High dose oral tamoxifen and subcutaneous interferon alpha-2a for recurrent glioma

Chemotherapeutic regimens in present use for recurrent glioma have substantial toxicity. Activity against recurrent gliomas has been reported for both tamoxifen and interferon alpha, agents that have more acceptable toxicity profiles and that can be administered in an outpatient setting. We tested the efficacy and toxicity of the combination of high-dose tamoxifen and interferon alpha in adults with recurrent glioma in a phase II trial. Eligible patients had radiographically measurable recurrent gliomas of any grade after initial radiation therapy. Interferon-alpha (6 × 10⁶ U subcutaneously three times per week) and tamoxifen (240 mg/m²/day orally) were administered continuously. Treatment response was assessed at 6 week intervals using clinical and radiographic criteria. Eighteen patients (11 males and 7 females) were enrolled. Median age was 41 years (range 23–61 years). All patients had gliomas that progressed after radiation therapy and nitrosourea chemotherapy. The histologic diagnosis of the original tumor was glioblastoma multiforme in 8 patients, anaplastic astrocytoma in 5 patients, astrocytoma in 4 patients and mixed malignant glioma in 1 patient. Reversible moderate to severe neurological toxicity manifested by dizziness and unsteady gait was seen at tamoxifen doses of 240 mg/m²/day. Although the initial tamoxifen dose was reduced to 120 mg/m²/day, moderate neurotoxicity was noted at this dose as well and the trial was closed early. The combination of oral tamoxifen (120 to 240 mg/m²/day) and subcutaneous interferon-alpha (6 × 10⁶ U three times per week) was associated with significant neurotoxicity in this group of recurrent glioma patients, resulting in early study closure. Of 16 evaluable patients, 12 had progressive disease after one cycle of treatment, 3 had stable disease, and there was one minor response. Gradual dose escalation may be required if similar patients are to be treated with high dose tamoxifen in conjunction with interferon.     

New aspects in the treatment of AIDS-related lymphoma

Despite of changes in the use of antiviral or chemotherapy regimens, the median survival of patients with AIDS-related lymphoma has not significantly changed until recently. However, partly due to prolonged survival with the introduction of highly active antiretroviral therapy (HAART) prognosis in AIDS patients with lymphoma seems to improve. Recently, several new treatment options have been explored in patients with lymphoma. It is hoped that novel strategies will lead to a survival benefit in these patients. In this review, we discuss the current strategies for the treatment of AIDS-related lymphoma.     

Microtubule-associated protein tau facilitates the targeted killing of proliferating cancer cells in vitro and in a xenograft mouse tumour model in vivo

Background:

Antibody drug conjugates (ADCs) and immunotoxins (ITs) are promising anticancer immunotherapeutics. Despite their encouraging performance in clinical trials, both ADCs and ITs often suffer from disadvantages such as stoichiometrically undefined chemical linkage of the cytotoxic payload (ADCs) and the potential immunogenicity of toxins derived from bacteria and plants (ITs).

Methods:

Human microtubule-associated protein tau (MAP) was cloned in-frame with human EGF, expressed in E. coli and purified by standard chromatographic methods. The in vitro activity was confirmed by flow cytometry, cell viability assays and tubulin polymerisation assay. The in vivo efficacy was demonstrated using noninvasive far-red in vivo imaging.

Results:

The EGF-MAP selectively induced apoptosis in EGFR-overexpressing proliferating cancer cells through stabilisation of microtubules. Nonproliferating cells were not affected, demonstrating superior selectivity of EGF-MAP for cancer cells. The EGF-MAP was well tolerated at high doses in mice compared with the ETA''-based control. The in vivo efficacy of EGF-MAP was demonstrated in a tumour xenograft mouse model.

Conclusion:

Our data indicate the general mechanism of action for a new class of human immunotherapeutic reagents suitable for the treatment of cancer. This approach combines the binding specificity of targeting ligands with the selective cytotoxicity of MAP towards proliferating cells.     

Granzyme M as a novel effector molecule for human cytolytic fusion proteins: CD64-specific cytotoxicity of Gm-H22(scFv) against leukemic cells

Immunotoxins are promising targeted therapeutic agents comprising an antibody-based ligand that specifically binds to diseased cells, and a pro-apoptotic protein. Toxic components from bacteria or plants can trigger a neutralizing immune response, so that human effector molecules are more suitable. In this context, the protease granzyme B has been successfully tested in cytotoxicity assays against different cancer cells in vitro and in vivo. Our aim here was to introduce granzyme M as an alternative and novel component of human cytolytic fusion proteins. We fused it to the humanized single-chain antibody fragment (scFv) H22 which specifically binds to CD64, an FcγRI receptor overexpressed on activated myeloid cells and leukemic cells. We show that the humanized cytolytic fusion protein Gm-H22(scFv) specifically targets the acute myeloid leukemia cell line HL60 in vitro and is cytotoxic with an IC₅₀ between 1.2 and 6.4 nM. These findings were confirmed ex vivo using leukemic primary cells from patients, which were killed by granzyme M despite the presence of the granzyme B inhibitor serpin B9. In conclusion, granzyme M is a promising new cell-death inducing component for hCFPs because it specifically and efficiently kills target cells when fused to a targeting component.     

Hemorrhage in the endolymphatic sac: a cause of hearing fluctuation in enlarged vestibular aqueduct

Objective

Most of the patients with enlarged vestibular aqueduct (EVA) experience sudden hearing deterioration, but the exact mechanism is unclear. We analyzed magnetic resonance (MR) images and the cellular components of endolymph obtained from the endolymphatic sac in patients with EVA, in order to demonstrate the cause of sudden hearing loss.

Methods

A total of 25 patients (50 ears) with EVA, who had severe to profound hearing loss, were included in this retrospective clinical study. MR examinations were performed by a 3.0-T MR system using an 8-channel sensitivity-encoding head coil. We analyzed endolymphatic fluid harvested from the endolymphatic sac during cochlear implantations in four patients.

Results

The area of low signal intensity in the endolymphatic sac was observed on T2-weighted MR images for 15 of 50 ears. This area was observed more frequently in patients who experienced recent sudden hearing loss (10/12, 83%) than those with stable hearing (5/38, 13%)(Fisher's exact test, p < 0.001). In addition, this area showed high signal intensity on fluid attenuated inversion recovery images. Cytologic analysis of the aspirated endolymph from the endolymphatic sac in the patients with this area revealed many erythrocytes.

Conclusion

Our data suggests that hemorrhage in the endolymphatic sac could be a cause of sudden hearing deterioration in patients with EVA.     

Magnesium Sulfate Does Not Reduce Postoperative Analgesic Requirements

Background: Because magnesium blocks the N-methyl-d-aspartate receptor and its associated ion channels, it can prevent central sensitization caused by peripheral nociceptive stimulation. However, transport of magnesium from blood to cerebrospinal fluid (CSF) across the blood-brain barrier is limited in normal humans. The current study was designed to evaluate whether perioperative intravenous magnesium sulfate infusion affects postoperative pain.

Methods: Sixty patients undergoing abdominal hysterectomy received 50 mg/kg intravenous magnesium sulfate as a bolus dose followed by a continuous infusion of 15 mg [middle dot] kg-1 [middle dot] h-1 for 6 h (magnesium group) or the same volume of isotonic saline (control group). At the end of surgery, serum and CSF magnesium concentration were measured in both groups. The cumulative postoperative analgesic consumption was measured to assess the analgesic effect using a patient-controlled epidural analgesia device. Pain intensities at rest and during forced expiration were evaluated at 6, 24, 48, and 72 h postoperatively.

Results: At the end of surgery, patients in the magnesium group had significantly greater postoperative serum magnesium concentrations compared with both preoperative and control group values (P < 0.001). Despite significantly higher serum magnesium concentrations in the magnesium group, there was no significant difference in magnesium concentration measured in postoperative CSF. Cumulative postoperative analgesic doses were similar in both groups. However, there was observed an inverse relation between cumulative postoperative analgesic consumption and the CSF magnesium concentration in both groups. Visual analog pain scores at rest and during forced expiration were similar and less than 4 in both groups.