Renal and Red Marrow Dosimetry in Peptide Receptor Radionuclide Therapy: 20 Years of History and Ahead.

The development of dosimetry and studies in peptide receptor radionuclide therapy (PRRT) over the past two decades are reviewed. Differences in kidney and bone marrow toxicity reported between 90Y, 177Lu and external beam radiotherapy (EBRT) are discussed with regard to the physical properties of these beta emitter radionuclides. The impact of these properties on the response to small and large tumors is also considered. Capacities of the imaging modalities to assess the dosimetry to target tissues are evaluated. Studies published in the past two years that confirm a red marrow uptake in 177Lu-DOTATATE therapy, as already observed 20 years ago in 86Y-DOTATOC PET studies, are analyzed in light of the recent developments in the transferrin transport mechanism. The review enlightens the importance (i) of using state-of-the-art imaging modalities, (ii) of individualizing the activity to be injected with regard to the huge tissue uptake variability observed between patients, (iii) of challenging the currently used but inappropriate blood-based red marrow dosimetry and (iv) of considering individual tandem therapy. Last, a smart individually optimized tandem therapy taking benefit of the bi-orthogonal toxicity-response pattern of 177Lu-DOTATATE and of 90Y-DOTATOC is proposed.

Microspheres Used in Liver Radioembolization: From Conception to Clinical Effects.

Inert microspheres, labeled with several radionuclides, have been developed during the last two decades for the intra-arterial treatment of liver tumors, generally called Selective Intrahepatic radiotherapy (SIRT). The aim is to embolize microspheres into the hepatic capillaries, accessible through the hepatic artery, to deliver high levels of local radiation to primary (such as hepatocarcinoma, HCC) or secondary (metastases from several primary cancers, e.g., colorectal, melanoma, neuro-endocrine tumors) liver tumors. Several types of microspheres were designed as medical devices, using different vehicles (glass, resin, poly-lactic acid) and labeled with different radionuclides, 90Y and 166Ho. The relationship between the microspheres' properties and the internal dosimetry parameters have been well studied over the last decade. This includes data derived from the clinics, but also computational data with various millimetric dosimetry and radiobiology models. The main purpose of this paper is to define the characteristics of these radiolabeled microspheres and explain their association with the microsphere distribution in the tissues and with the clinical efficacy and toxicity. This review focuses on avenues to follow in the future to optimize such particle therapy and benefit to patients.

The role of SPECT/CT in radioembolization of liver tumours.

Radioembolization (RE) with (90)Y microspheres is a promising catheter-based therapeutic option for patients with unresectable primary and metastatic liver tumours. Its rationale arises from the dual blood supply of liver tissue through the hepatic artery and the portal vein. Metastatic hepatic tumours measuring >3 mm derive 80 - 100 % of their blood supply from the arterial rather than the portal hepatic circulation. Typically, an angiographic evaluation combined with (99m)Tc-macroaggregated albumin ((99m)Tc-MAA) scan precedes therapy to map the tumour feeding vessels as well as to avoid the inadvertent deposition of microspheres in organs other than the liver. Prior to administration of (99m)Tc-MAA, prophylactic coil embolization of the gastroduodenal artery is recommended to avoid extrahepatic deposition of the microspheres. SPECT/CT allows direct correlation of anatomic and functional information in patients with unresectable liver disease. SPECT/CT is recommended to assess intrahepatic distribution as well as extrahepatic gastrointestinal uptake in these patients. Pretherapeutic SPECT/CT is an important component of treatment planning including catheter positioning and dose finding. A post-therapy bremsstrahlung (BS) scan should follow RE to verify the distribution of the administered tracer. BS SPECT/CT imaging enables better localization and definition of intrahepatic and possible extrahepatic sphere distribution and to a certain degree allows posttreatment dosimetry. In this paper we address the usefulness and significance of SPECT/CT in therapy planning and therapy monitoring of RE.

A Theranostic Approach in SIRT: Value of Pre-Therapy Imaging in Treatment Planning.

Selective internal radiation therapy (SIRT) is one of the treatment options for liver tumors. Microspheres labelled with a therapeutic radionuclide (90Y or 166Ho) are injected into the liver artery feeding the tumor(s), usually achieving a high tumor absorbed dose and a high tumor control rate. This treatment adopts a theranostic approach with a mandatory simulation phase, using a surrogate to radioactive microspheres (99mTc-macroaggregated albumin, MAA) or a scout dose of 166Ho microspheres, imaged by SPECT/CT. This pre-therapy imaging aims to evaluate the tumor targeting and detect potential contraindications to SIRT, i.e., digestive extrahepatic uptake or excessive lung shunt. Moreover, the absorbed doses to the tumor(s) and the healthy liver can be estimated and used for planning the therapeutic activity for SIRT optimization. The aim of this review is to evaluate the accuracy of this theranostic approach using pre-therapy imaging for simulating the biodistribution of the microspheres. This review synthesizes the recent publications demonstrating the advantages and limitations of pre-therapy imaging in SIRT, particularly for activity planning.

Optimization of the Clinical Effectiveness of Radioembolization in Hepatocellular Carcinoma with Dosimetry and Patient-Selection Criteria.

Selective internal radiation therapy (SIRT) is part of the treatment strategy for hepatocellular carcinoma (HCC). Strong clinical data demonstrated the effectiveness of this therapy in HCC with a significant improvement in patient outcomes. Recent studies demonstrated a strong correlation between the tumor response and the patient outcome when the tumor-absorbed dose was assessed by nuclear medicine imaging. Dosimetry plays a key role in predicting the clinical response and can be optimized using a personalized method of activity planning (multi-compartmental dosimetry). This paper reviews the main clinical results of SIRT in HCC and emphasizes the central role of dosimetry for improving it effectiveness. Moreover, some patient and tumor characteristics predict a worse outcome, and toxicity related to SIRT treatment of advanced HCC patient selection based on the performance status, liver function, tumor characteristics, and tumor targeting using technetium-99m macro-aggregated albumin scintigraphy can significantly improve the clinical performance of SIRT.

TCP post-radioembolization and TCP post-EBRT in HCC are similar and can be predicted using the in vitro radiosensitivity.

BACKGROUND: Tumor equivalent uniform dose (EUD) is proposed as a predictor of patient outcome after liver radioembolization (RE) of hepatocellular carcinoma (HCC) and can be evaluated with 90Y-TOF-PET. The aim is to evaluate the correlation between PET-based tumors EUD and the clinical response evaluated with dual molecular tracer (11C-acetate and 18F-FDG) PET/CT post-RE. METHODS: 34 HCC tumors in 22 patients were prospectively evaluated. The metabolic response was characterized by the total lesion metabolism variation (ΔTLM) between baseline and follow-up. This response allowed to compute a tumor control probability (TCP) as a function of the tumor EUD. RESULTS: The absorbed dose response correlation was highly significant (R = 0.72, P < 0.001). With an absorbed dose threshold of 40 Gy, the metabolic response was strongly different in both groups (median response 35% versus 100%, P < 0.001). Post-RE TCP as a function of the EUD was very similar to that observed in external beam radiation therapy (EBRT), with TCP values equal to 0.5 and 0.95 for a EUD of 51 Gy and 100 Gy, respectively. The TCP was perfectly predicted by the Poisson model assuming an inter tumor radiosensitivity variation of 30% around the HCC cell in vitro value. CONCLUSIONS: EUD-based 90Y TOF-PET/CT predicts the metabolic response post-RE in HCC assessed using dual molecular PET tracers and provides a similar TCP curve to that observed in EBRT. In vivo and in vitro HCC radiosensitivities are similar. Both TCPs show that a EUD of 100 Gy is needed to control HCC for the three devices (resin spheres, glass spheres, EBRT). Observed absorbed doses achieving this 100 Gy-EUD ranged from 190 to 1800 Gy!

Dual-layer collimator for improved spatial resolution in SPECT with CZT camera: an analytical and Monte Carlo study.

Purpose.Current hole matching pixel detector (HMPD) collimators for SPECT imaging exist in two configurations: one hole per pixel (1HMPD) or four holes per pixel (4HMPD). The aim of this study was to assess the performance of a dual-layer collimator made by stacking up these two collimator types (1H/4HMDP) for low- and medium energy gamma emitters.Method. Analytical equations describing geometrical efficiency and full width at half maximum (FWHM) of the 1H/4HMDP collimator were derived. In addition, a fast dedicated Monte Carlo (MC) code neglecting scattering and designed for the collimator geometry was developed to assess the collimator's point spread function and to simulate planar and SPECT acquisitions.Results.A relative agreement between analytical equations and MC simulations better than 3% was observed for the efficiency and for the FWHM. The length of the two layers was optimized to get the best spatial resolution while keeping the geometrical efficiency equal to that of the 45 mm length 1HMPD collimator. An optimized combination of the 1H/4HMPD configuration with respective hole lengths of 20 and 13 mm has been derived. For source-collimator distances above 5 cm and equal collimator geometrical efficiency, the spatial resolution of this optimal 1H/4HMDP collimator supersedes that of the 45 mm length 1HMPD collimator, and that of the 19.1 mm length 4HMPD collimator. This improvement was observed in simulations of bar phantom planar images and of hot rods phantom SPECT. Remarkably, the spatial resolution was preserved along the whole radial range within the Jaszczak phantom.Conclusion.The 1H/4HMDP collimator is a promising solution for CZT SPECT imaging of low- and medium energy emitters.

Effects of granulocyte-colony-stimulating factor on progenitor cell mobilization and heart perfusion and function in normal mice.

BACKGROUND AIMS: Mobilization of stem cells and progenitor cells from the bone marrow (BM) into the peripheral blood (PB) by granulocyte-colony-stimulating factor (G-CSF) is being investigated for cardiac regeneration in ischemic heart disease. However, hematopoietic (HPC), mesenchymal (MPC) and endothelial (EPC) progenitor mobilization have not been optimized and the effect of G-CSF on myocardial perfusion and cardiac function in a normal heart has never been studied. METHODS: Normal mice were injected daily for 1-10 days with subcutaneous recombinant human G-CSF. PB and BM were evaluated for HPC and EPC by flow cytometry and HPC and MPC by hematopoietic (CFU-GM) and mesenchymal (CFU-F) colony assays. Echocardiography, microSPECT imaging, cardiac catheterization and immunohistochemistry were performed in mice treated for 10 days. RESULTS: HPC and CFU-GM in PB peaked after 2 days, CFU-F after 4 days and EPC after 3 days. Thereafter, while HPC temporally decreased before showing a second peak, EPC remained detectable only at low levels. In BM, hematopoietic stem cells (HSC) and CFU-GM did not increase much overall but peaked twice on days 2 and 7. EPC (peak on day 7) production increased in the BM, but CFU-F formation declined considerably after day 2. G-CSF enhanced myocardial perfusion and vascularization but impaired hemodynamic performance of the heart through apparently increased ventricular wall rigidity. CONCLUSIONS: G-CSF induces the mobilization of HPC, EPC and CFU-F progenitors in PB according to very different patterns, and has a significant impact on perfusion and function of the normal heart.

Experimental facts supporting a red marrow uptake due to radiometal transchelation in 90Y-DOTATOC therapy and relationship to the decrease of platelet counts.

PURPOSE: The aim of this study was to retrospectively evaluate whether the red marrow (RM) takes up (111)In-diethylenetriaminepentaacetic acid (DTPA)-D-Phe(1)-octreotide and (86)Y-DOTATOC and to assess the correlation between the RM absorbed doses and platelet count reduction as a biological dose estimate. METHODS: Data from 12 patients who underwent at 24 h p.i. high statistics (111)In single photon emission computed tomography (SPECT) and (86)Y positron emission tomography (PET) acquisitions of the chest were analysed. Uptake was measured on >7 cm spine length and converted to total RM uptake using standard RM distribution in man. RM absorbed doses were calculated assuming specific RM uptake and using the plasma and remainder of the body models. RM doses were correlated with the platelet count reduction at 4 weeks. In vitro experiments explored the metabolism of (111)In-DTPA-D-Phe(1)-octreotide and (90)Y-DOTATOC in plasma. RESULTS: The correlation between the uptake of both tracers was excellent (R = 0.80), indicating that RM uptake of (86)Y-DOTATOC reflects a real physiological process and not reconstruction artefacts. The kinetics of (86)Y-DOTATOC RM activity was different than that in blood and tumours, with no activity at 4 h p.i. indicating that the uptake is not somatostatin receptor dependent. In vitro experiments showed a transchelation of both radiometals to free transferrin that could explain the RM uptake. In patients without chemotherapy and with a normal platelet count recovery, a good correlation (R = 0.96) was found between the RM doses and the platelet count reduction at the nadir. CONCLUSION: These experimental facts support the existence of a true RM uptake likely related to transchelation of the radiometal to transferrin. RM uptake correlates well with the observed acute RM toxicity.

Dosimetry of yttrium-labelled radiopharmaceuticals for internal therapy: 86Y or 90Y imaging?

This paper reviews issues concerning (86)Y positron emission tomography (PET), (90)Y PET and (90)Y bremsstrahlung imaging. Specific methods and corrections developed for quantitative imaging, for application in preclinical and clinical studies, and to assess (90)Y dosimetry are discussed. The potential imaging capabilities with the radioisotopes (87)Y and (88)Y are also considered. Additional studies required to assess specific unaddressed issues are also identified.

Autumn COVID-19 surge dates in Europe correlated to latitudes, not to temperature-humidity, pointing to vitamin D as contributing factor.

To determine the factor triggering the sudden surge of daily new COVID-19 cases arising in most European countries during the autumn of 2020. The dates of the surge were determined using a fitting of the two last months of reported daily new cases in 18 European countries with latitude ranging from 39° to 62°. The study proves no correlation between the country surge date and the 2 weeks preceding temperature or humidity but shows an impressive linear correlation with latitude. The country surge date corresponds to the time when its sun UV daily dose drops below ≈ 34% of that of 0° latitude. Introducing reported seasonal blood 25-hydroxyvitamin D (25(OH)D) concentration variation into the reported link between acute respiratory tract infection risk and 25(OH)D concentration quantitatively explains the surge dynamics. Several studies have already substantiated a 25(OH)D concentration impact on COVID-19 severity. However, by comparing different patient populations, discriminating whether a low 25(OH)D concentration is a real factor underlying COVID-19 severity or only a marker of another weakness that is the primary severity factor can be challenging. The date of the surge is an intrapopulation observation and has the benefit of being triggered only by a parameter globally affecting the population, i.e. decreases in the sun UV daily dose. The results indicate that a low 25(OH)D concentration is a contributing factor to COVID-19 severity, which, combined with previous studies, provides a convincing set of evidence.

Yttrium-90 TOF-PET-Based EUD Predicts Response Post Liver Radioembolizations Using Recommended Manufacturer FDG Reconstruction Parameters.

PURPOSE: Explaining why 90Y TOF-PET based equivalent uniform dose (EUD) using recommended manufacturer FDG reconstruction parameters has been shown to predict response. METHODS: The hot rods insert of a Jaszczak deluxe phantom was partially filled with a 2.65 GBq 90Y - 300ml DTPA water solution resulting in a 100 Gy mean absorbed dose in the 6 sectors. A two bed 20min/position acquisition was performed on a 550ps- and on a 320ps- TOF-PET/CT and reconstructed with recommended manufacturer FDG reconstruction parameters, without and with additional filtering. The whole procedure was repeated on both PET after adding 300ml of water (50Gy setup). The phantom was acquired again after decay by a factor of 10 (5Gy setup), but with 200min per bed position. For comparison, the phantom was also acquired with 18F activity corresponding to a clinical FDG whole body acquisition. RESULTS: The 100Gy-setup provided a hot rod sectors image almost as good as the 18F phantom. However, despite acquisition time compensation, the 5Gy-setup provides much lower quality imaging. TOF-PET based sectors EUDs for the three large rod sectors agreed with the actual EUDs computed with a radiosensitivity of 0.021Gy-1 well in the range observed in external beam radiotherapy (EBRT), i.e. 0.01-0.04Gy-1. This agreement explains the reunification of the dose-response relationships of the glass and resin spheres in HCC using the TOF-PET based EUD. Additional filtering reduced the EUDs agreement quality. CONCLUSIONS: Recommended manufacturer FDG reconstruction parameters are suitable in TOF-PET post 90Y liver radioembolization for accurate tumour EUD computation. The present results rule out the use of low specific activity phantom studies to optimize reconstruction parameters.

Hepatic Arterial Buffer Response in Liver Radioembolization and Potential Use for Improved Cancer Therapy.

Liver radioembolization is a treatment option for unresectable liver cancers, performed by infusion of 90Y or 166Ho loaded spheres in the hepatic artery. As tumoral cells are mainly perfused via the liver artery unlike hepatic lobules, a twofold tumor to normal liver dose ratio is commonly obtained. To improve tumoral cell killing while preserving lobules, co-infusion of arterial vasoconstrictor has been proposed but with limited success: the hepatic arterial buffer response (HABR) and hepatic vascular escape mechanism hamper the arterioles vasoconstriction. The proposed project aims to take benefit from the HABR by co-infusing a mesenteric arterial vasodilator: the portal flow enhancement inducing the vasoconstriction of the intra sinusoids arterioles barely impacts liver tumors that are mainly fed by novel and anarchic external arterioles. Animal studies were reviewed and dopexamine was identified as a promising safe candidate, reducing by four the hepatic lobules arterial flow. A clinical trial design is proposed. A four to sixfold improvement of the tumoral to normal tissue dose ratio is expected, pushing the therapy towards a real curative intention, especially in HCC where ultra-selective spheres delivery is often not possible.

Accurate non-tumoral 99mTc-MAA absorbed dose prediction to plan optimized activities in liver radioembolization using resin microspheres.

AIM: The manufacturers' recommended methods to calculate delivered activities in liver radioembolization are simplistic and only slightly personalized. Activity planning could also be based on a 99mTc-macroaggregated albumin SPECT/CT (MAA) using the partition model but its accuracy is controversial. This study evaluates the dose parameters in the normal liver and in the tumor compartments using MAA SPECT/CT (pre-therapeutic imaging) and 90Y TOF-PET/CT (post-therapy imaging). Finally, we propose a prescription of the activity as a function of the normal liver MAA distribution. METHOD: 66 procedures of RE (with resin microspheres) corresponding to 171 lesions were analyzed. Tumor to normal targeted liver uptake (T/NTL), tumor absorbed dose (TD) and whole normal liver absorbed (WNLD) were assessed with MAA and 90Y imaging. Secondly, activities were recalculated using the MAA distribution in the normal liver compartment to reach the maximal tolerable liver dose. These Activities were compared to activities defined with the BSA method. RESULTS: Compared to 90Y imaging, our study demonstrated an accurate estimation of the WNLD using MAA imaging (Pearson's R = 0.97, p < 0.001). On the contrary, significant variations were found for TD (R = 0.65, p < 0.001). The MAA T/NTL ratio has a 85% positive predictive value in identifying patients who will get a 90Y T/NTL ratio above 1.5. Moreover, activities calculated using the MAA distribution in the normal liver compartment were significantly higher to activities defined with the BSA method. CONCLUSION: Whole normal liver absorbed doses are accurately predicted with MAA imaging and could be used to optimize the activity planning.

Antireflux catheter improves tumor targeting in liver radioembolization with resin microspheres.

PURPOSE: We aimed to determine whether antireflux (ARC) catheter may result in better tumor targeting in liver radioembolization using 90Y-resin microspheres. METHODS: Patients treated with resin microspheres for hepatocellular carcinoma (HCC) and secondary liver malignancies were retrospectively analyzed. All patients underwent a 99mTc-macroaggregated albumin (99mTc-MAA) single photon emission computed tomography (SPECT) following the planning arteriography with a conventional end-hole catheter. For 90Y-microspheres injection, two groups were defined depending on the type of catheter used: an ARC group (n=38) and a control group treated with a conventional end-hole catheter (n=23). 90Y positron emission tomography computed tomography (PET/CT) was performed after the therapeutic arteriography. The choice of the catheter was not randomized, but left to the choice of the interventional radiologist. 99mTc-MAA SPECT and 90Y PET/CT were co-registered with the baseline imaging to determine a tumor to normal liver ratio (T/NL[MAA or 90Y]) and tumor dose (TD[MAA or 90Y]) for the planning and therapy. RESULTS: Overall, 38 patients (115 lesions) and 23 patients (75 lesions) were analyzed in the ARC and control groups, respectively. In the ARC group, T/NL90Y and TD90Y were significantly higher than T/NLMAA and TDMAA. Median (IQR) T/NL90Y was 2.16 (2.15) versus 1.74 (1.43) for T/NLMAA (p < 0.001). Median (IQR) TD90Y was 90.96 Gy (98.31 Gy) versus 73.72 Gy (63.82 Gy) for TDMAA (p < 0.001). In this group, the differences were highly significant for neuroendocrine metastases (NEM) and HCC and less significant for colorectal metastases (CRM). In the control group, no significant differences were demonstrated. CONCLUSION: The use of an ARC significantly improves tumor deposition in liver radioembolization with resin microspheres.

EANM dosimetry committee series on standard operational procedures: a unified methodology for 99mTc-MAA pre- and 90Y peri-therapy dosimetry in liver radioembolization with 90Y microspheres.

The aim of this standard operational procedure is to standardize the methodology employed for the evaluation of pre- and post-treatment absorbed dose calculations in 90Y microsphere liver radioembolization. Basic assumptions include the permanent trapping of microspheres, the local energy deposition method for voxel dosimetry, and the patient-relative calibration method for activity quantification.The identity of 99mTc albumin macro-aggregates (MAA) and 90Y microsphere biodistribution is also assumed. The large observed discrepancies in some patients between 99mTc-MAA predictions and actual 90Y microsphere distributions for lesions is discussed. Absorbed dose predictions to whole non-tumoural liver are considered more reliable and the basic predictors of toxicity. Treatment planning based on mean absorbed dose delivered to the whole non-tumoural liver is advised, except in super-selective treatments.Given the potential mismatch between MAA simulation and actual therapy, absorbed doses should be calculated both pre- and post-therapy. Distinct evaluation between target tumours and non-tumoural tissue, including lungs in cases of lung shunt, are vital for proper optimization of therapy. Dosimetry should be performed first according to a mean absorbed dose approach, with an optional, but important, voxel level evaluation. Fully corrected 99mTc-MAA Single Photon Emission Computed Tomography (SPECT)/computed tomography (CT) and 90Y TOF PET/CT are regarded as optimal acquisition methodologies, but, for institutes where SPECT/CT is not available, non-attenuation corrected 99mTc-MAA SPECT may be used. This offers better planning quality than non dosimetric methods such as Body Surface Area (BSA) or mono-compartmental dosimetry. Quantitative 90Y bremsstrahlung SPECT can be used if dedicated correction methods are available.The proposed methodology is feasible with standard camera software and a spreadsheet. Available commercial or free software can help facilitate the process and improve calculation time.

Prediction of tumor response and patient outcome after radioembolization of hepatocellular carcinoma using 90Y-PET-computed tomography dosimetry.

AIM: 90Y-radioembolization using glass or resin microspheres is increasingly used for the treatment of hepatocellular carcinoma (HCC). The aim of this retrospective study is to determine the prognostic relevance of dosimetric parameters defined with 90Y-PET-CT obtained immediately after radioembolization. METHODS: Forty-five HCC patients, mostly with multiple lesions, were treated by radioembolization between 2011 and 2017. After treatment, all underwent a 90Y PET-CT with time of flight reconstruction (90Y-TOF-PET-CT). Tumor absorbed dose and cumulative tumor dose-volume histogram were calculated using a dose point Kernel convolution algorithm. The radiological tumor response was assessed using modified (m)-RECIST criteria. Progression-free-survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox regression analysis. RESULTS: Twenty-six patients were treated with glass microspheres (73 lesions) and nineteen with resin microspheres (60 lesions). Thresholds of 118 and 61 Gy for glass and resin microspheres respectively correlate well with radiological response with a positive predictive value (PPV) of 98 and 80% and discriminate patient outcome with regard to PFS (P = 0.03 and 0.005) and OS (P = 0.003 and 0.007). Using dose volume histogram, a minimal absorbed dose of 40 Gy in 66% of the tumor volume (defined as D66) was highly predictive of radiological response (PPV = 94%), PFS (P < 0.001) and OS (P = 0. 008), for either device. CONCLUSION: Dosimetric parameters obtained using 90Y-PET-CT are predictive of tumor response, PFS and OS. In clinical practice, a systematic dosimetric evaluation using 90Y PET should be implemented to help predicting patient outcomes.

Single photon emission-computed tomography (SPECT) for functional investigation of the proximal tubule in conscious mice.

Noninvasive analysis of renal function in conscious mice is necessary to optimize the use of mouse models. In this study, we evaluated whether single photon emission-computed tomography (SPECT) using specific radionuclear tracers can be used to analyze changes in renal proximal tubule functions. The tracers included (99m)TC- dimercaptosuccinic acid ((99m)Tc-DMSA), which is used for cortex imaging; (99m)Tc-mercaptoacetyltriglycine ((99m)Tc-MAG3), used for dynamic renography; and (123)I-beta(2)-microglobulin, which monitors receptor-mediated endocytosis. (99m)Tc-DMSA SPECT imaging was shown to delineate the functional renal cortex with a approximately 1-mm spatial resolution and accumulated in the cortex reaching a plateau 5 h after injection. The cortical uptake of (99m)Tc-DMSA was abolished in Clcn5 knockout mice, a model of proximal tubule dysfunction. Dynamic renography with (99m)Tc-MAG3 in conscious mice demonstrated rapid extraction from blood, renal accumulation, and subsequent tubular secretion. Anesthesia induced a significant delay in the (99m)Tc-MAG3 clearance. The tubular reabsorption of (123)I-beta(2)-microglobulin was strongly impaired in the Clcn5 knockout mice, with defective tubular processing and loss of the native tracer in urine, reflecting proximal tubule dysfunction. Longitudinal studies in a model of cisplatin-induced acute tubular injury revealed a correlation between tubular recovery and (123)I-beta(2)-microglobulin uptake. These data show that SPECT imaging with well-validated radiotracers allows in vivo investigations of specific proximal tubule functions in conscious mice.

Feasibility of 90Y TOF PET-based dosimetry in liver metastasis therapy using SIR-Spheres.

PURPOSE: (90)Y-labelled compounds used in targeted radiotherapy are usually imaged with SPECT by recording the bremsstrahlung X-rays of the beta decay. The continuous shape of the X-ray spectrum induces the presence of a significant fraction of scatter rays in the acquisition energy window, reducing the accuracy of biodistribution and of dosimetry assessments. METHODS: The aim of this paper is to use instead the low branch of e(-) e(+) pair production in the (90)Y decay. After administration of (90)Y-labelled SIR-Spheres by catheterization of both liver lobes, the activity distribution is obtained by (90)Y time-of-flight (TOF) PET imaging. The activity distribution is convolved with a dose irradiation kernel in order to derive the regional dosimetry distribution. RESULTS: Evaluation on an anatomical phantom showed that the method provided an accurate dosimetry assessment. Preliminary results on a patient demonstrated a high-resolution absorbed dose distribution with a clear correlation with tumour response. CONCLUSION: This supports the implementation of (90)Y PET in selective internal radiation therapy of the liver.