HER2与胃癌的研究进展

本文综述了HER2与胃癌相关的研究进展,介绍了HER2的结构、相关信号途径、在胃癌中的检测方法和检出率以及人源化抗HER2单克隆抗体曲妥珠单抗与胃癌治疗、HER2与胃癌预后的关系。研究显示HER2阳性是胃癌预后不良的重要因子,曲妥珠单抗与化疗药物联合应用是HER2阳性进展期胃和胃食管连接部癌以及伴肝转移患者治疗的新选择,可明显改善患者预后。     

Advanced HER2-positive gastric cancer: Current and future targeted therapies

The prognostic value of human epidermal growth factor receptor 2 (HER2) in gastric cancer is controversial. Consensus guidelines have standardized the testing of HER2 status in gastric cancer. Overexpression of this receptor occurs in approximately 20% of gastric and gastro-esophageal junction adenocarcinomas, predominantly those of the intestinal type. Recently, trastuzumab has emerged as the first targeted drug to improve overall survival when combined with chemotherapy in advanced HER2-positive gastric cancer. Primary and secondary resistance to trastuzumab has become a major problem and new strategies to overcome this resistance are needed. A high percentage of advanced HER2-positive gastric cancer patients who progress on trastuzumab therapy are candidates for second-line therapy. New families of targeted drugs, including tyrosine kinase inhibitors (TKIs) such as lapatinib and PF-00299804, mammalian target of rapamycin (mTOR) pathway inhibitors such as everolimus, heat-shock protein 90 (HSP90) inhibitors such as AUY922, HER dimerization inhibitors such as pertuzumab, and antibody-chemotherapy conjugates such as trastuzumab-emtansine (T-DM1), could offer alternative second-line treatments when trastuzumab-based first-line therapy fails.     

进展期胃癌分子靶向治疗的新进展

胃癌（GC）是消化系统常见的恶性肿瘤,早期诊断困难,传统的手术和放化疗治疗进展期胃癌的有效率低。随着对肿瘤发病机制研究的不断深入,分子靶向治疗成为肿瘤治疗的发展趋势。目前针对GC的分子靶向治疗策略主要包括：表皮生长因子受体靶向治疗、血管内皮生长因子抑制剂、哺乳动物雷帕霉素靶蛋白抑制剂、细胞凋亡促进剂等。本文就进展期GC分子靶向治疗的研究进展作一综述。     

A Retrospective Comparison of Trastuzumab Plus Cisplatin and Trastuzumab Plus Capecitabine in Elderly HER2-Positive Advanced Gastric Cancer Patients

A combination of trastuzumab and cisplatin or trastuzumab and capecitabine has been confirmed to be effective for treating adverse effects in with HER2-positive advanced gastric cancer (AGC) patients. We retrospectively compared the activity and safety of trastuzumab plus cisplatin (HP) and trastuzumab plus capecitabine (HX) for elderly HER2-positive AGC patients.Ninety two HER2-positive AGC patients were included in this study; of those 48 patients received trastuzumab (course 1, 8 mg/kg followed by course 2, onward, 6 mg/kg on day 1) plus cisplatin (60 mg/m²) intravenously on day 1 of a 3-week cycle and 44 patients received trastuzumab (course 1, 8 mg/kg; course 2 onward, 6 mg/kg) plus intravenous oral capecitabine (1000 mg/m² twice daily on days 1–14), every 3 weeks. The primary end point was overall survival (OS). The secondary end points included objective response rate (ORR), progression-free survival (PFS), and toxicity.The median age was 71 years in both groups. The median OS was 15.5 months in the HP group and 17.0 months in the HX group, with no significant difference between the 2 groups (P = 0.78). There were also no significant differences in PFS (median 6.6 months vs 7.2 months, respectively; P = 0.90) and ORR (58.3% vs 59.1%, respectively; P = 1.00) between the HP group and the HX group. The major grade 3 or 4 adverse events in the HP group and the HX group were neutropenia (35.4% vs 29.5%, respectively), followed by anorexia (25.0% vs 22.7%, respectively), and anemia (16.7% vs 13.6%, respectively), no significant differences were observed.HP and HX were associated with similar efficacy and safety in HER2-positive AGC patients.     

Cardiotoxicity in HER2-positive breast cancer patients

Heart Failure Reviews - Due to the recent advances in diagnosis and management of patients with HER2-positive breast cancer, especially through novel HER2-targeted agents, cardiotoxicity becomes an...     

HER2 mRNA Status Contributes to the Discrepancy Between Gene Amplification and Protein Overexpression in Gastric Cancer

Background

Human epidermal growth factor receptor 2 (HER2) is an important proto-oncogene of prognostic use in gastric cancer (GC). Fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC) are the main clinical methods of detection of HER2, but consistency between the methods is poor and the cause of the discrepancy is unclear.

Aim

To investigate the involvement of HER2 mRNA status in the disparity between gene amplification and protein overexpression.

Methods

We investigated HER2 gene, mRNA, and protein profiles in gastric precancer and cancer tissues by use of the molecular approaches FISH, real-time polymerase chain reaction, and IHC. The relationships between HER2 and matrix metalloproteinase 9 (MMP9) and Smad7 expression were analyzed and the involvement of HER2 in the interaction between tumor cells and lymphocytes was investigated by coculturing GC cell lines with peripheral blood mononuclear cells (PBMCs).

Results

HER2 protein expression was significantly increased in cancer compared with precancer (P = 0.003), and the corresponding mRNA levels were significantly lower in precancer and cancer tissues than in normal tissues (κ = 0.290, P = 0.025). HER2 mRNA levels were significantly higher in tumor than in peritumor tissue (P = 0.028), and were positively correlated with MMP9 and Smad7 mRNA levels in tumor tissues. HER2 mRNA expression in GC cell lines was increased by coculture with PBMCs.

Conclusions

Different HER2 mRNA profiles, possibly in relation to contact between tumor cells and lymphocytes, might help to explain the discrepancy between gene amplification and protein overexpression results.     

胃癌相关基因及其在治疗中应用的研究进展

胃癌是我国最常见的恶性肿瘤之一,发病率和死亡率均较高。胃癌的发生由遗传和环境等诸多因素相互作用所致,是一个多因素、多基因、多步骤参与的癌变过程,涉及大量相关基因的结构和表达异常,其中c-met、Bmi-1、HER-2/neu和基质金属蛋白酶（MMP）-9等的活化在胃癌的发生、发展中起重要作用。本文就近年胃癌相关基因及其在胃癌治疗中的研究进展作一综述,旨在帮助理解胃癌发生、发展的分子机制,并为其基因靶向治疗提供一定的理论依据。     

蛋白质组学在胃癌中的研究进展

蛋白质组学研究基因编码的所有蛋白质,近年已成为全面分析蛋白质表达变化的有力手段,并广泛用于肿瘤研究.本文旨在介绍蛋白质组学相关技术在胃癌中的研究进展,通过对胃癌肿瘤组织、血清、细胞株、胃癌相关菌株的蛋白质组学研究,以阐明胃癌发生、发展的分子机制,发现特异性和敏感性较高的肿瘤标记物,从而为胃癌的临床诊治开辟新的途径.     

Defective Mucosal Movement at the Gastroesophageal Junction in Patients with Gastroesophageal Reflux Disease

Background

Little is known about the role of muscularis mucosa at the gastroesophageal junction (GEJ).

Aim

To evaluate the movement of the mucosa/muscularis-mucosa/submucosa (MMS) at the GEJ in normal subjects and in patients with gastroesophageal reflux disease (GERD).

Methods

Gastroesophageal junctions of 20 non-GERD subjects and 10 patients with GERD were evaluated during 5 mL swallows using two methods: in high-resolution endoluminal ultrasound and manometry, the change in the GEJ luminal pressures and cross-sectional area of esophageal wall layers were measured; in abdominal ultrasound, the MMS movement at the GEJ was analyzed.

Results

Endoluminal ultrasound: In the non-GERD subjects, the gastric MMS moved rostrally into the distal esophagus at 2.17 s after the bolus first reached the GEJ. In GERD patients, the gastric MMS did not move rostrally into the distal esophagus. The maximum change in cross-sectional area of gastroesophageal MMS in non-GERD subjects and in GERD patients was 289 % and 183 %, respectively. Abdominal ultrasound: In non-GERD subjects, the gastric MMS starts to move rostrally significantly earlier and to a greater distance than muscularis propria (MP) after the initiation of the swallow (1.75 vs. 3.00 s) and (13.97 vs. 8.91 mm). In GERD patients, there is no significant difference in the movement of gastric MMS compared to MP (6.74 vs. 6.09 mm). The independent movement of the gastric MMS in GERD subjects was significantly less than in non-GERD subjects.

Conclusion

In non-GERD subjects, the gastric MMS moves rostrally into the distal esophagus during deglutitive inhibition and forms a barrier. This movement of the MMS is defective in patients with GERD.     

HER2基因扩增和蛋白表达与胃癌临床病理特征和预后的关系

背景：曲妥珠单抗在人表皮生长因子受体2（HER2）阳性胃癌分子靶向治疗中的作用已得到确认,研究HER2评分与患者临床结局的关系可确定哪些患者可能从曲妥珠单抗治疗中获益。目的：探讨HER2基因扩增和蛋白表达与胃癌临床病理特征和预后的关系。方法：应用美国食品药品管理局（FDA）认证的检测试剂盒和Hofmann等报道的共识小组推荐胃癌HER2评分系统．采用荧光原位杂交（FISH）和免疫组化方法（IHC）检测177例胃癌组织的IqER2基因扩增和蛋白表达。比较不同临床病理特征胃癌亚组间HER2阳性率的差异．以Kaplan—Meier生存曲线分析HER2与预后的关系。结果：177例胃癌组织中31例（17．5％）HER2阳性．肠型胃癌阳性率显著高于弥漫型,混合型胃癌（28．1％对12．5％,P=0．0109）．分化较好的胃癌阳性率显著高于分化较差的胃癌（37．0％对10．7％,P〈0．0001）。HER2与性别、年龄、肿瘤部位和TNM分期无关。HER2阳性与阴性者总体生存率无明显差异,但在分化较好的胃癌中,HER2阳性者预后差于HER2阴性者（P=0．0084）。结论：肠型胃癌和分化较好的胃癌是曲妥珠单抗治疗的主要候选人群。HER2尚不能作为独立指标判断胃癌预后。     

Regional Postprandial Differences in pH Within the Stomach and Gastroesophageal Junction

Our objective was to determine regional differences in intragastric pH after different types of meals. Ten normal subjects underwent 27-hr esophagogastric pH monitoring using a four-probe pH catheter. Meals were a spicy lunch, a high-fat dinner, and a typical bland breakfast. The fatty dinner had the highest postprandial buffering effect, elevating proximal and mid/distal gastric pH to 4.9 ± 0.4 and 4.0 ± 0.4, respectively, significantly (P< 0.05) higher compared to 4.2 ± 0.3 and 3.0 ± 0.4 for the spicy lunch and 3.0 ± 0.3 and 2.5 ± 0.8 for the breakfast. The buffering effect of the high-volume fatty meal to pH > 4 was also longer (150 min) compared to that of the spicy lunch (45 min) and the bland breakfast, which did not increase gastric pH to > 4 at any time. Proximal gastric acid pockets were seen between 15 and 90 min postprandially. These were located 3.4 ± 0.8 cm below the proximal LES border, extending for a length of 2.3 ± 0.8 cm, with a drop in mean pH from 4.7 ± 0.4 to 1.5 ± 0.9. Acid pockets were seen equally after the spicy lunch and fatty dinner but less frequently after the bland breakfast. We conclude that a high-volume fatty meal has the highest buffering effect on gastric pH compared to a spicy lunch or a bland breakfast. Buffering effects of meals are significantly higher in the proximal than in the mid/distal stomach. Despite the intragastric buffering effect of meals, focal areas of acidity were observed in the region of the cardia–gastroesophageal junction during the postprandial period.     

组蛋白修饰在胃癌中的研究进展

表观遗传在肿瘤的发生、发展中起重要作用,组蛋白修饰作为表观遗传的重要组成部分,近年越来越引起重视.大量研究发现组蛋白修饰在各种恶性肿瘤中发生改变,且这种变化具有重要的临床应用价值,如作为判断患者预后的指标、监测对某些化疗药物的治疗反应、肿瘤早期诊断的标记物等.本文就组蛋白修饰在胃癌中的研究进展以及临床应用作一综述.     

晚期胰腺癌治疗的研究进展

胰腺癌是恶性程度最高的消化系统肿瘤,多数患者确诊时肿瘤已发生远处转移,5年存活率仅5%。吉西他滨为治疗晚期胰腺癌的最佳药物,以吉西他滨为基础的疗法广泛用于晚期患者的一线治疗,一旦吉西他滨治疗失败,目前尚缺乏统一的替代方法。晚期胰腺癌的治疗包括联合化疗、区域性动脉灌注、靶向放疗、HIFU、冷冻治疗、PDT等,本文就其研究进展作一综述。     

早期HR阳性/HER2阳性乳腺癌的治疗选择与思考

［摘要］　激素受体（HR）阳性/人表皮生长因子受体2（HER2）阳性乳腺癌在分子功能、生物过程、信号通路、临床行为、治疗敏感性和内在生物学方面与其他分子亚型乳腺癌存在差异,因此被认为是乳腺癌分子分型中较为特殊的一类。目前,HR阳性/HER2阳性乳腺癌在治疗策略的选择上存在较多的争议和不确定性。如何选择疗效更好、安全性更高、可及性更强的治疗策略,是目前及将来较长一段时间内需要探索的问题。该文将通过新辅助和辅助治疗阶段多个临床研究中HR阳性/HER2阳性乳腺癌患者的相关数据进行分析,从数据中找寻HR阳性/HER2阳性乳腺癌患者的特殊性,为制定更适合的个体化治疗策略提供依据。