Efficacy Of Long-term Treatment Research Articles

DOP005 Long-term efficacy and safety of mirikizumab treatment for Crohn’s Disease: Results from the VIVID-2 open-label extension study

Abstract Background VIVID-2 (NCT04232553) is an ongoing open-label long-term extension study of efficacy and safety of mirikizumab (MIRI), a selective interleukin-23p19 inhibitor, in patients with moderately to severely active Crohn’s disease (CD). We present efficacy and safety results from patients randomised to MIRI in the phase 3 VIVID-1 study (NCT03926130) who received MIRI for a second year in VIVID-2, with or without reinduction. Methods In VIVID-1, the MIRI group received induction with 900 mg intravenously (IV) at weeks (W) 0, 4, and 8, then 300 mg subcutaneously (SC) every 4W. Week 52 endoscopic responders (≥50% reduction from baseline in Simple Endoscopic Score for CD [SES-CD]) continued the same MIRI SC dosing in VIVID-2. Endoscopic non-responders received reinduction with MIRI IV at the start of VIVID-2 followed by SC dosing (IV-SC) as described. Outcomes at W104 of MIRI treatment included endoscopic response and endoscopic remission (SES-CD ≤4 and ≥2-point reduction from baseline with no subscore >1 for any individual variable). The cutoff date was 02 August 2024; VIVID-2 patients entered after 01 August 2023 were excluded from this interim analysis. Safety was assessed from the first dose in VIVID-2 through the cutoff date. Discontinuations or missing data were handled using modified nonresponder imputation (mNRI) and observed cases (OCs). Results Among MIRI endoscopic responders (N=251) who continued MIRI SC, 81.8% (mNRI)/87.6% (OC) maintained endoscopic response at W104 (Fig. 1A). At W104, endoscopic remission was maintained by 72.5% (mNRI)/78.6% (OC) of the 137 patients also in endoscopic remission at W52 and gained by a further 33.3% (mNRI)/35.4% (OC) of the 112 patients not in endoscopic remission at W52 (Fig. 1A). Among MIRI endoscopic nonresponders (N=179) who received reinduction with MIRI IV at the start of VIVID-2 followed by MIRI SC, 30.9% (mNRI)/36.1% (OC) gained endoscopic response; 12.1% (mNRI)/13.7% (OC) of the 174 patients not in endoscopic remission at W52 gained endoscopic remission at W104 (Fig. 1B). Treatment-emergent adverse events (AEs) were reported in 64.3% (MIRI SC) and 65.3% (MIRI IV-SC) of patients, and serious AEs were reported in 6.8% (MIRI SC) and 9.0% (MIRI IV-SC) of patients (Table 1). Conclusion In VIVID-2, high maintenance rates of endoscopic response and endoscopic remission were observed in patients with moderately to severely active CD who were endoscopic responders at 1 year, with additional patients gaining endoscopic remission in year 2 of MIRI treatment. Over 30% of endoscopic nonresponders at 1 year gained endoscopic response with MIRI reinduction. Overall, safety was consistent with the known MIRI safety profile.

DOP032 Extracellular vesicles from Bifidobacterium longum Subspecies infantis attenuate intestinal inflammation via macrophage polarization

Abstract Background Inflammatory Bowel Disease (IBD) is characterized by chronic intestinal inflammation driven by a complex interplay of genetic, environmental, and immune interactions1. Despite significant advancements in IBD therapies, many patients still face challenges in achieving complete remission or maintaining long-term treatment efficacy. We hypothesize that extracellular vesicles from Bifidobacterium longum subspecies infantis (B. infantis-EVs) can regulate immune responses, promote balanced macrophage polarization, and modulate the gut microbiota, ultimately attenuating intestinal inflammation. Methods B. infantis-EVs were isolated via tangential flow filtration (TFF)2. In vitro studies examined cellular morphology, expression of inflammatory cytokines, and immunofluorescence staining of activated RAW 264.7 macrophage cells34. In a 3% dextran sulfate sodium (DSS) mouse model, disease severity was assessed using the Disease Activity Index (DAI), colon length, survival rate, and metagenome analysis. To confirm the targeting capability of B. infantis-EVs for inflamed lesions, cellular uptake was analyzed using confocal microscopy, and biodistribution was assessed with an In Vivo Imaging System (IVIS). Results To investigate the effects of B. infantis-EVs on macrophage polarization, we examined the cellular morphology and macrophage markers of RAW 264.7 cells. B. infantis-EVs suppress macrophage cells from driving an M1-like phenotype, and downregulated M1 markers (iNOS and CD86) while upregulating M2 markers (Arg1 and CD200R) (Fig. 1a-c). They also decreased the expression of LPS-induced pro-inflammatory cytokines (IL-1β, IL-2, IL-6, and TNF-α) while increasing anti-inflammatory cytokines (IL-10 and TGF-β) (Fig. 1d). In vivo, oral administration of B. infantis-EVs mitigated weight loss (p=0.0120), preserved colon length (p=0.0018), reduced DAI (p=0.0079), lowered histological score (p=0.0003), and modulated gut microbiota composition in DSS-treated mice compared to the DSS + PBS groups. Additionally, fluorescence intensities were stronger in the inflamed group treated with Cy5-labeled B. infantis-EVs compared to non-inflamed group at all-time points tested both cellular uptake and biodistribution (Fig. 1e). These findings suggest that B. infantis-EVs have the capability to target inflamed lesions and exhibit significant anti-inflammatory effects. Conclusion In this study, B. infantis-EVs attenuated intestinal inflammation via the modulation of macrophage polarization with its targeting capability to inflamed lesions. B. infantis-EVs could emerge as an innovative and promising therapeutic option for future IBD treatment.

Construction of feature selection and efficacy prediction model for transformation therapy of locally advanced pancreatic cancer based on CT, 18F-FDG PET/CT, DNA mutation, and CA199

BackgroundImmunotherapy and radiotherapy play crucial roles in the transformation therapy of locally advanced pancreatic cancer; however, the exploration of effective predictive biomarkers has been unsatisfactory. With the rapid development of radiomics, next-generation sequencing, and machine learning, there is hope to identify biomarkers that can predict the efficacy of transformative treatment for locally advanced pancreatic cancer through simple and non-invasive clinical methods. Our study focuses on using computed tomography (CT), positron emission tomography/computed tomography (PET/CT), gene mutations, and baseline carbohydrate antigen 199 (CA199) to identify biomarkers for predicting the efficacy of transformative treatment.MethodsWe retrospectively collected data from 70 patients with locally advanced pancreatic cancer who had undergone a biopsy for pathological diagnosis. These patients had complete baseline enhanced CT images and baseline CA199 results. Among them, 65 patients had efficacy evaluation results after 4 treatment cycles, 54 patients had complete baseline PET/CT images, 51 patients had complete DNA mutation detection results, and 34 patients had both complete PET/CT images and DNA mutation detection results. Additionally, 47 patients had complete available CT images at baseline, after 2 treatment cycles, and after 4 treatment cycles. We extracted radiomic features from the original lesion-enhanced CT images (including baseline and subsequent follow-up CT scans), radiomic features from baseline 18F-fluoro-2-deoxy-2-D-glucose (18F-FDG) PET, and patient-specific features related to abdominal and visceral fat. We used short-term and long-term treatment efficacy as the prediction outcomes and performed statistical and machine learning-based feature selection and COX regression analysis to identify potentially predictive features. Subsequently, we separately or in combination modeled the CT features, PET features, baseline CA199, and gene mutation data to construct efficacy prediction models. Finally, we investigated the mixed effects model of the dynamic changes in CT features at baseline, after 2 treatment cycles, and after 4 treatment cycles on the prediction of short-term treatment efficacy.ResultsWe found that a combination of CT radiomic features, including F1_ gray level co-occurrence matrix (GLCM), F2_gray level run length matrix (GLRLM), F5_neighboring gray tone difference matrix (NGTDM), and F6_Shape, PET radiomic features such as visceral adipose tissue (VAT), tumor-to-liver ratio (T/L), standardized uptake value mean (SUVmean), and GLCM, as well as baseline CA199, can be used to predict short-term treatment efficacy. Baseline CA199, GLCM, IntensityDirect, Shape, and PET/CT features are independent factors for long-term treatment efficacy. In constructing the short-term treatment efficacy prediction model, ensemble learning methods such as adaptive boosting (AdaBoost), extreme gradient boosting (XGBoost), and RandomForest performed the best. However, in terms of model interpretability, decision tree methods provide the most intuitive display of the predictive details of the model. For the time series data of patients’ baseline CT, CT after 2 treatment cycles, and CT after 4 treatment cycles, long short-term memory (LSTM) modeling yielded better predictive models.ConclusionA multimodal combination of radiomics, DNA mutations, and baseline CA199 can predict the efficacy of transformative treatment in locally advanced pancreatic cancer. Various feature selection methods and multimodal fusion approaches contribute to guiding personalized and precise treatment for pancreatic cancer.

Controversies in Myopia Control Treatment: What Does it Mean for Future Research?

Treatment of myopia has been informed by more than 3 decades of clinical trials and other observations. However, controversies regarding myopia control remain, such as when to stop treatment and what is the long-term efficacy of treatment. This perspective aims to describe clinically relevant and current controversies regarding myopia treatment. Perspective. We reviewed clinical trial data and other studies regarding myopia control therapies. Controversies in myopia treatment are related to the efficacy of low dose atropine eyedrops and new lens design spectacles to substantially reduce progression of myopia. In addition to efficacy, safety of therapies including soft contact lenses, orthokeratology and low-level red light remains a concern. The therapeutic role of outdoor time in reducing myopia progression also requires further investigation. More research is necessary to confirm treatment effectiveness, duration of required treatment, tapering schedules and when to begin and stop treatment. Myopia management is evolving and maintaining competency in the multiple approaches poses a challenge. Key challenges include identifying high-risk children who would benefit most from treatment, limited evidence supporting the effectiveness of myopia progression control treatments in certain populations, and concerns regarding availability and cost of treatment, which may create socioeconomic barriers to access. The limitations of current methods to slow or stop myopia progression highlight the need for continuing rigorous investigation of new and improved strategies to reduce the burden of myopia.

Assessing the Long-Term Effectiveness of Fractional CO2 Laser Treatment in Perimenopausal Women with Genitourinary Syndrome of Menopause-Single Center Preliminary Study.

Background: Genitourinary Syndrome of Menopause (GSM) is a prevalent condition in postmenopausal women characterized by symptoms such as vaginal dryness, itching, and urinary tract issues due to declining estrogen levels. Despite its widespread impact on quality of life, GSM often remains underdiagnosed and without effective treatment. Methods: This study assessed the long-term efficacy of fractional CO2 laser treatment in alleviating GSM symptoms in perimenopausal women. The study involved 125 participants, with clinical evaluations conducted using vaginal pH, the Vaginal Health Index Score (VHIS), the Vaginal Maturation Index (VMI), and the Female Sexual Function Index (FSFI). Results: Results indicated significant improvements in these parameters, with pH levels decreasing, VHIS scores rising, and notable gains in VMI and FSFI observed up to 12 months post-treatment. This improvement has been validated through both subjective and objective assessments of GSM. Conclusions: The findings indicate that this method is effective and safe, with no significant side effects reported. However, conducting a long-term observational study on eventual longer protocol for maintaining the positive effect of this therapy should be conducted.

Cellular Response of Immune Cells in the Upper Respiratory Tract After Treatment with Cold Atmospheric Plasma In Vitro.

Cold atmospheric plasma (CAP) has antimicrobial properties and is also known to stimulate the immune system. These properties could be useful for the development of a novel therapeutic or preventive strategy against respiratory infections in the upper respiratory tract (URT) such as ventilator-associated pneumonia (VAP) without inducing an immune overreaction. This study investigated the cellular responses of polymorphonuclear neutrophils (PMNs) after exposure to CAP in a three-dimensional (3D) model of the URT. In vitro experiments were conducted using PMNs isolated from human blood to assess cell migration, intracellular production of reactive oxygen species (ROS), NETosis, surface marker expression (CD11b, CD62L, and CD66b), and cell death with live cell imaging and flow cytometry. CAP was applied for 5 min using two distinct modalities: pressurized air plasma with a plasma intensive care (PIC) device and nebulized air plasma (NP) with a new humidity resistent surface microdischarge (SMD) plasma source, both developed by Terraplasma Medical GmbH. There were no significant signs of cell damage or overstimulation with either device under the conditions tested. However, the NP device caused milder effects on PMN functionality compared to the PIC device, but also demonstrated reduced antibacterial efficacy and reactive oxygen/nitrogen species (RONS) production, as analyzed with colorimetric/fluorimetric assay kits. These findings highlight a trade-off between the two CAP modalities, each with distinct advantages and limitations. Further studies are necessary to investigate these effects in the clinical setting and evaluate the long-term safety and efficacy of CAP treatment in the URT.

Endovascular therapy for aneurysmal dilatation and arteriovenous fistula of the superior mesenteric artery.

We present a clinical case illustrating the feasibility of endovascular treatment of superior mesenteric aneurysm associated with an arteriovenous fistula. The patient presented with abdominal pain and diarrhea on admission. Computed tomography angiography revealed an aneurysmal dilatation of the superior mesenteric artery and vein with an arteriovenous fistula. Endovascular therapy successfully managed the condition by reconstructing the artery, closing the fistula, and occluding the aneurysm. No aneurysm rupture or endoleak occurred, and the patient's symptoms on admission resolved. Endovascular treatment is a viable alternative for patients with superior mesenteric aneurysms and arteriovenous fistulas, but larger studies and further follow-up are needed to evaluate the safety and long-term efficacy of endovascular treatment.

Exploring the interplay of prurigonodularis: unraveling links with Helicobacter pylori infection and psychological factors

Introduction: Prurigo nodularis (PN), a chronic skin condition causing distressing itching, poses challenges in conventional treatment. This study investigates links between PN, Helicobacter pylori (H. pylori) infection, and psychological factors.Aims and Objectives:Examining the association between PN and H. pylori infection, the study assesses psychological factors as potential links, offering insights into treatment approaches.Materials and Method:A cross-sectional study involving 30 clinically confirmed PN patients in Ahmedabad from January 2022 to September 2023. Psychological stress significantly associated with H. pylori infection (χ2 = 12.139, p = 0.000494), emphasizing holistic care. Treatment modalities, including pharmacological and psychological interventions, showed promise in managing PN.Conclusion:The study highlights significant correlations between psychological stress, H. pylori infection, and PN progression, emphasizing the importance of tailored, comprehensive care. Future research should establish causal relationships and explore long-term treatment efficacy. Keywords: Prurigo nodularis, H. pylori infection, psychological stress, comprehensive care.

Long-term efficacy of on-demand vonoprazan treatment for mild reflux esophagitis: success rates and predictors of treatment failure.

Concerns surrounding long-term proton pump inhibitor use have prompted the exploration of alternative treatments for reflux esophagitis (RE). We previously demonstrated that 24weeks of on-demand treatment with vonoprazan, a potassium-competitive acid blocker, effectively managed mild RE (Los Angeles classification grade A/B) in more than 80% of patients. However, its long-term efficacy remains unknown. Therefore, the present study investigated sustained effectiveness. We conducted a retrospective observational study on 30 participants with mild RE from our previous research. Participants with recurrent RE or symptom exacerbation were excluded and considered as treatment failure. Participants with the remission of RE and reflux symptoms under on-demand treatment until the clinic visit between October 2023 and February 2024 were regarded as treatment success. Predictors of treatment failure were analyzed. During the observation period, 5 participants failed treatment due to symptom exacerbation and 6 due to recurrent RE. Five participants were excluded from analyses due to non-GERD causes. Fourteen participants (56.0%) successfully continued on-demand treatment for 91.5months [89.3-92.8]. Age > 67years significantly predicted treatment failure with a sensitivity of 72.7% and specificity of 85.7%. Although none of the patients with RE grade A had recurrent RE, it was not a significant difference. Approximately 50% of patients with mild RE successfully continued on-demand treatment for more than 7years. Age > 67years was identified as a predictor of treatment failure. Prospective multi-center studies are warranted to validate these results.

Association Between Peptide Antigen-Related Antibody Levels and the Short- and Long-Term Efficacy of Antipsychotic Treatment in Drug-Naïve First-Episode Schizophrenia Patients.

This study investigated the relationships between baseline peptide antigen-related IgG levels and 8-week antipsychotic drug (APD) treatment response rates and one-year treatment outcomes, as well as the relationships between changes in peptide antigen-related IgG levels and one-year treatment outcomes, in first-episode schizophrenia (FES) patients. Sixteen peptide antigen-related IgGs from proteins encoded by schizophrenia-related genes were selected on the basis of several selection criteria from a 2022 genome-wide association study. Novel peptide antigen-related IgG levels were measured in drug-naïve FES patients at baseline (n = 155) and in plasma samples from 60 healthy controls (HCs). At the one-year follow-up, 57 patients completed both symptom and autoantibody assessments. Statistical analyses included t tests, Pearson correlation analysis, linear regression analysis, linear mixed-effects models, and simple slope analysis. Anti-MOB4 IgG and anti-PDIA3 IgG levels were significantly lower in drug-naïve FES patients compared to HCs and showed a negative correlation with baseline excitement factor scores. Baseline anti-EMB IgG levels were associated with the 8-week treatment response, whereas anti-MAD1L1 IgG levels were correlated with one-year outcomes in drug-naïve FES patients. The one-year trajectory of changes in anti-FURIN IgG, anti-MAPK3 IgG, and anti-ACTR1B IgG levels was related to remission. This study revealed that patients with schizophrenia had autoimmune abnormalities, with different peptide antigen-related IgG being associated with short-term or long-term treatment efficacy, and that these antibody levels were regulated by APDs.

Thyroid eye disease and ocular myasthenia gravis.

An overview of two ocular diseases, which significantly impact quality of life: thyroid eye disease (TED) and ocular myasthenia gravis (OMG). Additionally, we describe the clinical challenge when they occur simultaneously. We will describe the pathophysiology of both conditions, the currently available diagnostic tools, and the therapies available. Recent literature has described newer diagnostic modalities, predictors of disease severity and co-occurrence of TED and OMG, and novel therapies. There is also critical analysis of current therapeutics and risk factors. The findings from this review suggest a need for heightened clinical awareness and early detection strategies for TED and OMG due to their overlapping clinical presentation. Emerging therapies and diagnostic techniques should be integrated into practice. Further research is warranted to explore the long-term safety and efficacy of novel treatments and the potential genetic links between these conditions.

Bimekizumab 4-year Maintenance of Responses in Week 16 Responders with Moderate to Severe Plaque Psoriasis: Results from the BE BRIGHT Open-label Extension Phase 3 Trial

Introduction: Psoriasis is a chronic disease where loss of response to biologic therapies over time is commonly observed; studying long-term efficacy of new treatments is important.1 Maintenance of high responses to bimekizumab (BKZ) has been reported through 3 years (yrs) in patients with moderate to severe plaque psoriasis.2 This study evaluates the maintenance of clinical responses over 4 years among patients with moderate to severe plaque psoriasis who achieved complete or near-complete skin clearance after 16 weeks (wks) of BKZ treatment and entered the BE BRIGHT open-label extension. Responses were compared over 4 years between all patients who were randomized to BKZ and continued to receive bimekizumab (320 mg every 4 wks [Q4W] or Q8W) in the open-label extension, and those who received the BKZ dosing regimen that is approved for most patients: BKZ 320 mg Q4W to Wk 16 followed by 320 mg Q8W. Methods: Patients completing the 52-wk BE VIVID or 56-wk BE SURE/BE READY phase 3 trials could enter the BE BRIGHT open-label extension (OLE).2–5 Maintenance of PASI90/PASI100 (≥90%/100% improvements from baseline in Psoriasis Area and Severity Index) to Yr4 (OLE Wk144) was assessed in Wk16 responders. Analyzed patients were randomized to BKZ 320 mg Q4W to Wk16, received BKZ Q4W or Q8W until OLE entry, then BKZ Q4W or Q8W dependent on PASI response/prior dose (BKZ Total); the subset who received BKZ Q4W/Q8W/Q8W (initial/maintenance/OLE) were also analyzed. All received BKZ Q8W from OLE Wk48 or at their next scheduled visit. Patients who discontinued due to lack of efficacy/treatment-related adverse events were considered non-responders; multiple imputation was used for all other missing data (modified non-responder imputation). Results: Of 989 BKZ-randomized patients, 87.5% achieved PASI90 and 62.7% PASI100 at Wk16 (non-responder imputation). 693 Wk16 PASI90 and 503 PASI100 responders entered the OLE (BKZ Total); 186 and 147, respectively, received BKZ Q4W/Q8W/Q8W. 87.7%/73.3% of Wk16 PASI90/PASI100 responders maintained their responses to Yr4 (BKZ Total). In the Q4W/Q8W/Q8W subset, 89.0%/76.7% maintained their responses to Yr4. Conclusions: Among Wk16 responders, high efficacy responses were sustained through 4 yrs of BKZ treatment, including patients who received the approved Q4W/Q8W/Q8W dosing regimen.

Glioblastoma Drives Protease-Independent Extracellular Matrix Invasion of Microglia.

Glioblastoma (GBM) is the most common and lethal form of primary brain cancer. Microglia infiltration into the tumor microenvironment is associated with immunosuppression and poor prognosis. Improved physicochemical understanding of microglia activation and invasion may provide novel GBM therapeutic strategies essential for improving long-term treatment efficacy. Here, we combine microfluidic systems with 3-D collagen hydrogels to systematically investigate microglia activation, invasion, contractility and cytokine secretion in response of GBM-microglia crosstalk. GBM inflammatory biomolecules significantly promote activation and 3D invasion of microglia. Interestingly, microglia invasion is not significantly affected by inhibitors of MMP activity or cellular glycolysis. In contrast, ROCK-pathway inhibition significantly impedes microglia invasion. Infrared microscopy analyses show that GBM co-culture does not significantly alter microglia lipid content. Further, GBM conditioned media resulted in significantly increased collagen hydrogel contraction, suggesting the importance of microglia contractility to physically remodel the local extracellular matrix (ECM). We also identify a panel of soluble proteins that may contribute to microglia chemotaxis, such as TIMP-1 and CXCL12. Taken together, this study suggests that the presence of GBM cells can enhance microglia invasion via increased cellular contractility, independent of MMP activity and cellular glycolysis.

Comparison of long term efficacy and cost-effectiveness of omalizumab in 150 mg and 300 mg doses in patients with chronic spontaneous urticaria

BackgroundChronic spontaneous urticaria (CSU) is a clinical condition that affects patients quality of life. Omalizumab is preferred in antihistamines resistant CSU cases. Urticaria activity score-7 (UAS-7) is a scale that shows the severity of the disease. ObjectivesThe authors aimed to compare the long-term (60 months) efficacy and side effects of 150 mg and 300 mg doses of omalizumab in patients with CSU. Methods108 patients followed up at the clinic with the diagnosis of CSU were included. Omalizumab was started in patients who were resistant to conventional CSU treatment. Two groups were formed to receive 150 mg and 300 mg doses of omalizumab. Urticaria activity score (UAS-7), antihistamine usage, time to achieve disease-free stage, relapse after treatment, and side effects of omalizumab treatment were compared in the two groups. ResultsThere were no statistically significant differences between the groups regarding basal characteristics and laboratory findings. Average follow-up time was sixty months. UAS-7 scores were similar in the follow-up. There were no adverse events in both groups. Study limitationsRetroactive design and single-center nature to reach a more significant number of patients. Lack of patients receiving the lowest dose 75 mg and the highest dose 600 mg of omalizumab. Absence of total body mass indexes of all patients. Besides, the use of distinct drugs may contribute to non confident results and is another limitation of this study. ConclusionSince there is no significant difference between 150–300 mg omalizumab doses regarding long-term treatment efficacy and side effects in CSU patients, starting treatment with a 150 mg dose may be suitable. In patients who do not respond to 150 mg, the omalizumab dose can be increased to 300 mg. It will prevent unpredictable dose and time-dependent complications and will be a cost-effective approach even in strong economies.

Safety and tolerability of losartan to treat recessive dystrophic epidermolysis bullosa in children (REFLECT): an open-label, single-arm, phase 1/2 trial

Recessive dystrophic epidermolysis bullosa (RDEB) is a skin fragility disorder characterised by life-long mechanically induced skin blistering, fibrosis-driven pseudosyndactyly, and multi-organ involvement. Preclinical studies have suggested mitigated progression by angiotensin II type I receptor blockade through losartan. We aimed to determine the safety and tolerability of systemic losartan treatment among children with RDEB, and to obtain initial data on its clinical benefit. We conducted an open-label, single-arm, phase 1/2 trial at the Medical Center-University of Freiburg, Germany. Children with molecularly-confirmed RDEB, aged 2-16 years (starting from the 25th month of life) were eligible. Key exclusion criteria comprised anaemia with haemoglobin <8g/dl; hypotension (defined as age-related systolic blood pressure under the 5th percentile); cardiologic contraindications, requirement for any medications that are likely to cause interactions with losartan; renal artery stenosis or renal insufficiency with creatinine clearance <30ml/min; severe liver failure; severe, untreated electrolyte disturbances; history of cancer or chronic viral infections; hypersensitivity to losartan or any of the excipients and known or persistent abuse of medication, drugs, or alcohol. Treatment duration with losartan comprised 10 months, encompassing 16 weeks up-dosing of losartan, 24 weeks full dose losartan (final target dose of 1.4mg/kg), and 4 weeks losartan tapering, followed by 12 weeks follow-up without losartan. The primary endpoint was occurrence of a serious safety concern, defined as one of the following side effects of losartan: clinically relevant severe hypotension, immediate hypersensitivity reactions to the drug or clinical relevant severe hypo- and hyperkalaemia. EB-specific scores (the EBDASI activity and damage score, Birmingham Epidermolysis Bullosa Severity Score (BEBS)) and other clinical outcome parameters were evaluated at five clinical visits as secondary outcomes: pain (Wong-Baker FACES Scale for pain), quality of life (Quality Of Life in EB [QOLEB] questionnaire and Children's Dermatology Life Quality Index [CDLQI]), itch (Itch Assessment Scale for the Paediatric Burn Patients), dysphagia (Mayo Dysphagia Questionnaire-day 30 [MDQ-30]), pseudosyndactyly progression (our own morphometric scoring instrument), and hand function (Score of Colville and Terrill). All analyses (safety and efficacy) were performed in the safety population, defined as participants who received at least one dose of trial medication with losartan. This trial is registered with EudraCT, 2015-003670-32. Between Jul 28, 2017, and Feb 12, 2021, 29 children were enrolled. Of those 27 received the full treatment. Losartan was well tolerated, no treatment-related severe complications leading to a serious safety concern occurred. The patients revealed improvement in the RDEB clinical scores, namely a mean reduction at week 40 of-7.36 points (95%-CI:-16.13 to 1.41) in the EBDASI activity score and-10.50 points (95%-CI:-20.81 to-0.19) in the EBDASI damage score, while the Children's Dermatology Life Quality Index rose by 2.64 points (95%-CI:-4.55 to-0.90). Similar to the EBDASI score, the BEBS showed a mean reduction of-3 points, 95%-CI:-0.21 to-5,79, P=0.036). In the Wong-Baker FACES Scale for Pain an improvement of at least one level was identified for 9 of 28 patients between baseline and at month 9 (95%-CI: 15.9%-52.4%; P=0.57). Regarding the Quality of Life in EB Score, five of 28 patients showed an improvement in the total scale of at least one level at month 9 (95%-CI: 6.1%-36.9%; P=0.71). With the Itch assessment scale for the paediatric burn patients an improvement of at least one level could be observed in 12 of 28 patients (95%-CI: 24.5%-62.8%; P=0.24). The MDQ-30 showed no relevant difference at 9 months after treatment start, as compared to baseline. We observed improvement of finger span with our own morphometric scoring instrument of pseudosyndactyly progression, revealing an increase of the maximal distance between thumb and index finger at month 9 by 6.92mm, 95%-CI [3.48, 10.37] P=0.0009. With the Hand function assessment score of Colville and Terrill, an improvement of at least one level was documented for 3 of 28 patients, i.e., 10.7% (95%-CI: 2.3%-28.2%; P=0.63). Our results suggest that losartan was well tolerated by children with RDEB, and provide preliminary evidence that it may reduce disease burden. Further research with larger sample sizes and longer durations is needed to establish the treatment's long-term efficacy and safety. Debra International, the Department of Dermatology, Medical Center-University of Freiburg (Berta-Ottenstein Advanced Clinician Scientist Program of the Medical Faculty), and the German Research Foundation.

Long-term safety and efficacy of antibody ALXN2220 for depletion of cardiac amyloid transthyretin: results of treatment beyond 12 months in the open-label extension of study NI006-101

Abstract Introduction ALXN2220 (formerly NI006) is an investigational human monoclonal antibody in development for the treatment of transthyretin-mediated amyloid cardiomyopathy (ATTR-CM). ALXN2220 is designed to deplete cardiac amyloid transthyretin (ATTR) deposits in patients with ATTR-CM on top of standard of care. Data from the first-in-human, ascending dose study NI006-101 show that ALXN2220 is safe and well tolerated. A reduction of surrogate markers of cardiac amyloid load and cardiac biomarkers was observed in participants receiving doses of ≥ 10mg/kg of ALXN2220 over a period of 12 months of treatment. Purpose Long-term safety, tolerability and efficacy of ALXN2220 treatment beyond 12 months was studied in a prolonged Open-Label Extension (OLE) of the NI006-101 study. Methods Participants completing 12 months in dose cohorts ≤ 30 mg/kg were allowed to receive additional 6 to 12 monthly open-label ALXN2220 infusions with up-titration of all participants to 30 mg/kg. Cardiac biomarkers were measured centrally, and serial cardiac imaging was performed with echocardiography and cardiac MRI or scintigraphy. Results Out of 27 participants completing 12 months, 23 (18 ATTRwt, all male, median age 70 years at screening (range 28-83)) continued treatment in the prolonged OLE. Median number of infusions of ALXN2220 received and median time followed across the full study were 20 infusions (range 11-24) and 125 weeks (range 83-153). Overall adherence to treatment was high in the prolonged OLE, 97% of planned infusions administered, 87% of participants received all planned doses. No severe or serious adverse events were considered related to ALXN2220 or resulted in the discontinuation during OLE, and no events of cytokine release syndrome or thrombocytopenia were observed. None of the participants had anti-drug antibodies throughout the trial. Cardiac biomarkers (NT-proBNP, troponin) and cardiac imaging indicated continued treatment effects beyond 12 months and supported the up-titration of participants who previously received lower doses of ALXN2220. Conclusions Up-titration and long-term treatment at a dose level of 30 mg/kg in the OLE was safe and well tolerated, with overall good adherence to treatment. Cardiac imaging and cardiac biomarker data indicated continued treatment effects beyond 12 months and supported the up-titration of patients to 30 mg/kg.

Efficacy and safety of long-term edoxaban treatment for low body weight cancer patients with isolated distal deep vein thrombosis: a post-hoc subgroup analysis of the ONCO DVT study

Abstract Background Low body weight is known to be a bleeding risk in the anticoagulation treatment. ONCO DVT study revealed that 12-month edoxaban treatment for cancer patients with isolated distal deep vein thrombosis (DVT) reduced a composite outcome of a symptomatic recurrent venous thromboembolism (VTE) or VTE-related death compared with 3-month edoxaban treatment. However, the efficacy and safety of long-term edoxaban treatment for cancer patients with low body weight is unclear. Purpose In this subgroup analysis, we assessed the efficacy and safety of 12-month edoxaban treatment for low body weight cancer patients with isolated distal DVT. Methods We conducted a post-hoc subgroup analysis of the ONCO DVT study in the low body weight patients. ONCO DVT study was a multicenter, open-label, adjudicator-blinded, randomized clinical trial. Cancer patients with isolated distal DVT were assigned to 12-month or 3-month edoxaban treatment. The primary endpoint was a composite outcome of a symptomatic recurrent VTE or VTE-related death at 12 months. The major secondary endpoint was major bleeding at 12 months. We enrolled patients who met low body weight defined in Japanese Version of High Bleeding Risk criteria (&amp;lt;55 kg for men, &amp;lt;50 kg for women) and evaluated the efficacy and safety of 12-month edoxaban treatment using logistic regression models and log-rank test. Results Among 601 patients in the intention-to-treat population of ONCO DVT study, 322 patients (53.6%) met low body weight: 151 patients were in 12-month edoxaban group and 171 patients were in 3-month edoxaban group. The body weight was similar between two group (47.1±5.2 kg in 12-month edoxaban group vs. 46.9±5.4 kg in 3-month edoxaban group; P=0.77). All of them used a lower dose edoxaban (30 mg once daily) following the dose reduction criteria. 12-month edoxaban group had lower rates of the primary endpoint compared with 3-month edoxaban group (2 patients (1.3%) vs. 10 patients (5.8%); Odds ratio 0.22 [95% CI, 0.05–1.00]; Log-rank P=0.036). There was no significant difference in the major secondary endpoint of major bleeding (12 patients (7.9%) in 12-month edoxaban group vs. 16 patients (9.4%) in 3-month edoxaban group; Odds ratio 0.83 [95% CI, 0.38–1.83]; Log-rank P=0.65). All clinically relevant bleeding events occurred in 22 patients (14.6%) in 12-month edoxaban group and in 27 patients (15.8%) in 3-month edoxaban group (Odds ratio 1.40 [0.90–2.19]; Log rank P=0.13), resulting in the comparable risk of bleeding in the 12-month edoxaban group. Conclusions Our study suggests that 12-month edoxaban treatment for low body weight cancer patients with isolated distal DVT prevents recurrent VTE or VTE-related death without increasing the risk of bleeding compared to 3-month edoxaban treatment.primary endpointsecondary endpoint

Long-term efficacy of drug-coated balloon-based treatment for de novo left anterior descending artery disease

Drug-coated balloons (DCB) are increasingly utilized in percutaneous coronary intervention (PCI), but their effectiveness in coronary artery disease (CAD) needs further exploration. This study investigates the efficacy and safety of a DCB-based strategy for de novo left anterior descending artery (LAD) disease. Patients with de novo LAD lesions treated with DCB alone or combined with drug-eluting stents (DES) and were retrospectively enrolled from 2010 to 2023 (n = 268). The comparator group consisted of patients treated with second-generation DES from a Korean multicenter registry (n = 4,147). The primary endpoint was three-year major adverse cardiovascular events (MACE), including cardiac death, myocardial infarction, target vessel revascularization, target lesion thrombosis, and major bleeding. In the DCB-based group (n = 268), 218 (81.3%) received DCB-only, while 50 (18.7%) underwent a hybrid approach. After propensity score-matching of 243 paired subjects, baseline characteristics were balanced. The DCB-based PCI reduced overall stent burden by 86.7% and significantly lowered the risk of MACE at three years compared to DES-only PCI (4.5% vs. 7.6%, HR 0.50, 95% CI 0.28–0.90; p = 0.020). The most significant reduction was in major bleeding. The DCB-based approach offers an alternative to DES-only strategy for LAD PCI by reducing three-year MACE risk, supporting its use in treating de novo CAD.

Design of thermally programmable 3D shape memory polymer-based devices tailored for endovascular treatment of intracranial aneurysms

Despite recent technological advancements in endovascular embolization devices for treating intracranial aneurysms (ICAs), incomplete occlusion and aneurysm recanalization remain critical challenges. Shape memory polymer (SMP)-based devices, which can be manufactured and tailored to patient-specific aneurysm geometries, possess the potential to overcome the suboptimal treatment outcome of the gold standard: endovascular coiling. In this work, we propose a highly porous patient-specific SMP embolic device fabricated via 3D printing to optimize aneurysm occlusion, and thus, improve the long-term efficacy of endovascular treatment. To facilitate device deployment at the aneurysm via Joule-heating, we introduce a stable, homogeneous coating of poly-pyrrole (PPy) to enhance the electrical conductivity in the SMP material. Using an in-house pulse width modulation circuit, we induced Joule-heating and characterized the shape recovery of the PPy-coated SMP embolic devices. We found that the employed PPy coating enables enhanced electrical and thermal conductivity while only slightly altering the glass transition temperature of the SMP material. Additionally, from a series of parametric studies, we identified the combination of catalyst concentration and pyrrole polymerization time that yielded the shape recovery properties ideal for ICA endovascular therapy. Collectively, these findings highlight a promising material coating for a future coil-free, personalized shape memory polymer (SMP) embolic device, designed to achieve long-lasting, complete occlusion of aneurysms.

Comparative analysis of medical treatments for long-term control of normal tension glaucoma: A systematic review and model-based network meta-analysis.

To evaluate and compare the long-term efficacy of medical treatments for normal tension glaucoma (NTG) in controlling intraocular pressure (IOP), and establish a hierarchical ranking based on their effectiveness. 'Long-term' is defined as a treatment duration of over 12 weeks in randomised controlled trials (RCTs). This systematic review and model-based network meta-analysis (MBNMA) collected data of 795 patients with 997 eyes from RCTs. Patients with NTG were selected based on strict inclusion/exclusion criteria, with randomsation procedures and masking as reported in the individual trials. Eight different medications were compared, including prostaglandin analogues, beta-blockers, brimonidine, unoprostone isopropyl, brovincamine, and palmitoylethanolamide (PEA). Notably, PEA is an oral medication, while other drugs are topical agents. Primary outcome is the long-term efficacy of IOP control across medications with different follow-up durations. Among the eight medications, PEA demonstrates the highest efficacy (Surface under the cumulative ranking, SUCRA = 7.46%), followed by two prostaglandin analogues: travoprost (SUCRA = 6.86%) and latanoprost (SUCRA = 6.76%), then two beta-blockers: nipradilol (SUCRA = 4.90%) and timolol (SUCRA = 4.89%). Both brimonidine and unoprostone isopropyl have SUCRA scores below 4.0%, indicating modest but limited efficacy. Brovincamine has the lowest SUCRA score (1.32%), reflecting minimal effectiveness. This study revealed PEA as a promising agent for long-term IOP control in NTG patients, suggesting potential use as primary or adjunctive therapy. The outcomes call for PEA's consideration in clinical practice and highlight the need for further research into its long-term efficacy and safety for NTG.