Temozolomide, an alkylating agent, has shown promise in treating primary central nervous system lymphoma (PCNSL). The enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) repairs alkylating damage, such as that induced by temozolomide. We hypothesized that MGMT immunohistochemistry would predict resistance to temozolomide in PCNSL. A retrospective study of newly-diagnosed and recurrent PCNSL patients treated at our institution was conducted to study the predictive value of MGMT immunohistochemistry for response to temozolomide. 20 patients who were treated with temozolomide as a single agent were identified during the study time period. 6/20 patients demonstrated a response, corresponding to an objective response rate of 30 % (95 % CI 8-52). Five patients with low MGMT level (<30 %) showed a response to temozolomide. Only one of 10 patients (10 %) with high MGMT level (≥30 %) exhibited a response to temozolomide. Small sample numbers precluded formal statistical comparisons. Two patients with complete response remain alive without progressive disease 6.7 and 7.2 years after temozolomide initiation. Immunohistochemistry can be performed on small biopsies to selectively assess MGMT status in tumor versus surrounding inflammation. MGMT analysis by immunohistochemistry may predict response to temozolomide in PCNSL and should be prospectively investigated.

OBJECTIVE:

To describe and correlate neurotoxicity indicators in long-term primary CNS lymphoma (PCNSL) survivors who were treated with high-dose methotrexate-based regimens with or without whole-brain radiotherapy (WBRT).

METHODS:

Eighty PCNSL survivors from 4 treatment groups (1 with WBRT and 3 without WBRT) who were a minimum of 2 years after diagnosis and in complete remission underwent prospective neuropsychological, quality-of-life (QOL), and brain MRI evaluation. Clinical characteristics were compared among treatments by using the χ(2) test and analysis of variance. The association among neuroimaging, neuropsychological, and QOL outcomes was assessed by using the Pearson correlation coefficient.

RESULTS:

The median interval from diagnosis to evaluation was 5.5 years (minimum, 2 years; maximum, 26 years). Survivors treated with WBRT had lower mean scores in attention/executive function (p = 0.0011), motor skills (p = 0.0023), and neuropsychological composite score (p = 0.0051) compared with those treated without WBRT. Verbal memory was better in survivors with longer intervals from diagnosis to evaluation (p = 0.0045). On brain imaging, mean areas of total T2 abnormalities were different among treatments (p = 0.0006). Total T2 abnormalities after WBRT were more than twice the mean of any non-WBRT group and were associated with poorer neuropsychological and QOL outcomes.

CONCLUSIONS:

Our results suggest that in patients treated for PCNSL achieving complete remission and surviving at least 2 years, the addition of WBRT to methotrexate-based chemotherapy increases the risk of treatment-related neurotoxicity. Verbal memory may improve over time. CLASSIFICATION OF

EVIDENCE:

This study provides Class III evidence that in patients treated for PCNSL achieving complete remission and surviving at least 2 years, the addition of WBRT to methotrexate-based chemotherapy increases the risk of treatment-related neurotoxicity.

Primary CNS lymphoma (PCNSL) is a rare lymphoma that is confined to the CNS, with low tendency for systemic dissemination and a relatively aggressive course. Outcome in patients with PCNSL is often poor. Owing to its low incidence, current knowledge about optimal treatment of PCNSL is fragmentary. Chemotherapy regimens based on high-dose methotrexate are currently standard treatment for all patients with PCNSL who can tolerate such drugs. Whole-brain radiotherapy alone can lead to remission in up to 90% of patients, but often results in poor long-term disease control when given alone, and in delayed neurotoxicity when given after high-dose methotrexate. In this Review, we describe current approaches to diagnosis and treatment of PCNSL, and discuss novel therapeutic approaches that are currently in development, such as the use of rituximab and high-dose chemotherapy followed by autologous stem-cell transplantation. The possible use of intrathecal and intraventricular chemotherapy, optimal salvage treatment, and specific treatment approaches in elderly, paediatric and immunocompromised patients, are also considered.

Anaplastic Lymphoma Kinase (ALK) was initially discovered as an oncogene in human lymphoma and other cancers, including neuroblastoma. However, little is known about the physiological function of ALK. We identified the alk ortholog in zebrafish (Danio rerio) and found that it is highly expressed in the developing central nervous system (CNS). Heat-shock inducible transgenic zebrafish lines were generated to over-express alk during early neurogenesis. Its ectopic expression resulted in activation of the MEK/ERK pathway, increased cell proliferation, and aberrant neurogenesis leading to mis-positioning of differentiated neurons. Thus, overexpressed alk is capable of promoting cell proliferation in the nervous system, similar to the situation in ALK-related cancers. Next, we used Morpholino mediated gene knock-down and a pharmacological inhibitor to interfere with expression and function of endogenous Alk. Alk inhibition did not affect neuron progenitor formation but severely compromised neuronal differentiation and neuron survival in the CNS. These data indicate that tightly controlled alk expression is critical for the balance between neural progenitor proliferation, differentiation and survival during embryonic neurogenesis.

Objective AIDS-related lymphoma (ARL) often involves the central nervous system (CNS). Although the diagnostic value of Epstein-Barr virus (EBV)-DNA in cerebrospinal fluid (CSF) in detecting HIV-positive primary CNS lymphoma (PCNSL) has been established, its usefulness for identifying CNS involvement of systemic ARL remains elusive. In this study, we evaluated the utility of the EBV-DNA load in CSF in identifying CNS involvement in patients with systemic ARL. Methods We retrospectively reviewed the clinical and pathological data of consecutive ARL patients managed at our clinic between January 1998 and June 2012. Sixty-two patients with ARL, including eight PCNSL patients and 52 systemic ARL patients, and 63 controls underwent CSF EBV-DNA load evaluations before receiving chemotherapy. ARL-related CNS involvement was defined as any lesion diagnosed histologically or radiologically as a lymphoma in the brain, meninges, spine, cranial nerves or oculus. Results A cut off value of 200 copies/mL predicted the presence of CNS lesions with a sensitivity of 70% and a specificity of 85% in both the PCNSL and systemic ARL patients, while a sensitivity of 75% and a specificity of 93% were obtained for systemic ARL. A cut off value of 2,000 (3.30 log) copies/mL provided the best specificity (100%), with a sensitivity of 50%. Conclusion Our results support the clinical utility of evaluating the quantitative EBV-DNA load in the CSF for the diagnosis of CNS involvement of systemic ARL as well as PCNSL.

A 49-year-old woman had blurred vision and floaters of 4 days duration in the right eye. Ocular examination revealed granulomatous panuveitis, vitritis and diffuse retinal vasculitis. Following a strongly positive tuberculin skin test, she received antitubercular therapy with oral steroids and immunosuppressants. A year later, despite therapy, vitritis and vasculitis persisted. Additionally, yellowish white lesions appeared beneath the retinal pigment epithelium. Fluorescein angiography revealed a leopard skin appearance. Following a negative vitreous biopsy, she was subjected to a chorioretinal biopsy which revealed non-Hodgkin's lymphoma. MRI was normal. The ocular lesions resolved following intravitreal methotrexate injections. MRI of the brain was repeated every 3 months to rule out central nervous system (CNS) involvement. About 2.5 years after initial presentation, she complained of ataxia, hypersomnia and speech difficulty. MRI of the brain now showed lesions in the thalamocapsular region and the corpus callosum splenium suggestive of CNS lymphoma. She underwent a whole brain radiation with symptomatic improvement followed by chemotherapy.

Background:

Teenagers and young adults (TYA, 15-24 years) diagnosed with cancer report repeated visits to primary care before referral. We investigated associations of symptoms and consultation frequency in primary care with TYA cancers.

Methods:

Population-based, case-control study was carried out using data from the Clinical Practice Research Datalink (CPRD). A total of 1064 TYA diagnosed with cancer were matched to 13 206 controls. Symptoms independently associated with specific cancers were identified. Likelihood ratios (LRs) and positive predictive values (PPVs) were calculated.

Results:

In the 3 months before diagnosis, 397 (42.9%) cases consulted 4 times vs 593(11.5%) controls (odds ratio (OR): 12.1; 95% CI: 9.7, 15.1), yielding a PPV for any cancer of 0.018%. The LR of lymphoma with a head/neck mass was 434 (95% CI: 60, 3158), with a PPV of 0.5%. Corresponding figures in other cancers included - LR of leukaemia with lymphadenopathy (any site): 29 (95% CI: 8, 112), PPV 0.015%; LR of CNS tumour with seizure: 56 (95% CI: 19, 163), PPV 0.024%; and LR of sarcoma with lump/mass/swelling: 79 (95% CI: 24, 264), PPV 0.042%.

Conclusion:

Teenagers and young adults with cancer consulted more frequently than controls in the 3 months before diagnosis. Primary care features of cancer match secondary care reports, but were of very low risk; nonetheless, some features increased the likelihood of cancer substantially and should be taken seriously when assessing TYA.British Journal of Cancer advance online publication, 25 April 2013; doi:10.1038/bjc.2013.191 www.bjcancer.com.

BACKGROUND:

Central nervous system (CNS) involvement in mantle cell lymphoma (MCL) is uncommon, and the manifestations and natural history are not well described.

PATIENTS AND METHODS:

We present the data on 57 patients with MCL who developed CNS involvement, from a database of 1396 consecutively treated patients at 14 institutions.

RESULTS:

The crude incidence of CNS involvement was 4.1%, with 0.9% having CNS involvement at diagnosis. Blastoid histology, B-symptoms, elevated lactate dehydrogenase, Eastern Cooperative Group performance status ≥2 and a high Mantle Cell Lymphoma International Prognostic Index score were enriched in the cohort with CNS involvement, and the presence of ≥1 of these features defined a high-risk subset (an actuarial risk of CNS involvement 15% at 5 years) in a single-institution subset. The median time to CNS relapse was 15.2 months, and the median survival from time of CNS diagnosis was 3.7 months. The white blood cell count at diagnosis <10.9 × 10(9)/l, treatment of CNS involvement with high-dose anti-metabolites, consolidation with stem cell transplant and achievement of complete response were all associated with improved survival.

CONCLUSIONS:

In MCL, CNS involvement is uncommon, although some features may predict risk. Once manifest outlook is poor; however, some patients who receive intensive therapy survive longer than 12 months.

Mucosa-associated lymphoid tissue (MALT) cells are present in gastrointestinal mucosa but rarely found in the central nervous system (CNS). We describe an unusual and rare case of CNS MALT lymphoma in a patient presenting with stroke-like symptoms.