Can we use statins to prevent stroke in Fabry disease?

Summary  Fabry disease is a rare, X-linked lysosomal storage disease caused by an inborn deficiency of α-galactosidase A, which results in the progressive accumulation of globotriaosylceramide and other neutral glycolipids in a range of cells and tissues. In association with the renal and cardiac insufficiency, cerebrovascular complications can result in the death of the patients. Several mechanisms causing vascular damage that leads to the development of deep-white matter lesions have been described. Recent clinical trials strongly suggest that statins protect against stroke by neuroprotective properties or pleiotropic effects. Aim: To evaluate evidence and potential beneficial effects of statins in the vasculopathy of Fabry disease. Competing interests: None declared     

Can we influence fibrosis in Crohn's disease?

Despite recent advances in the therapy of active Crohn's disease (CD) fibrostenosis remains a challenging complication of the disease. Transmural inflammation of CD is associated with phenotypic switch of the mesenchymal cells resulting in proliferation and collagen deposition. Both resident myofibroblasts and smooth muscle are candidate progenitor cells of the fibrogenic cells in CD stenoses. The principal growth factors involved in intestinal fibrosis have not been identified although TGF-beta 1 and 2, PDGF and IL-1 may be involved. Research aimed at elucidating the basic mechanisms underlying fibrosis in the gut has been hindered by the lack of an adequate animal model. Recently, however, new rodent models of chronic inflammation with distinct fibrosis have been described. Cell culture research has provided more information about possible pathways that may limit uncontrolled mesenchymal proliferation in the inflamed intestinal wall. The modulator role of neurotransmitters such as VIP, nitric oxide and prostaglandines is an important target for therapeutic intervention. Interfering with the phenotypic switch of mesenchymal cells may offer new therapeutic perspectives in the prevention of fibrostenosis. Further in vitro and animal studies as well as restenosis prevention studies are needed to develop pharmacological tools in the prevention of Crohn's disease fibrostenosis.     

Minimal residual disease in chronic lymphocytic leukaemia: is it ready for primetime?

New therapeutic modalities have substantially improved response rates and outcomes in chronic lymphocytic leukaemia (CLL), yet the mindset remains that palliation is the only goal of therapy because the disease is considered incurable. Ultimately, all patients relapse despite achieving an initial response, as minimal residual disease (MRD) persisting after therapy eventually evolves into morphological and clinical recurrence. The emergence of immune-based combination therapies capable of inducing molecular remissions, the availability of highly sensitive assays that detect MRD, and emerging data showing a longer duration of response or longer survival in patients with no detectable disease, suggest that eradicating MRD may be a reasonable option for some patients. Moreover, novel biological prognostic markers have divided CLL into favourable and unfavourable subtypes, arguing in favour of defining different goals of therapy for different patients. Clinicians are increasingly challenged with the task of how best to incorporate MRD assessment into clinical practice, especially in an era when these novel prognostic factors exist. This review summarises the current understanding of MRD from a clinical standpoint, suggests that MRD eradication maybe a reasonable option for some patients, and argues in favour of designing large randomised studies to determine whether MRD-negative remission improves outcome.     

A highly unusual cluster of acute promyelocytic leukaemia: an environmental aetiology?

We report three consecutive cases of acute promyelocytic leukaemia (APML) that were diagnosed within a 4-month period. This unexpected sequence of events was made all the more notable following our discovery of co-incidental geographic, social, and occupational factors that linked them together. Our data strongly suggests that environmental agents may play a greater role in the aetiology of APML than is commonly perceived.     

A highly unusual cluster of acute promyelocytic leukaemia: an environmental aetiology?

We report three consecutive cases of acute promyelocytic leukaemia (APML) that were diagnosed within a 4‐month period. This unexpected sequence of events was made all the more notable following our discovery of co‐incidental geographic, social, and occupational factors that linked them together. Our data strongly suggests that environmental agents may play a greater role in the aetiology of APML than is commonly perceived.     

Higher than normal mitochondrial DNA content associated with better outcome in acute promyelocytic leukaemia? Maybe

Mitochondrial biology may influence the outcome of therapy for acute promyelocytic leukemia if arsenic trioxide is not part of the treatment. Inclusion of arsenic trioxide in the treatment regimen may cancel the adverse impact of certain mitochondrial abnormalities frequently associated with the disease. Commentary on: Pereira-Martins et al. Clinical significance of mitochondrial DNA content in acute promyelocytic leukaemia. Br J Haematol 2023;200:170-174.     

Can we afford to eliminate restenosis? Can we afford not to?

Over the past decade, coronary stenting has emerged as the dominant form of percutaneous coronary revascularization. However, bare metal stents remain limited by a high incidence of restenosis, leading to frequent repeat revascularization procedures and substantial economic burden. Antiproliferative drug-eluting stents (DES) have recently demonstrated dramatic reductions in rates of restenosis, compared with conventional stenting, but important concerns about their costs have been raised. In this article, we summarize current evidence on the economic impact of restenosis and explore the potential benefits and economic outcomes of DES. In addition to examining the long-term costs of this promising technology, we consider the potential cost-effectiveness of DES from a health care system perspective and the impact of specific patient, lesion, and provider characteristics on these parameters.     

Can we say that senescent cells cause ageing?

Replicative senescence, the irreversible loss of proliferative capacity, is a common feature of somatic cells derived from many different species. The molecular mechanisms controlling senescence in mammals, and especially in humans, have now been substantively elucidated. However, to date, attempts to link the senescence of cells with the ageing of the organisms they comprise has not met with any similar degree of success, largely due to a lack of systematic investigation and the absence of the necessary biochemical tools. This review will summarise current data linking replicative senescence and organismal ageing. It will also suggest some essential tests of the cell senescence hypothesis and some necessary ground work which must be carried out before such tests can be fruitfully performed. It will not discuss the detailed molecular 'clockwork' controlling the decision to exit the cell cycle irreversibly because this is covered by other authors in this special issue.     

Measurable residual disease in acute lymphoblastic leukemia: How low is low enough?

Quantification of measurable residual disease (MRD) in acute lymphoblastic leukemia (ALL) is a well-established clinical tool used to risk stratify patients during the course of chemotherapy, immunotherapy, and/or transplant therapy. As technologies evolve, the sensitivity for quantifying exceptionally low disease burden using either next generation sequencing (NGS) or next generation flow cytometry (NGF) has improved. It is now possible to detect MRD and quantify it precisely in patients who would previously have been deemed MRD negative by older, lower sensitivity methods. Persistence or recurrence of ALL disease burden above 10^?4 (0.01%) is accepted as the minimum threshold for making clinical decisions, but with NGS and NGF, clinicians now confront decision-making with disease burdens sometimes quantified to as low as 10^?6 (0.0001%, or one leukemia cell in a million leukocytes). Emerging data suggest these higher sensitivity methods are superior for identifying patients at lowest risk for relapse, but it remains controversial whether to institute therapies such as blinatumomab or chimeric antigen receptor (CAR)-T cells or move patients to allogeneic hematopoietic cell transplant (alloHCT) when they have quantifiable disease burden less than 10^?4. With additional evidence to facilitate integration of highly sensitive MRD quantification into clinical care and to contextualize MRD within the genotype of individual patients, it will likely be increasingly possible to identify patients able to avoid alloHCT and potentially even de-escalate therapy.     

Should we T cell deplete sibling grafts for acute myeloid leukaemia in first remission?

There is controversy regarding the best approach to the management of patients with acute myeloid leukaemia (AML) in first remission (CR1). The impact of matched related allogeneic transplant in CR1 on the overall survival is equivocal, but what is not in doubt is a significant reduction in the relapse risk, compared to both autologous transplants and intensive chemotherapy, which is because of the allogeneic or the graft-versus-leukaemia (GVL) effect. Yet, this does not always translate to improved survival. T cell depletion (TCD) can reduce deaths related to graft-versus-host disease (GVHD) and its therapy, but might increase the relapse risk. The existing literature suggests that TCD is associated with a disease-free survival (DFS) of 53-80% and is associated with a lower relapse risk than anticipated (0-30%). We discuss the evolution of TCD in allogeneic transplantation and its relevance in AML-CR1 with regard to GVHD, DFS, immune reconstitution and GVL effect. It is possible that by reducing TRM related to GVHD and extramedullary toxicities, particularly in the older patients, TCD might improve the impact of allogeneic transplantation in AML-CR1, provided the immune reconstitution and the relapse risk are not adversely affected. Randomised studies are underway to address these issues.