Amifostine-related fever-rash during fractionated radiotherapy: diagnostic and predictive role of C-reactive protein.

INTRODUCTION: Fever/rash is a side-effect of amifostine that demands immediate interruption of the drug. Here, we focus on the role of C-reactive protein (CRP) as a putative marker linked with amifostine fever/rash. MATERIALS AND METHODS: The CRP serum values were analyzed in 496 patients receiving radiotherapy supported with amifostine (500-1000 mg/d). CRP levels were recorded before the onset of radiotherapy (day 0), on day 15 and when the fever/rash appeared. For 121 out of 496 patients, CRP values on day 7 were also available. About 79 patients (15.9%) developed fever/rash symptoms. RESULTS: The CRP levels before the onset of therapy were 0 to 20.7 mg/dL (normal, ≤0.5 mg/dL). For patients who did not develop fever/rash, the CRP levels increased from a median of 0.30 to 0.50 on day 15; P = 0.001. Patients who developed fever/rash showed a more than 7-fold increase of the median CRP levels (median, 3.50; P < 0.0001). This sharp CRP rise was specific for amifostine-related fever/rash. Initially abnormal CRP levels were linked with a 2-fold risk for fever/rash (P = 0.01), while abnormal levels on day 7 were linked with a 3-fold higher risk (P = 0.08). The occurrence of fever/rash was independent of the amifostine dose level. CONCLUSIONS: Sharp rise of CRP levels on the day after the fever/rash development suggest amifostine-related etiology of fever/rash. Abnormal initial CRP levels and/or high CRP levels on day 7 should be considered as an alert signal as the probability to develop fever/rash reaches the 30%.

Erythropoietin receptors in endometrial carcinoma as related to HIF1{alpha} and VEGF expression.

Erythropoietin receptors (EpoRs) are expressed in a large percentage of cells in many human malignancies, including endometrial adenocarcinoma. In such tumors, administration of recombinant human erythropoietin (rhEpo) during radiotherapy and chemotherapy may oppose tumor progression by interfering with growth and invasion pathways. In the present study, a strong EpoR expression was demonstrated in 58.8% of 72 stage I endometrial adenocarcinomas, and this pattern was linked with a high degree of tumor differentiation (p=0.01), deep myometrial invasion (p=0.04) and, marginally, with poor prognosis (p=0.06). In addition, a strong association with the immunohistochemical expression of hypoxia-inducible factor 1alpha (HIF1alpha) and the downstream angiogenic protein vascular endothelial growth factor (VEGF) was noted. In multivariate analysis, HIF1alpha, but not EpoR, was associated with the depth of myometrial invasion (p=0.04) and marginally with prognosis (p=0.07). It is concluded that EpoR are common constituents of endometrial adenocarcinomas and are related to tumor aggressiveness, although this is probably a result of their involvement in an active HIF pathway.

Serum C-reactive protein (CRP) levels in cancer patients are linked with tumor burden and are reduced by anti-hypertensive medication.

High levels of CRP relate with advanced disease and poor prognosis of cancer patients. CRP serum levels were measured in 684 cancer patients who had undergone complete surgery or inoperable patients. Patients with inoperable tumors had significantly higher CRP levels (1.21 +/- 2.2 vs. 0.40 +/- 0.4 mg/dL; p < 0.0001). No association with gender, diabetes, autoimmune disease, thyroid disease or allergy was noted. Significantly higher CRP levels were noted in operated patients with hypertension (0.55 +/- 0.5 vs. 0.35 +/- 0.4; p = 0.001), coronary disease (0.73 +/- 0.8 vs. 0.39 +/- 0.4; p = 0.01) and obesity (0.51 +/- 0.5 vs. 0.37 +/- 0.4; p = 0.04). On the contrary, analysis in the group of inoperable patients showed that hypertensive patients had significantly lower CRP levels (0.64 +/- 1.0 vs. 1.36 +/- 2.4; p = 0.008). Although the tumor itself is the main factor defining increased CRP levels in cancer patients, hypertension, coronary disease and obesity are also linked with high CRP levels. Anti-hypertensive drugs appear as potent suppressors of the tumor-induced CRP production.

Effect of 4 weeks of basic military training on peripheral blood leucocytes and urinary excretion of catecholamines and cortisol.

In this study, we assessed the effects of a 4 week basic military physical training programme for male recruits of the Hellenic Air Force on the number and distribution of circulating immune cells and adrenergic and adrenocortical hormonal responses. One group of recruits (exercised, n = 48) participated in moderate intermittent physical exercise, whereas a second group (non-exercised controls, n = 9) performed only light work in the barracks. Both groups participated in the same non-physical, classroom-type training and testing. Military training by the exercised group resulted in significant increases in CD4+ T-lymphocytes, renal cortisol excretion and the urinary noradrenaline/adrenaline ratio, together with reductions in neutrophils and the neutrophil/lymphocyte ratio. In the exercised group, the urinary noradrenaline/adrenaline ratio correlated positively with the training-induced changes in CD4+ T-lymphocytes and negatively with changes in the neutrophil/lymphocyte ratio. No significant relationship was found between training-induced increases in cortisol excretion and any of the peripheral blood cell alterations. Our results indicate that 4 weeks of military training consisting of intermittent moderate exercise resulted in a significant increase in CD4+ T-lymphocytes and reduction in neutrophils. These changes were probably driven by alterations in hormonal status, including the significant impact of sympathetic nervous system activation.

Amifostine protects lymphocytes during radiotherapy and stimulates expansion of the CD95/Fas and CD31 expressing T-cells, in breast cancer patients.

A large body of experimental research supports the anti-neoplastic activity of cellular and humoral immunity. Disease and therapy-related immune suppression may be important on the treatment outcome or on the subsequent course of the malignant disease. The aim of the study was to investigate the efficacy of amifostine in preventing the immunological toxicity of post-operative radiotherapy (RT) in breast cancer patients. Using flow-cytometry, we examined comparatively the peripheral blood lymphocytic subpopulations in breast cancer patients undergoing conventional post-operative RT versus a hypofractionated accelerated RT scheme combined with amifostine (HypoARC) administration. Despite the higher radiation dose intensity delivered in the HypoARC group, a significant protection of CD4, CD8, CD19 and CD56 subtypes by amifostine was noted. We further focused on two interesting CD4/CD8 subpopulations involved in cellular apoptosis and trans-endothelial migration, namely the CD95/Fas and CD31 positive lymphocytes. Amifostine protected and induced expansion of these subtypes, which could contribute to the maintenance of a high burden of tumor infiltrating lymphocytes during therapy. It is suggested that amifostine effectively protects lymphocytes against RT, which may enhance the efficacy of the latter. The clinical impact of the CD95(+) and CD31(+) T-cell immunological modulation induced by amifostine requires further investigation.