Despite recent therapeutic advances, managing liver cancer remains a significant medical and economic priority for many countries. Patients often present at an advanced stage, preventing them from benefiting from salvage surgery. Consequently, palliative treatments play a crucial role in managing these cancers. Interventional radiology techniques are well-known for providing significant benefits to patients. [90Y]Y-L4-Lipo/Lipiodol® Ultra-Fluid is a novel transarterial radioembolization formulation designed for selective arterial injection to deliver localized radiation treatment of advanced unresectable liver tumors. This study aimed to confirm the stability of [90Y]Y-L4-Lipo/Lipiodol® Ultra-Fluid, investigate its biodistribution in an animal model, and conduct an initial dosimetry evaluation. Less than 3

Abstract Background Positron emission tomography/computed tomography (PET/CT) using radiotracers that bind to the prostate-specific membrane antigen (PSMA) is mainly used in biochemical recurring prostate cancer. The aim of our study was to assess the usefulness of 18F-JK-PSMA-7 PET/CT for local and nodal staging in patients with intermediate- and high-risk prostate cancer (PCa) prior to radical prostatectomy, as compared to conventional imaging techniques. Methods We enrolled a total of 10 patients with intermediate- and high-risk PCa diagnosed by multiparametric-MRI followed by systematic and targeted biopsies, eligible for radical prostatectomy with extended lymph node dissection. Clinical team was blind to the results of the pre-surgery 18F-JK-PSMA-7 PET/CT at times of clinical decision and surgery. One month post-surgery, 18F-JK-PSMA-7 PET/CT was repeated and the results of both scans were unblinded. A third 18F-JK-PSMA-7 PET/CT could be acquired at a later time point depending on PSA progression. Results All pre-surgery 18F-JK-PSMA-7 PET/CT was positive in the prostatic region, while MRI was negative in the prostate in one patient. We also detected positive pelvic lymph nodes in two patients (one high-risk, one intermediate-risk PCa) on pre-surgery and post-surgery 18F-JK-PSMA-7 PET/CT. No positive pelvic lymph nodes were reported on pre-surgical CT and MRI. 18F-JK-PSMA-7 PET/CT detected bladder involvement in one patient and seminal vesicles involvement in two patients; this malignant extension was undetected by the conventional imaging techniques. SUVmax in prostate lesions had an average value of 11.51 (range 6.90–21.49). SUVmean in prostate lesions had an average value of 7.59 (range 5.26–14.02). Conclusion This pilot study indicates that pre-surgery 18F-JK-PSMA-7 PET/CT provides valuable information in intermediate- and high-risk PCa, for surgery planning with curative intent.

Objectives: To evaluate the diagnostic and prognostic value of quantitative biomarkers derived from optical coherence tomography (OCT) measurements for the management of patients with systemic sclerosis (SSc) and to compare their clinical utility with the modified Rodnan skin score (mRSS). Methods: Thirty-seven patients and 38 healthy volunteers were selected. The mRSS was performed in both groups over 17 anatomical sites and OCT images were obtained over 7 of the 17 anatomical sites using 2 commercially available systems. For all sites, both types of images were processed to quantify the optical absorption, area and thickness of the different layers of the skin. Results: For both systems, the 3 most extreme results and usually more affected locations provided statistically relevant data. For one system, the dermal-epidermal junction area, i.e. the integral sum of the optical density, led to significant difference between both groups. For the other system, the junction slope (JS), i.e. the optical density gradient, demonstrated an excellent accuracy in scleroderma diagnosis when mRSS was high in the most relevant lesions, and superior sensitivity and specificity when mRSS was low. Conclusions: This study shows promising results for OCT to provide an objective non-invasive examination tool for early diagnosis of SSc.

AbstractAdjusting the molecular size, the valency and the pharmacokinetics of drug conjugates are as many leverages to improve their therapeutic window, notably by affecting tumor penetration, renal clearance, and short systemic exposure. In that regard, small tumor-targeting ligands are gaining attention. In this study, we demonstrate the benefits of the small Nanofitin alternative scaffolds (7 kDa) as selective tumor-targeting modules for the generation of drug conjugates, focusing on Nanofitins B10 and D8 directed against the EGFR. Owing to their small size and monovalent format, the two Nanofitins displayed a fast and deep tumor penetration in EGFR-positive A431 xenografts in BALB/c nude mice after intravenous administration, yielding to a targeting of respectively 67.9% ± 14.1 and 98.9% ± 0.7 of the tumor cells as demonstrated by IHC. Conjugation with the monomethyl auristatin E toxin provided homogeneous Nanofitin-drug conjugates, with an overall yield of ≥97%, for in vivo assessment in a curative xenograft model using bioluminescent, EGFR-positive, A431 cells in BALB/c nude mice. Internalization was found critical for efficient release of the toxin. Hence, the intravenous administration of the D8-based construct showed significant antitumor effect in vivo as determined by monitoring tumor volumes and bioluminescence levels over 2 months.

Fibroblast activation protein-α (FAPα) is a marker of activated fibroblasts that can be selectively targeted by an inhibitor (FAPI) and visualised by PET/CT imaging. We evaluated whether the measurement of FAPα in bronchoalveolar lavage fluids (BALF) and the uptake of FAPI by PET/CT could be used as biomarkers of fibrogenesis. The dynamics of lung uptake of 18F-labeled FAPI ([18F]FAPI-74) was assessed in the bleomycin mouse model at various time points and using different concentrations of bleomycin by PET/CT. FAPα was measured in BALFs from these bleomycin-treated and control mice. FAPα levels were also assessed in BALFs from controls and patients with idiopathic pulmonary fibrosis (IPF). Bleomycin-treated mice presented a significantly higher uptake of [18F]FAPI-74 during lung fibrinogenesis (days 10 and 16 after instillation) compared to control mice. No significant difference was observed at initial inflammatory phase (3 days) and when fibrosis was already established (28 days). [18F]FAPI-74 tracer was unable to show a dose-response to bleomycin treatment. On the other hand, BALF FAPα levels were steeply higher in bleomycin-treated mice at day 10 and a significant dose-response effect was observed. Moreover, FAPα levels were strongly correlated with lung fibrosis as measured by the modified Aschroft histological analysis, hydroxyproline and the percentage of weight loss. Importantly, higher levels of FAPα were observed in IPF patients where the disease was progressing as compared to stable patients and controls. Moreover, patients with FAPα BALF levels higher than 192.5 pg/mL presented a higher risk of progression, transplantation or death compared to patients with lower levels. Our preclinical data highlight a specific increase of [18F]FAPI-74 lung uptake during the fibrotic phase of the bleomycin murine model. The measurement of FAPα in BALF appears to be a promising marker of the fibrotic activity in preclinical models of lung fibrosis and in IPF patients. Further studies are required to confirm the role of FAPα in BALF as biomarker of IPF activity and assess the relationship between FAPα levels in BALF and [18F]FAPI-74 uptake on PET/CT in patients with fibrotic lung disease.

Reaction-diffusion models have been proposed for decades to capture the growth of gliomas, the most common primary brain tumors. However, ill-posedness of the initialization at diagnosis time and parameter estimation of such models have restrained their clinical use as a personalized predictive tool. In this work, we investigate the ability of deep convolutional neural networks (DCNNs) to address commonly encountered pitfalls in the field. Based on 1200 synthetic tumors grown over real brain geometries derived from magnetic resonance (MR) data of six healthy subjects, we demonstrate the ability of DCNNs to reconstruct a whole tumor cell-density distribution from only two imaging contours at a single time point. With an additional imaging contour extracted at a prior time point, we also demonstrate the ability of DCNNs to accurately estimate the individual diffusivity and proliferation parameters of the model. From this knowledge, the spatio-temporal evolution of the tumor cell-density distribution at later time points can ultimately be precisely captured using the model. We finally show the applicability of our approach to MR data of a real glioblastoma patient. This approach may open the perspective of a clinical application of reaction-diffusion growth models for tumor prognosis and treatment planning.

The most common idiopathic interstitial lung disease (ILD) is idiopathic pulmonary fibrosis (IPF). It can be identified by the presence of usual interstitial pneumonia (UIP) via high-resolution computed tomography (HRCT) or with the use of a lung biopsy. We hypothesized that a CT-based approach using handcrafted radiomics might be able to identify IPF patients with a radiological or histological UIP pattern from those with an ILD or normal lungs. A total of 328 patients from one center and two databases participated in this study. Each participant had their lungs automatically contoured and sectorized. The best radiomic features were selected for the random forest classifier and performance was assessed using the area under the receiver operator characteristics curve (AUC). A significant difference in the volume of the trachea was seen between a normal state, IPF, and non-IPF ILD. Between normal and fibrotic lungs, the AUC of the classification model was 1.0 in validation. When classifying between IPF with a typical HRCT UIP pattern and non-IPF ILD the AUC was 0.96 in validation. When classifying between IPF with UIP (radiological or biopsy-proved) and non-IPF ILD, an AUC of 0.66 was achieved in the testing dataset. Classification between normal, IPF/UIP, and other ILDs using radiomics could help discriminate between different types of ILDs via HRCT, which are hardly recognizable with visual assessments. Radiomic features could become a valuable tool for computer-aided decision-making in imaging, and reduce the need for unnecessary biopsies.

Concerted alteration of immune and metabolic homeostasis underlies several inflammation-related pathologies, ranging from metabolic syndrome to infectious diseases. Here, we explored the coordination of nucleic acid-dependent inflammatory responses and metabolic homeostasis. We reveal that the STING (stimulator of interferon genes) protein regulates metabolic homeostasis through inhibition of the fatty acid desaturase 2 (FADS2) rate-limiting enzyme in polyunsaturated fatty acid (PUFA) desaturation. STING ablation and agonist-mediated degradation increased FADS2-associated desaturase activity and led to accumulation of PUFA derivatives that drive thermogenesis. STING agonists directly activated FADS2-dependent desaturation, promoting metabolic alterations. PUFAs in turn inhibited STING, thereby regulating antiviral responses and contributing to resolving STING-associated inflammation. Thus, we have unveiled a negative regulatory feedback loop between STING and FADS2 that fine-tunes inflammatory responses. Our results highlight the role of metabolic alterations in human pathologies associated with aberrant STING activation and STING-targeting therapies.

Digital PET/CT systems make use of a new technology with higher sensitivity and other better technological features than the analog ones. They require adaptation of the trade-off between performance, tracer dose and acquisition time. The aim of the study was to explore the performance of 18F-JK-PSMA-7 imaging when performed on a digital PET/CT with an adapted protocol, in a population of patients with prostate cancer patients (PCa). Influence of previous therapy on PET/CT performance is generally disregarded in PSMA-based imaging, despite potential influence of hormono-chemotherapy on the target expression. This potential influence was also tested in this work. A total of 54 PCa patients experiencing biochemical recurrence were included in the study, in which we analysed the diagnostic performance of digital 18F-JK-PSMA-7 PET/CT. Compared to our protocol applied for acquisition on an analog system, administered dose and acquisition time were reduced by 20% and 50% respectively. We specifically took into consideration the influence of previous treatments on recurrence detection. We detected overall 18F-JK-PSMA-7-positive lesions in 38/54 patients (70.3%). There was no statistically significant difference regarding the detection rate between the groups of patients who had hormono-chemotherapy any time after initial diagnosis and those who never got any hormonal or chemotherapeutic treatment. Regarding the SUV max values, there was not significant difference between the two groups of patients neither in pelvic ganglions nor in other metastatic sites or the prostate region. 18F-JK-PSMA7 PET/CT with administered dose and acquisition time adapted to the digital technology provides valuable information in PCa patients with biochemical recurrence.

Preoperative molecular imaging is paramount to direct surgery in primary hyperparathyroidism (pHPT). We investigated the diagnostic performance of F-18-fluorocholine (F-18-FCH) PET/CT compared with C-11-methionine (C-11-MET) PET/CT for localization of hyperfunctioning parathyroid tissue in patients with pHPT and negative or inconclusive Tc-99m-sestaMIBI (99mTc-MIBI) SPECT findings. Methods: Fifty-eight patients with biochemical evidence of pHPT and negative or inconclusive Tc-99m-MIBI SPECT findings were referred for presurgical detection and localization of hyperfunctioning parathyroid tissue by C-11-MET and F-18-FCH PET/CT. The PET/CT results were classified into 3 categories (positive, inconclusive, or negative) based on the nodular aspect of tracer uptake and the visualization of corresponding nodules on CT. The PET/CT results were correlated with the surgical and histopathologic findings, which were used as the gold standard. Results: Fifty-three patients were included for analysis. F-18-FCH PET/CT was positive in 39 patients (74%), inconclusive in 5 (9%), and negative in 9 (17%), compared with 25 (47%), 12 (23%), and 16 (30%), respectively, for C-11-MET PET/CT. F-18-FCH localized (11) additional foci (6 positive and 5 inconclusive), compared with C-11-MET. Twenty-six patients (sex ratio, 10/16 M/F) underwent surgery, with resection of 31 lesions (22 adenomas, 6 hyperplastic glands, and 3 carcinomas) and 1 normal gland. At followup, 21 patients (81%) were considered cured after surgery, whereas 3 patients (12%) had persistence of hypercalcemia. With inconclusive cases being considered negative, 18F-FCH PET/CT correctly localized 26 lesions in 24 of 26 patients (92%), compared with 16 lesions in 15 of 26 patients (58%) localized by C-11-MET PET/CT. Per-patient-based sensitivity and positive predictive value were 96% and 96%, respectively, for F-18-FCH and 60% and 94%, respectively, for 11C-MET (P < 0.0001). Per-lesion-based sensitivity and positive predictive value were 84% and 90%, respectively, for F-18-FCH and 52% and 94%, respectively, for C-11-MET (P < 0.0001). Conclusion: In the presence of biochemical evidence of pHPT with negative or inconclusive Tc-99m-MIBI SPECT findings, F-18-FCH PET/CT performs better than C-11-MET PET/CT for the detection of pathologic parathyroid tissue, allowing localization of parathyroid adenoma or hyperplasia in 96% of patients.

The thyroid gland captures iodide in order to synthesize hormones that act on almost all tissues and are essential for normal growth and metabolism. Low plasma levels of thyroid hormones lead to hypothyroidism, which is one of the most common disorder in humans and is not always satisfactorily treated by lifelong hormone replacement. Therefore, in addition to the lack of in vitro tractable models to study human thyroid development, differentiation and maturation, functional human thyroid organoids could pave the way to explore new therapeutic approaches. Here we report the generation of transplantable thyroid organoids derived from human embryonic stem cells capable of restoring plasma thyroid hormone in athyreotic mice as a proof of concept for future therapeutic development.

Reaction-diffusion models have been proposed for decades to capture the growth of gliomas. Nevertheless, these models require an initial condition: the tumor cell density distribution over the whole brain at diagnosis time. Several works have proposed to relate this distribution to abnormalities visible on magnetic resonance imaging (MRI). In this work, we verify these hypotheses by stereotactic histological analysis of a non-operated brain with glioblastoma using a 3D-printed slicer. Cell density maps are computed from histological slides using a deep learning approach. The density maps are then registered to a postmortem MR image and related to an MR-derived geodesic distance map to the tumor core. The relation between the edema outlines visible on T2-FLAIR MRI and the distance to the core is also investigated. Our results suggest that (i) the previously proposed exponential decrease of the tumor cell density with the distance to the core is reasonable but (ii) the edema outlines would not correspond to a cell density iso-contour and (iii) the suggested tumor cell density at these outlines is likely overestimated. These findings highlight the limitations of conventional MRI to derive glioma cell density maps and the need for other initialization methods for reaction-diffusion models to be used in clinical practice.

Recent works have demonstrated the added value of dynamic amino acid positron emission tomography (PET) for glioma grading and genotyping, biopsy targeting, and recurrence diagnosis. However, most of these studies are based on hand-crafted qualitative or semi-quantitative features extracted from the mean time activity curve within predefined volumes. Voxelwise dynamic PET data analysis could instead provide a better insight into intra-tumor heterogeneity of gliomas. In this work, we investigate the ability of principal component analysis (PCA) to extract relevant quantitative features from a large number of motion-corrected [S-methyl-11C]methionine ([11C]MET) PET frames. We first demonstrate the robustness of our methodology to noise by means of numerical simulations. We then build a PCA model from dynamic [11C]MET acquisitions of 20 glioma patients. In a distinct cohort of 13 glioma patients, we compare the parametric maps derived from our PCA model to these provided by the classical one-compartment pharmacokinetic model (1TCM). We show that our PCA model outperforms the 1TCM to distinguish characteristic dynamic uptake behaviors within the tumor while being less computationally expensive and not requiring arterial sampling. Such methodology could be valuable to assess the tumor aggressiveness locally with applications for treatment planning and response evaluation. This work further supports the added value of dynamic over static [11C]MET PET in gliomas.

1411 Objectives: Gliomas are the most common primary brain tumors whose diagnosis and follow-up often rely on MRI and amino acid (AA) PET. Recently, the added value of dynamic over static AA PET imaging has been demonstrated for biopsy targeting, classification, and recurrence diagnosis in gliomas. However, the analysis performed on such data is mostly qualitative or semi-quantitative and based on the mean time-activity curve (TAC) within a pre-delineated biological tumor volume (BTV). Nevertheless, gliomas are known to be highly heterogeneous tumors made of multiple genotypic populations. In this work, the ability of principal component analysis (PCA) to extract biologically relevant parametric maps from high-dimensional dynamic [S-methyl-11C]methionine ([11C]MET) PET data is investigated. The derived parametric map obtained are also compared to these provided by the classical one-tissue compartment pharmacokinetic model (1TCM). Methods: 33 glioma patients (20 males, median age 55 yr, 28 surgically treated, WHO grades II to IV, all histological types) were enrolled in this study. For each patient, a 30-minutes-and-30-seconds acquisition was started 30 seconds before the injection of 287 to 555 MBq of [11C]MET. 906 overlapping frames with duration 20 seconds and time spacing 2 seconds were reconstructed from the list file. The 33 reconstructed dynamic volumes were corrected for patient motion and inter-patient injection-to-carotid delay. In total, 6,420,534 voxel TACs were extracted from the segmented brain region of the 33 volumes, smoothed by averaging within 3x3x3 voxels neighborhood, and analyzed using PCA. To evaluate the robustness of our approach, the component definitions were determined on the brain TACs of 20 patients (3,974,466 TACs), then used to generate parametric maps from the brain TACs of the other 13 patients (2,446,068 TACs). Kinetic parameter maps were also generated from each patient’s smoothed TACs using the 1TCM and an image-derived function with PVE and population-based metabolite corrections. Results: Four of the first 6 principal component maps were found to be of clinical interest and are depicted in Figure 1e-h. The first component map (PC1, Figure 1e) is similar to the static PET image (Figure 1a) but has a higher tumor-to-background ratio and does not depend on an arbitrarily chosen injection-to-acquisition delay. PC2 (Figure 1f) reflects the vascular component of the TACs. PC3 (Figure 1g) distinguishes fast increasing then decreasing TACs from progressively increasing TACs within the BTV. Such behaviors were previously reported at the whole tumor level for high-grade and low-grade gliomas, respectively. PC3 would thus reflect intra-tumor heterogeneity of the proliferation potential possibly related to the local over-expression of the LAT1 trans-membrane amino-acid transporter. PC5 (Figure 1h) is related to the carotid-to-voxel delay and could reflect the effectiveness of the micro-vasculature. These maps also strongly to very strongly correlate with the 1TCM kinetic parameter maps depicted in Figure 1i-l. However, the different dynamic uptake behaviors are more clearly reflected by the PC3 map than the homologous 1/K2 map, as highlighted by TAC A, B, and C at voxels pointed by the red, blue, and green arrows in Figure 1. Conclusion: We proposed a novel methodology for the analysis of high-dimensional dynamic PET data based on PCA which does not require invasive arterial sampling. Principal components are determined from the whole brain TACs of multiple patients, which make them robust to inter-patient variations. We applied this methodology to dynamic [11C]MET PET data of glioma patients. One of the derived component maps highlighted intra-tumor heterogeneity in the uptake dynamics potentially linked to the local aggressiveness of the tumor. Such a parametric map could be of interest for biopsy targeting, surgery and radiotherapy planning, and recurrence diagnosis in gliomas.

This preclinical study aims to evaluate the extent to which a change in prostate-specific membrane antigen (PSMA) expression of castration-resistant prostate cancer (CRPC) following standard treatment is reflected in [18F]JK-PSMA-7 PET/CT. Castrated mice supplemented with testosterone implant were xenografted with human LNCaP CRPC. After appropriate tumour growth, androgen deprivation therapy (ADT) was carried out by the removal of the implant followed by a single injection of docetaxel (400 μg/20-g mouse) 2 weeks later. [18F]JK-PSMA-7 PET/CT were performed before ADT, then before and at days 12, 26, 47 and 69 after docetaxel administration. The [18F]JK-PSMA-7 PET data were compared to corresponding unspecific metabolic [18F]FDG PET/CT and ex vivo quantification of PSMA expression estimated by flow cytometry on repeated tumour biopsies. ADT alone had no early effect on LNCaP tumours that pursued their progression. Until day 12 post-docetaxel, the [18F]JK-PSMA7 uptake was significantly higher than that of [18F]FDG, indicating the persistence of PSMA expression at those time points. From day 26 onwards when the tumours were rapidly expanding, both [18F]JK-PSMA7 and [18F]FDG uptake continuously decreased although the decrease in [18F]JK-PSMA uptake was markedly faster. The fraction of PSMA-positive cells in tumour biopsies decreased similarly over time to reach a non-specific level after the same time period. Applying PSMA-based imaging for therapy monitoring in patients with CRPC should be considered with caution since a reduction in [18F]JK-PSMA-7 PET uptake after successive ADT and chemotherapy may be related to downregulation of PSMA expression in dedifferentiated and rapidly proliferating tumour cells.

INTRODUCTION:Cabozantinib is a tyrosine kinase inhibitor (TKI) approved for the treatment of medullary thyroid cancer, renal cell carcinoma and hepatocellular carcinoma, and is currently in clinical trials for the treatment of prostate cancer and others. It exerts its therapeutic effect mainly through inhibition of the tyrosine kinases MET (hepatocyte growth factor receptor) and VEGFR2 (vascular endothelial growth factor receptor 2), in addition to several other kinases involved in cancer. PET imaging with TKIs such as [18F]cabozantinib could potentially aid in cancer diagnosis and guide treatment. This study aims to evaluate the utility of [18F]cabozantinib as a PET imaging probe in PC3 tumor xenografted mice. METHODS:[18F]cabozantinib was evaluated in non-tumor and tumor bearing (PC3 xenografted) male mice by ex vivo biodistribution studies and in vivo μPET imaging. Pretreatment studies were performed in the tumor bearing mice with the MET inhibitor PF04217903. Mouse plasma was analyzed with HPLC to quantify radiometabolites. To further evaluate the binding specificity of [18F]cabozantinib, in vitro autoradiography studies on heart and PC3 tumor sections were performed in the presence of authentic cabozantinib or specific MET and VEGFR2 inhibitors. RESULTS:Tissue distribution studies in non-tumor bearing mice revealed slow blood clearance, absence of brain uptake and a high myocardial uptake. In the tumor bearing mice, tumor uptake was low (0.58 ± 0.20% ID/g at 30 min post tracer injection), which was confirmed by μPET imaging. No differences in tissue distribution and kinetics were observed in both biodistributions and μPET studies after pretreatment with the MET inhibitor PF04217903. At 30 min post tracer injection, 60 ± 3% of the recovered radioactivity in plasma in non-tumor bearing mice was present as intact tracer. [18F]cabozantinib binding in vitro to heart and tumor tissues was partly blocked in the presence of selective MET and VEGFR2 inhibitors (up to 40% block). The fraction of non-specific binding was relatively high for both tissues (66% for heart and 39% for tumor). CONCLUSION:[18F]cabozantinib exhibits non-favorable properties as a PET imaging probe, demonstrated by slow excretion kinetics along with low tumor uptake and high non-specific binding in tumor and heart tissue. The results reflect cabozantinibs multi-kinase activity, making PET imaging of tumor specific kinase expression with [18F]cabozantinib challenging.

Colorectal cancer (CRC) cells are traditionally considered unresponsive to TGFβ due to mutations in the receptors and/or downstream signaling molecules. TGFβ influences CRC cells only indirectly via stromal cells, such as cancer-associated fibroblasts. However, CRC cell ability to directly respond to TGFβ currently remains unexplored. This represents a missed opportunity for diagnostic and therapeutic interventions. Methods: We examined whether cancer cells from primary CRC and liver metastases respond to TGFβ by inducing TGFβ-induced protein ig-h3 (TGFBI) expression, and the contribution of canonical and non-canonical TGFβ signaling pathways to this effect. We then investigated in vitro and in vivo TGFBI impact on metastasis formation and angiogenesis. Using patient serum samples and an orthotopic mouse model of CRC liver metastases we assessed the diagnostic/tumor targeting value of novel antibodies against TGFBI. Results: Metastatic CRC cells, such as circulating tumor cells, directly respond to TGFβ. These cells were characterized by the absence of TGFβ receptor mutations and the frequent presence of p53 mutations. The pro-tumorigenic program orchestrated by TGFβ in CRC cells was mediated through TGFBI, the expression of which was positively regulated by non-canonical TGFβ signaling cascades. TGFBI inhibition was sufficient to significantly reduce liver metastasis formation in vivo. Moreover, TGFBI pro-tumorigenic function was linked to its ability to stimulate angiogenesis. TGFBI levels were higher in serum samples from untreated patients with CRC than in patients who were receiving chemotherapy. A radiolabeled anti-TGFBI antibody selectively targeted metastatic lesions in vivo, underscoring its diagnostic and therapeutic potential. Conclusions: TGFβ signaling in CRC cells directly contributes to their metastatic potential and stromal cell-independence. Proteins downstream of activated TGFβ, such as TGFBI, represent novel diagnostic and therapeutic targets for more specific anti-metastatic therapies.

e15094 Background: Selection for surgery in patients with colorectal liver metastases (CRLM) remains poorly accurate. We evaluated if baseline metabolic characteristics of CRLM, as assessed by [18]-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18FDG-PET/CT), may predict the postoperative outcome in patients operated for CRLM. Methods: In a series of 450 patients operated for CRLM, we retrospectively identified 2 groups: The long-term survival (LTS), as defined by postoperative recurrence-free survival (RFS)≥5 years, and the early relapse groups (ER), as defined by RFS < 1 year. Clinicopathologic characteristics, Clinical Risk Score (CRS) and baseline 18FDG-PET/CT metabolic parameters were analyzed. Baseline 18FDG-PET/CT was performed at the time of diagnosis of CRLM, before any preoperative treatment. Low and high-risk CRS were defined by scores of 0 to 2 and 3 to 5, respectively. Metabolic CRS (mCRS) was implemented, using 1 additional point to the standard CRS when the highest tumor standardized uptake value (SUVmax) and normal liver mean SUV (SUVmean(liver)) ratio was > 4.3. Low and high-risk mCRS were defined by scores of 0 to 2 and 3 to 6, respectively. Results: We analyzed 53 patients. No difference was observed between LTS (n = 23) and ER (n = 30) groups for clinicopathologic parameters related to the primary tumor and CRLM, CRS and rates of low/high risk CRS. All metabolic parameters analyzed, including SUVmax and SUVpeak, at the exception of metabolic tumor volume, were significantly increased in ER group. Median SUVmax/SUVmean(liver) ratio was significantly increased in the ER vs LTS, respectively of 4.2 and 2.8 (p = 0.008). mCRS was significantly higher in ER as compared to LTS patients (p = 0.024), while 61% of the LTS patients had a low-risk mCRS and 73% of the ER patients had a high-risk mCRS (p = 0.023). Conclusions: Baseline 18FDG-PET/CT characteristics demonstrate an increased tumor glucose uptake in patients who rapidly recur after curative-intent surgery for CRLM. The introduction of these data into clinical risk model may represent a new tool to improve selection for surgery in patients with CRLM.