Does brachytherapy improve survival in addition to external beam radiation therapy in patients with high risk stage I and II endometrial carcinoma?

INTRODUCTION: The benefit of adjuvant external beam radiation therapy (EBRT) in combination with intravaginal brachytherapy (BT) in stage I and II endometrial adenocarcinoma remains controversial. We evaluated the effect of adjuvant EBRT and combined EBRT + BT on overall survival and relative survival within a large US population database. METHODS: We performed an analysis of retrospective data from the Surveillance, Epidemiology, and End Results (SEER) program of the US National Cancer Institute from January 1, 1998 to December 31, 2005. A total of 3395 patients with stages IB, IC, and II node-negative endometrial adenocarcinoma comprised the population. Overall survival (OS) and relative survival (RS) curves were constructed via the Kaplan-Meier method and subgroups were compared via stratified log-rank test within T stage/grade combinations. Cox proportional hazards modeling was performed to evaluate the effect of multiple variables. RESULTS: EBRT alone was used in 2128 patients (62.7%) and 1267 patients (37.3%) received a combination of EBRT + BT. Higher grade, black race, older age at diagnosis, and later year of diagnosis are associated with worse overall survival, while lymphadenectomy is associated statistically with improved survival. The addition of BT revealed no statistically significant effect on OS. CONCLUSIONS: This large population-based study revealed no improvement in OS or RS with the addition of BT to EBRT in high risk stage I and stage II endometrial cancer. Although specific patient cohorts may benefit from combined EBRT and BT, additional analysis is warranted to further elucidate optimal treatment strategies for adjuvant radiotherapy based on specific clinical and pathologic features.

Methamphetamine-induced dopaminergic deficits and refractoriness to subsequent treatment.

Repeated high-dose methamphetamine administrations can cause persistent dopaminergic deficits. As individuals abusing methamphetamine are often exposed to recurrent high-dose administration, the impact of its repeated exposure merits investigation. Accordingly, rats were pretreated with repeated high-dose injections of methamphetamine, and subsequently "challenged" with the same neurotoxic regimen 7 or 30 days later. Results revealed that the initial methamphetamine treatment caused persistent deficits in striatal dopamine levels, dopamine transporter function, and vesicular monoamine transporter-2 function. The subsequent methamphetamine challenge treatment was without further persistent effects on these parameters, as assessed 7 days after the challenge, regardless of the interval (7 or 30 days) between the initial and challenge drug exposures. Similarly, a methamphetamine challenge treatment administered 7 days after the initial drug treatment was without further acute effect on dopamine transporter or VMAT-2 function, as assessed 1 h later. Thus, this study describes a model of resistance, possibly explained by: 1) the existence of dopaminergic neurons that are a priori refractory to deficits caused by methamphetamine; 2) the existence of dopaminergic neurons made persistently resistant consequent to a neurotoxic methamphetamine exposure; and/or 3) altered activation of post-synaptic basal ganglia systems necessary for the elaboration of methamphetamine-induced dopamine neurotoxicity.