Thalidomide in combination with dexamethasone for pretreated patients with multiple myeloma: serum level of soluble interleukin-2 receptor as a predictive factor for response rate and for survival

The aim of this study was to assess the side effects and the efficacy of thalidomide alone or in combination with dexamethasone in relapsed multiple myeloma (MM) and to evaluate possible predictive factors for response rate and survival. Twenty-nine pretreated patients were enrolled, including 13 patients with a relapse after high-dose chemotherapy. The median number of relapses was 3 (range: 1–7). Twenty-two patients received thalidomide in combination with dexamethasone and seven patients thalidomide alone. The dosage of thalidomide was 400 mg/day and the dosage of dexamethasone 20 mg/m² daily for 4 consecutive days every 3 weeks. Cycles of dexamethasone were given until maximal decline of myeloma protein was achieved, whereas therapy with thalidomide was maintained until disease progression. Responses occurred in 62% of patients, including 5 (17%) complete remissions and 13 (45%) partial remissions. The median event-free survival (EFS) was 7.2 months and the median overall survival (OS) 26.1 months. In multivariate analysis, pretreatment serum levels of soluble interleukin-2 receptor (sIL-2R) were a significant prognostic factor for EFS, and those of ₂-microglobulin (2M) and sIL-2R for OS. Serum levels of sIL-2R significantly increased after 3 weeks of treatment in 89% of patients, possibly representing lymphocyte activation induced by thalidomide. Two patients died of septic complications within 3 months after starting treatment with thalidomide and dexamethasone and one patient of herpes encephalitis after 26 months of treatment with thalidomide alone. Also, one case of pneumonia and one case of deep venous thrombosis of the lower limb occurred. Other side effects were somnolence, peripheral neuropathy, and bradycardia occurring in 35, 55, 38 and 55% of patients, respectively. The combination of thalidomide and dexamethasone is an effective therapy in heavily pretreated myeloma patients with a high response rate and acceptable toxicities. A powerful predictive factor both for EFS and OS was the pretreatment serum level of sIL-2R.     

The effects of dexamethasone in vitro on the production of collagenase and inhibitor by synovial and cartilage explants from the joints of rabbits with a proliferative arthritis

Summary Using a rabbit model arthritis we have investigated the ability of dexamethasone to alter the production of collagenase and the specific metallo-proteinase inhibitor TIMP by explants of synovium and cartilage in vitro. The patterns of collagenase and TIMP production by untreated explants from arthritic joint tissues in culture were similar to those described previously [1, 2]. Dexamethasone dramatically altered the patterns of production of collagenase and TIMP. At a dose of 10 nM, or above, the patterns of production by treated synovium resembled those of normal rabbit synovium: collagenase production was suppressed and TIMP increased compared with untreated arthritic synovium. The levels of latent collagenase in cartilage also fell with increasing doses of dexamethasone and TIMP levels were higher, although normal levels were not reached.These experiments have been conducted as a prelude to testing the effects of various anti-rheumatic drugs in vivo, and attempting to correlate changes in clinical parameters with the subsequent production of collagenase and TIMP in vitro. The data are discussed in relation to the therapeutic use of corticosteroids and to their mode of action on joint tissues.     

Postnatal handling does not attenuate hypothalamic-pituitary-adrenal hyperresponsiveness after prenatal ethanol exposure

BACKGROUND: Prenatal ethanol exposure results in hypothalamic-pituitary-adrenal (HPA) hyperresponsiveness to stress in the adult animal. In contrast, an early environmental manipulation, termed "postnatal handling," has been shown to result in decreased and/or less prolonged HPA activity in response to moderate stressors throughout the lifespan of the animal. The effects of both prenatal ethanol exposure and postnatal handling on HPA activity may be mediated by altered feedback regulation of the HPA axis. The present study tested the hypothesis that postnatal handling could attenuate the impact of prenatal ethanol exposure on hormonal responses to stressors. METHODS: Male and female Sprague Dawley rats from prenatal ethanol (E), pair-fed (PF), and ad libitum-fed control (C) groups were either handled (H) or nonhandled (NH) during the preweaning period and were tested at 4 to 5 months of age. Animals were subjected to a 60 min restraint stress, 3 hr after intraperitoneal injection with either saline (SAL) or a synthetic glucocorticoid, dexamethasone-21-phosphate (DEX), in order to examine HPA responsiveness after DEX blockade of endogenous HPA activity. Blood samples were collected via jugular cannulae immediately before restraint (0 min), during restraint (10, 30, and 60 min), and 30 min after the termination of restraint (90 min). RESULTS: For both males and females, DEX administration significantly reduced plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT) concentrations compared with SAL administration. H animals showed greater suppression of HPA activity (i.e., lower ACTH and/or CORT levels) than NH animals regardless of prenatal group. In addition, E females from both the H and NH treatments showed elevated ACTH and CORT after both SAL and DEX administration, whereas H and NH E males showed elevations in ACTH and CORT only after SAL, compared with their PF and C counterparts. CONCLUSIONS: These data extend results from previous studies that demonstrated HPA hyperresponsiveness in E animals. The finding that E females but not males exhibit elevated ACTH and CORT after DEX administration suggests that prenatal ethanol exposure results in sex-specific alterations of HPA feedback. Consistent with previous data, handling in itself reduced the HPA response to restraint stress. However, handling did not attenuate either HPA hyperresponsiveness or feedback deficits in E animals.     

Effects of insulin, dexamethasone and glucagon on the production of apolipoprotein A-I in cultured rat hepatocytes

Cultured rat hepatocytes were used to study the effects of hormones on the production of apo A-I. In addition, we compared these effects with the production of albumin. Hepatocytes were isolated from normal adult rat livers and cultured in MEM, as nearly confluent monolayers. In the absence of hormones, apo A-I and albumin accumulated in the culture medium almost linearly for periods up to 24 h. The rates of accumulation of apo A-1 and albumin in the medium were 22 ng/mg cell protein per h and 1.2 μg/mg cell protein per h, respectively. During the incubations the cellular contents of apo A-1 remained constant.

Insulin stimulated the production of albumin at concentrations over 10⁻¹⁰ M, but inhibited the production of apo A-I at concentrations over 10⁻⁸ M. Dexamethasone showed no significant effects on albumin production but stimulated apo A-1 production at concentrations over 10⁻⁶ M. Glucagon inhibited the production of albumin and apo A-I dose-dependently at concentrations over 10⁻¹⁰ M. Thus, the production of albumin and apo A-1 are presumably controlled by different regulatory mechanisms.     

地塞米松鞘内注射与静脉注射在显微血管减压术后无菌性脑膜炎中的疗效比较

目的比较腰椎穿刺鞘内注射地塞米松与静脉推注地塞米松治疗显微血管减压术（MVD）术后无菌性脑膜炎（AM）的临床疗效。 方法选择自2015年1月至2020年1月于胜利油田中心医院神经外科就诊行MVD并诊断为AM的138例患者为研究对象,将患者分为对照组（68例）和观察组（70例）。对照组患者采用静脉推注地塞米松（10 mg/次）治疗,频率为按需给药;观察组患者采用腰穿放液联合鞘内注射地塞米松[60 μg/（kg·次）]治疗,频率为每日或隔日1次。比较2组患者治疗后的头痛及发热缓解情况、术后住院时间、治疗次数及激素不良反应情况。 结果治疗后8、72 h后,2组患者头痛、发热症状均明显好转,且观察组明显优于对照组,差异均有统计学意义（P<0.05）;观察组患者的术后住院时间[（7.68±2.23）d]短于对照组[（12.76±2.37）d],治疗次数[（3.5±0.6）次]明显低于对照组[（6.8±0.9）次],差异具有统计学意义（P<0.05）,2组患者均未见明显的激素不良反应。 结论腰穿放液联合鞘内注射地塞米松在治疗MVD术后AM患者中疗效确切,可有效改善患者头痛、发热等临床症状,减轻激素用量,缩短术后住院时间,具有重要的临床推广价值。     

Elevated levels of T-cell immune response cDNA 7 in patients with immune thrombocytopenia

Objectives

This study aimed to investigate the expression levels of T-cell immune response cDNA 7 (TIRC7) in immune thrombocytopenia (ITP) patients before and after high-dose dexamethasone (HD-DXM) treatment.

Methods

Forty-four patients with ITP were enrolled and received dexamethasone (40 mg/day) for 4 consecutive days. Patients who had platelet counts more than 50 × 10⁹/l or less were defined as responders or non-responders, respectively. Quantitative polymerase chain reaction and enzyme-linked immunosorbent assay were used to measure RNA level and plasma level of TIRC7, respectively.

Results

TIRC7 levels (RNA and plasma level) were significantly higher in ITP than that in control (P < 0.0001). However, after treatment, TIRC7 levels were significantly decreased in responders (P < 0.0001) but not in non-responders (P > 0.05).

Discussions

TIRC7 might be associated with the pathogenesis of ITP, and TIRC7 levels could be used as an indicator to evaluate patients’ response to HD-DXM treatment.     

模拟临床的中性粒细胞性激素抵抗型支气管哮喘小鼠模型的建立及意义

目的建立一种模拟临床的中性粒细胞性激素抵抗型支气管哮喘(哮喘)小鼠模型并探讨其意义。方法采用屋尘螨(house dust mite,HDM)和脂多糖(lipopolysaccharide,LPS)混合液,气管内给药建立哮喘小鼠模型。将18只雌性C57BL/6小鼠按照数字表法随机分为对照组、哮喘组(HDM+LPS)和地塞米松(dexamethasone,Dex)组(HDM+LPS+Dex)。肺功能仪测定小鼠气道阻力,HE染色观察肺组织炎症细胞浸润,过碘酸-雪夫染色(PAS)观察杯状细胞增生,瑞氏染色检测BALF炎症细胞总数及分类计数,聚合酶链式反应(PCR)和酶联免疫吸附试验(ELISA)检测肺组织和BALF炎症因子。流式细胞术检测肺组织Th17细胞分化。结果HE染色显示,哮喘组肺组织炎症较对照组显著增高(P<0.05),地塞米松组肺组织炎症较哮喘组稍减轻(P>0.05);BALF细胞分类计数显示,哮喘组炎症细胞(除外嗜酸粒细胞)浸润较对照组显著增加[炎症细胞总数分别为(2797±400)×106/L和(105±75)×106/L,中性粒细胞计数分别为(1151±395)×106/L和(12±6)×106/L,淋巴细胞计数分别为(897±135)×106/L和(11±5)×106/L,巨噬细胞计数分别为(215±51)×106/L和(34±16)×106/L,均P<0.05],地塞米松组肺组织炎症细胞总数及巨噬细胞计数较哮喘组显著下降[炎症细胞总数(1140±418)×106/L vs(2797±400)×106/L,巨噬细胞计数(117±31)×106/L vs(215±51)×106/L,均P<0.05],但淋巴细胞和中性粒细胞计数无统计学意义[淋巴细胞计数(587±208)×106/L vs(897±135)×106/L,中性粒细胞计数(294±134)×106/L vs(1151±395)×106/L,均P>0.05];免疫组织化学检测结果同样证实,地塞米松组肺组织中性粒细胞浸润较哮喘组不能被有效抑制;哮喘组和地塞米松组气道阻力较对照组均显著增高(P<0.05),但两组间气道阻力差异无统计学意义(P>0.05);与哮喘组相比,地塞米松组肺组织Th2炎症指标显著降低(均P<0.05),而Th17细胞炎症指标有升高趋势,Th1炎症指标无显著改善;流式细胞术显示,地塞米松组肺组织Th17细胞浸润较哮喘组显著增多[分别为(5.8±1.9)%和(2.3±0.8)%,P<0.01]。结论成功建立了一种模拟临床的中性粒细胞性哮喘小鼠模型。地塞米松非但不能抑制小鼠中性粒细胞气道炎症和气道高反应性,而且促进Th17细胞分化,印证该哮喘模型存在激素抵抗。     

地塞米松冠周注射预防下颌阻生第三磨牙拔除后肿胀及张口受限的系统评价

目的 评价地塞米松（DM）冠周注射对下颌阻生第三磨牙拔除术后肿胀及张口受限的预防效果。方法 检索Cochrane图书馆临床随机对照试验库、PUBMED、荷兰医学文摘（EMBASE）和中国生物医学文献数据库;同时手检纳入文献的参考文献及中文口腔医学杂志。偏倚风险评价由2位评价者使用Cochrane系统评价者手册5.0版介绍的偏倚风险评价标准独立完成,同时独立进行数据提取。运用Revman 5.1软件进行Meta分析。结果 共纳入7篇随机对照试验,涉及患者684名,偏倚风险评价显示6个研究为中度偏倚风险,1个研究为高度偏倚风险。Meta分析的结果显示,4～5 mg DM冠周注射能够使患者术后1～2 d内最大张口度大6.77 mm（P=0.02）,同时能够减少51%的中-重度张口受限的发生率（P<0.000 01）,并且在控制面部肿胀方面效果显著（P<0.05）。注射4 mg DM与8 mg DM在各项指标中无显著差别（P>0.05）。结论 选择4～5 mg的DM冠周注射能够较好地控制下颌阻生第三磨牙拔除术后面部肿胀和张口受限,但还需要更多的临床随机对照试验的支持。     

Treatment with Thalidomide and Cyclophosphamide (TCID) is Superior to Vincristine (VID) and to Vinorelbine (VRID) Regimens in Patients with Refractory or Recurrent Multiple Myeloma

Treatment of relapsed or refractory multiple myeloma remains a challenge and novel treatment regimen are required. Here, a matched pair analysis was performed comparing TCID (thalidomide, cyclophosphamide, idarubicin, dexamethasone) treatment to the treatment of patients with VID (vincristine, idarubicin, dexamethasone) or with VRID (vinorelbine, idarubicin, dexamethasone) for relapsed or refractory multiple myeloma. In total, 197 patients were enrolled in multicenter trials. After matching for important prognostic variables 46 matched-pairs (total of 138 patients) could be analysed with regard to survival, toxicity and efficacy. Interestingly, a significant improvement of overall response rate (ORR) for TCID treatment compared to VID and VRID was found. In addition, TCID treatment also led to a significantly higher overall survival (OS) as well as progression-free survival (PFS) compared to VID and VRID. In conclusion, TCID treatment appears to be superior to VRID and VID treatment in patients with progressive or refractory myeloma.