Global abnormalities in lymphatic function following systemic therapy in patients with breast cancer.

BACKGROUND: Breast cancer-related lymphoedema (BCRL) is a result of interaction between several pathophysiological processes, and is not simply a 'stopcock' effect resulting from removal of axillary lymph nodes. The aim of this study was to test the hypothesis that there is a constitutional 'global' lymphatic dysfunction in patients who develop BCRL. METHODS: Lower-limb lymphoscintigraphy was performed in 30 women who had undergone axillary lymph node dissection at least 3 years previously, of whom 15 had BCRL and 15 did not. No patient had any clinical abnormality of the lower limb. The control group comprised 24 women with no history of cancer or lower-limb lymphoedema. (99m) Tc-Nanocoll was injected subcutaneously into the first webspace of each foot, followed by whole-body imaging. Scans were reported as abnormal if there was delay in lymph transport or rerouting through skin or deep system. Quantification was expressed as the percentage injected activity accumulating in ilioinguinal nodes. RESULTS: Mean(s.d.) ilioinguinal nodal accumulation at 150 min was significantly lower in women with BCRL than in those without (2·7(2·5) versus 5·9(4·8) per cent respectively; P = 0·006). Abnormal findings on lower-limb lymphoscintigraphy were observed in 17 of the 30 patients: ten of the 15 women who had BCRL and seven of the 15 who did not. None of the 24 control subjects had abnormal scan findings. CONCLUSION: Women with BCRL had reduced lower-limb lymph drainage, supporting the hypothesis of a predisposition to BCRL. A surprisingly high proportion of patients with breast cancer also demonstrated lymphatic dysfunction, despite clinically normal lower limbs. Possible explanations could be a systemic effect of breast cancer or its treatment, or an unidentified association between breast cancer and lymphatic dysfunction. REGISTRATION NUMBER: ISRCTN84866416 ( http://www.isrctn.com).

Estimation of lean body mass in children.

BACKGROUND: In adults, dosages of some anaesthetic agents are based on lean body mass (LBM) rather than body weight. Our aim was to derive an equation for estimating LBM in children. METHODS: Patients comprised three groups: prospective kidney transplant donors from two separate centres (centres 1 and 3) and children referred to a further centre (centre 2) for the routine clinical measurement of glomerular filtration rate (GFR). GFR and extracellular fluid volume (ECV) were measured using Cr-51-EDTA. LBM was directly estimated (eLBM) in adults using an equation based on height and weight. ECV in children was estimated (eECV) from another equation based on height and weight, converted to eLBM using the relationship between eLBM and ECV determined in the adults from centre 1 and then compared with adult data from centre 3. RESULTS: In children, the ratio of eECV to ECV was 1.04 (SD 0.18). In centre 1, eLBM (kg) was 3.81 (SD 0.55) times greater than ECV (litres) in men (n=50) and 3.77 (0.77) times greater in women (n=51). eLBM in children was therefore derived by multiplying eECV by 3.8. In children, eLBM showed a close linear correlation with measured ECV (eLBM=3.50ECV+2.0; R(2)=0.857), similar to adults (eLBM=2.82ECV+14.5; R(2)=0.582). In all groups, eLBM/weight correlated inversely with weight. CONCLUSIONS: In terms of the relationships between eLBM, ECV, and weight, children are similar to adults. Therefore, drug dosage in children should also be based on eLBM rather than weight.

Obesity does not accelerate the decline in glomerular filtration rate associated with advancing age.

Obesity has been suggested as a risk factor for chronic kidney disease. However, it has also been suggested that the association between obesity and impaired glomerular filtration rate (GFR) arises from the invalid use of body surface area (BSA) for scaling. This study assesses the effect of obesity on GFR by comparing the age-dependent decline in obese (body mass index (BMI) >30 kg/m(2); n=149) and non-obese patients (n=589), aged >30 years, referred for measurement of GFR (Cr-51-EDTA and three blood samples). GFR was scaled to a BSA of 1.73 m(2) (GFR/BSA) and extracellular fluid volume of 13 l (GFR/ECV), both corrected for the one-compartment assumption. When non-obese patients were categorized into 10-year age brackets (from 31 to >70), GFR/BSA and GFR/ECV declined from 92 ml per min per 1.73 m(2) and 95 ml per min per 13 l, respectively, at 31-40 years to 58 and 59 at >70. The declines in obese patients were similar with corresponding values of 88 ml per min per 1.73 m(2) and 97 ml per min per 13 l at 31-40 and 57 and 59 at >70 years. Linear regression analysis of non-categorized data from age 40 years showed rates of decline slightly slower in the obese (0.82 vs 0.95 ml per min per 1.73 m(2) per year and 0.87 vs 1.02 ml per min per 13 l per year). No effect of obesity on renal function was shown. Scaling to BSA did not distort the results.

Measurement of lymphatic function with technetium-99m-labelled polyclonal immunoglobulin.

A reliable method for measuring lymph flow in physiological units would be valuable, especially in conditions in which it is uncertain whether lymph flow is increased or decreased. The requirements of a radiopharmaceutical for such measurement include stable radionuclide labelling and rapid access to lymphatic vessels following tissue injection but no access to blood vessels. A soluble macromolecule is likely to come closest to meeting these requirements. Technetium-99m-labelled human polyclonal immunoglobulin (HIG) was therefore investigated firstly in comparison with 99mTc-labelled human serum albumin (HSA) in patients undergoing routine lymphoscintigraphy and secondly with respect to injection site in a group of volunteers with post-mastectomy oedema (PMO). Subcutaneous injection of 99mTc-HIG into the web space of a distal extremity gave images in which lymphatic vessels were more clearly defined compared with images obtained after injection of 99mTc-HSA. Lymph nodes were also more clearly defined, suggesting specific retention of HIG, possibly through Fc-mediated binding. Peripheral blood sampling showed a delayed arrival in blood of radioactivity after 99mTc-HIG compared with 99mTc-HSA, although ultimately, the blood recovery of 99mTc-HIG was significantly higher (P < 0.05) than that of 99mTc-HSA. Clearance rates of radioactivity from the injection site were not significantly different, however, between the two agents. In patients with PMO, web space injection of 99mTc-HIG gave excellent images of normal lymphatic vessels, of lymph nodes and of abnormal lymph drainage such as dermal backflow in swollen arms. In contrast, neither lymphatic vessels nor lymph nodes were visualised after injection into the skin of the dorsum of the distal forearm. Although there was no difference in clearance rates from the injection sites between normal and swollen arms with either agent in PMO, clearance was significantly faster following injection into the web space (0.11% per minute for normal and swollen arms combined) than into the forearm (0.053% per minute; P < 0.05). These results suggest that (a) 99mTc-HIG is a potentially useful agent for measuring lymph flow and lymph node function; but (b) injection into the dorsum of the forearm is not a useful method of administration for these measurements; and (c) clearance rates from the injection site do not support the notion that PMO is the result of decreased lymph flow. Further studies are warranted to evaluate 99mTc-HIG as an agent for assessment of lymphatic function, especially with respect to measurement of lymph flow and possibly also for the evaluation of lymph node Fc-mediated immunocompetence.

Effects of treatment of rheumatoid arthritis patients with an antibody against tumour necrosis factor alpha on reticuloendothelial and intrapulmonary granulocyte traffic.

The therapeutic effects of a monoclonal antibody against tumour necrosis factor alpha (TNFalpha) were evaluated objectively in 10 patients with rheumatoid arthritis by 111In-labelled granulocyte imaging before and after treatment, and compared with changes in granulocyte kinetics with respect to the liver, spleen and lungs. Anti-TNFalpha resulted in a decrease in the size of the whole-body pool of marginating granulocytes, as reflected by a significant increase in the 30 min intravascular recovery of labelled granulocytes from 40% (S.D. 10) to 47% (S.D. 16) of injected activity (P<0.02). The 111In contents of the spleen, liver and lungs were unchanged, so the origin of the increment in recovery was presumed to be a reduction in granulocyte margination in inflamed synovium, although this was not quantifiable. The sizes of the granulocyte pools in the liver and lungs, expressed as the 111In content of the organ per unit of circulating 111In-labelled cells, were not significantly different after treatment, but the splenic granulocyte pool decreased by 16% (S.D. 19) (P<0.05). Individual changes in the size of the splenic pool showed no significant correlation with corresponding changes in 30 min recovery or with corresponding indices of inflammation (24 h 111In-granulocyte joint activity and C-reactive protein). We conclude that anti-TNFalpha produces an obvious resolution in inflammatory joint activity that is accompanied by an increased circulating component of the total blood granulocyte pool, as a result of decreased margination at sites of inflammation. Anti-TNFalpha may also produce a specific decrease in splenic granulocyte pooling, independent of any anti-inflammatory effects, although a similar decrease in the lungs, which might be anticipated as a result of reduced cytokine-induced granulocyte activation, could not be detected.

Bimodal granulocyte transit time through the human lung demonstrated by deconvolution analysis.

The lungs are an important site of granulocyte pooling. The aim of the study is to quantify pulmonary vascular granulocyte transit time using deconvolution analysis, as has previously been performed to measure pulmonary red cell transit time. Granulocyte and red cell studies were performed in separate groups of patients. Both cell types were labelled with Tc-99m, which for granulocyte labelling was complexed with hexamethylpropyleneamine oxime (HMPAO). The red cell impulse response function (IRF) was monoexponential with a median transit time of 4.3 s. The granulocyte IRF was biexponential in 19 of 22 subjects, 18 of whom had systemic inflammation (inflammatory bowel disease, systemic vasculitis or graft-vs-host disease) and four were controls without inflammatory disease. The median transit time of the fast component ranged from 20 to 25 s and of the slow component 120-138 s in the four patient groups. The fraction of cells undergoing slow transit correlated significantly with (a) mean granulocyte transit time and (b) the fraction showing shape change in vitro. We conclude that granulocyte transit time through the pulmonary circulation is bimodal and that shape-changed (activated) cells transit more slowly that non-activated cells. The size of the fraction undergoing slow transit is closely related to mean granulocyte transit time and is an important determinant of the size of the pulmonary vascular granulocyte pool.

The ureteric jet index: a novel measure of divided renal function.

The aim of this study was to evaluate an index of divided renal function based on the quantification of the ureteric jets seen on colour Doppler ultrasound of the bladder. Thirty-one patients attending for scintigraphic renography underwent colour Doppler ultrasound with video recording for 5 min. Divided renal function was calculated as the proportion of jets from the right-sided orifice ('jet index'). This was compared with the corresponding 'scintigraphic index' found using Patlak-Rutland graphical analysis. Absolute discrepancies were calculated. Twenty-eight of thirty-one (90%) of studies were diagnostic for the calculation of jet indices. The mean jet index was 52% (n=28, SEM=5.8%) compared to a mean scintigraphic index of 54% (n = 28, SEM = 4.0%). The two scores were correlated, with a correlation coefficient of 0.72 and the median absolute difference between the two scores was 7.7%. Forty-three per cent (12/28) of subjects had discrepancies in the two scores of 5% or less. The score differences, however, showed a highly skewed distribution with 32% (9/28) subjects showing discrepancies over 20%. This discordant group (> 20% difference) included three patients with functional pelviureteric obstruction, one with a pelvic mass and one with an underfilled bladder. Two patients with very poor quality jets had impaired renal function. In one case, the index improved after angioplasty for renal artery stenosis. This simple test is a useful adjunct to urinary tract ultrasound but should be interpreted alongside evidence of renal obstruction, and complements rather than replaces existing tests.

A comparison between 111In-anti-E-selectin mAb and 99Tcm-labelled human non-specific immunoglobulin in radionuclide imaging of rheumatoid arthritis.

We have developed and validated a method for imaging inflammation using a monoclonal antibody (1.2B6) against E-selectin, an endothelial-cell specific adhesion molecule. This study was undertaken to compare 111In-1.2B6 with 99Tcm-labelled non-specific IgG (99Tcm-HIG) in the detection of synovitis in 11 patients with rheumatoid arthritis (RA). Imaging was performed 4 h and 20-24 h post-injection (pi) of 555 MBq 99Tcm-HIG and 15 MBq 111In-1.2B6. Scintigraphic results were compared with clinical scores of joint involvement. Joint uptake was semiquantitated. The scintigraphic appearances with both tracers correlated well, although 111In-1.2B6 at 24 h showed the highest detection rate. Taking joint tenderness or swelling as evidence of clinical activity, the sensitivity of 111In-1.2B6 at 4 h and 24 h was 69% and 82%, respectively, compared with 69% and 62% for 99Tcm-HIG. 111In-1.2B6 also displayed abnormal activity over a number of joints that appeared silent on clinical examination. Joint-to-soft tissue ratios were higher for 111In-1.2B6 at 24 h (4.0 +/- 1.9; p < 0.0001 vs all) than at 4 h (2.4 +/- 1.4) or than for 99Tcm-HIG at 4 h and 24 h (1.6 +/- 0.5 and 2.3 +/- 0.7, respectively). Net 111In counts over joints increased significantly between 4 h and 24 h (mean change: 54 +/- 40%). This study demonstrates that 111In-1.2B6 scintigraphy is a sensitive method by which to assess RA activity and that targeting is more intense and specific than using 99Tcm-HIG. However, the optimum time for 111In-1.2B6 scintigraphy is 24 h whereas good results are already obtained with 99Tc-HIG at 4 h pi. Current efforts are directed at developing 99Tcm-labelled 1.2B6 for imaging endothelial activation.

Case report: imaging of central nervous system sarcoidosis with gallium-67 single photon emission computed tomography.

Involvement of the nervous system is an uncommon and underdiagnosed complication of sarcoidosis. We used gallium single photon emission computed tomography (SPECT) to define areas of meningeal involvement in a patient with neurosarcoidosis. This technique may be of value in the assessment of patients with sarcoidosis and suspected central nervous system involvement.

Case report: the need for caution when using the spleen to assess renal blood flow in renography.

Visual assessment of renal blood flow from renography is usually achieved by comparing the count rate from the kidney with that of the spleen during the first pass of the radiopharmaceutical agent. This is not justifiable if splenic blood flow is abnormal. In nine subjects without evidence of renal or other significant disease, the mean ratio of the slopes of the first pass curves over the left kidney and the spleen was 1.7 (SD 0.32). However, an additional patient, a 67-year-old female with type-II cryoglobulinaemia, illustrated the need for caution when using this approach. Her splenic blood flow was significantly elevated, resulting in a kidney/spleen slope ratio of only 0.66, even though her renal function was thought to be normal.

Measurement of the pulmonary vascular granulocyte pool.

We have developed a technique for measuring the pulmonary granulocyte pool (PGP) as a fraction of the whole body total blood granulocyte pool (TBGP). The technique "captures" a dose of 99mTc-labeled granulocytes in a region of interest (ROI) over the lung during first pass by integrating an input time-activity curve from an ROI over the pulmonary artery, superior vena cava, or right ventricle. The ratio of the estimated first-pass count rate and the count rate in the same lung ROI after equilibration of the cells between the circulating and pulmonary pools (15-30 min) represents the PGP/TBGP. The technique was validated in eight subjects by using 99mTc-labeled macroaggregated human serum albumin. With corrections for background and injected doses, the ratios of first-pass granulocyte-to-macroaggregated human serum albumin count rates given by the three input ROIs were close to unity [superior vena cava 0.98 +/- 0.079 (SD), right ventricle 1.01 +/- 0.070, and pulmonary artery 0.97 +/- 0.073]. Significant increases in PGP/TBGP were demonstrated in systemic inflammation. Thus, in patients with inflammatory bowel disease, it was 0.22 +/- 0.07 (n = 7) compared with 0.08 +/- 0.01 (n = 5) in control subjects. It was also elevated in patients with systemic vasculitis (0.34 +/- 0.07; n = 5), in transplant recipients (0.33 +/- 0.08; n = 5), and in patients with osteomyelitis (0.15 +/- 0.06; n = 4). We conclude that this is a valid technique for quantifying the PGP that is expanded in several conditions associated with systemic inflammation.