The RAS/RAF/MEK/MAPK and the PTEN/PI3K/AKT/mTOR pathways are key regulators of proliferation and survival in human cancer cells. Selective inhibitors of different transducer molecules in these pathways have been developed as molecular targeted anti‐cancer therapies. The in vitro and in vivo anti‐tumor activity of pimasertib, a selective MEK 1/2 inhibitor, alone or in combination with a PI3K inhibitor (PI3Ki), a mTOR inhibitor (everolimus), or with multi‐targeted kinase inhibitors (sorafenib and regorafenib), that block also BRAF and CRAF, were tested in a panel of eight human lung and colon cancer cell lines. Following pimasertib treatment, cancer cell lines were classified as pimasertib‐sensitive (IC₅₀ for cell growth inhibition of 0.001 µM) or pimasertib‐resistant. Evaluation of basal gene expression profiles by microarrays identified several genes that were up‐regulated in pimasertib‐resistant cancer cells and that were involved in both RAS/RAF/MEK/MAPK and PTEN/PI3K/AKT/mTOR pathways. Therefore, a series of combination experiments with pimasertib and either PI3Ki, everolimus, sorafenib or regorafenib were conducted, demonstrating a synergistic effect in cell growth inhibition and induction of apoptosis with sustained blockade in MAPK‐ and AKT‐dependent signaling pathways in pimasertib‐resistant human colon carcinoma (HCT15) and lung adenocarcinoma (H1975) cells. Finally, in nude mice bearing established HCT15 and H1975 subcutaneous tumor xenografts, the combined treatment with pimasertib and BEZ235 (a dual PI3K/mTOR inhibitor) or with sorafenib caused significant tumor growth delays and increase in mice survival as compared to single agent treatment. These results suggest that dual blockade of MAPK and PI3K pathways could overcome intrinsic resistance to MEK inhibition.

Cetuximab is a monoclonal antibody to the EGFR that induces antibody-dependent cell cytotoxicity (ADCC) through Fcγ receptors on immune cells. Although SNPs in genes encoding Fcγ receptors are functionally relevant to cetuximab-mediated ADCC in colorectal cancer, a direct correlation between in vitro ADCC and clinical response to cetuximab is not defined. We therefore enrolled 96 consecutive metastatic colorectal cancer (mCRC) patients at diagnosis in a study that assessed FcγR status and cetuximab-mediated ADCC. Patients carrying the FcγRIIa H alleles 131H/H and 131H/R had significantly higher ADCC compared with patients with the 131R/R alleles (P = 0.013). Patients carrying FcγRIIIa genotypes with the V alleles 158V/V and 158V/F displayed higher ADCC compared with patients carrying the 158F/F genotype (P = 0.001). Progression-free survival of patients with an FcγRIIIa 158V allele was significantly longer compared with patients carrying 158F/F (P = 0.05), whereas no significant difference was observed for overall survival. Twenty-eight of 50 mCRC patients with wild-type KRAS received cetuximab. The average ADCC-mediated killing was 30% of assay targets for patients who experienced cetuximab complete or partial response, 21% in patients with stable disease and 9% in patients with progressive disease. To characterize basal natural killer (NK) activity, cytotoxicity was evaluated in 39 of 96 mCRC patients. Patients who responded to first-line treatment had higher NK-cell cytotoxicity. Thus, although limited to this cohort of patients, in vitro cetuximab-mediated ADCC correlated with FcγR polymorphisms and predicted cetuximab responsiveness. Cancer Immunol Res; 4(4); 366–74. ©2016 AACR.

We investigated the diagnostic performance of Somatostatin Receptor Positron Emission Tomography/Computed Tomography (SSR-PET/CT) for the detection of primary lesion and initial staging of pancreatic neuroendocrine tumors (pNETs). A comprehensive literature search up to January 2020 was performed selecting studies in presence of: sample size ≥10 patients; index test (i.e., 68Ga-DOTATOC or 68Ga-DOTANOC or 68Ga-DOTATATE PET/CT); and outcomes (i.e., detection rate (DR), true positive, true negative, false positive, and false-negative). The methodological quality was evaluated with QUADAS-2. Pooled DR and pooled sensitivity and specificity for the identification of the primary tumor were assessed by a patient-based and a lesion-based analysis. Thirty-eight studies were selected for the qualitative analysis, while 18 papers were included in the meta-analysis. The number of pNET patients ranged from 10 to 142, for a total of 1143 subjects. At patient-based analysis, the pooled sensitivity and specificity for the assessment of primary pNET were 79.6% (95% confidence interval (95%CI): 71–87%) and 95% (95%CI: 75–100%) with a heterogeneity of 59.6% and 51.5%, respectively. Pooled DR for the primary lesion was 81% (95%CI: 65–90%) and 92% (95%CI: 80–97%), respectively, at patient-based and lesion-based analysis. In conclusion, SSR-PET/CT has high DR and diagnostic performances for primary lesion and initial staging of pNETs.

Trans-1-amino-3-¹⁸F-fluorocyclobutanecarboxylic-acid (anti-[¹⁸F]-FACBC) has been approved for the detection of prostate cancer (PCa) in patients with elevated prostate-specific-antigen following prior treatment. This review and meta-analysis aimed to investigate the diagnostic performance of ¹⁸F-FACBC positron emission tomography/computed-tomography (PET/CT) in the detection of primary/recurrent PCa. A bibliographic search was performed including several databases, using the following terms: “FACBC”/“fluciclovine” AND “prostate cancer”/“prostate” AND “PET”/“Positron Emission Tomography”. Fifteen and 9 studies were included in the systematic reviews and meta-analysis, respectively. At patient-based analysis, the pooled sensitivity and specificity of ¹⁸F-FACBC-PET/CT for the assessment of PCa were 86.3% and 75.9%, respectively. The pooled diagnostic odds-ratio value was 16.453, with heterogeneity of 30%. At the regional-based-analysis, the pooled sensitivity of ¹⁸F-FACBC-PET/CT for the evaluation of primary/recurrent disease in the prostatic bed was higher than in the extra-prostatic regions (90.4% vs. 76.5%, respectively); conversely, the pooled specificity was higher for the evaluation of extra-prostatic region than the prostatic bed (89% vs. 45%, respectively). ¹⁸F-FACBC-PET/CT seems to be promising in recurrent PCa, particularly for the evaluation of the prostatic bed. Additional studies to evaluate its utility in clinical routine are mandatory.

Aim: In this comprehensive review we present an update on the most relevant studies evaluating the utility of amino acid PET radiotracers for the evaluation of glioma recurrence as compared to magnetic resonance imaging (MRI). Methods: A literature search extended until June 2020 on the PubMed/MEDLINE literature database was conducted using the terms “high-grade glioma”, “glioblastoma”, “brain tumors”, “positron emission tomography”, “PET”, “amino acid PET”, “[¹¹C]methyl-l-methionine”, “[¹⁸F]fluoroethyl-tyrosine”, “[¹⁸F]fluoro-l-dihydroxy-phenylalanine”, “MET”, “FET”, “DOPA”, “magnetic resonance imaging”, “MRI”, “advanced MRI”, “magnetic resonance spectroscopy”, “perfusion-weighted imaging”, “diffusion-weighted imaging”, “MRS”, “PWI”, “DWI”, “hybrid PET/MR”, “glioma recurrence”, “pseudoprogression”, “PSP”, “treatment-related change”, and “radiation necrosis” alone and in combination. Only original articles edited in English and about humans with at least 10 patients were included. Results: Forty-four articles were finally selected. Conventional amino acid PET tracers were demonstrated to be reliable diagnostic techniques in differentiating tumor recurrence thanks to their high uptake from tumor tissue and low background in normal grey matter, giving additional and early information to standard modalities. Among them, MET–PET seems to present the highest diagnostic value but its use is limited to on-site cyclotron facilities. [¹⁸F]labelled amino acids, such as FDOPA and FET, were developed to provide a more suitable PET tracer for routine clinical applications, and demonstrated similar diagnostic performance. When compared to the gold standard MRI, amino acid PET provides complementary and comparable information to standard modalities and seems to represent an essential tool in the differentiation between tumor recurrence and other entities such as pseudoprogression, radiation necrosis, and pseudoresponse. Conclusions: Despite the introduction of new advanced imaging techniques, the diagnosis of glioma recurrence remains challenging. In this scenario, the growing knowledge about imaging techniques and analysis, such as the combined PET/MRI and the application of artificial intelligence (AI) and machine learning (ML), could represent promising tools to face this difficult and debated clinical issue.

Immunotherapy is a promising therapeutic strategy both for solid and hematologic tumors, such as in Hodgkin (HL) and non-Hodgkin lymphoma (NHL). In particular, immune-checkpoint inhibitors, such as nivolumab and pembrolizumab, are increasingly used for the treatment of refractory/relapsed HL. At the same time, evidence of chimeric antigen receptor (CAR)-T-cell immunotherapy efficacy mostly in NHL is growing. In this setting, the challenge is to identify an appropriate imaging method to evaluate immunotherapy response. The role of 18F-Fluorodeoxyglucose (18F-FDG) positron-emission tomography/computed tomography (PET/CT), especially in early evaluation, is under investigation in order to guide therapeutic strategies, taking into account the possible atypical responses (hyperprogression and pseudoprogression) and immune-related adverse events that could appear on PET images. Herein, we aimed to present a critical overview about the role of 18F-FDG PET/CT in evaluating treatment response to immunotherapy in lymphoma patients.