Central Nervous System Occurrence Research Articles

Clinical networking results in continuous improvement of the outcome of patients with acute promyelocytic leukemia

AbstractThe introduction of all-trans retinoic acid combined with anthracyclines has significantly improved the outcomes for patients diagnosed with acute promyelocytic leukemia (APL), and this strategy remains the standard of care in countries in which arsenic trioxide is not affordable. However, data from national registries and real-world databases indicate that low- and middle-income countries (LMIC) still face disappointing results, mainly because of high induction mortality and suboptimal management of complications. The American Society of Hematology established the International Consortium on Acute Leukemias (ICAL) to address this challenge through international clinical networking. Here, we present the findings from the International Consortium on Acute Promyelocytic Leukemia study involving 806 patients with APL recruited from 2005 to 2020 in Brazil, Chile, Paraguay, Peru, and Uruguay. The induction mortality rate has notably decreased to 14.6% compared with the pre-ICAL rate of 32%. Multivariable logistic regression analysis revealed as factors associated with induction death: age of ≥40 years, Eastern Cooperative Oncology Group performance status score of 3, high-risk status based on the Programa Español de Tratamiento en Hematologia/Gruppo Italiano Malattie EMatologiche dell'Adulto classification, albumin level of ≤3.5 g/dL, bcr3 PML/RARA isoform, the interval between presenting symptoms to diagnosis exceeding 48 hours, and the occurrence of central nervous system and pulmonary bleeding. With a median follow-up of 53 months, the estimated 4-year overall survival rate is 81%, the 4-year disease-free survival rate is 80%, and the 4-year cumulative incidence of relapse rate is 15%. These results parallel those observed in studies conducted in high-income countries, highlighting the long-term effectiveness of developing clinical networks to improve clinical care and infrastructure in LMIC.

Research of Pesticide Metabolites in Human Brain Tumor Tissues by Chemometrics-Based Gas Chromatography-Mass Spectrometry Analysis for a Hypothetical Correlation between Pesticide Exposure and Risk Factor of Central Nervous System Tumors.

Pesticides are widely used, resulting in continuing human exposure with potential health impacts. Some exposures related to agricultural works have been associated with neurological disorders. Since the 2000s, the hypothesis of the role of pesticides in the occurrence of central nervous system (CNS) tumors has been better documented in the literature. However, the etiology of childhood brain cancers still remains largely unknown. The major objective of this work was to assess the potential role of pesticide exposure as a risk factor for CNS tumors based on questionnaires and statistical analysis of information collected from patients hospitalized in the Neurosurgery Department of the Habib Bourguiba Hospital Medium in Sfax, Tunisia, during the period from January 1, 2022, to May 31, 2023. It also aimed to develop a simple and rapid analytical method by the gas chromatography-mass spectrometry technique for the research traces of pesticide metabolites in some collected human brain tumor tissues in order to more emphasize our hypothesis for such a correlation between pesticide exposure and brain tumor development. Patients with a history of high-risk exposure were selected to conduct further analysis. Chemometric methods were adapted to discern intrinsic variation between pathological and control groups and ascertain effective separation with the identification of differentially expressed metabolites accountable for such variations. Three samples revealed traces of pesticide metabolites that were mostly detected at an early age. The histopathological diagnosis was medulloblastoma for a 10-year-old child and high-grade gliomas for 27- and 35-year-old adults. The bivariate analyses (odds ratio >1 and P value <5%) confirmed the great probability of developing cancer by an exposure case. The Cox proportional hazards model revealed the risk of carcinogenicity beyond the age of 50 as a long-term effect of pesticide toxicity. Our study supports the correlation between pesticide exposure and the risk of development of human brain tumors, suggesting that preconception pesticide exposure, and possibly exposure during pregnancy, is associated with an increased childhood brain tumor risk. This hypothesis was enhanced in identifying traces of metabolites from the carbamate insecticide class known for their neurotoxicity and others from pyridazinone, organochlorines (OCs), triazole fungicide, and N-nitroso compounds known for their carcinogenicity. The 2D-OXYBLOT analysis confirmed the neurotoxicity effect of insecticides to induce oxidative damage in CNS cells. Aldicarb was implicated in brain carcinogenicity confirmed by the identification of oxime metabolites in a stress degradation study. Revealing "aziridine" metabolites from the OC class may better emphasize the theory of detecting traces of pesticide metabolites at an early age. Overall, our findings lead to the recommendation of limiting the residential use of pesticides and the support of public health policies serving this objective that we need to be vigilant in the postmarketing surveillance of human health impacts.

Analysis of risk factors of central nervous system complications supported on extracorporeal membrane oxygenation

Objective: To investigate the risk factors of central nervous system (CNS) complications in children undergoing extracorporeal membrane oxygenation (ECMO) support. Methods: The clinical data, ECMO parameters, laboratory examination and outcome (follow-up to 90 d after discharge) of 82 children treated with ECMO in the pediatric intensive care unit (PICU) of Shanghai Children's Hospital from December 2015 to December 2021 were analyzed retrospectively in this study. The patients were divided into CNS complication group and non-CNS complication group. The ECMO mode, ECMO catheterization mode, clinical and laboratory indicators pre-ECMO and 24 h after ECMO initiation, in-hospital mortality and 90-day mortality were compared with Chi-square test, t test and nonparametric rank sum test. Kaplan-Meier method was used to draw survival curve, and Log-rank test was used to compare the difference in survival rate. The receiver operating characteristic (ROC) curve was used to evaluate the power of variables to predict CNS complications. Results: A total of 82 children were treated with ECMO, including 49 males and 33 females, aged 34 (8, 80) months. There were 18 cases suffering CNS complications, including cerebral hemorrhage in 8 cases, epilepsy in 6 cases, simple cerebral infarction in 3 cases, and cerebral hemorrhage combined with cerebral infarction in 1 case. Veno-arterial ECMO accounted for a greater proportion in CNS complication group (17/18 vs. 67% (43/64), χ2=4.02, P=0.045). A higher percentage of children with CNS complications underwent surgical cannulation compared to those in non-CNS complication group (16/18 vs. 53% (34/64), χ2=7.55, P=0.006). The laboratory results indicated that lower pre-ECMO pH value (7.24 (7.15, 7.28) vs. 7.35 (7.26, 7.45), Z=-3.65, P<0.001) and platelet count 24 h after ECMO initiation (66 (27, 135) ×109/L vs. 107 (61, 157) ×109/L, Z=-2.04, P=0.041) were associated with CNS complications. In the CNS complication group, 7 children died during hospitalization and 7 died during 90-day after admission, and there was no significant difference compared with those in the non-CNS complication group (7/18 vs. 31% (20/64), 7/18 vs. 34% (22/64), both P>0.05). The ROC curve analysis indicated that the area under the ROC curve for pre-ECMO pH value was 0.738 (95%CI 0.598-0.877), and the optimal cut-off value was 7.325. Conclusions: CNS complications in children undergoing ECMO support are common. Pre-ECMO pH value <7.325 is a risk factor for CNS complications. Reducing the veno-arterial ECMO and surgical cannulation can help reduce the occurrence of CNS complications.

Evaluation of multiplexed biomarkers in assessment of CSF infiltration in pediatric acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is a very common pediatric malignancy with high survival rates. The course of treatment is modified according to the occurrence of central nervous system (CNS) disease. Aim: To relate serum and cerebrospinal fluid levels of five biomarkers (matrix metalloprotienase 9, CCL-2, sVCAM-1, IFN-γ and inducible protein 10) at diagnosis to the development of CNS infiltration. Methods: The present study was carried on 64 children with ALL and 20 controls. Multiplexed cytokines were measured by Luminex technology (Matrix metalloprotienase 9, CCL-2, sVCAM-1, IFN-γ and inducible protein 10). Results: Significantly higher sMMP-9 and lower sCCL2 were found in patients who developed CNS leukemia. Conclusion: Serum multiplexed parameters at diagnosis of childhood ALL may predict of development of CNS leukemia.

The Associations between Central Nervous System Diseases and Haemostatic Disorders.

The aim of this review was to examine the relationship between the occurrence of central nervous system (CNS) diseases, the medicines used in their treatment and the blood coagulation process. The paper mainly focuses on the effects of antidepressant and antipsychotic drugs. Special attention has been paid to the influence of drugs on platelets, the vascular endothelium, plasma coagulation and fibrinolysis, regarding coagulation.

Shunt tapping versus lumbar puncture for evaluating cerebrospinal fluid infections in pediatric population.

To compare the results of lumbar puncture (LP) and shunt tapping in pediatric patients with suspected ventriculoperitoneal shunt infection. Medical records of pediatric patients with suspected shunt infections were retrospectively analyzed. All patients had cerebrospinal fluid samples obtained either via shunt tapping, LP or both. The diagnosis of infection was made when at least one cerebrospinal fluid had positive culture results. The patients with negative cerebrospinal fluid culture results were followed up for at least 6 months to monitor the occurrence of central nervous system infection. There were 20 patients in the study (12 males, 8 females). Cerebrospinal fluid was obtained by shunt tapping in 11, by lumbar puncture in 9 and by both methods in one patient. Thirteen patients [ Shunt tapping: 5/11 (45%), LP: 7/9 (78%), Both: 1) ] were diagnosed with shunt infection on the basis of cerebrospinal fluid culture. Seven patients with negative cerebrospinal fluid culture were found to have infections unrelated to shunts and did not show evidence of cerebrospinal fluid infection during the follow-up period. Although the percentage of detecting the infection was higher in LP group, both groups showed negative predictive value of 100%. Both shunt tapping and LP are effective in establishing the diagnosis of shunt infection in suspected patients.

Central nervous system tumors and agricultural exposures in the prospective cohort AGRICAN.

Studies in farmers suggest a possible role of pesticides in the occurrence of Central Nervous System (CNS) tumors but scientific evidence is still insufficient. Using data from the French prospective agricultural cohort AGRICAN (Agriculture & Cancer), we investigated the associations between exposure of farmers and pesticide users to various kinds of crops and animal farming and the incidence of CNS tumors, overall and by subtypes. Over the 2005-2007, 181,842 participants completed the enrollment questionnaire that collected a complete job calendar with lifetime history of farming types. Associations were estimated using proportional hazards models with age as underlying timescale. During a 5.2 years average follow-up, 273 incident cases of CNS tumors occurred, including 126 gliomas and 87 meningiomas. Analyses showed several increased risks of CNS tumors in farmers, especially in pesticide users (hazard ratio = 1.96; 95% confidence interval: 1.11-3.47). Associations varied with tumor subtypes and kinds of crop and animal farming. The main increases in risk were observed for meningiomas in pig farmers and in farmers growing sunflowers, beets and potatoes and for gliomas in farmers growing grasslands. In most cases, more pronounced risk excesses were observed among pesticide applicators. Even if we cannot completely rule out the contribution of other factors, pesticide exposures could be of primary concern to explain these findings.

Assessment of central nervous system (CNS) and dose reduction events in patients treated with abiraterone acetate plus prednisone (AA+P) or enzalutamide (ENZ).

5078 Background: The prognosis of patients with metastatic castrate resistant prostate cancer (PC) has improved with the availability of recent treatments such as AA+P or ENZ. However, concerns regarding adverse events such as CNS conditions, fatigue, and pain potentially leading to dose reductions or treatment interruption are rising. This study assessed CNS, fatigue, pain, and dose reduction events in AA+P or ENZ-treated patients. Methods: The MarketScan databases were used to conduct a retrospective analysis, in which patients initiated on AA+P or ENZ (index date) after 10/2012 with ≥ 6 months of continuous eligibility prior to index date and ≥ 1 PC diagnosis were included. Inverse probability of treatment weighting (IPTW) was used to adjust for observed baseline confounders between groups. Weighted Kaplan-Meier (KM) rates and Cox proportional hazard models were used to compare the occurrence of CNS, pain, fatigue, or dose reduction (i.e., relative dose intensity [RDI] ≤ 80%, and ≤ 85%) events between groups. CNS, pain, and fatigue events were assessed in patients without respective event at baseline. Results: A total of 2,196 AA+P and 807 ENZ patients were identified. IPTW resulted in balanced baseline demographic, comorbidities, and disease characteristics (AA+P = 1,493 and ENZ = 1,510). At 12 months, 30.3% of patients on AA+P had a CNS event compared to 37.5% of patients on ENZ (P = 0.005). Similarly, 25.0% of patients on AA+P had a fatigue event compared to 28.6% of patients on ENZ (P = 0.013). Respectively, 13.6% and 20.0% of AA+P and ENZ patients had a dose reduction event (RDI ≤ 80%, P < 0.001; Table). Conclusions: This national study showed that mCRPC patients treated with ENZ were more likely to experience a CNS or fatigue event, and to reduce their treatment dose than patients treated with AA+P. Event KM Rates HRs for Development of Event AA+P ENZ Log-Rank P-value ENZ vs. AA+P (95% CI) P-value CNS 30.3% 37.5% 0.005 1.32 (1.05, 1.66) 0.017 Fatigue 25.0% 28.6% 0.013 1.30 (1.02, 1.66) 0.033 Pain 12.9% 15.3% 0.267 1.17 (0.84, 1.63) 0.351 RDI ≤ 85% 19.4% 24.4% 0.006 1.29 (1.04, 1.61) 0.022 RDI ≤ 80% 13.6% 20.0% < .001 1.44 (1.11, 1.86) 0.006

PARS PLANA VITRECTOMY IN ADVANCED CASES OF VON HIPPEL-LINDAU EYE DISEASE.

To investigate spectrum of patients with Von Hippel-Lindau disease (VHL) that required pars plana vitrectomy and evaluate anatomical and functional outcomes of surgery. Twenty-three patients who underwent surgery for advanced VHL eye disease were assessed by genetic tests, diagnostic tests for systemic lesions, and clinical eye examination. The vitrectomized eyes were divided into two groups: with or without retinotomy (group R vs. NR). Functional and anatomical outcome was analyzed and compared between the groups. All patients had central nervous system hemangioblastomas and 57% had other systemic tumors. Point germline mutations, large partial deletions, and complete vhl gene deletions were found in 64%, 27%, and 9% of patients, accordingly. Destruction of hemangioblastomas by retinotomy, laser, or cryotherapy and anatomical attachment of the retina were achieved in all eyes. Preoperative mean distance best-corrected visual acuity was logarithm of the minimum angle of resolution 2.66 (20/9,140) in group R and 1.76 (20/1,150) in group NR (P < 0.05). At 6 months postoperatively, distance best-corrected visual acuity improved in 20 eyes (83%). After over 24 months postoperatively, distance best-corrected visual acuity remained better than preoperatively in 36% in the R group and in 70% in the NR group of eyes. During 24 months postoperatively in 17 eyes, new retinal capillary hemangiomas developed. The mean number of new retinal capillary hemangiomas per eye was higher in group R than in group NR (3.14 vs. 0.70; P < 0.01). In group R, number of new retinal capillary hemangioblastoma was higher in retinal segments where retinotomy was performed (n = 29) than in other areas (n = 13) (P < 0.01). Advanced VHL eye disease correlates with occurrence of central nervous system and systemic lesions. Spectrum of vhl gene mutation in the patients corresponds to that of the general VHL population. Pars plana vitrectomy in advanced VHL eye disease can improve or preserve visual function, but postoperative progression of ocular VHL disease can be accelerated in cases where retinotomy is performed.

Influence of Rituximab on Central Nervous System Relapse in Diffuse Large B-Cell Lymphoma and Role of Prophylaxis--A Systematic Review of Prospective Studies.

Despite the improvement in overall survival in patients with diffuse large B-cell lymphoma (DLBCL) in the rituximab era, the occurrence of central nervous system (CNS) relapse heralds a very poor prognosis. The evidence is conflicting on the incidence and pattern of CNS relapse in the rituximab era compared with before the rituximab era and on the role of CNS prophylaxis. We conducted a systematic analysis of the data from 7 prospective studies, studying the incidence and type of CNS relapse, the role of prophylaxis, and survival after CNS relapse, with and without rituximab-based chemotherapy. No statistically significant difference was found in the incidence of CNS relapse with the use of rituximab-based chemotherapy compared with CHOP (cyclophosphamide, doxorubicin, vincristine [Oncovin], prednisone) chemotherapy. Leptomeningeal disease was more common and the survival after CNS disease was better in the rituximab era. No difference was found in the incidence of isolated CNS relapse. Chemoprophylaxis significantly decreased the incidence of CNS recurrence. The use of rituximab has not influenced the incidence of CNS relapse compared with the use of CHOP. Chemoprophylaxis plays a significant role in high-risk patients with DLBCL in decreasing CNS recurrence. Large randomized clinical trials are warranted to differentiate between intrathecal and systemic chemoprophylaxis.

Management and prognosis of 66 patients with B-cell non-Hodgkin lymphoma presenting with initial spinal cord compression: a French retrospective multicenter study

Initial spinal cord compression (ISCC) in B-cell non-Hodgkin lymphoma (NHL) is rarely present at diagnosis. We performed a multicenter retrospective analysis of 66 patients with ISCC, including diffuse large B-cell (DLBCL) (70%), follicular (20%), small lymphocytic (6%), marginal zone (2%) and B-cell unclassified (2%) lymphomas, with the aim of describing their management and outcomes, as well as the occurrence of central nervous system (CNS) relapses. All but two patients received cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOP-like regimens, with rituximab in 61% of cases. Forty-six patients received CNS prophylaxis. The 5-year overall survival and progression-free survival were 78% and 65% for DLBCL, and 60% and 48% for indolent lymphomas, respectively. CNS relapses occurred in four (6%) patients, all with DLBCL and all in the cerebellum. Initial decompressive procedures, intradural involvement, cerebrospinal fluid infiltration and lack of CNS prophylaxis did not influence survival. Adverse prognostic factors were male sex, poor performance status, elevated lactate dehydrogenase and high age-adjusted international prognostic index.

Abstract P6-11-10: Central nervous system metastases in breast cancer: Impact of tumour sub-type and outcome from current treatments

Abstract Background: The use of more effective systemic therapies in the management of metastatic breast cancer has led to increased response rates, progression-free survival and overall survival. The incidence of central nervous system (CNS) metastases has become an increasingly important area of unmet need. It is important to identify tumour-related factors which may predict for CNS occurrence and assess the efficacy of treatments in current use. Methods: Consecutive patients (pts) with breast cancer (BC) seen at 2 institutions following establishment of breast cancer databases were included: January 2000 (institution A) and January 2003 (institution B) to December 2012. Patient demographic data, tumour pathology and systemic treatment given were reviewed in those patients who developed CNS metastases. Multivariate analysis of factors impacting on overall survival in this patient population will be performed. Results: Over the study period, 4751 pts with a median age of 52.7 yrs were seen, where 86.4% and 13.6% of pts presented with early and metastatic disease, respectively. In the entire population, 77% of tumours were hormone receptor positive, 21% HER2 positive, and 15% triple negative. Overall, 228 (4.8%) pts had CNS metastases with a median age of 48.9 yrs. CNS involvement was present at the time of first metastatic recurrence in 27% of pts who had CNS metastases. The proportion of pts developing CNS metastases according to tumour subtypes were: 48% hormone receptor positive, 36% Her2 positive, and 20% triple negative. Median time from diagnosis to development of CNS metastases (excluding pts with CNS involvement at the time of first metastatic disease) was 48.9 (4.7-248 months, m). The median time to development of CNS recurrence was 61m, 43m, 23m respectively, according to tumour subtype. CNS disease was parenchymal only, leptomeningeal only or both in 78%, 9%, 13% respectively. Pts who died from BC, had a median overall survival from initial BC diagnosis of 53.6m, whereas median overall survival from CNS metastases was 4.8 m. The impact of whole brain radiation with or without stereotactic therapy, surgical resection of brain metastases and type of systemic therapy administered following development of CNS disease on overall survival will be presented. Discussion: CNS metastases occurred in up to 5% of breast cancer pts seen at two large cancer centres. Despite improvements in overall survival of metastatic BC pts with the use of more effective systemic treatments, the prognosis following CNS involvement remains extremely poor. Until specific interventions are available to manage CNS metastases in pts with breast cancer, it remains important to assess outcomes from current standard treatment in these pts. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-11-10.

Secondary central nervous system involvement in 599 patients with diffuse large B-cell lymphoma: are there any changes in the rituximab era?

The introduction of rituximab has improved the overall prognosis of diffuse large B-cell lymphoma (DLBCL). However, the impact of rituximab on central nervous system (CNS) involvement in DLBCL remains a matter of debate. Patients with DLBCL and no CNS involvement at initial diagnosis were eligible for this analysis. Patients must have received treatment either with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP plus rituximab (R-CHOP). We analyzed the incidence, clinical features and outcomes of CNS involvement that developed during or after completion of therapy. A cohort of 599 patients was eligible for this analysis. With a median follow-up of 26 and 21 months, respectively, 19 of 294 (6.5 %) in the CHOP group and 13 of 305 (4.3 %) in the R-CHOP group developed CNS involvement. Rituximab did not significantly reduce the risk of CNS involvement either in the univariate (P = 0.354) or in the multivariate analysis (RR 0.632, 95 % CI 0.301–1.327, P = 0.225). No patient developed CNS disease after 19 months in the R-CHOP group whereas four patients (21.1 %) in the CHOP group developed CNS disease 2 years after initial diagnosis (range 34–83 months). Systemic disease prior to or coincident with CNS occurrence was more common in the CHOP group than in the R-CHOP group (73.7 versus 38.5 %, P = 0.046). Isolated CNS events were more common in the R-CHOP group than those in the CHOP group (53.8 versus 10.5 %, P = 0.015). This study indicates that isolated CNS events are more common in DLBCL patients treated with R-CHOP than those treated with CHOP alone. Our data also suggest that the time and pattern of CNS events and systemic disease status differ with the addition of rituximab. Better methods for earlier detection and prophylaxis of CNS involvement are needed in the rituximab era.

Abstract WP75: Dual Antiplatelet Therapy in Addition to Post-Operative Heparin and Dextran Reduces Clinically Symptomatic Thromboembolic Events During Elective Aneurysm Coiling

BACKGROUND: Thromboembolism is a feared complication of coiling a cerebral aneurysm. The purpose of this study was to compare the thromboembolic events between cerebral aneurysms coiled with an anti-thromboembolic regimen versus those with no regimen. METHODS: This retrospective cohort study included all adult patients who underwent elective coiling of an intracranial aneurysm between January 1, 2005 and February 1, 2012. All aneurysms were treated with conventional coiling. Patients were started on aspirin and clopidogrel for seven days prior to treatment with aspirin continued indefinitely and clopidogrel for 4 weeks post-coiling. During the coiling procedure patients were given heparin to maintain an activated clotting time 2.5x baseline. Additionally, dextran-40 and heparin were infused for 24 hours post coil placement. The primary endpoint was the presence of a clinically significant thromboembolic event as determine by physical exam and/or MRI diffusion weighted imaging. Each variable was analyzed for its independent association with the occurrence of an embolic event. RESULTS: 312 aneurysms were electively treated. 261 of 312 aneurysms received our anti-thromboembolic regimen versus 51 who did not. There were a total of 6 (1.9%) embolic events. Patients who received the anti-thromboembolic regimen had 3 (1.1%) embolic events versus 3 (5.9%) in those not receiving the regimen ( p = 0.024). Patients receiving the anti-thromboembolic regimen had significantly more active tobacco use but the two groups did not differ in age, sex, or the presence of obesity, diabetes, or hypercoagulable state. There was no difference in the occurrence of central nervous system or systemic hemorrhages between the two groups. In univariate analysis, the presence of a hypercoagulable state ( p = 0.014) and the lack of anti-embolic regimen ( p = 0.043) were associated with the occurrence of an embolic event. Both remained significant in multivariate analysis ( p = 0.016 and p = 0.048, respectively). CONCLUSION: An anti-thromboembolic regimen consisting of dual antiplatelet therapy plus post-operative heparin and dextran reduced the risk of embolic events during elective aneurysm coiling. This regimen was safe, with no observed increase in hemorrhagic complications.

Central nervous system involvement in adult patients with diffuse large B-cell lymphoma: Influence of rituximab

CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone)-like chemotherapy, in combination with rituximab (R-CHOP-like), improves outcome in patients with diffuse large B-cell lymphoma (DLBCL). We aimed to investigate the impact of rituximab on central nervous system (CNS) disease in adult patients. We studied 315 patients (aged 18-60 years old) from six hospitals between July 2003 and May 2008. All patients received CHOP-like (n=165) or R-CHOP-like (n=150) regimen every 3 weeks. With a median follow-up of 3.69 years, 10 patients (3.17%) developed CNS disease. The cumulative risk of CNS occurrence was not significantly different between the two treatment groups (P=0.871). We conclude that the addition of rituximab did not reduce the risk of CNS disease in adult patients with DLBCL.

CNS disease in younger patients with aggressive B-cell lymphoma: an analysis of patients treated on the Mabthera International Trial and trials of the German High-Grade Non-Hodgkin Lymphoma Study Group

To describe incidence, risk factors, and influence of treatment on occurrence of central nervous system (CNS) relapse or progression in younger patients with aggressive B-cell lymphoma. We analyzed 2210 patients with aggressive B-cell lymphoma treated on various studies for CNS relapse/progression. Treatment consisted of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) ± etoposide. Six hundred and twenty patients also received rituximab. CNS prophylaxis was intrathecal methotrexate on High-CHOEP and MegaCHOEP phase III studies if upper neck, head, bone marrow, or testes were involved. Fifty-six of 2196 patients (2.6%) developed CNS disease. It occurred early (median 7.0 months), median survival was 5.0 months. Patients with age-adjusted International Prognostic Index (aaIPI) 0 or 1 treated with rituximab showed a low risk for CNS disease (2-year rates: 0% or 0.5%), and rituximab decreased the risk (relative risk 0.3, 95% confidence interval 0.1-0.9, P = 0.029). Patients with aaIPI 2 or 3 showed a moderate risk (4.2%-9.7%) and no significant reduction of CNS disease with rituximab. CNS prophylaxis was of no significant benefit. In younger patients with aaIPI 0 or 1, CNS relapse/progression is very rare; in patients with aaIPI 2 or 3, the risk is higher (up to 10%) and requires new diagnostic strategies and treatment.

Targeted immunotherapy for Epstein-Barr virus: Positive central nervous system lymphoma in immunosuppressed patients.

e12529 Background: The occurrence of central nervous system (CNS) lymphoma in patients who have been treated with immunosuppressive therapy after organ transplantation or for chronic autoimmune dis...

Lipopolysaccharide treatment and inoculation of influenza A virus results in influenza virus–associated encephalopathy–like changes in neonatal mice

Influenza virus-associated encephalopathy (IAE) is a highly mortal neural complication of influenza A virus (IAV) infection, mostly affecting children younger than 5 years old, and the brain pathology of IAE is characterized by peracute brain edema with evidence of an impaired blood-brain barrier. The pathogenesis of IAE is unknown, but hypercytokinemia of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 is suspected of playing a central role in the development of IAE. Because the brain pathology of IAE is similar to that of septic encephalopathy due to endotoxemia, the effect of combined treatment of IAV and lipopolysaccharide (LPS) was tested using suckling mice. The results show that pulmonary infection with non-neurotropic IAV enhanced the neuropathogenicity of LPS and induced encephalopathy that was similar to IAE with respect to the occurrence of central nervous system (CNS) histopathology and the absence of direct infection of IAV in the brain. Influenza A virus also increased blood-brain barrier (BBB) permeability and induced inflammatory cytokines in the blood. These results suggested that the mice treated with IAV+LPS are possible animal models of IAE, and that hypercytokinemia and/or the involvement of endotoxemia in IAV infection are possible causes of IAE.

9212 Rituximab does not seem to influence the risk of central nervous system occurrence in patients with diffuse large B cell lymphoma

9212 Rituximab does not seem to influence the risk of central nervous system occurrence in patients with diffuse large B cell lymphoma

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

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. 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. 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. 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.