Maintenance Phase Of Treatment Research Articles

Optimization of individualized faricimab dosing for patients with diabetic macular edema: Protocol for the SWAN open-label, single-arm clinical trial.

In patients with diabetic macular edema (DME) from YOSEMITE/RHINE, dual angiopoietin-2/vascular endothelial growth factor-A (VEGF-A) inhibition with faricimab resulted in visual/anatomic improvements with extended dosing. The SWAN trial (jRCTs031230213) will assess the efficacy, durability, and safety of faricimab during the treatment maintenance phase in patients with DME using a treat-and-extend (T&E)-based regimen adapted to clinical practice and the characteristics of patients achieving extended dosing intervals. SWAN is a 2-year, open-label, single-arm, interventional, multicenter trial enrolling adults with center-involving DME. All patients will receive three initial faricimab 6.0 mg doses every 4 weeks (Q4W). From week 12 onwards, in patients without active DME, dosing intervals will be extended in 8-week increments up to Q24W. In contrast, patients with active DME (central subfield thickness [CST] >325 μm and intraretinal fluid [IRF] or subretinal fluid [SRF] resulting in vision loss/disease aggravation) will receive a dose within a day and the dosing interval will be shortened by 4 weeks to a minimum of Q8W relative to the previous dosing interval. Recruitment commenced in August 2023 across a planned 16 sites in Japan. The primary endpoint is change in best-corrected visual acuity (BCVA) from baseline at 1 year (averaged over weeks 52, 56, and 60). Key secondary endpoints include: change from baseline in BCVA, CST, and National Eye Institute Visual Function Questionnaire scores over time; proportion of patients with BCVA (decimal visual acuity) ≥0.5, ≥0.7, ≥1.0, or ≤0.1; proportion of patients with absence of DME, and IRF and/or SRF over time. Safety endpoints include incidence/severity of ocular/nonocular adverse events. The SWAN trial is expected to provide evidence to support individualized faricimab dosing regimens, with the potential to reduce the burden of frequent treatments on patients, caregivers, and healthcare systems.

Safety and efficacy of S1P receptor modulators for the induction and maintenance phases in inflammatory bowel disease: A systematic review and meta-analysis of randomized controlled trials.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition that significantly affects quality of life. Conventional treatments have had limited success. this study evaluates the safety and efficacy of Sphingosine 1-phosphate receptor modulators (S1PrMs) as a potential treatment for IBD. We conducted a thorough search of published literature on PubMed, EMBASE, and Google Scholar from 2000 to 2023. The inclusion criteria were randomized controlled trials (RCTs) with a target population comprising of IBD patients receiving either S1PrMs or placebo and a comparison of the 2. The statistical analysis was conducted using RevMan (version 5.4). Forest plots presented the results as risk ratios (RR) with a 95% confidence interval. A total of 7 RCTs involving 2471 patients were included. The results were reported for both the induction and maintenance phases of treatment. in the induction phase, the intervention group proved to have a significantly higher incidence of histological remission (RR = 2.67; 95% CI [1.97, 3.60]; P < .00001), endoscopic improvement (RR = 2.06; 95% CI [1.66, 2.56]; P < .00001), clinical remission (RR = 2.23; 95% CI [1.43, 3.46]; P < .0004) and clinical response (RR = 1.37; 95% CI [1.01, 1.84]; P = .04) compared to the placebo group. Outcomes assessed in maintenance phase significantly favored the intervention group over placebo as well, histologic remission (RR = 2.39; 95% CI [1.83, 3.11]; P < .00001), endoscopic improvement (RR = 2.20; 95% CI [1.28, 3.77]; P = .004), clinical remission (RR = 3.03; 95% CI [1.84, 4.99]; P < .0001), and clinical response (RR = 1.74; 95% CI [1.25, 2.42]; P = .001). S1PrMs show promising potential for establishing histologic remission, endoscopic improvement, clinical remission, and corticosteroid-free clinical remission. With more studies and clinical trials, these modulators may become a reliable therapeutic choice for UC patients everywhere.

Mental health problems among children with lupus nephritis

Aim of the workTo assess and compare depression, anxiety, and cognitive impairments in juvenile systemic erythematous lupus (JSLE) children with lupus nephritis (LN) during the induction and maintenance phases of treatment and to investigate the association with disease activity, damage and immunosuppressive medications. Patients and methodsThis study included 33 patients diagnosed as JSLE with LN. Attention and working memory were assessed by the working memory index Wechsler Intelligence Scale (WISC). Depression and anxiety were assessed by the Children Depression Inventory (CDI) and the Spence Children Anxiety Scale respectively. The SLE disease activity index 2000 (SLEDAI-2 K) was recorded. ResultsThe mean age of the children was 11.6 ± 2.2 years, 88 % were females and 12 % males with disease duration of 16.9 ± 9.2 months and age at onset of 10.2 ± 2.3 years. Mean anxiety scores were higher among patients during the induction phase than those during maintenance phase (62.1 ± 7.2 and 40.2 ± 8.8 respectively; p < 0.001). The depression score was higher in the induction (19 ± 5.5) than in the maintenance group (12.4 ± 5.6) (p = 0.002). Mean anxiety scores significantly correlated with SLEDAI-2 K and corticosteroids dose (r = 0.58 and r = 0.43, p = 0.0004 and p = 0.013 respectively) and a significant negative correlation with duration of corticosteroids and number of cyclophosphamide doses (r = 0.46 and r = 0.69, p = 0.008 and p = 0.0001 respectively). ConclusionDepression and anxiety levels were higher in children with LN during the induction phase of treatment than those in the maintenance phase. Mental health problems must be screened among children with LN and treating these problems can improve the medical and psychosocial outcomes.

Population Pharmacokinetics of Adalimumab in Juvenile Idiopathic Arthritis Patients: A Retrospective Cohort Study Using Clinical Care Data.

Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disorder that primarily affects the joints in children. Notably, it is known to co-occur with uveitis. Adalimumab, a monoclonal anti-TNF antibody, is effective in treating both conditions. A deeper understanding of the pharmacokinetics (PK) of adalimumab in JIA is crucial to advance in more personalized treatment approaches. The objective of this study is to evaluate the population PK profile of adalimumab in JIA and to explain causes for its variability. Adalimumab and antidrug antibody concentrations were retrospectively retrieved from the charts of patients with JIA. Initially, five literature-based population PK models of adalimumab were evaluated to assess their ability to describe the observed concentration-time profiles in the JIA cohort. These models included one specifically for the pediatric Crohn's disease population and four derived from studies in adult populations in healthy subjects and rheumatoid arthritis patients. Subsequently, a novel population PK model tailored to the JIA population was developed using NONMEM software. Monte Carlo simulations were then conducted utilizing the final PK model to visualize the concentration-time profile of adalimumab in patients with JIA and the impact of covariates. A cohort of 50 patients with JIA with 78 available adalimumab samples was assessed. The mean age was 11.8±3.9years, with a median body weight of 49kg (interquartile range 29.4-59.8kg). All literature models adequately described the concentration-time profiles in JIA. The best model, which was developed in patients with rheumatoid arthritis during the maintenance phase of treatment, served as a basis for estimating clearance in JIA, resulting in a value of 0.37L per day per 70kg. Patient body weight, antidrug antibodies, methotrexate use, CRP level, and comorbidity of uveitis were found to have a significant impact on adalimumab clearance, and these reduced the inter-patient variability from 58.6 to 28.0%. On steady state in the simulated patient population, the mean trough level was 7.4±5.5mg/L. The two dosing regimens of 20 and 40mg every other week, based on patients' body weight, resulted in comparable simulated overall drug exposure. Five literature models effectively described adalimumab PK in this pediatric cohort, highlighting the potential for extrapolating existing models to the pediatric population. The new JIA model confirmed the effect of several known covariates and found a novel association for drug clearance with methotrexate use (lower) and uveitis (higher), which might have clinical relevance for personalized dosing in JIA.

Analysis toolkit for evaluation of drug titration practice in acute lymphoblastic leukemia maintenance.

During the 2-year maintenance treatment phase (MT) of acute lymphoblastic leukemia (ALL), personalized patient-specified titration of oral antimetabolite drug doses is required to ensure maximum tolerated systemic drug exposure. Drug titration is difficult to implement in practice and insufficient systemic drug exposure resulting from inadequate dose titration increases risk of ALL relapse. We developed an open-source R-based analytical toolkit, including the allMT R package and an interactive web-based R Shiny VIATAMIN application, to evaluate antimetabolite drug titration during MT. Evaluation is initiated with basic visualization analysis of drug titration, in both individual patients and patient cohorts. Observations are supplemented with descriptive analyses of hematological toxicity frequency and prescriber compliance rates with protocol drug titration rules. In individual patients, visual and quantitative analyses indicate recurring potentially correctable suboptimal drug titration patterns. In patient cohorts, the toolkit enables evaluation of the impact of interventions to optimize MT drug titration. Incorporation of the toolkit in a forthcoming clinical decision support system for MT would enable real-time examination and course correction of drug titration practice. Future versions will be enhanced to include other variables that influence drug titration practice, including clinical toxicity data and later, pharmacological markers of antimetabolite, adherence, and drug activity.

Elevated level of multibranched complex glycan reveals an allergic tolerance status

BackgroundAllergen immunotherapy (AIT) is the only disease-modifying therapy that can achieve immune tolerance in patients through long-term allergen stimulation. Glycans play crucial roles in allergic disease, but no information on changes in glycosylation related to an allergic tolerance status has been reported.MethodsFifty-seven patients with house dust mite (HDM) allergies were enrolled. Twenty-eight patients were not treated with AIT, 19 patients had just entered the AIT maintenance treatment phase, and 10 patients had been in the AIT maintenance phase for more than 1 year. Serum protein N-glycans were analyzed by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), which included linkage-specific sialylation information.ResultsEighty-four N-glycans were identified in all three groups. Compared with the patients treated without AIT, the patients treated with AIT for a shorter time showed downregulated expression of high-mannose glycans and upregulated expression of α2,6 sialic acid. The patients treated with AIT in the maintenance phase for over 1 year, which was considered the start of immunological tolerance, showed downregulated expression of biantennary N-glycans and upregulated expression of multibranched and complex N-glycans. Nine N-glycans were changed between allergic and allergic-tolerant patients.ConclusionsThe glycan form changed from mannose to a more complex type as treatment time increased, and multibranched complex glycans have the potential to be used as a monitoring indicator of immune tolerance. This serum N-glycome analysis provided important information for a deeper understanding of AIT treatment at the molecular level.

ENLIGHTED phase 3 study: Efficacy and safety of padeliporfin vascular targeted photodynamic therapy (VTP) for treatment of low-grade upper tract urothelial cancer (LG UTUC).

TPS4622 Background: Padeliporfin VTP has demonstrated safety and efficacy for UTUC treatment in a Phase 1 study (NCT03617003). Padeliporfin VTP is a combination product: a drug, padeliporfin administered IV; a device: a laser light delivery system/laser-source of light emitting near-infrared (NIR) light at 753nm; and an optic fiber delivering the light endoluminally to the vicinity of UTUC tumors within the collecting system. We report the preliminary efficacy and safety outcomes of Padeliporfin VTP for Treatment of LG UTUC in ENLIGHTED, a Phase 3 trial (NCT04620239). Methods: This is an open-label phase 3 study from USA, EU and Israel. Key inclusion criteria is up to 2 biopsy-proven LG UTUC with index tumor ≤15mm in the kidney and≤20mm in the ureter with an absence of high-grade cells on cytology. VTP is performed via retrograde upper tract endoscopy under anesthetic and low light conditions, Padeliporfin is injected IV and a laser light diffuser fiber 20-40 mm is positioned in proximity of the tumor through the scope. After Padeliporfin injection, the laser fiber is illuminated for 10 min. The fiber can be repositioned to provide up to 3 treatments within the upper tract. Patients are treated in two phases: Induction(ITP) and Maintenance Treatment Phases (MTP). ITP consists of 1-3 VTPs provided at 4-week intervals until achieving complete response (CR) or treatment failure. Patients achieving CR will proceed to the MTP and be followed with endoscopic evaluation every 3 months with VTP provided for recurrent tumors only up to 12 months. Patients with high-grade recurrences will be deemed treatment failures and removed from the study to standard of care treatment. Patients completing the MTP, will be followed for an additional 48 months for long-term outcomes. Primary outcome is CR on endoscopic evaluation and selective cytology at the time of primary response evaluation (28 ± 3 days post last treatment) during padeliporfin VTP ITP. A total of 100 patients are to be enrolled. As of 21 Jan 2024, 17 patients have been treated. 13 patients completed ITP and had CR 10/13 (77%) and PR 3/13 (23%). Patients baseline characteristics: age 67±12 years; gender: 9(53%) males and 8(47%) females; tumors location: 5(29%) in ureter, 13(76%) in the kidney; number of tumors: 7(41%) 2 tumors, 10(59%) 1 tumor. The most frequent treatment related adverse events were: flank pain 17%, vomiting 8%, fatigue 8%, nausea 6%, hematuria 6%, all Grade 1-2, resolved within few days. Grade 3 serious adverse events 9% (flank pain, hypertension, renal colic, urinary tract infection) were resolved within 2-7 days. To date Padeliporfin VTP has shown evidence of safety and efficacy with preliminary data that is consistent with prior experience. Recruitment for the ENLIGHTED trial is ongoing with results expected to provide basis for approval of a new therapy that clinically benefits pts. Clinical trial information: NCT04620239 .

Compartmental Exudative Dynamics in Neovascular Age-Related Macular Degeneration: Volumetric Outcomes and Impact of Volatility in a Phase III Clinical Trial

PurposeTo examine retinal feature dynamics in eyes with neovascular age-related macular degeneration (nAMD) treated with anti-vascular endothelial growth factor (anti-VEGF) therapy and the relationship of these features with visual acuity. DesignPost hoc analysis of the phase 3, randomized, HAWK nAMD clinical trial. ParticipantsParticipants randomized to the brolucizumab 6 mg or aflibercept 2 mg arms of the trial. MethodsSpectral domain optical coherence tomography (OCT) scans collected at 4-week intervals were analyzed using an automated machine learning-enhanced segmentation and feature-extraction platform with manual verification. Quantitative volumetric measures of retinal and exudative features were exported at multiple timepoints over 48 weeks. Volatility of exudative features was calculated as the standard deviation of each feature value during the maintenance phase (week 12–48) of treatment. These features were examined for their associations with anatomic and functional outcomes. Main Outcome MeasuresLongitudinal intraretinal fluid (IRF) and subretinal fluid (SRF) volume, subretinal hyperreflective material (SHRM) volume, ellipsoid zone (EZ) integrity (EZ-retinal pigment epithelium [RPE] volume/thickness), and correlation with best corrected visual acuity (BCVA). ResultsIRF, SRF, and SHRM demonstrated significant volumetric reduction from baseline with anti-VEGF therapy (P<0.001 at each timepoint). EZ integrity measures demonstrated significant improvement from baseline (P<0.001 at each timepoint). Both EZ integrity and SHRM measures significantly correlated with BCVA at all timepoints (EZ-RPE volume: 0.38≤ r ≤0.47; EZ-RPE central subfield thickness: 0.22≤ r ≤0.41; SHRM volume: -0.33≤ r ≤-0.44). Following treatment initiation, correlations of IRF and SRF volume with BCVA were weak or nonsignificant. Eyes with lower volatility of IRF, SRF, and SHRM volumes during the maintenance phase showed greater improvements in EZ integrity (all P<0.01) and greater gains in BCVA (all P<0.01) at week 48 compared to eyes with higher volatility in those exudative parameters. ConclusionsQuantitative measures of SHRM volume and EZ integrity correlated more strongly with BCVA than retinal fluid volumes during treatment. High volatility of exudative parameters, including SRF, during the maintenance phase of treatment was associated with loss of EZ integrity and BCVA.

REAL-WORLD EFFECTIVENESS OF USTEKINUMAB IN PATIENTS WITH ULCERATIVE COLITIS IN THE UNITED STATES OF AMERICA

Abstract BACKGROUND Primary treatment goals for ulcerative colitis (UC) are to induce and maintain long-term disease remission and reduce the prevalence of symptoms such as bowel urgency and abdominal pain. Ustekinumab (UST) is a biologic approved for treating adult patients with moderate-severe UC, but real-world effectiveness data remain limited. OBJECTIVE We aimed to assess real-world effectiveness of UST in patients with UC. METHODS Data were drawn from the Adelphi Real World UC Disease Specific Programme™, a cross-sectional survey with retrospective data collection of gastroenterologists and their patients in the United States of America (USA) from December 2022–September 2023. Two samples were utilised; a sample where physicians provided data for their next six consecutive patients with UC, and an oversample where physicians provided data for their next four consulting patients with UC receiving UST. Patients receiving UST for &amp;gt;1 day at time of consultation (assumed to have received ≥1 UST dose) from either sample were included in the analysis. Data collected included clinical status, disease duration and location, symptoms and treatment profiles. Remission defined by Mayo score was reported separately for advanced therapy (AT)-naïve (UST received as first AT) and AT-experienced (UST received as second or later line of AT) patients. Descriptive statistics for each variable were reported for patients with known data. McNemar’s test was used for symptom prevalence and disease severity comparisons. RESULTS Data for 160 patients were included in this study from 50 physicians. Patients had been diagnosed with UC for median (interquartile range; IQR) of 2.2 (0.5, 4.5) years; mean (standard deviation) age was 39.7 (13.0) years and 50.0% of patients were male. UST was received as first AT for 68.1% of patients, second AT for 18.1% and third AT for 11.3%. Median (IQR) time on UST was 8.7 (4.1, 18.6) months, with 83.9% of patients receiving UST for ≥3 months. For patients in maintenance phase of treatment, 65.8% were on UST USA label dose, 17.9% were receiving an increased and 16.3% decreased dose. According to Mayo scores, 53.6% of AT-naïve and 58.3% of AT-experienced patients were in remission at consultation (Table 1). Improvement in disease severity was evidenced by a reduced proportion of patients with moderate/severe disease at consultation (34.4%) compared to prior to initiation of UST (90.9%; p&amp;lt;0.01). Similarly, there was a significantly lower prevalence of all symptoms between UST initiation and consultation, including abdominal pain (72.1% vs 30.2%), bowel urgency (55.1% vs 22.0%) and bloody diarrhea (54.4% vs 17.6%) (all p&amp;lt;0.01; Figure 1). CONCLUSION Our study showed real-world effectiveness of UST in patients with UC in the USA; most patients receiving UST achieved remission and demonstrated reduced prevalence of symptoms following UST initiation. Table 1 Physician-reported characteristics of patients receiving ustekinumab at the time of consultation. Figure 1 Physician-reported prevalence of (A) symptoms and (B) moderate/severe disease severity prior to initiation of ustekinumab and at time of consultation.

P628 Vedolizumab in Indian patients with Inflammatory Bowel Disease: Interim results from a prospective, multicentre, open-label, phase 4 study

Abstract Background Although anti-tumour necrosis factor (TNF)-α agents have revolutionised the management of ulcerative colitis (UC) and Crohn’s disease (CD), they have demonstrated a therapeutic ceiling with numerous safety concerns. Vedolizumab (VDZ) has consistently demonstrated safety and efficacy in patients with UC and CD in pivotal clinical trials, but its efficacy and safety data are very limited in the developing world where infectious diseases predominate. Methods This prospective, multicentre, open-label, single-arm, phase 4 study (Clinicaltrial.gov: NCT04804540) included patients (aged 18-65 years [yrs]) with moderate-to-severe active UC and CD who were non-responsive to available conventional therapies and/or anti-TNF agents. Patients received VDZ 300 mg through intravenous infusion for induction (Week [W]0, W2, W6) and maintenance (W14, W22, W30, W38, and W46) treatment phase. This interim analysis included data collected till the last patient completed W14 visit. Safety endpoints including incidence of adverse events (AE), serious AEs (SAE), adverse drug reactions (ADR), and adverse events with special interest (AESI), and efficacy endpoints including clinical response and clinical remission were analysed. Results Of 215 patients screened, 150 were eligible (UC, 102 [68.0%], median age: 39 yrs; CD, 48 [32.0%], median age: 31 yrs). Median VDZ treatment duration was 155 days in UC and 143 days in CD groups. Overall, 71 (47.3%) patients (UC, 49 [48.0%]; CD, 22 [45.8%]) experienced ≥1 AE; of these, 40.7% patients had mild AEs (UC, 40.2%; CD, 41.7%). Forty-six (45.1%) patients with UC and 22 (45.8%) patients with CD had ≥1 treatment-emergent AE (TEAE); 5 (4.9%) patients with UC had treatment-related TEAEs. Seven (4.7%) patients (UC, 6 [5.9%]; CD, 1 [2.1%]) had ≥1 SAE (2 [1.3%] were treatment-related), 5 (3.3%) had ≥1 ADR, and 4 (2.7%) had ≥1 AESI. One patient (0.7%) each reported pulmonary tuberculosis and tuberculous pleural effusion as ADR/AESI. Anaemia and small intestinal obstruction were the frequently reported TEAE and SAE, respectively. Most of the AEs were resolved and no AE-related death was reported during study (Table 1). Overall, 90 (60.0%) patients (UC, 56 [54.9%]; CD, 34 [70.8%]) at W14, 37 (63.8%) patients (UC, 29 [61.7%]; CD, 8 [72.7%]) at W30, and 4 (57.1%) patients (UC, 4 [66.7%]) at W46 had the clinical response. Similarly, 62 (41.3%) patients (UC, 40 [39.2%]; CD, 22 [45.8%]) at W14, 23 (39.7%) patients (UC, 19 [40.4%]; CD, 4 [36.4%]) at W30, and 3 (42.9%) patients (UC, 3 [50.0%]) at W46 had the clinical remission (Figure 1). Conclusion Treatment with vedolizumab was safe and effective in Indian patients with moderate-to-severe active UC and CD as per this first multicentre prospective study on vedolizumab from India.

Is the Absence of Manual Lymphatic Drainage-Based Treatment in Lymphedema after Breast Cancer Harmful? A Randomized Crossover Study.

(1) Background: Manual lymphatic drainage (MLD), included within the complex decongestive therapy, as a therapy for the treatment of lymphedema has raised controversy about its benefits for lymphedema after breast cancer. The aim of this research is to test the effects of MLD on lymphedema after breast cancer during the treatment maintenance phase. (2) Methods: A randomized, single-blinded, controlled crossover trial was conducted to analyze the effects of a manual lymphatic drainage intervention compared to a control group without MLD intervention for the treatment of lymphedema. Arm volume measured by circumference measurement, subcutaneous tissue thickness measured by ultrasound, and the sensation of pain, heaviness, and swelling were evaluated as outcome measures. (3) Results: For the control group, an increase in volume was found in some of the circumference and subcutaneous tissue thickness measurements, in addition to a worsening of arm pain, swelling and heaviness. (4) Conclusion: The absence of treatment based on MLD in lymphedema after breast cancer worsens volume measurements, as well as arm heaviness. Therefore, it would be advisable to carry out this type of therapy as part of the maintenance treatment for lymphedema in breast cancer.

Severe pulmonary hypertension-interstitial lung disease presenting as right ventricular failure: stabilisation with intravenous prostacyclin and maintenance with inhaled prostacyclin.

Pulmonary hypertension (PH) leads to increased morbidity and mortality in interstitial lung disease (ILD). While the INCREASE trial highlighted the use of inhaled prostacyclin in PH-ILD patients, such therapy may be inadequate when right ventricular failure (RVF) is also present. In this study, we report the use of intravenous prostacyclin in three PH-ILD patients to stabilise right ventricular (RV) function, with a subsequent transition to maintenance therapy with inhaled prostacyclin. We evaluated three consecutive PH-ILD patients with RVF. RV afterload and pulmonary vascular resistance (PVR) were treated with intravenous prostacyclin during the induction phase of the therapy. Patients transitioned from intravenous prostacyclin to the maintenance phase of the treatment with inhaled prostacyclin once three transition criteria were met: cardiac index (CI) >2 L·min-1·m-2, PVR <7 Wood units (WU) and tricuspid annular plane systolic excursion (TAPSE) change >1 mm or TAPSE >1.6 cm. Pre-treatment parameters for the three patients were a mean PVR of 14.3 WU, a mean Fick CI of 1.8 L·min-1·m-2 and a mean TAPSE of 1.4 cm. The average intravenous prostacyclin dose at the time of transition to maintenance therapy was 20.7 ng·kg-1·m-2 of treprostinil. At 3-months follow-up, the mean PVR was 6.3 WU, Fick CI 2.2 L·min-1·m-2 and TAPSE 1.7 cm. This case series of three PH-ILD patients with RVF introduces the concept of an initial intravenous prostacyclin induction phase, followed by a transition to maintenance therapy with inhaled prostacyclin. Further development of this treatment algorithm with a refinement of the transition criteria, potential testing in a clinical trial and a longer-term follow-up period is warranted to improve the outcomes of advanced PH-ILD patients with concomitant RVF.

Empagliflozin and Rapid Kidney Function Decline Incidence in Type 2 Diabetes: An Exploratory Analysis From the EMPA-REG OUTCOME Trial

Kidney function progressively declines in most patients with type 2 diabetes (T2DM). Many develop progressive chronic kidney disease (CKD), but some experience a more rapid decline, with a greater risk of kidney failure and cardiovascular disease. In EMPA-REG OUTCOME, empagliflozin was associated with slower kidney disease progression. This post hoc analysis evaluated the effect of empagliflozin (pooled doses) on the prevalence of a "rapid decliner" phenotype, defined by an annual estimated glomerular filtration rate (eGFR) decline of>3mL/min/1.73m2. This was an exploratory analysis of EMPA-REG OUTCOME, a large randomized, double-blind, placebo-controlled trial in adults with T2DM, established cardiovascular disease and an eGFR of≥30mL/min/1.73m2. Analysis was undertaken on 6,967 participants (99.2%) in whom serial eGFR data was available. Patients were randomized (1:1:1) to empagliflozin 10mg, 25mg, or placebo in addition to standard of care. Annual change in eGFR over the maintenance phase of treatment (week 4 to last value on treatment) was calculated using linear regression models. Logistic regression analysis was used to investigate differences in rapid decline between the treatment groups. Over the study period, a rapid decliner phenotype was observed in 188 (9.5%) participants receiving placebo and 134 (3.4%) receiving empagliflozin. After adjusting for other risk factors, this equated to a two-third reduction in odds (OR, 0.32; 95% CI, 0.25-0.40; P<0.001) among participants receiving empagliflozin versus placebo. A comparable risk reduction was observed using a threshold of eGFR decline of>5mL/min/1.73m2/y (empagliflozin vs placebo, 43 [1.1%] vs 44 [2.2%] participants; OR, 0.47; 95% CI, 0.31-0.72; P<0.001). This is a post hoc analysis of a trial undertaken in participants with T2DM and CVD. Generalization of findings to other settings remains to be established. Patients receiving empagliflozin were significantly less likely to experience a rapid decline in eGFR over a median of 2.6 years of exposure to the study drug. The Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance. clinicaltrials.gov ID: NCT01131676.

A Phase II Study of Intermittent Duvelisib Dosing in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Background. Targeting phosphatidylinositol 3-kinase (PI3K) has emerged as an efficacious approach for treatment of chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). However, toxicities of the PI3K inhibitors are an important concern limiting their use. Duvelisib is a potent oral inhibitor of both the PI3K-δ and PI3K-γ isoforms with proven efficacy in CLL/SLL. Here we report the results of a phase 2 study evaluating efficacy and safety of duvelisib with intermittent dosing in patients with relapsed/refractory CLL/SLL Methods. This open-label, single arm, phase 2 study enrolled patients with CLL/SLL treated with at least 1 prior line of therapy with active disease as defined by the iWCLL 2008 criteria. Duvelisib was given at a dose of 25 mg PO BID for 28-day cycles for a total of 12 weeks during the induction phase, followed by 75 mg PO BID 2 days on and 5 days off for repeated 28-day cycles during the maintenance phase until death, intolerance or disease progression. The primary endpoint was progression free survival (PFS) at 12 months; secondary endpoints were safety and clinical benefit. The trial was originally planned to enroll 27 patients but was stopped early due to difficulties with enrollment following changing FDA guidance for the use of PI3K inhibitors. Results. Fifteen patients were enrolled. Median age was 74 (59-82) years, 8/15 (53%) were female; patients were primarily Caucasian (13/15; 87%); performance status was 0-1, with 27% (4/15) ECOG 0 and 73% (11/15) ECOG 1. This was a heavily pre-treated patient population with a median of 3 prior lines of therapy (1-6). Among patients where results were available, 79% (11/14) had abnormal FISH results including 36% with TP53 gene loss, 27% del(13q), and 18% del(11q). Sixty-seven percent (8/12) had unmutated IGHV. Of the 15 patients treated, 4 were not evaluable for efficacy due to coming off study early for toxicity (2), development of MDS unrelated to study drug (1) or death due to complications from COVID-19 infection (1). Among the 11 efficacy-evaluable patients, 82% achieved PR, and 18% had stable disease. The 12-month PFS was 43% (95%CI: 18%-66%) and the median PFS was 9.9 months (95% CI: 5.5-NA). Among the 9 responders, the median duration of response (DOR) was 5.3 months (95%CI: 1.9-NA) and 12-month DOR was 22% (95%CI:3%-51%). Five patients (33%) discontinued therapy due to adverse events, which occurred during the induction phase in 4/5 of the patients. Five patients (33%) discontinued due to progressive disease - all during the maintenance phase of treatment. Additionally, 2 patients discontinued due to MD decision; one patient developed MDS which was unrelated to duvelisib; one patient died during treatment due to complications from COVID-19. Treatment was generally well tolerated with the most common grade 3 or higher adverse events being leukocytosis (20%), alanine aminotransferase (ALT) increase (13%), aspartate aminotransferase (AST) increase (13%), oral mucositis (13%) and colitis (13%). The adverse events leading to treatment discontinuation occurred primarily during induction. The most common adverse events of any grade included fatigue in 5 patients (33%), leukocytosis, vomiting, ALT increase, AST increase, diarrhea, and elevation of alkaline phosphatase, which occurred in 4 patients each (27%). Conclusions. We report the results of an open-label, phase 2 study utilizing a continuous dosing induction phase followed by an intermittent dosing maintenance phase of the PI3K inhibitor duvelisib in patients with relapsed/refractory CLL/SLL. Patients who received duvelisib on an intermittent schedule achieved some clinical benefit, however, the desired 12-month PFS goal of 50% was not reached. Adverse events in general were manageable and mainly related to gastrointestinal and liver toxicity, and patient died during treatment from complications from COVID-19 pneumonia. After an initial 12 weeks of continuous duvelisib treatment, the incorporation of intermittent dosing appears to be a viable option for patients with previously treated CLL/SLL.

Long-term maintenance treatment of rosacea: experts' opinion.

Rosacea is a chronic inflammatory dermatosis characterized by remissions and flares. Although the rosacea active treatment phase is well established, the long-term maintenance phase is still challenging. To discuss and make recommendations on how to treat patients during the long-term maintenance phase for the main rosacea phenotypes. A panel of six board-certified Brazilian dermatologists and one American dermatologist gathered to compose a consensus based upon an initial statement on how to treat rosacea during the long-term maintenance phase based on the methodology Nominal Group Technique. The experts discussed each factor based upon an initial statement on how to treat rosacea patients in the long-term maintenance phase. A sequence of comprehensive narrative reviews was performed; a questionnaire preparation about the definition of the maintenance phase and its management was presented; an interpersonal discussion and ranking of the ideas were conducted. Recommendations were made if the specialists had 75% agreement. The maintenance treatment phase, which starts by achieving IGA 0 or 1 grades at the active phase, should be considered at least during the 9-month period after remission. The recommendations of all treatments target this period. Daily skincare regimen and sunscreen are crucial. Active treatment phase should be recommended if signs or symptoms reappear or worsen. Maintenance phase success depends on patient's adherence to daily skin care, appropriate treatments, continued follow-up with dermatologist, and self-assessment to identify new signs and symptoms indicating disease relapse.

Addition of Chidamide to a Sandwich Protocol, Pegaspargase, Gemcitabine and Oxaliplatin Chemotherapy Combined with Radiotherapy, As First-Line Treatment in Early Stage NK/T-Cell Lymphoma: Real World Outcomes in a Retrospective Study

Background: Extranodal NK/T-cell lymphoma, nasal type (ENKTL-NT) is a highly invasive tumor with a short doubling time and poor prognosis. Clinically, it usually involves the upper aerodigestive tract and mainly presents with early-stage. Initially, intensity modulated radiation therapy (IMRT) has been considered the preferred first-line therapy for early-stage ENKTL due to its high response rate. In recent years, more and more studies show that adding chemotherapy, especially asparaginase (ASP)-based regimens, provide survival benefit in early-stage patients. However, the optimal chemotherapy regimen has not been fully defined. Epigenetic regulatory mechanisms related to histone deacetylase (HDAC) have been found to play a role in the evolution and progression of ENKTL. Chidamide, a new HDAC inhibitor, has been confirmed to be effective and tolerable to treat lymphoma. Recently, Xue et al showed that chidamide in combination with cisplatin, etoposide or gemcitabine showed synergistic effect and reversed the chemotherapy resistance in the relapsed/refractory B-cell lymphoma. Here, we investigate the safety and efficacy of adding chidamide to a sandwich protocol, P-GEMOX (pegaspargase/gemcitabine/oxaliplatin) regimen (CP-GEMOX) combined with IMRT as first-line treatment in early-stage ENKTL-NT patients. Methods: We retrospectively reviewed data of early-stage ENKTL-NT patients in the first affiliated hospital of Soochow University from March 2020 to April 2023. A total of 21 patients diagnosed with early-stage (stage Ⅰ or Ⅱ) ENKTL-NT were enrolled and treated with 2 cycles of CP-GEMOX followed by IMRT and 1 or 2 cycles of CP-GEMOX sequentially as consolidation. After consolidation, chidamide was administrated as a maintenance therapy for 1 year. In the induction therapy phase, chidamide was administered orally at a dose of 20 mg twice a week for two weeks, with a one-week discontinuation period; During the maintenance treatment phase, the original dose of chidamide was still maintained and used without pause. The baseline clinical features for the 21 patients were summarized in Table 1. Results: Among 21 patients, 14 were males and 7 were females, and their median age was 57 (range, 41-75) years. Elevated lactate dehydrogenase, elevated β2-microglobulin, stage II disease and primary tumor invasion were present in 4.8% (1/21), 19.0% (4/21), 61.9% (13/21) and 61.9% (13/21) patients. According to the early stage-adjusted nomogram-revised risk index, the majority of patients (76.2%, 16/21) were classified into intermediate- (1-2) and high (≥3) risk groups. The baseline clinical features for the 21 patients were summarized in Table 1. During treatment, all patients were well-tolerated and the most common adverse events were hematological toxicities with neutropenia, thrombocytopenia and anemia. Among non-hematological adverse events, nausea, vomiting and reduced appetite were most common. Other side effects included coagulation dysfunction, skin reaction, diarrhea, serum amylase and alanine aminotransferas /aspartate aminotransferase /bilirubin elevation. No anaphylactic reaction to pegaspargase, hemophagocytic syndrome, pancreatitis or sepsis were observed during chemotherapy. Some patients had mucositis and xerostomia when receiving local radiotherapy. All side effects could be reversed with proper treatment, and there were no therapy related mortality. All patients completed 2 cycles of CP-GEMOX, 19 patients achieved complete remission (CR) and 2 patients achieved partial remission (PR) with a CR rate of 90.5% (19/21) and overall response rate (ORR) of 100.0% (21/21) after 2 cycles of CP-GEMOX. Among the 21 patients, 18 patients completed treatment and CR rate was improved to 100.0% (18/18), giving an ORR of 100% (18/18). After a median follow-up of 25.6(range, 2.6-39) months , all patients were alive except one patient relapsed 20 months after treatment and died of COVID-19 related pneumonia 1 month later. The 2-year progression-free survival and overall survival were all 91.5% (Figure 1). Conclusions: This study demonstrates that sandwich CP-GEMOX chemoradiotherapy is a safe and promising approach to managing patients with early-stage ENKTL-NT. Keywords: Extranodal NK/T-cell lymphoma; chidamide; pegaspargase; gemcitabine; radiation therapy.

Effect of MEF2A and SLC22A3-LPAL2-LPA gene polymorphisms on warfarin sensitivity and responsiveness in Jordanian cardiovascular patients.

This study aims to investigate the influence of MEF2A and SLC22A3-LPAL2-LPA polymorphisms on cardiovascular disease susceptibility and responsiveness to warfarin medication in Jordanian patients, during the initiation and maintenance phases of treatment. Several candidate genes have been reported to be involved in warfarin metabolism and studying such genes may help in finding an accurate way to determine the needed warfarin dose to lower the risk of adverse drug effects, resulting in more safe anticoagulant therapy. The study population included 212 cardiovascular patients and 213 healthy controls. Genotyping of MEF2A and SLC22A3-LPAL2-LPA polymorphisms was conducted to examine their effects on warfarin efficiency and cardiovascular disease susceptibility using PCR-based methods. One SNP (SLC22A3-LPAL2-LPA rs10455872) has been associated with cardiovascular disease in the Jordanian population, whereas the other SNPs in the MEF2A gene and SLC22A3-LPAL2-LPA gene cluster did not have any significant differences between cardiovascular patients and healthy individuals. Moreover, SLC22A3-LPAL2-LPA rs10455872 was correlated with moderate warfarin sensitivity, the other SNPs examined in the current study have not shown any significant associations with warfarin sensitivity and responsiveness. Our data refer to a lack of correlation between the MEF2A polymorphism and the efficacy of warfarin treatment in both phases of treatment, the initiation, and maintenance phases. However, only rs10455872 SNP was associated with sensitivity to warfarin during the initiation phase. Furthermore, rs3125050 has been found to be associated with the international normalized number treatment outcomes in the maintenance phase.

Lost and Found: A Mixed Methods Study on Treatment Abandonment in Acute Leukemia

Introduction: Acute leukemias represent an important public health problem due to their high morbidity and mortality. Treatment failure due to abandonment or loss of follow-up (LOF) is a contributing factor to poor outcomes. Objective: to determine the causes and outcomes of LOF in a cohort of adults with a diagnosis of acute leukemia and its impact on survival in a limited-resource setting. Materials and Methods: We conducted a prospective, single-center cohort study from 2016 to 2022 in the university hospital; this institution is subsidized with funds from private and public sources. We included patients undergoing induction, consolidation, and maintenance phases of treatment for acute lymphoblastic (ALL) and acute myeloid leukemia (AML). LOF events were defined as discontinuation of follow-up beyond the last documented visit in the electronic medical records, with a timeframe of 2 to 4 weeks during the induction and 4 to 8 weeks in the consolidation or maintenance phases. Patients with LOF were contacted via telephone. Those who responded underwent a structured interview that assessed factors potentially contributing to the discontinuation of treatment. Treatment response, event-free survival (EFS), and overall survival (OS) in patients who lost follow-up were also assessed. Results: From January 1, 2016, to October 31, 2022, a total of 391 patients were treated n=99 patients were found to have lost follow-up during first-line treatment, and 73 patients, (%) answered the phone call, 75.3% had been diagnosed with ALL, and 24.7% with AML. Of the 55 patients diagnosed with ALL, 52.7% were women, the median age was 26 years (range 18-86), and 96.4% were classified as a high-risk disease according to age, white blood cell count at diagnosis, CNS involvement, or steroid response. Most patients lived in an urban area (90.9%), and 74.5% didn't have healthcare coverage. Among the patients diagnosed with AML, 50% were male, the median age of diagnosis was 33 years (range 23-67), 94.4% resided in urban areas, and 83.3% of the patients did not have healthcare coverage, thus and molecular risk could not be determined due to the high cost of comprehensive genetic analysis. All patients were classified as low socioeconomic status, with a median income of $130 US dollars per month, (range, 81 -378 USD) for the ALL cohort and $180 USD for the AML group. Based on the findings of the telephone survey, it was evident that economic constraints were the primary driver of treatment abandonment in both ALL and AML patients, accounting for 92.8% and 94.4% of cases, respectively. Specifically, 92.7% of the ALL group expressed difficulties in covering the costs of treatment, while 83.3% in the AML group faced similar challenges. For ALL patients LOF was more frequent during the maintenance phase, (61.8%) compared to consolidation in AML patients (44%). Despite telephone contact, 76.4% of those with ALL and 77.8% of those with AML, could not continue follow-up. Concerning disease status, 11.1% of patients diagnosed with ALL and 34.5% of patients with AML that resumed follow-up after the phone call were diagnosed with relapsed disease. OS at 2 years from the time LOF was identified 49.1% for ALL and 61.1% for AML. Additionally, the 2-year EFS rates were 43.6% for ALL and 44.4% for AML. Conclusions: Lack of access to financial resources and catastrophic healthcare expenditures were the main reason for abandoning treatment in patients with acute leukemia. Despite the loss of follow-up, the overall survival in both groups of patients showed favorable long-term outcomes; however, risk assessment strategies should be employed, and support programs implemented to improve outcomes in vulnerable populations.

Enhancing panic disorder treatment with mobile-aided case management: an exploratory study based on a 3-year cohort analysis.

Individuals with panic disorder frequently face ongoing symptoms, suboptimal treatment adherence, and increased relapse rates. Although mobile health interventions have shown promise in improving treatment outcomes for numerous mental health conditions, their effectiveness, specifically for panic disorder, has yet to be determined. This study investigates the effects of a mobile-aided case management program on symptom reduction and quality of care among individuals with panic disorder. This 3-year cohort study enrolled 138 participants diagnosed with panic disorder. One hundred and eight participants joined the mobile-aided case management group and 30 in the treatment-as-usual group. Data were collected at baseline, 3-month, 6-month, and 12-month treatment checkpoints using self-report questionnaires, in-depth interviews, direct observation, and medical record analysis. During the maintenance treatment phase, the mobile-assisted case management group decreased both panic severity (p = 0.008) and state anxiety (p = 0.016) more than the control group at 6 months. Participants who underwent case management experienced enhanced control over panic symptoms, heightened self-awareness, and elevated interpersonal support. The mobile-aided case management is beneficial in managing panic disorder, especially maintenance treatment.

Repetitive transcranial magnetic stimulation use in neuropathic pain with comorbid depression: a review of efficient treatment protocols’ parameters

Neuropathic pain affects 7 % of the general population worldwide, it is often resistant to analgesic treatments and is complicated with depressive states in 57–65 % of this patients’ cohort. Ongoing research of current therapeutic approaches, including repetitive transcranial magnetic stimulation (rTMS) use in neuropathic pain and depression, grants new data about the details of treatment protocols’ designs. The aim of our literature review was to evaluate those parameters of the treatment protocols which proved significant efficacy in the management of the neuropathic pain with comorbid depression.Focusing on the Scopus, Elsevier and PubMed databases search, we have found 639 peer‑review articles. 23 studies have been included into the data analysis, whereas others were excluded based on their heterogeneous study design. Across the data analysis we evaluated such rTMS parameters as the type of a coil, type of stimulation area, locus of gained evoked motor potential, amplitude of stimulation, duration of session, frequency/number of sessions per day/month, tie duration between sessions, number and frequency of trains, amount and frequency of pulses containing and efficacy of treatment. Those studies that performed repetitive transcranial magnetic stimulation using the figure‑of‑8 coil over the M1 brain area, for 10 or more daily sessions with duration from 7 up to 40 minutes, of 10–20 Hz frequency, intensity 80–90 % of resting motor threshold and total pulses number over 1500 per session demonstrated the greater efficacy in pain level decrease and depression scores reduction among neuropathic pain patients with comorbid depression. Conducting an additional maintenance phase of treatment prolonged the therapeutic effect of the course.Based on the data review, the parameters of the most efficient rTMS protocols’ designs in management of patients with neuropathic pain and comorbid depression have been revealed. Further research requires investigation of other promising indicators of rTMS efficacy use in neuropathic pain with comorbid depression, such as stimulation over multiple brain areas, the duration/timing of additional maintenance phase of treatment, and the figure‑of‑8 coil orientation options.