Safety and Preliminary Efficacy of Ramucirumab in Combination with FOLFOX4 in Patients with Advanced Hepatocellular Carcinoma: A Nonrandomized,Open‐Label,Phase Ib Study

Lessons Learned

• The combination of ramucirumab (8 mg/kg intravenous, day 1 every 2 weeks) and FOLFOX4 as first‐line treatment in patients with advanced hepatocellular carcinoma (HCC) was not sufficiently tolerated.
• Preliminary efficacy data suggest that the combination may provide clinical benefit to patients with HCC.
• Dose modification and patient selection should be considered for the future development of ramucirumab plus FOLFOX chemotherapy for advanced HCC.

BackgroundThe objective of this study was to investigate the safety, preliminary efficacy, pharmacokinetics, and immunogenicity of ramucirumab plus FOLFOX4 as first‐line treatment in patients with advanced hepatocellular carcinoma (HCC).MethodsPatients received ramucirumab (8 mg/kg) intravenously (IV) on day 1, followed by FOLFOX4 (oxaliplatin 85 mg/m² IV on day 1, folinic acid 200 mg/m² IV, bolus fluorouracil [5‐FU] 400 mg/m², and a continuous infusion of 5‐FU 600 mg/m² over 22 hours, on days 1 and 2) every 2 weeks. The primary endpoint was to assess the safety and tolerability of the combination therapy.ResultsEight patients (6 men, 2 women) were treated; all eight patients experienced at least one treatment‐emergent adverse event (TEAE) of grade ≥3. Dose‐limiting toxicities occurred in three patients (37.5%): hepatic hemorrhage (grade 4), blood bilirubin increased (grade 3), and febrile neutropenia (grade 3). Two patients discontinued study because of hepatic hemorrhage (grade 4) and blood bilirubin increase (grade 3). Six deaths occurred due to progressive disease, and no deaths due to TEAEs.ConclusionThere were no unexpected safety findings with ramucirumab plus FOLFOX4 based on the known safety and toxicity of this regimen. The combination was not sufficiently tolerated in patients with advanced HCC at the specified dose and schedule.     

多种放射性肺损伤动物模型的建立和效应评价研究

放射性肺损伤是胸部肿瘤放疗后常见并发症,随着对放射性肺炎研究不断深入,如何为基础研究和药物干预寻求最佳的动物模型和效应评价已成为当前亟待解决的难题之一。通过检索近10年文献,对不同放射性肺损伤模型动物及放射部位的选择、照射剂量的确定、照射方法的比较和动物模型效应评价进行了对比研究,以期寻找建立放射性肺损伤动物模型的稳定方法和较为明确的效应机制,为防护和减缓放射性肺损伤的发生发展而进行的基础研究和药物研制提供可靠的方法。     

Immune checkpoint inhibitors in advanced nasopharyngeal carcinoma: Beyond an era of chemoradiation?

Now is an exciting era of development in immunotherapy checkpoint inhibitors and their effect on the treatment of NPC. While the general prognosis of R/M disease is poor, immunotherapy offers some promise in a malignancy associated with EBV and characterized by a peritumoural immune infiltrate. Our study aims to review past and on-going clinical trials of monoclonal antibody therapies against the checkpoint inhibitors (e.g. PD1 and CTLA-4), in R/M NPC. All randomized and nonrandomized controlled trials involving immune checkpoint inhibitor interventions for treatment of NPC were included in the study. We utilized a validated “risk of bias” tool to assess study quality. Four separate Phase I–II trials report the potential of PD1 inhibitor treatment for patients with NPC. Within the observed groups, camrelizumab combined with chemotherapy achieved an objective response in 91% of patients as first-line treatment for metastatic NPC (PFS 68% at 1-year) but this was associated with a high rate of grade >3 adverse events (87%; CTCAE version 4.03). The remaining three studies focused on recurrent NPC disease in patients who had received at least one line of prior chemotherapy. Within this group, camrelizumab monotherapy achieved an objective response in 34% of patients (PFS 27% at 1-year; range across all three studies 20.5–34%). No NPC trial has yet reported on specific outcomes for non-PD1 checkpoint inhibitors but 11 on-going studies include alternative targets (e.g. PD-L1/CTLA-4) as combination or monotherapy treatments. In considering checkpoint immunotherapies for NPC, initial results show promise for anti-PD1 interventions. Further phase I–III trials are in progress to clarify clinical outcomes, fully determine safety profiles, and optimize drug combinations and administration schedules.     

Molecular profiling of Chinese R-CHOP treated DLBCL patients: Identifying a high-risk subgroup

Diffuse large B-cell lymphoma (DLBCL) is a clinically aggressive and heterogenous disease. Although most patients can be cured by immunochemotherapy, 30% to 40% patient will ultimately develop relapsed or refractory disease. Here, we investigated the molecular landscapes of patients with diverse responses to R-CHOP. We performed capture-based targeted sequencing on baseline samples of 105 DLBCL patients using a panel consisting of 112 lymphoma-related genes. Subsequently, 81 treatment-naïve patients with measurable disease and followed for over 1 year were included for survival analysis. Collectively, the most commonly seen mutations included IGH fusion (69%), PIM1(33%), MYD88 (29%), BCL2 (29%), TP53 (29%), CD79B (25%) and KMT2D (24%). Patients with TP53 mutations were more likely to have primary refractory disease (87.0% vs 50.0%, P = .009). For those with TP53 disruptive mutations, 91.7% patients were in the primary refractory group. Interestingly, BCL-2 somatic hypermutation was only seen in patients without primary refractory disease (P = .014). In multivariate analysis, BCL-2 amplification (hazard ratio [HR] = 2.94, P = .022), B2M mutation (HR = 2.99, P = .017) and TP53 mutation (HR = 3.19, P < .001) were independently associated with shorter time to progression (TTP). Furthermore, TP53 mutations was correlated with worse overall survival (P = .049). Next, we investigated mutation landscape in patients with wild-type (WT) TP53 (n = 58) and found that patients harboring MYD88 L265P had significantly inferior TTP than those with WT or non-265P (P = .046). Our study reveals the mutation spectrum of treatment-naive Chinese DLBCL patients. It also confirms the clinical significance of TP53 mutations and indicates the prognostic value of MYD88 L265P in TP53 WT patients.     

旋覆代赭汤对反流性食管炎大鼠模型TLR4/NF-κB的影响

目的观察旋覆代赭汤对反流性食管炎(RE)模型大鼠食管黏膜与脂多糖(LPS)、Toll样受体4(TLR4)、核因子κB(NF-κB)表达的影响。方法将60只雄性Wistar大鼠按随机数字表法分为正常对照组、模型组、旋覆代赭汤组(简称中药组,9.89 g/kg)、西药(奥美拉唑+莫沙比利,2.58 mg/kg)组,每组15只。除正常对照组外大鼠采用“4.2 mm幽门夹+2/3胃底结扎术”制备酸碱混合反流RE大鼠模型。术后第7天予相应药物干预,持续干预14天。利用光学显微镜观察大鼠食管下段黏膜组织形态学变化;应用ELISA法检测定外周血中LPS含量;采用Western Blot法与RT-PCR法检测食管黏膜组织中TLR4、NF-κB蛋白和基因表达。结果与正常对照组比较,模型组大鼠食管黏膜镜下损伤最为严重,食管黏膜呈炎性改变,可见急慢性炎细胞浸润,病理积分和外周血中LPS含量升高(P<0.05),食管组织中TLR4、NF-κB蛋白和基因表达升高(P<0.05)。与模型组比较,中药组、西药组病理积分和外周血中LPS含量降低(P<0.05),食管组织中TLR4、NF-κB蛋白和基因表达亦明显降低(P<0.05)。结论旋覆代赭汤能够减轻RE模型大鼠食管黏膜的损伤,抑制TLR4、NF-κB的表达,促进食管黏膜损伤的恢复。     

Dietary citrus and/or its extracts intake contributed to weight control: Evidence from a systematic review and meta‐analysis of 13 randomized clinical trials

Randomized controlled trials, being published in English and investigating the associations of at least 4 weeks intervention of citrus and/or its extracts on weight loss among adults, were searched from PubMed, Web of Science, Scopus, and Cochrane by June 2019 to conduct a meta‐analysis. Thirteen articles, including 921 participants, were selected and evaluated by modified Jadad scale. Pooled results by the random‐effects model showed that citrus and/or its extracts administration significantly reduced 1.280 kg body weight (95% CI: ?1.818 to ?0.741, p = 0.000, I² = 81.4%), 0.322 kg/m² BMI (95% CI: ?0.599 to ?0.046, p = 0.022, I² = 87.0%), 2.185 cm WC (95% CI: ?3.804 to ?0.566, p = 0.008, I² = 98.3%), and 2.137 cm HC (95% CI: ?3.775 to ?0.500, p = 0.011, I² = 96.2%), respectively, but no significantly decreased effects on WHR and body fat were observed. Subgroup analysis deduced the different effects of study location, intervention duration on body weight associated indices. No publication bias was observed. Our meta‐analysis supported the beneficial effects of citrus and/or its extracts supplement on body weight control, and future well‐designed studies are required to firmly establish the clinical efficacy of citrus and/or its extracts intervention on body weight.     

解毒化浊促愈汤联合美沙拉嗪肠溶片治疗溃疡性结肠炎的疗效及对炎性细胞因子的影响

目的:研究解毒化浊促愈汤治疗溃疡性结肠炎的疗效及对白细胞介素-6(Interleukin-6,IL-6)、肿瘤坏死因子(Tumor Necrosis Factor-alpha,TNF-α)水平的影响。方法:选取自2017年8月-2018年10月在河南省中医院肛肠科就诊的溃疡性结肠炎患者60例为研究对象,随机将分为观察组与对照组,每组各30例。对照组用美沙拉嗪治疗,观察组在对照组治疗基础上联合解毒化浊促愈汤治疗。两组均连续治疗6周,比较两组患者治疗后的临床疗效以及治疗前后的IL-6、TNF-α水平变化情况。结果:治疗后观察组临床症状明显改善,总有效率为93.3%(28/30),明显高于对照组的70.0%(21/30)。治疗后,两组患者的血清IL-6、TNF-α水平分别较治疗前显著降低(P<0.05),且观察组各指标水平均低于对照组,差异显著(P<0.05)。结论:此方治疗方法能够明显缓解患者的临床症状,抑制炎症反应,提高临床疗效,具有临床推广价值。     

营养风险与腹膜后肿瘤患者住院时间的相关性研究

目的 探讨营养风险与腹膜后肿瘤患者住院时间的相关性。方法 采用回顾性研究，选取2012年1月至2018年12月四川大学华西医院血管外科新入院腹膜后肿瘤患者60例，采用营养风险筛查表评估患者营养风险，收集患者体质指数、围术期血红蛋白和白蛋白水平、住院天数、术后恶心呕吐发生情况、术后排气、排便时间和首次进食时间。采用单因素分析比较不同患者住院时间，采用多重线性逐步回归分析患者住院时间的影响因素。结果 纳入的60例腹膜后肿瘤患者中，40例患者（66.7%）术前存在营养风险，52例患者（86.7%）术后存在营养风险；单因素分析显示，患者术前、术后营养风险 （术前P<0.001，术后P=0.043）、术前白蛋白 （P=0.019）、术后血红蛋白 （P=0.019）、术后白蛋白（P=0.025） 水平以及术后恶心呕吐 （P=0.001） 均会影响患者的住院时间；患者住院时间与围术期营养风险筛查工具评分、术后首次进食时间、术后排气时间和排便时间具有相关性，且相关性强（r=0.759~0.770； P<0.01）；多因素分析显示术前营养风险是腹膜后肿瘤患者住院时间的重要预测因素（β=0.399）。结论 术前营养风险是腹膜后肿瘤患者住院时间的预测因子。     

高迁移率族蛋白A2与肿瘤关系的研究进展

高迁移率族蛋白A2(HMGA2)是一种非组蛋白,本身不具有转录活性,但它可通过与染色质结合改变其结构,继而调节其他基因的转录,从而促进肿瘤的侵袭和转移。相关RNA基因能够调控HMGA2在肿瘤中的作用,同时肿瘤的侵袭性与上皮间质转化密切相关,可以通过靶向HMGA2基因治疗相关肿瘤。文章主要介绍HMGA2与肿瘤之间关系的研究进展。     

Endostar,an Antiangiogenesis Inhibitor,Combined With Chemoradiotherapy for Locally Advanced Cervical Cancer

This phase II randomized clinical trial aimed to assess the efficacy and toxicity of Endostar, an antiangiogenesis inhibitor, combined with concurrent chemoradiotherapy (CCRT) for locally advanced cervical cancer (LACC). Patients with LACC were randomly assigned to either CCRT plus Endostar (CCRT+E arm) or CCRT alone (CCRT arm). All patients received pelvic intensity-modulated radiation therapy (IMRT) and brachytherapy. Weekly cisplatin was administered concurrently with IMRT. Patients in the CCRT+E arm also received concurrent Endostar every 3 weeks for two cycles. The primary endpoint was progression-free survival (PFS) and acute toxicities. The exploratory endpoint was the impact of vascular endothelial growth factor receptor-2 (VEGFR2) expression on long-term survival. A total of 116 patients were enrolled. Patients in the CCRT+E arm and in the CCRT arm had similar acute and late toxicity profile. The 1- and 2-year PFS were 91.4% versus 82.1% and 80.8% versus 63.5% (p=0.091), respectively. The 1- and 2-year distance metastasis-free survival (DMFS) were 92.7% versus 81.1% and 86.0% versus 65.1% (p=0.031), respectively. Patients with positive VEGFR2 expression had significant longer PFS and overall survival (OS) compared with those with negative VEGFR2 expression. Patients in the CCRT+E arm had significantly longer PFS, OS, and DMFS than those in the CCRT arm when VEGFR2 expression was positive. In conclusion, CCRT plus Endostar significantly improved DMFS but not PFS over CCRT alone. The addition of Endostar could significantly improve survival for patients with positive VEGFR2 expression.