Lymph proteins may access peripheral blood without entering thoracic duct in patients with lymphatic dysfunction.

OBJECTIVE: The objective was to investigate the hypothesis that lymphovenous communications, which allow lymph proteins to access peripheral blood without first entering the thoracic duct, open in patients with abnormal lymphatic function. METHODS: Routine lymphoscintigraphy of 182 patients, including 27 without clinical evidence of lymphedema (controls), was performed immediately and 45 and 150 minutes after subcutaneous injection of technetium Tc 99m nanocolloid into both feet. Counts per pixel in a region of interest over the liver (L) were divided by total counts in bilateral ilioinguinal nodes (N) at 45 minutes (L/N45) and 150 minutes (L/N150). If all activity leaving ilioinguinal lymph nodes entered the thoracic duct, these L/N ratios would be similar from patient to patient. RESULTS: Eight patients were excluded because of immediate liver activity suggesting inadvertent intravascular injection of tracer. In controls (group 1), L/N150 displayed a normal distribution with mean (± standard deviation) of 0.16 (0.09) × 10(-4) pixels(-1). Patients with L/N150 >0.34 × 10(-4) pixels(-1) (ie, 0.16 + 2 standard deviations) were assumed to have lymphovenous communications. Of 34 patients with clinical evidence of lymphedema but with normal findings on lymphoscintigraphy (group 2), 3 (9%) had lymphovenous communications; of 114 with abnormalities on lymphoscintigraphy (group 3), 43 (38%) had lymphovenous communications (P = .001). N45/150 was significantly higher than L45/150 in all four groups, indicating arrival of activity in nodes before the liver. Abnormal features of lymphoscintigraphy-lymph transport delay, popliteal node visualization, and diversion of lymph through the skin-showed no association with L/N ratios. CONCLUSIONS: Lymphovenous communications exist in about one-third of patients with abnormalities detected on lymphoscintigraphy. The timings of tracer arrival in the liver and lymph nodes is consistent with lymphovenous communication within lymph nodes themselves.

Lymphatic dysfunction in the apparently clinically normal contralateral limbs of patients with unilateral lower limb swelling.

PURPOSE: To determine how often lymphatic dysfunction is bilateral when, clinically, lymphedema appears unilateral. METHODS: Lymphoscintigraphy was performed after subcutaneous Tc-99m-nanocolloid injection in the first webspaces of both feet. The percentage of injected radioactivity accumulating in the ilioinguinal regions was recorded in dedicated images separately acquired at 60 and 180 minutes after injection. RESULTS: Within a consecutive series of 204 patients, 74 had unilateral clinical lymphedema of whom 68 had abnormal scintigraphy. Of these 68 patients, 46 had unilateral abnormal scintigraphy affecting the clinically abnormal limb, but 20 patients had bilateral abnormal scintigraphy and 2 had unilateral abnormal scintigraphy in the clinically unaffected limb. Thus, 32% (22/68) of patients in whom clinical lymphedema appeared to be unilateral, nevertheless, had abnormal scintigraphy in the clinically normal limb. Twenty-nine patients had no clinical evidence of lymphedema in either limb and were scintigraphically normal bilaterally. Mean ilioinguinal nodal accumulation at 180 minutes in the 44 limbs of 22 of these clinically and scintigraphically normal patients (dedicated ilioinguinal imaging was not performed in all patients) was 13.1% (standard deviation, 8.8%), higher (P = 0.02) than the mean value of 9.3% (standard deviation, 5.0%) in the clinically and scintigraphically normal contralateral limbs of 39 patients with unilateral clinical lymphedema. CONCLUSIONS: In the presence of unilateral lymphedema, the contralateral limb is often also abnormal. On lymphoscintigraphy, therefore, care should be taken before diagnosing unilateral lymphatic dysfunction. Quantification should be included in routine lymphoscintigraphy, as reduced ilioinguinal nodal accumulation may be the only apparent abnormality.

Popliteal node visualization during standard pedal lymphoscintigraphy for a swollen limb indicates impaired lymph drainage.

OBJECTIVE: The objective of our study was to examine the frequency and significance of visualization of popliteal nodes during lymphoscintigraphy for the investigation of lower extremity swelling. MATERIALS AND METHODS: Technetium-99m-labeled nanocolloid was injected subcutaneously in the first web spaces of both feet of 204 consecutive patients (69 males, 135 females; age range, 11-79 years) undergoing routine, clinically indicated lymphoscintigraphy; imaging was performed 5, 45, and 150 minutes after injection. The patients were asked not to undertake any vigorous exercise between the injection and completion of imaging. RESULTS: No popliteal nodes were visualized in 29 patients in whom there was no evidence of lymphedema on clinical or lymphoscintigraphic examination (group 1). Unilateral or bilateral popliteal nodes were visualized in 10 of 39 patients (25.6%) with clinical evidence of lymphedema but normal lymphoscintigraphy findings (group 2) (p < 0.005 vs group 1). In 136 patients with clinical evidence of lymphedema and abnormal lymphoscintigraphy findings (group 3), unilateral or bilateral popliteal nodes were visualized in 59 (43.4%) (p < 0.0001 vs group 1). Popliteal nodes were visualized in 40 of 73 limbs with "dermal backflow" (54.8%) and 42 of 335 limbs without dermal backflow (12.5%) (p < 0.0001). CONCLUSION: Popliteal node visualization after subcutaneous foot web space injection is an important sign of abnormal lymphatic function in patients with clinical lymphedema of the lower extremities.

Extracellular fluid volume and glomerular filtration rate: their relation and variabilities in patients with renal disease and healthy individuals.

INTRODUCTION: The slope-only technique for measuring glomerular filtration rate (GFR) relies on extracellular fluid volume (ECV) remaining within narrow limits. Although this requirement is met in healthy individuals, ECV may deviate or vary more in patients with abnormal renal function. METHODS: We examined the correlation between surface area-scaled ECV and GFR, and their coefficients of variation (CVs), measured from simultaneous, multisample clearances of 51Cr-EDTA and iohexol in 20 healthy volunteers and 60 patients with a range of renal functions. We also compared scaled GFR and ECV, and their CVs, measured from three-sample, slope-intercept clearance of 51Cr-EDTA in 921 patients routinely referred for GFR measurement. RESULTS: In the 80 participants undergoing multisample, dual-indicator clearance, there was no correlation between GFR measured with one indicator and ECV measured with the other. CVs of GFR in the 60 patients were 48.1 and 44.6% for 51Cr-EDTA and iohexol, respectively, but the CVs of ECV were only 12.3 and 15.4%. These differences were less marked in the healthy participants with corresponding CVs of 13.9 and 14.9% for GFR, and 11.7 and 12.2% for ECV. There was no correlation between scaled GFR and ECV in patients having slope-intercept clearance; CVs of GFR and ECV were 32.4 and 17.8%, respectively. CONCLUSION: In unselected patient populations, there is no correlation between GFR and ECV. The CV of ECV is slightly higher in patients than healthy individuals but, in both, is less than the CV of GFR. These data do not detract from the use of slope-only GFR.

Slope-only glomerular filtration rate and single-sample glomerular filtration rate as measurements of the ratio of glomerular filtration rate to extracellular fluid volume.

AIMS: The Jacobsson single-sample equation for measuring glomerular filtration rate (GFR) after bolus injection is based on two factors of questionable theoretical validity for correcting the single-compartment assumption. The aims were to redevelop a more transparent equation, show its fundamental similarity with 'slope-only' GFR and compare it with the original equation and with slope-only GFR. METHODOLOGY: The modified Jacobsson equation is k = (1/t).ln[V(t)/V(0)], where k is the rate constant of the terminal exponential and V(0) and V(t) are distribution volumes at times 0 and t. V(0) exceeds extracellular fluid volume (ECV): that is k' = (1/t).ln[V(t)/ECV], where k' > k. Moreover, [GFR/ECV] >k (= k + [15.4.k(2)]). The ratio k/k' was determined in 476 patients to calculate single-sample k (3 or 4 h post-injection). Slope-only and single-sample GFR/ECV were measured using Cr-51-EDTA in 105 further studies, multiplied by ECV (estimated from weight), scaled to 1.73 m(2) and compared with GFR/1.73 m(2) from the original Jacobsson equation against reference multi-sample GFR/1.73 m(2) simultaneously and independently measured with iohexol. RESULTS: The relation between k and k' was linear. k/k' was 0.827 at 3 h and 0.864 at 4 h. There was no difference in bias or precision between the original Jacobsson and modified equations. In both, precision was better than slope-only GFR/BSA. When GFR remained scaled to ECV, slope-only GFR showed marginally better precision against reference GFR/ECV. CONCLUSIONS: Single-sample and slope-only techniques give GFR as k. Although the theory of the modified Jacobsson equation is more transparent than the original equation, it gives the same result. It is, however, easier to use.

Estimated lean body mass is more appropriate than body surface area for scaling glomerular filtration rate and extracellular fluid volume.

BACKGROUND/AIMS: To compare body surface area (BSA) with lean body mass (LBM) for scaling extracellular fluid volume (ECV) and glomerular filtration rate (GFR). METHODS: Phase 1: Total body water (TBW), bromide space and LBM were measured with (3)H-water, (77)Br and dual X-ray absorptiometry, respectively, in 6 healthy adults. Phase 2: ECV and GFR were measured with (51)Cr-EDTA in 95 healthy adults and 56 children (0.5-13 years). ECV was calculated as GFR divided by GFR/ECV, both corrected for the one-compartment assumption. LBM was estimated (eLBM) in adults from height and weight and in children using a height/weight formula for estimating ECV and a constant derived from a separate adult population relating ECV to eLBM. RESULTS: Phase 1: LBM and BSA correlated closely with TBW and bromide space. With LBM, the regressions passed through the origin, but with BSA, the intercepts were significantly below zero. Phase 2: GFR/BSA and ECV/BSA were higher in men than women but no difference was recorded in GFR/eLBM, GFR/ECV or ECV/eLBM. ECV showed a linear relation with eLBM and a non-linear relation with BSA. GFR/BSA and ECV/BSA correlated significantly with BSA but neither GFR/eLBM nor ECV/eLBM correlated with eLBM. CONCLUSION: eLBM is preferable to BSA for scaling GFR and ECV.

Extracellular fluid volume in patients with cancer.

AIMS: Cancer patients may have extracellular fluid volume (ECV) abnormalities that potentially invalidate glomerular filtration rate (GFR) measured using the slope-intercept technique. The aim was to test this concern by measuring ECV in cancer patients in comparison with noncancer patients and healthy kidney donors. METHODS: GFR was measured with Cr-EDTA and the slope-intercept technique in patients from two hospitals, the first using three samples (540 adults, including 382 with cancer, and 124 children, including 40 with cancer) and the second using four samples (256 adults, including 132 with cancer and 75 donors), scaled to body surface area (BSA) of 1.73 m and corrected using Brochner-Mortensen's equations (GFR/BSA). GFR/ECV was measured from the exponential rate constant with an appropriate one-compartment correction. ECV/BSA was calculated as the quotient, GFR/BSA:GFR/ECV. ECV was also expressed in adults in relation to lean body mass and in children as a fraction of ECV estimated from height and weight (eECV). RESULTS: In men from both centres, neither ECV/BSA nor ECV/lean body mass showed an increase in cancer patients. In women from both centres, however, they were both significantly higher in cancer patients than in noncancer patients and, in centre 2, than in donors. In children from centre 1, ECV/BSA, but not ECV/eECV, was significantly higher in cancer patients. CONCLUSION: ECV is expanded in female cancer patients but not male cancer patients. ECV may be expanded in children with cancer but the recorded difference in ECV/BSA is probably related to differences in patient size and a nonproportionate relationship between ECV and BSA.

Use of body surface area for assessing extracellular fluid volume and glomerular filtration rate in obesity.

OBJECTIVE: To examine body surface area (BSA) for scaling extracellular fluid volume (ECV) in obesity. ECV varies less than glomerular filtration rate (GFR) in a clinical population and was therefore used as a surrogate for GFR on the grounds that if BSA is unsuitable for scaling GFR, it will also be unsuitable for ECV. METHODS: GFR was measured in 917 patients using (51)Cr-EDTA. GFR scaled to ECV was measured exclusively from the slope rate constant. ECV was calculated as GFR divided by GFR/ECV. RESULTS: BSA correlated strongly with body mass index (BMI). ECV correlated strongly with BSA but the intercept was significantly lower than zero, indicating a disproportionate relation. ECV/BSA correlated with BSA but not with BMI. ECV in obese subjects was significantly less than in non-obese subjects individually matched for BSA. ECV/BSA was similar between obese and lean subjects matched for GFR/ECV and height. CONCLUSIONS: For subjects of similar BSA, a high BMI decreases ECV (the 'obesity effect'). Subjects with high BMI generally have high BSA, which tends to increase ECV/BSA because of the disproportionate relation between ECV and BSA (the 'BSA effect'). These opposing effects serendipitously and erroneously create the impression that BSA is suitable for scaling ECV (and by implication, GFR) in obesity.

99mTc-sestamibi imaging in the assessment of toremifene as a modulator of multidrug resistance in patients with breast cancer.

UNLABELLED: Multidrug resistance (MDR) due to expression of a membrane-associated permeability glycoprotein (P-glycoprotein [Pgp]) prevents successful cytotoxic chemotherapy for breast cancer. Identification of MDR would facilitate selection of chemotherapy regimens and MDR modulators. This study aimed to evaluate (99m)Tc-sestamibi imaging for predicting overexpression of Pgp in primary breast cancer and to measure the efficacy of toremifene, the MDR modulator, in vivo. METHODS: Twenty patients with untreated breast cancer had (99m)Tc-sestamibi imaging 20 and 120 min after tracer injection before and after a 3-d course of toremifene (780 mg/d). Tumor samples were obtained during surgery for correlation of imaging and Pgp immunohistochemistry. RESULTS: Sixteen of 20 tumors were visualized with sestamibi. Before toremifene, there was a significant inverse correlation (Spearman rank correlation coefficient [R(S)]) between staining intensity, based on the anti-Pgp monoclonal antibodies C494 and C219, and the tumor-to-background ratio (T/B) at 120 min (R(S) = -0.85; P < 0.001 and R(S) = -0.71; P < 0.001, respectively). However, the correlation between the T/B and immunohistochemistry at 20 min was significant only for C494 (R(S) = -0.57; P < 0.01). Similarly, before toremifene, there was an inverse correlation between staining intensity and the change in the T/B between 20 and 120 min (R(S) = -0.77; P < 0.001 and -0.75; P < 0.001 for C494 and C219). After toremifene, an inverse correlation between staining intensity and the T/B was seen only at 120 min and only with C494 (R(S) = -0.68; P < 0.01). However, the change in the T/B between 20 and 120 min correlated significantly with staining intensity for C494 and C219 (R(S) = -0.68; P < 0.01 and -0.7; P < 0.01 for C494 and C219, respectively). Toremifene did not significantly alter the overall T/B at either 20 or 120 min when data were compared before and after toremifene. Nevertheless, at 120 min, 8 of 8 tumors with low Pgp expression showed reduced uptake after toremifene, whereas 5 of 6 tumors with strong expression showed increased uptake (P < 0.003). Moreover, there was a significant correlation between the change in the T/B and staining intensity with C494 (R(S) = 0.59; P < 0.05) and C219 (R(S) = 0.56; P < 0.05) at 120 min but not at 20 min. CONCLUSION: (99m)Tc-Sestamibi accumulation in breast cancer correlates with Pgp expression. Toremifene has a dual effect on this accumulation, increasing it through an inhibitory effect on Pgp while at the same time reducing it by a direct competition with sestamibi. The latter implies that in response to Pgp modulation the efflux of various agents may be affected differently.