Luigi Aloj

Preliminary evaluation of radioimmunotherapy with an 131I labelled small immunoprotein targeted against the extra domain B of fibronectin in combination with whole brain radiation therapy in patients with multiple brain metastases from solid tumors.

e12502 Background: The extradomain B (ED-B) of fibronectin (FN) is a highly expressed marker of tumor angiogenesis and thus provides a molecular target for radioimmunotherapy (RIT). The RIT agent 131I-L19SIP is a small immunoprotein (SIP) labeled with I-131 recognizing the ED-B domain. Previous phase I/II 131I-L19SIP RIT studies have have shown efficacy in a variety of cancer types. We are now evaluating uptake of 131I-L19SIP in brain metastases, the safety of combined RIT and whole brain radiation therapy (WBRT) and efficacy. METHODS Ten patients (7 M, 3 F, 40-72 yo, 3 melanoma, 1 breast, 4 lung and 2 colorectal cancer) with brain metastases not amenable to local treatment, were enrolled (October 2009 - November 2010). Workup included whole body FDG-PET and contrast enhanced MRI and/or CT. All patients underwent WBRT (30 Gy). ImmunoPET with I-124 labeled L19SIP was performed in 9/10 patients (one had 131I-L19-SIP SPECT) to measure uptake in target lesions. Lesion uptake >4 times higher than contra-lateral normal brain was required for eligibility for 131I-L19SIP therapy (4.1 GBq/m2). 131I-L19SIP was administered within 3 weeks from completion of WBRT. No other treatment was given from 6 weeks prior to enrollment and until first assessment (5.3 ± 1.3 weeks after treatment). RESULTS Six patients were treated with 131I-L19SIP (6740 ± 347 MBq), 1 was ineligible for low lesion uptake, and 3 were excluded for rapidly progressing systemic disease. The estimated dose boost delivered to brain lesions ranged from 3.4 to 25.4 Gy. One patient developed grade 4 neutropenia requiring hospitalization. All other hematologic toxicity (grade 3 or lower) required no further action. The first assessment evaluation showed a partial response in 2 patients, disease stabilization in 2 patients, and progressive disease in 2 patients. CONCLUSIONS In this patient population with very poor prognosis the application of 131I-L19SIP in addition to WBRT is feasible, well tolerated and provides acceptable levels of toxicity. Further studies are needed to assess the therapeutic efficacy of this approach.

P.1.031 Expression of glucose metabolism genes in a psychosis model: a molecular link between NMDA receptor hypofunction and metabolism disorders?

of bisulfite-treated DNA (EpigenDx, Worcester MA). Altogether, we examined the methylation level across 39 CpG sites in the GR exon 1F promoter region for each subject. Two genes were genotyped; the 5HTTLPR and the ESR1. All statistical tests were carried out using SPSS version 15. A linear regression model was used to ascertain the effects of sex, GR methylation level and genes on stress response. Statistical normality of the data was checked using the Kolmogorov-Smirnov test. Results: Marked individual differences were observed in methylation levels of GR exon 1F at individual CpG sites for females and males. Overall, women showed significantly greater methylation levels than did men (t = 2.538, p = 0.013). There was a correlation between total cortisol output (area under the curve, AUC) and average methylation level at GR exon 1F in female subjects (R2D= 0.214, F(1,44) = 11.997, p = 0.001) accounting for 21.4% of the variance. Additionally, variations in the ESR1 and the 5-HTTLPR genes were significant predictors of AUC. A significant main effect of 5-HTTLPR (R2D= 0.172, F1,42 = 12.032, p = 0.001) and ESR1 (R2D= 0.132, F2,40 = 5.634, p = 0.007) was observed on AUC but there was no interaction between methylation and either gene. The full model accounted for nearly half of the variance (48%) in total cortisol output. Conclusions: We provide the first evidence that accumulated epigenetic changes at the peripheral GR exon 1F correlate with HPAA reactivity. Importantly, women show significantly greater methylation across the GR promoter exon 1F compared to men. The averaged methylation levels and each of the two polymorphisms are highly significant independent predictors of total cortisol response (AUC) in the TSST. These findings have important implications for understanding the molecular mechanisms underlying gender differences in stressrelated mental health disorders, and underscore the unique value of modeling both epigenetic and genetic information in conferring vulnerability to stress.

Postsynaptic density protein gene expression after typical or atypical antipsychotics administration

The affinities of antipsychotics at receptor and re-uptake sites were compared to deduce differences that might underlie the low incidence of weight gain observed with ziprasidone compared with other novel antipsychotics. Ziprasidone, olanzapine, risperidone, clozapine, quetiapine and haloperidol were evaluated in human or bovine radioligand binding and rat synaptosomal re-uptake studies. Relative to D2 receptor affinities, clozapine has higher affinity for 5HT2A&C, ml, HI, ~-1 and 7-2; olanzapine for 5HT2A&C, ml, and H1; risperidone for 5HT2A and ct-1; and quetiapine for H1, ml, and ~-1 receptors. In contrast, ziprasidone has higher affinity for the combination of serotonin 5HT2A&C, 5HT1A, and 5HT1D and reduced affinity for ~-1 receptors. Like risperidone, ziprasidone has reduced relative affinity for H1 receptors. Only ziprasidone moderately inhibits 5HT and NE re-uptake and has high affinity for 5HT1D receptors. In studies of patients with psychotic disorders ziprasidone is associated with significantly less weight gain than clozapine, olanzapine and risperidone and also less than quetiapine. The differences observed with ziprasidone suggest that the reduced H1 and ~-1 receptor binding affinities as well as its unique profile of potent 5HT receptor interactions (including 5HT1A agonism) and its moderate inhibition of 5HT and NE neuronal re-uptake all might contribute to its low potential for weight gain.