Development of the Metronomic Biofeedback Pump for leptomeningeal carcinomatosis: technical note

Chen, Thomas C.; Napolitano, Gina R.; Adell, Frank; Schönthal, Axel H.; Shachar, Yehoshua

doi:10.3171/2014.10.jns14343

Cited by 13 publications

(6 citation statements)

References 21 publications

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“…16,17 Recently we have demonstrated that an implanted piezoelectric pump can be used in a leptomeningeal carcinomatosis model. 6 Thus, bypassing the BBB is critical and may be accomplished by several techniques.…”

Section: Discussionmentioning

confidence: 99%

Intratumoral delivery of bortezomib: impact on survival in an intracranial glioma tumor model

Wang¹,

Cho²,

Rosenstein-Sisson³

et al. 2018

Journal of Neurosurgery

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OBJECTIVE Glioblastoma (GBM) is the most prevalent and the most aggressive of primary brain tumors. There is currently no effective treatment for this tumor. The proteasome inhibitor bortezomib is effective for a variety of tumors, but not for GBM. The authors' goal was to demonstrate that bortezomib can be effective in the orthotopic GBM murine model if the appropriate method of drug delivery is used. In this study the Alzet mini-osmotic pump was used to bring the drug directly to the tumor in the brain, circumventing the blood-brain barrier; thus making bortezomib an effective treatment for GBM. METHODS The 2 human glioma cell lines, U87 and U251, were labeled with luciferase and used in the subcutaneous and intracranial in vivo tumor models. Glioma cells were implanted subcutaneously into the right flank, or intracranially into the frontal cortex of athymic nude mice. Mice bearing intracranial glioma tumors were implanted with an Alzet mini-osmotic pump containing different doses of bortezomib. The Alzet pumps were introduced directly into the tumor bed in the brain. Survival was documented for mice with intracranial tumors. RESULTS Glioma cells were sensitive to bortezomib at nanomolar quantities in vitro. In the subcutaneous in vivo xenograft tumor model, bortezomib given intravenously was effective in reducing tumor progression. However, in the intracranial glioma model, bortezomib given systemically did not affect survival. By sharp contrast, animals treated with bortezomib intracranially at the tumor site exhibited significantly increased survival. CONCLUSIONS Bypassing the blood-brain barrier by using the osmotic pump resulted in an increase in the efficacy of bortezomib for the treatment of intracranial tumors. Thus, the intratumoral administration of bortezomib into the cranial cavity is an effective approach for glioma therapy.

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Section: Discussionmentioning

confidence: 99%

Intratumoral delivery of bortezomib: impact on survival in an intracranial glioma tumor model

Wang¹,

Cho²,

Rosenstein-Sisson³

et al. 2018

Journal of Neurosurgery

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“…Wafer implants of the chemotherapeutic drug BCNU/carmustine, have been approved by the FDA and licensed for the treatment of malignant gliomas [36]. The Ommaya or Rickham reservoirs have been extensively used for intracavitary delivery [37,38] and new catheters and pump prototypes for CED have been recently developed [33,35,39].…”

Section: Discussionmentioning

confidence: 99%

Convection-enhanced delivery of temozolomide and whole cell tumor immunizations in GL261 and KR158 experimental mouse gliomas

et al. 2020

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Background: Glioblastomas (GBM) are therapy-resistant tumors with a profoundly immunosuppressive tumor microenvironment. Chemotherapy has shown limited efficacy against GBM. Systemic delivery of chemotherapeutic drugs is hampered by the difficulty of achieving intratumoral levels as systemic toxicity is a dose-limiting factor. Although some of its effects might be mediated by immune reactivity, systemic chemotherapy can also inhibit induced or spontaneous antitumor immune reactivity. Convection-enhanced delivery of temozolomide (CED-TMZ) can tentatively increase intratumoral drug concentration while reducing systemic side effects. The objective of this study was to evaluate the therapeutic effect of intratumorally delivered temozolomide in combination with immunotherapy and whether such therapy can generate a cellular antitumor immune response. Methods: Single bolus intratumoral injection and 3-day mini-osmotic pumps (Alzet®) were used to deliver intratumoral TMZ in C57BL6 mice bearing orthotopic gliomas. Immunotherapy consisted of subcutaneous injections of irradiated GL261 or KR158 glioma cells. Tumor size and intratumoral immune cell populations were analyzed by immunohistochemistry.Results: Combined CED-TMZ and immunotherapy had a synergistic antitumor effect in the GL261 model, compared to CED-TMZ or immunotherapy as monotherapies. In the KR158 model, immunization cured a small proportion of the mice whereas addition of CED-TMZ did not have a synergistic effect. However, CED-TMZ as monotherapy prolonged the median survival. Moreover, TMZ bolus injection in the GL261 model induced neurotoxicity and lower cure rate than its equivalent dose delivered by CED. In addition, we found that T-cells were the predominant cells responsible for the TMZ antitumor effect in the GL261 model. Finally, CED-TMZ combined with immunotherapy significantly reduced tumor volume and increased the intratumoral influx of T-cells in both models. Conclusions: We show that immunotherapy synergized with CED-TMZ in the GL261 model and cured animals in the KR158 model. Single bolus administration of TMZ was effective with a narrower therapeutic window than CED-TMZ. Combined CED-TMZ and immunotherapy led to an increase in the intratumoral influx of T-cells. These results form part of the basis for the translation of the therapy to patients with GBM but the dosing and timing of delivery will have to be explored in depth both experimentally and clinically.

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“…Whether CED of bevacizumab can be used in long-term therapy may soon be addressed by the use of implantable programmable pumps currently in development. 5 Thus, the positive effects of bevacizumab on vessel reduction make CED of bevacizumab a more efficient and effective means of therapy.…”

Section: Discussionmentioning

confidence: 99%

Effects of convection-enhanced delivery of bevacizumab on survival of glioma-bearing animals

Wang¹,

Sivakumar²,

Torres³

et al. 2015

FOC

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OBJECT Bevacizumab (Avastin), an antibody to vascular endothelial growth factor (VEGF), alone or in combination with irinotecan (Camptosar [CPT-11]), is a promising treatment for recurrent glioblastoma. However, the intravenous (IV) administration of bevacizumab produces a number of systemic side effects, and the increase in survival it provides for patients with recurrent glioblastoma is still only a few months. Because bevacizumab is an antibody against VEGF, which is secreted into the extracellular milieu by glioma cells, the authors hypothesized that direct chronic intratumoral delivery techniques (i.e., convection-enhanced delivery [CED]) can be more effective than IV administration. To test this hypothesis, the authors compared outcomes for these routes of bevacizumab application with respect to animal survival, microvessel density (MVD), and inflammatory cell distribution. METHODS Two human glioma cell lines, U87 and U251, were used as sources of intracranial tumor cells. The glioma cell lines were implanted into the brains of mice in an orthotopic xenograft mouse tumor model. After 7 days, the mice were treated with one of the following: 1) vehicle, 2) CED bevacizumab, 3) IV bevacizumab, 4) intraperitoneal (IP) irinotecan, 5) CED bevacizumab plus IP irinotecan, or 6) IV bevacizumab plus IP irinotecan. Alzet micro-osmotic pumps were used to introduce bevacizumab directly into the tumor. Survival was monitored. Excised tumor tissue samples were immunostained to measure MVD and inflammatory cell and growth factor levels. RESULTS The results demonstrate that mice treated with CED of bevacizumab alone or in combination with irinotecan survived longer than those treated systemically; CED-treated animals survived 30% longer than IV-treated animals. In combination studies, CED bevacizumab plus CPT-11 increased survival by more than 90%, whereas IV bevacizumab plus CPT-11 increased survival by 40%. Furthermore, CED bevacizumab-treated tissues exhibited decreased MVD compared with that of IV-treated tissues. In additional studies, the infiltration of macrophages and dendritic cells into CED-treated animals were increased compared with those in IV-treated animals, suggesting a highly active inflammatory response taking place in CED-treated mice. CONCLUSIONS The administration of bevacizumab via CED increases survival over that of treatment with IV bevacizumab. Thus, CED of bevacizumab alone or in combination with chemotherapy can be an effective protocol for treating gliomas.

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Development of the Metronomic Biofeedback Pump for leptomeningeal carcinomatosis: technical note

Cited by 13 publications

References 21 publications

Intratumoral delivery of bortezomib: impact on survival in an intracranial glioma tumor model

Intratumoral delivery of bortezomib: impact on survival in an intracranial glioma tumor model

Convection-enhanced delivery of temozolomide and whole cell tumor immunizations in GL261 and KR158 experimental mouse gliomas

Effects of convection-enhanced delivery of bevacizumab on survival of glioma-bearing animals

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