Microarray profile of the humoral immune response to influenza vaccination in breast cancer patients treated with chemotherapy.

BACKGROUND: Patients treated with chemotherapy have an impaired response to influenza virus vaccination compared to healthy controls. Little is known about the broadness of the antibody response in these patients. METHODS: Breast cancer patients on FEC (5-fluorouracil, epirubicin and cyclophosphamide) chemotherapy regimens were vaccinated with influenza virus vaccine. Sera were obtained before and three weeks after vaccination. In addition to the determination of virus-specific antibody titres by hemagglutination inhibition assay, the broadness of the response was assessed by the use of a protein microarray and baseline titres were compared with an age-matched reference group. RESULTS: We included 38 breast cancer patients and found a wide variety in serum antibody response after vaccination. Patients with a history of influenza vaccination had higher pre-vaccination titres, which were comparable to the reference group. Increasing number of cycles of chemotherapy did not have a negative effect on influenza array antibody levels, nor on the HI antibody response. CONCLUSIONS: Overall there was a broad serum antibody response to the influenza virus vaccine in patients treated with chemotherapy for breast cancer.

Response to influenza virus vaccination during chemotherapy in patients with breast cancer.

BACKGROUND: Patients receiving chemotherapy are at increased risk for influenza virus infection. Little is known about the preferred moment of vaccination during chemotherapy. PATIENTS AND METHODS: Breast cancer patients received influenza vaccination during FEC (5-fluorouracil, epirubicin and cyclophosphamide)-containing chemotherapy regimens. Patients were randomised for early (day 4) or late (day 16) vaccination during the chemotherapy cycle. Influenza virus-specific antibody titres were determined before and 3 weeks after vaccination by haemagglutination inhibition. RESULTS: We included 38 breast cancer patients (20 in the early and 18 in the late group) and 21 healthy controls. The overall patient group had significant lower responses to the vaccine compared with healthy controls. Patients vaccinated at day 4 tended to have higher antibody titres as compared with patients vaccinated at day 16, although the difference in post-vaccination titres is not statistically significant. Geometric mean titres post-vaccination for day 4 versus day 16 were 63.7 versus 29.5 (H3N2), 28.2 versus 19.6 (H1N1) and 29.8 versus 16.0 (B/Brisbane), respectively. CONCLUSIONS: Patients on chemotherapy have significantly lower responses to influenza virus vaccination compared with healthy controls. Vaccination early during the chemotherapy cycle induces better responses than does vaccination at day 16 of the cycle. Follow-up studies are needed to confirm this effect.

The effect of different treatment regimens in reducing fasting and postmethionine-load homocysteine concentrations.

OBJECTIVES: To determine the homocysteine-lowering effect of different treatment regimens on both fasting and postmethionine-load plasma total homocysteine (tHcy) concentrations. DESIGN: Descriptive study of consecutive hyperhomocysteinaemic subjects per treatment regimen. Homocysteine was measured in the fasting state and 6 h after methionine loading, both before and after 8 weeks of vitamin therapy. Hyperhomocysteinaemia was defined as a fasting tHcy and/or increase in tHcy (postmethionine-load minus fasting tHcy concentration) exceeding the 95th percentile of local controls. SETTING: Outpatient clinic of internal medicine of a large non-academic teaching hospital. SUBJECTS: One hundred and seventeen hyperhomocysteinaemic subjects (vascular patients and first-degree relatives). INTERVENTIONS: There were four regimens: pyridoxine, 200 mg; folic acid, 5 mg; combination of folic acid 0.5 mg and pyridoxine 100 mg; and folic acid, 0.5 mg daily. RESULTS: All regimens, except pyridoxine 200 mg, significantly reduced fasting tHcy without differences in the percentage reduction (32-38%). All regimens produced a significant reduction in the increase in tHcy and postmethionine-load tHcy. The reduction in postmethionine-load tHcy was smaller for pyridoxine 200 mg than for combination therapy. No differences were found in the percentage reduction (for both increase in tHcy and postmethionine-load tHcy) between folic acid 5 mg and folic acid 0.5 mg. CONCLUSIONS: Monotherapy folic acid (0.5 mg daily) is the lowest effective therapy for reducing both fasting and postmethionine-load tHcy concentrations, with the same results as high-dose folic acid (5 mg daily). Pyridoxine has no additional value.

Hyperhomocysteinaemia as a cardiovascular risk factor: an update.

There is overwhelming epidemiological evidence that hyperhomocysteinaemia is an independent and graded cardiovascular risk factor, although a cause-and-effect relationship is still unproven. Acquired causes of hyperhomocysteinaemia include B-vitamin deficiencies and renal insufficiency. The most important inherited cause is a point mutation in methylenetetrahydrofolate reductase gene, which is, remarkably, not associated with an increased cardiovascular risk. A methionine loading test identifies substantially more subjects with hyperhomocysteinaemia compared with a fasting homocysteine determination alone. Repeated blood sampling is necessary due to an intra-individual variability in homocysteine concentrations up to 25%. A conservative reference value for fasting homocysteine is 15 micromol/l, although there seems to be no definite threshold in the presumed linear relation between homocysteine concentration and cardiovascular risk. The pathophysiological mechanism of homocysteine-induced cardiovascular disease is still not elucidated. The concept of endothelial dysfunction, demonstrated by impaired endothelium-dependent vasodilation, by oxidant damage has been confirmed in hyperhomocysteinaemic healthy adults. Folic acid supplementation (0.5 mg daily) can be considered the optimum homocysteine lowering therapy, with the exception of renal failure patients. Ongoing large prospective, randomised controlled clinical trials are investigating the potential beneficial effect of homocysteine lowering therapy on cardiovascular morbidity and mortality in subjects with hyperhomocysteinaemia.

Erythropoietin treatment for non-uremic patients: a personal view.

The correction of anemia in patients with chronic renal failure (CRF) has become the most important application of recombinant human erythropoietin (rHuEpo). The merits of rHuEpo therapy in patients with CRF are overt. Firstly, patients with CRF have an absolute deficiency in endogenous erythropoietin production and a relatively low maintenance dose of rHuEpo (often less than 100 IU/kg body weight per week) is effective in avoiding regular transfusions in the majority of the patients with CRF. Secondly, rHuEpo is able to avoid long-term complications of frequent transfusions (hemochromatosis, transfusion-transmissible diseases). Thirdly, patients with uremia notice a considerable improvement in quality of life (QOL) after initiation of rHuEpo. These advantages justify administration of this costly drug in CRF patients. The use of rHuEpo outside the setting of uremia do, however, not cover the complete spectrum of beneficial effects as compared to its use in (pre)dialysis patients. The aim of this overview is to provide some annotations on recently approved (cisplatin-induced anemia, preoperative anemia, zidovudine-related anemia) and possibly future (several types of malignancy and inflammation) indications for rHuEpo in non-uremic patients, leaving out the correction of anemia due to relatively uncommon disorders in the Dutch population (such as sickle cell anemia and thalassemia).

Iron metabolism and erythropoiesis after surgery.

BACKGROUND: This was a prospective study comparing the effect of major and minor surgery on haematological variables concerning erythropoiesis, iron metabolism and acute-phase response proteins. METHODS: Thirty-one otherwise healthy patients, 15 having major orthopaedic surgery and 16 undergoing minor surgery, were studied. Blood samples were taken before surgery and 1, 4, 10 and 28 days after operation. RESULTS: Haemoglobin concentration was decreased for up to 4 weeks after surgery. Serum erythropoietin concentration and reticulocyte count were raised after major surgery only. Serum iron concentration dropped the day after major (to 23 per cent of its preoperative level) and minor (to 46 per cent of its preoperative level) surgery and remained lower for up to 28 days after major surgery. Serum transferrin concentration and transferrin saturation decreased after both types of surgery while ferritin concentration increased. Serum transferrin receptor concentration increased only 4 weeks after major surgery (P < 0.01). The interleukin 6 peak (day 1) was greater after major than minor surgery, as was the C-reactive protein peak (day 4). CONCLUSION: Both major and minor surgery induce a state of hypoferraemia in the presence of adequate iron stores. The degree of this transient form of 'anaemia of chronic disease' is related to the extent of surgery. Iron supplementation in the first weeks after surgery (if iron stores were normal before operation) is ineffective.

Post-operative erythropoiesis is limited by the inflammatory effect of surgery on iron metabolism.

The decrease in haemoglobin concentration commonly observed after major surgery is usually corrected by red cell transfusions or oral iron medication. The increased awareness of blood-transmissible diseases has led to the restrictive use of homologous blood and to interest in alternatives for correcting anaemia. We investigated the pathophysiology of postoperative anaemia by studying variables of erythropoiesis, iron metabolism, and inflammation in 48 consecutive patients who underwent total hip replacement. Haemoglobin concentration remained low during 14 days after surgery with only a mild increase in erythropoietin concentration and reticulocyte count. No increase in serum transferrin receptor concentration was observed during the first 2 weeks after surgery. Postoperative serum ferritin increased, whereas serum iron, transferrin and transferrin saturation decreased significantly. There was a marked increase in interleukin-6 and C-reactive protein with maximal values on the 1st and 4th post-operative day, respectively. At 6 weeks after surgery, haemoglobin concentration and variables of iron metabolism were almost at the preoperative level and serum transferrin receptor concentration was significantly increased, indicating increased erythropoietic activity. These changes were preceded by the normalization of interleukin-6 and C-reactive protein levels. Haemoglobin, iron, transferrin, and ferritin concentrations were not influenced by iron therapy during the postoperative period and no differences of erythropoietic and iron variables were observed between transfused and non-transfused patients. In conclusion, post-operative erythropoiesis is associated with an inflammatory effect of surgery on iron metabolism, which can explain, despite a slightly increased production of erythropoietin, the persistence of anaemia and the lack of effect of iron supplementation after surgery.

Collection of autologous blood before elective hip replacement. A comparison of the results with the collection of two and four units.

The need for allogeneic blood can be reduced effectively with the use of preoperatively donated autologous blood. However, this collection also results in the waste of autologous blood in a considerable number of patients. In order to reduce overcollection, we requested that the amount of autologous blood donated before a total hip replacement be decreased from four units to two units. We then compared the amount of allogeneic blood required for fifty patients who had donated two units of autologous blood with that of fifty historical controls who had donated four units. The patients were matched for sex, initial hemoglobin concentration, and blood loss. There was no significant difference in the percentage of autologous donors who received additional allogeneic blood; 20 per cent (ten) of the patients who had donated two units and 16 per cent (eight) of the patients who had donated four units required allogeneic blood (p = 0.12). Eighteen autologous units from the patients who had donated two units and fifty-one units from the patients who had donated four units were discarded. The erythropoietic response, measured by the increase in the reticulocyte count, was comparable for the two groups. Iron stores, measured as the serum ferritin concentration, were lower after the drawing of four units (33 +/- 39 micrograms per liter) compared with after the drawing of two units (49 +/- 29 micrograms per liter) (p = 0.03). The donation of two units of blood does not increase the exposure to allogeneic blood compared with the exposure after the donation of four units by patients who are going to have a total hip replacement.(ABSTRACT TRUNCATED AT 250 WORDS)

Lower homologous blood requirement in autologous blood donors after treatment with recombinant human erythropoietin.

The risk of blood-borne diseases has substantially increased the use of autologous blood transfusion. Many autologous donors, however, still need homologous transfusions. To find out whether recombinant erythropoietin (rhEPO) reduces requirements for homologous blood transfusion, we carried out a randomised, controlled trial, in which patients were stratified according to blood volume. We studied 95 autologous blood donors undergoing elective hip surgery. 50 patients were randomly assigned 500 U/kg rhEPO subcutaneously twice a week for 3 weeks, and 45 patients received no treatment (control group). The patients each donated two units of blood before surgery. Only 5 (10%) rhEPO-treated patients received homologous transfusions compared with 16 (36%) controls (p < 0.01). rhEPO was most useful in patients with a blood volume below 4 L and an estimated blood loss below 2 L or with a blood volume of 4-5 L and blood loss of 1-2 L. Continued administration of rhEPO caused no further increase in reticulocyte counts after the fourth injection, which was accompanied by a pronounced depletion of storage iron. rhEPO treatment had no effect on renal function, platelet count, or blood pressure. Subcutaneous rhEPO is an effective and safe way to reduce exposure to homologous blood in autologous donors. Its use can be restricted to a subpopulation of autologous blood donors, which improves the cost-effectiveness of this expensive approach.

The effect of recombinant human erythropoietin on hemostasis, fibrinolysis, and blood rheology in autologous blood donors.

Treatment with recombinant human erythropoietin (rhEPO) for the anemia of end-stage renal disease has been associated with thrombotic complications. To detect prothrombotic changes in autologous blood donors given 500 U/kg rhEPO subcutaneously (twice weekly during a 3-week period), changes in variables of hemostasis and fibrinolysis and in blood rheology before and at the end of treatment were investigated. In 21 patients, platelet count increased from 272 +/- 55 x 10(9)/L to 313 +/- 55 x 10(9)/L (p < 0.05). Although activated partial thromboplastin time and protein C antigen decreased significantly during rhEPO treatment, these changes remained within normal ranges. No changes in the hemostatic variables prothrombin time, fibrinogen, factor V, von Willebrand factor antigen, antithrombin III activity, protein S antigen, and prothrombin fragments F 1 + 2 were found. Measurements of plasminogen activity, alpha 2-antiplasmin activity, tissue plasminogen activator, and plasminogen activator inhibitor-1, representing variables of fibrinolysis, were normal and constant during the study. In 5 patients no changes in red cell deformability and whole blood viscosity, corrected for differences in hematocrit, were observed. Plasma viscosity showed a slight but clinically not relevant increase in 4 out of 5 patients. The absence of evident (pro)thrombotc changes in this study confirms the safety of high-dose rhEPO therapy in autologous blood donors, who donate 2 units (i.e., 2 x 450 ml) of blood.

Erythropoietic activity and iron metabolism in autologous blood donors during recombinant human erythropoietin therapy.

The use of recombinant human erythropoietin (rhEPO) to intensify the erythropoietic response in autologous donors may reduce homologous blood requirement. We studied the effect of subcutaneous rhEPO (500 U kg-1 body weight twice weekly during a 3 week period) on variables of erythropoiesis and iron metabolism in 62 autologous blood donors, of whom 32 received rhEPO (epo group) and 30 did not (control group). Patients donated only 2 units of blood and received oral iron in order to restrict phlebotomy-induced decrease of iron stores. Pre-phlebotomy haemoglobin concentration (14.0 +/- 0.8 g dl-1) was completely regenerated in the epo group at surgery (13.7 +/- 1.3 g dl-1); haemoglobin concentration in the control group fell from 13.5 +/- 1.4 g dl-1 to 11.6 +/- 1.4 g dl-1 after the phlebotomies and did not improve during the pre-operative phase. Total erythropoietic activity expressed as serum transferrin receptor concentration (sTfR) showed a 4-fold increase from 3.8 +/- 0.9 micrograms ml-1 to 14.9 +/- 4.8 micrograms ml-1 in the epo group. Effective erythropoietic activity measured by absolute reticulocyte count, however, declined after the fourth rhEPO injection in the epo group. Serum ferritin was lower in the epo group, but no differences in serum iron, transferrin concentration and transferrin saturation were observed between the groups. A marked increase in free erythrocyte protoporphyrin (FEP) was observed in the epo group, whereas FEP levels in the controls remained within normal ranges. Despite oral iron supplementation and the limited number of phlebotomies, the effect of rhEPO therapy in autologous donors is restricted by iron depletion.

Red blood cell transfusions for total hip replacement in a regional hospital. A six-year analysis.

To evaluate changes in the need for homologous blood and to assess the impact of autologous blood transfusion, red cell transfusions in unilateral total hip replacement surgery, performed electively in the period 1986-1991, were studied in a regional hospital. Transfusion data, perioperative blood loss and post-operative haemoglobin concentration of 495 patients were analysed. From 1986 to 1991, the percentage of patients not transfused with homologous blood increased from 18.5 to 45.5%. After the introduction of an autologous blood transfusion programme in 1987, 116 of 430 patients (27.0%) donated autologous blood. No increase in the percentage of autologous donors was observed during the study. Most common reasons for nonparticipation were the patient's age, doctors' underordering and logistic limitations. 81.9% of autologous donors had total hip replacement surgery without homologous transfusions. Mean blood loss reduced significantly from 1,373 +/- 781 ml in 1986 to 958 +/- 582 ml in 1991 (p < 0.001). Transfusion requirement in the nonautologous patients fell from 2.6 +/- 1.8 units in 1986 to 1.4 +/- 1.4 units per patient in 1989 and increased thereafter to 2.2 +/- 2.1 units in 1991 (p < 0.01) and showed a strong correlation with blood loss (r = 0.58; p < 0.001). No changes in postoperative haemoglobin concentration were observed throughout the study. In conclusion, collection of autologous blood is effective, albeit still underutilized, to reduce homologous blood requirement. The close correlation between blood loss and transfusion requirement accentuates the role of surgical practice in the reduction of homologous transfusions.

Recombinant human erythropoietin in autologous blood donors: a dose-finding study.

A dose-finding study of recombinant human erythropoietin (rhEPO) was performed in 60 autologous donors who donated 2 units of blood prior to orthopaedic or vascular surgery. The correction of phlebotomy-induced anaemia was studied in four groups of 15 patients who received 500 U/kg, 250 U/kg, 125 U/kg or no (controls) rhEPO subcutaneously twice per week during a 3-week period. Haemoglobin concentration in the 500 U/kg, 250 U/kg and 125 U/kg group and in the controls reached respectively 99.2, 98.8, 91.9 and 87.1% of pre-phlebotomy value. Flow cytometric analysis of reticulocytes showed a steady increase of reticulocyte count as the dose increased. Maximal levels of high fluorescence reticulocytes which represent early changes of erythropoiesis were reached after 7 d and decreased thereafter in each group. Serum ferritin decreased significantly to approximately 50% of baseline values in all groups; no differences in the decrease of serum ferritin were observed between the patients who received rhEPO and the controls. No severe adverse events were observed. This study demonstrates a dose-related effect of rhEPO on erythropoiesis in autologous donors during the first 2 weeks. No further increase of reticulocytes was observed despite continued rhEPO therapy, which may be due to the inability of the mononuclear phagocytic system to release additional iron. To restore pre-phlebotomy haemoglobin concentration, a dose of 250 U/kg rhEPO was sufficient.

The efficacy of subcutaneous recombinant human erythropoietin in the correction of phlebotomy-induced anemia in autologous blood donors.

The efficacy of subcutaneous recombinant human erythropoietin (rhEPO) (500 U/kg; administered twice a week during the 3 weeks before surgery) in the recovery of preoperative hemoglobin concentrations within a 3-week period was studied in 40 patients, each of whom donated 2 units (900 mL) of blood for their own use before total hip replacement surgery. Twenty autologous blood donors received rhEPO (EPO group) and 20 were not treated (control group). The initial hemoglobin concentration (14.0 +/- 1.0 g/dL [140 +/- 10 g/L]) was completely recovered before surgery (14.0 +/- 1.6 g/dL [140 +/- 16 g/L]) in the EPO group, while a decrease from 13.8 +/- 1.1 to 12.2 +/- 1.3 g per dL (138 +/- 11 to 122 +/- 13 g/L) was observed in the control group. The preoperative reticulocyte count showed more than sixfold increase in the EPO group, whereas a twofold to threefold increase was found in the control group. Serum ferritin concentration fell to 42 +/- 29 micrograms per L in the EPO group and to 54 +/- 35 micrograms per L in the control group. The postoperative serum erythropoietin concentration in the EPO group was significantly lower than that in the control group, but it did not differ from the pretreatment value and was attended by a higher hemoglobin concentration after surgery. Only transient flu-like symptoms were mentioned by patients who were treated with rhEPO. Changes in blood pressure or platelet count or other adverse events were not observed.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of oral iron supplementation on erythropoiesis in autologous blood donors.

The effect of oral iron supplementation on erythropoiesis was studied prospectively in 34 autologous blood donors. The subjects, all of whom were to undergo total hip surgery, had normal iron status at the start of the study. During the preoperative period, in which 4 units of blood were collected, 17 patients received oral iron supplementation with 287 mg of ferrous sulfate (105 mg of elemental iron/day), while 17 patients did not use any iron supplementation. Oral iron supplementation during the 4-week preoperative period lessened the decrease in ferritin levels after two phlebotomies. Neither the decrease in hemoglobin nor the increase in erythropoietin levels was influenced by iron supplementation. In both iron-supplemented and control patients, serum erythropoietin levels returned to initial values within a few days after surgery. In autologous blood donors with a normal iron status, the use of supplemental iron does not affect erythropoiesis and is insufficient to maintain iron stores.

[Experiences in clinic and blood bank with a program for preoperative donation of autologous blood]. / Ervaringen van kliniek en bloedbank met een programma voor preoperatieve donatie van autoloog bloed.

In the period from March 1987 to January 1988 a programme for donation of autologous blood was carried out within the existing cooperation between a regional blood bank and a general hospital. Various organizational problems were avoided by means of a special consulting hour and introduction of a special consultation form. Blood was taken a total of 144 times from 49 orthopaedic patients. No serious problems were encountered; three times, withdrawal of a unit of blood had to be refrained from. Of the 144 units of red cell suspension, 107 (73.3%) were reinfused, while seven patients still required administration of homologous blood. The variations of haemoglobin level, haematocrit, reticulocyte count and red cell distribution width suggest stimulation of erythropoiesis by repeated withdrawal of blood at brief intervals. In the preoperative phase, there were no pronounced differences in this respect between patients who were and those who were not given supplementary iron. Autologous blood transfusion constitutes a safe, valuable addition to the current transfusion forms and is possible within the existing organizations in The Netherlands.