Median Percent Change Research Articles

Ixekizumab Improves Nail, Scalp, and Skin Response and Quality of Life Independent of Baseline Psoriasis Severity: Results From the Psoriasis in Special Areas (PSoSA) Study

Background: Ixekizumab has shown impressive efficacy among patients with nail, skin, and scalp psoriasis. Here, we present real-world data from the PSoSA study evaluating effectiveness of ixekizumab by cohorts of patients with mild and moderate/severe nail psoriasis. Methods: PSoSA is an ongoing, prospective, multicenter, single-arm, observational study enrolling adult patients with confirmed diagnosis of moderate-to-severe psoriasis and nail involvement, with or without scalp involvement, initiating ixekizumab in a US dermatology clinic. Assessment of improvements in nail (by modified Nail Psoriasis Severity Index [mNAPSI], with scoring range 0–130), skin (by Psoriasis Area and Severity Index [PASI], with scoring range 0–72), and scalp (by Psoriasis Scalp Severity Index [PSSI], with scoring range 0–72) response and in quality of life (by Dermatology Life Quality Index [DLQI], with scoring range 0–30) were collected at weeks (W) 4, 12, 24, and 52. Percent change was calculated for patients with non-missing baseline values. Data were stratified by nail psoriasis severity at baseline; patients with mNAPSI scores <20 were categorized as mild while those with scores ≥20 were categorized as moderate/severe. In our second interim analysis, we will be reporting data to W24. Results: Of 182 patients included in the analysis, 101 patients had baseline mNAPSI scores <20 and 81 had scores ≥20. Median percent changes from baseline in mNAPSI response at W4, W12, and W24 were −12.2, −33.3, and −71.9, respectively, for patients with baseline scores <20 and −6.1, −38.7, and −68.6, respectively, for patients with scores ≥20. Median percent changes from baseline in PASI response at W4, W12, and W24 were −60.0, −91.2, and −100.0, respectively, for patients with baseline mNAPSI scores <20 and −62.7, −91.4, and −96.7, respectively, for patients with scores ≥20. Median percent changes from baseline in PSSI response at W4, W12, and W24 were −79.3, −100.0, and −100.0, respectively, for patients with baseline mNAPSI scores <20 and −87.5, −100.0, and −100.0, respectively, for patients with scores ≥20. Median percent changes from baseline in DLQI response at W4, W12, and W24 were −66.7, −77.8, and −89.7, respectively for patients with baseline mNAPSI scores <20, and −57.1, −70.0, and −88.7, respectively, for patients with scores ≥20. Conclusions: In a real-world setting, patients with moderate-to-severe psoriasis initiating ixekizumab saw major improvements in nail, skin, and scalp response as well as quality of life as early as 4 weeks and sustained through 24 weeks, independent of nail psoriasis severity at baseline.

Zerlasiran—A Small-Interfering RNA Targeting Lipoprotein(a)

ImportanceElevated lipoprotein(a) increases the risk of atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis.ObjectiveTo evaluate the effects of zerlasiran, a small-interfering RNA targeting hepatic synthesis of apolipoprotein(a), on lipoprotein(a) serum concentration.Design, Setting, and ParticipantsA multicenter trial in patients with stable ASCVD with serum lipoprotein(a) concentrations greater than or equal to 125 nmol/L at 26 sites in Europe and South Africa between January 3, 2023, and April 27, 2023, with last follow-up on July 1, 2024.InterventionsParticipants randomized to receive a subcutaneous dose of placebo every 16 weeks for 3 doses (n = 23) or every 24 weeks for 2 doses (n = 24) or zerlasiran 450 mg every 24 weeks for 2 doses (n = 45), 300 mg every 16 weeks for 3 doses (n = 42), or 300 mg every 24 weeks for 2 doses (n = 44).Main Outcome and MeasuresThe primary outcome was the time-averaged percent change in lipoprotein(a) concentration from baseline to 36 weeks, with follow-up to 60 weeks.ResultsAmong 178 patients, mean (SD) age was 63.7 (9.4) years, 46 (25.8%) were female, with a median (IQR) baseline lipoprotein(a) concentration of 213 (177-282) nmol/L; 172 patients completed the trial. Compared with the pooled placebo group, the least-squares mean time-averaged percent change in lipoprotein(a) concentration from baseline to week 36 was −85.6% (95% CI, −90.9% to −80.3%), −82.8% (95% CI, −88.2% to −77.4%), and −81.3% (95% CI, −86.7% to −76.0%) for the 450 mg every 24 weeks, 300 mg every 16 weeks, and 300 mg every 24 weeks groups, respectively. Median (IQR) percent change in lipoprotein(a) concentration at week 36 was −94.5% (−97.3% to −84.2%) for the 450 mg every 24 weeks group, −96.4% (−97.7% to −92.3%) for the 300 mg every 16 weeks group, and −90.0% (−93.7% to −81.3%) for the 300 mg every 24 weeks group. The most common treatment-related adverse effects were injection site reactions, with mild pain occurring in 2.3% to 7.1% of participants in the first day following drug administration. There were 20 serious adverse events in 17 patients, none considered related to the study drug.ConclusionsZerlasiran was well-tolerated and reduced time-averaged lipoprotein(a) concentration by more than 80% during 36 weeks of treatment in patients with ASCVD.Trial RegistrationClinicalTrials.gov Identifier: NCT05537571

CTIM-24. PHASE II TRIAL OF RHIL-7-HYFC IN PATIENTS WITH HIGH-GRADE GLIOMA DEMONSTRATED ACCEPTABLE SAFETY PROFILE AND REDUCED LYMPHOPENIA

Abstract BACKGROUND Lymphopenia, a common finding in patients with high-grade gliomas (HGGs), is associated with poor outcomes including worse survival, fatigue, and in some cases, increased opportunistic infections. Interleukin-7 (IL-7) is a cytokine crucial for lymphocyte survival and proliferation. We previously demonstrated long-acting IL-7 (rhIL-7-hyFc, efineptakin alfa, NT-I7) increases absolute lymphocyte counts (ALCs) and extends survival in preclinical murine models of HGG. Here, we report results using rhIL-7-hyFc to effectively reduce lymphopenia in patients with HGG. METHODS We performed a phase II randomized, placebo-controlled, double-blind study of rhIL-7-hyFc in patients with newly diagnosed HGGs (82% IDH-wildtype glioblastoma in both groups). Patients received rhIL-7-hyFc (720mcg/kg) or placebo one-week post-radiation and temozolomide, with subsequent doses at weeks 13, 25, and 37. The primary endpoint was ALC four weeks post-initial administration; exploratory endpoints included CD4 count, progression-free survival (PFS), and overall survival (OS). RESULTS We enrolled 22 patients (median age 59.5 years, range 33-74; 40.9% female) with HGG. Both groups exhibited comparable demographics, including MGMT methylation status, and received a median of 2 doses of rhIL-7-hyFc or placebo. At 4 weeks, the pre-specified primary endpoint, ALC significantly increased relative to baseline in the treatment group, compared to placebo (median percent change=148% vs. 16.7%, p=0.007), as did CD4 count (121% vs. 10.5%, p=0.011). There were no treatment-related grade 4/5 adverse events. Exploratory endpoints of PFS and OS will be reported at time of conference. CONCLUSIONS rhIL-7-hyFc is safe and effective in improving ALC and CD4 count in patients with newly diagnosed HGG undergoing temozolomide and concurrent radiation therapy. This study was powered to meet the primary endpoint; larger trials will likely be required to demonstrate clinical efficacy. Nevertheless, these data support the continued exploration of rhIL-7-hyFc as an adjunct to standard therapy to mitigate lymphopenia and potentially extend survival for patients with HGG.

Zoledronate Sequential Therapy After Denosumab Discontinuation to Prevent Bone Mineral Density Reduction: A Randomized Clinical Trial.

Discontinuation of denosumab without transitioning to another antiresorptive agent results in rapid bone loss and an increased risk of fracture. Previous randomized studies reported inconsistent results regarding the efficacy of zoledronate as sequential therapy. To investigate the use of sequential therapy with zoledronate to prevent bone loss and decreased bone mineral density (BMD) after denosumab discontinuation in the first year. The Denosumab Sequential Therapy prospective, open-label, parallel-group randomized clinical trial was conducted at a referral center and 2 affiliated hospitals in Taiwan. Recruitment was conducted from April 1, 2019, to May 31, 2021, and a 2-year follow-up was planned. The trial included postmenopausal women and men aged 50 years or older who received regular denosumab treatment for at least 2 years and did not have previous exposure to other antiosteoporosis medication or meet other exclusion criteria. Participants were assigned via stratified randomization to 1 of 2 groups: group A received continuous denosumab treatment (60 mg twice yearly) as the positive control, whereas group ZOL received 1 dose of zoledronate (5 mg) in the first year. The coprimary outcomes were BMD percentage changes in the lumbar spine (LS-BMD), total hip (TH-BMD), and femoral neck (FN-BMD), respectively. An intention-to-treat analysis was performed. This study included 101 patients (95 women [94.1%]; median age, 72.0 [IQR, 67.0-76.0] years). There were 25 patients in group A (23 women [92.0%]; median age, 74.0 [IQR, 70.0 to 78.0] years) and 76 in group ZOL (72 women [94.7%]; median age, 71.0 [IQR, 65.7 to 76.0] years). In the first year, group ZOL had a significant median decrease in LS-BMD (-0.68% [IQR, -3.22% to 2.75%]) compared with group A (1.30% [IQR, -0.68% to 5.24%]) (P = .03). No significant differences between groups A and ZOL were observed for TH-BMD (median, 1.12% [IQR, -0.06% to 2.25%] vs 0% [-1.47% to 2.15%]) (P = .24) and FN-BMD (median, 0.17% [IQR, -2.29% to 2.90%] vs 0.18% [-2.73% to 3.88%]) (P = .71). We observed a significant difference in the median LS-BMD percentage change for the ZOL subgroup with 3 or more years of denosumab treatment before enrollment (-3.20% [IQR, -7.89% to 0.68%]) compared with group A (1.30% [IQR, -0.68% to 5.24%]) (P = .003). In this randomized trial of sequential therapy after denosumab discontinuation, bone loss was observed in LS-BMD in the first year among patients receiving zoledronate. A longer duration of denosumab treatment was associated with a further decrease in LS-BMD after zoledronate sequential therapy. Further randomized clinical trials and large-scale studies that investigate the strategies of sequential therapy after long-term denosumab treatment are needed. ClinicalTrials.gov Identifier: NCT03868033.

Long-term clinical course of heart failure across left ventricular ejection fraction phenotypes

Abstract Background Studies examining changes in cardiac features and long-term outcomes across heart failure (HF) phenotypes, particularly for normal and supranormal left ventricular ejection fraction (LVEF), are limited. Objectives Our objective was to assess changes in echocardiographic parameters and biomarkers over three years and investigate long-term outcomes across LVEF phenotypes in chronic HF. Methods Patients from the SUPPORT trial (mean age 66 years, 25% female, mean LVEF 54%), a prospective, randomized, open-label blinded endpoint study performed in Japan to determine the additional benefit of olmesartan on top of standard therapy in hypertensive patients with HF, were classified into four HF phenotypes based on baseline LVEF: reduced (HFrEF [LVEF ≤40%], n=200 [17.6%]), mildly reduced (HFmrEF [41% ≤ LVEF <50%], n=229 [20.1%]), normal (HFnEF [51% ≤ LVEF <65%], n=403 [35.4%]), and supranormal (HFsnEF [LVEF ≥65%], n=306 [26.9%]). Changes in echocardiographic parameters and biomarkers were assessed in patients with data available at baseline and three years. The composite outcome of HF hospitalization or all-cause death was analysed from baseline and three years (landmark analysis). Results Over three years, all-cause mortality rates were 15% in HFrEF, 10.0% in HFmrEF, 5.5% in HFnEF, and 4.2% in HFsnEF. The most significant decrease in left ventricular (LV) end-diastolic and -systolic diameter occurred in HFrEF (median percent change; LVDd -5.8% and LVDs -8.8%). Left atrial diameter did not change across HF phenotypes. N-terminal pro-brain natriuretic peptide (NT-proBNP) decreased in HFrEF (-35.7%) but increased in HFnEF and HFsnEF (12.5% and 18.2%, respectively). Troponin increased in all groups except for HFrEF. Growth differentiating factor-15 (GDF15) increased consistently across all HF phenotypes (18.5% in HFrEF, 18.0% in HFmrEF, 16.0% in HFnEF, 22.8% in HFsnEF) (Figure 1). Over a median follow-up of 8.6 years, compared to HFnEF, the risk of the composite outcome was higher in HFrEF (adjusted HR 1.40, 95% CI [1.08-1.82]), but was not different in HFmrEF (1.15, [0.90-1.47]). This trend persisted in the landmark analysis. Up to three years, the risk in HFsnEF compared to HFnEF was not different (1.13, [0.70-1.82]), but it was lower after three years (0.73, [0.55-0.95]). The incident curves show a diverging time point at around three years between HFnEF and HFsnEF (Figure 2). Conclusions In patients with chronic HF and three-year follow-up data, there was minimal decrease in LV dimension, most pronounced in HFrEF. Changes in biomarkers were more diverse, except for consistently elevated GDF15 across all HF phenotypes. The risk of HF hospitalization or all-cause death diverged between HFnEF and HFsnEF after three years.Figure 1Figure 2

Long-term safety and efficacy of adjunctive lacosamide in the treatment of generalized onset tonic-clonic seizures: An open-label extension trial.

This study was undertaken to assess long-term safety, tolerability, and efficacy of lacosamide (LCM) as adjunctive therapy for generalized onset tonic-clonic seizures (GTCS) in patients aged ≥4 years with idiopathic generalized epilepsy (IGE). EP0012 (NCT02408549) was a phase 3, multicenter, open-label extension (OLE) trial. Patients were enrolled from SP0982 (NCT02408523). Trial duration was ≥2 years (adults) and ≤5 years (children). The trial consisted of a treatment period, ≤4-week taper period, and 30-day safety follow-up. Safety (primary) variables were incidence of treatment-emergent adverse events (TEAEs), discontinuations due to TEAEs, incidence of onset of absence or myoclonic seizures, and increase in days with absence or myoclonic seizures per 28 days. Efficacy (secondary) variable was percent change in GTCS frequency per 28 days. Kaplan-Meier estimated retention rates and analyses by number of lifetime antiseizure medications (ASMs) were performed post hoc. Overall, 239 patients (mean age = 27.9 years, 56.1% female, 18.4% children) were enrolled and received ≥1 dose of LCM in this OLE (median treatment duration = 3.2 years); 157 (65.7%) completed the trial, and 82 (34.3%) discontinued. The most common reason for discontinuation (≥10%) was withdrawn consent (30 [12.6%]). Kaplan-Meier estimated retention rate was 87%, 72%, and 60% at 1, 3, and 5 years, respectively. Overall, 222 (92.9%) patients reported TEAEs; 19 (7.9%) discontinued due to TEAEs. Few patients had an increase in number of days with absence or myoclonic seizures, or incidence of new absence or myoclonic seizures. Median percent change in GTCS frequency per 28 days from the combined baseline was -88.6% (range = -100.0 to 465.4, n = 238). Post hoc analyses demonstrated small numerical differences between patients with 1, 2, and ≥3 lifetime ASMs. The results support the use of long-term adjunctive LCM for GTCS in patients with IGE. Long-term adjunctive LCM was efficacious and well tolerated independent of the number of ASMs used before LCM initiation. ClinicalTrials.gov: NCT02408549.

Asia-Pacific Real-World Evolocumab Use, LDL-C Reduction, Physician Goals, and Patient Perceptions: HALES Observational Study.

Real-world data are needed to understand the effectiveness of new therapeutic options for low-density lipoprotein cholesterol (LDL-C) reduction in Asia-Pacific clinical practice. Description of evolocumab use among adults with establisHed Atherosclerotic cardiovascuLar diseasE or hypercholesterolemia in ASia-Pacific region (HALES) was performed to better understand characteristics of and clinical decision-making for adults with established atherosclerotic cardiovascular disease/hypercholesterolemia after local evolocumab approval. The HALES observational study, conducted at 33 sites (Hong Kong, Thailand, South Korea, Singapore, Taiwan, and Australia) comprised (1) chart review of patients who received evolocumab, a proprotein convertase subtilisin/kexin type9 inhibitor (PCSK9i), and (2) physician/patient survey and one-time data collection of patients with high cardiovascular risk initiating evolocumab or initiating/continuing non-PCSK9i lipid-lowering therapy. Patients could only enroll in (1) or (2). Chart review included 724 very high-risk patients initiating evolocumab from regulatory approval to 2021. From median baseline LDL-C of 3.2mmol/L (123.7mg/dL), patients had a median percent change in LDL-C of - 60.8% at 1-6months. Goal achievement increased from 7.9% to 69.8% for < 1.8mmol/L (< 70mg/dL) and 4.4% to 57.8% for < 1.4mmol/L (< 55mg/dL) from baseline to 12months. In the one-time data collection, more patients had ≥ 1.8mmol/L (≥ 70mg/dL) baseline LDL-C in the evolocumab vs non-PCSK9i group (95.2% and 48.5%, respectively). Surveys found that physicians applied guideline-recommended treatment targets, and patients demonstrated gaps in understanding cardiovascular risk. Real-world, Asia-Pacific data showed that LDL-C reduction after initiating evolocumab was consistent with that observed in other clinical trials and patient populations. Graphical abstract available for this article.·.

Abstract B013: Host phenotype profiling predicts progression to resection in neoadjuvant pancreatic cancer

Abstract Introduction Neoadjuvant chemotherapy offers a modest survival benefit in pancreatic cancer. Current methods for assessing response to chemotherapy are limited to CA19-9 and post- treatment imaging. However, these methods are not without caveats and focus heavily on tumour biology and staging the tumour, without consideration of host biology or staging the host. We sought to explore the relationship between host biology and outcomes in neoadjuvantly- treated pancreatic cancer, and determine the utility of host phenotype profiling as a tool for predicting chemotherapy response and subsequent progression to resection. Methods Host phenotype profiling was performed by measuring body composition (BC) pre- and post- neoadjuvant chemotherapy in a large international pancreatic cancer cohort (n = 301). Patients with resectable or borderline resectable disease were included if they received chemotherapy with neoadjuvant intent. BC was determined with contrast-enhanced CT scans by measuring single-slice L3 cross-sectional area. Results There were significant differences in BC change from baseline to post-treatment between resected (n = 174) and non-resected patients (n = 127). Patients who did not progress to resection exhibited greater loss in all BC compartments vs those who progressed to resection (muscle area -3.4 vs -0.7, visceral fat -10.1 vs -2.1, subcutaneous fat -12.0 vs -1.4, all p &amp;lt; 0.001, median percentage change per 100 days). We used these values to define a adverse and favourable host phenotypes, which significantly correlated with progression to resection (58.8% adverse phenotype, 74.3% favourable phenotype, p &amp;lt; 0.001). The independence of this effect was confirmed in a logistic regression model with well-established clinico-pathological variables including CA19-19 rise (adverse phenotype OR of non-resection 4.57, 95% CI 1.55-13.48, p = 0.006). Conclusion Host phenotype profiling represents a useful addition to an otherwise limited toolbox of methods for assessing treatment response and selecting for surgery in neoadjuvant pancreatic cancer. Clinicians will be familiar with the subjective “gut feeling” of identifying patients in the clinic who are unlikely to be candidates for surgery, and we demonstrate an objective measurement of this. Early identification of patients on an adverse trajectory may highlight those who would benefit from early intervention such as prehabilitation, salvage change of chemotherapy regimen, or nutritional optimization to switch the phenotype from adverse to favourable and reverse adverse host biology. Citation Format: Adam Bryce, Stephan Dreyer, Ross Dolan, Fieke Froeling, Dario Solinas, Alice Cattelani, Antonio Pea, David Chang. Host phenotype profiling predicts progression to resection in neoadjuvant pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B013.

Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk.

Persistent chylomicronemia is a genetic recessive disorder that is classically caused by familial chylomicronemia syndrome (FCS), but it also has multifactorial causes. The disorder is associated with the risk of recurrent acute pancreatitis. Plozasiran is a small interfering RNA that reduces hepatic production of apolipoprotein C-III and circulating triglycerides. In a phase 3 trial, we randomly assigned 75 patients with persistent chylomicronemia (with or without a genetic diagnosis) to receive subcutaneous plozasiran (25 mg or 50 mg) or placebo every 3 months for 12 months. The primary end point was the median percent change from baseline in the fasting triglyceride level at 10 months. Key secondary end points were the percent change in the fasting triglyceride level from baseline to the mean of values at 10 months and 12 months, changes in the fasting apolipoprotein C-III level from baseline to 10 months and 12 months, and the incidence of acute pancreatitis. At baseline, the median triglyceride level was 2044 mg per deciliter. At 10 months, the median change from baseline in the fasting triglyceride level (the primary end point) was -80% in the 25-mg plozasiran group, -78% in the 50-mg plozasiran group, and -17% in the placebo group (P<0.001). The key secondary end points showed better results in the plozasiran groups than in the placebo group, including the incidence of acute pancreatitis (odds ratio, 0.17; 95% confidence interval, 0.03 to 0.94; P = 0.03). The risk of adverse events was similar across groups; the most common adverse events were abdominal pain, nasopharyngitis, headache, and nausea. Severe and serious adverse events were less common with plozasiran than with placebo. Hyperglycemia with plozasiran occurred in some patients with prediabetes or diabetes at baseline. Patients with persistent chylomicronemia who received plozasiran had significantly lower triglyceride levels and a lower incidence of pancreatitis than those who received placebo. (Funded by Arrowhead Pharmaceuticals; PALISADE ClinicalTrials.gov number, NCT05089084.).

Lipiodol Versus Imipenem/Cilastatin in Genicular Artery Embolization: A Retrospective Study on Safety and Clinical Success.

This study aims to evaluate the safety and effectiveness of genicular artery embolization (GAE) using lipiodol in comparison to imipenem/cilastatin (IPM-CS). This retrospective study screened patients who underwent GAE between January 2022 and February 2023 for inclusion. Clinical outcomes were assessed at 1, 3, and 6months post-procedure using the Visual Analog Scale (VAS) for pain and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) for pain, stiffness, functional capacity, and total scores. Technical and clinical success rates, complications, and patient-reported outcomes were assessed. A total of 42 patients were included in the study, with 13 patients treated with lipiodol and 29 with IPM-CS for GAE. Transient skin discoloration was noted in 23.1% of lipiodol patients and 31% of the IPM-CS group (p = 0.722). One patient (7.6%) in the lipiodol group developed knee edema and erythema due to drug-induced vasculitis (p = 0.309). Clinical success rates in the lipiodol group were 76.9% at 1month, consistent at 3months, and 69.2% at 6months. For the IPM-CS group, success rates were 89.7, 86.2, and 75.9%, respectively, with no significant differences (p = 0.353, p = 0.657, p = 0.713). The median percentage change in WOMAC stiffness scores for the lipiodol group at 1, 3, and 6months post-GAE were - 25%, - 16.7%, and - 16.7%, respectively, while the IPM-CS group showed decreases of - 40%, - 50%, and - 50%. Significant differences were found between the groups at all time points (p = 0.017, p = 0.009, and p = 0.002, respectively). Lipiodol shows comparable clinical success to IPM-CS in GAE.

Multichannel tDCS with advanced targeting for major depressive disorder: a tele-supervised at-home pilot study.

Proof-of-principle human studies suggest that transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) may improve depression severity. This open-label multicenter study tested remotely supervised multichannel tDCS delivered at home in patients (N=35) with major depressive disorder (MDD). The primary aim was to assess the feasibility and safety of our protocol. As an exploratory aim, we evaluated therapeutic efficacy: the primary efficacy measure was the median percent change from baseline to the end of the 4-week post-treatment follow-up period in the observer-rated Montgomery-Asberg Depression Mood Rating Scale (MADRS). Participants received 37 at-home stimulation sessions (30 minutes each) of specifically designed multichannel tDCS targeting the left DLPFC administered over eight weeks (4 weeks of daily treatments plus 4 weeks of taper), with a follow-up period of 4 weeks following the final stimulation session. The stimulation montage (electrode positions and currents) was optimized by employing computational models of the electric field generated by multichannel tDCS using available structural data from a similar population (group optimization). Conducted entirely remotely, the study employed the MADRS for assessment at baseline, at weeks 4 and 8 during treatment, and at 4-week follow-up visits. 34 patients (85.3% women) with a mean age of 59 years, a diagnosis of MDD according to DSM-5 criteria, and a MADRS score ≥20 at the time of study enrolment completed all study visits. At baseline, the mean time since MDD diagnosis was 24.0 (SD 19.1) months. Concerning compliance, 85% of the participants (n=29) completed the complete course of 37 stimulation sessions at home, while 97% completed at least 36 sessions. No detrimental effects were observed, including suicidal ideation and/or behavior. The study observed a median MADRS score reduction of 64.5% (48.6, 72.4) 4 weeks post-treatment (Hedge's g = -3.1). We observed a response rate (≥ 50% improvement in MADRS scores) of 72.7% (n=24) from baseline to the last visit 4 weeks post-treatment. Secondary measures reflected similar improvements. These results suggest that remotely supervised and supported multichannel home-based tDCS is safe and feasible, and antidepressant efficacy motivates further appropriately controlled clinical studies. https://clinicaltrials.gov/study/NCT05205915?tab=results, identifier NCT05205915.

Dupilumab reduces inflammatory biomarkers in pediatric patients with moderate-to-severe atopic dermatitis

BackgroundPatients with atopic dermatitis (AD) often have elevated type 2 inflammatory serum biomarkers. ObjectiveTo report changes in thymus- and activation-regulated chemokine (TARC)/CC chemokine ligand 17 (CCL17), total immunoglobulin E (IgE), lactate dehydrogenase (LDH), and eosinophils in pediatric patients treated with dupilumab or placebo. MethodsBiomarker data were analyzed from three randomized, double-blind, placebo-controlled, phase 3 studies of patients with moderate-to-severe AD. Patients aged 6 months–5 years were randomized to weight-dependent dupilumab 200/300mg every 4 weeks (q4w) or placebo; aged 6–11 years to dupilumab 100/200mg every 2 weeks (q2w), dupilumab 300mg q4w, or placebo; aged 12–17 years to dupilumab 200/300mg q2w, dupilumab 300mg q4w, or placebo. The youngest two groups also applied topical corticosteroids. Median percent changes from baseline to week 16 reported using last observation carried forward method, censoring after rescue treatment. ResultsPediatric patients who received dupilumab vs placebo achieved significantly greater median percent reductions at week 16 in: TARC/CCL17 (−83.3% to −72.4% vs −14.9% to −1.8%), total IgE (−71.2% to −58.4% vs −21.0% to +28.1%), and LDH (−26.2% to −9.8% vs −1.5% to +1.5%). All comparisons were significantly different (P < .0001) between each dupilumab dosing group and respective placebo groups. In contrast, absolute changes in eosinophils were small in all groups. ConclusionsDupilumab treatment for pediatric patients with moderate-to-severe AD significantly reduced levels of TARC/CCL17, total IgE, and LDH to levels comparable to those of healthy controls, reflecting a reduction in systemic type 2 and general inflammation.

Impact of dexmedetomidine as an adjuvant to peribulbar anesthesia on the retinal vasculature in glaucoma patients: an optical coherence tomography angiography study

Objectives To assess Dexmedetomidine’s effect as an adjuvant to peribulbar anesthesia on the retinal vasculature in patients with glaucoma undergoing cataract extraction surgery via optical coherence tomography angiography (OCT-A). Participants Thirty-nine glaucoma participants planned for phacoemulsification were allocated into two groups. A 10 ml mixture of peribulbar anesthesia was administered to group I. This anesthetic mixture consisted of 4.5 ml of lidocaine 2% mixed with 4.5 ml of bupivacaine 0.5%,1 ml of dexmedetomidine (50 µg), and 150 IU hyaluronidase. Group II was administered a peribulbar anesthetic mixture consisting of 4.5 ml of lidocaine 2% combined with 4.5 ml of bupivacaine 0.5%,150 IU of hyaluronidase, and 1 ml of normal saline, totaling 10 ml. Optical coherence tomography angiography was used 10 mi before and 10 min after injection to scan optic disc total vessel density, foveal superficial deep capillary plexuses (DCP) density, radial peripapillary capillary network density, and total vessel density plus foveal avascular zone (FAZ) diameter. We also checked the intraocular pressure (IOP) before and 10 min after the anesthetic injection. Results After the administration of the peribulbar anesthetic, group II demonstrated a notably higher significance in the DCP fovea median percent change (–43.7%) compared with group I (-2%) (P&lt;0.001). Additionally, group II experienced a considerably greater median percent change in DCP total density (–22.4%) postinjection compared to group I (–0.8%) (P value &lt; 0.001). The postinjection median percent changes in foveal total vessel density and superficial vessel density were −16.2% and −56.8% in group II, and −1% and −2.4% in group I, respectively, with a P value less than 0.001. Moreover, following the injection, the median percentage change in the diameter of the foveal avascular zone was significantly higher in group II (–40.6%) than in group I (–2.3%) (P value &lt; 0.001). Additionally, there was a noteworthy increase in the optic disc’s total vessel density and the median percentage shift in radial peripapillary capillary network density in group II (–13.1 and −13.7%, respectively) compared with group I (–1.2 and −1%, respectively, P value &lt; 0.001). IOP before and after injecting the anesthesia was insignificantly different between the studied groups (P =0.198 and 0.069, respectively). Conclusion The addition of dexmedetomidine to the peribulbar anesthesia demonstrates a protective effect on the retinal microvasculature against the ischemic impact of anesthetic drugs with no significant effect on the IOP. This effect holds significant implications for glaucoma patients.

Endobronchial Phenylephrine in Airway Bleeding During Bronchoscopy Does not Cause Hypertension: A Retrospective Observational Study.

Bleeding is a known complication during bronchoscopy, with increased incidence in patients undergoing a more invasive procedure. Phenylephrine is a potent vasoconstrictor that can control airway bleeding when applied topically and has been used as an alternative to epinephrine. The clinical effects of endobronchial phenylephrine on systemic vasoconstriction have not been clearly evaluated. Here, we compared the effects of endobronchial phenylephrine versus cold saline on systemic blood pressure. In all, 160 patients who underwent bronchoscopy and received either endobronchial phenylephrine or cold saline from July 1, 2017 to June 30, 2022 were included in this retrospective observational study. Intra-procedural blood pressure absolute and percent changes were measured and compared between the 2 groups. There were no observed statistical differences in blood pressure changes between groups. The median absolute change between the median and the maximum intra-procedural systolic blood pressure in the cold saline group was 29mmHg (IQR 19 to 41) compared with 31.8mmHg (IQR 18 to 45.5) in the phenylephrine group. The corresponding median percent changes in SBP were 33.6 % (IQR 18.8 to 39.4) and 28% (IQR 16.8 to 43.5) for the cold saline and phenylephrine groups, respectively. Similarly, there were no statistically significant differences in diastolic and mean arterial blood pressure changes between both groups. We found no significant differences in median intra-procedural systemic blood pressure changes comparing patients who received endobronchial cold saline to those receiving phenylephrine. Overall, this argues for the vascular and systemic safety of phenylephrine for airway bleeding as a reasonable alternative to epinephrine.

Temporal Analysis of the Incidence, Mortality and Disability-Adjusted Life Years of Benign Gallbladder and Biliary Diseases in High-Income Nations, 1990-2019.

The aim of this observational study was to analyze trends in the incidence, mortality, and disability-adjusted life years (DALYs) of benign gallbladder and biliary diseases across high-income countries between 1990 and 2019. Benign gallbladder and biliary diseases place a substantial burden on healthcare systems in high-income countries. Accurate characterization of the disease burden may help optimize healthcare policy and resource distribution. Age-standardized incidence rates (ASIRs), age-standardized mortality rates (ASMRs), and DALYs data for gallbladder and biliary diseases in males and females were extracted from the 2019 Global Burden of Disease (GBD) study. A mortality-incidence index (MII) was also calculated. Joinpoint regression analysis was performed. The median ASIRs across the European Union 15+ countries in 2019 were 758/100,000 for females and 282/100,000 for males. Between 1990 and 2019 the median percentage change in ASIR was +2.49% for females and +1.07% for males. The median ASMRs in 2019 were 1.22/100,000 for females and 1.49/100,000 for males with a median percentage change over the observation period of -21.93% and -23.01%, respectively. In 2019, the median DALYs was 65/100,000 for females and 37/100,000 among males, with comparable percentage decreases over the observation period of -21.27% and -19.23%, respectively. International variation in lifestyle factors, diagnostic and management strategies likely account for national and sex disparities. This study highlights the importance of ongoing clinical efforts to optimize treatment pathways for gallbladder and biliary diseases, particularly in the provision of emergency surgical services and efforts to address population risk factors.

A phase Ib study of JMT103, a receptor activator of NF-kB ligand (RANKL) antibody, in patients (pts) with bone metastases from solid tumors.

e15190 Background: JMT103 is a human IgG4 monoclonal antibody against RANKL and blocks the RANK signaling in osteoclasts, thus suppressing bone resorption. This phase Ib study aims to demonstrate the activity of JMT103 in bone metastases patients with solid tumors. Methods: In this randomized, multi-center, open-label, phase Ib study, adult pts with bone metastases from solid tumors were enrolled and randomized at a 1:1:1 ratio to receive JMT103 subcutaneously at 120mg every 4 weeks (Q4W, Cohort 1), 120mg every 8 weeks (Q8W, Cohort 2) and 180mg Q8W (Cohort 3) up to 49 weeks. The primary endpoint was the percent change from baseline to week 13 in creatinine-adjusted urinary N-telopeptide (uNTx/Cr). Secondary endpoints included safety, anti-drug antibodies (ADA) positivity, the percentage of patients who experienced on-study skeletal-related events (SREs), and ≥ 2-point decreases in pain with Brief Pain Inventory – Short Form. Results: At database lock (Mar. 31, 2023), 295 pts were enrolled; 293 were treated with JMT103 and eligible for efficacy and safety evaluation (96 pts in Cohort 1, 97 pts in Cohort 2, and 100 pts in Cohort 3). The median age was 58 years (Interquartile range [IQR] 51, 66), and the primary tumor types were mainly breast (145, 50%) and prostate cancer (44, 15%). At week 13, the median (IQR) percent change in uNTx/Cr was - 80% (- 93%, - 50%) in Cohort 1, - 73% (- 94%, - 34%) in Cohort 2, and - 76% (- 92%, - 40%) in Cohort 3, respectively. The incidence of SREs in the three cohorts was 3%, 6%, and 7%, respectively. Among the 33 pts in Cohort 1, 35 pts in Cohort 2, and 37 pts in Cohort 3 with baseline pain scores ≥ 2, 61% in Cohort 1, 46% in Cohort 2, and 54% in Cohort 3 experienced ≥ 2-point decreases in pain at the first post-treatment visit (Day 15). For ADA analysis, only 1 (1%) pt in Cohort 2 with a negative result at baseline tested positive after treatment. The table shows the overall summary of the safety profile. Most of TRAEs were low in grade and resolved quickly. The most common TRAEs (any grade) were hypocalcemia (68, 23%), hypophosphatemia (67, 23%), and increased aspartate transaminase (35, 12%). Among the 40 cases of grade-5 TEAE, only 1 was reported as a TRAE (pneumonia); the rest were unrelated to JMT103. Conclusions: Our study demonstrated a promising efficacy of JMT103 in reducing bone metabolism biomarker and a good safety profile with low immunogenicity. Clinical trial information: NCT04630522 . [Table: see text]

Artemether–lumefantrine with or without single-dose primaquine and sulfadoxine–pyrimethamine plus amodiaquine with or without single-dose tafenoquine to reduce Plasmodium falciparum transmission: a phase 2, single-blind, randomised clinical trial in Ouelessebougou, Mali

Artemether-lumefantrine is widely used for uncomplicated Plasmodium falciparum malaria; sulfadoxine-pyrimethamine plus amodiaquine is used for seasonal malaria chemoprevention. We aimed to determine the efficacy of artemether-lumefantrine with and without primaquine and sulfadoxine-pyrimethamine plus amodiaquine with and without tafenoquine for reducing gametocyte carriage and transmission to mosquitoes. In this phase 2, single-blind, randomised clinical trial conducted in Ouelessebougou, Mali, asymptomatic individuals aged 10-50 years with P falciparum gametocytaemia were recruited from the community and randomly assigned (1:1:1:1) to receive either artemether-lumefantrine, artemether-lumefantrine with a single dose of 0·25mg/kg primaquine, sulfadoxine-pyrimethamine plus amodiaquine, or sulfadoxine-pyrimethamine plus amodiaquine with a single dose of 1·66 mg/kg tafenoquine. All trial staff other than the pharmacist were masked to group allocation. Participants were not masked to group allocation. Randomisation was done with a computer-generated randomisation list and concealed with sealed, opaque envelopes. The primary outcome was the median within-person percent change in mosquito infection rate in infectious individuals from baseline to day 2 (artemether-lumefantrine groups) or day 7 (sulfadoxine-pyrimethamine plus amodiaquine groups) after treatment, assessed by direct membrane feeding assay. All participants who received any trial drug were included in the safety analysis. This study is registered with ClinicalTrials.gov, NCT05081089. Between Oct 13 and Dec 16, 2021, 1290 individuals were screened and 80 were enrolled and randomly assigned to one of the four treatment groups (20 per group). The median age of participants was 13 (IQR 11-20); 37(46%) of 80 participants were female and 43 (54%) were male. In individuals who were infectious before treatment, the median percentage reduction in mosquito infection rate 2 days after treatment was 100·0% (IQR 100·0-100·0; n=19; p=0·0011) with artemether-lumefantrine and 100·0% (100·0-100·0; n=19; p=0·0001) with artemether-lumefantrine with primaquine. Only two individuals who were infectious at baseline infected mosquitoes on day 2 after artemether-lumefantrine and none at day 5. By contrast, the median percentage reduction in mosquito infection rate 7 days after treatment was 63·6% (IQR 0·0-100·0; n=20; p=0·013) with sulfadoxine-pyrimethamine plus amodiaquine and 100% (100·0-100·0; n=19; p<0·0001) with sulfadoxine-pyrimethamine plus amodiaquine with tafenoquine. No grade 3-4 or serious adverse events occurred. These data support the effectiveness of artemether-lumefantrine alone for preventing nearly all mosquito infections. By contrast, there was considerable post-treatment transmission after sulfadoxine-pyrimethamine plus amodiaquine; therefore, the addition of a transmission-blocking drug might be beneficial in maximising its community impact. Bill & Melinda Gates Foundation.

Abstract PS08-06: A Phase Ib/II Study to Assess the Safety and Efficacy of PM8002 (Anti-PD-L1 x VEGF-A Bispecific Antibody) in Combination with Nab-Paclitaxel for First Line Treatment of Locally Advanced or Metastatic Triple-Negative Breast Cancer

Abstract Background: PD-L1 and VEGF play important roles in immune evasion and pro-tumor angiogenesis promoting cancer growth and metastasis. PM8002 is a bispecific antibody targeting PD-L1 and VEGF-A for treating cancer. Here, we present results from a Phase Ib/II study of PM8002 in combination with nab-paclitaxel in patients with locally-advanced or metastatic triple-negative breast cancer (TNBC). Methods: 42 patients with locally-advanced or metastatic TNBC (without prior systemic treatment) were enrolled in this Phase Ib/II study to test the safety and efficacy of PM8002 in combination with nab-paclitaxel. The first 6 patients were enrolled during Phase Ib with safety as the primary endpoint, and the remaining patients were enrolled during Phase II with objective response rate (ORR) as the primary endpoint. Each treatment cycle lasts 28 days. All patients received PM8002 at 20 mg/kg (Q2W) and nab-paclitaxel at 100 mg/m2 on the 1st, 8th, and 15th days of each cycle until unacceptable toxicity or disease progression were observed. Tumor responses were evaluated every 8 weeks according to RECIST 1.1. Safety was evaluated according to CTCAE 5.0. Nab-paclitaxel dose was reduced according to toxicity, while PM8002 dose was kept consistent according to body weight. PD-L1 expression in tumors was tested, and subgroup analysis of ORR data stratified by PD-L1 expression was also included. Results: As of June 30, 2023, 42 patients were treated and evaluated at least once for treatment efficacy. The median duration of drug exposure was 4.6 months (min, max: 2.0, 7.6). The best overall ORR was 76.2% (32/42), including 1 complete response (CR) and 31 partial responses (PRs) with 29 objective responses occurring at the patient's first evaluation. The confirmed ORR was 57.2% (24/42) and the overall disease control rate (DCR) was 95.2% (40/42). The median time to response (TTR) was 1.9 months (95% CI:1.8~2.0) and the median best percentage change from baseline for target lesions was -47.2% (Q1, Q3: -56.9%, -33.5%). Among 13 patients with PD-L1 combined positive scores (CPS) &amp;lt; 1, the best ORR and DCR were 69.2% (9/13) and 100.0% (13/13), respectively. Among 25 patients with PD-L1 CPS ≥1, the best ORR and DCR were 80.0% (20/25) and 96.0% (24/25), respectively. Among 9 patients with PD-L1 CPS ≥10, the best ORR and DCR were both 100.0% (9/9). At the cut-off date of data analysis, 38 patients were still on treatment with a median progression-free survival (mPFS) of 7.4 months (95% CI: 7.4~NA); 38 patients were censored due to no disease progression or death. The incidence of treatment-related adverse events (TRAEs) was 95.2%, of which 26.2% were Grade 3 or 4; no Grade 5 TRAEs were observed. The incidence of drug-related TRAEs related to PM8002 was 92.9%, of which 23.8% were Grade 3 or 4. The incidence of drug-related TRAEs related to nab-paclitaxel was 95.2%, of which 26.2% were Grade 3 or 4. 1 patient (2.4%) reduced nab-paclitaxel dose due to diarrhea. 1 patient (2.4%) discontinued PM8002 and nab-paclitaxel treatment due to diarrhea. The most common TRAEs related to PM8002 and nab-paclitaxel included neutropenia (69.0%), leukocytopenia (59.5%), anemia (52.4%) and proteinuria (26.2%). The incidence of immune-related adverse events (irAEs) was 11.9%, which included hyperthyroidism, hypothyroidism, and rash. No ≥ Grade 3 irAEs were observed. AEs related to targeting VEGF were also analyzed, including hypertension 19.0% (4.8% at Grade 1, 11.9% at Grade 2, and 2.4% at Grade 3) and proteinuria 26.2% (9.5% at Grade 1, and 16.7% at Grade 2). Conclusions: Rapid, deep, and durable tumor responses were observed for the combination of PM8002 and nab-paclitaxel in patients with first line TNBC. PM8002 did not enhance toxicity that is typically observed for nab-paclitaxel. This Phase II study is still ongoing with plans for entering late-stage clinical development for solid tumors. Citation Format: Jiong Wu, Jian Zhang, Zhongsheng Tong, Qingyuan Zhang, Yong-Sheng Wang, Qiao Cheng, Xin Chen, Zhihua Li, Yongmei Yin. A Phase Ib/II Study to Assess the Safety and Efficacy of PM8002 (Anti-PD-L1 x VEGF-A Bispecific Antibody) in Combination with Nab-Paclitaxel for First Line Treatment of Locally Advanced or Metastatic Triple-Negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS08-06.

Prospective pilot study utilizing changes in quantitative values obtained on serial fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET/CT) in dogs with appendicular osteosarcoma before and after stereotactic body radiation therapy (SBRT) and carboplatin chemotherapy to assess for prediction of survival and therapeutic effectiveness.

Serial fluorine 18 fluorodeoxyglucose (18F-FDG) positron emission tomography-CT (PET/CT) is commonly used in human oncology to prognosticate and evaluate for therapeutic effectiveness. In this pilot study, dogs with naturally occurring appendicular osteosarcoma were evaluated with serial 18F-FDG PET/CT in an attempt to assess for response to therapy, prognostic factors, and appropriateness of imaging intervals. Fourteen dogs were enrolled in the trial. All dogs had the initial 18F-FDG PET/CT (PET1), with nine dogs having their end-of-therapy 18F-FDG PET/CT (EoT PET) 3 months after stereotactic body radiation therapy (SBRT) to the primary tumor. The median percent change from the PET1 to the EoT PET for the standard uptake value maximum (SUVmax%) was -58% (range: -17 to -88%), metabolic tumor volume (MTV%) was -99.8% (range: -65 to -100%), and total lesion glycolysis (TLG%) was -99.8% (range: -75 to -100%), all of which were significant (P<.05, <.05, and <.05, respectively). On evaluation, it was found that volumes of GTV and CTV were significant for survival (P<.05 and <.05), MTV1, TLG1, and SUVmax on the EoT PET (SUVmaxEoT) were predictive of metastasis (P<.05), and the SUVmax% was significantly correlated to the time to first event (P<.05). Based on this data, serial 18F-FDG PET/CT performed 3 months after SBRT can show a significant reduction in avidity, and the quantitative data collected may help predict metastatic disease in canine appendicular osteosarcoma.

Abstract CT118: Phase I dose escalation of ASKC202, a novel cMET tyrosine kinase inhibitor, in patients with advanced solid tumors

Abstract Background ASKC202 is an oral and highly selective small molecule inhibitor which inhibits mesenchymal-epithelial transition. We report preliminary safety and efficacy data from an ongoing Phase I, FIH, dose-escalation study of ASKC202 in patients (pts) with advanced solid tumors (NCT05306132). Methods A two-part study was initiated to evaluate MTD, safety and tolerability, pharmacokinetics and preliminary antitumor activity of ASKC202, including dose escalation study (Part A) and dose expansion study (Part B). Responses were assessed per RECIST 1.1 every 2 cycles (6 weeks). AEs were graded using CTCAE v5.0.In Part A, dose escalation followed the accelerated titration combined with the "3+3" design. Patients with heavily pre-treated solid tumors received ASKC202 orally at doses of 50, 150, 300, 450 and 600 mg/day once daily. The treatment continued until disease progression, unacceptable toxicity or treatment termination. If the subject in the 50mg dose group developed DLT, the dose group was switched to a "3+3" design. Results As of November 30, 2023, 16 patients who are refractory or don’t respond to standard therapy were available received ASKC202 (50mg: N=1; 150mg: N=3; 300mg: N=6; 450mg: N=3; 600mg: N=3). 15/16 pts had pathological confirmation of non-small-cell lung cancer (except for 1 case of PSC). 8/16 pts had brain metastasis. 10/16 pts had cMET dysregulation including MET amplification (N=9; gene copy number 1.3-8.3) and MET missense mutation (N=1; p.S186L) with no patient having Exon 14 skipping mutation.ASKC202 was well-tolerated in all patients. No dose-limiting toxicity was observed in all dose levels (50 to 600 mg). The common TRAEs occurring in more than 20% of patients included: anemia (5/16), blood glucose elevation (5/16), ALT elevation (4/16), AST elevation (4/16) and peripheral edema (4/16). Grade 3 TRAEs were only observed in one patient (300mg QD), including anemia and hypokalemia. Among 14pts who had at least one post-baseline anti-tumor assessment, 5 pts achieved a confirmed partial response. The confirmed ORR is 35.7%. The median best percentage change in target lesion size from baseline (depth of response) was 51.8% and 3pts had duration of tumor response ≥ 6 months. ORR and DCR for patients with cMET alteration (N=8) was 62.5% (5/8) and 75.0% (6/8) respectively. One subject (150mg QD) with MET missense mutation (p.S186L) had a 67% tumor reduction in intracranial lesion from baseline. Exposure of ASKC202 increased dose-proportionally at dose range 50mg to 300mg, but less than dose-proportionally increased at 300mg to 600mg. Conclusions ASKC202 monotherapy was well-tolerated with manageable safety profile and showed anti-tumor signal and the central nervous system efficacy. Citation Format: Tingting Song, Caicun Zhou, Wei Li, Xingya Li, Lin Wu, Shan Zeng, Liyun Miao, Baogang Liu, Xuyu Wei, Jing Chen, Luwei Han. Phase I dose escalation of ASKC202, a novel cMET tyrosine kinase inhibitor, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT118.