The Experts below are selected from a list of 453 Experts worldwide ranked by ideXlab platform
Marc C. Chamberlain - One of the best experts on this subject based on the ideXlab platform.
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Neoplastic Meningitis due to lung breast and melanoma metastases
Cancer Control, 2017Co-Authors: Emilie Le Rhun, Sophie Taillibert, Marc C. ChamberlainAbstract:Background Neoplastic Meningitis, a central nervous system (CNS) complication of cancer metastatic to the meninges and cerebrospinal fluid (CSF), is relevant to oncologists due to the impact of the disease on patient quality of life and survival rates. Methods A review of the literature of articles published in English was conducted with regard to Neoplastic Meningitis. Results The incidence of Neoplastic Meningitis is increasing because patients with cancer are surviving longer in part because of the use of novel therapies with poor CNS penetration. Up to 5% of patients with solid tumors develop Neoplastic Meningitis during the disease course (breast cancer, lung cancer, and melanoma being the predominantly causative cancers). The rate of median survival in patients with untreated Neoplastic Meningitis is 1 to 2 months, although it can be as long as 5 months in some cases. Therapeutic options for the treatment of Neoplastic Meningitis include systemic therapy (cancer-specific, CNS-penetrating chemotherapy or targeted therapies), intra-CSF administration of chemotherapy (methotrexate, cytarabine, thiotepa) and CNS site-specific radiotherapy. Determining whom to treat with Neoplastic Meningitis remains challenging and, in part, relates to the extent of systemic disease, the neurological burden of disease, the available systemic therapies, and estimated rates of survival. Conclusions The prognosis of Neoplastic Meningitis remains poor. The increasing use of novel, targeted therapies and immunotherapy in solid tumors and its impact on Neoplastic Meningitis remains to be determined and is an area of active research. Thus, well conducted trials are needed.
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cerebrospinal fluid dissemination and Neoplastic Meningitis in primary brain tumors
Cancer Control, 2017Co-Authors: Sajeel Chowdhary, Sherri Damlo, Marc C. ChamberlainAbstract:Background Neoplastic Meningitis, also known as leptomeningeal disease, affects the entire neuraxis. The clinical manifestations of the disease may affect the cranial nerves, cerebral hemispheres, or the spine. Because of the extent of disease involvement, treatment options and disease staging should involve all compartments of the cerebrospinal fluid (CSF) and subarachnoid space. Few studies of patients with primary brain tumors have specifically addressed treatment for the secondary complication of Neoplastic Meningitis. Therapy for Neoplastic Meningitis is palliative in nature and, rarely, may have a curative intent. Methods A review of the medical literature pertinent to Neoplastic Meningitis in primary brain tumors was performed. The complication of Neoplastic Meningitis is described in detail for the various types of primary brain tumors. Results Treatment of Neoplastic Meningitis is complicated because determining who should receive aggressive, central nervous system (CNS)-directed therapy is difficult. In general, the therapeutic response of Neoplastic Meningitis is a function of CSF cytology and, secondarily, of the clinical improvement in neurological manifestations related to the disease. CSF cytology may manifest a rostrocaudal disassociation; thus, consecutive, negative findings require that both lumbar and ventricular cytological testing are performed to confirm the complete response. Based on data from several prospective, randomized trials extrapolated to primary brain tumors, the median rate of survival for Neoplastic Meningitis is several months. Oftentimes, therapy directed at palliation may improve quality of life by protecting patients from experiencing continued neurological deterioration. Conclusions Neoplastic Meningitis is a complicated disease in which response to therapy varies by histology. Thus, survival rates after CNS-directed therapy will differ by the underlying primary tumor. Optimal therapy of Neoplastic Meningitis is poorly defined, and few guidelines exist to guide clinicians on the most appropriate choice of therapy.
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Neoplastic Meningitis and metastatic epidural spinal cord compression
Hematology-oncology Clinics of North America, 2012Co-Authors: Marc C. ChamberlainAbstract:Neoplastic Meningitis, commonly referred to as carcinomatosis Meningitis, leukemic Meningitis, or lymphomatous Meningitis, is the third most common central nervous system metastatic complication of systemic cancer and is the most morbid of central nervous system metastases. The disease is challenging to treat for a variety of reasons, including challenges in making a diagnosis of Neoplastic Meningitis and lack of standardized treatment due to the paucity of clinical trials addressing treatment of Neoplastic Meningitis.
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chapter 50 Neoplastic Meningitis
Handbook of Clinical Neurology, 2012Co-Authors: Marc C. ChamberlainAbstract:Neoplastic Meningitis (NM) is a common problem in neuro-oncology, occurring in approximately 5% of all patients with cancer, and is the third most common site of central nervous system (CNS) metastasis. NM is a disease affecting the entire neuraxis and thus clinical manifestations are pleomorphic, affecting the spine, cranial nerves, and cerebral hemispheres. Because of craniospinal disease involvement, staging and treatment need to encompass all cerebrospinal fluid (CSF) compartments. Treatment of NM utilizes involved-field radiotherapy of bulky or symptomatic disease sites and intra-CSF drug therapy. The inclusion of concomitant systemic therapy may benefit patients with NM and may obviate the need for intra-CSF chemotherapy. At present, intra-CSF drug therapy is confined to three chemotherapeutic agents (methotrexate, cytosine arabinoside, and thiotepa), administered in a variety of schedules by either intralumbar or intraventricular drug delivery. Although treatment of NM is palliative with an expected median patient survival of 2–6 months, it often affords stabilization and protection from further neurological deterioration in patients with NM.
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route of intracerebrospinal fluid chemotherapy administration and efficacy of therapy in Neoplastic Meningitis
Cancer, 2010Co-Authors: Michael Glantz, Alixis Van Horn, Rebecca Fisher, Marc C. ChamberlainAbstract:BACKGROUND: A study was undertaken to determine whether route (intraventricular vs intralumbar) of intracerebrospinal fluid (intra-CSF) drug administration influences progression-free survival in the treatment of patients with Neoplastic Meningitis, which occurs in 1% to 5% of patients with known cancer. Currently available treatment options result in modest responses, which is in part a reflection of obstacles to drug delivery into the leptomeningeal space. METHODS: One hundred patients with clinically and cytologically or radiographically documented Neoplastic Meningitis because of solid cancers received intra-CSF liposomal cytarabine or methotrexate as specified in a randomized phase 4 trial. The 2 treatment arms were well balanced for demographic and tumor-related characteristics of known prognostic importance, including age, performance status, tumor type, extent of systemic and other central nervous system (CNS) disease, prior CNS therapy, and concurrent systemic chemotherapy. RESULTS: One hundred patients were randomized and treated (52 with sustained-release cytarabine, and 48 with methotrexate). Progression-free survival (the primary study endpoint) was identical between the sustained-release cytarabine and methotrexate treatment arms for all 100 patients (35 vs 37.5 days, P = .79). When progression-free survival was examined as a function of route of chemotherapy administration (lumbar vs ventricular), there was no difference for patients treated with sustained-release cytarabine (29 vs 43 days, P = .35). For patients treated with methotrexate, however, there was a statistically significant difference favoring patients receiving intraventricular therapy (19 vs 43 days, P = .048). CONCLUSIONS: Site of intra-CSF chemotherapy drug administration is clinically relevant with short half-life drugs such as methotrexate. Cancer 2010. © 2010 American Cancer Society.
Henry S Friedman - One of the best experts on this subject based on the ideXlab platform.
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Intrathecal Melphalan Therapy of Human Neoplastic Meningitis in Athymic Nude Rats1
2013Co-Authors: James M. Schuster, Roger E. Mclendon, Gerald E Archer, Henry S Friedman, Contact The Aacr Publications, Michael O ColvinAbstract:We report the activity and toxicity of intrathecal melphalan in the treatment of human Neoplastic Meningitis in the subarachnoid space of athymic nude rats. Animals received injections via chronic indwelling subarachnoid catheters with 5 x IO5 or 5 x IO6 TE-67I human rhabdomyosarcoma cells or 5 x 10' ' D-54 MG human glioma cells and were treated with melphalan on days 8. 5, or 5, respectively. Melphalan toxicity in nontumor-bearing rats was assessed at single doses of a 2.0, 3.0, 4.0, or 5.0 HIMsolution, with clinical and histolÃgica! evidence of neurotoxicity observed at the 4.0 and 5.0 mM levels. Multiple-dose toxicity studies using a dosing schedule of twice a week for two weeks with a 0.25, 0.5, 0.75, 1.0, 1.5, or 2 HIMsolution revealed dose-dependent clinical and histolÃgica! evidence for toxicity at all dosages. Treatment of TE-671 with a single dos
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treatment of Neoplastic Meningitis with intrathecal 9 nitro camptothecin
Neurologia Medico-chirurgica, 2006Co-Authors: Gary E Archer, Roger E. Mclendon, Henry S Friedman, Hidenobu Ochiai, Chris T Pernell, Tracy A Chewning, John H SampsonAbstract:The topoisomerase I inhibitor, 9-nitro-camptothecin (9NC), is highly tumoricidal against glioblastoma multiforme (GBM) in vitro. However, systemic administration of 9NC has not shown the expected efficacy in clinical trials. This failure may be due to the rapid hydrolysis of 9NC in plasma from the active form to the inactive and myelosuppressive form in the presence of human albumin at physiologic pH. Concurrent treatment with anticonvulsants and dexamethasone, drugs indispensable for the supportive therapy of patients with GBM, has also been shown to decrease plasma concentrations of these drugs. Intrathecal drug delivery circumvents the blood-brain barrier and minimizes systemic toxicity. Intrathecal delivery of 9NC may also have the more specific advantage of significantly reducing the hydrolysis of 9NC that occurs after systemic delivery due to the more favorable pH and reduced albumin content in cerebrospinal fluid. The present study evaluated the toxicity and efficacy of intrathecal delivery of 9NC in an athymic rat model of Neoplastic Meningitis. Toxicity tests showed that 0.3 μmol (5000 μM), 0.03 μmol (500 μM), 0.003 μmol (50 μM), or 0.0003 μmol (5 μM) of 9NC administered intrathecally to the athymic rats caused no evidence of clinical or histological toxicity. Intrathecal administration of 0.3 μmol (5000 μM) of 9NC twice a week for three doses to athymic rats with Neoplastic Meningitis induced by the GBM cell line, U87MGΔEGFR, resulted in a 26% increase of median survival compared to the control group (p < 0.005). These results suggest that intrathecal treatment with 9NC may be useful for patients with GBM Neoplastic Meningitis.
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phase i trial of intrathecal spartaject busulfan in children with Neoplastic Meningitis a pediatric brain tumor consortium study pbtc 004
Clinical Cancer Research, 2006Co-Authors: Sridharan Gururangan, Henry S Friedman, Susan M Blaney, Lisa Bomgaars, William P Petros, Tina Young Poussaint, Michael L Hancock, Peter Phillips, Larry E Kun, James M BoyettAbstract:Purpose: A phase I trial of intrathecal Spartaject Busulfan (SuperGen, Inc., San Ramon, CA) was conducted in children with Neoplastic Meningitis following recurrent primary brain tumors to describe toxicities, estimate the maximum tolerated dose (MTD), and document evidence of responses to this agent. Experimental Design: The continuous reassessment method was used to assign cohorts of patients to doses of intrathecal Spartaject Busulfan via an Ommaya reservoir and/or lumbar puncture twice weekly for 2 weeks followed by an assessment of toxicity and response. Patients with stable disease or an objective response continued to receive intrathecal Spartaject Busulfan plus systemic chemotherapy at regular intervals. Cerebrospinal fluid and blood were obtained for pharmacokinetic studies in patients with Ommaya reservoirs after the first dose of intrathecal Spartaject Busulfan. Seven evaluable patients were assigned to the starting dose of 5 mg, two patients to 7.5 mg, three patients to 10 mg, seven patients to 13 mg, and four patients to 17 mg. Results: Between September 2000 and May 2003, 28 patients were enrolled in this study. Twenty-three patients (median age, 8.8 years; range, 2.5-19.5 years) were evaluable for estimating the MTD, and dose-limiting toxicities were observed in three and included grade 3 vomiting ( n = 1 at 5 mg), grade 3 headache ( n = 1 at 17 mg), and grade 3 arachnoiditis ( n = 1 at 17 mg). Pharmacokinetic data showed that post-infusion concentrations of busulfan ranged from 50 to 150 μg/mL and declined to Conclusions: Intrathecal Spartaject Busulfan was well tolerated in children with Neoplastic Meningitis from brain tumors, and the recommended dose for future phase II studies is 13 mg.
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Current Options for the Treatment of Neoplastic Meningitis
Journal of Neuro-Oncology, 2002Co-Authors: Ilkcan Cokgor, Allan H. Friedman, Henry S FriedmanAbstract:Neoplastic Meningitis, which is the diffuse involvement of the leptomeninges by infiltrating cancer cells, may be caused by many systemic tumors. The treatment options for Neoplastic Meningitis disease remain unsatisfactory. In this review article, we discuss the pathogenesis and cytology of Neoplastic Meningitis and the options for treatment, including intrathecal chemotherapy, systemic chemotherapy, and newer agents such as cytokines and monoclonal antibodies.
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temozolomide in early stages of newly diagnosed malignant glioma and Neoplastic Meningitis
Seminars in Oncology, 2000Co-Authors: Henry S FriedmanAbstract:Temozolomide is a novel, oral, second-generation alkylating agent. Preclinical and phase I/II studies have demonstrated its efficacy against newly diagnosed high-grade glioma and anaplastic astrocytoma. Its antiNeoplastic effect is accompanied by quality of life benefits in patients with these debilitating tumors. Neoplastic Meningitis, a refractory disorder, develops in approximately 3% to 8% of patients with systemic cancers. Traditional approaches to leptomeningeal metastases, such as radiation and intrathecal chemotherapy, have limited success and a high degree of toxicity. Temozolomide offers a number of potential therapeutic advantages in this disorder, including activity against a wide spectrum of human cancers that produce Neoplastic Meningitis and penetration of the blood-brain barrier. Patients treated with temozolomide benefit from both its systemic and intracranial activity. Recently, intrathecal temozolomide has been shown to increase median survival in athymic rats bearing subarachnoid human malignant glioma xenografts. Its efficacy, convenient dosing, and predictable safety profile make it an ideal agent for future study of these difficult-to-treat central nervous system malignancies.
Darrell D Bigner - One of the best experts on this subject based on the ideXlab platform.
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long term response in a patient with Neoplastic Meningitis secondary to melanoma treated with 131i radiolabeled antichondroitin proteoglycan sulfate mel 14 f ab 2
Cancer, 2001Co-Authors: M Ilkcan D Cokgor, Michael R Zalutsky, Gamal Akabani, S Henry M D Friedman, H Allan M D Friedman, M Lee M D Zehngebot, M James M D Provenzale, D Cynthia M D Guy, Carol J Wikstrand, Darrell D BignerAbstract:Even with novel chemotherapeutic agents and external beam radiation therapy, the prognosis of Neoplastic Meningitis secondary to malignant melanoma is still dismal. The authors report a case study of a 46-year-old white female who presented with progressive hearing loss, severe headaches, nausea, vomiting, and a rapid decline in neurologic status. She was referred to Duke University Medical Center after conventional chemotherapy for malignant melanoma failed. She was enrolled in a Phase I trial of 131I-labeled monoclonal antibody Mel-14 F(ab′)2 fragment administered intrathecally. Within a year after her treatment, she recovered, having a normal neurologic exam except for residual bilateral hearing loss. The authors discuss dosimetry, preclinical, and clinical studies conducted with Mel-14 F(ab′)2 and introduce a potentially promising therapy option in the treatment of Neoplastic Meningitis in patients with malignant melanoma. Currently, the patient remains neurologically normal except for a mild bilateral hearing loss more than 4 years after treatment and has no radiographic evidence of Neoplastic Meningitis. Cancer 2001;91:1809–13. © 2001 American Cancer Society.
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regional treatment of epidermal growth factor receptor viii expressing Neoplastic Meningitis with a single chain immunotoxin mr 1
Clinical Cancer Research, 1999Co-Authors: Gary E Archer, Roger E. Mclendon, Henry S Friedman, Allan H. Friedman, John H Sampson, Ian A J Lorimer, Chientsun Kuan, Ira Pastan, Darrell D BignerAbstract:The incidence of Neoplastic Meningitis is on the rise. Neoplastic Meningitis can result from a direct seeding of the neuraxis by primary brain tumors or by hematogeneous spread of systemic solid tumors. A frequent genetic alteration in primary brain tumors such as gliomas is an in-frame deletion in the epidermal growth factor receptor (EGFR) gene EGFRvIII, which brings together what were normally distant polypeptide sequences in the intact receptor. A novel glycine is formed at the fusion junction, resulting in a unique and tumor-specific target. By using phage display, we have isolated a single-chain antibody specific for the EGFRvIII mutation and expressed it with a modified form of the Pseudomonas exotoxin to form the immunotoxin MR1scFvPE38KDEL (MR-1). The multiple dose toxicity and therapeutic efficacy of MR-1 immunotoxin were tested in an athymic rat model of Neoplastic Meningitis. The maximally tolerated doses in non-tumor-bearing rats were three doses of 3 microg each. For therapeutic studies, the target was a Neoplastic Meningitis induced by intrathecal inoculation of the EGFRvIII-expressing human glioma U87MG.deltaEGFR. A dose escalation study compared the survival of three equal doses of 1, 2, and 3 microg of MR-1 immunotoxin with saline or 3 microg of the control immunotoxin specific for the interleukin 2 receptor, anti-Tac. All animals treated with three doses of saline or 3 microg of anti-Tac died, with median survival of 7 and 10 days, respectively. There were 75% (six of eight) long-term survivors in the group treated with three doses of 1 microg and 57% (four of seven) long-term survivors in the groups treated with three doses of either 2 or 3 microg of MR-1 immunotoxin. None of the MR-1 immunotoxin-treated groups reached median survival by the termination of the study at 53 days. Therefore, median survival was estimated to be >53 days, resulting in an estimated increase in median survival of >657% compared with saline and 430% versus anti-Tac. Compartmental therapy with three doses of 2 microg of MR-1 immunotoxin is effective in the treatment of EGFRvIII-expressing Neoplastic Meningitis. This dose was found to have no clinical or histopathological effects on non-tumor-bearing animals. MR-1 immunotoxin is, therefore, considered specific and safe within its therapeutic window. Phase I clinical trials for tumors invading the intrathecal space that express the EGFRvIII target should be initiated.
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treatment of Neoplastic Meningitis with intrathecal temozolomide
Clinical Cancer Research, 1999Co-Authors: John H Sampson, Gary E Archer, Roger E. Mclendon, Darrell D Bigner, Allan H. Friedman, Alan T Villavicencio, W R Bishop, Henry S FriedmanAbstract:Neoplastic Meningitis (NM) results from leptomeningeal dissemination of cancers arising within the central nervous system or metastasizing to the leptomeninges from systemic neoplasms. The inability to produce therapeutic drug levels intrathecally (IT) with systemic administration and the minimal efficacy of chemotherapeutic agents currently available for direct IT use limit therapy. Temozolomide [8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4([3H])-one] is a novel methylating agent with proven activity against intraparenchymal malignant gliomas (MGs). Insolubility of the standard formulation prevents its efficacious use as an IT agent, however. To overcome this obstacle, we have developed a unique microcrystalline formulation of temozolomide with greatly enhanced solubility. Treatment of athymic rats bearing subarachnoid MER- human MG xenografts with four doses of IT microcrystalline temozolomide over a 2-week period produced a 142% increase in median survival at individual doses of 2.2 μmol (P = 0.0073) and a >367% increase in median survival at individual doses of 6.8 μmol (P = 0.0015). At the higher dose tested, three of eight rats treated developed no neurological symptoms and had no evidence of residual tumor on histological examination after treatment. Use of this microcrystalline formulation in athymic rats bearing subarachnoid MER+ human MG xenografts increased median survival >132% (P These results suggest that a dose range for both toxicity and activity has been defined for IT microcrystalline temozolomide in the treatment of NM in athymic rats, and a Phase I trial for the treatment of patients with NM using IT microcrystalline temozolomide should now be undertaken.
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intrathecal busulfan treatment of human Neoplastic Meningitis in athymic nude rats
Journal of Neuro-oncology, 1999Co-Authors: Gary E Archer, Roger E. Mclendon, Herbert E Fuchs, Allan H. Friedman, John H Sampson, O M Colvin, M Rose, H Sands, W Mccullough, Darrell D BignerAbstract:The current study was designed to evaluate the toxicity and activity of Spartaject™ Busulfan, a microcrystalline preparation of busulfan, following its intrathecal administration into a nude rat model of human Neoplastic Meningitis. Animals were treated through permanent indwelling subarachnoid catheters. Human glioma D-456 MG growing in the subarachnoid space was treated with 8.1 µmol of intrathecal Spartaject™ Busulfan. Single-dose therapy was also subsequently compared with 4 doses of 8.1 and 2.0 µmol busulfan, respectively, against D-456 MG Neoplastic Meningitis. Additional experiments evaluated a saline control versus 8.1 µmol×1, 6.2 µmol×4 and 4.1 µmol×4, respectively, against D-456 MG. A single dose of 8.1 µmol of intrathecal Spartaject™ Busulfan resulted in an increase in median survival of 61.7% compared with the saline control. In experiment 2, all busulfan treatments showed increases in median survival of 142.8% (8.1 µmol×1), 52.3% (2.0 µmol×4), and 23% (8.1 µmol×4) (p<0.001 for all groups) compared with the saline control. These results suggest that a narrow therapeutic dose range for both toxicity and activity has been defined for intrathecal busulfan in the treatment of human Neoplastic Meningitis in athymic nude rats. Although busulfan has only limited activity against solid tumors, the high doses achievable in the CSF following intrathecal administration coupled with the steep dose–response relationships of alkylating agents, provide rationale for further evaluation of this agent.
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radioimmunotherapy of Neoplastic Meningitis in rats using an α particle emitting immunoconjugate
Cancer Research, 1994Co-Authors: Michael R Zalutsky, Pradeep K. Garg, Gary E Archer, James M. Schuster, Roger E. Mclendon, Darrell D BignerAbstract:Because of their short range and high linear energy transfer, α-particles may be particularly effective in the treatment of Neoplastic Meningitis. Monoclonal antibody 81C6 was labeled with α-particle-emitting 211At using N -succinimidyl3-[211At]astatobenzoate, and the efficacy and toxicity of this immunoconjugate were evaluated in an athymic rat model. Animals were given injections via a chronic indwelling catheter with 5 × 105 TE-671 human rhabdomyosarcoma cells and treated 8 days later with single intrathecal doses of either saline or 4–18 µCi of 211At-labeled specific 81C6 antibody or isotype-matched control 211At-labeled 45.6 antibody. In the first experiment, 4, 7, and 13 µCi 211At-labeled 81C6 produced statistically significant ( P = 0.004-0.02) increases in median survival of 33, 29, and 51%, respectively, as compared with saline. Two of 10 animals receiving the 13-µCi dose lived for 6 months before being killed for histological analysis. In the second experiment, 12 µCi of 211At-labeled 45.6 did not increase median survival significantly relative to saline control, while 12 µCi of 211At-labeled 81C6 increased median survival by 113% ( P < 0.005) and resulted in 33% apparent cures. Five of 10 animals receiving 18 µCi of 211At-labeled 81C6 survived until they were killed at 295 days. An additional study was performed in animals given intrathecal injections of 5 × 106 TE-671 cells and given a single dose of 18 µCi of 211At-labeled 81C6 or 211At-labeled 45.6. At this higher cell number, significantly prolonged survival was still seen for specific antibody as compared with saline ( P < 0.001) and control antibody ( P < 0.05). These results suggest that treatment with 211At-labeled monoclonal antibodies may be a valuable approach for Neoplastic Meningitis.
Gary E Archer - One of the best experts on this subject based on the ideXlab platform.
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treatment of Neoplastic Meningitis with intrathecal 9 nitro camptothecin
Neurologia Medico-chirurgica, 2006Co-Authors: Gary E Archer, Roger E. Mclendon, Henry S Friedman, Hidenobu Ochiai, Chris T Pernell, Tracy A Chewning, John H SampsonAbstract:The topoisomerase I inhibitor, 9-nitro-camptothecin (9NC), is highly tumoricidal against glioblastoma multiforme (GBM) in vitro. However, systemic administration of 9NC has not shown the expected efficacy in clinical trials. This failure may be due to the rapid hydrolysis of 9NC in plasma from the active form to the inactive and myelosuppressive form in the presence of human albumin at physiologic pH. Concurrent treatment with anticonvulsants and dexamethasone, drugs indispensable for the supportive therapy of patients with GBM, has also been shown to decrease plasma concentrations of these drugs. Intrathecal drug delivery circumvents the blood-brain barrier and minimizes systemic toxicity. Intrathecal delivery of 9NC may also have the more specific advantage of significantly reducing the hydrolysis of 9NC that occurs after systemic delivery due to the more favorable pH and reduced albumin content in cerebrospinal fluid. The present study evaluated the toxicity and efficacy of intrathecal delivery of 9NC in an athymic rat model of Neoplastic Meningitis. Toxicity tests showed that 0.3 μmol (5000 μM), 0.03 μmol (500 μM), 0.003 μmol (50 μM), or 0.0003 μmol (5 μM) of 9NC administered intrathecally to the athymic rats caused no evidence of clinical or histological toxicity. Intrathecal administration of 0.3 μmol (5000 μM) of 9NC twice a week for three doses to athymic rats with Neoplastic Meningitis induced by the GBM cell line, U87MGΔEGFR, resulted in a 26% increase of median survival compared to the control group (p < 0.005). These results suggest that intrathecal treatment with 9NC may be useful for patients with GBM Neoplastic Meningitis.
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targeted therapy for glioblastoma multiforme Neoplastic Meningitis with intrathecal delivery of an oncolytic recombinant poliovirus
Clinical Cancer Research, 2006Co-Authors: Hidenobu Ochiai, Gary E Archer, Tracy A Chewning, Matthias Gromeier, Stephanie A Campbell, Eugenia Dragunsky, Alexander P Ivanov, John H SampsonAbstract:PURPOSE: The toxicity and antitumor activity of regional intrathecal delivery of an oncolytic recombinant poliovirus, PVS-RIPO, was evaluated in rodent models of glioblastoma multiforme Neoplastic Meningitis. EXPERIMENTAL DESIGN: To evaluate for toxicity, PVS-RIPO was administered into the spinal cord of transgenic mice that express the human poliovirus receptor, CD155, and into the intrathecal space of athymic rats without tumor. To evaluate efficacy, two different doses of PVS-RIPO were administered intrathecally 3 days after athymic rats were inoculated intrathecally with an aggressive human glioblastoma multiforme xenograft. RESULTS: No clinical or histologic evidence of toxicity was found. In efficacy studies, median survival was increased by 174.47% from 8.5 days in the group treated with UV light-inactivated virus to 15 days in the rats treated with 1.0 x 10(7) plaque-forming units (pfu) of PVS-RIPO (P 60 days after tumor cell inoculation and had no evidence of residual tumor at autopsy. CONCLUSION: These results suggest that intrathecal treatment with PVS-RIPO may be useful for treatment of Neoplastic Meningitis in patients with glioblastoma multiforme and provides a rationale for clinical trials in this area.
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treatment of intracerebral neoplasia and Neoplastic Meningitis with regional delivery of oncolytic recombinant poliovirus
Clinical Cancer Research, 2004Co-Authors: Hidenobu Ochiai, Gary E Archer, Tracy A Chewning, John H Sampson, Stephanie A Moore, Tatsunori Okamura, Jeffrey R Marks, Matthias GromeierAbstract:Purpose: Spread to the central nervous system (CNS) and the leptomeninges is a frequent complication of systemic cancers that is associated with serious morbidity and high mortality. We have evaluated a novel therapeutic approach against CNS complications of breast cancer based on the human neuropathogen poliovirus (PV). Experimental Design: Susceptibility to PV infection and ensuing rapid cell lysis is mediated by the cellular receptor of PV, CD155. We evaluated CD155 expression in several human breast tumor tissue specimens and cultured breast cancer cell lines. In addition, we tested an oncolytic PV recombinant for efficacy in xenotransplantation models of Neoplastic Meningitis and cerebral metastasis secondary to breast cancer. Results: We observed that breast cancer tissues and cell lines derived thereof express CD155 at levels mediating exquisite sensitivity toward PV-induced oncolysis in the latter. An association with the immunoglobulin superfamily molecule CD155 renders breast cancer a likely target for oncolytic PV recombinants. This assumption was confirmed in xenotransplantation models for Neoplastic Meningitis or solitary cerebral metastasis, where local virus treatment dramatically improved survival. Conclusions: Our findings suggest oncolytic PV recombinants as a viable treatment option for CNS complications of breast cancer.
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regional treatment of epidermal growth factor receptor viii expressing Neoplastic Meningitis with a single chain immunotoxin mr 1
Clinical Cancer Research, 1999Co-Authors: Gary E Archer, Roger E. Mclendon, Henry S Friedman, Allan H. Friedman, John H Sampson, Ian A J Lorimer, Chientsun Kuan, Ira Pastan, Darrell D BignerAbstract:The incidence of Neoplastic Meningitis is on the rise. Neoplastic Meningitis can result from a direct seeding of the neuraxis by primary brain tumors or by hematogeneous spread of systemic solid tumors. A frequent genetic alteration in primary brain tumors such as gliomas is an in-frame deletion in the epidermal growth factor receptor (EGFR) gene EGFRvIII, which brings together what were normally distant polypeptide sequences in the intact receptor. A novel glycine is formed at the fusion junction, resulting in a unique and tumor-specific target. By using phage display, we have isolated a single-chain antibody specific for the EGFRvIII mutation and expressed it with a modified form of the Pseudomonas exotoxin to form the immunotoxin MR1scFvPE38KDEL (MR-1). The multiple dose toxicity and therapeutic efficacy of MR-1 immunotoxin were tested in an athymic rat model of Neoplastic Meningitis. The maximally tolerated doses in non-tumor-bearing rats were three doses of 3 microg each. For therapeutic studies, the target was a Neoplastic Meningitis induced by intrathecal inoculation of the EGFRvIII-expressing human glioma U87MG.deltaEGFR. A dose escalation study compared the survival of three equal doses of 1, 2, and 3 microg of MR-1 immunotoxin with saline or 3 microg of the control immunotoxin specific for the interleukin 2 receptor, anti-Tac. All animals treated with three doses of saline or 3 microg of anti-Tac died, with median survival of 7 and 10 days, respectively. There were 75% (six of eight) long-term survivors in the group treated with three doses of 1 microg and 57% (four of seven) long-term survivors in the groups treated with three doses of either 2 or 3 microg of MR-1 immunotoxin. None of the MR-1 immunotoxin-treated groups reached median survival by the termination of the study at 53 days. Therefore, median survival was estimated to be >53 days, resulting in an estimated increase in median survival of >657% compared with saline and 430% versus anti-Tac. Compartmental therapy with three doses of 2 microg of MR-1 immunotoxin is effective in the treatment of EGFRvIII-expressing Neoplastic Meningitis. This dose was found to have no clinical or histopathological effects on non-tumor-bearing animals. MR-1 immunotoxin is, therefore, considered specific and safe within its therapeutic window. Phase I clinical trials for tumors invading the intrathecal space that express the EGFRvIII target should be initiated.
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treatment of Neoplastic Meningitis with intrathecal temozolomide
Clinical Cancer Research, 1999Co-Authors: John H Sampson, Gary E Archer, Roger E. Mclendon, Darrell D Bigner, Allan H. Friedman, Alan T Villavicencio, W R Bishop, Henry S FriedmanAbstract:Neoplastic Meningitis (NM) results from leptomeningeal dissemination of cancers arising within the central nervous system or metastasizing to the leptomeninges from systemic neoplasms. The inability to produce therapeutic drug levels intrathecally (IT) with systemic administration and the minimal efficacy of chemotherapeutic agents currently available for direct IT use limit therapy. Temozolomide [8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4([3H])-one] is a novel methylating agent with proven activity against intraparenchymal malignant gliomas (MGs). Insolubility of the standard formulation prevents its efficacious use as an IT agent, however. To overcome this obstacle, we have developed a unique microcrystalline formulation of temozolomide with greatly enhanced solubility. Treatment of athymic rats bearing subarachnoid MER- human MG xenografts with four doses of IT microcrystalline temozolomide over a 2-week period produced a 142% increase in median survival at individual doses of 2.2 μmol (P = 0.0073) and a >367% increase in median survival at individual doses of 6.8 μmol (P = 0.0015). At the higher dose tested, three of eight rats treated developed no neurological symptoms and had no evidence of residual tumor on histological examination after treatment. Use of this microcrystalline formulation in athymic rats bearing subarachnoid MER+ human MG xenografts increased median survival >132% (P These results suggest that a dose range for both toxicity and activity has been defined for IT microcrystalline temozolomide in the treatment of NM in athymic rats, and a Phase I trial for the treatment of patients with NM using IT microcrystalline temozolomide should now be undertaken.
Michael Glantz - One of the best experts on this subject based on the ideXlab platform.
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the predictive value of protein glucose and lactate for a diagnosis of Neoplastic Meningitis
Journal of Clinical Oncology, 2012Co-Authors: Jonathan Mcclain, Michael GlantzAbstract:e12005 Background: Neoplastic Meningitis (NM) is a complication of many common cancers that occurs with an incidence as high as 15% in some cancer types. Diagnosis remains elusive with poor screening tools and insensitive diagnostic options. Methods: A retrospective analysis of 341 consecutive patients with suspected NM was undertaken. Clinical presentation, demographic, cytologic and MRI data were recorded. Using cytology as the diagnostic gold standard, sensitivity, specificity, ROC curves and likelihood ratios were calculated. Results: 210 patients met inclusion criteria, 87 with primary brain tumors (PBT), 72 with non-CNS solid tumors, and 44 with lymphomas. 111 patients were male; 123 (58.6%) ultimately had a positive cytology. Only 59% of patients with positive cytology presented with symptoms concerning for NM. 32.9% of patients with PBTs and positive CSF cytology exhibited neurologic symptoms suggestive of NM. Patients with non-CNS solid tumors and positive CSF cytology presented with symptoms con...
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novel use of mr spectroscopy in detecting csf lactate for diagnosis of Neoplastic Meningitis
Journal of Clinical Oncology, 2011Co-Authors: Cody Weston, Omar Zalatimo, Jonas M Sheehan, R Harbaugh, D A Bota, A Shedden, Michael GlantzAbstract:2071 Background: Neoplastic Meningitis is a devastating and increasingly frequent complication of solid tumor, hematologic, and primary brain cancers. Early diagnosis and intervention may prevent n...
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route of intracerebrospinal fluid chemotherapy administration and efficacy of therapy in Neoplastic Meningitis
Cancer, 2010Co-Authors: Michael Glantz, Alixis Van Horn, Rebecca Fisher, Marc C. ChamberlainAbstract:BACKGROUND: A study was undertaken to determine whether route (intraventricular vs intralumbar) of intracerebrospinal fluid (intra-CSF) drug administration influences progression-free survival in the treatment of patients with Neoplastic Meningitis, which occurs in 1% to 5% of patients with known cancer. Currently available treatment options result in modest responses, which is in part a reflection of obstacles to drug delivery into the leptomeningeal space. METHODS: One hundred patients with clinically and cytologically or radiographically documented Neoplastic Meningitis because of solid cancers received intra-CSF liposomal cytarabine or methotrexate as specified in a randomized phase 4 trial. The 2 treatment arms were well balanced for demographic and tumor-related characteristics of known prognostic importance, including age, performance status, tumor type, extent of systemic and other central nervous system (CNS) disease, prior CNS therapy, and concurrent systemic chemotherapy. RESULTS: One hundred patients were randomized and treated (52 with sustained-release cytarabine, and 48 with methotrexate). Progression-free survival (the primary study endpoint) was identical between the sustained-release cytarabine and methotrexate treatment arms for all 100 patients (35 vs 37.5 days, P = .79). When progression-free survival was examined as a function of route of chemotherapy administration (lumbar vs ventricular), there was no difference for patients treated with sustained-release cytarabine (29 vs 43 days, P = .35). For patients treated with methotrexate, however, there was a statistically significant difference favoring patients receiving intraventricular therapy (19 vs 43 days, P = .048). CONCLUSIONS: Site of intra-CSF chemotherapy drug administration is clinically relevant with short half-life drugs such as methotrexate. Cancer 2010. © 2010 American Cancer Society.
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intra csf trastuzumab in patients with Neoplastic Meningitis from breast cancer or primary brain tumors
Journal of Clinical Oncology, 2009Co-Authors: D L Allison, Michael Glantz, T L Werner, S L Kirkegaard, K Murdock, Randy L JensenAbstract:2066 Background: Neoplastic Meningitis is a devastating complication of extra-CNS malignancies and primary brain tumors with few available treatments and none of outstanding efficacy. Trastuzumab, ...
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Intrathecal topotecan in adult patients with Neoplastic Meningitis
American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 2006Co-Authors: David C. Gammon, Mansi S. Bhatt, Lan Tran, Alexis Van Horn, Matthew Benvenuti, Michael GlantzAbstract:Purpose. The efficacy and safety of intrathecal topotecan were assessed in patients with Neoplastic Meningitis (NM) by retrospective chart review. Summary. Fourteen patients (median age, 57 years) with NM were treated with the standard of care (i.e., regional or systemic chemotherapy or irradiation or both) plus intrathecal topotecan between January 2004 and September 2005. Three patients developed NM in the setting of systemic cancer; 11 patients had primary central nervous system (CNS) malignancies. All patients received 0.4 mg of topotecan intrathecally two times per week. The efficacy of intrathecal topotecan was assessed on the basis of the number of doses to cerebrospinal fluid (CSF) cytologic clearing—defined as the disappearance of malignant cells from a previously positive CSF cytology. Safety was evaluated by chart documentation of adverse events that might have been associated with topotecan given intrathecally. Of the 11 patients with primary CNS tumors, 6 patients achieved CSF clearing after the first dose of intrathecal topotecan, 2 patients after the second dose, and 1 patient after the fifth dose. For the 3 patients with secondary CSF tumors, 1 patient achieved CSF clearing after the third dose and 2 patients did not reach the primary endpoint. Overall, 6 of the 14 patients achieved CSF clearing after the first dose of intrathecal topotecan; in 10 of the 14 patients, CSF clearing of malignant cells was observed at some point during treatment. Toxicity was modest. The most common adverse effect reported was fatigue. Conclusion. Intrathecal topotecan appeared to be effective and safe in adult patients with NM.