Ⅰ期-Ⅲ期非转移性非小细胞肺癌的系统性治疗演变

早期肺癌患者的治疗是以治愈为目标的。针对手术可切除性和可操作性的多学科讨论模式决定了最终的局部治疗方式(手术或放疗)和相关的系统性治疗方案,从而进一步提高患者治愈的可能性。研究证据支持以顺铂为基础的辅助化疗用于切除术后,或与放疗同步使用。共识指南支持以新辅助化疗代替辅助化疗,并支持对不符合顺铂治疗条件的患者采用基于卡铂的治疗方案。由于研究设计效率低下,需要长时间随访来评估生存终点以及对晚期疾病的持续关注,将新药物(现在是IV期肺癌患者的标准药物)纳入以治愈为目标的治疗范式的工作一直滞后。目前正在研究中的替代性终点(例如病理缓解)将可能缩短研究的时间。2018年,抗程序性死亡配体(programmed cell death ligand 1,PD-L1)抗体度伐利尤单抗获批用于治疗同步放、化疗后的Ⅲ期肺癌患者,自那时起,针对早期肺癌患者的靶向治疗和免疫治疗的研究迅速发展。在本篇综述中,我们介绍了对于目前早期肺癌患者治疗方案的考虑因素,探讨并展望非转移性肺癌系统性治疗的临床研究现状和未来。

非小细胞肺癌的免疫治疗:改善患者预后的新方法

简介通常,非小细胞肺癌(non-small cell lung cancer,NSCLC)诊断已为晚期,且预后较差。目前的NSCLC标准治疗总体治愈率低,有必要开发新的治疗方法。我们在本综述中提供了最新的免疫治疗干预临床数据,该手段可能能够提高免疫系统对细胞的应答。方法我们针对临床应用免疫疗法治疗NSCLC,检索了PubMed上的文章以及最近肿瘤学术会议上的摘要。结果Ⅱ期临床研究结果表明,靶向肿瘤细胞本身或其异常表达的肿瘤标志物的疫苗治疗(mucin1,黑色素瘤相关抗原3,或表皮生长因子),有望作为NSCLC免疫疗法。非抗原免疫治疗,如抗细胞毒T淋巴细胞抗原4单克隆抗体、talactoferrin alfa和toll-样受体9拮抗剂,作用于激活的免疫系统,与肿瘤抗原无关,可用于晚期NSCLC的治疗。目前一些免疫治疗正在进行III期研究,以确定最佳治疗方案,并与NSCLC标准治疗对照,确定其临床疗效。结论越来越多的证据表明肺部肿瘤存在免疫应答。免疫治疗,包括疫苗治疗和非抗原免疫调节方法,可改善NSCLC的预后。而且,提高抗肿瘤免疫应答的治疗,与化疗有协同作用。生物标志物的明确以及免疫治疗作用机制的进一步阐明对于确定哪些患者更可能从免疫治疗中获益至关重要。

A pilot double-blind, randomized, placebo-controlled trial of curcumin/bioperine for lung cancer chemoprevention in patients with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease is an inflammatory condition with increased risk of lung cancer. We hypothesized that curcumin/ bioperine (CB), which has anti-inflammatory effects, may reduce cytological abnormalities in the sputum of patients with COPD. We conducted a 3-month, three-to-one randomized, doubleblind, pilot trial of escalating doses of CB in patients with moderate or worse COPD who were capable of producing sputum. The primary efficacy endpoint was changed in sputum cytology. We also explored changes in fluorescence in situ hybridization (FISH). We obtained sputum samples for cytology and chromosome abnormalities at baseline and each monthly follow-up visit. We enrolled 57 participants, with 35 completing the study. The participants’ mean age (standard deviation [SD]) was 66.6 (8.2) years, and they were mainly male (91.2%), with an average of 63.8 pack-years of smoking history. Also, 42.1% of participants were active smokers and the mean (SD) FEV1 was 37% (13%). At baseline, 13 subjects had moderate or worse dysplasia (22.8%). Subjects with moderate to severe sputum dysplasia had more chromosome abnormalities in epithelial cells and neutrophils, as measured by deletion and aneuploidy in 10q22.3. The changes in sputum cytology and chromosome abnormalities did not differ between the active and placebo arms. CB was well tolerated at the bid doses of 1, 1.5, and 2 gm of curcumin and 5 mg of bioperine, with minor side effects related to the gastrointestinal tract. In this short pilot trial, CB compared to placebo did not alter cytological and chromosomal abnormalities seen in sputum of patients with COPD.

Integrative genomic and transcriptomic profiling of pulmonary sarcomatoid carcinoma identifies molecular subtypes associated with distinct immune features and clinical outcomes

Background:Pulmonary sarcomatoid carcinoma(PSC)is a rare and aggressive subtype of non-small cell lung cancer(NSCLC),characterized by the presence of epithelial and sarcoma-like components.The molecular and immune landscape of PSC has not been well defined.Methods:Multiomics profiling of 21 pairs of PSCs with matched normal lung tissues was performed through targeted high-depth DNA panel,whole-exome,and RNA sequencing.We describe molecular and immune features that define subgroups of PSC with disparate genomic and immunogenic features as well as distinct clinical outcomes.Results:In total,27 canonical cancer gene mutations were identified,with TP53 the most frequently mutated gene,followed by KRAS.Interestingly,most TP53 and KRAS mutations were earlier genomic events mapped to the trunks of the tumors,suggesting branching evolution in most PSC tumors.We identified two distinct molecular subtypes of PSC,driven primarily by immune infiltration and signaling.The Immune High(IM-H)subtype was associated with superior survival,highlighting the impact of immune infiltration on the biological and clinical features of localized PSCs.Conclusions:We provided detailed insight into the mutational landscape of PSC and identified two molecular subtypes associated with prognosis.IM-H tumors were associated with favorable recurrence-free survival and overall survival,highlighting the importance of tumor immune infiltration in the biological and clinical features of PSCs.

Overcoming EGFR-TKI resistance by targeting the tumor microenvironment

Targeted therapy has ushered in a new era of precision medicine for non-small cell lung cancer(NSCLC).Currently,epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKIs)stand as the recommended first-line therapy for advanced NSCLC harboring sensitive EGFR mutations.Nevertheless,most patients inevitably confront the challenge of drug resistance.This phenomenon arises not solely from intrinsic alterations within cancer cells but also from the intricate dynamics of the tumor microenvironment and the complex interactions that occur between cancer cells and their immediate surroundings.This review consolidates the current knowledge regarding EGFR-TKI resistance mechanisms,with a specific emphasis on unraveling the role played by the tumor microenvironment.In addition,the review delineates strategic approaches to surmount TKI resistance,thereby enriching the understanding of the interplay between therapeutic agents and the intricate milieu surrounding cancer cells.

Critical role of △DNMT3B4/2 in regulating RASSF1A promoterspecific DNA methylation in non-small cell lung cancer

Background △DNMT3B （a new DNMT3B subfamily） expression is initiated through a novel promoter. We identified at least 7 transcription variants of △DNMT3B as a result of alternative pre-mRNA processing. The aim of this study was to detect the expression pattern of ,△DNMT3B variants in non-small cell lung cancer （NSCLC） and to explore the role of △DNMT3B variants in regulating the promoter-specific DNA methylation. Methods Specific polymerase chain reaction （PCR） primer sets were designed to distinguish individual △DNMT3B variants according to their splicing patterns. The expressions of seven △DNMT3B variants were measured in 13 cell lines, 109 NSCLC patients, and the corresponding normal lung tissues using reverse transcription-PCR （RT-PCR）. The status of the p16 and RASSFIA promoter methylations in the tumors was detected using a methylation specific PCR （MSP）. The relationships of the expression patterns of the △DNMT3B variants were analyzed by observing the status of p16 and RASSFIA promoter methylations in the tumors. The siRNA and the anti-sense oligo-dioxynucleotide specifically targeting the junction of exon 5 and 7 of △DNMT3B were designed and transfected by lipofectmane 2000 into H1299 and H358 cell lines. RASSFIA promoter methylation from cells treated by siRNA-△DNMT3B4/2 was detected using MSP and Bisulfite sequencing, and Western blotting was used to △DNMT3B. Cell growth and cell cycle distribution were measured flowcytometry, respectively. detect the protein expression of DNMT3B and by applying real-time cell growth analysis and Results △DNMT3B variants, not DNMT3B, were the predominant transcripts in both NSCLC cell lines and primary tumors. The expression of △DNMT3B4 strongly correlated to the promoter methylation status of RASSFIA in a primary NSCLC. The knockdown of △DNMT3B4/2 by RNA-interference or anti-sense approaches resulted in a complete demethylation of RASSFIA promoter with the reactivation of a RASSFIA gene expression in less than 12 hours, but no effect resulted from the p16INK4a promoter in the NSCLC cell lines. Conclusions These results demonstrate an important role of ,△DNMT3B4/2 in the maintenance of promoter-specific DNA methylation in a cell type specific manner and provide a novel cell model for the study of the regulation of replication-independent DNA methylation.