Tumor-to-background Ratio Research Articles

Combined early dynamic 18F-FDG PET/CT and conventional whole-body 18F-FDG PET/CT in hepatocellular carcinoma.

To investigate the diagnostic value of early dynamic 18F-FDG PET/CT(ED 18F-FDG PET/CT) combined with conventional whole-body 18F-FDG PET/CT(WB 18F-FDG PET/CT) in hepatocellular carcinoma (HCC), as well as the difference of early dynamic blood flow parameters and maximum standardized uptake value (SUVmax) in HCC patients with/without liver cirrhosis or microvascular invasion (MVI). Twenty-two consecutive patients (mean age 57.8years) with 28 established HCC lesions (mean size 4.5cm) underwent a blood flow study with an 18F-FDG dynamic scan divided into 24 sequences of 5s each and a standard PET/CT scan. On the ED PET/CT study, an experienced PET/CT physician obtained volumes of interest (VOIs) where three blood flow estimates (time to peak [TTP], blood flow [BF], and hepatic perfusion index [HPI]) were calculated. On the WB PET/CT study, a VOI was placed on the fused scan for each HCC and maximum standardized uptake value (SUVmax) was obtained. Comparison of blood flow estimates, SUVmax, and tumor/background ratio (TNR) was performed among HCCs with and without angioinvasion, as well as HCCs in cirrhotic and non-cirrhotic liver. Compared with WB 18F-FDG PET/CT alone, ED combined with WB 18F-FDG PET/CT can significantly increase the detection rate of moderately differentiated and poorly differentiated HCCs (both P < 0.05). HPI was higher in HCCs in patients with liver cirrhosis than those without liver cirrhosis (P = 0.044). There was no significant difference in TTP, BF, SUVmax, or TNR between HCCs in patients with liver cirrhosis and those without liver cirrhosis. There was no significant difference in blood flow estimates or SUVmax in background liver parenchyma between patients with and those without cirrhosis. TTP was shorter in HCCs with MVI than without MVI (P = 0.046). There was no significant difference in BF, HPI, SUVmax, or TNR between HCCs with MVI and without MVI. There was no significant difference in blood flow estimates or SUVmax in background liver parenchyma between patients with and those without MVI. ED combined with WB 18F-FDG PET/CT can significantly increase the detection rate of moderately differentiated and poorly differentiated HCCs. HPI was significantly higher in HCCs in patients with liver cirrhosis than those without liver cirrhosis. TTP was significantly shorter in HCCs with MVI than without MVI.

Fluorescence guided surgery using indocyanine green for pulmonary osteosarcoma metastasectomy in pediatric patients: A feasibility study

BackgroundIn osteosarcoma patients, resection of pulmonary metastases is considered necessary for long term survival. Radiologically detected lesions are sometimes difficult to identify intraoperatively, especially when no palpation is possible during thoracoscopy. In adults, fluorescence guided surgery (FGS) using indocyanine green (ICG) has been shown to be a safe method for intra-operative identification of pulmonary metastases of different primary tumors. Our aim is to determine the feasibility of using ICG for identification of pulmonary metastases in pediatric osteosarcoma patients. MethodsNine consecutive patients with pulmonary metastases received an intravenous dose of ICG 24 h preoperatively. We started with the adult dosage of 0.5 mg/kg and also used 1.0 mg/kg to confirm that maximum fluorescent signal was achieved. Intra-operatively and post-operatively, lesions were visualized with a near-infrared camera system. Fluorescence was quantified by calculating a tumor-to-background ratio (TBR). ResultsTwo (22%) patients underwent a thoracoscopy and seven (78%) underwent a thoracotomy. Five (56%) patients had a fluorescent metastasis during surgery. In four (44%) patients there were no fluorescent metastases. In two the metastases were necrotic. In the other two, intraoperative fluorescence was most likely hampered by the depth of the metastases. Ex vivo, all vital metastases were fluorescent and necrotic specimens were not. There was no difference between 1.0 mg/kg and 0.5 mg/kg concerning TBR. No adverse events occurred. ConclusionsICG for fluorescence guided metastasectomy of pulmonary osteosarcoma is a feasible procedure in the pediatric population. However, its additional value in intra-operative guidance still has to be investigated. Levels of evidenceLevel III evidence based on a Diagnostic test study: study without a universally applied “gold” standard.

Head-to-Head Comparison of [68Ga]Ga-DOTA.SA.FAPi and [68Ga]Ga-DOTANOC Positron Emission Tomography/Computed Tomography Imaging for the Follow-Up Surveillance of Patients with Medullary Thyroid Cancer.

Background: A theranostic probe for accurate staging and treatment is crucial for the management of medullary thyroid cancers (MTCs). The abundance of stroma in most of thyroid cancers, including MTC, opens new avenues for selecting cancer-associated fibroblasts (CAFs) as new molecular imaging and therapeutic targets. [68Ga]Ga-labeled fibroblast activation protein inhibitor (FAPi) molecules have gained importance as alternative molecular imaging agents in the imaging of thyroid cancers. The purpose of this study was to compare the detection efficiency of primary and metastatic lesions of MTCs between [68Ga]Ga-DOTA.SA.FAPi and [68Ga]Ga-DOTANOC positron emission tomography (PET) radiotracers. Materials and Methods: In this retrospective study, [68Ga]Ga-DOTANOC and [68Ga]Ga-DOTA.SA.FAPi PET/CT (computed tomography) images were compared using patient-based and lesion-based analysis in patients with MTC for follow-up assessment. The quantitative assessment included comparing standardized uptake values corrected for lean body mass (SULpeak) and tumor-to-background ratios (TBR). The findings on both scans were validated with the morphological findings of the diagnostic CT. Results: Twenty-seven patients (21 males and 6 females) with a mean age of 42.4 ± 13.2 years (range 14-66 years) were included in the study. [68Ga]Ga-DOTA.SA.FAPi had similar sensitivities as that of [68Ga]Ga-DOTANOC PET/CT for detecting primary tumors (100% [18 of 18] vs. 94.4% [17 of 18], p = 0.979) involved lymph nodes (98.3% [118 of 120] vs. 95% [114 of 120], p = 0.288), and brain metastases (100%). [68Ga]Ga-DOTA.SA.FAPi demonstrated significantly higher sensitivities than [68Ga]Ga-DOTANOC PET/CT for detecting lung nodules (93.5% [87 of 93] vs. 68.9% [64 of 93], p < 0.0001), liver (100% [105 of 105] vs. 46.4% [49 of 105], p < 0.0001), bone (92.4% [110 of 119] vs. 76.5% [91 of 119], p = 0.001), and pleural metastases 98.2% versus 0%. Higher uptake values and TBR values were reported with [68Ga]Ga-DOTA.SA.FAPi compared with that of [68Ga]Ga-DOTANOC. Conclusion: [68Ga]Ga-DOTA.SA.FAPi outperformed [68Ga]Ga-DOTANOC PET/CT in the detection of distant metastases with both patient-based and lesion-based analysis in MTCs.

Head-to-Head Intra-Individual Comparison of Biodistribution and Tumor Uptake of [18F]FAPI-74 with [18F]FDG in Patients with PDAC: A Prospective Exploratory Study.

Radiolabeled fibroblast activation protein (FAP) ligands, a novel class of tracers for PET/CT imaging, have demonstrated very promising results in various oncological, as well as in some benign, diseases with long-term potential to supplant the current pan-cancer agent [18F]FDG in some cancer types. Pancreatic ductal carcinoma (PDAC) belongs to the group of epithelial malignancies with a strong so-called "desmoplastic reaction", leading to a prominent tumor stroma with cancer-associated fibroblasts that exhibit a marked overexpression of fibroblast activation protein (FAP). The first clinical experiences in PDAC with 68Ga-labeled FAP ligands suggested superior sensitivity to [18F]FDG. However, there is limited data with 18F-labeled FAP derivatives, i.e. [18F]FAPI-74, yet prospective single- and multicenter trials are already ongoing. In this proof-of-concept study, we sought to evaluate the biodistribution, tumor uptake, and lesion detectability in patients with PDAC using [18F]FAPI-74 PET/CT as compared to [18F]FDG PET/CT scans for staging. This study includes 7 patients (median age 69) who underwent both [18F]FDG PET/CT with contrast-enhancement and [18F]FAPI-74 PET with low-dose CT for primary staging (n = 3) and therapy response control after neoadjuvant (n = 1) or re-staging after palliative therapy (n = 3). The mean interval between PET scans was 11 ± 4 days (range 1-15 days). The [18F]FDG and [18F]FAPI-74 PET/CT scans were acquired at 64 ± 4.1 min (range 61-91 min) and 66.4 ± 6.3 min (range 60-76 min), respectively, after administration of 200 ± 94 MBq (range 79-318 MBq) and 235 ± 88 MBq (range 90-321 MBq), respectively. Quantification of tracer uptake was determined with SUVmax and SUVmean. Furthermore, the tumor-to-background ratio (TBR) was derived by dividing the SUVmax of tumor lesions by the SUVmax of adipose tissue, skeletal muscle, and blood pool. Overall, 32 lesions were detected in 7 patients including primary (n = 7), lung (n = 7), bone (n = 3), lymph node (n = 13), and peritoneal metastases (n = 2). [18F]FAPI-74 detected 22% more lesions compared with [18F]FDG with a better TBR and visual lesion delineation. In one patient the primary lesion could be detected unequivocally with [18F]FAPI-74 but was missed by [18F]FDG imaging. Altogether, most of the lesions demonstrated markedly elevated uptake of [18F]FAPI-74 with a simultaneous lower uptake in the background, providing a very high visual contrast. To the best of our knowledge, this is the first, prospective, intra-individual investigation comparing [18F]FAPI-74 with [18F]FDG imaging in PDAC with encouraging results. These pivotalresults supporta larger, multicentric, prospective study to determine the value of [18F]FAPI-74 in detecting and staging PDAC in comparison with current standard of care imaging.

Biodistribution and radiation dosimetry in cancer patients of the ascorbic acid analogue 6-Deoxy-6-[18F] fluoro-L-ascorbic acid PET imaging: first-in-human study.

Clinical studies on the use of ascorbic acid (AA) have become a hot spot in cancer research. There remains an unmet need to assess AA utilization in normal tissues and tumors. 6-Deoxy-6-[18F]fluoro-L-ascorbic acid ([18F]DFA) displayed distinctive tumor localization and similar distribution as AA in mice. In this study, to evaluate the distribution, tumor detecting ability and radiation dosimetry of [18F]DFA in humans, we performed the first-in-human PET imaging study. Six patients with a variety of cancers underwent whole-body PET/CT scans after injection of 313-634MBq of [18F]DFA. Five sequential dynamic emission scans in each patient were acquired at 5-60min. Regions of interest (ROI) were delineated along the edge of the source-organ and tumor on the transverse PET slice. Tumor-to-background ratio (TBR) was obtained using the tumor SUVmax to background SUVmean. Organ residence times were calculated via time-activity curves, and human absorbed doses were estimated from organ residence time using the medical internal radiation dosimetry method. [18F]DFA was well tolerated in all subjects without serious adverse event. The high uptake was found in the liver, adrenal glands, kidneys, choroid plexus, and pituitary gland. [18F]DFA accumulated in tumor rapidly and the TBR increased over time. The average SUVmax of [18F]DFA in tumor lesions was 6.94 ± 3.92 (range 1.62-22.85, median 5.94). The organs with the highest absorbed doses were the liver, spleen, adrenal glands, and kidneys. The mean effective dose was estimated to be 1.68 ± 0.36 E-02mSv/MBq. [18F]DFA is safe to be used in humans. It showed a similar distribution pattern as AA, and displayed high uptake and retention in tumors with appropriate kinetics. [18F]DFA might be a promising radiopharmaceutical in identifying tumors with high affinity for SVCT2 and monitoring AA distribution in both normal tissues and tumors. Chinese Clinical Trial Registry; Registered Number: ChiCTR2200057842 (registered 19 March 2022).

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.

Clinical Evaluation of 68Ga-FAPI-RGD for Imaging of Fibroblast Activation Protein and Integrin αvβ3 in Various Cancer Types.

Radiolabeled fibroblast activation protein (FAP) inhibitors (FAPIs) and Arg-Gly-Asp (RGD) peptides have been extensively investigated for imaging of FAP- and integrin αvβ3-positive tumors. In this study, a FAPI-RGD heterodimer was radiolabeled with 68Ga and evaluated in patients with cancer. We hypothesized that the heterodimer, recognizing both FAP and integrin αvβ3, would be advantageous because of its dual-receptor-targeting property. Methods: The effective dose of 68Ga-FAPI-RGD was evaluated in 3 healthy volunteers. The clinical feasibility of 68Ga-FAPI-RGD PET/CT was evaluated in 22 patients with various types of cancer, and the results were compared with those of 18F-FDG and 68Ga-FAPI-46. Results: 68Ga-FAPI-RGD was tolerated well, with no adverse events in any of the healthy volunteers or patients. The effective dose from 68Ga-FAPI-RGD PET/CT was 1.01 × 10-2 mSv/MBq. In clinical investigations with different types of cancer, the radiotracer uptake and tumor-to-background ratio (TBR) of primary and metastatic lesions in 68Ga-FAPI-RGD PET/CT were significantly higher than those in 18F-FDG PET/CT (primary tumors: SUVmax, 18.0 vs. 9.1 [P < 0.001], and TBR, 15.2 vs. 5.5 [P < 0.001]; lymph node metastases: SUVmax, 12.1 vs. 6.1 [P < 0.001], and TBR, 13.3 vs. 4.1 [P < 0.001]), resulting in an improved lesion detection rate and tumor delineation, particularly for the diagnosis of lymph node (99% vs. 91%) and bone (100% vs. 80%) metastases. 68Ga-FAPI-RGD PET/CT also yielded a higher radiotracer uptake and TBR than 68Ga-FAPI-46 PET/CT did. Conclusion: 68Ga-FAPI-RGD exhibited improved tumor uptake and TBR compared with 18F-FDG and 68Ga-FAPI PET/CT. This study demonstrated the safety and clinical feasibility of 68Ga-FAPI-RGD PET/CT for imaging of various types of cancer.

Acidic tumor microenvironment-activatable fluorescent diagnostic probe for the rapid identification and resection of human tumors via spraying

A fluorescent diagnostic probe for real-time intraoperative image-guided tumor resection can significantly improve the efficiency and quality of oncological therapy, but their development is challenging. Herein, a novel fluorescent diagnostic probe called HLTC based on β-carboline was designed and synthesized. HLTC was found to show a ∼10-fold enhancement of fluorescence quantum field with pH from 7.4 to 4.0, indicating its imaging potential in acid environment which is a typical hallmark of the tumor microenvironment (TME). Following fluorescence microscopy imaging showed HLTC could emit specific signals in cancer cells and sections, by both one-photon excitation and two-photon excitation. Importantly, HLTC enabled the precise and rapid delineation of both transplanted tumor and clinical tumor tissues within several minutes of simple topical spray. The tumor-to-background ratio (TBR) was up to 10.2 ± 1.0 at clinical liver cancer tissues and 9.9 ± 0.3 at clinical colon cancer tissues, allowing precise tumor margin identification and the effective guidance of surgical tumor resection. Furthermore, CCK8 assay, pharmacokinetic evaluation, blood analysis and H&E staining were performed, which verified high biocompatibility and biosafety of HLTC at working concentration. These results reveal the exciting potential of this small-molecule fluorescent diagnostic probe for real-time fluorescence-based navigation during surgical tumor resection.

NIRDye 812: A molecular platform tailored for multimodal bioimaging applications of targeted fluorescence- and photoacoustic-guided surgery.

The primary treatment for malignant tumors remains to be surgical removal of the diseased tissue. The presence or absence of residual diseased tissue at the tumor margin is the strongest predictor of postoperative prognosis and recurrence. Accordingly, reliance on the ability of surgeons to visually distinguish diseased tissue from healthy tissue unambiguously in real time is crucial. Near infrared-I (NIRI) fluorescence-emitting targeting biomolecular constructs such as anticancer antibody-fluorophore conjugates, namely cetuximab-IRDye® 800CW (CTB-IRDye® 800CW), are FDA-approved for clinical trial usage in the fluorescence-guided resection of diseased tissue due to affording improved direct visualization of tumor tissue when compared to the use of either the unaided eye under standard white light illumination (WLI) surgical techniques or non-targeting fluorophores. Unfortunately, though helpful, CTB-IRDye® 800CW affords limited (i) identification of diseased tissue and (ii) tumor margin delineation, because the immunoconjugate generates suboptimal tumor-to-background ratios (TBRs) as a result of its spectral/photophysical profiles poorly aligning with the fixed optical windows of pre-/clinical setups. As such, CTB-IRDye® 800CW is more prone to affording incomplete resection compared to if TBRs were higher due to otherwise. To aid in accurately identifying deep-seated diseased tissue, photoacoustic (PA) tomography has been implemented alongside CTB-IRDye® 800CW to achieve PA signals that could result in higher TBRs. However, in clinical trial practice, using IRDye® 800CW for PA imaging also yields subpar TBRs due to it affording low PA signals. To overcome such limitations, we developed NIRDye 812, a structurally-modified topological equivalent of IRDye® 800CW, to confer it the capability to yield both higher TBRs and superior PA signal than that of the equivalent CTB-conjugate and fluorophore IRDye® 800CW itself, respectively. To do so, we substituted the oxygen atom at its meso-position with a sulfur atom. CTB-NIRDye 812 demonstrated a red-shifted absorption wavelength at 796nm and a peak NIR-I fluorescence emission wavelength at 820nm, which better dovetails with the fixed windows of preinstalled fixed emission filters within commercial pre-/clinical NIR-I fluorescence imaging instruments. Overall, CTB-NIRDye 812 provided a∼2-fold increase in TBRs compared to those of CTB-IRDye® 800CW in vivo. Also, NIRDye 812 displayed an ∼60% higher PA signal than that of IRDye® 800CW. Collectively, we achieved our goal of improving upon the spectral/photophysical and PA properties of IRDye® 800CW via introducing a subtle modification to its electronic core such that its CTB immunoconjugate could potentially allow for fast track or breakthrough designation by the FDA due to its near-identical structure displaying considerably improved efficacy.

Near-Infrared Fluorescent Hydroxyapatite Nanoparticles for Targeted Photothermal Cancer Therapy.

Near-infrared (NIR) fluorophores have attracted great attention due to their excellent optical and photothermal properties. Among them, a bone-targeted NIR fluorophore (named P800SO3) contains two phosphonate groups, which play important roles in binding with hydroxyapatite (HAP) as the main mineral component of bones. In this study, biocompatible and NIR fluorescent HAP nanoparticles functionalized with P800SO3 and polyethylene glycol (PEG) were readily prepared for tumor-targeted imaging and photothermal therapy (PTT). The PEGylated HAP nanoparticle (HAP800-PEG) demonstrated improved tumor targetability with high tumor-to-background ratios (TBR). Moreover, the HAP800-PEG also showed excellent photothermal properties, and the temperature of tumor tissue reached 52.3 °C under NIR laser irradiation, which could completely ablate the tumor tissue without recurrence. Therefore, this new type of HAP nanoparticle has great potential as a biocompatible and effective phototheranostic material, which enables the use of P800SO3 for targeted photothermal cancer treatment.

Impact of uptake time on image quality of [68 Ga]Ga-PSMA-11 PET/CT.

With the introduction of prostate specific membrane antigen (PSMA) PET/CT, the detection rate of prostate cancer metastases has improved significantly, both for primary staging and for biochemical recurrence. EANM/SNMMI guidelines recommend a 60min time interval between [68 Ga]Ga-PSMA administration and acquisition. This study evaluates the possibility of a shorter time interval by investigating the dynamic change in image quality measures. We retrospectively analyzed 10 consecutive prostate cancer patients who underwent a dynamic whole body [68 Ga]Ga-PSMA-11 PET/CT of 75min from skull vertex to mid-thigh using Siemens FlowMotion. PET images were acquired directly after injection of 1.5MBq/kg [68 Ga]Ga-PSMA-11. Image quality measures included lesion maximum standardized uptake value corrected for lean body mass (SULmax ), tumor-to-background ratio (TBR), and contrast-to-noise ratio (CNR). Quantitative analysis of image quality in dynamic PET was performed using PMOD (version 4.2). Regions of interest (ROIs), drawn included different types of prostate lesions (primary tumor, lymph nodes, and bone metastasis), organ tissue (liver, spleen, lacrimal gland, submandibular gland, parotid gland, urinary bladder, kidneys blood pool [ascending aorta], left ventricle), bone tissue (4th lumbar vertebral body [L4]) and muscle tissue (gluteus maximus). To further investigate image quality four 10min multi-frame reconstructions with clinical parameters were made at different post-injection times (15, 30, 45, and 60min). A nuclear medicine physician performed a blinded lesion detectability evaluation on these multi-frame reconstructions for different prostate cancer lesions. Six primary prostate tumors in seven patients with prostate in situ, 13 lymph node metastases in six patients and up to 12 bone metastases in three patients were found. The different prostate lesion types (lymph nodes metastases, bone metastases, and primary prostate tumor) all show an increase in average SULmax , TBR, and CNR over time during the scan. The normalized average SULmax , TBR, and CNR of the combined prostate lesions at 15, 30, and 45min post-injection scans were all significant p<0.05 lower from the 60min post-injection [68 Ga]Ga-PSMA-11 PET/CT (9.5±4.5, 12.7±6.2, and 41.8±24.5, respectively). At patient level, the reader concluded the same regarding the presence/absence of primary prostate cancer recurrence, lymph node metastases, and/or bone metastases on all <60min post-injection [68 Ga]Ga-PSMA-11 PET/CT's in comparison to the reference scan (60min post-injection). At lesion level, all bone metastases seen on the reference scan were also seen on all <60min post-injection [68 Ga]Ga-PSMA-11 PET/CT's but there were some lymph nodes (n=2) metastases missed on the 15, 30, and 45min post-injection scans. One lymph node metastasis on both the 15 and 30min post-injection [68 Ga]Ga-PSMA-11 PET/CT's was missed and one lymph node metastasis was missed, only on the 45min post-injection [68 Ga]Ga-PSMA-11 PET/CT. Shorter post-injection times (15, 30, and 45min) compared to the recommended post-injection time of 60min are not optimal. However, the impact of a shorter time interval of 45min instead of 60min between [68 Ga]Ga-PSMA-11 administration and the start of PET/CT acquisition on both image quality (SULmax , TBR, and CNR) and lesion detection, while significant, is small.

Abstract 2380: Fluorescence labeling of human gastric cancer using novel tumor specific near infrared labeled antibodies

Abstract Introduction: Gastric cancer has a global incidence of ~1 million cases per year. Currently, complete surgical resection is the only opportunity for cure for patients. Bright labeling of tumor margins with tumor specific markers could improve outcomes. This report demonstrates the advantages of targeting gastric cancer with humanized anti-CEA and TAG-72 antibodies in mouse models. Methods: A cell line of human gastric cancer, MKN45, and a patient-derived tumor, KG8, were used to create xenograft models. To establish orthotopic models for each, ~1mm tumor fragments were harvested from subcutaneous models of these lines and sutured to the lesser curvature of the stomach. Humanized versions of TAG-72 (huCC44) and CEA (M5A) were conjugated to the near infrared dye IRDye800CW. IgG was conjugated to IRDye800CW and used as a control. For CEA-IR800 and IgG-IR800, mice received 50 µg IV and were imaged after 72 hours. For Tag72-IR800, mice received 75 µg IV and were imaged after 96 hours. Fluorescence imaging was performed on the mice using the LI-COR Pearl Imaging System. A tumor to background ratio (TBR) was calculated by dividing mean fluorescence intensity of the tumor versus normal gastric tissue. Results: Humanized anti-CEA and TAG-72 brightly labeled multiple mouse models of human gastric cancer (Table 1). The TBR for TAG-72 labeling of KG8 was 2.777. CEA had a superior TBR of 3.528 compared to 0.606 for the control (IgG) in KG8 models. In MKN models labelled with CEA, an excellent average TBR of 7.407 were seen compared to 0.668 for the control. Conclusion: Humanized anti-CEA and TAG-72 antibodies conjugated to near-infrared fluorescent dyes provide specific labeling of gastric cancers in orthotopic models. These tumor-specific fluorescent antibodies are promising potential clinical tools for visualization of gastric cancer margins at the time of surgical resection and improved surgical outcomes. Orthotopic Model Antibody Tumor to Background Ratio KG8 anti-TAG-72 2.777 KG8 anti-CEA 3.528 KG8 Control 0.606 MKN anti-CEA 7.407 MKN Control 0.668 Citation Format: Kristin E. Cox, Michael A. Turner, Siamak Amirfakhri, Thinzar M. Lwin, Pradipta Ghosh, Marygorret Obonyo, Kaitlyn M. Kelly, Robert M. Hoffman, Paul J. Yazaki, Michael Bouvet. Fluorescence labeling of human gastric cancer using novel tumor specific near infrared labeled antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2380.

Abstract 3576: Molecular imaging of CD8 infiltration following combination immunotherapy in preclinical glioblastoma

Abstract Background: Novel immune-promoting therapeutics for glioblastoma multiforme (GBM), such as oncolytic herpes simplex viruses (oHSV) and immune checkpoint inhibitors (ICI), have the potential to improve overall survival and lead to long-term remission, however their clinical benefit remains inconsistent. Under standard of care imaging, assessment of immunotherapeutic response can be limited by apparent radiological tumor progression associated with treatment-induced inflammation and immune infiltration. This has led to a need for better understanding of immune cell dynamics and immunotherapy response in GBM. The objective of this study is to evaluate changes in CD8+ infiltration and its relation to therapy response, through positron emission tomography (PET) imaging, in preclinical GBM. Methods: GSC005-luc orthotopic GBM models (n= 40) were treated with saline, M002 oHSV, anti-PD1 or combination immunotherapy following three weeks of tumor growth. One-week post-treatment, [89Zr]-CD8 PET imaging was performed and biologically validated through ex vivo PET, autoradiography and staining for H&amp;E and CD8 immunohistochemistry (IHC). Further, longitudinal changes in CD8 infiltration were evaluated via [89Zr]-CD8 PET imaging one- and three-weeks post-immunotherapy with responses monitored every three days via bioluminescence imaging (BLI). Statistical analysis involved one-way ANOVA and unpaired T-test, with p&amp;lt;0.05 considered significant. Results: Linear correlations were seen between in vivo PET signal and ex vivo uptake (r=0.61, p&amp;lt;0.01), autoradiography (r=0.46, p&amp;lt;0.01), and IHC tumor CD8+ cell density (r=0.55, p&amp;lt;0.01) one-week post-treatment. Immunotherapy efficacy, defined by decreased BLI signal, resembled clinical findings as only a subset of mice exhibited long-term positive response measured by BLI signal decrease (n=9/24). Response classification revealed increased CD8+ cell tumor localization, as measured by peak standardized uptake value (SUVpeak) tumor to background ratio (TBR), in non-responders (p&amp;lt;0.01) and decreased heterogeneity in signal distribution in responders (p&amp;lt;0.05) relative to controls early in the course of therapy. Conclusions: Early CD8 infiltration and uptake distribution from CD8-PET imaging provides potential imaging metrics of therapeutic response to oHSV immunotherapy in GBM. Development of these immune-focused imaging approaches for the assessment of positive immunotherapeutic effects in GBM is beneficial for the better understanding of immune cell dynamics and their relation to clinical outcomes. Citation Format: Carlos A. Gallegos, Yun Lu, Alessandro Mascioni, Fang Jia, Jennifer C. Clements, Patrick N. Song, Shannon E. Lynch, Jason M. Warram, James M. Markert, Anna Sorace. Molecular imaging of CD8 infiltration following combination immunotherapy in preclinical glioblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3576.

Indocyanine green fluorescence imaging to localize insulinoma and provide three-dimensional demarcation for laparoscopic enucleation: a retrospective single-arm cohort study.

Indocyanine green (ICG) fluorescence imaging is a new technology that can improve the real-time location of tumor edges and small nodules during surgery. However, no study has investigated its application in laparoscopic insulinoma enucleation. This study aimed to evaluate the feasibility and accuracy of this method for intraoperative localization of insulinomas and margin assessment during laparoscopic insulinoma enucleation. Eight patients who underwent laparoscopic insulinoma enucleation from October 2016 to June 2022 were enrolled. Two methods of ICG administration, ICG dynamic perfusion and three-dimensional (3D) demarcation staining, were utilized in the laparoscopic insulinoma enucleation. Tumor-to-background ratio (TBR) and histopathologic analysis were used to evaluate the feasibility and accuracy of these novel navigation methods in laparoscopic insulinoma enucleation. All eight enrolled patients underwent both ICG dynamic perfusion and 3D demarcation staining. ICG dynamic perfusion images were available for six of them, among which five tumors could be recognized by TBR (largest TBR in each case 4.42±2.76), while the other could be distinguished by the disordered blood vessels in the tumor area. Seven out of eight specimens had successful 3D demarcation staining (TBR 7.62±2.62). All wound bed margins had negative frozen sections and final histopathologic diagnoses. ICG dynamic perfusion may be helpful in observing the abnormal vascular perfusion of tumors, providing similar functionality to intraoperative real-time angiography. ICG injection under the tumor pseudocapsule may be a useful method for acquiring real-time, 3D demarcation for the resection of insulinoma.

Head-to-Head Comparison between [68Ga]Ga-DOTA.SA.FAPi and [18F]F-FDG PET/CT Imaging in Patients with Breast Cancer.

This study aimed to compare the diagnostic performance of [68Ga]Ga-DOTA.SA.FAPi with that of [18F]F-FDG PET/CT in detecting primary and metastatic lesions of breast cancer. [18F]F-FDG and [68Ga]Ga-DOTA.SA.FAPi PET/CT scans of histologically proven breast cancer patients were compared according to patient-based and lesion-based analysis. Forty-seven patients with a mean age of 44.8 ± 9.9 years (range: 31-66 years) were evaluated. A total of 85% of patients had invasive ductal carcinoma, and 15% had invasive lobular carcinoma. The tracer uptake [SULpeak, SULavg, and the median tumor-to-background ratio (TBR)] was significantly higher in [68Ga]Ga-DOTA.SA.FAPi than with [18F]F-FDG PET/CT for lymph nodes, pleural metastases, and liver lesions (p < 0.05). However, for brain metastasis, only the median TBR was significantly higher (p < 0.05) compared to [18F]F-FDG. In patient-based analysis the sensitivity of [68Ga]Ga-DOTA.SA.FAPi PET/CT was higher, but not significant than that of [18F]F-FDG PET/CT in the detection of both primary tumors and metastatic lesions. According to lesion-based analysis, on diagnostic CT, 47 patients had 44 primary tumors, 248 lymph nodes, 15 pleural, 88 liver, and 42 brain metastases. [68Ga]Ga-DOTA.SA.FAPi scan identified more abnormal lesions than [18F]F-FDG in all the primary and metastatic sites with a maximum marked difference in the primary site [88.6% vs. 81.8%; p-0.001], lymph nodes [89.1% vs. 83.8%; p-0.0001], pleural metastases [93.3% vs. 73%; p-0.096] and brain metastasis [100% vs. 59.5%; p-0.0001]. [68Ga]Ga-DOTA.SA.FAPi PET/CT was superior to [18F]F-FDG PET/CT in the imaging of breast cancers.

Harmonization of standard uptake values across different positron emission tomography/computed tomography systems and different reconstruction algorithms: validation in oncology patients

BackgroundEQ.PET is a software package that overcomes the reconstruction-dependent variation of standard uptake values (SUV). In this study, we validated the use of EQ.PET for harmonizing SUVs between different positron emission tomography/computed tomography (PET/CT) systems and reconstruction algorithms.MethodsIn this retrospective study, 49 patients with various cancers were scanned on a Biograph mCT (mCT) or Gemini TF 16 (Gemini) after [18F]FDG injections. Three groups of patient data were collected: Group 1, patients scanned on mCT or Gemini with data reconstructed using two parameters; Group 2, patients scanned twice on different PET scanners (interval between two scans, 68.9 ± 41.4 days); and Group 3, patients scanned twice using mCT with data reconstructed using different algorithms (interval between two scans, 109.5 ± 60.6 days). The SUVs of the lesions and background were measured, and the tumor-to-background ratios (TBRs) were calculated. In addition, the consistency between the two reconstruction algorithms and confounding factors were evaluated.ResultsIn Group 1, the consistency of SUV and TBR between different reconstruction algorithms improved when the EQ.PET filter was applied. In Group 2, by comparing ΔSUV, ΔSUV%, ΔTBR, and ΔTBR% with and without the EQ.PET, the results showed significant differences (P < 0.05). In Group 3, Bland–Altman analysis of ΔSUV with EQ.PET showed an improved consistency relative to that without EQ.PET.ConclusionsEQ.PET is an efficient tool to harmonize SUVs and TBRs across different reconstruction algorithms. Patients could benefit from the harmonized SUV, ΔSUV, and ΔSUV% for therapy responses and follow-up evaluations.

Enhanced glypican-3-targeted identification of hepatocellular carcinoma with liver fibrosis by pre-degrading excess fibrotic collagen.

Most hepatocellular carcinomas (HCCs) occur in cirrhotic livers, but unequivocal diagnosis of early HCC from the fibrotic microenvironment remains a formidable challenge with conventional imaging strategies, mainly because of the massive fibrotic collagen deposition leading to hepatic nodules formation and dysfunction of contrast agent metabolism. Here, we developed a "sweep-and-illuminate" imaging strategy, pre-degrade hepatic fibrotic collagen with collagenase I conjugated human serum albumin (HSA-C) and then targeting visualize HCC lesion with GPC3 targeting nanoparticles (TSI NPs, TJ2 peptide-superparamagnetic iron oxide-indocyanine green) via fluorescence imaging (FLI) and magnetic particle imaging (MPI). TSI NPs delineated a clear boundary of HCC and normal liver, and the tumor-to-background ratios (TBRs) detected by FLI and MPI were 5.43- and 1.34-fold higher than the non-targeted group, respectively. HSA-C could degrade 24.7% fibrotic collagen, followed by 27.2% reduction of nonspecific NPs retention in mice with liver fibrosis. In a pathological state in which HCC occurs in the fibrotic microenvironment, HSA-C-mediated pre-degradation of fibrotic collagen reduced background signal interference in fibrotic tissues and enhanced the intratumoral uptake of TSI NPs, resulting in the clear demarcation between HCC and liver fibrosis, and the TBR was increased 2.61-fold compared to the group without HSA-C pretreatment. We demonstrated the feasibility of combined pre-degradation of fibrotic collagen and application of a GPC3-targeted FLI/MPI contrast agent for early HCC identification, as well as its clinical value in the management of patients with advanced liver fibrosis. STATEMENT OF SIGNIFICANCE: Given that liver fibrosis hinders early detection and treatment options of hepatocellular carcinomas (HCCs), we report a "sweep-and-illuminate" imaging strategy to enhance the efficiency of HCC identification by modulating the irreversible liver fibrosis. We first "sweep" nonspecific interference of contrast agent by pre-degrading fibrotic collagen with human serum albumin-carried collagenase I (HSA-C); and then specifically "illuminate" HCC lesions with GPC3-targeted-SPIO-ICG nanoparticles (TSI NPs). HSA-C can degrade 24.7% fibrotic collagen, followed by 27.2% reduction of nonspecific NPs retention in mice with liver fibrosis. Furthermore, in HCC models coexisting with liver fibrosis, the combined application of HSA-C and TSI NPs can clarify the demarcation between HCC and liver fibrosis with a 2.61-fold increase in the tumor-to-background ratio. This study may expand the potential of combinatorial biomaterials for early HCC diagnosis.

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.

Sex-specific radiomic features of L-[S-methyl-11C] methionine PET in patients with newly-diagnosed gliomas in relation to IDH1 predictability.

Amino-acid positron emission tomography (PET) is a validated metabolic imaging approach for the diagnostic work-up of gliomas. This study aimed to evaluate sex-specific radiomic characteristics of L-[S-methyl-11Cmethionine (MET)-PET images of glioma patients in consideration of the prognostically relevant biomarker isocitrate dehydrogenase (IDH) mutation status. MET-PET of 35 astrocytic gliomas (13 females, mean age 41 ± 13 yrs. and 22 males, mean age 46 ± 17 yrs.) and known IDH mutation status were included. All patients underwent radiomic analysis following imaging biomarker standardization initiative (IBSI)-conform guidelines both from standardized uptake value (SUV) and tumor-to-background ratio (TBR) PET values. Aligned Monte Carlo (MC) 100-fold split was utilized for SUV and TBR dataset pairs for both sex and IDH-specific analysis. Borderline and outlier scores were calculated for both sex and IDH-specific MC folds. Feature ranking was performed by R-squared ranking and Mann-Whitney U-test together with Bonferroni correction. Correlation of SUV and TBR radiomics in relation to IDH mutational status in male and female patients were also investigated. There were no significant features in either SUV or TBR radiomics to distinguish female and male patients. In contrast, intensity histogram coefficient of variation (ih.cov) and intensity skewness (stat.skew) were identified as significant to predict IDH +/-. In addition, IDH+ females had significant ih.cov deviation (0.031) and mean stat.skew (-0.327) differences compared to IDH+ male patients (0.068 and -0.123, respectively) with two-times higher standard deviations of the normal brain background MET uptake as well. We demonstrated that female and male glioma patients have significantly different radiomic profiles in MET PET imaging data. Future IDH prediction models shall not be built on mixed female-male cohorts, but shall rely on sex-specific cohorts and radiomic imaging biomarkers.

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.