The University of breast cancer Texas MD Anderson Cancer Center, Houston, TX 77030, USA. festeva@mdanderson.org

Despite the recent trend toward treatment of early stage breast cancer aggressively with anthracyclines and taxanes, nearly half of those women will have metastatic recurrence. Moreover, because of the increasing prior exposure to these drugs, far more women facing first-line therapy for recurrent disease will now have developed anthracycline- and taxane-refractory metastatic breast cancer (ATRMBC), presenting a major therapeutic challenge. A number of established drugs are showing promise in this setting: capecitabine alone or combined with lapatinib; gemcitabine; vinorelbine; and oxaliplatin. At the same time, a variety of new drugs are emerging for potential use in ATRMBC. Among the drugs in clinical development that have shown promising activity include novel classes of compounds (camptothecins and epothilones), newer members of established classes (pemetrexed and vinflunine), and breast cancer agents with novel mechanisms of action (the mitosis inhibitor E7389 and the ascidian-derived anticancer compound trabectedin). Several molecularly targeted agents are also being evaluated in ATRMBC, including interleukin-2 receptor-binding denileukin diftitox, and 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), which inhibits the protein chaperone heat shock protein 90.

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Department of Otolaryngology, Tokyo Metropolitan Police Hospital, Tokyo, Japan. k-akinori@mbg.ocn.ce.jp

We report the case of a 39-year-old woman with a left side meningioma, suffering from bilateral sensorineural hearing loss, who recovered audiometric hearing in both ears after surgery. A preoperative pure tone audiogram (PTA) revealed a bilateral sensorineural hearing loss. Several examinations for sensorineural hearing loss indicated cochlear and retrocochlear hearing loss in the left ear and cochlear hearing loss in the right ear. After the operation, bilateral hearing loss due to a left posterior fossa meningioma gradually improved. One year after surgery, with the exception of hearing at frequencies of 4 and 8 kHz in the left ear, the postoperative audiogram had improved to an almost normal level. We speculate that hearing loss in the left ear may have been induced by the indirect compression of the cochlear nerve caused by the tumor’s edema, whereas that in the right ear may have resulted from changes in CSF pressure caused by the mass effects of the tumor.

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Department for Neurology, University Hospital Dubrava, Zagreb, Croatia.

In order to determine possible differences in serum gangliosides content and composition before and after surgical removal of tumor, gangliosides isolated from preoperative and postoperative sera of patients with brain tumors were analyzed. Serum samples were collected from patients with glioblastoma, meningioma, acoustic neurinoma, haemangioma, oligodendroglioma and astrocytoma, one week before and one week after surgical removal of the tumor. Serum gangliosides were qualitatively and quantitatively analyzed by high performance thin layer chromatography and laser densitometry. Results showed changes of total gangliosides concentrations in analyzed postoperative sera comparing to preoperative sera. There was not a significant difference in ganglioside pattern of preoperative vs. preoperative sera. However, a postoperative decreased proportion of ganglioside GD3 was observed in sera derived from patients with complete tumor removal. The results of this study indicate that comparative quantitative and compositional analysis of both preoperative and postoperative serum gangliosides may provide useful information concerning tumor progression, surgical success and prognosis.

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Department of Neurosurgery, Hôpital Gui de Chauliac, CHU de Montpellier, 80 avenue Augustin Fliche, 34295 Montpellier Cedex 5, France. h-duffau@chu-montpellier.fr

Dominant temporal lobectomy is classically performed based on two criteria: a perfect knowledge of the temporo-mesial microsurgical anatomy and cortical landmarks laterally. However, the functional anatomy of the subcortical white matter tracts is taken into account less, despite the risk of inducing a permanent deficit (especially aphasia) if damaged. Even if Klinger’s technique allows dissection of fibres on cadaveric specimens, the exact three dimensional geometry of these fasciculi remains poorly described. Tractography, based on diffusion tensor imaging (DTI), is a powerful tool to build three dimensional images of several fasciculi, helping neurosurgeons to create a mental representation of their relationships. Moreover, intraoperative subcortical electrostimulation enables mapping of the function of these pathways. Here we review the recent findings on the white matter anatomo-functional connectivity of the dominant temporal lobe, based on combined anatomical data provided by DTI and functional information provided by intraoperative stimulation. We then discuss their implications for temporal lobectomy, by using white matter functional connectivity as an additional landmark.

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Authors’ Affiliations: Cell Death Regulation Laboratory, Departments of Medicine and Cell and Molecular Biology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois and Division of Medical Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

PURPOSE: Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic antibodies targeting its receptors are promising cancer therapies because of their tumor selectivity, many tumors are resistant to TRAIL-based therapies. We examined whether the nonsteroidal anti-inflammatory drug aspirin sensitized cancer cells to TRAIL agonists in vitro and in vivo and investigated the underlying mechanism. EXPERIMENTAL DESIGN: The effects of aspirin on sensitivity to TRAIL agonists and expression of apoptosis regulators was determined in human breast cancer cell lines and xenograft tumors. The specific role of survivin depletion in the TRAIL-sensitizing effects of aspirin was determined by silencing survivin. RESULTS: Aspirin sensitized human breast cancer cells, but not untransformed human mammary epithelial cells, to TRAIL-induced caspase activation and apoptosis by a cyclooxygenase-2-independent mechanism. Aspirin also sensitized breast cancer cells to apoptosis induced by a human agonistic TRAIL receptor-2 monoclonal antibody (lexatumumab). Aspirin treatment led to G(1) cell cycle arrest and a robust reduction in the levels of the antiapoptotic protein survivin by inducing its proteasomal degradation, but did not affect the levels of many other apoptosis regulators. Silencing survivin with small interfering RNAs sensitized breast cancer cells to TRAIL-induced apoptosis, underscoring the functional role of survivin depletion in the TRAIL-sensitizing actions of aspirin. Moreover, aspirin acted synergistically with TRAIL to promote apoptosis and reduce tumor burden in an orthotopic breast cancer xenograft model. CONCLUSIONS: Aspirin sensitizes transformed breast epithelial cells to TRAIL-based therapies in vitro and in vivo by a novel mechanism involving survivin depletion. These findings provide the first in vivo evidence for the therapeutic utility of this combination.

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