Phase I Trial of Hyperthermic Intraperitoneal Chemoperfusion (HIPEC) with Cisplatin, Mitomycin, and Paclitaxel in Patients with Gastric Adenocarcinoma and Associated Carcinomatosis or Positive Cytology.
胃腺癌伴相关癌病或细胞学阳性患者腹腔热灌注化疗 (HIPEC) 联合顺铂、丝裂霉素和紫杉醇的 I 期试验。
- 作者列表："Blum Murphy M","Ikoma N","Wang X","Estrella J","Roy-Chowdhuri S","Das P","Minsky BD","Song S","Mansfield P","Ajani J","Badgwell B
BACKGROUND:The purpose of this phase I trial is to evaluate the safety and toxicity of laparoscopic hyperthermic intraperitoneal perfusion with chemotherapy (HIPEC), combining mitomycin, cisplatin, and paclitaxel for patients with gastric cancer metastatic to the peritoneum. PATIENTS AND METHODS:A Bayesian optimal interval design was used to prospectively identify the safety and tolerability of escalating doses of paclitaxel in combination with flat doses of mitomycin (30 mg) and cisplatin (200 mg) during laparoscopic HIPEC. The primary objective is to define the maximum tolerated dose. Secondary endpoints include surgical complications and overall survival (OS). RESULTS:A total of 27 patients were treated between 11/2017 and 11/2018. No dose-limiting toxicities were observed. Treatment-related grade 1-2 toxicities were leukopenia (11%), oral dysesthesia (4%), arthralgia (4%), and diarrhea (4%). Treatment-related grade 3-4 toxicities included leukopenia (4%) and neutropenia (4%). The maximum dose for paclitaxel was 60 mg/m2. Rates of Clavien-Dindo surgical complications were grade I 96% (all electrolyte deficiencies requiring replacement), II 4%, III 0%, IV 0%, and V 4%. The median follow-up time was 15 months. One- and 2-year OS rates from date of metastatic disease were 73.9% and 58.1%, respectively. CONCLUSIONS:Laparoscopic HIPEC with mitomycin, cisplatin, and paclitaxel may be safely used at intraperitoneal doses of 30 mg, 200 mg, and 60 mg/m2, respectively. Although electrolyte abnormalities were common, systemic toxicity was low. Survival rates were promising, supporting further research into intraperitoneal therapy for stage IV gastric cancer.
背景: 本 I 期试验的目的是评估腹腔镜腹腔热灌注化疗 (HIPEC) 联合丝裂霉素、顺铂、和紫杉醇用于胃癌转移至腹膜的患者。 患者和方法: 采用贝叶斯最佳间隔设计，前瞻性地确定递增剂量的紫杉醇联合丝裂霉素 (30 mg) 和顺铂 (200 mg) 的安全性和耐受性腹腔镜 HIPEC 期间。主要目标是定义最大耐受剂量。次要终点包括手术并发症和总生存期 (OS)。 结果: 共有 27 例患者接受了 11/2017 至 11/2018 的治疗。未观察到剂量限制性毒性。治疗相关的 1-2 级毒性反应为白细胞减少 (11%)，口腔感觉迟钝 (4)，关节痛 (4%) 和腹泻 (4%)。治疗相关的 3-4 级毒性反应包括白细胞减少 (4%) 和中性粒细胞减少 (4%)。紫杉醇的最大剂量为 60 mg/m2。Clavien-Dindo 手术并发症发生率为 I 级 96% (所有电解质缺乏需要更换) 、 II 级 4% 、 III 级 0% 、 IV 级 0% 和 V 级 4%。中位随访时间为 15 个月。从转移性疾病发生之日起，1 年和 2 年 OS 率分别为 73.9% 和 58.1%。 结论: 腹腔镜 HIPEC 联合丝裂霉素、顺铂和紫杉醇可安全使用，腹腔剂量分别为 30 mg 、 200 mg 和 60 mg/m2。尽管电解质异常很常见，但全身毒性较低。生存率是有希望的，支持进一步研究 IV 期胃癌的腹腔内治疗。
METHODS::Diffuse gastric cancer (DGC) is a lethal malignancy lacking effective systemic therapy. Among the most provocative recent results in DGC has been that the alter of the cellular cytoskeleton and intercellular adhesion. CD2-associated protein (CD2AP) is one of the critical proteins regulating cytoskeleton assembly and intercellular adhesion. However, no study has investigated the expression and biological significance of CD2AP in gastric cancer (GC) to date. Therefore, the aim of our study was to explore if the expression of CD2AP is associated with any clinical features of GC and to elucidate the underlying mechanism. Immunohistochemistry of 620 patient tissue samples indicated that the expression of CD2AP is downregulated in DGC. Moreover, a low CD2AP level was indicative of poor patient prognosis. In vitro, forced expression of CD2AP caused a significant decrease in the migration and invasion of GC cells, whereas depletion of CD2AP had the opposite effect. Immunofluorescence analysis indicated that CD2AP promoted cellular adhesion and influenced cell cytoskeleton assembly via interaction with the F-actin capping protein CAPZA1. Overall, the upregulation of CD2AP could attenuate GC metastasis, suggesting CD2AP as a novel biomarker for the prognosis and treatment of patients with GC.
METHODS::Aim: To identify the methylated-differentially expressed genes (MDEGs) that may serve as diagnostic markers and therapeutic targets in Epstein-Barr virus-associated gastric cancer (EBVaGC) and to explore the methylation-based pathways for elucidating biological mechanisms of EBVaGC. Materials & methods: Gene expression and methylation profiles were downloaded from GEO database. MDEGs were identified by GEO2R. Pathway enrichment analyses were conducted based on DAVID database. Hub genes were identified by Cytoscape, which were further verified by The Cancer Genome Atlas database. Results: A total of 367 hypermethylated, lowly expressed genes were enriched in specific patterns of cell differentiation. 31 hypomethylated, highly expressed genes demonstrated enrichment in regulation of immune system process. After validation using The Cancer Genome Atlas database, seven genes were confirmed to be significantly different hub genes in EBVaGC. Conclusion: EBVaGC-specific MDEGs and pathways can be served as potential biomarkers for precise diagnosis and treatment of EBVaGC and provide novel insights into the mechanisms involved.
METHODS:Gastric adenocarcinoma, like other cancers, is a multifactorial genetic disease, andmetastasis of cancer cells is one of the main features of this illness. The expressionlevels of the CFL1 gene have been modulated in this pathway. Using small interferingRNA (siRNA) in the treatment of gastric cancer is considered a hopeful genetherapeutic approach. The present study reported the level of CFL1 genes betweentumor and margin and healthy tissue of gastric cancer. Also, the features of a cationicnanoparticle with a polymer coating containing polyacrylic acid and polyethylenei-mine that were used in the delivery of CFL1 siRNA, were shown. Then thecytotoxicity, cellular uptake, and gene silencing efficiency of this nanoparticle wereevaluated with CFL1siRNA. Method:In this study, the CFL1 gene expression was measured in 40 gastricadenocarcinoma, marginal and 15 healthy biopsy samples by a real‐time polymerasechain reaction. Physicochemical characteristics, apoptosis, and inhibition of migrationof the delivery of CFL1 siRNA by nanoparticle and lipofectamine were investigated ingastric cancer cells. Result:The CFL1 expression was remarkably increased in gastric cancer tissues incomparison with the marginal samples and normal tissues (p< .05) and the biomarkerindex for CFL1 was obtained as 0.94, then this gene can be probably used as abiomarker for gastric cancer. After treatment of the AGS cell line by CFL1 siRNA, theCFL1 expression level of mRNA and migration in AGS cells were remarkablysuppressed after transfection. Furthermore, the amount of apoptosis increased(p< .05). Conclusion:Our results demonstrated that CFL1 downregulation in AGS cells caninterdict cell migration. Finally, our outcomes propose that CFL1 can function as anoncogenic gene in gastric cancer and would be considered as a potential purpose ofgene therapy for gastric cancer treatment