Variation in treatment and survival of older patients with non-metastatic breast cancer in five European countries: a population-based cohort study from the EURECCA Breast Cancer Group.

BACKGROUND: Older patients are poorly represented in breast cancer research and guidelines do not provide evidence based recommendations for this specific group. We compared treatment strategies and survival outcomes between European countries and assessed whether variance in treatment patterns may be associated with variation in survival. METHODS: Population-based study including patients aged ≥ 70 with non-metastatic BC from cancer registries from the Netherlands, Belgium, Ireland, England and Greater Poland. Proportions of local and systemic treatments, five-year relative survival and relative excess risks (RER) between countries were calculated. RESULTS: In total, 236,015 patients were included. The proportion of stage I BC receiving endocrine therapy ranged from 19.6% (Netherlands) to 84.6% (Belgium). The proportion of stage III BC receiving no breast surgery varied between 22.0% (Belgium) and 50.8% (Ireland). For stage I BC, relative survival was lower in England compared with Belgium (RER 2.96, 95%CI 1.30-6.72, P < .001). For stage III BC, England, Ireland and Greater Poland showed significantly worse relative survival compared with Belgium. CONCLUSIONS: There is substantial variation in treatment strategies and survival outcomes in elderly with BC in Europe. For early-stage BC, we observed large variation in endocrine therapy but no variation in relative survival, suggesting potential overtreatment. For advanced BC, we observed higher survival in countries with lower proportions of omission of surgery, suggesting potential undertreatment.

Beneficial Effects of Early Enteral Nutrition After Major Rectal Surgery: A Possible Role for Conditionally Essential Amino Acids? Results of a Randomized Clinical Trial.

OBJECTIVES: To investigate direct postoperative outcome and plasma amino acid concentrations in a study comparing early enteral nutrition versus early parenteral nutrition after major rectal surgery. Previously, it was shown that a low plasma glutamine concentration represents poor prognosis in ICU patients. DESIGN: A preplanned substudy of a previous prospective, randomized, open-label, single-centre study, comparing early enteral nutrition versus early parenteral nutrition in patients at high risk of postoperative ileus after surgery for locally advanced or locally recurrent rectal cancer. Early enteral nutrition reduced postoperative ileus, anastomotic leakage, and hospital stay. SETTING: Tertiary referral centre for locally advanced and recurrent rectal cancer. PATIENTS: A total of 123 patients with locally advanced or recurrent rectal carcinoma requiring major rectal surgery. INTERVENTIONS: Patients were randomized (ALEA web-based external randomization) preoperatively into two groups: early enteral nutrition (early enteral nutrition, intervention) by nasojejunal tube (n = 61) or early parenteral nutrition (early parenteral nutrition, control) by jugular vein catheter (n = 62). Eight hours after the surgical procedure artificial nutrition was started in hemodynamically stable patients, stimulating oral intake in both groups. Blood samples were collected to measure plasma glutamine, citrulline, and arginine concentrations using a validated ultra performance liquid chromatography-tandem mass spectrometric method. MEASUREMENTS AND MAIN RESULTS: Baseline concentrations were comparable for both groups. Directly after rectal surgery, a decrease in plasma amino acids was observed. Plasma glutamine concentrations were higher in the parenteral group than in the enteral group on postoperative day 1 (p = 0.027) and day 5 (p = 0.008). Arginine concentrations were also significantly increased in the parenteral group at day 1 (p < 0.001) and day 5 (p = 0.001). CONCLUSIONS: Lower plasma glutamine and arginine concentrations were measured in the enteral group, whereas a better clinical outcome was observed. We conclude that plasma amino acids do not provide a causal explanation for the observed beneficial effects of early enteral feeding after major rectal surgery.

Reduction of postoperative ileus by early enteral nutrition in patients undergoing major rectal surgery: prospective, randomized, controlled trial.

BACKGROUND: The current trend in postoperative nutrition is to promote a normal oral diet as early as possible. However, postoperative ileus is a frequent and common problem after major abdominal surgery. This study was designed to investigate whether early enteral nutrition (EEN), as a bridge to a normal diet, can reduce postoperative ileus. METHODS: Patients undergoing major rectal surgery for locally advanced primary or recurrent rectal carcinoma (after neoadjuvant (chemo)-radiation, with or without intraoperative radiotherapy) were randomly assigned to EEN (n = 61) or early parenteral nutrition (EPN, n = 62) in addition to an oral diet. Early nutrition was started 8 hours after surgery. Early parenteral nutrition was given as control nutrition to obtain caloric equivalence and minimize confounding. The primary endpoint was time to first defecation; secondary outcomes were morbidity, other ileus symptoms, and length of hospital stay. RESULTS: Baseline characteristics were similar for both groups. In intention-to-treat analysis, the time to first defecation was significantly shorter in the enteral nutrition arm than in the control arm (P = 0.04). Moreover, anastomotic leakage occurred significantly less frequently in the enteral group (1 patient) compared with parenteral supplementation (9 patients, P = 0.009). Mean length of stay in the enteral group was 13.4 ± 2.2 days versus 16.7 ± 2.3 days in the parenteral group (P = 0.007). CONCLUSIONS: Early enteral nutrition is safe and associated with significantly less ileus. Early enteral nutrition is associated with less anastomotic leakage in patients undergoing extensive rectal surgery.

Antioxidant-enriched enteral nutrition and immuno-inflammatory response after major gastrointestinal tract surgery.

Major surgery induces an immuno-inflammatory response accompanied by oxidative stress that may impair cellular function and delay recovery. The objective of the study was to investigate the effect of an enteral supplement, containing glutamine and antioxidants, on circulating levels of immuno-inflammatory markers after major gastrointestinal tract surgery. Patients (n 21) undergoing major gastrointestinal tract surgery were randomised in a single-centre, open-label study. The effects on circulating levels of immuno-inflammatory markers were determined on the day before surgery and on days 1, 3, 5 and 7 after surgery. Major gastrointestinal surgery increased IL-6, TNF receptor 55/60 (TNF-R55) and C-reactive protein (CRP). Surgery reduced human leucocyte antigen-DR (HLA-DR) expression on monocytes. CRP decrease was more pronounced in the first 7 d in the treatment group compared with the control group. In the treatment group, from the moment Module AOX was administered on day 1 after surgery, TNF receptor 75/80 (TNF-R75) level decreased until the third post-operative day and then stabilised, whereas in the control group the TNF-R75 level continued to increase. The results of the present pilot study suggest that enteral nutrition enriched with glutamine and antioxidants possibly moderates the immuno-inflammatory response (CRP, TNF-R75) after surgery.

Antioxidant enriched enteral nutrition and oxidative stress after major gastrointestinal tract surgery.

AIM: To investigate the effects of an enteral supplement containing antioxidants on circulating levels of antioxidants and indicators of oxidative stress after major gastrointestinal surgery. METHODS: Twenty-one patients undergoing major upper gastrointestinal tract surgery were randomised in a single centre, open label study on the effect of postoperative enteral nutrition supplemented with antioxidants. The effect on circulating levels of antioxidants and indicators of oxidative stress, such as F2-isoprostane, was studied. RESULTS: The antioxidant enteral supplement showed no adverse effects and was well tolerated. After surgery a decrease in the circulating levels of antioxidant parameters was observed. Only selenium and glutamine levels were restored to pre-operative values one week after surgery. F2-isoprostane increased in the first three postoperative days only in the antioxidant supplemented group. Lipopolysaccharide binding protein (LBP) levels decreased faster in the antioxidant group after surgery. CONCLUSION: Despite lower antioxidant levels there was no increase in the circulating markers of oxidative stress on the first day after major abdominal surgery. The rise in F2-isoprostane in patients receiving the antioxidant supplement may be related to the conversion of antioxidants to oxidants which raises questions on antioxidant supplementation. Module AOX restored the postoperative decrease in selenium levels. The rapid decrease in LBP levels in the antioxidant group suggests a possible protective effect on gut wall integrity. Further studies are needed on the role of oxidative stress on outcome and the use of antioxidants in patients undergoing major abdominal surgery.

A European, Observational Study of Endocrine Therapy Administration in Patients With an Initial Diagnosis of Hormone Receptor-Positive Advanced Breast Cancer.

BACKGROUND: Despite guideline recommendations, reports suggest that a proportion of patients with hormone receptor (HR)-positive locally advanced or metastatic breast cancer (LA/MBC) might not receive endocrine therapy. The aims of this study were to estimate the proportion of postmenopausal patients with an initial (primary) diagnosis of HR-positive LA/MBC in Europe, and to assess the administration of endocrine treatment in these patients. MATERIALS AND METHODS: Fourteen national and regional cancer registries across Europe were invited to participate in this observational study. Six registries each provided anonymized clinical information on > 5000 postmenopausal women with breast cancer diagnosed between January 2000 and December 2014, including age at diagnosis, estrogen and/or progesterone receptor status, disease stage, and receipt of endocrine therapy. The proportion of patients with an initial diagnosis of HR-positive LA/MBC and, of these, the proportion who received endocrine therapy, was calculated. RESULTS: Registries from Belgium, England, Ireland, Norway, The Netherlands, and Munich, Germany provided data. In total, 316,680 postmenopausal women were diagnosed with breast cancer, including 244,268 with known HR status and disease stage. Of these patients, 19,002 (7.8%) had a primary diagnosis of HR-positive LA/MBC. This proportion ranged from 5.4% (N = 4484) in England to 12.7% (N = 4085) in Germany. Most of these patients (n = 14,157; 74.5%) received endocrine treatment, ranging from 55.5% (n = 445) in Norway to 88.1% (n = 443) in Belgium. CONCLUSION: These results indicate that a sizeable proportion of postmenopausal patients in Europe received a primary diagnosis of HR-positive LA/MBC, and that almost three-quarters received subsequent endocrine therapy as per guideline recommendations.

Interorgan amino acid exchange in humans: consequences for arginine and citrulline metabolism.

BACKGROUND: The liver plays a central role in amino acid metabolism. However, because of limited accessibility of the portal vein, human data on this subject are scarce. OBJECTIVE: We studied hepatic amino acid metabolism in noncirrhotic fasting patients undergoing liver surgery. DESIGN: Twenty patients undergoing hepatectomy for colorectal metastases in a normal liver were studied. Before resection, blood was sampled from a radial artery, portal vein, hepatic vein, and renal vein. Organ blood flow was measured by duplex ultrasound scan. RESULTS: The intestine consumed glutamine and released citrulline. Citrulline was taken up by the kidney. This was accompanied by renal arginine release, which supports the view that glutamine is a precursor for arginine synthesis through an intestinal-renal pathway. The liver was found to extract citrulline from this pathway at a rate that was dependent on intestinal citrulline release (P < 0.0001) and hepatic citrulline influx (P = 0.03). Fractional hepatic extractions of citrulline (8.4%) and arginine (11.5%) were not significantly different. Eighty-eight percent of arginine reaching the liver passed it unchanged. Splanchnic citrulline release could account for one-third of renal citrulline uptake. CONCLUSIONS: This is the first study of hepatic and interorgan amino acid metabolism in humans with a normal liver. The data indicate that glutamine is a precursor of ornithine, which can be converted to citrulline by the intestine; citrulline is transformed in the kidneys to arginine. Hepatic citrulline uptake limits the amount of gut-derived citrulline reaching the kidney. These findings may have implications for interventions aimed at increasing systemic arginine concentrations.

The route of administration (enteral or parenteral) affects the conversion of isotopically labeled L-[2-15N]glutamine into citrulline and arginine in humans.

BACKGROUND: Glutamine exhibits numerous beneficial effects in experimental and clinical studies. It has been suggested that these effects may be partly mediated by the conversion of glutamine into citrulline and arginine. The intestinal metabolism of glutamine appears to be crucial in this pathway. The present study was designed to establish the effect of the feeding route, enteral or parenteral, on the conversion of exogenously administered glutamine into citrulline and arginine at an organ level in humans, with a focus on gut metabolism. METHODS: Sixteen patients undergoing upper gastrointestinal surgery received an IV or enteral (EN) infusion of L-[2-(15)N]glutamine. Blood was sampled from a radial artery and from the portal and right renal vein. Amino acid concentrations and enrichments were measured, and net fluxes of [(15)N]-labeled substrates across the portal drained viscera (PDV) and kidneys were calculated from arteriovenous differences and plasma flow. RESULTS: Arterial [(15)N]glutamine enrichments were significantly lower during enteral tracer infusion (tracer-to-tracee ratio [labeled vs unlabeled substrate, TTR%] IV: 6.66 +/- 0.35 vs EN: 3.04 +/- 0.45; p < .01), reflecting first-pass intestinal metabolism of glutamine during absorption. Compared with IV administration, enteral administration of the glutamine tracer resulted in a significantly higher intestinal fractional extraction of [(15)N]glutamine (IV: 0.15 +/- 0.03 vs EN: 0.44 +/- 0.08 micromol/kg/h; p < .01). Furthermore, enteral administration of the glutamine tracer resulted in higher arterial enrichments of [(15)N]citrulline (TTR% IV: 5.52 +/- 0.44 vs EN: 8.81 +/- 1.1; p = .02), and both routes of administration generated a significant enrichment of [(15)N]arginine (TTR% IV: 1.43 +/- 0.12 vs EN: 1.68 +/- 0.18). This was accompanied by intestinal release of [(15)N]citrulline across the PDV, which was higher with enteral glutamine (IV: 0.38 +/- 0.07 vs EN: 0.72 +/- 0.11 micromol/kg/h; p = .02), and subsequent [(15)N]arginine release in both groups. CONCLUSIONS: In humans, the gut preferably takes up enterally administered glutamine compared with intravenously provided glutamine. The route of administration, enteral or IV, affects the quantitative conversion of glutamine into citrulline and subsequent renal arginine synthesis in humans.

Effects of preoperative flavonoid supplementation on different organ functions in rats.

BACKGROUND: Previously it has been reported that preoperative feeding preserves heart function in rats after intestinal ischemia-reperfusion. To further improve postoperative organ function, bioactive nutrition compounds were selected in vitro against the xanthine oxidase radical cascade, an enzyme suggested to play a key role in the induction of single- or multiple-organ dysfunction. METHODS: Flavonoids were selected in vitro for their capacity to (1) inhibit xanthine oxidase, (2) scavenge superoxide, and (3) scavenge peroxylradicals. The most bioactive flavonoids were added to the preoperative nutrition to study their effect on postintestinal ischemia-reperfusion organ function. RESULTS: A combination of flavonoids selected on basis of effective flavonoid xanthine oxidase inhibition and superoxide scavenging resulted in increased superoxide scavenging. In vivo, the selected flavonoid mixture significantly lowered postischemic intestinal apoptosis and intestinal oxidative stress indicated by malondialdehyde concentration when compared with ischemia-reperfusion fasted and sham-fasted animals. Moreover, this flavonoid mixture significantly lowered plasma creatinine and urea concentration, both indicating a better postoperative kidney function. Furthermore, oxidative stress measured as this flavonoid mixture when compared with control significantly lowered plasma malondialdehyde concentration in fed rats. CONCLUSIONS: Coadministration of bioactive flavonoid mixture to preoperative nutrition, in contrast to fasting, attenuates ischemia-reperfusion injury by preserving kidney function in the rat and decreasing apoptosis in the intestine.

Preoperative feeding preserves heart function and decreases oxidative injury in rats.

OBJECTIVE: The nutritional status of a patient has been implicated as an important factor in the development of postoperative complications. Fasting before an operation may have detrimental effects on the metabolic state. We hypothesized that there was a positive correlation between preoperative nutritional status and postoperative organ function. METHODS: Preoperative feeding was compared with fasting with respect to effects on organ function and biochemical parameters in an animal model of extensive large abdominal surgery. Male Wistar rats were fed ad libitum or fasted for 16 h, after which the arteria mesenterica superior was clamped for 60 min followed by 180 min of reperfusion. RESULTS: After the ischemic period, heart function was significantly better in animals that were fed ad libitum than in fasted animals. Moreover, after intestinal ischemia and reperfusion, fed rats showed significantly higher levels of intestinal adenosine triphosphate and a significantly higher malondialdehyde concentration in the intestine and lung than did fasted rats. The ratio of adenosine triphosphate to adenosine diphosphate in the liver, an indicator of energy status, in fed rats was similar to that in a sham group, whereas fasted animals showed a significantly lower value. CONCLUSIONS: Preoperative nutrition in contrast to fasting may attenuate ischemia/reperfusion-induced injury and preserve organ function in the rat.

The role of Kupffer cells after major liver surgery.

BACKGROUND: Kupffer cells (KCs) are the resident macrophages of the liver. KCs have an enormous endotoxin eliminating capacity. Endotoxins play an important role in the development of systemic complications after partial hepatectomy by activating KCs. The role of KCs and endotoxins after partial hepatectomy is investigated. METHODS: Wistar rats (n = 16, 250-275 g) were randomly assigned to have 1 mL dichloromethylene-diphosphonate (CL2MDP) or 1 mL NaCl 0.9% i.v. Forty-eight hours later, all rats received a two-thirds liver resection. Twenty-four hours later, rats received at random 50 microg/kg endotoxin (LPS) in 1 mL or 1 mL of NaCl 0.9% IV. The rats were killed 4 hours after LPS or SAL infusion. RESULTS: CL2MDP infusion resulted in a complete KC elimination. KC-depleted rats had the lowest mean arterial pressure, the highest heart and ventilatory rate after endotoxemia. All rats were able to maintain pH in normal ranges. The KC-depleted rats after partial hepatectomy had the lowest CO2 levels and the highest levels of lactate during endotoxemia. Oxygen levels were similar in all groups. Hepatic, pulmonary, and renal mRNA expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta were decreased in KC-depleted rats. Plasma levels of TNF-alpha were significantly decreased in KC-depleted rats. Furthermore, the highest influx of macrophages and polymorphonuclear cells in the lung and kidney were measured in KC-depleted rats during endotoxemia. CONCLUSIONS: Partial hepatectomy in KC-depleted rats result in a more pronounced endotoxin-mediated systemic inflammation and decreased synthesis of cytokines.

Colorectal cancer.

Colorectal cancer had a low incidence several decades ago. However, it has become a predominant cancer and now accounts for approximately 10% of cancer-related mortality in western countries. The 'rise' of colorectal cancer in developed countries can be attributed to the increasingly ageing population, unfavourable modern dietary habits and an increase in risk factors, such as smoking, low physical exercise and obesity. New treatments for primary and metastatic colorectal cancer have emerged, providing additional options for patients; these treatments include laparoscopic surgery for primary disease, more-aggressive resection of metastatic disease (such as liver and pulmonary metastases), radiotherapy for rectal cancer, and neoadjuvant and palliative chemotherapies. However, these new treatment options have had limited impact on cure rates and long-term survival. For these reasons, and the recognition that colorectal cancer is long preceded by a polypoid precursor, screening programmes have gained momentum. This Primer provides an overview of the current state of the art of knowledge on the epidemiology and mechanisms of colorectal cancer, as well as on diagnosis and treatment.

Variations in compliance to quality indicators by age for 41,871 breast cancer patients across Europe: a European Society of Breast Cancer Specialists database analysis.

OBJECTIVE: The aim of this study is to assess age-specific compliance to quality indicators (QIs) regarding the treatment of breast cancer as defined by European Society of Breast Cancer Specialists (EUSOMA) for patients across Europe. METHODS: All patients entered into this study were affected by in situ or invasive breast cancer, diagnosed and treated between 2003 and 2012 at 27 Breast Units across Europe, who were entered into the EUSOMA database. Patients were categorised according to age; compliance to thirteen QIs was assessed for each age group and per time period (2003-2007 and 2008-2012). Compliance to QIs was tested by multivariable logistic regression models adjusted for breast unit, incidence year and tumour characteristics. RESULTS: Overall, 41,871 patients with a mean age of 59.6years were available for analysis. The highest compliance was reached for patients aged 55-64years and in the time period 2008-2012, whilst the lowest compliance was observed for women aged over 74 or under 40years and in the earlier time period. In multivariable logistic regression models, a significant difference between age categories was shown for 12 out of 13 QIs (P<0.001). Compliance to the QIs for patients aged ⩾75years was significantly lower when compared to patients aged 55-64years for ten QIs, whilst for patients in the youngest age group this was true for seven QIs. CONCLUSION: In conclusion, we found that among the 27 included breast units across Europe, compliance to QIs for breast cancer treatment is often lower in the youngest and oldest breast cancer patients, with a tendency to overtreatment in the youngest patients, and to under-treatment in the elderly.

Treatment strategies and survival of older breast cancer patients - an international comparison between the Netherlands and Ireland.

OBJECTIVES: Forty percent of breast cancers occur among older patients. Unfortunately, there is a lack of evidence for treatment guidelines for older breast cancer patients. The aim of this study is to compare treatment strategy and relative survival for operable breast cancer in the elderly between The Netherlands and Ireland. MATERIAL AND METHODS: From the Dutch and Irish national cancer registries, women aged ≥65 years with non-metastatic breast cancer were included (2001-2009). Proportions of patients receiving guideline-adherent locoregional treatment, endocrine therapy, and chemotherapy were calculated and compared between the countries by stage. Secondly, 5-year relative survival was calculated by stage and compared between countries. RESULTS: Overall, 41,055 patients from The Netherlands and 5,826 patients from Ireland were included. Overall, more patients received guideline-adherent locoregional treatment in The Netherlands, overall (80% vs. 68%, adjusted p<0.001), stage I (83% vs. 65%, p<0.001), stage II (80% vs. 74%, p<0.001) and stage III (74% vs. 57%, P<0.001) disease. On the other hand, more systemic treatment was provided in Ireland, where endocrine therapy was prescribed to 92% of hormone receptor-positive patients, compared to 59% in The Netherlands. In The Netherlands, only 6% received chemotherapy, as compared 24% in Ireland. But relative survival was poorer in Ireland (5 years relative survival 89% vs. 83%), especially in stage II (87% vs. 85%) and stage III (61% vs. 58%) patients. CONCLUSION: Treatment for older breast cancer patients differed significantly on all treatment modalities between The Netherlands and Ireland. More locoregional treatment was provided in The Netherlands, and more systemic therapy was provided in Ireland. Relative survival for Irish patients was worse than for their Dutch counterparts. This finding should be a strong recommendation to study breast cancer treatment and survival internationally, with the ultimate goal to equalize the survival rates for breast cancer patients across Europe.

Plasma taurine concentrations increase after enteral glutamine supplementation in trauma patients and stressed rats.

BACKGROUND: Taurine is a unique amino acid with antioxidant and osmolytic properties. Glutamine serves as the preferred fuel for the gut, liver, and immune cells and as a precursor for antioxidants. Trauma patients have low glutamine concentrations. OBJECTIVES: We investigated the effect of glutamine-enriched enteral nutrition on plasma taurine concentrations in patients with severe trauma (injury severity score >20). Additionally, plasma taurine concentrations and organ fluxes were studied in a stressed rat model. DESIGN: Twenty-nine patients with multiple trauma received glutamine-enriched nutrition and 31 patients received isocaloric, isonitrogenous control solution for 5 d. Plasma taurine and glutamine concentrations were measured. Male Wistar rats (250-300 g) received a glutamine-enriched diet (12%, by wt) or a control solution for 2 wk. Plasma taurine concentrations were measured. Taurine fluxes and fractional extraction rates in the liver, kidneys, and gut were assessed with a radioactive microsphere technique. RESULTS: Both patient groups had low taurine concentrations on day 1. From day 3 onward, the glutamine-fed patients had significantly higher taurine concentrations. Rats fed a glutamine-enriched diet had significantly higher plasma taurine concentrations than did the controls. A high taurine uptake was found in the liver, kidneys, and gut of the glutamine-fed rats. Fractional extraction rates were not significantly different between the rat groups. CONCLUSIONS: Glutamine enrichment increases plasma taurine in trauma patients and in stressed rats. Because of increased availability, organ fluxes showed a higher taurine uptake in the liver, kidneys, and gut. The reduction in morbidity with glutamine enrichment could be explained in part by increased taurine availability.

Kupffer cell-depleted rats have a diminished acute-phase response following major liver resection.

Partial hepatectomy (PH)-induced Kupffer cell (KC) activation results in a rapid release of cytokines inducing the acute-phase response (APR). This study was done to evaluate the role of Kupffer cells (KCs) in the course of the APR following PH and a consecutive endotoxin challenge. KC depletion was performed in rats by i.v. administration of 1 mL liposome-encapsulated dichloromethylene diphosohonate (Cl2MDP). Control rats received 1 mL NaCl 0.9%. Forty-eight hours later, PH was performed. At 24 h after PH, rats were randomized to receive either 1 mL NaCl 0.9% (saline) or 50 microg/kg LPS i.v. in 1 mL. Animals were sacrificed at 4 h after LPS or saline infusion. The APR was determined by measuring hepatic gene expression of alpha 2-macroglobulin, alpha 1-acid glycoprotein, and IL-6 and expression of hepatic albumin. The APR was significantly depressed in KC-depleted rats. Despite increased IL-6 mRNA synthesis in response to low-dose LPS, no enhancement of acute-phase protein synthesis (APP) was found in KC-depleted rats. Hepatic failure was most profound in KC-depleted rats, as indicated by elevated plasma levels of liver transaminases and ammonia. We conclude that after PH, KC function in the remnant liver is important for the acute-phase reaction and reduces endotoxin-induced hepatocyte damage.

Glutamine-enriched enteral nutrition increases in vitro interferon-gamma production but does not influence the in vivo specific antibody response to KLH after severe trauma. A prospective, double blind, randomized clinical study.

BACKGROUND & AIMS: Severe trauma leads to an immune suppression, characterized by a Type 2 T-lymphocyte response, contributing to the susceptibility of infectious complications. Plasma concentrations of glutamine (GLN), the preferred fuel for immunocompetent cells, severely decrease after trauma. Since administering glutamine-enriched enteral nutrition (EN) reduces infectious complications in trauma patients, we compared the effect of glutamine-enriched EN with an isocaloric, isonitrogenous enteral control (Con) feeding, on the Type 1 and 2 T-lymphocyte responses. METHODS: Thirty-eight trauma patients (Injury Severity Score >20) were sensitized with Keyhole Limpet Hemocyanin (KLH) within 12 h after trauma (17 GLN group). Healthy volunteers served as controls (HV, n=17). In vitro interferon-gamma (IFN-gamma), IL-4 and IL-10 productions of phytohemagglutinin (PHA)-stimulated PBMCs were determined by ELISA technique. KLH-specific IgG, IgM, IgA, IgG1, IgG2, IgG3, IgG4 and IgE were measured in serum. RESULTS: Both patient groups had a low in vitro (IFN-) production of stimulated PBMCs on d1. On d14, the IFN-gamma production increased significantly in the glutamine group as compared to the controls. IL-4 production was not different between the groups on day 1 (d1). On d14, IL-4 decreased in the control group as compared to the glutamine group. KLH-specific antibodies reached comparable levels in both patients groups and healthy volunteers at d14. CONCLUSIONS: In conclusion, trauma caused a suppressed in vitro cellular immune response presented by a low IFN-gamma production and depressed the IgG and IgM response to KLH directly after trauma. Glutamine increased IFN-gamma production (d14), maintained a normal IL-4 production, but was not acquired for the development of KLH-specific humoral response on d14, in sync suggesting that dietary glutamine supports the restoration of the Type-1 T-lymphocyte responsiveness.

EURECCA consensus conference highlights about rectal cancer clinical management: the radiation oncologist's expert review.

BACKGROUND AND PURPOSE: Although rectal and colon cancer management has progressed greatly in the last few decades clinical outcomes still need to be optimized. Furthermore, consensus is required on several issues as some of the main international guidelines provide different recommendations. The European Registration of Cancer Care (EURECCA) drew up documents to standardize management and care in Europe and aid in decision-making. MATERIAL AND METHODS: In the present section the panel of experts reviews and discusses data from the literature on rectal cancer, focusing on recommendations for selecting between short-course radiotherapy (SCRT) and long-course radio-chemotherapy (LCRTCT) as preoperative treatment as well as on the controversies about adjuvant treatment in patients who had received a pre-operative treatment. RESULTS: The starting-point of the present EURECCA document is that adding SCRT or LCRTCT to TME improved loco-regional control but did not increase overall survival in any single trial which, in any case, had improved with the introduction of total mesorectal excision (TME) into clinical practice. Moderate consensus was achieved for cT3 anyNM0 disease. In this frame, agreement was reached on either SCRT followed by immediate surgery or LCRTCT with delayed surgery for mesorectal fascia (MRF) negative tumors at presentation. LCRTCT was recommended for tumor shrinkage in MRF+ at presentations but if patients were not candidates for chemotherapy, SCRT with delayed surgery is an option/alternative. LCRTCT was recommended for cT4 anycNM0. SCRT offers the advantages of less acute toxicity and lower costs, and LCRTCT tumor shrinkage and down-staging, with 13-36% pathological complete response (pCR) rates. To improve the efficacy of preoperative treatment both SCRT and LCRTCT have been, or are being, associated with diverse schedules of chemotherapy and even new targeted therapies but without any definitive evidence of benefit. Nowadays, standard treatment is fluoropyrimidine alone since alternative agents and regimens have not been shown to be more active, only more toxic. CONCLUSIONS: The EURECCA panel summarized available evidence in an attempt to reduce variance in rectal cancer management. This is expected to benefit patients. Results from ongoing randomized trials will help clarify some of the issues that are still under debate.

Involving patients in a multidisciplinary European consensus process and in the development of a 'patient summary of the consensus document for colon and rectal cancer care'.

CONTEXT: High-quality cancer care should be accessible for patients and healthcare professionals. Involvement of patients as partners in guideline formation and consensus processes is still rarely found. EURECCA, short for European Registration of Cancer Care, is the platform to improve outcomes of cancer care by reducing variation in the diagnostic and treatment process. EURECCA acknowledges the important role of patients in implementation of consensus information in clinical practice. OBJECTIVE: The aim of this article is to describe the process of involving patients in the consensus process and in developing the patient summary of the consensus for colon and rectal cancer care. METHODS: The Delphi method for achieving consensus was used. Three online voting rounds and one tele-voting round were offered to an expert panel of oncology professionals and patient representatives. At four different stages, patients and/or patient representatives were involved in the process: (1) during the consensus process, (2) lecturing about the role of the patient, (3) development of the patient summary, and (4) testing the patient summary. RESULTS: Representatives were invited to the voting and commenting rounds of this process and given an equal vote. Although patients were not consulted during the planning stages of this process, patient involvement increased following the panel's discussion of the implementation of the consensus among the patient population. After the consensus meeting, the patient summary was written by patient representatives, oncologists and nurses. A selection of proactive patients reviewed the draft patient summary; responses were positive and several patient-reported outcomes were added. Questionnaires to evaluate the use and implementation of the patient summary in daily practice are currently being developed and tested. Patient consultation will be needed in future planning for selection of topics. DISCUSSION: The present study may function as a model for future consensus processes to involve patients at different stages and to implement both patient and healthcare professional versions in daily practice.