A nanoemulsion of an anti-oxidant synergy formulation reduces tumor growth rate in neuroblastoma-bearing nude mice

Neuroblastoma, the most common form of childhood cancer, may arise from a biochemical block of cellular differentiation and a resultant continuation of a proliferative state. Neuroblastoma often spontaneously reverts by undergoing partial differentiation and ultimate degeneration and may be associated with the generation of reactive oxygen species (ROS). We have recently reported in neuroblastoma cell culture studies that an anti-oxidant synergy formulation (ASF) can induce differentiation and buffer neuronal degeneration and oxidative stress in cultured cortical neurons and in central nervous system tissue of apolipoprotein E-deficient mice. The objective of the present study was to investigate whether a subcutaneous injection and/or transdermal application of a nanoemulsion preparation of ASF would reduce tumor growth rate in a neuroblastoma xenograph mouse model. The results indicate that whereas suspensions of ASF were ineffective in decreasing tumor growth rate in the neuroblastoma mouse model, tumor growth rate was similarly reduced an average 65% by either subcutaneous injection or transdermal application of an ASF nanoemulsion preparation to the tumor. In conclusion, the data suggest that subcutaneous and/or transdermal application of an ASF nanoemulsion preparation is effective in reducing tumor growth rate in this neuroblastoma mouse model.     

Clinical outcome in posthysterectomy cervical cancer patients treated with concurrent Cisplatin and intensity-modulated pelvic radiotherapy: comparison with conventional radiotherapy

PURPOSE: To assess local control and acute and chronic toxicity with intensity-modulated radiation therapy (IMRT) as adjuvant treatment of cervical cancer. METHODS AND MATERIALS: Between April 2002 and February 2006, 68 patients at high risk of cervical cancer after hysterectomy were treated with adjuvant pelvic radiotherapy and concurrent chemotherapy. Adjuvant chemotherapy consisted of cisplatin (50 mg/m(2)) for six cycles every week. Thirty-three patients received adjuvant radiotherapy by IMRT. Before the IMRT series was initiated, 35 other patients underwent conventional four-field radiotherapy (Box-RT). The two groups did not differ significantly in respect of clinicopathologic and treatment factors. RESULTS: IMRT provided compatible local tumor control compared with Box-RT. The actuarial 1-year locoregional control for patients in the IMRT and Box-RT groups was 93% and 94%, respectively. IMRT was well tolerated, with significant reduction in acute gastrointestinal (GI) and genitourinary (GU) toxicities compared with the Box-RT group (GI 36 vs. 80%, p = 0.00012; GU 30 vs. 60%, p = 0.022). Furthermore, the IMRT group had lower rates of chronic GI and GU toxicities than the Box-RT patients (GI 6 vs. 34%, p = 0.002; GU 9 vs. 23%, p = 0.231). CONCLUSION: Our results suggest that IMRT significantly improved the tolerance to adjuvant chemoradiotherapy with compatible locoregional control compared with conventional Box-RT. However, longer follow-up and more patients are needed to confirm the benefits of IMRT.     

Distribution of brain metastases in relation to the hippocampus: implications for neurocognitive functional preservation

PURPOSE: With the advent of intensity-modulated radiotherapy, the ability to limit the radiation dose to normal tissue offers an avenue to limit side effects. This study attempted to delineate the distribution of brain metastases with relation to the hippocampus for the purpose of exploring the viability of tomotherapy-guided hippocampal sparing therapy potentially to reduce neurocognitive deficits from radiation. METHODS AND MATERIALS: The pre-radiotherapy T1-weighted, postcontrast axial MR images of 100 patients who received whole brain radiotherapy, stereotactic radiosurgery, or a radiosurgical boost following whole brain radiotherapy between 2002 and 2006 were examined. We contoured brain metastases as well as hippocampi with 5-, 10-, and 15-mm expansion envelopes. RESULTS: Of the 272 identified metastases, 3.3% (n = 9) were within 5 mm of the hippocampus, and 86.4% of metastases were greater than 15 mm from the hippocampus (n = 235). The most common location for metastatic disease was the frontal lobe (31.6%, n = 86). This was followed by the cerebellum (24.3%, n = 66), parietal lobe (16.9%, n = 46), temporal lobe (12.9%, n = 35), occipital lobe (7.7%, n = 21), deep brain nuclei (4.0%, n = 11), and brainstem (2.6%, n = 7). CONCLUSIONS: Of the 100 patients, 8 had metastases within 5 mm of the hippocampus. Hence, a 5-mm margin around the hippocampus for conformal avoidance whole brain radiotherapy represents an acceptable risk, especially because these patients in the absence of any other intracranial disease could be salvaged using stereotactic radiosurgery. Moreover, we developed a hippocampal sparing tomotherapy plan as proof of principle to verify the feasibility of this therapy in the setting of brain metastases.     

CD44 crosslinking-mediated matrix metalloproteinase-9 relocation in breast tumor cells leads to enhanced metastasis

CD44 plays a major role in multiple physiological processes, including cell-cell adhesion, cell-substrate interaction, lymphocyte homing, and tumor metastasis. It has been reported that highly expressed CD44 in certain types of tumors is associated with the hematogenic spread of tumor cells. The ability of CD44 to bind hyaluronan has been shown to correlate with tumor cell invasiveness, and it is likely that this ability may enhance tumor cell migration at several points during metastasis. However, the mechanism as to how CD44 stimulates metastasis remains unknown. The human breast tumor cell line, MDA-MB-435s, was used to investigate the effect of antibody-mediated CD44 crosslinking on the cellular level and localization of matrix metalloproteinase-9 (MMP-9). Confocal microscopy and immunocytochemical analyses were performed to demonstrate colocalization of CD44 and MMP-9 after CD44 crosslinking. Furthermore, the CD44-MMP-9 complex was purified by immunoprecipitation. G8 myoblast monolayers were employed to evaluate the invasiveness of human breast tumor cells after CD44 crosslinking in the presence or absence of protease inhibitors. CD44 crosslinking augmented the level of MMP-9 in the membrane of human breast tumor cells and clustering of CD44 serves as an MMP-9 docking molecule allowing MMP-9 to retain its concentrated proteolytic activity on the cell surface. Furthermore, crosslinking of CD44 enhances the ability of breast tumor cells to invade G8 myoblast monolayers and migrate through the basal membranes which was inhibited in the presence of anti-MMP-9 antibody or the MMP inhibitors GM6001 or 1,10-phenanthroline. This study demonstrates for the first time that CD44 crosslinking leads to an enhanced level and relocation of MMP-9 in human breast tumor cells accompanied by increased tumor invasion and metastasis.     

Arachnoid cyst with GnRH-dependent sexual precocity and growth hormone deficiency

The coexistence of gonadotropin-releasing hormone (GnRH)-dependent sexual precocity and growth hormone deficiency in patients with arachnoid cysts is rarely reported, and its pathogenesis is not well recognized. This report describes an 11-year-old female who had a huge intracranial arachnoid cyst with initial symptoms and signs of sexual precocity. Her brain magnetic resonance imaging revealed distorted hypothalamus with a thin and stretched pituitary stalk. After treatment with cysto-peritoneal shunting and gonadotropin-releasing hormone analogue, her puberty was arrested and subnormal growth rate was observed. Catch-up growth was detected after growth hormone therapy. Hence, coexistence of gonadotropin-releasing hormone-dependent sexual precocity and growth hormone deficiency in this patient was confirmed.     

Periodic lateralized epileptiform discharges of pediatric patients in Taiwan

Periodic lateralized epileptiform discharges are special electroencephalographic abnormalities present in adults with stroke, brain tumor, intracranial hemorrhage, or other rare etiologies. Few reports focused on the etiologies in pediatric patients. We retrospectively reviewed 8002 of our pediatric electroencephalographic records for the past 12 years and listed all associated illness and their outcomes. Forty-four children with periodic lateralized epileptiform discharges were collected. We found that there was an obvious difference in etiologies of our pediatric patients from those reported in the literature. Nearly two thirds of our patients (28 children) were associated with central nervous system infections. The other etiologies included head injury, encephalopathy, epilepsy, and others. Herpes simplex virus was responsible for two thirds (12) of the 18 children with identified pathogens causing a central nervous system infection. Ten patients failed to have a defined pathogen. Periodic lateralized epileptiform discharges have a different clinical significance in pediatric patients than in adults. In Taiwan, central nervous system infection is the most common etiology of periodic lateralized epileptiform discharges in pediatric patients. Herpes simplex virus, although the most common pathogen, should not be considered to be the only cause of encephalitis in children with periodic lateralized epileptiform discharges.