Angiogenesis in primary central nervous system lymphoma (PCNSL)

Angiogenesis and angiogenic growth factors have a major role in the pathogenesis of malignancies. However, very little is known about the clinical and histopathological relevance of angiogenesis in primary central nervous system lymphoma (PCNSL). We investigated that expression of vascular endothelial growth factor (VEGF) of the lymphoma cells and microvessel density (MVD) were examined in 19 patients with PCNSL. Additionally, the presence of the blood–brain barrier (BBB) was examined using immunohistochemistry and the electron microscopy. MVD was significantly higher in nine cases with VEGF immunoreactivity (VEGF+) than in ten cases with negative immunoreactivity for VEGF (VEGF−) (P < 0.001). VEGF expression was significantly associated with a longer survival (P < 0.005). BBB markers were negative in angiogenic vessels of VEGF+. BBB markers were identified in vessels surrounding tumor cells and tight junctions were also preserved in the capillary endothelium surrounding tumor cells in VEGF−. Angiogenesis is associated with VEGF expression and an absent BBB in the vessels of PCNSL. The BBB may be preserved in lesions with lymphoma cell infiltration, especially in VEGF− PCNSL. VEGF may have a prognostic effect in PCNSL.     

Potential of chemo-immunotherapy and radioimmunotherapy in relapsed primary central nervous system (CNS) lymphoma

Five patients with relapsed PCNSL were given chemo-immunotherapy (rituximab followed by carboplatin and methotrexate) with osmotic blood-brain barrier (BBB) opening. Four patients achieved CR and one patient had stable disease. Two patients (2/5) had durable responses (survival: 230+, 122+, 82, 42, 38 weeks). One patient later received Indium-111-ibritumomab tiuxetan and Yttrium-90-ibritumomab tiuxetan intravenous, without BBB opening. There was good uptake of Indium-111 ibritumomab tiuxetan in tumor on SPECT scan after 48 h. Estimated radiation doses to brain around and distant from tumor were within safe limits. After Ytrium-90 ibritumomab tiuxetan there was CR in enhancing tumor where the BBB was leaky, but lesions occurred in other brain regions, where the BBB was intact during Yttrium-90 ibritumomab tiuxetan infusion. Imaging and dosimetry with Indium-111 ibritumomab tiuxetan and efficacy with Yttrium-90 ibritumomab tiuxetan suggest the need for future enhanced CNS delivery when using monoclonal or radiolabeled antibodies, as intravenous delivery alone may provide modest clinical benefit due to limited BBB permeability.     

Methotrexate based chemotherapy and deferred radiotherapy for primary central nervous system lymphoma (PCNSL): single institution experience

In the following study, we present our experience in the treatment of PCNSL patients using a multi-step schedule combining chemotherapy and deferred radiotherapy. Patients were treated with two modified M-BACOD cycles and then differently according to radiological response For PR, SD and PD patients, chemotherapy was interrupted and radiotherapy initiated immediately (45 Gy Whole-brain RT). With CR patients, chemotherapy was continued with a combination of HMTX, VCZ, PCB and HD Ara-C up to a total of nine cycles. In 36 patients suitable for evaluation (2 patients had undergone tumour resection): 69.4% (25 of 36) had a complete response (CR), 19.4% (7 of 36) had a partial response(PR), 8.3% (3 of 36) had stable disease(SD), and 2.7% (one of 36) had progressive disease (PD). The PR, SD and PD patients were immediately treated by radiotherapy. In this cohort of patients, we observed 6 CR, 4 PR and 2 PD, respectively, following radiotherapy. At first relapse, a total of 16 CR patients were treated by radiotherapy for a total dose of 45 Gy. The OS was 42.1 months for the entire group of patients. In CR patients treated at the moment of recurrence by salvage radiotherapy, the TTP (time lasting from histological diagnosis until recurrence of disease before RT) was 28.3 months, with a 43.4% of disease free patients observed at 2 years. The median disease-free time observed after complete response to radiotherapy was 10.5 months. In 16 patients (34%), further progression of disease was observed following radiotherapy. Two patients developed extra-CNS disease in the breast and testis. When taking into account the patients with radiotherapy delayed at recurrence, the OS was 48 months and the survival rates were 70% and 60% at 2 years and 5 years, respectively.     

Cerebrospinal fluid interleukin-10 is a potentially useful biomarker in immunocompetent primary central nervous system lymphoma (PCNSL)

The diagnosis of primary central nervous system lymphoma (PCNSL) by radiographical examination is often difficult because of its similarity to other brain tumors. To test whether interleukin-10 (IL-10) and IL-6 can be used to distinguish PCNSL from other brain tumors that are radiographically similar, cerebrospinal fluid (CSF) levels of IL-10 and IL-6 were measured in 66 patients with intracranial tumors (PCNSLs: 26 cases; other brain tumors: 40 cases). In the patients with PCNSLs, the median CSF levels of IL-10 and IL-6 were 27 pg/mL and 5.4 pg/mL, respectively. The CSF IL-10 and IL-6 levels were significantly higher in PCNSLs than in the other brain tumors. To validate the diagnostic value of CSF IL-10 in PCNSL, we prospectively examined 24 patients with brain lesions that were suspected to be PCNSL. We observed that the CSF IL-10 levels were significantly higher in PCNSLs than in other brain tumors. At an IL-10 cutoff level of 9.5 pg/mL, the sensitivity and specificity were 71.0% and 100%, respectively. After therapy, the CSF IL-10 levels were decreased in all patients and were increased at relapse in most of these patients. Immunohistochemically, all PCNSLs, except for 1 unclassified PCNSL, expressed both IL-10 and IL-10 receptor-A. In the patients with high CSF IL-10, IL-10 expression levels in tumor were relatively higher, compared with low CSF IL-10; however, there was no significant difference between these groups. In addition, elevated CSF level of IL-10 was significantly associated with having a shorter progression-free survival (hazard ratio, 3.37; 95% confidence interval, 0.985-11.528; log-rank, P= .038). These results indicate that the CSF level of IL-10 may be a useful diagnostic and prognostic biomarker in patients with PCNSLs.     

17例复发性原发中枢神经系统淋巴瘤的临床观察

目的 探讨原发性中枢神经系统淋巴瘤（PCNSL）复发后的临床特征、影像学特点、治疗疗效和预后。方法 回顾性分析2008年6月至2012年6月我科收治的17例复发性PCNSL患者的临床资料。复发后7例PCNSL患者行大剂量（900mg／m²）培美曲塞化疗;10例行替莫唑胺+奈达铂+长春新碱联合化疗,其中3例联合局部照射20～30Gy,3例患者行Ommaya囊置入术,术后给予利妥昔单抗30mg经Ommaya囊内注射治疗。结果 全组患者脑实质内异位复发9例（52.9％）,原位复发5例（29.4％）,脑脊膜转移2例（11.8％）,颅外腰椎转移1例（5.9％）。多体素质子磁共振波谱（1H-MRS）检查显示,全组患者肿瘤实质区及瘤周近侧水肿区胆碱（Cho）峰升高及N 乙酰天门冬氨酸（NAA）、肌酸（Cr）峰降低,肿瘤实质区有明显升高的Lip峰。复发PCNSL患者经治疗后有6例（35.3％）获CR,4例（23.5％）PR,5例（29.4％）SD,2例（11.8％）PD,有效率（RR）为58.8％（10／17）。至随访截止时间,全组患者的中位生存期（OS）为111个月,含替莫唑胺方案与培美曲塞方案患者的中位OS无明显差异（P＞0.05）。结论 PCNSL以脑内异位复发为主,复发后治疗困难,预后差,含替莫唑胺或培美曲塞综合治疗可能有一定程度的获益。     

Prevention of recurrence and prolonged survival in primary central nervous system lymphoma (PCNSL) patients treated with adjuvant high-dose methylprednisolone

Five patients at risk for primary central nervous system lymphoma (PCNSL) recurrence were treated with high-dose methylprednisolone (HDMP) to prevent 'trafficking' of malignant lymphocytes into the central nervous system (CNS). HDMP was chosen because of its ability to stabilize the 'blood brain barrier (BBB)'. Three men with newly diagnosed PCNSL, ages 62, 76 and 78y, whose survival was projected to be 6.6 months, began treatment after achieving complete response (CR) to initial radiation therapy alone and survived 27, 37 and 59 months after treatment. In none was death from recurrent disease in CNS but one patient did die of systemic non-Hodgkin's lymphoma (NHL) five years after PCNSL diagnosis. A 20 y old man was treated with HDMP after successful combined modality therapy and is alive 75+ months after initial diagnosis without evidence of disease recurrence. A 34 y old man relapsed after combined modality initial treatment and failed to respond to HDMP when treatment was begun after unsuccessful salvage therapy; he died of disease 12 months after initial diagnosis. There were no treatment complications. The promising results in this pilot study from the basis for a North Central Cancer Treatment Group (NCCTG) 96-73-51, a Phase 2 clinical trial of brain radiotherapy and HDMP for PCNSL patients 70y of age and older, a group of patients at high risk for toxicity from intensive combined modality therapy.     

替莫唑胺联合利妥昔单抗对复发的老年原发中枢神经淋巴瘤的应用

Objective: The aim of our study was to analyze the long-term results of rituximab combined with temozolomide in treatment of elderly patients (> 60 years) with relapsed primary central nervous system lymphoma (PCNSL). Methods: Twelve postoperative elderly patients (> 60 years) were treated between August 2004 and October 2009. Temozolomide 100 mg/m2 to 200 mg/m2 days 1 to 7 and 15 to 21 and rituximab 375 mg/m2 days 1, 5, 8, 22. The maximum number of rituximab cycles was two. After one or two cycles of this ...     

Pemetrexed in the treatment of relapsed/refractory primary central nervous system lymphoma

BACKGROUND:

Despite initial treatment with high‐dose methotrexate‐based regimens, many patients with primary central nervous system lymphoma (PCNSL) relapse and die from their disease. No standard of care exists at progression or relapse, but chemotherapy and in some cases radiation are usually used. Pemetrexed is a multitargeted antifolate, similar to methotrexate, but with a broader spectrum of activity. Because methotrexate is an integral part of PCSNL treatment, the authors assessed the antitumor activity and safety of pemetrexed in recurrent PCNSL.

METHODS:

Patients with relapsed/refractory PCNSL were enrolled in this trial. Treatment consisted of pemetrexed 900 mg/m² given every 3 weeks with low‐dose dexamethasone, folate, and B12 supplementation. Each cycle was 6 weeks, and follow‐up imaging was done before each new cycle. Treatment was continued until complete remission, progression, or toxicity.

RESULTS:

Eleven patients were treated, with a median age of 69.8 years and Karnofsky performance status of 70%; 10 of 11 patients had failed prior high‐dose methotrexate. The median number of pemetrexed cycles given was 5, with an associated overall response rate of 55% and disease control rate of 91%. The 6‐month progression‐free survival (PFS) was 45%, median PFS was 5.7 months, and median overall survival was 10.1 months. Toxicities were primarily hematologic and infectious.

CONCLUSIONS:

Pemetrexed has single‐agent activity in relapsed/refractory PCNSL. Toxicities were seen likely because of the higher than standard dose used. Further investigation of this agent or other multitargeted antifolates in PCNSL is warranted to determine optimal dose and efficacy in a more homogeneous population. Cancer 2012. © 2011 American Cancer Society.     

Topotecan as salvage therapy for relapsed or refractory primary central nervous system lymphoma

Treatment for patients with refractory or relapsed primary CNS lymphoma (PCNSL) remains unsatisfactory. Topotecan is an intravenous topoisomerase I inhibitor with good CSF penetration and documented efficacy in patients with relapsed systemic non-Hodgkin’s lymphoma. In this study 15 patients with refractory or relapsed PCNSL were treated with intravenous topotecan (1.5 mg/m²) for five consecutive days during each 21-day cycle. All 15 patients had measurable, contrast-enhancing tumor on cranial MRI at the time of relapse. Three (20%) patients achieved a complete response after one, three and four cycles, respectively, while three (20%) patients achieved a partial response after two cycles each, for a total response proportion of 40%. Three patients had stable disease at the end of topotecan treatment. Six patients (40%) had progressive disease during treatment. Median overall survival was 981 days (95% CI: 275, NA) and median progression free survival was 60 days (95% CI: 46, 945). Three out of 15 patients had grade 3 thrombocytopenia. Six out of 15 patients had grade 3 neutropenia, while 5/15 patients had grade 4 neutropenia, and 13/15 patients received g-CSF at some point during treatment. There were no deaths directly related to treatment toxicity. Our study shows that topotecan, as a salvage therapy in patients with relapsed or refractory PCNSL, is associated with an overall response proportion of 40% and should be considered in patients who have failed prior methotrexate-based chemotherapy and/or whole brain irradiation. However, progression is frequent and early and most patients required growth factor support due to myelotoxicity.     

Salvage treatment with temozolomide in refractory or relapsed primary central nervous system lymphoma and assessment of the MGMT status

High-dose methotrexate (HD-MTX) is effective in the initial treatment of primary central nervous system lymphoma (PCNSL). Because treatment options in patients with progressive or recurrent PCNSL are limited, prognosis is poor. Temozolomide, a well-tolerated oral alkylating agent that permeates the blood brain barrier (BBB), is effective against malignant glioma and recurrent PCNSL. The gene for the deoxyribonucleic acid (DNA) repair enzyme O⁶-methylguanine-DNA methyltransferase (MGMT), which is closely related to cellular sensitivity to alkylating agents, is inactivated by promoter hypermethylation. We evaluated the results of temozolomide treatment and the methylation status of the promoter region of the MGMT gene in 17 patients (median age 68 years) with refractory or relapsed PCNSL. They were immunocompetent and had received initial treatment with HD-MTX (3.5 g/m²) with or without irradiation. All were treated with temozolomide 150–200 mg/m², for 5 days in the course of 28 days; treatment was continued until disease progression. We observed five complete remissions, five partial responses (PRs) with stable disease (SD), and seven with disease progression. Median overall survival after the temozolomide treatment was 6.7 months. One patient manifested grade 3 neutropenia and thrombocytopenia. Eleven tumor specimens were available for MGMT analysis. MGMT promoter methylation (mMGMT) in the tumor tissue was found in 4 (36.4%), the other seven harbored a non-methylated MGMT promoter (nmMGMT). There was no statistically significant difference in median overall survival between patients with mMGMT (11.1 months) and nmMGMT (6.7 months) (P = 0.63). Although some patients were elderly and had been heavily pre-treated, temozolomide resulted in a complete response (CR) in 29% and was well tolerated without any major toxicity.     

AIDS-related primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) can develop in the setting of profound immunosuppression, including late-stage infection with HIV. The management of such patients has yet to be defined optimally and differs substantially from that of immunocompetent patients who have PCNSL. The clinical features, diagnosis, and management of AIDS-related PCNSL are reviewed. The authors focus on commonly encountered diagnostic and therapeutic dilemmas and explore some promises and pitfalls of Epstein-Barr virus-directed therapies.     

Deletion 6q and +X in one primary central nervous system lymphoma (PCNSL) arising in a patient without immune defects

Describimos el hallazgo citogenético en un linfoma cerebral primario de localización parietotemporooccipital izquierdo, que se presenta en un varón de 56 a?os sin antecedentes de terapia o enfermedad inmunosupresiva. El estudio citogenético de las células neoplásicas demostró un complemento cro-mosómico: 48,XY,+X, del (6) (q21), +mar, mientras que el paciente mostraba un cariotipo constitucional normal. La deleción 6q representa la alteración más frecuente en linfomas cerebrales primarios y podría asociarse a cortos períodos de supervivencia.     

Treatment of primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare neoplasm that has captured popular attention because of its rising incidence and marked chemosensitivity. It is a non-Hodgkins B-cell lymphoma (NHL) that appears confined to the central nervous system (CNS) at presentation but may be multifocal within the brain or involve the leptomeninges or eyes at diagnosis. Like systemic lymphoma, it is highly sensitive to corticosteroids, and administration of steroids should be withheld until the diagnosis has been confirmed histologically. Currently, the initial treatment of choice incorporates high-dose methotrexate (HD-MTX) either as a single agent or in combination with other systemic chemotherapies. Whole-brain radiotherapy (WBRT) can be a highly effective treatment modality when combined with MTX, but the combination causes an unacceptably high incidence of severe permanent neurotoxicity, particularly in patients over age 60. Therefore, chemotherapy alone is the initial treatment of choice in older patients. This approach is also being explored in younger patients, but it is possible that deferring radiotherapy may compromise disease control. Consequently, the role of radiotherapy remains to be clarified in newly diagnosed younger patients with PCNSL.     

Treatment of primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) describes a malignant non-Hodgkin's lymphoma (NHL) whose sole site of involvement is the central nervous system (CNS). The diagnosis of PCNSL must be differentiated from systemic NHL with metastasis to the CNS, which usually occurs late in the course of systemic disease. PCNSL accounts for approximately 4% to 7% of primary brain tumors, and its incidence has been increasing since the mid-1970s. Compared with other more common malignant primary brain tumors, PCNSL tends to be more amenable to radiotherapeutic and chemotherapeutic intervention. In this article, the authors review the standard treatment for upfront and recurrent PCNSL.     

原发性中枢神经系统淋巴瘤的治疗

原发性中枢神经系统淋巴瘤(PCNSL)是一种较少见的中枢神经系统恶性肿瘤,总体预后欠佳,主要治疗方法包括手术、放疗和化疗.立体定向活检术以其微创、便捷的优点,已经成为确诊PCNSL的常规方法.全脑放疗是多病灶性PCNSL的标准化治疗方法,可短期内延缓肿瘤进展.以大剂量甲氨蝶呤为基础的治疗方案大大改善了PCNSL的治疗效果,成为PCNSL的有效治疗措施.有效的综合治疗是延长PCNSL患者生存期和改善生命质量的关键.     

原发中枢神经系统淋巴瘤研究进展

原发中枢神经系统淋巴瘤(PCNSL)是原发于颅内的结外非霍奇金淋巴瘤,是一种罕见的高侵袭性淋巴瘤,预后较差.近年来,关于PCNSL的治疗方案尚无定论,以往的治疗包括手术、放疗、化疗等.目前大多认为综合治疗可以提高患者的生存率,而联合化疗药物的选择和预防性鞘内注射化疗药物在其治疗中占有重要地位.     

首次复发?难治原发性中枢神经系统淋巴瘤预后影响因素分析

  目的  分析复发/难治原发性中枢神经系统淋巴瘤（primary central nervous system lymphoma,PCNSL）患者临床特点并探讨其影响预后的因素,为临床诊疗提供依据。  方法  选取复旦大学附属华山医院2006年10月至2015年8月确诊的64例复发/难治PCNSL患者的病例资料、治疗方案、实验室辅助检查指标进行回顾性分析。采用Cox回归多因素分析。  结果  单因素和多因素分析结果显示,首次无疾病进展生存期（progression-free survival of first time,PFS1）≤1年、Karnofsky评分（Karnofsky performance score,KPS） < 70分为影响复发/难治PCNSL预后的独立危险因素。PFS1≥1年患者中位第二次无疾病进展生存期（median progression-free survival of second time,mPFS2）和中位第二次总生存时间（median overall survival of second time,mOS2）分别为19个月和21个月,而PFS1 < 1年患者mPFS2和mOS2分别为10个月和14个月。复发/难治时KPS评分≥70分患者与KPS评分 < 70分患者mPFS2分别为40个月和10个月,mOS2分别为43个月和12个月。另外,单因素分析首次复发/难治PCNSL患者选用含有大剂量甲氨蝶呤（high-dose methotrexate,HD-MTX）化疗方案的mPFS2为18个月,而选用不含HD-MTX化疗方案的mPFS2为10个月,差异具有统计学意义。多因素分析结果显示,挽救方案为影响患者PFS的相关因素;单因素分析结果显示,挽救方案含有HD-MTX与不含有HD-MTX组的mOS2分别为23个月和12个月,差异无统计学意义,考虑与样本量较小有关。  结论  PFS1≤1年、KPS评分 < 70分是影响复发/难治PCNSL预后的独立危险因素。首次复发/难治PCNSL患者挽救治疗继续给予HD-MTX为基础的化疗方案可能会提高患者的远期疗效。      

Natural history and prognostic factors for survival in patients with acquired immune deficiency syndrome (AIDS)-related primary central nervous system lymphoma (PCNSL)

The incidence of primary central nervous system lymphoma (PCNSL) is increasing rapidly. It will be the most common primary malignant neoplasm of the brain by the year 2000. PCNSL is an important lethal complication in acquired immunodeficiency syndrome (AIDS) patients. Our objective was to study the natural history and prognostic factors for survival in patients with AIDS-related PCNSL. This is a retrospective cohort study of 75 patients with the diagnosis of AIDS-related PCNSL followed at Jackson Memorial Hospital/University of Miami. Medical records were abstracted for information about age, gender, race, and ethnicity. The method of diagnosis, treatment, and outcome of AIDS and PCNSL in this group were examined. Univariate and multivariate analyses were performed to identify prognostic factors for survival. The median age was 37 years. Males comprised 84% of the patients and 55% of the patients were Hispanic. The most common human immunodeficiency virus (HIV) risk factors were homosexuality and multiple sexual partners. The median cluster designation (CD) 4 count was 15/microl and the median lactic dehydrogensase (LDH) was 1.5x normal. Computed-assisted tomographic (CT) scans of the brain showed multiple lesions in 44% of the patients. Single-photon emission CT scan (SPECT) Thallium-201 of the brain was performed in two-thirds of patients. The most common histologies were immunoblastic and large cell lymphoma. Cranial radiation was given to 72% of the patients, and 55% of them did not complete treatment. The median survival of the group was 1.3 months. Univariate and multivariate analysis showed that longer survival was associated with good performance status (ECOG = 1 to 2 vs. 3 to 4). The presence of prior opportunistic infections, risk factors for AIDS, CD4 counts, level of LDH, ethnicity, gender, duration of symptoms before diagnosis, and race did not influence survival. PCNSL is a neoplasm with a very poor prognosis and short survival even with CNS radiation therapy. Performance status appears to be the main prognostic factor for survival. No significant differences in presentation or outcome were detected between the Hispanic and non-Hispanic patients.     

原发中枢神经系统淋巴瘤的治疗

原发中枢神经系统淋巴瘤(PCNSL)是一种少见的非霍奇金淋巴瘤(NHL),其治疗观念在过去的20年中发生了巨大的改变,现总结探索其治疗方式的研究工作.     

Advances for the treatment of primary central nervous system lymphoma (review)

Primary central nervous system lymphoma (PCNSL) is a non-Hodgkin's lymphoma arising in the CNS. This review will focus on the recent advances in the treatment of PCNSL. Combined methotrexate-based chemotherapy and radiation therapy is the standard treatment for PCNSL. A median overall survival of 40-60 months is obtained, however, neurotoxicity is a major problem. Preservation of cognitive function appears better after chemotherapy alone, therefore, there are increasing reports that radiotherapy is deferred after chemotherapy. At the moment, the findings of multicenter randomized trials should be awaited to clarify whether deferring radiotherapy in patients responding to chemotherapy allows them to maintain a better quality of life without increasing the risk of local recurrence. The well-designed, multicenter and randomized trials will elucidate the issues, such as best chemotherapy regimen, no brain irradiation in responder and second-line treatment.