Na^+-依赖性谷氨酰胺载体ASCT2的生物学功能及表皮生长因子的调控作用

目的:Na+-依赖性中性氨基酸载体ASCT2,是一种广谱的氨基酸载体,它的生理功能主要是转运肠腔内谷氨酰胺、丙氨酸、丝氨酸和半胱氨酸等中性氨基酸。本研究拟对ASCT2载体转运特性及表皮生长因子对其的调控机制作一探讨。方法:体外培养Caco-2细胞,观察ASCT2对核素标记谷氨酰胺的转运特性、动力学特征及底物特异性;利用ASCT2多克隆抗体及TaqMan实时定量PCR方法,研究表皮生长因子对ASCT2功能的调控作用。结果:Caco-2细胞中Na+-依赖性3H-L-谷氨酰胺(50μmol)的转运速率为(635±80.1)pmol/(mgprotein·min),大部分中性氨基酸如丙氨酸、丝氨酸、半胱氨酸等可对其产生竞争性抑制;在表皮生长因子(100μg/L)孵育下,可以提高其转运活性约100%(P<0.01),Western-blot及real-timePCR显示其蛋白及mRNA表达增高。结论:谷氨酰胺载体ASCT2对核素标记谷氨酰胺具有强大的转运活性,对中性氨基酸底物具有亲和特异性;表皮生长因子对其转运活性、蛋白表达、mRNA丰度具有上调作用。

家兔注射^(125)I-标记重组人表皮生长因子后的药代动力学

用Ｉｏｄｏｇｅｎ法制备１２５ＩｒｈＥＧＦ，ＳＤＳＰＡＧＥ鉴定放射纯度为（９７．１±０．４５）％。家兔静脉注射１２５ＩｒｈＥＧＦ后８ｈ内血浆总放射性保持在高水平，反相高压液相色谱（ＲＨＰＬＣ）测得１２５ＩｒｈＥＧＦ分量迅速下降，亲水性１２５Ｉ标记物分量增高。１２５ＩｒｈＥＧＦ浓度时间曲线符合二室开放模型，ｔ１／２α和ｔ１／２β分别为９ｍｉｎ和１１．６ｈ。组织浓度梯度为尿＞甲状腺＞肠内容＞肾＞血浆＞胆汁＞颌下腺＞肺。８ｈ内尿排泄（２０．３±５．１）％的注入放射性。

消化性溃疡西医内科临床治疗效果观察

探究分析消化性溃疡西医内科临床治疗效果观察。方法:选取院内2021年01月~2022年12月收治的102例消化性溃疡患者,予以西医内科治疗,对比分析治疗前后的治疗有效率、炎症因子水平、血清胃肠激素指标、表皮生长因子水平以及肠道菌群情况。结果:观察组各项指标优于对照组(P<0.05)。结论:对消化性溃疡患者采用西医内科治疗模式进行干预,能够有效改善患者的炎症因子水平、血清胃肠激素指标、表皮生长因子水平、肠道菌群情况,同时能够保障终的治疗有效率,值得推广与应用。

4-氨基-2-三氟甲基苯基维甲酸酯诱导的肺癌细胞的RARα、EGFR转录水平的变化

目的探讨4-氨基-2-三氟甲基苯基维甲酸酯对肺癌细胞RARα、表皮生长因子受体(EGFR)表达的影响。方法用4-氨基-2-三氟甲基苯基维甲酸酯处理肺癌细胞24、48、72h后,用RT-PCR方法分析细胞RARα、EGFR表达的变化。结果4-氨基-2-三氟甲基苯基维甲酸酯作用于肺癌细胞24、48、72后,A549和L78细胞的EGFR表达下降显著,并呈时间依赖(P<0.01);A549和L78细胞的RARα表达增加并呈时间依赖(P<0.05)。结论4-氨基-2-三氟甲基苯基维甲酸酯可以显著降低肺癌细胞EGFR的表达,同时显著增加肺鳞癌细胞RARα表达。

曲妥珠单抗联合PC单周化疗方案治疗HER2阳性晚期乳腺癌患者的临床研究

目的:探究曲妥珠单抗联合PC单周化疗方案治疗(HER2)阳性晚期乳腺癌患者的临床效果。方法:选取我院2014年3月～2017年3月收治的64例HER2阳性晚期乳腺癌患者为研究对象,采用随机数字表法分为对照组与观察组,每组32例。对照组予以PC单周化疗方案治疗,观察组在对照组基础上予以曲妥珠单抗治疗。比较两组治疗效果、治疗前后血清CA125、CEA水平及Bax、Bcl-2基因表达水平。结果:观察组治疗有效率明显高于对照组,P<0.05;治疗后,观察组血清CA125、CEA水平均明显低于对照组,P<0.05;观察组Bax表达水平明显高于对照组,Bcl-2表达水平明显低于对照组,P<0.05。结论:曲妥珠单抗联合PC单周化疗方案治疗HER2阳性晚期乳腺癌患者,能提高治疗效果,调节Bcl-2、Bax基因表达,加快肿瘤细胞凋亡,有效控制病程进展。

Leaf epidermal characters of Lonicera japonica and Lonicera confuse and their ecology adaptation

The leaf epidermis of Japanese honeysuckle （Lonicera japonica Thunb.） and Wild Honeysuckle （Lonicera confusa） in the genus of Flos Lonicerae were mainly observed by scanning electron microscopes （SEM） to study the characteristics of stomata, trichomes and dermal cell, etc.. The results showed that stoma exists only on the lower epidermis and its distribution is irregular, and leaf epidermis consist of epidermis cells, stoma complexes and bushy trichomes including glandular hair and non-glandular hair. On the upper epidermis, anticlinal wall caves in sinuous groove to countercheck the transpiration. Evidences from leaf morphological structures serve as another proof on drought-resistant mechanisms. Some strumaes distributing regularly are hypothesized as oxalic calcium on the lower epidermis under laser scanning confocal microscopy （LSCM） with Fluo-3/AM, which can increase their endurance to drought stress. Therefore, the above characteristics of Flos Lonicerae can reduce the loss of water and make Japanese honeysuckle and Wild Honeysuckle adapt to the droughty environment at Karst area in southwest China. However, there is some difference of the two species. From the SEM （Scanning Electron Microscopy） result, it is shown that on the upper epidermis, some glandular hair regularly present along the midrib of Japanese honeysuckle, but Wild Honeysuckle has no glandular hair on the upper epidermis, which can verify the relationships of Flos Lonicerae species and provide the significance for classification of Flos Lonicerae.

Reduced secretion of epidermal growth factor in duodenal ulcer patients with Helicobacter pylori infection

AIM To investigate the concentration changes of epidermal growth factor (EGF) in duodenal ulcer patients with H. pylori infection.

全脑放疗联合吉非替尼治疗EGFR突变阳性肺腺癌脑转移

【目的】评价全脑放疗（wBRT）联合吉非替尼治疗表皮生长因子受体（EGFR）突变阳性肺腺癌脑转移的疗效。【方法】回顾性分析70例EGFR突变阳性肺腺癌脑转移患者的临床资料，根据经济情况及意愿分为观察组40例和对照组30例。观察组行wBRT同时口服吉非替尼250mg，1次／天。对照组行WBRT同时口服替莫唑胺：150mg／m2，d1～5，28d重复，连续4个周期。分析比较两组患者近期疗效、无进展生存期、总生存期及治疗的毒副反应情况。【结果】治疗后第12周观察组和对照组的近期有效率分别为92．5％和70．0％，差异有统计学意义（X2=6．110，P=0．013）。观察组的中位无进展生存期和总生存期分别为16和27个月，对照组分别为7和13个月，差异均有统计学意义（均P=0．000）。两组的Ⅲ～Ⅳ级毒副反应：观察组痤疮样皮疹6例，对照组为0例，差异有统计学意义。两组乏力、恶心呕吐、腹泻、骨髓抑制等发生率差异均无统计学意义。【结论】WBRT联合吉非替尼治疗EGFR突变阳性肺腺癌脑转移患者的近、远期疗效显著，副反应可以耐受。

Expression of Angiopoietin-2 and Vascular Endothelial Growth Factor in Oral Squamous Cell Carcinoma and Its Significance

Objective： To investigate the expression of angiopoietin-2 （Ang-2） and vascular endothelialcell growth factor （VEGF） in oral squamous cell carcinoma （OSCC） and their correlations with clinicopathologic parameters, angiogenesis and vessel maturation of OSCC. Methods： The expression of Ang-2 and VEGF was detected in 41 speciments of human OSCC, 30 adjacent noncancerous oral tissues and 10 specimens of normal oral mucosa by conventional immumohistochemistry. Microvessel density （MVD） and vessel maturation index （VMI） were also assessed by double-labelling immumohistochemistry staining against CD34, a marker of pan-endothelial cells, and that against alpha-smooth muscle actin （α-SMA）, a marker of mural cells （pericytes/smooth muscle cells）. Results： The positive expression rate of Ang-2 and VEGF in 41 OSCC tissues was 51.22% and 63.42%, respectively. The expression of Ang-2 and VEGF was significantly higher in OSCC than in adjacent noncancerous oral tissues （all P〈0.05） and normal oral mucosa （all P〈0.05）. In the clinicopathologic parameters, the Ang-2 expression was closely correlated with tumor lymph node metastasis （P〈0.01） and the VEGF expression was correlated with tumor differentiated degree （P〈0.05）, but there was no significant correlation among the Ang-2 and VEGF expression and patients＇ sex, age and TNM stages （all P〉0.05）. The MVD of OSCC positive for both Ang-2 and VEGF was significantly higher than that of OSCC negative for both Ang-2 and VEGF （P〈0.05）. The VMI of OSCC positive for Ang-2 was significantly lower than that of OSCC negative for Ang-2 （P〈0.05）. When Ang-2 expression was combined with the staus of VEGF expression, MVD of OSCC positive for both Ang-2 and VEGF was the highest （51.08±2.99） as compared with that of other status in patient with OSCC （all P〈0.05）. Conclusion： The overexpression of Ang-2 and VEGF may play a crucial role in the development of OSCC. They are closely associated with angiogenesis and vessel maturation of tumor.

Effects of epidermal growth factor on the growth of human gastric cancer cell and the implanted tumor of nude mice

AIM: Epidermal growth factor (EGF) plays an important role in the regulation of gastrointestinal tissue growth and development, and it can stimulate epithelial proliferation, cell differentiation and growth. It has been established that the EGF can promote gastric cytoprotection and ulcer healing. But the potential ability of EGF to regulate the gastric cancer growth is unknown. This study is to investigate the influence of EGF on human gastric cancer cell and the implanted tumor growth of nude mice. METHODS: The cell growth rates of human gastric adenocarcinoma cell lines MKN-28, MKN-45, SGC-7901 and normal human gastric epithelial cells 3T3 were assessed when incubated with recombinant human EGF (rhEGF, 0.05, 0.1, 0.5, 1.0, 10, 50, 100 mg.L(-1)) using MTT method. The cells of MKN-28, MKN-45, SGC-7901 (gastric cancer tissue 1.5mm(3)) were implanted in the BALB/cA nude mice for 10 days.The EGF was given intraperitoneally (15, 30, 60 microg.kg(-1)) for 3 weeks. The body weights of the tumor-bearing animals and their tumor mass were measured afterwards to assess the mitogenic effect of rhEGF in the nude mice. RESULTS: Within the concentration range of 0.05-100mg.L(-1), rhEGF could increase the cell growth of normal 3T3 cells (cell growth rate 100% vs 102.8%, P【0.05), but partially restrain the gastric cancer cell growth. The latter effect was related to cell differentiation. In 15-60 microg/kg rhEGF groups, the mean implanted tumor mass of MKN-28 cell were 1.75 g, 1.91 g, 2.08 g/NS group 1.97 g (P】0.05), the mean tumor mass of SGC-7901 cell were 1.53 g, 1.07 g, 1.20 g/NS group 1.07 g (P】0.05), and for MKN-45 cell, the tumor mass were respectively 1.92 g, 1.29 g, 1.77 /NS group 1.82 g (P】0.05). So rhEGF had no obvious effect on implanted MKN-28, SGC-7901 and MKN-45 tumor growth. CONCLUSION: EGF has no stimulating effect on the human gastric cancer cell growth neither in vitro nor in vivo.

Identification of EGFR kinase domain mutations among lung cancer patients in China:implication for targeted cancer therapy

Lung cancer is one of the leading causes of death with one of the lowest survival rates. However, a subset of lung cancer patients who are of Asian origin and carry somatic mutations in epidermal growth factor receptor or EGFR have responded remarkable well to two tyrosine kinase inhibitors, gefitinib and erlotinib. While EGFR mutation profiles have been reported from Japan, South Korea, and Taiwan, there is no such report from mainland of China where the largest pool of patients reside. In this report, we identified ten somatic mutations from a total of 41 lung cancer patients in China. Among them, seven mutations were found in 17 adenocarcinomas. In contrast to previous reports, eight of these mutations are deletions in exon 19 and two of these deletions are homozygous. These results suggest that a large portion of Chinese adenocarcinoma patients could benefit from gefitinib or erlotinib. This unique mutation profile provides a rationale to develop the next generation of EGFR inhibitors more suitable for the Chinese population.

Genetic alterations in pancreatic cancer

The diagnosis of pancreatic patients and their relatives cancer is devastating for as the incidence rate is approximately the same as mortality rate. Only a small percentage, which ranges from 0.4% to 4% of patients who have been given this diagnosis, will be alive at five years. At the time of diagnosis, 80% of pancreatic cancer patients have unresectable or metastatic disease. Moreover, the therapeutic alternatives offered by chemotherapy or radiotherapy are few, if not zero. For all these reasons, there is an imperative need of analyzing and understanding the primitive lesions that lead to invasive pancreatic adenocarcinoma. Molecular pathology of these lesions is the key of our understanding of the mechanisms underlying the development of this cancer and will probably help us in earlier diagnosis and better therapeutic results. This review focuses on medical research on pancreatic cancer models and the underlying genetic alterations.

Prognosis of HER2 over-expressing gastric cancer patients with liver metastasis

AIM:To study the risk factors for liver metastasis and the prognosis in patients with human epidermal growth factor receptor 2(HER2) over-expressing gastric cancer(GC).METHODS:A total of 84 GC patients recruited from the General Hospital of the People's Liberation Army(PLA) between 2003 and 2010 were randomly enrolled in this study.HER2 expression was detected by immunohistochemistry in 84 GC patients with liver metastases.The study group consisted of 66 men and 18 women,with an average age of 54 years(range:19-74 years).Liver metastasis was diagnosed by magnetic resonance imaging or computed tomography.Patients were followed-up and predictive factors of liver metastasis were evaluated.RESULTS:The median follow-up period was 47 mo(range:6-85 mo).The characteristics of 35(25.7%) patients with HER2 over-expression of liver metastatic GC are presented.HER2 over-expression was detected in 23 out of 49(46.9%) patients with intestinal GC,and 9 out of 35(25.7%) patients with diffuse GC.29 out of 59(49.2%) patients aged < 60 years were HER2positive,while 8 out of 25(32%) patients aged ≥ 60 were HER2-positive;a significant difference(P < 0.05).Univariate analysis(log-rank test) showed that HER2 over-expression,sex,Lauren classification,differentiation and disease-free interval were correlated with poor survival(P < 0.05).Survival analysis with a survival curve showed that HER2 over-expression was significantly relevant,with a reduced survival time in GC patients with liver metastases(P < 0.01).2-year survival was not associated with the patient's age.A diseasefree survival longer than 12 mo has a significant association with extended overall survival(OS) in GC patients with liver metastases.The median survival time after the diagnosis of liver metastases was 18 mo [95% confidence interval(CI):9.07-26.94] among HER2 positive GC patients with liver metastases.In comparison,for 49(69.4%) out of 84 HER2 negative patients with liver metastatic GC,the median survival time was 47 mo(95% CI:19.37-74.63).In patients with HER2 positive liver metastatic GC,the median OS was significantly shorter than in HER2 negative patients(median,20.32 mo;95% CI:16.51-24.13 vs median,50.14 mo;95% CI:37.83-62.45;P < 0.01).CONCLUSION:HER2 over-expressing GC patients with liver metastases have a poor prognosis.Overall survival was significantly lower in HER2 positive patients.HER2overexpression is correlated with a lower survival rate.

Alterations in the human epidermal growth factor receptor 2-phosphatidylinositol 3-kinase-v-Akt pathway in gastric cancer

AIM:To investigate human epidermal growth factor receptor 2(HER2)-phosphatidylinositol 3-kinase(PI3K)-vAkt murine thymoma viral oncogene homolog signaling pathway.METHODS:We analyzed 231 formalin-fixed,paraffinembedded gastric cancer tissue specimens from Japanese patients who had undergone surgical treatment.The patients' age,sex,tumor location,depth of invasion,pathological type,lymph node metastasis,and pathological stage were determined by a review of the medical records.Expression of HER2 was analyzed by immunohistochemistry(IHC) using the HercepTest TM kit.Standard criteria for HER2 positivity(0,1+,2+,and 3+) were used.Tumors that scored 3+ were considered HER2-positive.Expression of phospho Akt(pAkt) was also analyzed by IHC.Tumors were considered pAkt-positive when the percentage of positive tumor cells was 10% or more.PI3K,catalytic,alpha polypeptide(PIK3CA) mutations in exons 1,9 and 20 were analyzed by pyrosequencing.Epstein-Barr virus(EBV) infection was analyzed by in situ hybridization targeting EBV-encoded small RNA(EBER) with an EBER-RNA probe.Microsatellite instability(MSI) was analyzed by polymerase chain reaction using the mononucleotide markers BAT25 and BAT26.RESULTS:HER2 expression levels of 0,1+,2+ and 3+ were found in 167(72%),32(14%),12(5%) and 20(8.7%) samples,respectively.HER2 overexpression(IHC 3+) significantly correlated with intestinal histological type(15/20 vs 98 /205,P = 0.05).PIK3CA mutations were present in 20 cases(8.7%) and significantly correlated with MSI(10/20 vs 9/211,P < 0.01).The mutation frequency was high(21%) in T4 cancers and very low(6%) in T2 cancers.Mutations in exons 1,9 and 20 were detected in 5(2%),9(4%) and 7(3%) cases,respectively.Two new types of PIK3CA mutation,R88Q and R108H,were found in exon1.All PIK3CA mutations were heterozygous missense singlebase substitutions,the most common being H1047R(6/20,30%) in exon20.Eighteen cancers(8%) were EBV-positive and this positivity significantly correlated with a diffuse histological type(13/18 vs 93/198,P = 0.04).There were 7 cases of lymphoepithelioma-like carcinomas(LELC) and 6 of those cases were EBV-positive(percent/EBV:6/18,33%;percent/all LELC:6/7,86%).pAkt expression was positive in 119(53%) cases but showed no correlation with clinicopathological characteristics.pAkt expression was significantly correlated with HER2 overexpression(16/20 vs 103/211,P < 0.01) but not with PIK3CA mutations(12/20 vs 107/211,P = 0.37) or EBV infection(8/18 vs 103/211,P = 0.69).The frequency of pAkt expression was higher in cancers with exon20 mutations(100%) than in those with exon1(40%) or exon9(56%) mutations.One case showed both HER2 overexpression and EBV infection and 3 cases showed both PIK3CA mutations and EBV infection.However,no cases showed both PIK3CA mutations and HER2 overexpression.One EBVpositive cancer with PIK3CA mutation(H1047R) was MSI-positive.Three of these 4 cases were positive for pAkt expression.In survival analysis,pAkt expression significantly correlated with a poor prognosis(hazard ratio 1.75;95%CI:1.12-2.80,P = 0.02).CONCLUSION:HER2 expression,PIK3CA mutations and EBV infection in gastric cancer were characterized.pAkt expression significantly correlates with HER2 expression and with a poor prognosis.

Advanced gastric cancer:Is there enough evidence to call second-line therapy standard?

Gastric cancer and cancer of the gastro-oesophageal junction(GOJ) are the 4th most common cancer diagnoses worldwide with regional differences in incidence rates.The treatment of gastric and GOJ cancers is complex and requires multimodality treatment including chemotherapy treatment,surgery,and radiotherapy.During the past decade considerable improvements were achieved by advanced surgical techniques,tailored chemotherapies/radiotherapy and technical innovations in clinical diagnostics.In patients with advanced or metastatic gastric/GOJ cancer systemic chemotherapy with fluoropyrimidine/platinum-based regimens(+/-human epidermal growth factor receptor-2 antibody) is the mainstay of treatment.Despite these improvements,the clinical outcome for patients with advanced or metastatic disease is generally poor with 5-year survival rates ranging between 5%-15%.These poor survival rates may to some extent be related that standard therapies beyond first-line therapies have never been defined.Considering that this patient population is often not fit enough to receive further treatments there is an increasing body of evidence from phase-2 studies that in fact second-line therapies may have a positive impact in terms of overall survival.Moreover two recently published phase-3 studies support the use of second-line chemotherapy.A South Korean study compared either,irinotecan or docetaxel with best supportive care and a German study compared irinotecan with best supportive care-both studies met their primary endpoint overall survival.In this "Field of Vision" article,we review these recently published phase-3 studies and put them into the context of clinical prognostic factors helping to guide treatment decisions in patients who most likely benefit.

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.

EGFR and HER2 expression in advanced biliary tract cancer

AIM:To analyze the pathogenetic role and potential clinical usefulness of the epidermal growth factor receptor(EGFR)and the human epidermal growth factor receptor 2(HER2)in patients with advanced biliary tract cancer(BTC). METHODS:EGFR and HER2 expression was studied in biopsy samples from 124 patients(51%women; median age 64.8 years),with advanced BTC diagnosed between 1997 and 2004.Five micrometers sections of paraffin embedded tissue were examined by standard, FDA approved immunohistochemistry.Tumors with scores of 2+or 3+for HER2 expression on immunochemistry were additionally tested for HER2 gene amplification by fluorescence in situ hybridisation(FISH).RESULTS:34/124 patients(27.4%)had gallbladder cancer,47(37.9%)had intrahepatic BTC and 43(34.7%)had extrahepatic or perihilar BTC.EGFR expression was examined in a subset of 56 samples. EGFR expression was absent in 22/56 tumors(39.3%). Of the remaining samples expression was scored as 1+in 12(21.5%),2+in 13(23.2%)and 3+in 9(16%), respectively.HER2 expression was as follows:score 0 73/124(58.8%),score 1+27/124(21.8%),score 2+ 21/124(17%)and score 3+4/124(3.2%).HER2 gene amplification was present in 6/124,resulting in an overall amplification rate of 5%. CONCLUSION:Our data suggest that routine testing and therapeutic targeting of HER2 does not seem to be useful in patients with BTC,while targeting EGFR may be promising.

KRAS mutation testing in metastatic colorectal cancer

The KRAS oncogene is mutated in approximately 35%-45% of colorectal cancers, and KRAS mutational status testing has been highlighted in recent years. The most frequent mutations in this gene, point substitutions in codons 12 and 13, were validated as negative predictors of response to anti-epidermal growth factor receptor antibodies. Therefore, determining the KRAS mutational status of tumor samples has become an essential tool for managing patients with colorectal cancers. Currently, a variety of detection methods have been established to analyze the mutation status in the key regions of the KRAS gene; however, several challenges remain related to standardized and uniform testing, including the selection of tumor samples, tumor sample processing and optimal testing methods. Moreover, new testing strategies, in combination with the mutation analysis of BRAF , PIK3CA and loss of PTEN proposed by many researchers and pathologists, should be promoted. In addition, we recommend that microsatellite instability, a prognostic factor, be added to the abovementioned concomitant analysis. This review provides an overview of KRAS biology and the recent advances in KRAS mutation testing. This review also addresses other aspects of status testing for determining the appropriate treatment and offers insight into the potential drawbacks of mutational testing.

Antitumor effect of Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, combined with cytotoxic agent on murine hepatocellular carcinoma

AIM: To investigate the inhibitory effect of gefitinib combined with cytotoxic agent cisplatin (CDDP) on hepatocellular carcinoma (HCC). METHODS: Female Kunming mice and H22 hepatocarcinoma cells were used. Gefitinib at daily dose of 100 mg/kg body weight (BW) or lecithin liquid was given by gastrogavage once a day for 5 or 10 successive days. CDDP or normal saline (NS) was administered intraperitoneally (i.p.) once a day for 5 successive days. Mice were randomly divided into control group (lecithin, or NS, i.p.), CDDP group (daily dose, 1.2 mg/kg BW; d1-5, or d6-10), Gefitinib (d1-5, or d6-10, or d1-10), and Gefitinib combined with CDDP groups. The inhibitory rate (IR) of tumor, net BW, spleen index (SI), thymus index (TI) and the amount of peripheral blood cells of mice were detected on the 12th experiment day. RESULTS: The growth of HCC in mice was inhibited by Gefitinib alone (IR: 41% in d1-10 group and 30% in d1-5 group, respectively) or CDDP alone (IR: 32-54% in d1-5 group or d6-10 group). The highest inhibitory effect (IR: 56%) on HCC growth was observed in Gefitinib (d1-10) combined with CDDP (d1-5) group. Higher inhibition was also observed in CDDP (d1-5) followed by Gefitinib (d6-10) group than that in Gefitinib (d1-5) followed by CDDP (d6-10) group (IR: 61% vs 36%, P<0.01) in the independent study. Net BW, SI, TI and the amount of blood cells of mice in Gefitinib alone group were not significantly different from those in control groups. CONCLUSION: Gefitinib can significantly inhibit the growth of murine H22 hepatocellular carcinoma. If Gefitinib is used after CDDP treatment in animal experiments, the inhibitory effect could be enhanced.

Cardiac toxicity of trastuzumab in elderly patients with breast cancer

Breast cancer （BC） is diagnosed in 〉 65 year old women in about half of cases. Experts currently recommend that systemic therapy is offered to elderly patients with BC, if, based on their overall conditions and life expectancy, it can be reasonably anticipated that the benefits will outweigh the risks of treatment. Like for young subjects, the monoclonal antibody against human epidermal growth factor receptor-2 （HER-2）, trastuzumab, represents a valid therapeutic option when BC over-expresses this receptor. Unforttmately, administration of trastu- zumab is associated with the occurrence of left ventricular dysfunction and chronic heart failure （CHF）, possibly because of interference with the homeostatic functions of HER-2 in the heart. Registry-based, retrospective analyses have reported an incidence of CHF around 25% in elderly women receiving trastuzumab compared with 10%-15% in those not given any therapy for BC, and the risk of CHF has been estimated to be two-fold higher in 〉 60455 year old trastuzumab users vs. non-users. Extremely advanced age and preexisting cardiac disease have been shown to predispose to trastuzumab cardiotoxicity. Therefore, selection of older patients for treatment with trastuzumab should be primarily based on their general status and the presence of comorbidities; previous chemotherapy, especially with anthracyclines, should be also taken into account. Once therapy has started, efforts should be made to ensure regular cardiac surveillance. The role of selected biomarkers, such as cardiac troponin, or new imaging techniques （three-dimension, tissue Doppler echocardiography, magnetic resonance imaging） is promising, but must be further investigated especially in the elderly. Moreover, additional studies are needed in order to better understand the mechanisms by which trastuzumab affects the old heart.