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Objectives. Diagnostic errors are a known patient safety concern across all clinical settings, including the emergency department (ED). We conducted a systematic review to determine the most frequent diseases and clinical presentations associated with diagnostic errors (and resulting harms) in the ED, measure error and harm frequency, as well as assess causal factors. Methods. We searched PubMed®, Cumulative Index to Nursing and Allied Health Literature (CINAHL®), and Embase® from January 2000 through September 2021. We included research studies and targeted grey literature reporting diagnostic errors or misdiagnosis-related harms in EDs in the United States or other developed countries with ED care deemed comparable by a technical expert panel. We applied standard definitions for diagnostic errors, misdiagnosis-related harms (adverse events), and serious harms (permanent disability or death). Preventability was determined by original study authors or differences in harms across groups. Two reviewers independently screened search results for eligibility; serially extracted data regarding common diseases, error/harm rates, and causes/risk factors; and independently assessed risk of bias of included studies. We synthesized results for each question and extrapolated U.S. estimates. We present 95 percent confidence intervals (CIs) or plausible range (PR) bounds, as appropriate. Results. We identified 19,127 citations and included 279 studies. The top 15 clinical conditions associated with serious misdiagnosis-related harms (accounting for 68% [95% CI 66 to 71] of serious harms) were (1) stroke, (2) myocardial infarction, (3) aortic aneurysm and dissection, (4) spinal cord compression and injury, (5) venous thromboembolism, (6/7 – tie) meningitis and encephalitis, (6/7 – tie) sepsis, (8) lung cancer, (9) traumatic brain injury and traumatic intracranial hemorrhage, (10) arterial thromboembolism, (11) spinal and intracranial abscess, (12) cardiac arrhythmia, (13) pneumonia, (14) gastrointestinal perforation and rupture, and (15) intestinal obstruction. Average disease-specific error rates ranged from 1.5 percent (myocardial infarction) to 56 percent (spinal abscess), with additional variation by clinical presentation (e.g., missed stroke average 17%, but 4% for weakness and 40% for dizziness/vertigo). There was also wide, superimposed variation by hospital (e.g., missed myocardial infarction 0% to 29% across hospitals within a single study). An estimated 5.7 percent (95% CI 4.4 to 7.1) of all ED visits had at least one diagnostic error. Estimated preventable adverse event rates were as follows: any harm severity (2.0%, 95% CI 1.0 to 3.6), any serious harms (0.3%, PR 0.1 to 0.7), and deaths (0.2%, PR 0.1 to 0.4). While most disease-specific error rates derived from mainly U.S.-based studies, overall error and harm rates were derived from three prospective studies conducted outside the United States (in Canada, Spain, and Switzerland, with combined n=1,758). If overall rates are generalizable to all U.S. ED visits (130 million, 95% CI 116 to 144), this would translate to 7.4 million (PR 5.1 to 10.2) ED diagnostic errors annually; 2.6 million (PR 1.1 to 5.2) diagnostic adverse events with preventable harms; and 371,000 (PR 142,000 to 909,000) serious misdiagnosis-related harms, including more than 100,000 permanent, high-severity disabilities and 250,000 deaths. Although errors were often multifactorial, 89 percent (95% CI 88 to 90) of diagnostic error malpractice claims involved failures of clinical decision-making or judgment, regardless of the underlying disease present. Key process failures were errors in diagnostic assessment, test ordering, and test interpretation. Most often these were attributed to inadequate knowledge, skills, or reasoning, particularly in “atypical” or otherwise subtle case presentations. Limitations included use of malpractice claims and incident reports for distribution of diseases leading to serious harms, reliance on a small number of non-U.S. studies for overall (disease-agnostic) diagnostic error and harm rates, and methodologic variability across studies in measuring disease-specific rates, determining preventability, and assessing causal factors. Conclusions. Although estimated ED error rates are low (and comparable to those found in other clinical settings), the number of patients potentially impacted is large. Not all diagnostic errors or harms are preventable, but wide variability in diagnostic error rates across diseases, symptoms, and hospitals suggests improvement is possible. With 130 million U.S. ED visits, estimated rates for diagnostic error (5.7%), misdiagnosis-related harms (2.0%), and serious misdiagnosis-related harms (0.3%) could translate to more than 7 million errors, 2.5 million harms, and 350,000 patients suffering potentially preventable permanent disability or death. Over two-thirds of serious harms are attributable to just 15 diseases and linked to cognitive errors, particularly in cases with “atypical” manifestations. Scalable solutions to enhance bedside diagnostic processes are needed, and these should target the most commonly misdiagnosed clinical presentations of key diseases causing serious harms. New studies should confirm overall rates are representative of current U.S.-based ED practice and focus on identified evidence gaps (errors among common diseases with lower-severity harms, pediatric ED errors and harms, dynamic systems factors such as overcrowding, and false positives). Policy changes to consider based on this review include: (1) standardizing measurement and research results reporting to maximize comparability of measures of diagnostic error and misdiagnosis-related harms; (2) creating a National Diagnostic Performance Dashboard to track performance; and (3) using multiple policy levers (e.g., research funding, public accountability, payment reforms) to facilitate the rapid development and deployment of solutions to address this critically important patient safety concern.

The branchiobdellidan slide collection of Professor Hideji Yamaguchi was rediscovered in 1995; however, all of the written records associated with it appear to have been lost. The slide collection has been examined, cataloged and deposited in the Invertebrate Collection of the Hokkaido University Museum, Sapporo, Japan (ICHAM). The collection was found to contain whole mounted specimens of all 17 species described by Prof. Yamaguchi, together with specimens of three other Oriental species described after his death. In addition, mounted specimens of some of these species were designated syntypes. Many sectioned and stained specimens were also cataloged, but those were not identified to species at this time.

Purpose This pilot study was done to determine the feasibility and accuracy of University of Florida/National Cancer Institute (UF/NCI) phantoms and Monte Carlo (MC) retrospective dosimetry and had two aims: (1) to determine the anatomic accuracy of UF/NCI phantoms by comparing 3D organ doses in National Wilms Tumor Study (NWTS) patient-matched UF/NCI phantoms to organ doses in corresponding patient-matched CT scans and (2) to compare infield and out-of-field organ dosimetry using two dosimetry methods-standard radiation therapy (RT) treatment planning systems (TPS) and MC dosimetry in these two anatomic models. Methods Twenty NWTS patient-matched Digital Imaging and Communications in Medicine (DICOM) files of UF/NCI phantoms and CT scans were imported into the Pinnacle RT TPS. The NWTS RT fields (whole abdomen, flank, whole lung, or a combination) and RT doses (10-45 Gy) were reconstructed in both models. Both TPS and MC dose calculations were performed. For aim 1, the mean doses to the heart, kidney, thyroid gland, testes, and ovaries using TPS and MC in both models were statistically compared. For aim 2, the TPS and MC dosimetry for these organs in both models were statistically compared. Results For aim 1, there was no significant difference between phantom and CT scan dosimetry for any of the organs using either TPS or MC dosimetry. For aim 2, there was a significant difference between TPS and MC dosimetry for both CT scan and phantoms for all organs. Although the doses for infield organs were similar for both TPS and MC, the doses for near-field and out-of-field organs were consistently higher for 90% to 100% of MC doses; however, the absolute dose difference was small ( Conclusions This pilot study has demonstrated that the patient-matched UF/NCI phantoms together with MC dosimetry is an accurate model for performing retrospective 3D dosimetry in large-scale epidemiology studies such as the NWTS.

BACKGROUND The standard treatment of pulmonary metastases in patients with Wilms tumor (WT) includes 12-gray radiotherapy (RT) to the entire chest. To the authors' knowledge, the risk of breast cancer (BC) in a large cohort of female survivors of WT has not previously been reported. METHODS A total of 2492 female participants in National Wilms Tumor Studies 1 through 4 (1969-1995) were followed from age 15 years through the middle of 2013 for incident BC. The median age at the time of last contact was 27.3 years. The authors calculated cumulative risk at age 40 years (CR40), hazard ratios (HR) by Cox regression, standardized incidence ratios (SIRs) relative to US population rates, and 95% confidence intervals (95% CIs). RESULTS The numbers of survivors with invasive BC divided by the numbers at risk were 16 of 369 (CR40, 14.8% [95% CI, 8.7-24.5]) for women who received chest RT for metastatic WT, 10 of 894 (CR40, 3.1% [95% CI, 1.3-7.41]) for those who received only abdominal RT, and 2 of 1229 (CR40, 0.3% [95% CI, 0.0-2.3]) for those who received no RT. The SIRs for these 3 groups were 27.6 (95% CI, 16.1-44.2) based on 5010 person-years (PY) of follow-up, 6.0 (95% CI, 2.9-11.0) based on 13,185 PY of follow-up, and 2.2 (95% CI, 0.3-7.8) based on 13,560 PY of follow-up, respectively. The risk was high regardless of the use of chest RT among women diagnosed with WT at age ≥10 years, with 9 of 90 women developing BC (CR40, 13.5% [95% CI, 5.6-30.6]; SIR, 23.6 [95% CI, 10.8-44.8] [PY, 1463]). CONCLUSIONS Female survivors of WT who were treated with chest RT had a high risk of developing early BC, with nearly 15% developing invasive disease by age 40 years. Current guidelines that recommend screening only those survivors who received ≥20 Gy of RT to the chest might be reevaluated. Cancer 2014;120:3722–3730. © 2014 American Cancer Society.

BACKGROUND Intra-operative tumor spill increases the risk of local recurrence of Wilms tumor, and adversely impacts relapse-free (RFS) and overall survival (OS) rates.

Purpose This study was undertaken to evaluate the incidence of pulmonary disease among patients treated with radiation therapy (RT) for pulmonary metastases (PM) from Wilms tumor (WT). Patients and Methods We reviewed records of 6,449 patients treated on National Wilms Tumor Studies-1, -2, -3, and -4 whose flow sheets or annual status reports documented one of several pulmonary conditions. Cases were fully evaluable if pulmonary function test (PFT) results were available, pulmonary fibrosis was identified on a chest radiograph or was listed as the primary or a contributing factor to death. Partially evaluable cases were those for whom PFT results could not be obtained. We evaluated the relationship between RT factors and the occurrence of pulmonary disease using hazard ratios (HRs) and cumulative incidence, treating death as a competing risk. Results Sixty-four fully evaluable and 16 partially evaluable cases of pulmonary disease were identified. The cumulative incidence of pulmonary disease at 15 years since WT diagnosis was 4.0% (95% confidence interval [CI] 2.6–5.4%) among fully evaluable and 4.8% (95% CI 3.3–6.4%) among fully and partially evaluable patients who received lung RT for PM at initial diagnosis. Rates of pulmonary disease were substantially higher among those who received lung RT for PM present at initial diagnosis or relapse compared to those who received no RT or only abdominal RT (HR 30.2, 95% CI 16.9–53.9). Conclusion The risk of pulmonary disease must be considered in evaluating the risk:benefit ratio of lung RT for the management of PM from WT. Pediatr Blood Cancer 2013;60:1721–1726. © 2013 Wiley Periodicals, Inc.

We assessed risk factors for end stage renal disease in patients with Wilms tumor without known WT1 related syndromes. We hypothesized that patients with characteristics suggestive of a WT1 etiology (early onset, stromal predominant histology, intralobar nephrogenic rests) would have a higher risk of end stage renal disease due to chronic renal failure. We predicted a high risk of end stage renal disease due to progressive bilateral Wilms tumor in patients with metachronous bilateral disease.End stage renal disease was ascertained in 100 of 7,950 nonsyndromic patients enrolled in a National Wilms Tumor Study during 1969 to 2002. Risk factors were evaluated with cumulative incidence curves and proportional hazard regressions.The cumulative incidence of end stage renal disease due to chronic renal failure 20 years after Wilms tumor diagnosis was 0.7%. For end stage renal disease due to progressive bilateral Wilms tumor the incidence was 4.0% at 3 years after diagnosis in patients with synchronous bilateral Wilms tumor and 19.3% in those with metachronous bilateral Wilms tumor. For end stage renal disease due to chronic renal failure stromal predominant histology had a HR of 6.4 relative to mixed (95% CI 3.4, 11.9; p0.001), intralobar rests had a HR of 5.9 relative to no rests (95% CI 2.0, 17.3; p=0.001), and Wilms tumor diagnosis at less than 24 months had a HR of 1.7 relative to 24 to 48 months and 2.8 relative to greater than 48 months (p=0.003 for trend).Metachronous bilateral Wilms tumor is associated with high rates of end stage renal disease due to surgery for progressive Wilms tumor. Characteristics associated with a WT1 etiology markedly increased the risk of end stage renal disease due to chronic renal failure despite the low risk in non-WT1 syndromic cases overall.

The National Lung Screening Trial (NLST) is a randomized multicenter study comparing low-dose helical computed tomography (CT) with chest radiography in the screening of older current and former heavy smokers for early detection of lung cancer, which is the leading cause of cancer-related death in the United States. Five-year survival rates approach 70% with surgical resection of stage IA disease; however, more than 75% of individuals have incurable locally advanced or metastatic disease, the latter having a 5-year survival of less than 5%. It is plausible that treatment should be more effective and the likelihood of death decreased if asymptomatic lung cancer is detected through screening early enough in its preclinical phase. For these reasons, there is intense interest and intuitive appeal in lung cancer screening with low-dose CT. The use of survival as the determinant of screening effectiveness is, however, confounded by the well-described biases of lead time, length, and overdiagnosis. Despite previous attempts, no test has been shown to reduce lung cancer mortality, an endpoint that circumvents screening biases and provides a definitive measure of benefit when assessed in a randomized controlled trial that enables comparison of mortality rates between screened individuals and a control group that does not undergo the screening intervention of interest. The NLST is such a trial. The rationale for and design of the NLST are presented.

Purpose This study was undertaken to evaluate the effect of prior treatment with radiation therapy or chemotherapy for unilateral Wilms tumor (WT) diagnosed during childhood on pregnancy complications, birth weight, and the frequency of congenital malformations in live-born offspring. Patients and Methods We reviewed pregnancy outcomes among female survivors and partners of male survivors of WT treated on National Wilms Tumor Studies 1, 2, 3, and 4 by using a maternal questionnaire and a review of both maternal and offspring medical records. Results We received reports of 1,021 pregnancies with duration of 20 weeks or longer, including 955 live-born singletons, for whom 700 sets of maternal and offspring medical records were reviewed. Rates of hypertension complicating pregnancy (International Classification of Diseases [ICD] code 642), early or threatened labor (ICD-644) and malposition of the fetus (ICD-652) increased with increasing radiation dose in female patients. The percentages of offspring weighing less than 2,500 g at birth and of those having less than 37 weeks of gestation also increased with dose. There was no significant trend with radiation dose in the number of congenital anomalies recorded in offspring of female patients. Conclusion Women who receive flank radiation therapy as part of the treatment for unilateral WT are at increased risk of hypertension complicating pregnancy, fetal malposition, and premature labor. The offspring of these women are at risk for low birth weight and premature (ie, < 37 weeks gestation) birth. These risks must be considered in the obstetrical management of female survivors of WT.

Background CT scan measures of emphysema and airway disease have been correlated with lung function in cohorts of subjects with a range of COPD severity. The contribution of CT scan-assessed airway disease to objective measures of lung function and respiratory symptoms such as dyspnea in severe emphysema is less clear. Methods Using data from 338 subjects in the National Emphysema Treatment Trial (NETT) Genetics Ancillary Study, densitometric measures of emphysema using a threshold of −950 Hounsfield units (%LAA-950) and airway wall phenotypes of the wall thickness (WT) and the square root of wall area (SRWA) of a 10-mm luminal perimeter airway were calculated for each subject. Linear regression analysis was performed for outcome variables FEV 1 and percent predicted value of FEV 1 with CT scan measures of emphysema and airway disease. Results In univariate analysis, there were significant negative correlations between %LAA-950 and both the WT ( r = −0.28, p = 0.0001) and SRWA ( r = −0.19, p = 0.0008). Airway wall thickness was weakly but significantly correlated with postbronchodilator FEV 1 % predicted (R = −0.12, p = 0.02). Multivariate analysis showed significant associations between either WT or SRWA (β = −5.2, p = 0.009; β = −2.6, p = 0.008, respectively) and %LAA-950 (β = −10.6, p = 0.03) with the postbronchodilator FEV 1 % predicted. Male subjects exhibited significantly thicker airway wall phenotypes (p = 0.007 for WT and p = 0.0006 for SRWA). Conclusions Airway disease and emphysema detected by CT scanning are inversely related in patients with severe COPD. Airway wall phenotypes were influenced by gender and associated with lung function in subjects with severe emphysema.

We sought to assess accurately the full spectrum of end stage renal disease (ESRD) in Wilms tumor survivors by combining the unique resources of the National Wilms Tumor Study Group (NWTSG) and the United States Renal Data System (USRDS), and to confirm preliminary reports of an increased incidence of ESRD in patients with the Wilms tumor-aniridia syndrome (WAGR).ESRD was ascertained in 5,910 patients enrolled in NWTSG studies during 1969 to 1994 by record linkage to USRDS and by direct followup. Cumulative ESRD incidence was estimated accounting for intercurrent mortality.Of 115 cases of ESRD 10 (9%) were ascertained by the NWTSG alone, 13 (11%) by USRDS alone and 92 (80%) by both. Cumulative incidence of ESRD at 20 years from diagnosis of unilateral Wilms tumor was 74% for 17 patients with the Denys-Drash syndrome, 36% for 37 patients with WAGR, 7% for 125 male patients with hypospadias or cryptorchidism (genitourinary [GU] anomalies) and 0.6% for 5,347 patients with none of these conditions. The incidence of ESRD after diagnosis of bilateral Wilms tumor was 50% for the Denys-Drash syndrome (6 patients), 90% for WAGR (10), 25% for GU anomaly (25) and 12% for other (409). ESRD in patients with WAGR or GU anomalies tended to occur relatively late, often during or after adolescence.The risk of ESRD is remarkably low for the majority of patients with Wilms tumor. However, those with WAGR or associated GU anomalies are at higher risk and should be screened indefinitely to facilitate prospective treatment of impaired renal function.

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.

The standard treatment of pulmonary metastases in patients with Wilms tumor (WT) includes 12-gray radiotherapy (RT) to the entire chest. To the authors' knowledge, the risk of breast cancer (BC) in a large cohort of female survivors of WT has not previously been reported.A total of 2492 female participants in National Wilms Tumor Studies 1 through 4 (1969-1995) were followed from age 15 years through the middle of 2013 for incident BC. The median age at the time of last contact was 27.3 years. The authors calculated cumulative risk at age 40 years (CR40), hazard ratios (HR) by Cox regression, standardized incidence ratios (SIRs) relative to US population rates, and 95% confidence intervals (95% CIs).The numbers of survivors with invasive BC divided by the numbers at risk were 16 of 369 (CR40, 14.8% [95% CI, 8.7-24.5]) for women who received chest RT for metastatic WT, 10 of 894 (CR40, 3.1% [95% CI, 1.3-7.41]) for those who received only abdominal RT, and 2 of 1229 (CR40, 0.3% [95% CI, 0.0-2.3]) for those who received no RT. The SIRs for these 3 groups were 27.6 (95% CI, 16.1-44.2) based on 5010 person-years (PY) of follow-up, 6.0 (95% CI, 2.9-11.0) based on 13,185 PY of follow-up, and 2.2 (95% CI, 0.3-7.8) based on 13,560 PY of follow-up, respectively. The risk was high regardless of the use of chest RT among women diagnosed with WT at age ≥10 years, with 9 of 90 women developing BC (CR40, 13.5% [95% CI, 5.6-30.6]; SIR, 23.6 [95% CI, 10.8-44.8] [PY, 1463]).Female survivors of WT who were treated with chest RT had a high risk of developing early BC, with nearly 15% developing invasive disease by age 40 years. Current guidelines that recommend screening only those survivors who received ≥20 Gy of RT to the chest might be reevaluated.

To provide guidelines for future trials, we reviewed the outcomes of children with synchronous bilateral Wilms tumors (BWT) treated on National Wilms Tumor Study-4 (NWTS-4).NWTS-4 enrolled 3335 patients including 188 patients with BWT (5.6%). Treatment and outcome data were collected.Among 188 BWT patients registered with NWTS-4, 195 kidneys in 123 patients had initial open biopsy, 44 kidneys in 31 patients had needle biopsies. Although pre-resection chemotherapy was recommended, 87 kidneys in 83 patients were managed with primary resection: Complete nephrectomy 48 in 48 patients, 31 partial/wedge nephrectomies in 27 patients, enucleations 8 in 8 patients. No initial surgery was performed in 45 kidneys in 43 patients, 5 kidneys in 3 patients not coded. Anaplasia was diagnosed after completion of the initial course of chemotherapy in 14 patients (initial surgical procedure: 9 open biopsies, 4 needle biopsies, 1 partial nephrectomy). The average number of days from the start of chemotherapy to diagnosis of anaplasia was 390 (range 44-1925 days). Relapse or progression of disease occurred in 54 children. End stage renal failure occurred in 23 children, 6 of whom had bilateral nephrectomies. The 8 year event free survival for BWT with favorable histology was 74%, and overall survival was 89%; whereas the event free survival for BWT with unfavorable histology was 40%, overall survival was 45%.The current analysis of patients with BWT treated on NWTS-4 shows that preservation of renal parenchyma is possible in many patients after initial preoperative chemotherapy. The incidence of end-stage renal disease remains significantly higher in children with BWT. Future studies are warranted to address the need for earlier biopsy in nonresponsive tumors and earlier definitive surgery to recognize unfavorable histology in these high-risk patients.

A combined cohort of 8,884 North American, 2,893 British and 1,574 Nordic subjects with Wilms tumor (WT) diagnosed before 15 years of age during 1960–2004 was established to determine the risk of secondary malignant neoplasms (SMN). After 169,641 person-years (PY) of observation through 2005, 174 solid tumors (exclusive of basal cell carcinomas) and 28 leukemias were ascertained in 195 subjects. Median survival time following a solid SMN diagnosis 5 years or more from WT was 11 years; it was 10 months for all leukemia. Age-specific incidence of secondary solid tumors increased from approximately 1 case per 1,000 PY at age 15 to 5 cases per 1,000 PY at age 40. The cumulative incidence of solid tumors at age 40 for subjects who survived free of SMNs to age 15 was 6.7%. Leukemia risk, by contrast, was highest during the first 5 years following WT diagnosis. Standardized incidence ratios (SIRs) for solid tumors and leukemias were 5.1 and 5.0, respectively. Results for solid tumors for the 3 geographic areas were remarkably consistent; statistical tests for differences in incidence rates and SIRs were all negative. Age-specific incidence rates and SIRs for solid tumors were lower for patients whose WT was diagnosed after 1980, though the trends with decade of diagnosis were not statistically significant. Incidence rates and SIRs for leukemia were highest among those diagnosed after 1990 (p-trend =0.003). These trends may reflect the decreasing use of radiation therapy and increasing intensity of chemotherapy in modern protocols for treatment of WT.

Purpose This analysis was undertaken to determine the cumulative risk of and risk factors for portal hypertension (PHTN) in patients with Wilms' tumor (WT). Methods and Materials Medical records were reviewed to identify cases of PHTN identified with late liver/spleen/gastric toxicities in a cohort of 5,195 patients treated with National Wilms' Tumor Studies (NWTS) protocols 1 to 4. A nested case control study (5 controls/case) was conducted to determine relationships among doxorubicin, radiation therapy (RT) dose to the liver, patient gender, and PHTN. Conditional logistic regression was used to estimate adjusted hazard ratios (HR) of PHTN associated with these factors. Results Cumulative risk of PHTN at 6 years from WT diagnosis was 0.7% for patients with right-sided tumors vs. 0.1% for those with left-sided tumors ( p = 0.002). Seventeen of 19 cases were evaluable for RT. The majority of cases (16/17 [94%]) received right-flank RT either alone or as part of whole-abdomen RT and received >15 Gy to the liver. Fifteen of 17 (88%) patients received a higher dose to the liver than they would have with modern WT protocols. Controlling for RT dose, the HR was 3.0 for patients who received doxorubicin ( p = 0.32) and 2.8 for females ( p = 0.15). Controlling for doxorubicin, the 95% lower confidence bound on the HR associating PHTN with a minimum liver RT dose of >15 Gy vs. ≤15 Gy was 2.5 ( p = 0.001); it was 2.4 for a maximum liver dose of >15 Gy vs. ≤15 Gy ( p = 0.001). Conclusions There was a strong association between higher doses of liver RT (>15 Gy) and the development of PHTN among WT patients.

Purpose To assess rates and causes of mortality in patients with Wilms tumor (WT). Methods Through 2002, 6,185 patients enrolled onto the National Wilms Tumor Study between 1969 and 1995 were actively observed. Deaths were classified on the basis of medical records as the result of original disease, late effects (including second malignant neoplasms [SMNs], cardiac causes, pulmonary disease, and renal failure), or other causes. Standardized mortality ratios (SMRs) and Cox regression were used to assess the effects of sex, age, and calendar period of diagnosis on mortality. Results Within 5 years of WT diagnosis, 819 deaths occurred, and 159 deaths occurred among 4,972 known 5-year survivors. The SMR was 24.3 (95% CI, 22.6 to 26.0) for the first 5 years, was 12.6 (95% CI, 10.0 to 15.7) for the next 5 years, and remained greater than 3.0 thereafter. For deaths in the first 5 years, the mortality risk decreased by 5-year calendar period of diagnosis (rate ratio [RR] = 0.78 per period). No such trend occurred for later deaths. Among 5-year survivors, 62 deaths were attributed to late effects of treatment or disease, including 27 to SMNs. A trend of decreased risk with calendar period of diagnosis was observed for late-effects mortality (RR = 0.86; 95% CI, 0.67 to 1.10) and for SMN mortality (RR = 0.82; 95% CI, 0.55 to 1.21). Conclusion Although the survival outlook for WT patients has improved greatly over time, survivors remain at elevated risk for death many years after their original diagnosis.

Purpose: In children undergoing nephrectomy for Wilms tumor exploration of the contralateral kidney has been recommended to detect occult tumors missed on preoperative evaluation. In this review of the National Wilms Tumor Study (NWTS) 4 cases of bilateral Wilms tumors (BWT) we evaluate incidence and outcome of missed bilateral lesions. Materials and Methods: NWTS-4 enrolled 3,335 patients from August 1986 through September 1994. There were 188 patients with BWT or 5.6% of the total registered. The operative records, pathology and imaging reports were reviewed. Results: In 11 cases synchronous BWT was diagnosed at surgical exploration, which represents 5.9% of the bilateral cases but only 0.3% of all NWTS-4 cases. Two patients did not undergo preoperative imaging and were excluded from analysis. The size of the missed lesions was less than 1 cm in 6 patients and 1 to 2 cm in 3. Computerized tomography was performed in all patients except one who entered early in the study. Management of missed lesions included enucleation in 2 cases, biopsy in 6 and no surgery in 1. No patient underwent irradiation. The postoperative chemotherapy regimen consisted of doxorubicin, dactinomycin and vincristine in 6 children, and dactinomycin and vincristine in 3. Median followup was 9 years. There were no recurrences in any kidney with a missed lesion. All 9 patients were alive and disease-free at last followup. Conclusions: Routine contralateral renal exploration will identify few occult tumors not detected on preoperative imaging. Omission of routine exploration will not likely affect the outcome or management of newly diagnosed Wilms tumor provided preoperative computerized tomography or magnetic resonance imaging is performed. The outcome in these patients was excellent.

Purpose This report describes the pregnancy outcomes among 7 survivors of childhood Wilms tumor, who were treated on one of the National Wilms Tumor Studies (NWTS) with radiation therapy (RT) portals that extended beyond the flank. Methods and materials Pregnancy outcomes among female survivors of childhood Wilms tumor treated with abdominal irradiation in NWTS 1–4 were analyzed as part of the long-term follow-up study. Medical records and maternal questionnaires were used to gather information on pregnancy outcomes. Results A total of 130 patients received abdominal RT and survived to at least 15 years of age. Seven patients (5.4%) had at least 1 recorded pregnancy. The extent of RT fields was ascertained in 126 patients. For 4 patients, the extent of RT fields could not be determined. Twelve girls received RT using portals that included the upper abdomen but not the entire pelvis. Ten pregnancies were recorded in 5 of these patients; 9 resulted in live births, and 1 resulted in a miscarriage. One hundred fourteen girls received RT using portals that included the entire abdomen and pelvis. The abdominal RT dose distribution among these 114 patients was as follows: 9 received 0–10.49 Gy, 22 patients received 10.5–14.99 Gy, and 83 patients received 15+ Gy. Four pregnancies were recorded in 2 of these patients. After 21 Gy to the abdomen and pelvis in 1 patient, all 3 pregnancies resulted in miscarriages and fetal deaths. However, after 10.5 Gy, a normal live birth was reported in the other patient. Pregnancy-related complications were also more common if the RT portals included the pelvis. Conclusions Fertility can be preserved in children with Wilms tumor after upper abdominal RT (10–20 Gy) that does not include the entire pelvis. In rare instances, fertility can be preserved after low-dose whole-abdominal RT (10.5 Gy). The indications and dosages for RT currently used have been greatly refined compared to NWTS-1 and NWTS-2. Childhood Wilms tumor survivors should be considered to be at a high risk for infertility and pregnancy-related complications during their reproductive years. Prompt obstetric evaluation is indicated for optimal prenatal, antenatal, and postnatal care.

Severe von Willebrand disease (VWD) is a rare bleeding disorder with markedly decreased or absent von Willebrand factor (VWF) protein, with a parallel decrease in VWF function and FVIII activity. Patients experience excessive mucosal bleeding, characteristic of VWD, but may also experience joint bleeding, a phenotype more typical of hemophilia A. The CDC sponsored Universal Data Collection (UDC) project collects joint range of motion (ROM) as well as other clinical data on patients with blood disorders followed at Hemophilia Treatment Centers (HTCs) in the U.S. As of 1/07, 253 patients in the UDC were classified as having severe VWD. The goal of this study was to further characterize these patients and assess relations between levels of FVIII/VWF and joint bleeding and function. Methods: To validate the diagnosis of severe VWD, HTCs were contacted to obtain baseline laboratory values. Patients with VWF:Ag < 10%, and consistent VWF:RCo and FVIII levels, were considered to have severe VWD. Of 253 patients, laboratory values were obtained in 201, 162 were confirmed to have severe VWD and 150 had joint ROM data. For the analyses, joint bleeding was categorized as either present or absent at each visit. In addition, the joint function measure was calculated for each patient as the overall proportion of normal joint ROM based on measures taken of 10 joints. Results: The 150 severe VWD subjects consisted of 73 females (49%) and 77 males (51%), with a mean age of 25 yrs (2–75). Racial distribution was Caucasian: 121; African-American: 8; Hispanic: 8, and other: 13. 86/150 gave a family history of a bleeding disorder. 147/150 subjects reported bleeding episodes. Mean age of first documented bleed was 3, but first use of an HTC was not until a mean age of 8. Of the first bleeding episodes, 79 were mucosal, 10 during circumcision, 12 joint, 6 cranial, 7 were from I.M. injections, 21 were other sites, and 12 were unknown. 137/150 subjects had received blood/factor products and 75 had received them at home. 12 subjects had experienced an ICH. Patients with FVIII levels ≤ 5% (n=105) had a lower mean age of first bleed than those with FVIII > 5% (1.5 vs. 6.1 yrs, p=0.0005), but there was no significant association with VWF:Ag level (p=0.08). Lower FVIII and VWF levels were associated with higher risk of joint bleeding [OR 2.95 (p=0.006) and OR 3 (p=0.02), respectively] but not with non-muscle other bleeding. In a longitudinal multivariate analysis, lower FVIII level (p=0.02), increasing age (p Conclusion: Patients with severe VWD in the U.S. have bleeding symptoms beginning at an early age, with mucosal bleeding most common, but also joint and intracranial bleeding, consistent with a severe bleeding phenotype. Our results verify the strong associations between low levels of FVIII and VWF and both joint bleeding and joint function in this disorder. Further analyses will examine whether levels of these proteins are responsible for the phenotypic similarity between severe VWD and hemophilia A.

5'-0-(Dimethoxytrityl)-2'-0-(benzoyl or 3,4,5-trimethoxybenzoyl)-base protected ribonucleosides have been prepared by selective benzoylation of the 2'-hydroxyl group. The isomerization of the 2'-benzoates to the 3'-benzoates was studied. The protected ribonucleosides have been converted to either methylphosphochloridites or methylphosphoamidites and used to synthesize oligoribonucleotides on silica gel solid support. The synthetic RNA were deprotected and isolated using conditions that minimize internucleotide cleavage. The use of 2'-benzoates as protecting groups for ribonucleosides has made it possible to easily prepare and isolate mixtures of DNA and RNA.

The implications of being involved in either the design of changes or the applica tion of a QWL change for four aspects of experienced influence are considered. The results indicate that while organization-wide experiences and perceptions of increased influence occurred, the people who experienced the most increase in influence were those who helped design the change.

A growth hormone releasing factor analog [Leu27,Hse44]GRF(1–44)lactone has been made by recombinant DNA techniques. The peptide was expressed from a multiple–copied GRF gene fused to lacZ. The monomeric GRF peptide analog with a C–terminal homoserine lactone was obtained upon treatment of the isolated fusion protein with cyanogen bromide. The yield of the analog increased with the number of copies fused to β–galactosidase. The C–terminal homoserine moiety was chemically converted to the primary amide, [Leu27,Hse44]GRF(1–44)NH2 and also the n–butyl and n–dodecyl amides, [Leu27, Hse44]GRF(1–44)NHC4H9 and [Leu27,Hse44]GRF(1–44)NHC12H25. The primary amide exhibited a slightly higher releasing activity than the naturally occurring hpGRF(1–44)NH2 whereas the secondary amide analogs had lower activities.

Long term studies of childhood cancer survivors are hampered by difficulties in tracking young adult participants. After performing a National Death Index (NDI) search we sought to identify which factors best predicted a match among known decedents from the National Wilms Tumor Study (NWTS) and to determine if record linkage could substitute for missing follow-up in a cohort of NWTS survivors. To our knowledge, this is the first study to compare passive mortality follow-up using the NDI to active follow-up of a childhood and young adult population.Records for 984 known decedents and 3,406 subjects whose January 1, 2002 vital status was unknown were sent to the NDI in June 2003. In April 2005 NWTS follow-up records were used to reassess January 1, 2002 vital status. Matches were established for 709 of 789 known decedents (sensitivity 89.9%) with a date of death between 1979 and 2001, the calendar period covered by the NDI at the time of the search. No matches were identified among 1,052 subjects known to be alive in 2002 (specificity 100%). Factors associated with decreased sensitivity were an unknown social security number (sensitivity 87.8%), Hispanic ethnicity (76.4%) and foreign birth (56.5%). For 2,351 subjects with 2002 vital status unknown who had 13,166 pre 2002 person-years of missing observation, only 18 deaths were ascertained by the NDI whereas 79.3 were expected based on NWTS mortality data. Mortality analyses based strictly on NDI search results and those based on NWTS follow-up augmented with NDI search results yielded inflated estimates of the 15 year survival rate when compared with estimates based on NWTS active follow-up.Match rates were comparable to those observed in adult populations. Since the same selection factors were likely associated with NDI failure to match and NWTS loss to follow-up, use of the NDI to fill in missing follow-up data appears unwarranted.