Nutritional immunomodulation of acute pancreatitis.

Despite the great advances in our understanding of the pathophysiology of acute pancreatitis, no specific therapy has emerged, and treatment remains supportive. In patients with the severe form of the disease, in which mortality remains high at 20% to 30%, the function of the upper gastrointestinal tract is disturbed due to extrinsic compression by the inflamed and swollen pancreas, and normal eating is impossible. Such patients often develop multiple organ failure, necessitating intensive-care management and artificial ventilation for weeks on end. In this setting, protein catabolism will rapidly result in protein deficiency and further complications unless nutritional support is commenced. Recent studies have shown that, despite the risk of disease exacerbation through pancreatic stimulation, enteral feeding is more effective than parenteral feeding in improving outcome. Experimental studies suggest that this can be attributed to its content of specific immunomodulating nutrients, such as glutamine, arginine, and n-3 fatty acids, and by its stabilizing effect on the gut flora through the provision of prebiotics. Further studies are indicated to examine whether dietary enrichment with these substrates, along with regulation of the gut bacteria with probiotics, can improve outcome further.

Preoperative isolated limb infusion of Doxorubicin and external irradiation for limb-threatening soft tissue sarcomas.

BACKGROUND: At present, limb-sparing surgery is the most appropriate and acceptable treatment option for soft tissue sarcomas of the extremities. To increase the number of limb-sparing resections in the treatment of locally advanced soft tissue sarcomas of the extremities, preoperative radiotherapy and/or chemotherapy are often used. Isolated limb perfusion of cytostatic agents is an effective alternative option but technically complex. Isolated limb infusion, essentially a low-flow isolated limb perfusion without oxygenation via a percutaneous catheter, had been developed as a simple alternative. OBJECTIVE: The objective of this study was to achieve limb-sparing surgery in patients with locally advanced soft tissue sarcomas of the extremities that would otherwise have required an amputation or a functionally mutilating surgery by performing preoperative isolated limb infusion with doxorubicin and external beam irradiation to obtain local control and make limb-sparing surgery feasible. METHODS: A total of 40 patients with locally advanced soft tissue sarcomas of the extremities were evaluated between 2002 and 2005. Tumors were located in the lower limb in 28 patients (70%) and in the upper limb in 12 patients (30%). All of these patients were felt to be unresectable and were referred because amputation was considered the only available treatment option. They underwent preoperative isolated limb infusion with doxorubicin (0.7 and 1.4 mg/kg for the upper and lower limbs, respectively). Preoperative external beam radiotherapy started within 3-7 days after isolated limb infusion was administered. The total dose was 35 Gy in ten fractions. After 3-7 weeks, surgery was performed aiming at limb preservation. RESULTS: Tumor response was seen in 85% of patients, rendering these large sarcomas resectable in most cases. The mean values of pretreatment tumor volume and post-treatment volume were 2797 cm(3) and 1781 cm(3), respectively, with a significant p value of 0.0001. Histologic response was seen in 80% of patients. At a median followup of 15 months (range = 5-35), limb salvage was achieved in 82.5%. Procedure-related complications were limited and easily managed. CONCLUSION: Isolated limb infusion with doxorubicin is a simple and safe method of regional chemotherapy. The addition of preoperative external beam irradiation helped to increase the rate of limb salvage in patients with large and/or high-grade soft tissue sarcomas of the extremities.

Dietary fatty acids modulate chronic colitis, colitis-associated colon neoplasia and COX-2 expression in IL-10 knockout mice.

OBJECTIVE: The effects of different dietary oils on the development of colitis-associated colon cancer have not been studied. The present study examined the effect of different dietary oils on the severity of chronic colitis, development of colitis-associated premalignant changes, and colonic expression of cyclooxygenase-2 (COX-2) in interleukin-10 knockout (IL-10-/-) mice. METHODS: IL-10-/- mice were fed chow supplemented with corn oil (CO; control, n=28), olive oil (OO; n=29), or fish oil (FO; n=35) for 12 wk and their colons were studied for colitis score, premalignant changes, and COX-2 expression. RESULTS: The average colitis score was higher in the FO than in the CO group. Similarly, the incidence of severe colitis (score>or=3) was significantly higher in the FO than in the CO and OO groups (50% versus 7.7% and 3.7%, respectively, P<0.05). Dysplasia was more frequent in the FO and less frequent in the OO than in the CO group (47% and 4% versus 15%, respectively, P<0.05). Conversely, aberrant crypt foci and crypt index were significantly higher in the FO than in the CO group. Colitis score, aberrant crypt foci, and crypt index did not differ between the OO and CO groups. COX-2 immunostaining was significantly lower in the OO than in CO group (P<0.05) but not different between the FO and CO groups. CONCLUSIONS: In IL-10-/- mice, fish oil exacerbates chronic colitis and colitis-associated premalignant changes. Conversely, olive oil inhibits COX-2 immunostaining and decreases the risk of neoplasia associated with chronic colitis.

Carbon monoxide ameliorates chronic murine colitis through a heme oxygenase 1-dependent pathway.

Heme oxygenase (HO)-1 and its metabolic product carbon monoxide (CO) play regulatory roles in acute inflammatory states. In this study, we demonstrate that CO administration is effective as a therapeutic modality in mice with established chronic colitis. CO administration ameliorates chronic intestinal inflammation in a T helper (Th)1-mediated model of murine colitis, interleukin (IL)-10-deficient (IL-10(-/-)) mice. In Th1-mediated inflammation, CO abrogates the synergistic effect of interferon (IFN)-gamma on lipopolysaccharide-induced IL-12 p40 in murine macrophages and alters IFN-gamma signaling by inhibiting a member of the IFN regulatory factor (IRF) family of transcription factors, IRF-8. A specific signaling pathway, not previously identified, is delineated that involves an obligatory role for HO-1 induction in the protection afforded by CO. Moreover, CO antagonizes the inhibitory effect of IFN-gamma on HO-1 expression in macrophages. In macrophages and in Th1-mediated colitis, pharmacologic induction of HO-1 recapitulates the immunosuppressive effects of CO. In conclusion, this study begins to elucidate potential etiologic and therapeutic implications of CO and the HO-1 pathway in chronic inflammatory bowel diseases.

Neoadjuvant chemotherapy versus primary surgery in advanced ovarian carcinoma.

BACKGROUND: Patients with advanced ovarian cancer should be treated by radical debulking surgery aiming at complete tumor resection. Unfortunately about 70% of the patients present with advanced disease, when optimal debulking can not be obtained, and therefore these patients gain little benefit from surgery. Neoadjuvant chemotherapy (NACT) has been proposed as a novel therapeutic approach in such cases. In this study, we report our results with primary surgery or neoadjuvant chemotherapy as treatment modalities in the specific indication of operable patients with advanced ovarian carcinoma (no medical contraindication to debulking surgery). PATIENTS AND METHODS: A total of 59 patients with stage III or IV epithelial ovarian carcinomas were evaluated between 1998 and 2003. All patients were submitted to surgical exploration aiming to evaluate tumor resectability. Neoadjuvant chemotherapy was given (in 27 patients) where optimal cytoreduction was not feasible. Conversely primary debulking surgery was performed when we considered that optimal cytoreduction could be achieved by the standard surgery (32 patients). RESULTS: Optimal cytoreduction was higher in the NACT group (72.2%) than the conventional group (62.4%), though not statistically significant (P = 0.5). More important was the finding that parameters of surgical aggressiveness (blood loss rates, ICU stay and total hospital stay) were significantly lower in NACT group than the conventional group. The median overall survival time was 28 months in the conventional group and 25 months in NACT group with a P value of 0.5. The median disease free survival was 19 months in the conventional group and 21 months in NACT group (P = 0.4). In multivariate analysis, the pathologic type and degree of debulking were found to affect the disease free survival significantly. Overall survival was not affected by any of the study parameters. CONCLUSION: Primary chemotherapy followed by interval debulking surgery in select group of patients doesn't appear to worsen the prognosis, but it permits a less aggressive surgery to be performed.

Are pANCA, ASCA, or cytokine gene polymorphisms associated with pouchitis? Long-term follow-up in 102 ulcerative colitis patients.

OBJECTIVE: Pouchitis is the most frequent complication after ileal pouch-anal anastomosis for ulcerative colitis. This study aims to analyze the frequency and characteristics of pouchitis in long-term follow-up in a large population, and to determine whether a significant association exists between five immunogenetic markers and pouchitis. METHODS: From a population of over 500 ulcerative colitis patients who had undergone ileal pouch-anal anastamosis 5-12 yr earlier, 102 subjects participated in the study. Using clinical data obtained from interviews and chart reviews, patients were classified into three groups: no pouchitis; 1-2 episodes per year; and >2 episodes per year. Coded sera from the patients were analyzed for ulcerative colitis-associated perinuclear antineutrophil cytoplasmic antibodies and Crohn's disease-associated anti-saccharomyces cerevesiae antibodies. Interleukin-1 receptor antagonist, tumor necrosis factor (TNF), and lymphotoxin beta (lymphotoxin) polymorphisms were also analyzed. RESULTS: Pouchitis affected 49% of the study population. Antineutrophil cytoplasmic antibodies, anti-saccharomyces cerevesiae antibodies, and lymphotoxin-beta polymorphisms were not associated with pouchitis. Carriage of interleukin-1 receptor antagonist allele 2 was significantly greater among those without pouchitis than those with pouchitis. Patients without pouchitis had a significantly greater carriage rate of TNF allele 2. CONCLUSIONS: Perinuclear antineutrophil cytoplasmic antibodies and anti-saccharomyces cerevesiae antibodies are not correlated with pouchitis, but interleukin-1 receptor antagonist and TNF may play a role in its development. Further evaluation of these markers in pouchitis will require larger populations, long-term prospective observation, and studies that correlate polymorphisms with specific immunologic functions.

Relationship of adiposity to subclinical atherosclerosis in obese patients with type 2 diabetes.

OBJECTIVE: There is an increased prevalence of macrovascular disease in type 2 diabetes. The pathogenesis has been related to metabolic risk factors, insulin resistance, and obesity. One of the strongest predictors is the presence of subclinical atherosclerosis. This study was designed to examine the relationship between obesity and regional patterns of adiposity, insulin resistance, and five independent measures of subclinical atherosclerosis. RESEARCH METHODS AND PROCEDURES: Fifty-two overweight and obese men and women with type 2 diabetes of relatively short known duration were examined. Measures of subclinical vascular disease were assessment of arterial stiffness by pulse wave velocity, ultrasound measurement of the carotid artery intimal-medial thickness and plaque index, and measurement of the extent of coronary and aortic calcification using electron beam computed tomography. Insulin resistance was measured using the hyperinsulinemic euglycemic clamp. Body composition was measured using DXA and computed tomography. RESULTS: Adiposity was a strong determinant of pulse wave velocity. Carotid intimal-medial thickness was correlated with age, low-density lipoprotein-cholesterol, and hyperglycemia, but not with adiposity. Hyperglycemia and plasma activator inhibitor-1 were significant correlates of the carotid artery plaque index. Coronary calcium scores were significantly correlated with age and interleukin-6 and significantly and negatively correlated to insulin sensitivity index. DISCUSSION: These findings suggest that obesity may play an important role in the early phase of subclinical macrovascular disease related to vessel stiffness, whereas hyperglycemia and insulin resistance in conjunction with other risk factors have important roles in progression from vessel stiffness to atheroma formation in type 2 diabetes.

Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance.

The current study was undertaken to examine metabolic and body composition correlates of fatty liver in type 2 diabetes mellitus (DM). Eighty-three men and women with type 2 DM [mean body mass index (BMI): 34 +/- 0.5 kg/m2] and without clinical or laboratory evidence of liver dysfunction had body composition assessments of fat mass (FM), visceral adipose tissue (VAT), liver and spleen computed tomography (CT) attenuation (ratio of liver to spleen), muscle CT attenuation, and thigh adiposity; these assessments were also performed in 12 lean and 15 obese nondiabetic volunteers. Insulin sensitivity was measured with a euglycemic insulin infusion (40 mU. m-2. min-1) combined with systemic indirect calorimetry to assess glucose and lipid oxidation, and with infusions of [2H2]glucose for assessment of endogenous glucose production. A majority of those with type 2 DM (63%) met CT criteria for fatty liver, compared with 20% of obese and none of the lean nondiabetic volunteers. Fatty liver was most strongly correlated with VAT (r = -0.57, P < 0.0001) and less strongly but significantly associated with BMI (r = -0.42, P < 0.001) and FM (r = -0.37, P < 0.001), but only weakly associated with subcutaneous adiposity (r = -0.29; P < 0.01). Fatty liver was also correlated with subfascial adiposity of skeletal muscle (r = -0.44; P < 0.01). Volunteers with type 2 DM and fatty liver were substantially more insulin resistant those with type 2 DM but without fatty liver (P < 0.001) and had higher levels of plasma free fatty acids (P < 0.01) and more severe dyslipidemia (P < 0.01), a pattern observed in both genders. Plasma levels of cytokines were increased in relation to fatty liver (r = -0.34; P < 0.01). In summary, fatty liver is relatively common in overweight and obese volunteers with type 2 DM and is an aspect of body composition related to severity of insulin resistance, dyslipidemia, and inflammatory markers.

Celecoxib and rofecoxib potentiate chronic colitis and premalignant changes in interleukin 10 knockout mice.

Nonsteroidal anti-inflammatory drugs decrease sporadic colorectal carcinoma and adenomas in patients with familial adenomatous polyposis and in rodent models of sporadic colon cancer and familial adenomatous polyposis. Similarly, selective cyclooxygenase 2 inhibitors decrease adenomas in humans and rodents. However, their effects on chronic colitis and colitis-associated neoplasia are unknown. Interleukin 10-/- mice (C57/B6) were fed regular chow (n = 20) or chow with celecoxib (1,500 ppm, n = 18) or rofecoxib (75 ppm, n = 20) for 12 weeks. Twenty-eight percent of the celecoxib group died versus 5% of the control and rofecoxib groups (p < 0.05 compared with control). Celecoxib and rofecoxib increased the incidence of colitis (26% vs. 92% and 68%, p < 0.01), colitis score (0.4 +/- 0.2 vs. 2.5 +/- 0.3 and 2 +/- 0.4, p < 0.01), aberrant crypt foci (0.5 +/- 0.3 vs. 3.7 +/- 2.6 and 2.8 +/- 0.7, p < 0.01), aberrant crypts per mouse (4.11 +/- 2.1 vs. 41.2 +/- 9.7 and 27.1 +/- 7.5, p < 0.01) and dysplasia (11% vs. 54% and 42%, p < 0.01). Similarly, indomethacin (9 ppm, n = 15) increased colitis score, aberrant crypt foci, and dysplasia after 27 days of treatment. Two selective cyclooxygenase 2 inhibitors exacerbate colitis and premalignant changes in the interleukin 10-/- mouse model of chronic colitis and colitis-associated colon carcinoma.