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      Tissue-to-Blood Transport of Radiolabelled Immunoglobulin Injected into the Web Spaces of the Hands of Normal Subjects and Patients with Breast Cancer-Related Lymphoedema

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          Aim: The ability to return interstitial protein to central blood is key to the defence against oedema. The aim of this study was to quantify this ability by measuring the rate at which radiolabelled human immunoglobulin (HIgG) accumulated in blood following injection into the subcutis of the hand in normal volunteers and in patients with breast cancer-related lymphoedema (BCRL). Methods: A total of 37 control subjects (healthy normal volunteers or breast cancer patients prior to treatment) and 18 women with BCRL were studied with dual-isotope lymphoscintigraphy. Each received bilateral subcutaneous depot injection in the dorsal web space of HIgG labelled with Tc-99m on one side and In-111 on the other. Activities remaining at the depot and accumulating in blood were measured at regular intervals for 3 h. Clearance from the depot was exponential and expressed as the rate constant k<sub>depot</sub> (min<sup>–1</sup>). Accumulation in blood was essentially linear and, using an estimate of blood volume based on height and weight, was expressed as the linear constant b<sub>blood</sub> (% administered activity·min<sup>–1</sup>). The time axis intercept of this linear fit was recorded as an index of the minimum time to arrival of radioprotein in blood. The efficiency with which radioprotein that has left the depot (extra-depot activity) is transported into blood [tissue-to-blood (T-B) transport] was quantified (1) as the quotient b<sub>blood</sub>/k<sub>depot</sub>, and (2) as a function of time after injection by comparing the total amount of radioprotein in blood at any time with the total amount of radioprotein that was no longer in the depot at the same time. Results: Tc-99m-HIgG and In-111-HIgG behaved similarly and are interchangeable. At all times between 60 and 180 min in controls, about 50% of protein that had left the depot was present in blood. T-B transport was reduced to about 20% in BCRL arms in which the hand was involved in swelling (p < 0.001 versus controls), but remained unchanged in patients in whom the hand was spared. The minimum time to arrival of radioprotein in blood was not reduced in BCRL; on the contrary, there appeared to be a small proportion of injected activity that arrived rapidly in blood in BCRL patients but not in controls. Conclusion: We conclude that T-B transport is only impaired in BCRL when radioprotein is injected into swollen tissue. Significant quantities of radioprotein may escape from the arm via local access to blood. Individual variation in this capacity may explain the regional sparing observed in BCRL.

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          The preparation and labeling of DTPA-coupled albumin.

          A new method has been developed for the coupling of diethylenetriaminepentaacetic acid (DTPA) to proteins using the cyclic anhydride of DTPA. The anhydride, prepared by a simple one-step synthesis, is added as the solid to the solid protein. Coupling is completed in minutes at room temperature following the addition of aqueous pH 7 buffer. The coupling has been characterized by the use of exhaustive dialysis, gel chromatography, and u.v. spectrophotometry. Under optimal conditions of anhydride: protein molar ratio and protein concentration, up to 70% of the DTPA groups may be coupled to protein. Essentially all free DTPA may be removed from DTPA-coupled albumin preparations by a single passage through a 20-cm gel filtration column. Biodistributions in normal mice at 45 min obtained for 111In-albumin showed 33 +/- 1% injected dose per gram in blood compared to 35 +/- 3% for 125I-albumin. Results for all tissue samples are in agreement within two standard deviations. The simplicity with which albumin has been coupled with DTPA by this method contrasts sharply with existing methods and is an attractive area of research for the labeling of a variety of proteins with a variety of metallic radionuclides.
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            Assessment of abnormal lymph drainage for the diagnosis of lymphedema by isotopic lymphangiography and by indirect lymphography

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              Differences in lymph drainage between swollen and non-swollen regions in arms with breast-cancer-related lymphoedema.

              Recent research indicates that the pathophysiology of breast-cancer-related lymphoedema (BCRL) is more complex than simple axillary lymphatic obstruction as a result of the cancer treatment. Uneven distribution of swelling (involvement of the mid-arm region is common, but the hand is often spared) is puzzling. Our aim was to test the hypothesis that local differences in lymphatic drainage contribute to the regionality of the oedema. Using lymphoscintigraphy, we measured the removal rate constant, k (representing local lymph flow per unit distribution volume, VD), for 99mTc-labelled human immunoglobulin G in the oedematous proximal forearm, and in the hand (finger web) in women in whom the hand was unaffected. Tracer was injected subcutaneously, and the depot plus the rest of the arm was monitored with a gamma-radiation camera for up to 6 h. VD was assessed from image width. Contralateral arms served as controls. k was 25% lower in oedematous forearm tissue than in the control arm (BCRL, -0.070+/-0.026% x min(-1); control, -0.093+/-0.028% x min(-1); mean+/-S.D.; P=0.012) and VD was greater. In the non-oedematous hand of the BCRL arm, k was 18% higher than in the control hand (BCRL, -0.110+/-0.027% x min(-1); control, -0.095+/-0.028% x min(-1); P=0.057) and 59% higher than forearm k on the BCRL side (P=0.0014). VD did not differ between the hands. Images of the BCRL arm following hand injection showed diffuse activity in the superficial tissues, sometimes extending almost to the shoulder. A possible interpretation is that the hand is spared in some patients because local lymph flow is increased and diverted along collateral dermal routes. The results support the hypothesis that regional differences in surviving lymphatic function contribute to the distribution of swelling.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                April 2004
                21 April 2004
                : 41
                : 2
                : 183-192
                aCambridge Breast Unit, bDepartment of Nuclear Medicine, Addenbrooke’s Hospital, Cambridge, cDepartment of Physiological Medicine, St George’s Hospital Medical School, London, UK
                77289 J Vasc Res 2004;41:183–192
                © 2004 S. Karger AG, Basel

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                Page count
                Figures: 5, Tables: 1, References: 30, Pages: 10
                Research Paper


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