Intrathecal Methotrexate Treatment Research Articles

Leptomeningeal spread in high-grade gliomas: Is surgery or adjuvant therapy after leptomeningeal spread associated with survival benefit?

PurposeThis study aimed to identify prognostic factors associated with survival in patients with high-grade glioma (HGG) after leptomeningeal spread (LMS) and to clarify the behavior and treatment response.MethodsThis retrospective study included 114 patients with HGGs diagnosed with LMS from August 1, 2014, to July 30, 2021, at our institution. Clinical, radiological, pathological, and outcome data were collected. Univariable and multivariable Cox regression were used for overall survival (OS) and post-LMS survival (PLS) analysis.ResultsThe median OS was 17.0 months and the median PLS was 6.0 months. Gross total resection (GTR) after LMS diagnosis and pathology grade III were statistically significantly associated with longer OS in all patients. GTR after LMS diagnosis and nodular LMS were independent favorable prognostic factors on PLS. Non-adjuvant therapy after LMS diagnosis was associated with shorter OS and PLS. In glioblastoma (GBM) subgroup analysis, GTR after LMS diagnosis and secondary LMS were independent favorable prognostic factors on OS. Karnofsky Performance Status (KPS) of ≥80 at LMS diagnosis, chemotherapy after LMS and intrathecal methotrexate (MTX) treatment were statistically significantly associated with longer PLS. MRI type II was a predictor of shorter PLS.ConclusionThe treatment of patients with glioma after LMS diagnosis is very challenging and limited. Safe GTR of tumor and subsequent adjuvant therapy after LMS remains a powerful weapon to improve survival for HGG patients with LMS. Chemotherapy and Intrathecal MTX treatment are feasible treatments after LMS. The extent of tumor dissemination may affect the survival after LMS.

Progressive Lower Extremity Paralysis Caused by Intrathecal MTX-Induced Myelopathy Mimicking Guillain-Barre Syndrome: A Case Report.

Methotrexate (MTX) is commonly used in intrathecal chemotherapy for patients with acute lymphocytic leukemia (ALL) to prevent central nervous system (CNS) involvement. However, the use of MTX-based chemotherapy can lead to rare yet severe complications, such as MTX-induced myelopathy. Here, we report the case of MTX-induced myelopathy initially misdiagnosed as Guillain-Barre syndrome, leading to a delay in diagnosis and treatment. We present a case of a 39-year-old male with a history of B-cell acute lymphoblastic leukemia (B-ALL) who experienced bilateral foot paresthesia and progressive lower extremity weakness after intrathecal methotrexate (MTX) treatment. Initially, the patient was suspected as having Guillain-Barre syndrome (GBS) due to similar clinical features and nerve conduction studies. The patient received intravenous immunoglobulin (IVIG) treatment, but his condition worsened. T2-weighted images of the thoracic spinal cord revealed high signal intensity in both lateral and posterior columns, typically associated with subacute combined degeneration. However, elevated vitamin B12 levels ruled out SCD in this case. Based on the aforementioned findings, intrathecal methotrexate-induced myelopathy was diagnosed. This case highlights the diagnostic challenge posed by the similarity in clinical presentation between MTX-induced myelopathy and GBS. Differentiating between these conditions is critical for appropriate management. Prompt recognition and treatment with folate metabolism compounds may mitigate neurological sequelae.

Effectiveness of intra-thecal methotrexate in refractory Anti-N-methyl-d-aspartate receptor encephalitis

BackgroundAnti-N-methyl-d-aspartate “anti-NMDA” receptor encephalitis is one of the most common autoimmune encephalitis for which first- and second-line therapies have been recommended following international consensus. However, some refractory cases do not respond to the first- and second-line therapy and require further immune-modulatory therapies such as intra-thecal methotrexate. In this study, we reviewed six confirmed cases of refractory anti-NMDA receptor encephalitis from two tertiary centers in Saudi Arabia that required escalation of treatment and received a six-month course of intra-thecal methotrexate. The aim of this study was to evaluate the effectiveness of intra-thecal methotrexate as immunomodulatory therapy for refractory anti-NMDA receptor encephalitis.MethodsWe retrospectively evaluated six confirmed cases of refractory anti-NMDA receptor encephalitis who did not improve after first- and second-line therapy and received monthly intra-thecal methotrexate treatment course for six consecutive months. We reviewed patient demography, underlying etiologies, and compared their modified Rankin score prior to receiving intra-thecal methotrexate and six months after completing the treatment.ResultsThree of the six patients showed a marked response to intra-thecal methotrexate with a modified Rankin scale of 0–1 at 6-month follow-up. None of the patients experienced any side effects during or after intra-thecal methotrexate treatment, and no flareups were observed.ConclusionIntra-thecal methotrexate may be a potentially effective and relatively safe escalation option for immunomodulatory therapy of refractory anti-NMDA receptor encephalitis. Future studies on intra-thecal methotrexate -specific treatment regimens may further support its utility, efficacy, and safety in treating refractory anti-NMDA receptor encephalitis.

Melatonin protects against methotrexate hepatotoxicity in young rats: Impact of PI3K/Akt/mTOR signaling.

With the improvement in children's acute lymphoblastic leukemia (ALL) care, the survival rate in children ALL has improved much. Methotrexate (MTX) plays an essential role in the success of children's ALL treatment. Since hepatotoxicity is commonly reported in individuals treated with intravenous or oral MTX, our study further examined the hepatic effect following intrathecal MTX treatment, which is an essential treatment for leukemia patients. Specifically, we examined the pathogenesis of MTX hepatotoxicity in young rats and explored the impact of melatonin treatment in protection against MTX hepatotoxicity. Successfully, we found that melatonin was able to protect against MTX hepatotoxicity.

P16.01.A Factors predicting cognitive impairment after intrathecal methotrexate treatment in patients with non-small cell lung cancer and leptomeningeal disease

Abstract Background Leptomeningeal disease (LD) is a devastating cancer-related neurological complication. LD accounts for 4-15% of patients with non-small cell lung cancer (NSCLC). In this population, the median overall survival (OS) with intrathecal (IT) methotrexate (MTX) plus systemic therapy (ST) is 4-6 months (m). Until now, disease and treatment-related cognitive impairment (CI) has been poorly studied in this group. Material and Methods Patients with NSCLC and LD treated with IT MTX in our institution between 2010 and 2021 were retrospectively studied. LD was diagnosed based on positive cerebrospinal fluid cytology or radiological findings in the brain/spinal MRI plus suitable clinical signs/symptoms. IT MTX (12mg twice weekly for 4 weeks, then 12mg weekly for 4 weeks) was given in combination with ST. Patients’ clinical characteristics and patient-reported CI were assessed at baseline and at 3-months post IT MTX. A Kaplan-Meier survival analysis was performed. Primary endpoint: predictive factors of CI at 3m post IT MTX. Secondary endpoint: prognostic factors. Results Out of 55 patients included, 51% were male and median age at LD diagnosis was 59 years old (range 38-78). Most patients had an ECOG PS≤1 (76.4%) and adenocarcinoma histology (83.6%). 47% of patients harbored EGFR mutation. In 23.6% of patients LD was diagnosed synchronously with lung tumor and for patients without LD at tumor diagnosis, the median time to LD development was 8m (range 0-73). Clinical features at LD diagnosis were 43.7% infratentorial symptoms, 29% CI, 20% multiple symptoms and 7% asymptomatic. At LD diagnosis, 53% of patients had synchronous brain metastases (BM) and in 38% the systemic disease was not controlled. 85.5% of patients received ST concurrently with IT MTX (N=22 chemotherapy, N=22 TKIs and N=3 immunotherapy). 14.5% of patients did not receive ST. Median OS from IT was 5m (95% CI 1.3-8.6). ECOG PS and ST administered concurrently with IT MTX was associated with longer OS (p<0.05). 23.6% of patients developed CI at 3m post IT therapy. Median OS for patients without and with CI post IT therapy was 6m (95% CI 0.7-11.3) vs 4m (95% CI 0.5-75) respectively (p=0.15). Patients with leukoencephalopathy at baseline (score≥2in the periventricular Fazekas’ score) (p=0.033), women (p<0.01) and those ≥60 years (p=0.04) were more likely to present CI 3m post IT MTX. The presence of cardiovascular risk factors, previous brain radiotherapy and concurrent BM was not statistically associated with CI. Conclusion In this cohort, 24% of patients with NSCLC and LD treated with IT MTX will develop CI 3m post treatment. Baseline leukoencephalopathy, female gender, elder than 60 years old were more likely to exhibit CI after IT MTX. A better characterization of these patients is warranted to develop new treatment strategies to prevent/reduce CI.

Leptomeningeal Carcinomatosis in a Patient with Pancreatic Cancer: A Rare Phenomenon?

Complication of leptomeningeal carcinomatosis (LMC) is critical. It causes rapid neurological deterioration, and subsequently, discontinuation of the ineffective treatment even in body tumor dormancy. Large molecular chemotherapeutic agents that are unlikely to penetrate the CSF space, are more likely to not treat LMC, typically in chemo-sensitive tumors. With the introduction of novel regimens, significant advances in overall survival have been observed even in formerly chemo-resistant tumors, such as pancreatic cancer. Although such cases are still rare, the number of pancreatic cancer patients complicated with LMC are increasing, and this therefore needs more recognition. A 49-year-old woman was diagnosed with stage IVa pancreatic cancer. She underwent surgery, and subsequent adjuvant chemotherapy. After three lines of chemotherapy over a 3-year period, where the body disease remained dormant, the patient was complicated by LMC. The diagnosis was made 4 months after the onset of headache. The patient received intrathecal methotrexate treatment but succumbed shortly after treatment induction. Pancreatic cancer is still relatively chemo-resistant and is one of the least likely types of tumor to be complicated by LMC due to patients dying of the primary tumor. Advancements in treatments have led to a prolonged period of primary tumor control, but not in the CNS due to the poor penetration of chemo-agents to this site. The present case seems to be a typical result of modern era anti-cancer therapy. Therefore, we emphasize the necessity of earlier recognition of this complication so that we can initiate specific treatment targeting the CSF space, especially in this formerly chemo-resistant tumor in order to improve its prognosis.

Melatonin rescued methotrexate-induced spatial deficit and hyperhomocysteinemia and increased asymmetric dimethylarginine in plasma and dorsal hippocampus in developing rats

AimsWith the improvement of the survival rates in children acute lymphoblastic leukemia (ALL), some children ALL survivors show impaired cognitive function. Methotrexate (MTX), an essential component in ALL treatment, has been reported to be related to neurologic sequelae and to increased oxidative stress through its interactions with enzymes in the folate pathway. Asymmetric dimethylarginine (ADMA) is the main endogenous inhibitor of nitric oxide synthase, and increased ADMA may result from increased oxidants. Melatonin is an antioxidant; however, its role in MTX neuropathy is not well studied. We developed a rat model mimicking child ALL treatment to explore peripheral and central homocysteine and ADMA regulation after MTX and found potential treatment choice. Main methodsPreweaning male Sprague-Dawley rats were used in this study. Experiment 1 evaluated spatial performance in rats with intrathecal (IT) MTX, intraperitoneal (IP) MTX, or combined IT and IP MTX, protocols mimicking ALL treatment in children. Experiment 2 focused on rats with combined IT and IP MTX, evaluating spatial performance and plasma and dorsal hippocampal homocysteine and ADMA levels, their regulation, and the protective effect of melatonin. Key findingsCombined IT and IP MTX treatment caused in spatial deficits in developing rats, and melatonin restored the spatial performance. Alterations in peripheral and central homocysteine and ADMA concentrations and their regulation were found and could be alleviated by melatonin treatment. SignificancesCombined IP and IT MTX treatment caused spatial deficits in developing rats. Melatonin could restore spatial performance through alleviating the effects on the imbalance of oxidative stress.

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.

Utility and Safety of Intrathecal Methotrexate Treatment in Severe Anti-N-methyl-D-aspartate Receptor Encephalitis: A Pilot Study.

Background:Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a treatable autoimmune neurologic syndrome that occurs with or without tumor association. However, some severe cases are refractory to systemic immunotherapy. This pilot study aimed to evaluate the utility and safety of intrathecal methotrexate injection for severe patients with anti-NMDAR encephalitis who did not respond to first-line immunotherapy.Methods:Intrathecal injections with methotrexate and dexamethasone were performed weekly in four legible patients within consecutive 4 weeks. Cerebrospinal fluid (CSF) was collected at baseline and each time of intrathecal injection for identification of anti-NMDAR antibody titers.Results:Significant clinical improvement was observed in three patients associated with a stepwise decrease of CSF anti-NMDAR antibody titers (maximum: 1/320 to minimum: 1/10). After 2 months of follow-up, they were able to follow simple commands and had appropriate interactions with people (modified Rankin scale [mRS] of 0–2). At 12 months of follow-up, they all had returned to most activities of daily life (mRS of 0), and no relapses were reported. One patient showed no clinical improvement and died of neurologic complications.Conclusions:Intrathecal treatment may be a potentially useful supplementary therapy in severely affected patients with anti-NMDAR encephalitis. Further large cohort study and animal experiment may help us elaborate the utility of intrathecal injection of methotrexate and its mechanism of action.

Changes in cognition and dendritic complexity following intrathecal methotrexate and cytarabine treatment in a juvenile murine model

Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer and accounts for 26.8% of cancer diagnoses among children, worldwide—approximately 3000 children each year. While advancements in treating ALL have led to a remission rate of more than 90%, many survivors experience adverse neurocognitive and/or neurobehavioral effects as a result of intrathecal chemotherapy. Methotrexate (MTX) is commonly administered with cytosine arabinoside (AraC, cytarabine) during intrathecal chemotherapy for ALL. To date, few studies exist that test the cognitive effects of intrathecal injections of MTX/AraC on juvenile populations. The purpose of our study was to investigate the combined effects of MTX/AraC on cognition and dendritic structure in the hippocampus in juvenile male mice. Twenty, 21-day-old male C57BL/6 mice were used in this study; 10 mice received intrathecal MTX/AraC treatment, and 10 were given intrathecal saline injections. Five weeks after injections, we tested the animals’ hippocampus-dependent cognitive performance in the Morris water maze. After the first day of hidden-platform training, we observed that the mice that received MTX/AraC treatment showed signs of significant impairment in spatial memory retention. MTX/AraC treatment significantly compromised the dendritic architecture and reduced mushroom spine density in the dorsal ganglion (DG), CA1, and CA3 areas of the hippocampus. The present data provided evidence that MTX/AraC compromised the dendritic architecture and impaired hippocampal dependent cognition. This could provide insight into chemotherapy-induced cognitive decline in juvenile patients treated for ALL.

A Case of Relapsed Chronic Myeloid Leukemia Admitted with the Complaints of Paraplegia and Urinary Incontinence

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell malignancy. In CML, extramedullary blastic crisis is a very rare condition in which the prognosis is even worse. Herein we presented a rare case of relapsed CML patient as blastic crisis with serious neurological symptoms because of central nervous system (CNS) infiltration. A 69-year-old male patient diagnosed with CML was admitted to hospital with complaints of weakness in legs, urinary incontinence, abnormal speech, and impaired vision. Deep tendon reflexes were bilaterally hypoactive in lower and upper extremities and Babinski reflex was negative. Immunophenotyping and cytological examination of CSF showed blastic cell infiltration. Also BCR-ABL mutation was positive in CSF and MR showed CNS involvement. So the patient diagnosed as “Myeloid blastic phase of CML with CNS involvement”. Imatinib therapy was replaced with dasatinib and intrathecal methotrexate, cytarabine and dexamethasone treatment was applied. Complaints of weakness, fatigue, urinary incontinence, leg weakness and inability to walk were completely resolved in three months. Extramedullary blastic crisis such as CNS involvement has been reported in a limited number in CML. Even if hematological and cytogenetic remission is provided, CML patients should be followed regularly. Any new clinical detail should be considered carefully and extramedullary involvement including CNS should be kept in mind.

Progressive motor polyradiculopathy and myelopathy associated with lymphoma and intrathecal methotrexate treatment, a case report and systemic review

Progressive motor polyradiculopathy and myelopathy associated with lymphoma and intrathecal methotrexate treatment, a case report and systemic review

Subdural Hematoma Associated with Dasatinib and Intrathecal Methotrexate Treatment in Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia.

Dasatinib has been associated with an increased risk of bleeding, with the most prominent risk noted in patients with advanced-stage chronic myeloid leukemia and thrombocytopenia. We herein report two cases of Philadelphia chromosome-positive acute lymphoblastic leukemia in which a subdural hematoma developed in association with low-dose (40-50 mg/day) dasatinib treatment and lumbar puncture for intrathecal methotrexate injection. Both patients were in complete remission, with normal platelet counts and coagulation status. We suggest that dasatinib, even at a low dose, may impair platelet aggregation and that lumbar puncture may increase the risk of a subdural hematoma (occasionally bilateral) in patients receiving dasatinib.

Intrathecal dexamethasone and methotrexate treatment of neoplastic meningitis from solid tumors

Aim: Neoplastic meningitis (NM) from solid tumors is an advanced malignancy with poor prognosis. Intrathecal chemotherapy is a reliable treatment, and we have obtained some experiences in the treatment of NM with intrathecal dexamethasone and methotrexate (IT DXM and MTX). Methods: Retrospective study of 23 patients with NM from lung cancer ( n = 11), breast cancer ( n = 3), gastric cancer ( n = 1), malignant melanoma ( n = 1), unknown cancer ( n = 7) was conducted. Among these patients, eight received IT DXM and MTX treatment, and 15 patients were placed into a palliative care group. Overall survival (OS) was compared, and the patients' characteristics, symptoms, and some laboratory examinations were analyzed to find the risk factors affecting OS. Results: OS of IT DXM and MTX group was significantly longer than that of the palliative care group ( P = 0.01). The median survival (MS) of palliative care group was 7.53 weeks (5.50-9.57; n = 15), and of the IT DXM and MTX group, 28.63 weeks (12.50-44.75; n = 8); IT DXM and MTX prolonged the OS of NM patients (regression coefficient = −2.923), with odds ratio (OR) being 0.054 (0.09-0.323). Spinal nerves damage decreased the OS (regression coefficient = 1.595), with OR being 4.928 (1.382-17.579). Conclusion: IT DXM and MTX have prolonged the patients' MS, which could be used as a fundamental treatment of NM. Time of induction treatment should be flexible and individualized, and induction treatment could restart when central nervous system relapse. Patients with spinal nerves damage are apt to live shorter.

CN-02 * MYELOPATHY FOLLOWING INTRATHECAL CHEMOTHERAPY: A CASE SERIES IN ADULTS

Intrathecal (IT) chemotherapy in combination with systemic chemotherapy is an effective treatment modality used in the prophylaxis and treatment of CNS disease in hematological malignancies. IT agents commonly used in various chemotherapeutic regimens include methotrexate and cytarabine arabinoside (Ara-C).Side effects from IT chemotherapies described in the literature vary from mild asymptomatic forms of arachnoiditis diagnosed on MRI to leukoencephalopathy and myelopathy. These complications have been reported more frequently in the pediatric literature than in adults. We here describe 7 adult patients treated at a single institution for hematological malignancies that developed myelopathy following intrathecal chemotherapy. 5 out of our 7 patients demonstrated longitudinal hyperintenities involving mostly the dorsal columns and to varying degrees the lateral corticospinal tracts; a picture suggesting methotrexate induced toxicity. In the 2 cases where myelobasic protein was checked in the CSF, it was significantly elevated supporting the role of a potential CSF biomarker to diagnose cord injury and distinguish the pathology from leukemic infiltration. Median survival was 3.1 months from the time of myelopathy diagnosis despite various treatment strategies employed. We did not find any correlation between number of IT methotrexate doses given and development of myelopathy indicating a potential individual sensitivity to methotrexate. Based on what is known, immediate discontinuation of intrathecal methotrexate treatment would be recommended once a diagnosis of IT induced melopathy is made with consideration of methionine or S-adenosylmethionine supplementation for patients who received IT methotrexate.

Intrathecal Methotrexate-Induced Posterior Reversible Encephalopathy Syndrome (PRES).

Posterior reversible encephalopathy syndrome (PRES) is an acute neuroradiological diagnosis presenting with headache, vomiting, seizure, abnormalities of the mental status, and visual disturbances associated with a breakdown in cerebral vasculature regulation. It has a unique neuroradiological pattern of symmetrical parietooccipital vasogenic edema [1]. The most common causes of this syndrome are sudden arterial hypertension, preeclampsia, eclampsia, uremia, immunosuppressive drugs, and cancer chemotherapies such as cyclosporine, tacrolimus, L-asparaginase, vincristine, gemcitabine, cytarabine, and cisplatin, typically used in cases of hematopoietic malignancies [2,3,4,5,6,7]. Intrathecal methotrexate-induced PRES in an adult is exceedingly rare [8]. A 43-year-old woman was admitted to gynecology with metrorrhagia. Cervical cancer was diagnosed and radical hysterectomy with lymph node dissection was performed. Final pathology and immunohistochemical analyses revealed B-cell phenotype malign lymphoma, which is consistent with Burkitt lymphoma. A chemotherapy treatment protocol with R-Hyper CVAD, consisting of rituximab, cyclophosphamide, vincristine, adriamycin, and dexamethasone plus 12 mg of intrathecal methotrexate without preservative, was then started. Twelve days after chemotherapy she had severe analgesic-irresponsive headache, nausea, motor agitation, and cooperation failure. Her vital signs and laboratory findings were normal. Cranial computed tomography revealed hypodense areas due to edema in the bilateral cerebral hemispheres, predominantly in the posterior regions. Magnetic resonance imaging (MRI) of the brain showed multiple confluent hyperintense lesions in T2-weighted and fluid-attenuated inverse recovery (FLAIR) sequences (Figure 1a), with no contrast enhancement in T1-weighted sequences. PRES was diagnosed and she was admitted to the intensive care unit (ICU) because of decreased alertness and agitation. Intrathecal methotrexate treatment was discontinued. On the second day in the ICU her blood pressure rose and was then normalized by diltiazem infusion. On the third day in the ICU, myoclonic jerks were seen in all extremities. Levetiracetam was started. Myoclonic symptoms were no longer observed. After treatment she had no neurological symptoms. Three weeks later, cranial MRI showed significantly improved brain lesions (Figure 1b). The 6-month follow-up was uneventful. Informed consent was obtained. Figure 1a MRI FLAIR images show bilateral multiple subcortical and cortical hyperintense lesions. Figure 1b MRI images 3 weeks after developing PRES revealed significant improvement. During chemotherapy for hematopoietic malignancies, possible causes of neurological symptoms (cerebrovascular disease, metabolic disturbances, neoplasia, and infections) must be excluded by clinical, biological, and imaging findings. During chemotherapy, various types of anticancer drugs are administered, and it is difficult to identify which drug induces PRES. In our case, intrathecal methotrexate treatment was stopped, and the patient’s symptoms were relieved and did not reoccur while her treatment was continued with other anticancer drugs. In treatment, the causal factor must be discontinued. The treatment of overdose of intrathecal methotrexate is dilution and removal from the cerebrospinal fluid with specific antidotal therapy. Leucovorin and anti-inflammatory agents are useful [9]. Although PRES is usually reversible with patient recovery and resolution of the imaging findings, it might be recurrent or result in permanent damage [10,11].

Use of Long-Term Intrathecal Methotrexate in Progressive Forms of MS (P04.139)

Objective: To establish the safety and tolerability of long-term therapy with intrathecal methotrexate (ITMTX) in patients with treatment-resistant progressive forms of multiple sclerosis (MS). Background Currently there are no treatment options that successfully treat progressive MS, especially in the most severely disabled patients (EDSS > 6.0). We previosuly reported results of IT administration of MTX in the treatment of 121 patients with severe MS for up to 8 treatments. However, long-term safety has not been reported. This study is a IRB-approved retrospective chart analysis of patients who have had 18 or more treatments (3-6 years) to further examine the long-term safety and tolerability of ITMTX in this select cohort of advanced MS patients. Design/Methods: Thirty three patients, 27 secondary progressive (SPMS) and 6 primary progressive (PPMS) were clinically assessed every two months while receiving ITMTX at a dose of 12.5mgs every 8-11 weeks for a period of 3-6 years (range of 18 to 38 treatments). Assessments included EDSS, documentation of infections, other adverse events and hospitalizations. Results: There were no deaths or hospitalizations related to ITMTX and no serious adverse effects occurred. Headaches occurred at least once in 12% of patients, possibly minimized by the use of 25-gauge spinal needles and transient fatigue was reported in 6%. No cases of MTX associated leukoencephalopathy were seen. Almost all patients with SPMS had stable EDSS scores over the study period wheres the 6 PPMS patients had a mean decline on EDSS of 0.7. Conclusions: ITMTX was remarkably well tolerated over a period of 3-6 years in progressive MS patients with no serious adverse effects noted. Although this study was not controlled there was evidence of disease stabilization given the poor natural history of severe progressive MS. These findings support the use of ITMTX treatment as an inexpensive and relatively safe treatment for progressive MS. Supported by: MSRCNY funding. Disclosure: Dr. Stark has nothing to disclose. Dr. Dulak has nothing to disclose. Dr. Sadiq has nothing to disclose.

ALK inhibitor crizotinib combined with intrathecal methotrexate treatment for non-small cell lung cancer with leptomeningeal carcinomatosis

Anaplastic lymphoma kinase (ALK) inhibitor has shown dramatic efficacy in non-small cell lung cancer (NSCLC) patients harboring ALK rearrangements in phase I trial. Herein we report two cases of NSCLC patients with leptomeningeal carcinomatosis (LM), treated with ALK inhibitor under emergent use of investigational new drug combined with intrathecal methotrexate treatment. Progression free survival was 10 months and 6 months, respectively, and little additional toxicities were observed. These results suggest that ALK inhibitor might be safely administered even in patients or those with metastases in central nervous system.

Leptomeningeal carcinomatosis of gastric adenocarcinoma

Gastric cancer is the third most common malignancy among gastrointestinal malignancies. With the advance of new treatments, overall survival in gastric cancer is extending, and metastasis to atypical sites is seen more commonly. Leptomeningeal metastasis is one such atypical metastasis for gastric cancer. We report a case of gastric adenocarcinoma with leptomeningeal metastasis as an atypical involvement. A 39-year-old female, presenting with headache, vertigo, horizontal gaze palsy, visual disturbances, and seizures, was admitted to our hospital in August 2009. The funduscopic examination revealed the presence of bilateral papilledema. Magnetic resonance imaging of the brain showed diffuse leptomeningeal enhancement and biventricular dilatation. Cytological examination of the cerebrospinal fluid revealed malignant cells. These findings were consistent with leptomeningeal carcinomatosis. Six months before, she was diagnosed as having gastric cancer by upper gastrointestinal tract endoscopy, which was performed as a part of the diagnostic work-up to clarify the cause of her abdominal ascites. She received six cycles of docetaxel-cisplatin-5-fluorouracil for metastatic gastric cancer, and she developed the above-mentioned symptoms under chemotherapy. She was included in a craniospinal radiotherapy program and received intrathecal methotrexate treatment. We present this case report since leptomeningeal carcinomatosis of gastric cancers is a rare clinical entity, and treatment strategies remain challenging for clinicians.

Intrathecal methotrexate treatment in multiple sclerosis

This study reports on the feasibility of using intrathecal methotrexate (ITMTX) in treatment unresponsive multiple sclerosis (MS) patients with progressive forms of the disease. A retrospective, open-label, chart review analysis was conducted following patients (n=121) with MS for up to eight treatments given every 8-11weeks. Patients were considered for ITMTX treatment if they were unresponsive to or intolerant of FDA-approved treatments. There was a 1year follow-up after their eighth or last treatment (if discontinued earlier). Patients underwent neurological assessments and expanded disability status scale (EDSS) evaluations. No serious adverse effects were noted during the study period. In 87 secondary progressive MS patients, EDSS scores were stable or improved in 89%, with significantly improved mean EDSS post-treatment compared to baseline (P=0.014). Of 34 primary progressive patients, EDSS scores were stable in 82%, with no significant progression in EDSS post-treatment compared to baseline. ITMTX may have a beneficial role in progressive forms of MS and is well tolerated with no serious adverse events.