骨髓增生异常综合征患者p15INK4B基因甲基化与疾病进展的Meta分析

目的 分析骨髓增生异常综合征(MDS)患者p15INK4B基因甲基化与疾病进展的关系.方法 搜索Cochrane Library、Medline、PubMed、Embase、OVID、Springlink、CBMdisc、VIP、万方和CNKI数据库(1979 to 2012),查找报道MDS患者及sAML(MDS转化的白血病)患者p15INK4B基因甲基化发生率的文献,使用RevMan 5.0对数据进行统计分析.结果 共有20篇文献检测了MDS患者p15INK4B基因甲基化状态,并报道了患者骨髓原始细胞数;其中9篇文献包括sAML患者(共690名患者).p15INK4B基因甲基化状态在骨髓原始细胞5％～19％组中高于原始细胞＜5％组(RR=0.41,95％CI:0.33～0.50),sAML组高于MDS原始细胞5％～19％组(RR=0.51,95％CI:0.41～0.64).4篇文献报道了MDS患者疾病的进展(包括179名患者).p15INK4B基因甲基化阳性组疾病进展率高于甲基化阴性组(RR=3.09,95％CI:2.04～4.68).结论 p15INK4B基因甲基化与MDS患者疾病进展及白血病转化密切相关.     

Society of Hematologic Oncology (SOHO) State of the Art Updates and Next Questions: Myelodysplastic Syndromes

In the past few months, 2 main streams of research have dominated the panorama of myelodysplastic syndrome (MDS) investigations: deepening the insight into the pathogenic role, hierarchy, and prognostic effect of somatic mutations and, as a consequence, into the effect of inherited congenital predisposing conditions and the second, quite interlinked with the first, analyzing inflammation and innate immunity in patients with MDS. The research devoted to clarifying the mechanisms of action and mechanisms of resistance to hypomethylating agents has also advanced, mostly resulting from different approaches to the study of DNA methylation. Recent observations have reinforced support for targeted therapies for selected subgroups of MDS patients.     

The Role of Intensive Chemotherapy in Myelodysplastic Syndromes

We review results of intensive chemotherapy (IC) obtained in myelodysplastic syndromes (MDS). Overall, the complete remission (CR) rates and median CR duration obtained with IC are low in MDS, especially when compared to results obtained in de novo AML treated with the same chemotherapy regimens; very few MDS patients achieve prolonged remissions. Failure to achieve CR, in MDS, results both from a high incidence of resistant disease and toxic deaths, the latter being due to longer periods of aplasia than in de novo AML. However some subgroups of MDS seem to obtain higher CR rates and more prolonged remissions. These include patients younger than 45 to 50 years, those with a large excess of marrow blasts or Auer rods at diagnosis, and patients with a normal karyotype or at least without involvement of chromosomes 5 and/or 7.

Results of IC clearly have to be improved in MDS. Higher CR rates may possibly be obtained by intensifying induction regimens, but this will probably require the addition of growth factors, in order to reduce the already very long periods of aplasia seen with IC in MDS. For consolidation therapy, new approaches, and especially autologous bone marrow transplantation, will have to be investigated.     

Allogeneic Stem-Cell Transplantation in Patients With Myelodysplastic Syndromes and Prevention of Relapse

Myelodysplastic syndromes (MDS) mainly affect the elderly population, which implies that the majority of patients cannot tolerate intensive therapeutic approaches, including allogeneic hematopoietic stem-cell transplantation (allo-HSCT). The underlying impaired stem-cell function leads to peripheral cytopenia, including a propensity to progress to acute myeloid leukemia. Allo-HSCT is considered the only potentially curable therapy. Reduced-intensity conditioning regimens have shown to improve early tolerability of the procedure, but late effects like graft-versus-host disease and relapse remain major challenges in the care of these patients. Therefore, special attention should be paid to posttransplantation care in terms of graft-versus-host disease management, measurable residual disease monitoring, and prevention of relapse. In fact, recent advances in the field have shown that minimal residual disease measurement and preemptive therapies may be a promising approach to prevent or at least delay relapse. This review briefly discusses indication and selection of patients for allo-HSCT in MDS, pretransplantation evaluation and choice of conditioning regimens, and prophylactic and preemptive approaches to prevent relapse after allo-HSCT.     

Lenalidomide and Prednisone in Low and Intermediate-1 IPSS Risk,Non-Del(5q) Patients With Myelodysplastic Syndromes: Phase 2 Clinical Trial

PurposeTo test the hypothesis that combination treatment with lenalidomide and prednisone will yield a higher erythroid response rate in patients with non-del(5q) lower-risk myelodysplastic syndromes compared to the historical clinical trial data with lenalidomide monotherapy, which reported a 26% transfusion independence rate.Patients and MethodsThe study enrolled 25 patients with lower-risk myelodysplastic syndromes by the International Prognostic Scoring System who were transfusion dependent or who had symptomatic anemia and prior erythroid stimulating agent failure or low chance of response. The planned dose of lenalidomide was 10 mg per day. Prednisone dose was 30 mg by mouth, daily cycle 1 tapered by 10 mg after each cycle to 5 mg by mouth every other day for those with response beyond cycle 6. The primary objective was best response (hematologic improvement–erythroid, HI-E) by International Working Group 2006 criteria within 24 weeks.ResultsThe HI-E rate was 20% (5/25) and was 22% (5/23) for patients with evaluable data. All those with response became red blood cell–transfusion independent (5/23). The median time to response was 57 days. The median duration of response was 80 days (95% confidence interval, 69–91). Three of 5 of those with response did not have prior hypomethylating agent, while 14 of 20 those without response received a hypomethylating agent.ConclusionThe combination was relatively well tolerated, with no additional observed toxicity to single-agent lenalidomide.     

Therapeutic Outcomes and Prognostic Impact of Gene Mutations Including TP53 and SF3B1 in Patients with Del(5q) Myelodysplastic Syndromes (MDS)

BackgroundGenetic alterations are increasingly being recognized to play an important role in both diagnosis and prognosis of MDS. In general, MDS patients with SF3B1 mutations (MT) are known to have favorable outcomes whereas those with TP53 mutations have dismal survivals. However, it is unclear if the impact of these mutations applies to all subtypes of MDS including del(5q) which is known for its response to lenalidomide and better prognosis.Materials and MethodsWe retrospectively reviewed 132 del(5q) MDS patients who were treated at the Moffitt Cancer Center (2001-2019).ResultsAmong patients who received lenalidomide (n = 98), 50%, 42.9%, and 7.1% achieved hematologic improvement or better, no response, and disease progression/death with a median overall survival (mOS) of 93.2, 72.4, and 25.6 months, respectively (P < .0001). The mOS was 73.3 months but only 25.6 months after patients stopped lenalidomide. TP53 was the most common mutation accounting for 23.8% of the patients. Of the 63 patients with molecular data available, 23.8% harbored TP53 MT and 10% with SF3B1 MT. TP53 status did not impact OS (MT 86.4 vs. wild-type (WT) 73.3 months; P = .72) but those with SF3B1 mutations had a significantly shorter mOS compared to WT (23.9 vs. 83.5 months; P = .001). Multivariate analysis confirmed lenalidomide response and SF3B1 mutations are independently associated with outcomes.ConclusionOur findings indicate many del(5q) MDS patients will benefit from lenalidomide but survival after its failure is limited. Mutations known to have prognostic impact in MDS at large may not have the same implications in the del(5q) subset.     

Inactivation of the p15INK4B and p16INK4 Genes in Hematologic Malignancies

The recently discovered p15^INK4B and p16^INK4 genes encoding cell cycle regulating proteins, map to a region on chromosome 9p21 that is commonly deleted in a variety of malignant diseases. The p16^INK4 gene has now been shown to be a tumor suppressor gene. It is frequently inactivated in cancer and is possibly the second most often mutated gene in human malignant disease after p53. The role of the p15^INK4B and p16^INK4 genes in hematologic malignancies has been the subject of intense investigation since their discovery. In this review we address the function and possible role in tumorigenesis of the p15^INK4B and p16^INK4 genes and discuss their significance as prognostic markers in hematologic malignancies.     

骨髓增生异常综合征49例实验室指标分析

目的：观察MDS骨髓细胞形态学病态改变血特点。方法：对49例MDS的骨髓涂片及血片，应用瑞氏-姬姆萨混合染液染色，进行骨髓及外周血细胞学分析。结果：粒、红、巨核三系都有不同程度的病态造血。粒系主要以细胞核浆发育不平衡、内外浆、中性粒细胞核分叶不能或pelger-Huet样畸形。红系以双核、花瓣核、碎核及巨幼样变为主。结论：MDS患以中老年居多，三系均有不同程度的病态改变，分型主要以RA为主。     

SOHO State of the Art & Next Questions: Myelodysplastic Syndromes: A New Decade

Myelodysplastic syndromes (MDS) are a group of heterogeneous clonal hematopoietic stem cell disorders. The 2020 Surveillance, Epidemiology, and End Results data demonstrates the incidence rate of MDS increases with age especially in those greater than 70 years of age. Risk stratification that impact prognosis, survival, and rate of acute myeloid leukemia (AML) transformation in MDS is largely dependent on revised International Prognostic Scoring System along with molecular genetic testing as a supplement. Low risk MDS typically have a more indolent disease course in which treatment is only initiated to ameliorate symptoms of cytopenias. In many, anemia is the most common cytopenia requiring treatment and erythroid stimulating agents, are considered first line. In contrast, high risk MDS tend to behave more aggressively for which treatment should be initiated rapidly with Hypomethylating Agents (HMA) being in the frontline. In those with high risk MDS and eligible, evaluation for allogeneic stem cell transplant should be considered as this is the only potential curative option for MDS. With the use of molecular genetic testing, a personalized approach to therapy in MDS has ensued. As the treatment landscape in MDS continues to flourish with novel targeted agents, we ambitiously seek to improve survival rates especially among the relapsed/refractory and transplant ineligible.     

DNA Methylation Architecture Provides Insight into the Pathogenesis of Upper Tract Urothelial Carcinoma: A Systematic Review and Meta-Analysis

PurposeNumerous studies suggested methylation modifications play an important role in upper tract urothelial carcinoma (UTUC), but few have depicted DNA methylation architecture on the pathological process of UTUC. We aimed to better understand the pathogenesis of UTUC and provide precision medicine references when managing UTUC patients.MethodsPubMed, Cochrane Library, EMBASE, and Scopus were searched for UTUC until December 31, 2020. Methodological quality assessment was conducted according to NIH recommendations. Meta-analysis was conducted to assess the prognostic effect of methylated genes. Kaplan-Meier survival analyses were performed to validate methylated genes and cytosine-phosphate-guanine (CpG) sites.ResultsEleven studies (3619 patients) were eligible to investigate 12 methylated genes and 10 CpGs. The quality of all the studies was fair to good. Meta-analysis found the pooled effect of eligible methylated genes had a low risk of tumor recurrence (HR = 0·67; 95% CI: 0·51-0·87; P = ·003), but a high risk of tumor progression (HR = 1·60; 95% CI: 1·17-2·18; P = ·003) and cancer-specific mortality (HR = 1·35; 95% CI: 1·06-1·72; P = ·01). For individual methylation status of GDF15, HSPA2, RASSF1A, TMEFF2, and VIM, the pooled effect of each gene was found pleiotropic on both diagnosis and prognosis. Survival analysis suggested higher methylation of SPARCL1 had a better disease-specific survival (P = ·048).ConclusionWe combined meta-analysis and Kaplan-Meier survival analysis using the most updated evidence on the methylation of UTUC. Candidate biomarkers with essential diagnosis and prognosis function might provide precision medicine references for personalized therapies.     

Fluorescence in Situ Hybridization (FISH) Utility for Risk Score Assessment in Patients With MDS With Normal Metaphase Karyotype

BackgroundCytogenetic profile is an essential parameter in myelodysplastic syndromes (MDS) risk stratification by both International Prognostic Symptom Score (IPSS) and Revised (R)-IPSS. Almost one-half of patients with MDS have normal cytogenetics by metaphase karyotype. Here we report the yield of MDS fluorescence in situ hybridization (FISH) panel detecting cytogenetic abnormalities in these patients and its impact on risk stratification.Patients and MethodsAmong patients with normal metaphase karyotype, we assessed those patients who had cytogenetic abnormalities detected by an MDS FISH panel, which included probes for del (5), del (7), del (20), trisomy 8, and del (17p). Risk stratification was calculated by both IPSS and R-IPSS.ResultsOf 1600 patients with MDS with normal metaphase karyotype, 53 (3%) patients had cytogenetic abnormality detected by MDS FISH panel. Integrating the MDS FISH panel cytogenetics (IPSS + FISH restaging) resulted in upstaging the score, where 53% of low-risk IPSS were upstaged to intermediate (int)-1, 56% of int-1 were upstaged to int-2, and 78% of int-2 were upstaged to high risk. Based on the R-IPSS, 61% of very low-risk patients, all low-risk patients, 92% of intermediate-risk patients, and 50% of high-risk patients with FISH abnormalities were upstaged, respectively.ConclusionThe yield of MDS FISH panel detecting cytogenetic abnormalities in patients with normal karyotype by G-banding is low and may not warrant ordering the panel in all patients. Among the 3% of patients with normal karyotype who had cytogenetic abnormality detected by FISH, the risk score assignment by IPSS and R-IPSS was upstaged.     

Aberrations of p16INK4A,p14ARF and p15INK4B genes in pediatric solid tumors

Expression of the p16INK4A (p16), p15INK4B (p15), and p14ARF genes, located at 9p21, was examined in pediatric neuroblastoma (NB), Ewing's sarcoma (ES), and rhabdomyosarcoma (RMS). p16 expression was absent in 4 of 5 ESs, and 2 of these 4 cases died. p16 expression was reduced or absent in 10 of 12 RMSs, and 4 of these 10 cases died. These results suggested the possibility that p16 expression was associated with the progression of ES and RMS. There has been no previous report on p14ARF in NB. Our investigation might indicate that abnormal expression of the p16 and p14ARF was associated with a poor prognosis in NB, although in some cases of NB normal p16 and abnormal p14ARF expression was seen. These findings suggest an important role of p14ARF gene in the tumorigenesis of NB. The different incidence of expression of the p16, p15, and p14ARF genes in these 3 tumor types may reflect differences of the molecular process through which the 3 tumors develop. Our results suggest that abnormal expression of the p16 and/or p14ARF may be associated with a poor prognosis in these 3 tumors.     

Influence of Acute Myeloid Leukemia Progression on the Prognosis of 831 Patients With Myelodysplastic Syndromes From the Argentine Database

BackgroundA large group of patients with myelodysplastic syndromes (MDS) will die of causes intrinsic to bone marrow failure. One third of patients will develop acute myeloid leukemia (AML), which is associated with an extremely poor outcome and a short survival. Our objectives were to analyze the prognostic variables and scoring systems in the attempt to determine the influence of progression on the overall survival of MDS patients.Patients and MethodsWe performed a retrospective analysis of 831 MDS patients, including those from the Argentine Registry.ResultsOf the 831 MDS patients, 158 (19.0%) experienced transformation, with a median overall survival of 17.9 months from diagnosis and 3.5 months after progression. The survival of patients with adverse karyotypes or greater risk, according to the International Prognostic Scoring System-revised (IPSS-R) or World Health Organization-based Prognostic Scoring System (WPSS) was not affected when stratified by patients with and without evolution to AML (P > .05). In contrast, the survival of lower risk patients was significantly reduced for those patients with progression to AML (P < .001) and those younger (P = .024) than those who died of non–AML-related causes. The intermediate-risk patients were heterogeneously distributed; however, an upgrade from a lower IPSS-R to a higher WPSS-hemoglobin risk category was associated with a worse outcome, not affected by progression (P = .420), with a median event-free survival of 16 months.ConclusionThe use of the IPSS-R and WPSS systems simultaneously might help in identifying those patients who require more aggressive treatment. Nevertheless, more efforts are needed to improve the identification of those lower risk patients whose survival is significantly reduced by progression to AML.     

Inactivation of the p14(ARF), p15(INK4B) and p16(INK4A) genes is a frequent event in human oral squamous cell carcinomas.

The p14(ARF), p15(INK4B) and p16(INK4A) genes were localized to 9p21, where genetic alterations have been reported frequently in various human tumors. We performed a molecular analysis of the mechanism of inactivation in cell lines and 32 oral squamous cell carcinoma (OSCC), using deletion screening, PCR-SSCP, methylation-specific-PCR and cycle sequencing. We detected homozygous deletion of p14(ARF)-1Ebeta in 9 (26.5%), of p15(INK4B) in one (3.1%), and of p16(INK4A) in 22 (56.3%) tumor samples. Three mutations were detected in the p16(INK4A) genes. We detected aberrant methylation of the p14(ARF) genes in 14 (43.8%), of the p15(INK4B) gene in 9 (28.1%), and of the p16(INK4A) gene in 16 (50.0%) tumor samples. Altogether, 87.5% of the samples harbored at least one of the alterations in the p14(ARF), p15(INK4B), and p16(INK4A) genes, indicating that the frequent inactivation of these genes may be an important mechanism during OSCC development.     

Clinical Outcomes With Ring Sideroblasts and SF3B1 Mutations in Myelodysplastic Syndromes: MDS Clinical Research Consortium Analysis

Background

Recurrent somatic mutations in SF3B1 have been identified in patients with myelodysplastic syndromes (MDS) and are associated with ring sideroblasts (RS) and relatively favorable clinical outcomes. The 2016 World Health Organization classification categorizes patients with ≥ 5% RS and SF3B1 mutation as MDS-RS, in contrast to its prior MDS-RS classification (≥ 15% RS, no genotyping data). Treatment responses in MDS patients with mutated SF3B1 are not well described.

Hypermethylation of p16(INK4a) and p15(INK4b) genes in non-small cell lung cancer.

Hypermethylation of CpG island is a common mechanism by which tumor suppressor genes are inactivated. The tumor suppressor genes p16(INK4a) and p15(INK4b) are important components of the cell cycles. We have studied the feasibility of detecting tumor-associated aberrant p16(INK4a) and p15(INK4b) methylation in non-small cell lung cancer (NSCLC) using methylation-specific PCR. We found a high frequency of hypermethylation of the p16(INK4a) gene in 17 of 45 cases of NSCLC. In this study, there was no difference between the clinicopathological features or overall survival of patients with and without p16(INK4a) methylation. On the other hand, p15(INK4b) promoter hypermethylation is rare (5/45) in lung cancer and occurs in association with p16(INK4a) methylation. The overall survival of patients with p15(INK4b) methylation was markedly shortened in this series. We also analyzed cells in bronchial washings, and p16(INK4a) methylation was detected in 4 of 17 cases of NSCLC. Moreover, 1 of 10 plasma samples from patients with NSCLC was positive for p16(INK4a) methylation. Our results suggest a possible prognostic role of p15(INK4b) methylation in NSCLC, and that the detection of aberrant p16(INK4a) methylation in both bronchial washings and plasma may be useful for cancer diagnosis.     

慢性乙型肝炎病毒感染与p16INK4A基因启动子甲基化关系的研究

目的探讨慢性乙型肝炎病毒(HBV)感染对p16INK4A基因启动子甲基化的影响及其在HBV相关肝细胞癌(HCC)形成中的作用。方法选取23例HBV相关HCC癌及癌旁组织、25例慢性乙型肝炎肝穿刺组织,采用甲基化特异性PCR(MSP)检测p16INK4A基因启动子的甲基化状态;免疫组化EnVision二步法测定肝组织内HBsAg、HBcAg、HBeAg和HBx蛋白的表达;荧光实时定量PCR检测肝组织HBV DNA含量;PCR扩增和直接测序检测HBV x基因变异。结果癌组织p16INK4A基因启动子甲基化阳性率(47.83%)明显高于癌旁组织(17.39%),慢性乙型肝炎患者p16INK4A基因启动子甲基化阳性率(36.00%)与癌组织、癌旁组织差异无统计学意义。在癌旁组织和慢性乙型肝炎, p16INK4A基因启动子甲基化者HBx蛋白表达中位数分别为3.000和0.250,明显高于非甲基化者(0.500和0.000),但在癌组织中,HBx蛋白的表达与p16INK4A基因启动子甲基化状态无关。HBsAg、HBcAg、组织HBV DNA含量和x基因突变均与p16INK4A基因启动子甲基化状态无关。结论在癌前病变中,p16INK4A基因启动子甲基化与HBx蛋白高表达有关,HBx蛋白可能通过诱导p16INK4A基因启动子甲基化而使该抑癌基因失活,在HBV相关HCC形成中起重要作用。     

低剂量亚砷酸及维甲酸方案对儿童骨髓增生异常综合征p15INK4B基因的影响

目的 探讨低剂量亚砷酸及维甲酸双诱导方案对骨髓增生异常综合征(MDS)患儿p15INK44B基因表达的影响及患儿p15INK4B基因甲基化水平的变化.方法 11例MDS患儿接受低剂量亚砷酸及维甲酸双诱导方案治疗,应用实时荧光定量聚合酶链反应(PCR)方法检测治疗前后p15INK4B基因的表达,应用亚硫酸氢钠修饰及实时荧光定量PCR方法检测p15INK4B基因的甲基化水平.结果 11例MDS患儿经过双诱导方案治疗后,9例获益.治疗后10例患儿p15INK4B基因表达水平显著升高,治疗前后p15INK4B基因甲基化水平分别为(1.68±0.58)％、(1.44±0.65)％,二者差异无统计学意义(t=-0.885,P＞0.05).结论 低剂量亚砷酸及维甲酸双诱导方案治疗儿童MDS疗效较好,该方案的作用机制可能与p15INK4B基因表达升高有关,但p15INK4B基因表达升高与去甲基化无相关性.     

小剂量地西他滨治疗中高危骨髓增生异常综合征的Meta分析

目的 系统评价小剂量地西他滨治疗中高危骨髓增生异常综合征（MDS）疗效和安全性。方法 计算机检索PubMed、Cochrane Library、Embase、中国期刊全文数据库（CNKI）、中国生物医学文献数据库（CBM）1995-2012年间发表的关于小剂量地西他滨治疗MDS的文献资料。并纳入随机对照试验（RCT）,采用Review manager5.0软件进行Meta分析。结果 共纳入3篇随机对照试验（RCT）,共894例患者。Meta分析结果显示,地西他滨与支持治疗相比,总生存率（OR）[OR=22.9,95%CI(7.51,69.85),P＜0.00001]、部分缓解率(PR) [OR=17.23,95%CI(2.27,130.76),P=0.006]、血液学改善（HI）[OR=3.21,95%CI(1.53,6.75),P=0.002]、中位生存期（MST）[13.5月 vs. 7.3月,P＜0.05]、Ⅲ/Ⅳ级发热伴中性粒细胞减少[OR=4.85,95%CI(2.55,9.21),P＜0.00001] 差异有统计学意义。完全缓解率（CR）[OR=6.39,95%CI(0.25,166.49),P=0.26] 、Ⅲ/Ⅳ级血小板减少症[OR=2.35,95%CI(0.63,8.69),P=0.20]差异无统计学意义。结论 小剂量地西他滨可提高骨髓增生异常综合征患者总体生存率和部分缓解率,有助于血液学改善。但是增加Ⅲ/Ⅳ级中性粒细胞减少症的发生,部分患者也会出现血小板减少症、恶心呕吐、腹泻等不良反应。