非M3型急性髓系白血病细胞遗传学及分子生物学特征及预后分析

目的：探讨和分析非M3型急性髓系白血病（Acute myeloid leukemia, AML）细胞遗传学及分子生物学特征以及预后影响因素。方法：回归性分析我院99例非M3型初治AML患者临床及实验室数据,探讨和分析患者性别、年龄、初诊时白细胞数、血小板数、有无贫血、乳酸脱氢酶水平、染色体核型以及融合基因等因素对AML患者无疾病进展生存时间（Disease free survival, DFS）及总体生存时间（Overall survival, OS）的影响。结果：患者中位发病年龄为44岁（1-84）,中位随访时间为12.6月（0.33-59.47）,化疗后达完全缓解（complete remission, CR）率为62.7%,复发率为44.1%。不同年龄段患者CR率有明显差异（P=0.035）;单因素及多因素分析显示老年及染色体数目异常为AML患者OS的独立预后不良因素,t(8,21)/inv(16)系其独立预后良好因素。结论：老年及染色体数目异常为非M3型AML患者独立预后不良因素;t(8,21)/inv(16)是其独立预后良好因素。AML临床应结合年龄、细胞遗传学及分子生物学等预后因素进行预后评估,据此制定个体化治疗,对延长患者生存时间,提高生活质量,具有重要指导意义。     

214例急性髓细胞白血病染色体改变及预后分析

目的应用染色体核型分析技术,研究急性髓细胞白血病（AML）染色体改变与预后的关系。方法根据细胞遗传学改变,将214例初诊AML患者分为4组：伴t（15;17）改变患者为A组;伴t（8;21）/inv（16）改变患者为B组;正常核型及无其他组染色体改变为C组;伴t（9;22）或-7或复杂核型为D组,对各组患者进行预后分析。结果 214例AML患者染色体畸变率为57.01%。214例患者的平均生存时间为（13.16±8.497）月,A、B、C、D各组3年生存率分别为97.30%、86.36%、72.04%、47.5%,差异具有统计学意义（P值为0.001）。结论染色体是AML独立的预后因素,用于诊断及预后分析,有利于个体化治疗。     

诱导缓解期残留白血病细胞比例在中间核型急性髓系白血病中的预后价值

目的 评价诱导缓解期残留白血病细胞比例在中间核型急性髓系白血病(AML)的预后价值.方法 60例中间核型AML患者在诱导缓解化疗末(T1时点)及骨髓抑制期(T2时点)取骨髓涂片行形态学检查,分析不同时点骨髓白血病细胞比例对完全缓解(CR)、无病生存(DFS)及总体生存(OS)的影响.结果 单个时点(T1或T2)白血病细胞比例划分的2组CR率、3年DFS及3年OS比较差异均有统计学意义(P＜0.05),多变量分析显示单时点的白血病细胞比例是影响CR、DFS、OS的独立预后因素(P＜0.01).联合两个时点的白血病细胞比例划分的4组在CR率、3年DFS及3年OS差异均有统计学意义(P＜0.01).结论 联合两时点的白血病细胞比例可对中间核型AML再精确分组,指导个体化治疗.     

pT4aN0M0期胃癌预后的影响因素分析

目的 探讨影响pT_4aN₀M₀期胃癌预后的相关因素。方法 回顾性分析57例行根治性手术治疗且术后病理分期为pT_4aN₀M₀的胃癌患者临床病理资料，比较病理特征与临床预后的关系。结果 pT_4aN₀M₀期胃癌患者发病年龄多≥60岁，男性多于女性，BMI多低于24 kg/m²，肿瘤部位多位于胃中上部；肿瘤大小≥5 cm、阴性淋巴结数目≥15个、术后辅助化疗、肿瘤分化程度与pT_4aN₀M₀期胃癌预后相关（r=0.266，0.478，0.971，0.515，P<0.05，）；COX模型多因素分析显示，肿瘤大小、阴性淋巴结数目、术后辅助化疗、肿瘤分化程度是影响其预后的独立危险因素（P<0.05）。结论 肿瘤大小、阴性淋巴结数目、术后辅助化疗、肿瘤分化程度可能与pT_4aN₀M₀期胃癌患者预后有关，其中术后辅助化疗是最重要因素。     

Fms样酪氨酸激酶3表达对评估急性髓系白血病预后的意义

目的 探讨Fms样酪氨酸激酶3(FLT3)表达对评估急性髓系白血病(AML)预后的意义.方法 选取AML患者50例,其中核型正常的AML患者20例,核型异常的AML患者30例.分别于化疗前抽取骨髓3 ml,用PCR方法检测白血病细胞FLT3的表达情况.结果 核型正常的AMLFLT3的表达率为5.0％,核型异常的AMLFLT3的表达率为26.7％.难治复发的AMLFLT3的表达率是33.3％,持续完全缓解的AMLFLT3的表达率是4.5％.FLT3的表达情况与骨髓中高白血病细胞所占比例和高外周血白细胞计数有关,与FAB亚型无关.有FLT3表达的AML患者无病生存(DFS)和总体生存(OS)时间短,无FLT3表达的AML患者DFS和OS时间长,二者差异有统计学意义(x2=4.17,P＜0.05).结论 FLT3是AML患者预后不好的因素,可以指导临床个体化治疗AML.     

老年初治非转移鼻咽癌的预后分析

目的探索老年初治非转移鼻咽癌的预后因素。方法选择我院收治的98例年龄≥70岁的鼻咽癌患者为研究对象,主要研究终点为总生存时间(OS)。采用Kaplan-Meier法模拟生存曲线,COX比例风险模型进行多因素分析。结果患者3年和5年OS分别为74.3%和54.3%。多因素分析显示,年龄、KPS评分和ACE-27评分是患者OS的独立预后因素,其中年龄≥75岁(HR=2.315,P=0.009)、KPS评分<80分(HR=2.258,P=0.025)和ACE-27评分2~3分(HR=3.349,P<0.001)为不良预后因素。结论年龄、KPS评分和ACE-27评分为老年鼻咽癌患者的重要预后因素,治疗前需充分评价患者一般状况与合并症情况。     

伴t(8;21)急性髓系白血病的特征及预后因素分析

目的探讨伴t(8;21)急性髓细胞白血病的临床特征及预后影响因素。方法回顾分析50例我院伴有t(8;21)AML患者的临床特征,包括血象、细胞形态学、染色体、融合基因等,并分析预后影响因素。结果 50例患者中,男性32例,女性18例,平均中位年龄45岁,初诊时中位白细胞计数18.6×10~9/L,中位血红蛋白54 g/L,中位PLT 23×109/L。中位原始幼稚细胞54%。M2 45例(占90%),M5 3例(占6%),M4 2例(占4%)。32例(64%)为单纯t(8;21),无附加染色体异常,18例(36%)为具有附加染色体异常。21例行AML/ETO融合基因测定的病例中,21例均存在AML/ETO阳性。在18例进行c-kit基因测定中5例伴c-kit阳性,13例阴性。CR率90%。截止到随访日期,25例死亡(50%),25例存活(50%)。其中2年OS为60%,5年存活50%。结论性别、年龄、初诊时血红蛋白、血小板数、骨髓幼稚细胞比例等因素与预后无相关性。附加染色体、伴c-kit基因、初诊时白细胞数≥20×10~9/L是影响患者OS的不良预后因素,异基因造血干细胞移植可提高OS率。     

放疗在美罗华时代对局限期原发韦氏环弥漫大B细胞淋巴瘤的治疗价值

目的 分析在美罗华联合化疗背景下,放疗对局限期韦氏环弥漫大B细胞淋巴瘤的治疗价值。方法 收集2010年—2017年收治的93例Ⅰ-Ⅱ期原发韦氏环弥漫大B细胞淋巴瘤患者的临床资料,将仅接受美罗华联合CHOP或CHOP类似方案化疗的38例患者分为单纯化疗组,将接受化疗+巩固放疗的55例患者分为综合治疗组。采用Kaplan-Meier法计算无进展生存（PFS）、总生存（OS）、局部区域控制率（LRC）,并行单因素分析;采用Log-rank法检验两组患者生存差异,并行Cox多因素回归分析。结果 本研究患者随访中位时间47个月,3年存活病例67例。单纯化疗组和综合治疗组患者的3年PFS分别为76.1%和94.2%（P=0.036）,3年OS分别为78.6%和96.0%（P=0.032）,3年LRC分别为83.1%和98.1%（P=0.015）。其中62例化疗后疗效评估为完全缓解（CR）的患者中,单纯化疗组和综合治疗组的3年PFS、OS和LRC分别为87.8%和97.6%（P=0.164）、93.8%和97.4%（P=0.522）、87.8%和100.0%（P=0.028）。进一步单因素分析结果显示,年龄>60岁和化疗疗效未达CR是PFS和OS的不良预后因素,B症状和化疗疗效未达CR是LRC的不良预后因素。多因素分析结果显示,年龄>60岁、B症状、化疗疗效未达CR是患者PFS的不良预后因素,年龄>60岁、化疗疗效未达CR是OS的不良预后因素,B症状、化疗疗效未达CR和未放疗是LRC的不良预后因素。结论 Ⅰ-Ⅱ期原发韦氏环弥漫大B细胞淋巴瘤采用美罗华联合CHOP为主的化疗后的巩固性放疗可显著改善患者的PFS、OS和LRC,但仍需大样本和前瞻性研究进一步证实。     

LC/DAD/MSD技术研究大鼠服药胆汁中盐酸非洛普I相代谢产物

目的　研究大鼠服药后胆汁中盐酸非洛普(DDPH)I相代谢物。方法　大鼠做胆管插管,分别收集ipDDPH之前的空白胆汁及服药后12h内的服药胆汁,将大鼠胆汁以葡糖醛酸酶水解后进C-18SPE小柱进行纯化富集,再进行LC/DAD/MSD分析;同时将合成的6个DDPH模拟代谢物M₁-M₆的对照品混合液按相同条件进行LC/DAD/MSD分析对照。结果　大鼠服药胆汁色谱图中峰A,B,C,D,E和F分别与M₁,M₂,M₃,M₅,M₄和M₆的保留时间、紫外吸收光谱、分子量及碎片离子完全一致。结论　M₁,M₂,M₃,M₄,M₅和M₆为大鼠ipDDPH后产生的体内I相代谢物。     

CC类趋化因子22、叉头框蛋白P1在急性髓系白血病外周血中的表达及对预后的预测价值

目的 探讨急性髓系白血病（AML）病人外周血中CC类趋化因子22(CCL22)、叉头框蛋白P1(FOXP1)表达水平及其预后预测价值。方法 选择2018年5月至2019年5月在孝感市中心医院、华中科技大学医学院附属同济医院及咸宁市中心医院确诊的68例AML病人设为观察组,另取同期健康体检者68例作为对照组,采用酶联免疫法测定外周血CCL22,FOXP1表达水平,分析其与临床特征的关系;采用Pearson法分析AML病人外周血中CCL22,FOXP1表达的相关性;采用Kaplan-Meier生存分析法分析CCL22,FOXP1表达与总体生存时间（OS）的关系;采用Cox比例风险回归模型分析病人预后死亡的影响因素。结果与对照组相比,观察组CCL22[(600.27±62.89)ng/L比（756.84±100.86）ng/L],FOXP1[(56.02±13.68)ng/L比（103.06±22.16）ng/L]表达均明显升高（t=10.86,14.90,均P<0.05）;CCL22,FOXP1表达水平与AML病人年龄、性别、染色体预后、血红蛋白（HGB）、血小板计数（PLT）、FM...     

Association of nitric oxide synthase 3 (NOS3) 894 G>T polymorphism with prognostic outcomes of anthracycline in Chinese patients with acute myeloid leukaemia

The aim of the present study was to investigate the influence of the nitric oxide synthase 3 (NOS3) 894 G>T polymorphism on prognostic outcomes of anthracycline in Chinese patients with de novo intermediate‐risk acute myeloid leukaemia (AML) and to examine the gene expression level in relation to genetic variation. In all, 225 Chinese patients with intermediate‐risk AML (at the complete remission stage) treated with anthracycline were enrolled in the study. The 894 G>T polymorphism of the NOS3 gene was analysed by allele‐specific matrix‐assisted laser desorption ionization time‐of‐flight. Expression of NOS3 mRNA was tested in 72 patients of known genotype for NOS3 894 G>T. The clinical characteristics of these patients were obtained from medical records. Survival analysis showed that patients with AML (GG genotype) had a longer overall survival (OS; P = 0.006). After adjusting for age, gender, leucocyte count, haemoglobin level, platelet level, French, American and Britain (FAB) classification, lactate dehydrogenase levels, Eastern Cooperative Oncology Group Performance Status, nucleophosmin gene and fms‐related tyrosine kinase 3 gene, multivariate survival analysis showed that the NOS3 894 G>T polymorphism appeared to be a predicting factor for OS (P = 0.014; hazard ratio = 1.856). However, no significant associations between the NOS3 894 G>T polymorphism and relapse‐free survival and relapse in patients with AML were observed. Gene expression levels were significantly higher in patients with the GG genotype than in patients with the GT and TT genotypes (P = 0.033). The findings suggest that the NOS3 894 G>T variant may be a biomarker for the prediction of OS in Chinese patients with AML.     

Flexible low-intensity combination chemotherapy for elderly patients with acute myeloid leukaemia: a multicentre, phase II study

OBJECTIVE: To evaluate the efficacy of a flexible low-intensity combination chemotherapy (FLICC) protocol in a multicentre, phase II study of elderly patients with acute myeloid leukaemia (AML). METHOD: Twenty-five patients aged 61-78 years (median 70 years) with de novo (n = 17) or secondary (n = 8) AML (cytogenetic risk: favourable 2, intermediate 18, adverse 2, unknown 3) from eight Australian centres were enrolled. Treatment comprised mitoxantrone 6 mg/m(2) intravenously daily for 3 days, cytarabine 10mg/m(2) subcutaneously every 12 hours for 7-14 days and etoposide 100mg orally for 7-14 days. RESULTS: The treatment was generally well tolerated, and 13 patients (52%) achieved a complete remission (CR). One patient achieved a partial remission but died on day 28 due to pneumonia. Five patients (20%) had no response, whilst six (24%) died on or before day 30 and so were not evaluable. The median overall survival (OS) was 6.5 months, and the median remission duration was 7.7 months. Estimated 1-year survival was 32%, but patients achieving CR had an estimated 1-year survival of 64%, whereas none in the non-CR group survived to 1 year. Two of the CR patients have survived beyond 2 years. OS was significantly shorter in the adverse cytogenetic risk group of patients compared with the favourable- and intermediate-risk groups, with the rates of death relative to the adverse group being 0.02 and 0.08 in the favourable- and intermediate-risk groups, respectively. There was no significant association between CR rate and pre-existing myelodysplasia or the presence of multilineage dysplasia.The median durations of significant neutropenia (<0.5 x 10(9)/L) and thrombocytopenia (<20 x10(9)/L) with the first course of treatment in the 19 evaluable patients were 19 days (range 12-26) and 11 days (range 1-25), respectively. The median duration of stay in the hospital was 27 days (range 14-42). These values were much shorter for the second course of treatment: 6 days, 5 days and 15 days, respectively. CONCLUSION: The findings of this multicentre, phase II study validate the previously reported single-institution experience with the FLICC protocol in elderly patients with AML. The clinical outcome with this protocol is comparable to those reported with more aggressive anti-leukaemia protocols.     

t（8；21）急性髓系白血病的特征及预后分析

目的探讨t（8;21）急性髓系白血病的特征及预后。方法回顾性分析80例初治t（8;21）AML患者,包括细胞遗传学G显带核型、免疫表型、细胞形态学、AMLl／ETO融合基因、血象、乳酸脱氢酶（LDH）值及临床特征,并分析其预后因素。按染色体核型把患者分为单纯t（8;21）组（48例）、伴附加染色体异常组（32例）。结果80例t（8;21）AML患者中M：77例,M4 1例,M4EO2例;流式细胞仪检测t（8;21）AML患者免疫分型阳性率为：CD3481．48％、CDl3：96．29％、CD33：83．33％、HLA—DR90．74％、CD19：48．15％、CD56：55．55％;遗传学：48例（60．00％）为单纯t（8,21）,32例（40．00％）有附加染色体异常,其中25例（31．25％）伴单纯性染色体丢失,7例（8,75％）为复杂变异型t（8;21）易位;初治时单纯t（8,21）组和伴有附加染色体组的年龄、性别、外周血和骨髓原始细胞数、血红蛋白（Hb）和血小板（PLT）计数、Auer小体、肝脾淋巴结浸润、LDH值、皮肤黏膜出血均无统计学意义（P均〉0．05）;伴有附加染色体组的外周血白细胞（WBC）计数和CD56阳性率均低于单纯组（P均〈0．05）。伴附加染色体组与单纯组的CR率无明显差异（P〉0．05）;伴附加异常组的中位生存时间低于单纯t（8;21）组（P〈0．05）。6例伴有髓外浸润患者的CR率和3年Os率均为0。结论伴附加染色体组与单纯t（8,21）组AML的临床特征有差异,附加染色体异常是t（8;21）AML的一种预后不良因素,伴有附加染色体异常的t（8;21）AML生存时间短于单纯t（8;21）者。     

Significance of GRP78 expression in acute myeloid leukemias

The GRP78 (glucose-regulated protein 78) is a major endoplasmic reticulum (ER) chaperone facilitating proper folding of the newly synthesized proteins. By the interaction with caspases, GRP78 has antiapoptotic properties allowing cells to survive under stress condition. GRP78 expression and its association with tumor proliferation, metastasis and resistance to chemotherapy were observed in solid tumors. There are limited data on the expression and impact of this protein on the clinical course and treatment response in acute myeloid leukemia (AML). The aim of this study was to evaluate the expression of GRP78 mRNA in patients with de novo AML. These results were compared to healthy controls, blast phenotype, molecular and cytogenetic status and clinical features of AML. 101 non-M3 AML patients and 26 healthy individuals were included in this study. The expression of GRP78 mRNA in bone marrow was analyzed by real-time quantitative polymerase chain reaction (RQ-PCR). We demonstrated increased GRP78 mRNA expression in AML patients compared to healthy controls, although this difference was statistically significant only in CD34⁺ leukemias. There was also no significant correlation between GRP78 mRNA expression and complete remission rate, relapse-free survival and overall survival. These results indicate that GRP78 expression is increased in CD34⁺ leukemias and has no prognostic impact on clinical outcome in AML.     

Influence of methotrexate exposure on outcome in patients treated with MBVP chemotherapy for primary central nervous system lymphoma

AIMS

Although the standard treatment for primary central nervous system lymphoma (PCNSL) consists of three cycles of MBVP (methotrexate, BCNU, VP16, methylprednisolone) and radiotherapy, early failure of treatment may require modification of the treatment. However, our understanding of the outcome in such patients and of the factors involved in early failure of treatment is poor. In addition to known prognostic factors, we evaluated the influence of methotrexate (MTX) exposure on the response to MBVP chemotherapy in patients treated for PCNSL after the first two cycles.

METHODS

We retrospectively analyzed all patients with PCNSL treated with the MBVP regimen over the previous 10 years. Clinical, personal data and known prognostic factors were studied. The parameters of MTX exposure were estimated using a population pharmacokinetic approach with NONMEM. Objective response (OR), overall survival (OS) and failure-free survival (FFS) were evaluated in all patients.

RESULTS

Thirty-seven patients were studied. We observed lower FFS and OS (0.49 years) in patients who were not able to receive the planned treatment (group 1, n = 12) than in those who received three cycles (8.04 years) (group 2, n = 25). Known prognostic factors were comparable in both groups, but mean dose of MTX and mean AUC tended to be lower in patients who failed prematurely or showed no response after two cycles.

CONCLUSIONS

We found that patients who were early non-responders to MBVP chemotherapy had poor survival, without major influence of MTX exposure. It is thus probably unlikely that increasing the dose of MTX would improve outcome.     

Only grading has independent impact on breast cancer survival after adjustment for pathological response to preoperative chemotherapy

Our objective was to determine pretreatment factors with an independent impact on survival after adjusting for response to preoperative chemotherapy and to describe parameters predictive for achieving a pathological complete remission (pCR) after preoperative chemotherapy containing an anthracycline. We performed univariate and multivariate analyses to describe the impact of the following pretreatment characteristics of 240 primary breast cancer patients who received preoperative chemotherapy containing an anthracycline at our institution on disease-free survival (DFS), distant disease-free survival (DDFS) and overall survival (OS): age, stage, clinical tumor size, clinical nodal status, grading, and expression of estrogen receptor, progesterone receptor, Her2/neu, Ki67, Bcl-2 and p53. Afterwards, the response to preoperative chemotherapy was added to the multivariate model in order to evaluate which pretreatment parameters retained their prognostic impact. In addition, univariate analysis was performed to describe pretreatment variables predictive for achieving a pCR. With a median follow-up of 6.4 years (range 0-10.4), only grading retained its independent impact on DFS, DDFS and OS [hazard ratio (HR) 1.5, 1.7 and 2.9, respectively; p<0.05] after adjusting for the strongest independent prognostic factors pathological T category at surgery (HR 1.6, 1.8 and 1.7, respectively; p<0.001) and pathological N category at surgery (HR 2.3, 2.4 and 2.1, respectively; p<0.001). Predictive factors for the achievement of pCR (p<0.05) were age under 35 years, lower stage or smaller clinical tumor size and higher expression of Bcl-2 at diagnosis. We conclude that only grading retained its independent prognostic impact on DFS, DDFS and OS after adjusting for pathological response of breast tumor and axillary lymph node metastases to preoperative chemotherapy. According to our data, it could be hypothesized that young patients with early tumor stage and small primary tumors might profit most from preoperative chemotherapy.     

Guadecitabine (SGI-110): an investigational drug for the treatment of myelodysplastic syndrome and acute myeloid leukemia

ABSTRACT

Introduction: The incidence of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) is increasing with the aging population. Prognosis and overall survival (OS) remain poor in elderly patients and in those not eligible for intensive treatment. Hypomethylating agents (HMAs) have played an important role in this group of patients but their efficacy is limited.

Areas covered: This article reviews the mechanism of action, pharmacology, safety profile and clinical efficacy of subcutaneous guadecitabine, a second-generation DNA methylation inhibitor in development for the treatment of AML and MDS.

Expert opinion: Although guadecitabine did not yield improved complete remission (CR) rates and OS compared to the control arm in patients with treatment-naïve AML who were ineligible for intensive chemotherapy, subgroup analysis in patients who received ≥4 cycles of therapy demonstrated superior outcomes in favor of guadecitabine. Given its stability, ease of administration, safety profile and prolonged exposure time, guadecitabine would be the more appropriate HMA, replacing azacitidine and decitabine, to be used combination treatment regimens in patients with myeloid malignancies.     

A five-immune-related genes-based prognostic signature for colorectal cancer

BackgroundColorectal cancer (CRC) is a common malignancy with high morbidity and mortality. Prognosis of CRC is highly heterogeneous which hinders the making of appropriate clinical decision tremendously.AimsWe here propose to comprehensively define prognosis of CRC patients in the context of mRNA levels of immune-related genes (IRGs).MethodsCRC samples were acquired from both the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). IRGs were obtained from ImmProt database. Univariate Cox-regression analysis was adopted to screen prognostically significant IRGs for CRC patients. LASSO Cox-regression analysis was used to identify the optimal prognostic IRGs and construct the prognostic model. Multivariate Cox-regression analysis was performed to determine the independence of associations of specific factors with CRC’s OS. Nomogram that combines the independent prognostic factors was constructed to predict CRC patients’ 1-year, 3-years, and 5-years OS probability.ResultsThere were a total of 76 differentially expressed IRGs (DEGs) in CRC tumor compared with paracancerous samples. Five out of those DEGs were significantly associated with the CRC patients’ OS probability and used for the construction of prognostic model. CRC samples were divided into high-risk and low-risk group based on prognostic model. Significant differences in OS probability were obtained between high-risk and low-risk CRC patients. Additionally, a nomogram containing risk score, age and stage could effectively predict long-term OS probability of CRC patients.ConclusionIn conclusion, we developed a robust IRGs-based prognostic signature which should be helpful for the understanding of heterogeneity of OS probability and the future clinical research.