Quality of skeletal muscles during allogeneic stem-cell transplantation: a pilot study.

OBJECTIVES: This study investigated the muscle fat fraction (FF) and muscle-related parameters before and after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: Fat and water signals were derived from the in-phase and out-of-phase MR signal intensities of the pelvis and thigh using the two-point Dixon technique. They were analysed using Synapse Vincent, and muscle quality was evaluated using the FF. The muscle mass was assessed by measuring the thigh and gluteal muscle areas using a manual trace on the MR image. The association between the muscle FF and clinical data was retrospectively determined. RESULTS: This study included 11 patients (6 males). Their mean age was 42.7 years, and eight had leukaemia. Eight were assessed at a mean of 65.4 days post-HSCT. The hip and thigh skeletal muscle FFs were not significantly different during HSCT. The grip and lower limb muscle strengths decreased significantly after HSCT. Patients with low FFs before transplantation tended to lose muscle strength, and the increase in FF and decrease of muscle strength were correlated. CONCLUSIONS: Muscle strength and quantity decrease during the early phase after HSCT, especially in patients with low FF muscles. Therefore, interventions based on muscle quality and quantity are essential.

Insights into existing and futuristic treatment approach for chronic myeloid leukaemia.

Oncogenes play a crucial part in human cancer development, and when particular drugs obstruct the proteins produced by these oncogenes, the tumoural process can be ceased. For instance, in chronic myeloid leukaemia (CML), all pathological traits are associated with a single oncogene, BCR-ABL1. CML is a triphasic cancerous disorder of haematopoietic stem cells, marked by a balanced translocation between chromosomes 9 and 22, leading to the genesis of a Philadelphia chromosome encompassing the BCR-ABL1 fusion gene. This fusion oncogene further produces a constitutive active tyrosine kinase protein, enhancing the downstream signalling pathways and constitutes cancer. The treatment for CML has been entirely altered from chemotherapy and immunotherapy to targeted therapy with the emergence of tyrosine kinase inhibitors (TKIs) which inhibit BCR-ABL1 kinase activity. However, the inhibitory mechanism of TKIs is constrained by BCR-ABL1 dependent and independent resistance mechanisms, prompting the exploration of novel therapeutics through extensive clinical trials to develop next-generation drugs with enhanced potency. The persistent challenges posed by CML have motivated researchers to seek innovative strategies for its eradication, such as the application of the genome editing tool CRISPR/Cas9. This review provides insights into existing CML diagnoses, treatment modalities, resistance mechanisms, drugs under trial phases and new potential therapeutic drugs. Furthermore, the review looks ahead to a visionary perspective wherein the CRISPR/Cas9 approach holds the potential to evolve into a prospective curative measure for CML.

Molecular characterization and biomarker identification in paediatric B-cell acute lymphoblastic leukaemia.

B-cell acute lymphoblastic leukaemia (B-ALL) is the most prevalent hematologic malignancy in children and a leading cause of mortality. Managing B-ALL remains challenging due to its heterogeneity and relapse risk. This study aimed to delineate the molecular features of paediatric B-ALL and explore the clinical utility of circulating tumour DNA (ctDNA). We analysed 146 patients with paediatric B-ALL who received systemic chemotherapy. The mutational landscape was profiled in bone marrow (BM) and plasma samples using next-generation sequencing. Minimal residual disease (MRD) testing on day 19 of induction therapy evaluated treatment efficacy. RNA sequencing identified gene fusions in 61% of patients, including 37 novel fusions. Specifically, the KMT2A-TRIM29 novel fusion was validated in a boy who responded well to initial therapy but relapsed after 1 year. Elevated mutation counts and maximum variant allele frequency in baseline BM were associated with significantly poorer chemotherapy response (p = 0.0012 and 0.028, respectively). MRD-negative patients exhibited upregulation of immune-related pathways (p < 0.01) and increased CD8+ T cell infiltration (p = 0.047). Baseline plasma ctDNA exhibited high mutational concordance with the paired BM samples and was significantly associated with chemotherapy efficacy. These findings suggest that ctDNA and BM profiling offer promising prognostic insights for paediatric B-ALL management.

Therapeutic strategies targeting aberrant RNA splicing in myeloid malignancies.

In recent years, large-scale sequencing efforts have identified targetable driver mutations in haematopoietic stem cells. These efforts have led to the development and approval of nine novel agents for relapsed or refractory acute myelogenous leukaemia (R/R AML). However, despite an expansion in targeted therapies, achieving a durable remission in AML and high-risk myelodysplastic syndrome (HR-MDS) remains a significant challenge, and there is an urgent need for new effective treatments. Modulation of aberrant RNA splicing has emerged as a novel therapeutic approach in myeloid diseases. Aberrant splicing drives dysregulated gene expression that promotes tumourigenesis through increased proliferation and metastatic potential, immune evasion, decreased apoptosis, and chemotherapy resistance. Mutations in spliceosomal components have been identified in numerous cancer subtypes, with mutations in RNA binding proteins SF3B1, SRSF2, U2AF1, and ZRSR2 occurring frequently in AML and in up to 60% of patients with MDS, as well as in chronic myelomonocytic leukaemia and in 10% of patients with chronic lymphocytic leukaemia. In this review, we explore therapeutic strategies targeting aberrant splicing and the potential of these approaches to drive clinical responses.

Pediatric Acute Myeloid Leukemia: Unraveling Complexities in Intensive Chemotherapy and the Emergence of Superbugs - A Case Study.

Background: This case report underscores the intricate challenges in managing paediatric patients with acute myeloid leukaemia (AML) undergoing intensive chemotherapy, particularly when complicated by the emergence of multidrug-resistant pathogens such as Carbapenem-Resistant Pseudomonas aeruginosa (CRPA). Case Presentation: An 11-year-old male with AML presented with skin purpura and persistent cough. Clinical and laboratory assessments revealed a high-risk AML profile with genetic mutations, leading to the initiation of intensive chemotherapy per the C-HUANA-AML-2015 protocol. Despite successful disease remission after initial chemotherapy courses, the patient experienced unexpected complications. Notably, septic shock, bone marrow failure, and the emergence of CRPA were encountered during the clinical course. Septic shock occurred following Course B3 chemotherapy, marked by a fever unresponsive to initial antibiotic therapy. Despite negative blood cultures, meropenem and vancomycin were initiated, successfully normalizing temperature. Subsequent challenges included persistent bone marrow suppression, perianal dermatitis, and the identification of CRPA in stool cultures, leading to altered antibiotic therapy guided by minimum inhibitory concentration (MIC) considerations. Whole-genome sequencing (WGS) of the CRPA strain revealed a highly virulent clone (ST-970) with numerous resistance and virulence genes. Conclusion: This case report offers new insights into the complexities of pediatric AML management, with a focus on the emergence of CRPA. The discovery of a high-risk CRPA clone with detailed genomic data underscores the growing challenge of antimicrobial resistance in pediatric oncology. The persistent presence of CRPA and ongoing bone marrow failure highlight the difficulties in managing these complications. This case calls for a reassessment of treatment strategies and encourages further research to improve outcomes in pediatric AML, emphasizing the need for a multidisciplinary approach to address infectious complications and antimicrobial resistance.

HTLV-1 infected T cells cause bone loss via small extracellular vesicles.

Adult T cell leukaemia (ATL), caused by infection with human T- lymphotropic virus type 1 (HTLV-1), is often complicated by hypercalcemia and osteolytic lesions. Therefore, we studied the communication between patient-derived ATL cells (ATL-PDX) and HTLV-1 immortalized CD4+ T cell lines (HTLV/T) with osteoclasts and their effects on bone mass in mice. Intratibial inoculation of some HTLV/T leads to a profound local decrease in bone mass similar to marrow-replacing ATL-PDX, despite the fact that few HTLV/T cells persisted in the bone. To study the direct effect of HTLV/T and ATL-PDX on osteoclasts, supernatants were added to murine and human osteoclast precursors. ATL-PDX supernatants from hypercalcemic patients promoted the formation of mature osteoclasts, while those from HTLV/T were variably stimulatory, but had largely consistent effects between human and murine cultures. Interestingly, this osteoclastic activity did not correlate with expression of osteoclastogenic cytokine receptor activator of nuclear factor kappa-B ligand (RANKL), suggesting an alternative mechanism. HTLV/T and ATL-PDX produce small extracellular vesicles (sEV), known to facilitate HTLV-1 infection. We hypothesized that these sEV also mediate bone loss by targeting osteoclasts. We isolated sEV from both HTLV/T and ATL-PDX, and found they carried most of the activity found in supernatants. In contrast, sEV from uninfected activated T cells had little effect. Analysis of sEV (both active and inactive) by mass spectrometry and electron microscopy confirmed absence of RANKL and intact virus. Viral proteins Tax and Env were only present in sEV from the active, osteoclast-stimulatory group, along with increased representation of proteins involved in osteoclastogenesis and bone resorption. sEV from osteoclast-active HTLV/T injected over mouse calvaria in the presence of low-dose RANKL caused more osteolysis than osteoclast-inactive sEV or RANKL alone. Thus, HTLV-1 infection of T cells can cause release of sEV with strong osteolytic potential, providing a mechanism beyond RANKL production that modifies the bone microenvironment, even in the absence of overt leukaemia.

Cytomegalovirus in haematopoietic cell transplantation - The troll is still there.

Patients undergoing allogeneic haematopoietic cell transplantation are prone to complications caused by viral infections. Cytomegalovirus (CMV) considerably impacts transplantation as it frequently requires antiviral intervention that evokes substantial side effects depending on the antiviral drug. Intermittent antiviral treatment may become necessary if CMV DNAemia cannot be permanently suppressed, and drug resistance may emerge that hampers and prolongs treatment. Despite sedulous endeavours, vaccination against CMV is not yet available. This review concisely summarises current approaches in managing CMV infection comprising risk factors, diagnostics including indications for resistance testing, and therapeutic options from antiviral drugs to virus-specific T cells.

The Anti-Leukemic Activities of Campesterol and Α-Tocopherol Against BCL-2 Target through Computational Drug Design Approaches.

INTRODUCTION: Heterogeneous Acute Myeloid Leukemia (AML) causes substantial worldwide morbidity and death. AML is characterized by excessive proliferation of immature myeloid cells in the bone marrow and impaired apoptotic regulator expression. METHOD: B-Cell Lymphoma 2 (BCL-2), an anti-apoptotic protein overexpressed in AML, promotes leukemic cell survival and chemoresistance. Thus, reducing BCL-2 may treat AML. Anticancer activities are found in Aloe barbadensis Miller (Aloe vera). Thus, this work used molecular modeling to assess Aloe vera bioactive chemicals as BCL-2 inhibitors. Molecular docking simulation showed that all identified Aloe vera phytocompounds have strong BCL-2 binding affinities (-6.7 to -8.7 kcal/mol). RESULT: Campesterol and α-tocopherol were identified as promising compounds for BCL-2 inhibitor research based on their drug-likeness, pharmacokinetics, and toxicity profiles. The stability and conformational of the BCL-2-compound complexes showed that the compounds were stable in BCL-2's binding pocket. CONCLUSION: Campesterol and α-tocopherol are promising BCL-2 inhibitors that might become effective anti-leukemic therapies with additional in vitro and in vivo research.

The discovery of the RCC1::IRF4 Fusion in CLL patients with t(1;6)(p35.3;p25.2) chromosomal translocation.

Jayne et al. provide a molecular characterization of the t(1;6)(p35.3;p25.2) chromosomal translocation in patients with chronic lymphocytic leukaemia. They indicate that this translocation involves the gene encoding interferon regulatory factor 4 (IRF4) on chromosome 6p25.2 with the regulator of chromosome condensation 1 (RCC1) gene on chromosome 1p35.3. This translocations may have important prognostic value. Commentary on: Jayne et al. The chromosomal translocation t(1;6)(p35.3;p25.2), recurrent in chronic lymphocytic leukaemia leads to RCC1::IRF4 fusion. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19790.

A Case of Plasma Cell Leukemia Arising De Novo: A Rare and Fatal Disease.

Plasma cell leukemia (PCL) is an aggressive form of multiple myeloma characterized by an increasing number of circulating plasma cells in the peripheral (circulating) blood. Primary PCL (pPCL) is the form of monoclonal gammopathy that is the most severe with a high mortality rate. Its incidence will be increasing, given the expected changes in clinical criteria for diagnosis. We present a case to help further understand the disease and the proposed criteria changes, as more research will be needed to better understand the impact of specific genetic findings on the prognosis of pPCL and secondary PCL (sPCL). We also feature the presentation, morphological changes in the peripheral smear, and cytogenetics of this rare disease.

Effects on Iron Metabolism and System Xc- /GPX4 Pathway from Hydroquinone Suggest Ferroptosis of Jurkat Cells.

Prolonged exposure to hydroquinone (HQ), a metabolite of benzene, can cause severe haematologic disorders in humans. However, the mechanism is still unclear. In the present study, we investigated whether HQ can induce haematological diseases through ferroptosis, which is another form of cell death apart from apoptosis. The results showed that HQ inhibited the viability of Jurkat cells in a dose-dependent and time-dependent manner. The half inhibitory concentrations (IC50s) of HQ-treated Jurkat cells for 12 h, 24 h and 48 h were 107.16 µmol/L, 33.29 µmol/L, and 14.78 µmol/L. The exposure of Jurkat cells to HQ increased intracellular Fe2+, malondialdehyde (MDA) and lipid reactive oxygen species (ROS) levels and down-regulated glutathione (GSH) levels. We used erastin-treated cells as a positive control and cells treated with HQ combined with deferoxamine mesylate (DFO) and ferrostain-1 (Fer-1)-treated cells as the negative controls. DFO and Fer-1 partially restored the degradation of cell viability and GSH content and the accumulation of Fe2+, MDA and lipid ROS caused by HQ. In addition, we found that cellular mitochondria in the HQ-treated group showed a decrease in volume, an increase in the density of the bilayer membrane and a decrease or disappearance of mitochondrial cristae. Changes in the erastin-treated group were similar to those in the HQ-treated group. We inferred that HQ induces ferroptosis in Jurkat cells. Subsequently, we found that HQ up-regulated the levels of transferrin receptor 1 (TFRC) mRNA and protein expression and down-regulated FTH1, SLC7A11 and synthetic substrate of antioxidant enzyme 4 (GPX4) mRNA levels and protein expression levels. However, the exposure of Jurkat cells to HQ with DFO and Fer-1 alleviated these changes. Notably, the activation of TFRC and the inhibition of FTH1 and System Xc- (cystine-glutamate reverse transporter protein) /GPX4 were associated with HQ-induced ferroptosis. These results provide novel insights into how HQ exacerbates haematopoietic cytotoxicity and provide potential targets for the prevention of HQ-induced diseases.

Assessing a decade of leukaemia-related premature mortality costs: impact on productivity loss in Spain.

INTRODUCTION: Cancer mortality is one of the dominant causes of productivity loss; and within all cancer sites, blood cancer is the fourth most common cause of death in Spain. Thus, its impacts in work productivity are a major concern and represent a high social impact. The aim of this study was to evaluate the productivity losses resulting from of premature deaths due to leukaemia in Spain. METHODS: The productivity costs stemming from premature mortality due to leukaemia were estimated using the human capital method. Information pertaining to mortality rates, typical incomes, and joblessness figures was gathered throughout a decade-long period spanning from 2012 to 2021. RESULTS: Leukaemia caused 40% of haematological malignancies losses. It represented a 3.39% of all cancer-related deaths. In addition, it was responsible for 7,851 years of potential productive life lost (YPLPLL) in 2021, and productivity losses of €4,206.52 million over the 10-year period. All these numbers are relevant for Spain as will help on a more efficient distribution of resource. CONCLUSIONS: These productivity losses obtained, highlight the burden of leukaemia on the Spanish population, providing novel data on the number of deaths, trends and productivity losses for this type of cancer. This evaluation offers fresh insights that can aid policymakers in efficiently distributing resources, thereby lessening the economic burden it imposes on individuals of working age.

The effect of exposure to radiofrequency fields on cancer risk in the general and working population: A systematic review of human observational studies - Part I: Most researched outcomes.

BACKGROUND: The objective of this review was to assess the quality and strength of the evidence provided by human observational studies for a causal association between exposure to radiofrequency electromagnetic fields (RF-EMF) and risk of the most investigated neoplastic diseases. METHODS: Eligibility criteria: We included cohort and case-control studies of neoplasia risks in relation to three types of exposure to RF-EMF: near-field, head-localized, exposure from wireless phone use (SR-A); far-field, whole body, environmental exposure from fixed-site transmitters (SR-B); near/far-field occupational exposures from use of hand-held transceivers or RF-emitting equipment in the workplace (SR-C). While no restrictions on tumour type were applied, in the current paper we focus on incidence-based studies of selected "critical" neoplasms of the central nervous system (brain, meninges, pituitary gland, acoustic nerve) and salivary gland tumours (SR-A); brain tumours and leukaemias (SR-B, SR-C). We focussed on investigations of specific neoplasms in relation to specific exposure sources (i.e. E-O pairs), noting that a single article may address multiple E-O pairs. INFORMATION SOURCES: Eligible studies were identified by literature searches through Medline, Embase, and EMF-Portal. Risk-of-bias (RoB) assessment: We used a tailored version of the Office of Health Assessment and Translation (OHAT) RoB tool to evaluate each study's internal validity. At the summary RoB step, studies were classified into three tiers according to their overall potential for bias (low, moderate and high). DATA SYNTHESIS: We synthesized the study results using random effects restricted maximum likelihood (REML) models (overall and subgroup meta-analyses of dichotomous and categorical exposure variables), and weighted mixed effects models (dose-response meta-analyses of lifetime exposure intensity). Evidence assessment: Confidence in evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. RESULTS: We included 63 aetiological articles, published between 1994 and 2022, with participants from 22 countries, reporting on 119 different E-O pairs. RF-EMF exposure from mobile phones (ever or regular use vs no or non-regular use) was not associated with an increased risk of glioma [meta-estimate of the relative risk (mRR) = 1.01, 95 % CI = 0.89-1.13), meningioma (mRR = 0.92, 95 % CI = 0.82-1.02), acoustic neuroma (mRR = 1.03, 95 % CI = 0.85-1.24), pituitary tumours (mRR = 0.81, 95 % CI = 0.61-1.06), salivary gland tumours (mRR = 0.91, 95 % CI = 0.78-1.06), or paediatric (children, adolescents and young adults) brain tumours (mRR = 1.06, 95 % CI = 0.74-1.51), with variable degree of across-study heterogeneity (I2 = 0 %-62 %). There was no observable increase in mRRs for the most investigated neoplasms (glioma, meningioma, and acoustic neuroma) with increasing time since start (TSS) use of mobile phones, cumulative call time (CCT), or cumulative number of calls (CNC). Cordless phone use was not significantly associated with risks of glioma [mRR = 1.04, 95 % CI = 0.74-1.46; I2 = 74 %) meningioma, (mRR = 0.91, 95 % CI = 0.70-1.18; I2 = 59 %), or acoustic neuroma (mRR = 1.16; 95 % CI = 0.83-1.61; I2 = 63 %). Exposure from fixed-site transmitters (broadcasting antennas or base stations) was not associated with childhood leukaemia or paediatric brain tumour risks, independently of the level of the modelled RF exposure. Glioma risk was not significantly increased following occupational RF exposure (ever vs never), and no differences were detected between increasing categories of modelled cumulative exposure levels. DISCUSSION: In the sensitivity analyses of glioma, meningioma, and acoustic neuroma risks in relation to mobile phone use (ever use, TSS, CCT, and CNC) the presented results were robust and not affected by changes in study aggregation. In a leave-one-out meta-analyses of glioma risk in relation to mobile phone use we identified one influential study. In subsequent meta-analyses performed after excluding this study, we observed a substantial reduction in the mRR and the heterogeneity between studies, for both the contrast Ever vs Never (regular) use (mRR = 0.96, 95 % CI = 0.87-1.07, I2 = 47 %), and in the analysis by increasing categories of TSS ("<5 years": mRR = 0.97, 95 % CI = 0.83-1.14, I2 = 41 %; "5-9 years ": mRR = 0.96, 95 % CI = 0.83-1.11, I2 = 34 %; "10+ years": mRR = 0.97, 95 % CI = 0.87-1.08, I2 = 10 %). There was limited variation across studies in RoB for the priority domains (selection/attrition, exposure and outcome information), with the number of studies evenly classified as at low and moderate risk of bias (49 % tier-1 and 51 % tier-2), and no studies classified as at high risk of bias (tier-3). The impact of the biases on the study results (amount and direction) proved difficult to predict, and the RoB tool was inherently unable to account for the effect of competing biases. However, the sensitivity meta-analyses stratified on bias-tier, showed that the heterogeneity observed in our main meta-analyses across studies of glioma and acoustic neuroma in the upper TSS stratum (I2 = 77 % and 76 %), was explained by the summary RoB-tier. In the tier-1 study subgroup, the mRRs (95 % CI; I2) in long-term (10+ years) users were 0.95 (0.85-1.05; 5.5 %) for glioma, and 1.00 (0.78-1.29; 35 %) for acoustic neuroma. The time-trend simulation studies, evaluated as complementary evidence in line with a triangulation approach for external validity, were consistent in showing that the increased risks observed in some case-control studies were incompatible with the actual incidence rates of glioma/brain cancer observed in several countries and over long periods. Three of these simulation studies consistently reported that RR estimates > 1.5 with a 10+ years induction period were definitely implausible, and could be used to set a "credibility benchmark". In the sensitivity meta-analyses of glioma risk in the upper category of TSS excluding five studies reporting implausible effect sizes, we observed strong reductions in both the mRR [mRR of 0.95 (95 % CI = 0.86-1.05)], and the degree of heterogeneity across studies (I2 = 3.6 %). CONCLUSIONS: Consistently with the published protocol, our final conclusions were formulated separately for each exposure-outcome combination, and primarily based on the line of evidence with the highest confidence, taking into account the ranking of RF sources by exposure level as inferred from dosimetric studies, and the external coherence with findings from time-trend simulation studies (limited to glioma in relation to mobile phone use). For near field RF-EMF exposure to the head from mobile phone use, there was moderate certainty evidence that it likely does not increase the risk of glioma, meningioma, acoustic neuroma, pituitary tumours, and salivary gland tumours in adults, or of paediatric brain tumours. For near field RF-EMF exposure to the head from cordless phone use, there was low certainty evidence that it may not increase the risk of glioma, meningioma or acoustic neuroma. For whole-body far-field RF-EMF exposure from fixed-site transmitters (broadcasting antennas or base stations), there was moderate certainty evidence that it likely does not increase childhood leukaemia risk and low certainty evidence that it may not increase the risk of paediatric brain tumours. There were no studies eligible for inclusion investigating RF-EMF exposure from fixed-site transmitters and critical tumours in adults. For occupational RF-EMF exposure, there was low certainty evidence that it may not increase the risk of brain cancer/glioma, but there were no included studies of leukemias (the second critical outcome in SR-C). The evidence rating regarding paediatric brain tumours in relation to environmental RF exposure from fixed-site transmitters should be interpreted with caution, due to the small number of studies. Similar interpretative cautions apply to the evidence rating of the relation between glioma/brain cancer and occupational RF exposure, due to differences in exposure sources and metrics across the few included studies. OTHER: This project was commissioned and partially funded by the World Health Organization (WHO). Co-financing was provided by the New Zealand Ministry of Health; the Istituto Superiore di Sanità in its capacity as a WHO Collaborating Centre for Radiation and Health; and ARPANSA as a WHO Collaborating Centre for Radiation Protection. REGISTRATION: PROSPERO CRD42021236798. Published protocol: [(Lagorio et al., 2021) DOI https://doi.org/10.1016/j.envint.2021.106828].

Ibrutinib-Related Uveitis: A Case Series from Two Tertiary Centres in the United Kingdom.

PURPOSE: Ibrutinib is an irreversible Bruton's tyrosine kinase inhibitor that disrupts B-cell receptor signalling. It is licensed for treatment of low-grade B-cell malignancies, including chronic lymphocytic leukaemia, mantle cell lymphoma and lymphoplasmacytic lymphoma. A few case reports in the literature suggest that uveitis may be a side effect of ibrutinib treatment. A strong association between ibrutinib and uveitis is yet to be established in significant numbers. METHODS: The study is a retrospective case series, reporting cases of uveitis associated with ibrutinib from two tertiary centres in the United Kingdom: Liverpool University Hospitals NHS Foundation Trust and University Hospitals of Leicester NHS Trust. RESULTS: The study reports eight cases presenting over a four year period, with mean age of 66.8 years. Onset of uveitis was between 9 and 48 (median 14) months from commencing ibrutinib, categorising it as a Type D or delayed drug reaction. Cases included unilateral and bilateral; anterior, intermediate, posterior and panuveitis. There was an association with cystoid macular oedema or disc swelling. Severity varied from mild, to severe and vision threatening. Presenting visual acuity ranged from 6/9 to 6/60. In all eight cases, uveitis resolved after ibrutinib cessation. In two cases, reintroducing ibrutinib caused uveitis recurrence. CONCLUSION: Our case series provides evidence suggestive of a connection between ibrutinib and development of uveitis. Ibrutinib related uveitis appears to be more common than previously recognised. Ibrutinib cessation, if appropriate, appears to be the definitive management. Patients with ibrutinib-related uveitis benefit from multidisciplinary management involving communication between ophthalmologist and haemato-oncologist.

Phosphoproteomics predict response to midostaurin plus chemotherapy in independent cohorts of FLT3-mutated acute myeloid leukaemia.

BACKGROUND: Acute myeloid leukaemia (AML) is a bone marrow malignancy with poor prognosis. One of several treatments for AML is midostaurin combined with intensive chemotherapy (MIC), currently approved for FLT3 mutation-positive (FLT3-MP) AML. However, many patients carrying FLT3 mutations are refractory or experience an early relapse following MIC treatment, and might benefit more from receiving a different treatment. Development of a stratification method that outperforms FLT3 mutational status in predicting MIC response would thus benefit a large number of patients. METHODS: We employed mass spectrometry phosphoproteomics to analyse 71 diagnosis samples of 47 patients with FLT3-MP AML who subsequently received MIC. We then used machine learning to identify biomarkers of response to MIC, and validated the resulting predictive model in two independent validation cohorts (n = 20). FINDINGS: We identified three distinct phosphoproteomic AML subtypes amongst long-term survivors. The subtypes showed similar duration of MIC response, but different modulation of AML-implicated pathways, and exhibited distinct, highly-predictive biomarkers of MIC response. Using these biomarkers, we built a phosphoproteomics-based predictive model of MIC response, which we called MPhos. When applied to two retrospective real-world patient test cohorts (n = 20), MPhos predicted MIC response with 83% sensitivity and 100% specificity (log-rank p < 7∗10-5, HR = 0.005 [95% CI: 0-0.31]). INTERPRETATION: In validation, MPhos outperformed the currently-used FLT3-based stratification method. Our findings have the potential to transform clinical decision-making, and highlight the important role that phosphoproteomics is destined to play in precision oncology. FUNDING: This work was funded by Innovate UK grants (application numbers: 22217 and 10054602) and by Kinomica Ltd.

Maternal autoimmune disease and offspring risk of haematological malignancies: a case-control study.

Background: Autoimmune diseases are known to be associated with an increased risk of cancer. Whether maternal immune dysregulation can have an impact on the development of haematological malignancies in offspring remains uncertain. Therefore, we explored the association between offspring risk of haematological malignancies and maternal autoimmune disease using a real-world nationwide population-based study. Methods: In this case-control study, we identified 2172 children with haematological malignancies between 2004 and 2019 from Taiwan's National Health Insurance program and compared them with population-based controls without haematologic malignancies, who were matched with each individual at a ratio of 1:4. The medical information of the autoimmune mothers were obtained from the Taiwan Maternal and Child Health Database. Conditional logistic regression was used to estimate the odds ratio for haematologic malignancy in offspring. Furthermore, subgroup and stratified analyses were conducted. Findings: Among the rheumatologic diseases in our study, Crohn's disease was the most common disease both in the haematological malignancy group (1.1%) and the control group (0.9%). In multivariable analysis, the odds ratio for haematological malignancy in offspring with maternal autoimmune diseases was 1.2 (95% confidence interval [CI] 0.91-1.58). The overall risk of haematologic malignancy was not significantly higher when adjusted for specific risk factors, including neonatal age, maternal age, family income, urbanization, maternal occupation, birth weight, or maternal comorbidity, except for prematurity. When comparing different autoimmune diseases among haematological malignancies and the control group, maternal psoriatic arthritis/psoriasis had the highest adjusted overall risk for haematological malignancies (adjusted OR 2.11, CI 0.89-5), followed by ankylosing spondylitis (adjusted OR 1.45, CI 0.7-3), autoimmune thyroiditis (OR 1.26, CI 0.57-2.81), systemic lupus erythematosus (OR 1.21, CI 0.48-3.02), Crohn's disease (OR 1.19, CI 0.75-1.9), and Sjogren's syndrome (OR 1.18, CI 0.65-2.15), but no significance was reached in these analyses. Multivariable analysis of risk factors associated with haematological malignancy subtypes was done. It showed no associations between maternal autoimmune disease and childhood haematological malignancies. Interpretation: We found no significant relationship between maternal autoimmune disease and childhood haematological malignancies. The influence of maternal immune dysregulation on the next generation with respect to haematological malignancies development may be limited. Funding: There was no funding source for this study.

Irradiation alters extracellular vesicle microRNA load in the serum of patients with leukaemia.

PURPOSE: Recent data suggest an impact of extracellular vesicles (EVs) and their micro(mi)RNA cargo on cell-cell interactions to contribute to pathophysiology of leukaemia and radiation response. Here, we investigated differential miRNA cargo of EVs from serum derived from patients with leukaemia (n = 11) before and after total body irradiation with 2â€¯× 2 Gy as compared to healthy donors (n = 6). METHODS: RNA was isolated from EVs and subjected to next generation sequencing of miRNAs. Analysis of sequencing data was performed with miRDeep29 software and differentially expressed miRNAs were filtered using R package edgeR10,11. Signaling pathways were identified using Kyoto Encyclopedia of Genes and Genomes database (KEGG) pathway analysis. RESULTS: Flow cytometric and Western blot analyses confirmed the presence of characteristic EV markers TSG-101, CD­9 and CD-81. miRNA sequencing revealed a differential cargo in serum of patients with leukaemia in comparison to healthy donors with 23 significantly upregulated and 16 downregulated miRNAs affecting hedgehog, estrogen, glutathione metabolism and peroxisome proliferator-activated receptor (PPAR) signaling pathways amongst others. Whole body irradiation of patients with leukaemia significantly increased 11 miRNAs, involved in cell cycle regulation and platinum drug resistance, and decreased 15 miRNAs, contributing to apoptosis or cytokine-receptor interactions. CONCLUSION: As compared to healthy controls and following irradiation, we have identified differentially regulated miRNAs in serum-derived EVs from patients with leukaemia that may serve as possible biomarkers of leukaemic disease and treatment and radiation exposure.

Case report: NUP98::LEDGF fusion gene drives malignant hematological tumor with mixed immunological phenotype.

This is the first report of NUP98::LEDGF positive malignant hematological tumor expressing T cell and myeloid lineage antigens. Patients carrying this fusion gene have a high relapse rate and a poor prognosis, allo-HSCT may be an option to cure this disease. This patient underwent allo-HSCT, a relapse occurred three months post-transplantation. Subsequent screening at our hospital confirmed the presence of the NUP98::LEDGF fusion gene, salvage therapy was administered, followed by a successful second allo-HSCT. Furthermore, we included eight previously reported cases from the literature for analysis and discuss.

Musculoskeletal Symptoms and Misdiagnoses in Children With Acute Myeloid Leukaemia: A Nationwide Cohort Study.

OBJECTIVES: Childhood cancer often presents with non-specific signs and symptoms that might mimic non-malignant disorders including musculoskeletal diseases, potentially leading to rheumatic and orthopaedic misdiagnoses. We aimed to compare clinical presentation, diagnostic interval and survival in paediatric acute myeloid leukaemia (AML) with and without initial musculoskeletal symptoms. METHODS: This nationwide retrospective, cohort study reviewed medical records of 144 children below 15 years diagnosed with AML in Denmark from 1996 to 2018. RESULTS: Musculoskeletal symptoms occurred in 29% (42/144) of children with AML and 8% (11/144) received an initial musculoskeletal misdiagnosis, being mainly non-specific and pain-related. The children with and without musculoskeletal symptoms did not differ markedly up to the diagnosis of AML and blood counts were affected equally in both groups. However, the children with prior musculoskeletal symptoms were more likely to have elevated levels of LDH and ferritin. Furthermore, they revealed a tendency towards a longer total interval (median 53 days vs. 32 days, p = 0.07), but the overall survival did not differ. CONCLUSION: AML should be considered as an underlying cause in children with unexplained musculoskeletal symptoms and abnormal blood counts. Concomitant elevation of LDH and ferritin should strengthen the suspicion.