Purpose: Adenosine is a ubiquitous nucleoside that accumulates at high levels in hypoxic regions of solid tumors, and A 3 adenosine receptors have been recently demonstrated to play a pivotal role in the adenosine-mediated inhibition of tumor cell proliferation. In the present work, we addressed the question of the putative relevance of A 3 subtypes in colorectal adenocarcinomas.Experimental Design: Seventy-three paired samples of tumor and surrounding peritumoral normal mucosa at a distance of 2 and 10 cm from the tumor and blood samples obtained from a cohort of 30 patients with colorectal cancer were investigated to determine the presence of A 3 receptors by means of binding, immunocytochemistry, and real-time reverse transcription-polymerase chain reaction studies.Results: As measured by receptor binding assays, the density of A 3 receptor was higher in colon carcinomas as compared with normal mucosa originating from the same individuals (P < 0.05). Overexpression of A 3 receptors at the protein level was confirmed by immunohistochemical studies, whereas no changes in A 3 mRNA accumulation in tumors as compared with the corresponding normal tissue were revealed. The overexpression of A 3 receptors in tumors was reflected in peripheral blood cells, where the density was approximately 3-fold higher compared with healthy subjects (P < 0.01). In a cohort of 10 patients studied longitudinally, expression of A 3 receptors in circulating blood cells returned to normal after surgical resection for colorectal cancer.Conclusions: This study provides the first evidence that A 3 receptor plays a role in colon tumorigenesis and, more importantly, can potentially be used as a diagnostic marker or a therapeutic target for colon cancer.

The present study investigates mRNA and protein levels of A 3 adenosine receptors in resting (R) and activated (A) human lymphocytes. The receptors were evaluated by the antagonist radioligand ϩ cell fraction. Real-time reverse transcription-polymerase chain reaction experiments confirmed the rapid increase of A 3 mRNA after T cell activation. Competition of radioligand binding by adenosine ligands displayed a rank order of potency typical of the A 3 subtype. Thermodynamic data indicated that the binding is enthalpy-and entropy-driven in both R and A cells, suggesting that the activation process does not involve, at a molecular level, receptor alterations leading to modifications in the A 3 -related binding mechanisms. Functionally, the up-regulation of A 3 adenosine receptors in A versus R cells corresponded to a potency increase of the A 3 agonist N 6 -(3-iodo-benzyl)-2-chloro-adenosine-5Ј-N-methyluronamide in inhibiting cAMP accumulation (IC 50 ϭ 1.5 Ϯ 0.4 and 2.7 Ϯ 0.3 nM, respectively); this effect was antagonized by MRE 3008F20 (IC 50 ϭ 5.0 Ϯ 0.3 nM). In conclusion, our results provide, for the first time, an in-depth investigation of A 3 receptors in human lymphocytes and demonstrate that, under activating conditions, they are up-regulated and may contribute to the effects triggered by adenosine.

Background: Recently, new evidence of the next-generation sequencing (NGS) liquid biopsy utility in clinical practice has been developed. This assay is emerging as a new promising tool to use as a noninvasive biomarker for cancer mutation profiling. Additional data supporting the clinical validity of cell free DNA (cfDNA) based testing is necessary to inform optimal use of these assays in the clinic. Materials and methods: A total of 398 cancer patients were analyzed by FoundationOne Liquid Analysis (F1LA), a genomic profiling assay and by standard NGS diagnostic ThermoFisher platform. The association between diagnostic technique was evaluated using a Poisson regression model. FoundationOne Liquid (F1L) and FoundationOne Liquid CDx (F1LCDx) detect 70 and 324 cancer-related genes alterations, respectively, including genomic signatures tumor fraction, blood tumor mutational burden (only for the 324 genes version), and microsatellite instability high status. Both assays used a single DNA extraction method to obtain cfDNA. The real-life clinical impact and feasibility of F1L and F1LCDx were evaluated across different solid tumors in our department. Results: Between 1 January 2019 and 28 February 2021, 398 samples of different tumor types from 398 patients were analyzed (overall success rate: 92%, in FoundationOne Liquid CDx Analysis success rate: 97%). Most frequent molecular alterations were TP53 (74), APC (40), DNMT3A (39), KRAS (23). The comprehensive clinical impact of F1LA compared with standard diagnostic was 64.7% versus 22.1% [risk ratio (RR) = 2.94; p < 0.001] and the potential clinical impact was 58.6% versus 11.0% (RR = 5.32; p < 0.001), respectively. Furthermore, some clinical cases were selected, in which F1LA detected actionable alterations offering an unexpected therapeutic choice. Conclusions: Although additional studies are needed to better select patients and setting, NGS F1LA is a useful, noninvasive, and repeatable assay to guide therapeutic choice in oncology. It provides a snapshot of cancer heterogeneity profile that could be incorporated in routinely clinical practice.

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Treatment of lung cancer depends on the stage of the tumor and the histological type. In recent years, the histological confirmation of lung non-small-cell lung cancer has become crucial since the availability of selective target therapeutic approaches. The aim of the study was to develop a validated procedure to estimate the incidence and prevalence of non-small-cell and small-cell lung cancer from healthcare administrative data. A latent class model for categorical variables was applied. The following observed variables were included in the analysis: ICD-9-CM codes in the Hospital Discharge Registry, ATC codes of medications dispensed present in the Drugs Prescriptions Registry, and the procedure codes in the Outpatient Registry. The proportion of non-small-cell lung cancer diagnoses was estimated to be 85% of the total number of lung cancer on the cohort of incident cases and 89% on the cohort of prevalent cases. External validation on a cohort of 107 patients with a lung cancer diagnosis and histological confirmation showed a sensitivity of 95.6% (95%CI: 89–98.8%) and specificity of 94.1% (95%CI: 71.3–99.9%). The procedure is an easy-to-use tool to design subpopulation-based studies on lung cancer and to better plan resource allocation, which is important since the introduction of new targeted therapies in non-small-cell lung carcinoma.