Targeting Metabolic Dependencies Fueling the TCA Cycle to Circumvent Therapy Resistance in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is one of the most prevalent blood cancers, characterized by a dismal survival rate. This poor outcome is largely attributed to AML cells that persist despite treatment and eventually result in relapse. Relapse-initiating cells exhibit diverse resistance mechanisms, encompassing genetic factors and, more recently discovered, nongenetic factors such as metabolic adaptations. Leukemic stem cells (LSC) rely on mitochondrial metabolism for their survival, whereas hematopoietic stem cells primarily depend on glycolysis. Furthermore, following treatments such as cytarabine, a standard in AML treatment for over four decades, drug-persisting leukemic cells exhibit an enhanced reliance on mitochondrial metabolism. In this issue of Cancer Research, two studies investigated dependencies of AML cells on two respiratory substrates, α-ketoglutarate and lactate-derived pyruvate, that support mitochondrial oxidative phosphorylation (OXPHOS) following treatment with the imipridone ONC-213 and the BET inhibitor INCB054329, respectively. Targeting lactate utilization by interfering with monocarboxylate transporter 1 (MCT1 or SLC16A1) or lactate dehydrogenase effectively sensitized cells to BET inhibition in vitro and in vivo. In addition, ONC-213 affected αKGDH, a pivotal NADH-producing enzyme of the TCA cycle, to induce a mitochondrial stress response through ATF4 activation that diminished the expression of the antiapoptotic protein MCL1, consequently promoting apoptosis of AML cells. In summary, targeting these mitochondrial dependencies might be a promising strategy to kill therapy-naïve and treatment-resistant OXPHOS-reliant LSCs and to delay or prevent relapse. See related articles by Monteith et al., p. 1101 and Su et al., p. 1084.

[Clinical study of ear keloids with surgical excision and intraoperative low-energy X-ray irradiation therapy].

Objective:To explore the clinical efficacy of surgical excision combined with low-energy X-ray irradiation in the treatment of ear keloids. Methods:Clinical data of 32 cases of ear keloid lesions that received surgical treatment alone or surgery combined with radiotherapy from March 2019 to November 2022 in the Department of Otorhinolaryngology Head and Neck Surgery of the Tianjin First Central Hospital were retrospectively analyzed. Among them, 10 cases received radiotherapy and 22 cases did not receive radiotherapy. The radiotherapy group received irradiation with a large divided dose of 50 kV low-energy X-rays. The mode of fractionation radiotherapy was as follows: the first was 10 Gy of intraoperative radiation therapy and the second was 8 Gy on the 3rd postoperative day for a total of 18 Gy. The local efficacy and skin radiation reaction were observed at a follow-up of 8-52 months. Results:The median follow-up was 26 months, and as of the date of the last follow-up, 9 cases were cured and 1 case was ineffective in the radiotherapy group, with an effective rate of 90.0%, while 9 cases were cured and 13 cases were ineffective in the no-radiotherapy group, with an effective rate of 40.9%. The recurrence of ear keloids was not related to the side, site, or etiology of the patient's onset（P>0.05）. Recurrence was related to whether or not the patients received radiotherapy（χ²=4.885, P<0.05）, and the recurrence rate in the radiotherapy group（10.0%） was significantly lower than that in the non-radiotherapy group（59.1%）. Conclusion:Surgical excision combined with low-energy X-ray irradiation therapy is an effective method of treating keloids in the ear, especially with intraoperative radiation therapy can achieve more satisfactory results.

Comparative Analysis of Ventral Hernia Repair and Transverse Abdominis Release With and Without Panniculectomy: A 4-Year Match-Pair Analysis.

INTRODUCTION: Amid rising obesity, concurrent ventral hernia repair and panniculectomy procedures are increasing. Long-term outcomes of transverse abdominis release (TAR) combined with panniculectomy remain understudied. This study compares clinical outcomes and quality of life (QoL) after TAR, with or without panniculectomy. METHODS: A single-center retrospective review from 2016 to 2022 evaluated patients undergoing TAR with and without panniculectomy. Propensity-scored matching was based on age, body mass index, ASA, and ventral hernia working group. Patients with parastomal hernias were excluded. Patient/operative characteristics, postoperative outcomes, and QoL were analyzed. RESULTS: Fifty subjects were identified (25 per group) with a median follow-up of 48.8 months (interquartile range, 43-69.7 months). The median age and body mass index were 57 years (47-64 years) and 31.8 kg/m2 (28-36 kg/m2), respectively. The average hernia defect size was 354.5 cm2 ± 188.5 cm2. There were no significant differences in hernia recurrence, emergency visits, readmissions, or reoperations between groups. However, ventral hernia repair with TAR and panniculectomy demonstrated a significant increase in delayed healing (44% vs 4%, P < 0.05) and seromas (24% vs 4%, P < 0.05). Postoperative QoL improved significantly in both groups (P < 0.005) across multiple domains, which continued throughout the 4-year follow-up period. There were no significant differences in QoL among ventral hernia working group, wound class, surgical site occurrences, or surgical site occurrences requiring intervention (P > 0.05). Patients with concurrent panniculectomy demonstrated a significantly greater percentage change in overall scores and appearance scores. CONCLUSIONS: Ventral hernia repair with TAR and panniculectomy can be performed safely with low recurrence and complication rates at long-term follow-up. Despite increased short-term postoperative complications, patients have a significantly greater improvement in disease specific QoL.

Outcomes and Quality of Life After Resorbable Synthetic Ventral Hernia Repair in Contaminated Fields.

INTRODUCTION: The ideal mesh type for hernia repair in a contaminated field remains controversial. Data regarding outcomes beyond 1 year and the impact on quality of life (QoL) are unknown. This study aims to evaluate the long-term surgical outcomes and patient-reported outcomes (PROs) after contaminated repair with poly-4-hydroxybutyrate (P4HB) mesh. MATERIALS METHODS: Patients undergoing a contaminated hernia repair with P4HB between 2015 and 2020 were identified. Surgical site occurrences and hernia recurrences were recorded. Long-term PROs as defined by the Abdominal Hernia-Q and Hernia-Related Quality-of-Life Survey were assessed. RESULTS: Fifty-five patients were included with a mean age of 54.5 years, a body mass index of 34 kg/m2, and a defect size of 356.9 ± 227.7 cm2. Median follow-up time was 49 months with a reoperation rate of 14.5% and a hernia recurrence rate of 7.3%. Of the 55 patients, 37 completed preoperative and postoperative PRO questionnaires. When comparing preoperative with postoperative Abdominal Hernia-Q, there was significant improvement in overall PROs (2.1 vs 3.5, P < 0.001). This improvement was maintained with no significant changes between postoperative scores over the course of 5 years. Patients with complications saw the same improvement in postoperative PRO scores as those without complications. CONCLUSIONS: Our study found a low hernia recurrence and acceptable long-term reoperation rates in patients undergoing hernia repair with P4HB mesh in a contaminated setting. We demonstrate a sustained significant improvement in QoL scores after hernia repair. These data yield insight into the long-term outcomes and QoL improvement, providing physicians further knowledge to better counsel their patients.

Hernia Recurrence and Complications After Abdominal Reconstruction With Reinforced Versus Nonreinforced Biologic Mesh.

INTRODUCTION: Both biologic and permanent (synthetic) meshes are used for abdominal wall reconstruction. Biologic mesh has the advantage of eventual incorporation, which makes it generally preferred in contaminated patients compared with synthetic mesh (Ann Surg. 2013;257:991-996). However, synthetic mesh has been shown to have decreased long-term hernia recurrence despite increased complications (JAMA Surg. 2022;157:293-301). Ovitex (TelaBio, Ltd, Auckland, New Zealand) is a combined reinforced biologic mesh with a permanent Prolene suture weave that theoretically combines incorporation with a long-term strength component. We hypothesize that a reinforced biologic will have a similar complication profile but decreased long-term hernia recurrence. METHODS: A single-center retrospective review was performed from January 2013 to January 2022. Baseline patient characteristics and outcomes including 90-day complications and recurrence were compared. Categorical and continuous variables were analyzed with χ2 and Wilcoxon rank sum tests, respectively. Predictors of postoperative complications and hernia recurrence were analyzed via univariate logistic regression and multivariate logistic regression with backward stepwise selection with a threshold of P < 0.2. RESULTS: Two hundred fifty-four patients underwent abdominal wall reconstruction biologic mesh (Strattice, Allergan; FlexHD, MTF Biologics; Alloderm, Allergan; Surgisis Gold, Cook Biotech; Ovitex, Telabio) with retrorectus (66.5%) or intraperitoneal (33.5%) mesh placement. Sixty-six of these used reinforced biologic mesh (Ovitex, TelaBio). Baseline characteristics were comparable including preoperative hernia size measured on CT. The mean follow-up time was 343 days. The majority of patients underwent component separation (80.3% bilateral, 11.4% unilateral, 8.3% none). On univariate analysis, reinforced biologic mesh did not impact 90-day complication rates (P = 0.391) or hernia recurrence rates (P = 0.349). On multivariate analysis, reinforced mesh had no impact on complication or recurrence rates (P > 0.2). A previous history of infected mesh was an independent risk factor for hernia recurrence (P = 0.019). Nonreinforced biologics were more likely to be used in instances of previous mesh infection (P = 0.025), bowel resection (P = 0.026), and concomitantly at the time of stoma takedown (P = 0.04). Reinforced biologics were more likely to be used with a history of previous hernia repair with recurrence not due to infection (P = 0.001). Body mass index >35 was an independent risk factor across both groups for 90-day complications (P = 0.028). CONCLUSIONS: Reinforced versus nonreinforced biologics have similar risk profile and recurrence rate when placed primary fascial repair achieved. In abdominal walls with history of infection, or abdominal wall reconstruction performed concomitantly at the time of stoma takedown or bowel resection/anastomosis, nonreinforced biologics were used more commonly with no difference in negative outcomes. This implies that they may have a role for use in contaminated surgical cases. Reinforced biologics were more commonly used as a mesh choice in the setting of previous hernia repair with recurrence with no difference in outcomes. This implies that the reinforced nature may be useful in situations where extra reinforcement of already traumatized abdominal wall tissue is needed. Retrorectus or intraperitoneal placement of any biologic mesh is acceptable and should be chosen based off surgeon comfort and anticipated cost saving of individual mesh brands. There may be a role for reinforced mesh in the setting of previous failed hernia repair with weakened fascia, as well as nonreinforced in contaminated cases.

Clinical features and prognosis of ANCA-associated vasculitis patients who were double-seropositive for myeloperoxidase-ANCA and proteinase 3-ANCA.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patients with dual positivity for proteinase 3-ANCA (PR3-ANCA) and myeloperoxidase-ANCA (MPO-ANCA) are uncommon. We aimed to investigate these idiopathic double-positive AAV patients' clinical features, histological characteristics, and prognosis. We reviewed all the electronic medical records of patients diagnosed with AAV to obtain clinical data and renal histological information from January 2010 to December 2020 in a large center in China. Patients were assigned to the MPO-AAV group or PR3-AAV group or idiopathic double-positive AAV group by ANCA specificity. We explored features of idiopathic double-positive AAV. Of the 340 patients who fulfilled the study inclusion criteria, 159 (46.76%) were female, with a mean age of 58.41 years at the time of AAV diagnosis. Similar to MPO-AAV, idiopathic double-positive AAV patients were older and had more severe anemia, lower Birmingham Vasculitis Activity Score (BVAS) and C-reactive protein (CRP) levels, less ear, nose, and throat (ENT) involvement, higher initial serum creatinine and a lower estimated glomerular filtration rate (eGFR) when compared with PR3-AAV (P < 0.05). The proportion of normal glomeruli of idiopathic double-positive AAV was the lowest among the three groups (P < 0.05). The idiopathic double-positive AAV patients had the worst remission rate (58.8%) among the three groups (P < 0.05). The relapse rate of double-positive AAV (40.0%) was comparable with PR3-AAV (44.8%) (P > 0.05). Although there was a trend toward a higher relapse rate of idiopathic double-positive AAV (40.0%) compared with MPO-AAV (23.5%), this did not reach statistical significance (P > 0.05). The proportion of patients who progressed to ESRD was 47.1% and 44.4% in the idiopathic double-positive AAV group and MPO-AAV group respectively, without statistical significance. Long-term patient survival also varied among the three groups (P < 0.05). Idiopathic double-positive AAV is a rare clinical entity with hybrid features of MPO-AAV and PR3-AAV. MPO-AAV is the "dominant" phenotype in idiopathic double-positive AAV.

Modified sutureless and glue-free method versus conventional sutures for conjunctival autograft fixation in primary pterygium surgery: a systematic review and meta-analysis.

BACKGROUND: Pterygium is a common ocular surface disorder that requires surgical intervention for treatment. Conjunctival autografts are preferred over simple excision due to lower recurrence rates. This systematic review and meta-analysis compared the modified sutureless glue-free (MSGF) method with conventional sutures (CS) for conjunctival autograft fixation in primary pterygium surgery. METHODS: A comprehensive search was conducted in MEDLINE, Embase, CENTRAL, Google Scholar and ClinicalTrials.gov for randomised controlled trials (RCTs) comparing MSGF and CS conjunctival autografts. Outcome measures included operation time, recurrence and postoperative complications. Standardised mean difference (SMD) and risk ratio (RR) were used for continuous and dichotomous outcomes, respectively. RESULTS: 11 RCTs involving 833 participants were included. The analysis revealed that MSGF had a significantly shorter operation time compared with CS (SMD -3.704, 95% CI -5.122 to -2.287, p<0.001). CS was associated with a higher risk of foreign body sensation (RR 0.22, 95% CI 0.06 to 0.74, p=0.01). MSGF was associated with a higher risk of graft dehiscence (RR 9.01, 95% CI 2.74 to 29.68, p=0.000) and graft retraction (RR 2.37, 95% CI 1.17 to 4.77, p=0.02). No significant differences were found in recurrence, graft haemorrhage, granuloma, Dellen and conjunctival oedema. CONCLUSION: Using the MSGF technique in conjunctival autograft fixation for pterygium surgery reduces operation time by relying solely on the patient's blood for fixation. However, it increases the risk of graft dehiscence and retraction. However, CS is linked to a higher likelihood of experiencing foreign body sensations. Understanding the learning curve and surgeon familiarity with novel techniques is crucial for optimising patient care and surgical outcomes, while individualised decision-making is necessary considering the advantages and disadvantages of each approach. Further research is warranted to minimise complications and optimise surgical outcomes.

Biomarkers Profile in Provoked Versus Unprovoked Deep Venous Thrombosis.

Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), represents a substantial healthcare challenge. Provoked and unprovoked DVT cases carry distinct risks and treatment considerations. Recognizing the limitations of this classification, molecular markers may enhance diagnostic precision and guide anticoagulation therapy duration relying on patient history and risk factors. This preliminary, open-label, prospective cohort study was conducted including 15 patients (10 provoked DVT and 5 unprovoked DVT) and a control group of healthy plasmatic subjects. Plasma levels of 9 biomarkers were measured at diagnosis (baseline, day 0, and D0) and after 30 days (day 30-D30). Patient demographics, clinical data, and biomarker concentrations were analyzed. Serum concentrations of D-dimer, von Willebrand factor, C-reactive protein, and Anti-Xa were elevated in DVT groups at D0 compared to controls. No significant differences were observed between the provoked and unprovoked groups on the day of diagnosis and 30 days later. Over 30 days, the provoked group exhibited significant biomarker changes related to temporal assessment. No significant differences were noted in the biomarker profile between provoked and unprovoked DVT groups. This study is indicative of the concept of individualized thrombosis assessment and subsequent treatment for VTE. Larger cohorts are warranted to validate these findings and further define the most appropriate use of the molecular markers.

Vitamin D receptor gene BsmI (rs1544410) polymorphism: role in multiple sclerosis and genotype-phenotype correlations.

BACKGROUND: Multiple sclerosis (MS) has a complex pathophysiology which depends on many endogenous and exogenous factors. Vitamin D involvement has been largely studied in MS. The large distribution of the vitamin D receptor (VDR) in different immune cells is suggestive of an immunomodulatory role. The VDR gene polymorphisms have been proposed as potential risk factors for MS development or evolution with non-conclusive results. METHODS AND RESULTS: We conducted a cross-sectional study including patients ≥ 18 years, with a diagnosis of relapsing remitting MS according to the McDonald Criteria and having a minimum follow-up period of one year after starting a disease modifying therapy. Two study groups were compared based on the Multiple Sclerosis Severity Scale or MSSS: "a slow progressor" group for an MSSS ≤ 5, and a "fast progressor" group for an MSSS > 5. The rs1544410 VDR gene polymorphism was studied for all patients. Eighty patients were included. The fast progressor groups had a higher EDSS at onset, a higher total number of relapses, more frequent and shorter time to secondary progression. The progression profile was not statistically different between genotypes and alleles of the VDR gene polymorphism rs1544410. The CC genotype and wild-type allele exhibited a more aggressive disease phenotype with a higher number of relapses the first year, shorter time to secondary progression and cerebral atrophy on assessment. CONCLUSIONS: Our results suggest potential genotype-phenotype correlations for the rs1544410 VDR gene polymorphism in the disease course of MS. Future research on a larger scale is needed to confirm these findings.

Recurrence of severe diverticulitis is associated with age and birth decade.

BACKGROUND: The risk of recurrence is an important consideration when deciding to treat patients medically or with elective colectomy after recovery from diverticulitis. It is unclear whether age is associated with recurrence. This study aimed to examine the relationship between age and the risk of recurrent diverticulitis while considering important epidemiologic factors, such as birth decade. METHODS: The Utah Population Database was used to identify individuals with incident severe diverticulitis, defined as requiring an emergency department visit or hospitalization, between 1998 and 2018. This study measured the relationship between age and recurrent severe diverticulitis after adjusting for birth decade and other important variables, such as sex, urban/rural status, complicated diverticulitis, and body mass index using a Cox proportional hazards model. RESULTS: The cohort included 8606 individuals with a median age of 61 years at index diverticulitis diagnosis. After adjustment, among individuals born in the same birth decade, increasing age at diverticulitis onset was associated with an increased risk of recurrent diverticulitis (hazard ratio [HR] for 10 years, 1.8; 95% CI, 1.5-2.1). Among individuals with the same age of onset, those born in a more recent birth decade were also at greater risk of recurrent diverticulitis (HR, 1.9; 95% CI, 1.6-2.3). CONCLUSION: Among individuals with an index episode of severe diverticulitis, recurrence was associated with increasing age and more recent birth decade. Clinicians may wish to employ age-specific strategies when counseling patients regarding treatment options after a diverticulitis diagnosis.

Evaluation of Some Prognostic Biomarkers in Human Papillomavirus-Related Multiphenotypic Sinonasal Carcinoma.

Background: Human papillomavirus (HPV)-related multi phenotypic sinonasal carcinoma (HMSC) is a recently described tumor subtype with an unknown prognosis, often misdiagnosed with other sinonasal carcinomas, and associated with high-risk HPV (HR-HPV). The present study aimed to evaluate the expression of vascular endothelial growth factor (VEGF), Bcl-2-associated X protein (BAX), epidermal growth factor receptors (EGFR), ProExTMC, and human telomerase reverse transcriptase (hTERT) and assess their association with survival and clinicopathological characteristics. Methods: Between 2017 and 2022, 40 HMSC patients underwent surgical resection at the School of Medicine, Zagazig University Hospitals (Zagazig, Egypt). Tissue samples were examined for the presence of HR-HPV; absence of myeloblastosis (MYB), MYB proto-oncogene like 1 (MYBL1), and nuclear factor I/B (NFIB) fusions and the presence of myoepithelial proteins (calponin, S100, SMA), squamous differentiation markers (p63, p40, calponin), VEGF, BAX, ProExTMC, and hTERT by immunohistochemistry. All patients were followed up for about 54 months until death or the last known survival data. Data were analyzed using the Chi square test and Kaplan-Meier method. Results: The expression of VEGF, hTERT, and ProExTMC was significantly associated with age, advanced tumor stages, lymph node metastasis, tumor size, mortality, relapse, poor disease-free survival (DFS), and overall survival (OS) (P<0.001). BAX expression was significantly associated with tumor size, age, poor DFS, and relapse (P=0.01, P<0.001, P=0.035, and P=0.002, respectively). Conclusion: HMSC is strongly associated with HR-HPV. The expression of VEGF, EGFR, BAX, hTERT, and ProExTMC is associated with aggressive malignant behavior, poor survival, and poor prognosis, making them novel prognostic biomarkers for targeted therapeutics in HMSC.

Real-world experience of teriflunomide in relapsing multiple sclerosis: paramagnetic rim lesions may play a role.

Objectives: The aims of this study were to report the effectiveness and safety of teriflunomide in Chinese patients with relapsing-remitting multiple sclerosis (RRMS) and to explore the association of paramagnetic rim lesion (PRL) burden with patient outcome in the context of teriflunomide treatment and the impact of teriflunomide on PRL burden. Methods: This is a prospective observational study. A total of 100 RRMS patients treated with teriflunomide ≥3 months were included in analyzing drug persistence and safety. Among them, 96 patients treated ≥6 months were included in assessing drug effectiveness in aspects of no evidence of disease activity (NEDA) 3. The number and total volume of PRL were calculated in 76 patients with baseline susceptibility-weighted imaging (SWI), and their association with NEDA3 failure during teriflunomide treatment was investigated. Results: Over a treatment period of 19.7 (3.1-51.7) months, teriflunomide reduced annualized relapse rate (ARR) from 1.1 ± 0.8 to 0.3 ± 0.5, and Expanded Disability Status Scale (EDSS) scores remained stable. At month 24, the NEDA3% and drug persistence rate were 43.8% and 65.1%, respectively. In patients with a baseline SWI, 81.6% had at least 1 PRL, and 42.1% had ≥4 PRLs. The total volume of PRL per patient was 0.3 (0.0-11.5) mL, accounting for 2.3% (0.0%-49.0%) of the total T2 lesion volume. Baseline PRL number ≥ 4 (OR = 4.24, p = 0.009), younger onset age (OR = 0.94, p = 0.039), and frequent relapses in initial 2 years of disease (OR = 13.40, p = 0.026) were associated with NEDA3 failure. The PRL number and volume were not reduced (p = 0.343 and 0.051) after teriflunomide treatment for more than 24 months. No new safety concerns were identified in this study. Conclusion: Teriflunomide is effective in reducing ARR in Chinese patients with RRMS. Patients with less PRL burden, less frequent relapses, and relatively older age are likely to benefit more from teriflunomide, indicating that PRL might be a valuable measurement to inform clinical treatment decision.

Combining CRISPR-Cas9 and TCR exchange to generate a safe and efficient cord blood-derived T cell product for pediatric relapsed AML.

BACKGROUND: Hematopoietic cell transplantation (HCT) is an effective treatment for pediatric patients with high-risk, refractory, or relapsed acute myeloid leukemia (AML). However, a large proportion of transplanted patients eventually die due to relapse. To improve overall survival, we propose a combined strategy based on cord blood (CB)-HCT with the application of AML-specific T cell receptor (TCR)-engineered T cell therapy derived from the same CB graft. METHODS: We produced CB-CD8+ T cells expressing a recombinant TCR (rTCR) against Wilms tumor 1 (WT1) while lacking endogenous TCR (eTCR) expression to avoid mispairing and competition. CRISPR-Cas9 multiplexing was used to target the constant region of the endogenous TCRα (TRAC) and TCRß (TRBC) chains. Next, an optimized method for lentiviral transduction was used to introduce recombinant WT1-TCR. The cytotoxic and migration capacity of the product was evaluated in coculture assays for both cell lines and primary pediatric AML blasts. RESULTS: The gene editing and transduction procedures achieved high efficiency, with up to 95% of cells lacking eTCR and over 70% of T cells expressing rWT1-TCR. WT1-TCR-engineered T cells lacking the expression of their eTCR (eTCR-/- WT1-TCR) showed increased cell surface expression of the rTCR and production of cytotoxic cytokines, such as granzyme A and B, perforin, interferon-γ (IFNγ), and tumor necrosis factor-α (TNFα), on antigen recognition when compared with WT1-TCR-engineered T cells still expressing their eTCR (eTCR+/+ WT1-TCR). CRISPR-Cas9 editing did not affect immunophenotypic characteristics or T cell activation and did not induce increased expression of inhibitory molecules. eTCR-/- WT1-TCR CD8+ CB-T cells showed effective migratory and killing capacity in cocultures with neoplastic cell lines and primary AML blasts, but did not show toxicity toward healthy cells. CONCLUSIONS: In summary, we show the feasibility of developing a potent CB-derived CD8+ T cell product targeting WT1, providing an option for post-transplant allogeneic immune cell therapy or as an off-the-shelf product, to prevent relapse and improve the clinical outcome of children with AML.

The HLA region in ANCA-associated vasculitis: characterisation of genetic associations in a Scandinavian patient population.

OBJECTIVE: The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are inflammatory disorders with ANCA autoantibodies recognising either proteinase 3 (PR3-AAV) or myeloperoxidase (MPO-AAV). PR3-AAV and MPO-AAV have been associated with distinct loci in the human leucocyte antigen (HLA) region. While the association between MPO-AAV and HLA has been well characterised in East Asian populations where MPO-AAV is more common, studies in populations of European descent are limited. The aim of this study was to thoroughly characterise associations to the HLA region in Scandinavian patients with PR3-AAV as well as MPO-AAV. METHODS: Genotypes of single-nucleotide polymorphisms (SNPs) located in the HLA region were extracted from a targeted exome-sequencing dataset comprising Scandinavian AAV cases and controls. Classical HLA alleles were called using xHLA. After quality control, association analyses were performed of a joint SNP/classical HLA allele dataset for cases with PR3-AAV (n=411) and MPO-AAV (n=162) versus controls (n=1595). Disease-associated genetic variants were analysed for association with organ involvement, age at diagnosis and relapse, respectively. RESULTS: PR3-AAV was significantly associated with both HLA-DPB1*04:01 and rs1042335 at the HLA-DPB1 locus, also after stepwise conditional analysis. MPO-AAV was significantly associated with HLA-DRB1*04:04. Neither carriage of HLA-DPB1*04:01 alleles in PR3-AAV nor of HLA-DRB1*04:04 alleles in MPO-AAV were associated with organ involvement, age at diagnosis or relapse. CONCLUSIONS: The association to the HLA region was distinct in Scandinavian cases with MPO-AAV compared with cases of East Asian descent. In PR3-AAV, the two separate signals of association to the HLD-DPB1 region mediate potentially different functional effects.

Literature review and protocol for a prospective multicentre cohort study on multimodal prediction of seizure recurrence after unprovoked first seizure.

INTRODUCTION: Epilepsy is a common neurological disorder characterised by recurrent seizures. Almost half of patients who have an unprovoked first seizure (UFS) have additional seizures and develop epilepsy. No current predictive models exist to determine who has a higher risk of recurrence to guide treatment. Emerging evidence suggests alterations in cognition, mood and brain connectivity exist in the population with UFS. Baseline evaluations of these factors following a UFS will enable the development of the first multimodal biomarker-based predictive model of seizure recurrence in adults with UFS. METHODS AND ANALYSIS: 200 patients and 75 matched healthy controls (aged 18-65) from the Kingston and Halifax First Seizure Clinics will undergo neuropsychological assessments, structural and functional MRI, and electroencephalography. Seizure recurrence will be assessed prospectively. Regular follow-ups will occur at 3, 6, 9 and 12 months to monitor recurrence. Comparisons will be made between patients with UFS and healthy control groups, as well as between patients with and without seizure recurrence at follow-up. A multimodal machine-learning model will be trained to predict seizure recurrence at 12 months. ETHICS AND DISSEMINATION: This study was approved by the Health Sciences and Affiliated Teaching Hospitals Research Ethics Board at Queen's University (DMED-2681-22) and the Nova Scotia Research Ethics Board (1028519). It is supported by the Canadian Institutes of Health Research (PJT-183906). Findings will be presented at national and international conferences, published in peer-reviewed journals and presented to the public via patient support organisation newsletters and talks. TRIAL REGISTRATION NUMBER: NCT05724719.

Pursuing dynamics of minimal residual leukemic subclones in relapsed and refractory acute myeloid leukemia during conventional therapy.

BACKGROUND: Acute myeloid leukemia (AML) is characterized by clonal heterogeneity, leading to frequent relapses and drug resistance despite intensive clinical therapy. Although AML's clonal architecture has been addressed in many studies, practical monitoring of dynamic changes in those subclones during relapse and treatment is still understudied. METHOD: Fifteen longitudinal bone marrow (BM) samples were collected from three relapsed and refractory (R/R) AML patients. Using droplet digital polymerase chain reaction (ddPCR), the frequencies of patient's leukemic variants were assessed in seven cell populations that were isolated from each BM sample based on cellular phenotypes. By quantifying mutant clones at the diagnosis, remission, and relapse stages, the distribution of AML subclones was sequentially monitored. RESULTS: Minimal residual (MR) leukemic subclones exhibit heterogeneous distribution among BM cell populations, including mature leukocyte populations. During AML progression, these subclones undergo active phenotypic transitions and repopulate into distinct cell population regardless of normal hematopoiesis hierarchic order. Of these, MR subclones in progenitor populations of patient BM predominantly carry MR leukemic properties, leading to more robust expansion and stubborn persistence than those in mature populations. Moreover, a minor subset of MR leukemic subclones could be sustained at an extremely low frequency without clonal expansion during relapse. CONCLUSIONS: In this study, we observed treatment persistent MR leukemic subclones and their phenotypic changes during the treatment process of R/R AML patients. This underscores the importance of preemptive inhibition of clonal promiscuity in R/R AML, proposing a practical method for monitoring AML MR subclones.

Application of a circular-shaped pulsed field ablation catheter with magnetic sensors for pulmonary vein isolation: a multi-centre clinical study report.

AIMS: A few studies have reported the effect and safety of pulsed field ablation (PFA) catheters for ablating atrial fibrillation (AF), which were mainly based on basket-shaped or flower-shaped designs. However, the clinical application of a circular-shaped multi-electrode catheter with magnetic sensors is very limited. To study the efficacy and safety of a PFA system in patients with paroxysmal AF using a circular-shaped multi-electrode catheter equipped with magnetic sensors for pulmonary vein isolation (PVI). METHODS AND RESULTS: A novel proprietary bipolar PFA system was used for PVI, which utilized a circular-shaped multi-electrode catheter with magnetic sensors and allowed for three-dimensional model reconstruction, mapping, and ablation in one map. To evaluate the efficacy, efficiency, and safety of this PFA system, a prospective, multi-centre, single-armed, pre-market clinical study was performed. From July 2021 to December 2022, 151 patients with paroxysmal AF were included and underwent PVI. The study examined procedure time, immediate success rate, procedural success rate at 12 months, and relevant complications. In all 151 patients, all the pulmonary veins were acutely isolated using the studied system. Pulsed field ablation delivery was 78.4 ± 41.8 times and 31.3 ± 16.7 ms per patient. Skin-to-skin procedure time was 74.2 ± 29.8 min, and fluoroscopy time was 13.1 ± 7.6 min. The initial 11 (7.2%) cases underwent procedures with deep sedation anaesthesia, and the following cases underwent local anaesthesia. In the initial 11 cases, 4 cases (36.4%) presented transient vagal responses, and the rest were all successfully preventatively treated with atropine injection and rapid fluid infusion. No severe complications were found during or after the procedure. During follow-up, 3 cases experienced atrial flutter, and 11 cases had AF recurrence. The estimated 12-month Kaplan-Meier of freedom from arrhythmia was 88.4%. CONCLUSION: The PFA system, comprised of a circular PFA catheter with magnetic sensors, could rapidly achieve PVI under three-dimensional guidance and demonstrated excellent safety with comparable effects.

[Clinical study on growth impairment induced by oral glucocorticoids based on FGF23/Klotho homeostasis observations]. / 基于FGF23/Klothoç¨³æ€è§‚å¯Ÿå£æœç³–çš®è´¨æ¿€ç´ è‡´ç”Ÿé•¿éšœç¢çš„ä¸´åºŠç ”ç©¶.

OBJECTIVES: To observe the correlation between growth impairment induced by long-term oral glucocorticoids (GC) therapy and the ratio of FGF23/Klotho in children with primary nephrotic syndrome (PNS). METHODS: A prospective study was conducted on 56 children with GC-sensitive PNS who had discontinued GC therapy for more than 3 months and revisited the Department of Pediatrics of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine between June 2022 and December 2022. After monitoring qualitative and quantitative urine protein levels upon admission, the children with proteinuria relapse were treated with GC (GC group; n=29), while those without relapse did not receive GC treatment (non-GC group; n=27). In addition, 29 healthy children aged 3 to prepuberty were selected as the control group. Height, bone age, growth rate, and the FGF23/Klotho ratio were compared among the groups. The correlations of the FGF23/Klotho ratio with height, bone age, and growth rate were analyzed. RESULTS: The FGF23/Klotho ratio in the GC group was significantly higher than that in the non-GC group after 1 month of GC therapy (P<0.05), and the height and bone age growth rates within 6 months were lower than those in the non-GC group (P<0.05). Correlation analysis showed significant negative correlations between the FGF23/Klotho ratio after 1 month of treatment and the growth rates of height and bone age within 6 months in children with PNS (r=-0.356 and -0.436, respectively; P<0.05). CONCLUSIONS: The disturbance in FGF23/Klotho homeostasis is one of the mechanisms underlying the growth impairment caused by long-term oral GC therapy.