Avram Denburg

Allergen-induced murine upper airway inflammation: local and systemic changes in murine experimental allergic rhinitis

The role of inflammatory effector cells in the pathogenesis of airway allergy has been the subject of much investigation. However, whether systemic factors are involved in the development of local responses in both upper and lower airways has not been fully clarified. The present study was performed to investigate aspects of the pathogenesis of isolated allergic rhinitis in a murine model sensitized to ovalbumin (OVA). Both upper‐ and lower‐airway physiological responsiveness and inflammatory changes were assessed, as well as bone marrow progenitor responses, by culture and immunohistological methods. Significant nasal symptoms and hyper‐responsiveness appeared after intranasal OVA challenge (P < 0·0001 and P < 0·01, respectively), accompanied with significant nasal mucosal changes in CD4+ cells (P < 0·001), interleukin (IL)‐4+ cells (P < 0·01), IL‐5+ cells (P < 0·01), basophilic cells (P < 0·02) and eosinophils (P < 0·001), in the complete absence of hyper‐responsiveness or inflammatory changes in the lower airway. In the bone marrow, there were significant increases in CD34+ cells, as well as in eosinophils and basophilic cells. In the presence in vitro of mouse recombinant IL‐5, IL‐3 or granulocyte–macrophage colony‐stimulating factor (GM‐CSF), the level of bone marrow eosinophil/basophil (Eo/Baso) colony‐forming cells increased significantly in the OVA‐sensitized group. We conclude that, in this murine model of allergic rhinitis, haemopoietic progenitors are upregulated, which is consistent with the involvement of bone marrow in the pathogenesis of nasal mucosal inflammation. Both local and systemic events, initiated in response to allergen provocation, may be required for the pathogenesis of allergic rhinitis. Understanding these events and their regulation could provide new therapeutic targets for rhinitis and asthma.

Pathogenesis of Murine Experimental Allergic Rhinitis: A Study of Local and Systemic Consequences of IL-5 Deficiency

Recent studies have demonstrated an important role for IL-5-dependent bone marrow eosinophil progenitors in allergic inflammation. However, studies using anti-IL-5 mAbs in human asthmatics have failed to suppress lower airway hyperresponsiveness despite suppression of eosinophilia; therefore, it is critical to examine the role of IL-5 and bone marrow responses in the pathogenesis of allergic airway disease. To do this, we studied the effects of IL-5 deficiency (IL-5−/−) on bone marrow function as well as clinical and local events, using an established experimental murine model of allergic rhinitis. Age-matched IL-5+/+ and IL-5−/− BALB/c mice were sensitized to OVA followed by 2 wk of daily OVA intranasal challenge. IL-5−/− OVA-sensitized mice had significantly higher nasal mucosal CD4+ cells and basophilic cell counts as well as nasal symptoms and histamine hyperresponsiveness than the nonsensitized group; however, there was no eosinophilia in either nasal mucosa or bone marrow; significantly lower numbers of eosinophil/basophil CFU and maturing CFU eosinophils in the presence of recombinant mouse IL-5 in vitro; and significantly lower expression of IL-5Rα on bone marrow CD34+CD45+ progenitor cells in IL-5−/− mice. These findings suggest that IL-5 is required for normal bone marrow eosinophilopoiesis, in response to specific Ag sensitization, during the development of experimental allergic rhinitis. However, the results also suggest that suppression of the IL-5-eosinophil pathway in this model of allergic rhinitis may not completely suppress clinical symptoms or nasal histamine hyperresponsiveness, because of the existence of other cytokine-progenitor pathways that may induce and maintain the presence of other inflammatory cell populations.

Clinical Trials Infrastructure as a Quality Improvement Intervention in Low- and Middle-Income Countries

Mounting evidence suggests that participation in clinical trials confers neither advantage nor disadvantage on those enrolled. Narrow focus on the question of a “trial effect,” however, distracts from a broader mechanism by which patients may benefit from ongoing clinical research. We hypothesize that the existence of clinical trials infrastructure—the organizational culture, systems, and expertise that develop as a product of sustained participation in cooperative clinical trials research—may function as a quality improvement lever, improving the quality of care and outcomes of all patients within an institution or region independent of their individual participation in trials. We further contend that this “infrastructure effect” can yield particular benefits for patients in low- and middle-income countries (LMICs). The hypothesis of an infrastructure effect as a quality improvement intervention, if correct, justifies enhanced research capacity in LMIC as a pillar of health system development.

Pediatric oncology research in low income countries: ethical concepts and challenges.

Uneven strides in research and care have led to discrepancies in childhood cancer outcomes between high and low income countries (LICs). Collaborative research may help improve outcomes in LICs by generating knowledge for local scientific communities, augmenting knowledge translation, and fostering context‐specific evaluation of treatment protocols. However, the risks of such research have received little attention. This paper investigates the relationship between pediatric oncology research in LICs and four core issues in the ethics literature: standard of care, trial benefits, ethics review, and informed consent. Our aims are to highlight the importance of this field and the need for further inquiry. Pediatr Blood Cancer 2012; 58: 492–497.

Beyond the bench and the bedside: Economic and health systems dimensions of global childhood cancer outcomes

Globally, the number of new cases of childhood cancer continues to rise, with a widening gulf in outcomes across countries, despite the availability of effective cure options for many pediatric cancers. Economic forces and health system realities are deeply embedded in the foundation of disparities in global childhood cancer outcomes. A truly global effort to close the childhood cancer divide therefore requires systemic solutions. Analysis of the economic and health system dimensions of childhood cancer outcomes is essential to progress in childhood cancer survival around the globe. The conceptual power of this approach is significant. It provides insight into how and where pediatric oncology entwines with broader political and economic conditions, and highlights the mutual benefit derived from systems‐oriented solutions. Pediatr Blood Cancer 2014;61:572–576.

Evidence From Ghana Indicates That Childhood Cancer Treatment in Sub-Saharan Africa Is Very Cost Effective: A Report From the Childhood Cancer 2030 Network

Purpose No published study to date has examined total cost and cost-effectiveness of maintaining a pediatric oncology treatment center in an African setting, thus limiting childhood cancer advocacy and policy efforts. Methods Within the Korle Bu Teaching Hospital in Accra, Ghana, costing data were gathered for all inputs related to operating a pediatric cancer unit. Cost and volume data for relevant clinical services (eg, laboratory, pathology, medications) were obtained retrospectively or prospectively. Salaries were determined and multiplied by proportion of time dedicated toward pediatric patients with cancer. Costs associated with inpatient bed use, outpatient clinic use, administrative fees, and overhead were estimated. Costs were summed for a total annual operating cost. Cost-effectiveness was calculated based on annual patients with newly diagnosed disease, survival rates, and life expectancy. Results The Korle Bu Teaching Hospital pediatric cancer unit treats on average 170 new diagnoses annually. Total operating cost was

Improving childhood cancer care in Latin America and the Caribbean: a PAHO childhood cancer working group position statement

1.7 million/y. Personnel salaries and operating room costs were the most expensive inputs, contributing 45% and 21% of total costs. Together, medications, imaging, radiation, and pathology services accounted for 7%. The cost per disability-adjusted life-year averted was

Institutional Knots: A Comparative Analysis of Cord Blood Policy in Canada and the United States

1,034, less than the Ghanaian per capita income, and thus considered very cost effective as per WHO-CHOICE methodology. Conclusion To our knowledge, this study is the first to examine institution-level costs and cost-effectiveness of a childhood cancer program in an African setting, demonstrating that operating such a program in this setting is very cost effective. These results will inform national childhood cancer strategies in Africa and other low- and middle-income country settings.

Pascal's Wager: from science to policy on early childhood development.

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Advancing the development of national childhood cancer care strategies in Latin America

Umbilical cord blood is a rich source of blood stem cells, which are of critical clinical importance in the treatment of a variety of malignant and genetic conditions requiring stem cell transplantation. Many countries have established national public cord blood banks; such banks often coexist with a panoply of private options for cord blood banking. Until recently, Canada was the only G8 country without a national cord blood bank. This differs markedly from the United States, which years ago established a national cord blood bank policy and inventory. This article investigates potential reasons for this discrepancy through a comparative analysis of the evolution of programs and policies on national cord blood banking in Canada and the United States. My analysis suggests that cross-national discrepancies in policy on public cord blood banking were determined primarily by institutional factors, principal among them formal governmental structure and the legacy of past policies. Institutional entrepreneurialism in the health sector played a constitutive role in the earlier evolution of national cord blood policy in the United States as compared to Canada.