Ion homeostasis is extremely important for the survival of both normal as well as neoplastic cells. The altered ion homeostasis found in cancer cells prompted the investigation of several ionophores as potential anticancer agents. Few ionophores, such as Salinomycin, Nigericin and Obatoclax, have demonstrated potent anticancer activities against cancer stem-like cells that are considered highly resistant to chemotherapy and responsible for tumor relapse. The preclinical success of these compounds in in vitro and in vivo models have not been translated into clinical trials. At present, phase I/II clinical trials demonstrated limited benefit of Obatoclax alone or in combination with other anticancer drugs. However, future development in targeted drug delivery may be useful to improve the efficacy of these compounds. Alternatively, these compounds may be used as leading molecules for the development of less toxic derivatives.

Medulloblastoma is the most common malignant cancer of the central nervous system in children. AKT kinases are part of a survival pathway that has been found to be significantly elevated in medulloblastoma. This pathway is a point of convergence for many growth factors and controls cellular processes that are critical for tumor cell survival and proliferation. The alkyl-phospholipid perifosine [octadecyl-(1,1-dimethyl-4-piperidylio) phosphate] is a small molecule inhibitor in clinical trials in peripheral cancers which acts as a competitive inhibitor of AKT kinases. Medulloblastoma cell cultures were used to study the effects of perifosine response in preclinical studies in vitro. Perifosine treatment led to the rapid induction of cell death in medulloblastoma cell lines, with pronounced suppression of phosphorylated AKT in a time-dependent and concentration-dependent manner. LD₅₀ concentrations were established using viability assays for perifosine, cisplatin, and etoposide. LD₅₀ treatment of medulloblastoma cells with perifosine led to the cleavage of caspase 9, caspase 7, caspase 3, and poly-ADP ribosylation protein, although caspase 8 was not detectable. Combination single-dose treatment regimens of perifosine with sublethal doses of etoposide or irradiation showed a greater than additive effect in medulloblastoma cells. Lower perifosine concentrations induced cell cycle arrest at the G₁ and G₂ cell cycle checkpoints, accompanied by increased expression of the cell cycle inhibitor p21^cip1/waf1. Treatment with p21 small interfering RNA prevented perifosine-induced cell cycle arrest. These findings indicate that perifosine, either alone or in combination with other chemotherapeutic drugs, might be an effective therapeutic agent for the treatment of medulloblastoma. (Mol Cancer Res 2009;7(11):1813–21)

Cocaine use has been known to cause a number of adverse neurological conditions, such as cerebral ischemia and posterior reversible leukoencephalopathy. The radiologic appearance of cocaine-induced leukoencephalopathy is confounded by a common contaminant, levamisole, which is also known to cause multifocal leukoencephalopathy. However, we encountered a case of diffuse leukoencephalopathy in a patient with cocaine use that had extensive involvement of the cerebral white matter, globus pallidi as well as the cerebellum. Our case also presented with a severe clinical presentation, with the patient demonstrating minimal neurologic response after a prolonged period of critical care management. The severe clinical course and diffuse radiologic involvement of our case differs from previously reported cases of cocaine- or levamisole-induced leukoencephalopathy.

Rhombencephalitis is a rare and potentially fatal condition involving the brainstem, with infectious, autoimmune, and paraneoplastic etiologies. We present a patient presenting with left-extremity weakness and dysphonia who had brainstem imaging findings suggestive of rhombencephalitis. We suspect that the case was due to inoculation of the brainstem from nasopharyngeal adenoviral infection. Due to heavy cocaine use, extensive basiocciput erosion led to direct contact between the brainstem and the nasopharyngeal mucosa. The patient's milder clinical course might have been due to some degree of pre-existing immunity against adenovirus. Additionally, clinicians need to be aware of the proximity of the brainstem to the nasopharynx when there is basiocciput erosion, due to the potential risk of injury during instrumentation.

Dedifferentiated parosteal osteosarcoma is a rare tumor and is even rarer when involving the skull bones. We present a case of a 57-year-old man with a partially ossified progressive enlarging left skull mass in the left temporoparietal region, with erosion of the outer table. Radiological diagnosis of dedifferentiated parosteal osteosarcoma was suggested, and histopathology confirmed the diagnosis.