Impact of prior therapies on the relative efficacy of bortezomib compared with dexamethasone in patients with relapsed/refractory multiple myeloma

This subgroup analysis of the phase III APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial examined whether prior exposure to specific therapies affected the relative efficacy of bortezomib versus dexamethasone in relapsed/refractory myeloma. Time to progression and overall survival were superior with bortezomib in all subgroups, with no evidence of interaction between any prior therapies and assignment to study therapy. Patients with prior thalidomide exposure had worse outcomes overall, but neither prior thalidomide nor prior autologous stem cell transplantation affected the relative efficacy of bortezomib versus dexamethasone. These results confirm the superiority of bortezomib over dexamethasone, regardless of prior exposure to specific therapies (clinicaltrials.gov: NCT00048230).     

BDT和VADT方案治疗多发性骨髓瘤的临床研究

目的比较BDT与VADT方案治疗多发性骨髓瘤(MM)的疗效及不良反应。方法回顾分析72例MM病人,其中24例病人(初治13例,复发难治11例)接受BDT(硼替佐米联合地塞米松、沙利度胺)方案治疗,48例病人(初治36例,复发难治12例)接受VADT(长春地辛联合表柔比星、地塞米松、沙利度胺)方案化疗。所有病人均接受4～6个疗程治疗后进行全面评价,自动放弃治疗、疗程不符合标准以及失访病人不计入。结果 BDT组和VADT组的总完全缓解(TR)率分别为68.42%和35.42%,初治病人TR率分别为80.00%、44.44%,复发难治病人TR率分别为55.56%、8.33%,两组比较差异均有显著性(2χ=3.965～5.996,P<0.05);两组的总体有效(RR)率分别为89.47%和70.83%,两组比较差异无显著性(P>0.05)。两组初治病人达到最大反应中位疗程数分别为3和5个,复发难治病人分别为4和7个。常见的不良反应有骨髓抑制、消化道症状、肝肾功能损害、周围神经病变、乏力、血栓形成、血凝异常、带状疱疹病毒感染、精神症状、皮疹等,两组比较差异无显著意义(P>0.05)。结论 BDT方案治疗MM比VADT方案有较高的TR率,对复发难治性MM效果明确,且起效更快,副作用多可耐受,值得临床推广。     

The natural history of occult or angiodysplastic gastrointestinal bleeding in von Willebrand disease

Recurrent gastrointestinal bleeding is one of the most challenging complications encountered in the management of patients with von Willebrand disease (VWD). The commonest cause is angiodysplasia, but often no cause is identified due to the difficulty in making the diagnosis. The optimal treatment to prevent recurrences remains unknown. We performed a retrospective study of VWD patients with occult or angiodysplastic bleeding within the setting of the von Willebrand Disease Prophylaxis Network (VWD PN) to describe diagnostic and treatment strategies. Centres participating in the VWD PN recruited subjects under their care with a history of congenital VWD and gastrointestinal (GI) bleeding due to angiodysplasia, or cases in which the cause was not identified despite investigation. Patients with acquired von Willebrand syndrome or those for whom the GI bleeding was due to another cause were excluded. Forty‐eight patients from 18 centres in 10 countries were recruited. Seven individuals had a family history of GI bleeding and all VWD types except 2N were represented. Angiodysplasia was confirmed in 38%, with video capsule endoscopy and GI tract endoscopies being the most common methods of making the diagnosis. Recurrent GI bleeding in VWD is associated with significant morbidity and required hospital admission on up to 30 occasions. Patients were treated with multiple pharmacological agents with prophylactic von Willebrand factor concentrate being the most efficient in preventing recurrence of the GI bleeding. The diagnosis and treatment of recurrent GI bleeding in congenital VWD remains challenging and is associated with significant morbidity. Prophylactic treatment with von Willebrand factor concentrate was the most effective method of preventing recurrent bleeding but its efficacy remains to be confirmed in a prospective study.     

沙利度胺在口腔黏膜病临床治疗实践中的安全性分析

沙利度胺诞生至今已经超过60年,目前广泛应用于炎症性疾病和自身免疫性疾病的治疗,包括多种口腔黏膜疾病的治疗。由于沙利度胺曾造成严重的致畸不良事件,所以较多医生对其在临床具体应用过程中的安全性尚存在一些疑问和顾虑。本文通过回顾分析有关沙利度胺的药物代谢动力学、药物作用机制以及临床治疗试验研究的文献,着重探讨沙利度胺的药物安全性、对育龄期患者的影响以及对儿童患者的影响等问题,以期为口腔黏膜病科医生提供更为全面的信息,确保其安全有效的应用。     

Administrations of thalidomide into the rostral ventromedial medulla produce antinociceptive effects in a rat model of postoperative pain

The rostral ventromedial medulla (RVM) is highly involved in pain signal transmissions. Previous studies have shown that thalidomide is anti‐nociceptive. Thus, we evaluated the neurobiological mechanisms of thalidomide in the RVM in the regulation of postoperative pain. We used a rat model of postoperative pain to investigate the effects of intra‐RVM thalidomide treatments on postoperative pain, and evaluate the role of cannabinoid receptors in the effects of intra‐RVM thalidomide treatments on GABAergic neurotransmission in the RVM neurons. We found intra‐RVM thalidomide treatments reduced incisional surgery induced mechanical allodynia. This phenomenon was associated with attenuation of the frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs) and spontaneous IPSCs (sIPSCs) in RVM neurons. Furthermore, applications of WIN 55,212‐3 mesylate, a non‐selective cannabinoid receptor antagonist reversed the effects of repeated thalidomide treatment on the frequency but not the amplitude of mIPSCs and sIPSCs. Finally, we found that repeated thalidomide treatment robustly enhanced CB2 receptor expression, but slightly reduced CB1 receptor expression, in the RVM. These results suggested that the antinociceptive effects of thalidomide in the RVM likely involve the attenuation of GABA release, which are critically regulated by cannabinoid receptors.     

多发性骨髓瘤维持治疗的研究进展

多发性骨髓瘤(multiple mfeloma,MM)是第二常见的血液肿瘤病,目前仍无法治愈。诱导治疗后序贯自体干细胞移植（ASCT）已经成为一种标准化治疗,但依然可能存在复发。使用维持治疗的目的是通过增加无进展生存期（PFS）,加深缓解,进而增加总生存期(OS)。本文主要对新药时代MM的维持治疗的进展作一综述。     

Poor tolerability of thalidomide in end-stage oesophageal cancer

Oesophageal cancer cachexia is a significant clinical problem, resulting in excessive morbidity and mortality. In a pilot study, 10 patients with cachexia due to advanced cancer of the oesophagus gained weight, including lean tissue, after 14-day treatment with thalidomide. Here, we present randomised placebo controlled trial data over a 6-week period to test the hypothesis that thalidomide is superior to placebo in terms of weight gain in patients with cachexia caused by oesophageal cancer. Thalidomide, 200 mg daily, or an identical placebo was given to patients with advanced oesophageal cancer. Total body weight and lean body mass were assessed in addition to drug tolerability and performance indices. Thirty-four patients were recruited. Of these, six given thalidomide and 16 given placebo completed the protocol; all withdrawals were due to adverse drug reactions or complications of disease. Thalidomide showed no benefit over placebo in participants who completed the protocol. These data suggest that thalidomide is poorly tolerated in patients with advanced cancer of the oesophagus and may not ameliorate the progression of cachexia. In the absence of hard supportive evidence, off-licence treatment with thalidomide should be used with great caution as an adjunct to nutritional support in patients with advanced cancer.     

Differential Effects of Thalidomide on Angiogenesis and Tumor Growth in Mice

Thalidomide, clinically used as an antiinflammatory and antitumoral drug, inhibited sponge-induced angiogenesis when administered systemically (100 mg/kg^–1) in mice. However, it failed to inhibit solid Ehrlich tumor in the same mouse strain. We have used functional, biochemical and histological parameters to assess neovascularization and fibrovascular tissue infiltration of the mice sponge granuloma. The neovascularization growth as detected by development of blood flow and hemoglobin content extracted from the implants showed that thalidomide inhibited fibrovascular tissue formation by 40%. The functional and biochemical parameters correlated well with the histological study. Thalidomide had no inhibitory effect in the development of Ehrlich tumor. The detection of this selective action using the same animal strain bearing two different processes, supports the hypothesis that rather than species specificity, thalidomide is tissue specific. This approach may be used to identify the specificity of other therapeutic agents against distinct angiogenesis-dependent diseases.