Cytokines, the acute-phase response, and resting energy expenditure in cachectic patients with pancreatic cancer.

OBJECTIVE: To determine whether resting energy expenditure (REE) is increased in cachectic patients with pancreatic cancer and to define the relation of tumor necrosis factor (TNF) and interleukin-6 (IL-6) production to the acute-phase response and to REE. METHODS: Measurement of REE (indirect calorimetry) and assessment of body composition (bioelectrical impedance analysis) were done in 21 patients with unresectable pancreatic cancer and on 16 age-related controls. The systemic inflammatory response in peripheral blood of the cancer patients was assessed using the acute-phase protein, C-reactive protein, and the cytokines TNF and IL-6. Production of these cytokines by peripheral blood mononuclear cells in vitro was also measured. RESULTS: Patients with pancreatic cancer had an elevated REE when compared with controls (73.4 +/- 5.0 vs. 53.5 +/- 1.6 kcal/kg body cell mass; p < 0.003). Resting energy expenditure was significantly greater in cancer patients with an acute-phase response (C-reactive protein > 10 mg/L) than in those who did not have such a response (85.5 +/- 10.0 [n = 9] vs. 64.3 +/- 3.0 [n = 12] kcal/kg body cell mass; p < 0.04). Tumor necrosis factor was not detected in the serum of any of the cancer patients. Serum IL-6 was detected but levels were not significantly different among cancer patients with or without an acute-phase response. In contrast, spontaneous production of TNF and IL-6 by isolated peripheral blood mononuclear cells was significantly greater in cancer patients with an acute-phase response that in those without (TNF: 1231 +/- 244 vs. 210 +/- 54 pg/ml/10(5) cells; p < 0.001; IL-6: 11.5 +/- 1.7 vs. 3.6 +/- 1.4 ng/mL/10(5) cells; p < 0.003). CONCLUSIONS: In pancreatic cancer at least a component of weight loss is due to increased REE. Furthermore, the presence of an acute-phase response identifies a group of patients who are markedly hypermetabolic. The serum concentration of TNF of IL-6 does not correlate with the presence of an acute-phase response, whereas rates of cytokine production by peripheral blood mononuclear cells are significantly greater in patients with such a response. This suggests that local rather than systemic cytokine production may be important in regulating the acute-phase response.     

Elevated circulating interleukin-6 is associated with an acute-phase response but reduced fixed hepatic protein synthesis in patients with cancer.

It has been suggested that, as part of the inflammatory response to the presence of a tumor, various cytokines are produced and these induce hepatic synthesis of acute-phase proteins (APP). Under these circumstances it is not known what changes occur in the fixed component of hepatic protein synthesis. The aim of this study was to compare circulating interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) concentrations and fixed hepatic protein synthesis rates in a group of healthy controls (n = 6) with a group of patients with an established APP response secondary to hepatic metastasis from colorectal cancer (n = 6). Fixed hepatic protein synthesis rates were measured following a primed, constant 20-hour infusion of 15N-glycine. The liver was biopsied at laparotomy. The APP response was assessed by serum C-reactive protein concentration and cytokines were assayed by a combination of immunoassay and bioassay. The patients with advanced cancer and an on-going APP response had elevated circulating IL-6 concentrations (p less than 0.01). Rates of fixed hepatic protein synthesis were 30% lower than those observed in controls (p less than 0.01). These findings demonstrate that in patients with hepatic metastasis, although the synthesis of certain acute-phase export proteins can be increased, fixed protein synthesis is reduced. Whether these changes in the distribution of hepatic protein synthesis are mediated by IL-6 will require further investigation.     

Role of carnitine in modulating acute-phase protein synthesis in hemodialysis patients.

Increased serum levels of C-reactive protein (CRP) in uremic and dialysis patients are associated with low serum prealbumin and albumin concentrations and increased mortality and greater risk of cardiovascular disease. Proinflammatory cytokines may cause malnutrition by increasing protein catabolism. Many studies have shown that L-carnitine supplementation leads to improvements in several conditions seen in uremic patients, including cardiac complications, impaired exercise and functional capacities, muscle symptoms, increased symptomatic intradialytic hypotension, and erythropoietin-resistant anemia. L-carnitine therapy may either suppress the inflammatory response or act independently on both inflammation and appetite and/or anabolic processes. Moreover, L-carnitine may suppress proinflammatory cytokines in sick individuals without renal disease and may improve protein synthesis or nitrogen balance in patients without renal disease and in hemodialysis and peritoneal dialysis patients. In a pilot study, we provided preliminary evidence that treatment with L-carnitine, 20 mg/kg 3 times weekly at the end of each hemodialysis treatment, was associated with a reduction in serum CRP levels and improvement in anabolic status. The improvement or normalization of serum concentrations of serum CRP also was correlated with increased serum concentrations of albumin, transferrin, and blood hemoglobin. The possibility that some or all of these changes may have been caused by improved nutritional intake cannot be ruled out. Further randomized clinical trials will be necessary to confirm the role of L-carnitine as a modulator of inflammatory protein synthesis in hemodialysis patients.     

Dietary protein intake does not affect IgG synthesis in patients with nephrotic syndrome.

BACKGROUND: Low plasma IgG levels have long been reported as an important complication of the nephrotic syndrome. Few studies in vivo have evaluated IgG synthesis in nephrotic patients and no data are available on the effect of dietary protein restriction on the rate of IgG synthesis. METHODS: We compared the IgG synthesis rates of seven nephrotic patients who assumed, for 4 weeks, either a normal protein diet (NPD) (1.20+/-0.06 g/kg/day) or a low-protein diet (LPD) (0.66+/-0.04 g/kg/day) with those of seven normal subjects (matched for age and body mass index). The post-absorptive fractional synthesis rate (FSR) and absolute synthesis rate (ASR) of IgG were evaluated during the last 120 min of a 5 h 5,5,5-D3-l-leucine infusion. RESULTS: Compared with controls, in nephrotic patients the plasma IgG levels and pool were significantly reduced (P<0.05), while IgG FSR and ASR were increased by 4- and 2.5-fold, respectively (P<0.05). The LPD regimen did not affect plasma IgG FSR, ASR, circulating concentrations and intravascular pool (P = NS). There was a significant negative correlation between plasma IgG FSR and the IgG intravascular pool in nephrotic patients evaluated during both the NPD (r = -0.828; P<0.05) and LPD (r = -0.861; P<0.05) regimens. CONCLUSIONS: Nephrotic syndrome patients with low plasma IgG levels have increased IgG FSR and ASR which are not affected by reduced dietary protein intake.     

Sepsis score and acute-phase protein response as predictors of outcome in septic surgical patients

In a series of 135 patients with severe surgical infections, we determined the sepsis score and the plasma level of the acute-phase proteins alpha-1-acid glycoprotein, alpha 1-antitrypsin, complement factor B, and C3. The initial sepsis score was a strong determinant of survival: in survivors it was significantly lower than in nonsurvivors. Only 8% of patients with a sepsis score above 20 survived. At the onset of severe sepsis, the plasma levels of all four acute-phase proteins were significantly lower in nonsurvivors. A significant elevation of C3a levels in the plasma of both surviving and nonsurviving patients indicated marked consumption of complement components in all patients with severe sepsis. A linear equation was developed to predict survival: sepsis index of survival (SIS) % = 121 + 0.26 (complement factor B) + 0.36 (alpha-1-acid glycoprotein)-6 (sepsis score). Based on our analysis, at the onset of severe sepsis, an SIS of 50% or more can correctly predict 88% of survivors and an SIS less than 50% can correctly predict 86% of nonsurvivors several days in advance of clinical outcome.     

Influence of hypercortisolemia on the acute-phase protein response to endotoxin in humans.

BACKGROUND. The response to systemic infection includes the coordinated appearance of hepatic acute-phase proteins, the production of which may be influenced by a counterregulatory hormonal background. This study sought to assess the potential for hypercortisolemic conditions to influence fibrinogen kinetics and other acute-phase protein responses in humans with endotoxemia. METHODS. Eleven hospitalized healthy male volunteers underwent two separate determinations of fibrinogen kinetics, one baseline and one after administration of endotoxin (2 ng/kg intravenously; lot EC-5). Seven volunteers were studied without hormonal manipulation and four in the presence of a hypercortisolemic background (hydrocortisone infusion, 3 micrograms/kg/min). Fibrinogen fractional synthetic rates were estimated from the incorporation of orally administered 15N-glycine, and fibrinogen, C-reactive protein, cortisol, tumor necrosis factor-alpha, and interleukin-6 levels were also determined. RESULTS. The presence of an antecedent hypercortisolemic background resulted in an attenuated interleukin-6 response, as well as decreased fibrinogen synthesis and C-reactive protein appearance. CONCLUSIONS. The current data suggest that glucocorticoid hormonal influences are of importance in the regulation of endotoxin-induced cytokine and acute-phase protein responses.     

Postoperative antibiotics are not associated with decreased wound complications among patients undergoing appendectomy for complicated appendicitis

Background

The objective of this study was to determine the role of postoperative antibiotics in reducing complications in patients undergoing appendectomy for complicated appendicitis.

Methods

We performed a 5-year retrospective cohort study of adult patients who underwent appendectomy for acute appendicitis. Patients with complicated appendicitis (perforated or gangrenous) were analyzed on the basis of whether they received postoperative antibiotics. Main outcome measures were wound complications, length of stay (LOS), and readmission to hospital.

Results

Of 410 patients with complicated appendicitis, postoperative antibiotics were administered to 274 patients (66.8%). On univariate and multivariate analyses, postoperative antibiotics were not associated with decreased wound complications or readmission, but independently predicted an increased LOS (P = .01).

Conclusions

Among patients with complicated appendicitis, postoperative antibiotics were not associated with a decrease in wound complications but did result in an increased hospital LOS.     

Amylin fasting plasma levels are decreased in patients with osteoporosis

Amylin is a polypeptide hormone produced in pancreatic beta-cells that belongs to the family of calcitonin gene-related peptides. There is a 20% sequence homology between amylin and calcitonin and 44% homology with calcitonin gene-related peptide. Amylin and its fragments stimulate the proliferation of osteoblasts, inhibit bone resorption, and increase bone density and the amount of bone mass. We measured amylin total and unreduced amylin fasting plasma levels in patients with osteoporosis (n=28; 3 men, 25 women; mean age 65 years), type 2 diabetes mellitus (n=10; 5 men, 5 women; 64 years), and in the control group (n=24; 11 men, 13 women; 53 years) using an ELISA kit with immunofluorescent detection (Linco). Amylin total plasma levels in patients with osteoporosis were 3.33±0.46 pmol/l (mean±SEM), in patients with type 2 diabetes 6.29±1.47 pmol/l (mean±SEM), and in the control group 8.48±3.12 pmol/l (mean±SEM). Mean plasma levels were lower in patients with osteoporosis than in patients with type 2 diabetes and in the control group. Unreduced amylin plasma levels in patients with osteoporosis (n=28) were 2.51±0.87 pmol/l (mean±SEM), in patients with type 2 diabetes (n=10) 4.15±0.95 pmol/l (mean±SEM) and in the control group (n=5) 13.50±3.94 pmol/l (mean±SEM). Plasma levels were significantly lower in patients with osteoporosis than in patients with type 2 diabetes (P<0.01) and in the control group (P<0.001). Amylin plasma levels are decreased in patients with osteoporosis. Amylin deficiency in these patients may contribute to the development of osteoporosis. Amylin should be investigated in relation to the pharmacological treatment of osteoporosis.     

Liver nonparenchymal cells are stimulated to provide interleukin 6 for induction of the hepatic acute-phase response in endotoxemia but not in remote localized inflammation.

It has been postulated that Kupffer cells provide signals that regulate hepatocyte responses in sepsis and inflammation. Although in vitro data support such a hypothesis, to our knowledge, no in vivo evidence has been reported. We injected rats with lipopolysaccharide intraperitoneally to simulate sepsis or turpentine intramuscularly to mimic localized inflammation. Both treatments are known to induce the hepatic acute-phase response. Liver nonparenchymal cells and hepatocytes were isolated and placed in culture. Hepatocyte fibrinogen synthesis was measured as an indication of interleukin 6 exposure, while nonparenchymal interleukin 6 production was measured directly. Both lipopolysaccharide and turpentine stimulated a sharp increase in hepatocyte fibrinogen synthesis (turpentine greater than lipopolysaccharide). However, only lipopolysaccharide injection was associated with increased nonparenchymal cell interleukin 6 synthesis. Increased circulating levels of interleukin 6 could be found only after lipopolysaccharide injection. In addition, tumor necrosis factor synthesis was enhanced by lipopolysaccharide but not turpentine. Our data show that nonparenchymal cells are stimulated to provide the interleukin 6 signal to hepatocytes in endotoxemia but not in remote localized inflammation, even though both treatments stimulate the hepatic acute-phase response. Our findings support paracrine functions for liver sinusoidal cells in certain septic states.     

Improving survival rates for patients with colorectal cancer.

Between 1 January 1984 and 31 December 1990, 575 patients were operated on for colorectal cancer. The surgical procedure was performed consistently and no patients were lost to follow-up. Almost half of the patients (284 of 575) had tumours of stage I or II, with 5-year survival rates over 90 per cent. After extending the resection margins in 28 cases of colonic carcinoma there has been no case of tumour recurrence. The overall 5-year survival rate for patients with colonic carcinoma was 81 per cent. Complete resection of the mesorectum was mandatory for rectal resection. One-third of the carcinomas in the lower third of the rectum could be resected with maintenance of bowel continuity and an abdominoperineal resection avoided. Not only was the tumour recurrence rate in the former patients lower (10.5 per cent) compared with that in those undergoing abdominoperineal resection (14.3 per cent) but the 5-year survival rate at 90 versus 52 per cent was significantly higher. The overall 5-year survival rate for patients with rectal carcinoma was 71 per cent.     

Decreased angiotensin II receptors mediate decreased vascular response in hepatocellular cancer.

OBJECTIVE: The authors' objective was to determine the origin of the diminished pressor responsiveness of angiotensin II infusion in hepatoma by evaluating angiotensin II receptor status in normal liver, hepatoma tumor, and cultured hepatocytes and H4IIE cells. SUMMARY BACKGROUND DATA: Hepatocellular cancer is a highly vascular tumor, where the neovasculature is unique in that it arises only from the hepatic arterial circulation, whereas normal liver has both hepatic arterial and portal venous blood supply. The tumor neovasculature is also characterized by an abnormal vascular reactivity to vasoconstrictors, including the response to angiotensin II. The altered response of tumor vasculature to angiotensin II offers a potential therapeutic opportunity for modulation of tumor blood flow. However, the origin of the decreased vascular response is unknown. METHODS: The authors evaluated the hepatic vascular response to angiotensin II infusion by determining hepatic arterial blood flow to normal liver and to tumor by means of radioactive microspheres. The angiotensin II receptor status in the normal liver, hepatoma tumor, and cultured hepatocytes and H4IIE cells was determined br radioligand binding analysis and in cryostat sections derived from normal liver and hepatoma tumor by means of in situ binding analysis with biotinylated angiotensin II. RESULTS: Angiotensin II infusion decreased the hepatic arterial flow to normal liver and increased hepatoma to liver flow ratio. The number of angiotensin II receptors in normal liver was significantly higher than that in hepatoma (239 +/- 20 fmol/mg protein in normal liver vs. 162 +/- 15 fmol/mg protein in hepatoma) without a change in the affinity (4.4 +/- 0.8 nM in normal liver vs. 4.7 +/- 1.2 nM in hepatoma). H4IIE cells and primary hepatocytes had low receptor density. In situ binding analysis revealed that angiotensin II receptors were mainly on the smooth muscle cells of the neovasculature. CONCLUSIONS: The data suggests that the diminished vascular response to angiotensin II hepatoma may relate a loss of angiotensin II receptor on tumor neovasculature.     

Urinary protein binding does not affect response to furosemide in patients with nephrotic syndrome

Response to loop diuretics in patients with nephrotic syndrome (NS) is subnormal. Studies in animal models of NS have suggested that binding of diuretic to urinary albumin is one of the mechanisms that may be operative in this diuretic resistance. To explore this hypothesis, 12 patients with NS were studied to determine whether displacement from urinary protein binding with sulfisoxazole would restore response to 120 mg of furosemide. The study was stopped after treating seven patients because it was clear that sulfizoxazole had no effect. Sodium excretion (mean +/- SD) from furosemide alone was 239 +/- 90 versus 240 +/- 115 mEq/8 h with sulfisoxazole. Sulfisoxazole had modest effects on serum pharmacokinetics of furosemide but had no effect on either the time course of furosemide urinary excretion or overall amount excreted: 49 +/- 15 mg versus 54 +/- 12 mg for furosemide alone and furosemide plus sulfisoxazole, respectively. It is concluded that urinary protein binding of loop diuretics is not a major mechanism for the diuretic resistance of NS. In turn, strategies aimed at displacing such binding are unlikely to be clinically helpful.     

Extra protein loss not caused by surgical bleeding in patients with ovarian cancer

Backround : Clinical experience in patients with ovarian cancer has shown special difficulties in maintaining cardiovascular stability during surgery.
Methods : To evaluate the causes for this observation, 15 patients with benign ovarian tumours (group I) and 13 patients with ovarian cancer (group II) were investigated perioperatively. Plasma volume (indocyanine green-dilution technique), hae-matocrit, plasma protein concentration, mean arterial pressure, heart rate, and central venous pressure were measured immediately before and after cytoreductive surgery.
Results : Normal values of blood-, plasma-, and red cell volume were determined preoperatively in both groups, and in relation to body surface area there were no intergroup differences of these parameters. In group I, the significant decrease in red cell volume of 313 ml postoperatively was compensated for by an increase in plasma volume of 371 ml (median values). In contrast to group I, the decrease in red cell volume of 328 ml in group II was not related to a significant increase in plasma volume, so that blood volume postoperatively was 483 ml lower than preoperatively, although the same standardized infusion regimen as in group I was applied. Patients of group II had a significantly higher loss of intravascular protein (49 g vs 13 g in group I), which left the intravascular space by another way than by surgical bleeding. This extra protein loss is termed Intraoperative Protein Shift (IPS).
Conclusion : IPS could be an important quantity in perioperative fluid balance. We assume that different surgical procedures predispose to occurrence of differing amounts of IPS.     

MMP-2 and TIMP-1 are derived from, not in response to, pancreatic cancer.

INTRODUCTION: Genetic therapy aimed at disturbing the balance between matrix metalloproteinases (MMP) and their natural tissue inhibitors (TIMP) in treatment of pancreatic cancer requires an understanding of whether MMP and TIMP are tumor- or host-derived. This study was undertaken to determine whether production of MMP-2 and TIMP-1 is by, or in response to, pancreatic cancer. METHODS: PANC-1 (poorly differentiated human pancreatic cancer) or CD-1 (PANC cells transfected to overproduce TIMP-1) cells were implanted into the pancreata of 20 nude mice. After sacrifice, tumors and peritumoral stroma underwent immunohistochemical staining for human and murine MMP-2 and TIMP-1. Normal murine pancreas served as control. All stains were reviewed in a "blinded" manner by a pathologist and graded relative to normal control pancreata. RESULTS: Control pancreata displayed faint murine MMP-2 and TIMP-1 staining and no human MMP-2 or TIMP-1. MMP-2 was most prominent in peritumoral stroma, while TIMP-1 was most prominent in tumors. CD-1 tumors contained very high levels of TIMP-1 compared to PANC-1 tumors and control pancreata. Tumoral and peritumoral MMP-2 were overwhelmingly human. As well, tumoral TIMP-1 was predominantly human. CONCLUSIONS: In a murine model for human pancreatic cancer, nearly all TIMP-1 and MMP-2 expression is tumor-derived (i.e., human). Pharmacologic and gene therapy aimed at disturbing the MMP/TIMP balance in pancreatic cancer should be targeted toward tumor-specific mechanisms and warrants continued investigation.     

Patella fractures are not associated with an increased risk of mortality in elderly patients

IntroductionThe modern literature includes only limited information regarding mortality rates and cumulative survival following patella fractures. The aim was to report the 30-day, six-month, and one-year mortality of patients with patella fractures and compare this to the mortality of a matched reference population.MethodsAll patients who sustained a patella fracture in Denmark between 1996 and 2000 were included in the study. The survival status of these patients was monitored until 2015. We compare the mortality with a ten-fold reference population matched on age and gender without a prior patella fracture.Results6096 patients were treated for 6114 patella fractures. The mean age of patients was 48.9 years. The overall mortality rates at 30 days, six months, and one year were 0.7%, 1.8%, and 2.8%. The mortality rates for patients > 65 years at 30 days, six months, and one year were 1.3%, 3.9%, and 6.2%. The mortality rates for patients at ≤ 65 years at 30 days, six months, and one year were 0.4%, 0.9%, and 1.3%. Compared to the matched reference population, the relative risk of mortality in patients > 65 years at 30 days, six months, and one year were 1.9 (95% CI 1.2–2.9), 1.0 (95% CI 0.8–1.3), and 0.9 (95% CI 0.7–1.1).ConclusionThe overall one-year mortality rate of patella fractures was 2.8% and this was increased to 6.2% in patients older than 65 years. In elderly patients above 65 years, the relative risk of death was 0.9, indicating that patella fractures in elderly patients were not associated with an increased mortality rate.     

The acute-phase response varies with time and predicts serum albumin levels in hemodialysis patients. The HEMO Study Group

BACKGROUND: Cross sectional studies have established that the serum albumin level is dependent on serum levels of acute-phase proteins (APPs) or cytokine levels in hemodialysis patients. While the acute-phase response is generally associated with acute inflammatory events, a cross sectional analysis relating laboratory values to outcomes assumes these values to be unchanging. The longitudinal relationship among laboratory measurements and how they vary over time in a population of patients are unknown. METHODS: Patients who were enrolled in the HEMO Study were recruited into an ancillary longitudinal study to establish the predictive effect of temporal variation in the levels of APPs and of temporal variation in normalized protein catabolic rate (nPCR) on the serum albumin concentration. nPCR was measured monthly using a double-pool method. The positive APPs-C-reactive protein (CRP), alpha1 acid glycoprotein (alpha1-AG), and ceruloplasmin-and the negative APP-transferrin (Trf)-were measured in serum obtained before each dialysis session for six weeks and then monthly in 37 hemodialysis patients. A random coefficient regression analysis was used to assess the association of serum albumin with other measured parameters at each time point, as well as fixed patient characteristics. RESULTS: The within-subject coefficients of variation of albumin (median, range of 25th to 75th percentiles; median, 0.0614; range, 0.0485 to 0.0690) were significantly less than that of APPs (CRP, median, 0.878; range, 0.595 to 1.314, P < 0. 05; and alpha1 AG, median, 0.173; range, 0.116 to 0.247, P < 0.05). The levels of APPs and albumin varied considerably over time. The primary predictor of current albumin was the current CRP level (P = 0.0014). nPCR also was a significant predictor for albumin levels (P = 0.0440) after controlling for the effect of APPs, suggesting an effect of nPCR on serum albumin concentration irrespective of the acute-phase response. Age and the presence of an arteriovenous graft were significant predictors that were associated with reduced albumin. CONCLUSIONS: The acute-phase response is intermittent and is not a continuous feature in individual dialysis patients. Levels of APPs are the most powerful predictors for the levels of albumin concentration in hemodialysis in a longitudinal setting. Since variations in albumin are small, measurement of variations in APPs may provide greater insight into the dynamics of clinically relevant processes.