Blocking “don't eat me” signal of CD47-SIRPα in hematological malignancies,an in-depth review

Hematological malignancies express high levels of CD47 as a mechanism of immune evasion. CD47-SIRPα triggers a cascade of events that inhibit phagocytosis. Preclinical research supports several models of antibody-mediated blockade of CD47-SIRPα resulting in cell death signaling, phagocytosis of cells bearing stress signals, and priming of tumor-specific T cell responses. Four different antibody molecules designed to target the CD47-SIRPα interaction in malignancy are currently being studied in clinical trials: Hu5F9-G4, CC-90002, TTI-621, and ALX-148. Hu5F9-G4, a humanized anti-CD47 blocking antibody is currently being studied in four different Phase I trials. These studies may lay the groundwork for therapeutic bispecific antibodies. Bispecific antibody (CD20-CD47SL) fusion of anti-CD20 (Rituximab) and anti-CD47 also demonstrated a synergistic effect against lymphoma in preclinical models. This review summarizes the large body of preclinical evidence and emerging clinical data supporting the use of antibodies designed to target the CD47-SIRPα interaction in leukemia, lymphoma and multiple myeloma.     

The safety profile of vorinostat (suberoylanilide hydroxamic acid) in hematologic malignancies: A review of clinical studies

Histone acetyltransferases and histone deacetylases (HDACs) are multifunctional enzymes that posttranslationally modify both histone and nonhistone acetylation sites, affecting a broad range of cellular processes (e.g., cell cycle, apoptosis, and protein folding) often dysregulated in cancer. HDAC inhibitors are small molecules that directly interact with HDAC catalytic sites preventing the removal of acetyl groups, thereby counteracting the effects of HDACs. Since the first HDAC inhibitor, valproic acid, was investigated as a potential antitumor agent, there have been a number of other HDAC inhibitors developed to improve efficacy and safety. Despite significant progress in the management of patients with hematologic malignancies, overall survival is still poor. The discovery that HDACs may play a role in hematologic malignancies and preclinical studies showing promising activity with HDAC inhibitors in various tumor types, led to clinical evaluation of HDAC inhibitors as potential treatment options for patients with advanced hematologic malignancies. The Food and Drug Administration has approved two HDAC inhibitors, vorinostat (2006) and romidepsin (2009), for the treatment of cutaneous T-cell lymphoma. This review highlights the safety of HDAC inhibitors currently approved or being investigated for the treatment of hematologic malignancies, with a specific focus on the safety experience with vorinostat in cutaneous T-cell lymphoma.     

Health and Ecological Effects of Adiponitrile

Adiponitrile (ADN) has moderate acute toxicity with an oral LD₅₀ in rats of 100 to 500 mg/kg and a 4‐hr LC₅₀ in rats of 1.71 mg/L (vapor plus aerosol). ADN produced slight eye but no skin irritation in rabbits. Repeated exposures by inhalation produced changes in the hematologic profile with effects seen at 100 or 300 mg/m³. The hematologic changes were reversible upon cessation of further inhalation exposures. Dogs fed up to 500 ppm (equivalent to 12–15 mg/kg) showed no effects but 1,000 ppm produced vomiting and nausea which limited further testing at that concentration. ADN was not a genetic toxin, developmental toxin, reproductive toxin nor did it produce an increase in tumors in a 2‐yr drinking water study in rats. Human experience reports are limited to one accidental poisoning case and a few skin exposures resulting in transient irritation and inflammation. ADN is rapidly absorbed and excreted by mammals, and is metabolized to some extent although unchanged ADN is readily detected in urine, and does not bioaccumulate.     

脐血移植治疗37例儿童恶性血液病的临床研究-单中心经验

目的 探讨脐血造血干细胞移植（UCBT）治疗儿童恶性血液病的疗效。方法 回顾性分析接受UCBT 的37 例恶性血液病患儿的临床资料，包括急性淋巴细胞性白血病14 例，急性髓细胞性白血病9 例，幼年粒单细胞白血病5 例，慢性粒细胞白血病和骨髓增生异常综合征各3 例，急性混合型白血病2 例，淋巴肉瘤性白血病1 例。其中34 例非血缘相关，3 例血缘相关。HLA 配型6/6 相合5 例，5/6 相合12 例，4/6 相合11 例，3/6 相合9 例。移植中位年龄5.7 岁，中位体重20 kg。结果 中性粒细胞和血小板植入中位天数分别是12 d 和25 d，植入率分别为95% 和78%。中性粒细胞植入率与CD34+ 细胞数呈正相关（P=0.011）。血小板植入率与CD34+ 细胞数和有核细胞数均有关（分别P=0.001、0.014）。急性移植物抗宿主病（GVHD）的发生率为49%，慢性GVHD 为11%。随访中位时间54 个月，5 年移植相关病死率、总生存率和无病生存率分别为27%、57%和41%。结论 脐血移植是快速获得的造血干细胞来源之一，为恶性疾病患儿争取了治疗时间。     

PICC置管在恶性血液病患者中的应用

目的：规范经外周静脉置入中心静脉导管（PICC ）在恶性血液病患者治疗中的应用，促进PICC置管的安全、有效使用。方法2011年3月～2013年3月对137例需长期静脉输注药物的恶性血液病患者经外周静脉穿刺行 PICC置管进行全程护理。结果 PICC置管穿刺成功率100％，置管最长时间363 d ，最短7 d。经管给药顺利进行，拔管顺利。结论在置管前及置管后全程精心护理是PICC置管安全、有效、长时间留置的重要保证。     

Therapy Effect: Impact on Bone Marrow Morphology

This article highlights the most common morphologic features identified in the bone marrow after chemotherapy for hematologic malignancies, growth-stimulating agents, and specific targeted therapies. The key is to be aware of these changes while reviewing post-therapeutic bone marrow biopsies and to not mistake reactive patterns for neoplastic processes. In addition, given the development and prevalent use of targeted therapy, such as tyrosine kinase inhibitors and immune modulators, knowledge of drug-specific morphologic changes is required for proper bone marrow interpretation and diagnosis.     

女性血液系统恶性肿瘤的生殖保护策略

血液系统恶性肿瘤是造血系统的恶性疾病,发病率在患恶性肿瘤的年轻人中居首位.化疗是其早期治疗的主要手段,但这会对女性的卵巢结构和功能产生严重的甚至是不可逆的损害.因此,对于患有血液系统恶性肿瘤的妇女,既要保护其卵巢的生殖功能,又不能影响其原发病的治疗效果.目前可能有效的生殖保护手段是胚胎冷冻、卵子冷冻、卵巢及卵巢组织冷冻、卵巢移位、促性腺激素释放激素(GnRH)类似物、避孕药和激素疗法等.     

间充质干细胞治疗糖皮质激素耐药性慢性移植物抗宿主病临床疗效观察

Objective To assess whether treatment with mesenchymal stem cells (MSCs) is an effective adjunct therapy for refractory extensive chronic graft-versus-host disease (GVHD) resistant to conventional therapy. Methods 12 patients with steroid-resistant extensive chronic GVHD were treated with MSCs. One patient received one dose, 10 received two doses, and the remaining three doses. The MSCs were obtained from HI,A-identical sibling donors (n = 14), haploidentical donors (n = 2), unrelated mismatched donor (n = 1) and third-party HLA-mismatched donors (n = 7). Of the 11 patients treated with multiple infusions, 5 received cells derived from two donors. The median first dose of MSCs was 1.0 (0. 4-2. 1) × 106/kg , the median second dose was 1.2(0. 8-1.9) × 106/kg , and the third dose in one patient was 1.1 × 106/kg. Meanwhile the proportion of CD3+ ,CD4+,CD8+ ,CD19+,CD4+ CD25+ ,FOXP3+,FOXP3+CD4+ and FOXP3+ CD25+ was determined with double fluorescent-labeled antibodies and flow cytometry before and 4 weeks after the MSCs infusion. Results No patients had side-effects during or immediately after the infusions of MSCs. After a treatment course of one to three doses, 3 patients had complete response(CR), 6 showed partial response(PR) and 3 did not respond; the total effective rate was 75% (9/12). Complete resolution was seen in the involvement of skin (3/12), lung (1/3), joints (1/5), liver (3/10), oralcavity (4/12) and eye (2/7). Response rate was not related to donor HLA-match. 3 CR patients discontinued all of the immunosuppressive agents without relapse 100 to 292 days after the MSC infusion and 6 PR patients taped all immunosuppressive agents after 60 to 79 days. Mean follow-up period was 1152(795-1914) days, leukemia free survival rate was 91.7% (11/12) and the overall survival rate was 75% (9/12). The ratio of CD4/CD8 and the proportion of regulatory T cells were significantly higher than that before MSCs treatment. Conclusion Third-party MSCs were as effective as HLA-identical or haploidentical cells. This finding has practical implications and suggests that third-party cells can be prepared and stored frozen to be used for steroid-resistant extensive chronic GVHD therapy. It is concluded that MSCs may prevent the lethal cGVHD after allogeneic hematopoietic stem cell transplantation and raise the survival rate by increasing the ratio of CD4/CD8 and proportion of regulatory T cells in vivo.     

痰热清注射液治疗血液肿瘤并肺部感染有效性及安全性的Meta分析

目的 系统分析痰热清注射液治疗血液肿瘤合并肺部感染的有效性与安全性,为制订临床治疗策略提供依据。 方法 系统检索CBM、CNKI、维普、万方、Pubmed及Embase数据库,采用Cochrane协作网RCT质量评价标准评价纳入研究质量,Meta分析对提取的数据进行分析。 结果 纳入4个随机对照研究,血液肿瘤并肺部感染335例,痰热清注射液治疗组175例,抗生素治疗组160例,纳入研究质量一般; Meta分析合并OR或MD值分别为临床总体疗效1.05(0.92~1.20)、临床治愈0.93(0.68~1.26)、临床显效1.33(0.73~2.42)及临床有效1.00(0.74~1.33)、平均退热时间-0.06(-0.38~0.26)、平均肺部啰音消失时间0.21(-0.33~0.75)、肺部阴影缓解时间0.18(-0.19~0.54)、细菌阳性率1.02(0.45~2.33)及细菌清除率0.95(0.77~1.17), 指标差异均无统计学意义(P>0.05)。 结论 单独使用痰热清注射液治疗血液肿瘤并肺部感染的临床疗效、症状体征缓解及细菌清除效果较好,可能与单独使用抗生素效果相当,安全性较好,但尚需高质量证据予以进一步证实。     

Diagnostic yield of bronchoscopy with bronchoalveolar lavage in febrile patients with hematologic malignancies and pulmonary infiltrates

Infectious complications are a major cause of morbidity and mortality in immunosuppressed patients. Febrile patients with hematologic malignancies and pulmonary infiltrates have high mortality rates, especially if mechanical ventilation is required. The diagnostic value of fiberoptic bronchoscopy (FOB) with bronchoalveolar lavage (BAL) in these patients is controversial. We retrospectively analyzed the microbiological results of BAL samples obtained during 249 FOB examinations from 199 febrile patients with hematologic malignancies and pulmonary infiltrates (underlying diseases: acute leukemia 103 patients, lymphoma 84 patients, other malignancies 12 patients). Two hundred forty-six examinations could be evaluated. Seventy-three out of 246 BAL samples were sterile; 55 samples showed microbiological findings classified as contamination or colonization. One hundred eighteen samples showed positive microbiological results of bacteria and/or fungi classified as causative pathogens. Thereof, in 70 samples, only bacterial pathogens were detectable (Gram-positive, 35; Gram-negative, 30; mixed Gram-positive and Gram-negative, 5). Thirteen samples showed both fungi and bacterial pathogens. In 33 samples, only fungi were detectable, thereof, in 15 samples Aspergillus species, in 16 samples Candida species, and in 2 both. In two samples, a viral pathogen could be detected. Three nonlethal complications (bleeding, arrhythmia) occurred that required early termination of FOB. In 94 (38.2%) patient episodes, antibiotic treatment was modified as a result of microbiological findings in BAL samples. Our results show that FOB with BAL is a valuable diagnostic tool with low complication rates in high-risk febrile patients with hematologic malignancies and pulmonary infiltrates, contributing crucial results for the individual case, and also improving epidemiologic knowledge.