Quantification of myocardial blood flow with 82Rb positron emission tomography: clinical validation with 15O-water

Purpose: Quantification of myocardial blood flow (MBF) with generator-produced 82Rb is an attractive alternative for centres without an on-site cyclotron. Our aim was to validate 82Rb-measured MBF in relation to that measured using 15O-water, as a tracer 100% of which can be extracted from the circulation even at high flow rates, in healthy control subject and patients with mild coronary artery disease (CAD). Methods: MBF was measured at rest and during adenosine-induced hyperaemia with 82Rb and 15O-water PET in 33 participants (22 control subjects, aged 30 ± 13years; 11 CAD patients without transmural infarction, aged 60 ± 13years). A one-tissue compartment 82Rb model with ventricular spillover correction was used. The 82Rb flow-dependent extraction rate was derived from 15O-water measurements in a subset of 11 control subjects. Myocardial flow reserve (MFR) was defined as the hyperaemic/rest MBF. Pearson's correlation r, Bland-Altman 95% limits of agreement (LoA), and Lin's concordance correlation ρ c (measuring both precision and accuracy) were used. Results: Over the entire MBF range (0.66-4.7ml/min/g), concordance was excellent for MBF (r = 0.90, [82Rb-15O-water] mean difference ± SD = 0.04 ± 0.66ml/min/g, LoA = −1.26 to 1.33ml/min/g, ρ c = 0.88) and MFR (range 1.79-5.81, r = 0.83, mean difference = 0.14 ± 0.58, LoA = −0.99 to 1.28, ρ c = 0.82). Hyperaemic MBF was reduced in CAD patients compared with the subset of 11 control subjects (2.53 ± 0.74 vs. 3.62 ± 0.68ml/min/g, p = 0.002, for 15O-water; 2.53 ± 1.01 vs. 3.82 ± 1.21ml/min/g, p = 0.013, for 82Rb) and this was paralleled by a lower MFR (2.65 ± 0.62 vs. 3.79 ± 0.98, p = 0.004, for 15O-water; 2.85 ± 0.91 vs. 3.88 ± 0.91, p = 0.012, for 82Rb). Myocardial perfusion was homogeneous in 1,114 of 1,122 segments (99.3%) and there were no differences in MBF among the coronary artery territories (p > 0.31). Conclusion: Quantification of MBF with 82Rb with a newly derived correction for the nonlinear extraction function was validated against MBF measured using 15O-water in control subjects and patients with mild CAD, where it was found to be accurate at high flow rates. 82Rb-derived MBF estimates seem robust for clinical research, advancing a step further towards its implementation in clinical routin

Repeated injections of 131I-rituximab show patient-specific stable biodistribution and tissue kinetics

Purpose: It is generally assumed that the biodistribution and pharmacokinetics of radiolabelled antibodies remain similar between dosimetric and therapeutic injections in radioimmunotherapy. However, circulation half-lives of unlabelled rituximab have been reported to increase progressively after the weekly injections of standard therapy doses. The aim of this study was to evaluate the evolution of the pharmacokinetics of repeated 131I-rituximab injections during treatment with unlabelled rituximab in patients with non-Hodgkin's lymphoma (NHL). Methods: Patients received standard weekly therapy with rituximab (375mg/m2) for 4 weeks and a fifth injection at 7 or 8 weeks. Each patient had three additional injections of 185MBq 131I-rituximab in either treatment weeks 1, 3 and 7 (two patients) or weeks 2, 4 and 8 (two patients). The 12 radiolabelled antibody injections were followed by three whole-body (WB) scintigraphic studies during 1 week and blood sampling on the same occasions. Additional WB scans were performed after 2 and 4 weeks post 131I-rituximab injection prior to the second and third injections, respectively. Results: A single exponential radioactivity decrease for WB, liver, spleen, kidneys and heart was observed. Biodistribution and half-lives were patient specific, and without significant change after the second or third injection compared with the first one. Blood T1/2β, calculated from the sequential blood samples and fitted to a bi-exponential curve, was similar to the T1/2 of heart and liver but shorter than that of WB and kidneys. Effective radiation dose calculated from attenuation-corrected WB scans and blood using Mirdose3.1 was 0.53+0.05mSv/MBq (range 0.48-0.59mSv/MBq). Radiation dose was highest for spleen and kidneys, followed by heart and liver. Conclusion: These results show that the biodistribution and tissue kinetics of 131I-rituximab, while specific to each patient, remained constant during unlabelled antibody therapy. RIT radiation doses can therefore be reliably extrapolated from a preceding dosimetry stud

Biokinetics and dosimetry of 111In-DOTA-NOC-ATE compared with 111In-DTPA-octreotide

Purpose: The biokinetics and dosimetry of 111In-DOTA-NOC-ATE (NOCATE), a high-affinity ligand of SSTR-2 and SSTR-5, and 111In-DTPA-octreotide (Octreoscan™, OCTREO) were compared in the same patients. Methods: Seventeen patients (10 men, 7 women; mean age 60years), referred for an OCTREO scan for imaging of a neuroendocrine tumour (15), thymoma (1) or medullary thyroid carcinoma (1), agreed to undergo a second study with NOCATE. Whole-body anterior-posterior scans were recorded 0.5 (100% reference scan), 4, 24 and 48h (17 patients) and 120h (5 patients) after injection. In 16 patients the OCTREO scan (178 ± 15MBq) was performed 16 ± 5days before the NOCATE scan (108 ± 14MBq) with identical timing; 1 patient had the NOCATE scan before the OCTREO scan. Blood samples were obtained from 14 patients 5min to 48h after injection. Activities expressed as percent of the initial (reference) activity in the whole body, lung, kidney, liver, spleen and blood were fitted to biexponential or single exponential functions. Dosimetry was performed using OLINDA/EXM. Results: Initial whole-body, lung and kidney activities were similar, but retention of NOCATE was higher than that of OCTREO. Liver and spleen uptakes of NOCATE were higher from the start (p < 0.001) and remained so over time. Whole-body activity showed similar α and β half-lives, but the β fraction of NOCATE was double that of OCTREO. Blood T 1/2β for NOCATE was longer (19 vs. 6h). As a result, the effective dose of NOCATE (105μSv/MBq) exceeded that of OCTREO (52μSv/MBq), and the latter result was similar to the ICRP 106 value of 54μSv/MBq. Differential activity measurement in blood cells and plasma showed an average of <5% of NOCATE and OCTREO attached to globular blood components. Conclusion: NOCATE showed a slower clearance from normal tissues and its effective dose was roughly double that of OCTRE

Antitumour effects of single or combined monoclonal antibodies directed against membrane antigens expressed by human B cells leukaemia

Background: The increasing availability of different monoclonal antibodies (mAbs) opens the way to more specific biologic therapy of cancer patients. However, despite the significant success of therapy in breast and ovarian carcinomas with anti-HER2 mAbs as well as in non-Hodkin B cell lymphomas with anti-CD20 mAbs, certain B cell malignancies such as B chronic lymphocytic leukaemia (B-CLL) respond poorly to anti-CD20 mAb, due to the low surface expression of this molecule. Thus, new mAbs adapted to each types of tumour will help to develop personalised mAb treatment. To this aim, we analyse the biological and therapeutic properties of three mAbs directed against the CD5, CD71 or HLA-DR molecules highly expressed on B-CLL cells. Results: The three mAbs, after purification and radiolabelling demonstrated high and specific binding capacity to various human leukaemia target cells. Further in vitro analysis showed that mAb anti-CD5 induced neither growth inhibition nor apoptosis, mAb anti-CD71 induced proliferation inhibition with no early sign of cell death and mAb anti-HLA-DR induced specific cell aggregation, but without evidence of apoptosis. All three mAbs induced various degrees of ADCC by NK cells, as well as phagocytosis by macrophages. Only the anti-HLA-DR mAb induced complement mediated lysis. Coincubation of different pairs of mAbs did not significantly modify the in vitro results. In contrast with these discrete and heterogeneous in vitro effects, in vivo the three mAbs demonstrated marked anti-tumour efficacy and prolongation of mice survival in two models of SCID mice, grafted either intraperitoneally or intravenously with the CD5 transfected JOK1-5.3 cells. This cell line was derived from a human hairy cell leukaemia, a type of malignancy known to have very similar biological properties as the B-CLL, whose cells constitutively express CD5. Interestingly, the combined injection of anti-CD5 with anti-HLA-DR or with anti-CD71 led to longer mouse survival, as compared to single mAb injection, up to complete inhibition of tumour growth in 100% mice treated with both anti-HLA-DR and anti-CD5. Conclusions: Altogether these data suggest that the combined use of two mAbs, such as anti-HLA-DR and anti-CD5, may significantly enhance their therapeutic potential

Increase of [18F]FLT Tumor Uptake In Vivo Mediated by FdUrd: Toward Improving Cell Proliferation Positron Emission Tomography

Purpose: 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT), a cell proliferation positron emission tomography (PET) tracer, has been shown in numerous tumors to be more specific than 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) but less sensitive. We studied the capacity of a nontoxic concentration of 5-fluoro-2′-deoxyuridine (FdUrd), a thymidine synthesis inhibitor, to increase uptake of [18F]FLT in tumor xenografts. Methods: The duration of the FdUrd effect in vivo on tumor cell cycling and thymidine analogue uptake was studied by varying FdUrd pretreatment timing and holding constant the timing of subsequent flow cytometry and 5-[125I]iodo-2′-deoxyuridine biodistribution measurements. In [18F]FLT studies, FdUrd pretreatment was generally performed 1h before radiotracer injection. [18F]FLT biodistributions were measured 1 to 3h after radiotracer injection of mice grafted with five different human tumors and pretreated or not with FdUrd and compared with [18F]FDG tumor uptake. Using microPET, the dynamic distribution of [18F]FLT was followed for 1.5h in FdUrd pretreated mice. High-field T2-weighted magnetic resonance imaging (MRI) and histology were used comparatively in assessing tumor viability and proliferation. Results: FdUrd induced an immediate increase in tumor uptake of 5-[125I]iodo-2′-deoxyuridine, that vanished after 6h, as also confirmed by flow cytometry. Biodistribution measurements showed that FdUrd pretreatment increased [18F]FLT uptake in all tumors by factors of 3.2 to 7.8 compared with controls, while [18F]FDG tumor uptake was about fourfold and sixfold lower in breast cancers and lymphoma. Dynamic PET in FdUrd pretreated mice showed that [18F]FLT uptake in all tumors increased steadily up to 1.5h. MRI showed a well-vascularized homogenous lymphoma with high [18F]FLT uptake, while in breast cancer, a central necrosis shown by MRI was inactive in PET, consistent with the histomorphological analysis. Conclusion: We showed a reliable and significant uptake increase of [18F]FLT in different tumor xenografts after low-dose FdUrd pretreatment. These results show promise for a clinical application of FdUrd aimed at increasing the sensitivity of [18F]FLT PE

Polish Society of Gynecology and Obstetrics statement on safety measures and performance of ultrasound examinations in obstetrics and gynecology during the SARS-CoV-2 pandemic

We present recommendations on performance and safety measures of ultrasound examinations in obstetrics and gynecologyduring the SARS COV-2 pandemic. The statement was prepared based on the current knowledge on the coronavirusby the Ultrasound Section of the Polish Society of Obstetrics and Gynecology. It has to be noted that the presented guidanceis based on limited evidence and is primarily based on experiences published by authors from areas most affected bythe virus thus far, such as China, Singapore, Hong Kong, and Italy. We realize that the pandemic situation is very dynamic.New data is published every day. Despite the imposed limitations related to the necessity of social distancing, it is crucialto remember that providing optimal care in safe conditions should remain the primary goal of healthcare providers. Weplan to update the current guidelines as the situation develops

\kappa-deformations of D=4 Weyl and conformal symmetries

We provide first explicite examples of quantum deformations of D=4 conformal algebra with mass-like deformation parameters, in applications to quantum gravity effects related with Planck mass. It is shown that one of the classical $r$-matrices defined on the Borel subalgebra of $sl(4)$ with $o(4,2)$ reality conditions describes the light-cone $\kappa$-deformation of D=4 Poincar\'{e} algebra. We embed this deformation into the three-parameter family of generalized $\kappa$-deformations, with $r$-matrices depending additionally on the dilatation generator. Using the extended Jordanian twists framework we describe these deformations in the form of noncocommutative Hopf algebra. We describe also another four-parameter class of generalized $\kappa$-deformations, which is obtained by continuous deformation of distinguished $\kappa$-deformation of D=4 Weyl algebra, called here the standard $\kappa$-deformation of Weyl algebra.Comment: LaTeX, 14 pages, corrected some typo

Biokinetics and dosimetry of (111)In-DOTA-NOC-ATE compared with (111)In-DTPA-octreotide.

PURPOSE: The biokinetics and dosimetry of (111)In-DOTA-NOC-ATE (NOCATE), a high-affinity ligand of SSTR-2 and SSTR-5, and (111)In-DTPA-octreotide (Octreoscan?, OCTREO) were compared in the same patients. METHODS: Seventeen patients (10 men, 7 women; mean age 60 years), referred for an OCTREO scan for imaging of a neuroendocrine tumour (15), thymoma (1) or medullary thyroid carcinoma (1), agreed to undergo a second study with NOCATE. Whole-body anterior-posterior scans were recorded 0.5 (100 % reference scan), 4, 24 and 48 h (17 patients) and 120 h (5 patients) after injection. In 16 patients the OCTREO scan (178 ± 15 MBq) was performed 16 ± 5 days before the NOCATE scan (108 ± 14 MBq) with identical timing; 1 patient had the NOCATE scan before the OCTREO scan. Blood samples were obtained from 14 patients 5 min to 48 h after injection. Activities expressed as percent of the initial (reference) activity in the whole body, lung, kidney, liver, spleen and blood were fitted to biexponential or single exponential functions. Dosimetry was performed using OLINDA/EXM. RESULTS: Initial whole-body, lung and kidney activities were similar, but retention of NOCATE was higher than that of OCTREO. Liver and spleen uptakes of NOCATE were higher from the start (p &lt; 0.001) and remained so over time. Whole-body activity showed similar α and β half-lives, but the β fraction of NOCATE was double that of OCTREO. Blood T (1/2)β for NOCATE was longer (19 vs. 6 h). As a result, the effective dose of NOCATE (105 μSv/MBq) exceeded that of OCTREO (52 μSv/MBq), and the latter result was similar to the ICRP 106 value of 54 μSv/MBq. Differential activity measurement in blood cells and plasma showed an average of &lt;5 % of NOCATE and OCTREO attached to globular blood components. CONCLUSION: NOCATE showed a slower clearance from normal tissues and its effective dose was roughly double that of OCTREO

Quantification of myocardial blood flow with 82Rb positron emission tomography: clinical validation with 15O-water

PURPOSE: Quantification of myocardial blood flow (MBF) with generator-produced (82)Rb is an attractive alternative for centres without an on-site cyclotron. Our aim was to validate (82)Rb-measured MBF in relation to that measured using (15)O-water, as a tracer 100% of which can be extracted from the circulation even at high flow rates, in healthy control subject and patients with mild coronary artery disease (CAD). METHODS: MBF was measured at rest and during adenosine-induced hyperaemia with (82)Rb and (15)O-water PET in 33 participants (22 control subjects, aged 30 ± 13 years; 11 CAD patients without transmural infarction, aged 60 ± 13 years). A one-tissue compartment (82)Rb model with ventricular spillover correction was used. The (82)Rb flow-dependent extraction rate was derived from (15)O-water measurements in a subset of 11 control subjects. Myocardial flow reserve (MFR) was defined as the hyperaemic/rest MBF. Pearson's correlation r, Bland-Altman 95% limits of agreement (LoA), and Lin's concordance correlation ρ (c) (measuring both precision and accuracy) were used. RESULTS: Over the entire MBF range (0.66-4.7 ml/min/g), concordance was excellent for MBF (r = 0.90, [(82)Rb-(15)O-water] mean difference ± SD = 0.04 ± 0.66 ml/min/g, LoA = -1.26 to 1.33 ml/min/g, ρ(c) = 0.88) and MFR (range 1.79-5.81, r = 0.83, mean difference = 0.14 ± 0.58, LoA = -0.99 to 1.28, ρ(c) = 0.82). Hyperaemic MBF was reduced in CAD patients compared with the subset of 11 control subjects (2.53 ± 0.74 vs. 3.62 ± 0.68 ml/min/g, p = 0.002, for (15)O-water; 2.53 ± 1.01 vs. 3.82 ± 1.21 ml/min/g, p = 0.013, for (82)Rb) and this was paralleled by a lower MFR (2.65 ± 0.62 vs. 3.79 ± 0.98, p = 0.004, for (15)O-water; 2.85 ± 0.91 vs. 3.88 ± 0.91, p = 0.012, for (82)Rb). Myocardial perfusion was homogeneous in 1,114 of 1,122 segments (99.3%) and there were no differences in MBF among the coronary artery territories (p &gt; 0.31). CONCLUSION: Quantification of MBF with (82)Rb with a newly derived correction for the nonlinear extraction function was validated against MBF measured using (15)O-water in control subjects and patients with mild CAD, where it was found to be accurate at high flow rates. (82)Rb-derived MBF estimates seem robust for clinical research, advancing a step further towards its implementation in clinical routine