Selective estrogen receptor modulators (SERMs) are potentially useful in treating various endometrial disorders, including endometrial cancer, as they block some of the detrimental effects of estrogen. It remains unclear whether each SERM regulates a unique subset of genes and, if so, whether the combination of a SERM and 17b-estradiol has an additive or synergistic effect on gene expression. We performed microarray analysis with Affymetrix Mouse Genome 430 2.0 short oligomer arrays to determine gene expression changes in uteri of ovariectomized mice treated with estradiol (low and high dose), methyl-piperidino-pyrazole (MPP), ICI 182 780, raloxifene, and combinations of high dose of estradiol with one of the SERM and dimethyl sulfoxide (DMSO) vehicle control. The nine treatments clustered into two groups, with MPP, raloxifene, and high dose of estradiol in one, and low dose of estradiol, ICI C estradiol, ICI, MPP C estradiol, and raloxifene C estradiol in the second group. Surprisingly, combining a high dose of estradiol with a SERM markedly increased (P!0 . 02) the number of regulated genes compared with each individual treatment. Analysis of expression for selected genes in uteri of estradiol and SERM-treated mice by quantitative (Q)RT-PCR generally supported the microarray results. For some cancer-associated genes, including Klk1, Ihh, Cdc45l, and Cdca8, administration of MPP or raloxifene with estradiol resulted in greater expression than estradiol alone (P!0 . 05). By contrast, ICI 182 780 suppressed more genes governing DNA replication compared with MPP and raloxifene treatments. Therefore, ICI 182 780 might be superior to MPP and raloxifene to treat estrogen-induced endometrial cancer in women.

Background and Purpose: Interfractional anatomical changes might affect the outcome of proton therapy (PT). We aimed to prospectively evaluate the role of Magnetic Resonance Imaging (MRI) based adaptive PT for children with tumors of the head and neck and base of skull. Methods: MRI verification images were acquired at half of the treatment course. A synthetic computed tomography (CT) image was created using this MRI and a deformable image registration (DIR) to the reference MRI. The methodology was verified with in-silico phantoms and validated using a clinical case with a shrinking cystic hygroma on the basis of dosimetric quantities of contoured structures. The dose distributions on the verification X-ray CT and on the synthetic CT were compared with a gamma-index test using global 2 mm/2% criteria. Results: Regarding the clinical validation case, the gamma-index pass rate was 98.3%. Eleven patients were included in the clinical study. The most common diagnosis was rhabdomyosarcoma (73%). Craniofacial tumor site was predominant in 64% of patients, followed by base of skull (18%). For one individual case the synthetic CT showed an increase in the median D2 and Dmax dose on the spinal cord from 20.5 GyRBE to 24.8 GyRBE and 14.7 GyRBE to 25.1 GyRBE, respectively. Otherwise, doses received by OARs remained relatively stable. Similarly, the target volume coverage seen by D95% and V95% remained unchanged. Conclusions: The method of transferring anatomical changes from MRIs to a synthetic CTs was successfully implemented and validated with simple, commonly available tools. In the frame of our early results on a small cohort, no clinical relevant deterioration for neither PTV coverage nor an increased dose burden to OARs occurred. However, the study will be continued to identify a pediatric patient cohort, which benefits from adaptive treatment planning.

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