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Development of any real-time neutron beam sensor for boron neutron catch therapy by using a slender rubber sensor.
The discovery of actionable oncogenic driver alterations has significantly improved treatment options for patients with advanced non-small cell lung cancer (NSCLC). In lung adenocarcinoma (LUAD), approved drugs or drugs in clinical development can target more than half of these altered oncogenic driver genes. In particular, several gene fusions have been discovered in LUAD, including ALK, ROS1, NTRK, RET, NRG1 and FGFR. All these fusions involve tyrosine kinases (TK), which are activated due to structural rearrangements on the DNA level. Although the overall prevalence of these fusions in LUAD is rare, their detection is extremely important, as they are linked to an excellent response to TK inhibitors. Therefore, reliable screening methods applicable to small tumor samples (biopsies and cytology specimens) are required in the diagnostic workup of advanced NSCLC. Several methods are at disposal in a routine laboratory to demonstrate, directly or indirectly, the presence of a gene fusion. These methods include immunohistochemistry (IHC), fluorescence in-situ hybridization (FISH), reverse transcriptase-polymerase chain reaction (RT-PCR), multiplex digital color-coded barcode technology or next-generation sequencing (NGS) either on DNA or RNA level. In our review, we will summarize the increasing number of relevant fusion genes in NSCLC, point out their underlining molecular mechanisms and discuss different methods for the detection of fusion genes.Lung cancer currently stands out as both the most common and the most lethal type of cancer, the latter feature being partly explained by the fact that the majority of lung cancer patients already display advanced disease at the time of diagnosis. In recent years, the development of specific tyrosine kinase inhibitors (TKI) for the therapeutic benefit of patients harboring certain molecular aberrations and the introduction of prospective molecular profiling in the clinical practice have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). However, the identification of the best strategies to enhance treatment effectiveness and to avoid the critical phenomenon of drug tolerance and acquired resistance in patients with lung cancer still remains an unmet medical need. Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) are two complementary approaches to define tumor heterogeneity and clonal evolution in a non-invasive manner and to perform functional studies on metastatic cells. Finally, the recent discovery that the tumor microenvironment architecture can be faithfully recapitulated in vitro represents a novel pre-clinical frontier with the potential to optimize more effective immunology-based precision therapies that could rapidly move forward to the clinic.Recent evidence has shown that gene fusions caused by chromosomal rearrangements are frequent events in the initiation and during progression of solid tumors, including non-small cell lung cancers (NSCLCs). Since the discoveries of ALK and ROS1 fusions in 2007 and the subsequent successes of pharmacological targeting for these fusions, numerous efforts have identified additional oncogenic driver fusions in NSCLCs, especially in lung adenocarcinomas. In this review, we will summarize recent advances in this field focusing on novel oncogenic fusions other than ALK, ROS1, NTRK, and RET fusions, which are summarized in other articles in this thematic issue. These novel gene fusions include neuregulin-1 (NRG1) fusions, MET fusions, fusion genes involving fibroblast growth factor receptor (FGFR) family members, EGFR fusions, and other rare fusions. In addition, evidence has suggested that acquisition of gene fusions by cancer cells can be a molecular mechanism of acquired resistance to targeted therapies. Most of the current data are from analyses of resistance mechanisms to EGFR tyrosine kinase inhibitors in lung cancers with oncogenic EGFR mutations. However, a few recent studies suggest that gene fusions can also be a resistance mechanism to ALK-tyrosine kinase inhibitors in lung cancers with oncogenic ALK fusions. Detection, validation, and pharmacological inhibition of these fusion genes are becoming more important in the treatment of NSCLC patients.Up to 70% of non-small cell lung cancer (NSCLC) patients develop central nervous system (CNS) metastases during the course of their disease, especially those with oncogenic drivers treated with a first-generation tyrosine kinase inhibitor (TKI), because of the relatively poor CNS penetration. CNS metastases are associated with a negative impact on quality of life and survival. As, with the introduction of newer generation TKIs, the survival rates are increasing in this particular population, treatment and/or prevention of CNS metastases becomes even more relevant and the TKI with the best CNS efficacy should be selected. Unfortunately, CNS efficacy data in clinical trials are not fully comparable. Furthermore, oligoprogression to the brain without extracranial progression regularly occurs in the oncogenic driver population and both local therapy and switch of systemic therapy are possible treatment options. However, the best order of systemic and local therapy is still not precisely known. selleckchem In this narrative review, we will summarize incidence and treatment of CNS metastases in oncogene driven NSCLC, including the optimal treatment of CNS oligometastatic disease (synchronous as well as oligoprogressive).During the last several years, multiple gene rearrangements with oncogenic potential have been described in NSCLC, identifying specific clinic-pathological subgroups of patients that benefit from a targeted therapeutic approach, including anaplastic lymphoma kinase (ALK), c-ros protooncogene 1 (ROS1) and, more recently, REarranged during Transfection (RET) and neurotrophic tyrosine receptor kinases (NTRK) genes. Despite initial impressive antitumor activity, the use of targeted therapies in oncogene-addicted NSCLC subgroups is invariably associated with the development of acquired resistance through multiple mechanisms that can include both on-target and off-target mechanisms. However, the process of acquired resistance is a rapidly evolving clinical scenario that constantly evolves under the selective pressure of tyrosine kinase inhibitors. The development of increasingly higher selective and potent inhibitors, traditionally used to overcome resistance to first generation inhibitors, is associated with the development of novel mechanisms of resistance that encompass complex resistance mutations, highly recalcitrant to available TKIs, and bypass track mechanisms.
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