A single-day polychemotherapy regimen with proteasome inhibitor combinations for relapsed/refractory myeloma in the era of novel therapies.

PCAB (prednisone, cyclophosphamide, doxorubicin, carmustine) is a single-day regimen previously used for induction and now in relapsed/refractory multiple myeloma (RRMM). We retrospectively analysed the outcomes of 85 patients from five Australian centres. These included 30 patients (35.3%) who received PCAB with one additional agent (bortezomib most frequently). Median age of the patients was 65 years (37-80), with a median of four (1-8) prior lines of therapy. ORR was 37% (CR 4.9%). Median progression free survival and overall survival were 4.4 months (95% CI 3.5-6.7) and 7.4 months (95% CI 6.4-10.2), respectively. Extramedullary disease (EMD) was associated with shorter survival. Grade 3 or 4 cytopenia and febrile neutropenia occurred in 76.2% and 39.1%, respectively, with six (7.1%) treatment-related mortalities. Median inpatient stay was 3.3 days/28-day cycle (IQR 0.6-13), and for patients who died, a median of 20.2% of days alive were spent inpatient (IQR 6.4-39.1%). Three patients were successfully bridged to CAR T-cell therapy using PCAB, despite being penta-exposed and having EMD. PCAB may be considered as a useful salvage therapy amongst other polychemotherapy regimens in late relapse. Further studies is warranted to investigate and define its role as a bridging therapy to novel therapeutics.

Decoding the Implications of Glucagon-like Peptide-1 Receptor Agonists on Accelerated Facial and Skin Aging.

Following the advent of glucagon-like peptide-1 receptor agonists (GLP-1RAs), subsequent unintended effects such as accelerated facial aging and altered skin health have been noted. This review delves deeper into the causative underlying mechanisms and provides insights into the intricate relationship between GLP-1RAs, adipose tissue, and premature facial aging, thereby highlighting the need for a nuanced understanding of their effects on facial alterations and skin health. Studies exploring the potential effects of GLP-1RAs on facial alterations and offering insights into the possible underlying mechanisms, causes, and clinical implications were included. The accelerated facial aging and altered skin health observed in GLP-1RA patients appears to be multifactorial, involving loss of dermal and subcutaneous white adipose tissue, and altered proliferation and differentiation of adipose-derived stem cells (ADSCs), and impacts on the production and secretion of hormonal and metabolic factors. These changes compromise the structural integrity and barrier function of the skin and may lead to diminished facial muscle mass, further exacerbating the appearance of aging. The insights presented call for a paradigm shift in the clinical management of facial changes induced by GLP-1RAs, with a focus on treatment strategies aimed at targeting ADSC stimulation. These include autologous fat transfers to reintroduce cells rich in ADSCs for rejuvenation, composite fat grafting combining autologous fat with/without stromal vascular fraction, and the strategic use of soft tissue fillers for volume restoration and biostimulation. This review highlights the potential role of GLP-1RAs in modulating adipose tissue dynamics, thereby contributing to accelerated aging through metabolic, structural, and hormonal pathways.

Care of suspected long bone fractures in the emergency department: Families' perspectives and priorities.

OBJECTIVE: Despite growing interests in patient-reported outcomes, youth and families are rarely involved in designing quality improvement measures. Few quality indicators exist for the care of children with injuries in the Emergency Department (ED) and extremity fractures are among the most common injuries in children. This study's aim was to identify both parents' and youth's perspectives about ED care in the context of a suspected long-bone fracture. METHODS: Youth (10-18 years old) and their parents were surveyed prospectively during their ED visit. Participants were asked: 1) to identify their main concerns, 2) to identify quality measures that were most important to them, and 3) to evaluate the ED care they received. Descriptive analyses present participants' responses. Continuous data was analyzed using a Student t-test and categorical data using a Chi-square test. RESULTS: Over 15 months, 350 families met eligibility criteria and were approached to participate, of which 300 participants consented and 249 surveys were completed (71% response rate): 148 parents and 101 youth (median age: 12) completed their respective surveys. Participants placed a high importance on several themes: pain management, short length of stay, and quality interactions with ED clinicians. Youth as a group prioritized their overall wellbeing and the ED environment (e.g., waiting room comfort, signage), while parents focused on accurate diagnoses and treatments. The following items were less prioritized: that radiology be close to the ED, to see the radiograph, to have access to a wheelchair, to know the identities of clinicians on the team, and to have access to entertainment. Parents and youth within the same family often did not share the same priorities. Ninety-two percent of parents reported their child's pain was treated, while 81% and 63% of youth reported their pain was treated sufficiently and quickly, respectively. CONCLUSIONS: Parents and youth can identify their priorities for ED care and should be engaged in efforts to improve and report on the quality of care in the ED. Youths' and parents' perspectives are complimentary and may not align, even within families. The priorities identified in this study can help inform quality improvement initiatives and personalized patient care.

Predictors of slow colonic transit in children.

PURPOSE: Slow transit constipation (STC) and functional fecal retention (FFR) are two forms of severe intractable constipation in childhood diagnosed by nuclear transit studies (NTS). This retrospective study aims to identify the predicting factors for STC and FFR by looking at the association with neuropsychiatric disorders (NPD), obesity, family history of constipation and atopic disease. PATIENTS AND METHODS: A retrospective chart review was conducted on children with intractable constipation referred for NTS between 1st April 2003 and 1st April 2014. Comparisons were made between STC, FFR and normal transit patients with regards to NPD, obesity (BMI z score >95th percentile), family history of constipation in first and second-degree relatives and atopic disease which included food allergy, asthma and eczema. RESULTS: Between 2003 and 2014, 97 patients were referred for a NTS. Out of 36 patients with NPD, 21 (58.3 %) had STC and 13 (36.1 %) had FFR (p < 0.05). 15.8 % of patients with constipation were obese, compared to 6.4 % in the general Australian paediatric population (p < 0.05). There was no significant association between constipation and atopic disease or family history. CONCLUSION: Neuropsychiatric disorders, in particular autism, are useful predictors of STC and FFR in children. Obesity may be associated with a higher risk of developing chronic constipation.

Intravascular diffuse large B-cell lymphoma with acquired ichthyosis: A case report.

Intravascular diffuse large B-cell lymphoma is an exceedingly rare subtype of B-cell lymphomas. This cancer is often associated with poor prognosis and can be lethal if left untreated. Intravascular diffuse large B-cell lymphoma is divided into three variants: the 'classical variant', the hemophagocytic syndrome-associated variant or 'Asian variant', and the 'cutaneous variant', according to the clinical presentation and affected organs. We present a unique case of 'classic variant' intravascular diffuse large B-cell lymphoma with cutaneous findings, peripheral nervous system involvement and acquired ichthyosis in a patient of Asian descent. This case highlights the importance of a prompt dermatology consultation in the diagnosis of intravascular diffuse large B-cell lymphoma. As bone marrow biopsy is often negative, clinicians must recognize the cutaneous findings and acknowledge that skin biopsy can be an essential tool to establish the diagnosis rapidly. Additional finding making this case unique is the concurrent presence of acquired ichthyosis, which has only been previously reported in one case of intravascular diffuse large B-cell lymphoma.

Successful treatment of acrodermatitis continua of Hallopeau with tildrakizumab: A case report.

Acrodermatitis continua of Hallopeau is a rare, localized variant of pustular psoriasis commonly associated with join disease and severe quality of life impairment. While there are no standard treatment guidelines, therapies used for psoriasis vulgaris are commonly tried. We report a case of severe acrodermatitis continua of Hallopeau in a patient with multiple comorbidities (advanced malignancy, recurrent empyema, psoriatic arthritis) where tildrakizumab lead to a rapid resolution of skin and joint disease which was maintained 1 year later. To date, there are only four cases reporting the use of IL-23 inhibitors class in acrodermatitis continua of Hallopeau and none for tildrakizumab. However, IL-23 inhibitors should be strongly considered among the treatment of choice for acrodermatitis continua of Hallopeau, especially in patients with ongoing malignancy and/or high risk of infections.

Current knowledge of the implication of lipid mediators in psoriasis.

The skin is an organ involved in several biological processes essential to the proper functioning of the organism. One of these essential biological functions of the skin is its barrier function, mediated notably by the lipids of the stratum corneum, and which prevents both penetration from external aggression, and transepidermal water loss. Bioactive lipid mediators derived from polyunsaturated fatty acids (PUFAs) constitute a complex bioactive lipid network greatly involved in skin homeostasis. Bioactive lipid mediators derived from n-3 and n-6 PUFAs have well-documented anti- and pro-inflammatory properties and are recognized as playing numerous and complex roles in the behavior of diverse skin diseases, including psoriasis. Psoriasis is an inflammatory autoimmune disease with many comorbidities and is associated with enhanced levels of pro-inflammatory lipid mediators. Studies have shown that a high intake of n-3 PUFAs can influence the development and progression of psoriasis, mainly by reducing the severity and frequency of psoriatic plaques. Herein, we provide an overview of the differential effects of n-3 and n-6 PUFA lipid mediators, including prostanoids, hydroxy-fatty acids, leukotrienes, specialized pro-resolving mediators, N-acylethanolamines, monoacylglycerols and endocannabinoids. This review summarizes current findings on lipid mediators playing a role in the skin and their potential as therapeutic targets for psoriatic patients.

Novel role of long non-coding RNAs in autoimmune cutaneous disease.

Systemic autoimmune rheumatic diseases (SARDs) are a heterogeneous group of chronic multisystem inflammatory disorders that are thought to have a complex pathophysiology, which is not yet fully understood. Recently, the role of non-coding RNAs, including long non-coding RNA (lncRNA), has been of particular interest in the pathogenesis of SARDs. We aimed to summarize the potential roles of lncRNA in SARDs affecting the skin including, systemic sclerosis (SSc), dermatomyositis (DM) and cutaneous lupus erythematosus (CLE). We conducted a narrative review summarizing original articles published until July 19, 2021, regarding lncRNA associated with SSc, DM, and CLE. Several lncRNAs were hypothesized to play an important role in disease pathogenesis of SSc, DM and CLE. In SSc, Negative Regulator of IFN Response (NRIR) was thought to modulate Interferon (IFN) response in monocytes, anti-sense gene to X-inactivation specific transcript (TSIX) to regulate increased collagen stability, HOX transcript antisense RNA (HOTAIR) to increase numbers of myofibroblasts, OTUD6B-Anti-Sense RNA 1 to decrease fibroblast apoptosis, ncRNA00201 to regulate pathways in SSc pathogenesis and carcinogenesis, H19X potentiating TGF-ß-driven extracellular matrix production, and finally PSMB8-AS1 potentiates IFN response. In DM, linc-DGCR6-1 expression was hypothesized to target the USP18 protein, a type 1 IFN-inducible protein that is considered a key regulator of IFN signaling. Additionally, AL136018.1 is suggested to regulate the expression Cathepsin G, which increases the permeability of vascular endothelial cells and the chemotaxis of inflammatory cells in peripheral blood and muscle tissue in DM. Lastly, lnc-MIPOL1-6 and lnc-DDX47-3 in discoid CLE were thought to be associated with the expression of chemokines, which are significant in Th1 mediated disease. In this review, we summarize the key lncRNAs that may drive pathogenesis of these connective tissue diseases and could potentially serve as therapeutic targets in the future.

Treatment Guidelines for Atopic Dermatitis Since the Approval of Dupilumab: A Systematic Review and Quality Appraisal Using AGREE-II.

Introduction: Since its approval for adults with moderate-to-severe atopic dermatitis (AD) in 2017, dupilumab has been incorporated into clinical practice guidelines (CPGs). However, recommendations differ internationally, and the quality assessment of their development is unclear. Objective: We aimed to systematically review and appraise the quality of CPGs for adult AD reported since 2017 and map the recommendations for dupilumab initiation relative to conventional systemic therapy (CST). Materials and Methods: A literature search was conducted in June 2020 in MEDLINE, EMBASE, SCOPUS, and CINAHL. Twelve CPGs were retrieved. Methodological quality was assessed using the validated Appraisal of Guidelines for Research & Evaluation II tool (AGREE-II). Recommendations were extracted and compared. Results: AGREE-II median scores per domain of the CPGs were (%, r = range): scope/purpose, 78% (50-96); stakeholder involvement, 54% (28-85); rigor of development, 39% (21-63); clarity of presentation, 85% (69-100); applicability, 27% (6-51); and editorial independence, 76% (42-100). Neither met the threshold of 70% quality criteria for rigor of development nor the applicability domains. Three CPGs met the criteria for recommendation without modification. CPGs' approach to dupilumab initiation was as follows: second line, preferred over CST and nbUVB (n = 1/12 CPG); second line, equivalent to CST or nbUVB (n = 3/12 CPGs); third line, after nbUVB or CST (n = 5/12 CPGs); and fourth line after nbUVB and CST (n = 2/12). No consensus was reached for n = 1/12 CPG. Conclusion and Relevance: Dupilumab is now incorporated into CPGs for adult AD. These CPGs exhibited good quality in scope/purpose, clarity, and editorial independence domains. However, none met AGREE-II criteria for methodological rigor/applicability. Gaps were found in mechanisms for updates, facilitators/barriers, resource implications, and stakeholder involvement. Only n = 3/12 CPGs met quality criteria for recommendation without modifications. Of these, two favored a conservative sequential approach for the initiation of dupilumab relative to CST, while one did not reach consensus. Our findings highlight divergent recommendations AD treatment, underlining a need to incorporate quality criteria into future guideline development.

Adult-onset en coup de sabre scleroderma in a patient with linear localized scleroderma profunda: A case report and literature review.

The en coup de sabre variant of linear scleroderma typically occurs in children. We report a unique case of adult-onset en coup de sabre scleroderma in a patient with linear localized scleroderma profunda. The patient was treated with oral steroids and oral methotrexate improving her cutaneous disease. This case highlights the importance of a thorough cutaneous examination as this adult patient developed an entity traditionally believed to occur in childhood.

Tiotropium bromide as adjunct therapy in children with asthma: a clinical experience.

BACKGROUND: The Global Initiative for Asthma has only recently added tiotropium bromide as adjunct controller therapy in severe asthma (Step 4 or 5) in adults (2015) and children (2019). Although not yet approved for pediatric use by Health Canada, it has been occasionally offered by asthma specialists as a therapeutic trial in children with troublesome asthma or treatment for adverse effects. The objective of this study was to describe the indications and real-life clinical experience in initiating tiotropium in children with asthma. METHODS: We designed a retrospective mixed-method case series study of children aged 1-17 years who initiated tiotropium in our tertiary-care centre between 2013 and 2020. Clinical information was extracted from electronic medical records and tiotropium dispensing, from drug claims. Parents/children and physicians independently completed a questionnaire about treatment goals, perceived efficacy, safety, satisfaction, and lessons learned. RESULTS: The 34 (11 females; 23 males) children had a median (range) age of 9.1 (1.4-17.8) years. Children were primarily on Step 4 (85%) or 5 (6%) prior to tiotropium initiation, yet most (84%) did not increase their treatment step after tiotropium initiation. The physicians' treatment goals were to improve asthma control, alleviate adverse effects of current therapy, and/or improve lung function. The most improved symptoms were coughing/moist cough, difficulty breathing, whistling breath, and bronchial secretions/mucus. Although most parents and physicians reported a significant benefit with tiotropium bromide, physicians particularly remarked, as their "lesson learned', on the improvement in chronic symptoms in asthmatic children, particularly those with prominent moist cough and in lung function, in those with seemingly none (or incompletely) reversible obstruction as well as the ability to decrease the ICS and/or LABA dose to lessen adverse effects. A few physicians raised caution on the risk of lower adherence with an additional inhaler. CONCLUSION: In children with severe asthma on Step 4 or 5, tiotropium bromide was primarily used as substitute, rather than additional, adjunct therapy to improve asthma control, alleviate adverse effects, and/or to improve lung function. The latter two indications, combined with its perceived effectiveness in children with prominent moist cough, also suggest additional indications of tiotropium to be formally explored.

Transcriptome Profiling Analyses in Psoriasis: A Dynamic Contribution of Keratinocytes to the Pathogenesis.

Psoriasis is an immune-mediated inflammatory skin disease with a complex etiology involving environmental and genetic factors. A better insight into related genomic alteration helps design precise therapies leading to better treatment outcome. Gene expression in psoriasis can provide relevant information about the altered expression of mRNA transcripts, thus giving new insights into the disease onset. Techniques for transcriptome analyses, such as microarray and RNA sequencing (RNA-seq), are relevant tools for the discovery of new biomarkers as well as new therapeutic targets. This review summarizes the findings related to the contribution of keratinocytes in the pathogenesis of psoriasis by an in-depth review of studies that have examined psoriatic transcriptomes in the past years. It also provides valuable information on reconstructed 3D psoriatic skin models using cells isolated from psoriatic patients for transcriptomic studies.

Pharmacogenetic and ethnicity influence on oxaliplatin therapy for colorectal cancer: a meta-analysis.

AIMS: Oxaliplatin-based chemotherapy for colorectal cancer demonstrates interindividual variability in response, and polymorphisms of ERCC1, ERCC2, XRCC1, GSTP1 and GSTM1 genes may be contributing factors. Additionally, the effect of these genotypes may differ between ethnic groups. Material & Methods: A meta-analysis of the association between these genotypes and response, progression-free survival and overall survival (OS) for patients with colorectal cancer treated with oxaliplatin-based therapy is reported. Results: ERCC1 C118T (TT vs CC OS [hazard ratio (HR): 2.59; p = 0.001]), ERCC2 A2251C (CC or AC vs AA OS [HR: 1.53; p = 0.04]) and GSTP1 A313G (GG vs AA OS, [HR: 0.47; p < 0.001]) polymorphisms were associated with survival. The effect size may be larger for ERCC1 C118T and XRCC1 G1196A in Asian compared with Caucasian populations. No association was apparent for the GSTM1 genotype. CONCLUSION: ERCC1 C118T, ERCC2 A2251C and GSTP1 A313G polymorphisms were associated with clinical outcomes.