A Comprehensive Safety Trial of Chimeric Antibody 14.18 With GM-CSF, IL-2, and Isotretinoin in High-Risk Neuroblastoma Patients Following Myeloablative Therapy: Children\u27s Oncology Group Study ANBL0931

Purpose: A phase 3 randomized study (COG ANBL0032) demonstrated significantly improved outcome by adding immunotherapy with ch14.18 antibody to isotretinoin as post-consolidation therapy for high-risk neuroblastoma (NB). This study, ANBL0931, was designed to collect FDA-required safety/toxicity data to support FDA registration of ch14.18. Experimental design: Newly diagnosed high-risk NB patients who achieved at least a partial response to induction therapy and received myeloablative consolidation with stem cell rescue were enrolled to receive six courses of isotretinoin with five concomitant cycles of ch14.18 combined with GM-CSF or IL2. Ch14.18 infusion time was 10-20 h per dose. Blood was collected for cytokine analysis and its association with toxicities and outcome. Results: Of 105 patients enrolled, five patients developed protocol-defined unacceptable toxicities. The most common grade \u3e/= 3 non-hematologic toxicities of immunotherapy for cycles 1-5, respectively, were neuropathic pain (41, 28, 22, 31, 24%), hypotension (10, 17, 4, 14, 8%), allergic reactions (ARs) (3, 10, 5, 7, 2%), capillary leak syndrome (1, 4, 0, 2, 0%), and fever (21, 59, 6, 32, 5%). The 3-year event-free survival and overall survival were 67.6 +/- 4.8% and 79.1 +/- 4.2%, respectively. AR during course 1 was associated with elevated serum levels of IL-1Ra and IFNgamma, while severe hypotension during this course was associated with low IL5 and nitrate. Higher pretreatment CXCL9 level was associated with poorer event-free survival (EFS). Conclusion: This study has confirmed the significant, but manageable treatment-related toxicities of this immunotherapy and identified possible cytokine biomarkers associated with select toxicities and outcome. EFS and OS appear similar to that previously reported on ANBL0032

Association of FEV1 in asthmatic children with personal and microenvironmental exposure to airborne particulate matter.

Exposure to particulate matter (PM) air pollution has been shown to exacerbate children's asthma, but the exposure sources and temporal characteristics are still under study. Children's exposure to PM is likely to involve both combustion-related ambient PM and PM related to a child's activity in various indoor and outdoor microenvironments. Among 19 children with asthma, 9-17 years of age, we examined the relationship of temporal changes in percent predicted forced expiratory volume in 1 sec (FEV1) to personal continuous PM exposure and to 24-hr average gravimetric PM mass measured at home and central sites. Subjects were followed for 2 weeks during either the fall of 1999 or the spring of 2000, in a southern California region affected by transported air pollution. FEV(subscript)1(/subscript) was measured by subjects in the morning, afternoon, and evening. Exposure measurements included continuous PM using a passive nephelometer carried by subjects; indoor, outdoor home, and central-site 24-hr gravimetric PM2.5 (PM of aerodynamic diameter < 2.5 microm) and PM10; and central-site hourly PM10, nitrogen dioxide, and ozone. Data were analyzed with linear mixed models controlling for within-subject autocorrelation, FEV1 maneuver time, and exposure period. We found inverse associations of FEV1 with increasing PM exposure during the 24 hr before the FEV1 maneuver and with increasing multiday PM averages. Deficits in percent predicted FEV1 (95% confidence interval) for given PM interquartile ranges measured during the preceding 24-hr were as follows: 128 microg/m3 1-hr maximum personal PM, -6.0% (-10.5 to -1.4); 30 microg/m3 24-hr average personal PM, -5.9% (-10.8 to -1.0); 6.7 microg/m3 indoor home PM2.5, -1.6% (-2.8 to -0.4); 16 microg/m3 indoor home PM10, -2.1% (-3.7 to -0.4); 7.1 microg/m3 outdoor home PM2.5, -1.1% (-2.4 to 0.1); and 7.5 microg/m3 central-site PM2.5, -0.7% (-1.9 to 0.4). Stronger associations were found for multiday moving averages of PM for both personal and stationary-site PM. Stronger associations with personal PM were found in boys allergic to indoor allergens. FEV1 was weakly associated with NO2 but not with O3. Results suggest mixed respiratory effects of PM in asthmatic children from both ambient background exposures and personal exposures in various microenvironments

A Method for Assaying Deubiquitinating Enzymes

A general method for the assay of deubiquitinating enzymes was described in detail using (125)I-labeled ubiquitin-fused αNH-MHISPPEPESEEEEEHYC (referred to as Ub-PESTc) as a substrate. Since the tyrosine residue in the PESTc portion of the fusion protein was almost exclusively radioiodinated under a mild labeling condition, such as using IODO-BEADS, the enzymes could be assayed directly by simple measurement of the radioactivity released into acid soluble products. Using this assay protocol, we could purify six deubiquitinating enzymes from chick skeletal muscle and yeast and compare their specific activities. Since the extracts of E. coli showed little or no activity against the substrate, the assay protocol should be useful for identification and purification of eukaryotic deubiquitinating enzymes cloned and expressed in the cells

Transplantation tolerance: lessons from experimental rodent models

Immunological tolerance or functional unresponsiveness to a transplant is arguably the only approach that is likely to provide long-term graft survival without the problems associated with life-long global immunosuppression. Over the past 50 years, rodent models have become an invaluable tool for elucidating the mechanisms of tolerance to alloantigens. Importantly, rodent models can be adapted to ensure that they reflect more accurately the immune status of human transplant recipients. More recently, the development of genetically modified mice has enabled specific insights into the cellular and molecular mechanisms that play a key role in both the induction and maintenance of tolerance to be obtained and more complex questions to be addressed. This review highlights strategies designed to induce alloantigen specific immunological unresponsiveness leading to transplantation tolerance that have been developed through the use of experimental models