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Background: Several studies on 18F-FDG-PET/CT have investigated the prognostic role of this imaging modality in different tumors after treatment. Nevertheless, its role in restaging patients with recurrent CM still needs to be defined. Objective: The aim of this retrospective multicenter study was to evaluate the clinical and prognostic impact of 18F-FDG-PET/CT on the restaging process of cutaneous melanoma (CM) after surgery in patients with suspected distant recurrent disease or suspected metastatic progression disease. Materials and Methods: 74 patients surgically treated for CM underwent 18F-FDG-PET/CT for suspected distant recurrent disease or suspected metastatic progression disease. The diagnostic accuracy of visually interpreted 18F-FDG-PET/CT was obtained by considering histology (n=21 patients), other diagnostic imaging modalities performed within 2 months of PET/CT (CT in 52/74 patients and Whole-Body MRI in 18/74 patients) and clinical follow-up (n=74 patients) for at least 24 months containing all the clinical and diagnostic information useful for the PET performance assessment and outcome. Progression-free survival (PFS) and overall survival (OS) were assessed by using the Kaplan- Meier method. The risk of progression (Hazard Ratio-HR) was computed by the Cox regression analysis. Results: Suspicion of recurrent CM was confirmed in 24/27 patients with a positive 18F-FDG-PET/CT scan. Overall, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 18F-FDG-PET/CT were 82%, 93%, 88%, 89%, and 89%, respectively, with area under the curve being 0.87 (95%IC 0.78-0.97; p Conclusion: 18F-FDG-PET/CT showed a valuable diagnostic performance in patients with suspicion of recurrent CM. This imaging modality might have an important prognostic value in predicting the survival outcomes, assessing the risk of disease progression, and guiding treatment decision making.

Simple Summary Colorectal cancer stem cells (CR-CSCs) play a pivotal role in the therapy resistance and relapse of CRC patients. Herein we demonstrate that new treatment approaches comprising polymethoxyflavones and prenylflavonoids extracted from Citrus sinensis and Humulus lupulus, respectively, hamper the viability of CR-CSCs as well as synergizing with 5-fluorouracil and oxaliplatin (FOX)-based chemotherapy. Extract fractions containing Nobiletin and Xanthohumol, in combination with chemotherapy, decreased stemness properties of CR-CSCs and restrained the outgrowth of chemoresistant metastatic CR-CSCs. These data pinpoint Nobiletin and Xanthohumol as efficacious anti-cancer compounds in metastatic settings. Abstract Colorectal cancer (CRC) mortality is mainly caused by patient refractoriness to common anti-cancer therapies and consequent metastasis formation. Besides, the notorious toxic side effects of chemotherapy are a concurrent obstacle to be tackled. Thus, new treatment approaches are needed to effectively improve patient outcomes. Compelling evidence demonstrated that cancer stem cells (CSCs) are responsible for treatment failure and relapse. New natural treatment approaches showed capabilities to selectively target the CSC subpopulation by rendering them targetable by standard cytotoxic compounds. Herein we show the anti-cancer properties of the polymethoxyflavones and prenylflavonoids extracted from Citrus sinensis and Humulus lupulus, respectively. The natural biofunctional fractions, singularly and in combination, reduced the cell viability of CRC stem cells (CR-CSCs) and synergized with 5-fluorouracil and oxaliplatin (FOX) chemotherapy. These phenomena were accompanied by a reduced S and G2/M phase of the cell cycle and upregulation of cell death-related genes. Notably, both phytoextracts in combination with FOX thwarted stemness features in CR-CSCs as demonstrated by the impaired clonogenic potential and decreased Wnt pathway activation. Extracts lowered the expression of CD44v6 and affected the expansion of metastatic CR-CSCs in patients refractory to chemotherapy. Together, this study highlights the importance of polymethoxyflavones and prenylflavonoids as natural remedies to aid oncological therapies.

ObjectiveCancer stem cells are responsible for tumour spreading and relapse. Human epidermal growth factor receptor 2 (HER2) expression is a negative prognostic factor in colorectal cancer (CRC) and a potential target in tumours carrying the gene amplification. Our aim was to define the expression of HER2 in colorectal cancer stem cells (CR-CSCs) and its possible role as therapeutic target in CRC resistant to anti- epidermal growth factor receptor (EGFR) therapy.DesignA collection of primary sphere cell cultures obtained from 60 CRC specimens was used to generate CR-CSC mouse avatars to preclinically validate therapeutic options. We also made use of the ChIP-seq analysis for transcriptional evaluation of HER2 activation and global RNA-seq to identify the mechanisms underlying therapy resistance.ResultsHere we show that in CD44v6-positive CR-CSCs, high HER2 expression levels are associated with an activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which promotes the acetylation at the regulatory elements of the Erbb2 gene. HER2 targeting in combination with phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase kinase (MEK) inhibitors induces CR-CSC death and regression of tumour xenografts, including those carrying Kras and Pik3ca mutation. Requirement for the triple targeting is due to the presence of cancer-associated fibroblasts, which release cytokines able to confer CR-CSC resistance to PI3K/AKT inhibitors. In contrast, targeting of PI3K/AKT as monotherapy is sufficient to kill liver-disseminating CR-CSCs in a model of adjuvant therapy.ConclusionsWhile PI3K targeting kills liver-colonising CR-CSCs, the concomitant inhibition of PI3K, HER2 and MEK is required to induce regression of tumours resistant to anti-EGFR therapies. These data may provide a rationale for designing clinical trials in the adjuvant and metastatic setting.

Background Radiomic features are increasingly utilized to evaluate tumor heterogeneity in PET imaging but to date its role has not been investigated for Cho-PET in prostate cancer. The potential application of radiomics features analysis using a machine-learning radiomics algorithm was evaluated to select 18F-Cho PET/CT imaging features to predict disease progression in PCa. Methods We retrospectively analyzed high-risk PCa patients who underwent restaging 18F-Cho PET/CT from November 2013 to May 2018. 18F-Cho PET/CT studies and related structures containing volumetric segmentations were imported in the "CGITA" toolbox to extract imaging features from each lesion. A Machine-learning model has been adapted using NCA for feature selection, while DA was used as a method for feature classification and performance analysis. Results 106 imaging features were extracted for 46 lesions for a total of 4876 features analyzed. No significant differences between the training and validating sets in terms of age, sex, PSA values, lesion location and size (p > 0.05) were demonstrated by the machine-learning model. Thirteen features were able to discriminate FU disease status after NCA selection. Best performance in DA classification was obtained using the combination of the 13 selected features (sensitivity 74%, specificity 58% and accuracy 66%) compared to the use of all features (sensitivity 40%, specificity 52%, and accuracy 51%). Per-site performance of the 13 selected features in DA classification were as follow: T= sensitivity 63%, specificity 83%, accuracy 71%; N= sensitivity 87%, specificity 91% of and accuracy 90%; bone-M= sensitivity 33%, specificity 77% and accuracy 66%. Conclusions An artificial intelligence model demonstrated to be feasible and able to select a panel of 18F-Cho PET/CT features with valuable association with PCa patients' outcome.

Several studies on 18F-FDG-PET/CT have investigated the prognostic role of this imaging modality in different tumors after treatment. Nevertheless, its role in restaging patients with recurrent CM still needs to be defined.The aim of this retrospective multicenter study was to evaluate the clinical and prognostic impact of 18F-FDG-PET/CT on the restaging process of cutaneous melanoma (CM) after surgery in patients with suspected distant recurrent disease or suspected metastatic progression disease.74 patients surgically treated for CM underwent 18F-FDG-PET/CT for suspected distant recurrent disease or suspected metastatic progression disease. The diagnostic accuracy of visually interpreted 18F-FDG-PET/CT was obtained by considering histology (n=21 patients), other diagnostic imaging modalities performed within 2 months of PET/CT (CT in 52/74 patients and Whole-Body MRI in 18/74 patients) and clinical follow-up (n=74 patients) for at least 24 months containing all the clinical and diagnostic information useful for the PET performance assessment and outcome. Progression-free survival (PFS) and overall survival (OS) were assessed by using the Kaplan- Meier method. The risk of progression (Hazard Ratio-HR) was computed by the Cox regression analysis.Suspicion of recurrent CM was confirmed in 24/27 patients with a positive 18F-FDG-PET/CT scan. Overall, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 18F-FDG-PET/CT were 82%, 93%, 88%, 89%, and 89%, respectively, with area under the curve being 0.87 (95%IC 0.78-0.97; p0.05). 18F-FDG-PET/CT findings significantly influenced the therapeutic management in 18 patients (modifying therapy in 10 patients; guiding surgery in 8 patients). After 2 years of follow-up, PFS was significantly longer in patients with a negative vs. a positive 18F-FDG-PET/CT scan (90% vs 46%, p0.05; Fig. 1). Moreover, a negative scan was associated with a significantly longer OS than a positive one (76% vs 39% after 2 years, p0.05; Fig. 2). In addition, a positive 18F-FDG-PET/CT scan was associated with an increased risk of disease progression (HR=8.2; p0,05).18F-FDG-PET/CT showed a valuable diagnostic performance in patients with suspicion of recurrent CM. This imaging modality might have an important prognostic value in predicting the survival outcomes, assessing the risk of disease progression, and guiding treatment decision making.