Blinatumomab vs historical standard therapy of adult relapsed/refractory acute lymphoblastic leukemia.

We compared outcomes from a single-arm study of blinatumomab in adult patients with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia (R/R ALL) with a historical data set from Europe and the United States. Estimates of complete remission (CR) and overall survival (OS) were weighted by the frequency distribution of prognostic factors in the blinatumomab trial. Outcomes were also compared between the trial and historical data using propensity score methods. The historical cohort included 694 patients with CR data and 1112 patients with OS data compared with 189 patients with CR and survival data in the blinatumomab trial. The weighted analysis revealed a CR rate of 24% (95% CI: 20-27%) and a median OS of 3.3 months (95% CI: 2.8-3.6) in the historical cohort compared with a CR/CRh rate of 43% (95% CI: 36-50%) and a median OS of 6.1 months (95% CI: 4.2-7.5) in the blinatumomab trial. Propensity score analysis estimated increased odds of CR/CRh (OR=2.68, 95% CI: 1.67-4.31) and improved OS (HR=0.536, 95% CI: 0.394-0.730) with blinatumomab. The analysis demonstrates the application of different study designs and statistical methods to compare novel therapies for R/R ALL with historical data.

Occupational trichloroethylene exposure and non-Hodgkin's lymphoma: a meta-analysis and review.

METHODS: Meta-analysis and review of 14 occupational cohort and four case-control studies of workers exposed to trichloroethylene (TCE) to investigate the relation between TCE exposure and the risk of non-Hodgkin's lymphoma (NHL). Studies were selected and categorised based on a priori criteria, and results from random effects meta-analyses are presented. RESULTS: The summary relative risk estimates (SRRE) for the group of cohort studies that had more detailed information on TCE exposure was 1.29 (95% CI 1.00 to 1.66) for the total cohort and 1.59 (95% CI 1.21 to 2.08) for the seven studies that identified a specific TCE exposed sub-cohort. SRREs for three studies with cumulative exposure information were 1.8 (95% CI 0.62 to 5.26) for the lowest exposure category and 1.41 (95% CI 0.61 to 3.23) for the highest category. Comparison of SRREs by levels of TCE exposure did not indicate exposure-response trends. The remaining cohort studies that identified TCE exposure but lacked detailed exposure information had an SRRE of 0.843 (95% CI 0.72 to 0.98). Case-control studies had an SRRE of 1.39 (95% CI 0.62 to 3.10). Statistically significant findings for the Group 1 studies were driven by the results from the subgroup of multiple industry cohort studies (conducted in Europe) (SRRE = 1.86; 95% CI 1.27 to 2.71). The SRRE for single industry cohort studies was not significantly elevated (SRRE = 1.25; 95% CI 0.87 to 1.79). CONCLUSIONS: Interpretation of overall findings is hampered by variability in results across the Group 1 studies, limited exposure assessments, lack of evidence of exposure response trends, lack of supportive information from toxicological and mechanistic data, and absence of consistent findings in epidemiologic studies of exposure and NHL. Although a modest positive association was found in the TCE sub-cohort analysis, a finding attributable to studies that included workers from multiple industries, there is insufficient evidence to suggest a causal link between TCE exposure and NHL.

Weather changes associated with hospitalizations for cardiovascular diseases and stroke in California, 1983-1998.

Poisson regression models were used to evaluate associations between temperature, precipitation, days of extreme heat, and other weather changes (lagged 7 days), as well as El Niño events, with hospitalizations for acute myocardial infarction, angina pectoris, congestive heart failure, and stroke in three California regions. Temperature changes were defined as a 3 degrees C decrease in maximum temperature or a 3 degrees C increase in minimum temperature. Temperature and precipitation were analyzed separately for normal weather periods and El Niño events, and for both weather periods combined. Associations varied by region, age, and gender. In Los Angeles, temperature changes resulted in small changes in hospitalizations. Among San Francisco residents 70+ years of age, temperature changes increased hospitalizations for nearly all outcomes from 6% to 13%. Associations among Sacramento residents were similar to those in San Francisco: among men 70+ years of age, temperature changes increased hospitalizations by 6%-11% for acute myocardial infarction and congestive heart failure, and 10%-18% for stroke. El Niño events were consistently and significantly associated with hospitalizations only in San Francisco and Sacramento, and then only for angina pectoris (increasing hospitalizations during El Niño events). These exploratory analyses merit further confirmation to improve our understanding of how admissions to hospitals for cardiovascular disease and stroke change with changing weather. Such an understanding is useful for developing current public health responses, for evaluating population vulnerability, and for designing future adaptation measures.

Association of normal weather periods and El Niño events with hospitalization for viral pneumonia in females: California, 1983-1998.

OBJECTIVES: This study examined associations between weather and hospitalizations of females for viral pneumonia during normal weather periods and El Niño events in the California counties of Sacramento and Yolo, San Francisco and San Mateo, and Los Angeles and Orange. METHODS: Associations between weather and hospitalizations (lagged 7 days) for January 1983 through June 1998 were evaluated with Poisson regression models. Generalized estimating equations were used to adjust for autocorrelation and overdispersion. Data were summed over 4 days. RESULTS: Associations varied by region. Hospitalizations in San Francisco and Los Angeles increased significantly (30%-50%) with a 5 degrees F decrease in minimum temperature. Hospitalizations in Sacramento increased significantly (25%-40%) with a 5 degrees F decrease in maximum temperature difference. The associations were independent of season. El Niño events were associated with hospitalizations only in Sacramento, with significant decreases for girls and increases for women. CONCLUSIONS: The results suggest that viral pneumonia could continue to be a major public health issue, with a significant association between weather and hospitalizations, even as the global mean temperature continues to rise. An understanding of population sensitivity under different weather conditions could lead to an improved understanding of virus transmission.

Beryllium sensitization, chronic beryllium disease, and exposures at a beryllium mining and extraction facility.

In this study, we examine beryllium sensitization, chronic beryllium disease (CBD), and workplace exposures at a beryllium mining (mine) and extraction facility (mill) in Delta, Utah. Historical airborne beryllium data collected between 1970-1999 included general area (GA), breathing zone (BZ), and personal lapel (LP) measurements and calculations of job-specific quarterly daily-weighted averages (DWVAs). We compared GA, BZ, and DWA data to airborne beryllium data from a mixed beryllium products facility and a beryllium ceramics facility located in Elmore, Ohio and Tucson, Arizona, respectively. At the Delta facility, jobs involving beryllium hydrolysis and wet-grinding activities had the highest air concentrations; annual median GA concentrations were less than 0.3 microg/m3 or both areas. Annual median GA sample concentrations ranged from 0.1-0.4 microg/m(-3) at Delta. These levels were generally lower than Elmore (0.1-1.0 microg/m3) and were comparable to the Tucson facility (0.1-0.4 microg/m3). Median BZ concentrations were higher, whereas DWAs were lower at the Delta facility than at the other two facilities. Among the 87 employees at the Delta facility, 75 participated in the medical survey; there were three persons sensitized, one with CBD. The individual with CBD previously worked at the Elmore facility for 10 years. Cumulative CBD incidence rates were significantly lower at the Delta facility: 0.3 percent compared to 2.0 percent for Elmore and 2.5 percent for the Tucson facility. Sensitization and CBD prevalence rates determined from cross-sectional surveys for the Delta facility were lower than but not significantly different from rates at the other two facilities. There was no sensitization or CBD among those who worked only at the mine where the only exposure to beryllium results from working with bertrandite ore. Although these results are derived from a small sample, this study suggests that the form of beryllium may affect the likelihood of developing CBD. Specifically, exposure to beryl and bertrandite ore dusts or to beryllium salts, in the absence of exposure to beryllium oxide particulates appears to pose a lower risk for developing CBD.

A comparison and critique of historical and current exposure assessment methods for beryllium: implications for evaluating risk of chronic beryllium disease.

The primary beryllium industry has generated a large amount of data on airborne beryllium concentrations that has been used to characterize exposure by task-specific activities, job category, individual worker, and processing area using a variety of methods. These methods have included high-volume breathing zone sampling, high-volume process sampling, high- and low-volume respirable and area sampling, real-time monitoring, and personal sampling. Many of the beryllium studies have used these air sampling methods to assess inhalation exposure and chronic beryllium disease (CBD) risk to beryllium; however, available data do not show a consistent dose-response relationship between airborne concentrations of beryllium and the incidence of CBD. In this article, we describe the air sampling and exposure assessment methods that have been used, review the studies that have estimated worker exposures, discuss the uncertainties associated with the level of beryllium for which these studies have reported an increased risk of CBD, and identify future investigative exposure assessment strategies. Our evaluation indicated that studies of beryllium workers are often not directly comparable because they (1) used a variety of exposure assessment methods that are not necessarily representative of individual worker exposures, (2) rarely considered respirator use, and (3) have not evaluated changes in work practices. It appears that the current exposure metric for beryllium, total beryllium mass, may not be an appropriate measurement to predict the risk of CBD. Other exposure metrics such as mass of respirable particles, chemical form, and particle surface chemistry may be more related to the prevalence of CBD than total mass of airborne beryllium mass. In addition, assessing beryllium exposure by all routes of exposure (e.g., inhalation, dermal uptake, and ingestion) rather than only inhalation exposure in future studies may prove useful.

Development of an occupational illness and injury surveillance database for the electric energy sector.

Currently available occupational injury and illness data for electric energy companies provide only overall summary rates. Specific information about types of injury or illnesses, rates by occupational or work environments, and injury costs and severity are generally not readily available. Relevant data such as personnel and claims information are frequently not integrated into a comprehensive health and safety surveillance system suitable for epidemiologic and health and safety research purposes. Epidemiological methods are valuable for identifying key risk factors for work-related injuries and illnesses and assessing their magnitude, as well establishing priorities for health and safety research. Application of such methods can result in long-term reductions in injury and illness rates and their attendant costs. Aggregation of relevant health and safety data across companies improves statistical power for the assessment of rare (yet costly) injuries or illness or specific at-risk subgroups within the electric energy sector. A pilot occupational injury and illness database has been developed that can incorporate and standardize data across a spectrum of companies of differing sizes and configurations. In illustrative data analyses, injury trends were summarized by company size, occupation, and demographic factors, among others. Trends observed in these illustrative analyses were consistent with results previously reported in the epidemiological literature, however, results are considered preliminary pending development of the full database. This study shows that development of a standardized surveillance occupational injury and illness database across companies with different database configurations is feasible. This database will ultimately provide a stable and accurate occupational health and safety assessment tool not currently available for this sector.

Radiofrequency exposure and mortality from cancer of the brain and lymphatic/hematopoietic systems.

The proliferation of wireless communication technologies has raised public concern regarding potential health effects of radiofrequency (RF) exposures. This is the first report of findings from a large-cohort mortality study among employees of Motorola, a manufacturer of wireless communication products. We examined all major causes of mortality, with brain cancers, lymphomas, and leukemias as a priori outcomes of interest. Using job titles, we classified workers into high, moderate, low, and background RF exposure groups. A total of 195,775 workers contributed 2.7 million person-years during the 1976-1996 period. Using external comparisons, the standardized mortality ratios for RF-exposed workers were 0.53 [95% confidence interval (CI) = 0.21-1.09] and 0.54 (95% CI = 0.33-0.83) for central nervous system/brain cancers and all lymphomas/leukemias. Rate ratios calculated from Poisson regression models based on internal comparisons were near 1.0 for brain cancers and below 1.0 for all lymphomas and leukemias. These findings were consistent across cumulative, peak, and usual exposure classifications. We did not observe higher risk with increased exposure duration or latency. Although this study is limited by the use of a qualitative exposure matrix and the relatively young age of the cohort, our findings do not support an association between occupational RF exposure and brain cancers or lymphoma/leukemia.

A pooled analysis of magnetic fields, wire codes, and childhood leukemia. Childhood Leukemia-EMF Study Group.

We obtained original individual data from 15 studies of magnetic fields or wire codes and childhood leukemia, and we estimated magnetic field exposure for subjects with sufficient data to do so. Summary estimates from 12 studies that supplied magnetic field measures exhibited little or no association of magnetic fields with leukemia when comparing 0.1-0.2 and 0.2-0.3 microtesla (microT) categories with the 0-0.1 microT category, but the Mantel-Haenszel summary odds ratio comparing >0.3 microT to 0-0.1 microT was 1.7 (95% confidence limits = 1.2, 2.3). Similar results were obtained using covariate adjustment and spline regression. The study-specific relations appeared consistent despite the numerous methodologic differences among the studies. The association of wire codes with leukemia varied considerably across studies, with odds ratio estimates for very high current vs low current configurations ranging from 0.7 to 3.0 (homogeneity P = 0.005). Based on a survey of household magnetic fields, an estimate of the U.S. population attributable fraction of childhood leukemia associated with residential exposure is 3% (95% confidence limits = -2%, 8%). Our results contradict the idea that the magnetic field association with leukemia is less consistent than the wire code association with leukemia, although analysis of the four studies with both measures indicates that the wire code association is not explained by measured fields. The results also suggest that appreciable magnetic field effects, if any, may be concentrated among relatively high and uncommon exposures, and that studies of highly exposed populations would be needed to clarify the relation of magnetic fields to childhood leukemia.

The impact of work environment, utility, and sampling design on occupational magnetic field exposure summaries.

Most recent epidemiologic studies investigating the potential health effects of occupational magnetic field (MF) exposure have relied on MF measurement data linked to job titles. These measurements are summarized by occupational categories, which represent similar groups of job titles. However, job titles alone explain only a small proportion of exposure variability. A comprehensive MF occupational exposure database was used to (1) develop summary job-specific estimates of magnetic field exposure, (2) evaluate the impact of incorporating work environment data to improve electric and magnetic field exposure assessment, and (3) evaluate the use of random versus nonrandom sampling when estimating mean MF exposure levels by occupational categories. Uniform classification systems were developed for occupational and work environment data. A factorial design was used to summarize and calculate arithmetic means and 95% confidence intervals for occupational MF data, assuming that the total variation in MF exposure resulted from variation in occupation, work environment, utility, worker, and day. Occupation-specific means varied across different work environments, particularly for craft workers. Although within-worker and between-worker variability account for a large proportion (over 50%) of exposure variation, work environment (24%) accounted for more exposure variability than occupation (4.9%) or utility (15%). Some differences were observed when results were compared from surveys that used random and nonrandom sampling; however, these differences were not consistent or systematic. It was concluded that MF exposure assessment should consider work environment in addition to job title to reduce exposure misclassification.

Mortality of aerospace workers exposed to trichloroethylene.

We measured mortality rates in a cohort of 20,508 aerospace workers who were followed up over the period 1950-1993. A total of 4,733 workers had occupational exposure to trichloroethylene. In addition, trichloroethylene was present in some of the washing and drinking water used at the work site. We developed a job-exposure matrix to classify all jobs by trichloroethylene exposure levels into four categories ranging from "none" to "high" exposure. We calculated standardized mortality ratios for the entire cohort and the trichloroethylene exposed subcohort. In the standardized mortality ratio analyses, we observed a consistent elevation for nonmalignant respiratory disease, which we attribute primarily to the higher background rates of respiratory disease in this region. We also compared trichloroethylene-exposed workers with workers in the "low" and "none" exposure categories. Mortality rate ratios for nonmalignant respiratory disease were near or less than 1.00 for trichloroethylene exposure groups. We observed elevated rare ratios for ovarian cancer among those with peak exposure at medium and high levels] relative risk (RR) = 2.74; 95% confidence interval (CI) = 0.84-8.99] and among women with high cumulative exposure (RR = 7.09; 95% CI = 2.14-23.54). Among those with peak exposures at medium and high levels, we observed slightly elevated rate ratios for cancers of the kidney (RR = 1.89; 95% CI = 0.85-4.23), bladder (RR = 1.41; 95% CI = 0.52-3.81), and prostate (RR = 1.47; 95% CI = 0.85-2.55). Our findings do not indicate an association between trichloroethylene exposure and respiratory cancer, liver cancer, leukemia or lymphoma, or all cancers combined.

Cytogenetic effects in human exposure to arsenic.

The cytogenetic effects of arsenic exposure were studied among rural populations that live in the same geographical area and have similar socioeconomic status, but different degree of exposure to inorganic arsenic (As) via drinking water. A group of inhabitants of Santa Ana (408.17 micrograms/l of As in drinking water) were considered the exposed individuals and a group of inhabitants of Nazareno (29.88 micrograms/l) were considered as controls. Blood and urine samples were obtained from volunteers. Past and current exposure, health, and nutritional status as well as the presence of arsenic skin lesions were ascertained in study participants through questionnaires and physical examination. The frequencies and types of chromosomal aberrations in first-division metaphases were studied in whole blood lymphocyte cultures while the presence of micronuclei (MN) was studied in exfoliated epithelial cells obtained from the oral mucosa and from urine samples. Total arsenic (TAs) content, and the relative proportions of inorganic arsenic (IAs), and the metabolites monomethylarsonic (MMA) and dimethylarsinic (DMA) acid were determined in urine samples. Exposed individuals showed a significant increase in the frequency of chromatid and isochromatid deletions in lymphocytes and of MN in oral and urinary epithelial cells. Males were more affected than females, and a higher number of micronucleated oral cells were found among those individuals with skin lesions. The type of cytogenetic damage observed gives evidence of arsenic as a clastogenic/aneugenic carcinogen.

Mortality among a cohort of electric utility workers, 1960-1991.

Overall mortality trends among an electric utility workforce are examined. The study cohort (n = 40,335) included all workers with at least 1 year of work experience from 1960-1991; 3,753 deaths were observed in this cohort. Standardized mortality ratios (SMRs) and internal cohort analyses were used to assess mortality trends for the entire cohort and for specific occupational groups. Most SMRs were < or = 1.0 and were generally lower for noncancer (cardiovascular, COPD, and injuries) than for cancer mortality. Compared to office staff, rate ratios (RR) were higher for respiratory cancers for field staff [(RR = 2.3, 95% CI, 1.0-5.0) linecrew (RR = 2.2 95% CI, 1.5-3.1), and power plant occupations (RR = 2.4, 95% CI, 1.6-3.6)]. Nonmanagement occupations had rate ratios for motor vehicle injuries and all types of injuries, within a range of 2.5-4.7, with all lower CIs > 1.0. The healthy worker effect is an important factor in explaining the difference between SMR and internal cohort analyses results. The SMR results indicate that this workforce has lower rates for overall mortality, cardiovascular disease, cancer and nonintentional injury. A consistent finding in the internal cohort analyses that merits further research was higher mortality rates for respiratory cancer and injuries among nonoffice staff.

Acute work injuries among electric utility meter readers.

This report provides estimates of incidence rates for acute work injuries for a well defined cohort of electric utility meter readers. Specifically, person-time rates by sex, age, and job experience are evaluated by part of body injured and type of injury. Meter readers experienced 731 acute lost time [11.1 per 100 person-work years; 95% confidence interval (CI) = 10.3-11.9] and 4,401 acute non-lost time (66.5 per 100 person-work years; 95% CI = 64.6-68.5) work injuries over the study period, 1980-1992. Women had nearly twice the lost time injury rate as men (17.5 vs 9.6 per 100 person-work years). There is an inverse relation between job experience and both lost time and non-lost time injuries. Although these data are limited to the electric utility industry, they may be relevant to occupations with similar tasks and environments, including residential gas and water supply industry meter readers and postal carriers.

Acute work injuries among electric utility linemen.

This analysis presents differences in acute work injury rates among electric utility linemen who perform different work tasks. Incidence-density rate ratios were the primary measure of association and are based on the work injury and person-time data for each job title. Logistic regression was used to model race, age, job experience, total inservice, prior injury, and time from prior injury. Transmission linemen had the lower acute injury rate with 18.9 per 100 person-work-years (95% CI 16-20), distribution linemen had 27.8 per 100 person-work-years (95% CI 27-28), and apprentice linemen had 43.3 per 100 person-work-years (95% CI 41-45). Injuries to the trunk and sprains and strains are the predominant injury categories. Having a prior lost time injury increases the risk for subsequent lost time injury for transmission linemen (OR = 1.6, 95% CI = 1.0-2.7) and for distribution linemen (OR = 1.5, 95% CI = 1.3-1.6).

Altered profile of urinary arsenic metabolites in adults with chronic arsenicism. A pilot study.

Relationships between alterations in the profile of urinary arsenic (As) species and the presence of cutaneous signs of arsenicism were studied in Region Lagunera, Mexico. The use of urinary concentrations of putative substrates and products of the As metabolism pathway, as indicators of metabolic efficiency is also discussed. Arsenic was determined by hydride generation atomic absorption spectrophotometry and separation of As species was performed by ion exchange chromatography. The exposed group had an average of 0.408 mg As/l of total As (TAs) in their drinking water, whereas "control' individuals had 0.031 mg/l. Urinary concentrations of arsenic species and TAs were 20 to 95 times higher in the exposed group. Significant increases in the relative proportions of inorganic arsenic (Asi) and monomethylarsonic acid (MMA), accompanied by decreases of dimethylarsinic acid (DMA) were also found in exposed individuals. Therefore, significant decreases in the value of the MMA/Asi, DMA/MMA and DMA/ Asi ratios were observed, suggesting a decreased As methylating ability. Exposed individuals bearing cutaneous signs had a significantly longer time of exposure, higher urinary concentrations and proportions of MMA and MMA/Asi values, and significantly lower DMA/ MMA than exposed individuals without cutaneous signs. Further research is needed to identify better parameters for assessing the efficiency of As metabolism in chronically exposed populations and to confirm the potential relationship between metabolic alterations and overt signs of As toxicity.

Sex differences in work-related injury rates among electric utility workers.

Few epidemiologic studies have evaluated sex differences in work-related injury rates. In this study, the authors examined injury trends by type of injury, severity of injury, and how the injury occurred among a cohort of 9,582 female and 26,898 male electric utility workers employed during 1980-1992 by the Southern California Edison Company. Sex-specific unadjusted injury rates were higher throughout the period for male workers. However, after adjustment for occupation, job experience, and age, elevated rate ratios indicate that female workers have higher injury rates. Mantel-Haenszel summary rate ratios and 95% confidence intervals were 1.49 (1.43-1.54) for all types of injuries, 1.27 (1.16-1.39) for head and neck injuries, 1.48 (1.38-1.58) for upper extremity injuries, 1.11 (1.01-1.21) for back injuries, and 2.11 (1.97-2.25) for lower extremity injuries. The rate ratios were slightly higher for more severe injuries, which suggests that potential reporting bias was not a likely explanation for these findings. The authors conclude that differences between male and female workers in training, physical capacity, task assignments, and other factors could explain these injury trends.

Exposure to 60 Hz magnetic fields in the electric utility work environment.

Research that has attempted to examine the relationship between work exposures to magnetic fields and health effects has suffered from limited exposure information. Power-frequency electric and magnetic (EM) field exposures vary substantially between industries, occupations, and individuals. In this study magnetic field data were collected for a variety of occupational categories within an electric utility. The sampling procedures emphasized craft occupations that were presumed to have higher exposures to magnetic fields. The objectives were to provide better exposure information for an ongoing cancer mortality study, examine the relationship between different summary measures of magnetic field exposure, and make available descriptive information useful for exposure reduction and worker education. Principal components analysis (PCA) and Varimax rotation were used to explore the relationships between the different summary measures among all utility workers and among the subset of electrical craft occupations. Discriminant analysis was used to assess summary measures of exposure that differentiated occupational groups. Measurements for 770 days generated a total of 42378 hours of magnetic field data. Eleven summary indices of exposure were calculated for specific occupational groups. These include arithmetic mean, geometric mean, median, 95th and 99th percentiles, and fraction of measurements exceeding .5, 1, 5, 10, and 100 microT. Electrical craft occupations had higher work exposures than non-craft occupations. Electricians and substation operators had the highest exposures among craft occupations. We identified subsets of summary measures that were intercorrelated. The first PCA axis included the geometric mean, median, and the fractions exceeding 0.5 and 1.0 microT. This set of measures also were best at discriminating occupational groups. The relevance of these findings may become more important if consistent associations are found between particular occupations and disease and particular occupations and magnetic field summary measures. Further research is needed to evaluate these exposure assessment findings.