Malignant pleural mesothelioma:The disdained member of thoracic oncology!

Pleural mesothelioma is a very aggressive malignancy that arises from the pleural mesothelial cell lining and is linked strongly to prior asbestos exposure.The ban on asbestos has helped to lower the incidence,but in developing countries like India,it is expected to rise.It has an extended latency period usually progressing over decades and presents with nonspecific symptoms.It has a median survival ranging between 10-22 months.The diagnosis of malignant pleural mesothelioma is challenging and is done using computed tomography(CT),magnetic resonance imaging,or positron emission tomography-CT,with the last two predicting the resectability of the tumor better than CT alone.A pleural biopsy along with an array of immunohistochemical markers,such as p16,BRCA1 associated protein 1,and claudin-4,are required for a definitive diagnosis.Several genetic alterations have prognostic significance as well.The current histological subtype identification is indispensable for decision making because of the new therapeutic avenues being explored.The combination of nivolumab and ipilimumab-based immunotherapy outperformed platinum and pemetrexed-based chemotherapy in terms of survival benefit and improved quality of life especially for non-epithelioid subtypes.However,the latter continues to be a robust treatment option for patients with the epithelioid subtype.Surgery is recommended for resectable cases with radiotherapy being indicated in neoadjuvant,adjuvant,and palliative settings along with systemic treatment.This review article provides an overview of epidemiology,etiology,clinical manifestations,diagnostic approaches(including immunohistochemical and genetic markers),staging,and multidisciplinary approaches to current treatment for malignant pleural mesothelioma using surgery,chemotherapy,immunotherapy,and radiotherapy.It also sheds light on some recent studies(EMPHACIS,CALGB30901,Checkmate-743,etc.)that have led to significant developments in recent years with clinically meaningful results.

Malignant pleural mesothelioma mimics thoracic empyema: A case report

BACKGROUND Thoracic empyema and malignant pleural mesothelioma(MPM)are distinct medical conditions with similar symptoms,including cough,chest pain,and breathing difficulty.We present a rare MPM case mimicking thoracic empyema.Physicians must consider MPM risks for patients exposed to building material who exhibit lobulated pleural effusions,indicating thoracic empyema.CASE SUMMARY A 68-year-old retired male construction worker suffered from shortness of breath and chest tightness over 10 d,particularly during physical activity.A poor appetite and 4 kg weight loss over the past 3 wk were also reported.Chest images and laboratory data concluded a tentative impression of empyema thoracis(right).Video-assisted thoracic surgery with decortication and delobulation(right)was conducted.The pathological report yielded an MPM diagnosis.Refractory pleural bilateral effusions and respiratory failure developed postoperatively,and the patient died three weeks after the operation.CONCLUSION Thoracic empyema and MPM are distinct medical conditions that can present similar symptoms,and video-assisted thoracic surgery facilitates an accurate diagnosis.Empyema-mimicking presentations and postoperative refractory pleural effusion may indicate a poor MPM outcome.

Complex Target Volume Delineation and Treatment Planning in Radiotherapy for Malignant Pleural Mesothelioma (MPM)

Introduction: Radiotherapy alone or combined with surgery and/or chemotherapy is being investigated in the treatment of malignant pleural mesothelioma (MPM). This study aimed to simulate a Volumetric Modulated Arc Therapy (VMAT) treatment of a patient with MPM. Materials and Methods: CT images from a patient with intact lungs were imported via DICOM into the Pinnacle3 treatment planning (TP) system (TPS) and used as a model for MPM to delineate organs at risk (OAR) and both clinical and planning target volumes (CTV and PTV) with a margin of 5 mm. Elekta Synergy with 6 MV photons and 80 leafs MLCi2 was employed. VMAT plans were generated using two coplanar arcs with gantry rotation angles of 178° - 182°, the collimator angles of each arc were set to 90°, Octavius® 4D 729 was employed for quality assurance while the calculated and measured doses were compared using VeriSoft. Results: A TP was achieved. The Gamma volume analysis with criteria of 3 mm distance to agreement and 3% dose difference yielded the gamma passing rate = 99.9%. The reference isodose was 42.75 Gy with the coverage constraints for the PTV D95 and V95 = 95.0% of 45 Gy. The remaining dosimetric parameters met the recommendations from the clinically acceptable guidelines for the radiotherapy of MPM. Conclusion: Using well-defined TV and VMAT, a consistent TP compared to similar ones from publications was achieved. We obtained a high agreement between the 3D dose reconstructed and the dose calculated.

GOECP/SEOR clinical guidelines on radiotherapy for malignant pleural mesothelioma

Malignant pleural mesothelioma(MPM)is a rare tumor with poor prognosis and rising incidence.Palliative care is common in MPM as radical treatment with curative intent is often not possible due to metastasis or extensive locoregional involvement.Numerous therapeutic advances have been made in recent years,including the use of less aggressive surgical techniques associated with lower morbidity and mortality(e.g.,pleurectomy/decortication),technological advancements in the field of radiotherapy(intensity-modulated radiotherapy,image-guided radiotherapy,stereotactic body radiotherapy,proton therapy),and developments in systemic therapies(chemotherapy and immunotherapy).These improvements have had as yet only a modest effect on local control and survival.Advances in the management of MPM and standardization of care are hampered by the evidence to date,limited by high heterogeneity among studies and small sample sizes.In this clinical guideline prepared by the oncological group for the study of lung cancer of the Spanish Society of Radiation Oncology,we review clinical,histologic,and therapeutic aspects of MPM,with a particular focus on all aspects relating to radiotherapy,including the current evidence base,associations with chemotherapy and surgery,treatment volumes and planning,technological advances,and reradiation.

Results of flexible 3D-conformal radiotherapy for patients with diffuse malignant pleural mesothelioma and comparative study of this technique with conventional radiotherapy

Objective： To observe the effects of the new technique of flexible 3D-conformal radiotherapy with combination of photon and electron （3DCRT） in the treatment of the patients with diffuse malignant pleural mesothelioma （MPM）, and carry out the comparative study between flexible 3DCRT and hemithoracic conventional radiotherapy （CRT）. Methods： From January 2004 to October 2007, 8 patients with MPM were treated with flexible 3DCRT. 5 patients had received cycles of chemotherapy before radiation. New technique of flexible 3DCRT with combination of photon and electron was used in our study, and DT 32.2-64 Gy with conventional split were delivered. CRT technique was mimicked to compare with 3DCRT technique to predict the possibility of lung damage in two methods. Results： One patient reached CR and other 7 patients got PR after radiation. Two patients died during the follow-up. The median survival time （MST） was 15.4 months and it was 18.8 months for sequential chemotherapy and radiotherapy group and 9.7 months for radiotherapy alone group. The V20, V30, and ipsilateral and contralateral median lung dosage （MLD） were 20.5%, 15.6%, 18.8 Gy and 2.2 Gy respectively when the flexible 3DCRT technique was used, whereas they were 36.8%, 27.9%, 31.1 Gy and 1.2 Gy respectively when the CRT technique was used. They were statistically different for the lung V20, V30 and ipsilateral MLD between the two techniques （P 〈 0.01）, whereas there was no different for the contralateral MLD （P = 0.08）. All patients received radiation were found to have lung fibrosis and classified as grades 1-2 radiation pneumonitis. The quality of life was increased from score 2.83 to 3.76 and it was significantly different （P 〈 0.01）. Conclusion： MPM is moderately sensitive to radiation. The flexible 3DCRT technique is feasible in the treatment of MPM and lung damage is reduced apparently comparing with the CRT technique. The quality of life of patients with MPM is improved after irradiation.

Intrathoracic latissimus dorsi muscle transposition: a reliable technique for prevention of bronchopleural fistula developing after extrapleural pneumonectomy and external beam radiotherapy in malignant pleural mesothelioma

Objective: Bronchopleural fistula (BPF) is a life threatening complication after pneumonectomy. Extra thoracic skeletal muscle transposition especially latissimus dorsi muscle flap (LDMF) had been used to prevent this complication. The aim of this study was to assess the effectiveness of LDMF in preventing BPF developing after extrapleural pneumonectomy (EPP) and external radiation therapy in malignant pleural mesothelioma (MPM). Methods: Between May 1999 and Dec. 2008, 37 patients with MPM were operated upon by EPP using LDMF prophylactically to reinforce the bronchial stump, and then received external radiation therapy with or without postoperative chemotherapy. Results: The mean age of all patients was 46.7 (range 26-57) years. Twenty five patients were males and 12 patients were females. Twenty three patients had MPM of the right side and 14 patients had MPM of the left side. The peri-operative mortality was 2.7% and only few flap related postoperative morbidity were reported in the form of minor seroma and subcutaneous surgical emphysema. The median follow up was 17 (range 9-43) months. All cases completed their postoperative external radiation therapy with no reported cases of early or late BPF. Conclusion: Intrathoracic pedicled LDMF transposition is proved to be effective in prevention of BPF developing after EPP and external radiation therapy in MPM and it is advised to be a routine step in EPP in these cases and to use more sophisticated technique of postoperative external beam radiotherapy (3D conformal or IMRT) to minimize this complication.

Multiple bowel intussusceptions from metastatic localized malignant pleural mesothelioma:A case report

Localized malignant pleural mesothelioma (LMPM) is a rare occurrence, and gastrointestinal intra-luminal metastases have not previously been reported. Herein, we report a patient with LMPM who presented with a local recurrence 10 mo after initial en bloc surgical resection. Abdominal computed tomography was performed for intractable, vague abdominal pain with episodic vomiting, which showed a "target sign" over the left lower quadrant. Laparotomy revealed several intra-luminal metastatic tumors in the small intestine and colon and a segmental resection of metastatic lesions was performed. Unfortunately, the patient died of sepsis despite successful surgical intervention. Though local recurrence is more frequent in LMPM, the possibility of distant metastasis should not be ignored in patients with non-specifi c abdominal pain.

The Role of Thymidylate Synthase in Pemetrexed-Resistant Malignant Pleural Mesothelioma Cells

We established new pemetrexed-resistant cells originating from malignant pleural mesothelioma MSTO-211H cells to clarify the mechanism involved in pemetrexed resistance in malignant pleural mesothelioma. In the pemetrexed-resistant cells, only thymidylate synthase (TYMS) mRNA was overexpressed among other well-known molecular targets and chemosensitivity determinants of pemetrexed, and the role of the TYMS gene was ascertained by artificial regulation induced by specific siRNA. Silencing the TYMS expression partially restored the cytotoxicity of pemetrexed. The resistant cells did not display other gene alterations related to folate metabolism. We conclude that the primary mechanism imparting resistance to these cells is specific up-regulation of TYMS function. Further, the TYMS gene may serve as a useful biomarker for the prediction of pemetrexed chemosensitivity in patients with malignant pleural mesothelioma. We also investigated the efficacy of 1-(3-C-ethynyl-β-D-ribo-pento furanosyl)cytosine (ECyd) in overcoming pemetrexed resistance;this compound is presently undergoing clinical trials in the USA as TAS-106. ECyd had a similar antitumor effect on the resistant cells as that on the parental cells. In the clinical treatment of malignant pleural mesothelioma, ECyd promises to emerge as a novel drug.

Malignant Pleural Mesothelioma in Young People

Background: malignant pleural mesothelioma (MPM) is characterized by long latency period between exposure to asbestos and development of the disease so we hypothesize that MPM in the young has different characteristics. Patients and Methods: This is a retrospective study including all eligible patients with malignant pleural mesothelioma presenting to National Cancer Institute, Cairo University during the period from 2008 to 2013. Patients were divided into two groups: Group 1: patients aged ≤45 years. Group 2: Patients aged >45 years. Both groups were assessed regarding different clinicpathological features. Primary Objectives: comparison of different epidemiological features of both groups. Secondary Objectives: assessment of clinical response (CR), progression free survival (PFS) and overall survival (OS) in both groups. Results: 102 Patients were included with median follow up of 14.4 months. Group (1) included 35 patients with mean age 40 ± 3.65 years (31 to 45 years). Group (2) included 67 patients with mean age of 58.6 ± 8.5 years (46 to 87 years). 68% of group (1) came from endemic areas which is significantly higher than group (2): (35.8%), p = 0.02. History of Asbestos exposure was highly significantly different between the 2 groups, 77.1% in group (1) versus 38.8% in group (2), p < 0.001. Other factors showed no significant differences between the two groups. Overall clinical response (CR + PR) was 20% in group (1) versus 17.9% in group (2). P = 0.7. There was a trend towards longer median PFS in young patients, (19.8 ± 8.4 versus 6.9 ± 1.4 months). p = 0.09. The median OS of young patients is significantly longer (20.6 ± 6.3 months) than older patients (11.4 ± 3.6). p = 0.05. Conclusions: Mesothelioma in the young is more sensitive to asbestos exposure, has better OS and likely a different disease entity which needs further studies to understand its underlying biological features.

Extra-pleural pneumonectomy in the setting of tri-modality therapy for patients with malignant pleural mesothelioma

Although declining in the US due to restrictions of asbestos exposure, malignant pleura/mesothelioma （MPP） remains a very serious thoracic malignancy that is rising in incidence worldwide （1）. Trirnodality therapy with chemotherapy and radiotherapy combined with extrapleural pneumonectomy （EPP） has gained acceptance given the acceptable mortality rate （〈5%） and long term survival reported in patients with epithelial histology, negative margins, and no extrapleural lymph node involvement after trimodalitv treatment （2）.

恶性胸膜间皮瘤细胞培养条件及CDKN2B对癌细胞的作用

目的探讨不同培养条件(RPMI-1640、DMEM和DMEM/F12培养液)对人恶性胸膜间皮瘤(malignant pleural mesothelioma,MPM)组织中分离的MPM细胞传代的影响以及细胞周期蛋白依赖性激酶抑制剂2B(cyclin dependent kinase inhibitor 2B,CDKN2B)对MPM细胞增殖、侵袭和凋亡的作用。方法从MPM组织中分离细胞分别用RPMI-1640、DMEM和DMEM/F12培养液培养。CCK-8检测细胞增殖,细胞核及染色体利用瑞氏-吉姆萨染色观察,免疫荧光实验检测MPM标志物Calretinin、CD141、CK5、EMA和WT-1荧光强度。RT-qPCR和Western blot分别检测CDKN2B的mRNA和蛋白表达能力。Transwell检测细胞侵袭能力,流式细胞术检测细胞凋亡率。结果建立的MPM细胞在RPMI-1640、DMEM和DMEM/F12培养液中传至第10代仍具有较好的活力,且MPM标志物Calretinin、CD141、CK5、EMA和WT-1在细胞中均表达,MPM细胞在RPMI-1640培养液中活力较为稳定。CDKN2B在MPM细胞中低表达(P<0.05),过表达CDKN2B显著抑制MPM细胞的增殖(P<0.05)、侵袭(P<0.05)和上皮间质转化(P<0.01),促进细胞凋亡(P<0.01)。结论建立的MPM细胞可在RPMI-1640培养液中稳定传代,CDKN2B可作为MPM诊断和治疗的潜在靶标。

恶性胸膜间皮瘤靶向治疗的研究进展

恶性胸膜间皮瘤(malignant pleural mesothelioma, MPM)是侵袭性极强的罕见胸膜表面恶性肿瘤,危险因素包括吸入石棉、遗传因素、基因突变等。现有的化疗、抗血管生成治疗、免疫治疗的效果均不佳,患者的生存期极短。亟需寻找治疗MPM的潜在靶点,目前发现有基因突变靶点如BRCA1相关蛋白1(BRCA associated protein1, BAP1)和细胞周期蛋白依赖性激酶抑制剂2A(cyclin-dependent kinase 2A, CDKN2A)等;表观遗传靶点如组蛋白赖氨酸去甲基酶4A[lysine (K)-specific demethylase 4A, KDM4A]和赖氨酸特异性去甲基酶1(lysine-specific demethylase1, LSD1)等;信号蛋白靶点如葡萄糖调节蛋白78(glucose-regulated protein 78, GRP78)及信号转导和转录激活因子3(signal transducer and activator of transcription 3, STAT3)等。迄今为止,可查询的临床试验有组蛋白甲基转移酶抑制剂Tazemetostat、多聚ADP-核糖聚合酶[poly (ADP-ribose) polymerase, PARP]抑制剂Rucaparib和细胞周期蛋白依赖性激酶4/6(cyclin-dependent kinases 4 and 6, CDK4/6)抑制剂Abemaciclib的II期临床试验,以及靶向间皮素的嵌合抗原受体T细胞免疫疗法(chimeric antigen receptor T-cell immunotherapy, CAR-T)细胞胸腔注射、TEA结构域家族成员(TEA domain family member, TEAD)抑制剂VT3989和IK-930的I期临床试验,显示出一定的临床疗效。

Integrative decomposition procedure and Kappa statistics set up ATF2 ion binding module in malignant pleural mesothelioma(MPM)

Activating transcription factor 2(ATF2)is a member of the ATF/cyclic AMP-responsive element bind-ing protein family of transcription factors.However,the information concerning ATF2 ion-mediated DNA binding module and function of ATF2 in malignant pleural mesothelioma(MPM)has never been addressed.In this study,by using GRNInfer and GVedit based on linear pro-gramming and a decomposition procedure,with integrated analysis of the function cluster using Kappa statistics and fuzzy heuristic clustering in MPM,we identified one ATF2 ion-mediated DNA binding module involved in invasive function including ATF2 inhibition to target genes FALZ,C20orf31,NME2,PLOD2,RNF10,and RNASEH1,upstream RNF10 and PLOD2 activation to ATF2,upstream RNASEH1 and FALZ inhibition to ATF2 from 40 MPM tumors and 5 normal pleural tissues.Remarkably,our results showed that the predominant effect of ATF2 occupancy is to suppress the activation of target genes on MPM.Importantly,the ATF2 ion-mediated DNA binding module reflects‘mutual’positive and negative feedback regulation mechanism of ATF2 with up-and down-stream genes.It may be useful for developing novel prognostic markers and therapeutic targets in MPM.

从正虚邪实论治恶性胸膜间皮瘤伴急性呼吸困难思路探析

恶性胸膜间皮瘤是肿瘤内科恶性程度较高的癌种之一,近年国内外指南中的治疗方案有限且疗效欠佳,同时伴随药物毒副反应较大,致使该类患者较其他癌种的预后更差。恶性胸膜间皮瘤常常侵犯胸膜及纵隔,伴随呼吸困难、胸痛咳嗽等一系列不适症状,严重影响了患者的生活质量及后续的规范治疗。中医学认为恶性胸膜间皮瘤多因长期邪毒侵袭以及素体内虚所致,属于中医学“胸痹”范畴。本病病因病机以脾肾亏虚为主,气滞血瘀及痰瘀互结贯穿疾病全程。恶性胸膜间皮瘤伴急性呼吸困难的治疗应注意从正虚邪实论治,运用健脾化痰止咳、清热解毒平喘、活血散瘀利水三联疗法,在此基础上灵活运用对药和角药辨证辨病施治,获效显著。

帕博利珠单抗联合化疗治疗晚期恶性胸膜间皮瘤的成本-效用分析

目的从我国卫生医疗系统视角出发,评估帕博利珠单抗联合化疗一线治疗晚期恶性胸膜间皮瘤的经济性,为临床用药和卫生决议提供经济学参考。方法以IND227试验为基础,构建分区生存模型,周期为21 d,模拟至99%的患者死亡。模型产出指标为质量调整生命年(QALY),采用成本-效用分析法评价帕博利珠单抗联合化疗相对于单纯化疗治疗晚期恶性胸膜间皮瘤的经济性,并通过单因素敏感性分析和概率敏感性分析证明基础分析结果的稳健性。结果基础分析结果显示,与单纯化疗方案相比,帕博利珠单抗联合化疗方案的增量成本-效用比(ICUR)为1447296.58元/QALY,大于以3倍我国2023年人均国内生产总值(GDP)(268074元/QALY)作为的意愿支付(WTP)阈值,不具有经济性。患者在接受慈善赠药的情况下,ICUR为102236.18元/QALY,低于WTP阈值。单因素敏感性分析结果显示,帕博利珠单抗成本、效用贴现率和单纯化疗组支持治疗费用对结果的影响更显著。概率敏感性分析结果显示,基础分析结果稳健性较好。结论在WTP阈值为3倍我国2023年人均GDP时,与单纯化疗方案相比,帕博利珠单抗联合化疗治疗晚期恶性胸膜间皮瘤不具有经济性。但若患者接受慈善赠药,则帕博利珠单抗联合化疗方案更具有经济性。

基于TCGA数据库分析UHRF1基因在恶性胸膜间皮瘤中的表达及预后意义

利用生物信息学数据库分析泛素样含PHD和环指结构域蛋白1(UHRF1)在恶性胸膜间皮瘤(MPM)中的表达水平及临床意义。基于TCGA数据库和GTEx数据库差异表达分析UHRF1 m RNA在MPM组织和正常肺组织中的表达水平;使用R软件分析UHRF1 mRNA表达量与临床病理参数的相关性;构建Kaplan-Meier模型和单因素多因素COX回归模型分析UHRF1基因在MPM中的预后;利用TIMER2.0数据库分析UHRF1基因与免疫细胞浸润的关系;GSEA分析UHRF1基因发挥功能的主要富集通路。选取8例MPM组织及4例非MPM胸膜组织,通过RT-q PCR的方法验证UHRF1在MPM与非MPM胸膜组织的表达情况。数据库分析结果表明,与正常肺组织相比,UHRF1 m RNA在MPM组织中高表达;UHRF1高表达患者提示MPM患者预后不良;UHRF1基因表达量与CD4^(+)辅助型T细胞2、CD4^(+)效应记忆性T细胞、巨噬细胞等多种免疫细胞浸润水平具有显著的相关性(P<0.01),且显著影响MPM患者的预后。功能富集分析显示,UHRF1主要在DNA复制、蛋白酶体、同源重组等通路中起作用。在收集到的病例样本中,与非MPM胸膜组织相比,UHRF1 mRNA在MPM组织中的表达显著增高(P<0.001)。UHRF1在MPM组织中高表达,可能通过调节DNA甲基化和免疫细胞浸润来影响MPM患者预后,有望成为MPM治疗和预后评估的潜在靶点。

恶性胸膜间皮瘤化疗抵抗机制研究进展

恶性胸膜间皮瘤(MPM)是一种发病率不高,但侵袭性强、预后差、致死率高的肿瘤,生存期为4个月~1年,5年生存率仅为10%左右。MPM具有很强的化疗抵抗性,顺铂联合培美曲塞或者雷替曲塞的常规治疗只在20%左右患者中有一定的效果。近年来,随着对MPM遗传特征研究的不断深入,对MPM化疗抵抗分子机制的研究也取得一定进展。本文总结了近年来MPM化疗抵抗分子机制的研究进展,包括BAP1基因突变、MicroRNA、MTA1介导的DNA损伤修复通路、GITR-GITRL通路、TGFa通路、肿瘤干细胞、EGFR、PTEN等,旨在为探索MPM新治疗靶点、新联合治疗方案提供参考。

自噬相关基因5在人恶性胸膜间皮瘤中的表达及其意义

目的探讨自噬相关基因5(ATG5)在人恶性胸膜间皮瘤(MPM)细胞和组织中的表达情况,分析ATG5与MPM患者临床病理参数和预后的相关性。方法实时定量PCR(RT-qPCR)和Western blotting检测正常人胸膜间皮细胞和MPM细胞、非MPM胸膜间皮组织和MPM组织中ATG5的表达差异。应用TCGA数据库分析ATG5与MPM患者临床病理特征和预后的相关性。构建Cox回归模型,分析影响MPM患者预后的因素。GEPIA数据库评估ATG5与MPM肿瘤标志物和新型血清标志物的相关性。TIMER数据库分析ATG5与MPM免疫细胞浸润和关键免疫调节基因的相关性。结果ATG5在MPM细胞和组织中显著高表达,且与MPM患者的肿瘤分期呈正相关(P<0.05)。生存分析显示,ATG5高表达组MPM患者的预后更差,肿瘤病理类型可能是患者预后不良的危险因素(P<0.05)。ATG5与多种MPM肿瘤标志物(MTAP、SETD2、NF2、FIB3)和新型血清标志物(HMGB1、SMPR、THBS2、KRAS)显著相关(P<0.05)。ATG5表达与MPM中免疫细胞浸润(B细胞、CD4^(+)T细胞和巨噬细胞)和免疫相关基因(CD28、CUL48B、CD166、MMP14)呈显著正相关(P<0.05)。结论ATG5在MPM中表达上调,且与患者不良预后和免疫浸润水平相关,有望成为MPM早期筛查、诊断和预后评估的重要生物标志物。

基于铁死亡基因的恶性胸膜间皮瘤风险预测模型构建及其肿瘤免疫微环境研究

目的:筛选恶性胸膜间皮瘤(MPM)预后相关的铁死亡基因,探索铁死亡与肿瘤免疫微环境的联系,为MPM患者的靶向及免疫治疗提供新的视角。方法:分析GEO数据集中MPM肿瘤组和正常组的差异表达基因(DEGs),与铁死亡基因取交集得到MPM中铁死亡相关的DEGs(DE-FRGs);进行GO、KEGG功能富集和蛋白-蛋白互作(PPI)等分析明确DE-FRGs主要参与的信号通路;通过单因素COX分析鉴定出预后相关的铁死亡基因,LASSO回归分析筛选建立风险预测模型的最佳DEFRGs,并通过多因素COX分析建立基于最佳DE-FRGs的风险预测模型,对模型的预测效果进行一系列验证。最后通过CIBERSORT等算法对模型进行肿瘤免疫细胞浸润分析及免疫微环境评价。结果:筛选出24个预后相关的DE-FRGs,主要富集于铁死亡、转录调控和对无机物的反应,建立并验证了1个基于5个铁死亡相关基因(ALDH3A2、CAV1、HRAS、CDCA3、RRM2)的MPM风险预测模型,模型中高风险组CD8+T细胞、巨噬细胞比例较高,而B淋巴细胞占比较低。此外,免疫检查点PD-1、CTLA-4及其配体在高风险组中有更高的表达状态。结论:建立了基于5个铁死亡相关基因的MPM风险预测模型,并明确了模型中的免疫状态。为MPM的靶向及免疫治疗提供了一定的研究基础,该模型在MPM中的预测能力需要临床上进一步验证,以更好地预测疾病分层和治疗管理。

基于TCGA数据分析NEK2基因在恶性胸膜间皮瘤中的表达及预后意义

目的 分析永不有丝分裂基因A相关激酶2(NEK2)基因在恶性胸膜间皮瘤(MPM)中的表达及预后意义。方法 下载癌症基因组图谱(TCGA)数据库MPM基因表达数据、临床病理数据和生存状态数据;使用perl软件和R语言的limma、timeROC等程序包作NEK2基因在MPM中的差异分析、临床病理相关性分析、COX单因素和多因素分析以及基因富集分析,并绘制ROC曲线;利用TIMER2.0数据库分析MPM中NEK2表达与常见的免疫细胞浸润的相关性。选取12例MPM组织和6例非MPM胸膜组织,通过RT-qPCR的方法验证NEK2基因在MPM与非瘤组织中的表达情况。结果 与正常肺组织相比,NEK2在MPM组织中高表达(P<0.001)。NEK2基因mRNA表达量与MPM淋巴结分期具有显著相关性(P<0.05);NEK2高表达与MPM患者预后不良相关(P<0.001);NEK2基因表达与MPM中B淋巴细胞、巨噬细胞、树突状细胞浸润水平呈正相关(P<0.05),并在细胞周期、DNA复制、剪接体、mRNA监测等通路显著富集。在收集到的病例样本中,与非MPM胸膜组织相比,NEK2基因在MPM组织中的表达量显著增高(P<0.01)。结论 NEK2在MPM组织中高表达,且NEK2在MPM中高表达提示预后不良,可能成为治疗MPM的潜在靶点。