C57BL/6 mice bearing either a transplantable methylcholanthrene-induced sarcoma or Lewis lung adenocarcinoma were passively immunized every other day with a rabbit immunoglobulin fraction raised against murine cachectin/tumor necrosis factor-alpha. Mice bearing methylcholanthrene-induced sarcoma developed tumor-associated hypophagia that was attenuated by anticachectin immunoglobulin treatment. In the same tumor-bearing animals, anticachectin treatment also significantly reduced the extent of carcass protein and fat loss, and reduced tumor weight. Mice bearing Lewis lung adenocarcinoma did not develop significant anorexia or carcass lean tissue depletion as tumor growth progressed, but they lost carcass lipid. Treatment of Lewis lung adenocarcinoma bearing mice with anticachectin antibodies diminished the degree of carcass lipid depletion and prevented plasma hypertriglyceridemia. However, in both tumor models, anticachectin treatment did not affect either the development of anemia, hypoalbuminemia or the increase in serum amyloid P concentrations seen with increasing tumor burden. We conclude that an endogenous cachectin response, inhibitable by exogenously administered antibody, contributes to anorexia and to changes in body fat and protein metabolism in these tumor-bearing animals. Neutralizing endogenous cachectin production with antibodies offers the potential to reduce tissue wasting that is frequently associated with neoplastic disease, but it does not appear to affect all of the hematologic and acute phase responses in these murine tumor models.

More than 100 years ago, Trousseau reported migratory thrombophlebitis in cancer patients (Trosseau A, Lectures on Clinical Medicine, delivered at the Hotel-Dieu, Paris, London: New Sydenham Society; 1872; p 281-95). Subsequently, patients with DVT or pulmonary embolism (PE) have been shown to have up to a fourfold increased risk of cancer in the first year after the venous thromboembolic (VTE) event (Baron JA et al, Br J Cancer 2004;91:92-5). However, only one previous study has investigated the relationship between SVT and cancer risk (van Doormaal FF et al, Ann Fam Med 2010;8:47-50). In an effort to understand the broader cancer risk associated with all types of venous thrombosis, the authors used populationbased registries in Denmark to investigate associations of cancer with SVT, DVT, and PE. They identified all patients in Denmark from 1994 to 2009 with a diagnosis of SVT, DVT in the legs, or PE. The occurrence of cancer in each of the venous cohorts was compared with expected numbers of cases using national incidence rates to compute standardized incidence ratios (SIRs). The authors identified 763 patients with SVT, 45,252 with DVT, and 24,332 with PE. Very similar proportions of patients in the three cohorts in the first year of follow-up were diagnosed with cancer. The SIRs (95% confidence intervals) were 2.46 (2.10-2.86) for SVT, 2.75 (2.6-2.9) for DVT, and 3.27 (3.03-3.52) for PE, and declined after 1 year to 1.05 (0.96-1.16), 1.11 (1.07-1.16), and 1.15 (1.09-1.22), respectively. Venous thrombotic cohorts showed strong associations for particular cancers (liver, lung, ovaries, pancreas, and non-Hodgkin lymphoma).Comment:The key point here is that all forms of lower extremity venous thrombosis, SVT, DVT, and potential sequelae, such as PE, are markers for a clearly higher occurrence rate of cancer, particularly during the first year after diagnosis. Practical implications for screening for cancer in patients with VTE are unclear. If someone has cancer and a VTE event within 1 year of diagnosis, the prognosis is poor, with only a 12% survival (Sorensen HT et al, N Engl J Med 2000;343:1846-50). However, the implications for screening derived from this particular study are also unclear. The authors point out 45,981 individuals with VTE would have to be investigated to find 304 excess cancers during the first year of follow-up. That is a lot of investigation for not many cancers, especially when it is unclear that an early cancer diagnosis stemming from evaluation of a VTE event would ultimately prolong the life of a VTE patient with underlying cancer.

During inflammation, activated monocytes and lymphocytes synthesize and release many soluble protein mediators, such as interleukin (IL) 1, tumor necrosis factor-alpha, and IL-2. It is presently unclear which cytokines, if any, contribute to the anorexia and hepatic protein changes frequently seen during inflammation. To evaluate their potential role, food intake and liver and plasma protein synthesis were determined in both endotoxin-sensitive C57Bl/6j mice and endotoxin-resistant C3H/HeJ mice given either crude secretory products of Staphylococcus albus-stimulated human blood monocytes or murine recombinant IL-1-alpha, human recombinant IL-1-alpha or -beta, human recombinant tumor necrosis factor-alpha, or human IL-2. When given intraperitoneally to healthy animals, 2,000 lymphocyte-activating factor U/day of secretory products of activated human blood monocytes or recombinant murine IL-1-alpha depressed spontaneous food intake by 42 and 53%, respectively. Human IL-1-alpha and -beta and human tumor necrosis factor-alpha produced smaller reductions in food intake. In contrast, human IL-2, when given in equimolar quantities, had no appreciable effect on food intake or body weight. Administration of crude secretory products of activated blood monocytes, recombinant IL-1, or tumor necrosis factor-alpha increased liver weight, protein, and RNA content. In addition, plasma protein synthesis was significantly increased, as were serum amyloid P concentrations. Administration of recombinant tumor necrosis factor-alpha resulted in IL-1 production by peritoneal adherent cells. However, IL-2 had no effect on any hepatic parameter.

Recent studies have claimed that interleukin 1-containing preparations increase skeletal protein degradation similar to that seen during infection and inflammation. However, preparations employed have contained other products of activated macrophages, including tumor necrosis factor-alpha. In the present report, we investigated the capability of recombinant-derived murine and human interleukins 1-alpha and 1-beta and human tumor necrosis factor-alpha to affect skeletal protein synthesis and degradation both in vitro and in vivo. Partially purified products of Staphylococcus albus-stimulated human blood monocytes increased skeletal protein degradation both in vivo and in vitro. However, none of the recombinant interleukin 1 nor the human tumor necrosis factor-alpha preparations had any impact on skeletal protein balance. Both recombinant interleukin 1 and tumor necrosis factor-alpha stimulated the production of prostaglandin E2 (PGE2). Furthermore, a polyclonal antibody to human interleukin 1 eliminated the lymphoproliferative response to partially purified monocyte preparations (interleukin 1 activity), but failed to abrogate the increased skeletal protein degradation in vitro. This study demonstrates that although interleukin 1 and tumor necrosis factor-alpha induce a PGE2 response by skeletal muscle in vitro, some macrophage product distinct from either interleukin 1 or tumor necrosis factor-alpha is responsible for the accelerated skeletal protein degradation seen with partially purified human blood monocyte products. Elevated PGE2 levels do not appear to regulate skeletal protein balance in vitro.