Overview of the Mutational Landscape in Primary Myelofibrosis and Advances in Novel Therapeutics

Primary Myelofibrosis is a BCR-ABL negative myeloproliferative neoplasm with a variety of hematologicalpresentations, including thrombosis, bleeding diathesis and marrow fibrosis. It is estimated to have an incidence of1.5 per 100,000 people each year. Although JAK2 or MPL mutations are seen in PMF, several other mutations haverecently been documented, including mutations in CALR, epigenetic regulators like TET, ASXL1, and 13q deletions.The identification of these mutations has improved the ability to develop novel treatment options. These include JAKinhibitors like ruxolitinib, heat shock protein-90 inhibitors like ganetespib, histone deacetylase inhibitors includingpanobinostat, pracinostat, vorinostat and givinostat, hypomethylating agents like decitabine, hedgehog inhibitors likeglasdegib, PI3K, AKT and mTOR inhibitors like everolimus as well as telomerase inhibitors like imtelstat. Researchon novel therapeutic options is being actively pursued in order to expand treatment options for primary myelofibrosishowever currently, there is no curative therapy other than allogenic hematopoietic stem cell transplantation (ASCT)which is possible in select patients.     

Thrombocytosis at secondary cytoreduction for recurrent ovarian cancer predicts suboptimal resection and poor survival

Objectives

A growing body of evidence supports a role for thrombocytosis in the promotion of epithelial ovarian cancer biology. However, studies have only linked preoperative platelet count at time of initial cytoreductive surgery to clinical outcome. Here, we sought to determine the impact of elevated platelet count at time of secondary cytoreductive surgery (SCS) for recurrent disease.

Methods

Under an IRB-approved protocol, we identified 107 women with invasive epithelial ovarian cancer who underwent SCS between January 1997 and June 2012. We reviewed clinical, laboratory, and pathologic records from this retrospective cohort. The data was analyzed using the chi-squared, Fisher's exact, Cox proportional hazards, and Kaplan–Meier tests. We defined thrombocytosis as a platelet count ≥ 350 × 10⁹/L and optimal resection at SCS as microscopic residual disease.

Results

Thirteen of 107 women (12%) with recurrent ovarian cancer had thrombocytosis prior to SCS. Preoperative thrombocytosis at SCS was associated with failure to undergo optimal resection (p = 0.0001). Women with preoperative thrombocytosis at time of SCS demonstrated shorter overall survival (33 months) compared to those with normal platelet counts (46 months, p = 0.004). On multivariate analysis, only preoperative platelet count retained significance as an independent prognostic factor (p = 0.025) after controlling for age at SCS (p = 0.90), disease free interval from primary treatment (0.06), and initial stage of disease (0.66).

Conclusions

Elevated platelet count at time of SCS is associated with suboptimal resection and shortened overall survival. These data provide further evidence supporting a plausible role for thrombocytosis in aggressive ovarian tumor biology.     

The possible value of platelet aggregation studies in patients with increased platelet number

Summary ADP, adrenalin and collagen platelet aggregation studies were performed in 54 patients with elevated platelet counts: 38 patients showed primary thrombocythemia and 16 secondary thrombocytosis. Patients with primary thrombocythemia (78.7%) showed a decreased aggregation pattern while in patients with secondary thrombocytosis platelet aggregation response was entirely normal. An increase in platelet aggregation was obtained in four patients with primary thrombocythemia. The platelet aggregation response did not appear to be related to circulating platelet number. A relationship between increased platelet aggregation and the occurrence of thrombosis was demonstrated. Similarly, a correction between impaired platelet aggregation and bleeding was also present. These results emphasize the diagnostic value of platelet aggregation studies in patients with elevated platelet number.Supported by grants from the M.P.I., Rome (grant 1592–1979), from the C.N.R., Rome (grant 78.012123.04) and from the Venetian Regional Government, Venice.     

严重多发伤并发继发性血小板增多症的临床分析

目的 总结分析严重多发伤并发继发性血小板增多症的发病特征及对预后的影响,探讨适宜的干预措施.方法 回顾性分析重庆市急救医疗中心创伤数据库中2010年3月至2013年3月共680例存活超过72 h的严重多发伤患者临床资料.总结严重多发伤并发继发性血小板增多症(血小板计数＞450×109 L-1)的发病率、时间特征及相关因素,分析其对严重多发伤患者总住院病死率、总住院时间及血栓栓塞事件(包括静脉血栓栓塞事件和动脉血栓栓塞事件)等预后指标的影响.计量资料间比较采用t检验或秩和检验,百分数或率的比较采用x2检验或Fisher精确检验.结果 本组严重多发伤并发继发性血小板增多症的发病率为14.56％,血小板计数中位数为584×109 L-1(最低478×109 L-1,最高1 072×109 L-1);血小板增多均发生在病程1周以后,中位时间点为第27天(最早8d,最晚304 d),持续时间(18.62±4.38)d.继发性血小板增多组的脾切除比例、使用血管活性药物超过48 h、使用刺激骨髓造血药物及7d后预防性抗凝治疗比例显著高于血小板正常组(14.14％ vs.7.06％,P=0.03;62.63％ vs.39.07％,P＜0.01; 28.28％vs.6.71％,P＜0.01;90.91％ vs.19.45％,P＜0.01).血小板增多组患者血小板增多期间最高血浆D-二聚体(mg/L)显著高于血小板正常组患者1周后的最高水平[(11.68±11.90) vs.(5.05±5.11),P=0.004].两组的总住院病死率(8.08％ vs.8.78％,P=0.82)、总住院时间[34 d(28.5,54.5)d vs.45 d(23,67)d,P=0.41]、总血栓栓塞事件(10.10％ vs.10.50％,P=0.91)及静脉血栓栓塞事件(7.07％ vs.7.92％,P=0.77)差异无统计学意义;血小板增多患者动脉血栓栓塞事件有增多趋势(4.04％ vs.3.10％,P=0.62),但差异无统计学意义.结论 严重多发伤并发继发性血小板增多症的发生率较高.创伤后脾切除、较长时间使用血管活性药物及使用刺激骨髓造血药物等因素可能诱发继发性血小板增多.在没有充分抗凝治疗情况下,继发性血小板增多可能增加严重多发伤患者的血栓栓塞事件;对于存在动脉血栓风险患者可考虑联合抗血小板治疗.     

L’érythromélalgie : approche diagnostique et thérapeutique actuelle

Erythromelalgia is a rare intermittent vascular acrosyndrome characterized by the combination of recurrent burning pain, warmth and redness of the extremities. It is considered in its primary form as an autosomal dominant neuropathy related to mutations of SCN9A, the encoding gene of a voltage-gated sodium channel subtype Nav1.7. Secondary erythromelalgia is associated with myeloproliferative disorders, drugs (bromocriptine, calcium channel blockers), or clinical conditions such as rheumatic diseases or viral infection. Primary familial erythromelalgia include genetics and sporadic forms associated with small fibers neuropathy. Aspirin is a useful treatment of erythromelagia associated with myeloproliferative disorders. Treatment of primary erythromelalgia is difficult, individualized, with sodium channel blockers such as lidocaine, carbamazepine and mexiletine.     

比阿培南致继发性血小板增多症1例报道并碳青霉烯抗生素不良反应文献复习

【】 目的：提高对碳青霉烯抗生素不良反应的认识。方法：报道1例外伤并感染患者使用比阿培南而导致继发性血小板增多症,并且复习碳青霉烯类抗生素不良反应相关文献。结果：停用比阿培南一周后,该患者血小板逐渐降至正常。结论：碳青霉烯类抗生素有可能引起血小板增多症,临床需关注由此可能导致的血管栓塞等不良反应。     

Thrombocytosis in splenic trauma: In-hospital course and association with venous thromboembolism

IntroductionThrombocytosis is common following elective splenectomy and major trauma. However, little is known about the in-hospital course of platelet count (PC) and incidence of thrombocytosis after splenic trauma. Extreme thrombocytosis (PC > 1000 × 10⁹) is associated with increased risk of venous thromboembolism (VTE) in primary thrombocytosis leading to the use of acetylsalicylic acid (ASA) for risk reduction, but the need for this agent in splenic trauma is undefined.MethodsRetrospective cohort study of all patients with splenic trauma between April 1, 2010 and March 31, 2014. The in-hospital course of PC was assessed based on splenic injury management type. The association of management type with thrombocytosis was evaluated using a multivariable logistic regression model adjusting for potential confounders. The association of thrombocytosis, extreme thrombocytosis, and ASA use for the outcome of VTE was explored.Results156 patients were eligible, PC initially increased in all patients with the highest peak after total splenectomy. The incidence of thrombocytosis was 41.0% (64/156). Thrombocytosis was more likely following splenectomy compared with spleen preserving strategies independent of length of stay, injury grade, ISS, age and transfusion (OR 7.58, 95% CI: 2.26–25.45). Splenectomy was associated with extreme thrombocytosis (OR 10.39, 95% CI: 3.59–30.07).ConclusionsThrombocytosis in splenic trauma is more likely after splenectomy than with spleen preserving strategies. Splenectomy is associated with extreme thrombocytosis. There was insufficient data in our study to determine the use of ASA as primary prevention of VTE after splenic trauma.     

血小板衍生生长因子BB在川崎病血小板增多中的作用及机制研究

目的 通过体内外实验探究血小板衍生生长因子BB (platelet-derived growth factor BB,PDGF-BB)对川崎病（Kawasaki disease,KD）小鼠和人巨核细胞株Dami细胞生成血小板的作用及机制。方法 ELISA检测KD及健康儿童各40例血清PDGF表达水平。C57BL/6小鼠构建KD模型,随机分为正常组、KD组、伊马替尼组,每组30只。检测各组血常规及PDGF-BB、巨核细胞集落形成单位（megakaryocyte colony forming unit,CFU-MK）、巨核细胞标记物CD41表达。采用CCK-8、流式细胞术、实时定量PCR、Western blot检测PDGF-BB对Dami细胞生成血小板的作用和机制。结果 PDGF-BB在KD患儿血清中高表达（P<0.001）。KD组小鼠血清PDGF-BB高表达（P<0.05）、CFU-MK及巨核细胞标记物CD41表达增加（P<0.001）;伊马替尼组CFU-MK及CD41表达减少（P<0.001）。体外实验结果显示,PDGF-BB促进Dami细胞增殖、血小板生成、...     

伴多中心Castleman病和血小板增多症的POEMS综合征一例

患者男,48岁,入院前3年无明显诱因出现持续性四肢肌肉疼痛、无力;皮肤感觉异常,呈烧灼感,肤色逐渐加深、粗糙;下肢皮肤增厚略发硬,表面呈蛇皮状外观.2年前查肌电图示周围神经病;CT示肝、脾、淋巴结肿大,腹水,胸腔、心包积液.取多个淋巴结活检:淋巴滤泡间血管明显增生,并累及淋巴滤泡,结合组化及特殊染色,提示为Castleman病,透明血管型.3个月前,双大腿出现红斑,逐渐扩大,并出现疼痛感,进而皮损中央颜色逐渐加深变黑,皮损周围皮肤发红;2个月前右大腿内侧出现一黄豆大小结节,破溃,留少许脓液,而后形成浅溃疡.体检:下肢肌肉略萎缩,双上肢肌力5级,双下肢肌力4级.躯干、四肢皮肤粗糙,弥漫性颜色加深,四肢皮肤呈现鱼鳞病样外观,皮肤弥漫性增厚,均以四肢皮肤为著.双大腿内侧均可见约5 cm×2 cm的紫黑色斑片,中央表面粗糙,呈糙纸样外观,表面附有干燥结痂及脱屑,皮损周围皮肤呈环状淡紫红色晕,压之褪色.实验室检查提示甲状腺功能减退、血胰岛素分泌水平降低以及钙磷代谢异常,血清免疫固定电泳IgG型轻链M带弱阳性;多次复查外周血,血小板呈进行性升高.诊断:PEOMS综合征伴多中心Castleman病、血小板增多症.治疗:口服甲泼尼龙和沙利度胺等治疗后,POEMS综合征主要症候群均得到有效改善,但血小板增多现象反而逐渐加重.