In Vitro Assessment of 177Lu-Labeled Trastuzumab-Targeted Mesoporous Carbon@Silica Nanostructure for the Treatment of HER2-Positive Breast Cancer.

This study assessed the effectiveness of a trastuzumab-targeted 177Lu-labeled mesoporous Carbon@Silica nanostructure (DOTA@TRA/MC@Si) for HER2-positive breast cancer treatment, focusing on its uptake, internalization, and efflux in breast cancer cells. The synthesized PEI-MC@Si nanocomposite was reacted with DOTA-NHS-ester, confirmed by the Arsenazo(III) assay. Following this, TRA was conjugated to the DOTA@PEI-MC@Si for targeting. DOTA@PEI-MC@Si and DOTA@TRA/MC@Si nanocomposites were labeled with 177Lu, and their efficacy was evaluated through in vitro radiolabeling experiments. According to the results, the DOTA@TRA/MC@Si nanocomposite was successfully labeled with 177Lu, yielding a radiochemical yield of 93.0 ± 2.4%. In vitro studies revealed a higher uptake of the [177Lu]Lu-DOTA@TRA/MC@Si nanocomposite in HER2-positive SK-BR-3 cells (44.0 ± 4.6% after 24 h) compared to MDA-MB-231 cells (21.0 ± 2.3%). The IC50 values for TRA-dependent uptake in the SK-BR-3 and BT-474 cells were 0.9 µM and 1.3 µM, respectively, indicating affinity toward HER-2 receptor-expressing cells. The lipophilic distribution coefficients of the radiolabeled nanocomposites were determined to be 1.7 ± 0.3 for [177Lu]Lu-DOTA@TRA/MC@Si and 1.5 ± 0.2 for [177Lu]Lu-DOTA@PEI-MC@Si, suggesting sufficient passive transport through the cell membrane and increased accumulation in target tissues. The [177Lu]Lu-DOTA@TRA/MC@Si nanocomposite showed an uptake into HER2-positive cell lines, marking a valuable step toward the development of a nanoparticle-based therapeutic agent for an improved treatment strategy for HER2-positive breast cancer.

Assessment of myocardial fibrosis in patients with systemic sclerosis using [68Ga]Ga-FAPI-04-PET-CT.

PURPOSE: Myocardial fibrosis (MF) is a factor of poor prognosis in systemic sclerosis (SSc). Direct in-vivo visualization of fibroblast activation as early readout of MF has not been feasible to date. Here, we characterize 68Gallium-labeled-Fibroblast-Activation-Inhibitor-04 ([68Ga]Ga-FAPI-04)-PET-CT as a diagnostic tool in SSc-related MF. METHODS: In this proof-of-concept trial, six SSc patients with and eight without MF of the EUSTAR cohort Erlangen underwent [68Ga]Ga-FAPI-04-PET-CT and cardiac MRI (cMRI) and clinical and serologic investigations just before baseline and during follow-up between January 2020 and December 2020. Myocardial biopsy was performed as clinically indicated. RESULTS: [68Ga]Ga-FAPI-04 tracer uptake was increased in SSc-related MF with higher uptake in SSc patients with arrhythmias, elevated serum-NT-pro-BNP, and increased late gadolinium enhancement (LGE) in cMRI. Histologically, myocardial biopsies from cMRI- and [68Ga]Ga-FAPI-04-positive regions confirmed the accumulation of FAP+ fibroblasts surrounded by collagen deposits. We observed similar but not equal spatial distributions of [68Ga]Ga-FAPI-04 uptake and quantitative cMRI-based techniques. Using sequential [68Ga]Ga-FAPI-04-PET-CTs, we observed dynamic changes of [68Ga]Ga-FAPI-04 uptake associated with changes in the activity of SSc-related MF, while cMRI parameters remained stable after regression of molecular activity and rather indicated tissue damage. CONCLUSIONS: We present first in-human evidence that [68Ga]Ga-FAPI-04 uptake visualizes fibroblast activation in SSc-related MF and may be a diagnostic option to monitor cardiac fibroblast activity in situ.

68Ga-FAPI-04 PET-CT for molecular assessment of fibroblast activation and risk evaluation in systemic sclerosis-associated interstitial lung disease: a single-centre, pilot study.

BACKGROUND: Interstitial lung disease (ILD) is the most common cause of death in systemic sclerosis. To date, the progression of systemic sclerosis-associated ILD is judged by the accrual of lung damage on CT and pulmonary function tests. However, diagnostic tools to assess disease activity are not available. Here, we tested the hypothesis that quantification of fibroblast activation by PET-CT using a 68Ga-labelled selective inhibitor of prolyl endopeptidase FAP (68Ga-FAPI-04) would correlate with ILD activity and disease progression in patients with systemic sclerosis-associated ILD. METHODS: Between Sept 10, 2018, and April 8, 2020, 21 patients with systemic sclerosis-associated ILD confirmed by high-resolution CT (HRCT) within 12 months of inclusion and with onset of systemic sclerosis-associated ILD within 5 years or signs of progressive ILD and 21 controls without ILD were consecutively enrolled. All participants underwent 68Ga-FAPI-04 PET-CT imaging and standard-of-care procedures, including HRCT and pulmonary function tests at baseline. Patients with systemic sclerosis-associated ILD were followed for 6 months with HRCT and pulmonary function tests. We compared baseline 68Ga-FAPI-04 PET-CT uptake with standard diagnostic tools and predictors of ILD progression. The association of 68Ga-FAPI-04 uptake with changes in forced vital capacity was analysed using mixed-effects models. Follow-up 68Ga-FAPI-04 PET-CT scans were obtained in a subset of patients treated with nintedanib (follow-up between 6-10 months) to assess change over time. FINDINGS: 68Ga-FAPI-04 accumulated in fibrotic areas of the lungs in patients with systemic sclerosis-associated ILD compared with controls, with a median standardised uptake value (SUV) mean over the whole lung of 0·80 (IQR 0·60-2·10) in the systemic sclerosis-ILD group and 0·50 (0·40-0·50) in the control group (p<0·0001) and a mean whole lung maximal SUV of 4·40 (range 3·05-5·20) in the systemic sclerosis-ILD group compared with 0·70 (0·65-0·70) in the control group (p<0·0001). Whole-lung FAPI metabolic active volume (wlFAPI-MAV) and whole-lung total lesion FAPI (wlTL-FAPI) were not measurable in control participants, because no 68Ga-FAPI-04 uptake above background level was observed. In the systemic sclerosis-ILD group the median wlFAPI-MAV was 254·00 cm3 (IQR 163·40-442·30), and the median wlTL-FAPI was 183·60 cm3 (98·04-960·70). 68Ga-FAPI-04 uptake was higher in patients with extensive disease, with previous ILD progression, or high EUSTAR activity scores than in those with with limited disease, previously stable ILD, or low EUSTAR activity scores. Increased 68Ga-FAPI-04 uptake at baseline was associated with progression of ILD independently of extent of involvement on HRCT scan and the forced vital capacity at baseline. In consecutive 68Ga-FAPI-04 PET-CTs, changes in 68Ga-FAPI-04 uptake was concordant with the observed response to the fibroblast-targeting antifibrotic drug nintedanib. INTERPRETATION: Our study presents the first in-human evidence that fibroblast activation correlates with fibrotic activity and disease progression in the lungs of patients with systemic sclerosis-associated ILD and that 68Ga-FAPI-04 PET-CT might improve risk assessment of systemic sclerosis-associated ILD. FUNDING: German Research Foundation, Erlangen Anschubs-und Nachwuchsfinanzierung, Interdisziplinäres Zentrum für Klinische Forschung Erlangen, Bundesministerium für Bildung und Forschung, Deutsche Stiftung Systemische Sklerose, Wilhelm-Sander-Foundation, Else-Kröner-Fresenius-Foundation, European Research Council, Ernst-Jung-Foundation, and Clinician Scientist Program Erlangen.

Estimation of [177Lu]PSMA-617 tumor uptake based on voxel-wise 3D Monte Carlo tumor dosimetry in patients with metastasized castration resistant prostate cancer.

OBJECTIVE: Patients with advanced prostate cancer are suitable candidates for [177Lu]PSMA-617 therapy. Integrated SPECT/CT systems have the potential to improve the accuracy of patient-specific tumor dosimetry. We present a novel patient-specific Monte Carlo based voxel-wise dosimetry approach to determine organ and total tumor doses (TTD). METHODS: 13 patients with histologically confirmed metastasized castration-resistant prostate cancer were treated with a total of 18 cycles of [177Lu]PSMA-617 therapy. In each patient, dosimetry was performed after the first cycle of [177Lu]PSMA-617 therapy. Regions of interest were defined manually on the SPECT/CT images for the kidneys, spleen and all 295 PSMA-positive tumor lesions in the field of view. The absorbed dose to normal organs and to all tumor lesions were calculated by a three dimensional dosimetry method based on Monte Carlo Simulations. RESULTS: The average dose values yielded the following results: 2.59 ±â€Š0.63 Gy (1.67-3.92 Gy) for the kidneys, 0.79 ± 0.46 Gy (0.31-1.90 Gy) for the spleen and 11.00 ±â€Š11.97 Gy (1.28-49.10 Gy) for all tracer-positive tumor lesions. A trend towards higher TTD was observed in patients with Gleason Scores > 8 compared to Gleason Scores ≤ 8 and in lymph node metastases compared to bone metastases. A significant correlation was determined between the serum-PSA level before RLT and the TTD (r = -0.57, p < 0.05), as well as between the TTD with the percentage change of serum-PSA levels before and after therapy was observed (r = -0.57, p < 0.05). Patients with higher total tumor volumes of PSMA-positive lesions demonstrated significantly lower kidney average dose values (r = -0.58, p < 0.05). CONCLUSION: The presented novel Monte Carlo based voxel-wise dosimetry calculates a patient specific whole-body dose distribution, thus taking into account individual anatomies and tissue compositions showing promising results for the estimation of radiation doses of normal organs and PSMA-positive tumor lesions.

99mTc-MIP-1404 SPECT/CT for Assessment of Whole-Body Tumor Burden and Treatment Response in Patients With Biochemical Recurrence of Prostate Cancer.

OBJECTIVE: This study aims to investigate the value of Tc-MIP-1404 SPECT/CT for assessment of whole-body tumor burden and treatment response in patients with biochemical recurrence of prostate cancer who undergo androgen deprivation therapy (ADT) or external beam radiation therapy (EBRT). METHODS: A total of 125 patients with biochemical recurrence of prostate cancer underwent Tc-MIP-1404 SPECT/CT. All 364 prostate-specific membrane antigen (PSMA)-positive lesions in the field of view were assessed quantitatively to calculate PSMA-derived metabolic tumor parameters, including whole-body PSMA tumor volume and whole-body total lesion PSMA. These metrics were correlated with serum prostate-specific antigen (PSA) levels and Gleason scores. In a subset of 50 patients who underwent Tc-MIP-1404 SPECT/CT before the initiation of ADT or EBRT, TL-PSMA and SUVmax were compared with radiographic response assessment by CT based on RECIST 1.1 and to biochemical response (BR) determined by changes in serum PSA levels. RESULTS: Serum PSA levels correlated with SUVmax, whole-body PSMA tumor volume, and whole-body total lesion PSMA in patients with 1 and in those with more than 1 PSMA-positive lesion (P < 0.05). The correlations were significant for both well-differentiated (Gleason score ≤7) and poorly differentiated tumors (Gleason score ≥8) (P < 0.05). The agreement between TL-PSMA derived from SPECT and BR in patients who underwent Tc-MIP-1404 SPECT/CT before and after initiation of ADT was 80% (95% confidence interval [CI], 0.43-0.91; Cohen κ = 0.68; P < 0.05); in these patients, the agreement between TL-PSMA and CT was 60% (95% CI, 0.20-0.72; Cohen κ = 0.46; P < 0.05) and the agreement between BR and CT was 52% (0.07-0.61; Cohen κ = 0.34; P < 0.05). Comparable results were found for patients who underwent SPECT/CT before and after initiation of EBRT, with the strongest agreement between TL-PSMA and BR (80%; 95% CI, 0.38-0.93; Cohen κ = 0.66; P < 0.05) compared with the agreement between TL-PSMA and CT (60%; 95% CI, 0.13-0.69; Cohen κ = 0.69; P < 0.05) and between BR and CT (48%; 95% CI, 0-0.54; Cohen κ = 0.26; P = 0.11). Discordant findings between SPECT and CT were most likely due to limitations in the assessment of small lymph node metastases and bone involvement, which were detectable on SPECT but not on CT. CONCLUSIONS: The results of our study show that Tc-MIP-1404 SPECT/CT is a promising method for the evaluation of treatment response in patients with biochemical recurrence of prostate cancer who undergo either ADT or EBRT. TL-PSMA for assessment of treatment response has the strongest correlation with serum PSA levels, superior to SUVmax-based evaluation and response assessment based on CT data and RECIST 1.1.

Correction to: Assessment of treatment responses in children and adolescents with Ewing sarcoma with metabolic tumor parameters derived from 18F-FDG-PET/CT and circulating tumor DNA.

The author names and family names of the originally published article was inversed. Correct presentation is presented here.

Assessment of treatment responses in children and adolescents with Ewing sarcoma with metabolic tumor parameters derived from 18F-FDG-PET/CT and circulating tumor DNA.

PURPOSE: The purpose of this study was to perform a prospective integrated analysis of 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET)/computed tomography (CT) and circulating tumor DNA (ctDNA) to assess responses to multimodal chemotherapy in children and adolescents suffering from Ewing sarcoma (EwS). METHODS: A total of 20 patients with histologically confirmed EwS underwent multiple 18F-FDG-PET/CT, performed at the time of each patient's initial diagnosis and after the second and fifth induction chemotherapy block (EWING2008 treatment protocol, NCT00987636). Additional PET examinations were performed as clinically indicated in some patients, e.g., in patients suspected of having progressive or relapsing disease. All 263 18F-FDG-positive lesions in the field of view suggestive of tumor tissue were assessed quantitatively to calculate PET-derived parameters, including whole-body metabolic tumor volume (wb-MTV) and whole-body total lesion glycolysis (wb-TLG), as well as the following data: standardized uptake value (SUV)max and SUVmean. Tumor-specific ctDNA in patient plasma samples was quantified using digital droplet PCR (ddPCR), and the correlations between ctDNA levels and PET-derived parameters were analyzed. Metabolic responses to multimodal chemotherapy as assessed with PET-parameters were compared to biochemical responses as assessed with changes in ctDNA levels. RESULTS: Twenty patients underwent a total of 87 18F-FDG-PET/CT scans, which detected 263 FDG-positive tumor lesions. Significant correlations between SUVmax, SUVmean, wb-MTV and wb-TLG values, and ctDNA levels were observed (all p < 0.0001). All patients suffering from EwS, with histology serving as gold standard, also presented with a positive corresponding ctDNA sample and a positive 18F-FDG-PET/CT examination before initiation of therapy. There were no false-negative results. Evaluation of treatment response after the fifth block of induction chemotherapy showed that the agreement between the metabolic response and biochemical response was 90%, which was statistically significant (Cohen κ = 0.62; p < 0.05). Non-detectable ctDNA after the second block of induction chemotherapy was associated with complete biochemical and metabolic responses after the fifth block of induction chemotherapy in 16/17 patients (94%). During a median follow-up period of 36 months (range: 8-104 months), four patients had tumor relapses, which, in all cases, were accompanied by an increase in plasma ctDNA levels and a positive 18F-FDG-PET/CT. No false-negative results were observed in the study cohort. Complete biochemical and metabolic responses after the fifth block of induction chemotherapy had a high positive predictive value for disease remission during the follow-up period; specifically, the positive predictive value was 88%. CONCLUSION: The combination of 18F-FDG-PET/CT and ctDNA quantification is a very promising noninvasive tool for assessing treatment responses and detecting tumor relapses in children and young adolescents suffering from EwS who are undergoing multimodal chemotherapy.

Assessment of Treatment Response by 99mTc-MIP-1404 SPECT/CT: A Pilot Study in Patients With Metastatic Prostate Cancer.

BACKGROUND: We investigated the role of Tc-MIP-1404 (Progenics Pharmaceuticals, Inc, New York, NY) SPECT/CT of PSMA expression in the assessment of treatment response in patients with metastatic prostate cancer. METHODS: We retrospectively analyzed Tc-MIP-1404 SPECT/CT scans from 28 patients with metastatic prostate cancer examined before initiation and after completion of therapy. Eight of these patients had been treated with androgen deprivation therapy, 10 with docetaxel, and another 10 with external beam radiotherapy. On the CT images from SPECT/CT, treatment response was assessed according to RECIST 1.1 criteria; independently from that analysis, maximal standardized uptake values (SUVmax) were quantified in representative tumor lesions and treatment response assumed at differences in SUVmax greater than 30%. Radiographic response assessment was correlated to biochemical response (BR) based on prostate-specific antigen serum levels. RESULTS: The concordance rate between SPECT and BR was 75% (95% confidence interval [CI], 0.55-0.89) (Cohen κ = 0.57; 95% CI, 0.29-0.85; P ≤ 0.01), higher than for that between SPECT and CT with 57% (95% CI, 0.37-0.76) (κ = 0.40; 95% CI, 0.14-0.65; P ≤ 0.01), as well as that between CT and BR with 50% (95% CI, 0.31-0.69) (κ = 0.31; 95% CI, 0.06-0.57, P ≤ 0.05). Discordant findings between SPECT and CT were most likely due to limitations of CT in assessing metastases in lymph nodes, as well as bone involvement, which was sometimes not detectable on CT scans. CONCLUSIONS: The high agreement between treatment response, as assessed by Tc-MIP-1404 SPECT/CT and BR, suggests a possible role of that imaging tool for monitoring treatment in metastatic prostate cancer. Larger, ideally prospective trials are needed to help to reveal the full potential of SPECT imaging of PSMA expression in that regard.