Citations

Abstract Purpose: Metastatic cancer patients exhibit systemic dysregulation of immune polarity and are biased toward Th-2 immune responses. This is due, at least in part, to effects of VEGF on antigen presenting cell (APC) function. We therefore compared immune polarity changes in mouse models of cancer with those seen in human patients. Experimental Design: We measured plasma levels of vascular growth factors and multiple cytokines via ELISA and multiplex analysis in mice with transplantable and spontaneous tumors. We compared immune cell subsets in naive and vaccinated mice with and without tumors. We assessed cytokine immune responses by multiplex analysis. Finally, we assessed gene expression and receptor surface expression in response to VEGF in mouse and human APCs. Results: Although human patients have elevated plasma cytokines and altered immune polarity in response to antigen, mice have minimal immune abnormalities. Mouse VEGF does not mediate immune repolarization in vitro. Human but not mouse APCs upregulate VEGFR2 and downregulate interleukin (IL)-12β in response to VEGF. Conclusions: Whereas humans with metastatic cancer demonstrate dysregulated immune polarity in response to excess plasma VEGF, tumor mice do not. This appears to be due to differences in APC responses to VEGF stimulation. Differential immune effects of VEGF may represent a key species difference in the context of translation of preclinical cancer immunotherapeutics into early clinical testing. Clin Cancer Res; 17(7); 1776–83. ©2011 AACR.

Altered natural killer (NK) cell function is a component of the global immune dysregulation that occurs in advanced malignancies. Another condition associated with altered NK homeostasis is normal pregnancy, where robust infiltration with CD16− CD9+ NK cells can be identified in decidual tissues, along with a concomitant expansion of CD16− NK cells in the maternal peripheral blood. In metastatic melanoma, we identified a similar expansion of peripheral blood CD16− NK cells (median 7.4% in 41 patients with melanoma compared with 3.0% in 29 controls,P<.001). A subset of NK cells in melanoma patients also expresses CD9, which is characteristically expressed only on NK cells within the female reproductive tract. Expansion of CD16− NK cells was associated with elevated plasma transforming growth factor-beta (TGF-βlevels (median 20 ng/ml, Spearman'sρ=0.81,P=.015)). These findings suggest the possibility of exploring anti-TGF-βtherapy to restore NK function in melanoma.

Background: Medial elbow distraction during pitching as the primary mechanism contributing to adaptations in ulnar collateral ligament (UCL) appearance during magnetic resonance imaging (MRI) evaluation has not been established. Hypothesis: Uninjured high school–aged pitchers with unilateral adaptations of the UCL exhibit a higher peak internal elbow adduction moment than those without UCL adaptations. Study Design: Cohort study (Prevalence); Level of evidence, 2. Methods: Twenty uninjured, asymptomatic high school–aged pitchers underwent bilateral elbow MRI examinations. Three-dimensional motion analysis testing was performed to collect throwing arm biomechanics as participants pitched from an indoor mound. Nonparametric tests were performed to compare peak internal elbow adduction moment in uninjured participants with and without adaptations in UCL appearance and to determine the nature of the relationship between the peak internal adduction moment and UCL appearance. Results: Uninjured participants with UCL thickening exhibited a higher peak internal elbow adduction moment of 53.3 ± 6.8 N·m compared with uninjured participants without adaptations in UCL appearance, 38.8 ± 10.9 N·m ( P = .05), as higher moments were correlated with ligament thickening (correlation coefficient, 0.45) ( P = .02). Conclusion: This study establishes the association between medial elbow distraction captured by the internal adduction moment during pitching and UCL adaptations visible during MRI evaluation.

Abstract Immune thrombocytopenia (ITP) is commonly encountered in clinical practice. In 1996 the American Society of Hematology published a landmark guidance paper designed to assist clinicians in the management of this disorder. Since 1996 there have been numerous advances in the management of both adult and pediatric ITP. These changes mandated an update in the guidelines. This guideline uses a rigorous, evidence-based approach to the location, interpretation, and presentation of the available evidence. We have endeavored to identify, abstract, and present all available methodologically rigorous data informing the treatment of ITP. We provide evidence-based treatment recommendations using the GRADE system in those areas in which such evidence exists. We do not provide evidence in those areas in which evidence is lacking, or is of lower quality—interested readers are referred to a number of recent, consensus-based recommendations for expert opinion in these clinical areas. Our review identified the need for additional studies in many key areas of the therapy of ITP such as comparative studies of “front-line” therapy for ITP, the management of serious bleeding in patients with ITP, and studies that will provide guidance about which therapy should be used as salvage therapy for patients after failure of a first-line intervention.

Background: Tissue adaptations in response to pitching are an expected finding during magnetic resonance imaging (MRI) evaluation of the throwing elbow of adult pitchers. These changes are considered normal in the absence of symptom complaints. It is unclear when during the playing career these tissue adaptations are initiated. Hypothesis: Abnormalities in the appearance of the throwing elbow compared with the nonthrowing elbow would be visible during MRI assessment of this asymptomatic population of high school–aged throwers. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Twenty-three uninjured, asymptomatic male high school–aged baseball pitchers (mean age, 16 years) with no history of elbow injury were recruited for the study. Participants had a minimum of 3 years’ experience with pitching as their primary position (mean experience, 6 years). Bilateral elbow MRI examinations were performed using a standardized protocol including fast spin-echo proton-density (axial and coronal), T1-weighted (sagittal), and T2-weighted fat-saturated (axial, sagittal, and coronal) sequences. Osteoarticular, ligamentous, musculotendinous, and neural structures were evaluated and compared bilaterally. The images were reviewed by a musculoskeletal radiologist who was blinded to all the gathered data on these athletes, including limb dominance. Results: Three participants (13%) had no abnormalities. Fifteen individuals (65%) had asymmetrical anterior band ulnar collateral ligament thickening, including 4 individuals who also had mild sublime tubercle/anteromedial facet edema. Fourteen participants (61%) had posteromedial subchondral sclerosis of the ulnotrochlear articulation, including 8 (35%) with a posteromedial ulnotrochlear osteophyte, and 4 (17%) with mild posteromedial ulnotrochlear chondromalacia. Ten individuals (43%) had multiple abnormal findings in the throwing elbow. Conclusion: Thickening of the anterior band of the ulnar collateral ligament and posteromedial subchondral sclerosis of the trochlea are common findings in the high school–aged pitcher and may be considered normal clinical findings in the absence of symptom complaints. Other changes in tissue appearance of the throwing elbow are uncommon in this age group and should be regarded with a higher level of caution when evaluating for the presence of injury. An understanding of the MRI appearance of the uninjured youth pitcher is necessary for clinicians to distinguish between normal adaptations and the presence of injury.

Abstract Background: There is growing evidence linking genetic variations to non–Hodgkin lymphoma (NHL) etiology. To complement ongoing agnostic approaches for identifying susceptibility genes, we evaluated 488 candidate gene regions and their relation to risk for NHL and NHL subtypes. Methods: We genotyped 6,679 tag single nucleotide polymorphisms (SNPs) in 947 cases and 826 population-based controls from a multicenter U.S. case–control study. Gene-level summary of associations were obtained by computing the minimum P value (“minP test”) on the basis of 10,000 permutations. We used logistic regression to evaluate the association between genotypes and haplotypes with NHL. For NHL subtypes, we conducted polytomous multivariate unconditional logistic regression (adjusted for sex, race, age). We calculated P-trends under the codominant model for each SNP. Results: Fourteen gene regions were associated with NHL (P &lt; 0.01). The most significant SNP associated with NHL maps to the SYK gene (rs2991216, P-trend = 0.00005). The three most significant gene regions were on chromosome 6p21.3 (RING1/RXRB; AIF1; BAT4). Accordingly, SNPs in RING1/RXRB (rs2855429), AIF1 (rs2857597), and BAT4 (rs3115667) were associated with NHL (P-trends ≤ 0.0002) and both diffuse large B-cell and follicular lymphomas (P-trends &lt; 0.05). Conclusions: Our results suggest potential importance for SYK on chromosome 9 with NHL etiology. Our results further implicate 6p21.3 gene variants, supporting the need for full characterization of this chromosomal region in relation to lymphomagenesis. Impact: Gene variants on chromosome 9 may represent a new region of interesting for NHL etiology. The independence of the reported variants in 6p21.3 from implicated variants (TNF/HLA) supports the need to confirm causal variants in this region Cancer Epidemiol Biomarkers Prev; 20(1); 42–9. ©2011 AACR.

ABSTRACTObjectives:Variation in the prevalence of eosinophilic gastrointestinal diseases in different geographical regions has not been extensively studied. The aim of the present study was to define the regional and national prevalence of eosinophilic gastrointestinal diseases, and differences in practice approaches.Patients and Methods:We administered a survey electronically to members of the American College of Gastroenterology, the American Academy of Allergy, Asthma, and Immunology, and the North American Society Pediatric Gastroenterology, Hepatology, and Nutrition. Questions pertained to the number and proportion of patients seen with eosinophilic gastroenteritis or colitis and eosinophilic esophagitis (EoE), and methods used to diagnose and treat these conditions.Results:A total of 1836 physicians responded from 10,874 requests (17% response). Extrapolating responses from our US sample, we estimated an overall prevalence of 52 and 28/100,000 for EoE and eosinophilic gastroenteritis or colitis. The patient burden of EoE is higher in urban (0.58) and suburban (0.44) compared with rural settings (0.36, P < 0.0065), observations consistent with other allergic disorders. There was also increased prevalence in northeast region when calculated by prevalence per 100,000. There was considerable variability in criteria and initial treatment options used to diagnose EoE. Only one‐third of respondents reported using diagnostic criteria proposed in a 2007 consensus document. Seventy‐one and 35% of respondents reported treating some patients with EoE with a food elimination or elemental diet, respectively.Conclusions:EoE is diagnosed more often in northeastern states and urban areas. There is considerable variability in diagnostic criteria and initial treatment approach supporting the need for additional clinical trials and consensus development.

Background: There is an assumption that baseball athletes who reside in warm-weather climates experience larger magnitude adaptations in throwing shoulder motion and strength compared with their peers who reside in cold-weather climates. Hypotheses: (1) The warm-weather climate (WWC) group would exhibit more pronounced shoulder motion and strength adaptations than the cold-weather climate (CWC) group, and (2) the WWC group would participate in pitching activities for a greater proportion of the year than the CWC group, with the time spent pitching predicting throwing shoulder motion and strength in both groups. Study Design: Cross-sectional study; Level of evidence, 3. Methods: One hundred uninjured high school pitchers (50 each WWC, CWC) were recruited. Rotational shoulder motion and isometric strength were measured and participants reported the number of months per year they pitched. To identify differences between groups, t tests were performed; linear regression was used to determine the influence of pitching volume on shoulder motion and strength. Results: The WWC group pitched more months per year than athletes from the CWC group, with the number of months spent pitching negatively related to internal rotation motion and external rotation strength. The WWC group exhibited greater shoulder range of motion in all planes compared with the CWC group, as well as significantly lower external rotation strength and external/internal rotation strength ratios. There was no difference in internal rotation strength between groups, nor a difference in the magnitude of side-to-side differences for strength or motion measures. Conclusion: Athletes who reside in cold- and warm-weather climates exhibit differences in throwing shoulder motion and strength, related in part to the number of months spent participating in pitching activities. The amount of time spent participating in pitching activities and the magnitude of range of motion and strength adaptations in athletes who reside in warm-weather climates may make these athletes more susceptible to throwing-related injuries.

Abstract Background Previous epidemiologic findings suggest an association between exposure to trichloroethylene (TCE), a chlorinated solvent primarily used for vapor degreasing of metal parts, and non-Hodgkin lymphoma (NHL). Objectives We investigated the association between occupational TCE exposure and NHL within a population-based case–control study using detailed exposure assessment methods. Methods Cases (n = 1,189; 76% participation rate) and controls (n = 982; 52% participation rate) provided information on their occupational histories and, for selected occupations, on possible workplace exposure to TCE using job-specific interview modules. An industrial hygienist assessed potential TCE exposure based on this information and a review of the TCE industrial hygiene literature. We computed odds ratios (ORs) and 95% confidence intervals (CIs) relating NHL and different metrics of estimated TCE exposure, categorized using tertiles among exposed controls, with unexposed subjects as the reference group. Results We observed associations with NHL for the highest tertiles of estimated average weekly exposure (23 exposed cases; OR = 2.5; 95% CI, 1.1–6.1) and cumulative exposure (24 exposed cases; OR = 2.3; 95% CI, 1.0–5.0) to TCE. Tests for trend with these metrics surpassed or approached statistical significance (p-value for trend = 0.02 and 0.08, respectively); however, we did not observe dose–response relationships across the exposure levels. Overall, neither duration nor intensity of exposure was associated with NHL, although we observed an association with the lowest tertile of exposure duration (OR = 2.1; 95% CI, 1.0–4.7). Conclusions Our findings offer additional support for an association between high levels of exposure to TCE and increased risk of NHL. However, we cannot rule out the possibility of confounding from other chlorinated solvents used for vapor degreasing and note that our exposure assessment methods have not been validated.