Anaemia is not an inconsequential side effect of cancer and its treatment should not be ignored. Current practice for anaemia management varies and its role in influencing outcome in cancer patients is under recognized. As a common complication of cancer, anaemia is prevalent in virtually all tumour types to varying degrees. Predictive factors for anaemia include baseline haemoglobin concentration, decrease in haemoglobin concentration within the first month of treatment, tumour type, duration of treatment and prior blood transfusions. Interest in the prognostic significance of anaemia in cancer patients has generated extensive clinical research. Data is now published in a wide range of tumour types confirming that anaemia is a negative prognostic indicator of outcome (e.g. survival, disease-free recurrence and local relapse), with the strongest association in patients receiving radiotherapy. The association has also been documented in patients undergoing chemotherapy and chemoradiation. A retrospective meta-analysis has shown an overall 65% increased risk of death associated with anaemia in cancer patients. The impact of anaemia as an independent prognostic factor for outcome may be mediated by several factors, however the emerging consensus is on the central role of tumour hypoxia. It has been nearly 50 years since R. Thomlinson and L. Gray (British Journal of Cancer 1955, 9: 539) first documented the existence of hypoxia in tumours and it is now well accepted that tumour hypoxia protects tumour cells from therapeutic damage directly by reducing the availability of oxygen-free radicals which are necessary for optimal impact of radiotherapy, certain chemotherapeutic agents and photodynamic therapy. The indirect effects include the impact of hypoxia on gene expression, which affects genetic stability, proliferation kinetics and cellular metabolism. There has been an emergence of preclinical and circumstantial data over recent years that are suggestive of the ability to correct the negative effect of anaemia on outcome by the use of repeated blood transfusions or recombinant human erythropoietin. This has led to some attempts to measure the impact on survival in cancer patients of treating anaemia, but early attempts have served to underline the complexity of the relationship and have produced unexpected results.

Recombinant human erythropoietin (rHuEPO) is an effective treatment for anemia in patients with cancer, and recent studies show that over two-thirds of patients can be expected to respond with a large increase (>2 g/dl) in hemoglobin concentration. However, it would be helpful to identify likely responders and nonresponders before initiating treatment. Previous studies have suggested that high pretreatment endogenous erythropoietin levels are associated with a lower response to erythropoietin, especially in certain patient groups, such as patients with hematological malignancies, nonchemotherapy patients, or patients with myelodysplastic syndrome. Various algorithms have therefore been developed to predict patient response to rHuEPO using baseline serum erythropoietin levels and other baseline factors. We performed an analysis of data pooled from four randomized clinical trials of 604 patients with nonmyeloid malignancies, examining the clinical usefulness of pretreatment and early treatment factors for predicting response to erythropoietin. The analysis confirms several other reports that the most predictive models combined pretreatment and early treatment factors, including change in hemoglobin at 4 weeks, but even these models did not increase sensitivity above 85% (total response in unselected patients was 68.1%), while specificity remained poor. We conclude that clinically useful prediction of response to erythropoietin is not possible using baseline or early response variables because of poor sensitivity and specificity of prediction compared with generally accepted clinical tests. The Oncologist 2003;8:99-107 The Oncologist 2003;8:99-107 www.TheOncologist.com

:  Pure red cell aplasia (PRCA) is a rare condition characterised by an arrest in red blood cell production, which may be congenital or acquired. Recombinant human erythropoietin (epoetin) was introduced in 1989 for the treatment of anaemia of chronic kidney disease patients and has maintained an excellent therapeutic and safety record while treating hundreds of thousands of patients. A very rare, but serious adverse event associated with epoetin administration is a condition in which patients develop neutralising anti‐erythropoietin antibodies and, consequently, PRCA. This condition is referred to as epoetin‐induced PRCA (epo‐PRCA). Since it is a rare condition, many haematologists and nephrologists around the world see the condition infrequently and may be uncertain about the diagnosis. For this reason, an ad hoc international working group of expert haematologists and nephrologists met together to derive new recommendations for the haematological diagnosis of epo‐PRCA. These recommendations, which represent the consensus opinions of the working group, address haematological approaches to monitor and investigate suspected epo‐PRCA and should help physicians differentiate between PRCA and other bone marrow diseases, as well as, between PRCA and epo‐PRCA.

The enzyme vitamin K1 2,3 epoxide reductase is responsible for converting vitamin K1 2,3 epoxide to vitamin K1 quinone thus completing the vitamin K cycle. The enzyme is also the target of inhibition by the oral anticoagulant, R,S-warfarin. Purification of this protein would enable the interaction of the inhibitor with its target to be elucidated. To date a single protein possessing vitamin K1 2,3 epoxide reductase activity and binding R,S-warfarin has yet to be purified to homogeneity, but recent studies have indicated that the enzyme is in fact at least two interacting proteins. We report on the attempted purification of the vitamin K1 2,3 epoxide reductase complex from rat liver microsomes by ion exchange and size exclusion chromatography techniques. The intact system consisted of a warfarin-binding factor, which possessed no vitamin K1 2,3 epoxide reductase activity and a catalytic protein. This catalytic protein was purified 327-fold and was insensitive to R,S-warfarin inhibition at concentrations up to 5 mM. The addition of the S-200 size exclusion chromatography fraction containing the inhibitor-binding factor resulted in the return of R,S-warfarin inhibition. Thus, to function normally, the rat liver endoplasmic reticulum vitamin K1 2,3 epoxide reductase system requires the association of two components, one with catalytic activity for the conversion of the epoxide to the quinone and the second, the inhibitor binding factor. This latter enzyme forms the thiol-disulphide redox centre that in the oxidized form binds R,S-warfarin.

The type III tyrosine kinase receptor c-KIT and its ligand stem cell factor (SCF; also known as KIT ligand, mast cell growth factor and steel factor) are closely involved in the regulation of a wide range of tissues at different stages of life. This review provides an outline of the discovery, structure and expression of SCF and c-KIT but concentrates on their respective roles in the regulation of human haemopoiesis and how this knowledge might be exploited in the clinical setting.