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 JAK2
, CALR
or CALR
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.
Summary
The guideline group regarding the diagnosis and management of myelofibrosis was selected to be representative of UK‐based medical experts, together with a contribution from a single expert ...from the USA. MEDLINE and EMBASE were searched systematically for publications in English from 1966 until August 2011 using a variety of key words. The writing group produced the draft guideline, which was subsequently revised by consensus of the members of the General Haematology and Haemato‐oncology Task Forces of the British Committee for Standards in Haematology (BCSH). The guideline was then reviewed by a sounding board of UK haematologists, the BCSH and the British Society for Haematology Committee and comments incorporated where appropriate. The criteria used to state levels and grades of evidence are as outlined in the Procedure for Guidelines commissioned by the BCSH; the ‘GRADE‘ system was used to score strength and quality of evidence. The objective of this guideline is to provide healthcare professionals with clear guidance on the investigation and management of primary myelofibrosis, as well as post‐polycythaemic myelofibrosis (post‐PV MF) and post‐thrombocythemic myelofibrosis (post‐ET MF) in both adult and paediatric patients.
Aims
The occurrence of AIDS in 1980s posed difficult problems for haemophilia clinicians worldwide. The impact of these events is substantial, and the events continue to be subject to judicial ...proceedings and publications. The stance of haemophilia physicians, particularly their professional resilience, is of importance and remains unexamined.
Methods
Deploying oral histories informed by literature review of scientific publications and past inquiry reports, this qualitative study addresses how physicians continued to work in haemophilia during those years and attributes that contributed to their resilience.
Results and conclusions
Experience and role in laboratory aspects were of value in handling and communicating uncertainty. Collegiality, peer support and scholarship were important in sustaining their roles, in clinical decision‐making and re‐instating confidence in the therapeutic relationship during the toughest years of their practice.
Trust forms the core of healing relationships. Mistrust can co-exist and complement trust by enabling patients’ to challenge medical decisions without fear of repercussion, thereby negotiating a more ...patient-centric approach. While trust can safeguard the therapeutic relationship during periods of medical uncertainty, a reappraisal of trust at such times can lead to its loss, adversely affecting this relationship. This occurred during the 1980s when haemophilia patients contracted AIDS from their treatment, a situation of iatrogenic harm at a time of evolving uncertainty. Published literature on how this impacted on doctor’s response is absent. Using legal and narrative material from the UK and elsewhere, this paper will address profoundly distressing dilemmas in the stance of haemophilia physicians towards their patients during the 1980s and how this impacted on trust. The paper argues that trust and mistrust are fluid during times of uncertainty. This trust is subject to social forces that are ethically challenging and beyond individual control. Its recovery requires fresh societal debate. This understanding is of fundamental importance in the training of medical students and doctors to become better physicians.
Melphalan is widely used as a preparative agent in patients with multiple myeloma (MM) undergoing autologous stem cell transplantation (SCT). Although disease relapse is the major cause of death ...after a melphalan-conditioned autograft, the mechanism remains unclear. Melphalan produces a number of DNA adducts with the DNA interstrand crosslink (ICL) considered to be the critical cytotoxic lesion. By using a modification of the single-cell gel electrophoresis (Comet) assay, we have measured formation and repair of DNA ICL in plasma cells from melphalan- naive and melphalan-treated patients (ie, those who have relapsed after a melphalan-conditioned autologous SCT or oral melphalan therapy). Similar levels of dose-dependent DNA interstand crosslinking were observed in cells from both melphalan-naive and -treated patients. However, marked differences in ICL repair were observed: cells from naive patients showed no repair, whereas those from treated patients exhibited between 42% and 100% repair at 40 hours. In vitro sensitivity to melphalan in plasma cells was found to correlate with ICL repair. These findings suggest that ICL repair may be an important mechanism by which melphalan resistance emerges after autologous SCT or oral therapy. This mechanism may have implications for MM patients undergoing melphalan therapy.
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