Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis.

Current therapies for myeloproliferative neoplasms (MPNs) improve symptoms but have limited effect on tumor size. In preclinical studies, tamoxifen restored normal apoptosis in mutated hematopoietic stem/progenitor cells (HSPCs). TAMARIN Phase-II, multicenter, single-arm clinical trial assessed tamoxifen's safety and activity in patients with stable MPNs, no prior thrombotic events and mutated JAK2V617F, CALRins5 or CALRdel52 peripheral blood allele burden ≥20% (EudraCT 2015-005497-38). 38 patients were recruited over 112w and 32 completed 24w-treatment. The study's A'herns success criteria were met as the primary outcome ( ≥ 50% reduction in mutant allele burden at 24w) was observed in 3/38 patients. Secondary outcomes included ≥25% reduction at 24w (5/38), ≥50% reduction at 12w (0/38), thrombotic events (2/38), toxicities, hematological response, proportion of patients in each IWG-MRT response category and ELN response criteria. As exploratory outcomes, baseline analysis of HSPC transcriptome segregates responders and non-responders, suggesting a predictive signature. In responder HSPCs, longitudinal analysis shows high baseline expression of JAK-STAT signaling and oxidative phosphorylation genes, which are downregulated by tamoxifen. We further demonstrate in preclinical studies that in JAK2V617F+ cells, 4-hydroxytamoxifen inhibits mitochondrial complex-I, activates integrated stress response and decreases pathogenic JAK2-signaling. These results warrant further investigation of tamoxifen in MPN, with careful consideration of thrombotic risk.

A web-based team-oriented medical error communication assessment tool: development, preliminary reliability, validity, and user ratings.

BACKGROUND: Multiple-choice exams are not well suited for assessing communication skills. Standardized patient assessments are costly and patient and peer assessments are often biased. Web-based assessment using video content offers the possibility of reliable, valid, and cost-efficient means for measuring complex communication skills, including interprofessional communication. DESCRIPTION: We report development of the Web-based Team-Oriented Medical Error Communication Assessment Tool, which uses videotaped cases for assessing skills in error disclosure and team communication. Steps in development included (a) defining communication behaviors, (b) creating scenarios, (c) developing scripts, (d) filming video with professional actors, and (e) writing assessment questions targeting team communication during planning and error disclosure. EVALUATION: Using valid data from 78 participants in the intervention group, coefficient alpha estimates of internal consistency were calculated based on the Likert-scale questions and ranged from α=.79 to α=.89 for each set of 7 Likert-type discussion/planning items and from α=.70 to α=.86 for each set of 8 Likert-type disclosure items. The preliminary test-retest Pearson correlation based on the scores of the intervention group was r=.59 for discussion/planning and r=.25 for error disclosure sections, respectively. Content validity was established through reliance on empirically driven published principles of effective disclosure as well as integration of expert views across all aspects of the development process. In addition, data from 122 medicine and surgical physicians and nurses showed high ratings for video quality (4.3 of 5.0), acting (4.3), and case content (4.5). CONCLUSIONS: Web assessment of communication skills appears promising. Physicians and nurses across specialties respond favorably to the tool.

Origin and subset distribution of peripheral blood dendritic cells in patients with chronic graft-versus-host disease.

BACKGROUND: After allogeneic hematopoietic stem cell transplantation, donor T cells interact with an antigen-presenting cell environment that is distorted in number, level of activation, and origin. The role of antigen presentation in the development of chronic graft-versus host disease (cGVHD) is unknown. METHODS: The number and origin of peripheral blood immature myeloid (CD19- CD1c+) and plasmacytoid (BDCA-2+) dendritic cells (DCs) was determined in 30 patients at more than 100 days after allogeneic hematopoietic stem cell transplantation. RESULTS: Patients with cGVHD had significantly higher plasmacytoid DC numbers than individuals without this complication (9.1+/-2.0 x 10(6)/L versus 3.8+/-0.6 x 10(6)/L, =0.025). Chimerism studies demonstrated that DCs in patients with cGVHD were exclusively of donor origin, whereas persistence of host DCs was observed in some control patients. CONCLUSIONS: The antigen-presenting cell environment in patients with cGVHD, as represented by immature blood DCs, is of donor origin but distorted in terms of subset distribution.

Role of dendritic cells in graft-versus-host disease.

A major barrier to successful allogeneic hematopoietic stem cell transplantation is graft-versus-host disease (GVHD). Until recently, the role of antigen presentation in the development of this disorder was unknown. The experimental finding that recipient antigen-presenting cells (APCs) were required for the development of CD8(+) T cell-dependent GVHD has led to a fundamental reappraisal of our ideas concerning the pathogenesis of this disease. Following transplantation, the origin (donor or recipient), number, lineage, and function of APCs within the recipient are altered significantly. Studies that test the influence of each of these factors upon graft-versus-host responses, including graft-versus-tumor responses, are beginning to emerge and suggest that APCs, such as dendritic cells, constitute a potential target for therapeutic manipulation.

Chronic graft-versus-host disease is associated with increased numbers of peripheral blood CD4+CD25high regulatory T cells.

Chronic graft-versus-host disease (cGVHD) is characterized by a state of profound immunodeficiency in association with alloreactive and autoimmune phenomena. These observations indicate an impairment of immunologic tolerance that could involve both central and peripheral mechanisms. Defective thymic function may contribute to dysregulation of central tolerance, but few studies have addressed peripheral tolerance. Recently a population of CD4+CD25+ T cells (Treg cells) has been characterized, which controls immunologic reactivity in vivo and which on transfer can prevent experimental acute GVHD. We investigated the number and function of peripheral blood CD4+CD25high T cells in patients more than 100 days after allogeneic hematopoietic stem cell transplantation. Patients with cGVHD had markedly elevated numbers of CD4+CD25high T cells as compared to patients without GVHD. CD4+CD25high T cells derived from patients in both groups were of donor origin, lacked markers of recent activation, and expressed intracellular CD152. In contrast to controls, CD4+CD25high T cells derived from patients with cGVHD were characterized by lower surface CD62L expression. In vitro, CD4+CD25high T cells were hyporesponsive to polyclonal stimulation and suppressed the proliferation and cytokine synthesis of CD4+CD25- cells, an effect that was independent of interleukin 10. These results indicate that chronic graft-versus-host injury does not occur as a result of Treg cell deficiency.

The toxicity and efficacy of donor lymphocyte infusions given after reduced-intensity conditioning allogeneic stem cell transplantation.

We describe the toxicity and efficacy of donor lymphocyte infusions (DLIs) given to 81 patients (median age, 50 years) after reduced-intensity conditioning (RIC) transplantations performed at 16 centers in the United Kingdom. The diseases treated included non-Hodgkin lymphoma (NHL; n = 29), chronic myeloid leukemia (CML; n = 12), myeloma (n = 11), acute myeloid leukemia (AML; n = 10), and chronic lymphocytic leukemia (CLL; n = 9). Eighty-eight percent received stem cells from sibling donors. The patients received 130 infusions (median, 1; range, 1-4). Indications for DLI were unsatisfactory response/disease progression in 51 patients, mixed chimerism in 18, preemptive in 10, and other in 2. Graft hypoplasia was uncommon (11%). Grade II to IV graft-versus-host disease (GVHD) occurred in 23 of 81 patients (28%) and limited and extensive chronic GVHD in 5 of 69 and 18 of 69 evaluable patients (total incidence 33%). Conversion from mixed to full donor chimerism occurred in 19 of 55 evaluable patients (35%) at a median of 48 days after the DLI; partial responses occurred in 6 patients (total response rate 45%). Eighteen of 51 (35%) patients with measurable disease after stem cell transplantation had a complete response (2 molecular), and 5 a partial response (total response rate 45%). Eleven of 17 evaluable complete responders had full donor chimerism. Eight of 13 patients with follicular NHL had complete responses as did 4 of 12 patients with CML. Clinical and chimeric responses correlated strongly with acute and chronic GVHD. Forty-seven patients (58%) survive at a median of 508 days after transplantation (range, 155-1171 days) with a median Karnofsky score of 90. Thirty-four patients (42%) died at a median of 211 days after transplantation with the major causes being progressive disease (26%) and GVHD (9%). Further systematic studies are required to determine the efficacy and optimum use of DLI for patients with each disease treated by nonmyeloablative stem cell transplantation.