Relationship Between Absorbed Dose and Response in Neuroendocrine Tumors Treated with [177Lu]Lu-DOTATATE.

Peptide receptor radionuclide therapy presents the possibility of tracing and quantifying the uptake of the drug in the body and performing dosimetry, potentially allowing individualization of treatment schemes. However, the details of how neuroendocrine tumors (NETs) respond to different absorbed doses are insufficiently known. Here, we investigated the relationship between tumor-absorbed dose and tumor response in a cohort of patients with NETs treated with [177Lu]Lu-DOTATATE. Methods: This was a retrospective study based on 69 tumors in 32 patients treated within a clinical trial. Dosimetry was performed at each cycle of [177Lu]Lu-DOTATATE, rendering 366 individual absorbed dose assessments. Hybrid planar-SPECT/CT imaging using [177Lu]Lu-DOTATATE was used, including quantitative SPECT reconstruction, voxel-based absorbed dose rate calculation, semiautomatic image segmentation, and partial-volume correction. Changes in tumor volume were used to determine tumor response. The volume for each tumor was manually delineated on consecutive CT scans, giving a total of 712 individual tumor volume assessments. Tumors were stratified according to grade. The relationship between absorbed dose and response was investigated using mixed-effects models and logistic regression. Tumors smaller than 4 cm3 were excluded. Results: In grade 2 NETs, a clear relationship between absorbed dose and volume reduction was observed. Our observations suggest a 90% probability of partial tumor response for an accumulated tumor-absorbed dose of at least 135 Gy. Conclusion: Our findings are in accordance with previous observations regarding the relationship between tumor shrinkage and absorbed dose. Moreover, our data suggest an absorbed dose threshold for partial response in grade 2 NETs. These observations provide valuable insights for the design of dosimetry-guided peptide receptor radionuclide therapy schemes.

Radiolabeled Somatostatin Receptor Antagonist Versus Agonist for Peptide Receptor Radionuclide Therapy in Patients with Therapy-Resistant Meningioma: PROMENADE Phase 0 Study.

Our primary aim was to compare the therapeutic index (tumor-to-bone marrow and tumor-to-kidney absorbed-dose ratios) of the new radiolabeled somatostatin receptor antagonist [177Lu]Lu-DOTA-JR11 with the established radiolabeled somatostatin receptor agonist [177Lu]Lu-DOTATOC in the same patients with progressive, standard therapy-refractory meningioma. Methods: In this prospective, single-center, open-label phase 0 study (NCT04997317), 6 consecutive patients were included: 3 men and 3 women (mean age, 63.5 y). Patients received 6.9-7.3 GBq (standard injected radioactivity) of [177Lu]Lu-DOTATOC followed by 3.3-4.9 GBq (2 GBq/m2 × body surface area) of [177Lu]Lu-DOTA-JR11 at an interval of 10 ± 1 wk. In total, 1 [177Lu]Lu-DOTATOC and 2-3 [177Lu]Lu-DOTA-JR11 treatment cycles were performed. Quantitative SPECT/CT was done at approximately 24, 48, and 168 h after injection of both radiopharmaceuticals to calculate meningioma and organ absorbed doses as well as tumor-to-organ absorbed-dose ratios (3-dimensional segmentation approach for meningioma, kidneys, liver, bone marrow, and spleen). Results: The median of the meningioma absorbed dose of 1 treatment cycle was 3.4 Gy (range, 0.8-10.2 Gy) for [177Lu]Lu-DOTATOC and 11.5 Gy (range, 4.7-22.7 Gy) for [177Lu]Lu-DOTA-JR11. The median bone marrow and kidney absorbed doses after 1 treatment cycle were 0.11 Gy (range, 0.05-0.17 Gy) and 2.7 Gy (range, 1.3-5.3 Gy) for [177Lu]Lu-DOTATOC and 0.29 Gy (range, 0.16-0.39 Gy) and 3.3 Gy (range, 1.6-5.9 Gy) for [177Lu]Lu-DOTA-JR11, resulting in a 1.4 (range, 0.9-1.9) times higher median tumor-to-bone marrow absorbed-dose ratio and a 2.9 (range, 2.0-4.8) times higher median tumor-to-kidney absorbed-dose ratio with [177Lu]Lu-DOTA-JR11. According to the Common Terminology Criteria for Adverse Events version 5.0, 2 patients developed reversible grade 2 lymphopenia after 1 cycle of [177Lu]Lu-DOTATOC. Afterward, 2 patients developed reversible grade 3 lymphopenia and 1 patient developed reversible grade 3 lymphopenia and neutropenia after 2-3 cycles of [177Lu]Lu-DOTA-JR11. No grade 4 or 5 adverse events were observed at 15 mo or more after the start of therapy. The disease control rate was 83% (95% CI, 53%-100%) at 12 mo or more after inclusion. Conclusion: Treatment with 1 cycle of [177Lu]Lu-DOTA-JR11 showed 2.2-5.7 times higher meningioma absorbed doses and a favorable therapeutic index compared with [177Lu]Lu-DOTATOC after injection of 1.4-2.1 times lower activities. The first efficacy results demonstrated a high disease control rate with an acceptable safety profile in the standard therapy for refractory meningioma patients. Therefore, larger studies with [177Lu]Lu-DOTA-JR11 are warranted in meningioma patients.

On-site CT-derived cFFR in patients with suspected coronary artery disease: Feasibility on a 128-row CT scanner in everyday clinical practice.

PURPOSE: Technical feasibility of CT-based calculation of fractional flow reserve (cFFR) using a 128-row computed tomography scanner in an everyday routine setting. Post-processing and everyday practicability should be analyzed on the scanner on-site in connection with clinical parameters. MATERIALS AND METHODS: This single-center retrospective analysis included 230 patients (74 female; mean age 63.8 years) with CCTA within 21 months between 01/2018 and 09/2019 without non-pathological examinations. cFFR values were obtained using a deep learning-based non-commercial research prototype (cFFR Version3.5.0; Siemens Healthineers GmbH, Erlangen). cFFR values were evaluated at two points: at the maximum point of the stenosis and 1.0 cm distal to the stenosis. Comparison with invasive coronary angiography in 57/230 patients (24.7 %) was performed. CT parameters and quality were evaluated. Further subgroup classification concerning criteria of technical postprocessing was performed: no changes necessary, minor corrections necessary, major corrections necessary, and no evaluation was possible. The required time from starting the software to the final result was evaluated. RESULTS: A total of 116/448 (25.9 %) mild, 223/448 (49.8 %) moderate, and 109/448 (24.3 %) obstructive stenoses was found. The mean cFFR at the maximum point of the stenosis was 0.92 ±â€Š0.09 and significantly higher than the cFRR value of 0.89 ±â€Š0.13 distal to the stenosis (p < 0.001*). The mean degree of stenosis was 44.02 ±â€Š26.99 % (range: 1-99 %) with an area of 5.39 ±â€Š3.30 mm2. In a total of 45 patients (19.1 %), a relevant reduction in cFFR below 0.80 was determined. Overall, in 57/230 patients (24.8 %), catheter angiography was performed. No significant difference in the degree of maximal stenosis (CAD-RADS 0-2/3/4) was detected between the classification of CCTA and ICA (p = 0.171). The mean post-processing time varied significantly with 8.34 ±â€Š4.66 min. in single-vessel CAD vs. 12.91 ±â€Š3.92 min. in two-vessel CAD vs. 21.80 ± 5.94 min. in three-vessel CAD (each p < 0.001). CONCLUSION: Noninvasive onsite quantification of cFFR is feasible with minimal observer interaction in a routine real-world setting on a 128-row scanner. Deep learning-based algorithms allow a robust and semi-automatic on-site determination of cFFR based on data from standard CT scanners. KEY POINTS: · Non-invasive on-site quantification of cFFR is feasible with minimal observer interaction.. · Deep-learning based algorithms allow robust and semi-automatic on-site determination of cFFR.. · The mean follow-up time varied significantly with the extent of vascular CAD..

Myocardial deformation parameters assessed by CMR feature tracking in chronic heart failure: the influence of an optimal medical therapy on myocardial remodelling.

BACKGROUND: Myocardial deformation parameters have been shown to yield early detection of pathological changes in chronic heart failure (CHF). Aim of our study was to evaluate myocardial deformation changes under optimal medical therapy (OMT) in CHF patients. METHODS: CHF patients were examined longitudinally with two cardiac magnetic resonance imaging (CMR) examinations at a median time interval of 140 days. Left and right ventricular volumes were quantified, and deformation analysis was performed using feature tracking, respectively. RESULTS: 57 patients were included into the study. There was a high rate of OMT with a prescription of beta blockers in 98.2% and ACE-inhibitors/Angiotensin receptor blockers in 93.0%. In the total cohort, there were indications of positive remodelling with a significant improvement in left ventricular (LV) ejection fraction (38.9% ± 11.6 vs. 43.0% ± 12.7, p = 0.009), LV enddiastolic volume indexed (92.1 ml/m2 ± 23.5 vs. 87.2 ml/m2 ± 21.2, p = 0.007), LV mass (140.3 g ± 35.7 vs. 128.0 g ± 34.4, p = 0.001) and right ventricular global longitudinal strain (RV GLS) (-18.1% ± 5.1 vs. -20.3% ± 4.5, p < 0.001) during follow-up. DISCUSSION: Patients with CHF and OMT show positive reverse remodelling with improvement of LV volumes and function and RV GLS. This has a potential impact on the surveillance of this patient group, which should be further investigated in larger prospective studies.

Baseline angina burden predicts quality of life and functional improvement in patients with viable myocardium treated for chronic total occlusion.

Chronic total occlusion (CTO) is a common finding in patients with known or suspected coronary artery disease and has a distinctive role in these patients' quality of life. However, there is still a lack of evidence of correct patient selection for percutaneous coronary intervention (PCI). From July 2017 to August 2020, 68 patients with successful PCI of a CTO and previous evidence of viability for PCI by cardiovascular magnetic resonance imaging (CMR) were prospectively included in this single-centre observational study. Of these patients, 62 underwent follow-up CMR, and 56 underwent surveys using the Seattle Angina Questionnaire before PCI and 3, 12 and 24 months after PCI. The CMR results were assessed for volumetric, functional and deformation parameters. From the baseline to the follow-up, there was a significant reduction in the left ventricular volumes (all p < 0.001) and an increase in the left ventricular ejection fraction (57.6 ± 11.6% vs. 60.3 ± 9.4%, p = 0.006). Among the deformation parameters, only the left ventricular radial strain showed significant improvement. The SAQ showed an early improvement that emphasised angina stability and frequency as well as a summary score, which persisted after 24 months. A low SAQ summary score before PCI was the best predictive factor of good clinical improvement thereafter. Improvements in myocardial function and quality of life can be achieved with PCI of a CTO. Patient selection for PCI should be performed primarily among relevantly symptomatic patients when evidence of viability for PCI is present. The SAQ can help guide such patient selection.Trial registration ISRCTN, identifier: ISRCTN33203221. Retrospectively registered on 01.04.2020. https://www.isrctn.com/ISRCTN33203221.

Albumin-Binding and Conventional PSMA Ligands in Combination with 161Tb: Biodistribution, Dosimetry, and Preclinical Therapy.

The favorable decay characteristics of 161Tb attracted the interest of clinicians in using this novel radionuclide for radioligand therapy (RLT). 161Tb decays with a similar half-life to 177Lu, but beyond the emission of ß--particles and γ-rays, 161Tb also emits conversion and Auger electrons, which may be particularly effective to eliminate micrometastases. The aim of this study was to compare the dosimetry and therapeutic efficacy of 161Tb and 177Lu in tumor-bearing mice using SibuDAB and PSMA-I&T, which differ in their blood residence time and tumor uptake. Methods: [161Tb]Tb-SibuDAB and [161Tb]Tb-PSMA-I&T were evaluated in vitro and investigated in biodistribution, imaging, and therapy studies using PC-3 PIP tumor-bearing mice. The 177Lu-labeled counterparts served for dose calculations and comparison of therapeutic efficacy. The tolerability of RLT in mice was monitored on the basis of body mass, blood plasma parameters, blood cell counts, and the histology of relevant organs and tissues. Results: The prostate-specific membrane antigen (PSMA)-targeting radioligands, irrespective of whether labeled with 161Tb or 177Lu, showed similar in vitro data and comparable tissue distribution profiles. As a result of the albumin-binding properties, [161Tb]Tb/[177Lu]Lu-SibuDAB had an enhanced blood residence time and higher tumor uptake (62%-69% injected activity per gram at 24 h after injection) than [161Tb]Tb/[177Lu]Lu-PSMA-I&T (30%-35% injected activity per gram at 24 h after injection). [161Tb]Tb-SibuDAB inhibited tumor growth more effectively than [161Tb]Tb-PSMA-I&T, as can be ascribed to its 4-fold increased absorbed tumor dose. At any of the applied activities, the 161Tb-based radioligands were therapeutically more effective than their 177Lu-labeled counterparts, as agreed with the approximately 40% increased tumor dose of 161Tb compared with that of 177Lu. Under the given experimental conditions, no obvious adverse events were observed. Conclusion: The data of this study indicate the promising potential of 161Tb in combination with SibuDAB for RLT of prostate cancer. Future clinical studies using 161Tb-based RLT will shed light on a potential clinical benefit of 161Tb over 177Lu.

Specific Uptake in the Bone Marrow Causes High Absorbed Red Marrow Doses During [177Lu]Lu-DOTATATE Treatment.

Bone marrow suppression is a common side effect after [177Lu]Lu-DOTATATE treatment of neuroendocrine neoplasms. Neuroendocrine neoplasms share expression of somatostatin receptor type 2 with CD34-positive hematopoietic progenitor cells, potentially leading to active uptake in the radiosensitive red marrow region where these cells are located. This study aimed to identify and quantify specific red marrow uptake using SPECT/CT images collected after the first treatment cycle. Methods: Seventeen patients diagnosed with neuroendocrine neoplasms were treated with [177Lu]Lu-DOTATATE. Seven of them had confirmed bone metastases. After the first treatment cycle, each patient went through 4 SPECT/CT imaging sessions 4, 24, 48, and 168 h after administration. Monte Carlo-based reconstructions were used to quantify activity concentrations in tumors and multiple skeletal sites presumed to house red marrow: the T9-L5 vertebrae and the ilium portion of the hip bones. The activity concentration from the descending aorta was used as input in a compartment model intended to establish a pure red marrow biodistribution by separating the nonspecific blood-based contribution from the specific activity concentration in red marrow. The biodistributions from the compartment model were used to perform red marrow dosimetry at each skeletal site. Results: Increased uptake of [177Lu]Lu-DOTATATE was observed in the T9-L5 vertebrae and hip bones in all 17 patients compared with activity concentrations in the aorta. The mean specific red marrow uptake was 49% (range, 0%-93%) higher than the nonspecific uptake. The median (±SD) total absorbed dose to the red marrow was 0.056 ± 0.023 Gy/GBq and 0.043 ± 0.022 Gy/GBq for the mean of all vertebrae and hip bones, respectively. The patients with bone metastases had an absorbed dose of 0.085 ± 0.046 Gy/GBq and 0.069 ± 0.033 Gy/GBq for the vertebrae and hip bones, respectively. The red marrow elimination phase was statistically slower in patients with fast tumor elimination, which is in line with transferrin transport of 177Lu back to the red marrow. Conclusion: Our results suggest that specific red marrow uptake of [177Lu]Lu-DOTATATE is in line with observations of somatostatin receptor type 2-expressing hematopoietic progenitor cells within the bone marrow. Blood-based dosimetry methods fail to account for the prolonged elimination of specific uptake and underestimate the absorbed dose to red marrow.

Evaluation of reconstruction methods and image noise levels concerning visual assessment of simulated liver lesions in 111In-octreotide SPECT imaging.

BACKGROUND: Early cancer detection is crucial for patients' survival. The image quality in 111In-octreotide SPECT imaging could be improved by using Monte Carlo (MC)-based reconstruction. The aim of this observational study was to determine the detection rate of simulated liver lesions for MC-based ordered subset expectation maximization (OSEM) reconstruction compared to conventional attenuation-corrected OSEM reconstruction. METHODS: Thirty-seven SPECT/CT examinations with 111In-octreotide were randomly selected. The inclusion criterion was no liver lesions at the time of examination and for the following 3 years. SPECT images of spheres representing lesions were simulated using MC. The raw data of the spheres were added to the raw data of the established healthy patients in 26 of the examinations, and the remaining 11 examinations were not modified. The images were reconstructed using conventional OSEM reconstruction with attenuation correction and post filtering (fAC OSEM) and MC-based OSEM reconstruction without and with post filtering (MC OSEM and fMC OSEM, respectively). The images were visually and blindly evaluated by a nuclear medicine specialist. The criteria evaluated were liver lesion yes or no, including coordinates if yes, with confidence level 1-3. The percentage of detected lesions and accuracy (percentage of correctly classified cases), as well as tumor-to-normal tissue concentration (TNC) ratios and signal-to-noise ratios (SNRs), were evaluated. RESULTS: The detection rates were 30.8% for fAC OSEM, 42.3% for fMC OSEM, and 50.0% for MC OSEM. The accuracies were 45.9% for fAC OSEM, 45.9% for fMC OSEM, and 54.1% for MC OSEM. The number of false positives was higher for fMC and MC OSEM. The observer's confidence level was higher in filtered images than in unfiltered images. TNC ratios were significantly higher, statistically, with MC OSEM and fMC OSEM than with AC OSEM, but SNRs were similar due to higher noise with MC OSEM. CONCLUSION: One in two lesions were found using MC OSEM versus one in three using conventional reconstruction. TNC ratios were significantly improved, statistically, using MC-based reconstruction, but the noise levels increased and consequently the confidence level of the observer decreased. For further improvements, image noise needs to be suppressed.

Cardiovascular Outcomes in De Novo Kidney Transplant Recipients Receiving Everolimus and Reduced Calcineurin Inhibitor or Standard Triple Therapy: 24-month Post Hoc Analysis From TRANSFORM Study.

BACKGROUND: The comparative impact of everolimus (EVR)-based regimens versus standard of care (mycophenolic acid+standard calcineurin inhibitor [MPA+sCNI]) on cardiovascular outcomes in de novo kidney transplant recipients (KTRs) is poorly understood. The incidence of major adverse cardiac events (MACEs) in KTRs receiving EVR+reduced CNI (rCNI) or MPA+sCNI from the TRANSplant eFficacy and safety Outcomes with an eveRolimus-based regiMen study was evaluated. METHODS: The incidence of MACE was determined for all randomized patients receiving at least 1 dose of the study drug. Factors associated with MACEs were determined by logistic regression. Risk of MACE out to 3 y post-study was calculated using the Patient Outcome in Renal Transplantation equation. RESULTS: MACE occurred in 81 of 1014 (8.0%; EVR+rCNI) versus 89 of 1012 (8.8%; MPA+sCNI) KTRs (risk ratio, 0.91 [95% confidence interval [CI], 0.68-1.21]). The incidence of circulatory death, myocardial infarction, revascularization, or angina was similar between the arms. Incidence of MACE was similar between EVR+rCNI and MPA+sCNI arms with a higher incidence in prespecified risk groups: older age, pretransplant diabetes (15.1% versus 15.9%), statin use (8.5% versus 10.8%), and low estimated glomerular filtration rate (Month 2 estimated glomerular filtration rate <30 versus >60 mL/min/1.73 m 2 ; odds ratio, 2.23 [95% CI, 1.02-4.86]; P = 0.044), respectively. Predicted risk of MACE within 3 y of follow-up did not differ between the treatment arms. CONCLUSIONS: Cardiovascular morbidity and mortality were similar between de novo KTRs receiving EVR+rCNI and MPA+sCNI. EVR+rCNI is a viable alternative to the current standard of care in KTRs.

Observations on the pollination and breeding systems of two Corybas species (Diurideae; Orchidaceae) by fungus gnats (Mycetophilidae) in southwestern Yunnan, China.

Modes of floral presentation in some angiosperms attract flies that eat and/or oviposit on seasonal fruiting bodies of fungi. Mushroom mimesis by orchid flowers has been speculated in the geoflorous, Indo-Malaysian-Australasian, genus Corybas s.l. for decades but most studies remain fragmentary and are often inconclusive. Here we report the roles of fungus gnats as pollinators of Corybas geminigibbus and C. shanlinshiensis in southwestern Yunnan, China, combining results of field observations, lab analyses, and manipulative experiments. Hand pollination experiments suggested both species were self-compatible but incapable of mechanical self-pollination, thereby requiring pollinators for fruit production. A female of a Phthinia sp. (Mycetophilidae) carried a pollinarium of C. geminigibbus dorsally on its thorax. Two females and one male of Exechia sp. (Mycetophilidae) visiting flowers of C. shanlinshiensis carried dorsal depositions of pollinaria on their thoraces. Mycetophilid eggs were not found in the flowers of either species. The comparative fragrance analyses of these flowers and three co-fruiting mushroom species did not suggest that either orchid species was a brood-site mimic. This is the first confirmation of the dispersal of pollinaria of Corybas species by fungus gnats in subtropical-temperate Asia.

Active bone marrow S-values for the low-energy electron emitter terbium-161 compared to S-values for lutetium-177 and yttrium-90.

BACKGROUND: Based on theoretical and preclinical results, terbium-161 may be a valid alternative to lutetium-177 and yttrium-90 in radionuclide therapies. The large low-energy electron emission from terbium-161 is a favorable feature in the treatment of disseminated disease, but its impact on the radiosensitive bone marrow needs to be evaluated. Using voxel-based skeletal dosimetry models in which active bone marrow is defined as regions containing stem cells and progenitor cells of the hematopoietic lineage, we generated S-values (absorbed dose per decay) for terbium-161 and evaluated its distribution-dependence in bone marrow cavities. METHODS: S-values in the active bone marrow were calculated for terbium-161, lutetium-177, and yttrium-90 irradiation using two (male/female) image-based bone marrow dosimetry models. The radionuclides were distributed to one of the three structures that define the spongiosa bone region in the skeletal models: (i) active bone marrow, (ii) inactive bone marrow, or (iii) surface or whole volume of the trabecular bone. Decay data from ICRP 107 were combined with specific absorbed fractions to calculate S-values for 13 skeletal sites. To increase the utility, the skeletal site-specific S-values were averaged to produce whole-body average S-values and spongiosa average S-values. RESULTS: For yttrium-90, the high-energy ß particles irradiate the active marrow regardless of the source compartment, consistently generating the highest S-values (65-90% higher). Between terbium-161 and lutetium-177, the largest differences in S-values were with an active marrow source (50%), such as self-irradiation, due to the contribution of the short-ranged conversion and Auger electrons from terbium-161. Their influence decreased as the source moved to inactive marrow or the surface or volume of the trabecular bone, reducing the S-values and the differences between terbium-161 and lutetium-177 (15-35%). CONCLUSION: The S-values of terbium-161 for active bone marrow and, consequently, the bone marrow toxicity profile were more dependent on the radionuclide distribution within the bone marrow cavity than the S-values of lutetium-177 and yttrium-90. This effect was attributed to the considerable low-energy electron emission of terbium-161. Therefore, it will be critical to investigate the bone marrow distribution of a particular radiopharmaceutical for accurate estimation of the active bone marrow dose.

Structural Basis of Stereospecific Vanadium-Dependent Haloperoxidase Family Enzymes in Napyradiomycin Biosynthesis.

Vanadium-dependent haloperoxidases (VHPOs) from Streptomyces bacteria differ from their counterparts in fungi, macroalgae, and other bacteria by catalyzing organohalogenating reactions with strict regiochemical and stereochemical control. While this group of enzymes collectively uses hydrogen peroxide to oxidize halides for incorporation into electron-rich organic molecules, the mechanism for the controlled transfer of highly reactive chloronium ions in the biosynthesis of napyradiomycin and merochlorin antibiotics sets the Streptomyces vanadium-dependent chloroperoxidases apart. Here we report high-resolution crystal structures of two homologous VHPO family members associated with napyradiomycin biosynthesis, NapH1 and NapH3, that catalyze distinctive chemical reactions in the construction of meroterpenoid natural products. The structures, combined with site-directed mutagenesis and intact protein mass spectrometry studies, afforded a mechanistic model for the asymmetric alkene and arene chlorination reactions catalyzed by NapH1 and the isomerase activity catalyzed by NapH3. A key lysine residue in NapH1 situated between the coordinated vanadate and the putative substrate binding pocket was shown to be essential for catalysis. This observation suggested the involvement of the ε-NH2, possibly through formation of a transient chloramine, as the chlorinating species much as proposed in structurally distinct flavin-dependent halogenases. Unexpectedly, NapH3 is modified post-translationally by phosphorylation of an active site His (τ-pHis) consistent with its repurposed halogenation-independent, α-hydroxyketone isomerase activity. These structural studies deepen our understanding of the mechanistic underpinnings of VHPO enzymes and their evolution as enantioselective biocatalysts.

What Is Normal for an Aging Heart?: A Prospective CMR Cohort Study.

BACKGROUND: This study aims to investigate normal changes throughout aging of the heart in cardiac magnetic resonance (CMR) imaging in healthy volunteers. While type 2 diabetes mellitus is a frequent finding in the elderly population, also the influence of this circumstance in otherwise healthy persons is part of our study. METHODS: In this prospective single-center trial, 75 healthy subjects in distinct age groups and 10 otherwise healthy diabetics were enrolled. All subjects underwent functional, flow sensitive, native T2- and T1-mapping in a 1.5T CMR scanner. RESULTS: No differences in right and left ventricular ejection fractions were observed between aging healthy groups. Bi-ventricular volumes lowered significantly (p<0.001) between the age groups. There was also a significant decrease in myocardial T1 values, aortic distensibility, and left ventricular peak diastolic strain rates. There were no differences in T2 mapping and the other deformation parameters. Patients with type 2 diabetes mellitus had lower end-diastolic volume indexes; all the other measurements were comparable. CONCLUSIONS: Aging processes in the healthy heart involve a decrease in ventricular volumes, with ejection fractions remaining normal. Stiffening of the myocardium and aorta and a decrease in T1 values are potential indications of age-related remodeling. Type 2 diabetes mellitus seems to have no major influence on aging processes of the heart. TRIAL REGISTRATION: EudraCT Identifier: EudraCT 2017-000045-42.

Preclinical investigations using [177Lu]Lu-Ibu-DAB-PSMA toward its clinical translation for radioligand therapy of prostate cancer.

[177Lu]Lu-Ibu-DAB-PSMA was previously characterized with moderate albumin-binding properties enabling high tumor accumulation but reasonably low retention in the blood. The aim of this study was to investigate [177Lu]Lu-Ibu-DAB-PSMA in preclinical in vivo experiments and compare its therapeutic efficacy and potential undesired side effects with those of [177Lu]Lu-PSMA-617 and the previously developed [177Lu]Lu-PSMA-ALB-56. BALB/c nude mice without tumors were investigated on Day 10 and 28 after injection of 10 MBq radioligand. It was revealed that most plasma parameters were in the same range for all groups of mice and histopathological examinations of healthy tissue did not show any alternations in treated mice as compared to untreated controls. Based on these results, a therapy study over twelve weeks was conducted with PC-3 PIP tumor-bearing mice for comparison of the radioligands's therapeutic efficacy up to an activity of 10 MBq (1 nmol) per mouse. In agreement with the increased mean absorbed tumor dose, [177Lu]Lu-Ibu-DAB-PSMA (~ 6.6 Gy/MBq) was more effective to inhibit tumor growth than [177Lu]Lu-PSMA-617 (~ 4.5 Gy/MBq) and only moderately less potent than [177Lu]Lu-PSMA-ALB-56 (~ 8.1 Gy/MBq). As a result, the survival of mice treated with 2 MBq of an albumin-binding radioligand was significantly increased (p < 0.05) compared to that of mice injected with [177Lu]Lu-PSMA-617 or untreated controls. The majority of mice treated with 5 MBq or 10 MBq [177Lu]Lu-Ibu-DAB-PSMA or [177Lu]Lu-PSMA-ALB-56 were still alive at study end. Hemograms of immunocompetent mice injected with 30 MBq [177Lu]Lu-Ibu-DAB-PSMA or 30 MBq [177Lu]Lu-PSMA-617 showed values in the same range as untreated controls. This was, however, not the case for mice treated with [177Lu]Lu-PSMA-ALB-56 which revealed a drop in lymphocytes and hemoglobin at Day 10 and Day 28 after injection. The data of this study demonstrated a significant therapeutic advantage of [177Lu]Lu-Ibu-DAB-PSMA over [177Lu]Lu-PSMA-617 and a more favorable safety profile as compared to that of [177Lu]Lu-PSMA-ALB-56. Based on these results, [177Lu]Lu-Ibu-DAB-PSMA may has the potential for a clinical translation.

Phase II trial demonstrates the efficacy and safety of individualized, dosimetry-based 177Lu-DOTATATE treatment of NET patients.

PURPOSE: Radionuclide therapy with 177Lu-DOTATATE is well established for patients with advanced somatostatin receptor-positive neuroendocrine tumors with a standard schedule of 7.4 GBq at four occasions. However, this approach does not consider individual variability affecting the tumor radiation dose or dose to organs at risk. Therefore, it is important to assess more personalized strategies. The aim of this phase II trial was to evaluate individualized 177Lu-DOTATATE for which the number of cycles varied based on renal dosimetry. METHODS: Patients were eligible if they had a progressive, somatostatin receptor-positive neuroendocrine tumor with a Ki 67 labeling index < 20%. They received cycles of 7.4 GBq of 177Lu-DOTATATE at 10 ± 2-week intervals until a predefined radiation dose to the kidneys was reached. The primary endpoint was objective tumor response (RECIST v 1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity (CTCAE v. 4.0). RESULTS: Ninety-six patients who had received a median of 5 cycles (range 1-9) were evaluable for efficacy. The objective tumor response was 16% partial response, 66% stable disease, and 19% progressive disease. The median PFS and OS were 29 months and 47 months, respectively, and were significantly associated with kidney dose, performance status, and Ki 67 levels but not with tumor origin. The overall toxicity was mild, and the most common events were grade 1-2 anemia, thrombocytopenia, fatigue, nausea, and diarrhea. Grade 3-4 toxicity occurred in < 10% of patients and was mostly hematological, with no grade 3-4 renal toxicity. CONCLUSION: Individualized treatment with 177Lu-DOTATATE based on renal dosimetry is clearly feasible with low toxicity and promising efficacy, showing the potential to further improve outcome beyond the standard approach, and should be further assessed in randomized trials. TRIAL REGISTRATION: EudraCT 2011-000,240-16. NCT01456078. https://clinicaltrials.gov/ct2/show/NCT01456078.

EANM dosimetry committee recommendations for dosimetry of 177Lu-labelled somatostatin-receptor- and PSMA-targeting ligands.

The purpose of the EANM Dosimetry Committee is to provide recommendations and guidance to scientists and clinicians on patient-specific dosimetry. Radiopharmaceuticals labelled with lutetium-177 (177Lu) are increasingly used for therapeutic applications, in particular for the treatment of metastatic neuroendocrine tumours using ligands for somatostatin receptors and prostate adenocarcinoma with small-molecule PSMA-targeting ligands. This paper provides an overview of reported dosimetry data for these therapies and summarises current knowledge about radiation-induced side effects on normal tissues and dose-effect relationships for tumours. Dosimetry methods and data are summarised for kidneys, bone marrow, salivary glands, lacrimal glands, pituitary glands, tumours, and the skin in case of radiopharmaceutical extravasation. Where applicable, taking into account the present status of the field and recent evidence in the literature, guidance is provided. The purpose of these recommendations is to encourage the practice of patient-specific dosimetry in therapy with 177Lu-labelled compounds. The proposed methods should be within the scope of centres offering therapy with 177Lu-labelled ligands for somatostatin receptors or small-molecule PSMA.

An overview of the efficacy and safety of everolimus in adult solid organ transplant recipients.

As the risk of graft loss due to acute rejection has declined, the goal of post-transplant management has switched to long-term preservation of organ function. Minimizing calcineurin inhibitor (CNI)-related nephrotoxicity is a key component of this objective. Everolimus is a mammalian target of rapamycin inhibitor/proliferation-signal inhibitor with potent immunosuppressive and anti-proliferative effects. It has been widely investigated in large randomized clinical studies that have shown it to have similar anti-rejection efficacy compared with standard-of-care regimens across organ transplant indications. With demonstrated potential to facilitate the reduction of CNI therapy and preserve renal function, everolimus is an alternative to the current standard-of-care CNI-based regimens used in de novo and maintenance solid organ transplantation recipients. Here, we provide an overview of the evidence from the everolimus clinical study program across kidney, liver, heart, and lung transplants, as well as other key data associated with its use in CNI reduction strategies in adult transplant recipients.

Optimizing the Schedule of PARP Inhibitors in Combination with 177Lu-DOTATATE: A Dosimetry Rationale.

177Lu-DOTATATE for neuroendocrine tumours is considered a low-toxicity treatment and may therefore be combined with other pharmaceuticals to potentiate its efficacy. One approach is to add a poly-[ADP-ribose]-polymerase (PARP) inhibitor to decrease the ability of tumour cells to repair 177Lu-induced DNA damage. To decrease the risk of side effects, the sequencing should be optimized according to the tumour-to-normal tissue enhanced dose ratio (TNED). The aim of this study was to investigate how to enhance 177Lu-DOTATATE by optimal timing of the addition of a PARP inhibitor. Biokinetic modelling was performed based on the absorbed dose to the bone marrow, kidneys and tumour; determined from SPECT/CT and planar images from 17 patients treated with 177Lu-DOTATATE. To investigate the theoretical enhanced biological effect of a PARP inhibitor during 177Lu-DOTATATE treatment, the concept of relative biological effectiveness (RBE) was used, and PARP inhibitor administration was simulated over different time intervals. The absorbed dose rate for the tumour tissue demonstrated an initial increase phase until 12 h after infusion followed by a slow decrease. In contrast, the bone marrow showed a rapid initial dose rate decrease. Twenty-eight days after infusion of 177Lu-DOTATATE, the full absorbed dose to the bone marrow and kidney was reached. Using an RBE value of 2 for both the tumour and normal tissues, the TNED was increased compared to 177Lu-DOTATATE alone. According to the modelling, the PARP inhibitor should be introduced approximately 24 h after the start of 177Lu-DOTATATE treatment and be continued for up to four weeks to optimize the TNED. Based on these results, a phase I trial assessing the combination of olaparib and 177Lu-DOTATATE in somatostatin receptor-positive tumours was launched in 2020 (NCT04375267).