Central nervous system involvement in mantle cell lymphoma.

BACKGROUND: Extranodal involvement, including central nervous system (CNS), is a frequent event in patients with mantle cell lymphoma (MCL). However, the incidence, risk factors, and impact on outcome remain controversial. PATIENTS AND METHODS: Main clinical, biological, and evolutive features of 82 patients (60 males/22 females; median age: 61 years) diagnosed with MCL (blastoid, 26%) in a single institution were analyzed for risk of CNS involvement and prognosis. RESULTS: Most patients had advanced stage and intermediate or high-risk International Prognostic Index (IPI). Eleven patients eventually developed CNS involvement with an actuarial 5-year risk of 26% (95% confidence interval 10% to 42%). In one asymptomatic patient, cerebrospinal fluid infiltration was detected at staging maneuvers (1/62; 1.6%). The remaining 10 patients developed neurological symptoms during the course of the disease (median time from diagnosis, 25 months). Initial variables predicting CNS involvement were blastoid histology, high proliferative index measured by Ki-67 staining, high lactate dehydrogenase (LDH) and intermediate- or high-risk IPI. Histological subtype and serum LDH maintained significance in multivariate analysis. Treatment of CNS infiltration consisted of intrathecal chemotherapy (two cases), and intrathecal chemotherapy plus systemic treatment (seven cases). Median survival after CNS involvement was 4.8 months, patients with this complication having shorter survival than those with no CNS disease. CONCLUSION: This study confirms the high incidence of CNS involvement in MCL patients. Treatments aimed at preventing this complication are warranted.     

Relevance of intraocular involvement in the management of primary central nervous system lymphomas.

BACKGROUND: Reported data regarding intraocular lymphoma (IOL) management are anecdotal. Cases of IOL included in an international multicentre series of 378 immunocompetent patients with primary central nervous system lymphomas (PCNSLs) were reviewed. PATIENTS AND METHODS: Staging included slit-lamp examination in 170 patients: IOL was diagnosed in 22 cases (13%). A concomitant brain lesion was detected in 21 cases. Planned treatment was chemotherapy followed by radiotherapy in 13 cases, chemotherapy alone in three and radiotherapy, followed by or not by chemotherapy in five; one patient was not treated. Chemotherapy included high-dose methotrexate in 12 cases. Ten patients received intrathecal chemotherapy. Radiotherapy consisted of whole brain irradiation, followed by or not by a tumour bed boost; ocular irradiation was planned in 15 cases. Irradiation in one patient without brain lesions was limited to the orbits only (50 Gy). RESULTS: IOL was positively correlated to systemic symptoms and meningeal disease. Fifteen patients (71%) achieved an objective response; 16 patients experienced a failure (2-year failure-free survival 34+/-10%). Failures involved the eyes in eight cases, with a 2-year time to ocular relapse of 59+/-11%. Ocular failure was less common in patients treated with chemotherapy plus ocular irradiation and was associated with a significantly shorter survival. Seven patients are alive [median follow-up 53 months, 2-year overall survival (OS): 39+/-11%] , five of whom were treated with ocular irradiation. The patient with isolated IOL is alive and disease-free at 14 months. OS of the entire series was similar to that of PCNSL patients with negative slit-lamp examination. CONCLUSIONS: IOL is usually associated with concomitant brain disease and shows a survival similar to that of the rest of PCNSLs. Chemotherapy combined with ocular irradiation resulted in better control of ocular disease, which seems to be associated with survival. In view of the potential role of ocular irradiation, the use of chemotherapy alone in phase II trials should be critically reconsidered in PCNSL patients with ocular disease.     

Central nervous system involvement following diagnosis of non-Hodgkin's lymphoma: a risk model.

BACKGROUND: To determine the incidence and risk factors for central nervous system (CNS) relapse in patients with non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Patient records were registered prospectively in successive patients with NHL admitted to the Norwegian Radium Hospital from 1980 to 1996. A total of 2514 patients had no CNS involvement at diagnosis and were treated according to standard protocols. The incidence and risk factors for CNS progression or relapse were examined retrospectively. RESULTS: In low-grade (L)-NHL, the risk of CNS involvement was low (2.8%). In high-grade (H)-NHL, lymphoblastic and Burkitt's NHL patients had a high risk of CNS recurrence (24.4%) at 5 years, and prophylaxis seemed to reduce this risk. For the other patients with H-NHL, the proportion with CNS involvement at 5 years was 5.2%. Multivariate analysis identified five independent risk factors, each present in >5% of patients: elevated serum lactate dehydrogenase, serum albumin <35 g/l, <60 years of age, retroperitoneal lymph node involvement and involvement of more than one extranodal site. If four or five of these risk factors were present, the risk of CNS recurrence was in excess of 25% at 5 years. CONCLUSIONS: The risk of CNS involvement in this study is comparable with the results from other large series. CNS prophylaxis is not recommended in any subgroup of L-NHL. The risk of CNS involvement among patients with either Burkitt's or lymphoblastic lymphomas is considerable and these patients should therefore receive intensive chemotherapy including systemic and intrathecal methotrexate. Patients with other types of H-NHL should receive adequate CNS prophylaxis if at least four of the five risk factors identified are present.     

Central nervous system occurrence in elderly patients with aggressive lymphoma and a long-term follow-up.

BACKGROUND: Secondary central nervous system (CNS) involvement by aggressive lymphoma is a well-known and dreadful clinical complication. The incidence and risk factors for CNS manifestation were studied in a large cohort of elderly (>60 years) patients with aggressive lymphoma. PATIENTS AND METHODS: In all, 444 previously untreated patients were randomized to receive 3-weekly combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone or cyclophosphamide, mitoxantrone, vincristine and prednisone (CNOP) (doxorubicin substituted by mitoxantrone) chemotherapy with or without filgrastim. Prophylactic intrathecal methotrexate was given to patients with lymphoma involvement of bone marrow, testis and CNS near sites. RESULTS: In all 29 of 444 (6.5%) developed CNS disease after a median observation time of 115 months. CNS was the only site of progression/relapse in 13 patients while part of a systemic disease manifestation in 16 patients. In univariate risk factor analysis, CNS occurrence was associated with extranodal involvement of testis (P = 0.002), advanced clinical stage (P = 0.005) and increased age-adjusted International Prognostic Index score (aaIPI; P = 0.035). In multivariate analysis, initial involvement of testis remained significant and clinical stage was of borderline significance. The median survival time was 2 months after presentation of CNS disease. CONCLUSION: A significant proportion of elderly patients with advanced aggressive lymphoma will develop CNS disease. CNS occurrence is related to testis involvement, advanced clinical stage and high aaIPI and the prognosis is dismal.     

惰性淋巴瘤治疗进展

惰性淋巴瘤诊断时多为晚期,一般认为常规化疗不能治愈。随着新的化疗药物以及免疫靶向治疗抗CD20单克隆抗体利妥昔的广泛用于惰性淋巴瘤治疗,研究结果显示了利妥昔单药治疗复发/难治性惰性淋巴瘤的突出疗效;利妥昔单药或与化疗联合用于惰性淋巴瘤的一线诱导治疗以及维持治疗的显著效果,并可获得分子学缓解,使得惰性淋巴瘤的有效率和长期生存得到了明显改善。     

Primary Central Nervous System Lymphoma: From Clinical Presentation to Diagnosis

Immunocompetent patients with primary central nervous system lymphoma (PCNSL) present with a median age of 55 years, immunosuppressed patients with a median age of 40 years. They show a broad range of signs and symptoms. Symptoms of increased intracranial pressure and personality change are most frequent, followed in frequency by ataxia and hemiparesis. The median time from onset of symptoms to diagnosis is 3–5 months in immunocompetent patients and 2 months in immunodeficient patients. The time to diagnosis can be considerably longer in patients with slowly developing personality change or fluctuating symptoms due to spontaneous or steroid-induced remission of so-called sentinel lesions. Native CT scans show iso- or hyperdense lesions with homogenous contrast enhancement. T1-weighted MRI scans show hypointense and T2-weighted scans hyperintense lesions. The definitive diagnosis of PCNSL requires biopsy. In some cases, however, the definitive diagnosis may exclusively be made by the demonstration of malignant B-lymphocytes in the cerebrospinal fluid.     

Low dose radiotherapy in indolent lymphomas,enough is enough

Follicular lymphomas, as a prototype of all indolent lymphomas, are exquisitely radiation sensitive. This review paper highlights the clinical presentation of this lymphoma entity. Literature data are presented on first line curative irradiation in stage I and II patients, low‐dose total body irradiation (TBI) in stage III and IV patients in first line and low‐dose IF‐RT (involved field radiotherapy) in patients with relapse. The clinical aspects of 2 × 2 Gy IF‐RT in follicular lymphoma (FL) are presented as well as the in vivo imaging of the apoptotic cell death underlying the clinical response. Finally, by gene expression profiling, possible molecular‐biological pathways are described involved in the low dose irradiation of FL. Copyright © 2009 John Wiley & Sons, Ltd.     

For which patients with aggressive non-Hodgkin's lymphoma is prophylaxis for central nervous system disease mandatory?

Purpose: Data of a multicenter study in non-Hodgkin's lymphoma (NHL) by the Dutch Hovon Group were reanalyzed to assess the risk of relapse in the central nervous system (CNS) related to the international risk index for NHL. In addition we assessed the risk for CNS disease in relation to the presence of bone marrow localisation at presentation.Design: We focused our analysis on those patients reaching a complete remission (CR). Two hundred eighty-six patients (histological subtypes D–H Working Formulation) and with stages II–IV were analyzed. One hundred ninety-three (67%) patients reached a CR.Results: Relapse occurred in 78 patients of whom 10 patients with concomitant or isolated CNS disease. According to the international risk index the following observations were made: low risk (n = 38) nine out of 34 CR relapsed, none had CNS involvement; low-intermediate risk (n = 115) 27 out of 83 CR relapsed, three had CNS involvement; high-intermediate risk (n = 110) 37 out of 68 CR relapsed, six had CNS involvement; high risk (n = 22) four out of seven CR relapsed, one had CNS involvement. Two out of 10 developed isolated CNS disease and eight out of 10 patients developed CNS disease with systemic relapse.Conclusion: Our data show that the number of CNS relapses after CR is relatively low (10 out of 193 = 5%), with an increasing incidence in the high-risk groups according to the international risk index. The occurrence of CNS relapse seems to be related to the risk of systemic relapse after CR. No subgroup could be discriminated in which prophylactic treatment would be of substantial benefit.     

Central nervous system dissemination in immunocompetent patients with aggressive lymphomas: incidence,risk factors and therapeutic options

Central nervous system (CNS) dissemination is a rare (4–5%) but usually fatal complication of aggressive lymphomas. Prophylaxis modalities to prevent CNS dissemination in aggressive lymphomas cannot be widely applied to every lymphoma patient since it is associated with increased risk of neurotoxicity. Therefore, identification of high‐risk patients as the best candidates to receive CNS prophylaxis constitutes a major endpoint in the management of these malignancies. Various risk factors and models for CNS recurrence have been described. Parameters reflecting the extent and proliferation of the disease, like elevated serum lactate dehydrogenase levels, involvement of multiple extranodal sites, advanced stage and high age‐adjusted International Prognostic Index (IPI) score, as well as the involvement of specific anatomic sites, like testes, orbit, paranasal sinuses, have been identified and confirmed as important to predict CNS dissemination. Management of this complication in aggressive lymphomas with conventional‐dose chemotherapy is associated with disappointing results, while some preliminary but encouraging experiences suggest a potential role of high‐dose chemotherapy and stem cell transplantation. The analysis of recent clinical studies could lead to advancement in the prognosis of aggressive lymphomas, but several questions regarding the optimum chemotherapy combination, the best conditioning regimen and the role of radiation therapy and intrathecal chemotherapy remain still unanswered. The purposes of the present review are to critically analyse current data on the risk of CNS dissemination in aggressive lymphomas, the clinical presentation of secondary CNS lymphomas and the efficacy of CNS prophylaxis as well as to discuss the available therapeutic options for this devastating event. Copyright © 2009 John Wiley & Sons, Ltd.     

Primary central nervous system lymphomas: incidence and survival in the Southern and Eastern Netherlands

BACKGROUND: An excessive increase in the incidence of primary central nervous system lymphoma (PCNSL) has been reported since the mid-1980s in the U.S. and U.K. Clinical studies have shown that radiotherapy and chemotherapy may prolong survival. In the current study, the authors describe the incidence, treatment, and survival of an unselected group of patients with PCNSL in the southern and eastern Netherlands. METHODS: Data regarding patients diagnosed between 1989-1994 were obtained from 4 population-based regional cancer registries in the southern and eastern Netherlands (n = 86) and the Eindhoven Cancer Registry for 1980-1988 (n = 6). Lymphomas were registered as PCNSL when a tissue diagnosis of CNS lymphoma was established for a patient with neurologic symptoms (i.e., lymphomas were not necessarily restricted to the CNS at the time of diagnosis). Only patients diagnosed during their lifetime with Stage I disease, Stage "IV" disease (i.e., diffuse CNS lymphoma), or disease of unknown stage were included (63 patients, 8 patients, and 15 patients, respectively, between 1989-1994). For 80 patients (93%) follow-up was complete until January 1, 1997. RESULTS: Between 1989-1994, an average World Standardized Rate of 2.3 cases and 1.7 cases per 1 million person-years, respectively, was reported for males and females. The median age of the patients at the time of diagnosis was 62 years, and was 66 years for patients with an unknown disease stage. In the area of the Eindhoven Cancer Registry the occurrence of PCNSL more than doubled from < 2% of all histologically confirmed primary CNS malignancies diagnosed between 1980-1985 to approximately 4% of cases diagnosed between 1986-1994. The median survival of all the patients was 4.1 months; the median survival was 5.8 months for patients with limited (Stage I and Stage IV) disease and was 0.6 months for patients with an unknown stage of disease. Approximately 65% of the patients with limited disease received radiotherapy and approximately 35% of such patients received chemotherapy. Furthermore, chemotherapy was given more often to patients age < 60 years who tended to have a slightly better survival than patients age > or = 60 years. CONCLUSIONS: The increase in the incidence of PCNSL in the 1980s may be explained in large part by changes in diagnostics and registration. The relatively high incidence and low survival rate of PCNSL in the southern and eastern Netherlands reported in the 1990s may be due in part to the inclusion of patients with systemic lymphoma and immunodeficiency disorders. However, a significant improvement in the prognosis of patients with PCNSL in the southern and eastern Netherlands diagnosed in the 1990s is unlikely.     

Phase I and pharmacokinetic study of oral fludarabine phosphate in relapsed indolent B-cell non-Hodgkin's lymphoma.

BACKGROUND: The primary objective of this study was to investigate the tolerability, efficacy and pharmacokinetic profile of oral fludarabine phosphate in relapsed patients with indolent B-cell non-Hodgkin's lymphoma (B-NHL). PATIENTS AND METHODS: Patients received fludarabine phosphate orally for 5 days, for a total of one to three cycles. Tolerability was assessed using the National Cancer Institute Common Toxicity Criteria. Efficacy was assessed using the International Workshop Criteria for NHL. Pharmacokinetic samples were taken on day 1 and day 5 of the first treatment cycle. RESULTS: Twelve patients were enrolled. One patient at 40 mg/m2/day developed grade 4 hyperuricemia. At 50 mg/m2/day, one patient developed grade 3 febrile neutropenia and grade 4 leukopenia, and another patient showed lasting grade 4 neutropenia. Most common toxicities included grade 3 or 4 lymphopenia (83%), leukopenia (50%) and neutropenia (50%). All the toxicities were reversible. The overall response rate was 67%. The AUC0-24h values on day 5 indicated a dose-dependent increase in systemically available 2-fluoro-arabinofuranosyl-adenine (2F-ara-A). CONCLUSIONS: Oral fludarabine phosphate is safe and effective for relapsed patients with indolent B-NHL. The dose of 40 mg/m2/day is recommended for a following pivotal phase II study.     

Ocular involvement in primary central nervous system lymphoma: An increasing clinical problem?

A case of unilateral vitreous relapse in a patient with primary central nervous system lymphoma (PCNSL) following sequential systemic chemotherapy and radiotherapy is reported. A literature review reveals that ocular involvement may occur in up to 15–25% of cases during the course of this disease. Full ophthalmological assessment, including slit lamp examination, should be included in the routine staging of PCNSL at the time of initial diagnosis and subsequently if relapse occurs.     

原发中枢神经系统淋巴瘤放疗作用观察

目的 探索放疗在原发中枢神经系统淋巴瘤治疗中的作用。方法 回顾分析2010年9月至2017年12月确诊的免疫功能正常的原发中枢神经系统淋巴瘤60例资料,其中50例经由手术或立体定向活检后病理诊断,10例影像学临床诊断。52例患者接受了化疗,其中45例为大剂量甲氨喋呤为主方案,25例为含利妥昔单抗方案。27例患者行计划性放疗,33例未行计划性放疗,其中治疗失败后9例接受了挽救性放疗。结果 中位随访时间28个月(5~70个月)。全组中位生存、中位无进展生存期分别为22个月(5~65个月)、13个月(5~55个月),4年总生存率、无进展生存率分别为61%、33%。计划性放疗组、非计划性放疗组4年总生存率分别为68%、54%(P=0.083),无进展生存率分别为47%、20%(P=0.014)。挽救性放疗组与计划性放疗组4年总生存率差异无统计学意义(P=0.398),全脑放疗≤36Gy、>36Gy组4年总生存率差异也无统计学意义(P=0.136)。结论 放疗是原发中枢神经系统淋巴瘤的综合治疗的一部分,计划性放疗可能使患者在综合治疗中获益,较高的照射剂量不能使患者获益。     

非霍奇金淋巴瘤中枢神经系统累及早期预防的研究进展

中枢神经系统（CNS）累及是非霍奇金淋巴瘤（NHL）的严重并发症,转归极度不佳。大多数病例CNS复发表现为软脑膜病变,在自然病程的早期即发生脑脊液播种,所以CNS预防需在最初治疗时进行。因为NHL患者CNS复发率相对低（5%-7%）,不同类型侵袭性NHL患者CNS预防仍有争议,最佳的治疗和方案尚不一致。明确侵袭性NHL患者CNS复发的危险因素有助于确定CNS预防患者亚群。由于目前CNS预防的措施尚欠一致和极少高质量验证,为预防治疗的过度需进行充分的设计和随机对照试验。     

非霍奇金淋巴瘤中枢神经系统累及早期预防的研究进展

中枢神经系统(CNS)累及是非霍奇金淋巴瘤(NHL)的严重并发症,转归极度不佳。大多数病例CNS复发表现为软脑膜病变,在自然病程的早期即发生脑脊液播种,所以CNS预防需在最初治疗时进行。因为NHL患者CNS复发率相对低(5%-7%),不同类型侵袭性NHL患者CNS预防仍有争议,最佳的治疗和方案尚不一致。明确侵袭性NHL患者CNS复发的危险因素有助于确定CNS预防患者亚群。由于目前CNS预防的措施尚欠一致和极少高质量验证,为预防治疗的过度需进行充分的设计和随机对照试验。     

利妥昔单抗联合大剂量甲氨蝶呤在原发性中枢神经系统淋巴瘤患者中的应用效果

目的 探讨利妥昔单抗联合大剂量甲氨蝶呤在原发性中枢神经系统淋巴瘤患者中的应用效果.方法 按照入院顺序将84例原发性中枢神经系统淋巴瘤患者分为对照组和观察组,每组42例,对照组接受大量甲氨蝶呤治疗,观察组患者接受利妥昔单抗联合大剂量甲氨蝶呤治疗.比较两组患者的临床疗效、不良反应、生存期和生活质量.结果 观察组患者的治疗总...     

Central nervous system aspergillus infection complicating renal transplantation

A case of catastrophic intracerebral haemorrhage secondary to aspergillus infection in an immunocompromised renal transplant patient is presented. The pathological features and related images are described and the radiology of CNS aspergillus infection is reviewed.     

Central nervous system involvement in ALK-rearranged NSCLC: promising strategies to overcome crizotinib resistance

Introduction: ALK rearranged Non Small Cell Lung Cancers (NSCLCs) represent a distinct subgroup of patients with peculiar clinic-pathological features. These patients exhibit dramatic responses when treated with the ALK tyrosine kinase inhibitor Crizotinib, albeit Central Nervous System (CNS) activity is much less impressive than that observed against extracranial lesions. CNS involvement has become increasingly observed in these patients, given their prolonged survival. Several novel generation ALK inhibitors have been developing to increase CNS penetration and to provide more complete ALK inhibition..

Areas covered: The CNS activity of Crizotinib and novel generation ALK inhibitors will be summarized in this review, evaluating the strengths and weaknesses of the therapeutic strategies developed to date in this specific subgroup of NSCLCs with a look towards the future.

Expert commentary: In the next few years, the results of ongoing comparative head-to-head trials will provide the definitive conclusions on the optimal treatment sequence in ALK-rearranged NSCLCs. Moreover, ongoing clinical trials with novel-generation ALK inhibitors will produce more evidences on the best approach in the growing number of ALK-positive NSCLCs with CNS involvement.     

Primary central nervous system lymphoma in immunocompetent patients: a retrospective review of MRI features

Introduction: To define the features of primary central nervous system lymphoma (PCNSL) on MRI in immunocompetent patients. Methods: A retrospective review of the authors' institutional database was performed to identify histologically proven cases of PCNSL. Images were retrieved and reviewed with respect to location, lesion number, size, signal intensity, enhancement characteristics, oedema and necrosis. Results: Thirty‐one cases of histologically proven PCNSL had available imaging. One patient was excluded due to immunosuppression. Of the 30 remaining cases, the average age was 65.5 years, and males and females were equally represented. A total of 68 lesions (average of 2.5 per patient) were identified. With diffusion‐weighted imaging, all but two had restricted diffusion (40.3% mild and 55.6% marked) and all but one had enhancement (51.5% homogeneous, 42.6% heterogeneous and ring 4.4%). Most lesions were isointense to grey matter (75.8% on T2‐weighted image (WI) and 82.5% on T1‐WI). Oedema was mild in 43.4% and marked in 55.2%. Necrosis was seen in only five lesions (7.4%). On a per patient basis, 50% had bilateral lesions and 96.7% had lesions contacting a cerebrospinal fluid (CSF) surface. 16.7% of patients had posterior fossa involvement and 30% had lesions in the basal ganglia or thalami. Conclusion: The vast majority of cases of PCNSL in immunocompetent patients have lesions contacting a CSF surface, enhancement and restricted diffusion with no necrosis. These features should alert radiologists to the diagnosis of PCNSL.