Relapse of hairy cell leukemia after 2-chlorodeoxyadenosine: long-term follow-up of the Northwestern University experience

Although 2-chlorodeoxyadenosine (2-CdA) is effective in inducing complete remissions (CRs) in the majority of patients with hairy cell leukemia (HCL), neither the actual relapse rate, the clinical factors that may predict relapse, the long-term outcome, nor the response rate to re-treatment at relapse has been clearly determined. Fifty-two consecutive patients with previously untreated or treated HCL were treated with 2-CdA at a dose of 0.1 mg/kg/d by continuous intravenous infusion for 7 days. Of 50 assessable patients, 40 (80%) achieved CR, and 9 (18%) achieved partial remission (PR). A total of 7 patients (14%) have relapsed, at a median duration of 24 months (range, 12 to 44). Of the 7 relapsed patients, 5 were re-treated with a second cycle of 2-CdA; 2 achieved a second CR and 3 attained a PR. The progression- free survival (PFS) rate is 72% at 4 years for all 52 patients and 83% for patients achieving CR. The overall survival (OS) rate is 86% at 4 years. Only prior therapy was predictive of relapse. The majority of patients achieve durable CRs with a single cycle of 2-CdA. The relapse rate is low and the long-term prognosis is excellent. The few patients who relapse can attain second remissions after re-treatment with 2-CdA.     

Elimination of clonogenic stem cells from human multiple myeloma cell lines by a plasma cell-reactive monoclonal antibody and complement

The monoclonal antibody (MoAb) MM4 reacts with human multiple myeloma (MM) cell lines and bone marrow from patients with plasma cell dyscrasias but not with normal peripheral blood or bone marrow cells. Treatment with MM4 and rabbit complement (C') was cytotoxic to the plasma cell-derived cell lines GM 1312, RPMI 8226, and ARH-77, as demonstrated by chromium release microcytotoxicity and trypan blue exclusion assays. The same treatment eliminated greater than 99% of clonogenic myeloma stem cell colony formation of these cell lines, with less than 20% inhibition of normal human bone marrow pleuripotent progenitor colony formation in vitro. As an experimental model to explore the efficacy of MM4 + C' in purging MM-involved bone marrow, normal marrow cells were mixed with RPMI 8226 or GM 1312 cells in the ratio of 90:10 or 50:50 (marrow:myeloma cells). Colony growth assays indicated that MM4 + C' eliminated at least 2 logs of clonogenic myeloma stem cells in both 90:10 and 50:50 preparations, while sparing the majority of normal marrow progenitors (inhibition of CFU-C:10% to 13%; BFU-E:0%). The selectivity of MM4-mediated cytotoxicity may be useful for eliminating myeloma clonogenic stem cells from bone marrow of patients with multiple myeloma.     

Mast cells as rapid innate sensors of cytomegalovirus by TLR3/TRIF signaling-dependent and -independent mechanisms

The succinct metaphor, ‘the immune system''s loaded gun'', has been used to describe the role of mast cells (MCs) due to their storage of a wide range of potent pro-inflammatory and antimicrobial mediators in secretory granules that can be released almost instantly on demand to fight invaders. Located at host–environment boundaries and equipped with an arsenal of pattern recognition receptors, MCs are destined to be rapid innate sensors of pathogens penetrating endothelial and epithelial surfaces. Although the importance of MCs in antimicrobial and antiparasitic defense has long been appreciated, their role in raising the alarm against viral infections has been noted only recently. Work on cytomegalovirus (CMV) infection in the murine model has revealed MCs as players in a novel cross-talk axis between innate and adaptive immune surveillance of CMV, in that infection of MCs, which is associated with MC degranulation and release of the chemokine CCL5, enhances the recruitment of protective CD8 T cells to extravascular sites of virus replication, specifically to lung interstitium and alveolar epithelium. Here, we have expanded on these studies by investigating the conditions for MC activation and the consequent degranulation in response to host infection. Surprisingly, the data revealed two temporally and mechanistically distinct waves of MC activation: an almost instant indirect activation that depended on TLR3/TRIF signaling and delayed activation by direct infection of MCs that did not involve TLR3/TRIF signaling. Cell type-specific Cre-recombination that yielded eGFP-expressing reporter virus selectively originating from MCs identified MC as a new in vivo, first-hit target cell of productive murine CMV infection.     

应用经胸超声心动图评估快速左心耳起搏心房颤动模型心脏结构及功能的变化

目的:应用经胸超声心动图观察高频率左心耳起搏致猪慢性心房颤动模型心脏结构和功能的变化。方法:实验于2005-09/2006-08在南京医科大学第一附属医院江苏省实验动物中心完成。①12只苏钟种猪随机分为实验组及对照组各6只,所有动物均开胸,将起搏电极固定在左心耳根部,高频率脉冲发生器植入左侧胸部囊袋。实验组术后恢复1周后起搏器以500次/min的频率快速起搏左心耳8周;对照组始终不起搏。②术后心电图定期监测起搏、心房颤动的发生情况;于术前、起搏后1周、起搏后4,8周超声心动图观察实验动物左房内径、心室收缩及舒张末左房面积、左房和左室射血分数、左室舒张及收缩末内径、左心室短轴缩短率等变化。结果:①实验组5只完成了实验,术后2周复查心电图,1只动物发生房颤,起搏8周3只发生阵发性房颤,1只未发生房颤;对照组则未发生任何心律失常情况。②左心房相关指标:起搏后1周,实验组左房内径、收缩末期左心房面积和舒张末期左房容积均较起搏前增加[(2.70±0.12),(2.50±0.12)cm;(6.78±0.81),(6.21±0.93)cm2;(4.66±0.53),(3.78±0.57)mL;P均<0.05],左房射血分数较起搏前下降[(55.6±6.0)%,(63.8±4.0)%,P<0.01],至起搏4,8周,左房射血分数进一步降低,左房内径等指标则继续增大。③左心室相关指标:起搏后1周,实验组左室舒张、收缩末期内径较起搏前增加[(3.64±0.13),(3.46±0.15)cm;(2.48±0.08),(2.14±0.09)cm;P均<0.01],左心室短轴缩短率和左室射血分数较起搏前下降[(31.6±2.0)%,(37.8±3.0)%;(60.8±2.0)%,(69.2±4.0)%;P均<0.01];至起搏4,8周,左心室短轴缩短率和射血分数进一步降低,左室舒张、收缩末期内径则继续增大,与对照组比较也差异显著(P<0.05,0.001)。结论:①超声心动图是监测房颤模型建立过程中心房、心室结构和功能变化的有效手段。②高频起搏左心耳是建立猪心房颤动模型的有效方法,快速心房起搏可导致左心房左心室增大及心功能减退。     

自主研制镍钛记忆合金左心耳封堵器封闭左心耳对实验动物左心功能的影响

目的:应用经胸彩色多普勒超声技术评价自主研制的镍钛记忆合金左心耳封堵器封闭左心耳对实验动物猪左心房、左心室功能的影响。方法:实验于2005-09/2006-08在南京医科大学第一附属医院江苏省实验动物中心完成。①实验分组:选用苏钟小型种猪17只,随机分为实验组12只和对照组5只。②实验干预:实验组12只苏钟小型种猪使用自主研制的左心耳封堵器(发明专利号码:200610037789.3,公开号CN1799521,由镍钛合金骨架、多聚四氟乙烯膜和传送连接部分等构成。其外观呈单盘状,封堵器的左心房面呈圆盘状,直接连接放入心耳内的圆柱体结构)行左心耳封堵,对照组5只手术步骤相同而不采用封堵器行左心耳封堵。③实验评估:两组动物分别于术前、术后1周、2周、4周采用经胸超声心动图检查观察心功能的改变,测量左心房内径、最大及最小容积、左房射血分数、左心房搏出量、血流分数等左房功能参数以及左室射血分数、左室短轴缩短率、Tei指数、E/A比值等指标。结果:①实验动物数量分析:在施行左心耳封堵后,1头猪于术中出血过多并出现室颤后死亡,1头猪因封堵器脱入左房,卡在二尖瓣口导致死亡。其余动物封堵效果良好。②两组动物术后1,2,4周左房功能指标各参数与术前比较无明显变化(P>0.05);与术前相比,实验组术后1周、2周左室射血分数、左心室短轴缩短率、E/A比值分别由术前的0.70±0.04、0.39±0.03、1.33±0.28降低至术后1周的0.59±0.05、0.31±0.03、0.95±0.11(P<均0.01)及术后2周的0.62±0.05、0.33±0.05、0.90±0.05(P<均0.01);Tei指数由术前的0.48±0.02增加至术后1周的0.59±0.03(P<0.01)及术后2周的0.58±0.04(P<0.01)。对照组手术前后左室功能指标差异无显著性。结论:自主研制左心耳封堵器可以有效的封堵左心耳;左心耳封堵后短期内对实验动物左房功能无明显影响;封堵后短期内对左心室功能具有短期的减弱,更长期的安全性有待于进一步研究。