Soft-Tissue Sarcomas of the Genitourinary Tract with Radiologic-Pathologic Correlation.

Genitourinary tract soft-tissue sarcomas are rare neoplasms with varied pathologic and clinical features. While some of these tumors may be aggressive high-grade malignancies, others are low grade with a relatively better prognosis. Given that the grade and extent of the disease are important prognostic factors in these tumors, timely diagnosis is crucial. Unfortunately, most imaging features of these malignancies are not pathognomonic, and various histologic subtypes do not manifest with typical classic imaging features. Therefore, reliable differentiation of the various histologic tumor types is not always possible based solely on the radiologic manifestations. Imaging findings need to be considered in the context of clinical history in corroboration with radiologic-pathologic correlation. The authors discuss the specific imaging and pathologic characteristics of various genitourinary tract soft-tissue sarcomas, emphasizing diagnostic difficulties and differential diagnoses. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

Overexpression of EZH2 in conjunctival melanoma offers a new therapeutic target.

Malignant melanoma of the conjunctiva (CM) is an uncommon but potentially deadly disorder. Many malignancies show an increased activity of the epigenetic modifier enhancer of zeste homolog 2 (EZH2). We studied whether EZH2 is expressed in CM, and whether it may be a target for therapy in this malignancy. Immunohistochemical analysis showed that EZH2 protein expression was absent in normal conjunctival melanocytes and primary acquired melanosis, while EZH2 was highly expressed in 13 (50%) of 26 primary CM and seven (88%) of eight lymph node metastases. Increased expression was positively associated with tumour thickness (p =0.03). Next, we targeted EZH2 with specific inhibitors (GSK503 and UNC1999) or depleted EZH2 by stable shRNA knockdown in three primary CM cell lines. Both pharmacological and genetic inactivation of EZH2 inhibited cell growth and colony formation and influenced EZH2-mediated gene transcription and cell cycle profile in vitro. The tumour suppressor gene p21/CDKN1A was especially upregulated in CM cells after EZH2 knockdown in CM cells. Additionally, the potency of GSK503 against CM cells was monitored in zebrafish xenografts. GSK503 profoundly attenuated tumour growth in CM xenografts at a well-tolerated concentration. Our results indicate that elevated levels of EZH2 are relevant to CM tumourigenesis and progression, and that EZH2 may become a potential therapeutic target for patients with CM. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

MDMX Regulates Transcriptional Activity of p53 and FOXO Proteins to Stimulate Proliferation of Melanoma Cells.

The tumor suppressor protein p53 has an important role in cell-fate determination. In cancer cells, the activity of p53 is frequently repressed by high levels of MDMX and/or MDM2. MDM2 is a ubiquitin ligase whose activity results in ubiquitin- and proteasome-dependent p53 degradation, while MDMX inhibits p53-activated transcription by shielding the p53 transactivation domain. Interestingly, the oncogenic functions of MDMX appear to be more wide-spread than inhibition of p53. The present study aimed to elucidate the MDMX-controlled transcriptome. Therefore, we depleted MDMX with four distinct shRNAs from a high MDMX expressing uveal melanoma cell line and determined the effect on the transcriptome by RNAseq. Biological function analyses indicate the inhibition of the cell cycle regulatory genes and stimulation of cell death activating genes upon MDMX depletion. Although the inhibition of p53 activity clearly contributes to the transcription regulation controlled by MDMX, it appeared that the transcriptional regulation of multiple genes did not only rely on p53 expression. Analysis of gene regulatory networks indicated a role for Forkhead box (FOX) transcription factors. Depletion of FOXO proteins partly prevented the transcriptional changes upon MDMX depletion. Furthermore, depletion of FOXO proteins relatively diminished the growth inhibition upon MDMX knockdown, although the knockdown of the FOXO transcription factors also reduces cell growth. In conclusion, the p53-independent oncogenic functions of MDMX could be partially explained by its regulation of FOXO activity.

Targeting of the MAPK and AKT pathways in conjunctival melanoma shows potential synergy.

PURPOSE: Conjunctival melanoma (CM) is a rare but lethal form of cancer. Similar to cutaneous melanoma, CM frequently carries activating mutations in BRAF and NRAS. We studied whether CM as well as conjunctival benign and premalignant melanocytic lesions express targets in the mitogen-activated protein kinase (MAPK) and AKT pathways, and whether specific inhibitors can suppress CM growth in vitro. METHODS: 131 conjunctival lesions obtained from 129 patients were collected. The presence of BRAF V600E mutation and expression of phosphorylated (p)-ERK and p-AKT were assessed by immunohistochemistry. We studied cell proliferation, phosphorylation, cell cycling and apoptosis in three CM cell lines using two BRAF inhibitors (Vemurafenib and Dabrafenib), a MEK inhibitor (MEK162) and an AKT inhibitor (MK2206). RESULTS: The BRAF V600E mutation was present in 19% of nevi and 26% of melanomas, but not in primary acquired melanosis (PAM). Nuclear and cytoplasmic p-ERK and p-AKT were expressed in all conjunctival lesions. Both BRAF inhibitors suppressed growth of both BRAF mutant CM cell lines, but only one induced cell death. MEK162 and MK2206 inhibited proliferation of CM cells in a dose-dependent manner, and the combination of these two drugs led to synergistic growth inhibition and cell death in all CM cell lines. CONCLUSION: ERK and AKT are constitutively activated in conjunctival nevi, PAM and melanoma. While BRAF inhibitors prohibited cell growth, they were not always cytotoxic. Combining MEK and AKT inhibitors led to more growth inhibition and cell death in CM cells. The combination may benefit patients suffering from metastatic conjunctival melanoma.

Sports and recreational injuries: regional rural injury study-II: impact on agricultural households and operations.

OBJECTIVES: To identify the incidence, severity, and potential risk factors for sports/recreational injuries incurred by children and adults in a five state, rural, Midwest, agricultural household population. METHODS: Computer assisted telephone interviews that included questions about all injuries were completed for eligible, participating households for 1999; 16,538 people participated, including 8488 children less than 20 years of age. Rates and 95% confidence intervals were calculated, and causal models guided multivariate models. RESULTS: Of a total of 2586 injuries, 1301 (50%) were not related to agricultural activity. Among these, 733 (28%) were associated with sports/recreational activities including multiple person sports (64%), general play activities (19%), and single person sports (14%). The overall rate was 46.4 injury events per 1000 persons per year. Rates for children were 99.4 for boys and 64.3 for girls. For adults (aged 20 and above), rates were 11.9 for men and 4.8 for women. For children, 93% received health care, 44% were restricted for seven or more days, and 18% lost agricultural work time of seven or more days; the respective proportions for adults were 88%, 45%, and 17%. Multivariate analysis for children showed increased risks for Nebraska residents, males, and those 10-14 or 15-19 years. For adults, increased risks were identified for males and those 20-24 years; decreased risks were observed for Nebraska residents and those 45-54 years. CONCLUSIONS: Sports/recreational activities are an important source of injury with relevant consequences for this population, including significant restricted daily activity and lost agricultural work time. Key findings provide a basis for further study to address these burdens.

No involvement of bovine leukemia virus in childhood acute lymphoblastic leukemia and non-Hodgkin's lymphoma.

Bovine leukemia virus (BLV) is the causative agent of enzootic bovine lymphosarcoma. Much speculation continues to be directed at the role of BLV in human leukemia. To test this hypothesis rigorously, a case-control study of childhood acute lymphoblastic leukemia and non-Hodgkin's lymphoma was conducted between December 1983 and February 1986. Cases (less than or equal to 16 years at diagnosis) derived from patients diagnosed at the primary institutions and affiliated hospitals were matched (age, sex, and race) with regional population controls. DNA samples from bone marrow or peripheral blood from 157 cases (131 acute lymphoblastic leukemia, 26 non-Hodgkin's lymphoma) and peripheral blood from 136 controls were analyzed by Southern blot technique, under highly stringent conditions, using cloned BLV DNA as a probe. None of the 157 case or 136 control DNA samples hybridized with the probe. The high statistical power and specificity of this study provide the best evidence to date that genomic integration of BLV is not a factor in childhood acute lymphoblastic leukemia/non-Hodgkin's lymphoma.

Activin Receptor-like Kinase 1 Ligand Trap Reduces Microvascular Density and Improves Chemotherapy Efficiency to Various Solid Tumors.

PURPOSE: Antiangiogenic therapy, mostly targeting VEGF, has been applied in cancer patients for the last decade. However, resistance to anti-VEGF therapy and/or no significant benefit as monotherapeutic agent is often observed. Therefore, new antiangiogenic strategies are needed. In the current study, we investigated the therapeutic effect of interfering with the bone morphogenetic protein (BMP)9/activin receptor-like kinase (ALK)1 signaling pathway by using an ALK1-Fc ligand trap. EXPERIMENTAL DESIGN: We analyzed the potential antiangiogenic and antitumor effects of ALK1-Fc protein as monotherapy and in combination with chemotherapy in vivo in mouse models of melanoma, head and neck cancer, and invasive lobular breast carcinomas. ALK1-Fc sequesters BMP9 and 10 and prevents binding of these ligands to endothelial ALK1, which regulates angiogenesis. RESULTS: Treatment of mice with ALK1-Fc strongly decreased the tumors' microvascular density in the three different mouse cancer models. However, this effect was not accompanied by a reduction in tumor volume. An immunohistochemical analysis of the tumor samples revealed that ALK1-Fc treatment increased the pericyte coverage of the remaining tumor vessels and decreased the hypoxia within the tumor. Next, we observed that combining ALK1-Fc with cisplatin inhibited tumor growth in the breast and head and neck cancer models more efficiently than chemotherapy alone. CONCLUSIONS: The addition of ALK1-Fc to the cisplatin treatment was able to enhance the cytotoxic effect of the chemotherapy. Our results provide strong rationale to explore combined targeting of ALK1 with chemotherapy in a clinical setting, especially in the ongoing phase II clinical trials with ALK1-Fc.

An epidemiological study of roadway fatalities related to farm vehicles: United States, 1988 to 1993.

Compared with the estimated injury fatality rate for workers in all occupations (nine in 100,000 in 1988) the farm fatality rate (48 in 100,000) was among the highest in the nation; in 1993, these rates were eight and 35 in 100,000, respectively. On-road farm-vehicle fatalities have been identified as a significant problem, yet these events apparently have not been investigated in a comprehensive manner. The purpose of this study was to investigate the circumstances surrounding all on-road, non-truck, farm-vehicle crash fatalities in the United States form 1988 through 1993. The National Highway Traffic Safety Administration's Fatal Accident Reporting System, which includes data for all US fatal on-road motor vehicle crashes, was the source of data. Driver-related variables were compared among farm vehicles, vehicles in collisions with farm vehicles, and all other vehicles in rural, fatal crashes; environmental variables were compared between rural farm-vehicle and non-farm-vehicle crashes. During 1988 to 1993, in rural areas, 444 farm-vehicle occupants were killed; in addition, 238 occupants of other vehicles or pedestrians were killed in collisions with the farm vehicles. The farm vehicles were disproportionately involved in overturns, rear-end collisions, and incidents in which the injured person fell from the vehicle, when compared with all other non-farm vehicles involved in rural-area fatal crashes. Of the farm vehicles involved in fatal crashes at night, dawn, or dusk, 65% were struck in the rear, compared with 4% of vehicles involved in fatal non-farm-vehicle crashes. Compared with drivers in all other rural crashes, farm-vehicle operators were more likely to be male, have a greater proportion of convictions for driving while intoxicated, and a lower proportion of previous speeding convictions. From this initial investigation, it appears that the fatal-crash involvement of farm vehicles are related to vehicle and environmental factors that are changeable. Given the proportion of overturns associated with farm-vehicle crashes (21%) compared with non-farm vehicles (9%), there is a need to investigate design characteristics of the farm vehicles. The large proportion of farm vehicles struck in the rear during daylight (24%) as well as night, dawn, or dusk hours (65%), compared with non-farm vehicles (4% and 4%, respectively), suggest factors related to visibility and perception of the farm vehicles' speed that provide a basis for further study.

A population-based study of tractor-related injuries: Regional Rural Injury Study-I (RRIS-I).

Although tractors account for the majority of fatal farming-related injuries, little is known about the magnitude of this problem. The study population in this article was obtained from the five state Regional Rural Injury Study-I (RRIS-I) database that included 3939 farm households and 13,144 persons interviewed during 1990. Rates were calculated for sociodemographic variables and various exposures; logistic regression was used to calculate the relative risks and respective confidence intervals. Among the total farming-related injury events (n = 764), 65 (8.4%) were related to regular tractor (> or = 20 horsepower) use (495 injured persons per 100,000 persons per year). The rates increased incrementally for those persons working between 20 to 39 and 60 to 79 hours per week (range, 529 to 1430 per 100,000 persons). Among the 12 rollover events, there were only three injuries. The majority of injury events occurred while persons were mounting or dismounting the tractor (42%). Although only 7% of the cases were hospitalized, 83% required some type of health care. Among all injured persons, 43% were restricted from regular activities for 1 week or more and 20% were restricted for 1 month or more; 28% continued to have persistent problems. The finding of the large proportion of events associated with activities of mounting and dismounting suggests a need to investigate specific design characteristics of the tractors associated with these events and, in general, the tractors to which the population is exposed.

Machinery-related injuries: regional rural injury study--I (RRIS--I).

Although it is known that farm machinery is a source of serious and catastrophic farm work-related injuries, little is known about the magnitude of, and potential risk factors for, this problem. The study population is from the five-state Regional Rural Injury Study--I (RRIS--I) that included 3,939 farm households and 13,144 persons who were interviewed about their injury experience and farming operation-related exposures during 1990. Rates were calculated for sociodemographic variables and various exposures pertinent to large farm machinery (excluding tractors). Multivariate analyses were conducted using logistic regression, based on a model developed a priori and further confirmed using backward stepwise logistic regression. Among the total farming-related injury events (n = 764), 151 (20%) were related to large machinery use (1,127 injured persons per 100,000 persons per year). Through multivariate analyses, several variables were associated with elevated rate ratios that were important in both models: hours worked per week on the farm (40-59, 60-79, 80+); operation of an auger; field crops as the enterprise requiring the most time; and male gender. In addition, in the backward stepwise model, certain marital status categories (married; separated/widowed/divorced) were also associated with elevated rate ratios that were important. The majority of injury events occurred while persons were lifting, pushing, or pulling (21%), adjusting a machine (20%), or repairing a machine (17%). While only 5% of the cases were hospitalized, 79% required some type of health care. Among all injured persons, 34% were restricted from regular activities for 1 week or more and 19% were restricted for 1 month or more; 25% continued to have persistent problems. In summary, the RRIS-I permitted one of the most comprehensive studies of agricultural machinery-related injuries, to date. The findings indicate that these injuries represent a significant problem, based on the relevant rates, potential risk factors, and consequences from trauma.

[The importance of the canine model in medical genetics]. / Intérêt du modèle canin pour la génétique médicale.

Dog domestication dates back to as early as 100,000 years ago, or 10,000 years depending upon the data used, and nowadays more than 350 breeds are duly registered in the different kennel clubs around the world. Due to intensive selection in the course of breeding, dog presently comes in any shape, size, color one can imagine, in addition to displaying a wide panel of characters, capacities and behaviours. As a consequence of excessive breeding, numerous breeds are plagued by a large variety of genetic diseases, many of them resembling those observed in human. All this makes dog an attractive model to track down genes and alleles responsible for those phenotypic behavioural or pathological traits, provided a genome map with polymorphic markers, and genes is available.

Health care for the uninsured in Duluth.

Providing health care for Minnesota's uninsured population continues to be both a clinical and political challenge. Between October 1, 1991, and September 30, 1993, 1,260 previously uninsured people received charity health care in Duluth. No one was excluded because of pre-existing conditions. Their utilization of services and associated costs can help project the health care needs and costs of care for uninsured Minnesotans. This group of uninsured people used a different mix of health care services compared with insured Minnesotans, and their total costs (including prescriptions) were about 15% greater. A large proportion of these uninsured Minnesotans had chronic health conditions and a "pent-up need" for services and medications. This experience demonstrated that it is possible to administer a limited benefits plan in coordination with existing public and private resources.

Community-based screening for childhood lead poisoning. Identification of risk factors and susceptible populations in Duluth.

The purpose of this matched case-controlled study was to identify local risk factors and susceptible populations for childhood lead poisoning in Duluth, Minnesota. We mailed questionnaires to the parents of 20 children with known elevated capillary lead levels > or = 10 micrograms/dL; 76 age-matched controls had capillary lead levels < 10 micrograms/dL. The study identified these risk factors for elevated capillary lead levels in children: not attending daycare, having nonwhite parents, living in rental property in central Duluth, and moving with family three or more times in the previous five years. We conclude that these risk factors are related to socioeconomics. Minority children and children living in poverty in the Duluth area should be screened for lead poisoning according to the Centers for Disease Control and Prevention screening guidelines for high-risk lead exposure.

Agricultural injuries among operation household members: RRIS-II 1999.

The purpose of this study was to determine the magnitude and consequences of agricultural injuries, and to reveal potential risk factors among agricultural household members. The Regional Rural Injury Study (RRIS-II) collected injury and exposure data on agricultural households of 16,538 people in Minnesota, Wisconsin, North Dakota, South Dakota, and Nebraska for each six-month period of 1999. Adjusted injury rates, consequences, and potential risk factors were identified through analyses. Selection of variables for multivariate analyses was based on a causal model. Injuries reported here occurred while the individuals were involved in activities associated with their own farm or ranch, unless otherwise stated. Estimates of injury rates and the effects of various exposures were derived by Poisson and logistic regression. These models accounted for correlation within both subject and household, and were adjusted for non-response. The rate of agricultural injury to household members on their own operation was 74.5 injuries per 1,000 persons per year. Differences in rates due to age and gender diminished when rates were calculated according to hours worked. Although only 5% of injured persons required in-patient hospitalization, 28% required emergency department treatment, and 84% required some type of professional health care. Moreover, 47% of all injuries required time off from agricultural work, and 7% required time off from non-agricultural work. In multivariate analyses, decreased risks were associated with Minnesota, and increased risks were identified for those with prior injuries and for males.This study provides a basis for further research on agricultural injuries and their prevention.

Atopic eczema unresponsive to evening primrose oil (linoleic and gamma-linolenic acids).

This study was designed to look at the effect of evening primrose oil (linoleic and gamma-linolenic acids) as an oral supplement for patients with atopic eczema. We used a double-blind, blocked crossover design with random assignment of patients to treatment groups. We used Wilcoxon's signed-ranks method of comparing changes during the trial. We observed no significant effect on erythema, scale, excoriation, lichenification, or overall severity in 123 patients with atopic eczema of average severity while they took oral doses of evening primrose oil (2 or 4 gm in children, 6 or 8 gm in adults).

Design and validation of instruments to measure knowledge.

BACKGROUND: Measuring health care providers' learning after they have participated in educational interventions that use experimental designs requires valid, reliable, and practical instruments. METHODS: A literature review was conducted. In addition, experience gained from designing and validating instruments for measuring the effect of an educational intervention informed this process. RESULTS: The eight main steps for designing, validating, and testing the reliability of instruments for measuring learning outcomes are presented. The key considerations and rationale for this process are discussed. Methods for critiquing and adapting existent instruments and creating new ones are offered. CONCLUSIONS: This study may help other investigators in developing valid, reliable, and practical instruments for measuring the outcomes of educational activities.

Characterization of 463 type I markers suitable for dog genome mapping.

In total, 463 canine gene markers were identified and characterized to serve as reagents in canine genome map projects. These markers are distributed over 221 canine gene markers, 139 TOASTs (Traced Orthologous Sequence Tags), 27 canine TOASTs, and 76 huESTs (human Expressed Sequence Tags). Out of 310 canine gene markers, 59%-84% were successfully amplified on dog DNA, the highest rates of success being observed when the exon/intron structure is known. Concerning TOASTs and human ESTs, of the 225 and 300 markers analyzed, 62% and 25% respectively were able to produce a dog positive amplification. As part of an ongoing project to map the canine genome using a dog/hamster radiation hybrid panel, these markers were tested for their specificity on dog versus hamster DNA. Thus 61%, 21%, and 12% of dog gene markers, TOASTs, and huESTs met the criteria required for radiation hybrid mapping, respectively. All of these 463 canine gene markers, however, are available and will be of value to any other mapping strategies.

Risk factors for work-related violent victimization.

This case-control study used the National Crime Victimization Survey database (a national sample of housing addresses) to examine sociodemographic risk factors for becoming a victim of work-related robbery and assault. Cases (N = 267) reported having been violently victimized in the previous 6 months. Controls (N = 1,783) were chosen from all nonvictims of violent crime at the end of the 6-month period. Risk factors varied by type of victimization, and differences were evident between men and women. Men less than 45 years of age had an increased risk for assault [odds ratio (OR) = 2.0-2.7], compared with those 55 years of age and older; and those with a family income of less than $40,000 had an increased risk for assault (OR = 1.7-1.9), compared with those having a family income of $50,000 or more. We found a decreased risk for those with a high school education (OR = 0.6), compared with those with some college education. For women, an increased risk was seen for ages 16-18 years (OR = 3.3) and 25-34 years (OR = 2.3), compared with those 55 years of age or older. Women who were divorced or separated (OR = 4.4) and never-married (OR = 2.1) were at higher risk than women who were married. We found a decreased risk for nonwhites (OR = 0.5), compared with whites.

A whole-genome radiation hybrid map of the dog genome.

A whole genome radiation hybrid (RH) map of the canine genome was constructed by typing 400 markers, including 218 genes and 182 microsatellites, on a panel of 126 radiation hybrid cell lines. Fifty-seven RH groups have been determined with lod scores greater than 6, and 180 framework landmarks were ordered with odds greater than 1000:1. Average spacing between adjacent markers is 23 cR5000, an estimated physical distance of 3.8 Mb. Fourteen groups have been assigned to 9 of the canine chromosomes, and a comparison of RH and genetic groups allowed the successful bridging of both types of data on one map composed of 31 RH and 13 syntenic RH groups. Comparison of canine, human, mouse, and pig maps underlined regions of conserved synteny. This integrated map, covering an estimated 80% of the dog genome, should prove a powerful tool for localizing and identifiying genes implicated in pathological and phenotypical traits.