Reduce Treatment Failure Research Articles

Low Anti-Tumor Necrosis Factor Levels During Maintenance Phase Are Associated With Treatment Failure in Children With Crohn's Disease.

Higher drug levels and combination therapy with low-dose oral methotrexate (LD-MTX) may reduce anti-tumor necrosis factor (TNF) treatment failure in pediatric Crohn's disease. We sought to (1) evaluate whether combination therapy with LD-MTX was associated with higher anti-TNF levels, (2) evaluate associations between anti-TNF levels and subsequent treatment failure, and (3) explore the effect of combination therapy on maintenance of remission among patients with therapeutic drug levels (>5 µg/mL for infliximab and >7.5 µg/mL for adalimumab). We conducted a post hoc analysis of the COMBINE trial, which compared anti-TNF monotherapy to combination therapy with LD-MTX. We included participants who entered maintenance therapy and provided a serum sample approximately 4 months from randomization. Among 112 infliximab and 41 adalimumab initiators, median drug levels were similar between combination therapy and monotherapy (infliximab: 8.8 vs 7.5 μg/mL [P = .49]; adalimumab: 11.1 vs 10.5 μg/mL [P = .11]). Median drug levels were lower in patients experiencing treatment failure (infliximab: 4.2 vs 9.6 μg/mL [P < .01]; adalimumab: 9.1 vs 12.3 μg/mL [P < .01]). Among patients treated with infliximab with therapeutic drug levels, we observed no difference in treatment failure between participants assigned monotherapy or combination therapy. Among patients treated with adalimumab, a trend towards reduced treatment failure in the combination therapy arm was not statistically significant (P = .14). LD-MTX combination was not associated with higher drug levels, but higher drug levels were associated with reduced risk of treatment failure. Among patients with therapeutic drug levels, we observed no benefit of LD-MTX for patients treated with infliximab. A nonsignificant trend towards reduced treatment failure with the addition of LD-MTX patients treated with adalimumab warrants further investigation.

Treatment failure among Sub-Sahara African children living with HIV: a systematic review and meta-analysis

BackgroundAntiretroviral treatment failure is a global issue, particularly in developing countries such as Sub-Saharan Africa. Prior research findings were highly variable and inconsistent across areas. As a result, the goal of this systematic review and meta-analysis was to determine the pooled prevalence of treatment failure among children receiving antiretroviral medication in Sub-Saharan Africa.MethodsTo find qualifying papers, we searched databases (such as PubMed, Google Scholar, African Journals Online, Scopus, and the Cochrane Library). The data were retrieved using Microsoft Excel and exported to STATA Version 14 for analysis. To check for publication bias, we employed Egger and Begg’s regression tests. A random-effects model was used to assess the pooled prevalence of treatment failure due to high levels of variability.ResultsFollowing the removal of duplicated articles and quality screening, a total of 33 primary articles were determined to be appropriate for inclusion in the final analysis for this study. Overall, the pooled prevalence of treatment failure among HIV-infected children was 25.86% (95% CI: 21.46, 30.26). There is great variety across the included studies, with the majority of them being conducted in Ethiopia. Cameroon had the greatest pooled prevalence of treatment failure among HIV-infected children, at 39.41% (95% CI: 21.54, 57.28), while Ethiopia had the lowest, at 13.77% (95% CI: 10.08, 17.47).ConclusionsThe pooled estimate prevalence of treatment failure among HIV-infected children in Sub-Saharan Africa was high. The implementation of national and international policies and strategies on ART clinic care services should be given special focus in order to reduce treatment failure in children living with HIV/AIDS.Trial registrationThe protocol has been registered in the PROSPERO database under the registration number CRD-429011.

Molecular transmission network analysis reveals the challenge of HIV-1 in ageing patients in China: elderly people play a crucial role in the transmission of subtypes and high pretreatment drug resistance in developed Eastern China, 2019–2023

BackgroundThe number and proportion of HIV/AIDS patients among older people are continuously and rapidly increasing in China. We conducted a detailed molecular epidemiological analysis of HIV-1 epidemic strains in a developed city in eastern China and found that elderly people play a crucial role in the transmission of subtypes and high pretreatment drug resistance (PDR).MethodsA total of 1048 samples were obtained from 1129 (92.8%) newly confirmed HIV-1-positive and treatment-naive patients between 2019 and 2023. The 1316 bp target fragment of the pol gene was amplified by reverse transcription polymerase chain reaction (RT‒PCR) and nested PCR, and Maximum-likelihood (ML) phylogenetic trees and molecular transmission network were constructed to analyse the subtypes and transmission clusters. Molecular transmission network was visualized using Cytoscape with the distance threshold of 0.0075. PDR-associated mutations were determined according to the Stanford University HIV Drug Resistance Database.ResultsA total of 933 pol sequences (89.0%, 933/1048) were successfully obtained, and twelve HIV-1 subtypes were detected. CRF07_BC was the predominant subtype, accounting for 48.1% (449/933) of sequences, followed by CRF01_AE (29.4%, 274/933). A total of 398 individuals (42.7%, 398/933) formed 89 clusters in the network. Multivariable logistic regression analysis revealed that age, nationality, subtype, and PDR were the most significant factors associated with clustering in the transmission network. The prevalence of PDR was 14.6% (136/933).PDR associated with non-nucleoside reverse transcriptase inhibitors (10.0%, 93/933) was much more common than that associated with nucleoside reverse transcriptase inhibitors (1.8%, 17/933) and protease inhibitors (3.2%, 30/933) (χ2 = 77.961, p < 0.001). The most frequent NNRTI mutations were K103N/S/KN/NS (52.2%, 71/136), which led to the highest proportion of high-level resistance to nevirapine and efavirenz (52.2%).ConclusionsOur study revealed the important influence of elderly people on CRF07_BC transmission and the high prevalence of PDR. The clustering of drug-resistant cases was significant, which suggested the potential for localized widespread transmission of drug-resistant strains. HIV screening and the determination of PDR are recommended for older patients to improve early detection and reduce treatment failure and second-generation transmission.

Genomic Characterization of Methicillin-Resistant and Methicillin-Susceptible Staphylococcus aureus Implicated in Bloodstream Infections, KwaZulu-Natal, South Africa: A Pilot Study.

Staphylococcus aureus is an opportunistic pathogen and a leading cause of bloodstream infections, with its capacity to acquire antibiotic resistance genes posing significant treatment challenges. This pilot study characterizes the genomic profiles of S. aureus isolates from patients with bloodstream infections in KwaZulu-Natal, South Africa, to gain insights into their resistance mechanisms, virulence factors, and clonal and phylogenetic relationships. Six multidrug-resistant (MDR) S. aureus isolates, comprising three methicillin-resistant S. aureus (MRSA) and three methicillin-susceptible S. aureus (MSSA), underwent whole genome sequencing and bioinformatics analysis. These isolates carried a range of resistance genes, including blaZ, aac(6')-aph(2″), ant(9)-Ia, ant(6)-Ia, and fosB. The mecA gene, which confers methicillin resistance, was detected only in MRSA strains. The isolates exhibited six distinct spa types (t9475, t355, t045, t1265, t1257, and t7888) and varied in virulence gene profiles. Panton-Valentine leukocidin (Luk-PV) was found in one MSSA isolate. Two SCCmec types, IVd(2B) and I(1B), were identified, and the isolates were classified into four multilocus sequence types (MLSTs), with ST5 (n = 3) being the most common. These sequence types clustered into two clonal complexes, CC5 and CC8. Notably, two MRSA clones were identified: ST5-CC5-t045-SCCmec_I(1B) and the human-associated endemic clone ST612-CC8-t1257-SCCmec_IVd(2B). Phylogenomic analysis revealed clustering by MLST, indicating strong genetic relationships within clonal complexes. These findings highlight the value of genomic surveillance in guiding targeted interventions to reduce treatment failures and mortality.

Phylogenetic Diversity, Antibiotic Resistance, and Virulence of Escherichia coli Strains from Urinary Tract Infections in Algeria.

Urinary tract infections (UTIs) caused by Escherichia coli represent a significant public health concern due to the high virulence and antimicrobial resistance exhibited by these pathogens. This study aimed to analyze the phylogenetic diversity and antibiotic resistance profiles of Uropathogenic E. coli (UPEC) strains isolated from UTI patients in Algeria, focusing on virulence factors such as extended β-lactamase (ESBL) production, biofilm formation, and hemolytic activity. Phylogenetic grouping of 86 clinical imipenem resistant E. coli isolates showed the prevalence of group B2 (48.9%), followed by groups E (22.1%), unknown (12.8%), A (8.1%), and B1 (4.7%), and Clade I, D, Clade I, or Clade II (1.2%). The highest resistance rates were observed towards amoxicillin (86.04%), ticarcillin (82.55%), piperacillin (73.25%), nitrofurantoin (84.88%), and trimethoprim-sulfamethoxazole (51.16%). Notably, 69.8% of UPEC strains were multidrug-resistant (MDR) and 23.2% were extensively drug-resistant (XDR). Additionally, 48.9%, 42%, and 71% of strains demonstrated ESBL production, hemolytic activity, and weak biofilm production, respectively. Continuous monitoring and characterization of UPEC strains are essential to track the spread of the most resistant and virulent phylogenetic groups over time, facilitating rapid therapeutic decisions to treat infections and prevent the emergence of new resistant organisms, helping choose the most effective antibiotics and reducing treatment failure.

Efficacy of linezolid in the treatment of tuberculous meningitis: a meta-analysis.

Tuberculous meningitis (TBM) is a severe extra-pulmonary tuberculosis with high fatality. This meta-analysis aimed to assess the impact of linezolid on TBM treatment outcomes. We searched multiple databases for studies published up to May 18, 2024 comparing the effects of linezolid on TBM. Meta-analysis was conducted using Review Manager 5.4. Our findings indicated that linezolid may reduce treatment failure risk (RR = 0.42 (0.20, 0.89), p = 0.02) and improve temperature recovery (RR = 1.56 (1.21, 2.02), p < 0.001) in TBM patients. The analysis suggests a positive association between linezolid treatment and therapeutic improvements, with no significant adverse reactions reported.

Phenotypic and genotypic characterization of methicillin and vancomycin-resistant Staphylococcus aureus isolated from human clinical samples in Kerman hospitals, Iran

Today, methicillin-resistant S. aureus (MRSA) isolates are widely spread in both communities and hospitals, causing high morbidity and mortality worldwide. However, the emergence of vancomycin resistance among MRSA isolates has been perceived as a formidable threat to therapeutic management. Therefore, the present study aimed to determine the frequency and antibiotic susceptibility of MRSA and vancomycin-resistant S. aureus (VRSA) strains in Kerman hospitals in Iran. A total of 455 human clinical samples were collected from Kerman hospitals. The samples were examined for the presence of S. aureus and the isolates were tested for their susceptibility to antibiotics by disk diffusion method. MRSA and VRSA isolates were detected by a combination of phenotypic and genotypic methods. Sixty-five coagulase-positive S. aureus strains were isolated, and the higher isolation rate was from wound samples (47.7%) compared with blood (18.5%), respiratory tract secretions (10.8%), urine (10.8%), body fluids (9.2%), abscess (1.5%), and cerebrospinal fluids (1.5%). The isolates exhibited high resistance toward tetracycline (69.2%). Thirty-four isolates (52.3%) were categorized as MRSA (phenotypically resistant to cefoxitin). mecA gene was amplified in 97.1% of MRSA strains. Moreover, only one MRSA strain was resistant to vancomycin (MIC=128), and this isolate carried the vanA gene. The frequency of MRSA was not significantly associated with gender, age, sample type, and sampling locality (p&gt;0.05). Given the alarming rate of resistance among MRSA isolates, monitoring of antibiotic resistance should be performed to reduce treatment failure in patients with staphylococcal infections. Although vancomycin remains a drug of choice for MRSA, our study suggests that its efficacy may be limited by resistance development.

Improvement in axial rotation with bracing reduces the risk of curve progression in patients with adolescent idiopathic scoliosis.

New evidence highlights the significance of 3D in-brace correction for Adolescent Idiopathic Scoliosis (AIS) patients. This study explores how axial parameters relate to treatment failure in braced AIS patients. AIS patients (Sanders 1-5) undergoing Rigo-Chêneau bracing at a single institution were included. Axial vertebral rotation (AVR) was determined by utilizing pre-brace and in-brace 3D reconstructions from EOS® radiographs. The primary outcome was treatment failure: surgery or coronal curve progression > 5°. Minimum follow-up was two years. 75 patients (81% female) were included. Mean age at bracing initiation was 12.8 ± 1.3years and patients had a pre-brace major curve of 31.0° ± 6.5°. 25 patients (76% female) experienced curve progression > 5°, and 18/25 required surgical intervention. The treatment failure group had larger in-brace AVR than the success group (5.8° ± 4.1° vs. 9.9° ± 7.6°, p = 0.003), but also larger initial coronal curve measures. In-brace AVR did not appear to be associated with treatment failure after adjusting for the pre-brace major curve (Hazard Ratio (HR):0.99, 95% Confidence Interval (CI):0.94-1.05, p = 0.833). Adjusting for pre-brace major curve, patients with AVR improvement with bracing had an 85% risk reduction in treatment failure versus those without (HR:0.15, 95% CI:0.02-1.13, p = 0.066). At the final follow-up, 42/50 (84%) patients without progression had Sanders ≥ 7. While in-brace rotation was not an independent predictor of curve progression (due to its correlation with curve magnitude), improved AVR with bracing was a significant predictor of curve progression. This study is the first step toward investigating the interplay between 3D parameters, skeletal maturity, compliance, and brace efficacy, allowing a future prospective multicenter study. Retrospective study; Level III.

OPT-In; Optimized Patient Treatment Outcomes in Plaque Psoriasis: A 3-Year State-Transition Treatment-Sequencing Model in the Italian Setting.

There are several treatment options for plaque psoriasis (PsO), but uncertainty remains around the optimal sequencing of treatments. The aims of this study were to investigate how adopting a best-treatment-first treatment sequence impacts patient outcomes and healthcare systems and to quantify the cost of treatment failure to the healthcare system. A 3-year state-transition treatment-sequencing model which identifies all possible treatment sequences in PsO was adapted to the Italian healthcare setting. Treatments considered in the model are those with European Medicines Agency marketing authorization and reimbursement in Italy as of December 2022. Italian market share data (2019-2021) and list prices (2022) informed the current prescribed sequences; these sequences were compared against all possible sequences to determine opportunities for improvement. Both the national perspective in Italy as well as the local perspective from seven regions were considered. The cost of treatment failure was informed through a questionnaire circulated to Italian dermatologists. Overall, 1284 possible treatment sequences are possible when four lines of treatment are considered for patients with moderate-to-severe PsO in Italy. Within the estimated range of treatment failures across those sequences (0.97-2.56 per patient over 3 years), current prescribing behavior from the national perspective suggests patients will face 1.44 failures on average; this highlights the potential for improvement. For every treatment failure, the cost borne by the Italian National Healthcare Service (NHS) is €676.80. Overall, prescribing more optimized treatment sequences results in a 22.95% reduction in failures with a 2.27% increase in costs. The regional analyses found similar trends. Results suggest that selecting the most effective treatment sequences for incident patients provides the greatest opportunity to reduce treatment failures and maximize patient outcomes with a modest impact on costs. While regional variations exist, there is room for improvement across the board, which could translate to more efficient local healthcare systems.

Retreatment for Lower Urinary Tract Symptoms After Water Vapor Thermal Therapy

ObjectivesTo identify predictors of retreatment for symptomatic recurrence among men who undergo water vapor thermal therapy (WVTT; Rezum, Boston Scientific, Marlborough, MA, USA), a minimally invasive surgical treatment for lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). MethodsWe retrospectively reviewed patients treated with WVTT at a single institution from August 2017 to February 2022. Patients who underwent a second BPH procedure for persistent or recurrent LUTS within 2 years of original treatment were compared to the remaining cohort who did not undergo retreatment. Multivariate analysis was used to assess for predictors of retreatment. ResultsData was obtained from 192 patients. 10 (5%) patients were retreated. The retreatment cohort had smaller prostate volumes (50.4 + 18.2 cc vs 48.5 + 35.7 cc; p=0.003) and received a greater number of water vapor injections (4.4 + 1.8 vs 5.2 + 3.9; p<0.001). At 6 month follow-up, total International Prostate Symptom Score (IPSS; 10.13 ± 7.40 vs 18.5 ± 11.55, p=0.044) and voiding sub-scores (4.59 ± 4.39 vs 9.5 ±7.84, p=0.006) were significantly worse in the retreatment group. On multivariate analysis, >1 treatment per lobe was independently associated with increased risk of retreatment (HR 8.509, 95% CI [1.109 – 65.293]; p=0.039). ConclusionsWVTT has a low retreatment rate. Men who required retreatment received more injections and showed worsened voiding symptom scores 6 months postoperatively. Decreasing the number of injections may help reduce treatment failure rates.

Numerical Simulations of the Epley Maneuver With Clinical Implications.

Canalith repositioning procedures to treat benign paroxysmal positional vertigo are often applied following standardized criteria, without considering the possible anatomical singularities of the membranous labyrinth for each individual. As a result, certain patients may become refractory to the treatment due to significant deviations from the ideal membranous labyrinth, that was considered when the maneuvers were designed. This study aims to understand the dynamics of the endolymphatic fluid and otoconia, within the membranous labyrinth geometry, which may contribute to the ineffectiveness of the Epley maneuver. Simultaneously, the study seeks to explore methods to avoid or reduce treatment failure. We conducted a study on the Epley maneuver using numerical simulations based on a three-dimensional medical image reconstruction of the human left membranous labyrinth. A high-quality micro-computed tomography of a human temporal bone specimen was utilized for the image reconstruction, and a mathematical model for the endolymphatic fluid was developed and coupled with a spherical particle model representing otoconia inside the fluid. This allowed us to measure the position and time of each particle throughout all the steps of the maneuver, using equations that describe the physics behind benign paroxysmal positional vertigo. Numerical simulations of the standard Epley maneuver applied to this membranous labyrinth model yielded unsatisfactory results, as otoconia do not reach the frontside of the utricle, which in this study is used as the measure of success. The resting times between subsequent steps indicated that longer intervals are required for smaller otoconia. Using different angles of rotation can prevent otoconia from entering the superior semicircular canal or the posterior ampulla. Steps 3, 4, and 5 exhibited a heightened susceptibility to failure, as otoconia could be accidentally displaced into these regions. We demonstrate that modifying the Epley maneuver based on the numerical results obtained in the membranous labyrinth of the human specimen under study can have a significant effect on the success or failure of the treatment. The use of numerical simulations appears to be a useful tool for future canalith repositioning procedures that aim to personalize the treatment by modifying the rotation planes currently defined as the standard criteria.

Antibiogram Profiling of Antibiotics in Ear, Nose, and Throat Infections in Tertiary Healthcare Settings.

Introduction Antibiotic resistance is an emerging threat in tertiary healthcare settings, with increased usage of antibiotics on patients havingear, nose, and throat (ENT) infections, the bacterial strains are becomingresistant to its treatment causing antibiotic resistance and ineffective treatment. This study focuses on the antibiogram profiling of bacterial pathogens by the conventional disc diffusion method in a tertiary healthcare setting and the recent method using a matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF) to identify bacterial strains isolated from infections of the ENT. Materials and methods Swab samples were collected from patients with ENT infections and were subjected to bacteriological andproteomic studies to assess the status of drug-resistant pathogens. About 125 samples were subjected to an antimicrobial susceptibility test by disc diffusion, and the bacterial isolates were screened on MALDI-TOF for identification. Result The study identified beta-hemolytic Streptococci as the most prevalent bacterial species, followed by Pseudomonas aeruginosaand Staphylococcus aureus. MALDI-TOF analysis yielded high identification accuracy for beta-hemolytic Streptococcus pyogenes,and the antibiogram profile of bacterial isolates indicated that most of the bacteria are resistant to penicillin, amoxicillin, and chloramphenicol. Conclusion The study emphasized the importance of appropriate antibiotic selection in treating ENT infections, considering local antibiograms and understanding antibiotic resistance patterns. This shall aid clinicians in choosing effective antibiotics, reducing treatment failure, and preventing the emergence of antibiotic resistance. Overall, the research provides valuable insights into antibiotic resistance in ENT infections.

The Wound Healing of Autologous Regenerative Factor on Recurrent Benign Airway Stenosis: A Canine Experimental and Pilot Study

Introduction: Benign airway stenosis (BAS) is a severe pathologic condition. Complex stenosis has a high recurrence rate and requires repeated bronchoscopic interventions for achieving optimal control, leading to recurrent BAS (RBAS) due to intraluminal granulation. Methods: This study explored the potential of autologous regenerative factor (ARF) for treating RBAS using a post-intubation tracheal stenosis canine model. Bronchoscopic follow-ups were conducted, and RNA-seq analysis of airway tissue was performed. A clinical study was also initiated involving 17 patients with recurrent airway stenosis. Results: In the animal model, ARF demonstrated significant effectiveness in preventing further collapse of the injured airway, maintaining airway patency and promoting tissue regeneration. RNA-seq results showed differential gene expression, signifying alterations in cellular components and signaling pathways. The clinical study found that ARF treatment was well-tolerated by patients with no severe adverse events requiring hospitalization. ARF treatment yielded a high response rate, especially for post-intubation tracheal stenosis and idiopathic tracheal stenosis patients. Conclusion: The study concludes that ARF presents a promising, effective, and less-invasive method for treating RBAS. ARF has shown potential in prolonging the intermittent period and reducing treatment failure in patients with recurrent tracheal stenosis by facilitating tracheal mucosal wound repair and ameliorating tracheal fibrosis. This novel approach could significantly impact future clinical applications.

Impact of a discharge prescription for dexamethasone on outcomes of children treated in the emergency department for acute asthma exacerbations

Objective To evaluate dexamethasone prescribing practices, patient adherence, and outcomes by dosing regimen in children with acute asthma discharged from the emergency department (ED). Study design Prospective study of children 2–18 years treated with dexamethasone for acute asthma prior to discharge from an urban, tertiary care ED between 2018 and 2022. Demographics, clinical characteristics, ED treatment, and discharge prescriptions were collected via chart review. The exposure was discharge prescription (additional dose) versus no discharge prescription for dexamethasone. The primary outcome was treatment failure, defined as return ED visit, unplanned primary care visit, and/or ongoing bronchodilator use. Secondary outcomes included medication adherence, symptom persistence, quality-of-life, and school/work absenteeism. Outcomes were assessed by telephone 7–10 days after discharge. Results 564 subjects were enrolled; 338 caregivers (60%) completed follow-up. Children were a median age 7 years, 30% Black or African American, 49% Hispanic, and 79% had public insurance. A discharge prescription for dexamethasone was written for 482 (86%) children and was significantly associated with exacerbation severity, number of combined albuterol/ipratropium treatments, and longer length of stay. There was no difference in treatment failure between the discharge prescription and no discharge prescription groups (RR 0.87; 0.67, 1.12), including after adjusting for potential confounders; there was no difference between groups in secondary outcomes. Conclusions Prescription for an additional dexamethasone dose was not associated with reduced treatment failure or improved outcomes for children with acute asthma discharged from the ED. Single, ED-dose of dexamethasone prior to discharge may be sufficient for children with mild to moderate asthma exacerbations.

Predicting treatment response using machine learning: A registered report.

Previous research on psychotherapy treatment response has mainly focused on outpatients or clinical trial data which may have low ecological validity regarding naturalistic inpatient samples. To reduce treatment failures by proactively screening for patients at risk of low treatment response, gain more knowledge about risk factors and to evaluate treatments, accurate insights about predictors of treatment response in naturalistic inpatient samples are needed. We compared the performance of different machine learning algorithms in predicting treatment response, operationalized as a substantial reduction in symptom severity as expressed in the Patient Health Questionnaire Anxiety and Depression Scale. To achieve this goal, we used different sets of variables-(a) demographics, (b) physical indicators, (c) psychological indicators and (d) treatment-related variables-in a naturalistic inpatient sample (N = 723) to specify their joint and unique contribution to treatment success. There was a strong link between symptom severity at baseline and post-treatment (R2 = .32). When using all available variables, both machine learning algorithms outperformed the linear regressions and led to an increment in predictive performance of R2 = .12. Treatment-related variables were the most predictive, followed psychological indicators. Physical indicators and demographics were negligible. Treatment response in naturalistic inpatient settings can be predicted to a considerable degree by using baseline indicators. Regularization via machine learning algorithms leads to higher predictive performances as opposed to including nonlinear and interaction effects. Heterogenous aspects of mental health have incremental predictive value and should be considered as prognostic markers when modelling treatment processes.

Outcome of Patients with Chronic Myeloid Leukemia in Chronic Phase Showing Clinical Resistance to Frontline Treatment with Second Generation Tyrosine Kinase Inhibitors. an Italian Prospective Study from the CML Campus

BACKGROUND: Frontline treatment with second generation tyrosine-kinase inhibitors (2G-TKIs) in patients with chronic myeloid leukemia in chronic phase (CP-CML) demonstrated higher efficacy as compared to imatinib therapy in inducing deeper molecular responses. However, its ability to reduce treatment failure and progressive disease is debated. Furthermore, limited information is currently available on the outcome of those CML patients showing clinical resistance to first-line treatment with a 2G-TKI. AIM: To describe the clinical outcome of CP-CML patients showing resistance to a frontline 2G-TKI and that switched to alternative TKIs therapy. PATIENTS AND METHODS: We performed this investigation on patients drawn from a web-based database (www.epiclin.it/lmc) used to collect clinical and biological data of CML patients enrolled in 24 Italian Hematology Centers from January 2013 onwards. Definitive information about first-line TKI treatment was available in 1277 prospective and consecutive CP-CML patients: 607 received imatinib and 670 dasatinib or nilotinib (2G-TKIs) as frontline therapy. Main inclusion criteria were: i) diagnosis of CP-CML; ii) first-line treatment with a 2G-TKI; iii) switch to second-line treatment in case of clinical resistance (i.e. failure according to ELN 2020 recommendations). Exclusion criteria was switch to second-line treatment for intolerance or for low adherence to therapy. Patients were treated according to the Center policy and the molecular data were obtained in accordance to the IS% parameters. RESULTS: Fifty-four CML patients met the inclusion/exclusion criteria and were identified as failure according to the ELN 2020 recommendations. The median age of these patients was 48.5 (20-81) years; male sex in 30 (55.5%) and female 24 (44.4%), Sokal risk score was low in 16 (29.6%), intermediate in 22 (40.7%) and high in 16 (29.6%) patients respectively;ELTS score was low in 26 (48.1%), intermediate in 14 (25.9%) and high in 14 (25.9%) patients. Additional chromosomal abnormalities were present at diagnosis in 4 out of 54 patients (7.4%: 3 additional Ph-chromosome and 1 trisomy 8). Nilotinib was administered in 27 (50%) and dasatinib in 27 (50%) of the patients.At 6 months, 30 out of 50 evaluable patients (60%) had BCR::ABL1 transcript values &amp;gt;1% and at 12 months 9 of 33 evaluable patients (28%) had BCR::ABL1 values still &amp;gt;1%. Second-line treatment after 2G-TKIs frontline failure started in all patients after a median time of 12 months (3-83) with ponatinib (30 pts, 55.5%), dasatinib (8 pts, 14.8%), nilotinib (4 pts, 7.4%), bosutinib (7 pts, 12.9%) or imatinib (5 pts, 9.2%).At 12 months the switch to second-line treatment induced the achievement of BCR::ABL1 values &amp;lt;1% in 45% of the evaluable cases. Eighteen patients (in which no mutations were found) switched to third-line treatment after a median time of 11 months (0-45) (ponatinib, 8 pts; nilotinib, 1 pt; dasatinib, 3 pts; imatinib, 3 pts; bosutinib, 1 pts; asciminib, 2 pts). MMR or a better response was reached by 6 of these patients and allogeneic stem-cell transplantation (SCT) was performed in 7 patients.Progression to CML advanced phase occurred in 8 pts. After a median follow-up of 59.9 months (15.6 - 99.3) 44 patients were still alive and death occurred in 10 pts (18.5%) (7 CML-related and 3 unrelated). Overall survival (OS) at 5 years was 82% (see Figure below). Indeed, OS at 5 years was 94% for the total 670 patients treated frontline with 2G-TKIs. In this population, 12 out of 32 observed deaths were CML-related and all were recorded in patients who changed TKI therapy, whereas in 19 cases the death was CML-unrelated and in 1 case was not specified. However, those patients who maintained the same therapy for 5 years showed an OS of 96%, whereas those who had to change treatment for any cause showed an OS of 89% at 5 years. CONCLUSION: Our findings, collected from the prospective cohort of the CML Italian observational registry, show that CP-CML patients failing frontline 2G-TKI therapy, despite a complex management, may have still an acceptable prognosis and survival due to the availability of both multiple TKI options and SCT.

Which parameters, related to the female urethra and pelvic floor, determine therapy selection for recurrent female stress urinary incontinence: ICI-RS 2023?

The evidence basis for therapy selection in women who have failed primary stress urinary incontinence (SUI) surgery is limited. The ICI-RS group discussed the available data at its meeting in June 2023, particularly the anatomical characteristics as assessed using magnetic resonance imaging (MRI) and ultrasound (US) modalities, functional characteristics associated with storage and voiding urodynamic assessment, as well as the patient characteristics that might influence outcomes. This paper summarizes the evidence base that supported these discussions and offers the basis for research proposals for future groups. A literature search of MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials was performed, and the data is presented. Research questions are based on the knowledge gaps highlighted. Possible MRI parameters that may influence outcomes were striated urethral sphincter volume, bladder and proximal urethral funneling, pubo-urethral ligament integrity, distance of the bladder neck below the pubococcygeal line, posterior urethra-vesical angle, and bladder neck to levator ani distance. US parameters included sling distance to the urethral lumen and pubis, sling position, bladder neck mobility, and lateral arm asymmetry, twisting, or curling. Urodynamic parameters included detrusor overactivity, Valsalva leak point pressure, maximum urethral closure pressure, and bladder outlet obstruction. Important patient parameters included body mass index, age, and previous interventions. Identifying and quantifying causative factors in patients with recurrent SUI, that allow clinicians to modify subsequent treatment choices and techniques may help reduce treatment failure and complications. Formulating algorithms is the next step in optimizing patient counseling, surgical selection, and healthcare allocation.

Blood eosinophil-guided oral prednisolone for COPD exacerbations in primary care in the UK (STARR2): a non-inferiority, multicentre, double-blind, placebo-controlled, randomised controlled trial

Systemic glucocorticoids are recommended for use in chronic obstructive pulmonary disease (COPD) exacerbations; however, there is increased harm associated with their use. We hypothesised that the use of eosinophil biomarker-directed oral prednisolone therapy at the time of an exacerbation of COPD was effective at reducing prednisolone use without affecting adverse outcomes. The studying acute exacerbations and response (STARR2) study was a multicentre, randomised, double-blind, placebo-controlled trial conducted in 14 primary care practices in the UK. We included adults (aged ≥40 years), who were current or former smokers (with at least a 10 pack year smoking history) with a diagnosis of COPD, defined as a post-bronchodilator FEV1/forced vital capacity ratio of less than 0·7 previously recorded by the primary care physician, and a history of at least one exacerbation in the previous 12 months requiring systemic corticosteroids with or without antibiotics. All study staff and participants were masked to study group allocation and to treatment allocation. Participants were randomly assigned (1:1) to blood eosinophil-directed treatment (BET; to receive oral prednisolone 30 mg once daily if eosinophil count was high [≥2%] or placebo if eosinophil count was low [<2%]) or to standard care treatment (ST; to receive prednisolone 30 mg once daily irrespective of the point-of-care eosinophil result). Treatment was prescribed for 14 days and all patients also received antibiotics. The primary outcome was the rate of treatment failure, defined as any need for re-treatment with antibiotics or steroids, hospitalisation for any cause, or death, assessed at 30 days after exacerbation in the modified intention-to-treat population. Participants were eligible for re-randomisation at further exacerbations (with a maximum of four exacerbations per participant). A safety analysis was conducted on all randomly assigned participants. Although designed as a superiority trial, after identification of an error in the randomisation code before data lock the study converted to show non-inferiority. An upper margin of 1·105 for the 95% CI was defined as the non-inferiority margin. This study was registered with EudraCT, 2017-001586-24, and is complete. Between Nov 6, 2017, and April 30, 2020, 308 participants were recruited from 14 general practices. 144 exacerbations (73 in the BET group and 71 in the ST group) from 93 participants (mean age 70 years [range 46-84] and mean percent predicted FEV1 60·9% [SD 19·4]; 52 [56%] male and 41 [44%] female; ethnicity data was not collected]) were included in the modified intention-to-treat analysis. There were 14 (19%) treatment failures at 30 days post-exacerbation in the BET group and 23 (32%) in the ST group; we found a large non-significant estimated effect between BET and ST (RR 0·60 [95% CI 0·33-1·04]; p=0·070) in reducing treatment failures after a COPD exacerbation. The non-inferiority analysis supported that BET was non-inferior to ST. Frequency of adverse events were similar between the study groups; glycosuria (2/102 [2%] in BET group and 1/101 [1%] in the ST group) and hospital admission for COPD exacerbation (2/102 [2%] in BET group and 1/101 [1%] in the ST group) were the two most common adverse events in both groups. No deaths occurred in the study. Blood eosinophil-directed prednisolone therapy at the time of an acute exacerbation of COPD is non-inferior to standard care and can be used to safely reduce systemic glucocorticoid use in clinical practice. National Institute for Health and Care Research.

Comparative outcomes of middle meningeal artery embolization with statins versus embolization alone in the treatment of chronic subdural hematoma: a systematic review and meta-analysis.

Chronic subdural hematoma (cSDH) is common among the elderly, with surgical evacuation as a prevalent treatment, facing recurrence rates up to 30%. Recently, middle meningeal artery embolization (MMAE) has emerged as a promising approach, offering reduced treatment failures and recurrence rates. Additionally, statins, known for their anti-inflammatory properties, have been considered as a potential adjunctive or sole treatment for cSDH. However, the combination of MMAE with statins remains understudied. This systematic review and meta-analysis aims to evaluate the comparative outcomes of MMAE with statins versus MMAE alone in the treatment of cSDH. A comprehensive systematic search of the PubMed, Web of Science, and SCOPUS databases was conducted. Inclusion criteria were: studies published in English between the dates of inception of each database and August 2023, studies comparing the treatment of cSDH with either MMAE + statin or MMAE alone were included. Main outcome measures were complete resolution of the hematoma at follow-up and the recurrence rates. Two studies comprising 715 patients were included; 408 patients underwent MMAE + statin; and 307 underwent MMAE alone. MMAE + statin was not significantly superior to MMAE alone in achieving complete resolution of the hematoma at follow-up (RR: 0.99; CI: 0.91 to 1.07, P = 0.84), nor was it a significant difference in rates of recurrence (RR: 1.35; CI: 0.83 to 2.17, P = 0.21) between the two groups. MMAE + statin did not demonstrate significant superiority over MMAE alone for achieving complete resolution and decreasing the recurrence rates in cSDH patients. Further research with larger, randomized studies may be required to fully elucidate the potential synergistic effects of MMAE and statins in this patient population.

Skin Clearance is Associated with Reduced Treatment Failure in Patients with Psoriasis: Real-World Evidence from the CorEvitas Psoriasis Registry.

Complete and near-complete skin clearance have become achievable treatment goals for patients with psoriasis receiving systemic biologic therapies. However, there is limited real-world evidence regarding the impact of the degree of skin clearance on biologic treatment patterns among these patients. This longitudinal cohort study assessed the relationship between degree of skin clearance following initiation of a systemic biologic therapy and treatment failure among patients from the CorEvitas Psoriasis Registry (April 2015-August 2021). Patients had Psoriasis Area and Severity Index (PASI) score > 5 at systemic biologic therapy initiation and ≥ 1 follow-up visit(s) within 15months of initiation. Treatment failure (discontinuation due to poor response/adverse event; addition of non-biologic therapy) and degree of skin clearance (measured by PASI) were assessed following biologic initiation. Proportional hazards regression was used to estimate the association between PASI response level and treatment failure over follow-up. This study included 2701 patient initiations from 2516 unique patients with 3846 total visits over follow-up. Over half of the patient initiations (n = 1412; 52.3%) were among patients with PASI >10. Treatment failure occurred in 1.3% of visits at which PASI100 was achieved, while those achieving PASI90 - < 100 and PASI75 - < 90 had treatment failure rates of 3.4% and 3.5%, respectively. After adjustment for confounders, the risk of treatment failure was two to three times higher in the PASI90- < 100 (hazard ratio [HR] = 2.61; 95% confidence interval [CI] 1.35, 5.02; p = 0.004) and PASI75 < 90 (HR = 2.97; CI 1.58, 5.58; p = 0.001) groups compared to the PASI100 group. The risk of treatment failure was more than 20 times higher in the < PASI75 group versus the PASI100 group (HR = 22.26; CI 13.32, 37.21; p < 0.001). The results suggest that patients are more likely to remain on a systemic biologic therapy if they achieve near-complete or complete skin clearance, supporting the continued need to target skin clearance as a treatment goal in psoriasis. ClinicalTrials.gov identifier, NCT02707341.