Risk Of Central Nervous System Disease Research Articles

Impact of central nervous system (CNS) prophylaxis on the incidence of CNS relapse in patients with high-risk diffuse large B cell/follicular grade 3B lymphoma

Although overall survival in diffuse large B cell lymphomas (DLBCL) has improved, central nervous system (CNS) relapse is still a fatal complication of DLBCL. For this reason, CNS prophylaxis is recommended for patients at high risk of CNS disease. However, no consensus exists on definition of high-risk patient and optimal CNS prophylaxis. Systemic high-dose methotrexate in combination with R-CHOP has been suggested as a potential prophylactic method, since methotrexate penetrates the blood-brain barrier and achieves high concentration in the CNS. In this retrospective analysis, we report treatment outcome of 95 high-risk DLBCL/FL grade 3B patients treated with R-CHOP or its derivatives with (N = 57) or without (N = 38) CNS prophylaxis. At a median follow-up time (51 months), CNS relapses were detected in twelve patients (12.6%). Ten out of twelve (83%) of CNS events were confined to CNS system only. Median overall survival after CNS relapse was 9 months. Five-year isolated CNS relapse rates were 5% in the prophylaxis group and 26% in the group without prophylaxis. These findings suggest that high-dose methotrexate-containing prophylaxis decreases the risk of CNS failure.

Central nervous system involvement in T-cell lymphomas: A single center experience.

8069 Background: Large experiences have reviewed the risk of central nervous system (CNS) involvement in diffuse large B-cell lymphoma (DLBCL), but there are limited data on CNS involvement by peripheral T cell lymphomas (PTCL). We characterized the incidence of CNS involvement, risk factors and outcome in a large single institution dataset of PTCL. Methods: Retrospective review of the T-cell lymphoma database at Memorial Sloan Kettering Cancer Center. We identified 232 patients with any subtype of PTCL between 1994-2011 with a minimum 6 months of follow-up or an event defined as relapse or death. We excluded indolent forms of cutaneous T cell lymphoma. Results: Histologies included PTCL-NOS (31%), angioimmunoblastic (16.8%), anaplastic (ALCL), ALK negative (12%), ALCL, ALK positive (6%), extranodal NK/T cell lymphoma (7.3%), adult T cell leukemia/lymphoma (ATLL) (7.3%), and transformed MF (8.6%). Median age was 58 years with 59.9% men. CNS disease was found in 17 patients (7.32%). 8 (47%) had pathologic confirmation and 7 (41.2%) were clinically diagnosed. Two had other diagnoses at biopsy: DLBCL and glioblastoma. Median time to CNS involvement was 2.33 months (range, 0.16 to 103.1). CNS prophylaxis was given to 24 (10.34%), primarily intrathecal methotrexate. There was no difference in CNS involvement in patients who received prophylaxis vs. those who did not: 3/24 (12.5%) vs. 12/208 (5.77%) (p=0.192) respectively. Univariate analysis identified: stage III-IV (p=0.03), bone marrow involvement (p=0.018), >1 extranodal site (p<0.001), and ATLL vs. all other subtypes, 23.5% vs. 6.4% (p=0.003) as risk factors for CNS disease. On multivariate analysis, >1 extranodal site (p=0.004) and high intermediate (H-I) and high (H) IPI (IPI 3-5 & 4-5) were predictive for CNS involvement (p<0.05). The median survival of patients with CNS involvement was 2.628 months. Conclusions: Despite high relapse rates, PTCL carries a low risk of CNS involvement other than the ATLL subtype. As with other aggressive lymphomas, survival of patients with CNS involvement is poor and risk factors include: >1 extra nodal site and H-I-H IPI. In this dataset, prophylactic intrathecal chemotherapy does not appear to reduce the risk of CNS disease.

The Expression of p-STAT3 in Stage IV Melanoma: Risk of CNS Metastasis and Survival

The signal transducer and activator of transcription 3 (STAT3) is a key molecular hub of tumorigenesis and immune suppression. The expression of phosphorylated STAT3 (p-STAT3) has been shown to be higher in melanoma metastasis to the central nervous system (CNS) relative to distant metastasis in the rest of the body (systemic). We sought to determine whether the increased expression of p-STAT3 in non-CNS systemic melanoma metastasis is associated with an increased risk of developing CNS metastasis and is a negative prognostic factor for overall survival time. We retrospectively identified 299 patients with stage IV melanoma. In a tissue microarray of systemic non-CNS metastasis specimens from these patients, we used immunohistochemical analysis to measure the percentage of cells with p-STAT3 expression and Kaplan-Meier survival estimates to analyze the association of p-STAT3 expression with median survival time, time to first CNS metastasis, and development of CNS metastasis. Lung metastases exhibited the highest level of p-STAT3 expression while spleen lesions had the lowest. The p-STAT3 expression was not associated with an increased risk of developing CNS metastasis or time to CNS metastasis. However, p-STAT3 expression was a negative prognostic factor for overall survival time in patients that did not develop CNS metastasis. Stage IV melanoma patients without CNS metastasis treated with p-STAT3 inhibitors in efficacy studies should be stratified based on tumor expression of p-STAT3; however since p-STAT3 expression is not associated with the risk of CNS disease, increased MRI surveillance of the brain is not likely necessary.

Platelet decline: An early predictive hematologic marker of simian immunodeficiency virus central nervous system disease

As the prevalence of human immunodeficiency virus (HIV)-induced central nervous system (CNS) disease has increased with antiretroviral treatment, there is a critical need for identifying biomarkers that predict HIV CNS disease. To identify novel hematologic markers that precede and predict CNS disease, the authors examined longitudinal hematology data from 47 simian immunodeficiency virus (SIV)-infected macaques. This study demonstrated that the magnitude of decline in circulating platelet counts beginning at day 28 post infection, during asymptomatic SIV infection, predicted the eventual development of SIV encephalitis. Univariate analysis performed on platelet values obtained day 56 post inoculation demonstrated that SIV-infected macaques with the greatest decline in platelet numbers were 18 times more likely to develop SIV CNS disease than SIV-infected animals with minimal to no decline in circulating platelet counts. Decline in platelet number was a more robust marker than decline in hemoglobin levels, a previously identified marker of HIV CNS disease. The identification of an association between decline in platelets and the development of encephalitis demonstrates that monitoring platelet decline in HIV-infected individuals may serve as a predictive marker for clinical progression to HIV-induced CNS disease. Identifying those HIV-infected individuals at risk for CNS disease during asymptomatic stages of infection would promote early interventive, neuroprotective therapy to prevent neuronal damage and loss.

Prophylactic Cranial Irradiation in the Treatment of Small-Cell Carcinoma of the Lung

The high incidence of central nervous system (CNS) failure in patients given chemotherapy for small-cell lung cancer led to the use of prophylactic cranial irradiation (PCI) to prevent the development of metastases. Seven randomized trials have investigated the use of PCI, 5 of which reported a statistically significant reduction in risk of CNS disease though none demonstrated improvement in overall survival. Recent reports have demonstrated the potential for severe toxicity with PCI, leading some investigators to recommend discontinuing its use, while others have suggested improvements in timing and dose fractionation. It appears that the subgroup of patients most likely to benefit from PCI are those with limited-stage disease in complete response after chemotherapy, in whom a reduction in the risk of CNS failure may translate into improved survival. The recommended radiation dose is 30 to 36 Gy in 2 Gy/day fractions.

Involvement of the Central Nervous System in Non-Hodgkin's Lymphoma

Fifteen of 146 (10%) adult patients with non-Hodgkin's lymphoma showed clinical and pathologic evidence of involvement of the central nervous system (CNS): in 6 patients, the CNS lymphoma was present at the onset of disease, in 3 of them it was the only sign detected. In the remaining 9 cases, CNS involvement appeared during the course of systemic disease. In all cases symptoms related to infiltration of the CNS were associated with advanced disease (stage IV); bone marrow or bone involvement was found in 9 patients (60%). The histologic subtypes were mostly of high-grade malignancy according to the Kiel classification: immunoblastic (3), centroblastic (3), Burkitt type (2), lymphoblastic (1), LP immunocytoma in polymorphic variant (3), unclassifiable (3). The prominent signs and symptoms of CNS lymphoma are listed: the cranial nerve palsies are the most common finding. The principal means of detecting CNS involvement are discussed: cerebrospinal fluid cytology, brain scan and CAT scan were the most useful diagnostic procedures. The reported data allow identification of patients at high risk of CNS lymphoma: this includes histologies of high-grade malignancy, advanced stage of disease, and bone marrow or bone infiltration. Therefore, either intensive systemic chemotherapy or CNS prophylaxis are recommended for patients with high risk of CNS disease.