Expression Of Cyclin D3 And LMO2 In Primary Central Nervous System Lymphoma And Clinical Analysis

PARTI Expression of Cyclin D3 and LMO2 in Primary Central Nervous System Lymphoma and its SignificanceBackground 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 LymphomaBackground 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.