Plasma concentrations of lactoferrin were measured in immediately separated EDTA samples from 5 subjects who had received HLA identical bone marrow transplants for leukaemia or aplastic anaemia and from 7 subjects who were leukopenic as a consequence of chemotherapy for a variety of malignant conditions. Plasma lactoferrin concentrations were found to closely parallel the leucocyte count and were not found to either predict or to antedate leucocyte regeneration. Serial measurements of plasma lactoferrin in a subject with no circulating neutrophils who received a bone marrow graft revealed that the clearance of lactoferrin followed an exponential pattern and had an initial half time of 2.2 h.

59 patients with active pulmonary tuberculosis were evaluated in terms of haematological indices, iron-related measurements and markers of inflammation. The variables evaluated included the Hb, mean cell volume (MCV), serum iron, total iron-binding capacity, percentage saturation, serum ferritin, erythrocyte sedimentation rate (ESR) and C-reactive protein. In addition, marrow iron stores were assessed both histologically and chemically. Among the changes noted was a raised S-Ferritin, which appeared in part to be a component of the acute phase response, since it correlated with C-reactive protein concentration (r 0.59, p less than 0.0001). In addition, there was a good correlation between the S-Ferritin and the concentrations of non-haem iron in the marrow, as assessed chemically on trephine biopsies (r 0.78, p less than 0.0001) and histologically on aspirated and biopsy material (rS 0.78, p less than 0.0001 and rS 0.68, p less than 0.0001, respectively). Furthermore, the quantitative relationship between the S-Ferritin and the chemical concentrations of non-haem iron in the marrow was similar to that found previously in a heterogeneous group of subjects without infections. While the present findings confirm that iron is diverted into reticuloendothelial stores in active pulmonary tuberculosis, no evidence was found to suggest that the anaemia which was present in 45 of the 59 patients was secondary to iron-deficient erythropoiesis; the percentage saturations in the 2 groups were 30.3 and 31.1 respectively. In a final analysis, the present findings were compared with previous ones obtained in a group of patients with Hodgkin's disease. The degree of rise in the S-Ferritin for a given marrow non-haem iron concentration was significantly less in the patients with tuberculosis (p less than 0.0001).

A survey conducted in rural southern African black subjects indicated that dietary iron overload remains a major health problem. A full blood count, erythrocyte sedimentation rate, serum concentrations of iron, total iron-binding capacity, ferritin, C-reactive protein (CRP), 1'-glutamyltransferase (GGn and serological screening for hepatitis B and human immunodeficiency virus (HIV) infections were carried out in 370 subjects (214 inpatients and 156 ambulatory Mozambican refugees). The fact that the geometric mean (SO range) serum ferritin concentration was much higher in the male hospital patients than in subjects living in the commpnity [1 581 j.Lg/l (421 5944 j.Lg/l) and 448 j.Lg/l (103 1945 j.Lg/l) respectively] suggested that dietary iron overload was not the only factor raising the serum ferritin concentration. The major additional factor appeared to be inflammation, since the geometric mean (SO range) serum CRP was significantly higher in male hospital patients [21 mgll (8 53 mg/l)] than in subjects in the community [3 mgll (1 5 mg)]. Alcohol ingestion, as judged by history and by serum GGT concentrations, was also associated with significantly raised serum ferritin concentrations. This finding was ascribed to the fact that traditional brews are not only associated with alcoholinduced hepatic damage but are also a very rich source of highly bio-available iron. The role of iron overload in the genesis of the raised serum ferritin concentrations are confirmed in the diagnostic liver biopsy study. The majority of biopsies showed heavy siderosis, with varying degrees of hepatic damage. No subject tested positive for HIV antibodies, while the hepatitis B infection rate was high (± 70%) in both hospital and community subjects, with a surface antigen carrier rate of roughly 10%.

Given that each year in the United States 180,000 new cases of breast cancer are diagnosed, with about 44,000 women succumbing to the disease, and that breast cancer is the second leading cause of cancer-related death in women, it is clear that existing therapy fails a large number of patients. Recently, a number of novel strategies have been developed in attempts to improve survival. These include agents used at very high dose requiring stem cell support. High-dose chemotherapy (HDC) with hematopoietic stem cell transplantation (HSCT), most frequently in the form of peripheral blood progenitor cell transplantation (PBPCT), is an highly active treatment approach in appropriate patients and the current data relating to this modality will be reviewed here. This article will attempt to place the recent randomized studies in perspective, to highlight the strengths and limitations of the data, and to offer some thoughts on future directions for the field.

(2000). High-Dose Chemotherapy and Autologous Stem Cell Transplantation for Breast Cancer. Cancer Investigation: Vol. 18, No. 5, pp. 440-455.

Outpatient bone marrow transplant (BMT) strategies, as reviewed by Dix and Geller, have evolved for various reasons—from social to medical. If high-dose approaches are to become a viable treatment for common cancers, such as breast cancer, the refinement of transplants to a “kinder and gentler” approach is essential.

Each year in the USA, 180,000 new cases of breast cancer are diagnosed and about 44,000 women die of the disease. Current primary treatment consists of adjuvant chemotherapy and hormone therapy, and statistics show that combination chemotherapy favorably influences the outcomes in both node-negative and node-positive primary disease. However, a significant number of breast cancer patients succumb to the disease, and nearly every patient diagnosed with metastatic breast cancer will be dead within five years. High-dose chemotherapy (HDC) and peripheral blood progenitor cell transplantation (PBPCT) are based upon laboratory and clinical observations of the ability to modify growth properties of quiescent and replicating cancer cells. A large number of HDC and PBPCT regimens have been evaluated for treatment of metastatic breast cancer, and recent autologous bone marrow transplantation data indicate that three HDC regimens (CPB, CTCb and cytoxan and thiotepa) predominate. Unfortunately, negative media coverage surrounding and subsequent to the presentation of preliminary findings reported at the May 1999 American Society of Clinical Oncologists, that were not allowed adequate follow-up time for full analysis of treatment results, has had a detrimental effect on the ability to conduct trials in this area. Several randomized trials have been conducted in both the metastatic and high risk primary disease settings. Thorough analysis of these studies indicates an evaluable improvement in favor of HDC and PBPCT in three of the four randomized studies performed in metastatic breast cancer and two of the four high risk primary studies. Also, initial evaluations found that quality of life appeared comparable in patients receiving either HDC or not. Each randomized trial studied asks a different question and, depending on the intensity of HDC regimen, the intensity and duration of the standard dose chemotherapy control and the schedule of events in relation to induction chemotherapy, the outcomes may be quite variable. Still, certain general trends are indentifiable. HDC alone will not completely cure breast cancer and should be considered as part of an overall therapeutic plan. In some of these studies, significantly longer follow-up is required before definitive analysis can be completed.

This review focuses on certain of the principles involved in high-dose chemotherapy and radiation therapy along with autologous hematopoietic stem cell transplantation for the treatment of certain malignancies. In addition, the evidence, wherever possible based on randomized data, for the application of this approach in certain malignancies is reviewed. The malignancies highlighted include acute myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin lymphoma, Hodgkin disease, and breast cancer.

Epoetin (recombinant human erythropoietin) is used by some endurance athletes to increase oxygen transport and aerobic power in an attempt to improve endurance capacity and recovery during training and competition. Although currently on the list of banned substances issued by the medical commission of the International Olympic Committee, the use of epoetin as an ergogenic agent remains uncontrollable using classical analytical techniques. In the present paper, after subcutaneous administration of repeated high doses (200 units/kg), the pharmacokinetics of epoetin were evaluated in 18 athletes. The mean elimination half-life was 42.0 hours. The total clearance/bioavailability (F) and the volume of distribution/F averaged 0.05 L/h/kg and 2.95 L/kg, respectively. Significant changes in ferritin (fr), soluble transferrin receptor (sTfR) and ratio (sTfR/fr) were observed after administration. A population sigmoidal asymptotic maximum expected effect concentration (emax) model has been developed to assess and quantify the relationship between the changes in sTfR, fr and the ratio sTfR/fr secondary to the repeated administration of epoetin. The mean population parameters were as follows: emax: 12.6 mg/L, 44.9 µtg/Land 2313.5; the concentration producing 50% of the emax(C50): 18.3,18.1 and 37.7 IU/L; the sigmoidicity factor (gamma): 2.96, 4.17 and 5.15; and ke0 (rate constant of transfer between central and effect compartment): 1.29 × 10−3, 7.14 × 10−3 and 3.47 × 10−3/h for the 3 markers, respectively. Moreover, in this paper, we propose an appropriate statistical methodology based on the measurement of sTfR, fr and sTfR/fr from blood samples to decide if the observed values of these markers could be related, at a given probability risk, to the administration of epoetin. Values greater than 10 mg/L for sTfR and 403 for sTfR/fr indicate a probable intake of epoetin. Because of the large interindividual variability of fr, it has not been possible to define a threshold value for this parameter. The sTfR seems to be the most effective marker in doping control. An increased haematocrit with concomitant changes in sTfR and sTfR/fr values seems to supply a valuable diagnostic tool that avoids false-positive doping and allows the identification of epoetin abusers. Blood samples could be collected using capillary blood from the fingertip or earflap. These controls could be carried out during training because they are easy to perform and do not add substantially to total screening costs. At present, this is the only tool available for detecting epoetin abusers during competition.

This brief review of developments relating to iron deficiency during the past year covers three main areas: iron supplementation, the regulation of iron absorption, and the use of the serum transferrin receptor for the assessment of iron status. The intermittent administration of iron supplement once or twice weekly rather than daily has been advocated by international health agencies in recent years, but radioiron absorption studies in human subjects have failed to demonstrate any absorptive advantage of the intermittent schedule. The value of prophylactic iron supplementation in elderly blood donors was evaluated and shown to offer limited benefit in maintaining donation frequency. A recent model of the regulation of iron absorption involving erythropoietic and store regulators is discussed and a recent article indicating a potential non-hematopoietic effect of hematopoietic growth factors on iron absorption by the gastrointestinal mucosal cell is reviewed. A new measure of functional iron deficiency, namely the serum transferrin receptor, is discussed, with particular reference to its mechanism of production and its great value in distinguishing iron deficiency anemia from the anemia of chronic disease.