Evaluation of cisplatin-hydrogel for improving localized antitumor efficacy in gastric cancer

Gastric cancer, one of the most common disease, has become a major public health problem worldwide. Cisplatin (DDP) has been a widely used drug for the treatment of cancer, also usually applied in gastric cancer in clinic. However, the side effects including toxicity and drug-resistance restricted the usage of DDP in clinic, so we prepared a DDP-complexed hydrogel (DDP-Gel) and investigated its efficacy in gastric cancer. For in vivo studies, MKN45-Luc cells were injected into BLAB/C node mice subcutaneously to establish gastric cancer with orthotopically grown tumors. Mice bearing tumors were treated with normal saline, DDP and DDP-Gel. Body weight and survival condition were observed and recorded. The treatment efficacy in vivo was detected by luciferase imaging and histological evaluation was performed by H&E staining of different organs. Additionally, normal ICR mice were treated with different doses of DDP/DDP-Gel to calculate their LD₅₀ in vivo. The results showed that DDP-Gel prolonged survival time and ameliorated body weight changes of mice bearing tumors. DDP-Gel exhibited higher efficacy to inhibit tumor growth and metastasis, compared to DDP. Besides, LD₅₀ of DDP-Gel was 166.0?mg/kg, 13.2 folds higher than DDP. As a conclusion, DDP-Gel showed a more effective and safer function than DDP in gastric cancer, which indicating that DDP-Gel might be a novel strategy for gastric cancer therapy.     

Nanoparticle formulations of histone deacetylase inhibitors for effective chemoradiotherapy in solid tumors

Histone deacetylase inhibitors (HDACIs) represent a class of promising agents that can improve radiotherapy in cancer treatment. However, the full therapeutic potential of HDACIs as radiosensitizers has been restricted by limited efficacy in solid malignancies. In this study, we report the development of nanoparticle (NP) formulations of HDACIs that overcome these limitations, illustrating their utility to improve the therapeutic ratio of the clinically established first generation HDACI vorinostat and a novel second generation HDACI quisinostat. We demonstrate that NP HDACIs are potent radiosensitizers in vitro and are more effective as radiosensitizers than small molecule HDACIs in vivo using mouse xenograft models of colorectal and prostate carcinomas. We found that NP HDACIs enhance the response of tumor cells to radiation through the prolongation of γ-H2AX foci. Our work illustrates an effective method for improving cancer radiotherapy treatment.     

Personalized primary tumor xenograft model established for the pre-clinical trial to guide postoperative chemotherapy

Despite of the fact that a large amount of therapeutic agents have been developed for cancer treatment, we are still sometimes in a dilemma of choosing a most effective regimen for individual. With the reference of several recent researches, positive clinical correlations have been identified with primary tumor xenografts models, but limitations in existed models reveals a need for improvement. Over the past decade, conceptual progress has been made that tumors had increasingly been recognized as organs in which ostensibly normal cells as well as cancer cells participate actively in tumorigenesis by creating the “tumor microenvironment”. Herein, we propose a hypothesis based on this novel conception that if transplanted as an organ, tumor implantation in nude mice would conserve most approximated biological traits with improved success rate, which make personalized tumor xenograft model practical for pre-clinical trials as substitutes for each patient. In our pilot study, intact tumor bloc was applied in implantation to evaluate this notion. As a result, 107 xenografts from all 20 patients of gastric cancer were transplanted successfully. Pathological comparison confirmed that no differences between xenografts and primary tumors while the therapeutic response to two chemotherapeutic agents, docetaxel and pemetrexed, exhibited differently. In conclusion, applying personalized primary tumor xenograft model derived from freshly excised tumor in pre-clinic trails would potentially lead to a more effective customized chemotherapy.     

China special issue on gastrointestinal tumors-Improved survival after multidisciplinary team decision for patients with advanced gastrointestinal cancer: A multicenter,noninterventional, controlled study

Formal multidisciplinary team (MDT) discussions in clinical practice require time and space but have unclear survival benefits for advanced gastrointestinal cancer patients. Our study aimed to investigate the long-term survival of patients with advanced gastrointestinal cancer after MDT decision. From June 2017 to June 2019, continuous MDT discussions on advanced gastrointestinal cancer were conducted in 13 medical centers in China. MDT decisions and actual treatment received by patients were prospectively recorded. The primary endpoint was the difference in overall survival (OS) between patients in the MDT decision implementation and nonimplementation groups. The secondary endpoints included the implementation rate of MDT decisions and subgroup survival analysis. A total of 461 MDT decisions of 455 patients were included in our study. The implementation rate of MDT decisions was 85.7%. Previous treatment had an impact on MDT decision-making. The OS was 24.0 months and 17.0 months in the implementation and nonimplementation groups, respectively. The implementation of MDT decisions significantly reduced the risk of death in multivariate analyses (hazard ratio = 0.518; 95% confidence interval: 0.304-0.884, P = .016). Subgroup analysis showed a significant difference in survival of patients with colorectal cancer, but not in survival of patients with gastric cancer. The rate of secondary MDT discussion was only 5.6% among patients who the MDT decisions were discontinued due to changes in their condition. MDT discussion can prolong the OS of patients with advanced gastrointestinal cancer, especially those with colorectal cancer. Timely scheduling of the subsequent MDT discussion is necessary when the disease condition changes.     

免疫检查点抑制剂相关胆管型肝毒性发生机制及治疗策略

肿瘤免疫检查点抑制剂（ICI）治疗近年来因疗效显著而备受瞩目。ICI引起的免疫介导肝毒性（IMH）是一类较常见的免疫相关不良反应（irAE）,但IMH中的一种亚分型,胆管型IMH(BIMH),却是一种少见的、对其认知极不充分、缺乏诊疗规范的irAE,存在临床隐患。BIMH以胆管酶显著升高、高胆红素血症为临床特点,组织病理学表现为胆管炎症、胆管损伤和消失。胆汁淤积阶段的BIMH对于免疫抑制治疗反应不佳,预后差。提高对BIMH的认识,早期诊断和干预是提高BIMH预后的关键。对BIMH流行病学特征、临床特征、组织病理学特点和发生机制及BIMH全程管理中存在之问题等认识的不断提高,有助于提出针对BIMH的有效诊疗策略。     

MET overexpression and amplification define a distinct molecular subgroup for targeted therapies in gastric cancer

Background

Currently, only trastuzumab, ramucirumab, and apatinib effectively treat gastric cancer. Thus, additional novel targets are required for this disease.

Methods

We investigated the immunohistochemical and fluorescence in situ hybridization expression of MET, ROS1, and ALK in four gastric cell lines and a cohort of 98 gastric cancer patients. Crizotinib response was studied in vitro and in vivo.

Results

Crizotinib potently inhibited in vitro cell growth in only one cell line, which also showed MET amplification. A positive correlation between crizotinib sensitivity and MET overexpression was observed (P = 0.045) in the histoculture drug response assay. Meanwhile, patient-derived tumor xenograft mouse models transplanted with tissues with higher MET protein expression displayed a highly selective sensitivity to crizotinib. In the 98 patients, MET overexpression was found in 42 (42.9 %) and MET was amplified in 4 (4.1 %). ROS1 and ALK overexpression were found in 25 (25.5 %) and 0 patients, respectively. However, none of the patients screened harbored ALK or ROS1 rearrangements. No significant association was found between overall survival and MET or ROS1 status. We also observed a stage IV gastric cancer patient with MET amplification who experienced tumor shrinkage and clinical benefit after 3 weeks of crizotinib as fourth-line treatment.

Conclusions

Crizotinib may induce clinically relevant anticancer effects in MET-overexpressed or MET-amplified gastric cancer patients.

     

新方向、新理念、新挑战：实体瘤内免疫治疗技术的前世今生

近年来肿瘤免疫治疗迅速发展,极大地改善了许多实体瘤患者的预后。但并非所有实体瘤患者都能产生持久的反 应,且其疗效也受到免疫治疗相关不良反应的限制。目前,实体瘤内免疫治疗作为一种局部免疫治疗手段越来越受到关注。本 文首先介绍当前实体瘤的免疫治疗研究现状,分析了实体瘤内免疫治疗这一新兴治疗手段在减少药物的系统性暴露及其不良反 应、增强肿瘤免疫原性、克服肿瘤异质性等方面的显著优势,然后就目前可用于实体瘤内免疫治疗的药物及其应用进展进行了简 要地归纳,最后从疗效评价、具体实施等方面总结了实体瘤内免疫治疗所面临的挑战与对策,以期达到对实体瘤内免疫治疗理念 的推广和普及作用。     

胃癌患者根治术后腹腔灌洗液中CEA mRNA表达的临床意义

目的：探讨胃癌患者根治术后腹腔冲洗液中CEA mRNA表达情况及其临床意义。方法: 回顾性分析了2013 年1 月至2017 年12 月在南京大学医学院附属鼓楼医院接受胃癌根治切除术后进行腹腔灌洗液CEA mRNA检测的139 名患者的病历资料,并进行术后常规随访。用RT-PCR检测139 胃癌患者根治术后腹腔灌洗液中CEA mRNA表达情况。卡方检验分析腹腔灌洗液中CEA mRNA表达与临床基本特征、组织病理学资料、血液学指标及复发方式之间的关系。采用Logistic 单因素及多因素回归分析筛查影响CEA mRNA表达水平的因素。结果：139 名患者中44 名（31.7%）患者腹腔灌洗液CEA mRNA阳性。分析显示,胃癌患者腹腔灌洗液CEA mRNA阳性表达与性别、年龄、病理分级、Lauren 分型和HER2、EGFR、VEGFR等标记物间均没有明显的关联（均P>0.05）,与病理类型、脉管是否侵犯、局部浸润深度、淋巴结转移程度和临床AJCC 分期有明显的关联（均P<0.05）。CEA mRNA阳性患者腹膜复发率明显高于阴性患者（P=0.012）。Logistic 单因素回归分析显示,印戒细胞癌（P=0.04,HR=2.810,95% CI: 1.050~7.520）、T 分期（P=0.016,HR=6.329,95% CI: 1.417~28.264）、N 分期（P=0.022,HR=3.068,95% CI: 1.172~8.027）、AJCC分期（P=0.016 ,HR=3.971 ,95% CI: 1.295~12.173 ）、神经侵犯（P=0.002 ,HR=6.738,95% CI: 1.995~22.757）、脉管侵犯（P<0.001,HR=16.36,95% CI: 3.85~69.512）为胃癌患者腹腔灌洗液CEA mRNA阳性表达的危险因素。Logistic 多因素回归分析显示,经过对其他因素的校正,脉管侵犯（P<0.001,HR=21.314,95% CI: 4.21~107.907）为胃癌患者腹腔灌洗液CEA mRNA阳性表达的独立危险因素。结论：胃癌腹腔灌洗CEA mRNA阳性的患者腹膜复发转移风险高且预后不良,应考虑包括腹腔局部治疗在内的更加积极的抗肿瘤治疗。     

肾神经内分泌肿瘤1例并文献复习

目的:探讨肾神经内分泌肿瘤的临床特征和治疗方法。方法:本文报道了1例38岁的男性患者，2004年因右肾占位行“右侧根治性肾切除术”，术后病理显示右肾神经内分泌肿瘤。手术后患者未接受任何抗肿瘤治疗。2015年1月，患者出现腹部和腹膜后转移，然后在全身麻醉下于2015年3月4日进行腹部肿瘤切除，肿瘤的大小约为20 cm×8 cm×5 cm，位于下腔静脉及腹主动脉之间，后方达脊柱前缘。术后病理显示神经内分泌肿瘤G2（非典型类癌），该患者被诊断为复发性右肾神经内分泌肿瘤。奥沙利铂加卡培他滨方案于2015年5月27日开始。经过2个疗程评估后，腹膜后肿瘤再次出现。结果:因患者生长抑素受体显像结果呈阳性，因此我们将治疗方案改为醋酸奥曲肽20 mg肌肉注射，每4周一次，目前已接受29次注射，患者目前一般状况可，多次复查结果评为病情稳定（SD）。结论:肾神经内分泌肿瘤罕见，对于术后或化疗后复发的患者，可从生长抑素类似物治疗中获益。