Intraprocedural MRI-based dosimetry during transarterial radioembolization of liver tumours with holmium-166 microspheres (EMERITUS-1):a phase I trial towards adaptive, image-controlled treatment delivery

PURPOSE: Transarterial radioembolization (TARE) is a treatment for liver tumours based on injection of radioactive microspheres in the hepatic arterial system. It is crucial to achieve a maximum tumour dose for an optimal treatment response, while minimizing healthy liver dose to prevent toxicity. There is, however, no intraprocedural feedback on the dose distribution, as nuclear imaging can only be performed after treatment. As holmium-166 ((166)Ho) microspheres can be quantified with MRI, we investigate the feasibility and safety of performing (166)Ho TARE within an MRI scanner and explore the potential of intraprocedural MRI-based dosimetry. METHODS: Six patients were treated with (166)Ho TARE in a hybrid operating room. Per injection position, a microcatheter was placed under angiography guidance, after which patients were transported to an adjacent 3-T MRI system. After MRI confirmation of unchanged catheter location, (166)Ho microspheres were injected in four fractions, consisting of 10%, 30%, 30% and 30% of the planned activity, alternated with holmium-sensitive MRI acquisition to assess the microsphere distribution. After the procedures, MRI-based dose maps were calculated from each intraprocedural image series using a dedicated dosimetry software package for (166)Ho TARE. RESULTS: Administration of (166)Ho microspheres within the MRI scanner was feasible in 9/11 (82%) injection positions. Intraprocedural holmium-sensitive MRI allowed for tumour dosimetry in 18/19 (95%) of treated tumours. Two CTCAE grade 3–4 toxicities were observed, and no adverse events were attributed to treatment in the MRI. Towards the last fraction, 4/18 tumours exhibited signs of saturation, while in 14/18 tumours, the microsphere uptake patterns did not deviate from the linear trend. CONCLUSION: This study demonstrated feasibility and preliminary safety of a first in-human application of TARE within a clinical MRI system. Intraprocedural MRI-based dosimetry enabled dynamic insight in the microsphere distribution during TARE. This proof of concept yields unique possibilities to better understand microsphere distribution in vivo and to potentially optimize treatment efficacy through treatment personalization. REGISTRATION: Clinicaltrials.gov, identifier NCT04269499, registered on February 13, 2020 (retrospectively registered). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-022-05902-w

Tumoral Ki67 and PSMA Expression in Fresh Pre-PSMA-RLT Biopsies and Its Relation With PSMA-PET Imaging and Outcomes of PSMA-RLT in Patients With mCRPC

Introduction: Prostate specific membrane antigen (PSMA) directed radioligand therapy (RLT) is a novel therapy for metastatic castration-resistant prostate cancer (mCRPC) patients. However, it is still poorly understood why approximately 40% of the patients does not respond to PSMA-RLT. The aims of this study were to evaluate the pretreatment PSMA expression on immunohistochemistry (IHC) and PSMA uptake on PET/CT imaging in mCRPC patients who underwent PSMA-RLT. We correlated these parameters and a cell proliferation marker (Ki67) to the therapeutic efficacy of PSMA-RLT. Patients and Methods: In this retrospective study, mCRPC patients who underwent PSMA-RLT were analyzed. Patients biopsies were scored for immunohistochemical Ki67 expression, PSMA staining intensity and percentage of cells with PSMA expression. Moreover, the PSMA tracer uptake of the tumor lesion(s) and healthy organs on PET/CT imaging was assessed. The primary outcome was to evaluate the association between histological PSMA protein expression of tumor in pre-PSMA-RLT biopsies and the PSMA uptake on PSMA PET/CT imaging of the biopsied lesion. Secondary outcomes were to assess the relationship between PSMA expression and Ki67 on IHC and the progression free survival (PFS) and overall survival (OS) following PSMA-RLT. Results: In total, 22 mCRPC patients were included in this study. Nineteen (86%) patients showed a high and homogenous PSMA expression of &gt;80% on IHC. Three (14%) patients had low PSMA expression on IHC. Although there was limited PSMA uptake on PET/CT imaging, these 3 patients had lower PSMA uptake on PET/CT imaging compared to the patients with high PSMA expression on IHC. Yet, no correlation was found between PSMA uptake on PET/CT imaging and PSMA expression on IHC (SUVmax: R2 = 0.046 and SUVavg: R2 = 0.036). The 3 patients had a shorter PFS compared to the patients with high PSMA expression on IHC (HR: 4.76, 95% CI: 1.14-19.99; P = .033). Patients with low Ki67 expression had a longer PFS and OS compared to patients with a high Ki67 expression (HR: 0.40, 95% CI: 0.15-1.06; P = .013) Conclusion: The PSMA uptake on PSMA-PET/CT generally followed the PSMA expression on IHC. However, heterogeneity may be missed on PSMA-PET/CT. Immunohistochemical PSMA and Ki67 expression in fresh tumor biopsies, may contribute to predict treatment efficacy of PSMA-RLT in mCRPC patients. This needs to be further explored in prospective cohorts.</p

Metabolic subtyping of pheochromocytoma and paraganglioma by 18F-FDG pharmacokinetics using dynamic PET/CT scanning

Static single–time-frame 18F-FDG PET/CT is useful for the localization and functional characterization of pheochromocytomas and paragangliomas (PPGLs). 18F-FDG uptake varies between PPGLs with different genotypes, and the highest SUVs are observed in cases of succinate dehydrogenase (SDH) mutations, possibly related to enhanced aerobic glycolysis in tumor cells. The exact determinants of 18F-FDG accumulation in PPGLs are unknown. We performed dynamic PET/CT scanning to assess whether in vivo 18F-FDG pharmacokinetics has added value over static PET to distinguish different genotypes. Methods: Dynamic 18F-FDG PET/CT was performed on 13 sporadic PPGLs and 13 PPGLs from 11 patients with mutations in SDH complex subunits B and D, von Hippel-Lindau (VHL), RET, and neurofibromin 1 (NF1). Pharmacokinetic analysis was performed using a 2-tissue-compartment tracer kinetic model. The derived transfer rate-constants for transmembranous glucose flux (K1 [in], k2 [out]) and intracellular phosphorylation (k3), along with the vascular blood fraction (Vb), were analyzed using nonlinear regression analysis. Glucose metabolic rate (MRglc) was calculated using Patlak linear regression analysis. The SUVmax of the lesions was determined on additional static PET/CT images. Results: Both MRglc and SUVmax were significantly higher for hereditary cluster 1 (SDHx, VHL) tumors than for hereditary cluster 2 (RET, NF1) and sporadic tumors (P, 0.01 and P, 0.05, respectively). Median k3 was significantly higher for cluster 1 than for sporadic tumors (P, 0.01). Median Vb was significantly higher for cluster 1 than for cluster 2 tumors (P, 0.01). No statistically significant differences in K1 and k2 were found between the groups. Cutoffs for k3 to distinguish between cluster 1 and other tumors were established at 0.015 min−1 (100% sensitivity, 15.8% specificity) and 0.636 min−1 (100% specificity, 85.7% sensitivity). MRglc significantly correlated with SUVmax (P 5 0.001) and k3 (P 5 0.002). Conclusion: In vivo metabolic tumor profiling in patients with PPGL can be achieved by assessing 18F-FDG pharmacokinetics using dynamic PET/CT scanning. Cluster 1 PPGLs can be reliably identified by a high 18F-FDG phosphorylation rate

Evaluation of the highly sensitive Roche thyroglobulin II assay and establishment of a reference limit for thyroglobulin-negative patient samples

Objectives: Thyroglobulin (Tg) measurements are used to monitor for residual thyroid tissue in patients with differentiated thyroid cancer (DTC) after thyroidectomy and radioiodine ablative therapy. In recent years highly sensitive Tg assays have been developed. In this study the analytical performance of the new Roche Elecsys Tg II assay was evaluated and compared with the well documented Access2 Tg assay (Beckman–Coulter). Design and methods: Analytical performance was examined using various Clinical and Laboratory Standards Institute (CLSI) evaluation protocols. Tg negative patient sera were used to establish an upper reference limit (URL) for the Elecsys Tg II assay. Results: Non-linearity, drift and carry-over according to CLSI EP10 and EP6 in a measuring range of 0.04–500 ng/mL were non-significant. Total precision according to CLSI EP5 was 10% at a Tg concentration of 0.08 ng/mL. A patient serum comparison performed according to a modified CLSI EP9 protocol showed a significant difference of a factor of approximately 1.4, despite using an identical CRM calibrator. The Elecsys Tg II assay measured Tg with a two-fold higher sensitivity than the Access2 assay. Finally, using human sera without Tg, an URL of 0.05 ng/mL was determined. Conclusions: In our hands the highly sensitive Elecsys Tg II assay shows a good analytical performance and a higher sensitivity compared to the Access2 Tg assay. An URL of 0.05 ng/mL for the Elecsys Tg II assay was determined which may improve the clinical utility of the assay for the detection of residual DTC or disease recurrence. Keywords: Thyroglobulin, Roche Elecsys Tg II assay, validation, reporting limi

The diagnostic value of 18F–FDG-PET/CT and MRI in suspected vertebral osteomyelitis – a prospective study

Purpose: The aim of this study was to determine the diagnostic value of 18F–fluorodeoxyglucose (FDG) positron emission tomography and computed tomography (PET/CT) and magnetic resonance imaging (MRI) in diagnosing vertebral osteomyelitis. Methods: From November 2015 until December 2016, 32 patients with suspected vertebral osteomyelitis were prospectively included. All patients underwent both 18F–FDG-PET/CT and MRI within 48 h. All images were independently reevaluated by two radiologists and two nuclear medicine physicians who were blinded to each others’ image interpretation. 18F–FDG-PET/CT and MRI were compared to the clinical diagnosis according to international guidelines. Results: For 18F–FDG-PET/CT, sensitivity, specificity, PPV, and NPV in diagnosing vertebral osteomyelitis were 100%, 83.3%, 90.9%, and 100%, respectively. For MRI, sensitivity, specificity, PPV, and NPV were 100%, 91.7%, 95.2%, and 100%, respectively. MRI detected more epidural/spinal abscesses. An important advantage of 18F–FDG-PET/CT is the detection of metastatic infection (16 patients, 50.0%). Conclusion: 18F–FDG-PET/CT and MRI are both necessary techniques in diagnosing vertebral osteomyelitis. An important advantage of 18F–FDG-PET/CT is the visualization of metastatic infection, especially in patients with bacteremia. MRI is more sensitive in detection of small epidural abscesses

Accuracy of 18F-FDG PET/CT in predicting residual disease after neoadjuvant chemoradiotherapy for esophageal cancer

Our purpose was to prospectively investigate optimal evaluation of qualitative and quantitative 18F-FDG PET/CT in response evaluations 12–14 wk after neoadjuvant chemoradiotherapy (nCRT) in esophageal cancer patients. Methods: This was a side study of the prospective diagnostic pre-SANO trial. 18F-FDG PET/CT scans at baseline and at 12–14 wk after nCRT were qualitatively assessed for the presence of tumor. Maximum SUVs normalized for lean body mass (SULmax) were measured in all scans. The primary endpoint was the proportion of false-negative patients with tumor regression grade (TRG) 3–4 (.10% vital residual tumor) in qualitative and quantitative analyses. Receiver-operating-characteristic curve analysis for TRG1 versus TRG3–4 using SULmax, SULmax tumor-to-esophagus ratio, and D%SULmax was performed to define optimal cutoffs. Secondary endpoints were sensitivity, specificity, negative predictive value, and positive predictive value for TRG1 versus TRG2–4. Results: In total, 129 of 219 patients were analyzed. Qualitative 18F-FDG PET/CT was unable to detect TRG3–4 in 15% of patients. Sensitivity, specificity, negative predictive value, and positive predictive value in qualitative analysis for detecting TRG1 versus TRG2–4 was 80%, 37%, 42%, and 77%, respectively. In 18 of 190 patients (10%) with follow-up scans after nCRT, 18F-FDG PET/CT identified new interval metastases. Quantitative parameters did not detect TRG3–4 tumor in 27%–61% of patients. The optimal cutoff for detecting TRG1 versus TRG2–4 was a post-nCRT SULmax of 2.93 (area under receiver-operating-characteristic curve, 0.70). Conclusion: Qualitative and quantitative analyses of 18F-FDG PET/CT are unable to accurately detect TRG3–4 and to discriminate substantial residual disease from benign inflammation-induced 18F-FDG uptake after nCRT. However, 18F-FDG PET/CT is useful for the detection of interval metastases and might become useful in an active surveillance strategy with serial 18F-FDG PET/CT scanning

Lutetium-177-PSMA-617 in low-volume hormone-sensitive metastatic prostate cancer: A prospective pilot study

Purpose: [177Lu]Lu-PSMA-617 radioligand therapy (177Lu-PSMA) is a novel treatment for metastatic castration-resistant prostate cancer (mCRPC), which could also be applied to patients with metastatic hormone-sensitive prostate cancer (mHSPC) with PSMA expression. In this prospective study (NCT03828838), we analyzed toxicity, radiation doses, and treatment effect of 177Lu-PSMA in pateints with low-volume mHSPC. Patients and Methods: Ten progressive patients with mHSPC following local treatment, with a maximum of ten metastatic lesions on [68Ga]Ga-PSMA-11 PET/diagnostic-CT imaging (PSMA-PET) and serum PSA doubling time <6 months received two cycles of 177Lu-PSMA. Whole-body single-photon emission CT/CT (SPECT/CT) and blood dosimetry was performed to calculate doses to the tumors and organs at risk (OAR). Adverse events (AE), laboratory values (monitoring response and toxicity), and quality of life were monitored until week 24 after cycle 2, the end of study (EOS). All patients underwent PSMA-PET at screening, 8 weeks after cycle 1, 12 weeks after cycle 2, and at EOS. Results: All patients received two cycles of 177Lu-PSMA without complications. No treatment-related grade III–IV adverse events were observed. According to dosimetry, none of the OAR reached threshold doses for radiation-related toxicity. Moreover, all target lesions received a higher radiation dose than the OAR. All 10 patients showed altered PSA kinetics, postponed androgen deprivation therapy, and maintained good quality of life. Half of the patients showed a PSA response of more than 50%. One patient had a complete response on PSMA-PET imaging until EOS and two others had only minimal residual disease. Conclusions: 177Lu-PSMA appeared to be a feasible and safe treatment modality in patients with low-volume mHSPC