Long-term results of the Malingue technique in the surgical treatment of Dupuytren's disease.

OBJECTIVES: The choice of surgical technique for aponeurectomy in Dupuytren's disease is controversial due to varying outcomes and complication rates. The Malingue plasty has shown mathematical and mechanical advantages, but long-term efficacy and results compared to other techniques have never been reported. This study aimed to evaluate the long-term functional, esthetic and recurrence outcomes of Malingue plasty in Dupuytren's disease. MATERIAL AND METHODS: The study included patients who underwent aponeurectomy with Malingue plasty performed by a highly experienced surgeon between January 2014 and December 2016, with a minimum follow-up of 5 years. Preoperative records were analyzed. At follow-up, extension lag was analyzed in each joint (metacarpophalangeal, proximal interphalangeal and distal interphalangeal) in each operated finger, as well as signs of recurrence or extension of the disease. Function and esthetics were assessed using the QuickDASH (Disabilities of the Arm, Shoulder and Hand) questionnaire and the Michigan Hand Outcomes Questionnaire. RESULTS: Out of 107 eligible patients, 55 were included in the study after exclusions and loss to follow-up. Three patients required revision surgery for recurrence during follow-up. All preoperative deformities of the proximal interphalangeal and metacarpophalangeal joints were corrected postoperatively, and no intraoperative or postoperative complications occurred. Mean extension deficit at follow-up was 18.1 °. Only the little finger showed significant loss of correction (p = 0.02). Mean QuickDASH score was 13.2 and the overall Michigan Hand Outcomes Questionnaire score was 91.8%. Recurrence affected 50% of patients according to the Leclercq criteria and 27.5% according to the Felici criteria. CONCLUSION: Although Malingue plasty did not improve the recurrence rate in Dupuytren's disease compared with other techniques, its advantages in terms of functional improvement and complications make it an interesting surgical option.

Population Pharmacokinetics of Fasinumab in Healthy Volunteers and Patients With Pain Due to Osteoarthritis of the Knee or Hip.

Osteoarthritis (OA) pain management options are currently limited. Fasinumab, an anti-nerve growth factor monoclonal antibody, has been investigated in healthy volunteers and patients with OA-related pain, among other conditions. Data from 12 Phase I-III clinical trials of 92 healthy volunteers and 7430 patients with OA were used to develop a population pharmacokinetic model to characterize fasinumab concentration-time profiles and assess the covariates' effect on fasinumab pharmacokinetic parameters. Participants received single or repeated fasinumab doses intravenously (IV)/subcutaneously (SC), based on body weight (0.03-1 mg/kg IV or 0.1-0.3 mg/kg SC)/fixed dose (9-12 mg IV or 1-12 mg SC). Fasinumab concentration-time data following IV and SC administration in healthy volunteers and patients with OA-related pain were adequately described by a 2-compartment model. Bioavailability increased with higher doses; estimated at 55.1% with 1 mg SC dose, increasing in a greater-than-proportional manner above this. Body weight had the largest predicted impact on fasinumab steady-state exposures, participants at the 5th and 95th percentiles had a 43%-45% higher/22%-23% lower exposure versus reference, respectively. Other covariates had small but clinically irrelevant impacts.

Evaluating the Quality and Usability of Artificial Intelligence-Generated Responses to Common Patient Questions in Foot and Ankle Surgery.

Background: Artificial intelligence (AI) platforms, such as ChatGPT, have become increasingly popular outlets for the consumption and distribution of health care-related advice. Because of a lack of regulation and oversight, the reliability of health care-related responses has become a topic of controversy in the medical community. To date, no study has explored the quality of AI-derived information as it relates to common foot and ankle pathologies. This study aims to assess the quality and educational benefit of ChatGPT responses to common foot and ankle-related questions. Methods: ChatGPT was asked a series of 5 questions, including "What is the optimal treatment for ankle arthritis?" "How should I decide on ankle arthroplasty versus ankle arthrodesis?" "Do I need surgery for Jones fracture?" "How can I prevent Charcot arthropathy?" and "Do I need to see a doctor for my ankle sprain?" Five responses (1 per each question) were included after applying the exclusion criteria. The content was graded using DISCERN (a well-validated informational analysis tool) and AIRM (a self-designed tool for exercise evaluation). Results: Health care professionals graded the ChatGPT-generated responses as bottom tier 4.5% of the time, middle tier 27.3% of the time, and top tier 68.2% of the time. Conclusion: Although ChatGPT and other related AI platforms have become a popular means for medical information distribution, the educational value of the AI-generated responses related to foot and ankle pathologies was variable. With 4.5% of responses receiving a bottom-tier rating, 27.3% of responses receiving a middle-tier rating, and 68.2% of responses receiving a top-tier rating, health care professionals should be aware of the high viewership of variable-quality content easily accessible on ChatGPT. Level of Evidence: Level III, cross sectional study.

Mouse models of pediatric high-grade gliomas with MYCN amplification reveal intratumoral heterogeneity and lineage signatures.

Pediatric high-grade gliomas of the subclass MYCN (HGG-MYCN) are highly aggressive tumors frequently carrying MYCN amplifications, TP53 mutations, or both alterations. Due to their rarity, such tumors have only recently been identified as a distinct entity, and biological as well as clinical characteristics have not been addressed specifically. To gain insights into tumorigenesis and molecular profiles of these tumors, and to ultimately suggest alternative treatment options, we generated a genetically engineered mouse model by breeding hGFAP-cre::Trp53Fl/Fl::lsl-MYCN mice. All mice developed aggressive forebrain tumors early in their lifetime that mimic human HGG-MYCN regarding histology, DNA methylation, and gene expression. Single-cell RNA sequencing revealed a high intratumoral heterogeneity with neuronal and oligodendroglial lineage signatures. High-throughput drug screening using both mouse and human tumor cells finally indicated high efficacy of Doxorubicin, Irinotecan, and Etoposide as possible therapy options that children with HGG-MYCN might benefit from.

The Effectiveness of Aquatic Therapy on Motor and Social Skill as Well as Executive Function in Children With Neurodevelopmental Disorder: A Systematic Review and Meta-analysis.

OBJECTIVE: To summarize the evidence on the efficacy of aquatic therapy on motor and social skill as well as executive function compared with land-based exercises in children with neurodevelopmental disorders. DATA SOURCES: The following 6 databases were searched: Cochrane Central Register of Controlled Trials, PubMed, Embase, Scopus, Google scholar (advance), and Web of Science from 1990 to June 2022. STUDY SELECTION: The search included only clinical trials. Two reviewers independently assessed the full text and conducted manuscript selection, data extraction, and quality assessment. DATA EXTRACTION: Using standardized forms, data were extracted and all points of disagreement were discussed between authors. DATA SYNTHESIS: Data synthesis was applied to summarize information from the included trials. The quantitative analysis incorporated fixed-effect models. Of the 150 studies identified in the initial search, 16 trials (248 children) met the eligibility criteria. Aquatic therapy improved factors related to the Humphries' Assessment of Aquatic Readiness (HAAR) checklist such as mental adjustment (standardized mean difference [SMD], 0.69; 95% confidence interval [CI], 0.20-1.19; I2=10%) compared with land-based exercises (control), water environment (SMD, 0.99; 95% CI, 0.43-1.54; I2=83%), Rotation (SMD, 0.63; 95% CI, 0.14-1.12; I2=0%), balance and control (SMD, 2.09; 95% CI, 1.47-2.72; I2=36%) and independent movement (eg, walking, moving upper body, standing, transferring) in water (SMD, 0.87; 95% CI, 0.37-1.38; I2=0%) compared with the control group in the 4 trails. The HAAR tool is based on the Halliwick method and aims to assess the appropriateness for an individual with disability to engage in aquatic therapy. The study protocol was also registered with PROSPERO number CRD42022341898. CONCLUSION: Aquatic therapy demonstrated a more robust positive effect on factors related to the HAAR checklist than land-based exercises. Further research is needed to further elucidate the clinical utility of aquatic therapy for children with neurodevelopmental disorder at long-term follow-up.

Wheelchair basketball, health, competitive analysis, and performance advantage: a review of theory and evidence.

The purpose of this study was to review the various risks and benefits of wheelchair basketball (WB) and explore some of the research which outlines factors that influence WB player performance and conditioning. WB offers several physical and psychological advantages. Physically, it can improve muscle strength, endurance, and cardiovascular fitness while decreasing the prevalence of chronic physical disorders. From a psychological standpoint, WB has been shown to alleviate anxiety and feelings of depression while also creating and improving social relationships. Despite the many benefits, WB can cause injuries, particularly in the upper extremities, and preventative measures should be employed. WB necessitates intense intermittent efforts and athletes must maintain excellent cardiovascular fitness, strength, and muscular endurance. Healthy sleeping patterns have also been shown to improve performance in WB players. Wheelchair mobility and biomechanical variables as well as wheelchair size and weight appear to be critical success elements in WB. WB can be a powerful tool for coaches and therapists to boost the physical and emotional health of individuals with disabilities and motivate them to participate in team-based sport.

The tumor suppressor CREBBP and the oncogene MYCN cooperate to induce malignant brain tumors in mice.

The tumor suppressor and chromatin modifier cAMP response element-binding protein binding protein (CREBBP) and v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), a member of the MYC oncogene family, are critically involved in brain development. Both genes are frequently mutated in the same tumor entities, including high-grade glioma and medulloblastoma. Therefore, we hypothesized that alterations in both genes cooperate to induce brain tumor formation. For further investigation, hGFAP-cre::CrebbpFl/Fl::lsl-MYCN mice were generated, which combine Crebbp deletion with overexpression of MYCN in neural stem cells (NSCs). Within eight months, these animals developed aggressive forebrain tumors. The first tumors were detectable in the olfactory bulbs of seven-day-old mice. This location raises the possibility that presumptive founder cells are derived from the ventricular-subventricular zone (V-SVZ). To examine the cellular biology of these tumors, single-cell RNA sequencing was performed, which revealed high intratumoral heterogeneity. Data comparison with reference CNS cell types indicated the highest similarity of tumor cells with transit-amplifying NSCs or activated NSCs of the V-SVZ. Consequently, we analyzed V-SVZ NSCs of our mouse model aiming to confirm that the tumors originate from this stem cell niche. Mutant V-SVZ NSCs showed significantly increased cell viability and proliferation as well as reduced glial and neural differentiation in vitro compared to control cells. In summary, we demonstrate the oncogenic potential of a combined loss of function of CREBBP and overexpression of MYCN in this cell population. hGFAP-cre::CrebbpFl/Fl::lsl-MYCN mice thus provide a valuable tool to study tumor-driving mechanisms in a key neural stem/ progenitor cell niche.

MAPK inhibitor sensitivity scores predict sensitivity driven by the immune infiltration in pediatric low-grade gliomas.

Pediatric low-grade gliomas (pLGG) show heterogeneous responses to MAPK inhibitors (MAPKi) in clinical trials. Thus, more complex stratification biomarkers are needed to identify patients likely to benefit from MAPKi therapy. Here, we identify MAPK-related genes enriched in MAPKi-sensitive cell lines using the GDSC dataset and apply them to calculate class-specific MAPKi sensitivity scores (MSSs) via single-sample gene set enrichment analysis. The MSSs discriminate MAPKi-sensitive and non-sensitive cells in the GDSC dataset and significantly correlate with response to MAPKi in an independent PDX dataset. The MSSs discern gliomas with varying MAPK alterations and are higher in pLGG compared to other pediatric CNS tumors. Heterogenous MSSs within pLGGs with the same MAPK alteration identify proportions of potentially sensitive patients. The MEKi MSS predicts treatment response in a small set of pLGG patients treated with trametinib. High MSSs correlate with a higher immune cell infiltration, with high expression in the microglia compartment in single-cell RNA sequencing data, while low MSSs correlate with low immune infiltration and increased neuronal score. The MSSs represent predictive tools for the stratification of pLGG patients and should be prospectively validated in clinical trials. Our data supports a role for microglia in the response to MAPKi.

Group-specific cellular metabolism in Medulloblastoma.

BACKGROUND: Cancer metabolism influences multiple aspects of tumorigenesis and causes diversity across malignancies. Although comprehensive research has extended our knowledge of molecular subgroups in medulloblastoma (MB), discrete analysis of metabolic heterogeneity is currently lacking. This study seeks to improve our understanding of metabolic phenotypes in MB and their impact on patients' outcomes. METHODS: Data from four independent MB cohorts encompassing 1,288 patients were analysed. We explored metabolic characteristics of 902 patients (ICGC and MAGIC cohorts) on bulk RNA level. Moreover, data from 491 patients (ICGC cohort) were searched for DNA alterations in genes regulating cell metabolism. To determine the role of intratumoral metabolic differences, we examined single-cell RNA-sequencing (scRNA-seq) data from 34 additional patients. Findings on metabolic heterogeneity were correlated to clinical data. RESULTS: Established MB groups exhibit substantial differences in metabolic gene expression. By employing unsupervised analyses, we identified three clusters of group 3 and 4 samples with distinct metabolic features in ICGC and MAGIC cohorts. Analysis of scRNA-seq data confirmed our results of intertumoral heterogeneity underlying the according differences in metabolic gene expression. On DNA level, we discovered clear associations between altered regulatory genes involved in MB development and lipid metabolism. Additionally, we determined the prognostic value of metabolic gene expression in MB and showed that expression of genes involved in metabolism of inositol phosphates and nucleotides correlates with patient survival. CONCLUSION: Our research underlines the biological and clinical relevance of metabolic alterations in MB. Thus, distinct metabolic signatures presented here might be the first step towards future metabolism-targeted therapeutic options.

A Carboxy-terminal Smarcb1 Point Mutation Induces Hydrocephalus Formation and Affects AP-1 and Neuronal Signalling Pathways in Mice.

The BAF (BRG1/BRM-associated factor) chromatin remodelling complex is essential for the regulation of DNA accessibility and gene expression during neuronal differentiation. Mutations of its core subunit SMARCB1 result in a broad spectrum of pathologies, including aggressive rhabdoid tumours or neurodevelopmental disorders. Other mouse models have addressed the influence of a homo- or heterozygous loss of Smarcb1, yet the impact of specific non-truncating mutations remains poorly understood. Here, we have established a new mouse model for the carboxy-terminal Smarcb1 c.1148del point mutation, which leads to the synthesis of elongated SMARCB1 proteins. We have investigated its impact on brain development in mice using magnetic resonance imaging, histology, and single-cell RNA sequencing. During adolescence, Smarcb11148del/1148del mice demonstrated rather slow weight gain and frequently developed hydrocephalus including enlarged lateral ventricles. In embryonic and neonatal stages, mutant brains did not differ anatomically and histologically from wild-type controls. Single-cell RNA sequencing of brains from newborn mutant mice revealed that a complete brain including all cell types of a physiologic mouse brain is formed despite the SMARCB1 mutation. However, neuronal signalling appeared disturbed in newborn mice, since genes of the AP-1 transcription factor family and neurite outgrowth-related transcripts were downregulated. These findings support the important role of SMARCB1 in neurodevelopment and extend the knowledge of different Smarcb1 mutations and their associated phenotypes.

Teleexercise for geriatric patients with failed back surgery syndrome.

Introduction: Failed back surgery syndrome (FBSS) is defined as back pain which either persists after attempted surgical intervention or originates after a spine surgery. There is a high risk of perioperative morbidity and a high likelihood of extensive revision surgery in geriatric patients with FBSS or post-laminectomy foraminal stenosis. Methods: There is a need for less invasive methodologies for the treatment of FBSS, such as patient-tailored exercise training, with attention to the cost and special needs of the geriatric patients with FBSS. This commentary will provide some background regarding teleexercise (utilizing an internet-based platform for the provision of exercise-related care) for FBSS and will propose three exercises which are easy to administer over online-based platforms and can be the subject of future investigation. Results: Given the documented benefits of regular rehabilitative exercises for patients with FBSS, the high cost of face-to-face services, and the need for infection mitigation in the wake of the COVID-19 Pandemic, teleexercise may be a practical and cost-beneficial method of exercise delivery, especially for geriatric patients with limitations in mobility and access to care. It should be noted that, prescription of these exercises should be done after face-to-face evaluation by the physician and careful evaluation for any "red flag" symptoms. Conclusion: In this commentary, we will suggest three practical exercise training methodologies and discuss the benefits of teleexercise for geriatric patients with FBSS. Future research should aim to assess the efficacy of these exercises, especially when administered through telehealth platforms.

Opioid Legislation Decreases Opioid Prescribing in Total Knee Arthroplasty.

The purpose of this study was to evaluate the impact of opioid-limiting legislation on perioperative opioid prescriptions in total knee arthroplasty. The hypothesis was that opioid legislation has reduced opioid prescription filling above levels anticipated by national trends. This study retrospectively evaluated opioid prescription filling for all patients undergoing total knee arthroplasty in a commercially available insurance database between 2010 and 2018 (n=1,068,764). Initial discharge and 90-day cumulative oxycodone 5-mg equivalents filled were tabulated. Opioid prescription filling was evaluated over time and between states with and without opioid-limiting legislation using analysis of variance and multivariable linear and logistic regression. States with and without opioid legislation had significant reductions in initial and cumulative opioid prescription filling volume (all P<.001). However, the magnitude of this reduction was larger in states with opioid legislation. Legislation targeting duration and volume had the largest impact on initial post-act opioid prescription filling volume compared with states without legislation in an estimated "pre-act" time frame. Legislation targeting duration and volume and no specific target had the largest impact on cumulative post-act opioid prescription filling volume. States without legislation still had large, significant reductions in filling volume, but the magnitude was not as great as in states with opioid legislation. States with and without opioid legislation had significant decreases in initial and cumulative opioid prescription filling volume. However, the magnitude of reduction was larger in states that enacted legislation. Younger age, pre-operative opioid use, and higher comorbidity burden were associated with greater opioid use postoperatively. [Orthopedics. 2023;46(3):142-150.].

The role of telehealth in the care of musculoskeletal pain conditions after COVID-19.

The rise of virtual medicine through the use of e-Health technology was accelerated by the COVID-19 pandemic and remains a vital part of health care delivery today. Telehealth, a virtual health care delivery system through either electronic or telecommunication technology, may improve the ability to deliver care in resource poor areas or where barriers to access occur. Despite the obvious advantages to telehealth, the efficacy of virtual visits when compared to face-to-face health care interactions is a topic of much debate, especially with regards to areas of medicine which rely heavily on physical examination or demonstration of therapeutic exercises and movements. In this commentary, we review the efficacy of telehealth with a focus on prevention and treatment of musculoskeletal pain conditions, and explore areas for future research.

Does Bracing Control the Progression of Adolescent Idiopathic Scoliosis in Curves Higher Than 40°? A Systematic Review and Meta-analysis.

Routinely, adolescent idiopathic scoliosis (AIS) curves that progress beyond 40° in skeletally immature adolescents require surgery. However, some adolescents with AIS and their parents utterly refuse surgery and insist on wearing a brace. Debate continues regarding the appropriateness of bracing for AIS curves exceeding 40° in patients who have rejected surgical intervention. This systematic review and meta-analysis was conducted to review the literature on the effectiveness of bracing and its predictive factors in largermagnitude AIS curves ≥40°. This study replicated the search strategy used by the PICOS system for formulating study questions, which include consideration of the patient/population (P), intervention (I), comparison (C), outcome (O), and study design (S). The search was conducted up to January 2022 in the following bibliographic online databases only in the English language: PubMed, Google Scholar, Scopus, and Web of Science. Two assessors reviewed the articles for qualification. Eligible studies were assessed for risk of bias at the study level using the Newcastle-Ottawa Scale. The effect size across the studies was determined using standardized mean differences (Cohen's d) and 95% confidence intervals for the meta-analysis. Among the eight included moderate quality studies, evidence of potential publication bias (p <0.05) for the trials included was found in the Cobb angle outcome. Results obtained through meta-analysis indicated that the effectiveness of bracing in controlling Cobb angle progression in curves ≥40° is significantly positive. Additionally, initial curve severity, Risser stage, in-brace curve correction, curve type, and apical vertebral rotation were considered risk factors associated with brace effectiveness. This systematic review revealed that bracing could alter the normal course of AIS curves ≥40° in patients refusing posterior spinal fusion (PSF). However, the suggested course for patients refusing PSF remains unclear because of the significant heterogeneity in the risk factors associated with bracing failure.

Does Bracing Control the Progression of Adolescent Idiopathic Scoliosis in Curves Higher Than 40°? A Systematic Review and Meta-analysis

Routinely, adolescent idiopathic scoliosis (AIS) curves that progress beyond 40° in skeletally immature adolescents require surgery. However, some adolescents with AIS and their parents utterly refuse surgery and insist on wearing a brace. Debate continues regarding the appropriateness of bracing for AIS curves exceeding 40° in patients who have rejected surgical intervention. This systematic review and meta-analysis was conducted to review the literature on the effectiveness of bracing and its predictive factors in largermagnitude AIS curves ≥40°. This study replicated the search strategy used by the PICOS system for formulating study questions, which include consideration of the patient/population (P), intervention (I), comparison (C), outcome (O), and study design (S). The search was conducted up to January 2022 in the following bibliographic online databases only in the English language: PubMed, Google Scholar, Scopus, and Web of Science. Two assessors reviewed the articles for qualification. Eligible studies were assessed for risk of bias at the study level using the Newcastle-Ottawa Scale. The effect size across the studies was determined using standardized mean differences (Cohen’s d) and 95% confidence intervals for the meta-analysis. Among the eight included moderate quality studies, evidence of potential publication bias (p <0.05) for the trials included was found in the Cobb angle outcome. Results obtained through meta-analysis indicated that the effectiveness of bracing in controlling Cobb angle progression in curves ≥40° is significantly positive. Additionally, initial curve severity, Risser stage, in-brace curve correction, curve type, and apical vertebral rotation were considered risk factors associated with brace effectiveness. This systematic review revealed that bracing could alter the normal course of AIS curves ≥40° in patients refusing posterior spinal fusion (PSF). However, the suggested course for patients refusing PSF remains unclear because of the significant heterogeneity in the risk factors associated with bracing failure.

Existing fixation modalities for Jones type fifth metatarsal fracture fixation pose high rates of complications and nonunion.

Jones type fifth metatarsal fractures pose a challenge to the foot and ankle surgeon, given documented high nonunion rates as well as high complication rates including hardware prominence, nerve injury, and screw breakage for existing treatment modalities including screw and plantar plate fixation. We call for the design of innovative Jones-fracture specific implants which contour to the natural curve of the fifth metatarsal. Future research should aim to expand upon existing literature for Jones fracture fixation and evaluate efficacy of novel implants which are designed to address unacceptably high complication rates for existing treatment modalities.

Smarcb1 Loss Results in a Deregulation of esBAF Binding and Impacts the Expression of Neurodevelopmental Genes.

The murine esBAF complex plays a major role in the regulation of gene expression during stem cell development and differentiation. As one of its core subunits, Smarcb1 is indispensable for its function and its loss is connected to neurodevelopmental disorders and participates in the carcinogenesis of entities such as rhabdoid tumours. We explored how Smarcb1 regulates gene programs in murine embryonic stem cells (mESC) and in this way orchestrates differentiation. Our data underline the importance of Smarcb1 expression and function for the development of the nervous system along with basic cellular functions, such as cell adhesion and cell organisation. Using ChIP-seq, we were able to portray the consequences of Smarcb1 knockdown (kd) for the binding of esBAF and PRC2 as well as its influence on histone marks H3K27me3, H3K4me3 and H3K27ac. Their signals are changed in gene and enhancer regions of genes connected to nervous system development and offers a plausible explanation for changes in gene expression. Further, we describe a group of genes that are, despite increased BAF binding, suppressed after Smarcb1 kd by mechanisms independent of PRC2 function.

Single-cell transcriptomics identifies potential cells of origin of MYC rhabdoid tumors.

Rhabdoid tumors (RT) are rare and highly aggressive pediatric neoplasms. Their epigenetically-driven intertumoral heterogeneity is well described; however, the cellular origin of RT remains an enigma. Here, we establish and characterize different genetically engineered mouse models driven under the control of distinct promoters and being active in early progenitor cell types with diverse embryonic onsets. From all models only Sox2-positive progenitor cells give rise to murine RT. Using single-cell analyses, we identify distinct cells of origin for the SHH and MYC subgroups of RT, rooting in early stages of embryogenesis. Intra- and extracranial MYC tumors harbor common genetic programs and potentially originate from fetal primordial germ cells (PGCs). Using PGC specific Smarcb1 knockout mouse models we validate that MYC RT originate from these progenitor cells. We uncover an epigenetic imbalance in MYC tumors compared to PGCs being sustained by epigenetically-driven subpopulations. Importantly, treatments with the DNA demethylating agent decitabine successfully impair tumor growth in vitro and in vivo. In summary, our work sheds light on the origin of RT and supports the clinical relevance of DNA methyltransferase inhibitors against this disease.