MYCN基因与PHOX2B基因联合检测对高危神经母细胞瘤患儿危险度及预后的评估价值

目的 探讨MYCN基因与PHOX2B基因联合检测在高危神经母细胞瘤(NB)患儿危险度与预后评估中的应用价值。方法 选取106例高危NB患儿，于初诊时检测MYCN、PHOX2B基因的表达情况，分析两项指标与患儿病理特征的关系，并在化疗6个疗程后随访1年，以Kaplan-Meier法分析MYCN基因与PHOX2B基因与患儿预后的关系。结果 106例患儿中MYCN基因扩增60例(56.60%),PHOX2B基因阳性45例(42.45%)。MYCN基因扩增患儿初诊时乳酸脱氢酶(LDH)≥1500 U/L占比高于基因正常患儿，PHOX2B基因阳性患儿中肿瘤转移部位≥3个与高神经元特异性烯醇化酶(NSE)≥370μg/L占比高于基因阴性患儿，差异有统计学意义(P<0.05)。Kaplan-Meier结果显示：MYCN基因扩增患儿与PHOX2B基因阳性患儿的1年生存率分别为48.33%(29/60)、44.44%(20/45),明显低于MYCN基因正常患儿65.22%(30/46)与PHOX2B基因阴性患儿63.93%(39/61),差异有统计学意义(P<0.05)。结论 MYCN基因与...     

神经母细胞瘤相关基因DDX1研究进展

摘 要：神经母细胞瘤（neuroblastoma,NB）是儿童常见恶性肿瘤之一。MYCN基因扩增与NB不良预后密切相关,但MYCN基因作为NB临床诊断重要分子标志物存在一定局限性。研究表明,与MYCN基因邻近的DEAD box 1基因（DDX1）在NB中存在与MYCN共扩增现象。DDX1蛋白是DEAD box家族中一员,目前研究显示其可能是一种依赖ATP的RNA解螺旋酶,与肿瘤发生发展关系密切,但DDX1基因对NB的作用尚不清楚,且DDX1与MYCN基因共扩增对NB患者预后影响也存在分歧。文章根据目前DDX1基因与NB研究进展,对DDX1与NB关系进行综述。     

MUC3A基因在神经母细胞瘤中的甲基化状态及其与预后的关系

  目的  探讨神经母细胞瘤中MUC3A基因甲基化状态与肿瘤预后的关系。  方法  收集2009年3月至2011年5月中国医科大学附属盛京医院小儿外科收治神经母细胞瘤新鲜冰冻原发肿瘤组织44例, 采用RT-PCR法检测44例肿瘤组织标本中MYCN基因扩增状态, MSP检测肿瘤组织MUC3A甲基化状态。  结果  NB中MUC3A基因甲基化发生率达79.55%(35/44), 且与患儿年龄、肿瘤分期及病理分型密切相关(P < 0.05), 低危组甲基化发生率38.46%明显低于中危组100%及高危组92.31%(P < 0.05);MYCN扩增的肿瘤患者MUC3A基因的甲基化发生率明显升高(RR=1.46, P < 0.005)。  结论  预后不良的NB中MUC3A基因呈高甲基化, 与MYCN基因扩增具有相关性, 该基因的表达对NB的预后评估具有重要临床意义, 是预后不良的主要因素之一。      

ZW10相互作用着丝粒蛋白对神经母细胞瘤增殖的影响及机制研究

目的:探讨ZW10相互作用着丝粒蛋白(ZW10 interacting kinetochore protein, ZWINT)对神经母细胞瘤(neuroblastoma, NB)细胞增殖的影响及作用机制。方法:利用NB数据集分析ZWINT表达水平与NB预后及临床分期的关系。EdU实验、流式细胞术和γH2AX免疫荧光染色分别检测干扰ZWINT表达对NB细胞增殖、周期分布和DNA损伤修复能力的影响。免疫组织化学/蛋白质印记(Western blot)检测MYCN扩增和无扩增组织及细胞系中ZWINT的表达情况。荧光定量PCR(qRT-PCR)和Western blot检测干扰/过表达MYCN对ZWINT表达的影响。在线预测ZWINT的启动子区域MYCN的结合位点,ChIP-PCR和荧光素酶实验验证MYCN靶向调控ZWINT表达。强力霉素诱导Tet-on MYCN SH-SY-5Y细胞过表达MYCN同时干扰ZWINT表达,检测ZWINT对MYCN介导的细胞增殖、周期和DNA损伤修复功能的影响。结果:ZWINT表达水平与NB患儿总生存率、无事件生存率呈负相关,其表达随NB分期升高而增高。ZWIN...     

血清神经元特异性烯醇化酶和尿香草扁桃酸与神经母细胞瘤临床病理特征的相关性

  目的  分析神经母细胞瘤（neuroblastoma,NB）患儿治疗前血清神经元特异性烯醇化酶（neuron-specific enolase,NSE）和尿香草扁桃酸（vanillymandelic acid,VMA）的水平,比较二者与NB临床病理特征的相关性以及二者预测高危组患儿的能力,为更好地诊断和评估病情提供依据。  方法  收集2011年9月至2019年9月天津医科大学肿瘤医院确诊的155例NB患儿的临床病理资料。回顾性分析不同临床特征的患儿血清NSE和尿VMA水平,包括年龄、性别、肿瘤体积及部位、病理类型、INSS分期、危险度分组、是否转移、MYCN基因扩增及有无IDRFs情况。采用非参数秩和检验比较组间差异,P < 0.05为差异具有统计学意义。为比较血清NSE和尿VMA在高危组患儿中的诊断价值,绘制ROC曲线,建立预测模型,比较二者鉴别高危组患儿的准确性。  结果  109例患儿检测尿VMA,其中阴性61例,阳性48例,阳性率44.0%。152例患儿检测血清NSE,其中阴性2例,阳性150例,阳性率98.7%。血清NSE和尿VMA水平在INSS 4期、COG高危组、伴有转移和有IDRFs的患儿中均显著增高（P < 0.05）。血清NSE在肿瘤部位、肿瘤体积和病理类型不同的患儿中具有显著性差异;肿瘤体积>500 cm3、INPC预后不良,病理类型为NB,原发灶位于腹膜后的患儿,血清NSE水平显著高于其他组（P < 0.001）。ROC曲线结果显示血清NSE鉴别高危组患儿的界值为98.50 ng/mL,曲线下面积AUC为0.943（95% CI:0.906~0.991）。尿VMA鉴别高危组患儿的界值为62.28 μmoL/24 h,AUC为0.791（95% CI:0.705~0.878）。联合二者鉴别高危组患儿,AUC为0.948（95% CI:0.900~0.997）。  结论  与尿VMA相比,血清NSE与更多的NB临床特征相关,可以更全面地辅助诊断疾病及评估病情。在高危组患儿中,血清NSE和尿VMA水平均显著增高。NSE鉴别高危组患儿的准确性、灵敏度和特异度均高于尿VMA,二者联合检测并不能提高诊断的准确性。      

神经母细胞瘤CCCG-NB-2015共识多中心应用总结

目的：对中国多中心应用CCCG-NB-2015共识方案诊治的儿童神经母细胞瘤（neuroblastoma,NB）病例进行回顾性分析总结,以期为改进NB诊疗工作提供有力依据。方法：回顾性分析2013年3月至2020年7月经统一规范的CCCG-NB-2015共识方案诊治的全国多中心500例NB患儿的临床和预后资料,通过Cox单因素和多因素回归分析明确影响NB预后的关键因素;分别绘制神经元特异性烯醇化酶（neuron-specific enolase,NSE）和乳酸脱氢酶（lactate dehydrogenase,LDH）在预测骨髓转移和复发的ROC曲线,明确NSE和LDH的临床价值;比对分析NB两种不同分期系统和危险度分组系统下患儿的预后差异,着重分析中危组人群的队列特征和预后结局。结果：通过单因素分析共确定10个潜在的预后因子,分别为年龄、肿瘤原发部位、INPC分类、骨髓转移、MYCN状态、INSS分期、INRGSS分期、诊断时NSE、LDH水平和影像学定义的危险因素（image-defined risk factors,IDRFs）,均P<0.05。Cox多因素分析结果显示与无...     

胃肠道外原发MALT淋巴瘤临床病理特征与预后分析

观察分析胃肠道外原发黏膜相关淋巴组织结外边缘区B细胞淋巴瘤（extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue,MALT淋巴瘤）的预后相关因素。方法:收集近10年具有完整临床病理资料的胃肠道外原发MALT淋巴瘤29例,肺11例,甲状腺7例,腮腺4例,睾丸2例,乳腺1例,眼附属器1例,扁桃体1例,肝脏1例,舌根1例,随访1～101个月（26例随访>12个月）;分析比较不同年龄、发病部位、组织学特征、临床分期等临床病理特点以及治疗方案与生存率的关系。结果:1）29例MALT淋巴瘤中位发病年龄55岁（29～80岁）,男女之比为1:3,首发症状多为局部肿块;9例（31%）为乙肝病毒（HBV）携带者,HBV感染可能与MALT淋巴瘤的发病机制有一定相关性（P<0.05）。2）组织学上,27例（93.1%）具有MALT淋巴瘤的典型组织学形态特征和免疫表型特征,4例伴有浆细胞样分化,10例伴大细胞转化;3例行IGH/IGK基因重排检测的结果为B细胞受体基因克隆性重排;3）ⅠE期、ⅡE期、ⅣE期的5年生存率分别为92%、100%和69%,ⅠE期和ⅡE期的生存率高于ⅣE期（P<0.05）。不同的原发部位、临床治疗方案以及形态学差异对生存率无影响（P>0.05）。结论:胃肠道外MALT淋巴瘤是一类病因机制尚未明确的惰性淋巴瘤,其预后与临床分期密切相关;HBV感染可能与肿瘤发生相关;不同的原发部位、临床治疗方案以及形态学差异对预后无影响。      

神经母细胞瘤基因组结构性变异特征的研究进展

神经母细胞瘤（neuroblastoma,NB）是起源于神经嵴细胞的儿童胚胎恶性肿瘤，表现为较强的生物学和临床异质性。基因组测序研究显示，NB具有较低的突变负荷和频发突变。NB表现为携带较多的基因组结构性变异，是其发生、发展的重要驱动因素。临床上已将MYCN扩增和11q缺失等基因组结构性变异纳入风险分组中，但目前对于NB基因组结构性变异的了解与NB的生物学、临床复杂性仍存在差距。高通量基因组学技术的发展推动了研究者对NB基因组特征尤其是结构性变异特征有了更加全面的认识，为探索NB发生、发展机制以及更加精细的风险分层提供了数据基础。本文就近年来NB的基因组结构性变异特征研究进展进行综述。     

17例原发胃肠道弥漫大B细胞淋巴瘤临床病例分析

目的:探讨原发胃肠道弥漫大B细胞淋巴瘤（PGI-DLBCL）的临床特点、治疗方案及疗效。方法:收集我院2006年12月至2013年4月诊治的17例PGI-DLBCL患者的临床资料,对其临床特征、治疗方法、疗效进行回顾性分析,临床分期采用Ann Arbor分期法,采用国际预后指数（IPI）和Ki-67评估,观察短期缓解率,分析临床因素对疗效的影响。结果:17例PGI-DLBCL患者中,男女比例为1.13∶1（男9例,女8例）,中位年龄47岁（15~69岁）;有B症状者6人,占35.3%;随访时间为4~70个月,中位随访时间为12个月;Ann Arbor分期Ⅰ/Ⅱ期10例（58.8%）,Ⅲ/Ⅳ期7例（41.2%）;IPI评分≤2分患者11例（64.7%）,IPI评分＞2分患者6例（35.3%）;6例可评估免疫分型的患者中生发中心型4例（66.7%）,非生发中心型2例（33.3%）;按部位,胃12例,结肠3例,直肠2例;所有患者均接受2疗程以上的化疗,采用CHOP、CHOP（E）方案化疗患者9例（52.9%）,采用利妥西单抗联合化疗者8例（47.1%）。近期疗效显示:16例可评估患者,5例CR（31.3%）,5例PR（31.3%）,3例SD（18.8%）,3例PD（18.8%）;IPI评分≤2分患者50%达CR,IPI评分>2分患者均未达CR;7例Ann Arbor分期Ⅲ-Ⅳ期患者,1例达CR（14.3%）,9例Ann Arbor分期Ⅰ-Ⅱ期患者,4例达CR（44.4%）;7例患者联合了利妥西单抗治疗,总有效率达71.4%（2例CR、3例PR）,9例未联合利妥西单抗治疗,总有效率为55.6%（3例CR、2例PR）。结论:17例PGI-DLBCL患者多为中年,确诊依靠手术或内镜病理活检,大部分患者Ki-67表达＞40%,需加强超声胃镜及PET-CT检查,以便更好的评估预后。预后相关因素分析显示IPI评分与其预后相关。治疗中利妥西单抗联合化疗的治疗反应较好,需扩大样本进一步研究。     

4期神经母细胞瘤手术切除范围对预后的影响

  目的  探讨4期神经母细胞瘤（neuroblstoma,NB）原发肿瘤手术切除程度与生存率的关系,分析不同手术切除程度对预后的影响。  方法  回顾分析2000年1月至2011年12月中山大学肿瘤防治中心收治的96例4期NB患者临床资料。根据原发灶手术切除程度将患者分为:A组:未手术或仅活检或手术切除 < 50%的原发肿瘤;B组:手术切除50%~90%的原发肿瘤;C组:手术切除 > 90%的原发肿瘤;D组:手术肉眼完全切除原发肿瘤。  结果  96例4期NB患者,3年PFS和OS分别为32.8%和36.7%。A组24例,B组10例,C组23例,D组39例。A组和B组间PFS比较差异无统计学意义（P=0.352）,C组和D组间PFS比较差异无统计学意义（P=0.792）。但C组+D组生存率高于A组+B组,3年PFS分别为42.2%和17.8%（P < 0.001）。  结论  4期NB原发肿瘤90%以上完全切除联合化疗和（或）放疗可提高生存率,少量肉眼残留或镜下残留并不影响生存率。      

Multifocal neuroblastoma: biologic behavior and surgical aspects

BACKGROUND: Although multifocal neuroblastoma is rare, its incidence has increased because of recent improvements in diagnostic tools and the introduction of mass screening. Among the 106 neuroblastoma cases treated at the authors' hospital between 1984 and 1998, 8 were multifocal neuroblastoma. METHODS: The authors examined clinicopathologic findings and biologic features, including MYCN amplification, NTRK1 and Ha-ras p21 expression, cellular DNA content, and telomerase activity in these 8 multifocal neuroblastoma cases. Moreover, clinicopathologic findings were investigated with a review of 53 published cases of multiple neuroblastoma in the literature published in English between 1966 and 1999. RESULTS: Among these eight cases, five were detected by mass screening and three were incidental neuroblastomas. Histologically, all tumors were classified as ganglioneuroma or favorable neuroblastoma except one advanced case. All tumors lacked the MYCN gene amplification and expressed NTRAK1 mRNA and Ha-ras p21 protein. Cellular DNA content showed that half of these tumors were near-triploid, and the proliferative index (%S-phase) of all tumors was less than 25%. High telomerase activity was detected in none of these cases. Four patients underwent multistage operation and five patients with bilateral adrenal neuroblastomas underwent tumor enucleation to preserve adrenal function. Currently, all patients are disease free and none have required corticosteroid replacement therapy. Among the previously reported 53 cases with multifocal neuroblastoma, 25 were incidentally detected, 18 had familiar history, and most patients without other major complications also had extremely good prognoses. CONCLUSIONS: These findings suggested that most multifocal neuroblastomas have favorable biologic features. Clinically, surgical approaches should be attempted to preserve organ function, especially adrenal function, and minimal invasive surgery should be performed. In cases of thoracoabdominal neuroblastoma, multistage surgery is effective and safe.     

Large cell neuroblastoma: a distinct phenotype of neuroblastoma with aggressive clinical behavior

BACKGROUND: Among cases of undifferentiated and poorly differentiated tumors in the neuroblastoma (Schwannian stroma-poor) category, the authors histologically identified a group of rare tumors, known as large cell neuroblastomas (LCNs), that are composed of large cells with sharply outlined nuclear membranes and 1-4 prominent nucleoli. METHODS: Histologic and immunohistochemical features of LCN were characterized. Morphologic characteristics, clinical features, and MYCN status were compared between LCNs and conventional neuroblastomas documented in the files of two European centers (the Sir James Spence Institute of Child Health, Royal Victoria Infirmary, University of Newcastle, Newcastle upon Tyne, United Kingdom, and the Medical and Health Sciences Center, University of Pécs, Pécs, Hungary). RESULTS: Of 92 peripheral neuroblastic tumors (pNTs; including neuroblastoma [n = 81]; ganglioneuroblastoma, intermixed [n = 6]; and ganglioneuroblastoma, nodular [n = 5]), 7 (7.6%) qualified as LCN. All 7 LCNs were classified as having unfavorable histology (UH) according to the International Neuroblastoma Pathology Classification. The LCNs were composed of monomorphous undifferentiated neuroblasts and shared certain histologic features, such as a high incidence of high mitosis-karyorrhexis index and a low incidence of calcification, with other neuroblastomas in the conventional UH (c-UH) group. These features were significantly different from those of neuroblastomas in the conventional favorable histology (c-FH) group. On immunohistochemical analysis, LCN tumor cells were positive for neuron-specific enolase (5 of 5 cases), protein gene product 9.5 (5 of 5 cases), synaptophysin (5 of 5 cases), tyrosine hydroxylase (focally in 3 of 3 cases), and NB84 (3 of 5 cases) and negative for CD99. Patients with LCN and patients with c-UH disease had similar clinical features (diagnosis at age > 1 year, often with distant metastasis). The clinical features of these patients also were significantly different from those of patients with c-FH disease. Further analysis demonstrated that the LCN group was significantly different from both the c-UH and c-FH groups with respect to MYCN status (MYCN amplification, 4 of 5 vs. 3 of 17 vs. 8 of 17, respectively; P = 0.023) and survival rate (4-year expected survival, 0% vs. 71% vs. 17%, respectively; P < 0.01). CONCLUSIONS: Because of its unique clinicopathologic features, the authors propose that LCN be recognized as a distinct entity within the undifferentiated and poorly differentiated subtypes of the neuroblastoma category.     

Neuroblastoma mass screening in late infancy: insights into the biology of neuroblastic tumors.

PURPOSE: Neuroblastoma screening in early infancy has detected predominantly "favorable" tumors. We postponed screening to an age between 7 and 12 months to test whether this shift of screening age might influence the detection rate of genetically/clinically unfavorable tumors. PATIENTS AND METHODS: In a 10-year period, 313,860 infants were screened by analysis of urine catecholamines. When a neuroblastoma was diagnosed, at least two different areas from every tumor were analyzed for genetic features (MYCN amplification, 1p status, ploidy). Furthermore, neuroblastoma incidence and mortality of the screened group and the cohort of 572,483 children not participating in the screening program were compared. RESULTS: Forty-six neuroblastomas were detected by mass screening. In 17 tumors (37%) at least one of the biologic features was "unfavorable." In 10 of 17 patients, one or more of these alterations were only focally present (tumor heterogeneity). In the screened cohort, neuroblastoma incidence was significantly higher when compared with unscreened children (18.2 v 11.2/100,000 births), while there was a trend towards lower incidence of stage 4 over 1 year (2.2 v 3.8). Mortality was not significantly different (0.96 v 1.57). CONCLUSION: In contrast to other neuroblastoma screening programs, more than one-third of patients were found with unfavorable genetic markers in our study. The high proportion of focal alterations suggests that biologically young neuroblastomas may consist of genetically favorable and unfavorable parts/areas/clones. We conclude that at least one-third of neuroblastomas detected by screening in late infancy are anticipated cases. This, however, does not result in significantly reduced mortality.     

Novel risk stratification of patients with neuroblastoma by genomic signature, which is independent of molecular signature

Human neuroblastoma remains enigmatic because it often shows spontaneous regression and aggressive growth. The prognosis of advanced stage of sporadic neuroblastomas is still poor. Here, we investigated whether genomic and molecular signatures could categorize new therapeutic risk groups in primary neuroblastomas. We conducted microarray-based comparative genomic hybridization (array-CGH) with a DNA chip carrying 2464 BAC clones to examine genomic aberrations of 236 neuroblastomas and used in-house cDNA microarrays for gene-expression profiling. Array-CGH demonstrated three major genomic groups of chromosomal aberrations: silent (GGS), partial gains and/or losses (GGP) and whole gains and/or losses (GGW), which well corresponded with the patterns of chromosome 17 abnormalities. They were further classified into subgroups with different outcomes. In 112 sporadic neuroblastomas, MYCN amplification was frequent in GGS (22%) and GGP (53%) and caused serious outcomes in patients. Sporadic tumors with a single copy of MYCN showed the 5-year cumulative survival rates of 89% in GGS, 53% in GGP and 85% in GGW. Molecular signatures also segregated patients into the favorable and unfavorable prognosis groups (P=0.001). Both univariate and multivariate analyses revealed that genomic and molecular signatures were mutually independent, powerful prognostic indicators. Thus, combined genomic and molecular signatures may categorize novel risk groups and confer new clues for allowing tailored or even individualized medicine to patients with neuroblastoma.     

Dickkopf-3 expression is a marker for neuroblastic tumor maturation and is down-regulated by MYCN

Neuroblastoma and ganglioneuroma are neuroblastic tumors originating from the developing sympathetic peripheral nervous system. Ganglioneuromas are usually benign, while neuroblastomas have a variable prognosis and include very aggressive tumors. Examples exist of neuroblastomas regressing to ganglioneuromas and ganglioneuromas progressing to neuroblastomas. Little is known of the molecular differences between the tumor types. Here we report that Dickkopf-3 (DKK3), a putative extra cellular inhibitor of the Wnt/beta-catenin pathway, showed a strongly differential expression between neuroblastoma and ganglioneuroma. Microarray analyses of 109 neuroblastic tumors revealed that DKK3 is strongly expressed in ganglioneuroma but only weakly in neuroblastoma. Low DKK3 expression in neuroblastoma correlated with a poor prognosis. The expression of DKK3 in the tumor series and in neuroblastoma cell lines was inversely correlated with the expression of the MYCN oncogene. Analysis of 2 neuroblastoma cell lines with inducible activity of MYCN showed that DKK3 is down-regulated by MYCN. We subsequently generated cell lines with inducible expression of DKK3, which revealed an inhibitory effect of DKK3 on proliferation. High DKK3 expression in the benign ganglioneuromas and down-regulation of DKK3 by MYCN in neuroblastoma might contribute to the strongly different clinical behavior of both neuroblastic tumor types.     

High Skp2 expression characterizes high-risk neuroblastomas independent of MYCN status.

PURPOSE: Amplified MYCN oncogene defines a subgroup of neuroblastomas with poor outcome. However, a substantial number of MYCN single-copy neuroblastomas exhibits an aggressive phenotype similar to that of MYCN-amplified neuroblastomas even in the absence of high MYCN mRNA and/or protein levels. EXPERIMENTAL DESIGN: To identify shared molecular mechanisms that mediate the aggressive phenotype in MYCN-amplified and single-copy high-risk neuroblastomas, we defined genetic programs evoked by ectopically expressed MYCN in vitro and analyzed them in high-risk versus low-risk neuroblastoma tumors (n = 49) using cDNA microarrays. Candidate gene expression was validated in a separate cohort of 117 patients using quantitative PCR, and protein expression was analyzed in neuroblastoma tumors by immunoblotting and immunohistochemistry. RESULTS: We identified a genetic signature characterized by a subset of MYCN/MYC and E2F targets, including Skp2, encoding the F-box protein of the SCF(Skp2) E3-ligase, to be highly expressed in high-risk neuroblastomas independent of amplified MYCN. We validated the findings for Skp2 and analyzed its expression in relation to MYCN and E2F-1 expression in a separate cohort (n = 117) using quantitative PCR. High Skp2 expression proved to be a highly significant marker of dire prognosis independent of both MYCN status and disease stage, on the basis of multivariate analysis of event-free survival (hazard ratio, 3.54; 95% confidence interval, 1.56-8.00; P = 0.002). Skp2 protein expression was inversely correlated with expression of p27, the primary target of the SCF(Skp2) E3-ligase, in neuroblastoma tumors. CONCLUSION: Skp2 may have a key role in the progression of neuroblastomas and should make an attractive target for therapeutic approaches.     

儿童纵隔神经母细胞瘤临床特征分析

  目的  探讨纵隔神经母细胞瘤临床特征。  方法  收集2008年3月至2012年9月中国医科大学附属第四医院儿科收治的神经母细胞瘤110例, 其中26例肿瘤位于纵隔, 其他部位84例。将纵隔神经母细胞瘤的临床表现、肿瘤标志物、生物学预后因素与其他部位对比。  结果  纵隔组平均年龄25.5个月, 与其他部位组相近。初诊时纵膈组88.5%有症状, 高于其他部位组60.7%（P < 0.05）; 早期病例（Ⅰ、Ⅱ期）34.6%, 高于其他部位组8.3%（P < 0.05）; 血清NSE>100 ng/L者达21.4%, 低于其他部位组86.1%（P < 0.001）。纵隔组N-myc基因拷贝数均 < 10, 其他部位组N-myc基因拷贝数>10者为23.1%（P < 0.05）。纵隔组4年总生存率为80.0%, 其中局限性肿瘤（Ⅰ、Ⅱ、Ⅲ期）达100%, 分别高于其他部位组44.0%、82.0%。  结论  多数纵隔神经母细胞瘤表现出临床分期早（Ⅰ、Ⅱ期）和良好的生物学预后因素, 这些特征可能与纵隔神经母细胞瘤良好的预后相关。      

Outcomes of children with intermediate-risk neuroblastoma after treatment stratified by MYCN status and tumor cell ploidy.

PURPOSE: The goal of Pediatric Oncology Group 9243 was to improve outcomes for children with intermediate-risk neuroblastoma (NB). PATIENTS AND METHODS: Patients were assigned to treatments on the basis of age, tumor MYCN status, and tumor cell ploidy. Children in the less intensive arm A received cyclophosphamide/doxorubicin and surgery. Patients not in complete remission postoperatively were treated with cisplatin/etoposide, cyclophosphamide/doxorubicin, and additional surgery. Patients with less favorable features were assigned to arm B, which consisted of carboplatin, etoposide, ifosfamide, and surgery. Survival rates were determined using an intent-to-treat approach. RESULTS: For arm-A patients, the 6-year event-free survival (EFS) was 86% with an SE of 3%. For arm-B patients, the 6-year EFS was 46% with an SE of 7%. MYCN status was the only statistically significant prognostic variable. Among patients whose tumors were MYCN nonamplified, a trend toward improved EFS was seen in children with hyperdiploid versus diploid tumors. However, many of these children responded well to salvage therapy, and overall survival rates did not differ on the basis of ploidy. Six-year EFS rates for arm B were patients with MYCN nonamplified, hyperdiploid tumors, 86% with an SE of 3%; patients with MYCN nonamplified, diploid tumors, 74% with an SE of 10%; patients with MYCN-amplified, hyperdiploid tumors, 46% with an SE of 15%; and patients with MYCN-amplified, diploid tumors, 22% with an SE of 10%. CONCLUSION: Outcomes for patients with MYCN-nonamplified, hyperdiploid tumors were excellent. Therapy reductions for these patients merit study. A trend toward less favorable outcomes for patients with MYCN-nonamplified, diploid tumors was observed; more children may need to be evaluated before therapy is reduced for this subgroup. For patients with MYCN-amplified tumors, new strategies are needed.     

Ataxin-2 promotes apoptosis of human neuroblastoma cells

Neuroblastoma is a highly heterogeneous tumor of young children. Although many advances have been made towards understanding the molecular mechanisms dictating the phenotypic heterogeneity, the prognosis of children with neuroblastoma, particularly of progressively growing variants, has remained dire. About 10% of neuroblastomas regress spontaneously, probably by apoptosis, while another 20% have amplified the MYCN gene resulting in a poor prognosis. In pursuit of identifying cell death-associated genes in neuroblastoma, we encountered the SCA2 gene, coding for ataxin-2, as an important player. Here, we report that enforced expression of wild-type ataxin-2, but not of mutant ataxin-2, sensitizes neuroblastoma cells for apoptosis. In line with this, higher levels of ataxin-2 were detected in apoptotic cells compared to nonapoptotic cells. Neuroblastoma tumors with amplified MYCN contain significantly less ataxin-2 protein than tumors without amplified MYCN. Collectively, our data suggest that ataxin-2 has an important role in regulating the susceptibility of neuroblastoma cells to apoptotic stimuli in vitro and in vivo.     

Differential expression and allelotyping of the p73 gene in neuroblastoma

p73 has recently been identified as a candidate imprinted tumor suppressor gene in neuroblastoma. To determine the possible involvement of this gene in the pathogenesis of neuroblastoma, we analyzed allelic expression, screened for mutations and determined MYCN copy numbers in 31 primary neuroblastoma tumor samples. Interestingly, the gene was biallelically expressed in 50% (4/8) of informative neuroblastomas, which suggests that activation of the normally silenced allele of this gene plays an important role in the tumorigenesis of neuroblastoma. However, no tumor-specific mutations were identified although 15 polymorphisms were detected in this gene. We also detected a very strong association between a C91T polymorphism and MYCN copy number in this tumor. The T allele was detected in 8/17 (47%) neuroblastomas without MYCN amplifications but not detected in cases with MYCN amplifications (0/14). The biological significance of this association, however, is unknown. Overall the data suggest that p73 may play an important role in the pathogenesis of neuroblastoma but that the true tumor suppressor gene localized to this area still remains to be identified.