• IMA sites
  • IMAJ services
  • IMA journals
  • Follow us
  • Alternate Text Alternate Text
עמוד בית
Wed, 17.07.24

Search results

July 2019
Hadar Simchony, Gil Diamant PhD, Zvi Ram MD and Ilan Volovitz PhD

Background: Tumor treating fields (TTFields) are low-intensity, intermediate frequency electric fields that affect proliferating cells. TTFields are FDA approved for treatment of newly diagnosed and recurrent glioblastoma. Combining TTFields with immunotherapy is a rational approach due to their different mechanisms of action (MOA) and to the ability of TTFields to induce immunogenic cell death. Conversely, TTFields may interfere with immune functions critical for effective T-cell responses.

Objectives: To evaluate the effects of TTFields on pivotal antitumoral T-cell functions.

Methods: T-cells from healthy donor peripheral blood (PB) or from viably dissociated human glioblastoma samples were cultured under normal or TTFields conditions, with or without superantigen stimulation. Multiparametric flow cytometry (8-color) was used to assess T-cell responses by monitoring select pivotal functions: proliferation (CFSE), IFNγ secretion, cytotoxic degranulation (CD107a), and activation/exhaustion (PD-1). Cellular viability was assessed in a dedicated assay. A chimeric antigen receptor (CAR) T-cell-based assay directly evaluated cellular cytotoxicity.

Results: Activated PB T-cells and tumor-infiltrating T-cells (TILs) preserved all monitored anti- tumoral functions under TTFields, apart from proliferation. This finding also applied specifically to PD-1 + TILs, comprised predominantly of tumor antigen-specific cells. Activated T-cells that attempted to proliferate under TTFields demonstrated decreased viability, in line with TTField MOA. Small or no reduction in viability was found in T-cells that did not attempt to proliferate, whether activated or resting.

Conclusions: All monitored anti-tumoral T cell functions, except for proliferation, were unhindered by TTFields. Our results support further investigation into combinations of TTFields with T-cell based immunotherapeutic approaches.

May 2007
R. Grossman, Z. Ram, A. Perel, Y. Yusim, R. Zaslansky and H. Berkenstadt

Background: Pain following brain surgery is a significant problem. Infiltration of the scalp with local intradermal anesthetics was suggested for postoperative pain control but was assessed only in the first hour postoperatively.

Objectives: To evaluate wound infiltration with a single dose of metamizol (dipyrone) for postoperative pain control in patients undergoing awake craniotomy.

Methods: This open, prospective, non-randomized observational study, conducted in anesthesiology and neurosurgical departments of a teaching hospital, included 40 patients undergoing awake craniotomy for the removal of brain tumor. Intraoperative anesthesia included wound infiltration with lidocaine and bupivacaine, conscious sedation using remifentanil and propofol, and a single dose of metamizol (dipyrone) for postoperative pain control. Outcome was assessed by the Numerical Pain Scale on arrival at the postoperative care unit, and 2, 4 and 12 hours after the end of surgery.

Results: On arrival at the postoperative care unit, patients reported NPS[1] scores of 1.2 ± 1.1 in a scale of 0–10 (mean ± SD) (median = 1, range 0–4). The scores were 0.8 ± 0.9, 0.9 ± 0.9, and 1 ± 0.9 at 2 hours, 4 hours, and 12 hours after the end of surgery, respectively. Based on patients' complaints and NPS lower then 3, 27 patients did not require any supplementary analgesia during the first 12 postoperative hours, 11 patients required a single dose of oral metamizol or intramuscular diclofenac, one patient was given 2 mg of intravenous morphine, and one patient required two separate doses of metamizol.

Conclusions: Although the clinical setup prevents the use of placebo local analgesia as a control group, the results suggest the possible role of local intradermal infiltration of the scalp combined with a single dose of metamizol to control postoperative pain in patients undergoing craniotomy.

[1] NPS = Numerical Pain Scale

February 2001
Zvi R. Cohen, MD, Revital Duvdevani, PhD, Dvora Nass, MD, Moshe Hadani, MD and Zvi Ram, MD

Background: The transfer of therapeutic genes into malignant brain tumors has been the subject of intense pre­clinical and clinical research in recent years. Most approaches have used direct intratumoral placement of a variety of vectors and genes, such as retroviruses or adenoviruses carrying drug-susceptibility genes, modified replication-competent herpes virus, and several vectors carrying tumor suppressor genes such as the p53 gene. However, clinical results have so far been disappointing, mainly due to the limited ability to effectively distribute the genetic material into the target cell population. Accordingly, alternative delivery approaches into the central nervous system, e.g., intravascular, are under investigation. Genetic vectors administered intravascularly are unlikely to penetrate the blood-brain barrier and transfer a gene into brain or tumor parenchyma. However, intravascular delivery of vectors may target endothelial cells lining the blood vessels of the brain. Since endothetial cells participate in a variety of physiological and pathological processes in the brain, their modulation by gene transfer may be used for a variety of therapeutic purposes. Angiogenically stimulated endothelial cells within tumors replicate rapidly and hence may become targets for retroviral-mediated gene transfer.

Objective: To assess the anti-tumor effect of transferring a drug-susceptibility gene into endothelial cells of the tumor vasculature.

Methods: As a model for this approach we delivered concentrated retroviral vectors carrying a drug-susceptibility gene via the internal carotid artery of rats with malignant brain tumors. The safety and efficacy of this approach, without and with subsequent treatment with a pro-drug (ganciclovir). was evaluated.

Results: No acute or long-term toxicity was observed after intraarterial infusion of the vector. Treatment with ganciclovir resulted in variable hemorrhagic necrosis of tumors, indicating preferential transduction of the angiogenically stimulated tumor vasculature. This was accompanied by severe toxicity caused by subarachnoid hemorrhage and intracerebral hemorrhage in vascular territories shared by the tumor and adjacent brain.

Conclusion: The data indicate that endothelial cells can be targeted by intraarterial delivery of retroviral vectors and can be used for devising new gene therapy strategies for the treatment of brain tumors.

Legal Disclaimer: The information contained in this website is provided for informational purposes only, and should not be construed as legal or medical advice on any matter.
The IMA is not responsible for and expressly disclaims liability for damages of any kind arising from the use of or reliance on information contained within the site.
© All rights to information on this site are reserved and are the property of the Israeli Medical Association. Privacy policy

2 Twin Towers, 35 Jabotinsky, POB 4292, Ramat Gan 5251108 Israel