Association of transcobalamin c. 776C>G with overall survival in patients with primary central nervous system lymphoma.

BACKGROUND: Chemotherapy for primary central nervous system lymphoma (PCNSL) is based on methotrexate (MTX), which interferes with both nucleic acid synthesis and methionine metabolism. We have reported previously that genetic variants with influence on methionine metabolism are associated with MTX side effects, that is, the occurrence of white matter lesions as a sign of MTX neurotoxicity. Here, we investigated whether such variants are associated with MTX efficacy in terms of overall survival in MTX-treated PCNSL patients. METHODS: We analysed seven genetic variants influencing methionine metabolism in 68 PCNSL patients treated with systemic and facultative intraventricular MTX-based polychemotherapy (Bonn protocol). RESULTS: Median age at diagnosis was 59 years (range: 28-77), 32 patients were female. Younger age (Wald=8.9; P=0.003) and the wild-type C (CC) allele of the genotype transcobalamin c (Tc2). 776C>G (Wald=6.7; P=0.010) were associated with longer overall survival in a multivariate COX regression analysis. CONCLUSION: This observation suggests that the missense variant Tc2. 776C>G influences both neurotoxicity and efficacy of MTX in the Bonn PCNSL protocol.

Relapse of primary central nervous system lymphoma 13 years after high-dose methotrexate-based polychemotherapy.

We report a now 74-year-old patient who was successfully treated with a methotrexate (MTX)-ssbased polychemotherapy protocol (Bonn protocol) for primary central nervous system lymphoma (PCNSL) in 1996. When presenting with an unusually late relapse after 13 years of tumor-free survival the diagnosis was made on the basis of clinical and radiological criteria. In the context of the very limited treatment options for recurrent PCNSL, it is reassuring that the re-application of high dose-MTX-based polychemotherapy, including intraventricular treatment, again succeeded in a sustained complete response with still low neurotoxicity.

Marked elevation in homocysteine and homocysteine sulfinic acid in the cerebrospinal fluid of lymphoma patients receiving intensive treatment with methotrexate.

OBJECTIVE: Interference of methotrexate (MTX) with the metabolism of homocysteine may contribute to MTX neurotoxicity. In this pilot study we measured the concentration of homocysteine and related metabolites in the cerebrospinal fluid (CSF) of patients with primary central nervous system lymphoma undergoing intensive treatment with MTX. MATERIAL AND METHODS: CSF samples from lymphoma patients (n = 4) were drawn at the end of high-dose MTX infusions (3-5 g/m2/24 h, HDMTX) and one day after intraventricular injections of MTX (3 mg, ICVMTX) or cytarabine (30 mg) and analyzed for homocysteine, cysteine, sulfur-containing excitatory amino acids (cysteine sulfinic acid, cysteic acid, homocysteine sulfinic acid and homocysteic acid), S-adenosylmethionine, 5-methyltetrahydrofolate and MTX. The concentration of homocysteine, cysteine and sulfur-containing excitatory amino acids were also measured in the CSF of a reference population not exposed to MTX. The Wilcoxon signed rank-test and the Friedman test were used to compare concentrations of homocysteine and its metabolites at various time-points during chemotherapy. Comparison of patient and control samples were performed using the Mann-Whitney U-test. Allelic variants of homocysteine metabolism previously shown to influence MTX neurotoxicity (MTHFR c.677C>T, MS c.2756A>G and Tc2 c.776C>G) were also analyzed. RESULTS: After application of HD- and ICVMTX, the CSF homocysteine concentrations in the lymphoma patients were markedly elevated and significantly higher than those in the control group (p < 0.05, Mann-Whitney U-test), whereas 5-methyltetrahydrofolate was depleted. A rapid elevation of homocysteine sulfinic acid, a sulfur-containg amino acid which was not detected in the CSF of the control group, was observed. One patient developed confluent white matter brain changes visible using MRI. This patient had the lowest concentration of S-adenosylmethionine in the CSF and carried two risk alleles for MTX neurotoxicity. CONCLUSIONS: In this pilot study, MTX administered either intravenously or intraventricularly, induced marked biochemical alterations in the CSF. Whether these changes can be used to predict MTX-induced neurotoxicity at an early stage in treatment needs to be elucidated in larger clinical trials.

Acute methotrexate-induced encephalopathy--causal relation to homozygous allelic state for MTR c.2756A>G (D919G)?

Methotrexate (MTX) is widely used in the treatment of hematological diseases. The typical side-effects of high-dose MTX chemotherapy on the CNS range from asymptomatic white matter changes to severe CNS demyelination. MTX neuro - toxicity has been described to be associated with homocysteine and folate levels as well as genetic variants affecting methionine metabolism. Here we describe a case of severe, acute MTX-induced encephalopathy in a patient who was found to be homozygous for the rare missense variant methionine synthase (MTR) c.2756A>G (D919G), which may have modified the effect of MTX on homocysteine metabolism. This finding encourages further studies to determine to what extent the individual conditions of folate and methionine metabolism influence the effects or side-effects of MTX treatment.

FDG-PET in immunocompetent patients with primary central nervous system lymphoma: correlation with MRI and clinical follow-up.

PURPOSE: The role of FDG-PET in primary central nervous system lymphoma (PCNSL) is unclear. It was the aim of this study to investigate the role of FDG-PET in detecting PCNSL and in predicting response to chemotherapy. METHODS: An FDG-PET scan of the brain was performed in 15 patients with histologically proven PCNSL (16 PET examinations, Siemens ECAT EXACT). PET was planned to investigate patients at the time of primary diagnosis, after chemotherapy and at the time of suspected relapse in seven, five and three cases, respectively. All except two patients simultaneously underwent MRI of the brain. FDG-PET results were correlated with histological results after stereotactic biopsy (primary diagnosis group) and with clinical data and MRI during follow-up. RESULTS: Six of the seven patients in the primary diagnosis group demonstrated a true positive finding (86%). In one of the true positive PET patients, there were two tumour lesions, one of which was only detectable on the FLAIR MRI sequence. In five patients, FDG-PET showed no sign of PCNSL during ongoing chemotherapy. These results were confirmed by the clinical follow-up (mean 26.6 months). MRI demonstrated minimal residual disease which had disappeared on further follow-up MRI in three of these five patients at the time of PET scanning. Recurrence of disease was confirmed concordantly by FDG-PET and MRI in three different patients. The standardised uptake value of all tumours was 10.2 (4.3-13.7). CONCLUSION: PCNSLs demonstrate high FDG uptake and can be diagnosed by FDG-PET with high sensitivity. It seems that FDG-PET is suitable for early therapeutic monitoring after chemotherapy.

Neuropsychological outcome after chemotherapy for primary CNS lymphoma: a prospective study.

BACKGROUND: Combined radio- and chemotherapy for primary CNS lymphoma (PCNSL) is associated with a considerable risk of long-term neurotoxicity. The impact of high-dose methotrexate (MTX)-based chemotherapy alone on cognition and quality of life (QOL) is controversial. OBJECTIVE: To assess the impact of the tumor itself and its treatment with high-dose MTX-based chemotherapy on long-term cognition and QOL in patients with PCNSL. METHODS: Prospective neuropsychological examinations and MRI were performed in patients with PCNSL who were in complete remission for more than 12 months after completion of chemotherapy. A QOL assessment was performed at long-term follow-up. RESULTS: Twenty-three patients were eligible. The median follow-up period was 44 months after diagnosis. In long-term follow-up, 22 (95%) of 23 patients showed either preserved or improved cognitive functions as compared with pretreatment and immediate posttreatment baseline assessment. One patient showed an isolated decline in psychomotor speed. Eleven (48%) of 23 patients displayed at least mild cognitive deficits at long-term follow-up not related to therapy. Nineteen (83%) of 23 patients reported a good QOL. MRI revealed confluent white matter abnormalities in eight patients that were not associated with cognitive decline. CONCLUSION: In patients with primary CNS lymphoma (PCNSL) treated with a methotrexate (MTX)-based chemotherapy, no gross cognitive decline has to be expected as a long-term treatment effect. MTX-induced white matter changes apparent on MRI are not inevitably associated with cognitive impairment. Nevertheless, a substantial fraction of patients with PCNSL retain cognitive deficits as a residual symptom of the tumor.

MTX-induced white matter changes are associated with polymorphisms of methionine metabolism.

Methotrexate (MTX) is a folate antagonist inhibiting nucleic acid and methionine synthesis. Methionine is necessary for CNS myelination. In 42 patients with primary CNS lymphoma (PCNSL) treated with a systemic and intraventricular high-dose MTX-based polychemotherapy, the presence of a risk haplotype defined by polymorphisms influencing methionine metabolism referred a relative risk for CNS white matter changes of 4.7 (p = 0.001). The authors conclude that methionine metabolism influences MTX neurotoxicity.

Clonal evolution as pathogenetic mechanism in relapse of primary CNS lymphoma.

Comparative investigation of immunoglobulin (Ig) heavy chain gene rearrangements and DNA sequence analyses of a primary lymphoma of the CNS (PCNSL) and its recurrence revealed that both tumors used the same Ig gene segment. In addition to shared somatic mutations, the primary and the recurrent PCNSLs harbored somatic mutations unique to each tumor. Clonal evolution rather than subclone selection appears to underlie the development of tumor recurrence in this case.

The methionine synthase polymorphism D919G alters susceptibility to primary central nervous system lymphoma.

Primary central nervous system lymphomas (PCNSL) frequently reveal genomic instability. We analysed different functional genetic variants affecting the folate and homocysteine metabolism important for DNA integrity in 31 PCNSL patients and 142 controls. We found significantly less carriers of the methionine synthase c.2756A>G (D919G) missense polymorphism among the patients (0.16 vs 0.42; odds ratio 0.26, CI(95%): 0.09-0.74; P=0.005), suggesting a protective function of the G allele. These data stimulate further epidemiological and functional studies focusing on the role of homocysteine and folate metabolism in lymphoma tumorigenesis.

Treatment of CNS lymphoma with the anti-CD20 antibody rituximab: experience with two cases and review of the literature.

Treatment with radio- and chemotherapy has become increasingly efficient in primary CNS lymphoma (PCNSL). However, time to tumor progression is often short, and the majority of patients eventually relapse. Therefore, new therapeutic modalities are needed. One possible new option is the use of monoclonal antibodies (moabs) such as the humanized anti-CD20 moab rituximab. Treatment with intravenous rituximab has resulted in response rates of 50% in systemic non-Hodgkin's lymphoma and was also efficient in PCNSL as well as in CNS involvement of systemic disease. However, rituximab concentrations in the cerebrospinal fluid are low after systemic application. Therefore, the authors performed an intraventricular rituximab treatment in 2 patients. The most recent results and the possible role of moabs in patients with PCNSL are summarized and discussed.

Intraventricular and intravenous treatment of a patient with refractory primary CNS lymphoma using rituximab.

The treatment of primary central nervous system lymphoma (PCNSL) with chemo- and radiotherapy is efficient in terms of tumor response. However, time to tumor progression often is of short duration and leptomeningeal relapse is common. We present a 66-year-old man in third relapse of a CD20-positive PCNSL. After treatment with intravenous and intraventricular administration of the chimeric anti-CD20 monoclonal antibody rituximab, a total clearing of lymphoma cells in the cerebrospinal fluid (CSF) was achieved. There was no change in the size of the parenchymal tumor mass but there was slight improvement of clinical symptoms after therapy. Rituximab infusions (375 mg/m2) were first given systemically on days 1 and 8. Intraventricular injections of rituximab via Ommaya reservoir were given on days 16 (10 mg), 17 (40 mg), 24 (25 mg) and 25 (25 mg). Reversible side effects such as nausea, chills and hypotension were observed only immediately after intraventricular administration of 40 mg rituximab. Antibody levels in CSF were measured at 7 timepoints during and after the treatment period. These data suggest that intraventicular treatment with rituximab is safe and feasible with a potential activity on leptomeningeal tumor manifestation. Efficacy and pharmacokinetics of rituximab in PCNSL should be investigated in future trials.

New aspects in the treatment of AIDS-related lymphoma.

Despite of changes in the use of antiviral or chemotherapy regimens, the median survival of patients with AIDS-related lymphoma has not significantly changed until recently. However, partly due to prolonged survival with the introduction of highly active antiretroviral therapy (HAART) prognosis in AIDS patients with lymphoma seems to improve. Recently, several new treatment options have been explored in patients with lymphoma. It is hoped that novel strategies will lead to a survival benefit in these patients. In this review, we discuss the current strategies for the treatment of AIDS-related lymphoma.

Proton magnetic resonance spectroscopy and transcranial magnetic stimulation for the detection of upper motor neuron degeneration in ALS patients.

Transcranial magnetic stimulation (TMS) was compared to proton magnetic resonance spectroscopy (1H-MRS) for the detection of upper motor neuron loss or dysfunction in 49 ALS patients classified according to the El Escorial criteria. Abnormal NAA/Cho ratios were detected in 53% of ALS patients. Abnormal TMS results (i.e. cortical inexcitability or prolonged CMCT's) were obtained in 63% of ALS patients. If one or both methods were considered for diagnosis of upper motor neuron degeneration/dysfunction, the percentage of abnormal findings was 77%, whilst in 39% of all patients both methods produced abnormal results. Compared to TMS, 1H-MRS detected more patients with upper motor neuron involvement in the suspected El Escorial subgroup (42% versus 25%), whereas TMS detected more patients with upper motor neuron involvement in the possible (81% versus 50%), probable (71% versus 57%) and definite El Escorial subgroup (71% versus 64%). We conclude that the combined use of 1H-MRS and TMS increases diagnostic accuracy for the detection of upper motor neuron involvement in ALS patients.

Combined systemic and intraventricular chemotherapy in primary CNS lymphoma: a pilot study.

The objective was to evaluate response rate, response duration, and toxicity after systemic and intraventricular chemotherapy in primary CNS lymphoma (PCNSL). From September 1995 to September 1998, 20 consecutive patients with PCNSL (median age 64, range 27 to 71 years) were enrolled in a pilot study evaluating chemotherapy without radiotherapy. A high dose methotrexate (MTX) (cycles 1, 2, 4, 5) and cytarabine (ara-C) (cycles 3, 6) based systemic therapy (including dexamethasone, vinca alkaloids, ifosfamide, and cyclophosphamide) was combined with intraventricular MTX, prednisolone, and ara-C. Complete response was achieved in 11 and partial remission in two patients; in one response could not be determined. Four patients showed progressive disease and two (70, 71 years) died from treatment related complications. Observation time was 2 to 59 months (median 31.5 months). Kaplan-Meier estimate for median time to treatment failure (TTF) was 20.5 months, and for median survival 54 months. Systemic toxicity was mainly hematological. Ommaya reservoir infection occurred in four patients and acute transient MTX induced encephalopathy in two (subacute in another). Cognitive dysfunction possibly due to treatment was seen in only one patient after relapse and after a total of 12 cycles (six at relapse). In conclusion, primary chemotherapy based on high dose MTX and ara-C is highly efficient in PCNSL. Toxicity is manageable in patients younger than 70 years.

A novel type of metastatically spreading subcutaneous aspergillosis without epidermal lesions following allogeneic stem cell transplantation.

Systemic mycosis is among the most feared opportunistic infections in the immunocompromised host. Difficulty and delay in diagnosis and treatment often result in poor outcomes. In this communication a metastatically spreading form of subcutaneous aspergillosis developed in a patient with a history of allogeneic stem cell transplantation for relapsed Hodgkin's lymphoma. Strikingly, necrotizing cutaneous papules or ulcerating lesions were absent. Diagnosis was accomplished after excision of a clinically non-suggestive subcutaneous nodule. Despite prompt initiation of antimycotic therapy the outcome was fatal; dosage of conventional and liposomal amphotericin B was limited due to treatment-related toxicities. This case report describes a novel form of aspergillosis and underlines the need for an aggressive diagnostic approach in severely immunocompromised patients.

Primary central nervous system immunocytoma: MRI and spectroscopy.

We report on a young woman with a primary cerebral immunocytoma. Most primary cerebral nervous system lymphomas (PCNSL) are highly malignant undifferentiated B-cell tumours, there are few data on the clinical course, MRI and spectroscopy findings of this rare PCNSL subtype. MRI revealed a radially enhancing tumour with mild perifocal oedema. MR spectroscopy indicated low cell turnover. Slow clinical progression, no significant changes with treatment, and imaging findings were consistent with a low-grade malignant tumour.

Primary non-Hodgkin's lymphoma of the spinal cord.

STUDY DESIGN: Case report. OBJECTIVE: To report a rare case of primary lymphoma of the spinal cord and to discuss therapeutic options. SUMMARY OF BACKGROUND DATA: Only few cases of primary spinal cord lymphomas are reported. Prognosis is often poor, and therapy is not yet established. METHODS: A primary lymphoplasmacytoid lymphoma of the thoracic cord in a 75-year-old woman was treated with focal radiotherapy (30 Gy) and three cycles of chemotherapy consisting of procarbazine, lomustine, and vincristine. RESULTS: Complete tumor response and partial recovery of neurologic symptoms were achieved. The patient was in complete remission at last follow-up (11 months after diagnosis). CONCLUSIONS: Primary spinal cord lymphomas should be considered in the differential diagnosis of spinal cord tumors, especially in older patients. Combination therapy with radiotherapy and chemotherapy may be superior to radiotherapy alone in these tumors. Rapid initiation of treatment is essential to achieve recovery of neurologic function.

Primary central nervous system lymphoma: a clinicopathological study of 28 cases.

A group of 28 consecutive patients (mean age 59 years) with primary central nervous system lymphoma (PCNSL) was treated with different regimens, including steroids only, radiotherapy (RT), chemotherapy or combinations of all. Lymphoma was classified as high grade malignant B-cell non-Hodgkin's lymphoma of the diffuse large cell type in each of these cases. RT alone led to tumour remission in more than 70 per cent, survival could be prolonged with additional chemotherapy. Thirteen patients were treated with chemotherapy alone; nine of them received a novel combined intraventricular and systemic polychemotherapy protocol based on high dose methotrexate (MTX) and high dose cytarabine (ara-C). The response rate was 90 per cent with 80 per cent complete responses. Neurotoxicity, i.e. white matter lesions associated with severe cognitive dysfunction affected both patients surviving RT more than a year and patients treated with combination RT/chemotherapy. Confluent white matter hyperintense lesions were detectable on MRI in three out of 13 patients treated with chemotherapy alone, however, cognitive dysfunction has not been detected in these patients.