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Postoperative arginine-enriched immune modulating nutrition: Long-term survival results from a randomised clinical trial in patients with oesophagogastric and pancreaticobiliary cancer.
Adiamah, A, Rollins, KE, Kapeleris, A, Welch, NT, Iftikhar, SY, Allison, SP, Lobo, DN
Clinical nutrition (Edinburgh, Scotland). 2021;(11):5482-5485
Abstract
BACKGROUND & AIMS Immune modulating nutrition (IMN) has been shown to reduce postoperative infectious complications and length of stay in patients with gastrointestinal cancer. Two studies of IMN in patients undergoing surgery for head and neck cancer also suggested that this treatment might improve long-term survival and progression-free survival. In the present study, we analysed follow-up data from our previous randomised controlled trial of IMN, in patients undergoing surgery for oesophagogastric and pancreaticobiliary cancer, in order to evaluate the long-term impact on survival of postoperative IMN versus an isocaloric, isonitrogenous control feed. METHODS This study included patients undergoing surgery for cancers of the pancreas, oesophagus and stomach, who had been randomised in a double-blind manner to receive postoperative jejunostomy feeding with IMN (Stresson, Nutricia Ltd.) or an isonitrogenous, isocaloric feed (Nutrison High Protein, Nutricia) for 10-15 days. The primary outcome was long-term overall survival. RESULTS There was complete follow-up for all 108 patients, with 54 patients randomised to each group. There were no statistically significant differences between groups by demographics [(age, p = 0.63), sex (p = 0.49) or site of cancer (p = 0.25)]. 30-day mortality was 11.1% in both groups. Mortality in the intervention group was 13%, 31.5%, 70.4%, 85.2%, 88.9%, and 96.3% at 90 days, and 1, 5, 10, 15 and 20 years respectively. Corresponding mortality in the control group was 14.8%, 35.2%, 68.6%, 79.6%, 85.2% and 98.1% (p > 0.05 for all comparisons). CONCLUSION Early postoperative feeding with arginine-enriched IMN had no impact on long-term survival in patients undergoing surgery for oesophagogastric and pancreaticobiliary cancer.
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The Role of Immunonutrition in Patients Undergoing Pancreaticoduodenectomy.
Jabłońska, B, Mrowiec, S
Nutrients. 2020;(9)
Abstract
Pancreaticoduodenectomy (PD) is one of the most difficult and complex surgical procedures in abdominal surgery. Malnutrition and immune dysfunction in patients with pancreatic cancer (PC) may lead to a higher risk of postoperative infectious complications. Although immunonutrition (IN) is recommended for enhanced recovery after surgery (ERAS) in patients undergoing PD for 5-7 days perioperatively, its role in patients undergoing pancreatectomy is still unclear and controversial. It is known that the proper surgical technique is very important in order to reduce a risk of postoperative complications, such as a pancreatic fistula, and to improve disease-free survival in patients following PD. However, it has been proven that IN decreases the risk of infectious complications, and shortens hospital stays in patients undergoing PD. This is a result of the impact on altered inflammatory responses in patients with cancer. Both enteral and parenteral, as well as preoperative and postoperative IN, using various nutrients, such as glutamine, arginine, omega-3 fatty acids and nucleotides, is administered. The most frequently used preoperative oral supplementation is recommended. The aim of this paper is to present the indications and benefits of IN in patients undergoing PD.
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Postoperative enteral immunonutrition in head and neck cancer patients: Impact on clinical outcomes.
Barajas-Galindo, DE, Vidal-Casariego, A, Pintor-de la Maza, B, Fernández-Martínez, P, Ramos-Martínez, T, García-Arias, S, Hernández-Moreno, A, Urioste-Fondo, A, Cano-Rodríguez, I, Ballesteros-Pomar, MD
Endocrinologia, diabetes y nutricion. 2020;(1):13-19
Abstract
BACKGROUND Head and neck cancer patients have a high rate of complications during the postoperative period that could increase their morbidity rate. Arginine has been shown to improve healing and to modulate inflammation and immune response. The aim of our study was to assess whether use of arginine-enriched enteral formulas could decrease fistulas and length of stay (LoS). METHODS A retrospective study was conducted in patients who had undergone head and neck cancer surgery and were receiving enteral nutrition through a nasogastric tube in the postoperative period between January 2012 and May 2018. The differences associated to use of immunoformula vs. standard formulas were analysed. Sociodemographic, anthropometric, and nutritional intervention variables, as well as nutritional parameters, were recorded during the early postoperative period. Occurrence of complications (fistulas), length of hospital stay, readmissions, and 90-day mortality were recorded. RESULTS In a univariate analysis, patients who received nutritional support with immunonutrition had a lower fistula occurrence rate (17.91% vs. 32.84%; p=0.047) and a shorter mean LoS [28.25 (SD 16.11) vs. 35.50 (SD 25.73) days; p=0.030]. After adjusting for age, energy intake, aggressiveness of surgery and tumour stage, fistula occurrence rate and LoS were similar in both groups irrespective of the type of formula. CONCLUSIONS Use of arginine-enriched enteral nutrition appears to decrease the occurrence of fistulas in the postoperative period in patients with head and neck cancer, with a resultant reduction in length of hospital stay. However, the differences disappeared after adjusting for age, tumour stage, or aggressiveness of the surgery.
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Combination of arginine, glutamine, and omega-3 fatty acid supplements for perioperative enteral nutrition in surgical patients with gastric adenocarcinoma or gastrointestinal stromal tumor (GIST): A prospective, randomized, double-blind study.
Ma, C, Tsai, H, Su, W, Sun, L, Shih, Y, Wang, J
Journal of postgraduate medicine. 2018;(3):155-163
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Abstract
BACKGROUND Perioperative enteral nutrition (EN) enriched with immune-modulating substrates is preferable for patients undergoing major abdominal cancer surgery. In this study, perioperative EN enriched with immune-modulating nutrients such as arginine, glutamine, and omega-3 fatty acids was evaluated for its anti-inflammatory efficacy in patients with gastric adenocarcinoma or gastrointestinal stromal tumor (GIST) receiving curative surgery. MATERIALS AND METHODS This prospective, randomized, double-blind study recruited 34 patients with gastric adenocarcinoma or gastric GIST undergoing elective curative surgery. These patients were randomly assigned to the study group, receiving immune-modulating nutrient-enriched EN, or the control group, receiving standard EN from 3 days before surgery (preoperative day 3) to up to postoperative day 14 or discharge. Laboratory and inflammatory parameters were assessed on preoperative day 3 and postoperative day 14 or at discharge. Adverse events (AEs) and clinical outcomes were documented daily and compared between groups. RESULTS No significant differences were observed between the two groups in selected laboratory and inflammatory parameters, or in their net change, before and after treatment. AEs and clinical outcomes, including infectious complications, overall complications, time to first bowel action, and length of hospital stay after surgery, were comparable between treatment groups (all P > 0.05). CONCLUSION Immune-modulating nutrient-enriched EN had no prominent immunomodulation effect compared with that of standard EN.
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Efficacy of arginine-enriched enteral formulas for the healing of pressure ulcers: a systematic review.
Liu, P, Shen, WQ, Chen, HL
Journal of wound care. 2017;(6):319-323
Abstract
OBJECTIVE Arginine improves healing and modulates inflammation and the immune response. This systematic review aimed to assess the effect of arginine-enriched enteral formulas in pressure ulcer (PU) healing. METHOD Systematic computerised searches of PubMed, Web of Knowledge, Scopus, ENTRAL and CINAHL databases were performed from their inception to 20 January 2016. Randomised controlled trials (RCTs) were included in this systematic review. We used the Jadad scale as a quality assessment tool. RESULTS There were seven RCTs with 369 patients included in this systematic review; four RCTs assessed healing by PU area reduction. All of them reported arginine-enriched enteral nutrition led to a significant improved PU healing compared with standard hospital diet in 2-12 weeks follow-up. Among these four RCTs, one enrolled malnourished patients, one enrolled non-malnourished patients, and the other two studies did not restrict the nutritional status of the patients. Using the Pressure Ulcer Scale for Healing (PUSH) four RCTs assessed healing of PU, all reporting arginine-enriched enteral nutrition resulted in a significant PUSH score improvement compared with control at follow-up. Using the Pressure Sore Status Tool (PSST) one RCT assessed healing of PUs, finding patients receiving arginine had the lowest PSST scores compared with controls. An RCT compared healing with two doses of arginine (4.5g versus 9g), but no difference was found between the doses. CONCLUSION Evidence showed that arginine-enriched enteral nutrition led to a significant improvement in PU healing. It was effective not only in malnourished patients, but also in non-malnourished patients.
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Perioperative glutamine supplementation restores disturbed renal arginine synthesis after open aortic surgery: a randomized controlled clinical trial.
Brinkmann, SJ, Buijs, N, Vermeulen, MA, Oosterink, E, Schierbeek, H, Beishuizen, A, de Vries, JP, Wisselink, W, van Leeuwen, PA
American journal of physiology. Renal physiology. 2016;(3):F567-75
Abstract
Postoperative renal failure is a common complication after open repair of an abdominal aortic aneurysm. The amino acid arginine is formed in the kidneys from its precursor citrulline, and citrulline is formed from glutamine in the intestines. Arginine enhances the function of the immune and cardiovascular systems, which is important for recovery after surgery. We hypothesized that renal arginine production is diminished after ischemia-reperfusion injury caused by clamping of the aorta during open abdominal aortic surgery and that parenteral glutamine supplementation might compensate for this impaired arginine synthesis. This open-label clinical trial randomized patients who underwent clamping of the aorta during open abdominal aortic surgery to receive a perioperative supplement of intravenous alanyl-glutamine (0.5 g·kg(-1)·day(-1); group A, n = 5) or no supplement (group B, n = 5). One day after surgery, stable isotopes and tracer methods were used to analyze the metabolism and conversion of glutamine, citrulline, and arginine. Whole body plasma flux of glutamine, citrulline, and arginine was significantly higher in group A than in group B (glutamine: 391 ± 34 vs. 258 ± 19 μmol·kg(-1)·h(-1), citrulline: 5.7 ± 0.4 vs. 2.8 ± 0.4 μmol·kg(-1)·h(-1), and arginine: 50 ± 4 vs. 26 ± 2 μmol·kg(-1)·h(-1), P < 0.01), as was the synthesis of citrulline from glutamine (4.8 ± 0.7 vs. 1.6 ± 0.3 μmol·kg(-1)·h(-1)), citrulline from arginine (2.3 ± 0.3 vs. 0.96 ± 0.1 μmol·kg(-1)·h(-1)), and arginine from glutamine (7.7 ± 0.4 vs. 2.8 ± 0.2 μmol·kg(-1)·h(-1)), respectively (P < 0.001 for all). In conclusion, the production of citrulline and arginine is severely reduced after clamping during aortic surgery. This study shows that an intravenous supplement of glutamine increases the production of citrulline and arginine and compensates for the inhibitory effect of ischemia-reperfusion injury.
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Arginine and citrulline and the immune response in sepsis.
Wijnands, KA, Castermans, TM, Hommen, MP, Meesters, DM, Poeze, M
Nutrients. 2015;(3):1426-63
Abstract
Arginine, a semi-essential amino acid is an important initiator of the immune response. Arginine serves as a precursor in several metabolic pathways in different organs. In the immune response, arginine metabolism and availability is determined by the nitric oxide synthases and the arginase enzymes, which convert arginine into nitric oxide (NO) and ornithine, respectively. Limitations in arginine availability during inflammatory conditions regulate macrophages and T-lymfocyte activation. Furthermore, over the past years more evidence has been gathered which showed that arginine and citrulline deficiencies may underlie the detrimental outcome of inflammatory conditions, such as sepsis and endotoxemia. Not only does the immune response contribute to the arginine deficiency, also the impaired arginine de novo synthesis in the kidney has a key role in the eventual observed arginine deficiency. The complex interplay between the immune response and the arginine-NO metabolism is further underscored by recent data of our group. In this review we give an overview of physiological arginine and citrulline metabolism and we address the experimental and clinical studies in which the arginine-citrulline NO pathway plays an essential role in the immune response, as initiator and therapeutic target.
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Efficacy of arginine-enriched enteral formulas in the reduction of surgical complications in head and neck cancer: a systematic review and meta-analysis.
Vidal-Casariego, A, Calleja-Fernández, A, Villar-Taibo, R, Kyriakos, G, Ballesteros-Pomar, MD
Clinical nutrition (Edinburgh, Scotland). 2014;(6):951-7
Abstract
INTRODUCTION Arginine improves healing and modulates inflammation and the immune response. A systematic review and meta-analysis were conducted to assess whether arginine-enriched enteral formulas reduce complications (fistulas, wound infections, other infections) and hospital length of stay (LoS) in patients undergoing surgery for head and neck cancer. METHODS Medline, CENTRAL, and Trip Database were searched using the search strategy "Head and Neck Neoplasms" AND "Enteral Nutrition" AND "Arginine" OR "Immunonutrition". Inclusion criteria comprised: type of study (RCT), language (English, Spanish), outcomes (complications of surgery, LoS), and methodological quality (Jadad scale). The odds ratio (OR) and confidence intervals (95% CI) were calculated using the Mantel-Haenszel method, and the mean difference (MD) with the random effects method. Heterogeneity was assessed using Cochran's Q. RESULTS Six studies were included, with 397 patients receiving peri/postoperative enteral nutrition with different doses of arginine (6.25-18.7 g/L). Enteral formulas containing arginine were associated with a reduction in fistulas [OR = 0.36 (95% CI 0.14-0.95), p = 0.039; Q = 3.93, p = 0.269], and LoS [MD = -6.8 (95% CI -12.6 to -0.9) days, p = 0.023; Q = 2.44, p = 0.486]. There were no reductions in wound infections [OR = 1.04 (95% CI 0.49-2.17), p = 0.925; Q = 1.60, p = 0.809] or other infections [OR = 0.79 (95% CI 0.48-1.31); p = 0.369; Q = 7.94, p = 0.094]. Arginine administration did not increase the occurrence of diarrhoea [OR = 1.80 (95% CI 0.50-6.52), p = 0.375; Q = 0.16, p = 0.691]. CONCLUSIONS The administration of arginine-enriched enteral nutrition led to a significant reduction in fistulas and hospital stay in patients undergoing surgery for head and neck cancer.
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Randomized controlled trial comparing antioxidant-enriched enteral nutrition with immune-enhancing enteral nutrition after esophagectomy for cancer: a pilot study.
Nagano, T, Fujita, H, Tanaka, T, Matono, S, Murata, K, Ishibashi, N, Shirouzu, K, Yanagawa, T
Surgery today. 2013;(11):1240-9
Abstract
PURPOSE The objective of this study was to compare the effects of two types of enteral supplements, an antioxidant-enriched enteral nutrition (AeEN) and an immune-enhancing enteral nutrition (IeEN), on the nutrition, immunoinflammatory response, antioxidant capacity and clinical outcomes in patients after esophagectomy for cancer. METHODS Patients (n = 20) undergoing esophagectomy for cancer were randomized in this single-center, open-label study. Two types of enteral supplements were used for 5 days before surgery and 7 days after surgery. The circulating levels of nutritional markers, immunoinflammatory markers, oxidative stress markers, and the antioxidant capacity were compared throughout the perioperative period, and the patients' clinical outcomes were also compared. RESULTS The circulating levels of nutritional markers decreased after surgery, but the changes were not significantly different between the AeEN group and the IeEN group throughout the perioperative period. Surgery increased the immunoinflammatory markers, and the levels were not significantly different between the groups after surgery. Surgery also increased the levels of oxidative stress markers, but there were no significant differences between the groups throughout the study period. CONCLUSIONS The results of this pilot study suggest that AeEN and IeEN have a similar effect on nutrition, the immunoinflammatory response, antioxidant capacity and clinical outcomes after esophagectomy for cancer. These findings, therefore, warrant further studies on a larger scale.
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Randomized clinical trial of arginine-supplemented enteral nutrition versus standard enteral nutrition in patients undergoing gastric cancer surgery.
Zhao, H, Zhao, H, Wang, Y, Jing, H, Ding, Q, Xue, J
Journal of cancer research and clinical oncology. 2013;(9):1465-70
Abstract
PURPOSE Significant malnutrition exists in a high percentage of patients with gastric cancer. It is, therefore, crucial to establish an effective means to provide nutrition for these patients. This prospective, randomized, double-blinded clinical trial aims to assess the long-term survival of arginine-supplementation enteral nutrition versus standard enteral nutrition in malnourished patients with gastric cancer. METHODS The control group (36 cases) received postoperative standard enteral nutrition. Meanwhile, the arginine-supplementation group (37 cases) adopted the same nutrition product but enriched with arginine (9.0 g/L). The primary study objective was overall survival (OS). Secondary endpoints were progression-free survival (PFS); serum parameters including total protein, albumin, proalbumin, and transferrin obtained on preoperative day 1, postoperative day 2, and day 12; CD4(+) and CD8(+) T cells, natural killer (NK) cells, immunoglobulin M (IgM), and immunoglobulin G (IgG) obtained on preoperative day 1 and postoperative day 7. RESULTS No significant differences in baseline characteristics were observed between groups. The group receiving arginine-enriched nutrition had a significantly better OS (P = 0.03, 41 vs. 30.5 months) and better PFS (P = 0.02, 18 vs. 11.5 months). On postoperative day 7, CD4(+) T cells, NK cells, IgM and IgG levels of the arginine-supplemented group increased prominently and were significantly higher than those of the control group and those on preoperative day 1. There is no significant difference in the serum total protein, albumin, proalbumin, and transferrin levels between the two arms. CONCLUSIONS Arginine-supplemented enteral nutrition significantly improves long-term survival and restores immunity in malnourished gastric cancer.