Epigenetic alterations affecting hematopoietic regulatory networks as drivers of mixed myeloid/lymphoid leukemia.

Leukemias with ambiguous lineage comprise several loosely defined entities, often without a clear mechanistic basis. Here, we extensively profile the epigenome and transcriptome of a subgroup of such leukemias with CpG Island Methylator Phenotype. These leukemias exhibit comparable hybrid myeloid/lymphoid epigenetic landscapes, yet heterogeneous genetic alterations, suggesting they are defined by their shared epigenetic profile rather than common genetic lesions. Gene expression enrichment reveals similarity with early T-cell precursor acute lymphoblastic leukemia and a lymphoid progenitor cell of origin. In line with this, integration of differential DNA methylation and gene expression shows widespread silencing of myeloid transcription factors. Moreover, binding sites for hematopoietic transcription factors, including CEBPA, SPI1 and LEF1, are uniquely inaccessible in these leukemias. Hypermethylation also results in loss of CTCF binding, accompanied by changes in chromatin interactions involving key transcription factors. In conclusion, epigenetic dysregulation, and not genetic lesions, explains the mixed phenotype of this group of leukemias with ambiguous lineage. The data collected here constitute a useful and comprehensive epigenomic reference for subsequent studies of acute myeloid leukemias, T-cell acute lymphoblastic leukemias and mixed-phenotype leukemias.

Impact of the Children's Oncology Group's supportive care clinical practice guideline endorsement program: An institutional survey.

BACKGROUND: Supportive care clinical practice guidelines (CPGs) facilitate the incorporation of the best available evidence into pediatric cancer care. We aimed to assess the impact of the work of the Children's Oncology Group (COG) Supportive Care Guideline Task Force on institutional supportive care practices. PROCEDURE: An online survey was distributed to representatives at 209 COG sites to assess the awareness, use, and helpfulness of COG-endorsed supportive care CPGs. Availability of institutional policies regarding 13 topics addressed by current COG-endorsed CPGs was also assessed. Respondents described their institutional processes for developing supportive care policies. RESULTS: Representatives from 92 COG sites responded to the survey, and 78% (72/92) were "very aware" of the COG-endorsed supportive care CPGs. On average, sites had policies that addressed seven COG-endorsed supportive care CPG topics (median = 7, range: 0-12). Only 45% (41/92) of sites reported having institutional processes for developing supportive care policies. Of these, most (76%, 31/41) reported that the COG-endorsed CPGs have a medium or large impact on policy development. Compared with sites without processes for supportive care policy development, sites with established processes had policies on a greater number of topics aligned with current COG-endorsed CPG topics (mean = 6.6, range: 0-12 vs mean = 7.9, range: 2-12; p = 0.027). CONCLUSIONS: Most site respondents were aware of the COG-endorsed supportive care CPGs. Less than half of the COG sites represented in the survey have processes in place to implement supportive care policies. Improvement in local implementation is required to ensure that patients at COG sites receive evidence-based supportive care.

Prophages are Infrequently Associated With Antibiotic Resistance in Pseudomonas aeruginosa Clinical Isolates.

Antimicrobial resistance (AMR) is a significant obstacle to the treatment of bacterial infections, including in the context of Pseudomonas aeruginosa infections in patients with cystic fibrosis (CF). Lysogenic bacteriophages can integrate their genome into the bacterial chromosome and are known to promote genetic transfer between bacterial strains. However, the contribution of lysogenic phages to the incidence of AMR is poorly understood. Here, in a set of 187 clinical isolates of Pseudomonas aeruginosa collected from 82 patients with CF, we evaluate the links between prophages and both genomic and phenotypic resistance to five anti-pseudomonal antibiotics: tobramycin, colistin, ciprofloxacin, meropenem, aztreonam, and tazobactam. We find that P. aeruginosa isolates contain on average 3.06 +/-1.84 (SD) predicted prophages. We find no significant association between the number of prophages per isolate and the mean inhibitory concentration (MIC) for any of these antibiotics. We then investigate the relationship between particular prophages and AMR. We identify a single lysogenic phage that is associated with phenotypic resistance to the antibiotic tobramycin. Consistent with this association, we identify AMR genes associated with resistance to tobramycin in these strains and find that they are not encoded directly on prophage sequences. These findings suggest that prophages are infrequently associated with the AMR genes in clinical isolates of P. aeruginosa .

Deep Brain Stimulation of Bilateral Centromedian Thalamic Nuclei in Pediatric Patients with Lennox-Gastaut Syndrome: An Institutional Experience.

BACKGROUND: Surgical management of pediatric patients with nonlesional, drug-resistant epilepsy, including patients with Lennox-Gastaut syndrome (LGS), remains a challenge given the lack of resective targets in most patients and shows seizure freedom rates <50% at 5 years. The efficacy of deep brain stimulation (DBS) is less certain in children than in adults. This study examined clinical and seizure outcomes for pediatric patients with LGS undergoing DBS targeting of the centromedian thalamic nuclei (CMTN). METHODS: An institutional review board-approved retrospective analysis was performed of patients aged ≤19 years with clinical diagnosis of LGS undergoing bilateral DBS placement to the CMTN from 2020 to 2021 by a single surgeon. RESULTS: Four females and 2 males aged 6-19 years were identified. Before surgery, each child experienced at least 6 years of refractory seizures; 4 children had experienced seizures since infancy. All took antiseizure medications at the time of surgery. Five children had previous placement of a vagus nerve stimulator and 2 had a previous corpus callosotomy. The mean length of stay after DBS was 2 days. No children experienced adverse neurologic effects from implantation; the mean follow-up time was 16.3 months. Four patients had >60% reduction in seizure frequency after surgery, 1 patient experienced 10% reduction, and 1 patient showed no change. No children reported worsening seizure symptoms after surgery. CONCLUSIONS: Our study contributes to the sparse literature describing CMTN DBS for children with drug-resistant epilepsy from LGS. Our results suggest that CMTN DBS is a safe and effective therapeutic modality that should be considered as an alternative or adjuvant therapy for this challenging patient population. Further studies with larger patient populations are warranted.

A Case Series on the Use of Brentuximab Vedotin for the Treatment of Mycosis Fungoides.

BACKGROUND: Brentuximab vedotin (BV) is an anti-CD30 monoclonal antibody that appears to be more effective against CD30-expressing cutaneous T-cell lymphoma (CTCL) compared to current standard-of-care treatments.   Objective: To determine the real-world efficacy and adverse effects of BV use in patients with mycosis fungoides (MF) who were treated with BV at Atrium Health Wake Forest Baptist Medical Center. METHODS: Study staff performed a retrospective chart review of patients diagnosed with MF who were prescribed BV at Atrium Health Wake Forest Baptist Comprehensive Cancer Center. RESULTS:   Regardless of their response to BV, all patients in our cohort had higher CD30 positivity on subsequent biopsies compared to their initial skin biopsy.  Conclusions: Improved understanding of appropriate CD30 testing and evaluation will allow for quicker invention of patients with BV responsive CTCL.  J Drugs Dermatol. 2023;22(12):e33-e34.    doi:10.36849/JDD.6981e.

Topical Ivermectin Is Associated With Improved Erythematotelangiectatic, Papulopustular, and Phymatous Rosacea in a Secondary Analysis.

Rosacea has variable clinical presentation consisting of four overlapping phenotypes: erythematotelangiectatic, papulopustular, phymatous, and ocular.1 Rosacea's pathogenesis involves increased cutaneous density of Demodex folliculorum mites, which drive inflammation through activation of Toll-like receptor-2.1,2 Thus, topical ivermectin (IVM) 1.0% cream's anti-inflammatory and acaricidal activity provides an effective and targeted treatment for moderate-to-severe rosacea. However, literature assessing IVM is limited to efficacy in treating the papulopustular presentation, limiting generalizability.1,3,4 Although our primary endpoint was to assess patient adherence, the objective of this secondary analysis was to assess IVM efficacy in rosacea, regardless of clinical presentation.

The role of traditional social determinants of health in referral patterns, timing of surgery, and Chiari Health Index for Pediatrics-determined quality of life in children with symptomatic Chiari type I malformation.

OBJECTIVE: Understanding the impact of the social determinants of health on the utilization of healthcare resources is an important step in eliminating inequalities. The goal of this study was to determine the role of social determinants of health in referral patterns, timing of consultation/intervention, and quality of life in children with Chiari malformation type I (CM-I). METHODS: A retrospective study was conducted of children aged 0 to 18 years who underwent surgical treatment for CM-I at a single pediatric facility from 2015 to 2019. The variables included demographic and socioeconomic characteristics, referral patterns, timing, and quality of life data based on the Chiari Health Index for Pediatrics (CHIP). RESULTS: The cohort consisted of 103 surgically treated CM-I patients. No differences were seen in race, sex, insurance, or household income when evaluating referral source (community, specialist, or emergency department) or when comparing patients with incidental versus symptomatic findings. In the evaluation of timing from initial evaluation to surgery, no statistical differences were seen between racial, sex, insurance status, or income groups. Children from households of lower median family income were significantly more likely to report pain at the time of consultation (pain group median [interquartile range] $46,660 [$41,004-$50,367] vs nonpain group $53,604 [$41,427-$59,828], p = 0.004). Those in the lower-income group also reported lower CHIP scores corresponding to increased symptomatology in the nonpain physical symptoms (p = 0.004) and psychosocial domains (p = 0.018). CONCLUSIONS: There was no evidence of a difference in referral patterns or a delay in time from clinic presentation to surgery based on the traditional social determinants of health categories. Children from households in the lower-income group were associated with increased severity of pain and nonpain symptoms.

The Patient-Physician Relationship and Adherence: Observations From a Clinical Study.

Improved patient-physician relationships (PPR) are associated with better patient satisfaction and disease outcomes, however, there is limited literature assessing how PPR affects adherence in dermatology. We recruited 30 subjects with a clinical diagnosis of rosacea. Subjects were instructed to use ivermectin 1% cream once daily for 3 months and adherence was measured using the Medication Event Monitoring System cap. The Patient-Doctor Relationship Questionnaire (PDRQ-9), a validated questionnaire assessing patients’ perceived strength of the relationship with their doctor, was completed. Mean adherence for all subjects over three months of the study was 62%. PDRQ-9 scores positively correlated with adherence rates for 3 months of treatment (r(26)=0.52; P=0.006). The perceived strength of the PPR may have a role in patients’ adherence to their medications. Improving the PPR, through empathy and effective communication, may facilitate better medication adherence and treatment outcomes. Perche PO, Singh R, Cook MK, et al. The patient-physician relationship and adherence: observations from a clinical study. J Drugs Dermatol. 2023;22(8):838-839. doi:10.36849/JDD.7103.

Full-endoscopic spine surgery diminishes surgical site infections - a propensity score-matched analysis.

BACKGROUND CONTEXT: Surgical site infections (SSI) are one the most frequent and costly complications following spinal surgery. The SSI rates of different surgical approaches need to be analyzed to successfully minimize SSI occurrence. PURPOSE: The purpose of this study was to define the rate of SSIs in patients undergoing full-endoscopic spine surgery (FESS) and then to compare this rate against a propensity score-matched cohort from the National Surgical Quality Improvement Program (NSQIP) database. DESIGN: This is a retrospective multicenter cohort study using a propensity score-matched analysis of prospectively maintained databases. PATIENT SAMPLE: A total of 1277 noninstrumented FESS cases between 2015 and 2021 were selected for analysis. In the nonendoscopic NSQIP cohort we selected data of 55,882 patients. OUTCOME MEASURES: The occurrence of any SSI was the primary outcome. We also collected any other perioperative complications, demographic data, comorbidities, operative details, history of smoking, and chronic steroid intake. METHODS: All FESS cases from a multi-institutional group that underwent surgery from 2015 to 2021 were identified for analysis. A cohort of cases for comparison was identified from the NSQIP database using Current Procedural Terminology of nonendoscopic cervical, thoracic, and lumbar procedures from 2015 to 2019. Trauma cases as well as arthrodesis procedures, surgeries to treat pathologies affecting more than 4 levels or spine tumors that required surgical treatment were excluded. In addition, nonelective cases, and patients with wounds worse than class 1 were also not included. Patient demographics, comorbidities, and operative details were analyzed for propensity matching. RESULTS: In the nonpropensity-matched dataset, the endoscopic cohort had a significantly higher incidence of medical comorbidities. The SSI rates for nonendoscopic and endoscopic patients were 1.2% and 0.001%, respectively, in the nonpropensity match cohort (p-value <.011). Propensity score matching yielded 5936 nonendoscopic patients with excellent matching (standard mean difference of 0.007). The SSI rate in the matched population was 1.1%, compared to 0.001% in endoscopic patients with an odds ratio 0.063 (95% confidence interval (CI) 0.009-0.461, p=.006) favoring FESS. CONCLUSIONS: FESS compares favorably for risk reduction in SSI following spinal decompression surgeries with similar operative characteristics. As a consequence, FESS may be considered the optimal strategy for minimizing SSI morbidity.

Perception of accountability decreases with age: observations from a clinical study of patients with rosacea.

Patient adherence to medications usually increases with age, however, it can also be impacted by other factors. Accountability is a psychosocial construct that is defined as the expectation for an individual to account for their actions. Accountability may also influence patients' motivation to adhere to their treatments. We assessed the relationship between age and perception of accountability as well as efficacy of interventions to improve accountability in a clinical study of 30 rosacea patients. Accountability was assessed using the validated Accountability Measurement Tool. Interventions to improve accountability included a digital interaction group and a digital skin analysis group. All patients were given ivermectin cream 1% and informed to apply it daily for 3-months. There was a negative association between age and AMT scores in all intervention groups, including the control group. Younger patients have a baseline greater perception of accountability that responded more to our interventions.

Real-world outcomes following switching from anti-TNF reference products to biosimilars for the treatment of psoriasis.

Tumor necrosis factor (TNF) inhibitors improved clinical outcomes for patients with psoriasis but are limited by their high cost. There are several biosimilar options approved for the treatment of psoriasis which provides a lower-cost alternative and the potential to increase treatment availability for both biologically naïve and bioexperienced patients. Numerous phase III randomized controlled trials (RCTs) have investigated the effects of switching from biologics to biosimilars; biosimilars had comparable safety and efficacy to their reference products. Real-world evidence may provide complementary information on the expected performance of biosimilars. In this literature review, we analyzed data from real-world studies on switching from biologics for psoriasis to their biosimilars. Effectiveness and safety profiles were comparable when switching from biologics to biosimilars of adalimumab, etanercept, and infliximab. These studies are limited by their sample sizes, duration of follow-up, and single-arm designs without control groups. Based on available real-world evidence, patients may safely and effectively undergo switching to biosimilar therapies for the treatment of psoriasis.

Treatment strategies, including antibiotics, to target the immune component of rosacea.

INTRODUCTION: Recent advances in the understanding of the pathophysiology of rosacea have led to increased focus on the disease's immunologic etiology and to the development of immunologically based treatments. With many patients suffering from incomplete control, addressing the immune components of the disease process may provide a more effective treatment option for rosacea patients that may improve quality of life. AREAS COVERED: This review will provide a brief overview of the pathophysiology of rosacea, as well as specific immunologic contributions to the disease state. Current standard-of-care treatments will be described, including anti-parasitic, anti-inflammatory agents, and antibiotics. Emphasis will be placed on treatments that target the immune components of the disease process. EXPERT OPINION: Rosacea remains a difficult dermatologic disease to treat, partially due to an incomplete understanding of the disease pathophysiology. The immune pathophysiology of rosacea, particularly the key role of inflammation, has been clarified over the past decade. Identification of specific molecules, including cytokines and nuclear transcription factors, may allow for the development of targeted rosacea-specific biologic and topical treatments. However, medication nonadherence is a limiting factor to achieving symptomatic control among rosacea patients. Focusing on the development of oral or injectable forms of therapy may circumvent poor adherence.

Alterations in Protein Translation and Carboxylic Acid Catabolic Processes in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) remains the leading cause of end-stage kidney disease despite decades of study. Alterations in the glomerulus and kidney tubules both contribute to the pathogenesis of DKD although the majority of investigative efforts have focused on the glomerulus. We sought to examine the differential expression signature of human DKD in the glomerulus and proximal tubule and corroborate our findings in the db/db mouse model of diabetes. A transcriptogram network analysis of RNAseq data from laser microdissected (LMD) human glomerulus and proximal tubule of DKD and reference nephrectomy samples revealed enriched pathways including rhodopsin-like receptors, olfactory signaling, and ribosome (protein translation) in the proximal tubule of human DKD biopsy samples. The translation pathway was also enriched in the glomerulus. Increased translation in diabetic kidneys was validated using polyribosomal profiling in the db/db mouse model of diabetes. Using single nuclear RNA sequencing (snRNAseq) of kidneys from db/db mice, we prioritized additional pathways identified in human DKD. The top overlapping pathway identified in the murine snRNAseq proximal tubule clusters and the human LMD proximal tubule compartment was carboxylic acid catabolism. Using ultra-performance liquid chromatography-mass spectrometry, the fatty acid catabolism pathway was also found to be dysregulated in the db/db mouse model. The Acetyl-CoA metabolite was down-regulated in db/db mice, aligning with the human differential expression of the genes ACOX1 and ACACB. In summary, our findings demonstrate that proximal tubular alterations in protein translation and carboxylic acid catabolism are key features in both human and murine DKD.

Comparing available JAK inhibitors for treating patients with psoriasis.

INTRODUCTION: Cytokine blockers have revolutionized the management of psoriasis. While efficacious, not all patients respond, and treatment may lose efficacy over time. Janus kinase (JAK) inhibitors target the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) transduction cascade from transmitting cytokine signals in psoriasis. AREAS COVERED: A PubMed search of phase I, II, and III clinical trials published between 2012 and 2021 utilizing the key terms: Janus kinase and psoriasis. Our search was expanded from clinical trials to further investigate the pathophysiology, standard of care, and safety and efficacy of JAK inhibitors in psoriasis. EXPERT OPINION: Current treatments for psoriasis include topicals, phototherapy, and systemic therapy. The subcutaneous or intravenous route of biologic administration presents a challenge as patients often prefer oral medications over injections and because of anti-drug antibody development. Tofacitinib is effective and has an overall mild-to-moderate safety profile but includes an FDA black box warning for increased risk of cardiovascular events and malignancy. Other JAK inhibitors have an acceptable safety profile and are effective in early clinical trials. Poor topical medication adherence should be considered when evaluating JAK inhibitors. Oral JAK inhibitors may provide a preferable route of administration and improved clinical outcomes.

Full Endoscopic Ligamentum Flavum Sparing Unilateral Laminotomy for Bilateral Recess Decompression: Surgical Technique and Clinical Results.

OBJECTIVE: Interlaminar endoscopic spine surgery has been introduced and utilized for lumbar lateral recess decompression. We modified this technique and utilized it for bilateral lateral recess stenoses without significant central stenosis. Here we present the surgical details and clinical outcome of ligamentum flavum sparing unilateral laminotomy for bilateral recess decompression (ULBRD). METHODS: Prospectively collected registry for full-endoscopic surgeries was reviewed retrospectively. One hundred eighty-two consecutive cases from a single center between September 2015 and March 2021 were reviewed and 57 of them whom underwent ULBRD were enrolled for analysis. Basic patient demographic data, perioperative details, surgeryrelated complications, and clinical outcome were reviewed. The detailed surgical technique is presented as well. RESULTS: Among the 57 patients enrolled, 37 were males while the other 20 were females. The mean age was 58.53 ± 14.51 years, and a bimodal age distribution at the age of mid-fifties and mid-sixties or older was noted. The later age-peak was related to coexistence of degenerative scoliosis. The average operative time per lamina was 70.34 ± 20.51 minutes and mean length of stay was 0.56 ± 0.85 days. Four perioperative complications were reported (7.0%) and the overall reoperation rate at the index level within 1 year was 8.8%. The preoperative back/leg visual analogue scale scores and functional outcome scales including EuroQol-5 dimension questionnaire, Oswestry Disability Index presented significant improvement immediately after surgery and were maintained until final follow-up. CONCLUSION: ULBRD for bilateral lateral recess stenoses without significant central stenosis resulted in good clinical outcomes with acceptably low perioperative complications rates. Sufficient decompression was achieved with the central ligamentum flavum being preserved.

Evaluating topical JAK inhibitors as a treatment option for atopic dermatitis.

INTRODUCTION: Atopic dermatitis (AD) is a chronic, inflammatory skin condition mediated by cytokines that utilize the Janus Kinase/Signal Transducer and Activator of Transcription (JAK-STAT) signaling cascade. Topical JAK inhibitors are an emerging alternative in the treatment of AD. AREAS COVERED: This expert review presents an overview of the underlying molecular pathophysiology of AD, current standards of care, and evaluation of the efficacy and safety of topical JAK inhibitors. A PubMed database search was utilized with a focus on the evidence from double-blind, randomized Phase I, II, and III clinical trials published between January 2015 and July 2021. EXPERT OPINION: Current topical therapies for AD are efficacious but limited by their adverse side effects. Long-term topical corticosteroid use leads to loss of pigmentation, striae, and skin atrophy. Patients may be concerned about topical calcineurin inhibitors' black box warning of increased risk of malignancy. Topical crisaborole, a phosphodiesterase four inhibitor, is limited by application site burning. Topical ruxolitinib is a JAK inhibitor comparable to triamcinolone in efficacy without the adverse effects seen with long-term topical corticosteroid use. Although topical JAK inhibitors have promising efficacy and safety profiles, poor medication adherence common to topical treatments may limit their utility in a clinical setting.

Patient assessment of 5-fluorouracil and imiquimod for the treatment of actinic keratoses: a retrospective study of real-world effectiveness.

BACKGROUND: Despite the superior efficacy of topical therapies for the treatment of actinic keratoses in clinical trials, cryosurgery remains a frequent treatment modality in clinical practice. Little is known about patients' experience of real-world use of topical therapy. OBJECTIVE: To determine the real-world effectiveness and tolerability of 5-fluorouracil and imiquimod in the treatment of actinic keratoses. METHODS: A phone survey and chart review was conducted among 51 patients prescribed 5-fluorouracil (N = 27) or imiquimod (N = 24) for actinic keratoses. RESULTS: Six patients (22%) in the 5-fluorouracil group and five patients (21%) in the imiquimod group reported severe local skin reactions, and three patients in both groups (11% and 13%, respectively) were unwilling to use the respective topical therapies again. Patients in the 5-fluorouracil group had, on average, 3.3 fewer cryosurgery spot treatments following topical treatment. Patients in the imiquimod group averaged 2.0 fewer spot treatments. LIMITATIONS: While this study provides information on real-world experiences, patients' responses were limited by the ability to recall treatment and potential adverse effects. CONCLUSION: High rates of skin reactions, prolonged discomfort, and the continued need for procedural treatments may make patients less willing to use topical 5-fluorouracil or imiquimod for actinic keratoses.