Biodistribution and radiation dosimetry of [99mTc]Tc-N4-BTG in patients with biochemical recurrence of prostate cancer.

BACKGROUND: In patients with prostate cancer (PCa), imaging with gastrin-releasing peptide receptor (GRPR) ligands is an alternative to PSMA-targeted tracers, particularly if PSMA expression is low or absent. [99mTc]Tc-N4-BTG is a newly developed GRPR-directed probe for conventional scintigraphy and single photon emission computed tomography (SPECT) imaging. The current study aims to investigate the safety, biodistribution and dosimetry of [99mTc]Tc-N4-BTG in patients with biochemical recurrence (BCR) of PCa. RESULTS: No adverse pharmacologic effects were observed. Injection of [99mTc]Tc-N4-BTG resulted in an effective dose of 0.0027 ± 0.0002 mSv/MBq. The urinary bladder was the critical organ with the highest mean absorbed dose of 0.028 ± 0.001 mGy/MBq, followed by the pancreas with 0.0043 ± 0.0015 mGy/MBq, osteogenic cells with 0.0039 ± 0.0005 mGy/MBq, the kidneys with 0.0034 ± 0.0003 mGy/MBq, and the liver with 0.0019 ± 0.0004 mGy/MBq, respectively. No focal tracer uptake suggestive of PCa recurrence could be revealed for any of the patients. CONCLUSION: [99mTc]Tc-N4-BTG appears to be a safe diagnostic agent. Compared to GRPR-targeted PET tracers, this 99mTc-labelled SPECT agent could contribute to a broader application and better availability of this novel approach. Further research to assess its clinical value is warranted.

First Safety and Efficacy Data with the Radiohybrid 177Lu-rhPSMA-10.1 for the Treatment of Metastatic Prostate Cancer.

We recently published the first dosimetry data, to our knowledge, for the radioligand therapy agent 177Lu-rhPSMA-10.1, providing an intrapatient comparison with 177Lu-PSMA-I&T in patients with metastatic prostate cancer. Here, we report efficacy and safety findings from these patients. Methods: Four consecutive patients with prostate-specific membrane antigen (PSMA)-positive metastatic prostate cancer received up to 6 cycles of 177Lu-rhPSMA-10.1 (7.4-7.7 GBq per cycle). Efficacy (prostate-specific antigen response according to Prostate Cancer Working Group 3 criteria and the Response Evaluation Criteria in PSMA PET/CT), progression-free survival, and overall survival were evaluated. Adverse events were recorded from the first dose until 16-24 mo after treatment. Results: The patients received a total activity of 29.6-59.4 GBq (4-6 cycles). Prostate-specific antigen was reduced by 100%, 99%, 88%, and 35%. Progression-free survival was not reached for 2 patients at 24 and 18 mo of follow-up and was 15 and 12 mo for the other 2 patients. One patient had a sustained complete response with 2 y of follow up. All patients were alive at the last time point of data collection. No serious adverse events were reported. Conclusion: 177Lu-rhPSMA-10.1 demonstrated encouraging preliminary efficacy and was well tolerated. Formal clinical trials are now under way to evaluate its potential prospectively (NCT05413850).

Preclinical Evaluation of Minigastrin Analogs and Proof-of-Concept [68Ga]Ga-DOTA-CCK-66 PET/CT in 2 Patients with Medullary Thyroid Cancer.

Because of the need for radiolabeled theranostics for the detection and treatment of medullary thyroid cancer (MTC), and the yet unresolved stability issues of minigastrin analogs targeting the cholecystokinin-2 receptor (CCK-2R), our aim was to address in vivo stability, our motivation being to develop and evaluate DOTA-CCK-66 (DOTA-γ-glu-PEG3-Trp-(N-Me)Nle-Asp-1-Nal-NH2, PEG: polyethylene glycol) and DOTA-CCK-66.2 (DOTA-glu-PEG3-Trp-(N-Me)Nle-Asp-1-Nal-NH2), both derived from DOTA-MGS5 (DOTA-glu-Ala-Tyr-Gly-Trp-(N-Me)Nle-Asp-1-Nal-NH2), and clinically translate [68Ga]Ga-DOTA-CCK-66. Methods: 64Cu and 67Ga labeling of DOTA-CCK-66, DOTA-CCK-66.2, and DOTA-MGS5 was performed at 90°C within 15 min (1.0 M NaOAc buffer, pH 5.5, and 2.5 M 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer, respectively). 177Lu labeling of these 3 compounds was performed at 90°C within 15 min (1.0 M NaOAc buffer, pH 5.5, 0.1 M sodium ascorbate). CCK-2R affinity of natGa/natCu/natLu-labeled DOTA-CCK-66, DOTA-CCK-66.2, and DOTA-MGS5 was examined on AR42J cells. The in vivo stability of 177Lu-labeled DOTA-CCK-66 and DOTA-MGS5 was examined at 30 min after injection in CB17-SCID mice. Biodistribution studies at 1 h ([67Ga]Ga-DOTA-CCK-66) and 24 h ([177Lu]Lu-DOTA-CCK-66/DOTA-MGS5) after injection were performed on AR42J tumor-bearing CB17-SCID mice. In a translation to the human setting, [68Ga]Ga-DOTA-CCK-66 was administered and whole-body PET/CT was acquired at 120 min after injection in 2 MTC patients. Results: Irrespective of the metal or radiometal used (copper, gallium, lutetium), high CCK-2R affinity (half-maximal inhibitory concentration, 3.6-6.0 nM) and favorable lipophilicity were determined. In vivo, increased numbers of intact peptide were found for [177Lu]Lu-DOTA-CCK-66 compared with [177Lu]Lu-DOTA-MGS5 in murine urine (23.7% ± 9.2% vs. 77.8% ± 2.3%). Overall tumor-to-background ratios were similar for both 177Lu-labeled analogs. [67Ga]Ga-DOTA-CCK-66 exhibited accumulation (percentage injected dose per gram) that was high in tumor (19.4 ± 3.5) and low in off-target areas (blood, 0.61 ± 0.07; liver, 0.31 ± 0.02; pancreas, 0.23 ± 0.07; stomach, 1.81 ± 0.19; kidney, 2.51 ± 0.49) at 1 h after injection. PET/CT examination in 2 MTC patients applying [68Ga]Ga-DOTA-CCK-66 confirmed multiple metastases. Conclusion: Because of the high in vivo stability and favorable overall preclinical performance of [nat/67Ga]Ga-/[nat/177Lu]Lu-DOTA-CCK-66, a proof-of-concept clinical investigation of [68Ga]Ga-DOTA-CCK-66 was completed. As several lesions could be identified and excellent biodistribution patterns were observed, further patient studies applying [68Ga]Ga- and [177Lu]Lu-DOTA-CCK-66 are warranted.

Chemokine Receptor PET/CT Provides Relevant Staging and Management Changes in Marginal Zone Lymphoma.

Because of gastral and extranodal manifestations, guideline-compatible diagnostic work-up of marginal zone lymphoma is challenging. We aimed to determine the diagnostic performance of C-X-C motif chemokine receptor 4 (CXCR4)-directed PET/CT compared with routine diagnostics, along with PET/CT-based retrospective changes in therapeutic management. The predictive potential of the PET signal was also investigated, and the number of patients eligible for CXCR4-directed radioligand therapy in a theranostic setting was determined. Methods: For this study, 100 marginal zone lymphoma patients underwent CXCR4-directed PET/CT. We compared staging results and treatment decisions from molecular imaging with respective results from guideline-compatible work-up (CT, esophagogastroduodenoscopy, and bone marrow-derived biopsy). Prognostic performance of the in vivo CXCR4 PET signal for progression-free survival (PFS) was evaluated (using log-rank test and Kaplan-Meier curves). Results: Relative to CT, CXCR4-directed imaging led to Ann Arbor (AA) staging changes for 27 of 100 patients (27.0%). Among those, clinically relevant upstaging from AA I or AA II to AA III or AA IV was observed for 23 patients (85.2%), along with respective changes in therapeutic management (escalation, 6/23 [26.1%]; deescalation, 17/23 [73.9%]). CXCR4 PET/CT yielded diagnostic accuracy of 94.0% relative to esophagogastroduodenoscopy and 76.8% relative to bone marrow-derived biopsy. An increased CXCR4 PET signal was linked to shorter PFS (707 d vs. median PFS not reached; hazard ratio, 3.18; 95% CI, 1.37-7.35; P = 0.01). CXCR4-directed radioligand therapy would have been feasible for 18 of 100 patients (18.0%). Conclusion: Relative to CT, CXCR4-directed PET/CT led to AA changes for 27 of 100 patients. Chemokine receptor PET/CT may improve current diagnostic algorithms and influence management relative to CT alone, potentially obviating some biopsies.

An Intrapatient Dosimetry Comparison of 177Lu-rhPSMA-10.1 and 177Lu-PSMA-I&T in Patients with Metastatic Castration-Resistant Prostate Cancer.

As the use of radioligand therapy moves earlier in the prostate cancer timeline, minimizing the absorbed dose to normal organs while maintaining high tumor radiation doses becomes more clinically important because of the longer life expectancy of patients. We performed an intrapatient comparison of pretherapeutic dosimetry with the novel radiohybrid prostate-specific membrane antigen-targeting radiopharmaceutical 177Lu-rhPSMA-10.1, along with 177Lu-PSMA-I&T, in patients with metastatic castration-resistant prostate cancer. Methods: Four consecutive patients with advanced histologically proven metastatic castration-resistant prostate cancer who were scheduled for radioligand therapy were evaluated. Before undergoing therapy, each patient received 1.06 ± 0.05 GBq of 177Lu-rhPSMA-10.1 and 1.09 ± 0.02 GBq of 177Lu-PSMA-I&T at least 7 d apart. For dosimetric assessment, whole-body planar scintigraphy was performed after 5 min, 4 h, 1 d, 2 d, and 7 d. In addition, SPECT/CT images were acquired over the thorax and the abdomen, 4 h, 1 d, 2 d, and 7 d after injection. Dosimetry of the whole body and salivary glands was based on the evaluation of the counts in whole-body planar imaging. Dosimetry of the kidneys, liver, spleen, bone marrow, and tumor lesions (≤4 per patient) was based on the activity in volumes drawn on SPECT/CT images. Doses were calculated using OLINDA/EXM version 1.0. The therapeutic index (TI), or ratio between mean dose of the metastases and mean dose of the kidneys, was calculated for each patient. Results: We found the dose to the kidneys to be higher with 177Lu-rhPSMA-10.1 than with 177Lu-PSMA-I&T (0.68 ± 0.30 vs. 0.46 ± 0.10 mGy/MBq); however, 177Lu-rhPSMA-10.1 delivered an average of a 3.3 times (range, 1.2-8.3 times) higher absorbed radiation dose to individual tumor lesions. Consequently, intraindividual comparison revealed a 1.1-3.1 times higher TI for 177Lu-rhPSMA-10.1 than for 177Lu-PSMA-I&T in all evaluated patients. The effective whole-body dose was 0.038 ± 0.008 mSv/MBq for 177Lu-rhPSMA-10.1 and 0.022 ± 0.005 mSv/MBq for 177Lu-PSMA-I&T. Conclusion: Using 177Lu-rhPSMA-10.1 can significantly increase the tumor-absorbed dose and improve the TI compared with 177Lu-PSMA-I&T. An improved TI gives the flexibility to maximize tumor-absorbed doses up to a predefined renal dose limit or, in earlier disease, to reduce the radiation exposure to the kidney while still achieving an effective tumor dose. The function of at-risk organs such as the kidneys is being assessed in a prospective clinical trial.

Vector autoregression: Useful in rare diseases?-Predicting organ response patterns in a rare case of secondary AA amyloidosis.

BACKGROUND: Statistical analyses of clinical data are a cornerstone in understanding pathomechanisms of disorders. In rare disorders, cross-sectional datasets of sufficient size are usually not available. Taking AA amyloidosis as an example of a life-threatening rare disorder resulting from of uncontrolled chronic inflammation, we propose techniques from time series analysis to predict organ response to treatment. The advantage of time-series analysis is that it solely relies on temporal variation and therefore allows analyzing organ response to treatment even when the cross-sectional dimension is small. METHODS: The joint temporal interdependence of inflammatory activity and organ response was modelled multivariately using vector autoregression (VAR) based on a unique 4.5 year spanning data set of routine laboratory, imaging data (e.g., 18F-Florbetaben-PET/CT) and functional investigations of a 68-year-old patient with multi-organ involvement of AA amyloidosis due to ongoing inflammatory activity of a malignant paraganglioma in stable disease for >20 years and excellent response to tocilizumab). RESULTS: VAR analysis showed that alterations in inflammatory activity forecasted alkaline phosphatase (AP). AP levels, but not inflammatory activity at the previous measurement time point predicted proteinuria. CONCLUSION: We demonstrate the feasibility and value of time series analysis for obtaining clinically reliable information when the rarity of a disease prevents conventional prognostic modelling approaches. We illustrate the comparative utility of blood, functional and imaging markers to monitor the development and regression of AA amyloidosis.

In-Vivo Somatostatin-Receptor Expression in Small Cell Lung Cancer as a Prognostic Image Biomarker and Therapeutic Target.

BACKGROUND: Given the dismal prognosis of small cell lung cancer (SCLC), novel therapeutic targets are urgently needed. We aimed to evaluate whether SSTR expression, as assessed by positron emission tomography (PET), can be applied as a prognostic image biomarker and determined subjects eligible for peptide receptor radionuclide therapy (PRRT). METHODS: A total of 67 patients (26 females; age, 41-80 years) with advanced SCLC underwent SSTR-directed PET/computed tomography (somatostatin receptor imaging, SRI). SRI-avid tumor burden was quantified by maximum standardized uptake values (SUVmax) and tumor-to-liver ratios (T/L) of the most intense SCLC lesion. Scan findings were correlated with progression-free (PFS) and overall survival (OS). In addition, subjects eligible for SSTR-directed radioligand therapy were identified, and treatment outcome and toxicity profile were recorded. RESULTS: On a patient basis, 36/67 (53.7%) subjects presented with mainly SSTR-positive SCLC lesions (>50% lesions positive); in 10/67 patients (14.9%), all lesions were positive. The median SUVmax was found to be 8.5, while the median T/L was 1.12. SRI-uptake was not associated with PFS or OS, respectively (SUVmax vs. PFS, ρ = 0.13 with p = 0.30 and vs. OS, ρ = 0.00 with p = 0.97; T/L vs. PFS, ρ = 0.07 with p = 0.58 and vs. OS, ρ = -0.05 with p = 0.70). PRRT was performed in 14 patients. One patient succumbed to treatment-independent infectious complications immediately after PRRT. In the remaining 13 subjects, disease control was achieved in 5/13 (38.5%) with a single patient achieving a partial response (stable disease in the remainder). In the sub-group of responding patients, PFS and OS were 357 days and 480 days, respectively. CONCLUSIONS: SSTR expression as detected by SRI is not predictive of outcome in patients with advanced SCLC. However, it might serve as a therapeutic target in selected patients.

177 Lu-rhPSMA-10.1 Induces Tumor Response in a Patient With mCRPC After PSMA-Directed Radioligand Therapy With 177 Lu-PSMA-I&T.

ABSTRACT: 177 Lu-rhPSMA-10.1 is a novel PSMA-targeting radiopharmaceutical that has been optimized in terms of pharmacological and pharmacokinetic properties and may be therefore advantageous in treatment of metastatic castrate-resistant prostate cancer. In this image, we present the case of an 86-year-old man with metastastic castrate-resistant prostate cancer undergoing 177 Lu-PSMA-I&T treatment. After initial partial response to radioligand therapy, another 2 treatment cycles resulted in a rising serum PSA level that could be correlated with increasingly PSMA-positive as well as a new bone lesion. Consequently, the patient was changed to 177 Lu-rhPSMA-10.1 treatment on a compassionate use basis achieving a renewed tumor response.

[18F]FET-PET in children and adolescents with central nervous system tumors: does it support difficult clinical decision-making?

PURPOSE: Positron emission tomography (PET) with O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) is a well-established tool for non-invasive assessment of adult central nervous system (CNS) tumors. However, data on its diagnostic utility and impact on clinical management in children and adolescents are limited. METHODS: Twenty-one children and young adults (13 males; mean age, 8.6 ± 5.2 years; range, 1-19 at initial diagnosis) with either newly diagnosed (n = 5) or pretreated (n = 16) CNS tumors were retrospectively analyzed. All patients had previously undergone neuro-oncological work-up including cranial magnetic resonance imaging. In all cases, [18F]FET-PET was indicated in a multidisciplinary team conference. The impact of PET imaging on clinical decision-making was assessed. Histopathology (n = 12) and/or clinical and imaging follow-up (n = 9) served as the standard of reference. RESULTS: The addition of [18F]FET-PET to the available information had an impact on further patient management in 14 out of 21 subjects, with avoidance of invasive surgery or biopsy in four patients, biopsy guidance in four patients, change of further treatment in another five patients, and confirmation of diagnosis in one patient. CONCLUSION: [18F]FET-PET may provide important additional information for treatment guidance in pediatric and adolescent patients with CNS tumors.

Prediction of left lobe hypertrophy after right lobe radioembolization of the liver using a clinical data model with external validation.

In cirrhotic patients with hepatocellular carcinoma (HCC), right-sided radioembolization (RE) with Yttrium-90-loaded microspheres is an established palliative therapy and can be considered a "curative intention" treatment when aiming for sequential tumor resection. To become surgical candidate, hypertrophy of the left liver lobe to > 40% (future liver remnant, FLR) is mandatory, which can develop after RE. The amount of radiation-induced shrinkage of the right lobe and compensatory hypertrophy of the left lobe is difficult for clinicians to predict. This study aimed to utilize machine learning to predict left lobe liver hypertrophy in patients with HCC and cirrhosis scheduled for right lobe RE, with external validation. The results revealed that machine learning can accurately predict relative and absolute volume changes of the left liver lobe after right lobe RE. This prediction algorithm could help to estimate the chances of conversion from palliative RE to curative major hepatectomy following significant FLR hypertrophy.

Lung perfusion assessed by SPECT/CT after a minimum of three months anticoagulation therapy in patients with SARS-CoV-2-associated acute pulmonary embolism: a retrospective observational study.

BACKGROUND: Anticoagulant treatment is recommended for at least three months after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related acute pulmonary embolism (PE), but the persistent pulmonary clot burden after that time is unknown. METHODS: Lung perfusion was assessed by ventilation-perfusion (V/Q) SPECT/CT in 20 consecutive patients with SARS-CoV-2-associated acute PE after a minimum of three months anticoagulation therapy in a retrospective observational study. RESULTS: Remaining perfusion defects after a median treatment period of six months were observed in only two patients. All patients (13 men, seven women, mean age 55.6 ± 14.5 years) were on non-vitamin K direct oral anticoagulants (DOACs). No recurrent venous thromboembolism or anticoagulant-related bleeding complications were observed. Among patients with partial clinical recovery, high-risk PE and persistent pulmonary infiltrates were significantly more frequent (p < 0.001, respectively). INTERPRETATION: Temporary DOAC treatment seems to be safe and efficacious for resolving pulmonary clot burden in SARS-CoV-2-associated acute PE. Partial clinical recovery is more likely caused by prolonged SARS-CoV-2-related parenchymal lung damage rather than by persistent pulmonary perfusion defects.

Reduced splenic uptake on 68Ga-Pentixafor-PET/CT imaging in multiple myeloma - a potential imaging biomarker for disease prognosis.

Beyond being a key factor for tumor growth and metastasis in human cancer, C-X-C motif chemokine receptor 4 (CXCR4) is also highly expressed by a number of immune cells, allowing for non-invasive read-out of inflammatory activity. With two recent studies reporting on prognostic implications of the spleen signal in diffusion-weighted magnetic resonance imaging in patients with plasma cell dyscrasias, the aim of this study was to correlate splenic 68Ga-Pentixafor uptake in multiple myeloma (MM) with clinical parameters and to evaluate its prognostic impact. Methods: Eighty-seven MM patients underwent molecular imaging with 68Ga-Pentixafor-PET/CT. Splenic CXCR4 expression was semi-quantitatively assessed by peak standardized uptake values (SUVpeak) and corresponding spleen-to-bloodpool ratios (TBR) and correlated with clinical and prognostic features as well as survival parameters. Results:68Ga-Pentixafor-PET/CT was visually positive in all MM patients with markedly heterogeneous tracer uptake in the spleen. CXCR4 expression determined by 68Ga-Pentixafor-PET/CT corresponded with advanced disease and was inversely associated with the number of previous treatment lines as compared to controls or untreated smouldering multiple myeloma patients (SUVpeakSpleen 4.06 ± 1.43 vs. 6.02 ± 1.16 vs. 7.33 ± 1.40; P < 0.001). Moreover, reduced splenic 68Ga-Pentixafor uptake was linked to unfavorable clinical outcome. Patients with a low SUVpeakSpleen (<3.35) experienced a significantly shorter overall survival of 5 months as compared to 62 months in patients with a high SUVpeakSpleen >5.79 (P < 0.001). Multivariate Cox analysis confirmed SUVpeakSpleen as an independent predictor of survival (HR 0.75; P = 0.009). Conclusion: These data suggest that splenic 68Ga-Pentixafor uptake might provide prognostic information in pre-treated MM patients similar to what was reported for diffusion-weighted magnetic resonance imaging. Further research to elucidate the underlying biologic implications is warranted.