Plasma miRNA-based signatures in CRC screening programs

Colorectal cancer (CRC) screening programs help diagnose cancer precursors and early cancers and help reduce CRC mortality. However, currently recommended tests, the fecal immunochemical test (FIT) and colonoscopy, have low uptake. There is therefore a pressing need for screening strategies that are minimally invasive and consequently more acceptable to patients, most likely blood based, to increase early CRC identification. MicroRNAs (miRNAs) released from cancer cells are detectable in plasma in a remarkably stable form, making them ideal cancer biomarkers. Using plasma samples from FIT-positive (FIT+) subjects in an Italian CRC screening program, we aimed to identify plasma circulating miRNAs that detect early CRC. miRNAs were initially investigated by quantitative real-time PCR in plasma from 60 FIT+ subjects undergoing colonoscopy at Fondazione IRCCS Istituto Nazionale dei Tumori, then tested on an internal validation cohort (IVC, 201 cases) and finally in a large multicenter prospective series (external validation cohort [EVC], 1121 cases). For each endoscopic lesion (low-grade adenoma [LgA], high-grade adenoma [HgA], cancer lesion [CL]), specific signatures were identified in the IVC and confirmed on the EVC. A two-miRNA-based signature for CL and six-miRNA signatures for LgA and HgA were selected. In a multivariate analysis including sex and age at blood collection, the areas under the receiver operating characteristic curve (95% confidence interval) of the signatures were 0.644 (0.607–0.682), 0.670 (0.626–0.714) and 0.682 (0.580–0.785) for LgA, HgA and CL, respectively. A miRNA-based test could be introduced into the FIT+ workflow of CRC screening programs so as to schedule colonoscopies only for subjects likely to benefit most.     

The use of Trichomonas vaginalis purine nucleoside phosphorylase to activate fludarabine in the treatment of solid tumors

Treatment with fludarabine phosphate (9-β-D-arabinofuranosyl-2-F-adenine 5′-phosphate, F-araAMP) leads to regressions and cures of human tumor xenografts that express Escherichia coli purine nucleoside phosphorylase (EcPNP). This occurs despite the fact that fludarabine (F-araA) is a relatively poor substrate for EcPNP, and is cleaved to liberate 2-fluoroadenine at a rate only 0.3% that of the natural E. coli PNP substrate, adenosine. In this study, we investigated a panel of naturally occurring PNPs to identify more efficient enzymes that may be suitable for metabolizing F-araA as part of experimental cancer therapy. We show that Trichomonas vaginalis PNP (TvPNP) cleaves F-araA with a catalytic efficiency 25-fold greater than the prototypic E. coli enzyme. Cellular extracts from human glioma cells (D54) transduced with lentivirus stably expressing TvPNP (D54/TvPNP) were found to cleave F-araA at a rate similar to extracts from D54 cells expressing EcPNP, although much less enzyme was expressed per cell in the TvPNP transduced condition. As a test of safety and efficacy using TvPNP, human head and neck squamous cell carcinoma (FaDu) xenografts expressing TvPNP were studied in nude mice and shown to exhibit robust tumor regressions, albeit with partial weight loss that resolved post-therapy. F-araAMP was also a very effective treatment for mice bearing D54/TvPNP xenografts in which approximately 10% of tumor cells expressed the enzyme, indicating pronounced ability to kill non-transduced tumor cells (high bystander activity). Moreover, F-araAMP demonstrated activity against D54 tumors injected with an E1, E3 deleted adenoviral vector encoding TvPNP. In that setting, despite higher F-araA cleavage activity using TvPNP, tumor responses were similar to those obtained with EcPNP, indicating factors other than F-Ade production may limit regressions of the D54 murine xenograft model. Our results establish that TvPNP is a favorable enzyme for activating F-araA, and support further studies in combination with F-araAMP for difficult-to-treat human cancers.     

IgE-mediated regulation of IL-10 and type I IFN enhances rhinovirus-induced Th2 differentiation by primary human monocytes

Rhinovirus (RV) infections are linked to the development and exacerbation of allergic diseases including allergic asthma. IgE, another contributor to atopic disease pathogenesis, has been shown to regulate DC antiviral functions and influence T cell priming by monocytes. We previously demonstrated that IgE-mediated stimulation of monocytes alters multiple cellular functions including cytokine secretion, phagocytosis, and influenza-induced Th1 development. In this study, we investigate the effects of IgE-mediated stimulation on monocyte-driven, RV-induced T cell development utilizing primary human monocyte-T cell co-cultures. We demonstrate that IgE crosslinking of RV-exposed monocytes enhances monocyte-driven Th2 differentiation. This increase in RV-induced Th2 development was regulated by IgE-mediated inhibition of virus-induced type I IFN and induction of IL-10. These findings suggest an additional mechanism by which two clinically significant risk factors for allergic disease exacerbations—IgE-mediated stimulation and rhinovirus infection—may synergistically promote Th2 differentiation and allergic inflammation.     

Treatment of oral manifestations of toxic epidermal necrolysis with low‐level laser therapy in a pediatric patient

Drug‐induced reactions are complications associated with high mortality and significant morbidity. Stevens–Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are examples of these conditions, which are characterized by skin and mucous lesions. Here, we report a case of a 9‐year‐old girl who presented with blisters associated with an extensive vesicular rash and multiple ulcerations on the lips and oral cavity. A drug‐induced hypersensitivity reaction to antibiotics was suspected, and a diagnosis of TEN was made. The patient was managed with withdrawal of the suspected causative agent, and the oral lesions were treated with low‐level laser therapy (LLLT) and oral hygiene. This case highlights that TEN requires interdisciplinary intervention with dental assistance and follow‐up to improve symptoms, nutrition, systemic condition, and quality of life.     

Manipulation and free will in shared decision making

In recent years, there has been an increased focus on patient involvement in treatment planning in the health care system. To reduce the risk of the clinician moving towards paternalism, various methods have been introduced—shared decision making, among others. The goal of shared decision making is for the clinician and patient to share available evidence on the best treatment and to raise awareness on the needs and preferences of the patient as to make a genuinely informed choice. However, in the present article, we discuss to which degree paternalism can be avoided in light of the clinician's role as an authority with certain knowledge and expertise. Through the philosophical theory of reasons‐responsiveness, we discuss to which extend free will and control applies to the patient. Through theoretical analysis, we come to suggest that the clinician has a role as an ally rather than manipulator.