Quantitative lymphoscintigraphy of the lower limbs for the diagnosis of phlebolymphoedema.

INTRODUCTION: Phlebolymphoedema is caused by the interaction of the venous and lymphatic systems in a state of chronic venous insufficiency in which increased microvascular filtration causes an increased rate of lymph production. Lymphatic drainage rate increases in response, but this is unsustainable and can cause lymphatic failure and oedema. We hypothesise that in phlebolymphoedema we could measure unusually high lymphatic drainage while the lymph system is still fully functional. METHOD: Patients referred for lymphoscintigraphic investigation of swollen legs between April 2021 and December 2022 were reviewed. Quantitative lymphoscintigraphy was performed following the technique of Keramida et al . (2017) and ilio-inguinal nodal uptake (IIQ%) was calculated. The presence of scintigraphic features of increased lymph production was noted for each limb. RESULTS: A total of 39 patients were reviewed (78 limbs, 29F, 10M). Seven limbs were identified with supranormal lymphatic function (IIQ > 30%) plus three borderline. Of these 10 limbs, all had at least two scintigraphic features of increased lymph production. CONCLUSION: Quantitative lymphoscintigraphy, although developed for diagnosing abnormally low lymphatic function, may also have utility at the upper end of the spectrum for identifying chronic venous insufficiency. An IIQ% upper normal limit of 30% could be used to diagnose venous insufficiency as the cause for limb swelling. This is of note for patients of large body habitus in whom venous ultrasound is difficult.

Tailoring the sampling time of single-sample GFR measurement according to expected renal function: a multisite audit.

BACKGROUND: The 2018 BNMS Glomerular Filtration Rate (GFR) guidelines recommend a single-sample technique with the sampling time dictated by the expected renal function, but this is not known with any accuracy before the test. We aimed to assess whether the sampling regime suggested in the guidelines is optimal and determine the error in GFR result if the sample time is chosen incorrectly. We can then infer the degree of flexibility in the sampling regime. METHODS: Data from 6328 patients referred for GFR assessment at 6 different hospitals for a variety of indications were reviewed. The difference between the single-sample (Fleming) GFR result at each sample time and the slope-intercept GFR result at each hospital was calculated. A second dataset of 777 studies from one hospital with nine samples collected from 5 min to 8 h post-injection was analysed to provide a reference GFR to which the single-sample results were compared. RESULTS: Recommended single-sample times have been revised: for an expected GFR above 90 ml/min/1.73m2 a 2-h sample is recommended; between 50 and 90 ml/min/1.73m2 a 3-h sample is recommended; and between 30 and 50 ml/min/1.73m2 a 4-h sample is recommended. Root mean square error in single-sample GFR result compared with slope-intercept can be kept less than or equal to 3.30 ml/min/1.73m2 by following these recommendations. CONCLUSION: The results of this multisite study demonstrate a reassuringly wide range of sample times for an acceptably accurate single-sample GFR result. Modified recommended single-sample times have been proposed in line with the results, and a lookup table has been produced of rms errors across the full range of GFR results for the three sample times which can be used for error reporting of a mistimed sample.

The role of serial 99mTc-DPD scintigraphy in monitoring cardiac transthyretin amyloidosis.

PURPOSE: Cardiac transthyretin amyloidosis is a usually fatal form of restrictive cardiomyopathy for which clinical trials of treatments are ongoing. It is anticipated that quantitative nuclear medicine scintigraphy, which is experiencing growing interest, will soon be used to evaluate treatment efficacy. We investigated its utility for monitoring changes in disease load over a significant time period. METHODS: Sixty-two treatment-naive patients underwent 99mTc-labelled 3,3-diphosphono-1,2propanodicarboxylic acid (99mTc-DPD) scintigraphy two to four times each over a five-year period. Quantitation of cardiac 99mTc-DPD retention was performed according to two established methods: measurement of heart-to-contralateral ratio (H/CL) in the anterior view (planar) and percentage of administered activity in the myocardium (SPECT). RESULTS: In total 170 datasets were analysed. Increased myocardial retention of 99mTc-DPD was demonstrable as early as 12 months from baseline. Year-on-year progression across the cohort was observed using SPECT-based quantitation, though on 30 occasions (27.8%) the change in our estimate was negative. CONCLUSIONS: The spread of our results was notably high compared to the year-on-year increases. If left unaccounted for, variance may draw fallacious conclusions about changes in disease load. We therefore urge caution in drawing conclusions solely from nuclear medicine scintigraphy on a patient-by-patient basis, particularly across a short time period.

DPD Quantification in Cardiac Amyloidosis: A Novel Imaging Biomarker.

OBJECTIVES: To assess whether single-photon emission computed tomography (SPECT/CT) quantification of bone scintigraphy would improve diagnostic accuracy and offer a means of quantifying amyloid burden. BACKGROUND: Transthyretin-related cardiac amyloidosis is common and can be diagnosed noninvasively using bone scintigraphy; interpretation, however, relies on planar images. SPECT/CT imaging offers 3-dimensional visualization. METHODS: This was a single-center, retrospective analysis of 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scans reported using the Perugini grading system (0 = negative; 1 to 3 = increasingly positive). Conventional planar quantification techniques (heart/contralateral lung, and heart/whole-body retention ratios) were performed. Heart, adjacent vertebra, paraspinal muscle and liver peak standardized uptake values (SUVpeak) were recorded from SPECT/CT acquisitions. An SUV retention index was also calculated: (cardiac SUVpeak/vertebral SUVpeak) × paraspinal muscle SUVpeak. In a subgroup of patients, SPECT/CT quantification was compared with myocardial extracellular volume quantification by CT imaging (ECVCT). RESULTS: A total of 100 DPD scans were analyzed (patient age 84 ± 9 years; 52% male): 40 were Perugini grade 0, 12 were grade 1, 41 were grade 2, and 7 were grade 3. Cardiac SUVpeak increased from grade 0 to grade 2; however, it plateaued between grades 2 and 3 (p < 0.001). Paraspinal muscle SUVpeak increased with grade (p < 0.001), whereas vertebral SUVpeak decreased (p < 0.001). The composite parameter of SUV retention index overcame the plateauing of the cardiac SUVpeak and increased across all grades (p < 0.001). Cardiac SUVpeak correlated well (r2 = 0.73; p < 0.001) with ECVCT. Both the cardiac SUVpeak and SUV retention index had excellent diagnostic accuracy (area under the curve [AUC]: 0.999). The heart to contralateral lung ratio performed the best of the planar quantification techniques (AUC: 0.987). CONCLUSIONS: SPECT/CT quantification in DPD scintigraphy is possible and outperforms planar quantification techniques. Differentiation of Perugini grade 2 or 3 is confounded by soft tissue uptake, which can be overcome by a composite SUV retention index. This index can help in the diagnosis of cardiac amyloidosis and may offer a means of monitoring response to therapy.

99mTc DTPA vs. 51Cr EDTA for glomerular filtration rate measurement: is there a systematic difference?

AIM: The study aimed to investigate whether a systematic difference exists between Cr EDTA and Tc DTPA for measurement of glomerular filtration rate (GFR). METHODS: The distribution of GFR results from candidates attending the Royal Free Hospital for assessment of suitability for kidney donation was compared before and after the change from Cr EDTA to Tc DTPA using three-sample slope-intercept GFR calculation with samples at 2, 3, and 4 hours. A second cohort of oncology patients attending Leeds Teaching Hospitals NHS Trust underwent simultaneous GFR measurement with both tracers by full characterisation of the plasma clearance curve with nine samples between 5 minutes and 8 hours post-injection. Three-sample slope-intercept GFR was also calculated for comparison with cohort 1. RESULTS: From the first cohort, a statistically significant (P = 0.008) systematic difference of 5.8% (95% confidence interval: 1.5%-10.1%) was found in the three-sample slope-intercept GFR, with Tc DTPA giving the higher result. From the second cohort, a statistically significant (P = 0.00001) systematic difference of 2.9% (95% confidence interval: 1.8%-3.9%) was found in three-sample slope-intercept GFR, with Tc DTPA giving the higher result. There was no statistically significant difference between the tracers when GFR was calculated by full characterisation of the plasma clearance curve. CONCLUSION: There is a small systematic difference between GFR measured with Tc DTPA and Cr EDTA using abbreviated techniques, which is removed when GFR is calculated by full characterisation of the plasma clearance curve. The difference is not clinically significant in the context of intra-patient variability of GFR measurement.

Quantitation of 99mTc-DPD uptake in patients with transthyretin-related cardiac amyloidosis.

PURPOSE: Transthyretin (ATTR) amyloidosis is a rare but serious infiltrative disease associated with a wide spectrum of morphologic and functional cardiac involvement. 99mTc-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD), initially developed as a bone-seeking radiotracer, is remarkably sensitive for imaging cardiac ATTR amyloid deposits. Our aim was to investigate the feasibility and utility of estimating 99mTc-DPD uptake in myocardial tissue; this has the potential to yield reliable quantitative information on cardiac amyloid burden, which is urgently required to monitor disease progression and response to novel treatments. METHODS: Three methods of quantitation were developed and tested on 74 patients with proven cardiac ATTR amyloidosis who had recently undergone 99mTc-DPD planar whole-body imaging and SPECT-CT. Quantitative results were compared to measurements of extracellular volume fraction (ECV) by cardiac magnetic resonance imaging, a validated technique for measuring amyloid burden. RESULTS: An experienced clinician graded uptake using a widely-used visual scoring system as 1 (n = 15), 2 (n = 39) or 3 (n = 20). Linear correlations between the SPECT and ECV data (p < .001) were demonstrated. None of the methods showed that 99mTc-DPD uptake in the heart was significantly greater in patients with grade-3 uptake than in those with grade-2 uptake. CONCLUSIONS: Quantitation of 99mTc-DPD uptake in cardiac transthyretin amyloid deposits is complex and is hindered by competition for radiotracer with amyloid in skeletal muscle. The latter underlies differences in uptake between grade-2 and grade-3 patients, not cardiac uptake.

A pilot study demonstrating cardiac uptake with 18F-florbetapir PET in AL amyloidosis patients with cardiac involvement.

18F-florbetapir is a promising tracer in amyloidosis. This study evaluates its use in patients with systemic AL amyloidosis (AL) before and after treatment as well as its serial utility in monitoring. Fifteen AL patients with cardiac involvement underwent 18F-florbetapir PET imaging and three patients underwent repeat imaging after chemotherapy. All patients had demonstrable cardiac uptake with 18F-florbetapir. Cardiac uptake appeared greater in chemotherapy-naïve vs. chemotherapy-established AL patients median (left ventricular retention index 0.21 vs. 0.14 min-1, respectively) and greater in patients that had not achieved at least a partial haematological response (left ventricular retention index 0.2 vs. 0.14 min-1, respectively). There was no interval difference in cardiac uptake and no correlation in cardiac uptake with cardiac biomarkers or serum free light chains. This is the largest study of 18F-florbetapir in patients with AL amyloidosis. It is the first study to include patients prior to starting chemotherapy and uniquely includes patients who underwent repeat imaging after chemotherapy. All patients had cardiac uptake with 18F-florbetapir, regardless of haematological or NT-proBNP response to chemotherapy. There was a suggestion that treatment-naïve patients may have higher cardiac uptake. Larger studies are required to establish the role of this tracer in screening patients with amyloidosis for cardiac involvement, discriminating between ATTR and AL amyloidosis, and in disease monitoring.

Prognostic utility of the Perugini grading of 99mTc-DPD scintigraphy in transthyretin (ATTR) amyloidosis and its relationship with skeletal muscle and soft tissue amyloid.

AIMS: High-grade (Perugini grade 2 or 3) cardiac uptake on bone scintigraphy with 99mTechnetium labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) has lately been confirmed to have high diagnostic sensitivity and specificity for cardiac transthyretin (ATTR) amyloidosis. We sought to determine whether patient stratification by Perugini grade on 99mTc-DPD scintigraphy has prognostic significance in ATTR amyloidosis. METHODS AND RESULTS: Patient survival from time of 99mTc-DPD scintigraphy was determined in 602 patients with ATTR amyloidosis, including 377 with wild-type ATTR (ATTRwt) and 225 with mutant ATTR (ATTRm) amyloidosis. Patients were stratified according to Perugini grade (0-3) on 99mTc-DPD scan. The prognostic significance of additional patient and disease-related factors at baseline were determined. In the whole cohort, the finding of a Perugini grade 0 99mTc-DPD scan (n = 28) was invariably associated with absence of cardiac amyloid according to consensus criteria as well as significantly better patient survival compared to a Perugini grade 1 (n = 28), 2 (n = 436) or 3 (n = 110) 99mTc-DPD scan (P < 0.005). There were no differences in survival between patients with a grade 1, grade 2 or grade 3 99mTc-DPD scan in ATTRwt (n = 369), V122I-associated ATTRm (n = 92) or T60A-associated ATTRm (n = 59) amyloidosis. Cardiac amyloid burden, determined by equilibrium contrast cardiac magnetic resonance imaging, was similar between patients with Perugini grade 2 and Perugini grade 3 99mTc-DPD scans but skeletal muscle/soft tissue to femur ratio was substantially higher in the latter group (P < 0.001). CONCLUSION: 99mTc-DPD scintigraphy is exquisitely sensitive for identification of cardiac ATTR amyloid, but stratification by Perugini grade of positivity at diagnosis has no prognostic significance.

Utility and limitations of 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy in systemic amyloidosis.

AIMS: Technetium-99m-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid ((99m)Tc-DPD) is a sensitive method for imaging cardiac transthyretin (ATTR) amyloid. We report utility and limitations of (99m)Tc-DPD scintigraphy in 321 patients with suspected cardiac amyloidosis. METHODS AND RESULTS: The cohort included wild-type ATTR (ATTRwt) amyloidosis in 94 (29%), ATTR-Val122Ile amyloidosis in 38 (12%), hereditary ATTR (ATTRmt) amyloidosis in 46 (14%), primary light-chain (AL) amyloidosis in 44 (14%), secondary (AA) amyloidosis in three (1%), other hereditary amyloidosis types in nine (3%), undetermined types in two (0.5%), and 85 (26.5%) patients in whom systemic amyloidosis was ultimately excluded. All 158 patients with ATTR amyloidosis with clinical cardiac involvement had cardiac (99m)Tc-DPD uptake, with median Grade 2 intensity. Thirteen further ATTR amyloidosis patients without clinical evidence of cardiac involvement also demonstrated (99m)Tc-DPD cardiac uptake. Eighteen of 35 (51%) AL patients with cardiac involvement had (99m)Tc-DPD cardiac uptake (median Grade 1 intensity). SPECT imaging indicates that the apparent reciprocal reduction in bone uptake is due to masking of bone uptake by extensive soft-tissue uptake in ATTR amyloidosis, especially ATTRwt, and ATTR-Val122Ile types. CONCLUSION: (99m)Tc-DPD scintigraphy is a highly sensitive technique for imaging cardiac ATTR amyloidosis and is an important investigation in the diagnostic pathway of patients with cardiac amyloidosis. It is not specific for ATTR in isolation but must be interpreted in a broad clinical context to avoid dangerous diagnostic errors. Diffuse skeletal muscle uptake identifies muscle as a hitherto unrecognized site that merits investigation as a target organ in ATTR amyloidosis.

Cystatin C in assessment of glomerular filtration rate in children and young adults suffering from cancer.

The study objective was to establish the diagnostic efficacy of cystatin C in the assessment of glomerular filtration rate (GFR) in paediatric oncology patients by investigating the relationships between serum cystatin C, serum creatinine and isotope clearance and determining whether these relationships are different from those seen in a group of patients of similar age with renal disease. This was a cohort study in which patients were divided into two groups: group A comprised renal patients and group B comprised oncology patients. All patients were referred for isotopic GFR assessment as part of routine clinical management and concurrently also had assessments made of their serum creatinine and cystatin C levels, together with height and weight measurements. Reciprocals of cystatin C correlate well with isotopic GFR; correlation coefficients from linear regression were 0.83 and 0.66 for the renal and oncology groups, respectively. However, when GFR was assessed from serum creatinine and cystatin C, levels of agreement were still very high (95% levels of agreement: -33 and 31 ml/min/1.73 m for cystatin C and -46 and 30 ml/min/1.73 m for the Counahan serum creatinine estimate). Receiver-operator characteristic curve analysis demonstrated that cystatin C has improved diagnostic utility for identifying patients with GFRs both below normal (90 ml/min/1.73 m) and below the point at which chemotherapy dose reduction may be considered (60 ml/min/1.73 m). Levels of intrapatient variability were similar for both tracers. Cystatin C was shown to be a better indicator of renal function compared with serum creatinine in oncology patients as demonstrated by receiver-operator characteristic curve and Bland-Altman analyses; however, sensitivity of the tracer to mild reductions in GFR is still low.

Evaluation of image enhancement software as a method of performing half-count bone scans.

Reducing the radiation dose and scanning time of diagnostic tests is often desirable. One method uses image enhancement software such as Pixon, which processes lower-count scans and aims to produce high-quality images. However, it is essential that diagnostic accuracy is not compromised. We compared the level of agreement between clinicians using standard scans, with half-count and Pixon-enhanced half-count scans. Bone scans from 150 patients referred to diagnose metastatic disease were degraded by a process of Poisson-preserving binomial resampling to generate equivalent half-count scans and then processed by Pixon software to recreate 'original' high-quality scans. Two experienced clinicians reported the scans in a randomized, blinded manner for metastatic disease (yes/no) and assigned a confidence level to this diagnosis. Levels of agreement between clinicians were calculated for the full-count, half-count, and Pixon-enhanced half-count scans and between scanning methods for each clinician. Agreement between clinicians for standard full-count scans was 92% (±4%, κ=0.80), compared with 92% (±4%, κ=0.79) for half-count scans and 87% (±5%, κ=0.70) for Pixon-processed half-count scans. Agreement for a single clinician viewing full-count versus half-count scans was 95% (±2%, κ=0.88), similar to the agreement for a single clinician viewing full-count versus Pixon-processed half-count scans (95%, ±2%, κ=0.88). With respect to confidence in diagnosis, 127 full-count scans were scored in the highest category, compared with 98 half-count and 88 Pixon-processed half-count scans. Switching to half-count scanning does not introduce more diagnostic disagreement than is already present between clinicians. However, clinicians feel less confident reporting half-count scans. The Pixon enhancement step improved neither objective diagnostic agreement nor clinician confidence.

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.

Can oncology patients' central venous catheters be used for isotope assessment of glomerular filtration rate? An in-vitro study.

BACKGROUND: Isotope assessment of glomerular filtration rate (GFR) is frequently performed in patients with central venous catheters (CVCs). Use of the CVCs for administration of tracer and subsequent blood sampling would be less distressing for patients (particularly paediatric) and would reduce the frequency of failed samples due to poor venous access. However, the GFR test is quantitative and could be affected by incomplete tracer delivery due to adhesion to the CVC and also by contamination of blood samples due to adhered tracer leaching back into the sampled blood as it passes through the CVC. AIM: This in vitro study aimed to quantify the effects on GFR assessment of tracer adhesion and leaching, in single-lumen and dual-lumen CVCs. METHOD: New and clinically used single-lumen CVCs were injected with tracer (99mTc-DTPA and 51Cr-EDTA) and then flushed repeatedly with saline. The outflows were assayed in a gamma counter and, where possible, the CVCs were imaged on a gamma camera to take snap shots of tracer movement throughout a GFR assessment. In a separate experiment, a phantom patient was used to compare blood sampling through a dual lumen CVC with peripheral sampling. RESULT AND CONCLUSION: A CVC successfully delivers >99% of tracer. Subsequent blood samples can be taken through the other lumen of a dual-lumen CVC but not through a single-lumen as this significantly alters the GFR result due to contamination.

Tissue perfusion in non-donor and donor forearm/hand after radial artery harvest: 1- and 5-year follow-up.

Radio-labeled red cell perfusion scan of the non-donor/donor forearm/hand was undertaken, 1- and 5-years post operation, in 12 patients who had received a radial artery graft during myocardial revascularisation. Results were analysed using a Wilcoxon Signed Rank test (P-value <0.05 was taken as statistically significant). Mean tissue perfusion (in milliliters/100 ml tissue/min) declined in the non-donor (-10.06%, P=0.07) and donor (-6.65%, P=0.15) forearm, respectively, compared to 1 year post radial artery harvest. The statistically significant observed difference in tissue perfusion between the non-donor (21.9+/-5.1) and donor (17.5+/-3.7) forearm (P=0.0007) at 1 year was maintained at 5 years, non-donor and donor, 19.5+/-3.7 and 16.2+/-3.4 (P=0.001), respectively. The same pattern in tissue perfusion was observed in the non-donor/donor hand. This study demonstrates that, over time, there is little recovery in perfusion in the donor forearm/hand from ulnar artery collateral circulation. There is a significant and persistent difference in tissue perfusion between the non-donor/donor forearm/hand at 5 years post radial artery harvest. Although no functional deficit or overt ischaemic events were recorded, these findings may influence the choice of conduit and the information given when obtaining consent in patients undergoing myocardial revascularisation.