原发性中枢神经系统淋巴瘤cyclin D3和LMO2的表达意义及临床疗效分析
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摘要
第一部分Cyclin D3及LMO2在原发中枢神经系统淋巴瘤的表达及其意义
背景和目的：原发性中枢神经系统淋巴瘤(Primary central nervous system lymphoma, PCNSL)是一种罕见的非霍奇金淋巴瘤(non-Hodgkin's lymphoma,NHL),其发病遍布全世界,临床过程有明显的异质性。西方国家的一些资料显示,PCNSL的发病率自上世纪七十年代后呈上升趋势。此病临床表现复杂、诊断和治疗困难都很困难,预后很差。近年来大量的研究认为年龄和体能状态(performance status, PS)是PCNSL主要的独立预后因素,但分子生物学标记对其预后的影响还不十分清楚。过去的研究主要集中在细胞来源相关标记和新生血管生成相关指标方面,并且缺乏大样本量的临床研究的支持。Cyclin D3是细胞周期从G1到S期转化的重要调控因子,近期有研究显示cyclin D3为系统性弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma, DLBCL)的不良预后因素。LM02是一种重要的转录调节因子,属于LIM-only家族,有研究证实LM02为系统性DLBCL的良好预后因素。但cyclin D3和LM02与PCNSL的相关性研究尚未见文献报道。我们收集71例PCNSLs的肿瘤标本,用免疫组化的方法检测cyclin D3和LM02在PCNSL的表达情况并评价其预后价值。
材料与方法：回顾分析2002年至2007年的71例PCNSL患者的临床资料。所有病例均经过活检组织病理学确诊,并且初诊时没有发现其他组织器官受累的证据。采用免疫组化染色法(SABC法)研究其中51例的标本的cyclin D3和LM02的表达情况。Fisher确切概率法分析cyclinD3、LMO2与临床指标间的相关性。用Kaplan-Meier法构建生存曲线,用Log-rank检验进行生存曲线的单因素分析,采用Cox风险比例回归模型进行多因素分析。Stata 10.0分析软件对数据进行处理。
结果：51例初发PCNSL患者中,31例观察到cyclin D3阳性表达,阳性率60.78%；LM02染色在14例标本中阳性表达,阳性率27.45%。未发现cyclin D3和LM02的表达与年龄、ECOG-PS评分、肿瘤多发、深部病变、颅高压表现、MIB-1相关。
所有患者的中位生存期22个月,3年生存率为31.6%. Cyclin D3阳性表达患者的生存期较低表达患者缩短。Kaplan-Meier法对患者的生存率进行估计：cyclinD3阳性表达患者2年生存率为22.74%；而cyclin D3阴性患者的2年生存率为63.56%(χ2=7.80,P=0.01)。包括cyclin D3、年龄、发病到诊断的时间、术前使用地塞米松的剂量、深部病变、颅高压症状等的多因素分析发现：cyclin D3阳性表达的风险比(hazard odds ratio, HR)为4.00(95%可信区间：1.18-13.61,P=0.03)；发病时伴颅高压症状的HR值为6.62(95%可信区间：1.93-22.73,P=0.00),cyclin D3可以独立作为PCNSL预后不良的因素。所有患者中位疾病进展时间(time to progression, TTP)为16个月,最长62个月。Cyclin D3阳性的PCNSL患者中位TTP为9个月,而cyclin D3阴性者中位TTP为31个月,但是这种差异并没有明显的统计学意义(χ2=2.86,P=0.09)。包括cyclin D3、年龄、发病到诊断的时间、术前使用地塞米松的剂量、深部病变、颅高压症状等的多因素分析提示深部病变和颅高压症状为影响PCNSL患者TTP的2个独立的预后因素。CyclinD3的表达水平对TTP仍有一定程度的影响,HR值为1.84(95%可信区间：0.65-5.17)。在我们的研究中,没有发现LM02的表达对PCNSL患者预后有明显的影响。
结论：Cyclin D3阳性表达在PCNSL中较系统性DLBCL多见,并且cyclin D3的阳性可以独立作为预测PCNSL临床预后不良的指标。LM02在PCNSL的表达程度低于系统性DLBCL,未发现其与PCNSL预后存在明显的相关性。Cyclin D3有可能成为PCNSL患者分层治疗的有价值的临床指标。
第二部分26例原发性中枢神经系统淋巴瘤的临床疗效分析
背景和目的：原发性中枢神经系统淋巴瘤(primary central nervous system lymphoma, PCNSL)是一种局限于脑、脊髓和眼内的罕见的非霍奇金淋巴瘤(non-Hodgkin' s, NHL)。其病理、治疗、预后特点均不同于系统性NHL,目前还没有标准的治疗方案。该病对放疗和化疗都是敏感的。早期放疗是主要治疗方法,通过放疗PCNSL一般都可以取得完全缓解(CR)或部分缓解(PR),但是放疗后的缓解维持的时间并不长,单纯化疗的生存期为11-14个月。在全颅放疗后给予MTX基础的化疗可以延长PCNSL患者生存期,但这种治疗方案常伴有远期神经毒性,这在年龄大于60岁的PCNSL患者中尤为严重。用单纯化疗的方法治疗PCNSL效果好,并且与放化疗联合的方法相比,神经毒性也比较少出现。是否这两种治疗方法对PCNSL的生存有相似的影响还不清楚。年龄、体能状态(performance status, PS)、接受包括高剂量甲氨喋呤(HD-MTX)的治疗是经普遍研究证实影响PCNSL预后的因素。其他有利的预后因素还包括：肿瘤单发、无脑膜和/或脑室周围累及、无免疫缺陷等,但目前还没有统一的预后指数建立起来。本研究总结我院26例PCNSL的治疗情况,并对预后因素和治疗反应进行评价,希望能够对PCNSL的规范化治疗有所帮助。
材料与方法：收集26例2002年-2007年在复旦大学附属华山医院住院治疗的初发PCNSL。所有病例均经过活检病理诊断,并无其他组织器官受累的证据。对这些病例的临床特点、治疗方案及临床疗效进行总结分析。用多重Logistic回归的方法评估对国际预后预后指数(international prognostic index, IPI)、鞘内注射、含HD-MTX的化疗方案、含去甲氧柔红霉素(ID)的化疗方案、含替尼泊甙(Vm-26)的化疗方案等因素对疗效的影响。用Kaplan-Meier生成生存曲线、Log-rank检验进行OS和PFS的单因素分析,通过Cox相对风险回归模型对包括年龄、PS评分、深部病变、含HD-MTX的化疗方案、含ID的化疗方案和含Vm-26的化疗方案进行多因素分析。用Stata 10.0分析软件对数据进行处理。
结果：大部分患者(23/26,88.46%)接受手术切除治疗。所有26例患者中,19例初治为单纯化疗方案,6例为WBRT治疗后1月进行辅助化疗,1例初治时仅行WBRT。26例患者中18例使用过含HD-MTX的静脉化疗方案。这些方案包括：单用MTX、MTX+Vm-26、MTX+ID、MTX+CHOP等。另有6例患者(6/24,25%)接受包括地塞米松(Dex)、阿糖胞苷(Ara-C)和MTX的鞘内注射。
以单纯化疗为初治方案的19例患者,在治疗3周期后8例达CR(42.11%)、4例达PR(21.05%),总的治疗反应率为63.16%。单因素分析中,含HD-MTX方案,总有效率83.40%(χ2=5.70,P=0.02)；含ID的方案总有效率75%(χ2=4.97,P=0.03)。对年龄、HD-MTX、ID进行治疗反应的多因素分析,发现含HD-MTX的治疗方案为影响治疗反应的唯一独立的影响因素(P=0.03),并且优势比为20.35(95%可信区间1.24-334.53)。7例一线治疗为WBRT的PCNSL患者在治疗后进行头颅MRI或CT评估,5例患者肿瘤减小>50%。复发难治者11例,其中8例接受了补救治疗。6例接受包含WBRT的补救治疗,4例接受HD-MTX基础的方案。另外有2例因WBRT补救治疗无效而接受大剂量化疗(intensive chemotherapy, ICT)+自体干细胞移植(autologous stem cell transplantation, ASCT),一半的补救方案使影像学上肿瘤减小>50%,复发后的中位PFS为12个月。
26例PCNSL患者有效随访22例,生存期4-70个月,中位生存期35个月。接受含HD-MTX的化疗方案者中位生存期35个月,化疗方案中不包括HD-MTX的一组中位生存期20个月(P=0.04)。HD-MTX的应用延长了PCNSL患者的生存期。单纯化疗与WBRT联合化疗的治疗策略对PCNSL患者生存方面的影响无显著差异(P=0.59)。多因素分析提示年龄≤60岁、PS评分<2分、无深部病变、含MTX和含ID的化疗方案为影响PCNSL患者生存期的有利因素。特别是年龄、PS评分和含ID的治疗对PCNSL患者的OS影响较大,HR值分别为36.82、31.81和25.98。PFS范围2-41个月,中位PFS为17个月。PFS的单因素分析提示：只有年龄是具有统计学意义的预后因素(P=0.00)。对PFS进行包括年龄、PS评分、深部病变、含MTX方案、含ID方案、含Vm-26方案和鞘内注射等多因素分析,显示年龄、PS评分和含ID方案的治疗为3个最重要的预后因素,HR分别为9.13、10.31和5.34。
结论：含HD-MTX的单纯化疗作为PCNSL患者初治方案有利于病情的缓解,且接受含HD-MTX化疗方案治疗的患者生存情况优于对照组。含ID的化疗方案在改善PCNSL患者临床结局方面显示出重要的价值。单纯化疗与WBRT联合化疗对PCNSL患者生存期的影响无显著差异。PCNSL患者在第一次缓解后容易复发,但复发后经过WBRT单独或联合包括HD-MTX的化疗方案治疗后仍然可以获得较高的缓解率。
PARTI Expression of Cyclin D3 and LMO2 in Primary Central Nervous System Lymphoma and its Significance
Background and objectives:Primary central nervous system lymphoma (PCNSL) is an uncommon form of non-Hodgkin's lymphoma (NHL), with a worldwide distribution and heterogeneous clinical course. PCNSL incidence among immunocompetent individuals has been progressively increasing in rencent years. Because of the complexed clinical manifestation, the difficulties in diagnosis and treatment, the clinical outcome of PCNSL is still poor. A large number of studies have consistently identified age and performance status as the main independent prognostic factors of PCNSL, while the prognostic significance of biomarkers remains unclear.Prevous reseaches mainly focused on markers related to B-cell origin and angiogenesis, under evaluation of large clinical trials. Cyclin D3 is an important regulator for transition from G1 to the S phase of the cell cycle. Recent studies have comfirmed that cyclin D3 is an unfavorable factor, predicting a shorter survival in patients with systematic diffuse large B-cell lymphoma (DLBCL). LM02 with a crucial role in transcription is a member of the LIM-only protein family. A series of researches associated LM02 with DLBCL prolonged survival. However, both cyclin D3 and LM02 have not been investigated in PCNSL, we have therefore reviewed 71 PCNSLs, detected expression levels of the two genes by immunohistochemistry method and evaluated their prognostic significance in PCNSL.
Materials and methods:Review clinical imformations of 71 patients with PCNSL between 2002 and 2009. All patients were diagnosed by pathology biopsy with no evidence of systematic involvement. Immunohistochemistry method (SABC)were performed with monoclonal antibody against cyclin D3 and LMO2 in 51 cases of PCNSL patients.Associations of both cyclin D3 and LM02 expressions with clinical parameters were assessed by the Fisher exact test. Survival curves were constructed using the Kaplan-Meier method. Univariate analyses of survival curves were performed using the log-rank test; Variables that considered significant prognostic factors were included in a multivariate analysis using the Cox proportional hazards regression model. The Stata 10.0 statistical software system was used for calculations.
Results:Cyclin D3 and expression was immunohistochemically determined in 51 previously untreated patients with PCNSL. High cyclin D3 expression was observed in 31(60.78%) patients and LMO2 staining was present in 14 of 51 cases.In clinical parameters including age,ECOG performance status, multiple lesions, deep structure involved, signs of raised intracranial pressure and proliferation marker MIB1,patients with high or low cyclin D3 expression did not differ signifiantly. LMO2 expression was observed the same state as cyclin D3.
The median follow-up of the total study population was 22 months, The estimated 3-year overall survival of all patients was 31.60%. Patients with high cyclin D3 expression had a shorter overall survival than those with low cyclin D3 expression. Kaplan-Meier estimate of survival at 2 years was 22.74% for patients with high cyclin D3 expression and 63.56% for patients with low cyclin D3 expression (χ2=7.80, P=0.01); In the multivariate analysis that include cyclin D3, age, the interval between occurrence and diagnosis of the disease, the dose of dexamethasone used before surgery, involvement of deep structure, signs of raised intracranial pressure, the hazard odds ratio for death was 4.00 for high cyclin D3 expression (95%CI,1.18-13.61, P=0.03) and 6.62 for the signs of raised intracranial pressure (95%CI,1.93-22.73, P=0.00).Thus, cyclin D3 expression was an independent factor predicting a shorter overall survival.
The median TTP was 16 months,and the maximum TTP was 62 months. Kaplan-Meier estimate of the median TTP for patients with high cyclin D3 expression was 9 months, and 31 months for patients with low cyclin D3 expression, but the difference between the two groups was not significant statistically(x2=2.86,P=0.09).In the multivariate analysis (including age, the interval between occurrence and diagnosis of the disease, the dose of dexamethasone used before surgery, involvement of deep structure, signs of raised intracranial pressure) comfirmed that involvement of deep structure, signs of raised intracranial pressure were independent prognostic factors. Cyclin D3 still impact on the TTP to some degree, the the hazard odds ratio for progression was 1.84 for high cyclin D3 expression (95%CI:0.65-5.17).The high expression of LMO2 was observed no prognostic significance statistically in our study.
Conclusion:Cyclin D3 expresses more frequently in PCNSL than in systematic DLBCL. High cyclin D3 expression is an independent predictive and prognostic factor associated with poor clinical outcome in patients with PCNSL. LMO2 expresses less frequently in PCNSL than in systematic DLBCL and dose not associated with prognosis of PCNSL. Cyclin D3 might become a clinically useful marker for the selection of patients for specific treatments, and modulation of cyclin D3 expression may be a potential therapeutic strategy to improve clinical outcome in patients with PCNSL in the future.
PART II Clinical efficacy of 26 patients with Primary Central Nervous System Lymphoma
Background and objectives:The primary central nervous system lymphoma (PCNSL) is a rare subtype of NHL confined to brain, spinal cord or eye. The pathologic, prognosis and treatment of PCNSL is different from systemic NHL. No standard treatment is available so far. PCNSL is sensitive to both irradiation and chemotherapy. Radiotherapy was earlier considered the mainstay of therapy.Although radiotherapy normally induce complete or partial tumor regression, responses to radiotherapy alone are short-lived, with the survival time reported to be 11-14 months. MTX-based chemotherapy followed by whole-brain radiotherapy prolonged survival but is associated with delayed neurotoxicity especially in patients older than 60 years. Chemotherapy alone has a well-documented effect on PCNSL and seems to cause less neurotoxicity than the combination of radio-and chemotherapy.Whether the two regimens lead to the similar survival in PCNSL is not clear. Age, performance status and use of HD-MTX containing regimen are the most consistent prognositic factors that have been confirmed by researches.Other favorable prognostic factors described to date include a single lesion, the absence of meningeal or periventricular tumor, the absence of immunodeficiency. But consensual prognostic index is lacking. analyzed. This study is to investigate treatment of 26 cases of patients with PCNSL in our hospital and to evaluate the prognostic factors and response to treatment systematically, as to make some help to clinical management of PCNSL in future.
Materials and methods:26 patients, newly diagnosed with PCNSL in Fudan University Affiliated Huashan Hospital between 2002 and 2007, were included. All patients were diagnosed by pathology biopsy with no evidence of systematic involvement. Clinical characters and regimens of the cases were summarized. Multiple logistic regression models were used to assess the independent effects of International Prognostic Index (IPI), intrathecal chemotherapy, HD-MTX based chemotherapy, idarubicin (ID) containing chemotherapy and teniposide (Vm-26) containing therapy on response rates. Survival curves were generated by the Kaplan-Meier method. Univariate analyses of OS and PFS were performed using the Log-rank test. Multivariate analysis including age, performance status, involvement of deep structure, HD-MTX based chemotherapy, ID containing chemotherapy and Vm-26 containing therapy, were described by Cox proportional hazards regression model. The Stata 10.0 statistical software system was used for calculations.
Results:Tumors in 23 cases were completely or partially resected.19 patients received chemotherapy alone,6 cases received chemotherapy after whole brain radiotherapy(WBRT),1 case received WBRT alone after surgery. Chemotherapy containing HD-MTX was used in 18 cases, including MTX alone, MTX combined with CHOP, MTX combined with ID and MTX combined with Vm-26. Additionally,6 cases received intrathecal chemotherapy.
The chemotherapy was evaluated after the third courses.8 patients (42.11%) had achieved a complete response,4 (21.05%) a partial response, with an overall response rate of 63.16%. Univariate analyses comfirmed response rate in HD-MTX containing theray is 83.40%(χ2=5.70, P=0.02) and 75% in ID containing theray (χ2=4.97, P=0.03).Multivariate analysis including age, HD-MTX containing chemotherapy, ID containing chemotherapy, demonstrated the independent association between overall response rate and the use of HD-MTX, with the odds ratio of 20.35 (95%CI:1.24-334.53). At least a 50% reduction in tumour size was observed in 5 of 7 cases who received WBRT as an initial treatment after evaluated with cranial MRI or CT. There were 11 cases with refractory or relapsed PCNSL, and 8 cases received salvage treatment. WBRT as a salvage regimen was observed in 6 cases, while HD-MTX based chemotherapy was used in 4 cases. In addition,2 patients received intensive chemotherapy with autologous stem cell transplantation(ICT-ASCT) because of no response to salvage treatment of WBRT. Half of these salvage regimens reduced tumor size at least 50%, and the mediate progression free time from relapse was 12 months.
22 of 26 patients with PCNSL were effectively followed.The median survival time was 35 months, in the range of 4 to 70 months. The median survival time of cases received HD-MTX based chemotherapies and other chemotherapies were 35 months and 20 months, respectively.The using of HD-MTX prolonged PCNSL survival time(P=0.04).Patients younger than 60 seems to had a favorable survival (P=0.10). Chemotheray alone and WBRT combined chemotherapy demonstrate similar effects on PCNSL survival (P=0.59). Multivariate analysis confirmed age≤60 years, performance status<2, no involvement of deep structure, HD-MTX containing chemotherapy and ID containing chemotherapy were favorable prognostic factors.Especially age, performance status and ID containing chemotherapy had significant effects on OS of PCNSL (hazard ratio: 36.82,31.81,25.98). The median PFS was 17 months, in the range of 2 to 41 months. Univariate analyses of PFS demonstrated only the patient age was a statistically significant factors(P=0.00). Multivariate analysis including age, performance status, involvement of deep structure, HD-MTX based chemotherapy, ID containing chemotherapy and Vm-26 containing therapy, indicated age, performance status and ID containing chemotherapy were main factors associated with PFS, and the hazard ratio were 9.13,10.31,5.34, respectively.
Conclusion:HD-MTX containing chemotherapy alone as an initial therapy is beneficial to the remission of PCNSL, and could achieve favorable survival, compared to the negative group. Chemotheray with ID has a significant value of improving clinical outcome of PCNSL Chemotheray alone and WBRT combined chemotherapy demonstrate similar effects on PCNSL survival. Although PCNSL tends to recurring after the first remission, salvage therapy including WBRT with or without HD-MTX based chemotherapy could induce a high response rate.
背景和目的：原发性中枢神经系统淋巴瘤(Primary central nervous system lymphoma, PCNSL)是一种罕见的非霍奇金淋巴瘤(non-Hodgkin's lymphoma,NHL),其发病遍布全世界,临床过程有明显的异质性。西方国家的一些资料显示,PCNSL的发病率自上世纪七十年代后呈上升趋势。此病临床表现复杂、诊断和治疗困难都很困难,预后很差。近年来大量的研究认为年龄和体能状态(performance status, PS)是PCNSL主要的独立预后因素,但分子生物学标记对其预后的影响还不十分清楚。过去的研究主要集中在细胞来源相关标记和新生血管生成相关指标方面,并且缺乏大样本量的临床研究的支持。Cyclin D3是细胞周期从G1到S期转化的重要调控因子,近期有研究显示cyclin D3为系统性弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma, DLBCL)的不良预后因素。LM02是一种重要的转录调节因子,属于LIM-only家族,有研究证实LM02为系统性DLBCL的良好预后因素。但cyclin D3和LM02与PCNSL的相关性研究尚未见文献报道。我们收集71例PCNSLs的肿瘤标本,用免疫组化的方法检测cyclin D3和LM02在PCNSL的表达情况并评价其预后价值。
材料与方法：回顾分析2002年至2007年的71例PCNSL患者的临床资料。所有病例均经过活检组织病理学确诊,并且初诊时没有发现其他组织器官受累的证据。采用免疫组化染色法(SABC法)研究其中51例的标本的cyclin D3和LM02的表达情况。Fisher确切概率法分析cyclinD3、LMO2与临床指标间的相关性。用Kaplan-Meier法构建生存曲线,用Log-rank检验进行生存曲线的单因素分析,采用Cox风险比例回归模型进行多因素分析。Stata 10.0分析软件对数据进行处理。
结果：51例初发PCNSL患者中,31例观察到cyclin D3阳性表达,阳性率60.78%；LM02染色在14例标本中阳性表达,阳性率27.45%。未发现cyclin D3和LM02的表达与年龄、ECOG-PS评分、肿瘤多发、深部病变、颅高压表现、MIB-1相关。
所有患者的中位生存期22个月,3年生存率为31.6%. Cyclin D3阳性表达患者的生存期较低表达患者缩短。Kaplan-Meier法对患者的生存率进行估计：cyclinD3阳性表达患者2年生存率为22.74%；而cyclin D3阴性患者的2年生存率为63.56%(χ2=7.80,P=0.01)。包括cyclin D3、年龄、发病到诊断的时间、术前使用地塞米松的剂量、深部病变、颅高压症状等的多因素分析发现：cyclin D3阳性表达的风险比(hazard odds ratio, HR)为4.00(95%可信区间：1.18-13.61,P=0.03)；发病时伴颅高压症状的HR值为6.62(95%可信区间：1.93-22.73,P=0.00),cyclin D3可以独立作为PCNSL预后不良的因素。所有患者中位疾病进展时间(time to progression, TTP)为16个月,最长62个月。Cyclin D3阳性的PCNSL患者中位TTP为9个月,而cyclin D3阴性者中位TTP为31个月,但是这种差异并没有明显的统计学意义(χ2=2.86,P=0.09)。包括cyclin D3、年龄、发病到诊断的时间、术前使用地塞米松的剂量、深部病变、颅高压症状等的多因素分析提示深部病变和颅高压症状为影响PCNSL患者TTP的2个独立的预后因素。CyclinD3的表达水平对TTP仍有一定程度的影响,HR值为1.84(95%可信区间：0.65-5.17)。在我们的研究中,没有发现LM02的表达对PCNSL患者预后有明显的影响。
结论：Cyclin D3阳性表达在PCNSL中较系统性DLBCL多见,并且cyclin D3的阳性可以独立作为预测PCNSL临床预后不良的指标。LM02在PCNSL的表达程度低于系统性DLBCL,未发现其与PCNSL预后存在明显的相关性。Cyclin D3有可能成为PCNSL患者分层治疗的有价值的临床指标。
第二部分26例原发性中枢神经系统淋巴瘤的临床疗效分析
背景和目的：原发性中枢神经系统淋巴瘤(primary central nervous system lymphoma, PCNSL)是一种局限于脑、脊髓和眼内的罕见的非霍奇金淋巴瘤(non-Hodgkin' s, NHL)。其病理、治疗、预后特点均不同于系统性NHL,目前还没有标准的治疗方案。该病对放疗和化疗都是敏感的。早期放疗是主要治疗方法,通过放疗PCNSL一般都可以取得完全缓解(CR)或部分缓解(PR),但是放疗后的缓解维持的时间并不长,单纯化疗的生存期为11-14个月。在全颅放疗后给予MTX基础的化疗可以延长PCNSL患者生存期,但这种治疗方案常伴有远期神经毒性,这在年龄大于60岁的PCNSL患者中尤为严重。用单纯化疗的方法治疗PCNSL效果好,并且与放化疗联合的方法相比,神经毒性也比较少出现。是否这两种治疗方法对PCNSL的生存有相似的影响还不清楚。年龄、体能状态(performance status, PS)、接受包括高剂量甲氨喋呤(HD-MTX)的治疗是经普遍研究证实影响PCNSL预后的因素。其他有利的预后因素还包括：肿瘤单发、无脑膜和/或脑室周围累及、无免疫缺陷等,但目前还没有统一的预后指数建立起来。本研究总结我院26例PCNSL的治疗情况,并对预后因素和治疗反应进行评价,希望能够对PCNSL的规范化治疗有所帮助。
材料与方法：收集26例2002年-2007年在复旦大学附属华山医院住院治疗的初发PCNSL。所有病例均经过活检病理诊断,并无其他组织器官受累的证据。对这些病例的临床特点、治疗方案及临床疗效进行总结分析。用多重Logistic回归的方法评估对国际预后预后指数(international prognostic index, IPI)、鞘内注射、含HD-MTX的化疗方案、含去甲氧柔红霉素(ID)的化疗方案、含替尼泊甙(Vm-26)的化疗方案等因素对疗效的影响。用Kaplan-Meier生成生存曲线、Log-rank检验进行OS和PFS的单因素分析,通过Cox相对风险回归模型对包括年龄、PS评分、深部病变、含HD-MTX的化疗方案、含ID的化疗方案和含Vm-26的化疗方案进行多因素分析。用Stata 10.0分析软件对数据进行处理。
结果：大部分患者(23/26,88.46%)接受手术切除治疗。所有26例患者中,19例初治为单纯化疗方案,6例为WBRT治疗后1月进行辅助化疗,1例初治时仅行WBRT。26例患者中18例使用过含HD-MTX的静脉化疗方案。这些方案包括：单用MTX、MTX+Vm-26、MTX+ID、MTX+CHOP等。另有6例患者(6/24,25%)接受包括地塞米松(Dex)、阿糖胞苷(Ara-C)和MTX的鞘内注射。
以单纯化疗为初治方案的19例患者,在治疗3周期后8例达CR(42.11%)、4例达PR(21.05%),总的治疗反应率为63.16%。单因素分析中,含HD-MTX方案,总有效率83.40%(χ2=5.70,P=0.02)；含ID的方案总有效率75%(χ2=4.97,P=0.03)。对年龄、HD-MTX、ID进行治疗反应的多因素分析,发现含HD-MTX的治疗方案为影响治疗反应的唯一独立的影响因素(P=0.03),并且优势比为20.35(95%可信区间1.24-334.53)。7例一线治疗为WBRT的PCNSL患者在治疗后进行头颅MRI或CT评估,5例患者肿瘤减小>50%。复发难治者11例,其中8例接受了补救治疗。6例接受包含WBRT的补救治疗,4例接受HD-MTX基础的方案。另外有2例因WBRT补救治疗无效而接受大剂量化疗(intensive chemotherapy, ICT)+自体干细胞移植(autologous stem cell transplantation, ASCT),一半的补救方案使影像学上肿瘤减小>50%,复发后的中位PFS为12个月。
26例PCNSL患者有效随访22例,生存期4-70个月,中位生存期35个月。接受含HD-MTX的化疗方案者中位生存期35个月,化疗方案中不包括HD-MTX的一组中位生存期20个月(P=0.04)。HD-MTX的应用延长了PCNSL患者的生存期。单纯化疗与WBRT联合化疗的治疗策略对PCNSL患者生存方面的影响无显著差异(P=0.59)。多因素分析提示年龄≤60岁、PS评分<2分、无深部病变、含MTX和含ID的化疗方案为影响PCNSL患者生存期的有利因素。特别是年龄、PS评分和含ID的治疗对PCNSL患者的OS影响较大,HR值分别为36.82、31.81和25.98。PFS范围2-41个月,中位PFS为17个月。PFS的单因素分析提示：只有年龄是具有统计学意义的预后因素(P=0.00)。对PFS进行包括年龄、PS评分、深部病变、含MTX方案、含ID方案、含Vm-26方案和鞘内注射等多因素分析,显示年龄、PS评分和含ID方案的治疗为3个最重要的预后因素,HR分别为9.13、10.31和5.34。
结论：含HD-MTX的单纯化疗作为PCNSL患者初治方案有利于病情的缓解,且接受含HD-MTX化疗方案治疗的患者生存情况优于对照组。含ID的化疗方案在改善PCNSL患者临床结局方面显示出重要的价值。单纯化疗与WBRT联合化疗对PCNSL患者生存期的影响无显著差异。PCNSL患者在第一次缓解后容易复发,但复发后经过WBRT单独或联合包括HD-MTX的化疗方案治疗后仍然可以获得较高的缓解率。
PARTI Expression of Cyclin D3 and LMO2 in Primary Central Nervous System Lymphoma and its Significance
Background and objectives:Primary central nervous system lymphoma (PCNSL) is an uncommon form of non-Hodgkin's lymphoma (NHL), with a worldwide distribution and heterogeneous clinical course. PCNSL incidence among immunocompetent individuals has been progressively increasing in rencent years. Because of the complexed clinical manifestation, the difficulties in diagnosis and treatment, the clinical outcome of PCNSL is still poor. A large number of studies have consistently identified age and performance status as the main independent prognostic factors of PCNSL, while the prognostic significance of biomarkers remains unclear.Prevous reseaches mainly focused on markers related to B-cell origin and angiogenesis, under evaluation of large clinical trials. Cyclin D3 is an important regulator for transition from G1 to the S phase of the cell cycle. Recent studies have comfirmed that cyclin D3 is an unfavorable factor, predicting a shorter survival in patients with systematic diffuse large B-cell lymphoma (DLBCL). LM02 with a crucial role in transcription is a member of the LIM-only protein family. A series of researches associated LM02 with DLBCL prolonged survival. However, both cyclin D3 and LM02 have not been investigated in PCNSL, we have therefore reviewed 71 PCNSLs, detected expression levels of the two genes by immunohistochemistry method and evaluated their prognostic significance in PCNSL.
Materials and methods:Review clinical imformations of 71 patients with PCNSL between 2002 and 2009. All patients were diagnosed by pathology biopsy with no evidence of systematic involvement. Immunohistochemistry method (SABC)were performed with monoclonal antibody against cyclin D3 and LMO2 in 51 cases of PCNSL patients.Associations of both cyclin D3 and LM02 expressions with clinical parameters were assessed by the Fisher exact test. Survival curves were constructed using the Kaplan-Meier method. Univariate analyses of survival curves were performed using the log-rank test; Variables that considered significant prognostic factors were included in a multivariate analysis using the Cox proportional hazards regression model. The Stata 10.0 statistical software system was used for calculations.
Results:Cyclin D3 and expression was immunohistochemically determined in 51 previously untreated patients with PCNSL. High cyclin D3 expression was observed in 31(60.78%) patients and LMO2 staining was present in 14 of 51 cases.In clinical parameters including age,ECOG performance status, multiple lesions, deep structure involved, signs of raised intracranial pressure and proliferation marker MIB1,patients with high or low cyclin D3 expression did not differ signifiantly. LMO2 expression was observed the same state as cyclin D3.
The median follow-up of the total study population was 22 months, The estimated 3-year overall survival of all patients was 31.60%. Patients with high cyclin D3 expression had a shorter overall survival than those with low cyclin D3 expression. Kaplan-Meier estimate of survival at 2 years was 22.74% for patients with high cyclin D3 expression and 63.56% for patients with low cyclin D3 expression (χ2=7.80, P=0.01); In the multivariate analysis that include cyclin D3, age, the interval between occurrence and diagnosis of the disease, the dose of dexamethasone used before surgery, involvement of deep structure, signs of raised intracranial pressure, the hazard odds ratio for death was 4.00 for high cyclin D3 expression (95%CI,1.18-13.61, P=0.03) and 6.62 for the signs of raised intracranial pressure (95%CI,1.93-22.73, P=0.00).Thus, cyclin D3 expression was an independent factor predicting a shorter overall survival.
The median TTP was 16 months,and the maximum TTP was 62 months. Kaplan-Meier estimate of the median TTP for patients with high cyclin D3 expression was 9 months, and 31 months for patients with low cyclin D3 expression, but the difference between the two groups was not significant statistically(x2=2.86,P=0.09).In the multivariate analysis (including age, the interval between occurrence and diagnosis of the disease, the dose of dexamethasone used before surgery, involvement of deep structure, signs of raised intracranial pressure) comfirmed that involvement of deep structure, signs of raised intracranial pressure were independent prognostic factors. Cyclin D3 still impact on the TTP to some degree, the the hazard odds ratio for progression was 1.84 for high cyclin D3 expression (95%CI:0.65-5.17).The high expression of LMO2 was observed no prognostic significance statistically in our study.
Conclusion:Cyclin D3 expresses more frequently in PCNSL than in systematic DLBCL. High cyclin D3 expression is an independent predictive and prognostic factor associated with poor clinical outcome in patients with PCNSL. LMO2 expresses less frequently in PCNSL than in systematic DLBCL and dose not associated with prognosis of PCNSL. Cyclin D3 might become a clinically useful marker for the selection of patients for specific treatments, and modulation of cyclin D3 expression may be a potential therapeutic strategy to improve clinical outcome in patients with PCNSL in the future.
PART II Clinical efficacy of 26 patients with Primary Central Nervous System Lymphoma
Background and objectives:The primary central nervous system lymphoma (PCNSL) is a rare subtype of NHL confined to brain, spinal cord or eye. The pathologic, prognosis and treatment of PCNSL is different from systemic NHL. No standard treatment is available so far. PCNSL is sensitive to both irradiation and chemotherapy. Radiotherapy was earlier considered the mainstay of therapy.Although radiotherapy normally induce complete or partial tumor regression, responses to radiotherapy alone are short-lived, with the survival time reported to be 11-14 months. MTX-based chemotherapy followed by whole-brain radiotherapy prolonged survival but is associated with delayed neurotoxicity especially in patients older than 60 years. Chemotherapy alone has a well-documented effect on PCNSL and seems to cause less neurotoxicity than the combination of radio-and chemotherapy.Whether the two regimens lead to the similar survival in PCNSL is not clear. Age, performance status and use of HD-MTX containing regimen are the most consistent prognositic factors that have been confirmed by researches.Other favorable prognostic factors described to date include a single lesion, the absence of meningeal or periventricular tumor, the absence of immunodeficiency. But consensual prognostic index is lacking. analyzed. This study is to investigate treatment of 26 cases of patients with PCNSL in our hospital and to evaluate the prognostic factors and response to treatment systematically, as to make some help to clinical management of PCNSL in future.
Materials and methods:26 patients, newly diagnosed with PCNSL in Fudan University Affiliated Huashan Hospital between 2002 and 2007, were included. All patients were diagnosed by pathology biopsy with no evidence of systematic involvement. Clinical characters and regimens of the cases were summarized. Multiple logistic regression models were used to assess the independent effects of International Prognostic Index (IPI), intrathecal chemotherapy, HD-MTX based chemotherapy, idarubicin (ID) containing chemotherapy and teniposide (Vm-26) containing therapy on response rates. Survival curves were generated by the Kaplan-Meier method. Univariate analyses of OS and PFS were performed using the Log-rank test. Multivariate analysis including age, performance status, involvement of deep structure, HD-MTX based chemotherapy, ID containing chemotherapy and Vm-26 containing therapy, were described by Cox proportional hazards regression model. The Stata 10.0 statistical software system was used for calculations.
Results:Tumors in 23 cases were completely or partially resected.19 patients received chemotherapy alone,6 cases received chemotherapy after whole brain radiotherapy(WBRT),1 case received WBRT alone after surgery. Chemotherapy containing HD-MTX was used in 18 cases, including MTX alone, MTX combined with CHOP, MTX combined with ID and MTX combined with Vm-26. Additionally,6 cases received intrathecal chemotherapy.
The chemotherapy was evaluated after the third courses.8 patients (42.11%) had achieved a complete response,4 (21.05%) a partial response, with an overall response rate of 63.16%. Univariate analyses comfirmed response rate in HD-MTX containing theray is 83.40%(χ2=5.70, P=0.02) and 75% in ID containing theray (χ2=4.97, P=0.03).Multivariate analysis including age, HD-MTX containing chemotherapy, ID containing chemotherapy, demonstrated the independent association between overall response rate and the use of HD-MTX, with the odds ratio of 20.35 (95%CI:1.24-334.53). At least a 50% reduction in tumour size was observed in 5 of 7 cases who received WBRT as an initial treatment after evaluated with cranial MRI or CT. There were 11 cases with refractory or relapsed PCNSL, and 8 cases received salvage treatment. WBRT as a salvage regimen was observed in 6 cases, while HD-MTX based chemotherapy was used in 4 cases. In addition,2 patients received intensive chemotherapy with autologous stem cell transplantation(ICT-ASCT) because of no response to salvage treatment of WBRT. Half of these salvage regimens reduced tumor size at least 50%, and the mediate progression free time from relapse was 12 months.
22 of 26 patients with PCNSL were effectively followed.The median survival time was 35 months, in the range of 4 to 70 months. The median survival time of cases received HD-MTX based chemotherapies and other chemotherapies were 35 months and 20 months, respectively.The using of HD-MTX prolonged PCNSL survival time(P=0.04).Patients younger than 60 seems to had a favorable survival (P=0.10). Chemotheray alone and WBRT combined chemotherapy demonstrate similar effects on PCNSL survival (P=0.59). Multivariate analysis confirmed age≤60 years, performance status<2, no involvement of deep structure, HD-MTX containing chemotherapy and ID containing chemotherapy were favorable prognostic factors.Especially age, performance status and ID containing chemotherapy had significant effects on OS of PCNSL (hazard ratio: 36.82,31.81,25.98). The median PFS was 17 months, in the range of 2 to 41 months. Univariate analyses of PFS demonstrated only the patient age was a statistically significant factors(P=0.00). Multivariate analysis including age, performance status, involvement of deep structure, HD-MTX based chemotherapy, ID containing chemotherapy and Vm-26 containing therapy, indicated age, performance status and ID containing chemotherapy were main factors associated with PFS, and the hazard ratio were 9.13,10.31,5.34, respectively.
Conclusion:HD-MTX containing chemotherapy alone as an initial therapy is beneficial to the remission of PCNSL, and could achieve favorable survival, compared to the negative group. Chemotheray with ID has a significant value of improving clinical outcome of PCNSL Chemotheray alone and WBRT combined chemotherapy demonstrate similar effects on PCNSL survival. Although PCNSL tends to recurring after the first remission, salvage therapy including WBRT with or without HD-MTX based chemotherapy could induce a high response rate.
引文
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