Bin Nan

Differentiation Between Brain Tumor Recurrence and Radiation Injury Using MR Spectroscopy

OBJECTIVE The purpose of our study was to explore the feasibility and utility of 2D chemical shift imaging (CSI) MR spectroscopy in the evaluation of new areas of contrast enhancement at the site of a previously treated brain neoplasm. MATERIALS AND METHODS Two-dimensional CSI (point-resolved spectroscopy sequence [PRESS]; TR/TE, 1,500/144) was performed in 29 consecutive patients (4-54 years old; mean age, 34 years) who had a new contrast-enhancing lesion in the vicinity of a previously diagnosed and treated brain neoplasm. Clinical and imaging follow-up, and histopathology in 16 patients, were used as indicators of the identity of a lesion. RESULTS Diagnostic-quality spectra were obtained in 97% of the patients. The Cho/Cr (choline/creatine) and Cho/NAA (choline/N-acetyl aspartate) ratios were significantly higher, and the NAA/Cr ratios significantly lower, in tumor than in radiation injury (all three differences, p < 0.0001). The Cho/Cr and Cho/NAA ratios were significantly higher in radiation injury than in normal-appearing white matter (p < 0.0003 and p < 0.0001, respectively), whereas NAA/Cr ratios were not different (p = 0.075). Mean Cho/Cr ratios were 2.52 for tumor, 1.57 for radiation injury, and 1.14 for normal-appearing white matter. Mean Cho/NAA ratios were 3.48, 1.31, 0.79, and mean NAA/Cr ratios were 0.79, 1.22, and 1.38, respectively. When values greater than 1.8 for either Cho/Cr or Cho/NAA ratios were considered evidence of tumor, 27 of 28 patients could be correctly classified. CONCLUSION Two-dimensional CSI MR spectroscopy can differentiate tumor from radiation injury in patients with recurrent contrast-enhancing intracranial lesions. In these lesions, the Cho/NAA and Cho/Cr ratios may be the best numeric discriminators.

Pregnancy Outcome After Treatment for Wilms Tumor: A Report From the National Wilms Tumor Study Group

PURPOSE This study was undertaken to determine the effect, if any, of prior treatment with radiation therapy or chemotherapy for Wilms tumor diagnosed during childhood or adolescence on live births, birthweight, and the frequency of congenital malformations. PATIENTS AND METHODS We reviewed pregnancy outcomes among survivors of Wilms tumor treated with or without irradiation to the flank or tumor bed on National Wilms Tumor Studies 1, 2, 3, and 4 using a maternal questionnaire and review of both maternal and offspring medical records. RESULTS We received reports regarding 427 pregnancies with duration of 20 weeks or longer, including 409 liveborn singletons for whom 309 sets of medical records were reviewed. Malposition of the fetus and early or threatened labor were more frequent among irradiated women. Both were more frequent among women who received higher radiation therapy doses. The offspring of the irradiated female patients were more likely to weigh less than 2,500 g at birth and to be of less than 36 weeks gestation, with both being more frequent after higher doses of radiation. An increased percentage of offspring of irradiated females had one or more congenital malformations. CONCLUSION Women who receive flank radiation therapy as part of their treatment for Wilms tumor are at increased risk of fetal malposition and premature labor. The offspring of these women are at risk for low birthweight, premature (< 36 weeks gestation) birth, and the occurrence of congenital malformations. These risks must be considered in the obstetrical management of female survivors of Wilms tumor.

Expression of Membrane Type 1 Matrix Metalloproteinase Is Associated with Cervical Carcinoma Progression and Invasion

Membrane type 1 matrix metalloproteinase (MT1-MMP) is frequently expressed by cancer cells and is believed to play an important role in cancer cell invasion and metastasis. However, little is known about the role of MT1-MMP in mediating invasiveness of cervical cancer cells. In this study, we examined MT1-MMP expression in 58 primary human cervical tissue specimens, including normal cervix, low-grade squamous intraepithelial lesions (LSIL), high-grade SILs (HSIL), and invasive carcinomas. We also evaluated MT1-MMP, MMP-2, and tissue inhibitor of metalloproteinase-2 expression in several cervical cancer-derived cell lines, human papillomavirus (HPV)-immortalized keratinocytes, and keratinocytes derived from a LSIL. Using in situ hybridization techniques to study the cervical tissue specimens, we found that MT1-MMP expression increases with cervical tumor progression (Spearman correlation coefficient = 0.66; P < 0.0001, exact test). Specifically, MT1-MMP expression is very low or absent in normal cervix and LSILs, is readily detectable in HSILs, and is very strongly expressed in nearly all invasive carcinomas. Most but not all cervical cancer-derived cell lines also expressed significant levels of MT1-MMP and MMP-2. Constitutive expression of exogenous MT1-MMP in cervical carcinoma-derived cells and HPV-immortalized keratinocytes with low endogenous levels of MT1-MMP induced invasiveness in collagen I, but this effect was not observed in LSIL-derived keratinocytes. Our results show that MT1-MMP is a key enzyme mediating cervical cancer progression. However, MT1-MMP alone is not always sufficient for inducing keratinocyte invasiveness at least in the collagen I invasion assay used in this study. Further studies of gene expression in preinvasive and invasive cervical cancers should assist with identification of additional critical factors mediating cervical cancer progression.

Gene expression analysis of preinvasive and invasive cervical squamous cell carcinomas identifies HOXC10 as a key mediator of invasion

If left untreated, a subset of high-grade squamous intraepithelial lesions (HSIL) of the cervix will progress to invasive squamous cell carcinomas (SCC). To identify genes whose differential expression is linked to cervical cancer progression, we compared gene expression in microdissected squamous epithelial samples from 10 normal cervices, 7 HSILs, and 21 SCCs using high-density oligonucleotide microarrays. We identified 171 distinct genes at least 1.5-fold up-regulated (and P < 0.001) in the SCCs relative to HSILs and normal cervix samples. Differential expression of a subset of these genes was confirmed by quantitative reverse transcription-PCR and immunohistochemical staining of cervical tissue samples. One of the genes up-regulated during progression, HOXC10, was selected for functional studies aimed at assessing its role in mediating invasive behavior of neoplastic squamous epithelial cells. Elevated HOXC10 expression was associated with increased invasiveness of human papillomavirus-immortalized keratinocytes and cervical cancer-derived cell lines in both in vitro and in vivo assays. Cervical cancer cells with high endogenous levels of HOXC10 were less invasive after short hairpin RNA-mediated knockdown of HOXC10 expression. Our findings support a key role for the HOXC10 homeobox protein in cervical cancer progression. Other genes with differential expression in invasive SCC versus HSIL may contribute to tumor progression or may be useful as markers for cancer diagnosis or progression risk.

Pulmonary nodule volumetric measurement variability as a function of CT slice thickness and nodule morphology.

OBJECTIVE The purpose of our study was to assess differences in volumetric measurements of pulmonary nodules obtained using different CT slice thicknesses; correlate these differences with nodule size, shape, and margination; and compare measurements generated by two different software packages. MATERIALS AND METHODS Seventy-five individual nodules identified on 29 lowdose, unenhanced, MDCT chest examinations were selected for volumetric analysis. Each image data set was reconstructed in three ways (slice thickness/reconstruction interval): 1.25 mm/0.625 mm, 2.5 mm/2 mm, and 5 mm/2.5 mm. Volumetric measurements were made on all 75 nodules at 1.25- and 2.5-mm slice thicknesses and on 57 of 75 nodules at the 5-mm thickness using Volume Analysis software. For 69 of 75 nodules, measurements were obtained on 1.25- and 2.5-mm-thick sections using a different commercially available software system, LN500 R2 software. Volume variability between different slice thicknesses was correlated with nodule diameter, shape, and margination using multiple linear regression. Percent differences between measurements obtained with the two software systems were calculated. Significance of relative volume differences between slice thicknesses and software packages was assessed using a one-sample Students t-test. RESULTS Although statistically significant differences in volumes between different section thicknesses were seen only for the tiny nodule size group, many individual nodules showed substantial volume variation. Significant differences were seen in nodule volume variability for smaller nodules (3-10 mm) compared with larger nodules (> or = 11 mm) (p < 0.0001), as well as spiculated compared with smooth nodules, within a single size group (p < 0.05). No effect of nodule shape (round vs elongated) was noted. Statistically significant differences in measurements obtained with the two software systems were seen only with 2.5-mm-thick sections (p = 0.001). CONCLUSION CT slice thickness variation resulted in significant differences in volume measurements for tiny nodules. A spiculated margin was shown to have a significant effect on nodule volume variability within a single size group. Use of different software packages resulted in significant volume measurement differences at the 2.5-mm CT slice thickness.

The relationship between components of metabolic syndrome and open-angle glaucoma.

PURPOSE To determine whether an association exists between various components of metabolic syndrome (diabetes mellitus [DM], systemic arterial hypertension [HTN], hyperlipidemia, and obesity) and open-angle glaucoma (OAG) in a large, diverse group of individuals throughout the United States. DESIGN Longitudinal cohort study. PARTICIPANTS All beneficiaries aged ≥40 years continuously enrolled in a managed care network who had 1 or more visits to an eye care provider during 2001 to 2007 were identified. METHODS Billing codes were used to identify individuals with OAG and those with components of metabolic syndrome. Cox regression was used to determine the hazard of developing OAG in enrollees with individual components or combinations of components of metabolic syndrome, with adjustment for sociodemographic factors, systemic medical conditions, and other ocular diseases. MAIN OUTCOME MEASURES Hazard of developing OAG. RESULTS Of the 2 182 315 enrollees who met the inclusion criteria, 55090 (2.5%) had OAG. After adjustment for confounding factors, those with DM (hazard ratio [HR] = 1.35 [95% confidence interval [CI], 1.21-1.50]) or HTN (HR = 1.17 [95% CI, 1.13-1.22]) alone or in combination (HR = 1.48 [95% CI, 1.39-1.58]) had an increased hazard of developing OAG relative to persons with neither of these conditions. By contrast, persons with hyperlipidemia alone had a 5% decreased hazard of OAG (HR = 0.95 [95% CI, 0.91-0.98]). Comorbid hyperlipidemia attenuated the increased hazard between HTN (HR = 1.09 [95% CI, 1.05-1.12]) or DM (HR = 1.13 [95% CI, 1.05-1.21]) and OAG. CONCLUSIONS At a time when the prevalence of metabolic disorders in the United States, is increasing this study furthers our understanding of risk factors associated with OAG and helps identify persons who may be at increased risk for this condition.

Estradiol Rates of Change in Relation to the Final Menstrual Period in a Population-Based Cohort of Women

CONTEXT/OBJECTIVE The aim was to characterize rates of change in serum estradiol (E2) levels across the menopausal transition and into early postmenopause. SETTING/PARTICIPANTS We studied the Michigan Bone Health and Metabolism Study cohort of 629 women with median age of 38 yr (interquartile range, 7) at the 1992-1993 baseline with annual assessment of E2 levels over the subsequent 15-yr period. DESIGN/MAIN OUTCOME MEASURES: The purpose was to describe patterns of acceleration/deceleration in (log)E2 rates of change before and after the final menstrual period (FMP) using nonparametric and piecewise regression modeling. RESULTS Between -10 to -2 yr to the FMP, mean fitted serum E2 population values were relatively stable. The 95% confidence bands around the slight increase in E2 rate of change 5 yr prior to the FMP included the value of no change. The fitted population mean E2 value declined 67% from 64.5 pg/ml (se = 3.6) to 21 pg/ml (se = 1.2) in the 4 yr between -2 < FMP < +2. A second significant mean E2 rate of change was identified from 6-8 yr after FMP. Fitted population mean E2 values declined 18% from 18.1 pg/ml (se = 1.3) at FMP = 6 to 14.8 pg/ml (se = 1.3) at FMP = 8. In nonobese women, the mean E2 percent decline was 42% from FMP = 6 to FMP = 8, whereas in obese women, the mean E2 percent decline over this time was 31%. CONCLUSIONS Population mean serum E2 levels were sustained until approximately 2 yr prior to the FMP. In the ensuing 4-yr period, E2 levels declined 67%. A secondary E2 decline, commencing about 6 yr after the FMP, was observed in nonobese but not obese women.

Follicle Stimulating Hormone and Its Rate of Change in Defining Menopause Transition Stages

CONTEXT/OBJECTIVE The objective of the study was to identify menopause transition stages using acceleration or deceleration patterns of FSH rates of change from the late reproductive years to postmenopause. SETTING/PARTICIPANTS Participants were the Michigan Bone Health and Metabolism Study cohort of 629 women, aged 24-44 yr (in 1992/3), with 5757 annual FSH data points over a 14-yr period. DESIGN/MAIN OUTCOME MEASURES: The study was designed to relate acceleration/deceleration patterns in FSH rate of change to time to final menstrual period (FMP) and chronological age using nonparametric and piecewise regression modeling. RESULTS Four major FSH stages, based on rate of FSH change patterns, were identifiable in relation to the FMP. In FSH stage 1, the rate of FSH change increased modestly up to -7 yr prior to the FMP; in FSH stage 2 (-7 to -2 yr prior to FMP), there was a major acceleration in FSH rate of change. FSH stage 3 had an acute increase in FSH rate of change (-2 to +1 yr around the FMP), with average FSH level of 34 mIU/ml. The fourth, or plateau, FSH stage began at 1 yr after FMP when the average FSH level was 54 mIU/ml. During the yr 28-60, there were eight age-specific epochs defined by significant changes of FSH trajectory accelerations or decelerations and rate of change. CONCLUSIONS Four menopause transition stages bounding the FMP and eight epochs in chronological aging from age 28 to 60 yr were defined by changes of FSH trajectory accelerations/decelerations and rates of change. This timing information, combined with knowledge of FSH levels and menstrual cycle characteristics, can help discern the likely status of women with respect to their reproductive viability and menopause transition stage.

Limits of the HEDIS Criteria in Determining Asthma Severity for Children

Objective. Although the Health Plan Employer Data Information Set (HEDIS) is a common method for evaluating the quality of asthma care, its accuracy in characterizing persistent asthma in children is unknown. The objective of this study was to compare the assessment of asthma severity (persistent vs nonpersistent asthma) using the HEDIS criteria versus clinical criteria using National Heart, Lung, and Blood Institute (NHLBI) guidelines. Methods. In a cross-sectional study, we analyzed baseline data from interviews with the parents of 896 children who had asthma and participated in a randomized controlled trial. Patients had an active clinical diagnosis of asthma, were between 2 and 12 years of age, and had no other pulmonary diseases. Patients had persistent asthma by parent report according to the HEDIS criteria when, within the last year, they had 1 asthma inpatient admission or emergency department visit or 4 asthma medication dispensing events, or 4 outpatient asthma visits and at least 2 asthma medication dispensing events. Patients had persistent asthma by parent report according to the NHLBI criteria when, within the last 2 months, they had nighttime asthma symptoms >2 nights/mo or daytime asthma symptoms >2 days/wk. We calculated the sensitivity of each HEDIS criterion, separately and then combined, using the NHLBI criteria as a gold standard. Results. On the basis of HEDIS criteria, 656 (73%) patients had persistent asthma, compared with 338 (38%) using NHLBI criteria. Although the HEDIS criteria for persistent asthma were fairly sensitive (0.89), they were not very specific (0.70). For children without daily controller medications (n = 346), the sensitivity was even lower (0.45), but the specificity was similar (0.68). We found that the test characteristics were fairly consistent across different age group strata (2–4, 5–9, and 10–12 years of age). Conclusions. HEDIS criteria used to determine the quality of asthma care should be interpreted with caution. Although the criteria for persistent disease—used to determine which children require daily controller medications—are fairly sensitive, they are not very specific and include children who may not require such medications.

Amount of bone loss in relation to time around the final menstrual period and follicle-stimulating hormone staging of the transmenopause.

BACKGROUND AND OBJECTIVE The objective of the study was to describe bone loss rates across the transmenopause related to FSH staging and the final menstrual period (FMP). DESIGN AND SETTING This was a population-based cohort of 629 women (baseline age 24-44 yr) with annual data points over 15 yr. MEASUREMENTS Measures were bone mineral density (BMD), FSH to define four FSH stages, and menstrual bleeding cessation to define the FMP. Bone loss rates were reported by obesity status. RESULTS Annualized rates of lumbar spine bone loss began in FSH stage 3, which occurs approximately 2 yr prior to the FMP (1.67%/yr); bone loss continued into FSH stage 4 (1.21%/yr). Mean spine BMD in FSH stage 4 was 6.4% less than spine BMD value in FSH stage 1. Annualized rates of femoral neck (FN) bone loss began in FSH stage 3 (0.55%/yr) and continued into FSH stage 4 (0.72%/yr). The FN difference between mean values in FSH stage 1 and FSH stage 4 was 5%. Annualized rates of spine bone loss in the 2 yr prior to the FMP were 1.7%/yr, 3.3%/yr in the 2 yr after the FMP, and 1.1%/yr in the 2- to 7-yr period after the FMP. Nonobese women had lower BMD levels and greater bone loss rates. CONCLUSIONS Spine and FN bone loss accelerates in FSH stage 3. Bone loss also began to accelerate 2 yr before the FMP with the greatest loss occurring in the 2 yr after the FMP. Bone loss rates in both spine and FN BMD were greater in nonobese women than obese women.