Intraventricular Treatment Research Articles

Intraventricular SHH inhibition proves efficient in SHH medulloblastoma mouse model and prevents systemic side effects.

Medulloblastoma (MB) is the most common malignant brain tumor in children and requires intensive multimodal therapy. Long-term survival is still dissatisfying and, most importantly, survivors frequently suffer from severe treatment-associated morbidities. The sonic hedgehog pathway (SHH) in SHH MB provides a promising target for specific therapeutic agents. The small molecule Vismodegib allosterically inhibits SMO, the main upstream activator of SHH. Vismodegib has proven effective in the treatment of MB in mice and in clinical studies. However, due to irreversible premature epiphyseal growth plate fusions after systemic application to infant mice and children, its implementation to pediatric patients has been limited. Intraventricular Vismodegib application might provide a promising novel treatment strategy for pediatric medulloblastoma patients. Infant medulloblastoma-bearing Math1-cre::Ptch1Fl/Fl mice were treated with intraventricular Vismodegib in order to evaluate efficacy on tumor growth and systemic side effects. We show that intraventricular Vismodegib treatment of Math1-cre::Ptch1Fl/Fl mice leads to complete or partial tumor remission only 2 days after completed treatment. Intraventricular treatment also significantly improved symptom-free survival in a dose-dependent manner. At the same time, intraventricular application prevented systemic side effects in the form of anatomical or histological bone deformities. We conclude that intraventricular application of a SHH pathway inhibitor combines the advantages of a specific treatment agent with precise drug delivery and might evolve as a promising new way of targeted treatment for SHH MB patients.

Early Intraventricular Antibiotic Therapy Improved In-Hospital-Mortality in Neurocritical Patients with Multidrug-Resistant Bacterial Nosocomial Meningitis and Ventriculitis.

Hospital-acquired multidrug-resistant (MDR) bacterial meningitis and/or ventriculitis (MEN) is a severe condition associated with high mortality. The risk factors related to in-hospital mortality of patients with MDR bacterial MEN are unknown. We aimed to examine factors related to in-hospital mortality and evaluate their prognostic value in patients with MDR bacterial MEN treated in the neurointensive care unit. This was a single-center retrospective cohort study of critically ill neurosurgical patients with MDR bacterial MEN admitted to our hospital between January 2003 and March 2021. Data on demographics, admission variables, treatment, time to start of intraventricular (IVT) therapy, and in-hospital mortality were analyzed. Both univariate and multivariable analyses were performed to identify determinants of in-hospital mortality. All 142 included patients received systemic antibiotic therapy, and 102 of them received concomitant IVT treatment. The median time to start of IVT treatment was 2days (interquartile range 1-5days). The time to start of IVT treatment had an effect on in-hospital mortality (hazard ratio 1.17; 95% confidence interval 1.02-1.34; adjusted p = 0.030). The cutoff time to initiate IVT treatment was identified at 3days: patients treated within 3days had a higher cerebrospinal fluid (CSF) sterilization rate (81.5%) and a shorter median time to CSF sterilization (7days) compared with patients who received delayed IVT treatment (> 3days) (48.6% and 11.5days, respectively) and those who received intravenous antibiotics alone (42.5% and 10days, respectively). Early IVT antibiotics were associated with superior outcomes in terms of the in-hospital mortality rate, time to CSF sterilization, and CSF sterilization rate compared with delayed IVT antibiotics and intravenous antibiotics alone.

The Use of Intraventricular Instillation of Vancomycin to Prevent External Ventricular Drainage Related Infection: A Clinical Prospective Study.

External ventricular drainage (EVD)-related infection (ERI) represents an important condition with potential high morbidity with significant impact on patient outcomes. Prophylactic systemic antibiotics are routinely administered to patients with EVD, but they do not significantly lower the incidence of ERIs. Intraventricular treatment with vancomycin appeared to be safe and effective, but most reports are case-reports/-series and retrospective studies. A prospective non-randomized case-control study was conducted in a consecutive series of 116 patients treated with EVD insertion. The study includes the group of patients treated with intrathecal vancomycin (Group A, 62 patients) compared with the control group treated with daily intravenous cefazolin (Group B, 54 patients). No statistically significant differences were found between the 2 groups with regard to the duration of catheterization and occurrence of ERI during hospitalization. EVD was replaced in 16 cases (25.8%) in group A and in 12 cases (22.2%) in the control group B (P 0.67). Three cases (4.8%) of ERI have been found in group A and 5 (9.3%) in the control group (P=0.34). All reported cases of infection in group A were caused by gram-negative agents; on the opposite, cases of infections in the control group B were caused above all by gram-positive bacteria with a statistical difference (P=0.03). In this first prospective study on this topic, we found that intrathecal Vancomycin administration in EVDs does not reduce the occurrence of ERI compared with intravenous cefazolin prophylaxis, but induces selection of gram-negative bacteria.

DDEL-05. Intraventricular therapy with topotecan is feasible and safe: Experience in 50 pediatric patients with various malignant brain tumors

BACKGROUND: Malignant brain tumors carry a high risk for leptomeningeal dissemination, but the CSF compartment is often not affected by systemic therapy. Intraventricular therapy via an Ommaya reservoir is one possibility to increase the cytotoxic drug concentration in the CSF. Unfortunately, the number of drugs that can be administered directly into the CSF is limited. We report on our experience with topotecan administered via an Ommaya reservoir. PATIENTS AND METHODS: Between 2015 and 2021, 50 patients aged 1 to 22 years (mean and median both 8 years) with various malignant brain tumors received intraventricular topotecan via an Ommaya reservoir. Topotecan was administered at 0.4mg twice a week (>1 and <2 years 0.25mg, >2 and <3 years 0.32mg). RESULTS: In total, 1168 doses of topotecan (1-87/patient, mean 23, median 18) were administered at our department. Treatment was given over a period of 0-65 months (mean and median 33 months). Intraventricular treatment with topotecan was generally well tolerated. Two patients reported side effects. One boy with multiple recurrences of an ependymoma in the posterior fossa showed increased tremor after intraventricular administration of topotecan, another girl with recurrent medulloblastoma reported fatigue. CONCLUSION: Intraventricular therapy with topotecan is feasible and generally well tolerated. Topotecan can be an important addition for patients with recurrent malignant brain tumors to increase cytotoxic drug concentrations in CSF.

The role of intraventricular antibiotic therapy in the treatment of ventriculo-peritoneal shunt infection in children.

In this study, the effectiveness of intraventricular (IVT) antibiotic administration was evaluated in the treatment of ventriculo-peritoneal (VP) shunt infection by comparing patients who received only systemic antibiotic treatment with patients who received antibiotics added to systemic therapy by IVT route. From July 2009 to July 2019, 78 shunt infection episodes of 74 pediatric patients with bacterial growth in cerebrospinal fluid (CSF) culture who were treated with the diagnosis of VP shunt infection were retrospectively analyzed. The demographic data, clinical and laboratory parameters, antimicrobial management, and treatment outcomes of patients with VP shunt infections were recorded. Thirty-eight of 78 shunt episodes received only systemic antibiotic treatment, and 40 had received IV plus IVT treatment. The mean age of the entire patient group was 16.7±21.3 months (range, 1 to 95 months). There was no significant difference between the two treatment groups in terms of mean age. The most common microorganism grown in CSF culture was coagulase-negative Staphylococcus. However, in the group that received IV plus IVT treatment, gram-negative bacteria were predominant (42.1% versus 20%), and this group had carbapenem-resistant and ESBL positive gram-negative bacteria growth. In the duration of CSF sterilization, hospital stay was statistically significantly shorter in the group receiving IV plus IVT treatment (p=0.000, p=0.000, respectively). Our study shows that IVT administration of antibiotics shortens the duration of CSF sterilization, duration of antibiotic use, and the duration of hospital stay. For the treatment of VP shunt infection, the usage of IVT treatment in a particular group of a pediatric age is promising. However, further efforts should be done for supporting the current results by randomized controlled studies.

Clinical and electrophysiological characteristics of methotrexate encephalopathy in paediatric practice

Methotrexate-induced subacute encephalopathy is one of the side effects of the aforementioned drug. The effect is characterized by certain neurological symptoms, presence of leukoencephalopathy on a magnetic resonance imaging (MRI) and slow-wave activity shown on an electroencephalogram (EEG). The aim of this work is to determine the clinical and electrophysiological characteristics of methotrexate-induced encephalopathy in paediatric patients with various types of cancer, as well as to compare the obtained data with researches and precedents presented in medical literature. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. A retrospective analysis of treatment results was performed on 31 patients aged 1.5-17 who had subacute methotrexate-induced encephalopathy. Most patients (n = 26) have been diagnosed with acute lymphoblastic leukemia (ALL). According to the theurapeutic protocols, the patients received intravenous, intrathecal and intraventricular methotrexate treatment. The severity of methotrexate-induced encephalopathy was determined according to the NCI-CTCAE scale (version 4.0). All the patients underwent the EEG study. MRI was performed on 26 patients. Methotrexate-induced encephalopathy developed after 2-12 (on average 5.3 ± 3.1) days after methotrexate administration. Encephalopathy of grade I occurred in 35.45% of cases, of grade II - in 19.6%, of grade III and IV - in 25.8 and 19.4% of cases. 5 patients had symptoms recurred after therapy continuation. The most frequent neurological symptoms were: pathological level of sleepiness (50.1%), impaired consciousness (32.3%), cognitive impairment (25.8%), epileptic seizures (19.6%) and ataxia (19.6%). Regression of neurological symptoms occurred in 26 patients after 1-10 (on average 3.3 ± 2.2) days, 5 patients had persistent neurological deficit. The EEG pattern was represented by diffuse theta-wave activity (39%), theta-delta activity (42%), delta activity (6.5%), beta activity (3.0%), a decrease of alpha rhythm amplitude (6.5%), where no changes occurred for only 1 patient. Pathologic changes were seen on MRI in 84.6% of cases. The interdependence between the EEG changes, the time of debut and resolution of encephalopathy has been established. However, there has been no connection found between the severity of encephalopathy, the EEG pattern, the way of methotrexate administration, the age of the patients, the clearance of methotrexate and previous neurological disoders. The data obtained on the clinical picture and the time frame of methotrexate-induced encephalopathy initiation were similar to foreign ones. In different cases of patients with methotrexate-induced encephalopathy, EEG is not always represented as diffuse slow-wave theta-activity. The patients are recommended to undergo initial EEG in order for the electrophysiological studies on methotrexate encephalopathy to be assessed correctly. Further studies of the risk factors of methotrexate-induced encephalopathy are required.

Multi-systemic melioidosis: a clinical, neurological, and radiological case study from Hainan Province, China

BackgroundMelioidosis is a tropical disease caused by Burkholderia pseudomallei (B. pseudomallei). It can infect any organ system and lead to multiple abscesses. A few studies reported that central nervous system (CNS) is also involved.We present a diabetic patient with multi-systemic melioidosis that affected the CNS, thorax, and spleen. The aim was to study the clinical and radiological features of melioidosis and enhance understanding of the disease.Case presentationA 38-year-old male presented with cough and expectoration mixed with blood for several days. Chest computed tomography (CT) showed a patchy opacity in his left lung, and multiple low-density lesions in his spleen. After 10 days of antibiotics treatment, his clinical symptoms improved and he was discharged from the hospital. But 8 months later, the patient experienced sudden onset of left limb weakness and seizure and was re-admitted to the hospital. Brain CT indicated a low-density lesion over the right frontal lobe, and magnetic resonance imaging (MRI) indicated a well-enhanced lobulated lesion with multiple diffusion restriction areas in the lesion. He had a neuronavigation-guided open surgery but no malignancy was found. B. pseudomallei was cultured from the operative samples. After 4 months of systemic and intraventricular antibiotic administration treatment, he recovered complete consciousness with left hemiparesis.ConclusionsMulti-systemic melioidosis may present atypical clinical, neurological, and radiological manifestations. It is extremely important to accurately diagnose before treatment is selected. CNS melioidosis in early stage manifests similar symptoms to malignancy or stroke. It might mislead to a false diagnose. Diffusion weighted imaging (DWI) can help in differentiate abscesses from cystic tumours.

The Comparative Treatment of Intraventricular Chemotherapy by Ommaya Reservoir vs. Lumbar Puncture in Patients With Leptomeningeal Carcinomatosis.

Object: Leptomeningeal Carcinomatosis (LCM) represents a state of systemic malignant disease with poor prognosis. The purpose of this study is to compare overall survival (OS) between intraventricular chemotherapy through Ommaya reservoir (OR) and chemotherapy through lumbar puncture (LP) in LCM.Patients and Methods: Forty adult patients with LCM were included. All patients underwent lumbar puncture and Magnetic resonance imaging (MRI). Thirty patients received chemotherapy through LP and 10 undergone colocation of Ommaya reservoir for intraventricular chemotherapy.Results: The most common symptom was headache (Present in 50%). The cranial nerves most affected were VI and VII. Leptomeningeal enhancement was the most frequent finding in MRI. The OS in the LP group was 4 months and Ommaya group was 9.2 months (p = 0.0006; CI:1.8-3), with statistical differences in favor to Intraventricular treatment. Proportional hazard regression showed that receiving chemotherapy through Ommaya reservoir was a protective factor (Hazard ratio = 0.258, Standard Error = 0.112, p = 0.002 and 95% CI 0.110-0.606). Using KPS as a factor did not affect the hazard ratio of Ommaya reservoir itself.Conclusions: OS was significantly higher in patients with Ommaya reservoir in spite of Karnofsky Performance Status (KPS) previous to chemotherapy. Therefore, intraventricular chemotherapy should be preferred over lumbar puncture chemotherapy administration if there are resources available.

The Role of Intraventricular Antibiotics in the Treatment of Nosocomial Ventriculitis/Meningitis from Gram-Negative Pathogens: A Systematic Review and Meta-Analysis

The emergence of multidrug-resistant pathogens has resulted in difficult-to-treat ventriculitis/meningitis (VM). We used a meta-analysis to study the role of intraventricular (IVT) antibiotic administration as an adjunct (IVT plus intravenous [IV]) to the classic intravenous antimicrobial therapy (IV-only) in the management of VM in terms of infection control, functional outcome, microbial eradication, complications, cost-benefit analysis, infectious mortality, and overall mortality. The electronic search focused on adult neurosurgical cases complicated by gram-negative VM and was limited to studies comparing IVT plus IV and IV-only. The quality of the overall body of evidence was assessed according to GRADE (Grading of Recommendations Assessment, Development, and Evaluation). The pooled estimates for each question were summarized as odds ratios (ORs) and visualized using forest plots. Every outcome was stratified according to carbapenem resistance. Eleven studies with 348 patients fulfilled the eligibility criteria. No evidence was found for infection control, functional outcome, or complications. For the remaining items evaluated, the overall quality of the best available evidence was low. IVT plus IV treatment was statistically superior to IV-only therapy in eradication (OR, 10.06; 95% confidence interval [CI], 2.62-38.65), infectious mortality (OR, 0.1; 95% CI, 0.03-0.36), and overall mortality (OR, 0.22; 95% CI, 0.08-0.60) in the management of carbapenem-resistant pathogens only. Combined IVT plus IV treatment did not prove superior to standard IV-only treatment in the management of VM. Nevertheless, weak evidence showed that IVT treatment might serve as an adjunct in the management of carbapenem-resistant pathogens.

Posterior Inferior Cerebellar Artery Aneurysm: Surgical or Endovascular Treatment in a Case Report

Introduction: PICA aneurysms answer for 3% of all intracranial aneurysms. The patients generally present Hunt- Hess I or II and have intraventricular hemorrhage needing treatment. Case presentation: This is a case study about an elderly woman complaining about a sudden headache. She had an aneurysm in the distal segment of the PICA, which was treated by clipping. The woman progressed well despite her hydrocephalus. Discussion: Information about the aneurysm positioning and anatomy guided the therapeutic decisions. Age and clinical presentation are the most prominent factors in positive clinical evolution. An interdisciplinary team should choose between surgical and endovascular treatment.

Outcomes in meningitis/ventriculitis treated with intravenous or intraventricular plus intravenous colistin.

The aim of this work is to evaluate the outcome of patients treated with intrathecal colistin for meningitis/ventriculitis. This retrospective case series study included patients presenting with nosocomial meningitis/ventriculitis following neurosurgical interventions and having intravenous (IVC group) or intravenous and intrathecal/intraventricular colistin (ITC group) treatment between 2006 and 2014. Thirty-four patients presented nosocomial meningitis/ventriculitis; 11 (32.5 %) were included in the IVC group and 23 (67.6 %) in the ITC group. The most frequent isolated bacteria were Acinetobacter baumannii. The mean dose was 170,000 (±400) IU and the duration of intraventricular treatment was 16.0 (±8.3) days. The duration of intravenous treatment was 16.0 (±8.3) days in the ITC group and 15.3 ± 7.6 days in IVC group. Hospital mortality was significantly lower in the ITC group compared with the IVC group (13 vs. 72.7 %, p = 0.001). The combination of intravenous plus intraventricular (IV-IVT) colistin therapy may improve outcomes in patients attending with meningitis/ventriculitis due to multi-drug resistance infections.

Diagnosis and treatment of pyogenic ventriculitis caused by gram-negative bacteria in severe neurosurgical patients

Objective To investigate the experiences in diagnosis and treatment pyogenic ventriculitis caused by gram-negative bacteria (G-) in severe neurosurgical patients. Methods Nineteen consecutive patients with pyogenic ventriculitis treated at the Neurosurgical Intensive Care Unit of the Department of Neurosurgery, Beijing Xuanwu Hospital, Capital Medical University from September 2009 to August 2014 were reviewed. Their bacteriological results, clinical treatment, and prognosis were analyzed. Results Ventricular drainage of cerebrospinal fluid bacterial smears in all cases were G-bacteria. Head CT scans confirmed as intraventricular empyema. Eighteen patients were positive in cerebrospinal fluid bacterial culture, 12 of them were Acinetobacter baumannii, 2 were Klebsiella pneumonia, 2 were Serratia marcescens, 1 was Pseudomonas maltophila, and 1 was Escherichia coli. The bacterial culture in one case was negative. The catheters which caused infections were removed and ventricular drainage was conducted in all cases. The patients were treated with intraventricular lavage in combination with intravenous drugs and intraventricular antibiotics according to the conditions. They were followed up for 3 months to 3 years. After treatment for 2 to 8 weeks, 14 patients were cured (74%) and 5 died (26%). In the cured patients, 8 patients underwent ventriculo-peritoneal shunt after the infection being cured in 2 to 6 weeks because of hydrocephalus. No reinfection occurred. Twelve patients came to consciousness, and 2 were in a persistent vegetative state before infection and did not have any improvement. Conclusions Suppurative ventriculitis in severe neurosurgical patients is mainly caused by G-negative bacteria. The mortality is higher. Early diagnosis, especially clarifying pathogens, timely ventricular irrigation, and ventricular drainage in combination with intravenous and intraventricular antibiotic treatment may increase the cure rate and improve the prognosis. Key words: Cerebral ventriculitis; Gram-negative bacteria; Intensive care unit; Acinetobacter baumannii

Studies on Anti-Inflammatory Action of Tryptanthrin, Using a Model of DSS-Induced Colitis of Mice and Magnetic Resonance Imaging

The action of tryptanthrin, a known natural alkaloid, a potent inhibitor of cyclooxygenase COX-2 and 5-lipoxygenase, was studied in a model of dextran sodium sulfate (DSS)-induced mouse colitis by magnetic resonance imaging (MRI). It was shown that the intra-ventricular treatment with tryptanthrin suspensions or emulsion at a dose of 25 mg/kg effectively diminishes lethality at experimental groups and normalizes morphometric parameters of intestine in the treated animals. MR imaging confirmed anti-inflammatory effect of this alkaloid and its capability to decrease the size of bowel walls in animals with colitis.

Spatial learning in the Morris water maze in mice genetically different in the predisposition to catalepsy: The effect of intraventricular treatment with brain-derived neurotrophic factor

Hereditary catalepsy in mice is accompanied with volume reduction of some brain structures and high vulnerability to inflammatory agents. Here an association between hereditary catalepsy and spatial learning deficit in the Morris water maze (MWM) in adult mouse males of catalepsy-resistant AKR, catalepsy-prone CBA and AKR.CBA-D13Mit76 (D13) strains was studied. Recombinant D13 strain was created by means of the transfer of the CBA-derived allele of the major gene of catalepsy to the AKR genome. D13 mice showed a low MWM performance in the acquisition test and high expression of the gene coding proinflammatory interleukin-6 (Il-6) in the hippocampus and cortex compared with mice of the parental AKR and CBA strains. An acute ivc administration of 300ng of brain derived neurotrophic factor (BDNF) normalized the performance in the MWM, but did not decrease the high Il-6 gene expression in the brain of D13 mice. These results indicated a possible association between the hereditary catalepsy, MWM performance, BDNF and level of Il-6 mRNA in the brain, although the relation between these characteristics seems to be more complex. D13 recombinant mice with deficit of spatial learning is a promising model for study of the genetic and molecular mechanisms of learning disorders as well as for screening potential cognitive enhancers.

Intraventricular hemorrhage treated with intraventricular fibrinolysis. A 10-year experience

PurposeWe evaluate the results and complications of our intraventricular fibrinolysis protocol. Material and methodsA retrospective analysis was made of the cases of intraventricular hemorrhage with 13-bed Intensive Care Unit. Graeb score 6 or above subjected to intraventricular fibrinolysis. We gathered demographic parameters, clinical risk scores, tomography data and case histories showing neurological status and complications related to intraventricular treatment. The results between those who died and the survivors were compared. ResultsIntraventricular fibrinolysis was performed in 42 patients (69% males) with intraventricular hemorrhage. The average age was 58.36 years (SD 16.67), with a median APACHE II score of 17.5 (r 3–29). A total of 16.7% were receiving acenocoumarol, and 7.1% were on antiplatelet drugs. The median Glasgow Coma Score at the start of treatment was 8 (r 3–13). The median Graeb score was 9 (r 6–12), and was severe (Graeb 9–12) in almost 62%. In turn, 26.2% of the patients developed ventriculitis, and there was further bleeding in 7.1%. Death occurred in 50% of the cases. None of the analyzed variables were significantly related to increased mortality. In the 21 survivors, the Glasgow Outcome Score at 3 months was 2 in 23.8% of the cases, 3 in 28.57%, 4 in 23.8% and 5 in 28.57% of the patients. ConclusionsIntraventricular fibrinolysis does not appear to involve a high rate of complications, and may result in lesser mortality, with a better functional outcome after three months than that estimated and published in the literature in reference to intraventricular hemorrhage.

Intraventricular hemorrhage treated with intraventricular fibrinolysis. A 10-year experience

PurposeWe evaluate the results and complications of our intraventricular fibrinolysis protocol. Material and methodsA retrospective analysis was made of the cases of intraventricular hemorrhage with 13-bed Intensive Care Unit. Graeb score 6 or above subjected to intraventricular fibrinolysis. We gathered demographic parameters, clinical risk scores, tomography data and case histories showing neurological status and complications related to intraventricular treatment. The results between those who died and the survivors were compared. ResultsIntraventricular fibrinolysis was performed in 42 patients (69% males) with intraventricular hemorrhage. The average age was 58.36 years (SD 16.67), with a median APACHE II score of 17.5 (r 3–29). A total of 16.7% were receiving acenocoumarol, and 7.1% were on antiplatelet drugs. The median Glasgow Coma Score at the start of treatment was 8 (r 3–13). The median Graeb score was 9 (r 6–12), and was severe (Graeb 9–12) in almost 62%. In turn, 26.2% of the patients developed ventriculitis, and there was further bleeding in 7.1%. Death occurred in 50% of the cases. None of the analyzed variables were significantly related to increased mortality. In the 21 survivors, the Glasgow Outcome Score at 3 months was 2 in 23.8% of the cases, 3 in 28.57%, 4 in 23.8% and 5 in 28.57% of the patients. ConclusionsIntraventricular fibrinolysis does not appear to involve a high rate of complications, and may result in lesser mortality, with a better functional outcome after three months than that estimated and published in the literature in reference to intraventricular hemorrhage.

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.

Inhibitory effect of ethanol extract of Magnolia officinalis and 4-O-methylhonokiol on memory impairment and neuronal toxicity induced by beta-amyloid

The components of the herb Magnolia officinalis have exhibited antioxidant and neuroprotective activities. In this study, we investigated effects of ethanol extract of M. officinalis and its major component 4- O-methylhonokiol on memory dysfunction and neuronal cell damages caused by Aβ. Oral pretreatment of ethanol extract of M. officinalis (2.5, 5 and 10 mg/kg) and 4- O-methylhonokiol (1 mg/kg) into drinking water for 5 weeks suppressed the intraventricular treatment of Aβ 1–42 (0.5 μg/mouse, i.c.v.)-induced memory impairments. In addition, 4- O-methylhonokiol prevented the Aβ 1–42-induced apoptotic cell death as well as β-secretase expression. 4- O-methylhonokiol also inhibited H 2O 2 and Aβ 1–42-induced neurotoxicity in cultured neurons as well as PC12 cells by prevention of the reactive oxygen species generation. 4- O-methylhonokiol also directly inhibited β-secretase activity and Aβ fibrilization in vitro. Thus, ethanol extract of M. officinalis may be useful for prevention of the development or progression of AD, and 4- O-methylhonokiol may be a major active component.

Association of genetic variants of methionine metabolism with methotrexate-induced CNS white matter changes in patients with primary CNS lymphoma

Methotrexate (MTX) is an important anticancer drug and the most efficient chemotherapy component in primary CNS lymphoma (PCNSL). A typical side effect of intravenous high-dose MTX is the occurrence of confluent CNS white matter changes (WMC). Because MTX directly interferes with methionine metabolism, we analyzed the impact of genetic variants of methionine metabolism on the occurrence of WMC as a model of MTX toxicity. In a retrospective analysis of 68 PCNSL patients treated with MTX-based polychemotherapy with (n = 42) or without (n = 26) intraventricular treatment, 10 genetic variants influencing methionine metabolism were analyzed. Pearson's chi(2) test and multinominal regression analysis were used to define the relevance of these genetic variants for the occurrence of WMC. In this patient sample, the occurrence of WMC was significantly predicted by the TT genotype of methylenetetrahydrofolate reductase c.677C>T (chi(2) = 8.67; p = 0.013; df = 2), the AA genotype of methylenetetrahydrofolate reductase c.1298A>C (chi(2) = 13.5; p = 0.001; df = 2), and the GG genotype of transcobalamin 2 c.776C>G (chi(2) = 19.73; p < 0.001), in addition to male gender (chi(2) = 11.95; p = 0.001). These data strengthen the hypothesis that MTX effects are influenced by methionine metabolism, which may offer new strategies to improve MTX-based therapies.

Early relapses in primary CNS lymphoma after response to polychemotherapy without intraventricular treatment: results of a phase II study

A systemic and intraventricular polychemotherapy regimen (the Bonn protocol) without radiotherapy resulted in durable responses in 75% of patients <60 years with primary CNS lymphoma (PCNSL), but was complicated by a high rate of Ommaya reservoir infections. Here, the efficacy and toxicity of this regimen without intraventricular treatment was evaluated in PCNSL. From August 2003 to November 2005, 18 patients with PCNSL <60 years (median age, 53 years) were treated in a phase II trial with a high-dose methotrexate (MTX; cycles 1, 2, 4 and 5) and cytarabine (Ara-C; cycles 3 and 6) based systemic therapy including dexamethasone, vinca-alkaloids, ifosfamide and cyclophosphamide. Study accrual was prematurely stopped in November 2005 due to a high rate of early relapses. Seventeen of 18 patients were assessable for response: nine (53%) achieved complete response (CR), two (12%) complete response/unconfirmed (CRu) and two (12%) partial response (PR); four (24%) showed progressive disease (PD). One treatment was stopped due to toxicity. Median follow-up was 23 months, median response duration was only 10 months in responding patients, and median time to treatment failure (TTF) was 8 months in the whole group. Median overall survival (OS) has not been reached. Systemic toxicity was mainly hematologic. In PCNSL patients <60 years, polychemotherapy without intraventricular treatment results in a high response rate, but is associated with early relapses in the majority of cases. This is in contrast to the results achieved with the same protocol but with intraventricular treatment.