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![Progression-free survival and response rate in epidermal growth factor receptor (EGFR) mutation positive patients following first-line treatment. Data from Mitsudomi et al. [2009] and Makato et al. [2010].](profile/Paul-Germonpre/publication/51636186/figure/tbl2/AS:667629664624640@1536186724259/Progression-free-survival-and-response-rate-in-epidermal-growth-factor-receptor-EGFR.png)
Progression-free survival and response rate in epidermal growth factor receptor (EGFR) mutation positive patients following first-line treatment. Data from Mitsudomi et al. [2009] and Makato et al. [2010].
Source publication
Lung cancer is the leading cause of cancer deaths worldwide. Standard chemotherapy has been shown to improve quality of life and has a modest influence on overall survival. This modest improvement in survival is partly due to the choice of chemotherapy regimens that have been based on prognostic factors such as age, performance status and comorbidi...
Context in source publication
Context 1
... several trials have examined the poten- tial role of EGFR-TKIs in the first-line treatment of patients with tumors with activating mutations on the EGFR [Mitsudomi et al. 2010;Maemondo et al. 2010]. These trials all showed that the pres- ence of EGFR mutation is a strong predictive marker for improved response rate and improved progression free survival with EGFR-TKI versus chemotherapy (Table 4). The IPASS trial, which Table 3. Pemetrexed and non-small cell lung cancer histology: squamous versus adenocarcinoma, large-cell carcinoma and not other specified types. ...
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Lung cancer is the leading cause of cancer death in South Korea since the year 2000 and it is more common in elderly patients, with a peak incidence at around 70~80 years of age. However, these elderly patients receive treatment less often than do the younger patients because of organ dysfunction related to their age and their comorbidities, and th...
Citations
... November 2020 | Volume 11 | Article 572616 10 DISCUSSION NSCLC represents a highly malignant and particularly aggressive cancer, and has characteristics of early, widespread metastases and poor prognosis (Wang et al., 2020). NSCLC metastasis is the main cause of significant morbidity and mortality associated with surgical resection, involving tumor cell motility, intravasation, and circulation in the blood or lymph system (Sadowska et al., 2011). Cisplatin, a platinum agent, due to its affinity for DNA and other intracellular nucleophiles, has strong anti-tumor activity against a variety of malignant tumors including lung cancer (Trendowski et al., 2019). ...
Background: Targeting inflammatory microenvironment is a promising anti-tumor strategy. Paeonol is a phenolic compound with effective anti-inflammatory and anti-tumor properties. However, the effects of paeonol on non-small cell carcinoma (NSCLC) have not been fully investigated. Here, we evaluated the effects of paeonol on proliferation and metastasis of NSCLC and elucidated the underlying mechanisms.
Methods: The effects of paeonol on inflammatory cytokines were determined by cell proliferation and ELISA assays. Assays of wound healing, single cell migration and perforation invasion were used to evaluate migration and invasion of NSCLC cells. Expression of marker proteins in epithelial-mesenchymal transition (EMT) and matrix metalloproteinase (MMP) family enzymes were detected by Western blot assays. Nude mouse A549 cells transplantation tumor model was used to study the anti-lung cancer effects of paeonol in vivo. TUNEL stanining were used to detect the apoptosis of tumor cells in A549 lung cancer mice, and Ki67 analysis was used to detect the proliferation of tumor cells in A549 lung cancer mice. Immunohistochemistry was used to detect the effects of paeonol on signaling molecules in tumor tissues.
Results: Paeonol inhibited A549 cancer cell migration and invasion in vitro. Paeonol inhibited secreaion of inflammatory cytokines in A549 cells, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and transforming growth factor (TGF)-β. Paeonol altered the expression of marker proteins involved in EMT and MMP family enzymes. In addition, paeonol inhibited the transcriptional activity of nuclear factor-κB (NF-κB) and phosphorylation of signal transducers and activators of transcription 3 (STAT3). Paeonol inhibited the growth of A549 cells transplanted tumors in nude mice.
Conclusion: Paeonol potently inhibited NSCLC cell growth, migration and invasion associated with disruption of STAT3 and NF-κB pathways, suggesting that it could be a promising anti-metastatic candidate for tumor chemotherapy.
... Chemotherapies, including pemetrexed or gemcitabine in combination with platinum, are frequently used as the first-line therapy for advanced NSCLC. [4][5][6] However, current chemotherapy regimens do not provide long-term disease control in most patients with NSCLC. 7,8 Those who receive chemotherapy eventually encounter drug resistance and disease progression. ...
Cancer stem cells (CSCs) play an important role in cancer treatment resistance and disease progression. Identifying an effective anti‐CSC agent may lead to improved disease control. We used CSC‐associated gene signatures to identify drug candidates that may inhibit CSC growth by reversing the CSC gene signature. Thiostrepton, a natural cyclic oligopeptide antibiotic, was the top‐ranked candidate. In non–small‐cell lung cancer (NSCLC) cells, thiostrepton inhibited CSC growth in vitro and reduced protein expression of cancer stemness markers, including CD133, Nanog and Oct4A. In addition, metastasis‐associated Src tyrosine kinase signalling, cell migration and epithelial‐to‐mesenchymal transition (EMT) were all inhibited by thiostrepton. Mechanistically, thiostrepton treatment led to elevated levels of tumour suppressor miR‐98. Thiostrepton combined with gemcitabine synergistically suppressed NSCLC cell growth and induced apoptosis. The inhibition of NSCLC tumours and CSC growth by thiostrepton was also demonstrated in vivo. Our findings indicate that thiostrepton, an established drug identified in silico, is an inhibitor of CSC growth and a potential enhancer of chemotherapy in NSCLC.
... They are found in 10.0-15.0% of the patients with adenocarcinomas and only 3.0% of other histological types. In advanced NSCLC, the presence of an activating mutation in EGFR gene confers better prognosis and predicts the sensitivity of tumor cells to EGFR tyrosine kinase inhibitors (TKIs) [4,5]. In Bulgaria, it is recommended that patients with adenocarcinoma be tested for the EGFR gene mutations, so they can be given EGFR TKI as a first-line therapy instead of chemotherapy. ...
Mutations in the receptor of the epidermal growth factor receptor ( EGFR ) in non-small cell lung cancer (NSCLC) are used as biomarkers for predicting the response of treatment with EGFR tyrosine kinase inhibitors (EGFR TKIs). Non-small cell lung cancer patients usually have activating EGFR mutations that leads to a very good response when they are treated with EGFR TKIs. Our tumor samples were examined for the presence of sensitive mutations in the EGFR gene, resistant mutations or the absence of mutations. To identify the types of the mutation, we used a real-time polymerase chain reaction (RT-PCR) method. Additionally, we evaluated the frequency of EGFR mutations and their association with smoking status, gender and histology. The tumor samples ( n = 551) were tested for 29 somatic mutations in the EGFR gene. Sensitive mutations in the EGFR genes were found in 55 NSCLC samples (10.0%). The prevalence of EGFR mutations was much higher for females than for males (27.1 vs . 3.9%, p <0.001). The prevalence of EGFR mutations was greater in subjects who had never smoked than in smokers (15.0 vs . 6.08%, p <0.003). Additionally, the frequency of EGFR mutations was higher in adenocarcinomas than in other histological types (14.9 vs . 5.1%; p <0.001). Our results show that activating mutations on the EGFR gene are more frequent in females than in males, in adenocarcinoma than other histological types and in non smokers than smokers.
... Cancer treatment is gradually moving toward personalized therapy, allowing patients to avoid unnecessary or ineffective treatments (1). Tailoring therapies to the genetic profile of tumors requires effective diagnostic tools that would accurately detect clinically relevant genetic alterations. ...
Detection of low-level DNA variations in the presence of wild-type DNA is important in several fields of medicine, including
cancer, prenatal diagnosis and infectious diseases. PCR-based methods to enrich mutations during amplification have limited
multiplexing capability, are mostly restricted to known mutations and are prone to polymerase or mis-priming errors. Here,
we present Differential Strand Separation at Critical Temperature (DISSECT), a method that enriches unknown mutations of targeted DNA sequences purely based on thermal denaturation
of DNA heteroduplexes without the need for enzymatic reactions. Target DNA is pre-amplified in a multiplex reaction and hybridized
onto complementary probes immobilized on magnetic beads that correspond to wild-type DNA sequences. Presence of any mutation
on the target DNA forms heteroduplexes that are subsequently denatured from the beads at a critical temperature and selectively
separated from wild-type DNA. We demonstrate multiplexed enrichment by 100- to 400-fold for KRAS and TP53 mutations at multiple positions of the targeted sequence using two to four successive cycles of DISSECT. Cancer and plasma-circulating
DNA samples containing traces of mutations undergo mutation enrichment allowing detection via Sanger sequencing or high-resolution
melting. The simplicity, scalability and reliability of DISSECT make it a powerful method for mutation enrichment that integrates
well with existing downstream detection methods.
... Cancer treatment is gradually moving toward personalized therapy, allowing patients to avoid unnecessary or ineffective treatments (1). Tailoring therapies to the genetic profile of tumors requires effective diagnostic tools that would accurately detect clinically relevant genetic alterations. ...
Objective
This is a retrospective study to assess the effectiveness of consolidation radiotherapy (CRT) following palliative chemotherapy in patients with metastatic or locally advanced non-small cell lung cancer (NSCLC) who are not suitable for radical treatment.
Methods
This study involved retrospective analysis of a prospective database of Northampton Oncology Centre from January 2005 to December 2010, 63 patients with advanced/metastatic NSCLC treated at the oncology centre were enrolled. Patients were either treated with high dose (39/36 Gy / 13–12 fractions, group 1) or low dose (20 Gy / 5 fractions, group 2) CRT or those were not offered any CRT (group 3).
Results
There was no significant difference between the three groups as regard age, sex, performance status, comorbidities or chemotherapy given. However there was a statistically significant difference as regard the stage P = 0.009 with more stage IV patients at group II and III compared to group I. The mean survival for the three groups was 27 months, 14 months &15 months, respectively. There was a statistically significant improvement of survival in patients treated with high dose palliative CRT compared to the other two groups (P = 0.006). In multivariate analysis only the radiotherapy dose remains as the only statistical significant factor affecting the survival with hazard ratio 0.372 and confidence interval (0.147–0.726).
Conclusion
Despite the limitation of our retrospective study, it is worth considering CRT approach for patients with advanced and metastatic NSCLC — not suitable for radical treatment — who have not progressed on chemotherapy.
Non-small cell lung carcinoma (NSCLC) is one of the most refractory cancers in the clinic; it is insensitive to chemotherapy and is usually excised. However, screening natural compounds from herbs is also considered a possible method for its therapy. In the present study, we investigated whether matrine, a natural compound isolated from Sophora flavescens Ait. and exerting an inhibitory effect on lung cancer cells, also indicates inhibition on NSCLC cells and elucidated its molecular mechanism. Firstly, it is confirmed that matrine induces apoptosis of human NSCLC cells with anti-apoptotic factors inhibited and dependent on caspase activity. In addition, we found that matrine increases the phosphorylation of p38 but not its total protein, and inhibition of the p38 pathway with SB202190 partially prevents matrine-induced apoptosis. Furthermore, matrine generates reactive oxygen species (ROS) in a dose- and time-dependent manner, which is reversed by pretreatment with N-acetyl-L-cysteine (NAC). Additionally, inhibition of cell proliferation and increase of phosphorylation of p38 was also partially reversed by NAC. Collectively, matrine activates p38 pathway leading to a caspase-dependent apoptosis by inducing generation of ROS in NSCLC cells and may be a potential chemical for NSCLC.
Mutation analysis of the epidermal growth factor receptor (EGFR) gene is an essential part of the diagnostic algorithm in patients with metastatic or recurrent non-small cell lung cancer (NSCLC). Small biopsies or cytology specimens represent >80% of the available diagnostic material. EGFR mutation analyses were realized on 835 samples (675 cytology specimens, 151 formalin-fixed paraffin-embedded blocks, 5 tumors, and 4 pleural effusions). EGFR mutation analysis was performed by high-resolution melting analysis in combination with mutant-enriched polymerase chain reaction and sequencing analysis. Because of increased risk of inaccuracy in histology diagnosis of small specimens, all subtypes of NSCLC were analyzed. EGFR mutations were detected in 83 cases (10%). EGFR mutation testing failed in 5% (42/835) and was associated with poor cellularity, low percentage of tumor cells, and bad quality of DNA. Although 281 samples were evaluated as insufficient material (poor cellularity and/or unrepresentative tumor content), mutation rates were 7%. Although only adenocarcinomas or NSCLC-not otherwise specified are recommended for EGFR mutation testing, EGFR mutations in 11% of the large cell carcinomas and 4% of the squamous cell carcinomas were observed. Our results indicate that defined algorithm for EGFR testing of small diagnostic samples is sensitive, fast, and suitable even for samples with poor cellularity. The results of this testing should be evaluated depending on tumor content and DNA quality for each sample individually. At the conclusion of our results, we recommend to realize EGFR mutation analysis of small diagnostic samples regardless of the histologic subtypes of NSCLC.
Objective. The objective of this study was to review the epigenetic modifications involved in the transition from acute to chronic pain and to identify potential targets for the development of novel, individualized pain therapeutics.
Background. Epigenetics is the study of heritable modifications in gene expression and phenotype that do not require a change in genetic sequence to manifest their effects. Environmental toxins, medications, diet, and psychological stresses can alter epigenetic processes such as DNA methylation, histone acetylation, and RNA interference. As epigenetic modifications potentially play an important role in inflammatory cytokine metabolism, steroid responsiveness, and opioid sensitivity, they are likely key factors in the development of chronic pain. Although our knowledge of the human genetic code and disease-associated polymorphisms has grown significantly in the past decade, we have not yet been able to elucidate the mechanisms that lead to the development of persistent pain after nerve injury or surgery.
Design. This is a focused literature review of epigenetic science and its relationship to chronic pain.
Results. Significant laboratory and clinical data support the notion that epigenetic modifications are affected by the environment and lead to differential gene expression. Similar to mechanisms involved in the development of cancer, neurodegenerative disease, and inflammatory disorders, the literature endorses an important potential role for epigenetics in chronic pain.
Conclusions. Epigenetic analysis may identify mechanisms critical to the development of chronic pain after injury, and may provide new pathways and target mechanisms for future drug development and individualized medicine.
