Summary. Background: Inhibitors are a serious complication for patients with severe hemophilia A. Immune tolerance induction (ITI) is the primary method for eradicating these inhibitors. The role of type of concentrate and in particular the use of von Willebrand factor-containing, plasma-derived factor VIII (VWF/pd-FVIII) concentrate in primary or rescue ITI remains unclear. Objectives: To report retrospective collection of data on the use of a single VWF/pd-FVIII concentrate in primary and rescue ITI. Methods: Retrospective chart review of hemophilia A inhibitor patients at 11 US institutions who received VWF/pd-FVIII concentrate in primary or rescue ITI. Results: Primary ITI was carried out in eight inhibitor patients with a 75% complete and partial success. Secondary ITI was carried out in 25 inhibitor patients, with 52% attaining complete or partial success. Conclusions: This report represents the largest group of primarily pediatric, high-titer inhibitor patients treated with a single VWF/pd-FVIII concentrate. It adds retrospective data to the use of VWF-containing plasma-derived factor VIII concentrate in primary and rescue ITI, particularly in those patients with characteristics of poor response to ITI.

Hemarthrosis is a common manifestation of haemophilia, and joint arthropathy remains a frequent complication. Even though the exact mechanisms related to blood-induced joint disease have not yet been fully elucidated, it is likely that iron deposition in the synovium induces an inflammatory response that causes not only immune system activation but also stimulates angiogenesis. This process ultimately results in cartilage and bone destruction. Investigating the processes that occur in the early stages of blood-induced joint disease in humans has been very limited. Therefore, the use of haemophilic animal models is critical to augment the understanding of this phenomenon. This article discusses three cellular regulators (p53, p21 and TRAIL) induced in synovial tissue that are important for iron metabolism. A cartilage remodelling programme induced by the release of cytokines and growth factors that result in articular damage is also discussed. Full elucidation of the pathogenesis of haemophilic joint disease is required to identify new avenues for prevention and therapy.

Although many people with haemophilia discontinue prophylaxis in their late teens or early adulthood, the consequences of this decision are largely not known. This 18-month, observational, case-controlled, multicentre study evaluated long-term prophylaxis and the consequences of switching from prophylaxis to on-demand treatment in late teens and young adults with severe haemophilia A. Participants with haemophilia (aged 14-29 years) on prophylaxis ≥ 60% of the time for the 5 years before study entry were enrolled into 1 of 2 prospective or 1 retrospective group. Group 1 was prophylaxis, group 2 had voluntarily discontinued prophylaxis ≤ 12 months before study entry and group 3 had voluntarily discontinued prophylaxis ≥ 13 months before study entry. Assessments included bleeding frequency (primary endpoint), Haemo-QoL-A health-related quality of life (HRQoL) scores, Gilbert score, development of target joints, Haemophilia Activities List, Godin Leisure-Time, treatment satisfaction and State-Trait Anxiety Inventory (secondary and exploratory endpoints). Descriptive statistics were provided for all variables. Thirty-eight participants (group 1, n = 22; group 2, n = 5; group 3, n = 11; median age, 19.5 years) were enrolled. The median annualized number of bleeding events was 0, 4.8 and 24 in groups 1, 2 and 3 respectively. HRQoL was lower in participants who discontinued prophylaxis vs. those who remained on prophylaxis. Changes in the remaining secondary and exploratory variables were small, but were generally worse in participants who discontinued prophylaxis. Following a switch from prophylaxis to on-demand therapy, the number of bleeding events increased and HRQoL worsened in late teens and young adults with severe haemophilia A.

Arthropathy remains a major cause of morbidity in patients with haemophilia. Frequent bleeding into the joints leads to joint damage with resultant contractures, joint deformities and arthritis. This in turn leads to muscle atrophy, limited physical activity, osteoporosis and disability. Even though several studies of prophylactic factor replacement for persons with severe haemophilia demonstrate improved joint function, this therapy is still not readily available to most people with haemophilia around the world and a universal treatment protocol has not been used. In this article, we discuss key issues in the treatment of severe haemophilia: the optimal timing of initiation and termination of therapy, dosing options and goals of therapy. The options for countries where prophylaxis is not readily available are also discussed. Most studies are small and not randomized making consensus treatment recommendations difficult to formulate. Randomized, clinical trials are needed to provide the answers regarding the optimal treatment of patients with severe haemophilia.

SummaryThe purpose of this study was to determine whether a correlation exists between tumor cyclooxygenase (COX)-2 expression and disease-specific survival in patients with osteosarcoma lung metastases. Thirty-six patients diagnosed with osteosarcoma lung metastases between the years 1990 and 2001 were included in this retrospective study. The majority of the patients (72%) presented newly -diagnosed osteosarcoma lung metastases whereas the remaining patients (28%) presented recurrent disease. Clinicopathologic parameters were obtained from patients' clinical records. Tissue samples were obtained at the time of resection of the lung metastases and stained for COX-2 using immunohistochemistry. Samples were graded according to the intensity of COX-2 staining (grade 0: negative, grade 1: very weak, grade 2: weak, grade 3: moderate, and grade 4: strong). COX-2 staining was correlated with disease-specific survival and clinicopathologic parameters using the Jonckheere-Terpstra and the Kruskal-Wallis tests. All patients with grade 3 or 4 COX-2 expression died of osteosarcoma lung metastases. Ten percent of patients with grade 2 COX-2 expression and 29% of patients with grade 1 expression were alive and free of disease at the last follow-up. By contrast, 60% of the patients with grade 0 COX-2 expression were alive and free of disease at the last follow-up. No association between COX-2 expression and clinicopathologic parameters was found. However, COX-2 expression correlated inversely with disease-specific survival in patients with osteosarcoma lung metastases. Our data indicate that COX-2 expression in metastatic osteosarcoma may have prognostic significance. KeywordsCOX-2; osteosarcoma; lung metastases Soft tissue and bone sarcomas comprise nearly 13% of all cancers in childhood. Approximately 1500 new cases of pediatric sarcoma are diagnosed each year in the United States.1 For osteosarcoma, the most common primary tumor site is the metaphysis of long bones, and the most common site of metastatic involvement is the lungs. Patients with Reprints: Nidra I. Rodriguez, MD, Children