End Point Research Articles

Clinical Features and Outcomes of Pediatric MYH7-Related Dilated Cardiomyopathy.

Although genetic variants in MYH7 are the most frequent cause of pediatric genetic dilated cardiomyopathy (DCM), there are no studies available describing this entity. We sought to describe clinical features, analyze variant location, and explore predictors of bad prognosis in pediatric MYH7-related DCM. We evaluated clinical records from 44 patients (24 men; median age at diagnosis, 0.54 [interquartile range, 0.01-10.8] years) with pathogenic/likely pathogenic variants in MYH7 diagnosed with DCM at pediatric age (<18 years) followed at 13 international centers. We also explored risk factors associated with a composite end point of end-stage heart failure defined as heart transplantation or heart failure-related death. Twenty-two patients (50%) were diagnosed at age <6 months, including 7 (16%) at birth. Left ventricular (LV) hypertrabeculation features were present in 15 (38%), particularly among patients with genetic variants in the head domain. After a median follow-up of 6.1 years (interquartile range, 1.9-13.4), 15 patients (36%) required a heart transplant (n=14) or died due to end-stage heart failure (n=1), 15 patients (36%) persisted with systolic dysfunction despite treatment, 12 (29%) had a significant increase in LV ejection fraction, and 2 were lost to follow-up. Overall, end-stage heart failure event rate was 25% at 5 years. New York Heart Association class III to IV (hazard ratio [HR], 7.67 [95% CI, 2.16-27.2]; P=0.002) and LV ejection fraction ≤35% (HR, 4.00 [95% CI, 1.11-14.4]; P=0.03) were the best predictors of bad prognosis. Pediatric MYH7-related DCM is characterized by early onset, frequent LV hypertrabeculation, and poor prognosis. Advanced New York Heart Association class and low LV ejection fraction emerged as predictors of end-stage heart failure.

Parkinson disease therapy: current strategies and future research priorities.

Parkinson disease (PD) is the fastestgrowing neurological disorder globally and poses substantial management challenges owing to progressive disability, emergence of levodopa-resistant symptoms, and treatment-related complications. In this Review, we examine the current state of research into PD therapies and outline future priorities for advancing our understanding and treatment of the disease. We identify two main research priorities for the coming years: first, slowing the progression of the disease through the integration of sensitive biomarkers and targeted biological therapies, and second, enhancing existing symptomatic treatments, encompassing surgical and infusion therapies, with the goal of postponing complications and improving long-term patient management. The path towards disease modification is impeded by the multifaceted pathophysiology and diverse mechanisms underlying PD. Ongoing studies are directed at α-synuclein aggregation, complemented by efforts to address specific pathways associated with the less common genetic forms of the disease. The success of these efforts relies on establishing robust end points, incorporating technology, and identifying reliable biomarkers for early diagnosis and continuous monitoring of disease progression. In the context of symptomatic treatment, the focus should shift towards refining existing approaches and fostering the development of novel therapeutic strategies that target levodopa-resistant symptoms and clinical manifestations that substantially impair quality of life.

Effect of Intravenous Tirofiban Versus Placebo on First-Pass Successful Reperfusion in Endovascular Stroke Thrombectomy: Insights From the RESCUE BT Randomized Clinical Trial.

First-pass successful reperfusion (FPSR), defined as a successful/complete reperfusion achieved after a single thrombectomy pass, is predictive of favorable outcome in patients with acute ischemic stroke with large-vessel occlusion. It is unknown whether intravenous tirofiban is effective in increasing the rate of FPSR in acute anterior large-vessel occlusion stroke. Patients who had acute large-vessel occlusion stroke presenting within 24 hours and underwent endovascular thrombectomy were analyzed from the RESCUE BT (Intravenous Tirofiban for Patients With Large Vessel Occlusion Stroke) clinical trial, of which the main analysis was neutral. The RESCUE BT trial randomized patients to receive either intravenous tirofiban or placebo before endovascular thrombectomy. The primary end point was FPSR, defined as successful reperfusion (extended thrombolysis in cerebral infarction scale 2b50, 2c, or 3) at first thrombectomy attempt. A modified Poisson regression analysis assessed the association between intravenous tirofiban treatment and FPSR. Of 948 enrolled patients, 463 patients were randomized to the tirofiban group and 485 to the placebo group. The mean age was 67 years, and 41.0% of the patients were women. FPSR was achieved more often in the tirofiban group (30.5% versus 23.5%; adjusted risk ratio, 1.24 [95% CI, 1.01-1.51]; P=0.04). FPSR was associated with a favorable shift to lower modified Rankin Scale disability levels at 90 days (common odds ratio, 1.42 [95% CI, 1.08-1.86]; P=0.01). In this post hoc analysis of the RESCUE BT trial, treatment with intravenous tirofiban before endovascular thrombectomy was associated with increased FPSR in patients with acute ischemic stroke due to large-vessel occlusion in the anterior circulation. FPSR was associated with reduced 90-day levels of disability. URL: http://chictr.org; Unique Identifier: ChiCTR-INR-17014167.

In-depth hemodynamic assessment in acute mild stroke patients with large vessel occlusion or stenosis

ObjectiveAcute treatment in mild stroke patients with acute anterior circulation large vessel occlusion/stenosis (AACLVO/S) had limited evidence. Hemodynamic play an important role in neurological deterioration. We aimed to investigate predictor value of hemodynamic assessment for clinical outcome predicting and guiding individual therapeutic decisions in those patients.MethodsWe retrospectively analyze the stroke database in our stroke center. We recruited patients with mild stroke, defined by National Institutes of Health Stroke Scale (NIHSS) score ≤ 5, caused by AACLVO/S treated with just medical management (MT). They all received cerebral autoregulation (CA) assessments within 72 h after stroke onset. The primary end point was clinical outcome at 90-day after stroke.ResultsLogistic regression analysis showed that bilateral higher baseline phase difference (PD) were independent variables related to favorable 90-day outcome, (OR 0.963, 95% CI 0.936–0.991, p = 0.040; OR 0.943, 95% CI 0.970–0.997; p = 0.008, respectively). The optimal cutoff value of bilateral PD was > 34.97º and > 14.29º respectively.ConclusionCA evaluation can provide hemodynamic status in mild stroke patients with AACLVO/S.

Strategy Optimization for a Combined Procedure in Patients With Atrial Fibrillation: The COMBINATION Randomized Clinical Trial.

The optimal strategy of combining left atrial appendage occlusion (LAAO) with catheter ablation (CA) in patients with atrial fibrillation (AF) during a single procedure remains unclear. To determine the effects of ablation-first vs occlusion-first strategies on long-term clinical outcomes among patients with atrial fibrillation undergoing a combined LAAO and CA procedure. The prospective, multicenter COMBINATION randomized clinical trial was conducted in 14 high-volume centers in China. Enrollment of patients with nonvalvular AF referred for the combined procedure began on July 24, 2020, and concluded on January 20, 2022. Patients were randomly assigned to either the ablation-first group or the occlusion-first group. Outcomes of LAAO using an occlusion device and CA using a contact force-sensing catheter following different combination strategies during long-term follow-up were evaluated. The primary end point was a composite of thromboembolic events including stroke or transient ischemic attack, device-related thrombus (DRT), clinically relevant bleeding, and cardiovascular rehospitalization or death. Freedom from AF or atrial tachyarrhythmia (ATA) after a single procedure without antiarrhythmic drugs, at both 1 year and long-term follow-up, was also evaluated. Of the 202 patients enrolled, 194 (96.0%) completed the trial (97 in the ablation-first group and 97 in the occlusion-first group). The mean (SD) age of the cohort was 67.3 (9.2) years, and 110 patients (56.7%) were male. All procedures achieved acute successful LAAO and restoration of sinus rhythm, with similar incidences of periprocedural complications. Compared with the ablation-first group, the occlusion-first group exhibited significantly higher event-free survival of the primary end point (83.5% vs 71.1%; hazard ratio [HR], 0.53 [95% CI, 0.29-0.95]; log-rank P = .04) during the median 2.5 (IQR, 2.3-2.8) years of follow-up. Subgroup analysis indicated that male patients and those with higher CHA2DS2-VASc scores (a composite of factors associated with stroke risk; higher scores indicate higher risk) were at lower risk of thromboembolic events. Rates of long-term freedom from AF (77.3% vs 63.5%; HR, 0.58 [95% CI, 0.34-0.97]; log-rank P = .04) and from ATA (70.1% vs 55.7%; HR, 0.62 [95% CI, 0.39-0.99]; log-rank P = .04) were higher in the occlusion-first group vs the ablation-first group. Additionally, a higher incidence of chronic peridevice leak (15 [15.5%] vs 5 [5.2%]; P = .03) and DRT (8 [8.2%] vs 1 [1.0%]; P = .04) was observed in the ablation-first group vs the occlusion-first group. In this randomized clinical trial, the occlusion-first approach was superior due to its higher event-free survival of the primary end point and long-term freedom from ATA. These findings suggest that the occlusion-first approach should be recommended for combined procedures with plug-like device implantation. Chinese Clinical Trial Registry Identifier: ChiCTR2000031486.

Looking back at the TEDDY study: lessons and future directions.

The goal of theTEDDY (The Environmental Determinants of Diabetes in the Young) study is to elucidate factors leading to the initiation of islet autoimmunity (first primary outcome) and those related to progression to type 1 diabetes mellitus (T1DM; second primary outcome). This Review outlines the key findings so far, particularly related to the first primary outcome. The background, history and organization of the study are discussed. Recruitment and follow-up (from age 4 months to 15 years) of 8,667 children showed high retention and compliance. End points of the presence of autoantibodies against insulin, GAD65, IA-2 and ZnT8 revealed the HLA-associated early appearance of insulin autoantibodies (1-3 years of age) and the later appearance of GAD65 autoantibodies. Competing autoantibodies against tissue transglutaminase (marking coeliac disease autoimmunity) also appeared early (2-4 years). Genetic and environmental factors, including enterovirus infection and gastroenteritis, support mechanistic differences underlying one phenotype of autoimmunity against insulin and another against GAD65. Infant growth and both probiotics and high protein intake affect the two phenotypes differently, as do serious life events during pregnancy. As the end of the TEDDY sampling phase is approaching, major omics approaches are in progress to further dissect the mechanisms that might explain the two possible endotypes of T1DM.

Preventing Allogeneic Stem Cell Transplant-Related Cardiovascular Dysfunction: ALLO-Active Trial.

Allogeneic stem cell transplantation (allo-SCT) is an efficacious treatment for hematologic malignancies but can be complicated by cardiac dysfunction and exercise intolerance impacting quality of life and longevity. We conducted a randomized controlled trial testing whether a multicomponent activity intervention could attenuate reductions in cardiorespiratory fitness and exercise cardiac function (co-primary end points) in adults undergoing allo-SCT. Sixty-two adults scheduled for allo-SCT were randomized to a 4-month activity program (n=30) or usual care (UC; n=32). Activity comprised multicomponent exercise training (3 days/week) and sedentary time reduction (≥30 min/day) program and was delivered throughout hospitalization (≈4 weeks) and for 12 weeks after discharge. Physiological assessments conducted before admission and at 12 weeks after discharge included cardiopulmonary exercise testing to quantify peak oxygen uptake ([Formula: see text]), exercise cardiac magnetic resonance imaging for peak cardiac volume (CIpeak) and stroke volume (SVIpeak) index, echocardiography-derived left ventricular ejection fraction and global longitudinal strain, and cardiac biomarkers (cTn-I [troponin-I] and BNP [B-type natriuretic peptide]). Fifty-two participants (84%) completed follow-up (25 activity and 27 UC); median (interquartile range [IQR]) adherence to the activity program was 74% (41-96%). There was a marked decline in [Formula: see text] in the UC program (-3.4 mL‧kg-1‧min-1 [95% CI, -4.9 to -1.8]) that was attenuated with activity (-0.9 mL‧kg-1‧min-1 [95% CI, -2.5 to 0.8]; interaction P=0.029). Activity preserved exercise cardiac function, with preservation of CIpeak (0.30 L‧min-1‧m-2 [95% CI, -0.34 to 0.41]) and SVIpeak (0.6 mL/m2 [95% CI, -1.3 to 2.5]), both of which declined with UC (CIpeak, -0.68 L‧min-1‧m-2 [95% CI, -1.3 to -0.32]; interaction P=0.008; SVIpeak, -2.7 mL/m2 [95% CI, -4.6 to -0.9]; interaction P=0.014). There were no treatment effects of activity on cardiac biomarkers or echocardiographic indices. Multicomponent activity intervention during and after allo-SCT is beneficial for preserving patient cardiorespiratory fitness and exercise cardiac function. These results may have important implications for cardiovascular morbidity and mortality after allo-SCT. URL: https://anzctr.org.au/; Unique identifier: ACTRN12619000741189.

Medical Devices Applying for Outpatient Medicare Supplemental Payments.

Medicare transitional pass-through payments (TPTPs) provide supplemental reimbursement that is intended to facilitate adoption of new devices in the outpatient setting. The US Centers for Medicare & Medicaid Services (CMS) have historically evaluated manufacturer applications for TPTPs based on newness, cost, and evidence of substantial clinical improvement, ie, the traditional pathway. In 2020, CMS introduced an alternative pathway to allow US Food and Drug Administration (FDA)-designated breakthrough devices to qualify for supplemental reimbursement without demonstrating substantial clinical improvement. To characterize CMS TPTP approval rates and the premarket evidence used by FDA to support authorization of new outpatient medical devices considered for CMS TPTP. This was a cross-sectional study of TPTP applications for new outpatient medical devices from 2017 to 2023. Using the Federal Register, CMS Outpatient Prospective Payment System final rules for fiscal years 2017 through 2023 were obtained, from which all manufacturer applications for TPTPs were identified. For each application, the CMS TPTP review pathway (traditional/alternative), CMS final decision (award/deny), and FDA authorization pathway were assessed. Characteristics of devices considered for CMS TPTPs and design, effectiveness end points, and patient demographic characteristics of premarket clinical studies used to support FDA authorization. CMS approved 17 of 43 (40%) applications for TPTPs, including all 8 (100%) alternative pathway applications for breakthrough devices and 9 of 35 applications (26%) using the traditional pathway. Devices approved for TPTPs were more likely to have been assessed in premarket clinical studies than devices denied TPTPs (12/17 [71%] vs 2/26 [8%]). Among the 14 premarket studies of TPTP-approved devices, 8 (57%) used surrogate markers as primary effectiveness end points and 5 (42%) did not meet all primary end points. The median (IQR) percentage of female, Black, and Hispanic patients among the trials that reported demographic data was 26% (17%-36%), 6% (2%-17%), and 4% (3%-5%), respectively. The findings of this cross-sectional analysis indicated that CMS more commonly awarded supplemental outpatient payment through TPTPs for devices assessed in premarket clinical studies to support FDA authorization. However, these studies often lacked generalizability to Medicare beneficiaries, used surrogate markers of effectiveness, or did not meet all primary end points. As more breakthrough devices receive FDA authorization and effectively qualify for automatic supplemental payments, strengthening premarket clinical evidence requirements for CMS TPTP approvals would provide better information to guide clinical decision-making and ensure that supplemental reimbursement enhances care for Medicare beneficiaries.

Neoadjuvant Atezolizumab in Patients With Surgically Resectable Advanced Cutaneous Squamous Cell Carcinoma

PURPOSE To evaluate the feasibility of administering three doses of neoadjuvant atezolizumab before curative surgical resection in patients with advanced cutaneous squamous cell carcinoma (cSCC). PATIENTS AND METHODS This single-arm phase II trial included patients with cSCC of the head and neck with stage III or IV disease, or stage II lesions for which standard therapy would incur an unacceptable morbidity. Patients received up to three doses of atezolizumab at a fixed dose of 1,200 mg every 21 days before undergoing surgical resection. The primary end point was the percentage of patients able to complete three doses of therapy and be eligible for surgical resection without discontinuation due to toxicity or progression. Secondary end points included unconfirmed RECIST 1.1 response rate, pathological response rate (major and complete pathological response), and safety and tolerability of atezolizumab. RESULTS Twenty patients were enrolled and treated. Sixteen (80%) of 20 patients completed three doses of atezolizumab, and all patients were eligible for surgical resection. A pathological complete response was seen in seven (35%; 95% CI, 15.4 to 59.2) patients, and a major pathological response (&lt;10% viable tumor) was seen in four (20%; 95% CI, 5.7 to 43.7) patients. RECIST responses were seen in eight (40%; 95% CI, 19.1 to 64.0) patients, and one (5%) patient progressed. Grade 3 or higher adverse events were seen in one (5%) patient who developed pneumonitis after the first dose of atezolizumab. CONCLUSION Neoadjuvant atezolizumab is feasible and well tolerated in patients with advanced cSCC and results in a high rate of major and complete pathological responses.

Proactive care management of AI-identified at-risk patients decreases preventable admissions.

We assessed whether proactive care management for artificial intelligence (AI)-identified at-risk patients reduced preventable emergency department (ED) visits and hospital admissions (HAs). Stepped-wedge cluster randomized design. Adults receiving primary care at 48 UCLA Health clinics and determined to be at risk based on a homegrown AI model were included. We employed a stepped-wedge cluster randomized design, assigning groups of clinics (pods) to 1 of 4 single-cohort waves during which the proactive care intervention was implemented. The primary end points were potentially preventable HAs and ED visits; secondary end points were all HAs and ED visits. Within each wave, we used an interrupted time series and segmented regression analysis to compare utilization trends. In the pooled analysis of high-risk and highest-risk patients (n = 3007), potentially preventable HAs showed a statistically significant level drop (-27% [95% CI, -44% to -6%]), without any corresponding change in trends. Potentially preventable ED visits did not show a substantial level drop in response to the intervention, although a nonsignificant differential change in trend was observed, with visit rates decelerating 7% faster in the intervention cohorts (95% CI, -13% to 0%). Nonsignificant drops were observed for all HAs (-19% [95% CI, -35% to 1%]; P = .06) and ED visits (-15% [95% CI, -28% to 1%]; P = .06). A care management intervention targeting AI-identified at-risk patients was followed by a onetime, significant, sizable reduction in preventable HA rates. Further exploration is needed to assess the potential of integrating AI and care management in preventing acute hospital encounters.

Effets du programme d'aide au retour à domicile (PRADO-IC) sur le parcours de soins à un an d'une population de patients insuffisants cardiaques

IntroductionCongestive heart failure (HF) is associated with prolonged and recurrent hospitalizations; the prognosis remains poor a better follow up might be beneficial. PRADO-IC program is provided in order to improve the transition of care. Aim of the studyTo evaluate PRADO-IC program in term of healthcare consumption and prognosis in a cohort of patients hospitalized for decompensated HF, using the insight of the national data base SNDS (Système National de Données de Santé). MethodsFrom September 2016 to September 2018, all patients hospitalized for heart failure at Saint-Joseph Hospital were included in an observational study. The inclusion in the PRADO-IC program was at physician's discretion. Two groups were compared according to the inclusion in PRADO-IC (P group) or not (control group (C)). The primary endpoints were the comparison of one-year mortality and heart failure readmission rate between the two groups. The secondary end points were time to the first contact with a general practitioner (GP), a cardiologist, CHF drugs prescription, and others follow up data. ResultsSix hundred and fifteen patients were included, 254 in the P group and 361 in the C group. Patients in the P cohort presented more frequently severity criteria (age, weight, BNP level, arrhythmia, anemia, renal failure). Mortality at one year (n = 47; 18.5% P group vs. n = 65; 16.2% C group, p = 0.87) did not differ in both groups. There was no significant difference in one-year re-hospitalization rate for HF (n = 93, 36.6% in P group vs. n = 133, 26.8% in C group, p = 0.95). Time to the first contact with the GP was shorter in P group (8.00 vs. 18.50 days, p < 0.0001). Time to first hospitalization (69.0 vs. 37.0 days, p = 0.028) and the length of hospitalization (6.0 vs. 4.0 days, p = 0.045) were longer in P group. There was no difference for HF drugs prescription rate between the two groups. ConclusionOur study shows that the PRADO-IC program concerned more severe patients. Despite this, the one-year mortality and the HF readmission rates are similar between the two groups. The follow up is improved in P group.

Efficacy and Safety of Biosimilar Cetuximab Versus Innovator Cetuximab in Indian Patients With Head and Neck Cancer: A Multicenter, Randomized, Double-Blind, Phase III Trial.

Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer, with approximately 225,419 new cases with over 125,000 deaths annually in India. This trial compared the efficacy and safety of biosimilar cetuximab versus innovator cetuximab (IC) in combination with platinum-based chemotherapy in patients with recurrent locoregional or metastatic SCCHN. This phase III trial is a multicenter, randomized, double-blind and parallel group study performed in Indian patients with recurrent locoregional or metastatic SCCHN. Patients were randomly assigned in 2:1 ratio to receive biosimilar cetuximab and IC in combination with cisplatin and fluorouracil via intravenous infusions. The primary end points were disease control rate (DCR) and overall response rate (ORR) as per response evaluation criteria in solid tumors version 1.1. The secondary end points included pharmacokinetics (PK), immunogenicity, safety, and tolerability. Of 180 patients enrolled, 120 patients received biosimilar cetuximab and 60 patients received IC treatment. No significant statistical difference was observed in the primary outcomes between two groups. Treatment difference in DCR and ORR response was found to be -5.21 (90% CI, -8.94 to -1.48) and -4.79 (90% CI, -19.42 to 9.84), respectively, indicating noninferiority to reference product. The incidence of treatment-emergent adverse events (AEs; biosimilar cetuximab: 89.2% v IC: 91.7%; P = .8364) and serious AEs (biosimilar cetuximab: 23.3% v IC: 13.3%; P = .0603) and PK parameters were comparable between treatment groups. The immunogenicity findings showed higher incidence of anticetuximab antibodies in the biosimilar cetuximab group compared with the IC group at the end of Study. The findings of this study demonstrated noninferiority along with comparable PK, safety, and immunogenicity of biosimilar cetuximab and IC in patients with recurrent or metastatic SCCHN.

NOVEL AGENTS IN THE MANAGEMENT OF DIABETES AND RISK OF WORSENING DIABETIC RETINOPATHY.

Novel therapies for diabetes have potent effects on glycemic control, obesity, and cardiovascular risk reduction, but some, including the popular drug semaglutide, have also been implicated in worsening of diabetic retinopathy (DR). Given the ubiquity of these new agents, understanding the risks to vision is important. Here, we review the data for several newly available agents in terms of systemic efficacy and retinal safety. Literature review. Novel antihyperglycemic treatments include incretin mimetics and enhancers, sodium-glucose cotransporter inhibitors, long-acting insulins, and insulin delivery systems. All improve glycemic control, and some have been shown to reduce major cardiovascular outcomes. In a pivotal trial, semaglutide was associated with approximately 75% increased risk of DR worsening. The novel long-acting insulin icodec, formulated for once weekly dosing, showed increased risk of DR worsening over a once daily insulin. No other recent antihyperglycemic agent was associated with DR worsening, although following the semaglutide trials, nearly all studies excluded patients with preexisting DR. Cases of DR worsening were rare in all instances. Dedicated safety studies for semaglutide in DR are currently underway. For most patients being considered for treatment with a novel antihyperglycemic agent, benefits on systemic metabolic and cardiovascular health are very likely to outweigh potential retinal harms. Although the true risks of the new agents on DR are unclear because their safety data come from secondary end points, the most vulnerable patients are those with preexisting high-risk DR, poor baseline glycemic control, and using insulin.

Cisplatin- or Carboplatin-Based Chemotherapy Plus Pembrolizumab in Advanced Urothelial Cancer: Exploratory Analysis From the Phase 3 KEYNOTE-361 Study

IntroductionKEYNOTE-361 evaluated first-line pembrolizumab with and without platinum-based chemotherapy versus chemotherapy alone in advanced or metastatic urothelial carcinoma. The primary end points of progression-free survival (PFS) or overall survival (OS) were not met. Exploratory analysis of efficacy by platinum agent (cisplatin or carboplatin) is reported. Patients and MethodsEligible patients were randomly assigned 1:1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles with or without chemotherapy (gemcitabine with investigator's choice of either cisplatin or carboplatin) or chemotherapy alone. This exploratory subset analysis evaluated PFS and objective response rate (ORR) per RECIST v1.1 by blinded independent central review and OS for cisplatin- or carboplatin-based chemotherapy with versus without pembrolizumab for patients assigned to chemotherapy-containing arms of KEYNOTE-361. ResultsOf 1010 patients enrolled, 703 were assigned to receive a chemotherapy-containing regimen (n = 312 cisplatin based; n = 391 carboplatin based). Median follow-up was 31.3 months. For cisplatin-based arms, with versus without pembrolizumab, median OS was 20.1 versus 16.4 months (HR 0.88, 95% CI 0.67-1.15) and median PFS was 8.5 versus 7.1 months (HR 0.67, 0.51-0.89). ORR was 64.1% versus 48.7%, respectively. For carboplatin-based arms, with versus without pembrolizumab, median OS was 15.5 versus 12.3 months (HR 0.84, 95% CI 0.67-1.06) and median PFS was 8.0 versus 6.7 months (HR 0.86, 0.68-1.09). ORR was 47.2% versus 41.8%, respectively. Among patients in the cisplatin-based versus carboplatin-based chemotherapy alone arms, 55.8% versus 41.8% received a subsequent anti–programmed cell death protein 1/ligand 1 therapy. The addition of pembrolizumab did not significantly increase the incidence of adverse events reported. ConclusionResults suggest trends towards OS and PFS improvements with the addition of pembrolizumab to gemcitabine-platinum doublet over gemcitabine-platinum alone regardless of whether cisplatin or carboplatin was the chosen platinum agent. OS may have been influenced by active subsequent therapies. MicroAbstractUntil recently, the standard first-line treatment for advanced urothelial carcinoma included platinum-based chemotherapy containing either cisplatin or carboplatin. This exploratory analysis from the KEYNOTE-361 study describes efficacy outcomes with the addition of pembrolizumab to cisplatin- or carboplatin-based chemotherapy to determine if there are differences in clinical benefit between patients who received cisplatin-based versus carboplatin-based combination therapy.

Scalp cooling therapy for chemotherapy-induced hair loss in patients with breast or gynecological cancers-an Asian tertiary institution experience.

Scalp cooling therapy (SCT) improves chemotherapy-induced alopecia (CIA), but there are few published data about its efficacy in an Asian-predominant population. We report our tertiary institution experience of SCT in patients with breast or gynaecological cancers undergoing chemotherapy. The Paxman scalp cooling system was employed for eligible women with breast or gynaecological cancers receiving anthracycline or taxane-based chemotherapy. Only patients with Grade (G) 0-1 alopecia by common terminology criteria for adverse events (CTCAE) version 4.0 were eligible initially, but patients with G2 alopecia were later included in the study. SCT was performed at each chemotherapy cycle, commencing 30min prior to and continuing up to 90min after completion of the drug infusion. Patients were assessed at the start and end of each session for hair preservation (defined as G0-2 alopecia) and comfort level of SCT (rated on a 5-point visual scale). The primary end point was success of hair preservation or hair regrowth after completion of all cycles of chemotherapy. Eighty-three patients were enrolled over a period of 18months from December 2017 to October 2019, with a total of 510 scalp cooling cycles performed. 94.0% (n = 78) of patients reported a comfort score of 3 and above, indicating that the procedure was comfortable, upon a 5-point visual scale. Patients receiving weekly paclitaxel had highest success in hair preservation at 76.7% (23/30 patients), with a lower rate of hair preservation observed for the 3 weekly paclitaxel regimen (50%, 2/4 patients). In contrast, only 1 patient (5.3%, 1/19 patients) who underwent chemotherapy with anthracycline and cyclophosphamide achieved hair preservation. SCT is well tolerated in an Asian-predominant population. Among women with breast or gynaecological cancers receiving taxane and/or anthracycline based chemotherapy, those who underwent SCT were about 50% more likely to achieve hair preservation or hair regrowth, as compared to historical controls.

Selenoprotein P as a prognostic biomarker of burn sepsis: A prospective cohort study

IntroductionSeverely burned patients exhibit increased nutritional requirements and are at high risk of developing sepsis. Selenium is an essential trace element supporting antioxidant and anti-inflammatory pathways, mediated by incorporation into selenoproteins. The selenium status may affect sepsis risk in burn injury. MethodsThis prospective cohort study included 90 adult patients admitted to Zurich Burn Center, Switzerland. All patients received a continuous intravenous infusion of 1000μg sodium selenite per day during the first week as part of local standard of care. Three complementary biomarkers of serum selenium status were determined at nine time-points up to six months postburn, namely total selenium, selenoprotein P, and glutathione peroxidase 3. The resulting data were correlated to clinical parameters and outcomes, with sepsis as primary end point. ResultsA high fraction of the patients displayed selenium deficiency already at admission, and developed sepsis during hospitalization (n = 55; 61%). Selenium status at admission was inversely related to burn severity. Low baseline selenoprotein P was associated with sepsis incidence, irrespective of trauma severity (adjusted HR, 1.94; 95% CI, 1.05–3.63; p = 0.035). Burn severity and baseline concentrations of selenoprotein P and white blood cells corporately predicted sepsis with an area under the curve of 0.84 (95% CI, 0.75–0.93; p < 0.0001). Supplemental selenium was associated with a transient normalization of selenium status. ConclusionConsidering its rapid decline following severe burn injury, the assessment of serum selenoprotein P upon admission may contribute to an early prediction of sepsis risk.

A phase III randomized trial on the addition of a contact x-ray brachytherapy boost to standard neoadjuvant chemo-radiotherapy for organ preservation in early rectal adenocarcinoma: 5 year results of the OPERA trial

The OPERA trial has shown that a contact X Ray Brachytherapy 50kV (CXB) boost with neoadjuvant chemoradiotherapy (NCRT) can increase organ preservation (OP) rate for early rectal adenocarcinoma (ADK) of low-mid rectum. We report the results after 5 years of follow-up. OPERA was a multicenter, phase III trial that included operable patients (pts), with cT2-cT3b low-mid rectal ADK, tumors <5 cm, cN0 or cN1 <8 mm. All pts received external beam radiotherapy (EBRT): 45Gy in 25 fractions with concurrent capecitabine. Pts were randomly assigned (1:1) to receive a boost of EBRT in group A (9Gy/5 fractions) or a boost with CXB (90Gy/3 fractions) in group B. The primary end point was OP rate. Out of 148 patients randomized, 141 were eligible. Between week 14-24, a clinical complete (or near) response was observed in 44 pts in group A (64%) vs 66 in group B (92%); p<0.001. The 3-year OP rate was 59% in group A vs 81% in group B (p=0.003). After update the median follow-up was 61.1 months [56.8-64.5]. The 5-year local regrowth was 39% in group A and 17% in group B (p=0.1). The difference in OP was still highly significant between both groups: A 56% vs B 79% (p=0.004). The difference was more significant if tumors < 3cm, with an OP rate of 93% in group B compared to 54% in group A. Of the 28 local regrowths, 3 occurred after 3 years of follow-up. Rectal bleeding (grade 1-2), which was the most prevalent toxicity during follow-up, disapeared most of the time after three years. Bowel function was not worsened by the CXB boost. The OPERA trial was the first trial to demonstrate that CXB dose escalation was increasing the OP rate with good bowel function at 3 years. At 5 years, these results are sustained, specially in small early-stage tumors. The occurrence of some local regrowth after 3 years necessitates close surveillance of these pts during the 5-year period.

ONS-5010 (bevacizumab-vikg) Safety and Efficacy in Subfoveal Choroidal Neovascularization Secondary to Age-related Macular Degeneration.

This was a prospective multicenter, randomized, double-masked, active-controlled study, the aim of which was to demonstrate the efficacy and safety of intravitreal ONS-5010 (bevacizumab-vikg) in eyes with neovascular age-related macular degeneration (nAMD). This was a phase III trial on ONS-5010 (NORSE TWO). Treatment-naïve nAMD patients aged 50 years and older with a best-corrected distance visual acuity (BCVA) of 25 to 67 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and evidence of disease activity were included. Subjects randomized to ONS-5010 received monthly intravitreal doses of 1.25 mg of ONS-5010, bevacizumab-vikg (Outlook Therapeutics) for 12 months. Subjects randomized to ranibizumab received 0.50 mg of ranibizumab on days 0, 30, 60, 150, and 240 based on the PIER study dosing regimen. The primary end point was the proportion of subjects who gained ≥ 15 letters from baseline in BCVA at 11 months, and evaluating the safety and tolerability of intravitreal injections of ONS-5010 administered monthly from baseline to 12 months. One hundred thirteen subjects were included in the ONS-5010 group and 115 subjects were included in the ranibizumab group. Respectively, 41.7% and 23.1% of patients gained ≥ 15 letters (3 lines) of visual acuity, with a risk difference of 0.1859 [95% CI = 0.0442, 0.3086]; P = 0.0052. The change in BCVA from baseline to 11 months was found to be 11.2 ± 12.19 and 5.8 ± 14.80 ETDRS letters, respectively. The number of subjects gaining ≥ 5 and ≥ 10 letters and subjects losing < 15 letters was significantly higher in the ONS-5010 group. Similarly, subjects with a Snellen visual acuity equivalent of 20/200 (35 ETDRS letters) or worse at 11 months were significantly fewer in the ONS-5010 group. Only one subject in the ONS-5010 group had a study-related serious ocular adverse event (SAE), namely, elevated intraocular pressure. The most common adverse event in the ONS-5010 group was conjunctival hemorrhage (8.8%), and reduced visual acuity in the ranibizumab group (12.2%). In the prescribed treatment plan, ONS-5010 exhibited strong effectiveness in improving or stabilizing visual acuity and was also well tolerated. Bevacizumab and ranibizumab displayed a comparable safety profile. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Cardiac lymphatics undergo distinct remodeling during hypertrophic and nonhypertrophic pregnancy.

Lymphatic vessels of the heart undergo dynamic remodeling in response to physiological and pathological cardiovascular events such as development, adult cardiac maintenance, and injury repair. During pregnancy, the cardiovascular system undergoes physiological changes to meet the increased demand for blood supply to the fetus. These extensive physiological changes make pregnancy and delivery a high-risk period in a woman's life. However, whether and how cardiac lymphatics change during pregnancy is largely undefined. Therefore, we used whole mount immunofluorescent labeling and quantitative morphometric analysis to characterize the changes in cardiac lymphatic vasculature during pregnancy using two genetically distinct inbred mouse strains, C57BL/6J and BALB/cJ. When compared with age-matched, nonpregnant C57BL/6J control mice, the hearts of C57BL/6J dams in late pregnancy [gestation day 17.5 (G17.5)] undergo physiological hypertrophy. However, there were no significant changes in the cardiac lymphatic vasculature. In contrast, BALB/cJ mice do not exhibit pregnancy-induced cardiac hypertrophy at G17.5 compared with age-matched, nonpregnant mice. Yet interestingly, the cardiac lymphatic vasculature of pregnant BALB/cJ dams undergoes extensive morphological changes, including decreased lymphatic length, number of end points, and vessel branch-point junctions on the ventral side of the heart. These findings underscore the complexity of genetic and physiological factors that contribute to the heterotypic remodeling of cardiac lymphatics during late pregnancy.NEW & NOTEWORTHY Cardiac lymphatics remodel in response to physiological and pathological stresses. This study is the first to investigate cardiac lymphatic vessel changes during pregnancy. BALB/cJ mice, which do not undergo pregnancy-induced cardiac hypertrophy, show decreased lymphatic length, number of end points, and junctions on the ventral side during pregnancy. In contrast, C57BL/6J mice, which undergo pregnancy-induced cardiac hypertrophy, had no such changes. These findings underscore the complexity of genetic and physiological factors contributing to cardiac lymphatic remodeling.

Dialysis modality and quality of life: more answers yet more questions

Persons with end-stage kidney disease treated with dialysis experience distressing reductions in quality of life and increased mortality. Few large, randomized trials in nephrology have reported on health-related quality of life. Rose etal. report beneficial effects of high-volume hemodiafiltration versus high-flux hemodialysis on secondary end points of health-related quality of life in the CONVINCE trial (Comparison of High Dose Hemodiafiltration with High Flux Hemodialysis Trial). These results raise questions regarding hemodiafiltration as a potential modality to preserve health-related quality of life in end-stage kidney disease.