Influence of estrogens and antiestrogens on the expression of selected hormone-responsive genes

Estrogen exerts a primary regulatory role on a wide variety of physiological processes in different tissues and organs. Agonistic ad antagonistic compounds are widely used in human health and, therefore, a deep understanding of their mechanisms of action at the molecular level is mandatory. The effect of 17beta-estradiol and three antiestrogenic drugs, comprising two selective estrogen receptor modulator (SERM, 4-OH-tamoxifen, Raloxifene) and the pure antiestrogen ICI 182,780, on genome-wide gene expression levels was evaluated in breast carcinoma cell lines by DNA microarray analysis. Different clusters of genes, showing specific coregulation patterns, were found. First, several groups of genes displaying temporal-specific up- or down-regulation were characterized. Second, clusters of genes responding to different antiestrogenic drugs in either antagonstic or agonistic fashion, were found. Genes responding specifically to antiestrogens, but not to estrogen, were also identified. In addition, each individual compound exhibited a very specific gene regulation. Bioinformatic analysis was applied to the regulatory sequences of different groups of genes and confirmed that specific pathways and secondary responses are activated at each temporal point and in response to different compounds. Our results underline the complexity of genomic responses to estrogen in breast cancer cells and strongly suggest that the molecular characterization of estrogen agonists and antagonists used in human therapy should be carefully studied.     

Scanning electron microscopy, x-ray diffraction, and electron microprobe analysis of calcific deposits on intrauterine contraceptive devices

Deposits found intrauterine contraceptive devices (IUDs) were studied by scanning electron microscopy, x-ray diffraction, and energy dispersive x-ray microanalysis. All seven devices, including five plastic and two copper IUDs, were coated with a crust containing cellular, acellular, and fibrillar material. The cellular material was composed of erythrocytes, leukocytes, cells of epithelial origin, sperm, and bacteria. Some of the bacteria were filamentous, with acute-angle branching. The fibrillar material appeared to be fibrin. Most of the acellular material was amorphous; calcite was identified by x-ray diffraction, and x-ray microanalysis showed only calcium. Some of the acellular material, particularly that on the IUD side of the crust, was organized in spherulitic crystals and was identified as calcium phosphate by x-ray microanalysis. The crust was joined to the IUD surface by a layer of fibrillar and amorphous material. It is suggested that the initial event in the formation of calcific deposits on IUD surfaces is the deposition of an amorphous and fibrillar layer. Various types of cells present in the endometrial environment adhere to this layer and then calcify. Thus, the deposition of calcific material on the IUDs is a calcification phenomenon, not unlike the formation of plaque on teeth. Hum Pathol 16:732-738, 1985.     

Radiographic predictors of IMRT for treating regional lymph nodes in breast cancer

Regional nodal irradiation (RNI) is an essential part of the treatment of high risk early stage (Stage IIb) and locally advanced (Stage III) breast cancer. Acceptable radiation plans can usually be achieved using 3-dimensional conformal radiation therapy with deep-inspiration breath hold to limit dose to the heart, although in some cases intensity-modulated radiation therapy produces superior results. The goal of this study is to identify radiographic parameters that predict the need for IMRT when delivering RNI. We retrospectively examined breast cancer patients treated with comprehensive RNI including internal mammary lymph nodes, supraclavicular lymph nodes, and undissected axillary lymph nodes at our institution from January 2016 to February 2018. Radiographic parameters including lung volume, internal mammary lymph nodes depth, modified central lung distance (mCLD), tangent length, and target height were recorded. Univariate and multivariate logistic regression was performed using IMRT as a binary endpoint (yes/no). A total of 46 patients were evaluated, of which 9 (20%) required IMRT. Five of the 9 (56%) IMRT patients were postmastectomy with a tissue expander in place. There was an increased likelihood of IMRT per 0.5 cm increase in mCLD (odds ratios [OR]: 3.27; 95% confidence interval [CI]: 1.39 to 9.63; p = 0.01) and per 1 cm increase in target height (OR: 1.77; 95% CI: 1.08 to 3.40; p = 0.04). A threshold value of 3.38 cm was identified for mCLD (OR 10.3; 95% CI: 2.14 to 61.4; p value = 0.005), and 25.2 cm for target height (OR 10.9; 95% CI: 2.19 to 82.7; p value = 0.007). When delivering RNI, larger values of mCLD and target height corresponded to the use of IMRT. Further investigations are warranted to confirm these findings, which may improve the efficiency of the treatment planning process and in turn patient care.     

Dosimetric comparison of intensity-modulated radiation therapy for early-stage glottic cancers with and without the air cavity in the planning target volume

For early-stage glottic cancers, intensity-modulated radiation therapy (IMRT) has been shown to have comparable local control to 3D-conformal radiotherapy with the advantage of decreased dose to the carotid arteries. The planning target volume (PTV) for early glottic cancers typically includes the entire larynx, plus a 3 to 5 mm uniform margin. The air cavity within the larynx creates a challenge for the inverse optimization process as the software attempts to “build up” dose within the air. This unnecessary attempt at dose build-up in air can lead to hot spots within the rest of the PTV and surrounding soft tissue. We hypothesized that removal of the air from the PTV would decrease hot spots and allow for a more homogeneous plan while still maintaining adequate coverage of the PTV.We analyzed 20 consecutive patients with early-stage glottic cancer, T1-2N0, who received IMRT at our institution from April 2015 to December 2016. Each patient received 63 to 65.25 Gy in 2.25 Gy per fraction. Two plans were created for each case: one in which the PTV included the laryngeal air cavity and one in which the air cavity was subtracted from the PTV to create a new PTV-air structure. Dosimetric variables were collected for PTV-air structure from both IMRT plans, including V100%, D98% D2%, and D0.2%. Dosimetric variables for spinal cord and the carotid arteries were also recorded. Homogeneity index (HI) defined as D98/D2 was calculated. Two-sided t-tests were used to compare dosimetric variables.The median PTV volume was 69.9 cc (standard deviation [SD] ± 28.7 cc) and the median air cavity volume removed was 11.0 cc (SD ± 3.4 cc). A 2-sided t-test revealed a statistically significant decrease in max dose (112.7% vs 108.8%, p value = 0.0002) and improvement of HI (0.93 vs 0.91, p value = 0.0023) for the PTV air in the IMRT plan optimized for PTV air, which had air excluded, compared to the IMRT plan optimized for PTV with air included. There was no significant worsening of PTV-air coverage or significant increase in doses to the organs at risk (OARs).The removal of the air cavity from the PTV for early-stage glottic cancers does not compromise PTV coverage or sparing of OARs and can result in a more homogeneous IMRT plan. A more homogeneous plan has the potential to reduce treatment morbidity, although further study is warranted to investigate the clinical impact of air cavity removal from the PTV.