, MART-10 is a promising agent against pancreatic cancer growth. Further clinical trial is warranted.

Mechanism of salutary effects of estrogen on cardiac function following trauma-hemorrhage: Akt-dependent HO-1 up-regulation.

Objectives:Because administration of 17&bgr;-estradiol following trauma-hemorrhage improves cardiovascular responses, we investigated whether the salutary effects of 17&bgr;-estradiol on cardiac function are mediated via Akt-dependent heme oxygenase-1 up-regulation under those conditions. Design:Experimental animal study. Setting:University laboratory. Subjects:Male Sprague-Dawley rats. Interventions:Rats underwent trauma-hemorrhage (mean blood pressure ∼40 mm Hg for 90 mins) followed by fluid resuscitation. Before resuscitation, rats received either vehicle, 17&bgr;-estradiol (1 mg/kg), or 17&bgr;-estradiol plus the phosphoinositide 3-kinase inhibitor wortmannin (1 mg/kg). At 2 hrs after trauma-hemorrhage or sham operation, the rats were killed. Measurements and Main Results:Cardiac function, heart tissue myeloperoxidase activity, cardiac and circulatory cytokine levels, cardiac intercellular adhesion molecule-1, and chemokine levels were measured. Cardiac Akt and heme oxygenase-1 were also determined. We found that 17&bgr;-estradiol prevented the trauma-hemorrhage-induced impairment in cardiac function and increase in cardiac myeloperoxidase activity. Cardiac and systemic interleukin-6 and tumor necrosis factor-&agr; levels as well as cardiac intercellular adhesion molecule-1, cytokine-induced neutrophil chemoattractant-1, and macrophage inflammatory protein-2 contents were increased following trauma-hemorrhage, which were normalized by 17&bgr;-estradiol. Administration of 17&bgr;-estradiol following trauma-hemorrhage restored cardiac Akt phosphorylation and further increased heme oxygenase-1 expression. Coadministration of wortmannin following trauma-hemorrhage abolished the previous effects by 17&bgr;-estradiol. Conclusions:These results suggest that the 17&bgr;-estradiol-meditated improvement in cardiac function following trauma-hemorrhage occurs via Akt-dependent heme oxygenase-1 up-regulation.