Concomitant epidermal growth factor receptor mutation/c-ros oncogene 1 rearrangement in non-small cell lung cancer: A case report

BACKGROUND Epidermal growth factor receptor(EGFR)mutation and c-ros oncogene 1(ROS1)rearrangement are key genetic alterations and predictive tumor markers for non-small cell lung cancer(NSCLC)and are typically considered to be mutually exc-lusive.EGFR/ROS1 co-mutation is a rare event,and the standard treatment appr-oach for such cases is still equivocal.CASE SUMMARY Herein,we report the case of a 64-year-old woman diagnosed with lung adenocar-cinoma,with concomitant EGFR L858R mutation and ROS1 rearrangement.The patient received two cycles of chemotherapy after surgery,but the disease prog-ressed.Following 1-month treatment with gefitinib,the disease progressed again.However,after switching to crizotinib,the lesion became stable.Currently,crizotinib has been administered for over 53 months with a remarkable treatment effect.CONCLUSION The efficacy of EGFR tyrosine kinase inhibitors and crizotinib was vastly different in this NSCLC patient with EGFR/ROS1 co-mutation.This report will aid future treatment of such patients.

Clinicopathological characteristics of human epidermal growth factor receptor 2-positive Barrett's adenocarcinoma

AIM:To compare the clinicopathological characteristics of human epidermal growth factor receptor 2 (HER2)-positive and HER2-negative Barrett's adenocarcinoma in Japan. METHODS:We performed immunohistochemical analysis of HER2 in 30 samples taken from patients with Barrett's adenocarcinoma and dual color in situ hybridization in cases showing 2+ reactions. We compared the clinicopathological characteristics of HER2-positive and HER2-negative patients.RESULTS:HER2 positivity was identified in 8 (27%) carcinoma samples. We found that HER2 expression was associated with p53 overexpression (100% vs 52.6% in pT1 tumor; 100% vs 54.5% in all stage tumor, P < 0.05) and protruding lesions at the early disease stage. There was no association between the mucin phenotype of the carcinomas and prognosis. HER2 expression and low clinical stage were unexpectedly different between Barrett's adenocarcinoma patients and gastric cancer patients, but the macroscopic features may be associated with earlier diagnosis in these patients. CONCLUSION:Our results suggest that HER2-positive Barrett's adenocarcinomas are associated with p53 overexpression and lesion protrusion at the early disease stage.

Coexistence of anaplastic lymphoma kinase rearrangement in lung adenocarcinoma harbouring epidermal growth factor receptor mutation:A single-center study

BACKGROUND Accumulating evidences confirm that epidermal growth factor receptor(EGFR)mutation and anaplastic lymphoma kinase(ALK)rearrangement have coexisted in lung adenocarcinoma(LUAD).However,Its biological mechanism,clinicopathological features,and optimization of targeted drugs have not yet been completely elucidated.AIM To explore the clinical profile of LUAD patients with co-mutations of EGFR and ALK genes,with hopes of scientifically guiding similar patients towards selected,targeted drugs.METHODS Two hundred and thirty-seven LUAD patients were enrolled.EGFR mutations were detected by the amplification refractory mutation system-peptide nucleic acid technique,while the expression of ALK rearrangement was screened by the 5′/3′imbalance strategy for reverse transcription followed by quantitative polymerase chain reaction analysis.The clinicopathological features of these patients were analysed retrospectively,and the follow-up data were collected.RESULTS There were six cases with co-mutations of EGFR and ALK genes,which were more common in women,non-smoking and stage IV LUAD patients with bone metastasis,hence a positive rate of 2.53%(6/237).EGFR-tyrosine kinase inhibitors(EGFR-TKIs)were their preferred drugs for targeted therapy in these patients,with progression-free survival ranging from two months to six months.CONCLUSION In Gannan region,the positive rate of co-mutations of EGFR and ALK genes in LUAD patients is relatively high,and the co-mutations are more common in women,non-smoking and stage IV patients with bone metastasis.These patients prefer EGFR-TKIs as their preferred targeted drugs,but the therapeutic effect is not good.EGFR/ALK dual-TKIs may be more effective targeted drugs,which needs further study.

Long-term omeprazole and esomeprazole treatment does not significantly increase gastric epithelial cell proliferation and epithelial growth factor receptor expression and has no effect on apoptosis and p53 expression

AIM： To study the effect of proton pump inhibitor （PPI） treatment on patients with reflux esophagitis and its in vivo effect on apoptosis, p53- and epidermal growth factor receptor （EGFR） expression. METHODS： After informed consent was obtained, gastric biopsies of the antrum were taken from patients with reflux oesophagitis prior to and after 6 mo of 20 mg omeprazole （n = 24） or 40 mg esomeprazole （n = 22） therapy. Patients did not take any other medications known to affect the gastric mucosa. All patients were Helicobacter pylori negative as confirmed by rapid urease test and histology, respectively. Cell proliferation, apoptosis, EGFR, and p53 expression were measured by immunohistochemical techniques. At least 600 glandular epithelial cells were encountered and results were expressed as percentage of total cells counted. Was considered statistically significant. RESULTS： Although there was a trend towards increase of cell proliferation and EGFR expression both in omeprazole and esomeprazole treated group, the difference was not statistically significant. Neither apoptosis nor p53 expression was affected. CONCLUSION： Long-term PPI treatment does not significantly increase gastric epithelial cell proliferation and EGFR expression and has no effect on apoptosis and p53 expression.

有和无内分泌分化大肠癌P^(53)和表皮生长因子受体表达的比较研究

目的：研究大肠癌内分泌分化与P53表皮生长因子受体（EGFR）表达的关系及意义。方法：采用免疫组织化学ABC法，检测79例大肠癌手术切除组织中嗜铬蛋白A（CGA），P53及EGFR的表达变化。结果：大肠癌组织中CGA，P53及EGFR的表达率分别为：35.4％（28／79〕，60．8％(48／79）和30．4％（24／79），有内分泌分化的大肠癌P53表达率及其免疫阳性细胞数分别为78．6％（22／28）和984．3士702．0／mm2，无内分泌分化者分别为51．0％和589．5士489．5／mm2，前者明显高于后者（P<O．025；P＜0．05）。有和无内分泌分化的大肠癌EGFR的表达率分别为46．4％（13／28）和21．6％（11／51），差异有显著性（P＜0．025）。结论：有内分泌分化的大肠癌P53及EGFR的表达明显高于无内分泌分化者。

浸润性乳腺癌PTEN、p53、EGFR与ER、PR及HER-2表达的关系

目的研究乳腺癌中雌激素受体(ER)、孕激素受体(PR)、表皮生长因子受体2(HER-2)与丢失性磷酸酶-张力蛋白基因(PTEN)、蛋白p53、表皮生长因子受体(EGFR)的关系。方法采用免疫组织化学S-P法检测ER、PR、HER-2、PTEN、p53和EGFR在68例乳腺浸润性癌和10例乳腺纤维腺瘤组织标本中的表达。结果 ER、PR、HER-2、PTEN、p53和EGFR的表达分别是44.1%、47.1%、54.4%、45.6%、51.5%、58.8%,PTEN蛋白表达与ER呈正相关;p53蛋白表达与ER、PR表达呈负相关;EGFR的表达与ER呈负相关、与HER-2呈正相关。结论联合检测ER、PR、HER-2、PTEN、p53、EGFR对临床上乳腺癌患者判断预后和靶向治疗有重要临床意义。

鼻咽癌P^(53),C-myc,EGFR基因表达的研究

目的：Ｐ５３，Ｃ－ｍｙｃ及ＥＧＦＲ基因在鼻咽癌（ＮＰＣ）的发生、发展中可能起重要作用，基因的研究结果可能为ＮＰＣ的预防及诊疗提供科学的依据。方法：用免疫组化Ｓ－Ｐ法检测了３０例ＮＰＣ组织、１０例无瘤鼻咽部（ＮＰ）组织的Ｐ５３，Ｃ－ｍｙｃ及ＥＧＦＲ基因的异常表达情况。结果：①三种基因在ＮＰＣ组织中均有较高水平的表达，Ｐ５３蛋白阳性率为８６．７％（２６／３０），Ｃ－ｍｙｃ和ＥＧＦＲ蛋白阳性率均为７０％（２１／３０）；相应对照的无瘤ＮＰ组织的阳性率分别为０．０％（０／１０）、１０％（１／１０）和３０％（３／１０）。ＮＰＣ组织与无瘤ＮＰ组织的Ｐ５３，Ｃ－ｍｙｃ及ＥＧＦＲ蛋白阳性率高于无瘤ＮＰ组织相应的阳性率，差异有统计学意义（Ｐ＝０．００００、Ｐ＝０．００１３及Ｐ＝０．０３１８）；②ＮＰＣ按ＴＮＭ临床分期，将其Ｔ、Ｎ级数分别与Ｐ５３、Ｃ－ｍｙｃ，ＥＧＦＲ蛋白染色阳性程度进行相关分析，皆无统计学意义（Ｐ＞０．０５）；③Ｃ－ｍｙｃ与ＥＧＦＲ的阳性表达之间有相关性（Ｐ＝０．０００９）。结论：①Ｐ５３，Ｃ－ｍｙｃ，ＥＧＦＲ三种基因的高表达，说明其与ＮＰＣ的发生有一定关系，认为Ｐ５３的免疫组化检测可作为ＮＰＣ的辅助诊断依据；?

Evaluation of malignancy using Ki-67,p53,EGFR and COX-2 expressions in gastrointestinal stromal tumors

AIM:To investigate the role of expressions of Ki-67, p53,epidermal growth factor receptor(EGFR)and cyclooxygenase-2(COX-2)in gastrointestinal stromal tumor(GIST)grading and prognosis. METHODS:Tumor tissue was collected retrospectively from 96 patients with GIST.Antibodies against Ki-67, p53,EGFR and COX-2 were used for immunohistochemical staining.Tumor grading was designated according to a consensus system and the staining was quantified in 3 categories for each antibody in the statistical analysis. RESULTS:The Ki-67 expression in GISTs was significantly associated with the size of the tumors,mitotic rate and the risk of malignancy(x2=15.51,P=0.02; x2=22.27,P<0.001;x2=20.05;P<0.001).The p53 expression was also significantly correlated with mitotic rate and the risk of malignancy(x2=9.92,P= 0.04;x2=9.97;P=0.04).Over-expression of Ki-67 was strongly correlated with poor survival(x2=10.44, P=0.006),but no correlation was found between the expression of p53,EGFR or COX-2 and survival. Multivariate analysis further demonstrated that Ki-67 expression(relative risk=15.78,95%CI:4.25-59.37) could be used as an independent prognostic value for GIST patients.Adjuvant imatinib therapy could improve clinical outcomes in the patients with high risk and intermediate risk of recurrence after complete tumor resections(median survival time:52 mo vs 37 mo, x2=7.618,P=0.006). CONCLUSION:Our results indicated that the expression of Ki-67 could be used as an independent prognostic factor for GIST patients.

靶向治疗联合化疗治疗表皮生长因子受体+肿瘤蛋白53共突变肺腺癌患者的疗效及安全性

目的探讨靶向治疗联合化疗治疗表皮生长因子受体(EGFR)+肿瘤蛋白53(TP53)共突变肺腺癌患者的疗效及安全性。方法将120例肺腺癌患者按照治疗方式的不同分为对照组及观察组,每组60例。对照组给予化疗,观察组给予化疗+靶向治疗(奥希替尼),评价两组患者疗效及不良反应,统计治疗前后两组患者肿瘤标志物[细胞角质蛋白19片段抗原21-1(CYFRA21-1)、鳞状细胞癌抗原(SCC-Ag)、糖类抗原125(CA125)、癌胚抗原(CEA)]及外周血淋巴细胞亚群水平。结果观察组患者客观缓解率、疾病控制率均高于对照组,差异均有统计学意义(P﹤0.05)。观察组患者中性粒细胞减少、血小板减少、贫血、甲状腺功能异常、肝肾功能减退发生率均低于对照组,差异均有统计学意义(P﹤0.05)。治疗后,两组患者CD3^(+)、CD4^(+)水平及CD4^(+)/CD8^(+)均高于本组治疗前,CD8^(+)水平均低于本组治疗前,且观察组患者CD3^(+)、CD4^(+)水平及CD4^(+)/CD8^(+)均高于对照组,CD8^(+)水平低于对照组,差异均有统计学意义(P﹤0.05)。治疗后,两组患者CYFRA21-1、SCC-Ag、CA125、CEA水平均低于本组治疗前,且观察组患者CYFRA21-1、SCC-Ag、CA125、CEA水平均低于对照组,差异均有统计学意义(P﹤0.05)。结论EGFR+TP53共突变时靶向治疗联合化疗治疗肺腺癌可提高治疗效果,降低肿瘤标志物水平,具有良好的耐受性。

健脾祛瘀解毒方治疗慢性胃炎伴胃黏膜低级别上皮内瘤变的临床研究

目的 观察健脾祛瘀解毒方治疗慢性胃炎伴胃黏膜低级别上皮内瘤变(LGIN)的临床疗效及对胃黏膜肿瘤高危标志物的影响。方法 将116例患者随机分为对照组(58例)和观察组(58例)。对照组口服健脾祛瘀解毒胶囊模拟剂+叶酸片;观察组口服健脾祛瘀解毒胶囊+叶酸片模拟剂,疗程12周。进行治疗前后电子胃镜检查,对胃镜下黏膜征象进行评分,并进行胃黏膜病理组织学检查,对萎缩、肠化生、炎症和异型增生情况评分;进行治疗前后中医症状评分;检测治疗前后胃组织人表皮生长因子受体2(HER2)、增殖相关的核抗体(Ki67)、肿瘤蛋白53(P53)和α-甲酰基辅酶A消旋酶(P504s)蛋白;并进行疗效及安全性评价。结果 (1)治疗后,两组患者胃镜下黏膜征象(黏膜充血、水肿、糜烂、黏膜白相、颗粒增生、血管透见、胆汁反流)评分均降低(P<0.01),且观察组低于对照组(P<0.01)。(2)治疗后,两组患者萎缩、肠化生、炎症和异型增生评分均降低(P<0.05,P<0.01),且观察组低于对照组(P<0.01)。(3)治疗后,两组患者主要症状(胃脘胀满、胃痛、食少纳呆、早饱)评分和中医症状总分均降低(P<0.01),且观察组低于对照组(P<0.01)。(4)治疗后,观察组HER2表达减轻(P<0.05),且观察组轻于对照组(P<0.05);治疗后,两组Ki67表达均减少(P<0.05),且观察组少于对照组(P<0.05),治疗后,两组Ki67阳性率均降低(P<0.01),且观察组低于对照组(P<0.05);治疗后,观察组P53和P504s表达减少(P<0.05),且观察组少于对照组(P<0.05),观察组P53和P504s蛋白阳性率均降低(P<0.05),且观察组低于对照组(P<0.05)。(5)观察组临床疗效总有效率为94.23%(49/52),高于对照组的79.25%(42/53)(χ^(2)=5.101,P<0.05)。(6)治疗期间没有发现服用健脾祛瘀解毒胶囊相关的不良反应。结论 健脾祛瘀解毒方治疗慢性胃炎伴LGIN可抑制胃黏膜癌前病变进展,减轻临床症状和胃镜下黏膜征象,可逆转萎缩、肠化生、异型增生等癌前病变,有较好的临床疗效,且临床使用安全。

Biomarkers in triple negative breast cancer:A review

Breast cancer is an intrinsically heterogeneous disease. In the world about 1 million cases of breast cancer are diagnosed annually and more than 170000 are triplenegative. Characteristic feature of triple negative breast cancer(TNBC) is that it lacks expression of oestrogen,progesterone and human epidermal growth factor receptor-2/neu receptors. They comprise 15%-20% of all breast cancers. We did a systematic review of Pub Med and conference databases to identify studies published on biomarkers in TNBC. We included studies with biomarkers including: Epidermal growth factor receptor,vascular endothelial growth factor,c-Myc,C-kit and basal cytokeratins,Poly(ADP-ribose) polymerase-1,p53,tyrosinase kinases,m-TOR,heat and shock proteins and TOP-2A in TNBC. We also looked for studies published on synthetic lethality and inhibition of angiogenesis,growth,and survival pathways. TNBC is a complex disease subtype with many subclasses. Majority TNBC have a basal-like molecular phenotype by gene expression profiling. Their clinical and pathologic features overlap with hereditary BRCA1 related breast cancers. Management of these tumours is a challenge to the clinician because of its aggressive behaviour,poor outcome,and absence of targeted therapies. As the complexity of this disease is being simplified over time new targets are also being discovered for the treatment of this disease. There are many biomarkers in TNBC being used in clinical practice. Biomarkers may be useful as prognostic or predictive indicators as well as suggest possible targets for novel therapies. Many targeted agents are being studied for treatment of TNBC.

Transient axonal glycoprotein-1 induces apoptosisrelated gene expression without triggering apoptosis in U251 glioma cells

Previous studies show that transient axonal glycoprotein-1, a ligand of amyloid precursor pro- tein, increases the secretion of amyloid precursor protein intracellular domain and is involved in apoptosis in Alzheimer＇s disease. In this study, we examined the effects of transient axonal glyco- protein-1 on U251 glioma cells. 3-（4,5-Dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide assay showed that transient axonal glycoprotein-1 did not inhibit the proliferation of U251 cells, but promoted cell viability. The terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed that transient axonal glycoprotein-1 did not induce U251 cell apoptosis. Real-time PCR revealed that transient axonal glycoprotein-1 substantially upregulated levels of amyloid precursor protein intracellular C-terminal domain, and p53 and epidermal growth factor recep- tor mRNA expression. Thus, transient axonal glycoprotein-1 increased apoptosis-related gene expression in U251 cells without inducing apoptosis. Instead, transient axonal glycoprotein-1 promoted the proliferation of these glioma cells.

USH2A mutation and specific driver mutation subtypes are associated with clinical efficacy of immune checkpoint inhibitors in lung cancer

This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors(ICIs)by conducting systematic literature search in electronic databases up to May 31,2021.The main outcomes including overall survival(OS),progression-free survival(PFS),objective response rate(ORR),and durable clinical benefit(DCB)were correlated with tumor genomic features.A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies.The Kirsten rat sarcoma viral oncogene homolog G12C(KRAS^(G12C))mutation combined with tumor protein P53(TP53)mutation revealed the promising efficacy of ICI therapy in these patients.Furthermore,patients with epidermal growth factor receptor(EGFR)classical activating mutations(including EGFRL858Rand EGFRΔ19)exhibited worse outcomes to ICIs in OS(adjusted hazard ratio(HR),1.40;95%confidence interval(CI),1.01-1.95;P=0.0411)and PFS(adjusted HR,1.98;95%CI,1.49-2.63;P<0.0001),while classical activating mutations with EGFR^(T790)Mshowed no difference compared to classical activating mutations without EGFR^(T790)Min OS(adjusted HR,0.96;95%CI,0.48-1.94;P=0.9157)or PFS(adjusted HR,0.72;95%CI,0.39-1.35;P=0.3050).Of note,for patients harboring the Usher syndrome type-2A(USH2A)missense mutation,correspondingly better outcomes were observed in OS(adjusted HR,0.52;95%CI,0.32-0.82;P=0.0077),PFS(adjusted HR,0.51;95%CI,0.38-0.69;P<0.0001),DCB(adjusted odds ratio(OR),4.74;95%CI,2.75-8.17;P<0.0001),and ORR(adjusted OR,3.45;95%CI,1.88-6.33;P<0.0001).Our findings indicated that,USH2A missense mutations and the KRAS^(G12C)mutation combined with TP53 mutation were associated with better efficacy and survival outcomes,but EGFR classical mutations irrespective of combination with EGFR^(T790)Mshowed the opposite role in the ICI therapy among lung cancer patients.Our findings might guide the selection of precise targets for effective immunotherapy in the clinic.

精准医疗在非小细胞肺癌中的应用

肺癌是全球发病率和死亡率增长最快，对人类健康和生命威胁最大的恶性肿瘤之一。下一代基因测序技术的应用为非小细胞肺癌（NSCLC）不同亚型的全面分析提供了平台。在NSCLC／患者基因组中，已鉴定出一些高频突变的基因，如克尔斯滕大鼠肉瘤病毒癌同源（KRAS）基因、肿瘤蛋白53（TP53）基因和表皮生长因子受体（EGFR）基因。虽然使用靶向EGFR和间变性淋巴瘤激酶基因（ALK）的精准治疗非常成功，但大部分NSCLC患者的这2个基因并不发生改变。汇集了目前针对肺腺癌（LAC）和鳞状细胞癌（SCC）的模式疗法并分析了其所对应的异常基因，及主要针对由KRAS、TP53等目前尚无靶向药物的突变靶点导致肿瘤的新型治疗策略。研究表明，只有在分子层面上深度解读NSCLC的致癌基因，运用高通量测序技术，才能实现NSCLC的精准治疗，大幅度降低肺癌的高死亡率。