Long-Term Results Following Antibiotic Treatment of Acute Appendicitis in Adults.

BACKGROUND: Antibiotic treatment of acute appendicitis has gained interest and inquiries. Reports have demonstrated both safety and high resolution of symptoms and inflammation following antibiotic treatment of appendicitis, but information on long-term results is required. Our present aim was therefore to evaluate long-term recurrence rate of initial antibiotics-alone treatment for suspected acute appendicitis. METHODS: Patients with favourable response to antibiotics in earlier randomized (RCT, n = 97) and population-based (PBT, n = 342) studies as well as subsequently treated non-randomized (Non-R, n = 271) patients are evaluated for long-term risk to relapse demanding surgical appendectomy; altogether 710 patients. RESULTS: Clinical characteristics among randomized and non-randomized patients were similar without any statistical difference according to abdominal symptoms and degree of systemic inflammation (CRP, WCC) when antibiotic treatment started. Females and males showed the same results. The median follow-up time was 2162 days (5.92 years), and the range across highest and lowest follow-up was 3495 days (range 2-3497) for the entire group, without significant differences among subgroups (RCT, PBT, Non-R). The cumulative probability for relapse of appendicitis demanding appendectomy was: 0.09, 0.12, 0.12 and 0.13 at 1-, 2-, 3- and 5-year follow-up, with a probability of 0.86 ± 0.013 without appendectomy after 8 years. This may imply an overall benefit of 60-70% by antibiotics during expected 10-year follow-up accounting for initial treatment failures at 10-23% in our published reports. CONCLUSION: Antibiotic treatment is safe and effective as a first-line therapy in unselected adults with acute appendicitis with a risk around 15% for long-term relapse following favourable initial treatment response.

Provision of rhIGF-I/IGFBP-3 complex attenuated development of cancer cachexia in an experimental tumor model.

UNLABELLED: Tumor growth is associated with development of cachexia which includes progressive wasting and anorexia. Our previous studies have indicated that insulin like growth factor-I (rhIGF-I) in complex with its binding protein 3 (IGFBP 3), but not free IGF-I, was a potent stimulator of muscle protein synthesis in rats with chronic undernutrition. The aim of the present study was to evaluate the effect of rhIGF-I/IGFBP-3 on the development of cancer cachexia, and to assess safety data on net tumor growth and progression during treatment. METHODS: A methylcholantrene induced sarcoma was implanted s.c. in C 57 bl mice. The animals were provided with rhIGF-I/rhIGFBP-3 (5 microg/g bw) i.v. twice daily (n= 18). Controls were provided with saline (n= 20). Body weight and food intake were registered daily. Net tumor growth was measured over 10 days. Protein synthesis in liver and muscle, as well as plasma concentrations of glucose, insulin, IGF-I and amino acids were measured at the end of the study. RESULTS: tumor size did not differ between control mice and rhIGF-I/rhIGFBP-3 treated mice (1.5 +/- 0.1 g wet tumor weight vs 1.6 +/- 0.2 g respectively). Saline treated tumor bearing controls lost 9.1 +/- 1.3 % body weight over 10 days due to rapid tumor growth while rhIGF-I/rhIGFBP-3 provision attenuated weight loss to 5.6 +/- 1.3% of body weight in study mice (P< 0.05). Food intake was improved and blood glucose concentration was reduced from 7.1 +/- 0.5 to 5.8 +/- 0.2 (P< 0.05) in response to treatment. CONCLUSION: Our results demonstrate that rhIGF-I/rhIGFBP-3 complex did not affect net tumor growth. Moreover rhIGF-I/rhIGFBP-3 complex improved tumor-host nutritional state by improving food intake, attenuating weight loss and improving glucose metabolism.

Role of insulin and IGF-I in activation of muscle protein synthesis after oral feeding.

The aim was to evaluate the role of insulin and insulin-like growth factor I (IGF-I) in activation of muscle protein synthesis after oral feeding. Synthesis rate of globular and myofibrillar proteins in muscle tissue was quantified by a flooding dose of radioactive phenylalanine. Muscle tissue expression of IGF-I mRNA was measured. Normal (C57 Bl) and diabetic mice (type I and type II) were subjected to an overnight fast (18 h) with subsequent refeeding procedures for 3 h with either oral chow intake or provision of insulin, IGF-I, glucose, and amino acids. Anti-insulin and anti-IGF-I were provided intraperitoneally before oral refeeding in some experiments. An overnight fast reduced synthesis of both globular (38 +/- 3%) and myofibrillar proteins (54 +/- 3%) in skeletal muscles, which was reversed by oral refeeding. Muscle protein synthesis, after starvation/ refeeding, was proportional and similar to changes in skeletal muscle IGF-I mRNA expression. Diabetic mice responded quantitatively similarly to starvation/refeeding in muscle protein synthesis compared with normal mice (C57 Bl). Both anti-insulin and anti-IGF-I attenuated significantly the stimulation of muscle protein synthesis in response to oral feeding, whereas exogenous provision of either insulin or IGF-I to overnight-starved and freely fed mice did not clearly stimulate protein synthesis in skeletal muscles. Our results support the suggestion that insulin and IGF-I either induce or facilitate the protein synthesis machinery in skeletal muscles rather than exerting a true stimulation of the biosynthetic process during feeding.

Effects related to indomethacin prolonged survival and decreased tumor-growth in a mouse-tumor model with cytokine dependent cancer cachexia.

Tumor-bearing mice with two different locally growing malignant tumors (epithelial like, MCG 101; malignant melanoma, K1735-M2) were used to evaluate the putative role of prostaglandins for survival and local tumor growth in experimental cancer. Daily systemic injections of indomethacin (1 mu g/g bw) were used to block prostaglandin production in normal and T-cell deficient tumor-bearing nude mice. Tumor progression was determined by measurements of tumor weight, DNA-synthesis, cell cycle kinetics in vivo and in vitro (flow cytometry), tumor tissue concentrations of polyamines (putrescine, spermidine, spermine) and tumor tissue gene expression of growth regulating factors (IL-1 alpha, IL-6, TNF alpha, A,B-PDGF, EGF, VEGF, bFGF, TGF beta(3), angiogenin and transferrin receptor). Tumor tissue content of von Willebrandt factor VIII was estimated by immunohistochemistry. Indomethacin had no effect on survival, host nutritional state or local tumor growth in mice bearing the malignant melanoma with low PGE(2) production. In contrast, indomethacin prolonged survival, improved cachexia and decreased tumor growth in mice bearing the MCG 101 tumor with hundredfold higher prostaglandin tumor production, leading to elevated liver and muscle tissue as well as plasma concentrations of PGE(2). Indomethacin inhibited almost completely the high tumor PGE(2) production in MCG tumors, leading to prolonged potential doubling time for tumor growth in vivo, and a trend to decreased tumor tissue concentration of polyamines (spermidine). Indomethacin had no inhibitory effect on tumor cell proliferation in vitro, although PGE(2) production was decreased by 75%. The effect of indomethacin in vivo was independent of T-cells and was observed with similar magnitude irrespective of the number of MCG cells (10(4)-10(6)) implanted or the site of implantation (s.c., i.p., liver, lung, skeletal muscles). Tumor growth inhibition by indomethacin was not intrinsically transferable by tumor cells from indomethacin treated tumor-animals. Tumor expression of mRNA for several growth regulating factors were either increased (IL-6, TNF alpha, GM-CSF, TGF beta(3)) unchanged (EGF, VEGF, PDGF A,B, IL-1 alpha, transferrin receptor) or decreased (b-FGF and angiogenin) (p<0.05) by indomethacin treatment of MCG mice. Decreased tumor content of von Willebrandt factor VIII in combination with an attenuated tumor vasculature were associated with decreased tumor growth (p<0.05). Our results confirm that high tumor production of prostaglandins was related to reduced survival. Tumor prostaglandins probably promote local tumor growth by stimulation of tumor surrounding cells to produce growth factor(s) for tumor angiogenesis including tumor and matrix cell proliferation unrelated to immune cells.

Isolation of radiopure plasma and hepatic albumin in acute phase conditions.

It is essential to obtain biochemically and radioactively pure albumin in studies on albumin metabolism and kinetics in stress and nutrition related conditions. However, published work on albumin metabolism, in both animals and man with acute phase reactions has usually been based on inadequate chemical methods for isolation of homogeneous albumin free from acute phase proteins and other contaminants. Applications of conventional antibody precipitating techniques was usually either not sufficient to give radiopure albumin, or did not allow determination of the true specific radioactivity during in vivo experiments. Thus, the lack of applicable methods to achieve radiopure albumin from small plasma and tissue samples for subsequent analyses and determination of the true specific radioactivity in albumin initiated the present method development. The combination of HPLC ionchromatography (DEAE-sepharose), affinity chromatography (Blue sepharose CL-6B, Con A sepharose) and HPLC based size exclusion chromatography (Protein PAK 300 SW, Waters) was applied. By this procedure we obtained radiopure albumin from both plasma and hepatic samples from individual mice with acute phase response as confirmed by two-dimensional electrophoresis and immune precipitation.

Acute-phase proteins in response to tumor growth.

This study has evaluated the relationship between tumor growth and induction of acute-phase proteins. It has also determined whether an intact cellular immunity is obligatory for a fully expressed acute-phase plasma protein response in the presence of a highly antigenic tumor. Quantitatively, acute-phase responses (protein synthesis, plasma concentrations, hepatic RNA content, anorexia) were proportional to tumor burden. Anti-inflammatory drugs (indomethacin 1 micrograms/g body wt, dexamethasone 0.5 micrograms/g body wt) had no direct effect on the attenuation of the systemic acute-phase responses, but did affect them indirectly by decreasing tumor growth. Immune suppression (cyclosporine A at 20 or 60 micrograms/g body wt) had no effect on either acute-phase reactions or local tumor growth. In endotoxin-stimulated (lipopolysaccharide) normal mice, immune suppression aggravated anorexia and caused high mortality, while dexamethasone partly reversed these effects in endotoxin-stimulated mice. Plasma levels of acute-phase proteins correlated to circulating levels of IL-6 in untreated tumor-bearing mice, but this relationship was not obvious in either drug-treated tumor-bearing or endotoxin-stimulated mice. Tumor tissue induced the synthesis of different acute-phase proteins compared to endotoxin. However, disintegrated normal liver tissue induced the synthesis of serum amyloid protein to the same extent as the growing tumor. This effect was primarily associated with the mitochondrial/lysosomal and microsomal liver cell fractions. In conclusion, the overall acute-phase protein response is not a modulating factor of tumor growth.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of the adrenals in the acute phase response to interleukin-1 and tumor necrosis factor-alpha.

The purpose of this study was to investigate the role of the adrenals, particularly the glucocorticoids, in the acute phase response following daily injections for 5 days of recombinant human interleukin-1 alpha,beta and tumor necrosis factor-alpha (TNF alpha). Adult weight-stable freely fed or pair-fed (to cytokine-injected mice) mice (C57Bl/6J) with and without adrenals were used. Adrenalectomized animals showed a sensitivity to both IL-1 alpha and -1 beta (40 ng IL-1/day) greater than 10-fold higher than that of normal mice (420 ng IL-1/day) in regard to mortality and anorexia. Microscopic examination of tissue specimens from adrenalectomized IL-1 alpha,beta-injected mice did not reveal any histologic alterations in lung, kidney, liver, brain, or gastrointestinal tract to explain the mortality. This mortality was not prevented by physiologic replacement doses of hydrocortisone (10-20 micrograms/day); however, a pharmacological dose of 2.5 mg hydrocortisone/day abolished completely the increased toxicity to IL-1 alpha,beta and the anorectic response to IL-1 alpha,beta and TNF alpha. Increased toxicity (mortality) was not observed in adrenalectomized animals with TNF alpha at the dose interval used (450 ng TNF alpha/day and lower). The hepatic acute phase response (liver weight and RNA and liver protein content) was increased by both IL-1 alpha,beta and TNF alpha in a glucocorticoid-independent way. The cytokine-induced alterations of plasma concentrations of acute phase proteins (serum amyloid P, transferrin, complement C3) were significantly dependent on glucocorticoids, while the decline in plasma albumin was not.(ABSTRACT TRUNCATED AT 250 WORDS)

Identification of tissue sites for increased albumin degradation in sarcoma-bearing mice.

Plasma albumin concentration declines in both experimental and clinical cancer. Previous investigations have demonstrated that this is partly explained by increased breakdown of albumin. The present study has identified the tissue sites for increased albumin degradation in a nonmetastasizing sarcoma mouse (C57/BL6J) model. Results have been compared to nontumor-bearing animals either freely fed or food restricted (pair-weighed) so that their body composition was similar to tumor-bearing animals. Tumor-bearing mice had increased albumin degradation (0.13 +/- 0.02 mg/hr/g bw) compared to both freely fed (0.09 +/- 0.007) and pair-weighed control animals (0.05 +/- 0.008). Radioactivity from circulating [3H]raffine aldehyde labeled albumin appeared with maximum peak values in lysosomes isolated from both tumor and nontumor tissues at 48 hr following iv injection. The intralysosomal accumulation of radioactivity was two- to threefold higher in tumor tissue compared to liver tissue, although the specific activity of protease(s) for albumin degradation measured in vitro was not higher in tumor tissue (30.4 +/- 3.6 mg/hr/g tissue) compared to normal liver tissue (36.9 +/- 1.7). Accounting for the entire tumor the proteolytic capacity for albumin breakdown was however much larger in the tumor (161.6 +/- 32.6 mg/organ) compared to both normal liver (37.5 +/- 2.3) and tumor-host liver (56.4 +/- 2.8). Pepstatin inhibited 78 +/- 6% of the proteolytic activity in the tumor measured by 125I-labeled undenatured mouse albumin as the substrate. Leupeptin inhibited 49 +/- 6%. There was a significantly decreased breakdown of albumin in both skeletal muscles and the gastrointestinal tract from tumor-bearing animals.(ABSTRACT TRUNCATED AT 250 WORDS)