Symptoms and signs of an acute myocardial ischemia caused by chemotherapy with Paclitaxel (Taxol) in a patient with metastatic ovarian carcinoma.

INTRODUCTION: Paclitaxel (Taxol) is an anticancer agent used for the treatment of breast and ovarian cancer. The major side effects are bone marrow suppression, alopecia, polyneuropathy and cardiac toxicity like bradycardia, myocardial infarction, congestive heart failure and cardiac death. SETTING: Intensive care unit (ICU) of a university hospital. PATIENT: We report on a 58-years-old woman with a metastatic ovarian carcinoma who had chest pain, nausea and collapse during their first Taxol infusion. The infusion was stopped and the patient was submitted to the intensive care unit (ICU) to exclude an acute coronary syndrome. RESULTS: The electrocardiography (ECG) showed a third-degree heart block and ST elevation in II, III and avF. In the initial and in the control laboratory investigation values of cardiac enzymes (creatininkinase and Troponine T) remained normal. The control ECG after 30 minutes turned back to normal. After one day the patient was submitted back to a normal ward. CONCLUSION: Symptomatic bradyarrhythmia and clinical sign of an myocardial infarction are rare but important cardiac side effects in patients treated with Taxol. Those patients should be under intensive care unit until patients conditions improve and acute myocardial ischemia has been excluded.

Interferon-gamma is not involved in the intestinal manifestations of the acute murine semiallogenic graft-versus-host disease.

BACKGROUND: The acute murine semiallogenic graft-versus-host disease (GvHD) is known to be associated with Th1 cytokines secreting lymphocytes in the spleen and lymph nodes. However, whether this cytokine secretion pattern is also involved in the intestinal manifestations of acute GvHD (crypt hyperplasia and villous atrophy) is not known, so far. METHODS: We first investigated the secretion of interleukin (IL) 4 (indicative of Th2-type differentiation) and interferon (IFN) 7 (Th1-type differentiation) by splenic and by small bowel lamina propria lymphocytes. In addition, animals were treated with neutralizing antibodies to IL-4 or IL-12. The effect of this treatment on the intestinal morphology was examined. Second, we also investigated the effect of donor-derived IFN-gamma by using donor lymphocytes from IFN-gamma knock-out animals. Third, animals were treated with the fusion protein OX40-Ig which interferes with the OX40-OX40L interaction and thereby inhibits the intestinal manifestations of acute GvHD. RESULTS: We found that, whereas splenic lymphocytes secrete an excess of IFN-gamma, lymphocytes of the intestinal lamina propria secrete less IFN-gamma and IL-4 than control animals. When OX40-Ig is administered to animals with acute GvHD, the intestinal histology normalizes as well as the secretion of IFN-y and IL-4, indicating that the intestinal morphology is not affected by the secretion of IFN-gamma by lamina propria lymphocytes. The treatment of animals suffering from acute GvHD with anti-IL-4 and anti-IL-12, which blocks the differentiation of IFN-gamma secreting T-lymphocytes, did not significantly affect the development of crypt hyperplasia or villous atrophy. Furthermore, donor lymphocytes of IFN-gamma knock-out animals also induced the intestinal manifestations of acute GvHD. CONCLUSIONS: These findings indicate that IFN-gamma is not crucial for the development of crypt hyperplasia and villous atrophy in the murine semiallogenic GvHD.

The expression of OX40 in immunologically mediated diseases of the gastrointestinal tract (celiac disease, Crohn's disease, ulcerative colitis).

BACKGROUND: The membrane bound receptor OX40 (CD134) - a member of the TNF-R/NGF-R superfamily - is expressed on activated CD4+-T cells in humans and rodents. The interaction of OX40 with its ligand (OX40L) has been shown to be important in T-cell dependent B cell-stimulation and T-cell costimulation in vitro and in vivo. Several studies in experimental animal models for immunologically mediated GI-diseases have stressed the important role of the OX40-OX40L interaction for their manifestations. To assess if the OX40-OX40L interaction is also crucial in the pathogenesis of immunologically mediated diseases of the human gastrointestinal tract (e.g. celiac disease, Crohn's disease, ulcerative colitis) we investigated, in a first line of experiments, the expression of OX40 in biopsy specimens of patients suffering from these diseases. METHODS: The biopsies were formalin fixed and paraffin-embedded and cut into 5 microm slides. To demask the antigen, the slides were consecutively cooked in citrate buffer for 20 min. Binding of anti-OX40 antibody was detected using the alkaline phosphatase-anti-alkaline phosphatase (APAAP) method. RESULTS: Nine of 11 biopsy specimens of patients with celiac disease were OX40-positive; none of the 20 control duodenal biopsies demonstrated OX40-positivity; and all biopsies of patients with ulcerative colitis (n = 11) or Crohn's disease (n = 11), respectively, stained positively for OX40. One of the 20 control biopsies showed OX40 staining. DISCUSSION: OX40 is highly expressed in the gastrointestinal tissue of patients with immunologically mediated bowel diseases. Together with previous studies in animal models for these diseases, the present results point to a potential role of OX40 in their pathogenesis.

Intestinal crypt cell apoptosis in murine acute graft versus host disease is mediated by tumour necrosis factor alpha and not by the FasL-Fas interaction: effect of pentoxifylline on the development of mucosal atrophy.

BACKGROUND: Murine T cell mediated acute semiallogeneic graft versus host disease (GVHD) is characterised by lymphocytic infiltrates, crypt hyperplasia, and villous atrophy. It has been shown that programmed cell death (apoptosis) of the crypt epithelium takes place during the intestinal manifestation of acute GVHD. AIMS: To investigate which of the two most investigated inductors of apoptosis (Fas ligand (FasL) and tumour necrosis factor alpha (TNF-alpha)) is responsible for the induction of apoptosis in this animal model. METHODS: Animals undergoing acute semiallogeneic GvH reaction were treated with neutralising anti-TNF-alpha, two different anti-FasL antibodies, or pentoxifylline. RESULTS: Anti-TNF-alpha application inhibited the appearance of apoptotic cells in the intestinal mucosa, whereas anti-FasL antibodies had no influence on mucosal apoptosis. In addition, the transfer of FasL deficient (gld) donor lymphocytes still induced crypt cell apoptosis, villous atrophy, and crypt hyperplasia. Furthermore, when the animals were treated with pentoxifylline, a known inhibitor of TNF-alpha secretion in vitro and in vivo, there was significant normalisation of the intestinal morphology accompanied by inhibition of epithelial apoptosis. CONCLUSIONS: The FasL-Fas interaction is not involved in the induction of apoptosis during acute GVHD. However, neutralisation of TNF-alpha by an antibody or by pentoxifylline inhibits the occurrence of apoptosis and of mucosal atrophy in this animal model. These results have implications for the treatment of immunologically mediated human atrophic gut diseases-for example, diet refractory cases of coeliac disease.

The effect of anti-gp39 treatment on the intestinal manifestations of acute murine graft-versus-host disease.

The changes in the intestinal morphology of murine T-cell-mediated acute semi-allogenic graft-versus-host disease (GvH) are characterized by lymphocytic infiltrates, crypt hyperplasia, and villous atrophy. In the present study, the role of CD40L (gp39)-an important member of the TNF/NGF superfamily of receptors and their ligands-for T-cell costimulation in vivo during the development of mucosal atrophy was investigated. We found that the inhibition of the CD40L-CD40 interaction in GvH animals by the administration of an anti-CD40L antibody (MR-1) completely prevents the development of crypt hyperplasia and villous atrophy in GvH animals. This includes a normalization of the rate of crypt cell apoptosis, which is augmented in untreated GvH animals. In conclusion, the CD40L-CD40 interaction is crucial in the pathogenesis of T-cell-mediated mucosal atrophy.

Involvement of OX40-OX40L interactions in the intestinal manifestations of the murine acute graft-versus-host disease.

BACKGROUND & AIMS: The intestinal histology of murine semiallogeneic graft-versus-host (GVH) disease is characterized by lymphocytic infiltrates, crypt hyperplasia, and villous atrophy. Mechanisms of T cell-mediated changes of the mucosal architecture were investigated. METHODS: The rate of cellular apoptosis and proliferation, changes in the composition of extracellular matrix (ECM), and the role of OX40-OX40L interactions in the pathogenesis of villous atrophy and crypt hyperplasia were examined. RESULTS: The rate of apoptosis and the number of proliferating cells were significantly increased in GVH animals compared with control animals. In addition, expression of tenascin, an ECM component, was down-regulated in GVH animals. Inhibition of OX40-OX40L interactions in GVH animals by administration of an OX40-Ig fusion protein completely prevented the development of crypt hyperplasia and villous atrophy in GVH animals. Tenascin expression was up-regulated in OX40-Ig-treated mice compared with GVH animals, suggesting an important function of this ECM component in mucosal repair. CONCLUSIONS: The OX40-OX40L interaction is crucial in the pathogenesis of GVH, a T cell-mediated intestinal disease. The data suggest that the ECM component tenascin is probably relevant for the regeneration and maintenance of intestinal tissue architecture.