High Tumor-to-background Ratios Research Articles

Diagnostic Potential of Supplemental Static and Dynamic 68Ga-FAPI-46 PET for Primary 18F-FDG-Negative Pulmonary Lesions.

PET using 68Ga-labeled fibroblast activation protein (FAP) inhibitors (FAPIs) holds high potential for diagnostic imaging of various malignancies, including lung cancer (LC). However, 18F-FDG PET is still the clinical gold standard for LC imaging. Several subtypes of LC, especially lepidic LC, are frequently 18F-FDG PET-negative, which markedly hampers the assessment of single pulmonary lesions suggestive of LC. Here, we evaluated the diagnostic potential of static and dynamic 68Ga-FAPI-46 PET in the 18F-FDG-negative pulmonary lesions of 19 patients who underwent surgery or biopsy for histologic diagnosis after PET imaging. For target validation, FAP expression in lepidic LC was confirmed by FAP immunohistochemistry. Methods: Hematoxylin and eosin staining and FAP immunohistochemistry of 24 tissue sections of lepidic LC from the local tissue bank were performed and analyzed visually. Clinically, 19 patients underwent static and dynamic 68Ga-FAPI-46 PET in addition to 18F-FDG PET based on individual clinical indications. Static PET data of both examinations were analyzed by determining SUVmax, SUVmean, and tumor-to-background ratio (TBR) against the blood pool, as well as relative parameters (68Ga-FAPI-46 in relation to18F-FDG), of histologically confirmed LC and benign lesions. Time-activity curves and dynamic parameters (time to peak, slope, k 1, k 2, k 3, and k 4) were extracted from dynamic 68Ga-FAPI-46 PET data. The sensitivity and specificity of all parameters were analyzed by calculating receiver-operating-characteristic curves. Results: FAP immunohistochemistry confirmed the presence of strongly FAP-positive cancer-associated fibroblasts in lepidic LC. LC showed markedly elevated 68Ga-FAPI-46 uptake, higher TBRs, and higher 68Ga-FAPI-46-to-18F-FDG ratios for all parameters than did benign pulmonary lesions. Dynamic imaging analysis revealed differential time-activity curves for LC and benign pulmonary lesions: initially increasing time-activity curves with a decent slope were typical of LC, and steadily decreasing time-activity curve indicated benign pulmonary lesions, as was reflected by a significantly increased time to peak and significantly smaller absolute values of the slope for LC. Relative 68Ga-FAPI-46-to-18F-FDG ratios regarding SUVmax and TBR showed the highest sensitivity and specificity for the discrimination of LC from benign pulmonary lesions. Conclusion: 68Ga-FAPI-46 PET is a powerful new tool for the assessment of single 18F-FDG-negative pulmonary lesions and may optimize patient stratification in this clinical setting.

Synthesis, preclinical, and initial clinical evaluation of integrin αVβ3 and gastrin-releasing peptide receptor (GRPR) dual-targeting radiotracer [68Ga]Ga-RGD-RM26-03.

LNC1015 was designed and synthesized by linking cyclic RGD and the RM26 peptide. Preclinical pharmacokinetics were detected in a PC3 xenograft model using microPET and biodistribution studies. The clinical feasibility of [68Ga]Ga-LNC1015 PET/CT was performed in patients with breast cancer, and the results were compared with those of 18F-fluorodeoxyglucose (FDG). [68Ga]Ga-LNC1015 had good stability in saline for at least 2h, and favorable binding affinity and specificity were demonstrated in vitro and in vivo. The tumor uptake and retention of [68Ga]Ga-LNC1015 during PET imaging were improved compared with its monomeric counterparts [68Ga]Ga-RGD and [68Ga]Ga-RM26 at all the time points examined. In our initial clinical studies, the tumor uptake and tumor-to-background ratio (TBR) of primary and metastatic lesions in [68Ga]Ga-LNC1015 PET/CT were significantly higher than those in [18F]FDG PET/CT, resulting in high lesion detection rate and tumor delineation. The dual targeting radiotracer [68Ga]Ga-LNC1015 showed significantly improved tumor uptake and retention, as well as lower liver uptake than [68Ga]Ga-RGD and [68Ga]Ga-RM26 monomer. The first-in-human study showed high TBRs in patients, suggesting favorable pharmacokinetics and high clinical feasibility for PET/CT imaging of cancer.

18F-FACBC and 18F-FDG PET/MRI in the evaluation of 3 patients with primary central nervous system lymphoma: a pilot study

BackgroundThis PET/MRI study compared contrast-enhanced MRI, 18F-FACBC-, and 18F-FDG-PET in the detection of primary central nervous system lymphomas (PCNSL) in patients before and after high-dose methotrexate chemotherapy. Three immunocompetent PCNSL patients with diffuse large B-cell lymphoma received dynamic 18F-FACBC- and 18F-FDG-PET/MRI at baseline and response assessment. Lesion detection was defined by clinical evaluation of contrast enhanced T1 MRI (ce-MRI) and visual PET tracer uptake. SUVs and tumor-to-background ratios (TBRs) (for 18F-FACBC and 18F-FDG) and time-activity curves (for 18F-FACBC) were assessed.ResultsAt baseline, seven ce-MRI detected lesions were also detected with 18F-FACBC with high SUVs and TBRs (SUVmax:mean, 4.73, TBRmax: mean, 9.32, SUVpeak: mean, 3.21, TBRpeak:mean: 6.30). High TBR values of 18F-FACBC detected lesions were attributed to low SUVbackground. Baseline 18F-FDG detected six lesions with high SUVs (SUVmax: mean, 13.88). In response scans, two lesions were detected with ce-MRI, while only one was detected with 18F-FACBC. The lesion not detected with 18F-FACBC was a small atypical MRI detected lesion, which may indicate no residual disease, as this patient was still in complete remission 12 months after initial diagnosis. No lesions were detected with 18F-FDG in the response scans.Conclusions18F-FACBC provided high tumor contrast, outperforming 18F-FDG in lesion detection at both baseline and in response assessment. 18F-FACBC may be a useful supplement to ce-MRI in PCNSL detection and response assessment, but further studies are required to validate these findings.Trial registration ClinicalTrials.gov. Registered 15th of June 2017 (Identifier: NCT03188354, https://clinicaltrials.gov/study/NCT03188354).

Near-infrared (NIR) imaging with indocyanine green (ICG) may assist in intraoperative decision making and improving surgical margin in bone and soft tissue tumor surgery.

Negative surgical margins are significant in improving patient outcomes. However, surgeons can only rely on visual and tactile information to identify tumor margins intraoperatively. We hypothesized that intraoperative fluorescence imaging with indocyanine green(ICG) could serve as an assistive technology to evaluate surgical margins and guide surgery in bone and soft tissue tumor surgery. Seventy patients with bone and soft tissue tumors were enrolled in this prospective, non-randomized, single-arm feasibility study. All patients received intravenous indocyanine green (0.5 mg/kg) before surgery. Near-infrared(NIR) imaging was performed on in situ tumors, wounds, and ex vivo specimens. 60/70 tumors were fluorescent at NIR imaging. The final surgical margins were positive in 2/55 cases, including 1/40 of the sarcomas. Surgical decisions were changed in 19 cases by NIR imaging, and in 7/19 cases final pathology demonstrated margins were improved. Fluorescence analysis showed that the tumor-to-background ratio (TBR) of primary malignant tumors was higher than that of benign, borderline, metastatic, and tumors ≥5 cm in size had higher TBR than those <5 cm. ICG fluorescence imaging may be a beneficial technique to assist in surgical decision making and improving surgical margins in bone and soft tissue tumor surgery.

Multi-timepoint imaging with PSMA-targeted [18F]F-Florastamin PET/CT: lesion detection and comparison to conventional imaging.

The aims of this study were to investigate the utility of [18F]F-Florastamin, a novel prostate-specific membrane antigen (PSMA)-targeted PET radiotracer with facile radiochemistry, relative to the conventional imaging for the detection of sties of disease and evaluate the effect of multi-timepoint imaging with [18F]F-Florastamin PET on lesion detectability. Eight prostate cancer patients with known or suspected recurrence who underwent [18F]F-Florastamin PET/CT at 1-h and 2-h imaging time-points were included in this prospective pilot study. [18F]F-Florastamin PET images were interpreted visually and quantitatively at both time points and compared with CIM. [18F]F-Florastamin PET was superior to CT in the detection of active osseous metastases and small-sized metastatic lymph nodes that do not fall under the anatomic imaging size criteria for metastasis. Multi-timepoint imaging showed a significant reduction in the blood pool, bone marrow and muscular uptake, and increase in liver uptake over time. There is a significant improvement in tumor-to-background ratio (TBR) at the 2-h imaging time-point (P = 0.04). The mean percentage change in TBR at 2-h was 21% (SD = 0.31). [18F]F-Florastamin is a promising new radioligand for PSMA-targeted PET with suitable lesion detectability and high TBR at both time points.

First Clinical Experience With [68Ga]Ga-FAPI-46-PET/CT Versus [18F]F-FDG PET/CT for Nodal Staging in Cervical Cancer.

In several solid tumors, fibroblast activation protein (FAP) is overexpressed by cancer-associated fibroblasts in the tumor microenvironment. Preliminary evidence suggests that detection and staging are feasible with PET/CT imaging using [68Ga]-radiolabeled inhibitors of FAP also in cervical cancer (CC). Our study aims to explore the accuracy of [68Ga]Ga-fibroblast activation protein inhibitor (FAPI)-46 PET/CT and [18F]F-FDG PET/CT compared with histopathological results of surgical lymph node (LN) staging before primary chemoradiation. Seven consecutive women with treatment-naive and biopsy-proven locally advanced CC underwent both whole-body [68Ga]Ga-FAPI-46- and [18F]F-FDG PET/CT, for imaging nodal staging before systematic laparoscopic lymphadenectomy of the pelvic and para-aortic region. Location and number of suspicious LNs in PET imaging were recorded and compared with the results of histopathological analysis, including immunohistochemical staining for FAP. All 7 patients had focal uptake above background in their tumor lesions in [68Ga]Ga-FAPI-46 PET/CT. [68Ga]Ga-FAPI-46 PET/CT showed a higher tumor-to-background ratio (TBR) in primary tumor as well as in LN metastasis. Median TBRmax values using liver were 32.02 and 5.15 for [68Ga]Ga-FAPI-46 PET/CT and [18F]F-FDG PET/CT, respectively. Median TBRmax using blood pool was 18.45 versus 6.85 for [68Ga]Ga-FAPI-46 PET/CT and [18F]F-FDG PET/CT, respectively. Higher TBR also applies for nodal metastasis: TBRmax was 14.55 versus 1.39 (liver) and 7.97 versus 1.8 (blood pool) for [68Ga]Ga-FAPI-46 PET/CT and [18F]F-FDG PET/CT, respectively. Overall, [68Ga]Ga-FAPI-46 PET/CT detected more lesions compared with [18F]F-FDG PET/CT. Following surgical staging, a total of 5 metastatic LNs could be pathologically confirmed, of which 2 and 4 were positive by [18F]F-FDG PET/CT and [68Ga]Ga-FAPI-46 PET/CT, respectively. [68Ga]Ga-FAPI-46 PET/CT seems useful to improve detection of nodal metastasis in patients with CCs. Future studies should aim to compare [68Ga]Ga-FAPI-46 PET/CT to surgical staging of pelvic and para-aortic LNs in patients with locally advanced CC.

Three-Time-Point PET Analysis of 68Ga-FAPI-46 in a Variety of Cancers.

A growing family of 68Ga-fibroblast activation protein inhibitor (FAPI) PET probes has shown promise in imaging a variety of medical conditions. 68Ga-FAPI-46, in particular, has emerged as unique for both its diagnostic and its theranostic applications; however, the optimal timing of PET remains unclear. Therefore, we evaluated uptake at 3 time points after 68Ga-FAPI-46 administration in a spectrum of tumor types. Methods: The cohort consisted of 43 patients with diverse cancer diagnoses undergoing 68Ga-FAPI-46 PET/CT at 3 time points (10 min, 1 h, and 3 h). We determined the tracer uptake based on SUVmean and SUVmax and on tumor-to-background-ratios (TBRs) (SUVmax/SUVmean). Results: There were 171 lesions in the 43 patients. Comparing all lesions at different time points, the mean SUVmax was maximal at 10 min (8.2) and declined slightly at 1 h (8.15) and 3 h (7.6) after tracer administration. Similarly, the mean SUVmax log still had a similar pattern in primary lesions at 10 min, 1 h, and 3 h (n = 30; 0.98, 1.01, and 0.98, respectively), lymph node metastases (n = 37; 0.82, 0.84, and 0.81, respectively), and distant metastases (n = 104; 0.81, 0.79, and 0.74, respectively). TBR also showed nonsignificant differences at the 3 times. Conclusion: 68Ga-FAPI-46 PET/CT imaging revealed remarkably stable tumor and background uptake as determined by SUV metrics and maintained high TBRs within 3 h of injection. Thus, it may be possible to scan with 68Ga-FAPI-46 within 10-20 min of injection, improving workflow and decreasing patient wait times. Confirmation of these findings in a larger cohort is under way.

Cyanine Masking: A Strategy to Test Functional Group Effects on Antibody Conjugate Targeting.

Conjugates of small molecules and antibodies are broadly employed diagnostic and therapeutic agents. Appending a small molecule to an antibody often significantly impacts the properties of the resulting conjugate. Here, we detail a systematic study investigating the effect of various functional groups on the properties of antibody-fluorophore conjugates. This was done through the preparation and analysis of a series of masked heptamethine cyanines (CyMasks)-bearing amides with varied functional groups. These were designed to exhibit a broad range of physical properties, and include hydrophobic (-NMe2), pegylated (NH-PEG-8 or NH-PEG-24), cationic (NH-(CH2)2NMe3+), anionic (NH-(CH2)2SO3-), and zwitterionic (N-(CH2)2NMe3+)-(CH2)3SO3-) variants. The CyMask series was appended to monoclonal antibodies (mAbs) and analyzed for the effects on tumor targeting, clearance, and non-specific organ uptake. Among the series, zwitterionic and pegylated dye conjugates had the highest tumor-to-background ratio (TBR) and a low liver-to-background ratio. By contrast, the cationic and zwitterionic probes had high tumor signal and high TBR, although the latter also exhibited an elevated liver-to-background ratio (LBR). Overall, these studies provide a strategy to test the functional group effects and suggest that zwitterionic substituents possess an optimal combination of high tumor signal, TBR, and low LBR. These results suggest an appealing strategy to mask hydrophobic payloads, with the potential to improve the properties of bioconjugates in vivo.

Synthesis, preclinical evaluation and radiation dosimetry of a dual targeting PET tracer [68Ga]Ga-FAPI-RGD.

To enhance tumor uptake and retention, we designed and developed bi-specific heterodimeric radiotracers targeting both FAP and αvβ3, [68Ga]Ga-FAPI-RGD. The present study aimed to evaluate the specificity, pharmacokinetics, and dosimetry of [68Ga]Ga-FAPI-RGD by preclinical and preliminary clinical studies.Methods: FAPI-RGD was designed and synthesized with the quinoline-based FAPI-02 and the cyclic RGDfK peptide. Preclinical pharmacokinetics were determined in Panc02 xenograft model using microPET and biodistribution experiments. The safety and effective dosimetry of [68Ga]Ga-FAPI-RGD was evaluated in 6 cancer patients, and compared with 2-[18F]FDG imaging.Results: The [68Ga]Ga-FAPI-RGD had good stability in saline for at least 4 h, and showed favorable binding affinity and specificity in vitro and in vivo. Compared to [68Ga]Ga-FAPI-02 and [68Ga]Ga-RGDfK, the tumor uptake and retention of [68Ga]Ga-FAPI-RGD were very much enhanced than its monomeric counterparts at all the time points examined by microPET imaging. A total of 6 patients with various malignant tumors were prospectively enrolled. The effective dose of [68Ga]Ga-FAPI-RGD was 1.94E-02 mSv/MBq. The biodistribution of [68Ga]Ga-FAPI-RGD from 0 to 2 h after injection demonstrated rapid and high tumor uptake, prolonged tumor retention, and high tumor-to-background ratios (TBRs) which further increased over time. No significant difference in mean SUVmax of [68Ga]Ga-FAPI-RGD and 2-[18F]FDG was present in primary tumors (8.9±3.2 vs. 10.3 ± 6.9; p = 0.459).Conclusion: The dual targeting PET tracer [68Ga]Ga-FAPI-RGD showed significantly improved tumor uptake and retention, as well as cleaner background over 68Ga-labeled FAPI and RGD monospecific tracers. The first-in-human biodistribution study showed high TBRs over time, suggesting high diagnostic performance and favorable tracer kinetics for potential therapeutic applications.

18F]FAPI-42 PET imaging in cancer patients: optimal acquisition time, biodistribution, and comparison with [68Ga]Ga-FAPI-04.

[18F]FAPI-42 is a new fibroblast activation protein (FAP)-specific tracer used for cancer imaging. Here, we describe the optimal acquisition time and in vivo evaluation of [18F]FAPI-42 and compared intra-individual biodistribution, tumor uptake, and detection ability to [68Ga]Ga-FAPI-04. A total of 22 patients with various types of cancer received [18F]FAPI-42 whole-body positron emission tomography/computed tomography (PET/CT). Among them, 4 patients underwent PET/CT scans, including an early dynamic 20-min, static 1-h, and static 2-h scans. The in vivo biodistribution in normal organs and tumor uptake were semiquantitatively evaluated using the standardized uptake value (SUV) and tumor-to-background ratio (TBR). Furthermore, both [18F]FAPI-42 and [68Ga]Ga-FAPI-04 PET/CT were performed in 12 patients to compare biodistribution, tumor uptake, and tumor detection ability. [18F]FAPI-42 uptake in the tumors was rapid and reached a high level with an average SUVmax of 15.8 at 18min, which stayed at a similarly high level to 2h. The optimal image acquisition time for [18F]FAPI-42 was determined to be 1h postinjection. For tumor detection, [18F]FAPI-42 had a high uptake and could be clearly visualized in the lesions. Compared to [68Ga]Ga-FAPI-04, [18F]FAPI-42 had the same detectability for 144 positive lesions. In addition, [18F]FAPI-42 showed a higher SUVmax in liver and bone lesions (P < 0.05) and higher TBRs in liver, bone, lymph node, pleura, and peritoneal lesions (all P < 0.05). The present study demonstrates that the optimal image acquisition time of [18F]FAPI-42 is 1h postinjection and that [18F]FAPI-42 exhibits comparable lesion detectability to [68Ga]Ga-FAPI-04. Chinese Clinical Trial Registry (ChiCTR2100045757).

Glioma Imaging by O-(2-18F-Fluoroethyl)-L-Tyrosine PET and Diffusion-Weighted MRI and Correlation With Molecular Phenotypes, Validated by PET/MR-Guided Biopsies.

Gliomas exhibit high intra-tumoral histological and molecular heterogeneity. Introducing stereotactic biopsy, we achieved a superior molecular analysis of glioma using O-(2-18F-fluoroethyl)-L-tyrosine (FET)-positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DWI). Patients underwent simultaneous DWI and FET-PET scans. Correlations between biopsy-derived tumor tissue values, such as the tumor-to-background ratio (TBR) and apparent diffusion coefficient (ADC)/exponential ADC (eADC) and histopathological diagnoses and those between relevant genes and TBR and ADC values were determined. Tumor regions with human telomerase reverse transcriptase (hTERT) mutation had higher TBR and lower ADC values. Tumor protein P53 mutation correlated with lower TBR and higher ADC values. α-thalassemia/mental-retardation-syndrome-X-linked gene (ATRX) correlated with higher ADC values. 1p/19q codeletion and epidermal growth factor receptor (EGFR) mutations correlated with lower ADC values. Isocitrate dehydrogenase 1 (IDH1) mutations correlated with higher TBRmean values. No correlation existed between TBRmax/TBRmean/ADC/eADC values and phosphatase and tensin homolog mutations (PTEN) or O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. Furthermore, TBR/ADC combination had a higher diagnostic accuracy than each single imaging method for high-grade and IDH1-, hTERT-, and EGFR-mutated gliomas. This is the first study establishing the accurate diagnostic criteria for glioma based on FET-PET and DWI.

PSMA PET Imaging in Glioblastoma: A Preclinical Evaluation and Theranostic Outlook

BackgroundProstate specific membrane antigen (PSMA) PET imaging has recently gained attention in glioblastoma (GBM) patients as a potential theranostic target for PSMA radioligand therapy. However, PSMA PET has not yet been established in a murine GBM model. Our goal was to investigate the potential of PSMA PET imaging in the syngeneic GL261 GBM model and to give an outlook regarding the potential of PMSA radioligand therapy in this model.MethodsWe performed an 18F-PSMA-1007 PET study in the orthotopic GL261 model (n=14 GBM, n=7 sham-operated mice) with imaging at day 4, 8, 11, 15, 18 and 22 post implantation. Time-activity-curves (TAC) were extracted from dynamic PET scans (0-120 min p. i.) in a subset of mice (n=4 GBM, n=3 sham-operated mice) to identify the optimal time frame for image analysis, and standardized-uptake-values (SUV) as well as tumor-to-background ratios (TBR) using contralateral normal brain as background were calculated in all mice. Additionally, computed tomography (CT), ex vivo and in vitro 18F-PSMA-1007 autoradiographies (ARG) were performed.ResultsTAC analysis of GBM mice revealed a plateau of TBR values after 40 min p. i. Therefore, a 30 min time frame between 40-70 min p. i. was chosen for PET quantification. At day 15 and later, GBM mice showed a discernible PSMA PET signal on the inoculation site, with highest TBRmean in GBM mice at day 18 (7.3 ± 1.3 vs. 1.6 ± 0.3 in shams; p=0.024). Ex vivo ARG confirmed high tracer signal in GBM compared to healthy background (TBRmean 26.9 ± 10.5 vs. 1.6 ± 0.7 in shams at day 18/22 post implantation; p=0.002). However, absolute uptake values in the GL261 tumor remained low (e.g., SUVmean 0.21 ± 0.04 g/ml at day 18) resulting in low ratios compared to dose-relevant organs (e.g., mean tumor-to-kidney ratio 1.5E-2 ± 0.5E-2).ConclusionsAlthough 18F-PSMA-1007 PET imaging of GL261 tumor-bearing mice is feasible and resulted in high TBRs, absolute tumoral uptake values remained low and hint to limited applicability of the GL261 model for PSMA-directed therapy studies. Further investigations are warranted to identify suitable models for preclinical evaluation of PSMA-targeted theranostic approaches in GBM.

FAP imaging in rare cancer entities—first clinical experience in a broad spectrum of malignancies

Purpose68 Ga-FAPI (fibroblast activation protein inhibitor) is a rapidly evolving and highly promising radiotracer for PET/CT imaging, presenting excellent results in a variety of tumor entities, particularly in epithelial carcinomas. This retrospective analysis sought to evaluate the potential and impact of FAPI-PET/CT in rare cancer diseases with respect to improvement in staging and therapy, based on tracer uptake in normal organs and tumors.Material and methodsFifty-five patients with rare tumor entities, defined by a prevalence of 1 person out of 2000 or less, received a 68 Ga-FAPI-PET/CT scan. Fourteen women and 41 men (median age 60) were included within the following subgroups: cancer of unknown primary (n = 10), head and neck cancer (n = 13), gastrointestinal and biliary-pancreatic cancer (n = 17), urinary tract cancer (n = 4), neuroendocrine cancer (n = 4), and others (n = 7). Tracer uptake was quantified by standardized uptake values SUVmax and SUVmean and the tumor-to-background ratio (TBR) was determined (SUVmax tumor/SUVmean organ).ResultsIn 20 out of 55 patients, the primary tumor was identified and 31 patients presented metastases (n = 88), characterized by a high mean SUVmax in primary (10.1) and metastatic lesions (7.6). The highest uptake was observed in liver metastases (n = 6) with a mean SUVmax of 9.8 and a high TBR of 8.7, closely followed by peritoneal carcinomatosis (n = 16) presenting a mean SUVmax of 9.8 and an excellent TBR of 29.6. In terms of the included subgroups, the highest uptake regarding mean SUVmax was determined in gastrointestinal and biliary-pancreatic cancer with 9.8 followed closely by urinary tract cancer with 9.5 and head and neck cancer (9.1).ConclusionDue to excellent tumor visualization and, thereby, sharp contrasts in terms of high TBRs in primary and metastatic lesions in different rare malignancies, 68 Ga-FAPI-PET/CT crystallizes as a powerful and valuable imaging tool, particularly with respect to epithelial carcinomas, and therefore an enhancement to standard diagnostics imaging methodologies. The realization of further and prospective studies is of large importance to confirm the potential of FAP imaging in oncology.

Quantitative evaluation of range and metabolic activity of hepatic alveolar echinococcosis lesion microenvironment using PET/CT and multi-site sampling method

BackgroundAlveolar echinococcosis (AE) lesion microenvironment (LME) is crucial site where parasite-host interactions happen and of great significance during surgery and obtaining liver samples for basic research. However, little is known about quantification of LME range and its’ metabolic activity regarding different lesion characteristics.MethodsA prospective and retrospective analysis of LME from surgical AE patients was performed. Patients (n = 75) received abdominal computed tomography (CT) and position emission tomography/computed tomography using 18F-fluodeoxyglucose (18F-FDG-PET/CT) within 1 week prior to surgery. Semiquantitatively, calcification was clustered with 0%, < 50% and ≥ 50% degrees at lesion periphery; liquefaction was clustered with 0%, < 50%, 50 ~ 75%, ≥75% degrees at lesion center using volumetric ratio. Tumor to background ratio (TBR) of 18F-FDG standard uptake value (SUV, n = 75) was calculated, and range of 18F-FDG uptake area was measured; Multi-site sampling method (MSS, n = 35) was introduced to obtain histological slides to evaluate immune cell infiltrative ranges.ResultsAltogether six major lesion groups have been identified (A: 0% calcified, 0% liquefied; B: ≥50% calcified, 0% liquefied; C: < 50% calcified, < 50% liquefied; D: ≥50% calcified, < 50% liquefied; E: < 50% calcified, 50 ~ 75% liquefied; F: ≥50% calcified, ≥75% liquefied). Statistically, TBR values respectively were 5.1 ± 1.9, 2.7 ± 1.2, 4.2 ± 1.2, 2.7 ± 0.7, 4.6 ± 1.2, 2.9 ± 1.1 in groups A ~ F, and comparisons showed A > B, A > D, A > F, E > B, E > D, E > F, C > B, C > D, C > F (P < 0.05); LME ranges indicated by PET/CT respectively were 14.9 ± 3.9, 10.6 ± 1.5, 12.3 ± 1.1, 7.8 ± 1.6, 11.1 ± 2.3, 7.0 ± 0.4 mm in groups A ~ F, and comparisons showed A > B, A > D, A > F, A > E, C > B, C > D, C > F, E > D, E > F, B > D, B > F (P < 0.05); LME ranges indicated by MSS respectively were 17.9 ± 4.9, 13.0 ± 2.7, 11.9 ± 2.6, 6.0 ± 2.2, 11.0 ± 4.1, 6.0 ± 2.2 mm in groups A ~ F, and comparisons showed A > C, A > D, A > F, B > D, B > F, C > D, C > F (P < 0.05). Generally, less calcifications indicated higher TBR values and wider LME ranges; and, severer liquefactions indicated smaller LME ranges. Additionally, patients with previous medication history had lower TBR values.ConclusionsPET/CT and MSS method showed distinct TBRs and LME ranges for different calcifications and liquefactions. This study would be able to provide references for both surgical resections of lesions and more accurate sample acquisitions for basic research targeted to immunology.

68Ga-FAPI-PET/CT in patients with various gynecological malignancies

Purpose68Ga-FAPI (fibroblast activation protein inhibitor) is a novel and highly promising radiotracer for PET/CT imaging. The aim of this retrospective analysis is to explore the potential of FAPI-PET/CT in gynecological malignancies. We assessed biodistribution, tumor uptake, and the influence of pre- or postmenopausal status on tracer accumulation in hormone-sensitive organs. Furthermore, a comparison with the current standard oncological tracer 18F-FDG was performed in selected cases.Patients and methodsA total of 31 patients (median age 59.5) from two centers with several gynecological tumors (breast cancer; ovarian cancer; cervical cancer; endometrial cancer; leiomyosarcoma of the uterus; tubal cancer) underwent 68Ga-FAPI-PET/CT. Out of 31 patients, 10 received an additional 18F-FDG scan within a median time interval of 12.5 days (range 1–76). Tracer uptake was quantified by standardized uptake values (SUV)max and (SUV)mean, and tumor-to-background ratio (TBR) was calculated (SUVmax tumor/ SUVmean organ). Moreover, a second cohort of 167 female patients with different malignancies was analyzed regarding their FAPI uptake in normal hormone-responsive organs: endometrium (n = 128), ovary (n = 64), and breast (n = 147). These patients were categorized by age as premenopausal (<35 years; n = 12), postmenopausal (>65 years; n = 68), and unknown menstrual status (35–65 years; n = 87), followed by an analysis of FAPI uptake of the pre- and postmenopausal group.ResultsIn 8 out of 31 patients, the primary tumor was present, and all 31 patients showed lesions suspicious for metastasis (n = 81) demonstrating a high mean SUVmax in both the primary (SUVmax 11.6) and metastatic lesions (SUVmax 9.7). TBR was significantly higher in 68Ga-FAPI compared to 18F-FDG for distant metastases (13.0 vs. 5.7; p = 0.047) and by trend for regional lymph node metastases (31.9 vs 27.3; p = 0.6). Biodistribution of 68Ga-FAPI-PET/CT presented significantly lower uptake or no significant differences in 15 out of 16 organs, compared to 18F-FDG-PET/CT. The highest uptake of all primary lesions was obtained in endometrial carcinomas (mean SUVmax 18.4), followed by cervical carcinomas (mean SUVmax 15.22). In the second cohort, uptake in premenopausal patients differed significantly from postmenopausal patients in endometrium (11.7 vs 3.9; p < 0.0001) and breast (1.8 vs 1.0; p = 0.004), whereas no significant difference concerning ovaries (2.8 vs 1.6; p = 0.141) was observed.ConclusionDue to high tracer uptake resulting in sharp contrasts in primary and metastatic lesions and higher TBRs than 18F-FDG-PET/CT, 68Ga-FAPI-PET/CT presents a promising imaging method for staging and follow-up of gynecological tumors. The presence or absence of the menstrual cycle seems to correlate with FAPI accumulation in the normal endometrium and breast. This first investigation of FAP ligands in gynecological tumor entities supports clinical application and further research in this field.

68Ga-FAPI-04 PET/CT, a new step in breast cancer imaging: a comparative pilot study with the 18F-FDG PET/CT.

We aimed to compare the roles of 68Ga-FAPI-04 PET/CT and 18F-FDG PET/CT in the evaluation of primary tumor and metastases in primary and recurrent breast cancer. Twenty female patients with histopathologically confirmed primary and recurrent breast cancer were included in the prospective study. All patients underwent FDG and FAPI PET/CT imaging in the same week. The number of primary and metastatic lesions, SUVmax values, and tumor-to-background ratios (TBR) were recorded from both scans. Data obtained were statistically compared. FAPI PET/CT was superior to FDG in detecting breast lesions, as well as hepatic, bone, lymph node, and cerebral metastases in terms of patient- and lesion-based assessments. The sensitivity and specificity of FAPI in detecting primary breast lesions were 100% and 95.6%, respectively, while the sensitivity and specificity of FDG were 78.2% and 100%, respectively. The SUVmax values of primary breast tumors, lymph nodes, lung metastases, and bone metastases were significantly higher on FAPI imaging than FDG imaging (p < 0.05). However, SUVmax values of hepatic metastases did not exhibit a statistically significant difference between two imaging techniques (p > 0.05). Also, FAPI imaging yielded significantly higher TBR in breast lesions as well as hepatic, bone, brain and lung metastases compared to FDG (p < 0.05). 68Ga-FAPI-04 PET/CT is superior to 18F-FDG PET/CT in detecting the primary tumor in patients with breast cancer with its high sensitivity, high SUVmax, and high TBR. 68Ga-FAPI-04 PET/CT is also superior to 18F-FDG PET/CT in detecting lymph node, hepatic, bone, and cerebral metastases because it has lower background activity and higher uptake in subcentimetric lesions.

Evaluation of Ac-Lys0(IRDye800CW)Tyr3-octreotate as a novel tracer for SSTR2-targeted molecular fluorescence guided surgery in meningioma

PurposeMeningioma recurrence rates can be reduced by optimizing surgical resection with the use of intraoperative molecular fluorescence guided surgery (MFGS). We evaluated the potential of the fluorescent tracer 800CW-TATE for MFGS using in vitro and in vivo models. It targets somatostatin receptor subtype 2 (SSTR2), which is overexpressed in all meningiomas.MethodsBinding affinity of 800CW-TATE was evaluated using [177Lu] Lu-DOTA-Tyr3-octreotate displacement assays. Tumor uptake was determined by injecting 800CW-TATE in (SSTR2-positive) NCI-H69 or (SSTR2-negative) CH-157MN xenograft bearing mice and FMT2500 imaging. SSTR2-specific binding was measured by comparing tumor uptake in NCI-H69 and CH-157MN xenografts, blocking experiments and non-targeted IRDye800CW-carboxylate binding. Tracer distribution was analyzed ex vivo, and the tumor-to-background ratio (TBR) was calculated. SSTR2 expression was determined by immunohistochemistry (IHC). Lastly, 800CW-TATE was incubated on frozen and fresh meningioma specimens and analyzed by microscopy.Results800CW-TATE binding affinity assays showed an IC50 value of 72 nM. NCI-H69 xenografted mice showed a TBR of 21.1. 800CW-TATE detection was reduced after co-administration of non-fluorescent DOTA-Tyr3-octreotate or administration of IRDye800CW. CH-157MN had no tumor specific tracer staining due to absence of SSTR2 expression, thereby serving as a negative control. The tracer bound specifically to SSTR2-positive meningioma tissues representing all WHO grades.Conclusion800CW-TATE demonstrated sufficient binding affinity, specific SSTR2-mediated tumor uptake, a favorable biodistribution, and high TBR. These features make this tracer very promising for use in MFGS and could potentially aid in safer and a more complete meningioma resection, especially in high-grade meningiomas or those at complex anatomical localizations.

Radiation Dosimetry of 99mTc-PSMA I&amp;S: A Single-Center Prospective Study

99mTc-PSMA I&S is a prostate-specific membrane antigen (PSMA) tracer that can be used for planar and SPECT/CT γ-imaging and radioguided surgery. The primary aim of this study was to estimate the dosimetry of 99mTc-PSMA I&S using a hybrid method (sequential γ-planar imaging and 1 single SPECT/CT) in healthy volunteers. The secondary aim was to depict the tracer biodistribution and tumor-to-background ratios (TBRs) in patients with prostate cancer (PCa). Methods: Dosimetry of 99mTc-PSMA I&S was investigated in 4 healthy volunteers. Whole-body planar imaging was acquired at 1, 2, 3, 6, and 24 h and SPECT/CT at 6 h after tracer injection. Contours of organs were drawn on all acquisitions to determine organ activity at each time point. Absorbed dose was estimated using 2 methods: independent curve-fitting manual method (Levenberg-Marquardt-based algorithm using dose factors from RAdiation Dose Assessment Resource [RADAR] website) and OLINDA/EXM software (version 2.0; HERMES Medical Solutions). Biodistribution of 99mTc-PSMA I&S was assessed in 10 patients with PCa on SPECT/CT images at 6 h. Tumor uptake (SUVmax), and TBR (tumor SUVmax/background organ SUVmean) using muscle (T/M), bladder (T/B), and intestine (T/I) as background organs were determined. Results: The mean injected activity of 99mTc-PSMA I&S was 717 MBq (range: 562-828 MBq). No adverse events related to the injection of 99mTc-PSMA I&S were reported. The average radiation effective dose was 0.0055 mSv/MBq with the RADAR manual method and 0.0052 mSv/MBq with OLINDA/EXM. Total body effective dose ranged between 3.33-4.42 and 3.11-4.23 mSv, respectively. All PCa patients showed high tracer uptake in primary and metastatic lesions with T/M, T/B, and T/I ranging from 5.29-110, 0.11-7.02, and 0.96-16.30, respectively. Conclusion: Effective doses of 99mTc-PSMA I&S were comparable to those known for most of the 99mTc tracers and was lower than for the 68Ga-labeled and 18F-labeled agents. 99mTc-PSMA I&S SPECT/CT showed high TBR in PCa patients. This study can provide required data for translation and approval of 99mTc-PSMA I&S by regulatory agencies.

Radiation Dosimetry and Biodistribution of 68Ga-FAPI-46 PET Imaging in Cancer Patients.

Targeting cancer-associated fibroblasts (CAFs) has become an attractive goal for diagnostic imaging and therapy because they can constitute as much as 90% of a tumor mass. The serine protease fibroblast activation protein (FAP) is overexpressed selectively in CAFs, drawing interest in FAP as a stromal target. The quinoline-based FAP inhibitor (FAPI) PET tracer 68Ga-FAPI-04 has been previously shown to yield high tumor-to-background ratios (TBRs) in patients with various cancers. Recent developments toward an improved compound for therapeutic application have identified FAPI-46 as a promising agent because of an increased tumor retention time in comparison with FAPI-04. Here, we present a PET biodistribution and radiation dosimetry study of 68Ga-FAPI-46 in cancer patients. Methods: Six patients with different cancers underwent serial 68Ga-FAPI-46 PET/CT scans at 3 time points after radiotracer injection: 10 min, 1 h, and 3 h. The source organs consisted of the kidneys, bladder, liver, heart, spleen, bone marrow, uterus, and remainder of body. OLINDA/EXM software, version 1.1, was used to fit and integrate the kinetic organ activity data to yield total-body and organ time-integrated activity coefficients and residence times and, finally, organ-absorbed doses. SUVs and TBR were generated from the contoured tumor and source-organ volumes. Spheric volumes in muscle and blood pool were also obtained for TBR (tumor SUVmax/organ SUVmean). Results: At all time points, average SUVmax was highest in the liver. Tumor and organ SUVmean decreased over time, whereas TBRs in all organs but the uterus increased. The organs with the highest effective doses were bladder wall (2.41E-03 mSv/MBq), followed by ovaries (1.15E-03 mSv/MBq) and red marrow (8.49E-04 mSv/MBq). The average effective total-body dose was 7.80E-03 mSv/MBq. Conclusion:68Ga-FAPI-46 PET/CT has a favorable dosimetry profile, with an estimated whole-body dose of 5.3 mSv for an administration of 200 MBq (5.4 mCi) of 68Ga-FAPI-46 (1.56 ± 0.26 mSv from the PET tracer and 3.7 mSv from 1 low-dose CT scan). The biodistribution study showed high TBRs increasing over time, suggesting high diagnostic performance and favorable tracer kinetics for potential therapeutic applications.

124I]CLR1404 PET/CT in High-Grade Primary and Metastatic Brain Tumors.

There is a continuous search for imaging techniques with high sensitivity and specificity for brain tumors. Positron emission tomography (PET) imaging has shown promise, though many PET agents either have a low tumor specificity or impractical physical half-lives. [124I]CLR1404 is a small molecule alkylphosphocholine analogue that is thought to bind to plasma membrane lipid rafts and has shown high tumor-to-background ratios (TBR) in a previous pilot study in brain tumor patients. This study attempts to define the clinical value of [124I]CLR1404 PET/CT (aka CLR124). Adult patients with new or suspected recurrence of high-grade primary or metastatic brain tumors (N = 27) were injected with [124I]CLR1404 followed by PET/CT at 6, 24, and 48h. Standard uptake values (SUV) and TBR values were calculated for all time points. Uptake of [124I]CLR1404 was qualitatively assessed, compared with magnetic resonance imaging (MRI), and correlated with clinical outcome. Final diagnosis (N = 25) was established based on surgically resected tissue or long-term follow-up. Positive uptake with high TBR was detected in all but one patient with a final diagnosis of primary/recurrent brain tumor (12/13) and in less than half of patients with treatment-related changes (5/12). Concordance between [124I]CLR1404 uptake and contrast enhancement on MRI was seen in < 40%, with no concordance between T2-hyperintensities and uptake. No significant difference in overall outcome was found between patients with and without [124I]CLR1404 uptake. The uptake pattern in these patients suggests a very high sensitivity of [124I]CLR1404 PET/CT for diagnosing tumor tissue; however, tumor specificity needs to be further defined. Relative lack of concordance with standard MRI characteristics suggests that [124I]CLR1404 PET/CT provides additional information about brain tumors compared to MRI alone, potentially improving clinical decision-making.