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PURPOSE: Clinical evidence of metastasis with ground-glass nodules (GGNs) has been reported, including pulmonary metastasis and distant metastasis. However, the clonal relationships of multiple GGNs at the genetic level remain unclear. EXPERIMENTAL DESIGN: Sixty tissue specimens were obtained from 19 patients with multiple GGN lung cancer who underwent surgery in 2019. Whole exome sequencing (WES) was performed on tissue samples, and genomic profiling and clone evolution analysis were conducted to investigate the genetic characteristics and clonality of multiple GGNs. RESULTS: A total of 15,435 nonsynonymous mutations were identified by WES, and GGNs with shared nonsynonymous mutations were observed in seven patients. Copy number variant (CNV) analysis showed that GGNs in ten patients had at least one shared arm-level CNV. Mutational spectrum analysis showed that GGNs in three patients had similar six substitution profiles and GGNs in fou patients had similar 96 substitution profiles. According to the clone evolution analysis, we found that GGNs in five patients had shared clonal driver gene mutations. Taken together, we identified that 5 patients may have multiple primary GGNs without any similar genetic features, 2 patients may have intrapulmonary metastatic GGNs with ≥ 3 similar genetic features, and the other 12 patients cannot be determined due to insufficient evidences in our cohort. CONCLUSIONS: Our findings suggest that the intrapulmonary metastasis exist in multiple GGNs, but the number of GGNs was not associated with the probability of metastasis. Application of genomic profiling may prove to be important to precise management of patients with multiple GGNs.
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Neoplasias Pulmonares , Neoplasias Primárias Múltiplas , Humanos , Neoplasias Pulmonares/patologia , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Sequenciamento do ExomaRESUMO
BACKGROUND: Ezrin-radixin-moesin (ERM) have been explored in many cancer processes. Moesin, as its component, has also been found to play an important role in the prognosis of cancer patients, tumor metastasis, drug resistance, and others. Especially in regulating the immunity, but most results came from direct studies on immune cells, there is no clear conclusion on whether moesin has similar effects in tumor cells. And moesin has certain research results in many cancers in other aspects, but there are few about moesin in lung adenocarcinoma (LUAD). METHODS: We detect the expression of moesin in 82 LUAD and matched normal tissue samples by immunohistochemistry. Besides, for the pathological feature, we did a detailed statistical analysis. And with the help of various databases, we have done in-depth exploration of moesin's ability to enhance the extent of immune lymphocyte infiltration. RESULTS: Moesin is a poor expression in lung cancer tissues than the corresponding normal samples. And this phenomenon had a strongly associated with the prognosis and TNM stage of these LUAD patients. Moesin can enhance the infiltration of multiple immune lymphocytes in lung cancer. And this may be related to the interaction between moesin and various inflammatory molecules. CONCLUSIONS: Moesin is a newly index for the prognosis of LUAD and improves the prognosis of LUAD patients by regulating a variety of inflammation-related molecules to enhance immune lymphocytes infiltration.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Proteínas dos Microfilamentos , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/imunologia , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/imunologia , PrognósticoRESUMO
First-generation EGFR-TKIs (gefitinib/erlotinib) and second-generation EGFR-TKI (afatinib) have become the current first-line treatments for EGFR-mutated non-small cell lung cancer (NSCLC), however, the effects of using second-generation EGFR-TKIs compared to those of using first-generation EGFR-TKIs as a first-line treatment for NSCLC patients with EGFR mutations remain unknown. We conducted this meta-analysis based on 4 retrospective and 2 randomized controlled studies published between 2016 and 2018. We surveyed the effectiveness of afatinib/dacomitinib and gefitinib/erlotinib as first-line treatments for stage III-IV EGFR-mutated NSCLC patients. The combined hazard ratio (HR) for the progression free survival (PFS) of second-generation EGFR-TKI group versus that first-generation drug group was 0.64 [95% confidence interval (95% CI) 0.55-0.74; P<0.001], demonstrating a superior PFS in the second-generation group. This outcome coincided with the subgroup analyses comparing the PFS of patients with EGFR exon 19 deletion (HR = 0.68 [95% CI 0.55-0.83; P = 0.0002]) or L858R mutation (HR = 0.64 [95% CI 0.51-0.81; p=0.0002]). Meanwhile, second-generation drugs could to significantly improve the time to progression (TTFs) compared to first-generation drugs (HR = 0.81 [95% CI 0.67-0.89; P = 0.03]). Afatinib and dacomitinib may be the superior first-line treatment for advanced NSCLC patients with EGFR mutations.
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Afatinib/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/uso terapêutico , Gefitinibe/uso terapêutico , Genes erbB-1/genética , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Neoplasias Pulmonares/genética , Mutação/genética , Resultado do TratamentoRESUMO
BACKGROUND: SH3-containing guanine nucleotide exchange factor (SGEF), a RhoG-specific guanine nucleotide exchange factor (GEF), was consider as a key signal that determines cancer cell invasion. Although SGEF has been considered to highly express in glioma and prostate cancer. However, it is not well illustrated in LAC. METHODS: In this experiment, expression of SGEF was detected in 92 LAC and corresponding normal tissue samples by immunohistochemistry. In addition, we evaluated the invasion and migration of lung adenocarcinoma cells by the gain and loss of SGEF expression. Furthermore, RhoG activity was measured by GST pull-down assay. RESULTS: SGEF is highly expressed in LAC tissues than in normal lung tissues and was associated with the TNM stage. Lung adenocarcinoma patients with low SGEF subgroup had longer overall survival compared to those with high expression. Furthermore, univariate analysis showed that SGEF expression was an independent prognostic factor for overall survival in lung adenocarcinoma. Silencing of SGEF effectively suppressed the invasion and migration of human lung adenocarcinoma cells in vitro by inhibiting RhoG activity, and over-expression of SGEF could reverse this phenomena. CONCLUSION: SGEF is a novel prognostic target in human lung adenocarcinoma.
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Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Movimento Celular , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Adenocarcinoma/cirurgia , Adenocarcinoma de Pulmão , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Taxa de Sobrevida , Células Tumorais CultivadasRESUMO
BACKGROUND: The purpose of this study is to detect the Parkinson's disease gene family mRNA relative expression in the non-small-cell lung cancer (NSCLC) tumor tissue and analyze the association between tumor characteristics and the Parkinson's disease gene family. METHODS: Tumor tissue and tumor-adjacent tissue of 114 NSCLC patients were collected and SYBR quantitative analysis was used to detect the relative expression level of nine Parkinson's disease gene mRNAs. Then, paired sample test, two-sided Student's t-test, or two-sided Wilcoxon rank sum test was performed to analyze the mRNA relative expression level of nine Parkinson's disease gene mRNAs in different gender, tumor histology, and tumor stage. RESULTS: Overexpression in the tumors was detected in 46/114 (40.35%) PARK1/4, 74/114 (64.91%) PARK2, 104/114 (91.23%) PARK5, 95/114 (83.33%) PARK6, 80/114 (70.18%) PARK7, 55/114 (48.25%) PARK8, 100/114 (87.72%) PARK9, 55/114 (48.25%) PARK15, and 99/114 (86.84%) glucocerebrosidase (GBA). Five genes PARK5 (91.23%), PARK6 (83.33%), PARK7 (70.18%), PARK9 (87.72%), and GBA (86.84%) were supposed to be overexpressed in the lung tumor tissues compared with tumor-adjacent tissues. There was no significant difference in PARK1/4, PARK2, PARK5, PARK9, and GBA mRNA expression by different tumor stage, whereas, PARK6, PARK7, PARK8, and PARK15 mRNA expression were found to have significant difference in the comparison of different tumor stages. The expression of PARK6 (P=0.01, P=0.03) and PARK15 (P<0.001, P<0.001) were significantly higher in stages I and II when compared with stage III, respectively. NSCLC patients in stage I showed the higher expression PARK7 compared to the patients in stage II (P=0.003). CONCLUSIONS: The high expression of PARK6, PARK7, and PARK15 might lead to the occurrence of a primary NSCLC tumor, and the tumor with a decreasing expression of these three genes tends to be stages II and III. The results of our study indicate that the Parkinson's disease gene family may be a potential marker for the prediction of NSCLC.
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Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Mutação/genética , Doença de Parkinson/genética , Adenocarcinoma/patologia , Adolescente , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Família Multigênica , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto JovemRESUMO
INTRODUCTION: LUAD (Lung adenocarcinoma), the most common subtype of lung carcinoma and one of the highest incidences and mortality cancers in the world remains still a substantial treatment challenge. Ivermectin, an avermectin derivative, has been traditionally used as an antiparasitic agent in human and veterinary medicine practice during the last few decades. Though ivermectin has been shown to be effective against a variety of cancers, however, there is few available data reporting the antitumor effects of ivermectin in LUAD. METHODS: The effect of ivermectin on cell viability and proliferative ability of LUAD cells was evaluated using CCK-8 and colony formation assay. Apoptosis rate and autophagy flux were detected using flow cytometry based on PI/Annexin V staining and confocal laser scanning microscope based on LC3-GFP/RFP puncta, respectively. Western blotting experiment was conducted to verify the results of changes in apoptosis and autophagy. LUAD-TCGA and GEO databases were used to analyse the expression and predictive value of PAK1 in LUAD patients. Xenograft model and immumohistochemical staining were used for verification of the inhibitor effect of ivermectin in vivo. RESULTS: Ivermectin treatment strikingly impeded the colony formation, and the viability of the cell, along with cell proliferation, and caused the apoptosis and enhanced autophagy flux in LUAD cells. In addition, ivermectin-induced nonprotective autophagy was confirmed by treating LUAD cells with 3-MA, an autophagy inhibitor. Mechanistically, we found that ivermectin inhibited PAK1 protein expression in LUAD cells and we confirmed that overexpression of PAK1 substantially inhibited ivermectin-induced autophagy in LUAD cells. Based on TCGA and GEO databases, PAK1 was highly expressed in LUAD tissues as compared with normal tissues. Furthermore, LUAD patients with high PAK1 level have poor overall survival. Finally, in vivo experiments revealed that ivermectin efficiently suppressed the cellular growth of LUAD among nude mice. CONCLUSION: This study not only revealed the mechanism of ivermectin inhibited the growth of LUAD but also supported an important theoretical basis for the development of ivermectin during the therapy for LUAD.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Animais , Camundongos , Humanos , Ivermectina/farmacologia , Camundongos Nus , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/patologia , Autofagia , Proliferação de Células , Apoptose , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismo , Quinases Ativadas por p21/farmacologiaRESUMO
OBJECTIVE: The genomic and molecular ecology involved in the stepwise continuum progression of lung adenocarcinoma (LUAD) from adenocarcinoma in situ (AIS) to minimally invasive adenocarcinoma (MIA) and subsequent invasive adenocarcinoma (IAC) remains unclear and requires further elucidation. We aimed to characterize gene mutations and expression landscapes, and explore the association between differentially expressed genes (DEGs) and significantly mutated genes (SMGs) during the dynamic evolution from AIS to IAC. METHODS: Thirty-five patients with ground-glass nodules (GGNs) lung adenocarcinomas were enrolled. Whole-exome sequencing (WES) and transcriptome sequencing (RNA-Seq) were conducted on all patients, encompassing both tumor samples and corresponding noncancerous tissues. Data obtained from WES and RNA-Seq were subsequently analyzed. RESULTS: The findings from WES delineated that the predominant mutations were observed in EGFR (49%) and ANKRD36C (17%). SMGs, including EGFR and RBM10, were associated with the dynamic evolution from AIS to IAC. Meanwhile, DEGs, including GPR143, CCR9, ADAMTS16, and others were associated with the entire process of invasive LUAD. We found that the signaling pathways related to cell migration and invasion were upregulated, and the signaling pathways of angiogenesis were downregulated across the pathological stages. Furthermore, we found that the messenger RNA (mRNA) levels of FAM83A, MAL2, DEPTOR, and others were significantly correlated with CNVs. Gene set enrichment analysis (GSEA) showed that heme metabolism and cholesterol homeostasis pathways were significantly upregulated in patients with EGFR/RBM10 co-mutations, and these patients may have poorer overall survival than those with EGFR mutations. Based on the six calculation methods for the immune infiltration score, NK/CD8+ T cells decreased, and Treg/B cells increased with the progression of early LUAD. CONCLUSIONS: Our findings offer valuable insights into the unique genomic and molecular features of LUAD, facilitating the identification and advancement of precision medicine strategies targeting the invasive progression of LUAD from AIS to IAC.
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Adenocarcinoma de Pulmão , Sequenciamento do Exoma , Neoplasias Pulmonares , Mutação , Invasividade Neoplásica , Humanos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Transcriptoma , Perfilação da Expressão Gênica , Adenocarcinoma in Situ/genética , Adenocarcinoma in Situ/patologia , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Biomarcadores Tumorais/genéticaRESUMO
Cancer remains a significant global health issue, despite advances in screening and treatment. While existing tumor treatment protocols such as surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy have proven effective in enhancing the prognosis for some patients, these treatments do not benefit all patients. Consequently, certain types of cancer continue to exhibit a relatively low 5-year survival rate. Therefore, the pursuit of novel tumor intervention strategies may help improve the current effectiveness of tumor treatment. Over the past few decades, numerous species of protozoa and their components have exhibited anti-tumor potential via immune and non-immune mechanisms. This discovery introduces a new research direction for the development of new and effective cancer treatments. Through in vitro experiments and studies involving tumor-bearing mice, the anti-tumor ability of Toxoplasma gondii, Plasmodium, Trypanosoma cruzi, and other protozoa have unveiled diverse mechanisms by which protozoa combat cancer, demonstrating encouraging prospects for their application. In this review, we summarize the anti-tumor ability and anti-tumor mechanisms of various protozoa and explore the potential for their clinical development and application.
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Neoplasias , Plasmodium , Toxoplasma , Trypanosoma cruzi , Humanos , Animais , Camundongos , Neoplasias/terapia , Imunoterapia/métodosRESUMO
The purpose of this work was to evaluate the effects of autologous bone marrow stem cell transplantation (AMSCT) and transarterial embolization (TAE) in patients with hepatocellular carcinoma (HCC) and hepatic dysfunction. A 58-year-old male with HCC and hepatic function of Child's class C was treated with 8 ml of a lipiodol emulsion by injection into the artery feeding of his tumor, and >10(8) bone marrow stem cells were isolated from 400 ml bone marrow and then injected into the right hepatic artery. The patient's laboratory examinations revealed a progressive decrease in total bilirubin (from 264.8 to 77.9 µmol/L) and direct bilirubin (from 222.0 to 59.7 µmol/L) after 1 month, and a repeat CT showed that most of the tumor was filled with lipiodol. The combined treatment using AMSCT and TAE is a good choice of treatment for HCC patients who are unable to tolerate TACE due to hepatic dysfunction.
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Transplante de Medula Óssea , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Transplante de Células-Tronco , Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/fisiopatologia , Terapia Combinada , Embolização Terapêutica , Óleo Etiodado/administração & dosagem , Seguimentos , Humanos , Injeções Intra-Arteriais , Cirrose Hepática/complicações , Testes de Função Hepática , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/fisiopatologia , Masculino , Pessoa de Meia-Idade , Transplante AutólogoRESUMO
PURPOSE: The efficacy of radiotherapy for treating thymomas is unclear. The goal of this study was to analyze overall survival (OS) and disease-free survival (DFS) among thymoma patients to determine the impact of postoperative radiotherapy (PORT) on thymoma outcomes. METHODS: Recorded cases of thymoma at Xinqiao Hospital were retrospectively analyzed from 1991 to 2019. Data on stage II and III thymomas were extracted from medical records. This study evaluated OS and DFS and compared outcomes between surgery and surgery-plus-radiation groups. The Kaplan-Meier method and Cox regression analysis were used to compare DFS and OS for these groups. RESULTS: Of the 205 patients included in the current study, 142 (69.3%) presented with stage II disease and 63 (30.7%) presented with stage III disease. The median follow-up was 84.3 months. PORT did not statistically significantly improve OS (P = 0.613) and DFS (P = 0.445) in stage II thymoma patients (compared with surgery alone). However, our subgroup analysis showed a statistically significant difference in DFS in patients with stage III thymoma (P = 0.044). CONCLUSION: Although the routine use of postoperative radiotherapy in patients with thymoma does not appear warranted, patients with stage III thymoma may benefit from adjuvant radiation. These findings, if confirmed, will provide valuable information to guide medical decision-making for thymoma treatment.
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Timoma , Neoplasias do Timo , Humanos , Timoma/radioterapia , Timoma/cirurgia , Estudos Retrospectivos , Estadiamento de Neoplasias , Taxa de Sobrevida , Neoplasias do Timo/radioterapia , Neoplasias do Timo/cirurgiaRESUMO
Background: Almost all lung adenocarcinoma (LUAD) patients with EGFR mutant will develop resistance to EGFR-TKIs, which limit the long-term clinical application of these agents. Accumulating evidence shows one of the main reasons for resistance to EGFR-TKIs is induction of autophagy in tumor cells. Our previous study found that circumsporozoite protein (CSP) in Plasmodium can suppress autophagy in host hepatocytes. However, it is unknown whether CSP-mediated inhibition of autophagy could improve the anti-tumor effect of EGFR-TKIs. Methods: We constructed A549 and H1975 cell lines with stable overexpression of CSP (OE-CSP cells). CCK-8, Lactate Dehydrogenase (LDH), flow cytometry, and colony analysis were performed to observe the effect of CSP overexpression on cell viability, apoptosis rate, and colony formation ratio. The sensitizing effect of CSP on gefitinib was evaluated in vivo using a subcutaneous tumor model in nude mice and immunohistochemical assay. The role of CSP in regulation of autophagy was investigated by laser confocal microscopy assay and western blotting. A transcriptome sequencing assay and real-time polymerase chain reaction were used to determine the levels of mRNA for autophagy-related proteins. Cycloheximide (CHX), MG132, TAK-243, and immunoprecipitation assays were used to detect and confirm proteasomal degradation of LC3B. Results: OE-CSP A549 and H1975 cells were more sensitive to gefitinib, demonstrating significant amounts of apoptosis and decreased viability. In the OE-CSP group, autophagy was significantly inhibited, and there was a decrease in LC3B protein after exposure to gefitinib. Cell viability and colony formed ability were recovered when OE-CSP cells were exposed to rapamycin. In nude mice with xenografts of LUAD cells, inhibition of autophagy by CSP resulted in suppression of cell growth, and more marked apoptosis during exposure to gefitinib. CSP promoted ubiquitin-proteasome degradation of LC3B, leading to inhibition of autophagy in LUAD cells after treatment with gefitinib. When LUAD cells were treated with ubiquitin activating enzyme inhibitor TAK-243, cell viability, apoptosis, and growth were comparable between the OE-CSP group and a control group both in vivo and in vitro. Conclusion: CSP can inhibit gefitinib-induced autophagy via proteasomal degradation of LC3B, which suggests that CSP could be used as an autophagy inhibitor to sensitize EGFR-TKIs.
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Drug repositioning is a strategy for identifying new antitumor drugs; this strategy allows existing and approved clinical drugs to be innovatively repurposed to treat tumors. Based on the similarities between parasitic diseases and cancer, recent studies aimed to investigate the efficacy of existing antiparasitic drugs in cancer. In this review, we selected two antihelminthic drugs (macrolides and benzimidazoles) and two antiprotozoal drugs (artemisinin and its derivatives, and quinolines) and summarized the research progresses made to date on the role of these drugs in cancer. Overall, these drugs regulate tumor growth via multiple targets, pathways, and modes of action. These antiparasitic drugs are good candidates for comprehensive, in-depth analyses of tumor occurrence and development. In-depth studies may improve the current tumor diagnoses and treatment regimens. However, for clinical application, current investigations are still insufficient, warranting more comprehensive analyses.
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Recent studies have revealed that antiparasitic agents showed promising inhibitory effects on tumors, raising a possibility that repositioning this class of drugs may shed new light on clinical therapy against tumors. CWHM-1008 is a novel class of antimalarial drug; however, the inhibitory impact of CWHM-1008 on lung adenocarcinoma (LUAD) cells remains unclear. This study aimed to explore the anticancer effect and underlying mechanisms of CWHM-1008 on LUAD cells in vitro and in vivo. Human LUAD cells, H358 and A549, were treated with varying concentrations of CWHM-1008 at different lengths of time. Cell viability, colony formation, cell count, flow cytometry findings, microtubule-associated protein-1 light chain 3-green- (LC3-) GFP/RFP adenovirus infection status, and the expression of apoptosis and autophagy-related proteins were examined. Potential effects of an autophagy inhibitor (LY294002) and constitutively active Akt plasmid (CA-Akt) on CWHM-1008-induced apoptosis were also examined. Our results showed that CWHM-1008 significantly inhibited proliferation, induced apoptosis, and enhanced autophagy flux by blocking the RAC-alpha serine/threonine-protein kinase/the mammalian target of rapamycin (Akt/mTOR) axis in two LUAD cells. In addition, autophagy inhibited by LY294002 or CA-Akt transfection accelerated CWHM-1008-induced apoptosis in those LUAD cells. Moreover, CWHM-1008 significantly inhibited the growth and induced apoptosis of A549 cell in nude mice in vivo. The present findings provide new insights into anticancer properties of CWHM-1008, suggesting that it may be an adjuvant treatment for LUAD treatment, warranting further study.
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Addressing the high false-positive rate of conventional low-dose computed tomography (LDCT) for lung cancer diagnosis, the efficacy of incorporating blood-based noninvasive testing for assisting practicing clinician's decision making in diagnosis of pulmonary nodules (PNs) is investigated. In this prospective observative study, next generation sequencing- (NGS-) based cell-free DNA (cfDNA) mutation profiling, NGS-based cfDNA methylation profiling, and blood-based protein cancer biomarker testing are performed for patients with PNs, who are diagnosed as high-risk patients through LDCT and subsequently undergo surgical resections, with tissue sections pathologically examined and classified. Using pathological classification as the gold standard, statistical and machine learning methods are used to select molecular markers associated with tissue's malignant classification based on a 98-patient discovery cohort (28 benign and 70 malignant), and to construct an integrative multianalytical model for tissue malignancy prediction. Predictive models based on individual testing platforms have shown varying levels of performance, while their final integrative model produces an area under the receiver operating characteristic curve (AUC) of 0.85. The model's performance is further confirmed on a 29-patient independent validation cohort (14 benign and 15 malignant, with power > 0.90), reproducing AUC of 0.86, which translates to an overall sensitivity of 80% and specificity of 85.7%.
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Metilação de DNA/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/diagnóstico , Nódulos Pulmonares Múltiplos/sangue , Nódulos Pulmonares Múltiplos/diagnóstico , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Diagnóstico Diferencial , Feminino , Humanos , Neoplasias Pulmonares/genética , Aprendizado de Máquina , Masculino , Nódulos Pulmonares Múltiplos/genética , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
In recent years, more and more studies have shown that antiparasitic drugs can affect a variety of biological processes of tumor cells and exhibit a potential anti-tumor activity. Although artesunate (ART), a strong bioactive derivative of artemisinin and widely used clinically against malaria, was found to have an inhibitory effect on tumor cells, it is still unclear whether ART could regulate the tumor malignancy of non-small-cell lung cancer (NSCLC) cells. In this study, we aimed to investigate the effect of ART on migration capacities in NSCLC cell lines of A549 and H1975. Cell migration capacity was remarkably inhibited by ART treatment. The expression of epithelial marker E-cadherin was upregulated, while mesenchymal markers (N-cadherin, vimentin and FN1) were inhibited by ART in both protein and mRNA levels in A549 and H1975 cells, indicating ART could suppress the epidermal interstitial transformation (EMT) of NSCLC cells. Meanwhile, BTBD7 was found highly expressed in tumor tissues of NSCLC patient and associated with poor prognosis. The anti-migration activity of ART was found to be mediated by the inhibition of BTBD7 mRNA expression and was reversed when the cells were transiently transfected with the BTBD7 overexpression plasmid. Our study demonstrated the potent anti-migratory activity of ART, thereby presenting it as a new candidate for clinical therapy in NSCLC.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Transição Epitelial-Mesenquimal/fisiologia , Células A549 , Proteínas Adaptadoras de Transdução de Sinal/genética , Artesunato/farmacologia , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Humanos , RNA Mensageiro/metabolismoRESUMO
Intraoperative radiotherapy (IORT) has been used to treat different residual solid tumors after tumor removal and has shown many advantages over other treatment methods. However, the use of IORT for invasive thymoma has not been reported. Therefore, in this study, we tried to determine the safety and efficacy of INTRABEAM IORT for the treatment of invasive thymoma.Among the patients admitted to our hospital from September to December 2016 who were diagnosed with invasive thymoma, 14 were selected as study subjects. With medical histories taken beforehand, 8 of these patients were diagnosed with Masaoka stage IIA and 6 with Masaoka stage IIB; furthermore, 5 of the patients were diagnosed with myasthenia gravis (MG). INTRABEAM radiation (8-10 Gy, low energy) was delivered to the postoperative tumor bed of each patient during surgery. The intra- and postoperative complications were observed and evaluated, and the improvement in symptoms was assessed. An additional 23 patients with stage II thymoma undergoing radical surgery from April to August 2016 were chosen as the control group.One month after the operation, only 1 patient in the IORT group had cough, increased levels of leucocytes and neutrophils, and pulmonary inflammation on chest computed tomography. Reactive inflammation and pleural effusion in the 2 groups were similar (Pâ>â.05). There was no significant difference between the 2 groups in the improvement of myasthenia gravis (Pâ>â.05). Postoperative chest computed tomography and routine blood examination at 3 and 12 months showed that all the patients recovered, with normal hemogram levels and no pulmonary fibrosis around the radiation field. In addition, ultrasonic cardiography and electrocardiography demonstrated no significant difference before or after surgery within the IORT group. At the end of the follow-up, all the patients were alive, no relapse or remote metastasis was observed in the IORT group, and 2 inpatients in the control group had experienced relapse at 24 and 26 months. There was a significant difference in disease-free survival between the 2 groups (Pâ=â.00).It is safe to administer low-energy INTRABEAM IORT at a dose of approximately 10 Gy in patients with stage II invasive thymoma. INTRABEAM IORT does not significantly increase operation- or radiation-related complications and has no significant effect on vital organs such as the lungs and heart. Its long-term efficacy is worth expecting.
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Timoma/radioterapia , Neoplasias do Timo/radioterapia , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/complicações , Dosagem Radioterapêutica , Radioterapia Adjuvante/instrumentação , Radioterapia Adjuvante/métodos , Cirurgia Torácica Vídeoassistida/métodos , Timoma/complicações , Timoma/patologia , Timoma/cirurgia , Neoplasias do Timo/complicações , Neoplasias do Timo/patologia , Neoplasias do Timo/cirurgiaRESUMO
BACKGROUND: Lung cancer remains the leading cause of cancer-related death worldwide. The human PINK1 gene (PTEN induced kinase 1, Park6), an important gene for Parkinson's disease, was found to be associated with tumor development although the molecular mechanisms underlying this relationship remain largely unknown. OBJECTIVE: To analyze the clinical value and molecular mechanism of PINK1 in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Western blot, qRT-PCR and Immunohistochemistry were employed to determine the levels of PINK1 in 87 paired NSCLC tissues, Oncomine and TCGA databases were also used for the evaluation of expression and prognosis of PINK1. The mitophagy, proliferation, migration, invasion, and apoptosis abilities of A549 and H1975 cells were detected, and the autophagy-related proteins in the cells were also determined. RESULTS: Immunohistochemical staining revealed higher PINK1 expression in tumor tissues, which was strongly linked to the tumor-node-metastasis classification. Survival analysis of 1085 NSCLC patients also revealed that low PINK1 expression levels were associated with significantly longer overall survival. Univariate and multivariate analyses indicated that PINK1 expression was an independent predictor of overall survival among patients with NSCLC. We also evaluated the influence of PINK1 deficiency in NSCLC cell lines (A549 and H1975), which revealed significant suppression of migration capability and cell viability, as well as a significantly elevated apoptosis ratio. In cells with stable interference of PINK1 expression, dysfunctional mitochondria accumulated while autophagy was inhibited, which indicated that cell activity suppression was mediated by the accumulation of dysfunctional mitochondria. The suppression of migration and autophagy was reversed in cells that overexpressed PINK1. CONCLUSION: Our results suggest that PINK1 may be a potential therapeutic target and prognostic biomarker in NSCLC.
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PURPOSE: Anastomotic leakage is the most feared postoperative complication after esophagectomy. Omentoplasty, wrapping the omentum around the alimentary tract anastomosis, is thought to decrease the anastomotic leakage rate. The purpose of this clinical study is to investigate the use of omentoplasty to reinforce cervical esophagogastrostomy after minimally invasive esophagectomy (MIE). PATIENTS AND METHODS: In this retrospective study, the data of 160 consecutive patients who underwent cervical esophagogastrostomy after MIE between September 2012 and May 2015 were analyzed, 87 who underwent omentoplasty (group A) and 73 who did not undergo omentoplasty (group B). The primary outcome was the incidence of anastomotic leakage and anastomotic strictures after the operation. Secondary outcomes were other complications and mortality rate. Univariate and multivariate analysis of variables associated with an increased risk for anastomotic leak was performed. RESULTS: The median age was 61 years (range, 37-82 years). The anastomotic leakage rates were 4.6% (4/87) in group A and 15.1% (11/73) in group B (P = 0.023). There was no statistical significance in anastomotic stricture rates between group A (6.9%) and group B (9.6%; P = 0.535). No difference was noted in other complications between the groups. There was a trend toward lower leak-associated mortality rates for group A (0%) compared with that for group B (4.1%). CONCLUSION: Cervical esophagogastrostomy with omentoplasty is more effective than esophagogastrostomy without omentoplasty for the prevention of anastomotic leakage in MIE with cervical anastomosis. Omentoplasty could be used as an adjunct technique to reduce the incidence of anastomotic leakage in cervical esophagogastrostomy following MIE.
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BACKGROUND: Chemotherapy is still the primary adjuvant strategy of cancer therapy; however, the emergence of multi-drug resistance has been a cause for concern. Autophagy has been demonstrated to have a protective role against chemotherapeutic drugs in cancer cells, and autophagy inhibition is generally considered to be a promising therapeutic strategy. However, the paucity of effective and specific autophagy inhibitors limits its application. PURPOSE: The objective of this study was to explore the effect of DCA, small molecular anti-tumor agent, on the autophagy regulation and chemosensitization in NSCLC cells. METHODS: We investigated the autophagy regulation of dichloroacetate (DCA) by laser confocal microscopy and western blotting in A549 and H1975 cell lines. The MTT assay and flow cytometry was performed for explore the chemosensitization effectiveness of DCA. The results were verified with subcutaneous tumor model in nude mice and the immunohistochemistry was applied for assessing the level of cell apoptosis and autophagy in vivo post treatment. RESULTS: We found that DCA, which exhibited antitumor properties in various carcinoma models, induced apoptosis of non-small cell lung cancer cells (NSCLC) by inhibiting cancer cell autophagy. Furthermore, Perifosine, an AKT inhibitor, can greatly weaken the capacity of inducing apoptosis by DCA. The results indicate that the AKT-mTOR pathway, a main negative regulator of autophagy, is involved in the DCA-induced inhibition of autophagy. Then, we detected the effectiveness of autophagy inhibition by DCA. When used in co-treatment with the chemotherapeutic drug paclitaxel (PTX), DCA markedly decreased cell autophagy, enhanced apoptosis and inhibited proliferation in A549 and H1975 cells. The results of the xenograft experiment demonstrate that co-treatment of PTX and DCA can significantly decrease cell proliferation in vivo and prolong the survival of mice. CONCLUSION: Our results suggest that DCA can inhibit cell autophagy induced by chemotherapeutics, providing a new avenue for cancer chemotherapy sensitization.