RXRα deletion and E6E7 oncogene expression are sufficient to induce cervical malignant lesions in vivo

Cervical cancer is the second leading cause of cancer deaths among women worldwide. High-Risk-Human Papillomaviruses (HR-HPVs) play an important etiologic role in the development of carcinoma of the uterine cervix. However, host factors are important in determining the outcome of genital HPV infection as most cervical precancerous lesions containing HR-HPVs do not progress to invasive carcinomas. Retinoids, acting through nuclear receptors (RARs, RXRs), play a crucial role in cervix development and homeostasis regulating growth and differentiation of a wide variety of cell types; indeed, they can inhibit cell proliferation, and induce cell differentiation or apoptotic cell death. Here we introduce a mouse model that develops spontaneously malignant cervical lesions allowing the study of the cooperative effect between HPV16E6E7 expression and the lack of RXRα in cervical cancer development. This model could be useful to study multistep carcinogenesis of uterine cervix tissue and might improve chemopreventive and chemotherapeutic strategies for this neoplasia.     

【In Press】 The prevalence of uncorrected refractive error in urban, suburban, exurban and rural primary school children in Indonesia

AIM: To determine the frequency and patterns of uncorrected refractive error (URE) across 4 gradients of residential densities (urban, exurban, suburban and rural) in Indonesia. METHODS: This was a cross-sectional study of school children from 3 districts in Yogyakarta and 1 district near Yogyakarta, Indonesia. The information regarding age, sex, school and school grader were recorded. The Snellen’s chart was used to measure the visual acuity and to perform the subjective refraction. The district was then divided into urban, suburban, exurban and rural area based on their location and population. RESULTS: In total, 410 school children were included in the analyses (urban=79, exurban=73, suburban=160 and rural=98 school children). Urban school children revealed the worst visual acuity (P<0.001) and it was significant when compared with exurban and rural. The proportion of URE among urban, suburban, exurban and rural area were 10.1%, 12.3%, 3.8%, and 1%, respectively, and it was significant when compared to the proportion of emetropia and corrected refractive error across residential densities (P=0.003). The risk of URE development in urban, suburban, exurban, and rural were 2.218 (CI: 0.914-5.385), 3.019 (CI: 1.266-7.197), 0.502(CI: 0.195-1.293), and 0.130 (CI: 0.017-0.972), respectively. CONCLUSION: URE is a major health problem among school children. Urban school children showed the worst VA. The school children in urban and suburban residential area had 2 and 3 times higher risk of developing the URE.     

Disruption of the NMDA receptor-PSD-95 interaction in hippocampal neurons with no obvious physiological short-term effect

PSD-95 binds to and co-localizes with NMDA receptors at postsynaptic sites. Their co-expression in COS7 cells induces the formation of aggregates containing both proteins. These findings have lead to the hypothesis that PSD-95 helps to cluster NMDA receptors at postsynaptic sites. In addition, PSD-95 binds various regulatory proteins including Src, Pyk2, SynGAP, and nNOS and may recruit signaling proteins to NMDA receptors. We tested whether synaptic transmission or plasticity was affected by acute dissociation of the PSD-95-NMDA receptor interaction with various peptides that bound to the first two PDZ domains of PSD-95 and its homologs and with antibodies directed against the very C-terminus of the NR2A and NR2B subunits of the NMDA receptor. Membrane-impermeable peptides injected via whole cell patch electrodes distributed within minutes throughout dendritic branches into spines in acute hippocampal slices and membrane-permeable peptides containing 11 arginine residues effectively accumulated in neurites in slices and primary hippocampal cultures. Neither peptides nor antibodies showed any effect on basal synaptic transmission or induction of long-term potentiation (LTP) in hippocampal slices. Pharmacologically isolated NMDA receptor activity was also not affected. However, the membrane-permeable peptide disrupted the NMDA receptor-PSD-95 interaction in slices as tested by immunoprecipitation and subsequent immunoblotting. These findings suggest that acute dissociation of PSD-95 and its homologs from the NMDA receptor and likely from other protein complexes does not result in any easily detectable physiological effects in hippocampal slices. However, we cannot exclude a role of PSD-95 in early events that lead to clustering of NMDA receptors or of other proteins including stargazin and AMPA receptors at postsynaptic sites nor do these experiments address the possibility of long-term changes in the slices. In fact, incubation of primary hippocampal cultures with the membrane-permeable peptide lead to a moderate decrease in the number of dendritic clusters of PSD-95 and NMDA receptors and their colocalization by 20-30%, suggesting some role of PSD-95 and its homologs in NMDA receptor clustering.     

Use of lymphoscintigraphy in radiation treatment of primary breast cancer in the context of lymphedema risk reduction

Purpose

The goal of this study was to determine the feasibility of SPECT/CT scintigraphic method for mapping lymphatic drainage for radiation therapy of breast cancer.

Materials and methods

Thirty-six patients were enrolled in a SPECT/CT lymphoscintigraphy study. ^99mTc sulfur colloid (1 mCi) was injected intradermally in the ipsilateral arm. After 5–8 h post-injection, the SPECT/CT scans were taken and analyzed on a GE eNTRGRA system. The SPECT/CT images were co-registered in the treatment planning system (TPS). The original treatment plan was recreated for nodal dosimetry. Intensity modulated radiation therapy (IMRT) planning was performed for reducing lymph node dose for reducing arm lymphedema.

Results

The number of lymph nodes varied from 0 to 10 with a mean value of 3.4 ± 5.4 nodes. The location of nodes varied in the axillary, supraclavicular, and breast regions depending upon the surgical procedure and the extent of the disease. The prescribed radiation dose to the breast varied from 45 to 50.4 Gy depending on the disease pattern in 32 evaluated patients having CT data. The dose to lymph nodes varied from 0 to 61.8 Gy depending upon the location and the radiation technique used. SPECT/CT study in conjunction with IMRT plan showed that it is possible to decrease nodal dose and thereby potentially reduce the risk of developing arm lymphedema.

Conclusions

The SPECT/CT device provides a novel method to map the lymph nodes in the radiation treatment fields that could be used to tailor the radiation dose.     

Daily CT localization for correcting portal errors in the treatment of prostate cancer

Introduction: Improved prostate localization techniques should allow the reduction of margins around the target to facilitate dose escalation in high-risk patients while minimizing the risk of normal tissue morbidity. A daily CT simulation technique is presented to assess setup variations in portal placement and organ motion for the treatment of localized prostate cancer.

Methods and Materials: Six patients who consented to this study underwent supine position CT simulation with an alpha cradle cast, intravenous contrast, and urethrogram. Patients received 46 Gy to the initial Planning Treatment Volume (PTV₁) in a four-field conformal technique that included the prostate, seminal vesicles, and lymph nodes as the Gross Tumor Volume (GTV₁). The prostate or prostate and seminal vesicles (GTV₂) then received 56 Gy to PTV₂. All doses were delivered in 2-Gy fractions.

After 5 weeks of treatment (50 Gy), a second CT simulation was performed. The alpha cradle was secured to a specially designed rigid sliding board. The prostate was contoured and a new isocenter was generated with appropriate surface markers. Prostate-only treatment portals for the final conedown (GTV₃) were created with a 0.25-cm margin from the GTV to PTV. On each subsequent treatment day, the patient was placed in his cast on the sliding board for a repeat CT simulation. The daily isocenter was recalculated in the anterior/posterior (A/P) and lateral dimension and compared to the 50-Gy CT simulation isocenter. Couch and surface marker shifts were calculated to produce portal alignment. To maintain proper positioning, the patients were transferred to a stretcher while on the sliding board in the cast and transported to the treatment room where they were then transferred to the treatment couch. The patients were then treated to the corrected isocenter. Portal films and electronic portal images were obtained for each field.

Results: Utilizing CT–CT image registration (fusion) of the daily and 50-Gy baseline CT scans, the isocenter changes were quantified to reflect the contribution of positional (surface marker shifts) error and absolute prostate motion relative to the bony pelvis. The maximum daily A/P shift was 7.3 mm. Motion was less than 5 mm in the remaining patients and the overall mean magnitude change was 2.9 mm. The overall variability was quantified by a pooled standard deviation of 1.7 mm. The maximum lateral shifts were less than 3 mm for all patients. With careful attention to patient positioning, maximal portal placement error was reduced to 3 mm.

Conclusion: In our experience, prostate motion after 50 Gy was significantly less than previously reported. This may reflect early physiologic changes due to radiation, which restrict prostate motion. This observation is being tested in a separate study. Intrapatient and overall population variance was minimal. With daily isocenter correction of setup and organ motion errors by CT imaging, PTV margins can be significantly reduced or eliminated. We believe this will facilitate further dose escalation in high-risk patients with minimal risk of increased morbidity. This technique may also be beneficial in low-risk patients by sparing more normal surrounding tissue.     

Detection of hyperacute parenchymal hemorrhage of the brain using echo-planar T2*-weighted and diffusion-weighted MRI

We investigated the usefulness of echo-planar imaging (EPI) as well as T2^*-weighted and diffusion-weighted MRI (DWI) to identify hyperacute hemorrhage (within 24 h after ictus) in the brain. Seven patients were examined 3.5 to 24 h after onset of symptoms using a whole-body 1.5-T MR system. Two diffusion-weighted sequences were run to obtain isotropic and anisotropic diffusion images. Apparent diffusion coefficients (ADC) were calculated from the isotropic diffusion images. All DWI images as well as the T2*-weighted EPI images showed the hematomas as either discrete, deeply hypointense homogeneous lesions, or as lesions of mixed signal intensity containing hypointense areas. We conclude that even in the early phase after hemorrhage, sufficient amounts of paramagnetic deoxyhemoglobin are present in intracerebral hemorrhages to cause hypointensity on EPI T2^*-weighted and DWI images; thus, use of ultrafast EPI allows identification of intracerebral hemorrhage. Received: 21 March 2000 Revised: 26 July 2000 Accepted: 27 July 2000     

Choice of beam energy and dosimetric implications for radiation treatment in a subpopulation of women with large breasts in the United States and Japan.

Radiation complications are often related to the dose inhomogeneity (hot spot) in breast tissue treated with conservative therapy, especially for large patients. The effect of photon energy on radiation dose distribution is analyzed to provide guidelines for the selection of beam energy when tangential fields and limited slices are used to treat women with large breasts. Forty-eight patients with chest wall separation > 22 cm were selected for dosimetric analysis. We compared the maximum dose in the central axis (CAX) plane (2D) using 6-, 10-, and 18-MV photon beams in all patients and 3D data set for 16 patients. Correlation between hot spot dose (HSD), separation, breast cup size, breast volume, and body weight was derived with beam energy. Among the 48 patients in this study, HSD > 10% in the CAX plane was noted in 98%, 46%, and 4% of the population when 2D dosimetry was performed; however, with 3D study, it was in 50%, 19%, and 6% of the patients with 6-MV, 10-MV and 18-MV beams, respectively. The chest wall separation, body weight, and breast volume were correlated with the HSD in both the 2D and 3D plans. Patient's bra size was not correlated with the hot spot. The chest wall separation was found to be the most important parameter to correlate with hot spot in tangential breast treatment. Simple guidelines are provided for dose uniformity in breast with respect to chest wall separation, body weight, bra size, and breast volume with tangential field irradiations.     

Extending slice coverage for breathhold fat-suppressed T2-weighted fast spin-echo of the liver at 3.0T: application of variable-rate selective-excitation (VERSE) RF pulses

PURPOSE: To determine the benefits of variable-rate selective-excitation (VERSE) radio frequency (RF) pulses for increased slice coverage in breathhold (BH) fat-suppressed T2-weighted fast spin-echo (FS-T2W-FSE) liver imaging at 3.0T. MATERIALS AND METHODS: A total of 12 healthy volunteers were imaged on 3.0T, using FS-T2W-FSE. Slice coverage and specific absorption rate (SAR) levels were monitored for VERSE-RF and standard-RF (sRF), respectively. BH time was 25 seconds; slice thickness 3.5 mm. Maximum coverage was recorded for interactive variation of repetition time (TR), bandwidth (BW), and echo-train length (ETL). Image quality was assessed qualitatively and quantitatively. RESULTS: Total slice coverage was always higher using VERSE-RF, but varied depending on the selected parameters. For BW > or = 62.5 kHz, slice coverage using VERSE increased between 38% (TR = 8200 msec) and 58% (TR = 2500 msec). Maximum coverage was obtained for TR = 5000 msec, ETL = 12, and BW > or = 62.5 kHz; with a mean of 31.8 slices for VERSE-RF and 22.5 slices for sRF, respectively (P < 0.005, 41% increased coverage). SAR was lower for VERSE-RF using BW < 41.67 kHz (P < 0.05), and equal to sRF for higher BW. Image quality was best for TR < or = 5000 msec (P < 0.05). FS was more homogeneous for lower ETL (P < 0.05). Blood suppression was best for TR < or = 5000 msec (P < 0.05). CONCLUSION: VERSE-RF pulses can be applied for thin-slice BH FS-T2W liver imaging at 3.0T, with significantly improved slice coverage.     

MR imaging of hepatocellular carcinoma: relationship between lesion size and imaging findings, including signal intensity and dynamic enhancement patterns

PURPOSE: To assess the relationship between lesion size and MR imaging findings of pathologically-proven hepatocellular carcinoma (HCC). MATERIALS AND METHODS: In a retrospective, single-center study, 37 consecutive patients were identified between 1999 and 2005 that underwent preoperative MRI and surgical resection of HCC. A total of 47 lesions (mean size = 6.85 cm, range = 1-25 cm) were assessed for signal intensity (SI), enhancement patterns, and secondary morphologic features. Interobserver rating, percentage enhancement, and contrast-to-noise-ratio (CNR) were determined. Lesions were assessed for combinations of typical MRI features. Regression analysis was used to assess relations between MRI findings and tumor size. RESULTS: On fat-suppressed T2-weighted (T2w) fast-spin-echo, smaller lesions had lower SI compared to larger lesions (P < 0.05). In the arterial phase, smaller lesions showed significantly higher percentage enhancement compared to larger lesions (P < 0.05). In the delayed phase, smaller lesions showed less pronounced washout (P < 0.05). Heterogeneity of the lesions, including fatty infiltration, internal nodules, or mosaic pattern, was observed significantly more frequently in larger lesions (P < 0.001). The classic combination of high T2w signal, strong arterial enhancement, and delayed phase washout was present in 23 of 44 lesions (52%). CONCLUSION: Smaller HCC often showed lower SI on T2w, more intense arterial enhancement, and less pronounced delayed washout compared to larger HCC.