Myocarditis temporally related to the use of gefitinib (Iressa)

Gefitinib is a new drug that was approved by the US Food and Drug Administration in May 2003 for non-small cell cancer of the lung refractory to first- and second-line therapy. It is regarded as a rather safe drug with common adverse effects that include nausea, vomiting, diarrhea, rash, acne, and dry skin. However, it was reported in Japan to be associated with interstitial pneumonitis (2%-3% of subjects), presumably as a manifestation of a hypersensitivity reaction. The Food and Drug Administration studied this in US patients and found only a 0.3% occurrence and a slightly less than 0.1% mortality due to interstitial pneumonitis. To our knowledge, there has not been an association with fulminant myocarditis or acute myocarditis. We report the case of a 71-year-old man who died as a result of fulminant myocarditis 1 week after starting to take this new class of agent, gefitinib. On the basis of his medical history and our findings, we feel it necessary to consider hypersensitivity myocarditis related to gefitinib the probable cause of death.     

Molecular predictors of EGFR-TKI sensitivity in advanced non-small cell lung cancer

The epidermal growth factor receptor (EGFR) is overexpressed in the majority of non-small cell lung cancers (NSCLC) and is a major target for new therapies. Specific EGFR tyrosine kinase inhibitors (TKIs) have been developed and used for the treatment of advanced NSCLC. The clinical response, however, varies dramatically among different patient cohorts. Females, East Asians, non-smokers, and patients with adenocarcinoma usually show higher response rates. Meanwhile, a number of biological factors are also associated with EGFR-TKIs responsiveness. In order to better understand the predictive value of these biomarkers and their significance in clinical application we prepared this brief review. Here we mainly focused on EGFR somatic mutations, MET amplification, K-ras mutations, EGFRvIII mutation, EGFR gene dosage and expression, HER2 gene dosage and expression, and Akt phosphorylation. We think EGFR somatic mutation probably is the most effective molecular predictor for EGFR-TKIs responsiveness and efficacy. Mutation screening test can provide the most direct and valuable guidance for clinicians to make decision on EGFR-TKIs therapy.     

Targeting of EGFR tyrosine kinase by ZD1839 ("Iressa") in androgen-responsive prostate cancer in vitro

EGFR, highly expressed in a variety of human malignancies, is correlated with poor tumour differentiation, high tumour growth and metastatic rate. EGF and several other ligands, such as transforming growth factor-alpha, amphiregulin, heparin-binding EGF, and betacellulin, activate Ras/Raf mitogen-activated protein kinases (MAPKs) and phosphatidyl inositol 3'-kinase (PI3K)/Akt signalling pathways. Therefore, EGFR can regulate multiple processes, i.e., gene expression, cellular proliferation, angiogenesis, and inhibition of apoptosis, which contribute to the development of malignancy. In this review, we discuss the inhibition of EGFR by the specific tyrosine kinase inhibitor Iressa (ZD1839) focusing on its effects in prostate cancer.     

Tamoxifen resistance in breast cancer cells is accompanied by an enhanced motile and invasive phenotype: Inhibition by gefitinib (`Iressa', ZD1839)

Despite an initial response to antihormonal therapies, the development of resistance will occur in a significant number of breast cancer patients. The mechanisms that underlie acquired resistance are not yet clear. Using a previously established in vitro cell model of tamoxifen resistance in MCF7 cells, shown to display autocrine epidermal growth factor receptor (EGFR) signalling, we assessed how resistance might modulate their metastatic phenotype in vitro, as metastatic disease is the single most important factor affecting the mortality of cancer patients. Furthermore, we investigated the effect of the EGFR tyrosine kinase inhibitor (EGFR-TKI), gefitinib ('Iressa', ZD1839; AstraZeneca), on this behaviour. The acquisition of tamoxifen resistance in MCF7 cells was accompanied by a dramatic and significant increase in their invasive and motile nature. The affinity of these cells for matrix components was also enhanced. Inhibition of EGFR signalling with gefitinib reduced both basal and TGF-alpha-stimulated invasion and motility and reduced cell-matrix adhesion. In conclusion, we demonstrate here that resistance to tamoxifen in breast cancer cells is accompanied by a significant increase in their basal motile and invasive activity, properties associated with increased metastatic potential. Inhibition of EGFR signalling by gefitinib significantly inhibited cell motility and invasion thus suggesting a role for the EGF receptor in the aggressive phenotype of tamoxifen-resistant breast cancer cells.     

吉妥辛对吉非替尼耐药性非小细胞肺癌的抑制作用

 目的 在细胞和动物水平评价强心苷药物吉妥辛对耐药性非小细胞肺癌的抑制作用,并对其抑癌的分子机制进行初步探索。方法 吉妥辛和吉非替尼处理H1975细胞后,用MTS法检测细胞的存活率,流式细胞分析法检测细胞的凋亡率;吉妥辛处理移植瘤裸鼠,测量并计算移植瘤体积;吉妥辛处理H1975细胞后,用Western blot检测Erk1/2的磷酸化水平。结果 吉妥辛比吉非替尼更有效地抑制H1975的生长(P＜0.05）,促进其凋亡(P＜0.05）,且能显著抑制裸鼠移植瘤的生长(P＜0.05）。吉妥辛能计量和时间依赖地抑制Erk1/2的磷酸化(P＜0.05）。结论 吉妥辛可作为治疗耐药性非小细胞肺癌的潜在替代药物。     

赫赛汀对吉非替尼诱导肺癌A549细胞凋亡的影响

目的： 研究吉非替尼与赫赛汀联合应用对人肺腺癌A549 细胞凋亡的影响。方法: 应用MTT法,流式细胞仪Annexin V－PI 双标法、DAPI荧光染色等多项方法,体外研究吉非替尼与赫赛汀联合对A549 细胞的促凋亡作用。结果: 吉非替尼与赫赛汀单独应用及联合应用均可以明显抑制人肺腺癌A549细胞的生长，促进细胞凋亡,并呈浓度及时间依赖性,2者联合作用人肺腺癌A549 细胞24 h、48 h、72 h 的凋亡率显著高于单用吉非替尼或赫赛汀组(P<0.05),2者呈现出相加的抗瘤效果。结论: 吉非替尼与赫赛汀联合应用在体外对人肺腺癌A549 细胞有明显的促凋亡作用。     

Cytoplasmic expression of c-erbB2 in non-small cell lung cancers

The aim of this study was to investigate the expression of c-erbB2 in non-small cell lung cancers (NSCLCs) with attention both to membranous and cytoplasmic reaction, and to try to elucidate the meaning of cytoplasmic expression of c-erbB2 in NSCLCs. Immunohistochemical c-erbB2 expression and related clinico-pathological features were examined in 312 surgically resected patient tissues of NSCLCs, including 175 cases of adenocarcinoma and 137 cases of squamous cell carcinoma. Immunostaining of inner- and ecto-domain of c-erbB2, mRNA expression and the quantitation of soluble c-erbB2 in cultured media were performed in five NSCLC cell lines. Cytoplasmic expression of c-erbB2 was observed more frequently than membranous, both in patient tissues and cell lines. Neither membranous nor cytoplasmic expression of c-erbB2 was significantly correlated with short outcome in NSCLCs. Membranous c-erbB2 was expressed by both inner and ecto-domain, while cytoplasmic c-erbB2 was expressed by either or both inner and ecto-domain. c-erbB2 mRNA was produced in most cell lines; however, the soluble form was only detectable in a cell line that only presented a membranous c-erbB2. In conclusion, cytoplasmic c-erbB2 of NSCLCs was not a full-length protein only expressed in cellular membrane, but reflected degenerated c-erbB2 fragments with less functional ability.     

B7-H6 expression in non-small cell lung cancers

B7 family has been known to be a negative regulator of immunity response in patients with lung cancer. B7-H6 as a novel identified member of B7 family is found to trigger natural killer (NK) cell cytotoxicity and cytokine secretion by binding natural cytotoxicity receptor NKp30. Up until now, no investigations have been made about B7-H6 expression in lung cancer. We present the result of the B7-H6 prognostic value in 65 non-small cell lung cancer (NSCLC) tissues and 65 matched adjacent non-tumor tissues by Immunohistochemistry (IHC). Meanwhile, fluorescence activated cell sorter (FACS) analysis was used to detect B7-H6 receptor NKp30 expression in 7 non-small cell lung cancer tissues and 7 adjacent non-tumor tissues. Here, the result showed B7-H6 immunoreactivity in 6/65 (9.23%) lung cancer patients and 4/65 (6.15%) in adjacent non-tumor tissues. No relationship was found between B7-H6 expression and clinic pathological features. Similarly, no relevance was found for NKp30 expression in lung cancer tissues and non-tumor tissues. However, B7-H6 positive carcinomas were significantly correlated with degree of differentiation (P = 0.044). Three year survival rate after operation did not show the prognostic value for B7-H6 expression. Our study suggests that B7-H6 has a limited value as a prognostic marker in the patients of lung cancer.     

The role of high dose rate (HDR) brachytherapy in advanced non-small cell lung cancer

The aim of this study was to determine the influence of brachytherapy on the prognosis in advanced NSCLC, elaboration of clinical criteria useful in patients qualification to brachytherapy and the radiation method optimization. Between January 1994 and June 1998, 325 patients with symptomatic inoperable endobronchial obstructing lung cancer received brachytherapy alone or combined with external beam irradiation with palliative or radical intent. Patients were given 1 to 4 temporary Ir-192 endobronchial implants at the site of obstruction. Implant doses ranged from 6 to 12 Gy specified at a radius of 1 cm from the centre of the source. Total implant doses ranged from 6 to 24 Gy. Depending on radical or palliative intents external beam irradiation doses ranged from 20 to 60 Gy. The results were compared with results achieved in control group (N = 191) treated exclusively with external beam irradiation. Patients who received combined treatment revealed higher frequency of release or disappearance of hemoptysis, dysponea and atelectasis. Also the duration of clinical remission was significantly longer with combined treatment. In the group treated with radical intent higher percentage of patients with total tumor regression in both endoscopic and radiologic view was observed after tele--and brachytherapy compared with teleradiotherapy alone (respectively 29.8% and 19.4%). The group treated with palliative intent brachytherapy alone provided response rates comparable to those achieved with external beam irradiation alone or tele and brachytherapy. The relative risk of fatal pulmonary haemorrhage (FPH) and radiation induced bronchitis (RIB) were higher when NTD > 70 Gy, brachytherapy and laser therapy were administered and in patients with lobar bronchus infiltration. Knowledge of risk doses of FPA and RIB allow to optimise brachytherapy in patients with advanced NSCLC.     

Histopathologic characteristics of advanced-stage ROS1-rearranged non-small cell lung cancers

Background: ROS1 rearrangement accounts for 1%–2% of non-small cell lung cancer (NSCLC) with a remarkable response to crizotinib. Although ROS1-rearranged tumors are known to have characteristic histologic features, only a few studies have investigated the histologic features of advanced-stage ROS1-rearranged tumors.Methods: We analyzed the histopathologic features of ROS1-rearranged tumors in advanced-stage NSCLC patients and assessed the ROS1 immunohistochemistry (IHC) staining patterns of ROS1-rearranged cases.Results: A total of 37 ROS1 fluorescence in situ hybridization (FISH)-positive cases and 64 ROS1 FISH-negative cases were analyzed, and all tumors were EGFR-, ALK-, and RET-negative. Solid pattern, round nuclei with macronucleoli, solid signet-ring cells, extracellular mucin, and a close relation with adjacent bronchioles were significantly associated with ROS1 rearrangement, and the solid signet-ring cell feature was exclusively identified in ROS1-rearranged tumors. ROS1 IHC showed a 97.3% sensitivity when weak to strong protein expression was considered positive.Conclusions: Our findings highlight distinct histologic features of ROS1-rearranged tumors, including their nuclear features. A thorough understanding of ROS1 rearrangement-related histologic features would be helpful to identify ROS1-rearranged tumors in advanced-stage NSCLC.     

Differential expression of RON in small and non-small cell lung cancers

RON is a MET related receptor tyrosine kinase (RTK) and its natural ligand is macrophage stimulating protein (MSP). RON plays a very important role in the regulation of inflammation. Several studies have previously reported overexpression of RON in a variety of cancers including lung and identified numerous RON alternate splice forms that very likely contribute to tumor growth and metastasis. Here, we have analyzed the expression of total RON protein as well as its kinase-active form (phospho-RON) in 175 archival lung tumor FFPE (formalin fixed paraffin embedded) samples that included non-small-cell lung cancer (NSCLC) and small cell lung cancer (SCLC), and their metastatic forms. The frequency and intensity of RON protein expression was much higher in lung tumors of neuroendocrine origin such as SCLC and in secondary tumors that metastasized to brain. In addition, the majority of the expressed RON protein was phospho-RON. We also identified 62, and 30 kDa isoforms of RON (GenBank accession numbers are JN689381 and JN689382) using RNA isolated from pooled lung cancer cell lines and RT-PCR. A majority of the NSCLC cell lines expressed a 150 kDa band that corresponded to the RON β chain and 120 kDa band in the panel of SCLC cell lines tested. RON was expressed on the cell surface in NSCLC cell lines. Finally, knock down of RON expression resulted in a significant loss in viability as well as motility in lung cancer cells suggesting that RON is a potential therapeutic target.     

Vaccination with BLP25 liposome vaccine to treat non-small cell lung and prostate cancers

The identification of tumor-associated/-specific antigens and an increased understanding of the ways in which antigens are processed and presented has led to a revived interest in cancer vaccines as a therapeutic strategy. BLP25 liposome (L-BLP25) vaccine is a cancer vaccine that targets the exposed core peptide of the MUC1 tumor-associated antigen. Studies in advanced-stage non-small cell lung cancer demonstrate that L-BLP25 vaccine has the potential to extend the survival of patients with Stage IIIB locoregional non-small cell lung cancer and maintain quality of life for longer. L-BLP25 vaccine also shows promise for prostate cancer patients, having the potential to prolong prostate-specific antigen doubling time in men with biochemical failure post prostatectomy. These clinically meaningful results with a relatively nontoxic therapeutic vaccine are very encouraging and suggest potential for L-BLP25 to fulfill an unmet medical need.     

阿帕替尼治疗晚期非小细胞肺癌的疗效

目的:探讨阿帕替尼在晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)中的治疗效果.方法:选取2015年1月至2016年3月于各成员单位收治的72例晚期NSCLC患者纳入研究对象,给予患者口服阿帕替尼,500 mg/次,1次/d,治疗至肿瘤进展、患者死亡或者出现药物毒性不耐受为止.随访并观察患者客观缓解率(objective response rate,ORR)、疾病控制率(disease control rate,DCR)、无进展生存期(progression-free survival,PFS)和毒副反应发生情况.采用单因素分析比较不同临床特征与PFS的关系.结果:患者中位PFS为4.8个月(95%CI 4.7~5.0).单因素分析显示不同性别、年龄、活动状态(performance status,PS)评分、组织学类型、驱动基因突变情况、有无转移灶、转移灶数量、转移部位、治疗史、治疗线数和病程的患者PFS差异均无统计学意义(P>0.05).患者ORR为13.89%,DCR为83.33%.疗效瀑布图显示有54例患者病灶缩小,以肿瘤病灶直径减少30%作为治疗有效标准,则有10例患者表现为部分缓解(partial response,PR).有60例(83.33%)患者发生各类不良事件,其中22例(30.55%)≥III级.结论:阿帕替尼治疗晚期NSCLC疗效显著,安全性高,可在临床进行更加深入的研究和应用.     

Cardiotoxicity of cisplatin-based chemotherapy in advanced non-small cell lung cancer patients

Cardiotoxicity is a well known consequence of cancer chemotherapy. Cisplatin-based combinations are standard regimens in the therapy of advanced non-small cell lung cancer. Administration of cisplatin-containing chemotherapy causes significant oxidative and nitrosative stress in some patients. Cardiac blood biomarkers can be used to evaluate cardiac status, may help to identify patients at risk myocardial damage evaluation and are able to detect subclinical, early-stage cisplatin-induced cardiotoxicity. The relevance of cardiovascular complications in cancer patients and identification of individual risk factors for developing cardiovascular toxicity merit further evaluation and a longer follow-up is needed.     

克唑替尼在ALK阳性中晚期非小细胞肺癌中的疗效观察

目的：探讨克唑替尼治疗晚期间变淋巴瘤激酶(anaplastic lymphoma kinase,ALK)融合基因阳性中晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的近期疗效及毒副反应。方法：回顾性分析43例ALK阳性的中晚期NSCLC患者,服用克唑替尼治疗,服用至病情进展或出现不可耐受的毒副反应,随访12个月,观察疗效。结果：克唑替尼治疗ALK阳性NSCLC的疾病控制率(disease control rate,DCR)为93%(3/43),客观缓解率(objective response rate,ORR)为62%(26/43),中位无进展生存时间(progression free survival,PFS)为7.0个月(95% CI,6.0~8.0月),不良反应主要为消化道症状,其次是谷丙转氨酶升高,视觉障碍,大部分为1~2级。结论：克唑替尼作为NSCLC患者的多靶点靶向治疗,具有良好的疗效及安全性,不良反应轻微。     

Comparative allelotype of early and advanced stage non-small cell lung carcinomas

To identify chromosomal loci of tumor suppressor genes involved in the genesis and progression of non-small cell lung carcinoma (NSCLC), comparative allelotype analysis was performed in 23 stage I primary lung tumors and in 22 metastatic lung tumors to the brain. In total, 84 loci on all 22 autosomal chromosomes were examined for loss of heterozygosity (LOH) by restriction fragment length polymorphism (RFLP) analysis with 40 polymorphic DNA probes and polymerase chain reaction (PCR)-LOH analysis of 44 polymorphic loci. LOH on chromosome arms 3p, 13q, and 17p was detected frequently (>60%) in both stage I primary lung tumors and brain metastases, whereas the incidence of LOH on chromosome arms 2q, 5q, 9p, 12q, 18q, and 22q was more than 60% only in brain metastases. In particular, the incidence of LOH on chromosome arms 2q, 9p, 18q, and 22q in brain metastases was significantly higher than that in stage I primary lung tumors (P < 0.05). These results indicate that tumor suppressor genes on chromosome arms 3p, 13q, and 17p are involved in the genesis of NSCLC, whereas those on several chromosome arms, especially on 2q, 9p, 18q and 22q, play an important role in the progression of NSCLC. Genes Chromosom Cancer 17:71–77 (1996). © 1996 Wiley-Liss, Inc.