Cereblon pathway biomarkers and immune profiles in patients with myeloma receiving post-ASCT lenalidomide maintenance (LEOPARD).

LEOPARD was a single arm, phase II study of lenalidomide (LEN) and alternate day prednisolone maintenance in patients with newly diagnosed multiple myeloma (MM) following autologous stem cell transplantation (ASCT). Sixty patients were enrolled. Estimated median potential follow-up was 44 m, median PFS was 38.3 m, median OS was not reached (landmark 36 m OS: 71.4%). Correlative immunohistochemistry performed on pre-ASCT trephines demonstrated high MM tumor cereblon (total/cytoplasmic) was associated with superior OS (p = .045, p = .031, respectively), whereas high c-Myc was associated with inferior PFS (p = .04). Patients with high cereblon (total/nuclear) were more likely to improve depth of response, whereas patients with high c-Myc were less likely, suggesting alternative/more effective post-ASCT strategies for patients with high c-Myc need identification. Peripheral blood immune profiling (mass cytometry) informed a more sustained response to LEN maintenance, demonstrating enrichment of activated/cytotoxic NK cells and cytotoxic T cells in patients with durable responses, contrasting with enrichment of B-regs in early relapsers.

Parental occupational exposures and the risk of childhood sporadic retinoblastoma: a report from the Children's Oncology Group.

OBJECTIVES: We examined associations between parental occupational chemical exposures up to 10 years before conception and the risk of sporadic retinoblastoma among offspring. METHODS: In our multicentre study on non-familial retinoblastoma, parents of 187 unilateral and 95 bilateral cases and 155 friend controls were interviewed by telephone. Exposure information was collected retroactively through a detailed occupational questionnaire that asked fathers to report every job held in the 10 years before conception, and mothers 1 month before and during the index pregnancy. An industrial hygienist reviewed all occupational data and assigned an overall exposure score to each job indicating the presence of nine hazardous agents. RESULTS: We estimated elevated ORs for unilateral and bilateral retinoblastoma among offspring of fathers who were exposed to polycyclic aromatic hydrocarbons or paints in the 10 years before conception. However, only for exposure to paints did confidence limits exclude the null for bilateral disease (OR: 8.76, 95% CI: 1.32 to 58.09). Maternal prenatal exposure to at least one of the nine agents was related to increased risk of unilateral disease in their children (OR: 5.25, 95% CI: 1.14 to 24.16). Fathers exposed to at least one of the nine agents and who were ≥30 years of age were at increased risk of having a child diagnosed with bilateral retinoblastoma (OR: 6.59, 95% CI: 1.34 to 32.42). CONCLUSIONS: Our results suggest a role for several hazardous occupational exposures in the development of childhood retinoblastoma.

Thalidomide and prednisolone versus prednisolone alone as consolidation therapy after autologous stem-cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the ALLG MM6 multicentre, open-label, randomised phase 3 study.

BACKGROUND: We previously showed that consolidation therapy with thalidomide and prednisolone improved progression-free and overall survival in patients with multiple myeloma who had undergone autologous stem-cell transplantation. We aimed to assess whether these survival advantages were durable at 5 years. METHODS: The ALLG MM6 trial was a multicentre, open-label, randomised phase 3 trial done between Jan 13, 2002, and March 15, 2005, at 29 sites in Australia and New Zealand. Patients with newly diagnosed multiple myeloma were randomly assigned (1:1), via computer-generated randomisation charts, to receive indefinite prednisolone maintenance alone (control group) or in combination with 12 months of thalidomide consolidation (thalidomide group) after autologous stem-cell transplantation. Randomisation was stratified by treating centre and pre-transplantation concentrations of ß2 microglobulin. Patients and treating physicians were not masked to treatment allocation. Primary endpoints were progression-free survival and overall survival. Analysis was by intention to treat. Secondary endpoints were overall response to salvage therapy, incidence of second primary malignancy incidence, and cost-effectiveness. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12607000382471. FINDINGS: We randomly assigned 269 patients to the thalidomide (n=114) or control group (n=129). After a median follow-up of 5·4 years (IQR 3·1-7·2), estimated 5-year progression-free survival was 27% (95% CI 23-32) in the thalidomide group and 15% (11-18) in the control group (hazard ratio [HR] 0·16, 95% CI 0·044-0·58; p=0·0054) and 5-year overall survival was 66% (95% CI 61-70) and 47% (42-51), respectively (HR 0·12, 95% CI 0·028-0·56; p=0·0072). There was no difference in overall response to salvage therapy, survival post-progression, or incidence of secondary malignancies between the two groups. Incremental cost-effectiveness ratio was AUS$26 996 per mean life-year gained. INTERPRETATION: Consolidation therapy with thalidomide and prednisolone after autologous stem-cell transplantaion is an acceptable therapeutic approach when alternative drugs are not available. FUNDING: Pharmion Corporation, Novartis Pharmaceuticals, Amgen Australia, The Merrin Foundation, and Alfred Health.

Particle release from respirators, part II: determination of the effect of tension applied in simulation of removal.

This study evaluated the potential for disposable filtering facepiece respirators (hereafter termed masks) contaminated with 1-µ m particles to release particles as a result of lateral tension applied to the mask. The lateral tension was designed to simulate the removal of a contaminated mask from a user's head. Four brands of filtering facepieces were loaded with approximately 20 million 1.0-µ m polystyrene latex (PSL) microspheres. The respirators were then placed in a test chamber and subjected to lateral tension between 17.8-26.7 N (4-6 lbs) for 1 to 2 sec. The findings suggest that neither mask type nor loading condition affects particle release. This supports our hypothesis that when filtering facepiece respirators are properly removed from the head they will not release a significant number of particles.

Particle release from respirators, part I: determination of the effect of particle size, drop height, and load.

In late 2001, some U.S. Postal Service workers and a few members of Congress were exposed to anthrax spores. This led to an increased effort to develop employable methods to protect workers from exposure to anthrax. Some investigations focused on selection and use of respirators to protect workers against airborne anthrax. The present study evaluated the potential for several types of half-mask respirators to release deposited particles. Four brands of the most commonly used filtering facepiece respirators (hereafter termed masks) were loaded with 0.59-µm, 1.0-µm, and 1.9-µm polystyrene latex (PSL) microspheres (nominally 0.6, 1.0, and 2.0 µm) and then dropped onto a rigid surface. The load conditions were 10, 20, or 40 million particles, and drop heights were 0.15, 0.76, and 1.37 m. For the average conditions of 0.76 m, 1.15 µm size and 22 million particles loaded, the average particle release was 0.604 particles per 10,000 (95% CI: .552, .662) particles loaded for all of the filtering facepieces tested. The averaging of conditions is a useful tool to provide generalized information and is also useful when making risk estimates. For most filtering facepiece respirators, particle release tended to increase with drop height and particle size, and there appeared to be a slight inverse relationship with particle load. Two brands of reusable elastomeric half-mask respirators with P100 high-efficiency particulate air (HEPA) filter cartridges were also evaluated. Results of these tests were inconclusive. Part II in this issue addresses the release of particles when simulating removal of a filtering facepiece from a wearer's head.

Design, demonstration and performance of a versatile electrospray aerosol generator for nanomaterial research and applications.

Carbon nanotubes are difficult to aerosolize in a controlled manner. We present a method for generating aerosols not only of carbon nanotubes, but also of many reference and proprietary materials including quantum dots, diesel particulate matter, urban dust, and their mixtures, using electrospraying. This method can be used as a teaching tool, or as the starting point for advanced research, or to deliver nanomaterials in animal exposure studies. This electrospray system generates 180 microg of nanotubes per m(3) of carrier gas, and thus aerosolizes an occupationally relevant mass concentration of nanotubes. The efficiency achievable for single-walled carbon nanotubes is 9.4%. This system is simple and quick to construct using ordinary lab techniques and affordable materials. Since it is easy to replace soiled parts with clean ones, experiments on different types of nanomaterial can be performed back to back without contamination from previous experiments. In this paper, the design, fabrication, operation and characterization of our versatile electrospray method are presented. Also, the morphological changes that carbon nanotubes undergo as they make the transition from dry powders to aerosol particles are presented.

Chronic boron exposure and human semen parameters.

Boron found as borates in soil, food, and water has important industrial and medical applications. A panel reviewing NTP reproductive toxicants identified boric acid as high priority for occupational studies to determine safe versus adverse reproductive effects. To address this, we collected boron exposure/dose measures in workplace inhalable dust, dietary food/fluids, blood, semen, and urine from boron workers and two comparison worker groups (n=192) over three months and determined correlations between boron and semen parameters (total sperm count, sperm concentration, motility, morphology, DNA breakage, apoptosis and aneuploidy). Blood boron averaged 499.2 ppb for boron workers, 96.1 and 47.9 ppb for workers from high and low environmental boron areas (p<0.0001). Boron concentrated in seminal fluid. No significant correlations were found between blood or urine boron and adverse semen parameters. Exposures did not reach those causing adverse effects published in animal toxicology work but exceeded those previously published for boron occupational groups.

Prognostically significant cytotoxic T cell clones are stimulated after thalidomide therapy in patients with multiple myeloma.

The expanded T cell clones are associated with a prolonged survival in patients with multiple myeloma. We sought to confirm this prognostic significance in a multicenter patient cohort and investigate the effect of thalidomide on clones and T regulatory cells (T(regs)). Blood was collected from 120 patients enrolled in a Phase III trial of maintenance therapy +/- thalidomide after autologous stem cell transplantation. TCR Vbeta repertoire analysis identified T cell expansions in 48% of patients pre-transplant and 68% after 8-month maintenance. T cell expansions, previously shown to be clonal, were predominantly CD8+ (93%) and all 24 TCR Vbeta families tested were represented. Thalidomide therapy was associated with a significant increase in the incidence of patients with multiple expansions (49% vs. 23%; chi2 = 6.8; p = 0.01). The presence of expansions regardless of therapy was associated with a significantly longer median progression free survival (PFS) (32.1 vs. 17.6 months; chi2 = 5.6; p = 0.02) and overall survival (OS) (chi2 = 3.9; p < 0.05). Median PFS in the thalidomide arm was 50.9 months for patients with expansions and 28.3 months for patients without expansions (chi2 = 19.4; p = 0.0002). Thalidomide did not appear to modulate T(reg) numbers. Expanded T cell clones are prognostically significant and have an impact on progression after thalidomide therapy in a proportion of patients.

Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure.

PURPOSE: Thalidomide is effective in the treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM). However, the role of thalidomide in the post-autologous stem cell transplantation (ASCT) context remains unclear. This study assessed whether the addition of thalidomide consolidation following ASCT would improve the durability of responses achieved and overall survival. PATIENTS AND METHODS: Between January 2002 and March 2005, 269 patients with newly diagnosed MM who achieved disease stabilization or better with conventional induction chemotherapy received a single high-dose melphalan conditioned ASCT. Post-ASCT, 129 patients were randomly assigned to receive indefinite prednisolone maintenance therapy (control group) and 114 to receive the same in addition to 12 months of thalidomide consolidation (thalidomide group). The primary study end points were progression-free survival (PFS) and overall survival (OS). The secondary end point was tolerability. RESULTS: After a median follow-up of 3 years, the postrandomization 3-year PFS rates were 42% and 23% (P < .001; hazard ratio [HR], 0.5; 95% CI, 0.35 to 0.71) and the OS rates were 86% and 75% (P = .004; HR, 0.41; 95% CI, 0.22 to 0.76) in the thalidomide and control groups, respectively. There was no difference in survival between groups 12 months after disease progression (79% v 77%; P = .237). Neurological toxicities were more common in the thalidomide arm but there were no differences between arms for thromboembolic events. CONCLUSION: Consolidation therapy with 12 months of thalidomide combined with prednisolone prolongs survival when used after a single high-dose therapy supported ASCT in patients with newly diagnosed MM. Furthermore, thalidomide consolidation therapy did not adversely impact on survival in the subsequent salvage setting.

Renal safety of zoledronic acid with thalidomide in patients with myeloma: a pharmacokinetic and safety sub-study.

BACKGROUND: Cases of impaired renal function have been reported in patients who had been treated with both zoledronic acid and thalidomide for myeloma. Hence, we conducted a safety study of zoledronic acid and thalidomide in myeloma patients participating in a trial of maintenance therapy. METHODS: Twenty-four patients who were enrolled in a large randomized trial of thalidomide vs no thalidomide maintenance therapy for myeloma, in which all patients also received zoledronic acid, were recruited to a pharmacokinetic and renal safety sub-study, and followed for up to 16 months. RESULTS: No significant differences by Wilcoxon rank-sum statistic were found in zoledronic acid pharmacokinetics or renal safety for up to 16 months in patients randomized to thalidomide or not. CONCLUSION: In myeloma patients receiving maintenance therapy, the combination of zoledronic acid and thalidomide appears to confer no additional renal safety risks over zoledronic acid alone.

Measurements of ultrafine particles and other vehicular pollutants inside a mobile exposure system on Los Angeles freeways.

A mobile exposure and air pollution measurement system was developed and used for on-freeway ultrafine particle health effects studies. A nine-passenger van was modified with a high-efficiency particulate air (HEPA) filtration system that can deliver filtered or unfiltered air to an exposure chamber inside the van. State-of-the-art instruments were used to measure concentration and size distribution of fine and ultrafine particles and the concentration of carbon monoxide (CO), black carbon (BC), particle-bound polycyclic aromatic hydrocarbons (PAHs), fine particulate matter (PM2.5) mass, and oxides of nitrogen (NOx) inside the exposure chamber. This paper presents the construction and technical details of the van and air pollutant concentrations collected in 32 2-hr runs on two major Los Angeles freeways, Interstate 405 (1-405; mostly gasoline traffic) and Interstate 710 (1-710; large proportion of heavy-duty diesel traffic). More than 97% of particles were removed when the flow through the filter box was switched from bypass mode to filter mode while the vehicle was driving on both freeways. The filtration system thus provides a great particulate matter exposure contrast while keeping gas-phase pollutant concentrations the same. Under bypass mode, average total particle number concentration observed inside the exposure chamber was around 8.4 x 10(4) and 1.3 x 10(5) particles cm(-3) on the I-405 and the I-710 freeways, respectively. Bimodal size distributions were consistent and similar for both freeways with the first mode around 16-20 nm and the second mode around 50-55 nm. BC and particle-bound PAH concentrations were more than two times greater on the I-710 than on the I-405 freeway. Very weak correlations were observed between total particle number concentrations and other vehicular pollutants on the freeways.

Biomarkers of environmental and workplace boron exposure.

The purpose of this work was to identify an accurate, noninvasive biomarker of boron exposure that could be used in worker populations. Occupational exposure to boron is of concern due to high numbers of workers exposed, animal toxicity data suggesting reproductive effects, and lack of human studies. Total daily boron exposure was determined from duplicate samples of 24-hr food and fluid intake, plus workplace personal air monitoring in boron workers and comparison groups in northern China during 2003 and 2004. Boron was also measured in blood, semen, creatinine-corrected postshift urine, and 24-hr urine. Total daily boron exposure (mg/day) averaged 41.2 for men working in the boron industry and 2.3 for the comparison group. Boron concentration in postshift urine was correlated with 24-hr urine boron concentration (Pearson correlation coefficient = 0.85, p < 0.0001). Boron concentration in postshift urine was correlated with total daily boron exposure measured through food, fluid, and personal air monitoring (Pearson correlation coefficient = 0.83, p < 0.0001). Boron concentration in postshift urine was also correlated with internal dose measures of boron in blood and semen (Pearson correlation coefficient = 0.85, 0.80 respectively, p < 0.0001). This work suggests that creatinine-corrected, postshift urine boron concentration can be used as a biomarker of human boron exposure in worker populations.

Nested case-control study of occupational physical activity and prostate cancer among workers using a job exposure matrix.

OBJECTIVE: We conducted a nested case-control study of 362 cases diagnosed between 1 January 1988 and 31 December 1999, and 1,805 matched controls to examine the association between occupational physical activity and prostate-cancer incidence among workers at a nuclear and rocket engine-testing facility in Southern California. METHODS: We obtained cancer incidence data from the California Cancer Registry and seven other state cancer registries. Data from company records were used to construct a job exposure matrix (JEM) for occupational physical activity during employment. Conditional logistic regression was used to estimate associations. RESULTS: With adjustment for occupational confounders, including socioeconomic status and trichloroethylene (TCE) exposure, high activity levels at work were inversely associated with prostate-cancer incidence among aerospace workers (odds ratio [OR] = 0.55; 95% CI = 0.32-0.95), but not among radiation workers (OR = 0.95; 95% CI = 0.43-2.1). CONCLUSIONS: Our results suggest that adult men who are more continually active at work may have a decreased risk of prostate cancer.

Nested case-control study of occupational chemical exposures and prostate cancer in aerospace and radiation workers.

BACKGROUND: To date, little is known about the potential contributions of occupational exposure to chemicals to the etiology of prostate cancer. Previous studies examining associations suffered from limitations including the reliance on mortality data and inadequate exposure assessment. METHODS: We conducted a nested case-control study of 362 cases and 1,805 matched controls to examine the association between occupational chemical exposures and prostate cancer incidence. Workers were employed between 1950 and 1992 at a nuclear energy and rocket engine-testing facility in Southern California. We obtained cancer-incidence data from the California Cancer Registry and seven other state cancer registries. Data from company records were used to construct a job exposure matrix (JEM) for occupational exposures to hydrazine, trichloroethylene (TCE), polycyclic aromatic hydrocarbons (PAHs), benzene and mineral oil. Associations between chemical exposures and prostate cancer incidence were assessed in conditional logistic regression models. RESULTS: With adjustment for occupational confounders, including socioeconomic status, occupational physical activity, and exposure to the other chemicals evaluated, the odds ratio for low/moderate TCE exposure was 1.3; 95%CI = 0.8 to 2.1, and for high TCE exposure was 2.1; 95%CI = 1.2 to 3.9. Furthermore, we noted a positive trend between increasing levels of TCE exposure and prostate cancer (P-value for trend = 0.02). CONCLUSION: Our results suggest that high levels of TCE exposure are associated with prostate cancer among workers in our study population.

Small airways response to naturalistic cat allergen exposure in subjects with asthma.

BACKGROUND: It is currently unclear whether the small airways (diameter <2 microm) contribute significantly to late asthmatic reactions to inhaled allergen. OBJECTIVES: We sought to determine whether naturalistic exposure to cat allergen induced late responses in the small airways as measured by pulmonary function testing and high-resolution computed tomography (HRCT) of the chest performed at end-expiration. METHODS: In a group of 10 subjects with cat-induced asthma, physiologic studies (spirometry and lung volumes, including closing volume) and HRCT were performed before and 6 and 23 hours after a cat room challenge that caused a 20% or greater acute fall in FEV(1). RESULTS: There was no significant decline in FEV(1) at 6 or 23 hours after cat exposure. Forced expiratory flow at 25% to 75% of forced vital capacity was significantly decreased at 6 hours after the challenge and returned to normal by 23 hours. HRCT image analysis as well as closing volume demonstrated increased air trapping from baseline at both 6 and 23 hours after the challenge. In addition, image analysis demonstrated a significant increase in small airways hyperresponsiveness to methacholine at 23 hours after the challenge. No significant mean changes were noted in lung volumes at either 6 or 23 hours or in PC(20) FEV(1) at 23 hours postchallenge. CONCLUSION: These findings demonstrate that naturalistic exposure to cat allergen results in significant small airways obstruction and hyperresponsiveness persisting for at least 23 hours, at which time these changes cannot be detected by conventional physiologic measures. CLINICAL IMPLICATIONS: Physiologically silent distal lung inflammation persists after an antigenic challenge.

Estimated effects of hydrazine exposure on cancer incidence and mortality in aerospace workers.

BACKGROUND: Animal studies suggest that hydrazine is a lung carcinogen, but human studies have been rare, rather small, and limited to cancer mortality. METHODS: We examined cancer mortality and incidence in a cohort of aerospace workers with varying exposure to hydrazine contained in rocket fuels-extending previous mortality follow-up from 1994 to 2001 and investigating cancer incidence for the period 1988-2000 using population-registry data. We newly estimated hydrazine effects adjusting for occupational exposures to other carcinogens assessed through a job-exposure matrix. Rate-ratio estimates were derived from Cox proportional hazards and random-effects models using time-dependent exposure measures for hydrazine adjusting for trichloroethylene, polycyclic aromatic hydrocarbons, benzene, and mineral oil exposures. RESULTS: Exposure to hydrazine was positively associated with lung cancer incidence (estimated rate ratio for high vs low exposure with 20-year lag = 2.5; 95% confidence interval = 1.3-4.9) and with colorectal cancer incidence (2.2; 1.0-4.6). Dose-response associations were observed for both outcomes; similar associations were found for lung cancer mortality but not for colorectal cancer mortality. Effect estimates for cancers of the pancreas, blood and lymph system, and kidneys were based on small numbers rendering our analyses uninformative, and patterns considering exposure levels and lags were inconsistent. Use of random-effect models did not change our results. CONCLUSIONS: The findings reported here are consistent with our previous results for lung cancer mortality; our new results suggest that exposure to hydrazine increases the risk of incident lung cancers. We also found, for the first time, an increased risk of colon cancers. Results for other cancer sites are inconclusive.

Estimated effects of solvents and mineral oils on cancer incidence and mortality in a cohort of aerospace workers.

BACKGROUND: A retrospective cohort study of workers employed at a California aerospace company between 1950 and 1993 was conducted; it examined cancer mortality from exposures to the rocket fuel hydrazine. METHODS: In this study, we employed a job exposure matrix (JEM) to assess exposures to other known or suspected carcinogens-including trichloroethylene (TCE), polycyclic aromatic hydrocarbons (PAHs), mineral oils, and benzene-on cancer mortality (1960-2001) and incidence (1988-2000) in 6,107 male workers. We derived rate- (hazard-) ratios estimates from Cox proportional hazard models with time-dependent exposures. RESULTS: High levels of TCE exposure were positively associated with cancer incidence of the bladder (rate ratio (RR): 1.98, 95% confidence interval (CI) 0.93-4.22) and kidney (4.90; 1.23-19.6). High levels of exposure to mineral oils increased mortality and incidence of lung cancer (1.56; 1.02-2.39 and 1.99; 1.03-3.85), and incidence of melanoma (3.32; 1.20-9.24). Mineral oil exposures also contributed to incidence and mortality of esophageal and stomach cancers and of non-Hodgkin's lymphoma and leukemia when adjusting for other chemical exposures. Lagging exposure measures by 20 years changed effect estimates only minimally. No associations were observed for benzene or PAH exposures in this cohort. CONCLUSIONS: Our findings suggest that these aerospace workers who were highly exposed to mineral oils experienced an increased risk of developing and/or dying from cancers of the lung, melanoma, and possibly from cancers of the esophagus and stomach and non-Hodgkin's lymphoma and leukemia. These results and the increases we observed for TCE and kidney cancers are consistent with findings of previous studies.

Release of simulated anthrax particles from disposable respirators.

A preliminary study was undertaken to evaluate the potential for a disposable respirator that has been contaminated with anthrax spores to release spores in handling after use. The release of inert particles from disposable respirators was measured for masks dropped 3 feet onto a hard surface. Ten experimental runs were conducted for each of two N95 mask types, the Moldex 2200N95 and the 3M 8210. Anthrax spores were simulated with a test aerosol of single and double 1-micron polystyrene spheres. For the Moldex mask loaded with approximately 20 million spheres on it, an average of 0.16% was released; for the 3M mask an average of 0.29% was released.