Focal Therapy Eligibility Determined by Magnetic Resonance Imaging/Ultrasound Fusion Biopsy.

PURPOSE: We assessed focal therapy eligibility in men who underwent multiparametric magnetic resonance imaging and targeted biopsy with correlation to whole mount histology after radical prostatectomy. MATERIALS AND METHODS: Subjects were selected from among the 454 men in whom targeted biopsy proven prostate cancer was derived from regions of interest on multiparametric magnetic resonance imaging from 2010 to 2016. Focal therapy eligibility was limited to a maximum Gleason score of 4 + 3 in regions of interest with or without other foci of low risk prostate cancer (Gleason score 3 + 3 and less than 4 mm). Men who did not meet NCCN® intermediate risk criteria were classified as ineligible for focal therapy. Of the 454 men 64 underwent radical prostatectomy and biopsy findings were compared to final pathology findings. RESULTS: Of the 454 men with a biopsy proven region of interest 175 (38.5%) were eligible for focal therapy. Fusion biopsy, which combined targeted and template biopsy, had 80.0% sensitivity (12 of 15 cases), 73.5% specificity (36 of 49) and 75.0% accuracy (48 of 64) for focal therapy eligibility. Targeted cores alone yielded 73.3% sensitivity (11 of 15 cases), 47.9% specificity (23 of 48) and 54.7% accuracy (35 of 64). Gleason score and extension across the midline differed in 4 and 9, respectively, of the 13 cases that showed discordant biopsy and whole mount histology. CONCLUSIONS: Using intermediate risk eligibility criteria more than a third of men with a targeted biopsy proven lesion identified on multiparametric magnetic resonance imaging would have been eligible for focal therapy. Eligibility determined by fusion biopsy was concordant with whole mount histology in 75% of cases. Improved selection criteria are needed to reliably determine focal therapy eligibility.

Value of Tracking Biopsy in Men Undergoing Active Surveillance of Prostate Cancer.

PURPOSE: We compared the upgrading rate obtained by resampling precise spots of prostate cancer (tracking biopsy) vs conventional systematic resampling during followup of men on active surveillance. MATERIALS AND METHODS: From 2009 to 2017 in 352 men prostate cancer was Gleason 3 + 3 in 268 and Gleason 3 + 4 in 84 at initial magnetic resonance imaging-ultrasound fusion biopsy. These men subsequently underwent a second fusion biopsy. At the first biopsy session all men underwent 12-core systematic biopsies and, when magnetic resonance imaging visible lesions were present, targeted biopsies. All cancerous sites were recorded electronically. During active surveillance at a second fusion biopsy session 6 to 18 months later tracking and systematic nontracking samples were obtained. The primary outcome measure was an increase in Gleason score (upgrading) at followup sampling, which was stratified by biopsy method. RESULTS: Overall 91 of the 352 men (25.9%) experienced upgrading at the second biopsy during a median 11-month interval. The upgrade rate in the Gleason 3 + 3 and 3 + 4 groups was 26.9% and 22.6%, respectively. The mean number of cores taken at second biopsy was 12.2 ± 3.3 in men with upgrading and 12.4 ± 4.1 in those who remained stable (p not significant). Men with grade 0 to 4 magnetic resonance imaging targets were all upgraded at approximately the same rate of 20% to 30% (p not significant). However, 58.8% of the men with grade 5 magnetic resonance imaging targets were upgraded. Of the 91 upgrades 48 (53%) were detected only by tracking. CONCLUSIONS: The tracking function of magnetic resonance imaging-ultrasound fusion biopsy warrants further study. When specific sites are resampled in men undergoing active surveillance of prostate cancer, upgrading is detected more often than by nontracking biopsy.

Targeted Biopsy to Detect Gleason Score Upgrading during Active Surveillance for Men with Low versus Intermediate Risk Prostate Cancer.

PURPOSE: We sought to determine the rate of upgrading to Gleason score 4 + 3 or greater using targeted biopsy for diagnosis and monitoring in men undergoing active surveillance of prostate cancer. MATERIALS AND METHODS: Study subjects comprised all 259 men, including 196 with Gleason score 3 + 3 and 63 with Gleason score 3 + 4, who were diagnosed by magnetic resonance imaging/ultrasound fusion guided biopsy from 2009 to 2015 and underwent subsequent fusion biopsy for as long as 4 years of active surveillance. The primary end point was the discovery of Gleason score 4 + 3 or greater prostate cancer. Followup biopsies included targeting of positive sites, which were tracked in an Artemis™ device. Kaplan-Meier curves were generated to determine upgrading rates, stratified by initial Gleason score and prostate specific antigen density. RESULTS: Based on a Cox proportional hazard model, men with Gleason score 3 + 4 were 4.65 times more likely to have upgrading than men with an initial Gleason score of 3 + 3 at 3 years (p <0.01). By the third surveillance year 63% of men with Gleason score 3 + 4 had been upgraded compared with 18.0% who started with Gleason score 3 + 3 (p <0.01). Of all 33 upgrades 32 (97%) occurred at a magnetic resonance imaging visible or a tracked site of tumor, rather than at a previously negative systematic site. Independent predictors of upgrading were Gleason score 3 + 4, prostate specific antigen density 0.15 ng/ml/cm3 or greater and a grade 5 lesion on magnetic resonance imaging. The incidence rate ratio of upgrading (Gleason score 3 + 4 vs 3 + 3) was 4.25 per year of patient followup (p <0.01). CONCLUSIONS: During active surveillance of prostate cancer, targeting of tracked tumor foci by magnetic resonance imaging/ultrasound fusion biopsy allows for heightened detection of Gleason score 4 + 3 or greater cancers. Baseline variables directly related to important upgrading that warrant increased vigilance include Gleason score 3 + 4, prostate specific antigen density 0.15 ng/ml/cm3 or greater and grade 5 lesions on magnetic resonance imaging.

Prostate cancer detection with magnetic resonance-ultrasound fusion biopsy: The role of systematic and targeted biopsies.

BACKGROUND: The current study was conducted to evaluate the performance of magnetic resonance (MR)-ultrasound-guided fusion biopsy in diagnosing clinically significant prostate cancer (csCaP). METHODS: A total of 1042 men underwent multiparametric MR imaging (mpMRI) and fusion biopsy consecutively in a prospective trial (2009-2014). An expert reader graded mpMRI regions of interest (ROIs) as 1 to 5 using published protocols. The fusion biopsy device was used to obtain targeted cores from ROIs (when present) followed by a fusion image-guided, 12-core systematic biopsy in all men, even if no suspicious ROI was noted. The primary endpoint of the study was the detection of csCaP (ie, Gleason score ≥ 7). RESULTS: Among 825 men with ≥ 1 suspicious ROI of ≥ grade 3, 289 (35%) were found to have csCaP. Powerful predictors of csCaP were ROI grade (grade 5 vs grade 3: odds ratio, 6.5 [P<.01]) and prostate-specific antigen density (each increase of 0.05 ng/mL/cc: odds ratio, 1.4 [P<.01]). Combining systematic and targeted biopsies resulted in the detection of more patients with csCaP (289 patients) than targeting (229 patients) or systematic (199 patients) biopsy alone. Among patients with no suspicious ROI, 35 (16%) were found to have csCaP on systematic biopsy. CONCLUSIONS: In this prospective trial, MR-ultrasound fusion biopsy allowed for the detection of csCaP, with a direct relationship noted with ROI grade and prostate-specific antigen density. The combination of targeted and systematic biopsy detected more csCaP than either modality alone; systematic biopsies revealed csCaP in 16% of men with no suspicious MRI target. The advantages of this new biopsy method are apparent, but issues of cost, training, and reliability await resolution before its widespread adoption.

Targeted prostate biopsy in select men for active surveillance: do the Epstein criteria still apply?

PURPOSE: Established in 1994, the Epstein histological criteria (Gleason score 6 or less, 2 or fewer cores positive and 50% or less of any core) have been widely used to select men for active surveillance. However, with the advent of targeted biopsy, which may be more accurate than conventional biopsy, we reevaluated the likelihood of reclassification upon confirmatory rebiopsy using multiparametric magnetic resonance imaging-ultrasound fusion. MATERIALS AND METHODS: We identified 113 men enrolled in active surveillance at our institution who met Epstein criteria and subsequently underwent confirmatory targeted biopsy via multiparametric magnetic resonance imaging-ultrasound fusion. Median patient age was 64 years, median prostate specific antigen was 4.2 ng/ml and median prostate volume was 46.8 cc. Targets or regions of interest on multiparametric magnetic resonance imaging-ultrasound fusion were graded by suspicion level and biopsied at 3 mm intervals along the longest axis (median 10.5 mm). Also, 12 systematic cores were obtained during confirmatory rebiopsy. Our reporting is consistent with START (Standards of Reporting for MRI-targeted Biopsy Studies) criteria. RESULTS: Confirmatory fusion biopsy resulted in reclassification in 41 men (36%), including 26 (23%) due to Gleason grade 6 or greater and 15 (13%) due to high volume Gleason 6 disease. When stratified by suspicion on multiparametric magnetic resonance imaging-ultrasound fusion, the likelihood of reclassification was 24% to 29% for target grade 0 to 3, 45% for grade 4 and 100% for grade 5 (p=0.001). Men with grade 4 and 5 vs lower grade targets were greater than 3 times more likely to be reclassified (OR 3.2, 95% CI 1.4-7.1, p=0.006). CONCLUSIONS: Upon confirmatory rebiopsy using multiparametric magnetic resonance imaging-ultrasound fusion men with high suspicion targets on imaging were reclassified 45% to 100% of the time. Criteria for active surveillance should be reevaluated when multiparametric magnetic resonance imaging-ultrasound fusion guided prostate biopsy is used.

Magnetic resonance imaging-ultrasound fusion biopsy for prediction of final prostate pathology.

PURPOSE: We explored the impact of magnetic resonance imaging-ultrasound fusion prostate biopsy on the prediction of final surgical pathology. MATERIALS AND METHODS: A total of 54 consecutive men undergoing radical prostatectomy at UCLA after fusion biopsy were included in this prospective, institutional review board approved pilot study. Using magnetic resonance imaging-ultrasound fusion, tissue was obtained from a 12-point systematic grid (mapping biopsy) and from regions of interest detected by multiparametric magnetic resonance imaging (targeted biopsy). A single radiologist read all magnetic resonance imaging, and a single pathologist independently rereviewed all biopsy and whole mount pathology, blinded to prior interpretation and matched specimen. Gleason score concordance between biopsy and prostatectomy was the primary end point. RESULTS: Mean patient age was 62 years and median prostate specific antigen was 6.2 ng/ml. Final Gleason score at prostatectomy was 6 (13%), 7 (70%) and 8-9 (17%). A tertiary pattern was detected in 17 (31%) men. Of 45 high suspicion (image grade 4-5) magnetic resonance imaging targets 32 (71%) contained prostate cancer. The per core cancer detection rate was 20% by systematic mapping biopsy and 42% by targeted biopsy. The highest Gleason pattern at prostatectomy was detected by systematic mapping biopsy in 54%, targeted biopsy in 54% and a combination in 81% of cases. Overall 17% of cases were upgraded from fusion biopsy to final pathology and 1 (2%) was downgraded. The combination of targeted biopsy and systematic mapping biopsy was needed to obtain the best predictive accuracy. CONCLUSIONS: In this pilot study magnetic resonance imaging-ultrasound fusion biopsy allowed for the prediction of final prostate pathology with greater accuracy than that reported previously using conventional methods (81% vs 40% to 65%). If confirmed, these results will have important clinical implications.

Targeted biopsy in the detection of prostate cancer using an office based magnetic resonance ultrasound fusion device.

PURPOSE: Targeted biopsy of lesions identified on magnetic resonance imaging may enhance the detection of clinically relevant prostate cancers. We evaluated prostate cancer detection rates in 171 consecutive men using magnetic resonance ultrasound fusion prostate biopsy. MATERIALS AND METHODS: Subjects underwent targeted biopsy for active surveillance (106) or persistently increased prostate specific antigen but negative prior conventional biopsy (65). Before biopsy, each man underwent multiparametric magnetic resonance imaging at 3.0 Tesla. Lesions on magnetic resonance imaging were outlined in 3 dimensions and assigned increasing cancer suspicion levels (image grade 1 to 5) by a uroradiologist. A biopsy tracking system was used to fuse the stored magnetic resonance imaging with real-time ultrasound, generating a 3-dimensional prostate model on the fly. Working from the 3-dimensional model, transrectal biopsy of target lesions and 12 systematic biopsies were performed with the patient under local anesthesia in the clinic. RESULTS: A total of 171 subjects (median age 65 years) underwent targeted biopsy. At biopsy, median prostate specific antigen was 4.9 ng/ml and prostate volume was 48 cc. A targeted biopsy was 3 times more likely to identify cancer than a systematic biopsy (21% vs 7%). Prostate cancer was found in 53% of men, 38% of whom had Gleason grade 7 or greater cancer. Of the men with Gleason 7 or greater cancer 38% had disease detected only on targeted biopsies. Targeted biopsy findings correlated with level of suspicion on magnetic resonance imaging. Of 16 men 15 (94%) with an image grade 5 target (highest suspicion) had prostate cancer, including 7 with Gleason 7 or greater cancer. CONCLUSIONS: Prostate lesions identified on magnetic resonance imaging can be accurately targeted using magnetic resonance ultrasound fusion biopsy by a urologist in clinic. Biopsy findings correlate with level of suspicion on magnetic resonance imaging.

Do ion concentrations after metal-on-metal hip resurfacing increase over time? A prospective study.

Thirteen male and five female patients received a Conserve Plus hip resurfacing and prospectively provided blood samples to measure cobalt and chromium levels for up to 11 years. Trends in metal levels over time in unilateral and bilateral patients were studied. A multi-variate regression model was used to account for potential covariates. For unilaterals over all time intervals, the median Serum Cobalt level (CoS) was 1.06 µg/L, while the median Serum Chromium level (CrS) was 1.58 µg/L. For bilaterals, the median post operative CoS was 2.80 µg/L, while the median CrS was 5.80 µg/L. Metal levels increased within the first year then decreased and stabilized. These results show that serum metal levels in well-functioning implants can be low and do not increase with time.

Racial disparity in fracture risk between white and nonwhite children in the United States.

OBJECTIVES: To examine risk factors for fracture in a racially diverse cohort of healthy children in the US. STUDY DESIGN: A total of 1470 healthy children, aged 6-17 years, underwent yearly evaluations of height, weight, body mass index, skeletal age, sexual maturation, calcium intake, physical activity levels, and dual-energy x-ray absorptiometry (DXA) bone and fat measurements for up to 6 years. Fracture information was obtained at each annual visit, and risk factors for fracture were examined using the time-dependent Cox proportional hazards model. RESULTS: The overall fracture incidence was 0.034 fracture per person-year with 212 children reporting a total of 257 fractures. Being white (hazard ratio [HR] = 2.1), being male (HR = 1.8), and having skeletal age of 10-14 years (HR = 2.2) were the strongest risk factors for fracture (all P ≤ .001). Increased sports participation (HR = 1.4), lower body fat percentage (HR = 0.97), and previous fracture in white girls (HR = 2.1) were also significant risk factors (all P ≤ .04). Overall, fracture risk decreased with higher DXA z scores, except in white boys, who had increased fracture risk with higher DXA z scores (HR = 1.7, P < .001). CONCLUSIONS: Boys and girls of European descent had double the fracture risk of children from other backgrounds, suggesting that the genetic predisposition to fractures seen in elderly adults also manifests in children.

Type II supracondylar humerus fractures: can some be treated nonoperatively?

BACKGROUND: The range of injury severity that can be seen within the category of type II supracondylar humerus fractures (SCHFs) raises the question whether some could be treated nonoperatively. However, the clinical difficulty in using this approach lies in determining which type II SCHFs can be managed successfully without a surgical intervention. METHODS: We reviewed clinical and radiographic information on 259 pediatric type II SCHFs that were enrolled in a prospective registry of elbow fractures. The characteristics of the patients who were treated without surgery were compared with those of patients who were treated surgically. Treatment outcomes, as assessed by the final clinical and radiographic alignment, range of motion of the elbow, and complications, were compared between the groups to define clinical and radiographic features that related to success or failure of nonoperative management. RESULTS: During the course of treatment, 39 fractures were found to have unsatisfactory alignment with nonoperative management and were taken for surgery. Ultimately, 150 fractures (57.9%) were treated nonoperatively, and 109 fractures (42.1%) were treated surgically. At final follow-up, outcome measures of change in carrying angle, range of motion, and complications did not show clinically significant differences between treatment groups. Fractures without rotational deformity or coronal angulation and with a shaft-condylar angle of >15 degrees were more likely to be associated with successful nonsurgical treatment. A scoring system was developed using these features to stratify the severity of the injury. Patients with isolated extension deformity, but none of the other features, were more likely to complete successful nonoperative management. CONCLUSIONS: This study suggests that some of the less severe pediatric type II SCHFs can be successfully treated without surgery if close follow-up is achieved. Fractures with initial rotational deformity, coronal malalignment, and significant extension of the distal fragment are likely to fail a nonoperative approach. An algorithm using the initial radiographic characteristics can aid in distinguishing groups.

Functional brown adipose tissue is related to muscle volume in children and adolescents.

OBJECTIVE: We examined whether the depiction of brown adipose tissue (BAT) with positron emission tomography/computed tomography (PET/CT) in pediatric patients is associated with anthropometric measures. STUDY DESIGN: We determined measures of body mass, adiposity, and musculature in 71 children and adolescents who underwent PET/CT examinations and compared patients with and without BAT. We used regression analyses to assess the relation between BAT and anthropometric measures. RESULTS: A total of 30 patients (42%) had BAT depicted on PET/CT, 10 of 26 girls (38%) and 20 of 45 boys (44%). Compared with patients without functional BAT, patients with BAT had significantly greater neck musculature (1880 ± 908 cm(3) versus 1299 ± 806 cm(3); P = .028 for boys and 1295 ± 586 cm(3) versus 854 ± 392 cm(3); P = .030 for girls) and gluteus musculature (1359 ± 373 cm(3) versus 1061 ± 500 cm(3); P = .032 for boys and 1138 ± 425 cm(3) versus 827 ± 297 cm(3); P = .038 for girls), but no differences in age, body mass index, or measures of subcutaneous fat. With logistic regression analyses, neck and pelvic musculature predicted the presence of BAT independently of age, sex, body size, and season of scan (P = .018 and .009, respectively). CONCLUSION: Pediatric patients with visualized BAT on PET/CT examinations had significantly greater muscle volume than patients with no visualized BAT.

Bone density and size in ambulatory children with cerebral palsy.

AIM: To examine the relation of axial and appendicular bone properties in ambulatory children with cerebral palsy (CP) to functional (Gross Motor Function Classification System [GMFCS]) level. METHOD: Quantitative computed tomography measurements were compared among 37 children with CP (12 children in GMFCS level I, five in level II, 18 in level III, two in level IV; five with hemiplegia, 23 with diplegia, two with triplegia, seven with quadriplegia; mean age 9y 4mo, SD 1y 6mo; 18 males, 19 females) and 37 children in a comparison group (same age and sex distributions). Linear regression was used to evaluate differences in volumetric cancellous bone density (vBMD) and geometric properties of the L3 vertebra and tibia, adjusting for height, weight, and sex as covariates. RESULTS: The comparison group had larger vertebrae than the children with CP (p = 0.02) owing to smaller vertebral size in GMFCS levels III and IV, but there was no difference in vertebral vBMD (p = 0.49). In the tibia, bone volumetric density (p = 0.09) and size (p = 0.02) decreased with increasing GMFCS level. GMFCS level had a greater effect on bone size in females than in males (p<0.07). INTERPRETATION: Children with CP of all levels may have less bone in their tibias, whereas spine deficits differentially affect more involved children. Because even small bone deficits may manifest as osteoporosis later in life, it is important to study bone acquisition in all children with CP.

Effect of high-frequency, low-magnitude vibration on bone and muscle in children with cerebral palsy.

BACKGROUND: Children with cerebral palsy (CP) have decreased strength, low bone mass, and an increased propensity to fracture. High-frequency, low-magnitude vibration might provide a noninvasive, nonpharmacologic, home-based treatment for these musculoskeletal deficits. The purpose of this study was to examine the effects of this intervention on bone and muscle in children with CP. METHODS: Thirty-one children with CP ages 6 to 12 years (mean 9.4, SD 1.4) stood on a vibrating platform (30 Hz, 0.3 g peak acceleration) at home for 10 min/d for 6 months and on the floor without the platform for another 6 months. The order of vibration and standing was randomized, and outcomes were measured at 0, 6, and 12 months. The outcome measures included computed tomography measurements of vertebral cancellous bone density (CBD) and cross-sectional area, CBD of the proximal tibia, geometric properties of the tibial diaphysis, and dynamometer measurements of plantarflexor strength. They were assessed using mixed model linear regression and Pearson correlation. RESULTS: The main difference between vibration and standing was that there was a greater increase in the cortical bone properties (cortical bone area and moments of inertia) during the vibration period (all P's ≤ 0.03). There was no difference in cancellous bone or muscle between vibration and standing (all P's > 0.10) and no correlation between compliance and outcome (all r's < 0.27; all P's > 0.15). The results did not depend on the order of treatment (P > 0.43) and were similar for children in gross motor function classification system (GMFCS) 1 to 2 and GMFCS 3 to 4. CONCLUSIONS: The primary benefit of the vibration intervention in children with CP was to the cortical bone in the appendicular skeleton. Increased cortical bone area and the structural (strength) properties could translate into a decreased risk of long bone fractures in some patients. More research is needed to corroborate these findings, to elucidate the mechanisms of the intervention, and to determine the most effective age and duration of the treatment. LEVEL OF EVIDENCE: Level II, prospective randomized cross-over study.

Quantitative CT reference values for vertebral trabecular bone density in children and young adults.

PURPOSE: To determine normative reference values for vertebral trabecular bone density (TBD) obtained by using quantitative computed tomography (CT) in healthy white children, teenagers, and young adults of both sexes. MATERIALS AND METHODS: The data presented in this HIPAA-compliant study are a compilation of data from multiple investigations on the determinants of bone acquisition in healthy children conducted at this institution from 1992 to 2006. The institutional review board for clinical investigations approved the protocols for each of these studies, and written informed consent was provided by all parents and/or participants. Quantitative CT measurements of TBD (in milligrams per cubic centimeter) were obtained at the first, second, and third lumbar vertebrae in 1222 healthy white male and female subjects aged 5-21 years (mean age for male subjects, 15.1 years +/- 3.6 [standard deviation]; range, 5.6-21.9 years; mean age for female subjects, 14.2 years +/- 3.9; range, 5.7-21.6 years; mean age for both sexes, 14.6 years +/- 3.8). Mean and standard deviations for TBD were determined for each age group in 1-year intervals, and Student t tests for unpaired data were performed to compare male subjects with female subjects. RESULTS: TBD increased equally during growth in male and female subjects. Although the percentage increase in TBD was similar for both sexes (23.7% [57 of 241] for male subjects, 22.2% [54 of 243] for female subjects), the rise began and reached peak values at an earlier age in female subjects; increases in TBD occurred from 10-15 years of age in female subjects, whereas in male subjects, these increases were not observed until age 12 years and were completed at 17 years. CONCLUSION: This study provides reference standards for quantitative CT bone measurements in children and young adults, which may aid in the diagnosis, prevention, and treatment of pediatric metabolic bone disorders.

Activity recommendations after total hip and knee arthroplasty: a survey of the American Association for Hip and Knee Surgeons.

There are limited data to guide surgeon recommendations regarding activities after total joint arthroplasty. The present study aims to better clarify the current community standards. A questionnaire was distributed to the members of the American Association for Hip and Knee Surgeons attending the 2007 annual meeting inquiring about recommendations for 15 activities for patients with total hip arthroplasty or total knee arthroplasty. One hundred thirty-nine surveys were returned. Spearman rank correlation was used to analyze the data. More than 95% of the responses placed no limitations on low-impact activities including level surface walking, stair climbing, level surface bicycling, swimming, and golf. Higher-impact activities were more commonly discouraged, although there was considerable variability. Recommendations after total hip arthroplasty were more liberal compared to those after total knee arthroplasty. Higher-volume surgeons tended to be more liberal in their recommendations. No responder indicated that there was strong scientific evidence for their recommendations. Investigations are needed to elucidate the long-term effects of higher load and/or higher cycle activities on total joint arthroplasty.

Reproducibility of carotid intima-media thickness measurements in young adults.

PURPOSE: To prospectively compare the reproducibility of carotid intima-media thickness (CIMT) measurements obtained from the right and left carotid arteries in young adults by using ultrasonographic (US) images acquired at the maximum dimension, minimum dimension, and electrocardiographically (ECG)-triggered cardiac end diastole. MATERIALS AND METHODS: This study was HIPAA compliant and approved by the institutional review board; all participants provided informed consent. Medical history, anthropometric measurements, and blood pressure (BP) values were obtained from 50 men and 50 women aged 18-25 years. Images of the common carotid arteries were acquired from three independent complete cardiac cycles by using a 15L8-MHz US transducer. CIMT was measured on the images of each cycle that depicted the narrowest and widest vessel diameters, and at the R wave of the ECG. Measurements from the right and left carotid arteries were analyzed by using paired t tests; possible sex differences, by using unpaired t tests. Reproducibility was determined by using coefficients of variation and intraclass correlations (ICCs). Pearson correlations and multiple regression analyses were used to compare CIMT, body mass index (BMI), and BP. RESULTS: CIMT values were 7.2% and 7% greater in frames showing the narrowest lumen diameter and in R-wave ECG-triggered frames, respectively, than in those with the widest diameter. CIMT measurements were 2.2%-3.1% greater in the right carotid artery than in the left (P < .001) and were significantly related to BMI (r = 0.40, P < .001) and systolic BP (r = 0.34, P < .001). ICCs were stronger when assessments were obtained in three different cardiac cycles (0.92-0.98), rather than in one (0.79-0.91). CONCLUSION: In healthy young adults, reproducibility of CIMT measurements is greatest when combining values from both carotid arteries and/or from the maximal and minimal arterial diameters.

Effects of busulfan dose escalation on engraftment of infant rhesus monkey hematopoietic stem cells after gene marking by a lentiviral vector.

OBJECTIVE: Non-myeloablative cytoreduction is used in clinical hematopoietic stem cell gene therapy trials to increase engraftment of gene-modified cells. We utilized an infant rhesus monkey model to identify an optimal dosage of busulfan that results in efficient long-term gene marking with minimal toxicities. METHODS: Bone marrow (BM) was harvested, followed by a single 2-hour intravenous infusion of busulfan at escalating dosages of 0 to 160 mg/m(2). CD34(+) cells were immunoselected from BM, transduced overnight with a simian immunodeficiency virus-based lentiviral vector carrying a non-expressed marker gene, and injected intravenously 48 hours post-busulfan administration. Pharmacokinetics were assessed, as well as adverse effects and peripheral blood and BM gene marking. RESULTS: Increasing dosages of busulfan resulted in increased area-under-the-curve (AUC) with some variability at each dosage level, suggesting interindividual variation in clearance. Blood chemistries were normal and no adverse effects were observed as a result of busulfan infusion. At 120 and 160 mg/m(2), transient neutropenia and thrombocytopenia were noted but not lymphopenia. Over the 6 months of study posttransplantation, a busulfan dosage-related increase in gene marking was observed ranging from undetectable (no busulfan) up to 0.1% gene-containing cells in animals achieving the highest busulfan AUC. This corresponds to a more than 100-fold increase in gene marking over the busulfan dosage range studied. CONCLUSIONS: These data indicate that increased gene marking of hematopoietic stem cells can be achieved by escalating busulfan dosages from 40 to 160 mg/m(2) without significant toxicity in infant nonhuman primates.

Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial.

CONTEXT: Prostate safety is a primary concern when aging men receive testosterone replacement therapy (TRT), but little information is available regarding the effects of TRT on prostate tissue in men. OBJECTIVE: To determine the effects of TRT on prostate tissue of aging men with low serum testosterone levels. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled trial of 44 men, aged 44 to 78 years, with screening serum testosterone levels lower than 300 ng/dL (<10.4 nmol/L) and related symptoms, conducted at a US community-based research center between February 2003 and November 2004. INTERVENTION: Participants were randomly assigned to receive 150 mg of testosterone enanthate or matching placebo intramuscularly every 2 weeks for 6 months. MAIN OUTCOME MEASURES: The primary outcome measure was the 6-month change in prostate tissue androgen levels (testosterone and dihydrotestosterone). Secondary outcome measures included 6-month changes in prostate-related clinical features, histology, biomarkers, and epithelial cell gene expression. RESULTS: Of the 44 men randomized, 40 had prostate biopsies performed both at baseline and at 6 months and qualified for per-protocol analysis (TRT, n = 21; placebo, n = 19). Testosterone replacement therapy increased serum testosterone levels to the mid-normal range (median at baseline, 282 ng/dL [9.8 nmol/L]; median at 6 months, 640 ng/dL [22.2 nmol/L]) with no significant change in serum testosterone levels in matched, placebo-treated men. However, median prostate tissue levels of testosterone (0.91 ng/g) and dihydrotestosterone (6.79 ng/g) did not change significantly in the TRT group. No treatment-related change was observed in prostate histology, tissue biomarkers (androgen receptor, Ki-67, CD34), gene expression (including AR, PSA, PAP2A, VEGF, NXK3, CLU [Clusterin]), or cancer incidence or severity. Treatment-related changes in prostate volume, serum prostate-specific antigen, voiding symptoms, and urinary flow were minor. CONCLUSIONS: These preliminary data suggest that in aging men with late-onset hypogonadism, 6 months of TRT normalizes serum androgen levels but appears to have little effect on prostate tissue androgen levels and cellular functions. Establishment of prostate safety for large populations of older men undergoing longer duration of TRT requires further study. Trial Registration clinicaltrials.gov Identifier: NCT00161304.

Use of the University of California Los Angeles integrated staging system to predict survival in renal cell carcinoma: an international multicenter study.

PURPOSE: To evaluate ability of the University of California Los Angeles Integrated Staging System (UISS) to stratify patients with localized and metastatic renal cell carcinoma (RCC) into risk groups in an international multicenter study. PATIENTS AND METHODS: 4,202 patients from eight international academic centers were classified according to the UISS, which combines TNM stage, Fuhrman grade, and Eastern Cooperative Oncology Group performance status. Distribution of the UISS categories was assessed in the overall population and in each center. RESULTS: The UISS stratified both localized and metastatic RCC into three different risk groups (P <.001). For localized RCC, the 5-year survival rates were 92%, 67%, and 44% for low-, intermediate-, and high-risk groups, respectively. A trend toward a higher risk of death was observed in all centers for increasing UISS risk category. For metastatic RCC, the 3-year survival rates were 37%, 23%, and 12% for low-, intermediate-, and high-risk groups, respectively; in 6 of 8 centers, a trend toward a higher risk of death was observed for increasing UISS risk category. A greater variability in survival rates among centers was observed for high-risk patients. CONCLUSION: This study defines the general applicability of the UISS for predicting survival in patients with RCC. The UISS is an accurate predictor of survival for patients with localized RCC applicable to external databases. Although the UISS may be useful for patients with metastatic RCC, it may be less accurate in this subset of patients due to the heterogeneity of patients and treatments.