Liposomal Cytarabine (DepoCyte) for Treatment of Myeloid CNS Relapse in CML Occurring during Therapy with Imatinib.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4556-4556
Author(s):  
Karl J. Aichberger ◽  
Susanne Herndlhofer ◽  
Hermine Agis ◽  
Wolfgang R. Sperr ◽  
Werner Rabitsch ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Clinical Symptoms ◽  
Local Therapy ◽  
Response To Therapy ◽  
Brain Barrier ◽  
Leukemic Cells ◽  
Molecular Response ◽  
Liposomal Cytarabine ◽  
Cns Relapse ◽  
Blood Brain

Abstract Central nervous system (CNS) relapse in chronic myeloid leukemia (CML) is rare and if recorded is usually found to occur in patients with lymphoblastic transformation or in those with a generalized myeloid relapse. The BCR/ABL tyrosine kinase (TK) inhibitor imatinib is highly effective in patients with CML, but hardly crosses the blood-brain-barrier. We report on two CML patients who developed a myeloid CNS relapse during treatment with imatinib. One patient was in major cytogenetic response at the time of CNS relapse. In both cases, the myeloid origin of neoplastic cells in the cerebrospinal fluid (CSF) was demonstrable by immunophenotyping, and their leukemic origin by detection of the BCR/ABL oncoprotein. No BCR/ABL kinase domain mutations could be detected. Both patients received intrathecal liposomal cytarabine (DepoCyte®) (50 mg each cycle; 6 cycles). In one patient, additional CNS radiation was performed, whereas in the other patient, consecutive treatment with dasatinib (70 mg per os twice daily) was started. In response to therapy, the clinical symptoms resolved and the leukemic cells in the CSF disappeared in both patients. After four months of observation, both patients are in complete cytogenetic and major molecular response, without evidence for a systemic or a CNS relapse. In conclusion, ‘anatomic’ resistance against imatinib in the CNS can lead to an (isolated) myeloid CNS relapse. Liposomal cytarabine with or without radiation is effective as local therapy in these patients. For treatment of patients with a systemic relapse involving the CNS and for prophylaxis, second-generation BCR/ABL TK inhibitors crossing the blood-brain-barrier such as dasatinib should be considered.

scholarly journals Immunodiagnostics of cerebral toxoplasmosis depending on permeability of blood-brain barrier

2020 ◽  
Vol 73 (2) ◽  
pp. 285-288
Author(s):  
Andriy V. Bondarenko ◽  
Dmitro V. Katsapov ◽  
Anatoliy V. Gavrylov ◽  
Tatiana V. Didova ◽  
Ivan A. Nahornyi
Keyword(s):  
Blood Serum ◽  
Blood Brain Barrier ◽  
Clinical Symptoms ◽  
Clinical Stage ◽  
Brain Barrier ◽  
Quantitative Detection ◽  
Albumin Concentration ◽  
Cerebral Toxoplasmosis ◽  
Local Production ◽  
Blood Brain

The aim of the work was to detect a diagnostic value of CNSToxoIndex – index of correlation between albumin concentration and anti-toxoplasma antibodies, which reflects local production of anti-toxoplasma IgG in CNS compared with their level in blood. Materials and methods: 30 HIV-infected persons with the IV clinical stage (16 man and 14 women) aged from 25 to 49 years with clinical and instrumental signs of cerebral toxoplasmosis were selected from the general array of the patients treated in the Regional Clinical Infectious Hospital. A retrospective parallel detection of IgG T. gondii was performed in serum and CSF in patients, whose results of ELISA or PCR on T. gondii were positive. Blood serum and CSF were obtained from patients at the same time. All samples for analysis were stored at −20 °C and then tested on the RT-2100C Rayto Life and Analytical Sciences Co., Ltd (China) immunoassay analyser for quantitative detection of the level of specific anti-Toxicoplasma IgG. Detection of albumin concentration in serum and CSF was performed on the Chemray-120 Automated Biochemical Analyzer Rayto Life and Analytical Sciences Co., Ltd (China) using the Liquick Cor-ALBUMIN Diagnostic Kit. Results: Specific IgG to T. gondii in blood plasma was found in 27 patients (90%) while in CSF only in 7 (23 %). The results of the research in this group of patients were represented by the following parameters: patient 1 (blood antiToxo IgG – 200 IU/ml, blood albumin – 36 g/l, CSF antiToxo IgG – 10 IU/ml, CSF albumin – 0.8 g/l, CNSToxolndex – 2.3); patient 2 (150 / 40 / 90 / 0.7 / 34.3, respectively); patient 3 (90 / 35 / 64 / 0.25 / 99.6); patient 4 (140 / 39/ 10/ 0.19/ 14.7); patient 5 (88 / 52 / 48 / 0.21 / 135.1); patient 6 (160 / 48 / 50 / 0.15 / 100.0); patient 7 (122 / 42 / 15 / 0.17 / 30.4). Consequently, taking into consideration the diagnostic marker CNSToxolndex more than 10.0, cerebral toxoplasmosis was diagnosed only in six patients from seven, in whom anti-toxoplasma antibodies in CSF were detected. Patient 1, despite clinical symptoms similar to cerebral toxoplasmosis, and substitute signs of cerebral toxoplasmosis detected with the help of neuroimaging methods (volumetric formation of the right frontal lobe with a ring-shaped enhancement), availability of specific anti-toxoplasma antibodies in blood serum and CSF, diagnosis of cerebral toxoplasmosis has not been confirmed. M. tuberculosis DNA was found in CSF by PCR. Conclusions: CNSToxoIndex allows evaluating the local production of anti-toxoplasmic IgG in CNS and their diffusion from blood as a result of the blood-brain barrier damage and it is a powerful method of cerebral toxoplasmosis diagnostics in HIV-positive people as well.

scholarly journals Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome–positive leukemia

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1005-1012 ◽  
Author(s):  
Kimmo Porkka ◽  
Perttu Koskenvesa ◽  
Tuija Lundán ◽  
Johanna Rimpiläinen ◽  
Satu Mustjoki ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Brain Barrier ◽  
Clinical Activity ◽  
Cns Relapse ◽  
Blood Brain ◽  
Philadelphia Chromosome Positive

Abstract Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome–positive (Ph+) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasa-tinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a preclinical mouse model of intracranial Ph+ leukemia. Clinical dasatinib treatment in patients with CNS Ph+ leukemia was assessed. In preclinical studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasa-tinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph+ leukemia. Eleven evaluable patients had clinically significant, long-lasting responses, which were complete in 7 patients. In 3 additional patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL–mutated dasatinib-resistant clone, implying selection pressure exerted by the compound in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials.gov as CA180006 (#NCT00108719) and CA180015 (#NCT00110097).

scholarly journals Failure To Open the Blood-Brain Barrier and Deliver Immune Effectors to Central Nervous System Tissues Leads to the Lethal Outcome of Silver-Haired Bat Rabies Virus Infection

2006 ◽  
Vol 81 (3) ◽  
pp. 1110-1118 ◽  
Author(s):  
Anirban Roy ◽  
Timothy W. Phares ◽  
Hilary Koprowski ◽  
D. Craig Hooper
Keyword(s):  
Central Nervous System ◽  
Immune Response ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
Rabies Virus ◽  
Neutralizing Antibodies ◽  
Clinical Symptoms ◽  
The United States ◽  
Brain Barrier ◽  
Blood Brain

ABSTRACT Rabies is a lethal disease caused by neurotropic viruses that are endemic in nature. When exposure to a potentially rabid animal is recognized, prompt administration of virus-neutralizing antibodies, together with active immunization, can prevent development of the disease. However, once the nonspecific clinical symptoms of rabies appear conventional postexposure treatment is unsuccessful. Over the last decade, rabies viruses associated with the silver-haired bat (SHBRV) have emerged as the leading cause of human deaths from rabies in the United States and Canada as a consequence of the fact that exposure to these viruses is often unnoticed. The need to treat SHBRV infection following the development of clinical rabies has lead us to investigate why the immune response to SHBRV fails to protect at a certain stage of infection. We have established that measurements of innate and adaptive immunity are indistinguishable between mice infected with the highly lethal SHBRV and mice infected with an attenuated laboratory rabies virus strain. While a fully functional immune response to SHBRV develops in the periphery of infected animals, the invasion of central nervous system (CNS) tissues by immune cells is reduced and, consequently, the virus is not cleared. Our data indicate that the specific deficit in the SHBRV-infected animal is an inability to enhance blood-brain barrier permeability in the cerebellum and deliver immune effectors to the CNS tissues. Conceivably, at the stage of infection where immune access to the infected CNS tissues is limited, either the provision or the development of antiviral immunity will be ineffective.

scholarly journals Causes of drug resistance and glioblastoma relapses

2021 ◽  
Vol 11 (1) ◽  
pp. 101-108
Author(s):  
A. A. Mitrofanov ◽  
D. R. Naskhletashvili ◽  
V. A. Aleshin ◽  
D. M. Belov ◽  
A. Kh. Bekyashev ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tumor Progression ◽  
Blood Brain Barrier ◽  
Evolutionary Dynamics ◽  
Checkpoint Inhibitors ◽  
Combined Therapy ◽  
Response To Therapy ◽  
Brain Barrier ◽  
T Cell Therapy ◽  
Blood Brain

Glioblastoma multiform^ is one of the most aggressive malignancies, wich standard of treatment not changed over the past decade, and the average life expectancy from diagnosis to death does not exceed two years in the most optimistic trials. The review examines the features of the glioblastoma microenvironment, its genetic heterogeneity, the development of recurrent glioblastoma, the formation of drug resistance, the influence of the blood-brain barrier and the brain lymphatic system on the development of immunotherapy and targeted therapy. Molecular subgroups of glioblastomas with an assumed prognostic value were analyzed. It was determined that numerous relationships between glioblastoma cells and the microenvironment are aimed at ensuring tumor progression, and also cause a state of reduced effector function of T cells. Data on the development of future molecular-targeted therapies for four types of cancer cells based on their different properties and response to therapy are summarized: primary GSC, RISC cells, and proliferating and postmitotic non-GSC fractions. The penetration of blood-brain barrier with chemotherapeutic drugs and antibodies currently remains the main limitation in the treatment of glioblastoma. The resulting analysis of the causes is reduced to the following conclusions. A detailed understanding of the evolutionary dynamics of tumor progression can provide insight into the related molecular and genetic mechanisms underlying glioblastoma recurrence. The most promising methods of treatment for glioblastoma are combined therapy using immune checkpoint inhibitors in combination with new treatment methods -vaccine therapy, CAR-T-cell therapy and viral therapy. A deeper study of the mechanisms of drug resistance and acquisition resistance, biology and subcloning clonal populations of glioblastoma and its microenvironment, with active consideration of combined trips to the treatment will increase the survival rate of patients, and may lead to stable remission of the disease.

scholarly journals Endothelial Iron Homeostasis Regulates Blood-Brain Barrier Integrity via the HIF2α—Ve-Cadherin Pathway

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 311
Author(s):  
Daniel Rand ◽  
Orly Ravid ◽  
Dana Atrakchi ◽  
Hila Israelov ◽  
Yael Bresler ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Iron Homeostasis ◽  
Apoptotic Cell ◽  
Neurological Diseases ◽  
Brain Barrier ◽  
Molecular Response ◽  
Critical Pathways ◽  
Barrier Integrity ◽  
Blood Brain

The objective of this study was to investigate the molecular response to damage at the blood-brain barrier (BBB) and to elucidate critical pathways that might lead to effective treatment in central nervous system (CNS) pathologies in which the BBB is compromised. We have used a human, stem-cell derived in-vitro BBB injury model to gain a better understanding of the mechanisms controlling BBB integrity. Chemical injury induced by exposure to an organophosphate resulted in rapid lipid peroxidation, initiating a ferroptosis-like process. Additionally, mitochondrial ROS formation (MRF) and increase in mitochondrial membrane permeability were induced, leading to apoptotic cell death. Yet, these processes did not directly result in damage to barrier functionality, since blocking them did not reverse the increased permeability. We found that the iron chelator, Desferal© significantly decreased MRF and apoptosis subsequent to barrier insult, while also rescuing barrier integrity by inhibiting the labile iron pool increase, inducing HIF2α expression and preventing the degradation of Ve-cadherin specifically on the endothelial cell surface. Moreover, the novel nitroxide JP4-039 significantly rescued both injury-induced endothelium cell toxicity and barrier functionality. Elucidating a regulatory pathway that maintains BBB integrity illuminates a potential therapeutic approach to protect the BBB degradation that is evident in many neurological diseases.

scholarly journals miRNAs Participate in MS Pathological Processes and Its Therapeutic Response

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Ting Wu ◽  
Guangjie Chen
Keyword(s):  
Multiple Sclerosis ◽  
Blood Brain Barrier ◽  
Therapeutic Response ◽  
Response To Therapy ◽  
Brain Barrier ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
The Central Nervous System ◽  
Brain Barrier Disruption ◽  
Cns Lesions

Multiple sclerosis is the most common autoimmune disease of the central nervous system. It is believed that the increased migration of autoreactive lymphocytes across the blood-brain barrier (BBB) may be responsible for axonal demyelination of neurons. In this review, we discuss microRNAs participating in the pathological processes of MS, including periphery inflammation, blood-brain barrier disruption, and CNS lesions, and in its therapeutic response, in order to find biomarkers of disease severity and to predict the response to therapy of the diseases.

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