| 1. |
- Beshara, Soheir, et al.
(författare)
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Anemia associated with advanced prostatic adenocarcinoma : Effects of recombinant human erythropoietin
- 1997
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Ingår i: The Prostate. - 0270-4137 .- 1097-0045. ; 31:3, s. 153-160
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND METHODS: Nine patients with hormone-refractory metastatic prostatic adenocarcinoma and anemia were treated with recombinant human erythropoietin (rHuEpo) at a median dose of 150 U/kg BW 3 times a week subcutaneously. Baseline hemoglobin (Hb) ranged from 70 to 116 g/L, and the study duration was 12 weeks (median patient participation period was 8 weeks). RESULTS: Four patients demonstrated a median Hb increase of 20 g/L and were considered responders. Three patients showed a median increase of 17 g/L but required blood transfusion once, and were therefore considered as partial responders. Baseline erythropoietic status showed a significant correlation between serum Epo and Hb. Inadequate Epo production, evaluated by the observed/predicted log Epo ratio, was found in two patients. Defective bone marrow activity, demonstrated by low transferrin receptor (TfR), and hypoferremia in spite of abundant iron stores were also shown. Hemorheological investigations showed elevated plasma viscosity. CONCLUSIONS: Our results indicate that suppression of erythropoiesis can be mainly explained by the depressed marrow activity. The altered hemorheology might contribute to the anemia. This anemia could possibly be corrected with rHuEpo.
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| 2. |
- Beshara, Soheir, et al.
(författare)
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Assessment of erythropoiesis following renal transplantation
- 1997
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Ingår i: European Journal of Haematology. - 0902-4441 .- 1600-0609. ; 58:3, s. 167-173
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Tidskriftsartikel (refereegranskat)abstract
- Ten patients, who received cadaveric kidneys, were followed for 24 wk with serial measurements of serum erythropoietin (S-Epo), transferrin receptor (S-TfR) and iron variables. The mean pretransplant creatinine clearance was 8.2 (range 0-22) ml/min and the mean haemoglobin (Hb) level was 99 +/- 18.6 (range 66-124) g/l. Nine patients demonstrated a gradual increase in S-Epo levels, which reached a peak, and was accompanied by a parallel increase in S-TfR levels with a median lag period of 3 wk between both peaks. Hb correction followed the S-TfR peak after a second lag period (median 7 wk). Elevated S-Epo and S-TfR did not result in correction of anaemia in 1 patient due to impaired graft function. Within 4 months, S-Epo levels reached the normal range while TfR levels were higher than normal. Follow-up of iron status demonstrated the development of iron deficiency in 5 patients, which was corrected spontaneously. Improvement in erythropoiesis after renal transplantation seems to occur by means of expansion of the erythroid marrow, as detected by increasing S-TfR levels, subsequent to a S-Epo peak. This expansion precedes Hb normalization. A nonuraemic environment is probably a prerequisite for the correction of anaemia but not for the increase in S-Epo or S-TfR levels. Iron deficiency may occur after transplantation due to an increase in iron utilization.
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| 3. |
- Beshara, Soheir
(författare)
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Erythropoiesis in anemia of rencl failure and malignancy : Studies on erythropoietin, iron, and transferrin receptor : by Soheir Beshara
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Erythropoietin (Epo) and iron are essential requirements for erythropoiesis. Serum transferrin receptor (S-TfR) is a marker of total erythropoiesis and tissue iron availability. In patients with renal insufficiency, successful renal transplantation leads to correction of anemia and improvement in erythropoiesis. Recombinant human erythropoietin (rHuEpo) has been shown to correct anemia in patients with solid tumors. Adjustment of the iron status remains a prerequisite for correction of the anemia. The aim of this work was to study erythropoiesis following renal transplantation and in patients with prostatic adenocarcinoma receiving rHuEpo therapy. Pharmacokinetics and red cell utilization of iron(III) hydroxide-sucrose complex were also studied.Follow-up of renal transplant patients showed a gradual increase in S-Epo levels, accompanied by a parallel increase in S-TfR levels, with a median lag period of 3 weeks between the two peaks. Hemoglobin (Hb) correction followed the S-TfR peak after a second lag period. These results indicate that improvement in erythropoiesis after renal transplantation seems to occur by means of expansion of the erythroid marrow subsequent to an Epo peak. This expansion precedes Hb normalization. Iron deficiency may occur after transplantation- as a result of an increase in iron utilization.Patients with prostatic adenocarcinoma and anemia displayed low S-TfR, hypoferremia in spite of abundant iron stores, and elevated plasma viscosity. Following treatment with rHuEpo, four patients showed a median Hb increase of 20 g/l, while in three patients there was a median increase of 17 g/I, but each of the latter three required blood transfusion on one occasion. The results indicate that suppression of erythropoiesis can be mainly explained by the depressed marrow activity. The altered hemorheology might contribute to this anemia, which could possibly be corrected with rHuEpo.Positron emission tomography (PET) was applied to study the distribution characteristics of a single intravenous injection of 100 mg iron(III) hydroxide-sucrose complex (Venofer®) labeled with 52Fe and followed for some hours. There was pronounced radioactive uptake by the liver, spleen and bone. The radioactive uptake by the macrophage-rich spleen demonstrates the reticuloendothelial uptake of this iron preparation, with its subsequent effective release for marrow utilization. Red cell utilization of the iron complex, followed for four weeks, ranged from 59% to 97%. A kinetic analysis using a three-compartment model (namely blood pool, reversible, and irreversible tissue pools) showed a fairly high distribution volume but a low influx rate constant in the liver as compared with the bone marrow. The bone marrow influx rate constant was steady, indicating non-saturation of the transport system.
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| 4. |
- Beshara, Soheir, et al.
(författare)
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Kinetic analysis of 52Fe-labelled iron(III) hydroxide-sucrose complex following bolus administration using positron emission tomography
- 1999
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 104:2, s. 288-295
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Tidskriftsartikel (refereegranskat)abstract
- Kinetic analysis of a single intravenous injection of 100 mg iron(III) hydroxide-sucrose complex (Venofer) mixed with 52Fe(III) hydroxide-sucrose as a tracer was followed for 3-6 h in four generally anaesthetized, artificially ventilated minipigs using positron emission tomography (PET). The amount of injected radioactivity ranged from 30 to 200 MBq. Blood radioactivity, measured by PET in the left ventricle of the heart, displayed a fast clearance phase followed by a slow one. In the liver and bone marrow a fast radioactivity uptake occurred during the first 30 min, followed by a slower steady increase. In the liver a slight decrease in radioactivity uptake was noted by the end of the study. A kinetic analysis using a three-compartment (namely blood pool, reversible and irreversible tissue pools) model showed a fairly high distribution volume in the liver as compared with the bone marrow. In conclusion, the pharmacokinetics of the injected complex was clearly visualized with the PET technique. The organs of particular interest, namely the heart (for blood kinetics), liver and bone marrow could all be viewed by a single setting of a PET tomograph with an axial field of view of 10 cm. The half-life (T1/2) of 52Fe (8.3 h) enables a detailed kinetic study up to 24 h. A novel method was introduced to verify the actual 52Fe contribution to the PET images by removing the interfering radioactive daughter 52mMn positron emissions. The kinetic data fitted the three-compartment model, from which rate constants could be obtained for iron transfer from the blood to a pool of iron in bone marrow or liver to which it was bound during the study period. In addition, there was a reversible tissue pool of iron, which in the liver slowly equilibrated with the blood, to give a net efflux from the liver some hours after i.v. administration. The liver uptake showed a relatively long distribution phase, whereas the injected iron was immediately incorporated into the bone marrow. Various transport mechanisms seem to be involved in the handling of the injected iron complex.
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| 5. |
- Beshara, Soheir, et al.
(författare)
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Pharmacokinetics and red cell utilization of 52Fe/59Fe-labelled iron polymaltose in anaemic patients using positron emission tomography
- 2003
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 120:5, s. 853-859
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Tidskriftsartikel (refereegranskat)abstract
- Parenteral iron-polysaccharide complexes are increasingly applied. The pharmacokinetics of iron sucrose have been assessed by our group using positron emission tomography (PET). A single intravenous injection of 100 mg iron as iron (III) hydroxide-polymaltose complex, labelled with a tracer in the form of 52Fe/59Fe, was similarly assessed in six patients using PET for about 8 h. Red cell utilization was followed for 4 weeks. Iron polymaltose was similarly distributed to the liver, spleen and bone marrow. However, a larger proportion of this complex was rapidly distributed to the bone marrow. The shorter equilibration phase for the liver, about 25 min, indicates the minimal role of the liver for direct distribution. Splenic uptake also reflected the reticuloendothelial handling of this complex. Red cell utilization ranged from 61% to 99%. Despite the relatively higher uptake by the bone marrow, there was no saturation of marrow transport systems at this dose level. In conclusion, high red cell utilization of iron polymaltose occurred in anaemic patients. The major portion of the injected dose was rapidly distributed to the bone marrow. In addition, the reticuloendothelial uptake of this complex may reflect the safety of polysaccharide complexes. Non-saturation of transport systems to the bone marrow indicated the presence of a large interstitial transport pool, which might possibly be transferrin.
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| 6. |
- Beshara, Soheir, et al.
(författare)
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Pharmacokinetics and red cell utilization of iron(III) hydroxide- sucrose complex in anaemic patients: a study using positron emission tomography
- 1999
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 104:2, s. 296-302
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Tidskriftsartikel (refereegranskat)abstract
- The pharmacokinetics of a single intravenous injection of 100 mg iron hydroxide-sucrose complex labelled with a tracer in the form of 52Fe/59Fe was followed in six anaemic patients for a period ranging from 6 to 8 3 h using positron emission tomography (PET). Red cell utilization of the labelled iron was followed for 4 weeks. PET data showed radioactive uptake by the liver, spleen and bone marrow. The uptake by the macrophage-rich spleen demonstrated the reticuloendothelial uptake of this iron preparation, with subsequent effective release of that iron for marrow utilization. Red cell utilization, followed for 4 weeks, ranged from 59% to 97%. The bone marrow influx rate constant was independent of blood iron concentration, indicating non-saturation of the transport system in bone marrow. This implied that higher doses of the iron complex can probably be used in the same setting. A higher influx rate into the marrow compared with the liver seemed to be consistent with higher red cell utilization. This would indicate that early distribution of the injected iron complex may predict the long-term utilization.
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| 7. |
- Beshara, Soheir, et al.
(författare)
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Varying intervals of subcutaneous epoetin alfa in hemodialysis patients
- 2004
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Ingår i: JN. Journal of Nephrology (Milano. 1992). - 1121-8428 .- 1724-6059. ; 17:4, s. 525-530
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUND: The optimal subcutaneous (SC) epoetin alfa strategy is unestablished. The individual variability in dose requirements needs consideration. In this study, prolonged intervals were assessed in relation to varying dose requirements. METHODS: The study included 153 hemodialysis (HD) patients on stable SC epoetin alfa. Based on dose requirements, the patients received either 4,000 U (group I, n=51) or 10,000 U (group II, n=102) as whole 1 mL vials at prolonged intervals. The study comprised three 8-week periods: an initial period maintaining the basal regimens, an adjustment period where the intervals were prolonged, and a maintenance period. Alterations in hemoglobin (Hb), weekly doses and intervals in each group were compared. RESULTS: One hundred and thirty-seven patients completed the study (48 in group I and 89 in group II). In group I, the mean interval was prolonged from 5.4 +/- 1.9 to 7.8 +/- 3.1 days (p=0,01) with stable Hb and EPO doses. In group II, prolonged intervals were associated with a reduction in mean Hb below target level and a significant increase in EPO doses (p=0,002). Iron deficiency and inflammation could explain the poor response in approximately one-third of the patients. CONCLUSIONS: In HD patients, the optimal injection frequency should be individually adjusted. Prolonged intervals can be applied to patients with low-dose requirements. Observing iron status and inflammation is necessary for optimal response.
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| 8. |
- Lorenz, Fryderyk, et al.
(författare)
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Ferritinemia and serum inflammatory cytokines in Swedish adults with Gaucher disease type 1
- 2018
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Ingår i: Blood Cells, Molecules & Diseases. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 1079-9796 .- 1096-0961. ; 68, s. 35-42
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Tidskriftsartikel (refereegranskat)abstract
- Background: The storage of glucosylceramide in macrophages produces an inflammatory response in Gaucher disease type 1 (GD1) resulting in iron metabolism dysregulation and cytokine release. Patients and methods: The study included 16 adults with GD1 aged 20-86 years. All but one patient carried at least one allele with the c.1226A > G (N370S) mutation in the GBA1 gene. Ferritinemia, iron metabolism profiles including hepcidin, and inflammatory cytokine concentrations were assessed in GD1 patients in Sweden. Results: Hyperferritinemia was present in 81% of patients. There was no correlation between hyperferritinemia and patient's gender, spleen status, or clinical status. Hepcidin was discrepantly low in relation to ferritin levels. TNF-alpha was moderately increased in 5 of 11 patients; 2 patients with the highest TNF-alpha concentrations showed mildly elevated IL-6 levels. The concentrations of IL-1 beta, IL-8, and IL-10 were normal in all patients. Upon treatment, ferritinemia ameliorated but S-ferritin levels did not normalize. The increased TNF-alpha level however, normalized in all treated patients, reaching the lowest values after 2 years of therapy and continued to be stable during the remaining 2 years of follow-up. Conclusions: Hyperferritinemia is a frequent finding in GD1 in Sweden. The relatively low hepcidin levels reveal a distorted relationship between hepcidin and ferritin in GD1. Therapy has the potential to not only ameliorate hyperferritinemia but to also normalize the serum TNF-alpha concentration in GD1.
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| 9. |
- Lubberink, Mark, et al.
(författare)
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Quantification aspects of patient studies with 52Fe in positron emission tomography
- 1999
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Ingår i: Applied Radiation and Isotopes. - 0969-8043 .- 1872-9800. ; 51:6, s. 707-715
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Tidskriftsartikel (refereegranskat)abstract
- Quantification accuracy in positron emission tomography (PET) using non-pure positron emitters, such as 52Fe, may be influenced by gamma radiation emitted in the decay of these isotopes. High-energy positrons, emitted in the decay of the 52Fe-daughter 52mMn, also affect the quantification accuracy. A specific problem of the 52Fe/52mMn decay chain in vivo is that the kinetics of iron and manganese are different, and that PET cannot discriminate between the two nuclides. The effect of the decay properties of 52Fe/52mMn on the performance of PET was investigated using phantoms. Minor degradation in PET performance was found for 52Fe/52mMn compared to the pure low-energy positron emitter 18F. A method is presented to obtain a correction factor for the 52mMn radioactivity in blood. A model for correction of 52mMn-radioactivity in organs, based on existing data on manganese kinetics, is given. The presented corrections are discussed and illustrated in a patient study.
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| 10. |
- Lundqvist, Hans, et al.
(författare)
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Positron emission tomography and radioimmunotargeting : general aspects
- 1999
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Ingår i: Acta Oncologica. - 0284-186X .- 1651-226X. ; 38:3, s. 335-341
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Tidskriftsartikel (refereegranskat)abstract
- To optimize radioimmunotherapy, in vivo information on individual patients, such as radionuclide uptake, kinetics, metabolic patterns and optimal administration methods, is important. An overriding problem is to determine accurately the absorbed dose in the target organ as well as critical organs. Positron Emission Tomography (PET) is a superior technique to quantify regional kinetics in vivo with a spatial resolution better than 1 cm3 and a temporal resolution better than 10 s. However, target molecules often have distribution times of several hours to days. Conventional PET nuclides are not applicable and alternative positron-emitting nuclides with matching half-lives and with suitable labelling properties are thus necessary. Over many years we have systematically developed convenient production methods and labelling techniques of suitable positron nuclides, such as 110In(T(1/2) = 1.15 h), 86Y(T(1/2) = 14 h), 76Br(T(1/2) = 16 h) and 124I(T(1/2) = 4 days). 'Dose planning' can be done, for example, with 86Y- or 124I-labelled ligands before therapy, and 90Y- and 131I-labelled analogues and double-labelling, e.g. with a 86Y/90Y-labelled ligand, can be used to determine the true radioactivity integral from a pure beta-emitting nuclide. The usefulness of these techniques was demonstrated in animal and patient studies by halogen-labelled MAbs and EGF-dextran conjugates and peptides chelated with metal ions.
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