Translational lung cancer research最新文献

{"title":"Pathological complete response and long-term survival by pembrolizumab based immunochemotherapy in epidermal growth factor receptor mutated non-small cell lung cancer post-tyrosine kinase inhibitor failure: a case report and tumor microenvironment analysis.","authors":"Sangtian Liu, Wenhua Liang, Shicui Quan, Qilin Deng, Wenhai Fu, Yalei Zhang, Hong Du, Jianxing He","doi":"10.21037/tlcr-24-711","DOIUrl":"https://doi.org/10.21037/tlcr-24-711","url":null,"abstract":"<p><strong>Background: </strong>Lung adenocarcinoma harboring epidermal growth factor receptor (<i>EGFR</i>) mutations remains a significant clinical challenge, particularly when patients experience progression following <i>EGFR</i>-tyrosine kinase inhibitor (TKI) therapy. This case report explores the efficacy of pembrolizumab-based immunochemotherapy (ICT) in achieving a pathological complete response (pCR) and prolonged survival in a patient with <i>EGFR</i>-mutated non-small cell lung cancer (NSCLC) after TKI failure.</p><p><strong>Case description: </strong>A 74-year-old female patient with stage IVa <i>EGFR L858R</i>-mutated lung adenocarcinoma, progressing under multiple lines of <i>EGFR</i>-TKI therapy, was treated with pembrolizumab in combination with pemetrexed and carboplatin. Tumor response was assessed using radiological imaging and positron emission tomography-computed tomography (PET-CT). Pathological evaluation was conducted post-surgery, and the tumor microenvironment (TME) was analyzed using multiplex immunofluorescence (mIF) staining. Following four cycles of pembrolizumab-based ICT, the patient exhibited a significant reduction in tumor burden and mediastinal lymph node involvement, as confirmed by PET-CT. Surgical resection revealed a pCR with no viable tumor cells existed. The microenvironment analysis for tumor samples obtained post-progression on targeted therapy demonstrated that more than 50% of tumor cells expressing programmed cell death 1 ligand 1 (PD-L1), accompanying with higher infiltration of programmed death receptor 1 (PD-1)⁺ CD8⁺ T cells and PD-L1⁺ CD68⁺ macrophages in the tumor area compared to the stromal area. As for resected samples, substantial infiltration of CD45⁺ immune cells, CD8⁺ T lymphocytes, CD68⁺ macrophages and immature tertiary lymphoid structures (TLSs) were detected.</p><p><strong>Conclusions: </strong>This case report highlights the potential of pembrolizumab-based ICT to induce a pCR and achieve long-term survival in <i>EGFR</i>-mutated NSCLC patients post-TKI failure. The favorable TME observed supports the rationale for this therapeutic approach and warrants further investigation in prospective clinical trials.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"14 3","pages":"1032-1041"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144001023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of baseline interstitial lung abnormality on the risk of checkpoint inhibitor-related pneumonitis and survival in advanced non-small cell lung cancer patients treated with first-line PD-1/PD-L1 inhibitors.","authors":"Yu Li, Shuo Liang, Yanjun Du, Jun Yao, Yuxin Jiang, Wanjun Lu, Qiuxia Wu, Fumihiro Yamaguchi, Marko Jakopović, Wolfgang M Brueckl, Dong Wang, Fang Zhang, Qin Wang, Tangfeng Lv, Ping Zhan","doi":"10.21037/tlcr-2025-150","DOIUrl":"https://doi.org/10.21037/tlcr-2025-150","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Chest computed tomography (CT) can be used to identify interstitial lung abnormality (ILA), which is known to lead to an increased risk of post-operative complications, and is related to a worse prognosis in early-stage lung cancer. However, research on the role of ILA in advanced non-small cell lung cancer (NSCLC) patients receiving immunotherapy is limited. This study sought to investigate the effect of pre-existing ILA and pulmonary function test (PFT) results on the occurrence of checkpoint inhibitor-related pneumonitis (CIP) and survival in advanced NSCLC patients after programmed cell death protein-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) inhibitor therapy.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We retrospectively divided the patients with advanced NSCLC into two groups: the with ILA group, and the without ILA group. We also divided the patients into two groups based on whether they developed CIP during treatment. After first-line immunotherapy, we followed up with all patients and recorded their progression-free survival (PFS) and overall survival (OS). Two respiratory specialists recorded the cases of CIP and the existence of ILA on chest CT, and assessed the consistency of ILA. A logistic regression analysis was performed to explore the independent risk factors for CIP, and a Cox regression analysis was performed to investigate the factors influencing PFS and OS.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Of the 269 patients with advanced NSCLC enrolled in the study, 93 (34.57%) had ILA, and 176 (65.43%) did not have ILA. Additionally, 39 (14.50%) of the patients developed CIP. The univariate analysis showed that pre-existing ILA [odds ratio (OR): 3.733; 95% confidence interval (CI): 1.846-7.549; P&lt;0.001], body mass index (BMI) (≥24.12 kg/m&lt;sup&gt;2&lt;/sup&gt;) (OR: 2.616; 95% CI: 1.312-5.214; P=0.006), and lactate dehydrogenase (LDH) (≥186.50 U/L) (OR: 2.231; 95% CI: 1.038-4.792; P=0.04) were highly correlated with CIP. In the multivariate analysis, ILA remained a robust independent predictor of CIP (OR: 4.128; 95% CI: 1.984-8.587; P&lt;0.001). In terms of CIP, compared to the patients with mild CIP (grades 1/2), those with severe CIP (grades 3/4) had a worse OS (median for patients with grades 3/4: 12.4 months; median for patients with grades 1/2: 35.8 months) [hazard ratio (HR): 4.808; 95% CI: 1.671-13.830; P=0.004]. ILA was linked to a shorter OS time, such that the patients with ILA had a median OS of 21.1 months, while those without ILA had a median OS of 42.5 months (HR: 2.213; 95% CI: 1.404-3.488; P&lt;0.001). The multivariable Cox regression analysis showed that ILA was also significantly associated with an increased risk of death (HR: 1.899; 95% CI: 1.253-2.878; P=0.002). However, no significant association was found between the PFTs before immunotherapy and CIP.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Pre-existing ILA is an independent risk factor that is strongly associated with CIP, and significantly correlated with wo","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"14 3","pages":"912-930"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144049794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent advancements in lung cancer research: a narrative review.","authors":"Fuk Hay Tang, Heylie Y T Wong, Phyllis S W Tsang, Mabel Yau, Shing Yau Tam, Lawla Law, Katherine Yau, Jade Wong, Fatema Hassan Mustafa Farah, Jacky Wong","doi":"10.21037/tlcr-24-979","DOIUrl":"https://doi.org/10.21037/tlcr-24-979","url":null,"abstract":"<p><strong>Background and objective: </strong>Lung cancer remains the leading cause of cancer-related mortality worldwide, with a 5-year survival rate ranging from 10% to 20%. The majority of cases are categorized as non-small cell lung cancer (NSCLC) (80%) and small cell lung cancer (SCLC) (20%), with NSCLC being the more prevalent type. Tobacco use, particularly cigarette smoking, is a significant contributor to over 80% of lung cancer cases. Early diagnosis is challenging due to limitations in screening methods, resulting in many cases being identified only in advanced stages. Moreover, current treatment options often exhibit low efficacy, partly due to an inadequate understanding of the disease's pathogenesis. This narrative review aims to summarize recent discoveries and advancements in lung cancer research, focusing on improvements in diagnosis, treatment, and understanding of the disease.</p><p><strong>Methods: </strong>A comprehensive literature review was performed utilizing the PubMed Central database to identify recent studies relevant to lung cancer. This review synthesizes findings from various research articles to provide a cohesive summary of advancements in the field.</p><p><strong>Key content and findings: </strong>In the past decade, notable progress has been achieved in lung cancer research, particularly concerning diagnostics and treatment strategies. Novel therapeutic approaches, including immunotherapy and genomic-targeted therapies, have demonstrated promising results. Understanding the tumor microenvironment (TME) and the role of T lymphocytes has become crucial for developing effective treatments. Additionally, advancements in immune checkpoint inhibitors (ICIs) have shown potential in enhancing patient outcomes. Improvements in tumor detection technologies are also anticipated to facilitate earlier diagnosis, ultimately contributing to better survival rates.</p><p><strong>Conclusions: </strong>Significant strides have been made in lung cancer research over the last ten years, particularly in diagnostics and treatment methodologies. Future research should prioritize exploring the TME, the function of T lymphocytes, and the efficacy of ICIs while continuing to innovate in tumor detection technologies. Such efforts are essential for enhancing treatment outcomes and improving the overall quality of life for lung cancer patients.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"14 3","pages":"975-990"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated multiomics machine learning and mediated Mendelian randomization investigate the molecular subtypes and prognosis lung squamous cell carcinoma.","authors":"Zhanghao Huang, Jing Li, You Lang Zhou, Jiahai Shi","doi":"10.21037/tlcr-24-891","DOIUrl":"https://doi.org/10.21037/tlcr-24-891","url":null,"abstract":"<p><strong>Background: </strong>Lung squamous cell carcinoma (LUSC) lacks specific early diagnostic markers. Given the critical role of 5'-Nucleotidase Ecto (NT5E) in immune evasion and therapy resistance of cancer cells and the involvement of Dual Specificity Phosphatase 4 (DUSP4) in tumor cell proliferation through inhibition of the ERK signaling pathway, incorporating NT5E and DUSP4 into the consensus machine learning signature (CMLS) system in this study holds significant potential for investigating the early diagnosis and immune microenvironment of LUSC. The objective of this study was to explore the prognostic targets of LUSC.</p><p><strong>Methods: </strong>Employing integrated algorithms enhances the ability to identify molecular subtypes and key features from multiple perspectives. A combination of 10 clustering algorithms and multi-omics data from LUSC patients, merged with 10 machine learning algorithms, was used to analyze and identify high-resolution molecular subsets and develop a CMLS. Mediated Mendelian randomization (MR) was utilized to explore mediations between immune cells and metabolites associated with CMLS.</p><p><strong>Results: </strong>Cluster 1 demonstrated elevated infiltration of immune and stromal components, indicating an immunosuppressive microenvironment predominantly driven by tumor-associated macrophages or other inhibitory cells. In contrast, Cluster 2 displayed a metabolism-driven phenotype associated with improved prognosis. Mediated MR provided further insights into the causal relationships among CMLS, macrophages, and metabolites in LUSC. Validation of the RAS-RAF-MEK-ERK signaling pathway in conjunction with CMLS reinforced the immune characteristics of CMLS.</p><p><strong>Conclusions: </strong>The integration of CMLS with multi-omics offers a robust framework for predicting prognosis, elucidating the causal interactions between the immune microenvironment and metabolic reprogramming in LUSC, and identifying patient subgroups likely to benefit from immunotherapy.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"14 3","pages":"857-877"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144064794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multidisciplinary management of N2 stage III non-small cell lung cancer: opportunities and challenges for radiation oncology.","authors":"Hongcheng Zhu, Daniel G Schep, Marta Isolano, Piergiorgio Muriana, Sarayut L Geater, Giulia Veronesi, Fangqiu Fu, Roberto Ferrara, Kuaile Zhao, Alexander V Louie","doi":"10.21037/tlcr-24-974","DOIUrl":"https://doi.org/10.21037/tlcr-24-974","url":null,"abstract":"<p><p>Stage III non-small cell lung cancer (NSCLC) constitutes a heterogeneous ailment, with optimal treatment evolving. This is especially true in N2 disease, where definitive treatment is often a discussion of surgery versus definitive chemoradiotherapy (CRT). New developments in neoadjuvant and adjuvant systemic therapeutics have shifted treatment paradigms, emphasizing the importance of multidisciplinary team discussions. The recent revisions to the ninth edition of the American Joint Commission on Cancer (AJCC) staging system have prompted a realignment in nodal stage categorization, introducing refined subcategories of N2 disease (N2a and N2b), which enhance prognostic accuracy. Critical questions including defining resectability and operability, feasibility of definitive CRT for operable patients, radiotherapy in operative and non-operative disease, and advanced radiation technology for definitive CRT are needed to be considered and answered in clinical practice. The current review aims to present a comprehensive overview of radiation oncology in management of N2 stage NSCLC by summarizing key clinical trials as well as most advanced evidence, including defining resectability and operability, feasibility of definitive CRT for operable patients, radiotherapy in operative and non-operative disease, and advanced radiation technology for definitive CRT. The review summarizes the most recent evidence and insights for radiation oncologists and other specialists involved in the multidisciplinary thoracic oncology team, to provide a better understanding of the opportunities and challenges for radiotherapy in the management of N2 stage III NSCLC.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"14 3","pages":"991-1006"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144043445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Persistent and novel changes in plasma microRNA profiles in patients with non-small cell lung cancer following tumour resection.","authors":"Maria Sromek, Maciej Głogowski, Magdalena Chechlińska, Mariusz Kulińczak, Michalina Zajdel, Natalia Żeber-Lubecka, Aneta Bałabas, Łukasz M Szafron, Maria Kulecka, Jan K Siwicki","doi":"10.21037/tlcr-24-626","DOIUrl":"https://doi.org/10.21037/tlcr-24-626","url":null,"abstract":"<p><strong>Background: </strong>Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancers, the leading cause of cancer mortality. microRNAs (miRNA, miR) have emerged as important components of carcinogenesis and promising biomarkers. We aimed to analyse global plasma miRs in NSCLC patients before and at least one year after tumour resection.</p><p><strong>Methods: </strong>Plasma was collected from the peripheral blood of 24 donors without cancer and of NSCLC patients before surgery (n=36) and at least 1 year after surgery (n=12). Next-generation sequencing (NGS)-based miR profiling was performed. Patients were followed-up for 4 to 12 years after surgery to assess disease recurrence.</p><p><strong>Results: </strong>Untreated NSCLC patients exhibited significant changes in plasma miR levels compared to cancer-free donors (48 up- and 17 down-regulated miRs). miR profiles in patients with adenocarcinoma (ADC) (n=18) and squamous cell carcinoma (SCC) significantly differed (16 and 86 miRs up-, and 15 and 16 miRs down-regulated, respectively). A subset of pre-surgery deregulated miRs was found to be associated with recurrence (49 miRs). Six miRs were shown to have independent prognostic value. After tumour resection, some pre-surgery miR alterations returned to control levels (18 miRs), some others persisted (27 miRs), while also novel plasma miR changes emerged (75 miRs) in patients with no clinical evidence of recurrence.</p><p><strong>Conclusions: </strong>Untreated NSCLC patients present deregulated plasma miRs, some of which may have a potential of prognostic markers. After tumour excision plasma miR profiles change, some miR levels normalise, some changes persist and novel miR changes are observed despite no clinical symptoms of recurrence. Plasma miR profiles in NSCLC patients may suggest systemic abnormalities predisposing to lung cancer and/or reflect a systemic response to pre-cancer/dormant cancer cells.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"14 3","pages":"677-706"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Connecting the dots: (RANKL⁺) extracellular vesicle count in blood plasma in relation to bone metastases, skeletal related events and osimertinib treatment in patients with EGFR mutated non-small cell lung cancer.","authors":"Anita J W M Brouns, Iris J Robbesom-van den Berge, Sophie M Ernst, Christi M J Steendam, Wouter W Woud, Liang Wu, Anne-Marie C Dingemans, Lizza E L Hendriks, Marjolein van Driel","doi":"10.21037/tlcr-24-1007","DOIUrl":"https://doi.org/10.21037/tlcr-24-1007","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The biological mechanisms responsible for the different incidences of bone metastases in molecular subgroups of non-small cell lung cancer (NSCLC) are not identified. Extracellular vesicles (EVs) may play a role, as they are involved in organotrophic metastasis. Phosphorylation of epidermal growth factor receptor (EGFR) in exosomes possibly leads to an increase in receptor activator of nuclear factor κB ligand (RANKL) triggering osteoclastogenesis. In search for new biomarkers with focus on EVs and RANKL, we studied in plasma of patients with &lt;i&gt;EGFR&lt;/i&gt; &lt;sup&gt;+&lt;/sup&gt; NSCLC the associations between the total concentration of EVs, RANKL&lt;sup&gt;+&lt;/sup&gt; EVs, RANKL, and osteoprotegerin (OPG) protein levels, osimertinib treatment, presence of bone metastases and skeletal related events (SREs).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;From the prospective biomarker cohort study START-TKI (NCT05221372), including patients with metastatic &lt;i&gt;EGFR&lt;/i&gt; &lt;sup&gt;+&lt;/sup&gt; NSCLC, we collected deep frozen plasma samples at initiation and during osimertinib treatment. Imaging flow cytometry (IFC) was used to determine the concentration of tetraspanin positive EVs and detection of RANKL on EVs. RANKL and OPG levels were measured by enzyme-linked immunosorbent assay (ELISA). Data on demographics, date of NSCLC diagnosis, date of initiation of osimertinib, presence of bone metastases and SREs were collected. Primary endpoint was the relation between (RANKL&lt;sup&gt;+&lt;/sup&gt;) EV levels and bone metastases.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Forty unique patients with in total 50 plasma samples (45% at initiation of osimertinib, 55% during osimertinib treatment) were included. Identification of EVs was possible in 38/40 patients, and determination of RANKL and OPG plasma levels in all samples. Of these 40 patients, 25 (63%) had bone metastases at sample collection. Both total EV and RANKL&lt;sup&gt;+&lt;/sup&gt; EV concentrations were significantly higher in samples at initiation of osimertinib compared to samples during treatment [mean ± standard deviation (SD), 6.3×10&lt;sup&gt;12&lt;/sup&gt;±2.1×10&lt;sup&gt;12&lt;/sup&gt;/mL plasma &lt;i&gt;vs.&lt;/i&gt; 3.2×10&lt;sup&gt;12&lt;/sup&gt;±1.9×10&lt;sup&gt;12&lt;/sup&gt;/mL plasma, P≤0.001 for total EV concentrations; and 2.2×10&lt;sup&gt;10&lt;/sup&gt;±9.3×10&lt;sup&gt;9&lt;/sup&gt;/mL plasma &lt;i&gt;vs.&lt;/i&gt; 1.1×10&lt;sup&gt;10&lt;/sup&gt;±8.0×10&lt;sup&gt;9&lt;/sup&gt;/mL plasma, P=0.001 for RANKL&lt;sup&gt;+&lt;/sup&gt; EVs]. Patients without a SRE had a significantly higher concentration of RANKL&lt;sup&gt;+&lt;/sup&gt; EVs compared to patients with an SRE (mean ± SD, 1.8×10&lt;sup&gt;10&lt;/sup&gt;±1.1×10&lt;sup&gt;10&lt;/sup&gt;/mL plasma &lt;i&gt;vs.&lt;/i&gt; 1.1×10&lt;sup&gt;10&lt;/sup&gt;±7.4×10&lt;sup&gt;9&lt;/sup&gt;/mL plasma, P=0.02). No association was found between the total EV concentration or RANKL&lt;sup&gt;+&lt;/sup&gt; EVs, plasma levels of OPG and RANKL and bone metastases.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;No association was found between the presence of bone metastases and the total concentration of EVs, RANKL&lt;sup&gt;+&lt;/sup&gt; EVs, or plasma values of RANKL and OPG. In patients without SREs the concentratio","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"14 3","pages":"761-774"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating lung cancer exosomes damage the niche of intestinal stem cells.","authors":"Ke Wang, Lu Xu, Jianhua Feng, Shubin Wang, Xi Wang, Junyi Zou, Zhenni Xu, Lingxiao Huang, Wenjun Jiang, Jin Zhou, Xudan Lei, Dengqun Liu","doi":"10.21037/tlcr-24-758","DOIUrl":"https://doi.org/10.21037/tlcr-24-758","url":null,"abstract":"<p><strong>Background: </strong>Cancer-associated weight loss occurs frequently in patients with advanced lung cancer. Many studies have demonstrated that tumor-derived exosomes could mediate the interplay between tumor cells and distal organs. In this study, we explored the interaction between lung cancer cell-derived exosomes (LCCDEs) and the niche of intestinal stem cells (ISCs).</p><p><strong>Methods: </strong>Lewis lung carcinoma-1 (LLC1)-conditional medium (LLC1-CM), N,N'-Bis[5-(2,3-dihydro-1H-indol-1-yl)pentyl]-1,6-hexanediamine (GW4869)-conditional medium (GW4869-CM), LCCDEs and phosphate-buffered saline (PBS) were used to treat 6- to 8-week-old healthy male C57BL/6J mice (18-22 g) and B6.129P2-Lgr5^{tm1(cre/ERT2)Cle}/J (Lgr5-EGFP-IRES-creERT2) mice (Lgr5-EGFP mice). Additionally, enteroids were treated with LLC1-CM, A549 human lung adenocarcinoma cells (A549)-CM, LCCDEs of LLC1 cells and A549 cells and PBS. LCCDEs were characterized by transmission electron microscopy, Western blot, and nanoparticle tracking analysis. The influence of LCCDEs on intestine and ISCs was explored by hematoxylin & eosin staining, proliferation, differentiation, enteroid culture, and quantitative polymerase chain reaction. PKH26-labeled LCCDEs were detected in intestinal epithelial cell line 6 (IEC-6) cells and Lgr5-EGFP mice. The changes of ISCs' niche caused by LCCDEs were examined by p-S6, pERK1/2 and p-STAT3 immunostaining.</p><p><strong>Results: </strong>LLC1-CM damaged the small intestines and small intestinal organoids. The inhibition of exosomes by GW4869 partially alleviated these effects. Purified LCCDEs altered the structure of the intestines, changed the proliferation and differentiation of ISCs and inhibited the growth of enteroids. In addition, PKH26-labeled LCCDEs entered the cytoplasm of IECs and Paneth cells and changed the messenger ribonucleic acid (mRNA) expression of many genes, including stem cell marker genes, growth factor genes, and epithelial marker genes. Mechanistically, LCCDEs decreased mTORC1 activity in Paneth cells and inhibited p-ERK1/2 signaling in ISCs.</p><p><strong>Conclusions: </strong>We demonstrated that circulating exosomes derived from lung cancer could impair ISCs and alter their niche in mice, which further explained the interaction between lung cancer and the gastrointestinal tract. This study proposes a promising and novel therapy to overcome weight loss in patients by decreasing LCCDEs secretion and blocking their binding to the intestine, which might be a feasible therapeutic approach in future clinical practice.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"14 3","pages":"718-735"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification and validation of crotonylation-related diagnostic markers for lung adenocarcinoma via weighted correlation network analysis and machine learning.","authors":"Bowen Hu, Xin Chen, Dan Zou, Xiaoyue Du, Sitong Feng, Yiwen Shen, Xiaofeng Sha, Feng Jiang, Guoren Zhou, Fan Lin, Lukas Käsmann, Bo Shen","doi":"10.21037/tlcr-2025-204","DOIUrl":"https://doi.org/10.21037/tlcr-2025-204","url":null,"abstract":"<p><strong>Background: </strong>Lung adenocarcinoma (LUAD) is one of the most common tumors in terms of incidence and mortality worldwide. Posttranslational modifications, including crotonylation, play a crucial role in various biological processes and diseases. However, the role of crotonylation in LUAD remains unclear. Our research focuses on identifying key genes in LUAD that are linked to crotonylation and prognosis. We also aim to clarify their role in the LUAD microenvironment to advance clinical translation of related targets.</p><p><strong>Methods: </strong>We used RNA-sequencing data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) database to identify differentially expressed genes (DEGs) related to crotonylation in LUAD. Weighted correlation network analysis (WGCNA) was applied to construct gene networks, and hub genes were identified using protein-protein interaction (PPI) analysis. The prognostic value of hub genes was assessed using Kaplan-Meier plots, and the correlation with immune infiltration was analyzed via Tumor Immune Estimation Resource (TIMER) and other algorithms. We then verified these genes through clinical samples and confirmed the role of <i>MMACHC</i> in LUAD.</p><p><strong>Results: </strong>We identified <i>GAPDH</i>, <i>SLC25A13</i>, <i>MMACHC</i>, and <i>HDAC1</i> as potential crotonylation-related biomarkers for LUAD. These genes were found to be overexpressed in LUAD and were associated with poor prognosis. They also showed significant correlations with immune cell infiltration and immune-inflammatory pathways. Functional experiments confirmed that <i>MMACHC</i> knockdown inhibited cell proliferation and migration, induced apoptosis, and enhanced the efficacy of immunotherapy in LUAD.</p><p><strong>Conclusions: </strong>Our study suggests that crotonylation-related genes, particularly <i>MMACHC</i>, may serve as novel therapeutic targets and diagnostic markers for LUAD.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"14 3","pages":"940-962"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metachronous development of L858R and T790M EGFR mutations following ALK inhibitor therapy in stage IV lung adenocarcinoma: a case report.","authors":"So-Yun Kim, Jisoo Lee, Dongil Park, Jeong Eun Lee, Joo-Eun Lee, Hyun-Yi Kim, Da Hyun Kang, Chaeuk Chung","doi":"10.21037/tlcr-2024-1071","DOIUrl":"https://doi.org/10.21037/tlcr-2024-1071","url":null,"abstract":"<p><strong>Background: </strong>Metachronous lung cancers with distinct driver mutations are rare, particularly following targeted therapy. This report presents a unique case of tumor evolution in non-small cell lung cancer (NSCLC).</p><p><strong>Case description: </strong>A 73-year-old East Asian woman was diagnosed with stage IV anaplastic lymphoma kinase (ALK)-rearranged lung adenocarcinoma in the right middle lobe (RML). After 18 months of alectinib treatment, while the initial lesion regressed, a new nodule developed in the right upper lobe (RUL). Biopsy revealed adenocarcinoma with epidermal growth factor receptor (EGFR) L858R/T790M co-mutations without ALK rearrangement. We conducted a comparative analysis of genetic alterations in biopsies from 2022 and 2024 using targeted next-generation sequencing (NGS), revealing significant molecular evolution over time, with a marked increase in single nucleotide variants (SNVs) and copy number variants (CNVs) and distinct changes in key mutations such as ALK-EML4 and EGFR. The patient received stereotactic body radiotherapy (SBRT) for the new lesion while continuing alectinib, resulting in significant improvement until now.</p><p><strong>Conclusions: </strong>This case represents the first documented occurrence of metachronous L858R and T790M EGFR mutations following ALK inhibitor therapy, highlighting the emergence of distinct driver mutations over time and reflecting temporal and spatial tumor heterogeneity. These findings underscore the importance of monitoring clonal evolution to guide tailored therapeutic strategies in NSCLC. Furthermore, re-biopsy is essential to assess tumor heterogeneity, identify potential drug resistance, and detect new mutations, ensuring that treatment strategies remain optimized for evolving disease conditions.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"14 3","pages":"1021-1031"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}