非霍奇金淋巴瘤采用CHOP方案治疗与护理

目的探讨NHL采用CHOP方案治疗中护理的重要性.方法对115例NHL采用CTX,750mg/m2 静滴第1日,VCR 1.4g/m2静滴第1.8日,PDN100mg/m2PO第1～5日,每21天为1周期,本组病例用药4～6个周期.结果顺利地完成了115例NHL的化疗,无1例出现化疗作用.结论肿瘤专科护理的措施是顺利完成化疗,减轻副作用,提高生活质量的保证.     

Failure of intensive chemotherapy in poor prognosis non-Hodgkin's lymphoma

In an attempt to improve response and survival rates in patients with non-Hodgkin's lymphoma, a relatively intense six drug regimen MATCOP was developed comprising four-weekly cycles of methotrexate (100mg/m², IV_Y day 8), Adriamycin (30mg/m², IV_Y days 1,2), teniposide (75 mg/rn², IV, day 1), cyclophophamide (300 mg/m², po, days one to five), Oncovin (1.4 mg/m², IV: maximum 2 mg, days 8,15) and prednisolone (100 mg, po, days one to five). A randomised trial was conducted comparing MATCOP with the standard CHOP regimen, comprising three-weekly cycles of cyclophosphamide (750 mg/m², IV, day 1), Adriamycin (50 mg/m², IV, day 1), Oncovin (1.4 mg/m² IV: maximum 2 mg, day 1) and prednisolone (100 mg, PO, days two to six). Eighty patients with large cell lymphoma, diffuse mixed small cleaved and large cell lymphoma or diffuse small cleaved cell lymphoma were randomised, 47 to MATCOP and 33 to CHOP. MATCOP patients experienced increased granulocytopenia, thrombocytopenia (p 0.0001), mucositis (p= 0.002) and infections (p= 0.01) compared to CHOP patients. Complete response rates were similar: 66% for MATCOP patients and 61% for CHOP patients. There were no apparent differences in the time to relapse for patients achieving CR, the time to treatment failure or the overall survival time. Thus despite an increase in toxicity, the more intense regimen MATCOP failed to confer any therapeutic benefit compared with the standard CHOP regimen. Survival was not influenced but toxicity was increased by dose intensification. (Aust NZ J Med 1992; 22: 123–128.)     

PERK/CHOP contributes to the CGK733-induced vesicular calcium sequestration which is accompanied by non-apoptotic cell death

Calcium ions (Ca²⁺) are indispensable for the physiology of organisms and the molecular regulation of cells. We observed that CGK733, a synthetic chemical substance, induced non-apoptotic cell death and stimulated reversible calcium sequestration by vesicles in pancreatic cancer cells. The endoplasmic reticulum (ER) stress eukaryotic translation initiation factor 2-alpha kinase 3/C/EBP homologous protein (PERK/CHOP) signaling pathway was shown to be activated by treatment with CGK733. Ionomycin, an ER stress drug and calcium ionophore, can activate PERK/CHOP signaling and accelerate CGK733-induced calcium sequestration. Knockdown of CHOP diminished CGK733-induced vesicular calcium sequestration, but had no effects on the cell death. Proteomic analysis demonstrated that the ER-located calcium-binding proteins, calumenin and protein S100-A11, were altered in CGK733-treated cells compared to non-treated controls. Our study reveals that CGK733-induced intracellular calcium sequestration is correlated with the PERK/CHOP signaling pathway and may also be involved in the dysregulations of calcium-binding proteins.     

The ALK inhibitor ASP3026 eradicates NPM-ALK+ T-cell anaplastic large-cell lymphoma in vitro and in a systemic xenograft lymphoma model

NPM-ALK⁺ T-cell anaplastic large-cell lymphoma (ALCL) is an aggressive type of cancer. Standard treatment of NPM-ALK⁺ ALCL is CHOP polychemotherapy. Although patients initially respond favorably to CHOP, resistance, relapse, and death frequently occur. Recently, selective targeting of ALK has emerged as an alternative therapeutic strategy. ASP3026 is a second-generation ALK inhibitor that can overcome crizotinib resistance in non-small cell lung cancer, and is currently being evaluated in clinical trials of patients with ALK⁺ solid tumors. However, NPM-ALK⁺ ALCL patients are not included in these trials. We studied the effects of ASP3026 on NPM-ALK⁺ ALCL cell lines in vitro and on systemic lymphoma growth in vivo. ASP3026 decreased the viability, proliferation, and colony formation, as well as induced apoptotic cell death of NPM-ALK⁺ ALCL cells. In addition, ASP3026 significantly reduced the proliferation of 293T cells transfected with NPM-ALK mutants that are resistant to crizotinib and downregulated tyrosine phosphorylation of these mutants. Moreover, ASP3026 abrogated systemic NPM-ALK⁺ ALCL growth in mice. Importantly, the survival of ASP3026-treated mice was superior to that of control and CHOP-treated mice. Our data suggest that ASP3026 is an effective treatment for NPM-ALK⁺ ALCL, and support the enrollment of patients with this lymphoma in the ongoing clinical trials.     

Primary non-Hodgkin’s lymphoma of the gallbladder diagnosed by laparoscopic cholecystectomy

Primary lymphoma of the gallbladder is an exceedingly rare disease. We experienced an asymptomatic case of primary non-Hodgkin’s lymphoma of the gallbladder in a 55-year-old woman in whom laparoscopic cholecystectomy made a definite diagnosis. Abdominal computed tomography revealed a 4-cm gallbladder tumor with markedly enlarged lymph nodes in the retropancreatic area. Despite the marked involvement of lymph nodes, serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 were not elevated. The discrepancy between the imaging findings and the patient’s mild clinical presentation led us to suspect that the tumor was a lymphoma. We examined serum markers of lymphoma, revealing slight elevations of interleukin (IL)-2 receptor and thymidine kinase. Laparoscopic cholecystectomy for a total biopsy was performed successfully, and the results of intraoperative frozen-section examination led us to have a high suspicion of malignant lymphoma. The final diagnosis was large diffuse B-cell lymphoma of the gallbladder with a positive CD20 antibody reaction. The patient received postoperative chemotherapy with R-CHOP (rituximab, 500 mg; cyclophosphamide, 1000 mg; adriamycin, 68 mg; vincristine, 1.9 mg; and prednisone, 80 mg) starting on postoperative day 12. She achieved complete remission and is still in complete remission 3 years and 2 months after the cholecystectomy. In conclusion, gallbladder lymphoma should be added to the differential diagnosis of gallbladder tumors, especially when the imaging findings and clinical presentation are not consistent with typical signs of gallbladder carcinoma, and laparoscopic cholecystectomy is helpful for the confirmation of suspicious cases.     

美罗华联合CHOP方案治疗侵袭性B细胞淋巴瘤

目的:探讨美罗华联合CHOP方案治疗侵袭性B细胞淋巴瘤疗效。方法:选取患者102例,采用数字表法分为常规组和联合组,分别给予CHOP方案和美罗华联合CHOP方案治疗,评价其治疗有效率和不良反应率。结果:联合组治疗有效性(88.24%)高于常规组(66.67%)(P0.05);两组不良反应率(21.57%vs25.49%)差异对比无统计学意义(P0.05)。结论:美罗华联合CHOP方案治疗侵袭性B细胞淋巴瘤相比于常规方案,在不增加患者不良反应率的前提下,可提高患者症状缓解率。     

GRP78与 CHOP在缺血再灌注损伤中的作用

缺血再灌注（ischemia-reperfusion ,IR）过程中多种因素可导致内质网应激（endoplasmic reticulum stress response,ERS）, ERS参与缺血再灌注（ ischemia-reperfusion injury,IRI）的发展过程。总结ERS抗凋亡标志物GRP78与促凋亡标志物CHOP在IRI中的作用。 IRI时GRP78与CHOP表达的变化及其作用。明晰GRP78与CHOP参与IRI的机制。     

CHOP‐mediated hepcidin suppression modulates hepatic iron load

The liver is the central regulator of iron metabolism and accordingly, chronic liver diseases often lead to systemic iron overload due to diminished expression of the iron‐regulatory hormone hepcidin. To study the largely unknown regulation of iron metabolism in the context of hepatic disease, we used two established models of chronic liver injury, ie repeated carbon tetrachloride (CCl₄) or thioacetamide (TAA) injections. To determine the impact of CCAAT/enhancer‐binding protein (C/EBP)‐homologous protein (CHOP) on hepcidin production, the effect of a single TAA injection was determined in wild‐type and CHOP knockout mice. Furthermore, CHOP and hepcidin expression was assessed in control subjects and patients with alcoholic liver disease. Both chronic injury models developed a distinct iron overload in macrophages. TAA‐, but not CCl₄‐ injected mice displayed additional iron accumulation in hepatocytes, resulting in a significant hepatic and systemic iron overload which was due to suppressed hepcidin levels. C/EBPα signalling, a known hepcidin inducer, was markedly inhibited in TAA mice, due to lower C/EBPα levels and overexpression of CHOP, a C/EBPα inhibitor. A single TAA injection resulted in a long‐lasting (> 6 days) suppression of hepcidin levels and CHOP knockouts (compared to wild‐types) displayed significantly attenuated hepcidin down‐regulation in response to acute TAA administration. CHOP mRNA levels increased 5‐fold in alcoholic liver disease patients versus controls (p < 0.005) and negatively correlated with hepcidin expression. Our results establish CHOP as an important regulator of hepatic hepcidin expression in chronic liver disease. The differences in iron metabolism between the two widely used fibrosis models likely reflect the differential regulation of hepcidin expression in human liver disease. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Effect of high volume hemofiltration on CHOP protein from a canine model of multiple organ dysfunction syndrome

Objective To observe the effect of high volume hemofiltration (HVHF) on the expression of CCAAT enhancer binding protein(CHOP) during the treatment of multiple organ dysfunction syndrome (MODS). To investigate the role of CHOP protein act in apoptosis pathway mediated by the endoplasmic reticulum stress. Methods Twelve Beagle dogs were subjected to hemorrhagic shock plus resuscltation and endotixemia to establish MODS model, then they were randomly divided into two groups: HVHF group (n=6) and MODS group (n=6). After endotoxin injection completed, the HVHF group received HVHF treatment for 24 hours; MODS group did not receive. Vivo experiments: Blood samples were obtained at different time points(before operation, 0 h, 6 h, 12 h, 24 h after the injection of endotoxin). The dogs were killed and the tissue samples from lung, liver and kidney were took, then the expression of CHOP mRNA was determined. Vitro experiments: human umbilical vein endothelial cells (HUVECs) were induced by two groups’ blood samples to establish the apoptosis model. Gene expression, protein quantification and cell apoptosis rate were determined before and after the interference. Results Vivo experiments: The levels of CHOP mRNA from lung, liver and kidney had no significant difference between the two groups (P＞0.05). Vitro experiments: (1)The expression of CHOP mRNA: Compared with MODS group, the expression levels of CHOP mRNA were significantly decreased in HVHF group at 6 h, 24 h after the injection of endotoxin (P＜0.05). Compared with before, the expression levels of CHOP mRNA in the two groups were both significantly decreased after CHOP siRNA interference (P＜0.05). (2)The expression of CHOP protein: Compared with MODS group, the expression levels of CHOP protein were significantly decreased in HVHF group at each time points (P＜0.05). Compared with before, the expression levels of CHOP protein in the two groups were both significantly decreased after CHOP siRNA interference(P＜0.05). (3)Endothelial cell apoptosis rate: Compared with the preoperative rate, the two group’s endothelial cell apoptosis rate was decreased significantly at each time points(P＜0.05). Compared with MODS group, the endothelial cell apoptosis rate was significantly decreased in HVHF group at each time points(P＜0.05). Compared with before, the endothelial cell apoptosis rate in the two groups was both significantly decreased after CHOP siRNA interference(P＜0.05). Conclusion In the treatment of MODS process, HVHF can reduce endothelial cell apoptosis which may be related to the inhibition of CHOP mRNA expression and protein synthesis.     

Role of PERK/eIF2α/CHOP Endoplasmic Reticulum Stress Pathway in Oxidized Low-density Lipoprotein Mediated Induction of Endothelial Apoptosis

Objective PERK/eI F2α/CHOP is a major signaling pathway mediating endoplasmic reticulum(ER) stress related with atherosclerosis.Oxidized LDL(ox-LDL) also induces endothelial apoptosis and plays a vital role in the initiation and progression of atherosclerosis.The present study was conducted to explore the regulatory effect of ox-LDL on PERK/e IF2α/CHOP signaling pathway in vascular endothelial cells.Methods The effects of ox-LDL on PERK and p-e IF2α protein expression of primary human umbilical vein endothelial cells(HUVECs) were investigated by Western blot analysis.PERK gene silencing and selective eI F2α phosphatase inhibitor,salubrinal were used to inhibit the process of ox-LDL induced endothelial cell apoptosis,caspase-3 activity,and CHOP mR NA level.Results Ox-LDL treatment significantly increased the expression of PERK,PERK-mediated inactivation of e IF2α phosphorylation,and the expression of CHOP,as well as the caspase-3 activity and apoptosis.The effects of ox-LDL were markedly decreased by knocking down PERK with stable transduction of lentiviral sh RNA or by selective eI F2α phosphatase inhibitor,salubrinal.Conclusion This study provides the first evidence that ox-LDL induces apoptosis in vascular endothelial cells mediated largely via the PERK/eI F2α/CHOP ER-stress pathway.It adds new insights into the molecular mechanisms underlying the pathogenesis and progression of atherosclerosis.