Mutations in the C. elegans Succinate Dehydrogenase Iron-Sulfur Subunit Promote Superoxide Generation and Premature Aging

The mitochondrial succinate dehydrogenase (SDH) is an iron-sulfur flavoenzyme linking the Krebs cycle and the mitochondrial respiratory chain. Mutations in the human SDHB, SDHC and SDHD genes are responsible for the development of paraganglioma and pheochromocytoma, tumors of the head and neck or the adrenal medulla, respectively. In recent years, SDH has become recognized as a source of reactive oxygen species, which may contribute to tumorigenesis. We have developed a Caenorhabditis elegans model to investigate the molecular and catalytic effects of mutations in the sdhb-1 gene, which encodes the SDH iron-sulfur subunit. We created mutations in Pro211; this residue is located near the site of ubiquinone reduction and is conserved in human SDHB (Pro197), where it is associated with tumorigenesis. Mutant phenotypes ranged from relatively benign to lethal and were characterized by hypersensitivity to oxidative stress, a shortened life span, impaired respiration and overproduction of superoxide. Our data suggest that the SDH ubiquinone-binding site can become a source of superoxide and that the pathological consequences of SDH mutations can be mitigated with antioxidants, such as ascorbate and N-acetyl-l-cysteine. Our work leads to a better understanding of the relationship between genotype and phenotype in respiratory chain mutations and of the mechanisms of aging and tumorigenesis.     

Differences in Clinical Manifestations and Tumor Features Between Metastatic Pheochromocytoma/Paraganglioma Patients With and Without Germline SDHB Mutation

ObjectiveTo compare metastatic pheochromocytoma/paraganglioma (MPP) patients with germline SDHB mutations (SDHB MPP) and without SDHB mutations (non-SDHB MPP) in terms of baseline clinical manifestations, tumor characteristics, and outcomes.MethodsClinical data were retrospectively reviewed in 101 MPP patients, including 34 SDHB MPP patients and 61 non-SDHB MPP patients.ResultsSDHB MPP patients presented at a younger age at onset, diagnosis, or metastasis (25 ± 16 vs 36 ± 14, 28 ± 17 vs 38 ± 15, and 31 ± 17 vs 44 ± 14 years old, respectively, P < .01 for all) than non-SDHB patients. Compared with their non-SDHB counterparts, SDHB patients were more likely to have paragangliomas (83% vs 47%, P < .05), synchronous metastases (44% vs 23%, P < .05), bone metastases (80% vs 48%, P < .01), and a shorter progression-free survival (3 years vs 5 years, P < .01). The Ki-67 index was higher in SDHB tumors (P < .05). The 5- and 10-year survival rates were 79% and 74%, respectively, in all patients. Seventeen patients died from MPP, and the time from metastasis to death in patients who had received systemic therapy was significantly longer than in those who had not (3.1 ± 1.5 vs 1.4 ± 0.7 years, P < .01).ConclusionCompared with MPP patients without SDHB mutations, MPP patients with SDHB mutations were younger at onset, diagnosis, or metastasis; had a higher incidence of synchronous metastases, higher ratio of paraganglioma, and higher Ki-67 index; had a shorter postoperative progression-free survival; and were more likely to develop bone metastasis or sole liver metastasis. Our results suggest that patients with SDHB mutations should be identified early and monitored regularly to achieve optimal clinical outcomes.     

Multiple ParagangliomaSyndrome Type 4 Due to Succinate Dehydrogenase B Mutation:Diagnostic and Therapeutic Challenges of a Skull Base Paraganglioma Masquerading as Nasopharyngeal Cancer

ObjectiveTo report a case of hereditary paragan- glioma and describe the underlying genetic mutation and response to iodine 131 metaiodobenzylguanidine (MIBG) therapy.MethodsWe describe the clinical course and labora- tory and imaging findings of the study patient.ResultsA 38-year-old man presented in May 2005 with pseudobulbar palsy and was initially thought to have nasopharyngeal cancer because computed tomography of the head showed a large, locally invasive nasopharyngeal tumor. During tumor staging, abdominal computed tomog- raphy showed a large, locally invasive left adrenal tumor. Urinary normetanephrine was extremely elevated at 39 831 μg/24 h (reference range, 0-580 μg/24 h), while metaneph- rine was normal. MIBG scan showed uptake in the left ad- renal gland and in the skull mass. Biopsy of the nasopha- ryngeal mass confirmed the diagnosis of paraganglioma. The patient underwent resection of the 13-cm pheochro- mocytoma in the left adrenal gland, with resection of part of the colon and kidney. Postoperatively, urinary normeta- nephrine dropped to 9339 μg/24 h. The nasopharyngeal paraganglioma was inoperable. The patient was treated with 3 doses of MIBG—201, 190, and 225 mCi in August 2007, January 2008, and January 2009, respectively.Urinary normetanephrine normalized, and follow-up mag- netic resonance imaging showed a 60% reduction in the size of the nasopharyngeal tumor. Genetic testing revealed a C to T transition at nucleotide 268 in exon 3 of the SDHB gene, resulting in a change from an arginine to a stop codon (Arg90X) and leading to a truncated SDHB protein.ConclusionsThis case illustrates the diagnostic and therapeutic challenges of hereditary paraganglioma and the value of genetic testing. It also demonstrates the effec- tiveness of MIBG therapy for inoperable paragangliomas.(Endocr Pract. 2010;16:452-458)     

不同原发肿瘤位置对于西妥昔单抗联合化疗治疗K-ras 基因 野生型的转移性结直肠癌患者的预后比较

目的:探讨不同原发肿瘤位置对于西妥昔单抗治疗K-ras基因野生型的转移性结直肠癌患者的预后影响。方法:回顾性分析2008年1月1日至2013年12月31日187例我院行西妥昔单抗联合FOLFOX或FOLFIRI治疗的转移性结直肠癌患者,根据原发肿瘤位置,以结肠左曲为分界点分为右半结肠癌和左半结肠癌两组,按照严格的配对标准进行1:2配对,最终获得右半结肠癌组16例,左半结肠癌组32例,进行分析,比较两组患者的近期疗效和无进展生存期。结果:右半结肠癌组ORR为56.3%,左半结肠癌组ORR为62.5%,2组比较差异无统计学意义(X2=0.174,P=0.676)。右半结肠癌组DCR为87.5%,左半结肠癌组DCR为93.7%。2组比较差异无统计学意义(X2=0.545,P=0.460)。右半结肠癌组的中位无进展生存时间(m PFS)为5.0个月,左半结肠癌组mPFS为7.7个月,两组差别有统计学意义(P0.05)。结论:K-Ras基因野生型的左半结肠癌患者应用西妥昔单抗治疗,预后好于右半结肠癌。     

循环肿瘤细胞在40例晚期转移性乳腺癌患者中的检测意义

目的:探讨循环肿瘤细胞CTCs在晚期转移性乳腺癌中的应用价值。方法:Cell Search系统检测本院40例复发转移性乳腺癌患者的CTCs水平,比较复发转移性乳腺癌患者血液中CTCs的差异,分析复发转移性乳腺癌患者CTCs与其疾病特征及预后的关系。结果:Cell Search系统检测复发转移性乳腺癌患者外周血CTCs阳性率达42.5%;在复发转移性乳腺癌患者中,CTCs≥5个/7.5 mL者的肝脏转移、骨转移、转移灶≥3处均较CTCs5个/7.5 mL者更高(P0.05),前者的PFS较之后者也表现出强烈的缩短趋势(X2=3.573,P=0.059),而肺转移、淋巴结转移、脑转移、胸壁复发、受体及HER2表达在两组间无差异。结论:Cell Search系统展现出较好的检测复发转移性乳腺癌患者外周血CTCs的能力。在复发转移性乳腺癌患者中,CTCs的高检出率与腹腔脏器转移、肝转移、骨转移相关。CTCs≥5个/7.5 mL患者的预后很可能要差于CTCs5个/7.5 mL者。     

Genetic Diversity of the KIR/HLA System and Outcome of Patients with Metastatic Colorectal Cancer Treated with Chemotherapy

Objective

To explore genes of the killer-cell immunoglobulin-like receptor (KIR) and of the HLA ligand and their relationship with the outcome of metastatic colorectal cancer (mCRC) patients treated with first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI).

Methods

A total of 224 mCRC patients were screened for KIR/HLA typing. The determination of the KIR/HLA combinations was based upon the gene content and variants. Genetic associations with complete response (CR), time to progression (TTP) and overall survival (OS) were evaluated by calculating odds and hazard ratios. Multivariate modeling with prognostic covariates was also performed.

Results

For CR, the presence of KIR2DL5A, 2DS5, 2DS1, 3DS1, and KIR3DS1/HLA-Bw4-I80 was associated with increased CR rates, with median ORs ranging from 2.1 to 4.3, while the absence of KIR2DS4 and 3DL1 was associated with increased CR rates (OR 3.1). After univariate analysis, patients that underwent resective surgery of tumor, absence of KIR2DS5, and presence of KIR3DL1/HLA-Bw4-I80 showed a significant better OS (HR 1.5 to 2.8). Multivariate analysis identified as parameters independently related to OS the type of treatment (surgery; HR 2.0) and KIR3DL1/HLA-Bw4-I80 genotype (HR for T-I80 2.7 and for no functional KIR/HLA interaction 1.8). For TTP, no association with KIR/HLA genes was observed.

Conclusion

This study, for the first time, evidences that the genotyping for KIR-HLA pairs are found predictive markers associated with complete response and improves overall survival prediction of FOLFIRI treatment response in metastatic colorectal cancer. These results suggest a role of the KIR/HLA system in patient outcome, and guide new research on the immunogenetics of mCRC through mechanistic studies and clinical validation.     

Detection of KRAS Exon 2 Mutations in Circulating Tumor Cells Isolated by the ISET System from Patients with RAS Wild Type Metastatic Colorectal Cancer

INTRODUCTION: The presence of KRAS mutations in patients with metastatic colorectal cancer (mCRC) predicts poor response to agents targeting the EGFR. Even in patients with RAS wild type (WT) tumors, resistance eventually develops due to multiple mechanisms, including the expansion of previously undetected KRAS mutated clones. In this feasibility study, we aimed to detect KRAS exon 2 mutations in serial samples of circulating tumor cells (CTCs) of RAS WT patients with mCRC captured by the Isolation by Size of Epithelial Tumor cells (ISET) system. METHODS: CTC isolation using the ISET system was performed from prospectively collected blood samples obtained from patients with RAS and BRAF WT mCRC prior to first-line therapy initiation, at first imaging assessment and on disease progression. CTCs were enumerated using hematoxylin & eosin and CD45 double stain on a single membrane spot. DNA was extracted from 5 spots and KRAS exon 2 mutations were detected using a custom quantitative Polymerase Chain Reaction (qPCR) assay. RESULTS: Fifteen patients were enrolled and 28 blood samples were analyzed. In 9 (60%) patients, at least one sample was positive for the presence of a KRAS exon 2 mutation. In 11 out of 28 samples (39.2%) with detectable CTCs a KRAS mutation was detected; the corresponding percentages for baseline and on progression samples were 27% and 37.5%, respectively. The most commonly detected mutations were G13D and G12C (n = 3). The presence of KRAS mutated CTCs at baseline was not prognostic for either PFS (P = .950) or OS (P = .383). CTC kinetics did not follow tumor response patterns. CONCLUSION: The results demonstrate that using a qPCR-based assay, KRAS exon 2 mutations could be detected in CTCs captured by the ISET system from patients with RAS WT primary tumors. However, the clinical relevance of these CTCs remains to be determined in future studies.     

腹腔热灌注化疗联合全身系统化疗对晚期胃癌腹膜转移患者细胞免疫功能、肿瘤标志物和肿瘤侵袭转移相关指标的影响

摘要 目的：探讨腹腔热灌注化疗（HIPEC）联合全身系统化疗（NIPS）对晚期胃癌腹膜转移患者细胞免疫功能、肿瘤标志物和肿瘤侵袭转移相关指标的影响。方法：选取2019年6月至2022年1月在新疆医科大学第一附属医院胃肠外科住院治疗的116例晚期胃癌腹膜转移患者,按照随机数字表法分为观察组和对照组,各58例。对照组患者接受NIPS,观察组患者接受HIPEC联合NIPS。观察两组疗效、生存率和不良反应情况,对比两组细胞免疫功能、肿瘤标志物和肿瘤侵袭转移相关指标变化情况。结果：观察组的临床总有效率（68.97%）高于对照组（50.00%）（P<0.05）。两组治疗后CD3⁺、CD4⁺、CD4⁺/CD8⁺下降,但观察组高于对照组（P<0.05）。CD8+升高,但观察组低于对照组（P<0.05）。两组治疗后癌胚抗原（CEA）、糖类抗原19-9（CA199）、糖类抗原125（CA125）下降,但观察组低于对照组（P<0.05）。两组治疗后内皮生长因子（VEGF）、基质金属蛋白酶-2（MMP-2）和基质金属蛋白酶-9（MMP-9）下降,但观察组低于对照组（P<0.05）。观察组的6个月、9个月、12个月生存率均高于对照组（P<0.05）。两组不良反应发生率对比无差异（P>0.05）。结论：HIPEC联合NIPS用于治疗晚期胃癌腹膜转移患者,可改善患者细胞免疫功能,调节肿瘤标志物和肿瘤侵袭转移相关指标水平,提高生存率。     

西妥昔单抗联合化疗治疗K-Ras野生型转移性结直肠癌的疗效及其影响因素分析

目的:探讨西妥昔单抗联合化疗治疗K-Ras野生型转移性结直肠癌(mCRC)的疗效及其影响因素。方法:选取2013年1月～2015年1月河北北方学院附属第一医院收治的K-Ras野生型mCRC患者96例,按照随机数字表法将患者分为对照组(n=48)和观察组(n=48)。对照组给予常规化疗方案治疗,观察组在此基础上给予西妥昔单抗治疗。比较两组临床疗效、中位无进展生存期(PFS)、中位总生存期(OS)以及不良反应发生情况,并分析观察组治疗疗效的影响因素。结果:观察组客观有效率(ORR)和疾病控制率(DCR)分别为54.17%和91.67%,均高于对照组的31.25%和81.25%(P0.05)。观察组患者中位PFS和中位OS均较对照组长(P0.05)。观察组皮肤痤疮样病变发生率高于对照组(P0.05)。单因素分析显示,西妥昔单抗联合化疗治疗K-Ras野生型mCRC的ORR、DCR与年龄、肿瘤部位、肿瘤转移部位、肿瘤分化程度以及西妥昔单抗治疗时间有关(P0.05)。结论:西妥昔单抗联合化疗治疗K-Ras野生型mCRC疗效确切,预后较好,患者对不良反应可耐受,患者年龄、肿瘤部位、转移部位、分化程度及西妥昔单抗治疗时间可能是其疗效的影响因素。     

伊立替康联合阿帕替尼治疗术后转移性胃癌患者临床疗效和安全性分析

摘要 目的：探讨伊立替康联合阿帕替尼治疗术后转移性胃癌患者临床疗效和安全性。方法：选取我院2017年5月-2018年10月期间收治的术后一线化疗失败转移性胃癌患者105例,根据随机数字表法分为研究组（53例）和对照组（52例）,对照组患者给予伊立替康静脉滴注治疗,研究组在此基础上使用阿帕替尼进行联合治疗,4周为一个周期,连续治疗两个周期。比较两组患者疾病控制率、生存情况,并对治疗前后两组患者肿瘤标志物[癌胚抗原（CEA）、糖类抗原125（CA125）和糖类抗原199（CA199）]水平、基质金属蛋白酶-9（MMP-9）和血管内皮生长因子（VEGF）水平进行比较,观察治疗过程中两组患者不良反应发生情况。结果：治疗后,研究组疾病控制率、中位生存时间和中位进展时间均优于对照组（P<0.05）。治疗后,两组肿瘤标志物、MMP-9和VEGF水平均降低,且研究组低于对照组（P<0.05）。研究组不良反应发生率低于对照组（P<0.05）。结论：伊立替康联合阿帕替尼治疗术后转移性胃癌患者临床疗效确切,可延长患者生存时间,延缓疾病进展,且安全性较好,其作用机制可能与降低肿瘤标志物及MMP-9、VEGF水平有关。     

Mutations in the L-arabinose operon of Escherichia coli B/r with reduced initiator function.

Partial reversion mutants derived from a strain containing a strongly polar initiator-defective mutation (araI1036) in the L-arabinose operon were found to have several characteristics expected of mutants with reduced initiator function. These reversion mutations are cotransduced with the ara region and are probably within the araI region. Furthermore, they permit induction of the L-arabinose operon to a level only one-third of the normal wild-type level. These partially functional initiator regions reduce the expression of structural genes in the cis position only; they function quite independently of wild-type or defective initiator regions in the trans position. These mutants exhibit a two- to threefold increase in the rate of expression of ara operon genes within one-tenth of a generation after a shift of the growth temperature from 28 to 42 degrees C. This suggests that the temperature optimum for initiation of operon expression is higher for the partial revertant strains than it is for strains containing a wild-type initiator region.     

血清ANXA2、ANXA3与转移性结直肠癌患者化疗疗效的关系

摘要 目的：探讨血清膜联蛋白（ANX）A2、ANXA3与转移性结直肠癌（mCRC）患者化疗疗效的关系。方法：选取2019年1月～2020年10月徐州医科大学附属医院收治的90例mCRC患者,根据mFOLFOX6化疗联合西妥昔单抗治疗后的疗效分为未缓解组和缓解组。采用酶联免疫吸附法检测血清ANXA2、ANXA3水平。分别采用单因素、多因素Logistic回归分析和受试者工作特征（ROC）曲线分析mCRC患者化疗未缓解的影响因素和血清ANXA2、ANXA3对mCRC患者化疗未缓解的预测价值。结果：90例mCRC患者客观缓解率为58.89%（53/90）。单因素分析显示,两组年龄、回盲部肿瘤、TNM分期、Zubrod-东部肿瘤协助组-世界卫生组织（ZPS）评分、治疗目标、ANXA2、ANXA3组间比较存在统计学差异（P＜0.05）。多因素Logistic回归分析显示,回盲部肿瘤、TNM分期Ⅳ期、ZPS评分1～2分和ANXA2、ANXA3升高为mCRC患者化疗未缓解的独立危险因素（P＜0.05）。ROC曲线分析显示,血清ANXA2预测mCRC患者化疗未缓解的曲线下面积（AUC）为0.787,ANXA3预测mCRC患者化疗未缓解的AUC为0.791,血清ANXA2、ANXA3联合预测为0.904,二者联合预测的AUC最大（P＜0.05）。结论：血清ANXA2、ANXA3水平升高为mCRC患者化疗未缓解的独立危险因素,可影响mCRC患者的化疗疗效,二者联合预测mCRC患者化疗未缓解的价值较高。     

Impact of Chemotherapy Delay on Overall Survival for AML with IDH1/2 Mutations: A Study in Adult Chinese Patients

The effect of time from diagnosis to treatment (TDT) on overall survival of patients with acute myeloid leukemia (AML) remains obscure. Furthermore, whether chemotherapy delay impacts overall survival (OS) of patients with a special molecular subtype has not been investigated. Here, we enrolled 364 cases of AML to assess the effect of TDT on OS by fractional polynomial regression in the context of clinical parameters and genes of FLT3ITD, NPM1, CEBPA, DNMT3a, and IDH1/2 mutations. Results of the current study show IDH1/2 mutations are associated with older age, M0 morphology, an intermediate cytogenetic risk group, and NPM1 mutations. TDT associates with OS for AML patients in a nonlinear pattern with a J shape. Moreover, adverse effect of delayed treatment on OS was observed in patients with IDH1/2 mutations, but not in those with IDH1/2 wildtype. Therefore, initiating chemotherapy as soon as possible after diagnosis might be a potential strategy to improve OS in AML patients with IDH1/2 mutations.     

DCs-CIK细胞免疫治疗联合化疗对转移性前列腺癌患者免疫功能及生活质量的影响

目的:探讨DCs-CIK细胞免疫(Dendritic cells-Cytokine induced killer cells,DCs-CIK)治疗联合化疗对转移性前列腺癌患者免疫功能及生活质量的影响。方法:选择106例确诊转移性前列腺癌患者随机分为观察组与对照组,每组各53例,对照组采用多西他赛联合表阿霉素~+泼尼松化疗方式进行治疗,观察组在此基础上给予DC-CIK细胞免疫治疗。比较两组患者治疗前后外周血CD3~+、CD3~+CD4~+、CD3~+CD8~+、CD3-CD56~+、CD4~+CD8~+、自然杀伤细胞(NK)、自然杀伤T细胞(NKT)表达水平;使用QLQ-C30问卷评价患者治疗前后生活质量的变化情况,观察并比较患者治疗过程中发生的不良反应情况。结果:组观察组患者治疗总有效率达73.58%远高于对照组41.51%水平(p0.05);观察组患者治疗后外周血CD3~+、CD3~+CD4~+、CD3~+CD8~+、CD3-CD56~+、CD4~+CD8~+、NK、NKT表达水平明显好于对照组(p0.05);观察组患者躯体功能、角色功能、情绪功能、认知功能、社会功能各项指标得分明显好于对照组(p0.05);两组患者接受治疗后,均有部分患者出现恶心呕吐、脱发、白细胞减少、血小板减少或肝功受损,其中观察组患者出现恶心呕吐、白细胞减少的人数明显少于对照组(p0.05)。结论:DCs-CIK细胞免疫治疗联合化疗有助于转移性前列腺癌患者的治疗,在明显改善患者免疫能力的同时有效改善患者生活质量,具有重要的临床指导意义。     

替吉奥联合阿帕替尼对晚期复发转移食管癌患者T细胞亚群和血清肿瘤标志物水平的影响

摘要 目的：观察晚期复发转移食管癌经阿帕替尼联合替吉奥治疗后的疗效及对患者T细胞亚群和血清肿瘤标志物水平的影响。方法：病例搜集时间为2015年3月至2018年3月,病例搜集范围为我院接收的晚期复发转移食管癌患者70例。采用信封抽签法将患者分为对照组和实验组,各为35例。对照组给予替吉奥治疗,实验组在对照组的基础上联合阿帕替尼治疗,两组均连续化疗2个周期。对比两组化疗2个周期后的客观缓解率、疾病控制率;对比两组化疗前、化疗2个周期后的T细胞亚群和血清肿瘤标志物水平;对比两组中位总生存期（mOS）、中位无进展生存期（mPFS）及生命质量评分,记录两组化疗期间毒副反应发生情况。结果：实验组的客观缓解率45.71%、疾病控制率68.57%高于对照组的22.86%、42.86%（P<0.05）。两组化疗2个周期后CD3⁺、CD4⁺、CD4⁺/ CD8⁺均较化疗前降低,但实验组高于对照组（P<0.05）;CD8⁺较化疗前升高,但实验组低于对照组（P<0.05）。两组化疗2个周期后肿瘤特异性生长因子（TSGF）、癌胚抗原（CEA）、糖类抗原199（CA199）较化疗前降低,且实验组低于对照组（P<0.05）。实验组的mOS、mPFS长于对照组（P<0.05）,两组化疗结束后3个月QLQ-OES24评分均升高,且实验组高于对照组（P<0.05）。两组不良反应发生率对比,差异无统计学意义（P>0.05）。结论：晚期复发转移食管癌经阿帕替尼联合替吉奥治疗后,病情得到有效控制,血清肿瘤标志物水平降低更为显著,同时还可减轻免疫抑制,延长mOS、mPFS,且不增加毒副反应,近期疗效可靠。     

PD-1免疫抑制剂联合化疗治疗晚期NSCLC的效果及对肿瘤标志物、预后的影响

摘要 目的：探究PD-1免疫抑制剂联合化疗治疗晚期非小细胞肺癌（NSCLC）的效果及对肿瘤标志物、预后的影响。方法：回顾性选取2020.6~2023.6间收治的处于III B期~IV期NSCLC患者为研究对象,依据其治疗方案分为化疗组（n=32,培美曲塞/紫杉类+铂类化疗方案）和联合组（n=36,免疫抑制剂+培美曲塞/紫杉类+铂类化疗方案）,治疗至少2个周期后比较两组实体瘤治疗效果[疾病控制率（DCR）、客观缓解率（ORR）],随访预后生存情况[无进展生存期（PFS）、总生存期（OS）],比较治疗期间药物不良反应,比较两组治疗前、治疗2个周期后的血清生化指标[癌胚抗原（CEA）、细胞角蛋白19片段抗原（CY-FRA21-1）和白蛋白（ALB）]水平变化。结果：治疗2个周期后,联合组DCR（83.33% vs 59.38%）显著高于化疗组（P<0.05）,但ORR（58.33% vs 40.63%）与化疗组比较无显著差异（P>0.05）;随访18个月,联合组PFS为（11.44±1.81）个月,死亡11例,OS为（15.17±1.42）个月;化疗组PFS为（6.87±3.05）个月,死亡16例,OS为（11.91±1.09）个月,联合组PFS显著高于化疗组（log rank x²=4.377,P<0.05）,两组OS比较无显著差异（log rank x²=3.442,P>0.05）;治疗期间,两组药物不良反应总发生率比较无显著差异（P>0.05）;治疗2个周期后,两组CEA和CY-FRA21-1水平逐渐降低（P<0.05）,ALB水平显著升高（P<0.05）,且联合组治疗2个周期指标变化显著高于化疗组（P<0.05）。结论：PD-1免疫抑制剂联合化疗治疗晚期NSCLC效果良好,可显著抑制肿瘤发展进程,延长患者PFS,改善预后,值得推荐。     

A Genomic Instability Score in Discriminating Nonequivalent Outcomes of BRCA1/2 Mutations and in Predicting Outcomes of Ovarian Cancer Treated with Platinum-Based Chemotherapy

Detecting mutation in BRCA1/2 is a generally accepted strategy for screening ovarian cancers that have impaired homologous recombination (HR) ability and improved sensitivity to PARP inhibitor. However, a substantial subset of BRCA-mutant ovarian cancer patients shows less impaired or unimpaired HR ability, resulting in nonequivalent outcome after ovarian cancer development. We hypothesize that genomic instability provides a lifetime record of DNA repair deficiency and predicts ovarian cancer outcome. Based on the multi-dimensional TCGA ovarian cancer data, we developed a biological rationale-driven genomic instability score integrating somatic mutation and copy number change in a tumor genome. The score successfully divided BRCA-mutant ovarian tumors into cases of significantly improved outcome and cases of unimproved outcome. The score was also capable of discriminating HR-deficiency indicated by BRCA1 epigenetically silencing, EMSY amplification and homozygous deletion of core HR genes. We further found that the score was positively correlated with the complete response rate of chemotherapy and the rate of platinum-sensitivity, and predicted improved outcome of ovarian cancer, regardless of BRCA-mutation status. The score may have important value in outcome prediction and clinical trial design.