Comparison of different methods for post-therapeutic dosimetry in [177Lu]Lu-PSMA-617 radioligand therapy

Background Dosimetry is of high importance for optimization of patient-individual PSMA-targeted radioligand therapy (PSMA-RLT). The aim of our study was to evaluate and compare the feasibility of different approaches of image-based absorbed dose estimation in terms of accuracy and effort in clinical routine. Methods Whole-body planar images and SPECT/CT images were acquired from 24 patients and 65 cycles at 24h, 48h, and ≥96h after administration of a mean activity of 6.4 GBq [177Lu]Lu-PSMA-617 (range 3–10.9 GBq). Dosimetry was performed by use of the following approaches: 2D planar-based dosimetry, 3D SPECT/CT-based dosimetry, and hybrid dosimetry combining 2D and 3D data. Absorbed doses were calculated according to IDAC 2.1 for the kidneys, the liver, the salivary glands, and bone metastases. Results Mean absorbed doses estimated by 3D dosimetry (the reference method) were 0.54 ± 0.28 Gy/GBq for the kidneys, 0.10 ± 0.05 Gy/GBq for the liver, 0.81 ± 0.34 Gy/GBq for the parotid gland, 0.72 ± 0.39 Gy/GBq for the submandibular gland, and 1.68 ± 1.32 Gy/GBq for bone metastases. Absorbed doses of normal organs estimated by hybrid dosimetry showed small, non-significant differences (median up to 4.0%) to the results of 3D dosimetry. Using 2D dosimetry, in contrast, significant differences (median up to 10.9%) were observed. Regarding bone metastases, small, but significant differences (median up to 7.0%) of absorbed dose were found for both, 2D dosimetry and hybrid dosimetry. Bland-Altman analysis revealed high agreement between hybrid dosimetry and 3D dosimetry for normal organs and bone metastases, but substantial differences between 2D dosimetry and 3D dosimetry. Conclusion Hybrid dosimetry provides high accuracy in estimation of absorbed dose in comparison to 3D dosimetry for all important organs and is therefore feasible for use in individualized PSMA-RLT

Detection efficacy of [89Zr]Zr-PSMA-617 PET/CT in [68Ga]Ga-PSMA-11 PET/CT-negative biochemical recurrence of prostate cancer

Rationale In patients with biochemical recurrence of prostate cancer (BCR), preliminary data suggest that prostate-specifc membrane antigen (PSMA) ligand radiotracers labeled with zirconium-89 (89Zr; half-life ~ 78.41 h), which allow imaging≥24 h post-injection, detect suspicious lesions that are missed when using tracers incorporating short-lived radionuclides. Materials and methods To confrm [ 89Zr]Zr-PSMA-617 positron emission tomography/computed tomography (PET/CT) detection efcacy regarding such lesions, and compare quality of 1-h, 24-h, and 48-h [ 89Zr]Zr-PSMA-617 scans, we retrospectively analyzed visual fndings and PET variables refecting lesional [ 89Zr]Zr-PSMA-617 uptake and lesion-to-background ratio. The cohort comprised 23 men with BCR post-prostatectomy, median (minimum–maximum) prostate-specifc antigen (PSA) 0.54 (0.11–2.50) ng/mL, and negative [ 68Ga]Ga-PSMA-11 scans 40±28 d earlier. Primary endpoints were percentages of patients with, and classifcations of, suspicious lesions. Results Altogether, 18/23 patients (78%) had 36 suspicious lesions (minimum–maximum per patient: 1–4) on both 24-h and 48-h scans (n=33 lesions) or only 48-h scans (n=3 lesions). Only one lesion appeared on a 1-h scan. Lesions putatively represented local recurrence in 11 cases, and nodal or bone metastasis in 21 or 4 cases, respectively; 1/1 lesion was histologically confrmed as a nodal metastasis. In all 15 patients given radiotherapy based on [ 89Zr]Zr-PSMA-617 PET/CT, PSA values decreased after this treatment. Comparison of PET variables in 24-h vs 48-h scans suggested no clear superiority of either regarding radiotracer uptake, but improved lesion-to-background ratio at 48 h. Conclusions In men with BCR and low PSA, [ 89Zr]Zr-PSMA-617 PET/CT seems efective in fnding prostate malignancy not seen on [ 68Ga]Ga-PSMA-11 PET/CT. The higher detection rates and lesion-to-background ratios of 48-h scans versus 24-h scans suggest that imaging at the later time may be preferable. Prospective study of [ 89Zr]Zr-PSMA-617 PET/CT is warranted

Tumor Sink Effect with Prostate-Specific Membrane Antigen-Targeted Theranostics in Patients with Metastatic Castration-Resistant Prostate Cancer: Intra-Individual Evaluations

“Tumor sink effects”, decreased physiological uptake of radiopharmaceuticals due to sequestration by a tumor, may impact radioligand therapy (RLT) toxicity and dosing. We investigated these effects with prostate-specific membrane antigen (PSMA)-targeted radiopharmaceuticals in the healthy organs-at-risk (the parotid glands, kidneys, liver, and spleen) of 33 patients with metastatic castration-resistant prostate cancer (mCRPC). We retrospectively performed three intra-individual comparisons. First, we correlated changes from baseline to post-RLT (after two 177-lutetium (177Lu)-PSMA-617 cycles) in total lesional PSMA (∆TLP) and organ mean standardized uptake values (∆SUVmean). Second, in 25 RLT responders, we compared the organ SUVmean post-RLT versus that at baseline. Lastly, we correlated the baseline TLP and organ SUVmean. Data were acquired via 68-gallium-PSMA-11 positron emission tomography before the first and after the second 177Lu-PSMA-617 cycle. In the parotid glands and spleen, ∆TLP and ∆SUVmean showed a significant inverse correlation (r = −0.40, p = 0.023 and r = −0.36, p = 0.042, respectively). Additionally, in those tissues, the median organ SUVmean rose significantly from baseline after the response to RLT (p ≤ 0.022), and the baseline TLP and SUVmean were significantly negatively correlated (r = −0.44, p = 0.01 and r = −0.42, p = 0.016, respectively). These observations suggest tumor sink effects with PSMA-targeted radiopharmaceuticals in the salivary glands and spleen of patients with mCRPC

[89Zr]Zr-PSMA-617 PET/CT in biochemical recurrence of prostate cancer : first clinical experience from a pilot study including biodistribution and dose estimates

Purpose Prostate-specific membrane antigen (PSMA)-targeted PET/CT has become increasingly important in the management of prostate cancer, especially in localization of biochemical recurrence (BCR). PSMA-targeted PET/CT imaging with long-lived radionuclides as 89Zr (T1/2=78.4 h) may improve diagnostics by allowing data acquisition on later time points. In this study, we present our frst clinical experience including preliminary biodistribution and dosimetry data of [ 89Zr]Zr-PSMA-617 PET/CT in patients with BCR of prostate cancer. Methods Seven patients with BCR of prostate cancer who revealed no (n =4) or undetermined (n =3) findings on [ 68Ga]Ga-PSMA-11 PET/CT imaging were referred to [ 89Zr]Zr-PSMA-617 PET/CT. PET/CT imaging was performed 1 h, 24 h, 48 h, and 72 h post injection (p.i.) of 111±11 MBq [ 89Zr]Zr-PSMA-617 (mean±standard deviation). Normal organ distribution and dosimetry were determined. Lesions visually considered as suggestive of prostate cancer were quantitatively analyzed. Results Intense physiological uptake was observed in the salivary and lacrimal glands, liver, spleen, kidneys, intestine and urinary tract. The parotid gland received the highest absorbed dose (0.601±0.185 mGy/MBq), followed by the kidneys (0.517±0.125 mGy/MBq). The estimated overall efective dose for the administration of 111 MBq was 10.1 mSv (0.0913±0.0118 mSv/MBq). In 6 patients, and in particular in 3 of 4 patients with negative [ 68Ga]Ga-PSMA-11 PET/CT, at least one prostate cancer lesion was detected in [ 89Zr]Zr-PSMA-617 PET/CT imaging at later time points. The majority of tumor lesions were frst visible at 24 h p.i. with continuously increasing tumor-to-background ratio over time. All tumor lesions were detectable at 48 h and 72 h p.i. Conclusion [ 89Zr]Zr-PSMA-617 PET/CT imaging is a promising new diagnostic tool with acceptable radiation exposure for patients with prostate cancer especially when [ 68Ga]Ga-PSMA-11 PET/CT imaging fails detecting recurrent disease. The long half-life of 89Zr enables late time point imaging (up to 72 h in our study) with increased tracer uptake in tumor lesions and higher tumor-to-background ratios allowing identifcation of lesions non-visible on [ 68Ga]Ga-PSMA-11 PET/CT imaging

Change of glucometabolic activity per PSMA expression predicts survival in mCRPC patients non-responding to PSMA radioligand therapy: introducing a novel dual imaging biomarker

PurposeThe value of [18F]fluorodeoxyglucose ([18F]FDG) PET/CT in monitoring prostate-specific membrane antigen (PSMA) targeted radioligand therapy (RLT) is still unclear. The aim of this study was to identify appropriate prognostic dynamic parameters derived from baseline and follow-up [18F]FDG and dual [18F]FDG/[68Ga]Ga-PSMA-11 PET/CT for monitoring early non-responding mCRPC patients undergoing PSMA-RLT.MethodsTwenty-three mCRPC patients of a prospective registry (NCT04833517), who were treated with [177Lu]Lu-PSMA-617 RLT and classified as early non-responders were included in this study. All patients received dual PET/CT imaging with [18F]FDG and [68Ga]Ga-PSMA-11 at baseline and after median two cycles of RLT. We tested potential biomarkers representing the “change of glucometabolic activity (cGA)” and “change of glucometabolic activity in relation to PSMA expression (cGAP)” composed of established parameters on [18F]FDG PET/CT as SUVmax, cumulative SUV of five lesions (SUV5), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) and its corresponding parameters on [68Ga]Ga-PSMA-11 PET/CT, respectively, for association with overall survival (OS).ResultsKaplan–Meier analyses showed no significant association with OS for each tested cGA (cGASUVmaxp = 0.904, cGASUV5, p = 0.747 cGAMTVp = 0.682 and cGATLGp = 0.700), likewise the dual imaging biomarkers cGAPSUVmax (p = 0.136), cGAPSUV5 (p = 0.097), and cGAPTV (p = 0.113) failed significance. In contrast, cGAPTL, which is based on TLG and total lesion PSMA (TLP) showed a significant association with OS (p = 0.004). Low cGAPTL (cut-off 0.7) was associated with significant longer survival (17.6 vs. 12.9 months).ConclusionThe novel biomarker cGAPTL, which represents the temporal change of whole-body TLG normalized by TLP, predicts overall survival in the challenging cohort of patients non-responding to PSMA-RLT

Efficacy and Toxicity of Different Chemotherapy Protocols for Concurrent Chemoradiation in Non-Small Cell Lung Cancer—A Secondary Analysis of the PET Plan Trial

(1) Background: The optimal chemotherapy (CHT) regimen for concurrent chemoradiation (cCRT) is not well defined. In this secondary analysis of the international randomized PET-Plan trial, we evaluate the efficacy of different CHT. (2) Methods: Patients with inoperable NSCLC were randomized at a 1:1 ratio regarding the target volume definition and received isotoxically dose-escalated cCRT using cisplatin 80 mg/m2 (day 1, 22) and vinorelbin 15 mg/m2 (day 1, 8, 22, 29) (P1) or cisplatin 20 mg/m2 (day 1–5, 29–33) and vinorelbin 12.5 mg/m2 (day 1, 8, 15, 29, 36, 43) (P2) or carboplatin AUC1 (day 1–5, 29–33) and vinorelbin 12.5 mg/m2 (day 1, 8, 15, 29, 36, 43) (P3) or other CHT at the treating physician’s discretion. (3) Results: Between 05/2009 and 11/2016, 205 patients were randomized and 172 included in the per-protocol analysis. Patients treated in P1 or P2 had a better overall survival (OS) compared to P3 (p = 0.015, p = 0.01, respectively). Patients treated with carboplatin had a worse OS compared to cisplatin (HR 1.78, p = 0.03), but the difference did not remain significant after adjusting for age, ECOG, cardiac function creatinine and completeness of CHT. (4) Conclusions: Carboplatin doublets show no significant difference compared to cisplatin, after adjusting for possibly relevant factors, probably due to existing selection bias

Stromal Interferon-γ Signaling and Cross-Presentation Are Required to Eliminate Antigen-Loss Variants of B Cell Lymphomas in Mice

To study mechanisms of T cell-mediated rejection of B cell lymphomas, we developed a murine lymphoma model wherein three potential rejection antigens, human c-MYC, chicken ovalbumin (OVA), and GFP are expressed. After transfer into wild-type mice 60–70% of systemically growing lymphomas expressing all three antigens were rejected; lymphomas expressing only human c-MYC protein were not rejected. OVA expressing lymphomas were infiltrated by T cells, showed MHC class I and II upregulation, and lost antigen expression, indicating immune escape. In contrast to wild-type recipients, 80–100% of STAT1-, IFN-γ-, or IFN-γ receptor-deficient recipients died of lymphoma, indicating that host IFN-γ signaling is critical for rejection. Lymphomas arising in IFN-γ- and IFN-γ-receptor-deficient mice had invariably lost antigen expression, suggesting that poor overall survival of these recipients was due to inefficient elimination of antigen-negative lymphoma variants. Antigen-dependent eradication of lymphoma cells in wild-type animals was dependent on cross-presentation of antigen by cells of the tumor stroma. These findings provide first evidence for an important role of the tumor stroma in T cell-mediated control of hematologic neoplasias and highlight the importance of incorporating stroma-targeting strategies into future immunotherapeutic approaches

Nuclear modification of Y states in pPb collisions at √SNN_{NN} = 5.02 TeV

Production cross sections of Υ(1S), Υ(2S), and Υ(3S) states decaying into μ+μ− in proton-lead (pPb) collisions are reported using data collected by the CMS experiment at √sNN = 5.02 TeV. A comparison is made with corresponding cross sections obtained with pp data measured at the same collision energy and scaled by the Pb nucleus mass number. The nuclear modification factor for Υ(1S) is found to be RpPb(Υ(1S)) = 0.806±0.024 (stat)±0.059 (syst). Similar results for the excited states indicate a sequential suppression pattern, such that RpPb(Υ(1S)) > RpPb(Υ(2S)) > RpPb(Υ(3S)). The suppression of all states is much less pronounced in pPb than in PbPb collisions, and independent of transverse momentum pΥT and center-of-mass rapidity yΥCM of the individual Υ state in the studied range p ΥT < 30 GeV/c and |yΥCM| <1.93. Models that incorporate final-state effects of bottomonia in pPb collisions are in better agreement with the data than those which only assume initial-state modifications

Measurements of (tt)over-barH Production and the CP Structure of the Yukawa Interaction between the Higgs Boson and Top Quark in the Diphoton Decay Channel

The first observation of the (tt) over barH process in a single Higgs boson decay channel with the full reconstruction of the final state (H -> gamma gamma) is presented, with a significance of 6.6 standard deviations (sigma). The CP structure of Higgs boson couplings to fermions is measured, resulting in an exclusion of the pure CP-odd structure of the top Yukawa coupling at 3.2 sigma. The measurements are based on a sample of protonproton collisions at a center-of-mass energy root s = 13 TeV collected by the CMS detector at the LHC, corresponding to an integrated luminosity of 137 fb(-1). The cross section times branching fraction of the (tt) over barH process is measured to be sigma B-(tt) over barH(gamma gamma) = 1.56(-0.32)(+0.34) th, which is compatible with the standard model prediction of 1.13(-0.11)(+0.08) fb. The fractional contribution of the CP-odd component is measured to be f(CP)(Hu) = 0.00 +/- 0.33.Peer reviewe

Observation of Two Excited B-c(+) States and Measurement of the B-c(+) (2S) Mass in pp Collisions at root s=13 TeV

Signals consistent with the B-c(+)(2S) and B-c*(+)(2S) states are observed in proton-proton collisions at root s = 13 TeV, in an event sample corresponding to an integrated luminosity of 143 fb(-1), collected by the CMS experiment during the 2015-2018 LHC running periods. These excited (b) over barc states are observed in the B-c(+)pi(+)pi(-) invariant mass spectrum, with the ground state B-c(+) reconstructed through its decay to J/psi pi(+). The two states are reconstructed as two well-resolved peaks, separated in mass by 29.1 +/- 1.5(stat) +/- 0.7(syst) MeV. The observation of two peaks, rather than one, is established with a significance exceeding five standard deviations. The mass of the B-c(+)(2S) meson is measured to be 6871.0 +/- 1.2(stat) +/- 0.8(syst) +/- 0.8(B-c(+)) MeV, where the last term corresponds to the uncertainty in the world-average B-c(+) mass.Peer reviewe