Predictive biomarkers for checkpoint inhibitor-based immunotherapy: The Galectin-3 signature in NSCLCs

Checkpoint inhibitor-based immunotherapy is opening a promising scenario in oncology, with objective responses registered in multiple cancer types. However, reliable predictive markers of tumor responsiveness are still lacking. These markers need to be urgently identified for a better selection of patients that can be candidates for immunotherapy. In this pilot study, a cohort of 34 consecutive patients bearing programmed death-ligand 1 (PD-L1)-positive non-small cell lung carcinoma (NSCLC), treated with pembrolizumab, was considered. The retrospective immuno-phenotypic analysis performed on the original tumor biopsies allowed for the identification of a specific “galectin signature”, which strongly correlated with tumor responsiveness to anti PD-1 immunotherapy. We observed that the large majority of patients (about 90%) with high galectin-3 tumor expression (score 3+) showed an early and dramatic progression of the disease after three cycles of treatments. In contrast, all patients with negative or low/intermediate expression of galectin-3 in tumor cells showed an early and durable objective response to pembrolizumab, indicating galectin-3 as an interesting predictive marker of tumor responsiveness. The galectin-3 signature, at least in NSCLCs, promises a better selection of patient candidates for immunotherapy, reducing unnecessary treatment exposures and social costs. A large multicenter study is ongoing to validate this finding

Thyroid-specific transcription factors control Hex promoter activity

The homeobox-containing gene Hex is expressed in several cell types, including thyroid follicular cells, in which it regulates the transcription of tissue-specific genes. In this study the regulation of Hex promoter activity was investigated. Using co-transfection experiments, we demonstrated that the transcriptional activity of the Hex gene promoter in rat thyroid FRTL-5 cells is ∼10-fold greater than that observed in HeLa and NIH 3T3 cell lines (which do not normally express the Hex gene). To identify the molecular mechanisms underlying these differences, we evaluated the effect of the thyroid-specific transcription factor TTF-1 on the Hex promoter activity. TTF-1 produced 3-4-fold increases in the Hex promoter activity. Gel-retardation assays and mutagenesis experiments revealed the presence of functionally relevant TTF-1 binding sites in the Hex promoter region. These in vitro data may also have functional relevance in vivo, since a positive correlation between TTF-1 and Hex mRNAs was demonstrated in human thyroid tissues by means of RT-PCR analysis. The TTF-1 effect, however, is not sufficient to explain the difference in Hex promoter activity between FRTL-5 and cells that do not express the Hex gene. For this reason, we tested whether Hex protein is able to activate the Hex promoter. Indeed, co-transfection experiments indicate that Hex protein is able to increase the activity of its own promoter in HeLa cells ∼4-fold. TTF-1 and Hex effects are additive: when transfected together in HeLa cells, the Hex promoter activity is increased 6-7-fold. Thus, the contemporary presence of both TTF-1 and Hex could be sufficient to explain the higher transcriptional activity of the Hex promoter in thyroid cells with respect to cell lines that do not express the Hex gene. These findings demonstrate the existence of direct cross-regulation between thyroid-specific transcription factors

Income Inequality and Economic Downturn in Europe: A Multi-Level Analysis of their Consequences for Political Participation

The ongoing rise of inequality and the outbreak of the economic crisis since 2008 have fueled the debate about the effects of macro-economic processes on democracy in general, and on political participation in particular. Whereas the effect of economic disparity is well documented in the literature, the implications of the economic downturn have not been sufficiently evaluated so far. The article addresses this gap by offering a comprehensive overview of the impact of these macro-economic factors on individual political participation in Europe. Using data from the first six rounds of the European Social Survey, it shows that income inequality reduces participation and enlarges the participatory gap between better- and worse-off. In contrast, economic contraction has no effect on the overall level of participation and makes the poor participate more and the rich less

Room temperature evolution of gold nanodots deposited on silicon

In this work, the morphological and structural evolution of gold nanodots deposited on Si substrates has been monitored for 2.4 × 103 h. Gold nanodots on Si are of great scientific interest because they can be used in numerous ways, for example as subwavelength antennas in plasmonics, as electrical contacts in nanometric devices, or as catalysts for the formation of quasi-1dimensional nanostructures. Their characteristics have been studied in a very large number of papers in literature, and among the several aspects, it is known that continuous Au films peculiarly interact with Si by interdiffusion even at room temperature. It would be expected that also small nanostructures could undergo to an interdiffusion and consequent modifications of their structure and shape after aging. Despite the cruciality of this topic, no literature papers have been found showing a detailed morphological and structural characterization of aged Au nanodots. Au nanoparticles have been deposited by sputtering on Si and stored in air at temperature between 20 and 23 °C and humidity of about 45 %, simulating the standard storage conditions of most of the fabrication labs. The morphological and structural characterizations have been performed by bright field transmission electron microscopy (TEM). A specific procedure has been used in order to avoid any modification of the material during the specimen preparation for the TEM analysis. A digital processing of the TEM images has allowed to get a large statistical analysis on the particles size distribution. Two different types of nanoparticles are found after the deposition: pure gold crystalline nanodots on the Si surface and gold amorphous nanoclusters interdiffused into the Si subsurface regions. While the nanodots preserve both morphology and structure all over the time, the amorphous agglomerates show an evolution during aging in morphology, structure, and chemical phase

New driver alterations in non-small cell lung cancer. A narrative review

Objective: This review aims to provide an up-to-date snapshot on the state of development of novel biomarker-driven treatments in non-small cell lung cancer (NSCLC). Background: The introduction of immune checkpoint inhibitors and target therapies has revolutionized the natural history of many NSCLCs, allowing for lasting and profound responses. In particular, mutations in the epidermal growth factor receptor (EGFR), rearrangements of the anaplastic lymphoma kinase (ALK), or oncogene c-Ros 1 (ROS1) have marked a paradigm shift in the treatment of NSCLC. Furthermore, new inhibitors for B-Raf proto-oncogene (BRAF), rearranged during transfection (RET), mesenchymal-to-epithelial transition factor (MET), or neurotrophic tyrosine kinase (NTRK) 1–3 have revealed fascinating data, obtaining accelerated approvals from the Food and Drug Administration (FDA) and European Medicines Agency (EMA). Today, the extensive use of next-generation sequencing (NGS) techniques has shown a broad molecular heterogeneity of NSCLC. Many of the mutations identified are considered potential therapeutic targets, and numerous studies are currently evaluating the efficacy of selective inhibitors. Methods: We carried out an extensive review of the literature on PubMed, Web of Science, and Scopus databases and the congress abstracts presented at the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), and World Conference on Lung Cancer (WCLC) in the last 5 years. Our analysis considered works regarding new inhibitors for alterations of Kirsten rat sarcoma viral oncogene homolog (KRAS), PIK3CA, neuregulin-1 (NRG-1), human epidermal growth factor receptor 2 (HER2), fibroblast growth factor receptor (FGFR), genes that have recently become no longer undruggable. Conclusions: Precision oncology is revolutionizing the natural history of NSCLC. Several alterations have been identified as possible treatment targets, and numerous inhibitors show promising results in ongoing clinical trials

Precision oncology for RET-related tumors

Aberrant activation of the RET proto-oncogene is implicated in a plethora of cancers. RET gain-of-function point mutations are driver events in multiple endocrine neoplasia 2 (MEN2) syndrome and in sporadic medullary thyroid cancer, while RET rearrangements are driver events in several non-medullary thyroid cancers. Drugs able to inhibit RET have been used to treat RET-mutated cancers. Multikinase inhibitors were initially used, though they showed modest efficacy and significant toxicity. However, new RET selective inhibitors, such as selpercatinib and pralsetinib, have recently been tested and have shown good efficacy and tolerability, even if no direct comparison is yet available between multikinase and selective inhibitors. The advent of high-throughput technology has identified cancers with rare RET alterations beyond point mutations and fusions, including RET deletions, raising questions about whether these alterations have a functional effect and can be targeted by RET inhibitors. In this mini review, we focus on tumors with RET deletions, including deletions/insertions (indels), and their response to RET inhibitors

CT based radiomic approach on first line pembrolizumab in lung cancer

Clinical evaluation poorly predicts outcomes in lung cancer treated with immunotherapy. The aim of the study is to assess whether CT-derived texture parameters can predict overall survival (OS) and progression-free survival (PFS) in patients with advanced non-small-cell lung cancer (NSCLC) treated with first line Pembrolizumab. Twenty-one patients with NSLC were prospectively enrolled; they underwent contrast enhanced CT (CECT) at baseline and during Pembrolizumab treatment. Response to therapy was assessed both with clinical and iRECIST criteria. Two radiologists drew a volume of interest of the tumor at baseline CECT, extracting several texture parameters. ROC curves, a univariate Kaplan-Meyer analysis and Cox proportional analysis were performed to evaluate the prognostic value of texture analysis. Twelve (57%) patients showed partial response to therapy while nine (43%) had confirmed progressive disease. Among texture parameters, mean value of positive pixels (MPP) at fine and medium filters showed an AUC of 72% and 74% respectively (P < 0.001). Kaplan-Meyer analysis showed that MPP < 56.2 were significantly associated with lower OS and PFS (P < 0.0035). Cox proportional analysis showed a significant correlation between MPP4 and OS (P = 0.0038; HR = 0.89[CI 95%:0.83,0.96]). In conclusion, MPP could be used as predictive imaging biomarkers of OS and PFS in patients with NSLC with first line immune treatment

Anaphylactic death: A new forensic workflow for diagnosis

Anaphylaxis is a life-threatening or fatal clinical emergency characterized by rapid onset, and death may be sudden. The margin of certainty about the diagnosis of anaphylactic death is not well established. The application of immunohistochemical techniques combined with the evaluation of blood tryptase concentrations opened up a new field of investigation into anaphylactic death. The present study investigated eleven autopsy cases of anaphylactic death, carried out between 2005 and 2017, by the Departments of Forensic Pathology of the Universities of Foggia and Catania (Italy). An analysis of the medical records was carried out in all autopsies. Seven autopsies were carried out on males and four on females. Of the eleven cases, one showed a history of asthma, one of food ingestion, two of oral administration of medications, six did not refer any allergy history, and one subject was unknown. All cases (100%) showed pulmonary congestion and edema; 7/11 (64%) of the cases had pharyngeal/laryngeal edema and mucus plugging in the airway; only one case (9%) had a skin reaction that was found during external examination. Serum tryptase concentration was measured in ten cases, and the mean value was 133.5 µg/L ± 177.9. The immunohistochemical examination using an anti-tryptase antibody on samples from the lungs, pharynx/larynx, and skin site of medication injection showed that all cases (100%) were strongly immunopositive for anti-tryptase antibody staining on lung samples; three cases (30%) were strongly immunopositive for anti-tryptase antibody staining on pharyngeal/laryngeal samples; and eight cases (80%) were strongly immunopositive for anti-tryptase antibody staining on skin samples. We conclude that a typical clinical history, blood tryptase level >40 µg/L, and strongly positive anti-tryptase antibody staining in the immunohistochemical investigation may represent reliable parameters in the determination of anaphylactic death with the accuracy needed for forensic purposes

Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up F. Pacini, M. G. Castagna, L. Brilli & G. Pentheroudakis On behalf of the ESMO Guidelines Working Group* Section of Endocrinology and Metabolism, Department of Internal Medicine, Endocrinology and Metabolism and Biochemistry, Section of Endocrinology and Metabolism, University of Siena, Siena, Italy; Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greec