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Maintaining good musculoskeletal health, including good oral health, is as important for women with bleeding disorders (WBD) as it is for men. Many people with bleeding disorders ignore bleeding from their gums, believing it to be part of their condition. However, it may be a sign of periodontal disease, which left untreated can lead to accelerated tooth loss and infection, adversely affecting overall health. A good diet and access to good dental care from childhood are important to maintaining good oral health in WBD. Joint bleeding and degeneration are not limited to people with more severe forms of haemophilia; joint-related diagnoses have been shown to be twice as common among haemophilia carriers and women with mild haemophilia than in the general population. Women with type 3 von Willebrand disease experience comparable joint outcomes to younger intensively treated patients with severe haemophilia. Neither gum nor joint bleeds should ever be considered normal, as both can be treated to avoid progressive disease. Dental and joint specialists and physiotherapists should work closely with haemophilia teams to ensure optimal care for long-term preservation of musculoskeletal health.

TNF-α is a major cytokine implicated in rheumatoid arthritis. Its expression is regulated both at the transcriptional and posttranscriptional levels and recent data demonstrated that miRNAs are implicated in TNF-α response in macrophages. LPS-activated FLS isolated from RA patients express TNF-α mRNA but not the mature protein. This prompted us to look for miRNAs which could be implicated in this anti-inflammatory effect. Using a microarray, we found two miRNAs, miR-125b and miR-939 predicted to target the 3'-UTR of TNF-α mRNA, to be up-regulated in RA FLS in response to LPS, but their repression did not restore mature TNF-α expression in FLS. We showed previously that miR-346, which is upregulated in LPS-activated FLS, inhibited Btk expression that stabilized TNF-α mRNA. Blocking miR-346 reestablished TNF-α expression in activated FLS. Interestingly, transfection of miR-346 in LPS-activated THP-1 cells inhibited TNF-α secretion. We also demonstrated that TTP, a RNA binding protein which inhibited TNF-α synthesis, is overexpressed in activated FLS and that inhibition of miR-346 decreases its expression. Conversely, transfection of miR-346 in LPS-activated THP-1 cells increased TTP mRNA expression and inhibited TNF-α release. These results indicate that miR-346 controls TNF-α synthesis by regulating TTP expression.

Gene-based therapy opens an entirely new paradigm in managing people with haemophilia (PWH), offering them the possibility of a functional cure by enabling continuous expression of factor VIII (FVIII) or factor IX (FIX) after transfer of a functional gene designed to replace the PWH’s own defective gene. In recent years, significant advances in gene therapy have been made, resulting in clotting factor activity attaining near-normal levels, as reflected by ‘zero bleeding rates’ in previously severely inflicted patients following a single administration of adeno-associated viral (AAV) vectors. While this new approach represents a major advancement, there are still several issues that must be resolved before applying this technology in clinical practice. First, awareness, communication, and education about the therapeutic potential and modalities of gene therapy must be further strengthened. To this end, objective, unbiased, transparent, and regularly updated information must be shared, in an appropriate way and understandable language with the support of patients’ organizations. Second, healthcare providers should adopt a patient-centred approach, as the ‘one size fits all’ approach is inappropriate when considering gene therapy. Instead, a holistic patient view taking into account their physical and mental dimensions, along with unexpressed expectations and preferences, is mandatory. Third, the consent procedure must be improved, ensuring that patients’ interests are maximally protected. Finally, gene therapy is likely to be first delivered in a few centres, with the highest expertise and experience in this domain. Thus, patients should be managed based on a hub-and-spoke model, taking into account that the key to gene therapy’s success lies in an optimal communication and collaboration both within and between haemophilia centres sharing their experiences in the frame of international registries. This review describes recent progress and explains outstanding hurdles that must be tackled to ease the implementation of this paradigm-changing new therapy.

Background Adult T-cell leukemia-lymphoma (ATL) is an aggressive mature lymphoid proliferation associated with poor prognosis. Standard of care includes chemotherapy and/or the combination of zidovudine and interferon-alpha. However, most patients experience relapse less than 6 months after diagnosis. Allogeneic stem cell transplantation is the only curative treatment, but is only feasible in a minority of cases. We previously showed in a mouse model that Arsenic trioxide (As 2 O 3 ) targets ATL leukemia initiating cells. Results As 2 O 3 consolidation was given in 9 patients with ATL (lymphoma n = 4; acute n = 2; and indolent n = 3), who were in complete (n = 4) and partial (n = 3) remission, in stable (n = 1) and in progressive (n = 1) disease. Patients received up to 8 weeks of As 2 O 3 at the dose of 0.15 mg/kg/day intravenously in combination with zidovudine and interferon-alpha. One patient in progression died rapidly. Of the remaining eight patients, three with indolent ATL subtype showed overall survivals of 48, 53 and 97 months, and duration of response to As 2 O 3 of 22, 25 and 73 months. The other 5 patients with aggressive ATL subtype had median OS of 36 months and a median duration of response of 10 months. Side effects were mostly hematological and cutaneous (one grade 3) and reversible with dose reduction of AZT/IFN and/or As 2 O 3 discontinuation. The virus integration analysis revealed the regression of the predominant malignant clone in one patient with a chronic subtype. Conclusion These results suggest that consolidation with As 2 O 3 could be an option for patients with ATL in response after induction therapy and who are not eligible for allogeneic stem cell transplantation.

Multiple myeloma (MM) is a chronic hematologic malignancy characterized by complex therapeutic strategies, repeated relapses, and substantial information and psychosocial needs. Advances in oral therapies and outpatient management have shifted greater responsibility to patients and caregivers, emphasizing the need for accessible, high-quality educational resources. Therapeutic patient education (TPE) aims to empower patients to understand and manage their condition more effectively. Digital education tools such as massive open online courses (MOOCs) represent an innovative approach to deliver structured, interactive, and scalable learning experiences to large patient populations. However, few MOOCs have been specifically designed for patients with oncological or hematological disorders, and even fewer have been rigorously evaluated for their educational impact. This study aimed to develop and evaluate a MOOC co-designed with patients, caregivers, and health care professionals to improve knowledge, skills, and empowerment among patients living with MM and their relatives. Secondary objectives included assessing participant satisfaction, engagement, and the feasibility of this digital education model at a national scale. The MOOC \"Understanding and Living with Myeloma\" was jointly developed by the French Association of Patients with Multiple Myeloma (AF3M) and the French-Speaking Myeloma Intergroup (IFM). The program consisted of 5 thematic modules delivered over 8 weeks, covering disease mechanisms, diagnosis, treatment options, side-effect management, and daily-life adaptation. Content combined educational videos, self-assessment quizzes, peer-tutoring forums, and live web conferences with experts. Participants self-assessed their knowledge using a 52-item questionnaire rated from 1 (poor) to 5 (excellent) before and after completing the program. Descriptive and inferential analyses were performed using the Wilcoxon signed-rank test (2-sided α=.05). During the first session, 254 participants registered for the course. Among them, 76 (30%) completed all modules and both evaluations. The mean global knowledge score increased from 3.06/5 before to 4.21/5 after the MOOC (mean gain + 1.15, + 38%; P<.001). Improvements were consistent across all knowledge domains, including understanding of treatments (+40%), recognition of warning signs (+35%), and self-management skills (+39%). Overall, 98% (74/76) of respondents reported being satisfied or very satisfied with the course, and 99% (75/76) would recommend it to other patients. Since 2018, the MOOC has been conducted 6 times at different periods, enrolling a cumulative total of 2400 participants, confirming its sustainability and scalability. Participation in this co-designed, patient-centered MOOC was associated with a statistically and educationally significant improvement in knowledge among patients with MM and their caregivers. The program was highly valued by users and demonstrates the feasibility of large-scale digital patient education in oncology. As a freely accessible, repeatable, and peer-supported resource, this MOOC complements medical consultations and traditional TPE programs. Its design and outcomes may serve as a model for future digital health education initiatives targeting other chronic diseases.

Background Selinexor is an oral, selective nuclear export inhibitor. STORM was a phase 2b, single-arm, open-label, multicenter trial of selinexor with low dose dexamethasone in patients with penta-exposed relapsed/refractory multiple myeloma (RRMM) that met its primary endpoint, with overall response of 26% (95% confidence interval [CI], 19 to 35%). Health-related quality of life (HRQoL) was a secondary endpoint measured using the Functional Assessment of Cancer Therapy – Multiple Myeloma (FACT-MM). This study examines impact of selinexor treatment on HRQoL of patients treated in STORM and reports two approaches to calculate minimal clinically important differences for the FACT-MM. Methods FACT-MM data were collected at baseline, on day 1 of each 4-week treatment cycle, and at end of treatment (EOT). Changes from baseline were analyzed for the FACT-MM total score, FACT-trial outcome index (TOI), FACT-General (FACT-G), and the MM-specific domain using mixed-effects regression models. Two approaches for evaluating minimal clinically important differences were explored: the first defined as 10% of the instrument range, and the second based on estimated mean baseline differences between Eastern Cooperative Oncology Group performance status (ECOG PS) scores. Post-hoc difference analysis compared change in scores from baseline to EOT for treatment responders and non-responders. Results Eighty patients were included in the analysis; the mean number of prior therapies was 7.9 (standard deviation [SD] 3.1), and mean duration of myeloma was 7.6 years (SD 3.4). Each exploratory minimal clinically important difference threshold yielded consistent results whereby most patients did not experience HRQoL decline during the first six cycles of treatment (range: 53.9 to 75.7% for the first approach; range: 52.6 to 72.9% for the second). Treatment responders experienced less decline in HRQoL from baseline to EOT than non-responders, which was significant for the FACT-G, but not for other scores. Conclusion The majority of patients did not experience decline in HRQoL based on minimal clinically important differences during early cycles of treatment with selinexor and dexamethasone in the STORM trial. An anchor-based approach utilizing patient-level data (ECOG PS score) to define minimal clinically important differences for the FACT-MM gave consistent results with a distribution-based approach. Trial registration This trial was registered on ClinicalTrials.gov under the trial-ID NCT02336815 on January 8, 2015.

Mastocytosis, a clonal disorder characterized by the accumulation of mast cells in various tissues, affects both adults and children. Adults frequently exhibit KIT activating mutations, usually in the phospho-transferase domain (PTD KIT mutations). Our previous findings revealed that children also harbor oncogenic KIT activating mutations, but more commonly within the extra-cellular domain (non-PTD KIT mutations). While the disease persists chronically in adults, it often regresses spontaneously in children through an unknown mechanism. Here, we report that tumor senescence in childhood mastocytosis may be triggered by significantly shortened telomeres in mast cells harboring non-PTD KIT mutations compared to those with PTD KIT mutations. In vitro models further demonstrated a senescent phenotype associated with shorter telomeres for the non-PTD KIT mutant compared to the PTD KIT mutant. Mechanistically, we found that telomere shortening in mast cells from children with non-PTD KIT mutations is linked with increased p38 MAP-kinase activation, resulting in lower TRF2 occupancy on telomeres. Thus, non-PTD KIT mutations trigger distinct signaling pathways leading to telomere shortening and cellular senescence, providing mechanistic insights into the differing outcomes between childhood- and adult-onset mastocytosis.

Aims/Background Recent agents have profoundly reshaped the multiple myeloma (MM) landscape. Their real‐world impacts need to be assessed over the long term. Methods EMMY is a non‐interventional, prospective dynamic cohort, conducted in France, since 2017, with 900 patients enrolled each year. Newly diagnosed MM (NDMM) who initiated a treatment from 2017 to 2020 are here described. Results A total of 1036 non‐transplant eligible (NTE) patients (median age: 74.9 years) and 561 patients who received autologous stem cell transplantation (ASCT) (median age: 60.6 years) were enrolled. For ASCT patients, a shift in induction treatment from bortezomib‐thalidomide‐dexamethasone (VTd) (29.1%) to bortezomib‐lenalidomide‐dexamethasone (VRd) (55.1%) marked the period. Maintenance treatment with R after ASCT became a standard (75% of patients). In NTE patients, R‐based regimens were increasingly used from 29.4% in 2017 (of whom Rd.: 17.0%, VRd: 10.6%) to 73.3% in 2020 (of whom Rd.: 21.8%, VRd: 48.5%). Median progression‐free survival (mPFS) was 46.5 months (95% CI: 37.8–50.6) and 18.7 months (95% CI: 16.3–20.8) in ASCT and NTE patients, respectively. In the ASCT group, patients treated with and without R maintenance had a mPFS of 51.8 (95% CI: 44.1–NA) and 29.6 months (95% CI: 21.8–40.9), respectively. In the NTE group, the mPFS was 26.3 (95% CI: 21.9–30.9) and 14.6 months (95% CI: 11.9–17.7) in patients who received an R‐based and non‐R‐based regimen, respectively. The estimated 48‐month overall survival rates were 89% (95% CI: 84.5–92.2) and 63% (95% CI: 58.5–67.1) for ASCT and NTE patients, respectively. Conclusions The 2017–2020 period was marked by the expansion of R use in both NDMM ASCT and NTE patients. A total of 1036 non‐transplant eligible (NTE) patients and 561 patients who received autologous stem cell transplantation (ASCT) were enrolled in Emmy. In the ASCT group, patients treated with and without R maintenance had a mPFS of 51.8 (95% CI: 44.1–NA) and 29.6 months (95% CI: 21.8–40.9), respectively. In the NTE group, the mPFS was 26.3 (95% CI: 21.9–30.9) and 14.6 months (95% CI: 11.9–17.7) in patients who received an R‐based and non‐R‐based regimen, respectively. The 2017–2020 period was marked by the expansion of R use in both NMDD ASCT and NTE patients.