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Effect of melatonin on the severity of L-arginine-induced experimental acute pancreatitis in rats

AIM： To determine the effect of melatonin pre- and post-treatment on the severity of L-arginine （L-Arg） -induced experimental pancreatitis in rats. METHODS： Male Wistar rats （25） were divided into five groups. Those in group A received two injections of 3.2 g/kg body weight L-Arg i.p. at an interval of 1 h. In group MA, the rats were treated with 50 mg/kg body weight melatonin i.p. 30 min prior to L-Arg administration. In group AM, the rats received the same dose of melatonin 1 h after L-Arg was given. In group M, a single dose of melatonin was administered as described previously. In group C the control animals received physiological saline injections i.p. All rats were exsanguinated 24 h after the second L-Arg injection. RESULTS： L-Arg administration caused severe necrotizing pancreatitis confirmed by the significant elevations in the serum amylase level, the pancreatic weight/body weight ratio （pw/bw）, the pancreatic IL-6 content and the myeloperoxidase activity, relative to the control values. Elevation of the serum amylase level was significantly reduced in rats given melatonin following L-Arg compared to rats injected with L-Arg only. The activities of the pancreatic antioxidant enzymes （Cu/Zn-superoxide dismutase （CulZn-SOD） and catalase （CAT）） were significantly increased 24 h after pancreatitis induction. Melatonin given in advance of L-Arg significantly reduced the pancreatic CAT activity relative to that in the rats treated with L-Arg alone. In the liver, L-Arg significantly increased the lipid peroxidation level, and the glutathione peroxidase and Cu/Zn-SOD activities, whereas the Mn-SOD activity was reduced as compared to the control rats. Melatonin pre-treatment prevented these changes. CONCLUSION： Melatonin is an antioxidant that is able to counteract some of the L-Arg-induced changes during acute pancreatitis, and may therefore be helpful in the supportive therapy of patients with acute necrotizing pancreatitis.

Melatonin reduces bacterial translocation and apoptosis in trinitrobenzene sulphonic acid-induced colitis of rats

AIM: To investigate the effects of exogenous melatonin on bacterial translocation and apoptosis in a rat ulcerati-ve colitis model. METHODS: Rats were randomly assigned to three groups: groupⅠ: control, group Ⅱ: experimental colitis, group Ⅲ: colitis plus melatonin treatment. On d 11 after colitis, plasma tumor necrosis factor-α, portal blood endotoxin levels, colon tissue myeloperoxidase and caspase-3 activity were measured. Bacterial translocation was quantified by blood, lymph node, liver and spleen culture. RESULTS: We observed a significantly reduced inciden-ce of bacterial translocation to the liver, spleen, mesen-teric lymph nodes, portal and systemic blood in animals treated with melatonin. Treatment with melatonin signifi-cantly decreased the caspase-3 activity in colonic tissues compared to that in trinitrobenzene sulphonic acid-trea-ted rats (16.11 ± 2.46 vs 32.97 ± 3.91, P < 0.01). CONCLUSION: Melatonin has a protective effect on ba-cterial translocation and apoptosis.

Antioxidative effect of melatonin, ascorbic acid and N-acetylcysteine on caerulein-induced pancreatitis and associated liver injury in rats

AIM： To investigate the role of oxidative injury in pancreatitis-induced hepatic damage and the effect of antioxidant agents such as melatonin, ascorbic acid and N-acetyl cysteine on caerulein-induced pancreatitis and associated liver injury in rats. METHODS： Thirty-eight female Wistar rats were used. Acute pancreatitis （AP） was induced by two i.p. injections of caerulein at 2-h intervals （at a total dose of 100 μg/kg b.wt）. The other two groups received additional melatonin （20 mg/kg b.wt） or an antioxidant mixture containing L（＋）-ascorbic acid （14.3 mg/kb.wt.） and N-acetyl cysteine （181 mg/kg b.wt.） i.p. shortly before each injection of caerulein. The rats were sacrificed by decapitation 12 h after the last injection of caerulein. Pancreatic and hepatic oxidative stress markers were evaluated by changes in the amount of lipid peroxides measured as malondialdehyde （MDA） and changes in tissue antioxidant enzyme levels, catalase （CAT） and glutathione peroxidase （GPx）. Histopathological examination was performed using scoring systems. RESULTS： The degree of hepatic cell degeneration, intracellular vacuolization, vascular congestion, sinusoidal dilatation and inflammatory infiltration showed a significant difference between caerulein and caerulein＋melatonin （P= 0.001）, and careulein and caerulein ＋ L（＋）- ascorbic acid ＋N-acetyl cysteine groups （P= 0.002）. The degree of aciner cell degeneration, pancreatic edema, intracellular vacuolization and inflammatory infiltration showed a significant difference between caerulein and caerulein ＋ melatonin （P=0.004）, and careulein and caerulein ＋ L（＋）-ascorbic acid ＋N-acetyl cysteine groups （P=0.002）. Caerulein-induced pancreatic and liver damage was accompanied with a significant increase in tissue MDA levels （P= 0.01, P= 0.003, respectively） whereas a significant decrease in CAT （P= 0.002, P=0.003, respectively） and GPx activities （P= 0.002, P= 0.03, respectively）. Melatonin and L（＋）-ascorbic acid ＋N-acetyl cysteine administration significantly decreased MDA levels in pancreas （P= 0.03, P= 0.002, respectively） and liver （P= 0.007, P= 0.01, respectively）. Administration of these agents increased pancreatic and hepatic CAT and GPx activities. Melatonin significantly increased pancreatic and hepatic CAT （P= 0.002, P= 0.001, respectively） and GPx activities （P=0.002, P=0.001）. Additionally, L（＋）-ascorbic acid＋N-acetyl cysteine significantly increased pancreatic GPx （P= 0.002） and hepatic CAT and GPx activities （P= 0.001, P= 0.007, respectively） CONCLUSION： Oxidative injury plays an important role not only in the pathogenesis of AP but also in pancreatitis-induced hepatic damage. Antioxidant agents such as melatonin and ascorbic acid＋N-acetyl cysteine, are capable of limiting pancreatic and hepatic damage produced during AP via restoring tissue antioxidant enzyme activities.

Primary epithelial tumours of the appendix in a black population:A review of cases

AIM： To determine the and clinical features of prevalence, histologic types primary epithelial tumours of the vermiform appendix in a predominantly black population.METHODS： All cases of primary tumours of the appendix identified by review of the histopathology records at the University of the West Indies between January 1987 and June 2007 were selected. Relevant pathologic and clinical data were extracted with supplementation from patient charts where available. Non-epithelial tumours were excluded. The total number of appendectomy specimens over the period was also ascertained.RESULTS： Forty-two primary epithelial tumours were identified out of 6 824 appendectomies yielding a prevalence rate of approximately 0.62%. Welldifferentiated neuroendocrine cell tumours （carcinoids, 47.6%） and benign non-endocrine cell tumours （adenomas, 45.2%） were most common with nearly equal frequency. The median age was 43 years, with no sex predilection. Carcinoid tumours occurred in younger patients （mean age 32 years）, with a male-to-female ratio of 1.2：1. A clinical diagnosis of acute appendicitis was the most common reason for appendectomy （57.1%） and was histologically confirmed in 75% （18 of 24） of cases. In total, 16.7% of cases were diagnosed after incidental appendectomy.CONCLUSION： Appendiceal epithelial tumours are rare in our experience, and are represented principally by carcinoid turnours and adenornas. Carcinoid tumours occurred in younger patients but were slightly more common in men than women. Tumours were not suspected clinically and were diagnosed incidentally in specimens submitted for acute appendicitis supporting the need for histological evaluation in all resection specimens.

Metastatic melanoma of the gallbladder: An unusual clinical presentation of acute cholecystitis

Metastatic disease from cutaneous melanoma can af-fect all organs of the body, and varies in its biological behavior and clinical presentation. We present the case of a 58-year-old man who arrived at our clinic with acute abdominal pain, which, after investigation, was diagnosed as acute cholecystitis. The patient under-went laparotomy and cholecystectomy. Two years ago, he underwent surgical removal of a primary cutaneous melanoma on his right upper back. Pathological exami-nation revealed the presence of malignant melanoma with a metastatic lesion of the gallbladder.

Melatonin attenuates acute pancreatitis-associated lung injury in rats by modulating interleukin 22

AIM： To investigate whether therapeutic treatment with melatonin could protect rats against acute pan- creatitis and its associated lung injury. METHODS： Seventy-two male Sprague-Dawley rats were randomly divided into three groups： the sham op- eration （SO）, severe acute pancreatitis （SAP）, and mel- atonin treatment （MT） groups. Acute pancreatitis was induced by infusion of 1 mL/kg of sodium taurocholate （4% solution） into the biliopancreatic duct. Melatonin （50 mg/kg） was administered 30 min before pancre- atitis was induced, and the severity of pancreatic and pulmonary injuries was evaluated 1, 4 and 8 h after induction. Serum samples were collected to measure amylase activities, and lung tissues were removed to measure levels of mRNAs encoding interleukin 22 （IL-22） and T helper cell 22 （Th22）, as well as levels of IL-22.ing IL-22 and Th22 were significantly higher （P 〈 0.001） in the MT group than in the SAP group （0.526 ± 0.143 vs 0.156 ± 0.027, respectively, here and throughout, after 1 h; 0.489 ± 0.150 vs 0.113 ± 0.014 after 4 h; 0.524 ± 0.168 vs 0.069 ± 0.013 after 8 h, 0.378 ± 0.134 vs 0.122 ± 0.015 after 1 h; 0.205 ± 0.041 vs 0.076 ± 0.019 after 4 h; 0.302 ± 0.108 vs 0.045 ± 0.013 after 8 h, respectively） and significantly lower （P 〈 0.001） in the SAP group than in the SO group （0.156 ± 0.027 vs 1.000 ± 0.010 after 1 h; 0.113 ± 0.014 vs 1.041 ± 0.235 after 4 h; 0.069 ± 0.013 vs 1.110 ± 0.213 after 8 h, 0.122 ± 0.015 vs 1.000 ± 0.188 after 1 h; 0.076 ± 0.019 vs 0.899 ± 0.125 after 4 h; 0.045 ± 0.013 vs 0.991 ± 0.222 after 8 h, respectively）. The mean pathologi- cal scores for pancreatic tissues in the MT group were significantly higher （P 〈 0.01） than those for samples in the SO group （1.088 ± 0.187 vs 0.488 ± 0.183 after 1 h, 2.450 ± 0.212 vs 0.469 ± 0.242 after 4 h; 4.994 ± 0.184 vs 0.513 ± 0.210 after 8 h）, but were significantly lower （P 〈 0.01） than those for samples in the SAP group at each time point （1.088 ± 0.187 vs 1.969 ± 0.290 after 1 h; 2.450 ± 0.212 vs 3.344 ± 0.386 after 4 h; 4.994 ± 0.184 vs 6.981 ± 0.301 after 8 h）. The severity of SAP increased significantly （P 〈 0.01） over time in the SAP group （1.088 ± 0.187 vs 2.450 ± 0.212 between 1 h and 4 h after inducing pancreatitis; and 2.450 ± 0.212 vs 4.994 ± 0.184 between 4 and 8 h after inducing pan- creatitis）. CONCLUSION： Melatonin protects rats against acute pancreatitis-associated lung injury, probably through the upregulation of IL-22 and Th22, which increases the innate immunity of tissue cells and enhances their regeneration.

Sustained Viral Response to Ipilimumab Treatment in a Patient with HCV Chronic Infection and Metastatic Melanoma： A Case Report

The treatment of metastic melanoma has rapidly evolved in the last 5 years, giving clinicians and patients the hope for long lasting responses. In the field of modern immunotherapy, we are reaching the point of an expressive percentage of patients achieving long term survival with anti-CTLA4 and anti-PD1 checkpoint inhibitors. Of note, there is a considerable amount of patients excluded from the checkpoint blockade trials because of comorbidities like chronic viral infections. A precaution to avoid autoimmune induced hepatitis rendered HBV （hepatitis B virus） and HCV （hepatitis C virus） infected patients usually ineligible, but real life data in those patients, who are getting treatment despite of that, is pointing toward the feasibility and safety of immunotherapy in this context. To ilustrate that, we report the case of a metastatic non-BRAF mutated melanoma patient with HCV chronic infection and a surprising benefit derived from ipilimumab and pembrolizumab for his latter condition.