本文選題：噬血細胞淋巴組織細胞增生癥 + 血液系統(tǒng)腫瘤�。� 參考：《南京醫(yī)科大學(xué)》2017年博士論文

【摘要】：第一部分成人噬血細胞淋巴組織細胞增生癥目的成人噬血細胞淋巴組織細胞增生癥(AHLH)大部分為繼發(fā)性,少部分為遲發(fā)型FHLH。AHLH的臨床癥狀多種多樣,但是無特異性,一般表現(xiàn)為高熱、肝脾腫大、全血細胞減少、凝血功能異常、高甘油三酯血癥、高細胞因子血癥、高鐵蛋白血癥,高乳酸脫氫酶血癥及多器官功能衰竭等。目前為止尚未發(fā)現(xiàn)能夠預(yù)測其早期死亡的明確的參數(shù)。本文通過收集我院327例成人HLH的臨床資料并進行分析,探討其臨床特征、治療及識別與早期死亡相關(guān)的危險因素,加強臨床醫(yī)生對成人HLH的認識。方法收集患者的詳細臨床病例資料、實驗室檢查結(jié)果,以電話形式對患者進行隨訪,隨訪截止時間為2016-03-31。327例患者中,8例患者失訪,隨訪率97.6%。死亡日期作為研究截止日期,失訪或截止隨訪患者仍存活歸類為刪失(也稱截尾或終檢)。采用回顧性分析方法,計數(shù)資料以比例或百分比表示,采用Cox回歸模型對相關(guān)因素進行單因素分析,篩選出有統(tǒng)計學(xué)意義的因素行多因素分析,生存曲線由Kaplan-Meier法繪制并估計中位生存時間,組間生存率比較采用Log-Rank檢驗法,P0.05被認為有統(tǒng)計學(xué)意義。結(jié)果入組的327例患者中位年齡為53歲(18～93歲)。其中男181例,女146例。大多數(shù)患者起病時表現(xiàn)為發(fā)熱、肝、脾及淋巴結(jié)腫大和骨髓標(biāo)本中血細胞吞噬。133例(42%)患者在診斷后8周內(nèi)死亡。繼發(fā)性因素包括感染(n= 129;39%)、血液系統(tǒng)腫瘤(n=107;33%)、不明原因(n = 68;21%)和自身免疫性疾病(n = 21;7%)。本研究隨訪發(fā)現(xiàn)與早期死亡風(fēng)險因素包括(1)EBV-DNA陽性(HR3.594,95%CI;[1.443,8.952];P=0.001)、(2)低蛋白血癥(HR 1.10[1.01,1.20];P = 0.046)和(3)正電子發(fā)射斷層掃描(PET)的最大標(biāo)準(zhǔn)攝取值(SUVmax)在診斷≥14.9(HR6.802;[1.233,37.519];P = 0.028)。結(jié)論起病時患者EBV-DNA陽性、低白蛋白血癥和高SUVmax三者可預(yù)測成人HLH的早期死亡。如果出現(xiàn)這些高危因素,早期積極的干預(yù)可能使患者從中受益。第二部分自體造血干細胞移植在成人淋巴瘤相關(guān)的噬血細胞淋巴組織細胞增多癥中的應(yīng)用目的淋巴瘤相關(guān)的HLH(LAHS)特點是少見、異質(zhì)性強以及死亡率高。目前尚無標(biāo)準(zhǔn)治療方案可循。對于后續(xù)的移植,臨床報道極少,大部分參照兒童HLH的治療方案。對于大部分患者,臨床上選擇異基因造血干細胞移植來鞏固、強化治療,目標(biāo)為治愈該病,但是移植相關(guān)死亡率高、供體難尋以及年齡因素等因素限制其廣泛使用。自體造血干細胞移植(ASCT)在成人淋巴瘤相關(guān)的噬血細胞淋巴組織細胞增生癥(HLH)中的作用一直不明確。本文的目的在于探討ASCT治療HLH中的療效。方法2009年9月至2016年9月在我院血液科住院的LAHS經(jīng)化療聯(lián)合ASCT的患者有8例。8例中男3例、女5例,中位年齡為52.5歲(范圍:21～64歲),中位隨訪時間為10個月(18～59個月)�；颊邔Τ跏蓟煼桨赣行Р⑷〉镁徑夂�,給予動員采集外周血造血干細胞進行ASCT。7例患者的預(yù)處理方案為BEAM方案,另外1例為CBV方案�；仡櫺苑治�8例淋巴瘤相關(guān)的HLH患者使用自體造血干細胞移植治療的效果。結(jié)果患者起病的中位年齡為54.5歲(21～64歲);3例男性和5例女性。8例患者中,外周T細胞淋巴瘤為2例,5例為B細胞非霍奇金淋巴瘤(其中1例為彌漫大B細胞淋巴瘤),還有1例未明確細胞來源。在8例患者中,7例可見骨髓侵犯。所有患者的乳酸脫氫酶均升高。根據(jù)國際預(yù)后指數(shù),所有患者均為高�；颊�(高-中危4例;高危4例)。2例患者的EBV-DNA為陽性。7例患者接受劑量調(diào)整的EPOCH方案誘導(dǎo)化療,另1例為CHOP方案。如系B細胞淋巴瘤,則聯(lián)合利妥昔單抗治療。移植前患者經(jīng)過化療,6例患者取得了完全緩解(CR),2例取得部分緩解;移植后,8例患者均為完全緩解。沒有移植相關(guān)死亡發(fā)生。中位隨訪54.5個月(范圍:18～59月),所有患者均存活且處于CR中。結(jié)論一線選擇EPOCH方案后續(xù)以BEAM方案預(yù)處理行ASCT可能是一種有效的治療選擇,從而改善淋巴瘤相關(guān)HLH患者的預(yù)后。第三部分103例成人噬血細胞淋巴組織細胞增多癥的靶向基因測序研究目的噬血細胞淋巴組織細胞增多癥(HLH)分為原發(fā)性HLH與繼發(fā)性HLH兩種類型。原發(fā)性HLH通常好發(fā)于兒童,并可能具有殺傷細胞功能相關(guān)的基因突變。迄今為止,成人HLH是否具有原發(fā)性HLH相關(guān)性遺傳學(xué)異常尚不清楚。方法利用Illumina Miseq或Nextseq在103例成人HLH的進行了原發(fā)HLH相關(guān)基因測序。測序的基因包括PRF1、UNC13D、STXBP2、STX11、RAB27、LYST和AP3B1等18個基因,測序深度為1000×。在正常東亞人群中出現(xiàn)頻率低于1%的突變或變異位點納入進一步研究。結(jié)果入選的103例患者中,男63例,占61.2%;女40例,占38.8%,男、女比例為1.5:1。中位發(fā)病年齡為48歲,年齡范圍18～85歲之間。103例患者中,22例為感染相關(guān)HLH,61例為腫瘤相關(guān)(59例為淋巴瘤)HLH,3例為自身免疫性疾病相關(guān)HLH,17例患者為原因不明的成人HLH。共在43例患者中檢測到噬血相關(guān)基因的突變位點,其中1例患者具有純合突變位點(UNC1c.G2588A[P.G863D]),2例患者具有復(fù)合雜合突變,3例患者具有雙雜合位點突變。在檢測到的變異位點中,共有檢測到7個重現(xiàn)性變異位點,分別為UNC13D P.G863D、ITK p.R581 W、AP3B1p.T310A、STXBP2 p.T163M、UNC13D p.R411Q、LYST p.H123R及STX11 p.F281C突變。在這些位點中,其中UNC13D p.G863D在103例HLH的出現(xiàn)的頻率高于正常東亞人群(3/206[1.5%]對37/8638[0.4%],比值比[OR]4.514,95%可信區(qū)間[CI]1.054-11.28;p=0.0651),盡管該結(jié)果尚不具有統(tǒng)計學(xué)意義,AP3B1 p.T310A出現(xiàn)的頻率也顯著高于正常東亞人群(2/206 對 2/8648,OR 42.98,95%CI 5.938-302.5,p0.0001),ITKp.R581W的突變頻率在本組患者中的頻率也要高于正常東亞人群(4/206[2.0%]對70/8652[0.8%],OR 2.428,95%CI 0.878-6.715,p=0.093),此外 STX11 P.F281C的頻率在本組患者中出現(xiàn)的頻率也顯著高于東亞人群(2/206[0.97%]對1/8382[0.01%],OR160.0,p=0.0005),提示這些位點與HLH的發(fā)生相關(guān)。而對于STXBP2 p.T163M、UNC13D p.R411Q及LYSTp.H123R則沒有發(fā)現(xiàn)其分布頻率上在本組患者和東亞人群之間有顯著差異。結(jié)論成人HLH亦具有原發(fā)性HLH相關(guān)的遺傳學(xué)異常,利用靶向測序進行HLH相關(guān)基因篩查可以用于成人HLH的輔助診斷。
[Abstract]:The first part of adult hemophagocytic lymphoid cell lymphohistiocytosis, most of the adult hemophagocytic lymphohistiocytosis (AHLH) is secondary, and the clinical symptoms of a small part of the delayed type FHLH.AHLH are varied, but there is no specificity. The general manifestations are hyperthermia, liver and spleen enlargement, hemocytosis, abnormal coagulation function, and high glycerin oil three. Hyperglycemia, hyperferremia, Hyperferritinemia, hyperlactate dehydrogenase, and multiple organ failure have not been found so far. The clinical data of 327 adult HLH patients in our hospital were collected and analyzed to explore the clinical features, treatment and identification with early death. The risk factors of HLH were strengthened by clinicians. Methods the detailed clinical data of the patients were collected, the results of the laboratory examination were collected, and the patients were followed up with the telephone form. The follow-up deadline was 2016-03-31.327 patients, 8 cases were lost and the follow-up rate was 97.6%. The date of death was the deadline of study, the loss of visits or cut-off follow. The patients were still classified as Censorship (also called truncation or final examination). The retrospective analysis method was used, the count data were expressed in proportion or percentage, and the Cox regression model was used to analyze the related factors by single factor analysis. The factors of statistical significance were screened by multi factor analysis. The survival curve was drawn by Kaplan-Meier method and the median survival time was estimated. Between groups, the survival rate was compared with Log-Rank test, and P0.05 was considered to be statistically significant. Results the median age of 327 patients in the group was 53 years (18~93 years old), of which 181 were male and 146 female. Most of the patients showed fever, liver, spleen and lymph nodes were enlarged and the blood cell phagocytosis of.133 (42%) in the bone marrow specimens (42%) was 8 after diagnosis. The secondary factors included infection (n= 129; 39%), blood system tumor (n=107; 33%), unexplained cause (n = 68; 21%) and autoimmune diseases (n = 21; 7%). This study was followed up with (1) EBV-DNA positive (HR3.594,95%CI; [1.443,8.952]; P=0.001), and (2) low proteinemia (HR 1.10[1.01,1.20]; P = 0.046). And (3) the maximum standard uptake value (SUVmax) of positron emission tomography (PET) is more than 14.9 (HR6.802; [1.233,37.519]; P = 0.028). Conclusion patients with EBV-DNA positive, hypoalbuminemia, and high SUVmax three can predict early death of adult HLH. If these high-risk factors occur, early active intervention may lead to patients. Benefit. Second parts of autologous hematopoietic stem cell transplantation in adult lymphoma related hemophagocytic lymphohistiocytosis. Objective lymphoma related HLH (LAHS) characteristics are rare, heterogeneity and high mortality. There is no standard treatment yet to follow. Few clinical reports for subsequent transplantation, most of the references HLH treatment for children. For most patients, allogeneic hematopoietic stem cell transplantation is selected to consolidate and strengthen the treatment. The goal is to cure the disease, but the high mortality rate, difficult donor search, and age factors are widely used. Autologous hematopoietic stem cell transplantation (ASCT) is used in adult lymphoma related hemophagy. The role of cytosycyhistiocytic cell proliferation (HLH) is not clear. The purpose of this article is to explore the effect of ASCT in the treatment of HLH. Methods from September 2009 to September 2016, there were 8 cases of.8 cases in the Department of Hematology of our hospital in the Department of Hematology with ASCT, male 3, female 5, the median age of 52.5 years (range: 21~64 years), and the median follow-up time For 10 months (18~59 months). After the patients were effective and remission of the initial chemotherapy regimen, the preconditioning regimen of mobilizing and collecting peripheral blood hematopoietic stem cells for ASCT.7 patients was BEAM scheme and 1 cases were CBV. The results of 8 cases of lymphoma related HLH patients treated with autologous hematopoietic stem cell transplantation were retrospectively analyzed. The median age of the patient was 54.5 years (21~64 years); of 3 men and 5 women with.8, peripheral T cell lymphoma was 2, 5 cases were B cell non Hodgkin's lymphoma (1 of the diffuse large B cell lymphoma), and 1 undefined cell sources. In 8 patients, bone marrow invasion was seen. All patients with lactate dehydrogenase were all According to the international prognostic index, all patients were high risk patients (high risk 4 cases, high risk 4; high risk 4 cases), EBV-DNA was positive.7 patients received dose adjusted EPOCH regimen chemotherapy, the other 1 were CHOP scheme, such as B cell lymphoma, combined with rituximab. The pre transplant patients were treated with chemotherapy and 6 patients obtained Complete remission (CR), 2 cases had partial remission; after transplantation, 8 patients were completely remitted. No transplant related death occurred. The median follow-up was 54.5 months (range: 18~59 months), all patients survived and were in CR. Conclusion a first-line selection of EPOCH regimens followed by BEAM regimen preconditioning may be an effective treatment option, thereby modifying the treatment. The prognosis of HLH patients associated with good lymphoma. Third part 103 cases of target gene sequencing of hemophagocytic lymphohistiocytosis in adult patients. Target hemophagocytic lymphohistiocytosis (HLH) is divided into two types of primary HLH and secondary HLH. Primary HLH usually occurs in children, and may be associated with cytotoxic function. Gene mutation. To date, it is not clear whether adult HLH has primary HLH related genetic abnormalities. Methods the original HLH related genes were sequenced using Illumina Miseq or Nextseq in 103 adult HLH. The sequencing genes included PRF1, UNC13D, STXBP2, STX11, RAB27, and Miseq. The sequence was 1000 *. Among the 103 cases of common East Asia, there were more than 1% mutation or mutation sites in further study. Among the 103 patients enrolled, 63 were male, 61.2%, 40 women, 38.8%, male and female with 1.5:1. median age 48, and 18~85 years old among the patients, 22 were infection related HLH, 61 cases were tumor related (59 cases) Lymphoma) HLH, 3 cases of autoimmune disease related HLH, 17 cases of unexplained adult HLH. in 43 patients with the detection of mutation site of the blood related genes, of which 1 cases have homozygous mutation site (UNC1c.G2588A[P.G863D]), 2 cases with complex heterozygous mutation, 3 cases with double heterozygous site mutation. In the locus of variation, 7 reproducible loci were detected, such as UNC13D P.G863D, ITK p.R581 W, AP3B1p.T310A, STXBP2 p.T163M, UNC13D p.R411Q, LYST p.H123R and mutation. 4%], the ratio Ratio [OR]4.514,95% confidence interval [CI]1.054-11.28; p=0.0651), although the results are not statistically significant, the frequency of AP3B1 p.T310A appears significantly higher than the normal East Asian population (2/206 versus 2/8648, OR 42.98,95%CI 5.938-302.5, P0.0001), and the frequency of mutation is higher in this group than in the normal East Asia. The frequencies of the group (4/206[2.0%] to 70/8652[0.8%], OR 2.428,95%CI 0.878-6.715, p=0.093), and the frequency of STX11 P.F281C in this group were also significantly higher than those in the East Asian population (2/206[0.97%] for 1/8382[0.01%], OR160.0, p=0.0005). R did not find a significant difference in the frequency of distribution between the patients in this group and the East Asian population. Conclusion the adult HLH also has the genetic abnormalities associated with primary HLH, and the targeted sequencing of HLH related genes can be used for the adjuvant diagnosis of adult HLH.

【學(xué)位授予單位】：南京醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R733.1;R55

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本文編號：1863530