Lung cancer is still the leading cause of cancer related death worldwide. Fibroblast growth factor receptor (FGFR) is a tirosine-kinase receptor that is seen to be amplified or mutated in non-small ...cell lung cancer (NSCLC) and it plays a crucial role in tumour development and maintenance. The authors analyzed the state of the art of FGFR by reviewing the current literature. Fibroblast growth factor (FGF)-FGFR pathway and their aberrations are described, with the evaluation of their possible prognostic role in NSCLC and in particular in squamous cell carcinomas, in which FGFR is more often amplified. New therapeutic agents targeting FGFR signaling have been developed and are now in clinical evaluation. Dysregulation of FGF signaling in tumour cells is related to FGFR gene amplification or mutation, although it is still uncertain which of these aberrations represents a real predictor of response to specific inhibitors. However, recent evidence has questioned whether FGFR is a real target in squamous cell histology. The effectiveness of FGFR inhibitors is also still unclear since there are no clinical data on selected patients. Moreover, the management of specific side effects related to inhibition of the physiological role of FGF should be more thorough.
The inhibition of the epidermal growth factor receptor (EGFR) through tyrosine kinase inhibitors (TKIs) represents an effective strategy for EGFR-mutated NSCLC. Afatinib is an irreversible ...erythroblastosis oncogene B (ErbB) family blocker, able to inhibit the kinase domains of EGFR, HER2 and HER4, and the transphosphorylation of ErbB3 that has recently been approved in the United States for the first-line treatment of EGFR-mutated NSCLC and in Europe and Japan for the treatment of EGFR-mutated TKI-naive patients.
The authors analyzed the pharmacology and the clinical activity of afatinib in NSCLC through a review of the literature. Trials exploring different settings have been reported, including LUX-Lung 3 and LUX-Lung 6, where the drug achieved better outcomes in terms of response rate, progression-free survival and quality of life compared with chemotherapy. The main toxicities of afatinib are gastrointestinal and skin-related adverse events.
Afatinib showed remarkable efficacy as a first-line treatment in the presence of common EGFR mutations. Afatinib showed some activity in NSCLC with acquired resistance to EGFR TKIs, although, currently, its efficacy after the failure of erlotinib or gefitinib has not been clearly stated. Direct clinical data comparing the activity and tolerability of different inhibitors are still needed.
Non-small cell lung cancer (NSCLC) is a major cause of cancer-related death worldwide. Although advanced NSCLC is still incurable, various anti-neoplastic agents have become available for the ...treatment of this disease. Pemetrexed , a multi-target folate antagonist, has improved the survival of non-squamous NSCLC patients. Currently, pemetrexed is approved for first-line treatment in combination with a platinum derivate, for second-line treatment as a single agent and, more recently, as maintenance treatment after first-line chemotherapy.
The authors analyzed the state of the art of pemetrexed through a review of the literature. Clinical trials and meta-analyses involving pemetrexed in NSCLC were evaluated. Pemetrexed improved survival of non-squamous NSCLC in first-line, maintenance, and second-line treatments; this benefit is limited to non-squamous histology. Because pemetrexed has become part of the standard of care, current clinical trials are designed to compare it to other investigational combinations. Limited data on resectable disease are available, and additional clinical trials are being conducted.
Pemetrexed has shown effectiveness and a favorable toxicity profile. Histology-driven indications and the relationship of pemetrexed with thymidylate synthase expression suggest that a more precise definition of predictive biomarkers could be further investigated.
The mucosae of the oral cavity are different at the histological level but appear all equally exposed to common genotoxic agents. As a result of this exposure, changes in the mucosal epithelia may ...develop giving rise to Oral Potentially Malignant Lesions (OPMLs), which with time may in turn progress to Oral Squamous Cell Carcinomas (OSCCs). Therefore, much effort should be devoted to identify features able to predict the likeliness of progression associated with an OPML. Such features may be helpful in assisting the clinician to establish both appropriate therapies and follow-up schedules. Here, we report a pilot study that compared the occurrence of DNA aneuploidy and chromosomal copy number aberrations (CNAs) in the OPMLs from different oral anatomical subsites.
Samples from histologically diagnosed OPMLs were processed for high resolution DNA flow cytometry (hr DNA-FCM) in order to determine the relative DNA content expressed by the DNA index (DI). Additionally, array-Comparative Genomic Hybridization (a-CGH) analysis was performed on DNA obtained from diploid nuclei suspensions directly. When aneuploid nuclei were detected, these were physically separated from diploid nuclei on the base of their DI values by means of a DNA-FCM-Sorter in order to improve the a-CGH analysis.
Tongue OPMLs were more frequently associated with DNA aneuploidy and CNAs than OPMLs arising from all the other mucosal subsites.
We suggest that the follow-up and the management of the patients with tongue OPMLs should receive a distinctive special attention. Clearly, this hypothesis should be validated in a prospective clinical study.
•Platelets can act as tumor ‘defenders’ and active ‘players’ promoting cancer progression.•Tumor cells give rise to ‘tumor-educated platelets’ by direct/indirect mechanisms.•Platelets can, in turn, ...educate tumor cells, giving rise to ‘platelet-educated tumors’.•Platelet number and platelet-EV concentration are altered in NSCLC patients.•Platelets and their derived EVs are potential diagnostic/prognostic markers in NSCLC.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death. Circulating elements have gained significant interest in the diagnosis and prognosis of NSCLC patients. Among these, platelets (PLTs) and their derived extracellular vesicles (P-EVs) are emerging eligible biosources both in terms of number and carriers of genetic materials (RNA, proteins, and lipids). PLTs are mainly produced by the shedding of megakaryocytes and together with P-EVs, participate in a variety of pathological processes including thrombosis, tumor progression, and metastasis. Here, we performed an extensive literature review focusing on PLTs and P-EVs as potential diagnostic, prognostic, and predictive markers for NSCLC patient management.
Exosomes: a new horizon in lung cancer Vanni, Irene; Alama, Angela; Grossi, Francesco ...
Drug discovery today,
June 2017, 2017-Jun, 2017-06-00, 20170601, Letnik:
22, Številka:
6
Journal Article
Recenzirano
•Exosomes play a key part in tumorigenesis and progression of cancer.•Exosomes can be isolated from cell culture media and almost all body fluids.•Exosomes are cargos of DNA, mRNA, miRNAs and ...proteins.•Exosomes are candidates as diagnostic/prognostic/predictive markers in lung cancer.•Exosomes can represent emerging therapeutic drug carriers.
Circulating exosomes are the major mediators of cell–cell communication. They have been found in various body fluids of healthy individuals and patients with malignancies as cargos of several molecules including miRNAs. Several studies have underlined the role of exosome miRNAs in different tumor types, including lung cancer, suggesting their potential use as biomarkers and therapeutic agents. An overview of the biology and function of exosomes and exosome miRNAs as indicators of diagnosis and treatment response in lung cancer is presented. In addition, preliminary data on exosomes as potential therapeutic agents are reported.
Epigenetic Silencing of DKK3 in medulloblastoma Valdora, Francesca; Banelli, Barbara; Stigliani, Sara ...
International journal of molecular sciences,
04/2013, Letnik:
14, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Medulloblastoma (MB) is a malignant pediatric brain tumor arising in the cerebellum consisting of four distinct subgroups: WNT, SHH, Group 3 and Group 4, which exhibit different molecular phenotypes. ...We studied the expression of Dickkopf (DKK) 1-4 family genes, inhibitors of the Wnt signaling cascade, in MB by screening 355 expression profiles derived from four independent datasets. Upregulation of DKK1, DKK2 and DKK4 mRNA was observed in the WNT subgroup, whereas DKK3 was downregulated in 80% MBs across subgroups with respect to the normal cerebellum (p < 0.001). Since copy number aberrations targeting the DKK3 locus (11p15.3) are rare events, we hypothesized that epigenetic factors could play a role in DKK3 regulation. Accordingly, we studied 77 miRNAs predicting to repress DKK3; however, no significant inverse correlation between miRNA/mRNA expression was observed. Moreover, the low methylation levels in the DKK3 promoters (median: 3%, 5% and 5% for promoter 1, 2 and 3, respectively) excluded the downregulation of gene expression by methylation. On the other hand, the treatment of MB cells with Trichostatin A (TSA), a potent inhibitor of histone deacetylases (HDAC), was able to restore both DKK3 mRNA and protein. In conclusion, DKK3 downregulation across all MB subgroups may be due to epigenetic mechanisms, in particular, through chromatin condensation.
Non-small cell lung cancer is one leading cause of death worldwide, and patients would greatly benefit from an early diagnosis. Since targeted and immunotherapies have emerged as novel approaches for ...more tailored treatments, repeated assessments of the tumor biology have become pivotal to drive clinical decisions. Currently, tumor tissue biopsy is the gold standard to investigate potentially actionable biomarkers, but this procedure is invasive and may prove inadequate to represent the whole malignancy. In this regard, liquid biopsy represents a minimally invasive and more comprehensive option for early detection and investigation of this tumor. Today, cell-free DNA is the only approved circulating marker to select patients for a targeted therapy. Conversely, the other tumor-derived markers (i.e., circulating tumor cells, miRNAs, exosomes, and tumor educated platelets) are still at a pre-clinical phase, although they show promising results for their application in screening programs or as prognostic/predictive biomarkers. The main challenges for their clinical translation are the lack of reliable cutoffs and, especially for miRNAs, the great variability among the studies. Moreover, no established tool has been approved for circulating tumor cells and exosome isolation. Finally, large prospective clinical trials are mandatory to provide evidence of their clinical utility.
Ultra Conserved Regions (UCRs) are a class of 481 noncoding sequences located in both intra- and inter-genic regions of the genome. The recent findings that they are significantly altered in adult ...chronic lymphocytic leukemias, carcinomas, and pediatric neuroblastomas lead to the hypothesis that UCRs may play a role in tumorigenesis.
We present a novel application of Ribo-SPIA isothermal linear amplification of minute RNA quantities for quantifying Transcribed-UCR (T-UCR) expression by quantitative PCR. Direct comparison of non-amplified with amplified cDNA in two neuroblastoma cell lines showed that the amplification approach increases sensitivity and repeatability in T-UCR quantification. It is noteworthy that the Ribo-SPIA step allowed us to analyze all 481 T-UCRs by using 150 ng of RNA, while introducing a minimal bias and preserving the magnitude of relative expression. Only the less abundant T-UCRs have high intra-assay variability, consistently with the Poisson distribution statistics and stochastic effects on PCR repeatability.
We demonstrated that the quantification procedure shown here is an accurate and reliable technique for genome-wide non coding gene (i.e., UCRs) profiling using small amounts of RNA. This issue is particularly important because studies of transcription regulation are increasingly conducted in small homogeneous samples, such as laser capture microdissected or sorted cell populations.
Radiomic Detection of EGFR Mutations in NSCLC Rossi, Giovanni; Barabino, Emanuele; Fedeli, Alessandro ...
Cancer research (Chicago, Ill.),
02/2021, Letnik:
81, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Radiomics is defined as the use of automated or semi-automated post-processing and analysis of multiple features derived from imaging exams. Extracted features might generate models able to predict ...the molecular profile of solid tumors. The aim of this study was to develop a predictive algorithm to define the mutational status of EGFR in treatment-naïve patients with advanced non-small cell lung cancer (NSCLC). CT scans from 109 treatment-naïve patients with NSCLC (21
-mutant and 88
-wild type) underwent radiomics analysis to develop a machine learning model able to recognize
-mutant from
-WT patients via CT scans. A "test-retest" approach was used to identify stable radiomics features. The accuracy of the model was tested on an external validation set from another institution and on a dataset from the Cancer Imaging Archive (TCIA). The machine learning model that considered both radiomic and clinical features (gender and smoking status) reached a diagnostic accuracy of 88.1% in our dataset with an AUC at the ROC curve of 0.85, whereas the accuracy values in the datasets from TCIA and the external institution were 76.6% and 83.3%, respectively. Furthermore, 17 distinct radiomics features detected at baseline CT scan were associated with subsequent development of T790M during treatment with an EGFR inhibitor. In conclusion, our machine learning model was able to identify
-mutant patients in multiple validation sets with globally good accuracy, especially after data optimization. More comprehensive training sets might result in further improvement of radiomics-based algorithms. SIGNIFICANCE: These findings demonstrate that data normalization and "test-retest" methods might improve the performance of machine learning models on radiomics images and increase their reliability when used on external validation datasets.
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